U.S. patent application number 12/639986 was filed with the patent office on 2010-04-22 for method for treating thrombosis or embolism and related diseases.
This patent application is currently assigned to DAIICHI PHARMACEUTICAL CO., LTD.. Invention is credited to Noriyasu Haginoya, Hideyuki Kanno, Syozo Kobayashi, Satoshi Komoriya, Akiyoshi Mochizuki, Masatoshi Nagamochi, Tsutomu Nagata, Hiroyuki Naito, Yumi Nakamoto, Toshiharu Ohta, Makoto Ono, Kouichi Uoto, Kenji Yoshikawa, Toshiharu Yoshino.
Application Number | 20100099660 12/639986 |
Document ID | / |
Family ID | 32684223 |
Filed Date | 2010-04-22 |
United States Patent
Application |
20100099660 |
Kind Code |
A1 |
Ohta; Toshiharu ; et
al. |
April 22, 2010 |
METHOD FOR TREATING THROMBOSIS OR EMBOLISM AND RELATED DISEASES
Abstract
A method for treating cerebral infarction, cerebral embolism,
myocardial infarction, angina pectoris, pulmonary infarction,
pulmonary embolism, Buerger's disease, deep venous thrombosis,
disseminated intravascular coagulation syndrome, thrombus formation
after artificial valve or joint replacement, thrombus formation and
reocclusion after angioplasty, multiple organ dysfunction syndrome
(MODS), thrombus formation during extracorporeal circulation, or
blood clotting upon blood drawing is provided. The method includes
administration of an effective amount of a compound represented by
formula (1): ##STR00001##
Inventors: |
Ohta; Toshiharu; (Tokyo,
JP) ; Komoriya; Satoshi; (Tokyo, JP) ;
Yoshino; Toshiharu; (Tokyo, JP) ; Uoto; Kouichi;
(Tokyo, JP) ; Nakamoto; Yumi; (Tokyo, JP) ;
Naito; Hiroyuki; (Tokyo, JP) ; Mochizuki;
Akiyoshi; (Tokyo, JP) ; Nagata; Tsutomu;
(Tokyo, JP) ; Kanno; Hideyuki; (Tokyo, JP)
; Haginoya; Noriyasu; (Tokyo, JP) ; Yoshikawa;
Kenji; (Tokyo, JP) ; Nagamochi; Masatoshi;
(Tokyo, JP) ; Kobayashi; Syozo; (Tokyo, JP)
; Ono; Makoto; (Tokyo, JP) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND MAIER & NEUSTADT, L.L.P.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
DAIICHI PHARMACEUTICAL CO.,
LTD.
Tokyo
JP
|
Family ID: |
32684223 |
Appl. No.: |
12/639986 |
Filed: |
December 16, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12250586 |
Oct 14, 2008 |
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12639986 |
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10540259 |
Jun 5, 2006 |
7576135 |
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PCT/JP03/16783 |
Dec 25, 2003 |
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12250586 |
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Current U.S.
Class: |
514/210.18 ;
514/215; 514/235.5; 514/248; 514/301 |
Current CPC
Class: |
C07D 417/14 20130101;
C07D 471/04 20130101; C07D 498/04 20130101; C07D 409/04 20130101;
C07D 413/14 20130101; C07D 513/14 20130101; C07D 409/12 20130101;
C07D 401/12 20130101; C07D 401/14 20130101; C07D 413/12 20130101;
C07D 487/04 20130101; C07D 519/00 20130101; C07D 213/75
20130101 |
Class at
Publication: |
514/210.18 ;
514/301; 514/248; 514/235.5; 514/215 |
International
Class: |
A61K 31/397 20060101
A61K031/397; A61K 31/437 20060101 A61K031/437; A61K 31/502 20060101
A61K031/502; A61K 31/5377 20060101 A61K031/5377; A61K 31/55
20060101 A61K031/55 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 25, 2002 |
JP |
2002-373787 |
Nov 7, 2003 |
JP |
2003-379163 |
Claims
1-52. (canceled)
53. A method for treating cerebral infarction, cerebral embolism,
myocardial infarction, angina pectoris, pulmonary infarction,
pulmonary embolism, Buerger's disease, deep venous thrombosis,
disseminated intravascular coagulation syndrome, thrombus formation
after artificial valve or joint replacement, thrombus formation and
reocclusion after angioplasty, multiple organ dysfunction syndrome
(MODS), thrombus formation during extracorporeal circulation, or
blood clotting upon blood drawing, comprising administering to a
patient in need thereof an effective amount of a compound a
compound represented by formula (1): ##STR01084## wherein R.sup.1,
R.sup.2 and R.sup.3 represent a hydrogen atom; R.sup.4 represents a
5 or 6 membered heterocyclic group; Q.sup.1 represents a saturated
or unsaturated, 5- or 6-membered cyclic hydrocarbon group which may
be substituted, a saturated or unsaturated, 5- to 7-membered
heterocyclic group which may be substituted, a saturated or
unsaturated, bicyclic or tricyclic condensed hydrocarbon group
which may be substituted, or a saturated or unsaturated, bicyclic
or tricyclic condensed heterocyclic group which may be substituted;
Q.sup.2 represents a single bond, a linear or branched alkylene
group having 1 to 6 carbon atoms, a linear or branched alkenylene
group having 2 to 6 carbon atoms, a linear or branched alkynylene
group having 2 to 6 carbon atoms, a saturated or unsaturated, 5- or
6-membered divalent cyclic hydrocarbon group which may be
substituted, a saturated or unsaturated, 5- to 7-membered divalent
heterocyclic group which may be substituted, a saturated or
unsaturated, divalent bicyclic or tricyclic condensed hydrocarbon
group which may be substituted, or a saturated or unsaturated,
divalent bicyclic or tricyclic condensed heterocyclic group which
may be substituted; Q.sup.4 represents an aryl group which may be
substituted, an arylalkenyl group which may be substituted, an
arylalkynyl group which may be substituted, a heteroaryl group
which may be substituted, a heteroarylalkenyl group which may be
substituted, a saturated or unsaturated, bicyclic or tricyclic
condensed hydrocarbon group which may be substituted, or a
saturated or unsaturated, bicyclic or tricyclic condensed
heterocyclic group which may be substituted; T.sup.0 represents a
carbonyl or thiocarbonyl group; and T.sup.1 represents a carbonyl
group, sulfonyl group, group --C(.dbd.O)--C(.dbd.O)--N(R')--, group
--C(.dbd.S)--C(.dbd.O)--N(R')--, group
--C(.dbd.O)--C(.dbd.S)--N(R')--, group
--C(.dbd.S)--C(.dbd.S)--N(R')-- (wherein R' represents a hydrogen
atom, hydroxyl group, alkyl group or alkoxy group), group
--C(.dbd.O)-A.sup.1-N(R'')-- (wherein A.sup.1 represents an
alkylene group which has 1 to 5 carbon atoms and may be
substituted, and R'' represents a hydrogen atom, hydroxyl group,
alkyl group or alkoxy group, group), --C(.dbd.O)--NH--, group
--C(.dbd.S)--NH--, group --C(.dbd.O)--NH--NH--, group
--C(.dbd.O)-A.sup.2-C(.dbd.O)-- (wherein A.sup.2 represents a
single bond or alkylene group having 1 to 5 carbon atoms), group
--C(.dbd.O)-A.sup.3-C(.dbd.O)--NH-- (wherein A.sup.3 represents an
alkylene group having 1 to 5 carbon atoms), group
--C(.dbd.O)--C(.dbd.NOR.sup.a13 N(R.sup.b), group
--C(.dbd.S)-C(.dbd.NOR.sup.a)--N(R.sup.b)-- (wherein R.sup.a
represents a hydrogen atom, alkyl group or alkanoyl group, and
R.sup.b represents a hydrogen atom, hydroxyl group, alkyl group or
alkoxy group), group --C(.dbd.O)--N.dbd.N--, group
--C(.dbd.S)--N.dbd.N--, group
--C(.dbd.NOR.sup.c)--C(.dbd.O)--N(R.sup.d)-- (wherein R.sup.c
represents a hydrogen atom, alkyl group, alkanoyl group, aryl group
or aralkyl group, and R.sup.d represents a hydrogen atom, hydroxyl
group, alkyl group or alkoxy group), group
--C(.dbd.N--N(R.sup.e)(R.sup.f))--C(.dbd.O)--N(R.sup.g)-- (wherein
R.sup.e and R.sup.f each independently represent a hydrogen atom,
alkyl group, alkanoyl group or alkyl(thiocarbonyl) group, and
R.sup.g represents a hydrogen atom, hydroxyl group, alkyl group or
alkoxy group), group --C(.dbd.O)--NH--C(.dbd.O)--, group
--C(.dbd.S)--NH--C(.dbd.O)--, group --C(.dbd.O)--NH--C(.dbd.S)--,
group -- C(.dbd.S)--NHC(.dbd.S)--, group
--C(.dbd.O)--NH--SO.sub.2--, group --SO.sub.2--NH--, group
--C(.dbd.NCN)--NH--C(.dbd.O)--, group --C(.dbd.S)--C(.dbd.O)-- or
thiocarbonyl group; or a salt thereof.
54-62. (canceled)
63. The method for treatment of cerebral infarction, cerebral
embolism, myocardial infarction, angina pectoris, pulmonary
infarction, pulmonary embolism, Buerger's disease, deep venous
thrombosis, disseminated intravascular coagulation syndrome,
thrombus formation after artificial valve or joint replacement,
thrombus formation and reocclusion after angioplasty, multiple
organ dysfunction syndrome (MODS), thrombus formation during
extracorporeal circulation, or blood clotting upon blood drawing,
according to claim 53, wherein the effective amount of the compound
represented by formula (1) is from about 1 mg to about 1 g.
64-65. (canceled)
66. A method for treatment of cerebral infarction, cerebral
embolism, myocardial infarction, angina pectoris, pulmonary
infarction, pulmonary embolism, Buerger's disease, deep venous
thrombosis, disseminated intravascular coagulation syndrome,
thrombus formation after artificial valve or joint replacement,
thrombus formation and reocclusion after angioplasty, multiple
organ dysfunction syndrome (MODS), thrombus formation during
extracorporeal circulation, or blood clotting upon blood drawing,
comprising orally administering to a patient in need thereof, an
effective amount of the a solid drug composition comprising: at
least one pharmaceutically acceptable additive selected from the
group consisting of additives consisting of a filler, an extender,
a binder, a disintegrator, a dissolution accelerator, a humectant
and a lubricant; and the compound of formula (1) according to claim
53.
67. A method for treatment of cerebral infarction, cerebral
embolism, myocardial infarction, angina pectoris, pulmonary
infarction, pulmonary embolism, Buerger's disease, deep venous
thrombosis, disseminated intravascular coagulation syndrome,
thrombus formation after artificial valve or joint replacement,
thrombus formation and reocclusion after angioplasty, multiple
organ dysfunction syndrome (MODS), thrombus formation during
extracorporeal circulation, or blood clotting upon blood drawing,
comprising administering by injection to a patient in need thereof,
an effective amount of a liquid drug composition comprising: water,
a pharmaceutically acceptable solvent or a mixture of water and a
pharmaceutically acceptable solvent; at least one additive selected
from the group of additives consisting of a stabilizer, a
preservative, a dissolution aid, a suspending agent and an
emulsifier; and the compound of formula (1) according to claim 53.
Description
TECHNICAL FIELD
[0001] The present invention relates to novel compounds which
inhibit activated blood coagulation factor X (hereinafter
abbreviated as "FXa") to exhibit a potent anticoagulant effect and
can be orally administered, and anticoagulants or agents for
preventing and/or treating thrombosis or embolism, which comprise
such a novel compound as an active ingredient.
BACKGROUND ART
[0002] Hypercoagulable state is one of the pivotal factors that
account for unstable angina, cerebral infarction, cerebral
embolism, myocardial infarction, pulmonary infarction, pulmonary
embolism, Buerger's disease, deep venous thrombosis, disseminated
intravascular coagulation syndrome, thrombus formation after
artificial valve replacement, reocclusion after angioplasty and
thrombus formation during extracorporeal circulation. Therefore,
there is a demand for development of excellent anticoagulants which
have good dose responsiveness, long duration, low risk of
hemorrhage and little side effects and fast onset of sufficient
effects even by oral administration (Thrombosis Research, Vol. 68,
pp. 507-512, 1992).
[0003] Based on the research of anticoagulants worked through
various mechanism of action, it is suggested that FXa inhibitors
are promising anticoagulants. A blood coagulation system comprises
a series of reactions in which a great amount of thrombin is
produced through an amplification process by multi-stage enzyme
reactions to form insoluble fibrin. In an endogenous system,
activated factor IX activates factor X on a phospholipid membrane
in the presence of activated factor VIII and calcium ions after
multi-stage reactions subsequent to activation of a contact factor.
In an exogenous system, activated factor VII activates factor X in
the presence of a tissue factor. More specifically, the activation
of the factor X into FXa in the coagulation system is a crucial
reaction in the formation of thrombin. The activated factor X (FXa)
limitedly decomposes prothrombin to produce thrombin in the both
systems. Since the produced thrombin activates coagulation factors
in the upper stream, the formation of thrombin is further
amplified. As described above, the coagulation system in the upper
stream of FXa is divided into the endogenous system and the
exogenous system, thus production of FXa cannot be sufficiently
suppressed by inhibiting the enzymes involved in the coagulation
system in the upper stream of FXa, leading to production of
thrombin. Since the coagulation system comprises self-amplification
reactions, inhibition of the coagulation system can be more
efficiently achieved by inhibiting FXa in the upper stream of
thrombin than the inhibition of the product; namely, thrombin
(Thrombosis Research, Vol. 15, pp. 617-629, 1979). Another
excellent point of FXa inhibitors is a great difference between an
effective dose in a thrombosis model and a dose which allows
elongation of bleeding time in an experimental hemorrhagic model.
From this experimental result, FXa inhibitors are considered to be
anticoagulants having low risk of hemorrhage.
[0004] Various compounds have been reported as FXa inhibitors. It
is generally known that antithrombin III and antithrombin III
dependent pentasacchrides can not inhibit prothrombinase complexes
which play a practical role in the thrombus formation in a living
body (Thrombosis Research, Vol. 68, pp. 507-512, 1992; Journal of
Clinical Investigation, Vol. 71, pp. 1383-1389, 1983; Mebio, Vol.
14, the August number, pp. 92-97). In addition, they do not exhibit
effectiveness by oral administration. Tick anticoagulant peptide
(TAP) (Science, Vol. 248, pp. 593-596, 1990) and antistasin (AST)
(Journal of Biological Chemistry, Vol. 263, pp. 10162-10167, 1988)
isolated from mites or leeches, which are bloodsuckers, also
inhibit Fxa and exhibit anti-thrombotic effects against venous
thrombosis and arterial thrombosis. However, these compounds are
high-molecular weight peptides and are not effective by oral
administration. As described above, development of antithrombin III
independent low-molecular weight FXa inhibitors which directly
inhibit coagulation factors and which can be orally administered
has been conducted.
DISCLOSURE OF THE INVENTION
[0005] It is therefore an object of the present invention to
provide a novel compound which has a potent FXa-inhibiting effect
and exhibits an anti-thrombotic effect quickly, sufficiently and
persistently by oral administration.
[0006] The present inventors have investigated synthesis and
pharmacological effects of novel FXa inhibitors. As a result,
diamine derivatives, salts thereof, and solvates and N-oxides
thereof, which exhibit potent FXa-inhibiting effect and
anticoagulant effect, have been found. It has also been found that
these compounds promptly, persistently and potently inhibit FXa and
exhibit potent anticoagulant effect and anti-thrombotic effect by
oral administration, and are hence useful as prophylactics and
remedies for various diseases based on thromboembolism, thus
leading to completion of the present invention.
[0007] This invention provides a compound represented by the
general formula (1):
Q.sup.1-Q.sup.2-T.sup.0-N(R.sup.1)-Q.sup.3-N(R.sup.2)-T.sup.1-Q.sup.4
(1)
wherein
[0008] R.sup.1 and R.sup.2 each independently represent a hydrogen
atom, hydroxyl group, alkyl group or alkoxy group;
[0009] Q.sup.1 represents a saturated or unsaturated, 5- or
6-membered cyclic hydrocarbon group which may be substituted, a
saturated or unsaturated, 5- to 7-membered heterocyclic group which
may be substituted, a saturated or unsaturated, bicyclic or
tricyclic condensed hydrocarbon group which may be substituted, or
a saturated or unsaturated, bicyclic or tricyclic condensed
heterocyclic group which may be substituted;
[0010] Q.sup.2 represents a single bond, a linear or branched
alkylene group having 1 to 6 carbon atoms, a linear or branched
alkenylene group having 2 to 6 carbon atoms, a linear or branched
alkynylene group having 2 to 6 carbon atoms, a saturated or
unsaturated, 5- or 6-membered divalent cyclic hydrocarbon group
which may be substituted, a saturated or unsaturated, 5- to
7-membered divalent heterocyclic group which may be substituted, a
saturated or unsaturated, divalent bicyclic or tricyclic condensed
hydrocarbon group which may be substituted, or a saturated or
unsaturated, divalent bicyclic or tricyclic condensed heterocyclic
group which may be substituted;
[0011] Q.sup.3 represents the following group:
##STR00002##
in which Q.sup.5 represents an alkylene group having 1 to 8 carbon
atoms, an alkenylene group having 2 to 8 carbon atoms, or a group
--(CH.sub.2).sub.m--CH.sub.2-A-CH.sub.2--(CH.sub.2).sub.n-- (in
which m and n are each independently 0 or an integer of 1-3, and A
represents an oxygen atom, nitrogen atom, sulfur atom, --SO--,
--SO.sub.2--, --NH--, --O--NH--, --NH--NH--, --S--NH--, --SO--NH--
or --SO.sub.2--NH--), and;
[0012] R.sup.3 and R.sup.4 are substituents on carbon atom(s),
nitrogen atom(s) or a sulfur atoms of a ring comprising Q.sup.5 and
are each independently a hydrogen atom, hydroxyl group, alkyl
group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl
group, cyano group, cyanoalkyl group, amino group, aminoalkyl
group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl
group, acylalkyl group, acylamino group which may be substituted,
alkoxyimino group, hydroxyimino group, acylaminoalkyl group, alkoxy
group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group,
carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl
group, alkoxycarbonylalkylamino group, carboxyalkylamino group,
alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group,
carbamoyl group, N-alkylcarbamoyl group which may have a
substituent on the alkyl group, N,N-dialkylcarbamoyl group which
may have a substituent on the alkyl group(s), N-alkenylcarbamoyl
group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl
group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl
group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl
group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazolyl group which
may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group,
alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl
group which may be substituted, carbamoylalkyl group,
N-alkylcarbamoylalkyl group which may have a substituent on the
alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a
substituent on the alkyl group(s), carbamoyloxyalkyl group,
N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group,
3- to 6-membered heterocyclic carbonylalkyl group which may be
substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group
which may be substituted, aryl group, aralkyl group, 3- to
6-membered heterocyclic group which may be substituted, 3- to
6-membered heterocyclic alkyl group which may be substituted,
alkylsulfonylamino group, arylsulfonylamino group,
alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group,
alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group,
alkylsulfonyl-aminocarbonylalkyl group,
arylsulfonylaminocarbonylalkyl group, oxo group, carbamoyloxy
group, aralkyloxy group, carboxyalkyloxy group,
alkoxycarbonylalkyloxy group, acyloxy group, acyloxyalkyl group,
arylsulfonyl group, alkoxycarbonylalkylsulfonyl group,
carboxyalkylsulfonyl group, alkoxycarbonylacyl group,
alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group,
halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl
group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group,
alkoxyalkylsulfonyl group, 3- to 6-membered heterocyclic sulfonyl
group which may be substituted, 3- to 6-membered heterocyclic oxy
group which may be substituted, N-alkylaminoacyl group,
N,N-dialkylaminoacyl group, N,N-dialkylcarbamoylacyl group which
may have a substituent on the alkyl group(s),
N,N-dialkylcarbamoylalkylsulfonyl group which may have a
substituent on the alkyl group(s), alkylsulfonylacyl group,
N-arylcarbamoyl group, N-(3- to 6-membered heterocyclic) carbamoyl
group, N-alkyl-N-arylcarbamoyl group, N-alkyl-N-(3- to 6-membered
heterocyclic) carbamoyl group, N-arylcarbamoylalkyl group, N-(3- to
6-membered heterocyclic) carbamoylalkyl group,
N-alkyl-N-arylcarbamoylalkyl group, N-alkyl-N-(3- to 6-membered
heterocyclic) carbamoylalkyl group, aminocarbothioyl group,
N-alkylaminocarbothioyl group, N,N-dialkylaminocarbothioyl group,
alkoxyalkyl(thiocarbonyl) group, alkylthioalkyl group or
N-acyl-N-alkylaminoalkyl group, or R.sup.3 and R.sup.4 together
form an alkylene group having 1 to 5 carbon atoms, alkenylene group
having 2 to 5 carbon atoms, alkylenedioxy group having 1 to 5
carbon atoms or carbonyldioxy group;
[0013] Q.sup.4 represents an aryl group which may be substituted,
an arylalkenyl group which may be substituted, an arylalkynyl group
which may be substituted, a heteroaryl group which may be
substituted, a heteroarylalkenyl group which may be substituted, a
saturated or unsaturated, bicyclic or tricyclic condensed
hydrocarbon group which may be substituted, or a saturated or
unsaturated, bicyclic or tricyclic condensed heterocyclic group
which may be substituted;
[0014] T.sup.0 represents a carbonyl or thiocarbonyl group; and
[0015] T.sup.1 represents a carbonyl group, sulfonyl group, group
--C(.dbd.O)--C(.dbd.O)--N(R')--, group
--C(.dbd.S)--C(.dbd.O)--N(R')--, group
--C(.dbd.O)--C(.dbd.S)--N(R')--, group
--C(.dbd.S)--C(.dbd.S)--N(R')-- (in which R' represents a hydrogen
atom, hydroxyl group, alkyl group or alkoxy group), group
--C(.dbd.O)-A.sup.1-N(R'')-- (in which A.sup.1 represents an
alkylene group having 1 to 5 carbon atoms, which may be
substituted, and R'' represents a hydrogen atom, hydroxyl group,
alkyl group or alkoxy group), group --C(.dbd.O)--NH--, group
--C(.dbd.S)--NH--, group --C(.dbd.O)--NH--NH--, group
--C(.dbd.O)-A.sup.2-C(.dbd.O)-- (in which A.sup.2 represents a
single bond or alkylene group having 1 to 5 carbon atoms), group
--C(.dbd.O)-A.sup.3-C(.dbd.O)--NH-- (in which A.sup.3 represents an
alkylene group having 1 to 5 carbon atoms), group
--C(.dbd.O)--C(.dbd.NOR.sup.a)--N(R.sup.b)--, group
--C(.dbd.S)--C(.dbd.NOR.sup.a)--N(R.sup.b)-- (in which R.sup.a
represents a hydrogen atom, alkyl group or alkanoyl group, and
R.sup.b represents a hydrogen atom, hydroxyl group, alkyl group or
alkoxy group), group --C(.dbd.O)--N.dbd.N--, group
--C(.dbd.S)--N.dbd.N--, group
--C(.dbd.NOR.sup.c)--C(.dbd.O)--N(R.sup.d)-- (in which R.sup.c
represents a hydrogen atom, alkyl group, alkanoyl group, aryl group
or aralkyl group, and R.sup.d represents a hydrogen atom, hydroxyl
group, alkyl group or alkoxy group), group
--C(.dbd.N--N(R.sup.e)(R.sup.f))--C(.dbd.O)--N(R.sup.g)-- (in which
R.sup.e and R.sup.f each independently represent a hydrogen atom,
alkyl group, alkanoyl or alkyl(thiocarbonyl) group, and R.sup.g
represents a hydrogen atom, hydroxyl group, alkyl group or alkoxy
group), group --C(.dbd.O)--NH--C(.dbd.O)--, group
--C(.dbd.S)--NH--C(.dbd.O)--, group --C(.dbd.O)--NH--C(.dbd.S)--,
group --C(.dbd.S)--NHC(.dbd.S)--, group
--C(.dbd.O)--NH--SO.sub.2--, group --SO.sub.2--NH--, group
--C(.dbd.NCN)--NH--C(.dbd.O)--, group --C(.dbd.S)--C(.dbd.O)--, or
thiocarbonyl group;
[0016] a salt thereof, a solvate thereof, or an N-oxide
thereof.
[0017] This invention also provides a drug, an activated blood
coagulation factor X inhibitor, an anticoagulant, an agent for
preventing and/or treating thrombosis or embolism and an agent for
preventing and/or treating cerebral infarction, cerebral embolism,
myocardial infarction, angina pectoris, pulmonary infarction,
pulmonary embolism, Buerger's disease, deep venous thrombosis,
disseminated intravascular coagulation syndrome, thrombus formation
after artificial valve or joint replacement, thrombus formation and
reocclusion after angioplasty, systemic inflammatory response
syndrome (SIRS), multiple organ dysfunction syndrome (MODS),
thrombus formation during extracorporeal circulation, or blood
clotting upon blood gathering, which each comprises the compound
represented by the general formula (1), a salt thereof, a solvate
thereof, or an N-oxide thereof.
[0018] This invention further provides an intermediate for
preparing the compound represented by the general formula (1).
[0019] This invention still further provides use of the compound
represented by the general formula (1), a salt thereof, a solvate
thereof, or an N-oxide thereof for preparation of a drug.
[0020] This invention yet still further provides a method for
treating thrombosis or embolism, which comprises administering an
effective amount of the compound represented by the general formula
(1), a salt thereof, a solvate thereof, or an N-oxide thereof.
[0021] The cyclic diamine derivatives of the present invention
exhibit a potent inhibitory effect on activated blood coagulation
factor X. Therefore, the derivatives are useful as a drug, an
activated blood coagulation factor X inhibitor, an anticoagulant,
an agent for preventing and/or treating thrombosis or embolism, an
agent for preventing and/or treating thrombotic diseases, and an
agent for preventing and/or treating cerebral infarction, cerebral
embolism, myocardial infarction, angina pectoris, pulmonary
infarction, pulmonary embolism, Buerger's disease, deep venous
thrombosis, disseminated intravascular coagulation syndrome,
thrombus formation after artificial valve or joint replacement,
thrombus formation and reocclusion after angioplasty, systemic
inflammatory response syndrome (SIRS), multiple organ dysfunction
syndrome (MODS), thrombus formation during extracorporeal
circulation, or blood clotting upon blood gathering.
BEST MODE FOR CARRYING OUT THE INVENTION
[0022] Substituents in the diamine derivatives according to the
present invention represented by the general formula (1) will
hereinafter be described.
<On Group Q.sup.4>
[0023] The group Q.sup.4 represents an aryl group which may be
substituted, an arylalkenyl group which may be substituted, an
arylalkynyl group which may be substituted, a heteroaryl group
which may be substituted, a heteroarylalkenyl group which may be
substituted, a saturated or unsaturated, bicyclic or tricyclic
condensed hydrocarbon group which may be substituted, or a
saturated or unsaturated, bicyclic or tricyclic condensed
heterocyclic group which may be substituted.
[0024] In the group Q.sup.4, the aryl group may include aryl groups
having 6 to 14 carbon atoms, for example, phenyl, naphthyl, anthryl
and phenanthryl groups. The arylalkenyl group means a group formed
by an aryl group having 6 to 14 carbon atoms and an alkenylene
group having 2 to 6 carbon atoms, and examples thereof may include
a styryl group. The arylalkynyl group means a group formed by an
aryl group having 6 to 14 carbon atoms and an alkynylene group
having 2 to 6 carbon atoms, and examples thereof may include a
phenylethynyl group.
[0025] The heteroaryl group means a monovalent aromatic group
having at least one hetero atom selected from oxygen, sulfur and
nitrogen atoms, and examples thereof may include 5- or 6-membered
heteroaryl groups, for example, pyridyl, pyridazinyl, pyrazinyl,
furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, pyrimidinyl and
tetrazolyl groups. The heteroarylalkenyl group means a group formed
by the above-described heteroaryl group and an alkenylene group
having 2 to 6 carbon atoms, and examples thereof may include
thienylethenyl and pyridylethenyl groups.
[0026] The saturated or unsaturated, bicyclic or tricyclic
condensed hydrocarbon group means a monovalent group derived from a
saturated or unsaturated, bicyclic or tricyclic condensed
hydrocarbon. The saturated or unsaturated, bicyclic or tricyclic
condensed hydrocarbon denotes a bicyclic or tricyclic condensed
hydrocarbon formed by condensing 2 or 3 saturated or unsaturated,
5- or 6-membered cyclic hydrocarbons which are the same or
different from each other. In this case, examples of the saturated
or unsaturated, 5- or 6-membered cyclic hydrocarbons may include
cyclopentane, cyclopentene, cyclohexane, cyclohexene,
cyclohexadiene and benzene. Specific examples of the saturated or
unsaturated, bicyclic or tricyclic condensed hydrocarbon group may
include indenyl, indanyl, tetrahydronaphthyl and naphthyl groups.
Incidentally, the position of the saturated or unsaturated,
bicyclic or tricyclic condensed hydrocarbon group bonded to T.sup.1
in the general formula (1) is not particularly limited.
[0027] The saturated or unsaturated, bicyclic or tricyclic
condensed heterocyclic group means a monovalent group derived from
a saturated or unsaturated, bicyclic or tricyclic condensed
heterocyclic ring. The saturated or unsaturated, bicyclic or
tricyclic condensed heterocyclic ring denotes the following
heterocyclic ring 1), 2), or 3):
[0028] 1) a bicyclic or tricyclic condensed heterocyclic ring
formed by condensing 2 or 3 saturated or unsaturated, 5- to
7-membered heterocyclic rings which are the same or different from
each other;
[0029] 2) a bicyclic or tricyclic condensed heterocyclic ring
formed by condensing a saturated or unsaturated, 5- to 7-membered
heterocyclic ring with 1 or 2 saturated or unsaturated, 5- or
6-membered cyclic hydrocarbons; or
[0030] 3) a tricyclic condensed heterocyclic ring formed by
condensing 2 saturated or unsaturated, 5- to 7-membered
heterocyclic rings with a saturated or unsaturated, 5- or
6-membered cyclic hydrocarbon.
[0031] The position of the saturated or unsaturated, bicyclic or
tricyclic condensed heterocyclic group bonded to T.sup.1 in the
general formula (1) is not particularly limited.
[0032] The saturated or unsaturated, 5- to 7-membered heterocyclic
ring denotes a heterocyclic ring having at least one hetero atom
selected from oxygen, sulfur and nitrogen atoms, and specific
examples thereof may include furan, pyrrole, thiophene, pyrazole,
imidazole, oxazole, oxazolidine, thiazole, thiadiazole, furazane,
pyrane, pyridine, pyrimidine, pyridazine, pyrrolidine, piperazine,
piperidine, oxazine, oxadiazine, morpholine, thiazine, thiadiazine,
thiomorpholine, tetrazole, triazole, triazine, thiadiazine,
oxadiazine, azepine, diazepine, triazepine, thiazepine and
oxazepine. The saturated or unsaturated, 5- or 6-membered cyclic
hydrocarbon denotes the same saturated or unsaturated, 5- or
6-membered cyclic hydrocarbon as shown in the description of the
saturated or unsaturated, bicyclic or tricyclic condensed
hydrocarbon group. Specific examples of the saturated or
unsaturated, bicyclic or tricyclic condensed heterocyclic group may
include benzofuryl, isobenzofuryl, benzothienyl, indolyl,
indolinyl, isoindolyl, isoindolinyl, indazolyl, quinolyl,
dihydroquinolyl, 4-oxodihydroquinolyl(dihydroquinolin-4-one),
tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, chromenyl,
chromanyl, isochromanyl, 4H-4-oxobenzopyranyl,
3,4-dihydro-4H-4-oxobenzopyranyl, 4H-quinolizinyl, quinazolinyl,
dihydroquinazolinyl, tetrahydroquinazolinyl, quinoxalinyl,
tetrahydroquinoxalinyl, cinnolinyl, tetrahydrocinnolinyl,
indolizinyl, tetrahydroindolizinyl, benzothiazolyl,
tetrahydrobenzothiazolyl, benzoxazolyl, benzoisothiazolyl,
benzoisoxazolyl, benzimidazolyl, naphthyridinyl,
tetrahydronaphthyridinyl, thienopyridyl, tetrahydro-thienopyridyl,
thiazolopyridyl, tetrahydrothiazolopyridyl, thiazolopyridazinyl,
tetrahydrothiazolopyridazinyl, pyrrolopyridyl,
dihydropyrrolopyridyl, tetrahydropyrrolopyridyl,
pyrrolopyrimidinyl, dihydropyrrolopyrimidinyl, pyridoquinazolinyl,
dihydropyridoquinazolinyl, pyridopyrimidinyl,
tetrahydropyridopyrimidinyl, pyranothiazolyl,
dihydropyranothiazolyl, furopyridyl, tetrahydrofuropyridyl,
oxazolopyridyl, tetrahydrooxazolopyridyl, oxazolopyridazinyl,
tetrahydrooxazolopyridazinyl, pyrrolothiazolyl,
dihydropyrrolothiazolyl, pyrrolooxazolyl, dihydropyrrolooxazolyl,
thienopyrrolyl, thiazolopyrimidinyl, 4-oxotetrahydrocinnolinyl,
1,2,4-benzothiadiazinyl, 1,1-dioxy-2H-1,2,4-benzothiadiazinyl,
1,2,4-benzoxadiazinyl, cyclopentapyranyl, thienofuranyl,
furopyranyl, pyridoxazinyl, pyrazoloxazolyl, imidazothiazolyl,
imidazopyridyl, tetrahydroimidazopyridyl, pyrazinopyridazinyl,
benzoisoquinolyl, furocinnolyl, pyrazolothiazolopyridazinyl,
tetrahydropyrazolothiazolopyridazinyl,
hexahydrothiazolopyridazinopyridazinyl, imidazotriazinyl,
oxazolopyridyl, benzoxepinyl, benzoazepinyl,
tetrahydrobenzoazepinyl, benzodiazepinyl, benzotriazepinyl,
thienoazepinyl, tetrahydrothienoazepinyl, thienodiazepinyl,
thienotriazepinyl, thiazoloazepinyl, tetrahydrothiazolo-azepinyl,
4,5,6,7-tetrahydro-5,6-tetramethylenethiazolo-pyridazinyl and
5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl groups.
[0033] No particular limitation is imposed on the condensing form
of the condensed heterocyclic group. For example, the
naphthyridinyl group may be any of 1,5-, 1,6-, 1,7-, 1,8-, 2,6- and
2,7-naphthyridinyl groups, the thienopyridyl group may be any of
thieno[2,3-b]pyridyl, thieno[2,3-c]pyridyl, thieno[3,2-b]pyridyl,
thieno[3,2-c]pyridyl, thieno[3,4-b]pyridyl and thieno[3,4-c]pyridyl
groups, the thienopyrrolyl group may be any of
thieno[2,3-b]pyrrolyl and thieno[2,3-b]pyrrolyl groups, the
thiazolopyridyl group may be any of thiazolo[4,5-b]pyridyl,
thiazolo[4,5-c]pyridyl, thiazolo[5,4-b]pyridyl,
thiazolo[5,4-c]pyridyl, thiazolo[3,4-a]pyridyl and
thiazolo[3,2-a]pyridyl groups, the thiazolopyridazinyl group may be
any of thiazolo[4,5-c]pyridazinyl, thiazolo[4,5-d]pyridazinyl,
thiazolo[5,4-c]pyridazinyl and thiazolo[3,2-b]pyridazinyl groups,
the pyrrolopyridyl group may be any of pyrrolo[2,3-b]pyridyl,
pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-b]pyridyl,
pyrrolo[3,2-c]pyridyl, pyrrolo[3,4-b]pyridyl and
pyrrolo[3,4-c]pyridyl group, the pyridopyrimidinyl group may be any
of pyrido[2,3-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl,
pyrido[3,4-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl,
pyrido[1,2-c]pyrimidinyl and pyrido[1,2-a]pyrimidinyl groups, the
pyranothiazolyl group may be any of pyrano[2,3-d]thiazolyl,
pyrano[4,3-d]thiazolyl, pyrano[3,4-d]thiazolyl and
pyrano[3,2-d]thiazolyl groups, the furopyridyl group may be any of
furo[2,3-b]pyridyl, furo[2,3-c]pyridyl, furo[3,2-b]pyridyl,
furo[3,2-c]pyridyl, furo[3,4-b]pyridyl and furo[3,4-c]pyridyl
groups, the oxazolopyridyl group may be any of
oxazolo[4,5-b]pyridyl, oxazolo[4,5-c]pyridyl,
oxazolo[5,4-b]pyridyl, oxazolo[5,4-c]pyridyl, oxazolo[3,4-a]pyridyl
and oxazolo[3,2-a]pyridyl groups, the oxazolopyridazinyl group may
be any of oxazolo[4,5-c]pyridazinyl, oxazolo[4,5-d]pyridazinyl,
oxazolo[5,4-c]pyridazinyl and oxazolo[3,4-b]pyridazinyl groups, the
pyrrolothiazolyl group may be any of pyrrolo[2,1-b]thiazolyl,
pyrrolo[1,2-c]thiazolyl, pyrrolo[2,3-d]thiazolyl,
pyrrolo[3,2-d]thiazolyl and pyrrolo[3,4-d]thiazolyl groups, the
pyrrolooxazolyl group may be any of pyrrolo[2,1-b]oxazolyl,
pyrrolo[1,2-c]oxazolyl, pyrrolo[2,3-d]oxazolyl,
pyrrolo[3,2-d]oxazolyl and pyrrolo[3,4-d]oxazolyl groups, the
benzoazepinyl group may be any of 1H-1-benzoazepinyl,
1H-2-benzoazepinyl and 1H-3-benzoazepinyl groups, or may be a
dihydro-oxo derivative type benzoazepinyl group such as
4,5-dihydro-1-oxo-1H-2-benzoazepinyl group, the benzodiazepinyl
group may be any of 1H-1,3-benzodiazepinyl, 1H-1,4-benzodiazepinyl
and 1H-1,5-benzodiazepinyl groups, or may be a dihydro-oxo
derivative type benzodiazepinyl group such as
4,5-dihydro-4-oxo-1H-1,3-benzodiazepinyl group, the
benzotriazepinyl group may be any of 1H-1,3,4-benzotriazepinyl and
1H-1,3,5-benzotriazepinyl groups, or may be a dihydro-oxo
derivative type benzotriazepinyl group such as
4,5-dihydro-5-oxo-1H-1,3,4-benzotriazepinyl group, and the
thienoazepinyl group may be any of thieno[2,3-b]azepinyl,
thieno[2,3-c]azepinyl, thieno[2,3-d]azepinyl, thieno[3,2-c]azepinyl
and thieno[3,2-b]azepinyl groups, or may be a dihydro-oxo
derivative type thienoazepinyl group such as
5,6,7,8-tetrahydro-4-oxo-4H-thieno[3,2-c]azepinyl group.
Thienodiazepinyl and thienotriazepinyl groups may also be any
condensing forms, or may be those of the dihydro-oxo derivative
type. The benzothiazepinyl group may be any of
1H-1-benzothiazepinyl, 1H-2-benzothiazepinyl and
1H-3-benzothiazepinyl groups, or may be a dihydro-oxo derivative
type benzothiazepinyl group such as
4,5-dihydro-1-oxo-1H-2-benzothiazepinyl group, and the
benzoxazepinyl group may be any of 1H-1-benzoxazepinyl,
1H-2-benzoxazepinyl and 1H-3-benzoxazepinyl groups, or may be a
dihydro-oxo derivative type benzoxazepinyl group such as
4,5-dihydro-1-oxo-1H-2-benzoxazepinyl group. Other condensing forms
than these may be allowed.
[0034] The above-described aryl groups, heteroaryl groups,
arylalkenyl group, heteroarylalkenyl groups, saturated or
unsaturated, bicyclic or tricyclic condensed hydrocarbon groups and
saturated or unsaturated, bicyclic or tricyclic condensed
heterocyclic groups may each have 1 to 3 substituents. Examples of
the substituents may include a hydroxyl group, halogen atoms such
as fluorine atom, chlorine atom, bromine atom and iodine atom,
halogenoalkyl groups having 1 to 6 carbon atoms substituted by 1 to
3 halogen atoms, an amino group, a cyano group, aminoalkyl groups,
a nitro group, hydroxyalkyl groups (for example, hydroxymethyl
group, 2-hydroxyethyl group, etc.), alkoxyalkyl groups (for
example, methoxymethyl group, 2-methoxyethyl group, etc.), a
carboxyl group, carboxyalkyl groups (for example, carboxymethyl
group, 2-carboxyethyl group, etc.), alkoxycarbonylalkyl groups (for
example, methoxycarbonylmethyl group, ethoxycarbonylmethyl group,
etc.), acyl groups (for example, alkanoyl groups such as formyl
group, acetyl group and propionyl group), an amidino group, a
hydroxyamidino group (amino(hydroxyimino)methyl group), linear,
branched or cyclic alkyl groups having 1 to 6 carbon atoms (for
example, methyl group, ethyl group, etc.), linear, branched or
cyclic alkoxy groups having 1 to 6 carbon atom (for example,
methoxy group, ethoxy group, etc.), amidino groups substituted by a
linear, branched or cyclic alkyl group having 1 to 6 carbon atoms
(for example, imino(methylamino)methyl group), amidino groups
substituted by a linear, branched or cyclic alkoxy group having 1
to 6 carbon atoms (for example, amino(methoxyimino)methyl group),
amidino groups substituted by a linear, branched or cyclic
alkoxycarbonyl group having 2 to 7 carbon atoms (for example,
amino(methoxycarbonylimino)methyl group and
amino(ethoxycarbonylimino)methyl group), linear, branched or cyclic
alkenyl groups having 2 to 6 carbon atoms (for example, vinyl
group, allyl group, etc.), linear or branched alkynyl groups having
2 to 6 carbon atoms (for example, ethynyl group, propynyl group,
etc.), linear, branched or cyclic alkoxycarbonyl groups having 2 to
6 carbon atoms (for example, methoxycarbonyl group, ethoxycarbonyl
group, etc.), a carbamoyl group, mono- or di-alkylcarbamoyl groups
having on the nitrogen atom one or two linear, branched or cyclic
alkyl group havings 1 to 6 carbon atoms (for example,
methylcarbamoyl group, ethylcarbamoyl group, dimethylcarbamoyl
group, ethylmethylcarbamoyl group, etc.), mono- or di-alkylamino
groups substituted by a linear, branched or cyclic alkyl group
having 1 to 6 carbon atoms (for example, ethylamino, dimethylamino
and methylethylamino groups), and 5- or 6-membered
nitrogen-containing heterocyclic groups (for example, pyrrolidino
group, piperidino group, piperazino group, morpholino group,
etc.).
[0035] As the group Q.sup.4, the following 12 groups (a) to (1)
among the above-described groups are preferred. Namely,
##STR00003##
wherein R.sup.5 and R.sup.6 each independently represent a hydrogen
atom, cyano group, halogen atom, alkyl group, hydroxyalkyl group,
alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl
group, acyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group,
or phenyl group which may be substituted by a cyano group, hydroxyl
group, halogen atom, alkyl group or alkoxy group, and R.sup.7 and
R.sup.8 each independently represent a hydrogen atom, hydroxyl
group, nitro group, amino group, cyano group, halogen atom, alkyl
group, alkenyl group, alkynyl group, halogenoalkyl group,
hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl
group, carboxyalkyl group, acyl group, carbamoyl group,
N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl
group, amidino group or alkoxycarbonylalkyl group;
##STR00004##
wherein R.sup.9 and R.sup.10 each independently represent a
hydrogen atom, hydroxyl group, nitro group, amino group, cyano
group, halogen atom, alkyl group, alkenyl group, alkynyl group,
halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl
group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl
group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group,
alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl
group;
##STR00005##
wherein R.sup.11, R.sup.12 and R.sup.13 each independently
represent a hydrogen atom, hydroxyl group, nitro group, amino
group, cyano group, halogen atom, alkyl group, alkenyl group,
alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy
group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl
group, carbamoyl group, N-alkylcarbamoyl group,
N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or
alkoxycarbonylalkyl group;
##STR00006##
wherein X.sup.1 represents CH.sub.2, CH, NH, NOH, N, O or S, and
R.sup.14, R.sup.15 and R.sup.16 each independently represent a
hydrogen atom, hydroxyl group, nitro group, amino group, cyano
group, halogen atom, alkyl group, alkenyl group, alkynyl group,
halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl
group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl
group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group,
alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl
group;
##STR00007##
wherein X.sup.2 represents NH, N, O or S, X.sup.3 represents N, C
or CH, X.sup.4 represents N, C or CH, and R.sup.17 and R.sup.18
each independently represent a hydrogen atom, hydroxyl group, nitro
group, amino group, cyano group, halogen atom, alkyl group, alkenyl
group, alkynyl group, halogenoalkyl group, hydroxyalkyl group,
alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl
group, acyl group, carbamoyl group, N-alkylcarbamoyl group,
N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or
alkoxycarbonylalkyl group, excluding the cases where X.sup.3 and
X.sup.4 are combinations of C and CH, and are both C or CH;
##STR00008##
wherein N indicates that 1 or 2 carbon atoms of the ring
substituted by R.sup.19 have been substituted by a nitrogen atom,
and R.sup.19, R.sup.20 and R.sup.21 each independently represent a
hydrogen atom, hydroxyl group, nitro group, amino group, cyano
group, halogen atom, alkyl group, alkenyl group, alkynyl group,
halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl
group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl
group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group,
alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl
group;
##STR00009##
wherein X.sup.5 represents CH.sub.2, CH, N or NH, Z.sup.1
represents N, NH or O, Z.sup.2 represents CH.sub.2, CH, C or N,
Z.sup.3 represents CH.sub.2, CH, S, SO.sub.2 or C.dbd.O,
X.sup.5--Z.sup.2 indicates that X.sup.5 and Z.sup.2 are bonded to
each other by a single bond or double bond, R.sup.22 and R.sup.23
each independently represent a hydrogen atom, hydroxyl group, nitro
group, amino group, cyano group, halogen atom, alkyl group, alkenyl
group, alkynyl group, halogenoalkyl group, hydroxyalkyl group,
alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl
group, acyl group, carbamoyl group, N-alkylcarbamoyl group,
N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or
alkoxycarbonylalkyl group, and R.sup.24 represents a hydrogen atom
or alkyl group;
##STR00010##
wherein X.sup.6 represents O or S, and R.sup.25 and R.sup.26 each
independently represent a hydrogen atom, hydroxyl group, nitro
group, amino group, cyano group, halogen atom, alkyl group, alkenyl
group, alkynyl group, halogenoalkyl group, hydroxyalkyl group,
alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl
group, acyl group, carbamoyl group, N-alkylcarbamoyl group,
N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or
alkoxycarbonylalkyl group;
##STR00011##
wherein R.sup.27 and R.sup.28 each independently represent a
hydrogen atom, hydroxyl group, nitro group, amino group, cyano
group, halogen atom, alkyl group, alkenyl group, alkynyl group,
halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl
group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl
group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group,
alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl
group;
##STR00012##
wherein E.sup.1 and E.sup.2 each independently represent N or CH,
and R.sup.29 and R.sup.30 each independently represent a hydrogen
atom, hydroxyl group, nitro group, amino group, cyano group,
halogen atom, alkyl group, alkenyl group, alkynyl group,
halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl
group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl
group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group,
alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl
group;
##STR00013##
wherein Y.sup.1 represents CH or N, Y.sup.2 represents
--N(R.sup.33)-- (in which R.sup.33 represents a hydrogen atom or
alkyl group having 1 to 6 carbon atoms), O or S, and R.sup.31 and
R.sup.32 each independently represent a hydrogen atom, hydroxyl
group, nitro group, amino group, cyano group, halogen atom, alkyl
group, alkenyl group, alkynyl group, halogenoalkyl group,
hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl
group, carboxyalkyl group, acyl group, carbamoyl group,
N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl
group, amidino group or alkoxycarbonylalkyl group; and
##STR00014##
wherein numerals 1 to 8 indicate positions, each N indicates that
any one of carbon atoms of positions 1 to 4 and any one of carbon
atoms of positions 5 to 8 has been substituted by a nitrogen atom,
and R.sup.34, R.sup.35 and R.sup.36 each independently represent a
hydrogen atom, hydroxyl group, nitro group, amino group, cyano
group, halogen atom, alkyl group, alkenyl group, alkynyl group,
halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl
group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl
group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group,
alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl
group.
[0036] These groups will hereinafter be described.
[0037] In the description of R.sup.5 to R.sup.36, the halogen atom
is a fluorine, chlorine, bromine or iodine atom, the alkyl group is
a linear, branched or cyclic alkyl group having 1 to 6 carbon
atoms, the alkenyl group is a linear, branched or cyclic alkenyl
group having 2 to 6 carbon atoms, the alkynyl group is a linear or
branched alkynyl group having 2 to 6 carbon atoms, the hydroxyalkyl
group means the above-described C.sub.1-C.sub.6 alkyl group
substituted by one hydroxyl group, the alkoxy group is a linear,
branched or cyclic alkoxy group having 1 to 6 carbon atoms, the
alkoxyalkyl group means the above-described C.sub.1-C.sub.6 alkyl
group substituted by one C.sub.1-C.sub.6 alkoxy group, the
carboxyalkyl group means the above-described C.sub.1-C.sub.6 alkyl
group substituted by one carboxyl group, the acyl group is an
alkanoyl group (including formyl) having 1 to 6 carbon atoms, an
aroyl group such as a benzoyl or naphthoyl group, or an
arylalkanoyl group with the above-described C.sub.6-C.sub.14 aryl
group substituted on the above-described C.sub.1-C.sub.6 alkanoyl
group, the N-alkylcarbamoyl group means a carbamoyl group with the
above-described C.sub.1-C.sub.6 alkyl group substituted on the
nitrogen atom, the N,N-dialkylcarbamoyl group means a carbamoyl
group with two C.sub.1-C.sub.6 alkyl groups substituted on the
nitrogen atom, the alkoxycarbonyl group is a group composed of the
above-described C.sub.1-C.sub.6 alkoxy group and a carbonyl group,
the alkoxycarbonylalkyl group means the above-described
C.sub.1-C.sub.6 alkyl group substituted by one C.sub.1-C.sub.6
alkoxycarbonyl group, and the halogenoalkyl group means the
above-described C.sub.1-C.sub.6 alkyl group substituted by 1 to 3
halogen atoms. Incidentally, in the above description, no
particular limitation is imposed on the substituting position.
[0038] In the following group:
##STR00015##
wherein R.sup.5, R.sup.6, R.sup.7 and R.sup.8 have the same
meanings as defined above, and numerals 1 to 6 indicate positions,
R.sup.5 and R.sup.6 are each independently preferably a hydrogen
atom, cyano group, halogen atom, alkyl group, alkenyl group,
alkynyl group or halogenoalkyl group. R.sup.5 and R.sup.6 are more
preferably hydrogen atoms or alkyl groups. In the case of the alkyl
group, a methyl group is preferred. It is preferable that one of
R.sup.7 and R.sup.8 is a hydrogen atom, and the other is a hydrogen
atom, cyano group, halogen atom, alkyl group, alkenyl group,
alkynyl group or halogenoalkyl group. Among others, it is
particularly preferred that the other group be a hydrogen atom,
halogen atom, alkyl group or alkynyl group. In this case, the
halogen atom is preferably a fluorine, chlorine or bromine atom. As
the alkyl group, is preferred a methyl group. As the alkynyl group,
is particularly preferred an ethynyl group. As specific preferable
examples of the group represented by the above formula, may be
mentioned chlorostyryl, fluorostyryl, bromostyryl and ethynylstyryl
groups. The position substituted by the halogen atom, alkyl group
or alkynyl group is particularly preferably a 4-position in the
above formula though it should not be particularly limited. As
specific preferable examples thereof, may be mentioned
4-chlorostyryl, 4-fluorostyryl, 4-bromostyryl and 4-ethynylstyryl
groups.
[0039] In the following group:
##STR00016##
wherein R.sup.9 and R.sup.10 have the same meanings as defined
above, and numerals 1 to 6 indicate positions, R.sup.9 and R.sup.10
are each independently preferably a hydrogen atom, halogen atom,
alkyl group or alkynyl group. It is further preferable that R.sup.9
is a hydrogen atom, and R.sup.10 is a hydrogen atom, halogen atom,
alkyl group or alkynyl group. In this case, the halogen atom is
preferably a fluorine, chlorine or bromine atom. As the alkyl
group, is preferred a methyl group. As the alkynyl group, is
particularly preferred an ethynyl group. As specific preferable
examples of the group represented by the above formula, may be
mentioned chlorophenylethynyl, fluorophenylethynyl,
bromophenylethynyl and ethynylphenylethynyl groups. The position
substituted by the halogen atom, alkyl group or alkynyl group is
particularly preferably a 4-position in the above formula though it
should not be particularly limited. As specific preferable examples
thereof, may be mentioned 4-chlorophenylethynyl,
4-fluorophenylethynyl, 4-bromophenylethynyl and
4-ethynylphenylethynyl groups.
[0040] In the following group:
##STR00017##
wherein R.sup.11, R.sup.12 and R.sup.13 have the same meanings as
defined above, and numerals 1 to 8 indicate positions, R.sup.11,
R.sup.12 and R.sup.13 are each independently preferably a hydrogen
atom, cyano group, halogen atom, alkyl group, alkenyl group,
alkynyl group or halogenoalkyl group. R.sup.11 is preferably a
hydrogen atom, alkyl group, halogen atom or hydroxyl group, with a
hydrogen atom being particularly preferred. It is preferable that
one of R.sup.12 and R.sup.13 is a hydrogen atom, and the other is a
hydrogen atom, cyano group, halogen atom, alkyl group, alkenyl
group, alkynyl group or halogenoalkyl group. Among others, it is
particularly preferred that the other group be a hydrogen atom,
halogen atom, alkyl group or alkynyl group. In this case, the
halogen atom is preferably a fluorine, chlorine or bromine atom. As
the alkyl group, is preferred a methyl group. As the alkynyl group,
is preferred an ethynyl group. In the naphthyl group, a 2-naphthyl
group is preferred to a 1-naphthyl group. In the case of the
2-naphthyl group, the position substituted by a halogen atom, alkyl
group or alkynyl group is preferably a 6- or 7-position in the
above formula though it should not be particularly limited, with a
6-position being most preferred. These naphthyl groups are
preferably substituted by a chlorine, fluorine or bromine atom, an
alkynyl group, or the like, with a group having a substituent such
as a chlorine, fluorine or bromine atom, an alkynyl group, or the
like at the above-described position in the above formula being
particularly preferred. As specific preferable examples thereof,
may be mentioned 6-chloro-2-naphthyl, 6-fluoro-2-naphthyl,
6-bromo-2-naphthyl, 6-ethynyl-2-naphthyl, 7-chloro-2-naphthyl,
7-fluoro-2-naphthyl, 7-bromo-2-naphthyl and 7-ethynyl-2-naphthyl
groups.
[0041] In the following group:
##STR00018##
wherein X.sup.1, R.sup.14, R.sup.15 and R.sup.16 have the same
meanings as defined above, and numerals 4 to 7 indicate positions,
X.sup.1 is preferably NH, NOH, N, O or S, with NH, O or S being
particularly preferred. R.sup.14 is preferably a hydrogen atom,
halogen atom, acyl group, N-alkylcarbamoyl group,
N,N-dialkylcarbamoyl group or alkyl group, and R.sup.15 and
R.sup.16 are each independently preferably a hydrogen atom, cyano
group, halogen atom, alkyl group, alkenyl group, alkynyl group or
halogenoalkyl group. It is preferable that one of R.sup.16 and
R.sup.16 is a hydrogen or a halogen atom, preferably fluorine atom
or chlorine atom, and the other is a hydrogen atom, cyano group,
halogen atom, alkyl group, alkenyl group, alkynyl group or
halogenoalkyl group. Among others, it is particularly preferred
that the other group be a hydrogen atom, halogen atom, alkyl group
or alkynyl group. In this case, the halogen atom is preferably a
fluorine, chlorine or bromine atom. As the alkyl group, is
preferred a methyl group. As the alkynyl group, is preferred an
ethynyl group. The position substituted by the halogen atom, alkyl
group or alkynyl group is preferably a 4-, 5- or 6-position in the
above formula though it should be not particularly limited. As
specific preferable examples of the group represented by the above
formula, may be mentioned 5-chloroindolyl, 5-fluoroindolyl,
5-bromoindolyl, 5-ethynylindolyl, 5-methylindolyl,
5-chloro-4-fluoroindolyl, 5-chloro-3-fluoroindolyl,
5-fluoro-3-chloroindolyl, 5-ethynyl-3-fluoroindolyl,
5-chloro-3-(N,N-dimethylcarbamoyl)indolyl,
5-fluoro-3-(N,N-dimethylcarbamoyl)indolyl,
5-chloro-3-formylindolyl, 5-fluoro-3-formylindolyl,
6-chloroindolyl, 6-fluoroindolyl, 6-bromoindolyl, 6-ethynylindolyl,
6-methylindolyl, 5-chlorobenzothienyl, 5-fluorobenzothienyl,
5-bromobenzothienyl, 5-ethynylbenzothienyl, 5-methylbenzothienyl,
5-chloro-4-fluorobenzothienyl, 6-chlorobenzothienyl,
6-fluorobenzothienyl, 6-bromobenzothienyl, 6-ethynylbenzothienyl,
6-methylbenzothienyl, 5-chlorobenzofuryl, 5-fluorobenzofuryl,
5-bromobenzofuryl, 5-ethynylbenzofuryl, 5-methylbenzofuryl,
5-chloro-4-fluorobenzofuryl, 6-chlorobenzofuryl,
6-fluorobenzofuryl, 6-bromobenzofuryl, 6-ethynylbenzofuryl and
6-methylbenzofuryl groups. The position of the above-described
substituent group bonded to T.sup.1 is not particularly limited,
but is preferably a 2-position or 3-position in the formula (d).
Specifically, more preferred are 5-chloroindol-2-yl,
5-fluoroindol-2-yl, 5-bromoindol-2-yl, 5-ethynylindol-2-yl,
5-methylindol-2-yl, 5-chloro-4-fluoroindol-2-yl,
5-chloro-3-fluoroindol-2-yl, 3-bromo-5-chloroindol-2-yl,
3-chloro-5-fluoroindol-2-yl, 3-bromo-5-fluoroindol-2-yl,
5-bromo-3-chloroindol-2-yl, 5-bromo-3-fluoroindol-2-yl,
5-chloro-3-formylindol-2-yl, 5-fluoro-3-formylindol-2-yl,
5-bromo-3-formylindol-2-yl, 5-ethynyl-3-formylindol-2-yl,
5-chloro-3-(N,N-dimethylcarbamoyl)indol-2-yl,
5-fluoro-3-(N,N-dimethylcarbamoyl)indol-2-yl,
5-bromo-3-(N,N-dimethylcarbamoyl)indol-2-yl,
5-ethynyl-3-(N,N-dimethylcarbamoyl)indol-2-yl, 6-chloroindol-2-yl,
6-fluoroindol-2-yl, 6-bromoindol-2-yl, 6-ethynylindol-2-yl,
6-methylindol-2-yl, 5-chloroindol-3-yl, 5-fluoroindol-3-yl,
5-bromoindol-3-yl, 5-ethynylindol-3-yl, 5-methylindol-3-yl,
5-chloro-4-fluoroindol-3-yl, 6-chloroindol-3-yl,
6-fluoroindol-3-yl, 6-bromoindol-3-yl, 6-ethynylindol-3-yl,
6-methylindol-3-yl, 5-chlorobenzothiophen-2-yl,
5-fluorobenzothiophen-2-yl, 5-bromobenzothiophen-2-yl,
5-ethynylbenzothiophen-2-yl, 5-methylbenzothiophen-2-yl,
5-chloro-4-fluorobenzothiophen-2-yl, 6-chlorobenzothiophen-2-yl,
6-fluorobenzothiophen-2-yl, 6-bromobenzothiophen-2-yl,
6-ethynylbenzothiophen-2-yl, 6-methylbenzothiophen-2-yl,
5-chlorobenzothiophen-3-yl, 5-fluorobenzothiophen-3-yl,
5-bromobenzothiophen-3-yl, 5-ethynylbenzothiophen-3-yl,
5-methylbenzothiophen-3-yl, 5-chloro-4-fluorobenzothiophen-3-yl,
6-chlorobenzothiophen-3-yl, 6-fluorobenzothiophen-3-yl,
6-bromobenzothiophen-3-yl, 6-ethynylbenzothiophen-3-yl,
6-methylbenzothiophen-3-yl, 5-chlorobenzofuran-2-yl,
5-fluorobenzofuran-2-yl, 5-bromobenzofuran-2-yl,
5-ethynylbenzofuran-2-yl, 5-methylbenzofuran-2-yl,
5-chloro-4-fluorobenzofuran-2-yl, 6-chlorobenzofuran-2-yl,
6-fluorobenzofuran-2-yl, 6-bromobenzofuran-2-yl,
6-ethynylbenzofuran-2-yl, 6-methylbenzofuran-2-yl,
5-chlorobenzofuran-3-yl, 5-fluorobenzofuran-3-yl,
5-bromobenzofuran-3-yl, 5-ethynylbenzofuran-3-yl,
5-methylbenzofuran-3-yl, 5-chloro-4-fluorobenzofuran-3-yl,
6-chlorobenzofuran-3-yl, 6-fluorobenzofuran-3-yl,
6-bromobenzofuran-3-yl, 6-ethynylbenzofuran-3-yl and
6-methylbenzofuran-3-yl groups, with 5-chloroindol-2-yl,
5-fluoroindol-2-yl, 5-bromoindol-2-yl, 5-ethynylindol-2-yl,
5-methyindol-2-yl, 5-chloro-4-fluoroindol-2-yl, 6-chloroindol-2-yl,
6-fluoroindol-2-yl, 6-bromoindol-2-yl, 6-ethynylindol-2-yl,
6-methyindol-2-yl, 5-chloro-3-fluoroindol-2-yl,
3-bromo-5-chloroindol-2-yl, 3-chloro-5-fluoroindol-2-yl,
3-bromo-5-fluoroindol-2-yl, 5-bromo-3-chloroindol-2-yl,
5-bromo-3-fluoroindol-2-yl, 5-chloro-3-formylindol-2-yl,
5-fluoro-3-formylindol-2-yl, 5-bromo-3-formylindol-2-yl,
5-ethynyl-3-formylindol-2-yl,
5-chloro-3-(N,N-dimethylcarbamoyl)indol-2-yl,
5-fluoro-3-(N,N-dimethylcarbamoyl)indol-2-yl,
5-bromo-3-(N,N-dimethylcarbamoyl)indol-2-yl,
5-ethynyl-3-(N,N-dimethylcarbamoyl)indol-2-yl,
5-chlorobenzothiophen-2-yl, 5-fluorobenzothiophen-2-yl,
5-bromobenzothiophen-2-yl, 5-ethynylbenzothiophen-2-yl,
5-methylbenzothiophen-2-yl, 5-chloro-4-fluorobenzothiophen-2-yl,
6-chlorobenzothiophen-2-yl, 6-fluorobenzothiophen-2-yl,
6-bromobenzothiophen-2-yl, 6-ethynylbenzothiophen-2-yl,
6-methylbenzothiophen-2-yl, 5-chlorobenzofuran-2-yl,
5-fluorobenzofuran-2-yl, 5-bromobenzofuran-2-yl,
5-ethynylbenzofuran-2-yl, 5-methylbenzofuran-2-yl,
5-chloro-4-fluorobenzofuran-2-yl, 6-chlorobenzofuran-2-yl,
6-fluorobenzofuran-2-yl, 6-bromobenzofuran-2-yl,
6-ethynylbenzofuran-2-yl and 6-methylbenzofuran-2-yl groups being
particularly preferred.
[0042] In the following group:
##STR00019##
wherein X.sup.2, X.sup.3, X.sup.4, R.sup.17 and R.sup.18 have the
same meanings as defined above, and numerals 4 to 7 indicate
positions, X.sup.2 is preferably NH, O or S, any one of X.sup.3 and
X.sup.4 is preferably CH or C, particularly preferably C. R.sup.17
and R.sup.18 are each independently preferably a hydrogen atom,
cyano group, halogen atom, alkyl group, alkenyl group, alkynyl
group or halogenoalkyl group. It is preferable that one of R.sup.17
and R.sup.18 is a hydrogen atom, and the other is a hydrogen atom,
cyano group, halogen atom, alkyl group, alkenyl group, alkynyl
group or halogenoalkyl group. Among others, it is particularly
preferred that the other group be a hydrogen atom, halogen atom,
alkyl group or alkynyl group. In this case, the halogen atom is
preferably a fluorine, chlorine or bromine atom. As the alkyl
group, is preferred a methyl group. As the alkynyl group, is
preferred an ethynyl group. The position substituted by the halogen
atom, alkyl group or alkynyl group is preferably a 5- or 6-position
in the above formula though it should not be particularly limited.
As specific preferable examples of the group represented by the
above formula, may be mentioned 5-chloroindazolyl,
5-fluoroindazolyl, 5-bromoindazolyl, 5-ethynylindazolyl,
6-chloroindazolyl, 6-fluoroindazolyl, 6-bromoindazolyl,
6-ethynylindazolyl, 5-chlorobenzimidazolyl, 5-fluorobenzimidazolyl,
5-bromobenzimidazolyl, 5-ethynylbenzimidazolyl,
6-chlorobenzimidazolyl, 6-fluorobenzimidazolyl,
6-bromobenzimidazolyl, 6-ethynylbenzimidazolyl,
5-chlorobenzothiazolyl, 5-fluorobenzothiazolyl,
5-bromobenzothiazolyl, 5-ethynylbenzothiazolyl,
6-chlorobenzothiazolyl, 6-fluorobenzothiazolyl,
6-bromobenzothiazolyl, 6-ethynylbenzothiazolyl,
5-chlorobenzoxazolyl, 5-fluorobenzoxazolyl, 5-bromobenzoxazolyl,
5-ethynylbenzoxazolyl, 6-chlorobenzoxazolyl, 6-fluorobenzoxazolyl,
6-bromobenzoxazolyl, 6-ethynylbenzoxazolyl,
5-chlorobenzoisothiazolyl, 5-fluorobenzoisothiazolyl,
5-bromobenzoisothiazolyl, 5-ethynylbenzoisothiazolyl,
6-chlorobenzoisothiazolyl, 6-fluorobenzoisothiazolyl,
6-bromobenzoisothiazolyl, 6-ethynylbenzoisothiazolyl,
5-chlorobenzoisoxazolyl, 5-fluorobenzoisoxazolyl,
5-bromobenzoisoxazolyl, 5-ethynylbenzoisoxazolyl,
6-chlorobenzoisoxazolyl, 6-fluorobenzoisoxazolyl,
6-bromobenzoisoxazolyl and 6-ethynylbenzoisoxazolyl groups. The
position of the above-described substituent group bonded to T.sup.1
is not particularly limited. More preferred are
5-chloroindazol-3-yl, 5-fluoroindazol-3-yl, 5-bromoindazol-3-yl,
5-ethynylindazol-3-yl, 6-chloroindazol-3-yl, 6-fluoroindazol-3-yl,
6-bromoindazol-3-yl, 6-ethynylindazol-3-yl,
5-chlorobenzimidazol-2-yl, 5-fluorobenzimidazol-2-yl,
5-bromobenzimidazol-2-yl, 5-ethynylbenzimidazol-2-yl,
6-chlorobenzimidazol-2-yl, 6-fluorobenzimidazol-2-yl,
6-bromobenzimidazol-2-yl, 6-ethynylbenzimidazol-2-yl,
5-chlorobenzothiazol-2-yl, 5-fluorobenzothiazol-2-yl,
5-bromobenzothiazol-2-yl, 5-ethynylbenzothiazol-2-yl,
6-chlorobenzothiazol-2-yl, 6-fluorobenzothiazol-2-yl,
6-bromobenzothiazol-2-yl, 6-ethynylbenzothiazol-2-yl,
5-chlorobenzoxazol-2-yl, 5-fluorobenzoxazol-2-yl,
5-bromobenzoxazol-2-yl, 5-ethynylbenzoxazol-2-yl,
6-chlorobenzoxazol-2-yl, 6-fluorobenzoxazol-2-yl,
6-bromobenzoxazol-2-yl, 6-ethynylbenzoxazol-2-yl,
5-chlorobenzoisothiazol-3-yl, 5-fluorobenzoisothiazol-3-yl,
5-bromobenzoisothiazol-3-yl, 5-ethynylbenzoisothiazol-3-yl,
6-chlorobenzoisothiazol-3-yl, 6-fluorobenzoisothiazol-3-yl,
6-bromobenzoisothiazol-3-yl, 6-ethynylbenzoisothiazol-3-yl,
5-chlorobenzoisoxazol-3-yl, 5-fluorobenzoisoxazol-3-yl,
5-bromobenzoisoxazol-3-yl, 5-ethynylbenzoisoxazol-3-yl,
6-chlorobenzoisoxazol-3-yl, 6-fluorobenzoisoxazol-3-yl,
6-bromobenzoisoxazol-3-yl and 6-ethynylbenzoisoxazol-3-yl groups,
with 5-chlorobenzimidazol-2-yl, 5-fluorobenzimidazol-2-yl,
5-bromobenzimidazol-2-yl, 5-ethynylbenzimidazol-2-yl,
6-chlorobenzimidazol-2-yl, 6-fluorobenzimidazol-2-yl,
6-bromobenzimidazol-2-yl, 6-ethynylbenzimidazol-2-yl,
5-chlorobenzothiazol-2-yl, 5-fluorobenzothiazol-2-yl,
5-bromobenzothiazol-2-yl, 5-ethynylbenzothiazol-2-yl,
6-chlorobenzothiazol-2-yl, 6-fluorobenzothiazol-2-yl,
6-bromobenzothiazol-2-yl, 6-ethynylbenzothiazol-2-yl,
5-chlorobenzoxazol-2-yl, 5-fluorobenzoxazol-2-yl,
5-bromobenzoxazol-2-yl, 5-ethynylbenzoxazol-2-yl,
6-chlorobenzoxazol-2-yl, 6-fluorobenzoxazol-2-yl,
6-bromobenzoxazol-2-yl and 6-ethynylbenzoxazol-2-yl groups being
particularly preferred. Among these, 5-chlorobenzimidazol-2-yl,
5-fluorobenzimidazol-2-yl, 5-bromobenzimidazol-2-yl and
5-ethynylbenzimidazol-2-yl groups are further preferred.
[0043] In the following group:
##STR00020##
wherein N indicates that 1 or 2 carbon atoms of the ring
substituted by R.sup.19 have been substituted by a nitrogen atom,
R.sup.19, R.sup.20 and R.sup.21 have the same meanings as defined
above, and numerals 5 to 8 indicate positions, R.sup.19, R.sup.20
and R.sup.21 are each independently preferably a hydrogen atom,
cyano group, halogen atom, alkyl group, alkenyl group, alkynyl
group or halogenoalkyl group. R.sup.19 is particularly preferably a
hydrogen atom. It is preferable that one of R.sup.20 and R.sup.21
is a hydrogen atom, and the other is a hydrogen atom, cyano group,
halogen atom, alkyl group, alkenyl group, alkynyl group or
halogenoalkyl group. Among others, it is particularly preferred
that the other group be a hydrogen atom, halogen atom, alkyl group
or alkynyl group. In this case, the halogen atom is preferably a
fluorine, chlorine or bromine atom. As the alkyl group, is
preferred a methyl group. As the alkynyl group, is preferred an
ethynyl group. The position substituted by the halogen atom, alkyl
group or alkynyl group is preferably a 6- or 7-position in the
above formula though it should not be particularly limited. As
specific preferable examples thereof, may be mentioned quinolinyl,
isoquinolinyl and cinnolinyl groups. More preferred are
6-chloroquinolinyl, 6-fluoroquinolinyl, 6-bromoquinolinyl,
6-ethynylquinolinyl, 6-chloroisoquinolinyl, 6-fluoroisoquinolinyl,
6-bromoisoquinolinyl, 6-ethynylisoquinolinyl, 7-chlorocinnolinyl,
7-fluorocinnolinyl, 7-bromocinnolinyl and 7-ethynylcinnolinyl
groups, with 6-chloroquinolin-2-yl, 6-fluoroquinolin-2-yl,
6-bromoquinolin-2-yl, 6-ethynylquinolin-2-yl,
6-chloroquinolin-3-yl, 6-fluoroquinolin-3-yl, 6-bromoquinolin-3-yl,
6-ethynylquinolin-3-yl, 7-chloroquinolin-2-yl,
7-fluoroquinolin-2-yl, 7-bromoquinolin-2-yl,
7-ethynylquinolin-2-yl, 7-chloroquinolin-3-yl,
7-fluoroquinolin-3-yl, 7-bromoquinolin-3-yl,
7-ethynylquinolin-3-yl, 6-chloroisoquinolin-3-yl,
6-fluoroisoquinolin-3-yl, 6-bromoisoquinolin-3-yl,
6-ethynylisoquinolin-3-yl, 7-chloroisoquinolin-3-yl,
7-fluoroisoquinolin-3-yl, 7-bromoisoquinolin-3-yl,
7-ethynylisoquinolin-3-yl, 7-chlorocinnolin-3-yl,
7-fluorocinnolin-3-yl, 7-bromocinnolin-3-yl and
7-ethynylcinnolin-3-yl groups being particularly preferred. Among
these, 6-chloroquinolin-2-yl, 6-fluoroquinolin-2-yl,
6-bromoquinolin-2-yl, 6-ethynylquinolin-2-yl,
7-chloroquinolin-3-yl, 7-fluoroquinolin-3-yl, 7-bromoquinolin-3-yl,
7-ethynylquinolin-3-yl, 7-chloroisoquinolin-3-yl,
7-fluoroisoquinolin-3-yl, 7-bromoisoquinolin-3-yl,
7-ethynylisoquinolin-3-yl, 7-chlorocinnolin-3-yl,
7-fluorocinnolin-3-yl, 7-bromocinnolin-3-yl and
7-ethynylcinnolin-3-yl groups are further preferred.
[0044] In the following group:
##STR00021##
wherein numerals 5 to 8 indicate positions, X.sup.5 represents
CH.sub.2, CH, N or NH, Z.sup.1 represents N, NH or O, Z.sup.2
represents CH.sub.2, CH, C or N, Z.sup.3 represents CH.sub.2, CH,
S, SO.sub.2 or C.dbd.O, X.sup.5--Z.sup.2 indicates that X.sup.5 and
Z.sup.2 are bonded to each other by a single bond or double bond,
and R.sup.22, R.sup.23 and R.sup.24 have the same meanings as
defined above, R.sup.22 and R.sup.23 are each independently
preferably a hydrogen atom, cyano group, halogen atom, alkyl group,
alkenyl group, alkynyl group or halogenoalkyl group. It is
preferable that one of R.sup.22 and R.sup.23 is a hydrogen atom,
and the other is a hydrogen atom, cyano group, halogen atom, alkyl
group, alkenyl group, alkynyl group or halogenoalkyl group. Among
others, it is particularly preferred that the other group be a
hydrogen atom, halogen atom, alkyl group or alkynyl group. In this
case, the halogen atom is preferably a fluorine, chlorine or
bromine atom. As the alkyl group, is preferred a methyl group. As
the alkynyl group, is preferred an ethynyl group. The position
substituted by the halogen atom, alkyl group or alkynyl group is
preferably a 6- or 7-position in the above formula though it should
be not particularly limited. R.sup.24 is preferably a hydrogen atom
or alkyl group, and a methyl group is preferred as the alkyl group.
As R.sup.24, is particularly preferred a hydrogen atom. As specific
preferable examples of the group represented by the above formula,
may be mentioned 4-oxodihydroquinolinyl, tetrahydroquinolinyl,
4-oxodihydroquinazolin-2-yl, 4-oxotetrahydrocinnolinyl,
4-oxobenzopyranyl, 4-oxobenzothiadiazinyl,
1,1-dioxy-4-oxobenzothiadiazinyl and benzoxadiazinyl groups. As
specific preferable examples thereof, may be mentioned
6-chloro-4-oxodihydroquinolinyl, 6-fluoro-4-oxodihydroquinolinyl,
6-bromo-4-oxodihydroquinolinyl, 6-ethynyl-4-oxodihydroquinolinyl,
7-chloro-4-oxodihydroquinolinyl, 7-fluoro-4-oxodihydroquinolinyl,
7-bromo-4-oxodihydroquinolinyl, 7-ethynyl-4-oxodihydroquinolinyl,
6-chloro-4-oxo-1,4-dihydroquinazolinyl,
6-fluoro-4-oxo-1,4-dihydroquinazolinyl,
6-bromo-4-oxo-1,4-dihydroquinazolinyl,
6-ethynyl-4-oxo-1,4-dihydroquinazolinyl,
7-chloro-4-oxo-1,4-dihydroquinazolinyl,
7-fluoro-4-oxo-1,4-dihydroquinazolinyl,
7-bromo-4-oxo-1,4-dihydroquinazolinyl,
7-ethynyl-4-oxo-1,4-dihydroquinazolinyl,
6-chloro-1,2,3,4-tetrahydroquinolinyl,
6-fluoro-1,2,3,4-tetrahydroquinolinyl,
6-bromo-1,2,3,4-tetrahydroquinolinyl,
6-ethynyl-1,2,3,4-tetrahydroquinolinyl,
7-chloro-1,2,3,4-tetrahydroquinolinyl,
7-fluoro-1,2,3,4-tetrahydroquinolinyl,
7-bromo-1,2,3,4-tetrahydroquinolinyl,
7-ethynyl-1,2,3,4-tetrahydroquinolinyl,
6-chloro-1,2,3,4-tetrahydro-4-oxocinnolinyl,
6-fluoro-1,2,3,4-tetrahydro-4-oxocinnolinyl,
6-bromo-1,2,3,4-tetrahydro-4-oxocinnolinyl,
6-ethynyl-1,2,3,4-tetrahydro-4-oxocinnolinyl,
7-chloro-1,2,3,4-tetrahydro-4-oxocinnolinyl,
7-fluoro-1,2,3,4-tetrahydro-4-oxocinnolinyl,
7-bromo-1,2,3,4-tetrahydro-4-oxocinnolinyl,
7-ethynyl-1,2,3,4-tetrahydro-4-oxocinnolinyl,
6-chloro-4H-4-oxobenzopyranyl, 6-fluoro-4H-4-oxobenzopyranyl,
6-bromo-4H-4-oxobenzopyranyl, 6-ethynyl-4H-4-oxobenzopyranyl,
7-chloro-4H-4-oxobenzopyranyl, 7-fluoro-4H-4-oxobenzopyranyl,
7-bromo-4H-4-oxobenzopyranyl, 7-ethynyl-4H-4-oxobenzopyranyl,
6-chloro-1,1-dioxy-2H-1,2,4-benzothiadiazinyl,
6-fluoro-1,1-dioxy-2H-1,2,4-benzothiadiazinyl,
6-bromo-1,1-dioxy-2H-1,2,4-benzothiadiazinyl,
6-ethynyl-1,1-dioxy-2H-1,2,4-benzothiadiazinyl,
7-chloro-1,1-dioxy-2H-1,2,4-benzothiadiazinyl,
7-fluoro-1,1-dioxy-2H-1,2,4-benzothiadiazinyl,
7-bromo-1,1-dioxy-2H-1,2,4-benzothiadiazinyl,
7-ethynyl-1,1-dioxy-2H-1,2,4-benzothiadiazinyl,
6-chloro-2H-1,2,4-benzoxadiazinyl,
6-fluoro-2H-1,2,4-benzoxadiazinyl,
6-bromo-2H-1,2,4-benzoxadiazinyl,
6-ethynyl-2H-1,2,4-benzoxadiazinyl,
7-chloro-2H-1,2,4-benzoxadiazinyl,
7-fluoro-2H-1,2,4-benzoxadiazinyl, 7-bromo-2H-1,2,4-benzoxadiazinyl
and 7-ethynyl-2H-1,2,4-benzoxadiazinyl groups; with
6-chloro-4-oxo-1,4-dihydroquinolin-2-yl,
6-fluoro-4-oxo-1,4-dihydroquinolin-2-yl,
6-bromo-4-oxo-1,4-dihydroquinolin-2-yl,
6-ethynyl-4-oxo-1,4-dihydroquinolin-2-yl,
7-chloro-4-oxo-1,4-dihydroquinolin-2-yl,
7-fluoro-4-oxo-1,4-dihydroquinolin-2-yl,
7-bromo-4-oxo-1,4-dihydroquinolin-2-yl,
7-ethynyl-4-oxo-1,4-dihydroquinolin-2-yl,
6-chloro-4-oxo-1,4-dihydroquinazolin-2-yl,
6-fluoro-4-oxo-1,4-dihydroquinazolin-2-yl,
6-bromo-4-oxo-1,4-dihydroquinazolin-2-yl,
6-ethynyl-4-oxo-1,4-dihydroquinazolin-2-yl,
7-chloro-4-oxo-1,4-dihydroquinazolin-2-yl,
7-fluoro-4-oxo-1,4-dihydroquinazolin-2-yl,
7-bromo-4-oxo-1,4-dihydroquinazolin-2-yl,
7-ethynyl-4-oxo-1,4-dihydroquinazolin-2-yl,
6-chloro-1,2,3,4-tetrahydroquinolin-2-yl,
6-fluoro-1,2,3,4-tetrahydroquinolin-2-yl,
6-bromo-1,2,3,4-tetrahydroquinolin-2-yl,
6-ethynyl-1,2,3,4-tetrahydroquinolin-2-yl,
6-chloro-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl,
6-fluoro-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl,
6-bromo-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl,
6-ethynyl-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl,
7-chloro-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl,
7-fluoro-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl,
7-bromo-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl,
7-ethynyl-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl,
6-chloro-4H-4-oxobenzopyran-2-yl, 6-fluoro-4H-4-oxobenzopyran-2-yl,
6-bromo-4H-4-oxobenzopyran-2-yl, 6-ethynyl-4H-4-oxobenzopyran-2-yl,
7-chloro-4H-4-oxobenzopyran-2-yl, 7-fluoro-4H-4-oxobenzopyran-2-yl,
7-bromo-4H-4-oxobenzopyran-2-yl, 7-ethynyl-4H-4-oxobenzopyran-2-yl,
6-chloro-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl,
6-fluoro-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl,
6-bromo-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl,
6-ethynyl-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl,
7-chloro-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl,
7-fluoro-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl,
7-bromo-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl,
7-ethynyl-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl,
6-chloro-2H-1,2,4-benzoxadiazin-3-yl,
6-fluoro-2H-1,2,4-benzoxadiazin-3-yl,
6-bromo-2H-1,2,4-benzoxadiazin-3-yl,
6-ethynyl-2H-1,2,4-benzoxadiazin-3-yl,
7-chloro-2H-1,2,4-benzoxadiazin-3-yl,
7-fluoro-2H-1,2,4-benzoxadiazin-3-yl,
7-bromo-2H-1,2,4-benzoxadiazin-3-yl and
7-ethynyl-2H-1,2,4-benzoxadiazin-3-yl groups being preferred. Among
these, 6-chloro-4-oxo-1,4-dihydroquinolin-2-yl,
6-fluoro-4-oxo-1,4-dihydroquinolin-2-yl,
6-bromo-4-oxo-1,4-dihydroquinolin-2-yl,
6-ethynyl-4-oxo-1,4-dihydroquinolin-2-yl,
6-chloro-4-oxo-1,4-dihydroquinazolin-2-yl,
6-fluoro-4-oxo-1,4-dihydroquinazolin-2-yl,
6-bromo-4-oxo-1,4-dihydro-quinazolin-2-yl and
6-ethynyl-4-oxo-1,4-dihydroquinazolin-2-yl are particularly
preferred.
[0045] In the following group:
##STR00022##
wherein X.sup.6 represents O or S, R.sup.25 and R.sup.26 have the
same meanings as defined above, and numerals 5 to 8 indicate
positions, X.sup.6 is preferably O, and R.sup.25 and R.sup.26 are
each independently preferably a hydrogen atom, cyano group, halogen
atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl
group. It is preferable that one of R.sup.25 and R.sup.26 is a
hydrogen atom, and the other is a hydrogen atom, cyano group,
halogen atom, alkyl group, alkenyl group, alkynyl group or
halogenoalkyl group. Among others, it is particularly preferred
that the other group be a hydrogen atom, halogen atom, alkyl group
or alkynyl group. In this case, the halogen atom is preferably a
fluorine, chlorine or bromine atom. As the alkyl group, is
preferred a methyl group. As the alkynyl group, is preferred an
ethynyl group. The position substituted by the halogen atom, alkyl
group or alkynyl group is preferably a 6- or 7-position in the
above formula though it should be not particularly limited. As
specific preferable examples thereof, may be mentioned
6-chloro-2H-chromen-3-yl, 6-fluoro-2H-chromen-3-yl,
6-bromo-2H-chromen-3-yl, 6-ethynyl-2H-chromen-3-yl,
7-chloro-2H-chromen-3-yl, 7-fluoro-2H-chromen-3-yl,
7-bromo-2H-chromen-3-yl and 7-ethynyl-2H-chromen-3-yl groups, with
7-chloro-2H-chromen-3-yl, 7-fluoro-2H-chromen-3-yl,
7-bromo-2H-chromen-3-yl and 7-ethynyl-2H-chromen-3-yl groups being
particularly preferred.
[0046] In the following group:
##STR00023##
wherein R.sup.27 and R.sup.28 have the same meanings as defined
above, and numerals 1 to 6 indicate positions, it is preferable
that one of R.sup.27 and R.sup.28 is a hydrogen atom or halogen
atom, and the other is a hydrogen atom, cyano group, nitro group,
amino group, halogen atom, alkyl group, alkenyl group, alkynyl
group, halogenoalkyl group or N,N-dialkylcarbamoyl group. Among
others, it is particularly preferred that the other group be a
hydrogen atom, halogen atom, alkyl group or alkynyl group. In this
case, the halogen atom is preferably a fluorine, chlorine or
bromine atom. As the alkyl group, is preferred a methyl group. As
the alkynyl group, is particularly preferred an ethynyl group. As
specific preferable examples of the group represented by the above
formula, may be mentioned phenyl, chlorophenyl, fluorophenyl,
bromophenyl, ethynylphenyl and chlorofluorophenyl groups. The
position substituted by the halogen atom, alkyl group or alkynyl
group in these groups is particularly preferably a 3- or 4-position
in the above formula in the case of one substituent or a
combination of a 4-position and a 2- or 3-position in the above
formula in the case of two substituents though it should be not
particularly limited. As specific preferable examples thereof, may
be mentioned phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl,
4-ethynylphenyl, 3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl,
3-ethynylphenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl,
4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl,
4-bromo-2-fluorophenyl, 2-bromo-4-fluorophenyl, 2,4-dichlorophenyl,
2,4-difluorophenyl, 2,4-dibromophenyl, 4-chloro-3-methylphenyl,
4-fluoro-3-methylphenyl, 4-bromo-3-methylphenyl,
4-chloro-2-methylphenyl, 4-fluoro-2-methylphenyl,
4-bromo-2-methylphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl and
3,4-dibromophenyl groups.
[0047] In the following group:
##STR00024##
wherein E.sup.1, E.sup.2, R.sup.29 and R.sup.30 have the same
meanings as defined above, and numerals 1 to 6 indicate positions,
it is preferable that one of R.sup.29 and R.sup.30 is a hydrogen
atom or halogen atom, and the other is a hydrogen atom, cyano
group, halogen atom, alkyl group, alkenyl group, alkynyl group or
halogenoalkyl group. Among others, it is particularly preferred
that the other group be a hydrogen atom, halogen atom, alkyl group
or alkynyl group. In this case, the halogen atom is preferably a
fluorine, chlorine or bromine atom. As the alkyl group, is
preferred a methyl group. As the alkynyl group, is particularly
preferred an ethynyl group. As specific examples of the group
represented by the above formula, may be mentioned pyridyl,
pyrimidyl and pyridazinyl groups. The position substituted by the
halogen atom, alkyl group or alkynyl group in these groups is
particularly preferably a 4- or 5-position in the above formula in
the case where its bonding to the group T.sup.1 is at a 2-position
in the above formula though it should be not particularly limited.
As specific preferable examples thereof, may be mentioned
2-pyridyl, 3-pyridyl, 4-pyridyl, 4-chloro-2-pyridyl,
4-fluoro-2-pyridyl, 4-bromo-2-pyridyl, 4-ethynyl-2-pyridyl,
4-chloro-3-pyridyl, 4-fluoro-3-pyridyl, 4-bromo-3-pyridyl,
4-ethynyl-3-pyridyl, 5-chloro-2-pyridyl, 5-fluoro-2-pyridyl,
5-bromo-2-pyridyl, 5-ethynyl-2-pyridyl,
4-chloro-5-fluoro-2-pyridyl, 5-chloro-4-fluoro-2-pyridyl,
5-chloro-3-pyridyl, 5-fluoro-3-pyridyl, 5-bromo-3-pyridyl,
5-ethynyl-3-pyridyl, 5-chloro-2-pyrimidyl, 5-fluoro-2-pyrimidyl,
5-bromo-2-pyrimidyl, 5-ethynyl-2-pyrimidyl, 4-chloro-3-pyridazinyl,
4-fluoro-3-pyridazinyl, 4-bromo-3-pyridazinyl,
4-ethynyl-3-pyridazinyl, 6-chloro-3-pyridazinyl,
6-fluoro-3-pyridazinyl, 6-bromo-3-pyridazinyl and
6-ethynyl-3-pyridazinyl groups. Particularly preferred are
2-pyridyl, 3-pyridyl, 4-pyridyl, 4-chloro-2-pyridyl,
4-fluoro-2-pyridyl, 4-bromo-2-pyridyl, 4-ethynyl-2-pyridyl,
4-chloro-3-pyridyl, 4-fluoro-3-pyridyl, 4-bromo-3-pyridyl,
4-ethynyl-3-pyridyl, 5-chloro-2-pyridyl, 5-fluoro-2-pyridyl,
5-bromo-2-pyridyl, 5-ethynyl-2-pyridyl,
4-chloro-5-fluoro-2-pyridyl, 5-chloro-4-fluoro-2-pyridyl,
5-chloro-3-pyridyl, 5-fluoro-3-pyridyl, 5-bromo-3-pyridyl,
5-ethynyl-3-pyridyl, 6-chloro-3-pyridazinyl,
6-fluoro-3-pyridazinyl, 6-bromo-3-pyridazinyl,
6-ethynyl-3-pyridazinyl, 4-chloro-3-pyridazinyl,
4-fluoro-3-pyridazinyl, 4-bromo-3-pyridazinyl and
4-ethynyl-3-pyridazinyl groups. Among these, 2-pyridyl, 3-pyridyl,
4-pyridyl, 5-chloro-2-pyridyl, 5-fluoro-2-pyridyl,
5-bromo-2-pyridyl, 5-ethynyl-2-pyridyl,
5-chloro-4-fluoro-2-pyridyl, 4-chloro-5-fluoro-2-pyridyl,
4-chloro-3-pyridazinyl, 4-fluoro-3-pyridazinyl,
4-bromo-3-pyridazinyl and 4-ethynyl-3-pyridazinyl groups are
further preferred.
[0048] In the following group:
##STR00025##
wherein Y.sup.1, Y.sup.2, R.sup.31 and R.sup.32 have the same
meanings as defined above, and numerals 1 to 5 indicate positions,
it is preferable that one of R.sup.31 and R.sup.32 is a hydrogen
atom or halogen atom, and the other is a hydrogen atom, cyano
group, halogen atom, alkyl group, alkenyl group, alkynyl group or
halogenoalkyl group. Among others, it is particularly preferred
that the other group be a hydrogen atom, halogen atom, alkyl group
or alkynyl group. In this case, the halogen atom is preferably a
fluorine, chlorine or bromine atom. As the alkyl group, is
preferred a methyl group. As the alkynyl group, is particularly
preferred an ethynyl group. As specific examples of the group
represented by the above formula, may be mentioned thienyl,
pyrrolyl, furyl, oxazolyl and thiazolyl groups. The position
substituted by the halogen atom, alkyl group or alkynyl group in
these groups is particularly preferably a 4- or 5-position in the
above formula though it should be not particularly limited. As
specific preferable examples thereof, may be mentioned
4-chloro-2-thienyl, 4-fluoro-2-thienyl, 4-bromo-2-thienyl,
4-ethynyl-2-thienyl, 4-chloro-2-pyrrolyl, 4-fluoro-2-pyrrolyl,
4-bromo-2-pyrrolyl, 4-ethynyl-2-pyrrolyl, 4-chloro-2-furyl,
4-fluoro-2-furyl, 4-bromo-2-furyl, 4-ethynyl-2-furyl,
5-chloro-2-thienyl, 5-fluoro-2-thienyl, 5-bromo-2-thienyl,
5-ethynyl-2-thienyl, 5-chloro-2-thiazolyl, 5-fluoro-2-thiazolyl,
5-bromo-2-thiazolyl, 5-ethynyl-2-thiazolyl, 5-chloro-2-oxazolyl,
5-fluoro-2-oxazolyl, 5-bromo-2-oxazolyl and 5-ethynyl-2-oxazolyl
groups. Particularly preferred are 5-chloro-2-thiazolyl,
5-fluoro-2-thiazolyl, 5-bromo-2-thiazolyl and 5-ethynyl-2-thiazolyl
groups.
[0049] In the following group:
##STR00026##
wherein numerals 1 to 8 indicate positions, each N indicates that
any one of 4 carbon atoms at positions 1 to 4 and any one of 4
carbon atoms at positions 5 to 8 have been substituted by a
nitrogen atom, and R.sup.34 to R.sup.36 have the same meanings as
defined above, the position of each nitrogen atom may be in any
positional relation, and R.sup.34 is preferably a hydrogen atom or
halogen atom. It is preferable that one of R.sup.35 and R.sup.36 is
a hydrogen atom or halogen atom, and the other is a hydrogen atom,
cyano group, halogen atom, alkyl group, alkenyl group, alkynyl
group or halogenoalkyl group. Among others, it is particularly
preferred that the other group be a hydrogen atom, halogen atom,
alkyl group or alkynyl group. In this case, the halogen atom is
preferably a fluorine, chlorine or bromine atom. As the alkyl
group, is preferred a methyl group. As the alkynyl group, is
particularly preferred an ethynyl group. The position substituted
by the halogen atom, alkyl group or alkynyl group should not be
particularly limited. As preferable examples of specific groups
represented by the above formula, may be mentioned
6-chloro-1,5-naphthyridin-2-yl, 6-fluoro-1,5-naphthyridin-2-yl,
6-bromo-1,5-naphthyridin-2-yl, 6-ethynyl-1,5-naphthyridin-2-yl,
7-chloro-1,5-naphthyridin-2-yl, 7-fluoro-1,5-naphthyridin-2-yl,
7-bromo-1,5-naphthyridin-2-yl, 7-ethynyl-1,5-naphthyridin-2-yl,
6-chloro-1,5-naphthyridin-3-yl, 6-fluoro-1,5-naphthyridin-3-yl,
6-bromo-1,5-naphthyridin-3-yl, 6-ethynyl-1,5-naphthyridin-3-yl,
7-chloro-1,5-naphthyridin-3-yl, 7-fluoro-1,5-naphthyridin-3-yl,
7-bromo-1,5-naphthyridin-3-yl, 7-ethynyl-1,5-naphthyridin-3-yl,
6-chloro-1,7-naphthyridin-2-yl, 6-fluoro-1,7-naphthyridin-2-yl,
6-bromo-1,7-naphthyridin-2-yl, 6-ethynyl-1,7-naphthyridin-2-yl,
6-chloro-1,7-naphthyridin-3-yl, 6-fluoro-1,7-naphthyridin-3-yl,
6-bromo-1,7-naphthyridin-3-yl, 6-ethynyl-1,7-naphthyridin-3-yl,
6-chloro-1,8-naphthyridin-2-yl, 6-fluoro-1,8-naphthyridin-2-yl,
6-bromo-1,8-naphthyridin-2-yl, 6-ethynyl-1,8-naphthyridin-2-yl,
7-chloro-1,8-naphthyridin-2-yl, 7-fluoro-1,8-naphthyridin-2-yl,
7-bromo-1,8-naphthyridin-2-yl, 7-ethynyl-1,8-naphthyridin-2-yl,
6-chloro-1,8-naphthyridin-3-yl, 6-fluoro-1,8-naphthyridin-3-yl,
6-bromo-1,8-naphthyridin-3-yl, 6-ethynyl-1,8-naphthyridin-3-yl,
7-chloro-1,8-naphthyridin-3-yl, 7-fluoro-1,8-naphthyridin-3-yl,
7-bromo-1,8-naphthyridin-3-yl, 7-ethynyl-1,8-naphthyridin-3-yl,
6-chloro-2,5-naphthyridin-3-yl, 6-fluoro-2,5-naphthyridin-3-yl,
6-bromo-2,5-naphthyridin-3-yl, 6-ethynyl-2,5-naphthyridin-3-yl,
7-chloro-2,5-naphthyridin-3-yl, 7-fluoro-2,5-naphthyridin-3-yl,
7-bromo-2,5-naphthyridin-3-yl, 7-ethynyl-2,5-naphthyridin-3-yl,
7-chloro-2,6-naphthyridin-3-yl, 7-fluoro-2,6-naphthyridin-3-yl,
7-bromo-2,6-naphthyridin-3-yl, 7-ethynyl-2,6-naphthyridin-3-yl,
6-chloro-2,8-naphthyridin-3-yl, 6-fluoro-2,8-naphthyridin-3-yl,
6-bromo-2,8-naphthyridin-3-yl, 6-ethynyl-2,8-naphthyridin-3-yl,
7-chloro-2,8-naphthyridin-3-yl, 7-fluoro-2,8-naphthyridin-3-yl,
7-bromo-2,8-naphthyridin-3-yl and 7-ethynyl-2,8-naphthyridin-3-yl
groups. Particularly preferable examples thereof include
7-chloro-2,5-naphthyridin-3-yl, 7-fluoro-2,5-naphthyridin-3-yl,
7-bromo-2,5-naphthyridin-3-yl and 7-ethynyl-2,5-naphthyridin-3-yl
groups.
[0050] In addition to the above-mentioned 12 groups (a) to (1), a
thienopyrrolyl group which may be substituted is preferred. This
group may have 1 to 3 substituents, and examples of the
substituents include a hydroxyl group, a nitro group, an amino
group, a cyano group, halogen atoms, alkyl groups, alkenyl groups,
alkynyl groups, halagenoalkyl groups, hydroxyalkyl groups, alkoxy
groups, alkoxyalkyl groups, a carboxyl group, carboxyalkyl groups,
acyl groups, a carbamoyl group, N-alkylcarbamoyl groups,
N,N-dialkylcarbamoyl groups, alkoxycarbonyl groups, an amidino
group and alkoxycarbonylalkyl groups. Among these, a cyano group,
halogen atoms, alkyl groups, alkenyl groups, alkynyl groups and
halogenoalkyl groups are preferred. As specific preferable examples
thereof, may be mentioned 2-chlorothieno[2,3-b]pyrrol-5-yl,
2-fluorothieno[2,3-b]pyrrol-5-yl, 2-bromothieno[2,3-b]pyrrol-5-yl,
and 2-ethynylthieno[2,3-b]pyrrol-5-yl groups.
<On Group Q.sup.1>
[0051] In the present invention, Q.sup.1 means a saturated or
unsaturated, 5- or 6-membered cyclic hydrocarbon group which may be
substituted, a saturated or unsaturated, 5- to 7-membered
heterocyclic group which may be substituted, a saturated or
unsaturated, bicyclic or tricyclic condensed hydrocarbon group
which may be substituted, or a saturated or unsaturated, bicyclic
or tricyclic condensed heterocyclic group which may be
substituted.
[0052] As examples of the saturated or unsaturated, 5- or
6-membered cyclic hydrocarbon group, may be mentioned cyclopentyl,
cyclopentenyl, cyclohexyl, cyclohexenyl and phenyl groups.
Cyclopentyl, cyclohexyl and phenyl groups are preferred, with a
phenyl group being more preferred.
[0053] The saturated or unsaturated, 5- to 7-membered heterocyclic
group means a monovalent heterocyclic group having at least one
hetero atom selected from among oxygen, sulfur and nitrogen atoms,
and examples thereof may include furyl, pyrrolyl, thienyl,
pyrazolyl, imidazolyl, pyrazolinyl, oxazolyl, oxazolinyl,
thiazolyl, thiazolinyl, thiadiazolyl, furazanyl, pyranyl, pyridyl,
pyrimidyl, pyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl,
oxazinyl, oxadiazinyl, morpholinyl, thiazinyl, thiadiazinyl,
thiomorpholinyl, tetrazolyl, triazolyl, triazinyl, azepinyl,
diazepinyl and triazepinyl groups. Of these, thienyl, pyrazolyl,
imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, furazanyl, pyridyl,
pyrimidyl, pyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl,
morpholinyl, thiadiazinyl and triazolyl groups are preferred, with
thienyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl,
pyridazinyl, pyrrolidinyl, piperazinyl and piperidinyl groups being
more preferred. Of these heterocyclic groups, the
nitrogen-containing heterocyclic groups may be in the form of an
N-oxide.
[0054] The saturated or unsaturated, bicyclic or tricyclic
condensed hydrocarbon group means the same saturated or
unsaturated, bicyclic or tricyclic condensed hydrocarbon group as
described in the description of Q.sup.4 in the general formula (1).
As specific examples thereof, may be mentioned indenyl, indanyl,
naphthyl, tetrahydronaphthyl, anthryl and phenanthryl groups, with
indenyl, indanyl, naphthyl and tetrahydronaphthyl groups being
preferred.
[0055] The saturated or unsaturated, bicyclic or tricyclic
condensed heterocyclic group means the same saturated or
unsaturated, bicyclic or tricyclic condensed heterocyclic group as
described in the description of Q.sup.4 in the general formula (1).
As specific examples thereof, may be mentioned benzofuryl,
isobenzofuryl, benzothienyl, indolyl, indolinyl, isoindolyl,
isoindolinyl, indazolyl, quinolyl, dihydroquinolyl,
4-oxo-dihydroquinolyl(dihydroquinolin-4-one), tetrahydroquinolyl,
isoquinolyl, tetrahydroisoquinolyl, chromenyl, chromanyl,
isochromanyl, 4H-4-oxobenzopyranyl,
3,4-dihydro-4H-4-oxobenzopyranyl, 4H-quinolizinyl, quinazolinyl,
dihydroquinazolinyl, tetrahydroquinazolinyl, quinoxalinyl,
tetrahydroquinoxalinyl, cinnolinyl, tetrahydrocinnolinyl,
indolizinyl, tetrahydroindolizinyl, benzothiazolyl,
tetrahydrobenzothiazolyl, benzoxazolyl, benzoisothiazolyl,
benzoisoxazolyl, benzimidazoyl, naphthyridinyl,
tetrahydronaphthyridinyl, thienopyridyl, tetrahydrothienopyridyl,
thiazolopyridyl, tetrahydrothiazolopyridyl, thiazolopyridazinyl,
tetrahydrothiazolopyridazinyl, pyrrolopyridyl,
dihydropyrrolopyridyl, tetrahydropyrrolopyridyl,
pyrrolopyrimidinyl, dihydropyrrolopyrimidinyl, pyridoquinazolinyl,
dihydropyridoquinazolinyl, pyridopyrimidinyl,
tetrahydropyridopyrimidinyl, pyranothiazolyl,
dihydropyranothiazolyl, furopyridyl, tetrahydrofuropyridyl,
oxazolopyridyl, tetrahydrooxazolopyridyl, oxazolopyridazinyl,
tetrahydrooxazolopyridazinyl, pyrrolothiazolyl,
dihydropyrrolothiazolyl, pyrrolooxazolyl, dihydropyrrolooxazolyl,
thienopyrrolyl, thiazolopyrimidinyl, dihydrothiazolopyrimidinyl,
4-oxo-tetrahydrocinnolinyl, 1,2,4-benzothiadiazinyl,
1,1-dioxy-2H-1,2,4-benzothiadiazinyl, 1,2,4-benzoxadiazinyl,
cyclopentapyranyl, thienofuranyl, furopyranyl, pyridoxazinyl,
pyrazoloxazolyl, imidazothiazolyl, imidazopyridyl,
tetrahydroimidazopyridyl, pyrazinopyridazinyl, benzisoquinolyl,
furocinnolyl, pyrazolothiazolopyridazinyl,
tetrahydropyrazolothiazolopyridazinyl,
hexahydrothiazolopyridazinopyridazinyl, imidazotriazinyl,
oxazolopyridyl, benzoxepinyl, benzoazepinyl,
tetrahydrobenzoazepinyl, benzodiazepinyl, benzotriazepinyl,
thienoazepinyl, tetrahydrothienoazepinyl, thienodiazepinyl,
thienotriazepinyl, thiazoloazepinyl, tetrahydrothiazoloazepinyl,
4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl and
5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl groups.
Preferred are benzothiazolyl, tetrahydrobenzothiazolyl,
thienopyridyl, tetrahydrothienopyridyl, thienopyrrolyl,
thiazolopyridyl, tetrahydrothiazolopyridyl, thiazolopyridazinyl,
tetrahydrothiazolopyridazinyl, pyrrolopyrimidinyl,
dihydropyrrolopyrimidinyl, pyranothiazolyl, dihydropyranothiazolyl,
furopyridyl, tetrahydrofuropyridyl, oxazolopyridyl,
tetrahydrooxazolopyridyl, pyrrolopyridyl, dihydropyrrolopyridyl,
tetrahydropyrrolopyridyl, oxazolopyridazinyl,
tetrahydrooxazolopyridazinyl, pyrrolothiazolyl,
dihydropyrrolothiazolyl, pyrrolooxazolyl, dihydropyrrolooxazolyl,
thiazolopyrimidinyl, dihydrothiazolopyrimidinyl, benzoazepinyl,
tetrahydrobenzoazepinyl, thiazoloazepinyl,
tetrahydrothiazoloazepinyl, thienoazepinyl,
tetrahydrothienoazepinyl,
4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl and
5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl groups, with
tetrahydrobenzothiazolyl, tetrahydrothienopyridyl,
tetrahydrothiazolopyridyl, tetrahydrothiazolopyridazinyl,
dihydropyrrolopyrimidinyl, dihydropyranothiazolyl,
tetrahydrooxazolopyridyl, dihydropyrrolothiazolyl,
4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl and
5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl groups being
particularly preferred.
[0056] No particular limitation is imposed on the condensing form
of the condensed heterocyclic groups. For example, thienopyridine
may be any of thieno[2,3-b]pyridine, thieno[2,3-c]pyridine,
thieno[3,2-b]pyridine, thieno[3,2-c]pyridine, thieno[3,4-b]pyridine
and thieno[3,4-c]pyridine, with thieno[2,3-c]pyridine and
thieno[3,2-c]-pyridine being preferred. Thienopyrrolyl may be any
of thieno[2,3-b]pyrrolyl and thieno[3,2-b]pyrrolyl.
Thiazolopyridine may be any of thiazolo[4,5-b]pyridine,
thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine,
thiazolo[5,4-c]pyridine, thiazolo[3,4-a]pyridine and
thiazolo[3,2-a]pyridine, with thiazolo[4,5-c]pyridine and
thiazolo[5,4-c]pyridine being preferred. Thiazolopyridazine may be
any of thiazolo[4,5-c]pyridazine, thiazolo[4,5-d]pyridazine,
thiazolo[5,4-c]pyridazine and thiazolo[3,2-b]pyridazine, with
thiazolo[4,5-d]pyridazine being preferred. Pyrrolopyridine may be
any of pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine,
pyrrolo[3,2-b]pyridine, pyrrolo[3,2-c]pyridine,
pyrrolo[3,4-b]pyridine and pyrrolo[3,4-c]pyridine, with
pyrrolo[2,3-c]pyridine and pyrrolo[3,2-c]pyridine being preferred.
Pyrrolopyrimidine may be any of pyrrolo[3,4-d]pyrimidine,
pyrrolo[3,2-d]pyrimidine and pyrrolo[2,3-d]pyrimidine, with
pyrrolo[3,4-d]pyrimidine being preferred. Pyridopyrimidine may be
any of pyrido[2,3-d]pyrimidine, pyrido[3,2-d]pyrimidine,
pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine,
pyrido[1,2-c]pyrimidine and pyrido[1,2-a]pyrimidine, with
pyrido[3,4-d]pyrimidine and pyrido[4,3-d]pyrimidine being
preferred. Pyranothiazole may be any of pyrano[2,3-d]thiazole,
pyrano[4,3-d]thiazole, pyrano[3,4-d]thiazole and
pyrano[3,2-d]thiazole, with pyrano[4,3-d]thiazole and
pyrano[3,4-d]thiazole being preferred. Furopyridine may be any of
furo[2,3-b]pyridine, furo[2,3-c]pyridine, furo[3,2-b]pyridine,
furo[3,2-c]pyridine, furo[3,4-b]pyridine and furo[3,4-c]pyridine,
with furo[2,3-c]pyridine and furo[3,2-c]pyridine being preferred.
Oxazolopyridine may be any of oxazolo[4,5-b]pyridine,
oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine,
oxazolo[5,4-c]pyridine, oxazolo[3,4-a]pyridine and
oxazolo[3,2-a]pyridine, with oxazolo[4,5-c]pyridine and
oxazolo[5,4-c]pyridine being preferred. Oxazolopyridazine may be
any of oxazolo[4,5-c]pyridazine, oxazolo[4,5-d]pyridazine,
oxazolo[5,4-c]pyridazine and oxazolo[3,4-b]pyridazine, with
oxazolo[4,5-d]pyridazine being preferred. Pyrrolothiazole may be
any of pyrrolo[2,1-b]thiazole, pyrrolo[1,2-c]thiazole,
pyrrolo[2,3-d]thiazole, pyrrolo[3,2-d]thiazole and
pyrrolo[3,4-d]thiazole, with pyrrolo[3,4-d]thiazole being
preferred. Pyrrolooxazole may be any of pyrrolo[2,1-b]oxazole,
pyrrolo[1,2-c]oxazole, pyrrolo[2,3-d]oxazole, pyrrolo[3,2-d]oxazole
and pyrrolo[3,4-d]oxazole, with pyrrolo[3,4-d]oxazole being
preferred. Benzoazepine may be any of 1H-1-benzoazepine,
1H-2-benzoazepine and 1H-3-benzoazepine, with 1H-3-benzoazepine
being preferred. Thiazolo[4,5-c]azepine may be any of
4H-thiazolo[4,5-c]azepine, 4H-thiazolo[4,5-d]azepine and
4H-thiazolo[5,4-c]azepine, with 4H-thiazolo[4,5-d]azepine being
preferred. Thieno[2,3-c]azepine may be any of
4H-thieno[2,3-d]azepine and 4H-thieno[3,2-c]azepine, with
4H-thieno[2,3-d]azepine being preferred.
[0057] Of these heterocyclic groups, the nitrogen-containing
heterocyclic groups may be in the form of an N-oxide. Incidentally,
the position of the above substituent group bonded to Q.sup.2 is
not particularly limited.
[0058] The above-described saturated or unsaturated, 5- or
6-membered cyclic hydrocarbon groups, saturated or unsaturated, 5-
to 7-membered heterocyclic groups, saturated or unsaturated,
bicyclic or tricyclic condensed hydrocarbon groups and saturated or
unsaturated, bicyclic or tricyclic condensed heterocyclic groups
may each have 1 to 3 substituents. Examples of the substituents may
include a hydroxyl group; halogen atoms such as fluorine atom,
chlorine atom, bromine atom and iodine atom; halogenoalkyl groups
having 1 to 3 halogen atoms; an amino group; a cyano group; an
amidino group; a hydroxyamidino group; linear, branched or cyclic
alkyl groups having 1 to 6 carbon atoms (hereinafter referred to as
C.sub.1-C.sub.6 alkyl groups which mean linear, branched and cyclic
alkyl groups; for example, linear or branched C.sub.1-C.sub.6 alkyl
groups such as methyl group, ethyl group, isopropyl group and
tert-butyl group; C.sub.3-C.sub.6 cycloalkyl groups such as
cyclopropyl group, cyclobutyl group, cyclopentyl group and
1-methylcyclopropyl group; and C.sub.3-C.sub.6
cycloalkyl-C.sub.1-C.sub.6 alkyl groups such as cyclopropylmethyl
group); hydroxy-C.sub.1-C.sub.6 alkyl groups (such as hydroxyethyl
and 1,1-dimethyl-2-hydroxyethyl groups); C.sub.1-C.sub.6 alkoxy
groups (for example, methoxy group, ethoxy group and the like);
C.sub.1-C.sub.6 alkoxy-C.sub.1-C.sub.6 alkyl groups; a carboxyl
group; C.sub.2-C.sub.6 carboxyalkyl groups (for example,
carboxymethyl group and the like); C.sub.2-C.sub.6
alkoxycarbonyl-C.sub.1-C.sub.6 alkyl groups (for example,
methoxycarbonylmethyl group, tert-butoxycarbonylmethyl group and
the like); amidino groups substituted by a C.sub.2-C.sub.6
alkoxycarbonyl group; C.sub.2-C.sub.6 alkenyl groups (for example,
vinyl group, allyl group and the like); C.sub.2-C.sub.6 alkynyl
groups (for example, ethynyl group, propynyl group and the like);
C.sub.2-C.sub.6 alkoxycarbonyl groups (for example, methoxycarbonyl
group, ethoxycarbonyl group, tert-butoxycarbonyl group and the
like); amino C.sub.1-C.sub.6 alkyl groups (for example, aminomethyl
group, aminoethyl group and the like); C.sub.1-C.sub.6
alkylamino-C.sub.1-C.sub.6 alkyl groups (for example,
N-methylaminomethyl group, N-ethylaminomethyl group and the like);
di(C.sub.1-C.sub.6 alkyl)amino-C.sub.1-C.sub.6 alkyl groups (for
example, N,N-dimethylaminomethyl group, N,N-diethylaminomethyl
group, N-ethyl-N-methylaminoethyl group and the like);
C.sub.2-C.sub.6 alkoxycarbonylamino-C.sub.1-C.sub.6 alkyl groups
(for example, methoxycarbonylaminoethyl group,
tert-butoxycarbonylaminoethyl group and the like); C.sub.1-C.sub.6
alkanoyl groups (for example, formyl group, acetyl group,
methylpropionyl group, cyclopentanecarbonyl group and the like);
C.sub.1-C.sub.6 alkanoylamino-C.sub.1-C.sub.6 alkyl groups (for
example, acetylaminomethyl group and the like); C.sub.1-C.sub.6
alkylsulfonyl groups (for example, methanesulfonyl group and the
like); C.sub.1-C.sub.6 alkylsulfonylamino-C.sub.1-C.sub.6 alkyl
groups (for example, methanesulfonylaminomethyl group and the
like); a carbamoyl group; C.sub.1-C.sub.6 alkylcarbamoyl groups
(for example, methylcarbamoyl group, ethylcarbamoyl group,
isopropylcarbamoyl group, tert-butylcarbamoyl group and the like);
N,N-di(C.sub.1-C.sub.6 alkyl)carbamoyl groups (for example,
dimethylcarbamoyl group, diethylcarbamoyl group,
methylethylcarbamoyl group and the like); C.sub.1-C.sub.6
alkylamino groups (for example, N-methylamino group, N-ethylamino
group and the like); di(C.sub.1-C.sub.6 alkyl)amino groups (for
example, N,N-dimethylamino group, N,N-diethylamino group,
N-ethyl-N-methylamino group and the like); an aminosulfonyl group;
arylsulfonyl groups (for example, phenylsulfonyl group and the
like); arylcarbonyl groups which may be substituted by, for
example, a halogen atom (for example, benzoyl group,
4-fluoro-benzoyl group and the like); C.sub.2-C.sub.6
alkoxycarbonyl (C.sub.1-C.sub.6 alkyl)amino C.sub.1-C.sub.6 alkyl
groups (for example, methoxycarbonyl(methyl)aminomethyl group,
tert-butoxycarbonyl(methyl)aminomethyl group and the like);
C.sub.1-C.sub.6 alkylsulfonyl C.sub.1-C.sub.6 alkyl groups (for
example, methylsulfonylmethyl group and the like); 5- or 6-membered
heterocyclic groups containing one of nitrogen, oxygen and sulfur
or the same or different two atoms thereof (for example,
pyrrolidinyl group, piperidinyl group, piperazinyl group,
morpholinyl group, pyridyl group, pyrimidinyl group,
tetrahydropyranyl group and the like); the above 5- or 6-membered
heterocyclic-C.sub.1-C.sub.4 alkyl groups (for example,
morpholinomethyl group and the like); the above 5- or 6-membered
heterocyclic-carbonyl groups (for example, pyrrolidinocarbonyl
group and the like); the above 5- or 6-membered
heterocyclic-amino-C.sub.1-C.sub.4 alkyl groups (for example,
N-(oxazol-2-yl)aminomethyl group and the like); the above 5- or
6-membered heterocyclic-amino groups (for example, pyridylamino
group and the like); the above 5- or 6-membered heterocyclic-oxy
groups (for example, 4-pyridinyloxy group,
(1-methyliminopiperidin-4-yl)oxy group and the like); 3- to
6-membered heterocyclic-carbonyl-C.sub.1-C.sub.4 alkyl groups (for
example, 4,4-dioxothiomorpholin-1-yl)carbonylmethyl group and the
like); and the above 5- or 6-membered heterocyclic (C.sub.1-C.sub.6
alkyl)amino-C.sub.1-C.sub.4 alkyl groups (for example,
N-(4,5-dihydro-1,3-oxazol-2-yl)-N-methylaminomethyl group and the
like).
[0059] As specific examples of Q.sup.1, may be mentioned 5- or
6-membered cyclic hydrocarbon groups such as 2-aminosulfonylphenyl
group; bicyclic heterocyclic groups such as
5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl,
4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl,
5-cyclopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl,
5-carboxymethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl,
5-butyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl,
5-(4-pyridyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl,
5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl,
6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl,
5-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl,
5-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-2-yl,
5,7-dihydro-6-methylpyrrolo[3,4-d]pyrimidin-2-yl,
5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[4, 5-d]pyridazin-2-yl,
5,6-dimethyl-4,5,6,7-tetrahydrooxazolo[4,5-d]pyridazin-2-yl,
5-dimethylamino-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl,
5-(4-pyridyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl and
6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl groups; and 5- or
6-membered heterocyclic groups such as pyridyl groups such as
4-pyridyl and 2-pyridyl; dihydrooxazolyl groups such as
4,5-dihydrooxazol-2-yl;
4-[N-(4,5-dihydrooxazol-2-yl)-N-methylaminomethyl]thiophen-2-yl,
4-[N-(4,5-dihydrooxazol-2-yl)-N-methylaminomethyl]-3-chlorothiophen-2-yl,
5-(N-methylaminomethyl)thiazol-2-yl,
5-(N-methylaminomethyl)thiophen-2-yl,
5-(N,N-dimethylaminomethyl)thiazol-2-yl,
5-(N,N-dimethylaminomethyl)thiophen-2-yl and
5-(N,N-dimethylaminomethyl)pyridin-2-yl groups. Incidentally,
Q.sup.1 is not limited by these examples at all.
<On Group Q.sup.2>
[0060] The group Q.sup.2 represents a single bond, a linear or
branched alkylene group having 1 to 6 carbon atoms, a linear or
branched alkenylene group having 2 to 6 carbon atoms, a linear or
branched alkynylene group having 2 to 6 carbon atoms, a saturated
or unsaturated, 5- or 6-membered divalent cyclic hydrocarbon group
which may be substituted, a saturated or unsaturated, 5- to
7-membered divalent heterocyclic group which may be substituted, a
saturated or unsaturated, divalent bicyclic or tricyclic condensed
hydrocarbon group which may be substituted, or a saturated or
unsaturated, divalent bicyclic or tricyclic condensed heterocyclic
group which may be substituted.
[0061] In the group Q.sup.2, examples of the linear or branched
alkylene group having 1 to 6 carbon atoms include methylene,
ethylene, trimethylene, propylene, tetramethylene, pentamethylene
and hexamethylene groups.
[0062] Examples of the linear or branched alkenylene group having 2
to 6 carbon atoms include vinylene, propenylene, butenylene and
pentenylene groups. No particular limitation is imposed on the
position of a carbon-carbon double bond.
[0063] Examples of the linear or branched alkynylene group having 2
to 6 carbon atoms include ethynylene, propynylene, butynylene,
pentynylene and hexynylene groups. No particular limitation is
imposed on the position of a carbon-carbon triple bond.
[0064] The saturated or unsaturated, 5- or 6-membered divalent
cyclic hydrocarbon group means a divalent group derived from the
saturated or unsaturated, 5- or 6-membered cyclic hydrocarbon
described in the description of Q.sup.4 in the general formula (1).
As specific examples thereof, may be mentioned cyclohexylene,
cyclohexenylene and phenylene groups, with cyclohexylene and
phenylene groups being preferred.
[0065] The saturated or unsaturated, 5- to 7-membered divalent
heterocyclic group means a divalent group derived from the
saturated or unsaturated, 5- to 7-membered heterocyclic ring
described in the description of Q.sup.4 in the general formula (1).
As specific examples thereof, may be mentioned divalent groups
derived from furan, pyrrole, thiophene, pyrazole, imidazole,
oxazole, oxazolidine, thiazole, thiadiazole, furazane, pyrane,
pyridine, pyrimidine, pyridazine, pyrrolidine, piperazine,
piperidine, oxazine, oxadiazine, morpholine, thiazine, thiadiazine,
thiomorpholine, tetrazole, triazole, triazine, azepien, diazepine
and triazepine. Among these, preferable examples thereof include
divalent groups derived from pyrazole, imidazole, oxazole,
thiazole, thiadiazole, furazane, pyridine, pyrimidine, pyridazine,
pyrrolidine, piperazine, piperidine, triazole, triazine, azepien,
diazepine and triazepine.
[0066] The saturated or unsaturated, divalent bicyclic or tricyclic
condensed hydrocarbon means a divalent group derived from the
saturated or unsaturated, bicyclic or tricyclic condensed
hydrocarbon group described in the description of Q.sup.4 in the
general formula (1). As specific examples thereof, may be mentioned
divalent groups derived from indene, indane, naphthalene,
tetrahydronaphthalene, anthracene, phenanthrene and the like. As
preferable examples thereof, may be mentioned divalent groups
derived from indane and naphthalene.
[0067] The saturated or unsaturated, divalent bicyclic or tricyclic
condensed heterocyclic group means a divalent group derived from
the saturated or unsaturated, bicyclic or tricyclic condensed
heterocyclic ring described in the description of Q.sup.4 in the
general formula (1). As specific examples thereof, may be mentioned
divalent groups derived from benzofuran, benzothiophene, indole,
isoindole, indazole, quinoline, tetrahydroquinoline, isoquinoline,
tetrahydroisoquinoline, quinazoline, dihydroquinazoline,
tetrahydroquinazoline, quinoxaline, tetrahydroquinoxaline,
cinnoline, tetrahydrocinnoline, indolizine, tetrahydroindolizine,
benzothiazole, tetrahydrobenzothiazole, naphthyridine,
tetrahydronaphthyridine, thienopyridine, tetrahydrothienopyridine,
thiazolopyridine, tetrahydrothiazolopyridine, thiazolopyridazine,
tetrahydrothiazolopyridazine, pyrrolopyridine,
dihydropyrrolopyridine, tetrahydropyrrolopyridine,
pyrrolopyrimidine, dihydropyrrolopyrimidine,
dihydropyridoquinazoline, pyranothiazole, dihydropyranothiazole,
furopyridine, tetrahydrofuropyridine, oxazolopyridine,
tetrahydrooxazolopyridine, oxazolopyridazine,
tetrahydrooxazolopyridazine, pyrrolothiazole,
dihydropyrrolothiazole, pyrrolooxazole, dihydropyrrolooxazole and
benzoazepine. As preferable examples thereof, may be mentioned
divalent groups derived from benzofuran, benzothiophene, indole,
indazole, quinoline, isoquinoline, tetrahydroisoquinoline,
benzothiazole, naphthyridine, thienopyridine, thiazolopyridine,
tetrahydrothiazolopyridine, thiazolopyridazine, pyrrolopyridine,
tetrahydropyrrolopyridine, pyridopyrimidine, pyranothiazole,
dihydropyranothiazole, furopyridine, oxazolopyridine,
oxazolopyridazine, pyrrolothiazole, dihydropyrrolothiazole,
pyrrolooxazole and dihydropyrrolooxazole. No particular limitation
is imposed on the condensing form of the condensed heterocyclic
group. For example, naphthyridine may be any of 1,5-, 1,6-, 1,7-,
1,8-, 2,6- and 2,7-naphthyridine, thienopyridine may be any of
thieno[2,3-b]pyridine, thieno[2,3-c]pyridine,
thieno[3,2-b]pyridine, thieno[3,2-c]pyridine, thieno[3,4-b]pyridine
and thieno[3,4-c]pyridine, thiazolopyridine may be any of
thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine,
thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine,
thiazolo[3,4-a]pyridine and thiazolo[3,2-a]pyridine,
thiazolopyridazine may be any of thiazolo[4,5-c]pyridazine,
thiazolo[4,5-d]pyridazine, thiazolo[5,4-c]pyridazine and
thiazolo[3,2-b]pyridazine, pyrrolopyridine may be any of
pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine,
pyrrolo[3,2-b]pyridine, pyrrolo[3,2-c]pyridine,
pyrrolo[3,4-b]pyridine and pyrrolo[3,4-c]pyridine,
pyrrolopyrimidine may be any of pyrrolo[3,4-d]pyrimidine,
pyrrolo[3,2-d]pyrimidine and pyrrolo[2,3-d]pyrimidine,
pyridopyrimidine may be any of pyrido[2,3-d]pyrimidine,
pyrido[3,2-d]pyrimidine and pyrido[3,4-d]pyrimidine, pyranothiazole
may be any of pyrano[2,3-d]thiazole, pyrano[4,3-d]thiazole,
pyrano[3,4-d]thiazole and pyrano[3,2-d]thiazole, furopyridine may
be any of furo[2,3-b]pyridine, furo[2,3-c]pyridine,
furo[3,2-b]pyridine, furo[3,2-c]pyridine, furo[3,4-b]pyridine and
furo[3,4-c]pyridine, oxazolopyridine may be any of
oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine,
oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine,
oxazolo[3,4-a]pyridine and oxazolo[3,2-a]pyridine,
oxazolopyridazine may be any of oxazolo[4,5-c]pyridazine,
oxazolo[4,5-d]pyridazine, oxazolo[5,4-c]pyridazine and
oxazolo[3,4-b]pyridazine, pyrrolothiazole may be any of
pyrrolo[2,1-b]thiazole, pyrrolo[1,2-c]thiazole,
pyrrolo[3,2-d]thiazole and pyrrolo[3,4-d]thiazole, and
pyrrolooxazole may be any of pyrrolo[2,1-b]oxazole,
pyrrolo[1,2-c]oxazole, pyrrolo[2,3-d]oxazole, pyrrolo[3,2-d]oxazole
and pyrrolo[3,4-d]oxazole. Other condensing forms than these may be
allowed.
[0068] The above-described saturated or unsaturated, 5- or
6-membered divalent cyclic hydrocarbon groups, saturated or
unsaturated, 5- to 7-membered divalent heterocyclic groups,
saturated or unsaturated, divalent bicyclic or tricyclic condensed
hydrocarbon groups and saturated or unsaturated, divalent bicyclic
or tricyclic condensed heterocyclic groups may each have 1 to 3
substituents. Examples of the substituents may include a hydroxyl
group, halogen atoms such as a fluorine, chlorine, bromine and
iodine atoms, halogenoalkyl groups having 1 to 3 halogen atoms, an
amino group, a cyano group, aminoalkyl groups, an amidino group, a
hydroxyamidino group, linear, branched or cyclic alkyl groups
having 1 to 6 carbon atoms (for example, methyl group, ethyl group,
etc.), linear, branched or cyclic alkoxy groups having 1 to 6
carbon atoms (for example, methoxy group, ethoxy group, etc.), an
amidino group substituted by a linear, branched or cyclic
alkoxycarbonyl groups having 2 to 7 carbon atoms (for example,
methoxycarbonylamidino group, ethoxycarbonylamidino group, etc.),
linear, branched or cyclic alkenyl groups having 2 to 6 carbon
atoms (for example, vinyl group, allyl group, etc.), linear or
branched alkynyl groups having 2 to 6 carbon atoms (for example,
ethynyl group, propynyl group, etc.), linear, branched or cyclic
alkoxycarbonyl group having 2 to 6 carbon atoms (for example,
methoxycarbonyl group, ethoxycarbonyl group, etc.), and a carbamoyl
group.
[0069] Preferable groups in Q.sup.2 described above are a single
bond, saturated or unsaturated, 5- or 6-membered divalent cyclic
hydrocarbon groups which may be substituted, saturated or
unsaturated, 5- to 7-membered divalent heterocyclic groups which
may be substituted, and saturated or unsaturated, divalent bicyclic
or tricyclic condensed heterocyclic groups which may be
substituted. Of these, a single bond, saturated or unsaturated,
divalent 5- or 6-membered cyclic hydrocarbon groups, saturated or
unsaturated, 5- to 7-membered divalent heterocyclic groups are
preferred.
[0070] When Q.sup.1 is a saturated or unsaturated, bicyclic or
tricyclic condensed hydrocarbon group which may be substituted, or
a saturated or unsaturated, bicyclic or tricyclic condensed
heterocyclic group which may be substituted, the group Q.sup.2 is
preferably a single bond. The case where Q.sup.2 is a single bond
in the above-described combination means that the general formula
(1):
Q.sup.1-Q.sup.2-T.sup.0-N(R.sup.1)-Q.sup.3-N(R.sup.2)-T.sup.1-Q.sup.4
(1)
wherein R.sup.1, R.sup.2, Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4,
T.sup.0 and T.sup.1 have the same meanings as defined above, comes
to the following general formula (1'):
Q.sup.1-T.sup.0-N(R.sup.1)-Q.sup.3-N(R.sup.2)-T.sup.1-Q.sup.4
(1')
wherein Q.sup.1 represents the above bicyclic or tricyclic
condensed hydrocarbon group or bicyclic or tricyclic condensed
heterocyclic group, and R.sup.1, R.sup.2, Q.sup.3, Q.sup.4, T.sup.0
and T.sup.1 have the same meanings as defined above.
[0071] Specifically, are preferred those in which the group Q.sup.1
is a thienopyridyl group which may be substituted; a
tetrahydrothienopyridyl group which may be substituted; a
thiazolopyridyl group which may be substituted; a
tetrahydrothiazolopyridyl group which may be substituted; a
thiazolopyridazinyl group which may be substituted; a
tetrahydrothiazolopyridazinyl group which may be substituted; a
pyranothiazolyl group which may be substituted; a
dihydropyranothiazolyl group which may be substituted; a
furopyridyl group which may be substituted; a tetrahydrofuropyridyl
group which may be substituted; an oxazolopyridyl group which may
be substituted; a tetrahydrooxazolopyridyl group which may be
substituted; a pyrrolopyridyl group which may be substituted; a
dihydropyrrolopyridyl group which may be substituted; a
tetrahydropyrrolopyridyl group which may be substituted; a
pyrrolopyrimidinyl group which may be substituted; a
dihydropyrrolopyrimidinyl group which may be substituted; an
oxazolopyridazinyl group which may be substituted; a
tetrahydrooxazolopyridazinyl group which may be substituted; a
pyrrolothiazolyl group which may be substituted; a
dihydropyrrolothiazolyl group which may be substituted; a
pyrrolooxazolyl group which may be substituted; a
dihydropyrrolooxazolyl group which may be substituted; a
benzothiazolyl group which may be substituted; a
tetrahydrobenzothiazolyl group which may be substituted; a
thiazolopyrimidinyl which may be substituted; a
dihydrothiazolopyrimidinyl which may be substituted; a
benzoazepinyl which may be substituted; a tetrahydrobenzoazepinyl
which may be substituted; a thiazoloazepinyl which may be
substituted; a tetrahydrothiazoloazepinyl which may be substituted;
a thienoazepinyl which may be substituted; a
tetrahydrothienoazepinyl which may be substituted; a
4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl group
which may be substituted; or a
5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group which
may be substituted, and Q.sup.2 is a single bond.
[0072] When Q.sup.1 is a saturated or unsaturated, 5- or 6-membered
cyclic hydrocarbon group which may be substituted, or a saturated
or unsaturated, 5- to 7-membered heterocyclic group which may be
substituted, the group Q.sup.2 is preferably a saturated or
unsaturated, 5- or 6-membered divalent cyclic hydrocarbon group
which may be substituted, or a saturated or unsaturated, 5- to
7-membered divalent heterocyclic group which may be substituted. As
preferable examples of the group Q.sup.1-Q.sup.2, may be mentioned
4-(4-pyridyl)phenyl, 4-(2-pyridyl)phenyl, 5-(4-pyridyl)thiazolyl,
1-(4-pyridyl)piperidyl, 4-(4-pyridyl)piperidyl,
4-hydroxy-1-(4-pyridyl)piperidin-4-yl, biphenylyl,
4-(2-aminosulfonylphenyl)phenyl, 4-(2-amidinophenyl)phenyl,
4-(2-methylsulfonylphenyl)phenyl, 4-(2-aminomethylphenyl)phenyl,
4-(2-carbamoylphenyl)phenyl, 4-(2-imidazolyl)phenyl,
4-(1-methyl-2-imidazolyl)phenyl,
4-(2,3,4,5-tetrahydropyrimidin-2-yl)phenyl,
4-(1-methyl-2,3,4,5-tetrahydropyrimidin-2-yl)phenyl,
4-(5-tetrazolyl)phenyl, 1-(4-pyridyl)piperidin-4-yl,
3-(4-piperidyl)isoxazolin-5-yl, 3-(4-amidinophenyl)isoxazolin-5-yl,
3-(4-piperidyl)isoxazolidin-5-yl,
3-(4-amidinophenyl)isoxazolidin-5-yl,
2-(4-piperidyl)-1,3,4-thiadiazol-5-yl,
2-(4-aminophenyl)-1,3,4-oxadiazol-5-yl,
4-(4-piperidyl)piperidin-1-yl, 4-(4-piperidyl)piperazin-1-yl,
4-(4-piperazinyl)piperazin-1-yl, 1-(4-pyrimidinyl)piperidin-1-yl,
1-(2-methylpyrimidin-4-yl)piperidin-4-yl,
1-(4-pyrimidinyl)pyrrolidin-3-yl,
1-(4-methylpyrimidin-6-yl)piperazin-4-yl,
1-(2-methylpyrimidin-4-yl)pyrrolidin-4-yl,
1-(6-chloropyrimidin-4-yl)piperidin-4-yl,
5-(4-chlorophenyl)thiophen-2-yl, 2-(4-chlorophenyl)thiazol-4-yl,
3-(4-chlorophenyl)-1H-pyrrol-2-yl, 4-(4-pyrimidinyl)phenyl,
4-(4-imidazolyl)phenyl, 5-(pyridin-4-yl)pyrimidin-2-yl,
2'-[(dimethylamino)methyl][1,1'-biphenyl]-4-yl,
4-[2-(hydroxymethyl)pyridin-4-yl]phenyl,
4-[2-(aminomethyl)pyridin-4-yl]phenyl,
2'-(aminosulfonyl)[1,1'-biphenyl]-4-yl and
4-(3-oxomorpholin-4-yl)phenyl groups.
<On Group Q.sup.3>
[0073] The group Q.sup.3 represents the following group:
##STR00027##
wherein Q.sup.5 represents an alkylene group having 1 to 8 carbon
atoms, an alkenylene group having 2 to 8 carbon atoms, or a group
--(CH.sub.2).sub.m--CH.sub.2-A-CH.sub.2--(CH.sub.2).sub.n-- (in
which m and n are each independently 0 or an integer of 1-3, and A
represents an oxygen atom, nitrogen atom, sulfur atom, --SO--,
--SO.sub.2--, --NH--, --O--NH--, --NH--NH--, --S--NH--, --SO--NH--
or --SO.sub.2--NH--, numerals 1 and 2 indicate positions) and;
[0074] R.sup.3 and R.sup.4 are substituents on carbon atom(s),
nitrogen atom(s) or sulfur atom(s) of a ring comprising Q.sup.5 and
are each independently a hydrogen atom, hydroxyl group, alkyl
group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl
group, cyano group, cyanoalkyl group, amino group, aminoalkyl
group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl
group, acylalkyl group, acylamino group which may be substituted,
alkoxyimino group, hydroxyimino group, acylaminoalkyl group, alkoxy
group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group,
carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl
group, alkoxycarbonylalkylamino group, carboxyalkylamino group,
alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group,
carbamoyl group, N-alkylcarbamoyl group which may have a
substituent on the alkyl group, N,N-dialkylcarbamoyl group which
may have a substituent on the alkyl group(s), N-alkenylcarbamoyl
group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl
group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl
group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl
group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazolyl group which
may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group,
alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl
group which may be substituted, carbamoylalkyl group,
N-alkylcarbamoylalkyl group which may have a substituent on the
alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a
substituent on the alkyl group(s), carbamoyloxyalkyl group,
N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group,
3- to 6-membered heterocyclic carbonylalkyl group which may be
substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group
which may be substituted, aryl group, aralkyl group, 3- to
6-membered heterocyclic group which may be substituted, 3- to
6-membered heterocyclic alkyl group which may be substituted,
alkylsulfonylamino group, arylsulfonylamino group,
alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group,
alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group,
alkylsulfonylaminocarbonylalkyl group,
arylsulfonylaminocarbonylalkyl group, oxo group, carbamoyloxy
group, aralkyloxy group, carboxyalkyloxy group,
alkoxycarbonylalkyloxy group, acyloxy group, acyloxyalkyl group,
arylsulfonyl group, alkoxycarbonylalkylsulfonyl group,
carboxyalkylsulfonyl group, alkoxycarbonylacyl group,
alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group,
halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl
group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group,
alkoxyalkylsulfonyl group, 3- to 6-membered heterocyclic sulfonyl
group which may be substituted, 3- to 6-membered heterocyclic oxy
group which may be substituted, N-alkylaminoacyl group,
N,N-dialkylaminoacyl group, N,N-dialkylcarbamoylacyl group which
may have a substituent on the alkyl group(s),
N,N-dialkylcarbamoylalkylsulfonyl group which may have a
substituent on the alkyl group(s), alkylsulfonylacyl group,
N-arylcarbamoyl group, N-(3- to 6-membered heterocyclic) carbamoyl
group, N-alkyl-N-arylcarbamoyl group, N-alkyl-N-(3- to 6-membered
heterocyclic) carbamoyl group, N-arylcarbamoylalkyl group, N-(3- to
6-membered heterocyclic) carbamoylalkyl group,
N-alkyl-N-arylcarbamoylalkyl group, N-alkyl-N-(3- to 6-membered
heterocyclic) carbamoylalkyl group, aminocarbothioyl group,
N-alkylaminocarbothioyl group, N,N-dialkylaminocarbothioyl group,
alkoxyalkyl(thiocarbonyl) group, alkylthioalkyl group or
N-acyl-N-alkylaminoalkyl group, or R.sup.3 and R.sup.4 together
form an alkylene group having 1 to 5 carbon atoms, alkenylene group
having 2 to 5 carbon atoms, alkylenedioxy group having 1 to 5
carbon atoms or carbonyldioxy group.
[0075] The following group will be described in detail.
##STR00028##
wherein Q.sup.5, R.sup.3 and R.sup.4 have the same meanings as
defined above, and numerals 1 and 2 indicate positions.
[0076] A portion of the cyclic structure having the group Q.sup.5
is a 3- to 10-membered divalent cyclic hydrocarbon group which may
have a double bond, or a 5- to 12-membered divalent heterocyclic
group containing 1 or 2 hetero atoms, preferably a 3- to 8-membered
divalent cyclic hydrocarbon group or a 5- to 8-membered divalent
heterocyclic group, more preferably a 5- to 7-membered divalent
cyclic hydrocarbon group or a 5- to 7-membered divalent
heterocyclic group. Among others, a group in which Q.sup.5 is an
alkylene group having 3 to 6 carbon atoms or a group
--(CH.sub.2).sub.m--CH.sub.2-A-CH.sub.2--(CH.sub.2).sub.n-- (in
which m and n are each independently 0 or 1, and A has the same
meaning as defined above) is preferred. In particular, a group in
which Q.sup.5 is an alkylene group having 4 carbon atoms is
preferred.
[0077] This cyclic hydrocarbon group or heterocyclic group may have
both cis and trans structures in the relation between position 1
and position 2. However, the trans-form is preferred in the case of
the 5-membered ring, while both cis-form and trans-form are
preferred in the 6- or 7-membered ring.
[0078] The substituents R.sup.3 and R.sup.4 will now be described
in detail. The halogen atom means a fluorine, chlorine, bromine or
iodine atom. Examples of the alkyl group include linear, branched
or cyclic C.sub.1-C.sub.6 alkyl groups (for example, methyl group,
cyclopropyl group, isobutyl group and the like). Examples of the
halogenoalkyl group include the 1 to 3 halogen-substituted alkyl
groups (for example, chloromethyl group, 1-bromoethyl group,
trifluoromethyl group and the like). Examples of the cyanoalkyl
group include the C.sub.1-C.sub.6 alkyl groups substituted with one
cyano group (for example, cyanomethyl group, 1-cyanoethyl group and
the like). Examples of the alkenyl group include linear or branched
alkenyl groups having 2 to 6 carbon atoms and a double bond (for
example, vinyl group, allyl group and the like). Examples of the
alkynyl group include linear or branched alkynyl groups having 2 to
6 carbon atoms and a triple bond (for example, ethynyl group,
propynyl group and the like). Examples of the acyl group include
C.sub.1-C.sub.6 alkanoyl groups (for example, formyl group, acetyl
group and the like), C.sub.7-C.sub.15 aroyl groups such as a
benzoyl group and a naphthoyl group, and arylalkanoyl groups that
are the C.sub.1-C.sub.6 alkanoyl groups substituted with one
C.sub.6-C.sub.14 aryl group (for example, phenacetyl group and the
like). Examples of the acylalkyl group include the C.sub.1-C.sub.6
alkyl groups substituted with one acyl group (for example,
acethylmethyl group and the like). Examples of the alkoxy group
include linear, branched or cyclic C.sub.1-C.sub.6 alkoxy groups
(for example, methoxy group, cyclopropoxy group, an isopropoxy
group and the like). Examples of the alkoxyalkyl group include the
C.sub.1-C.sub.6 alkyl groups substituted with one C.sub.1-C.sub.6
alkoxy group (for example, methoxymethyl group, ethoxymethyl group
and the like). Examples of the hydroxyalkyl group include the
C.sub.1-C.sub.6 alkyl groups substituted with one hydroxyl group
(for example, hydroxymethyl group, 1-hydroxyethyl group and the
like). Examples of the carboxyalkyl group include the
C.sub.1-C.sub.6 alkyl groups substituted with one carboxyl group
(for example, carboxymethyl group, 1-carboxyethyl group and the
like). Examples of the alkoxycarbonyl group include groups composed
of the C.sub.1-C.sub.6 alkoxy group and a carbonyl group (for
example, methoxycarbonyl group, ethoxycarbonyl group and the like).
Examples of the alkoxycarbonylalkyl group include the
C.sub.1-C.sub.6 alkyl groups substituted with one alkoxycarbonyl
group (for example, methoxycarbonylethyl group, ethoxycarbonylethyl
group and the like). Examples of the carbamoylalkyl group include
the C.sub.1-C.sub.6 alkyl groups substituted a carbamoyl group (for
example, carbamoylmethyl group, carbamoylethyl group and the
like).
[0079] The 3- to 6-membered heterocyclic group which may be
substituted means a saturated or unsaturated 3- to 6-membered
heterocyclic group which may contain 1 to 3 hetero atoms (nitrogen
atom, oxygen atom, sulfur atom, etc.). The heterocyclic group may
have a substituent such as a hydroxy group, halogen atom, amino
group, C.sub.1-C.sub.6 alkyl group, oxo group, or halogenoalkyl
group. Examples of the 3- to 6-membered heterocyclic group include
pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyrazolinyl, oxazolyl,
oxazolinyl, oxadiazolyl, oxazolidinyl, thiazolyl, thiazolinyl,
thiadiazolyl, furazanyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl,
pyrrolidinyl, piperazinyl, piperidinyl, oxazinyl, oxadiazinyl,
morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl, tetrazolyl,
triazolyl, and triazinyl groups. Specific examples include
thiazolyl, 4,5-dihydrothiazolyl, oxazolyl, 4,5-dihydrooxazolyl,
5-methyloxazolyl, imidazolyl, pyrrolidinyl, 3-hydroxypyrrolidinyl,
piperidyl, piperazinyl, morpholinyl, thiomorpholinyl,
1,1-dioxothiomorpholinyl, tetrahydropyranyl, pyridyl,
1,2,4-oxadiazolyl, 3-methyl-1,2,4-oxadiazolyl,
5-methyl-1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,
5-methyl-1,3,4-oxadiazolyl, 5-(trifluoromethyl)-1,3,4-oxadiazolyl,
1,3-oxazolyl, 1,3,4-thiadiazolyl, 5-methyl-1,3,4-thiadiazolyl, and
1,3-oxazolidinyl groups. Examples of the 3- to 6-membered
heterocyclic alkyl group which may be substituted include groups
obtained by substituting one of the above-described 3- to
6-membered heterocyclic group which may be substituted by an alkyl
group (for example, thiazolylmethyl, 4,5-dihydrothiazolylmethyl,
morpholinylmethyl, and 1,1-dioxothiomorpholinylmethyl groups).
Examples of the aryl group include aryl groups having 6 to 14
carbon atoms, such as phenyl group and naphthyl group. The aryl
groups may have 1 to 3 substituents selected from among the
C.sub.1-C.sub.6 alkyl groups, the C.sub.1-C.sub.6 alkanoyl groups,
a hydroxyl group, a nitro group, a cyano group, halogen atoms, the
C.sub.2-C.sub.6 alkenyl groups, the C.sub.2-C.sub.6 alkynyl groups,
the C.sub.1-C.sub.6 halogenoalkyl groups, the C.sub.1-C.sub.6
alkoxy groups, a carboxy group, a carbamoyl group, the
C.sub.1-C.sub.6 alkoxycarbonyl groups and the like. Examples of the
aralkyl group include the C.sub.1-C.sub.6 alkyl groups substituted
with one C.sub.6-C.sub.14 aryl group (for example, benzyl group,
phenethyl group and the like). Incidentally, in the above
description, no particular limitation is imposed on the
substituting position. Examples of the acylamino group which may be
substituted include the amino groups substituted with the
C.sub.1-C.sub.6 acyl group (for example, formylamino group,
acetylamino group and the like) and besides acyl groups having 1 to
several substituents selected from among halogen atoms, a hydroxyl
group, C.sub.1-C.sub.6 alkoxy groups, a amino group,
N--C.sub.1-C.sub.6 alkylamino groups, N,N-di-C.sub.1-C.sub.6
alkylamino groups, a carboxyl group, C.sub.2-C.sub.6 alkoxycarbonyl
groups and the like (for example, 2-methoxyacetylamino group,
3-aminopropionylamino group and the like). Examples of the
acylaminoalkyl group include the C.sub.1-C.sub.6 alkyl groups
substituted with the C.sub.1-C.sub.6 acylamino group (for example,
formylaminomethyl group, acetylaminomethyl group and the like).
Examples of the aminoalkyl group include the C.sub.1-C.sub.6 alkyl
groups substituted with one amino group (for example, aminomethyl
group, 1-aminoethyl group and the like). Examples of the
N-alkylaminoalkyl group include the amino-C.sub.1-C.sub.6 alkyl
groups substituted with one C.sub.1-C.sub.6 alkyl group on the
nitrogen atom (for example, N-methylaminomethyl group,
N-methylaminoethyl group and the like). Examples of
N,N-dialkylaminoalkyl group include the amino-C.sub.1-C.sub.6 alkyl
groups respectively substituted with two C.sub.1-C.sub.6 alkyl
groups on the nitrogen atom (for example, N,N-dimethylaminomethyl
group, N-ethyl-N-methylaminoethyl group and the like). Examples of
the N-alkenylcarbamoyl group include carbamoyl groups substituted
with a linear or branched C.sub.2-C.sub.6 alkenyl group (for
example, allylcarbamoyl group and the like). Examples of the
N-alkenylcarbamoylalkyl group include the C.sub.1-C.sub.6 alkyl
groups substituted with the N--C.sub.2-C.sub.6 alkenylcarbamoyl
group (for example, allylcarbamoylethyl group and the like).
Examples of the N-alkenyl-N-alkylcarbamoyl group include the
N--C.sub.2-C.sub.6 alkenylcarbamoyl groups substituted with a
linear or branched C.sub.1-C.sub.6 alkyl group on the nitrogen atom
(for example, N-allyl-N-methylcarbamoyl group and the like).
Examples of the N-alkenyl-N-alkylcarbamoylalkyl group include the
N--C.sub.2-C.sub.6 alkenylcarbamoylalkyl groups substituted with a
linear or branched C.sub.1-C.sub.6 alkyl group on the nitrogen atom
(for example, N-allyl-N-methylcarbamoylmethyl group and the like).
Example of the N-alkoxycarbamoyl group include carbamoyl groups
substituted with a linear or branched C.sub.1-C.sub.6 alkoxy group
(for example, methoxycarbamoyl group and the like). Examples of the
N-alkoxycarbamoylalkyl group include linear or branched
C.sub.1-C.sub.6 alkyl groups substituted with the
N--C.sub.1-C.sub.6 alkoxycarbamoyl group (for example,
methoxycarbamoylmethyl group and the like). Examples of the
N-alkyl-N-alkoxycarbamoyl group include carbamoyl groups
substituted with linear or branched C.sub.1-C.sub.6 alkoxy group
and C.sub.1-C.sub.6 alkyl group (for example,
N-ethyl-N-methoxycarbamoyl group and the like). Examples of the
N-alkyl-N-alkoxycarbamoylalkyl group include linear or branched
C.sub.1-C.sub.6 alkyl groups substituted with the
N--C.sub.1-C.sub.6 alkyl-N--C.sub.1-C.sub.6 alkoxycarbamoyl group
(for example, N-ethyl-N-methoxycarbamoylmethyl group and the like).
Examples of the carbazolyl group which may be substituted by 1 to 3
alkyl groups include a carbazolyl group, and besides carbazolyl
groups substituted with 1 to 3 linear or branched C.sub.1-C.sub.6
alkyl groups (for example, 1-methylcarbazolyl group,
1,2-dimethylcarbazolyl group and the like). Examples of the
alkylsulfonyl group include linear, branched or cyclic
C.sub.1-C.sub.6 alkylsulfonyl groups (for example, methanesulfonyl
group and the like). Examples of the alkylsulfonylalkyl group
include linear or branched C.sub.1-C.sub.6 alkyl groups substituted
with the C.sub.1-C.sub.6 alkylsulfonyl group (for example,
methanesulfonylmethyl group and the like). Examples of the
alkoxyimino group include C.sub.1-C.sub.6 alkoxyimino groups (for
example, methoxyimino group, ethoxyimino group and the like).
Examples of the alkoxycarbonylalkylamino group include amino groups
substituted with one C.sub.1-C.sub.6 alkoxycarbonylalkyl group (for
example, methoxycarbonylmethylamino group,
ethoxycarbonylpropylamino group and the like). Examples of the
carboxyalkylamino group include amino groups substituted with one
carboxy-C.sub.1-C.sub.6 alkyl group (for example,
carboxymethylamino group, carboxyethylamino group and the like).
Examples of the alkoxycarbonylamino group include amino groups
substituted with one C.sub.1-C.sub.6 alkoxycarbonyl group (for
example, methoxycarbonylamino group, tert-butoxycarbonylamino group
and the like). Examples of the alkoxycarbonylaminoalkyl group
include the alkyl groups substituted with one C.sub.1-C.sub.6
alkoxycarbonylamino group (for example, methoxycarbonylaminomethyl
group, tert-butoxycarbonylaminoethyl group and the like). The
N-alkylcarbamoyl group which may have a substituent on the alkyl
group means a carbamoyl group substituted with a linear, branched
or cyclic C.sub.1-C.sub.6 alkyl group which may be substituted with
a hydroxyl group, amino group, N--C.sub.1-C.sub.6 alkylamino group,
amidino group, halogen atom, carboxyl group, cyano group, carbamoyl
group, C.sub.1-C.sub.6 alkoxy group, C.sub.1-C.sub.6 alkanoyl
group, C.sub.1-C.sub.6 alkanoylamino group, C.sub.1-C.sub.6
alkylsulfonylamino group or the like, and examples thereof include
N-methylcarbamoyl group, N-ethylcarbamoyl group,
N-isopropylcarbamoyl group, N-cyclopropylcarbamoyl group,
N-(2-hydroxyethyl)carbamoyl group, N-(2-fluoroethyl)carbamoyl
group, N-(2-cyanoethyl)carbamoyl group, N-(2-methoxyethyl)carbamoyl
group, N-carboxymethylcarbamoyl group, N-(2-aminoethyl)carbamoyl
group, N-(2-amidinoethyl)carbamoyl group and the like. Examples of
the N,N-dialkylcarbamoyl group which may have a substituent on the
alkyl group(s) means a carbamoyl group substituted with 2 linear,
branched or cyclic C.sub.1-C.sub.6 alkyl groups which may be
substituted with a hydroxyl group, amino group, N--C.sub.1-C.sub.6
alkylamino group, amidino group, halogen atom, carboxyl group,
cyano group, carbamoyl group, C.sub.1-C.sub.6 alkoxy group,
C.sub.1-C.sub.6 alkanoyl group, C.sub.1-C.sub.6 alkanoylamino
group, C.sub.1-C.sub.6 alkylsulfonylamino group or the like, and
examples thereof include N,N-dimethylcarbamoyl group,
N,N-diethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group,
N-isopropyl-N-methylcarbamoyl group,
N-(2-hydroxyethyl)-N-methylcarbamoyl group,
N,N-bis(2-hydroxyethyl)carbamoyl group,
N,N-bis(2-fluoroethyl)carbamoyl group,
N-(2-cyanoethyl)-N-methylcarbamoyl group,
N-(2-methoxyethyl)-N-methylcarbamoyl group,
N-carboxymethyl-N-methylcarbamoyl group,
N,N-bis(2-aminoethyl)carbamoyl group and the like. Examples of the
N-alkylcarbamoylalkyl group which may have a substituent on the
alkyl group(s) include linear or branched C.sub.1-C.sub.6 alkyl
groups substituted with the N-alkylcarbamoyl group which may have a
substituent on the C.sub.1-C.sub.6 alkyl group (for example,
N-methylcarbamoylmethyl group, N-(2-hydroxyethyl)carbamoylmethyl
group and the like). Examples of the N,N-dialkylcarbamoylalkyl
group which may have a substituent on the alkyl group(s) include
linear or branched C.sub.1-C.sub.6 alkyl groups substituted with
the N,N-dialkylcarbamoyl group which may have a substituent on the
C.sub.1-C.sub.6 alkyl group(s) (for example,
N,N-dimethylcarbamoylmethyl group,
N-(2-hydroxyethyl)-N-methylcarbamoylmethyl group and the like).
Examples of the 3- to 6-membered heterocyclic carbonyl group which
may be substituted include groups composed of the 3- to 6-membered
heterocyclic group which may be substituted and a carbonyl group
(for example, aziridinylcarbonyl group, azetidinylcarbonyl group,
3-hydroxyazetidinylcarbonyl group, 3-methoxyazetidinylcarbonyl
group, pyrrolidinylcarbonyl group, 3-hydroxypyrrolidinylcarbonyl
group, 3-fluoropyrrolidinylcarbonyl group, piperidylcarbonyl group,
piperazinylcarbonyl group, morpholinylcarbonyl group,
thiomorpholinylcarbonyl group, 1,1-dioxothiomorpholinylcarbonyl
group, tetrahydropyranylcarbonyl group, pyridylcarbonyl group,
furoyl group, and thiophenecarbonyl group). Examples of the 3- to
6-membered heterocyclic carbonylalkyl group which may be
substituted include the C.sub.1-C.sub.6 alkyl groups substituted
with one 3- to 6-membered heterocyclic carbonyl group which may be
substituted (for example, azetidinylcarbonylmethyl group,
pyrrolidinylcarbonylethyl group and the like). Examples of the 3-
to 6-membered heterocyclic carbonyloxyalkyl group which may be
substituted include the C.sub.1-C.sub.6 alkyl groups substituted
with one 3- to 6-membered heterocyclic carbonyloxy group which is
composed of the 3- to 6-membered heterocyclic carbonyl group and an
oxygen atom (for example, piperidinylcarbonyloxyethyl group,
morpholinylcarbonyloxymethyl group and the like). Examples of the
carbamoyloxyalkyl group include the C.sub.1-C.sub.6 alkyl groups
substituted with one carbamoyloxy group which is composed of a
carbamoyl group and an oxygen atom (for example, carbamoyloxymethyl
group, carbamoyloxyethyl group and the like). Examples of the
N-alkylcarbamoyloxyalkyl group include the C.sub.1-C.sub.6 alkyl
groups substituted with one N-alkylcarbamoyloxy group which is
composed of the N-alkylcarbamoyl group, which may have a
substituent on the C.sub.1-C.sub.6 alkyl group, and an oxygen atom
(for example, N-methylcarbamoyloxymethyl group,
N-methylcarbamoyloxyethyl group and the like). Examples of the
N,N-dialkylcarbamoyloxyalkyl group include the C.sub.1-C.sub.6
alkyl groups substituted with one N,N-dialkylcarbamoyloxy group
which is composed of the N,N-dialkylcarbamoyl group, which may have
a substituent on the alkyl group(s), and an oxygen atom (for
example, N,N-dimethylcarbamoyloxymethyl group,
N-ethyl-N-methylcarbamoyloxyethyl group and the like). Examples of
the alkylsulfonylamino group include amino groups substituted with
one alkylsulfonyl group having the C.sub.1-C.sub.6 alkyl group (for
example, methylsulfonylamino group, isopropylsulfonylamino group
and the like). Examples of the arylsulfonylamino group include
amino groups substituted with one arylsulfonyl group having the
aryl group (for example, phenylsulfonylamino group,
naphthylsulfonylamino group and the like). Examples of the
alkylsulfonylaminoalkyl group include the C.sub.1-C.sub.6 alkyl
groups substituted with one C.sub.1-C.sub.6 alkylsulfonylamino
group (for example, methylsulfonylaminomethyl group,
methylsulfonylaminoethyl group and the like). Examples of the
arylsulfonylaminoalkyl group include the C.sub.1-C.sub.6 alkyl
groups substituted with one arylsulfonylamino group (for example,
phenylsulfonylaminomethyl group, naphthylsulfonylaminoethyl group
and the like). Examples of the alkylsulfonylaminocarbonyl group
include groups composed of the C.sub.1-C.sub.6 alkylsulfonylamino
group and a carbonyl group (for example,
methylsulfonylaminocarbonyl group, isopropylsulfonylaminocarbonyl
group and the like). Examples of the arylsulfonylaminocarbonyl
group include groups composed of the arylsulfonylamino group and a
carbonyl group (for example, phenylsulfonylaminocarbonyl group,
naphthylsulfonylaminocarbonyl group and the like). Examples of the
alkylsulfonylaminocarbonylalkyl group include the C.sub.1-C.sub.6
alkyl groups substituted with the C.sub.1-C.sub.6
alkylsulfonylaminocarbonyl group (for example,
methylsulfonylaminocarbonylmethyl group,
isopropylsulfonylaminocarbonylmethyl group and the like). Examples
of the arylsulfonylaminocarbonylalkyl group include the
C.sub.1-C.sub.6 alkyl groups substituted with the
arylsulfonylaminocarbonyl group (for example,
phenylsulfonylaminocarbonylmethyl group,
naphthylsulfonylaminocarbonylmethyl group and the like). Examples
of the alkoxycarbonylalkyloxy group include the C.sub.1-C.sub.6
alkoxy groups substituted with the alkoxycarbonyl group (for
example, methoxycarbonylmethyloxy group). The acyloxy group means a
group composed of the acyl group and an oxygen atom (for example,
formyloxy group, acetyloxy group and the like). Examples of the
acyloxyalkyl group include the C.sub.1-C.sub.6 alkyl groups
substituted with the acyloxy group (for example, formyloxymethyl
group, acetyloxymethyl group and the like). Examples of the
aralkyloxy group include the C.sub.1-C.sub.6 alkoxy groups
substituted with the aryl group (for example, benzyloxy group,
naphthylmethoxy group and the like). Examples of the
carboxyalkyloxy group include the alkoxy groups substituted with a
carboxyl group (for example, carboxymethoxy group, carboxyethoxy
group and the like).
[0080] Examples of the arylsulfonyl group include C.sub.6-C.sub.14
arylsulfonyl groups (for example, phenylsulfonyl group,
naphthylsulfonyl group and the like). Examples of the
alkoxycarbonylalkylsulfonyl group include groups composed of the
C.sub.1-C.sub.6 alkoxycarbonylalkyl group and a sulfonyl group (for
example, methoxycarbonylethylsulfonyl group,
ethoxycarbonylethylsulfonyl group and the like). Examples of the
carboxyalkylsulfonyl group include groups composed of the
carboxyalkyl group and a sulfonyl group (for example,
carboxymethylsulfonyl group, carboxyethylsulfonyl group and the
like). Examples of the alkoxycarbonylacyl group include groups
composed of the alkoxycarbonylalkyl group and a carbonyl group (for
example, methoxycarbonylmethylcarbonyl group,
ethoxycarbonylmethylcarbonyl group and the like). Examples of the
alkoxyalkyloxycarbonyl group include the alkoxycarbonyl groups
substituted with one C.sub.1-C.sub.6 alkoxy group (for examples,
methoxymethyloxycarbonyl group, methoxyethyloxycarbonyl group and
the like). Examples of the hydroxyacyl group include the acyl
groups (including C.sub.1-C.sub.6 alkanoyl and aroyl) substituted
with one hydroxyl group (for example, glycoloyl group, lactoyl
group, benziloyl group and the like). Examples of the alkoxyacyl
group include the acyl groups substituted with one C.sub.1-C.sub.6
alkoxy group (for example, methoxyacetyl group, ethoxyacetyl group
and the like). Examples of the halogenoacyl group include groups
composed of the halogenoalkyl group and a carbonyl group (for
example, chloromethylcarbonyl group, trifluoromethylcarbonyl group
and the like). Examples of the carboxyacyl group include the acyl
groups substituted with one carboxyl group (for example,
carboxyacetyl group, 2-carboxypropionyl group and the like).
Examples of the aminoacyl group include the acyl groups (including
C.sub.1-C.sub.6 alkanoyl and aroyl) substituted with one amino
group (for example, aminomethylcarbonyl group, 1-aminoethylcarbonyl
group and the like). Examples of the acyloxyacyl group include
groups composed of the acyloxyalkyl and a carbonyl group (for
example, formyloxymethylcarbonyl group, acetyloxymethylcarbonyl
group and the like). Examples of the acyloxyalkylsulfonyl group
include groups composed of the acyloxyalkyl and a sulfonyl group
(for example, formyloxymethylsulfonyl group,
acetyloxymethylsulfonyl group and the like). Examples of the
hydroxyalkylsulfonyl group include groups composed of the
C.sub.1-C.sub.6 hydroxyalkyl group and a sulfonyl group (for
example, hydroxymethylsulfonyl group, 1-hydroxyethylsulfonyl group
and the like). Examples of the alkoxyalkylsulfonyl group include
the groups composed of C.sub.1-C.sub.6 alkoxyalkyl group and a
sulfonyl group (for example, methoxymethylsulfonyl group,
ethoxyethylsulfonyl group and the like). Examples of the 3- to
6-membered heterocyclic sulfonyl group which may be substituted
include groups composed of the 3- to 6-membered heterocyclic group
which may be substituted and a sulfonyl group (for example,
aziridinylsulfonyl group, azetidinylsulfonyl group,
pyrrolidinylsulfonyl group, piperidylsulfonyl group,
piperazinylsulfonyl group, morpholinylsulfonyl group,
tetrahydropyranylsulfonyl group and the like). Examples of the 3-
to 6-membered heterocyclic oxy group which may be substituted
include groups composed of the 3- to 6-membered heterocyclic group
which may be substituted and an oxygen atom (for example,
tetrahydrofuranyloxy group). Examples of the N-alkylaminoacyl group
include the aminoacyl groups substituted with one C.sub.1-C.sub.6
alkyl group on the nitrogen atom (for example, N-methylaminoacetyl
group, N-ethylaminoacetyl group and the like). Examples of the
N,N-dialkylaminoacyl group include the aminoacyl groups substituted
with two C.sub.1-C.sub.6 alkyl groups on the nitrogen atoms (for
example, N,N-dimethylaminoacetyl group, N-ethyl-N-methylaminoacetyl
group and the like). Examples of the N,N-dialkylcarbamoylacyl group
which may have a substituent on the alkyl group(s) include the acyl
groups substituted with the N,N-dialkylcarbamoyl group which may
have a substituent on the C.sub.1-C.sub.6 alkyl group(s) (for
example, N,N-dimethylcarbamoylacetyl group,
N,N-diethylcarbamoylacyl group, N-ethyl-N-methylcarbamoylacetyl
group and the like). Examples of the
N,N-dialkylcarbamoylalkylsulfonyl group which may have a
substituent on the alkyl group(s) include groups composed of the
N,N-dialkylcarbamoyl group which may have a substituent on the
C.sub.1-C.sub.6 alkyl group(s) and a sulfonyl group (for example,
N,N-dimethylcarbamoylmethylsulfonyl group,
N-(2-hydroxyethyl)-N-methylcarbamoylmethylsulfonyl group and the
like). Examples of the alkylsulfonylacyl group include the acyl
groups substituted with one alkylsulfonyl group having the
C.sub.1-C.sub.6 alkyl group (for example, methylsulfonylacetyl
group, isopropylsulfonylacetyl group and the like).
[0081] Examples of the N-arylcarbamoyl group include groups
obtained through substitution of the above-described aryl group
with a carbamoyl group (for example, phenylcarbamoyl group and
naphthylcarbamoyl group). Examples of the N-(3- to 6-membered
heterocyclic) carbamoyl group include groups obtained through
substitution of the above-described 3- to 6-membered heterocyclic
group which may be substituted with a carbamoyl group (for example,
pyridylcarbamoyl group and thienylcarbamoyl group). Examples of the
N-alkyl-N-arylcarbamoyl group include groups obtained through
substitution of the hydrogen atom on the nitrogen atom of the
above-described N-arylcarbamoyl group with a linear or branched
C.sub.1-C.sub.6 alkyl group (for example,
N-methyl-N-phenylcarbamoyl group). Examples of the N-alkyl-N-(3- to
6-membered heterocyclic) carbamoyl group include groups obtained
through substitution of the hydrogen atom on the nitrogen atom of
the above-described N-(3- to 6-membered heterocyclic) carbamoyl
group with a linear or branched C.sub.1-C.sub.6 alkyl group (for
example, N-methyl-N-thienylcarbamoyl group). Examples of the
N-arylcarbamoylalkyl group include groups obtained through
substitution of the above-described N-arylcarbamoyl with a linear
or branched C.sub.1-C.sub.6 alkyl group (for example,
phenylcarbamoylmethyl group). Examples of the N-(3- to 6-membered
heterocyclic) carbamoylalkyl group include groups obtained through
substitution of the above-described N-(3- to 6-membered
heterocyclic) carbamoyl group with a linear or branched
C.sub.1-C.sub.6 alkyl group (for example, pyridylcarbamoylmethyl
group). Examples of the N-alkyl-N-arylcarbamoylalkyl group include
groups obtained through substitution of the hydrogen atom on the
nitrogen atom of the above-described N-arylcarbamoylalkyl group
with a linear or branched C.sub.1-C.sub.6 alkyl group (for example,
N-methyl-N-phenylcarbamoylmethyl group). Examples of the
N-alkyl-N-(3- to 6-membered heterocyclic) carbamoylalkyl group
include groups obtained through substitution of the hydrogen atom
on the nitrogen atom of the above-described N-(3- to 6-membered
heterocyclic) carbamoylalkyl group with a linear or branched
C.sub.1-C.sub.6 alkyl group (for example,
N-methyl-N-thienylcarbamoylmethyl group).
[0082] The aminocarbothioyl group is a group represented by
--C(.dbd.S)--NH.sub.2, and the N-alkylaminocarbothioyl group means
an aminothiocarbonyl group substituted by one of the
above-described alkyl groups, and examples thereof include
(methylamino)carbothioyl group, (ethylamino)carbothioyl group and
the like. The N,N-dialkylaminocarbothioyl group means an
aminothiocarbonyl group substituted by two of the above-described
alkyl groups, and examples thereof include
(dimethylamino)carbothioyl group, (diethylamino)carbothioyl group
and (ethylmethylamino)carbothioyl group. The
alkoxyalkyl(thiocarbonyl) group means a group composed of the
above-described alkoxyalkyl group and a thiocarbonyl group, and
examples thereof include 2-ethoxyethanethioyl group and the like.
Examples of the alkylthioalkyl group include groups obtained
through substitution of a linear, branched, or cyclic
C.sub.1-C.sub.6 alkylthio group with a linear, branched, or cyclic
C.sub.1-C.sub.6 alkyl group (for example, methylthiomethyl group
and 1-methylthioethyl group). Examples of the
N-acyl-N-alkylaminoalkyl group include groups obtained through
substitution of the hydrogen atoms on the nitrogen atom of an
amino-C.sub.1-C.sub.6 alkyl group with a C.sub.1-C.sub.6 alkyl
group and an acyl group (for example, N-acetyl-N-methylaminomethyl
group).
[0083] The alkylene group means a linear or branched alkylene group
having 1 to 5 carbon atoms, and examples thereof include methylene
group, ethylene group, propylene group and the like. The alkenylene
group is an alkenylene group having 2 to 5 carbon atoms and a
double bond, and examples thereof include vinylene group,
propenylene group and the like. Examples of the alkylenedioxy group
include those having 1 to 5 carbon atoms, such as methylenedioxy
group, ethylenedioxy group and propylenedioxy group. The
carbonyldioxy group is a group represented by --O--C(.dbd.O)--O--.
Incidentally, no particular limitation is imposed on the
substituting position in the above description.
[0084] Among these substituents represented by R.sup.3 and R.sup.4,
the hydrogen atom, hydroxyl group, alkyl group, alkenyl group,
alkynyl group, halogen atom, halogenoalkyl group, amino group,
hydroxyimino group, alkoxyimino group, aminoalkyl group,
N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group,
acylalkyl group, acylamino group which may be substituted,
acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl
group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group,
alkoxycarbonylalkyl group, alkoxycarbonylamino group,
alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl
group which may have a substituent on the alkyl group,
N,N-dialkylcarbamoyl group which may have a substituent on the
alkyl group(s), N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl
group, N-alkenyl-N-alkylcarbamoyl group,
N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group,
N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group,
N-alkyl-N-alkoxycarbamoylalkyl group, carbazolyl group which may be
substituted by 1 to 3 alkyl groups, alkylsulfonyl group,
alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl
group which may be substituted, 3- to 6-membered heterocyclic
carbonyloxyalkyl group which may be substituted, 3- to 6-membered
heterocyclic group which may be substituted, carbamoylalkyl group,
carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group,
N,N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group
which may have a substituent on the alkyl group(s),
N,N-dialkylcarbamoylalkyl group which may have a substituent on the
alkyl group(s), alkylsulfonylamino group, alkylsulfonylaminoalkyl
group, oxo group, acyloxy group, acyloxyalkyl group, arylsulfonyl
group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl
group, alkoxycarbonylacyl group, carboxyacyl group,
alkoxyalkyloxycarbonyl group, halogenoacyl group,
N,N-dialkylaminoacyl group, acyloxyacyl group, hydroxyacyl group,
alkoxyacyl group, alkoxyalkylsulfonyl group,
N,N-dialkylcarbamoylacyl group, N,N-dialkylcarbamoylalkylsulfonyl
group, alkylsulfonylacyl group, aminocarbothioyl group,
N-alkylaminocarbothioyl group, N,N-dialkylaminocarbothioyl group,
alkoxyalkyl(thiocarbonyl) group and the like are preferred. The
alkylene group, alkenylene group, alkylenedioxy group,
carbonyldioxy group and the like which are formed by R.sup.3 and
R.sup.4 together are also preferred.
[0085] It is preferred that R.sup.3 be a hydrogen atom, and R.sup.4
be one of the substituents mentioned above as preferable groups. In
this case, examples of a group more preferred as R.sup.4 include
the hydrogen atom, hydroxyl group, alkyl group, halogen atom,
hydroxyimino group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl
group, acyl group, acylamino group which may be substituted,
acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl
group, carboxyl group, alkoxycarbonyl group, alkoxycarbonylalkyl
group, alkoxycarbonylamino group, carbamoyl group, N-alkylcarbamoyl
group which may have a substituent on the alkyl group,
N,N-dialkylcarbamoyl group which may have a substituent on the
alkyl group(s), N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl
group, N-alkenyl-N-alkylcarbamoyl group,
N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group,
N-alkyl-N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoylalkyl
group, carbazolyl group which may be substituted by 1 to 3 alkyl
groups, alkylsulfonyl group, alkylsulfonylalkyl group, 3- to
6-membered heterocyclic carbonyl group which may be substituted, 3-
to 6-membered heterocyclic carbonyloxyalkyl group which may be
substituted, 3- to 6-membered heterocyclic group which may be
substituted, carbamoylalkyl group, N,N-dialkylcarbamoyloxyalkyl
group, N-alkylcarbamoylalkyl group which may have a substituent on
the alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have
a substituent on the alkyl group(s), alkylsulfonylamino group,
alkylsulfonylaminoalkyl group, acyloxy group, arylsulfonyl group,
alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group,
alkoxycarbonylacyl group, carboxyacyl group, alkoxyalkyloxycarbonyl
group, halogenoacyl group, N,N-dialkylaminoacyl group, acyloxyacyl
group, hydroxyacyl group, alkoxyacyl group, alkoxyalkylsulfonyl
group, N,N-dialkylcarbamoylacyl group,
N,N-dialkylcarbamoylalkylsulfonyl group, alkylsulfonylacyl group,
aminocarbothioyl group, N-alkylaminocarbothioyl group,
N,N-dialkylaminocarbothioyl group, alkoxyalkyl(thiocarbonyl) group
and the like.
[0086] Of these, as examples of R.sup.4, are particularly preferred
the hydrogen atom, hydroxyl group, alkyl group,
N,N-dialkylaminoalkyl group, acylamino group which may be
substituted, acylaminoalkyl group, alkoxy group, alkoxyalkyl group,
hydroxyalkyl group, alkoxycarbonyl group, alkoxycarbonylamino
group, carbamoyl group, N-alkylcarbamoyl group which may have a
substituent on the alkyl group, N,N-dialkylcarbamoyl group which
may have a substituent on the alkyl group(s), N-alkenylcarbamoyl
group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl
group, N-alkenyl-N-alkylcarbamoylalkyl group,
N-alkyl-N-alkoxycarbamoyl group, carbazolyl group which may be
substituted by 1 to 3 alkyl groups, alkylsulfonyl group,
alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl
group which may be substituted, 3- to 6-membered heterocyclic group
which may be substituted, N,N-dialkylcarbamoyloxyalkyl group,
N-alkylcarbamoylalkyl group which may have a substituent on the
alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a
substituent on the alkyl group(s), alkylsulfonylamino group,
alkylsulfonylaminoalkyl group, acyloxy group, acyl group,
alkoxyalkyloxycarbonyl group, halogenoacyl group,
N,N-dialkylaminoacyl group, hydroxyacyl group, alkoxyacyl group,
aminocarbothioyl group, N-alkylaminocarbothioyl group,
N,N-dialkylaminocarbothioyl group, alkoxyalkyl(thiocarbonyl) group
and the like.
[0087] As specific preferable examples of R.sup.3 and R.sup.4, may
be mentioned a hydrogen atom, hydroxyl group, methyl group, ethyl
group, isopropyl group, N,N-dimethylaminomethyl group,
N,N-dimethylaminoethyl group, N,N-diethylaminomethyl group,
acetylamino group, methoxyacetylamino group, acetylaminomethyl
group, acetylaminoethyl group, methoxy group, ethoxy group,
methoxymethyl group, methoxyethyl group, hydroxymethyl group,
2-hydroxyethyl group, 1-hydroxy-1-methylethyl group,
methoxycarbonyl group, ethoxycarbonyl group, methoxycarbonylamino
group, ethoxycarbonylamino group, N-allylcarbamoyl group,
N-allylcarbamoylmethyl group, N-allyl-N-methylcarbamoyl group,
N-allyl-N-methylcarbamoylmethyl group, N-methoxy-N-methylcarbamoyl
group, N,N-dimethylcarbazolyl group, N,N,N'-trimethylcarbazolyl
group, methanesulfonyl group, methanesulfonylmethyl group,
ethanesulfonylmethyl group, N-methylcarbamoyl group,
N-ethylcarbamoyl group, N-propylcarbamoyl group,
N-isopropylcarbamoyl group, N-tert-butylcarbamoyl group,
N-cyclopropylcarbamoyl group, N-cyclopropylmethylcarbamoyl group,
N-(1-ethoxycarbonylcyclopropyl)carbamoyl group,
N-(2-hydroxyethyl)carbamoyl group, N-(2-fluoroethyl)carbamoyl
group, N-(2-methoxyethyl)carbamoyl group,
N-(carboxymethyl)carbamoyl group, N-(2-aminoethyl)carbamoyl group,
N-(2-amidinoethyl)carbamoyl group, N,N-dimethylcarbamoyl group,
N,N-diethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group,
N-isopropyl-N-methylcarbamoyl group, N-methyl-N-propylcarbamoyl
group, N-(2-hydroxyethyl)-N-methylcarbamoyl group,
N-(2-fluoroethyl)-N-methylcarbamoyl group,
N,N-bis(2-hydroxyethyl)carbamoyl group,
N,N-bis(2-fluoroethyl)carbamoyl group,
N-(2-methoxyethyl)-N-methylcarbamoyl group,
N-carboxymethyl-N-methylcarbamoyl group,
N,N-bis(2-aminoethyl)carbamoyl group, azetidinocarbonyl group,
3-methoxyazetidinocarbonyl group, 3-hydroxyazetidinocarbonyl group,
pyrrolidinocarbonyl group, 3-hydroxypyrrolidinocarbonyl group,
3-fluoropyrrolidinocarbonyl group, 3,4-dimethoxypyrrolidinocarbonyl
group, piperidinocarbonyl group, piperazinocarbonyl group,
morpholinocarbonyl group, (tetrahydropyran-4-yl)carbonyl group,
benzoyl group, pyridylcarbonyl group, thiazolyl group,
4,5-dihydrothiazolyl group, oxazolyl group, 4,5-dihydrooxazolyl
group, 5-methyloxazolyl group, imidazolyl group, pyrrolidinyl
group, 3-hydroxypyrrolidinyl group, piperidyl group, piperazinyl
group, morpholinyl group, thiomorpholinyl group,
1,1-dioxothiomorpholinyl group, tetrahydropyranyl group, pyridyl
group, 1,2,4-oxadiazolyl group, 3-methyl-1,2,4-oxadiazolyl group,
5-methyl-1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group,
5-methyl-1,3,4-oxadiazolyl group,
5-(trifluoromethyl)-1,3,4-oxadiazolyl group, 1,3-oxazolyl group,
1,3,4-thiadiazolyl group, 5-methyl-1,3,4-thiadiazolyl group,
1,3-oxazolidinyl group, N-methylcarbamoylmethyl group,
N-methylcarbamoylethyl group, N-ethylcarbamoylmethyl group,
N-(2-fluoroethyl)carbamoylmethyl group,
N-(2-methoxyethyl)carbamoylmethyl group,
N,N-dimethylcarbamoylmethyl group, N,N-dimethylcarbamoylethyl
group, N-(2-fluoroethyl)-N-methylcarbamoylmethyl group,
N-(2-methoxyethyl)-N-methylcarbamoylmethyl group,
N,N-dimethylcarbamoyloxymethyl group,
2-(N-ethyl-N-methylcarbamoyloxy)ethyl group, methylsulfonylamino
group, ethylsulfonylamino group, methylsulfonylaminomethyl group,
methylsulfonylaminoethyl group, acetyl group, propionyl group,
isobutyryl group, 2-methoxyethoxycarbonyl group, trifluoroacetyl
group, N,N-dimethylaminoacetyl group, N-ethyl-N-methylaminoacetyl
group, hydroxyacetyl group, 1,1-dimethyl-2-hydroxyethylcarbonyl
group, methoxyacetyl group, 1,1-dimethyl-2-methoxyethylcarbonyl
group, aminocarbothioyl group, (dimethylamino)carbothioyl group,
2-methoxyethanethioyl group and the like.
[0088] As described above, it is preferred that R.sup.3 be a
hydrogen atom, and R.sup.4 be one of these specified substituents,
preferably, an N,N-dialkylcarbamoyl group which may have a
substituent on the alkyl group(s), particularly preferably, an
N,N-dimethylcarbamoyl group. However, R.sup.3 and R.sup.4 are not
limited to these specific substituents at all.
<On Group T.sup.0>
[0089] The group T.sup.0 represents a carbonyl group or
thiocarbonyl group, with the carbonyl group being preferred.
<On Group T.sup.1>
[0090] The group T.sup.1 represents a carbonyl group, sulfonyl
group, group --C(.dbd.O)--C(.dbd.O)--N(R')--, group
--C(.dbd.S)--C(.dbd.O)--N(R')--, group
--C(.dbd.O)--C(.dbd.S)--N(R')--, group
--C(.dbd.S)--C(.dbd.S)--N(R')-- (in which R' represents a hydrogen
atom, hydroxyl group, alkyl group or alkoxy group), group
--C(.dbd.O)-A.sup.1-N(R'')-- (in which A.sup.1 represents an
alkylene group having 1 to 5 carbon atoms, which may be
substituted, and R'' represents a hydrogen atom, hydroxyl group,
alkyl group or alkoxy group), group --C(.dbd.O)--NH--, group
--C(.dbd.S)--NH--, group --C(.dbd.O)--NH--NH--, group
--C(.dbd.O)-A.sup.2-C(.dbd.O)-- (in which A.sup.2 represents a
single bond or alkylene group having 1 to 5 carbon atoms), group
--C(.dbd.O)-A.sup.3-C(.dbd.O)--NH-- (in which A.sup.3 represents an
alkylene group having 1 to 5 carbon atoms), group
--C(.dbd.O)--C(.dbd.NOR.sup.a)--N(R.sup.b)--, group
--C(.dbd.S)--C(.dbd.NOR.sup.a)--N(R.sup.b)-- (in which R.sup.a
represents a hydrogen atom, alkyl group or alkanoyl group, and
R.sup.b represents a hydrogen atom, hydroxyl group, alkyl group or
alkoxy group), group --C(.dbd.O)--N.dbd.N--, group
--C(.dbd.S)--N.dbd.N--, group
--C(.dbd.NOR.sup.c)--C(.dbd.O)--N(R.sup.d)-- (in which R.sup.c
represents a hydrogen atom, alkyl group, alkanoyl group, aryl group
or aralkyl group, and R.sup.d represents a hydrogen atom, hydroxyl
group, alkyl group or alkoxy group), group
--C(.dbd.N--N(R.sup.e)(R.sup.f))--C(.dbd.O)--N(R.sup.g)-- (in which
R.sup.e and R.sup.f each independently represent a hydrogen atom,
alkyl group, alkanoyl group or alkyl(thiocarbonyl) group, and
R.sup.g represents a hydrogen atom, hydroxyl group, alkyl group or
alkoxy group), group --C(.dbd.O)--NH--C(.dbd.O)--, group
--C(.dbd.S)--NH--C(.dbd.O)--, group --C(.dbd.O)--NH--C(.dbd.S)--,
group --C(.dbd.S)--NHC(.dbd.S)--, group
--C(.dbd.O)--NH--SO.sub.2--, group --SO.sub.2--NH--, group
--C(.dbd.NCN)--NH--C(.dbd.O)--, group --C(.dbd.S)--C(.dbd.O)--, or
thiocarbonyl group.
[0091] In the above group, the alkylene group having 1 to 5 carbon
atoms in A.sup.1, A.sup.2 and A.sup.3 represents a linear, branched
or cyclic alkylene group having 1 to 5 carbon atoms, and examples
thereof include methylene, ethylene, propylene, cyclopropylene,
1,3-cyclopentylene groups and the like. The alkyl group in R', R'',
R.sup.a, R.sup.b, R.sup.c, R.sup.d, R.sup.e, R.sup.f and R.sup.g
represents a linear, branched or cyclic alkyl group having 1 to 6
carbon atoms, and examples thereof include methyl, ethyl groups and
the like. The alkoxy group means a linear, branched or cyclic
alkoxy group having 1 to 6 carbon atoms, and examples thereof
include methoxy, ethoxy groups and the like.
[0092] In R.sup.a, R.sup.c, R.sup.e and R.sup.f, the alkanoyl group
means a group composed of a linear, branched or cyclic alkyl group
having 1 to 6 carbon atoms and a carbonyl group, and examples
thereof include acetyl, propionyl groups and the like.
[0093] In R.sup.c, the aryl group means an aryl group having 6 to
14 carbon atoms, and examples thereof include phenyl, naphthyl
groups and the like. The aralkyl group means a linear, branched or
cyclic alkyl group having 1 to 6 carbon atoms substituted with the
aryl group having 6 to 14 carbon atoms, and examples thereof
include benzyl, phenethyl groups and the like.
[0094] As T.sup.1, is preferred a carbonyl group, group
--C(.dbd.O)--C(.dbd.O)--N(R')--, group
--C(.dbd.S)--C(.dbd.O)--N(R')--, group
--C(.dbd.O)--C(.dbd.S)--N(R')--, group
--C(.dbd.S)--C(.dbd.S)--N(R')-- and group
--C(.dbd.O)--CH.sub.2--N(R'')--, with a carbonyl group, group
--C(.dbd.O)--C(.dbd.O)--N(R')--, group
--C(.dbd.S)--C(.dbd.O)--N(R')--, group
--C(.dbd.O)--C(.dbd.S)--N(R')-- and group
--C(.dbd.S)--C(.dbd.S)--N(R')-- being particularly preferred.
<On Group R.sup.1 and Group R.sup.2>
[0095] R.sup.1 and R.sup.2 are each independently a hydrogen atom,
hydroxyl group, alkyl group or alkoxy group, preferably a hydrogen
atom or alkyl group, more preferably a hydrogen atom.
[0096] In R.sup.1 and R.sup.2, the alkyl group means a linear,
branched or cyclic alkyl group having 1 to 6 carbon atoms, and
examples thereof include methyl, ethyl groups and the like. The
alkoxy group means a linear, branched or cyclic alkoxy group having
1 to 6 carbon atoms, and examples thereof include methoxy, ethoxy
groups and the like. R.sup.1 and R.sup.2 are preferably each
independently a hydrogen atom or alkyl group, more preferably both
hydrogen atoms.
[0097] When T.sup.1 is a carbonyl or sulfonyl group, and Q.sup.5 in
the group Q.sup.3 is an alkylene group having 1 to 8 carbon atoms
or an alkenylene group having 2 to 8 carbon atoms, Q.sup.4 is
preferably a group (b), (f), (g), (h), (i), (j), (k) and (l) of the
above-described 12 groups, with the proviso that N in the group (f)
indicates that 2 carbon atoms of the ring substituted by R.sup.19
have been substituted by a nitrogen atom.
[0098] When T.sup.1 is a carbonyl or sulfonyl group, and Q.sup.5 in
the group Q.sup.3 is an alkylene group having 1 to 8 carbon atoms
or an alkenylene group having 2 to 8 carbon atoms, the substituent
on the group Q.sup.5 is preferably an N-alkylcarbamoyl or
N,N-dialkylcarbamoyl group.
[0099] When T.sup.1 is a group --C(.dbd.O)--C(.dbd.O)--N(R')--,
group --C(.dbd.S)--C(.dbd.O)--N(R')--, group
--C(.dbd.O)--C(.dbd.S)--N(R')-- or group
--C(.dbd.S)--C(.dbd.S)--N(R')--, and Q.sup.5 in the group Q.sup.3
is an alkylene group having 1 to 8 carbon atoms or an alkenylene
group having 2 to 8 carbon atoms, Q.sup.4 is preferably a group
(i), (j) or (k) of the above-described 12 groups.
[0100] When T.sup.1 is a group --C(.dbd.O)--C(.dbd.O)--N(R')--,
group --C(.dbd.S)--C(.dbd.O)--N(R')--, group
--C(.dbd.O)--C(.dbd.S)--N(R')-- or group
--C(.dbd.S)--C(.dbd.S)--N(R')--, and Q.sup.5 in the group Q.sup.3
is an alkylene group having 1 to 8 carbon atoms or an alkenylene
group having 2 to 8 carbon atoms, the substituent on the group
Q.sup.5 is preferably an N-alkylcarbamoyl or N,N-dialkylcarbamoyl
group.
[0101] A feature of the compounds of the present invention
represented by the general formula (1), the salts thereof, the
solvates thereof, or the N-oxides thereof resides in a combination
of the group T.sup.1 and the group Q.sup.3. The combination is
roughly divided into the following two cases (I) and (II): [0102]
(I) A case where T.sup.1 is a carbonyl, sulfonyl, group
--C(.dbd.O)--NH--C(.dbd.O)--, group --C(.dbd.S)--NH--C(.dbd.O)--,
group --C(.dbd.O)--NH--C(.dbd.S)--, group
--C(.dbd.S)--NHC(.dbd.S)--, group --C(.dbd.O)--NH--SO.sub.2--,
group --SO.sub.2--NH--, group --C(.dbd.NCN)--NH--C(.dbd.O)--, group
--C(.dbd.S)--C(.dbd.O)-- or thiocarbonyl group, and Q.sup.3 is the
following group:
##STR00029##
[0102] wherein Q.sup.5 represents a group
--(CH.sub.2).sub.m--CH.sub.2-A-CH.sub.2--(CH.sub.2).sub.n-- (in
which m and n are each independently 0 or an integer of 1-3, and A
represents an oxygen atom, nitrogen atom, sulfur atom, --SO--,
--SO.sub.2--, --NH--, --O--NH--, --NH--NH--, --S--NH--, --SO--NH--
or --SO.sub.2--NH--); and [0103] (II) a case where T.sup.1 is a
group --C(.dbd.O)--C(.dbd.O)--N(R')--, group
--C(.dbd.S)--C(.dbd.O)--N(R')--, group
--C(.dbd.O)--C(.dbd.S)--N(R')-- or group
--C(.dbd.S)--C(.dbd.S)--N(R')-- (in which R' represents a hydrogen
atom, hydroxyl group, alkyl group or alkoxy group), group
--C(.dbd.O)-A.sup.1-N(R'')-- (in which A.sup.1 represents an
alkylene group having 1 to 5 carbon atoms, which may be
substituted, and R'' represents a hydrogen atom, hydroxyl group,
alkyl group or alkoxy group), group --C(.dbd.O)--NH--, group
--C(.dbd.S)--NH--, group --C(.dbd.O)--NH--NH--, group
--C(.dbd.O)-A.sup.2-C(.dbd.O)-- (in which A.sup.2 represents a
single bond or alkylene group having 1 to 5 carbon atoms), group
--C(.dbd.O)-A.sup.3-C(.dbd.O)--NH-- (in which A.sup.3 represents an
alkylene group having 1 to 5 carbon atoms), group
--C(.dbd.O)--C(.dbd.NOR.sup.a)--N(R.sup.b)--, group
--C(.dbd.S)--C(.dbd.NOR.sup.a)--N(R.sup.b)-- (in which R.sup.a
represents a hydrogen atom, alkyl group or alkanoyl group, and
R.sup.b represents a hydrogen atom, hydroxyl group, alkyl group or
alkoxy group), group --C(.dbd.O)--N.dbd.N--, group
--C(.dbd.S)--N.dbd.N--, group
--C(.dbd.NOR.sup.c)--C(.dbd.O)--N(R.sup.d)-- (in which R.sup.c
represents a hydrogen atom, alkyl group, alkanoyl group, aryl group
or aralkyl group, and R.sup.d represents a hydrogen atom, hydroxy
group, alkyl group or alkoxy group), group
--C(.dbd.N--N(R.sup.e)(R.sup.f))--C(.dbd.O)--N(R.sup.g)-- (in which
R.sup.e and R.sup.f are each independently a hydrogen atom, alkyl
group, alkanoyl group or alkyl(thiocarbonyl)group, and R.sup.g
represents a hydrogen atom, hydroxy group, alkyl group or alkoxy
group), group --C(.dbd.O)--NH--C(.dbd.O)--, group
--C(.dbd.S)--NH--C(.dbd.O)--, group --C(.dbd.O)--NH--C(.dbd.S)--,
group --C(.dbd.S)--NHC(.dbd.S)--, group
--C(.dbd.O)--NH--SO.sub.2--, group --SO.sub.2--NH--, group
--C(.dbd.NCN)--NH--C(.dbd.O)--, group --C(.dbd.S)--C(.dbd.O)--, or
thiocarbonyl group, and Q.sup.3 is the following group:
##STR00030##
[0103] wherein Q.sup.5 represents an alkylene group having 1 to 8
carbon atoms, an alkenylene group having 2 to 8 carbon atoms or a
group --(CH.sub.2).sub.m--CH.sub.2-A-CH.sub.2--(CH.sub.2).sub.n--
(in which m and n are each independently 0 or an integer of 1-3,
and A represents an oxygen atom, nitrogen atom, sulfur atom,
--SO--, --SO.sub.2--, --NH--, --O--NH--, --NH--NH--, --S--NH--,
--SO--NH-- or --SO.sub.2--NH--).
[0104] In the cases (I) and (II), the following (i) and (ii) are
mentioned as preferred examples, respectively. [0105] (i) An
example where the group R.sup.1 and the group R.sup.2 are each
independently a hydrogen atom or alkyl group, the group Q.sup.1 is
a saturated or unsaturated, bicyclic or tricyclic condensed
hydrocarbon group which may be substituted, or a saturated or
unsaturated, bicyclic or tricyclic condensed heterocyclic group
which may be substituted, the group Q.sup.2 is a single bond, the
group Q.sup.5 in the group Q.sup.3 is a group
--(CH.sub.2).sub.m--CH.sub.2-A-CH.sub.2--(CH.sub.2).sub.n-- (in
which m and n are each independently 0 or 1, and A has the same
meaning as defined above), the group Q.sup.4 is selected from 9
groups (a) to (h) and (l) of the above-described 12 groups, the
group T.sup.0 is a carbonyl group or thiocarbonyl group, and the
group T.sup.1 is a carbonyl group or sulfonyl group; and [0106]
(ii) An example where in the generally formula (1), the groups
R.sup.1 and R.sup.2 are each independently a hydrogen atom or alkyl
group, the group Q.sup.1 is a saturated or unsaturated, bicyclic or
tricyclic condensed hydrocarbon group which may be substituted, or
a saturated or unsaturated, bicyclic or tricyclic condensed
heterocyclic group which may be substituted, the group Q.sup.2 is a
single bond, the group Q.sup.5 in the group Q.sup.3 is an alkylene
group having 3 to 6 carbon atoms or a group
--(CH.sub.2).sub.m--CH.sub.2-A-CH.sub.2--(CH.sub.2).sub.n-- (in
which m and n are each independently 0 or 1, and A has the same
meaning as defined above), the group Q.sup.4 is selected from 3
groups (i), (j) and (k) of the above-described 12 groups, the group
T.sup.0 is a carbonyl group or thiocarbonyl group, and the group
T.sup.1 is a group --C(.dbd.O)--C(.dbd.O)--N(R')--, group
--C(.dbd.S)--C(.dbd.O)--N(R')--, group
--C(.dbd.O)--C(.dbd.S)--N(R')-- or group
--C(.dbd.S)--C(.dbd.S)--N(R')--.
[0107] Stereoisomers or optical isomers derived from an asymmetric
carbon atom may be present in the compounds of the present
invention represented by the general formula (1). However, these
stereoisomers, optical isomers and mixtures thereof are all
included in the present invention.
[0108] No particular limitation is imposed on salts of the
compounds of the present invention represented by the general
formula (1) so far as they are pharmaceutically acceptable salts.
However, specific examples thereof include mineral acid salts such
as hydrochlorides, hydrobromides, hydriodides, phosphates, nitrates
and sulfates; benzoates; organic sulfonates such as
methanesulfonates, 2-hydroxyethanesulfonates and
p-toluenesulfonates; and organic carboxylates such as acetates,
propanoates, oxalates, malonates, succinates, glutarates, adipates,
tartrates, maleates, malates and mandelates. In the case where the
compounds represented by the general formula (1) have an acidic
group, they may be salts of alkali metal ions or alkaline earth
metal ions. No particular limitation is imposed on the solvates
thereof so far as they are pharmaceutically acceptable solvates. As
specific examples thereof, however, may be mentioned hydrates and
solvates with ethanol. When a nitrogen atom is present in the
general formula (1), such a compound may be converted to an N-oxide
thereof.
[0109] As the compounds according to the present invention, are
preferred the compounds described in the following Examples and
salts thereof as well as the following compounds and salts thereof.
[0110] 1)
3-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl)]-2-{[(5-methyl-4,5,6,7-
-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)[1,6]naph-
thyridine-7-carboxamide; [0111] 2)
7-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7--
tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-4-fluoroc-
innoline-3-carboxamide; [0112] 3)
7-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7--
tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-4a,8a-dih-
ydro-4H-1,2,4-benzoxadiazine-3-carboxamide; [0113] 4)
N-((1S,2R,4S)-4-[(Dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydr-
othiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-6-fluoro-4-oxo-1,4-
-dihydroquinoline-2-carboxamide; [0114] 5)
7-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7--
tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-5-oxo-4,5-
-dihydro-1H-1,3,4-benzotriazepine-2-carboxamide; [0115] 6)
6-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[5-methyl-4,5,6,7-t-
etrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-4-oxo-3,4--
dihydro-2(1H)-cinnolinecarboxamide; [0116] 7)
6-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7--
tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-1,2,3,4-t-
etrahydroquinoline-2-carboxamide; [0117] 8)
N-{(1R,2S,5S)-2-{[3-(3-chlorophenyl)-2-propinoyl]amino}-5-[(dimethylamino-
)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2--
carboxamide; [0118] 9)
N-{(1R,2S,5S)-2-[(4-chlorobenzoyl)amino]-5-[(dimethylamino)carbonyl]cyclo-
hexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-carboxamide;
[0119] 10)
N-{(1R,2S,5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)c-
arbonyl]cyclohexyl}-6-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin-2-
-carboxamide; [0120] 11)
5-Chloro-N-[(1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-({[5-(3-pyrrolidinyl-
oxy)thiazol-2-yl]carbonyl}amino)-cyclohexyl]indole-2-carboxamide;
[0121] 12)
N.sup.1-(4-Chlorophenyl)-N.sup.2-((1S,2R)-2-{[(5-methyl-4,5,6,7-tetra-
hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide;
[0122] 13)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R)-2-{[(5-methyl-4,5,6,7-tet-
rahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide-
; [0123] 14)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R)-2-{[(5-methyl-5,6-dihydro-
-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)ethanediamide;
[0124] 15)
N.sup.1-(4-Chlorophenyl)-N.sup.2-((1S,2R)-2-{[(5-methyl-5,6-dihydro-4H-py-
rrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)ethanediamide;
[0125] 16)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1R,2R)-2-{[(5-methyl-5,6-dih-
ydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclopentyl)ethanediamid-
e; [0126] 17)
N.sup.1-(4-Chlorophenyl)-N.sup.2-((1R,2R)-2-{[(5-methyl-5,6-dihydro-4H-py-
rrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclopentyl)ethanediamide;
[0127] 18)
N.sup.1-(4-Chlorophenyl)-N.sup.2-((1R,2R)-2-{[(5-methyl-4,5,6,7-tetra-
hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cycloheptyl)ethanediamide;
[0128] 19)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1R,2R)-2-{[(5-methyl-4,5,6,7-tet-
rahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cycloheptyl)ethanediamid-
e; [0129] 20)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1R,2R)-2-{[(5-methyl-5,6-dihydro-
-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cycloheptyl)ethanediamide;
[0130] 21)
N.sup.1-(4-Chlorophenyl)-N.sup.2-((1R,2R)-2-{[(5-methyl-5,6-dihydro-4H-py-
rrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cycloheptyl)ethanediamide;
[0131] 22)
N.sup.1-(5-Chloro-6-methylpyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimet-
hylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin--
2-yl)carbonyl]amino}cyclohexyl)ethanediamide; [0132] 23)
N.sup.1-(5-Chloro-3-methylpyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethyla-
mino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl-
)carbonyl]amino}cyclohexyl)ethanediamide; [0133] 24)
N.sup.1-(5-Chloro-4-methylpyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethyla-
mino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl-
)carbonyl]amino}cyclohexyl)ethanediamide; [0134] 25)
N.sup.1-(4-Chloro-3-hydroxyphenyl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)-
carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carb-
onyl]amino}cyclohexyl)ethanediamide; [0135] 26)
N.sup.1-(4-Chloro-2-hydroxyphenyl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)-
carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carb-
onyl]amino}cyclohexyl)ethanediamide; [0136] 27)
N.sup.1-[4-Chloro-2-(fluoromethyl)phenyl]-N.sup.2-((1S,2R,4S)-4-[(dimethy-
lamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2--
yl)carbonyl]amino}cyclohexyl)ethanediamide; [0137] 28)
N.sup.1-[4-Chloro-2-(methoxymethyl)phenyl]-N.sup.2-((1S,2R,4S)-4-[(dimeth-
ylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-
-yl)carbonyl]amino}cyclohexyl)ethanediamide; [0138] 29)
N-{(1R,2S,5S)-2-({[1-(4-Chloroanilino)cyclopropyl]carbonyl}amino)-5-[(dim-
ethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-
pyridin-2-carboxamide; [0139] 30)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1R,2R,4R)-4-(hydroxymethyl)-2-{[-
(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyc-
lopentyl)ethanediamide; [0140] 31)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1R,2R,4S)-4-(hydroxymethyl)-2-{[-
(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyc-
lopentyl)ethanediamide; [0141] 32)
N.sup.1-((3R,4S)-1-Acetyl-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-
pyridin-2-yl)carbonyl]amino}piperidin-4-yl)-N.sup.2-(5-chloropyridin-2-yl)-
ethanediamide; [0142] 33)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((3R,4S)-1-(methylsulfonyl)-3-{[(5-
-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piper-
idin-4-yl)ethanediamide; [0143] 34)
N.sup.1-{(1S,2R,4S)-2-{[(3-Chlorobenzothiophen-2-yl)carbonyl]amino}-4-[(d-
imethylamino)carbonyl]cyclohexyl}-N.sup.2-(5-chloropyridin-2-yl)ethanediam-
ide; [0144] 35)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carb-
othioyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbo-
nyl]amino}cyclohexyl)ethanediamide; [0145] 36)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carb-
onyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbothi-
oyl]amino}cyclohexyl)ethanediamide; [0146] 37)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((3R,4S)-1-(2-methoxyethanethioyl)-
-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amin-
o}piperidin-4-yl)ethanediamide; [0147] 38)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((3R,4S)-1-(2-methoxyacetyl)-3-{[(-
5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbothioyl]amino}p-
iperidin-4-yl)ethanediamide; [0148] 39)
N-[(3R,4S)-4-({2-[(5-Chloropyridin-2-yl)amino]-2-oxoethanethioyl}amino)-1-
-(2-methoxyacetyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4--
c]pyridine-2-carboxamide; [0149] 40)
N-[(3R,4S)-4-({2-[(5-Chloropyridin-2-yl)amino]-2-thioxoacetyl}amino)-1-(2-
-methoxyacetyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]p-
yridine-2-carboxamide; [0150] 41)
N.sup.1-(4-Chlorophenyl)-N.sup.2-((3R,4S)-1-(2-methoxyethanethioyl)-3-{[(-
5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pipe-
ridin-4-yl)ethanediamide; [0151] 42)
N.sup.1-(4-Chlorophenyl)-N.sup.2-((3R,4S)-1-(2-methoxyacetyl)-3-{[(5-meth-
yl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbothioyl]amino}piperid-
in-4-yl)ethanediamide; [0152] 43)
N-[(3R,4S)-4-{[2-[(4-Chloroanilino)-2-oxoethanethioyl]amino}-1-(2-methoxy-
acetyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine--
2-carboxamide; [0153] 44)
N-[(3R,4S)-4-({2-[(4-Chlorophenyl)amino]-2-thioxoacetyl}amino)-1-(2-metho-
xyacetyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-
e-2-carboxamide; [0154] 45)
N.sup.1-((1S,2R,4S)-4-(1-azetidinylcarbonyl)-2-{[(5-methyl-4,5,6,7-tetrah-
ydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N.sup.2-(5-chlo-
ropyridin-2-yl)ethanediamide; [0155] 46)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-[(1S,2R,4S)-2-{[(5-methyl-4,5,6,7--
tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(1-pyrrolidinylcar-
bonyl)cyclohexyl]ethanediamide; [0156] 47)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-[(1S,2R,4S)-2-{[(5-methyl-4,5,6,7--
tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino)-4-(1-piperidinylcarb-
onyl)cyclohexyl]ethanediamide; [0157] 48)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-[(1S,2R,4S)-2-{[(5-methyl-4,5,6,7--
tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(4-morpholinylcarb-
onyl)cyclohexyl]ethanediamide; [0158] 49)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(methylamino)carbon-
yl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]a-
mino}cyclohexyl)ethanediamide; [0159] 50)
N.sup.1-{(1R,2S,5S)-2-({2-[(6-Chloropyridazin-3-yl)amino]-2-oxoethanethio-
yl}amino)-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahyd-
rothiazolo[5,4-c]pyridine-2-carboxamide; [0160] 51)
N.sup.1-(4-Bromophenyl)-N.sup.2-((3R,4S)-1-(2-methoxyacetyl)-3-{[(5-methy-
l-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-
-yl)ethanediamide; [0161] 52)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((3R,4S)-1-(2-methoxyacetyl)-3-{[4-
-(pyridin-4-yl)benzoyl]amino}piperidin-4-yl)ethanediamide; [0162]
53)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-[(3R,4S)-1-(2-methoxyacetyl)-3-({[-
2-(pyridin-4-yl)pyrimidin-5-yl]carbonyl}amino)piperidin-4-yl]ethanediamide-
; [0163] 54)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-[(1S,2R,4S)-4-[(dimethylamino)carb-
onyl]-2-({[2-(pyridin-4-yl)pyrimidin-5-yl]carbonyl}amino)cyclohexyl]ethane-
diamide; [0164] 55)
N-{(1R,2S,5S)-2-{[2-(4-Chloroanilino)-2-oxoethane(methoxy)imidoyl]amino}--
5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo-
[5,4-c]pyridine-2-carboxamide; [0165] 56)
N-{(1R,2S,5S)-2-{[2-(4-Chloroanilino)-2-(methoxyimino)acetyl]amino}-5-[(d-
imethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4--
c]pyridine-2-carboxamide; [0166] 57)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carb-
onyl]-2-{[(4,4,5-trimethyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbo-
nyl]amino}cyclohexyl)ethanediamide; [0167] 58)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carb-
onyl]-2-{[(4,4-ethylene-5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl-
)carbonyl]amino}cyclohexyl)ethanediamide; [0168] 59)
N-{(1R,2S,5S)-2-({[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl}amino)-5-[(dime-
thylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]p-
yridine-2-carboxamide; [0169] 60)
N-{(1R,2S,5S)-2-{[(4-Chlorobenzyl)sulfonyl]amino}-5-[(dimethylamino)carbo-
nyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbo-
xamide; [0170] 61)
N-{(1R,2S,5S)-2-[(2-{[(4-Chlorophenyl)sulfonyl]amino}acetyl)amino]-5-[(di-
methylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c-
]pyridine-2-carboxamide; [0171] 62)
N-{(1R,2S,5S)-2-({2-[(5-Chloropymiridin-2-yl)amino]-2-oxoethanethioyl}ami-
no)-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothia-
zolo[5,4-c]pyridine-2-carboxamide; [0172] 63)
N-{(1R,2S,5S)-2-({2-[(5-Chloropyrazin-2-yl)amino]-2-oxoethanethioyl}amino-
)-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazo-
lo[5,4-c]pyridine-2-carboxamide; [0173] 64)
N-[(1R,2S,5S)-5-[(Dimethylamino)carbonyl]-2-({2-[(5-fluoro-2-thienyl)amin-
o]-2-oxoethanethioyl}amino)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo-
[5,4-c]pyridine-2-carboxamide; [0174] 65)
N-{(1R,2S,5S)-2-{[2-(3-Amino-4-chloroanilino)-2-oxoethanethioyl]amino}-5--
[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5-
,4-c]pyridine-2-carboxamide; [0175] 66)
N.sup.1-(4-Chlorothiazol-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carb-
onyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl-
]amino}cyclohexyl)ethanediamide; [0176] 67)
N.sup.1-((1S,2R,4S)-4-[(Dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tet-
rahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N.sup.2-(3-f-
luorophenyl)ethanediamide; [0177] 68)
N.sup.1-((1S,2R,4S)-4-[(Dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tet-
rahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N.sup.2-phen-
ylethanediamide; [0178] 69)
N.sup.1-((1S,2R,4S)-4-[(Dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tet-
rahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N.sup.2-(pyr-
idin-2-yl)ethanediamide; [0179] 70)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carb-
onyl]-2-{[(5,6,6-trimethyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbo-
nyl]amino}cyclohexyl)ethanediamide; [0180] 71)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carb-
onyl]-2-{[(4,4,5,6,6-pentamethyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl-
)carbonyl]amino}cyclohexyl)ethanediamide; [0181] 72)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carb-
onyl]-2-{[(2-methyl-2,3-dihydrothiazolo[5,4-d]isooxazol-5-yl)carbonyl]amin-
o}cyclohexyl)ethanediamide; [0182] 73)
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carb-
onyl]-2-{[(2-methyl-2,3-dihydrothiazolo[4,5-d]isooxazol-5-yl)carbonyl]amin-
o}cyclohexyl)ethanediamide; [0183] 74)
N.sup.1-(5-Chloro-2-furyl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carbonyl-
]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]ami-
no}cyclohexyl)ethanediamide; [0184] 75)
N.sup.1-(5-Chloroxazol-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carbon-
yl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]a-
mino}cyclohexyl)ethanediamide; [0185] 76)
N.sup.1-(5-Chloro-1H-imidazol-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino-
)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)car-
bonyl]amino}cyclohexyl)ethanediamide; [0186] 77)
N-{(1R,2S,5S)-2-{[2-(4-Chloroanilino)-1-ethoxyimino-2-oxoethyl]amino}-5-[-
(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,-
4-c]pyridine-2-carboxamide; [0187] 78)
N-{(1R,2S,5S)-2-{[2-(4-Chloroanilino)-1-phenoxyimino-2-oxoethyl]amino}-5--
[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5-
,4-c]pyridine-2-carboxamide; [0188] 79)
N-{(1R,2S,5S)-2-{[1-Benzyloxyimino-2-(4-chloroanilino)-2-oxoethyl]amino}--
5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo-
[5,4-c]pyridine-2-carboxamide; [0189] 80)
N-{(1R,2S,5S)-2-({2-(4-Chloroanilino)-1-hydrazono-2-oxoethyl}amino)-5-[(d-
imethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4--
c]pyridine-2-carboxamide; [0190] 81)
N-{(1R,2S,5S)-2-({2-(4-Chloroanilino)-1-(2-methylhydrazono)-2-oxoethyl}am-
ino)-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothi-
azolo[5,4-c]pyridine-2-carboxamide; [0191] 82)
N-{(1R,2S,5S)-2-({2-[(5-Chloropyridin-2-yl)amino]-1-(2,2-dimethylhydrazon-
o)-2-oxoethyl}amino)-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6-
,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide;
[0192] 83)
N-{(1R,2S,5S)-2-{[2-(4-Chloroanilino)-1-methylimino-2-oxoethyl]amino}-5-[-
(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,-
4-c]pyridine-2-carboxamide; [0193] 84)
N-{(1R,2S,5S)-2-{[1-(2-Acetylhydrazono)-2-(4-chloroanilino)-2-oxoethyl]am-
ino}-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothi-
azolo[5,4-c]pyridine-2-carboxamide; [0194] 85)
N-{(1R,2S,5S)-2-({2-(4-Chloroanilino)-1-[(2-ethanethioylhydrazono)-2-oxoe-
thyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl)-5-methyl-4,5,6,7-tetrah-
ydrothiazolo[5,4-c]pyridine-2-carboxamide; and [0195] 86)
N-{(1R,2S,5S)-2-{[(E)-3-(5-Chloropyridin-2-yl)-2-propenoyl]amino}-5-[(dim-
ethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-
pyridine-2-carboxamide.
[0196] The preparation process of the diamine derivatives (1)
according to the present invention will hereinafter be
described.
[Preparation Process 1]
[0197] A compound represented by the general formula (1), a salt
thereof, a solvate thereof, or an N-oxide thereof can be prepared
in accordance with, for example, the following process:
##STR00031##
wherein Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1 and R.sup.2
have the same meanings as defined above, and T.sup.1 represents a
carbonyl group.
[0198] A mixed acid anhydride, acid halide, activated ester or the
like, which is derived from carboxylic acid (3), may react with
diamine (2), giving compound (4). The resultant compound (4) may
react with carboxylic acid (5) under the same conditions, giving
compound (1) according to the present invention. In the above
reaction steps, reagents and conditions, which are generally used
in peptide synthesis, may be applied. The mixed acid anhydride can
be prepared by, for example, reaction of a chloroformate such as
ethyl chloroformate or isobutyl chloroformate with carboxylic acid
(3) in the presence of a base. The acid halide can be prepared by
treating carboxylic acid (3) with an acid halide such as thionyl
chloride or oxalyl chloride. The activated ester includes various
kinds of esters. Such an ester can be prepared by, for example,
reaction of a phenol such as p-nitrophenol, N-hydroxybenzotriazole,
or N-hydroxysuccinimide with carboxylic acid (3) using a condensing
agent such as N,N'-dicyclohexylcarbodiimide or
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The
activated ester can also be prepared by reaction of carboxylic acid
(3) with pentafluorophenyl trifluoroacetate or the like, reaction
of carboxylic acid (3) with
1-benzotriazolyloxytripyrrolidinophosphonium hexafluorophosphite,
reaction of carboxylic acid (3) with diethyl cyanophosphonate
(Shioiri method), reaction of carboxylic acid (3) with
triphenylphosphine and 2,2'-dipyridyl disulfide (Mukaiyama method)
or the like. The thus-obtained mixed acid anhydride, acid halide or
activated ester of carboxylic acid (3) may react with diamine (2)
at -78.degree. C. to 150.degree. C. in the presence of a proper
base in an inert solvent, giving compound (4). Thus-obtained
compound (4) may react with a mixed acid anhydride, acid halide or
activated ester of carboxylic acid (5) under the same conditions,
giving compound (1) according to the present invention. The
reagents and reaction conditions in the reaction of compound (4)
with carboxylic acid (5) are the same as those in the reaction of
diamine (2) with carboxylic acid (3).
[0199] As specific examples of the base used in each of the above
mentioned steps, may be carbonates of alkali metals or alkaline
earth metals, such as sodium carbonate and potassium carbonate,
alkali metal alkoxides such as sodium ethoxide and potassium
butoxide, alkali metal hydroxides such as sodium hydroxide and
potassium hydroxide, and hydrides of alkali metals or alkaline
earth metals, such as sodium hydride and potassium hydride; organic
metal bases exemplified by alkyllithium such as n-butyllithium, and
dialkylaminolithium such as lithium diisopropylamide; organic metal
bases exemplified by bis(silyl)amine, such as lithium
bis(trimethylsilyl)amide; and organic bases such as pyridine,
2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,
N-methylmorpholine, diisopropylethylamine and
diazabicyclo[5.4.0]undec-7-ene (DBU).
[0200] Examples of the inert solvent used in this reaction include
alkyl halide type solvents such as dichloromethane, chloroform and
carbon tetrachloride, etheric solvents such as tetrahydrofuran,
1,2-dimethoxyethane and dioxane, aromatic solvents such as benzene
and toluene, and amide solvents such as N,N-dimethylformamide,
N,N-dimethylacetamide and N-methylpyrrolidin-2-one. In addition to
these solvent, a sulfoxide solvent such as dimethyl sulfoxide or
sulfolane, a ketone solvent such as acetone or methyl ethyl ketone,
or the like may be used in some cases.
[Preparation Process 2]
[0201] Compound (1) according to the present invention can also be
prepared in accordance with the following process:
##STR00032##
wherein Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1 and R.sup.2
have the same meanings as defined above, T.sup.1 represents a
carbonyl group, Boc represents a tert-butoxycarbonyl group, and
Boc-ON represents
2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile.
[0202] As described above, diamine (2) is treated with Boc-ON (6)
to prepare compound (7) in which one of 2 amino groups has been
protected with tert-butoxycarbonyl group. The resultant compound
(7) reacts with carboxylic acid (5) and affords compound (8).
Compound (8) is successively treated with an acid to give compound
(9). Compound (9) then reacts with the carboxylic acid (3), giving
compound (1) according to the present invention. Compound (7) can
be prepared by a reaction at -10.degree. C. to 40.degree. C. in the
presence of triethylamine in a solvent such as dichloromethane.
Reaction of compound (7) with the mixed acid anhydride, acid halide
or activated ester of the carboxylic acid (5) is carried out using
the same reagents and reaction conditions as those described in
Preparation Process 1, whereby compound (8) can be prepared. The
resultant compound (8) is treated with trifluoroacetic acid or the
like at -20.degree. C. to 70.degree. C., whereby amine (9) can be
prepared. In the reaction of the resultant amine (9) with
carboxylic acid (3), the same reagents and conditions as those
described in Preparation Process 1 may be used.
[0203] By the way, the tert-butoxycarbonyl group of compound (7)
may be replaced by other amino-protecting groups. In this case,
reagent (6) is also changed to other reagents, and reaction
conditions and the like according to the reagents must be used. As
examples of other protecting groups for amino groups, may be
mentioned alkanoyl groups such as an acetyl group, alkoxycarbonyl
groups such as methoxycarbonyl and ethoxycarbonyl groups,
arylmethoxycarbonyl groups such as benzyloxycarbonyl,
p-methoxybenzyloxycarbonyl and p- or o-nitrobenzyloxycarbonyl
groups, arylmethyl groups such as benzyl and triphenylmethyl
groups, aroyl groups such as a benzoyl group, and arylsulfonyl
groups such as 2,4-dinitrobenzenesulfonyl and
o-nitrobenzenesulfonyl groups. These protecting groups may be
chosen for use according to the nature and the like of the compound
of which amino group is to be protected. Upon leaving such a
protecting group, reagents and conditions may be employed according
to the protecting group.
[Preparation Process 3]
[0204] Compound (1) according to the present invention can be
prepared by reacting diamine (2) with sulfonyl halide (10) and then
condensing the reaction product with carboxylic acid (5).
##STR00033##
wherein Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1 and R.sup.2
have the same meanings as defined above, T.sup.1 represents a
sulfonyl group, and X represents a halogen atom.
[0205] Diamine (2) reacts with sulfonyl halide (10) at -10.degree.
C. to 30.degree. C. in the presence of a base such as triethylamine
in an inert solvent, giving compound (4). The inert solvent and
base may be suitably chosen for use from those described in
Preparation Process 1. The resultant compound (4) is condensed with
carboxylic acid (5) using the reagents and conditions described in
Preparation Process 1, whereby compound (1) according to the
present invention can be prepared. Sulfonyl halide (10) may be
synthesized in the presence of a proper base in accordance with the
publicly known process (WO96/10022, WO00/09480) or a process
according to it.
[Preparation Process 4]
[0206] Compound (1) according to the present invention can also be
prepared in accordance with the following process:
##STR00034##
wherein Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2 and X
have the same meanings as defined above, and T.sup.1 represents a
sulfonyl group.
[0207] More specifically, amine (9) may react with sulfonyl halide
(10) at -10.degree. C. to 30.degree. C. in the presence of a base
in an inert solvent, giving compound (1). The inert solvent and
base may be suitably chosen for use from those described in
Preparation Process 1.
[Preparation Process 5]
[0208] In the compounds (1) according to the present invention,
geometrical isomers of trans-form and cis-form in the relation
between position 1 and position 2 are present when Q.sup.3 is the
following group:
##STR00035##
wherein R.sup.3, R.sup.4 and Q.sup.5 have the same meanings as
defined above, and numerals 1 and 2 indicate positions. The
preparation processes of such compounds (1) having the trans-form
and the cis-form will hereinafter be described.
<Preparation Process of Trans-Form>
##STR00036##
[0209] wherein Q.sup.5, R.sup.3 and R.sup.4 have the same meanings
as defined above.
[0210] As an example of preparation of trans-diol (12a) from cyclic
alkene (11), conversion from, for example, cyclohexene to
trans-cyclohexanediol (Organic Synthesis, 1955, Vol. III, p. 217)
is known. As an example of preparation of trans-diamine (2a) from
trans-diol (12a), conversion from trans-cyclopentanediol to
trans-cyclopentanediamine (WO98/30574) is reported. Trans-diamine
(2a) can be prepared from the cyclic alkene (11) according to these
reports.
[0211] Trans-diamine (2a) prepared in accordance with the
above-described process can be converted into trans-compound (1) by
any of the above-described Preparation Processes 1 to 4.
<Preparation Process of Cis-Form>
##STR00037##
[0212] wherein Q.sup.5, R.sup.3 and R.sup.4 have the same meanings
as defined above.
[0213] As an example of preparation of cis-diol (12b) from cyclic
alkene (11), conversion from cyclohexene to cis-cyclohexanediol (J.
Org. Chem., 1998, Vol. 63, p. 6094) and the like is known. As an
example of preparation of cis-diamine (2b) from cis-diol (12b),
conversion from cis-cyclopentanediol to cis-cyclopentanediamine
(WO98/30574) and the like is reported. Cis-diamine (2b) can be
prepared from cyclic alkene (11) according to these reports.
[0214] Cis-diamine (2b) prepared in accordance with the
above-described process can be converted into the cis-compound (1)
by any of the above-described Preparation Processes 1 to 4.
[Preparation Process 6]
[0215] As described above, either cis-form or trans-form generated
in Q.sup.3 may be present in the compounds (1) according to the
present invention, and so geometrical isomers are present. Further,
optical isomers may be present in the respective geometrical
isomers. The preparation process of an optically active substance
will hereinafter be described.
##STR00038##
wherein Q.sup.5, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the
same meanings as defined above, and R.sup.50 represents a
protecting group for amino group.
[0216] With respect to the preparation process of optically active
aminoalcohol derivative (15) of 1,2-trans-form, for example, the
preparation process of optically active
1,2-trans-2-aminocyclopentanol from cyclopentene oxide or the
preparation process of optically active
1,2-trans-2-aminocyclohexanol from cyclohexene oxide is known
(Tetrahedron: Asymmetry, 1996, Vol. 7, p. 843; J. Org. Chem., 1985,
Vol. 50, p. 4154; J. Med. Chem., 1998, Vol. 41, p. 38). When the
amino group of optically active aminoalcohol derivative (15)
prepared by such an already known process or by applying such a
process reacts with a proper protecting reagent, compound (16) can
be produced. As a protecting group corresponding to R.sup.50 in
compound (16), is preferred, among the ordinary acyl type
protecting groups, an alkoxycarbonyl group such as methoxycarbonyl,
ethoxycarbonyl, tert-butoxycarbonyl group and the like, an
arylmethoxycarbonyl group such as benzyloxycarbonyl,
p-methoxybenzyloxycarbonyl, p- or o-nitrobenzyloxycarbonyl group
and the like, or an arylsulfonyl group such as
2,4-dinitrobenzenesulfonyl, o-nitrobenzenesulfonyl group and the
like. When the amino group is protected with, for example, a
tert-butoxycarbonyl group, aminoalcohol derivative (15) may react
with di-tert-butyl dicarbonate at -78.degree. C. to 50.degree. C.
in an inert solvent, giving compound (16). The inert solvent may be
suitably chosen for use from those described in Preparation Process
1.
[0217] Compound (16) may react with methanesulfonyl chloride at
-78.degree. C. to 50.degree. C. in the presence of a base in an
inert solvent, giving compound (17). The inert solvent may be
suitably chosen for use from those described in Preparation Process
1. As the base, is preferred an organic base such as pyridine,
2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,
N-methylmorpholine, diisopropylethylamine and
diazabicyclo[5.4.0]undec-7-ene (DBU) and the like.
[0218] Compound (17) may react with sodium azide at -10.degree. C.
to 150.degree. C. in a proper solvent, giving compound (18). As the
solvent, an amide solvent such as N,N-dimethylformamide,
N,N-dimethylacetamide or N-methylpyrrolidin-2-one, an alcoholic
solvent such as methanol or ethanol, an etheric solvent such as
tetrahydrofuran, 1,2-dimethoxyethane or dioxane, benzenoid solvent
such as toluene, a carbon halogenide such as dichloromethane,
chloroform or carbon tetrachloride, acetone, dimethyl sulfoxide, or
a mixed solvent of such a solvent with water is suitable.
[0219] As a process for converting azide derivative (18) into
compound (7a), there are many processes such as a process of
conducting hydrogenation with a palladium catalyst, Raney nickel
catalyst or platinum catalyst, a reaction using a reducing agent
such as lithium aluminum hydride, sodium borohydride or zinc
borohydride, a reaction using zinc in the presence of nickel
chloride or cobalt chloride, a reaction using triphenylphosphine
and the like. Suitable reaction conditions may be selected
according to the nature of the compound. For example, azide
derivative (18) is hydrogenated at a temperature of -10.degree. C.
to 70.degree. C. using 1 to 20% palladium carbon as a catalyst in a
proper solvent, whereby compound (7a) can be prepared. The hydrogen
pressure may be raised higher than atmospheric pressure. As the
solvent, an alcoholic solvent such as methanol or ethanol, an
etheric solvent such as tetrahydrofuran, 1,2-dimethoxyethane or
dioxane, an amide solvent such as N,N-dimethylformamide,
N,N-dimethylacetamide or N-methylpyrrolidin-2-one, an ester solvent
such as ethyl acetate, acetic acid, hydrochloric acid, water, a
mixed solvent thereof and the like is suitable.
[0220] Optically active amine (7a) prepared in accordance with the
above-described process can be converted to optically active
compound (1) in accordance with the above-described Preparation
Process 2. Antipode (1) of optically active substance (1) obtained
from optically active amine (7a) may also be prepared in accordance
with a similar process.
[0221] Optically active compound (1) may be prepared by separating
racemic compound (1) through a column composed of an optically
active carrier. It is also possible to separate intermediate (2),
(4), (7), (8) or (9) for preparing racemic compound (1) through a
column composed of an optically active carrier to isolate optically
active intermediate (2), (4), (7), (8) or (9), and then prepare
optically active compound (1) in accordance with any of Preparation
Processes 1 to 4. As a process for isolating optically active
compound (1), optically active intermediate (2), (4), (7), (8) or
(9), a process of fractionally crystallizing a salt with an
optically active carboxylic acid, or a process of fractionally
crystallizing a salt with an optically active base on the contrary
may be used.
[Preparation Process 7]
[0222] Among the compounds (1) according to the present invention,
a preparation process of compound (1c) containing heteroatom(s) in
the group Q.sup.3 will hereinafter be described in detail.
[0223] A compound represented by the general formula (1c), a salt
thereof, a solvate thereof, or an N-oxide thereof can be prepared
in accordance with, for example, the following process:
##STR00039##
wherein Q.sup.1, Q.sup.2, Q.sup.4, R.sup.3, R.sup.4, A, m and n
have the same meanings as defined above, and T.sup.1 represents a
carbonyl group.
[0224] A mixed acid anhydride, acid halide, activated ester or the
like, which is derived from carboxylic acid (3), may react with
compound (2c), giving compound (4c). The resultant compound (4c)
may react with carboxylic acid (5) under the same conditions,
giving compound (1c) according to the present invention.
[0225] In the above reaction steps, reagents and conditions, which
are generally used in peptide synthesis, may be applied. The mixed
acid anhydride can be prepared by, for example, reaction of a
chloroformate such as ethyl chloroformate or isobutyl chloroformate
with carboxylic acid (3) in the presence of a base. The acid halide
can be prepared by treating carboxylic acid (3) with an acid halide
such as thionyl chloride or oxalyl chloride. The activated ester
includes various kinds of esters. Such an ester can be prepared by,
for example, reaction of a phenol such as p-nitrophenol,
N-hydroxybenzotriazole, or N-hydroxysuccinimide with carboxylic
acid (3) using a condensing agent such as
N,N'-dicyclohexylcarbodiimide (DCC) or
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The
activated ester can also be prepared by reaction of carboxylic acid
(3) with pentafluorophenyl trifluoroacetate or the like, reaction
of carboxylic acid (3) with
1-benzotriazolyloxytripyrrolidinophosphonium hexafluorophosphite,
reaction of carboxylic acid (3) with diethyl cyanophosphonate
(Shioiri method), reaction of carboxylic acid (3) with
triphenylphosphine and 2,2'-dipyridyl disulfide (Mukaiyama method)
or the like. The thus-obtained mixed acid anhydride, acid halide or
activated ester of carboxylic acid (3) may react with diamine (2c)
at a temperature under cooling to a temperature under heating in
the presence of a proper base in an inert solvent, giving compound
(4c). Thus-obtained compound (4c) may react with a mixed acid
anhydride, acid halide or activated ester of carboxylic acid (5)
under the same conditions, giving compound (1c) according to the
present invention. The reagents and reaction conditions in the
reaction of compound (4c) with carboxylic acid (5) are the same as
those in the reaction of diamine (2c) with carboxylic acid (3).
[0226] As specific examples of the base used in each step, may be
mentioned carbonates of alkali metals or alkaline earth metals,
such as sodium carbonate and potassium carbonate, alkali metal
alkoxides such as sodium ethoxide and potassium butoxide, alkali
metal hydroxides such as sodium hydroxide and potassium hydroxide,
and hydrides of alkali metals, such as sodium hydride and potassium
hydride; organic metal bases exemplified by alkyllithium such as
n-butyllithium, and dialkylaminolithium such as lithium
diisopropylamide; organic metal bases exemplified by
bis(silyl)amine, such as lithium-bis(trimethylsilyl)amide; and
organic bases such as pyridine, 2,6-lutidine,
4-dimethylaminopyridine, triethylamine, N-methylmorpholine,
diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU).
[0227] Examples of the inert solvent used in this reaction include
alkyl halide type solvents such as dichloromethane and chloroform,
etheric solvents such as tetrahydrofuran and 1,4-dioxane, aromatic
solvents such as benzene and toluene, and amide solvents such as
N,N-dimethylformamide. In addition to these solvent, a sulfoxide
solvent such as dimethyl sulfoxide, a ketone solvent such as
acetone, or the like may be used in some cases.
[0228] In the above-described preparation steps, processes such as
attaching and leaving of a protecting group, and conversion of a
functional group can be suitably applied, thereby preparing
compound (1c) of the present invention.
[0229] As the protecting group for amino group, it is only
necessary to use a protecting group, which is generally used as a
protecting group for amino group in syntheses of organic compounds,
particularly, peptide synthesis. As examples thereof, may be
mentioned alkoxycarbonyl groups such as tert-butoxycarbonyl,
methoxycarbonyl and ethoxycarbonyl groups, arylmethoxycarbonyl
groups such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl and p-
or o-nitrobenzyloxycarbonyl groups, arylmethyl groups such as
benzyl, 4-methoxybenzyl and triphenylmethyl groups, alkanoyl groups
such as formyl and acetyl groups, aroyl groups such as a benzoyl
group, and arylsulfonyl groups such as 2,4-dinitrobenzenesulfonyl
and o-nitrobenzenesulfonyl groups.
[0230] As the protecting group for hydroxyl group, it is only
necessary to use a protecting group for hydroxyl group, which is
generally used in syntheses of organic compounds. As examples
thereof, may be mentioned alkoxymethyl groups such as a
methoxymethyl group, arylmethyl groups such as benzyl,
4-methoxybenzyl and triphenylmethyl groups, alkanoyl groups such as
an acetyl group, aroyl groups such as a benzoyl group, and a
tert-butyldiphenylsilyloxy group. A carboxyl group can be protected
as an ester with an alkyl group such as a methyl, ethyl or
tert-butyl group or an arylmethyl group such as a benzyl group. The
attaching and leaving of the protecting group may be conducted in
accordance with a method known per se in the art.
[0231] Compound (1c) according to the present invention can be
converted into various derivatives by converting its functional
group. For example, a compound in which A is a nitrogen atom having
no substituent can be converted into an amide compound by acylation
using a mixed acid anhydride, acid halide, activated ester or the
like in accordance with ordinary organic chemical methods, a
sulfonamide compound by reaction with a sulfonyl halide, an N-alkyl
compound by reaction with an alkyl halide, an N-aryl compound by
reaction with an aryl halide or a carbamate compound by reaction
with an isocyanate. Incidentally, the compound in which A is a
nitrogen atom having no substituent can be prepared by, for
example, treating compound (1c) prepared from diamine (2c), in
which A has been protected with tert-butoxycarbonyl group, in
accordance with Preparation Process 7 with an acid.
[0232] The compounds according to the present invention thus
prepared can be isolated and purified by publicly known methods,
for example, extraction, precipitation, fractional chromatography,
fractional crystallization, recrystallization, etc. The compounds
according to the present invention can be converted into desired
salts in accordance with ordinary salt-forming reactions.
[0233] Optical isomers derived from an asymmetric carbon atom are
present in the compounds of the present invention. Such an
optically active isomer can be prepared by the process of preparing
from optically active diamine (2c), and besides, a process of
forming an optically active amine or acid and a salt from racemic
compound (1c) and fractionally crystallizing it, a process of
separating it by column chromatography using an optically active
carrier.
[0234] Compound (1c), in which T.sup.1 is a sulfonyl group, can be
prepared by changing carboxylic acid (3) to sulfonyl halide (10) in
the reaction of compound (2c) with carboxylic acid (3).
[Preparation Process 8]
[0235] Compound (1c) according to the present invention can also be
prepared in accordance with the following process:
##STR00040##
wherein Q.sup.1, Q.sup.2, Q.sup.4, R.sup.3, R.sup.4, A, m and n
have the same meanings as defined above, T.sup.1 represents a
carbonyl group, and R.sup.51 and R.sup.61 represent protecting
groups for amino group.
[0236] Compound (21) can be prepared by removing the protecting
group R.sup.61 of compound (19) obtained by protecting the amino
groups of compound (2c). No particular limitation is imposed on the
protecting groups for amino acid illustrated as R.sup.51 and
R.sup.61 so far as they are groups generally used in protection of
the amino group. However, as typical examples thereof, may be
mentioned the protecting groups for amino group described in
Preparation Process 7. In this case, R.sup.51 and R.sup.61 are
required to be protecting groups capable of leaving by different
methods or conditions from each other. As typical examples thereof,
may be mentioned a combination that R.sup.51 is a
tert-butoxycarbonyl group, and R.sup.61 is a benzyloxycarbonyl
group. These protecting groups may be chosen for use according to
the nature and the like of the compound of which amino groups are
to be protected. Upon leaving such a protecting group, reagents and
conditions may be employed according to the protecting group.
[0237] Compound (21) can also be prepared by converting the
hydroxyl group in aminoalcohol derivative (20) into an amino group.
As an example of the preparation of aminoalcohol derivative (20),
is known conversion of methionine into
3-hydroxy-4-aminothiopyrane-1,1-dioxide (Tetrahedron Lett., Vol.
37, p. 7457, 1996).
[0238] As a process for converting the hydroxyl group in
aminoalcohol derivative (20) into an amino group, may be mentioned
a process in which aminoalcohol derivative (20) may react with
methanesulfonyl chloride, p-toluenesulfonyl chloride,
trifluoromethanesulfonic anhydride or the like, the resultant
product may then react with ammonia, a primary arylalkylamine such
as benzylamine, p-methoxybenzylamine or 2,4-dimethoxybenzylamine, a
secondary arylalkylamine such as dibenzylamine, or a hydroxylamine
such as N-benzylhydroxylamine or N,O-dibenzylhydroxylamine, and
benzyl group or the like is then removed as needed, thereby
preparing diamine (21). Aminoalcohol derivative (20) can also be
converted into diamine (21) by reacting it with phthalimide or
succinimide in accordance with the reaction with triphenylphosphine
and ethyl azodicarboxylate (Mukaiyama method) or the like, and then
treating the reaction product with hydrazine or N-methylhydrazine.
When A in the formula is SO.sub.2, and n is 0, diamine (21) can be
prepared by adding ammonia, a primary arylalkylamine such as
benzylamine, p-methoxybenzylamine or 2,4-dimethoxybenzylamine, a
secondary arylalkylamine such as dibenzylamine, or a hydroxylamine
such as N-benzylhydroxylamine or N,O-dibenzylhydroxylamine to an
.alpha.,.beta.-unsaturated cyclic sulfone formed by reacting
aminoalcohol derivative (20) with methanesulfonyl chloride,
p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride or
the like and then treating the reaction product with a proper base
or directly reacting aminoalcohol derivative (20) with
triphenylphosphine and ethyl azodicarboxylate, and removing the
benzyl group or the like as needed.
[0239] The resultant diamine (21) may react with carboxylic acid
(3), giving compound (22). The protecting group R.sup.51 is
successively removed, giving compound (4c). Compound (4c) may react
with carboxylic acid (5), giving compound (1c) according to the
present invention. The reagents and reaction conditions in the
reaction of compound (21) with carboxylic acid (3) and the reaction
of compound (4c) with carboxylic acid (5) may be the same as those
described in Preparation Process 7.
[0240] Similarly, compound (1c) in which T.sup.1 is a sulfonyl
group can be prepared by changing carboxylic acid (3) to sulfonyl
halide (10) in the reaction of compound (21) with carboxylic acid
(3).
[Preparation Process 9]
[0241] A typical preparation process of intermediate (2c) for
preparation described in Preparation Process 7 will be
described.
##STR00041##
wherein R.sup.3, R.sup.4, A, m and n have the same meanings as
defined above.
[0242] As preparation processes of diol derivative (23), are known,
for example, conversion of 1,2,3,6-tetrahydropyridine into
1-benzyloxycarbonyl-3,4-cis-dihydroxypyrrolidine (Japanese Patent
Application Laid-Open (kokai) No. 138264/1995), conversion of
L-tartaric acid into (R,R)-tetrahydrofurandiol or
(R,R)--N-benzylpyrrolidinediol (Tetrahedron: Asymmetry, Vol. 8, p.
1861, 1997). Diol derivative (23) can be prepared by using such an
already known process or applying such a process and removing a
protecting group or converting a functional group as needed.
[0243] Diol derivative (23) may react with methanesulfonyl chloride
at a temperature under cooling to room temperature in the presence
of a base in an inert solvent, giving compound (24). The inert
solvent may be suitably chosen for use from those described in
Preparation Process 7. However, particularly preferred are alkyl
halide type solvents such as dichloromethane and chloroform, and
etheric solvents such as tetrahydrofuran and 1,4-dioxane. As the
base, is preferred an organic base such as pyridine, 2,6-lutidine,
4-dimethylaminopyridine, triethylamine, N-methylmorpholine,
diisopropylethylamine or diazabicyclo[5.4.0]undec-7-ene (DBU).
[0244] Compound (24) may react with sodium azide at a temperature
under cooling to a temperature under heating in a proper solvent,
giving azide derivative (25). As the solvent, an amide solvent such
as N,N-dimethylformamide or N-methylpyrrolidin-2-one, an alcoholic
solvent such as methanol or ethanol, an etheric solvent such as
tetrahydrofuran or 1,4-dioxane, an aromatic solvent such as benzene
or toluene, an alkyl halogenide such as dichloromethane or
chloroform, dimethyl sulfoxide, acetone, or the like is suitable.
Such a solvent may be a mixed solvent with water.
[0245] As a process for converting azide derivative (25) into
compound (2c), there are many processes such as a process of
conducting hydrogenation with a palladium catalyst, Raney nickel
catalyst or platinum catalyst, a reaction using a reducing agent
such as lithium aluminum hydride or sodium borohydride, a reaction
using zinc in the presence of nickel chloride or cobalt chloride,
and a reaction using triphenylphosphine. Suitable reagents and
reaction conditions may be selected according to the nature of the
compound. The hydrogen pressure may be raised higher than
atmospheric pressure. As the solvent, an alcoholic solvent such as
methanol or ethanol, an etheric solvent such as tetrahydrofuran or
1,4-dioxane, an amide solvent such as N,N-dimethylformamide or
N-methylpyrrolidin-2-one, an ester solvent such as ethyl acetate,
acetic acid, hydrochloric acid, water, or a mixed solvent thereof
is suitable. Compound (1c) according to the present invention can
be derived from diamine derivative (2c) prepared in accordance with
the above-described process in accordance with Preparation Process
7.
[0246] When diol derivative (23) is
trans-3,4-dihydroxytetrahydrofuran or trans-1-substituted
3,4-dihydroxypyrrolidine, optically active substances are present.
These optically active diol derivatives (23) can be converted into
optically active diamine derivatives (2c), and further into
optically active compounds (1c) according to the present invention
in accordance with Preparation Process 7.
[Preparation Process 10]
[0247] A typical preparation process of optically active compounds
(30), (31) and (32) included in compound (19) described in
Preparation Process 8 will be described. Incidentally, the position
of an asymmetric carbon atom shown in the following preparation
scheme is indicated as an example.
##STR00042##
wherein m, n, R.sup.3, R.sup.51 and R.sup.61 have the same meanings
as defined above, and R.sup.71 represents a protecting group for
carboxyl group.
[0248] Optically active .alpha.,.beta.-unsaturated ester derivative
(26) can be prepared in accordance with the process described in
literature (J. Org. Chem., Vol. 61, p. 581, 1996; J. Org. Chem.,
Vol. 57, p. 6279, 1992, etc.) or by applying such a process.
Optically active .alpha.,.beta.-unsaturated ester derivative (26)
may react with an amine at a temperature under cooling to a
temperature under heating in a proper solvent, giving diastereomers
(27a) and (27b). The amine may be suitably chosen for use from
those described in Preparation Process 8. The solvent is desirably
an organic solvent unreactive to a substrate, product or reagent,
particularly, an alcoholic solvent such as methanol or ethanol, or
an etheric solvent such as tetrahydrofuran, 1,2-dimethoxyethane or
1,4-dioxane. Diastereomers (27a) and (27b) can also be prepared by
reaction of .alpha.,.beta.-unsaturated ester derivative (26) with
an organometallic base such as lithium
N-benzyl-(trimethylsilyl)amide by applying the process described in
literature (J. Org. Chem., Vol. 63, p. 7263, 1998). The
diastereomers may be separated to use, for example, diastereomer
(27a) in the next reaction.
[0249] Compound (27a) is treated with an acid at a temperature
under cooling to a temperature under heating in a proper solvent,
giving compound (28). Examples of the acid used include
hydrochloric acid, sulfuric acid, Lewis acids such as boron
trifluoride, trifluoroacetic acid and p-toluenesulfonic acid. As
the solvent, is used water or an alcoholic solvent such as methanol
or ethanol. Such a solvent may be a mixed solvent with water. In
this reaction, the protecting group R.sup.61 may be left in some
cases. In such a case, such a compound is required to react with a
proper protecting reagent for amino group as needed.
[0250] Compound (28) may be treated with an acid at a temperature
under cooling to a temperature under heating in a solvent, giving
optically active compound (30). The acid used may be suitably
chosen for use from the acids mentioned above, with a Lewis acid
such as boron trifluoride, or p-toluenesulfonic acid being
particularly preferred. As the solvent used in the reaction, is
used an etheric solvent such as 1,4-dioxane or tetrahydrofuran, or
an aromatic solvent such as benzene or toluene. Compound (30) can
also be prepared from azide derivative (29). As examples of the
preparation of optically active azide derivative (29), are known
conversion of L-aspartic acid into
(R,R)-(3S,4S)-3-amino-4-azide-5-oxotetrahydrofuran (Can. J. Chem.,
Vol. 71, p. 1407, 1993) and the like. Optically active azide
derivative (29) can be prepared by using such an already known
process or applying such a process and removing a protecting group
or converting a functional group as needed. The azide in azide
derivative (29) may be reduced into an amino group, and the
resultant product may react with a proper protecting reagent for
amino group, giving compound (30). The reagents and reaction
conditions used in the reduction of azide (29) may be the same as
those described in the process of converting azide derivative (25)
into compound (2c) in Preparation Process 9.
[0251] The hydroxyl group portion of compound (28) may be converted
into an amino group and then treated with a base, giving compound
(31). The conversion of the hydroxyl group in compound (28) into
the amino group can be performed in accordance with, for example,
Preparation Process 8. Compound (31) can also be prepared by
treating alcohol derivative (28) with an oxidizing agent and then
reductively aminating the resultant aldehyde derivative. Specific
preferable examples of the oxidizing agent used in the above
reaction include pyridinium chlorochromate (PCC), pyridinium
dichromate (PDC) and sulfur trioxide pyridine complexes. Example of
the amine include ammonia, primary alkylamines such as methylamine
and ethylamine, and primary arylalkylamine such as benzylamine,
p-methoxybenzylamine and 2,4-dimethoxybenzylamine. As the reducing
process, there are a process of conducting hydrogenation with a
palladium catalyst, Raney nickel catalyst or platinum catalyst, a
reaction using a reducing agent such as sodium borohydride, sodium
triacetoxyborohydride or sodium cyanoborohydride, and suitable
reagents and reaction conditions may be selected according to the
nature of the compound. The base used in the above process may be
suitably chosen for use from those described in Preparation Process
7. Compound (31) can also be prepared by using compound (30) and an
amine in accordance with the process described in the literature
(Tetrahedron Lett., Vol. 41, p. 1141, 2000; Heterocycles, Vol. 53,
p. 173, 2000) or by applying such a process. Examples of the amine
used include ammonia, primary alkylamines such as methylamine and
ethylamine, primary arylalkylamine such as benzylamine and
p-methoxybenzylamine, and aniline.
[0252] Compound (31) may be treated with a reducing agent at a
temperature under cooling to a temperature under heating in a
solvent, giving compound (32). Examples of the reducing agent
include borane.tetrahydrofuran complexes, borane.methyl sulfide
complexes and lithium aluminum hydride. However, suitable reagents
and reaction conditions may be selected according to the nature of
the compound. The solvent is desirably an organic solvent
unreactive to a substrate, product or reagent, particularly, an
etheric solvent such as tetrahydrofuran or 1,4-dioxane.
[0253] In accordance with the above-described Preparation Process
8, optically active substances (1c) of the compounds according to
the present invention can be derived from the compounds (30), (31)
and (32) prepared by the processes described above.
[0254] In the above-described preparation scheme, one of optically
active substances has been described by way of example. However,
other optically active substances different in conformation from
each other may also be prepared in accordance with similar
preparation schemes by respectively using starting materials
different in conformation from each other.
[Preparation Process 11]
[0255] Compound (1) in which T.sup.1 is a group --CO--CO--N(R')--
(in which R' has the same meaning as defined above) can be prepared
in accordance with the following scheme:
##STR00043##
wherein Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2 and R'
have the same meanings as defined above, and T.sup.1 represents a
group --CO--CO--N(R')-- (in which R' has the same meaning as
defined above).
[0256] An acid halide, activated ester or the like, which is
derived from carboxylic acid (33), may react with diamine (2),
giving compound (4). The resultant compound (4) may react with
carboxylic acid (5) under the same conditions, giving compound (1)
according to the present invention. In the above reaction steps,
reagents and conditions, which are generally used in peptide
synthesis, may be applied. The acid halide can be prepared by
treating carboxylic acid (33) with an acid halide such as thionyl
chloride or oxalyl chloride. The activated ester includes various
kinds of esters. Such an ester can be prepared by, for example,
reaction of a phenol such as p-nitrophenol, N-hydroxybenzotriazole,
or N-hydroxysuccinimide with carboxylic acid (33) using a
condensing agent such as N,N'-dicyclohexylcarbodiimide or
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The
activated ester can also be prepared by reaction of carboxylic acid
(33) with pentafluorophenyl trifluoroacetate or the like, reaction
of carboxylic acid (33) with
1-benzotriazolyloxytripyrrolidinophosphonium hexafluorophosphite,
reaction of carboxylic acid (33) with diethyl cyanophosphonate
(Shioiri method), reaction of carboxylic acid (33) with
triphenylphosphine and 2,2'-dipyridyl disulfide (Mukaiyama method)
or the like. The thus-obtained mixed acid anhydride, acid halide or
activated ester of carboxylic acid (33) may react with diamine (2)
at -78.degree. C. to 150.degree. C. in the presence of a proper
base in an inert solvent, giving compound (4). Thus-obtained
compound (4) may react with a mixed acid anhydride, acid halide or
activated ester of carboxylic acid (5) under the same conditions,
giving compound (1) according to the present invention. The
reagents and reaction conditions in the reaction of compound (4)
with carboxylic acid (5) are the same as those in the reaction of
diamine (2) with carboxylic acid (33). The bases and solvents used
in the above respective steps may be suitably chosen from those
described in Preparation Process 1.
[0257] When compound (1) in which Q.sup.3 is the following
group:
##STR00044##
wherein R.sup.3, R.sup.4 and Q.sup.5 have the same meanings as
defined above, and numerals 1 and 2 indicate positions, and the
relation between position 1 and position 2 is a trans-form or
cis-form is prepared, it is only necessary to use diamine (2a) or
(2b) described in Preparation Process 5.
[0258] When compound (1) in which a heteroatom such as a nitrogen
atom, oxygen atom or sulfur atom is contained in Q.sup.5 is
prepared, it is only necessary to change carboxylic acid (3) to
carboxylic acid (33) in the reaction of compound (2c) with
carboxylic acid (3) as described in Preparation Process 7. Namely,
compound (1) in which a heteroatom is contained in Q.sup.5; i.e.,
compound (1c) can be prepared through the following reaction
scheme.
##STR00045##
wherein Q.sup.1, Q.sup.2, Q.sup.4, R.sup.3, R.sup.4, R', A, m and n
have the same meanings as defined above, and T.sup.1 represents a
group --CO--CO--N(R')-- (in which R' has the same meaning as
defined above).
[Preparation Process 12]
[0259] Compound (1) in which T.sup.1 is a group --CO--CO--N(R')--
(in which R' has the same meaning as defined above) can also be
prepared in accordance with the following scheme:
##STR00046##
wherein Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2 and R'
have the same meanings as defined above, and T.sup.1 represents a
group --CO--CO--N(R')-- (in which R' has the same meaning as
defined above).
[0260] In the reaction of amine (9) with carboxylic acid (33), the
same reagents and conditions as those described in Preparation
Process 1 may be used.
[0261] Amine (9) used herein can also be prepared in accordance
with the following scheme shown as a preparation scheme of amine
(41) in addition to the scheme described in Preparation Process
2.
##STR00047##
wherein R.sup.3, R.sup.4, Q.sup.1, Q.sup.2 and Q.sup.5 have the
same meanings as defined above, and R.sup.52 represents a
protecting group for amino group.
[0262] Compound (34) in the above preparation scheme can be
prepared by treating a cycloalkene with perbenzoic acid or a
derivative thereof in a solvent such as dichloromethane to
epoxidate it. Ordinary conditions for epoxidation of an alkene may
be applied to the conditions of this reaction. Compound (34) can
also be prepared in accordance with the process described in J.
Org. Chem., Vol. 61, pp. 8687-8691 (1996) or a process
corresponding thereto.
[0263] Compound (34) may react with sodium azide in accordance with
a method known per se in the art, giving azide (35). Azide (35) may
be catalytically reduced, and the amino group of the resultant
compound may be protected, giving compound (36). As examples of the
protecting group for amino group in this reaction, may be mentioned
those described in Preparation Process 2. Compound (36) may be
converted into azide (38) in a manner similar to the process
described Preparation Process 5, and the protecting group for the
amino group thereof may be left, giving compound (39). Compound
(39) may react with carboxylic acid (5), giving compound (40). The
compound (40) may then be catalytically reduced, giving compound
(41).
[Preparation Process 13]
[0264] Compound (1) in which T.sup.1 is a group --CO--CO--N(R')--
(in which R' has the same meaning as defined above) can also be
prepared by changing the reaction of compound (9) with carboxylic
acid (3) in the scheme described in Preparation Process 2 to a
reaction of compound (9) with carboxylic acid (33).
##STR00048##
wherein Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2 and R'
have the same meanings as defined above, and T.sup.1 represents a
group --CO--CO--N(R')-- (in which R' has the same meaning as
defined above).
[0265] As the reaction conditions, may be applied those described
in Preparation Process 2.
[0266] When compound (1) in which Q.sup.3 is the following
group:
##STR00049##
wherein R.sup.3, R.sup.4 and Q.sup.5 have the same meanings as
defined above, and numerals 1 and 2 indicate positions, and a
heteroatom such as a nitrogen atom, oxygen atom or sulfur atom is
contained in Q.sup.5 is prepared, it is only necessary to change
carboxylic acid (3) to carboxylic acid (33) in the reaction of
compound (21) with carboxylic acid (3) as described in Preparation
Process 8. Namely, compound (1) in which a heteroatom is contained
in Q.sup.5; i.e., compound (1c) can be prepared through the
following reaction scheme.
##STR00050##
wherein Q.sup.1, Q.sup.2, Q.sup.4, R.sup.3, R.sup.4, R', A, m and n
have the same meanings as defined above, and T.sup.1 represents a
group --CO--CO--N(R')-- (in which R' has the same meaning as
defined above), and R.sup.51 represents a protecting group for
amino group.
[Preparation Process 14]
[0267] Compound (1) in which T.sup.1 is a group
--CO-A.sup.1-N(R'')-- (in which R'' represents a hydrogen atom,
hydroxyl group, alkyl group or alkoxy group, and A.sup.1 represents
an alkylene group having 1 to 5 carbon atoms, which may be
substituted) can be prepared by reaction of compound (9) described
in Preparation Process 2 with Q.sup.4-N(R'')-A.sup.1-CO.sub.2H (42)
at -50 to 50.degree. C. using a condensing agent in an inert
solvent. As examples of the condensing agent, may be mentioned
N,N'-dicyclohexylcarbodiimide and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. As
examples of the inert solvent, may be mentioned alkyl halide type
solvents such as dichloromethane, chloroform and carbon
tetrachloride, etheric solvents such as tetrahydrofuran,
1,2-dimethoxyethane and dioxane, aromatic solvents such as benzene
and toluene, and amide solvents such as N,N-dimethylformamide.
##STR00051##
wherein Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2 and
R'' have the same meanings as defined above, and T.sup.1 represents
a group --CO-A.sup.1-N(R'')-- (in which R'' represents a hydrogen
atom, hydroxyl group, alkyl group or alkoxy group, and A.sup.1
represents an alkylene group having 1 to 5 carbon atoms, which may
be substituted).
[0268] Compound (42) described in the preparation process described
above can be prepared by, for example, reacting an arylamine such
as 4-chloroaniline with an ester of a bromoalkanoic acid at 40 to
120.degree. C. in the presence of a base such as potassium
carbonate in a solvent such as acetonitrile or
N,N-dimethylformamide and then hydrolyzing the ester with an alkali
such as lithium hydroxide, potassium hydroxide or sodium hydroxide.
Compound (42) may be used in reaction in the form of a salt such as
a potassium salt as it is.
[Preparation Process 15]
[0269] Compound (1) in which T.sup.1 is a group --C(.dbd.O)--NH--
or a group --C(.dbd.S)--NH-- can be prepared by reaction of
compound (9) described in Preparation Process 2 with isocyanate
(Q.sup.4-N.dbd.C.dbd.O) or isothiocyanate (Q.sup.4-N.dbd.C.dbd.S)
at -20 to 50.degree. C. in an inert solvent. A typical example of
the inert solvent is described in Preparation Process 14. When an
isocyanate or isothiocyanate to be used is not commercialized, the
isocyanate or isothiocyanate can be prepared through methods
generally used for preparation of isocyanate or isothiocyanate.
##STR00052##
wherein Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1 and R.sup.2
have the same meanings as defined above, and T.sup.1 represents a
group --C(.dbd.O)--NH-- or --C(.dbd.S)--NH--.
[Preparation Process 16]
[0270] Compound (1) in which T.sup.1 is a group --CO--NH--NH-- can
be prepared by reaction of compound (9) described in Preparation
Process 2 with Q.sup.4-NH--NH--CO.sub.2Ph (43) at room temperature
to 150.degree. C. in an inert solvent in the presence of a base if
necessary. As typical examples of the inert solvent, may be
mentioned acetonitrile and N,N-dimethylformamide, and besides those
described in Preparation Process 14. As examples of the base, may
be mentioned pyridine, 2,6-lutidine, collidine,
4-dimethylaminopyridine, triethylamine, N-methylmorpholine,
diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU).
##STR00053##
wherein Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1 and R.sup.2
have the same meanings as defined above, T.sup.1 represents a group
--CO--NH--NH--, and Ph represents a phenyl group.
[0271] Compound (43) described in the preparation process described
above can be prepared by, for example, reacting an arylhydrazine
such as 4-chlorophenylhydrazine with diphenyl carbonate at room
temperature to 120.degree. C. in a solvent such as acetonitrile,
N,N-dimethylformamide, dichloromethane, chloroform,
tetrahydrofuran, 1,2-dimethoxyethane, dioxane, benzene or
toluene.
[Preparation Process 17]
[0272] Compound (1) in which T.sup.1 is a group --CO-A.sup.2-CO--
(in which A.sup.2 represents a single bond or alkylene group having
1 to 5 carbon atoms) can be prepared by reaction of compound (9)
described in Preparation Process 2 with
Q.sup.4-CO-A.sup.2-CO.sub.2H (44) at -50 to 50.degree. C. using a
condensing agent in an inert solvent. As examples of the condensing
agent, may be mentioned N,N'-dicyclohexylcarbodiimide and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. As
examples of the solvent, may be mentioned those described in
Preparation Process 16.
##STR00054##
wherein Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1 and R.sup.2
have the same meanings as defined above, and T.sup.1 represents a
group --CO-A.sup.2-CO-- (in which A.sup.2 represents a single bond
or alkylene group having 1 to 5 carbon atoms).
[0273] When A.sup.2 is a single bond, compound (44) described in
the preparation process described above can be prepared by, for
example, hydrolyzing a compound (for example,
Q.sup.4-CO--CO.sub.2Et) prepared by the Friedel-Crafts reaction of
an aromatic hydrocarbon such as chlorobenzene or an aromatic
heterocyclic compound such as thiophene with a chloroxoacetate (for
example, ClCO--CO.sub.2Et) using an alkali such as lithium
hydroxide, potassium hydroxide or sodium hydroxide.
[0274] When A.sup.2 is a methylene group, compound (44) can be
prepared by, for example, hydrolyzing a ketoester derivative (for
example, Q.sup.4-CO--CH.sub.2--CO.sub.2Et) obtained by reaction of
an arylcarbonyl chloride such as 4-chlorobenzoyl chloride or a
heteroarylcarbonyl chloride such as thiophenecarbonyl chloride with
potassium malonic monoester monocarboxylate in the presence of
magnesium chloride and triethylamine with an alkali such as lithium
hydroxide, potassium hydroxide or sodium hydroxide. The ketoester
derivative may be used in the reaction with compound (9) in the
form of a carboxylic acid obtained by hydrolysis after conversion
of its carbonyl group into ethyleneketal. When A.sup.2 is an
alkylene group having 2 or more carbon atoms, compound (44) can be
prepared by, for example, hydrolyzing a ketoester derivative (for
example, Q.sup.4-CO-A.sup.2-CO.sub.2Et) obtained by the
Friedel-Crafts reaction of an aromatic hydrocarbon such as benzene
or an aromatic heterocyclic compound such as thiophene with an
alkylenedicarboxylic monoester monochloride using an alkali such as
lithium hydroxide, potassium hydroxide or sodium hydroxide.
[Preparation Process 18]
[0275] Compound (1) in which T.sup.1 is a group
--CO-A.sup.3-CO--NH-- (in which A.sup.3 represents an alkylene
group having 1 to 5 carbon atoms) can be prepared by reaction of
compound (9) described in Preparation Process 2 with
Q.sup.4-NH--CO-A.sup.3-CO.sub.2H (45) at -50 to 50.degree. C. using
a condensing agent in an inert solvent. As examples of the
condensing agent, may be mentioned N,N'-dicyclohexylcarbodiimide
and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.
Examples of the inert solvent include alkyl halide type solvents
such as dichloromethane, chloroform, and carbon tetrachloride;
etheric solvents such as tetrahydrofuran, 1,2-dimethoxyethane and
dioxane; aromatic solvents such as benzene and toluene; and amide
solvents such as N,N-dimethylformamide.
##STR00055##
wherein Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1 and R.sup.2
have the same meanings as defined above, and T.sup.1 represents a
group --CO-A.sup.3-CO-- (in which A.sup.3 represents an alkylene
group having 1 to 5 carbon atoms).
[0276] Compound (45) can be prepared by hydrolyzing a compound (for
example, Q.sup.4-NH--CO-A.sup.3-CO.sub.2Et) obtained by reaction of
an arylamine such as 4-chloroaniline or a heteroarylamine such as
aminopyridine corresponding to Q.sup.4-NH.sub.2 with potassium
alkylenedicarboxylic monoester monocarboxylate at -50 to 50.degree.
C. using a condensing agent in an inert solvent with an alkali such
as lithium hydroxide, potassium hydroxide or sodium hydroxide.
[Preparation Process 19]
[0277] Compound (1) in which T.sup.1 is a group --CS--CO--N(R')--
(in which R' has the same meaning as defined above) can be prepared
in accordance with the following scheme:
##STR00056##
wherein Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2 and R'
have the same meanings as defined above, and T.sup.1 represents a
group --CS--CO--N(R')-- (in which R' has the same meaning as
defined above).
[0278] More specifically, sodium thiosulfate (46) and compound (9)
may be dissolved or suspended in a solvent and heated, giving
compound (1) according to the present invention. The reaction
temperature is preferably 80 to 200.degree. C., particularly
preferably about 150.degree. C. As the solvents used in this
reaction, may be mentioned water, alcohols such as methanol and
ethanol, basic solvents such as pyridine and N-methylmorpholine,
alkyl halide type solvents such as dichloromethane and chloroform,
etheric solvents such as tetrahydrofuran, 1,2-dimethoxyethane and
dioxane, and amide solvents such as N,N-dimethylformamide. These
solvents may be suitably mixed for use. As examples of mixed
solvents, may be mentioned a mixed solvent of methanol and
dichloromethane. In this reaction, the solvent is not necessarily
refluxed. For example, when the mixed solvent of methanol and
dichloromethane is used, a reaction solution (or a reaction
mixture) is heated at an external temperature of 150.degree. C. to
distill off the solvent, and the residue is then heated at the same
temperature.
[Preparation Process 20]
[0279] Compound (1) in which T.sup.1 is a group --CO--CS--N(R')--
(in which R' has the same meaning as defined above) can be prepared
in accordance with the following scheme:
##STR00057##
wherein Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2 and R'
have the same meanings as defined above, and T.sup.1 represents a
group --CO--CS--N(R')-- (in which R' has the same meaning as
defined above).
[0280] More specifically, compound (9) may react with chloroacetyl
chloride in the presence of a base, giving compound (47). Compound
(47) may be heated together with sodium thiosulfate in a solvent,
giving sodium thiosulfate derivative (48). The thus-obtained sodium
thiosulfate derivative (48) may be heated with an amine (i.e.,
HN(R')-Q.sup.4), giving compound (1) according to the present
invention.
[0281] As conditions, solvent and the like for preparing compound
(47) from compound (9), may be applied those commonly used in
reaction of an amine with acid chloride. In order to prepare
compound (48) from compound (47), it is only necessary to heat
compound (47) together with sodium thiosulfate under reflux for
about 1 hour in a solvent such as ethanol. When compound (47) is a
salt with hydrochloric acid or the like, the reaction may be
performed in the presence of a base such as sodium
hydrogencarbonate. The preparation conditions of compound (48) are
not limited to those described herein, and the temperature and the
kinds of the solvent and base may be suitably changed. The
conditions for the reaction of compound (48) with HN(R')-Q.sup.4
are the same as those described in Preparation Process 19.
[Preparation Process 21]
[0282] Compound (1) in which T.sup.0 is a thiocarbonyl group
(--CS--) can be prepared in accordance with the following
scheme:
##STR00058##
wherein Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4 and R.sup.2 have the
same meanings as defined above, and T.sup.1 represents a group
--SO.sub.2--, --CO--, --CO--NH--, --CS--NH--, --CO--NH--NH--,
--CO--CO--N(R')-- (in which R' has the same meaning as defined
above), --CO--CS--N(R')-- (in which R' has the same meaning as
defined above), --CS--CO--N(R')-- (in which R' has the same meaning
as defined above), --CS--CS--N(R')-- (in which R' has the same
meaning as defined above), --CO-A.sup.1-N(R'')-- (in which A.sup.1
and R'' have the same meanings as defined above), --CO-A.sup.2-CO--
(in which A.sup.2 has the same meaning as defined above),
--CO-A.sup.3-CO--NH-- (in which A.sup.3 has the same meanings as
defined above), or --CO-A.sup.3-CO-- (in which A.sup.3 has the same
meaning as defined above).
[0283] More specifically, compound (49) may be subjected to
dehydration reaction with amine (50) in the presence of an acid
catalyst such as p-toluenesulfonic acid, giving compound (51).
Compound (51) may be heated together with sulfur powder in a
solvent such as a mixed solvent of methanol/dichloromethane, giving
compound (1) according to the present invention. As conditions for
preparing compound (51) from compound (49) and amine (50), may be
applied those commonly used in preparation of a Schiff base.
Specifically, heating under reflux may be conducted in the presence
of an acid catalyst in benzene or toluene under conditions that
water is removed from the reaction system by, for example, using a
Dean-Stark trap. Molecular sieve may also be used in removing water
from the reaction system.
[Preparation Process 22]
[0284] Compound (1) in which T.sup.1 is a group --CS--CO--N(R')--
(in which R' has the same meaning as defined above) can be prepared
in accordance with the following scheme:
##STR00059##
wherein Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2 and R'
have the same meanings as defined above, and T.sup.1 represents a
group --CS--CO--N(R')-- (in which R' has the same meaning as
defined above).
[0285] Compound (52) can be prepared by reacting an arylamine
(e.g., 4-chloroaniline) or a heteroarylamine (e.g., aminopyridine),
which corresponds to HN(R')Q.sup.4, with dichloroacetyl chloride in
an inert solvent such as N,N-dimethylformamide or in a basic
solvent such as pyridine at -78.degree. C. to 150.degree. C.
Compound (52) can also be prepared through reaction of
dichloroacetic acid with an amine corresponding to HN(R')Q.sup.4 by
use of the reagents and conditions described in Preparation Process
1.
[0286] Compound (1) can be more efficiently prepared through the
following procedure: compound (52) and sulfur powder are suspended
in a solvent, and a base (e.g., diisopropylethylamine or
triethylamine) and diamine (9) are added to the resultant
suspension, followed by reaction at a reaction temperature of
0.degree. C. to 200.degree. C. The amount of the sulfur powder to
be used in the reaction is preferably 1 equivalent. The reaction
temperature is preferably 60.degree. C. to 160.degree. C.,
particularly preferably 90.degree. C. to 140.degree. C. Examples of
the solvent to be used in this reaction include amide solvents such
as N,N-dimethylformamide; basic solvents such as N-methylmorpholine
and pyridine; alcohols such as ethanol and butanol; etheric
solvents such as dioxane; acetonitrile; and water.
[Preparation Process 23]
[0287] Compound (1) in which T.sup.1 is a group --CS--CO--N(R')--
(in which R' has the same meaning as defined above) can be prepared
in accordance with the following scheme:
##STR00060##
wherein Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2 and R'
have the same meanings as defined above, and T.sup.1 represents a
group --CS--CO--N(R')-- (in which R' has the same meaning as
defined above).
[0288] Compound (53) can be prepared by reacting an arylamine
(e.g., 4-chloroaniline) or a heteroarylamine (e.g., aminopyridine),
which corresponds to HN(R')Q.sup.4, with chloroacetyl chloride in
an inert solvent such as N,N-dimethylformamide or in a basic
solvent such as pyridine at -78.degree. C. to 150.degree. C.
Compound (53) can also be prepared through reaction of chloroacetic
acid with an amine corresponding to HN(R')Q.sup.4 by use of the
reagents and conditions described in Preparation Process 1.
[0289] Compound (1) can be prepared through the following
procedure: compound (53) and sulfur powder are suspended in a
solvent, a base (e.g., diisopropylethylamine or triethylamine) is
added to the resultant suspension, followed by stirring for five
minutes to eight hours, and then diamine (9) and a condensing agent
added to the resultant mixture, followed by reaction. The amount of
the sulfur powder to be used in the reaction is preferably 2
equivalents or more. The reaction temperature is preferably
0.degree. C. to 80.degree. C. Examples of the condensing agent to
be used include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride and N,N'-dicyclohexylcarbodiimide. Examples of the
solvent to be used in this reaction include amide solvents such as
N,N-dimethylformamide; basic solvents such as N-methylmorpholine
and pyridine; alkyl halide solvents such as dichloromethane and
chloroform; etheric solvents such as dioxane; and acetonitrile.
This reaction may proceed in the absence of a condensing agent,
yielding compound (1). In such a case, in addition to the
above-described solvents, for example, an alcohol such as methanol
or ethanol, or water may be used.
[Preparation Process 24]
[0290] Compound (1) in which T.sup.1 is a group --CS--CO--N(R')--
(in which R' has the same meaning as defined above) can be prepared
in accordance with the following scheme via preparation of compound
(4) in which T.sup.1 is a group --CS--CO--N(R')-- (in which R' has
the same meaning as defined above):
##STR00061##
wherein Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2 and R'
have the same meanings as defined above, and T.sup.1 represents a
group --CS--CO--N(R')-- (in which R' has the same meaning as
defined above).
[0291] Specifically, dichloroacetamide derivative (52) or
chloroacetamide derivative (53), sulfur powder, and amine (7) are
reacted together in a solvent in the presence of a base; a
protective group is removed from the resultant reaction product,
thereby yielding compound (4); and the resultant compound (4) is
condensed with carboxylic acid (5), thereby yielding compound (1)
of the present invention. Compound (54) can be more efficiently
prepared through the following procedure: compound (52) and sulfur
powder are suspended in a solvent, and a base (e.g.,
diisopropylethylamine or triethylamine) and amine (7) are added to
the resultant suspension, followed by reaction at a reaction
temperature of 0.degree. C. to 200.degree. C. The amount of the
sulfur powder to be used in the reaction is preferably 1
equivalent. The reaction temperature is preferably 60.degree. C. to
160.degree. C., particularly preferably 90.degree. C. to
140.degree. C. Examples of the solvent to be used in this reaction
include amide solvents such as N,N-dimethylformamide; basic
solvents such as N-methylmorpholine and pyridine; alcohols such as
ethanol and butanol; etheric solvents such as dioxane;
acetonitrile; and water. Compound (54) can also be prepared through
the following procedure: compound (53) and sulfur powder are
suspended in a solvent, a base (e.g., diisopropylethylamine or
triethylamine) is added to the resultant suspension, followed by
stirring for five minutes to five hours, and then amine (7) and a
condensing agent added to the resultant mixture, followed by
reaction. The amount of the sulfur powder to be used in the
reaction is preferably 2 equivalents or more. The reaction
temperature is preferably 0.degree. C. to 80.degree. C. Examples of
the condensing agent to be used include
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and
N,N'-dicyclohexylcarbodiimide. Examples of the solvent to be used
in this reaction include amide solvents such as
N,N-dimethylformamide; basic solvents such as N-methylmorpholine
and pyridine; alkyl halide solvents such as dichloromethane and
chloroform; etheric solvents such as dioxane; and acetonitrile.
This reaction may proceed in the absence of a condensing agent,
yielding compound (54). In such a case, in addition to the
above-described solvents, for example, an alcohol such as methanol
or ethanol, or water may be used. Compound (54) can also be
prepared by reacting sodium thiosulfate (46) with amine (7) under
the reaction conditions described in Preparation Process 19.
[0292] Compound (4) can be prepared by treating compound (54) with
trifluoroacetic acid or the like at -20.degree. C. to 70.degree.
C.
[0293] The thus-prepared compound (4) in which T.sup.1 is a group
--CS--CO--N(R')-- (in which R' has the same meaning as defined
above) is reacted with carboxylic acid (5) through the method
described in Preparation Process 1, thereby yielding compound (1)
of the present invention.
[0294] The tert-butoxycarbonyl group of compound (7) may be
replaced by another protecting group for amino group as described
in Preparation Process 2. The type of the protecting group may be
selected in accordance with the nature and the like of the
compound. Upon leaving such a protecting group, reagents and
conditions may be selected in accordance with the protecting
group.
[Preparation Process 25]
[0295] Compound (1) in which T.sup.1 is a group --CO--N(R')--CO--
(in which R' has the same meaning as defined above) can be prepared
in accordance with the following scheme:
##STR00062##
wherein Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2 and R'
have the same meanings as defined above, and T.sup.1 represents a
group --CO--N(R')--CO-- (in which R' has the same meaning as
defined above).
[0296] Specifically, compound (1) of the present invention can be
prepared through the following procedure: an arylamide (e.g.,
4-chlorobenzamide) or a heteroarylamide (e.g., picolinamide), which
corresponds to HN(R')COQ.sup.4 (55), is formed into an acyl
isocyanate intermediate, and the intermediate is reacted with amine
(7), thereby yielding compound (54); the protective group of the
compound (54) is removed to yield compound (4); and the resultant
compound (4) is condensed with carboxylic acid (5).
[0297] For example, amide (55) is reacted with oxalyl chloride at a
reaction temperature of 20.degree. C. to 100.degree. C. in an inert
solvent, thereby yielding an acyl isocyanate derivative, and the
resultant derivative is reacted with amine (7) at a reaction
temperature of 0.degree. C. to 100.degree. C., to thereby yield
compound (54). Examples of the inert solvent to be used in this
reaction include alkyl halide solvents such as dichloromethane,
chloroform, and dichloroethane; etheric solvents such as
tetrahydrofuran and dioxane; aromatic solvents such as benzene and
toluene; amide solvents such as N,N-dimethylformamide and
N,N-dimethylacetamide; and acetonitrile.
[0298] Compound (4) can be prepared by treating compound (54) with
trifluoroacetic acid or the like at -20.degree. C. to 70.degree.
C.
[0299] The thus-prepared compound (4) in which T.sup.1 is a group
--CO--N(R')--CO-- (in which R' has the same meaning as defined
above) is reacted with carboxylic acid (5) through the method
described in Preparation Process 1, thereby yielding compound (1)
of the present invention.
[0300] The tert-butoxycarbonyl group of compound (7) may be
replaced by another protecting group for amino group as described
in Preparation Process 2. The type of the protecting group may be
selected in accordance with the nature and the like of the
compound. Upon leaving such a protecting group, reagents and
conditions may be selected in accordance with the protecting
group.
[Preparation Process 26]
[0301] Compound (1) in which T.sup.1 is a group --SO.sub.2--N(R')--
(in which R' has the same meaning as defined above) can be prepared
in accordance with the following scheme:
##STR00063##
wherein Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, R.sup.1, R.sup.2 and R'
have the same meanings as defined above, and T.sup.1 represents a
group --SO.sub.2--N(R')-- (in which R' has the same meaning as
defined above).
[0302] Compound (1) can be prepared through the following
procedure: an amine (e.g., 4-chloroaniline) corresponding to
HN(R')Q.sup.4 is reacted with chlorosulfuric acid in an inert
solvent at a reaction temperature of -78.degree. C. to 30.degree.
C., thereby yielding an amidosulfate derivative; the derivative is
activated with a reagent such as phosphorus pentachloride; and the
thus-activated derivative is reacted with amine (9). The reagent
for activating the amidosulfate derivative may be a halogenating
reagent such as phosphorus pentachloride or phosphorus oxychloride,
or a condensing agent such as 1,1'-carbonyldiimidazole. When the
amidosulfate derivative is activated with a halogenating agent
(e.g., phosphorus pentachloride or phosphorus oxychloride) in this
reaction, preferably, the derivative is heated at 50.degree. C. to
120.degree. C. Examples of the inert solvent to be used in this
reaction include alkyl halide solvents such as dichloromethane,
chloroform, and dichloroethane; etheric solvents such as
tetrahydrofuran and dioxane; aromatic solvents such as benzene and
toluene; amide solvents such as N,N-dimethylformamide and
N,N-dimethylacetamide; and acetonitrile.
[0303] The important intermediates described in Preparation
Processes 1 to 21 of the compounds (1) according to the present
invention will hereinafter be described. [0304] 1) The compounds
described in Preparation Process 1, 3 and 11 and represented by the
following general formula (4):
[0304] HN(R.sup.1)-Q.sup.3-N(R.sup.2)-T.sup.1-Q.sup.4 (4)
wherein R.sup.1, R.sup.2, Q.sup.3 and Q.sup.4 have the same
meanings as defined above, and T.sup.1 represents a carbonyl group,
sulfonyl group or group --CO--CO--N(R') (in which R' has the same
meaning as defined above) are important as intermediates for
preparing compounds (1) according to the present invention.
[0305] Among the above-described intermediates, are preferred
compounds in which T.sup.1 is a group --C(.dbd.O)--C(.dbd.O)--N(R')
(in which R' means a hydrogen atom, hydroxyl group, alkyl group or
alkoxy group), and compounds in which T.sup.1 in the above formula
is a carbonyl group, and Q.sup.3 is the following group:
##STR00064##
in which R.sup.3 and R.sup.4 have the same meanings as defined
above, and Q.sup.5 represents a group
--(CH.sub.2).sub.m--CH.sub.2-A-CH.sub.2--(CH.sub.2).sub.n-- (in
which m and n are each independently 0 or an integer of 1-3, and A
represents an oxygen atom, nitrogen atom, sulfur atom, --SO--,
--SO.sub.2--, --NH--, --O--NH--, --NH--NH--, --S--NH--, --SO--NH--
or --SO.sub.2--NH--). [0306] 2) The compounds described in
Preparation Processes 2, 4 and 12 and represented by the following
general formula (9):
[0306] Q.sup.1-Q.sup.2-C(.dbd.O)--N(R.sup.1)-Q.sup.3-NHR.sup.2
(9)
wherein R.sup.1, R.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3 have the
same meanings as defined above, are important as intermediates for
preparing compounds (1) according to the present invention.
[0307] Among the above-described intermediates, are preferred
compounds in which Q.sup.3 is the following group:
##STR00065##
in which R.sup.3 and R.sup.4 have the same meanings as defined
above, and Q.sup.5 represents a group
--(CH.sub.2).sub.m--CH.sub.2-A-CH.sub.2--(CH.sub.2).sub.n-- (in
which m and n are each independently 0 or an integer of 1-3, and A
represents an oxygen atom, nitrogen atom, sulfur atom, --SO--,
--SO.sub.2--, --NH--, --O--NH--, --NH--NH--, --S--NH--, --SO--NH--
or --SO.sub.2--NH--). [0308] 3) The following compounds (4c)
described in Preparation Processes 7, 11 and 13 are important as
intermediates for preparing compounds (1) according to the present
invention.
##STR00066##
[0308] wherein Q.sup.4, R.sup.3, R.sup.4, A, m and n have the same
meanings as defined above, and T.sup.1 represents a carbonyl group,
sulfonyl group or group --CO--CO--N(R') (in which R' has the same
meaning as defined above).
[0309] Among the above-described intermediates, are preferred
compounds in which T.sup.1 in the above formula is a group
--CO--CO--N(R')-- (in which R' has the same meaning as defined
above), and compounds in which T.sup.1 is a carbonyl group, and A
is an oxygen atom, nitrogen atom, sulfur atom, --SO--,
--SO.sub.2--, --NH--, --O--NH--, --NH--NH--, --S--NH--, --SO--NH--
or --SO.sub.2--NH--. 4) The following compounds (22) described in
Preparation Process 8 and 13 are important as intermediates for
preparing compounds (1) according to the present invention.
##STR00067##
wherein Q.sup.4, R.sup.3, R.sup.4, A, m and n have the same
meanings as defined above, T.sup.1 represents a carbonyl group,
sulfonyl group or group --CO--CO--N(R')-- (in which R' has the same
meaning as defined above), and R.sup.51 represents a protecting
group for amino group.
[0310] Among the above-described intermediates, are preferred
compounds in which T.sup.1 in the above formula is a group
--CO--CO--N(R')-- (in which R' has the same meaning as defined
above), and compounds in which T.sup.1 is a carbonyl group, and A
is an oxygen atom, nitrogen atom, sulfur atom, --SO--,
--SO.sub.2--, --NH--, --O--NH--, --NH--NH--, --S--NH--, --SO--NH--
or --SO.sub.2--NH--. [0311] 5) The following optically active
compounds (7a) described in Preparation Process 6 are important as
intermediates for preparing compounds (1) according to the present
invention.
##STR00068##
[0311] wherein Q.sup.5, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have
the same meanings as defined above, and R.sup.50 represents a
protecting group for amino group.
[0312] Among the above-described intermediates, are preferred
compounds in which Q.sup.5 in the above formula is a group
--(CH.sub.2).sub.m--CH.sub.2-A-CH.sub.2--(CH.sub.2).sub.n-- (in
which m and n are each independently 0 or an integer of 1-3, and A
represents an oxygen atom, nitrogen atom, sulfur atom, --SO--,
--SO.sub.2--, --NH--, --O--NH--, --NH--NH--, --S--NH--, --SO--NH--
or --SO.sub.2--NH--). [0313] 6) The following compounds (21)
described in Preparation Process 8 are important as intermediates
for preparing compounds (1) according to the present invention.
##STR00069##
[0313] wherein R.sup.3, R.sup.4, A, m and n have the same meanings
as defined above, and R.sup.51 represents a protecting group for
amino group.
[0314] Among the above-described intermediates, are preferred
compounds in which A in the above formula is an oxygen atom,
nitrogen atom, sulfur atom, --SO--, --SO.sub.2--, --NH--,
--O--NH--, --NH--NH--, --S--NH--, --SO--NH-- or --SO.sub.2--NH--.
[0315] 7) The following compounds described in Preparation Process
10 are important as intermediates for preparing compounds (1)
according to the present invention.
[0316] More specifically, the following optically active trans-form
compounds (30), (31) and (32):
##STR00070##
wherein R.sup.3, m and n have the same meanings as defined above,
and R.sup.51 and R.sup.61 represent protecting groups for amino
group;
[0317] enantiomers (30a), (31a) and (32a) of the above compounds
prepared in a similar manner:
##STR00071##
wherein R.sup.3, m and n have the same meanings as defined above,
and R.sup.51 and R.sup.61 represent protecting groups for amino
group;
[0318] cis-form compounds (30b), (31b) and (32b):
##STR00072##
wherein R.sup.3, m and n have the same meanings as defined above,
and R.sup.51 and R.sup.61 represent protecting groups for amino
group; and
[0319] enantiomers (30c), (31c) and (32c) thereof:
##STR00073##
wherein R.sup.3, m and n have the same meanings as defined above,
and R.sup.51 and R.sup.61 represent protecting groups for amino
group, are important as intermediates for preparing compounds (1)
according to the present invention.
[0320] The diamine derivatives according to the present invention
exhibit strong inhibitory effects on activated blood coagulation
factor X and are thus useful for drugs for mammal including human,
in particular, activated blood coagulation factor X inhibitors,
anticoagulants, agents for preventing and/or treating thrombosis or
embolism, agents for preventing and/or treating thrombtic diseases,
and agents for preventing and/or treating cerebral infarction,
cerebral embolism, myocardial infarction, angina pectoris,
pulmonary infarction, pulmonary embolism, Buerger's disease, deep
venous thrombosis, disseminated intravascular coagulation syndrome,
thrombus formation after artificial valve or joint replacement,
thrombus formation and reocclusion after angioplasty, systemic
inflammatory reaction syndrome (SIRS), multiple organ disease
syndrome (MODS), thrombus formation during extracorporeal
circulation, or blood clotting upon blood gathering.
[0321] When a compound according to the present invention is used
as a drug for human body, the dose is within a range of 1 mg to 1
g, preferably 10 mg to 300 mg, per day for an adult. The dose for
animal varies according to the object (treatment or prevention) of
the administration, the kind and size of an animal to be treated,
the kind of a contagium, and the condition of a disease attacked.
However, it is generally within a range of 0.1 mg to 200 mg,
preferably 0.5 mg to 100 mg, per kg of weight a day. Meanwhile, the
administration may be once per day, or may be divided into 2 to 4
times per day. The dose per day may exceed the above range if
necessary.
[0322] Drug compositions comprising the compound according to the
present invention can be prepared by selecting a suitable
preparation form according to an administration method in
accordance with a preparation method for the preparation form used.
As examples of the preparation forms of the drug compositions
comprising the compound according to the present invention as a
main component, may be mentioned tablets, powder, granules,
capsules, solutions, syrups, elixirs, oil or aqueous suspensions
for oral preparations.
[0323] In the case of an injection, a stabilizer, a preservative
and a dissolution aid may be used in a preparation. A solution
which may contain these auxiliaries in some cases may also be
provided as a solid form for preparing upon use by storing the
solution in a container and then drying the solution by
lyophilization or the like. A dose or doses of the injection may
also be contained in a container.
[0324] As examples of preparation forms for external application,
may be mentioned solutions, suspensions, emulsions, ointments, gel,
creams, lotions, sprays and plasters.
[0325] A solid preparation may contain pharmaceutically acceptable
additives in addition to the compound according to the present
invention. For example, fillers, extenders, binders,
disintegrators, dissolution accelerators, humectants, lubricants,
etc. may be suitably selected and mixed, giving a preparation.
[0326] As examples of liquid preparations, may be mentioned
solutions, suspensions and emulsions. They may contain a suspending
agent, an emulsifier or the like in some cases.
[0327] The compounds of the present invention include the following
compounds (A) to (E). [0328] (A) A compound represented by the
general formula (1):
[0328]
Q.sup.1-C(.dbd.O)--N(R.sup.1)-Q.sup.2-N(R.sup.2)-T.sup.1-Q.sup.3
(1)
wherein
[0329] R.sup.1 and R.sup.2 each independently represent a hydrogen
atom, hydroxyl group, alkyl group or an alkoxy group;
[0330] Q.sup.1 represents a saturated or unsaturated, 5- or
6-membered cyclic hydrocarbon group which may be substituted, a
saturated or unsaturated, 5- or 6-membered heterocyclic group which
may be substituted, a saturated or unsaturated, bicyclic or
tricyclic condensed hydrocarbon group which may be substituted, or
a saturated or unsaturated, bicyclic or tricyclic condensed
heterocyclic group which may be substituted;
[0331] Q.sup.2 represents the following group:
##STR00074##
in which Q.sup.4 represents an alkylene group having 1 to 8 carbon
atoms, an alkenylene group having 2 to 8 carbon atoms or a group
--(CH.sub.2).sub.m--CH.sub.2-A-CH.sub.2--(CH.sub.2).sub.n-- (in
which m and n are each independently 0 or an integer of 1-3, and A
represents an oxygen atom, a sulfur atom, --SO--, --SO.sub.2--,
--NH--, --O--NH--, --NH--NH--, --S--NH--, --SO--NH-- or
--SO.sub.2--NH--, and numbers 1 and 2 indicate positions); and
[0332] R.sup.3 and R.sup.4 are substituents on carbon atom(s),
nitrogen atom(s) or sulfur atom(s) of a ring comprising Q.sup.4 and
are each independently a hydrogen atom, hydroxyl group, alkyl
group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl
group, cyano group, cyanoalkyl group, amino group, aminoalkyl
group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl
group, acylalkyl group, acylamino group which may be substituted,
alkoxyimino group, hydroxyimino group, acylaminoalkyl group, alkoxy
group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group,
carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl
group, alkoxycarbonylalkylamino group, carboxyalkylamino group,
alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group,
carbamoyl group, N-alkylcarbamoyl group which may have a
substituent on the alkyl group, N,N-dialkylcarbamoyl group which
may have a substituent on the alkyl group(s), N-alkenylcarbamoyl
group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl
group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl
group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl
group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazolyl group which
may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group,
alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl
group which may be substituted, carbamoylalkyl group,
N-alkylcarbamoylalkyl group which may have a substituent on the
alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a
substituent on the alkyl group(s), carbamoyloxyalkyl group,
N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group,
3- to 6-membered heterocyclic carbonylalkyl group which may be
substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group
which may be substituted, aryl group, aralkyl group, heteroaryl
group, heteroarylalkyl group, alkylsulfonylamino group,
arylsulfonylamino group, alkylsulfonylaminoalkyl group,
arylsulfonylaminoalkyl group, alkylsulfonylaminocarbonyl group,
arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl
group, arylsulfonylaminocarbonylalkyl group, oxo group,
carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group,
acyloxy group, acyloxyalkyl group, arylsulfonyl group,
alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group,
alkoxycarbonylacyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl
group, alkoxyacyl group, halogenoacyl group, carboxyacyl group,
aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group,
hydroxyalkylsulfonyl group, alkoxyalkylsulfonyl group, 3- to
6-membered heterocyclic sulfonyl group which may be substituted,
N-alkylaminoacyl group, N,N-dialkylaminoacyl group,
N,N-dialkylcarbamoylacyl group which may have a substituent on the
alkyl group(s), N,N-dialkylcarbamoylalkylsulfonyl group which may
have a substituent on the alkyl group(s), alkylsulfonylacyl group,
or the like, or R.sup.3 and R.sup.4 together form an alkylene group
having 1 to 5 carbon atoms, alkenylene group having 2 to 5 carbon
atoms, alkylenedioxy group having 1 to 5 carbon atoms or
carbonyldioxy group;
[0333] Q.sup.3 represents an aryl group which may be substituted,
an arylalkenyl group which may be substituted, a heteroaryl group
which may be substituted, a heteroarylalkenyl group which may be
substituted, a saturated or unsaturated, bicyclic or tricyclic
condensed hydrocarbon group which may be substituted, or a
saturated or unsaturated, bicyclic or tricyclic condensed
heterocyclic group which may be substituted; and
[0334] T.sup.1 represents a carbonyl or sulfonyl group;
[0335] a salt thereof, a solvate thereof, or an N-oxide thereof.
[0336] (B) A compound represented by the general formula (1):
[0336]
Q.sup.1-Q.sup.2-C(.dbd.O)--N(R.sup.1)-Q.sup.3-N(R.sup.2)-T.sup.1--
Q.sup.4 (1)
wherein
[0337] R.sup.1 and R.sup.2 each independently represent a hydrogen
atom, hydroxyl group, alkyl group or alkoxy group;
[0338] Q.sup.1 represents a saturated or unsaturated, 5- or
6-membered cyclic hydrocarbon group which may be substituted, a
saturated or unsaturated, 5- or 6-membered heterocyclic group which
may be substituted, a saturated or unsaturated, bicyclic or
tricyclic condensed hydrocarbon group which may be substituted, or
a saturated or unsaturated, bicyclic or tricyclic condensed
heterocyclic group which may be substituted;
[0339] Q.sup.2 represents a single bond, a saturated or
unsaturated, 5- or 6-membered divalent cyclic hydrocarbon group
which may be substituted, a saturated or unsaturated, 5- or
6-membered divalent heterocyclic group which may be substituted, a
saturated or unsaturated, divalent bicyclic or tricyclic condensed
hydrocarbon group which may be substituted, or a saturated or
unsaturated, divalent bicyclic or tricyclic condensed heterocyclic
group which may be substituted;
[0340] Q.sup.3 represents the following group:
##STR00075##
in which Q.sup.5 represents an alkylene group having 1 to 8 carbon
atoms, an alkenylene group having 2 to 8 carbon atoms or a group
--(CH.sub.2).sub.m--CH.sub.2-A-CH.sub.2--(CH.sub.2).sub.n-- (in
which m and n are each independently 0 or an integer of 1-3, and A
represents an oxygen atom, nitrogen atom, sulfur atom, --SO--,
--SO.sub.2--, --NH--, --O--NH--, --NH--NH--, --S--NH--, --SO--NH--
or --SO.sub.2--NH--); and
[0341] R.sup.3 and R.sup.4 are substituents on carbon atom(s),
nitrogen atom(s) or sulfur atom(s) of a ring comprising Q.sup.5 and
are each independently a hydrogen atom, hydroxyl group, alkyl
group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl
group, cyano group, cyanoalkyl group, amino group, aminoalkyl
group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl
group, acylalkyl group, acylamino group which may be substituted,
alkoxyimino group, hydroxyimino group, acylaminoalkyl group, alkoxy
group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group,
carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl
group, alkoxycarbonylalkylamino group, carboxyalkylamino group,
alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group,
carbamoyl group, N-alkylcarbamoyl group which may have a
substituent on the alkyl group, N,N-dialkylcarbamoyl group which
may have a substituent on the alkyl group(s), N-alkenylcarbamoyl
group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl
group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl
group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl
group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazolyl group which
may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group,
alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl
group which may be substituted, carbamoylalkyl group,
N-alkylcarbamoylalkyl group which may have a substituent on the
alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a
substituent on the alkyl group(s), carbamoyloxyalkyl group,
N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group,
3- to 6-membered heterocyclic carbonylalkyl group which may be
substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group
which may be substituted, aryl group, aralkyl group, heteroaryl
group, heteroarylalkyl group, alkylsulfonylamino group,
arylsulfonylamino group, alkylsulfonylaminoalkyl group,
arylsulfonylaminoalkyl group, alkylsulfonylaminocarbonyl group,
arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl
group, arylsulfonylaminocarbonylalkyl group, oxo group,
carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group,
acyloxy group, acyloxyalkyl group, arylsulfonyl group,
alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group,
alkoxycarbonylacyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl
group, alkoxyacyl group, halogenoacyl group, carboxyacyl group,
aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group,
hydroxyalkylsulfonyl group, alkoxyalkylsulfonyl group, 3- to
6-membered heterocyclic sulfonyl group which may be substituted,
N-alkylaminoacyl group, N,N-dialkylaminoacyl group,
N,N-dialkylcarbamoylacyl group which may have a substituent on the
alkyl group(s), N,N-dialkylcarbamoylalkylsulfonyl group which may
have a substituent on the alkyl group(s), alkylsulfonylacyl group,
or the like, or R.sup.3 and R.sup.4 together form an alkylene group
having 1 to 5 carbon atoms, alkenylene group having 2 to 5 carbon
atoms, alkylenedioxy group having 1 to 5 carbon atoms or
carbonyldioxy group;
[0342] Q.sup.4 represents an aryl group which may be substituted,
an arylalkenyl group which may be substituted, a heteroaryl group
which may be substituted, a heteroarylalkenyl group which may be
substituted, a saturated or unsaturated, bicyclic or tricyclic
condensed hydrocarbon group which may be substituted, or a
saturated or unsaturated, bicyclic or tricyclic condensed
heterocyclic group which may be substituted; and
[0343] T.sup.1 represents a carbonyl group, sulfonyl group, or
group --C(.dbd.O)--C(.dbd.O)--N(R')-- (in which R' represents a
hydrogen atom, hydroxyl group, alkyl group or alkoxy group);
[0344] a salt thereof, a solvate thereof, or an N-oxide thereof.
[0345] (C) A compound represented by the general formula (1):
[0345]
Q.sup.1-Q.sup.2-C(.dbd.O)--N(R.sup.1)-Q.sup.3-N(R.sup.2)-T.sup.1--
Q.sup.4 (1)
wherein
[0346] R.sup.1 and R.sup.2 each independently represent a hydrogen
atom, hydroxyl group, alkyl group or alkoxy group;
[0347] Q.sup.1 represents a saturated or unsaturated, 5- or
6-membered cyclic hydrocarbon group which may be substituted, a
saturated or unsaturated, 5- to 7-membered heterocyclic group which
may be substituted, a saturated or unsaturated, bicyclic or
tricyclic condensed hydrocarbon group which may be substituted, or
a saturated or unsaturated, bicyclic or tricyclic condensed
heterocyclic group which may be substituted;
[0348] Q.sup.2 represents a single bond, a saturated or
unsaturated, 5- or 6-membered divalent cyclic hydrocarbon group
which may be substituted, a saturated or unsaturated, 5- to
7-membered divalent heterocyclic group which may be substituted, a
saturated or unsaturated, divalent bicyclic or tricyclic condensed
hydrocarbon group which may be substituted, or a saturated or
unsaturated, divalent bicyclic or tricyclic condensed heterocyclic
group which may be substituted; Q.sup.3 represents the following
group:
##STR00076##
in which Q.sup.5 represents an alkylene group having 1 to 8 carbon
atoms, an alkenylene group having 2 to 8 carbon atoms or a group
--(CH.sub.2).sub.m--CH.sub.2-A-CH.sub.2--(CH.sub.2).sub.n-- (in
which m and n are each independently 0 or an integer of 1-3, and A
represents an oxygen atom, nitrogen atom, sulfur atom, --SO--,
--SO.sub.2--, --NH--, --O--NH--, --NH--NH--, --S--NH--, --SO--NH--
or --SO.sub.2--NH--); and
[0349] R.sup.3 and R.sup.4 are substituents on carbon atom(s),
nitrogen atom(s) or sulfur atom(s) of a ring comprising Q.sup.5 and
are each independently a hydrogen atom, hydroxyl group, alkyl
group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl
group, cyano group, cyanoalkyl group, amino group, aminoalkyl
group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl
group, acylalkyl group, acylamino group which may be substituted,
alkoxyimino group, hydroxyimino group, acylaminoalkyl group, alkoxy
group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group,
carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl
group, alkoxycarbonylalkylamino group, carboxyalkylamino group,
alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group,
carbamoyl group, N-alkylcarbamoyl group which may have a
substituent on the alkyl group, N,N-dialkylcarbamoyl group which
may have a substituent on the alkyl group(s), N-alkenylcarbamoyl
group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl
group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl
group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl
group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazolyl group which
may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group,
alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl
group which may be substituted, carbamoylalkyl group,
N-alkylcarbamoylalkyl group which may have a substituent on the
alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a
substituent on the alkyl group(s), carbamoyloxyalkyl group,
N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group,
3- to 6-membered heterocyclic carbonylalkyl group which may be
substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group
which may be substituted, aryl group, aralkyl group, heteroaryl
group, heteroarylalkyl group, alkylsulfonylamino group,
arylsulfonylamino group, alkylsulfonylaminoalkyl group,
arylsulfonylaminoalkyl group, alkylsulfonylaminocarbonyl group,
arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl
group, arylsulfonylaminocarbonylalkyl group, oxo group,
carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group,
acyloxy group, acyloxyalkyl group, arylsulfonyl group,
alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group,
alkoxycarbonylacyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl
group, alkoxyacyl group, halogenoacyl group, carboxyacyl group,
aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group,
hydroxyalkylsulfonyl group, alkoxyalkylsulfonyl group, 3- to
6-membered heterocyclic sulfonyl group which may be substituted,
N-alkylaminoacyl group, N,N-dialkylaminoacyl group,
N,N-dialkylcarbamoylacyl group which may have a substituent on the
alkyl group(s), N,N-dialkylcarbamoylalkylsulfonyl group which may
have a substituent on the alkyl group(s), alkylsulfonylacyl group,
or R.sup.3 and R.sup.4 together form an alkylene group having 1 to
5 carbon atoms, alkenylene group having 2 to 5 carbon atoms,
alkylenedioxy group having 1 to 5 carbon atoms or carbonyldioxy
group;
[0350] Q.sup.4 represents an aryl group which may be substituted,
an arylalkenyl group which may be substituted, an arylalkynyl group
which may be substituted, a heteroaryl group which may be
substituted, a heteroarylalkenyl group which may be substituted, a
saturated or unsaturated, bicyclic or tricyclic condensed
hydrocarbon group which may be substituted, or a saturated or
unsaturated, bicyclic or tricyclic condensed heterocyclic group
which may be substituted; and
[0351] T.sup.1 represents a carbonyl group, sulfonyl group, group
--C(.dbd.O)--C(.dbd.O)--N(R')-- (in which R' represents a hydrogen
atom, hydroxyl group, alkyl group or alkoxy group), group
--C(.dbd.O)-A.sup.1-N(R'')-- (in which A.sup.1 represents an
alkylene group having 1 to 5 carbon atoms, which may be
substituted, and R'' represents a hydrogen atom, hydroxyl group,
alkyl group or alkoxy group), group --C(.dbd.O)--NH--, group
--C(.dbd.S)--NH--, group --C(.dbd.O)--NH--NH--, group
--C(.dbd.O)-A.sup.2-C(.dbd.O)-- (in which A.sup.2 represents a
single bond or alkylene group having 1 to 5 carbon atoms), group
--C(.dbd.O)-A.sup.3-C(.dbd.O)--NH-- (in which A.sup.3 represents an
alkylene group having 1 to 5 carbon atoms), or thiocarbonyl
group;
[0352] a salt thereof, a solvate thereof, or an N-oxide thereof.
[0353] (D) A compound represented by the general formula (1):
[0353]
Q.sup.1-Q.sup.2-T.sup.0-N(R.sup.1)-Q.sup.3-N(R.sup.2)-T.sup.1-Q.s-
up.4 (1)
wherein
[0354] R.sup.1 and R.sup.2 each independently represent a hydrogen
atom, hydroxyl group, alkyl group or alkoxy group;
[0355] Q.sup.1 represents a saturated or unsaturated, 5- or
6-membered cyclic hydrocarbon group which may be substituted, a
saturated or unsaturated, 5- to 7-membered heterocyclic group which
may be substituted, a saturated or unsaturated, bicyclic or
tricyclic condensed hydrocarbon group which may be substituted, or
a saturated or unsaturated, bicyclic or tricyclic condensed
heterocyclic group which may be substituted;
[0356] Q.sup.2 represents a single bond, a saturated or
unsaturated, 5- or 6-membered divalent cyclic hydrocarbon group
which may be substituted, a saturated or unsaturated, 5- to
7-membered divalent heterocyclic group which may be substituted, a
saturated or unsaturated, divalent bicyclic or tricyclic condensed
hydrocarbon group which may be substituted, or a saturated or
unsaturated, divalent bicyclic or tricyclic condensed heterocyclic
group which may be substituted;
[0357] Q.sup.3 represents the following group:
##STR00077##
in which Q.sup.5 represents an alkylene group having 1 to 8 carbon
atoms, an alkenylene group having 2 to 8 carbon atoms, or a group
--(CH.sub.2).sub.m--CH.sub.2-A-CH.sub.2-(CH.sub.2).sub.n-- (in
which m and n are each independently 0 or an integer of 1-3, and A
represents an oxygen atom, nitrogen atom, sulfur atom, --SO--,
--SO.sub.2--, --NH--, --O--NH--, --NH--NH--, --S--NH--, --SO--NH--
or --SO.sub.2--NH--), and;
[0358] R.sup.3 and R.sup.4 are substituents on carbon atom(s),
nitrogen atom(s) or sulfur atom(s) of a ring comprising Q.sup.5 and
are each independently a hydrogen atom, hydroxyl group, alkyl
group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl
group, cyano group, cyanoalkyl group, amino group, aminoalkyl
group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl
group, acylalkyl group, acylamino group which may be substituted,
alkoxyimino group, hydroxyimino group, acylaminoalkyl group, alkoxy
group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group,
carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl
group, alkoxycarbonylalkylamino group, carboxyalkylamino group,
alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group,
carbamoyl group, N-alkylcarbamoyl group which may have a
substituent on the alkyl group, N,N-dialkylcarbamoyl group which
may have a substituent on the alkyl group(s), N-alkenylcarbamoyl
group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl
group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl
group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl
group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazolyl group which
may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group,
alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl
group which may be substituted, carbamoylalkyl group,
N-alkylcarbamoylalkyl group which may have a substituent on the
alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a
substituent on the alkyl group(s), carbamoyloxyalkyl group,
N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group,
3- to 6-membered heterocyclic carbonylalkyl group which may be
substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group
which may be substituted, aryl group, aralkyl group, heteroaryl
group, heteroarylalkyl group, alkylsulfonylamino group,
arylsulfonylamino group, alkylsulfonylaminoalkyl group,
arylsulfonylaminoalkyl group, alkylsulfonylaminocarbonyl group,
arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl
group, arylsulfonylaminocarbonylalkyl group, oxo group,
carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group,
acyloxy group, acyloxyalkyl group, arylsulfonyl group,
alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group,
alkoxycarbonylacyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl
group, alkoxyacyl group, halogenoacyl group, carboxyacyl group,
aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group,
hydroxyalkylsulfonyl group, alkoxyalkylsulfonyl group, 3- to
6-membered heterocyclic sulfonyl group which may be substituted,
N-alkylaminoacyl group, N,N-dialkylaminoacyl group,
N,N-dialkylcarbamoylacyl group which may have a substituent on the
alkyl group(s), N,N-dialkylcarbamoylalkylsulfonyl group which may
have a substituent on the alkyl group(s) or alkylsulfonylacyl
group, or R.sup.3 and R.sup.4 together form an alkylene group
having 1 to 5 carbon atoms, alkenylene group having 2 to 5 carbon
atoms, alkylenedioxy group having 1 to 5 carbon atoms or
carbonyldioxy group;
[0359] Q.sup.4 represents an aryl group which may be substituted,
an arylalkenyl group which may be substituted, an arylalkynyl group
which may be substituted, a heteroaryl group which may be
substituted, a heteroarylalkenyl group which may be substituted, a
saturated or unsaturated, bicyclic or tricyclic condensed
hydrocarbon group which may be substituted, or a saturated or
unsaturated, bicyclic or tricyclic condensed heterocyclic group
which may be substituted;
[0360] T.sup.0 represents a carbonyl or thiocarbonyl group; and
[0361] T.sup.1 represents a carbonyl group, sulfonyl group, group
--C(.dbd.O)--C(.dbd.O)--N(R')--, group
--C(.dbd.S)--C(.dbd.O)--N(R')--, group
--C(.dbd.O)--C(.dbd.S)--N(R')--, group
--C(.dbd.S)--C(.dbd.S)--N(R')-- (in which R' represents a hydrogen
atom, hydroxyl group, alkyl group or alkoxy group), group
--C(.dbd.O)-A.sup.1-N(R'')-- (in which A.sup.1 represents an
alkylene group having 1 to 5 carbon atoms, which may be
substituted, and R'' represents a hydrogen atom, hydroxyl group,
alkyl group or alkoxy group), group --C(.dbd.O)--NH--, group
--C(.dbd.S)--NH--, group --C(.dbd.O)--NH--NH--, group
--C(.dbd.O)-A.sup.2-C(.dbd.O)-- (in which A.sup.2 represents a
single bond or alkylene group having 1 to 5 carbon atoms), group
--C(.dbd.O)-A.sup.3-C(.dbd.O)--NH-- (in which A.sup.3 represents an
alkylene group having 1 to 5 carbon atoms), group
--C(.dbd.O)--C(.dbd.NOR.sup.a)--N(R.sup.b)--, group
--C(.dbd.S)--C(.dbd.NOR.sup.a)--N(R.sup.b)-- (in which R.sup.a
represents a hydrogen atom, alkyl group or alkanoyl group, and
R.sup.b represents a hydrogen atom, hydroxyl group, alkyl group or
alkoxy group), group --C(.dbd.O)--N.dbd.N--, group
--C(.dbd.S)--N.dbd.N--, or thiocarbonyl group;
[0362] a salt thereof, a solvate thereof, or an N-oxide thereof.
[0363] (E) A compound represented by the general formula (1):
[0363]
Q.sup.1-Q.sup.2-T.sup.0-N(R.sup.1)-Q.sup.3-N(R.sup.2)-T-Q.sup.4
(1)
wherein
[0364] R.sup.1 and R.sup.2 each independently represent a hydrogen
atom, hydroxyl group, alkyl group or alkoxy group;
[0365] Q.sup.1 represents a saturated or unsaturated, 5- or
6-membered cyclic hydrocarbon group which may be substituted, a
saturated or unsaturated, 5- to 7-membered heterocyclic group which
may be substituted, a saturated or unsaturated, bicyclic or
tricyclic condensed hydrocarbon group which may be substituted, or
a saturated or unsaturated, bicyclic or tricyclic condensed
heterocyclic group which may be substituted;
[0366] Q.sup.2 represents a single bond, a saturated or
unsaturated, 5- or 6-membered divalent cyclic hydrocarbon group
which may be substituted, a saturated or unsaturated, 5- to
7-membered divalent heterocyclic group which may be substituted, a
saturated or unsaturated, divalent bicyclic or tricyclic condensed
hydrocarbon group which may be substituted, or a saturated or
unsaturated, divalent bicyclic or tricyclic condensed heterocyclic
group which may be substituted;
[0367] Q.sup.3 represents the following group:
##STR00078##
in which Q.sup.5 represents an alkylene group having 1 to 8 carbon
atoms, an alkenylene group having 2 to 8 carbon atoms, or a group
--(CH.sub.2).sub.m--CH.sub.2-A-CH.sub.2--(CH.sub.2).sub.n-- (in
which m and n are each independently 0 or an integer of 1-3, and A
represents an oxygen atom, nitrogen atom, sulfur atom, --SO--,
--SO.sub.2--, --NH--, --O--NH--, --NH--NH--, --S--NH--, --SO--NH--
or --SO.sub.2--NH--), and;
[0368] R.sup.3 and R.sup.4 are substituents on carbon atom(s),
nitrogen atom(s) or sulfur atom(s) of a ring comprising Q.sup.5 and
are each independently a hydrogen atom, hydroxyl group, alkyl
group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl
group, cyano group, cyanoalkyl group, amino group, aminoalkyl
group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl
group, acylalkyl group, acylamino group which may be substituted,
alkoxyimino group, hydroxyimino group, acylaminoalkyl group, alkoxy
group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group,
carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl
group, alkoxycarbonylalkylamino group, carboxyalkylamino group,
alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group,
carbamoyl group, N-alkylcarbamoyl group which may have a
substituent on the alkyl group, N,N-dialkylcarbamoyl group which
may have a substituent on the alkyl group(s), N-alkenylcarbamoyl
group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl
group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl
group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl
group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazolyl group which
may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group,
alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl
group which may be substituted, carbamoylalkyl group,
N-alkylcarbamoylalkyl group which may have a substituent on the
alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a
substituent on the alkyl group(s), carbamoyloxyalkyl group,
N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group,
3- to 6-membered heterocyclic carbonylalkyl group which may be
substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group
which may be substituted, aryl group, aralkyl group, heteroaryl
group, heteroarylalkyl group, alkylsulfonylamino group,
arylsulfonylamino group, alkylsulfonylaminoalkyl group,
arylsulfonylaminoalkyl group, alkylsulfonylaminocarbonyl group,
arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl
group, arylsulfonylaminocarbonylalkyl group, oxo group,
carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group,
acyloxy group, acyloxyalkyl group, arylsulfonyl group,
alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group,
alkoxycarbonylacyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl
group, alkoxyacyl group, halogenoacyl group, carboxyacyl group,
aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group,
hydroxyalkylsulfonyl group, alkoxyalkylsulfonyl group, 3- to
6-membered heterocyclic sulfonyl group which may be substituted,
N-alkylaminoacyl group, N,N-dialkylaminoacyl group,
N,N-dialkylcarbamoylacyl group which may have a substituent on the
alkyl group(s), N,N-dialkylcarbamoylalkylsulfonyl group which may
have a substituent on the alkyl group(s) or alkylsulfonylacyl
group, or R.sup.3 and R.sup.4 together form an alkylene group
having 1 to 5 carbon atoms, alkenylene group having 2 to 5 carbon
atoms, alkylenedioxy group having 1 to 5 carbon atoms or
carbonyldioxy group;
[0369] Q.sup.4 represents an aryl group which may be substituted,
an arylalkenyl group which may be substituted, an arylalkynyl group
which may be substituted, a heteroaryl group which may be
substituted, a heteroarylalkenyl group which may be substituted, a
saturated or unsaturated, bicyclic or tricyclic condensed
hydrocarbon group which may be substituted, or a saturated or
unsaturated, bicyclic or tricyclic condensed heterocyclic group
which may be substituted;
[0370] T.sup.0 represents a carbonyl or thiocarbonyl group; and
[0371] T.sup.1 represents a carbonyl group, sulfonyl group, group
--C(.dbd.O)--C(.dbd.O)--N(R')--, group
--C(.dbd.S)--C(.dbd.O)--N(R')--, group
--C(.dbd.O)--C(.dbd.S)--N(R')--, group
--C(.dbd.S)--C(.dbd.S)--N(R')-- (in which R' represents a hydrogen
atom, hydroxyl group, alkyl group or alkoxy group), group
--C(.dbd.O)-A.sup.1-N(R'')-- (in which A.sup.1 represents an
alkylene group having 1 to 5 carbon atoms, which may be
substituted, and R'' represents a hydrogen atom, hydroxyl group,
alkyl group or alkoxy group), group --C(.dbd.O)--NH--, group
--C(.dbd.S)--NH--, group --C(.dbd.O)--NH--NH--, group
--C(.dbd.O)-A.sup.2-C(.dbd.O)-- (in which A.sup.2 represents a
single bond or alkylene group having 1 to 5 carbon atoms), group
--C(.dbd.O)-A.sup.3-C(.dbd.O)--NH-- (in which A.sup.3 represents an
alkylene group having 1 to 5 carbon atoms), group
--C(.dbd.O)--C(.dbd.NOR.sup.a)--N(R.sup.b)--, group
--C(.dbd.S)--C(.dbd.NOR.sup.a)--N(R.sup.b)-- (in which R.sup.a
represents a hydrogen atom, alkyl group or alkanoyl group, and
R.sup.b represents a hydrogen atom, hydroxyl group, alkyl group or
alkoxy group), group --C(.dbd.O)--N.dbd.N--, group
--C(.dbd.S)--N.dbd.N--, or thiocarbonyl group;
[0372] a salt thereof, a solvate thereof, or an N-oxide
thereof.
Examples
[0373] The present invention will next be described by way of
Examples.
Referential Example 1
pyridin-4-ylcarbamic acid tert-butyl ester
[0374] 4-Aminopyridine (10 g) was dissolved in tetrahydrofuran (500
mL), and di-tert-butyl dicarbonate (25.5 g) was added thereto. The
mixture was stirred at room temperature for 10 minutes. The
reaction mixture was concentrated under reduced pressure, and the
resultant solid was washed with hexane, to thereby give the title
compound (16.9 g).
[0375] .sup.1H-NMR(CDCl.sub.3).delta.: 1.53(9H, s), 6.86(1H, br.s),
7.30(2H, dd, J=1.5, 4.9 Hz), 8.44(2H, dd, J=1.5, 4.9 Hz).
[0376] MS(FAB)m/z: 195(M+H).sup.+.
Referential Example 2
3-sulfanylpyridin-4-ylcarbamic acid tert-butyl ester
##STR00079##
[0378] The compound obtained in Referential Example 1 (61.6 g) was
dissolved in tetrahydrofuran (2000 mL), and the solution was
stirred at -78.degree. C. for 10 minutes. n-Butyllithium (as 1.59N
hexane solution, 500 mL) was added dropwise to the reaction
mixture, followed by stirring for 10 minutes. The mixture was
further stirred for 2 hours under ice cooling. The reaction mixture
was cooled to -78.degree. C., and after sulfur powder (12.2 g) was
added thereto, the mixture was heated to room temperature, followed
by stirring for 1 hour. Water (1000 mL) was added to the reaction
mixture to partition the mixture. 3N HCl was added to the aqueous
phase, to thereby adjust pH to 3 to 4. Methylene chloride was added
for partitioning the mixture. The organic layer was dried over
sodium sulfate anhydrate, and the solvent was distilled away under
reduced pressure. The residue was purified by silica gel column
chromatography (methylene chloride:methanol=50:1), to thereby give
the title compound (33.2 g).
[0379] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.52(9H, s), 7.89(1H, d,
J=6.4 Hz), 7.99(1H, d, J=6.4 Hz), 8.20(1H, s), 9.91(1H, br.s).
[0380] MS(FAB)m/z: 227(M+H).sup.+.
Referential Example 3
thiazolo[5,4-c]pyridine
##STR00080##
[0382] The compound obtained in Referential Example 2 (33.2 g) was
dissolved in formic acid (250 mL), and the solution was heated
under reflux for 3 days. The reaction mixture was concentrated
under reduced pressure, and to the residue were added 5N aqueous
potassium hydroxide (100 mL) and diethyl ether to partition the
residue. The organic layer was dried over sodium sulfate anhydrate,
and the solvent was distilled away under reduced pressure. The
residue was purified by silica gel column chromatography (methylene
chloride:methanol=25:1), to thereby give the title compound (9.03
g).
[0383] .sup.1H-NMR(CDCl.sub.3).delta.: 8.05(1H, d, J=5.4 Hz),
8.70(1H, d, J=5.4 Hz), 9.23(1H, s), 9.34(1H, s).
[0384] MS(FAB)m/z: 137(M+H).sup.+.
Referential Example 4
5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine
##STR00081##
[0386] The compound obtained in Referential Example 3 (1.61 g) was
dissolved in N,N-dimethylformamide (50 mL), and methyl iodide (1.50
mL) was added thereto, followed by stirring at 80.degree. C. for 4
hours. The reaction mixture was concentrated under reduced
pressure. The residue was dissolved in methanol (100 mL), and
sodium borohydride (1.53 g) was added thereto, followed by stirring
at room temperature for 1 hour. The reaction mixture was
concentrated under reduced pressure, and to the residue were added
saturated aqueous potassium carbonate and diethyl ether to
partition the residue. The organic layer was dried over sodium
sulfate anhydrate, and the solvent was distilled away under reduced
pressure. The residue was purified by silica gel column
chromatography (methylene chloride:methanol=25:1), to thereby give
the title compound (1.28 g).
[0387] .sup.1H-NMR(CDCl.sub.3).delta.: 2.52(3H, s), 2.83(2H, t,
J=5.9 Hz), 2.98(2H, t, J=5.9 Hz), 3.70(2H, s), 8.63(1H, s).
[0388] MS(FAB)m/z: 155(M+H).sup.+.
Referential Example 5
5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic
acid lithium salt
##STR00082##
[0390] The compound obtained in Referential Example 4 (6.43 g) was
dissolved in anhydrous tetrahydrofuran (200 mL), and n-butyllithium
(as 1.47N hexane solution, 34.0 mL) was added dropwise to the
solution at -78.degree. C., followed by stirring for 40 minutes.
After carbon dioxide gas was introduced into the reaction mixture
at -78.degree. C. for 1 hour, the reaction mixture was heated to
room temperature, and was concentrated under reduced pressure, to
thereby give the title compound (9.42 g).
[0391] .sup.1H-NMR(DMSO-d.sub.6).delta.: 2.37(3H, s), 2.64-2.77(4H,
m), 3.54(2H, s).
[0392] MS(FAB)m/z: 199(M+H).sup.+.
Referential Example 6
2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5[4H]-carboxylic acid
tert-butyl ester
##STR00083##
[0394] 1-tert-Butoxycarbonyl-4-piperidone (40.0 g) was dissolved in
cyclohexane (80 mL), and to the solution were added
p-toluenesulfonic acid monohydrate (191 mg) and pyrrolidine (17.6
mL). The reaction mixture was heated under reflux for 2 hours while
water was removed with Dean-Stark apparatus. The resultant mixture
was concentrated under reduced pressure, and the residue was
dissolved in methanol (60 mL). After sulfur powder (6.42 g) was
added to the solution, a solution of cyanamide (8.44 g) in methanol
(10 mL) was slowly added dropwise to the mixture under ice cooling,
followed by stirring at room temperature for 5 hours. The resultant
precipitated solid was collected by filtration, to thereby give the
title compound (31.0 g).
[0395] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.41 (9H, s), 2.44(2H, t,
J=5.6 Hz), 3.57(2H, t, J=5.6 Hz), 4.29(2H, s), 6.79(2H, s).
[0396] MS(EI)m/z: 255(M.sup.+).
Referential Example 7
2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5[4H]-carboxylic acid
tert-butyl ester
##STR00084##
[0398] Cupric bromide (1.05 g) was suspended in
N,N-dimethylformamide (20 mL), and to the suspension were added
tert-butyl nitrite (0.696 mL) and the compound obtained in
Referential Example 6 (1.00 g) under ice cooling, followed by
stirring at 40.degree. C. for 30 minutes. The reaction mixture was
concentrated under reduced pressure, and the residue was purified
by silica gel column chromatography (ethyl acetate:hexane=1:5), to
thereby give the title compound (568 mg).
[0399] .sup.1H-NMR(CDCl.sub.3).delta.: 1.48(9H, s), 2.85(2H, br.s),
3.72(2H, br.s), 4.56(2H, br.s).
[0400] MS(FAB)m/z: 319(M+H).sup.+.
Referential Example 8
2-bromo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine trifluoroacetic
acid salt
##STR00085##
[0402] The compound obtained in Referential Example 7 (890 mg) was
dissolved in methylene chloride (2 mL), and trifluoroacetic acid
(15 mL) was added thereto, followed by stirring at room temperature
for 30 seconds. The reaction mixture was concentrated under reduced
pressure, and diethyl ether was added to the residue. The resultant
precipitated solid was collected by filtration, to thereby give the
title compound (867 mg).
[0403] .sup.1H-NMR(DMSO-d.sub.6).delta.: 2.98 (2H, t, J=6.1 Hz),
3.45(2H, t, J=6.1 Hz), 4.35(2H, s), 9.53(2H, br.s).
[0404] MS(FAB)m/z: 219(M+H).sup.+.
Referential Example 9
2-bromo-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine
##STR00086##
[0406] The compound obtained in Referential Example 8 (422 mg) was
suspended in methylene chloride (10 mL), and triethylamine (0.356
mL) was dissolved therein. To the thus-obtained mixture were
sequentially added acetic acid (0.216 mL), aqueous formaldehyde (as
35% solution, 0.202 mL), and sodium triacetoxyborohydride (428 mg),
followed by stirring at room temperature for 1 hour. To the
reaction mixture were added saturated aqueous sodium
hydrogencarbonate (100 mL), methylene chloride (100 mL), and 3N
aqueous sodium hydroxide (3 mL) to partition the mixture. The
organic layer was dried over sodium sulfate anhydrate, and the
solvent was distilled away under reduced pressure. The residue was
purified by silica gel column chromatography (methylene chloride :
methanol=100:3), to thereby give the title compound (286 mg).
[0407] .sup.1H-NMR (CDCl.sub.3) .delta.:2.49(3H, s), 2.79 (2H, t,
J=5.7 Hz), 2.85-2.93 (2H, m), 3.58 (2H, t, J=1.8 Hz).
[0408] MS (FAB) m/z:233 (M+H).sup.+.
Referential Example 10
5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic
acid lithium salt
##STR00087##
[0410] The compound obtained in Referential Example 9 (531 mg) was
dissolved in anhydrous diethyl ether (20 mL), and n-butyllithium
(as 1.54N hexane solution, 1.63 mL) was added dropwise thereto at
-78.degree. C., followed by stirring for 30 minutes under ice
cooling. After carbon dioxide gas was introduced into the reaction
mixture at -78.degree. C. for 10 minutes, the mixture was heated to
room temperature, and the reaction mixture was concentrated under
reduced pressure, to thereby give the title compound (523 mg).
[0411] .sup.1H-NMR (DMSO-d.sub.6) .delta.:2.37 (3H, s), 2.64-2.85
(4H, m), 3.54 (2H, s).
Referential Example 11
2-[(E)-2-phenylethenyl]oxazole-4-carboxylic acid ethyl ester
##STR00088##
[0413] Synthesis was performed as described by Panek et al. (J.
Org. Chem., vol. 61, p. 6496 (1996)). Sodium hydrogencarbonate
(22.8 g) and ethyl bromopyruvate (10.5 mL) were added to a solution
of cinnamamide (10.0 g) in tetrahydrofuran (250 mL) at room
temperature, and the mixture was heated under reflux for 48 hours.
After the reaction mixture was left to cool to room temperature,
the mixture was filtered through Celite, and the filtrate was
concentrated under reduced pressure. The residue was dissolved in
tetrahydrofuran (30 mL), and trifluoroacetic acid anhydride (30 mL)
was added to the solution at 0.degree. C. The mixture was gradually
heated to room temperature, and was stirred for 63 hours. Saturated
aqueous sodium hydrogencarbonate (500 mL) and ethyl acetate (150
mL) were added to the reaction mixture to partition the mixture.
The aqueous layer was extracted with ethyl acetate (150 mL), and
the organic layers were combined. The combined organic layer was
washed with saturated brine (150 mL), dried over sodium sulfate
anhydrate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=5:1.fwdarw.3:1), to thereby give the title compound (10.9
g).
[0414] .sup.1H-NMR (CDCl.sub.3) .delta.:1.41 (3H, t, J=7.0 Hz),
4.42 (2H, q, J=7.0 Hz), 6.96 (1H, d, J=16.6 Hz), 7.30-7.40 (3H, m),
7.53 (2H, d, J=6.8 Hz), 7.63 (1H, d, J=16.6 Hz), 8.20 (1H, s).
Referential Example 12
2-[(E)-2-phenylethenyl]oxazole-4-carbaldehyde
##STR00089##
[0416] The compound obtained in Referential Example 11 (8.57 g) was
dissolved in methylene chloride (80 mL), and diisobutylaluminium
hydride (as 1.0N hexane solution, 66 mL) was added dropwise to the
solution at -78.degree. C., followed by stirring for 15 minutes.
Subsequently, methanol (11 mL) was added dropwise to the resultant
mixture, and the mixture was heated to room temperature over 1
hour. The reaction mixture was filtered through Celite, and the
resultant paste matter was partitioned between ethyl acetate (200
mL) and saturated aqueous ammonium chloride (200 mL). The aqueous
layer was extracted with methylene chloride (2.times.100 mL), and
the organic layers were combined. The combined organic layer was
washed with saturated aqueous sodium hydrogencarbonate (100 mL) and
saturated brine (100 mL). The washed organic layer was combined
with the filtrate from the above-described Celite filtration, and
the thus-obtained mixture was dried over sodium sulfate anhydrate.
The solvent was distilled away under reduced pressure, and the
residue was purified by silica gel column chromatography (methylene
chloride:ethyl acetate=5:1 methylene chloride:methanol=10:1), to
thereby give the title compound (5.86 g).
[0417] .sup.1H-NMR (CDCl.sub.3) .delta.:6.96 (1H, d, J=16.6 Hz),
7.35-7.45 (3H, m), 7.56 (2H, d, J=6.4 Hz), 7.67 (1H, d, J=16.6 Hz),
8.26 (1H, s), 9.98 (1H, s).
[0418] MS (FAB )m/z:200 (M+H).sup.+.
Referential Example 13
2-[(E)-2-phenylethenyl]-4-vinyloxazole
##STR00090##
[0420] n-Butyllithium (as 1.54N hexane solution, 14.2 mL) was added
dropwise to a solution of (methyl)triphenylphosphonium bromide
(8.16 g) in tetrahydrofuran (80 mL) at 0.degree. C., and the
mixture was stirred at room temperature for 30 minutes. After the
reaction mixture was cooled back to 0.degree. C., a solution of the
compound obtained in Referential Example 12 (3.64 g) in
tetrahydrofuran (20 mL) was added to the mixture, and the
thus-obtained mixture was heated to room temperature. After the
mixture was stirred for 2 hours, water (200 mL) and ethyl acetate
(100 mL) were added thereto to partition the mixture. The aqueous
layer was extracted with ethyl acetate (50 mL), and the organic
layers were combined. The combined organic layer was washed with
saturated brine (100 mL), and dried over sodium sulfate anhydrate.
The solvent was distilled away under reduced pressure, and the
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=4:1.fwdarw.4 3:1), to thereby give the title
compound (2.84 g).
[0421] .sup.1H-NMR (CDCl.sub.3) .delta.:5.33 (1H, dd, J=1.5, 10.7
Hz), 5.98 (1H, dd, J=1.5, 17.6 Hz), 6.56 (1H, dd, J=10.7, 17.6 Hz),
6.95 (1H, d, J=16.6 Hz), 7.31-7.42 (3H, m), 7.49-7.56 (4H, m).
[0422] MS (FAB )m/z:198 (M+H).sup.+.
Referential Example 14
2-{2-[(E)-2-phenylethenyl]oxazol-4-yl}-1-ethanol
##STR00091##
[0424] 9-Borabicyclo[3.3.1]nonane (as 0.5N tetrahydrofuran
solution, 158 mL) was added to a solution of the compound obtained
in Referential Example 13 (13.0 g) in tetrahydrofuran (500 mL) at
0.degree. C., and the mixture was stirred at room temperature for
15 hours. To the reaction mixture were sequentially added dropwise
water (10 mL), 3N aqueous sodium hydroxide (80 mL), and aqueous
hydrogen peroxide (80 mL) at 0.degree. C., and the mixture was
stirred at room temperature for 6 hours. Water (600 mL) and ethyl
acetate (200 mL) were added to the reaction mixture to partition
the mixture, and the aqueous layer was extracted with ethyl acetate
(200 mL). The organic layers were combined, and the combined
organic layer was washed with saturated brine (200 mL), and dried
over sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure, and the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=2:1.fwdarw.pure ethyl
acetate), to thereby give the title compound (14.1 g).
[0425] .sup.1H-NMR (CDCl.sub.3) .delta.:2.69 (1H, br.s), 2.80 (2H,
t, J=5.6 Hz), 3.90-3.97 (2H, m), 6.91 (1H, d, J=16.6 Hz), 7.30-7.42
(4H, m), 7.43-7.56 (3H, m).
[0426] MS (FAB )m/z:216 (M+H).sup.+.
Referential Example 15
2-(2-{2-[(E)-2-phenylethenyl]oxazol-4-yl}ethyl)-1H-isoindole-1, 3
(2H)-dione
##STR00092##
[0428] To a solution of the compound obtained in Referential
Example 14 (292 mg) in tetrahydrofuran (15 mL) were added
phthalimide (200 mg), triphenylphosphine (357 mg), and diethyl
azodicarboxylate (0.214 mL) at room temperature, and the mixture
was stirred for 4 hours. The solvent was distilled away from the
reaction mixture under reduced pressure, and the residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=3:1), to thereby give the title compound (447 mg).
[0429] .sup.1H-NMR (CDCl.sub.3) .delta.:2.98 (2H, t, J=7.2 Hz),
4.03 (2H, t, J=7.2 Hz), 6.88 (1H, d, J=16.6 Hz), 7.28-7.45 (5H, m),
7.48 (2H, d, J=7.3 Hz), 7.71 (2H, dd, J=2.9, 5.4 Hz), 7.84 (2H, dd,
J=2.9, 5.4 Hz).
[0430] MS (FAB )m/z:345 (M+H).sup.+.
Referential Example 16
2-{2-[(E)-2-phenylethenyl]oxazol-4-yl}ethylcarbamic acid tert-butyl
ester
##STR00093##
[0432] Hydrazine monohydrate (1.50 mL) was added to a solution of
the compound obtained in Referential Example 15 (6.40 g) in ethanol
(150 mL) at room temperature, and the mixture was stirred for 1
hour. Subsequently, an additional hydrazine monohydrate (0.500 mL)
was added thereto at room temperature, and the mixture was stirred
for 2 hours. To the reaction mixture were added methylene chloride
(150 mL), saturated aqueous sodium hydrogencarbonate (150 mL), and
di-tert-butyl dicarbonate (13.4 g) at room temperature, and the
mixture was stirred for 30 minutes. After the mixture was
partitioned, the aqueous layer was extracted with methylene
chloride (50 mL). The organic layers were combined, and the
combined organic layer was dried over sodium sulfate anhydrate. The
solvent was distilled away under reduced pressure, and the residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=2:1.fwdarw.1:1), to thereby give the title compound (5.06
g).
[0433] .sup.1H-NMR (CDCl.sub.3) .delta.:1.45 (9H, s), 2.75 (2H, t,
J=6.6 Hz), 3.46 (2H, dt, J=5.9, 6.6 Hz), 4.92 (1H, br.s), 6.91 (1H,
d, J=16.6 Hz), 7.29-7.45 (4H, m), 7.48 (1H, d, J=16.6 Hz), 7.52
(2H, d, J=7.3 Hz).
[0434] MS (FAB )m/z:315 (M+H).sup.+, 259 (M-isobutene+H).sup.+, 315
(M-Boc+H).sup.+.
Referential Example 17
2-[(E)-2-phenylethenyl]-6,7-dihydroxazolo[5,4-c]pyridine-5(4H)-carboxylic
acid tert-butyl ester
##STR00094##
[0436] To a solution of the compound obtained in Referential
Example 16 (190 mg) in toluene (15 mL) were added paraformaldehyde
(54.5 mg) and p-toluenesulfonic acid (7.2 mg) at room temperature.
The mixture was heated under reflux for 1 hour, and was left to
cool. To the reaction mixture were added ethyl acetate (15 mL) and
saturated aqueous sodium hydrogencarbonate (15 mL) to partition the
mixture, and the aqueous layer was extracted with ethyl acetate (10
mL). The organic layers were combined, and the combined organic
layer was dried over sodium sulfate anhydrate. The solvent was
distilled away under reduced pressure, and the residue was purified
by silica gel column chromatography (hexane:ethyl
acetate=3:1.fwdarw.2:1), to thereby give the title compound (153
mg).
[0437] .sup.1H-NMR (CDCl.sub.3) .delta.:1.50 (9H, s), 2.67 (2H,
br.s), 3.73 (2H, br.s), 4.55 (2H, s), 6.90 (1H, d, J=16.1 Hz),
7.29-7.42 (3H, m), 7.46 (1H, d, J=16.1 Hz), 7.52 (2H, d, J=7.3
Hz).
[0438] MS (FAB) m/z:327 (M+H).sup.+, 271 (M-isobutene+H).sup.+, 227
(M-Boc+H).sup.+.
Referential Example 18
2-formyl-6,7-dihydroxazolo[5,4-c]pyridine-5(4H)-carboxylic acid
tert-butyl ester
##STR00095##
[0440] To a solution of the compound obtained in Referential
Example 17 (803 mg) in tetrahydrofuran (16 mL) were added acetone
(8.0 mL), water (4.0 mL), N-methylmorpholine N-oxide (577 mg), and
0.039M aqueous osmium tetraoxide (3.20 mL) at room temperature, and
the mixture was stirred overnight. Ethyl acetate (50 mL) and 10%
aqueous sodium thiosulfate (50 mL) were added to the reaction
mixture to partition the mixture. The aqueous layer was extracted
with ethyl acetate (30 mL). The organic layers were combined, and
the combined organic layer was dried over sodium sulfate anhydrate.
The solvent was distilled away under reduced pressure, and the
residue was dissolved in tetrahydrofuran (16 mL). To the solution
were added methanol (8.0 mL), water (8.0 mL), and sodium
metaperiodate (790 mg) at room temperature, and the mixture was
stirred for 3 hours. Subsequently, ethyl acetate (30 mL) and water
(50 mL) were added to the reaction mixture to partition the
mixture, and the aqueous layer was extracted with ethyl acetate (20
mL). The organic layers were combined, and the combined organic
layer was washed with saturated aqueous sodium hydrogencarbonate
(50 mL), and dried over sodium sulfate anhydrate. The solvent was
distilled away under reduced pressure, and the residue was purified
by silica gel column chromatography (hexane:ethyl
acetate=4:1.fwdarw.2:1), to thereby give the title compound (234
mg). This aldehyde was unstable and thus was immediately used for
subsequent reaction.
[0441] .sup.1H-NMR (CDCl.sub.3) .delta.:1.49 (9H, s), 2.77 (2H,
br.s), 3.77 (2H, br.s), 4.62 (2H, s), 9.70 (1H, s).
Referential Example 19
6,7-dihydroxazolo[5,4-c]pyridine-2,5(4H)-dicarboxylic acid
5-(tert-butyl) 2-methyl ester
##STR00096##
[0443] To a solution of the compound obtained in Referential
Example 18 (225 mg) in methanol (9.0 mL) were added sodium cyanide
(220 mg) and manganese dioxide (780 mg) at room temperature, and
the mixture was stirred for 30 minutes. Subsequently, the mixture
was filtered through Celite by use of ethyl acetate, and the
filtrate was washed with water (50 mL) and saturated brine (50 mL),
and dried over sodium sulfate anhydrate. The solvent was distilled
away under reduced pressure, and the residue was purified by silica
gel column chromatography (hexane:ethyl acetate=3:2.fwdarw.1:1), to
thereby give the title compound (120 mg).
[0444] .sup.1H-NMR (CDCl.sub.3) .delta.:1.49 (9H, s), 2.73 (2H,
br.s), 3.74 (2H, br.s), 4.01 (3H, s), 4.59 (2H, s).
[0445] MS (FAB) m/z:283 (M+H).sup.+.
Referential Example 20
5-methyl-4,5,6,7-tetrahydroxazolo[5,4-c]pyridine-2-carboxylic acid
methyl ester
##STR00097##
[0447] Trifluoroacetic acid (15 mL) was added to a solution of the
compound obtained in Referential Example 19 (500 mg) in methylene
chloride (15 mL) at room temperature, and the mixture was stirred
for 10 minutes. The reaction mixture was concentrated under reduced
pressure, and to the resulting residue were added methylene
chloride (20 mL), triethylamine (0.495 mL), acetic acid (205 mL),
formalin (0.230 mL), and sodium triacetoxyborohydride (570 mg) at
room temperature, followed by stirring for 15 minutes.
Subsequently, methylene chloride (20 mL) and saturated aqueous
sodium hydrogencarbonate (50 mL) were added to the reaction mixture
to partition the mixture, and the aqueous layer was extracted with
methylene chloride (3.times.20 mL). The organic layers were
combined, and the combined organic layer was dried over sodium
sulfate anhydrate. The solvent was distilled away under reduced
pressure, and the residue was purified by silica gel column
chromatography (chloroform:methanol=20:1.fwdarw.10:1), to thereby
give the title compound (257 mg).
[0448] .sup.1H-NMR (CDCl.sub.3) .delta.:2.52 (3H, s), 2.72-2.78
(2H, m), 2.78-2.83 (2H, m), 3.61 (2H, t, J=1.7 Hz), 4.00 (3H,
s).
[0449] MS (FAB) m/z:197 (M+H).sup.+, 165 (M-OCH.sub.3).sup.+.
Referential Example 21
5-methyl-4,5,6,7-tetrahydroxazolo[5,4-c]pyridine-2-carboxylic acid
lithium salt
##STR00098##
[0451] To a solution of the compound obtained in Referential
Example 20 (800 mg) in tetrahydrofuran (24 mL) were added water
(6.0 mL) and lithium hydroxide (99.7 mg) at room temperature, and
the mixture was stirred for 10 minutes. The reaction mixture was
concentrated under reduced pressure, to thereby give the title
compound (825 mg).
[0452] .sup.1H-NMR (DMSO-d.sub.6) .delta.:2.37 (3H, s), 2.47 (2H,
t, J=5.6 Hz), 2.64 (2H, t, J=5.6 Hz), 3.43 (2H, s).
Referential Example 22
5-chloro-6-fluoroindole-2-carboxylic acid methyl ester
##STR00099##
[0454] A mixture of 3-chloro-4-fluoro-.alpha.-azidocinnamic acid
methyl ester (Japanese Patent Application Laid-Open (kokai) No.
7-149723) (1.85 g) and xylene (140 mL) was heated under reflux for
1 hour, and the solvent was distilled away. The residue was
purified by silica gel column chromatography (methylene chloride),
to thereby give the title compound (491 mg).
[0455] .sup.1H-NMR (CDCl.sub.3) .delta.:3.95 (3H, s), 7.13-7.15
(1H, m), 7.20 (1H, dd, J=9.3, 0.49 Hz), 7.71 (1H, d, J=7.3 Hz),
8.93 (1H, br.s).
[0456] MS (FAB) m/z:227 (M.sup.+).
Referential Example 23
5-chloro-6-fluoroindole-2-carboxylic acid
##STR00100##
[0458] The compound obtained in Referential Example 22 (461 mg) was
dissolved in a solvent mixture of tetrahydrofuran (15 mL), methanol
(10 mL), and water (10 mL), and lithium hydroxide (283 mg) was
added to the solution at room temperature, followed by stirring for
4 hours. The solvent was distilled away under reduced pressure, and
to the residue was added 1N HCl, to thereby make the mixture
slightly acidic. The resultant powder was collected by filtration,
and the powder was dried, to thereby give the title compound (422
mg).
[0459] .sup.1H-NMR (CDCl.sub.3) .delta.:7.08-7.10 (1H, m), 7.34
(1H, d, J=9.5 Hz), 7.88 (1H, d, J=7.6 Hz), 12.04 (1H, s), 13.16
(1H, s).
[0460] MS (FAB) m/z:213 (M.sup.+).
Referential Example 24
5-(pyridin-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine
##STR00101##
[0462] 1) Diphosphorus pentasulfide (500 g) was suspended in
formamide (3000 mL) under ice cooling, and the suspension was
stirred overnight. The reaction mixture was partitioned by adding
water and diethyl ether. The organic layer was dried over anhydrous
magnesium sulfate, and the solvent was distilled away, to thereby
give an oily matter. The oily matter was dissolved in n-butanol
(350 mL), and to the solution was added
3-chloro-4-oxo-1-piperidinecarboxylic acid ethyl ester (150 g)
which had been synthesized in accordance with the method described
in Tetrahedron, vol. 39, p. 3767 (1983), followed by stirring at
100.degree. C. for 2.5 hours. The reaction mixture was filtered
through Celite, and the filtrate was washed sequentially with
saturated aqueous sodium hydrogencarbonate and saturated brine. The
washed filtrate was dried over sodium sulfate anhydrate, and the
solvent was distilled away. The residue was purified by silica gel
column chromatography (methylene chloride.fwdarw.ethyl
acetate:hexane=1:2), to thereby give
6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylic acid ethyl
ester (79.0 g).
[0463] .sup.1H-NMR (CDCl.sub.3) .delta.:1.30 (3H, t, J=7.3 Hz),
2.96 (2H, br.s), 3.82 (2H, br.s), 4.19 (2H, q, J=7.3 Hz), 4.73 (2H,
br.s)8.68 (1H, s).
[0464] MS (FAB) m/z:213 (M+H).sup.+.
[0465] 2) To the above product (33.5 g) was added 3.5N aqueous
sodium hydroxide (250 mL), and the mixture was heated under reflux
overnight. After the reaction mixture was cooled to room
temperature, di-tert-butyl dicarbonate (103 g) was added to the
mixture under ice cooling, followed by stirring overnight at room
temperature. 3N HCl was added to the reaction mixture, to thereby
adjust pH to 1 to 2. Methylene chloride was added to the mixture to
partition the mixture. The organic layer was sequentially washed
with saturated aqueous sodium hydrogencarbonate and saturated
brine, and dried over sodium sulfate anhydrate. The mixture was
concentrated under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=1:2), to thereby give
6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylic acid tert-butyl
ester (21.1 g).
[0466] .sup.1H-NMR (CDCl.sub.3) .delta.:1.49 (9H, s), 2.94 (2H,
br.s), 3.76 (2H, br.s), 4.68 (2H, s), 8.67 (1H, s).
[0467] MS (FAB) m/z:241 (M+H).sup.+.
[0468] 3) Trifluoroacetic acid (25 mL) was added to the solution of
the compound obtained in the above-described step 2) (5.00 g) in
methylene chloride (25 mL) at room temperature, and the mixture was
stirred for 10 minutes. The reaction mixture was concentrated under
reduced pressure, and to the resulting residue were added
4-bromopyridine (5.20 g), N,N-dimethylformamide (30 mL), and
triethylamine (15.5 mL) at room temperature, followed by stirring
at 150.degree. C. for 2 days. The resultant mixture was left to
cool to room temperature, and the resultant colorless precipitate
was separated by filtration. The filtrate was concentrated under
reduced pressure, and methylene chloride (50 mL) and saturated
aqueous sodium hydrogencarbonate (100 mL) were added thereto. The
aqueous layer was saturated with sodium chloride. After the
resultant mixture was partitioned, the aqueous layer was extracted
with methylene chloride (5.times.30 mL), and the organic layers
were combined. The combined organic layer was dried over sodium
sulfate anhydrate. The solvent was distilled away under reduced
pressure, and the residue was purified by silica gel column
chromatography (methylene chloride:methanol=20:1.fwdarw.8:1), to
thereby give the title compound (2.97 g).
[0469] .sup.1H-NMR (CDCl.sub.3) .delta.:3.07 (2H, t, J=5.9 Hz),
3.81 (2H, t, J=5.9 Hz), 4.61 (2H, s), 6.74 (2H, t, J=6.5 Hz), 8.30
(2H, t, J=6.5 Hz), 8.70 (1H, s).
[0470] MS (ESI) m/z:218 (M+H).sup.+.
Referential Example 25
2-chloro-6,7-dihydro-4H-pyrano[4,3-d]thiazole
##STR00102##
[0472] 1) Tetrahydro-4H-pyran-4-one (5.0 g) was dissolved in
cyclohexane (20 mL), and to the solution were added pyrrolidine
(4.35 mL) and p-toluenesulfonic acid monohydrate (48 mg). The
mixture was heated under reflux for 70 minutes while water was
removed with Dean-Stark apparatus. The reaction mixture was cooled
to room temperature, and the supernatant was separated and
concentrated under reduced pressure. The residue was dissolved in
methanol (15 mL), and sulfur powder (1.60 g) was added thereto
under water cooling. After an additional 15 minutes, a solution of
cyanamide (2.10 g) in methanol (10 mL) was added dropwise thereto
over 20 minutes, and the thus-obtained mixture was stirred for 3
days. The solvent was distilled away under reduced pressure, and
the residue was separated by silica gel column chromatography
(methylene chloride:methanol=20:1.fwdarw.10:1.fwdarw.4:1), to
thereby give 6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-ylamine (3.97
g).
[0473] .sup.1H-NMR (CDCl.sub.3) .delta.:2.66-2.70 (2H, m), 3.97
(2H, t, J=5.6 Hz), 4.63 (2H, s), 4.94 (2H, br.s).
[0474] MS (FAB) m/z:157 (M+H).sup.+.
[0475] 2) Cupric chloride (4.10 g) was dissolved in acetonitrile
(50 mL), and tert-butyl nitrite (3.93 g) was added thereto all at
once under water cooling. After 10 minutes, to the mixture was
added the compound obtained by the above-described reaction (3.97
g) over approximately 1 hour, and the thus-obtained mixture was
stirred at room temperature for 1 hour. Subsequently, the reaction
mixture was heated to 65.degree. C. and stirring was continued for
2 hours. After silica gel (20 g) was added to the reaction mixture,
the solvent was distilled away under reduced pressure, and the
residue was subjected to silica gel column chromatography
(hexane:ethyl acetate=3:1), to thereby give the title compound
(1.78 g).
[0476] .sup.1H-NMR (CDCl.sub.3) .delta.:2.85-2.89 (2H, m), 4.02
(2H, t, J=5.6 Hz), 4.73 (2H, s).
[0477] MS (FAB) m/z:175 (M+H).sup.+.
Referential Example 26
6,7-dihydro-4H-pyrano[4,3-d]thiazole-2-carboxylic acid lithium
salt
##STR00103##
[0479] 1) The compound obtained in Referential Example 25 (1.78 g)
was dissolved in methanol (30 mL), and to the solution were added
10% palladium on carbon (300 mg) and sodium acetate (830 mg),
followed by stirring for 5 days under hydrogen stream at a pressure
of 5 atm. After the catalyst was filtered off, the solvent was
concentrated, and the residue was subjected to silica gel column
chromatography (hexane : ethyl acetate=2:1), to thereby give
6,7-dihydro-4H-pyrano[4,3-d]thiazole (1.14 g).
[0480] .sup.1H-NMR (CDCl.sub.3) .delta.:2.97-3.01 (2H, m), 4.04
(2H, t, J=5.6 Hz), 4.87 (2H, s), 8.69 (1H, s).
[0481] MS (FAB) m/z:142 (M+H).sup.+.
[0482] 2) The above-prepared product (1.14 g) was dissolved in
diethyl ether (30 mL), and after the solution was cooled to
-78.degree. C., 1.6N butyllithium (6.6 mL) was added thereto,
followed by stirring. After 20 minutes, carbon dioxide gas was
introduced into the mixture for 15 minutes. The reaction mixture
was brought back to room temperature, and the mixture was
concentrated under reduced pressure, to thereby give the title
compound (1.65 g).
[0483] .sup.1H-NMR (DMSO-d.sub.6) .delta.:2.83 (2H, t, J=5.6 Hz),
3.92 (2H, t, J=5.6 Hz), 4.73 (2H, s).
Referential Example 27
thiazolo[4,5-c]pyridine
##STR00104##
[0485] 3-(tert-Butoxycarbonylamino)-4-mercaptopyridine (Japanese
Patent Application Laid-Open (kokai) No. 4-321691) (9.20 g) was
dissolved in formic acid (60 mL), and the solution was heated under
reflux for 4 hours. The reaction mixture was concentrated under
reduced pressure, and to the residue were added 5N aqueous
potassium hydroxide (100 mL) and diethyl ether to partition the
residue. The organic layer was dried over sodium sulfate anhydrate,
and the solvent was distilled away under reduced pressure. Diethyl
ether was added to the residue, and the resultant precipitated
solid was collected by filtration, to thereby give the title
compound (3.97 g).
[0486] .sup.1H-NMR (CDCl.sub.3) .delta.:7.93 (1H, d, J=5.4 Hz),
8.60 (1H, d, J=5.4 Hz), 9.07 (1H, s), 9.46 (1H, s).
Referential Example 28
5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine
##STR00105##
[0488] In a manner similar to that employed in Referential Example
4, the title compound was prepared from the compound obtained in
Referential Example 27.
[0489] .sup.1H-NMR (CDCl.sub.3) .delta.:2.52 (3H, s), 2.77 (2H, t,
J=5.4 Hz), 2.92-3.00 (2H, m), 3.69 (2H, t, J=2.0 Hz), 8.61 (1H,
s).
[0490] MS (FAB) m/z:155 (M+H).sup.+.
Referential Example 29
5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine-2-carboxylic
acid lithium salt
##STR00106##
[0492] In a manner similar to that employed in Referential Example
5, the title compound was prepared from the compound obtained in
Referential Example 28.
[0493] .sup.1H-NMR (DMSO-d.sub.6) .delta.:2.38 (3H, s), 2.64 (2H,
br.s), 2.80 (2H, br.s), 3.44 (2H, br.s).
Referential Example 30
2-chloro-N,N-dimethyl-4,5,6,7-tetrahydro-benzothiazol-6-amine
##STR00107##
[0495] 2-Chloro-4,7-dihydro-1,3-benzothiazol-6(5H)-one (Helv. Cim.
Acta., vol. 77, p. 1256 (1994)) (2.0 g) was dissolved in methanol
(100 mL), and to the solution were added ammonium acetate (8.2 g)
and sodium cyanoborohydride (4.0 g), followed by heating under
reflux for 20 hours. Hydrochloric acid was added to the reaction
mixture, to thereby decompose excess sodium cyanoborohydride, and
the solvent was distilled away under reduced pressure. A 1N sodium
hydroxide solution was added to the residue, to thereby make the
mixture alkaline. The mixture was extracted with methylene
chloride. The organic layer was dried over anhydrous magnesium
sulfate, and the solvent was distilled away under reduced pressure,
to thereby give a pale-yellow oily matter. This oily matter was
dissolved in methanol (50 mL), and to the solution were added
aqueous formaldehyde (4.29 g) and sodium cyanoborohydride (3.49 g),
followed by stirring at room temperature for 12 hours. The solvent
was distilled away under reduced pressure, and methylene chloride
was added to the residue. The thus-obtained mixture was washed with
saturated sodium hydrogencarbonate, and the organic layer was dried
over anhydrous magnesium sulfate. The solvent was distilled away
under reduced pressure, and the residue was purified by silica gel
column chromatography (methylene chloride : methanol=10:1), to
thereby give the title compound (740 mg).
[0496] .sup.1H-NMR (CDCl.sub.3) .delta.:1.71-1.78 (1H, m),
2.10-2.19 (1H, m), 2.35 (6H, s), 2.66-2.94 (5H, m).
[0497] MS (FAB) m/z:217 (M+H).sup.+.
Referential Example 31
6-(dimethylamino)-4,5,6,7-tetrahydrobenzothiazole-2-carboxylic acid
lithium salt
##STR00108##
[0499] The compound obtained in Referential Example 30 (750 mg) was
dissolved in diethyl ether (15 mL), and after the solution was
cooled to -78.degree. C., 1.5N tert-butyllithium (3.5 mL) was added
thereto, followed by stirring for 20 minutes. After carbon dioxide
gas was introduced into the resultant mixture for approximately 15
minutes, the reaction mixture was brought back to room temperature,
and was concentrated under reduced pressure, to thereby give the
title compound.
[0500] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.75-1.78 (1H, m),
1.98-2.07 (1H, m), 2.50 (6H, s), 2.64-2.88 (5H, m).
Referential Example 32
2-amino-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylic acid
tert-butyl ester
##STR00109##
[0502] 1-tert-Butoxycarbonyl-3-pyrrolidone (1.58 g) was dissolved
in cyclohexane (10 mL), and to the solution were added
p-toluenesulfonic acid monohydrate (8.12 mg) and pyrrolidine (607
mg). The thus-obtained mixture was heated under reflux for 1.5
hours while water was removed with Dean-Stark apparatus. The
supernatant was separated, and was concentrated under reduced
pressure. The residue was dissolved in methanol (5 mL), and after
sulfur powder (274 mg) was added thereto, the thus-obtained mixture
was stirred for 15 minutes under ice cooling. A solution of
cyanamide (377 mg) in methanol (2 mL) was slowly added dropwise to
the reaction mixture. The thus-obtained mixture was stirred at room
temperature overnight, and was further heated under reflux for an
additional 2 hours. The reaction mixture was concentrated, and
methylene chloride and saturated aqueous sodium hydrogencarbonate
were added thereto. The organic layer was dried over sodium sulfate
anhydrate, and the solvent was distilled away under reduced
pressure. The residue was purified by silica gel column
chromatography (methanol:methylene chloride=1:39), to thereby give
the title compound (248 mg).
[0503] .sup.1H-NMR (CDCl.sub.3) .delta.1.50 (9H, s), 4.34-4.37 (1H,
m), 4.40-4.45 (1H, m), 4.49-4.55 (2H, m), 4.99 (2H, m).
Referential Example 33
2-bromo-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylic acid
tert-butyl ester
##STR00110##
[0505] Cupric bromide (445 mg) was suspended in
N,N-dimethylformamide, and tert-butyl nitrite (256 mg) was added
dropwise thereto at room temperature. To the thus-obtained mixture
was added a solution of the compound obtained in Referential
Example 32 (400 mg) in N,N-dimethylformamide (1 mL) under ice
cooling, and the reaction mixture was stirred at 60.degree. C. for
1.5 hours. Diethyl ether and saturated brine were added to the
reaction mixture. The organic layer was dried over anhydrous
magnesium sulfate, and was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (ethyl
acetate:hexane=1:4), to thereby give the title compound (174
mg).
[0506] .sup.1H-NMR (CDCl.sub.3) .delta.:1.51 (9H, s), 4.52-4.55
(1H, m), 4.57-4.67 (3H, m).
[0507] MS (FAB) m/z:305 (M+H).sup.+.
Referential Example 34
5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbox-
ylic acid lithium salt
##STR00111##
[0509] In a manner similar to that employed in Referential Example
10, the title compound was prepared from the compound obtained in
Referential Example 7.
[0510] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.42 (9H, s), 2.69-2.77
(2H, m), 3.60-3.68 (2H, m), 4.51-4.58 (2H, m).
Referential Example 35
2-bromo-4-(2-methoxy-2-oxoethyl)thiazole-5-carboxylic acid methyl
ester
##STR00112##
[0512] Cupric bromide (26.8 g) was added all at once to a solution
of tert-butyl nitrite (15.5 g) in acetonitrile (500 mL) under ice
cooling. To the reaction mixture was added dropwise a solution of
2-amino-5-methoxycarbonyl-4-thiazoleacetic acid methyl ester
(Yakugaku Zasshi (Journal of the Pharmaceutical Society of Japan),
vol. 86, p. 300 (1966)) (23.0 g) in acetonitrile (500 mL) over 45
minutes, and the thus-obtained mixture was stirred for 1 hour under
ice cooling, and then at room temperature for 30 minutes. The
reaction mixture was concentrated, and 10% hydrochloric acid and
diethyl ether were added to the residue. The organic layer was
separated, and was dried over anhydrous magnesium sulfate. The
solvent was distilled away under reduced pressure, and the residue
was purified by silica gel column chromatography (ethyl
acetate:hexane=1:4), to thereby give the title compound (25.9
g).
[0513] .sup.1H-NMR (CDCl.sub.3) .delta.:3.73 (3H, s), 3.87 (3H, s),
4.21 (2H, s).
Referential Example 36
2-[5-(hydroxymethyl)thiazol-4-yl]-1-ethanol
##STR00113##
[0515] A solution of the compound obtained in Referential Example
35 (23.4 g) in tetrahydrofuran (500 mL) was added dropwise to a
suspension of lithium aluminium hydride (9.03 g) in tetrahydrofuran
(500 mL) under ice cooling over 1 hour. The thus-obtained mixture
was stirred for an additional 1 hour under ice cooling, and to the
resultant mixture were sequentially added water (9 mL), 35% aqueous
sodium hydroxide (9 mL), and water (27 mL), followed by stirring at
room temperature for 1 hour. Anhydrous magnesium sulfate was added
to the reaction mixture, and after the thus-obtained mixture was
stirred, any insoluble matter was removed by filtration through
Celite, and the filtrate was concentrated. The residue was purified
by silica gel column chromatography (methanol:methylene
chloride=7:93), to thereby give the title compound (8.64 g).
[0516] .sup.1H-NMR (CDCl.sub.3) .delta.:3.01 (2H, t, J=5.5 Hz),
3.30 (1H, br.s), 3.57 (1H, br.s), 3.90 (2H, br.s), 4.75 (2H, br.s),
8.66 (1H, s).
[0517] MS (ESI) m/z:160 (M+H).sup.+.
Referential Example 37
methanesulfonic acid
2-(5-{[(methylsulfonyl)oxy]methyl}thiazol-4-yl)ethyl ester
##STR00114##
[0519] To a solution of the compound obtained in Referential
Example 36 (8.64 g) and triethylamine (45.4 mL) in methylene
chloride (500 mL) was added dropwise a solution of methanesulfonyl
chloride (12.6 mL) in methylene chloride at -78.degree. C. over 20
minutes. The thus-obtained mixture was stirred at -78.degree. C.
for 15 minutes, and then at 0.degree. C. for 1 hour. Water was
added to the resultant mixture. The organic layer was separated,
and was dried over sodium sulfate anhydrate. The solvent was
distilled away under reduced pressure, to thereby give the title
compound (13.4 g).
[0520] .sup.1H-NMR (CDCl.sub.3) .delta.:2.93 (3H, s), 3.03 (3H, s),
3.28 (2H, t, J=6.3 Hz), 4.61 (2H, t, J=6.3 Hz), 5.44 (2H, s), 8.84
(1H, s).
Referential Example 38
5-(1-methylcyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine
##STR00115##
[0522] To the compound obtained in Referential Example 37 (4.46 g)
in methylene chloride (20 mL) was added 1-methylcyclopropylamine
hydrochloride (J. Org. Chem., vol. 54, p. 1815 (1989)) (1.89 g)
under ice cooling, and the thus-obtained mixture was stirred at
room temperature overnight. Additional 1-methylcyclopropylamine
hydrochloride (1.89 g) was added thereto, and the thus-obtained
mixture was stirred at room temperature for 20 hours, followed by
heating under reflux for 5 hours with stirring. After methylene
chloride and water were added to the reaction mixture, the organic
layer was separated, and was dried over sodium sulfate anhydrate.
The solvent was distilled away under reduced pressure, and the
residue was purified by silica gel column chromatography
(methanol:methylene chloride=1:49), to thereby give the title
compound (944 mg).
[0523] .sup.1H-NMR (CDCl.sub.3) .delta.:0.40-0.50 (2H, m),
0.68-0.73 (2H, m), 1.16 (3H, s), 2.88-2.94 (2H, m), 3.03 (2H, t,
J=5.7 Hz), 3.89 (2H, br.s), 8.60 (1H, s).
[0524] MS (ESI) m/z:195 (M+H).sup.+.
Referential Example 39
5-(1-methylcyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbox-
ylic acid lithium salt
##STR00116##
[0526] In a manner similar to that employed in Referential Example
5, the title compound was prepared from the compound obtained in
Referential Example 38.
[0527] .sup.1H-NMR (DMSO-d.sub.6) .delta.:0.39 (2H, br.s), 0.56
(2H, br.s), 1.10 (3H, br.s), 2.66 (2H, br.s), 2.89 (2H, br.s), 3.75
(2H, br.s).
Referential Example 40
2-[6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl]-2-methyl-1-propanol
##STR00117##
[0529] In a manner similar to that employed in Referential Example
38, the title compound was prepared from the compound obtained in
Referential Example 37 and 2-amino-2-methyl-1-propanol.
[0530] .sup.1H-NMR (CDCl.sub.3) .delta.:1.15 (6H, s), 2.91 (4H, s),
3.45 (2H, s), 3.87 (2H, s), 8.63 (1H, s).
Referential Example 41
5-(2-{[tert-butyl(diphenyl)silyl]oxy}-1,1-dimethylethyl)-4,5,6,7-tetrahydr-
othiazolo[5,4-c]pyridine
##STR00118##
[0532] To a solution of the compound obtained in Referential
Example 40 (1.24 g) in N,N-dimethylformamide (5 mL) were added
tert-butylchlorodiphenylsilane (1.93 g) and imidazole (994 mg) at
room temperature, and the thus-obtained mixture was stirred
overnight. Water and diethyl ether were added to the reaction
mixture. The organic layer was separated, and was dried over
anhydrous magnesium sulfate. The solvent was distilled away under
reduced pressure, and the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=1:2), to thereby give the
title compound (2.46 g).
[0533] .sup.1H-NMR (CDCl.sub.3) .delta.:1.07 (9H, s), 1.15 (6H, s),
2.83-2.90 (2H, m), 2.93-3.00 (2H, m), 3.63 (2H, s), 3.97 (2H, s),
7.35-7.48 (6H, m), 7.63-7.70 (4H, m), 8.58 (1H, s).
[0534] MS (ESI) m/z:451 (M+H).sup.+.
Referential Example 42
5-(2-{[tert-butyl(diphenyl)silyl]oxy}-1,1-dimethylethyl)-4,5,6,7-tetrahydr-
othiazolo[5,4-c]pyridine-2-carboxylic acid lithium salt
##STR00119##
[0536] In a manner similar to that employed in Referential Example
5, the title compound was prepared from the compound obtained in
Referential Example 41.
[0537] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.01 (9H, s), 1.11 (6H,
s), 2.55-2.65 (2H, m), 2.80-2.90 (2H, m), 3.57 (2H, s), 3.80 (2H,
br.s), 7.40-7.52 (6H, m), 7.60-7.65 (4H, m).
Referential Example 43
4,7,8,10-tetrahydro-6H-pyrazolo[1,2-a]thiazolo[4,5-d]pyridazine
##STR00120##
[0539] 1) 4,5-Dimethylthiazole (5.00 g), N-bromosuccinimide (15.7
g), and .alpha.,.alpha.'-azobisisobutyronitrile (362 mg) were
dissolved in ethylene dichloride (500 mL) at room temperature, and
the solution was heated under reflux for 1 hour. The solvent was
distilled away, and the residue was purified by silica gel column
chromatography (hexane:diethyl ether=1:4), to thereby give
4,5-bis(bromomethyl)thiazole (5.24 g).
[0540] .sup.1H-NMR (CDCl.sub.3) .delta.:4.64 (2H, s), 4.74 (2H, s),
8.75 (1H, s).
[0541] 2) 4,5-Bis(bromomethyl)thiazole (1.37 g) and
1,2-trimethylenehydrazine hydrochloride (W09532965) (732 mg) were
suspended in ethanol (15 mL) under ice cooling, and triethylamine
(2.82 mL) was added dropwise thereto over 5 minutes, followed by
stirring at room temperature for 2 hours. The solvent was distilled
away, and methylene chloride (50 mL) and saturated aqueous sodium
hydrogencarbonate were added to the residue. The organic layer was
separated, and was dried over sodium sulfate anhydrate. The solvent
was distilled away under reduced pressure, and the residue was
purified by silica gel column chromatography (methanol : methylene
chloride=3:47), to thereby give the title compound (358 mg).
[0542] .sup.1H-NMR (CDCl.sub.3) .delta.:2.10-2.25 (2H, m), 3.01
(4H, br.s), 3.95 (2H, s), 3.99 (2H, br.s), 8.64 (1H, s). MS (FAB)
m/z:182 (M+H).sup.+.
Referential Example 44
4,7,8,10-tetrahydro-6H-pyrazolo[1,2-a]thiazolo[4,5-d)pyridazine-2-carboxyl-
ic acid lithium salt
##STR00121##
[0544] In a manner similar to that employed in Referential Example
5, the title compound was prepared from the compound obtained in
Referential Example 43.
[0545] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.90-2.10 (2H, m),
2.60-3.10 (4H, br.s), 3.65-4.00 (4H, m).
Referential Example 45
4,6,7,8,9,11-hexahydropyridaziino[1,2-a]thiazolo[4,5-d]pyridazine
##STR00122##
[0547] In a manner similar to that employed in Referential Example
43, the title compound was prepared from
4,5-bis(bromomethyl)thiazole (2.20 g) obtained in the step 1) of
Referential Example 43 and 1,2-tetramethylenehydrazine
hydrochloride (U.S. Pat. No. 5,726,126).
[0548] .sup.1H-NMR (CDCl.sub.3) .delta.:1.77 (4H, br.s), 2.20-3.50
(4H, br), 3.92 (4H, br.s), 8.65 (1H, s).
[0549] MS (FAB) m/z:196 (M+H).sup.+.
Referential Example 46
4,6,7,8,9,11-hexahydropyridazino[1,2-a]thiazolo[4,5-d]pyridazine-2-carboxy-
lic acid lithium salt
##STR00123##
[0551] In a manner similar to that employed in Referential Example
5, the title compound was prepared from the compound obtained in
Referential Example 45.
Referential Example 47
2-(methylsulfanyl)-5,7-dihydro-6H-pyrolo[3,4-d]pyrimidine-6-carboxylic
acid tert-butyl ester
##STR00124##
[0553] 1-(tert-Butoxycarbonyl)-3-pyrrolidone (4.57 g) was added to
N,N-dimethylformamide dimethylacetal (30 mL) at room temperature,
and the mixture was heated at 140.degree. C. for 1 hour. After the
reaction mixture was left to cool to room temperature, the mixture
was concentrated under reduced pressure, and hexane was added to
the residue. The resultant precipitated yellow powder was collected
by filtration. The powder was dissolved in ethanol (100 mL), and to
the solution were added methylisothiourea sulfate (9.24 g) and
sodium ethoxide (4.52 g) at room temperature, followed by heating
under reflux for 24 hours. The reaction mixture was partitioned by
adding saturated brine and diethyl ether. The organic layer was
dried over sodium sulfate anhydrate, and was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (methanol : methylene chloride=1:99), to thereby
give the title compound (1.10 g).
[0554] .sup.1H-NMR (CDCl.sub.3) .delta.:1.51 (9H, s), 2.57 (3H, m),
4.15-4.45 (4H, m), 8.39 (1/2H, s), 8.43 (1/2H, s).
[0555] MS (FAB) m/z:268 (M+H).sup.+.
Referential Example 48
2-(methylsulfonyl)-5,7-dihydro-6H-pyrolo[3,4-d]pyrimidine-6-carboxylic
acid tert-butyl ester
##STR00125##
[0557] To a solution of the compound obtained in Referential
Example 47 (1.08 g) in methylene chloride (20 mL) was added
m-chloroperbenzoic acid (1.99 g) under ice cooling, and the mixture
was stirred for 5 hours. To the reaction mixture were added
saturated aqueous sodium sulfite, saturated aqueous sodium
hydrogencarbonate, and methylene chloride, to thereby partition the
mixture. The organic layer was dried over sodium sulfate anhydrate,
and the solvent was distilled away under reduced pressure. Hexane
was added to the residue, and the resultant precipitated powder was
collected by filtration, to thereby give the title compound (1.09
g).
[0558] .sup.1H-NMR (CDCl.sub.3) .delta.:1.53 (9H, s), 3.36 (3H, m),
4.77-4.90 (4H, m), 8.77 (1/2H, s), 8.81 (1/2H, s).
[0559] MS (FAB) m/z:300 (M+H).sup.+.
Referential Example 49
2-cyano-5,7-dihydro-6H-pyrolo[3,4-d]pyrimidine-6-carboxylic acid
tert-butyl ester
##STR00126##
[0561] To a solution of the compound obtained in Referential
Example 48 (1.05 g) in methylene chloride (30 mL) was added
tetrabutylammonium cyanide (1.04 g) at room temperature, and the
mixture was stirred at room temperature for 1 hour. To the reaction
mixture was added 1N sodium hydroxide. The organic layer was
separated, and was dried over sodium sulfate anhydrate. The solvent
was distilled away under reduced pressure, and the residue was
purified by silica gel column chromatography (methylene
chloride:acetone=20:1), to thereby give the title compound (776
mg).
[0562] .sup.1H-NMR (CDCl.sub.3) .delta.:1.52 (9H, s), 4.70-4.85
(4H, m), 8.68-8.77 (1H, m).
[0563] MS (FAB) m/z:247 (M+H).sup.+.
Referential Example 50
5,7-dihydro-6H-pyrolo[3,4-d]pyrimidine-2,6-dicarboxylic acid
6-(tert-butyl)2-methyl ester
##STR00127##
[0565] To a solution of the compound obtained in Referential
Example 49 (776 mg) in methanol (10 mL) was added concentrated
hydrochloric acid (5 mL) at room temperature, and the mixture was
stirred at 100.degree. C. for 1 hour. The reaction mixture was left
to cool, and was concentrated under reduced pressure. The residue
was dissolved in methanol (10 mL), and to the solution were added
triethylamine (2.20 mL) and di-tert-butyl dicarbonate (1.37 g) at
room temperature, followed by stirring for 1 hour. The resultant
mixture was concentrated under reduced pressure, and was
partitioned by adding methylene chloride and saturated brine. The
organic layer was dried over sodium sulfate anhydrate, and the
solvent was distilled away. The residue was purified by silica gel
column chromatography (methanol:methylene chloride=3:97), to
thereby give the title compound (317 mg).
[0566] .sup.1H-NMR (CDCl.sub.3) .delta.:1.53 (9H, s), 4.09 (3H, s),
4.75-4.85 (4H, m), 8.81 (1/2H, s), 8.85 (1/2H, s).
[0567] MS (FAB) m/z:280 (M+H).sup.+.
Referential Example 51
5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-d]pyridazine-2-carboxylic
acid lithium salt
##STR00128##
[0569] 1) 4,5-Bis(bromomethyl)thiazole (600 mg) obtained in the
step 1) of Referential Example 43 was dissolved in ethanol (20 mL),
and 1,2-dimethylhydrazine hydrochloride (294 mg) was added to the
solution under ice cooling, followed by addition of triethylamine
(1.23 mL) all at once. The thus-obtained mixture was stirred at
room temperature for 30 minutes, and then at 50.degree. C. for 30
minutes. The solvent was distilled away, and the residue was
purified by silica gel column chromatography (methanol:methylene
chloride=1:19), to thereby give
5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-d]pyridazine (90
mg).
[0570] .sup.1H-NMR (CDCl.sub.3) .delta.:2.43 (3H, s), 2.56 (3H, s),
3.92 (2H, s), 4.06 (2H, br.s), 8.68 (1H, s). MS (FAB) m/z:170
(M+H).sup.+.
[0571] 2) In a manner similar to that employed in Referential
Example 5, the title compound was prepared from
5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-d]pyridazine.
[0572] .sup.1H-NMR (DMSO-d.sub.6) .delta.:2.28 (3H, s), 2.39 (3H,
s), 3.66 (2H, br.s), 3.88 (2H, br.s).
Referential Example 52
5-chloroindole-2-carboxylic acid 4-nitronhenyl ester
##STR00129##
[0574] 5-Chloroindole-2-carboxylic acid (20 g) was suspended in
methylene chloride (1500 mL), and N,N-dimethylformamide (2 mL) was
added thereto, followed by dropwise addition of thionyl chloride
(11 mL) at room temperature. The reaction mixture was heated under
reflux overnight, and the resultant mixture was concentrated under
reduced pressure. The residue was dissolved in methylene chloride
(1000 mL). Triethylamine (84.7 mL) was added to the solution under
ice cooling, and p-nitrophenol (14.2 g) was added thereto, followed
by stirring at room temperature for 1 hour. The reaction mixture
was concentrated under reduced pressure, and the residue was
partitioned by adding ethyl acetate and 0.2N hydrochloric acid. The
organic layer was sequentially washed with saturated aqueous sodium
hydrogencarbonate and saturated brine, and was dried over sodium
sulfate anhydrate. The solvent was distilled away under reduced
pressure, to thereby give the title compound (29.9 g).
[0575] .sup.1H-NMR (CDCl.sub.3) .delta.:7.35 (1H, dd, J=9.0, 1.7
Hz), 7.39-7.42 (2H, m), 7.45 (2H, dd, J=7.3, 1.7 Hz), 7.73 (1H, d,
J=1.0 Hz), 8.35 (2H, dd, J=7.3, 1.7 Hz), 9.09 (1H, br.s).
[0576] MS (FD)m/z:316 (M.sup.+).
Referential Example 53
6-chloro-2-quinolinecarbonitrile
##STR00130##
[0578] 6-Chloroquinoline (2.50 g) was dissolved in methylene
chloride (25 mL), and m-chloroperbenzoic acid (3.71 g) was added to
the solution under ice cooling, followed by stirring at room
temperature for 1 hour. The thus-obtained mixture was diluted with
methylene chloride, and the diluted mixture was washed with aqueous
sodium thiosulfate and aqueous sodium hydroxide, followed by drying
over sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure, and the residue was dissolved in methylene
chloride (40 mL). To the solution were added trimethylsilyl cyanide
(2.0 mL) and N,N-dimethylcarbamoyl chloride (1.50 mL), and the
thus-obtained mixture was heated under reflux for 9 hours. To the
resultant mixture were added additional trimethylsilyl cyanide (1.0
mL) and N,N-dimethylcarbamoyl chloride (0.80 mL), and the
thus-obtained mixture was heated under reflux for 16 hours. The
resultant mixture was diluted with methylene chloride, and 10%
aqueous potassium carbonate (40 mL) was added thereto, followed by
stirring for 30 minutes. The organic layer was separated, and was
dried over sodium sulfate anhydrate. The solvent was distilled away
under reduced pressure, and methylene chloride was added to the
residue. The resultant precipitated crystals were collected by
filtration, to thereby give the title compound (1.77 g).
Furthermore, the filtrate was concentrated, and was purified by
silica gel column chromatography (methylene chloride), to thereby
give the title compound (0.80 g).
[0579] .sup.1H-NMR (DMSO-d.sub.6) .delta.:7.94 (1H, dd, J=9.0, 2.2
Hz), 8.09 (1H, d, J=8.5 Hz), 8.15 (1H, d, J=9.0 Hz), 8.29 (1H, d,
J=2.2 Hz), 8.63 (1H, d, J=8.5 Hz).
[0580] MS (FAB) m/z:189 (M+H).sup.+.
Referential Example 54
6-chloro-2-quinolinecarboxylic acid
##STR00131##
[0582] The compound obtained in Referential Example 53 (1.73 g) was
dissolved in concentrated hydrochloric acid (40 mL), and the
solution was heated under reflux for 19 hours. After the resultant
mixture was cooled to room temperature, the precipitate was
collected by filtration, and was washed with water, to thereby give
the title compound (1.81 g).
[0583] .sup.1H-NMR (DMSO-d.sub.6) .delta.:7.87 (1H, dd, J=9.0, 2.4
Hz), 8.10-8.20 (2H, m), 8.24 (1H, d, J=2.2 Hz), 8.52 (1H, d, J=8.5
Hz).
[0584] MS (FAB) m/z:208 (M+H).sup.+.
Referential Example 55
3-(4-chlorophenyl)-2-(formylamino)propionic acid methyl ester
##STR00132##
[0586] (.+-.)-(4-Chlorophenyl)alanine methyl ester hydrochloride
(2.00 g) was suspended in methylene chloride (20 mL), and to the
suspension were added 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (1.60 g), 1-hydroxybenzotriazole
monohydrate (1.23 g), N-methylmorpholine (1.90 mL), and formic acid
(0.30 mL), followed by stirring for 15 minutes. Subsequently,
formic acid (0.30 mL) addition and subsequent stirring for 15
minutes were repeated 3 times. The reaction mixture was diluted
with methylene chloride. The organic layer was washed with water,
and was dried over sodium sulfate anhydrate. The solvent was
distilled away under reduced pressure, and the residue was purified
by silica gel column chromatography (methylene chloride :
methanol=40:1), to thereby give the title compound (1.21 g).
[0587] .sup.1H-NMR (CDCl.sub.3) .delta.:3.10 (1H, dd, J=13.9, 5.6
Hz), 3.18 (1H, dd, J=13.9, 5.9 Hz), 3.75 (3H, s), 4.95 (1H, m),
6.07 (1H, br), 7.05 (2H, d, J=8.3 Hz), 7.27 (2H, d, J=8.3 Hz), 8.18
(1H, s).
[0588] MS (FAB) m/z:242 (M+H).sup.+.
Referential Example 56
7-chloro-3-isoquinolinecarboxylic acid methyl ester
##STR00133##
[0590] The compound obtained in Referential Example 55 (1.45 g) was
dissolved in methylene chloride (40 mL), and oxalyl chloride (0.57
mL) was added dropwise thereto, followed by stirring at room
temperature for 30 minutes. Ferric chloride (1.17 g) was added to
the resultant mixture at an external temperature of -10.degree. C.,
and the mixture was stirred at room temperature for 4 days. To the
resultant mixture was added 1N hydrochloric acid, and the mixture
was diluted with methylene chloride. The organic layer was
separated, and was dried over sodium sulfate anhydrate. The solvent
was distilled away under reduced pressure, and the residue was
dissolved in methanol (38 mL). Concentrated sulfuric acid (2 mL)
was added to the solution, and the thus-obtained mixture was heated
under reflux for 20 hours. Aqueous sodium hydrogencarbonate was
added to the reaction mixture, and the mixture was extracted with
methylene chloride, followed by drying over sodium sulfate
anhydrate. The solvent was distilled away under reduced pressure,
and the residue was purified by silica gel column chromatography
(hexane:ethyl acetate=2:1 ethyl acetate), to thereby give the title
compound (0.25 g).
[0591] .sup.1H-NMR (CDCl.sub.3) .delta.:4.07 (3H, s), 7.74 (1H, dd,
J=8.8, 2.0 Hz), 7.94 (1H, d, J=8.8 Hz), 8.06 (1H, d, J=2.0 Hz),
8.59 (1H, s), 9.28 (1H, s).
Referential Example 57
7-chloro-3-isoquinolinecarboxylic acid hydrochloride
##STR00134##
[0593] The compound obtained in Referential Example 56 (0.23 g) was
dissolved in concentrated hydrochloric acid (10 mL), and the
solution was heated under reflux for 18 hours. After the reaction
mixture was cooled to room temperature, the precipitate was
collected by filtration, and was washed with water, to thereby give
the title compound (0.21 g).
[0594] .sup.1H-NMR (DMSO-d.sub.6) .delta.:7.96 (1H, m), 8.29 (1H,
d, J=8.5 Hz), 8.44 (1H, s), 8.72 (1H, s), 9.45 (1H, d, J=6.6
Hz).
[0595] MS (FAB) m/z:208 (M+H).sup.+.
Referential Example 58
(3R)-1-benzyl-3-{[tert-butyl(diphenyl)silyl]oxy}pyrrolidine
##STR00135##
[0597] (3R)-1-Benzyl-3-hydroxypyrrolidine (500 .mu.L) and imidazole
(466 mg) were dissolved in N,N-dimethylformamide (15 mL), and
tert-butyldiphenylsilyl chloride (1.57 mL) was added to the
solution under ice cooling, followed by stirring at room
temperature for 9 days. The solvent was distilled away under
reduced pressure, and the residue was partitioned by adding
methylene chloride and water. The organic layer was dried over
sodium sulfate anhydrate, and the solvent was distilled away under
reduced pressure. The residue was subjected to silica gel flash
column chromatography (hexane:ethyl acetate=3:1), to thereby give
the title compound (1.27 g).
[0598] .sup.1H-NMR (CDCl.sub.3) .delta.:1.05 (9H, s), 1.70-1.85
(1H, m), 1.90-2.00 (1H, m), 2.45-2.65 (3H, m), 2.70-2.80 (1H, m),
3.50-3.70 (2H, m), 4.35-4.45 (1H, m), 7.20-7.45 (11H, m), 7.60-7.70
(4H, m).
[0599] MS (ESI) m/z:416 (M+H).sup.+.
Referential Example 59
N-[(1R*, 2S*)-2-aminocyclopropyl]-5-chloroindole-2-carboxamide
##STR00136##
[0601] To a solution of cis-1,2-cyclopropanediamine hydrochloride
(J. Med. Chem., vol. 41, pp. 4723-4732 (1998)) (405 mg) and
5-chloroindole-2-carboxylic acid (546 mg) in N,N-dimethylformamide
(10 mL) were added 1-hydroxybenzotriazole monohydrate (377 mg),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (642
mg), and diisopropylethylamine (1.95 mL) at room temperature,
followed by stirring for 50 hours.. The reaction mixture was
concentrated under reduced pressure, and thereto were added
methylene chloride (50 mL) and saturated aqueous sodium
hydrogencarbonate (200 mL). The precipitated colorless solid was
filtered off. The filtrate was partitioned, and aqueous layer was
extracted with methylene chloride. The organic layers were
combined, and the combined organic layer was dried over sodium
sulfate anhydrate. The solvent was distilled away under reduced
pressure, and the resultant residue was purified by silica gel
flash column chromatography (methylene
chloride:methanol=100:7.fwdarw.10:1), to thereby give the title
compound (110 mg).
[0602] .sup.1H-NMR (DMSO-d.sub.6) .delta.:0.44 (1H, dd, J=10.7, 4.4
Hz), 1.11 (1H, dd, J=14.0, 7.4 Hz), 2.63-2.70 (1H, m), 3.07-3.16
(1H, m), 6.77 (1H, s), 6.97 (1H, br.s), 7.23 (1H, dd, J=8.9, 1.8
Hz), 7.36 (1H, d, J=8.9 Hz), 7.60 (1H, s), 9.32 (1H, s).
[0603] MS (FAB) m/z:250 (M+H).sup.+.
Referential Example 60
N-[(1R*, 2S*)-2-aminocyclobutyl]-5- chloroindole-2-carboxamide
##STR00137##
[0605] In a manner similar to that employed in Referential Example
59, the title compound was prepared from cis-1,2-cyclobutanediamine
hydrochloride (J, Am. Chem. Soc., vol. 64, pp. 2696-2700
(1942)).
[0606] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.55-2.20 (4H, m),
3.52-3.62 (1H, m), 4.35-4.50 (1H, m), 7.16 (1H, dd, J=8.7, 2.1 Hz),
7.19 (1H, s), 7.42 (1H, d, J=8.7 Hz), 7.70 (1H, d, J=2.1 Hz), 8.36
(1H, d, J=7.8 Hz), 11.77 (1H, br.s).
[0607] MS (ESI) m/z:264 (M+H).sup.+.
Referential Example 61
(1R*, 2R*)-2-aminocyclopentylcarbamic acid tert-butyl ester
##STR00138##
[0609] (.+-.)-trans-1,2-Cyclopentanediamine (WO98/30574) (692 mg)
was dissolved in methylene chloride (10 mL), and to the solution
were added triethylamine (1.1 mL) and
2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (493 mg) at
0.degree. C., followed by stirring at 0.degree. C. for 1 hour.
Subsequently, additional
2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (493 mg) was
added thereto, and the thus-obtained mixture was stirred at room
temperature for 7 hours. Water was added to the reaction mixture to
partition the mixture. The organic layer was washed with saturated
brine, and was dried over sodium sulfate anhydrate. The residue was
purified by silica gel flash column chromatography (methylene
chloride:methanol=9:1), to thereby give the title compound (395
mg).
[0610] .sup.1H-NMR (CDCl.sub.3) .delta.:1.25-1.40 (2H, m), 1.49
(9H, s), 1.59-1.77 (2H, m), 1.92-2.08 (1H, m), 2.10-2.17 (1H, m),
2.98 (1H, q, J=7.2 Hz), 3.48-3.53 (1H, m), 4.49 (1H, br.s).
[0611] MS (ESI) m/z:201 (M+H).sup.+.
Referential Example 62
N-[(1R*,
2R*)-2-aminocyclopentyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4--
c]pyridine-2-carboxamide hydrochloride
##STR00139##
[0613] The compound obtained in Referential Example 61 (175 mg) was
dissolved in N,N-dimethylformamide (3 mL), and to the solution were
added
5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic
acid lithium salt (90% purity, 258 mg),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (252
mg), 1-hydroxybenzotriazole monohydrate (60 mg), followed by
stirring at room temperature for 2 days. The solvent was distilled
away under reduced pressure by means of a pump, and the residue was
partitioned by adding methylene chloride and saturated aqueous
sodium hydrogencarbonate. The organic layer was washed with
saturated brine, and was dried over sodium sulfate anhydrate. The
solvent was distilled away under reduced pressure, and the residue
was purified by silica gel flash column chromatography (methylene
chloride:methanol=47:3). The resultant pale-yellow oily matter was
dissolved in hydrochloric acid-ethanol (5 mL), and the solution was
stirred at room temperature for 1 hour. Ethyl acetate was added
thereto, and the solvent was removed under reduced pressure. Ethyl
acetate was added to the residue, and the resultant precipitate was
collected by filtration, to thereby give the title compound (120
mg).
[0614] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.63-1.73 (4H, m),
1.99-2.06 (2H, m), 2.91 (3H, s), 3.09-3.14 (1H, m), 3.25-3.70 (4H,
m), 4.27-4.32 (1H, m), 4.42-4.46 (1H, m), 4.68-4.71 (1H, m),
8.20-8.23 (3H, m), 9.09 (1H, d, J=8.3 Hz), 11.82-12.01 (1H, m).
[0615] MS (ESI) m/z:281 (M+H).sup.+.
Referential Example 63
N-[(1R*, 2R*)-2-aminocyclopentyl]-5-chloro-1H-indole-2-carboxamide
hydrochloride
##STR00140##
[0617] The compound obtained in Referential Example 61 (1.40 g) was
dissolved in N,N-dimethylformamide (15 mL), and to the solution
were added 5-chloroindole-2-carboxylic acid (1.64 g),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.68
g), and 1-hydroxybenzotriazole monohydrate (473 mg), followed by
stirring at room temperature for 23 hours. The solvent was
distilled away under reduced pressure, and to the residue were
added methylene chloride and saturated aqueous sodium
hydrogencarbonate. The resultant precipitate was collected by
filtration, and the precipitate was washed with ethyl acetate,
methylene chloride, and methanol. Aside from this, the filtrate was
partitioned, and the organic layer was separated, followed by
drying over sodium sulfate anhydrate. The solvent was distilled
away under reduced pressure, and the residue was purified by silica
gel flash column chromatography (methylene chloride:methanol=19:1),
to thereby give a pale-yellow solid. This pale-yellow solid was
combined with the precipitate collected by the above-described
filtration, and this mixture was dissolved in methylene chloride
(10 mL). Trifluoroacetic acid (10 mL) was added thereto, and the
thus-obtained mixture was stirred at room temperature for 3 hours.
The solvent was distilled away under reduced pressure, and to the
residue were added methylene chloride and 1N aqueous sodium
hydroxide. The resultant precipitate was collected by filtration.
The organic layer of the filtrate was separated, and was dried over
sodium sulfate anhydrate. To the solution was added the precipitate
collected by the above-described filtration, and a 4N HCl-dioxane
solution (20 mL) was added thereto. The solvent was distilled away
under reduced pressure, and after methylene chloride (10 mL) and a
4N HCl-dioxane solution (10 mL) were added to the residue, the
solvent was distilled away again under reduced pressure. Ethyl
acetate was added to the residue, and the resultant precipitate was
collected by filtration, to thereby give the title compound (1.83
g).
[0618] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.60-1.75 (4H, m),
2.05-2.10 (2H, m), 3.49 (1H, q, J=7.6 Hz), 4.27 (4H, quintet, J=7.6
Hz), 7.17 (1H, d, J=8.6 Hz), 7.19 (1H, s), 7.42 (1H, d, J=8.6 Hz),
7.70 (1H, s), 8.24 (3H, br.s), 8.85 (1H, d, J=7.3 Hz), 11.91 (1H,
s).
[0619] MS (ESI) m/z:278 (M+H).sup.+.
Referential Example 64
(1R*, 2R* )-2-aminocyclohexylcarbamic acid tert-butyl ester
##STR00141##
[0621] In a manner similar to that employed in Referential Example
61, the title compound was prepared from
(.+-.)-trans-1,2-cyclohexanediamine. m.p.79-81.degree. C.
[0622] .sup.1H-NMR (CDCl.sub.3) .delta.:1.05-1.34 (4H, m), 1.45
(9H, s), 1.68-1.75 (2H, m), 1.92-2.02 (2H, m), 2.32 (1H, dt,
J=10.3, 3.9 Hz), 3.08-3.20 (1H, m), 4.50 (1H, br.s).
[0623] MS (FAB) m/z:215 (M+H).sup.+.
Referential Example 65
N-[(1R*, 2R*)-2-aminocyclohexyl]-5-
methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
trifluoroacetic acid salt (and hydrochloride)
##STR00142##
[0625] In a manner similar to that employed in Referential Example
62, the title compound was prepared from the compound obtained in
Referential Example 64.
[0626] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.10-1.80 (7H, m),
1.95-2.05 (1H, m), 2.97 (3H, s), 3.00-3.20 (3H, m), 3.63 (2H,
br.s), 3.72-3.88 (1H, m), 4.61 (2H, br.s), 7.98 (3H, s), 8.89 (1H,
d, J=9.2 Hz).
[0627] MS (FAB) m/z:295 (M+H).sup.+.
[0628] In a manner similar to that described above, the
hydrochloride was also prepared.
Referential Example 66
(1R*, 2S*)-2-aminocyclohexylcarbamic acid tert-butyl ester
##STR00143##
[0630] In a manner similar to that employed in Referential Example
61, the title compound was prepared from
cis-1,2-cyclohexanediamine.
[0631] .sup.1H-NMR (CDCl.sub.3) .delta.:1.30-1.70 (17H, m),
2.98-3.05 (1H, m), 3.60 (1H, br.s), 4.98 (1H, br.s).
[0632] MS (FAB) m/z:215 (M+H).sup.+.
Referential Example 67
N-[(1R*,
2S*)-2-aminocyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c-
]pyridine-2-carboxamide hydrochloride (and trifluoroacetic acid
salt)
##STR00144##
[0634] In a manner similar to that employed in Referential Example
62, the title compound was prepared from the compound obtained in
Referential Example 66.
[0635] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.30-1.90 (8H, m), 2.92
(3H, s), 3.05-3.79 (5H, m), 4.23 (1H, br.s), 4.34-4.79 (2H, m),
8.01-8.34 (3H, m), 8.30-8.49 (1H, m), 11.90-12.30 (1H, m).
[0636] MS (FAB) m/z:295 (M+H).sup.+.
[0637] In a manner similar to that described above, trifluoroacetic
acid salt was also prepared.
Referential Example 68
(1R*,
2R*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexylcarbamic acid
tert-butyl ester
##STR00145##
[0639] To a solution of the compound obtained in Referential
Example 64 (3.00 g) in N,N-dimethylformamide (10 mL) were added
5-chloroindole-2-carboxylic acid (2.88 g), 1-hydroxybenzotriazole
monohydrate (2.08 g), and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.95
g) at room temperature, and the thus-obtained mixture was stirred
for 3 days. The reaction mixture was concentrated under reduced
pressure, and to the resultant residue were added methylene
chloride (30 mL), saturated aqueous sodium hydrogencarbonate (150
mL), and water (150 mL). The resultant colorless precipitate was
collected by filtration, and was dried, to thereby give the title
compound (5.21 g).
[0640] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.10-1.45 (4H, m), 1.21
(9H, s), 1.68 (2H, d, J=8.1 Hz), 1.86 (2H, t, J=16.2 Hz), 3.22-3.42
(1H, m), 3.69 (1H, br.s), 6.66 (1H, d, J=8.5 Hz), 7.02 (1H, s),
7.15 (1H, dd, J=8.5, 2.0 Hz), 7.41 (1H, d, J=8.5 Hz), 7.67 (1H, d,
J=2.0 Hz), 8.15 (1H, d, J=8.1 Hz), 11.73 (1H, br.s).
[0641] MS (ESI) m/z:392 (M+H).sup.+.
Referential Example 69
N-[(1R*, 2R*)-2-aminocyclohexyl]-5-chloroindole-2-carboxamide
hydrochloride
##STR00146##
[0643] To a solution of the compound obtained in Referential
Example 68 (5.18 g) in methylene chloride (100 mL) was added a
HCl-ethanol solution (100 mL) at room temperature, and the mixture
was stirred for 2 days. The reaction mixture was concentrated under
reduced pressure, and diethyl ether (300 mL) was added to the
resultant residue. The resultant colorless precipitate was
collected by filtration, and was dried, to thereby give the title
compound (4.30 g).
[0644] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.20-1.36 (2H, m),
1.36-1.50 (2H, m), 1.60 (2H, br.s), 1.90 (1H, d, J=13.0 Hz), 2.07
(1H, d, J=13.7 Hz), 3.06 (1H, br.s), 3.83-3.96 (1H, m), 7.15-7.24
(2H, m), 7.45 (1H, d, J=8.6 Hz), 7.73 (1H, s), 8.00 (3H, br.s),
8.60 (1H, d, J=8.3 Hz), 11.86 (1H, s).
[0645] MS (ESI) m/z:292 (M+H).sup.+.
Referential Example 70
(1R*,
2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexylcarbamic acid
tert-butyl ester
##STR00147##
[0647] In a manner similar to that employed in Referential Example
68, the title compound was prepared from the compound obtained in
Referential Example 66.
[0648] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.20-1.45 (11H, m),
1.45-1.70 (4H, m), 1.70-1.85 (2H, m), 3.76 (1H, br.s), 4.08 (1H,
br.s), 6.64 (1H, d, J=7.6 Hz), 7.12 (1H, s), 7.16 (1H, dd, J=8.8,
2.0 Hz), 7.43 (1H, d, J=8.8 Hz), 7.69 (1H, d, J=2.0 Hz), 7.85 (1H,
d, J=6.9 Hz), 11.80 (1H, br.s).
[0649] MS (ESI) m/z:392 (M+H).sup.+.
Referential Example 71
N-[(1R*, 2S*)-2-aminocyclohexyl]-5- chloroindole-2-carboxamide
hydrochloride
##STR00148##
[0651] In a manner similar to that employed in Referential
[0652] Example 69, the title compound was prepared from the
compound obtained in Referential Example 70.
[0653] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.30-1.50 (2H, m),
1.55-1.95 (6H, m), 3.41 (1H, br.s), 4.32 (1H, br.s), 7.19 (1H, dd,
J=8.7, 2.0 Hz), 7.33 (1H, s), 7.45 (1H, d, J=8.7 Hz), 7.60-7.90
(4H, m), 8.17 (1H, d, J=7.1 Hz), 11.91 (1H, s).
[0654] MS (FAB) m/z:292 (M+H).sup.+.
Referential Example 72
(1R*, 2R*)-1,2-cycloheptanediol
##STR00149##
[0656] Cycloheptene (3.85 g) was added in small portions to 30%
hydrogen peroxide (45 mL) and 88% formic acid (180 mL), and the
thus-obtained mixture was stirred for 1 hour at 40-50.degree. C.,
and then at room temperature overnight. The solvent was distilled
away under reduced pressure, and to the residue was added 35%
aqueous sodium hydroxide, to thereby make the mixture basic. The
resultant mixture was stirred at 40-50.degree. C. for 10 minutes,
and ethyl acetate was added to the mixture to partition the
mixture. The aqueous layer was extracted with ethyl acetate 4
times. The organic layers were combined, and the combined organic
layer was dried over sodium sulfate anhydrate. The solvent was
distilled away under reduced pressure, to thereby give the title
compound (4.56 g).
[0657] .sup.1H-NMR (CDCl.sub.3) .delta.:1.44-1.56 (6H, m),
1.63-1.70 (2H, m), 1.83-1.91 (2H, m), 2.91 (2H, br.s), 3.40-3.44
(2H, m).
[0658] MS (FAB) m/z:131 (M+H).sup.+.
Referential Example 73
(1R*, 2R*)-1,2-cycloheptanediamine hydrochloride
##STR00150##
[0660] The compound obtained in Referential Example 72 (4.56 g) was
dissolved in methylene chloride (35 mL), and triethylamine (29 mL)
was added thereto, followed by cooling to -78.degree. C. To the
mixture was added dropwise methanesulfonyl chloride (8.13 mL), and
additional methylene chloride (10 mL) was added thereto. The
reaction mixture was stirred at the same temperature for 20
minutes, and then at 0.degree. C. for 1.5 hours. Water was added to
the reaction mixture to partition the mixture. The organic layer
was washed with saturated aqueous sodium hydrogencarbonate, and was
dried over sodium sulfate anhydrate. The solvent was distilled away
under reduced pressure, to thereby give an oily matter. This oily
matter was dissolved in N,N-dimethylformamide (90 mL), and sodium
azide (13.65 g) was added thereto, followed by stirring at
65.degree. C. for 18 hours. The resultant mixture was partitioned
by adding diethyl ether and water. The diethyl ether layer was
washed with saturated aqueous sodium hydrogencarbonate and
saturated brine, and was dried over sodium sulfate anhydrate. The
solvent was distilled away under reduced pressure, to thereby give
an oily matter.
[0661] This oily matter was dissolved in ethanol (70 mL), and 10%
palladium on carbon (50% water content, 4 g) was added thereto,
followed by stirring for 4 days under hydrogen atmosphere (3.5
atm). The 10% palladium on carbon was filtered off, and a 1N
HCl-ethanol solution (70 mL) was added to the filtrate. The solvent
was distilled away under reduced pressure, and the residue was
dissolved in methanol. Ethyl acetate was added to the solution, and
the solvent was distilled away again under reduced pressure. The
resultant precipitate was collected by filtration, to thereby give
the title compound (3.57 g).
[0662] .sup.1H-NMR (DMSO) .delta.:1.44 (4H, br.s), 1.73-1.81 (6H,
m), 3.43 (2H, br.s), 8.63 (6H, br.s). MS (ESI) m/z:129
(M+H).sup.+.
Referential Example 74
N-[(1R*, 2R*)-2-aminocycloheptyl-5-chloroindole-2-carboxamide
##STR00151##
[0664] In a manner similar to that employed in Referential Example
59, the title compound was prepared from the compound obtained in
Referential Example 73.
[0665] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.49-1.52 (4H, m),
1.72-1.91 (6H, m), 4.04-4.10 (1H, m), 7.17-7.23 (2H, m), 7.44 (1H,
d, J=8.8 Hz), 7.72 (1H, d, J=2.0 Hz), 7.96 (2H, br.s), 8.75 (1H, d,
J=8.5 Hz), 11.89 (1H, br.s).
[0666] MS (ESI) m/z:306 (M+H).sup.+.
Referential Example 75
(1R*, 2S*)-1,2-cyclooctanediol
##STR00152##
[0668] Cyclooctene (4.41 g) was dissolved in acetonitrile (45 mL)
and water (15 mL), and to the solution were added
N-methylmorpholine N-oxide (5.15 g), microencapsulated osmium
tetraoxide (1 g, 10% osmium tetraoxide content), followed by
stirring at 40-50.degree. C. for 21 hours. Any insoluble
microencapsulated osmium was filtered off, and was washed with
acetonitrile. The filtrate was concentrated under reduced pressure,
and the residue was purified by silica gel flash column
chromatography (hexane:ethyl acetate=1:1), to thereby give the
title compound (4.97 g).
[0669] .sup.1H-NMR (CDCl.sub.3) .delta.:1.48-1.58 (6H, m),
1.64-1.75 (4H, m), 1.86-1.96 (2H, m), 2.28 (2H, d, J=2.9 Hz), 3.90
(2H, d, J=8.3 Hz).
[0670] MS (FAB) m/z:145 (M+H).sup.+.
Referential Example 76
(1R*, 2S*)-1,2-diazidocyclooctane
##STR00153##
[0672] cis-1,2-Cyclooctanediol (4.82 g) was dissolved in methylene
chloride (60 mL), and triethylamine (27.7 mL) was added thereto.
After the reaction container was purged with argon, the reaction
mixture was cooled to -78.degree. C., and methanesulfonyl chloride
(7.7 mL, 100 mmol) was added dropwise thereto. The mixture was
stirred at the same temperature for 1 hour in total, and then at
0.degree. C. for 1 hour. Water was added to the reaction mixture to
partition the mixture. The organic layer was washed with water,
0.5N aqueous hydrochloric acid, water, and saturated aqueous sodium
hydrogencarbonate, and was dried over sodium sulfate anhydrate. The
solvent was distilled away under reduced pressure. The residue was
dissolved in N,N-dimethylformamide (80 mL), and sodium azide (13.0
g) was added thereto, followed by stirring at 65.degree. C. for 19
hours. The reaction mixture was partitioned by adding diethyl ether
and water. The diethyl ether layer was washed with saturated
aqueous sodium hydrogencarbonate and saturated brine, and was dried
over sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure, and the residue was purified by silica gel flash
column chromatography (hexane:ethyl acetate=6:1), to thereby give
the title compound (4.85 g).
[0673] .sup.1H-NMR (CDCl.sub.3) .delta.:1.49-1.64 (6H, m),
1.67-1.78 (2H, m), 1.81-1.97 (4H, m), 3.74-3.76 (2H, m).
Referential Example 77
(1R*, 2S*)-1,2-cyclooctanediamine hydrochloride
##STR00154##
[0675] The compound obtained in Referential Example 76 (4.85 g) was
dissolved in ethanol (55 mL), and 10% palladium on carbon (50%
water content, 3.0 g) was added thereto, followed by stirring for
21 hours under hydrogen atmosphere (4.5 atm). The catalyst was
filtered off, and to the filtrate was added a 1N HCl-ethanol
solution (50 mL). The solvent was distilled away under reduced
pressure, and ethyl acetate was added to the residue. The resultant
precipitate was collected by filtration, to thereby give the title
compound (4.14 g).
[0676] .sup.1H-NMR (DMSO) .delta.:1.51 (6H, br.s), 1.69 (2H, br.s),
1.79-1.99 (4H, m), 3.68-3.70 (2H, m), 8.66 (6H, br.s).
[0677] MS (ESI) m/z:143 (M+H).sup.+.
Referential Example 78
N-[(1R*, 2S*)-2-aminocyclooctyl]-5- chloroindole-2-carboxamide
##STR00155##
[0679] In a manner similar to that employed in Referential Example
59, the title compound was prepared from the compound obtained in
Referential Example 77.
[0680] MS (ESI) m/z:320 (M+H).sup.+.
Referential Example 79
(1R*, 2R*)-4-methoxy-1,2-cyclopentanediol (mixture of 4-position
stereoisomers)
##STR00156##
[0682] To a solution of 3-cyclopenten-1-ol (1.68 g) and methyl
iodide (1.25 mL) in tetrahydrofuran (20 mL), 60% sodium hydride
(800 mg) was added in small portions under ice cooling, and the
thus-obtained mixture was stirred at room temperature overnight.
The reaction mixture was partitioned by adding water and diethyl
ether, and the organic layer was dried over anhydrous magnesium
sulfate. The solvent was distilled away under reduced pressure
under ice cooling, to thereby give crude
4-methoxy-1-cyclopentene.
[0683] To the thus-obtained 4-methoxy-1-cyclopentene were added 88%
formic acid (90 mL) and 30% hydrogen peroxide (3.17 mL) at room
temperature, and the mixture was stirred at room temperature
overnight. The reaction mixture was concentrated under reduced
pressure, and 35% aqueous sodium hydroxide was added to the
residue, to thereby make the reaction mixture basic, followed by
stirring at 50.degree. C. for 10 minutes. The resultant mixture was
cooled to room temperature, and was extracted with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate, and
the solvent was distilled away. The residue was purified by silica
gel column chromatography (methanol:methylene chloride=1:19), to
thereby give the title compound (1.21 g).
[0684] .sup.1H-NMR (CDCl.sub.3) .delta.:1.65-1.85 (2H, m),
2.15-2.30 (2H, m), 3.28 (3H, s), 3.90-4.00 (2H, m), 4.26 (1H,
br.s).
Referential Example 80
(1R*, 2R*)-1,2-diazido-4-methoxycyclopentane (mixture of 4-position
stereoisomers)
##STR00157##
[0686] The compound obtained in Referential Example 79 (1.21 g) and
triethylamine (7.66 mL) were dissolved in methylene chloride (20
mL), and methanesulfonyl chloride (2.13 mL) was added dropwise
thereto at -78.degree. C. over 20 minutes. After completion of the
addition, the reaction mixture was heated to 0.degree. C., and was
stirred for 80 minutes, to thereby give crude
(1R*,2R*)-1,2-bis(methanesulfonyloxy)-4-methoxycyclopentane. This
crude product was dissolved in N,N-dimethylformamide (20 mL), and
sodium azide (3.57 g) was added thereto, followed by stirring at
65.degree. C. for 22 hours, and additional sodium azide (3.57 g)
was added thereto, followed by stirring at 70.degree. C. for 2
days. After the reaction mixture was left to cool, the mixture was
partitioned by adding water and diethyl ether, and the organic
layer was dried over anhydrous magnesium sulfate. The solvent was
distilled away, and the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=2:1), to thereby give the
title compound (584 mg).
[0687] .sup.1H-NMR (CDCl.sub.3) .delta.:1.65-1.80 (2H, m),
2.05-2.18 (1H, m), 2.25-2.40 (1H, m), 3.21 (3H, s), 3.55-3.65 (1H,
m), 3.75-3.90 (2H, m).
Referential Example 81
(1R*, 2R*)-4-methoxy-1,2-cyclopentanediamine hydrochloride (mixture
of 4-position stereoisomers)
##STR00158##
[0689] The compound obtained in Referential Example 80 (584 mg) was
dissolved in ethanol, and 10% palladium on carbon (321 mg) was
added thereto. The reaction mixture was subjected to hydrogenation
at ambient temperature and at atmospheric pressure for 2 days. The
catalyst was filtered off, and the filtrate was concentrated. To
the residue were added a 1N HCl-ethanol solution and ethyl acetate,
and the mixture was concentrated, to thereby give the title
compound (488 mg).
[0690] .sup.1H-NMR (CDCl.sub.3) .delta.:1.72-1.83 (1H, m),
1.91-2.03 (1H, m), 2.07-2.18 (1H, m), 2.37-2.50 (1H, m), 3.19 (3H,
s), 3.55-3.75 (2H, br), 3.85-3.95 (1H, m), 8.60-8.90 (6H, br).
[0691] MS (ESI) m/z:261 (2M+H).sup.+.
Referential Example 82
N-[(1R*,
2R*)-2-amino-4-methoxycyclopentyl]-5-chloroindole-2-carboxamide
(mixture of 4-position stereoisomers)
##STR00159##
[0693] The compound obtained in Referential Example 81 (470 mg) was
suspended in N,N-dimethylformamide (5 mL), and to the suspension
were added triethylamine (0.966 mL) and 5-chloroindole-2-carboxylic
acid p-nitrophenyl ester (805 mg), followed by stirring at room
temperature for 4 days. The solvent was distilled away under
reduced pressure, and the residue was partitioned by adding
methylene chloride and saturated, aqueous sodium hydrogencarbonate.
The organic layer was dried over sodium sulfate anhydrate, and the
solvent was distilled away under reduced pressure. The residue was
purified by silica gel column chromatography (methanol:methylene
chloride=1:9), to thereby give the title compound (268. mg).
Referential Example 83
(1R*, 2R*)-4-[(benzyloxy)methyl-1,2-cyclopentanediol (mixture of
4-position stereoisomers)
##STR00160##
[0695] In a manner similar to that employed in Referential Example
79, 4-hydroxymethyl-1-cyclopentene (J. Heterocycl. Chem., vol. 26,
p. 451 (1989)) was benzylated with benzyl bromide, and the
benzylated compound was reacted with formic acid-hydrogen peroxide,
to thereby give the title compound.
[0696] .sup.1H-NMR (CDCl.sub.3) .delta.:1.44-1.52 (1H, m),
1.77-1.85 (1H, m), 1.89-1.97 (1H, m), 2.25-2.35 (1H, m), 2.46-2.58
(1H, m), 3.40-3.50 (2H, m), 3.89 (1H, br.s), 4.08 (1H, br.s), 4.54
(2H, s), 7.27-7.39 (5H, m).
[0697] MS (FAB) m/z:223 (M+H).sup.+.
Referential Example 84
(1R*, 2R*)-4-[(benzyloxy)methyl]-1,2-cyclopentanediamine (mixture
of 4-position stereoisomers)
##STR00161##
[0699] In a manner similar to that employed in Referential Example
80, (1R*, 2R*)-4-benzyloxymethyl-1,2-diazidocyclopentane was
prepared from the compound obtained in Referential Example 83. This
compound was used in the next step without further purification,
and in a manner similar to that employed in Referential Example 81,
the title compound was prepared from the compound described
above.
Referential Example 85
N-{(1R*,
2R*)-2-amino-4-[(benzyloxy)methyl]cyclopentyl}-5-chloroindole-2-c-
arboxamide (mixture of 4-position stereoisomers)
##STR00162##
[0701] In a manner similar to that employed in Referential Example
59, the title compound was prepared from the compound obtained in
Referential Example 84.
[0702] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.07-1.15 (0.5H, m),
1.26-1.35 (0.5H, m), 1.47-1.55 (0.5H, m), 1.61-1.79 (1H, m),
1.83-1.92 (0.5H, m), 1.99-2.10 (0.5H, m), 2.12-2.20 (0.5H, m),
2.27-2.40 (1H, m), 3.10-3.20 (1H, m), 3.33-3.39 (2H, m), 3.81-3.92
(1H, m), 4.48 (2H, s), 7.13-7.20 (2H, m), 7.22-7.39 (5H, m), 7.43
(1H, d, J=8.5 Hz), 7.69 (1H, d, J=2.2 Hz), 8.34 (1H, t, J=7.1
Hz).
[0703] MS (FAB) m/z:398 (M+H).sup.+.
Referential Example 86
(1R*, 3R*, 6S*)-7-oxabicyclo[4.1.0]heptane-3-carboxylic acid ethyl
ester
##STR00163##
[0705] (1R*,4R*,5R*)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one (J. Org.
Chem., vol. 61, p. 8687 (1996)) (14.3 g) was dissolved in ethanol
(130 mL), and 2N aqueous sodium hydroxide (34.5 mL) was added to
the solution under ice cooling, followed by stirring at room
temperature for 7 hours. The solvent was distilled away under
reduced pressure, and water was added to the residue. The mixture
was extracted with methylene chloride, and the extract was dried
over sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure, and the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=83:17), to thereby give the
title compound (6.54 g).
[0706] .sup.1H-NMR (CDCl.sub.3) .delta.:1.25 (3H, t, J=7.1 Hz),
1.50-1.70 (2H, m), 1.71-1.82 (1H, m), 2.08-2.28 (4H, m), 3.16 (2H,
s), 4.12 (2H, q, J=7.1 Hz).
Referential Example 87
(1R*, 3S*, 4S*)-3-azido-4-hydroxycyclohexanecarboxylic acid ethyl
ester
##STR00164##
[0708] The compound obtained in Referential Example 86 (13.6 g) was
dissolved in N,N-dimethylformamide (100 mL), and to the solution
were sequentially added ammonium chloride (6.45 g) and sodium azide
(7.8 g) at room temperature, followed by stirring at 75.degree. C.
for 12 hours. The resultant mixture was concentrated to about
one-third of its original volume, and the resultant mixture was
diluted with water and ethyl acetate, followed by stirring for 3
minutes. The organic layer was washed with water and saturated
brine, and was dried over anhydrous magnesium sulfate. The solvent
was distilled away under reduced pressure, and the residue was
purified by silica gel column chromatography (ethyl acetate :
hexane=1:4), to thereby give the title compound (15.8 g).
[0709] .sup.1H-NMR (CDCl.sub.3) .delta.:1.28 (3H, t, J=7.1 Hz),
1.37-1.67 (2H, m), 1.86-1.95 (1H, m), 2.04-2.18 (2H, m), 2.32-2.43
(1H, m), 2.68-2.78 (1H, m), 3.40-3.60 (2H, m), 4.17 (2H, q, J=7.1
Hz).
Referential Example 88
(1R*, 3S*, 4S*)-3-[(tert-
butoxycarbonyl)amino]-4-hydroxycyclohexanecarboxylic acid ethyl
ester
##STR00165##
[0711] The compound obtained in Referential Example 87 (100 mg) and
di-tert-butyl dicarbonate (133 mg) were dissolved in ethyl acetate
(12 mL), and a catalytic amount of 10% palladium on carbon was
added thereto, followed by stirring at room temperature for 12
hours under hydrogen flow. After any insoluble matter was filtered
off, the solvent was distilled away under reduced pressure, and the
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=3:1), to thereby give the title compound (145
mg).
[0712] .sup.1H-NMR (CDCl.sub.3) .delta.:1.28 (3H, t, J=7.1 Hz),
1.45 (9H, s), 1.38-1.57 (2H, m), 1.86-1.95 (1H, m), 2.05-2.17 (1H,
m), 2.29-2.39 (2H, m), 2.61-2.68 (1H, m), 3.25-3.66 (3H, m), 4.17
(2H, q, J=7.1 Hz), 4.53 (1H, br.s).
Referential Example 89
(1R*, 3S*,
4R*)-4-azido-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxyli- c
acid ethyl ester and (1R*, 3S*,
4S*)-4-azido-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic
acid ethyl ester
##STR00166##
[0714] The compound obtained in Referential Example 88 (16 g) and
triethylamine (38 mL) were dissolved in methylene chloride (150
mL), and after the solution was cooled to -78.degree. C.,
methanesulfonyl chloride (13 mL) was added dropwise thereto at the
same temperature, followed by stirring at the same temperature for
15 minutes. The resultant mixture was heated to 0.degree. C., and
was stirred for 30 minutes and then at room temperature for 2
hours. To the thus-obtained mixture was added 0.1N HCl, and the
mixture was diluted with methylene chloride. The organic layer was
separated, and was washed with saturated aqueous sodium
hydrogencarbonate and saturated brine, followed by drying over
anhydrous magnesium sulfate. The solvent was distilled away under
reduced pressure, to thereby give crude
(1R*,3S*,4S*)-3-[(tert-butoxycarbonyl)amino]-4-[(methylsulfonyl)oxy]cyclo-
hexanecarboxylic acid ethyl ester.
[0715] The thus-obtained product was dissolved in
N,N-dimethylformamide (100 mL), and sodium azide (18 g) was added
thereto at room temperature. The mixture was heated to 75.degree.
C., and was stirred for 12 hours. The resultant mixture was
concentrated to about one-third of its original volume, and the
resultant mixture was diluted with water and ethyl acetate,
followed by stirring for 3 minutes. The organic layer was
separated, and was washed with saturated brine, followed by drying
over anhydrous magnesium sulfate. The solvent was distilled away
under reduced pressure, and the residue was purified by silica gel
column chromatography (ethyl acetate:hexane=1:4), to thereby give
the (1R*, 3S*, 4R*)-isomer (6.74 g) and the (1R*, 3S*, 4S*)-isomer
(1.32 g) of the title compound.
[0716] (1R*, 3S*, 4R*)-isomer:
[0717] .sup.1H-NMR (CDCl.sub.3) .delta.:1.26 (3H, t, J=7.1 Hz),
1.45 (9H, s), 1.38-2.33 (6H, m), 2.57-2.68 (1H, m), 3.77-4.20 (4H,
m), 4.63 (1H, br.s).
[0718] (1R*, 3S*, 4S*)-isomer:
[0719] .sup.1H-NMR (CDCl.sub.3) .delta.:1.27 (3H, t, J=7.1 Hz),
1.46 (9H, s), 1.53-2.30 (6H, m), 2.50-2.65 (1H, m), 3.42-3.72 (2H,
m), 4.15 (2H, q. J=7.1 Hz), 4.67 (1H, br.s).
Referential Example 90
(1R*, 3S*,
4R*)-4-amino-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxyli- c
acid ethyl ester
##STR00167##
[0721] (1R*, 3S*, 4R*)-4-Azido-3-
(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid ethyl ester
(5.4 g) obtained in Referential Example 89 was dissolved in a
solvent mixture of ethanol (10 mL) and ethyl acetate (10 mL), and a
catalytic amount of 10% palladium on carbon was added thereto,
followed by stirring at room temperature for 20 hours under
hydrogen flow. After any insoluble matter was filtered off, the
solvent was distilled away under reduced pressure, to thereby give
the title compound (4.7 g).
Referential Example 91
(1R*, 3S*,
4R*)-3-[(tert-butoxycarbonyl)amino]-4-{[(5-chloroindol-2-
yl)carbonyl]amino}cyclohexanecarboxylic acid ethyl ester
##STR00168##
[0723] The compound obtained in Referential Example 90 (4.62 g) was
dissolved in methylene chloride (50 mL), and to the solution were
added 5-chloroindole-2-carboxylic acid (3.63 g),
1-hydroxybenzotriazole monohydrate (2.43 g), and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.45
g) at room temperature, followed by stirring for 12 hours.
[0724] To the reaction mixture was added 0.1N aqueous HCl, and the
mixture was extracted with methylene chloride. The organic layer
was washed with saturated aqueous sodium hydrogencarbonate and
saturated brine, and was dried over anhydrous magnesium sulfate.
The solvent was distilled away under reduced pressure, and the
residue was purified by silica gel column chromatography (ethyl
acetate:hexane=2:3), to thereby give the title compound (5.3
g).
[0725] .sup.1H-NMR (CDCl.sub.3) .delta.:1.26 (3H, t, J=7.1 Hz),
1.43 (9H, s), 1.35-2.46 (7H, m), 3.91-4.02 (1H, m), 4.10-4.22 (2H,
m), 4.79 (1H, br.s), 6.79 (1H, s), 7.18-7.40 (2H, m), 7.59 (1H, s),
8.00 (1H, br.s), 9.13 (1H, br.s).
Referential Example 92
(1S, 3S, 6R)-7-oxabicyclo[4.1.0]heptane-3-carboxylic acid ethyl
ester
[0726] (1S, 4S, 5S)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one (J. Org.
Chem., vol. 61, p. 8687 (1996)) (89.3 g) was suspended in ethanol
(810 mL), and 2N aqueous sodium hydroxide (213 mL) was added
thereto, followed by stirring at room temperature for 3 hours. The
solvent was distilled away under reduced pressure, and water was
added to the residue. The thus-obtained mixture was extracted with
methylene chloride, and the extract was dried over anhydrous
magnesium sulfate. The solvent was distilled away under reduced
pressure, and the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=17:3), to thereby give the
title compound (41.3 g).
[0727] [.alpha.].sub.D.sup.25=-58.degree. (c=1.0, chloroform).
Referential Example 93
(1S, 3R, 4R)-3-azido-4-hydroxycyclohexanecarboxylic acid ethyl
ester
[0728] The compound obtained in Referential Example 92 (41 g) was
dissolved in N,N-dimethylformamide (300 mL), and to the solution
were sequentially added ammonium chloride (19.3 g) and sodium azide
(23.5 g) at room temperature, followed by stirring at 76.degree. C.
for 13 hours. The reaction mixture was filtered, and the filtrate
was concentrated. The residue was combined with the solid matter
obtained from the above-described filtration, and the thus-obtained
mixture was dissolved in water. The solution was extracted with
ethyl acetate. The organic layer was washed with water and
saturated brine, and was dried over anhydrous magnesium sulfate.
The solvent was distilled away under reduced pressure, to thereby
give the title compound (51.5 g).
[0729] [.alpha.].sub.D.sup.25=+8.degree. (c=1.0, chloroform)
Referential Example 94
(1S, 3R,
4R)-3-[(tert-butoxycarbonyl)amino]-4-hydroxycyclohexanecarboxylic
acid ethyl ester
[0730] The compound obtained in Referential Example 93 (51.2 g) and
di-tert-butyl dicarbonate (68.1 g) were dissolved in ethyl acetate
(1000 mL), and 5% palladium on carbon (5.0 g) was added thereto,
followed by stirring at room temperature overnight under hydrogen
at a pressure of 7 kg/cm.sup.2. After any insoluble matter was
filtered off, the solvent was removed under reduced pressure, and
the residue was purified by silica gel column chromatography
(hexane:ethyl acetate=4:1.fwdarw.3:1), followed by precipitation by
addition of hexane, to thereby give the title compound (46.9
g).
[0731] [.alpha.].sub.D.sup.25=+25.degree. (c=1.0, chloroform).
Referential Example 95
(1S, 3R,
4S)-4-azido-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic
acid ethyl ester and (1S, 3R,
4R)-4-azido-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic
acid ethyl ester
[0732] The compound obtained in Referential Example 94 (53.5 g) and
triethylamine (130 mL) were dissolved in methylene chloride (500
mL), and methanesulfonyl chloride (42 mL) was added dropwise
thereto at -10 to -15.degree. C. over 20 minutes, followed by
stirring at the same temperature for 20 minutes, and the resultant
mixture was heated to room temperature over 2 hours. The reaction
mixture was cooled to 0.degree. C., and 0.5N HCl (800 mL) was added
dropwise thereto, followed by extraction with methylene chloride.
The organic layer was washed with saturated aqueous sodium
hydrogencarbonate and saturated brine, and was dried over anhydrous
magnesium sulfate. The solvent was distilled away under reduced
pressure, to thereby give crude (1S, 3R,
4R)-3-[(tert-butoxycarbonyl)amino]-4-[(methylsulfonyl)oxy]cyclohexanecarb-
oxylic acid ethyl ester.
[0733] The crude product was dissolved in N,N-dimethylformamide
(335 mL), and sodium azide (60.5 g) was added thereto, followed by
stirring at 67 to 75.degree. C. for 16 hours. The reaction mixture
was filtered, and the filtrate was concentrated, to thereby
evaporate 250 mL of the solvent. The residue was combined with the
solid matter collected by the above-described filtration, and the
thus-obtained mixture was dissolved in water, followed by
extraction with ethyl acetate. The organic layer was washed with
saturated brine, and was dried over anhydrous magnesium sulfate.
The solvent was distilled away under reduced pressure. The residue
was purified by silica gel column chromatography (ethyl
acetate:hexane=1:4), to thereby give the (1S, 3R, 4S)-isomer (18.4
g) of the title compound and the (1S, 3R, 4R)-isomer (3.3 g) of the
title compound.
[0734] (1S, 3R, 4S)-isomer: [.alpha.].sub.D.sup.25=+62.degree.
(c=1.0, chloroform).
[0735] (1S, 3R, 4R)-isomer: [.alpha.].sub.D.sup.25=-19.degree.
(c=1.0, chloroform).
Referential Example 96
(1S, 3R,
4S)-4-amino-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic
acid ethyl ester
[0736] The compound obtained in Referential Example 95 (4.0 g) was
dissolved in a solvent mixture of ethanol (150 mL) and ethyl
acetate (150 mL), and 5% palladium on carbon (0.5 g) was added
thereto, followed by stirring at room temperature for 17 hours
under hydrogen atmosphere (5 kg/cm.sup.2). After any insoluble
matter was filtered off, the solvent was distilled away under
reduced pressure, to thereby give the title compound (4.2 g).
Referential Example 97
(1S, 3R, 4S)-3-[(tert-butoxycarbonyl)amino]-4-{[(5-chloroindol-2-
yl)carbonyl]amino}cyclohexanecarboxylic acid ethyl ester
##STR00169##
[0738] The compound obtained in Referential Example 96 (4.2 g) was
dissolved in methylene chloride (50 mL), and to the solution were
added 5-chloroindole-2-carboxylic acid (3.33 g),
1-hydroxybenzotriazole monohydrate (2.52 g), and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.15
g) at room temperature, followed by stirring for 12 hours. To the
reaction mixture was added 0.1N aqueous HCl, and the mixture was
extracted with methylene chloride. The organic layer was washed
with saturated aqueous sodium hydrogencarbonate and saturated
brine, and was dried over anhydrous magnesium sulfate. The solvent
was distilled away under reduced pressure, and the residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=1:1), to thereby give the title compound (4.36
g).
[0739] [.alpha.].sub.D=-27.degree. (c=1.0, chloroform).
Referential Example 98
(1R*, 3S*,
4R*)-3-[(tert-butoxycarbonyl)amino]-4-{[(5-methyl-4,5,6,7-tetra-
hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl)amino}cyclohexanecarboxylic
acid ethyl ester
##STR00170##
[0741] In a manner similar to that employed in Referential Example
91, the title compound was prepared from the compound obtained in
Referential Example 90 and the compound obtained in Referential
Example 10.
Referential Example 99
3-cyclohexene-1-carboxylic acid benzyl ester
##STR00171##
[0743] (.+-.)-3-Cyclohexene-1-carboxylic acid (50 g) was dissolved
in N,N-dimethylformamide (550 mL), and to the solution were added
triethylamine (170 mL) and benzyl bromide (61 mL) under ice
cooling, followed by stirring at room temperature for 12 hours.
Water was added to the resultant mixture, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine, and was dried over anhydrous magnesium sulfate.
The solvent was distilled away under reduced pressure, and the
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=3:1), to thereby give the title compound
(70.8 g).
[0744] .sup.1H-NMR (CDCl.sub.3) .delta.:1.66-1.76 (1H, m),
2.00-2.13 (3H, m), 2.27-2.29 (2H, m), 2.58-2.65 (1H, m), 5.13 (2H,
s), 5.66 (2H, br.s), 7.29-7.38 (5H, m).
Referential Example 100
(1R* , 3S*, 6S*)-7-oxabicyclo[4.1.0]heptane-3-carboxylic acid
benzyl ester
##STR00172##
[0746] The compound obtained in Referential Example 99 (40 g) was
dissolved in methylene chloride (500 mL), and m-chloroperbenzoic
acid (86 g) was added thereto under ice cooling, followed by
stirring for 2 hours. To the resultant mixture was added 10%
aqueous sodium thiosulfate, and the mixture was stirred for 20
minutes. The organic layer was separated, and was washed with
saturated sodium hydrogencarbonate and saturated brine, followed by
drying over anhydrous magnesium sulfate. The solvent was distilled
away under reduced pressure, and the residue was purified by silica
gel column chromatography (ethyl acetate:hexane=1:9), to thereby
give the title compound (23.4 g) and (1R*, 3R*,
6S*)-7-oxabicyclo[4.1.0]heptane-3-carboxylic acid benzyl ester
(12.1 g).
[0747] .sup.1H-NMR (CDCl.sub.3) .delta.:1.39-1.49 (1H, m),
1.75-1.82 (1H, m), 1.90-2.04 (3H, m), 2.30 (1H, dd, J=14.9, 4.9
Hz), 2.54-2.61 (1H, m), 3.12-3.14 (1H, m), 3.22-3.24 (1H, m), 5.12
(2H, s), 7.30-7.39 (5H, m).
[0748] MS (FAB) m/z:233 (M+H).sup.+.
Referential Example 101
(1R*, 3S*, 4S*)-4-azido-3-hydroxycyclohexanecarboxylic acid benzyl
ester
##STR00173##
[0750] The compound obtained in Referential Example 100 (52.3 g)
was dissolved in N,N-dimethylformamide (1000 mL), and to the
solution were added ammonium chloride (21.9 g) and sodium azide
(18.1 g), followed by stirring at 70.degree. C. for 24 hours. The
solvent was distilled away under reduced pressure, and water was
added to the residue, followed by extraction with ethyl acetate.
The organic layer was washed with saturated brine, and was dried
over anhydrous magnesium sulfate. The solvent was distilled away
under reduced pressure, to thereby give the title compound (61.8
g).
[0751] .sup.1H-NMR (CDCl.sub.3) .delta.:1.51-1.66 (2H, m),
1.91-1.98 (1H, m), 2.07-2.10 (1H, m), 2.27-2.32 (1H, m), 2.51-2.52
(1H, m), 2.81-2.86 (1H, m), 3.30-3.36 (1H, m), 3.70-3.75 (1H, m),
5.13 (2H, s), 7.30-7.39 (5H, m).
Referential Example 102
(1R*, 3S*,
4S*)-4-[(tert-butoxycarbonyl)amino]-3-hydroxycyclohexanecarboxy-
lic acid benzyl ester
##STR00174##
[0753] The compound obtained in Referential Example 101 (5.27 g)
was dissolved in tetrahydrofuran (25 mL), and triphenylphosphine
(5.53 g) and water (0.55 mL) were added to the solution, followed
by stirring at room temperature for 20 hours. To the reaction
mixture was added di-tert-butyl dicarbonate (4.82 g), and the
mixture was stirred for an additional 2 hours. The solvent was
distilled away under reduced pressure, and the residue was purified
by silica gel column chromatography (hexane:ethyl acetate=2:1), to
thereby give the title compound (6.22 g).
[0754] .sup.1H-NMR (CDCl.sub.3) .delta.:1.44 (9H, s), 1.59-1.66
(2H, m), 1.88-2.00 (2H, m), 2.29-2.32 (1H, m), 2.80-2.85 (1H, m),
3.02 (1H, br.s), 3.42 (1H, br.s), 3.59-3.65 (1H, m), 4.56 (1H,
br.s), 5.12 (2H, q, J=12.5 Hz), 7.30-7.38 (5H, m).
[0755] MS (FAB) m/z:350 (M+H).sup.+.
Referential Example 103
(1R*, 3S*,
4S*)-4-[(tert-butoxycarbonyl)amino]-3-hydroxycyclohexanecarboxy-
lic acid methyl ester
##STR00175##
[0757] The compound obtained in Referential Example 102 (2.54 g)
was dissolved in ethyl acetate (15 mL), and a catalytic amount of
10% palladium on carbon was added thereto, followed by stirring at
room temperature for 20 hours under hydrogen flow. The catalyst was
filtered off, and the filtrate was concentrated under reduced
pressure, to thereby give (1R*, 3S*,
4S*)-4-[(tert-butoxycarbonyl)amino]-3-hydroxycyclohexanecarboxylic
acid as a colorless oily matter. This oily matter was dissolved in
a solvent mixture of methanol (8 mL) and toluene (15 mL), and a 2N
solution of trimethylsilyldiazomethane in hexane (10 mL) was added
to the solution under ice cooling, followed by stirring at room
temperature for 30 minutes. The solvent was distilled away under
reduced pressure, and was purified by silica gel column
chromatography (hexane:ethyl acetate=1:1), to thereby give the
title compound (1.82 g).
[0758] .sup.1H-NMR (CDCl.sub.3) .delta.:1.44 (9H, s), 1.36-2.32
(7H, m), 2.74-2.82 (1H, m), 3.04 (1H, br.s), 3.33-3.47 (1H, m),
3.55-3.65 (1H, m), 3.68 (3H, s), 4.56 (1H, br.s).
[0759] MS (FAB) m/z:274 (M+H).sup.+.
Referential Example 104
(1R*, 3R*,
4S*)-3-azido-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxyli- c
acid methyl ester and (1R*, 3S*,
4S*)-3-azido-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic
acid methyl ester
##STR00176##
[0761] The compound obtained in Referential Example 103 (1.81 g)
was dissolved in methylene chloride (36 mL), and to the solution
were added triethylamine (4.6 mL) and methanesulfonyl chloride
(1.63 mL) at -78.degree. C. After 30 minutes, the reaction mixture
was heated to 0.degree. C., and was further stirred for an
additional 30 minutes. To the resultant mixture was added 1N HCl,
and the mixture was extracted with methylene chloride. The organic
layer was washed with saturated brine, and was dried over anhydrous
magnesium sulfate. The solvent was distilled away under reduced
pressure, to thereby give crude (1R*, 3S*,
4S*)-4-[(tert-butoxycarbonyl)amino]-3-[(methylsulfonyl)oxy]cyclohexanecar-
boxylic acid methyl ester.
[0762] This crude product was dissolved in N,N-dimethylformamide
(23 mL), and sodium azide (1.29 g) was added thereto, followed by
stirring at 70.degree. C. for 12 hours. Water was added to the
reaction mixture, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine, and was dried
over anhydrous magnesium sulfate. The solvent was distilled away
under reduced pressure, and the residue was purified by silica gel
column chromatography (ethyl acetate:hexane=3:17), to thereby give
(1R*, 3S*,
4S*)-3-azido-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic
acid methyl ester (85 mg) and (1R*, 3R*,
4S*)-3-azido-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic
acid methyl ester (590 mg).
[0763] (1R*, 3R*, 4S*)-isomer :.sup.1H-NMR (CDCl.sub.3)
.delta.:1.45 (9H, s), 1.35-2.35 (7H, m), 2.45-2.55 (1H, m), 3.73
(3H, s), 3.67-3.84 (2H, m), 4.70 (1H, br.s).
[0764] MS (FAB) m/z:299 (M+H).sup.+.
[0765] (1R*, 3S*, 4S*)-isomer: .sup.1H-NMR (CDCl.sub.3)
.delta.:1.45 (9H, s), 1.56-2.25 (7H, m), 2.68-2.80 (1H, m), 3.70
(3H, s), 3.48-3.68 (2H, m), 4.56 (1H, br.s).
[0766] MS (FAB) m/z:299 (M+H).sup.+.
Referential Example 105
(1R*, 3R*,
4S*)-3-amino-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxyli- c
acid methyl ester
##STR00177##
[0768] The (1R*, 3R*, 4S*)-compound (230 mg) obtained in
Referential Example 104 was dissolved in ethyl acetate (8 mL), and
a catalytic amount of 10% palladium on carbon was added thereto,
followed by stirring for 20 hours under hydrogen flow. Any
insoluble matter was filtered off, and the filtrate was
concentrated under reduced pressure, to thereby give the title
compound (220 mg).
Referential Example 106
(1R*, 3R*,
4S*)-4-[(tert-butoxycarbonyl)amino]-3-{[(5-methyl-4,5,6,7-tetra-
hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic
acid methyl ester
##STR00178##
[0770] In a manner similar to that employed in Referential Example
91, the title compound was prepared from the compound obtained in
Referential Example 105 and the compound obtained in Referential
Example 10.
[0771] .sup.1H-NMR (CDCl.sub.3) .delta.:1.46 (9H, s), 1.53-1.95
(5H, m), 2.17-2.24 (1H, m), 2.50 (3H, s), 2.50-2.53 (1H, m),
2.80-2.96 (4H, m), 3.67 (3H, s), 3.69-3.74 (1H, m), 4.10 (2H,
br.s), 4.88 (1H, br.s).
[0772] MS (FAB) m/z:453 (M+H).sup.+.
Referential Example 107
(1R*, 3R*,
4S*)-4-[(tert-butoxycarbonyl)amino]-3-{[(5-chloroindol-2-yl)car-
bonyl]amino}cyclohexanecarboxylic acid methyl ester
##STR00179##
[0774] In a manner similar to that employed in Referential Example
91, the title compound was prepared from the compound obtained in
Referential Example 105.
[0775] .sup.1H-NMR (CDCl.sub.3) .delta.:1.33 (9H, s), 1.42-2.47
(6H, m), 2.78-2.88 (1H, m), 3.70 (3H, s), 3.86-4.15 (2H, m),
4.65-4.75 (1H, m), 6.86 (1H, br.s), 7.18-7.38 (2H, m), 7.57-7.61
(1H, m), 8.32 (1H, br.s). MS (ESI) m/z:450 (M+H).sup.+.
Referential Example 108
(1S, 3R, 6R)-7-oxabicyclo[4.1.0]heptane-3-carboxylic acid benzyl
ester
[0776] 1) In a manner similar to that employed in Referential
Example 99, (1R)-3-cyclohexene-1-carboxylic acid benzyl ester was
prepared from (1R)-3-cyclohexene-1-carboxylic acid (J. Am. Chem.
Soc, vol. 100, p. 5199 (1978)).
[0777] 2) In a manner similar to that employed in Referential
Example 100, the title compound was prepared from the thus-obtained
product.
[0778] MS (FAB) m/z:233 (M+H).sup.+.
Referential Example 109
(1R, 3S,
4S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxycyclohexanecarboxylic
acid benzyl ester
[0779] 1) In a manner similar to that employed in Referential
Example 101, (1R, 3S, 4S)-4-azido-3-hydroxycyclohexanecarboxylic
acid benzyl ester was prepared from the compound obtained in
Referential Example 108.
[0780] 2) In a manner similar to that employed in Referential
Example 102, the title compound was prepared from the thus-obtained
product.
[0781] MS (FAB) m/z:350 (M+H).sup.+.
Referential Example 110
(1R, 3R,
4S)-3-azido-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic
acid benzyl ester
##STR00180##
[0783] In a manner similar to that employed in Referential Example
104, the title compound was prepared from the compound obtained in
Referential Example 109.
[0784] .sup.1H-NMR (CDCl.sub.3) .delta.:1.45 (9H, s), 1.52-1.66
(2H, m), 1.83-2.01 (3H, m), 2.20-2.28 (1H, m), 2.51-2.54 (1H, m),
3.77 (2H, br.s), 4.70 (1H, br.s), 5.15 (2H, ABq, J=12.2 Hz),
7.33-7.38 (5H, m).
[0785] MS (FAB) m/z:375 (M+H).sup.+.
Referential Example 111
(1R, 3R,
4S)-3-azido-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic
acid methyl ester
##STR00181##
[0787] The compound obtained in Referential Example 110 (3.5 g) was
dissolved in tetrahydrofuran (130 mL) and water (16 mL), and
lithium hydroxide (291 mg) was added to the solution under ice
cooling. After 10 minutes, the reaction mixture was brought back to
room temperature, and was stirred for 20 hours. The solvent was
distilled away under reduced pressure, and the residue was
subjected to silica gel column chromatography (methanol:methylene
chloride=1:20), to thereby give (1R, 3R,
4S)-3-azido-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic
acid (3.34 g) as a pale-yellow oily matter. This oily matter was
dissolved in methanol (18 mL) and toluene (64 mL), and to the
solution was added a 2M solution of trimethylsilyldiazomethane in
hexane (6.1 mL) under ice cooling. After 10 minutes, the reaction
mixture was brought back to room temperature, and was stirred for 2
hours. The solvent was distilled away under reduced pressure, and
the residue was purified by silica gel column chromatography (ethyl
acetate:hexane=1:4), to thereby give the title compound (3.35
g).
[0788] .sup.1H-NMR (CDCl.sub.3) .delta.:1.45 (9H, s), 1.57-1.63
(2H, m), 1.82-1.85 (1H, m), 1.95-1.99 (2H, m), 2.20-2.28 (1H, m),
2.48-2.51 (1H, m), 3.73 (3H, s), 3.78 (2H, br.s), 4.70-4.72 (1H,
m).
[0789] MS (FAB) m/z:299 (M+H).sup.+.
Referential Example 112
(1R, 3R,
4S)-4-[(tert-butoxycarbonyl)amino]-3-{[(5-methyl-4,5,6,7-tetrahyd-
rothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic
acid methyl ester
##STR00182##
[0791] 1) In a manner similar to that employed in Referential
Example 105, (1R, 3R,
4S)-3-amino-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic
acid methyl ester was prepared from the compound obtained in
Referential Example 111.
[0792] 2) In a manner similar to that employed in Referential
Example 106, the title compound was prepared from the thus-obtained
product and the compound obtained in Referential Example 10.
[0793] MS (FAB) m/z:453 (M+H).sup.+.
Referential Example 113
(1R*, 2S*,
5S*)-5-aminocarbonyl-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyc-
lohexylcarbamic acid tert-butyl ester
##STR00183##
[0795] The compound obtained in Referential Example 91 (590 mg) was
dissolved in a solvent mixture of ethanol (3 mL) and
tetrahydrofuran (6 mL), and 1N aqueous sodium hydroxide (2.5 mL)
was added thereto at room temperature, followed by stirring for 12
hours. The solvent was distilled away, to thereby give (1R*, 3S*,
4R*)-3-[(tert-butoxycarbonyl)amino]-4-{8
(5-chloroindol-2-yl)carbonyl]amino}cyclohexanecarboxylic acid
sodium salt. This compound was suspended in N,N-dimethylformamide
(4 mL), and to the suspension were added di-tert-butyl dicarbonate
(654 mg) and ammonium hydrogencarbonate (1 g) at room temperature,
followed by stirring for 18 hours. The solvent was distilled away
under reduced pressure, and water was added thereto. The resultant
mixture was extracted with chloroform. The organic layer was washed
with saturated brine, and was dried over anhydrous magnesium
sulfate. The solvent was distilled away under reduced pressure, and
the residue was purified by silica gel column chromatography
(methylene chloride:methanol=47:3), to thereby give the title
compound (82 mg).
[0796] MS (ESI) m/z:435 (M+H).sup.+.
Referential Example 114
(1R, 6S)-6-{[(benzyloxy)carbonyl]amino]-3-cyclohexen-1-ylcarbamic
acid benzyl ester
##STR00184##
[0798] 4-Cyclohexene-1,2-diamine hydrochloride (4.0 g) was
dissolved in a solvent mixture of water (20 mL) and acetonitrile
(20 mL), and to the solution were added benzyl chloroformate (7.66
mL) and potassium carbonate (14.9 g), followed by stirring at room
temperature for 3 days. The reaction mixture was poured into water,
and the thus-obtained mixture was extracted with methylene
chloride. The organic layer was washed with saturated brine, and
was dried over sodium sulfate anhydrate. The solvent was distilled
away under reduced pressure, and the residue was purified by silica
gel column chromatography (methylene chloride), to thereby give the
title compound (8.22 g).
[0799] .sup.1H-NMR (CDCl.sub.3) .delta.:2.03 (2H, m), 2.53 (2H, d,
J=17.1 Hz), 3.77 (2H, m), 5.03 (2H, q, J=12.3 Hz), 5.09 (2H, q,
J=12.3 Hz), 5.59 (2H, s), 7.32 (10H, m).
[0800] MS (ESI) m/z:381 (M+H).sup.+.
Referential Example 115
(1R*,
2S*)-2-{[(benzyloxy)carbonyl]amino}-5-hydroxycyclohexylcarbamic
acid benzyl ester
##STR00185##
[0802] The compound obtained in Referential Example 114 (10 g) was
dissolved in anhydrous tetrahydrofuran (70 mL), and borane-dimethyl
sulfide complex (7.4 mL) was added thereto at 0.degree. C. The
thus-obtained mixture was gradually heated to room temperature,
followed by stirring for 14 hours, and ice was added to the
reaction mixture, to thereby decompose excess borane. To the
resultant mixture were added 1N aqueous sodium hydroxide (80 mL)
and 30% hydrogen peroxide (80 mL), and the thus-obtained mixture
was stirred for 1 hour. The resultant mixture was extracted with
ethyl acetate. The organic layer was washed with saturated brine,
and was dried over sodium sulfate anhydrate. The solvent was
distilled away under reduced pressure, and the residue was purified
by silica gel column chromatography (ethyl acetate:hexane=2:1), to
thereby give the title compound (9.2 g).
[0803] .sup.1H-NMR (CDCl.sub.3) .delta.:1.98 (1H, m), 2.08 (1H, m),
2.30 (1H, m), 3.43 (2H, m), 3.73 (1H, m), 5.06 (6H, m), 7.32 (10H,
s).
[0804] MS (ESI) m/z:399 (M+H).sup.+.
Referential Example 116
(1R*, 2S*)-2-{[(benzyloxy)carbonyl]amino}-5-oxocyclohexylcarbamic
acid benzyl ester
##STR00186##
[0806] Dimethyl sulfoxide (8.2 mL) was added to a solution of
oxalyl chloride (9.9 mL) in methylene chloride (90 mL) while being
stirred at -60.degree. C. Subsequently, a solution of the compound
obtained in Referential Example 115 (9.2 g) in tetrahydrofuran (90
mL) was added thereto all at once. After 1 hour, the resultant
mixture was heated to -40.degree. C., and triethylamine (26 mL) was
added thereto all at once. The thus-obtained mixture was heated to
room temperature, and was stirred for 3 hours. The reaction mixture
was poured into water, and the mixture was extracted with methylene
chloride. The organic layer was washed with saturated brine, and
was dried over sodium sulfate anhydrate. The solvent was distilled
away under reduced pressure, and the residue was purified by silica
gel column chromatography (ethyl acetate : hexane=1:1), to thereby
give the title compound (8.0 g).
[0807] .sup.1H-NMR (CDCl.sub.3) .delta.:2.27-2.43 (4H, m), 2.78
(1H, dd, J=14.4,3.9 Hz), 3.86 (2H, m), 5.08 (4H, m), 5.22 (2H, m),
7.32 (10H, m).
[0808] MS (ESI) m/z: 397 (M+H).sup.+.
Referential Example 117
(1R*, 2S*)-2-{[(benzyloxy)carbonyl]amino}-5,
5-dimethoxycyclohexylcarbamic acid benzyl ester
##STR00187##
[0810] The compound obtained in Referential Example 116 (3.89 g)
was dissolved in a solvent mixture of methanol (15 mL) and
tetrahydrofuran (15 mL), and to the solution were added
2,2-dimethoxypropane (10.7 mL) and p-toluenesulfonic acid (187 mg),
followed by stirring at room temperature for 3 hours. The solution
was concentrated, and saturated aqueous sodium hydrogencarbonate
was added thereto, followed by extraction with ethyl acetate. The
organic layer was washed with saturated brine, and was dried over
sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure, and the residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:2), to thereby give the
title compound (3.54 g).
[0811] .sup.1H-NMR (CDCl.sub.3) .delta.:1.30-1.41 (4H, m), 1.93
(1H, m), 2.38 (1H, m), 3.19 (6H, s), 3.46 (1H, m), 3.59 (1H, m),
5.03 (2H, q, J=12.5 Hz), 5.09 (2H, q, J=12.5 Hz), 7.32 (10H,
s).
Referential Example 118
N-[(1R*,
2S*)-2-amino-4,4-dimethoxycyclohexyl]-5-chloroindole-2-carboxamid-
e and N-[(1R*,
2S*)-2-amino-5,5-dimethoxycyclohexyl]-5-chloroindole-2-
carboxamide
##STR00188##
[0813] The compound obtained in Referential Example 117 (1.45 g)
was dissolved in methanol (12 mL), and 10% palladium on carbon (290
mg) was added thereto, followed by stirring at room temperature for
20 hours under hydrogen atmosphere. Additional 10% palladium on
carbon (290 mg) and methanol (10 mL) were added thereto, and the
thus-obtained mixture was stirred for 8 hours. The reaction mixture
was filtered through Celite, and the filtrate was concentrated. The
residue was dissolved in N,N-dimethylformamide (10 mL), and to the
solution were added 5-chloroindole-2-carboxylic acid (320 mg),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (377
mg), 1-hydroxybenzotriazole monohydrate (301 mg), and
N-methylmorpholine (360 mL), followed by stirring at room
temperature for 14 hours. The reaction mixture was poured into
aqueous sodium hydrogencarbonate, and the mixture was extracted
with ethyl acetate. The organic layer was washed with saturated
brine, and was dried over sodium sulfate anhydrate. The solvent was
distilled away under reduced pressure, and the residue was purified
by silica gel thin layer chromatography (methylene chloride :
methanol=93:7), to thereby isolate
N-[(1R*,2S*)-2-amino-4,4-dimethoxycyclohexyl]-5-chloroindole-2-carboxamid-
e (or N-[(1R*,
2S*)-2-amino-5,5-dimethoxycyclohexyl]-5-chloroindole-2-carboxamide)
(98 mg) and N-[(1R*,
2S*)-2-amino-5,5-dimethoxycyclohexyl]-5-chloroindole-2-carboxamide
(or N-[(1R*,
2S*)-2-amino-4,4-dimethoxycyclohexyl]-5-chloroindole-2-carboxami-
de) (105 mg).
N-[(1R*,
2S*)-2-amino-4,4-dimethoxycyclohexyl]-5-chloroindole-2-carboxamid-
e
[0814] .sup.1H-NMR (CDCl.sub.3) .delta.:1.45-1.50 (2H, m),
2.06-2.10 (2H, m), 2.34 (1H, d, J=13.1 Hz), 2.78 (1H, dt, J=2.9,
13.1 Hz), 3.18 (3H, s), 3.23 (3H, s), 3.75-3.77 (1H, m), 6.24 (1H,
d, J=8.3 Hz), 6.79 (1H, s), 7.23 (1H, dd, J=8.8, 2.0 Hz), 7.35 (1H,
d, J=8.8 Hz), 7.60 (1H, d, J=8.8 Hz), 9.53 (1H, br.s).
[0815] MS (ESI) m/z:352 (M+H).sup.+.
N-[(1R*,
2S*)-2-amino-5,5-dimethoxycyclohexyl]-5-chloroindole-2-carboxamid-
e:
[0816] .sup.1H-NMR (CDCl.sub.3) .delta.:1.83-1.87 (1H, m),
1.97-2.01 (1H, m), 2.39 (1H, br, J=13.2 Hz), 2.86-2.90 (1H, m),
3.22-3.28 (10H, m), 4.00-4.02 (1H, m), 6.77 (1H, s), 7.23 (1H, d,
J=8.5 Hz), 7.37 (1H, d, J=8.5 Hz), 7.61 (1H, s), 9.49 (1H,
br.s).
[0817] MS (ESI) m/z:352 (M+H).sup.+.
Referential Example 119
(7R*,
8S*)-7-{[(benzyloxy)carbonyl]amino}-1,4-dioxaspiro[4.5]dec-8-ylcarba-
mic acid benzyl ester
##STR00189##
[0819] The compound obtained in Referential Example 116 (4.0 g) was
dissolved in anhydrous tetrahydrofuran (30 mL), and to the solution
were added ethylene glycol (5.6 mL) and p-toluenesulfonic acid (192
mg), followed by stirring at room temperature for 17 hours. The
reaction mixture was poured into saturated aqueous sodium
hydrogencarbonate, and the mixture was extracted with ethyl
acetate. The organic layer was washed with saturated brine, and was
dried over sodium sulfate anhydrate. The solvent was distilled away
under reduced pressure, and the residue was purified by silica gel
column chromatography (ethyl acetate:hexane=1:1), to thereby give
the title compound (4.23 g).
[0820] .sup.1H-NMR (CDCl.sub.3) .delta.:1.65-1.71 (4H, m), 2.00
(1H, m), 2.11 (1H, m), 3.49 (1H, m), 3.73 (1H, m), 3.93 (4H, s),
5.03 (2H, q, J=12.2 Hz), 5.08 (2H, q, J=12.2 Hz), 7.32 (10H,
s).
[0821] MS (ESI) m/z:441 (M+H).sup.+.
Referential Example 120
N-[(7R*,
8S*)-7-amino-1,4-dioxaspiro[4.5]dec-8-yl]-5-chloroindole-2-carbox-
amide and N-[(7R*, 8S*)-8-amino-1,4-dioxaspiro
[4.5]dec-7-yl]-5-chloroindole-2-carboxamide
##STR00190##
[0823] In a manner similar to that employed in Referential Example
118, N-[(7R*, 8S *)-7-amino-1,4-dioxaspiro
[4.5]dec-8-yl]-5-chloroindole-2-carboxamide (or N-[(7R*,
8S*)-8-amino-1,4-dioxaspiro[4.5]dec-7-yl]-5-chloroindole-2-carboxamide)
and N-[(7R*,
8S*)-8-amino-1,4-dioxaspiro[4.5]dec-7-yl]-5-chloroindole-2-carboxamide
(or N-[(7R*,
8S*)-7-amino-1,4-dioxaspiro[4.5]dec-8-yl]-5-chloroindole-2-carboxamide)
were prepared from the compound obtained in Referential Example
119.
N-[(7R*,
8S*)-8-amino-1,4-dioxaspiro[4.5]dec-7-yl]-5-chloroindole-2-carbox-
amide (or N-[(7R*,
8S*)-7-amino-1,4-dioxaspiro[4.5]dec-8-yl]-5-chloroindole-2-carboxamide)
[0824] .sup.1H-NMR (CDCl.sub.3) .delta.:1.68-1.81 (4H, m), 2.11
(2H, m), 2.87 (1H, td, J=3.9, 11.2 Hz), 3.77 (1H, m), 3.97 (4H, s),
6.27 (1H, d, J=7.6 Hz), 6.80 (1H, s), 7.24 (1H, d, J=9.0 Hz), 7.35
(1H, d, J=9.0 Hz), 7.61 (1H, s), 9.47 (br.s, 1H).
[0825] MS (ESI) m/z:350 (M+H).sup.+.
N-[(7R*,
8S*)-8-amino-1,4-dioxaspiro[4.5]dec-7-yl]-5-chloroindole-2-carbox-
amide (or N-[(7R*,
8S*)-7-amino-1,4-dioxaspiro[4.5]dec-8-yl]-5-chloroindole-2-carboxamide)
[0826] .sup.1H-NMR (CDCl.sub.3) .delta.:1.65 (2H, m), 1.88 (1H, m),
1.96 (1H, m), 2.31 (1H, dd, J=12.9, 3.2 Hz), 2.96 (1H, m), 3.98
(1H, m), 4.02 (4H, s), 4.12 (1H, m), 6.77 (1H, s), 7.06 (1H, br.s),
7.23 (1H, dd, J=8.8, 2.0 Hz), 7.37 (1H, d, J=8.8 Hz), 7.62 (1H, d,
J=2.0 Hz), 9.49 (1H, br.s).
[0827] MS (ESI) m/z:350 (M+H).sup.+.
Referential Example 121
(1R, 6S)-6-[(tert-butoxycarbonyl)amino]-3-cyclohexen-1-ylcarbamic
acid tert-butyl ester
##STR00191##
[0829] cis-4-Cyclohexene-1,2-diamine hydrochloride (4.0 g) was
dissolved in water (40 mL) and acetonitrile (40 mL), and to the
solution were added di-tert-butoxycarbonate (11.8 g) and
triethylamine (12 mL), followed by stirring at room temperature for
4.5 hours. The reaction mixture was poured into water, and the
mixture was extracted with methylene chloride. The methylene
chloride layer was washed with saturated brine, and was dried over
sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure, and the residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:4), to thereby give the
title compound (6.12 g).
[0830] .sup.1H-NMR (CDCl.sub.3) .delta.:1.44 (18H, s), 1.98 (2H,
dd, J=9.3, 15.9 Hz), 2.48 (2H, br.d, J=15.9 Hz), 3.66 (2H, br.s),
4.88 (2H, br.s), 5.58 (2H, d, J=2.7 Hz).
Referential Example 122
(1R*,
2S*)-2-[(tert-butoxycarbonyl)amino]-5-hydroxycyclohexylcarbamic
acid tert-butyl ester (stereoisomeric mixture)
##STR00192##
[0832] The compound obtained in Referential Example 121 (6.1 g) was
dissolved in anhydrous tetrahydrofuran (40 mL), and borane-dimethyl
sulfide complex (2.22 mL) was added to the solution under ice
cooling. The reaction mixture was gradually heated to room
temperature while being stirred for 16 hours. Ice was added to the
reaction mixture, and to the mixture were added 1N aqueous sodium
hydroxide and 30% hydrogen peroxide (50 mL). The thus-obtained
mixture was stirred at room temperature for 2 hours. The resultant
mixture was extracted with ethyl acetate. The organic layer was
washed with saturated brine, and was dried over sodium sulfate
anhydrate. The solvent was distilled away under reduced pressure,
and the residue was purified by silica gel column chromatography
(ethyl acetate:hexane=1:2.fwdarw.2:1), to thereby give the title
compound (6.1 g).
[0833] .sup.1H-NMR (CDCl.sub.3) .delta.:1.42 (9H, s), 1.43 (9H, s),
1.83-1.67 (5H, m), 2.15 (1H, m), 2.22 (1H, s), 3.34 (1H, m), 3.78
(1H, m), 4.15 (1H, s), 4.98 (1H, q, J=9.0 Hz), 5.02 (1H, q, J=9.0
Hz).
[0834] MS (ESI) m/z:331 (M+H).sup.+.
Referential Example 123
(1R*, 2S*)-2-[(tert-butoxycarbonyl)amino]-5-oxocyclohexylcarbamic
acid tert-butyl ester
##STR00193##
[0836] Oxalyl chloride (8.2 mL) and dimethyl sulfoxide (6.8 mL)
were dissolved in methylene chloride (100 mL), and the solution was
cooled to -60.degree. C. Subsequently, a solution of the compound
obtained in Referential Example 122 (stereoisomeric mixture) (6.32
g) in tetrahydrofuran (80 mL) was added thereto all at once,
followed by stirring for 1 hour. The resultant mixture was heated
to -40.degree. C., and triethylamine (21 mL) was added thereto,
followed by heating to room temperature. After 3 hours, the mixture
was poured into water, and the thus-obtained mixture was extracted
with methylene chloride. The organic layer was washed with
saturated brine, and was dried over sodium sulfate anhydrate. The
solvent was distilled away under reduced pressure, and the residue
was purified by silica gel column chromatography (ethyl
acetate:hexane=1:1), to thereby give the title compound (3.8
g).
[0837] .sup.1H-NMR (CDCl.sub.3) .delta.:1.43 (9H, s), 1.44 (9H, s),
2.24-2.36 (3H, m), 2.39-2.44 (2H, m), 2.75 (1H, dd, J=14.6, 2.9
Hz), 3.66-3.81 (2H, m), 4.95-4.90 (1H, m), 4.97-5.03 (1H, m).
[0838] MS (ESI) m/z:329 (M+H).sup.+.
Referential Example 124
(1R*,
2S*)-2-[(tert-butoxycarbonyl)amino]-5-(methoxyimino)cyclohexylcarbam-
ic acid tert-butyl ester
##STR00194##
[0840] The compound obtained in Referential Example 123 (1.5 g) was
dissolved in methanol (30 mL), and to the solution were added
o-methylhydroxylamine hydrochloride (572 mg) and pyridine (737 mL),
followed by stirring at room temperature for 17 hours. After the
reaction mixture was concentrated, water was added to the residue,
and the mixture was extracted with ethyl acetate. The organic layer
was washed with saturated brine, and was dried over sodium sulfate
anhydrate. The solvent was distilled away under reduced pressure,
and the residue was purified by silica gel column chromatography
(ethyl acetate:hexane=1:4), to thereby give the title compound
(1.52 g).
[0841] .sup.1H-NMR (CDCl.sub.3) .delta.:1.44(18H, s), 1.64(1H, m),
2.16(2H, m), 2.44(1H, m), 3.45-3.63(3H, m), 3.82(3H, s), 4.93(1H,
m).
[0842] MS (ESI) m/z:358 (M+H).sup.+.
Referential Example 125
(1R*,
2S*)-2-[(tert-butoxycarbonyl)amino]-5-{[tert-butyl(diphenyl)silyl]ox-
y}cyclohexylcarbamic acid tert-butyl ester (stereoisomer A)
##STR00195##
[0844] In a manner similar to that employed in Referential Example
58, the title compound was prepared from the compound obtained in
Referential Example 122 (stereoisomeric mixture). At the same time,
(1R*,2S*)-2-[(tert-Butoxycarbonyl)amino]-5-hydroxycyclohexylcarbamic
acid tert-butyl ester (stereoisomer B) was also recovered.
[0845] .sup.1H-NMR (CDCl.sub.3) .delta.:1.03(9H, s), 1.39(9H, s),
1.40(9H, s), 1.72(1H, m), 1.86(1H, m), 2.13(1H, m), 3.24(2H, m),
3.65(1H, m), 4.83(1H, m), 7.37(10H, m).
Referential Example 126
(1R*,
2S*)-2-{[(benzyloxy)carbonyl]amino}-5-hydroxy-5-methylcyclohexylcarb-
amic acid benzyl ester
##STR00196##
[0847] Anhydrous cerium chloride (6.4 g) was suspended in
tetrahydrofuran (50 mL), and the suspension was cooled to
-78.degree. C. under argon flow. Methyllithium solution (as 1.14N
diethyl ether solution, 22.5 mL) was added to the suspension, and
the thus-obtained mixture was stirred at -78.degree. C. for 30
minutes. To the resultant mixture was added dropwise a solution of
the compound obtained in Referential Example 116 (3.0 g) in
tetrahydrofuran (50 mL) at -78.degree. C., followed by stirring for
30 minutes. The reaction mixture was poured into 3% aqueous acetic
acid (100 mL), and diethyl ether (50 mL) was added thereto,
followed by stirring at room temperature for 10 minutes. The
reaction mixture was extracted with ethyl acetate. The organic
layer was sequentially washed with saturated aqueous sodium
hydrogencarbonate and saturated brine, and was dried over sodium
sulfate anhydrate. The solvent was distilled away under reduced
pressure, and the residue was purified by silica gel column
chromatography (methanol:chloroform 0:100 to 1:19) twice, to
thereby give the title compound (stereoisomer A) (780 mg) and the
title compound (stereoisomer B) (1.1 g).
[0848] stereoisomer A:
[0849] .sup.1H-NMR (CDCl.sub.3) .delta.:1.26(3H, s), 1.27-2.08(6H,
m), 3.48(1H, br.s), 3.59(1H, br.s), 5.02-5.09(5H, m), 5.33(1H,
br.s), 7.30-7.32(10H, s)
[0850] MS (FAB) m/z:413 (M+H).sup.+.
[0851] stereoisomer B:
[0852] .sup.1H-NMR (CDCl.sub.3) .delta.:1.25(3H, s), 1.29-2.07(6H,
m), 3.39(1H, br.s), 3.82(1H, br.s), 5.02-5.23(6H, m), 7.30(10H,
s)
[0853] MS (FAB) m/z:413 (M+H).sup.+.
Referential Example 127
(3R*, 4S*)-3, 4-diamino-1-methylcyclohexanol (stereoisomer A)
##STR00197##
[0855] In a solution of the compound obtained in Referential
Example 126 (stereoisomer A) (780 mg) in methanol (100 mL) was
suspended 10% palladium on carbon (350 mg), and the suspension was
stirred for 5 hours under hydrogen flow. The catalyst was filtered
off, and the filtrate was concentrated under reduced pressure. The
residue was dissolved in methylene chloride (100 mL), and the
solution was dried over sodium sulfate anhydrate. The solvent was
distilled away, to thereby give the title compound (stereoisomer A)
(190 mg).
[0856] .sup.1H-NMR (CDCl.sub.3) .delta.:1.22(3H, s), 1.25-2.48(11H,
m), 2.62(1H, br.s), 2.78(1H, br.s).
Referential Example 128
Mixture of N-[(1R*,
2S*)-2-amino-4-hydroxy-4-methylcyclohexyl]-5-chloroindole-2-carboxamide
(stereoisomer A) and N-[(1R*,
2S*)-2-amino-5-hydroxy-5-methylcyclohexyl]-5-chloroindole-2-carboxamide
(stereoisomer A)
##STR00198##
[0858] In a manner similar to that employed in Referential Example
59, the title compound was prepared from the compound obtained in
Referential Example 127 (stereoisomer A) and
5-chloroindole-2-carboxylic acid.
[0859] .sup.1H-NMR (CDCl.sub.3) .delta.:1.32(3H, s), 1.34-2.29(6H,
m), 4.42-4.70(4H, br), 7.13(2H, s), 7.50(2H, s), 8.00(1H, s),
11.0(1H, br).
Referential Example 129
(1R*, 2R*,
5S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-(hydroxymethyl)c-
yclohexylcarbamic acid tert-butyl ester
##STR00199##
[0861] 1) In a manner similar to that employed in Referential
Examples 90 to 91,
(1R*,3S*,4S*)-3-[(tert-butoxycarbonyl)amino]-4-{[(5-chloroindol-2--
yl)carbonyl]amino}cyclohexanecarboxylic acid ethyl ester was
prepared from the (1R*,3S*,4S*)-isomer obtained in Referential
Example 89.
[0862] .sup.1H-NMR (CDCl.sub.3) .delta.:1.22-1.72(6H, m),
2.15-2.28(2H, m), 2.41-2.49(1H, m), 2.85(1H, brs), 3.62-3.75(1H,
m), 3.78-3.92(1H, m), 4.12-4.28(2H, m), 4.56-4.63(1H, m), 6.88(1H,
brs), 7.20(1H, dd, J=8.8 and 2.0 Hz), 7.33(1H, d, J=8.8 Hz),
7.52-7.57(1H, m), 7.59(1H, d, J=2.0 Hz), 9.24(1H, s).
[0863] MS (ESI) m/z:464 (M+H).sup.+.
[0864] 2) The thus-obtained product (735 mg) was dissolved in
methylene chloride (10 mL), and to the solution was added a 1N
solution of diisobutylaluminium hydride in hexane (5 mL) at
-78.degree. C., followed by stirring for 3 hours, and then at
0.degree. C. for 30 minutes. Saturated aqueous ammonium chloride
was added to the reaction mixture at -78.degree. C., and the
thus-obtained mixture was extracted with methylene chloride. The
organic layer was washed with saturated aqueous sodium
hydrogencarbonate and saturated brine, and was dried over anhydrous
magnesium sulfate. The solvent was distilled away under reduced
pressure, and the residue was purified by silica gel column
chromatography (methylene chloride:methanol=19:1), to thereby give
the title compound (480 mg).
[0865] .sup.1H-NMR (CDCl.sub.3) .delta.:1.20-2.30(7H, m),
3.60-3.86(4H, m), 4.64(1H, br.s), 6.87(1H, s), 7.20-7.48(3H, m),
9.15(1H, br.s).
[0866] MS (ESI) m/z:422 (M+H).sup.+.
Referential Example 130
(1R*, 3R*, 6S*)-3-(methoxymethyl)oxabicyclo[4.1.0]heptane
##STR00200##
[0868] 1) (1R*, 4R*, 5R*) -4-Iodo-6-oxabicyclo [3.2.1] octan-7-one
(2.8 g) was dissolved in a solvent mixture of tetrahydrofuran (27
mL) and water (3 mL), and concentrated HCl (0.1 mL) was added
thereto, followed by heating under reflux for 1 hour. The solvent
was distilled away under reduced pressure, to thereby give
(1R*,3R*,4R*)-3-hydroxy-4-iodocyclohexanecarboxylic acid (3.23 g)
as a colorless solid.
[0869] 2) The product obtained from the above-described reaction
(3.22 g) was dissolved in tetrahydrofuran (50 mL), and
borane-dimethyl sulfide complex (as 2M tetrahydrofuran solution, 47
mL) was added to the solution under ice cooling, followed by
stirring at room temperature for 12 hours. The solvent was
distilled away under reduced pressure, and the residue was
dissolved in isopropanol (10 mL). To the solution was added 1N
aqueous sodium hydroxide (12 mL) at room temperature, and the
mixture was stirred for 12 hours. After the mixture was
concentrated to about one-fifth of its original volume, the
resultant mixture was diluted with water and methylene chloride,
followed by stirring for 10 minutes. The organic layer was
separated, and was sequentially washed with saturated aqueous
ammonium chloride and saturated brine, followed by drying over
anhydrous magnesium sulfate. The solvent was distilled away under
reduced pressure, and the residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:2), to thereby give
(1R*,3R*,6S*)-7-oxabicyclo[4.1.0]hept-3-ylmethanol (1.25 g) as a
colorless oily matter.
[0870] 3) The product obtained from the reaction in the above step
2) (4.63 g) was dissolved in tetrahydrofuran (50 mL), and to the
solution was added potassium bis(trimethylsilyl)amide (as 0.5N
toluene solution, 80 mL) at -78.degree. C., followed by stirring at
the same temperature for 10 minutes, and methyl iodide (2.93 mL)
was added thereto. The resultant mixture was heated to 0.degree.
C., and was stirred for 1 hour. Saturated aqueous ammonium chloride
was added to the thus-obtained mixture, and the mixture was diluted
with diethyl ether. The organic layer was separated, and was washed
with saturated brine, followed by drying over anhydrous magnesium
sulfate. The solvent was distilled away under reduced pressure, and
the residue was purified by silica gel column chromatography (ethyl
acetate:hexane=1:4), to thereby give the title compound (3.7
g).
[0871] .sup.1H-NMR (CDCl.sub.3) .delta.:0.89-1.63(5H, m),
1.80-2.05(2H, m), 1.89-3.06(4H, m), 3.16(3H, s).
Referential Example 131
(1R*, 2R*, 4S*)-2-azido-4-(methoxymethyl)cyclohexanol
##STR00201##
[0873] In a manner similar to that employed in Referential Example
87, the title compound was prepared from the compound obtained in
Referential Example 130.
[0874] .sup.1H-NMR (CDCl.sub.3) .delta.:1.45-1.70(5H, m),
1.77-1.95(2H, m), 1.98-2.08(1H, m), 3.30(2H, d, J=6.8 Hz), 3.35(3H,
s), 3.45-3.65(2H, m).
Referential Example 132
(1R*, 2R*, 5S*)-2-hydroxy-5-(methoxymethyl)cyclohexylcarbamic acid
tert-butyl ester
##STR00202##
[0876] In a manner similar to that employed in Referential Example
88, the title compound was prepared from the compound obtained in
Referential Example 131.
[0877] .sup.1H-NMR (CDCl.sub.3) .delta.:1.35-2.01(16H, m), 3.05(1H,
br.s), 3.32(2H, d, J=7.1 Hz), 3.34(3H, s), 3.44-3.62(2H, m),
4.59(1H, br.s).
Referential Example 133
(1R*, 2S*, 5S*)-2-azido-5-(methoxymethyl)cyclohexylcarbamic acid
tert-butyl ester
##STR00203##
[0879] In a manner similar to that employed in Referential Example
89, a methanesulfonic acid ester was prepared from the compound
obtained in Referential Example 132, and the title compound was
prepared from the methanesulfonic acid ester.
[0880] .sup.1H-NMR (CDCl.sub.3).delta.:1.31-1.93(16H, m), 3.27(2H,
d, J=6.4 Hz), 3.32(3H, s), 3.57-3.70(1H, m), 3.67(1H, br.s),
3.95(1H, br.s).
Referential Example 134
(1R*, 2S*, 5S*)-2-amino-5-(methoxymethyl)cyclohexylcarbamic acid
tert-butyl ester
##STR00204##
[0882] In a manner similar to that employed in Referential Example
90, the title compound was prepared from the compound obtained in
Referential Example 133.
Referential Example 135
(1R*, 2S*,
5S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-(methoxymethyl)c-
yclohexylcarbamic acid tert-butyl ester
##STR00205##
[0884] In a manner similar to that employed in Referential Example
91, the title compound was prepared from the compound obtained in
Referential Example 134 and 5-chloroindole-2-carboxylic acid.
[0885] .sup.1H-NMR (CDCl.sub.3) .delta.:1.12-2.31(16H, m),
3.14-3.30(2H, m), 3.34(3H, s), 3.92(1H, br.s), 4.13(1H, br.s),
4.88(1H, br.s), 6.82(1H, s), 7.21(1H, br.d, J=8.8 Hz), 7.33(1H, d,
J=8.8 Hz), 7.60(1H, s), 8.09(1H, br.s), 9.42(1H, br.s).
[0886] MS (ESI) m/z:436 (M+H).sup.+.
Referential Example 136
(1R*, 2S*,
5S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-(hydroxymethyl)c-
yclohexylcarbamic acid tert-butyl ester
##STR00206##
[0888] In a manner similar to that employed in Referential Example
129, the title compound was prepared from the compound obtained in
Referential Example 91.
[0889] .sup.1H-NMR (CDCl.sub.3) .delta.:0.78-2.30(16H, m),
3.41-3.59(3H, m), 3.86-3.95(1H, m), 4.12-4.20(1H, m), 4.82-4.91(1H,
m), 6.81(1H, s), 7.17-7.40(2H, m), 7.60(1H, s), 8.03(1H, br.s),
9.18(1H, br.s).
[0890] MS (ESI) m/z:422 (M+H).sup.+.
Referential Example 137
(1R*, 2S*,
5S*)-5-(azidomethyl)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyc-
lohexylcarbamic acid tert-butyl ester
##STR00207##
[0892] In a manner similar to that employed in Referential Example
80, the title compound was prepared from the compound obtained in
Referential Example 136.
Referential Example 138
3-cyclohexen-1-ylcarbamic acid tert-butyl ester
##STR00208##
[0894] 3-Cyclohexene-1-carboxylic acid (25.3 g) was dissolved in
tert-butanol (250 mL), and to the solution were added triethylamine
(28 mL) and diphenylphosphoryl azide (43.0 mL), followed by
stirring at room temperature for 1 hour, and then at 90.degree. C.
for 2 days. The solvent was distilled away under reduced pressure,
and the residue was purified by silica gel column chromatography
(methylene chloride). The purified product was further purified by
silica gel column chromatography (hexane:ethyl acetate=20:1) to
thereby give the title compound (24.9 g).
[0895] .sup.1H-NMR (CDCl.sub.3) .delta.:1.45(9H, s), 1.45-1.60(1H,
m), 1.80-1.90(2H, m), 2.05-2.20(2H, m), 2.35-2.45(1H, m), 3.78(1H,
br), 4.56(1H, br), 5.55-5.65(1H, m), 5.65-5.75(1H, m).
Referential Example 139
(3R*, 4S*)-3, 4-dihydroxycyclohexylcarbamic acid tert-butyl
ester
##STR00209##
[0897] The compound obtained in Referential Example 138 (1.24 g)
was dissolved in a solvent mixture of acetonitrile (15 mL) and
water (5 mL), and to the solution were added N-methylmorpholine
N-oxide (0.90 g) and microencapsulated 10% osmium tetraoxide (1 g),
followed by stirring at about 80.degree. C. for 1 day. Any
insoluble matter was filtered off, and the filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (methylene
chloride:methanol=20:1), to thereby give the title compound (1.28
g).
[0898] .sup.1H-NMR (CDCl.sub.3) .delta.:1.15-1.30(1/2H, m),
1.35-2.00(15H, m), 2.15-2.30(3/2H, m), 2.40-2.60(1H, m), 3.64(1H,
br), 3.75-3.90(3/2H, m), 4.00(1/2H, br).
[0899] MS (FAB) m/z:232 (M+H).sup.+.
Referential Example 140
(3R*, 4S*)-3, 4-diazidocyclohexylcarbamic acid tert-butyl ester
(stereoisomer A and stereoisomer B)
##STR00210##
[0901] In a manner similar to that employed in Referential Example
80, the title compounds (stereoisomer A and stereoisomer B) were
prepared from the compound obtained in Referential Example 139.
[0902] stereoisomer A:
[0903] .sup.1H-NMR (CDCl.sub.3) .delta.:1.45(9H, s), 1.40-1.55(1H,
m), 1.55-1.80(3H, m), 1.95-2.15(2H, m), 3.53(1H, m), 3.59(1H, br),
3.80(1H, m), 4.70(1H, br).
[0904] stereoisomer B:
[0905] .sup.1H-NMR (CDCl.sub.3) .delta.:1.27(1H, m), 1.44(9H, s),
1.40-1.55(1H, m), 1.80-2.00(2H, m), 2.00-2.15(1H, m), 2.21(1H, m),
3.48(1H, m), 3.77(1H, br), 3.89(1H, br), 4.34(1H, br).
Referential Example 141
(1S, 3R,
4S)-4-{[(benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)amino]-
cyclohexanecarboxylic acid ethyl ester
##STR00211##
[0907] The compound obtained in Referential Example 96 (3.10 g) was
dissolved in tetrahydrofuran (50 mL), and saturated aqueous sodium
hydrogencarbonate (50 mL) was added thereto. Benzyloxycarbonyl
chloride (1.71 mL) was added dropwise to the reaction mixture under
ice cooling, and the thus-obtained mixture was stirred at room
temperature for 4 days. The reaction mixture was partitioned
between ethyl acetate (200 mL) and water (200 mL). The organic
layer was dried over sodium sulfate anhydrate, and the solvent was
distilled away under reduced pressure. The resultant solid was
collected by filtration, to thereby give the title compound (3.24
g).
[0908] .sup.1H-NMR (CDCl.sub.3) .delta.:1.24(3H, t, J=7.1 Hz),
1.29-1.44(1H, m), 1.44(9H, s), 1.51-1.64(1H, m), 1.72-2.10(4H, m),
2.27-2.43(1H, m), 3.60-3.73(1H, m), 4.00-4.18(3H, m), 4.62(1H,
br.s), 5.01-5.13(2H, m), 5.26(1H, br.s), 7.27-7.38(5H, m).
Referential Example 142
(1S, 3R,
4S)-4-{[(benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)amino]-
cyclohexanecarboxylic acid
##STR00212##
[0910] The compound obtained in Referential Example 141 (620 mg)
was dissolved in tetrahydrofuran (20 mL), and an aqueous solution
(10 mL) of lithium hydroxide monohydrate (93 mg) was added thereto,
followed by stirring at room temperature for 16 hours. Additional
lithium hydroxide monohydrate (217 mg) was added to the reaction
mixture, and the thus-obtained mixture was stirred at room
temperature for 2 hours. Subsequently, the resultant mixture was
neutralized with 1N aqueous HCl, and was extracted with methylene
chloride. The organic layer was washed with saturated brine, and
was dried over sodium sulfate anhydrate. The solvent was distilled
away, to thereby give the title compound (600 mg).
[0911] .sup.1H-NMR (CDCl.sub.3) .delta.:1.22-2.20(6H, m), 1.44(9H,
s), 2.45(1H, br.s), 3.60-3.80(1H, br), 4.09(1H, br.s), 4.66(1H,
br.s), 5.00-5.20(2H, m), 5.26(1H, br.s), 7.20-7.40(5H, m).
[0912] MS (ESI) m/z:393 (M+H).sup.+.
Referential Example 143
(1S, 2R,
4S)-2-[(tert-butoxycarbonyl)amino]-4-[(dimethylamino)carbonyl]cyc-
lohexylcarbamic acid benzyl ester
##STR00213##
[0914] The compound obtained in Referential Example 142 (600 mg)
and dimethylamine hydrochloride (240 mg) were suspended in
methylene chloride (50 mL), and a proper amount of tetrahydrofuran
was added thereto, to thereby dissolve any solid matter. To the
solution were added triethylamine (0.41 mL),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (422
mg), and 1-hydroxybenzotriazole monohydrate (338 mg), and the
thus-obtained mixture was stirred at room temperature for 1 hour.
To the reaction mixture were further added dimethylamine
hydrochloride (480 mg) and triethylamine (0.82 mL), and the
thus-obtained mixture was stirred at room temperature for an
additional 18 hours. The reaction mixture was poured into water.
The organic layer was separated, and was washed with 1N HCl and
saturated brine, followed by drying over sodium sulfate anhydrate.
The solvent was distilled away under reduced pressure, and the
residue was purified by silica gel column chromatography
(methanol:methylene chloride=3:47.fwdarw.2:23), to thereby give the
title compound (620 mg).
[0915] .sup.1H-NMR (CDCl.sub.3) .delta.:1.20-1.50(2H, m), 1.44(9H,
s), 1.50-2.10(4H, m), 2.60(1H, br.t, J=11.6 Hz), 2.93(3H, s),
3.02(3H, s), 3.70(1H, br.s), 4.14(1H, br.s), 4.65(1H, br.s),
5.00-5.30(3H, m), 7.26-7.40(5H, m).
[0916] MS (ESI) m/z=420 (M+H).sup.+.
Referential Example 144
(1R, 2S, 5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexylcarbamic
acid tert-butyl ester
##STR00214##
[0918] To a solution of the compound obtained in Referential
Example 143 (190 g) in methanol (8000 mL) was added 10% palladium
on carbon (57 g), and the thus-obtained mixture was stirred for 3
hours under hydrogen at a pressure of 7 atm. After the catalyst was
filtered off, the filtrate was concentrated under reduced pressure.
Toluene was added to the residue, and the thus-obtained mixture was
concentrated under reduced pressure, followed by precipitation by
addition of hexane (2500 mL). The resultant solid was collected by
filtration, and was dried, to thereby give the title compound (121
g).
[0919] .sup.1H-NMR (CDCl.sub.3) .delta.:1.20-1.77(6H, m), 1.45(9H,
s), 2.20-2.35(1H, br), 2.63-2.74(1H, m), 2.92(3H, s), 3.02(3H, s),
3.02-3.11(2H, m), 3.74-3.82(1H, m), 4.88-5.00(1H, br) MS (ESI)
m/z:286 (M+H).sup.+.
Referential Example 145
(1R, 2S,
5S)-2-{[(6-chloroquinolin-2-yl)carbonyl]amino}-5-[(dimethylamino)-
carbonyl]cyclohexylcarbamic acid tert-butyl ester
##STR00215##
[0921] In a manner similar to that employed in Referential Example
91, the title compound was prepared from the compound obtained in
Referential Example 144 and the compound obtained in Referential
Example 54.
[0922] .sup.1H-NMR (CDCl.sub.3) .delta.:1.41(9H, br), 1.50-1.70(1H,
m), 1.75-1.95(2H, m), 1.95-2.25(3H, m), 2.65-2.80(1H, m), 2.96(3H,
s), 3.07(3H, s), 4.15-4.30(1H, m), 4.30-4.40(1H, m), 4.95(1H, br),
7.66(1H, d, J=8.8 Hz), 7.84(1H, s), 8.00(1H, d, J=8.8 Hz), 8.19(1H,
d, J=8.6 Hz), 8.30(1H, d, J=8.6 Hz).
[0923] MS (FAB) m/z:475 (M+H).sup.+.
Referential Example 146
(1R, 2S,
5S)-2-{[(7-chloroquinolin-3-yl)carbonyl]amino}-5-[(dimethylamino)-
carbonyl]cyclohexylcarbamic acid tert-butyl ester
##STR00216##
[0925] In a manner similar to that employed in Referential Example
91, the title compound was prepared from the compound obtained in
Referential Example 144 and the compound obtained in Referential
Example 57.
[0926] .sup.1H-NMR (CDCl.sub.3) .delta.:1.30-1.65(10H, br),
1.75-1.90(2H, m), 1.90-2.25(3H, m), 2.65-2.90(1H, br), 2.96(3H, s),
3.08(3H, s), 4.20-4.30(1H, m), 4.30-4.40(1H, m), 4.93(1H, br),
7.68(1H, m), 7.90(1H, br), 7.99(1H, s), 8.35-8.70(2H, m), 9.01(1H,
br).
[0927] MS (FAB) m/z:475 (M+H).sup.+.
Referential Example 147
2-bromo-5-isopropyl-4, 5, 6, 7-tetrahydrothiazolo[5,
4-c]pyridine
##STR00217##
[0929] In a manner similar to that employed in Referential Example
9, the title compound was prepared from the compound obtained in
Referential Example 8.
[0930] .sup.1H-NMR (CDCl.sub.3) .delta.:1.13(6H, d, J=6.5 Hz),
2.86(4H, s), 2.89-3.00(1H, m), 3.70(2H, s).
Referential Example 148
5-ispopropyl-4, 5, 6, 7-tetrahydrothiazolo[5,
4-c]pyridine-2-carboxylic acid lithium salt
##STR00218##
[0932] In a manner similar to that employed in Referential Example
10, the title compound was prepared from the compound obtained in
Referential Example 147.
[0933] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.05 (6H, d, J=6.4 Hz),
2.68-2.70(2H, m), 2.75-2.77(2H, m), 2.87-2.93(1H, m), 3.66(2H,
s).
Referential Example 149
5-methyl-4, 5, 6, 7-tetrahydrothiazolo[5, 4-c]pyridine-2-carboxylic
acid 4-nitrophenyl ester
##STR00219##
[0935] In a manner similar to that employed in Referential Example
52, the title compound was prepared from the compound obtained in
Referential Example 10 and p-nitrophenol.
[0936] .sup.1H-NMR (CDCl.sub.3) .delta.:2.55(3H, s), 2.88(2H, t,
J=5.7 Hz), 3.06-3.12(2H, m), 3.80(2H, s), 7.46(2H, d, J=9.3 Hz),
8.32(2H, d, J=9.3 Hz).
[0937] MS (ESI) m/z:320 (M+H.sup.+).
Referential Example 150
3-oxocyclobutanecarboxylic acid benzyl ester
##STR00220##
[0939] Triethylamine (2.0 mL) and benzyl bromide (1.2 mL) were
added to a solution of 3-oxocyclobutanecarboxylic acid (J. Org.
Chem., vol. 53, pp. 3841-3843 (1981)) (995 mg) in tetrahydrofuran
(5.0 mL), and the mixture was stirred at room temperature for 2
hours. The reaction mixture was diluted with ethyl acetate, and was
sequentially washed with 1N aqueous HCl, saturated aqueous sodium
hydrogencarbonate, and saturated brine, followed by drying over
sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure, and the residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:6), to thereby give the
title compound (886 mg).
[0940] .sup.1H-NMR (CDCl.sub.3) .delta.:3.22-3.33(3H, m),
3.37-3.48(2H, m), 5.19(2H, s), 7.31-7.42(5H, m). MS (FAB) m/z:205
(M+H.sup.+).
Referential Example 151
3-hydroxycyclobutanecarboxylic acid benzyl ester
##STR00221##
[0942] To a mixture of the compound obtained in Referential Example
150 (781 mg), tetrahydrofuran (10 mL), and methanol (0.5 mL) was
added sodium borohydride (76 mg) at 0.degree. C., and the
thus-obtained mixture was stirred at the same temperature for 30
minutes. The reaction mixture was diluted with ethyl acetate, and
the diluted mixture was sequentially washed with saturated aqueous
sodium hydrogencarbonate and saturated brine, followed by drying
over sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure, and the residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:2), to thereby give the
title compound (770 mg).
[0943] .sup.1H-NMR (CDCl.sub.3) .delta.:2.13-2.27(3H, m),
2.55-2.71(3H, m), 4.14-4.23(1H, m), 5.12(2H, s), 7.28-7.39(5H,
m).
[0944] MS (FAB) m/z:207 (M+H.sup.+).
Referential Example 152
3-hydroxycyclobutanecarboxylic acid
##STR00222##
[0946] To a solution of the compound obtained in Referential
Example 151 (706 mg) in ethanol (10 mL) was added 10% palladium on
carbon (108 mg), and the mixture was stirred at room temperature
for 2 hours under hydrogen atmosphere. The catalyst was removed by
filtration through Celite, and the filtrate was concentrated under
reduced pressure, to thereby give the title compound (399 mg).
[0947] .sup.1H-NMR (CD.sub.3OD) .delta.:2.00-2.21 (2H, m),
2.41-2.61(3H, m), 4.01-4.13(1H, m).
Referential Example 153
3-methoxycyclobutanecarboxylic acid benzyl ester
##STR00223##
[0949] To a solution of the compound obtained in Referential
Example 151 (317 mg) in N,N-dimethylformamide (3.0 mL) were added
methyl iodide (194 and silver oxide (237 mg), followed by stirring
at 45.degree. C. for 1 hour. To the reaction mixture were added
additional methyl iodide (194 .mu.L) and silver oxide (226 mg),
followed by stirring at 45.degree. C. for 16 hours. The catalyst
was filtered off, and the filtrate was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:10), to thereby give the
title compound (152 mg).
[0950] .sup.1H-NMR (CDCl.sub.3) .delta.:2.14-2.24(2H, m),
2.44-2.54(2H, m), 2.59-2.72(1H, m), 3.21(3H, s), 3.73-3.81(1H, m),
5.11(2H, s), 7.22-7.39(5H, m).
[0951] MS (ESI) m/z:221 (M+H.sup.+).
Referential Example 154
3-methoxycyclobutanecarboxylic acid
##STR00224##
[0953] In a manner similar to that employed in Referential Example
152, the title compound was prepared from the compound obtained in
Referential Example 153.
[0954] .sup.1H-NMR (CDCl.sub.3) .delta.:2.17-2.27(2H, m),
2.48-2.58(2H, m), 2.62-2.73(1H, m), 3.25(3H, s), 3.76-3.86(1H, m),
8.60-9.30(1H, br).
Referential Example 155
3-methoxy-2-(methoxymethyl)propionic acid methyl ester
##STR00225##
[0956] Sodium methoxide (1.21 g) was added to a solution of
2-(bromomethyl)acrylic acid methyl ester (1.0 mL) in methanol (10
mL), and the mixture was heated under reflux for 26 hours. The
reaction mixture was cooled, and was diluted with diethyl ether.
The precipitate was filtered off, and the filtrate was concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (ethyl acetate:hexane=1:4), to thereby give
the title compound (726 mg).
[0957] .sup.1H-NMR (CDCl.sub.3) .delta.:2.90-2.96(1H, m), 3.34(6H,
s), 3.57(2H, dd, J=9.3, 5.9 Hz), 3.64(2H, dd, J=9.3, 6.6 Hz),
3.73(3H, s).
[0958] .sup.13C-NMR (CDCl.sub.3) .delta.:172.71, 70.31, 59.91,
46.49.
[0959] MS (ESI) m/z:163 (M+H.sup.+).
Referential Example 156
tetrahydro-2H-pyran-4-carboxylic acid
##STR00226##
[0961] To tetrahydro-4H-pyran-4,4-dicarboxylic acid dimethyl ester
(4.04 g) was added 20% HCl (20 mL), and the mixture was heated
under reflux for 19 hours. Water was added to the reaction mixture,
and the thus-obtained mixture was extracted with diethyl ether. The
organic layer was washed with saturated brine, and was dried over
sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure, and hexane was added to the residue. The
resultant solid was collected by filtration, and was washed, to
thereby give the title compound (2.63 g).
[0962] .sup.1H-NMR (CDCl.sub.3) .delta.:1.75-1.95(4H, m),
2.55-2.65(1H, m), 3.40-3.52(2H, m), 3.93-4.05(2H, m).
Referential Example 157
3-{[tert-butyl(diphenyl)silyl]oxy}-2, 2-dimethylpropionic acid
methyl ester
##STR00227##
[0964] In a manner similar to that employed in Referential Example
41, the title compound was prepared from
2,2-dimethyl-3-hydroxypropionic acid methyl ester.
[0965] .sup.1H-NMR (CDCl.sub.3) .delta.:1.03(9H, s), 1.20(6H, s),
3.64-3.68(5H, m), 7.38-7.44(6H, m), 7.63-7.65(4H, m).
Referential Example 158
3-{[tert-butyl(diphenyl)silyl]oxy}-2, 2-dimethylpropionic acid
##STR00228##
[0967] Water (0.24 mL) was added to a suspension comprising
potassium tert-butoxide (5.32 g) and diethyl ether (100 mL) under
ice cooling. After the thus-obtained mixture was stirred for 5
minutes, the compound obtained in Referential Example 157 (2.22 g)
was added thereto, followed by stirring at room temperature
overnight. Water was added to the reaction mixture, and 1N aqueous
HCl was added thereto, to thereby make the mixture acidic. The
resultant mixture was extracted with diethyl ether 3 times, and the
organic layer was dried over sodium sulfate anhydrate. The solvent
was distilled away under reduced pressure, and the residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=1:6), to thereby give the title compound (735
mg).
[0968] .sup.1H-NMR (CDCl.sub.3) .delta.:1.04 (9H, d, J=0.7 Hz),
1.22(6H, s), 3.65(2H, s), 7.36-7.45(6H, m), 7.64-7.66(4H, m).
Referential Example 159
3-methoxy-2, 2-dimethylpropionic acid methyl ester
##STR00229##
[0970] A solution of 3-hydroxy-2,2-dimethyl-propionic acid methyl
ester (25.0 g) in tetrahydrofuran (300 mL) was added dropwise to a
suspension comprising sodium hydride (as 60% oil suspension, 8.32
g) and tetrahydrofuran (100 mL) under ice cooling, followed by
stirring at 60.degree. C. for 1 hour. Methyl iodide (53.7 g) was
added to the reaction mixture, and the thus-obtained mixture was
stirred at room temperature for an additional 2 hours. After water
was carefully added thereto, the reaction mixture was extracted
with methylene chloride twice. The organic layer was washed with
saturated brine, and was dried over sodium sulfate anhydrate. The
solvent was distilled away under reduced pressure, and the
resultant oily matter was subjected to distillation, to thereby
give the title compound (12.8 g).
[0971] b.p.:140-142.degree. C. (atmospheric pressure).
[0972] .sup.1H-NMR (CDCl.sub.3) .delta.:1.19(6H, d, J=1.0 Hz),
3.33(3H, d, J=1.0 Hz), 3.38(2H, d, J=1.0 Hz), 3.69(3H, d, J=1.0
Hz).
Referential Example 160
3-methoxy-2, 2-dimethylpropionic acid
##STR00230##
[0974] In a manner similar to that employed in Referential Example
158, the title compound was prepared from the compound obtained in
Referential Example 159.
[0975] .sup.1H-NMR (CDCl.sub.3) .delta.:1.22(6H, d, J=0.7 Hz),
3.38(3H, d, J=0.7 Hz), 3.40(2H, d, J=0.7 Hz).
Referential Example 161
1-(methoxycarbonyl)cyclopropanecarboxylic acid
##STR00231##
[0977] 1,1-Cyclopropanedicarboxylic acid dimethyl ester (25 g) was
dissolved in methanol (250 mL). The solution was cooled under ice
Cooling, and 1N aqueous sodium hydroxide (158 mL) was added
dropwise thereto. The thus-obtained mixture was brought back to
room temperature, and was stirred overnight. Methanol was distilled
away, and the residue was washed with chloroform. The aqueous layer
was cooled under ice cooling, and concentrated aqueous HCl was
added thereto, to thereby adjust to pH 2. The resultant mixture was
extracted with ethyl acetate, and the extract was dried over sodium
sulfate anhydrate. The solvent was distilled away under reduced
pressure, to thereby give the title compound (16.8 g).
[0978] .sup.1H-NMR (CDCl.sub.3) .delta.:1.76-1.80(2H, m),
1.82-1.88(2H, m), 3.79(3H, s), 12.73(1H, br).
Referential Example 162
1-(hydroxymethyl)cyclopropanecarboxylic acid methyl ester
##STR00232##
[0980] The compound obtained in Referential Example 161 (9.0 g) and
triethylamine (9.7 mL) were dissolved in tetrahydrofuran (180 mL).
After the solution was cooled to -10.degree. C., isobutyl
chloroformate (9.1 mL) was added dropwise thereto, followed by
stirring for 1 hour. Sodium borohydride (7.1 g) was dissolved in a
mixture of tetrahydrofuran (100 mL) and water (25 mL). After this
solution was cooled under ice cooling, the previously prepared
solution was added dropwise thereto while insoluble matter was
removed by filtration, and the thus-obtained mixture was stirred at
the same temperature for 1 hour. The reaction mixture was poured
into a chilled 10% aqueous citric acid, and the thus-obtained
mixture was extracted with ethyl acetate. The extract was washed
with saturated brine, and was dried over sodium sulfate anhydrate.
The solvent was distilled away under reduced pressure, and the
residue was purified by silica gel column chromatography (ethyl
acetate:hexane=1:9 to 2:1), to thereby give the title compound
(4.25 g).
[0981] .sup.1H-NMR (CDCl.sub.3) .delta.:0.87-0.93(2H, m),
1.28-1.30(2H, m), 3.63(2H, s), 3.70(3H, s).
Referential Example 163
1-(bromomethyl)cyclopropanecarboxylic acid methyl ester
##STR00233##
[0983] To a solution of the compound obtained in Referential
Example 162 (4.20 g) in methylene chloride (168 mL) were added
triphenylphosphine (10 g) and carbon tetrabromide (16 g) at room
temperature under nitrogen atmosphere, and after 2 minutes,
saturated aqueous sodium hydrogencarbonate was added thereto. The
organic layer was washed with saturated brine, and was dried over
sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure, and the residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:19), to thereby give the
title compound (2.15 g).
[0984] .sup.1H-NMR (CDCl.sub.3) .delta.:1.00-1.05(2H, m),
1.52-1.59(2H, m), 3.61(2H, s), 3.73(3H, s).
Referential Example 164
(4S)-4-[(E)-3-ethoxy-3-oxo-1-propenyl]-2, 2-dimethyl-1,
3-oxazolidine-3-carboxylic acid tert-butyl ester
##STR00234##
[0986] A mixture comprising
(4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid
tert-butyl ester (11.7 g),
(carbethoxymethylene)triphenylphosphorane (20.7 g), and toluene
(100 mL) was stirred at 100.degree. C. for 18 hours. The reaction
mixture was concentrated, and the residue was purified by silica
gel column chromatography (hexane:ethyl acetate=8:1), to thereby
give the title compound (17 g).
[0987] .sup.1H-NMR (CDCl.sub.3) .delta.:1.29(3H, t, J=6.6 Hz),
1.43-1.56(15H, m), 3.80(1H, dd, J=9.0, 2.4 Hz), 4.09(1H, dd, J=9.0,
6.6 Hz), 4.11-4.23(2H, m), 4.30-4.61(1H, m), 5.83-6.02(1H, m),
6.74-6.89(1H, m).
Referential Example 165
(4S)-4-[1-(benzylamino)-3-ethoxy-3-oxopropyl]-2, 2-dimethyl-1,
3-oxazolidine-3-carboxylic acid tert-butyl ester
##STR00235##
[0989] A mixture comprising the compound obtained in Referential
Example 164 (22.2 g), benzylamine (16 g) and ethanol (100 mL) was
heated under reflux for 2 days. The reaction mixture was
concentrated, and the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=8:1), to thereby give the
title compound (26 g).
[0990] .sup.1H-NMR (CDCl.sub.3) .delta.:1.25(3H, t, J=6.6 Hz),
1.42-1.63(15H, m), 2.24-2.33(0.5H, m), 2.40-2.50(1H, m),
2.63-2.74(0.5H, m), 3.41-3.52(1H, m), 3.67-3.80(1H, m), 3.83(2H,
s), 3.89-4.00(1H, m), 4.03-4.22(4H, m), 7.23-7.45(5H, m).
Referential Example 166
(4S)-4-(1-amino-3-ethoxy-3-oxopropyl)-2, 2-dimethyl-1,
3-oxazolidine-3-carboxylic acid tert-butyl ester
##STR00236##
[0992] To a solution of the compound obtained in Referential
Example 165 (13.6 g) in ethanol (200 mL) was added 10% palladium on
carbon (10 g), and the thus-obtained mixture was stirred for 2 days
under hydrogen atmosphere. Any insoluble matter was filtered off
through a Celite pad, and the filtrate was concentrated under
reduced pressure, to thereby give the title compound (10.5 g).
[0993] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.19(1.5H, t, J=6.6 Hz),
1.20(1.5H, t, J=6.6 Hz), 1.32-1.50(15H, m), 2.63-2.81(2H, m),
3.22-3.34(2H, m), 3.93(1H, dd, J=10.0, 6.8 Hz), 4.08(2H, q, J=6.6
Hz), 4.20-4.30(1H, m).
Referential Example 167
(4S)-4-(1-{[(benzyloxy)carbonyl]amino}-3-ethoxy-3-oxopropyl)-2,
2-dimethyl-1, 3-oxazolidine-3-carboxylic acid tert-butyl ester
##STR00237##
[0995] The compound obtained in Referential Example 166 (3.0 g) was
suspended in 9% aqueous sodium hydrogencarbonate (56 mL), and to
the suspension was added dropwise a solution of
N-(benzyloxycarbonyloxy)succinimide (2.3 g) in dioxane (12 mL)
under ice cooling. The thus-obtained mixture was gradually brought
back to room temperature while being stirred. After the reaction
mixture was stirred for 3 hours, the mixture was diluted with ethyl
acetate. The diluted mixture was washed with water, 10% aqueous
citric acid, and saturated brine, and was dried over sodium sulfate
anhydrate. The solvent was distilled away under reduced pressure,
and the residue was purified by silica gel column chromatography
(chloroform), to thereby give the title compound (3.8 g).
[0996] .sup.1H-NMR (CDCl.sub.3) .delta.:1.23(3H, t, J=6.6 Hz),
1.48(9H, s), 1.56(6H, s), 2.40-2.51(2H, m), 2.63-2.70(2H, m),
3.92-4.04(1H, m), 4.06-4.10(2H, m), 4.14-4.22(1H, m), 5.09(2H, s),
7.30-7.43(5H, m).
Referential Example 168
(3S,
4S)-3-{[(benzyloxy)carbonyl]amino}-4-[(tert-butoxycarbonyl)amino]-5-h-
ydroxyvaleric acid ethyl ester (low-polar compound) and (3R,
4S)-3-{[(benzyloxy)carbonyl]amino}-4-[(tert-butoxycarbonyl)amino]-5-hydro-
xyvaleric acid ethyl ester (High-Polar Compound)
##STR00238##
[0998] To a solution of the compound obtained in Referential
Example 167 (30 g) in methylene chloride (100 mL) was added
dropwise trifluoroacetic acid (100 mL) under ice cooling, and the
thus-obtained mixture was gradually brought back to room
temperature while being stirred. After the reaction mixture was
stirred for 3 hours, the mixture was concentrated under reduced
pressure, and the residue was dissolved in methylene chloride (100
mL). To the solution were sequentially added dropwise triethylamine
(20 mL) and a solution of di-tert-butyl dicarbonate (19 g) in
methylene chloride (100 mL) under ice cooling, and the
thus-obtained mixture was gradually brought back to room
temperature while being stirred. After the reaction mixture was
stirred for 4 hours, the mixture was concentrated under reduced
pressure, and the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=2:1), to thereby give the
title low-polar compound (7.6 g) and the title high-polar compound
(10 g).
[0999] Low-Polar Compound:
[1000] .sup.1H-NMR (CDCl.sub.3) .delta.:1.24(3H, t, J=6.6 Hz),
1.42(9H, s), 2.63(2H, d, J=4.4 Hz), 3.30-3.41(1H, m), 3.50(1H, t,
J=9.7 Hz), 3.65(1H, t, J=9.7 Hz), 3.75(1H, d, J=11.7 Hz),
3.90-4.00(1H, m), 4.03-4.23(2H, m), 5.12(2H, s), 5.13-5.25(1H, m),
5.79-6.02(1H, m), 7.32-7.41(5H, m).
[1001] High-Polar Compound:
[1002] .sup.1H-NMR (CDCl.sub.3) .delta.:1.22(3H, t, J=6.6 Hz),
1.41(9H, s), 2.50-2.70(2H, m), 3.20-3.31(1H, m), 3.43-3.51(1H, m),
3.56-3.70(1H, m), 3.74-3.78(1H, m), 4.00-4.19(2H, m), 4.23-4.30(1H,
m), 4.78-4.89(1H, m), 5.10(2H, s), 5.56-5.67(1H, m), 7.31-7.40(5H,
m).
Referential Example 169
methanesulfonic acid (3R,
4S)-4-[(methylsulfonyl)oxy]tetrahydro-3-furanyl ester
##STR00239##
[1004] Triethylamine (12.0 mL) and methanesulfonyl chloride (3.6
mL) were sequentially added dropwise to a solution of
1,4-anhydroerythritol (5.0 g) in methylene chloride (50 mL) under
ice cooling, followed by stirring for 10 minutes under ice cooling.
The reaction mixture was diluted with methylene chloride, and the
diluted mixture was washed with 10% aqueous HCl, saturated aqueous
sodium hydrogencarbonate, and saturated brine. The organic layer
was dried over sodium sulfate anhydrate, and the solvent was
distilled away under reduced pressure, to thereby give the title
compound (9.2 g).
[1005] .sup.1H-NMR (CDCl.sub.3) .delta.:3.15(6H, s), 3.99(2H, dd,
J=11.2, 2.5 Hz), 4.16(2H, dd, J=11.2, 4.6 Hz), 5.10-5.20(2H,
m).
Referential Example 170
(3R, 4S)-3, 4-diazidotetrahydrofuran
##STR00240##
[1007] The compound obtained in Referential Example 169 (9.2 g) was
dissolved in N,N-dimethylformamide (50 mL), and sodium azide (18 g)
was added thereto, followed by stirring at 100.degree. C. for 18
hours. The reaction mixture was diluted with ethyl acetate, and the
diluted mixture was washed with water and saturated brine. The
organic layer was dried over sodium sulfate anhydrate, and the
solvent was distilled away under reduced pressure, to thereby give
the title compound (3.8 g).
[1008] .sup.1H-NMR (CDCl.sub.3).delta.:3.83(2H, dd, J=8.6, 2.0 Hz),
3.96-4.12(4H, m).
Referential Example 171
(3R, 4S)-tetrahydro-3, 4-furandiamine dihydrochloride
##STR00241##
[1010] The compound obtained in Referential Example 170 (3.8 g) was
dissolved in ethanol (50 mL), and 10% palladium on carbon (1.0 g)
was added thereto, followed by stirring for 18 hours under hydrogen
atmosphere. After any insoluble matter was removed by filtration
through a Celite pad, the filtrate was concentrated under reduced
pressure. To the residue was added 1N HCl-ethanol, to thereby give
an hydrochloride salt, and this compound was recrystallized from a
solvent mixture of ethanol and diethyl ether, to thereby give the
title compound (2.0 g).
[1011] .sup.1H-NMR (CDCl.sub.3) .delta.:3.90(2H, dd, J=9.0, 3.7
Hz), 4.01-4.13(4H, m), 8.84(6H, s).
Referential Example 172
N-[(3R*,
4S*)-4-aminotetrahydro-3-furanyl]-5-chloroindole-2-carboxamide
##STR00242##
[1013] To a solution of the compound obtained in Referential
Example 171 (0.5 g) in N,N-dimethylformamide (10 mL) were
sequentially added 5-chloroindole-2-carboxylic acid (0.29 g),
1-hydroxybenzotriazole (0.2 g), and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g)
at room temperature, followed by stirring at 50.degree. C. for 1
day. The reaction mixture was concentrated, and the residue was
diluted with a solvent mixture comprising chloroform and methanol
(9:1). The diluted mixture was washed with saturated aqueous sodium
hydrogencarbonate and saturated brine, and the organic layer was
dried over sodium sulfate anhydrate. The solvent was distilled away
under reduced pressure, and the residue was purified by silica gel
column chromatography (chloroform:methanol=95:5), to thereby give
the title compound (0.2 g).
[1014] .sup.1H-NMR (CDCl.sub.3) .delta.:1.80-1.92(1H, m), 3.62(1H,
dd, J=9.3, 4.2 Hz), 3.68-3.80(2H, m), 4.06(1H, dd, J=9.3, 5.6 Hz),
4.21(1H, dd, J=9.3, 6.8 Hz), 4.36-4.52(2H, m), 6.87(1H, s),
7.24(1H, dd, J=8.8, 2.0 Hz), 7.36(1H, d, J=8.8 Hz), 7.44-7.56(1H,
m), 7.62(1H, d, J=2.0 Hz), 9.41(1H, s).
Referential Example 173
(4R)-4-[(E)-3-ethoxy-3-oxo-1-propenyl]-2, 2-dimethyl-1,
3-oxazolidine-3-carboxylic acid tert-butyl ester
##STR00243##
[1016] In a manner similar to that employed in Referential Example
164, the title compound was prepared from
(4S)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid
tert-butyl ester.
[1017] .sup.1H-NMR (CDCl.sub.3) .delta.:1.29(3H, t, J=6.6 Hz),
1.40-1.60(15H, m), 3.80(1H, dd, J=9.0, 2.4 Hz), 4.09(1H, dd, J=9.0,
6.6 Hz), 4.11-4.21(2H, m), 4.32-4.64(1H, m), 5.78-6.01(1H, m),
6.67-6.89(1H, m).
Referential Example 174
(4R)-4-[1-(benzylamino)-3-ethoxy-3-oxopropyl]-2, 2-dimethyl-1,
3-oxazolidine-3-carboxylic acid tert-butyl ester
##STR00244##
[1019] In a manner similar to that employed in Referential Example
165, the title compound was prepared from the compound obtained in
Referential Example 173.
[1020] .sup.1H-NMR (CDCl.sub.3) .delta.:1.25(3H, t, J=6.6 Hz),
1.40-1.61(15H, m), 2.21-2.32(0.5H, m), 2.40-2.51(1H, m),
2.61-2.72(0.5H, m), 3.43-3.50(1H, m), 3.67-3.80(1H, m), 3.83(2H,
s), 3.90-4.03(1H, m), 4.04-4.22(4H, m), 7.20-7.40(5H, m).
Referential Example 175
(4R)-4-(1-{[(5-chloroindol-2-yl)carbonyl]amino}-3-ethoxy-3-oxopropyl)-2,
2-dimethyl-1, 3-oxazolidine-3-carboxylic acid tert-butyl ester
##STR00245##
[1022] In a manner similar to that employed in Referential Example
166, the compound obtained in Referential Example 174 was subjected
to catalytic reduction, to thereby eliminate the benzyl group.
Subsequently the thus-obtained compound was subjected to
condensation reaction with 5-chloroindole-2-carboxylic acid in a
manner similar to that employed in Referential Example 172, to
thereby give the title compound.
[1023] .sup.1H-NMR (CDCl.sub.3) .delta.:1.23(1.5H, t, J=6.6 Hz),
1.25(1.5H, t, J=6.6 Hz), 1.50(4.5H, s), 1.54(4.5H, s), 1.62(6H, s),
2.50-2.70(1.5H, m), 2.86(0.5H, dd, J=16.4, 5.5 Hz), 3.80-3.90(0.5H,
m), 4.00-4.31(5H, m), 4.41-4.67(0.5H, m), 6.85(0.5H, s), 6.87(0.5H,
s), 7.10-7.20(1H, m), 7.34(0.5H, d, J=8.8 Hz), 7.38(0.5H, d, J=8.8
Hz), 7.57(0.5H, s), 7.63(0.5H, s), 7.88(0.5H, d, J=7.6 Hz),
8.54(0.5H, d, J=7.6 Hz), 9.40(0.5H, s), 9.54(0.5H, s).
Referential Example 176
(3R,
4R)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-6-oxotetrahydro-2H-pyran--
3-ylcarbamic acid tert-butyl ester (low-polar compound) and (3R,
4S)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-6-oxotetrahydro-2H-pyran-3-yl-
carbamic acid tert-butyl ester (High-Polar Compound)
##STR00246##
[1025] To a solution of the compound obtained in Referential
Example 175 (1.0 g) in ethanol (20 mL) was added 1N aqueous sodium
hydroxide (4.0 mL), and after the thus-obtained mixture was stirred
for 4 hours, citric acid was added to the reaction mixture, to
thereby adjust pH to 4.0. The resultant mixture was extracted with
ethyl acetate. The organic layer was washed with saturated brine,
and was dried over sodium sulfate anhydrate. The solvent was
distilled away under reduced pressure. The residue was dissolved in
methanol (50 mL), and toluenesulfonic acid monohydrate (0.1 g) was
added thereto, followed by stirring for 18 hours. The reaction
mixture was diluted with ethyl acetate, and the diluted mixture was
washed with saturated aqueous sodium hydrogencarbonate and
saturated brine. The organic layer was dried over sodium sulfate
anhydrate, and the solvent was distilled away under reduced
pressure. The residue was purified by silica gel column
chromatography (chloroform:methanol=99:1), to thereby give the
title low-polar compound (0.3 g) and the title high-polar compound
(0.3 g).
[1026] Low-Polar Compound:
[1027] .sup.1H-NMR (CDCl.sub.3) .delta.:1.45(9H, s), 2.70(1H, dd,
J=16.5, 4.9 Hz), 2.85(1H, dd, J=16.5, 4.6 Hz), 3.50-3.61(1H, m),
3.71-3.81(2H, m), 4.30-4.40(1H, m), 5.30(1H, d, J=9.5 Hz), 6.89(1H,
s), 7.23(1H, dd, J=8.8, 2.0 Hz), 7.38(1H, d, J=8.8 Hz), 7.62(1H, d,
J=2.0 Hz), 7.93(1H, d, J=9.5 Hz), 9.30(1H, s).
[1028] High-Polar Compound:
[1029] .sup.1H-NMR (CDCl.sub.3) .delta.:1.39(9H, s), 2.75(1H, dd,
J=16.5, 4.9 Hz), 2.82(1H, dd, J=16.5, 4.6 Hz), 3.41-3.52(2H, m),
3.71-3.82(1H, m), 3.85-3.94(1H, m), 5.03(1H, d, J=9.3 Hz), 6.99(1H,
s), 7.22-7.31(1H, m), 7.34(1H, d, J=8.8 Hz), 7.61(1H, d, J=2.0 Hz),
7.83(1H, d, J=9.3 Hz), 9.28(1H, s).
Referential Example 177
1, 1, 3,-trioxohexahydro-1-thiopyran-4-ylcarbamic acid tert-butyl
ester
##STR00247##
[1031] A solution of N-tert-butoxycarbonyl-L-methionine sulfone
methyl ester (60.2 g) in tetrahydrofuran (900 mL) was cooled to
-78.degree. C., and potassium bis(trimethylsilyl)amide (as 0.5M
toluene solution, 900 mL) was added dropwise thereto, followed by
stirring at -78.degree. C. for 2 hours, and then at room
temperature for 4.5 hours. To the resultant mixture was added 1M
aqueous ammonium chloride, and the thus-obtained mixture was
stirred. The reaction mixture was separated, and the organic layer
was washed with water and saturated brine, followed by drying over
anhydrous magnesium sulfate. The solvent was distilled away under
reduced pressure, and the resultant solid was collected by
filtration, to thereby give the title compound (12.4 g). The
aqueous layer previously separated was extracted with ethyl acetate
twice, and the organic layers were combined. The combined organic
layer was washed with water and saturated brine, and was dried over
anhydrous magnesium sulfate. Furthermore, the aqueous layers used
for the washing of the organic layer were combined, and the mixture
was further extracted with ethyl acetate. The extract was washed
with saturated brine, and was dried over anhydrous magnesium
sulfate. The ethyl acetate extracts were combined. The mixture was
concentrated under reduced pressure, to thereby give the title
compound (27.7 g) (total amount of the title compound: 40.1 g).
[1032] .sup.1H-NMR (CDCl.sub.3) .delta.:1.45(9H, s), 1.85-1.96(1H,
m), 2.76-2.78(1H, m), 3.34-3.46(2H, m), 4.05(1H, dd, J=13.5, 3.7
Hz), 4.14(1H, d, J=13.5 Hz), 4.38-4.44(1H, m), 5.46(1H, br).
[1033] MS (ESI) m/z:262 (M-H).sup.-.
Referential Example 178
(3R*, 4R*)-3-hydroxy-1, 1-dioxohexahydro-1-thiopyran-4-ylcarbamic
acid tert-butyl ester
##STR00248##
[1035] To a suspension of the compound obtained in Referential
Example 177 (10.1 g) in methanol (200 mL) was added sodium
borohydride (2.17 g), and the thus-obtained mixture was stirred at
room temperature for 2 hours. The reaction mixture was concentrated
under reduced pressure, and ethyl acetate and saturated aqueous
sodium hydrogencarbonate were added to the residue. The aqueous
layer was separated, and was extracted with ethyl acetate twice.
The organic layers were combined. The combined organic layer was
dried over magnesium sulfate, and was concentrated under reduced
pressure, to thereby give the title compound (9.96 g).
[1036] .sup.1H-NMR (CDCl.sub.3) .delta.:1.44(9H, s), 2.21-2.36(2H,
m), 3.03-3.17(2H, m), 3.26-3.28(2H, m), 3.77-3.80(2H, m),
4.26-4.28(1H, m), 5.05-5.07(1H, m).
[1037] MS (ESI) m/z:264 [(M-H).sup.-].
Referential Example 179
(3R*, 4R*)-3-amino-1, 1-dioxohexahydro-1-thiopyran-4-ylcarbamic
acid tert-butyl ester (Low-Polar Compound) and (3R*,
4S*)-3-amino-1, 1-dioxohexahydro-1-thiopyran-4-ylcarbamic acid
tert-butyl ester (High-Polar Compound)
##STR00249##
[1039] To a solution of the compound obtained in Referential
Example 178 (9.66 g) and triphenylphosphine (10.5 g) in
tetrahydrofuran (150 mL) was added diethyl azodicarboxylate (6.96
g), and the thus-obtained mixture was stirred at room temperature
for 4.5 hours. The reaction mixture was concentrated under reduced
pressure, and diethyl ether was added to the residue. The resultant
solid was collected by filtration, and the thus-obtained solid was
purified by silica gel column chromatography (hexane:ethyl
acetate=7:3), to thereby give a mixture (7.25 g) containing
1,1-dioxo-1,2,3,4-tetrahydrothiopyran-4-ylcarbamic acid tert-butyl
ester as a colorless solid. Furthermore, the filtrate was
concentrated under reduced pressure, and the residue was purified
by silica gel column chromatography (hexane:ethyl acetate=7:3), to
thereby give a mixture (9.18 g) containing
1,1-dioxo-1,2,3,4-tetrahydrothiopyran-4-ylcarbamic acid tert-butyl
ester as a colorless solid (total amount: 16.4 g). The
thus-obtained mixture was dissolved in dioxane (60 mL), and 28%
aqueous ammonia (60 mL) was added thereto, followed by stirring at
60.degree. C. for 4.5 hours in a sealed tube. After the reaction
mixture was left to cool, the mixture was concentrated under
reduced pressure. After dioxane was distilled away, the residue was
extracted with methylene chloride five times. The organic layers
were combined, and the mixture was concentrated under reduced
pressure. The residue was separated and purified by silica gel
column chromatography (methylene chloride:methanol=96:4), to
thereby give the title low-polar compound (2.31 g) and the title
high-polar compound (4.31 g).
[1040] Low-Polar Compound:
[1041] .sup.1H-NMR (CDCl.sub.3) .delta.:1.44(9H, s), 2.14-2.28(2H,
m), 3.01-3.08(3H, m), 3.23(1H, dd, J=13.8, 3.9 Hz), 3.47-3.49(1H,
m), 3.71-3.76(1H, m), 5.32 (1H, d, J=7.3 Hz).
[1042] MS (ESI) m/z:265 (M+H.sup.+).
[1043] High-Polar Compound:
[1044] .sup.1H-NMR (CDCl.sub.3) .delta.:1.45(9H, s), 1.94-2.01(1H,
m), 2.37-2.44(1H, m), 2.91(1H, dd, J=11.2, 14.1 Hz), 3.04-3.07(2H,
m), 3.12-3.19(1H, m), 3.26-3.30(1H, m), 3.39-3.42(1H, m), 4.62(1H,
br).
[1045] MS (ESI) m/z:265 (M+H.sup.+).
Referential Example 180
(2S, 3S)-2, 3-bis(methoxymethoxy)-1, 4-butanediol
##STR00250##
[1047] Chloromethyl methyl ether (4.8 mL) was added dropwise to a
mixture comprising diethyl L-tartrate (8.6 g),
diisopropylethylamine (40 mL), and methylene chloride (40 mL) under
ice cooling, and the thus-obtained mixture was gradually brought
back to room temperature while being stirred. After the mixture was
stirred for 18 hours, the reaction mixture was concentrated, and
the residue was diluted with ethyl acetate. The diluted mixture was
washed with 10% aqueous HCl, saturated aqueous sodium
hydrogencarbonate, and saturated brine. The organic layer was dried
over sodium sulfate anhydrate, and the solvent was distilled away
under reduced pressure. The residue was dissolved in
tetrahydrofuran, and the thus-obtained solution was added dropwise
to a suspension of lithium aluminium hydride (2.2 g) in
tetrahydrofuran under ice cooling, followed by stirring for 2 hours
under ice cooling. Subsequently, 10% aqueous sodium hydrogen
sulfate was carefully added to the reaction mixture under ice
cooling, and the thus-obtained mixture was stirred for 1 hour. The
resultant mixture was diluted with saturated brine, and the diluted
mixture was extracted with ethyl acetate. The organic layer was
dried over sodium sulfate anhydrate, and the solvent was distilled
away under reduced pressure, to thereby give the title compound
(3.0 g).
[1048] .sup.1H-NMR (CDCl.sub.3) .delta.:1.55-1.64(2H, m), 3.44(6H,
s), 3.70-3.81(6H, m), 4.70(2H, d, J=6.9 Hz), 4.76(2H, d, J=6.9
Hz).
Referential Example 181
(3S, 4S)-3, 4-bis(methoxymethoxy)tetrahydrofuran
##STR00251##
[1050] To a mixture comprising the compound obtained in Referential
Example 180 (3.0 g), triphenylphosphine (4.5 g), tetrahydrofuran
(10 mL), and toluene (40 mL) was added dropwise diethyl
azodicarboxylate (2.64 mL), and the thus-obtained mixture was
stirred at room temperature for 4 days. The reaction mixture was
concentrated, and to the residue was added a solvent mixture (160
mL) comprising hexane and diethyl ether (1:1), followed by stirring
for 3 hours. The resultant insoluble matter was removed by
filtration, and the filtrate was concentrated. The residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=4:1), to thereby give the title compound (1.95 g).
[1051] .sup.1H-NMR (CDCl.sub.3) .delta.:3.38(6H, s), 3.80(2H, dd,
J=9.2, 1.7 Hz), 4.00(2H, dd, J=9.2, 4.4 Hz), 4.23(2H, dd, J=4.4,
1.7 Hz), 4.67(2H, d, J=6.9 Hz), 4.71(2H, d, J=6.9 Hz).
Referential Example 182
(3S, 4S)tetrahydro-3, 4-furandiol
##STR00252##
[1053] To a solution of the compound obtained in Referential
Example 181 (1.95 g) in methanol (6.0 mL) was added concentrated
HCl (2.1 mL), and the thus-obtained mixture was stirred for 18
hours. The reaction mixture was concentrated, and the residue was
diluted with chloroform, followed by drying over potassium
carbonate. The solvent was distilled away under reduced pressure,
to thereby give the title compound (0.52 g).
[1054] .sup.1H-NMR (CDCl.sub.3) .delta.:1.77(2H, d, J=4.7 Hz),
3.73(2H, d, J=10.2 Hz), 4.08(2H, dd, J=10.2, 3.7 Hz), 4.18-4.34(2H,
m).
Referential Example 183
(3S, 4S)tetrahydro-3, 4-furandiamine
##STR00253##
[1056] In a manner similar to that employed in Referential Examples
169 to 171, the title compound was prepared from the compound
obtained in Referential Example 182.
[1057] .sup.1H-NMR (CDCl.sub.3) .delta.:1.35-1.46(4H, m), 3.19(2H,
dd, J=5.6, 4.1 Hz), 3.50(2H, dd, J=9.0, 4.1 Hz), 4.09(2H, dd,
J=9.0, 5.6 Hz).
Referential Example 184
(2R, 3R)-2, 3-bis(methoxymethoxy)-1, 4-butanediol
##STR00254##
[1059] In a manner similar to that employed in Referential Example
180, the title compound was prepared from diethyl D-tartrate.
[1060] .sup.1H-NMR: The data was coincided with that of its
enantiomer in Referential Example 180.
Referential Example 185
(3R, 4R)-3, 4-bis(methoxymethoxy)tetrahydrofuran
##STR00255##
[1062] In a manner similar to that employed in Referential Example
181, the title compound was prepared from the compound obtained in
Referential Example 184.
[1063] .sup.1H-NMR: The data was coincided with that of its
enantiomer in Referential Example 181.
Referential Example 186
(3R, 4R)tetrahydro-3, 4-furandiol
##STR00256##
[1065] In a manner similar to that employed in Referential Example
182, the title compound was prepared from the compound obtained in
Referential Example 185.
[1066] .sup.1H-NMR: The data was coincided with that of its
enantiomer in Referential Example 182.
Referential Example 187
(3R, 4R)tetrahydro-3, 4-furandiamine
##STR00257##
[1068] In a manner similar to that employed in Referential Example
183, the title compound was prepared from the compound obtained in
Referential Example 186.
[1069] .sup.1H-NMR: The data was coincided with that of its
enantiomer in Referential Example 183.
Referential Example 188
(3R, 4R)-1-benzyl-3, 4-dihydroxy-2, 5-pyrrolidinedione
##STR00258##
[1071] L-Tartaric acid (30 g) and benzylamine (22 mL) were added to
xylene (150 mL), and the mixture was heated under reflux at
150.degree. C. for 3 hours while water was removed with Dean-Stark
apparatus. After the reaction mixture was left to cool overnight,
the resultant crystals were collected by filtration, and were
washed with acetone. The thus-obtained crude product was
recrystallized from ethanol, to thereby give the title compound
(23.2 g).
[1072] .sup.1H-NMR (DMSO-d.sub.6) .delta.:4.36-4.40 (2H, m),
4.55(each 1H, AB type d, J=15 Hz), 6.26-6.30(2H, m), 7.25-7.35(5H,
m).
Referential Example 189
(3S, 4S)-1-benzyl-3, 4-pyrrolidinediol
##STR00259##
[1074] The compound obtained in Referential Example 188 (11 g) was
dissolved in tetrahydrofuran (110 mL), and lithium aluminium
hydride (5.69 g) was added thereto in small portions under ice
cooling. The thus-obtained mixture was heated to room temperature,
and after 1 hour, the mixture was heated under reflux overnight.
The resultant mixture was left to cool, and to the mixture were
sequentially added water (5.7 mL), 15% aqueous sodium hydroxide
(5.7 mL), water (17.1 mL) under ice cooling. The reaction mixture
was brought back to room temperature, and was stirred for 1 hour.
The resultant precipitate was filtered through Celite, and the
filtrate was concentrated. The residue was recrystallized from
ethyl acetate, to thereby give the title compound (6.35 g).
[1075] .sup.1H-NMR (CDCl.sub.3) .delta.:2.40-2.44(2H, m),
2.88-2.92(2H, m), 3.58(each 1H, AB type d, J=7.8 Hz), 4.04(2H, t,
J=4.2 Hz), 7.25-7.34(5H, m).
Referential Example 190
methanesulfonic acid (3S,
4S)-1-benzyl-4-[(methylsulfonyl)oxy]pyrrolidinyl ester
##STR00260##
[1077] In a manner similar to that employed in Referential Example
169, the title compound was prepared from the compound obtained in
Referential Example 189.
[1078] .sup.1H-NMR (CDCl.sub.3) .delta.:2.76(2H, dd, J=11, 4.6 Hz),
3.08(6H, s), 3.64(2H, d, J=2.5 Hz), 3.68-3.75(2H, m), 5.12-5.15(2H,
m), 7.27-7.35(5H, m).
Referential Example 191
(3S, 4S)-3, 4-bis[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylic acid
tert-butyl ester
##STR00261##
[1080] The compound obtained in Referential Example 190 (1.57 g)
was dissolved in 1,2-dichloroethane (16 mL), and 1-chloroethyl
chloroformate (0.73 mL) was added thereto at room temperature,
followed by heating under reflux for 4 hours. The solvent was
distilled away under reduced pressure, and methanol (16 mL) was
added to the residue, followed by heating under reflux for 1 hour.
The resultant mixture was left to cool, and was concentrated. The
residue was crystallized from ethyl acetate, and the crystals were
collected by filtration, to thereby give (3S,
4S)-3,4-bis-[(methylsulfonyl)oxy]pyrrolidine hydrochloride (1.30 g)
as colorless crystals. To a solution of the thus-obtained
hydrochloride salt and triethylamine (1.40 mL) in methylene
chloride (26 mL) was added di-tert-butyl dicarbonate (1.15 mL), and
the thus-obtained mixture was stirred at room temperature
overnight. The resultant mixture was concentrated, and the residue
was diluted with ethyl acetate. The diluted mixture was washed with
water and saturated brine, and was dried over sodium sulfate
anhydrate. The solvent was distilled away under reduced pressure,
and the residue was purified by silica gel column chromatography
(ethyl acetate:hexane=1:9 to 1:1), to thereby give the title
compound (1.40 g).
[1081] .sup.1H-NMR (CDCl.sub.3) .delta.:1.47(9H, s), 3.12(6H, s),
3.70-3.73(2H, m), 3.79(1H, d, J=4.5 Hz), 3.82(1H, d, J=4.5 Hz),
5.19(2H, br).
Referential Example 192
(3R, 4R)-3, 4-diazido-1-pyrrolidinecarboxylic acid tert-butyl
ester
##STR00262##
[1083] In a manner similar to that employed in Referential Example
170, the title compound was prepared from the compound obtained in
Referential Example 191.
[1084] .sup.1H-NMR (CDCl.sub.3) .delta.:1.47(9H, s), 3.37-3.46(2H,
m), 3.64-3.71(2H, m), 3.96(2H, t, J=3.2 Hz).
Referential Example 193
(3R,
4R)-3-amino-4-{[(5-chloroindol-2-yl)carbonyl]amino}pyrrolidine-1-carb-
oxylic acid tert-butyl ester
##STR00263##
[1086] In a manner similar to that employed in Referential Examples
171 and 172, the title compound was prepared from the compound
obtained in Referential Example 192.
[1087] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.39(9H, s),
2.95-3.00(1H, m), 3.09-3.13(1H, m), 3.52(1H, dd, J=10, 6.5 Hz),
3.68(1H, dd, J=10, 7.8 Hz), 4.04-4.09(2H, m), 7.16(1H, s), 7.18(1H,
s), 7.42(1H, d, J=8.5 Hz), 7.69(1H, d, J=1.5 Hz), 8.50(1H, d, J=6.5
Hz), 11.77(1H, br).
Referential Example 194
(3S)-5-oxotetrahydro-3-furanylcarbamic acid tert-butyl ester
##STR00264##
[1089] To a solution of (3S)-(-)-tetrahydro-5-oxo-3-furanylcarbamic
acid benzyl ester (3.3 g) in tetrahydrofuran (20 mL) were added
di-tert-butyl dicarbonate (4.1 g) and 10% palladium on carbon (0.4
g), followed by stirring for 1 day under hydrogen atmosphere. Any
insoluble matter was removed by filtration through a Celite pad,
and the filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=4:1), to thereby give the title compound (1.5
g).
[1090] .sup.1H-NMR (CDCl.sub.3) .delta.:1.45(9H, s), 2.45(1H, dd,
J=17.8, 2.7 Hz), 2.86(1H, dd, J=17.8, 7.3 Hz), 4.12-4.23(1H, m),
4.54-4.62(2H, m), 4.85-4.95(1H, m).
Referential Example 195
(3S, 4S)-4-azido-5-oxotetrahydro-3-furanylcarbamic acid tert-butyl
ester
##STR00265##
[1092] To a solution of the compound obtained in Referential
Example 194 (0.87 g) in tetrahydrofuran (20 mL) was added dropwise
lithium bis(trimethylsilyl)amide (as 1M tetrahydrofuran solution,
8.65 mL) at -78.degree. C., and the thus-obtained mixture was
stirred for 30 minutes. Subsequently, a solution of
p-toluenesulfonyl azide (1.02 g) in tetrahydrofuran (10 mL) was
added thereto, followed by stirring for 5 minutes, and after
trimethylchlorosilane (1.7 mL) was added thereto, the thus-obtained
mixture was gradually brought back to room temperature while being
stirred. After the reaction mixture was stirred for 2 hours, the
mixture was diluted with diethyl ether, and the diluted mixture was
washed with 10% aqueous HCl, 5% saturated aqueous sodium
hydrogencarbonate, and saturated brine, followed by drying over
sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure, and the residue was purified by silica gel column
chromatography (hexane:ethylacetate=4:1), to thereby give the title
compound (0.62 g).
[1093] .sup.1H-NMR (CDCl.sub.3) .delta.:1.46(9H, s), 4.09(1H, dt,
J=15.3, 7.6 Hz), 4.12-4.23(1H, m), 4.37-4.50(1H, m), 4.54(1H, dd,
J=9.0, 7.6 Hz), 4.81-4.90(1H, m).
Referential Example 196
(3S,
4S)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-5-oxotetrahydro-3-furanyl-
carbamic acid tert-butyl ester
##STR00266##
[1095] In a manner similar to that employed in Referential Examples
90 and 91, the title compound was prepared from the compound
obtained in Referential Example 195.
[1096] .sup.1H-NMR (CDCl.sub.3) .delta.:1.44(9H, s), 4.01-4.13(1H,
m), 4.20-4.36(1H, m), 4.78-4.93(2H, m), 6.15(1H, s), 6.93(1H, s),
7.03-7.11(1H, m), 7.20-7.28(1H, m), 7.30(1H, d, J=8.8 Hz), 7.61(1H,
s), 9.27(1H, s).
Referential Example 197
(3S, 4S)-4-{[(5-methyl-4, 5, 6, 7-tetrahydrothiazolo[5,
4-c]pyridin-2-yl)carbonyl]amino]-5-oxotetrahydro-3-furanylcarbamic
acid tert-butyl ester
##STR00267##
[1098] In a manner similar to that employed in Referential Example
90, (3S,4S)-4-amino-5-oxotetrahydro-3-furanylcarbamic acid
tert-butyl ester was prepared from the compound obtained in
Referential Example 195. Subsequently, the thus-obtained compound
was reacted with the compound obtained in Referential Example 10 in
accordance with the reaction conditions described in Referential
Example 91, to thereby give the title compound.
[1099] .sup.1H-NMR (CDCl.sub.3) .delta.:1.44(9H, s), 2.52(3H, s),
2.83(2H, t, J=5.9 Hz), 2.79-3.02(2H, m), 3.74(2H, s), 4.03-4.12(1H,
m), 4.21-4.36(1H, m), 4.80-4.95(2H, m), 6.14-6.24(1H, m),
7.76-7.85(1H, m).
Referential Example 198
2-[((3S)-3-[(tert-butoxycarbonyl)amino]-2-{[(5-chloroindol-2-yl)carbonyl]a-
mino}-4-hydroxybutanoyl)amino]acetic acid ethyl ester
##STR00268##
[1101] The compound obtained in Referential Example 196 (0.4 g),
glycine ethyl ester hydrochloride (1.0 g), and triethylamine (1.0
mL) were added to ethanol (20 mL), and the mixture was stirred at
60.degree. C. for 18 hours. The reaction mixture was diluted with
chloroform, and the diluted mixture was washed with 10% aqueous
citric acid and saturated brine. The organic layer was dried over
sodium sulfate anhydrate, and the solvent was distilled away under
reduced pressure. The residue was purified by silica gel column
chromatography (chloroform:methanol=98:2), to thereby give the
title compound (0.31 g).
[1102] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.17(3H, t, J=7.0 Hz),
1.34(6H, s), 1.36(3H, s), 3.51-3.63(0.6H, m), 3.72-3.80(2H, m),
4.06(2H, q, J=7.0 Hz), 4.11-4.23(1.4H, m), 4.67-4.82(1H, m),
4.85-4.91(1H, m), 6.48(0.4H, d, J=9.5 Hz), 6.80(0.6H, d, J=9.5 Hz),
7.10-7.22(2H, m), 7.42(1H, d, J=8.8 Hz), 7.72(0.4H, d, J=2.0 Hz),
7.73(0.6H, d, J=2.0 Hz), 8.23-8.31(0.6H, m), 8.34-8.41(0.4H, m),
8.43-8.50(1H, m), 11.83(1H, s).
Referential Example 199
2-((4R)-4-amino-3-{[(5-chloroindol-2-yl)carbonyl]amino}-2-oxopyrrolidin-1--
yl)acetic acid ethyl ester hydrochloride
##STR00269##
[1104] In accordance with the reaction conditions described in
Referential Example 181, the compound obtained in Referential
Example 198 was converted to a pyrrolidone derivative.
Subsequently, the tert-butoxycarbonyl group was eliminated in a
manner similar to that employed in Referential Example 69, to
thereby give the title compound.
[1105] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.17 (2H, t, J=7.0 Hz),
1.23(1H, t, J=7.0 Hz), 3.31-3.40(0.6H, m), 3.57(0.4H, d, J=11.2
Hz), 3.90-4.23(4H, m), 4.42(0.6H, dd, J=12.0, 6.1 Hz),
4.50-4.60(0.4H, m), 4.62(0.6H, dd, J=12.0, 3.9 Hz), 5.12-5.23(0.4H,
m), 7.17(0.4H, s), 7.20(0.4H, dd, J=8.8, 2.0 Hz), 7.28(0.6H, dd,
J=8.8, 2.0 Hz), 7.30(0.6H, s), 7.44(0.4H, d, J=8.8 Hz), 7.50(0.6H,
d, J=8.8 Hz), 7.75(1H, d, J=2.0 Hz), 8.20-8.33(1H, m),
8.71-8.94(3.6H, m), 9.22-9.35(0.4H, m), 11.97(0.4H, s), 12.44(0.6H,
s).
Referential Example 200
(3R,
4S)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-methyl-5-oxopyrrolidin--
3-ylcarbamic acid tert-butyl ester
##STR00270##
[1107] In a manner similar to that employed in Referential Example
198, the compound obtained in Referential Example 196 was reacted
with methylamine (as 40% methanol solution). Subsequently, the
title compound was prepared from the thus-obtained compound in a
manner similar to that employed in Referential Example 181.
[1108] .sup.1H-NMR (CDCl.sub.3) .delta.:1.43(9H, s), 2.90(3H, s),
4.26(1H, br.s), 4.36(2H, m), 4.51-4.52(1H, m), 5.35(1H, br.s),
6.95-6.99(2H, m), 7.22-7.32(3H, m), 7.63(1H, s), 8.95(1H, br.s)
Referential Example 201
N-[(3S,
4R)-4-amino-1-methyl-2-oxopyrrolidin-3-yl]-5-chloroindole-2-carbox-
amide
##STR00271##
[1110] In a manner similar to that employed in Referential Example
69, the title compound was prepared from the compound obtained in
Referential Example 200.
[1111] .sup.1H-NMR (CDCl.sub.3) .delta.:2.95(3H, d, J=5.1 Hz),
3.91-3.93(1H, m), 4.19(1H, d, J=3.7 Hz), 4.36(1H, dd, J=11, 1.7
Hz), 4.48(1H, dd, J=11, 2.0 Hz), 6.90-6.97(2H, m), 7.21-7.33(2H,
m), 7.62(1H, d, J=2.0 Hz), 8.90(1H, s)
Referential Example 202
3, 6-dihydro-1(2H)-pyridinecarboxylic acid tert-butyl ester
##STR00272##
[1113] di-tert-Butyl dicarbonate (6.55 g) was added to a mixture of
1,2,3,6-tetrahydropyridine (2.50 g) and 10% aqueous sodium
carbonate (3.0 mL), and the thus-obtained mixture was stirred at
room temperature for 20 hours. Water was added to the reaction
mixture, and the mixture was extracted with ethyl acetate. The
organic layer was sequentially washed with 0.5N HCl, water,
saturated aqueous sodium hydrogencarbonate, and saturated brine,
and was dried over sodium sulfate anhydrate. The solvent was
distilled away under reduced pressure, to thereby give the title
compound (5.08 g).
[1114] .sup.1H-NMR (CDCl.sub.3) .delta.:1.47(9H, s), 2.12(2H,
br.s), 3.48(2H, t, J=5.6 Hz), 3.88(2H, br.s), 5.60(1H, br.s),
5.78-5.90(1H, m).
Referential Example 203
(3R*, 4S*)-3, 4-dihydroxy-1-piperidinecarboxylic acid tert-butyl
ester
##STR00273##
[1116] The compound obtained in Referential Example 202 (18.45 g)
was dissolved in acetonitrile (200 mL), and to the solution were
added water (38 mL), 0.039M aqueous osmium tetraoxide (82 mL), and
N-methylmorpholine N-oxide (23.13 g), followed by stirring at room
temperature for 17 hours. After any excess oxidizing agent was
treated with saturated aqueous sodium sulfite, the thus-obtained
mixture was extracted with ethyl acetate. The organic layer was
sequentially washed with water, 0.5N HCl, water, saturated aqueous
sodium hydrogencarbonate, and saturated brine, and was dried over
sodium sulfate anhydrate, followed by concentration under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate=1:3), to thereby give the
title compound (15.0 g).
[1117] .sup.1H-NMR (CDCl.sub.3) .delta.:1.46(9H, s), 1.60-1.73(1H,
m), 1.77-1.90(1H, m), 2.68(1H, br.s), 2.80-3.20(1H, br),
3.22-3.32(1H, m), 3.42(1H, dd, J=14.3, 3.4 Hz), 3.50-3.62(2H, m),
3.77(1H, brs), 3.81-3.92(1H, m).
Referential Example 204
(3R*, 4S*)-3, 4-bis[(methylsulfonyl)oxy]-1-piperidinecarboxylic
acid tert-butyl ester
##STR00274##
[1119] In a manner similar to that employed in Referential Example
169, the title compound was prepared from the compound obtained in
Referential Example 203.
[1120] .sup.1H-NMR (CDCl.sub.3) .delta.:1.47(9H, s), 1.85-1.97(1H,
m), 2.08-2.20(1H, m), 3.00-4.20(4H, m), 3.12(6H, s), 4.85(1H,
br.s), 4.94(1H, br.s).
Referential Example 205
(3R*, 4S*)-3, 4-diazido-1-piperidinecarboxylic acid tert-butyl
ester
##STR00275##
[1122] In a manner similar to that employed in Referential Example
170, the title compound was prepared from the compound obtained in
Referential Example 204.
[1123] .sup.1H-NMR (CDCl.sub.3) .delta.:1.47(9H, s), 1.70-1.80(1H,
m), 1.90-2.00(1H, m), 3.05-4.00(6H, m).
Referential Example 206
(3R*, 4S*)-3, 4-diamino-1-piperidinecarboxylic acid tert-butyl
ester
##STR00276##
[1125] In a manner similar to that employed in Referential Example
171, the title compound was prepared from the compound obtained in
Referential Example 205.
[1126] .sup.1H-NMR (CDCl.sub.3) .delta.:1.46(9H, s), 1.48-1.60(2H,
m), 1.80-2.10(4H, br), 2.85-2.91(2H, m), 2.97(1H, br.s), 3.09(1H,
dd, J=13.6, 2.7 Hz), 3.74(1H, dd, J=13.6, 4.2 Hz), 3.81(1H, s).
Referential Example 207
(3R*,
4S*)-3-amino-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-piperidinecar-
boxylic acid tert-butyl ester
##STR00277##
[1128] The compound obtained in Referential Example 206 (3.23 g)
was dissolved in N,N-dimethylformamide (100 mL), and to the
solution were added triethylamine (2.08 mL) and the compound
obtained in Referential Example 52 (3.80 g), followed by stirring
at room temperature for 3 days. The reaction mixture was
concentrated under reduced pressure, and water was added to the
residue. The thus-obtained mixture was extracted with methylene
chloride. The organic layer was washed with saturated aqueous
sodium hydrogencarbonate and saturated brine, and was dried over
sodium sulfate anhydrate, followed by concentration under reduced
pressure. The residue was purified by silica gel column
chromatography (methylene chloride:methanol=20:1 to 10:1), to
thereby give the title compound (2.70 g).
[1129] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.40-1.58(3H, m),
1.41(9H, s), 1.75-1.90(1H, m), 2.95(1H, br.s), 2.98-3.05(1H, m),
3.19-3.28(1H, m), 3.74(1H, dd, J=19.5, 15.4 Hz), 3.79(1H, br.s),
4.04-4.12(1H, m), 7.17(1H, dd, J=8.7, 1.9 Hz), 7.21(1H, s),
7.42(1H, d, J=8.7 Hz), 7.68(1H, d, J=1.9 Hz), 8.00(1H, br.d, J=7.6
Hz), 11.80(1H, s).
Referential Example 208
(3R*, 4S*)-3-amino-4-{[(5-methyl-4, 5, 6, 7-tetrahydrothiazolo[5,
4-c]pyridin-2-yl)carbonyl]amino}-1-piperidinecarboxylic acid
tert-butyl ester
##STR00278##
[1131] The compound obtained in Referential Example 206 (3.23 g)
was dissolved in N,N-dimethylformamide (100 mL), and triethylamine
(2.08 mL) was added thereto. Subsequently, the compound obtained in
Referential Example 149 (3.83 g) was added thereto, and the
thus-obtained mixture was stirred at room temperature for 3 days.
The reaction mixture was concentrated under reduced pressure, and
water was added to the residue. The thus-obtained mixture was
extracted with methylene chloride. The organic layer was washed
with saturated aqueous sodium hydrogencarbonate and saturated
brine, and was dried over sodium sulfate anhydrate. The solvent was
distilled away under reduced pressure, and the residue was
separated by silica gel column chromatography (methylene
chloride:methanol=10:1 to 5:1), to thereby give the title compound
(2.27 g).
[1132] .sup.1H-NMR (CDCl.sub.3) .delta.:1.30-1.62(3H, m), 1.47(9H,
s), 1.78-1.88(1H, m), 2.51(3H, s), 2.81(2H, t, J=5.9 Hz),
2.85-2.98(3H, m), 3.00-3.15(2H, m), 3.71(2H, s), 3.80-4.15(3H, m),
7.79(1H, br.s).
Referential Example 209
(3R*,
4S*)-3-amino-4-{[(5-fluoroindol-2-yl)carbonyl]amino}-1-piperidinecar-
boxylic acid tert-butyl ester
##STR00279##
[1134] In a manner similar to that employed in Referential Example
172, the title compound was prepared from the compound obtained in
Referential Example 206 and 5-fluoroindole-2-carboxylic acid.
[1135] .sup.1H-NMR (CDCl.sub.3) .delta.:1.40-1.70(3H, m), 1.48(9H,
s), 2.79-2.92(1H, m), 2.99-3.14(1H, m), 4.00-4.23(3H, m), 6.85(1H,
s), 7.04(1H, td, J=9.0, 2.4 Hz), 7.07-7.20(1H, br), 7.27(1H, dd,
J=9.0, 2.4 Hz), 7.35(1H, d, J=9.0, 4.4 Hz), 9.25-9.50(1H, br).
[1136] MS (ESI) m/z:377 (M+H).sup.+.
Referential Example 210
(3S,
4R)-5-azido-3-{[benzyloxy)carbonyl]amino}-4-[(tert-butoxycarbonyl)ami-
no]valeric acid ethyl ester
##STR00280##
[1138] To a solution of the (3S,4S)-isomer (low-polar compound)
obtained in Referential Example 168 (7.1 g) in methylene chloride
(100 mL) were sequentially added dropwise triethylamine (4.80 mL)
and methanesulfonyl chloride (1.55 mL) under ice cooling, followed
by stirring for 30 minutes under ice cooling. The reaction mixture
was diluted with chloroform, and the diluted mixture was washed
with 10% aqueous citric acid, saturated aqueous sodium
hydrogencarbonate, and saturated brine. The organic layer was dried
over sodium sulfate anhydrate, and the solvent was distilled away
under reduced pressure, to thereby give a methanesulfonyl compound
(9.20 g). A mixture comprising the thus-obtained methanesulfonyl
compound, sodium azide (5.64 g), and N,N-dimethylformamide (100 mL)
was stirred at 80.degree. C. for 20 hours. Subsequently, the
reaction mixture was diluted with ethyl acetate, and the diluted
mixture was washed with water and saturated brine. The organic
layer was dried over sodium sulfate anhydrate, and the solvent was
distilled away under reduced pressure. The residue was purified by
silica gel column chromatography (chloroform), to thereby give the
title compound (5.42 g).
[1139] .sup.1H-NMR (CDCl.sub.3) .delta.:1.24(3H, t, J=7.1 Hz),
1.43(9H, s), 2.56-2.68(2H, m), 3.48-3.60(2H, m), 3.88-3.97(1H, m),
4.04-4.20(3H, m), 4.88-4.97(1H, br), 5.10(2H, s), 5.60-5.75(1H,
br), 7.30-7.40(5H, m).
[1140] MS (ESI) m/z:436 (M+H).sup.+.
Referential Example 211
(4S, 5R)-5-[(tert-butoxycarbonyl)amino]-2-oxopiperidin-4-ylcarbamic
acid benzyl ester
##STR00281##
[1142] To a mixture of the compound obtained in Referential Example
210 (5.42 g), ethanol (150 mL), and tetrahydrofuran (10.0 mL) was
added Lindlar catalyst (2.71 g), and the thus-obtained mixture was
stirred for 3 hours under hydrogen atmosphere, and then for 14
hours under nitrogen conditions. Any insoluble matter was removed
by filtration through a Celite pad, and the filtrate was
concentrated under reduced pressure. The residue was dissolved in
tetrahydrofuran (30 mL), and triethylamine (3.0 mL) was added
thereto, followed by stirring at room temperature for 1.5 hours.
The reaction mixture was diluted with ethyl acetate, and the
diluted mixture was washed with 10% aqueous citric acid, saturated
aqueous sodium hydrogencarbonate and saturated brine. The organic
layer was dried over sodium sulfate anhydrite, and the solvent was
distilled away under reduced pressure. The residue was purified by
silica gel column chromatography (chloroform:methanol=25:1), to
thereby give the title compound (2.50 g).
[1143] .sup.1H-NMR (CDCl.sub.3) .delta.:1.44(9H, s), 2.30-2.50(1H,
br), 2.65-2.90(1H, br), 3.15-3.30(1H, br), 3.35-3.65(1H, br),
4.00-4.25(2H, br), 5.11(2H, s), 5.55-5.60(1H, br), 5.65-5.90(1H,
br), 6.25-6.55(1H, br), 7.28-7.40(5H, m).
[1144] MS (ESI) m/z:364 (M+H).sup.+.
Referential Example 212
(3R, 4S)-3-[(tert-butoxycarbonyl)amino]piperidin-4-ylcarbamic acid
benzyl ester
##STR00282##
[1146] To a solution of the compound obtained in Referential
Example 211 (2.49 g) in tetrahydrofuran (70 mL) was added dropwise
borane-tetrahydrofuran complex (as 1M tetrahydrofuran solution,
34.0 mL) under ice cooling, and the thus-obtained mixture was
gradually brought back to room temperature while being stirred.
After the mixture was stirred for 20 hours, methanol (100 mL) was
added to the reaction mixture, and the solvent was distilled away
under reduced pressure. To the residue were added ethanol (45 mL),
water (5 mL), and triethylamine (10 mL), and the thus-obtained
mixture was heated under reflux for 24 hours. The reaction mixture
was concentrated, and the residue was purified by silica gel column
chromatography (chloroform:methanol:water=7:3:1, lower layer), to
thereby give the title compound (1.61 g).
[1147] .sup.1H-NMR (CDCl.sub.3) .delta.:1.44(9H, s), 1.65-1.72(2H,
m), 2.67(1H, t, J=12.0 Hz), 2.82(12H, d, J=12.0 Hz), 2.90-3.10(1H,
br), 3.60-3.80(2H, m), 3.90-4.00(1H, m), 5.00-5.20(2H, m),
5.40-5.60(2H, br), 7.25-7.74(5H, m). MS
(FAB)m/z:350(M+H).sup.+.
Referential Example 213
(3R,
4S)-1-acetyl-4-{[(benzyloxy)carbonyl]amino}piperidin-3-ylcarbamic
acid tert-butyl ester
##STR00283##
[1149] The compound obtained in Referential Example 212 was reacted
with acetyl chloride in the presence of triethylamine in methylene
chloride, to thereby give the title compound.
[1150] .sup.1H-NMR (CDCl.sub.3) .delta.:1.44(9H, s), 1.85-2.15(2H,
m), 2.07(1.5H, s), 2.14(1.5H, s), 2.75-2.90(1H, m), 3.10-3.20(0.5H,
m), 3.25-3.35(0.5H, br.d, J=14.2 Hz), 3.65-4.05(3H, m),
4.38-4.47(0.5H, br.d, J=13.0 Hz), 4.5, 4-4.63(0.5H, m),
4.69-4.83(1H, br), 4.98-5.20(2.5H, m), 5.90-6.05(0.5H, br),
7.30-7.40(5H, m).
[1151] MS (ESI) m/z:392 (M+H.sup.+).
Referential Example 214
(3R,
4S)-1-acetyl-4-{[(5-chloroindol-2-yl)carbonyl]amino}piperidin-3-ylcar-
bamic acid tert-butyl ester
##STR00284##
[1153] To a solution of the compound obtained in Referential
Example 213 (745 mg) in ethanol (50 mL) was added 10% palladium on
carbon (532 mg), and the thus-obtained mixture was stirred at room
temperature for 16 hours under hydrogen atmosphere. Any insoluble
matter was removed by filtration through Celite, and the filtrate
was concentrated under reduced pressure. The residue was reacted
with 5-chloroindole-2-carboxylic acid (467 mg) in a manner similar
to that employed in Referential Example 68, to thereby give the
title compound (650 mg).
[1154] .sup.1H-NMR (CDCl.sub.3) .delta.:1.52(9H, s), 1.60-1.80(2H,
m), 2.12(1H, s), 2.16(2H, s), 2.30-2.45(0.5H, m), 2.67-2.82(0.3H,
m), 2.89(0.7H, d, J=13.7 Hz), 3.23(0.7H, t, J=12.9 Hz), 3.37(0.3H,
d, J=13.7 Hz), 3.81-3.95(1H, m), 4.05-4.33(2H, m), 4.62-4.72(0.3H,
br), 4.77(0.7H, d, J=13.7 Hz), 5.10-5.27(1H, m), 6.81(0.3H, br.s),
6.85(0.7H, s), 7.21(1H, br.d, J=8.8 Hz), 7.34(1H, d, J=8.8 Hz),
7.57(0.3H, br.s), 7.61(0.7H, s), 8.55-8.65(0.5H, br),
9.43-9.53(0.7H, br), 9.60-9.70(0.3H, br).
[1155] MS (ESI) m/z:435 (M+H.sup.+).
Referential Example 215
(3R,
4R)-5-azido-3-{[(benzyloxy)carbonyl]amino}-4-[(tert-butoxycarbonyl)am-
ino]valeric acid ethyl ester
##STR00285##
[1157] In a manner similar to that employed in Referential Example
210, the title compound was prepared from the (3R,4S)-isomer
(high-polar compound) obtained in Referential Example 168.
[1158] .sup.1H-NMR (CDCl.sub.3) .delta.:1.23(3H, t, J=6.6 Hz),
1.42(9H, s), 2.51-2.63(2H, m), 3.43-3.50(2H, m), 3.84-3.92(1H, m),
4.03-4.23(3H, m), 5.10(2H, s), 5.11-5.24(1H, m), 5.54-5.60(1H, m),
7.32-7.44(5H, m).
Referential Example 216
(4R, 5R)-5-[(tert-butoxycarbonyl)amino]-2-oxopiperidin-4-ylcarbamic
acid benzyl ester
##STR00286##
[1160] In a manner similar to that employed-in Referential Example
211, the title compound was prepared from the compound obtained in
Referential Example 215.
[1161] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.35(9H, s), 2.19(1H, dd,
J=17.4, 9.1 Hz), 2.41-2.51(1H, m), 2.97(1H, t, J=9.1 Hz),
3.00-3.11(1H, m), 3.51-3.64(1H, m), 3.67-3.73(1H, m), 5.00(2H, s),
6.71-6.80(1H, m), 7.20-7.30(5H, m), 7.44-7.52(1H, m), 8.30(1H,
s).
Referential Example 217
(3R, 4R)-3-[(tert-butoxycarbonyl)amino]piperidin-4-ylcarbamic acid
benzyl ester
##STR00287##
[1163] In a manner similar to that employed in Referential Example
212, the title compound was prepared from the compound obtained in
Referential Example 216.
[1164] .sup.1H-NMR (CDCl.sub.3) .delta.:1.39(9H, s), 2.05(2H, d,
J=12.9 Hz), 2.40(1H, t, J=11.0 Hz), 2.63(1H, t, J=12.0 Hz),
3.09(1H, d, J=12.0 Hz), 3.31(1H, d, J=11.0 Hz), 3.42-3.53(2H, m),
4.80-4.91(1H, m), 5.09(2H, s), 5.23-5.32(1H, m), 7.34-7.41(5H,
m).
Referential Example 218
(3R,
4R)-1-acetyl-4-{[(benzyloxy)carbonyl]amino}piperidin-3-ylcarbamic
acid tert-butyl ester
##STR00288##
[1166] In a manner similar to that employed in Referential Example
213, the title compound was prepared from the compound obtained in
Referential Example 217.
[1167] .sup.1H-NMR (CDCl.sub.3) .delta.:1.42(9H, s), 1.53-1.67(1H,
m), 1.89-2.00(1H, m), 2.09(1.5H, s), 2.15(1.5H, s), 2.57(1H, t,
J=12.0 Hz), 2.78(1H, t, J=12.0 Hz), 3.20-3.30(1H, m), 3.40-3.56(2H,
m), 4.23-4.31(1H, m), 4.45-4.56(1H, m), 5.01-5.08(1H, m), 5.10(2H,
s), 7.32-7.44(5H, m).
Referential Example 219
(3R,
4R)-1-acetyl-4-{[(5-chloroindol-2-yl)carbonyl]amino}piperidin-3-ylcar-
bamic acid tert-butyl ester
##STR00289##
[1169] In a manner similar to that employed in Referential Example
214, the title compound was prepared from the compound obtained in
Referential Example 218.
[1170] .sup.1H-NMR (CDCl.sub.3) .delta.:1.35(9H, s), 1.42-1.56(2H,
m), 2.00-2.10(1H, m), 2.12(1.5H, s), 2.17(1.5H, s), 2.31-2.43(1H,
m), 2.67-3.00(1H, m), 3.55-3.63(1H, m), 3.78-4.00(1H, m),
4.03-4.21(1H, m), 4.78-5.24(2H, m), 6.91(0.5H, s), 6.92(0.5H, s),
7.22-7.32(1H, m), 7.33(1H, d, J=8.8 Hz), 7.58(1H, s), 9.45(0.5H,
s), 9.51(0.5H, s).
Referential Example 220
(3R,
4S)-3-[(tert-butoxycarbonyl)amino]-1-(2-methoxyacetyl)piperidin-4-ylc-
arbamic acid benzyl ester
##STR00290##
[1172] In a manner similar to that employed in Referential Example
213, the title compound was prepared from the compound obtained in
Referential Example 212 and methoxyacetyl chloride.
[1173] .sup.1H-NMR (CDCl.sub.3) .delta.:1.44 (9H, s), 1.70-2.15(2H,
m), 2.70-2.85(1H, m), 2.90-3.30(1H.m), 3.35-3.70(1H, m), 3.43(3H,
s), 3.75-3.90(2H, m), 3.90-4.25(3H, m), 4.40-4.80(1H, m),
5.05-5.09(1H, m), 5.10(2H, br.s), 7.30-7.40(5H, m).
[1174] MS (ESI) m/z:322 (M+H.sup.+).
Referential Example 221
(3R,
4S)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-(2-methoxyacetyl)piperi-
din-3-ylcarbamic acid tert-butyl ester
##STR00291##
[1176] In a manner similar to that employed in Referential Example
214, the title compound was prepared from the compound obtained in
Referential Example 220.
[1177] .sup.1H-NMR (CDCl.sub.3) .delta.:1.52(9H, s), 1.60-1.80(1H,
m), 2.20-2.40(1H, m), 2.70-2.80(0.6H, m), 2.90-3.00(0.4H, m),
3.15-3.30(0.4H, m), 3.32-3.40(0.6H, m), 3.46, 3.49(total 3H, each
s), 3.85-4.30(5H, m), 4.55-4.80(1H, m), 5.11(0.4H, br.s),
6.05(0.6H, br.s), 6.86(1H, s), 7.20(1H, dd, J=8.7, 2.0 Hz),
7.33(1H, d, J=8.7 Hz), 7.61(1H, s), 8.40-8.60(1H, m), 9.41(1H,
br.s).
[1178] MS (FAB) m/z:465 (M+H.sup.+).
Referential Example 222
(3R,
4R)-3-[(tert-butoxycarbonyl)amino]-1-(2-methoxyacetyl)piperidin-4-ylc-
arbamic acid benzyl ester
##STR00292##
[1180] In a manner similar to that employed in Referential Example
213, the title compound was prepared from the compound obtained in
Referential Example 217 and methoxyacetyl chloride.
[1181] .sup.1H-NMR (CDCl.sub.3) .delta.:1.41(9H, s), 1.45-1.67(1H,
m), 2.01-2.14(1H, m), 2.63(1H, t, J=12.0 Hz), 2.75(1H, t, J=12.0
Hz), 3.20-3.30(1H, m), 3.32-3.41(5H, m), 3.44-3.56(2H, m),
4.21-4.32(1H, m), 4.50-4.63(1H, m), 5.03-5.08(1H, m), 5.09(2H, s),
7.32-7.40(5H, m).
Referential Example 223
(3R,
4R)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-(2-methoxyacetyl)piperi-
din-3-ylcarbamic acid tert-butyl ester
##STR00293##
[1183] In a manner similar to that employed in Referential Example
214, the title compound was prepared from the compound obtained in
Referential Example 222 and 5-chloroindole-2-carboxylic acid.
[1184] .sup.1H-NMR (CDCl.sub.3) .delta.:1.35(9H, s), 1.41-1.56(2H,
m), 2.11-2.23(0.5H, m), 2.34-2.50(0.5H, m), 2.78-2.89(0.5H, m),
3.01-3.12(0.5H, m), 3.42(5H, s), 3.45-3.56(1H, m), 3.78-3.89(1H,
m), 4.00-4.21(2H, m), 4.78-5.21(2H, m), 6.91(0.5H, s), 6.93(0.5H,
s), 7.23(1H, dd, J=8.8, 2.0 Hz), 7.33(1H, d, J=8.8 Hz), 7.59(1H,
s), 9.37(0.5H, s), 9.54(0.5H, s).
Referential Example 224
(3R,
4S)-3-{[benzyloxy)carbonyl]amino}-4-[(tert-butoxycarbonyl)amino]-5-{[-
tert-butyl(diphenyl)silyl]oxy}valeric acid ethyl ester
##STR00294##
[1186] To a solution of the (3R,4S)-isomer (high-polar compound)
obtained in Referential Example 168 (0.74 g) in
N,N-dimethylformamide (30 mL) were sequentially added triethylamine
(0.47 mL), imidazole (0.19 g), and tert-butylchlorodiphenylsilane
(0.7 mL) under ice cooling, and the thus-obtained mixture was
gradually brought back to room temperature while being stirred.
After the mixture was stirred for 4 days, the reaction mixture was
diluted with ethyl acetate, and the diluted mixture was washed with
10% aqueous citric acid and saturated brine. The organic layer was
dried over sodium sulfate anhydrate, and the solvent was distilled
away under reduced pressure. The residue was purified by silica gel
column chromatography (hexane:ethyl acetate=8:1), to thereby give
the title compound (0.85 g).
[1187] .sup.1H-NMR (CDCl.sub.3) .delta.:1.07(9H, s), 1.19(3H, t,
J=7.4 Hz), 1.40(9H, s), 2.40-2.50(1H, m), 2.60(1H, dd, J=15.9, 4.5
Hz), 3.56-3.67(1H, m), 3.74(1H, dd, J=11.2, 4.5 Hz), 3.78-3.89(1H,
m), 4.08(2H, q, J=7.4 Hz), 4.21-4.30(1H, m), 4.99-5.13(3H, m),
5.41-5.52(1H, m), 7.40-7.53(6H, m), 7.60-7.72(4H, m).
Referential Example 225
(3R,
4S)-4-[(tert-butoxycarbonyl)amino]-5-{[tert-butyl(diphenyl)silyl]oxy}-
-3-{[(5-chloroindol-2-yl)carbonyl]amino}valeric acid ethyl
ester
##STR00295##
[1189] In a manner similar to that employed in Referential Example
214, the benzyloxycarbonyl group was eliminated from the compound
obtained in Referential Example 224, and the thus-obtained compound
was subjected to condensation reaction with
5-chloroindole-2-carboxylic acid, to thereby give the title
compound.
[1190] .sup.1H-NMR (CDCl.sub.3) .delta.:1.10(9H, s), 1.20(3H, t,
J=7.4 Hz), 1.32(9H, s), 2.40-2.52(1H, m), 2.71(1H, dd, J=15.9, 4.5
Hz), 3.67-3.81(2H, m), 4.00-4.20(2H, m), 4.56-4.74(1H, m),
5.00-5.11(1H, m), 6.81(1H, s), 7.21(1H, dd, J=8.8, 2.0 Hz),
7.32(1H, d, J=8.8 Hz), 7.40-7.50(6H, m), 7.58(1H, d, J=8.5 Hz),
7.63-7.74(5H, m), 9.01-9.14(1H, m).
Referential Example 226
(3R*, 4R*)-3-{[(5-methyl-4, 5, 6, 7-tetrahydrothiazolo[5,
4-c]pyridin-2-yl)carbonyl]amino}-1,
1-dioxohexahydro-1-thiopyran-4-ylcarbamic acid tert-butyl ester
##STR00296##
[1192] In a manner similar to that employed in Referential Example
68, the title compound was prepared from the (3R*,4R*)-isomer
(low-polar compound) obtained in Referential Example 179 and the
compound obtained in Referential Example 10.
[1193] .sup.1H-NMR (CDCl.sub.3) .delta.:1.43(9H, s), 2.30-2.37(2H,
m), 2.51(3H, s), 2.82-2.85(2H, m), 2.92-2.95(2H, m), 3.17-3.20(4H,
m), 3.40-3.43(1H, m), 3.69-3.77(2H, m), 3.97-3.98(1H, m), 4.98(1H,
br), 5.25(1H, br).
Referential Example 227
N-(3R*, 4R*)-4-amino-1,
1-dioxohexahydro-1-thiopyran-3-yl]-5-methyl-4, 5, 6,
7-tetrahydrothiazolo[5, 4-c]pyridine-2-carboxamide
hydrochloride
##STR00297##
[1195] In a manner similar to that employed in Referential Example
69, the title compound was prepared from the compound obtained in
Referential Example 226.
[1196] .sup.1H-NMR (DMSO-d.sub.6) .delta.:2.29-2.33(2H, m),
2.93(3H, s), 3.16(2H, br), 3.40(2H, br), 3.52(2H, br),
3.69-3.76(3H, m), 4.48(1H, br), 4.71-4.82(2H, m), 8.34(2H, br),
8.82(1H, br).
[1197] MS (ESI) m/z:345 (M+H).sup.+.
Referential Example 228
(3R*, 4R*)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-1,
1-dioxohexahydro-1-thiopyran-4-ylcarbamic acid tert-butyl ester
##STR00298##
[1199] In a manner similar to that employed in Referential Example
68, the title compound was prepared from the (3R*,4R*)-isomer
(low-polar compound) obtained in Referential Example 179 and
5-chloroindole-2-carboxylic acid.
[1200] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.34(9H, s), 2.09(2H,
br), 3.07(1H, d, J=12.6 Hz), 3.24-3.28(1H, m), 3.48(2H, br),
4.12(1H, br), 4.53(1H, br), 7.04(1H, s), 7.16-7.18(2H, m), 7.44(1H,
d, J=8.7 Hz), 7.67(1H, s), 8.37(1H, br), 11.81(1H, s).
[1201] MS (ESI) m/z:442 (M+H).sup.+.
Referential Example 229
N-[(3R*, 4R*)-4-amino-1,
1-dioxohexahydro-1-thiopyran-3-yl]-5-chloroindole-2-carboxamide
hydrochloride
##STR00299##
[1203] In a manner similar to that employed in Referential Example
69, the title compound was prepared from the compound obtained in
Referential Example 228.
[1204] .sup.1H-NMR (DMSO-d.sub.6) .delta.:2.24-2.33 (2H, m),
3.43-3.55(3H, m), 3.60-3.66(1H, m), 3.77(1H, br), 4.75-4.79(1H, m),
7.18-7.21(2H, m), 7.46(1H, d, J=8.8 Hz), 7.72(1H, d, J=1.7 Hz),
8.39(2H, br), 8.58(1H, d, J=6.8 Hz), 11.93(1H, s).
[1205] MS (ESI) m/z:342 (M+H.sup.+).
Referential Example 230
(3R*, 4S*)-3-{[(5-methyl-4, 5, 6, 7-tetrahydrothiazolo[5,
4-c]pyridin-2-yl)carbonyl]amino}-1,
1-dioxohexahydro-1-thiopyran-4-ylcarbamic acid tert-butyl ester
##STR00300##
[1207] In a manner similar to that employed in Referential Example
98, the title compound was prepared from the (3R*,4S*)-isomer
(high-polar compound) obtained in Referential Example 179 and the
compound obtained in Referential Example 10.
[1208] .sup.1H-NMR (CDCl.sub.3) .delta.:1.32(9H, s), 2.14-2.24(1H,
m), 2.33-2.38(1H, m), 2.50(3H, s), 2.78-2.83(2H, m), 2.86-2.95(2H,
m), 3.08-3.14(3H, m), 3.55(1H, d, J=13.4 Hz), 3.68(1H, d, J=15.5
Hz), 3.72(1H, d, J=15.5 Hz), 3.86-3.88(1H, m), 4.45-4.53(1H, m),
4.75(1H, d, J=8.5 Hz), 7.76(1H, d, J=8.3 Hz).
[1209] MS (ESI) m/z:445 (M+H).sup.+.
Referential Example 231
N-[(3R*, 4S*)-4-amino-1,
1-dioxohexahydro-1-thiopyran-3-yl]-5-methyl-4, 5, 6,
7-tetrahydrothiazolo[5, 4-c]pyridine-2-carboxamide
hydrochloride
##STR00301##
[1211] In a manner similar to that employed in Referential Example
69, the title compound was prepared from the compound obtained in
Referential Example 230.
[1212] .sup.1H-NMR (DMSO-d.sub.6) .delta.:2.03-2.12(1H, m),
2.51(1H, br), 2.93(3H, s), 3.14(2H, d, J=12.2 Hz), 3.28(2H, br),
3.33(2H, br), 3.48(3H, br), 3.72(2H, br), 4.49(2H, br),
4.71-4.74(1H, m), 8.38(2H, br), 9.21-9.24(1H, m).
[1213] MS (ESI) m/z:345 (M+H.sup.+).
Referential Example 232
(3R*, 4R*)-3-{[(5-fluoroindol-2-yl)carbonyl]amino}-1,
1-dioxohexahydro-1-thiopyran-4-ylcarbamic acid tert-butyl ester
##STR00302##
[1215] In a manner similar to that employed in Referential Example
68, the title compound was prepared from the (3R*,4R*)-isomer
(low-polar compound) obtained in Referential Example 179 and
5-fluoroindole-2-carboxylic acid.
[1216] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.37 (9H, s),
2.10-2.13(2H, m), 3.06(1H, br), 3.37-3.49(3H, m), 4.13(1H, br),
4.57(1H, br), 6.95-7.01(2H, m), 7.14(1H, br), 7.30(1H, d, J=8.5
Hz), 7.41(1H, dd, J=8.8, 4.5 Hz), 8.28(1H, br), 11.68(1H, s).
[1217] MS (ESI) m/z:426 (M+H.sup.+).
Referential Example 233
N-[(3R*, 4R*)-4-amino-1,
1-dioxohexahydro-1-thiopyran-3-yl]-5-fluoroindole-2-carboxamide
hydrochloride
##STR00303##
[1219] In a manner similar to that employed in Referential Example
69, the title compound was prepared from the compound obtained in
Referential Example 232.
[1220] .sup.1H-NMR (DMSO-d.sub.6) .delta.:2.25-2.31 (1H, m),
2.47(1H, br), 3.30(1H, br), 3.49-3.53(2H, m), 3.60-3.66(1H, m),
3.78(1H, br), 4.79(1H, br), 7.01-7.05(1H, m), 7.21(1H, s), 7.38(1H,
d, J=9.0 Hz), 7.44(1H, dd, J=8.8, 4.4 Hz), 8.40(2H, br), 8.56(1H,
br), 11.81(1H, s).
[1221] MS (ESI) m/z:326 (M+H.sup.+).
Referential Example 234
(3R)-3-{[(benzyloxy)carbonyl]amino}-4-[(tert-butoxycarbonyl)amino]-5-oxova-
leric acid ethyl ester
##STR00304##
[1223] To a mixture comprising the (3R,4S)-isomer (high-polar
compound) obtained in Referential Example 168 (0.5 g), dimethyl
sulfoxide (6.8 mL), and triethylamine (2.6 mL) was gradually added
sulfur trioxide-pyridine complex (1.5 g) at room temperature, and
the thus-obtained mixture was stirred for 20 minutes. The reaction
mixture was poured into water, and the thus-obtained mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated aqueous ammonium chloride, saturated aqueous sodium
hydrogencarbonate, and saturated brine, and was dried over sodium
sulfate anhydrate. The solvent was distilled away under reduced
pressure, and the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=3:1), to thereby give the
title compound (0.51 g).
[1224] .sup.1H-NMR (CDCl.sub.3) .delta.:1.25(3H, t, J=7.4 Hz),
1.44(9H, s), 2.51-2.70(2H, m), 4.01-4.23(2H, m), 4.45-4.67(1H, m),
5.00-5.23(2H, s), 5.24-5.42(1H, m), 7.23-7.43(5H, m), 9.63(0.5H,
s), 9.67(0.5H, s).
Referential Example 235
(4R)-5-[(tert-butoxycarbonyl)amino]-1-methyl-2-oxopiperidin-4-ylcarbamic
acid benzyl ester
##STR00305##
[1226] To a solution of the compound obtained in Referential
Example 234 (0.51 g) in ethanol (10 mL) were sequentially added
acetic acid (0.27 mL) and methylamine (as 2M tetrahydrofuran
solution, 1.0 mL) under ice cooling, and the thus-obtained mixture
was gradually brought back to room temperature while being stirred.
After the mixture was stirred for 1 hour, sodium cyanoborohydride
(0.15 g) was added thereto, and the thus-obtained mixture was
stirred for 18 hours. The reaction mixture was diluted with
chloroform, and the diluted mixture was washed with saturated
aqueous sodium hydrogencarbonate and saturated brine. The organic
layer was dried over sodium sulfate anhydrate, and the solvent was
distilled away under reduced pressure. The residue was dissolved in
toluene (20 mL), and triethylamine (2 mL) was added to the
solution, followed by heating under reflux for 2 hours. The
reaction mixture was concentrated under reduced pressure, and the
residue was purified by silica gel column chromatography
(chloroform:methanol=98:2), to thereby give the title compound
(0.28 g).
[1227] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.36(3.6H, s), 1.38(5.4H,
s), 2.22-2.43(1H, m), 2.44-2.61(1H, m), 2.72(1.2H.s), 2.80(1.8H.s),
3.10(0.5H, dd, J=12.5, 8.3 Hz), 3.21-3.30(0.5H, m), 3.33-3.45(1H,
m), 3.56-3.82(1H, m), 3.89-4.00(1H, m), 4.94(1H, d, J=8.1 Hz),
5.00(1.2H.s), 5.01(0.8H, s), 6.89-7.02(0.5H, m), 7.23-7.44(5.5H,
m).
Referential Example 236
(4R)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-methyl-6-oxopiperidin-3-ylc-
arbamic acid tert-butyl ester
##STR00306##
[1229] In a manner similar to that employed in Referential Example
214, the title compound was prepared from the compound obtained in
Referential Example 235 and 5-chloroindole-2-carboxylic acid.
[1230] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.24 (5.4H, s),
1.35(3.6H, s), 2.43-2.56(2H, m), 2.80(3H, s), 3.10-3.20(1H, m),
3.30-3.52(1H, m), 3.83-3.91(0.4H, m), 4.02-4.10(0.6H, m),
4.20-4.31(0.6H, m), 4.43-4.54(0.4H, m), 6.94(0.6H, d, J=8.1 Hz),
7.08(1H, s), 7.16(1H, dd, J=8.8, 2.0 Hz), 7.42(1H, d, J=8.8 Hz),
7.69(1H, d, J=2.0 Hz), 8.30(0.4H, s), 8.36(0.4H, d, J=7.3 Hz),
8.43(0.6H, d, J=8.3 Hz), 11.75(0.6H, s), 11.78(0.4H, s).
Referential Example 237
4-(pyridin-4-yl)benzoic acid hydrochloride
##STR00307##
[1232] 4-Bromopyridine hydrochloride (11.7 g) and
4-carboxyphenylboronic acid (10.0 g) were dissolved in a solvent
mixture of toluene (250 mL) and water (250 mL), and to the solution
were sequentially added tetrakis(triphenylphosphine)palladium(0)
(5.0 g) and anhydrous sodium carbonate (25.4 g), followed by
heating under reflux at 120.degree. C. for 19 hours. After the
resultant mixture was cooled to room temperature, ethyl acetate was
added thereto, and the thus-obtained mixture was extracted with
water. Concentrated HCl was added to the aqueous layer, to thereby
make the mixture acidic. The aqueous layer was washed with ethyl
acetate, and was concentrated. The resultant solid was collected by
filtration, to thereby give the title compound (8.37 g).
[1233] .sup.1H-NMR (DMSO-d.sub.6) .delta.:8.11(2H, d, J=8.8 Hz),
8.14(2H, dJ=8.8 Hz), 8.35(2H, d, J=6.6 Hz), 8.97(2H, d, J=6.6
Hz).
[1234] MS (FAB) m/z:200 (M+H).sup.+.
Referential Example 238
4-(pyridin-4-yl)benzoic acid methyl ester
##STR00308##
[1236] The compound obtained in Referential Example 237 (12.4 g)
was dissolved in methanol (200 mL), and concentrated sulfuric acid
(5 mL) was added thereto at room temperature, followed by heating
under reflux for 3 hours. After completion of the reaction, the
solvent was distilled away, and saturated aqueous sodium
hydrogencarbonate was added to the residue. The thus-obtained
mixture was extracted with ethyl acetate, and the extract was dried
over sodium sulfate anhydrate. The solvent was distilled away, and
hexane was added to the residue, to thereby precipitate the title
compound (9.86 g).
[1237] .sup.1H-NMR (CDCl.sub.3) .delta.:3.96(3H, s), 7.54(2H, d,
J=5.9 Hz), 7.71(2H, d,J=8.3 Hz), 8.16(2H, d, J=8.3 Hz), 8.71(2H, d,
J=5.9 Hz).
Referential Example 239
4-[4-(methoxycarbonyl)phenyl]pyridine N-oxide
##STR00309##
[1239] The compound obtained in Referential Example 238 (1.49 g)
was dissolved in methylene chloride (30 mL), and 70%
m-chloroperbenzoic acid (3.46 g) was added thereto, followed by
stirring at room temperature for 1 hour. Aqueous sodium sulfite was
added to the resultant mixture to partition the mixture. The
organic layer was washed with saturated aqueous sodium
hydrogencarbonate, and was dried over sodium sulfate anhydrate. The
solvent was distilled away under reduced pressure, to thereby give
the title compound (1.33 g).
[1240] .sup.1H-NMR (DMSO) .delta.:3.88(3H, s), 7.86(2H, d, J=7.2
Hz), 7.94(2H, d, J=8.3 Hz), 8.05(2H, d, J=8.3 Hz), 8.30(2H, d,
J=7.2 Hz).
[1241] MS (FAB) m/z:230 (M+H).sup.+.
Referential Example 240
4-(4-carboxyphenyl)pyridine N-oxide
##STR00310##
[1243] The compound obtained in Referential Example 239 (802 mg)
was dissolved in dioxane (20 mL), and 1N aqueous sodium hydroxide
(5 mL) was added thereto. The reaction mixture was refluxed for 1
hour, and was stirred at room temperature for 2 hours. The
resultant mixture was neutralized with 1N aqueous HCl (5 mL), and
water (5 mL) was added thereto. The resultant precipitate was
collected by filtration, to thereby give the title compound (627
mg).
[1244] .sup.1H-NMR (DMSO) .delta.:7.85(2H, d, J=7.2 Hz), 7.91(2H,
d, J=8.3 Hz), 8.03(2H, d, J=8.3 Hz), 8.30(2H, d, J=7.2 Hz).
Referential Example 241
2-(4-carboxylphenyl)-1-pyridine N-oxide
##STR00311##
[1246] In a manner similar to that employed in Referential Examples
237, 238, 239, and 240, the title compound was prepared from
2-bromopyridine.
[1247] .sup.1H-NMR (DMSO-d.sub.6) .delta.:7.41-7.45(2H, m),
7.65-7.69(1H, m), 7.94(2H, d, J=8.3 Hz), 8.02(2H, d, J=8.3 Hz),
8.34-8.38(1H, m), 13.09(1H, s).
[1248] MS (FAB) m/z:216 (M+H).sup.+.
Referential Example 242
2-(4-chloroanilino)-2-oxoacetic acid ethyl ester
##STR00312##
[1250] To a solution of 4-chloroaniline (1.16 g) in methylene
chloride (26 mL) were sequentially added triethylamine (1.52 mL)
and ethyl chlorooxoacetate (1.11 mL) under ice cooling, and the
thus-obtained mixture was stirred at room temperature for 14 hours.
Saturated aqueous sodium hydrogencarbonate was added to the
reaction mixture to partition the mixture. The organic layer was
sequentially washed with 10% aqueous citric acid and saturated
brine, and was dried over sodium sulfate anhydrate. The solvent was
concentrated under reduced pressure, and hexane was added to the
residue. The precipitated crystals were collected by filtration,
and were dried, to thereby give the title compound (1.89 g).
[1251] .sup.1H-NMR (CDCl.sub.3) .delta.:1.43(3H, t, J=7.1 Hz),
4.42(2H, q, J=7.1 Hz), 7.34(2H, d, J=8.8 Hz), 7.60(2H, d, J=8.8
Hz), 8.86(1H, br.s).
[1252] MS (ESI) m/z:228 (M+H).sup.+.
Referential Example 243
2-[(5-chloropyridin-2-yl)amino]-2-oxoacetic acid methyl ester
##STR00313##
[1254] 2-Amino-5-chloropyridine (1.16 g) and triethylamine (1.51
mL) were dissolved in methylene chloride (26 mL), and ethyl
chlorooxoacetate (1.10 mL) was added thereto under ice cooling,
followed by stirring at room temperature for 14 hours. Saturated
aqueous sodium hydrogencarbonate was added to the reaction mixture
to partition the mixture, and the organic layer was dried over
sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure, and the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=3:1). The resultant
pale-yellow solid was dissolved in methanol (20 mL), and the
solution was stirred at 50.degree. C. for 11 hours. The reaction
mixture was concentrated under reduced pressure. The precipitated
crystals were collected by filtration, and were dried, to thereby
give the title compound (0.43 g).
[1255] .sup.1H-NMR (CDCl.sub.3) .delta.:3.99(3H, s), 7.73(1H, dd,
J=8.8, 2.2 Hz), 8.24(1H, d, J=8.8 Hz), 8.31(1H, d, J=2.2 Hz),
9.39(1H, br.s).
[1256] MS (ESI) m/z:215 (M+H).sup.+.
Referential Example 244
(1S)-3-cyclohexene-1-carboxylic acid
##STR00314##
[1258] (R)-(+)-.alpha.-Methylbenzylamine salt of
(1S)-3-cyclohexene-1-carboxylic acid (J. Am. Chem. Soc., vol. 100,
pp. 5199-5203 (1978)) (95.0 g) was dissolved in ethyl acetate (1.6
L) and 2N HCl (1.6 L). After the organic layer was separated, the
aqueous layer was extracted with ethyl acetate (500 mL.times.2).
The organic layers were combined, and the combined organic layer
was washed with saturated brine (300 mL.times.2). After the organic
layer was separated, the aqueous layer was extracted with ethyl
acetate (200 mL), and the organic layer was washed with saturated
brine (100 mL). All organic layers were combined, and the combined
organic layer was dried over sodium sulfate anhydrate, followed by
concentration under reduced pressure, to thereby give the title
compound (48.3 g).
[1259] [.alpha.] .sup.25.sub.D=104.degree. (c=1, chloroform).
[1260] .sup.1H-NMR (CDCl.sub.3) .delta.:1.66-1.77(1H, m),
2.00-2.20(3H, m), 2.20-2.38(2H, m), 2.57-2.65(1H, m), 5.65-5.75(2H,
m).
Referential Example 245
(1S, 4S, 5S)-4-iodo-6-oxabicyclo[3.2.11octan-7-one
##STR00315##
[1262] To a mixture of the compound obtained in Referential Example
244 (48.0 g), methylene chloride (580 mL), potassium iodide (82.1
g), sodium hydrogencarbonate (42.0 g), and water (530 mL) was added
iodine (125.4 g) at an internal temperature of 5.degree. C.,
followed by stirring at room temperature for 3 hours. To the
reaction mixture was added 1N aqueous sodium thiosulfate (800 mL),
and the thus-obtained mixture was extracted with methylene chloride
(1 L, 500 mL). The organic layer was washed with aqueous sodium
hydrogencarbonate (300 mL), water (500 mL), and saturated brine
(300 mL), and was dried over anhydrous magnesium sulfate, followed
by concentration. The precipitated crystals were collected by
filtration, and were washed with hexane, followed by drying, to
thereby give the title compound (89.5 g).
[1263] m.p.: 130-131.degree. C.
[1264] [.alpha.] .sup.25.sub.D=41.degree. (c=1, chloroform)
[1265] .sup.1H-NMR (CDCl.sub.3) .delta.:1.78-1.96(2H, m), 2.12(1H,
dd, J=16.5 Hz, 5.2 Hz), 2.35-2.50(2H, m), 2.65-2.70(1H, m),
2.80(1H, d, J=12.2 Hz), 4.45-4.55(1H, m), 4.77-4.87(1H, m).
Referential Example 246
(1S, 3S, 6R)-7-oxabicyclo[4.1.0]heptane-3-carboxylic acid ethyl
ester
##STR00316##
[1267] To a suspension of the compound obtained in Referential
Example 245 (89.3 g) in ethanol (810 mL) was added 2N aqueous
sodium hydroxide (213 mL) at room temperature while being stirred,
and the thus-obtained mixture was stirred for 3 hours. The reaction
mixture was concentrated in a bath at a temperature of 35.degree.
C. under reduced pressure. Water (500 mL) was added to the
resultant oily matter, and the thus-obtained mixture was extracted
with methylene chloride (500 mL and 300 mL). The organic layer was
washed with water (300 mL), and was dried over anhydrous magnesium
sulfate, followed by concentration under reduced pressure. The
resultant oily matter was purified by silica gel column
chromatography (hexane:ethyl acetate=85:15), to thereby give the
title compound (41.3 g).
[1268] [.alpha.] .sup.25.sub.D=58.degree. (c=1, chloroform).
[1269] .sup.1H-NMR (CDCl.sub.3) .delta.:1.25(3H, t, J=7.2 Hz),
1.50-1.70(2H, m), 1.71-1.82(1H, m), 2.08-2.28(4H, m), 3.16(2H, s),
4.12(2H, q, J=7.2 Hz).
Referential Example 247
(1S, 3R, 4R)-3-azido-4-hydroxycyclohexanecarboxylic acid ethyl
ester
##STR00317##
[1271] A mixture of the compound obtained in Referential Example
246 (41.0 g), N,N-dimethylformamide (300 mL), ammonium chloride
(19.3 g), and sodium azide (23.5 g) was stirred at 76.degree. C.
for 13 hours. After any insoluble matter was collected by
filtration, the filtrate was concentrated under reduced pressure
while not allowing the solvent to evaporate to dryness. The residue
was combined with the solid matter collected by the previous
filtration, and the thus-obtained mixture was dissolved in water
(500 mL). The solution was extracted with ethyl acetate (500 mL,
300 mL). The extract was washed with water and saturated brine, and
was dried over anhydrous magnesium sulfate, followed by
concentration, to thereby give the title compound (51.5 g).
[1272] [.alpha.] .sup.25.sub.D=+8.degree. (c=1, chloroform)
[1273] .sup.1H-NMR(CDCl.sub.3).delta.: 1.28(3H, t, J=7.1 Hz),
1.37-1.64(3H, m), 1.86-1.95(1H, m), 2.04-2.16(1H, m), 2.32-2.41(1H,
m), 2.44(1H, br.s), 2.68-2.78(1H, m), 3.45-3.60(2H, m), 4.17(2H, q,
J=7.1 Hz).
Referential Example 248
(1S, 3R,
4R)-3-[(tert-butoxycarbonyl)amino]-4-hydroxycyclohexanecarboxylic
acid ethyl ester
##STR00318##
[1275] A mixture of the compound obtained in Referential Example
247 (51.2 g), di-tert-butyl dicarbonate (68.1 g), 5% palladium on
carbon (5.0 g), and ethyl acetate (1000 mL) was stirred at room
temperature overnight at a hydrogen pressure of 7 kg/cm.sup.2.
After the reaction mixture was filtered, the filtrate was
concentrated, and the thus-obtained oily matter was purified by
silica gel column chromatography (hexane:ethyl
acetate=4:1.fwdarw.3:1). The thus-obtained compound was
crystallized from hexane, to thereby give the title compound (46.9
g). Furthermore, the mother liquor was purified by silica gel
column chromatography (chloroform : methanol =100:1), to thereby
give the title compound (6.74 g).
[1276] [.alpha.] .sup.25.sub.D=+25.degree. (c=1, chloroform).
[1277] .sup.1H-NMR(CDCl.sub.3).delta.: 1.28(3H, t, J=7.1 Hz),
1.38-1.57(3H, m), 1.45(9H, s), 1.86-1.95(1H, m), 2.05-2.17(1H, m),
2.29-2.39(1H, m), 2.61-2.68(1H, m), 3.34(1H, br.s), 3.39-3.48(1H,
m), 3.53-3.64(1H, m), 4.10-4.24(2H, m), 4.54(1H, br.s).
Referential Example 249
(1S, 3R,
4S)-4-azido-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic
acid ethyl ester
##STR00319##
[1279] To a solution of the compound obtained in Referential
Example 248 (53.5 g) in methylene chloride (500 mL) and
triethylamine (130 mL) was added dropwise methanesulfonyl chloride
(42 mL) at -10.degree. C. to -15.degree. C. over 20 minutes. The
thus-obtained mixture was heated to room temperature over 2 hours,
and was stirred for an additional 2 hours. To the reaction mixture
was added dropwise 0.5N HCl (800 mL) at 0.degree. C., to thereby
make the mixture acidic, and the resultant mixture was extracted
with methylene chloride (500 mL, 300 mL). The organic layer was
washed with saturated aqueous sodium hydrogencarbonate and
saturated brine, and was dried over anhydrous magnesium sulfate,
followed by concentration. The resultant crystals were dissolved in
N,N-dimethylformamide (335 mL), and sodium azide (60.5 g) was added
thereto, followed by stirring at 67 to 75.degree. C. for 16 hours.
The reaction mixture was filtrated, and the filtrate was
concentrated under reduced pressure, to thereby evaporate 250 mL of
the solvent. The residue was combined with the solid matter
collected by the previous filtration, and the thus-obtained mixture
was dissolved in water (500 mL). The solution was extracted with
ethyl acetate (1 L and 300 mL). The organic layer was washed with
saturated brine (400 mL, 200 mL), and was dried over anhydrous
magnesium sulfate, followed by concentration. The resultant
crystals were purified by silica gel column chromatography
(hexane:ethyl acetate=4:1), to thereby give the title compound
(18.4 g).
[1280] [.alpha.] .sup.25.sub.D=+62.degree. (c=1, chloroform).
[1281] .sup.1H-NMR(CDCl.sub.3).delta.: 1.26(3H, t, J=7.1 Hz),
1.35-2.00(15H, s), 2.60-2.68(1H, m), 3.80-3.96(2H, m), 4.15(2H, q,
J=7.1 Hz), 4.61(1H, br.s).
Referential Example 250
(1S, 3R,
4S)-4-azido-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic
acid
##STR00320##
[1283] To a solution of the compound obtained in Referential
Example 249 (1.0 g) in tetrahydrofuran (25 mL) were added lithium
hydroxide (102 mg) and water (5 mL), and after the thus-obtained
mixture was stirred for 17 hours, additional lithium hydroxide (50
mg) was added thereto, followed by stirring for 4 hours. To the
reaction mixture was added 1N aqueous HCl (6.3 mL), and the
thus-obtained mixture was extracted with ethyl acetate. The organic
layer was dried, and the solvent was distilled away under reduced
pressure, to thereby give the title compound (980 mg).
[1284] .sup.1H-NMR(CDCl.sub.3).delta.: 1.30-2.20(6H, m), 1.45(9H,
s), 2.70-2.80(1H, m), 3.94(2H, br.s), 4.73(1H, br.s).
Referential Example 251
(1R, 2S, 5S)-2-azido-5-[(dimethylamino)carbonyl]cyclohexylcarbamic
acid tert-butyl ester
##STR00321##
[1286] The compound obtained in Referential Example 250 (4.77 g)
was dissolved in methylene chloride (150 mL), and to the solution
were added dimethylamine hydrochloride (3.26 g),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.60
g), 1-hydroxybenzotriazole monohydrate (3.24 g), and
N-methylmorpholine (8.09 g), followed by stirring at room
temperature for 18 hours. Saturated aqueous sodium
hydrogencarbonate was added to the reaction mixture to partition
the mixture. The organic layer was dried, and the solvent was
distilled away under reduced pressure. The residue was purified by
silica gel column chromatography (methanol:methylene
chloride=1:50), to thereby give the title compound (4.90 g).
[1287] .sup.1HNMR(CDCl.sub.3).delta.: 1.30-1.90(4H, m), 1.45(9H,
s), 1.97-2.18(2H, m), 2.75-2.85(1H, m), 2.92(3H, s), 3.02(3H, s),
3.68-3.80(1H, m), 4.05-4.20(1H, m), 4.55-4.75(1H, m).
Referential Example 252
N-{(1R, 2S,
5S)-2-azido-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetra-
hydrothiazolo[5,4-c]pyridine-2-carboxamide
##STR00322##
[1289] The compound obtained in Referential Example 251 (9.13 g)
was dissolved in methylene chloride (100 mL), and HCl-ethanol (100
mL) was added thereto, followed by stirring at room temperature for
1 minute. The reaction mixture was concentrated under reduced
pressure, and the residue was dissolved in N,N-dimethylformamide
(200 mL). To the solution were added the compound obtained in
Referential Example 10 (7.75 g), 1-hydroxybenzotriazole monohydrate
(4.47 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (11.2 g), and triethylamine (2.02 mL), followed by
stirring at room temperature overnight. To the resultant mixture
were further added the compound obtained in Referential Example 10
(2.38 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (5.60 g), followed by stirring for 3 days. The
reaction mixture was concentrated under reduced pressure, and the
residue was partitioned between methylene chloride and saturated
aqueous sodium hydrogencarbonate. The organic layer was dried over
sodium sulfate anhydrate, and the solvent was distilled away under
reduced pressure. The residue was purified by silica gel column
chromatography (methylene chloride:methanol=47:3), to thereby give
the title compound (7.38 g).
[1290] .sup.1H-NMR(CDCl.sub.3).delta.: 1.72-1.97(4H, m),
2.10-2.27(2H, m), 2.51(3H, s), 2.77-3.05(11H, m), 3.68(1H, d,
J=15.4 Hz), 3.74(1H, d, J=15.4 Hz), 3.86-3.93(1H, m), 4.54-4.60(1H,
m), 7.25(1H, d, J=7.6 Hz).
Referential Example 253
N-{(1R, 2S,
5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetra-
hydrothiazolo[5,4-c]pyridine-2-carboxamide
##STR00323##
[1292] To a solution of the compound obtained in Referential
Example 252 (9.0 g) in methanol (300 mL) was added 10% palladium on
carbon (6.0 g), and the thus-obtained mixture was vigorously
stirred at room temperature for 11 hours at a hydrogen pressure of
4 atm. The catalyst was filtered off, and the filtrate was
concentrated, to thereby give the title compound (7.67 g).
[1293] .sup.1H-NMR(CDCl.sub.3).delta.: 1.42-1.54(1H, m),
1.66-1.89(5H, m), 2.30-2.40(1H, m), 2.51(3H, s), 2.68-3.05(6H, m),
2.92(3H, s), 3.00(3H, s), 3.10-3.18(1H, m), 3.65-3.77(2H, m),
4.21-4.28(1H, m), 7.52(1H, d, J=6.1 Hz).
Referential Example 254
2-(4-fluoroanilino)-2-oxoacetic acid methyl ester
##STR00324##
[1295] In a manner similar to that employed in Referential Example
242, the title compound was prepared from 4-fluoroaniline and
methyl chlorooxoacetate.
[1296] .sup.1H-NMR(CDCl.sub.3).delta.: 3.98(3H, s), 7.00-7.14(2H,
m), 7.55-7.68(2H, m), 8.85(1H, br.s).
[1297] MS(ESI)m/z: 198(M+H).sup.+.
Referential Example 255
2-(4-bromoanilino)-2-oxoacetic acid methyl ester
##STR00325##
[1299] In a manner similar to that employed in Referential Example
242, the title compound was prepared from 4-bromoaniline and methyl
chlorooxoacetate.
[1300] .sup.1H-NMR(CDCl.sub.3).delta.: 3.98(3H, s), 7.49(2H, d,
J=9.0 Hz), 7.55(2H, d, J=9.0 Hz), 8.85(1H, br.s).
[1301] MS(FAB)m/z: 258M.sup.+.
Referential Example 256
2-(4-chloro-2-methylanilino)-2-oxoacetic acid methyl ester
##STR00326##
[1303] In a manner similar to that employed in Referential Example
242, the title compound was prepared from 4-chloro-2-methylaniline
and methyl chlorooxoacetate.
[1304] .sup.1H-NMR(CDCl.sub.3).delta.: 2.31(3H, s), 3.99(3H, s),
7.15-7.30(2H, m), 7.98(1H, d, J=8.8 Hz), 8.77(1H, br).
[1305] MS(FAB)m/z: 228(M+H).sup.+.
Referential Example 257
2-[(4-chloro-3-methylanilino)-2-oxoacetic acid methyl ester
##STR00327##
[1307] In a manner similar to that employed in Referential Example
242, the title compound was prepared from 4-chloro-3-methylaniline
and methyl chlorooxoacetate.
[1308] .sup.1H-NMR(CDCl.sub.3).delta.: 2.39(3H, s), 3.98(3H, s),
7.33(1H, d, J=12.5 Hz), 7.44(1H, dd, J=12.5, 2.5 Hz), 7.53(1H, d,
J=2.5 Hz), 8.81(1H, br.s).
[1309] MS(ESI)m/z: 228(M+H).sup.+.
Referential Example 258
2-(4-chloro-2-fluoroanilino)-2-oxoacetic acid methyl ester
##STR00328##
[1311] In a manner similar to that employed in Referential Example
242, the title compound was prepared from 4-chloro-2-fluoroaniline
and methyl chlorooxoacetate.
[1312] .sup.1H-NMR(CDCl.sub.3).delta.: 3.99(3H, s), 7.15-7.24(2H,
m), 8.33(1H, t, J=8.4 Hz), 9.05(1H, br.s).
[1313] MS(ESI)m/z: 232(M+H).sup.+.
Referential Example 259
2-(2,4-difluoroanilino)-2-oxoacetic acid methyl ester
##STR00329##
[1315] In a manner similar to that employed in Referential Example
242, the title compound was prepared from 2,4-difluoroaniline and
methyl chlorooxoacetate.
[1316] .sup.1H-NMR(CDCl.sub.3).delta.: 3.99(3H, s), 6.87-7.00(2H,
m), 8.29-8.38(1H, m), 8.99(1H, br.s).
[1317] MS(ESI)m/z: 215M.sup.+.
Referential Example 260
2-(3,4-difluoroanilino)-2-oxoacetic acid methyl ester
##STR00330##
[1319] In a manner similar to that employed in Referential Example
242, the title compound was prepared from 3,4-difluoroaniline and
methyl chlorooxoacetate.
[1320] .sup.1H-NMR(CDCl.sub.3).delta.: 3.98(3H, s), 7.10-7.28(2H,
m), 7.67-7.78(1H, m), 8.83(1H, br.s).
[1321] MS(ESI)m/z: 215M.sup.+.
Referential Example 261
2-oxo-2-(pyridin-4-ylamino)acetic acid methyl ester
##STR00331##
[1323] In a manner similar to that employed in Referential Example
242, the title compound was prepared from 4-aminopyridine and
methyl chlorooxoacetate.
[1324] .sup.1H-NMR(CDCl.sub.3).delta.: 3.99(3H, s), 7.58(2H, dd,
J=4.8, 1.6 Hz), 8.60(2H, dd, J=4.8, 1.6 Hz), 9.04(1H, br.s).
[1325] MS(ESI)m/z: 181(M+H).sup.+.
Referential Example 262
2-[(5-bromopyridin-2-yl)amino]-2-oxoacetic acid methyl ester
##STR00332##
[1327] In a manner similar to that employed in Referential Example
242, the title compound was prepared from 2-amino-5-bromopyridine
and methyl chlorooxoacetate.
[1328] .sup.1H-NMR(CDCl.sub.3).delta.: 3.99(3H, s), 7.87(1H, dd,
J=8.8, 2.4 Hz), 8.19(1H, d, J=8.8 Hz), 8.41(1H, d, J=2.4 Hz),
9.38(1H, br.s).
[1329] MS(FAB)m/z: 259 M.sup.+.
Referential Example 263
2-[(6-chloropyridin-3-yl)amino]-2-oxoacetic acid ethyl ester
##STR00333##
[1331] 5-Amino-2-chloropyridine (386 mg) was dissolved in
N,N-dimethylformamide (8 mL), and to the solution were added
potassium 2-ethoxy-2-oxoacetate (469 mg),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (863
mg), and 1-hydroxybenzotriazole monohydrate (203 mg), followed by
stirring at room temperature for 2 days. The solvent was distilled
away under reduced pressure, and the residue was partitioned
between methylene chloride and saturated aqueous sodium
hydrogencarbonate. The organic layer was dried over sodium sulfate
anhydrate, and the solvent was removed under reduced pressure. The
residue was purified by silica gel flash column chromatography
(hexane:ethyl acetate=2:1), to thereby give the residue (200 mg)
containing the title compound.
[1332] .sup.1H-NMR(CDCl.sub.3).delta.: 1.43(3H, t, J=7.2 Hz),
4.44(2H, q, J=7.2 Hz), 7.36(1H, d, J=8.7 Hz), 8.24(1H, dd, J=8.7,
2.7 Hz), 8.55(1H, d, J=2.7 Hz), 9.03(1H, br.s).
Referential Example 264
2-[(6-chloropyridazin-3-yl)amino]-2-oxoacetic acid methyl ester
##STR00334##
[1334] 3-Amino-6-chloropyridazine (516 mg) was dissolved in
pyridine (26 mL), and to the solution were sequentially added
triethylamine (665 .mu.L) and methyl chlorooxoacetate (441 .mu.L)
under ice cooling, followed by stirring at room temperature for 14
hours. Water was added to the reaction mixture to partition the
mixture, and the organic layer was dried over sodium sulfate
anhydrate. The solvent was distilled away under reduced pressure,
to thereby give the title compound (748 mg).
[1335] .sup.1H-NMR(CDCl.sub.3).delta.: 4.03(3H, s), 7.59(1H, d,
J=9.3 Hz), 8.52(1H, d, J=9.3 Hz), 9.88(1H, br.s).
[1336] MS(FAB)m/z: 215M.sup.+.
Referential Example 265
2-[(5-chlorothiazol-2-yl)amino]-2-oxoacetic acid methyl ester
##STR00335##
[1338] In a manner similar to that employed in Referential Example
242, the title compound was prepared from 2-amino-5-chlorothiazole
and methyl chlorooxoacetate.
[1339] .sup.1H-NMR(CDCl.sub.3).delta.: 4.02(3H, s), 7.48(1H, s),
11.03(1H, br.s).
[1340] MS(ESI)m/z: 221(M+H).sup.+.
Referential Example 266
2-[(5-chloropyridin-2-yl)amino]-2-oxoacetic acid lithium salt
##STR00336##
[1342] To a solution of the compound obtained in Referential
Example 243 (1.12 g) in tetrahydrofuran (20 mL) were added water
(5.0 mL) and lithium hydroxide (128 mg) at room temperature, and
the thus-obtained mixture was stirred for 5 hours. The solvent was
distilled away under reduced pressure, and to the resultant white
solid was added hexane (30 mL), followed by stirring for 30
minutes. The resultant solid matter was collected by filtration,
and was dried, to thereby give the title compound (1.02 g).
[1343] .sup.1H-NMR(DMSO-d.sub.6).delta.: 7.90(1H, dd, J=8.9, 2.6
Hz), 8.12(1H, d, J=8.9 Hz), 8.34(1H, d, J=2.6 Hz), 10.18(1H,
s).
Referential Example 267
2-(4-chloroanilino)acetic acid ethyl ester
##STR00337##
[1345] 4-Chloroaniline (2.0 g) was dissolved in acetonitrile (20
mL), and bromoethyl acetate (2.1 g) and potassium carbonate (2.2 g)
were added thereto, followed by stirring at 60.degree. C. for 2
days: The reaction mixture was filtered through a Celite pad, and
the filtrate was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography
(hexane:chloroform=2:1), to thereby give the title compound (2.3
g).
[1346] .sup.1H-NMR(CDCl.sub.3).delta.: 1.30(3H, t, J=7.3 Hz),
3.86(2H, s), 4.24(2H, q, J=7.3 Hz), 4.26-4.35(1H, m), 6.53(2H, dd,
J=6.6, 2.2 Hz), 7.14(2H, dd, J=6.6, 2.2 Hz).
Referential Example 268
2-(4-chloro-2-fluoroanilino)acetic acid ethyl ester
##STR00338##
[1348] In a manner similar to that employed in Referential Example
267, the title compound was prepared from 4-chloro-2-fluoroaniline
and bromoethyl acetate.
[1349] .sup.1H-NMR(CDCl.sub.3).delta.: 1.29(3H, t, J=7.3 Hz),
3.91(2H, s), 4.22(2H, q, J=7.3 Hz), 4.42-4.51(1H, m), 6.49(1H, t,
J=8.8 Hz), 6.98(1H, dt, J=8.8, 2.5 Hz), 7.01(1H, dd, J=11.3, 2.5
Hz).
Referential Example 269
2-[((1S, 2R,
4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[-
5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)amino]-2-oxoacetic
acid ethyl ester
##STR00339##
[1351] The compound obtained in Referential Example 253 (1.5 g) was
dissolved in N,N-dimethylformamide (15 mL), and to the solution
were added potassium 2-ethoxy-2-oxoacetate (962 mg),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.18
g), and 1-hydroxybenzotriazole monohydrate (277 mg), followed by
stirring at room temperature for 14 hours. The solvent was
distilled away under reduced pressure, and the residue was
partitioned between saturated aqueous sodium hydrogencarbonate and
methylene chloride. The organic layer was dried over sodium sulfate
anhydrate, and the solvent was distilled away under reduced
pressure. The residue was purified by silica gel flash column
chromatography (methylene chloride:methanol=47:3), to thereby give
the title compound (1.13 g).
[1352] .sup.1H-NMR(CDCl.sub.3).delta.: 1.37(3H, t, J=7.1 Hz),
1.55-2.15(6H, m), 2.52(3H, s), 2.77-2.89(3H, m), 2.94(5H, br.s),
3.06(3H, s), 3.71(1H, d, J=15.5 Hz), 3.73(1H, d, J=15.5 Hz),
4.06-4.13(1H, m), 4.32(2H, q, J=7.1 Hz), 4.60-4.63(1H, m), 7.39(1H,
d, J=8.3 Hz), 7.83(1H, d, J=7.6 Hz).
[1353] MS(ESI)m/z: 466(M+H).sup.+.
Referential Example 270
2-[((1S, 2R,
4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[-
5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)amino]-2-oxoacetic
acid lithium salt
##STR00340##
[1355] The compound obtained in Referential Example 269 (1.13 g)
was dissolved in tetrahydrofuran (20 mL), methanol (10 mL), and
water (10 mL), and lithium hydroxide (58 mg) was added thereto,
followed by stirring at room temperature for 30 minutes. The
solvent was distilled away under reduced pressure, to thereby give
the title compound (1.10 g).
[1356] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.41-1.73(4H, m),
2.00-2.07(2H, m), 2.39(3H, s), 2.74-2.99(11H, m), 3.67(2H, s),
3.82-3.88(1H, m), 4.28-4.30(1H, m), 8.66-8.70(2H, m).
Referential Example 271
N-[(1R, 2S,
5S)-2-azido-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-5,6-dihydro-4-
H-pyrolo[3,4-d]thiazole-2-carboxamide
##STR00341##
[1358] In a manner similar to that employed in Referential Example
252, the title compound was prepared from the compound obtained in
Referential Example 293 and the compound obtained in Referential
Example 251.
[1359] .sup.1H-NMR(CDCl.sub.3).delta.: 1.73-1.87(4H, m),
2.11-2.20(2H, m), 2.67(3H, s), 2.85-2.90(1H, m), 2.93(3H, s),
3.00(3H, s), 3.90-4.10(5H, m), 4.57-4.62(1H, m), 7.20-7.22(1H,
m).
[1360] MS(FAB)m/z: 378(M+H).sup.+.
Referential Example 272
N-{(1R, 2S,
5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-5,6-dihydro-4-
H-pyrolo[3,4-d]thiazole-2-carboxamide
##STR00342##
[1362] In a manner similar to that employed in Referential Example
253, the title compound was prepared from the compound obtained in
Referential Example 271.
[1363] .sup.1H-NMR(CDCl.sub.3).delta.: 1.67-1.97(6H, m),
2.36-2.40(1H, m), 2.67(3H, s), 2.92(3H, s), 3.00(3H, s),
3.07-3.18(1H, m), 3.92-3.95(2H, m), 4.02-4.06(2H, m), 4.23-4.26(1H,
m), 7.50-7.52(1H, m).
Referential Example 273
5-chloro-4-fluoroindole-2-carboxylic acid methyl ester
##STR00343##
[1365] Ethanol (100 mL) was added to sodium hydride (60% sodium
hydride content, 4.7 g) at 0.degree. C. under argon atmosphere, and
the mixture was stirred for 10 minutes. 2-Nitropropane (11 mL) was
added to the reaction mixture, and after the thus-obtained mixture
was stirred for 10 minutes,
1-(bromomethyl)-3-chloro-2-fluorobenzene (10 g) was added thereto,
followed by stirring at room temperature for 3.5 hours. The
precipitate was filtered off, and the filtrate was concentrated
under reduced pressure. The residue was partitioned between diethyl
ether and water. The organic layer was sequentially washed with 1N
aqueous sodium hydroxide, water, and saturated brine, and was dried
over sodium sulfate anhydrate. The solvent was distilled away, and
the residue was purified by silica gel column chromatography (ethyl
acetate:hexane=3:7), to thereby give crude
3-chloro-2-fluorobenzaldehyde (5.5 g) as a pale-yellow oily
compound. Methanol (20 mL) was added to sodium hydride (60% sodium
hydride content, 1.6 g) under argon atmosphere at 0.degree. C., and
the thus-obtained mixture was stirred for 10 minutes. After the
reaction mixture was cooled to -20.degree. C., a solution of the
crude 3-chloro-2-fluorobenzaldehyde (5.5 g) and methyl
2-azidoacetate (5.0 g) in methanol (10 mL) was added thereto within
20 minutes. After the reaction mixture was heated to 0.degree. C.,
the mixture was stirred for 2.5 hours, and water (40 mL) was added
thereto. The reaction mixture was concentrated under reduced
pressure, and the residue was extracted with a mixture of methylene
chloride and ethyl acetate. The extract was washed with saturated
brine, and was dried over sodium sulfate anhydrate. The solvent was
distilled away, and the residue was purified by silica gel column
chromatography (toluene:hexane=3:17), to thereby give crude
2-azido-3-[(3-chloro-2-fluoro)phenyl]acrylic acid methyl ester (2.6
g). This compound was dissolved in xylene (50 mL), and the solution
was stirred at 130-140.degree. C. for 3 hours. The reaction mixture
was concentrated, and the residue was purified by silica gel column
chromatography (methylene chloride). The thus-obtained compound was
crystallized from diethyl ether-hexane, to thereby give the title
compound (440 mg).
[1366] .sup.1H-NMR(DMSO-d.sub.6).delta.: 4.08(3H, s), 7.20(1H, s),
7.31-7.38(2H, m).
[1367] MS(FAB)m/z: 228(M+H).sup.+.
Referential Example 274
5-chloro-4-fluoroindole-2-carboxylic acid
##STR00344##
[1369] The compound obtained in Referential Example 273 (440 mg)
was dissolved in tetrahydrofuran (10 mL), and an aqueous solution
(5 mL) of lithium hydroxide (160 mg) was added thereto, followed by
stirring at room temperature for 3 hours. To the reaction mixture
was further added an aqueous solution (5 mL) of lithium hydroxide
(240 mg), and the thus-obtained mixture was stirred at room
temperature for an additional 1 hour. The reaction mixture was
concentrated under reduced pressure, and the residue was
neutralized with 1N aqueous HCl. The thus-obtained mixture was
extracted with ethyl acetate 3 times, and the organic layers were
combined. The combined organic layer was washed with saturated
brine, and was dried over sodium sulfate anhydrate. The solvent was
distilled away under reduced pressure, to thereby give the title
compound (390 mg).
[1370] .sup.1H-NMR(DMSO-d.sub.6).delta.: 6.79(1H, s), 7.16-7.26(2H,
m)
[1371] MS(FAB)m/z: 214(M+H).sup.+.
Referential Example 275
1-benzyl-5-chloroindole-2-carboxylic acid ethyl ester
##STR00345##
[1373] 5-Chloroindole-2-carboxylic acid ethyl ester (1.4 g) was
dissolved in N,N-dimethylformamide (30 mL), and to the solution
were added potassium carbonate (2.9 g) and benzyl chloride (2.4
mL), followed by stirring in a bath at a temperature of 100.degree.
C. for 1.5 hours. The reaction mixture was concentrated, and the
residue was poured into ice water. The thus-obtained mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine, and was dried over sodium sulfate anhydrate. The
solvent was distilled away, and the residue was purified by silica
gel column chromatography (ethyl acetate:hexane=1:19). The
thus-obtained compound was crystallized from diethyl ether-hexane,
to thereby give the title compound (1.6 g).
[1374] .sup.1H-NMR(CDCl.sub.3).delta.: 1.36(3H, t, J=7.1 Hz),
4.33(2H, q, J=7.1 Hz), 5.83(2H, s), 7.00-7.02(2H, d), 7.20-7.38(6H,
m), 7.67(1H, d, J=1.7 Hz).
Referential Example 276
1-benzyl-5-chloro-3-fluoroindole-2-carboxylic acid ethyl ester
##STR00346##
[1376] To a solution of the compound obtained in Referential
Example 275 (2.2 g) in methylene chloride (30 mL) was added
1-fluoro-2,6-dichloropyridinium triflate (4.4 g), and the
thus-obtained mixture was heated under reflux for 3 days. The
reaction mixture was partitioned between ethyl acetate and water.
The aqueous layer was extracted with ethyl acetate, and the organic
layers were combined. The combined organic layer was sequentially
washed with 1N HCl, water, and saturated brine, and was dried over
sodium sulfate anhydrate. The solvent was distilled away, and the
residue was purified by silica gel column chromatography (ethyl
acetate:hexane=1:24), to thereby give the crude title compound (2.8
g). A portion of the thus-obtained compound was purified by silica
gel thin layer chromatography, to thereby give the title
compound.
[1377] .sup.1H-NMR (DMSO-d.sub.6).delta.: 1.25 (3H, t, J=7.1 Hz),
4.29(2H, q, J=7.1 Hz), 5.77(2H, s), 6.97-6.99(2H, m), 7.18-7.28(3H,
m), 7.39(1H, dd, J=9.0, 2.1 Hz), 7.69(1H, dd, J=9.0, 2.1 Hz),
7.78(1H, d, J=2.1 Hz)
Referential Example 277
5-chloro-3-fluoroindole-2-carboxylic acid ethyl ester
##STR00347##
[1379] The crude compound obtained in Referential Example 276 (1.4
g) was dissolved in anisole (30 mL), and aluminium chloride (2.9 g)
was added thereto in small portions under ice cooling, followed by
stirring at room temperature for 30 minutes. Additional aluminium
chloride (2.9 g) was added thereto, and the thus-obtained mixture
was stirred for 18 hours. To the reaction mixture was added
aluminium chloride (8.0 g), and the mixture was stirred for 5
hours. After water was added thereto, the reaction mixture was
extracted with ethyl acetate, and the organic layers were combined.
The combined organic layer was sequentially washed with saturated
aqueous sodium hydrogencarbonate and saturated brine, and was dried
over sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure, and the residue was purified by silica gel column
chromatography (methylene chloride), to thereby give the title
compound (470 mg).
[1380] .sup.1H-NMR(CDCl.sub.3).delta.: 1.43(3H, t, J=7.2 Hz),
4.45(2H, q, J=7.2 Hz), 7.25-7.31(2H, m), 7.66(1H, d, J=0.73 Hz),
8.53(1H, br.s).
[1381] MS(FAB)m/z: 242(M+H).sup.+.
Referential Example 278
5-chloro-3-fluoroindole-2-carboxylic acid
##STR00348##
[1383] In a manner similar to that employed in Referential Example
274, the title compound was prepared from the compound obtained in
Referential Example 277.
[1384] .sup.1H-NMR(DMSO-d.sub.6).delta.: 7.31(1H, dd, J=8.8, 1.9
Hz), 7.42(1H, dd, J=8.8, 1.9 Hz), 7.70(1H, d, J=1.9 Hz), 11.78(1H,
s)
[1385] MS(FAB)m/z: 214(M+H).sup.+.
Referential Example 279
(1R, 2S,
5S)-{[(5-chloro-3-fluoroindol-2-yl)carbonyl]amino}-5-[(dimethylam-
ino)carbonyl]cyclohexylcarbamic acid tert-butyl ester
##STR00349##
[1387] In a manner similar to that employed in Referential Example
97, the title compound was prepared from the compound obtained in
Referential Example 144 and the compound obtained in Referential
Example 278.
[1388] .sup.1H-NMR(CDCl.sub.3).delta.: 1.45(9H, s), 1.73-2.11(6H,
m), 2.65(1H, br.s), 2.96(3H, s), 3.07(3H, s), 4.20(1H, br.s),
4.28(1H, br.s), 4.78(1H, br), 7.23-7.30(3H, m), 7.58(1H, s),
9.03(1H, s).
[1389] MS(FAB)m/z: 481(M+H).sup.+.
Referential Example 280
3-bromo-5-chloroindole-2-carboxylic acid ethyl ester
##STR00350##
[1391] N-Bromosuccinimide (440 mg) was added to a solution of
5-chloroindole-2-carboxylic acid ethyl ester (500 mg) in
N,N-dimethylformamide (10 mL) under ice cooling. The reaction
mixture was stirred at room temperature for 18 hours, and the
solvent was distilled away under reduced pressure. The residue was
partitioned between ethyl acetate and water. The aqueous layer was
extracted with ethyl acetate, and the organic layers were combined.
The combined organic layer was washed with saturated brine, and was
dried over sodium sulfate anhydrate. The solvent was distilled
away, and the residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:9). The thus-obtained white
powder was washed with hexane, to thereby give the title compound
(680 mg).
[1392] .sup.1H-NMR(CDCl.sub.3).delta.: 1.42-1.48(3H, m),
4.43-4.49(2H, m), 7.30-7.32(2H, m), 7.65(1H, d, J=0.74 Hz),
9.11(1H, s)
[1393] MS(FAB)m/z: 303(M+H).sup.+.
Referential Example 281
3-bromo-5-chloroindole-2-carboxylic acid
##STR00351##
[1395] In a manner similar to that employed in Referential Example
274, the title compound was prepared from the compound obtained in
Referential Example 280.
[1396] .sup.1H-NMR(DMSO-d.sub.6).delta.: 7.35(1H, dd, J=8.8, 2.0
Hz), 7.48-7.53(2H, m), 12.33(1H, s)
[1397] MS(FAB)m/z: 275(M+H).sup.+.
Referential Example 282
(1R, 2S,
5S)-2-{[(3-bromo-5-chloroindol-2-yl)carbonyl]amino}-5-[(dimethyla-
mino) carbonyl]cyclohexylcarbamic acid tert-butyl ester
##STR00352##
[1399] In a manner similar to that employed in Referential Example
97, the title compound was prepared from the compound obtained in
Referential Example 144 and the compound obtained in Referential
Example 281.
[1400] .sup.1H-NMR(CDCl.sub.3).delta.: 1.42(9H, s), 1.58-2.17(6H,
m), 2.70(1H, br.s), 2.96(3H, s), 3.07(3H, s), 4.23-4.28(2H, m),
4.83(1H, br), 7.34-7.41(3H, m), 7.52(1H, s), 9.76(1H, s).
[1401] MS(FAB)m/z: 542(M+H).sup.+.
Referential Example 283
3-chloro-5-fluoroindole-2-carboxylic acid ethyl ester
##STR00353##
[1403] 5-Fluoroindole-2-carboxylic acid ethyl ester (2.0 g) was
dissolved in N,N-dimethylformamide (20 mL), and a solution of
N-chlorosuccinimide (1.4 g) in N,N-dimethylformamide (10 mL) was
added dropwise thereto under ice cooling, followed by stirring at
room temperature for 18 hours. The reaction mixture was diluted
with ethyl acetate, and the diluted mixture was sequentially washed
with saturated aqueous sodium hydrogencarbonate and saturated
brine. The organic layer was dried over sodium sulfate anhydrate,
and the solvent was distilled away under reduced pressure. The
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=5:1), to thereby give the title compound (1.9
g).
[1404] .sup.1H-NMR(CDCl.sub.3).delta.: 1.45(3H, t, J=7.4 Hz),
4.46(2H, q, J=7.4 Hz), 7.14(1H, dt, J=8.0, 2.7 Hz), 7.32-7.36(2H,
m), 8.91(1H, br).
Referential Example 284
3-chloro-5-fluoroindole-2-carboxylic acid
##STR00354##
[1406] In a manner similar to that employed in Referential Example
274, the title compound was prepared from the compound obtained in
Referential Example 283.
[1407] .sup.1H-NMR(DMSO-d.sub.6).delta.: 7.20 (1H, dt, J=8.8, 2.4
Hz), 7.31(1H, dd, J=8.8, 2.4 Hz), 7.46(1H, dd, J=8.8, 4.4 Hz),
12.12(1H, br).
Referential Example 285
5-chloro-3-formylindole-2-carboxylic acid ethyl ester
##STR00355##
[1409] Phosphorus oxychloride (2.0 mL) was added to
N-methylformanilide (2.9 g), and after the mixture was stirred for
15 minutes, 1,2-dichloroethane (50 mL) and
5-chloroindole-2-carboxylic acid ethyl ester (4.0 g) were added
thereto, followed by heating under reflux for 1 hour. The reaction
mixture was poured into an aqueous solution (28 mL) of sodium
acetate (14 g) under ice cooling, and the thus-obtained mixture was
stirred for 18 hours. Insoluble matter was collected by filtration,
and was sequentially washed with water and diethyl ether, to
thereby give the title compound (3.56 g).
[1410] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.38(3H, t, J=7.1 Hz),
4.44(2H, q, J=7.1 Hz), 7.38(1H, dd, J=8.0, 1.4 Hz), 7.56(1H, d,
J=8.0 Hz), 8.19(1H, d, J=1.4 Hz), 10.53(1H, s).
Referential Example 286
5-chloro-3-formylindole-2-carboxylic acid
##STR00356##
[1412] The compound obtained in Referential Example 285 (1.0 g) was
dissolved in ethanol (10 mL), and 1N aqueous sodium hydroxide (10
mL) was added dropwise thereto, followed by stirring at 50.degree.
C. for 2 hours. To the reaction mixture was added 1N aqueous HCL
(11 mL), and the thus-obtained mixture was stirred. The resultant
insoluble matter was collected by filtration, to thereby give the
title compound (0.86 g).
[1413] .sup.1H-NMR(DMSO-d.sub.6).delta.: 7.39(1H, d, J=8.0 Hz),
7.55(1H, d, J=8.0 Hz), 8.20(1H, s), 10.58(1H, s), 12.90(1H,
br).
Referential Example 287
5-chloro-2-ethoxycarbonylindole-3-carboxylic acid
##STR00357##
[1415] The compound obtained in Referential Example 286 (1.5 g) and
sulfamic acid (1.7 g) were dissolved in tert-butanol (30 mL) and
water (30 mL), and sodium chlorite (1.6 g) was added thereto,
followed by stirring for 8 hours. The reaction mixture was diluted
with water, and the diluted mixture was extracted with ethyl
acetate. The extract was sequentially washed with 1N aqueous HCl
and saturated brine, and was dried over sodium sulfate anhydrate.
The solvent was distilled away under reduced pressure, and the
residue was recrystallized from a solvent mixture comprising
isopropyl ether and hexane, to thereby give the title compound (0.7
g).
[1416] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.34(3H, t, J=7.1 Hz),
4.38(2H, q, J=7.1 Hz), 7.33(1H, dd, J=8.0, 1.4 Hz), 7.52(1H, d,
J=8.0 Hz), 7.97(1H, d, J=1.4 Hz), 12.75(1H, br).
Referential Example 288
5-chloro-3-[(dimethylamino)carbonyl]indole-2-carboxylic acid ethyl
ester
##STR00358##
[1418] The compound obtained in Referential Example 287 (0.7 g) was
dissolved in N,N-dimethylformamide (10 mL), and to the solution
were added dimethylamine hydrochloride (0.26 g),
1-hydroxybenzotriazole monohydrate (0.43 g), and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0
g), followed by stirring at room temperature for 2 days. The
reaction mixture was diluted with ethyl acetate, and the diluted
mixture was sequentially washed with 1N aqueous HCl, saturated
aqueous sodium hydrogencarbonate, and saturated brine. The organic
layer was dried over sodium sulfate anhydrate. The solvent was
distilled away under reduced pressure, and the residue was
recrystallized from a solvent mixture comprising isopropyl ether
and hexane, to thereby give the title compound (0.6 g).
[1419] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.29(3H, t, J=7.1 Hz),
2.78(3H, s), 3.04(3H, s), 4.30(2H, q, J=7.1 Hz), 7.31(1H, dd,
J=8.0, 1.4 Hz), 7.45(1H, d, J=1.4 Hz), 7.48(1H, d, J=8.0 Hz),
12.29(1H, s).
Referential Example 289
5-chloro-3-[(dimethylamino)carbonyl]indole-2-carboxylic acid
##STR00359##
[1421] In a manner similar to that employed in Referential Example
286, the title compound was prepared from the compound obtained in
Referential Example 288.
[1422] .sup.1H-NMR(DMSO-d.sub.6).delta.: 2.91 (6H, s), 7.29(1H, d,
J=8.0 Hz), 7.44 (1H, d, J=8.0 Hz), 7.47(1H, s), 12.16(1H, s).
Referential Example 290
5-(phenylsulfonyl)-5,6-dihydro-4H-pyrolo[3,4-d]thiazole
##STR00360##
[1424] Benzenesulfonamide (638 mg) and 4,5-bis(bromomethyl)thiazole
(M. Al. Hariri, O. Galley, F. Pautet, H. Fillion, Eur. J. Org.
Chem., pp. 593-594 (1998)) (1.10 g) were dissolved in
N,N-dimethylformamide (10 mL) under ice cooling, and sodium hydride
(60% in oil, 357 mg) was added thereto at a time, followed by
stirring at room temperature for 3 hours. The resultant mixture was
partitioned between water and methylene chloride, and the organic
layer was dried over sodium sulfate anhydrate. The solvent was
distilled away, and the residue was purified by silica gel column
chromatography (methylene chloride:ethyl acetate=9:1), to thereby
give the title compound (137 mg).
[1425] .sup.1H-NMR(CDCl.sub.3).delta.: 4.60-4.63(2H, m),
4.70-4.73(2H, m), 7.52-7.64(3H, m), 7.88-7.92(2H, m), 8.71(1H,
s).
[1426] MS(FAB)m/z: 267(M+H).sup.+.
Referential Example 291
5,6-dihydro-4H-pyrolo[3,4-d]thiazole dihydrobromide
##STR00361##
[1428] A mixture of the compound obtained in Referential Example
290 (800 mg), phenol (800 .mu.L), and 47% aqueous hydrobromic acid
(5.00 mL) was heated under reflux for 2 hours. After the resultant
mixture was cooled to room temperature, the mixture was partitioned
between ethyl acetate and water. The solvent of the aqueous layer
was distilled away under reduced pressure. After ethyl acetate was
added to the residue, the resultant precipitate was collected by
filtration, and was dried, to thereby give the title compound (521
mg).
[1429] .sup.1H-NMR(DMSO-d.sub.6).delta.: 4.42(2H, br s), 4.56(2H,
br s), 9.14(1H, s).
[1430] MS(FAB)m/z: 127(M+H).sup.+.
Referential Example 292
5-methyl-5,6-dihydro-4H-pyrolo[3, 4-d]thiazole
##STR00362##
[1432] In a manner similar to that employed in Referential Example
9, the title compound was prepared from the compound obtained in
Referential Example 291.
[1433] .sup.1H-NMR(CDCl.sub.3).delta.: 2.67(3H, s), 3.95-3.99(2H,
m), 4.01-4.05(2H, m), 8.69(1H, s).
[1434] MS(ESI)m/z: 141(M+H).sup.+.
Referential Example 293]5-methyl-5,6-dihydro-4H-pyrolo[3,
4-d]thiazole-2-carboxylic acid lithium salt
##STR00363##
[1436] In a manner similar to that employed in Referential Example
5, the title compound was prepared from the compound obtained in
Referential Example 292.
[1437] .sup.1H-NMR(DMSO-d.sub.6).delta.: 2.52 (3H, s), 3.73(2H, t,
J=3.2 Hz), 3.87(2H, t, J=3.2 Hz).
Referential Example 294
(1R, 2S,
5S)-2-[(6-chloro-2-naphthoyl)amino]-5-[(dimethylamino)carbonyl]cy-
clohexylcarbamic acid tert-butyl ester
##STR00364##
[1439] In a manner similar to that employed in Referential Example
97, the title compound was prepared from the compound obtained in
Referential Example 144 and 6-chloronaphthalene-2-carboxylic acid
(Eur. J. Chem-Chim. Ther., vol. 19, pp. 205-214 (1984)).
[1440] .sup.1H-NMR(CDCl.sub.3).delta.: 1.30-2.00(15H, m),
2.60-2.80(1H, m), 2.96(3H, s), 3.09(3H, s), 4.00-4.20(1H, m),
4.20-4.30(1H, m), 4.75-4.95(1H, m), 7.44(1H, d, J=9.0 Hz),
7.70-7.95(5H, m), 8.31(1H, s).
[1441] MS(FAB)m/z: 474(M+H).sup.+.
Referential Example 295
(E)-3-(morpholin-4-yl)-2-acrylic acid ethyl ester
##STR00365##
[1443] Propionic acid ethyl ester (2.0 mL) was dissolved in
methylene chloride (20 mL), and morpholine (1.70 mL) was added
dropwise thereto under ice cooling, followed by stirring at room
temperature for 1 hour. The resultant mixture was concentrated
under reduced pressure, and the residue was purified by silica gel
column chromatography (methylene chloride:methanol=20:1), to
thereby give the title compound (3.72 g).
[1444] .sup.1H-NMR(CDCl.sub.3).delta.: 1.26(3H, t, J=7.1 Hz),
3.21(4H, t, J=5.1 Hz), 3.71(4H, t, J=5.1 Hz), 4.14(2H, q, J=7.1
Hz), 4.70(1H, d, J=13.4 Hz), 7.36(1H, d, J=13.4 Hz).
[1445] MS(FAB)m/z: 186(M+H).sup.+.
Referential Example 296
3-chlorobenzenediazonium tetrafluoroborate
##STR00366##
[1447] 3-Chloroaniline (2.0 g) was dissolved in a solvent mixture
of water (30 mL) and concentrated HCl (3.5 mL), and sodium nitrite
(1.30 g) was added thereto under ice cooling, followed by stirring
for 10 minutes. To the resultant mixture were added concentrated
HCl (5.3 mL) and sodium tetrafluoroborate (6.90 g), followed by
stirring for 30 minutes under ice cooling. The precipitate was
collected by filtration, and was washed with water, methanol, and
diethyl ether, to thereby give the title compound (2.63 g). The
compound was directly used for the next reaction.
Referential Example 297
7-chlorocinnoline-3-carboxylic acid ethyl ester
##STR00367##
[1449] The compound obtained in Referential Example 295 (1.45 g)
was dissolved in acetonitrile (100 mL), and the compound obtained
in Referential Example 296 (1.73 g) was added thereto. The
thus-obtained mixture was stirred at room temperature for 1 hour,
and was heated under reflux for 7 days. The solvent was distilled
away under reduced pressure, and the residue was purified by silica
gel column chromatography (methylene chloride.fwdarw.methylene
chloride:ethyl acetate=10:1, followed by hexane:ethyl
acetate=4:1.fwdarw.1:1), to thereby give the title compound (0.25
g).
[1450] .sup.1H-NMR(CDCl.sub.3).delta.: 1.53(3H, t, J=7.1 Hz),
4.62(2H, q, J=7.1 Hz), 7.80(1H, dd, J=8.8, 2.0 Hz), 7.95(1H, d,
J=8.8 Hz), 8.64(1H, s), 8.68(1H, d, J=2.0 Hz).
Referential Example 298
7-chlorocinnoline-3-carboxylic acid
##STR00368##
[1452] In a manner similar to that employed in Referential Example
286, the title compound was prepared from the compound obtained in
Referential Example 297.
[1453] .sup.1H-NMR(DMSO-d.sub.6).delta.: 8.02 (1H, dd, J=8.8, 2.0
Hz), 8.34(1H, d, J=8.8 Hz), 8.70(1H, s), 8.90(1H, s).
[1454] MS(FAB)m/z: 209(M+H).sup.+.
Referential Example 299
(1R, 2S,
5S)-2-{[(7-chlorocinnolin-3-yl)carbonyl]amino}-5-[(dimethylamino)-
carbonyl]cyclohexylcarbamic acid tert-butyl ester
##STR00369##
[1456] In a manner similar to that employed in Referential Example
97, the title compound was prepared from the compound obtained in
Referential Example 144 and the compound obtained in Referential
Example 298.
[1457] .sup.1H-NMR(CDCl.sub.3).delta.: 1.36(9H, s), 1.80-2.20(5H,
m), 2.72(1H, m), 2.96(3H, s), 3.07(3H, s), 3.49(1H, d, J=3.7 Hz),
4.30-4.45(2H, m), 4.87(1H, br), 7.77(1H, dd, J=8.8, 2.0 Hz),
7.96(1H, d, J=8.8 Hz), 8.59(2H, br), 8.72(1H, s).
[1458] MS(FAB)m/z: 476(M+H).sup.+.
Referential Example 300
(1R, 2S,
5S)-2-{[(5-chloro-1H-benzimidazol-2-yl)carbonyl]amino)-5-[(dimeth-
ylamino)carbonyl]cyclohexylcarbamic acid tert-butyl ester
##STR00370##
[1460] To a solution of the compound obtained in Referential
Example 143 (235 mg) in tetrahydrofuran (5.0 mL) was added 10%
palladium on carbon (50 mg), and the thus-obtained mixture was
stirred at room temperature overnight under hydrogen atmosphere.
The reaction mixture was filtered, and the filtrate was
concentrated. The residue and 5-chlorobenzimidazole-2-carboxylic
acid (Bull. Chem. Soc. Jpn., vol. 62, p. 2668 (1989)) (165 mg) were
dissolved in N,N-dimethylformamide (5.0 mL), and to the solution
were added 1-hydroxybenzotriazole monohydrate (100 mg) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (171
mg) at room temperature, followed by stirring for 4 days. The
reaction mixture was concentrated, and to the residue were added
methylene chloride, aqueous sodium hydrogencarbonate, and water to
partition the residue. The aqueous layer was extracted with
methylene chloride, and the organic layers were combined. The
combined organic layer was dried over sodium sulfate anhydrate, and
the solvent was distilled away under reduced pressure. The residue
was purified by silica gel flash column chromatography (methylene
chloride:methanol=10:1), to thereby give the title compound (250
mg).
[1461] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.01-2.00 (6H, m),
1.34(9H, s), 2.79(3H, s). 2.80-2.95(1H, m), 2.98(3H, s),
3.89-4.06(2H, m), 7.08(1H, d, J=6.6 Hz), 7.31(1H, d, J=8.5 Hz),
7.62(2H, br.s), 8.47(1H, d, J=8.5 Hz), 13.46(1H, br.s).
[1462] MS(ESI)m/z: 466(M+H).sup.+.
Referential Example 301
3-(4-fluorophenyl)-2-}[(4-methylphenyl)sulfonyl]amino}propionic
acid methyl ester
##STR00371##
[1464] 2-Amino-3-(4-fluorophenyl)propionic acid methyl ester (2.01
g), p-toluenesulfonyl chloride (2.25 g), and
4-dimethylaminopyridine (309 mg) were dissolved in chloroform (30
mL), and pyridine (3.0 mL) was added thereto, followed by heating
under reflux for 4.5 hours. Additional p-toluenesulfonyl chloride
(2.20 g) was added thereto, and the thus-obtained mixture was
heated under reflux for 3.5 hours. The reaction mixture was poured
into ice and 1N HCl (17 mL) to partition the mixture. The organic
layer was sequentially washed with saturated aqueous sodium
hydrogencarbonate and saturated brine, and was dried over sodium
sulfate anhydrate. The solvent was distilled away under reduced
pressure, and the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=9:1.fwdarw.2:1), to thereby
give the title compound (2.89 g).
[1465] .sup.1H-NMR(CDCl.sub.3).delta.: 2.41(3H, s), 2.90-3.10(2H,
m), 3.51(3H, s), 4.10-4.20(1H, m), 5.04(1H, d, J=9.0 Hz),
6.85-6.95(2H, m), 7.00-7.10(2H, m), 7.20-7.30(2H, m), 7.60-7.70(2H,
m).
[1466] MS(ESI)m/z: 352(M+H).sup.+.
Referential Example 302
7-fluoro-2-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydroisoquinoline-3-car-
boxylic acid methyl ester
##STR00372##
[1468] The compound obtained in Referential Example 301 (1.50 g)
and paraformaldehyde (207 mg) were dissolved in chloroform (40 mL),
and after the reaction vessel was purged with argon,
trifluoroborane-diethyl ether complex (1.20 mL) was added thereto,
followed by stirring at room temperature for 7.5 hours. The
reaction mixture was poured into ice and saturated aqueous sodium
hydrogencarbonate to partition the mixture, and the organic layer
was dried over sodium sulfate anhydrate. The solvent was distilled
away under reduced pressure, and the residue was purified by silica
gel column chromatography (hexane:ethyl acetate=3:1), to thereby
give the title compound (1.45 g).
[1469] .sup.1H-NMR(CDCl.sub.3).delta.: 2.42(3H, s), 3.15(2H, d,
J=3.9 Hz), 3.46(3H, s), 4.45(1H, d, J=15.9 Hz), 4.69(1H, d, J=15.9
Hz), 5.01(1H, t, J=4.4 Hz), 6.70-6.80 (1H, m), 6.80-6.90(1H, m),
7.00-7.10(1H, m), 7.29(2H, d, J=8.1 Hz), 7.72(2H, d, J=8.3 Hz).
[1470] MS(ESI)m/z: 364(M+H).sup.+.
Referential Example 303
7-fluoroisoquinoline-3-carboxylic acid methyl ester
##STR00373##
[1472] The compound obtained in Referential Example 302 (1.45 g)
was dissolved in N,N-dimethylformamide (40 mL), and oxygen gas was
introduced into the reaction mixture, followed by stirring at
100.degree. C. for 3.5 hours. The reaction mixture was concentrated
under reduced pressure, and the residue was partitioned between
saturated aqueous sodium hydrogencarbonate and methylene chloride.
The organic layer was sequentially washed with 10% aqueous citric
acid and saturated brine, and was dried over sodium sulfate
anhydrate. The solvent was distilled away under reduced pressure,
and the residue was purified by silica gel column chromatography
(hexane:ethyl acetate=1:1), to thereby give the title compound
(0.59 g).
[1473] .sup.1H-NMR(CDCl.sub.3).delta.: 4.07(3H, s), 7.55-7.65(1H,
m), 7.65-7.75(1H, m), 8.00-8.05(1H, m), 8.61(1H, s), 9.30(1H,
s).
[1474] MS(ESI)m/z: 206(M+H).sup.+.
Referential Example 304
7-fluoroisoquinoline-3-carboxylic acid hydrochloride
##STR00374##
[1476] The compound obtained in Referential Example 303 (1.45 g)
was dissolved in concentrated HCl (18 mL), and the solution was
heated under reflux for 2.5 hours. The reaction mixture was cooled,
and the precipitated crystals were collected by filtration. The
crystals were washed with water, and was dried, to thereby give the
title compound (0.46 g).
[1477] .sup.1H-NMR(DMSO-d.sub.6).delta.: 7.90-8.00(1H, m),
8.15-8.25(1H, m), 8.40-8.50(1H, m), 8.82(1H, s), 9.55(1H, s).
[1478] MS(FAB)m/z: 192(M+H).sup.+.
Referential Example 305
7-chloro-2H-chromene-3-carboxylic acid ethyl ester
##STR00375##
[1480] 4-Chloro-2-hydroxybenzaldehyde (Acta. Chem. Scand., vol. 53,
p. 258 (1999)) (510 mg) was dissolved in tetrahydrofuran (40 mL),
and sodium hydride (60% in oil, 157 mg) was added thereto, followed
by stirring at room temperature for 2 hours. To the reaction
mixture was added a solution of 2-diethylphosphonoacrylic acid
ethyl ester (J. Org. Chem., vol. 43, p. 1256 (1978)) (769 mg) in
tetrahydrofuran (10 mL), and the thus-obtained mixture was stirred
at room temperature for 2 hours, followed by heating under reflux
overnight. After the reaction mixture was cooled to room
temperature, the mixture was partitioned between water and diethyl
ether. The organic layer was dried over sodium sulfate anhydrate,
and the solvent was distilled away under reduced pressure. The
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=10:1), to thereby give the title compound
(247 mg).
[1481] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.33(3H, t, J=7.1 Hz),
4.27(2H, q, J=7.1 Hz), 4.99(2H, d, J=1.2 Hz), 6.85(1H, d, J=1.2
Hz), 6.89(1H, dd, J=8.1, 2.0 Hz), 7.04(1H, d, J=8.1 Hz), 7.38(1H,
d, J=1.0 Hz).
[1482] MS(EI)m/z: 238(M.sup.+).
Referential Example 306
7-chloro-2H-chromene-3-carboxylic acid
##STR00376##
[1484] In a manner similar to that employed in Referential Example
274, the title compound was prepared from the compound obtained in
Referential Example 305.
[1485] .sup.1H-NMR(DMSO-d.sub.6).delta.: 4.92 (1H, d, J=2.0 Hz),
6.95(1H, d, J=2.0 Hz), 7.01(1H, dd, J=8.1, 2.2 Hz), 7.35(1H, d,
J=8.1 Hz), 7.44(1H, s). MS(EI)m/z: 210(M).sup.+.
Referential Example 307
(1R, 2S,
5S)-2-{[(E)-3-(4-chlorophenyl)-2-propenoyl]amino}-5-[(dimethylami-
no)carbonyl]cyclohexylcarbamic acid tert-butyl ester
##STR00377##
[1487] In a manner similar to that employed in Referential Example
97, the title compound was prepared from the compound obtained in
Referential Example 144 and 4-chlorocinnamic acid.
[1488] .sup.1H-NMR(CDCl.sub.3).delta.: 1.30-1.55(3H, m), 1.48(9H,
s), 1.60-2.30(4H, m), 2.57-2.70(1H, m), 2.95(3H, s), 3.06(3H, s),
4.01(1H, br s), 4.10-4.20(1H, m), 4.78(1H, br.s), 6.30(1H, d,
J=15.6 Hz), 7.02(1H, s), 7.31(2H, d, J=8.5 Hz), 7.40(2H, d, J=8.5
Hz), 7.52(1H, d, J=15.6 Hz).
[1489] MS(ESI)m/z: 450(M+H).sup.+.
Referential Example 308
6-chloro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid methyl
ester
##STR00378##
[1491] Dimethyl acetylenedicarboxylate (13.5 mL) was added to a
solution of 4-chloroaniline (12.76 g) in methanol (150 mL), and the
thus-obtained mixture was heated under reflux for 8 hours. The
reaction mixture was concentrated under reduced pressure, and the
residue was dissolved in diphenyl ether (70 mL), followed by
stirring at 240.degree. C. for 4 hours. After the reaction mixture
was cooled, a solvent mixture of hexane and diethyl ether was added
thereto. The precipitated crystals were collected by filtration,
and were washed, to thereby give the title compound (11.09 g).
[1492] .sup.1H-NMR(DMSO-d.sub.6).delta.: 3.97(3H, s), 7.76(1H, dd,
J=9.0, 2.5 Hz), 7.90-8.05(2H, m), 12.28(1H, br.s).
[1493] MS(ESI)m/z: 238(M+H).sup.+.
Referential Example 309
6-chloro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid
##STR00379##
[1495] In a manner similar to that employed in Referential Example
286, the title compound was prepared from the compound obtained in
Referential Example 308.
[1496] .sup.1H-NMR(DMSO-d.sub.6).delta.: 6.90-7.05(1H, m),
7.90-8.05(2H, m), 10.10-10.30(1H, m), 12.13(1H, br.s).
[1497] MS(ESI)m/z: 224(M+H).sup.+.
Referential Example 310
(1R, 2S,
5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)
carbonyl]cyclohexylcarbamic acid tert-butyl ester
##STR00380##
[1499] To a solution of the compound obtained in Referential
Example 97 (5.00 g) in tetrahydrofuran (40 mL) were added water (10
mL) and lithium hydroxide (263 mg), and the thus-obtained mixture
was stirred at room temperature overnight. The reaction mixture was
filtered, and the filtrate was concentrated. The residue and
dimethylamine hydrochloride (1.85 g) were dissolved in
N,N-dimethylformamide (100 mL), and to the solution were added
1-hydroxybenzotriazole monohydrate (1.75 g),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.32
g), and diisopropylethylamine (11.3 mL) at room temperature,
followed by stirring for 2 days. The reaction mixture was
concentrated, and to the residue were added methylene chloride,
aqueous sodium hydrogencarbonate, and water to partition the
residue. The aqueous layer was extracted with methylene chloride,
and the organic layers were combined. The combined organic layer
was dried over sodium sulfate anhydrate, and the solvent was
distilled away under reduced pressure. The residue was purified by
silica gel column chromatography (methylene
chloride:acetone=2:1.fwdarw.1:1), to thereby give the title
compound (4.59 g).
[1500] .sup.1H-NMR(CDCl.sub.3).delta.: 1.60-1.76(2H, m), 1.73(9H,
s), 1.76-1.87(1H, m), 1.93(1H, br.s), 2.14(1H, br.s), 2.28(1H,
br.s), 2.65(1H, br.s), 2.95(3H, s), 3.05(3H, s), 4.01(1H, br.s),
4.21(1H, br.s), 4.84(1H, br.s), 6.81(1H, br.s), 7.20(1H, dd, J=8.8,
1.9 Hz), 7.36(1H, d, J=8.8 Hz), 7.59(1H, br.s), 8.02(1H, br.s),
10.06(1H, br.s).
[1501] MS(FAB)m/z: 465(M+H).sup.+.
Referential Example 311
(1R, 2S,
5S)-2-{[(5-fluoroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)car-
bonyl]cyclohexylcarbamic acid tert-butyl ester
[1502] ##STR00381## [1503] 1) In a manner similar to that employed
in Referential Example 91,
(1S,3R,4S)-3-[(tert-butoxycarbonyl)amino]-4-{[(5-fluoroindol-2-yl)carbony-
l]amino}cyclohexanecarboxylic acid ethyl ester was prepared from
the compound obtained in Referential Example 96 and
5-fluoroindole-2-carboxylic acid.
[1504] .sup.1H-NMR(CDCl.sub.3).delta.: 1.26(3H, t, J=7.1 Hz),
1.52(9H, s), 1.67-2.41(7H, m), 3.97(1H, br.s), 4.15(2H, q, J=7.1
Hz), 4.08-4.22(1H, m), 6.83(1H, s), 7.00-7.05(1H, m), 7.32-7.36(1H,
m), 8.02(1H, s), 9.51(1H, s).
[1505] MS(FAB)m/z: 448(M+H).sup.+. [1506] 2) In a manner similar to
that employed in Referential Example 310, the title compound was
prepared from the above-described compound.
[1507] .sup.1H-NMR(CDCl.sub.3).delta.: 1.52(9H, s), 1.57-1.79(2H,
m), 1.79-2.00(2H, m), 2.14(1H, br.s), 2.31(1H, br.s), 2.65(1H,
br.s), 2.95(3H, s), 3.07(3H, s), 4.02(1H, br.s), 4.17-4.25(1H, m),
4.80(1H, br.s), 6.82(1H, br.s), 7.02(1H, dt, J=2.3, 9.0 Hz),
7.24(1H, br.s), 7.35(1H, dd, J=9.0, 4.3 Hz), 7.91(1H, br.s),
9.49(1H, br.s).
[1508] MS(FAB)m/z: 447(M+H).sup.+.
Referential Example 312
2-amino-6,6-dimethyl-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylic
acid ethyl ester
##STR00382##
[1510] Cuprous cyanide (918 mg) was suspended in tetrahydrofuran
(50 mL) under argon flow, and after the suspension was cooled to
-20.degree. C., n-butyllithium (as 1.56N hexane solution, 6.41 mL)
was added dropwise thereto over 5 minutes, followed by stirring at
-20.degree. C. for 30 minutes. The reaction mixture was cooled to
-50.degree. C., and diisobutylaluminium hydride (as 1.00M hexane
solution) was added dropwise thereto over 20 minutes, followed by
stirring at -50.degree. C. for 1 hour. To the reaction mixture was
added dropwise a solution of
2,2-dimethyl-5-oxo-5,6-dihydro-2H-pyridine-1-carboxylic acid ethyl
ester (Hely. Chim. Acta, vol. 81, p. 303 (1998)) (986 mg) in
tetrahydrofuran (5 mL) over 5 minutes, followed by stirring at
-50.degree. C. for 2 hours. The resultant mixture was heated to
-20.degree. C., and bromine (4.90 mL) was added thereto at a time,
followed by stirring at -20.degree. C. for 30 minutes. The reaction
mixture was partitioned between water and ethyl acetate. The
organic layer was washed with saturated aqueous sodium sulfite, and
was dried over anhydrous magnesium sulfate. The solvent was
distilled away, and the residue was dissolved in
N,N-dimethylformamide (10 mL). Thiourea (760 mg) was added thereto,
and the thus-obtained mixture was stirred at 50.degree. C.
overnight. The solvent was distilled away, and the residue was
partitioned between methylene chloride and saturated aqueous sodium
hydrogencarbonate. The organic layer was dried over sodium sulfate
anhydrate, and the solvent was distilled away. The residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=4:1), to thereby give the title compound (412
mg).
[1511] .sup.1H-NMR(CDCl.sub.3).delta.: 1.25(3H, t, J=7.1 Hz),
1.54(6H, s), 2.65-2.67(2H, m), 4.09(2H, q, J=7.1 Hz), 4.44-4.46(2H,
m), 4.78(2H, br.s).
Referential Example 313
2-bromo-6,6-dimethyl-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylic
acid ethyl ester
##STR00383##
[1513] Cupric bromide (431 mg) was suspended in acetonitrile (8
mL), and tert-butyl nitrite (249 mg) was added dropwise thereto at
room temperature. To the reaction mixture was added a solution of
the compound obtained in Referential Example 312 (412 mg) in
acetonitrile (8 mL) under ice cooling, and the thus-obtained
mixture was heated to 50.degree. C., followed by stirring for 15
minutes. The solvent was distilled away, and the residue was
partitioned between diethyl ether and 10% HCl. The organic layer
was dried over anhydrous magnesium sulfate, and was concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane:ethyl acetate=6:1), to thereby give
the title compound (151 mg).
[1514] .sup.1H-NMR(CDCl.sub.3).delta.: 1.26(3H, t, J=7.1 Hz),
1.55(6H, s), 2.79-2.81(2H, m), 4.10(2H, q, J=7.1 Hz), 4.65-4.67(2H,
m).
[1515] MS(ESI)m/z: 319(M+H).sup.+.
Referential Example 314
6,6-dimethyl-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylic
acid ethyl ester
##STR00384##
[1517] To a solution of the compound obtained in Referential
Example 313 (432 mg) in diethyl ether (5 mL) was added
n-butyllithium (as 1.56N hexane solution, 1.04 mL) at -78.degree.
C., and the thus-obtained mixture was stirred at -78.degree. C. for
30 minutes. The reaction mixture was partitioned between water and
diethyl ether, and the organic layer was dried over anhydrous
magnesium sulfate. The solvent was distilled away, to thereby give
the title compound (307 mg).
[1518] .sup.1H-NMR(CDCl.sub.3).delta.: 1.28(3H, t, J=7.1 Hz),
1.55(6H, s), 2.90(2H, s), 4.12(2H, q, J=7.1 Hz), 4.75(2H, m),
8.63(1H, s).
Referential Example 315
6,6-dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine
##STR00385##
[1520] The compound obtained in Referential Example 314 (307 mg)
was dissolved in a solvent mixture of water (5 mL), ethanol (5 mL),
and dioxane (5 mL), and lithium hydroxide (598 mg) was added to the
reaction mixture, followed by heating under reflux for 7 days. The
resultant mixture was left to cool to room temperature, and was
partitioned between water and methylene chloride. The aqueous layer
was extracted with methylene chloride 6 times, and the organic
layer was dried over sodium sulfate anhydrate. The solvent was
distilled away, to thereby give the title compound (207 mg).
[1521] .sup.1H-NMR(CDCl.sub.3).delta.: 1.23(6H, s), 2.71-2.73(2H,
m), 4.09-4.11(2H, m), 8.61(1H, s).
[1522] MS(ESI)m/z: 168(M.sup.+).
Referential Example 316
6,6-dimethyl-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylic
acid tert-butyl ester
##STR00386##
[1524] The compound obtained in Referential Example 315 (207 mg)
was dissolved in methylene chloride (5 mL), and to the solution
were added di-tert-butyl dicarbonate (404 mg) and
4-(N,N-dimethylamino)pyridine (151 mg), followed by stirring at
room temperature for 2 hours. After additional di-tert-butyl
dicarbonate (404 mg) was added thereto, the thus-obtained mixture
was stirred at room temperature overnight, and additional
di-tert-butyl dicarbonate (1.00 g) was further added thereto,
followed by stirring for 1 hour. The resultant mixture was
partitioned between methylene chloride and 10% aqueous HCl, and the
organic layer was dried over sodium sulfate anhydrate. The solvent
was distilled away, and the residue was purified by silica gel
column chromatography (hexane:ethyl acetate=4:1), to thereby give
the title compound (95.4 mg).
[1525] .sup.1H-NMR(CDCl.sub.3).delta.: 1.47(9H, s), 1.52(6H, s),
2.87(2H, s), 4.69(2H, s), 8.62(1H, s).
[1526] MS(ESI)m/z: 269(M+H).sup.+.
Referential Example 317
4-chloro-5-(1,3-dioxolan-2-yl)thiazole-2-carboxylic acid lithium
salt
##STR00387##
[1528] 2,4-Dichlorothiazole-5-carbaldehyde ethylene acetal (J.
Chem. Soc. Perkin Trans. 1, p. 973 (1992)) (2.26 g) was dissolved
in tetrahydrofuran (15 mL), and n-butyllithium (as 1.5N hexane
solution, 6.8 mL) was added thereto while being cooled with dry
ice-acetone. After the reaction mixture was stirred for 20 minutes,
carbon dioxide gas was introduced into the mixture at the same
temperature. The reaction mixture was gradually heated to room
temperature over 1.5 hours, and the mixture was concentrated under
reduced pressure. Hexane was added to the residue, and the
resultant powder was collected by filtration. The powder was
suspended in ethyl acetate, and the powder was collected by
filtration again, to thereby give the title compound (1.65 g).
Referential Example 318
4-chloro-5-(1,3-dioxolan-2-yl)thiazole-2-carboxylic acid ethyl
ester
##STR00388##
[1530] The compound obtained in Referential Example 317 (242 mg)
and ethanol (0.2 mL) were dissolved in N,N-dimethylformamide (2
mL), and to the solution were added 1-hydroxybenzotriazole
monohydrate (136 mg) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (250
mg), followed by stirring at room temperature overnight. The
solvent was concentrated under reduced pressure, and diethyl ether
and diluted HCL were added thereto. The organic layer was
separated, and was washed with water and saturated aqueous sodium
hydrogencarbonate, followed by drying over anhydrous magnesium
sulfate. The solvent was distilled away under reduced pressure, to
thereby give the title compound (170 mg).
[1531] .sup.1H-NMR(CDCl.sub.3).delta.: 1.43(3H, t, J=7.3 Hz),
4.00-4.10(2H, m), 4.10-4.20(2H, m), 4.48(2H, q, J=7.3 Hz), 6.15(1H,
s).
[1532] MS(ESI)m/z: 264(M+H).sup.+.
Referential Example 319
4-chloro-5-formylthiazole-2-carboxylic acid ethyl ester
##STR00389##
[1534] The compound obtained in Referential Example 318 (132 mg)
was dissolved in diethyl ether (5 mL), and 20% aqueous HCl (0.3 mL)
was added thereto, followed by stirring at room temperature for 7
hours. Saturated aqueous sodium hydrogencarbonate was added to the
reaction mixture, and the thus-obtained mixture was extracted with
diethyl ether, followed by drying over anhydrous magnesium sulfate.
The solvent was distilled away under reduced pressure, to thereby
give the title compound (110 mg).
[1535] .sup.1H-NMR(CDCl.sub.3).delta.: 1.46(3H, t, J=7.1 Hz),
4.52(2H, q, J=7.1 Hz), 10.12(1H, s).
Referential Example 320
4-azido-5-formylthiazole-2-carboxylic acid ethyl ester
##STR00390##
[1537] The compound obtained in Referential Example 319 (5.15 g)
was dissolved in dimethyl sulfoxide (30 mL), and sodium azide (1.52
g) was added thereto, followed by stirring at room temperature for
2.5 hours. Ice water was added to the reaction mixture, and the
thus-obtained mixture was extracted with diethyl ether. The extract
was washed with water twice, and was dried over anhydrous magnesium
sulfate. The solvent was distilled away under reduced pressure, and
the residue was purified by silica gel column chromatography
(methylene chloride:methanol=24:1), to thereby give the title
compound (1.78 g).
[1538] .sup.1H-NMR(CDCl.sub.3).delta.: 1.45(3H, t, J=7.1 Hz),
4.50(2H, q, J=7.1 Hz), 9.95(1H, s).
Referential Example 321
Ethyl
6-methyl-6,7-dihydrothiazolo[4,5-d]pyrimidine-2-carboxylate
##STR00391##
[1540] The compound (1.56 g) obtained in Referential Example 320
was dissolved in methylene chloride (20 mL), and acetic acid (2
mL), methylamine (2N tetrahydrofuran solution, 21 mL), and sodium
triacetoxyborohydride (2.98 g) were added to the solution, followed
by stirring. After 1 hour, sodium triacetoxyborohydride (2.98 g)
was additionally added to the mixture, and the stirring was
continued for additional 4.5 hours. 0.5N Aqueous sodium hydroxide
(100 mL) was added to the reaction mixture to alkalify it. After
the reaction mixture was extracted with methylene chloride, the
extract was dried over magnesium sulfate anhydrate. The solvent was
distilled away under reduced pressure, to thereby give a brown oil
(1.43 g). This oil was dissolved in ethanol (50 mL), and 10%
palladium on carbon (2.0 g) was added to the solution, followed by
hydrogenation at normal temperature and normal pressure. After 2.5
hours, the catalyst was removed by filtration, and the filtrate was
concentrated. The residue was dissolved in methylene chloride (30
mL), and trimethyl orthoformate (0.7 mL) and boron
trifluoride-diethyl ether complex (0.3 mL) were added to the
solution, followed by stirring at room temperature for 15 hours.
Saturated aqueous sodium hydrogencarbonate was added to the
reaction mixture, and the resultant mixture was extracted with
methylene chloride. The extract was dried over sodium sulfate
anhydrate. The solvent was distilled away under reduced pressure,
and the residue was purified by silica gel column chromatography
(methylene chloride:methanol=97:3), to thereby give the title
compound (100 mg).
[1541] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.41(3H,t,J=7.1 Hz),
2.95(3H,s), 4.44(2H,q,J=7.1 Hz), 4.87(2H,s), 7.06(1H,s).
[1542] MS (ESI) m/z: 226(M+H).sup.+.
Referential Example 322
Lithium
6-methyl-6,7-dihydrothiazolo[4,5-d]pyrimidine-2-carboxylate
##STR00392##
[1544] The compound (463 mg) obtained in Referential Example 321
was dissolved in tetrahydrofuran (20 mL), and lithium hydroxide
(54.1 mg) and water (4 mL) were added to the solution, followed by
stirring at room temperature for 4.5 hours. The solvent was
distilled away under reduced pressure, and the residue was dried by
means of a vacuum pump, to thereby give the title compound (460
mg).
[1545] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.86(3H,s), 4.71(2H,s),
7.03(1H,s).
Referential Example 323
tert-Butyl
(1R,2S,5S)-2-azido-5-{[ethyl(methyl)amino]carbonyl}cyclohexylca-
rbamate
##STR00393##
[1547] The title compound was obtained by condensing the compound
obtained in Referential Example 250 with ethylmethylamine.
[1548] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.08,1.18(total 3H,each
t,J=7.1 Hz), 1.46(9H,s), 1.52-1.80(4H,m), 2.04-2.08(2H,m),
2.71-2.77(1H,m), 2.89,2.98(total 3H,each s), 3.32,3.39(total
2H,each q,J=7.1 Hz), 3.74-3.76(1H,m), 4.09-4.11(1H,m),
4.60(1H,br.s).
[1549] MS (EI) m/z: 326(M+H).sup.+.
Referential Example 324
tert-Butyl
(1R,2S,5S)-2-{[(7-chloroisoquinolin-3-yl)carbonyl]amino}-5-{[et-
hyl(methyl)amino]carbonyl}cyclohexylcarbamate
##STR00394##
[1551] The compound (1.44 g) obtained in Referential Example 323
was dissolved in methanol (20 mL), 10% palladium on carbon (150 mg)
was added, and the mixture was stirred under a hydrogen atmosphere.
After 24 hours, the catalyst was removed by filtration, and the
solvent was then concentrated under reduced pressure, to thereby
give a colorless oil. This oil as such was used in the next
reaction.
[1552] The above-obtained oil was dissolved in methylene chloride
(30 mL), and the compound (850 mg) obtained in Referential Example
57, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(1.27 g), 1-hydroxybenzotriazole monohydrate (900 mg), and
N-methylmorpholine (1.34 g) were added to the solution, followed by
stirring at room temperature. After 17 hours had elapsed, methylene
chloride and saturated aqueous sodium hydrogencarbonate were added
to the reaction mixture for partitioning the mixture, and the
resultant organic layer was dried over magnesium sulfate anhydrate.
The solvent was distilled away under reduced pressure, and the
residue was subjected to silica gel column chromatography
(methanol:methylene chloride=1:50), to thereby give the title
compound (1.61 g).
[1553] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10,1.22(total 3H, each
t, J=7.1 Hz), 1.43(9H,s), 1.84-2.17(6H,m), 2.66(1H,br.s), 2.92,
3.03(total 3H,each s), 3.35-3.44(2H,m), 4.20-4.30(2H,m),
5.30(1H,br.s), 7.70(1H,d,J=8.6 Hz), 7.92(1H,d,J=8.6 Hz),
8.00(1H,s), 8.40(1H,br.s), 8.56(1H,s), 9.03(1H,s).
[1554] MS (FAB) m/z: 489(M+H).sup.+.
Referential Example 325
N-((1S,2R,4S)-2-Amino-4-[(7-chloroisoquinolin-3-yl)-carbonyl]-4-{[ethyl(me-
thyl)amino]carbonyl}cyclohexyl)-7-chloroisoquinoline-3-carboxamide
##STR00395##
[1556] The compound (1.60 g) obtained in Referential Example 324
was dissolved in HCL-ethanol (25 mL), and the solution was stirred
at room temperature for 30 minutes. The solvent was distilled away
under reduced pressure, and methylene chloride and 1N aqueous
sodium hydroxide were added to the residue for partitioning the
mixture. The resultant aqueous layer was extracted with methylene
chloride, and the organic layers were combined and dried over
potassium carbonate. The solvent was distilled away under reduced
pressure, hexane was added to the residue, and precipitate was
collected by filtration, to thereby give the title compound (1.22
g).
[1557] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.10,1.23(total 3H,each
t,J=7.1 Hz), 1.26(2H,br.s), 1.69-2.11(6H,m), 2.89(1H,br.s),
2.93,3.05(total 3H,each s), 3.38-3.45(2H,m), 3.52(1H,s),
4.18(1H,br.s), 7.70(1H,dd,J=8.8,2.0 Hz), 7.94(1H,d,J=8.8 Hz),
8.02(1H,d,J=2.0 Hz), 8.50(1H,br.s), 8.59(1H,s), 9.11(1H,s).
[1558] MS (FAB) m/z: 389(M+H).sup.+.
Referential Example 326
Ethyl
(1R*,3S*,4S*)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(diphenyl-
)silyl]oxy}cyclohexanecarboxylate
##STR00396##
[1560] The compound (28.0 g) obtained in Referential Example 88 was
dissolved in N,N-dimethylformamide (500 mL), and
tert-butyldiphenylsilyl chloride (63.5 mL) and imidazole (19.9 g)
were added. After the mixture was stirred at room temperature for
10 hours, ethyl acetate and water were added to the reaction
mixture for partitioning the mixture. The resultant aqueous layer
was extracted with ethyl acetate, and the organic layers were
combined, washed twice with water and dried over sodium sulfate
anhydrate. After the solvent was distilled away under reduced
pressure, the residue was purified by silica gel column
chromatography (methylene chloride:methanol=1:0.fwdarw.47:3), to
thereby give the title compound (52.5 g) containing 0.4 molecules
of N,N-dimethylformamide.
[1561] .sup.1H-NMR (CDCl.sub.3) 1.07(9H,s), 1.27(3H,t,J=7.1 Hz),
1.38(9H,s), 1.43-1.59(3H,m), 1.63-1.67(1H,m), 1.92-1.98(1H,m),
2.25-2.32(1H,m), 2.37-2.42(1H,m), 3.66(1H,br.s), 3.80(1H,br.s),
4.16(2H,q,J=7.1 Hz), 4.32(1H,d,J=8.1 Hz), 7.34-7.46(6H,m),
7.65-7.73(4H,m).
Referential Example 327
tert-Butyl
(1R*,2R*,5S*)-2-{[tert-butyl(diphenyl)silyl}oxyl-5-(hydroxymeth-
yl)cyclohexanecarbmate
##STR00397##
[1563] Lithium aluminum hydride (7.11 g) was suspended in absolute
diethyl ether (100 mL) at 0.degree. C. while purging with argon,
and a diethyl ether solution (500 mL) of the compound (52.5 g)
obtained in Referential Example 326 was added dropwise over 30
minutes. After stirring at 0.degree. C. for 30 minutes, methanol
(100 mL) was added dropwise to the reaction mixture. The resultant
slurry was removed by filtration through Celite, and the filtrate
was concentrated. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate=3:1), to thereby give the
title compound (29.6 g).
[1564] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.07(9H,s),
1.32-1.74(16H,m), 1.87(1H,t,J=10.4 Hz), 3.35-3.55(2H,m),
3.71(1H,br.s), 3.79(1H,br.s), 4.36(1H,br.s), 7.34-7.44(6H,m),
7.65-7.72(4H,m).
Referential Example 328
((1R*,3S*,4S*)-3-[(tert-Butoxycarbonyl)amino]-4-{[tert-butyl(diphenyl)sily-
l]oxy}cyclohexyl)methyl methane-sulfonate
##STR00398##
[1566] The compound (29.5 g) obtained in Referential Example 327
was dissolved in methylene chloride (200 mL) and pyridine (20 mL).
To the solution, methanesulfonyl chloride (9.5 mL) was added, and
the mixture was stirred at room temperature for 6 hours. The
solvent was distilled away under reduced pressure, and ethyl
acetate and water were added to the residue for partitioning the
mixture. The resultant aqueous layer was extracted with ethyl
acetate, and the organic layers were combined, washed twice with
water and then dried over sodium sulfate anhydrate. The solvent was
distilled away under reduced pressure, and the residue was purified
by silica gel column chromatography (hexane:ethyl acetate=2:1), to
thereby give the title compound (29.8 g).
[1567] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.08(9H,s), 1.38(9H,s),
1.43-1.61(5H,m), 1.86-1.89(2H,m), 3.02(3H,s), 3.77(1H,br.s),
3.81(1H,br.s), 4.10(2H,d,J=5.4 Hz), 4.32(1H,br.s), 7.35-7.45(6H,m),
7.64-7.68(4H,m).
[1568] MS (ESI) m/z: 562(M+H).sup.+.
Referential Example 329
tert-Butyl
(1R*,2R*,5S*)-2-{[tert-butyl(diphenyl)silyl]oxy}-5-(cyanomethyl-
)cyclohexanecarbamate
##STR00399##
[1570] The compound (29.8 g) obtained in Referential Example 328
was dissolved in N,N-dimethylformamide (400 mL), and sodium cyanide
(3.64 g) was added to the solution, followed by stirring at
80.degree. C. for 11 hours. Ethyl acetate and saturated aqueous
sodium hydrogencarbonate were added to the reaction mixture for
partitioning the mixture. The resultant aqueous layer was extracted
twice with ethyl acetate, and the organic layers were combined,
washed with saturated aqueous sodium hydrogencarbonate and
saturated brine and then dried over sodium sulfate anhydrate. The
solvent was distilled away under reduced pressure, and the residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=5:1), to thereby give the title compound (20.6 g).
[1571] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.08(9H,s), 1.38(9H,s),
1.43-1.68(5H,m), 1.79-1.85(1H,m), 1.88-1.95(1H,m), 2.32(2H,d,J=7.1
Hz), 3.77(1H,br.s), 3.82(1H,br.s), 4.32(1H,br.d,J=6.8 Hz),
7.35-7.45(6H,m), 7.65-7.71(4H,m).
Referential Example 330
tert-Butyl
(1R*,2R*,5S*)-2-{[tert-butyl(diphenyl)silyl]oxy}-5-(2-oxoethyl)-
cyclohexanecarbamate
##STR00400##
[1573] The compound (2.00 g) obtained in Referential Example 329
was dissolved in absolute methylene chloride (20 mL), and the
system was purged with argon and then cooled to -78.degree. C. To
the solution, was added dropwise diisobutylaluminum hydride (0.95 M
hexane solution, 8.55 mL). The temperature of the mixture was then
allowed to elevate to room temperature, and the mixture was stirred
for 3 hours. The reaction mixture was cooled to 0.degree. C., and
methanol (10 mL) was added dropwise. The resultant slurry was
removed by filtration through Celite, and the filtrate was removed
under reduced pressure. The residue was purified by silica gel
column chromatography (methylene
chloride:methanol=1:0.fwdarw.49:1), to thereby give the title
compound (1.45 g).
[1574] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.07(9H,s), 1.38(9H,s),
1.43-1.54(5H,m), 1.82-1.88(1H,m), 2.06(1H,br.s), 2.42-2.43(2H,m),
3.72(1H,br.s), 3.77(1H,br.s), 4.38(1H,br.s), 7.34-7.44(6H,m),
7.65-7.68(4H,m), 9.77(1H,t,J=1.7 Hz).
[1575] MS (FAB) m/z: 496(M+H).sup.+.
Referential Example 331
2-((1R*,3S*,4S*)-3-[(tert-Butoxycarbonyl)amino]-4-{[tert-butyl(diphenyl)si-
lyl]oxy}cyclohexyl)acetic acid
##STR00401##
[1577] The compound (8.40 g) obtained in Referential Example 330
was dissolved in a solvent mixture of water (33 mL) and
tert-butanol (120 mL). To the solution, 2-methyl-2-butene (8.08
mL), sodium dihydrogenphosphate dihydrate (2.64 g), and sodium
chlorite (3.45 g) were added, and the mixture was stirred at room
temperature for 1.5 hours. Methylene chloride and water were added
to the reaction mixture for dilution. The resultant aqueous layer
was adjusted to pH of about 4 with 1N hydrochloric acid. The
mixture was partitioned, and the resultant aqueous layer was
extracted twice with methylene chloride. The organic layers were
combined and dried over magnesium sulfate anhydrate, and the
solvent was distilled away under reduced pressure. The residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=2:1.fwdarw.1:1), to thereby give the title compound (7.62
g).
[1578] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.07(9H,s),
1.22-1.63(15H,m), 1.82(1H,br.s), 2.17(1H,br.s), 2.27-2.33(1H,m),
3.69(1H,br.s), 3.84(1H,br.s), 7.00(1H,br.s), 7.33-7.42(6H,m),
7.63-7.65(4H,m).
[1579] MS (ESI) m/z: 512(M+H).sup.+.
Referential Example 332
tert-Butyl
(1R*,2R*,5S*)-2-{[tert-butyl(diphenyl)silyl]oxy}-5-[2-(dimethyl-
amino)-2-oxoethyl]cyclohexanecarbamate
##STR00402##
[1581] The compound (7.62 g) obtained in Referential Example 331
was dissolved in N,N-dimethylformamide (150 mL). To the solution,
dimethylamine hydrochloride (6.07 g),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.56
g), 1-hydroxybenzotriazole monohydrate (1.01 g), and triethylamine
(10.3 mL) were added, and the mixture was stirred at room
temperature for 4 days. The solvent was distilled away under
reduced pressure, and methylene chloride and saturated aqueous
sodium hydrogencarbonate were added to the residue for partitioning
the mixture. The resultant aqueous layer was extracted with
methylene chloride, and the organic layers were combined and dried
over sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure, and the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=1:1). The solvent was
distilled away, hexane was added to the residue, and formed white
precipitate was collected by filtration, to thereby give the title
compound (6.42 g).
[1582] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.08(9H,s), 1.38(9H,br.s),
1.43-1.55(5H,m), 1.79-1.86(1H,m), 2.03(1H,br.s), 2.21-2.32(2H,s),
2.94(3H,s), 3.03(3H,s), 3.74(1H,br.s), 3.80(1H,br.s),
4.49(1H,br.s), 7.33-7.44(6H,m), 7.64-7.69(4H,m).
[1583] MS (ESI) m/z: 539(M+H).sup.+.
Referential Example 333
tert-Butyl
(1R*,2R*,5S*)-5-[2-(dimethylamino)-2-oxoethyl]-2-hydroxycyclohe-
xanecarbamate
##STR00403##
[1585] The compound (6.36 g) obtained in Referential Example 332
was dissolved in tetrahydrofuran (50 mL), and tetrabutylammonium
fluoride (1N tetrahydrofuran solution, 17.85 mL) was added to the
solution, followed by stirring at room temperature for 13 hours.
The solvent was distilled away under reduced pressure, and the
residue was purified by flash silica gel column chromatography
(methylene chloride:methanol=24:1), to thereby give the title
compound (3.49 g).
[1586] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44(9H,s),
1.46-1.60(4H,m), 1.79-1.84(2H,m), 2.28-2.35(3H,s), 2.82(1H,br.s),
2.95(3H,s), 3.01(3H,s),3.56(2H,br.s), 4.67(1H,br.s).
[1587] MS (ESI) m/z: 301(M+H).sup.+.
Referential Example 334
(1R*,2R*,4S*)-2-[(tert-Butoxycarbonyl)amino]-4-[2-(dimethylamino)-2-oxoeth-
yl]cyclohexyl methanesulfonate
##STR00404##
[1589] The compound (8.05 mg) obtained in Referential Example 333
was dissolved in methylene chloride (50 mL), and the solution was
cooled to -78.degree. C. under an argon atmosphere to add dropwise
methanesulfonyl chloride (2.70 mL). After the temperature of the
mixture was allowed to elevate to 0.degree. C., the mixture was
stirred for 30 minutes and then stirred for 2 hours at room
temperature. Water was added to the reaction mixture for
partitioning the mixture, and the resultant aqueous layer was
extracted with methylene chloride. The organic layers were
combined, washed with water and dried over sodium sulfate
anhydrate. The solvent was distilled away under reduced pressure,
and the residue was purified by flash silica gel column
chromatography (hexane:ethyl acetate=1:1.fwdarw.0:1), to thereby
give the title compound (3.63 g).
[1590] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.43(9H,s),
1.59-1.74(4H,m), 1.85-2.30(5H,m), 2.95(3H,s), 3.00(3H,s),
3.10(3H,s), 3.79-3.83(1H,m), 4.72(1H,br.s), 4.91(1H,br.s).
[1591] MS (ESI) m/z: 379(M+H).sup.+.
Referential Example 335
tert-Butyl
(1R*,2S*,5S*)-2-azido-5-[2-(dimethylamino)-2-oxoethyl]cyclohexa-
necarbamate
##STR00405##
[1593] The compound (3.62 g) obtained in Referential Example 334
was dissolved in N,N-dimethylformamide (20 mL), and sodium azide
(3.11 g) was added to the solution, followed by stirring at
75.degree. C. for 17 hours. The reaction mixture was poured into a
solvent mixture of water and ethyl acetate for partitioning the
mixture. The resultant aqueous layer was extracted twice with ethyl
acetate, and the organic layers were combined, washed with water,
saturated aqueous sodium hydrogencarbonate and saturated brine and
dried over sodium sulfate anhydrate. The solvent was distilled away
under reduced pressure, and the residue was purified by flash
silica gel column chromatography (ethyl acetate), to thereby give
the title compound (1.30 g).
[1594] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14-1.21(1H,m),
1.33-1.40(1H,m), 1.45(9H,s), 1.61-1.71(1H,m), 1.78-1.91(3H,m),
2.22-2.27(3H,m), 2.94(3H,s), 3.00(3H,s), 3.60-3.62(1H,m),
3.97(1H,br.s), 4.76(1H,br.s).
[1595] MS (ESI) m/z: 326(M+H).sup.+.
Referential Example 336
N-{(1R*,2S*,4R*)-2-Amino-4-[2-(dimethylamino)-2-oxoethyl]cyclohexyl}-5-chl-
oroindole-2-carboxamide hydrochloride
##STR00406##
[1597] In a manner similar to that employed in Referential Example
324, the compound obtained in Referential Example 335 was
catalytically reduced, and the product was condensed with
5-chloroindole-2-carboxylic acid, followed by treatment in a manner
similar to that employed in Referential Example 69, to thereby give
the title compound.
[1598] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.16-1.19(1H,m),
1.51-1.56(1H,m), 1.70-1.73(1H,m), 1.81-1.91(2H,m), 1.99-2.03(1H,m),
2.19-2.30(3H,m), 2.83(3H,s), 2.99(3H,s), 3.63(1H,br.s),
4.08(1H,br.s), 7.19(1H,dd,J=8.7,1.7 Hz), 7.35(1H,s),
7.44(1H,d,J=8.7 Hz). 7.69(1H,d,J=1.7 Hz), 8.22(3H,br.s),
8.62(1H,d,J=7.1 Hz), 11.91(1H,s).
[1599] MS (ESI) m/z: 377(M+H).sup.+.
Referential Example 337
tert-Butyl
(1R,2S,5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-(hydroxyme-
thyl)cyclohexanecarbamate
##STR00407##
[1601] In a manner similar to that employed in step 2) of
Referential Example 129, the title compound was obtained from the
compound obtained in Referential Example 97.
Referential Example 338
((1S,3R,4S)-3-[(tert-butoxycarbonyl)amino]-4-{[(5-chloroindol-2-yl)carbony-
l]amino}cyclohexyl)methyl methanesulfonate
##STR00408##
[1603] The compound (500 mg) obtained in Referential Example 337
and triethylamine (329 mL) were suspended in tetrahydrofuran (8
mL)-methylene chloride (8 mL), and the suspension was cooled to
-78.degree. C. After methanesulfonyl chloride (138 mL) was added
dropwise to the suspension, the temperature of the suspension was
gradually elevated to -5.degree. C., and the suspension was stirred
for 15 hours at the same temperature. After the reaction mixture
was concentrated, water was added to the residue, and the mixture
was extracted 3 times with methylene chloride. The resultant
organic layers were washed with saturated brine and dried over
sodium sulfate anhydrate, and the solvent was then distilled away
under reduced pressure, to thereby give the title compound (654
mg).
[1604] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.57(9H,s),
1.84-2.01(4H,m), 2.28-2.31(1H,m), 3.04(3H,s), 3.68(1H,s),
3.74-3.75(1H, m), 3.91-3.93 (1H,m), 4.02-4.12 (2H,m), 4.18-4.20
(1H,m), 4.85(1H,br.s), 6.81(1H,s), 7.21(1H,dd,J=2.0,8.8 Hz),
7.34(1H,d,J=8.8 Hz), 7.60(1H,s), 8.02(1H,br.s), 9.27(1H,br.s).
[1605] MS (ESI) m/z: 500(M+H).sup.+.
Referential Example 339
tert-Butyl
(1R,2S,5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-[(methylsu-
lfanyl)methyl]cyclohexanecarbamate
##STR00409##
[1607] The compound (654 mg) obtained in Referential Example 338
was dissolved in N,N-dimethylformamide (8 mL), and 15% aqueous
sodium thiomethoxide (1.8 mL) was added to the solution, followed
by stirring at room temperature for 4 hours. The reaction mixture
was poured into water and extracted 3 times with ethyl acetate. The
resultant organic layers were washed with saturated brine, dried
over sodium sulfate anhydrate and then concentrated. The residue
was purified by silica gel column chromatography (methylene
chloride:methanol=24:1), to thereby give the title compound (492
mg).
[1608] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.52(9H,s),
1.87-3.04(13H,m), 3.91-3.94(1H,m), 4.12-4.15(1H,m), 4.95(1H,br.s),
6.81(1H,s), 7.19(1H,dd,J=8.8,1.2 Hz), 7.35(1H,d,J=8.8 Hz),
7.57(1H,s), 9.82(1H,br.s).
[1609] MS (ESI) m/z: 452(M+H).sup.+.
Referential Example 340
tert-Butyl
(1R,2S,5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-[(methylsu-
lfonyl)methyl]cyclohexanecarbamate
##STR00410##
[1611] The compound (300 mg) obtained in Referential Example 339
was dissolved in methylene chloride (10 mL), and m-chloroperbenzoic
acid (70%, 400 mg) was added to the solution under stirring at
0.degree. C. After the mixture was stirred for 1 hour, the reaction
mixture was poured into water and extracted 3 times with methylene
chloride. The resultant organic layers were washed with saturated
brine, dried over sodium sulfate anhydrate and then concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (methylene chloride:methanol=24:1), and then
subjected to partition between saturated aqueous sodium
hydrogencarbonate and ethyl acetate, and the resultant organic
layer was concentrated, to thereby give the title compound (254
mg).
[1612] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44-2.19(13H,m),
2.22-2.30(2H,m), 2.89-3.25(7H,m), 3.93-4.15(2H,m), 4.98(1H,br.s),
6.82(1H,s), 7.21(1H,dd,J=8.8,2.0 Hz), 7.34(1H,d,J=8.8 Hz),
7.60(1H,br.s), 9.54(1H,br.s).
Referential Example 341
(5-Chlorothien-3-yl)methanol
##STR00411##
[1614] 5-Chlorothiophene-3-carboxylic acid (Monatsh. Chem., Vol.
120, p. 53, 1989) (6.93 g) was dissolved in tetrahydrofuran (750
mL), and triethylamine (27.3 mL) and ethyl chloroformate (18.7 mL)
were added to the solution, followed by stirring at room
temperature for 2.5 hours. An aqueous solution (41 mL) of sodium
borohydride (19.3 g) was added dropwise over 10 minutes, and the
mixture was stirred at room temperature for 18.5 hours. After
acetic acid was added to the reaction mixture to acidify it, the
solvent was distilled away under reduced pressure. Water and
methylene chloride were added to the residue for partitioning the
mixture. The resultant organic layer was washed with water and
saturated aqueous sodium hydrogencarbonate. The organic layer was
dried over magnesium sulfate anhydrate, the solvent was distilled
away under reduced pressure. The residue was purified by flash
silica gel column chromatography (ethyl acetate:hexane=1:4), to
thereby give the title compound (5.17 g).
[1615] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.63(1H,t,J=5.8 Hz),
4.59(2H,d,J=5.3 Hz), 6.91(1H,d,J=1.7 Hz), 6.98-6.99(1H,m).
Referential Example 342
5-Chlorothiophene-3-carbaldehyde
##STR00412##
[1617] The compound (5.17 g) obtained in Referential Example 341
was dissolved in methylene chloride (400 mL), and manganese dioxide
(51.3 g) was added to the solution, followed by stirring at room
temperature for 15 hours. After the reaction mixture was filtered,
the solvent was distilled away under reduced pressure, to thereby
give the title compound (2.84 g).
[1618] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.35(1H,d,J=1.7 Hz),
7.88(1H,d,J=1.7 Hz), 9.75(1H,s).
Referential Example 343
Ethyl 2-azido-3-(5-chlorothien-3-yl)acrylate
##STR00413##
[1620] After ethanol (15 mL) was added to a 20% ethanol solution
(10.7 mL) of sodium ethoxide, and the mixture was cooled to
0.degree. C., a mixture of the compound (1.01 g) obtained in
Referential Example 342 and ethyl azidoacetate (3.55 g) was added
dropwise over 30 minutes, and the resultant mixture was stirred at
0.degree. C. for 3 hours. A cooled aqueous ammonium chloride was
added to the reaction mixture, and the resultant mixture was
extracted 3 times with diethyl ether. The organic layers were
combined, and the solvent was distilled away under reduced
pressure. The residue was purified by flash silica gel column
chromatography (ethyl acetate:hexane=1:49), to thereby give the
title compound (1:04 g).
[1621] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.38(3H,t,J=7.1 Hz),
4.34(2H,q,J=7.1 Hz), 6.75(1H,s), 7.39(1H,d,J=1.7 Hz),
7.54(1H,d,J=1.7 Hz).
Referential Example 344
Ethyl 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylate
##STR00414##
[1623] The compound (0.97 g) obtained in Referential Example 343
was dissolved in xylene (20 mL), and the solution was heated under
reflux for 30 minutes. After allowing the reaction mixture to cool,
the solvent was distilled away under reduced pressure. Hexane was
added to the residue, solids formed were collected by filtration,
to thereby give the title compound (0.608 g).
[1624] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.38(3H,t,J=7.0 Hz),
4.35(2H,q,J=7.0 Hz), 6.90(1H,s), 7.00(1H,d,J=1.9 Hz),
9.32(1H,br).
Referential Example 345
2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid
##STR00415##
[1626] In a manner similar to that employed in Referential
[1627] Example 274, the title compound was obtained from the
compound obtained in Referential Example 344.
[1628] .sup.1H-NMR (CD.sub.3OD) .delta.: 3.35(1H,s), 6.94(1H,s),
6.96(1H,s).
[1629] MS (ESI) m/z: 200(M-H).sup.-.
Referential Example 346
1-Chloro-4-(2,2-dibromovinyl)benzene
##STR00416##
[1631] 4-Chlorobenzaldehyde (2.81 g) was dissolved in methylene
chloride (300 mL), and carbon tetrabromide (13.3 g) and
triphenylphosphine (21.0 g) were added to the solution, followed by
stirring at room temperature for 90 minutes. After insoluble matter
precipitated was removed by filtration, the filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane:ethyl acetate=20:1), to
thereby give the title compound (5.54 g).
[1632] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.33(2H,d,J=8.5 Hz),
7.43(1H,s), 7.47(2H,d,J=8.5 Hz).
[1633] MS (EI) m/z: 296(M.sup.+).
Referential Example 347
3-(4-Chlorophenyl)-2-propiolic acid
##STR00417##
[1635] The compound (1.0 g) obtained in Referential Example 346 was
dissolved in tetrahydrofuran (30 mL), and n-butyllithium (1.59 N
hexane solution, 4.46 mL) was added dropwise at -78.degree. C.
under an argon atmosphere. The temperature of the reaction mixture
was allowed to elevate to room temperature and stirred for 1 hour.
The reaction mixture was cooled again to -78.degree. C., stirred
for 2 minutes under a carbon dioxide atmosphere and then warmed to
room temperature. After the reaction mixture was concentrated under
reduced pressure, saturated brine and ethyl acetate were added to
the residue for partitioning the mixture. The aqueous layer was
acidified with 3N Hydrochloric acid and extracted with ethyl
acetate. The resultant organic layer was dried over sodium sulfate
anhydrate and concentrated under reduced pressure, to thereby give
the title compound (453 mg).
[1636] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 7.55(2H,d,J=8.5 Hz),
7.66(2H,d,J=8.5 Hz), 13.90(1H,br.s).
[1637] MS (EI) m/z: 180(M.sup.+).
Referential Example 348
Ethyl 6-chloro-4-oxo-1,4-dihydroquinazoline-2-carboxylate
##STR00418##
[1639] Ethyl chlorooxoacetate (2.0 mL) was added to a solution of
2-amino-5-chlorobenzamide (2.50 g) in pyridine (15 mL), and the
mixture was stirred at room temperature for 18 hours. The reaction
mixture was concentrated under reduced pressure, and the resultant
residue was dissolved in acetic acid (50 mL). Acetic anhydride (5.0
mL) was added to the solution, and the mixture was heated under
reflux for 16 hours. The solvent was distilled away under reduced
pressure, and ethanol was added to the residue. Crystals
precipitated were collected by filtration and washed, to thereby
give the title. compound (2.71 g).
[1640] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35(3H,t,J=7.1 Hz),
4.38(2H,q,J=7.1 Hz), 7.85(1H,d,J=8.6 Hz), 7.91(1H,dd,J=8.6,2.3 Hz),
8.10(1H,d,J=2.3 Hz), 12.85(1H,br.s).
[1641] MS (ESI) m/z: 253(M+H).sup.+.
Referential Example 349
6-Chloro-4-oxo-1,4-dihydroquinazoline-2-carboxylic acid
##STR00419##
[1643] Lithium hydroxide (263 mg) was added to a solution of the
compound (1.26 g) obtained in Referential Example 348 in a solvent
mixture of water (5 mL) and tetrahydrofuran (15 mL), and the
mixture was stirred at room temperature for 18 hours. The reaction
mixture was neutralized with 1N hydrochloric acid (11 mL) under ice
cooling and stirred for 1 hour. Crystals precipitated were
collected by filtration and washed with water, to thereby give the
title compound (0.96 g).
[1644] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 7.50-8.20(3H,m),
12.44(1H,br.s).
[1645] MS (ESI) m/z: 265(M+H+CH.sub.3CN).sup.+.
Referential Example 350
2-Chloro-N-(4-chlorophenyl)acetamide
##STR00420##
[1647] p-Chloroaniline (3.82 g) was dissolved in ethyl acetate (30
mL), and, at room temperature, chloroacetyl chloride (2.39 mL) was
added to the solution, followed by stirring for 1 hour. After the
reaction mixture was heated and stirred at 60.degree. C. for 3.5
hours, crystals precipitated were collected by filtration, to
thereby give the title compound (4.78 g). The filtrate was
concentrated to about 1/4, and crystals precipitated were collected
by filtration, to thereby give the title compound (1.01 g).
[1648] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.19(2H,s),
7.33(2H,d,J=9.0 Hz), 7.51(2H,d,J=9.0 Hz), 8.22(1H,br.s).
Referential Example 351
Sodium S-[2-(4-chloroanilino)-2-oxoethyl]thiosulfate
##STR00421##
[1650] The compound (5.79 g) obtained in Referential Example 350
was dissolved in ethanol (140 mL), and an aqueous solution (140 mL)
of sodium thiosulfate pentahydrate (7.04 g) was added to the
solution at a time under stirring at 70.degree. C., followed by
heating under reflux for 1.5 hours. The reaction mixture was
concentrated to about 1/10, and crystals precipitated were
collected by filtration, to thereby give the title compound (8.20
g).
[1651] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.73(2H,s),
7.35(2H,d,J=8.8 Hz), 7.57(2H,d,J=8.8 Hz), 10.30(1H,s).
Referential Example 352
2-Chloro-N-(5-chloropyridin-2-yl)acetamide hydrochloride
##STR00422##
[1653] 2-Amino-5-chloropyridine (3.85 g) was dissolved in ethyl
acetate (60 mL), and, at room temperature, chloroacetyl chloride
(2.39 mL) was added to the solution, followed by stirring for 1
hour. After the reaction mixture was heated and stirred at
60.degree. C. for 30 minutes, chloroacetyl chloride (0.5 mL) was
additionally added, and the mixture was stirred at 60.degree. C.
for additional 1 hour. Powder precipitated was collected by
filtration, to thereby give the title compound (6.18 g).
[1654] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 4.36(2H,s),
7.94(1H,dd,J=8.8,2.7 Hz), 8.09(1H,d,J=8.8 Hz), 8.40(1H,d,J=2.7 Hz),
11.03(1H,s).
Referential Example 353
Sodium
S-{2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl}thiosulfate
##STR00423##
[1656] The compound (6.18 g) obtained in Referential Example 352
was dissolved in ethanol (130 mL), and an aqueous solution (130 mL)
of sodium thiosulfate pentahydrate (6.35 g) and sodium
hydrogencarbonate (2.15 g) dissolved therein was added to the
solution at a time at 80.degree. C. under stirring, and the mixture
was heated under reflux for 2 hours at an exterior temperature of
110.degree. C. The reaction mixture was concentrated to solids
under reduced pressure, and ethanol (500 mL) was added to the
residue. The resultant mixture was heated and extracted twice. The
extract was concentrated to about 1/20, and diethyl ether was
added. Insoluble matter precipitated was collected by filtration,
to thereby give the title compound (6.65 g).
[1657] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.77(2H,s),
7.89(1H,dd,J=9.0,2.7 Hz), 8.09(1H,d,J=9.0 Hz), 8.34(1H,d,J=2.7 Hz),
10.57(1H,s).
Referential Example 354
N-{(1R,2S,5S)-2-[(2-chloroacetyl)amino]-5-[(dimethylamino)carbonyl]cyclohe-
xyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-carboxamide
hydrochloride
##STR00424##
[1659] The compound (100 mg) obtained in Referential Example 253
was disslved in ethyl acetate (10 mL), and chloroacetyl chloride
(21.6 .mu.l) was added to heat and stir the mixture at 60.degree.
C. for 30 minutes. After allowing the reaction mixture to cool,
insoluble matter was collected by filtration and dissolved in
methylene chloride-methanol, and the solvent was distilled away
under reduced pressure, to thereby give the title compound (112 mg)
as a non-purified form.
[1660] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35-1.50(1H,m),
1.55-2.00(5H,m), 2.78(3H,s), 2.98(3H,s), 3.00-3.25(5H,m),
3.17(3H,s), 3.80-3.90(1H, m), 3.96(1H,d,J=12.9 Hz),
4.00-4.15(1H,m), 4.02(1H,d,J=12.9 Hz), 4.45-4,70(2H,m),
7.85-8.00(1H,br), 8.12(1H,d,J=7.3 Hz), 8.35(1H,d,J=8.3 Hz).
[1661] MS (ESI) m/z: 442(M+H).sup.+.
Referential Example 355
Sodium
S-{2-[((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-
-tetrathiazolo[5,4-c]pyridine-2-yl)-carbonyl]amino}cyclohexyl)amino]-2-oxo-
ethyl}thiosulfate
##STR00425##
[1663] The compound (106 mg) obtained in Referential Example 354
was dissolved in ethanol (1.5 mL), and an aqueous solution (1.5 mL)
of sodium thiosulfate pentahydrate (55 mg) and sodium
hydrogencarbonate (18.6 mg) dissolved therein was added to the
solution at a time at 90.degree. C. under stirring. The resultant
mixture was heated under reflux for 1 hour. The reaction mixture
was concentrated to solids under reduced pressure, and ethanol (10
mL) was added to the residue. The resultant mixture was extracted
under heating. The extract was concentrated to about 1/2, and
isopropyl ether (10 mL) was added. Insoluble matter precipitated
was collected by filtration, to thereby give the title compound (72
mg).
[1664] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35-1.50(1H,m),
1.55-1.90(5H,m), 2.40(3H,s), 2.78(3H,s), 2.80-3.10(5H,m),
2.96(3H,s), 3.44(1H,d,J=14.2 Hz), 3.50(1H,d,J=14.2 Hz), 3.68(2H,s),
3.75-3.90(1H,m), 4.45-4.50(1H,m), 8.01(1H,d,J=7.4 Hz),
8.15(1H,d,J=8.3 Hz).
Referential Example 356
Methyl 2-[(5-chlorothien-2-yl)amino]-2-oxoacetate
##STR00426##
[1666] Triethylamine (1.25 mL) and diphenylphosphoryl azide (1.55
mL) were added to a suspension of 5-chlorothiophene-2-carboxylic
acid (0.99 g) in toluene (20 mL), and the mixture was stirred at
80.degree. C. for 1 hour. After the reaction mixture was cooled to
room temperature, tert-butanol (2 mL) was added, and the mixture
was heated under reflux for 19 hours. The reaction mixture was
concentrated under reduced pressure, and methylene chloride (200
mL) was added to the resultant residue. The resultant mixture was
successively washed with distilled water, 10% aqueous citric acid,
distilled water, saturated aqueous sodium hydrogencarbonate and
saturated brine and then dried over sodium sulfate anhydrate. The
solvent was distilled away under reduced pressure, and the residue
was subjected to silica gel column chromatography (hexane:ethyl
acetate=4:1), to thereby give tert-butyl
5-chloro-2-thienylcarbamate (1.05 g).
[1667] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.51(9H,s),
6.21(1H,d,J=3.1 Hz), 6.60(1H,d,J=3.1 Hz), 6.91(1H,br.s).
[1668] MS (ESI) m/z: 234(M+H).sup.+.
[1669] The product (1.87 g) obtained above was added to a 4N
HCl-dioxane (40 mL), and the mixture was stirred at room
temperature for 4 hours. The solvent was distilled away under
reduced pressure, and the residue was suspended in tetrahydrofuran
(50 mL). Sodium hydrogencarbonate (2.02 g) and methyl
chlorooxoacetate (0.883 mL) were added to the suspension under ice
cooling, and the mixture was stirred at room temperature for 18
hours. After the solvent was distilled away under reduced pressure,
and water and methylene chloride were added to the residue for
partitioning the mixture, the resultant organic layer was washed
with saturated brine and dried over sodium sulfate anhydrate and
then concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (hexane:ethyl acetate=3:1), and
the solvent was distilled away, to thereby give the title compound
(1.44 g).
[1670] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.98(3H,s),
6.61(1H,d,J=4.2 Hz), 6.75(1H,d,J=4.2 Hz), 9.42(1H,br.s).
[1671] MS (FAB) m/z: 220(M+H).sup.+.
Referential Example 357
Methyl 2-[(5-fluoropyridin-2-yl)amino]-2-oxoacetate
##STR00427##
[1673] The title compound was obtained from
2-amino-5-fluoropyridine and methyl chlorooxoacetate in a manner
similar to the process described in Referential Example 242.
[1674] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.99(3H,s),
7.48-7.53(1H,m), 8.21(1H,d,J=2.9 Hz), 8.27-8.31(1H,m),
9.41(1H,br.s).
[1675] MS (FAB) m/z: 198(M+H).sup.+.
Referential Example 358
Methyl 2-[4-chloro-2-(trifluoromethyl)anilino]-2-oxoacetate
##STR00428##
[1677] The title compound was obtained from
4-chloro-2-trifluoroaniline and methyl chlorooxoacetate in a manner
similar to the process described in Referential Example 242.
[1678] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.01(3H,s), 7.58(1H,dd,
J=8.8,2.2 Hz), 7.65(1H,d,J=2.2 Hz), 8.34(1H,d,J=8.8 Hz),
9.30(1H,br.s).
[1679] MS (EI) m/z: 281(M+H).sup.+.
Referential Example 359
2-[4-Chloro-2-(trifluoromethyl)anilino]-2-oxoacetic acid
##STR00429##
[1681] Lithium hydroxide (28 mg) was added to a solution of the
compound (297 mg) obtained in Referential Example 358 in a solvent
mixture of tetrahydrofuran (7 mL) and water (3 mL), and the mixture
was stirred at room temperature for 2 hours. 1N Hydrochloric acid
(8 mL) and methylene chloride (20 mL) were added to the reaction
mixture for partitioning the mixture. After the resultant organic
layer was dried over sodium sulfate anhydrate, the solvent was
distilled away under reduced pressure, and the residue was dried,
to thereby give the title compound (291 mg).
[1682] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.61(1H,dd,J=8.8,2.5 Hz),
7.68(1H,d,J=2.5 Hz), 8.26(1H,d,J=8.8 Hz), 9.36(1H,br.s).
[1683] MS(ESI, anion)m/z: 267(M-H).sup.-
Referential Example 360
5-Chloro-N,N-dimethyl-2-nitrobenzamide
##STR00430##
[1685] The title compound was obtained by condensing
5-chloro-2-nitrobenzoic acid with dimethylamine in a manner similar
to the process described in Referential Example 143.
[1686] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.86(3H,s), 3.16(3H,s),
7.38(1H,d,J=2.2 Hz), 7.51(1H,dd,J=8.8,2.2 Hz), 8.15(1H,d,J=8.8
Hz).
Referential Example 361
2-Amino-5-chloro-N,N-dimethylbenzamide
##STR00431##
[1688] Iron (III) chloride hexahydrate (9.93 g) and zinc powder
(8.01 g) were added to a solution of the compound (2.8 g) obtained
in Referential Example 360 in a solvent mixture of
N,N-dimethylformamide (80 mL) and water (40 mL), and the mixture
was heated under reflux for 20 minutes. The reaction mixture was
filtered through Celite 545, and ethyl acetate (200 mL) was added
to the filtrate for partitioning the mixture. The resultant aqueous
layer was washed with ethyl acetate (100 ml.times.2), and the
organic layers were combined, washed with distilled water (100 mL)
and dried over sodium sulfate anhydrate. The solvent was distilled
away under reduced pressure, and the resultant residue was
subjected to silica gel column chromatography (methylene
chloride:hexane=1:1.fwdarw.1:0.fwdarw.methanol:methylene
chloride=1:100), to thereby give the title compound (2.41 g).
[1689] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.13(6H,s), 4.33(2H,br),
6.65(1H,d,J=8.5 Hz), 7.07(1H,d,J=2.2 Hz), 7.11(1H,dd,J=8.5,2.2
Hz).
[1690] MS (ESI) m/z: 240(M+MeCN).sup.+.
Referential Example 362
Methyl
2-{4-chloro-2-[(dimethylamino)carbonyl]anilino}-2-oxoacetate
##STR00432##
[1692] In a manner similar to that employed in Referential Example
242, the title compound was produced from the compound obtained in
Referential Example 361 and methyl chlorooxoacetate.
[1693] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.09(6H,br), 3.96(3H,s),
7.30(1H,d,J=2.4 Hz), 7.41(1H,d,J=8.8,2.4 Hz), 8.34(1H,d,J=8.8 Hz),
10.46(1H,br).
[1694] MS (ESI) m/z: 285(M+H).sup.+.
Referential Example 363
4-Chloro-2-methoxyaniline
##STR00433##
[1696] In a manner similar to that employed in Referential Example
361, the title compound was obtained from
5-chloro-2-nitroanisole.
[1697] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.65-3.95(2H,br),
3.87(3H,s), 6.61(1H,d,J=8.8 Hz), 6.74-6.78(2H,m).
[1698] MS (ESI) m/z: 199(M+MeCN+H).sup.+.
Referential Example 364
Methyl 2-(4-chloro-2-methoxyanilino)-2-oxoacetate
##STR00434##
[1700] The title compound was obtained from the compound obtained
in Referential Example 363 and methyl chlorooxoacetate in a manner
similar to the process described in Referential Example 242.
[1701] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.92(3H,s), 3.97(3H,s),
6.90(1H,d,J=2.2 Hz), 6.98(1H,dd,J=8.8,2.2 Hz), 8.35(1H,d,J=8.8 Hz),
9.33-9.44(1H,br).
[1702] MS (ESI) m/z: 244(M+H).sup.+.
Referential Example 365
Ethyl 2-(4-chloroanilino)-2-(hydroxyimino)-acetate
##STR00435##
[1704] The title compound was obtained from 4-chloroaniline (3.03
g) and ethyl 2-chloro-2-hydroxyiminoacetate in a manner similar to
the process described in literature (Gilchrist, T. L.; Peek, M. E.;
Rees, C. W.; J. Chem. Soc. Chem. Commun., 1975, 913).
[1705] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.26(3H,t,J=7.1 Hz),
1.60-1.80(1H,br), 4.28(2H,q,J=7.1 Hz), 6.85(2H,d,J=8.6 Hz),
7.24(2H,d,J=8.6 Hz), 8.15-8.45(1H,br).
[1706] MS (ESI) m/z: 243(M+H).sup.+.
Referential Example 366
tert-Butyl
(1R,2S,5S)-2-{[2-(4-chloroanilino)-2-(hydroxyimino)acetyl]amino-
}-5-[(dimethylamino)carbonyl]-cyclohexylcarbamate
##STR00436##
[1708] The compound (597 mg) obtained in Referential Example 144
was added to a solution of the compound (350 mg) obtained in
Referential Example 365 in ethanol (5.0 mL), and the mixture was
stirred at 70.degree. C. for 3 days. After the reaction mixture was
concentrated under reduced pressure, the residue was purified by
silica gel column chromatography (methylene
chloride:methanol=30:1), to thereby give the title compound (180
mg).
[1709] .sup.1H-NMR (CD.sub.3OD) .delta.: 1.46(9H,s),
1.47-1.84(6H,m), 1.88-1.95(1H,m), 2.90(3H,s), 3.08(3H,s),
3.90-3.97(1H,m), 4.11-4.17(1H,m), 6.84(2H,d,J=8.8 Hz),
7.18(2H,d,J=8.8 Hz).
[1710] MS (ESI) m/z: 504(M+Na).sup.+.
Referential Example 367
(3R,
4S)-4-{[2-(4-chloroanilino)-2-oxoacetyl]amino}-1-(2-methoxyacetyl)pip-
eridin-3-ylcarbamic acid tert-butyl ester
##STR00437##
[1712] The method described in Referential Example 214 was
performed by use of the compound obtained in Referential Example
374 and the compound obtained in Referential Example 220, whereby
the title compound was obtained.
[1713] .sup.1H-NMR(CDCl.sub.3).delta.: 1.45(9H, s), 1.55-1.75(1H,
br), 1.94-2.07(1H, br), 2.70-3.00(1H, m), 3.10-3.37(1H, m),
3.44(3H, s), 3.88-4.22(4H, m), 4.55-4.69(1H, br), 4.80-4.90(0.5H,
br), 5.36-5.48(0.5H, br), 7.20-7.30(1H, br), 7.32(2H, d, J=8.8 Hz),
7.62(2H, d, J=8.8 Hz), 8.20-8.40(1H, br), 9.15-9.25(1H, br).
[1714] MS(ESI)m/z: 469(M+H).sup.+.
Referential Example 368
(3R,
4S)-4-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-1-(2-metho-
xyacetyl)piperidin-3-ylcarbamic acid tert-butyl ester
##STR00438##
[1716] The method described in Referential Example 214 was
performed by use of the compound obtained in Referential Example
266 and the compound obtained in Referential Example 220, whereby
the title compound was obtained.
[1717] .sup.1H-NMR(CDCl.sub.3).delta.: 1.45(9H, s), 1.65-2.30(2H,
br), 2.68-3.02(1H, m), 3.10-3.35(1H, m), 3.44(3H, s), 3.80-4.25(4H,
m), 4.45-4.70(1H, m), 5.05-5.20(0.5H, m), 5.80-5.93(0.5H, m),
7.30-7.40(1H, br), 7.71(1H, br d, J=8.7 Hz), 7.95-8.05(0.3H, br),
8.19(1H, br d, J=8.8 Hz), 8.31(1H, br.s), 8.38-8.53(0.7H, br),
9.74-9.84(1H, br).
[1718] MS(ESI)m/z: 470(M+H).sup.+.
Referential Example 369
(3R,
4S)-4-({2-[(5-bromopyridin-2-yl)amino]-2-oxoacetyl}amino)-1-(2-methox-
yacetyl)piperidin-3-ylcarbamic acid tert-butyl ester
##STR00439##
[1720] The method described in Referential Example 214 was
performed by use of the compound obtained in Referential Example
375 and the compound obtained in Referential Example 220, whereby
the title compound was obtained.
[1721] .sup.1H-NMR(CDCl.sub.3).delta.: 1.47(9H, s), 1.50-1.75(1H,
m), 1.95-2.13(1H, br), 2.70-2.98(1H, m), 3.05-3.36(1H, m), 3.45(3H,
s), 3.80-4.24(4H, m), 4.57-4.73(1H, br), 4.85-4.95(0.25H, br),
5.10-5.15(0.25H, br), 5.45-5.58(0.5H, br), 7.30-7.38(1H, m),
7.84(1H, dd, J=8.8, 2.2 Hz), 8.16(1H, d, J=8.8 Hz), 8.30-8.55(1H,
br), 8.40(1H, d, J=2.2 Hz), 9.68(1H, br.s).
Referential Example 370
3-(4-chloroanilino)-3-oxopropionic acid ethyl ester
##STR00440##
[1723] To a solution of 4-chloroaniline (2.0 g) in
N,N-dimethylformamide (20 mL) were sequentially added at room
temperature potassium ethyl malonate (3.2 g),
1-hydroxybenzotriazole (2.1 g), and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.5
g), followed by stirring at room temperature for 2 hours. The
reaction mixture was diluted with ethyl acetate and washed with
saturated aqueous sodium hydrogencarbonate, 10% aqueous citric
acid, and saturated brine. The organic layer was dried over sodium
sulfate anhydrate, and the solvent was distilled away under reduced
pressure, to thereby give the title compound (4.0 g).
[1724] .sup.1H-NMR(CDCl.sub.3).delta.: 1.33(3H, t, J=7.3 Hz),
3.47(2H, s), 4.26(2H, q, J=7.3 Hz), 7.29(2H, d, J=8.8 Hz),
7.51(2H,d, J=8.8 Hz), 9.32(1H, br.s).
Referential Example 371
3-(4-chloroanilino)-3-oxopropionic acid
##STR00441##
[1726] To a solution of the compound (1.0 g) obtained in
Referential Example 370 in ethanol (10 mL), 1N aqueous sodium
hydroxide (10 mL) was added dropwise at room temperature, followed
by stirring for 2 hours. 1N Aqueous hydrochloric acid (10 mL) was
added to the reaction mixture, followed by stirring, and the
precipitated insoluble material was recovered by filtration, to
thereby give the title compound (0.5 g).
[1727] .sup.1H-NMR(DMSO-d.sub.6).delta.: 3.34 (2H, s), 7.35(2H, d,
J=8.8 Hz), 7.59(2H, d, J=8.8 Hz), 10.26(1H, s), 12.66(1H,
br.s).
Referential Example 372
3-(3-chloroanilino)-3-oxopropionic acid ethyl ester
##STR00442##
[1729] In a manner similar to that described in Referential Example
370, 3-chloroaniline was condensed with potassium ethyl malonate,
whereby the title compound was obtained.
[1730] .sup.1H-NMR(CDCl.sub.3).delta.: 1.33(3H, t, J=7.3 Hz),
3.47(2H, s), 4.26(2H, q, J=7.3 Hz), 7.09(1H, d, J=8.8 Hz),
7.22-7.26(1H, m), 7.39(1H, d, J=8.8 Hz), 7.69(1H, s), 9.35(1H,
br.s).
Referential Example 373
3-(3-chloroanilino)-3-oxopropionic acid
##STR00443##
[1732] The method described in Referential Example 371 was
performed by use of the compound obtained in Referential Example
372, whereby the title compound was obtained.
[1733] .sup.1H-NMR(DMSO-d.sub.6).delta.: 3.35(2H, s), 7.11(1H, d,
J=8.8 Hz), 7.33(1H, t, J=8.8 Hz), 7.39(1H, d, J=8.8 Hz), 7.78(1H,
s), 10.31(1H, s), 12.67(1H, br.s).
Referential Example 374
2-(4-chloroanilino)-2-oxoacetic acid
##STR00444##
[1735] The method described in Referential Example 359 was
performed by use of the compound obtained in Referential Example
242, whereby the title compound was obtained.
[1736] .sup.1H-NMR(DMSO-d.sub.6).delta.: 7.37 (2H, d, J=8.8 Hz),
7.79(2H, d, J=8.8 Hz), 10.66(1H, s).
Referential Example 375
2-[(5-bromopyridin-2-yl)amino]-2-oxoacetic acid
##STR00445##
[1738] The method described in Referential Example 359 was
performed by use of the compound obtained in Referential Example
262, whereby the title compound was obtained.
[1739] .sup.1H-NMR(DMSO-d.sub.6).delta.: 7.95-8.00 (1H, m),
8.08(1H, dd, J=8.8, 2.0 Hz), 8.50(1H, d, J=2.0 Hz), 10.74(1H,
s).
Referential Example 376
4-chloro-3-fluorobenzoic acid
##STR00446##
[1741] Sodium chlorite (17 g) was added dropwise to a mixture of
4-chloro-3-fluorobenzaldehyde (10 g), amidesulfuric acid (18 g),
tert-butyl alcohol (50 mL), and water (50 mL) under ice cooling.
The temperature of the mixture was returned gradually to room
temperature, and the mixture was stirred for 4 days. The reaction
mixture was diluted with ethyl acetate, and the resultant mixture
was washed with water, 1N hydrochloric acid, and saturated brine.
The organic layer was dried over sodium sulfate anhydrate, and the
solvent was distilled away under reduced pressure. The residue was
recrystallized from a solvent mixture of diisopropyl ether and
hexane, to thereby give the title compound (11.2 g).
[1742] .sup.1H-NMR(DMSO-d.sub.6).delta.: 7.72 (1H, dt, J=8.3, 1.5
Hz), 7.77 (1H, dt, J=8.3, 1.6 Hz), 7.82(1H, dt, J=9.7, 1.5 Hz),
13.45(1H, s).
Referential Example 377
2-(4-chloro-3-fluoroanilino)-2-oxoacetic acid methyl ester
##STR00447##
[1744] In a manner similar to that described in Referential Example
356, the compound obtained in Referential Example 376 was subjected
to Curtius transition reaction. The resultant compound was
condensed with methyl chlorooxoacetate, whereby the title compound
was obtained.
[1745] .sup.1H-NMR(CDCl.sub.3).delta.: 3.99(3H, s), 7.25-7.27(1H,
m), 7.39(1H, t, J=8.5 Hz), 7.72(1H, dd, J=10.4, 2.4 Hz), 8.90(1H,
br.s).
Referential Example 378
2-(4-chloro-3-fluoroanilino)-2-oxoacetic acid
##STR00448##
[1747] The method described in Referential Example 359 was
performed by use of the compound obtained in Referential Example
377, whereby the title compound was obtained.
[1748] .sup.1H-NMR(DMSO-d.sub.6).delta.: 7.52 (1H, t, J=8.8 Hz),
7.63(1H, dd, J=8.8, 2.2 Hz), 7.88(1H, dd, J=12.0, 2.2 Hz),
10.83(1H, br.s).
Referential Example 379
3-(4-chlorophenyl)-3-oxopropionic acid ethyl ester
##STR00449##
[1750] To a suspension of potassium ethyl malonate (8.2 g) in ethyl
acetate (100 mL), triethylamine (17 mL) and magnesium chloride (5.5
g) were added under ice cooling. The temperature of the resultant
mixture was returned gradually to room temperature, and the mixture
was stirred for 18 hours. In addition, a suspension of
4-chlorobenzoic acid (5.0 g), thionyl chloride (12 mL),
N,N-dimethylformamide (1 drop), and toluene (100 mL) was heated
under reflux for 1 hour, and the reaction mixture was concentrated.
The residue was dissolved in ethyl acetate, and the solution was
added dropwise to the above mixture under ice cooling. The
temperature of the mixture was gradually returned to room
temperature, and the mixture was stirred for 18 hours. 10% Aqueous
citric acid was added to the reaction mixture, and the mixture was
stirred for 30 minutes, and the organic layer was partitioned. The
resultant organic layer was washed with saturated brine, followed
by drying over sodium sulfate anhydrate. The solvent was distilled
away under reduced pressure. The residue was separated and purified
by silica gel column chromatography (chloroform), to thereby give
the title compound (6.4 g).
[1751] .sup.1H-NMR(CDCl.sub.3).delta.: 1.26(3H, t, J=7.3 Hz),
3.96(2H, s), 4.21(2H, q, J=7.3 Hz), 7.46(2H, d, J=8.8 Hz), 7.89(2H,
d, J=8.8 Hz).
Referential Example 380
3-(4-chlorophenyl)-3-hydroxypropionic acid ethyl ester
##STR00450##
[1753] To the compound (1.0 g) obtained in Referential Example 379
dissolved in tetrahydrofuran (10 mL), sodium borohydride (0.2 g)
was added dropwise under ice cooling. The temperature of the
mixture was gradually returned to room temperature, and the mixture
was stirred for 2 hours. 10% Aqueous citric acid was added to the
reaction mixture, and the resultant mixture was extracted with
ethyl acetate. The organic layer was washed with saturated brine,
followed by drying over sodium sulfate anhydrate. The solvent was
distilled away under reduced pressure. The residue was separated
and purified by silica gel column chromatography (chloroform), to
thereby give the title compound (0.56 g).
[1754] .sup.1H-NMR(CDCl.sub.3).delta.: 1.27(3H, t, J=7.3 Hz),
2.70(1H, d, J=7.8 Hz), 2.71(1H, d, J=3.4 Hz), 3.37(1H, d, J=3.4
Hz), 4.18(2H, q, J=7.3 Hz), 5.09-5.13(1H, m), 7.30-7.35(5H, m).
Referential Example 381
3-(4-chlorophenyl)-3-hydroxypropionic acid
##STR00451##
[1756] The method described in Referential Example 359 was
performed by use of the compound obtained in Referential Example
380, whereby the title compound was obtained.
[1757] .sup.1H-NMR(DMSO-d.sub.6).delta.: 3.25-3.32 (1H, m),
4.89-4.95(1H, m), 5.45-5.53(1H, m), 7.35-7.36(5H, m),
12.11-12.18(1H, m).
[1758] MS(ESI, anion)m/z: 198(M-H).sup.-.
Referential Example 382
(1R, 2S,
5S)-2-{[3-(4-chlorophenyl)-3-hydroxypropanoyl]amino}-5-[(dimethyl-
amino)carbonyl]cyclohexylcarbamic acid tert-butyl ester
##STR00452##
[1760] In a manner similar to that described in Referential Example
91, the compound obtained in Referential Example 144 was condensed
with the compound obtained in Referential Example 381, whereby the
title compound was obtained.
[1761] .sup.1H-NMR(CDCl.sub.3).delta.: 1.21-1.44(2H, m), 1.46(9H,
s), 1.76-1.92(2H, m), 1.95-2.10(2H, m), 2.40-2.55(2H, m),
2.55-2.68(1H, m), 2.94(3H, s), 3.05(3H, s), 3.82-3.96(1H, m),
4.02-4.17(1H, m), 4.65-4.80(2H, m), 5.03-5.13(1H, m), 7.28-7.33(5H,
m).
[1762] MS(ESI)m/z: 468(M+H).sup.+.
Referential Example 383
(1R, 2S,
5S)-2-{[3-(4-chlorophenyl)-3-oxopropanoyl]amino}-5-[(dimethylamin-
o)carbonyl]cyclohexylcarbamic acid tert-butyl ester
##STR00453##
[1764] To a solution of the compound (0.5 g) obtained in
Referential Example 382 in 1, 4-dioxane (20 mL), manganese dioxide
(0.47 g) was added at room temperature, followed by stirring for 4
days. The insoluble material was removed through filtration through
a celite pad. The resultant filtrate was concentrated under reduced
pressure, to thereby give the title compound (0.46 g).
[1765] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.28-1.39(1H, m), 1.40(9H,
s), 1.41-1.63(3H, m), 2.25-2.42(2H, m), 2.76(3H, s), 2.90-2.97(1H,
m), 2.98(3H, s), 3.56(2H, s), 3.89-3.97(1H, m), 4.88-4.98(1H, m),
6.65-6.70(1H, m), 7.30-7.35(4H, m), 7.33(1H, dd, J=2.9, 1.7
Hz).
[1766] MS (ESI, anion)m/z: 464 (M-H).sup.-.
Referential Example 384
(1S, 3R,
4R)-4-azido-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic
acid ethyl ester
##STR00454##
[1768] The method described in Referential Example 249 was
performed by use of the compound obtained in Referential Example
248, whereby the title compound was obtained.
[1769] [.alpha.] .sub.D.sup.25+62.degree. (c=1, chloroform)
[1770] .sup.1H-NMR(CDCl.sub.3).delta.: 1.27(3H, t, J=7.1 Hz),
1.46(9H, s), 1.61(1H, s), 1.61-1.71(2H, m), 1.81-1.90(1H, m),
1.97-2.03(1H, m), 2.22-2.28(1H, m), 2.56-2.60(1H, m), 3.54(1H,
br.s), 3.63-3.68(1H, m), 4.16(2H, q, J=7.1 Hz), 4.58(1H, br.s),
Referential Example 385
(1R, 2R, 5S)-2-azido-5-[(dimethylamino)carbonyl]cyclohexylcarbamic
acid tert-butyl ester
##STR00455##
[1772] The methods described in Referential Example 250 and
Referential Example 251 were performed by use of the compound
obtained in Referential Example 384, whereby the title compound was
obtained.
[1773] .sup.1H-NMR(CDCl.sub.3).delta.: 1.46(9H, s), 1.40-2.20(6H,
m), 2.70-2.80(1H, m), 2.93(3H, s), 3.03(3H, s), 3.60-3.78(1H, m),
3.83-3.95(1H, m), 4.65(1H, d, J=7.2 Hz).
Referential Example 386
(1R, 2R,
5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-[(di-
methylamino)carbonyl]cyclohexylcarbamic acid tert-butyl ester
##STR00456##
[1775] In a manner similar to that described in Referential Example
90, the azido group of the compound obtained in Referential Example
385 was converted to an amino group. In a manner similar to that
described in Referential Example 91, the converted compound was
condensed with the compound obtained in Referential Example 266,
whereby the title compound was obtained.
[1776] .sup.1H-NMR(CDCl.sub.3).delta.: 1.13-2.25(16H, m), 2.94(3H,
s), 3.03(3H, s), 3.60-3.78(1H, m), 4.13-4.31(1H, m), 4.45-4.65(1H,
m), 7.80(1H, dd, J=8.8, 2.4 Hz), 8.03(1H, br.s), 8.21(1H, d, J=8.8
Hz), 8.29(1H, d, J=2.4 Hz), 9.71(1H, s).
[1777] MS(ESI)m/z: 468(M+H).sup.+.
Referential Example 387
N-{(1R, 2R,
5S)-2-azido-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetra-
hydrothiazolo[5,4-c]pyridine-2-carboxamide
##STR00457##
[1779] The method described in Referential Example 252 was
performed by use of the compound obtained in Referential Example
385 and the compound obtained in Referential Example 10, whereby
the title compound was obtained.
[1780] .sup.1H-NMR(CDCl.sub.3).delta.: 1.75-2.08(6H, m),
2.20-2.32(1H, m), 2.51(3H, s), 2.75-2.97 (4H, m), 2.95(3H, s),
3.04(3H, s), 3.65-3.80(3H, m), 4.27-4.39(1H, m), 7.17-7.28(1H,
m).
[1781] MS(ESI)m/z: 392(M+H).sup.+.
Referential Example 388
4-[(2-methoxy-2-oxoacetyl)amino]piperidine-1-carboxylic acid
tert-butyl ester
##STR00458##
[1783] The method described in Referential Example 242 was
performed by use of (4-amino-N-tert-butoxycarbonyl)piperidine and
methyl chlorooxoacetate, whereby the title compound was
obtained.
[1784] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.46(9H, s), 1.34-1.51(2H,
m), 1.89-1.98(2H, m), 2.82-2.96(2H, m), 3.91(3H, s), 3.88-4.14(3H,
m), 6.96-7.07(1H, m).
[1785] MS(FAB)m/z: 287(M+H).sup.+.
Referential Example 389
4-{[2-({(1R, 2S,
5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cy-
clohexyl}amino)-2-oxoacetyl]amino}piperidine-1-carboxylic acid
tert-butyl ester
##STR00459##
[1787] The method described in Example 191 was performed by use of
the compound obtained in Referential Example 310 and the compound
obtained in Referential Example 388, whereby the title compound was
obtained.
[1788] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.46(9H, s),
1.35-2.28(11H, m), 2.70-3.18(9H, m), 3.80-4.57(4H, m), 6.78(1H, s),
7.15-8.12(6H, m), 9.45(1H, s).
[1789] MS(FAB)m/z: 617(M+H).sup.+.
Referential Example 390
2-[(5-chloropyridin-2-yl)(methyl)amino]-2-oxoacetic acid methyl
ester
##STR00460##
[1791] The method described in Referential Example 242 was
performed by use of 5-chloro-N-methyl-2-pyridinamine and methyl
chlorooxoacetate, whereby the title compound was obtained.
.sup.1H-NMR(CDCl.sub.3).delta.: 3.43(3H, s), 3.81(3H, s), 7.08(1H,
br.s), 7.68-7.78(1H, m), 8.27(1H, br.s).
[1792] MS(ESI)m/z: 229(M+H).sup.+.
Referential Example 391
2-[(5-chloro-pyrimidin-2-yl)amino]-2-oxoacetic acid methyl
ester
##STR00461##
[1794] The method described in Referential Example 242 was
performed by use of 2-amino-5-chloropyrimidine and methyl
chlorooxoacetate, whereby the title compound was obtained.
[1795] .sup.1H-NMR (CDCl.sub.3) .delta.:4.00(3H, s), 8.63(2H, s),
9.58(1H, br.s).
[1796] MS (ESI) m/z:215 (M+H).sup.+.
Referential Example 392
N-((1R, 2S,
5S)-2-azido-5-.DELTA.[ethyl(methyl)amino]carbonyl}cyclohexyl)-5-methyl-5,-
6-dihydro-4H-pyrrolo[3,4-d]thiazole-2-carboxamide
##STR00462##
[1798] The method described in Referential Example 252 was
performed by use of the compound obtained in Referential Example
323 and the compound obtained in Referential Example 293, whereby
the title compound was obtained.
[1799] .sup.1H-NMR (CDCl.sub.3) .delta.:1.08, 1.15(3H, each t,
J=7.1 Hz), 1.74-1.88(4H, m), 2.12-2.22(2H, m), 2.67(3H, s),
2.81-2.86(1H, m), 2.89, 2.96(3H, each s), 3.28-3.43(2H, m),
3.91-4.10(5H, m), 4.60-4.62(1H, m), 7.21(1H, d, J=7.6 Hz).
[1800] MS (ESI) m/z:392 (M+H).sup.+.
Referential Example 393
2-(4-chloro-3-methoxyanilino)-2-oxoacetic acid methyl ester
##STR00463##
[1802] In a manner similar to that described in Referential Example
361, 2-chloro-5-nitroanisole was reduced to the corresponding amino
compound. In a manner similar to that described in Referential
Example 242, the amino compound was condensed with methyl
chlorooxoacetate, whereby the title compound was obtained.
[1803] .sup.1H-NMR(CDCl.sub.3) .delta.:3.93(3H, s), 3.98(3H, s),
7.00(1H, dd, J=8.5, 2.4 Hz), 7.33(1H, d, J=8.5 Hz), 7.57(1H, d,
J=2.4 Hz), 8.89(1H, br.s).
Referential Example 394
2-(4-chloro-3-methoxyanilino)-2-oxoacetic acid
##STR00464##
[1805] In a manner similar to that described in Referential Example
359, the compound obtained in Referential Example 393 was
hydrolyzed, whereby the title compound was obtained.
[1806] .sup.1H-NMR (DMSO-d.sub.6) .delta.:3.81 (3H, s), 7.36(1H, d,
J=8.7 Hz), 7.43(1H, d, J=8.7 Hz), 7.65(1H, d, J=2.2 Hz), 10.79(1H,
s).
[1807] MS (ESI, anion) m/z:228 (M-H).sup.-.
Referential Example 395
N.sup.1-{(1S, 2R,
4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl)-N.sup.2-(4-chloro-3-me-
thoxyphenyl)ethanediamide
##STR00465##
[1809] In a manner similar to that described in Referential Example
97, the compound obtained in Referential Example 144 was condensed
with the compound obtained in Referential Example 394. In a manner
similar to that described in Referential Example 69, the condensed
compound was treated with hydrochloric acid and neutralized with 1N
aqueous sodium hydroxide, whereby the title compound was
obtained.
[1810] .sup.1H-NMR (CDCl.sub.3) .delta.:1.48-2.00(8H, m),
2.84-2.93(1H, m), 2.95(3H, s), 3.08(3H, s), 3.33-3.35(1H, m),
3.89-3.94(4H, m), 7.06(1H, dd, J=8.5, 2.2 Hz), 7.32(1H, d, J=8.5
Hz), 7.56(1H, d, J=2.2 Hz), 8.05(1H, d, J=8.5 Hz), 9.43(1H,
br.s).
[1811] MS (ESI) m/z:397 (M.sup.+).
Referential Example 396
2-(4-ethynylanilino)-2-oxoacetic acid methyl ester
##STR00466##
[1813] The method described in Referential Example 242 was
performed by use of 4-ethynylaniline and methyl chlorooxoacetate,
whereby the title compound was obtained.
[1814] .sup.1H-NMR (CDCl.sub.3) .delta.:3.09(1H, s), 3.98(3H, s),
7.50(2H, d, J=8.4 Hz), 7.62(2H, d, J=8.4 Hz), 8.89(1H, br.s).
Referential Example 397
2-(4-ethynylanilino)-2-oxoacetic acid sodium salt
##STR00467##
[1816] In a manner similar to that described in Referential Example
266, the compound obtained in Referential Example 396 was
hydrolyzed with sodium hydroxide, whereby the title compound was
obtained.
[1817] .sup.1H-NMR (DMSO-d.sub.6) .delta.:4.06(1H, s), 7.39(2H, d,
J=8.4 Hz), 7.80(2H, d, J=8.4 Hz), 10.33(1H, br.s).
Referential Example 398
2-[(5-chloropyrazin-2-yl)amino]-2-oxoacetic acid methyl ester
##STR00468##
[1819] In a manner similar to that employed in Referential Example
242, the title compound was obtained from methyl chlorooxoacetate
and 2-amino-5-chloropyrazine which had been synthesized according
to the literature (Sato, Nobuhiro et al., J. Heterocycl. Chem.
1982, 19(3), 673-4).
[1820] .sup.1H-NMR (CDCl.sub.3) .delta.:4.02(3H, s), 8.35(1H, d,
J=1.5 Hz), 9.37(1H, d, J=1.5 Hz), 9.41(1H, br.s).
[1821] MS (FAB) m/z:216 (M+H).sup.+.
Referential Example 399
2-[(5-chloropyrazin-2-yl)amino]-2-oxoacetic acid
##STR00469##
[1823] The method described in Referential Example 359 was
performed by use of the compound obtained in Referential Example
398, whereby the title compound was obtained.
[1824] .sup.1H-NMR (DMSO-d.sub.6) .delta.:8.62(1H, s), 9.02(1H,
br.s), 11.30(1H, s).
[1825] MS (EI) m/z:201 M.sup.+.
Referential Example 400
2-(4-chloro-3-nitroanilino)-2-oxoacetic acid
##STR00470##
[1827] In a manner similar to that described in Referential Example
242, 4-chloro-3-nitroaniline was condensed with methyl
chlorooxoacetate. In a manner similar to that described in
Referential Example 359, the condensed compound was hydrolyzed,
whereby the title compound was obtained.
[1828] .sup.1H-NMR (DMSO-d.sub.6) .delta.:7.76(1H, dd, J=8.8 Hz),
8.04(1H, dd, J=8.8, 2.4 Hz), 8.55(1H, d, J=2.4 Hz), 11.24(1H, s).
carboxylic acid proton unobserved.
[1829] MS (EI) m/z:244 M.sup.+.
Referential Example 401
2-(4-chloro-2-nitroanilino)-2-oxoacetic acid sodium salt
##STR00471##
[1831] In a manner similar to that described in Referential Example
242, 4-chloro-2-nitroaniline was condensed with methyl
chlorooxoacetate. In a manner similar to that described in
Referential Example 266, the condensed compound was hydrolyzed. The
residue was dissolved in methanol, 1N aqueous sodium hydroxide was
added thereto, and the precipitated material was recovered by
filtration, whereby the title compound was obtained.
[1832] .sup.1H-NMR (DMSO-d.sub.6) .delta.:7.84 (1H, dd, J=9.0, 2.5
Hz), 8.20(1H, d, J=2.5 Hz), 8.67(1H, d, J=9.0 Hz), 11.89(1H,
s).
Referential Example 402
6-chloro-4-methyl-3-pyridineamine
##STR00472##
[1834] 2-Chloro-4-methyl-5-nitropyridine (173 mg) was dissolved in
ethanol (5 mL). To the solution, a catalytic amount of Raney nickel
was added, and the resultant mixture was stirred in a hydrogen
atmosphere at room temperature for 9 hours. The catalyst was
removed through filtration, and the solvent was distilled away
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane:ethyl acetate=3:2), to thereby give
the title compound (113 mg).
[1835] .sup.1H-NMR (CDCl.sub.3) .delta.:2.13(3H, s), 3.85(2H,
br.s), 6.96(1H, s), 7.74(1H, s).
[1836] MS (EI) m/z:142 M.sup.+.
Referential Example 403
N.sup.1-(2-aminophenyl)-N.sup.2-(4-chlorophenyl)ethanediamide
##STR00473##
[1838] In a manner similar to that described in Referential Example
59, 1, 2-benzenediamine was condensed with the compound obtained in
Referential Example 374, whereby the title compound was
obtained.
[1839] .sup.1H-NMR (DMSO-d.sub.6) .delta.:5.00 (2H, s),
6.59-6.63(1H, m), 6.78(1H, dd, J=8.1, 1.2 Hz), 6.96-7.01(1H, m),
7.25(1H, dd, J=7.8, 1.2 Hz), 7.44(2H, d, J=8.8 Hz), 7.91(2H, d,
J=8.8 Hz), 10.04(1H, s), 10.91(1H, s).
[1840] MS (FAB):290 (M+H).sup.+.
Referential Example 404
N-((1R, 2S,
5S)-2-azido-5-{[ethyl(methyl)amino]carbonyl}cyclohexyl)-5-methyl-4,5,6,7--
tetrahydrothiazolo[5, 4-c]pyridine-2-carboxamide
##STR00474##
[1842] In a manner similar to that described in Referential Example
252, the compound obtained in Referential Example 323 was treated
with hydrochloric acid for deprotection. The deprotected compound
was condensed with the compound obtained in Referential Example 10,
whereby the title compound was obtained.
[1843] .sup.1H-NMR (CDCl.sub.3) .delta.:1.08(1/2 of 3H, t, J=7.2
Hz), 1.14(1/2 of 3H, t, J=7.2 Hz), 1.70-1.90(4H, m), 2.10-2.25(2H,
m), 2.52(3H, s), 2.78-3.00(8H, m), 3.25-3.45(2H, m), 3.69(1H, d,
J=13.4 Hz), 3.73(1H, d, J=13.4 Hz), 3.87-3.95(1H, m), 4.55-4.62(1H,
m), 7.26(1H, d, J=7.6 Hz).
Referential Example 405
2-(4-chlorophenyl)-1-hydrazinecarboxylic acid phenyl ester
##STR00475##
[1845] (4-Chlorophenyl)hydrazine hydrochloride (3.00 g) was added
to a mixture of tetrahydrofuran (50 mL), diethyl ether (50 mL), and
saturated aqueous sodium hydrogencarbonate. The organic layer was
separated, followed by drying over sodium sulfate anhydrate and
concentrating, to thereby give (4-chlorophenyl)hydrazine as a brown
solid. The solid was dissolved in benzene (15 mL), and the solution
was heated under reflux. Under refluxing, diphenyl carbonate (5.22
g) dissolved in benzene (8.0 mL) was added dropwise thereto over 30
minutes or more. The mixture was refluxed for 19 hours, allowed to
cool to room temperature, and concentrated. Benzene (15 mL) was
added thereto, and the mixture was slurried by ultrasonic wave.
Hexane (50 mL) was added thereto, and the resultant mixture was
stirred for 30 minutes. The insoluble material was recovered by
filtration, followed by drying, to thereby give the title compound
(1.05 g).
[1846] .sup.1H-NMR (CDCl.sub.3) .delta.:5.86(1H, br.s),
6.83-6.92(3H, m), 7.17 (1H, br.s), 7.20-7.32(4H, m), 7.37(2H, t,
J=7.7 Hz).
[1847] MS (ESI) m/z:263 (M+H).sup.+.
Referential Example 406
5-tert-butoxycarbonyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole-2-carboxylic
acid lithium salt
##STR00476##
[1849] The method described in Referential Example 10 was performed
by use of the compound obtained in Referential Example 33, whereby
the title compound was obtained.
[1850] .sup.1H-NMR (DMSO-d.sub.6) .delta.1.46(9H, s), 4.30-4.70(4H,
m).
Referential Example 407
1-hydroxycyclopropanecarboxylic acid benzyl ester
##STR00477##
[1852] Triethylamine (1.0 mL) and benzyl bromide (650 .mu.L) were
added to a solution of 1-hydroxycyclopropanecarboxylic acid (409
mg) in tetrahydrofuran (3.0 mL), and the mixture was stirred at
room temperature for 23 hours. To the reaction mixture were added
methylene chloride and 1N aqueous hydrochloric acid to thereby give
two layers. The organic layer was washed with saturated aqueous
sodium hydrogencarbonate and saturated brine, followed by drying
over sodium sulfate, to thereby give a crude product. The crude
product was subjected to purification through silica gel column
chromatography (hexane:ethyl acetate=4:1), to thereby give the
title compound (607 mg).
[1853] .sup.1H-NMR (CDCl.sub.3) .delta.:1.16(2H, dd, J=7.9, 4.9
Hz), 1.32(2H, dd, J=7.9, 4.9 Hz), 3.09(0.5H, s), 3.11(0.5H, s),
5.17(2H, s), 7.30-7.39(5H, m).
[1854] MS (FAB) m/z:192 (M+H).sup.+.
Referential Example 408
1-methoxycyclopropanecarboxylic acid benzyl ester
##STR00478##
[1856] The compound (600 mg) obtained in Referential Example 407
was dissolved in tetrahydrofuran (5.0 mL). To the solution, 60%
oily sodium hydride (345 mg) and methyl iodide (900 .mu.L) were
added, and the mixture was refluxed for 28 hours. Ethyl acetate and
saturated aqueous ammonium chloride were added to the reaction
mixture to thereby give two layers. The organic layer was washed
with saturated brine, followed by drying over sodium sulfate, to
thereby give a crude product. The crude product was subjected to
purification through silica gel column chromatography (hexane:ethyl
acetate=10:1), to thereby give the title compound (340 mg).
[1857] .sup.1H-NMR (CDCl.sub.3) .delta.:1.16(2H, dd, J=7.9, 4.8
Hz), 1.31(2H, dd, J=7.9, 4.8 Hz), 3.42(3H, s), 5.18(2H, s),
7.30-7.39(5H, m).
[1858] MS (FAB) m/z:207 (M+H).sup.+.
Referential Example 409
1-methoxycyclopropanecarboxylic acid
##STR00479##
[1860] The method described in Referential Example 152 was
performed by use of the compound obtained in Referential Example
408, whereby the title compound was obtained.
[1861] .sup.1H-NMR (CDCl.sub.3) .delta.:1.23(2H, dd, J=8.0, 4.9
Hz), 1.38(2H, dd, J=8.0, 4.9 Hz), 3.45(3H, s), 8.80-9.00(1H,
br).
Referential Example 410
(3R,
4S)-4-{[(7-chloroisoquinolin-3-yl)carbonyl]amino}-1-(2-methoxyacetyl)-
piperidin-3-ylcarbamic acid tert-butyl ester
##STR00480##
[1863] The method described in Referential Example 214 was
performed by use of the compound obtained in Referential Example
220 and the compound obtained in Referential Example 57, whereby
the title compound was obtained.
[1864] .sup.1H-NMR (CDCl.sub.3) .delta.:1.46(9H, br s),
1.62-1.80(1H, m), 2.04-2.22(1H, m), 2.95-3.32(1H, m), 3.38-3.53(1H,
m), 3.46(3H, s), 3.84-3.95(1H, m), 4.02-4.27(3H, m), 4.30-4.65(2H,
m), 4.87-4.98(0.5H, br), 5.32-5.43(0.5H, br), 7.71(1H, dd, J=8.8,
2.0 Hz), 7.94(1H, d, J=8.8 Hz), 8.02(1H, s), 8.55-8.66(0.7H, br),
8.58(1H, s), 8.73-8.85(0.3H, br), 9.14(1H, br s).
[1865] MS (ESI) m/z:477 (M+H).sup.+.
Referential Example 411
(3R,
4S)-4-([2-(4-chloro-3-fluoroanilino)-2-oxoacetyl]amino}-1-(2-methoxya-
cetyl)piperidin-3-ylcarbamic acid tert-butyl ester
##STR00481##
[1867] In a manner similar to that described in Referential Example
214, the compound obtained in Referential Example 220 was condensed
with the compound obtained in Referential Example 377, whereby the
title compound was obtained.
[1868] .sup.1H-NMR (CDCl.sub.3) .delta.:1.46(9H, s), 1.60-1.75(1H,
m), 1.92-2.08(1H, m), 2.68-2.80(0.5H, m), 2.88-3.03(0.5H, m),
3.06-3.24(0.5H, m), 3.27-3.36(0.5H, m), 3.45(3H, s), 3.90-4.22(5H,
m), 4.56-4.71(1H, m), 4.80-4.92(0.3H, br), 5.44-5.54(0.7H, br),
7.24(1H, d, J=12.9 Hz), 7.35(1H, t, J=8.3 Hz), 7.72(1H, dd, J=8.3,
2.3 Hz), 8.20-8.42(1H, br), 9.18-9.28(1H, br).
[1869] MS (ESI) m/z:487 (M+H).sup.+.
Referential Example 412
(3R,
4S)-4-({2-[(5-chloro-2-thienyl)amino]-2-oxoacetyl}amino)-1-(2-methoxy-
acetyl)piperidin-3-ylcarbamic acid tert-butyl ester
##STR00482##
[1871] The method described in Referential Example 214 was
performed by use of the compound obtained in Referential Example
220 and a lithium salt of carboxylic acid prepared by hydrolysis of
the compound obtained in Referential Example 356, whereby the title
compound was obtained.
[1872] .sup.1H-NMR (CDCl.sub.3) .delta.:1.45(9H, s), 1.55-1.75(1H,
br), 1.90-2.10(1H, br), 2.68-2.80(0.7H, m), 2.90-3.03(0.3H, br),
3.07-3.22(0.3H, br), 3.25-3.35(0.7H, br), 3.45(3H, s),
3.83-4.22(5H, m), 4.55-4.70(1H, br), 4.80-4.90(0.2H, br),
5.07-5.14(0.2H, br), 5.44-5.55(0.6H, br), 6.58-6.64(1H, br),
6.73(1H, d, J=3.9 Hz), 8.05-8.27(1H, br), 9.65-9.88(1H, br).
[1873] MS (FAB) m/z:475 (M+H).sup.+.
Referential Example 413
5-methyl-5H-pyrrolo[3,4-d]thiazolo-2-carboxylic acid ethyl
ester
##STR00483##
[1875] 1) To a solution of 3-bromo-2-butanone (26.36 g) in ethanol
(250 mL), was added ethyl 2-thioxoacetate (26.75 g), and the
mixture was refluxed for 14 hours. The reaction mixture was cooled,
and concentrated under reduced pressure. Ethyl acetate and
saturated brine were added to the residue to thereby give two
layers. The organic layer was washed with saturated aqueous sodium
hydrogencarbonate and saturated brine, followed by drying over
sodium sulfate anhydrate. The solvent was concentrated under
reduced pressure, and the residue was purified by silica gel column
chromatography (hexane : ethyl acetate =6:1), to thereby give ethyl
4,5-dimethylthiazole-2-carboxylate (19.53 g).
[1876] .sup.1H-NMR (CDCl.sub.3) .delta.:1.42(3H, t, J=7.1 Hz),
2.42(3H, s), 2.44(3H, s), 4.45(2H, q, J=7.1 Hz).
[1877] 2) The above product (19.53 g) was dissolved in
1,2-dichloroethane (500 mL). To the solution were added
N-bromosuccinimide (62.42 g) and 2,2'-azobisisobutyronitrile (227
mg), and the mixture was refluxed for 42 hours. The reaction
mixture was cooled, and water and methylene chloride were added
thereto to thereby give two layers. The organic layer was washed
with saturated brine, followed by concentrating under reduced
pressure, thereby yielding a crude product (40.54 g) as dark brown
oil. The crude product (8.41 g) was dissolved in acetonitrile (400
mL). To the solution, triethylamine (8.0 mL) and a solution (11.0
mL) of methylamine (2 mol) in tetrahydrofuran were added at
0.degree. C., and the mixture was stirred at room temperature for 3
days. The reaction mixture was concentrated under reduced pressure.
Methylene chloride and saturated brine were added to the residue to
thereby give two layers. The organic layer was washed with
saturated brine, followed by drying over sodium sulfate anhydrate.
The solvent was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=3:1), to thereby give the title compound (270 mg).
[1878] .sup.1H-NMR (CDCl.sub.3) .delta.:1.45(3H, t, J=7.1 Hz),
3.91(3H, s), 4.48 (2H, q, J=7.1 Hz), 6.73(1H, d, J=1.7 Hz),
7.30(1H, d, J=1.7 Hz).
[1879] MS (ESI) m/z:211 (M+H).sup.+.
Referential Example 414
6-chloro-4-oxo-4H-chromene-2-carboxylic acid ethyl ester
##STR00484##
[1881] In an argon atmosphere, ca. 60% oily sodium hydride (1.68 g)
was added to ethanol (10 mL). The mixture was stirred at room
temperature for 10 minutes. Diethyl oxalate (3.36 mL) was added
thereto, 5'-chloro-2'-hydroxyacetophenone (2.82 g) dissolved in
ethanol (20 mL) was added dropwise to the resultant mixture, and
ethanol (40 mL) was further added, followed by refluxing for 1.5
hours and stirring at 50.degree. C. for 14 hours. To the reaction
mixture, concentrated sulfuric acid (1.5 mL) and ethanol (10 mL)
were added, and the mixture was refluxed for 4 hours. The resultant
mixture was cooled, concentrated under reduced pressure to reduce
the solvent by half, and toluene and 1N aqueous sodium hydroxide
(15 mL) were added to the concentrated mixture. The resultant
mixture was extracted with ethyl acetate, and the organic layer was
washed with saturated brine, followed by drying over sodium sulfate
anhydrate. The solvent was concentrated under reduced pressure, and
the residue was purified by silica gel column chromatography
(hexane:ethyl acetate=7:1). The resultant solid was washed with
hexane, to thereby give the title compound (1.20 g).
[1882] .sup.1H-NMR (CDCl.sub.3) .delta.:1.44(3H, t, J=7.1 Hz),
4.47(2H, q, J=7.1 Hz), 7.12(1H, s), 7.58(1H, d, J=9.0 Hz), 7.69(1H,
dd, J=9.0, 2.7 Hz), 8.16(1H, d, J=2.7 Hz).
[1883] MS (ESI) m/z:293 (M+MeCN+H).sup.+.
Referential Example 415
6-chloro-4-oxo-4H-chromene-2-carboxylic acid
##STR00485##
[1885] The method described in Referential Example 359 was
performed by use of the compound obtained in Referential Example
414, whereby the title compound was obtained.
[1886] .sup.1H-NMR (CDCl.sub.3) .delta.:7.12(1H, s), 7.60(1H, d,
J=8.8 Hz), 7.69(1H, dd, J=8.8, 2.7 Hz), 8.15(1H, d, J=2.7 Hz).
[1887] MS (FAB) m/z:225 (M+H).sup.+.
Referential Example 416
(1S, 3R,
4S)-4-amino-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic
acid ethyl ester
##STR00486##
[1889] The method described in Referential Example 90 was performed
by use of the compound obtained in Referential Example 249, whereby
the title compound was obtained.
[1890] .sup.1H-NMR (CDCl.sub.3) .delta.:1.20-1.80(4H, m), 1.25(3H,
t, J=7.3 Hz), 1.46(9H, s), 1.85-2.00(1H, m), 2.10-2.20(1H, m),
2.30-2.45(1H, m), 2.90-3.00(1H, m), 3.84(1H, br s), 4.12(2H, q,
J=7.3 Hz), 4.75(1H, br s).
Referential Example 417
(1R, 2S,
5S)-2-{[(6-chloro-4-oxo-4H-chromen-2-yl)carbonyl]amino)-5-[(dimet-
hylamino)carbonyl]cyclohexylcarbamic acid tert-butyl ester
##STR00487##
[1892] The compound (213 mg) obtained in Referential Example 415
was dissolved in thionyl chloride (2.0 mL). N,N-Dimethylformamide
(0.02 mL) was added thereto, and the mixture was refluxed for 15
minutes. The reaction mixture was concentrated under reduced
pressure, and the residue was dissolved in tetrahydrofuran (4.0
mL). To the solution, triethylamine (500 .mu.L) and the compound
(294 mg) obtained in Referential Example 144 were added, followed
by stirring at room temperature for 15 minutes. To the reaction
mixture, ethyl acetate and 10% aqueous citric acid were added to
thereby give two layers. The organic layer was washed with
saturated aqueous sodium hydrogencarbonate and saturated brine,
followed by drying over sodium sulfate anhydrate and concentrating
under reduced pressure. The residue was purified by silica gel
column chromatography (methylene chloride:methanol=30:1), to
thereby give the title compound (230 mg).
[1893] .sup.1H-NMR (CDCl.sub.3) .delta.:1.33-1.77(3H, m), 1.50(9H,
s), 1.81-2.34(3H, m), 2.63-2.80(1H, m), 2.95(3H, s), 3.10(3H, s),
3.90-4.04(1H, br), 4.18-4.31(1H, br), 4.93-5.12(1H, br), 7.13(1H,
s), 7.55(1H, d, J=8.8 Hz), 7.66(1H, dd, J=8.8, 2.4 Hz), 8.14(1H, d,
J=2.4 Hz), 8.77-8.92(1H, br).
[1894] MS (ESI) m/z:492 (M+H).sup.+.
Referential Example 418
(3R,
4S)-4-{[(7-chlorocinnolin-3-yl)carbonyl]amino}-1-(2-methoxyacetyl)pip-
eridin-3-ylcarbamic acid tert-butyl ester
##STR00488##
[1896] The method described in Referential Example 214 was
performed by use of the compound obtained in Referential Example
220 and a lithium salt of carboxylic acid obtained by hydrolysis of
the ester described in Referential Example 297, whereby the title
compound was obtained.
[1897] .sup.1H-NMR (CDCl.sub.3) .delta.:1.38(9H, s), 1.65-1.90(1H,
m), 1.90-2.15(1H, m), 2.80-3.00(0.6H, m), 3.00-3.15(0.4H, m),
3.20-3.50(1H, m), 3.46(3H, s), 3.80-4.70(6H, m), 4.87(0.4H, br s),
5.30(0.6H, br s), 7.78(1H, d, J=8.8 Hz), 7.97(1H, d, J=8.8 Hz),
8.61(1H, s), 8.62-8.90(1H, br), 8.73(1H, s).
[1898] MS (ESI) m/z:478 (M+H).sup.+.
Referential Example 419
(1R, 2S,
5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-[(di-
methylamino)carbonyl]cyclohexylcarbamic acid tert-butyl ester
##STR00489##
[1900] In a manner similar to that described in Referential Example
68, the compound obtained in Referential Example 144 was condensed
with the compound obtained in Referential Example 266, whereby the
title compound was obtained.
[1901] .sup.1H-NMR (CDCl.sub.3) .delta.:1.35-1.65(1H, m), 1.45(9H,
s), 1.65-1.89(2H, m), 1.90-2.10(3H, m), 2.56-2.74(1H, br), 2.95(3H,
s), 3.06(3H, s), 3.94-4.01(1H, m), 4.18-4.27(1H, m),
4.70-4.90(0.7H, br), 5.80-6.20(0.3H, br), 7.68(1H, dd, J=8.9, 2.6
Hz), 7.83(1H, br s), 8.14(1H, br d, J=7.8 Hz), 8.30(1H, s),
9.72(1H, s).
[1902] MS (ESI) m/z:468 (M+H).sup.+.
Referential Example 420
N.sup.1-{(1S, 2R,
4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl}-N.sup.2-(5-chloropyrid-
in-2-yl)ethanediamide hydrochloride
##STR00490##
[1904] The method described in Referential Example 69 was performed
by use of the compound obtained in Referential Example 419, whereby
the title compound was obtained.
[1905] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.38-1.51 (1H, m),
1.65-1.85(3H, m), 1.96-2.10(2H, m), 2.81(3H, s), 3.07(3H, s),
3.23-3.33(1H, m), 3.74(1H, br s), 3.84-3.92(1H, m), 8.02(1H, dd,
J=9.0, 2.5 Hz), 8.07(1H, d, J=9.0 Hz), 8.34(3H, br s), 8.46(1H, d,
J=2.5 Hz), 8.96(1H, d, J=6.6 Hz), 10.34(1H, s).
[1906] MS (ESI) m/z:368 (M+H).sup.+.
Referential Example 421
2-[({(1R, 2S,
5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-[(dimethylam-
ino)carbonyl]cyclohexyl]amino)carbonyl]-6,7-dihydrothieno[3,2-c]pyridine-5-
(4H)-carboxylic acid tert-butyl ester
##STR00491##
[1908] The compound obtained in Referential Example 420 was
condensed with
5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxy-
lic acid (WO94/21599), whereby the title compound was obtained.
[1909] .sup.1H-NMR (CDCl.sub.3) .delta.:1.50(9H, s), 1.73-1.95(3H,
m), 1.95-2.06(1H, m), 2.08-2.20(2H, m), 2.82(3H, br s), 2.94(3H,
s), 3.03(3H, s), 3.60-3.80(2H, m), 3.96-4.08(1H, m), 4.44(2H, br
s), 4.66(1H, br s), 6.74(1H, br s), 7.20-7.32(1H, m), 7.66(1H, dd,
J=9.0, 2.4 Hz), 8.13(1H, d, J=9.0 Hz), 8.13-8.25(1H, m), 8.28(1H,
d, J=2.4 Hz), 9.75(1H, s).
[1910] MS (ESI) m/z:633 (M+H).sup.+.
Referential Example 422
2-chloro-N-(4-fluorophenyl)acetamide
##STR00492##
[1912] The method described in Referential Example 350 was
performed by use of p-fluoroaniline, whereby the title compound was
obtained.
[1913] .sup.1H-NMR (CDCl.sub.3) .delta.:4.19(2H, s), 7.05(2H, t,
J=8.6 Hz), 7.51(2H, dd, J=9.1, 4.7 Hz), 8.19(1H, br s).
Referential Example 423
S-[2-(4-fluoroanilino)-2-oxoethyl]thiosulfuric acid sodium salt
##STR00493##
[1915] The method described in Referential Example 351 was
performed by use of the compound obtained in Referential Example
422, whereby the title compound was obtained.
[1916] .sup.1H-NMR (DMSO-d.sub.6) .delta.:3.72 (2H, s), 7.14(2H, t,
J=9.0 Hz), 7.56(2H, dd, 5.1 Hz), 10.21(1H, s).
Referential Example 424
(1R, 2S,
5S)-5-[(dimethylamino)carbonyl]-2-{[2-(4-fluoroanilino)-2-oxoetha-
nethioyl]amino)cyclohexylcarbamic acid tert-butyl ester
##STR00494##
[1918] The compound (1.1 g) obtained in Referential Example 144 and
the compound (1.24 g) obtained in Referential Example 423 were
dissolved in N-methylmorpholine (20 mL). The solution was heated
from room temperature to 140.degree. C. on a bath over 15 minutes
and stirred at 140.degree. C. for 15 minutes. The reaction mixture
was allowed to cool to room temperature, a mixture of ice and water
was added thereto, and the insoluble material was recovered by
filtration. The material was purified by silica gel column
chromatography (methylene chloride:methanol=200:1.fwdarw.197:3), to
thereby give the title compound (1.43 g).
[1919] .sup.1H-NMR (CDCl.sub.3) .delta.:1.45(9H, s), 1.70-2.10(5H,
m), 2.10-2.30(1H, m), 2.60-2.80(1H, m), 2.96(3H, s), 3.07(3H, s),
4.30-4.50(2H, m), 4.65-4.85(1H, m), 7.06(2H, t, J=8.5 Hz),
7.50-7.70(2H, m), 9.75-9.95(1H, m), 10.13(1H, s).
[1920] MS (ESI) m/z:467 (M+H).sup.+.
Referential Example 425
2-chloro-N-(5-fluoropyridin-2-yl)acetamide hydrochloride
##STR00495##
[1922] The method described in Referential Example 352 was
performed by use of 2-amino-5-fluoropyridine, whereby the title
compound was obtained.
[1923] .sup.1H-NMR (DMSO-d.sub.6) .delta.:4.35(2H, s),
7.74-7.82(1H, m), 8.10(1H, dd, J=9.0, 4.2 Hz), 8.36(1H, d, J=2.9
Hz), (1H, br s).
[1924] MS (ESI) m/z:188 (M+H).sup.+.
Referential Example 426
S-{2-[(5-fluoropyridin-2-yl)amino]-2-oxoethyl}thiosulfuric acid
sodium salt
##STR00496##
[1926] The method described in Referential Example 353 was
performed by use of the compound obtained in Referential Example
425, whereby the title compound was obtained.
[1927] .sup.1H-NMR (DMSO-d.sub.6) .delta.:3.75(2H, s),
7.67-7.77(1H, m), 8.07(1H, dd, J=9.2, 4.2 Hz), 8.28(1H, d, J=2.9
Hz), 10.48(1H, s).
Referential Example 427
(1R, 2S,
5S)-5-[(dimethylamino)carbonyl]-2-({2-[(5-fluoropyridin-2-yl)amin-
o]-2-oxoethanethioyl}amino)cyclohexylcarbamic acid tert-butyl
ester
##STR00497##
[1929] The compound (1.20 g) obtained in Referential Example 144
was dissolved in pyridine (70 mL). The resultant solution was
heated at 120.degree. C., and the compound (2.42 g) obtained in
Referential Example 426 was added thereto. The resultant mixture
was stirred for 30 minutes and then allowed to cool to room
temperature, and the solvent was distilled away under reduced
pressure. Methylene chloride (100 mL), saturated aqueous sodium
hydrogencarbonate (100 mL), and water (50 mL) were added to the
residue for partitioning the mixture. The aqueous layer was
extracted with methylene chloride. The organic layers were
combined, followed by drying over sodium sulfate anhydrate. The
solvent was distilled away under reduced pressure, and the residue
was purified by silica gel column chromatography
(hexane:tetrahydrofuran=1:1). The resultant solid was slurried in
isopropyl ether (40 mL) for 1 hour, and the solid was recovered by
filtration, followed by drying, to thereby give the title compound
(920 mg).
[1930] .sup.1H-NMR (CDCl.sub.3) .delta.:1.47(9H, s), 1.70-2.10(5H,
m), 2.27(1H, br s), 2.70(1H, br s), 2.96(3H, s), 3.08(3H, s),
4.34-4.44(2H, m), 4.77(1H, br s), 7.44-7.51(1H, m), 8.18-8.27(2H,
m), 9.90(1H, br s), 10.57(1H, s).
[1931] MS (ESI) m/z:468 (M+H).sup.+.
Referential Example 428
(1R, 2S,
5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoethanethioyl}amino)--
5-[(dimethylamino)carbonyl]cyclohexylcarbamic acid tert-butyl
ester
##STR00498##
[1933] The method described in Referential Example 427 was
performed by use of the compound obtained in Referential Example
144 and the compound obtained in Referential Example 353, whereby
the title compound was obtained.
[1934] .sup.1H-NMR (CDCl.sub.3) .delta.:1.43(9H, s), 1.65-2.35(6H,
m), 2.70(1H, br s), 2.95(3H, s), 3.09(3H, s), 4.30-4.60(2H, m),
4.87(1/2H, br s), 6.92(1/2H, br s), 7.69(1H, dd, J=8.9, 2.6 Hz),
7.95-8.20(1H, br), 8.29(1H, s), 9.67(1/2H, br s), 9.93(1/2H, br s),
10.54(1H, br s).
Referential Example 429
2-chloro-4,5,6,7-tetrahydrobenzothiazol-6-ylformamide
##STR00499##
[1936] To a solution of
2-chloro-5-oxo.sup.-4,5,6,7-tetrahydrobenzo[d]thiazole (Helv. Cim.
Acta., 1994, Vol.77, 1256) (4.53 g) in methanol (200 mL), were
added ammonium acetate (18.58 g) and sodium cyanoborohydride (10.68
g), and the mixture was heated under reflux. After 19 hours had
elapsed, hydrochloric acid was added thereto to decompose excess
reagents. The reaction mixture was concentrated under reduced
pressure, alkalized with 1N aqueous sodium hydroxide, and methylene
chloride was added thereto for partitioning the mixture. The
organic layer was dried over magnesium sulfate anhydrate, and the
solvent was distilled away under reduced pressure. The residue was
subjected to silica gel column chromatography (methylene
chloride:methanol=20:1), and the solvent was distilled away to
thereby give a light yellow oily compound (2.42 g). The oily
compound was dissolved in methylene chloride (100 mL). To the
resultant solution were added formic acid (530 .mu.L),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.68
g), 1-hydroxybenzotriazole (2.60 g), and N-methylmorpholine (3.88
g), followed by stirring at room temperature. After 20 hours had
elapsed, methylene chloride and saturated aqueous sodium
hydrogencarbonate were added to the reaction mixture for
partitioning the mixture. The organic layer was dried over
magnesium sulfate anhydrate, and the solvent was distilled away
under reduced pressure. The residue was subjected to silica gel
column chromatography (methylene chloride:methanol=20:1), to
thereby give the title compound (2.21 g).
[1937] .sup.1H-NMR (CDCl.sub.3) .delta.:1.93-2.11(2H, m),
2.63-2.69(1H, m), 2.83-2.89(2H, m), 3.13(1H, dd, J=16.2, 4.4 Hz),
4.46-4.48(1H, m), 5.76(1H, br s), 8.17(1H, s).
Referential Example 430
N-(2-chloro-4,5,6,7-tetrahydrobenzothiazol-6-yl)-N-methylcarbamic
acid tert-butyl ester
##STR00500##
[1939] The compound (2.11 g) obtained in Referential Example 429
was dissolved in tetrahydrofuran (50 mL). To the solution, a 1M
solution (14.6 mL) of borane-tetrahydrofuran complex in
tetrahydrofuran was added, and the resultant mixture was heated
under reflux. After 15 hours had elapsed, a 1M solution (6.0 mL) of
borane-tetrahydrofuran complex in tetrahydrofuran was further added
thereto, followed by refluxing under heat. After 4 hours had
elapsed, ethanol (10 mL) and 1N hydrochloric acid (15 mL) were
added thereto, and the resultant mixture was heated under reflux.
After 3 hours had elapsed, the reaction mixture was concentrated
under reduced pressure. 1N Aqueous sodium hydroxide and methylene
chloride were added thereto for partitioning the mixture. The
organic layer was dried over magnesium sulfate anhydrate, and the
solvent was distilled away under reduced pressure. The residue was
dissolved in methylene chloride (50 mL), and triethylamine (1.28 g)
and di-tert-butyl dicarbonate (2.21 g) were added thereto, followed
by stirring at room temperature. After 30 minutes had elapsed,
methylene chloride and 1N hydrochloric acid were added to the
reaction mixture for partitioning the mixture. The organic layer
was dried over magnesium sulfate anhydrate, and the solvent was
distilled away under reduced pressure. The residue was subjected to
silica gel column chromatography (hexane:ethyl acetate=2:1), to
thereby give the title compound (2.26 g).
[1940] .sup.1H-NMR (CDCl.sub.3) .delta.:1.47(9H, s), 1.96-1.98(2H,
m), 2.80-2.96(7H, m), 4.40-4.50(1H, m).
[1941] MS (FAB) m/z:303 (M+H).sup.+.
Referential Example 431
N-(2-[({(1R, 2S,
5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-[(dimethylam-
ino)carbonyl]cyclohexyl}amino)carbonyl]-4,5,6,7-tetrahydrobenzothiazol-6-y-
l)-N-methylcarbamic acid tert-butyl ester
##STR00501##
[1943] The compound (1.0 g) obtained in Referential Example 430 was
dissolved in diethyl ether (10 mL)-tetrahydrofuran (5 mL), and the
solution was cooled to -78.degree. C. 1.6N Tert-butyllithium
pentane solution (3.1 mL) was added thereto, the resultant mixture
was stirred for 20 minutes, and carbon dioxide gas was injected
thereto for 20 minutes. The temperature of the reaction mixture was
returned to room temperature, and the mixture was concentrated
under reduced pressure, to thereby give
6-[(tert-butoxycarbonyl)(methyl)amino]-4,5,6,7-tetrahydrobenzothiazole-2--
carboxylic acid lithium salt.
[1944] The compound (490.5 mg) obtained in Referential Example 420
was dissolved in N,N-dimethylformamide (20 mL). To the resultant
solution were added the above carboxylic acid lithium salt (350.2
mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(287.6 mg), 1-hydroxybenzotriazole (202.7 mg), and
N-methylmorpholine (0.319 mL), followed by stirring at room
temperature for 4 days. The solvent was distilled away under
reduced pressure. Water and methylene chloride were added to the
residue for partitioning the mixture. The organic layer was
sequentially washed with saturated aqueous sodium hydrogencarbonate
and saturated brine. The resultant mixture was dried over sodium
sulfate anhydrate, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (methylene
chloride:methanol=40:1 -4 20:1), to thereby give the title compound
(323.9 mg).
[1945] .sup.1H-NMR (CDCl.sub.3) .delta.:1.48, 1.49(total 9H, each
s), 1.60-1.92(4H, m), 1.95-2.20(6H, m), 2.78-3.10(3H, m), 2.83 (3H,
s), 2.95(3H, s), 3.06, 3.07 (total 3H, each s), 4.05-4.15(1H, m),
4.20-4.60(1H, m), 4.63-4.73(1H, m), 7.39(1H, d, J=8.6 Hz), 7.68(1H,
dt, J=8.8, 2.6 Hz), 7.95-8.10(1H, m), 8.13-8.22(1H, m),
8.30-8.35(1H, m), 9.72(1H, brs).
[1946] MS (ESI) m/z:662 (M+H).sup.+.
Referential Example 432
N-{(1S, 2R,
4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl}-5-chloroindole-2-carbo-
xamide hydrochloride
##STR00502##
[1948] In a manner similar to that described in Referential Example
69, the compound obtained in Referential Example 310 was
deprotected, whereby the title compound was obtained.
[1949] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.43-1.56(0.5H, m),
1.72-1.97(4.5H, m), 2.82(3H, s), 3.06(3H, s), 3.11-3.26(1H, m),
3.75-3.84(1H, m), 4.07-4.14(1H, m), 4.22-4.41(1H, m), 7.19(1H, dd,
J=2.0, 8.8 Hz), 7.29(1H, d, J=2.0 Hz), 7.45(1H, d, J=8.8 Hz),
7.72(1H, s), 8.07(3H, br), 8.47(1H, m), 11.85(1H, br).
Referential Example 433
2-[(5-chloropyridin-2-yl)amino]-2-oxoacetic acid lithium salt
##STR00503##
[1951] Methyl chlorooxoacetate (78.7 mL) was added dropwise at
0.degree. C. to a suspension of 2-amino-5-chloropyridine (100 g)
and sodium hydrogencarbonate (78.4 g) in tetrahydrofuran (2,000
mL), the resultant mixture was stirred at room temperature for 2
hours. Under stirring, the reaction mixture was added to a mixture
of diethyl ether (2,000 mL), ammonium chloride (62.4 g), and water
(1,000 mL). The resultant mixture was partitioned, and the aqueous
layer was extracted with methylene chloride. The organic layers
were combined, followed by drying over sodium sulfate anhydrate.
The solvent was distilled away under reduced pressure, followed by
drying to thereby give 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetic
acid methyl ester (162 g). The ester (160 g) was dissolved in
tetrahydrofuran (1,800 mL), and water (450 mL) and lithium
hydroxide (18.2 g) were added to the solution, followed by stirring
at room temperature for 2 hours. The solvent was distilled away
under reduced pressure, and hexane (3,000 mL) was added to the
residue. The resultant mixture was stirred for 3 hours. The
resultant solid was recovered by filtration, followed by drying.
Acetonitrile (1,000 mL) was added to the solid (190 g), and the
resultant mixture was stirred for 1 hour. The resultant solid was
recovered by filtration, followed by washing with diethyl ether
(500 mL) and drying, to thereby give the title compound (158
g).
[1952] .sup.1H-NMR (DMSO-d.sub.6) .delta.:7.92(1H, dd, J=9.1, 2.7
Hz), 8.13(1H, dd, J=9.1, 0.5 Hz), 8.36(1H, dd, J=2.7, 0.5 Hz),
10.19(1H, s).
Referential Example 434
(1R, 2S,
5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-[(di-
methylamino)carbonyl]cyclohexylcarbamic acid tert-butyl ester
##STR00504##
[1954] The method described in Referential Example 91 was performed
by use of the compound obtained in Referential Example 144 and the
compound obtained in Referential Example 433, whereby the title
compound was obtained.
[1955] .sup.1H-NMR (CDCl.sub.3) .delta.:1.25-1.55(1H, m), 1.45(9H,
s), 1.60-2.15(5H, m), 2.56-2.74(1H, br), 2.95(3H, s), 3.06(3H, s),
3.90-4.01(1H, m), 4.18-4.27(1H, m), 4.70-4.85(0.7H, br),
5.70-6.00(0.3H, br), 7.70(1H, dd, J=8.8, 2.4 Hz), 7.75-8.00(1H,
br), 8.16(1H, br d, J=8.8 Hz), 8.30(1H, d, J=2.4 Hz), 9.73(1H,
s).
[1956] MS (ESI) m/z:468 (M+H).sup.+.
Referential Example 435
N.sup.1-{(1S, 2R,
4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl}-N.sup.2-(5-chloropyrid-
in-2-yl)ethanediamide hydrochloride
##STR00505##
[1958] The method described in Referential Example 69 was performed
by use of the compound obtained in Referential Example 434, whereby
the title compound was obtained.
[1959] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.38-1.51(1H, m),
1.65-1.85(3H, m), 1.92-2.09(2H, m), 2.80(3H, s), 3.06(3H, s),
3.20-3.32(1H, m), 3.55-4.40(2H, br), 8.02(1H, dd, J=9.1,2.5 Hz),
8.07(1H, d, J=9.1 Hz), 8.15-8.40(3H, br), 8.45(1H, d, J=2.5 Hz),
8.96(1H, d, J=6.6 Hz), 10.33(1H, s).
Referential Example 436
(1S, 2R,
4S)-2-[(tert-butoxycarbonyl)amino]-4-[(methylamino)carbonyl]cyclo-
hexylcarbamic acid benzyl ester
##STR00506##
[1961] The method described in Referential Example 143 was
performed by use of the compound obtained in Referential Example
142 and methylamine hydrochloride, whereby the title compound was
obtained.
[1962] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.39(9H, s),
1.40-1.61(4H, m), 1.63-1.73(1H, m), 1.75-1.85(1H, m), 2.23-2.48(1H,
m), 2.53(3H, d, J=4.6 Hz), 3.48(1H, br.s), 3.80-3.91(1H, m),
5.01(1H, 1/2ABq, J=12.1 Hz), 5.03(1H, 1/2ABq, J=12.1 Hz),
6.28-6.40(1H, m), 6.82-6.98(1H, m), 7.25-7.40(5H, m), 7.50-7.60(1H,
m).
[1963] MS (FAB) m/z:406 (M+H).sup.+.
Referential Example 437
(1R, 2S,
5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-[(me-
thylamino)carbonyl]cyclohexylcarbamic acid tert-butyl ester
##STR00507##
[1965] In a manner similar to that described in Referential Example
144, the compound obtained in Referential Example 436 was
deprotected to obtain the corresponding amine compound. In a manner
similar to that described in Referential Example 91, the amine
compound was condensed with the compound obtained in Referential
Example 433, whereby the title compound was obtained.
[1966] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.35-1.75(3H, m),
1.39(9H, s), 1.75-1.86(2H, m), 1.87-1.95(1H, m), 2.30-2.40(1H, m),
2.55(3H, d, J=4.6 Hz), 3.79-3.90(2H, m), 6.73-6.90(1H, m),
7.58-7.70(1H, m), 8.00-8.13(2H, m), 8.46(1H, dd, J=2.2, 1.0 Hz),
8.67(1H, d, J=7.6 Hz), 10.26(1H, s).
[1967] MS (ESI:negative) m/z:452[(M-H).sup.-, Cl.sup.35],
454[(M-H).sup.-, Cl.sup.37].
Referential Example 438
2-chloro-N-(5-methylpyridin-2-yl)acetamide hydrochloride
##STR00508##
[1969] The method described in Referential Example 425 was
performed by use of 2-amino-5-picoline, whereby the title compound
was obtained.
[1970] .sup.1H-NMR (DMSO-d.sub.6) .delta.:2.30 (3H, s), 4.40 (2H,
s), 7.83(1H, d, J=8.8 Hz), 7.91(1H, d, J=8.5 Hz), 8.21(1H, s),
11.40(1H, s).
Referential Example 439
S-{2-[(5-methylpyridin-2-yl)amino]-2-oxoethyl}thiosulfuric acid
sodium salt
##STR00509##
[1972] The method described in Referential Example 353 was
performed by use of the compound obtained in Referential Example
438, whereby the title compound was obtained.
[1973] .sup.1H-NMR (DMSO-d.sub.6) .delta.:2.24 (3H, s), 3.74 (2H,
s), 7.59(1H, d, J=8.5 Hz), 7.94(1H, d, J=8.3 Hz), 8.12(1H, s),
10.26(1H, s).
Referential Example 440
(1R, 2S,
5S)-5-[(dimethylamino)carbonyl]-2-({2-[(5-methylpyridin-2-yl)amin-
o]-2-oxoethanethioyl}amino)cyclohexylcarbamic acid tert-butyl
ester
##STR00510##
[1975] The method described in Referential Example 427 was
performed by use of the compound obtained in Referential Example
144 and the compound obtained in Referential Example 439, whereby
the title compound was obtained.
[1976] .sup.1H-NMR (CDCl.sub.3) .delta.:1.46(9H, s), 1.60-2.10(5H,
m), 2.15-2.35(1H, m), 2.31(3H, s), 2.60-2.80(1H, m), 2.95(3H, s),
3.07(3H, s), 4.30-4.45(2H, m), 4.65-4.85(1H, m), 7.54(1H, dd,
J=8.5, 2.0 Hz), 8.06(1H, br.d), 8.18(1H, s), 9.70-9.90(1H, m),
10.48(1H, s).
[1977] MS (ESI) m/z:464 (M+H).sup.+.
Referential Example 441
(3R,
4S)-4-{[2-(4-chloroanilino)-2-oxoethanethioyl]amino}-1-(2-methoxyacet-
yl)piperidin-3-ylcarbamic acid tert-butyl ester
##STR00511##
[1979] In a manner similar to that described in Referential Example
214, the compound obtained in Referential Example 220 was
deprotected by catalytic reduction. In a manner similar to that
described in Referential Example 427, the resultant amine was
condensed with the compound obtained in Referential Example 351,
whereby the title compound was obtained. .sup.1H-NMR (CDCl.sub.3)
.delta.:1.46(9H, s), 1.59-1.84(1H, m), 2.10-2.33(1H, m),
2.68-2.81(0.7H, m), 2.94-2.04(0.3H, m), 3.15-3.40(1H, m), 3.44(3H,
s), 3.91-4.32(4H, m), 4.45-4.58(1H, m), 4.60-4.77(1H, m),
5.15-5.30(0.3H, br), 5.84-5.94(0.7H, m), 7.32(2H, d, J=8.6 Hz),
7.61(2H, d, J=8.6 Hz), 10.12(1H, s), 10.19-10.33(1H, br).
[1980] MS (FAB) m/z:485[(M+H).sup.+, Cl.sup.35], 487[(M+H).sup.+,
Cl.sup.37].
Referential Example 442
(1S, 2R,
4S)-2-[(tert-butoxycarbonyl)amino]-4-[(dimethylamino)carbonyl]cyc-
lohexylcarbamic acid 9H-fluoren-9-ylmethyl ester
##STR00512##
[1982] The compound (856 mg) obtained in Referential Example 144
was dissolved in acetone (10 mL). To the solution,
pentafluorophenylcarbamic acid 9-fluorenylmethyl ester (1.34 g) and
sodium hydrogencarbonate (302 mg) were added, followed by stirring
at room temperature for 2.5 hours. Pentafluorophenylcarbamic acid
9-fluorenylmethyl ester (609 mg) and sodium hydrogencarbonate (151
mg) were further added thereto, and the resulting mixture was
heated under reflux for 30 minutes. The solvent was distilled away
under reduced pressure. The residue was purified by silica gel
flash column chromatography (SI-40B, methylene
chloride:methanol=93:7), to thereby give the title compound (1.47
g).
[1983] .sup.1H-NMR (CDCl.sub.3) .delta.:1.45(9H, s), 1.30-2.05(6H,
m), 2.63(1H, br.s), 2.94(3H, s), 3.04(3H, s), 3.69(1H, br.s),
4.15(1H, br.s), 4.21(1H, br.s), 4.37(2H, br.s), 4.73(1H, br.s),
5.41(1H, br.s), 7.29(2H, t, J=7.3 Hz), 7.39(2H, t, J=7.3 Hz),
7.57(2H, d, J=7.3 Hz), 7.75(2H, d, J=7.3 Hz).
[1984] MS (ESI) m/z:508 (M+H).sup.+.
Referential Example 443
(1S, 2R,
4S)-2-[(tert-butoxycarbonyl)amino]-4-[(dimethylamino)carbothioyl]-
cyclohexylcarbamic acid 9H-fluoren-9-ylmethyl ester
##STR00513##
[1986] The compound (1.26 g) obtained in Referential Example 442
was dissolved in toluene (50 mL), and Lawson reagent (1.00 g) was
added thereto. The resultant mixture was stirred at 60.degree. C.
for 1 hour. Insoluble material was removed through filtration, and
the solvent was distilled away under reduced pressure. The residue
was dissolved in ethanol (50 mL), and di-tert-butyl dicarbonate
(541 mg) and sodium hydrogencarbonate (208 mg) were added thereto.
The resultant mixture was stirred at room temperature for 1 hour.
The solvent was distilled away under reduced pressure. The residue
was purified by silica gel flash column chromatography
(hexane:ethyl acetate=1:1.fwdarw.methylene chloride:methanol=9:1),
whereby the title compound (609 mg) was obtained as a white
solid.
[1987] .sup.1H-NMR (CDCl.sub.3) .delta.:1.43(9H, s), 1.43-2.10(6H,
m), 2.92(1H, br.s), 3.31(3H, s), 3.47(3H, s), 3.74(1H, br.s),
4.09-4.19(2H, m), 4.38(2H, br.s), 4.75(1H, br), 5.29(1H, br.s),
7.29(2H, t, J=7.3 Hz), 7.38(2H, t, J=7.3 Hz), 7.55(2H, br.s),
7.75(2H, d, J=7.3 Hz).
Referential Example 444
(1R, 2S,
5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-[(di-
methylamino)carbothioyl]cyclohexylcarbamic acid tert-butyl
ester
##STR00514##
[1989] The compound (1.11 g) obtained in Referential Example 443
was dissolved in N,N-dimethylformamide (30 mL), and piperazine (3.0
mL) was added thereto, followed by stirring at room temperature for
15 minutes. The solvent was distilled away under reduced pressure,
and ethyl acetate and water were added to the residue for
partitioning the mixture. The aqueous layer was extracted twice
with ethyl acetate. The organic layers were combined, followed by
drying over sodium sulfate anhydrate. The solvent was distilled
away under reduced pressure. In a manner similar to that described
in Referential Example 91, the residue was condensed with the
compound obtained in Referential Example 433, to thereby give the
title compound (629 mg).
[1990] .sup.1H-NMR (CDCl.sub.3) :1.45(9H, s), 1.48-2.23(6H, m),
2.98(1H, br.s), 3.36(3H, s), 3.49(3H, s), 3.98-4.04(1H, m),
4.22-4.25(1H, m), 4.75(1H, br.s), 7.70(1H, dd, J=8.8, 2.7 Hz),
7.85(1H, br.s), 8.16(1H, d, J=8.8 Hz), 8.30(1H, d, J=2.7 Hz),
9.73(1H, s).
[1991] MS (FAB) m/z:484[(M+H).sup.+, Cl.sup.35], 486[(M+H).sup.+,
Cl.sup.37].
Referential Example 445
N.sup.1-{(1S, 2R,
4S)-2-amino-4-[(dimethylamino)carbothioyl]cyclohexyl}-N.sup.2-(5-chloropy-
ridin-2-yl)ethanediamide dihydrochloride
##STR00515##
[1993] The method described in Referential Example 69 was performed
by use of the compound obtained in Referential Example 444, whereby
the title compound was obtained.
[1994] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.66-2.11 (6H, m),
3.38(3H, s), 3.42(3H, s), 3.52(1H, br.s), 3.75(1H, br.s), 3.88(1H,
br.s), 8.03-8.09(2H, m), 8.21(3H, br.s), 8.48(1H, d, J=2.2 Hz),
9.06(1H, d, J=6.8 Hz), 10.34(1H, s).
[1995] MS (FAB) m/z:384[(M+H).sup.+, Cl.sup.35], 386[(M+H).sup.+,
Cl.sup.37].
Referential Example 446
(3R,
4S)-3-[(tert-butoxycarbonyl)amino]-1-(2-methoxyacetyl)piperidin-4-ylc-
arbamic acid 9H-fluoren-9-ylmethyl ester
##STR00516##
[1997] In a manner similar to that described Referential Example
214, the compound obtained in Referential Example 220 was
deprotected by catalytic reduction to obtain the corresponding
amine. The method described in Referential Example 442 was
performed by use of the resultant amine, whereby the title compound
was obtained.
[1998] .sup.1H-NMR (CDCl.sub.3) .delta.:1.48(9H, s), 1.55-1.80(1H,
m), 1.92-2.20(1H, m), 2.70-3.35(2H, m), 3.44(3H, s), 3.77-4.90(10H,
m), 5.29-5.45(0.6H, br), 5.75-5.90(0.4H, br), 7.26-7.34(2H, m),
7.39(2H, t, J=7.6 Hz), 7.55-7.65(2H, m), 7.76(2H, d, J=7.6 Hz).
[1999] MS (FAB) m/z:510 (M+H).sup.+.
Referential Example 447
(3R,
4S)-3-[(tert-butoxycarbonyl)amino]-1-(2-methoxyethanethioyl)piperidin-
-4-ylcarbamic acid 9H-fluoren-9-ylmethyl ester
##STR00517##
[2001] The method described in Referential Example 443 was
performed by use of the compound obtained in Referential Example
446, whereby the title compound was obtained.
[2002] .sup.1H-NMR (CDCl.sub.3) .delta.:1.48(9H, s), 1.50-1.80(1H,
m), 2.07-2.23(1H, m), 3.04-3.18(0.5H, m), 3.25-3.37(0.5H, m),
3.44(1.5H, s), 3.47(1.5H, s), 3.88-4.75(9H, m), 5.00-5.70(2H, br),
5.98-6.23(1H, br), 7.26-7.29(2H, m), 7.39(2H, t, J=7.3 Hz),
7.55-7.68(2H, m), 7.77(2H, d, J=7.3 Hz).
[2003] MS (FAB) m/z:526 (M+H).sup.+.
Referential Example 448
(3R,
4S)-4-([2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-1-(2-metho-
xyethanethioyl)piperidin-3-ylcarbamic acid tert-butyl ester
##STR00518##
[2005] In a manner similar to that described in Referential Example
444, the compound obtained in Referential Example 447 was treated
with diethylamine for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 433,
whereby the title compound was obtained.
[2006] .sup.1H-NMR (CDCl.sub.3) .delta.:1.47(9H, s), 1.73-1.88(1H,
m), 2.07-2.22(1H, m), 3.05-3.15(1H, m), 3.27-3.42(1H, m), 3.45(1H,
s), 3.48(2H, s), 4.10-4.54(5H, m), 5.12-5.21(0.3H, br),
5.48-5.56(0.7H, br), 5.61-5.74(1H, br), 7.70(1H, dd, J=8.5, 2.0
Hz), 8.21(1H, d, J=8.5 Hz), 8.31(1H, d, J=2.0 Hz), 8.42-8.60(1H,
br), 9.72(1H, br.s).
[2007] MS (ESI) m/z:486[(M+H).sup.+, Cl.sup.35], 488[(M+H).sup.+,
Cl.sup.37].
Referential Example 449
(1S, 3R,
4S)-4-{[(allyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)amino]c-
yclohexanecarboxylic acid ethyl ester
##STR00519##
[2009] The compound (10.0 g) obtained in Referential Example 141
was dissolved in a mixture of tetrahydrofuran (40 mL) and ethanol
(40 mL), and 10% palladium carbon catalyst (10.2 g) was added to
the solution. The resultant mixture was stirred in a hydrogen
atmosphere at room temperature for 63 hours. The catalyst was
removed through filtration through celite, and the filtrate was
concentrated under reduced pressure. The resultant colorless oil
was dissolved in tetrahydrofuran (25 mL). Pyridine (2.3 mL) was
added thereto at room temperature. To the mixture, allyl
chloroformate (2.70 mL) was added dropwise at 0.degree. C.,
followed by stirring for 20 minutes. Ice and ethyl acetate were
added to the reaction mixture, followed by stirring for 5 minutes.
The resultant mixture was acidified with 10% aqueous citric acid.
The organic layer was washed with saturated aqueous sodium
hydrogencarbonate and saturated aqueous sodium chloride, followed
by drying over sodium sulfate anhydrate. The resultant mixture was
concentrated under reduced pressure to obtain the residue. The
residue was purified by silica gel column chromatography (methylene
chloride:methanol=40:1), to thereby give the title compound (6.03
g).
[2010] .sup.1H-NMR (CDCl.sub.3) .delta.:1.25(3H, t, J=7.1 Hz),
1.31-1.40(1H, m), 1.45(9H, s), 1.51-1.65(1H, m), 1.72-1.86(1H, m),
1.89-2.10(3H, m), 2.25-2.50(1H, br), 3.63-3.72(1H, m),
4.03-4.15(1H, br), 4.13(2H, q, J=7.1 Hz), 4.49-4.59(2H, m),
4.60-4.75(1H, m), 5.20(1H, d, J=10.5 Hz), 5.22-5.32(1H, br),
5.29(1H, dd, J=17.1, 1.7 Hz), 5.85-5.97(1H, m).
[2011] MS (ESI) m/z:371 (M+H).sup.+.
Referential Example 450
(1S, 3R,
4S)-4-{[(allyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)amino]c-
yclohexanecarboxylic acid
##STR00520##
[2013] The method described in Referential Example 142 was
performed by use of the compound obtained in Referential Example
449, whereby the title compound was obtained.
[2014] .sup.1H-NMR (CDCl.sub.3) .delta.:1.35-2.15(6H, br), 1.45(9H,
s), 2.35-2.65(1H, br), 3.65-3.75(1H, m), 4.00-4.15(1H, br),
4.48-4.63(2H, m), 4.63-4.80(1H, br), 5.03-5.33(1H, br), 5.21(1H, d,
J=10.3 Hz), 5.29(1H, dd, J=17.1, 1.5 Hz), 5.86-5.97(1H, m).
[2015] MS (ESI) m/z:343 (M+H).sup.+.
Referential Example 451
(1S, 3R,
4S)-4-{[allyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)amino]cy-
clohexanecarboxylic acid 2,2,2-trichloroethyl ester
##STR00521##
[2017] To a solution of the compound (5.93 g) obtained in
Referential Example 450 in N,N-dimethylformamide (40 mL), were
added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(4.99 g), 1-hydroxybenzotriazole (2.81 g), 2,2,2-trichloroethanol
(4.15 mL), and 4-dimethylaminopyridine (4.15 g). The resultant
mixture was stirred at room temperature for 1.5 hours. The reaction
mixture was concentrated under reduced pressure, and ethyl acetate
and water were added to the residue. The aqueous layer was
extracted with ethyl acetate. The organic layers were combined,
followed by washing with 10% aqueous citric acid, saturated aqueous
sodium hydrogencarbonate, and saturated aqueous sodium chloride.
The resultant mixture was dried over sodium sulfate anhydrate,
followed by concentrating under reduced pressure. The residue was
purified by silica gel column chromatography (methylene
chloride:methanol=40:1), to thereby give the title compound (8.88
g).
[2018] .sup.1H-NMR (CDCl.sub.3) .delta.:1.35-1.50(1H, m), 1.46(9H,
s), 1.55-1.73(1H, m), 1.77-2.22(4H, m), 2.50-2.65(1H, br),
3.66-3.75(1H, m), 4.05-4.20(1H, m), 4.50-4.60(2H, m), 4.60-4.80(1H,
br), 4.71(1H, d, J=11.8 Hz), 4.77(1H, d, J=11.8 Hz), 5.18-5.34(1H,
br), 5.20(1H, d, J=10.5 Hz), 5.30(1H, dd, J=17.4, 1.0 Hz),
5.86-5.97(1H, m).
[2019] MS (ESI) m/z:473[(M+H).sup.+, 3.times.Cl.sup.35],
475[(M+H).sup.+, 2.times.Cl.sup.35, Cl.sup.37], 477[(M+H).sup.+,
Cl.sup.35, 2.times.Cl.sup.37].
Referential Example 452
(1S, 3R,
4S)-4-amino-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic
acid 2,2,2-trichloroethyl ester
##STR00522##
[2021] To a solution of the compound (8.83 g) obtained in
Referential Example 451 in tetrahydrofuran (35 mL), were added
diethylamine (20 mL) and tetrakis(triphenylphosphine)palladium (719
mg). The mixture was stirred in an argon atmosphere at room
temperature for 2.5 hours. 10% Aqueous citric acid (250 mL) was
added to the reaction mixture to acidify, and diethyl ether was
added thereto. The aqueous layer was washed with diethyl ether, and
sodium carbonate was added thereto to basify, followed by
extracting with methylene chloride. Methylene chloride layer was
washed with saturated aqueous sodium chloride. The resultant
mixture was dried over sodium sulfate anhydrate, followed by
concentrating under reduced pressure to thereby give the title
compound (4.35 g).
[2022] .sup.1H-NMR (CDCl.sub.3) .delta.:1.20-1.50(3H, m), 1.46(9H,
s), 1.58-1.69(1H, m), 1.70-1.81(2H, m), 1.98-2.07(1H, m),
2.22-2.31(1H, m), 2.55-2.66(1H, m), 2.97-3.04(1H, m), 3.79-3.93(1H,
br), 4.70(1H, d, J=12.0 Hz), 4.75-4.85(1H, br), 4.78(1H, d, J=12.0
Hz).
[2023] MS (ESI) m/z:389[(M+H).sup.+, 3.times.Cl.sup.35],
391[(M+H).sup.+, 2.times.Cl.sup.35, Cl.sup.37], 393[(M+H).sup.+,
Cl.sup.35, 2.times.Cl.sup.37].
Referential Example 453
(1S, 3R,
4S)-3-[(tert-butoxycarbonyl)amino]-4-({2-[(5-chloropyridin-2-yl)a-
mino]-2-oxoacetyl}amino)cyclohexanecarboxylic acid
2,2,2-trichloroethyl ester
##STR00523##
[2025] In a manner similar to that described in Referential Example
91, the compound obtained in Referential Example 452 was condensed
with the compound obtained in Referential Example 433, whereby the
title compound was obtained.
[2026] .sup.1H-NMR (CDCl.sub.3) .delta.:1.46(9H, s), 1.50-1.63(1H,
m), 1.65-1.79(2H, m), 1.87-2.08(2H, m), 2.10-2.22(2H, m),
2.50-2.70(1H, br), 3.94-4.02(1H, m), 4.17-4.30(1H, br), 4.73(1H, d,
J=12.0 Hz), 4.78(1H, d, J=12.0 Hz), 7.70(1H, dd, J=8.8, 2.4 Hz),
7.90-8.07(1H, br), 8.18(1H, d, J=8.8 Hz), 8.31(1H, d, J=2.4 Hz),
9.72(1H, br.s).
[2027] MS (ESI) m/z:571[(M+H).sup.+, 3.times.Cl.sup.35],
573[(M+H).sup.+, 2.times.Cl.sup.35, Cl.sup.37], 575[(M+H).sup.+,
Cl.sup.35, 2.times.Cl.sup.37].
Referential Example 454
2-[((1S, 2R,
4S)-4-[(dimethylamino)carbonyl]-2-{([(5-methyl-4,5,6,7-tetrahydrothiazolo-
[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)amino]-2-(methoxyimino)aceti-
c acid methyl ester
##STR00524##
[2029] The compound (435 mg) obtained in Referential Example 144
and 2-(methoxyimino)-2-(methylsulfonyl)acetic acid methyl ester
(WO99/67209) (233 mg) were dissolved in tetrahydrofuran (5 mL).
Triethylamine (332 .mu.L) was added thereto, followed by stirring
at 70.degree. C. overnight. The reaction mixture was concentrated
under reduced pressure. Methylene chloride and saturated aqueous
sodium hydrogencarbonate were added thereto for partitioning the
mixture. The oil layer was dried over sodium sulfate anhydrate.
After concentration, the residue was purified by silica gel
chromatography (methylene chloride:methanol=91:9), to thereby give
the title compound (111 mg).
[2030] .sup.1H-NMR (CDCl.sub.3) .delta.:1.42-2.10(6H, m), 2.52(3H,
s), 2.70-3.10(11H, m), 3.71(2H, br.s), 3.83(3H, s), 3.84(3H, s),
4.22-4.35(1H, m), 4.55-4.65(1H, m), 5.16(1H, d, J=8.8 Hz),
7.25-7.30(1H, m).
[2031] MS (ESI) m/z:481 (M+H).sup.+.
Referential Example 455
N.sup.1-((1S, 2R,
4S)-4-[(dimethylamino)carbonyl]-2-[[(5-methyl-4,5,6,7-tetrahydrothiazolo[-
5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N.sup.2-{5-[2-(trimethylsily-
l)ethynyl]pyridin-2-yl}ethanediamide
##STR00525##
[2033] The compound (658 mg) obtained in Example 204 was dissolved
in tetrahydrofuran (10 mL), N,N-dimethylformamide (10 mL), and
triethylamine (20 mL). Triphenylphosphine (87 mg),
trimethylsilylacetylene (471 .mu.L), and palladium acetate (50 mg)
were added thereto. The resultant mixture was stirred in an argon
atmosphere at 80.degree. C. for 14 hours. The reaction mixture was
filtered through celite, followed by washing with methylene
chloride throughly. Water was added to the filtrate for
partitioning the mixture. The organic layer was decolored with
activated carbon (about 3 g), followed by drying over sodium
sulfate anhydrate. The resultant mixture was filtered and the
solvent was distilled away under reduced pressure. The residue was
purified by silica gel column chromatography (methylene
chloride:methanol=93:7), to thereby give the title compound (360
mg).
[2034] .sup.1H-NMR (CDCl.sub.3) .delta.:0.25(9H, s), 1.66-2.13(6H,
m), 2.52(3H, s), 2.78-2.96(8H, m), 3.05(3H, s), 3.70(1H, d, J=15.4
Hz), 3.73(1H, d, J=15.4 Hz), 4.08-4.15(1H, m), 4.66-4.69(1H, m),
7.42(1H, d, J=8.4 Hz), 7.77(1H, dd, J=8.4, 2.1 Hz), 8.03(1H, d,
J=8.1 Hz), 8.13(1H, d, J=8.8 Hz), 8.43(1H, d, J=2.1 Hz), 9.74(1H,
s).
[2035] MS (ESI) m/z:610 (M+H).sup.+.
Referential Example 456
5-methyl-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylic acid
methyl ester
##STR00526##
[2037] 4,5-Bis(chloromethyl)-2-thiophenecarboxylic acid methyl
ester (D. J. Zwanenburg and Hans Wynberg, J. Org. Chem., 34,
333-340, (1969)) (520 mg) was dissolved in acetonitrile (600 mL).
Methylamine (40% methanol solution, 722 .mu.L) was added thereto,
followed by stirring at room temperature for 3 days. The solvent
was distilled away under reduced pressure. The residue was purified
by silica gel column chromatography (methylene
chloride:methanol=1:0.fwdarw.19:1), to thereby give the title
compound (176 mg).
[2038] .sup.1H-NMR (CDCl.sub.3) .delta.:2.63(3H, s), 3.82-3.83(2H,
m), 3.86(3H, s), 3.97-3.99(2H, m), 7.51(1H, s).
[2039] MS (ESI) m/z:198 (M+H).sup.+.
Referential Example 457
2-chloro-N-(6-chloropyridazin-3-yl)acetamide
##STR00527##
[2041] 3-Amino-6-chloropyridazine (10.4 g) was dissolved in
N,N-dimethylformamide (200 mL). Chloroacetyl chloride (7.48 mL) was
added thereto, and the resultant mixture was stirred at room
temperature for 1 hour. The solvent was distilled away under
reduced pressure, and ethyl acetate and saturated aqueous sodium
hydrogencarbonate were added to the residue. The precipitated solid
was recovered by filtration, followed by washing with ethyl acetate
and water, to thereby give the title compound (9.39 g).
[2042] .sup.1H-NMR (CDCl.sub.3) .delta.:4.30(2H, s), 7.56(1H, d,
J=9.3 Hz), 8.51(1H, d, J=9.3 Hz), 9.68(1H, br.s).
Referential Example 458
S-{2-[(6-chloropyridazin-3-yl)amino]-2-oxoethyl}thiosulfuric acid
sodium salt
##STR00528##
[2044] The method described in Referential Example 353 was
performed by use of the compound obtained in Referential Example
457, whereby the title compound was obtained.
[2045] .sup.1H-NMR (DMSO-d.sub.6) .delta.:3.84 (2H, s), 7.87(1H, d,
J=9.4 Hz), 8.36(1H, d, J=9.4 Hz), 11.21(1H, br.s).
Referential Example 459
(1R, 2S,
5S)-2-({2-[(6-chloropyridazin-3-yl)amino]-2-oxoethanethioyl}amino-
)-5-[(dimethylamino)carbonyl]cyclohexylcarbamic acid tert-butyl
ester
##STR00529##
[2047] The method described in Referential Example 427 was
performed by use of the compound obtained in Referential Example
458 and the compound obtained in Referential Example 144, whereby
the title compound was obtained.
[2048] .sup.1H-NMR (CDCl.sub.3) .delta.:1.35-1.58(10H, m),
1.71-1.80(1H, m), 1.86-1.94(2H, m), 2.09(1H, br.s), 2.30(1H, br.s),
2.96(3H, s), 3.08(3H, s), 4.36(2H, br.s), 4.79(1H, br.s), 5.30(1H,
br.s), 7.54(1H, d, J=9.0 Hz), 8.47(1H, d, J=9.0 Hz), 10.03(1H,
br.s), 11.03(1H, s).
Referential Example 460
(1S, 3R,
4S)-3-amino-4-([2-[(6-chloropyridazin-3-yl)amino]-2-oxoethanethio-
yl}amino)-N,N-dimethylcyclohexanecarboxamide hydrochloride
##STR00530##
[2050] The method described in Referential Example 69 was performed
by use of the compound obtained in Referential Example 459, whereby
the title compound was obtained.
[2051] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.45-1.53(1H, m),
1.73-1.85(3H, m), 2.03-2.07(1H, m), 2.15-2.24(1H, m), 2.82(3H, s),
3.08(3H, s), 3.32-3.37(1H, m), 4.06(1H, br.s), 4.39(1H, br.s),
8.01(1H, d, J=9.3 Hz), 8.37(1H, d, J=9.3 Hz), 8.43(3H, br.s),
11.11(1H, d, J=6.6 Hz), 11.37(1H, s).
[2052] MS (FAB) m/z:385[(M+H).sup.+, Cl.sup.35], 387[(M+H).sup.+,
Cl.sup.37].
Referential Example 461
2-chloro-N-(6-chloropyridin-3-yl)acetamide
##STR00531##
[2054] The method described in Referential Example 457 was
performed by use of 5-amino-2-chloropyridine, whereby the title
compound was obtained.
[2055] .sup.1H-NMR (CDCl.sub.3) .delta.:4.22(2H, s), 7.34(1H, d,
J=8.5 Hz), 8.14(1H, dd, J=8.5, 2.7 Hz), 8.30(1H, br.s), 8.45(1H, d,
J=2.7 Hz).
Referential Example 462
S-{2-[(6-chloropyridin-3-yl)amino]-2-oxoethyl}thiosulfuric acid
sodium salt
##STR00532##
[2057] The method described in Referential Example 353 was
performed by use of the compound obtained in Referential Example
461, whereby the title compound was obtained.
[2058] .sup.1H-NMR (DMSO-d.sub.6) .delta.:3.77 (2H, s), 7.47(1H, d,
J=8.8 Hz), 8.04(1H, dd, J=8.8, 2.7 Hz), 8.57(1H, d, J=2.7 Hz),
10.51(1H, s).
Referential Example 463
(1R, 2S,
5S)-2-({2-[(6-chloropyridin-3-yl)amino]-2-oxoethanethioyl}amino)--
5-[(dimethylamino)carbonyl]cyclohexylcarbamic acid tert-butyl
ester
##STR00533##
[2060] The method described in Referential Example 427 was
performed by use of the compound obtained in Referential Example
462 and the compound obtained in Referential Example 144, whereby
the title compound was obtained.
[2061] .sup.1H-NMR (CDCl.sub.3) .delta.:1.46(9H, br.s),
1.60-2.23(6H, m), 2.68(1H, br.s), 2.96(3H, s), 3.08(3H, s),
4.34-4.38(2H, m), 4.78(1H, m), 7.33(1H, d, J=8.5 Hz), 8.09(1H,
br.s), 8.63(1H, s), 9.91(1H, br.s), 10.24(1H, s).
[2062] MS (ESI) m/z:506[(M+Na).sup.+, Cl.sup.35], 508[(M+Na).sup.+,
Cl.sup.37].
Referential Example 464
(1S, 3R,
4S)-3-amino-4-({2-[(6-chloropyridin-3-yl)amino]-2-oxoethanethioyl-
}amino)-N,N-dimethylcyclohexanecarboxamide hydrochloride
##STR00534##
[2064] The method described in Referential Example 69 was performed
by use of the compound obtained in Referential Example 463, whereby
the title compound was obtained.
[2065] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.46-1.49(1H, m),
1.79-1.81(3H, m), 1.99-2.03(1H, m), 2.14-2.16(1H, m), 2.82(3H, s),
3.06(3H, s), 3.25-3.28(1H, m), 3.99(1H, br.s), 4.30-4.60(1H, br),
7.55(1H, d, J=8.7 Hz), 8.26(1H, dd, J=8.7, 2.4 Hz), 8.38(3H, br.s),
8.85(1H, d, J=2.4 Hz), 10.90(1H, d, J=6.8 Hz), 11.07(1H, s).
[2066] MS (FAB) m/z:384[(M+H).sup.+, Cl.sup.35], 386[(M+H).sup.+,
Cl.sup.37].
Referential Example 465
2'-aminosulfonyl-1,1'-biphenyl-4-carboxylic acid
##STR00535##
[2068] 2-Bromobenzenesulfonamide (800 mg) and 4-carboxyphenyl
boronic acid (563 mg) were suspended in a solvent mixture of
toluene (5 mL) and water (5 mL). To the reaction mixture,
tetrakis(triphenylphosphine)palladium (392 mg) and sodium carbonate
anhydrate (1.08 g) were sequentially added, and the resultant
mixture was heated under reflux overnight. The resultant mixture
was cooled to room temperature, and diethyl ether and water were
added thereto for partitioning the mixture. The organic layer was
extracted twice with water. All the resultant aqueous layers were
combined together, and 12N aqueous hydrochloric acid was added
thereto to acidify. The mixture was concentrated to about 20 mL
under reduced pressure, and the precipitated colorless powder was
recovered by filtration, followed by drying under reduced pressure,
to thereby give the title compound (539 mg).
[2069] MS (EI) m/z:277M.sup.+.
Referential Example 466
2-[(5-methylpyridin-2-yl)amino]-2-oxoacetic acid methyl ester
##STR00536##
[2071] The method described in Referential Example 242 was
performed by use of 2-amino-5-methylpyridine and methyl
chlorooxoacetate, whereby the title compound was obtained.
[2072] .sup.1H-NMR (CDCl.sub.3) .delta.:2.33(3H, s), 3.98(3H, s),
7.57(1H, dd, J=8.4, 2.0 Hz), 8.14(1H, d, J=8.4 Hz), 8.17(1H, d,
J=2.0 Hz).
[2073] MS (ESI) m/z:195 (M+H).sup.+.
Referential Example 467
2-[(5-methylpyridin-2-yl)amino]-2-oxoacetic acid lithium salt
##STR00537##
[2075] The method described in Referential Example 266 was
performed by use of the compound obtained in Referential Example
466, whereby the title compound was obtained.
[2076] .sup.1H-NMR (DMSO-d.sub.6) .delta.:2.25 (3H, s), 7.63(1H, d,
J=8.2 Hz), 8.00(1H, d, J=8.2 Hz), 8.15(1H, s), 10.00(1H, br.s).
[2077] MS (FAB) m/z:181(M-Li+2H).sup.+.
Referential Example 468
2-oxo-2-(4-toluidino)acetic acid methyl ester
##STR00538##
[2079] The method described in Referential Example 242 was
performed by use of p-toluidine and methyl chlorooxoacetate,
whereby the title compound was obtained.
[2080] MS (ESI) m/z:194 (M+H).sup.+.
Referential Example 469
(1R, 2S,
5S)-5-[(dimethylamino)carbonyl]-2-{[2-oxo-2-(4-toluidino)acetyl]a-
mino}cyclohexylcarbamic acid tert-butyl ester
##STR00539##
[2082] In a manner similar to that described in Referential Example
91, a lithium salt of a carboxylic acid produced by hydrolyzing the
ester described in Referential Example 468 was condensed with the
compound obtained in Referential Example 144, whereby the title
compound was obtained.
[2083] MS (ESI) m/z:447 (M+H).sup.+.
Referential Example 470
4-bromomethyl-3-chlorothiophene-2-carboxylic acid methyl ester
##STR00540##
[2085] 3-Chloro-4-methyl-2-thiophenecarboxylic acid methyl ester
(3.81 g) was dissolved in carbon tetrachloride (40 mL). To the
solution, N-bromosuccinimide (3.56 g) and .alpha.,
.alpha.'-azobisisobutyronitrile (200 mg) were added, and the
mixture was heated under reflux for 2.5 hours. The insoluble
material was removed through filtration, and the filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl
acetate:hexane=1:19.fwdarw.1:9), to thereby give the title compound
(2.92 g) as a yellow oil.
[2086] .sup.1H-NMR (CDCl.sub.3) .delta.:3.91(3H, s), 4.46(2H, s),
7.59(1H, s).
[2087] MS (ESI) m/z:269 (M+H).sup.+.
Referential Example 471
4-[[(tert-butoxycarbonyl)(methyl)amino]methyl}-3-chloro-2-thiophenecarboxy-
lic acid
##STR00541##
[2089] To a solution of methylamine (2 mol/L tetrahydrofuran
solution, 27 mL) in tetrahydrofuran (30 mL), a solution of the
compound (2.92 g) obtained in Referential Example 470 in
tetrahydrofuran (50 mL) was added dropwise over 30 minutes. The
resultant mixture was stirred at room temperature for 1 hour. The
reaction mixture was concentrated in about half under reduced
pressure, and di-tert-butyl dicarbonate (3.0 g) was added thereto,
followed by stirring at room temperature for 75 minutes. The
reaction mixture was concentrated under reduced pressure, and ethyl
acetate was added to the residue. The resultant mixture was allowed
to stand overnight. Water was added to the resultant mixture for
partitioning the mixture. The resultant organic layer was dried
over magnesium sulfate anhydrate. The solvent was distilled away
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane:ethyl acetate=99:1.fwdarw.19:1), to
thereby give a colorless oil (4.0 g). To a solution of the oil (4.0
g) in methanol (35 mL), were added water (5 mL) and sodium
hydroxide (1.2 g), followed by stirring at room temperature for 30
minutes. The reaction mixture was concentrated under reduced
pressure, ice water was added to the residue, and the resultant
mixture was acidified with concentrated hydrochloric acid. The
mixture was extracted with ethyl acetate, and the extract was dried
over magnesium sulfate anhydrate. The solvent was distilled away
under reduced pressure, and the residue was crystallized from
hexane, to thereby give the title compound (2.67 g) as a colorless
powder.
[2090] .sup.1H-NMR (CDCl.sub.3) .delta.:1.48(9H, s), 2.74(3H,
br.s), 4.14(2H, br.s), 7.40(0.5H, br.s), 7.48(0.5H, br.s).
Referential Example 472
(1R,
2S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl)amino)cyclohexylc-
arbamic acid tert-butyl ester
##STR00542##
[2092] In a manner similar to that described in Referential Example
68, (1R, 2S)-2-aminocyclohexylcarbamic acid tert-butyl ester
(WO01/74774) was condensed with the compound obtained in
Referential 266, whereby the title compound was obtained.
[2093] .sup.1H-NMR (CDCl.sub.3) .delta.:1.35-1.90(8H, m), 1.46(9H,
s), 3.97(1H, br.s), 4.00-4.12(1H, m), 4.73-4.82(1H, m), 7.69(1H,
dd, J=8.8, 2.5 Hz), 7.90(1H, br. s), 8.17(1H, dd, J=8.8, 0.55 Hz),
8.29(1H, dd, J=2.5, 0.55 Hz), 9.76(1H, br.s).
[2094] MS (ESI) m/z:397 (M+H).sup.+.
Referential Example 473
5-[(4-methylphenyl)sulfonyl]-5,6,7,8-tetrahydro-4H-thiazolo[5,4-c]azepin-2-
-ylamine
##STR00543##
[2096] 3-Bromo-1-[(4-methylphenyl)sulfonyl]-4-azepanone (6.54 g)
(J. Chem. Soc. Perkin Trans., 1995, Vol. 1,2355) was dissolved in
N,N-dimethylformamide (100 mL). Thiourea (1.44 g) was added
thereto, followed by stirring at 60.degree. C. overnight. The
solvent was distilled away under reduced pressure. To the residue,
methylene chloride (100 mL) and saturated aqueous sodium
hydrogencarbonate (100 mL) were added for partitioning the mixture.
The aqueous layer was extracted with methylene chloride (100 mL).
All the organic layers were combined, followed by drying over
magnesium sulfate anhydrate. The solvent was distilled away under
reduced pressure. Ethyl acetate (100 mL) was added to the residue,
and the precipitated light yellow powder was recovered by
filtration to thereby give
5-[(4-methylphenyl)sulfonyl]-5,6,7,8-tetrahydro-4H-thiazolo[5,4-c]azepin--
2-ylfolmamide (1.86 g) in a crude form. The filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (methanol:methylene chloride=1:19), to
thereby give a mixture (4.01 g) of the title compound and
5-[(4-methylphenyl)sulfonyl]-5,6,7,8-tetrahydro-4H-thiazolo[5,4-c]azepin--
2-ylformamide. This mixture and the above crude product were
combined. The resultant mixture was suspended in dioxane (50 mL),
3N HCl (50 mL) was added thereto, and the resultant mixture was
heated under reflux for 1 hour. The solvent was distilled away
under reduced pressure. Methylene chloride (250 mL) and saturated
aqueous sodium carbonate (200 mL) were added thereto for
partitioning the mixture. The oil layer was dried over magnesium
sulfate anhydrate, and the solvent was distilled away. Diisopropyl
ether (100 mL) was added to the residue. The precipitated light
yellow powder was recovered by filtration, to thereby give the
title compound (4.47 g).
[2097] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.75-1.87(2H, m), 2.40(3H,
s), 2.62(2H, t, J=5.7 Hz), 3.53(2H, t, J=5.7 Hz), 4.37(2H, s),
4.73(2H, br.s), 7.25(2H, d, J=8.5 Hz), 7.61(2H, d, J=8.5 Hz).
[2098] MS (ESI) m/z:324 (M+H).sup.+.
Referential Example 474
5,6,7, 8-tetrahydro-4H-thiazolo[5,4-c]azepin-2-ylamine hydrobromic
acid salt
##STR00544##
[2100] The method described in Referential Example 291 was
performed by use of the compound obtained in Referential Example
473, whereby the title compound was obtained.
[2101] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.95 (2H, br.s),
2.70-2.90(2H, m), 3.38(2H, br.s), 4.56(2H, br.s), 9.07(3H,
br.s).
[2102] MS (ESI) m/z:170 (M+H).sup.+.
Referential Example 475
5-methyl-5,6,7, 8-tetrahydro-4H-thiazolo[5,4-c]azepin-2-ylamine
##STR00545##
[2104] The compound (2.73 g) obtained in Referential Example 474
was suspended in methanol. To the suspension, under ice cooling,
were added triethylamine (2.30 mL), acetic acid (453 .mu.L), 37%
aqueous formaldehyde (668 .mu.L), and sodium cyanoborohydride (544
mg). The mixture was stirred at room temperature overnight.
Saturated aqueous sodium hydrogencarbonate (20 mL) was added
thereto, and the resultant mixture was concentrated to dryness. The
residue was purified by silica gel chromatography
(methanol:methylene chloride=3:17). To the resultant crude product,
methanol (100 mL) and sodium carbonate anhydrate (20 g) were added,
followed by stirring at room temperature for 30 minutes. The
insoluble material was removed through filtration. The filtrate was
concentrated under reduced pressure. Methylene chloride (250 mL)
and methanol (50 mL) were added to the residue, and the insoluble
material was removed through filtration. The filtrate was
concentrated under reduced pressure. The resultant pale yellow
powder was washed with acetonitrile (100 mL), to thereby give the
title compound (1.23 g).
[2105] .sup.1H-NMR (CDCl.sub.3) .delta.:1.70-1.85(2H, s), 2.38(3H,
s), 2.77(2H, t, J=5.6 Hz), 2.97(2H, t, J=5.6 Hz), 3.65(2H, s),
4.68(2H, br.s).
[2106] MS (ESI) m/z:184 (M+H).sup.+.
Referential Example 476
2-bromo-5-methyl-5,6,7,8-tetrahydro-4H-thiazolo[5,4-c]azepine
##STR00546##
[2108] The compound (1.13 g) obtained in Referential Example 475
was suspended in water (10 mL). To the suspension, 48% hydrobromic
acid aqueous solution (7.0 mL) was added, followed by stirring
under ice cooling. To the reaction mixture, aqueous solution (3.0
mL) containing sodium nitrite (639 mg) was carefully added
dropwise. After dropping, this suspension was stirred at room
temperature overnight. Under ice cooling, Methylene chloride (100
mL) was added to the reaction mixture, and under stirring, the
resultant mixture was neutralized with saturated aqueous sodium
carbonate. After partition, the aqueous layer was extracted with
methylene chloride (100 mL). The organic layers were combined,
followed by drying over sodium sulfate anhydrate. The residue was
purified by silica gel chromatography (methanol;methylene
chloride=3:47), to thereby give the title compound (582 mg) as a
pale orange oil.
[2109] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.70-1.85(2H, s), 2.38(3H,
s), 2.95-3.05(4H, m), 3.79(2H, s).
[2110] MS (ESI) m/z:247 (M+H).sup.+.
Referential Example 477
5-methyl-5,6,7,8-tetrahydro-4H-thiazolo[5,4-c]azepine-2-carboxylic
acid lithium salt
##STR00547##
[2112] The method described in Referential Example 10 was performed
by use of the compound obtained in Referential Example 476, whereby
the title compound was obtained.
[2113] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.65(2H, br.s), 2.23(3H,
s), 2.80-2.97(4H, m), 3.75(2H, s).
Referential Example 478
4,4,5-trimethyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-ylamine
##STR00548##
[2115] 1,2,2-Trimethylpyrrolidin-3-one (1.00 g) was dissolved in
cyclohexane (5 mL). Pyrrolidine (1.31 mL) and p-toluenesulfonic
acid monohydrate (7.48 mg) were sequentially added thereto, and the
mixture was heated under reflux for 3 days, and allowed to cool to
room temperature. The resultant mixture was concentrated under
reduced pressure to thereby give a crude product of
1,2,2-trimethyl-3-(pyrrolidine-1-yl)-2,5-dihydro-1H-pyrrole (972
mg). To the product dissolved in dimethylformamide (10 mL),
formamidine disulfide hydrochloride (1.20 g) was added, followed by
stirring at room temperature for 4 days. The resultant mixture was
concentrated under reduced pressure. Methanol (50 mL) and sodium
carbonate anhydrate (20 g) were added to the residue, and the
resultant mixture was stirred at room temperature for 1 hour. The
insoluble material was removed through filtration, followed by
washing with methanol. The filtrate was concentrated under reduced
pressure. The residue was purified by silica gel chromatography
(methanol:methylene chloride=1:99 1:9), to thereby give the title
compound (580 mg).
[2116] .sup.1H-NMR (CDCl.sub.3) .delta.:1.25(6H, s), 2.48(3H, s),
3.83(2H, s), 4.83(2H, br.s).
[2117] MS (ESI) m/z:184 (M+H).sup.+.
Referential Example 479
2-bromo-4,4,5-trimethyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole
##STR00549##
[2119] The method described in Referential Example 476 was
performed by use of the compound obtained in Referential Example
478, whereby the title compound was obtained.
[2120] .sup.1H-NMR (CDCl.sub.3) .delta.:1.30(6H, s), 2.49(3H, s),
3.91(2H, s).
[2121] MS (ESI) m/z:247 (M+H).sup.+.
Referential Example 480
2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylic acid
##STR00550##
[2123] The method described in Referential Example 291 was
performed by use of
2-[(4-methylphenyl)sulfonyl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-
-6-carboxylic acid ethyl ester (Chem. Commun., 2001, 1102), whereby
the title compound was obtained.
[2124] .sup.1H-NMR (CDCl.sub.3) .delta.:4.60-4.75(4H, m), 8.17(1H,
s), 8.78(1H, s), 9.69(2H, br.s).
[2125] MS (ESI) m/z:165 (M+H).sup.+.
Referential Example 481
2-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylic
acid lithium salt
##STR00551##
[2127] The compound (1.66 g) obtained in Referential Example 480
was dissolved in methanol (100 mL). Thionyl chloride (3.0 mL) was
added thereto, and the mixture was heated under reflux overnight,
followed by allowing to cool to room temperature. The solvent was
distilled away under reduced pressure, and methylene chloride (100
mL) and saturated aqueous sodium hydrogencarbonate (100 mL) were
added thereto for partitioning the mixture. To the aqueous layer,
methylene chloride (100 mL) and di-tert-butyl dicarbonate (1.40 g)
were added. The resultant mixture was stirred at room temperature
for 2 hours. After partition, the organic layer was dried over
magnesium sulfate anhydrate, and the solvent was distilled away
under reduced pressure. Hexane (50 mL) was added to the residue,
and the precipitated light yellow powder was recovered by
filtration to thereby give a crude product of
2-(tert-butoxycarbonyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-6-carboxyli-
c acid methyl ester (602 mg). The crude product (564 mg) was
dissolved in methanol (10 mL), and 1N aqueous lithium hydroxide
(2.20 mL) was added thereto, followed by stirring at room
temperature overnight. The resultant mixture was distilled away
under reduced pressure, to thereby give the title compound (591 mg)
as a light brown solid.
[2128] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.46(9H, br.s), 4.63(2H,
br.s), 4.65(2H, br.s), 7.93(0.5H, br.s), 7.96(0.5H, br.s), 8.40(1H,
br.s).
[2129] MS (ESI) m/z:265(M-Li+2H).sup.+.
Referential Example 482
5-(pyridin-4-yl)pyrimidine-2-carboxylic acid methyl ester
##STR00552##
[2131] In a manner similar to that described in Referential Example
237, a compound was obtained from pyridin-4-yl boronic acid and
5-bromopyrimidine-2-carboxylic acid, and the resultant compound was
esterified with methanol through use of thionyl chloride, whereby
the title compound was obtained.
[2132] .sup.1H-NMR (CDCl.sub.3) .delta.:4.12(3H, s), 7.57(2H, d,
J=6.1 Hz), 8.83(2H, d, J=6.1 Hz), 9.18(2H, s).
[2133] MS (ESI) m/z:216 (M+H).sup.+.
Referential Example 483
5-(pyridin-4-yl)pyrimidine-2-carboxylic acid lithium salt
##STR00553##
[2135] The method described in Referential Example 322 was
performed by use of the compound obtained in Referential Example
482, whereby the title compound was obtained.
[2136] .sup.1H-NMR (DMSO-d.sub.6) .delta.:7.85(2H, d, J=6.0 Hz),
8.69(2H, d, J=6.0 Hz), 9.12(2H, s).
[2137] MS (ESI) m/z:202 (M-Li+2H).sup.+.
Referential Example 484
2'-methyl-[1,1'-bipheny1]-4-carbaldehyde
##STR00554##
[2139] The method described in Referential Example 237 was
performed by use of 2-bromotoluene and 4-formylbenzene boronic
acid, whereby the title compound was obtained.
[2140] .sup.1H-NMR (CDCl.sub.3) .delta.:2.28(3H, s), 7.20-7.33(4H,
m), 7.50(2H, d, J=8.2 Hz), 7.94(2H, d, J=8.2 Hz), 10.07(1H, s).
[2141] MS (ESI) m/z:197 (M+H).sup.+.
Referential Example 485
2'-methyl-[1,1'-biphenyl]-4-carboxylic acid
##STR00555##
[2143] The compound (1.51 g) obtained in Referential Example 484
was suspended in water (100 mL). To the suspension were
sequentially added tert-butanol (10 mL), 2-methyl-2-butene (20 mL),
sodium chloride (3.67 g), and sodium dihydrogen phosphate dihydrate
(3.62 g). The resultant mixture was stirred at room temperature
overnight. To the reaction mixture, diisopropyl ether (200 mL) was
added for partitioning the mixture. The organic layer was washed
with 3N HCl (50 mL), followed by drying over magnesium sulfate
anhydrate. The solvent was distilled away under reduced pressure.
The residue was washed with hexane, to thereby give the title
compound (1.43 g) as a colorless powder.
[2144] .sup.1H-NMR (CDCl.sub.3) .delta.:2.29(3H, s), 7.20-7.35(4H,
m), 7.65(2H, d, J=8.1 Hz), 8.18(2H, d, J=8.1 Hz).
[2145] MS (ESI) m/z:213 (M+H).sup.+.
Referential Example 486
2'-methyl-[1,1'-biphenyl]-4-carboxylic acid methyl ester
##STR00556##
[2147] The compound (1.42 g) obtained in Referential Example 485
was suspended in methanol. To the suspension, thionyl chloride (1
mL) was added, and the resultant mixture was heated under reflux
for 2 hours, followed by allowing to cool to room temperature.
Saturated aqueous sodium hydrogencarbonate (100 mL) and methylene
chloride (100 mL) were added to the reaction mixture for
partitioning the mixture. The organic layer was dried over sodium
sulfate anhydrate, and the solvent was distilled away under reduced
pressure, to thereby give the title compound (1.51 g) as a
colorless oil.
[2148] .sup.1H-NMR (CDCl.sub.3) .delta.:2.26(3H, s), 3.94(3H, s),
7.20-7.35(4H, m), 7.40(2H, d, J=7.8 Hz), 8.08(2H, d, J=7.8 Hz).
[2149] MS (ESI) m/z:227 (M+H).sup.+.
Referential Example 487
2'-[(dimethylamino)methyl]-[1,1'-biphenyl]-4-carboxylic acid methyl
ester
##STR00557##
[2151] The compound (663 mg) obtained in Referential Example 486
was dissolved in 1,2-dichloroethane (30 mL). To the solution,
N-bromosuccinimide (521 mg) and 2,2'-azobisisobutyronitrile (48.1
mg) were added, and the resultant mixture was heated under reflux
for 1 hour. After the completion of reaction, the mixture was
cooled to 0.degree. C., and dimethylamine (40% aqueous solution,
0.99 mL) was added thereto, followed by stirring at room
temperature for 3 days. Water (100 mL) and methylene chloride (100
mL) were added to this mixture for partitioning the mixture. The
organic layer was dried over sodium sulfate anhydrate. The solvent
was distilled away under reduced pressure. The residue was purified
by silica gel chromatography (methanol:methylene chloride=1:25), to
thereby give the title compound (607 mg) as a colorless oil.
[2152] .sup.1H-NMR (CDCl.sub.3) .delta.:2.13(6H, s), 3.31(2H, s),
3.95(3H, s), 7.23(1H, dd, J=7.4, 1.5 Hz), 7.31(1H, dt, J=1.5, 7.4
Hz), 7.37(1H, dt, J=1.5, 7.4 Hz), 7.46(2H, d, J=8.2 Hz), 7.52(1H,
dd, J=7.4, 1.5 Hz), 8.07(2H, d, J=8.2 Hz).
[2153] MS (ESI) m/z:270 (M+H).sup.+.
Referential Example 488
2'-[(dimethylamino)methyl]-[1,1'-biphenyl]-4-carboxylic acid
lithium salt
##STR00558##
[2155] The method described in Referential Example 322 was
performed by use of the compound obtained in Referential Example
487, whereby the title compound was obtained.
[2156] .sup.1H-NMR (DMSO-d.sub.6) .delta.:2.06(6H, s), 3.29(2H, s),
7.20-7.38(5H, m), 7.49(1H, d, J=7.3 Hz), 7.88(2H, d, J=8.0).
[2157] MS (ESI) m/z:256 (M-Li+2H).sup.+.
Referential Example 489
4-[4-(methoxycarbonyl)phenyl]-2-methyl-1-pyridine N-oxide
##STR00559##
[2159] The method described in Referential Example 239 was
performed by use of 4-(2-methylpyridin-4-yl)benzoic acid methyl
ester (Japanese Patent Application Laid-Open (kokai) No.
2000-143623), whereby the title compound was obtained.
[2160] .sup.1H-NMR (CDCl.sub.3) .delta.:2.60(3H, s), 3.96(3H, s),
7.42(1H, dd, J=6.8, 2.7 Hz), 7.53(1H, d, J=2.7 Hz), 7.66(2H, d,
J=8.2 Hz), 8.14(2H, d, J=8.2 Hz), 8.33(1H, d, J=6.8 Hz).
[2161] MS (FAB) m/z:244 (M+H).sup.+.
Referential Example 490
4-{2-[(acetyloxy)methyl]pyridin-4-yl}benzoic acid methyl ester
##STR00560##
[2163] The compound (980 mg) obtained in Referential Example 489
was dissolved in acetic anhydrate (25 mL), and the solution was
stirred at 130.degree. C. for 30 minutes. The resultant mixture was
cooled to 90.degree. C., and methanol (50 mL) was added thereto,
followed by stirring for 1 hour. Methylene chloride (50 mL) and
saturated aqueous sodium hydrogencarbonate (150 mL) were added to
the reaction mixture. Solid sodium hydrogencarbonate was added
thereto till the resultant mixture became basic, followed by
stirring for 3 hours and partitioning. The aqueous layer was
extracted with methylene chloride (2.times.50 mL). The organic
layers were combined, and dried over sodium sulfate anhydrate. The
solvent was distilled away under reduced pressure. The residue was
purified by silica gel column chromatography (methylene
chloride:methanol=40:1.fwdarw.10:1), and further purified by
medium-pressure silica gel column chromatography (hexane : ethyl
acetate=2:1.fwdarw.1:1), to thereby give the title compound (749
mg) as a white solid.
[2164] .sup.1H-NMR (CDCl.sub.3) .delta.:2.19(3H, s), 3.96(3H, s),
5.29(2H, s), 7.47(1H, dd, J=5.1, 1.7 Hz), 7.57-7.60(1H, m),
7.70(2H, d, J=8.5 Hz), 8.15(2H, d, J=8.5 Hz), 8.68(1H, d, J=5.1
Hz).
[2165] MS (ESI) m/z:286 (M+H).sup.+.
Referential Example 491
4-(2-{[(tert-butoxycarbonyl)amino]methyl}pyridin-4-yl)benzoic acid
methyl ester
##STR00561##
[2167] The compound (532 mg) obtained in Referential Example 490
was dissolved in tetrahydrofuran (4.0 mL), and water (1.0 mL) and
lithium hydroxide (137 mg) were added to the solution at room
temperature, followed by stirring for 24 hours. Tetrahydrofuran was
distilled away under reduced pressure, and water (4.0 mL) and 1N
hydrochloric acid (5.65 mL) were added thereto. The resultant solid
was recovered by filtration, followed by washing with water and
drying to thereby give a white solid (400 mg). A portion of the
solid (272 mg) was suspended in tetrahydrofuran (10 mL), and
methanol (2.0 mL) and trimethylsilyldiazomethane (2.0M hexane
solution, 890 .mu.L) were added thereto at room temperature,
followed by stirring for 1 hour. The reaction mixture was
concentrated under reduced pressure. To a methylene chloride
solution (10 mL) of the resultant solid were added ethyl acetate
(5.0 mL), trimethylamine hydrochloride (12 mg), methanesulfonyl
chloride (140 .mu.L), and triethylamine (252 .mu.L) at room
temperature. The resultant mixture was stirred for 3 hours, and
saturated aqueous sodium hydrogencarbonate (20 mL) and methylene
chloride (20 mL) were added thereto for partitioning the mixture.
The aqueous layer was extracted with methylene chloride (2.times.15
mL). The organic layers were combined, and dried over sodium
sulfate anhydrate. The solvent was distilled away under reduced
pressure. The resultant red-purple oil was dissolved in
N,N-dimethylformamide (5.0 mL). Sodium azide (155 mg) was added
thereto at room temperature, followed by stirring for 1 hour. Water
(100 mL) and methylene chloride (30 mL) were added to the resultant
mixture for partitioning the mixture. The aqueous layer was
extracted with methylene chloride (3.times.20 mL). The organic
layers were combined, and dried over sodium sulfate anhydrate,
followed by adding dioxane (5.0 mL) thereto. The resultant mixture
was concentrated to about 5 mL under reduced pressure. To the
resultant brown mixture were added tetrahydrofuran (5.0 mL),
di-tert-butyl dicarbonate (400 mg), and 10% palladium-carbon (100
mg). The resultant mixture was stirred in a hydrogen atmosphere at
room temperature for 14 hours. The reaction mixture was filtered,
and the filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (methylene
chloride:acetone=20:1), to thereby give the title compound (270 mg)
as a light yellow oil.
[2168] .sup.1H-NMR (CDCl.sub.3) .delta.:1.48(9H, s), 3.96(3H, s),
4.52(2H, d, J=5.4 Hz), 4.94(0.5H, br.s), 5.59(0.5H, br.s), 7.42(1H,
dd, J=5.1, 1.7 Hz), 7.51(1H, br.s), 7.69(2H, d, J=8.3 Hz), 8.15(2H,
d, J=8.3 Hz), 8.61(1H, d, J=5.1 Hz).
[2169] MS (ESI) m/z:343 (M+H).sup.+.
Referential Example 492
1-(phenylsulfonyl)pyperidine-4-carboxylic acid ethyl ester
##STR00562##
[2171] To isonipecotic acid ethyl ester (1.08 mL) dissolved in
tetrahydrofuran (10 mL), triethylamine (1.40 mL) was added, and
benzenesulfonyl chloride (1.02 mL) was added thereto at 0.degree.
C. The resultant mixture was stirred at room temperature for 21
hours. Ice was added to the mixture, followed by stirring for 10
minutes. Ethyl acetate and 0.5N hydrochloric acid were added
thereto to thereby give two layers. The organic layer was washed
with saturated aqueous sodium hydrogencarbonate and saturated
aqueous sodium chloride. The resultant mixture was dried over
sodium sulfate anhydrate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(hexane:ethyl acetate=4:1.fwdarw.2:1), to thereby give the title
compound (1.66 g) as a white solid.
[2172] .sup.1H-NMR (CDCl.sub.3) .delta.:1.21(3H, t, J=7.1 Hz),
1.76-1.87(2H, m), 1.92-2.01(2H, m), 2.20-2.29(1H, m), 2.49(2H, dt,
J=2.9, 11.4 Hz), 3.59-3.67(2H, m), 4.10(2H, q, J=7.1 Hz),
7.51-7.63(3H, m), 7.74-7.78(2H, m).
[2173] MS (ESI) m/z:298 (M+H).sup.+.
Referential Example 493
1-(phenylsulfonyl)pyperidine-4-carboxylic acid
##STR00563##
[2175] The method described in Referential Example 274 was
performed by use of the compound obtained in Referential Example
492, whereby the title compound was obtained.
[2176] .sup.1H-NMR (CDCl.sub.3) .delta.:1.74-1.90(2H, m),
1.90-2.04(2H, m), 2.23-2.33(1H, m), 2.39-2.54(2H, m), 3.58-3.72(2H,
m), 7.48-7.64(3H, m), 7.67-7.80(2H, m).
[2177] MS (ESI) m/z:270 (M+H).sup.+.
Referential Example 494
1-(4-fluorobenzoyl)pyperidine-4-carboxylic acid ethyl ester
##STR00564##
[2179] The method described in Referential Example 492 was
performed by use of isonipecotic acid ethyl ester and
p-fluorobenzoyl chloride, whereby the title compound was
obtained.
[2180] .sup.1H-NMR (CDCl.sub.3) .delta.:1.27(3H, t, J=7.1 Hz),
1.60-2.10(4H, br), 2.54-2.62(1H, m), 2.95-3.13(2H, m),
3.55-3.90(1H, br), 4.16(2H, q, J=7.1 Hz), 4.30-4.70(1H, br),
7.09(2H, t, J=8.8 Hz), 7.41(2H, dd, J=8.8, 5.4 Hz).
[2181] MS (ESI) m/z:280 (M+H).sup.+.
Referential Example 495
1-(4-fluorobenzoyl)piperidine-4-carboxylic acid
##STR00565##
[2183] The method described in Referential Example 274 was
performed by use of the compound obtained in Referential Example
494, whereby the title compound was obtained.
[2184] .sup.1H-NMR (CDCl.sub.3) .delta.:1.60-2.20(4H, br),
2.57-2.68(1H, m), 2.98-3.20(2H, m), 3.55-4.00(1H, br),
4.25-4.65(1H, br), 7.09(2H, t, J=8.5 Hz), 7.40(2H, dd, J=8.5, 5.4
Hz).
[2185] MS (ESI) m/z:252 (M+H).sup.+.
Referential Example 496
4-(pyrrolidin-1-ylcarbonyl)benzoic acid methyl ester
##STR00566##
[2187] The method described in Referential Example 492 was
performed by use of pyrrolidine and terephthalic acid monomethyl
chloride, whereby the title compound was obtained.
[2188] .sup.1H-NMR (CDCl.sub.3) .delta.:1.85-1.93(2H, m),
1.94-2.01(2H, m), 3.38(2H, t, J=6.6 Hz), 3.66(2H, t, J=6.6 Hz),
3.94(3H, s), 7.57(2H, d, J=8.6 Hz), 8.07(2H, d, J=8.6 Hz).
[2189] MS (ESI) m/z:234 (M+H).sup.+.
Referential Example 497
4-(pyrrolidin-1-ylcarbonyl)benzoic acid
##STR00567##
[2191] The method described in Referential Example 274 was
performed by use of the compound obtained in Referential Example
496, whereby the title compound was obtained.
[2192] .sup.1H-NMR (CDCl.sub.3) .delta.:1.85-2.03(4H, m), 3.43(2H,
t, J=6.6 Hz), 3.67(2H, t, J=6.6 Hz), 7.61(2H, d, J=8.6 Hz),
8.14(2H, d, J=8.6 Hz).
[2193] MS (ESI) m/z:220 (M+H).sup.+.
Referential Example 498
4-(pyrrolidin-1-ylmethyl)benzoic acid methyl ester
##STR00568##
[2195] The method described in Referential Example 212 was
performed by use of the compound obtained in Referential Example
496, whereby the title compound was obtained.
[2196] .sup.1H-NMR (CDCl.sub.3) .delta.:1.75-1.84(4H, m),
2.47-2.56(4H, m), 3.37(2H, s), 3.90(3H, s), 7.41(2H, d, J=8.3 Hz),
7.98(2H, d, J=8.3 Hz).
[2197] MS (ESI) m/z:220 (M+H).sup.+.
Referential Example 499
(1S, 2R,
4S)-2-[(tert-butoxycarbonyl)amino]-4-[(methylamino)carbonyl]cyclo-
hexylcarbamic acid 9H-fluoren-9-ylmethyl ester
##STR00569##
[2199] The compound (823 mg) obtained in Referential Example 436
was dissolved in methanol (20 mL), 10% palladium carbon catalyst
(117 mg) was added thereto, and the resultant mixture was stirred
in a hydrogen atmosphere at room temperature for 3 hours. The
catalyst was removed through filtration through a glass filter. The
filtrate was concentrated under reduced pressure. To the resultant
colorless viscous oil (622 mg) dissolved in 1,2-dimethoxyethane (15
mL) were added saturated aqueous sodium hydrogencarbonate (5 mL),
water (2 mL), and fluoren-9-ylmethyl succinimidylcarbonate (867
mg). The resultant mixture was stirred at room temperature for 13
hours. The reaction mixture was diluted with ethyl acetate,
followed by adding water thereto to thereby give two layers. The
organic layer was washed with saturated aqueous sodium chloride,
the resultant mixture was dried over sodium sulfate anhydrate, and
concentrated under reduced pressure. Ethyl acetate was added to the
residue, and the mixture was slurry-washed. A white powder was
recovered by filtration. The mother liquid was also concentrated
under reduced pressure, and was slurry-washed with diethyl ether. A
white powder was recovered by filtration. The respective powder was
dissolved in ethyl acetate, followed by mixing. The solvent was
distilled away under reduced pressure, followed by drying under
vacuum pump, to thereby give the title compound (939 mg) as a white
powder.
[2200] .sup.1H-NMR (CDCl.sub.3) .delta.:1.46(9H, br.s),
1.60-1.74(1H, m), 1.78-1.92(2H, m), 1.92-2.07(2H, m), 2.10-2.26(1H,
m), 2.81(3H, d, J=4.9 Hz), 3.62-3.77(1H, br), 3.85-4.63(5H, m),
5.30-5.67(2H, br), 7.24-7.33(2H, m), 7.39(2H, t, J=7.6 Hz),
7.58(2H, br.d, J=7.1 Hz), 7.76(2H, d, J=7.6 Hz).
[2201] MS (ESI) m/z:394 (M-COOtBu).sup.+.
Referential Example 500
(1S, 2R,
4S)-2-[(tert-butoxycarbonyl)amino]-4-[(methylamino)carbothioyl]cy-
clohexylcarbamic acid 9H-fluoren-9-ylmethyl ester
##STR00570##
[2203] The method described in Referential Example 443 was
performed by use of the compound obtained in Referential Example
499, whereby the title compound was obtained.
[2204] .sup.1H-NMR (CDCl.sub.3) .delta.:1.46(9H, br.s),
1.55-2.10(6H, m), 2.45-2.72(1H, br), 3.17(3H, d, J=4.4 Hz),
3.65-3.77(1H, br), 3.78-3.88(0.5H, m), 4.00-4.65(4H, br),
4.75-5.25(0.5H, br), 5.30-5.60(0.5H, br), 6.85-7.00(0.5H, br),
7.25-7.34(2H, m), 7.39(2H, t, J=7.6 Hz), 7.42-7.53(0.5H, br),
7.58(2H, br.d, J=6.6 Hz), 7.75(2H, d, J=7.6 Hz), 7.80-7.90(0.5H,
br).
[2205] MS (ESI) m/z:410 (M-COOtBu).sup.+.
Referential Example 501
(1R, 2S,
5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-[(me-
thylamino)carbothioyl]cyclohexylcarbamic acid tert-butyl ester
##STR00571##
[2207] The method described in Referential Example 444 was
performed by use of the compound obtained in Referential Example
500, whereby the title compound was obtained.
[2208] .sup.1H-NMR (CDCl.sub.3) .delta.:1.45(9H, s), 1.50-1.70(1H,
m), 1.80-2.16(5H, m), 2.60-2.75(1H, br), 3.19(3H, d, J=4.9 Hz),
3.94-4.05(1H, br), 4.10-4.28(1H, br), 4.80-5.00(0.8H, br),
5.75-5.90(0.2H, br), 7.40-7.55(1H, br), 7.68(1H, dd, J=8.8, 2.2
Hz), 7.96-8.07(1H, br), 8.17(1H, d, J=8.8 Hz), 8.30(1H, d, J=2.0
Hz), 9.76(1H, s).
[2209] MS (ESI) m/z :414 (M-.sup.tBu+H).sup.+.
Referential Example 502
2,2-dichloro-N-(5-chloropyrimidin-2-yl)acetamide
##STR00572##
[2211] To 2-amino-5-chloropyrimidine (1.30 g) dissolved in
N,N-dimethylformamide (30 mL), dichloroacetyl chloride (1.44 mL)
and sodium hydrogencarbonate (1.26 g) were added, and the resultant
mixture was stirred at room temperature for 1 hour. The solvent was
distilled away under reduced pressure. Methylene chloride and water
were added to the residue for partitioning the mixture. The aqueous
layer was extracted with methylene chloride. The organic layers
were combined, and the resultant mixture was washed with water,
followed by drying over sodium sulfate anhydrate. The solvent was
distilled away under reduced pressure. The residue was purified by
silica gel flash column chromatography (hexane:ethyl acetate=1:1).
The resultant white solid was slurry-washed with a solvent mixture
of hexane-diethyl ether (4:1), followed by filtration to recover,
to thereby give the title compound (1.24 g) as a white solid.
[2212] .sup.1H-NMR (CDCl.sub.3) .delta.:6.43(1H, br.s), 8.65(2H,
s), 9.07(1H, br.s). MS (ESI) m/z:240 (M+H).sup.+.
Referential Example 503
(1R, 2S,
5S)-2-({2-[(5-chloropyrimidin-2-yl)amino]-2-oxoethanethioyl}amino-
)-5-[(dimethylamino)carbonyl]cyclohexylcarbamic acid tert-butyl
ester
##STR00573##
[2214] The compound (8.03 g) obtained in Referential Example 144,
the compound (6.76 g) obtained in Referential Example 502, and
sulfur (947 mg) were added in N,N-dimethylformamide (90 mL). The
resultant mixture was heated at 120.degree. C.
Diisopropylethylamine (9.57 mL) was added thereto, followed by
stirring at 120.degree. C. for 10 minutes. The solvent was
distilled away under reduced pressure. Methylene chloride was added
to the residue, and the insoluble material was removed through
filtration through celite. Water was added to the filtrate for
partitioning the mixture, and the organic layer was washed with
water and then subjected to silica gel flash column chromatography
(methylene chloride:methanol=19:1), thereby yielding a crude
product. The crude product was dissolved in methylene chloride,
hexane was added thereto, and the resultant solid was recovered by
filtration, to thereby give the title compound (940 mg) as a light
yellow solid. The filtrate was also purified by silica gel column
chromatography, to thereby give the title compound (940 mg)
containing N,N-dimethylformamide as a light brown solid.
[2215] .sup.1H-NMR (DMSO) .delta.:1.28-2.22(15H, m), 2.71(1H,
br.s), 2.96(3H, s), 3.07(3H, s), 4.25-4.42(2H, m), 8.62(2H, s),
9.88(1H, br.s), 10.89(1H, s).
Referential Example 504
2-chloro-N-(4-chloro-3-nitrophenyl)acetamide
##STR00574##
[2217] The method described in Referential Example 502 was
performed by use of 4-chloro-3-nitroaniline and chloroacetyl
chloride, whereby the title compound was obtained.
[2218] .sup.1H-NMR (CDCl.sub.3) .delta.:4.23(2H, s), 7.54(1H, d,
J=8.8 Hz), 7.74(1H, dd, J=8.8, 2.4 Hz), 8.22(1H, d, J=2.4 Hz),
8.39(1H, br.s).
Referential Example 505
(1R, 2S,
5S)-2-{([2-(4-chloro-3-nitroanilino)-2-oxoethanethioyl]amino}-5-[-
(dimethylamino)carbonyl]cyclohexylcarbamic acid tert-butyl
ester
##STR00575##
[2220] The compound (498 mg) obtained in Referential Example 504
was dissolved in N,N-dimethylformamide (4 mL), and sulfur (128 mg)
and triethylamine(833 .mu.L) were added thereto, followed by
stirring at room temperature for 1 hour. To the reaction mixture
were added the compound (571 mg) obtained in Referential Example
144 and 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride
(767 mg). The resultant mixture was stirred at room temperature
overnight. The solvent was distilled away under reduced pressure.
Methylene chloride and water were added to the residue for
partitioning the mixture. The aqueous layer was extracted with
methylene chloride. The organic layers were combined. The resultant
mixture was washed with water, followed by drying over sodium
sulfate anhydrate. The solvent was distilled away under reduced
pressure. The residue was purified by silica gel flash column
chromatography (ethyl acetate), to thereby give the title compound
(688 mg) as a yellow solid.
[2221] .sup.1H-NMR (CDCl.sub.3) .delta.:1.47(9H, m), 1.48-1.59(1H,
m), 1.72-1.81(1H, m), 1.86-1.95(2H, m), 2.04(1H, br.s), 2.23(1H,
br.s), 2.69(1H, br.s), 2.96(3H, s), 3.09(3H, s), 4.34-4.39(2H, m),
4.78(1H, br.s), 7.52(1H, d, J=8.6 Hz), 7.69(1H, d, J=8.6 Hz),
8.39(1H, br.s), 9.95(1H, br.s), 10.37(1H, s).
[2222] MS (ESI) m/z:528 (M+H).sup.+.
Referential Example 506
(1S, 3R,
4S)-3-[(tert-butoxycarbonyl)amino]-4-{[(7-chlorocinnolin-3-yl)car-
bonyl]amino}cyclohexanecarboxylic acid ethyl ester
##STR00576##
[2224] In a manner similar to that described in Referential Example
97, the compound obtained in Referential Example 96 was condensed
with the compound obtained in Referential Example 298, whereby the
title compound was obtained.
[2225] .sup.1H-NMR (CDCl.sub.3) .delta.:1.28(3H, t, J=7.2 Hz ,
1.36(9H, s), 1.53-2.16(6H, m), 2.48(1H, br.s), 4.17(2H, q, J=7.2
Hz), 4.30-4.35(2H, m), 4.86(1H, br.s), 7.78(1H, dd, J=8.8, 2.0 Hz),
7.97(1H, d, J=8.8 Hz), 8.59-8.60(1H, m), 8.64(1H, d, J=8.6 Hz),
8.73(1H, s).
[2226] MS (ESI) m/z:477 (M+H).sup.+.
Referential Example 507
(1S, 3R,
4S)-3-[(tert-butoxycarbonyl)amino]-4-{[(7-chlorocinnolin-3-yl)car-
bothioyl]amino}cyclohexanecarboxylic acid ethyl ester
##STR00577##
[2228] The method described in Referential Example 443 was
performed by use of the compound obtained in Referential Example
506, whereby the title compound was obtained.
[2229] .sup.1H-NMR (CDCl.sub.3) .delta.:1.28(3H, t, J=7.1 Hz),
1.37(9H, br.s), 1.59-2.26(6H, m), 2.49(1H, br.s), 4.17(2H, q, J=7.1
Hz), 4.54(1H, br.s), 4.83-4.87(2H, m), 7.76(1H, dd, J=8.7, 1.8 Hz),
7.97(1H, d, J=8.7 Hz), 8.57(1H, s), 9.20(1H, s), 10.64(1H,
br.s).
[2230] MS (ESI) m/z:493 (M+H).sup.+.
Referential Example 508
(1R, 2S,
5S)-2-{[(7-chlorocinnolin-3-yl)carbothioyl]amino}-5-[(dimethylami-
no)carbonyl]cyclohexylcarbamic acid tert-butyl ester
##STR00578##
[2232] In a manner similar to that described in Referential Example
251, calboxylic acid prepared by hydrolysis of the compound
obtained in Referential Example 507 was condensed with
dimethylamine hydrochloride, whereby the title compound was
obtained.
[2233] .sup.1H-NMR (CDCl.sub.3) .delta.:1.37(9H, br.s), 1.66(1H,
br.s), 1.82-2.05(4H, m), 2.29-2.32(1H, m), 2.76(1H, br.s), 2.97(3H,
s), 3.09(3H, s), 4.56-4.59(1H, m), 4.90(2H, br.s), 7.75(1H, dd,
J=8.7, 2.0 Hz), 7.97(1H, d, J=8.7 Hz), 8.56(1H, s), 9.19(1H, br.s),
10.60(1H, d, J=7.8 Hz).
[2234] MS (ESI) m/z:492 (M+H).sup.+.
Referential Example 509
(1S, 3R,
4S)-3-amino-4-{[(7-chlorocinnolin-3-yl)carbothioyl]amino}-N,N-dim-
ethylcyclohexanecarboxamide
##STR00579##
[2236] The method described in Referential Example 325 was
performed by use of the compound obtained in Referential Example
508, whereby the title compound was obtained.
[2237] MS (ESI) m/z:392 (M+H).sup.+.
Referential Example 510
(1R, 2S,
5S)-2-({[(4-chlorobenzoyl)amino]carbonyl}amino)-5-[(dimethylamino-
)carbonyl]cyclohexylcarbamic acid tert-butyl ester
##STR00580##
[2239] To a dichloroethane (20 mL) solution of p-chlorobenzamide
(311 mg), oxalyl chloride (435 .mu.L) was added, and the resultant
mixture was heated under reflux for 3 hours. The solvent was
distilled away under reduced pressure. Acetonitrile (10 mL)
solution of the residue was added dropwise to solution of the
compound (571 mg) obtained in Referential Example 144 dissolved in
acetonitrile (20 mL), followed by stirring at room temperature for
10 minutes. The solvent was distilled away under reduced pressure.
Ether was added to the residue, and the resultant solid was
recovered by filtration, to thereby give the title compound (678
mg) as a white solid.
[2240] .sup.1H-NMR (CDCl.sub.3) .delta.:1.42(9H, s), 1.52-2.01(6H,
m), 2.68(1H, br.s), 2.95(3H, s), 3.08(3H, s), 3.95(1H, br.s),
4.29(1H, br.s), 4.84(1H, br.s), 7.41(2H, d, J=8.3 Hz), 7.88(2H,
br.s), 8.92(1H, d, J=7.6 Hz), 9.78(1H, s).
[2241] MS (ESI) m/z:489 (M+Na).sup.+.
Referential Example 511
(1S, 3R,
4S)-3-amino-4-({[(4-chlorobenzoy)amino]carbonyl}amino)-N,N-dimeth-
ylcyclohexanecarboxamide
##STR00581##
[2243] The method described in Referential Example 325 was
performed by use of the compound obtained in Referential Example
510, whereby the title compound was obtained.
[2244] .sup.1H-NMR (CDCl.sub.3) .delta.:1.51(2H, br.s),
1.67-1.96(6H, m), 2.90(1H, br.s), 2.95(3H, s), 3.08(3H, s),
3.44(1H, br.s), 3.93(1H, br.s), 7.47(2H, d, J=8.5 Hz), 7.86(2H, d,
J=8.5 Hz), 8.85(1H, br.s), 8.93(1H, d, J=7.3 Hz).
[2245] MS (ESI) m/z:367 (M+H).sup.+.
Referential Example 512
(E)-3-(5-chloropyridin-2-yl)-2-acrylic acid methyl ester
##STR00582##
[2247] Sodium hydride (60% oil, 580 mg) was suspended in
tetrahydrofuran (30 mL). At -30.degree. C.,
2-(dimethoxyphosphoryl)acetic acid methyl ester (2.35 mL) dissolved
in tetrahydrofuran (30 mL) was added dropwise thereto, followed by
stirring at -30.degree. C. for 30 minutes. To the resultant
mixture, tetrahydrofuran (10 mL) and
5-chloropyridine-2-carboxyaldehyde (J. Med. Chem. 1970, Vol. 13,
1124) (1.96 g) dissolved in tetrahydrofuran (15 mL) were added,
followed by heating gradually to room temperature over 1 hour.
Water (100 mL) and diethyl ether (50 mL) were added thereto for
partitioning the mixture. The aqueous layer was extracted with
diethyl ether (50 mL). The organic layers were combined, and the
resultant mixture was washed with saturated brine (50 mL), followed
by drying over sodium sulfate anhydrate. The solvent was distilled
away under reduced pressure. Hexane(30 mL) was added to the
resultant white solid, and the resultant mixture was stirred for 30
minutes, and filtered to recover, to thereby give the title
compound (1.89 g) as a white solid.
[2248] .sup.1H-NMR (CDCl.sub.3) .delta.:3.82(3H, s), 6.91(1H, dd,
J=15.7, 0.9 Hz), 7.36(1H, d, J=8.3 Hz), 7.64(1H, d, J=15.7 Hz),
7.68(1H, ddd, J=8.3, 2.4, 0.9 Hz), 8.59(1H, d, J=2.4 Hz).
[2249] MS (ESI) m/z:197(M.sup.+).
Referential Example 513
(1R, 2S,
5S)-2-{[(E)-3-(5-chloropyridin-2-yl)acryloyl]amino}-5-[(dimethyla-
mino)carbonyl]cyclohexylcarbamic acid tert-butyl ester
##STR00583##
[2251] In a manner similar to that described in Referential Example
97, carboxylic acid lithium salt prepared by hydrolysis of the
compound obtained in Referential Example 512 was condensed with the
compound obtained in Referential Example 144, whereby the title
compound was obtained.
[2252] .sup.1H-NMR (CDCl.sub.3) .delta.:1.47(9H, s), 1.65-1.88(3H,
m), 1.88-2.00(2H, m), 2.05-2.22(1H, m), 2.65(1H, br.s), 2.94(3H,
s), 3.05(3H, s), 4.05(1H, br.s), 4.10-4.18(1H, m), 4.78(1H, br.s),
6.71(1H, br.s), 6.89(1H, d, J=15.4 Hz), 7.30(1H, d, J=8.3 Hz),
7.54(1H, d, J=15.4 Hz), 7.65(1H, dd, J=8.3, 2.4 Hz), 8.53(1H, d,
J=2.4 Hz).
[2253] MS (ESI) m/z:451 (M+H).sup.+.
Referential Example 514
3-(4-chlorophenyl)-2-fluoro-3-hydroxypropionic acid ethyl ester
##STR00584##
[2255] Zinc powder (1.96 g) was added to 4-chlorobenzaldehyde (141
mg) dissolved in benzene. (20 mL), and a catalytic amount of iodine
was added to the mixture while refluxing by heating. Ethyl
bromofluoroacetate (185 mg) in benzene (2.5 mL) was added dropwise
thereto, followed by stirring for 2.5 hours. The reaction mixture
was cooled by ice, 1N hydrochloric acid (12.5 mL) was added
thereto, and the resultant mixture was stirred at room temperature
for 1.5 hours. Water and ethyl acetate were added thereto for
partition. The aqueous layer was extracted with ethyl acetate. The
organic layers were combined, and dried over sodium sulfate
anhydrate. The solvent was distilled away under reduced pressure.
The residue was purified by preparative thin layer chromatography
(hexane : ethyl acetate=3:1), to thereby give the title compound
(diastereomer mixture) (117 mg) as a colorless oil.
[2256] .sup.1H-NMR (CDCl.sub.3) .delta.:1.16-1.24(3H, m), 3.35(1H,
br.d, J=51.9 Hz), 4.15-4.25(2H, m), 4.89-5.11(2H, m), 7.31-7.33(4H,
m).
[2257] MS (EI) m/z:246(M.sup.+).
Referential Example 515
(Z)-3-(4-chlorophenyl)-2-fluoroacrylic acid ethyl ester
##STR00585##
[2259] The compound (51 mg) obtained in Referential Example 514 was
dissolved in methylene chloride (1.0 mL). Pyridine (100 .mu.L) was
added thereto, and the mixture was cooled to 0.degree. C. Thionyl
chloride (20 .mu.L) was added to the resultant mixture followed by
stirring at 0.degree. C. for 20 minutes. 1N Hydrochloric acid and
ethyl acetate were added thereto for partitioning the mixture. The
aqueous layer was extracted with ethyl acetate. The organic layers
were combined, and dried over sodium sulfate anhydrate. The solvent
was distilled away under reduced pressure. The residue was
dissolved in methylene chloride (2 mL), and
1,8-diazabicyclo[5.4.0]undec-7-ene (34 .mu.L) was added thereto,
followed by stirring at room temperature for 3.5 hours. 1N
Hydrochloric acid and methylene chloride were added to the
resultant mixture for partitioning the mixture. The aqueous layer
was extracted with methylene chloride. The organic layers were
combined, and dried over sodium sulfate anhydrate. The solvent was
distilled away under reduced pressure. The residue was purified by
preparative thin layer chromatography (hexane:ethyl acetate=4:1),
to thereby give the title compound (22 mg) as a pale yellow
solid.
[2260] .sup.1H-NMR (CDCl.sub.3) .delta.:1.38(3H, t, J=7.2 Hz),
4.35(2H, q, J=7.2 Hz), 6.87(1H, d, J=34.9 Hz), 7.37(2H, d, J=8.3
Hz), 7.57(2H, d, J=8.3 Hz).
Referential Example 516
(Z)-3-(4-chlorophenyl)-2-fluoroacrylic acid
##STR00586##
[2262] The method described in Referential Example 274 was
performed by use of the compound obtained in Referential Example
515, whereby the title compound was obtained.
[2263] .sup.1H-NMR (DMSO-d.sub.6) .delta.:7.06(1H, d, J=36.4 Hz),
7.52(2H, d, J=8.2 Hz), 7.72(2H, d, J=8.2 Hz).
[2264] MS (ESI-negative) m/z:198(M-H).sup.-.
Referential Example 517
(1S, 2R,
4S)-2-[(tert-butoxycarbonyl)amino]-4-[(dimethylamino)carbonyl]cyc-
lohexylcarbamic acid 2,2,2-trichloroethyl ester
##STR00587##
[2266] The compound (10.0 g) obtained in Referential Example 144
was dissolved in pyridine (175 mL). To the solution, 2,
2,2-trichloroethyl chloroformate (10.6 mL) was added dropwise,
followed by stirring at room temperature overnight.
[2267] The solvent was distilled away under reduced pressure.
Methylene chloride and 0.5N hydrochloric acid were added thereto
for partitioning the mixture. The resultant organic layer was
washed twice with 0.5N hydrochloric acid, and then washed once with
saturated brine, followed by drying over sodium sulfate anhydrate.
The solvent was distilled away under reduced pressure. The residue
was dissolved in a small amount of methylene chloride, and hexane
was added thereto. The resultant solid was recovered by filtration.
The solid was slurry-washed with diethyl ether, to thereby give the
title compound (13.6 g) as a white solid.
[2268] .sup.1H-NMR (CDCl.sub.3) .delta.:1.46(9H, s), 1.62-1.97(6H,
m), 2.67(1H, br.s), 2.94(3H, s), 3.05(3H, s), 3.71-3.76(1H, m),
4.16(1H, br.s), 4.64-4.86(3H, m), 5.62(1H, d, J=7.3 Hz).
[2269] MS (ESI) m/z:460 (M+H).sup.+.
Referential Example 518
(1S, 2R,
4S)-4-[(dimethylamino)carbonyl]-2-{([(5-methyl-4,5,6,7-tetrahydro-
[1 3]thiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexylcarbamic
acid 2,2,2-trichloroethyl ester
##STR00588##
[2271] In a manner similar to that described in Referential Example
252, the compound obtained in Referential Example 517 was treated
with hydrochloric acid for deprotection. The deprotected compound
was condensed with the compound obtained in Referential Example 10,
whereby the title compound was obtained.
[2272] .sup.1H-NMR (CDCl.sub.3) .delta.:1.53-2.17(6H, m), 2.52(3H,
s), 2.74-2.93(8H, m), 3.03(3H, s), 3.72(2H, br.s), 3.83-3.90(1H,
m), 4.62-4.79(3H, m), 5.65(1H, br.d, J=6.8 Hz), 7.36(1H, br.d,
J=8.5 Hz).
[2273] MS (ESI) m/z: 540(M+H).sup.+.
Referential Example 519
(1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydro[1,-
3]thiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexylcarbamic
acid tert-butyl ester
##STR00589##
[2275] The compound (5.01 g) obtained in Referential Example 518
was dissolved in a mixture of ethanol (100 mL) and water (5 mL).
Zinc (6.06 g) and ammonium chloride (2.48 g) were added thereto,
followed by stirring at 40.degree. C. for 4.5 hours. Zinc was
removed through filtration through celite. Sodium hydrogencarbonate
(7.78 g) and di-tert-butyl dicarbonate (6.08 g) were added to the
filtrate, and the mixture was stirred at room temperature
overnight. The solvent was distilled away under reduced pressure.
Methylene chloride and water were added to the residue for
partitioning the mixture. The aqueous layer was extracted twice
with methylene chloride. The organic layers were combined, and
dried over sodium sulfate anhydrate. The solvent was distilled away
under reduced pressure. The residue was purified by silica gel
flash column chromatography (ethyl acetate:methanol=7:3). The
residue was further purified by preparative recycle HPLC (Japan
Analytical Industry Co., LC908-C60, column:JAIGEL 1H-40 and 2H-40,
solvent:chloroform), to thereby give the title compound (2.30 g) as
a light yellow solid.
[2276] .sup.1H-NMR (CDCl.sub.3) .delta.:1.43(9H, s), 1.48-2.07(6H,
m), 2.52(3H, s), 2.70-2.96(8H, m), 3.00(3H, s), 3.68-3.77(3H, m),
4.57-4.60(1H, m), 4.94(1H, br.s), 7.33(1H, br.s).
[2277] MS (ESI) m/z: 466(M+H).sup.+.
Referential Example 520
2,2-dichloro-N-(5-chloropyridin-2-yl)acetamide
##STR00590##
[2279] The method described in Referential Example 457 was
performed by use of 2-amino-5-chloropyridine, whereby the title
compound was obtained.
[2280] .sup.1H-NMR (CDCl.sub.3).delta.:6.06(1H, s), 7.73(1H, dd,
J=8.8, 2.4 Hz), 8.15(1H, dd, J=9.0, 0.5 Hz), 8.30(1H, dd, J=2.5,
0.5 Hz), 8.78(1H, s).
[2281] MS (ESI) m/z: 239(M+H).sup./.
Referential Example 521
(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoethanethioyl}amino)-5--
[(methylamino)carbonyl]cyclohexylcarbamic acid tert-butyl ester
##STR00591##
[2283] The compound (1.01 g) obtained in Referential Example 436
was dissolved in methanol (50 mL). To the solution, 10% palladium
carbon catalyst (0.35 g) was added, and the mixture was stirred in
a hydrogen atmosphere at room temperature for 16 hours. The
catalyst was removed through filtration, and the filtrate was
concentrated under reduced pressure. The residue was dissolved in
N,N-dimethylformamide (5.0 mL). To the mixture were added the
compound obtained in Referential Example 520 (600 mg),
diisopropylethylamine (5.0 mL), and sulfur (80.3 mg), followed by
stirring at 120.degree. C. for 2 hours. The reaction mixture was
concentrated under reduced pressure. Water was added to the
residue, and the resultant mixture was extracted twice with
methylene chloride (200 mL). The organic layer was sequentially
washed with 10% aqueous citric acid, saturated aqueous sodium
hydrogencarbonate, and saturated brine. The resultant mixture was
dried over sodium sulfate anhydrate, and concentrated under reduced
pressure. The residue was purified by silica gel flash column
chromatography (methylene chloride:methanol=50:1.fwdarw.30:1), to
thereby give the title compound (812 mg) as a yellow glassy
solid.
[2284] .sup.1H-NMR (CDCl.sub.3).delta.:1.25-2.50(7H, m), 1.46(9H,
s), 2.82(3H, d, J=4.9 Hz), 4.23-4.43(2H, m), 4.80-5.10(0.8H, br),
5.50-5.80(1H, br), 5.80-6.05(0.2H, br), 7.69(1H, dd, J=8.8, 22.4
Hz), 8.02(1H, s), 8.10-8.23(1H, m), 8.31(1H, d, J=2.4 Hz),
9.50-9.85(0.2H, br), 9.85-10.15(0.8H, br), 10.56(1H, s).
[2285] MS (ESI) m/z: 470(M+H).sup.+.
Referential Example 522
(1S,3R,4S)-3-amino-4-({2-[(5-fluoropyridin-2-yl)amino]-2-oxoethanethioyl}a-
mino)-N,N-dimethylcyclohexanecarboxamide hydrochloride
##STR00592##
[2287] The method described in Referential Example 69 was performed
by use of the compound obtained in Referential Example 427, whereby
the title compound was obtained.
[2288] .sup.1H-NMR (DMSO-d.sub.6).delta.:1.42-1.55 (1H, m),
1.72-1.90(3H, m), 2.00-2.09(1H, m), 2.11-2.28(1H, m), 2.82(3H, s),
3.08(3H, s), 3.27-3.40(1H, m), 4.03(1H, br.s), 4.35-4.45(1H, m),
7.89(1H, dt, J=2.9, 9.0 Hz), 8.14(1H, dd, J=9.0, 4.2 Hz), 8.33(3H,
br.s), 8.44(1H, d, J=2.9 Hz), 10.64(1H, s), 10.97(1H, d, J=7.1
Hz).
[2289] MS (ESI) m/z: 368(M+H).sup.+.
Referential Example 523
3-amidinobenzoic acid ethyl ester hydrochloride
##STR00593##
[2291] To 3-cyanobenzoic acid (5 g) in ethanol (100 mL), under ice
cooling and stirring, Hcl gas was injected to saturation. Ethanol
(400 mL) was added to the resultant suspension to dissolve,
followed by heating to room temperature. The resultant mixture was
sealed, allowed to stand for 18 hours, and concentrated to dryness
under reduced pressure. The residue was dissolved in ethanol (100
mL), and under ice cooling and stirring, ammonia gas was injected
thereto to saturation. The resultant mixture was heated to room
temperature, sealed, and allowed to stand for 18 hours. The solvent
was distilled away under reduced pressure. The residue was purified
with a synthetic absorbent material HP-20
(water.fwdarw.acetonitrile:water=1:4). The resultant crude product
was dissolved in methanol/dichloromethane=1/4, and the insoluble
material was removed through filtration. The residue was further
purified by silica gel chromatography (methanol:methylene
chloride=1:4), to thereby give the title compound (5.53 g) as a
colorless powder.
[2292] .sup.1H-NMR (DMSO-d.sub.6).delta.:1.36(3H, t, J=7.0 Hz),
4.38(2H, q, J=7 Hz), 7.78(1H, t, J=7.8 Hz), 8.11(1H, dd, J=7.8, 1.0
Hz), 8.27(1H, d, J=7.8 Hz), 8.38(1H, d, J=1.5 Hz), 9.41(1H, br.s),
9.61(1H, br.s).
[2293] MS (FAB) m/z: 193(M+H).sup.+
Referential Example 524
3-[[(tert-butoxycarbonyl)amino](imino)methyl]benzoic acid ethyl
ester
##STR00594##
[2295] The compound (250 mg) obtained in Referential Example 523
was dissolved in methanol (5.0 mL). To the solution,
diisopropylethylamine (952 .mu.L) and di-tert-butoxycarbonate (480
mg) were added, followed by stirring for 3 days. The solvent was
distilled away under reduced pressure. The residue was purified by
medium-pressure silica gel column chromatography (methylene
chloride:methanol=25:1), to thereby the title compound (285 mg) as
a white foamed solid.
[2296] .sup.1H-NMR (CDCl.sub.3).delta.:1.41(3H, t, J=7.2 Hz),
1.56(9H, s), 4.41(2H, q, J=7.2 Hz), 7.52(1H, t, J=7.8 Hz), 8.14(1H,
d, J=7.8 Hz), 8.19(1H, d, J=7.8 Hz), 8.43(1H, s).
[2297] MS (ESI) m/z: 293(M+H).sup.+.
Referential Example 525
(1R,2S,5S)-2-[(3-cyanobenzoyl)amino]-5-[(dimethylamino)carbonyl]cyclohexyl-
carbamic acid tert-butyl ester
##STR00595##
[2299] The compound (800 mg) obtained in Referential Example 144
and 3-cyanobenzoyl chloride (560 mg) were dissolved in methylene
chloride (30 mL). To the solution, diisopropylethylamine (730
.mu.L) was added at room temperature. The resulting mixture was
stirred for 4 hours. Water and saturated aqueous ammonium chloride
were added thereto for partitioning the mixture. The aqueous layer
was extracted with methylene chloride. The organic layers were
combined, and dried over sodium sulfate anhydrate. The solvent was
distilled away under reduced pressure. The residue was purified by
silica gel column chromatography (methylene
chloride:acetone=5:1.fwdarw.1:1), to thereby give the title
compound (1.15 g) as a white foamy solid.
[2300] .sup.1H-NMR (CDCl.sub.3).delta.:1.40-1.78(2H, m), 1.47(9H,
s), 1.78-1.94(2H, m), 2.08-2.40(2H, m), 2.60-2.70(1H, m), 2.96(3H,
s), 3.09(3H, s), 3.94-4.08(1H, m), 4.16-4.34(1H, m), 4.79-4.88(1H,
m), 7.55(1H, t, J=7.9 Hz), 7.75(1H, d, J=7.9 Hz), 8.06-8.16(3H,
m).
[2301] MS (ESI) m/z: 415(M+H).sup.+.
Referential Example 526
3-[[Methoxycarbonyl)amino]imino)methyl]benzoic acid ethyl ester
##STR00596##
[2303] To the compound (250 mg) obtained in Referential Example 523
were added methylene chloride (10 mL), diisopropylethylamine (952
.mu.L), and chloroformic acid ethyl ester (160 .mu.L). The
resultant mixture was stirred for 8 hours. Saturated aqueous sodium
hydrogencarbonate and methylene chloride were added thereto for
partitioning the mixture. The aqueous layer was extracted with
methylene chloride. The organic layers were combined, and dried
over sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure. The residue was purified by medium-pressure
silica gel column chromatography (methylene
chloride:methanol=25:1), to thereby give the title compound (270
mg) as a white solid.
[2304] .sup.1H-NMR (CDCl.sub.3).delta.:1.36(3H, t, J=7.1 Hz),
1.40(3H, t, J=7.1 Hz), 4.23(2H, q, J=7.1 Hz), 4.39(2H, q, J=7.1
Hz), 6.84(1H, br.s), 7.51(1H, t, J=7.8 Hz), 8.10-8.25(2H, m),
8.45(1H, s), 9.63(1H, br.s).
[2305] MS (ESI) m/z: 265(M+H).sup.+.
Referential Example 527
2,2-dichloro-N-(5-fluoropyridin-2-yl)acetamide
##STR00597##
[2307] To 2-amino-5-fluoropyridine (250 mg) in ethyl acetate (10
mL), dichloroacetyl chloride (279 .mu.L) was added at room
temperature, followed by stirring at 60-70.degree. C. for 2.5
hours. The reaction mixture was cooled, and saturated aqueous
sodium hydrogencarbonate was added thereto for partitioning the
mixture. The resultant organic layer was dried over magnesium
sulfate anhydrate. The solvent was distilled away under reduced
pressure, to thereby give the title compound (438 mg) as acrude
product.
[2308] .sup.1H-NMR (CDCl.sub.3).delta.:6.05(1H, s), 7.45-7.55(1H,
m), 8.15-8.25(2H, m), 8.72(1H, s).
[2309] MS (ESI) m/z: 223(M+H).sup.+.
Referential Example 528
(1R,2S,5S)-5-[(dimethylamino)carbonyl]-2-({2-[(5-fluoropyridin-2-yl)amino]-
-2-oxoethanethioyl}amino)cyclohexylcarbamic acid tert-butyl
ester
##STR00598##
[2311] N,N-Dimethylformamide (1.0 mL) and diisopropylethylamine
(1.0 mL) were added to the compound (112 mg) obtained in
Referential Example 527, the compound (143 mg) obtained in
Referential Example 144, and sulfur (17 mg). The resultant mixture
was stirred at 130.degree. C. for 20 minutes. The solvent was
distilled away under reduced pressure. Saturated aqueous sodium
hydrogencarbonate was added to the residue, followed by extracting
with methylene chloride. This resultant mixture was purified by
silica gel column chromatography (methylene
chloride:methanol=99:1), followed by washing with diisopropyl
ether, to thereby give the title compound (121 mg). The NMR data
were agreed with that of the compound from Referential Example
424.
Referential Example 529
4-morpholinobenzoic acid methyl ester
##STR00599##
[2313] Under ice cooling, thionyl chloride (436 .mu.L) was added
dropwise to methanol (10 mL). 4-Morpholinobenzoic acid (207 mg) was
added thereto, and the resultant mixture was heated under reflux
for 1.5 hours. The solvent was distilled away under reduced
pressure. Methylene chloride and water were added to the residue
for partitioning the mixture. The organic layer was dried over
sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure, whereby the title compound was obtained.
[2314] .sup.1H-NMR (CDCl.sub.3).delta.:3.28 (4H, t, J=4.9 Hz),
3.84-3.87(7H, m), 6.86(2H, dt, J=9.6, 2.5 Hz), 7.94(2H, dt, J=9.6,
2.4 Hz).
[2315] MS (EI) m/z: 222(M+H).sup.+.
Referential Example 530
4-(3-oxomorpholin-4-yl)benzoic acid methyl ester
##STR00600##
[2317] To the compound (207 mg) obtained in Referential Example 529
dissolved in methylene chloride (10 mL), benzyltriethylammonium
chloride (639 mg) and potassium permanganate (222 mg) were added,
and the resultant mixture was stirred at room temperature for 2
hours. Saturated aqueous sodium hydrogensulfite was added to the
reaction mixture for partitioning the mixture. The organic layer
was washed with saturated brine, followed by drying over sodium
sulfate anhydrate. The solvent was distilled away under reduced
pressure. The residue was purified by silica gel flash column
chromatography (hexane:ethyl acetate=1:2), to thereby give the
title compound (41 mg).
[2318] .sup.1H-NMR (CDCl.sub.3).delta.:3.80-3.83(2H, m), 3.92(3H,
s), 4.03-4.07(2H, m), 4.36(2H, s), 7.47(2H, dt, J=9.0, 2.2 Hz),
8.08(2H, dt, J=9.0, 2.2 Hz).
[2319] MS (EI) m/z: 236(M+H).sup.+.
Referential Example 531
4-(3-oxomorpholin-4-yl)benzoic acid
##STR00601##
[2321] The method described in Referential Example 274 was
performed by use of the compound obtained in Referential Example
530, whereby the title compound was obtained.
[2322] .sup.1-NMR (DMSO-d.sub.6).delta.:3.78-3.82 (2H, m),
3.97-4.01(2H, m), 4.23(2H, s), 7.57(2H, dt, J=9.1, 2.2 Hz),
7.96(2H, dt, J=9.1, 2.2 Hz), 12.97(1H, br.s).
Referential Example 532
3-(5-chlorothien-2-yl)-2-fluoro-3-hydroxypropionic acid ethyl
ester
##STR00602##
[2324] To 5-chlorothiophene-2-carboxyaldehyde (1.07 mL) in benzene
(200 mL), zinc powder (19.6 g) was added, and the mixture was
heated under reflux. A catalytic amount of iodine was added
thereto, and bromofluoroethyl acetate (3.70 g) in benzene (25 mL)
was added dropwise thereto. The mixture was heated under reflux for
1.5 hours. A catalytic amount of iodine was further added thereto,
and the resultant mixture was heated under reflux for 3.5 hours.
The reaction mixture was allowed to cool, and under ice cooling, 1N
hydrochloric acid (125 mL) was added thereto, followed by stirring
for 1 hour. The insoluble material was filtered through celite,
followed by washing with ethyl acetate. The filtrate was
partitioned. The organic layer was washed with saturated brine, and
dried over sodium sulfate anhydrate. The solvent was distilled away
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane.fwdarw.hexane:ethyl acetate=4:1), to
thereby give the title compound (2.53 g).
[2325] .sup.1H-NMR (CDCl.sub.3).delta.:1.24-1.31(3H, m),
3.09-3.21(1H, m), 4.21-4.31(2H, m), 4.97-5.12(1H, m), 5.21-5.28(1H,
m), 6.79-6.86(2H, m).
[2326] MS (EI) m/z: 252(M.sup.+).
Referential Example 533
(Z)-3-(5-chlorothien-2-yl)-2-fluoroacrylic acid ethyl ester
##STR00603##
[2328] To the compound (2.46 g) obtained in Referential Example 532
dissolved in methylene chloride (50 mL), under ice cooling,
pyridine (4.70 mL) and thionyl chloride (849 .mu.L) were added. The
mixture was stirred at 0.degree. C. for 30 minutes, and stirred at
room temperature for 1 hour. 1N hydrochloric acid was added to the
reaction mixture for partitioning the mixture. The aqueous layer
was extracted with methylene chloride. The organic layer was washed
with 1N hydrochloric acid, followed by drying over sodium sulfate
anhydrate. The solvent was distilled away under reduced pressure.
The residue was dissolved in methylene chloride (150 mL).
1,8-Diazabicyclo[5.4.0]undec-7-ene(1.60 mL) was added thereto, and
the resultant mixture was stirred at room temperature for 1 hour.
The solvent was distilled away under reduced pressure. The residue
was purified by silica gel flash column chromatography
(hexane:ethyl acetate=7:1), to thereby give the title compound
(1.05 g).
[2329] .sup.1H-NMR (CDCl.sub.3).delta.:1.37(3H, t, J=7.1 Hz),
4.34(2H, q, J=7.1 Hz), 6.90(1H, dd, J=3.9, 2.0 Hz), 7.06(1H, d,
J=33.7 Hz), 7.08-7.10(1H, m).
[2330] MS (FAB) m/z: 235(M+H).sup.+.
Referential Example 534
(Z)-3-(5-chlorothien-2-yl)-2-fluoroacrylic acid
##STR00604##
[2332] The method described in Referential Example 274 was
performed by use of the compound obtained in Referential Example
533, whereby the title compound was obtained.
[2333] .sup.1H-NMR (DMSO-d.sub.6).delta.:7.22(1H, dd, J=3.9, 2.0
Hz), 7.35-7.40(2H, m), 13.76(1H, br.s).
[2334] MS (ESI-neg.) m/z: 205(M-H).sup.-.
Referential Example 535
6-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin-2-ylamine
##STR00605##
[2336] The method described in Referential Example 475 was
performed by use of
5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin-2-ylamine (Japanese
Patent Application Laid-Open (kokai) No. 2-45489), whereby the
title compound was obtained.
[2337] .sup.1H-NMR (CDCl.sub.3).delta.:2.44(3H, s), 2.66-2.69(2H,
m), 2.71(4H, s), 2.80-2.83(2H, m), 4.66(2H, s).
[2338] MS (ESI) m/z: 184(M+H).sup.+.
Referential Example 536
2-bromo-6-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine
##STR00606##
[2340] The method described in Referential Example 476 was
performed by use of the compound obtained in Referential Example
535, whereby the title compound was obtained.
[2341] .sup.1H-NMR (CDCl.sub.3).delta.:2.45(3H, s), 2.66-2.72(4H,
m), 2.85-2.88(2H, m), 3.03-3.06(2H, m).
[2342] MS (ESI) m/z: 247(M+H).sup.+.
Referential Example 537
6-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine-2-carboxylic
acid lithium salt
##STR00607##
[2344] The method described in Referential Example 10 was performed
by use of the compound obtained in Referential Example 536, whereby
the title compound was obtained.
[2345] .sup.1H-NMR (DMSO-d.sub.6).delta.:2.33 (3H, s),
2.56-2.63(4H, m), 2.77-2.93(4H, m).
[2346] MS (ESI) m/z: 213(M+H).sup.+.
Referential Example 538
5,6,7,8-tetrahydro[1,6]naphthyridine-2-carbonitrile
hydrochloride
##STR00608##
[2348] 2-Cyano-7,8-dihydro-5H-[1,6]naphthyridine-6-carboxylic acid
tert-butyl ester (WO00/09480) (3.74 g) was dissolved in methylene
chloride (5.0 mL). 4N HCl-dioxane solution (14 mL) was added
thereto. The resultant mixture was stirred at room temperature for
65 minutes, and stirred at 40.degree. C. for 40 minutes. 4N
HCl-dioxane solution (8 mL) was further added to the reaction
mixture, followed by stirring, at 45.degree. C. for 75 minutes.
Ethyl acetate was added to the reaction mixture, and the
precipitated powder was recovered by filtration, to thereby give
the title compound (3.20 g) as a colorless powder.
[2349] .sup.1H-NMR (DMSO-d.sub.6).delta.:3.14(2H, t, J=6.4 Hz),
3.50-3.70(2H, m), 4.40(2H, s), 7.93(1H, s), 8.30(1H, s), 9.49(1H,
br.s).
Referential Example 539
6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridine-2-carbonitrile
##STR00609##
[2351] The method described in Referential Example 9 was performed
by use of the compound obtained in Referential Example 538, whereby
the title compound was obtained.
[2352] .sup.1H-NMR (CDCl.sub.3).delta.:2.49(3H, s), 2.81(2H, q,
J=6.0 Hz), 3.10(2H, t, J=6.0 Hz), 3.71(2H, s), 7.44(1H, d, J=8.1
Hz), 7.47(1H, d, J=7.8 Hz).
Referential Example 540
6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridine-2-carboxylic acid
hydrochloride
##STR00610##
[2354] Concentrated hydrochloric acid (12 mL) was added to the
compound (2.46 g) obtained in Referential Example 539, and the
mixture was heated at 100-110.degree. C. for 5.5 hours. Water was
added to the reaction mixture, followed by concentrating under
reduced pressure. Water was added thereto, and the mixture was
basified with 1N sodium hydroxide. The resultant mixture was
concentrated in about half, and neutralized with 1N hydrochloric
acid. The solvent was distilled away under reduced pressure.
Ethanol was added to the residue, and the resultant mixture was
heated at 40-50.degree. C. The insoluble material was removed
through filtration through celite. The filtrate was concentrated
under reduced pressure. The residue was dissolved in ethanol, and
1N HCl-ethanol (18 mL) was added thereto. The solvent was distilled
away under reduced pressure. Ethyl acetate was added to the
residue. The insoluble material was recovered by filtration, to
thereby give the title compound (2.33 g) as a non-purified
form.
[2355] .sup.1H-NMR (DMSO-d.sub.6).delta.:2.93 (3H, s), 3.16(1H, d,
J=16.4 Hz), 3.37-3.80(3H, m), 4.35-4.47(1H, m), 4.59(1H, d, J=16.8
Hz), 7.83(1H, d, J=8.1 Hz), 7.93(1H, d, J=8.1 Hz).
Referential Example 541
(1S,3R,4S)-4-{[benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)amino]cyc-
lohexanecarboxylic acid tert-butyl ester
##STR00611##
[2357] The compound (7.15 g) obtained in Referential Example 142
was dissolved in methylene chloride (100 mL). To the solution were
added 2-methyl-2-propanol (4.88 mL),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.89
g), and 4-dimethylaminopyridine (2.08 g), followed by stirring at
room temperature for 19 hours. The reaction mixture was diluted
with methylene chloride (200 mL), and washed with 10% aqueous
citric acid, saturated aqueous sodium bicarbonate, and saturated
brine. The resultant mixture was dried over sodium sulfate
anhydrate, followed by concentrating under reduced pressure. The
residue was purified by silica gel column chromatography (methylene
chloride:acetone=30:1.fwdarw.20:1), to thereby give the title
compound (7.07 g).
[2358] .sup.1H-NMR (CDCl.sub.3).delta.:1.20-2.09(6H, m), 1.43(9H,
s), 1.44(9H, s), 2.26(1H, br.s), 3.62-3.72(1H, m), 4.10(1H, br.s),
4.52-5.40(4H, m), 7.27-7.38(5H, m).
[2359] MS (FAB) m/z: 449(M+H).sup.+.
Referential Example 542
(1S,3R,4S)-3-[(tert-butoxycarbonyl)amino]-4-({2-[(5-chloropyridin-2-yl)ami-
no]-2-oxoethanethioyl}amino)cyclohexanecarboxylic acid tert-butyl
ester
##STR00612##
[2361] The compound obtained (700 mg) in Referential Example 541
was dissolved in methanol (7.0 mL)-tetrahydrofuran (7.0 mL). 10%
Palladium carbon catalyst (wet, 350 mg) was added thereto, and the
mixture was stirred under a hydrogen atmosphere at room temperature
for 16 hours. The catalyst was removed through filtration, and the
filtrate was concentrated under reduced pressure. The residue was
dissolved in N,N-dimethylformamide (10 mL). Sulfur (65 mg), the
compound (374 mg) obtained in Referential Example 520, and
diisopropylethylamine (0.816 mL) were added thereto, and the
resultant mixture was stirred at 120.degree. C. for 8 hours. The
reaction mixture was concentrated under reduced pressure. Methylene
chloride was added to the residue, and the mixture was sequentially
washed with 10% aqueous citric acid, saturated aqueous sodium
hydrogencarbonate, and saturated brine. The resultant mixture was
dried over sodium sulfate anhydrate, followed by concentrating
under reduced pressure. The residue was purified by silica gel
flash column chromatography (methylene
chloride:methanol=100:1.fwdarw.50:1), to thereby give the title
compound (373 mg).
[2362] .sup.1H-NMR (CDCl.sub.3).delta.:1.45(9H, s), 1.48(9H, s),
1.49-1.70(2H, m), 1.80-2.40(5H, m), 4.26-4.39(2H, m), 4.79(1H,
br.s), 7.70(1H, dd, J=9.0, 2.4 Hz), 8.19(1H, d, J=9.0 Hz), 8.32(1H,
d, J=2.4 Hz), 10.01(1H, br.s), 10.58(1H, s).
[2363] MS (ESI) m/z: 513(M+H).sup.+.
Referential Example 543
(1S,3R,4S)-3-amino-4-({2-[(5-chloropyridin-2-yl)amino]-2-oxoethanethioyl}a-
mino)cyclohexanecarboxylic acid tert-butyl ester hydrochloride
##STR00613##
[2365] To the compound (530 mg) obtained in Referential Example 542
dissolved in ethyl acetate (3.90 mL), 1N HCl-ethyl acetate solution
(1.30 mL) was added. The resultant mixture was stirred at room
temperature for 3 hours. Ethyl acetate was added to the reaction
mixture. The precipitated solid was recovered by filtration,
followed by drying under reduced pressure, to thereby give the
title compound (284 mg).
[2366] .sup.1H-NMR (DMSO-d.sub.6).delta.:1.42 (9H, s),
1.49-1.61(1H, m), 1.71-1.88(2H, m), 1.88-2.03(1H, m), 2.04-2.26(2H,
m), 2.71-2.85(1H, m), 3.84-4.12(1H, m), 4.44(1H, br.s),
8.00-8.29(5H, m), 8.44-8.51(1H, m), 10.67(1H, s), 10.91(1H, d,
J=6.8 Hz).
[2367] MS (ESI) m/z: 413(M+H).sup.+.
Referential Example 544
(1S,3R,4S)-3-[(tert-butoxycarbonyl)amino]-4-({2-[(5-chloropyridin-2-yl)ami-
no]-2-oxoacetyl}amino)cyclohexanecarboxylic acid tert-butyl
ester
##STR00614##
[2369] The compound (1.00 g) obtained in Referential Example 541
was dissolved in methanol (20 mL)-tetrahydrofuran (20 mL). 10%
Palladium carbon catalyst (wet, 500 mg) was added thereto. The
mixture was stirred in a hydrogen atmosphere at room temperature
for 4 hours. The catalyst was removed through filtration, and the
filtrate was concentrated under reduced pressure. The residue was
dissolved in N,N-dimethylformamide (10 mL). To the resultant
mixture were sequentially added the compound (231 mg) obtained in
Referential Example 266, 1-hydroxybenzotriazole (139 mg), and
1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (288 mg),
followed by stirring at room temperature overnight. The reaction
mixture was concentrated under reduced pressure. Ethyl acetate and
10% aqueous citric acid were added to the residue for partitioning
the mixture. The oil layer was sequentially washed with saturated
brine, aqueous sodium hydrogencarbonate, and saturated brine. The
oil layer was dried over magnesium sulfate anhydrate, and the
solvent was distilled away under reduced pressure, to thereby give
the title compound (364 mg).
[2370] .sup.1H-NMR (CDCl.sub.3).delta.:1.44(9H, s), 1.46(9H, s),
1.54-2.09(6H, m), 2.20-2.38(1H, m), 3.83-3.98(1H, m), 4.08-4.29(1H,
m), 4.71(1H, br.s), 7.69(1H, dd, J=8.9, 2.6 Hz), 8.00(1H, br.s),
8.18(1H, d, J=8.9 Hz), 8.31(1H, d, J=2.5 Hz), 9.72(1H, br.s).
[2371] MS (ESI) m/z: 441(M-tBu).sup.+.
Referential Example 545
2-methyl-1,2,3,4-tetrahydro-6-isoquinolinecarboxylic acid methyl
ester
##STR00615##
[2373] To 3,4-dihydro(1H)isoquinoline-2,6-dicarboxylic acid
2-(tert-butyl) ester 6-methyl ester (WO00/09480) (344 mg) dissolved
in methylene chloride (6 mL), under ice cooling, trifluoroacetic
acid (3 mL) was added, followed by stirring for 30 minutes. The
reaction mixture was concentrated, and diluted with chloroform. The
resultant mixture was neutralized with saturated aqueous sodium
hydrogencarbonate, followed by extracting with chloroform/methanol
(4/1). The resultant organic layer was dried over sodium sulfate
anhydrate, and concentrated under reduced pressure. The residue was
purified by silica gel chromatography
(chloroform:methanol=20:1.fwdarw.1:1), to thereby give
1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid methyl ester (154
mg). This material was dissolved in methylene chloride (5 mL), and
formalin (90.6 .mu.L) was added thereto at room temperate, followed
by stirring for 10 minutes. Under ice cooling, acetic acid (46
.mu.L) and sodium triacetoxyborohydride (269 mg) were added
thereto. The mixture was stirred at room temperature for 105
minutes, and neutralized with saturated aqueous sodium
hydrogencarbonate. The resultant mixture was extracted with
chloroform. The organic layer was dried over sodium sulfate
anhydrate, and concentrated under reduced pressure, to thereby give
the title compound (162 mg).
[2374] .sup.1H-NMR (CDCl.sub.3).delta.:2.47(3H, s), 2.70(2H, dd,
J=6.0 Hz), 2.96(2H, dd, J=6.0 Hz), 3.62(2H, s), 3.90(3H, s),
7.08(1H, d, J=7.6 Hz), 7.78(1H, d, J=7.6 Hz), 7.80(1H, s).
[2375] MS (ESI) m/z: 206(M+H).sup.+.
Referential Example 546
(1S,2R,4S)-4-(aminocarbonyl)-2-[(tert-butoxycarbonyl)amino]cyclohexylcarba-
mic acid fluoren-9-ylmethyl ester
##STR00616##
[2377] The compound (1.92 g) obtained in Referential Example 142
was dissolved in N,N-dimethylformamide (30 mL) under ice cooling.
To the solution were sequentially added ammonium chloride (523 mg),
1-hydroxybenzotriazole (661 mg),
1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.41 g),
and diisopropylethylamine (1.70 mL). The temperature of the
resultant mixture was returned to room temperature, and the mixture
was stirred for 3 days. The reaction mixture was concentrated under
reduced pressure. Ethyl acetate and 10% aqueous citric acid were
added to the residue for partitioning the mixture. The oil layer
was sequentially washed with saturated brine, aqueous sodium
hydrogencarbonate, and saturated brine, followed by drying over
sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure. Hexane was added to the residue to solidify,
thereby yielding
(1R,2S,5S)-5-(aminocarbonyl)-2-{[(benzyloxy)carbonyl]amino)cyclohexylcarb-
amic acid tert-butyl ester (1.66 g) as a crude product. A mixture
of the crude product (1.65 g), 10% palladium carbon catalyst (400
mg), and methanol (150 mL) was stirred in a hydrogen atmosphere at
room temperature overnight. The catalyst was removed through
filtration, and the solvent was distilled away under reduced
pressure. To the residue were added succinimidylcarboxylic acid
9-fluorenylmethyl ester (2.13 g), 1,2-dimethoxyethane (130 mL), and
saturated aqueous sodium hydrogencarbonate (130 mL), followed by
stirring at room temperature overnight. Ethyl acetate, saturated
brine, and water were added to the reaction mixture for
partitioning the mixture. The resultant organic layer was dried
over magnesium sulfate anhydrate, and the solvent was distilled
away under reduced pressure, to thereby give the title compound
(1.99 g).
[2378] .sup.1H-NMR (CDCl.sub.3).delta.:1.45(9H, s), 1.53-2.08(6H,
m), 2.30(1H, br.s), 3.71(1H, br.s), 4.07-4.15(1H, m), 4.21(1H,
br.s), 4.37(2H, br.s), 4.70-5.80(4H, m), 7.26-7.33(2H, m), 7.39(2H,
t, J=7.3 Hz), 7.53-7.61(2H, m), 7.76(2H, d, J=7.3 Hz).
[2379] MS (ESI) m/z: 502(M+Na).sup.+.
Referential Example 547
(1S,2R,4S)-4-(aminocarbothioyl)-2-[(tert-butoxycarbonyl)amino]cyclohexylca-
rbamic acid fluoren-9-ylmethyl ester
##STR00617##
[2381] The compound (1.98 g) obtained in Referential Example 546
was dissolved in tetrahydrofuran (200 mL). Lawewson reagent (1.22
g) was added thereto, and the resultant mixture was stirred at room
temperature for 4 days. To the reaction mixture, Lawesson reagent
(0.50 g) was further added, followed by stirring overnight. Silica
gel was added to the reaction mixture, and the solvent was
distilled away under reduced pressure. The residue was purified by
silica gel chromatography (ethyl acetate:hexane=2:1). Diethyl ether
was added to the resultant oil, followed by stirring. The
precipitated powder was recovered by filtration, to thereby give
the title compound (1.25 g).
[2382] .sup.1H-NMR (CDCl.sub.3).delta.:1.45(9H, br.s),
1.57-2.10(6H, m), 2.69(1H, br.s), 3.71(1H, br.s), 4.06-4.27(2H, m),
4.36(2H, br.s), 4.89(1H, br.s), 5.46(1H, br.s), 7.11(1H, br.s),
7.26-7.34(2H, m), 7.39(2H, t, J=7.3 Hz), 7.57(3H, br.s), 7.76(2H,
d, J=7.1 Hz).
[2383] MS (ESI) m/z: 518(M+Na).sup.+.
Referential Example 548
(1R,2S,5S)-5-(aminocarbothioyl)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoa-
cetyl}amino)cyclohexylcarbamic acid tert-butyl ester, and
(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-cyano-
cyclohexylcarbamic acid tert-butyl ester
##STR00618##
[2385] The compound (4.64 g) obtained in Referential Example 547
was dissolved in N,N-dimethylformamide (50 mL). Piperidine (2.78
mL) was added thereto, and the resultant mixture was stirred at
room temperature for 30 minutes. The solvent was distilled away
under reduced pressure. The residue was purified by silica gel
chromatography (methanol:methylene chloride=3:47.fwdarw.3:17), to
thereby give
(1R,2S,5S)-2-amino-5-(aminocarbothioyl)cyclohexylcarbamic acid
tert-butyl ester (2.17 g) as a crude product. The crude product was
dissolved in N,N-dimethylformamide (100 mL). To this solution were
sequentially added the compound (1.78 g) obtained in Referential
Example 266, 1-hydroxybenzotriazole (1.07 g), and
1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.28 g),
followed by stirring at room temperature overnight. The reaction
mixture was concentrated under reduced pressure. Methylene chloride
and 10% aqueous citric acid were added to the residue for
partitioning the mixture. The oil layer was sequentially washed
with saturated brine, sodium hydrogencarbonate aqueous solution,
and saturated brine, followed by drying over magnesium sulfate
anhydrate. The solvent was distilled away under reduced pressure.
The residue was purified by silica gel chromatography (ethyl
acetate:hexane=2:1), to thereby give the title cyano compound (427
mg) having a cyano group at 5-position, and the title
aminocarbothioyl compound (718 mg) having a aminocarbothioyl group
at 5-position.
[2386] 5-cyano form:.sup.1H-NMR (CDCl.sub.3).delta.:1.46(9H, s),
1.56-1.66(1H, m), 1.74-1.87(1H, m), 1.90-2.23(4H, m), 2.72(1H,
br.s), 4.02-4.23(2H, m), 4.71(1H, br.s), 7.71(1H, dd, J=8.8, 2.4
Hz), 7.85(1H, br.s), 8.15(1H, d, J=8.8 Hz), 8.31(1H, d, J=2.4 Hz),
9.69(1H, br.s).
[2387] 5-(aminocarbothioyl) form:.sup.1H-NMR
(CDCl.sub.3).delta.:1.46(9H, s), 1.74-2.17(6H, m), 2.70(1H, s),
3.94-4.04(1H, m), 4.23(1H, br.s), 4.86(1H, br.s), 6.97(1H, br.s),
7.50(1H, br.s), 7.70(1H, dd, J=8.8, 2.4 Hz), 7.98(1H, br.s),
8.18(1H, d, J=8.8 Hz), 8.31(1H, d, J=2.4 Hz), 9.72(1H, s).
[2388] MS (ESI) m/z: 456(M+H).sup.+.
Referential Example 549
(1R,2S,5RS)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-(thia-
zol-2-yl)cyclohexylcarbamic acid tert-butyl ester
##STR00619##
[2390] The compound (72 mg) with an aminocarbothioyl group at
5-position obtained in Referential Example 548 and
bromoacetoaldehyde dimethyl acetal (20.4 .mu.L) were dissolved in
N,N-dimethylformamide (5 mL). The mixture was stirred at 50.degree.
C. for 8 hours. Bromoacetoaldehyde dimethyl acetal (80 .mu.L) was
further added thereto, followed by stirring for 13 hours. The
resultant mixture was allowed to cool to room temperature. To the
reaction mixture, di-tert-butyl dicarbonate (34.5 mg) and anhydrous
sodium hydrogencarbonate (200 mg) were added. The resultant mixture
was stirred at room temperature for 1 hour. Triethylamine (97
.mu.L) was added thereto, followed by stirring for 2 hours. Ethyl
acetate and 10% aqueous citric acid were added to the reaction
mixture for partitioning the mixture. The organic layer was
sequentially washed with saturated brine, saturated aqueous sodium
hydrogencarbonate, and saturated brine, followed by drying over
magnesium sulfate anhydrate. The solvent was distilled away under
reduced pressure. The residue was purified by silica gel
chromatography (ethyl acetate:hexane=2:1), to thereby give the
title compound (37.5 mg).
[2391] .sup.1H-NMR (CDCl.sub.3).delta.:1.40-1.51(9H, m),
1.75-2.16(5H, m), 2.19-2.39(1H, m), 3.10-3.38(1H, m), 3.91-4.08(1H,
m), 4.21-4.40(1H, m), 4.80-4.94(0.5H, m), 5.61-5.90(0.5H, m),
7.24-7.26(1H, m), 7.66-7.74(2H, m), 7.80-7.90(0.5H, m),
8.02-8.11(0.5H, m), 8.16-8.22(1H, m), 8.27-8.33(1H, m),
9.66-9.80(1H, m).
[2392] MS (ESI) m/z: 480(M+H).sup.+.
Referential Example 550
(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-(1,2,4-
-oxadiazol-3-yl)cyclohexylcarbamic acid tert-butyl ester
##STR00620##
[2394] The compound (427 mg) with a cyano group at 5-position
obtained in Referential Example 548 and anhydrous sodium
hydrogencarbonate (84.9 mg) were suspended in ethanol. To the
suspension, hydroxylamine sulfate (82.9 mg) was added, followed by
heating at 60.degree. C. and stirring for 6 days. The solvent was
distilled away under reduced pressure. The residue was subjected to
silica gel chromatography (methanol:methylene chloride=1:9), to
thereby give
(1R,2S,5S)-5-[amino(hydroxyimino)methyl]-2-({2-[(5-chloropyridin-2-yl)ami-
no]-2-oxoacetyl}amino)cyclohexylcarbamic acid tert-butyl ester (183
mg) as a crude product. To the crude product, methyl orthoformate
(5 mL) and boron trifluoride diethyl ether complex (1 drop) were
added at room temperature, followed by heating at 55.degree. C. and
stirring for 20 minutes. The resultant mixture was allowed to cool
to room temperature. The solvent was distilled away under reduced
pressure. The residue was purified by silica gel chromatography
(methanol:methylene chloride=1:19), to thereby give the title
compound (57.6 mg).
[2395] .sup.1H-NMR (CDCl.sub.3).delta.:1.47(9H, s), 1.53-1.70(1H,
m), 1.73-1.94(1H, m), 1.95-2.30(4H, m), 3.03(1H, br.s),
4.00-4.11(1H, m), 4.27(1H, br.s), 4.87(1H, br.s), 7.70(1H, dd,
J=8.9, 2.4 Hz), 8.04(1H, s), 8.19(1H, d, J=8.8 Hz), 8.31(1H, d,
J=2.4 Hz), 8.66(1H, s), 9.74(1H, br.s).
[2396] MS (ESI) m/z: 463(M-H).sup.-.
Referential Example 551
(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-(5-methyl-1,3,4-oxadiazol-2-yl-
)cyclohexylcarbamic acid benzyl ester
##STR00621##
[2398] The compound (4.0 g) obtained in Referential Example 142 was
dissolved in N,N-dimethylformamide (100 mL). To the solution were
added hydrazine monohydrate (765 mg), 1-hydroxybenzotriazole (1.38
g), and 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(2.93 g), followed by stirring at room temperature overnight. The
reaction mixture was concentrated under reduced pressure. Methylene
chloride and sodium hydrogencarbonate aqueous solution were added
to the residue for partitioning the mixture. The aqueous layer was
extracted with methylene chloride. The resultant organic layers
were combined, followed by drying over sodium sulfate anhydrate.
Sodium sulfate anhydrate was removed through filtration, and silica
gel (25 g) and methanol (15 mL) were added to the filtrate,
followed by stirring. The insoluble material was removed through
filtration. The solvent was distilled away under reduced pressure,
to thereby give
(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-(hydrazinocarbonyl)cyclohexyl-
carbamic acid benzyl ester (3.71 g) as a crude product. To the
crude product (1.73 g), methyl orthoacetate (10 mL) and boron
trifluoride diethyl ether complex (2 drops) were added, followed by
heating at 70.degree. C. and stirring overnight. The resultant
mixture was allowed to cool to room temperature. The solvent was
distilled away under reduced pressure. Methylene chloride and
sodium hydrogencarbonate aqueous solution were added to the residue
for partitioning the mixture. The aqueous layer was extracted with
methylene chloride. The resultant organic layers were combined,
followed by drying over sodium sulfate anhydrate. The solvent was
distilled away under reduced pressure. The residue was purified by
silica gel chromatography (methanol:methylene chloride=1:19), to
thereby give the title compound (1.10 g).
[2399] .sup.1H-NMR (CDCl.sub.3).delta.:1.44(9H, s), 1.68-2.27(6H,
m), 2.50(3H, s), 2.95-3.09(1H, m), 3.66-3.86(1H, m), 4.08-4.24(1H,
m), 4.76(1H, br.s), 5.04-5.16(2H, m), 5.27-5.36(1H, m),
7.29-7.39(5H, m).
[2400] MS (ESI) m/z: 431(M+H).sup.+.
Referential Example 552
(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-(5-met-
hyl-1,3,4-oxadiazol-2-yl)cyclohexylcarbamic acid tert-butyl
ester
##STR00622##
[2402] A mixture of the compound (1.10 g) obtained in Referential
Example 551, 10% palladium carbon catalyst (300 mg), and methanol
(50 mL) was stirred in a hydrogen atmosphere at room temperature
for 1 hour. The catalyst was removed through filtration, and the
solvent was distilled away under reduced pressure. The residue was
dissolved in N,N-dimethylformamide (50 mL). To the solution were
sequentially added the compound (632 mg) obtained in Referential
Example 266, 1-hydroxybenzotriazole (381 mg), and
1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (810 mg),
followed by stirring at room temperature overnight. The reaction
mixture was concentrated under reduced pressure. Ethyl acetate and
10% aqueous citric acid were added to the residue for partitioning
the mixture. The oil layer was sequentially washed with saturated
brine, sodium hydrogencarbonate aqueous solution, and saturated
brine, followed by drying over magnesium sulfate anhydrate. The
solvent was distilled away under reduced pressure, to thereby give
the title compound (944 mg)..sup.1H-NMR
(CDCl.sub.3).delta.:1.47(9H, s), 1.58-1.88(2H, m), 1.92-2.31(4H,
m), 2.52(3H, s), 3.04(1H, br.s), 3.98-4.09(1H, m), 4.27(1H, br.s),
4.83(1H, br.s), 7.71(1H, dd, J=8.8, 2.4 Hz), 8.02(1H, br.s),
8.19(1H, d, J=8.8 Hz), 8.32(1H, d, J=2.4 Hz), 9.72(1H, br.s).
[2403] MS (ESI) m/z: 479(M+H).sup.+.
Referential Example 553
(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-(1,3,4-oxadiazol-2-yl)cyclohex-
ylcarbamic acid benzyl ester
##STR00623##
[2405] In a manner similar to that described in Referential Example
551, the compound obtained in Referential Example 142 was condensed
with hydrazine. By use of methyl orthoformate, the condensed
compound was subjected to cyclization reaction, whereby the title
compound was obtained.
[2406] .sup.1H-NMR (CDCl.sub.3).delta.:1.45(9H, s), 1.71-2.30(6H,
m), 3.04-3.15(1H, m), 3.80(1H, br.s), 4.17(1H, br.s), 4.75(1H,
br.s), 5.05-5.15(2H, m), 5.25(1H, s), 7.30-7.38(5H, m), 8.35(1H,
s).
[2407] MS (ESI) m/z: 417(M+H).sup.+.
Referential Example 554
(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-(1,3,4-
-oxadiazol-2-yl)cyclohexylcarbamic acid tert-butyl ester
##STR00624##
[2409] In a manner similar to that described in Referential Example
552, the compound obtained in Referential Example 553 was
deprotected. The deprotected compound was condensed with the
compound obtained in Referential Example 266, whereby, the title
compound was obtained.
[2410] .sup.1H-NMR (CDCl.sub.3).delta.:1.47(9H, s), 1.59-1.92(2H,
m), 2.00-2.33(4H, m), 3.02-3.22(1H, m), 3.94-4.10(1H, m), 4.27(1H,
br.s), 4.83(1H, br.s), 7.71(1H, dd, J=8.9, 2.6 Hz), 8.00(1H, br.s),
8.19(1H, d, J=8.9 Hz), 8.32(1H, d, J=2.6 Hz), 8.37(1H, br.s),
9.72(1H, s).
[2411] MS (ESI) m/z: 465(M+H).sup.+.
Referential Example 555
(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-{[(2-hydroxyethyl)amino]carbon-
yl}cyclohexylcarbamic acid benzyl ester
##STR00625##
[2413] In a manner similar to that described in Referential Example
143, the compound obtained in Referential Example 142 was condensed
with 2-aminoethanol, whereby the title compound was obtained.
[2414] .sup.1H-NMR (CDCl.sub.3).delta.:1.44(9H, s), 1.50-2.07(6H,
m), 2.28-2.39(1H, m), 3.26-3.49(1H, m), 3.45-3.63(1H, m),
3.65-3.84(3H, m), 3.90-4.07(1H, m), 5.02-5.28(4H, m), 6.21-6.35(1H,
m), 7.28-7.39(5H, m).
[2415] MS (ESI) m/z: 436(M+H).sup.+.
Referential Example 556
(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-(1,3-o-
xazol-2-yl)cyclohexylcarbamic acid tert-butyl ester
##STR00626##
[2416] in a nitrogen atmosphere and being cooled at -60.degree. C.,
to oxalyl chloride (2.85 mL) in methylene chloride (50 mL),
dimethyl sulfoxide (3.47 mL) was added dropwise, and the compound
(3.55 g) obtained in Referential Example 555 dissolved in methylene
chloride (20 mL) was subsequently added dropwise thereto over 15
minutes. The resultant mixture was stirred at -60.degree. C. for 45
minutes, and triethylamine (11.4 mL) was added dropwise thereto,
followed by stirring for 30 minutes. Water was added to the
reaction mixture at -60.degree. C., and the temperature of the
resultant mixture was returned to room temperature, followed by
extracting with chloroform and drying over sodium sulfate
anhydrate. The solvent was distilled away under reduced pressure.
The residue was purified by silica gel chromatography
(chloroform:methanol=50:1.fwdarw.10:1), to thereby give a yellow
solid (2.43 g). To triphenylphosphine (4.41 g) in methylene
chloride (25 mL) were sequentially added hexachloroethane (3.32 g),
triethylamine (4.69 mL), and the yellow solid (2.43 g) dissolved in
methylene chloride (35 mL). The resultant mixture was stirred at
room temperature for 20 hours. Saturated aqueous sodium
hydrogencarbonate was added thereto, followed by stirring for 30
minutes. The reaction mixture was extracted with chloroform. The
resultant mixture was dried over sodium sulfate anhydrate, and
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (chloroform:methanol=50:1), to thereby
give oxazole cyclized material as a mixture containing
triphenylphosphine oxide. The mixture was dissolved in methanol (30
mL), and 10% palladium carbon catalyst (2.08 g) was added thereto.
The resultant mixture was stirred in a hydrogen atmosphere at room
temperature for 14 hours. 10% Palladium carbon catalyst (1.02 g)
was further added thereto, and the resultant mixture was stirred in
a hydrogen atmosphere for 6 hours. The catalyst was removed through
filtration, and the filtrate was concentrated under reduced
pressure. The residue was purified by silica gel chromatography
(chloroform:methanol=50:1.fwdarw.1:1). The resultant compound and
the compound (612 mg) obtained in Referential Example 266 were
dissolved in N,N-dimethylformamide (15 mL). To the resultant
mixture, 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(872 mg) and 1-hydroxybenzotriazole monohydrate (461 mg) were added
at room temperature. The reaction mixture was stirred for 12 hours,
and chloroform was added thereto. The resultant mixture was
sequentially washed with water and saturated aqueous sodium
hydrogencarbonate, followed by drying over sodium sulfate anhydrate
and concentrating under reduced pressure. The residue was purified
by silica gel flash column chromatography
(methanol:chloroform=50:1), to thereby give the title compound (390
mg).
[2417] .sup.1H-NMR (CDCl.sub.3).delta.:1.46(9H, s), 1.54-2.30(6H,
m), 2.90-3.07(1H, m), 3.97-4.08(1H, m), 4.15-4.30(1H, m),
4.91-5.10(1H, m), 7.03(1H, s), 7.58(1H, s), 7.70(1H, dd, J=8.8, 2.4
Hz), 7.98-8.11(1H, m), 8.25(1H, d, J=8.8 Hz), 8.31(1H, d, J=2.4
Hz), 9.75(1H, s).
[2418] MS (ESI) m/z: 464(M+H).sup.+.
Referential Example 557
(1S,3R,4S)-3-[(tert-butoxycarbonyl)amino]-4-({[2-(trimethylsilyl)ethoxy]ca-
rbonyl}amino)cyclohexanecarboxylic acid
##STR00627##
[2420] A mixture of the compound (4.20 g) obtained in Referential
Example 141, 10% palladium carbon catalyst (1.0 g), and ethanol
(100 mL) was stirred in a hydrogen atmosphere at room temperature
for 5 hours. The catalyst was removed through filtration, and the
solvent was distilled away under reduced pressure. To the residue,
dioxane (50 mL), water (50 mL), and triethylamine (2.09 mL) were
added, and the mixture was cooled with ice. To the resultant
mixture,
1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidine-2,5-dione (2.85
g) was added, followed by stirring at room temperature for 24
hours. The solvent was distilled away under reduced pressure. Ethyl
acetate and 10% aqueous citric acid were added to the residue for
partitioning the mixture. The oil layer was sequentially washed by
saturated brine, sodium hydrogencarbonate aqueous solution, and
saturated brine, followed by drying over magnesium sulfate
anhydrate. The solvent was distilled away under reduced pressure to
thereby give a light yellow oil (4.46 g). To the oil dissolved in
tetrahydrofuran (50 mL), water (10 mL) and lithium hydroxide (479
mg) were added. The resultant mixture was stirred at room
temperature overnight. The solvent was distilled away under reduced
pressure. Ethyl acetate and 10% aqueous citric acid were added to
the residue for partitioning the mixture. The oil layer was washed
with saturated brine, followed by drying over magnesium sulfate
anhydrate. The solvent was distilled away under reduced pressure.
The resultant colorless powder was washed with hexane, to thereby
give the title compound (3.51 g).
[2421] .sup.1H-NMR (CDCl.sub.3).delta.:0.06(9H, s), 0.97(2H, t,
J=7.8 Hz), 1.46(9H, br.s), 1.52-2.22(6H, m), 2.47(1H, br.s),
3.68(1H, s), 3.97-4.24(3H, m), 4.69(0.5H, br.s), 4.95(0.5H, br.s),
5.18(0.5H, br.s), 6.42(0.5H, br.s).
[2422] MS (ESI) m/z: 401(M-H).sup.-].
Referential Example 558
N-hydroxyacetamidine
##STR00628##
[2424] Hydroxyamine (50% aqueous, 661 mg) was dissolved in
acetonitrile (10 mL), followed by stirring at 60.degree. C.
overnight. The solvent was distilled away under reduced pressure.
The resultant colorless powder was washed with diethyl ether, to
thereby give the title compound (673 mg).
[2425] .sup.1H-NMR (DMSO-d.sub.6).delta.:1.62 (3H, s), 5.33(2H,
br.s), 8.66(1H, br.s).
Referential Example 559
(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-(3-methyl-1,2,4-oxadiazol-5-yl-
)cyclohexylcarbamic acid 2-(trimethylsilyl)ethyl ester
##STR00629##
[2427] The compound (201 mg) obtained in Referential Example 557
and the compound (37 mg) obtained in Referential Example 558 were
suspended in 1,2-dimethoxyethane (5 mL). To the suspension,
1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (115 mg)
was added, followed by stirring at room temperature overnight.
Molecular sieve (MS-4A, powder, 1.0 g) was subsequently added to
the reaction mixture. The resultant mixture was heated under reflux
overnight. The solvent was distilled away under reduced pressure.
The residue was purified by silica gel chromatography (hexane:ethyl
acetate=1:1), to thereby give the title compound (96.5 mg).
[2428] .sup.1H-NMR (CDCl.sub.3).delta.:0.04(9H, s), 0.98(2H, t,
J=8.4 Hz), 1.46(9H, s), 1.60-1.83(2H, m), 1.87-2.28(4H, m),
2.38(3H, s), 3.04(1H, br.s), 3.76(1H, br.s), 4.07-4.22(3H, m),
4.72(1H, br.s), 5.14(1H, br.s).
[2429] MS (ESI) m/z: 341(M-Boc+2H).sup.+.
Referential Example 560
(1S,2R,4S)-4-(3-methyl-1,2,4-oxadiazol-5-yl)-2-{[(5-methyl-4,5,6,7-tetrahy-
drothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexylcarbamic
acid 2-(trimethylsilyl)ethyl ester
##STR00630##
[2431] The compound (96.5 mg) obtained in Referential Example 559
was dissolved in ethanol (10 mL). To the solution,
p-toluenesulfonic acid (45.8 mg) was added at room temperature. The
reaction mixture was heated at 60.degree. C., and stirred
overnight. The resultant mixture was allowed to cool to room
temperature. The solvent was distilled away under reduced pressure
to thereby give a colorless powder. To the powder, the compound (67
mg) obtained in Referential Example 10 and N, N-dimethylformamide
(5 mL) were added. 1-Hydroxybenzotriazole (44.5 mg) and
1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg)
were added thereto, followed by stirring at room temperature
overnight. The solvent was distilled away under reduced pressure.
Methylene chloride and sodium hydrogencarbonate aqueous solution
were added to the residue for partitioning the mixture. The organic
layer was dried over sodium sulfate anhydrate, and the solvent was
distilled away under reduced pressure. The residue was purified by
silica gel chromatography (methanol:methylene chloride=3:47), to
thereby give the title compound (110 mg).
[2432] .sup.1H-NMR (CDCl.sub.3).delta.:0.02(9H, s), 0.97(2H, dd,
J=9.9, 7.0 Hz), 1.57-1.72(1H, m), 1.79-1.92(1H, m), 2.06-2.37(4H,
m), 2.38(3H, s), 2.53(3H, s), 2.84-2.89(2H, m), 2.93-2.99(2H, m),
3.12-3.23(1H, m), 3.76(2H, br.s), 3.85-3.94(1H, m), 4.14(2H, dd,
J=9.9, 7.0 Hz), 4.60-4.69(1H, m), 5.23(1H, d, J=7.6 Hz), 7.41(1H,
d, J=8.3 Hz).
[2433] MS (ESI) m/z: 521(M+H).sup.+.
Referential Example 561
(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-(1,3,4-thiadiazol-2-yl)cyclohe-
xylcarbamic acid 2-(trimethylsilyl)ethyl ester
##STR00631##
[2435] The compound (1.0 g) obtained in Referential Example 557 was
dissolved in N,N-dimethylformamide (20 mL). To the solution were
sequentially added formic acid hydrazide (149 mg),
1-hydroxybenzotriazole (335 mg), and
1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (713 mg),
followed by stirring at room temperature overnight. The reaction
mixture was concentrated under reduced pressure. Ethyl acetate and
10% aqueous citric acid were added to the residue for partitioning
the mixture. The oil layer was sequentially washed with saturated
brine, sodium hydrogencarbonate aqueous solution, and saturated
brine. The organic layer was dried over magnesium sulfate
anhydrate. The solvent was distilled away under reduced pressure to
thereby give a colorless powder (1.12 g). To the powder, toluene
(50 mL) and Lawesson reagent (2.0 g) were added at room
temperature, and the resultant mixture was heated under reflux for
1 hour, and allowed to cool to room temperature. Silica gel was
added thereto, and the solvent was distilled away under reduced
pressure. The residue was purified by silica gel chromatography
(hexane:ethyl acetate=1:1.fwdarw.0:1), to thereby give the title
compound (511 mg).
[2436] .sup.1H-NMR (CDCl.sub.3).delta.:0.04(9H, s), 0.99(2H, t,
J=8.4 Hz), 1.46(9H, s), 1.59-1.85(2H, m), 1.91-2.02(1H, m),
2.05-2.14(1H, m), 2.18-2.27(1H, m), 2.29-2.40(1H, m), 3.31-3.44(1H,
m), 3.69-3.86(1H, m), 4.09-4.23(3H, m), 4.71-4.93(1H, m),
5.07-5.34(1H, m), 9.05(1H, s).
[2437] MS (ESI) m/z: 443(M+H).sup.+.
Referential Example 562
(1S,2R,4S)-2-{[(5-methyl-4,5,67-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carb-
onyl]amino}-4-(1,3,4-thiadiazol-2-yl)cyclohexylcarbamic acid
2-(trimethylsilyl)ethyl ester
##STR00632##
[2439] In a manner similar to that described in Referential Example
560, the compound obtained in Referential Example 561 was treated
with p-toluenesulfonic acid for deprotection. The deprotected
compound was condensed with the compound obtained in Referential
Example 10, whereby the title compound was obtained.
[2440] .sup.1H-NMR (CDCl.sub.3).delta.:0.03(9H, s), 0.97(2H, t,
J=8.5 Hz), 1.63-1.75(1H, m), 1.81-1.93(1H, m), 2.01-2.22(2H, m),
2.25-2.37(1H, m), 2.42-2.51(1H, m), 2.52(3H, s), 2.81-2.89(2H, m),
2.92-2.99(2H, m), 3.47-3.57(1H, m), 3.73(2H, s), 3.86-3.96(1H, m),
4.14(2H, t, J=8.5 Hz), 4.61-4.69(1H, m), 5.21-5.28(1H, m),
7.41-7.53(1H, m), 9.06(1H, s).
[2441] MS (ESI) m/z: 523(M+H).sup.+.
Referential Example 563
(1S,3R,4S)-3-amino-4-({2-[(5-fluoropyridin-2-yl)amino]-2-oxoethanethioyl)a-
mino)-N,N-dimethylcyclohexanecarboxamide hydrochloride
##STR00633##
[2443] The compound (73.3 g) obtained in Referential Example 427
was suspended in dioxane (350 mL)-methanol (200 mL). To the
suspension, 4N HCl-dioxane solution (350 mL) was added dropwise
over 5 minutes. The resultant mixture was stirred under ice cooling
for 10 minutes, and stirred at room temperature for 2.5 hours. The
reaction mixture was concentrated under reduced pressure, and
azeotroped with dioxane and tetrahydrofuran, followed by drying, to
thereby give the title compound (76.4 g).
[2444] .sup.1H-NMR (DMSO-d.sub.6).delta.:1.34-1.55(1H, m),
1.64-1.84(3H, m), 1.97-2.11(1H, m), 2.11-2.30(1H, m), 2.80(3H,
br.s), 3.06(3H, br.s), 3.20-3.58(1H, m), 3.91-4.07(1H, m),
4.22-4.42(1H, m), 7.74-7.91(1H, m), 8.00-8.16(1H, m), 8.25-8.60(4H,
m), 10.64(1H, d, J=11.9 Hz), 10.89-10.99(1H, m).
[2445] MS (ESI) m/z: 367 (M+H).sup.+.
Referential Example 564
5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic
acid hydrochloride
##STR00634##
[2447] To the compound (3.00 g) obtained in Referential Example 10,
1N HCl in ethanol (36 mL) was added, and the resultant mixture was
stirred at room temperature for 1 hour. The precipitated crystal
was recovered by filtration, followed by washing with ethanol (9
mL). The wet material was dried at room temperature under reduced
pressure, to thereby give the title compound (2.76 g).
[2448] .sup.1H-NMR (D.sub.2O).delta.:4.82-4.88 (1H, d, J=16.0 Hz),
4.51-4.57(1H, d, J=16.0 Hz), 3.88-3.96(1H, m), 3.60-3.70(1H, m),
3.22-3.33(2H, m), 3.15(3H, s).
Referential Example 565
(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-(5-methyl-1,3,4-thiadiazol-2-y-
l)cyclohexylcarbamic acid 2-(trimethylsilyl)ethyl ester
##STR00635##
[2450] In a manner similar to that described in Referential Example
561, the compound obtained in Referential Example 557 was condensed
with acetohydrazide. The condensed compound was reacted with
Lawesson reagent, followed by heating, whereby the title compound
was obtained.
[2451] .sup.1H-NMR (CDCl.sub.3).delta.:0.04(9H, s), 0.98(2H, t,
J=8.5 Hz), 1.46(9H, s), 1.61-1.75(1H, m), 1.80-2.00(3H, m),
2.11-2.20(1H, m), 2.22-2.31(1H, m), 2.75(3H, s), 3.17-3.32(1H, m),
3.61-3.88(1H, m), 4.07-4.22(3H, m), 4.82(1H, br.s), 5.24(1H,
br.s).
[2452] MS (ESI) m/z: 457(M+H).sup.+.
Referential Example 566
(1S,2R,4S)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)car-
bonyl]amino)-4-(5-methyl-1,3,4-thiadiazol-2-yl)cyclohexylcarbamic
acid 2-(trimethylsilyl)ethyl ester
##STR00636##
[2454] In a manner similar to that described in Referential Example
560, the compound obtained in Referential Example 565 was treated
with p-toluenesulfonic acid for deprotection. The deprotected
compound was condensed with the compound obtained in Referential
Example 564, whereby the title compound was obtained.
[2455] .sup.1H-NMR (CDCl.sub.3) .delta.:0.02(9H, s), 0.97(2H, t,
J=7.8 Hz), 1.59-1.73(1H, m), 1.74-1.87(1H, m), 1.97-2.08(1H, m),
2.08-2.20(1H, m), 2.20-2.31(1H, m), 2.36-2.45(1H, m), 2.52(3H, s),
2.75(3H, s), 2.84(2H, t, J=5.5 Hz), 2.95(2H, t, J=5.5 Hz),
3.35-3.49(1H, m), 3.73(2H, br.s), 3.89(1H, br.s), 4.14(2H, t, J=7.8
Hz), 4.58-4.69(1H, m), 5.29(1H, br.s), 7.47(1H, d, J=8.1 Hz).
[2456] MS (ESI) m/z: 537(M+H).sup.+.
Referential Example 567
(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-(1,3-oxazol-5-yl)cyclohexylcar-
bamic acid benzyl ester
##STR00637##
[2458] To a mixture of quinoline (8.00 mL) and p-toluenesulfonyl
chloride (4.84 g), N-methylformamide (0.99 mL) was added dropwise
under reduced pressure at 75.degree. C. The resultant gas was
cooled with Liebig condenser to liquefy and recover in an eggplant
flask cooled at -78.degree. C., whereby methyl isocyanide (553 mg)
was obtained. To methyl isocyanide (349 mg) in tetrahydrofuran (10
mL), n-butyllithium (1.57M hexane solution, 6.95 mL) was added in a
nitrogen atmosphere at -78.degree. C., followed by stirring for 15
minutes. To the reaction mixture, the compound (1.02 g) obtained in
Referential Example 141 dissolved in tetrahydrofuran (10 mL) was
added dropwise at -78.degree. C., followed by stirring for 30
minutes. The reaction mixture was heated to 0.degree. C., and
stirred for 15 minutes. The reaction mixture was cooled to
-78.degree. C., and acetic acid (0.62 mL) was added thereto,
followed by stirring at 0.degree. C. for 45 minutes. The resultant
mixture was diluted with diethyl ether, and sequentially washed
with water and saturated brine. The resultant mixture was dried
over sodium sulfate anhydrate, and concentrated under reduced
pressure.
[2459] The residue was purified by silica gel flash column
chromatography (methanol:methylene chloride=1:49.fwdarw.3:97), to
thereby give the title compound (663 mg).
[2460] .sup.1H-NMR (CDCl.sub.3).delta.:1.45(9H, s), 1.50-2.20(6H,
m), 2.75-2.88(1H, m), 3.69-3.81(1H, m), 4.19-4.23(1H, m),
4.65-4.84(1H, m), 5.05-5.18(2H, m), 6.78(1H, s), 7.30-7.45(6H, m),
7.77(1H, s).
[2461] MS (ESI) m/z: 416(M+H).sup.+.
Referential Example 568
(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-(1,3-o-
xazol-5-yl)cyclohexylcarbamic acid tert-butyl ester
##STR00638##
[2463] In a manner similar to that described in Referential Example
552, the compound obtained in Referential Example 567 was
deprotected. The deprotected compound was condensed with the
compound obtained in Referential Example 266, whereby the title
compound was obtained.
[2464] .sup.1H-NMR (CDCl.sub.3).delta.:1.45(9H, s), 1.53-1.68(1H,
m), 1.70-1.92(2H, m), 1.94-2.24(3H, m), 2.78-2.95(1H, m),
3.94-4.05(1H, m), 4.16-4.30(1H, m), 4.88-5.04(1H, m), 6.78(1H, s),
7.69(1H, dd, J=8.8, 2.4 Hz), 7.78(1H, s), 7.95-8.10(1H, m),
8.17(1H, d, J=8.8 Hz), 8.30(1H, d, J=2.4 Hz), 9.74(1H, s).
[2465] MS (ESI) m/z: 464(M+H).sup.+.
Referential Example 569
(1S,2R,4S)-4-(aminocarbonyl)-2-[(tert-butoxycarbonyl)amino]cyclohexylcarba-
mic acid 2-(trimethylsilyl)ethyl ester
##STR00639##
[2467] In a manner similar to that described in Referential Example
143, the compound obtained in Referential Example 557 was condensed
with ammonium chloride, whereby the title compound was
obtained.
[2468] .sup.1H-NMR (CDCl.sub.3).delta.:0.04(9H, s), 0.97(2H, t,
J=8.3 Hz), 1.45(9H, s), 1.62-2.07(6H, m), 2.33(1H, br.s), 3.69(1H,
br.s), 4.00-4.21(3H, m), 4.93(1H, br.s), 5.15(1H, br.s), 5.60(1H,
br.s), 5.75(1H, br.s).
[2469] MS (ESI) m/z: 302(M-Boc).sup.+.
Referential Example 570
(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-cyanocyclohexylcarbamic
acid 2-(trimethylsilyl)ethyl ester
##STR00640##
[2471] The compound (1.48 g) obtained in Referential Example 569
and triethylamine (1.04 mL) were dissolved in methylene chloride
(25 mL). Under ice cooling, trifluoroacetic acid anhydride (0.790
mL) was added thereto, followed by stirring at room temperature for
1 hour. To the resultant mixture, saturated aqueous sodium
hydrogencarbonate and methylene chloride were added for
partitioning the mixture. The resultant organic layer was dried
over sodium sulfate anhydrate, and the solvent was distilled away
under reduced pressure. Hexane was added to the residue to
solidify, to thereby give the title compound (1.18 g).
[2472] .sup.1H-NMR (DMSO-d.sub.6).delta.:0.01(9H, s), 0.91(2H, dd,
J=9.0, 7.1 Hz), 1.38(9H, s), 1.48-1.64(3H, m), 1.65-1.77(1H, m),
1.81(2H, t, J=5.9 Hz), 3.03(1H, br.s), 3.62(1H, br.s), 3.78(1H,
br.s), 4.02(2H, dd, J=9.0, 7.1 Hz), 6.54(1H, br.s), 6.74(1H,
br.s).
[2473] MS (ESI) m/z: 406(M+Na).sup.+, 328(M-tBu).sup.+,
284(M-Boc).sup.+.
Referential Example 571
(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-(5-methyl-1,2,4-oxadiazol-3-yl-
)cyclohexylcarbamic acid 2-(trimethylsilyl)ethyl ester
##STR00641##
[2475] In a manner similar to that described in Referential Example
550, the compound obtained in Referential Example 570 was reacted
with hydroxylamine. By use of trimethyl orthoacetate, the resultant
compound was subjected to cyclization reaction, whereby the title
compound was obtained.
[2476] .sup.1H-NMR (CDCl.sub.3).delta.:0.03(9H, s), 0.98(2H, t,
J=8.4 Hz), 1.35-2.18(6H, m), 1.45(9H, s), 2.56(3H, s),
2.81-2.96(1H, m), 3.65-3.79(1H, m), 4.05-4.23(3H, m), 4.65-4.83(1H,
m), 5.10-5.30(1H, m).
Referential Example 572
(1S,2R,4S)-4-(5-methyl-1,2,4-oxadiazol-3-yl)-2-{[(5-methyl-1-4,5,6,7-tetra-
hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexylcarbamic
acid 2-(trimethylsilyl)ethyl ester
##STR00642##
[2478] In a manner similar to that described in Referential Example
560, the compound obtained in Referential Example 571 was treated
with p-toluenesulfonic acid for deprotection. The deprotected
compound was condensed with the compound obtained in Referential
Example 10, whereby the title compound was obtained.
[2479] .sup.1H-NMR (CDCl.sub.3).delta.:0.02(9H, s), 0.96(2H, t,
J=8.4 Hz), 1.52-1.66(1H, m), 1.73-1.90(1H, m), 2.00-2.29(4H, m),
2.56(3H, s), 2.58(3H, s), 2.85-3.11(5H, m), 3.73-3.93(3H, m),
4.13(2H, t, J=8.4 Hz), 4.59-4.68(1H, m), 5.15-5.26(1H, m),
7.34-7.45(1H, m).
[2480] MS (ESI) m/z: 521(M+H).sup.+.
Referential Example 573
(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-({[2-(trimethylsilyl)ethoxy]ca-
rbonyl}amino)cyclohexylcarbamic acid benzyl ester
##STR00643##
[2482] To the compound (3.14 g) obtained in Referential Example 142
in toluene (60 mL) were added triethylamine (1.67 mL) and
diphenylphosphoryl azide (2.06 mL), followed by stirring at
80.degree. C. for 2 hours. The mixture was cooled to room
temperature, and trimethylsilylethanol (4.59 mL) was added thereto.
The resultant mixture was stirred at 90.degree. C. for 16 hours.
The reaction mixture was cooled to room temperature, concentrated
under reduced pressure, and dissolved in ethyl acetate. The
solution was sequentially washed with 10% aqueous citric acid,
saturated aqueous solution of sodium hydrogencarbonate, and
saturated brine, followed by drying over sodium sulfate anhydrate
and concentrating under reduced pressure. The residue was purified
by silica gel column chromatography (methylene
chloride:methanol=50:1). Hexane was added to the resultant solid,
and the mixture was subjected to filtration, to thereby give the
title compound (2.72 g).
[2483] .sup.1H-NMR (CDCl.sub.3).delta.:0.03(9H, s), 0.91-1.01(2H,
m), 1.23-1.64(3H, m), 1.44(9H, s), 1.90-2.08(3H, m), 3.51-3.75(2H,
m), 4.04-4.18(3H, m), 4.49(1H, br.s), 4.78(1H, br.s), 5.03-5.14(2H,
m), 5.36(1H, br.s), 7.28-7.38(5H, m).
[2484] MS (ESI) m/z: 508(M+H).sup.+.
Referential Example 574
(1S,2R,4S)-4-amino-2-[(tert-butoxycarbonyl)amino]cyclohexylcarbamic
acid benzyl ester
##STR00644##
[2486] 1N Tetrabutylammonium tetrahydrofuran (6.0 mL) was added to
the compound (1.02 g) obtained in Referential Example 573 dissolved
in tetrahydrofuran (6.0 mL), followed by stirring at room
temperature for 3 days. Ethyl acetate was added thereto, and the
resultant mixture was sequentially washed with saturated aqueous
solution of sodium hydrogencarbonate, water, and saturated brine.
The organic layer was dried over sodium sulfate anhydrate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (methylene
chloride:methanol:concentrated aqueous ammonia=100:10:1), to
thereby give the title compound (660 mg).
[2487] .sup.1H-NMR (CDCl.sub.3).delta.:1.19-1.63(3H, m), 1.44(9H,
s), 1.80-2.06(3H, m), 2.79-2.91(1H, m), 3.63-3.72(1H, m), 4.11(1H,
br.s), 4.68(1H, br.s), 5.03-5.14(2H, m), 5.27(1H, br.s),
7.28-7.38(5H, m).
[2488] MS (ESI) m/z: 363(M+H).sup.+.
Referential Example 575
(1S,2R,4S)-2-[(tert-butoxycarbonyl)-4-(4H-1,2,4-triazol-4-yl)amino]cyclohe-
xylcarbamic acid benzyl ester
##STR00645##
[2490] To the compound (182 mg) obtained in Referential Example 574
in pyridine (3.0 mL) were added 1,2-diformylhydrazine (154 mg),
triethylamine (0.464 mL), and chlorotrimethylsilane (0.952 mL),
followed by stirring at 80.degree. C. for 6 hours. The reaction
mixture was cooled to room temperature, and saturated aqueous
solution of sodium hydrogencarbonate and methylene chloride were
added thereto for partition. The organic layer was washed with
saturated brine, followed by drying over sodium sulfate anhydrate
and concentrating under reduced pressure. The residue was purified
by flash silica gel column chromatography (methylene
chloride:methanol=30:1.fwdarw.10:1), to thereby give the title
compound (127 mg).
[2491] .sup.1H-NMR (CDCl.sub.3).delta.:1.45(9H, s), 1.54-1.91(3H,
m), 1.91-2.15(2H, m), 2.21(1H, d, J=12.5 Hz), 2.37(1H, d, J=12.9
Hz), 3.82(1H, br.s), 4.24(1H, br.s), 4.36(1H, br.s), 5.05-5.16(2H,
m), 5.35(1H, d, J=7.6 Hz), 7.30-7.40(5H, m), 8.26(2H, s).
[2492] MS (ESI) m/z: 416(M+H).sup.+.
Referential Example 576
(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-(4H-1,-
2,4-triazol-4-yl)cyclohexylcarbamic acid tert-butyl ester
##STR00646##
[2494] In a manner similar to that described in Referential Example
552, the compound obtained in Referential Example 575 was
deprotected. The deprotected compound was condensed with the
compound obtained in Referential Example 266, whereby the title
compound was obtained.
[2495] .sup.1H-NMR (CDCl.sub.3).delta.:1.47(9H, s), 1.60-1.98(2H,
m), 2.05-2.20(2H, m), 2.25-2.35(1H, m), 2.36-2.45(1H, m),
4.03-4.13(1H, m), 4.37(1H, br.s), 4.47(1H, br.s), 5.42(1H, br.s),
7.71(1H, dd, J=8.8, 2.4 Hz), 8.04(1H, br.s), 8.17(1H, d, J=8.8 Hz),
8.31-8.33(3H, m), 9.71(1H, s).
[2496] MS (ESI) m/z: 464(M+H).sup.+.
Referential Example 577
(1R,2S,5S)-2-amino-5-(5-methyl-1,3,4-oxadiazol-2-yl)cyclohexylcarbamic
acid tert-butyl ester
##STR00647##
[2498] The compound (5.74 g) obtained in Referential Example 551
was dissolved in methanol (110 mL), followed by adding 10%
palladium carbon catalyst (1.22 g) thereto and stirring in a
hydrogen atmosphere at room temperature for 17 hours. The catalyst
was filtered off, and the solvent was distilled away under reduced
pressure, to thereby give the title compound (3.95 g).
[2499] .sup.1H-NMR (CDCl.sub.3).delta.:1.47(9H, s), 1.65-2.45(6H,
m), 2.51(3H, s), 3.03-3.60(3H, m), 4.12-4.35(1H, m), 5.45-5.76(1H,
m), 6.86-7.17(1H, m).
[2500] MS (ESI) m/z: 297(M+H).sup.+.
Referential Example 578
2-[(5-bromopyridin-2-yl)amino]-2-oxoacetic acid lithium salt
##STR00648##
[2502] In a manner similar to that described in Referential Example
266, from the compound obtained in Referential Example 262, the
title compound was obtained.
[2503] .sup.1H-NMR (DMSO-d.sub.6).delta.:8.03 (1H, dd, J=8.8, 2.4
Hz), 8.09(1H, d, J=8.8 Hz), 8.44(1H, d, J=2.4 Hz), 10.18(1H,
s).
Referential Example 579
(1R,2S,5S)-2-({2-[(5-bromopyridin-2-yl)amino]-2-oxoacetyl}amino)-5-(5-meth-
yl-1,3,4-oxadiazol-2-yl)cyclohexylcarbamic acid tert-butyl
ester
##STR00649##
[2505] To the compound (900 mg) obtained in Referential Example 577
in N,N-dimethylformamide (40 mL) were added the compound (1.24 g)
obtained in Referential Example 578,
3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (1.17
g), and 1-hydroxybenzotriazole (205 mg), followed by stirring at
40.degree. C. for 7 hours. To the reaction mixture were added ethyl
acetate and water for partition. The organic layer was washed with
water, dried over sodium sulfate anhydrate, and the solvent was
distilled away under reduced pressure. The residue was purified by
flash silica gel column chromatography (methylene
chloride:methanol=19:1), to thereby give the title compound (1.51
g).
[2506] .sup.1H-NMR (CDCl.sub.3).delta.:1.46(9H, s), 1.56-2.31(6H,
m), 2.52(3H, s), 3.01-3.12(1H, m), 4.00-4.08(1H, m), 4.26(1H,
br.s), 4.92(1H, br.s), 7.84(1H, dd, J=8.8, 2.5 Hz), 8.03(1H, d,
J=2.9 Hz), 8.14(1H, d, J=8.8 Hz), 8.41(1H, d, J=2.5 Hz), 9.72(1H,
s).
Referential Example 580
(1R,2S,5S)-2-{[(7-chlorocinnolin-3-yl)carbonyl]amino}-5-(5-methyl-1,3,4-ox-
adiazol-2-yl)cyclohexylcarbamic acid tert-butyl ester
##STR00650##
[2508] In a manner similar to that described in Referential Example
579, carboxylic acid lithium salt prepared by hydrolysis of the
compound obtained in Referential Example 297 was condensed with the
compound obtained in Referential Example 577, whereby the title
compound was obtained.
[2509] .sup.1H-NMR (CDCl.sub.3).delta.:1.37(9H, s), 1.68-1.82(1H,
m), 1.82-1.99(1H, m), 2.01-2.37(4H, m), 2.53(3H, s), 3.12(1H,
br.s), 4.40(2H, br.s), 4.96(1H, br.s), 7.79(1H, dd, J=8.8, 1.8 Hz),
7.98(1H, d, J=8.8 Hz), 8.61(1H, s), 8.69(1H, d, J=7.8 Hz), 8.74(1H,
s).
[2510] MS (ESI) m/z: 487(M+H).sup.+.
Referential Example 581
(1R,2S,5S)-2-{[(7-chloroisoquinolin-3-yl)carbonyl]amino}-5-(5-methyl-1,3,4-
-oxadiazol-2-yl)cyclohexylcarbamic acid tert-butyl ester
##STR00651##
[2512] In a manner similar to that described in Referential Example
579, the compound obtained in Referential Example 577 was condensed
with the compound obtained in Referential Example 57, whereby the
title compound was obtained.
[2513] .sup.1H-NMR (CDCl.sub.3).delta.:1.45(9H, s), 1.57-1.74(1H,
m), 1.79-2.49(5H, m), 2.53(3H, s), 3.00-3.16(1H, m), 4.24-4.38(2H,
m), 5.00(1H, br.s), 7.71(1H, dd, J=8.8, 1.7 Hz), 7.90-7.97(1H, m),
8.02(1H, d, J=1.7 Hz), 8.45-8.62(2H, m), 9.05(1H, .s).
[2514] MS (ESI) m/z: 486(M+H).sup.+.
Referential Example 582
(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-(1,2,4-oxadiazol-5-yl)cyclohex-
ylcarbamic acid 2-(trimethylsilyl)ethyl ester
##STR00652##
[2516] A mixture of the compound (994 mg) obtained in Referential
Example 569 and N,N-dimethylformamide dimethylacetal (10 mL) was
stirred at 120.degree. C. for 2 hours. The reaction mixture was
allowed to cool to room temperature, and concentrated under reduced
pressure. Hexane was added to the residue to give colorless powder.
To the powder were added 70% aqueous acetic acid (10 mL) and
hydroxylamine (50% aqueous solution, 197 mg), followed by stirring
at room temperature overnight. The solvent was distilled away under
reduced pressure, and to the residue were added ethyl acetate and
saturated aqueous solution of sodium hydrogencarbonate for
partition. The organic layer was dried over sodium sulfate
anhydrate, and the solvent was distilled away under reduced
pressure. The residue was purified by silica gel chromatography
(hexane:ethyl acetate=2:1), to thereby give the title compound (759
mg).
[2517] .sup.1H-NMR (CDCl.sub.3).delta.:0.04(9H, s), 0.91-1.04(2H,
m), 1.46(9H, s), 1.61-2.44(6H, m), 2.98-3.49(1H, m), 3.73(1H,
br.s), 4.03-4.25(2H, m), 4.85(1H, br.s), 5.30(1H, br.s), 6.70(1H,
br.s), 8.34(1H, s).
[2518] MS (ESI) m/z: 449(M+Na).sup.+, 327(M-Boc).sup.+.
Referential Example 583
(1S,2R,4S)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)car-
bonyl]amino}-4-(1,2,4-oxadiazol-5-yl)cyclohexylcarbamic acid
2-(trimethylsilyl)ethyl ester
##STR00653##
[2520] In a manner similar to that described in Referential Example
560, the compound obtained in Referential Example 583 was treated
with p-toluenesulfonic acid for deprotection. The deprotected
compound was condensed with the compound obtained in Referential
Example 564, whereby the title compound was obtained.
[2521] .sup.1H-NMR (CDCl.sub.3) .delta.:0.02(9H, s), 0.97(2H, dd,
J=9.9, 7.0 Hz), 1.58-1.94(2H, m), 2.07-2.20(2H, m), 2.21-2.30(1H,
m), 2.35-2.44(1H, m), 2.53(3H, s), 2.85(2H, t, J=5.6 Hz), 2.95(2H,
t, J=5.6 Hz), 3.20-3.32(1H, m), 3.74(2H, s), 3.90(1H, br.s),
4.14(2H, dd, J=9.9, 7.0 Hz), 4.62-4.69(1H, m), 5.19(1H, br.s),
7.39(1H, d, J=8.1 Hz), 8.35(1H, s).
[2522] MS (ESI) m/z: 507(M+H).sup.+.
Referential Example 584
(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-{[2-(2,2,2-trifluoroacetyl)hyd-
razino]carbonyl}cyclohexylcarbamic acid benzyl ester
##STR00654##
[2524] To the compound (4.00 g) obtained in Referential Example 142
in N,N-dimethylformamide (100 mL) were added hydrazine monohydrate
(765 mg), 1-hydroxybenzotriazole (1.38 g), and
1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.93 g),
followed by stirring at room temperature overnight. The reaction
mixture was concentrated under reduced pressure, and to the residue
were added methylene chloride and aqueous solution of sodium
hydrogencarbonate for partition. The aqueous layer was extracted
with methylene chloride, and the obtained organic layers were
combined, followed by drying over sodium sulfate anhydrate. The
sodium sulfate anhydrate was filtered off, and to the obtained
filtrate were added silica gel (25 g) and methanol (15 mL),
followed by stirring and filtering to remove insoluble material.
The solvent was distilled away under reduced pressure, to thereby
give colorless oily crude material of
(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-(hydrazinocarbonyl)cyclohexyl-
carbamic acid benzyl ester (3.71 g). Methylene chloride (10 mL) and
triethylamine (115 .mu.L) were added to the resultant colorless
oily material (306 mg). Anhydrous trifluoroacetic acid (116 .mu.L)
was added thereto under ice cooling, followed by stirring at room
temperature for 5 hours. Moreover, triethylamine (115 .mu.L) and
anhydrous trifluoroacetic acid (116 .mu.L) were added, followed by
stirring at room temperature for 1 hour. To the reaction mixture
were added methylene chloride and water for partition. The aqueous
layer was extracted with methylene chloride, and the organic layers
were combined, followed by drying over sodium sulfate anhydrate.
The solvent was distilled away under reduced pressure, and the
residue was purified by silica gel chromatography
(methanol:methylene chloride=1:19), to thereby give the title
compound (283 mg).
[2525] .sup.1H-NMR (CDCl.sub.3).delta.:1.41(9H, s), 1.52-2.06(6H,
m), 2.53(1H, br.s), 3.73(1H, br.s), 4.09(1H, br.s), 4.99-5.15(3H,
m), 5.34(1H, d, J=7.3 Hz), 7.27-7.36(5H, m), 8.92-9.36(1H, m).
[2526] MS (ESI) m/z: 525(M+Na).sup.+, 403(M-Boc).sup.+.
Referential Example 585
(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-[5-(trifluoromethyl)-1,3,4-oxa-
diazol-2-yl]cyclohexylcarbamic acid benzyl ester
##STR00655##
[2528] Triphenylphosphine (392 mg) was dissolved in methylene
chloride (10 mL). To the resultant solution, hexachloroethane (296
mg), triethylamine (416 .mu.L), and the compound (250 mg) obtained
in Referential Example 584 in methylene chloride (5 mL) were
sequentially added under ice cooling. The mixture was stirred at
room temperature overnight, and to the reaction mixture were added
methylene chloride and 10% aqueous citric acid for partition. The
organic layer was sequentially washed with saturated brine, aqueous
solution of sodium hydrogencarbonate, and saturated brine, followed
by drying over sodium sulfate anhydrate. The solvent was distilled
away under reduced pressure. The residue was purified by silica gel
chromatography (hexane:ethyl acetate=1:1), to thereby give the
title compound (204 mg).
[2529] .sup.1H-NMR (CDCl.sub.3).delta.:1.44(9H, s), 1.51-1.62(1H,
m), 1.71-1.90(1H, m), 1.92-2.16(2H, m), 2.16-2.25(1H, m),
2.28-2.38(1H, m), 3.16(1H, br.s), 3.81(1H, br.s), 4.20(1H, br.s),
4.56-4.84(1H, m), 5.04-5.16(2H, m), 5.20-5.28(1H, m), 7.29-7.39(5H,
m).
[2530] MS (ESI) m/z: 429(M-tBu).sup.+, 385(M-Boc).sup.+.
Referential Example 586
(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-[5-(tr-
ifluoromethyl)-1,3,4-oxadiazol-2-yl]cyclohexylcarbamic acid
tert-butyl ester
##STR00656##
[2532] In a manner similar to that described in Referential Example
552, the compound obtained in Referential Example 585 was
deprotected. The deprotected compound was condensed with the
compound obtained in Referential Example 266, whereby the title
compound was obtained.
[2533] .sup.1H-NMR (CDCl.sub.3).delta.:1.46(9H, s), 1.55-1.66(1H,
m), 1.79-1.94(1H, m), 1.98-2.19(2H, m), 2.23-2.32(1H, m),
2.32-2.41(1H, m), 3.18(1H, br.s), 4.00-4.10(1H, m), 4.29(1H, br.s),
4.86(1H, br.s), 7.71(1H,dd, J=8.8, 2.4 Hz), 7.98(1H, br.s),
8.18(1H, d, J=8.8 Hz), 8.32(1H, d, J=2.4 Hz), 9.72(1H, s).
[2534] MS (ESI) m/z: 477(M-tBu).sup.+, 433(M-Boc).sup.+.
Referential Example 587
(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-{[(2-chloroethoxy)carbonyl]ami-
no}cyclohexylcarbamic acid benzyl ester
##STR00657##
[2536] To the compound (872 mg) obtained in Referential Example 574
in methylene chloride (30 mL), under ice cooling were added
chloroethyl chloroformate (323 .mu.L) and triethylamine (499
.mu.L), followed by stirring at 0.degree. C. for 1 hour. Water was
added to the reaction mixture for partition. The organic layer was
washed with water, and dried over sodium sulfate anhydrate. The
solvent was distilled away under reduced pressure, and the residue
was purified by flash silica gel column chromatography
(hexane:ethyl acetate=3:2), to thereby give the title compound
(1.03 g).
[2537] .sup.1H-NMR (CDCl.sub.3).delta.:1.24-1.70(12H, m),
1.99-2.03(3H, m), 3.59-3.73(4H, m), 4.06-4.13(1H, m), 4.29(2H, t,
J=5.5 Hz), 4.82(1H, br.s), 4.86(1H, br.s), 5.05-5.12(2H, m),
5.41(1H, br.s), 7.28-7.36(5H, m).
[2538] MS (ESI) m/z: 492(M+Na).sup.+.
Referential Example 588
(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-(2-oxo-1,3-oxazolidin-3-yl)cyc-
lohexylcarbamic acid benzyl ester
##STR00658##
[2540] To a suspension of 60% sodium hydride (87 mg) in
N,N-dimethylformamide (5.0 mL), the compound (926 mg) obtained in
Referential Example 587 in N,N-dimethylformamide (5.0 mL) was
added, and the mixture was stirred at room temperature for 1 hour.
Water and ethyl acetate were added to the reaction mixture for
partition therebetween. The organic layer was washed with water and
saturated brine. The organic layer was dried over sodium sulfate
anhydrate, and the solvent was distilled away under reduced
pressure. The residue was purified by flash silica gel column
chromatography (hexane:ethyl acetate=2:3), to thereby give the
title compound (680 mg).
[2541] .sup.1H-NMR (CDCl.sub.3).delta.:1.44(9H, s), 1.45-2.08(6H,
m), 3.44-3.54(2H, m), 3.64(1H, br.s), 3.77-3.87(1H, m), 4.20(1H,
br.s), 4.29-4.36(2H, m), 4.84(1H, br.s), 5.05-5.13(2H, m), 5.37(1H,
br.s), 7.27-7.36(5H, m).
[2542] MS (ESI) m/z: 434(M+H).sup.+.
Referential Example 589
(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-(2-oxo-
-1,3-oxazolidin-3-yl)cyclohexylcarbamic acid tert-butyl ester
##STR00659##
[2544] In a manner similar to that described in Referential Example
552, the compound obtained in Referential Example 588 was
deprotected. The deprotected compound was condensed with the
compound obtained in Referential Example 266, whereby the title
compound was obtained.
[2545] .sup.1H-NMR (CDCl.sub.3).delta.:1.46(9H, s), 1.58-1.65(2H,
m), 1.79-2.05(4H, m), 3.47-3.55(2H, m), 3.84-3.93(2H, m), 4.29(1H,
br.s), 4.33-4.39(2H, m), 5.08(1H, br.s), 7.70(1H, dd, J=8.8, 2.5
Hz), 8.10(1H, br.s), 8.19(1H, dd, J=8.8, 0.7 Hz), 8.31(1H, dd,
J=2.5, 0.7 Hz), 9.71(1H, s).
[2546] MS (ESI) m/z: 504(M+Na).sup.+.
Referential Example 590
(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-(formylamino)cyclohexylcarbami-
c acid benzyl ester
##STR00660##
[2548] To the compound (200 mg) obtained in Referential Example 574
in methylene chloride (5 mL) were added formic acid (31.1 .mu.L),
1-hydroxybenzotriazole (108 mg), triethylamine (115 .mu.L), and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (210
mg), followed by stirring at room temperature for 22 hours. The
solvent was distilled away under reduced pressure, and saturated
aqueous solution of sodium hydrogencarbonate was added to the
residue. The resultant mixture was extracted with methylene
chloride, followed by drying over anhydrous magnesium sulfate. The
solvent was distilled away under reduced pressure, and the residue
was purified by silica gel column chromatography (methylene
chloride:methanol=49:1.fwdarw.97:3), to thereby give the title
compound (100 mg).
[2549] .sup.1H-NMR (CDCl.sub.3).delta.:1.27-1.50(2H, m), 1.44(9H,
s), 1.94-2.07(4H, m), 3.66-3.74(1H, m), 3.97-4.07(1H, m),
4.08-4.15(1H, m), 4.80-4.88(1H, m), 5.05(1H, d, J=12.2 Hz),
5.10(1H, d, J=12.0 Hz), 5.33-5.41(1H, m), 5.43-5.50(1H, m),
7.30-7.37(5H, m), 8.12(1H, s).
[2550] MS (ESI) m/z: 392(M+H).sup.+.
Referential Example 591
(1R,2S,5S)-2-[(benzyloxycarbonyl)amino]-5-(tetrazol-1-yl)cyclohexylcarbami-
c acid tert-butyl ester
##STR00661##
[2552] The compound (792 mg) obtained in Referential Example 590
and pyridine (1.63 mL) were dissolved in methylene chloride (10
mL). Under ice cooling, trichloromethyl chloroformate (268 .mu.L)
was added thereto, followed by stirring at a constant temperature
for 10 minutes. The temperature of the reaction mixture was
returned to room temperature, and stirred for 15 minutes.
Trimethylsilylazide (295 .mu.L) was added thereto, and the mixture
was stirred for 22 hours. The solvent was distilled away under
reduced pressure, and aqueous solution of sodium hydrogencarbonate
was added to the residue. The insoluble material was recovered by
filtration, followed by washing with water. The resultant solid was
purified by silica gel column chromatography (methylene
chloride:methanol=199:1.fwdarw.49:1), to thereby give the title
compound (60 mg).
[2553] .sup.1H-NMR (CDCl.sub.3).delta.:1.45(9H, s), 1.55-1.59(1H,
m), 2.02-2.14 (2H, m), 2.21-2.32(2H, m), 2.41-2.49(1H, m),
3.84-3.92(1H, m), 4.20-4.25(1H, m), 4.65-4.76(1H, m), 5.07-5.16(3H,
m), 5.21-5.28(1H, m), 7.32-7.38 (5H, m), 8.68(1H, s).
[2554] MS (ESI) m/z: 417(M+H).sup.+.
Referential Example 592
(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-(tetra-
zol-1-yl)cyclohexylcarbamic acid tert-butyl ester
##STR00662##
[2556] In a manner similar to that described in Referential Example
552, the compound obtained in Referential Example 591 was
deprotected. The deprotected compound was condensed with the
compound obtained in Referential Example 266, whereby the title
compound was obtained.
[2557] .sup.1H-NMR (CDCl.sub.3).delta.:1.46(9H, s), 1.73-1.92(1H,
m), 2.07-2.21(2H, m), 2.28-2.41(2H, m), 2.45-2.53(1H, m),
4.10-4.19(1H, m), 4.33-4.40(1H, m), 4.71-4.89(1H, m), 4.99-5.14(1H,
m), 7.71(1H, dd, J=8.8, 2.4 Hz), 7.96-8.04 (1H, m), 8.17 (1H, d,
J=8.8 Hz), 8.32(1H, d, J=2.4 Hz), 8.69(1H, s), 9.71(1H, s).
[2558] MS (ESI) m/z: 465(M+H).sup.+.
Referential Example 593
(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-(1H-pyrrol-1-yl)cyclohexylcarb-
amic acid benzyl ester
##STR00663##
[2560] 1N Hydrochloric acid (550 .mu.L) was added to a mixture of
the compound (200 mg) obtained in Referential Example 574, 2,
5-dimethoxytetrahydrofuran (71.3 .mu.L), water (10 mL), and
1,2-dichloroethane (10 mL), followed by stirring at 80.degree. C.
for 2.5 hours. The reaction mixture was allowed to cool to room
temperature, and saturated aqueous solution of sodium
hydrogencarbonate and methylene chloride were added thereto for
partition. The organic layer was dried over sodium sulfate
anhydrate, and the solvent was distilled away under reduced
pressure. The residue was purified by silica gel chromatography
(hexane:ethyl acetate=4:1.fwdarw.1:1), to thereby give the title
compound (84 mg).
[2561] .sup.1H-NMR (CDCl.sub.3).delta.:1.45(9H, s), 1.71-2.20(5H,
m), 2.22-2.31(1H, m), 3.78(1H, br.s), 3.99(1H, br.s), 4.22(1H,
br.s), 4.73(1H, br.s), 5.04-5.16(2H, m), 5.29(1H, br.s), 6.15(2H,
t, J=2.2 Hz), 6.70(2H, t, J=2.2 Hz), 7.29-7.39(5H, m).
[2562] MS (ESI) m/z: 436(M+Na).sup.+.
Referential Example 594
(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-(1H-py-
rrol-1-yl)cyclohexylcarbamic acid tert-butyl ester
##STR00664##
[2564] In a manner similar to that described in Referential
[2565] Example 552, the compound obtained in Referential Example
593 was deprotected. The deprotected compound was condensed with
the compound obtained in Referential Example 266, whereby the title
compound was obtained.
[2566] .sup.1H-NMR (CDCl.sub.3).delta.:1.47(9H, s), 1.80-2.33(6H,
m), 3.92-4.08(2H, m), 4.31(1H, br.s), 4.89(1H, br.s), 6.17(2H, t,
J=2.0 Hz), 6.71(2H, t, J=2.0 Hz), 7.69(1H, dd, J=8.8, 2.2 Hz),
8.02(1H, br.s), 8.17(1H, d, J=8.8 Hz), 8.31(1H, d, J=2.2 Hz),
9.72(1H, br.s).
[2567] MS (ESI) m/z: 462(M+H).sup.+.
Referential Example 595
(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-(([(dimethylamino)methylidene]-
amino}carbonyl)cyclohexylcarbamic acid benzyl ester
##STR00665##
[2569] To the compound (1.50 g) obtained in Referential Example 142
in N,N-dimethylformamide (100 mL) were added ammonium chloride (409
mg), 1-hydroxybenzotriazole (516 mg),
1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.03 g),
and triethylamine (1.06 mL), followed by stirring at room
temperature overnight. The reaction mixture was concentrated under
reduced pressure, and ethyl acetate and 10% aqueous citric acid
were added to the residue for partition. The organic layer was
sequentially washed with saturated brine, aqueous solution of
sodium hydrogencarbonate, and saturated brine, followed by drying
over anhydrous magnesium sulfate and evaporating the solvent under
reduced pressure. The resultant powder was suspended in
N,N-dimethylformamide dimethylacetal (30 mL), followed by stirring
at 120.degree. C. for 2 hours. The resultant mixture was allowed to
cool to room temperature, and precipitated colorless powder was
collected by filtration, followed by washing with diethyl ether, to
thereby give the title compound (957 mg).
[2570] .sup.1H-NMR (CDCl.sub.3).delta.:1.25-1.40(1H, m), 1.44(9H,
s), 1.53-1.66(1H, m), 1.73-2.08(4H, m), 2.32-2.46(1H, m), 3.07(3H,
s), 3.11(3H, s), 3.63-3.75(1H, m), 4.13(1H, br.s), 4.59-4.75(1H,
m), 5.07(1H, d, J=12.2 Hz), 5.12(1H, d, J=12.2 Hz), 5.30-5.45(1H,
m), 7.28-7.37(5H, m), 8.40(1H, s).
[2571] MS (ESI) m/z: 447(M+H).sup.+.
Referential Example 596
(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-(1,2,4-triazol-5-yl)cyclohexyl-
carbamic acid benzyl ester
##STR00666##
[2573] To the compound (400 mg) obtained in Referential Example 595
in acetic acid (10 mL) was added hydrazine monohydrate (51.9
.mu.L), followed by stirring at room temperature for 2 hours. The
solvent was distilled away under reduced pressure, and saturated
aqueous solution of sodium hydrogencarbonate and ethyl acetate were
added to the residue for partition. The organic layer was washed
with saturated brine, and dried over anhydrous magnesium sulfate.
The solvent was distilled away under reduced pressure, to thereby
give the title compound (370 mg).
[2574] .sup.1H-NMR (DMSO-d.sub.6).delta.:1.39(9H, s), 1.48-1.62(2H,
m), 1.62-1.75(2H, m), 1.88-2.06(2H, m), 3.06(1H, br.s), 3.56(1H,
br.s), 3.95(1H, br.s), 4.95-5.10(2H, m), 6.62(1H, br.s), 7.00(1H,
br.s), 7.27-7.38(5H, m), 13.59(1H, br.s).
[2575] MS (ESI) m/z: 416(M+H).sup.+.
Referential Example 597
(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-(1,2,4-
-triazol-5-yl)cyclohexylcarbamic acid tert-butyl ester
##STR00667##
[2577] In a manner similar to that described in Referential Example
552, the compound obtained in Referential Example 596 was
deprotected. The deprotected compound was condensed with the
compound obtained in Referential Example 266, whereby the title
compound was obtained.
[2578] .sup.1H-NMR (DMSO-d.sub.6).delta.:1.39(9H, s), 1.50-2.03(5H,
m), 2.05-2.17(1H, m), 2.94-3.20(1H, m), 3.85-3.99(2H, m), 7.06(1H,
br.s), 7.80(0.5H, br.s), 8.03(1H, dd, J=8.8, 2.2 Hz), 8.06(1H, d,
J=8.8 Hz), 8.39(0.5H, s), 8.47(1H, d, J=2.2 Hz), 8.56-8.69(1H, m),
10.27(1H, s), 13.59-13.66(1H, m).
[2579] MS (ESI) m/z: 464(M+H).sup.+.
Referential Example 598
(1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-(1-methyl-1H-1,2,4-triazol-5-y-
l)cyclohexylcarbamic acid benzyl ester
##STR00668##
[2581] Methylhydrazine (56.9 .mu.L) was added to the compound (400
mg) obtained in Referential Example 595 in acetic acid (10 mL),
followed by stirring at room temperature overnight. The solvent was
distilled away under reduced pressure, and saturated aqueous
solution of sodium hydrogencarbonate and ethyl acetate were added
to the residue for partition. The organic layer was washed with
saturated brine, and dried over anhydrous magnesium sulfate. The
solvent was distilled away under reduced pressure. The residue was
purified by silica gel chromatography (methanol:methylene
chloride=1:19), to thereby give the title compound (224 mg).
[2582] .sup.1H-NMR (CDCl.sub.3).delta.:1.44(9H, s), 1.53-1.80(2H,
m), 1.88-2.18(4H, m), 2.77-2.89(1H, m), 3.71-3.83(1H, m), 3.86(3H,
s), 4.17(1H, br.s), 4.74(1H, br.s), 5.08(1H, d, J=12.2 Hz),
5.12(1H, d, J=12.2 Hz), 5.25-5.42(1H, m), 7.29-7.39(5H, m),
7.91(1H, s).
[2583] MS (ESI) m/z: 430(M+H).sup.+.
Referential Example 599
(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-(1-met-
hyl-1H-1,2,4-triazol-5-yl)cyclohexylcarbamic acid tert-butyl
ester
##STR00669##
[2585] In a manner similar to that described in Referential Example
552, the compound obtained in Referential Example 598 was
deprotected. The deprotected compound was condensed with the
compound obtained in Referential Example 266, whereby the title
compound was obtained.
[2586] .sup.1H-NMR (CDCl.sub.3).delta.:1.47(9H, s), 1.50-1.65(1H,
m), 1.72-1.87(1H, m), 1.95-2.22(4H, m), 2.81-2.94(1H, m), 3.87(3H,
s), 3.97-4.06(1H, m), 4.25(1H, br.s), 4.91(1H, d, J=8.8 Hz),
7.70(1H, dd, J=8.8, 2.4 Hz), 7.93(1H, s), 8.06(1H, br.s), 8.20(1H,
d, J=8.8 Hz), 8.31(1H, d, J=2.4 Hz), 9.74(1H, s).
[2587] MS (ESI) m/z: 478(M+H).sup.+.
Referential Example 600
(3R,4S)-4-[(benzyloxycarbonyl)amino]-3-[(tert-butoxycarbonyl)amino]piperid-
ine-1-carbamic acid 2-trimethylsilanylethyl ester
##STR00670##
[2589] 9% Aqueous sodium hydrogencarbonate (150 mL) was added to
the compound (5.98 g) obtained in Referential Example 212 in
dioxane (50 mL), and the mixture was cooled to 0.degree. C.
1-[(2-Trimethylsilyl)ethoxycarbonyloxy]pyrrolidine-2,5-dione (4.83
g) in dioxane (20 mL) was added thereto, followed by stirring at
room temperature for 20 hours. Ethyl acetate and water were added
to the reaction mixture, and the organic layer was washed with
saturated aqueous solution of sodium hydrogencarbonate, 10% aqueous
citric acid, and saturated aqueous sodium chloride, followed by
drying over sodium sulfate anhydrate. The solvent was distilled
away under reduced pressure, and the residue was purified by silica
gel column chromatography (hexane:ethyl acetate=4:1.fwdarw.2:1), to
thereby give the title compound (6.75 g).
[2590] .sup.1H-NMR (CDCl.sub.3).delta.:0.00(9H, s), 0.96(2H, t,
J=8.3 Hz), 1.36-1.53(1H, m), 1.41(9H, s), 1.82-2.00(1H, m),
2.85(1H, t, J=12.1 Hz), 3.01(1H, d, J=13.4 Hz), 3.66-3.81(1H, m),
3.87-4.25(5H, m), 4.63-4.81(1H, m), 5.06(2H, br.s), 5.22-5.69(1H,
br), 7.23-7.40(5H, m).
[2591] ESI-MS m/z: 394(M-Boc).sup.+.
Referential Example 601
(3R,4S)-4-([2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl)amino)-3-[(tert-bu-
toxycarbonyl)amino]piperidine-1-carbamic acid
2-trimethylsilanylethyl ester
##STR00671##
[2593] In a manner similar to that described in Referential Example
552, the compound obtained in Referential Example 600 was
deprotected. The deprotected compound was condensed with the
compound obtained in Referential Example 266, whereby the title
compound was obtained.
[2594] .sup.1H-NMR (CDCl.sub.3).delta.:0.05(9H, s), 0.84-0.92(2H,
m), 1.47(9H, s), 1.51-1.70(1H, m), 1.98(1H, d, J=11.2 Hz),
2.84-2.98(1H, m), 3.07(1H, d, J=13.9 Hz), 3.94-4.29(6H, m),
4.81-4.95(1H, br), 7.70(1H, d, J=9.0 Hz), 8.09-8.34(1H, br),
8.20(1H, d, J=9.0 Hz), 8.31(1H, s), 9.69(1H, s).
[2595] MS (ESI) m/z: 442(M-Boc).sup.+, 486(M-tBu).sup.+.
Referential Example 602
(3R,4S)-(4-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)piperidin-3-
-yl]carbamic acid tert-butyl ester
##STR00672##
[2597] To the compound (6.92 g) obtained in Referential
[2598] Example 601 in tetrahydrofuran (90 mL) was added 1.0 mmol/1
tetrabutylammonium fluoride in tetrahydrofuran (40 mL), followed by
stirring at room temperature for 5 days. Ethyl acetate and
saturated aqueous sodium chloride were added to the reaction
mixture. The aqueous layer was extracted with ethyl acetate and
methylene chloride. The organic layers were combined, and washed
with saturated aqueous solution of sodium hydrogencarbonate and
saturated aqueous sodium chloride, followed by drying over sodium
sulfate anhydrate. The solvent was distilled away under reduced
pressure, and the residue was purified by silica gel column
chromatography (methylene
chloride:methanol=30:1.fwdarw.20:1.fwdarw.10:1), to thereby give a
crude compound (7.96 g). Ethyl acetate was added to the crude
compound, and insoluble material was recovered by filtration, to
thereby give the title compound (466 mg). Water was added to the
filtrate, and the resultant mixture was extracted with ethyl
acetate and methylene chloride. The extract was washed with
saturated sodium chloride, followed by drying over sodium sulfate
anhydrate. The solvent was distilled away under reduced pressure,
to thereby give the title compound (4.86 g) in a mixture form
containing about 30% tetrabutylammonium fluoride.
[2599] .sup.1H-NMR (CDCl.sub.3).delta.:1.47(9H, s), 1.55-1.72(2H,
m), 1.84-1.99(1H, m), 2.71(1H, t, J=10.7 Hz), 2.85(1H, d, J=11.2
Hz), 3.03(2H, t, J=12.7 Hz), 3.85-3.98(1H, m), 3.98-4.09(1H, m),
5.40-5.71(1H, m), 7.70(1H, dd, J=8.8, 2.4 Hz), 8.13(1H, br.s),
8.21(1H, d, J=8.8 Hz), 8.31(1H, d, J=2.4 Hz), 9.75(1H, s).
[2600] MS (ESI) m/z: 398(M+H).sup.+.
Referential Example 603
(3R,4S)-[4-([2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-1-(thiazol-
-2-yl)piperidin-3-yl]carbamic acid tert-butyl ester
##STR00673##
[2602] The mixture-form product (401 mg) of Referential Example 602
containing the compound and tetrabutylammonium fluoride was
dissolved in toluene (4 mL). To the resultant solution were added
2-bromothiazole (115 .mu.L), sodium tert-butoxide (91 mg),
(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (65 mg), and
tris(dibenzylideneacetone)dipalladium(0) (28 mg), followed by
stirring under an argon atmosphere at 80.degree. C. for 3 days. The
reaction mixture was cooled, ethyl acetate was added thereto,
insoluble material was filtered off through celite, and saturated
aqueous sodium chloride was added to the filtrate, and the
resultant mixture was extracted with ethyl acetate. The organic
layers were combined, and washed with saturated aqueous sodium
chloride, followed by drying over sodium sulfate anhydrate and
evaporating the solvent under reduced pressure. The residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=2:1.fwdarw.1:1), to thereby give the title compound (169
mg).
[2603] .sup.1H-NMR (CDCl.sub.3).delta.:1.46(9H, s), 1.78-1.93(1H,
m), 2.07-2.18(1H, m), 3.05-3.19(1H, m), 3.27(1H, dd, J=13.2, 1.7
Hz), 3.98(1H, br.d, J=12.9 Hz), 4.04-4.15(2H, m), 4.18-4.29(1H,
br), 5.04-5.34(1H, m), 6.65(1H, d, J=3.7 Hz), 7.21(1H, d, J=3.7
Hz), 7.70(1H, dd, J=8.8, 2.4 Hz), 8.21(1H, d, J=8.8 Hz),
8.23-8.33(1H, br), 8.31(1H, d, J=2.4 Hz), 9.73(1H, br.s).
[2604] MS (ESI) m/z: 481(M+H).sup.+.
Example 1
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclopropyl)-5-methyl--
4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00674##
[2606] 1-Hydroxybenzotriazole monohydrate (71 mg) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100
mg) were added to a solution with the compound (108 mg) obtained in
Referential Example 59 and the compound (124 mg) obtained in
Referential Example 10 dissolved in N,N-dimethylformamide (3 mL) at
room temperature, and the mixture was stirred for 8 days. After
concentrating the reaction mixture under reduced pressure using a
vacuum pump, water (50 mL), and saturated aqueous sodium
hydrogencarbonate (50 mL) were added to the residue, and the
mixture was extracted with methylene chloride. The resultant
organic layers were combined and dried over sodium sulfate
anhydrate, the solvent was distilled away under reduced pressure,
and the residue was purified by silica gel thin layer
chromatography (methylene chloride:methanol=10:1). After 1N
hydrochloric acid, methylene chloride and methanol were added to
the thus-obtained amorphous substance, the mixture was concentrated
to give the title compound (72 mg).
[2607] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.15-1.35(2H,m),
2.88(3H,s), 2.95-3.25(4H,m), 3.35-3.75(2H,m), 4.32-4.45(1H,m),
4.68(1H,br,J=15.4 Hz), 7.08(1H,s), 7.17(1H,dd,J=8.6,2.1 Hz),
7.41(1H,d,J=8.6 Hz), 7.70(1H,s), 8.50(1H,br,J=11.0 Hz),
8.56(1H,br.s), 11.56(1H,br,J=19.3 Hz), 11.86(1H,s).
[2608] MS (FAB) m/z: 430(M+H).sup.+.
Example 2
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclobutyl)-5-methyl--
4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxamide
hydrochloride
##STR00675##
[2610] The compound (136 mg) obtained in Referential Example 10,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (255
mg) and 1-hydroxybenzotriazole monohydrate (90 mg) were added to a
solution with the compound (117 mg) obtained in Referential Example
60 dissolved in N,N-dimethylformamide (5 mL), and the mixture was
stirred overnight at room temperature. The solvent was then
distilled away under reduced pressure using a vacuum pump, and the
residue was partitioned between methylene chloride and saturated
aqueous sodium hydrogencarbonate. The resultant organic layer was
washed with saturated brine and dried over sodium sulfate
anhydrate, the solvent was distilled away under reduced pressure,
and the residue was purified by silica gel column chromatography
(methanol:methylene chloride=7:93). After ethyl acetate and 1N HCl
in ethanol were added to the thus-obtained compound for
acidification, and the solvent was distilled away under reduced
pressure. Ethyl acetate was added again, and the precipitate formed
was collected by filtration and dried to give the title compound
(56 mg).
[2611] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.00-2.35(4H,m),
2.88(3H,s), 3.10(2H,br.s), 3.20-3.75(3H,m), 4.20-4.85(3H,m),
7.09(1H,s), 7.16(1H,d,J=8.8 Hz), 7.38(1H,d,J=8.8 Hz), 7.71(1H,s),
8.63(1H,d,J=8.3 Hz), 8.85(1H,d,J=8.6 Hz), 10.85-11.20(1H,br),
11.81(1H,s).
[2612] MS (FAB) m/z: 444(M+H).sup.+.
Example 3
N-((1R*,2R*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclopentyl)-5-methyl-
-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxamide
hydrochloride
##STR00676##
[2614] 5-Chloroindole-2-carboxylic acid (80 mg),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (98
mg), 1-hydroxybenzotriazole monohydrate (23 mg) and triethylamine
(141 .mu.l) were added to a solution with the compound (120 mg)
obtained in Referential Example 62 dissolved in
N,N-dimethylformamide (5 mL), and the mixture was stirred at room
temperature for 3 days. The solvent was distilled away under
reduced pressure, and methylene chloride and saturated aqueous
sodium hydrogencarbonate were added to the residue for partitioning
the mixture. The resultant organic layer was dried over sodium
sulfate anhydrate, the solvent was distilled away under reduced
pressure, and the residue was purified by silica gel column
chromatography (methylene chloride:methanol=93:7). After methylene
chloride (5 mL) and 1N HCl in ethanol (282 .mu.l) were added to the
thus-obtained pale yellow solid, ethyl acetate was added. The
solvent was distilled away under reduced pressure, and the
precipitate formed was collected by filtration to give the title
compound (109 mg).
[2615] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.64-1.74(4H,m),
1.98-2.02(2H,m), 2.89(3H,s), 3.14(2H,br.s), 3.47-3.65(2H,m),
4.29-4.63(4H,m), 7.10(1H,d,J=1.5 Hz), 7.14(1H,dd,J=8.5,2.0 Hz),
7.38(1H,d,J=8.5 Hz), 7.68(1H,d,J=2.0 Hz), 8.55(1H,d,J=8.5 Hz),
8.91(1H,d,J=8.5 Hz), 11.49(1H,br.s), 11.76(1H,s).
[2616] MS (ESI) m/z: 458(M+H).sup.+.
Example 4
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)sulfonyl]amino}-cyclohexyl)-5-methyl--
4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxamide
hydrochloride
##STR00677##
[2618] The compound (400 mg) obtained in Referential Example 67 was
suspended in methylene chloride (10 mL), triethylamine (0.514 mL)
and 5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (Japanese
Patent Application Laid-Open (kokai) No. 2000-119253) (319 mg) were
added, and the mixture was stirred at room temperature for 15
minutes. After water was added to the reaction mixture for
partitioning the mixture, the resultant organic layer was dried
over sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure, and the residue was purified by silica gel column
chromatography (methylene chloride:methanol=100:3) to give a pale
yellow foamy substance. This substance was dissolved in
tetrahydrofuran (3 mL), and methanol (2 mL) and 1N aqueous sodium
hydroxide (1.5 mL) were added. The mixture was heated under reflux
for 2 hours. The reaction mixture was concentrated under reduced
pressure, and methylene chloride and 1N hydrochloric acid were
added to the residue for partitioning the mixture. After the
resultant organic layer was dried over sodium sulfate anhydrate,
the solvent was distilled away under reduced pressure, and the
residue was purified by silica gel column chromatography (methylene
chloride:methanol=100:3). 1N Hydrochloric acid (1 mL) was added to
the resultant product, and the mixture was concentrated under
reduced pressure to give the title compound (108 mg).
[2619] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.20-1.78(8H,m),
2.94(3H,s), 3.13(2H,br.s), 3.22-3.40(1H,m), 3.44-3.70(3H,m),
3.83-3.95(1H,m), 4.20-4.70(1H,m), 6.78(1H,s), 7.18-7.30(2H,m),
7.44(1H,s), 7.69(1H,br.s), 8.09(1H,br.s), 11.92(1H,s).
[2620] MS (FAB) m/z: 508(M+H).sup.+.
Example 5
N-((1R*,2R*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclohexyl)-5-methyl--
4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxamide
hydrochloride
##STR00678##
[2622] 5-Chloroindole-2-carboxylic acid (109 mg),
1-hydroxybenzotriazole monohydrate (9 mg),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (321
mg) and triethylamine (0.232 mL) were added to a solution with the
compound (300 mg) obtained in Referential Example 65 dissolved in
N,N-dimethylformamide (20 mL), and the mixture was stirred
overnight at room temperature. The reaction mixture was
concentrated under reduced pressure using a vacuum pump, and
methylene chloride and water were added to the residue for
partitioning the mixture. The resultant organic layer was dried
over sodium sulfate anhydrate, the solvent was distilled away under
reduced pressure, and the residue was purified by silica gel column
chromatography (methylene chloride:methanol=25:1) to give a
colorless foamy substance. This substance was suspended in 1N
hydrochloric acid (1 mL), and the suspension was concentrated under
reduced pressure to give the title compound (203 mg).
[2623] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.25-1.40(2H,m),
1.46-1.81(4H,m), 1.88-1.98(2H,m), 2.89(3H,s), 3.00-3.76(5H,m),
3.86-3.97(1H,m), 4.00-4.10(1H,m), 4.25-4.72(1H,m), 7.03(1H,s),
7.12(1H,dd,J=8.5,1.2 Hz), 7.38(1H,d,J=8.5 Hz), 7.64(1H,s),
8.28(1H,d,J=8.5 Hz), 8.54(1H,d,J=8.5 Hz), 11.70(1H,s).
[2624] MS (FAB) m/z: 472(M+H).sup.+.
Example 6
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino]-cyclohexyl)-5-methyl--
4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00679##
[2626] The title compound was obtained from the compound obtained
in Referential Example 67 and 5-chloroindole-2-carboxylic acid in a
similar manner to Example 5.
[2627] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35-1.70(6H,m),
1.80-2.06(2H,m), 2.89(3H,s), 3.00-3.27(2H,m), 3.35-3.51(1H,m),
3.57-3.82(1H,m), 4.15-4.30(2H,m), 4.32-4.48(1H,m), 4.60-4.74(1H,m),
7.15(1H,s), 7.17(1H,dd,J=8.8,2.0 Hz), 7.41(1H,d,J=8.6 Hz),
7.70(1H,d,J=2.0 Hz), 8.14(1H,br.s), 8.36-8.48(1H,m),
11.51(1H,br.s), 11.86(1H,s).
[2628] MS (FAB) m/z: 472(M+H).sup.+.
Example 7
N-{(1R*,2S*)-2-[(6-Chloro-2-naphthoyl)amino]cyclohexyl}-5-methyl-4,5,6,7-t-
etrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride
##STR00680##
[2630] In a manner similar to that employed in Example 5, the title
compound was produced. The compound (275 mg) obtained in
Referential Example 67, 6-chloronaphthalene-2-carboxylic acid (Eur.
J. Chem. Chim. Ther., 1984, Vol. 19, pp. 205-214) (148 mg),
triethylamine (0.298 mL), and 1-hydroxybenzotriazole monohydrate
(11 mg) were dissolved in N,N-dimethylformamide (20 mL). To the
resultant solution, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (412 mg) was added, and the mixture was allowed to
react, to thereby give the title compound (186 mg).
[2631] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.40-1.56(2H,m),
1.57-1.77(4H,m), 1.90-2.10(2H,m), 2.90(3H,s), 3.13(2H,br.s),
3.28-3.74(2H,m), 4.26(2H,br.s), 4.30-4.74(2H,m), 7.59(1H,d,J=8.6
Hz), 7.90(1H,d,J=8.6 Hz), 7.98(1H,d,J=8.3 Hz), 8.03-8.11(2H,m),
8.25-8.58(3H,m), 11.52(1H,br.s).
[2632] MS (FAB) m/z: 483(M+H).sup.+.
Example 8
N-((1R*,2R*)-2-{[(6-Chloro-1-benzothiophen-2-yl)carbonyl]amino}cyclohexyl)-
-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00681##
[2634] In a manner similar to that employed in Example 5, the title
compound was produced. The compound (255 mg) obtained in
Referential Example 65, 6-chlorobenzo[b]thiophene-2-carboxylic acid
(Japanese Patent Application Laid-Open (kokai) No. 2000-119253)
(141 mg), triethylamine (0.276 mL), and 1-hydroxybenzotriazole
monohydrate (10 mg) were dissolved in N,N-dimethylformamide (20
mL). To the resultant solution,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (382
mg) was added, and the mixture was allowed to react, to thereby
give the title compound (239 mg).
[2635] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.20-1.98(8H,m), 2.88
(3H, s), 3.00-3.72(4H,m), 3.84-4.09(2H,m), 4.20-4.75(2H,m),
7.41(1H,dd,J=8.6,1.7 Hz), 7.91(1H,d,J=8.6 Hz), 7.99(1H,s),
8.12(1H,s), 8.54-8.67(2H,m), 11.53(1H,br.s).
[2636] MS (FAB) m/z: 489(M+H).sup.+.
Example 9
N-((1R*,2R*)-2-{[(5-Fluoroindol-2-yl)carbonyl]amino}-cyclohexyl)-5-methyl--
4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxamide
hydrochloride
##STR00682##
[2638] The title compound was obtained from the compound obtained
in Referential Example 65 and 5-fluoroindole-2-carboxylic acid in a
similar manner to Example 5.
[2639] .sup.1H-NMR (DMSO-d.sub.6) 1.20-1.38(2H,m), 1.40-1.57(1H,m),
1.54-1.68(1H,m), 1.71(2H,d,J=7.3 Hz), 1.88(2H,d,J=12.0 Hz),
2.86(3H,s), 2.95-3.24(2H,m), 3.40(1H,br.s), 3.63(1H,br.s),
3.90(1H,br.s), 3.97-4.10(1H,m), 4.20-4.44(1H,m), 4.53-4.70(1H,m),
6.98(1H,dd,J=9.2,2.3 Hz), 7.01(1H,s), 7.31-7.39(2H,m),
8.26(1H,d,J=8.6 Hz), 8.59(1H,d,J=8.4 Hz), 11.21(1/2H,br.s),
11.42(1/2H,br.s), 11.60(1H,s).
[2640] MS (ESI) m/z: 456(M+H).sup.+.
Example 10
N-((1R*,2R*)-2-{[(5-Chloro-6-fluoroindol-2-yl)carbonyl]-amino}cyclohexyl)--
5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00683##
[2642] The title compound was obtained from the compound obtained
in Referential Example 65 and the compound obtained in Referential
Example 23 in a similar manner to Example 5.
[2643] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.20-1.40(2H,m),
1.40-1.80(4H,m), 1.80-2.00(2H,m), 2.87(3H,s), 3.01(2H,br.s),
3.30-3.80(2H,m), 3.81-3.97(2H,m), 4.20-4.80(2H,m), 7.06(1H,s),
7.28(1H,d,J=10.0 Hz), 7.86(1H,d,J=7.3 Hz), 8.32(1H,d,J=8.5 Hz),
8.59(1H,d,J=8.5 Hz), 11.77(1H,s).
[2644] MS (FAB) m/z: 490(M+H).sup.+.
Example 11
N-((1R*,2S*)-2-{[(5-Bromoindol-2-yl)carbonyl]amino}-cyclohexyl)-5-methyl-4-
,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxamide
hydrochloride
##STR00684##
[2646] The title compound was obtained from the compound obtained
in Referential Example 67 and 5-bromoindole-2-carboxylic acid in a
similar manner to Example 5.
[2647] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.43(2H,br.s),
1.61(4H,br.s), 1.80-2.10(2H,m), 2.88(3H,s), 3.00-3.26(2H,m),
3.40(1H,br.s), 3.65(1H,br.s), 4.22(1H,br.s), 4.26(1H,br.s),
4.41(1H,br.s), 4.67(1H,d,J=15.6 Hz), 7.14(1H,s), 7.28(1H,d,J=8.7
Hz), 7.37(1H,d,J=8.7 Hz), 7.84(1H,s), 8.13(1H,br.s),
8.33-8.52(1H,m), 11.51(1H,br.s), 11.86(1H,s).
[2648] MS (ESI) m/z: 515(M.sup.+).
Example 12
N-((1R*,2S*)-2-{[(5-Ethynylindol-2-yl)carbonyl]amino}-cyclohexyl)-5-methyl-
-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxamide
hydrochloride
##STR00685##
[2650] Triethylamine (6 mL), N,N-dimethylformamide (5 mL),
trimethylsilylacetylene (0.250 mL) and palladium acetate (20 mg)
were added to a tetrahydrofuran solution (2 mL) of the compound
(300 mg) obtained in Example 11 and triphenylphosphine (70 mg) at
room temperature. After stirring at 90.degree. C. for 2 hours, the
reaction mixture was allowed to cool to room temperature, and
methylene chloride (20 mL) and saturated aqueous sodium
hydrogencarbonate (30 mL) were added for partitioning the mixture.
The resultant aqueous layer was extracted with methylene chloride
(3.times.10 mL), the organic layers were combined and dried over
sodium sulfate anhydrate, and the solvent was distilled away under
reduced pressure to give residue. The resultant residue was
purified by silica gel thin layer chromatography (methylene
chloride:acetone:methanol=10:10:1) to give colorless solids. This
product was dissolved in methanol (6 mL), potassium carbonate (120
mg) was added thereto, and the mixture was stirred for 1 hour.
Methylene chloride (20 mL) and water (20 mL) were added to the
reaction mixture for partitioning the mixture. The resultant
aqueous layer was extracted with methylene chloride (2.times.15
mL), the organic layers were combined and dried over sodium sulfate
anhydrate, and the solvent was distilled away under reduced
pressure. The residue was purified by silica gel thin layer
chromatography (methylene chloride:acetone:methanol=10:10:1) and
dissolved in water-methanol-methylene chloride. The resultant
solution was then concentrated to give the title compound (72
mg).
[2651] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50-2.25(8H,m),
2.53(3H,s), 2.85(2H,br.s), 2.93(2H,br.s), 3.01(1H,s),
3.74(1H,d,J=14.1 Hz), 3.77(1H,d,J=14.1 Hz), 4.21(1H,br.s),
4.45(1H,br.s), 6.91(1H,s), 7.25-7.42(2H,m), 7.61(1H,br.s),
7.80-7.97(2H,m), 9.72(1H,s).
[2652] MS (FAB) m/z: 462(M+H).sup.+.
Example 13
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclohexyl)-5,6-dimet-
hyl-4,5,6,7-tetrahydrothiazolo[4,5-d]-pyridazine-2-carboxamide
hydrochloride
##STR00686##
[2654] The title compound was obtained from the compound obtained
in Referential Example 71 and the compound obtained in Referential
Example 51 in a similar manner to Example 2.
[2655] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35-1.50(2H,m),
1.50-1.75(4H,m), 1.80-2.10(2H,m), 2.70(3H,br.s), 2.79(3H,br.s),
4.10-4.70(6H,m), 7.10-7.27(2H,m), 7.41(1H,d,J=8.8 Hz), 7.70(1H,s),
8.12(1H,d,J=6.8 Hz), 8.47(1H,d,J=7.6 Hz), 11.85(1H,s).
[2656] MS (FAB) m/z: 487(M+H).sup.+.
Example 14
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclohexyl)-6,7-dihyd-
ro-4H-pyrano[4,3-d]thiazole-2-carboxamide
##STR00687##
[2658] The title compound was obtained from the compound obtained
in Referential Example 71 and the compound obtained in Referential
Example 26 in a similar manner to Example 2.
[2659] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.36-1.72(6H,m),
1.90-2.10(2H,m), 2.80-2.87(2H,m), 3.93(2H,t,J=5.6 Hz),
4.20-4.32(2H,m), 4.81(2H,s), 7.12(1H,s), 7.15 (1H, dd, J=8.8,2.0
Hz), 7.41(1H,d,J=8.8 Hz), 7.67(1H,d,J=1.7 Hz), 8.11(1H,d,J=6.6 Hz),
8.36(1H,d,J=8.3 Hz), 11.78(1H,s).
[2660] MS (FAB) m/z: 459(M+H).sup.+.
Example 15
N-((1R*,2S*)-2-([(5-Chloroindol-2-yl)carbonyl]amino}-cyclohexyl)-5-methyl--
4,5,6,7-tetrahydrothiazolo[4,5-c]-pyridine-2-carboxamide
hydrochloride
##STR00688##
[2662] The title compound was obtained from the compound obtained
in Referential Example 71 and the compound obtained in Referential
Example 29 in a similar manner to Example 2.
[2663] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.32-1.74(6H,m),
1.82-2.10(2H,m), 2.92(3H,s), 3.12-3.50(3H,m), 3.69(1H,br.s),
4.13-4.39(3H,m), 4.51(1H,br.s), 7.10-7.19(2H,m), 7.41(1H,d,J=8.6
Hz), 7.68(1H,s), 8.10(1H,br.s), 8.40(1H,br.s), 11.41(1H,br.s),
11.87(1H,s).
[2664] MS (FAB) m/z: 472(M+H).sup.+.
Example 16
N-((1R*,2R*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino)-cyclohexyl)-5-methyl--
4,5,6,7-tetrahydrooxazolo[5,4-c]-pyridine-2-carboxamide
hydrochloride
##STR00689##
[2666] The title compound was obtained from the compound obtained
in Referential Example 69 and the compound obtained in Referential
Example 21 in a similar manner to Example 2.
[2667] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.23-1.39(2H,m),
1.40-1.81(4H,m), 1.82-1.98(2H,m), 2.60-3.00(5H,m), 3.20-3.70(2H,m),
3.87-3.96(1H,m), 3.98-4.10(1H,m), 4.12-4.70(2H,m), 7.04(1H,d,J=1.5
Hz), 7.12(1H,dd,J=8.8,2.0 Hz), 7.38(1H,d,J=8.8 Hz), 7.65(1H,d,J=2.0
Hz), 8.33(1H,d,J=8.6 Hz), 8.72(1H,d,J=8.6 Hz), 11.61(1H,br.s),
11.72(1H,s).
[2668] MS (FAB) m/z: 456(M+H).sup.+.
Example 17
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclohexyl)-4,5,6,7-t-
etrahydrothieno[3,2-c]pyridine-2-carboxamide hydrochloride
##STR00690##
[2670] In a manner similar to that employed in Example 2, the title
compound was produced. The compound obtained in Referential Example
71 was condensed with
5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-carboxyl-
ic acid (WO94/21599), followed by treatment with hydrochloric acid
for deprotection, to thereby give the title compound.
[2671] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.42(2H,br.s),
1.56-1.76(4H,m), 1.98-2.11(2H,m), 3.04(2H,br.s), 3.32-3.45(2H,m),
4.15(3H,br.s), 4.26(1H,br.s), 7.14(1H,dd,J=8.8,2.0 Hz), 7.23(1H,s),
7.41(1H,d,J=8.8 Hz), 7.62(1H,s), 7.77(1H,s), 8.18-8.30(2H,m),
9.42(2H,br.s), 11.92(1H,s).
[2672] MS (FAB) m/z: 457(M+H).sup.+.
Example 18
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclohexyl)-5-methyl--
4,5,6,7-tetrahydrothieno[3,2-c]-pyridine-2-carboxamide
hydrochloride
##STR00691##
[2674] The compound (171 mg) obtained in Example 17 was suspended
in methylene chloride (10 mL), and triethylamine (0.104 mL) was
added, followed by stirring at room temperature for 10 minutes.
After acetic acid (0.059 mL) was added to the reaction mixture, a
35% formalin (0.070 mL) and sodium triacetoxyborohydride (118 mg)
were added, and the mixture was stirred at room temperature for 30
minutes. After 1N aqueous sodium hydroxide (3 mL) was added to the
reaction mixture, water was added for partitioning the mixture.
After the resultant organic layer was dried over sodium sulfate
anhydrate, the solvent was then distilled away under reduced
pressure, and the residue was purified by silica gel column
chromatography (methylene chloride:methanol=50:3) to give a
colorless foamy substance. This substance was suspended in 1N
hydrochloric acid, and the suspension was concentrated under
reduced pressure to give the title compound (85 mg).
[2675] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.40(2H,br.s),
1.50-1.71(4H,m), 1.97-2.05(2H,m), 2.87(3H,s), 2.98-3.20(1H,m),
3.30-3.38(2H,m), 3.54-3.70(1H,m), 4.05-4.42(4H,m), 7.14(1H,d,J=8.6
Hz), 7.23(1H,s), 7.40(1H,d,J=8.6 Hz), 7.63(1H,s), 7.77(1H,s),
8.17-8.27(2H,m), 10.83(1H,br.s), 11.92(1H,s).
[2676] MS (FAB) m/z: 471(M+H).sup.+.
Example 19
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclohexyl)-6-(dimeth-
ylamino)-4,5,6,7-tetrahydrobenzothiazole-2-carboxamide
hydrochloride
##STR00692##
[2678] The title compound was obtained from the compound obtained
in Referential Example 71 and the compound obtained in Referential
Example 31 in a similar manner to Example 2.
[2679] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.44(2H,br.s),
1.52-1.68(4H,m), 1.87-2.08(3H,m), 2.30-2.40(1H,m), 2.65-2.75(1H,m),
2.77(6H,s), 2.95-3.17(2H,m), 3.30-3.70(2H,m), 4.15-4.30(2H,m),
7.10-7.20(2H,m), 7.41(1H,d,J=8.6 Hz), 7.69(1H,s), 8.11(1H,d,J=5.1
Hz), 8.34(1H,d,J=8.1 Hz), 10.95(1H,br.s), 11.83(1H,s).
[2680] MS (FAB) m/z: 500(M+H).sup.+.
Example 20
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclohexyl)-5-(pyridi-
n-4-yl)-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00693##
[2682] After n-butyllithium (1.60N hexane solution, 0.704 mL) was
added dropwise to a solution of the compound (204 mg) obtained in
Referential Example 24 in tetrahydrofuran (3 mL) at -78.degree. C.,
the mixture was stirred at 0.degree. C. for 30 minutes. After the
reaction mixture was cooled to -78.degree. C. again, it was warmed
to room temperature in 20 minutes while blowing carbon dioxide, and
the reaction mixture was concentrated under reduced pressure. The
compound (400 mg) obtained in Referential Example 71,
1-hydroxy-benzotriazole monohydrate (254 mg),
1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (360
mg) and diisopropylamine (0.491 mL) were added to a solution of the
resultant residue in N,N-dimethylformamide (6 mL) at room
temperature. After stirring for 3 days, the reaction mixture was
concentrated under reduced pressure, and methylene chloride (30
mL), saturated aqueous sodium hydrogencarbonate (100 mL), and water
(100 mL) were added to the residue for partitioning the mixture.
The resultant aqueous layer was extracted with methylene chloride
(4.times.15 mL), the organic layers were combined and dried over
sodium sulfate anhydrate, and the solvent was distilled away under
reduced pressure. The resultant residue was purified by silica gel
column chromatography (methylene
chloride:methanol=20:1.fwdarw.10:1). The purified product was
dissolved in 1N hydrochloric acid-methanol-methylene chloride. The
resultant solution was then concentrated to give the title compound
(245 mg).
[2683] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.42(2H,br.s),
1.60(4H,br.s), 1.84-1.94(1H,m), 1.94-2.08(1H,m), 2.97(2H,br.s),
3.97-4.13(2H,m), 4.19(1H,br.s), 4.27(1H,br.s), 5.03(2H,s),
7.13(1H,br.s), 7.16(1H,dd,J=8.8,2.0 Hz), 7.32(2H,br.s),
7.40(1H,d,J=8.8 Hz), 7.68(1H,d,J=2.0 Hz), 8.15(1H,br,J=7.3 Hz),
8.31(2H,d,J=5.9 Hz), 8.39(1H,d,J=8.1 Hz), 11.90(1H,s),
14.03(1H,br.s).
[2684] MS (ESI) m/z: 535(M+H).sup.+.
Example 21
N-((1R*,2R*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cycloheptyl)-5-methyl-
-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxamide
hydrochloride
##STR00694##
[2686] The title compound was obtained from the compound obtained
in Referential Example 74 and the compound obtained in Referential
Example 10 in a similar manner to Example 2.
[2687] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.51-1.55(4H,m),
1.75-1.80(6H,m), 2.88(3H,s), 3.12(1H,br.s), 3.35-3.63(4H,m),
4.10-4.13(1H,m), 4.29-4.61(2H,m), 7.06(1H,s), 7.14(1H,dd,J=8.8,2.0
Hz), 7.39(1H,d,J=8.8 Hz), 7.67(1H,d,J=2.0 Hz), 8.46(1H,d,J=8.3 Hz),
8.77(1H,d,J=8.3 Hz), 11.21-11.35(1H,m), 11.71(1H,s).
[2688] MS (ESI) m/z: 486(M+H).sup.+.
Example 22
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclooctyl)-5-methyl--
4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxamide
hydrochloride
##STR00695##
[2690] The title compound was obtained from the compound obtained
in Referential Example 78 and the compound obtained in Referential
Example 10 in a similar manner to Example 2.
[2691] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.61-2.06(12H,m),
2.90(3H,s), 3.08-3.17(2H,m), 3.43-3.45(1H,m), 3.67(1H,br.s),
4.43(3H,br.s), 4.67(1H,br.s), 7.16-7.18(2H,m), 7.42(1H,d,J=8.8 Hz),
7.70(1H,s), 8.24(1H,br.s), 8.58(1H,d,J=8.3 Hz), 11.43,11.63(1H,each
br.s), 11.80(1H,s).
[2692] MS (ESI) m/z: 500(M+H).sup.+.
Example 23
N-((1R*,2R*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclopentyl)-4,5,6,7--
tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride
##STR00696##
[2694] In a manner similar to that employed in Example 2, a product
obtained through reaction between the compound obtained in
Referential Example 63 and the compound obtained in Referential
Example 34 was treated with hydrochloric acid, to thereby give the
title compound.
[2695] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.60-1.82(4H,m),
1.91-2.15(2H,m), 3.08(2H,s), 3.37-3.49(2H,m), 4.28-4.56(4H,m),
7.13(1H,s), 7.15(1H,d,J=8.8 Hz), 7.40(1H,d,J=8.8 Hz), 7.69(1H,s),
8.61(1H,d,J=8.3 Hz), 8.88(1H,d,J=8.3 Hz), 10.05(2H,br.s),
11.82(1H,s).
[2696] MS (FAB) m/z: 444(M+H).sup.+.
Example 24
N-((1R*,2R*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclopentyl)-5-isopro-
pyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00697##
[2698] The compound (30 mg) obtained in Example 23 was suspended in
methylene chloride (20 mL), and triethylamine (260 .mu.l) was
added, followed by stirring at room temperature for 15 minutes.
Acetic acid (179 .mu.l) and acetone (920 .mu.l) were added to the
reaction mixture, and the resultant mixture was stirred at room
temperature for 2 minutes. Sodium triacetoxyborohydride (796 mg)
was added to the reaction mixture to stir them at room temperature
for 5 hours. 1N aqueous sodium hydroxide (10 mL) was added to the
reaction mixture for partitioning the mixture. The resultant
organic layer was dried over sodium sulfate anhydrate, and the
solvent was distilled away under reduced pressure. The residue was
purified by silica gel column chromatography (methylene
chloride:methanol=100:3) to give a colorless foamy substance. This
product was dissolved in methylene chloride, and 1N HCl in ethanol
(1 mL) was added. The solution was concentrated under reduced
pressure to give the title compound (205 mg).
[2699] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.27-1.39(6H,m),
1.58-1.80(4H,m), 1.95-2.10(2H,m), 3.00-3.12(1H,m), 3.25-3.45(2H,m),
3.59-3.77(2H,m), 4.25-4.39(1H,m), 4.40-4.55(2H,m), 4.57-4.65(1H,m),
7.10(1H,s), 7.14(1H,d,J=8.8 Hz), 7.38(1H,d,J=8.8 Hz), 7.68(1H,s),
8.56(1H,d,J=8.8 Hz), 8.90(1H,d,J=8.8 Hz), 11.39(1H,br.s),
11.76(0.5H,s), 11.80(0.5H,s).
[2700] MS (FAB) m/z: 486(M+H).sup.+.
Example 25
N-((1R*,2R*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclopentyl)-5-ethyl--
4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxamide
hydrochloride
##STR00698##
[2702] The compound (500 mg) obtained in Example 23 was dissolved
in N,N-dimethylformamide (10 mL), and triethylamine (576 .mu.l) and
ethyl iodide (329 .mu.l) were added, followed by stirring overnight
at room temperature. The reaction mixture was concentrated under
reduced pressure, and water was added to the residue to collect
insoluble matter by filtration. This product was purified by silica
gel column chromatography (methylene chloride:methanol=100:3) to
give a pale brown foamy substance. This substance was suspended in
1N hydrochloric acid (2 mL), and the suspension was concentrated
under reduced pressure to give the title compound (180 mg).
[2703] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.32(3H,t,J=7.1 Hz),
1.60-1.80(4H,m), 1.96-2.10(2H,m), 3.20-3.39(5H,m), 3.70-3.80(1H,m),
4.26-4.58(3H,m), 4.68-4.79(1H,m), 7.11(1H,s), 7.15(1H,dd,J=8.8,2.0
Hz), 7.39(1H,d,J=8.8 Hz), 7.69(1H,d,J=1.5 Hz), 8.55(1H,d,J=8.5 Hz),
8.92(1H,d,J=8.5 Hz), 11.38(1H,br.s), 11.70-11.80(1H,m).
[2704] MS (FAB) m/z: 472(M+H).sup.+.
Example 26
N-((1R*,2R*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclopentyl)-5-(1-met-
hylcyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00699##
[2706] The title compound was obtained from the compound obtained
in Referential Example 63 and the compound obtained in Referential
Example 39 in a similar manner to Example 2.
[2707] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.81(2H,br.s),
1.20-1.55(5H,br), 1.55-1.80(4H,m), 1.95-2.12(2H,m),
3.05-3.40(2H,br), 3.60-3.80(2H,br), 4.25-4.80(4H,m), 7.10(1H,s),
7.16(1H,d,J=8.8 Hz), 7.39(1H,d,J=8.8 Hz), 7.69(1H,s),
8.53(1H,d,J=8.6 Hz), 8.85-8.95(1H,m), 10.60-10.90(1H,br),
11.73(1H,br.s).
[2708] MS (FAB) m/z: 498(M+H).sup.+.
Example 27
N-((1R*,2R*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-4-methoxycyclopentyl)-
-5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide
hydrochloride (Stereoisomer A and Stereoisomer B)
##STR00700##
[2710] A mixture of the title compounds; i.e., Stereoisomer A and
Stereoisomer B, was synthesized by condensing the compound (mixture
of 4-position stereoisomers) (268 mg) obtained in Referential
Example 82 with the compound obtained in Referential Example 10 in
a similar manner to Example 2. The isomers were isolated by silica
gel column chromatography and then converted into hydrochlorides to
give the title compounds [Stereoisomer A (75 mg) and Stereoisomer B
(70 mg)].
Stereoisomer A:
[2711] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.70-2.15(4H,m),
2.90(3H,s), 3.00-3.90(8H,m), 4.10-4.80(4H,m), 7.08(1H,s),
7.16(1H,d,J=8.8 Hz), 7.38(1H,d,J=8.8 Hz), 7.69(1H,s),
8.56(1H,d,J=8.8 Hz), 8.88(1H,d,J=8.3 Hz), 10.96(1H,br.s),
11.75(1H,br.s).
[2712] MS (FAB) m/z: 488(M+H).sup.+.
Stereoisomer B:
[2713] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.60-2.10(4H,m),
2.89(3H,s), 3.00-3.70(7H,m), 3.70-3.90(1H,m), 4.20-4.80(4H,m),
7.05-7.20(2H,m), 7.38(1H,d,J=8.8 Hz), 7.68(1H,s), 8.59(1H,d,J=8.3
Hz), 8.90(1H,d,J=8.5 Hz), 11.26(1H,br.s), 11.74(1H,br.s).
[2714] MS (FAB) m/z: 488(M+H).sup.+.
Example 28
N-((1R*,2R*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-4-(hydroxymethyl)cycl-
opentyl]-5-(1,1-dimethyl-2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]-
pyridine-2-carboxamide hydrochloride (Stereoisomer A)
##STR00701##
[2716] 1) Stereoisomers A and B of
N-((1R*,2R*)-4-[(benzyloxy)methyl]-2-{(5-chloroindol-2-yl)carbonyl}amino)-
cyclopentyl)-5-(2-{[tert-butyl(diphenyl)silyl]oxy}-1,1-dimethylethyl)-4,5,-
6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide were obtained
from the compound obtained in Referential Example 85 and the
compound obtained in Referential Example 42 in a similar manner to
Example 2.
Stereoisomer A:
[2717] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.05(9H,s), 1.168,
1.171(6H,each s), 1.53-1.61(1H,m), 1.76-1.88(1H,m),
2.30-2.37(2H,m), 2.78-2.79(2H,m), 2.87-2.90(1H,m), 2.96-3.00(1H,m),
3.37-3.47(2H,m), 3.58(2H,s), 3.96(1H,q,J=13.1 Hz), 4.41-4.45(1H,m),
4.51-4.57(2H,m), 6.88(1H,d,J=1.5 Hz), 7.17(1H,dd,J=8.8,2.0 Hz),
7.23-7.43 (12H,m), 7.52(1H,d,J=7.6 Hz), 9.37(1H,br.s).
Stereoisomer B:
[2718] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.05(9H,s), 1.17(6H,s),
1.43-1.47(1H,m), 1.85-1.88(1H,m), 2.09-2.14(1H,m), 2.58-2.63(1H,m),
2.78-2.79(2H,m), 2.86-2.90(1H,m), 2.96-3.00(1H,m), 3.38-3.46(2H,m),
3.59(2H,s), 3.95(1H,q,J=13.3 Hz), 4.15-4.20 (1H, m),
4.45-4.56(3H,m), 6.74(1H,d,J=2.0 Hz), 7.16(1H,dd,J=8.8,2.0 Hz),
7.27-7.43(12H,m), 7.57(1H,d,J=2.0 Hz), 9.48(1H,br.s). [2719] 2) The
above Stereoisomer A (288 mg) was suspended in methylene chloride
(20 mL), and dimethyl sulfide (1.15 mL) and anhydrous aluminum
chloride (350 mg) were added, followed by stirring at room
temperature for 1 hour. 1N aqueous sodium hydroxide (10 mL) was
added to the reaction mixture, and the mixture was extracted with
methylene chloride. The resultant organic layer was dried over
sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure, and the residue was purified by silica gel column
chromatography (methylene chloride:methanol=9:1) to give
5-(2-{[tert-butyl(diphenyl)silyl]oxy}-1,1-dimethylethyl)-N-[(1R*,2R*)-2-{-
[(5-Chloroindol-2-yl)carbonyl]amino}-4-(hydroxymethyl)cyclopentyl]-4,5,6,7-
-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide (Stereoisomer A)
(184 mg).
[2720] .sup.1H-NMR (CDCl.sub.3).delta.: 1.04(9H,s), 1.15(6H,s),
1.54-1.62(1H,m), 1.73-1.81(1H,m), 1.99-2.25(2H,m), 2.34-2.38(2H,m),
2.67-2.85(3H,m), 2.92-2.97(1H,m), 3.48-3.62(4H,m), 3.93(1H,q,J=15.6
Hz), 4.20-4.28(1H,m), 4.47-4.56(1H,m), 6.89(1H,s), 7.11-7.18(1H,m),
7.24-7.27(1H,m), 7.32-7.43(6H,m), 7.54(1H,d,J=1.7 Hz),
7.63(4H,dd,J=7.8,1.5 Hz), 7.90-7.92(2H,m), 10.13(1H,br.s).
[2721] MS (FAB) m/z: 784(M+H).sup.+. [2722] 3) Stereoisomer A (180
mg) obtained in the step 2) described above was dissolved in a 1N
tetrahydrofuran solution (2 mL) of tetrabutylammonium fluoride, and
the solution was stirred overnight at room temperature. Methylene
chloride, 1N aqueous sodium hydroxide and sodium chloride were
added to the reaction mixture for partitioning the mixture. The
resultant organic layer was dried over sodium sulfate anhydrate.
The solvent was distilled away under reduced pressure, and the
residue was purified by silica gel column chromatography (methylene
chloride:methanol=19:1). The thus-obtained powder was dissolved in
methanol, and 1N HCl in ethanol (229 .mu.l) was added, and then
ethyl acetate was added. The solvent was concentrated under reduced
pressure to give the title compound (63 mg).
[2723] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.33-1.50(8H,m),
1.70-1.91(2H,m), 2.07-2.14(1H,m), 2.23-2.24(1H,m), 3.04-3.10(1H,m),
3.27-3.44(4H,m), 3.57-3.70(2H,m), 3.92-3.95(1H,m), 4.29-4.72(4H,m),
5.81(1H,br.s), 7.11(1H,s), 7.15(1H,dd,J=8.6,2.0 Hz),
7.39(1H,d,J=8.6 Hz), 7.68(1H,d,J=2.0 Hz), 8.53-8.56(1H,m),
8.83(1H,d,J=8.3 Hz), 10.36(1H,br.s), 11.75,11.77(1H,each s).
[2724] MS (ESI) m/z: 546(M+H).sup.+.
Example 29
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)
carbonyl]amino}-cyclohexyl)-4,7,8,10-tetrahydro-6H-pyrazolo[1,2-a]-thiazo-
lo[4,5-d]pyridazine-2-carboxamide hydrochloride
##STR00702##
[2726] The title compound was obtained from the compound obtained
in Referential Example 71 and the compound obtained in Referential
Example 44 in a similar manner to Example 2.
[2727] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35-1.50(2H,m),
1.61(4H,br.s), 1.80-2.00(2H,m), 2.27(2H,br.s), 2.80-4.80(10H,m),
7.14(1H,d,J=1.5 Hz), 7.17(1H,dd,J=8.5,2.0 Hz), 7.41(1H,d,J=8.5 Hz),
7.70(1H,d,J=2.0 Hz), 8.09(1H,d,J=7.3 Hz), 8.44(1H,br.s),
11.81(1H,br.s).
[2728] MS (FAB) m/z: 499(M+H).sup.+.
Example 30
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclohexyl)-4,6,7,8,9-
,11-hexahydropyridazino[1,2-a]-thiazolo[4,5-d]pyridazine-2-carboxamide
hydrochloride
##STR00703##
[2730] The title compound was obtained from the compound obtained
in Referential Example 46 and the compound obtained in Referential
Example 71 in a similar manner to Example 2.
[2731] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35-1.55(2H,m),
1.55-2.10(10H,m), 2.80-4.80(10H,m), 7.10-7.25(2H,m),
7.42(1H,d,J=8.8 Hz), 7.72(1H,d,J=1.7 Hz), 8.12(1H,br.s),
8.41(1H,br.s), 11.83(1H,br.s).
[2732] MS (FAB) m/z: 513(M+H).sup.+.
Example 31
5-Chloro-N-{(1R*,2S*)-2-[(5,6-dihydro-4H-pyrrolo[3,4-d]-thiazol-2-ylcarbon-
yl)amino]cyclohexyl}indole-2-carboxamide hydrochloride
##STR00704##
[2734] The compound (171 mg) obtained in Referential Example 33 was
dissolved in diethyl ether (5 mL) in an argon atmosphere, and the
solution was cooled to -78.degree. C., and then n-butyllithium
(1.60N hexane solution, 385 .mu.l) was added dropwise. After the
reaction mixture was stirred for 10 minutes at -78.degree. C., and
carbon dioxide was blown into the reaction mixture for 20 minutes,
it was warmed to room temperature. After the reaction mixture was
concentrated under reduced pressure, the residue was dissolved in
N,N-dimethylformamide (10 mL). To the solution, were added the
compound (184 mg) obtained in Referential Example 71,
1-hydroxybenzotriazole monohydrate (76 mg) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (215
mg). The resultant mixture was stirred at room temperature for 3
days. The reaction mixture was concentrated, and methylene chloride
and saturated aqueous sodium hydrogencarbonate were added to the
residue to separate an organic layer. The organic layer was dried
over sodium sulfate anhydrate, and the solvent was then distilled
away under reduced pressure. The resultant residue was purified by
silica gel column chromatography (methanol:methylene
chloride=3:97). After HCl in ethanol (5 mL) was added to the
thus-obtained product, the mixture was stirred at room temperature
for 1 hour, and the reaction mixture was concentrated. Ethyl
acetate was added to the residue for solidification. The resultant
powder was collected by filtration to give the title compound (31
mg).
[2735] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35-1.52(2H,m),
1.55-1.80(4H,m), 1.82-2.05(2H,m), 4.22(1H,br.s), 4.28(1H,br.s),
4.38(2H,s), 4.56(2H,s), 7.14-7.20(2H,m), 7.42(1H,d,J=8.6 Hz),
7.71(1H,d,J=1.7 Hz), 8.10(1H,d,J=7.1 Hz), 8.45(1H,d,J=7.8 Hz),
10.10-10.50(2H,br), 11.83(1H,br.s).
[2736] MS (FAB) m/z: 444(M+H).sup.+.
Example 32
tert-Butyl
2-{[((1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexy-
l)amino]carbonyl}-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate
##STR00705##
[2738] The compound obtained in Referential Example 50 was
hydrolyzed with lithium hydroxide. Subsequently, in a manner
similar to that employed in Example 2, the resultant product was
reacted with the compound obtained in Referential Example 71, to
thereby give the title compound.
[2739] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.54(9H,s),
1.55-2.30(8H,m), 4.23(1H,br.s), 4.53(1H,br.s), 4.74-4.83(4H,m),
6.99(1H,d,J=1.5 Hz), 7.19(1H,dd,J=8.8,2.1 Hz), 7.34(1H,d,J=8.8 Hz),
7.62(1H,d,J=2.1 Hz), 8.11(1H,br.s), 8.48-8.53(1H,br),
8.70-8.76(1H,br), 9.60-9.70(1H,br).
[2740] MS (ESI) m/z: 539(M+H).sup.+.
Example 33
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclohexyl)-6-methyl--
6,7-dihydro-5H-pyrrolo[3,4-d]-pyrimidine-2-carboxamide
hydrochloride
##STR00706##
[2742] Trifluoroacetic acid (1 mL) was added to a solution of the
compound (34.0 mg) obtained in Example 32 dissolved in methylene
chloride (1 mL) at room temperature, and the mixture was stirred
for 1 hour. The reaction mixture was concentrated under reduced
pressure, and the residue was dissolved in methylene chloride (1
mL), and then triethylamine (17.6 .mu.l), acetic acid (7.21 .mu.l),
35% formalin (8.13 .mu.l) and sodium triacetoxyborohydride (20.1
mg) were added at room temperature. The resultant mixture was
stirred for 1 hour. Methylene chloride (10 mL) and saturated
aqueous sodium hydrogencarbonate were added to the reaction mixture
to separate an organic layer. The organic layer was dried over
sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure, and the residue was purified by silica gel column
chromatography (methanol:methylene chloride=7:93). A 1N HCl in
ethanol and ethyl acetate were added to the thus-obtained product
for solidification, and the resultant solids were collected by
filtration to give the title compound (8.00 mg).
[2743] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.40-1.55(2H,m),
1.55-1.75(4H,m), 1.80-2.05(2H,m), 2.98(3H,br.s), 4.28(2H,br.s),
4.65(4H,br.s), 7.14-7.20(2H,m), 7.41(1H,d,J=8.8 Hz),
7.69(1H,d,J=2.0 Hz), 8.17(1H,d,J=6.9 Hz),8.65(1H,d,J=8.3 Hz),
8.93(1H,s), 11.73(1H,br.s), 11.82(1H,br.s).
[2744] MS (FAB) m/z: 453(M+H).sup.+.
Example 34
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclohexyl)-4,5,6,7-t-
etrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride
##STR00707##
[2746] In a manner similar to that employed in Example 2, a product
obtained through reaction between the compound obtained in
Referential Example 71 and the compound obtained in Referential
Example 34 was treated with hydrochloric acid, to thereby give the
title compound.
[2747] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.39-1.52(2H,m),
1.62(4H,br.s), 1.86-2.09(2H,m), 3.03(2H,br.s), 3.40-3.47(2H,m),
4.17-4.32(2H,m), 4.44(2H,s), 7.15(1H,s), 7.17(1H,dd,J=8.6,2.0 Hz),
7.41(1H,d,J=8.6 Hz), 7.71 (1H, s), 8.10-8.15(1H,m),
8.40-8.47(1H,m), 9.69(2H,br.s), 11.85(1H,s).
[2748] MS (FAB) m/z: 458(M+H).sup.+.
Example 35
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclohexyl)-5-(2-meth-
oxyethyl)-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00708##
[2750] The title compound was obtained from the compound obtained
in Example 34 and 2-methoxyethyl bromide in a similar manner to
Example 25.
[2751] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.44(2H,br.s),
1.62(4H,br.s), 1.85-2.10(2H,m), 2.76-3.21(6H,m), 3.28(3H,s),
3.64(2H,br.s), 4.00-4.52(4H,m), 7.14(1H,s), 7.17(1H,dd,J=8.8,2.0
Hz), 7.41(1H,d,J=8.8 Hz), 7.70(1H,d,J=2.0 Hz), 8.08-8.20(1H,m),
8.36-8.48(1H,m), 11.84(1H,s).
[2752] MS (FAB) m/z: 516(M+H).sup.+.
Example 36
Methyl
2-[2-{[((1R*,2S*)-2-{[(5-chloroindol-2-yl)-carbonyl]amino}cyclohexy-
l)amino]carbonyl}-6,7-dihydro-thiazolo[5,4-c]pyridin-5(4H)-yl]acetate
hydrochloride
##STR00709##
[2754] The title compound was obtained from the compound obtained
in Example 34 and methyl bromoacetate in a similar manner to
Example 25.
[2755] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.52-1.98(7H,m),
2.17(1H,br.s), 2.87-3.10(4H,m), 3.49(2H,s), 3.76(3H,s),
3.93(1H,d,J=15.4 Hz), 3.99(1H,d,J=15.4 Hz), 4.22(1H,br.s),
4.45(1H,br.s), 6.86(1H,d,J=1.2 Hz), 7.18(1H,dd,J=8.8,2.0 Hz),
7.33(1H,d,J=8.8 Hz), 7.58-7.63(2H,m), 7.87(1H,br.s),
9.88(1H,br.s).
[2756] MS (FAB) m/z: 530(M+H).sup.+.
Example 37
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclohexyl)-5-isoprop-
yl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxamide
hydrochloride
##STR00710##
[2758] The title compound was obtained from the compound obtained
in Example 34 and acetone in a similar manner to Example 24.
[2759] .sup.1H-NMR (DMSO-d.sub.6).delta.: 1.18-1.73(8H,m),
1.81-2.10(2H,m), 2.97-3.16(1H,m), 3.20-3.41(2H,m), 3.52-3.80(2H,m),
4.19-4.31(2H,m), 4.34-4.77(2H,m), 7.17(1H,s), 7.18(1H,dd,J=8.8,2.0
Hz), 7.42(1H,d,J=8.8 Hz), 7.71(1H,d,J=2.0 Hz), 8.15(1H,br.s),
8.28-8.51(1H,m), 11.31(1H,br.s), 11.86(1H,s).
[2760] MS (FAB) m/z: 500(M+H).sup.+.
Example 38
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclohexyl)-5-(tetrah-
ydro-2H-pyran-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamid-
e hydrochloride
##STR00711##
[2762] The title compound was obtained from the compound obtained
in Example 34 and tetrahydro-4H-pyran-4-one in a similar manner to
Example 24.
[2763] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.30-3.56(19H,m),
3.70-4.01(3H,m), 4.17-4.30(2H,m), 4.32-4.80(1H,m), 7.15(1H,s),
7.17(1H,dd,J=8.6,2.0 Hz), 7.41(1H,d,J=8.6 Hz), 7.71(1H,d,J=2.0 Hz),
8.14(1H,br.s), 8.39(1H,br.s), 11.84(1H,s).
[2764] MS (FAB) m/z: 542(M+H).sup.+.
Example 39
tert-Butyl
2-[2-{[((1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cycloh-
exyl)amino]carbonyl}-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl]ethylcarba-
mate
##STR00712##
[2766] The title compound was obtained from the compound obtained
in Example 34 and N-(tert-butoxycarbonyl)aminoacetoaldehyde (J.
Org. Chem., 1988, Vol. 53, p. 3457) in a similar manner to Example
24.
[2767] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44(9H,s),
1.54-1.98(7H,m), 2.10-2.20(1H,m), 2.74(2H,br.s), 2.92(4H,br.s),
3.34(2H,br.s), 3.84(2H,br.s), 4.21(1H,br.s), 4.45(1H,br.s),
6.86(1H,s), 7.19(1H,dd,J=8.8,2.0 Hz), 7.33(1H,d,J=8.8 Hz),
7.57-7.63(2H,m), 7.81(1H,br.s), 9.66(1H,br.s).
[2768] MS (FAB) m/z: 601(M+H).sup.+.
Example 40
5-(2-Aminoethyl)-N-((1R*,2S*)-2-{[(5-chloroindol-2-yl)-carbonyl]amino}cycl-
ohexyl)-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00713##
[2770] The compound (450 mg) obtained in Example 39 was dissolved
in methylene chloride (5 mL), and HCl in ethanol (30 mL) was added,
followed by stirring at room temperature for 1 minute. The reaction
mixture was concentrated under reduced pressure, ethyl acetate was
added to the residue, and solids precipitated were collected by
filtration to give the title compound (367 mg).
[2771] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.38-1.50(2H,m),
1.61(4H,br.s), 1.85-2.08(2H,m), 3.00-4.62(12H,m), 7.14(1H,s),
7.16(1H,dd,J=8.8,2.0 Hz), 7.41(1H,d,J=8.8 Hz), 7.69(1H,d,J=2.0 Hz),
8.12(1H,d,J=6.6 Hz), 8.15-8.68(4H,m), 11.85(1H,s).
[2772] MS (FAB) m/z: 501(M+H).sup.+.
Example 41
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclohexyl)-5-{2-[(me-
thylsulfonyl)amino]ethyl}-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carb-
oxamide hydrochloride
##STR00714##
[2774] The compound (110 mg) obtained in Example 40 was dissolved
in pyridine (3 mL), methanesulfonyl chloride (30 .mu.l) was added,
and the mixture was stirred overnight at room temperature. The
reaction mixture was concentrated under reduced pressure. To the
residue, a 85:15 mixture of methylene chloride and methanol, and
water were added for partitioning the mixture. The resultant
organic layer was dried over sodium sulfate anhydrate. The solvent
was distilled away under reduced pressure, and the residue was
purified by silica gel column chromatography (methylene chloride:
methanol=100:3) to give a pale yellow foamy substance. This product
was suspended in 1N hydrochloric acid (0.3 mL), and the suspension
was concentrated under reduced pressure to give the title compound
(63 mg).
[2775] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.38-1.50(2H,m),
1.55-1.70(4H,m), 1.86-2.05(2H,m), 2.97(3H,s), 3.02-3.25(2H,m),
3.30-3.60(5H,m), 3.78(1H,br.s), 4.18-4.30(2H,m), 4.45-4.86(2H,m),
7.14(1H,s), 7.16(1H,dd,J=8.8,2.0 Hz), 7.40(1H,d,J=8.8 Hz),
7.41(1H,br.s), 7.69(1H,d,J=2.0 Hz), 8.09(1H,br.s), 8.43(1H,br.s),
11.18(1H,br.s), 11.82(1H,s).
[2776] MS (FAB) m/z: 579(M+H).sup.+.
Example 42
Methyl
2-[2-{[((1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl-
)amino]carbonyl}-6,7-dihydro-thiazolo[5,4-c]pyridin-5(4H)-yl]ethylcarbamat-
e hydrochloride
##STR00715##
[2778] The compound (144 mg) obtained in Example 40 was dissolved
in pyridine (3 mL), triethylamine (138 .mu.l) was added, and the
mixture was stirred at room temperature for 5 minutes. A solution
prepared by adding triphosgene (49 mg) to tetrahydrofuran (1 mL)
containing methanol (20 .mu.l) was added dropwise to this solution
at room temperature. After stirring for 1 hour, the reaction
mixture was concentrated under reduced pressure, and the residue
was dissolved in a 9:1 mixture of methylene chloride and methanol.
Water was added to the solution for partitioning the mixture. The
organic layer was separated and dried over sodium sulfate
anhydrate. The solvent was distilled away under reduced pressure,
and the residue was purified by silica gel column chromatography
(methylene chloride: methanol=100:3) to give a colorless foamy
substance. This product was suspended in 1N hydrochloric acid (0.2
mL), and the suspension was concentrated under reduced pressure to
give the title compound (60 mg).
[2779] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.38-1.50(2H,m),
1.61(4H,br.s), 1.85-2.04(2H,m), 2.80-3.49(8H,m), 3.52(3H,s),
3.62-4.91(4H,m), 7.14(1H,s), 7.16(1H,dd,J=8.8,2.0 Hz),
7.37(1H,br.s), 7.40(1H,d,J=8.8 Hz), 7.70(1H,s), 8.11(1H,d,J=6.8
Hz), 8.40(1H,br.s), 11.05(1H,br.s), 11.82(1H,br.s).
[2780] MS (FAB) m/z: 559(M+H).sup.+.
Example 43
5-[2-(Acetylamino)ethyl]-N-((1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]ami-
no}cyclohexyl)-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00716##
[2782] The compound (90 mg) obtained in Example 40 was dissolved in
N,N-dimethylformamide (3 mL), triethylamine (65 .mu.l) and acetic
anhydride (22 .mu.l) were added, and the mixture was stirred
overnight at room temperature. The reaction mixture was
concentrated under reduced pressure, and methylene chloride and
0.3N aqueous sodium hydroxide were added to the residue for
partitioning the mixture. The resultant organic layer was dried
over sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure, and the residue was purified by silica gel column
chromatography (methylene chloride: methanol=100:3) to give a
colorless foamy substance. This product was suspended in 1N
hydrochloric acid (0.3 mL), and the suspension was concentrated
under reduced pressure to give the title compound (73 mg).
[2783] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.39-1.52(2H,m),
1.54-1.70(4H,m), 1.83(3H,s), 1.84-2.06(2H,m), 3.02-3.87(8H,m),
4.16-4.32(2H,m), 4.40-4.52(1H,m), 4.78-4.88(1H,m), 7.14(1H,s),
7.16(1H,d,J=8.6 Hz), 7.40(1H,d,J=8.6 Hz), 7.70(1H,s),
8.07-8.17(1H,m), 8.22-8.30(1H,m), 8.38-8.52(1H,m), 11.14(1H,br.s),
11.83(1H,s).
[2784] MS (FAB) m/z: 543(M+H).sup.+.
Example 44
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-(2-hydro-
xyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
##STR00717##
[2786] The title compound was obtained from the compound obtained
in Example 34 and 2-bromoethanol in a similar manner to Example
25.
[2787] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.37-1.69(6H,m),
1.86-2.03(2H,m), 2.54-2.61(2H,m), 2.75-2.86(4H,m), 3.52-3.59(2H,m),
3.75(2H,s), 4.47(1H,t,J=5.4 Hz), 7.12(1H,s), 7.16(1H,dd,J=8.8,2.0
Hz), 7.40(1H,d,J=8.8 Hz), 7.70(1H,s), 8.05-8.13(1H,m),
8.28-8.35(1H,m), 11.78(1H,s).
[2788] MS (FAB) m/z: 502(M+H).sup.+.
Example 45
5-Butyl-N-((1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]-amino}cyclohexyl)-4-
,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxamide
hydrochloride
##STR00718##
[2790] The title compound was obtained from the compound obtained
in Example 34 and 1-bromobutane in a similar manner to Example
25.
[2791] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.88(3H,t,J=7.2 Hz),
1.20-1.70(10H,m), 1.87-2.05(2H,m), 2.55-3.40(8H,m),
4.16-4.30(2H,m), 7.13(1H,s), 7.16(1H,d,J=8.8 Hz), 7.40(1H,d,J=8.8
Hz), 7.69(1H,s), 8.05-8.14(1H,m), 8.35(1H,br.s), 11.81(1H,s).
[2792] MS (FAB) m/z: 514(M+H).sup.+.
Example 46
5-Acetyl-N-((1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]-amino}cyclohexyl)--
4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxamide
##STR00719##
[2794] The compound (1.00 mg) obtained in Example 34 was dissolved
in N,N-dimethylformamide (3 mL), triethylamine (84 .mu.l) and
acetic anhydride (29 .mu.l) were added, and the mixture was stirred
at room temperature for 3 hours. The reaction mixture was
concentrated under reduced pressure, and methylene chloride and 1N
hydrochloric acid were added to the residue for partitioning the
mixture. The resultant organic layer was dried over sodium sulfate
anhydrate. The solvent was distilled away under reduced pressure,
and the residue was purified by silica gel column chromatography
(methylene chloride: methanol=100:3) to give the title compound (86
mg).
[2795] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.52-1.85(5H,m),
1.91(2H,br.s), 2.10-2.28(4H,m), 2.77-3.00(2H,m), 3.70-4.00(2H,m),
4.19-4.38(1H,m), 4.45(1H,br.s), 4.68-4.99(2H,m), 6.85(1H,s),
7.17-7.22(1H,m), 7.30-7.39(1H,m), 7.50-7.84(3H,m),
9.72-10.05(1H,m).
[2796] MS (FAB) m/z: 500(M+H).sup.+.
Example 47
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclohexyl)-5-(methyl-
sulfonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxamide
##STR00720##
[2798] The compound (100 mg) obtained in Example 34 was dissolved
in pyridine (3 mL), triethylamine (168 .mu.l) and methanesulfonyl
chloride (48 .mu.l) were added, and the mixture was stirred
overnight at room temperature. The reaction mixture was
concentrated under reduced pressure, and methylene chloride and 1N
hydrochloric acid were added to the residue to separate an organic
layer. The resultant organic layer was dried over sodium sulfate
anhydrate. The solvent was distilled away under reduced pressure,
and the residue was purified by silica gel column chromatography
(methylene chloride:methanol=100:1) to give the title compound (79
mg).
[2799] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50-1.82(5H,m),
1.90(2H,br.s), 2.13(1H,br.s), 2.89(3H,s), 2.91-2.98(2H,m),
3.60-3.70(2H,m), 4.30(1H,br.s), 4.44(1H,br.s), 4.58(2H,s),
6.87(1H,s), 7.19(1H,d,J=8.8 Hz), 7.34(1H,d,J=8.8 Hz),
7.61(3H,br.s), 9.91(1H,br.s).
[2800] MS (FAB) m/z: 536(M+H).sup.+.
Example 48
5-Methyl-N-((1R*,2S*)-2-{[(5-methylindol-2-yl)carbonyl]-amino}cyclohexyl)--
4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxamide
hydrochloride
##STR00721##
[2802] The title compound was obtained from the compound obtained
in Referential Example 67 and 5-methylindole-2-carboxylic acid in a
similar manner to Example 5.
[2803] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35-1.50(2H,m),
1.50-1.80(4H,m), 1.85-2.07(2H,m), 2.36(3H,s),2.88(3H,s),
3.12(2H,br.s), 3.53(2H,br.s), 4.15-4.30(2H,m), 4.30-4.80(2H,br),
7.00(1H,dd,J=8.4,1.5 Hz), 7.05(1H,d,J=1.5 Hz), 7.30(1H,d,J=8.4 Hz),
7.38(1H,s), 8.00(1H,d,J=7.3 Hz), 8.43(1H,br.s), 11.45(1H,br.s),
11.49(1H,br.s).
[2804] MS (FAB) m/z: 452(M+H).sup.+.
Example 49
Ethyl
(1R*,3S*,4R*)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl--
4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amino}cyclohexanec-
arboxylate
##STR00722##
[2806] The compound (1.40 g) obtained in Referential Example 91 was
suspended in ethanol (8 mL), and HCl in ethanol (10 mL) was added
at room temperature, followed by stirring for 12 hours. The solvent
was distilled away under reduced pressure to give ethyl (1R*, 3S*,
4R*)-3-amino-4-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexanecarboxylat-
e hydrochloride (1.25 g).
[2807] The title compound was obtained from the above-described
product and the compound obtained in Referential Example 10 in a
similar manner to Example 2.
[2808] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.29(3H,t,J=7.1 Hz),
1.52-1.80(2H,m), 2.03-2.37(4H,m), 2.53(3H,s), 2.57-2.71(1H,m), 3.73
and 3.78(each 1H,each d,J=14.4 Hz), 4.08-4.17(1H,m),
4.18(2H,q,J=7.2 Hz), 4.55-4.65(1H,m), 6.85(1H,br.s),
7.21(1H,dd,J=8.8,2.0 Hz), 7.33(1H,d,J=8.8 Hz), 7.48(1H,d,J=7.6 Hz),
7.63(1H,d,J=2.0 Hz), 7.98(1H,d,J=7.6 Hz), 9.30(1H,s).
[2809] MS (ESI) m/z: 544(M+H).sup.+.
Example 50
Ethyl
(1S,3R,4S)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5-
,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarbo-
xylate
##STR00723##
[2811] The compound (4.2 g) obtained in Referential Example 97 was
suspended in ethanol (25 mL), and HCl in ethanol (55 mL) was added
at room temperature, followed by stirring for 11 hours. The solvent
was distilled away under reduced pressure to give colorless solids
(4.15 g).
[2812] This product (4.15 g) was dissolved in N,N-dimethylformamide
(40 mL), and the compound (2.86 g) obtained in Referential Example
10, 1-hydroxybenzotriazole monohydrate (1.72 g) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.15
g) were added to this solution at room temperature, followed by
stirring for 39 hours. The reaction mixture was concentrated under
reduced pressure, and water was added to the residue, followed by
extraction with chloroform. The resultant organic layer was washed
with saturated brine and dried over magnesium sulfate anhydrate.
The solvent was distilled away under reduced pressure, and the
resultant residue was purified by silica gel column chromatography
(chloroform:methanol=100:1) to give the title compound (1.71
g).
[2813] [.alpha.].sub.D -94.degree. (C=1.0, chloroform).
Example 51
Methyl
(1R*,3R*,4S*)-3-{[(5-chloroindol-2-yl)carbonyl]-amino}-4-{[(5-methy-
l-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amino}cyclohexan-
ecarboxylate
##STR00724##
[2815] In a manner similar to that employed in Example 49, the
compound obtained in Referential Example 107 was treated with HCl
in ethanol and then, condensed with the compound obtained in
Referential Example 10, to thereby give the title compound.
[2816] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.55-1.80(3H,m),
1.80-2.20(3H,m), 2.60-2.75(1H,m), 2.92(3H,s), 3.15-3.30(1H,m),
3.30-3.50(4H,m), 3.57(3H,s), 3.55-3.70(1H,m), 4.20-4.30(1H,m),
4.30-4.40(1H,m), 7.02(1H,s), 7.17(1H,dd,J=8.5,2.0 Hz),
7.41(1H,d,J=8.5 Hz), 7.71(1H,s), 8.20-8.35(1H,m), 8.35-8.45(1H,m),
11.82(1H,br).
[2817] MS (FAB) m/z: 530(M+H).sup.+.
Example 52
Ethyl
(1R*,3S*,4R*)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl--
4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amino}cyclohexanec-
arboxylate
##STR00725##
[2819] In a manner similar to that employed in Example 49, the
compound obtained in Referential Example 98 was treated with HCl in
ethanol and then, condensed with 5-chloroindole-2-carboxylic acid,
to thereby give the title compound.
[2820] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.29(3H,t,J=7.1 Hz),
1.82-2.30(6H,m), 2.49(3H,s), 2.62-2.73(1H,m), 3.74-3.85(2H,m),
3.85-3.93(2H,m), 3.71(2H,s), 4.12-4.29(3H,m), 4.49-4.59(1H,m),
6.89(1H,br.s), 7.21(1H,dd,J=8.8, 2.0 Hz), 7.32(1H,d,J=8.8 Hz),
7.33(1H,br.s), 7.41(1H,br.s), 7.62(1H,br.s), 9.37(1H,s).
[2821] MS (ESI) m/z: 544(M+H).sup.+.
Example 53
Methyl
(1R*,3R*,4S*)-4-{[(5-chloroindol-2-yl)carbonyl]-amino}-3-{[(5-methy-
l-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amino}cyclohexan-
ecarboxylate hydrochloride
##STR00726##
[2823] In a manner similar to that employed in Example 49, the
compound obtained in Referential Example 106 was treated with 4N
HCl-dioxane and then, condensed with 5-chloroindole-2-carboxylic
acid, to thereby give the title compound.
[2824] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.65-1.80(3H,m),
1.80-2.10(2H,m), 2.15-2.25(1H,m), 2.55-2.70(1H,m), 2.89(3H,s),
3.05-3.20(1H,m), 3.30-3.50(4H,m), 3.55-3.65(1H,m), 3.62(3H,s),
4.20-4.30(1H,m), 4.35-4.45(1H,m), 7.19(1H,dd,J=8.8,1.2 Hz),
7.23(1H,s), 7.43(1H,d,J=8.8 Hz), 7.73(1H,s), 8.03(1H,d,J=6.8 Hz),
8.73(1H,d,J=8.5 Hz), 11.15-11.38(1H,br), 11.85(1H,s).
[2825] MS (FAB) m/z: 530(M+H).sup.+.
Example 54
Methyl
(1R,3R,4S)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,-
5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarb-
oxylate
##STR00727##
[2827] In a manner similar to that employed in Example 49, the
compound obtained in Referential Example 112 was treated with 4N
HCl-dioxane and then, condensed with 5-chloroindole-2-carboxylic
acid, to thereby give the title compound.
[2828] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.67-1.76(3H,m),
1.88-1.91(1H,m), 2.01(1H,br.s), 2.13-2.22(1H,m), 2.52-2.67(4H,m),
2.86(2H,br.s), 3.04(2H,br.s), 3.33-3.41(1H,m), 3.61(3H,s),
4.22-4.36(3H,m), 7.17-7.22(2H,m), 7.42(1H,d,J=8.8 Hz), 7.72(1H,s),
8.00(1H,d,J=6.9 Hz), 8.68(1H,d,J=8.6 Hz), 11.80(1H,s).
[2829] MS (FAB) m/z: 530(M+H).sup.+.
Example 55
N-((1R*,2S*,5S*)-5-(Aminocarbonyl)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-
cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxami-
de
##STR00728##
[2831] In a manner similar to that employed in Example 49, the
compound obtained in Referential Example 113 was treated with 4N
HCl-dioxane and then, condensed with the compound obtained in
Referential Example 10, to thereby give the title compound.
[2832] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.78-2.40(7H,m),
2.53(3H,s), 2.80-2.89(1H,m), 2.91-3.00(1H,m), 3.68-3.76(2H,m),
4.08-4.19(1H,m), 4.54-4.65(1H,m), 6.80(1H,br.s), 7.21(1H,dd,J=8.4,
1.6 Hz), 7.33(1H,d,J=8.4 Hz), 7.38-7.43(1H,m), 7.49-7.55(1H,m),
7.63(1H,br.s), 9.14(1H,br.s).
[2833] MS (ESI) m/z: 515(M+H).sup.+.
Example 56
(1R*,3S*,4R*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,-
7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxyl-
ic acid
##STR00729##
[2835] The compound (916 mg) obtained in Example 49 was suspended
in a mixture of ethanol (10 mL) and tetrahydrofuran (8 mL), and 1N
aqueous sodium hydroxide (3.3 mL) was added at room temperature,
followed by stirring for 12 hours at the same temperature. After
adding 1N HCl in ethanol (3.3 mL), the solvent was distilled away
under reduced pressure, and the residue was washed with water and
diethyl ether to give the title compound (712 mg).
Example 57
N-{(1R*,2S*,5S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino-
)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-
-carboxamide hydrochloride
##STR00730##
[2837] Triethylamine (0.25 mL), dimethylamine hydrochloride (133
mg), 1-hydroxybenzotriazole monohydrate (53 mg) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (75 mg)
were added to a chloroform suspension (10 mL) of the compound (168
mg) obtained in Example 56, and the mixture was stirred for 72
hours. The solvent was distilled away under reduced pressure. Water
was added to the residue, and the mixture was extracted with
chloroform. The resultant organic layer was washed with saturated
brine and dried over magnesium sulfate anhydrate. The solvent was
distilled away under reduced pressure, and the resultant residue
was purified by silica gel column chromatography (methylene
chloride: methanol=93:7). The thus-obtained colorless solids (135
mg) were suspended in ethanol (5 mL), and then 1N HCl in ethanol
(0.5 mL) was added. The mixture was stirred for 2 hours, and the
solvent was distilled away to give the title compound (112 mg).
[2838] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.42-2.07(6H,m),
2.73-3.70(10H,m), 2.88(3H,s), 2.97(3H,s), 4.03-4.20(1H,m),
4.51-4.67(1H,m), 7.04(1H,br.s), 7.16(1H,br,J=8.8 Hz),
7.41(1H,d,J=8.8 Hz), 7.68(1H,br.s), 8.32-8.47(2H,m),
10.76(1H,br.s).
[2839] MS (ESI) m/z: 543(M+H).sup.+.
Example 58
[2840]
(1S,3R,4S)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,-
5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarb-
oxylic acid
##STR00731##
[2841] The compound (1.6 g) obtained in Example 50 was suspended in
a mixture of ethanol (20 mL) and tetrahydrofuran (15 mL), and 1N
aqueous sodium hydroxide (5.9 mL) was added at room temperature,
followed by stirring for 12 hours at the same temperature. After
adding 1N hydrochloric acid (5.9 mL), the solvent was distilled
away under reduced pressure, and the residue was washed with water
and diethyl ether to give the title compound (1.19 g).
[2842] m.p. 234-236.degree. C.
[2843] [.alpha.].sub.D -57.degree. (C=1.0, methanol).
Example 59
N-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(cyclopropylamino-
)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-
-carboxamide hydrochloride
##STR00732##
[2845] The title compound was obtained from the compound obtained
in Example 58 and cyclopropylamine in a similar manner to Example
57.
[2846] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.32-0.40(2H,m),
0.53-0.63(2H,m), 1.50-2.10(6H,m), 2.25-2.40(1H,m), 2.45-2.70(2H,m),
2.91(3H,s), 3.05-3.80(3H,m), 4.05-4.17(1H,m), 4.30-4.55(2H,m),
4.55-4.80(1H,m), 7.03(1H,d,J=1.5 Hz), 7.16(1H,dd,J=8.8,2.0 Hz),
7.41(1H,d,J=8.8 Hz), 7.68(1H,d,J=2.0 Hz), 7.86(1H,br,J=3.4 Hz),
8.06(1H,br.s), 8.40(1H,br,J=7.6 Hz), 11.20-11.60(1H,br),
11.79(1H,s).
[2847] MS (FAB) m/z: 555(M+H).sup.+.
Example 60
N-[(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-(pyrrolidin-1-ylca-
rbonyl)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-ca-
rboxamide hydrochloride
##STR00733##
[2849] The title compound was obtained from the compound obtained
in Example 58 and pyrrolidine in a similar manner to Example
57.
[2850] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.45-2.10(10H,m),
2.75-2.90(2H,m), 2.90(3H,s), 3.10-3.70(H,m), 4.05-4.20(1H,m),
4.25-4.80(3H,m), 7.05(1H,s), 7.17(1H,d,J=8.7 Hz), 7.41(1H,d,J=8.7
Hz), 7.69(1H,s), 8.32(1H,br,J=7.6 Hz), 8.38(1H,br,J=7.1 Hz),
11.22(1H,br.s), 11.78(1H,s).
[2851] MS (FAB) m/z: 569(M+H).sup.+.
Example 61
N-[(1R*,2S*,5S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-(4-morpholinylc-
arbonyl)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-c-
arboxamide hydrochloride
##STR00734##
[2853] The title compound was obtained from the compound obtained
in Example 56 and morpholine in a similar manner to Example 57.
[2854] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.40-2.05(6H,m),
2.75-3.70(18H,m), 4.02-4.17(1H,m), 4.55-4.69(1H,m), 7.05(1H,br.s),
7.17(1H,br,J=8.8 Hz), 7.41(1H,d,J=8.8 Hz), 7.67(1H,br.s),
8.35(1H,d,J=7.6 Hz), 8.40(1H,d,J=7.6 Hz), 10.79(1H,br.s).
[2855] MS (ESI) m/z: 585(M+H).sup.+.
Example 62
N-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(ethylamino)carbo-
nyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbo-
xamide hydrochloride
##STR00735##
[2857] The compound (150 mg) obtained in Example 58 was dissolved
in N,N-dimethylformamide (3 mL), and then N-ethylamine
hydrochloride (119 mg), 1-hydroxybenzotriazole monohydrate (79 mg),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (112
mg) and triethylamine (326 .mu.l) were added, and the mixture was
stirred at room temperature for 4 days. The solvent was distilled
away under reduced pressure, and saturated aqueous sodium
hydrogencarbonate was added to the residue, followed by extraction
with methylene chloride. The resultant organic layer was dried over
sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure, and the resultant residue was purified by silica
gel column chromatography (methylene chloride: methanol=47:3). The
thus-obtained solid was dissolved in methylene chloride, and then
1N HCl in ethanol (171 .mu.l) was added. The solvent was distilled
away under reduced pressure, and methanol and diethyl ether were
added to the residue to collect the precipitate formed by
filtration to give the title compound (74 mg).
[2858] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.99(3H,t,J=7.2 Hz),
1.57-2.02(6H,m), 2.33-2.38(1H,m), 2.92(3H,s), 3.01-3.08(2H,m),
3.17-3.20(2H,s), 3.45-3.70(2H,m), 4.10-4.17(1H,m), 4.40-4.69(3H,m),
7.04(1H,d,J=2.0 Hz), 7.17(1H,dd,J=8.8,2.0 Hz), 7.41(1H,d,J=8.8 Hz),
7.69(1H,d,J=2.0 Hz), 7.78-7.81(1H,m), 8.08-8.12(1H,m),
8.40(1H,d,J=8.1 Hz), 11.23(1H,br.s), 11.79(1H,br.s).
[2859] MS (FAB) m/z: 543(M+H).sup.+.
Example 63
N-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)ca-
rbonyl]cyclohexyl.ident.6-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridi-
ne-2-carboxamide hydrochloride
##STR00736##
[2861] The compound (900 mg) obtained in Example 58 was dissolved
in N,N-dimethylformamide (50 mL), and then dimethylamine
hydrochloride (304 mg), 1-hydroxybenzotriazole monohydrate (262
mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(369 mg) and diisopropylethylamine (1.83 mL) were added, and the
mixture was stirred at room temperature for 12 hours. The solvent
was distilled away under reduced pressure, and saturated aqueous
sodium hydrogencarbonate was added to the residue, followed by
extraction with methylene chloride. The resultant organic layer was
dried over sodium sulfate anhydrate. The solvent was distilled away
under reduced pressure, and the resultant residue was purified by
silica gel column chromatography (methylene chloride:
methanol=47:3). The thus-obtained white solids were dissolved in
methylene chloride, and then 1N HCl in ethanol (1.49 mL) was added.
The solvent was distilled away under reduced pressure, and methanol
and diethyl ether were added to the residue to collect the
precipitate formed by filtration to give the title compound (777
mg).
[2862] [.alpha.].sub.D =-53.9.degree. (18.degree. C., c=0.505,
methanol).
[2863] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.45-1.60(1H,m),
1.70-1.85(3H,m), 1.90-2.05(2H,m), 2.80(3H,s), 2.91(3H,s),
2.95-3.10(1H,m), 2.97(3H,s), 3.10-3.75(4H,m), 4.05-4.15(1H,m),
4.35-4.75(3H,m), 7.05(1H,s), 7.16(1H,dd,J=8.7,2.1 Hz),
7.41(1H,d,J=8.6 Hz), 7.67(1H,s), 8.30-8.45(2H,m), 11.63(1H,br),
11.78(1H,s).
[2864] MS (FAB) m/z: 543(M+H).sup.+.
Example 64
N-((1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-{[(2-methoxyethyl)-
(methyl)amino]carbonyl}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-
-c]pyridine-2-carboxamide hydrochloride
##STR00737##
[2866] The title compound was obtained from the compound obtained
in Example 58 in a similar manner to Example 57.
[2867] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.50-1.99(6H,m),
2.80,3.01(3H,each s), 2.91(3H,s), 3.03(1H,br.s), 3.16(2H,s),
3.23(3H,s), 3.35-3.67(6H,m), 4.09-4.16(1H,m), 4.43-4.67(3H,m),
7.04-7.06(1H,m), 7.16(1H,dd,J=8.8,2.0 Hz), 7.42(1H,d,J=8.8 Hz),
7.69(1H,br.s), 8.29-8.41(2H,m), 11.59(1H,br.s), 11.80(1H,br.s).
[2868] MS (FAB) m/z: 587(M+H).sup.+.
Example 65
N-((1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-{[(2-hydroxyethyl)-
(methyl)amino]carbonyl}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-
-c]pyridine-2-carboxamide hydrochloride
##STR00738##
[2870] The title compound was obtained from the compound obtained
in Example 58 in a similar manner to Example 57.
[2871] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.50-1.55(1H,m),
1.74-1.84(3H,m), 1.94-1.97(2H,m), 2.67,3.02(3H,each s), 2.91(3H,s),
3.10-3.68(9H,m), 4.11-4.13(1H,m), 4.43-4.66(4H,m), 7.05(1H,s),
7.16(1H,dd,J=8.7,2.0 Hz), 7.41(1H,d,J=8.7 Hz), 7.68(1H,s),
8.34-8.40(2H,m), 11.47(1H,br.s), 11.79(1H,s).
[2872] MS (FAB) m/z: 573(M+H).sup.+.
Example 66
N-((1R,2S,5S)-5-(1-Azetidinylcarbonyl)-2-{[(5-chloroindol-2-yl)carbonyl]am-
ino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbo-
xamide hydrochloride
##STR00739##
[2874] The title compound was obtained from the compound obtained
in Example 58 and azetidine hydrochloride in a similar manner to
Example 57.
[2875] .sup.1H-NMR (DMSO-d.sub.6).delta.: 1.47-1.55(1H,m),
1.65-1.82(3H,m), 1.88-2.01(2H,m), 2.16(2H,quint.,J=7.6 Hz),
3.17-3.67(5H,m), 3.82(2H,t,J=7.6 Hz), 4.02-4.14(3H,m),
4.43-4.67(3H,m), 7.06(1H,s), 7.17(1H,dd,J=8.7,1.7 Hz),
7.41(1H,d,J=8.7 Hz), 7.69(1H,br.s), 8.31(1H,d,J=7.6 Hz),
8.38(1H,d,J=7.6 Hz), 11.41(1H,br.s), 11.80(1H,s).
[2876] MS (FAB) m/z: 555(M+H).sup.+.
Example 67
N-((1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-{[(3S)-3-fluoropyr-
rolidinyl]carbonyl}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]p-
yridine-2-carboxamide hydrochloride
##STR00740##
[2878] The title compound was obtained from the compound obtained
in Example 58 and (S)-3-fluoropyrrolidine (Synlett., 1995, p. 55)
in a similar manner to Example 57.
[2879] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.23-3.77(22H,m),
4.11-4.16(1H,m), 4.58-4.51(1H,m), 5.23-5.42(1H,m), 7.05(1H,s),
7.16(1H,d,J=8.3 Hz), 7.42(1H,d,J=8.3 Hz), 7.68(1H,s),
8.34-8.37(2H,m), 11.78(1H,s).
[2880] MS (FAB) m/z: 587(M+H).sup.+.
Example 68
Lithium (1R*,3R*,4S*)-3-{[(5-Chloroindol-2-yl)
carbonyl]-amino}-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin--
2-yl)carbonyl]amino}cyclohexanecarboxylate
##STR00741##
[2882] The compound (1.20 g) obtained in Example 51 was dissolved
in tetrahydrofuran (32 mL), and lithium hydroxide (60.8 mg) and
water (4 mL) were successively added under ice cooling, followed by
stirring at room temperature for 14 hours. The solvent was
distilled away under reduced pressure to give the title compound
(1.12 g).
[2883] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.55-1.70(2H,m),
1.70-2.05(4H,m), 2.10-2.20(1H,m), 2.25-2.40(4H,m), 2.50-2.80(4H,m),
3.45-3.65(3H,m), 4.10-4.30(2H,m), 7.00-7.20(2H,m),
7.50-7.65(2H,m).
Example 69
N-{(1R*,2S*,4S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-4-[(dimethylamino-
)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-
-carboxamide hydrochloride
##STR00742##
[2885] The title compound was obtained from the compound obtained
in Example 68 and dimethylamine hydrochloride in a similar manner
to Example 57.
[2886] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.40-1.60(2H,m),
1.65-1.80(2H,m), 1.95-2.10(2H,m), 2.84(3H,s), 2.90-3.05(1H,m),
2.92(3H,s), 3.06(3H,s), 3.15-3.75(4H,m), 4.25-4.75(4H,m),
7.02(1H,d,J=1.5 Hz), 7.15(1H,dd,J=8.8,2.1 Hz), 7.41(1H,d,J=8.8 Hz),
7.69(1H,d,J=2.1 Hz), 8.05(1H,d,J=7.7 Hz), 8.63(1H,d,J=7.7 Hz),
11.20(1H,br), 11.79(1H,s).
[2887] MS (FAB) m/z: 543(M+H).sup.+.
Example 70
N-((1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-{[(3R)-3-hydroxypy-
rrolidinyl]carbonyl}cyclohexyl-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]p-
yridine-2-carboxamide hydrochloride
[2888] ##STR00743## [2889] 1) The compound (1.18 g) obtained in
Referential Example 58 was dissolved in methanol (12 mL), 1N
hydrochloric acid (240 .mu.l) and palladium hydroxide (221 mg) were
added, and hydrogen was introduced to conduct catalytic reduction
under normal pressure at room temperature for 4.5 hours. The
catalyst was removed by filtration, and the filtrate was
concentrated to solid under reduced pressure to give crude
(3R)-3-{[tert-butyl(diphenyl)silyl]oxy}pyrrolidine hydrochloride
(984 mg). The thus-obtained product (249 mg), the product (295 mg)
obtained in Example 58,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (126
mg) and 1-hydroxybenzotriazole monohydrate (87 mg) were dissolved
in N,N-dimethylformamide (10 mL). Diisopropylethylamine (450 .mu.l)
was added dropwise to the solution under ice cooling, and the
mixture was stirred at room temperature for 12 hours. The solvent
was distilled away under reduced pressure, methylene chloride and
saturated aqueous sodium hydrogencarbonate were added to the
residue for partitioning the mixture. The resultant organic layer
was dried over sodium sulfate anhydrate, and the solvent was
distilled away under reduced pressure. The residue was subjected to
silica gel column chromatography (methanol:methylene chloride=3:97)
to give
N-((1R,2S,5S)-5-[((3R)-3-{[tert-butyl(diphenyl)silyl]oxy}pyrrolidinyl)car-
bonyl]-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-
-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide (248 mg).
[2890] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.06(9H,s),
1.50-1.60(1H,m), 1.75-2.10(5H,m), 2.20-2.50(2H,m), 2.54(3H,d,J=2.8
Hz), 2.60-3.00(5H,m), 3.30-3.80(6H,m), 4.10-4.20(1H,m),
4.40-4.70(2H,m), 6.85(1H,s), 7.15-7.25(1H,m), 7.30-7.50(8H,m),
7.60-7.70(5H,m), 7.90-8.00(1H,m), 9.38(1H,s).
[2891] MS (FAB) m/z: 823(M+H).sup.+. [2892] 2) The above product
(240 mg) was dissolved in pyridine (10 mL), and hydrogen
fluoride-pyridine (3.0 mL) was added dropwise under ice cooling,
followed by stirring at 0.degree. C. for 4.5 hours. Ethyl acetate
(80 mL) was added to the reaction mixture under ice cooling for
dilution. The diluted reaction mixture was poured into ice. After
sodium hydrogencarbonate was added to this solution to make the
mixture alkaline, liquid partition was conducted. The resultant
organic layer was dried over sodium sulfate anhydrate. The solvent
was distilled away under reduced pressure, and the residue was
subjected to silica gel column chromatography (methanol:methylene
chloride=1:19.fwdarw.1:9). The resultant crude purified product was
dissolved in methylene chloride and methanol, and then 1N HCl in
ethanol (225 .mu.l) was added to dry it once. Methanol and diethyl
ether were added to the residue for solidification to give the
title compound (114 mg).
[2893] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.50-1.60(1H,m),
1.70-2.10(6H,m), 2.75-2.85(1H,m), 2.92(3H,s), 3.10-3.80(8H,m),
4.10-5.10(6H,m), 7.05(1H,d,J=1.7 Hz), 7.16(1H,dd,J=8.8,1.7 Hz),
7.42(1H,d,J=8.8 Hz), 7.68(1H,s), 8.30-8.45(2H,m),
11.10-11.40(1H,m), 11.78(1H,s).
[2894] MS (FAB) m/z: 585(M+H).sup.+.
Example 71
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5,5-dimethoxycyclohex-
yl)-5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide
or
N-((1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-4,4-dimethoxycyclohe-
xyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
[2895] The title compound was obtained from the compound obtained
in Referential Example 118 and the compound obtained in Referential
Example 10 in a similar manner to Example 2.
[2896] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.11-2.15(1H,m),
2.21-2.25(1H,m), 2.41-2.43(1H,m), 2.46(3H,s), 2.70-2.75(1H,m),
2.81-2.88(1H,m), 3.21(3H,s), 3.24(3H,s), 3.49(1H,s),
3.58(1H,d,J=15.6 Hz), 3.71(1H,d,J=15.6 Hz), 3.87-3.93(1H,m),
4.26-4.29(1H,m), 6.85(1H,d,J=2.0 Hz), 7.19(1H,dd,J=8.5,2.0 Hz),
7.30(1H,d,J=8.5 Hz), 7.62(1H,s), 9.21(1H,s).
Example 72
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-oxocyclohexyl)-5-me-
thyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxamide or
N-((1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-4-oxocyclohexyl)-5-m-
ethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
[2897] The compound (100 mg) obtained in Example 71 was dissolved
in chloroform (2 mL), and trifluoroacetic acid (0.5 mL) and water
(0.5 mL) were added, followed by stirring at room temperature for
3.5 hours. Saturated aqueous sodium hydrogencarbonate was added to
the reaction mixture, and the mixture was extracted with ethyl
acetate. The resultant organic layer was washed with saturated
brine and dried over sodium sulfate anhydrate. The solvent was
distilled away under reduced pressure, and the resultant residue
was purified by silica gel thin layer chromatography (methylene
chloride:methanol=19:1). The thus-obtained white solids were
dissolved in methanol (4 mL), and then 1N HCl in ethanol (0.38 mL)
was added. The solvent was distilled away under reduced pressure to
give the title compound (35 mg).
[2898] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.83-1.90(1H,m),
2.08-2.10(1H,m), 2.28-2.32(1H,m), 2.50-2.59(1H,m), 2.87(3H,s),
2.96(1H,t,J=13.0 Hz), 3.06-3.10(2H,m), 3.33-3.36(3H,m),
4.02-4.04(2H,m), 4.55-4.57(2H,m), 7.03(1H,s), 7.15(1H,d,J=8.8 Hz),
7.38(1H,d,J=8.8 Hz), 7.69 (1H, s), 8.43(1H,d,J=8.8 Hz),
8.91(1H,d,J=8.8 Hz), 11.75(1H,s).
Example 73
N-[(1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-(hydroxyimino)cyclo-
hexyl]-5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxamide
or
N-[(1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-4-(hydroxyimino)--
cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxami-
de
[2899] The compound (133 mg) obtained in Example 72 was dissolved
in a mixture of pyridine (8 mL) and methanol (8 mL), and
hydroxylamine hydrochloride (30 mg) was added, followed by stirring
at room temperature for 3 days. The reaction mixture was
concentrated, and water was added to the residue, followed by
extraction with ethyl acetate. The resultant organic layer was
washed with saturated brine and dried over sodium sulfate
anhydrate. The solvent was distilled away under reduced pressure,
and the resultant residue was purified by silica gel column
chromatography (methylene chloride:methanol=97:3.fwdarw.17:3) to
give the title compound (131 mg).
[2900] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.43-1.86(3H,m),
1.98-2.03(1H,m), 2.26-2.30(1H,m), 2.45(3H,s), 2.47-2.51(1H,m),
2.67-2.71(1H,m), 2.78-2.86(3H,m), 3.86-3.43(2H,m), 4.16-4.24(2H,m),
6.85(1H,s), 7.13-7.16(1H,m), 7.20-7.24(1H,m), 7.46,7.50(total
1H,s), 7.56-7.64(2H,m), 9.59,9.62(total 1H,s).
Example 74
N-((7R*,8S*)-8-{[(5-Chloroindol-2-yl)
carbonyl]amino}-1,4-dioxaspiro[4.5]dec-7-yl)-5-methyl-4,5,6,7-tetrahydro--
thiazolo[5,4-c]pyridine-2-carboxamide or
N-((7R*,8S*)-7-{[(5-chloroindol-2-yl)carbonyl]amino}-1,4-dioxaspiro-[4.5]-
dec-8-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
[2901] The title compound was obtained from the compound obtained
in Referential Example 120 and the compound obtained in Referential
Example 10 in a similar manner to Example 2.
[2902] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.69-1.87(6H,m),
2.14-2.17(1H,m), 2.30-2.32(1H,m), 2.47(3H,s), 2.70-2.75(1H,m),
2.81-2.89(2H,m), 3.58(1H,d,J=15.4 Hz), 3.72(1H,d,J=15.4 Hz),
3.89-3.91(1H,m), 3.99(4H,s), 4.37-4.40(1H,m), 6.86(1H,d,J=2.0 Hz),
7.19(1H,dd,J=8.8,2.0 Hz), 7.30(1H,d,J=8.8 Hz), 7.38(1H,d,J=7.3 Hz),
7.62(1H,d,J=2.0 Hz), 9.15(1H,s).
Example 75
N-[(1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-(methoxyimino)cyclo-
hexyl]-5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxamide
or
N-[(1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-4-(methoxyimino)--
cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxam-
ide
[2903] 1) The compound (2.21 g) obtained in Referential Example 124
was dissolved in methylene chloride (30 mL), and trifluoroacetic
acid (6 mL) was added, followed by stirring at room temperature for
1.5 hours. The reaction mixture was concentrated, dried with a
vacuum pump and then dissolved in N,N-dimethylformamide (20 mL),
and then 5-chloroindole-2-carboxylic acid (500 mg),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (593
mg), 1-hydroxybenzotriazole monohydrate (473 mg), and
N-methylmorpholine (2.8 mL) were added. The mixture was stirred at
room temperature for 10 hours. Additionally,
5-chloroindole-2-carboxylic acid (242 mg),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (237
mg), and 1-hydroxybenzotriazole monohydrate (189 mg) were added,
followed by stirring for 4 hours. Saturated aqueous sodium
hydrogencarbonate was added to the reaction mixture, and the
mixture was extracted with ethyl acetate and with a mixture of
ethyl acetate and tetrahydrofuran. The resultant organic layers
were washed with saturated brine and dried over sodium sulfate
anhydrate. The solvent was distilled away under reduced pressure,
and the resultant residue was purified by silica gel column
chromatography (methylene chloride:methanol=97:3.fwdarw.4:1) to
give
N-[(1R*,2S*)-2-amino-5-(methoxyimino)cyclohexyl]-5-chloroindole-2-carboxa-
mide (368 mg) and
N-[(1R*,2S*)-2-amino-4-(methoxyimino)cyclohexyl]-5-chloroindole-2-carboxa-
mide (300 mg). [2904] 2) The title compound (mixture of syn and
anti isomers in terms of the methoxyimino group) was obtained from
one of the above-obtained
N-[(1R*,2S*)-2-amino-5-(methoxyimino)cyclohexyl]-5-chloroindole-2-carboxa-
mide and
N-[(1R*,2S*)-2-amino-4-(methoxyimino)cyclohexyl]-5-chloroindole-2-
-carboxamide and the compound obtained in Referential Example 10 in
a similar manner to Example 2.
[2905] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.84-2.00(3H,m),
2.26-2.56(3H,m), 2.46(3H,s), 2.80-2.83(4H,m), 3.57(1H,q,J=15.4 Hz),
3.70(1H,q,J=15.4 Hz), 3.84,3.85(total 3H,s), 4.08-4.14(1H,m),
4.26-4.30(1H,m), 6.84(1H,s), 7.17(1H,d,J=8.8 Hz), 7.27(1H,d,J=8.8
Hz), 7.46-7.48(2H,m), 7.56(1H,m), 9.42,9.55(total 1H,s).
Example 76
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-hydroxycyclohexyl)--
5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide
(Stereoisomer A) or
N-((1R*,2S*)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-4-hydroxycyclohexyl)-
-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
(Stereoisomer A)
[2906] 1) In a manner similar to that employed in Example 49, the
compound obtained in Referential Example 113 was treated with 4N
HCl-dioxane and then, condensed with the compound obtained in
Referential Example 10, to thereby give the title compound. [2907]
2) In a manner similar to that employed in Example 2,
N-((1R*,2S*)-5-{[tert-butyl(diphenyl)silyl]oxy}-2-{[(5-chloroindol-2-yl)c-
arbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridi-
n-2-carboxamide (Stereoisomer A) or
N-((1R*,2S*)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-{[(5-chloroindol-2-yl)c-
arbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridi-
n-2-carboxamide (Stereoisomer A) was obtained from the above
product and the product obtained in Referential Example 10.
[2908] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.06(9H,s),
1.55-1.61(1H,m), 1.85-1.90(1H,m), 2.18-2.25(1H,m), 2.46(3H,s),
2.51(2H,d,J=7.6 Hz), 2.68-2.76(1H,m), 3.56(1H,s), 3.57(1H,d,J=15.3
Hz), 3.72(1H,d,J=15.3 Hz), 3.71-3.81(1H,m), 3.88-3.95(1H,m),
6.78(1H,s), 7.17(1H,dd,J=2.0,8.8 Hz), 7.37-7.44(7H,m), 7.59(1H,s),
7.65-7.68(6H,m), 9.30(1H,s). [2909] 3) In a manner similar to that
employed in the steps 3) of Example 28, the title compound was
obtained from the above reaction product.
[2910] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.25-1.30(2H,m),
1.45-1.64(2H,m), 1.86(1H,d,J=9.0 Hz), 1.98-2.03(1H,m), 2.33(3H,s),
2.66-2.73(2H,m), 2.75-2.79(2H,m), 3.54(1H,d,J=15.6 Hz),
3.62(1H,d,J=15.6 Hz), 3.96-4.02(2H,m), 4.78(1H,d,J=4.2 Hz), 7.00
(1H, s), 7.14(1H,dd,J=2.0,8.8 Hz), 7.38(1H,d,J=8.8 Hz), 7.66 (1H,
s), 8.20(1H,d,J=7.8 Hz), 8.54(1H,d,J=7.8 Hz), 11.69(1H,s).
Example 77
N-((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-hydroxy-5-methylcyc-
lohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
(Stereoisomer A1) or N-((1R*,2S*)-2-{[(5-chloroindol-2-yl)
carbonyl]amino}-4-hydroxy-4-methylcyclohexyl)-5-methyl-4,5,6,7-tetrahydro-
thiazolo[5,4-c]pyridine-2-carboxamide (Stereoisomer A2)
[2911] In a manner similar to that employed in Example 2, the
compound obtained in Referential Example 10 was reacted with the
compound obtained in Referential Example 128, to thereby give the
title compound.
Stereoisomer A1:
[2912] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.24(3H,s),
1.33-1.82(4H,m), 2.34(3H,s), 2.67-3.64(8H,m), 4.02-4.10(2H,m),
4.67(1H,br.s), 7.02(1H,s), 7.13(1H,d,J=8.6 Hz), 7.38(1H,d,J=8.6
Hz), 7.66(1H,d,J=2.0 Hz), 8.21-8.26(1H,m), 8.59(1H,d,J=8.1 Hz),
11.73(1H,br.s)
[2913] MS (FAB) m/z: 502(M+H).sup.+.
Stereoisomer A2:
[2914] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.25(3H,s),
1.33-1.79(4H,m), 2.33(3H,s), 2.65-3.63(8H,m), 3.88-3.94(1H,m),
4.20-4.25(1H,m), 4.59(1H,br), 7.01(1H,s), 7.13(1H,d,J=7.8 Hz),
7.38(1H,d,J=8.6 Hz), 7.67(1H,s), 8.29(1H,br), 8.43(1H,d,J=9.3 Hz),
11.67(1H,br)
[2915] MS (FAB) m/z: 502(M+H).sup.+.
Example 78
N-[(1R*,2R*,5S*)-2-{[(5-Chloroindol-2-yl)
carbonyl]amino}-5-(hydroxymethyl)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrot-
hiazolo[5,4-c]pyridine-2-carboxamide
##STR00744##
[2917] In a manner similar to that employed in Example 49, the
compound obtained in Referential Example 129 was treated with HCl
in ethanol and then, condensed with the compound obtained in
Referential Example 10, to thereby give the title compound.
[2918] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.42-1.90(5H,m),
2.07-2.26(3H,m), 2.46(3H,s), 2.67-2.95(4H,m), 3.55-3:80(4H,m),
3.80-3.95(1H,m), 4.13-4.25(1H,m), 6.84(1H,br.s),
7.17(1H,dd,J=8.8,2.0 Hz), 7.23-7.35(2H,m), 7.43(1H,d,J=7.2 Hz),
7.58(1H,br.s), 9.29(1H,s).
[2919] MS (ESI) m/z: 502(M+H).sup.+.
Example 79
N-[(1R*,2S*,5S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-(methoxymethyl)-
cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxami-
de
##STR00745##
[2921] In a manner similar to that employed in Example 49, the
compound obtained in Referential Example 135 was treated with HCl
in ethanol and then, condensed with the compound obtained in
Referential Example 10, to thereby give the title compound.
[2922] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20-1.38(1H,m),
1.50-1.67(2H,m), 1.88-2.03(2H,m), 2.03-2.14(1H,m), 2.21-2.32(1H,m),
2.53(3H,s), 2.75-2.95(2H,m), 3.20-3.35(2H,m), 3.37(3H,s), 3.73(1H,
d,J=16.0 Hz), 3.76(1H,d,J=16.0 Hz), 4.04-4.13(1H,m),
4.53-4.62(1H,m), 6.85(1H,d,J=2.0 Hz), 7.19(1H,dd,J=8.8,2.0 Hz),
7.33(1H,d,J=8.8 Hz), 7.54(1H,d,J=7.2 Hz), 7.63(1H,d,J=2.0 Hz),
8.07(1H,d,J=5.6 Hz), 9.49(1H,br.s).
Example 80
N-((1R*,2S*,5S*)-2-{[(5-Chloroindol-2-yl)
carbonyl]amino}-5-{[(methylsulfonyl)amino]methyl}cyclohexyl)-5-methyl-4,5-
,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
[2923] ##STR00746## [2924] 1) The compound (437 mg) obtained in
Referential Example 137 was dissolved in ethanol (5 mL), and 4N
Hcl-dioxane (5 mL) was added at room temperature, followed by
stirring for 13 hours. The solvent was distilled away, and the
residue was dissolved in N,N-dimethylformamide (10 mL), and then
triethylamine (0.7 mL), the compound (300 mg) obtained in
Referential Example 10, 1-hydroxybenzotriazole monohydrate (162 mg)
and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(230 mg) were added. The mixture was stirred for 13 hours. The
solvent was removed under reduced pressure, and water was added to
the reaction mixture, followed by extraction with chloroform. The
resultant organic layer was washed with saturated aqueous sodium
hydrogencarbonate and saturated brine and dried over magnesium
sulfate anhydrate. The solvent was distilled away under reduced
pressure, and the resultant residue was purified by silica gel
column chromatography (methylene chloride: methanol=97:3) to give
N-((1R*,2S*,5S*)-5-(azidomethyl)-2-{[(5-chloroindol-2-yl)carbonyl]amino}c-
yclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamid-
e (330 mg).
[2925] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.15-2.08(7H,m),
2.33(3H,s), 2.34-2.95(6H,m), 3.64(2H,s), 4.05-4.17(1H,m),
4.36-4.47(1H,m), 7.02(1H,s), 7.15(1H,dd,J=8.8,2.0 Hz),
7.40(1H,d,J=8.8 Hz), 7.67(1H,d,J=2.0 Hz), 8.02(1H,d,J=7.6 Hz),
8.44(1H,d,J=7.6 Hz), 11.8(1H,s). [2926] 2) The compound (300 mg)
obtained by the above reaction was dissolved in ethanol (8 mL), and
a catalytic amount of 10% palladium on carbon was added, followed
by stirring at room temperature for 168 hours in a hydrogen
atmosphere. Insoluble matter was filtered, and the solvent was
distilled away. The thus-obtained crude
N-((1R*,2S*,5S*)-5-(aminomethyl)-2-{[(5-chloroindol-2-yl)carbonyl]amino}c-
yclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamid-
e (150 mg) was dissolved in chloroform (6 mL), and triethylamine
(0.2 mL) and methanesulfonyl chloride (0.035 mL) were added under
ice cooling, followed by stirring for 13 hours. The solvent was
distilled away under reduced pressure, and water was added to the
residue, followed by extraction with chloroform. The resultant
organic layer was washed with saturated aqueous sodium
hydrogencarbonate and saturated brine and dried over magnesium
sulfate anhydrate. The solvent was distilled away under reduced
pressure, and the resultant residue was purified by silica gel
column chromatography (methylene chloride: methanol=24:1) to give
the title compound (56 mg).
[2927] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18-1.34(2H,m),
1.50-1.75(4H,m), 1.90-2.30(4H,m), 2.53(3H,s), 2.78-2.90(2H,m),
2.90-3.05(6H,m), 3.20-3.30(1H,m), 3.68-3.81(2H,m), 3.98-4.08(1H,m),
4.54-4.62(1H,m), 6.10-6.19(1H,m), 6.86(1H,s), 7.19(1H,dd,J=8.8,2.0
Hz), 7.35(1H,d,J=8.8 Hz), 7.52(1H,d,J=7.6 Hz), 7.62(1H,d,J=2.0 Hz),
8.21(1H,d,J=5.6 Hz), 9.89(1H,s).
[2928] MS (ESI) m/z: 579(M+H).sup.+.
Example 81
N-{(1R*,2S*,5S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino-
)methyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-c-
arboxamide trifluoroacetate
##STR00747##
[2930] The title compound was obtained from the amine obtained in
the step 2) of Example 80 in a similar manner to Example 24.
[2931] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.15-2.22(7H,m),
2.40-2.65(2H,m), 2.68-2.85(6H,m), 2.92-3.08(5H,m), 3.10-3.18(2H,m),
4.08-4.20(1H,m), 4.35-4.51(2H,m), 7.04(1H,s), 7.14-7.20(1H,m),
7.41(1H,d,J=8.8 Hz), 7.67(1H,s), 8.25-8.42(2H,m), 9.11(1H,br.s),
9.89(1H,s).
[2932] MS (ESI) m/z: 529(M+H).sup.+.
Example 82
tert-Butyl
(3R*,4S*)-4-{[(5-chloroindol-2-yl)carbonyl]-amino}-3-{[(5-methy-
l-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amino}cyclohexyl-
carbamate (Isomer B) and tert-butyl
(3R*,4S*)-3-{[(5-chloroindol-2-yl)carbonyl]-amino}-4-{[(5-methyl-4,5,6,7--
tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amino}cyclohexylcarbamate
(Isomer B):
##STR00748##
[2934] The compound (Stereoisomer B) (1.79 g) obtained in
Referential Example 140 was dissolved in tetrahydrofuran (36 mL),
and 10% palladium on carbon (0.40 g) was added, followed by
stirring at room temperature for 20 hours in a hydrogen atmosphere.
After the catalyst was removed by filtration, the filtrate was
concentrated under reduced pressure, and the residue was dissolved
in N,N-dimethylformamide (36 mL), and then p-nitrophenyl
5-chloroindole-2-carboxylate (2.02 g) was added, followed by
stirring for 16 hours. The reaction mixture was concentrated under
reduced pressure, and ethyl acetate and water were added to the
residue to collect insoluble matter by filtration. The product was
washed with ethyl acetate to give crude tert-butyl
(3R*,4S*)-3-amino-4-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexylcarbam-
ate (or
(3R*,4S*)-4-amino-3-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexy-
lcarbamate) (Isomer B1) (1.49 g). The organic layer of the filtrate
was washed with water and dried over sodium sulfate anhydrate. The
solvent was distilled away under reduced pressure, and the residue
was purified by silica gel column chromatography (methylene
chloride: methanol=30:1.fwdarw.10:1) to give tert-butyl
(3R*,4S*)-4-amino-3-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexylcarbam-
ate (or tert-butyl
(3R*,4S*)-3-amino-4-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexylcarbam-
ate) (Isomer B2) (0.37 g). One of the title compounds was obtained
from the Isomer B1 and the compound obtained in Referential Example
10 in a similar manner to Example 2.
[2935] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.25-1.50(1H,m),
1.37(9H,s), 1.50-1.65(1H,m), 1.75-2.20(4H,m),2.37(3H,s),
2.70-3.00(4H,m), 3.60-3.80(3H,m), 4.13(1H,br.a), 4.43(1H,br.s),
6.92(1H,d,J=7.1 Hz), 7.05(1H,s), 7.17(1H,dd,J=8.8,2.2 Hz),
7.41(1H,d,J=8.8 Hz), 7.69(1H,s), 8.15(1H,d,J=7.8 Hz),
8.37(1H,d,J=7.1 Hz), 11.78(1H,s).
[2936] MS (FAB) m/z: 587(M+H).sup.+.
[2937] The other title compound was obtained from the Isomer B2 in
the same manner.
[2938] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.15-1.30(1H,m),
1.35(9H,s), 1.45-1.60(1H,m), 1.65-1.75(1H,m), 1.85-1.95(1H,m),
2.05-2.20(2H,m), 2.34(3H,s), 2.65-2.85(4H,m), 3.55-3.70(3H,m),
4.05-4.14(1H,m),4.40(1H,br.s), 6.80(1H,d,J=7.3 Hz),
7.15-7.25(2H,m), 7.43(1H,d,J=8.8 Hz), 7.73(1H,d,J=2.0 Hz),
8.05(1H,d,J=6.6 Hz), 8.51(1H,d,J=8.8 Hz), 11.82(1H,s).
[2939] MS (FAB) m/z: 587(M+H).sup.+.
Example 83
N-((1R*,2S*)-5-Amino-2-{[(5-chloroindol-2-yl)carbonyl]-amino}cyclohexyl)-5-
-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide
(or
N-((1R*,2S*)-4-amino-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-
-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide)
hydrochloride (Stereoisomer B)
##STR00749##
[2941] The compound (Stereoisomer B) (1.11 g) synthesized from
Isomer B1 in Example 82 was suspended in methylene chloride (20
mL), and HCl in ethanol (20 mL) was added, followed by stirring at
room temperature for 2 hours. The solvent was distilled away under
reduced pressure, and the residue was purified by gel filtration
(Sephadex LH-20, methanol) to give the title compound (1.05 g).
[2942] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.55-1.65(1H,m),
1.75-1.90(2H,m), 1.95-2.20(2H,m), 2.20-2.40(1H,m), 2.90(3H,s),
3.10-3.20(1H,m), 3.20-3.50(3H,m), 3.65-3.75(1H,m), 4.10-4.20(1H,m),
4.35-4.50(1H,m), 4.55-4.65(1H,m), 4.65-4.75(1H,m), 7.07(1H,s),
7.17(1H,dd,J=8.8,2.0 Hz), 7.42(1H,d,J=8.8 Hz), 7.69(1H,s),
8.05-8.30(3H,br), 8.40-8.50(2H,m), 11.70-11.90(2H,m).
[2943] MS (FAB) m/z: 487(M+H).sup.+.
Example 84
N-{(1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(methylsulfonyl)am-
ino]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbo-
xamide or
N-{(1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-4-[(methyls-
ulfonyl)amino]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridi-
ne-2-carboxamide (Stereoisomer B)
##STR00750##
[2945] The compound (0.20 g) obtained in Example 83 was suspended
in methylene chloride (7 mL), and triethylamine (0.16 mL) and
methanesulfonyl chloride (28 .mu.l) were added, followed by
stirring at room temperature for 20 hours. After the reaction
mixture was diluted with methylene chloride, it was washed with
aqueous sodium hydroxide and dried over sodium sulfate anhydrate.
The solvent was distilled away under reduced pressure, and the
residue was purified by silica gel column chromatography (methylene
chloride:methanol=30:1.fwdarw.15:1) to give the title compound
(67.9 mg).
[2946] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.40-1.55(1H,m),
1.65-1.85(2H,m), 1.90-2.05(2H,m), 2.15-2.25(1H,m), 2.41(3H,s),
2.75-2.95(4H,m), 2.92(3H,s), 3.55-3.80(3H,m), 4.10-4.20(1H,m),
4.45-4.55(1H,m), 7.08(1H,s), 7.15-7.20(2H,m), 7.41(1H,d,J=8.8 Hz),
7.69(1H,s), 8.27(1H,d,J=7.3 Hz), 8.33(1H,d,J=8.1 Hz),
11.77(1H,s).
[2947] MS (FAB) m/z: 565 (M+H).sup.+.
Example 85
N-((1R*,2S*)-5-(Acetylamino)-2-{[(5-chloroindol-2-yl)-carbonyl]amino}cyclo-
hexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
or
N-((1R*,2S*)-4-(acetylamino)-2-{[(5-chloroindol-2-yl)-carbonyl]amino}cycl-
ohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
(Stereoisomer B)
##STR00751##
[2949] The compound (Stereoisomer B) (0.20 g) obtained in Example
83 was suspended in methylene chloride (7 mL), and triethylamine
(0.16 mL) and acetic anhydride (34 .mu.l) were added, followed by
stirring at room temperature for 20 hours. Methylene chloride and
aqueous sodium hydroxide were added to the reaction mixture to
separate insoluble matter by filtration. The organic layer of the
filtrate was separated and dried over sodium sulfate anhydrate, and
the solvent was then distilled away under reduced pressure. The
residue was purified by silica gel column chromatography (methylene
chloride:methanol=15:1.fwdarw.10:1) to give the title compound
(0.12 g).
[2950] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35-1.50(1H,m),
1.55-1.70(1H,m), 1.80(3H,s), 1.80-2.05(3H,m), 2.05-2.20(1H,m),
2.47(3H,s), 2.80-3.00(4H,m), 3.75-4.00(3H,m), 4.15-4.30(1H,m),
4.45-4.55(1H,m), 7.07(1H,s), 7.17(1H,dd,J=8.8,1.0 Hz),
7.41(1H,d,J=8.8 Hz), 7.69(1H,s), 7.89(1H,d,J=7.3 Hz),
8.24(1H,d,J=8.1 Hz), 8.31(1H,d,J=7.3 Hz), 11.77(1H,s).
[2951] MS (FAB) m/z: 528(M+H).sup.+.
Example 86
N-((1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-{[methoxy(methyl)a-
mino]carbonyl}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridi-
ne-2-carboxamide hydrochloride
##STR00752##
[2953] The compound (250 mg) obtained in Example 58 was dissolved
in N,N-dimethylformamide (5 mL), and N,O-dimethylhydroxylamine
hydrochloride (142 mg),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (111
mg), 1-hydroxybenzotriazole monohydrate (89 mg), and
N-methylmorpholine (213 mL) were added, followed by stirring at
room temperature for 19 hours. After the reaction mixture was
concentrated, an aqueous solution of sodium hydrogencarbonate was
added to the residue, and the mixture was extracted with ethyl
acetate. After the resultant organic layer was washed with
saturated brine and dried over sodium sulfate anhydrate, the
solvent was distilled away under reduced pressure. The residue was
purified by silica gel column chromatography (methylene
chloride:methanol=47:3.fwdarw.23:2) to give a colorless amorphous
solid (179 mg). This product was dissolved in
methanol-tetrahydrofuran, and 1N HCl in ethanol (960 mL) was added
to give the title compound.
[2954] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.57-1.91(4H,m),
1.96-2.00(1H,m), 2.10-2.21(1H,m), 2.92(3H,s), 2.93-3.03(2H,m),
3.08(3H,s), 3.10-3.28(2H,m), 4.16-4.19(1H,m), 4.50-4.52(1H,m),
4.69(1H,br.s), 7.06(1H,s), 7.17(1H,dd,J=8.8,1.5 Hz),
7.42(1H,d,J=8.8 Hz), 7.70(1H,s), 8.33(1H,br.s), 8.41(1H,d,J=7.8
Hz), 11.81(1H,br.s).
[2955] MS (ESI) m/z: 559(M+H).sup.+.
Example 87
N-((1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(2,2-dimethylhydr-
azino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyrid-
ine-2-carboxamide hydrochloride
##STR00753##
[2957] The title compound was obtained from the compound obtained
in Example 58 and N,N-dimethylhydrazine in a similar manner to
Example 57.
[2958] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.49-1.54(1H,m),
1.76-1.81(2H,m), 1.89-1.93(2H,m), 2.07-2.17(1H,m),
2.33-3.60(14H,m), 4.15-4.19(1H,m), 4.40-4.47(2H,m),
4.70-4.72(1H,m), 7.04(1H,s), 7.17(1H,dd,J=8.5,2.0 Hz),
7.42(1H,d,J=8.5 Hz), 7.70(1H,s), 8.17-8.22(1H,m), 8.41-8.43(1H,m),
11.80(1H,br.s).
[2959] MS (ESI) m/z: 558(M+H).sup.+.
Example 88
6-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-t-
etrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-2-quinolin-
ecarboxamide hydrochloride
##STR00754##
[2961] In a manner similar to that employed in Example 49, the
compound obtained in Referential Example 145 was treated with HCl
in ethanol and then, condensed with the compound obtained in
Referential Example 10, to thereby give the title compound.
[2962] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.45-1.60(1H,m),
1.75-1.90(3H,m), 1.90-2.00(1H,m), 2.00-2.20(1H,m), 2.80(3H,s),
2.90(3H,s), 2.99(3H,s), 3.10-3.30(5H,m), 3.56(1H,br),
4.10-4.20(1H,m), 4.40-4.70(2H,m), 7.88(2H,s), 8.15(1H,d,J=8.6 Hz),
8.22(1H,s), 8.52(1H,d,J=8.6 Hz), 8.72(1H,d,J=8.3 Hz),
8.89(1H,d,J=8.3 Hz).
[2963] MS (FAB) m/z: 555(M+H).sup.+.
Example 89
N-{(1R,2S,5S)-2-{[(5-Chloro-4-fluoroindol-2-yl)carbonyl]-amino}-5-[(dimeth-
ylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyr-
idine-2-carboxamide hydrochloride
##STR00755##
[2965] In a manner similar to that employed in Referential Example
91, the compound obtained in Referential Example 144 was condensed
with the compound obtained in Referential Example 274. The
thus-obtained compound was treated with 4N HCl-dioxane, followed by
condensation with the compound obtained in Referential Example 10,
to thereby give the title compound.
[2966] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.24-1.98(6H,m),
2.33-3.33(6H,m), 2.81(3H,s), 2.90(3H,s), 2.99(3H,s), 4.12(1H,br.s),
4.30-4.70(1H,m), 4.60(1H,br.s), 7.21(1H,s), 7.27(2H,br.s),
8.37(1H,d,J=8.1 Hz), 8.43(1H,d,J=7.6 Hz), 12.11(1H,s).
[2967] MS (FAB) m/z: 561(M+H).sup.+.
Example 90
7-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-t-
etrahydrothiazolo[5,4-c]pyridin-2-yl)-carbonyl]amino}cyclohexyl)isoquinoli-
ne-3-carboxamide hydrochloride
##STR00756##
[2969] In a manner similar to that employed in Example 49, the
compound obtained in Referential Example 146 was treated with HCl
in ethanol and then, condensed with the compound obtained in
Referential Example 10, to thereby give the title compound.
[2970] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.45-1.65(1H,m),
1.70-1.85(3H,m), 1.95-2.10(1H,m), 2.10-2.20(1H,m), 2.80(3H,s),
2.92(3H,s), 2.96(3H,s), 2.95-3.10(1H,m), 3.10-3.40(3H,m),
3.70-3.80(1H,m), 4.20-4.30(1H,m), 4.40-4.60(2H,m), 4.65-4.80(1H,m),
7.83-7.93(1H,m), 8.26(1H,d,J=8.8 Hz), 8.38(1H,s), 8.60(1H,s),
8.85-9.00(2H,m), 9.30-9.40(1H,m).
[2971] MS (FAB) m/z: 555(M+H).sup.+.
Example 91
N-((3R*,4S*)-4-{[(5-Chloroindol-2-yl)
carbonyl]amino}-tetrahydrofuran-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo-
-[5,4-c]pyridine-2-carboxamide hydrochloride
##STR00757##
[2973] The compound (0.1 g) obtained in Referential Example 10,
1-hydroxybenzotriazole monohydrate (78 mg), and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.2 g)
were successively added to a solution of the compound (0.12 g)
obtained in Referential Example 172 in N,N-dimethylformamide (20
mL), and the mixture was stirred at room temperature for 1 day.
After the reaction mixture was concentrated, and the resultant
residue was diluted with chloroform-methanol (9:1) and washed with
saturated aqueous sodium hydrogencarbonate and saturated brine, the
resultant organic layer was dried over sodium sulfate anhydrate,
and the solvent was distilled away under reduced pressure. The
residue was purified by silica gel column chromatography
(chloroform:methanol=95:5) to give a free base of the title
compound. This product was treated with HCl in ethanol to give the
title compound (0.1 g).
[2974] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.50(3H,s),
2.70-2.90(4H,m), 3.67(1H,s), 3.70(1H,s), 3.86(1H,dd,J=9.2,6.3 Hz),
3.97(1H,dd,J=9.7,4.1 Hz), 4.15(1H,dd,J=9.7,5.8 Hz),
4.24(1H,dd,J=9.2,7.0 Hz), 4.75-4.89(1H,m), 4.92-5.03(1H,m),
6.88(1H,s), 7.20(1H,dd,J=8.8,2.0 Hz), 7.33(1H,d,J=8.8 Hz),
7.35-7.43(1H,m), 7.58(1H,d,J=2.0 Hz), 7.64(1H,d,J=7.1 Hz),
9.38(1H,s).
[2975] MS (FAB) m/z: 460(M+H.sup.+).
Example 92
N-((3S,4S)-4-([(5-Chloroindol-2-yl)carbonyl]amino}-tetrahydrofuran-3-yl)-5-
-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide
##STR00758##
[2977] The title compound was obtained from the compound obtained
in Referential Example 183 in accordance with the processes of
Referential Example 172 and Example 91.
[2978] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.51(3H,s),
2.83(2H,t,J=5.3 Hz), 2.93(2H,t,J=5.3 Hz), 3.72(2H,s),
3.78-3.89(2H,m), 4.31(1H,dd,J=9.2,7.3 Hz), 4.41-4.56(2H,m),
4.63-4.75(1H,m), 6.88(1H,s), 7.22(1H,dd,J=8.8,2.0 Hz),
7.32(1H,d,J=8.8 Hz), 7.35-7.46(1H,m), 7.55(1H,d,J=7.1 Hz),
7.60(1H,d,J=2.0 Hz), 9.38(1H,s).
[2979] MS (FAB) m/z: 460(M+H.sup.+).
Example 93
N-((3R,4R)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-tetrahydrofuran-3-yl)-5-
-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00759##
[2981] The title compound was obtained from the compound obtained
in Referential Example 187 in accordance with the processes of
Referential Example 172 and Example 91.
[2982] .sup.1H-NMR and MS (FAB): The same as those of the
enantiomer in Example 92.
Example 94
tert-Butyl
(3R,4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4-
,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidine-1--
carboxylate
##STR00760##
[2984] The title compound was obtained from the compound obtained
in Referential Example 193 and the compound obtained in Referential
Example 10 in accordance with the process of Example 91.
[2985] Melting point: 190-192.degree. C.
[2986] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.45(9H,s), 2.46(3H,s),
2.74-2.81(4H,m), 3.24-3.37(2H,m), 3.54-3.70(2H,m), 3.96-4.00(1H,m),
4.15-4.23(1H,m), 4.50-4.65(1H,m), 4.77-4.82(1H,m), 6.79,6.87(total
1H,each s), 7.12-7.95(5H,m), 9.91,9.97(total 1H,each s).
[2987] MS (FAB) m/z: 559(M+H.sup.+).
Example 95
N-((3R,4R)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-pyrrolidin-3-yl)-5-meth-
yl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00761##
[2989] The compound (170 mg) obtained in Example 94 was dissolved
in methylene chloride (3 mL), and trifluoroacetic acid (2 mL) was
added at room temperature, followed by stirring for 1 hour. After
concentrating the reaction mixture, chloroform and saturated
aqueous sodium hydrogencarbonate were added. The resultant organic
layer was dried over sodium sulfate anhydrate, and the solvent was
distilled away under reduced pressure. The resultant residue was
purified by silica gel thin layer chromatography
(chloroform:methanol:water=7:3:1, under layer). HCl in methanol was
added to the resultant product to give the title compound (90 mg)
as a hydrochloride (NMR was measured in the form of a free
base).
[2990] Melting point: 248-250.degree. C. (decomposed).
[2991] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.44(3H,s),
2.70-2.80(4H,m), 2.97-3.05(2H,m), 3.46-3.68(4H,m), 4.49-4.52(1H,m),
4.60-4.65(1H,m), 6.86(1H,s), 7.05-7.08(1H,m), 7.20(1H,d,J=8.5 Hz),
7.44(1H,s), 7.89(2H,br), 10.51(1H,br).
[2992] MS (FAB) m/z: 459(M+H.sup.+).
Example 96
N-((3S,4S)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-oxotetrahydrofuran-3--
yl)-5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00762##
[2994] In a manner similar to that employed in Referential Example
69, the tert-butoxycarbonyl group of the compound obtained in
Referential Example 196 was removed. Subsequently, in a manner
similar to that employed in Example 91, the thus-obtained compound
was reacted with the compound obtained in Referential Example 10,
to thereby give the title compound.
[2995] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.90(3H,s),
3.02-3.17(2H,m), 3.23-3.34(4H,m), 4.20(1H,t,J=8.6 Hz),
4.61(1H,t,J=8.6 Hz), 4.92-5.01(1H,m), 5.14-5.26(1H,m), 7.09(1H,s),
7.19(1H,dd,J=8.8,2.0 Hz), 7.41(1H,d,J=8.8 Hz), 7.73(1H,d,J=2.0 Hz),
9.27(1H,d,J=6.8 Hz), 9.35(1H,d,J=6.8 Hz), 11.22-11.33(1H,m),
11.89(1H,s).
[2996] MS (FAB) m/z: 474(M+H.sup.+).
Example 97
N-((3S,4S)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-2-oxotetrahydrofuran-3--
yl)-5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00763##
[2998] In a manner similar to that employed in Referential Example
69, the tert-butoxycarbonyl group of the compound obtained in
Referential Example 197 was removed. Subsequently, in a manner
similar to that employed in Example 91, the thus-obtained compound
was reacted with 5-chloroindole-2-carboxylic acid, to thereby give
the title compound.
[2999] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.52(3H,s),
2.83(2H,t,J=5.9 Hz), 2.91-3.00(2H,m), 3.73(2H,s), 4.23(1H,t,J=8.6
Hz), 4.40-4.53(1H,m), 4.96(1H,dd,J=10.8,5.2 Hz),
5.16(1H,dd,J=9.2,7.3 Hz), 7.01(1H,s), 7.25(1H,dd,J=8.8,2.0 Hz),
7.34(1H,d,J=8.8 Hz), 7.52(1H,d,J=2.0 Hz), 8.01(1H,d,J=5.4 Hz),
8.51-8.63(1H,m),9.22(1H,s).
[3000] MS (FAB) m/z: 474(M+H.sup.+).
Example 98
Ethyl
(3S,4R)-2-(3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5-
,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-2-oxopyrrolidin-
-1-yl)acetate hydrochloride
##STR00764##
[3002] The title compound was obtained from the compound obtained
in Referential Example 199 and the compound obtained in Referential
Example 10 in a similar manner to Example 91. NMR was measured in
the form of a free base.
[3003] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.19(3H,t,J=7.1 Hz),
2.35(3H,s), 2.71-2.84(2H,m), 2.80-2.90(2H,m), 3.40(1H,d,J=10.3 Hz),
3.61(2H,d,J=10.8 Hz), 3.84(1H,dd,J=10.3,5.6 Hz), 4.01-4.23(4H,m),
4.80-4.94(1H,m), 5.04(1H,t,J=8.6 Hz), 7.01(1H,s),
7.16(1H,dd,J=8.8,2.0 Hz), 7.40(1H,d,J=8.8 Hz), 7.69(1H,d,J=2.0 Hz),
8.73(1H,d,J=8.6 Hz), 8.90(1H,d,J=8.8 Hz), 11.86(1H,s).
[3004] MS (FAB) m/z: 559(M+H.sup.+).
Example 99
N-((3R,4S)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-methyl-5-oxopyrrolidi-
n-3-yl)-5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxamide
##STR00765##
[3006] The title compound was obtained from the compound obtained
in Referential Example 201 and the compound obtained in Referential
Example 10 in a similar manner to Example 91.
[3007] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.49(3H,s),
2.77-2.82(2H,m), 2.86-2.91(5H,m), 3.69(2H,d,J=1.2 Hz),
4.39-4.54(3H,m), 4.93-4.98(1H,m), 6.98(1H,d,J=1.2 Hz),
7.05-7.34(3H,m), 7.63(1H,d,J=2.0 Hz), 8.11(1H,d,J=7.8 Hz),
9.00(1H,s)
[3008] MS (FAB) m/z: 487(M+H.sup.+).
Example 100
Methyl
2-[((3R,4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4-
,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-y-
l)sulfonyl]acetate
##STR00766##
[3010] The compound (230 mg) obtained in Example 95 and
triethylamine (0.10 mL) were dissolved in methylene chloride (6.9
mL), and the mixture was cooled with ice.
[3011] Methoxycarbonylmethanesulfonyl chloride (Synthesis, p. 321,
1975) (105 mg) was added. The temperature of the resultant mixture
was returned to room temperature, and the mixture was stirred
overnight. The reaction mixture was diluted with chloroform, washed
with water and saturated brine and then dried over sodium sulfate
anhydrate, and the solvent was distilled away under reduced
pressure. The resultant residue was purified by silica gel thin
layer chromatography (chloroform:methanol=20:1) and powdered with
methanol-water to give the title compound (150 mg).
[3012] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.48(3H,s),
2.76-2.86(4H,m), 3.49-3.73(4H,m), 3.87(3H,s), 3.94-3.98(1H,m),
4.08-4.11(1H,m), 4.13(2H,s), 4.69-4.72(1H,m), 4.88-4.91(1H,m),
6.89(1H,s), 7.12-7.15(1H,m), 7.27-7.28(1H,m), 7.50(1H,s),
7.81-7.86(2H,m), 9.92(1H,s).
[3013] MS (FAB) m/z: 595(M+H.sup.+).
Example 101
2-[((3R,4R)-3-{[(5-Chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7--
tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)sulfo-
nyl]acetic acid
##STR00767##
[3015] The compound (100 mg) obtained in Example 100 was dissolved
in tetrahydrofuran (4 mL)-water (1 mL), and the mixture was cooled
with ice. Lithium hydroxide monohydrate (7.8 mg) was added thereto.
The temperature of the resultant mixture was returned to room
temperature, and the mixture was stirred for 4 hours. After the
reaction mixture was neutralized with 1N hydrochloric acid, it was
concentrated. Precipitates were collected by filtration, washed
with water and 50% ethanol and dried overnight at 50.degree. C.
under reduced pressure to give the title compound (87 mg).
[3016] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.50(3H,s), 2.92(4H,s),
3.34-3.43(4H,m), 3.76-3.85(2H,m), 4.27(each 1H,AB type d,J=14.5
Hz), 4.65-4.71(1H,m), 4.78-4.84(1H,m), 7.14(1H,s), 7.18(1H,d,J=8.8
Hz), 7.40(1H,d,J=8.8 Hz), 7.72(1H,s), 8.87(1H,d,J=7.8 Hz),
9.12(1H,d,J=8.2 Hz), 11.83(1H,s).
Example 102
Methyl
2-((3R,4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,-
5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amino}pyrrolidin-1-y-
l)acetate
##STR00768##
[3018] The compound (230 mg) obtained in Example 95 and potassium
carbonate (90 mg) were dissolved in N,N-dimethylformamide (4.6 mL),
and the mixture was cooled with ice. Methyl bromoacetate (0.062 mL)
was added, and the resultant mixture was stirred for 45 minutes.
The reaction mixture was diluted with ethyl acetate, washed with
water and saturated brine and then dried over sodium sulfate
anhydrate, and the solvent was distilled away under reduced
pressure. The resultant residue was purified by silica gel thin
layer chromatography (chloroform:methanol=10:1) and powdered with
methanol-water to give the title compound (190 mg).
[3019] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.35(2H,s), 2.48(3H,s),
2.73-2.95(4H,m), 3.34-3.42(2H,m), 3.46(2H,q,J=6.5 Hz),
3.67(2H,q,J=6.5 Hz), 3.75(3H,s), 4.57-4.71(2H,m), 6.91(1H,s),
7.10-7.13(1H,m), 7.31(1H,d,J=9.0 Hz), 7.53(1H,s), 7.77(1H,d,J=8.0
Hz), 7.87(1H,d,J=6.8 Hz), 10.22(1H,s).
[3020] MS (FAB) m/z: 531(M+H.sup.+).
Example 103
2-((3R,4R)-3-{[(5-Chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-t-
etrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)acetic
acid
##STR00769##
[3022] The title compound was obtained from the compound obtained
in Example 102 in a similar manner to Example 101.
[3023] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.42(3H,s),
2.69-2.87(6H,m), 3.13(1H,t,J=9.0 Hz), 3.22(1H,t,J=9.0 Hz),
3.33(each 1H,AB type d,J=6.8 Hz), 3.72(2H,s), 4.53-4.60(1H,m),
4.65-4.72(1H,m), 7.16-7.20(2H,m), 7.42(1H,d,J=8.8 Hz), 7.70(1H,s),
8.85(1H,d,J=7.5 Hz), 9.00(1H,d,J=8.3 Hz), 11.79(1H,s).
Example 104
Methyl
3-((3R,4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,-
5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl-
)propionate
##STR00770##
[3025] The title compound was obtained from the compound obtained
in Example 95 and methyl 3-bromopropionate in a similar manner to
Example 102.
[3026] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.96-2.20(2H,m),
2.49(3H,s), 2.61-2.96(8H,m), 3.17-3.21(2H,m), 3.62-3.72(2H,m),
3.69(3H,s), 4.46-4.49(1H,m), 4.56-4.61(1H,m), 6.87(1H,s),
7.05-7.14(1H,m), 7.32(1H,d,J=9.2 Hz), 7.53(1H,s), 7.65-7.71(2H,m),
10.02(1H,s).
[3027] MS (FAB) m/z: 545(M+H.sup.+).
Example 105
3-((3R,4R)-3-{[(5-Chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-t-
etrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)propio-
nic acid
##STR00771##
[3029] The title compound was obtained from the compound obtained
in Example 104 in a similar manner to Example 101.
[3030] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.38(3H,s),
2.39-2.84(10H,m), 2.93(1H,t,J=8.8 Hz), 3.05(1H,t,J=8.8 Hz),
3.65(2H,s), 4.51-4.56(1H,m), 4.63-4.68(1H,m), 7.16-7.19(2H,m),
7.41(1H,d,J=8.8 Hz), 7.69(1H,s), 8.81(1H,d,J=7.8 Hz),
8.97(1H,d,J=8.3 Hz), 11.75(1H,s).
Example 106
Ethyl
3-((3R,4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5-
,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)-
-3-oxopropionate
##STR00772##
[3032] The title compound was obtained from the compound obtained
in Example 95 and ethylmalonyl chloride in a similar manner to
Example 100.
[3033] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.20(3H,t,J=7.0 Hz),
2.37(3H,s), 2.73-2.75(2H,m), 2.82-2.84(2H,m), 3.35-3.38(2H,m),
3.64(2H,s), 3.68-3.83(2H,m), 3.91-4.00(2H,m), 4.10(2H,q,J=7.0 Hz),
4.61-4.84(2H,m), 7.13 (1H, s), 7.18(1H,dd,J=8.5,2.0 Hz),
7.41(1H,d,J=8.5 Hz), 7.72(1H,s), 8.73(1H,t,J=9.0 Hz),
9.10(1H,d,J=9.0 Hz), 11.79(1H,s).
Example 107
3-((3R,4R)-3-{[(5-Chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-t-
etrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)-3-oxo-
propionic acid
##STR00773##
[3035] The title compound was obtained from the compound obtained
in Example 106 in a similar manner to Example 101.
[3036] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.39(3H,s), 2.77(2H,s),
2.85(2H,s), 3.29-3.55(4H,m), 3.68(2H,s), 3.82-4.01(2H,m),
4.62-4.68(1H,m), 4.77-4.86(1H,m), 7.14(1H,s), 7.18(1H,d,J=8.8 Hz),
7.41(1H,d,J=8.8 Hz), 7.72(1H,s), 8.75(1H,t,J=8.8 Hz),
9.12(1H,d,J=7.8 Hz), 11.81(1H,s).
Example 108
Methyl
1-[((3R,4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4-
,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-y-
l)methyl]-cyclopropanecarboxylate
##STR00774##
[3038] The title compound was obtained from the compound obtained
in Example 95 and methyl 1-(bromomethyl)-cyclopropanecarboxylate in
a similar manner to Example 102.
[3039] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.78-0.79(2H,m),
1.24-1.26(2H,m), 2.49(3H,s), 2.62-2.88(6H,m), 3.20-3.28(2H,m),
3.66(3H,s), 3.61-3.75(4H,m), 4.45-4.62(2H,m), 6.86(1H,s),
7.12-7.15(1H,m), 7.24-7.28(1H,m), 7.52(1H,d,J=8.5 Hz), 7.54(1H,s),
7.69(1H,d,J=8.0 Hz), 10.00(1H,s).
[3040] MS (ESI) m/z: 571(M+H.sup.+).
Example 109
1-[((3R,4R)-3-{[(5-Chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7--
tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)methy-
l]-cyclopropanecarboxylic acid
##STR00775##
[3042] The title compound was obtained from the compound obtained
in Example 108 in a similar manner to Example 101.
[3043] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.73-0.78(2H,m),
1.04-1.07(2H,m), 2.37(3H,s), 2.65-2.84(6H,m), 3.11-3.20(4H,m),
3.64(2H,s), 4.59-4.74(2H,m), 7.16(1H,s), 7.17(1H,d,J=8.5 Hz),
7.40(1H,d,J=8.5 Hz), 7.70(1H,s), 8.84(1H,d,J=7.5 Hz),
9.12(1H,d,J=7.5 Hz), 11.77(1H,s).
Example 110
tert-Butyl
(3R,4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-isopropy-
l-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidine-
-1-carboxylate
##STR00776##
[3045] The title compound was obtained from the compound obtained
in Referential Example 193 and the compound obtained in Referential
Example 148 in a similar manner to Example 91.
[3046] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12(6H,d,J=6.6 Hz),
1.47(9H,s), 2.83-2.88(4H,m), 2.94-2.99(1H,m), 3.20-3.29(1H,m),
3.31-3.42(1H,m), 3.75-3.81(2H,m), 3.98(1H,t,J=8.5 Hz),
4.15-4.35(2H,m), 4.50-4.65(1H,m), 6.85,6.91(total 1H,each s),
7.15-7.90(5H,m), 9.41,9.50(total 1H,each s).
Example 111
N-((3R,4R)-4-{[(5-chloroindol-2-yl)carbonyl]amino}pyrrolidin-3-yl)-5-isopr-
opyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
##STR00777##
[3048] The title compound was obtained from the compound obtained
in Example 110 in a similar manner to Example 95.
[3049] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13(6H,d,J=6.3 Hz),
2.85(4H,br.s), 2.96-3.05(3H,m), 4.51-4.52(1H,m), 4.76-4.80(2H,m),
5.36-5.39(2H,m), 5.53-5.58(1H,m), 7.17-7.19(1H,m), 7.27-7.31(2H,m),
7.57(1H,s), 7.64(2H,br), 9.82(1H,br).
Example 112
Ethyl
3-((3R,4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-isopropyl--
4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1--
yl)propionate
##STR00778##
[3051] The title compound was obtained from the compound obtained
in Example 111 and ethyl 3-bromopropionate in a similar manner to
Example 102.
[3052] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14(6H,d,J=6.5 Hz),
1.26(3H,t,J=7.0 Hz), 2.51(3H,t,J=7.0 Hz), 2.63(1H,dd,J=9.5,6.5 Hz),
2.73-2.91(6H,m), 2.95-3.02(1H,m), 3.22(2H,q,J=7.0 Hz), 3.81(each
1H,AB type d,J=14.5 Hz), 4.16(2H,q,J=7.0 Hz), 4.40-4.45(1H,m),
4.52-4.59(1H,m), 6.88(1H,d,J=2.0 Hz), 7.17-7.19(1H,m),
7.30-7.32(2H,m), 7.59(1H,s), 7.62(1H,s), 9.56(1H,s).
[3053] MS (FAB) m/z: 587(M+H.sup.+).
Example 113
3-((3R,4R)-3-{[(5-Chloroindol-2-yl)carbonyl]amino}-4-{[(5-isopropyl-4,5,6,-
7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)pro-
pionic acid
##STR00779##
[3055] The title compound was obtained from the compound obtained
in Example 112 in a similar manner to Example 101.
[3056] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.04(6H,d,J=6.6 Hz),
2.40(2H,q,J=7.0 Hz), 2.50(4H,s), 2.60-2.74(4H,m), 2.90-2.94(2H,m),
3.02-3.06(1H,m), 3.20-3.35(2H,m), 4.50-4.53(1H,m), 4.61-4.65(1H,m),
7.15-7.18(2H,m), 7.41(1H,d,J=8.8 Hz), 7.68(1H,s), 8.78(1H,d,J=7.5
Hz), 8.90(1H,d,J=8.0 Hz), 11.73(1H,s).
Example 114
N-((3R,4R)-1-Acetyl-4-{[(5-chloroindol-2-yl)carbonyl]-amino}pyrrolidin-3-y-
l)-5-isopropyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00780##
[3058] The title compound was obtained from the compound obtained
in Example 111 and acetic anhydride in a similar manner to Example
100.
[3059] Melting point: 254-258.degree. C. (decomposed).
[3060] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.34-1.37(6H,m),
1.96(3H,s), 3.30-3.55(5H,m), 3.66-3.82(3H,m), 3.95(1H,q,J=8.3 Hz),
4.45-4.82(4H,m), 7.15 (1H, s), 7.18(1H,d,J=9.0 Hz), 7.41(1H,d,J=9.0
Hz), 7.71(1H,s), 8.75-8.81(1H,m), 9.21(1H,d,J=8.0 Hz),
11.32(1H,br), 11.83(1H,d,J=7.3 Hz).
[3061] MS (FAB) m/z: 529(M+H.sup.+).
Example 115
N-[(3R,4R)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(methylsulfonyl)pyrro-
lidin-3-yl]-5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbox-
amide hydrochloride
##STR00781##
[3063] The title compound was obtained from the compound obtained
in Example 111 and methanesulfonyl chloride in a similar manner to
Example 100.
[3064] Melting point: 230-235.degree. C. (decomposed).
[3065] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.32-1.36(6H,m),
3.32(3H,s), 3.43-3.46(5H,m), 3.68-3.75(4H,m), 4.48(1H,m),
4.62-4.72(2H,m), 4.83(1H,t,J=5.5 Hz), 7.14(1H,s), 7.18(1H,d,J=8.6
Hz), 7.40(1H,d,J=8.6 Hz), 7.72(1H,s), 8.82(1H,br), 9.20(1H,d,J=8.3
Hz), 11.30(1H,br), 11.86(1H,d,J=7.5 Hz).
[3066] MS (FAB) m/z: 565(M+H.sup.+).
Example 116
Ethyl
(3R,4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-isopropyl-4,5-
,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidine-1-ca-
rboxylate hydrochloride
##STR00782##
[3068] The title compound was obtained from the compound obtained
in Example 111 and ethyl chloroformate in a similar manner to
Example 100.
[3069] Melting point: 225-228.degree. C. (decomposed).
[3070] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.20(3H,t,J=7.0 Hz),
1.31-1.37(6H,m), 3.33-3.45(5H,m), 3.66-3.75(4H,m), 4.05(2H,q,J=7.0
Hz), 4.45-4.77(4H,m), 7.15(1H,s), 7.17(1H,dd,J=8.8,2.0 Hz),
7.41(1H,d,J=8.8 Hz), 7.71(1H,d,J=2.0 Hz), 8.77(1H,d,J=7.0 Hz),
9.20(1H,d,J=8.0 Hz), 11.30(1H,br), 11.83(1H,d,J=7.5 Hz).
[3071] MS (FAB) m/z: 559(M+H.sup.+).
Example 117
tert-Butyl
(3R*,4S*)-4-{[(5-chloroindol-2-yl)carbonyl]-amino}-3-{[(5-methy-
l-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amino}piperidine-
-1-carboxylate
##STR00783##
[3073] The title compound was obtained from the compound obtained
in Referential Example 207 and the compound obtained in Referential
Example 10 in a similar manner to Example 91.
[3074] Melting point: 152-154.degree. C. (decomposed).
[3075] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.53(9H,s),
1.62-1.80(1H,m), 2.23-2.30(1H,m), 2.52(3H,s), 2.75-3.05(5H,m),
3.10-3.25(1H,m), 3.68-3.82(2H,m), 4.15-4.45(4H,m), 6.89(1H,s),
7.19(1H,dd,J=8.8,1.8 Hz), 7.32(1H,d,J=8.8 Hz), 7.92(1H,d,J=1.8 Hz),
7.75(1H,br.s), 8.21(1H,br.s), 9.39(1H,s).
[3076] MS (ESI) m/z: 573(M+H).sup.+.
Example 118
N-((3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-piperidin-3-yl)-5-met-
hyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
dihydrochloride
##STR00784##
[3078] The title compound was obtained from the compound obtained
in Example 117 in a similar manner to Example 95.
[3079] Melting point: 240-258.degree. C. (decomposed).
[3080] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.85-2.00(1H,m),
2.05-2.20(2H,m), 2.93(3H,s), 3.05-3.60(7H,m), 3.65-3.75(1H,m),
4.10-4.52(2H,m), 4.60-4.75(2H,m), 7.10-7.21(2H,m), 7.43(1H,d,J=8.6
Hz), 7.70(1H,s), 8.50(1H,br.d,J=7.8 Hz), 8.90-9.05(2H,m),
9.27(1H,br.s), 11.9(1H,br.d,J=13.4 Hz).
[3081] MS (ESI) m/z: 473(M+H).sup.+.
Example 119
tert-Butyl
(3R*,4S*)-3-{[(5-chloroindol-2-yl)carbonyl]-amino}-4-{[(5-methy-
l-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amino}piperidine-
-1-carboxylate
##STR00785##
[3083] The title compound was obtained from the compound obtained
in Referential Example 208 and 5-chloroindole-2-carboxylic acid in
a similar manner to Example 91.
[3084] Melting point: 187-189.degree. C. (decomposed).
[3085] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.48(9H,s),
1.72-1.90(1H,m), 2.00(1H,br.s), 2.00-2.10(1H,m), 2.45(3H,s),
2.60-2.70(2H,m), 2.70-2.80(2H,m), 3.23(1H,t,J=10.8 Hz),
3.35-3.50(1H,m), 3.50-3.72(2H,m), 3.90-4.20(2H,m), 4.30-4.40(1H,m),
4.45-4.55(1H,m), 6.85(1H,d,J=1.5 Hz), 7.17(1H,dd,J=8.8,1.9 Hz),
7.20-7.30(1H,m), 7.33(1H,d,J=8.8 Hz), 7.58(1H,d,J=1.9 Hz),
10.17(1H,s).
[3086] MS (ESI) m/z: 573(M+H.sup.+).
Example 120
N-((3R*,4S*)-3-{[(5-Chloroindol-2-yl)carbonyl]amino}-piperidin-4-yl)-5-met-
hyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide
dihydrochloride
##STR00786##
[3088] The title compound was obtained from the compound obtained
in Example 119 in a similar manner to Example 95.
[3089] Melting point: 276-278.degree. C. (decomposed).
[3090] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.77-1.88(1H,m),
2.40-2.50(2H,m), 2.89(3H,s), 2.90-3.20(4H,m), 3.30-3.50(2H,m),
3.63(1H,br.s), 4.33-4.47(2H,m), 4.62-4.75 (2H,m),
7.18(1H,dd,J=8.8,1.9 Hz), 7.42(1H,d,J=8.8 Hz), 7.48(1H,br.s),
7.71(1H,d,J=1.9 Hz), 8.66(1H,br.s), 8.95(1H,d,J=8.1 Hz),
9.20-9.30(1H,m), 9.45-9.70(1H,m), 11.61(1H,s), 11.90(1H,s).
[3091] MS (ESI) m/z: 473(M+H).sup.+.
Example 121
tert-Butyl
(3R*,4S*)-4-{[(5-fluoroindol-2-yl)carbonyl]-amino}-3-{[(5-methy-
l-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amino}piperidine-
-1-carboxylate
##STR00787##
[3093] The title compound was obtained from the compound obtained
in Referential Example 209 and the compound obtained in Referential
Example 10 in a similar manner to Example 91.
[3094] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.53(9H,s),
1.65-1.78(1H,m), 2.23-2.32(1H,br), 2.52(3H,s), 2.78-3.03(5H,m),
3.15-3.24(1H,br), 3.68-3.82(2H,br), 4.16-4.45(4H,br), 6.91(1H,s),
7.02(1H,td,J=9.0,2.7 Hz), 7.30(1H,dd,J=9.0,2.7 Hz),
7.34(1H,dd,J=9.0,4.4 Hz), 7.65-7.90(1H,br), 8.10-8.40(1H,br),
9.31-9.41(1H,br).
[3095] MS (ESI) m/z: 557(M+H.sup.+).
Example 122
N-((3R*,4S*)-4-{[(5-Fluoroindol-2-yl)carbonyl]amino}-piperidin-3-yl)-5-met-
hyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
dihydrochloride
##STR00788##
[3097] The title compound was obtained from the compound obtained
in Example 121 in a similar manner to Example 95.
[3098] Melting point: 236-245.degree. C. (decomposed).
[3099] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.85-1.98(1H,br),
2.06-2.18(1H,br), 2.89(3H,s), 3.05-3.75(8H,s), 4.34-4.54(2H,br),
4.60-4.75(2H,br), 7.04(1H,td,J=9.3,2.4 Hz), 7.15(1H,br.s),
7.37-7.44(2H,m), 8.46(1H,d,J=7.8 Hz), 8.88-9.00(1H,br),
9.09-9.27(2H,br), 11.55-11.75(1H,br), 11.76-11.84(1H,br).
[3100] MS (FAB) m/z: 457(M+H.sup.+).
Example 123
N-((3R*,4S*)-1-Acetyl-4-{[(5-chloroindol-2-yl)carbonyl]-amino}piperidin-3--
yl)-5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00789##
[3102] The title compound was obtained from the compound obtained
in Example 118 and acetic anhydride in a similar manner to Example
100.
[3103] Melting point: 215-225.degree. C. (decomposed).
[3104] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.65-1.85(1H,m),
1.88,2.06(total 3H,each s), 1.90-2.10(1H,m), 2.91(3H,s),
3.00-3.30(2H,m), 3.30-3.55(2H,m), 3.60-3.90(3H,m), 3.98-4.50(4H,m),
4.65-4.75(1H,m), 7.09(1H,d,J=15.6 Hz), 7.17(1H,d,J=8.8 Hz),
7.41(1H,d,J=8.8 Hz), 7.71(1H,s), 8.23-8.53(2H,m),
11.20-11.55(1H,m), 11.85(1H,br.d,J=5.4 Hz).
[3105] MS (ESI) m/z: 515(M+H.sup.+).
Example 124
N-((3R*,4S*)-1-Acetyl-3-{[(5-chloroindol-2-yl)carbonyl]-amino}piperidin-4--
yl)-5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00790##
[3107] The title compound was obtained from the compound obtained
in Example 120 and acetic anhydride in a similar manner to Example
100.
[3108] Melting point: 225-250.degree. C. (decomposed).
[3109] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.65-1.80(1H,m), 1.81,
2.05(total 3H,each s), 2.00-2.20(1H,m), 2.70-2.85(1H,m),
2.89(3H,s), 3.00-3.20(2H,m), 3.20-3.50(2H,m), 3.64(1H,br.s),
3.78-4.30(2H,m), 4.30-4.50(3H,m), 4.55-4.75(1H,m), 7.05-7.23(2H,m),
7.38-7.48(1H,m), 7.70-7.80(1H,m), 7.79,8.12(total 1H,each d,J=6.8
Hz), 8.73, 8.83(total 1H,each d,J=8.3 Hz), 11.20-11.50(1H,m),
11.89,11.92(total 1H,each s).
[3110] MS (FAB) m/z: 515(M+H.sup.+).
Example 125
N-((3R*,4S*)-1-Acetyl-4-{[(5-fluoroindol-2-yl)carbonyl]-amino}piperidin-3--
yl)-5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00791##
[3112] The title compound was obtained from the compound obtained
in Example 122 and acetic anhydride in a similar manner to Example
100.
[3113] Melting point: 202.degree. C. (decomposed).
[3114] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.67-1.85(1H,m),
1.87(1.5H,s), 1.87-2.10(1H,m), 2.06(1.5H,s), 2.88-2.96(3H,br.s),
3.05-3.30(2H,m), 3.32-3.83(5H,br), 3.97-4.33(2H,m),
4.35-4.50(2H,br), 4.67-4.78(1H,br), 7.01-7.14(2H,m),
7.38-7.44(2H,m), 8.25-8.50(2H,m), 10.85-11.15(1H,br),
11.72-11.80(1H,br).
[3115] MS (FAB) m/z: 499(M+H.sup.+).
Example 126
N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(methylsulfonyl)pip-
eridin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxam-
ide hydrochloride
##STR00792##
[3117] The title compound was obtained from the compound obtained
in Example 118 and methanesulfonyl chloride in a similar manner to
Example 100.
[3118] Melting point: 225-230.degree. C. (decomposed).
[3119] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.80-1.90(1H,m),
2.05-2.15(1H,m), 2.30-2.80(5H,m), 2.85-3.80(9H,m), 4.20-4.90(4H,m),
7.08(1H,d,J=1.7 Hz), 7.18(1H,dd,J=8.7,1.7 Hz), 7.42(1H,d,J=8.7 Hz),
7.77(1H,s), 8.02-8.20(1H,m), 8.40-8.50(1H,m), 11.00-11.60(1H,m),
11.87(1H,s).
[3120] MS (ESI) m/z: 551(M+H.sup.+).
Example 127
N-[(3R*,4S*)-3-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(methylsulfonyl)pip-
eridin-4-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxam-
ide hydrochloride
##STR00793##
[3122] The title compound was obtained from the compound obtained
in Example 120 and methanesulfonyl chloride in a similar manner to
Example 100.
[3123] Melting point: 228-245.degree. C. (decomposed).
[3124] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.75-1.85(1H,m),
2.25-2.40(1H,m), 2.40-2.60(2H,m), 2.76(3H,br.s), 2.90(3H,s),
2.93-3.05(3H,m), 3.12(1H,d,J=10.6 Hz), 3.55-3.80(2H,m),
4.25-4.40(4H,m), 7.17(1H,d,J=1.7 Hz), 7.19(1H,dd,J=8.7,2.0 Hz),
7.43(1H,d,J=8.7 Hz), 7.74(1H,d,J=2.0 Hz), 8.03(1H,d,J=6.6 Hz),
8.78(1H,d,J=7.4 Hz), 10.90-11.20(1H,br.s), 11.89(1H,s).
[3125] MS (ESI) m/z: 551(M+H.sup.+).
Example 128
N-[(3R*,4S*)-4-{[(5-Fluoroindol-2-yl)carbonyl]amino}-1-(methylsulfonyl)pip-
erazin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxam-
ide hydrochloride
##STR00794##
[3127] The title compound was obtained from the compound obtained
in Example 122 and methanesulfonyl chloride in a similar manner to
Example 100.
[3128] Melting point: 216-250.degree. C. (decomposed).
[3129] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.80-1.90(1H,m),
2.01-2.12(1H,m), 2.92(3H,s), 2.94(3H,s), 3.00-3.80(8H,m),
4.28-4.53(3H,m), 4.60-4.80(1H,br), 7.01-7.12(2H,m),
7.37-7.44(2H,m), 8.00-8.18(1H,br), 8.39-8.50(1H,br),
11.00-11.60(1H,br), 11.72-11.80(1H,br).
[3130] MS (FAB) m/z: 535(M+H.sup.+).
Example 129
Methyl
(3R*,4S*)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5-
,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidine-1-car-
boxylate hydrochloride
##STR00795##
[3132] The title compound was obtained from the compound obtained
in Example 118 and methyl chloroformate in a similar manner to
Example 100.
[3133] Melting point: 248-253.degree. C. (decomposed).
[3134] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.65-1.78(1H,m),
1.88-2.03(1H,m), 2.90(3H,s), 3.00-3.80(9H,m), 3.80-3.90(1H,m),
3.95-4.08(1H,m), 4.20-4.70(4H,m), 7.10(1H,s), 7.17(1H,dd,J=8.8,1.8
Hz), 7.42(1H,d,J=8.8 Hz), 7.71(1H,d,J=1.8 Hz), 8.29(1H,br.s),
8.41(1H,d,J=8.1 Hz), 11.29(1H,br.s), 11.85(1H,s).
[3135] MS (ESI) m/z: 531(M+H.sup.+).
Example 130
Ethyl
(3R*,4R*)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,-
6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidine-1-carb-
oxylate hydrochloride
##STR00796##
[3137] The title compound was obtained from the compound obtained
in Example 118 and ethyl chloroformate in a similar manner to
Example 100.
[3138] Melting point: 215-225.degree. C. (decomposed).
[3139] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.85-1.30(3H,m),
1.65-1.78(1H,m), 1.90-2.03(1H,m), 2.90(3H,s), 3.10-3.40(4H,m),
3.48(1H,br.s), 3.65(1H,br.s), 3.75-4.15(4H,m), 4.25(1H,br.s),
4.32-4.50(2H,m), 4.66(1H,br.s), 7.09(1H,s), 7.18(1H,dd,J=8.8,2.0
Hz), 7.41(1H,d,J=8.8 Hz), 7.71(1H,d,J=2.0 Hz), 8.23(1H,br.s),
8.45(1H,br.d,J=8.1 Hz), 11.50(1H,br.s), 11.86(1H,s).
[3140] MS (ESI) m/z: 545(M+H.sup.+).
Example 131
2-Methoxyethyl
(3R*,4S*)-4-{[(5-chloroindol-2-yl)-carbonyl]amino}-3-{[(5-methyl-4,5,6,7--
tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]amino}piperidine-1-carboxy-
late hydrochloride
##STR00797##
[3142] The title compound was obtained from the compound obtained
in Example 118 and 2-methoxyethyl chloroformate in a similar manner
to Example 100.
[3143] Melting point: 224-226.degree. C. (decomposed).
[3144] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.68-1.78(1H,m),
1.90-2.03(1H,m), 2.89(3H,s), 3.00-3.75(11H,m), 3.80-3.90(1H,m),
3.95-4.18(3H,m), 4.20-4.70(4H,m), 7.10(1H,s), 7.17(1H,dd,J=8.8,2.0
Hz), 7.41(1H,d,J=8.8 Hz), 7.71(1H,d,J=2.0 Hz), 8.26(1H,br.s),
8.42(1H,d,J=7.8 Hz), 11.30(1H,br.s), 11.86(1H,s).
[3145] MS (ESI) m/z: 575(M+H.sup.+).
Example 132
Ethyl
(3R*,4S*)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,-
6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidine-1-carb-
oxylate hydrochloride
##STR00798##
[3147] The title compound was obtained from the compound obtained
in Example 120 and ethyl chloroformate in a similar manner to
Example 100.
[3148] Melting point: 213-225.degree. C. (decomposed).
[3149] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.75-1.30(3H,m),
1.60-1.72(1H,m), 2.12-2.25(1H,m), 2.89(3H,s), 2.95-3.20(4H,m),
3.40-3.88(4H,m), 3.90-4.10(2H,m), 4.10-4.30(2H,m), 4.30-4.40(1H,m),
4.40-4.80(1H,m), 7.10(1H,s), 7.18(1H,dd,J=8.8,2.0 Hz),
7.43(1H,d,J=8.8 Hz), 7.74(1H,s), 8.03(1H,d,J=5.6 Hz), 8.79(1H,s),
11.37(1H,s), 11.88(1H,s).
[3150] MS (ESI) m/z: 545(M+H.sup.+).
Example 133
N-((3R*,4R*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-propionylpiperidin--
3-yl)-5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00799##
[3152] The title compound was obtained from the compound obtained
in Example 118 and propionyl chloride in a similar manner to
Example 100.
[3153] Melting point: 214-228.degree. C. (decomposed).
[3154] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.88-1.10(3H,m),
1.70-2.05(2H,m), 2.06-2.60(2H,m), 2.91(3H,s), 3.14(2H,br.s),
3.20-3.90(5H,m), 3.95-4.80(5H,m), 7.09(1H,d,J=11.0 Hz),
7.17(1H,dd,J=8.8,1.2 Hz), 7.41(1H,d,J=8.8 Hz), 7.71(1H,s),
8.20-8.50(2H,m), 11.00-11.40(1H,m), 11.86(1H,s).
[3155] MS (ESI) m/z: 529(M+H.sup.+).
Example 134
N-((3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-isobutyrylpiperidin-
-3-yl)-5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00800##
[3157] The title compound was obtained from the compound obtained
in Example 118 and isobutyryl chloride in a similar manner to
Example 100.
[3158] Melting point: 266-272.degree. C. (decomposed).
[3159] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.80-1.15(6H,m),
1.70-2.05(2H,m), 2.65-2.80(1H,m), 2.90(3H,s), 2.90-4.80(12H,m),
7.09(1H,d,J=11.0 Hz), 7.17(1H,dd,J=8.8,2.0 Hz), 7.41(1H,d,J=8.8
Hz), 7.71(1H,s), 8.00-8.30(1H,m), 8.30-8.50(1H,m),
10.95-11.50(1H,m), 11.86(1H,s).
[3160] MS (ESI) m/z: 543(M+H.sup.+).
Example 135
N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(2,2-dimethylpropan-
oyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-c-
arboxamide hydrochloride
##STR00801##
[3162] The title compound was obtained from the compound obtained
in Example 118 and pivaloyl chloride in a similar manner to Example
100.
[3163] Melting point: 250-255.degree. C. (decomposed).
[3164] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.20(9H,s),
1.70-1.81(1H,m), 1.90-2.00(1H,m), 2.88(3H,s), 3.10(2H,br.s),
3.20-3.70(4H,m), 3.95-4.08(1H,m), 4.10-4.20(1H,m), 4.25-4.35(1H,m),
4.35-4.80(3H,m), 7.10 (1H, s), 7.16(1H,dd,J=8.8,1.9 Hz),
7.41(1H,d,J=8.8 Hz), 7.69(1H,d,J=1.9 Hz), 8.06(1H,br.s),
8.38(1H,d,J=7.8 Hz), 11.31(1H,br.s), 11.84(1H,s).
[3165] MS (ESI) m/z: 557(M+H.sup.+).
Example 136
N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(3,3-dimethylbutano-
yl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-ca-
rboxamide hydrochloride
##STR00802##
[3167] The title compound was obtained from the compound obtained
in Example 118 and tert-butylacetyl chloride in a similar manner to
Example 100.
[3168] Melting point: 260-265.degree. C. (decomposed).
[3169] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.91,1.04(total 9H,each
s), 1.68-1.82(1H,m), 1.93-2.40(3H,m), 2.91(3H,s), 3.00-3.20(2H,m),
3.20-4.80(10H,m), 7.08(1H,s), 7.17(1H,dd,J=8.7,1.2 Hz),
7.41(1H,d,J=8.7 Hz), 7.69(1H,d,J=7.6 Hz), 7.93-8.18 (1H, m),
8.38-8.45(1H,m), 10.95-11.30(1H,m), 11.80-11.90(1H,m).
[3170] MS (ESI) m/z: 571(M+H.sup.+).
Example 137
N-[(3R*,4S*)-4-1[(5-Chloroindol-2-yl)carbonyl]amino}-1-(2,2,2-trifluoroace-
tyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-c-
arboxamide hydrochloride
##STR00803##
[3172] The title compound was obtained from the compound obtained
in Example 118 and trifluoroacetic anhydride in a similar manner to
Example 100.
[3173] Melting point: 262-267.degree. C. (decomposed).
[3174] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.82-1.98(1H,m),
2.05-2.21(1H,m), 2.89(3H,s), 3.05-3.20(2H,m), 3.40-3.75(4H,m),
3.85-3.95(1H,m), 4.00-4.07(1H,m), 4.20-4.70(4H,m), 7.10(1H,s),
7.18(1H,dd,J=8.6,1.9 Hz), 7.41(1H,d,J=8.6 Hz), 7.72(1H,s),
8.47(1H,dd,J=22.4,7.9 Hz), 8.60(1H,br), 11.08(1H,br.s),
11.87(1H,s).
[3175] MS (ESI) m/z: 569(M+H.sup.+).
Example 138
N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(cyclopropylcarbony-
l)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-car-
boxamide hydrochloride
##STR00804##
[3177] The title compound was obtained from the compound obtained
in Example 118 and cyclopropanecarbonyl chloride in a similar
manner to Example 100.
[3178] Melting point: 280-286.degree. C. (decomposed).
[3179] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.25-0.80(4H,m),
1.65-2.15(4H,m), 2.91(3H,s), 2.90-3.20(3H,m), 3.35-3.70(2H,m),
4.00-4.80(6H,m), 7.06(1H,s), 7.18(1H,d,J=8.8 Hz), 7.42(1H,d,J=8.7
Hz), 7.71(1H,s), 8.18(1H,br.s), 8.40,8.48(total 1H,each br.s),
11.11(1H,br.s), 11.85(1H,s).
[3180] MS (ESI) m/z: 542(M+H.sup.+).
Example 139
N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(cyclobutylcarbonyl-
)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carb-
oxamide hydrochloride
##STR00805##
[3182] The title compound was obtained from the compound obtained
in Example 118 and cyclobutanecarbonyl chloride in a similar manner
to Example 100.
[3183] Melting point: 271-275.degree. C. (decomposed).
[3184] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.60-2.30(8H,m),
2.89(3H,s), 3.12(2H,br.s), 3.20-3.75(6H,m), 3.75-3.90(1H,m),
4.05-4.80(4H,m), 7.08(1H,s), 7.15(1H,dd,J=9.0,2.0 Hz),
7.39(1H,d,J=9.0 Hz), 7.68(1H,d,J=2.0 Hz), 8.15(1H,br.s),
8.39(1H,br), 11.19(1H,br.s), 11.84(1H,s).
[3185] MS (ESI) m/z: 555(M+H.sup.+).
Example 140
N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(cyclopentylcarbony-
l)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-car-
boxamide hydrochloride
##STR00806##
[3187] The title compound was obtained from the compound obtained
in Example 118 and cyclopentanecarbonyl chloride in a similar
manner to Example 100.
[3188] Melting point: 254-260.degree. C. (decomposed).
[3189] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.30-2.10(10H,m),
2.90(3H,s), 3.00-3.20(2H,m), 3.20-3.75(5H,m), 3.80-4.80(6H,m),
7.09(1H,s), 7.17(1H,dd,J=8.7,2.0 Hz), 7.42(1H,d,J=8.7 Hz),
7.71(1H,s), 7.95-8.30(1H,m), 8.35-8.50(1H,m), 11.23(1H,br.s),
11.85(1H,s).
[3190] MS (ESI) m/z: 569 (M+H.sup.+).
Example 141
2-((3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,7-
-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-1-yl)-2-ox-
oethyl acetate
##STR00807##
[3192] The title compound was obtained from the compound obtained
in Example 118 and acetoxyacetyl chloride in a similar manner to
Example 100.
[3193] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.70-2.00(1H,m),
2.05-2.48(3H,m), 2.51(3H,s), 2.70-3.05(4H,m), 3.05-4.10(5H,m),
4.20-4.48(1H,m), 4.50-5.10(4H,m), 6.87(1H,br.s), 7.10-7.82(4H,m),
7.32(1H,d,J=8.8 Hz), 8.35(1H,br.s), 9.34,9.45(total 1H,each
br.s).
[3194] MS (ESI) m/z: 573(M+H.sup.+).
Example 142
N-((3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-glycoloylpiperidin--
3-yl)-5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00808##
[3196] The compound (301.8 mg) obtained in Example 141 was
dissolved in tetrahydrofuran (10 mL), and 1N aqueous sodium
hydroxide (0.53 mL) was added, followed by stirring at room
temperature for 18 hours. Water was added to the reaction mixture,
and the mixture was extracted with methylene chloride. The
resultant organic layer was successively washed with water and
saturated brine and dried over sodium sulfate anhydrate. The
solvent was distilled away under reduced pressure, the residue was
purified by silica gel column chromatography (methylene
chloride:methanol=20:1-10:1), and the solvent was distilled away
under reduced pressure. The thus-obtained purified product was
dissolved in ethanol (3 mL) and methylene chloride (2 mL), and 1N
HCl in ethanol (0.40 mL) was added thereto, followed by stirring
for 30 minutes. The solvent was distilled away under reduced
pressure, and the residue was solidified with diethyl ether to give
the title compound (195 mg).
[3197] Melting point: 216-230.degree. C. (decomposed).
[3198] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.70-1.80(1H,m),
1.88-2.10(2H,m), 2.68(3H,s), 3.18(2H,s), 3.08-3.70(5H,m),
3.80-3.95(1H,m), 4.00-4.25(3H,m), 4.25-4.50(2H,m), 4.50-4.65(1H,m),
7.09(1H,d,J=11.0 Hz), 7.17(1H,dd,J=8.8,2.0 Hz), 7.42(1H,d,J=8.8
Hz), 7.71(1H,s), 8.33(1H,br.s), 8.35-8.50(1H,m),
10.80-11.30(1H,br.s), 11.84(1H,br.s).
Example 143
N-[(3R*,4R*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(2-methoxyacetyl)pi-
peridin-3-yl]-5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carbox-
amide hydrochloride
##STR00809##
[3200] The title compound was obtained from the compound obtained
in Example 118 in a similar manner to Example 100.
[3201] Melting point: 214-228.degree. C. (decomposed).
[3202] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.70-1.80(1H,m),
1.85-2.05(1H,m), 2.90(3H,s), 3.00-3.20(2H,m), 3.16(3H,s),
3.22-3.82(7H,m), 3.88-4.80(5H,m), 7.09(1H,d,J=9.0 Hz),
7.17(1H,dd,J=8.8,1.9 Hz), 7.42(1H,d,J=8.8 Hz), 7.70(1H,d,J=1.9 Hz),
8.29(1H,br.s),8.40-8.50(1H,m), 11.34(1H,br.s), 11.86(1H,s).
[3203] MS (ESI) m/z: 545(M+H).sup.+.
Example 144
N-[(3R*,4S*)-4-{[(5-Fluoroindol-2-yl)carbonyl]amino}-1-(2-methoxyacetyl)pi-
peridin-3-yl]-5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carbox-
amide hydrochloride
##STR00810##
[3205] The title compound was obtained from the compound obtained
in Example 122 and methoxyacetyl chloride in a similar manner to
Example 100.
[3206] Melting point: 190-208.degree. C. (decomposed).
[3207] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.70-1.83(1H,br),
1.85-2.10(1H,m), 2.91(3H,s), 3.00-3.55(10H,m), 3.62-3.85(1H,m),
3.90-4.50(6H,m), 4.63-4.78(1H,br), 7.04(1H,td,J=9.4,2.4 Hz),
7.07-7.13(1H,br), 7.37-7.44(1H,m), 8.16-8.49(2H,m),
11.30-11.70(1H,br), 11.72-11.80(1H,br).
[3208] MS (FAB) m/z: 529(M+H.sup.+).
Example 145
N-((3R*,4S*)-1-(3-{tert-butyl(diphenyl)silyl}oxy)-2,2-dimethylpropanoyl)-4-
-{[(5-chloroindol-2-yl)carbonyl]-amino}piperidin-3-yl)-5-methyl-4,5,6,7-te-
trahydro-thiazolo[5,4-c]pyridine-2-carboxamide
##STR00811##
[3210] Thionyl chloride (3.0 mL) and a catalytic amount of
dimethylformamide were added to a solution of the compound (261 mg)
obtained in Referential Example 158 in chloroform (10 mL), and the
mixture was stirred overnight at 60.degree. C. The reaction mixture
was concentrated under reduced pressure, thereby giving a yellow
oil. The title compound (241 mL) was obtained from this product and
the compound (200 mg) obtained in Example 118 in a similar manner
to Example 100.
[3211] Melting point: 153.degree. C.
[3212] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.07(9H,s),
1.39(6H,d,J=3.9 Hz), 1.57(1H,br.s), 2.26(1H,d,J=10.7 Hz),
2.57(3H,s), 2.86(4H,s), 2.97-3.01(2H,m), 3.78(4H,s), 4.20(1H,br.s),
4.33(1H,d,J=13 Hz), 4.42(1H,br.s), 4.67(1H,d,J=13 Hz), 6.88(1H,s),
7.20-7.23(1H,m), 7.32-7.46(7H,m), 7.64-7.65(6H,m), 7.86(1H,d,J=6.8
Hz), 8.23(1H,s), 9.10(1H,s).
Example 146
N-[(3R*,4S*)-4-[(5-chloroindol-2-yl)carbonyl]amino}-1-(3-hydroxy-2,2-dimet-
hylpropanoyl)piperidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyr-
idine-2-carboxamide
##STR00812##
[3214] Tetrabutylammonium fluoride (1 M tetrahydrofuran solution,
0.594 mL) was added to a solution of the compound (241 mg) obtained
in Example 145 in tetrahydrofuran (30 mL) under ice cooling, and
the mixture was stirred overnight at room temperature. The reaction
mixture was concentrated under reduced pressure, and the resultant
residue was dissolved in methylene chloride. The solution was
washed with water and saturated brine and then dried over sodium
sulfate anhydrate, and the solvent was distilled away under reduced
pressure. The resultant residue was purified by silica gel thin
layer chromatography (methylene chloride:methanol=9:1) to give the
title compound (116 mg).
[3215] Melting point: 220.degree. C. (decomposed).
[3216] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.17(6H,d,J=8.3 Hz),
1.79(1H,br.s), 1.91-1.97(1H,m), 2.49 (3H, s), 2.87 (4H, s),
3.35-3.50(4H,m), 3.81(1H,br.s), 3.97(1H,m), 4.10-4.15(1H,m),
4.32(1H,br.s), 4.42(1H,br.s), 4.52(1H,t,J=5.7 Hz), 7.10(1H,s),
7.16-7.19(1H,m), 7.42(1H,d,J=8.8 Hz), 7.69(1H,s), 8.11(1H,d,J=8.8
Hz), 8.37(1H,d,J=7.3 Hz), 11.8(1H,s).
[3217] MS (FAB) m/z: 573(M+H.sup.+).
Example 147
N-(3R*,4S*)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-(3-methoxy-2,2-dimet-
hylpropanoyl)piperidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyr-
idine-2-carboxamide
##STR00813##
[3219] The title compound was obtained from the compound obtained
in Example 118 and the compound obtained in Referential Example 160
in a similar manner to Example 145.
[3220] Melting point: 240.degree. C. (decomposed).
[3221] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.34(3H,s), 1.37(3H,s),
1.65-1.77(1H,m), 2.33-2.37(1H,m), 2.53(3H,s), 2.82-3.29(6H,m),
3.34(3H,s), 3.41(1H,d,J=9.3 Hz), 3.56(1H,d,J=9.3 Hz),
3.76(2H,d,J=5.9 Hz), 4.26(1H,m),4.44-4.53(2H,m), 4.82(1H,d,J=13.7
Hz), 6.88(1H,d,J=1.5 Hz), 7.20-7.23(1H,m), 7.33(1H,d,J=8.8 Hz),
7.64(1H,d,J=1.5 Hz), 7.90(1H,d,J=7.1 Hz), 8.22(1H,d,J=5.1 Hz),
9.18(1H,s).
[3222] MS (FAB) m/z: 587(M+H.sup.+).
Example 148
2-((3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,7-
-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-1-yl)-1,1--
dimethyl-2-oxoethyl acetate
##STR00814##
[3224] The title compound was obtained from the compound obtained
in Example 118 and 2-acetoxyisobutyryl chloride in a similar manner
to Example 100.
[3225] Melting point: 190.degree. C. (decomposed).
[3226] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.56-1.67(8H,m),
2.08(3H,s), 2.35(1H,d,J=10.5 Hz), 2.52(3H,s), 2.82-2.84(2H,m),
2.90-2.96(2H,m), 3.14(1H,br.s), 3.75(2H,s), 4.25(1H,br.s),
4.40-4.47(1H,m), 4.54(1H,br.s), 4.80(1H,br.s), 6.86(1H,s),
7.20-7.33(3H,m), 7.64(1H,d,J=1.7 Hz), 7.76(1H,d,J=7.3 Hz),
9.11(1H,s).
[3227] MS (FAB) m/z: 601(M+H.sup.+).
Example 149
N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(2-hydroxy-2-methyl-
propanoyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridi-
ne-2-carboxamide
##STR00815##
[3229] Sodium methoxide (76.8 mg) was added to a solution of the
compound (190 mg) obtained in Example 148 in methanol (50 mL), and
the mixture was stirred overnight at room temperature. After the
reaction mixture was concentrated under reduced pressure, the
resultant residue was purified by silica gel thin layer
chromatography (methylene chloride:methanol=9:1) to give the title
compound (130 mg).
[3230] Melting point: 190.degree. C. (decomposed).
[3231] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.53(3H,s),
1.56-1.78(5H,m), 2.34(1H,d,J=10.5 Hz), 2.53(3H,s), 2.83-2.86(2H,m),
2.91-2.93 (2H,m), 3.30(1H,d,J=12.5 Hz), 3.75(2H,s), 4.28(1H,d,J=5.6
Hz), 4.43(1H,s), 4.65(1H,d,J=13.5 Hz), 4.95(1H,d,J=13.5 Hz),
6.92(1H,d,J=1.5 Hz), 7.20-7.23(1H,m), 7.33(1H,d,J=8.6 Hz),
7.65(1H,d,J=2.0 Hz), 8.43(1H,d,J=5.6 Hz), 9.14(1H,s).
[3232] MS (FAB) m/z: 559(M+H.sup.+).
Example 150
N-{(3R*,4S*)-4-[(5-Chloroindol-2-yl)carbonyl]amino}-1-[(3-hydroxycyclobuty-
l)carbonyl]piperidin-3-yl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyrid-
ine-2-carboxamide hydrochloride
##STR00816##
[3234] The compound (306 mg) obtained in Example 118,
N-methylmorpholine (200 .mu.l), 1-hydroxybenzotriazole monohydrate
(87 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (197 mg) were added to a solution of the compound
(117 mg) obtained Referential Example 152 in a mixture of
tetrahydrofuran (20 mL), methylene chloride (3.0 mL) and,
N,N-dimethylformamide (2.0 mL), and the mixture was stirred at room
temperature for 3 days. The reaction mixture was diluted with
methylene chloride, and saturated aqueous sodium hydrogencarbonate
was added for partitioning the mixture into two layers. The
resultant organic layer was washed with saturated brine, dried over
sodium sulfate anhydrate and then concentrated under reduced
pressure. The resultant residue was purified by silica gel column
chromatography (methylene chloride:methanol=10:1) to give a free
base (207 mg) of the title compound. The free base was treated with
1N HCl in ethanol to give the title compound.
[3235] Melting point: 200.degree. C. (decomposed).
[3236] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.78-2.10(4H,m),
2.24-2.68(3H,m), 2.75-5.20(14H,m), 2.91(3H,s), 7.08(0.5H,s),
7.09(0.5H,s), 7.18(1H,dd,J=8.8,2.0 Hz), 7.42(1H,d,J=8.8 Hz), 7.70
(1H,d,J=2.0 Hz), 8.05-8.28(1H,br), 8.38(0.5H,br.d,J=7.3 Hz),
8.43(0.5H,br.d,J=8.3 Hz), 10.80-11.25(1H,br), 11.84(1H,br.s).
[3237] MS (ESI) m/z: 571(M+H.sup.+).
Example 151
N-{(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-[(methoxycyclobutyl-
)carbonyl]piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridi-
ne-2-carboxamide hydrochloride
##STR00817##
[3239] The title compound was obtained from the compound obtained
in Example 118 and the compound obtained in Referential Example 154
in a similar manner to Example 150.
[3240] Melting point: 191.degree. C. (decomposed).
[3241] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.69-2.23(4H,m),
2.25-2.40(1H,m), 2.71-2.84(0.5H,m), 2.89-3.93(9.5H,m), 2.91(3H,s),
3.01(1H,s), 3.14(2H,s), 4.05-4.80(5H,m), 7.09(1H,s),
7.18(1H,d,J=8.4 Hz), 7.42(1H,d,J=8.4 Hz), 7.70(1H,s),
8.00-8.30(1H,br), 8.36-8.53(1H,m), 11.25-11.75(1H,br),
11.85(1H,br.s).
[3242] MS (ESI) m/z: 585(M+H.sup.+).
Example 152
N-{(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-[3-methoxy-2-(metho-
xymethyl)propanoyl]piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-
-c]pyridine-2-carboxamide hydrochloride
##STR00818##
[3244] In a manner similar to that employed in Example 150, the
compound obtained in Example 118 was condensed with the carboxylic
acid obtained through hydrolysis of the compound obtained in
Referential Example 155, to thereby give the title compound.
[3245] Melting point: 178-184.degree. C. (decomposed).
[3246] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.69-1.82(1H,m),
1.84-2.04(1H,m), 2.91(3H,s), 3.00-3.75(17H,m), 3.95-4.55(5H,m),
4.60-4.80(1H,m), 7.10(1H,br.s), 7.18(1H,dd,J=8.8,2.0 Hz),
7.42(1H,d,J=8.8 Hz), 7.69(0.5H,br.s), 7.71(1H,br.s),
8.18-8.28(1H,br), 8.35-8.50(1H,br), 11.83(1H,br.s).
[3247] MS (ESI) m/z: 603(M+H.sup.+).
Example 153
N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(tetrahydro-2H-pyra-
n-4-ylcarbonyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]p-
yridine-2-carboxamide hydrochloride
##STR00819##
[3249] The title compound was obtained from the compound obtained
in Example 118 and the compound obtained in Referential Example 156
in a similar manner to Example 150.
[3250] Melting point: 225-248.degree. C. (decomposed).
[3251] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.55-1.68(4H,m),
1.70-1.85(1H,m), 1.85-2.05(1H,m), 2.60-2.95(1H,m), 2.89(3H,s),
2.95-3.20(3H,m), 3.20-4.00(9H,m), 4.00-4.80(4H,m), 7.08(1H,s),
7.17(1H,dd,J=8.8,2.0 Hz), 7.42(1H,d,J=8.8 Hz), 7.71(1H,s),
8.00-8.30(1H,m), 8.35-8.50(1H,m), 11.16(1H,br.s), 11.85(1H,s).
[3252] MS (ESI) m/z: 585(M+H.sup.+).
Example 154
N-((3R*,4S*)-1-benzoyl-4-{[(5-Chloroindol-2-yl)carbonyl]amino}piperidin-3--
yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00820##
[3254] The title compound was obtained from the compound obtained
in Example 118 and benzoyl chloride in a similar manner to Example
100.
[3255] Melting point: 215-225.degree. C. (decomposed).
[3256] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.75-1.90(1H,m),
1.90-2.20(1H,m), 2.93(3H,s), 3.10-4.00(8H,m), 4.05-4.80(4H,m),
7.00-7.60(5H,m), 7.08(1H,s), 7.16(1H,dd,J=8.8,1.6 Hz),
7.40(1H,d,J=8.8 Hz), 7.71(1H,d,J=1.6 Hz), 8.31(1H,br.s),
8.46(1H,br.s), 11.39(1H,br.s),11.86(1H,s).
[3257] MS (FAB) m/z: 577(M+H.sup.+).
Example 155
tert-Butyl
(3R*,4S*)-3-({[5-(2-{[tert-butyl(diphenyl)-silyl]oxy}-1,1-dimet-
hylethyl)-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl]carbonyl}amino)-4-
-{[(5-chloroindol-2-yl)carbonyl]amino}piperidine-1-carboxylate
##STR00821##
[3259] The title compound was obtained from the compound obtained
in Referential Example 207 and the compound obtained in Referential
Example 42 in a similar manner to Example 91.
[3260] .sup.1H-NMR (DMSO-d.sub.6) .delta.:1.00(9H,s), 1.12(6H,s),
1.15-1.50(9H,m), 1.63-1.75(1H,m), 1.82-2.00(1H,m), 2.60-2.80(3H,m),
2.83-2.95(2H,m), 3.12-3.30(1H,m), 3.30(2H,s), 3.58(2H,s),
3.85-4.10(2H,m), 4.19(1H,br.s), 4.37(1H,br.s), 7.04(1H,s),
7.16(1H,d,J=9.0 Hz), 7.30-7.50(7H,m), 7.50-7.65(4H,m), 7.70(1H,s),
7.99(1H,d,J=6.8 Hz), 8.45(1H,br.s), 11.82(1H,s).
[3261] MS(ESI)m/z: 869(M+H).sup.+
Example 156
5-(2-{[tert-Butyl(diphenyl)silyl]oxy}-1,1-dimethylethyl)-N-((3R*,4S*)-4-{[-
(5-chloroindol-2-yl)carbonyl]amino}piperidin-3-yl)-4,5,6,7-tetrahydrothiaz-
olo[5,4-c]pyridine-2-carboxamide dihydrochloride
##STR00822##
[3263] The compound obtained in Example 155 was treated in a manner
similar to that employed in Example 95, to thereby give the title
compound.
[3264] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.04(9H,s), 1.43,
1.48(total 6H,each s), 1.85-2.00(1H,m), 2.05-2.20(1H,m),
2.95-3.20(2H,m), 3.25-3.60(6H,m), 3.80-3.90(1H,m), 3.95-4.05(1H,m),
4.45-4.55(1H,m), 4.60-4.85(3H,m), 7.10-7.20(2H,m), 7.35-7.55(7H,m),
7.55-7.75(5H,m), 8.52(1H,dd,J=14.4,7.8 Hz), 8.93(1H,br),
9.20-9.40(2H,m), 11.30-11.50(1H,m), 11.87,11.92(total 1H,each
s).
[3265] MS (ESI) m/z: 769(M+H.sup.+).
Example 157
5-(2-{[tert-Butyl(diphenyl)silyl]oxy}-1,1-dimethylethyl)-N-[(3R*,4S*)-4-{[-
(5-chloroindol-2-yl)carbonyl]amino}-1-(2-methoxyacetyl)piperidin-3-yl]-4,5-
,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide
##STR00823##
[3267] The title compound was obtained from the compound obtained
in Example 156 and methoxyacetyl chloride in a similar manner to
Example 100.
[3268] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.07(9H,s), 1.20(6H,s),
1.60-1.85(1H,m), 2.25-2.40(1H,m), 2.36(2H,s), 2.70-3.20(4H,m),
3.20-3.55(4H,m), 3.55-3.70(2H,m), 3.95-4.10(3H,m), 4.10-4.90(4H,m),
6.90(1H,d,J=1.5 Hz), 7.15-7.30(2H,m) , 7.30-7.50(6H,m),
7.60-7.70(5H,m), 8.15-8.22(1H,m), 8.46(1H,d,J=5.1 Hz),
9.28(1H,s).
[3269] MS (ESI) m/z: 842(M+H.sup.+).
Example 158
N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(2-methoxyacetyl)pi-
peridin-3-yl]-5-(2-hydroxy-1,1-dimethylethyl)-4,5,6,7-tetrahydrothiazolo[5-
,4-c]pyridine-2-carboxamide hydrochloride
##STR00824##
[3271] The title compound was obtained from the compound obtained
in Example 157 in a similar manner to Example 146.
[3272] Melting point: 221-232.degree. C. (decomposed).
[3273] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.32(3H,s), 1.40(3H,s),
1.70-1.85(1H,m), 1.85-2.10(1H,m), 2.60-3.35(8H,m), 3.40-3.82(3H,m),
3.85-4.05(3H,m), 4.05-4.35(2H,m), 4.50-4.60(1H,m), 4.55-4.80(2H,m),
5.75-5.85(1H,m), 7.08(1H,br.s), 7.17(1H,d,J=8.8 Hz),
7.41(1H,d,J=8.8 Hz); 7.71(1H,s), 8.20-8.35(1H,m), 8.40-8.55(1H,m),
10.00-10.35(1H,m), 11.87(1H,s).
[3274] MS (ESI) m/z: 603(M+H.sup.+).
Example 159
tert-Butyl
(3R*,4S*)-4-{[(5-fluoroindol-2-yl)carbonyl]-amino}-3-{[(5-isopr-
opyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amino}piperid-
ine-1-carboxylate
##STR00825##
[3276] The title compound was obtained from the compound obtained
in Referential Example 209 and the compound obtained in Referential
Example 148 in a similar manner to Example 91.
[3277] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.16(6H,d,J=6.6 Hz),
1.53(9H,s), 1.65-1.80(1H,m), 2.23-2.32(1H,m), 2.80-3.10(6H,m),
3.10-3.25(1H,m), 3.80-3.90(2H,m), 4.00-4.50(4H,m),
6.91(1H,s),6.95-7.05(1H,m), 7.25-7.40(2H,m), 7.74(1H,br.s),
8.21(1H,br.s), 9.30(1H,s).
[3278] MS (ESI) m/z: 585(M+H.sup.+).
Example 160
N-((3R*,4S*)-4-{[(5-Fluoroindol-2-yl)carbonyl]amino}-piperidin-3-yl)-5-iso-
propyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxamide
dihydrochloride
##STR00826##
[3280] The compound obtained in Example 159 was treated in a manner
similar to that employed in Example 95, to thereby give the title
compound.
[3281] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.28-1.40(6H,m),
1.85-2.00(1H,m), 2.05-2.20(1H,m), 2.40-2.60(1H,m), 2.95-3.90(8H,m),
4.40-4.55(2H,m), 4.60-4.75(2H,m), 7.00-7.20(2H,m), 7.30-7.50(2H,m),
8.45-8.60(1H,m), 8.85-9.05(1H,m), 9.05-9.50(2H,m),
11.60-11.90(2H,m).
[3282] MS (ESI) m/z: 485(M+H.sup.+).
Example 161
N-[(3R*,4S*)-4-{[(5-Fluoroindol-2-yl)carbonyl]amino}-1-(2-methoxyacetyl)pi-
peridin-3-yl]-5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carb-
oxamide hydrochloride
##STR00827##
[3284] The title compound was obtained from the compound obtained
in Example 160 and methoxyacetyl chloride in a similar manner to
Example 100.
[3285] Melting point: 214-228.degree. C. (decomposed).
[3286] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.25-1.40(6H,m),
1.68-1.82(1H,m), 1.85-2.10(1H,m), 2.90-3.60(8H,m), 3.60-3.85(2H,m),
3.85-4.40(5H,m), 4.40-4.55(2H,m), 4.60-4.75(1H,m), 7.00-7.15(2H,m),
7.35-7.50(2H,m), 8.15-8.50(2H,m), 10.80-11.30(1H,m),
11.73(1H,d,J=6.6 Hz).
[3287] MS (ESI) m/z: 557(M+H.sup.+).
Example 162
N-{(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-[(dimethylamino)car-
bonyl]piperidin-3-yl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-
-carboxamide hydrochloride
##STR00828##
[3289] The title compound was obtained from the compound obtained
in Example 118 and N,N-dimethylcarbamoyl chloride in a similar
manner to Example 100.
[3290] Melting point: 267-270.degree. C. (decomposed).
[3291] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.65-1.78(1H,m),
1.97-2.10(1H,m), 2.70(6H,s), 2.90(3H,s), 2.95-3.80(8H,m),
4.25-4.80(4H,m), 7.08(1H,s), 7.16(1H,dd,J=8.8,1.8 Hz),
7.41(1H,d,J=8.8 Hz), 7.70(1H,s), 8.31(1H,br.s), 8.40(1H,d,J=7.3
Hz), 11.15-11.60(1H,m), 11.82(1H,s).
[3292] MS (ESI) m/z: 544(M+H.sup.+).
Example 163
N-{(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-[(ethylamino)carbon-
yl]piperidin-3-yl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-ca-
rboxamide hydrochloride
##STR00829##
[3294] The title compound was obtained from the compound obtained
in Example 118 and ethyl isocyanate in a similar manner to Example
100.
[3295] Melting point: 221-235.degree. C. (decomposed).
[3296] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.98(3H,t,J=7.1 Hz),
1.60-1.70(1H,m), 1.80-1.95(1H,m), 2.90(3H,s), 2.95-3.40(6H,m),
3.40-4.00(4H,m), 4.25-4.80(4H,m), 6.60-6.80(1H,m), 7.09(1H,s),
7.16(1H,dd,J=8.8,1.9 Hz), 7.41(1H,d,J=8.8 Hz), 7.68(1H,d,J=1.9 Hz),
8.02(1H,br.s), 8.35(1H,d,J=7.1 Hz), 11.20-11.70(1H,m),
11.82(1H,s).
[3297] MS(FAB)m/z: 544(M+H.sup.+).
Example 164
N-((3R*,4S*)-1-[(tert-Butylamino)carbonyl]-4-{[(5-chloroindol-2-yl)carbony-
l]amino}piperidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-
-2-carboxamide hydrochloride
##STR00830##
[3299] The title compound was obtained from the compound obtained
in Example 118 and tert-butyl isocyanate in a similar manner to
Example 100.
[3300] Melting point: 236-238.degree. C. (decomposed).
[3301] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.21(9H,s),
1.60-1.70(1H,m), 1.80-1.90(1H,m), 2.87(3H,s), 3.00-3.40(6H,m),
3.49(1H,br.s), 3.80-3.90(1H,m), 3.90-4.00(1H,m), 4.20-4.35(2H,m),
4.47(1H,br.s), 5.90(1H,s), 7.06(1H,s), 7.16(1H,dd,J=8.8,1.9 Hz),
7.41(1H,d,J=8.8 Hz), 7.67(1H,d,J=1.9 Hz), 8.04(1H,d,J=6.8 Hz),
8.34(1H,d,J=7.3 Hz), 11.22(1H,br.s), 11.79(1H,s).
[3302] MS (FAB) m/z: 572(M+H.sup.+).
Example 165
Methyl
2-((3R*,4S*)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl--
4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amino}piperidin-3--
yl)acetate dihydrochloride
##STR00831##
[3304] The title compound was obtained from the compound obtained
in Example 118 and methyl bromoacetate in a similar manner to
Example 102.
[3305] Melting point: 253-255.degree. C. (decomposed).
[3306] .sup.1H-NMR (DMSO-d.sub.6,80.degree. C.) .delta.:
1.95-2.10(1H,m), 2.10-2.25(1H,m), 2.88(3H,s), 3.00-3.73(8H,m),
3.75(3H,s), 3.97-4.15(2H,m), 4.30-4.80(4H,m), 7.08-7.20(2H,m),
7.44(1H,d,J=8.6 Hz), 7.63(1H,d,J=2.0 Hz), 8.42(1H,d,J=7.3 Hz),
8.62(1H,br.s), 11.82(1H,br.s).
[3307] MS (ESI) m/z: 545(M+H.sup.+).
Example 166
2-((3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,7-
-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-3-yl)aceti-
c acid hydrochloride
##STR00832##
[3309] The compound obtained in Example 165 was treated in a manner
similar to that employed in Example 101, to thereby give the title
compound.
[3310] Melting point: 234-240.degree. C. (decomposed).
[3311] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.75-1.95(1H,m),
2.05-2.20(1H,m), 2.88(3H,s), 2.95-3.90(10H,m), 4.20-4.70(4H,m),
7.11(1H,s), 7.16(1H,dd,J=8.8,2.0 Hz), 7.41(1H,d,J=8.8 Hz),
7.66(1H,d,J=2.0 Hz), 8.46(1H,br.d,J=7.8 Hz), 8.65(1H,br.s),
11.60-12.70(2H,br.s), 11.91(1H,br.s).
Example 167
N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(2-methoxyethyl)pip-
eridin-3-yl]-5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxa-
mide dihydrochloride
##STR00833##
[3313] The title compound was obtained from the compound obtained
in Example 118 and 2-bromoethyl methyl ether in a similar manner to
Example 102 (NMR was measured in the form of a free base).
[3314] Melting point: 238-242.degree. C. (decomposed).
[3315] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.75-1.83(2H,m),
2.27-2.39(2H,m), 2.52(3H,s), 2.60-2.66(1H,m), 2.69-2.75(1H,m),
2.81-2.90(2H,m), 2.96-3.07(2H,m), 3.41(3H,s), 3.53-3.60(2H,m),
3.75(each 1H,AB type d,J=15.5 Hz), 4.02-4.05(1H,m), 4.40(1H,br),
6.88(1H,d,J=1.5 Hz), 7.18-7.21(1H,m), 7.31-7.33(1H,m),
7.63(1H,d,J=1.5 Hz), 8.17(1H,d,J=5.0 Hz), 8.26(1H,d,J=7.0 Hz),
9.30(1H,br.s).
[3316] MS (FAB) m/z: 531(M+H.sup.+).
Example 168
N-[(3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(2-fluoroethyl)pipe-
ridin-3-yl]-5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxam-
ide dihydrochloride
##STR00834##
[3318] The title compound was obtained from the compound obtained
in Example 118 and 2-fluoroethyl bromide in a similar manner to
Example 102 (NMR was measured in the form of a free base).
[3319] Melting point: 228-233.degree. C. (decomposed).
[3320] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.77(2H,dq,J=12.5,4.0 Hz),
2.28-2.32(1H,m), 2.41(1H,t,J=12.5 Hz), 2.52(3H,s), 2.65(1H,d,J=10.5
Hz), 2.76-2.81(1H,m), 2.83-2.86(3H,m), 2.98-3.05(3H,m), 3.75(each
1H,AB type d,J=15.5 Hz), 4.02-4.08(1H,m), 4.45(1H,br),
4.54-4.59(1H,m), 4.64-4.70(1H,m), 6.87(1H,d,J=1.5 Hz),
7.19-7.22(1H,m), 7.32(1H,d,J=8.5 Hz), 7.64(1H,d,J=2.0 Hz),
8.11(1H,d,J=5.5 Hz), 8.20(1H,d,J=7.3 Hz), 9.30(1H,br).
[3321] MS (FAB) m/z: 519(M+H.sup.+).
Example 169
N-((3R,4S)-1-Acetyl-4-{[(5-chloroindol-2-yl)carbonyl]-amino}piperidin-3-yl-
)-5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00835##
[3323] 4N HCl-dioxane (7.0 mL) was added to a dioxane solution (15
mL) of the compound (630 mg) obtained in Referential Example 214,
and the mixture was stirred at room temperature for 1 hour. The
reaction mixture was concentrated under reduced pressure. The
thus-obtained yellow solids (590 mg) and the compound (379 mg)
obtained in Referential Example 10 were used to give a free base
(330 mg) of the title compound in a similar manner to Example 91.
This free base was treated with HCl in ethanol to give the title
compound (NMR was measured in the form of a free base).
[3324] Melting point: 202-222.degree. C. (decomposed).
[3325] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.65-1.85(1H,m),
1.87,2.06(total 3H,each s), 1.88-2.10(1H,m), 2.37(3H,s),
2.65-2.77(2H,m), 2.79-2.89(2H,m), 2.99-3.09(0.5H,m),
3.30-3.52(2H,m), 3.64(2H,s), 3.70-3.80(0.5H,m), 3.96-4.21(2H,m),
4.27(1H,br.s), 4.35-4.48(1H,m), 7.07,7.11(total 1H,each s),
7.18(1H,d,J=8.8 Hz), 7.42(1H,d,J=8.8 Hz), 7.71(1H,s),
8.16-8.22(1H,m), 8.37,8.46(total 1H,each d,J=7.8 Hz),
11.81,11.83(total 1H,each s).
[3326] MS (ESI) m/z: 515(M+H.sup.+).
[3327] [.alpha.].sup.25.sub.D=-56.0.degree. (c=0.50, methanol).
Example 170
N-((3R,4R)-1-Acetyl-4-{[(5-chloroindol-2-yl)carbonyl]-amino}piperidin-3-yl-
)-5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00836##
[3329] The title compound was obtained from the compound obtained
in Referential Example 219 and the compound obtained in Referential
Example 10 in a similar manner to Example 169.
[3330] Melting point: 221-238.degree. C.
[3331] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.45-1.56(0.5H,m),
1.60-1.70(0.5H,m), 1.89-2.01(1H,m), 2.05(3H,s), 2.51-2.67(1H,m),
2.88(3H,s), 3.00-3.22(3H,m), 3.31-3.40(3H,m), 3.56-3.67(0.5H,m),
3.78-4.02(1.5H,m), 4.22-4.44(2H,m), 4.56-4.72(1H,m), 7.02(1H,s),
7.15(1H,dd,J=8.8,2.0 Hz), 7.37(1H,d,J=8.8 Hz), 7.67(1H,d,J=2.0 Hz),
8.42(1H,d,J=9.8 Hz), 8.67-8.78(1H,m), 11.02-11.14(1H,m),
11.72(0.5H,s), 11.74(0.5H,s).
[3332] MS (FAB) m/z: 515(M+H.sup.+).
[3333] [.alpha.].sup.25.sub.D=-105.4.degree. (c=0.58,
methanol).
Example 171
N-[(3R,4S)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(2-methoxyacetyl)pipe-
ridin-3-yl]-5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxam-
ide hydrochloride
##STR00837##
[3335] The title compound was obtained from the compound obtained
in Referential Example 221 in a similar manner to Example 169.
[3336] Melting point: 207-220.degree. C. (decomposed).
[3337] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.70-1.80(1H,m),
1.85-2.05(1H,m), 2.90(3H,s), 3.00-3.20(2H,m), 3.16(3H,s),
3.22-3.82(7H,m), 3.88-4.80(5H,m), 7.09(1H,d,J=9.0 Hz),
7.17(1H,dd,J=8.8,1.9 Hz), 7.42(1H,d,J=8.8 Hz), 7.70(1H,d,J=1.9 Hz),
8.29(1H,br.s), 8.40-8.50(1H,m), 11.20-11.50(1H,m), 11.85(1H,s).
[3338] MS (ESI) m/z: 545(M+H.sup.+).
[3339] [.alpha.].sup.25.sub.D=-53.4.degree. (c=0.52, methanol).
Example 172
N-[(3R,4R)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-(2-methoxyacetyl)pipe-
ridin-3-yl]-5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxam-
ide hydrochloride
##STR00838##
[3341] The title compound was obtained from the compound obtained
in Referential Example 223 in a similar manner to Example 169.
[3342] Melting point: 213-230.degree. C.
[3343] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.45-1.56(0.5H,m),
1.61-1.70(0.5H,m), 1.89-2.00(1H,m), 2.05(3H,s), 2.45-2.67(1H,m),
2.88(3H,s), 3.00-3.21(4H,m), 3.32-3.56(7H,m), 3.78-3.89(2H,m),
4.00-4.24(2H,m), 4.26-4.43(2H,m), 7.02(1H,s), 7.13(1H,dd,J=8.8,2.0
Hz), 7.37(1H,d,J=8.8 Hz), 7.67(1H,d,J=2.0 Hz), 8.41(1H,d,J=9.8 Hz),
8.74(1H,d,J=9.8 Hz), 10.80-10.90(1H,m), 11.72(1H,s).
[3344] MS (FAB) m/z: 545(M+H.sup.+).
[3345] [.alpha.].sup.25.sub.D=-100.3.degree. (c=0.51,
methanol).
Example 173
N-((3R,4R)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-6-oxotetrahydro-2H-pyra-
n-3-yl)-5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00839##
[3347] The title compound was obtained from the low-polar compound
obtained in Referential Example 176 and the compound obtained in
Referential Example 10 in a similar manner to Example 169.
[3348] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.41-2.56(2H,m),
2.91(3H,s), 3.01-3.23(1H,m), 3.24-3.56(5H,m), 3.62-3.67(1H,m),
4.21-4.44(1H,m), 4.56-4.78(2H,m), 7.11(1H,s), 7.16(1H,dd,J=8.8,2.0
Hz), 7.22(1H,d,J=8.5 Hz), 7.41(1H,d,J=8.8 Hz), 7.69(1H,d,J=2.0 Hz),
8.40-8.50(1H,m), 11.34-11.56(1H,m), 11.82(1H,s).
[3349] MS (FAB) m/z: 488(M+H.sup.+).
Example 174
N-((3R,4S)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-6-oxotetrahydro-2H-pyra-
n-3-yl)-5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00840##
[3351] The title compound was obtained from the high-polar compound
obtained in Referential Example 176 and the compound obtained in
Referential Example 10 in a similar manner to Example 169.
[3352] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.41-2.56(2H,m),
2.91(3H,s), 3.23-3.41(2H,m), 3.43-3.50(2H,m), 3.56-3.67(2H,m),
4.37(1H,dd,J=13.9,7.1 Hz), 4.40-4.50(1H,m), 4.56-4.78(2H,m),
7.12(1H,s), 7.17(1H,dd,J=8.8,2.0 Hz), 7.41(1H,d,J=8.8 Hz),
7.71(1H,d,J=2.0 Hz), 8.44(1H,d,J=8.5 Hz), 8.15(1H,d,J=8.5 Hz),
11.42-11.53(1H,m), 11.79(1H,s).
[3353] MS (FAB) m/z: 488(M+H.sup.+).
Example 175
Ethyl(3R,4S)-5-{[tert-butyl(diphenyl)silyl]oxy}-3-{[(5-chloroindol-2-yl)ca-
rbonyl]amino}-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-
carbonyl]amino}-valerate
##STR00841##
[3355] The title compound was obtained from the compound obtained
in Referential Example 225 in a similar manner to Example 169.
[3356] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.09(9H,s),
1.21(3H,t,J=7.4 Hz), 2.49(3H,s), 2.65(1H,dd,J=15.9,5.4 Hz),
2.67-2.90(5H,m), 3.60(1H,d,J=14.9 Hz), 3.72(1H,d,J=14.9 Hz),
3.78-3.91(2H,m), 4.00-4.21(2H,m), 4.43-4.50(1H,m), 4.78-4.89(1H,m),
6.81(1H,s), 7.20(1H,dd,J=8.8,2.0 Hz), 7.32-7.52(m,7H),
7.63-7.74(6H,m), 7.89-8.01(1H,m), 9.18(1H,s).
Example 176
Ethyl(3R,4S)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-5-hydroxy-4-{[(5-meth-
yl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amino}valerate
##STR00842##
[3358] After hydrogen fluoride.pyridine (0.4 mL) was added dropwise
to a mixture sulution composed of the compound (0.54 g) obtained in
Example 175, pyridine (4.0 mL), and tetrahydrofuran (10 mL) under
ice cooling, the reaction mixture was stirred for 18 hours while
the temperature thereof was gradually raised to room temperature.
The reaction mixture was concentrated, and the resultant residue
was purified by silica gel column chromatography
(chloroform:methanol=9:1) to give the title compound (0.31 g).
[3359] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20(3H,t,J=7.4 Hz),
2.49(3H,s), 2.67-2.90(6H,m), 3.62-3.74(3H,m), 3.78-3.94(1H,m),
4.00-4.20(2H,m), 4.30-4.40(1H,m), 4.80-4.89(1H,m), 6.93(1H,s),
7.23(1H,dd,J=8.8,2.0 Hz), 7.33(1H,d,J=8.8 Hz), 7.56(1H,d,J=8.5 Hz),
7.61(1H,d,J=2.0 Hz), 7.88(1H,d,J=8.5 Hz), 9.29(1H,s).
Example 177
N-((3S,4R)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-6-oxotetrahydro-2H-pyra-
n-3-yl]-5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00843##
[3361] 4N HCl-dioxane (20 mL) was added to the compound (0.31 g)
obtained in Example 176, and the mixture was heated under reflux
for 4 hours. The reaction mixture was concentrated, and the
resultant residue was recrystallized from diethyl ether to give the
title compound (0.23 g).
[3362] Melting point: 221-238.degree. C. (decomposed).
[3363] .sup.1H-NMR and MS: The same as those of the enantiomer in
Example 174.
Example 178
N-((3R*,4R*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1,1-dioxohexahydro-1--
thiopyran-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbo-
xamide hydrochloride
##STR00844##
[3365] A free base of the title compound was obtained from the
compound obtained in Referential Example 227 and
5-chloroindole-2-carboxylic acid in a similar manner to Example 91.
This free base was treated with HCl in ethanol to give the title
compound.
[3366] Melting point: 241-244.degree. C.
[3367] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.14(1H,br),
2.30-2.34(1H,m), 2.92(3H,s), 3.10-3.18(2H,m), 3.41(4H,br),
3.68(2H,br), 4.44(1H,br), 4.63-4.78(3H,m), 7.16-7.18(1H,m),
7.21(1H,s), 7.43(1H,d,J=8.5 Hz), 7.67(1H,d,J=4.6 Hz), 8.39(1H,br),
8.94(1H,br), 11.82(1H,br).
[3368] MS (ESI) m/z: 522(M+H.sup.+).
Example 179
N-((3R*,4R*)-4-{[(5-Fluoroindol-2-yl)carbonyl]amino}-1,1-dioxohexahydro-1--
thiopyran-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbo-
xamide hydrochloride
##STR00845##
[3370] A free base of the title compound was obtained from the
compound obtained in Referential Example 227 and
5-fluoroindole-2-carboxylic acid in a similar manner to Example 91.
This free base was treated with HCl in ethanol to give the title
compound.
[3371] Melting point: 243-245.degree. C.
[3372] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.14(1H,br),
2.30-2.33(1H,m), 2.92(3H,s), 3.13(2H,br), 3.51(4H,br), 3.63(2H,br),
4.63(3H,br), 4.78(1H,br), 7.01-7.05(1H,m), 7.21(1H,s),
7.37-7.44(2H,m), 8.36(1H,br), 8.93(1H,d,J=6.8 Hz),
11.72(1H,br).
[3373] MS (ESI) m/z: 506(M+H.sup.+).
Example 180
N-((3R*,4R*)-3-{[(5-Chloroindol-2-yl)carbonyl]amino}-1,1-dioxohexahydro-1--
thiopyran-4-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbo-
xamide hydrochloride
##STR00846##
[3375] A free base of the title compound was obtained from the
compound obtained in Referential Example 229 and the compound
obtained in Referential Example 10 in a similar manner to Example
91. This free base was treated with HCl in ethanol to give the
title compound.
[3376] Melting point: 242-247.degree. C.
[3377] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.16(1H,br),
2.45(1H,br), 2.93(3H,s), 3.13(2H,br), 3.26(4H,br), 3.69(2H,br),
4.45(1H,br), 4.65-4.77(3H,m), 7.01(1H,s), 7.17(1H,dd,J=8.7,1.4 Hz),
7.43(1H,d,J=8.5 Hz), 7.69(1H,s), 8.35-8.40(1H,m), 9.04(1H,br),
11.86(1H,s).
[3378] MS (ESI) m/z: 522(M+H.sup.+).
Example 181
N-((3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1,1-dioxohexahydro-1--
thiopyran-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbo-
xamide hydrochloride
##STR00847##
[3380] A free base of the title compound was obtained from the
compound obtained in Referential Example 231 and
5-chloroindole-2-carboxylic acid in a similar manner to Example 91.
This free base was treated with HCl in ethanol to give the title
compound.
[3381] Melting point: 244-249.degree. C.
[3382] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.17-2.27(2H,m),
2.90(3H,s), 3.09(1H,br), 3.18-3.21(2H,m), 3.31-3.34(2H,m),
3.60-3.67(3H,m), 4.41-4.49(2H,m), 4.54-4.59(2H,m), 7.04(1H,s),
7.09-7.13(1H,m), 7.39(1H,d,J=8.5 Hz), 7.61(1H,d,J=9.9 Hz),
8.52-8.56(1H,m), 8.83-8.85(1H,m), 11.65(1H,d,J=11.9 Hz).
[3383] MS (ESI) m/z: 522(M+H.sup.+).
Example 182
N-((3R*,4S*)-4-{[(5-Fluoroindol-2-yl)
carbonyl]amino}-1,1-dioxohexahydro-1-thiopyran-3-yl)-5-methyl-4,5,6,7-tet-
rahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride
##STR00848##
[3385] A free base of the title compound was obtained from the
compound obtained in Referential Example 231 and
5-fluoroindole-2-carboxylic acid in a similar manner to Example 91.
This free base was treated with HCl in ethanol to give the title
compound.
[3386] Melting point: 236-241.degree. C.
[3387] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.20-2.24(2H,m),
2.89(3H,s), 3.07(1H,br), 3.19-3.22(2H,m), 3.60-3.66(4H,m),
4.43-4.58(5H,m), 6.95-7.00(1H,m), 7.04(1H,s), 7.32-7.38(2H,m),
8.50(1H,d,J=8.5 Hz), 8.83(1H,d,J=8.5 Hz), 11.59(1H,s).
[3388] MS (ESI) m/z: 506(M+H.sup.+).
Example 183
N-((3R*,4R*)-3-{[(5-Fluoroindol-2-yl)carbonyl]amino}-1,1-dioxohexahydro-1--
thiopyran-4-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbo-
xamide hydrochloride
##STR00849##
[3390] A free base of the title compound was obtained from the
compound obtained in Referential Example 233 and the compound
obtained in Referential Example 10 in a similar manner to Example
91. This free base was treated with HCl in ethanol to give the
title compound.
[3391] Melting point: 244-249.degree. C.
[3392] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.12-2.18(1H,m),
2.50(1H,br), 2.92(3H,s), 3.17(3H,br), 3.50-3.61(5H,m), 4.45(1H,br),
4.62-4.78(3H,m), 6.98-7.03(2H,m), 7.36-7.42(2H,m), 8.30(1H,br),
9.00(1H,d,J=8.0 Hz), 11.74(1H,s).
[3393] MS (ESI) m/z: 506(M+H.sup.+).
Example 184
N-((3S,4R)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-methyl-6-oxopiperidin-
-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
(low-polar compound) and
N-((3R,4R)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-methyl-6-oxopiperidi-
n-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
(high-polar compound)
##STR00850##
[3395] The title compound was obtained from the compound obtained
in Referential Example 236 and the compound obtained in Referential
Example 10 in a similar manner to Example 169.
Low-Polar Compound:
[3396] Melting point: 189-203.degree. C. (decomposed).
[3397] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.52(3H,s),
2.59(1H,q,J=8.8 Hz), 2.71-2.78(2H,m), 2.89-3.00(2H,m), 3.03(3H,s),
3.12(1H,dd,J=17.6,5.4 Hz), 3.43(1H,dd,J=12.7,5.1 Hz),
3.70(1H,d,J=15.2 Hz), 3.77(1H,d,J=15.2 Hz), 3.83(1H,dd,J=12.7,3.9
Hz), 4.55-4.67(2H,m), 6.99(1H,s), 7.23(1H,dd,J=8.8,2.0 Hz),
7.33(1H,d,J=8.8 Hz), 7.65(1H,d,J=2.0 Hz), 8.07(1H,d,J=5.1 Hz),
8.16(1H,d,J=5.4 Hz), 9.43(1H,s).
[3398] MS (FAB) m/z: 501(M+H.sup.+).
High-Polar Compound:
[3399] Melting point: 183-195.degree. C. (decomposed).
[3400] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.33(3H,s),
2.41-2.50(1H,m), 2.62-2.73(3H,m), 2.75-2.81(1H,m), 2.82(3H,s),
3.21-3.32(2H,m), 3.34-3.50(2H,m), 3.55(1H,d,J=15.4 Hz),
3.63(1H,d,J=15.4 Hz), 4.30-4.40(0.5H,m), 4.50-4.60(0.5H,m),
7.04(1H,s), 7.15(1H,dd,J=8.8,2.0 Hz), 7.38(1H,d,J=8.8 Hz),
7.67(1H,d,J=2.0 Hz), 8.49(1H,d,J=8.5 Hz), 8.71(1H,d,J=8.5 Hz),
11.74(1H,s).
[3401] MS (FAB) m/z: 501(M+H.sup.+).
Example 185
5-Chloro-N-((1R*,2S*)-2-{[4-(pyridin-4-yl)benzoyl]-amino}cyclohexyl)indole-
-2-carboxamide hydrochloride
##STR00851##
[3403] The title compound was obtained from the compound obtained
in Referential Example 71 and the compound obtained in Referential
Example 237 in a similar manner to the process described in Example
2.
[3404] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.40-1.52(2H,m),
1.60-1.80(4H,m), 1.96-2.10(2H,m), 4.24-4.39(2H,m),
7.15(1H,dd,J=8.8,2.0 Hz), 7.21(1H,s), 7.40(1H,d,J=8.8 Hz),
7.64(1H,d,J=2.0 Hz), 8.06(4H,s), 8.18(1H,J=7.3 Hz),
8.34-8.42(3H,m), 8.94(2H,d,J=6.9 Hz),11.91(1H,s).
[3405] MS (FAB)m/z: 473(M+H).sup.+.
Example 186
[3406]
4-(4-{[((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclohexy-
l)amino]carbonyl}phenyl)pyridine N-oxide
##STR00852##
[3407] The title compound was obtained from the compound obtained
in Referential Example 71 and the compound obtained in Referential
Example 240 in a similar manner to the process described in Example
2.
[3408] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.40-1.52(2H,m),
1.60-1.80(4H,m), 1.88-2.00(2H,m), 4.21-4.36(2H,m), 7.12-7.18(2H,m),
7.41(1H,d,J=8.6 Hz), 7.66(1H,s), 7.80-7.87(4H,m), 7.91(2H,d,J=8.3
Hz), 8.01(1H,d,J=7.6 Hz), 8.09(1H,d,J=7.3 Hz), 8.27(2H,d,J=6.6 Hz),
11.79(1H,s).
[3409] MS (FAB) m/z: 489(M+H).sup.+.
Example 187
5-Chloro-N-((1R*,2S*)-2-.DELTA.[4-(pyridin-2-yl)benzoyl]-amino}cyclohexyl)-
indole-2-carboxamide hydrochloride
##STR00853##
[3411] The title compound was obtained from the compound obtained
in Referential Example 71 and 4-(2-pyridyl)benzoic acid (Japanese
Patent Application Laid-Open (kokai) No. 2000-119253) in a similar
manner to the process described in Example 2.
[3412] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.39-1.51(2H,m),
1.60-1.80(4H,m), 1.89-2.00(2H,m), 4.24-4.38(2H,m), 7.12-7.16(2H,m),
7.36-7.39(1H,m), 7.42(1H,d,J=8.8 Hz), 7.66(1H,d,J=2.0 Hz),
7.87-7.90(1H,m), 7.92(2H,d,J=8.3 Hz), 7.98-8.11(3H,m),
8.15(2H,d,J=8.3 Hz), 8.69(1H,d,J=4.6 Hz), 11.80(1H,s).
[3413] MS (FAB) m/z: 473(M+H).sup.+.
Example 188
2-(4-{[((1R*,2S*)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-cyclohexyl)amino-
]carbonyl}phenyl)pyridine N-oxide
##STR00854##
[3415] The title compound was obtained from the compound obtained
in Referential Example 71 and the compound obtained in Referential
Example 241 in a similar manner to the process described in Example
2.
[3416] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.39-1.51(2H,m),
1.60-1.79(4H,m), 1.89-2.00(2H,m), 4.23-4.37(2H,m), 7.12-7.17(2H,m),
7.39-7.43(3H,m), 7.61-7.64(1H,m), 7.67(1H,d,J=2.0 Hz), 7.89(4H,s),
8.00-8.06(1H.m), 8.08-8.02(1H,m), 8.32-8.35(1H,m), 11.79(1H,s).
[3417] MS (FAB) m/z: 489(M+H).sup.+.
Example 189
5-Chloro-N-[(1R*,2R*)-2-({[5-(4-pyridin-2-yl)thiazol-2-yl]carbonyl}amino)c-
yclohexyl]indole-2-carboxamide hydrochloride
##STR00855##
[3419] The title compound was obtained from the compound obtained
in Referential Example 69 and lithium
5-(4-pyridyl)thiazole-2-carboxylate (Japanese Patent Application
Laid-Open (kokai) No. 2000-143623) in a similar manner to the
process described in Example 2.
[3420] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.44(2H,br.s),
1.65(4H,br.s), 1.85-2.06(2H,m), 4.23(1H,br.s), 4.30(1H,br.s),
7.14-7.23(2H,m), 7.41(1H,d,J=8.8 Hz), 7.69(1H,s), 8.04-8.13(2H,m),
8.13(1H,d,J=8.8 Hz), 8.59(1H,d,J=8.0 Hz), 8.75-8.87(3H,m),
11.83(1H,s).
[3421] MS (ESI)m/z: 480(M+H).sup.+.
Example 190
5-Chloro-N-[(1R*,2S*)-2-({[1-(pyridin-4-yl)piperidin-4-yl]carbonyl}amino)c-
yclohexyl]indole-2-carboxamide hydrochloride
##STR00856##
[3423] 1-(4-Pyridyl)piperidine-4-carboxylic acid (Tetrahedron,
1998, Vol. 44, p. 7095) (206 mg) was suspended in methylene
chloride (50 mL), and thionyl chloride (144 .mu.l) was added under
ice cooling, followed by stirring for 30 minutes. After
triethylamine (969 .mu.l) was added to the reaction mixture, the
compound (328 mg) obtained in Referential Example 71 was added,
followed by stirring at room temperature for 30 minutes. The
reaction mixture was concentrated under reduced pressure, water was
added to the residue, the mixture was concentrated under reduced
pressure, and precipitate deposited was collected by filtration to
give the title compound (310 mg).
[3424] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.30-2.00(10H,m),
2.74(1H,br.s), 3.18(2H,q,J=12.3 Hz), 4.03(1H,br.s),
4.10-4.25(3H,m), 7.15-7.55(4H,m), 7.42(1H,d,J=8.8 Hz), 7.65(1H,s),
7.91(1H,d,J=8.8 Hz), 8.20-8.35(3H,m), 11.91(1H,s),
13.47(1H,br.s).
[3425] MS (FAB) m/z: 480(M+H).sup.+.
Example 191
N.sup.1-(4-Chlorophenyl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)-carbonyl]--
2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amin-
o}cyclohexyl)ethanediamide hydrochloride
##STR00857##
[3427] The compound (288 mg) obtained in Referential Example 242
was dissolved in tetrahydrofuran (8.0 mL), lithium hydroxide (46
mg) and water (1.0 mL) were successively added, and the mixture was
stirred at room temperature for 2 hours. The reaction mixture was
concentrated under reduced pressure to give a crude product (292
mg) of lithium 2-(4-chloroanilino)-2-oxoacetate as a colorless
solid. This crude product and the compound obtained in Referential
Example 253 were dissolved in N,N-dimethylformamide (15 mL), and
1-hydroxybenzotriazole monohydrate (164 mg) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (251
mg) were added, followed by stirring at room temperature for 64.5
hours. The solvent was distilled away under reduced pressure,
saturated aqueous sodium hydrogencarbonate and methylene chloride
were added to the residue for partitioning the mixture, and the
resultant organic layer was dried over sodium sulfate anhydrate.
After the solvent was distilled away under reduced pressure, the
residue was purified by silica gel column chromatography (methylene
chloride:methanol=47:3). The thus-obtained pale yellow solids were
dissolved in methylene chloride, 1N HCl in ethanol (0.52 mL) was
added, and the solvent was distilled away under reduced pressure.
Methanol and diethyl ether were added to the residue, and the
precipitate formed was collected by filtration to give the title
compound (245 mg).
[3428] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.45-1.55(1H,m),
1.60-1.80(3H,m), 1.95-2.10(2H,m), 2.79(3H,s), 2.80-3.00(1H,m),
2.92(3H,s), 2.94(3H,s), 3.10-3.40(2H,m), 3.40-3.80(2H,m),
3.95-4.05(1H,m), 4.40-4.80(3H,m), 7.40(2H,d,J=8.8 Hz),
7.83(2H,d,J=8.8 Hz), 8.75(1H,d,J=7.1 Hz), 9.00-9.10(1H,br),
10.81(1H,s), 11.45-11.75(1H,m).
[3429] MS (FAB) m/z: 547(M+H).sup.+.
Example 192
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-
-amino}cyclohexyl)ethanediamide hydrochloride
##STR00858##
[3431] The compound (240 mg) obtained in Referential Example 243
was dissolved in tetrahydrofuran (8.0 mL), lithium hydroxide (41
mg) and water (1.0 mL) were successively added to the solution, and
the mixture was stirred at room temperature for 2.5 hours. The
reaction mixture was concentrated under reduced pressure to give
lithium 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate (249 mg).
Separately, 10% palladium on carbon (200 mg) was added to a
solution of the compound (293 mg) obtained in Referential Example
252 in methanol (10 mL), and the mixture was stirred at room
temperature for 18 hours in a hydrogen atmosphere. After removing
palladium on carbon by filtration, the filtrate was concentrated
under reduced pressure to give a crude product (259 mg) of
N-{(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5-
,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxamide. This crude
product (259 mg) and the lithium salt (249 mg) prepared above were
added to N,N-dimethylformamide (15 mL), and 1-hydroxybenzotriazole
monohydrate (166 mg) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (235
mg) were added, followed by stirring at room temperature for 63.5
hours. The solvent was distilled away under reduced pressure,
saturated aqueous sodium hydrogencarbonate and methylene chloride
were added to the residue for partitioning the mixture, and the
resultant organic layer was dried over sodium sulfate anhydrate.
After the solvent was distilled away under reduced pressure, the
residue was purified by silica gel column chromatography (methylene
chloride:methanol=93:7). The thus-obtained pale yellow solids were
dissolved in methylene chloride, 1N HCl in ethanol (0.855 mL) was
added to the solution, and the solvent was distilled away under
reduced pressure. Methanol and diethyl ether were added to the
residue, and the precipitates formed were collected by filtration
to give the title compound (209 mg).
[3432] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.40-1.57(1H,m),
1.60-1.80(3H,m), 1.95-2.13(2H,m), 2.79(3H,s), 2.80-3.00(1H,m),
2.92(3H,s), 2.94(3H,s), 3.10-3.40(2H,m), 3.40-3.80(2H,m),
3.95-4.05(1H,m), 4.37-4.80(3H,m), 7.90-8.10(2H,m), 8.45(1H,d,J=2.2
Hz), 8.71(1H,d,J=7.6 Hz), 9.10-9.30(1H,br), 10.26(1H,s),
11.30-11.60(1H,br).
[3433] MS (FAB) m/z: 548(M+H).sup.+.
Example 193
N.sup.1-(3-Chlorophenyl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)-carbonyl]--
2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amin-
o}cyclohexyl)ethanediamide hydrochloride
##STR00859##
[3435] The compound (222 mg) obtained in Referential Example 270
and 3-chloroaniline (63 .mu.l) were dissolved in
N,N-dimethylformamide (10 mL), and 1-hydroxybenzotriazole
monohydrate (68 mg) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (144
mg) were added, followed by stirring at room temperature for 40
hours. The solvent was distilled away under reduced pressure,
saturated aqueous sodium hydrogencarbonate and methylene chloride
were added to the residue for partitioning the mixture, and the
resultant organic layer was dried over sodium sulfate anhydrate.
After the solvent was distilled away under reduced pressure, the
residue was purified by silica gel column chromatography (methylene
chloride:methanol=30:1). The thus-obtained pale yellow solids were
dissolved in methylene chloride, 1N HCl in ethanol (0.50 mL) was
added, and the solvent was distilled away under reduced pressure.
Diethyl ether was added to the residue, and the precipitate formed
was collected by filtration to give the title compound (174
mg).
[3436] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.45-1.62(1H,m),
1.65-1.90(3H,m), 1.98-2.20(2H,m), 2.79(3H,s), 2.88-3.10(1H,m),
2.93(3H,s), 2.94(3H,s), 3.15-3.40(2H,m), 3.40-3.90(2H,m),
3.95-4.10(1H,m), 4.40-4.80(3H,m), 7.19(1H,dd,J=9.3,2.0 Hz),
7.37(1H,d,J=8.2 Hz), 7.77(1H,d,J=8.3 Hz), 7.92-8.05(1H,m),
8.75(1H,d,J=7.3 Hz), 8.95-9.20(1H,br), 10.87(1H,s),
11.25-11.45(1H,br).
Example 194
N.sup.1-((1S,2R,4S)-4-[(Dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetr-
ahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N.sup.2-(4-fl-
uorophenyl)-ethanediamide hydrochloride
##STR00860##
[3438] In a manner similar to that described in Example 191, the
compound obtained in Referential Example 254 was hydrolyzed and
then, condensed with the compound obtained in Referential Example
253, followed by treatment with hydrochloric acid, to thereby give
the title compound.
[3439] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.40-2.13(6H,m),
2.77(3H,s), 2.93(3H,s), 2.97(3H,s), 3.12-3.82(7H,m),
3.93-4.04(1H,m), 4.38-4.46(1H,m), 4.35-4.75(1H,m), 7.11-7.21(2H,m),
7.72-7.84(2H,m), 8.73(1H,d,J=7.6 Hz), 8.93-9.02(1H,m),
10.70(1H,s).
[3440] MS (FAB) m/z: 531(M+H).sup.+.
Example 195
N.sup.1-(4-Bromophenyl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)-carbonyl]-2-
-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amino-
}cyclohexyl)ethanediamide hydrochloride
##STR00861##
[3442] The compound (152 mg) obtained in Referential Example 255
was dissolved in tetrahydrofuran (5.0 mL), 1N aqueous sodium
hydroxide (1.20 mL) and methanol (5.0 mL) were successively added,
and the mixture was stirred at room temperature for 2.5 hours. The
reaction mixture was concentrated under reduced pressure, and
methylene chloride (10 mL) and 1N hydrochloric acid (2.0 mL) were
added to the residue for partitioning the mixture. The resultant
organic layer was dried over sodium sulfate anhydrate, and the
solvent was distilled away under reduced pressure to give a crude
product (280 mg) of 2-(4-bromoanilino)-2-oxoacetic acid as a
colorless solid. This crude product and the compound (280 mg)
obtained in Referential Example 253 were dissolved in
N,N-dimethylformamide (30 mL), and 1-hydroxybenzotriazole
monohydrate (90 mg) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (226
mg) were added, followed by stirring at room temperature overnight.
The solvent was distilled away under reduced pressure, saturated
aqueous sodium hydrogencarbonate and methylene chloride were added
to the residue for partitioning the mixture, and the resultant
organic layer was dried over sodium sulfate anhydrate. After the
solvent was distilled away under reduced pressure, the residue was
purified by silica gel column chromatography (methylene
chloride:methanol=97:3). The thus-obtained pale yellow solids were
dissolved in methylene chloride, 1N HCl in ethanol (191 .mu.l) was
added, and the solvent was distilled away under reduced pressure.
Methanol and diethyl ether were added to the residue, and the
precipitate formed was collected by filtration to give the title
compound (103 mg).
[3443] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.43-1.57(1H,m),
1.59-1.80(3H,m), 1.97-2.10(2H,m), 2.79(3H,s), 2.84-2.98(7H,m),
3.18(2H,br.s), 3.39-3.72(2H,m), 3.95-4.05(1H,m), 4.20-4.80(3H,m),
7.53(2H,d,J=8.8 Hz), 7.77(2H,d,J=8.8 Hz), 8.75(1H,d,J=7.3 Hz),
8.97-9.09(1H,m), 10.82(1H,s), 11.11(1H,br.s).
[3444] MS (FAB) m/z: 591(M+H).sup.+.
Example 196
N.sup.1-(4-Chloro-2-methylphenyl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)ca-
rbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbon-
yl]-amino}cyclohexyl)ethanediamide hydrochloride
##STR00862##
[3446] In a manner similar to that described in Example 191, the
compound obtained in Referential Example 256 was hydrolyzed and
then, condensed with the compound obtained in Referential Example
253, followed by treatment with hydrochloric acid, to thereby give
the title compound.
[3447] 1H-NMR (DMSO-d6) .delta.: 1.45-1.55(1H,m), 1.60-1.80(3H,m),
2.00-2.10(2H,m), 2.19(3H,s), 2.79(3H,s), 2.80-3.00(7H,m),
3.31(2H,br.s), 3.40-3.70(2H,br), 3.95-4.05(1H,m), 4.35-4.70(3H,m),
7.20-7.30(1H,m), 7.35(1H,d,J=2.5 Hz), 7.43(1H,d,J=8.6 Hz),
8.76(1H,d,J=6.6 Hz), 9.00-9.15(1H,br), 10.19(1H,s).
[3448] MS (FAB) m/z: 561(M+H).sup.+.
Example 197
N.sup.1-(4-Chloro-3-methylphenyl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)ca-
rbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbo-
nyl]-amino}cyclohexyl)ethanediamide hydrochloride
##STR00863##
[3450] In a manner similar to that described in Example 191, the
compound obtained in Referential Example 257 was hydrolyzed and
then, condensed with the compound obtained in Referential Example
253, followed by treatment with hydrochloric acid, to thereby give
the title compound.
[3451] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.47-1.53(1H,m),
1.68-1.80(3H,m), 1.98-2.09(2H,m), 2.29(3H,s), 2.79(3H,s),
2.80-3.00(1H,m), 2.95(6H,s), 3.17-3.19(3H,m), 3.40-3.80(1H,m),
3.93-4.02(1H,m), 4.44-4.56(3H,m), 7.38(1H,d,J=8.8 Hz),
7.65(1H,d,J=8.8 Hz), 7.74(1H,s), 8.75(1H,d,J=7.8 Hz),
8.96(1H,d,J=8.0 Hz), 10.69(1H,s).
[3452] MS (FAB) m/z: 561(M+H).sup.+.
Example 198
N.sup.1-(4-Chloro-2-fluorophenyl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)ca-
rbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbo-
nyl]-amino}cyclohexyl)ethanediamide hydrochloride
##STR00864##
[3454] In a manner similar to that described in Example 191, the
compound obtained in Referential Example 258 was hydrolyzed and
then, condensed with the compound obtained in Referential Example
253, followed by treatment with hydrochloric acid, to thereby give
the title compound.
[3455] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.40-1.55(1H,m),
1.58-1.80(3H,m), 1.95-2.12(2H,m), 2.77(3H,s), 2.80-3.00(1H,m),
2.91(3H,s), 2.92(3H,s), 3.10-3.40(2H,m), 3.40-3.80(2H,m),
3.95-4.05(1H,m), 4.30-4.80(3H,m), 7.29(1H,d,J=8.5 Hz),
7.52(1H,dd,J=10.3,2.0 Hz), 7.61(1H,t,J=8.4 Hz), 8.72(1H,d,J=6.8
Hz), 9.00-9.20(1H,br), 10.38(1H,s), 11.20-11.45(1H,br).
[3456] MS (FAB) m/z: 565(M+H).sup.+.
Example 199
N.sup.1-(2,4-Dichlorophenyl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)-carbon-
yl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]-
amino}cyclohexyl)ethanediamide hydrochloride
##STR00865##
[3458] The compound (300 mg) obtained in Referential Example 270
was dissolved in N,N-dimethylformamide (5 mL), and
2,4-dichloroaniline (165 mg),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (260
mg), and 1-hydroxybenzotriazole monohydrate (91 mg) were added,
followed by stirring at room temperature for 2 days. The solvent
was distilled away under reduced pressure, saturated aqueous sodium
hydrogencarbonate and methylene chloride were added to the residue
for partitioning the mixture, and the resultant organic layer was
dried over sodium sulfate anhydrate. After the solvent was
distilled away under reduced pressure, the residue was purified by
silica gel column chromatography (methylene chloride:methanol=47:3)
to give a free base of the title compound. This product was
dissolved in methylene chloride, 1N HCl in ethanol (108 .mu.l) was
added, and the solvent was distilled away under reduced pressure. A
small amount of methanol was added to the residue, and diethyl
ether was added dropwise while irradiating with ultrasonic waves to
collect the precipitate formed by filtration. This product was
washed with diethyl ether to give the title compound (60 mg).
[3459] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.45-1.77(4H,m),
2.03-2.12(2H,m), 2.79(3H,s), 2.92-2.96(7H,m), 3.25(2H,br.s),
3.49(1H,br.s), 3.69(1H,br.s), 3.98-4.04(1H,m), 4.40-4.43(1H,m),
4.45(1H,br.s), 4.69(1H,br.s), 7.48(1H,dd,J=8.5,2.4 Hz),
7.75(1H,d,J=2.4 Hz), 7.89(1H,d,J=8.5 Hz), 8.75(1H,d,J=6.8 Hz),
9.21(1H,br.s), 10.25(1H,s), 11.55(1H,br.s).
[3460] MS (FAB) m/z: 581(M+H).sup.+.
Example 200
N.sup.1-(3,4-Dichlorophenyl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)-carbon-
yl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]-
amino}cyclohexyl)ethanediamide
##STR00866##
[3462] 3,4-Dichloroaniline (1.62 g) was dissolved in methylene
chloride (20 mL), and triethylamine (1.67 mL) and methyl
chlorooxoacetate (1.01 mL) were successively added under ice
cooling, and the mixture was stirred at room temperature for 21
hours. Water and methylene chloride were added to the reaction
mixture for partitioning the mixture. The resultant aqueous layer
was extracted with methylene chloride. Organic layers were combined
and dried over magnesium sulfate anhydrate, and the solvent was
distilled away under reduced pressure. The resultant residue was
dissolved in ethanol (50 mL), and water (25 mL) and lithium
hydroxide monohydrate (629 mg) were successively added, followed by
stirring at room temperature for 12.5 hours. Lithium hydroxide
monohydrate (629 mg) was additionally added, followed by stirring
at room temperature for 5.5 hours. The reaction mixture was
concentrated to solid under reduced pressure. Water and diethyl
ether were added to the residue for partitioning the mixture.
Hydrochloric acid was added to the resultant aqueous layer for
acidification. The Solid formed was collected by filtration to give
a crude product (1.62 g) of 2-(3,4-dichloroanilino)-2-oxoacetic
acid as a colorless solid. This crude product (191 mg) and the
compound (250 mg) obtained in Referential Example 253 were
dissolved in N,N-dimethylformamide (10 mL), and
1-hydroxybenzotriazole monohydrate (110 mg) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (157
mg) were added, followed by stirring at room temperature for 67
hours. The solvent was distilled away under reduced pressure,
saturated aqueous sodium hydrogencarbonate and ethyl acetate were
added to the residue for partitioning the mixture, and the
resultant aqueous layer was extracted 3 times with methylene
chloride. Organic layers were combined and dried over sodium
sulfate anhydrate. After the solvent was distilled away under
reduced pressure, the residue was purified by silica gel column
chromatography (methylene chloride:methanol=95:5) to give the title
compound (154 mg).
[3463] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.77-1.88(1H,m),
1.91-1.95(1H,m), 2.05-2.10(3H,m), 2.51(3H,s), 2.77-2.99(6H,m),
2.95(3H,s), 3.05(3H,s), 3.68(1H,d,J=15.5 Hz), 3.74(1H,d,J=15.5 Hz),
4.08-4.13(1H,m), 4.69-4.72(1H,m), 7.40(2H,s), 7.41(1H,d,J=7.7 Hz),
7.90(1H,s), 8.01(1H,d,J=7.7 Hz), 9.27(1H,s).
[3464] MS (ESI) m/z: 581(M+H).sup.+.
Example 201
N.sup.1-(2,
4-Difluorophenyl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)-carbonyl]-2-{[(5-
-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amino}cycl-
ohexyl)ethanediamide
##STR00867##
[3466] In a manner similar to that described in Example 191, the
compound obtained in Referential Example 259 was hydrolyzed,
followed by condensation with the compound obtained in Referential
Example 253, to thereby give the title compound.
[3467] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.55-1.62(1H,m),
1.67-1.98(2H,m), 2.01-2.18(4H,m), 2.52(3H,s), 2.77-3.00(4H,m),
2.95(3H,s),2.99(3H,s), 3.65-3.78(2H,m), 4.06-4.15(1H,m),
4.66-4.73(1H,m), 6.85-6.94(2H,m), 7.38(1H,d,J=8.5 Hz),
7.96(1H,d,J=7.3 Hz), 8.22-8.29(1H,m), 9.36(1H,br).
Example 202
N.sup.1-(3,4-Difluorophenyl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)-carbon-
yl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]-
amino}cyclohexyl)ethanediamide
##STR00868##
[3469] In a manner similar to that described in Example 191, the
compound obtained in Referential Example 260 was hydrolyzed,
followed by condensation with the compound obtained in Referential
Example 253, to thereby give the title compound.
[3470] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.56-1.73(1H,m),
1.77-1.99(2H,m), 2.00-2.18(4H,m), 2.52(3H,s), 2.75-3.00(4H,m),
2.95(3H,s), 3.06(3H,s), 3.64-3.79(2H,m), 4.05-4.14(1H,m),
4.68-4.75(1H,m), 7.09-7.21(2H,m), 7.38(1H,d,J=8.8 Hz),
7.72(1H,ddd,J=12.0, 7.1,2.6 Hz), 7.95(1H,d,J=7.8 Hz),
9.22(1H,br).
Example 203
N.sup.1-((1S,2R,4S)-4-[(Dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetr-
ahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-amino}cyclohexyl)-N.sup.2-(pyr-
idin-4-yl)ethanediamide hydrochloride
##STR00869##
[3472] In a manner similar to that described in Example 191, the
compound obtained in Referential Example 261 was hydrolyzed and
then, condensed with the compound obtained in Referential Example
253, followed by treatment with hydrochloric acid, to thereby give
the title compound.
[3473] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.40-2.10(6H,m),
2.77(3H,s), 2.927(3H,s), 2.933(3H,s), 3.05-4.20(8H,m),
4.40-4.55(1H,m), 8.27(2H,d,J=6.8 Hz), 8.67(1H,d,J=8.0 Hz),
8.71(2H,d,J=6.8 Hz), 9.10-9.30(1H,br), 11.81(1H,s).
[3474] MS (FAB) m/z: 514(M+H).sup.+.
Example 204
N.sup.1-(5-Bromopyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-(dimethylamino)-carbon-
yl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]-
amino}cyclohexyl)ethanediamide hydrochloride
##STR00870##
[3476] In a manner similar to that described in Example 195, the
compound obtained in Referential Example 262 was hydrolyzed and
then, condensed with the compound obtained in Referential Example
253, followed by treatment hydrochloric acid, to thereby give the
title compound.
[3477] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.43-1.57(1H,m),
1.61-1.81(3H,m), 1.98-2.15(2H,m), 2.79(3H,s), 2.86(3H,s),
2.89-3.01(4H,m), 3.18(2H,br.s), 3.50(2H,br.s), 3.95-4.05(1H,m),
4.35-4.62(3H,m), 7.97(1H,d,J=9.0 Hz), 8.12(1H,dd,J=9.0,2.4 Hz),
8.52(1H,d,J=2.4 Hz), 8.70(1H,d,J=7.5 Hz), 9.18(1H,d,J=7.5 Hz),
10.25(1H,br.s).
[3478] MS (FAB) m/z: 592(M+H).sup.+.
Example 205
N.sup.1-(6-Chloropyridin-3-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-
amino}-cyclohexyl)ethanediamide hydrochloride
##STR00871##
[3480] The compound (200 mg) obtained in Referential Example 263,
which was a crude product, was dissolved in methanol (10 mL) to
heat the solution to 50.degree. C., and 1N aqueous sodium hydroxide
(3 mL) was added thereto, followed by stirring for 5 minutes. To
this mixture was added 1N hydrochloric acid to adjust the pH to a
weak acidity. The solvent was distilled away under reduced pressure
to give residue containing
2-[(2-chloropyridin-5-yl)amino]-2-oxoacetic acid. This residue and
the compound (250 mg) obtained in Referential Example 253 were
added to N,N-dimethylformamide (5 mL), and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (328
mg) and 1-hydroxybenzotriazole monohydrate (46 mg) were added,
followed by stirring at room temperature for 3 days. The solvent
was distilled away under reduced pressure, and saturated aqueous
sodium hydrogencarbonate and methylene chloride were added to the
residue for partitioning the mixture. The resultant organic layer
was dried over sodium sulfate anhydrate, the solvent was distilled
away under reduced pressure, and the residue was purified by silica
gel column chromatography (methylene chloride:methanol=47:3) to
give a free base of the title compound as a pale yellow solid. This
product was dissolved in methylene chloride, 1N HCl in ethanol (862
.mu.l) was added, and the solvent was distilled away under reduced
pressure. A small amount of methanol was added to the residue, and
ethyl acetate and diethyl ether were added dropwise while
irradiating with ultrasonic waves to collect the precipitate formed
by filtration. This product was washed with diethyl ether to give
the title compound (229 mg).
[3481] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.46-1.75(4H,m),
1.99-2.09(2H,m), 2.79(3H,s), 2.92-2.95(7H,m), 3.12-3.53(3H,m),
3.70(1H,br.s), 3.99-4.06(1H,m), 4.44(2H,br.s), 4.69,4.73(1H,each
s), 7.53(1H,d,J=8.5 Hz), 8.23-8.25(1H,m), 8.72-8.77(1H,m),
8.85(1H,s), 9.07,9.16(1H,each d,J=8.1 Hz), 11.09(1H,d,J=8.1 Hz),
11.78(1H,br.s).
[3482] MS (FAB) m/z: 548(M+H).sup.+.
Example 206
N.sup.1-(6-Chloropyridazin-3-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)car-
bonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbony-
l]-amino}cyclohexyl)ethanediamide hydrochloride
##STR00872##
[3484] In a manner similar to that described in Example 191, the
compound obtained in Referential Example 264 was hydrolyzed and
then, condensed with the compound obtained in Referential Example
253, followed by treatment with hydrochloric acid, to thereby give
the title compound.
[3485] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.44-1.57(1H,m),
1.62-1.80(3H,m), 2.00-2.10(2H,m), 2.79(3H,s), 2.86(3H,br.s),
2.94(3H,s), 2.95-3.01(1H,m), 3.14-3.23(2H,m), 3.45-3.63(2H,m),
3.96-4.08(1H,m), 4.40-4.60(3H,m), 7.97(1H,d,J=9.3 Hz),
8.26(1H,d,J=9.3 Hz), 8.69(1H,d,J=7.6 Hz), 9.20(1H,d,J=7.6 Hz),
11.06(1H,s).
[3486] MS (FAB) m/z: 549(M+H).sup.+.
Example 207
N.sup.1-(5-Chlorothiazol-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-
-amino}cyclohexyl)ethanediamide hydrochloride
##STR00873##
[3488] In a manner similar to that described in Example 191, the
compound obtained in Referential Example 265 was hydrolyzed and
then, condensed with the compound obtained in Referential Example
253, followed by treatment with hydrochloric acid, to thereby give
the title compound.
[3489] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35-2.10(6H,m),
2.77(3H,s), 2.92(3H,s), 2.93(3H,s), 3.05-4.23(8H,m),
4.32-4.80(2H,m), 7.59(1H,s), 8.63(1H,d,J=7.6 Hz), 9.14(1H,d,J=7.6
Hz).
[3490] MS (FAB) m/z: 554(M+H).sup.+.
Example 208
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amin-
o}cyclohexyl)ethanediamide hydrochloride
##STR00874##
[3492] The compound (210 mg) obtained in Referential Example 266
and the compound (350 mg) obtained in Referential Example 272 were
dissolved in N,N-dimethylformamide (15 mL), and
1-hydroxybenzotriazole monohydrate (205 mg) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (290
mg) were added, followed by stirring at room temperature for 20
hours. The solvent was distilled away under reduced pressure, and
saturated aqueous sodium hydrogencarbonate and methylene chloride
were added to the residue for partitioning the mixture. The
resultant organic layer was dried over sodium sulfate anhydrate,
the solvent was distilled away under reduced pressure, and the
residue was purified by silica gel column chromatography (methylene
chloride:methanol=20:1). The thus-obtained pale yellow solids were
dissolved in methylene chloride, 1N HCl in ethanol (0.46 mL) was
added, and the solvent was distilled away under reduced pressure.
Methanol and diethyl ether were added to the residue, and the
precipitate formed was collected by filtration to give the title
compound (248 mg).
[3493] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.47-1.50(1H,m),
1.69-1.76(3H,m), 1.98-2.06(2H,m), 2.79(3H,s), 2.95(3H,s),
2.98-3.05(1H,m), 3.10(3H,s), 3.49-4.62(6H,m), 7.98-8.03(2H,m),
8.45(1H,s), 8.73(1H,d,J=7.6 Hz), 9.10(1H,d,J=8.0 Hz),
10.30(1H,s).
[3494] MS (FAB) m/z: 534(M+H).sup.+.
Example 209
N-{(1R,2S,5S)-2-{[2-(4-Chloroanilino)acetyl]amino}-5-[(dimethylamino)carbo-
nyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbo-
xamide hydrochloride
##STR00875##
[3496] The compound (2.3 g) obtained in Referential Example 267 was
dissolved in ethanol (10 mL), and 1N aqueous sodium hydroxide (20
mL) was added, followed by stirring at room temperature for 2
hours. After 1N hydrochloric acid (20 mL) was added to the reaction
mixture, the mixture was diluted with water and stirred for 30
minutes. Insoluble matter precipitated was collected by filtration
to give 2-(4-chloroanilino)acetic acid (1.05 g) as a colorless
solid. This solid and the compound (0.25 g) obtained in Referential
Example 253 were dissolved in N,N-dimethylformamide (10 mL), and
1-hydroxybenzotriazole monohydrate (0.11 g) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.23
g) were added, followed by stirring at room temperature for 4 days.
After the reaction mixture was diluted with chloroform and washed
with saturated aqueous sodium hydrogencarbonate and saturated
brine, the resultant organic layer was dried over sodium sulfate
anhydrate. The solvent was distilled away under reduced pressure,
and the residue was purified by silica gel column chromatography
(chloroform:methanol=97:3). The thus-obtained pale yellow solid was
dissolved in ethanol, 1N HCl in ethanol was added, and the solvent
was distilled away under reduced pressure. Methanol and diethyl
ether were added to the residue, and the precipitate formed was
collected by filtration to give the title compound (0.15 g).
[3497] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35-1.41(1H,m),
1.59-1.80(3H,m), 1.82-1.95(2H,m), 2.76(3H,s), 2.93(3H,s),
2.94(3H,s), 2.99-3.10(1H,m), 3.10-3.22(2H,m), 3.42-3.60(2H,m),
3.60-3.77(2H,m), 3.80-3.90(1H,m), 4.35-4.48(2H,m), 4.68-4.80(1H,m),
6.40(1H,d,J=6.7 Hz), 6.44(1H,d,J=6.7 Hz), 6.90(1H,d,J=6.7 Hz),
7.00(1H,d,J=6.7 Hz), 7.70-7.89(1H,m), 8.35-8.42(1H,m),
11.05-11.38(1H,m).
Example 210
N-{(1R,2S,5S)-2-{[2-(4-Chloro-2-fluoroanilino)acetyl]amino}-5-[(dimethylam-
ino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-
e-2-carboxamide hydrochloride
##STR00876##
[3499] In a manner similar to that described in Example 209, the
compound obtained in Referential Example 268 was hydrolyzed and
then, condensed with the compound obtained in Referential Example
253, followed by treatment with hydrochloric acid, to thereby give
the title compound.
[3500] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35-1.42(1H,m),
1.55-1.78(3H,m), 1.80-2.00(2H,m), 2.76(3H,s), 2.92(3H,s),
2.94(3H,s), 2.99-3.10(1H,m), 3.10-3.22(2H,m), 3.42-3.60(2H,m),
3.60-3.77(2H,m), 3.85-4.00(1H,m), 4.33-4.48(2H,m), 4.65-4.80(1H,m),
6.41(1H,t,J=8.8 Hz), 6.73(1H,dt,J=8.8,1.2 Hz),
7.08(1H,dd,J=11.7,1.2 Hz), 7.78-7.92(1H,m), 8.35-8.42(1H,m),
11.18-11.50(1H,m).
Example 211
N-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)ca-
rbonyl]cyclohexyl}-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
hydrochloride
##STR00877##
[3502] In a manner similar to that employed in Example 2, the
compound obtained in Referential Example 432 was condensed with the
compound obtained in Referential Example 34, followed by treatment
with hydrochloric acid, to thereby give the title compound.
[3503] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.45-1.60(1H,m),
1.70-2.15(6H,m), 2.80(3H,s), 2.97(3H,s), 2.95-3.15(2H,m),
3.35-3.55(2H,m), 4.05-4.20(1H,m), 4.46(2H,s), 4.50-4.65(1H,m),
7.05(1H,s), 7.16(1H,dd,J=8.8,2.2 Hz), 7.41(1H,d,J=8.8 Hz),
7.68(1H,s), 8.30-8.45(1H,br), 9.30-9.50(1H,br), 11.78(1H,s).
[3504] MS (ESI) m/z: 529(M+H).sup.+.
Example 212
N-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)ca-
rbonyl]cyclohexyl}-5-(4,5-dihydrooxazol-2-yl)-4,5,6,7-tetrahydrothiazolo[5-
,4-c]pyridine-2-carboxamide
##STR00878##
[3506] The compound (250 mg) obtained in Example 211 was suspended
in methylene chloride, and saturated aqueous sodium
hydrogencarbonate was added, followed by fully stirring the
mixture. The resultant organic layer was separated and dried over
magnesium sulfate anhydrate. Triethylamine (0.5 mL) and bromoethyl
isocyanate (43 .mu.l) were then added, followed by stirring at room
temperature for 20 hours. Saturated aqueous sodium
hydrogencarbonate was added to the reaction mixture to separate an
organic layer. The organic layer was dried over magnesium sulfate
anhydrate. The solvent was distilled away under reduced pressure,
and the residue was purified by silica gel column chromatography
(methylene chloride:methanol=22:3) to give the title compound (227
mg).
[3507] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50-2.15(4H,m),
2.15-2.40(2H,m), 2.80-3.00(1H,m), 2.97(3H,s), 3.11(3H,s),
3.70-3.95(4H,m), 4.10-4.30(1H,m), 4.30-4.50(2H,m), 4.60-4.70(1H,m),
4.74(2H,s), 6.85(1H,s),7.21(1H,dd,J =8.8,2.2 Hz), 7.34(1H,d,J=8.8
Hz), 7.50(1H,br.s), 7.62(1H,s), 7.87(1H,br.s), 9.48(1H,br.s).
[3508] MS (ESI) m/z: 598(M+H).sup.+.
Example 213
N-{(1R,2S,5S)-2-{[(5-Chloro-4-fluoroindol-2-yl)carbonyl]amino}-5-[(dimethy-
lamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyri-
dine-2-carboxamide hydrochloride
##STR00879##
[3510] The compound (140 mg) obtained in Referential Example 144
was dissolved in N,N-dimethylformamide (10 mL), and the compound
(100 mg) obtained in Referential Example 274,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (140
mg), and 1-hydroxybenzotriazole monohydrate (110 mg) were added,
followed by stirring at room temperature for 18 hours. The solvent
was distilled away under reduced pressure, and the residue was
partitioned in water-ethyl acetate, and an aqueous layer was
extracted with ethyl acetate. The resultant organic layers were
combined, washed with saturated brine and then dried over sodium
sulfate anhydrate. The solvent was distilled away under reduced
pressure, and the residue was purified by silica gel column
chromatography (methanol:methylene chloride=1:19) to give
tert-butyl
(1R,2S,5S)-2-{[(5-chloro-4-fluoroindol-2-yl)carbonyl]amino}-5-[(dimethyla-
mino)carbonyl]cyclohexylcarbamate (260 mg). The thus-obtained
powder was dissolved in methylene chloride (5 mL), and 4N
HCl-dioxane (1.2 mL) was added. After the reaction mixture was
stirred at room temperature for 3.5 hours, the solvent was
distilled away under reduced pressure. Methylene chloride (10 mL)
was added to the residue, and the mixture was concentrated. After
this process was repeated 3 times, the residue was dried under
reduced pressure to give crude
N-{(1S,2R,4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl}-5-chloro-4-f-
luoroindole-2-carboxamide. This product was dissolved in
N,N-dimethylformamide (50 mL), and the compound (150 mg) obtained
in Referential Example 10,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (140
mg) and 1-hydroxybenzotriazole monohydrate (110 mg) were added,
followed by stirring at room temperature for 18 hours. The solvent
was distilled away under reduced pressure, and the residue was
partitioned in a mixture of water-ethyl acetate-tetrahydrofuran,
and an aqueous layer was extracted with ethyl acetate. The
resultant organic layers were combined, washed with saturated brine
and then dried over sodium sulfate anhydrate. The solvent was
distilled away under reduced pressure, and the residue was purified
by silica gel column chromatography (methanol:methylene
chloride=1:19) to give a free base of the title compound (270 mg).
This product was dissolved in methylene chloride (10 mL), and 1N
HCl in ethanol (0.72 mL) was added, followed by stirring at room
temperature for 30 minutes. Crystals precipitated were collected by
filtration to give the title compound (200 mg).
[3511] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.24-1.98(6H,m),
2.33-3.33(6H,m), 2.81(3H,s), 2.90(3H,s), 2.99(3H,s), 4.12(1H,
br.s), 4.30-4.70(1H,m), 4.60(1H,br.s), 7.21(1H,s), 7.27(2H,br.s),
8.37(1H,d,J=8.1 Hz), 8.43(1H,d,J=7.6 Hz), 12.11(1H,s).
[3512] MS (FAB) m/z: 561(M+H).sup.+.
Example 214
N-{(1R,2S,5S)-2-{[(5-Chloro-3-fluoroindol-2-yl)carbonyl]amino}-5-[(dimethy-
lamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyri-
dine-2carboxamide hydrochloride
##STR00880##
[3514] The compound (250 mg) obtained in Referential Example 279
was dissolved in methylene chloride (60 mL), and 4N HCl-dioxane
(1.3 mL) was added. After the reaction mixture was stirred at room
temperature for 5.5 hours, 4N HCl-dioxane (0.65 mL) was
additionally added, and the mixture was stirred at room temperature
for 1 hour. The solvent was distilled away under reduced pressure,
methylene chloride (10 mL) was added to the residue, and the
mixture was concentrated. This process was repeated 3 times. The
residue was dried under reduced pressure, and the thus-obtained
crude product was dissolved in N,N-dimethylformamide (50 mL), and
the compound (160 mg) obtained in Referential Example 10,
1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (150
mg) and 1-hydroxybenzotriazole monohydrate (120 mg) were added,
followed by stirring at room temperature for 18 hours. The solvent
was distilled away under reduced pressure, and the residue was
partitioned in a mixture of water-ethyl acetate, and an aqueous
layer was extracted with ethyl acetate. The resultant organic
layers were combined, washed with saturated brine and then dried
over sodium sulfate anhydrate. The solvent was distilled away under
reduced pressure, and the residue was purified twice by silica gel
column chromatography (methanol:methylene chloride=2:23.fwdarw.1:9)
to give a free base (260 mg) of the title compound. This product
was dissolved in methylene chloride, and 1N HCl in ethanol (0.69
mL) was added, followed by stirring at room temperature for 30
minutes. The solvent was distilled away. The residue was dissolved
in methanol, and diethyl ether and hexane were added. The
thus-obtained crystals were collected by filtration to give the
title compound (230 mg).
[3515] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.50-1.56(1H,m),
1.73-1.78(3H,m), 1.94-2.02(2H,m), 2.33-3.55(6H,m), 2.80(3H,s),
2.92(3H,s), 2.98(3H,s), 4.17(1H,br.s), 4.30-4.80(1H,br),
4.62(1H,br.s), 7.25(1H,d,J=8.8,1.7 Hz), 7.40(1H,d,J=8.8,1.7 Hz),
7.65(1H,d,J=1.7 Hz), 7.72(1H,d,J=5.9 Hz), 8.74(1H,d,J=8.0 Hz),
10.85-11.35(1H,br), 11.71(1H,s).
[3516] MS (FAB) m/z: 561(M+H).sup.+.
Example 215
N-{(1R,2S,5S)-2-{[(3-Bromo-5-chloroindol-2-yl)carbonyl]-amino}-5-[(dimethy-
lamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyri-
dine-2-carboxamide hydrochloride
##STR00881##
[3518] In a manner similar to that employed in Example 214, the
compound obtained in Referential Example 282 was treated with 4N
HCl-dioxane, followed by condensation with the compound obtained in
Referential Example 10, to thereby give the title compound.
[3519] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.51-2.01(6H,m),
2.33-3.29(7H,m), 2.81(3H,s), 2.88(3H,s), 3.01(3H,s), 4.20(1H,br.s),
4.48(1H,br), 4.70-4.73(1H,m), 7.29(1H,dd,J=8.9,1.8 Hz),
7.45-7.49(2H,m), 7.80(1H,d,J=7.6 Hz), 8.76(1H,d,J=8.8 Hz),
12.31(1H,s).
[3520] MS (FAB) m/z: 622(M+H).sup.+.
Example 216
N-{(1R,2S,5S)-2-{[(3-Chloro-5-fluoroindol-2-yl)carbonyl]-amino}-5-[(dimeth-
ylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyr-
idine-2-carboxamide hydrochloride
##STR00882##
[3522] The title compound was obtained from the compound obtained
in Referential Example 253 and the compound obtained in Referential
Example 284 in a similar manner to the process described in Example
5.
[3523] .sup.1H-NMR (DMSO-d6) .delta.: 1.40-1.51(1H,m),
1.75-2.00(5H,m), 2.79(3H,s), 2.92(3H,s), 2.99(3H,s),
3.10-3.21(3H,m), 3.29-3.41(4H,m), 4.11-4.21(1H,m), 4.62-4.75(1H,m),
7.14(1H,dt,J=8.8,2.4 Hz), 7.24(1H,dd,J=8.8,2.4 Hz),
7.45(1H,dd,J=8.8,4.4 Hz), 7.69(1H,d,J=2.5 Hz), 8.79(1H,d,J=2.5 Hz),
12.10(1H,s).
[3524] MS (FAB) m/z: 561(M+H).sup.+.
Example 217
N-{(1R,2S,5S)-2-{[(5-Chloro-3-formylindol-2-yl)carbonyl]-amino}-5-[(dimeth-
ylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyr-
idine-2-carboxamide hydrochloride
##STR00883##
[3526] The title compound was obtained from the compound obtained
in Referential Example 253 and the compound obtained in Referential
Example 286 in a similar manner to the process described in Example
5.
[3527] .sup.1H-NMR (DMSO-d6) .delta.: 1.40-1.51(1H,m),
1.75-1.89(4H,m), 1.90-2.01(1H,m), 2.80(3H,s), 2.91(3H,s),
3.03(3H,s), 3.05-3.33(3H,m), 3.60-3.71(1H,m), 4.11-4.21(1H,m),
4.32-4.44(1H,m), 4.62-4.75(2H,m), 7.35(1H,dd,J=8.0,1.4 Hz),
7.56(1H,d,J=8.0 Hz), 8.21(1H,d,J=1.4 Hz), 8.65(1H,t,J=7.4 Hz),
9.92(1H,d,J=6.8 Hz), 10.15(1H,t,J=9.1 Hz), 13.00(1H,dt,J=6.4).
[3528] MS (FAB) m/z: 571(M+H).sup.+.
Example 218
5-Chloro-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5-
,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl-N.sup-
.3,N.sup.3-dimethylindole-2,3-dicarboxamide hydrochloride
##STR00884##
[3530] The title compound was obtained from the compound obtained
in Referential Example 253 and the compound obtained in Referential
Example 289 in a similar manner to the process described in Example
5.
[3531] .sup.1H-NMR (DMSO-d6) .delta.: 1.40-1.51(1H,m),
1.75-2.01(5H,m), 2.78(9H,s), 2.93(3H,s), 3.01(3H,s),
3.10-3.33(3H,m), 3.40-3.50(1H,m), 3.65-3.75(1H,m), 4.01-4.09(1H,m),
4.32-4.44(1H,m), 4.62-4.75(2H,m), 7.25(1H,d,J=8.0 Hz),
7.40-7.50(2H,m), 8.62(1H,br), 9.08(1H,br), 12.28(1H,br).
[3532] MS (FAB) m/z: 614(M+H).sup.+.
Example 219
N-{(1R,2S,5S)-2-[(6-Chloro-2-naphthoyl)amino]-5-[(dimethylamino)carbonyl]c-
yclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamid-
e hydrochloride
##STR00885##
[3534] The compound (270 mg) obtained in Referential Example 294
was dissolved in methylene chloride (10 mL), and 1N HCl in ethanol
(10 mL) was added, followed by stirring for 90 minutes. The solvent
was distilled away under reduced pressure, and the resultant
residue was dissolved in N,N-dimethylformamide (7 mL). The compound
(110 mg) obtained in Referential Example 10,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100
mg) and 1-hydroxybenzotriazole monohydrate (70 mg) were added,
followed by stirring at room temperature for 23 hours. The reaction
mixture was concentrated under reduced pressure, and water was
added, followed by extraction with ethyl acetate. The resultant
organic layer was dried over sodium sulfate anhydrate. The solvent
was distilled away under reduced pressure, and the residue was
purified twice by silica gel column chromatography (methylene
chloride: methanol=20:1.fwdarw.10:1). The thus-obtained free base
was dissolved in methanol, and 1N HCl in ethanol (0.30 mL) was
added. The solvent was distilled away under reduced pressure, and
the residue was washed with ethyl acetate to give the title
compound (130 mg).
[3535] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.45-1.60(1H,m),
1.70-1.90(3H,m), 1.90-2.10(2H,m), 2.81(3H,s), 2.91(3H,s),
3.00(3H,s), 3.00-3.22(3H,m), 3.53(2H,br), 4.10-4.20(1H,m),
4.30-4.70(3H,m), 7.59(1H,dd,J=8.8,2.2 Hz), 7.87(1H,d,J=8.5 Hz),
7.96(1H,d,J=8.5 Hz), 8.02(1H,d,J=8.8 Hz), 8.10(1H,d,J=2.2 Hz),
8.33(1H,s), 8.43(1H,d,J=8.1 Hz), 8.52(1H,d,J=7.3 Hz).
[3536] MS(FAB)m/z: 554(M+H).sup.+.
Example 220
7-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-t-
etrahydrothiazolo[5,4-c]pyridin-2-yl)-carbonyl]amino}cyclohexyl)cinnoline--
3-carboxamide hydrochloride
##STR00886##
[3538] In a manner similar to that employed in Example 219, the
compound obtained in Referential Example 299 was treated with HCl
in ethanol, followed by condensation with the compound obtained in
Referential Example 10, to thereby give the title compound.
[3539] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50-1.65(1H,m),
1.70-1.90(3H,m), 2.05-2.15(1H,m), 2.15-2.30(1H,m), 2.81(3H,s),
2.85-3.05(8H,m), 3.15-3.25(2H,m), 3.40-3.80(1H,m), 4.25-4.80(4H,m),
8.02(1H,dd,J=8.8,2.0 Hz), 8.38(1H,d,J=8.8 Hz), 8.66(1H,s),
8.91(1H,s), 8.96(1H,d,J=7.3 Hz), 9.53(1H,br).
[3540] MS (FAB) m/z: 556(M+H).sup.+.
Example 221
N-{(1R,2S,5S)-2-([(5-Chlorobenzimidazol-2-yl)carbonyl]amino}-5-[(dimethyla-
mino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridi-
ne-2-carboxamide hydrochloride
##STR00887##
[3542] In a manner similar to that employed in Example 219, the
compound obtained in Referential Example 300 was treated with HCl
in ethanol, followed by condensation with the compound obtained in
Referential Example 10, to thereby give the title compound.
[3543] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.45-1.60(1H,m),
1.60-1.83(3H,m), 2.00-2.20(2H,m), 2.78(3H,s), 2.92(6H,s),
3.00-3.30(3H,m), 3.47(2H,br.s), 4.10-4.sub.--75(4H,m),
7.30(1H,d,J=8.8 Hz), 7.62(1H,d,J=12.5 Hz), 7.63(1H,s),
8.75-8.87(1H,m), 9.09(1H,dd,J=12.5,8.8 Hz), 11.20-11.40(1H,m).
[3544] MS (FAB) m/z: 546(M+H).sup.+.
Example 222
N-((1S,2R,4S)-4-[(Dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydro-
thiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-7-fluoroisoquinolin-
e-3-carboxamide hydrochloride
##STR00888##
[3546] The title compound was obtained from the compound obtained
in Referential Example 253 and the compound obtained in Referential
Example 304 in a similar manner to the process described in Example
5.
[3547] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.50-1.60(1H,m),
1.70-1.85(3H,m), 1.95-2.05(1H,m), 2.10-2.20(1H,m), 2.80(3H,s),
2.90-3.90(5H,m), 2.93(3H,s), 2.96(3H,s), 4.10-4.75(4H,m),
7.75-7.85(1H,m), 8.00-8.05(1H,m), 8.30-8.35(1H,m), 8.61(1H,s),
8.93(2H,d,J=7.3 Hz), 9.31(1H,s).
[3548] MS (FAB) m/z: 539(M+H).sup.+.
Example 223
N-{(1R,2S,5S)-2-{[(7-Chloro-2H-chromen-3-yl)carbonyl]amino}-5-[(dimethylam-
ino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-
e-2-carboxamide hydrochloride
##STR00889##
[3550] The compound (220 mg) obtained in Referential Example 252
was dissolved in methanol (10 mL), and 10% palladium on carbon (180
mg) was added, followed by stirring at room temperature for 4 hours
in a hydrogen atmosphere. After the reaction mixture was filtered,
the filtrate was concentrated under reduced pressure, and the
residue was dissolved in N,N-dimethylformamide (30 mL). The
compound (108 mg) obtained in Referential Example 306,
1-hydroxybenzotriazole monohydrate (78 mg) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (196
mg) were added, followed by stirring at room temperature overnight.
The reaction mixture was concentrated under reduced pressure, and
methylene chloride and saturated aqueous sodium hydrogencarbonate
were added to the residue for partitioning the mixture. The
resultant organic layer was dried over sodium sulfate anhydrate.
The solvent was distilled away under reduced pressure, and the
residue was purified by silica gel column chromatography (methylene
chloride:methanol=100:3) to give a pale yellow foamy substance.
This foamy substance was dissolved in methylene chloride (2 mL), 1N
HCL in ethanol (363 .mu.l) was added, and the solvent was distilled
away under reduced pressure. Diethyl ether was added to the
residue. The the precipitate formed was collected by filtration to
give the title compound (175 mg).
[3551] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.40-1.52(1H,m),
1.55-1.96(5H,m), 2.78(3H,s), 2.90(3H,s), 2.98(3H,s),
3.01-3.12(1H,m), 3.13-3.28(2H,m), 3.40-3.85(2H,m), 3.92-4.00(1H,m),
4.35-4.80(3H,m), 4.84(1H,d,J=14.5 Hz), 4.89(1H,d,J=14.5 Hz),
6.92(1H,s), 6.98(1H,dd,J=8.1,1.7 Hz), 7.08(1H,s), 7.17(1H,d,J=8.3
Hz), 8.12(1H,d,J=8.1 Hz), 8.34(1H,d,J=8.1 Hz).
[3552] MS (FAB) m/z: 558(M+H).sup.+.
Example 224
N-{(1R,2S,5S)-2-{[(E)-3(4-Chlorophenyl)-2-propenoyl]amino}-5-[(dimethylami-
no)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-
-2-carboxamide hydrochloride
##STR00890##
[3554] In a manner similar to that employed in Example 219, the
compound obtained in Referential Example 307 was treated with HCl
in ethanol, followed by condensation with the compound obtained in
Referential Example 10, to thereby give the title compound.
[3555] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35-1.55(1H,m),
1.55-1.90(4H,m), 2.79(3H,s), 2.92(3H,s), 2.99(3H,s),
3.05-3.30(3H,m), 3.40-3.55(1H,m), 3.60-3.75(1H,m), 3.93-4.03(2H,m),
4.35-4.50(1H,m), 4.50-4.60(1H,m), 4.60-4.75(1H,m), 6.65(1H,d,J=15.7
Hz), 7.35(1H,d,J=15.7 Hz), 7.44(1H,d,J=8.6 Hz), 7.55(1H,d,J=8.6
Hz), 8.03(1H,d,J=8.1 Hz), 8.34(1H,br.s), 11.25-11.70(1H,br).
[3556] MS (ESI) m/z: 530(M+H).sup.+.
Example 225
6-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-t-
etrahydrothiazolo[5,4-c]pyridin-2-yl)-carbonyl]amino}cyclohexyl)-4-oxo-1,4-
-dihydroquinoline-2-carboxamide hydrochloride
##STR00891##
[3558] The title compound was obtained from the compound obtained
in Referential Example 253 and the compound obtained in Referential
Example 309 in a similar manner to the process described in Example
5.
[3559] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.43-1.60(1H,m),
1.65-2.10(3H,m), 2.79(3H,s), 2.92(3H,s), 2.99(3H,s),
3.05-3.20(2H,m), 3.20-3.80(5H,m), 4.08-4.20(1H,m), 4.35-4.50(1H,m),
4.60-4.70(1H,m), 4.70(1H,d,J=15.6 Hz), 6.77(1H,br.s),
7.73(1H,d,J=8.9 Hz), 7.94(1H,d,J=8.9 Hz), 7.97(1H,d,J=2.2 Hz),
8.54(1H,br.s), 8.80-9.00(1H,m), 11.18-11.42 (1H,br),
11.70-12.50(1H,br).
[3560] MS (ESI) m/z: 571(M+H).sup.+.
Example 226
tert-Butyl
2-[({(1R,2S,5S)-2-{[(5-chloroindol-2-yl)-carbonyl]amino}-5-[(di-
methylamino)carbonyl]cyclohexyl}-amino)carbonyl]-4,6-dihydro-5H-pyrrolo[3,-
4-d]thiazole-5-carboxylate
##STR00892##
[3562] 1) The compound (1.46 g) obtained in Referential Example 310
was dissolved in methylene chloride (10 mL), and HCl in ethanol (10
mL) was added at room temperature, followed by stirring for 1 hour.
After completion of the reaction, the solvent was distilled away,
ethanol was added, the mixture was concentrated, and diisopropyl
ether was added to the residue for solidification. The resultant
solids were collected by filtration to give
N-{(1S,2R,4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl}-5-chloroindo-
le-2-carboxamide hydrochloride.
[3563] 2) This product was dissolved in N,N-dimethylformamide (5
mL), and the compound (1.31 g) obtained in Referential Example 406,
1-hydroxybenzotriazole monohydrate (640 mg), and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.36
g) were added, followed by stirring at room temperature for 3 days.
The reaction mixture was concentrated, and methylene chloride and
saturated aqueous sodium hydrogencarbonate were added to the
residue for partitioning the mixture. The resultant organic layer
was dried over sodium sulfate anhydrate. After the solvent was
distilled away under reduced pressure, the residue was purified by
silica gel column chromatography (methanol:methylene chloride=1:19)
to give the title compound (1.22 g).
[3564] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.53(9H,s),
1.70-2.40(6H,m), 2.80-3.20(7H,m), 4.15-4.25(1H,m), 4.55-4.80(5H,m),
6.83(1H,d,J=1.5 Hz), 7.20(1H,dd,J=8.8,2.0 Hz), 7.33(1H,d,J=8.8 Hz),
7.40-7.50(1H,m), 7.61(1H,br.s), 7.72-7.80(1H,m), 9.41(1H,br.s).
[3565] MS (ESI) m/z: 615(M+H).sup.+.
Example 227
5-Chloro-N-{(1S,2R,4S)-2-[[(5,6-dihydro-4H-pyrrolo[3,4-d]-thiazol-2-yl)car-
bonyl]amino]-4-[(dimethylamino)carbonyl]-cyclohexyl}indole-2-carboxamide
hydrochloride
##STR00893##
[3567] The compound (1.22 g) obtained in Example 226 was dissolved
in methylene chloride (5 mL), and, at room temperature, HCl in
ethanol (10 mL) was added, followed by stirring for 1 hour. After
the reaction mixture was concentrated, saturated aqueous sodium
hydrogencarbonate and methylene chloride were added for
partitioning the mixture, and the resultant organic layer was dried
over sodium sulfate anhydrate. The solvent was distilled away, and
the residue was purified by silica gel column chromatography
(methanol:methylene chloride=1:9) to give a free base (636 mg) of
the title compound as a colorless glassy solid. The free base (200
mg) was dissolved in 1N HCl in ethanol (1 mL). After the solution
was concentrated, ethyl acetate was added to solidfy the residue.
The thus-obtained colorless powder was collected by filtration and
dried to give the title compound (195 mg).
[3568] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.45-1.60(1H,m),
1.70-1.90(3H,m), 1.90-2.05(2H,m), 2.80(3H,s), 2.98(3H,s),
2.98-3.15(1H,m), 4.05-4.20(1H,m), 4.44(2H,br.s), 4.58(3H,br.s),
7.05(1H,d,J=1.5 Hz), 7.16(1H,dd, J=8.7,1.8 Hz), 7.42(1H,d,J=8.7
Hz), 7.68(1H,d,J=1.8 Hz), 8.38(1H,d,J=7.8 Hz), 8.42(1H,d,J=7.8 Hz),
10.45-10.65(2H,br), 11.78(1H,br.s).
[3569] MS (FAB) m/z: 515(M+H).sup.+.
Example 228
5-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-5,6-dihyd-
ro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)indole-2-carbox-
amide hydrochloride
##STR00894##
[3571] The title compound was obtained from the compound obtained
in Example 227 and formalin in a similar manner to the process
described in Example 18.
[3572] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.45-1.60(1H,m),
1.65-1.90(3H,m), 1.90-2.05(2H,m), 2.80(3H,s), 2.98(3H,s),
2.98-3.06(1H,m), 3.06(3H,s),4.05-4.20(1H,m), 4.30-5.00(5H,br.s),
7.04(1H,d,J=1.7 Hz), 7.17(1H,dd,J=8.8,2.1 Hz),7.41(1H,d,J=8.8 Hz)
7.68(1H,d,J=2.1 Hz) 8.36(1H,d,J =7.8 Hz), 8.42(1H,d,J=8.1
Hz),11.78(1H,br.s),12.14(1H,br.s).
[3573] MS (FAB) m/z: 529(M+H).sup.+.
Example 229
tert-Butyl
2-{[((1R,2S,5S)-5-[(dimethylamino)carbonyl]-2-{[(5-fluoroindol--
2-yl)carbonyl]amino}cyclohexyl)amino]-carbonyl}-4,6-dihydro-5H-pyrrolo[3,4-
-d]thiazole-5-carboxylate
##STR00895##
[3575] The title compound was obtained from the compound obtained
in Referential Example 311 and the compound obtained in Referential
Example 406 in a similar manner to the process described in Example
226.
[3576] .sup.1H-NMR (CDCl.sub.3) .delta.:
1.53(9H,s),1.60-2.40(6H,m),2.80-3.20(7H,m),
4.15-4.25(1H,m),4.55-4.80(5H,m),6.84-6.87(1H,m),
7.01(1H,dt,J=2.4,9.1 Hz),7.25-7.30(1H,m), 7.34(1H,dd,J=9.1,4.3
Hz),7.42-7.49(1H,m),7.70-7.80(1H,m), 9.37-9.45(1H,m).
[3577] MS (ESI) m/z: 599(M+H).sup.+.
Example 230
N-{(1S,2R,4S)-2-[[(5,6-Dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amin-
o]-4-[(dimethylamino)carbonyl]cyclohexyl}-5-fluoroindole-2-carboxamide
hydrochloride
##STR00896##
[3579] The title compound was obtained from the compound obtained
in Example 229 in a similar manner to the process described in
Example 227.
[3580] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.45-1.60(1H,m),1.65-1.90(3H,m),1.90-2.10(2H,m),2.80(3H,s),2.97(3H,s),2.9-
8-3.15(1H,m),4.05-4.20(1H,m),4.35-4.50(2H,m),4.58(3H,br.s),6.97-7.10(2H,m)-
, 7.35-7.47(2H,m), 8.34(1H,d,J=7.8 Hz),8.41(1H,d,J=8.1 Hz),
10.53(2H,br.s),11.68(1H,br.s).
[3581] MS (FAB) m/z: 499(M+H).sup.+.
Example 231
N-((1S,2R,4S)-4-[(Dimethylamino)carbonyl]-2-{[(5-methyl-5,6-dihydro-4H-pyr-
rolo[3,4-d]thiazol-2-yl)carbonyl]amino}-cyclohexyl)-5-fluoroindole-2-carbo-
xamide hydrochloride
##STR00897##
[3583] The title compound was obtained from the compound obtained
in Example 230 and formalin in a similar manner to the process
described in Example 18.
[3584] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.45-1.60(1H,m),1.65-1.90(3H,m),1.90-2.10(2H,m),2.80(3H,s),2.90-3.20(7H,m-
),4.05-4.20(1H, m),
4.30-5.00(5H,br.s),6.95-7.10(2H,m),7.35-7.50(2H,m), 8.33(1H,d,J=7.6
Hz),8.41(1H,d,J=8.1 Hz),11.67(1H,br.s), 12.37(1H,br.s).
[3585] MS (FAB) m/z: 513(M+H).sup.+.
Example 232
N-{(1R,2S,5S)-2-[(6-Chloro-2-naphthoyl)amino]-5-[(dimethylamino)carbonyl]c-
yclohexyl}-5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole-2-carboxamide
hydrochloride
##STR00898##
[3587] The title compound was obtained from the compound obtained
in Referential Example 294 and the compound obtained in Referential
Example 293 in a similar manner to the process described in Example
226.
[3588] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.48-1.56(1H,m),1.71-1.84(3H,m),
1.95-2.04(2H,m);2.81(3H,s),3.00(3H,s),3.02(3H,s), 3.06-3.15(2H,m),
4.13-4.14(1H,m),4.52-4.63(4H,m), 7.60(1H,d,J=8.5
Hz),7.87(1H,d,J=8.8 Hz),7.96(1H,d,J=8.5 Hz), 8.01(1H,d,J=8.8
Hz),8.10(1H,s),8.32(1H,s), 8.45(1H,d,J=8.1 Hz),8.51(1H,d,J=7.3
Hz).
[3589] MS (FAB) m/z: 540(M+H).sup.+.
Example 233
7-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbony]-2-{[(5-methyl-5,6-dihydr-
o-4H-pyrrolo[3,4-d]thiazol-2-yl)-carbonyl]amino}cyclohexyl)cinnoline-3-car-
boxamide hydrochloride and
7-chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-5H-pyrro-
lo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)cinnoline-3-carboxamide
##STR00899##
[3591] 4N HCl-dioxane (3.0 mL) was added to a suspension of the
compound (330 mg) obtained in Referential Example 299 in a mixture
of dioxane (3.0 mL) and methylene chloride (3.0 mL), and the
mixture was stirred at room temperature for 30 minutes. The solvent
was distilled away under reduced pressure, and the thus-obtained
white powder was dissolved in N,N-dimethylformamide (5.0 mL), and
the compound (172 mg) obtained in Referential Example 293,
1-hydroxy-benzotriazole monohydrate (130 mg), and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (192
mg) were added, followed by stirring at room temperature for 15
hours. The solvent was distilled away under reduced pressure,
methylene chloride and saturated aqueous sodium hydrogencarbonate
were added to the residue. The resultant organic layer was washed
with saturated saline and then dried over sodium sulfate anhydrate.
The solvent was distilled away under reduced pressure, and the
residue was purified by silica gel column chromatography (methylene
chloride:methanol=20:1). 1N HCl in ethanol (0.35 mL) was added to
an ethanol solution (4.0 mL) of the thus-obtained primary product
of a high-polar compound, and the solvent was distilled away under
reduced pressure. Ethanol and diethyl ether were added to the
residue, and the precipitate formed was collected by filtration to
give
7-chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-5,6-dihy-
dro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)cinnoline-3-ca-
rboxamide hydrochloride (184 mg).
[3592] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.50-1.65(1H,m),1.70-1.90(3H,m),2.03-2.12(1H,
m),2.15-2.30(1H,m),2.81(3H,s),2.90-3.05(1H,m),
2.96(3H,s),3.07(3H,s),4.28-4.37(1H, m),4.40-4.95(5H,br),
8.02(1H,d,J=8.8 Hz),8.38(1H,d,J=8.8 Hz),8.66(1H,s),
8.91(1H,s),8.97(1H,d,J=7.1
Hz),9.43-9.57(1H,br),11.75-11.95(0.5H,br),12.35-11.55(0.5H,br).
[3593] MS (FAB) m/z: 542(M+H).sup.+.
[3594] In the purification by the silica gel column chromatography,
low-polar
7-chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-([(5-methy-
l-5H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)cinnoline-3-carb-
oxamide (98 mg) was also obtained as a by-product.
[3595] .sup.1H-NMR (CDCl.sub.3) .delta.:
1.90-2.25(6H,m),2.85-3.00(1H,m),
2.95(3H,s),3.05(3H,s),3.91(3H,s),4.43-4.54(1H,m),
4.86-4.95(1H,m),6.70(1H,d,J=1.5 Hz),7.19(1H,d,J=1.5 Hz),
7.59(1H,d,J=8.8 Hz),7.76(1H,d,J=8.8 Hz),7.95(1H,d,J=8.8 Hz),
8.53(1H,s),8.64(1H,d,J=8.0 Hz),8.73(1H,s).
[3596] MS (FAB) m/z: 540(M+H).sup.+.
Example 234
7-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-5,6-dihyd-
ro-4H-pyrrolo[3,4-d]thiazol-2-yl)-carbonyl]amino}cyclohexyl)isoquinoline-3-
-carboxamide hydrochloride
##STR00900##
[3598] The compound (500 mg) obtained in Referential Example 146
was dissolved in HCl in ethanol (5 mL), and the mixture was stirred
at room temperature for 30 minutes. The solvent was distilled away
under reduced pressure, and the residue was dissolved in
N,N-dimethylformamide (7 mL), and the compound (299 mg) obtained in
Referential Example 293, 1-hydroxybenzotriazole monohydrate (71
mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (403 mg) were added to the solution, followed by
stirring at room temperature overnight. The solvent was distilled
away under reduced pressure, saturated aqueous sodium
hydrogencarbonate and methylene chloride were added to the residue
for partitioning the mixture. The resultant aqueous layer was
extracted with methylene chloride. Organic layers were combined and
dried over sodium sulfate anhydrate. The solvent was distilled away
under reduced pressure, and the residue was purified by silica gel
column chromatography (methylene chloride:methanol=93:7) to give a
free base (260 mg) of the title compound as a pale yellow solid.
This product was dissolved in methylene chloride, 1N HCl in ethanol
(961 .mu.l) was added, and the solvent was distilled away under
reduced pressure. A small amount of methanol was added to the
residue, and diethyl ether was added dropwise to collect the
precipitate formed by filtration. This product was washed with
diethyl ether to give the title compound (260 mg).
[3599] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.47-1.56(1H,m),1.71-1.75(3H,m),
1.95-1.99(1H,m),2.12-2.15(1H,m),2.78(3H,s),2.95(3H,s),
2.98(1H,br.s),3.05(3H,s),4.19-4.22(1H,m),4.44-4.52(3H,m),
4.74-4.88(2H,m),7.87(1H,dd,J=8.8,1.7 Hz),8.24(1H,d,J=8.8 Hz),
8.36(1H,d,J=1.7 Hz),8.58(1H,s),8.90-8.92(2H,m),9.30(1H,s),
12.65-12.75(1H,m).
[3600] MS (FAB) m/z: 541(M+H).sup.+.
Example 235
tert-Butyl
2-[({(1R,2S,5S)-2-{[(5-chloroindol-2-yl)-carbonyl]amino}-5-[(di-
methylamino)carbonyl]cyclohexyl}-amino)carbonyl]-6,6-dimethyl-6,7-dihydrot-
hiazolo[4,5-c]pyridine-5(4H)-carboxylate
##STR00901##
[3602] The compound (95.4 mg) obtained in Referential Example 316
was dissolved in diethyl ether (1 mL) in an argon atmosphere, and
tert-butyllithium (1.60N pentane solution, 244 .mu.l) was added
dropwise at -78.degree. C. After the mixture was stirred for 1 hour
at -78.degree. C., carbon dioxide was blown into the reaction
mixture for 10 minutes. The reaction mixture was heated to room
temperature. After the reaction mixture was concentrated under
reduced pressure, the residue was dissolved in
N,N-dimethylformamide (5 mL). To the solution, were successively
added the compound (178 mg) obtained in Referential Example 432 ,
1-hydroxybenzotriazole monohydrate (48.0 mg) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (136
mg). The resultant mixture was stirred overnight at room
temperature. The reaction mixture was concentrated, and the residue
was partitioned between methylene chloride and saturated aqueous
sodium hydrogencarbonate. The organic layer was dried over sodium
sulfate anhydrate, and the solvent was then distilled away under
reduced pressure. The resultant residue was purified by silica gel
column chromatography (methanol:methylene chloride=1:19) to give
the title compound (140 mg).
[3603] .sup.1H-NMR (CDCl.sub.3) .delta.:
1.50(9H,s),1.52(3H,s),1.54(3H,s),
1.70-2.10(4H,m),2.15-2.45(2H,m),2.80-3.20(9H,m), 4.10-4.25(1H,br),
4.60-4.75(3H,m),6.85(1H,br.s), 7.21(1H,dd,J=8.8,1.8
Hz),7.34(1H,d,J=8.8 Hz), 7.48(1H,d,J=7.3
Hz),7.61-7.63(1H,m),7.89(1H,br.s), 9.27(1H,br.s).
[3604] MS (ESI) m/z: 657(M+H).sup.+.
Example 236
N-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)ca-
rbonyl]cyclohexyl}-6,6-dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine--
2-carboxamide hydrochloride
##STR00902##
[3606] The title compound was obtained from the compound obtained
in Example 235 in a similar manner to the process described in
Example 227.
[3607] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.40(6H,s),1.45-1.60(1H,m),
1.70-2.05(5H,m),2.81(3H,s),2.95-3.15(6H,m),
4.05-4.20(1H,br),4.25-4.45(2H,m),4.55-4.65(1H,m), 7.06(1H,d,J=1.7
Hz),7.17(1H,dd,J=8.8,2.0 Hz), 7.42(1H,d,J=8.8 Hz),7.68(1H,d,J=2.0
Hz),8.34-8.39(2H,m),
9.77(1H,br.s),9.84(1H,br.s),11.79(1H,br.s).
[3608] MS (ESI) m/z: 557(M+H).sup.+.
Example 237
tert-Butyl
2-[({(1R,2S,5S)-2-{[(5-chloroindol-2-yl)-carbonyl]amino}-5-[(di-
methylamino)carbonyl]cyclohexyl}-amino)carbonyl]-5,7-dihydro-6H-pyrrolo[3,-
4-d]pyrimidine-6-carboxylate
##STR00903##
[3610] The compound (1.27 g) obtained in Referential Example 50 was
dissolved in tetrahydrofuran (48 mL), and lithium hydroxide (117
mg) and water (6.0 mL) were added, followed by stirring at room
temperature for 4.5 hours. The reaction mixture was dried to solid
under reduced pressure to give a crude carboxylic acid lithim salt
(1.24 g). This product was condensed with the compound obtained in
Referential Example 432 in a similar manner to the process
described in the step 2) of Example 226 to give the title
compound.
[3611] .sup.1H-NMR (CDCl.sub.3) .delta.:
1.50-1.70(1H,m),1.54(9H,s),1.80-2.10(3H,m),2.25-2.50(2H,m),2.85-2.95(1H,m-
),2.99(3H,s),
3.14(3H,s),4.15-4.25(1H,m),4.65-4.75(1H,m),4.80-4.90(4H,m),
6.97(1H,s),7.15-7.25(1H,m),7.30-7.40(1H,m),7.60-7.65(1H,m),
8.15-8.25(1H,m),8.40-8.45(1H,m),8.75-8.85(1H,m),
9.40-9.45(1H,m).
[3612] MS (ESI) m/z: 611(M+H)+.
Example 238
N-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)ca-
rbonyl]cyclohexyl}-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-carb-
oxamide hydrochloride
##STR00904##
[3614] The compound (367 mg) obtained in Example 237 was dissolved
in methylene chloride (10 mL), and trifluoroacetic acid (10 mL) was
added, followed by stirring at room temperature for 2 hours. The
reaction mixture was dried to solid under reduced pressure. The
title compound was obtained from the thus-obtained crude product
and formalin in a similar manner to the process described in
Example 18.
[3615] .sup.1H-NMR (DMSO-d6) .delta.:
1.50-1.60(1H,m),1.65-2.10(5H,m),
2.81(3H,s),2.90-3.00(1H,m),2.96(3H,s),3.05(3H,s),
4.10-4.20(1H,m),4.55-4.65(1H,m),4.65-4.90(4H,br),
7.06(1H,s),7.15(1H,dd,J=8.7,2.1 Hz), 7.41(1H,d,J=8.8
Hz),7.66(1H,d,J=1.7 Hz),8.35-8.45(1H,m), 8.57(1H,d,J=8.1
Hz),9.00(1H,s),11.80(1H,s), 11.90-12.20(1H,m).
[3616] MS (FAB) m/z: 524(M+H).sup.+.
Example 239
7-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(6-methyl-6,7-dihyd-
rothiazolo[4,5-d]pyrimidin-2-yl)-carbonyl]amino}cyclohexyl)isoquinoline-3--
carboxamide hydrochloride
##STR00905##
[3618] In a manner similar to that employed in Example 49, the
compound obtained in Referential Example 146 was treated with HCl
in ethanol and condensed with the compound obtained in Referential
Example 322, to thereby give the title compound.
[3619] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.50-1.60(1H,m),1.70-1.90(3H,m),1.90-2.15(2H,m),2.81(3H,s),2.95(3H,s),2.9-
0-3.05(1H,m), 3.26(3H,s),4.20-4.55(2H,m),5.00(2H,s),7.91(1H,d,J=8.8
Hz), 8.27 (1H,d,J=8.8 Hz),8.37(1H,s),8.54(1H,s),8.62(1H,s),
8.79(1H,d,J=8.3 Hz),8.94(1H,d,J=8.1 Hz),9.32(1H,s).
[3620] MS (ESI) m/z: 554(M+H).sup.+.
Example 240
7-Chloro-N-((1S,2R,4S)-4-{[ethyl(methyl)amino]carbonyl}-2-{[(5-methyl-4,5,-
6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)isoqui-
noline-3-carboxamide hydrochloride
##STR00906##
[3622] The title compound was obtained from the compound obtained
in Referential Example 325 and the compound obtained in Referential
Example 10 in a similar manner to the process described in Example
2.
[3623] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.98, 1.04(3H,each
t,J=7.1 Hz), 1.52-1.60(1H,m),1.74-1.77(3H,m),1.96-2.05(1H,m),
2.15-2.18(1H,m),2.77-2.93(8H,m),3.17-3.32(3H,m),
3.49(1H,br.s),4.22(1H,br.s),4.41-4.45(1H,m),
4.51(1H,br.s),4.69-4.72(1H,m),7.89(1H,d,J=8.7 Hz), 8.26(1H,d,J=8.7
Hz),8.37(1H,s),8.60(1H,s),8.91-8.98(2H,m), 9.32(1H,d,J=6.6
Hz),11.39,11.53(1H,each m).
[3624] MS (FAB) m/z: 569(M+H).sup.+.
Example 241
N-{(1R*,2S*,5S*)-2-{[(5-Chloroindol-2-yl-carbonyl]amino}-5-[2-(dimethylami-
no)-2-oxoethyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyrid-
ine-2-carboxamide hydrochloride
##STR00907##
[3626] The title compound was obtained from the compound obtained
in Referential Example 336 and the compound obtained in Referential
Example 10 in a similar manner to the process described in Example
2.
[3627] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.13-1.22(1H,m),1.40-1.46(1H,m),
1.68-1.99(5H,m),2.18-2.29(2H,m),2.80(3H,s),2.92(3H,s),
2.96(3H,s),3.22(2H,br.s),3.49(1H,br.s),3.70(1H,br.s),
4.09-4.16(1H,m),4.42-4.46(2H,m),4.67(1H,br.s),7.03(1H,s),
7.16(1H,dd,J=8.5,1.5 Hz),7.42(1H,d,J=8.5 Hz),7.67(1H,s),
8.01(1H,d,J=8.5 Hz),8.40(1H,d,J=7.8 Hz),11.35-11.58(1H,m),
11.76(1H,br.s).
[3628] MS (FAB) m/z: 557(M+H).sup.+.
Example 242
N-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(methylsulfonyl)m-
ethyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-car-
boxamide hydrochloride
##STR00908##
[3630] In a manner similar to that employed in Example 219, the
compound obtained in Referential Example 340 was treated with HCl
in ethanol, followed by condensation with the compound obtained in
Referential Example 10, to thereby give the title compound.
[3631] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.35-1.40(1H,m),1.55-1.62(1H,m),
1.70-1.76(1H,m),1.88-1.94(1H,m),2.03-2.07(1H,m),
2.13-2.17(1H,m),2.30-2.33(1H,m),2.43-3.48(10H,m),
3.60-3.73(2H,m),4.11-4.16(1H,m),4.40-4.42(2H,m),
4.68-4.73(1H,m),7.05(1H,s),7.16(1H,dd,J=2.0,8.8 Hz),
7.41(1H,d,J=8.8 Hz),7.68(1H,s),8.26(1H,d,J=7.8 Hz), 8.39(1H,d,J=7.8
Hz),11.78(1H,br.s).
[3632] MS (ESI) m/z: 564(M+H).sup.+.
Example 243
N-{(1R,2S,5S)-2-{[(2-Chloro-6H-thieno[2,3-b]pyrrol-5-yl)carbonyl]amino}-5--
[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5-
,4-c]pyridine-2-carboxamide
##STR00909##
[3634] In a manner similar to that employed in Example 223, the
compound obtained in Referential Example 252 was subjected to
catalytic reduction, followed by condensation with the compound
obtained in Referential Example 345, to thereby give the title
compound.
[3635] .sup.1H-NMR (CDCl.sub.3) .delta.:
1.56-1.66(1H,m),1.76-1.93(2H,m),
2.02-2.06(1H,m),2.19-2.26(1H,m),2.30-2.34(1H,m),2.52(3H,s),
2.79-2.88(3H,m),2.91-2.94(2H,m),2.96(3H,s),3.09(3H,s),
3.69-3.77(2H,m),4.13-4.19(1H,m),4.58-4.61(1H,m),6.72(1H,s),
6.84(1H,s),7.50(1H,d,J=7.3 Hz),7.60(1H,d,J=5.8 Hz),
10.54(1H,br).
[3636] MS (ESI) m/z: 549(M+H).sup.+.
Example 244
N-{(1R,2S,5S)-2-{[3-(4-Chlorophenyl)-2-propynoyl]amino}-5-[(dimethylamino)-
carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2--
carboxamide hydrochloride
##STR00910##
[3638] In a manner similar to that employed in Example 223, the
compound obtained in Referential Example 252 was subjected to
catalytic reduction, followed by condensation with the compound
obtained in Referential Example 347, to thereby give the title
compound.
[3639] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.38-1.50(1H,m),1.58-1.92(4H,m), 2.78(3H,s),
2.90(3H,s),2.97(3H,s),3.01-3.24(3H,m),
3.26-3.80(2H,m),3.90-3.98(1H,m),4.30-4.78(3H,m), 7.51(1H,d,J=8.8
Hz),7.57(1H,d,J=8.8 Hz),8.34(1H,d,J=8.8 Hz), 8.83(1H,d,J=7.8
Hz).
[3640] MS (FAB) m/z: 528(M+H).sup.+.
Example 245
6-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-t-
etrahydrothiazolo[5,4-c]pyridin-2-yl)-carbonyl]amino}cyclohexyl)-4-oxo-1,4-
-dihydroquinazoline-2-carboxamide hydrochloride
##STR00911##
[3642] In a manner similar to that employed in Example 223, the
compound obtained in Referential Example 252 was subjected to
catalytic reduction, followed by condensation with the compound
obtained in Referential Example 349, to thereby give the title
compound.
[3643] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.45-1.60(1H,m),1.70-1.90(3H,m),
1.90-2.20(3H,m),2.80(3H,s),2.93(3H,s),2.97(3H,s), 2.98-3.80(4H,m),
4.05-4.20(2H,m),4.35-4.80(3H,m), 7.63(1H,d,J=8.3
Hz),7.90(1H,d,J=7.3 Hz),8.75-9.00(2H,m),
11.50(1H,br),12.53(1H,br.s).
[3644] MS (ESI) m/z: 573(M+H).sup.+.
Example 246
N-{(1R,2S,5S)-2-{[2-(4-Chloroanilino)-2-oxoethane-thioyl]amino}-5-[(dimeth-
ylamino)carbonyl]cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyr-
idine-2-carboxamide
##STR00912##
[3646] The compound (184 mg) obtained in Referential Example 253
and the compound (150 mg) obtained in Referential Example 351 were
dissolved in a mixture of methanol (1 mL)-methylene chloride (4
mL), the solution was stirred under heating at 150.degree. C., to
thereby evaporate the solvent, and the heating was continued for 5
minutes. After the reaction mixture was allowed to cool, the formed
product was purified by silica gel column chromatography (methylene
chloride:methanol=24:1) to give the title compound (59 mg).
[3647] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.65-1.90(2H,m),
1.90-2.00(1H,m),
2.00-2.15(2H,m),2.20-2.30(1H,m),2.52(3H,s),2.75-2.95(5H,m),
2.96(3H,s),3.07(3H,s),3.68(1H,d,J=15.2 Hz), 3.75(1H,d,J=15.7 Hz),
4.45-4,60(1H,m),4.80-4.85(1H,m), 7.31(2H,d,J=8.8
Hz),7.44(1H,d,J=8.6 Hz),7.60(2H,d,J=8.8 Hz), 9.99(1H,d,J=7.6
Hz),10.15(1H,s).
[3648] MS (ESI) m/z: 563(M+H).sup.+.
Example 247
N-{(1R,2S,5S)-2-({2-[(5-Chloropyridin-2-yl)amino]-2-oxoethanethioyl}amino)-
-5-[(dimethylamino)carbonyl]-cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazo-
lo[5,4-c]-pyridine-2-carboxamide
##STR00913##
[3650] The compound (184 mg) obtained in Referential Example 253
and the compound (150 mg) obtained in Referential Example 353 were
dissolved in a mixture of methanol (0.3 mL)-methylene chloride (0.3
mL). The solution was stirred under heating at 150.degree. C., to
thereby evaporate the solvent, and the heating was continued for 5
minutes. The reaction mixture was allowed to cool, the formed
product was purified by silica gel column chromatography (methylene
chloride:methanol =24:1) to give the title compound (52 mg).
[3651] .sup.1H-NMR (CDCl.sub.3) .delta.:
1.60-2.00(3H,m),2.00-2.20(2H,m),
2.25-2.40(1H,m),2.53(3H,s),2.80-2.95(5H,m),2.96(3H,s),
3.08(3H,s),3.70(1H,d,J=15.4 Hz),3.75(1H,d,J=15.4 Hz),
4.45-4,60(1H,m),4.75-4.85(1H,m),7.45(1H,d,J=8.3 Hz),
7.67(1H,dd,J=8.8,2.5 Hz),8.18(1H,d,J=8.8 Hz), 8.31(1H,d,J=2.0
Hz),10.06(1H,d,J=6.3 Hz),10.56(1H,s).
[3652] MS (ESI) m/z: 564(M+H).sup.+.
Example 248
N-{(1R,2S,5S)-2-({2-[(5-Chloropyridin-2-yl)amino]-2-thioxoacetyl}amino)-5--
[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5-
,4-c]-pyridine-2-carboxamide
##STR00914##
[3654] The compound (72 mg) obtained in Referential Example 355 and
2-amino-5-chloropyridine (100 mg) were dissolved in a mixture of
methanol (0.2 mL)-methylene chloride (0.2 mL), the solution was
stirred under heating at 150.degree. C., and the heating was
continued for 8 minutes after distilling off the solvent. After the
reaction mixture was allowed to cool, the formed product was
purified by silica gel thin layer chromatography (methylene
chloride:methanol=23:2) to give the title compound (4 mg).
[3655] .sup.1H-NMR (CDCl.sub.3) .delta.:
1.60-2.00(3H,m),2.00-2.20(3H,m),
2.53(3H,s),2.75-3.00(5H,m),2.95(3H,s),3.05(3H,s),
3.65-3.80(2H,m),4.05-4.15(1H,m),4.70-4.80(1H,m),7.28(1H,d),
7.43(1H,d,J=9.3 Hz),7.75(1H,dd,J=8.8,2.7 Hz), 8.41(1H,d,J=2.7
Hz),9.05(1H,d,J=8.8 Hz),11.56(1H,s).
[3656] MS (ESI) m/z: 564(M+H).sup.+.
Example 249
N.sup.1-(5-Chloro-2-thienyl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carbony-
l]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-a-
mino}cyclohexyl)ethanediamide hydrochloride
##STR00915##
[3658] In a manner similar to that described in Example 191, the
compound obtained in Referential Example 356 was hydrolyzed and
then, condensed with the compound obtained in Referential Example
253, followed by treatment with hydrochloric acid, to thereby give
the title compound.
[3659] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.40-1.55(1H,m),1.60-1.85(3H,m),
1.90-2.15(2H,m),2.79(3H,s),2.90-3.15(1H,m),2.92(3H,s),
2.94(3H,s),3.15-3.30(2H,m),3.50-3.80(2H,m),3.95-4.05(1H,m),
4.35-4.90(3H,m),6.90(1H,d,J=4.2 Hz),6.94(1H,d,J=4.2 Hz),
8.72(1H,d,J=7.3 Hz),9.13(1H,br.s),11.21(1H,br.s),
12.32(1H,br.s).
[3660] MS (ESI) m/z: 553(M+H).sup.+.
Example 250
N-{(1R,2S,5S)-2-([(4-Chloroanilino)carbonyl]amino}-5-[(dimethylamino)carbo-
nyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbo-
xamide hydrochloride
##STR00916##
[3662] 4-Chlorophenyl isocyanate (76.8 mg) was added to a solution
of the compound (183 mg) obtained in Referential Example 253 in
methylene chloride (20 mL), and the mixture was stirred at room
temperature for 24 hours. The solvent was distilled away under
reduced pressure, and the residue was purified by silica gel column
chromatography (methylene chloride:methanol=20:1.fwdarw.10:1) to
evaporate the solvent. The residue was dissolved in ethanol (2 mL)
and methylene chloride (2 mL), 1N HCl in ethanol (0.4 mL) was
added, followed by stirring at room temperature for 30 minutes. The
reaction mixture was concentrated under reduced pressure, and the
residue was solidified with diethyl ether to give the title
compound (160 mg).
[3663] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.35-1.50(1H,m),1.60-1.90(5H,m), 2.79(3H,s),
2.92(3H,s),3.00(3H,s),3.10-3.60(4H,m),
3.60-3.90(2H,m),4.35-4.80(3H,m),6.26(1H,br.s), 7.23(2H,d,J=9.0
Hz),7.37(2H,d,J=9.0 Hz),8.53(1H,br.s),
8.72(1H,br.s),11.35,11.67(total 1H,each s).
[3664] MS (ESI) m/z: 519(M+H).sup.+.
Example 251
N.sup.1-((1S,2R,4S)-4-[(Dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetr-
ahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]-amino}cyclohexyl)-N.sup.2-(5--
fluoropyridin-2-yl)ethanediamide hydrochloride
##STR00917##
[3666] In a manner similar to that described in Example 191, the
compound obtained in Referential Example 357 was hydrolyzed and
then, condensed with the compound obtained in Referential Example
253, followed by treatment with hydrochloric acid, to thereby give
the title compound.
[3667] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.47-1.53(1H,m),1.68-1.75(3H,m),
1.99-2.10(2H,m),2.80(3H,s),2.80-3.00(1H,m),2.95(6H,s),
3.18-3.21(2H,m),3.40-3.80(2H,m),3.87-4.82(4H,m), 7.82-7.85(1H,m),
8.01-8.05(1H,m),8.40(1H,d,J=2.9 Hz), 8.71(1H,d,J=7.7
Hz),9.13(1H,d,J=7.3 Hz),10.27(1H,s).
[3668] MS (FAB) m/z: 532(M+H).sup.+.
Example 252
N.sup.1-(4-Chlorophenyl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)-carbonyl]--
2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]-thiazol-2-yl)carbonyl]amino}cy-
clohexyl)ethanediamide hydrochloride
##STR00918##
[3670] The title compound was obtained from the compound obtained
in Referential Example 242 and the compound obtained in Referential
Example 272 in a similar manner to the process described in Example
191.
[3671] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.47-1.51(1H,m),1.69-1.75(3H,m),
1.98-2.05(2H,m),2.80(3H,s),2.95(3H,s),2.98.sup.-3.04(1H,m),
3.10(3H,s),3.40-4.61(6H,m),7.41(2H,d,J=8.8 Hz), 7.81(2H,d,J=8.8
Hz),8.76(1H,d,J=7.6 Hz),8.95(1H,d,J=8.3 Hz), 10.79(1H,s).
[3672] MS (FAB) m/z: 533(M+H).sup.+.
Example 253
N.sup.1-[4-Chloro-2-(trifluoromethyl)phenyl]-N.sup.2-((1S,2R,4S)-4-[(dimet-
hylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin--
2-yl)carbonyl]amino}-cyclohexyl)ethanediamide hydrochloride
##STR00919##
[3674] Thionyl chloride (1 mL) was added to a chloroform solution
(10 mL) of the compound (269 mg) obtained in Referential Example
359, and the mixture was stirred at 75.degree. C. for 30 minutes.
The solvent was distilled away under reduced pressure, and the
residue was dried. To the residue were added a methylene chloride
solution (7 mL) of the compound (286 mg) obtained in Referential
Example 253 and pyridine (3 mL) under ice cooling. The mixture was
stirred for 2 hours while the temperature of the system was raised
to room temperature. Saturated aqueous sodium hydrogencarbonate (10
mL) was added to the reaction mixture for partitioning the mixture.
The resultant organic layer was dried over sodium sulfate
anhydrate. The solvent was distilled away under reduced pressure,
and the resultant residue was subjected to silica gel column
chromatography (methylene chloride:methanol=20:1) and column
chromatography on LH-20 (molecular sieve, methanol) to give a free
base (90 mg) of the title compound as a pale yellow amorphous
solid. Methylene chloride (5 mL), ethanol (5 mL) and 1N HCl in
ethanol (1 mL) were added to this product. Under reduced pressure,
the solvent was distilled away, followed by drying to give the
title compound.
[3675] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.41-1.55(1H,m),1.59-1.80(3H,m),
1.98-2.13(2H,m),2.77(3H,s),2.91(6H,s),3.12-3.26(2H,m),
3.30-3.58(2H,m),3.60-3.78(1H,m),3.94-4.04(1H,m),
4.35-4.63(2H,m),4.64-4.80(1H,m),7.73-7.82(2H,m),7.85(1H,s),
8.68-8.73(1H,m),9.18(1H,br.s),10.31(1H,s).
[3676] MS (ESI)m/z: 615(M+H).
Example 25
N.sup.1-{4-Chloro-2-[(dimethylamino)carbonyl]phenyl}-N.sup.2-((1S,2R,4S)-4-
-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-
pyridin-2-yl)carbonyl]-amino}cyclohexyl)ethanediamide
hydrochloride
##STR00920##
[3678] In a manner similar to that described in Example 191, the
compound obtained in Referential Example 362 was hydrolyzed and
then, condensed with the compound obtained in Referential Example
253, followed by treatment with hydrochloric acid, to thereby give
the title compound.
[3679] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.42-1.56(1H,m),
1.59-1.82(3H,m), 1.98-2.14(2H,m),2.79(3H,s),2.91(3H,s),2.93(3H,s),
2.95(3H,s),2.98(3H,s),3.10-3.30(4H,m),3.62-3.79(1H,m),
3.92-4.01(1H,m),4.34-4.50(2H,m),4.66-4.79(1H,m), 7.52(1H,d,J=2.4
Hz),7.55(1H,dd,J=2.4,8.5 Hz), 8.05(1H,d,J=8.5
Hz),8.75(1H,br),9.10-9.24(1H,m),10.52(1H,s).
[3680] MS (ESI) m/z: 618(M+H).sup.+.
Example 255
[4-Chloro-2-(hydroxymethyl)phenyl]-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)c-
arbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbo-
nyl]amino}-cyclohexyl)ethanediamide hydrochloride
##STR00921##
[3682] In a manner similar to that described in Example 199, the
compound obtained in Referential Example 270 was condensed with
4-chloro-2-hydroxymethylaniline, followed by treatment with
hydrochloric acid, to thereby give the title compound.
[3683] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.42-1.57(1H,m),1.58-1.81(3H,m),
1.98-2.14(2H,m),2.79(3H,s),2.93(6H,s),3.12-3.58(4H,m),
3.67-3.80(1H,m),3.94-4.04(1H,m),4.37-4.50(1.5H,m),
4.55(2H,s),4.67-4.80(1H,m),5.77-5.92(0.5H,m), 7.37(1H,dd,J=2.4,8.6
Hz),7.42(1H,d,J=2.4 Hz), 7.91(1H,d,J=8.6
Hz),8.74-8.81(1H,m),9.03-9.19(1H,m), 10.79(1H,s).
[3684] MS (ESI) m/z: 577(M+H).sup.+.
Example 256
N.sup.1-(4-Chloro-2-methoxyphenyl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)c-
arbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbo-
nyl]amino}-cyclohexyl)ethanediamide hydrochloride
##STR00922##
[3686] In a manner similar to that described in Example 191, the
compound obtained in Referential Example 364 was hydrolyzed and
then, condensed with the compound obtained in Referential Example
253, followed by treatment with hydrochloric acid, to thereby give
the title compound.
[3687] .sup.1H-NMR (DMSO-d.sub.6)
1.40-1.55(1H,m),1.58-1.79(3H,m),1.94-2.11(2H,m),2.77(3H,s),2.92(6H,s),3.0-
5-3.55(4H,m),3.65-3.75(1H,br),3.90(3H,s),3.91-4.00(1H,m),4.36-4.47(2H,br),-
4.65-4.77(1H, br), 7.04(1H,dd,J=8.5,2.0 Hz), 7.20(1H,d,J=2.0
Hz),8.06(1H,d,J=8.5 Hz),8.65-8.80(1H,br),
9.10-9.25(1H,br),9.74(1H,s),11.10-11.35(1H,br).
[3688] MS (ESI) m/z: 577(M+H).sup.+.
Example 257
N.sup.1-{(1R,2S,5S)-2-{[2-(4-Chloroanilino)-2-(hydroxyimino)acetyl]amino}--
5-[(dimethylamino)carbonyl]-cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazol-
o[5,4-c]-pyridine-2-carboxamide hydrochloride
##STR00923##
[3690] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 366 was treated with
hydrochloric acid for deprotection, followed by condensation with
the compound obtained in Referential Example 10 and treatment with
hydrochloric acid, to thereby give the title compound.
[3691] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.41-1.53(1H,m),1.57-1.77(3H,m),
1.88-2.04(2H,m),2.77(3H,s),2.91(6H,s),3.00-3.60(4H,m),
3.65-3.74(1H,br),3.87-3.96(1H,m),4.37-4.48(2H,m),
4.66-4.76(1H,m),6.70(2H,d,J=8.8 Hz), 7.04(1H,d,J=8.8
Hz),7.10(1H,d,J=8.8 Hz),8.40-8.53(2H,m), 8.57-8.66(1H,m),
10.30-10.47(1H,br), 10.66-10.76(1H,br).
[3692] MS (ESI) m/z: 562(M+H).sup.+.
Example 258
N.sup.1-(4-Chlorophenyl)-N.sup.2-((3R,4S)-1-(2-methoxyacetyl)-3-{[(5-methy-
l-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-carbonyl]amino}piperidin--
4-yl)ethanediamide hydrochloride
##STR00924##
[3694] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 367 was treated with
hydrochloric acid for deprotection, followed by condensation with
the compound obtained in Referential Example 10 and treatment with
hydrochloric acid, to thereby give the title compound.
[3695] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.60-1.72(1H,m),1.99-2.22(1H,m),
2.90(3H,s),3.03-4.80(17H,m),7.40(2H,d,J=8.8 Hz), 7.83(2H,d,J=8.8
Hz),8.56-8.73(1H,br),9.14-9.33(1H,br),
10.83(1H,s),11.20-11.55(1H,br).
[3696] MS (ESI) m/z: 549(M+H).sup.+.
Example 259
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((3R,4S)-1-(2-methoxyacetyl)-3-{[(5-
-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piper-
idin-4-yl)ethanediamide hydrochloride
##STR00925##
[3698] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 368 was treated with
hydrochloric acid for deprotection, followed by condensation with
the compound obtained in Referential Example 10 and treatment with
hydrochloric acid, to thereby give the title compound.
[3699] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.60-1.72(1H,m),1.98-2.20(1H,m),
2.90(3H,s),3.00-4.77(17H,m),7.20-7.35(0.8H,br),
7.48-7.56(0.2H,br),7.94-8.07(1H,br),8.40-8.70(1H,br),
8.48-8.70(1H,br),9.23-9.45(1H,br),10.21-10.35(1H,br),
11.30-11.70(1H,br).
[3700] MS (ESI) m/z: 550(M+H).sup.+.
Example 260
N.sup.1-(5-Bromopyridin-2-yl)-N.sup.2-((3R,4S)-1-(2-methoxyacetyl)-3-{[(5--
methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperi-
din-4-yl)ethanediamide hydrochloride
##STR00926##
[3702] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 369 was treated with
hydrochloric acid for deprotection, followed by condensation with
the compound obtained in Referential Example 10 and treatment with
hydrochloric acid, to thereby give the title compound.
[3703] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.60-1.73(1H,m),1.97-2.20(1H,m),
2.90(3H,s),3.03-3.52(7H,m),3.64-4.07(5H,m),4.10-4.50(4H,m),
4.65-4.78(1H,m),7.28-7.35(0.2H,m),7.97(1H,d,J=8.8 Hz),
8.11(1H,dd,J=8.8,2.2 Hz),8.51(1H,d,J=2.2 Hz),8.55-8.67(1H,m),
9.22-9.41(1H,m),10.20-10.31(0.8H,m),11.25-11.70(1H,br).
[3704] MS (ESI) m/z: 594(M+H).sup.+.
Example 261
N.sup.1-(4-Chlorophenyl)-N.sup.3-((1S,2R,4S)-4-[(dimethylamino)-carbonyl]--
2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]amin-
o}cyclohexyl)malonamide hydrochloride
##STR00927##
[3706] In a manner similar to that described in Example 5, the
compound obtained in Referential Example 371 was condensed with the
compound obtained in Referential Example 253, followed by treatment
with hydrochloric acid, to thereby give the title compound.
[3707] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.32-1.50(1H,m),1.55-1.87(5H,m),
2.78(3H,m),2.92(3H,s),2.98(3H,s),2.99-3.00(1H,m),
3.05-3.50(5H,m),3.65-3.75(1H,m),3.80-3.92(1H,m),
4.35-4.45(1H,m),4.45-4.55(1H,m),4.65-4.80(1H,m), 7.34(2H,d,J=8.8
Hz),7.58(2H,d,J=8.8 Hz),8.00-8.10(1H,m),
8.30-8.40(1H,m),10.29(1H,d,J=12.5 Hz),12.40(1H,br.s)
[3708] MS (FAB) m/z: 561(M+H).sup.+.
Example 262
N.sup.1-(3-Chlorophenyl)-N.sup.3-((1S,2R,4S)-4-[(dimethylamino)-carbonyl]--
2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[.sup.5,4-c]-pyridin-2-yl)carbonyl-
]amino}cyclohexyl)malonamide hydrochloride
##STR00928##
[3710] In a manner similar to that described in Example 5, the
compound obtained in Referential Example 373 was condensed with the
compound obtained in Referential Example 253, followed by treatment
with hydrochloric acid, to thereby give the title compound.
[3711] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.32-1.50(1H,m),1.55-1.90(5H,m),
2.77(3H,s),2.91(3H,s),2.98(3H,s),2.99-3.00(1H,m),
3.05-3.50(5H,m),3.65-3.80(1H,m),3.80-3.90(1H,m),
4.35-4.50(1H,m),4.50-4.60(1H,m),4.65-4.80(1H,m), 7.09(1H,d,J=8.8
Hz),7.31(1H,d,J=8.8 Hz),7.38(1H,t,J=8.8 Hz),
7.79(1H,s),8.00-8.10(1H,m),8.30-8.40(1H,m), 10.28(1H,d,J=12.5 Hz),
11.67(1H,br.s).
[3712] MS (FAB) m/z: 561(M+H).sup.+.
Example 263
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-{[ethyl(methyl)amino]-
carbonyl}-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carb-
onyl]-amino}cyclohexyl)ethanediamide hydrochloride
##STR00929##
[3714] 10% Palladium on carbon (0.3 g) was added to a solution of
the compound (0.33 g) obtained in Referential Example 404 in
ethanol (20 mL), and the mixture was stirred at room temperature
for 24 hours in a hydrogen atmosphere. After removing insoluble
matter by filtration through Celite pad, the filtrate was
concentrated under reduced pressure. The resultant residue (0.37 g)
was dissolved in N,N-dimethylformamide (20 mL), and the compound
(0.3 g) obtained in Referential Example 266, 1-hydroxybenzotriazole
monohydrate (0.2 g) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.37
g) were successively added, followed by stirring at room
temperature for 18 hours. The reaction mixture was concentrated
under reduced pressure, and the resultant residue was diluted with
a mixture of chloroform-methanol (9:1) and washed with saturated
aqueous sodium hydrogencarbonate and saturated brine. After the
resultant organic layer was dried over sodium sulfate anhydrate,
and the solvent was distilled away under reduced pressure, the
resultant residue was subjected to saparation and purification by
silica gel column chromatography (chloroform:methanol=95:5). The
fraction of interest was concentrated. A 1N HCl in ethanol was
added to form a hydrochloride. This salt was recrystallized from a
mixture of methanol and diethyl ether to give the title compound
(0.28 g).
[3715] .sup.1H-NMR (DMSO-d.sub.6) 0.95(1.5H,t,J=6.9 Hz),
1.42(1.5H,t,J=6.9 Hz), 1.40-1.52(1H,m),1.60-1.78(3H,m),
1.92-2.11(2H,m),2.74(3H,s),2.90(3H,s),3.10-3.38(5H,m),
3.40-3.52(1H,m),3.68-3.70(1H,m),3.96-4.05(1H,m),4.41(2H,s),
4.70(1H,d,J=15.9 Hz),8.00-8.01(2H,m),8.44(1H,s),
8.71(1H,dd,J=10.1,2.2 Hz),9.14(0.5H,d,J=7.8 Hz), 9.22(0.5H,d,J=8.3
Hz),10.24(0.5H,s),10.28(0.5H,s), 11.48(1H,br.s),11.61(1H,br.s).
[3716] MS (FAB) m/z: 562(M+H).sup.+.
Example 264
N.sup.1-(4-Chlorophenyl)-N.sup.2-((1S,2R,4S)-4-{[ethyl (methyl)
amino]-carbonyl}-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin--
2-yl)carbonyl]amino}cyclohexyl)ethanediamide hydrochloride
##STR00930##
[3718] In a manner similar to that described in Example 263, the
compound obtained in Referential Example 404 was converted to the
corresponding amine, followed by condensation with the compound
obtained in Referential Example 374 and treatment with hydrochloric
acid, to thereby give the title compound.
[3719] .sup.1H-NMR (DMSO-d.sub.6) 6: 0.97(1.5H,t,J=6.9 Hz).
1.04(1.5H,t,J=6.9 Hz),1.40-1.60(1H,m),1.60-1.80(3H,m),
1.92-2.11(2H,m),2.74(3H,s),2.89(3H,s),3.10-3.32(5H,m),
3.40-3.52(1H,m),3.65-3.80(1H,m),3.90-4.05(1H,m),
4.40(2H,s),4.70(1H,d,J=15.9 Hz),7.39(2H,d,J=8.8 Hz),
7.82(2H,d,J=8.8 Hz),8.75(1H,dd,J=10.1,2.2 Hz), 9.00(0.5H,d,J=7.8
Hz),9.08(0.5H,d,J=8.3 Hz), 10.81(1H,d,J=4.9 Hz),11.45(1H,br.s).
[3720] MS (FAB) m/z: 561(M+H).sup.+.
Example 265
N.sup.1-(5-Bromopyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-{[ethyl(methyl)amino]c-
arbonyl}-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbo-
nyl]-amino}cyclohexyl)ethanediamide hydrochloride
##STR00931##
[3722] In a manner similar to that described in Example 263, the
compound obtained in Referential Example 404 was converted to the
corresponding amine, followed by condensation with the compound
obtained in Referential Example 375 and treatment with hydrochloric
acid, to thereby give the title compound.
[3723] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.02(1.5H,t,J=6.9 Hz),
1.08(1.5H,t,J=6.9 Hz),1.49-1.60(1H,m),1.60-1.86(3H,m),
2.00-2.20(2H,m),2.81(3H,s),2.97(3H,s),3.15-3.42(6H,m),
3.50-3.60(1H,m),3.70-3.82(1H,m),4.48(2H,s), 4.77(1H,d,J=15.9
Hz),8.04(1H,d,J=8.8 Hz),8.17(1H,d,J=8..sup.8 Hz),8.5
8(1H,s),8.78(1H,dd,J=10.1,2.2 Hz),9.21(0.5H,d,J=7.8 Hz),
9.29(0.5H,d,J=8.3 Hz),10.29(0.5H,s),10.33(0.5H,s),
11.53(0.5H,br.s),11.65(0.5H,br.s).
[3724] MS (FAB) m/z: 607(M+H).sup.+.
Example 266
N.sup.1-(4-Chloro-3-fluorophenyl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino}ca-
rbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbon-
yl]-amino}cyclohexyl)ethanediamide hydrochloride
##STR00932##
[3726] In a manner similar to that described in Example 263, the
compound obtained in Referential Example 252 was converted to the
corresponding amine, followed by condensation with the compound
obtained in Referential Example 378 and treatment with hydrochloric
acid, to thereby give the title compound.
[3727] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.44-1.52(1H,m),1.65-1.76(3H,m),
2.01-2.07(2H,m),2.77(3H,s),2.93(6H,s),2.94-3.00(1H,m),
3.10-3.38(3H,m),3.68-3.70(1H,m),3.96-4.05(1H,m),4.42(2H,s),
4.70(1H,d,J=15.9 Hz),7.56(1H,t,J=8.8 Hz),7.68(1H,d,J=8.8 Hz),7.9
0(1H,dd,J=11.7,1.5 Hz),8.73(1H,dd,J=12.5,7.3 Hz),
9.06(1H,dd,J=12.5,8.1 Hz),11.01(1H,d,J=5.8 Hz),
11.30-11.42(1H,m).
[3728] MS (FAB) m/z: 565(M+H).sup.+.
Example 267
N-{(1R,2S,5S)-2-{[3-(4-Chlorophenyl)-3-oxopropanoyl]amino}-5-[(dimethylami-
no)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-
e-2-carboxamide
##STR00933##
[3730] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 383 was treated with
hydrochloric acid for deprotection, followed by condensation with
the compound obtained in Referential Example 10 and treatment with
hydrochloric acid, to thereby give the title compound.
[3731] .sup.1H-NMR (CDCl.sub.3) (free base) .delta.:
1.22-1.32(1H,m),1.49-1.92(3H,m),1.95-2.10(2H,m),2.53(3H,s),2.70-2.79(1H,m-
), 2.80-2.90(2H,m),2.93(6H,s),2.95-3.09(2H,m),3.72(2H,s),
3.87(2H,s),4.05-4.19(1H,m),4.60-4.70(1H,m),7.20-7.40(2H,m),7.42(2H,d,J=8.-
3 Hz),7.87(2H,d,J=8.3 Hz).
[3732] MS (FAB) m/z: 546(M+H).sup.+.
Example 268
N.sup.1-(5-Chlroropyridin-2-yl)-N.sup.2-((1R,2R,4S)-4-[(dimethylamino)carb-
onyl]-2-{[(5-methyl-5H-pyrrolo[3,4-d]-thiazol-2-yl)carbonyl]amino}cyclohex-
yl)ethanediamide
##STR00934##
[3734] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 386 was treated with
hydrochloric acid for deprotection, followed by condensation with
the compound obtained in Referential Example 293, to thereby give
the title compound.
[3735] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.00-2.35(7H,m),2.96(3H,s),3.04(3H,s),
3.85-3.95(1H,m),3.88(3H,s),4.60-4.75(1H,m), 6.68(1H,d,J=2.0 Hz),
7.17(1H,d,J=2.0 Hz),7.20-7.32(1H,m), 7.67(1H,dd,J=8.8,2.8
Hz),7.99(1H,d,J=8.4 Hz), 8.21(1H,d,J=8.8 Hz),8.25(1H,d,J=2.8
Hz),9.64(1H,s).
[3736] HRMS (FAB) m/z: 532.1520(M+H).sup.+.
[3737] (Calculated; C.sub.23H.sub.27ClN.sub.7O.sub.4S:
532.1534).
Example 269
N.sup.1-[(5-Chlroropyridin-2-yl)amino]-N.sup.2-((1R,2R,4S)-4-[(dimethylami-
no)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)c-
arbonyl]-amino}cyclohexyl)ethanediamide hydrochloride
##STR00935##
[3739] In a manner similar to that described in Referential Example
253, the compound obtained in Referential Example 387 was reduced.
In a manner similar to that described in Example 208, the
thus-obtained compound was condensed with the compound obtained in
Referential Example 266, followed by treatment with hydrochloric
acid, to thereby give the title compound.
[3740] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.50-1.98(6H,m),
2.82(3H,s),2.91(3H,s),
2.95(3H,s),2.86-3.92(7H,m),4.30-4.81(2H,m),7.92-8.09(2H,m),
8.39-8.47(1H,m),8.56-8.72(2H,m),10.17(1H,s).
[3741] MS (ESI) m/z: 548(M+H).sup.+.
Example 270
[3742]
N.sup.1-(4-Chlorophenyl)-N.sup.2-((1R,2R,4S)-4-[(dimethylamino)-car-
bonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbon-
yl]amino}cyclohexyl)ethanediamide
##STR00936##
[3743] In a manner similar to that described in Referential Example
253, the compound obtained in Referential Example 387 was reduced.
In a manner similar to that described in Example 191, the compound
obtained in Referential Example 242 was hydrolyzed to form a
lithium salt, and the thus-reduced compound was condensed with the
lithium salt, followed by treatment with hydrochloric acid, to
thereby give the title compound.
[3744] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.50-1.97(6H,m),
2.82(3H,s),2.91(3H,s), 2.98(3H,s),2.83-3.88(7H,m),4.30-4.79(2H,m),
7.37(2H,d,J=8.8 Hz), 7.89(2H,d,J=8.8 Hz), 8.34(1H,d,J=8.4
Hz),8.63(1H,d,J=8.8 Hz),10.72(1H,s).
[3745] MS (ESI) m/z: 547(M+H).sup.+.
Example 271
N.sup.1-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(dimethylam-
ino)carbonyl]cyclohexyl}-N.sup.2-(pyridin-4-yl)-ethanediamide
hydrochloride
##STR00937##
[3747] The compound obtained in Referential Example 310 was treated
with hydrochloric acid for deprotection. In a manner similar to
that described in Example 191, the compound obtained in Referential
Example 261 was hydrolyzed to form lithium
2-[(pyridin-4-yl)amino]-2-oxoacetate, and the thus-deprotected
compound was condensed with the lithium salt, followed by treatment
with hydrochloric acid, to thereby give the title compound.
[3748] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.40-2.01(6H,m),2.79(3H,s),3.01(3H,s),
3.00-3.18(1H,m),4.02-4.19(1H,m),4.45-4.55(1H,m),7.09(1H,s),
7.13-7.22(1H,m),7.41(1H,d,J=8.4 Hz),7.64(1H,br.s), 8.28(2H,d,J=6.8
Hz),8.36(1H,d,J=8.0 Hz),8.62(1H,d,J=8.8Hz), 8.72(2H,d,J=6.8
Hz),11.74(1H,s),11.83(1H,s).
[3749] MS (FAB) m/z: 511(M+H).sup.+.
Example 272
N.sup.1-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(dimethylam-
ino)carbonyl]cyclohexyl}-N.sup.2-(pyridin-3-yl)-ethanediamide
hydrochloride
##STR00938##
[3751] In a manner similar to that described in Referential Example
242, 3-aminopyridine was condensed with methyl
2-chloro-2-oxoacetate to form methyl
2-[(pyridin-3-yl)amino]-2-oxoacetate. In a manner similar to that
described in Example 271, the title compound was obtained from the
thus-condensed ester product and the compound obtained in
Referential Example 310.
[3752] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.40-2.05(6H,m),2.80(3H,s),3.02(3H,s),
2.92-3.15(1H,m),4.02-4.17(1H,m),4.42-4.58(1H,m),7.10(1H,s),
7.12-7.19(1H,m),7.40(1H,d,J=8.4 Hz),7.62-7.87(2H,m),
8.36-8.64(4H,m),9.18(1H,s),11.39(1H,s),11.79(1H,s).
[3753] MS (FAB) m/z: 511(M+H).sup.+.
Example 273
N.sup.1-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(dimethylam-
ino)carbonyl]cyclohexyl}-N.sup.2-(piperidin-4-yl)-ethanediamide
hydrochloride
##STR00939##
[3755] 4N HCl-dioxane (8.0 mL) was added to a solution of the
compound (400 mg) obtained in Referential Example 389 in ethanol
(5.0 mL) at room temperature, and the mixture was stirred at the
same temperature for 5 hours. The solvent was distilled away under
reduced pressure, the residue was washed with methylene chloride,
and insoluble matter was filtered and washed to give the title
compound (320 mg).
[3756] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.38-1.92(10H,m),2.77(3H,s),2.96(3H,s),
2.82-3.35(6H,m),3.88-4.10(2H,m),4.34-4.43(1H,m),7.05(1H,s),
7.11-7.17(1H,m),7.38(1H,d,J=8.8 Hz),7.65(1H,s), 8.25(1H,d,J=8.0
Hz),8.34(1H,d,J=7.6 Hz),8.89(1H,d,J=8.4 Hz), 11.75(1H,s).
[3757] MS (ESI) m/z: 517(M+H).sup.+.
Example 274
N.sup.1-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-[(dimethylam-
ino)carbonyl]cyclohexyl}-N.sup.2-(1-methylpiperidin-4-yl)ethanediamide
hydrochloride
##STR00940##
[3759] In a manner similar to that described in Referential Example
9, the compound obtained in Example 273 was methylated. The
thus-methylated product was treated with hydrochloric acid, to
thereby give the title compound.
[3760] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.40-2.01(11H,m),2.67(3H,s),2.79(3H,s),
2.98(3H,s),2.85-4.48(7H,m),7.07(1H,s), 7.16(1H,dd,J=8.8,2.0 Hz),
7.40(1H,d,J=8.8 Hz), 7.68(1H,d,J=2.0 Hz),
8.25-8.35(1H,m),8.37(1H,d,J=7.6 Hz),
8.90-9.02(1H,m),9.82(1H,br.s),11.78(1H,s).
[3761] MS (ESI) m/z: 531(M+H).sup.+.
Example 275
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-
-amino}cyclohexyl)-N.sup.1-methylethanediamide hydrochloride
##STR00941##
[3763] In a manner similar to that described in Example 191, the
compound obtained in Referential Example 390 was hydrolyzed and
then, condensed with the compound obtained in Referential Example
253, followed by treatment with hydrochloric acid, to thereby give
the title compound.
[3764] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.32-1.97(6H,m),
2.42-2.51(1H,m), 2.76(3H,s), 2.91(3H,s),2.93(3H,s),3.27(3H,s),
3.00-4.80(8H,m), 7.45(1H,br.s),7.88-7.97(1H,m),
8.25-8.41(2H,m),8.78-8.91(1H,m).
[3765] MS (FAB) m/z: 562(M+H).sup.+.
Example 276
N.sup.1-(5-Chloropyrimidin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)car-
bonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbony-
l]-amino}cyclohexyl)ethanediamide hydrochloride
##STR00942##
[3767] In a manner similar to that described in Example 191, the
compound obtained in Referential Example 391 was hydrolyzed and
then, condensed with the compound obtained in Referential Example
253, followed by treatment with hydrochloric acid, to thereby give
the title compound.
[3768] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.38-2.10(7H,m),2.77(3H,s),2.90(3H,s), 2.93(3H,s),
3.04-4.80(8H,m),8.60-8.70(2H,m),8.82(2H,s),
9.08(1H,br.s),10.64(1H,s),11.57(1H,br.s).
[3769] MS (FAB) m/z: 549(M+H).sup.+.
Example 277
N.sup.1-(4-Chlorophenyl)-N.sup.2-((1S,2R,4S)-4-{[ethyl(methyl)amino]-carbo-
nyl}-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]-thiazol-2-yl)carbonyl]ami-
no}cyclohexyl)ethanediamide hydrochloride
##STR00943##
[3771] The compound obtained in Referential Example 392 was reduced
in a manner similar to that described in Referential Example 253.
In a manner similar to that described in Example 195, the compound
obtained in Referential Example 242 was hydrolyzed to form the
carboxylic acid, and the thus-reduced compound was condensed with
the carboxylic acid, followed by treatment with hydrochloric acid,
to thereby give the title compound.
[3772] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.96,1.02(3H,each
t,J=7.0 Hz), 1.47-1.58(1H,m),1.65-1.77(3H,m),1.98-2.08(2H,m),
2.76-2.91(4H,m),3.07(3H,s),3.19-3.41(2H,m),3.98-4.04(1H,m),
4.42(1H,br.s),4.46-4.94(4H,m),7.41(2H,d,J=8.8 Hz), 7.83(2H,d,J=8.8
Hz),8.74-8.80(1H,m),9.02(1H,d,J=7.3 Hz),
10.82(1H,s),12.41(1H,br.s).
[3773] MS (FAB) m/z: 547(M+H).sup.+.
Example 278
N.sup.1-(5-Bromopyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-{[ethyl(methyl)amino]c-
arbonyl}-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]-
amino}cyclohexyl)-ethanediamide hydrochloride
##STR00944##
[3775] The title compound was obtained from the compound obtained
in Referential Example 392 and the compound obtained in Referential
Example 262 in a similar manner to the process described in Example
277.
[3776] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
0.90-1.08(3H,m),1.40-2.13(6H,m),
2.70-3.53(13H,m),3.92-4.08(1H,m),4.35-4.47(1H,m), 7.95(1H,d,J=8.8
Hz),8.10(1H,dd,J=8.8,2.4 Hz),8.50-8.55(1H,m),
8.68-8.78(1H,m),9.12-9.18(1H,m),10.26(1H,s).
[3777] MS (FAB) m/z: 592(M+H).sup.+.
Example 279
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-{[ethyl(methyl)amino]-
carbonyl)-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl-
]amino}cyclohexyl)-ethanediamide hydrochloride
##STR00945##
[3779] The title compound was obtained from the compound obtained
in. Referential Example 392 and the compound obtained in
Referential Example 243 in a similar manner to the process
described in Example 277.
[3780] .sup.1H-NMR (DMSO-d.sub.6) .delta.: [0.95(t,J=7.0
Hz),1.01(t,J=6.8 Hz),3H],
1.45-1.72(4H,m),1.96-2.07(2H,m),2.74-2.90(4H,m),3.06(3H,s),
3.18-3.40(2H,m),3.95-4.02(1H,m),4.41(1H,br.s),4.54-4.90(4H,m),
8.00(2H,br.s),8.45(1H,s),8.70-8.75(1H,m),
9.15(1H,br.s),10.27(1H,br.s),12.29(1H,br.s).
[3781] MS (ESI) m/z: 548(M+H).sup.+.
Example 280
N.sup.1-(4-Chloro-3-methoxyphenyl)-N.sup.2-((1S,2R,4S)-4-[(dimethyl-amino)-
carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carb-
onyl]amino}cyclohexyl)ethanediamide hydrochloride
##STR00946##
[3783] In a manner similar to that described in Example 2, the
compound obtained in Referential Example 395 was condensed with the
compound obtained in Referential Example 10, followed by treatment
with hydrochloric acid, to thereby give the title compound.
[3784] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.46-1.54(1H,m),1.67-1.77(3H,m),
2.01-2.10(2H,m),2.79(3H,s),2.92-2.98(7H,m),3.21(2H,br.s),
3.49(1H,br.s),3.69(1H,br.s),3.80(3H,s),3.98-4.03(1H,m),
4.42-4.50(2H,m),4.69(1H,br.s),7.37(1H,d,J=8.7 Hz),
7.48(1H,dd,J=8.7,2.2 Hz),7.72(1H,d,J=2.2 Hz), 8.75(1H,d,J=7.3
Hz),9.06(1H,br.s),10.77(1H,s), 11.44(1H,br.s). MS (FAB) m/z:
577(M+H).sup.+.
Example 281
N.sup.1-(4-Chlorophenyl)-N.sup.2-((1R*,2R*)-2-{[(5-methyl-4,5,6,7-tetrahyd-
rothiazolo[5,4-c]pyridin-2-yl)carbonyl]-amino}cyclopentyl)ethanediamide
hydrochloride
##STR00947##
[3786] In a manner similar to that described in Example 195, the
compound obtained in Referential Example 242 was hydrolyzed,
followed by condensation with the compound obtained in Referential
Example 62 and treatment with hydrochloric acid, to thereby give
the title compound.
[3787] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.65-1.73(4H,m),
1.91-1.96(2H,m),
2.91(3H,s),3.15(2H,br.s),3.49(1H,br.s),3.66(1H,br.s),
4.32-4.42(3H,m),4.66(1H,br.s),7.40(2H,d,J=8.9 Hz), 7.84(2H,d,J=8.9
Hz),8.92(1H,d,J=8.5 Hz),9.03(1H,d,J=8.3 Hz),
10.76(1H,s),11.32(1H,br.s).
[3788] MS (FAB) m/z: 462(M+H).sup.+.
Example 282
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1R*,2R*)-2-{[(5-methyl-4,5,6,7-te-
trahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-amino}cyclopentyl)ethanediam-
ide hydrochloride
##STR00948##
[3790] In a manner similar to that described in Example 208, the
compound obtained in Referential Example 62 was condensed with the
compound obtained in Referential Example 266, followed by treatment
with hydrochloric acid, to thereby give the title compound.
[3791] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.71(4H,br.s),1.96(2H,br.s),2.90(3H,s),
3.14(1H,br.s),3.21(1H,br.s),3.47(1H,br.s),3.68(1H,br.s),
4.34-4.45(3H,m),4.66(1H,br.s),7.99-8.06(2H,m),8.43-8.44(1H,m),
8.94(1H,d,J=8.3 Hz),9.20(1H,d,J=8.5 Hz), 10.20(1H,br.s),
11.78(1.1H,br.s).
[3792] MS (FAB) m/z: 463(M+H).sup.+.
Example 283
N.sup.1-((1S,2R,4S)-4-[(Dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetr-
ahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-amino}cyclohexyl)-N.sup.2-(4-e-
thynylphenyl)ethanediamide
##STR00949##
[3794] In a manner similar to that described in Example 263, the
compound obtained in Referential Example 252 was condensed with the
compound obtained in Referential Example 397, to thereby give the
title compound.
[3795] .sup.1H-NMR (CDCl.sub.3)
1.67-2.16(6H,m),2.51(3H,s),2.76-2.91(5H,m),
2.94(3H,s),3.04(3H,s),3.07(1H,s),[3.65(1H,d,J=15.5 Hz),
3.73(1H,d,J=15.5 Hz)AB
pattern],4.09-4.16(1H,m),4.72-4.75(1H,m),7.42-7.46(3H,m),7.58(2H,d,-
J=8.5 Hz), 8.02(1H,d,J=8.1 Hz),9.36(1H,s).
[3796] MS (FAB) m/z: 537(M+H).sup.+.
Example 284
N.sup.1-(5-Chloropyrazin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-
-amino}cyclohexyl)ethanediamide hydrochloride
##STR00950##
[3798] In a manner similar to that described in Referential Example
97, the compound obtained in Referential Example 253 was condensed
with the compound obtained in Referential Example 399, followed by
treatment with hydrochloric acid, to thereby give the title
compound.
[3799] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.44-1.52(1H,m),1.65-1.77(3H,m),
2.00-2.10(2H,m),2.77(3H,s),2.91-2.97(7H,m),3.20(2H,br.s),
3.48(1H,br.s),3.68(1H,br.s),3.97-4.02(1H,m),4.40-4.46(2H,m),
4.68(1H,br.s),8.64(1H,d,J=1.2 Hz),8.70(1H,d,J=7.3 Hz),
9.02(1H,s),9.21(1H,br.s),10.91(1H,br.s),11.50(1H,br.s).
[3800] MS (FAB) m/z: 549(M+H).sup.+.
Example 285
N.sup.1-(4-Chloro-3-nitrophenyl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)car-
bonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbony-
l]-amino}cyclohexyl)ethanediamide hydrochloride
##STR00951##
[3802] In a manner similar to that described in Referential Example
97, the compound obtained in Referential Example 253 was condensed
with the compound obtained in Referential Example 400, followed by
treatment with hydrochloric acid, to thereby give the title
compound.
[3803] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.44-1.53(1H,m),1.66-1.73(3H,m),
1.97-2.07(2H,m),2.77(3H,s),2.89-3.05(7H,m),3.20(2H,br.s),
3.55(2H,br.s),4.00(1H,br.s),4.44(1H,br.s),4.52(2H,br.s),
7.75(1H,d,J=8.8 Hz),8.08(1H,d,J=8.8 Hz),8.59(1H,s), 8.71(1B,d,J=7.3
Hz),9.07(1H,d,J=8.0 Hz),11.24(1H,s), 11.58(1H,br.s).
[3804] MS (FAB) m/z: 592(M+H).sup.+.
Example 286
N.sup.1-(4-Chloro-2-nitrophenyl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)car-
bonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbony-
l]-amino}cyclohexyl)ethanediamide hydrochloride
##STR00952##
[3806] In a manner similar to that described in Example 208, the
compound obtained in Referential Example 253 was condensed with the
compound obtained in Referential Example 401, followed by treatment
with hydrochloric acid, to thereby give the title compound.
[3807] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.46-1.54(1H,m),
1.66-1.77(3H,m),
2.03-2.10(2H,m),2.79(3H,s),2.90-2.93(7H,m),3.17-3.28(2H,m),
3.49(1H,br.s),3.68(1H,br.s),3.99-4.04(1H,m),4.41(1H,br.s),
4.46(1H,br.s),4.68(1H,br.s),7.89(1H,d,J=9.0 Hz),8.20-8.21(2H,m),
8.73(1H,d,J=6.4 Hz),9.28(1H,br.s), 11.49(1H,br.s), 11.56(1H,s).
[3808] MS (FAB) m/z: 592(M+H).sup.+.
Example 287
N.sup.1-(3-Amino-4-chlorophenyl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)car-
bonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbony-
l]-amino}cyclohexyl)ethanediamide hydrochloride
##STR00953##
[3810] The compound (236 mg) obtained in Example 285 was dissolved
in ethanol (25 mL), and a catalytic amount of Raney nickel was
added, followed by stirring at room temperature for 17 hours in a
hydrogen atmosphere. Thereafter, a catalytic amount of Raney nickel
was additionally added, followed by stirring for additional 7
hours. The catalyst was removed by filtration, and the solvent was
distilled away under reduced pressure. The residue was purified by
silica gel column chromatography (methylene chloride:methanol=23:2)
to give a pale yellow solid (101 mg). This product was dissolved in
methylene chloride, and 1N HCl in ethanol (360 .mu.l) was added
thereto. The solvent was distilled away under reduced pressure, a
small amount of methanol was added to the residue, and diethyl
ether was added dropwise while irradiating with ultrasonic waves to
collect the precipitate formed. This product was washed with
diethyl ether to give the title compound (95 mg).
[3811] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.45-1.53(1H,m),1.66-1.73(3H,m),
1.97-2.10(2H,m),2.78(3H,s),2.91-2.94(7H,br.s),3.11-3.19(1H,m),3.29(1H,br.-
s),3.48(1H,br.s),3.69(1H,br.s),
3.95-4.02(1H,m),4.44(2H,br.s),4.68,4.72(1H,each br.s),
4.86(2.5H,br.s),6.98(1H,dd,J=8.5,1.9 Hz),7.14(1H,d,J=8.5 Hz),
7.35,7.38(1H,each br.s),8.72-8.77(1H,m),[8.91(d,J=7.8 Hz).
8.99(d,J=8.5 Hz),1H],10.45,10.47(1H,each br.s), 11.74(1H,br.s).
[3812] MS (FAB) m/z: 562(M+H).sup.+.
Example 288
N.sup.1-(2-Amino-4-chlorophenyl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)car-
bonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbony-
l]-amino}cyclohexyl)ethanediamide hydrochloride
##STR00954##
[3814] The title compound was obtained from the compound obtained
in Example 286 in a similar manner to the process described in
Example 287.
[3815] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.45-1.77(4H,m),2.06-2.09(2H,m),
2.78(3H,s),2.92(7H,br.s),3.12-3.19(1H,m),3.26-3.28(1H,m),
3.48(1H,br.s),3.70(1H,br.s),4.00-4.44(5.7H,m), 4.70,4.74(1H,each
br.s),6.63-6.66(1H,m),6.85(1H,br.s),
7.18-7.21(1H,m),8.77-8.81(1H,m),[8.97(d,J=7.8 Hz), 9.06(d,J=8.1
Hz),1H],9.98(1H,s),11.60(1H,br.s).
[3816] MS (FAB) m/z: 562(M+H).sup.+.
Example 289
N.sup.1-(6-Chloro-4-methylpyridin-3-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylam-
ino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-
carbonyl]-amino}cyclohexyl)ethanediamide hydrochloride
##STR00955##
[3818] In a manner similar to that described in Example 199, the
compound obtained in Referential Example 270 was condensed with the
compound obtained in Referential Example 402, followed by treatment
with hydrochloric acid, to thereby give the title compound.
[3819] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.45-1.54(1H,m),1.65-1.77(3H,m),
2.02-2.08(2H,m),2.22(3H,s),2.79(3H,s),2.89-2.93(7H,m),
3.19(2H,br.s),3.54(2H,br.s),3.99-4.04(1H,m),4.40-4.42(1H,m),
4.50(2H,br.s),7.49(1H,s),8.32(1H,s), 8.75(1H,d,J=7.1
Hz),9.09(1H,d,J=7.3 Hz),10.48(1H,s), 11.40(0.9H,br.s).
[3820] MS (FAB) m/z: 562(M+H).sup.+.
Example 290
N-{(1R,2S,5S)-2-({[(E)-2-(4-Chlorophenyl)diazenyl]-carbonyl}amino)-5-[(dim-
ethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-
pyridine-2-carboxamide hydrochloride
##STR00956##
[3822] After 10% Palladium on carbon (200 mg) was added to a
solution of the compound (700 mg) obtained in Referential Example
252 in tetrahydrofuran (10 mL), and the mixture was stirred at room
temperature for 2 days in a hydrogen atmosphere at a pressure of 1
atm, the reaction mixture was filtered, and the compound obtained
in Referential Example 405 (470 mg) was added to a solution of an
amine obtained by concentrating the filtrate in
N,N-dimethylformamide (5.0 mL), followed by stirring at 95.degree.
C. for 18 hours. After the reaction mixture was concentrated, and
saturated aqueous sodium hydrogencarbonate (50 mL), water (50 mL),
and methylene chloride (30 mL) were added for partitioning the
mixture, the resultant aqueous layer was extracted with methylene
chloride (2.times.20 mL). Organic layers were combined, dried over
sodium sulfate anhydrate, concentrated and purified by silica gel
column chromatography (methylene chloride:methanol=12:1). This
purified product was treated with 1N HCl in ethanol to give the
title compound (100 mg).
[3823] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.40-1.60(1H,m),1.65-2.05(5H,m), 2.80(3H,s),
2.91(3H,s),2.99(3H,s),3.00-3.20(2H,m),
3.20-3.32(1H,m),3.43(1H,br.s),3.69(1H,br.s),3.95(1H,br.s),
4.45(1H,br.s),4.60-4.80(2H,m),7.68(2H,d,J=8.7 Hz), 7.83(2H,d,J=8.7
Hz), 8.41(1H,br.s),8.68(1H,d,J=7.6 Hz), 11.40-11.80(1H,br).
[3824] MS (ESI) m/z: 532(M+H).sup.+.
Example 291
N-{(1R,2S,5S)-2-({[2-(4-Chlorophenyl)hydrazino]-carbonyl}amino)-5-[(dimeth-
ylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyr-
idine-2-carboxamide hydrochloride
##STR00957##
[3826] The procedure described in Example 290 was repeated, except
that reaction was performed at 40.degree. C. for 3 days under
stirring, to thereby give the title compound.
[3827] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.30-1.50(1H,m),
1.50-1.80(3H,m),
1.80-1.97(2H,m),2.76(3H,s),2.80-3.05(2H,m),2.91(6H,s),
3.05-3.30(2H,m),3.47(2H,br.s),4.30-4.50(2H,m), 4.72(1H,t,J=12.8
Hz),6.40-6.60(2H,m),6.55-6.70(2H,m),
6.95-7.20(2H,m),7.88(1H,d,J=11.3 Hz),8.48-8.65(1H,m),
11.48-11.80(1H,br).
[3828] MS (ESI) m/z: 534(M+H).sup.+.
Example 292
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-{[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-amino}cy-
clohexyl)ethanediamide hydrochloride
##STR00958##
[3830] In a manner similar to that described in Example 17, the
compound obtained in Referential Example 34 was condensed with the
compound obtained in Referential Example 420, followed by treatment
with hydrochloric acid, to thereby give the title compound.
[3831] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.45-1.55(1H,m),1.60-1.80(3H,m),
1.95-2.10(2H,m),2.78(3H,s),2.85-3.00(4H,m), 3.11(2H,br
s),3.40-3.55(2H,m),3.95-4.07(1H,m),4.37-4.45(1H,m),4.48(2H,br
s),8.00-8.01(2H,m), 8.10(1H,d,J=7.1 Hz), 8.43-8.47(1H,m),
9.16(1H,d,J=7.8 Hz),9.43(2H,br s), 10.27(1H,s).
[3832] MS (FAB) m/z: 534(M+H).sup.+.
Example 293
N-((3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-[(1-hydroxycyclopropy-
l)carbonyl]piperidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyrid-
ine-2-carboxamide hydrochloride
##STR00959##
[3834] In a manner similar to that described in Example 150, the
compound obtained in Example 118 was condensed with
1-hydroxy-1-cyclopropanecarboxylic acid, followed by treatment with
hydrochloric acid, to thereby give the title compound.
[3835] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
0.60-0.90(3H,br),0.92-1.03(1H,m),
1.71-1.84(1H,m),1.85-2.03(1H,m),2.91(3H,s), 3.00-3.80(7H,m),
4.05-4.80(5H,m),6.28-6.42(1H,br), 7.09(1H,s), 7.18(1H,dd,J=8.8,1.5
Hz), 7.42(1H,d,J=8.8 Hz), 7.70(1H,d,J=1.5
Hz),8.14-8.29(1H,br),8.41(1H,br d,J=7.6 Hz), 11.83(1H,s).
[3836] MS (ESI) m/z: 557(M+H).sup.+.
Example 294
N-((3R*,4S*)-4-{[(5-Chloroindol-2-yl)carbonyl]amino}-1-[(1-methoxycyclopro-
pyl)carbonyl]piperidin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyr-
idine-2-carboxamide hydrochloride
##STR00960##
[3838] In a manner similar to that described in Example 150, the
compound obtained in Example 118 was condensed with the compound
obtained in Referential Example 409, followed by treatment with
hydrochloric acid, to thereby give the title compound.
[3839] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
0.65-1.05(4H,m),1.74-1.88(1H,m),1.92-2.10(1H,m),2.91(3H,s),3.00-3.80(10H,-
m),4.05-4.83(6H,m), 7.08(1H,s),7.18(1H,dd,J=8.6,2.0
Hz),7.42(1H,d,J=8.6 Hz), 7.71(1H,d,J=2.0
Hz),8.08-8.30(1H,br),8.41(1H,br d,J=7.8 Hz),
10.60-10.80(0.5H,br),10.85-11.05(0.5H,br),11.84(1H,s).
Example 295
7-Chloro-N-((3R,4S)-1-(2-methoxyacetyl)-3-{[(5-methyl-4,5,6,7-tetrahydroth-
iazolo[5,4-c]pyridin-2-yl)carbonyl]-amino}piperidin-4-yl)-3-isoquinolineca-
rboxamide hydrochloride
##STR00961##
[3841] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 410 was treated with 4N
HCl-dioxane for deprotection, followed by condensation with the
compound obtained in Referential Example 10 and treatment with
hydrochloric acid, to thereby give the title compound.
[3842] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.60-1.80(1H,m),2.13-2.38(1H,m),
2.90(3H,s),3.00-3.87(10H,m),3.89-4.10(2H,m), 4.15-4.58(4H,m),
4.60-4.78(1H,m),7.89(1H,d,J=8.8 Hz), 8.25(1H,d,J=8.8
Hz),8.37(1H,s),8.61(1H,s),8.70-8.95(.sup.1H,m),
9.05-9.29(1H,m),9.36(1H,s),11.20-11.40(0.5H,br),
11.45-11.65(0.5H,br).
[3843] MS (ESI) m/z: 557(M+H).sup.+.
Example 296
N.sup.1-(4-chloro-3-fluorophenyl)-N.sup.2-((3R,4S)-1-(2-methoxyacetyl)-3-{-
[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pi-
peridin-4-yl)ethanediamide hydrochloride
##STR00962##
[3845] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 411 was treated with 4N
HCl-dioxane for deprotection, followed by condensation with the
compound obtained in Referential Example 10 and treatment with
hydrochloric acid, to thereby give the title compound.
[3846] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.60-1.72(1H,m),1.98-2.21(1H,m),
2.91(3H,s),3.00-3.52(9H,m),3.56-4.05(3H,m),4.08-4.50(4H,m),
4.60-4.78(1H,br),7.56(1H,t,J=8.8 Hz),7.70(1H,d,J=9.0 Hz),
7.91(1H,dd,J=8.8,2.3 Hz),8.50-8.72(1H,m),9.15-9.35(1H,m),
11.02(1H,s),11.15-11.33(0.5H,br),11.35-11.50(0.5H,br).
[3847] MS (FAB) m/z: 567(M+H).sup.+.
Example 297
N.sup.1-(5-chloro-2-thienyl)-N.sup.2-((3R,4S)-1-(2-methoxyacetyl)-3-{[(5-m-
ethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperid-
in-4-yl)ethanediamide hydrochloride
##STR00963##
[3849] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 412 was treated with 4N
HCl-dioxane for deprotection, followed by condensation with the
compound obtained in Referential Example 10 and treatment with
hydrochloric acid, to thereby give the title compound.
[3850] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.60-1.73(1H,m),1.96-2.19(1H,m),
2.91(3H,s),3.04-3.54(9H,m),3.60-4.05(3H,m),4.07-4.34(3H,m),
4.35-4.54(1H,br),4.60-4.80(1H,br),6.89(1H,d,J=4.2 Hz),
6.93(1H,d,J=4.2 Hz),8.48-8.70(1H,m),9.18-9.40(1H,m),
12.31(1H,s).
[3851] MS (ESI) m/z: 555(M+H).sup.+.
Example 298
N-{(1R,2S,5S)-2-{[2-(4-Chlorophenoxy)acetyl]amino}-5-[(dimethylamino)carbo-
nyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbo-
xamide hydrochloride
##STR00964##
[3853] In a manner similar to that described in Example 223, the
compound obtained in Referential Example 252 was reduced, followed
by condensation with p-chlorophenoxyacetic acid and treatment with
hydrochloric acid, to thereby give the title compound.
[3854] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.35-1.47(1H,m),1.55-1.90(5H,m),
2.77(3H,s),2.92(3H,s),2.96(3H,s),2.98-3.10(1H,m),
3.10-3.80(3H,m),3.85-3.95(1H,m),4.35-4.50(4H,m),
4.50-4.80(1H,br),6.85(2H,d,J=8.5 Hz),7.15-7.35(1H,br),
7.88-8.03(1H,br),8.46(1H,d,J=8.8 Hz),11.30-11.65(1H,br). MS (FAB)
m/z: 534(M+H).sup.+.
Example 299
7-Chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-5H-pyrrol-
o[3,4-d]thiazol-2-yl)carbonyl]amino}-cyclohexyl)-3-isoquinolinecarboxamide
hydrochloride
##STR00965##
[3856] The compound obtained in Referential Example 413 was
hydrolyzed to form the carboxylic acid lithium salt. The compound
obtained in Referential Example 146 was treated with acid for
deprotection, and the thus-deprotected compound was condensed with
the lithium salt, followed by treatment with hydrochloric acid, to
thereby give the title compound.
[3857] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.00-1.11(2H,m),1.45-1.60(1H,m),
1.65-1.85(1H,m),1.95-2.06(1H,m),2.10-2.24(1H,m),2.78(3H,s),
2.87-3.02(1H,m),2.94(3H,s),3.88(3H,s),4.16-4.27(1H,m),4.45-4.56(1H,m),7.0-
3(1H,s),7.55(1H,s), 7.87 (1H,br d,J=8.3 Hz),8.24(1H,br d,J=8.8
Hz),8.33(1H,s), 8.59(1H,s),8.85(1H,br d,J=7.6 Hz),9.01(1H,br
d,J=7.8 Hz), 9.28(1H,s).
[3858] MS (ESI) m/z: 539(M+H).sup.+.
Example 300
N-{(1R,2S,5S)-2-{[(6-Chloro-4-oxo-4H-chromen-2-yl)-carbonyl]amino)-5-[(dim-
ethylamino)carbonyl]cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-
pyridine-2-carboxamide hydrochloride
##STR00966##
[3860] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 417 was treated with 4N
HCl-dioxane, and the thus-obtained compound was condensed with the
compound obtained in Referential Example 10, followed by treatment
with hydrochloric acid, to thereby give the title compound.
[3861] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.40-1.53(1H,m),1.67-2.04(5H,m),
2.40-2.53(1H,m),2.80(3H,s),2.92(3H,s),3.01(3H,s),
3.09-3.22(3H,m),3.66-3.77(1H,m),4.01-4.10(1H,m),
4.34-4.49(1H,m),4.58-4.76(2H,m),6.80(1H,d,J=4.9 Hz),
7.59-7.70(1H,m),7.90-8.00(1H,m),7.96(1H,s),8.52-8.60(1H,m),
8.80-8.90(1H,m),11.10-11.25(0.5H,br),11.40-11.55(0.5H,br).
[3862] MS (ESI) m/z: 572(M+H).sup.+.
Example 301
7-Chloro-N-((3R,4S)-1-(2-methoxyacetyl)-3-{[(5-methyl-4,5,6,7-tetrahydroth-
iazolo[5,4-c]pyridin-2-yl)-carbonyl]amino}piperidin-4-yl)-3-cinnolinecarbo-
xamide hydrochloride
##STR00967##
[3864] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 418 was treated with 4N
HCl-dioxane, and the thus-obtained compound was condensed with the
compound obtained in Referential Example 10, followed by treatment
with hydrochloric acid, to thereby give the title compound.
[3865] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.70-1.80(1H,m),1.85-2.05(1H,m),
2.90(3H,s),3.00-3.20(2H,m),3.16(3H,s),3.22-3.82(7H,m),
3.88-4.80(5H,m),7.09(1H,d,J=9.0 Hz),7.17(1H,dd,J=8.8,1.9 Hz),
7.42(1H,d,J=8.8 Hz),7.70(1H,d,J=1.9 Hz),8.29(1H,br s),
8.40-8.50(1H,m),11.20-11.50(1H,br m),11.85(1H,s).
[3866] MS (ESI) m/z: 558(M+H).sup.+.
Example 302
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carbo-
nyl)-2-{[(5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]am-
ino}-cyclohexyl)ethanediamide hydrochloride
##STR00968##
[3868] The compound obtained in Referential Example 421 was
deprotected by use of hydrochloric acid. In a manner similar to
that described in Example 18, the thus-deprotected compound was
methylated, followed by treatment with hydrochloric acid, to
thereby give the title compound.
[3869] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.42-1.58(1H,m),1.59-1.80(3H,m),
1.83-1.95(1H,m),1.97-2.10(1H,m),2.78(3H,s), 2.89(3H,s),
2.96(3H,s),3.00-3.10(1H,m),3.10-3.20(2H, m), 3.45-3.80(1H,
m),3.90-4.00(2H,m),4.00-4.50(3H,m),
7.77(1H,s),7.95-8.05(3H,m),8.44(1H,t,J=1.6 Hz), 8.90(1H,d,J=8.6
Hz),10.25(1H,s),11.12(1H,br s).
[3870] MS (ESI) m/z: 547(M+H).sup.+.
Example 303
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-{[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbon-
yl]amino-cyclohexyl)ethanediamide hydrochloride
##STR00969##
[3872] In a manner similar to that described in Example 2, the
compound obtained in Referential Example 148 was condensed with the
compound obtained in Referential Example 420, followed by treatment
with hydrochloric acid, to thereby give the title compound.
[3873] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.30-1.40(6H,m),1.38-1.58(1H,m),
1.59-1.82(3H,m),1.95-2.13(2H,m),2.40-2.65(1H,m),2.49(3H,s),
2.87-3.55(4H,m),2.49(3H,s),3.60-3.82(2H,m),3.93-4.04(1H,m),
4.37-4.55(2H,m),4.55-4.72(1H,m),7.94-8.10(2H,m),8.43(1H,s),
8.64-8.77(1H,m),9.12(1/2H,d,J=7.8 Hz),9.24(1/2H,d,J=7.8 Hz),
10.22(1/2H,s),10.26(1/2H,s),11.25(1/2H,br s), 11.44(1/2H,br s).
[3874] MS (FAB) m/z: 578(M+H).sup.+.
Example 304
N-((1R,2S,5S)-5-[(Dimethylamino)carbonyl]-2-{[2-(4-fluoroanilino)-2-oxoeth-
anethioyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyri-
dine-2-carboxamide hydrochloride
##STR00970##
[3876] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 424 was treated with
hydrochloric acid for deprotection, followed by condensation with
the compound obtained in Referential Example 10 and treatment with
hydrochloric acid, to thereby give the title compound.
[3877] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.45-1.60(1H,m),1.60-1.80(3H,m),
2.00-2.10(1H,m),2.20-2.35(1H,m),2.79(3H,s),2.93(3H,s),
2.95(3H,s),2.95-3.10(1H,m),3.10-3.30(2H,m),3.40-3.60(1H,m),
3.60-3.80(1H,m),4.35-4.50(1H,m),4.50-4.60(1H,m), 4.60-4.80(2H,m),
7.20(2H,t,J=8.8 Hz), 7.77(2H,dd,J=9.0,5.1 Hz),
8.80(1H,br),10.42(1H,s), 10.93(1H,br), 11.28(1H,br).
[3878] MS (ESI) m/z: 547(M+H).sup.+.
Example 305
N-[(1R,2S,5S)-5-[(Dimethylamino)carbonyl]-2-({2-[(5-fluoropyridin-2-yl)ami-
no]-2-oxoethanethioyl}amino)-cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazo-
lo[5,4-c]-pyridine-2-carboxamide hydrochloride
##STR00971##
[3880] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 427 was treated with
hydrochloric acid for deprotection, followed by condensation with
the compound obtained in Referential Example 10 and treatment with
hydrochloric acid, to thereby give the title compound.
[3881] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.43-1.57(1H,m),1.64-1.87(3H,m), 2.00 (1H, br
s),2.17-2.34(1H,m),2.78(3H,s),2.90(3H,s),
2.95(3H,s),2.95-3.10(1H,m), 3.10-3.30(2H,m), 3.40-3.60(1H,m),
3.68(1H,br s),4.44(1H,br
s),4.45-4.56(1H,m),4.60-4.73(2H,m),7.80-7.90(1H,m),8.08(1H,dd,J=9.1,3.9
Hz), 8.41(1H,d,J=2.9 Hz),8.79(1H,d,J=6.6 Hz),10.49(1H,s),
11.07(1H,br s),11.69(1H,br).
[3882] MS (ESI) m/z: 548(M+H).sup.+.
Example 306
N-{(1R,2S,5S)-2-({2-[(5-Chloropyridin-2-yl)amino]-2-oxoethanethioyl}amino)-
-5-[(dimethylamino)carbonyl]-cyclohexyl}-5-methyl-5H-pyrrolo[3,4-d]thiazol-
e-2-carboxamide
##STR00972##
[3884] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 428 was treated with
hydrochloric acid for deprotection, followed by condensation with
the compound obtained in Referential Example 293, to thereby give
the title compound.
[3885] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.45-1.58(1H,m),1.63-1.73(2H,m),1.73-1.87(2H,m),2.00-2.10(1H,m),2.20-2.35-
(1H,m),2.79(3H,s),
2.95(3H,s),2.96-3.10(1H,m),3.89(3H,s),4.48-4.58(1H,m),4.60-4.70(1H,m),7.0-
5(1H,d,J=1.7 Hz), 7.55(1H,d,J=1.7 Hz),8.00(1H,dd,J=8.9,2.4 Hz),
8.05(1H,d,J=8.9 Hz),8.44(1H,d,J=2.4 Hz),8.71(1H,d,J=7.3 Hz),
10.57(1H,s), 11.13(1H,d,J=7.8 Hz). MS (FAB) m/z:
548(M+H).sup.+.
Example 307
N-{(1R,2S,5S)-2-({2-[(5-Chloropyridin-2-yl)amino]-2-oxoethanethioyl}amino)-
-5-[(dimethylamino)carbonyl]-cyclohexyl}-5-methyl-5,6-dihydro-4H-pyrrolo[3-
,4-d]thiazole-2-carboxamide hydrochloride
##STR00973##
[3887] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 428 was treated with
hydrochloric acid for deprotection, followed by condensation with
the compound obtained in Referential Example 293 in an argon
atmosphere and treatment with hydrochloric acid, to thereby give
the title compound.
[3888] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.42-1.58(1H,m),1.65-1.87(3H,m),
1.97-2.10(1H,m),2.17-2.30(1H,m),2.80(3H,s),2.96(3H,s),
2.98-3.10(1H,m),3.07(3H,s),4.30-5.00(6H,m),8.00-8.10(1H,m),
8.46(1H,d,J=2.4 Hz),8.79(1H,t,J=7.3 Hz),10.54(1H,s),
11.04(1H,d,J=7.8 Hz),12.24(1H,br s).
[3889] MS (ESI) m/z: 550(M+H).sup.+.
Example 308
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-[(1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-({[6-(dimethylamino)-4,5,6,7-tetrahydrobenzothiazol-2-yl]carbonyl}a-
mino)cyclohexyl]-ethanediamide
##STR00974##
[3891] The compound obtained in Referential Example 431 was treated
with hydrochloric acid for deprotection. In a manner similar to
that described in Example 18, the thus-deprotected product was
methylated, followed by treatment with hydrochloric acid, to
thereby give the title compound.
[3892] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.42-1.58(1H,m),1.59-1.80(3H,m),1.90-2.12(3H,m),2.30-2.45(1H,m),2.70-3.00-
(11H,m),2.92(3H,s),
3.00-3.20(2H,m),3.25-3.45(1H,m),3.63-3.80(1H,m),3.88-4.02(1H,m),4.35-4.47-
(1H,m),8.02(1H,s),8.42-8.55(1H,m),
8.60-8.68(1H,m),8.93(1H,dd,J=14.5,8.2 Hz), 9.19(1H,dd,J=17.7,8.2
Hz),10.28(1H,s),10.91(1H,br s).
[3893] MS (ESI) m/z: 576(M+H).sup.+.
Example 309
N-{(1R,2S,5S)-2-[({[(4-Chlorophenyl)sulfonyl]amino}-carbonyl)amino]-5[(dim-
ethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-
pyridine-2-carboxamide hydrochloride
##STR00975##
[3895] 4-Chlorophenylsulfonyl isocyanate (148 .mu.l) was added to a
solution of the compound (328.0 mg) obtained in Referential Example
253 in methylene chloride (10 mL), and the mixture was stirred at
room temperature for 24 hours. The solvent was distilled away under
reduced pressure, and residue was purified by preparative
thin-layer silica gel column chromatography (methylene
chloride:methanol=9:1). The thus-obtained product was dissolved in
ethanol (2 mL) and methylene chloride (2 mL), and 1N HCl in (0.25
mL) was added, followed by stirring at room temperature for 30
minutes. The reaction mixture was concentrated under reduced
pressure, and the residue was solidified with diethyl ether to give
the title compound (104.3 mg).
[3896] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.25-1.45(1H,m),1.45-1.80(5H,m),
2.76(3H,s),2.94(3H,s),2.97(3H,s),3.00-3.80(6H,m),
4.35-4.85(3H,m),6.53(1H,brs),7.66(2H,d,J=8.5 Hz), 7.86(2H,d,J=8.5
Hz),8.50-8.82(1H,m),10.64(1H,br s), 11.10-11.80(1H,br).
[3897] MS (ESI) m/z: 583(M+H).sup.+.
Example 310
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-
amino}cyclohexyl)ethanediamide
##STR00976##
[3899] The title compound was obtained from the compound obtained
in Referential Example 435 and the compound obtained in Referential
Example 10 in a similar manner to Example 2.
[3900] .sup.1H-NMR (CDCl.sub.3) .delta.:
1.60-1.98(3H,m),2.00-2.16(3H,m),
2.52(3H,s),2.78-2.90(3H,m),2.92-2.98(2H,m),2.95(3H,s),
3.06(3H,s),3.69(1H,d,J=15.4 Hz),3.75(1H,d,J=15.4 Hz),
4.07-4.15(1H,m),4.66-4.72(1H,m),7.40(1H,d,J=8.8,0.6 Hz),
7.68(1H,dd,J=8.8,2.4 Hz),8.03(1H,d,J=7.8 Hz), 8.16(1H,dd,J=8.8,0.6
Hz),8.30(1H,dd,J=2.4,0.6 Hz),9.72(1H,s).
[3901] MS (ESI) m/z: 548(M+H).sup.+.
Example 311
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-
amino}cyclohexyl)ethanediamide p-toluenesulfonate monohydrate
##STR00977##
[3903] The compound (6.2 g) obtained in Example 310 is dissolved in
methylene chloride (120 mL), a 1 mol/L ethanol solution (11.28 mL)
of p-toluenesulfonic acid was added to the solution, and the
solvent was distilled away. Ethanol (95 mL) containing 15% water
was added to the residue, and the mixture was stirred at 60.degree.
C. to dissolve it. The solution was then cooled to room temperature
and stirred for a day. Crystals precipitated were collected by
filtration, washed with ethanol and dried at room temperature for 2
hours under reduced pressure to give the title compound (7.4
g).
[3904] .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.45-1.54(1H,m),1.66-1.78(3H,m),2.03-2.10(2H,m),2.28(3H,s),2.79(3H,s),2.9-
1-3.02(1H,m),
2.93(3H,s),2.99(3H,s),3.13-3.24(2H,m),3.46-3.82(2H,m),
3.98-4.04(1H,m),4.43-4.80(3H,m),7.11(2H,d,J=7.8 Hz),
7.46(2H,d,J=8.2 Hz),8.01(2H,d,J=1.8 Hz),8.46(1H,t,J=1.8 Hz),
8.75(1H,d,J=6.9 Hz),9.10-9.28(1H,br),10.18(1H,br), 10.29(1H,s).
[3905] MS (ESI) m/z: 548(M+H).sup.+.
[3906] Elemental analysis:
C.sub.24H.sub.30ClN.sub.7O.sub.4S.C.sub.7H.sub.8O.sub.3S.H.sub.2O.
[3907] Calculated: C;50.43,H;5.46,N;13.28,C1;4.80,S;8.69.
[3908] Found: C;50.25,H;5.36,N;13.32,C1;4.93,S;8.79.
[3909] mp(decomposed): 245-248.degree. C.
Example 312
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(methylamino)-carbon-
yl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]-
amino}cyclohexyl)ethanediamide hydrochloride
##STR00978##
[3911] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 437 was treated with
hydrochloric acid for deprotection, followed by condensation with
the compound obtained in Referential Example 10 and treatment with
hydrochloric acid, to thereby give the title compound.
[3912] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.48-1.61(1H,m),
1.61-1.74(2H,m), 1.74-1.82(1H,m), 1.98-2.12(2H,m), 2.29-2.38(1H,m),
2.53(3H,d,J=4.2 Hz), 2.92(3H,s), 3.10-3.40(4H,br),
3.40-3.80(1H,br), 3.97-4.05(1H,m), 4.28-4.34(1H,m),
4.34-4.80(1H,br), 7.70-7.78(1H,m), 7.97-8.07(2H,m),
8.43-8.50(1H,m), 8.49(1H,br.s), 9.27(1H,d,J=7.8 Hz),
10.26(1H,br.s), 11.48(1H,br.s).
[3913] MS (ESI) m/z: 534[(M+H).sup.+,Cl.sup.35],
535[(M+H).sup.+,Cl.sup.37].
Example 313
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((3R,4S)-1-(2-methoxyacetyl)-3-{[4--
(pyridin-4-yl)benzoyl]amino}piperidin-4-yl)ethanediamide
hydrochloride
##STR00979##
[3915] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 368 was treated with 4N
HCl-dioxane for deprotetcion, followed by condensation with the
compound obtained in Referential Example 237 and treatment with
hydrochloric acid, to thereby give the title compound.
[3916] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.62-1.75(1H,m),
2.00-2.20(1H,m), 2.80-4.40(11H,m), 7.90-8.00(4H,m),
8.05-8.13(2H,m), 8.14-8.43(3H,m), 8.40-8.45(1H,m), 8.87-9.04(3H,m),
10.20-10.50(2H,br).
[3917] MS (FAB) m/z: 551[(M+H).sup.+,Cl.sup.35],
553[(M+H).sup.+,Cl.sup.37].
Example 314
N-{(1R,2S,5S)-5-[(Dimethyamino)carbonyl]-2-({2-[(5-methylpyridin-2-yl)amin-
o]-2-oxoethanethioyl}amino)-cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazol-
o[5,4-c]pyridin-2-carboxamide hydrochloride
##STR00980##
[3919] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 440 was treated with
hydrochloric acid for deprotection, followed by condensation with
the compound obtained in Referential Example 10 and treatment with
hydrochloric acid, to thereby give the title compound.
[3920] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.45-1.60(1H,m),
1.65-1.90(3H,m), 2.00-2.10(1H,m), 2.20-2.40(1H,m), 2.28(3H,s),
2.80(3H,s), 2.91(3H,s), 2.95-3.10(1H,m), 2.96(3H,s),
3.15-3.30(1H,m), 3.32(2H,s), 3.50-3.80(1H,m), 4.45-4.60(2H,m),
4.60-4.80(2H,m), 7.72(1H,d,J=8.5 Hz), 7.97(1H,d,J=8.5 Hz),
8.23(1H,s), 8.83(1H,d,J=7.3 Hz), 10.38(1H,s), 11.06(1H,d,J=7.6 Hz),
11.49(1H,br.s).
[3921] MS (ESI) m/z: 544(M+H).sup.+.
Example 315
N-[(3R,4S)-4-{[2-(4-Chloroanilino)-2-oxoethanethioyl]-amino}-1-(2-methoxya-
cetyl)pyperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2--
carboxamide hydrochloride
##STR00981##
[3923] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 441 was treated with
hydrochloric acid for deprotection, followed by condensation with
the compound obtained in Referential Example 10 and treatment with
hydrochloric acid, to thereby give the title compound.
[3924] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.71-1.82(1H,m),
2.18-2.44(1H,m), 2.89(3H,s), 3.00-4.85(17H,m), 7.41(2H,d,J=8.8 Hz),
7.77(2H,d,J=8.8 Hz), 8.48-8.73(1H,m), 10.48(1H,br.s),
10.90-11.06(1H,m), 11.45-11.90(1H,br).
[3925] MS (ESI) m/z: 565[(M+H).sup.+,Cl.sup.35],
567[(M+H).sup.+,Cl.sup.37].
Example 316
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carbo-
thioyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbon-
yl]amino}-cyclohexyl)ethanediamide hydrochloride
##STR00982##
[3927] In a manner similar to that described in Example 3, the
compound obtained in Referential Example 445 was condensed with the
compound obtained in Referential Example 10, followed by treatment
with hydrochloric acid, to thereby give the title compound.
[3928] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.66-2.15(6H,m),
2.93(3H,s), 3.15-3.40(9H,m), 3.49(1H,br.s), 3.71(1H,br.s),
3.97-4.01(1H,m), 4.42(2H,br.s), 4.70(1H,br.s), 8.01(2H,br.s),
8.46(1H,br.s), 8.78(1H,d,J=6.8 Hz), 9.24(1H,br.s), 10.28(1H,s),
11.29(1H,br.s).
[3929] MS (FAB) m/z: 564[(M+H).sup.+,Cl.sup.35],
566[(M+H).sup.+,Cl.sup.37].
Example 317
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((3R,4S)-1-(2-methoxyethanethioyl)--
3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino-
}-piperidin-4-yl)ethanediamide hydrochloride
##STR00983##
[3931] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 448 was treated with
hydrochloric acid for deprotection, followed by condensation with
the compound obtained in Referential Example 10 and treatment
hydrochloric acid, to thereby give the title compound.
[3932] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.74-1.85(1H,m),
2.13-2.35(1H,m), 2.89(3H,s), 2.95-3.98(9H,m), 4.05-5.33(8H,m),
7.95-8.06(2H,m), 8.43(1H,s), 8.48-8.73(1H,br), 9.29-9.45(1H,br),
10.21-10.34(1H,br), 11.45-11.90(1H,br).
[3933] MS (ESI) m/z: 566[(M+H).sup.+,Cl.sup.35],
568[(M+H).sup.+,Cl.sup.37].
Example 318
2,2,2-Trichloroethyl(1S,3R,4S)-4-({2-[(5-Chloropyridin-2-yl)amino]-2-oxoac-
etyl}amino)-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)ca-
rbonyl]amino}-cyclohexanecarboxylate
##STR00984##
[3935] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 453 was treated with
hydrochloric acid for deprotection, followed by condensation with
the compound obtained in Referential Example 10 and treatment with
hydrochloric acid, to thereby give the title compound.
[3936] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.60-1.87(2H,m),
2.04-2.15(2H,m), 2.21-2.32(2H,m), 2.52(3H,s), 2.73-2.89(3H,m),
2.92-2.98(2H,m), 3.71(1H,d,J=15.4 Hz), 3.73(1H,d,J=15.4 Hz),
4.08-4.16(1H,m), 4.66-4.71(1H,m), 4.72(1H,d,J=12.0 Hz),
4.82(1H,d,J=12.0 Hz), 7.37(1H,d,J=8.8 Hz), 7.69(1H,dd,J=8.8,2.4
Hz), 8.05(1H,d,J=8.1 Hz), 8.16(1H,d,J=8.8 Hz), 8.30(1H,d,J=2.4 Hz),
9.69(1H,s).
[3937] MS (ESI) m/z: 651[(M+H).sup.+,3.times.Cl.sup.35],
653[(M+H).sup.+,2.times.Cl.sup.35,Cl.sup.37], 655
(M+H).sup.+,Cl.sup.35,2.times.Cl.sup.37].
Example 319
(1S,3R,4S)-4-({2-[5-Chloropyridin-2-yl]amino}-2-oxoacetyl)amino)-3-{[(5-me-
thyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-cyclohe-
xane carboxylic acid
##STR00985##
[3939] The compound (475 mg) obtained in Example 318 was dissolved
in tetrahydrofuran (50 mL), zinc (2.85 g) and acetic acid (5.7 mL)
were successively added to the solution, and the mixture was
stirred at room temperature for 3 hours. Celite 545 (2.85 g) was
added to the reaction mixture to remove insoluble matter by
filtration. After the filtrate was concentrated under reduced
pressure, methylene chloride was added to the resultant residue,
and 1N aqueous sodium hydroxide was added with stirring to adjust
the pH of the reaction mixture to 7. After an organic layer was
separated, saturated brine (50 mL) was added to an aqueous layer,
and the mixture was extracted with methylene chloride (10.times.50
mL). The resultant organic layers were combined and dried over
magnesium sulfate anhydrate. The solvent was distilled away under
reduced pressure, and the resultant residue was purified by silica
gel column chromatography (methylene
chloride:methanol=95:5.fwdarw.9:1.fwdarw.4:1) to give the title
compound (140 mg).
[3940] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.50-1.80(3H,m),
1.84-1.95(1H,m), 1.95-2.10(1H,m), 2.15-2.30(1H,m), 2.38(3H,s),
2.40-2.50(1H,m), 2.67-2.80(2H,m), 2.80-2.95(2H,m), 3.66(2H,m),
4.03(1H,br.s), 4.33(1H,br.s), 7.97-8.10(2H,m), 8.45(1H,s),
8.53(1H,d,J=6.8 Hz), 9.19(1H,d,J=8.3 Hz), 10.27(1H,br.s).
[3941] MS (FAB) m/z: 521[(M+H).sup.+,.sup.35Cl],
523[(M+H).sup.+,.sup.37Cl].
Example 320
N-{(1R,2S,5S)-2-{[2-(4-Chloroanilino)-1-methoxyimino-2-oxoethyl]amino}-5-[-
(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,-
4-c]pyridin-2-carboxamide hydrochloride
##STR00986##
[3943] In a manner similar to that described in Referential Example
142, the ester compound obtained in Referential Example 454 was
hydrolyzed. In a manner similar to that described in Referential
Example 143, the resultant product was condensed with
4-chloroaniline, followed by treatment with hydrochloric acid, to
thereby give the title compound.
[3944] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.30-1.17(1H,m),
1.50-1.62(1H,m), 1.62-1.75(2H,m), 1.85-2.00(2H,m), 2.76(3H,s),
2.93(6H,br.s), 3.00-3.10(1H,m), 3.18(1H,br.s), 3.27(1H,br.s),
3.49(1H,br.s), 3.71(1H,br.s), 3.76(3H,s), 3.93(1H,br.s),
4.35-4.50(2H,m), 4.66-4.77(1H,m), 6.09(0.5H,d,J=7.8 Hz),
6.19(0.5H,d,J=7.8 Hz), 7.38(2H,d,J=8.8 Hz), 7.71(2H,d,J=8.8 Hz),
8.70-8.79(1H,m), 10.28(1H,d,J=11.0 Hz), 11.53(0.5H,br.s),
11.45(0.5H,br.s).
[3945] MS (FAB) m/z: 576[(M+H).sup.+,.sup.35Cl],
578[(M+H).sup.+,.sup.37Cl].
Example 321
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-[(1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-({[1-(pyridin-4-yl)piperidin-4-yl]carbonyl}amino)cyclohexyl]ethaned-
iamide hydrochloride
##STR00987##
[3947] In a manner similar to that described in Example 2, the
compound obtained in Referential Example 420 was condensed with
1-(pyridin-4-yl)piperidine-4-carboxylic acid (WO96/10022), followed
by treatment with hydrochloric acid, to thereby give the title
compound.
[3948] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35-1.49(1H,m),
1.49-1.78(6H,m), 1.78-1.98(3H,m), 2.75-2.90(1H,m), 2.78(3H,s),
3.02(3H,s), 3.03-3.14(1H,m), 3.14-3.28(2H,m), 3.74-3.85(1H,m),
4.13-4.30(3H,m), 7.18(2H,d,J=7.3 Hz), 7.99 (2H,s), 8.10-8.23
(3H,m), 8.41 (1H,s), 8.50(1H,d,J=8.1 Hz), 10.19(1H,s),
13.73(1H,br.s).
[3949] MS (FAB) m/z: 556[(M+H).sup.+,.sup.35Cl],
558[(M+H).sup.+,.sup.37Cl].
Example 322
N.sup.1-((1S,2R,4S)-4-[(Dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetr-
ahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-amino}cyclohexyl)-N.sup.2-(5-e-
thynylpyridin-2-yl) ethanediamide
##STR00988##
[3951] The compound (348 mg) obtained in Referential Example 455
was dissolved in tetrahydrofuran (14 mL), tetrabutylammonium
fluoride (1N tetrahydrofuran solution, 628 .mu.l) was added to the
solution, and the mixture was stirred at room temperature for 30
minutes. The reaction mixture was decolored with activated carbon
(about 1 g) and dried over sodium sulfate anhydrate. After
filtration, the solvent was distilled away under reduced pressure,
and the residue was purified by silica gel column chromatography
(methylene chloride:methanol=93:7) and then dissolved in methylene
chloride (about 1 mL). Hexane (about 10 mL) was added to the
solution, and the precipitate formed was collected by filtration to
give the title compound (116 mg).
[3952] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.62-2.14(8H,m),
2.52(3H,s), 2.79-2.95(6H,m), 3.05(3H,s), 3.19(1H,s), [AB pattern
3.71(1H,d,J=15.5 Hz), 3.74(1H,d,J=15.5 Hz)], 4.08-4.14(1H,m),
4.66-4.69(1H,m), 7.41(1H,d,J=8.6 Hz), 7.80(1H,dd,J=8.6,2.2 Hz),
8.03(1H,d,J=7.6 Hz), 8.15(1H,d,J=8.6 Hz), 8.46(1H,d,J=2.2 Hz),
9.75(1H,s).
[3953] MS (ESI) m/z: 538(M+H).sup.+.
Example 323
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-{[(5-methyl-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)carbonyl]amino}-
cyclohexyl)-ethanediamide
##STR00989##
[3955] In a manner similar to that described in Example 191, the
compound obtained in Referential Example 456 was hydrolyzed,
followed by condensation with the compound obtained in Referential
Example 420, to thereby give the title compound.
[3956] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.80-2.15(6H,m),
2.64(3H,s), 2.76-2.79(1H,m), 2.94(3H,s), 3.03(3H,s),
3.84-3.86(2H,m), 3.94-3.99(3H,m), 4.58-4.59(1H,m), 6.70(1H,d,J=6.3
Hz), 7.31(1H,s), 7.70(1H,dd,J=8.8,2.3 Hz), 8.15-8.18(2H,m),
8.30(1H,d,J=2.3 Hz), 9.72(1H,br.s).
[3957] MS (FAB) m/z: 533[(M+H).sup.+,Cl.sup.35],
535[(M+H).sup.+,Cl.sup.37].
Example 324
N-{(1R,2S,5S)-2-({2-[6-Chloropyridazin-3-yl]amino}-2-oxoethanethioyl)amino-
}-5-[(dimethylamino)carbonyl]-cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiaz-
olo[5,4-c]-pyridin-2-carboxamide hydrochloride
##STR00990##
[3959] In a manner similar to that described in Example 3, the
compound obtained in Referential Example 460 was condensed with the
compound obtained in Referential Example 10, followed by treatment
with hydrochloric acid, to thereby give the title compound.
[3960] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.48-1.51(1H,m),
1.71-1.79(3H,m), 2.00(1H,br.s), 2.20-2.23(1H,m), 2.78(3H,s),
2.90(3H,s), 2.96(3H,s), 3.05(1H,br.s), 3.16-3.47(3H,m),
3.69(1H,br.s), 4.43(1H,br.s), 4.53(1H,br.s), 4.69(2H,br.s),
7.97(1H,d,J=9.6 Hz), 8.32(1H,d,J=9.6 Hz), 8.73(1H,d,J=7.3 Hz),
11.08(2H,br.s), 11.61-11.75(1H,m).
[3961] MS (FAB) m/z: 565[(M+H).sup.+,Cl.sup.35],
567[(M+H).sup.+,Cl.sup.37].
Example 325
N-{(1R,2S,5S)-2-({2-[(6-Chloropyridin-3-yl)amino]-2-oxoethanethioyl}amino)-
-5-[(dimethylamino)carbonyl]-cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazo-
lo[5,4-c]pyridin-2-carboxamide hydrochloride
##STR00991##
[3963] In a manner similar to that described in Example 3, the
compound obtained in Referential Example 464 was condensed with the
compound obtained in Referential Example 10, followed by treatment
with hydrochloric acid, to thereby give the title compound.
[3964] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.47-1.55(1H,m),
1.66-1.78(3H,m), 2.02-2.05(1H,m), 2.21-2.33(1H,m), 2.79(3H,s),
2.91(3H,s), 2.95(3H,s), 2.99-3.04(1H,m), 3.21(2H,br.s),
3.45-3.75(2H,br), 4.40-4.75 (4H,m), 7.53(1H,d,J=8.6 Hz),
8.20(1H,dd,J=8.6,2.6 Hz), 8.77(1H,d,J=7.3 Hz), 8.80(1H,d,J=2.6 Hz),
10.73(1H,s), 10.94(1H,br.d,J=7.6 Hz), 11.37(1H,br.s).
[3965] MS (FAB) m/z: 564[(M+H).sup.+,Cl.sup.35],
566[(M+H).sup.+,Cl.sup.37].
Example 326
N.sup.1-[(3R,4S)-3-({[2'-(Aminosulfonyl)[1,1'-biphenyl]-4-yl]-carbonyl}ami-
no)-1-(2-methoxyacetyl)piperidin-4-yl]-N.sup.2-(5-chloropyridin-2-yl)ethan-
ediamide
##STR00992##
[3967] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 368 was treated with
hydrochloric acid for deprotection, followed by condensation with
the compound obtained in Referential Example 465, to thereby give
the title compound.
[3968] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.59-1.85(1H,m),
2.09-2.23(1H,m), 2.88-3.13(1H,m), 3.29-3.51(4H,m), 4.06-4.20(4H,m),
4.51-4.78(4H,m), 7.09(0.25H,br.s), 7.30(1H,d,J=7.1 Hz),
7.51-7.54(3.75H,m), 7.60(1H,t,J=7.0 Hz), 7.69(1H,dd,J=8.9,2.2 Hz),
7.94-7.96(2H,m), 8.13-8.22(2H,m), 8.30(1H,d,J=2.2 Hz),
8.91(0.75H,br.d,J=5,9 Hz), 9.18(0.25H,br.s), 9.70(1H,s).
[3969] MS (FAB) m/z: 629[(M+H).sup.+,Cl.sup.35],
631[(M+H).sup.+,Cl.sup.37]
Example 327
N.sup.1-(5-Chloropyridin-2-yl)-N.sup.2-{(1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-[(thieno[3,2-b]pyridin-2-yl-carbonyl)amino]cyclohexyl}ethanediamide
hydrochloride
##STR00993##
[3971] In a manner similar to that described in Example 2, the
compound obtained in Referential Example 420 was condensed with
lithium thieno[3,2-b]pyridin-2-carboxylate (Japanese Patent
Application Laid-Open (kokai) No. 2001-294572), followed by
treatment with hydrochloric acid, to thereby give the title
compound.
[3972] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.44-1.57(1H,m),
1.62-1.84(3H,m), 1.86-1.98(1H,m), 2.04-2.19(1H,m), 2.78(3H,s),
2.99(3H,s), 3.11-3.25(1H,m), 3.85-4.10(1H,br), 4.44-4.55(1H,br),
7.51-7.62(1H,m), 7.98(2H,br.s), 8.43(2H,br.s), 8.60(1H,s),
8.66(1H,br.d,J=8.1 Hz), 8.81(1H,br.d,J=4.2 Hz), 9.05(1H,br.d,J=7.8
Hz), 10.24(1H,s).
[3973] MS (ESI) m/z: 529[(M+H).sup.+,Cl.sup.35],
531[(M+H).sup.+,Cl.sup.37].
Example 328
N.sup.1-((1S,2R,4S)-4-[(dimethylamino)carbonyl)-2-([(5-methyl-4,5,6,7-tetr-
ahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N.sup.2-(5-me-
thylpyridin-2-yl)ethanediamide hydrochloride
##STR00994##
[3975] In a manner similar to that employed in Example 208, the
title compound was prepared from the compound obtained in
Referential Example 467 and the compound obtained in Referential
Example 253.
[3976] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.42-1.57 (1H, m),
1.60-1.80(3H, m), 1.95-2.15(2H, m), 2.28(3H, s), 2.78(3H, s),
2.90-3.10(1H, m), 2.92(3H, s), 2.94(3H, s), 3.07-3.38(2H, m),
3.40-3.58(1H, br), 3.60-3.80(1H, m), 3.95-4.05(1H, m),
4.36-4.50(2H, m), 4.66-4.80(1H, m), 7.73(1H, d, J=8.0 Hz),
7.90-7.94(1H, m), 8.24(1H, s), 8.70-8.80(1H, m), 9.13(0.5H, d,
J=7.3 Hz), 9.21(0.5H, d, J=8.0 Hz), 10.06(1H, s), 11.46(0.5H,
br.s), 11.57(0.5H, br.s). MS(FAB)m/z: 528(M+H).sup.+.
Example 329
N.sup.1-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetr-
ahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N.sup.2-(4-me-
thylphenyl)ethanediamide hydrochloride
##STR00995##
[3978] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 469 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 10, and
the product was again treated with hydrochloric acid, whereby the
title compound was obtained.
[3979] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.42-1.55(1H, m),
1.60-1.80(3H, m), 1.95-2.15(2H, m), 2.26(3H, s), 2.79(3H, s),
2.93(7H, br.s), 3.07-3.35(2H, m), 3.40-3.55(1H, m), 3.65-3.77(1H,
m), 3.95-4.06(1H, m), 4.38-4.52(2H, br), 4.67-4.80(1H, m), 7.13(2H,
d, J=8.3 Hz), 7.66(2H, d, J=8.3 Hz), 8.72-8.80(1H, m), 8.96(0.5H,
d, J=7.8 Hz), 9.04(0.5H, d, J=8.1 Hz), 10.56(1H, d, J=6.6 Hz),
11.30(1H, br.s). MS(FAB)m/z: 527(M+H).sup.+.
Example 330
{4-chloro-5-[({(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}-
amino)-5-[(dimethylamino)carbonyl]cyclohexyl}amino)carbonyl]-3-thienyl}met-
hyl(methyl)carbamic acid tert-butyl ester
##STR00996##
[3981] In a manner similar to that employed in Example 2, the
compound obtained in Referential Example 471 was condensed with the
compound obtained in Referential Example 420, to thereby yield the
title compound.
[3982] .sup.1H-NMR(CDCl.sub.3).delta.: 1.48(9H, s), 1.50-1.70(1H,
m), 1.80-2.00(2H, m), 2.00-2.12(2H, m), 2.14-2.22(1H, m),
2.72-2.83(1H, m), 2.88, 2.89(total 3H, each s), 2.96(3H, s),
3.04(3H, s), 4.05-4.15(1H, m), 4.32-4.50(1H, m), 4.73-4.80(1H, m),
7.22(1H, d, J=8.8 Hz), 7.38(1H, br.s), 7.69(1H, dd, J=8.8, 2.6 Hz),
7.99(1H, d, J=7.6 Hz), 8.17 (1H, d, J=8.8 Hz), 8.31 (1H, d, J=2.6
Hz), 9.70(1H, br.s).
[3983] MS(ESI)m/z: 655(M+H).sup.+.
Example 331
N.sup.1-{(1S,2R,4S)-2-[({3-chloro-4-[(methylamino)methyl]-2-thienyl}carbon-
yl)amino]-4-[(dimethylamino)carbonyl]cyclohexyl}-N.sup.2-(5-chloropyridin--
2-yl)ethanediamide
##STR00997##
[3985] In a manner similar to that employed in Example 227, the
title compound was prepared from the compound obtained in Example
330.
[3986] .sup.1H-NMR(CDCl.sub.3).delta.: 1.55-1.70(1H, m),
1.75-1.98(2H, m), 2.00-2.22(2H, m), 2.22-2.32(1H, m), 2.52(3H, s),
2.72-2.86(1H, m), 2.96(3H, s), 3.05(3H, s), 3.53-3.82(1H, m),
3.78(2H, s), 4.05-4.16(1H, m), 4.72-4.80(1H, m), 7.27(1H, d, J=7.8
Hz), 7.52(1H, s), 7.67(1H, dd, J=8.8, 2.6 Hz), 8.09(1H, d, J=7.6
Hz), 8.09(1H, d, J=7.6 Hz), 8.13(1H, d, J=8.8 Hz), 8.29(1H, d,
J=2.6 Hz), 9.90-11.00(1H, br).
[3987] MS(ESI)m/z: 555(M+H).sup.+.
Example 332
N.sup.1-{(1S,2R,4S)-2-{[(3-chloro-4-[4,5-dihydro-1,3-oxazol-2-yl(methyl)am-
ino]methyl}-2-thienyl)carbonyl]amino}-4-[(dimethylamino)carbonyl]cyclohexy-
l}-N.sup.2-(5-chloropyridin-2-yl)ethanediamide hydrochloride
##STR00998##
[3989] To a suspension of the compound obtained in Example 331 (590
mg) in methylene chloride (20 mL) were added triethylamine (0.735
mL) and 2-bromoethylisocyanate (0.106 mL), and the mixture was
stirred for 18 hours at room temperature. The reaction mixture was
diluted with methylene chloride, and the diluted solution was
washed sequentially with water, 0.5N hydrochloric acid, water,
saturated aqueous sodium bicarbonate, and saturated brine. The
resultant organic layer was dried over sodium sulfate anhydrate and
concentrated under reduced pressure. The residue was purified
through silica gel flash column chromatography (methylene
chloride:methanol=20:1), and the solvent was removed under reduced
pressure. The crude product was dissolved in methylene chloride (2
mL) and ethanol (3 mL), and 1N HCl in ethanol (0.5 mL) was added
thereto, followed by stirring for 30 minutes at room temperature
and concentration under reduced pressure. Diethyl ether was added
to the residue, and the precipitated solid was collected through
filtration and washed, to thereby yield the title compound (197 mg)
as a colorless powder.
[3990] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.45-1.60(1H, m),
1.60-1.83(3H, m), 1.85-2.02(3H, m), 2.80(3H, s), 2.84(3H, s),
2.90-3.01(1H, m), 2.97(3H, s), 3.25-3.40(2H, m), 3.60(2H, t, J=6.6
Hz), 3.95-4.05(1H, m), 4.30-4.45(3H, m), 6.80(1H, t, J=5.5 Hz),
7.51(1H, s), 7.94-8.06(2H, m), 8.10(1H, d, J=6.8 Hz), 8.42-8.50(1H,
m), 8.97(1H, d, J-8.6 Hz), 10.27(1H, s).
[3991] MS(ESI)m/z: 624(M+H).sup.+.
Example 333
[4-chloro-5-({[(1R,2S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}ami-
no)cyclohexyl]amino}carbonyl)-3-thienyl]methyl(methyl)carbamic acid
tert-butyl ester
##STR00999##
[3993] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 472 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 471,
whereby the title compound was obtained.
[3994] .sup.1H-NMR(CDCl.sub.3)5:1.15-2.00(6H, m), 1.46(9H, s),
2.87(3H, s), 4.15-4.25(1H, m), 4.30-4.45(2H, m), 4.48-4.56(1H, m),
7.20(1H, d, J=8.1 Hz), 7.27-7.32(1H, m), 7.70(1H, dd, J-8.8, 2.2
Hz), 8.01(1H, d, J=8.3 Hz), 8.18(1H, d, J=8.8 Hz), 8.30(1H, d,
J=2.6 Hz), 9.73(1H, br.s).
[3995] MS(ESI)m/z: 584(M+H).sup.+.
Example 334
N.sup.1-{(1S,2R)-2-[({3-chloro-4-[(methylamino)methyl]-2-thienyl}carbonyl)-
amino]cyclohexyl}-N.sup.2-(5-chloropyridin-2-yl)ethanediamide
##STR01000##
[3997] In a manner similar to that employed in Example 227, the
title compound was prepared from the compound obtained in Example
333.
[3998] .sup.1H-NMR(CDCl.sub.3).delta.: 1.48-2.02(8H, m), 2.46(3H,
s), 3.72(2H, s), 4.15-4.25(1H, m), 4.45-4.55(1H, m), 7.22(1H, d,
J=8.1 Hz), 7.42(1H, s), 7.71(1H, dd, J=8.8, 2.6 Hz), 8.03(1H, d,
J=9.3 Hz), 8.19(1H, dd, J=8.8, 0.73 Hz), 8.31(1H, dd, J=2.6, 0.73
Hz).
[3999] MS(ESI)m/z: 484(M+H).sup.+.
Example 335
N.sup.1-((1S,2R)-2-{[(3-chloro-4-{[4,5-dihydro-1,3-oxazol-2-yl(methyl)amin-
o]methyl}-2-thienyl)carbonyl]amino}cyclohexyl)-N.sup.2-(5-chloropyridin-2--
yl)ethanediamide
##STR01001##
[4001] In a manner similar to that employed in Example 332, the
title compound was prepared from the compound obtained in Example
334.
[4002] .sup.1H-NMR(CDCl.sub.3) .delta.: 1.50-2.00(8H, m), 2.94(3H,
s), 3.80(2H, t, J=8.5 Hz), 4.17-4.25(1H, m), 4.32(2H, t, J=8.5 Hz),
4.39(1H, d, J=16.5 Hz), 4.41(1H, d, J=16.5 Hz), 4.58-4.67(1H, m),
7.18(1H, d, J=8.3 Hz), 7.40(1H, s), 7.69(1H, dd, J=8.8, 2.4 Hz),
8.00(1H, d, J=8.1 Hz), 8.17 (1H, d, J=8.8 Hz), 8.29(1H, d, J-2.4
Hz), 9.73(1H, br.s).
[4003] MS(ESI)m/z: 553(M+H).sup.+.
Example 336
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-((1R,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-{[(5-methyl-5,6,7,8-tetrahydro-4H-thiazolo[5,4-c]azepin-2-yl)carbon-
yl]amino}cyclohexyl)ethanediamide hydrochloride
##STR01002##
[4005] In a manner similar to that employed in Example 2, the
compound obtained in Referential Example 477 was condensed with the
compound obtained in Referential Example 420, and the product was
treated with hydrochloric acid, to thereby yield the title
compound.
[4006] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.42-1.58 (1H, m),
1.60-1.84(3H, m), 1.85-2.15(4H, m), 2.79(6H, br.s), 2.93(4H, br.s),
3.05-3.25(2H, m), 3.49(1H, br.s), 3.63(1H, br.s), 3.95-4.05(1H, m),
4.42(1H, br.s), 4.64(1H, br.s), 4.78(1H, br.s), 8.01(2H, br.s),
8.46(1H, br.s), 8.65(1H, d, J=7.3 Hz), 9.19(1H, d, J-8.1 Hz),
10.29(1H, s), 10.64(1H, br.s).
[4007] MS(FAB)m/z: 562(M+H).sup.+.
Example 337
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-{[(4,4,5-trimethyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbon-
yl]amino}cyclohexyl)ethanediamide hydrochloride
##STR01003##
[4009] In a manner similar to that employed in Referential Example
10,
4,4,5-trimethyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-carboxylic
acid lithium salt was prepared from the compound obtained in
Referential Example 479.
[4010] Subsequently, in a manner similar to that employed in
Example 2, the lithium salt was condensed with the compound
obtained in Referential Example 420, and the product was treated
with hydrochloric acid, to thereby give the title compound.
[4011] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.45-1.55(4H, m),
1.60-1.85(6H, m), 1.85-2.10(2H, m), 2.78(3H, s), 2.85-3.08(7H, m),
3.93-4.05(1H, br), 4.41-4.53(1H, br), 4.52-4.68(1H, br),
4.70-4.83(1H, br), 8.01(2H, br.s), 8.45(1H, br.s), 8.63(0.5H, d,
J=7.6 Hz), 8.68(0.5H, d, J=7.6 Hz), 9.07-9.20(1H, m), 10.29(0.5H,
s), 10.26(0.5H, s), 11.83(0.5H, br.s), 11.76(0.5H, br.s).
[4012] MS(FAB)m/z: 562(M+H).sup.+.
Example 338
6-[({(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-[-
(dimethylamino)carbonyl]cyclohexyl}amino)carbonyl]-1,3-dihydro-2H-pyrrolo[-
3,4-c]pyridine-2-carboxylic acid tert-butyl ester
##STR01004##
[4014] In a manner similar to that employed in Example 2, the
compound obtained in Referential Example 481 was condensed with the
compound obtained in Referential Example 420, to thereby yield the
title compound.
[4015] .sup.1H-NMR(CDCl.sub.3).delta.: 1.53(4.5H, s), 1.61(4.5H,
s), 1.54-2.20(6H, m), 2.76-2.90, (1H, m), 2.96(3H, s), 3.07(3H, s),
4.05-4.15(1H, m), 4.46-4.85(5H, m), 7.67(1H, dd, J=8.8, 2.3 Hz),
8.10-8.23(3H, m), 8.30(1H, d, J=2.3 Hz), 8.30-8.40(1H, m),
8.45(0.5H, br.s), 8.49(0.5H, br.s), 9.72(1H, br.s).
[4016] MS(ESI)m/z: 614(M+H).sup.+.
Example 339
N.sup.1-(5-chloro-2-pyridinyl)-N.sup.2-{(1S,2R,4S)-2-[(2,3-dihydro-1H-pyrr-
olo[3,4-c]pyridine-6-ylcarbonyl)amino]-4-[(dimethylamino)carbonyl]cyclohex-
yl}ethanediamide hydrochloride
##STR01005##
[4018] In a manner similar to that employed in Example 227, the
title compound was prepared from the compound obtained in Example
338.
[4019] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.45-1.61 (1H, m),
1.62-1.84(3H, m), 1.95-2.10(2H, m), 2.78(3H, s), 2.79-2.90(1H, m),
2.90(3H, s), 3.90-4.15(1H, m), 4.45-4.53(1H, br), 4.55-4.68(4H, m),
8.00 (2H, br.s), 8.10(1H, s), 8.45(1H, d, J=1.5 Hz), 8.67(1H, d,
J=7.6 Hz), 8.75(1H, s), 9.19(1H, d, J=8.3 Hz), 10.11(2H, br.s),
10.26(1H, br.s).
[4020] MS(FAB)m/z: 514(M+H).sup.+.
Example 340
N.sup.1-(5-chloro-2-pyridinyl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-{[(2-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl)carbonyl]ami-
no}cyclohexyl)ethanediamide hydrochloride
##STR01006##
[4022] In a manner similar to that employed in Example 18, the
title compound was prepared from the compound obtained in Example
339 and formalin.
[4023] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.45-1.59(1H, m),
1.60-1.85(3H, m), 1.91-2.10(2H, m), 2.78(3H, br.s), 2.80-2.90(1H,
m), 2.90(1.5H, s), 2.92(1.5H, s), 3.01(1.5H, s), 3.02(1.5H, s),
3.90-4.05(1H, m), 4.42-4.60(3H, m), 4.80-5.00(2H, m), 8.00(2H,
br.s), 8.11(1H, s), 8.44(1H, d, J=1.5 Hz), 8.60-8.70(1H, m),
8.75(1H, s), 9.18(1H, d, J=7.8 Hz), 10.25(0.5H, s), 10.28(0.5H, s),
11.95(0.5H, s), 12.02(0.5H, s).
[4024] MS(FAB)m/z: 528(M+H).sup.+.
Example 341
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-{(1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-[(5,6,7,8-tetrahydro[1,6]naphthyridin-2-ylcarbonyl)amino]cyclohexyl-
}ethanediamide hydrochloride
##STR01007##
[4026] In a manner similar to that employed in Example 2, a lithium
salt of a carboxylic acid prepared by hydrolyzing
6-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro[1,6]naphthyridine-2-carboxylic
acid methyl ester (Japanese Patent Application Laid-Open (kokai)
No. 2000-119253) was condensed with the compound obtained in
Referential Example 420, and the product was treated with
hydrochloric acid, to thereby give the title compound.
[4027] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.45-1.62 (1H, m),
1.62-1.87(3H, m), 1.89-2.05(2H, m), 2.80(3H, s), 2.81-2.94(1H, m),
2.95(3H, s), 3.15-3.35(2H, m), 3.51(2H, br.s), 3.90-4.05(1H, m),
4.38(2H, br.s), 4.43-4.55(1H, m), 7.88(2H, br.s), 8.01(2H, br.s),
8.45(1H, d, J=1.5 Hz), 8.51(1H, d, J=8.3 Hz), 9.16(1H, J=7.8 Hz),
9.85(1H, br.s), 10.02(1H, br.s), 10.27(1H, br.s).
[4028] MS(FAB)m/z: 528(M+H).sup.+.
Example 342
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-{[(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-2-yl)carbonyl]amino-
}cyclohexyl)ethanediamide hydrochloride
##STR01008##
[4030] In a manner similar to that employed in Example 18, the
title compound was prepared from the compound obtained in Example
341 and formalin.
[4031] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.45-1.62(1H, m),
1.63-1.80(3H, m), 1.86-2.06(2H, m), 2.80(3H, br.s), 2.81-2.96(7H,
m), 3.14-3.27(1H, m), 3.11-3.63(2H, m), 3.76(1H, br.s), 3.99(1H,
br.s), 4.35-4.52(2H, m), 4.53-4.65(1H, m), 7.84(1H, J=8.0 Hz),
7.89(1H, J=8.0 Hz), 8.00(2H, br.s), 8.40-8.55(2H, m), 9.07(0.4H, d,
J=7.6 Hz), 9.19(0.6H, d, J=8.1 Hz), 10.24(0.6H, s), 10.28(0.4H, s),
11.42-11.80(1H, br).
[4032] MS(FAB)m/z: 542(M+H).sup.+.
Example 343
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-[(1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-({[5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl}amino)cyclohexyl]ethaned-
iamide hydrochloride
##STR01009##
[4034] In a manner similar to that employed in Example 2, the
compound obtained in Referential Example 420 was condensed with the
compound obtained in Referential Example 483, and the product was
treated with hydrochloric acid, to thereby yield the title
compound.
[4035] .sup.1H-NMR(DMSO-d05:1.50-1.63 (1H, m), 1.67-1.85(3H, m),
1.95-2.12(2H, m), 2.80(3H, s), 2.86-2.95(1H, m), 2.95(3H, s),
4.00-4.10(1H, m), 4.45-4.55(1H, m), 8.01(2H, br.s), 8.34(2H, d,
J=5.6 Hz), 8.44-8.47(1H, m), 8.79(1H, d, J=7.6 Hz), 8.99(2H, d,
J=5.6 Hz), 9.08(1H, d, J=8.3 Hz), 9.54(2H, s), 10.31(1H, s).
[4036] MS(FAB)m/z: 551(M+H).sup.+.
Example 344
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-{(1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-[({2'-[(dimethylamino)methyl][1,1'-biphenyl]-4-yl}carbonyl)amino]cy-
clohexyl}ethanediamide hydrochloride
##STR01010##
[4038] In a manner similar to that described in Example 2, the
compound obtained in Referential Example 420 was condensed with the
compound obtained in Referential Example 488, and the product was
treated with hydrochloric acid, whereby the title compound was
obtained.
[4039] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.45-1.56(1H, m),
1.60-1.85(3H, m), 1.85-2.15(2H, m), 2.40-2.55(6H, m), 2.80(3H, s),
2.99(3H, s), 3.05-3.20(1H, m), 3.93-4.06(1H, m), 4.25-4.33(2H, m),
4.45-4.55(1H, m), 7.30-7.37(1H, m), 7.48(2H, d, J=8.3 Hz),
7.50-7.58(2H, m), 7.84-7.90(1H, m), 7.95-8.05(4H, m), 8.15(1H, d,
J=7.3 Hz), 8.46(1H, br.s), 9.20(1H, d, J=8.3 Hz), 10.15-10.29(1H,
br), 10.30(1H, br.s).
[4040] MS(FAB)m/z:605(M+H).sup.+.
Example 345
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-[(1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-({4-[2-(hydroxymethyl)pyridin-4-yl]benzoyl}amino)
cyclohexyl]ethanediamide hydrochloride
##STR01011##
[4042] In a manner similar to that employed in Example 2, a lithium
salt of a carboxylic acid prepared by hydrolyzing the compound
obtained in Referential Example 490 was condensed with the compound
obtained in Referential Example 420, and the product was treated
with hydrochloric acid, to thereby give the title compound.
[4043] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.44-1.58 (1H, m),
1.63-1.81(3H, m), 1.89-1.99(1H, m), 1.99-2.13(1H, m), 2.79(3H, s),
2.97(3H, s), 3.06-3.17(1H, m), 3.93-4.02(1H, m), 4.44-4.51(1H, m),
4.89(2H, s), 7.99(2H, s), 8.08(4H, m), 8.19(1H, d, J=6.3 Hz),
8.24(1H, d, J=7.3 Hz), 7.29(1H, s), 8.44-8.46(1H, m), 8.80(1H, d,
J=5.9 Hz), 9.01(1H, d, J=8.3 Hz), 10.27(1H, s).
[4044] MS(ESI)m/z:579(M+H).sup.+.
Example 346
N.sup.1-{(1S,2R,4S)-2-({4-[2-(aminomethyl)pyridin-4-yl]benzoyl}amino)-4-[(-
dimethylamino)carbonyl]cyclohexyl}-N.sup.2-(5-chloropyridin-2-yl)ethanedia-
mide hydrochloride
##STR01012##
[4046] In a manner similar to that employed in Example 2, a lithium
salt of a carboxylic acid prepared by hydrolyzing the compound
obtained in Referential Example 491 was condensed with the compound
obtained in Referential Example 420, and the product was treated
with hydrochloric acid, to thereby give the title compound.
[4047] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.40-1.58(1H, m),
1.58-1.83(3H, m), 1.87-1.98(1H, m), 1.98-2.13(1H, m), 2.78(3H, s),
2.97(3H, s), 3.05-3.17(1H, m), 3.93-4.03(1H, m), 4.17-4.30(2H, m),
4.40-4-50(1H, m), 7.80(1H, dd, J=5.2, 1.6 Hz), 7.90-8.06(7H, m),
8.18(1H, d, J=7.6 Hz), 8.43-8.46(1H, m), 8.50(3H, br.s), 8.70(1H,
d, J=5.2 Hz), 9.01(1H, d, J=8.5 Hz), 10.27(1H, s).
[4048] MS(ESI)m/z:578(M+H).sup.+.
Example 347
N.sup.1-(5-chloropyridin-2-yl) -N.sup.2-[(1S,2R,4S)
-4-[(dimethylamino)carbonyl]-2-({[1-(phenylsulfonyl)piperidin-4-yl]carbon-
yl}amino)cyclohexyl]ethanediamide
##STR01013##
[4050] In a manner similar to that employed in Example 2, the
compound obtained in Referential Example 420 was condensed with the
compound obtained in Referential Example 493, to thereby yield the
title compound.
[4051] .sup.1H-NMR(CDCl.sub.3).delta.:1.60-2.10(10H, m),
2.12-2.21(1H, m), 2.40(2H, br.t, J=11.2 Hz), 2.65-2.77(1H, m),
2.92(3H, s), 2.99(3H, s), 3.77(2H, br.d, J=11.7 Hz), 3.92-4.05(1H,
m), 4.42-4.53(1H, m), 6.31(1H, br.d, J=7.3 Hz), 7.53(2H, t, J=7.3
Hz), 7.62(1H, t, J=7.3 Hz), 7.67-7.78(3H, m), 8.01(1H, brd, J=7.3
Hz), 8.16(1H, d, J=8.8 Hz), 8.31(1H, d, J=2.2 Hz), 9.72(1H, s).
[4052] MS(ESI)m/z:619(M+H).sup.+.
Example 348
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-[(1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-({([1-(4-fluorobenzoyl)piperidin-4-yl]carbonyl}amino)cyclohexyl]eth-
anediamide D22-5792
##STR01014##
[4054] In a manner similar to that employed in Example 2, the
compound obtained in Referential Example 420 was condensed with the
compound obtained in Referential Example 495, to thereby yield the
title compound.
[4055] .sup.1H-NMR(CDCl.sub.3).delta.:1.60-2.16(10H, m),
2.37-2.48(1H, m), 2.64-2.78(1H, m), 2.80-3.13(2H, m), 2.94(3H, s),
3.02(3H, s), 3.65-4.18(1H, br), 3.93-4.01(1H, m), 4.43-4.80(2H,
br), 6.32(1H, br.d, J=7.1 Hz), 7.09(2H, t, J=8.5 Hz), 7.40(2H, dd,
J=8.5, 5.4 Hz), 7.71(1H, dd, J=8.8, 2.4 Hz), 8.04(1H, br.d, J=7.6
Hz), 8.15(1H, d, J=8.8 Hz), 8.30(1H, d, J=2.4 Hz), 9.71(1H, s).
[4056] MS(ESI)m/z:601(M+H).sup.+.
Example 349
N.sup.1-(5-chloropyridin-2-yl) -N.sup.2-((1S,2R,4S)
-4-[(dimethylamino)carbonyl]-2-([4-(pyrrolidin-1-ylcarbonyl)benzoyl]amino-
}cyclohexyl)ethanediamide
##STR01015##
[4058] In a manner similar to that employed in Example 2, the
compound obtained in Referential Example 420 was condensed with the
compound obtained in Referential Example 497, to thereby yield the
title compound.
[4059] .sup.1H-NMR(CDCl.sub.3).delta.:1.68-2.23(9H, m), 2.33(1H,
br.d, J=7.4 Hz), 2.85-3.02(1H, m), 2.92(3H, s), 2.98(3H, s),
3.31(2H, t, J=6.8 Hz), 3.61(2H, t, J=6.8 Hz), 4, 13-4.22(1H, m),
4.54-4.63(1H, m), 7.28(2H, d, J=8.1 Hz), 7.63-7.69(1H, m), 7.66(2H,
d, J=8.1 Hz), 7.95(1H, br.d, J=5.6 Hz), 8.05(1H, d, J=8.8 Hz),
8.30(1H, d, J=2.4 Hz), 8.54(1H, brd, J=8.3 Hz), 9.76(1H, s).
[4060] MS(ESI)m/z:569(M+H).sup.+.
Example 350
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)
-4-[(dimethylamino)carbonyl)-2-{[4-(pyrrolidin-1-ylmethyl)benzoyl]amino}c-
yclohexyl)ethanediamide hydrochloride
##STR01016##
[4062] In a manner similar to that employed in Example 2, a lithium
salt of a carboxylic acid prepared by hydrolyzing the compound
obtained in Referential Example 498 was condensed with the compound
obtained in Referential Example 420, and the product was treated
with hydrochloric acid, to thereby give the title compound.
[4063] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.43-1.57(1H, m),
1.62-2.10(9H, m), 2.78(3H, s), 2.95(3H, s), 2.96-3.12(3H, m),
3.28-3.50(2H, m), 3.92-4.01(1H, m), 4.35-4.48(3H, m), 7.69(2H, d,
J=8.1 Hz), 7.92(2H, d, J=8.1 Hz), 7.99(2H, s), 8.09(1H, br.d, J=7.6
Hz), 8.44(1H, s), 8.99(1H, br.d, J=8.3 Hz), 10.27(1H, s),
10.65-10.80(1H, br).
[4064] MS(ESI)m/z:555(M+H).sup.+.
Example 351
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)
-4-[(methylamino)carbothioyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,-
4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide
hydrochloride
##STR01017##
[4066] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 501 was treated with 4N
HCl-dioxane for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 10, and
the product was again treated with hydrochloric acid, whereby the
title compound was obtained.
[4067] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.60-2.18(6H, m),
2.70-2.95(4H, m), 2.90(3H, s), 3.06-3.40(2H, m), 3.42-3.54(1H, br),
3.62-3.78(1H, br), 3.96-4.05(1H, m), 4.24-4.34(1H, br),
4.35-4.52(1H, br), 4.60-4.76(1H, m), 7.96-8.04(2H, m), 8.43(1H, s),
8.48-8.60(1H, br), 9.39(1H, br.d, J=7.8 Hz), 9.91-10.03(1H, br),
10.18-10.30(1H, m), 11.72-11.95(1H, br).
[4068] MS(ESI)m/z:550(M+H).sup.+.
Example 352
N-{(1R,2S,5S)-2-{[(4-chloroanilino)sulfonyl]amino}-5-[(dimethylamino)carbo-
nyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbo-
xamide hydrochloride
##STR01018##
[4070] To a solution of 4-chloroaniline (255 mg) in methylene
chloride (15 mL), chlorosulfuric acid (146 .mu.L) was added at
0.degree. C. The mixture was stirred for 1 hour at 0.degree. C. and
then for 2 hours at room temperature. Phosphorus pentachloride (458
mg) was added to the reaction mixture, followed by heating under
reflux for 2 hours. The mixture was cooled to room temperature, and
the compound obtained in Referential Example 253 (731 mg) was added
thereto. The pH of the mixture was adjusted to be neutral with
triethylamine. The resultant mixture was stirred for 17 hours at
room temperature, and water was added to the reaction mixture to
partition the mixture. The formed aqueous layer was extracted with
methylene chloride, and the organic layers were combined together,
followed by washing twice with water and drying over sodium sulfate
anhydrate. The solvent was removed under reduced pressure, and the
residue was purified through silica gel flash column chromatography
(methylene chloride:methanol=93:7) and then twice through
fractional thin-layer chromatography (methylene
chloride:methanol=9:1), to thereby yield a pale yellow solid
product (46 mg). The product was dissolved in methylene chloride,
and 1N HCl in ethanol (83 .mu.L) was added thereto. The solvent was
removed under reduced pressure, and small amounts of methanol and
ether were added thereto. The precipitate was collected through
filtration, to thereby yield the title compound (34 mg) as a pale
yellow solid.
[4071] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.34-1.69(5H, m), 1.98(1H,
br.$), 2.75(3H, s), 2.85-2.94(8H, m), 3.17(2H, br.s), 3.50(1H,
br.s), 3.69(1H, br.s), 4.39-4.50(2H, m), 4.69(1H, br.s),
7.08-7.15(4H, m), 7.74(1H, br.s), 7.98(1H, br.s), 9.90(1H, s),
11.35(1H, br.s).
[4072] MS(FAB)m/z:555(M+H).sup.+.
Example 353
N-((1R,2S,5S)-2-({2-[(5-chloropyrimidin-2-yl)amino]-2-oxoethanethioyl}amin-
o)-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiaz-
olo[5,4-c]pyridine-2-carboxamide hydrochloride
##STR01019##
[4074] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 503 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 10, and
the product was again treated with hydrochloric acid, whereby the
title compound was obtained.
[4075] .sup.1H-NMR(DMSO).delta.:1.49-1.54(1H, m), 1.68-1.79(3H, m),
1.99-2.02(1H, m), 2.16-2.22(1H, m), 2.80(3H, s), 2.91(3H, s),
2.97(3H, s), 3.06(1H, br.s), 3.20(2H, br.s), 3.49(1H, br.s),
3.64(1H, br.s), 4.40-4.55(2H, m), 4.70(2H, br.s), 8.68(1H, d, J=7.1
Hz), 8.81(2H, s), 10.87(1H, br.s), 10.99(1H, br.s), 11.47(1H,
br.s).
[4076] MS(FAB)m/z:565(M+H).sup.+.
Example 354
N-{(1R,2S,5S)-2-{[2-(4-chloro-3-nitroanilino)-2-oxoethanethioyl]amino}-5-[-
(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,-
4-c]pyridine-2-carboxamide hydrochloride
##STR01020##
[4078] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 505 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 10, and
the product was again treated with hydrochloric acid, whereby the
title compound was obtained.
[4079] .sup.1H-NMR(DMSO).delta.:1.48-1.54(1H, m), 1.67-1.78(3H, m),
1.99-2.03(1H, m), 2.22-2.33(1H, m), 2.79(3H, s), 2.91(3H, s),
2.96(3H, s), 3.01-3.67(5H, m), 4.40-4.80(4H, m), 7.78(1H, d, J=8.8
Hz), 8.05(1H, dd, J=8.8, 1.4 Hz), 8.59(1H, d, J=1.4 Hz), 8.75(1H,
d, J=7.6 Hz), 10.89-10.92(2H, m), 11.43(1H, br.s).
[4080] MS(ESI)m/z:608(M+H).sup.+.
Example 355
N-{(1R,2S,5S)-2-{[2-(3-amino-4-chloroanilino)-2-oxoethanethioyl]amino}-5-[-
(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,-
4-c]pyridine-2-carboxamide hydrochloride
##STR01021##
[4082] To a solution of the compound Example 354 (458 mg) in
ethanol (30 mL), 10% palladium carbon (1.00 g) was added, and the
mixture was stirred for 3 days at room temperature. The catalyst
was removed through filtration, and the solvent was removed under
reduced pressure. The residue was purified through silica gel flash
column chromatography (methylene chloride:methanol=94:6). The
thus-obtained yellow solid (137 mg) was dissolved in methylene
chloride (5 mL), and 1N HCl in ethanol (474 .mu.L) was added
thereto. Diethyl ether (20 mL) was added to the mixture, and the
formed solid was collected through filtration, followed by washing
with ether, to thereby yield the title compound (144 mg) as a
yellow solid.
[4083] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.46-1.54(1H, m),
1.70-1.78(3H, m), 1.98-2.07(1H, m), 2.21-2.23(1H, m), 2.79(3H, s),
2.91(3H, s), 2.96(3H, s), 3.03(1H, br.s), 3.11-3.19(1H, m),
3.30(1H, br.s), 3.47(1H, br.s), 3.69(1H, br.s), 4.10-4.51(4H, m),
4.68(2H, s), 6.95(1H, dd, J=8.6, 2.3 Hz), 7.18(1H, d, J=8.6 Hz),
7.31(0.5H, s), 7.33(0.5H, s), 8.74-8.80(1H, m), 10.18(1H, d, J=9.8
Hz), 10.83(0.5H, d, J=7.6 Hz), 10.89(0.5H, d, J=8.0 Hz),
11.79(0.5H, br.s), 11.87(0.5H, br.s).
[4084] MS(ESI)m/z:578(M+H).sup.+.
Example 356
6-[({(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl)amino)-5-[-
(dimethylamino)carbonyl]cyclohexyl}amino)carbonyl]-1,3-dihydro-2H-pyrrolo[-
3,4-c]pyridine-2-carboxylic acid tert-butyl ester
##STR01022##
[4086] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 428 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 481,
whereby the title compound was obtained.
[4087] .sup.1H-NMR(CDCl.sub.3).delta.:1.53(9H, s), 1.56-2.42(6H,
m), 2.85-2.94, (1H, m), 2.98(3H, s), 3.10(3H, s), 4.45-4.52(1H, m),
4.70-4.85(5H, m), 7.67(1H, dd, J=8.8, 2.4 Hz), 8.18(0.5H, br.s),
8.18(1H, d, J=8.8 Hz), 8.23(0.5H, br.s), 8.31(1H, d, J=2.4 Hz),
8.40-8.52(2H, m), 10.29(1H, br.s), 10.60(1H, br.s).
[4088] MS(ESI)m/z:630(M+H).sup.+.
Example 357
N-{(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoethanethioyl}amino)-
-5-[(dimethylamino)carbonyl]cyclohexyl}-2-methyl-2,3-dihydro-1H-pyrrolo[3,-
4-c]pyridine-6-carboxamide hydrochloride
##STR01023##
[4090] The compound obtained in Example 356 was treated with
hydrochloric acid for deprotection. The deprotected compound was
methylated in a manner similar to that described in Example 18, and
the product was again treated with hydrochloric acid, whereby the
title compound was obtained.
[4091] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.46-1.61 (1H, m),
1.62-1.95(3H, m), 1.95-2.10(1H, m), 2.10-2.30(1H, m), 2.79(3H,
br.s), 2.84-2.94(4H, m), 2.95(3H, s), 4.45-4.60(3H, m), 4.75(1H,
br.s), 4.80-5.00(2H, m), 7.97-8.13(2H, m), 8.16(1H, br.s), 8.46(1H,
br.s), 8.76(2H, br.s), 10.51(0.5H, s), 10.55(0.5H, s), 11.09(1H,
br.s), 11.92(0.5H, br.s), 11.99(0.5H, br.s).
[4092] MS(FAB)m/z:544(M+H).sup.+.
Example 358
N-{(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoethanethioyl}amino)-
-5-[(dimethylamino)carbonyl]cyclohexyl}-1-(pyridin-4-yl)-4-piperidinecarbo-
xamide hydrochloride
##STR01024##
[4094] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 428 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with 1-(pyridin-4-yl)-4-puperidinecarboxylic acid
(Tetrahedron, 1998, vol. 44, p. 7095), and the product was again
treated with hydrochloric acid, whereby the title compound was
obtained.
[4095] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.38-1.52(1H, m),
1.52-1.73(4H, m), 1.73-1.88(3H, m), 1.88-2.02(2H, m), 2.80(3H, s),
3.04(3H, s), 3.10-3.40(4H, m), 4.14-4.36(3H, m), 4.48-4.57(1H, m),
7.18(2H, d, J=6.8 Hz), 7.90-8.11(2H, m), 8.11-8.30(3H, m),
8.30-8.45(1H, m), 10.33(1H, s), 10.56(1H, d, J=7.3 Hz), 13.48(1H,
br.s).
[4096] MS(ESI)m/z:572(M+H).sup.+.
Example 359
N-{(1R,2S,5S)-2-{[(7-chlorocinnolin-3-yl)carbothioyl]amino}-5-[(dimethylam-
ino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-
e-2-carboxamide hydrochloride
##STR01025##
[4098] In a manner similar to that employed in Example 2, the
compound obtained in Referential Example 509 was condensed with the
compound obtained in Referential Example 10, and the product was
treated with hydrochloric acid, to thereby give the title
compound.
[4099] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.55-1.63(1H, m),
1.72-1.78(1H, m), 1.86-1.89(2H, m), 2.10(1H, br.s), 2.40-2.46(1H,
m), 2.81(3H, s), 2.91(3H, s), 2.97(3H, s), 3.04(1H, br.s),
3.15-3.20(1H, m), 3.27(1H, br.s), 3.49(1H, br.s), 3.69(1H, br.s),
4.43(1H, br.s), 4.67(1H, br.s), 4.81(1H, br.s), 4.95(1H, br.s),
8.00(1H, d, J=8.8 Hz), 8.41(1H, d, J=8.8 Hz), 8.65(1H, s), 9.06(1H,
br.s), 9.20(1H, s), 11.44(1H, br.s), 11.66(1H, br.s).
[4100] MS(ESI)m/z:572(M+H).sup.+.
Example 360
N-{(1R,2S,5S)-2-({[(4-chlorobenzoyl)amino]carbonyl}amino)-5-[(dimethylamin-
o)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine--
2-carboxamide hydrochloride
##STR01026##
[4102] In a manner similar to that employed in Example 2, the
compound obtained in Referential Example 511 was condensed with the
compound obtained in Referential Example 10, and the product was
treated with hydrochloric acid, to thereby give the title
compound.
[4103] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.45-1.50(1H, m),
1.74-1.84(4H, m), 1.87-1.95(1H, m), 2.80(3H, s), 2.92(3H, s),
3.02(3H, s), 3.13-3.35(3H, m), 3.47(1H, br.s), 3.69(1H, br.s),
3.97(1H, br.s), 4.41-4.44(1H, m), 4.62-4.72(2H, m), 7.56(2H, d,
J=8.6 Hz), 7.86-7.88(2H, m), 8.68(1H, br.s), 8.83(1H, br.s).
[4104] MS(FAB)m/z:547(M+H).sup.+.
Example 361
N-{(1R,2S,5S)-2-{[(E)-3-(5-chloropyridin-2-yl)acryloyl]amino}-5-[(dimethyl-
amino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyrid-
ine-2-carboxamide hydrochloride
##STR01027##
[4106] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 513 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 10, and
the product was again treated with hydrochloric acid, whereby the
title compound was obtained.
[4107] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.37-1.52(1H, m),
1.57-1.92(5H, m), 2.77(3H, s), 2.89(3H, s), 2.99(3H, s),
3.04-3.20(2H, m), 3.20-3.38(1H, m), 3.47(1H, br.s), 3.60-3.90(1H,
m), 3.90-4.03(1H, m), 4.36-4.48(1H, m), 4.52-4.62(1H, m), 4.67(1H,
br.d, J=16.2 Hz), 7.08(1H, d, J=15.4 Hz), 7.38(1H, dd, J=15.4, 3.9
Hz), 7.60(1H, d, J=8.4 Hz), 7.94(1H, d, J=8.4 Hz), 8.28(1H, d,
J=7.1 Hz), 8.35(1H, d, J=9.8 Hz), 8.59(1H, s), 11.72(0.5, br.s),
11.88(0.5H, br.s).
[4108] MS(ESI)m/z:531(M+H).sup.+.
Example 362
N-{(1R,2S,5S)-2-{[(Z)-3-(4-chlorophenyl)-2-fluoroacryloyl]amino}-5-[(dimet-
hylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]py-
ridine-2-carboxamide hydrochloride
##STR01028##
[4110] In a manner similar to that described in Example 49, the
compound obtained in Referential Example 519 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 516,
and the product was again treated with hydrochloric acid, whereby
the title compound was obtained.
[4111] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.47-1.75(4H, m),
1.97-2.20(2H, m), 2.79(3H, s), 2.92-2.96(7H, m), 3.20(2H, br.s),
3.50(1H, br.s), 3.67(1H, br.s), 4.03(1H, br.s), 4.47(2H, br.s),
4.66(1H, br.s), 6.88(1H, d, J=38.6 Hz), 7.50(2H, d, J=8.4 Hz),
7.66(2H, d, J=8.4 Hz), 8.52-8.56(2H, m), 11.36(1H, br.s).
[4112] MS(EI)m/z:547(M.sup.+).
Example 363
N-{(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoethanethioyl}amino)-
-5-[(methylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[-
5,4-c]pyridine-2-carboxamide hydrochloride
##STR01029##
[4114] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 521 was treated with 4N
HCL in dioxane for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 10, and
the product was again treated with hydrochloric acid, whereby the
title compound was obtained.
[4115] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.48-1.61(1H, m),
1.61-1.72(1H, m), 1.72-1.87(2H, m), 2.02-2.12(1H, m), 2.15-2.30(1H,
m), 2.33-3.43(1H, m), 2.52(3H, d, J=4.4 Hz), 2.86(3H, s), 3.17(2H,
br.s), 3.50(2H, br.s), 4.35-4.60(4H, m), 7.73-7.80(1H, m), 8.00(1H,
dd, J=9.0, 2.4 Hz), 8.05(1H, d, J=9.0 Hz), 8.43(1H, d, J=2.4 Hz),
8.51-8.58(1H, m), 10.55(1H, s), 11.13(1H, d, J=7.8 Hz).
[4116] MS(ESI)m/z:550(M+H).sup.+.
Example 364
N-[(1R,2S,5S)-5-[(dimethylamino)carbonyl]-2-({2-[(5-fluoropyridin-2-yl)ami-
no]-2-oxoethanethioyl}amino)cyclohexyl]-5-methyl-5,6,7,8-tetrahydro-4H-thi-
azolo[5,4-c]azepine-2-carboxamide hydrochloride
##STR01030##
[4118] In a manner similar to that employed in Example 2, the
compound obtained in Referential Example 522 was condensed with the
compound obtained in Referential Example 477, and the product was
treated with hydrochloric acid, to thereby give the title
compound.
[4119] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.43-1.60(1H, m),
1.61-1.90(3H, m), 1.92-2.18(3H, m), 2.18-2.35(1H, m), 2.70-2.88(6H,
m), 2.96(3H, br.s), 2.96-3.00(1H, m), 3.05-3.27(2H, m),
3.40-3.52(1H, br), 3.60-3.80(1H, br), 4.45-4.60(1H, m),
4.60-4.75(2H, m), 4.75-4.90(1H, m), 7.87(1H, dt, J=2.9, 9.0 Hz),
8.05-8.27(1H, m), 8.43(1H, d, J=2.9 Hz), 8.70-8.82(1H, m),
10.54(1H, s), 11.05-11.30(2H, m).
[4120] MS(FAB)m/z:562(M+H).sup.+.
Example 365
(3-{[((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahy-
drothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)amino]carbonyl}ph-
enyl)(imino)met hylcarbamic acid tert-butyl ester
##STR01031##
[4122] To a solution of the compound obtained in Referential
Example 524 (250 mg) in tetrahydrofuran (3.0 mL), were added water
(1.0 mL) and lithium hydroxide (20.5 mg) at room temperature. The
mixture was stirred for 15 hours and then concentrated under
reduced pressure. The thus-obtained solid and the compound obtained
in Referential Example 253 (464 mg) were dissolved in
N,N-dimethylformamide (5.0 mL), and, at room temperature,
1-hydroxybenzotriazole(140 mg) and
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (330
mg) were added to the solution. The resultant mixture was stirred
at the same temperature for 21 hours, and the solvent was removed
under reduced pressure. Methylene chloride, water, and saturated
aqueous sodium hydrogencarbonate were added to the residue to
partition the mixture, and the formed aqueous layer was extracted
with methylene chloride. The extract was combined with the organic
layer, and the mixture was dried over sodium sulfate anhydrate. The
solvent was removed under reduced pressure, and the residue was
purified through silica gel medium-pressure column chromatography
(methylene chloride:methanol=10:1), to thereby yield the title
compound (213 mg) as a pale brown foamy solid.
[4123] .sup.1H-NMR(CDCl.sub.3).delta.:1.40-2.32(6H, m), 1.56(9H,
s), 2.52(3H, s), 2.77-2.90(3H, m), 2.90-3.05(2H, m), 2.96(3H, s),
3.11(3H, s), 3.70(1H, d, J=15.5 Hz), 3.73(1H, d, J=15.5 Hz),
4.15-4.23(1H, m), 4.58-4.64(1H, m), 7.43-7.57(2H, m), 7.91(1H, d,
J=6.1 Hz), 7.98(1H, d, J=6.6 Hz), 8.12(1H, d, J=7.8 Hz), 8.23(1H,
s), 9.30-10.00(2H, br).
[4124] MS(ESI)m/z:612(M+H).sup.+.
Example 366
N-{(1R,2S,5S)-2-({3-[amino(imino)methyl]benzoyl)amino)-5-[(dimethylamino)c-
arbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-c-
arboxamide hydrochloride
##STR01032##
[4126] To a solution of the compound obtained in Example 365 (210
mg) in methylene chloride (4.0 mL), was added 4N HCl in dioxane
(4.0 mL) at room temperature. The mixture was stirred for 1 hour,
and saturated HCl in ethanol (20 mL) was added to the mixture. The
resultant mixture was stirred overnight, and the solvent was
removed under reduced pressure. Water (4.0 mL) was added to the
residue, and the solvent was removed under reduced pressure,
followed by drying, to thereby yield the title compound (210 mg) as
a pale brown solid.
[4127] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.20-2.10 (6H, m), 2.78(3H,
s), 2.90-3.20(1H, m), 2.91(3H, s), 2.99(3H, s), 3.20-3.35(1H, m),
3.35-3.80(3H, m), 4.00-4.13(1H, m), 4.35-4.80(3H, m), 7.60-7.75(1H,
m), 7.85-8.10(2H, m), 8.10-8.25(1H, m), 8.40-8.53(1H, m),
8.53-8.70(1H, m), 9.25-9.80(4H, m), 11.91(1H, br.s).
[4128] MS(ESI)m/z:512(M+H).sup.+.
Example 367
N-{(1R,2S,5S)-2-[(3-cyanobenzoyl)amino]-5-[(dimethylamino)carbonyl]cyclohe-
xyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
##STR01033##
[4130] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 525 was treated with 4N
HCl in dioxane for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 10,
whereby the title compound was obtained.
[4131] .sup.1H-NMR(CDCl.sub.3).delta.:1.50-1.66(1H, m),
1.74-1.88(1H, m), 1.90-2.07(2H, m), 2.22-2.37(2H, m), 2.53(3H, s),
2.79-2.91(3H, m), 2.91-3.03(2H, m), 2.97(3H, s), 3.13(3H, s),
3.73(1H, d, J=15.4 Hz), 3.74(1H, d, J=15.4 Hz), 4.13-4.21(1H, m),
4.58-4.64(1H, m), 7.47(1H, d, J=7.1 Hz), 7.55(1H, t, J=7.8 Hz),
7.74(1H, d, J=7.8 Hz), 8.03(1H, d, J=5.6 Hz), 8.06(1H, d, J=7.8
Hz), 8.12(1H, s).
[4132] MS(ESI)m/z:494(M.sup.+).
Example 368
N-{(1R,2S,5S)-2-({3-[amino(hydroxyimino)methyl]benzoyl}amino)-5-[(dimethyl-
amino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyrid-
ine-2-carboxamide hydrochloride
##STR01034##
[4134] Ethanol (5.0 mL) and tetrahydrofuran (2.0 mL) were added to
the compound obtained in Example 367 (270 mg) for dissoltion, and
hydroxylamine hydrochloride (114 mg) and triethylamine (230 .mu.L)
were added to the solution at room temperature. The mixture was
heated under reflux for 3 hours, and saturated aqueous sodium
hydrogencarbonate and methylene chloride were added to the reaction
mixture to partition the mixture, followed by extracting the formed
aqueous layer with methylene chloride. The extract was combined
with the organic layer, and the mixture was dried over sodium
sulfate anhydrate. The solvent was removed under reduced pressure.
The residue was purified through silica gel column chromatography
(methylene chloride:methanol=7:1), a sephadex column (methanol),
and fractional reversed phase high performance liquid
chromatography (acetonitrile-water-formic acid). The product was
converted to a hydrochloride with 1N HCl, and subsequently, the
salt was purified through use of a sephadex column (methanol), to
thereby yield the title compound (175 mg) as a white solid.
[4135] .sup.1H-NMR(CD.sub.3OD).delta.:1.53-1.67 (1H, m),
1.78-1.97(5H, m), 2.84(3H, s), 2.96-3.15(2H, m), 3.00(3H, s),
3.03(3H, s), 3.15-3.26(2H, m), 3.64(2H, br.s), 4.09-4.18(1H, m),
4.55(2H, br.s), 7.55(1H, t, J=7.8 Hz), 7.72(1H, d, J=7.8 Hz),
7.94(1H, d, J=7.8 Hz), 8.01(1H, s), 8.08(1H, d, J=9.1 Hz), 8.45(1H,
d, J=7.6 Hz).
[4136] MS(ESI)m/z:528(M+H).sup.+.
Example 369
(3-{[((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahy-
drothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)amino]carbonyl}ph-
enyl)(imino)met hylcarbamic acid ethyl ester
##STR01035##
[4138] In a manner similar to that described in Example 365, a
lithium salt of a carboxylic acid prepared through hydrolyzing the
compound obtained in Referential Example 526 was condensed with the
compound obtained in Referential Example 253, whereby the title
compound was obtained.
[4139] .sup.1H-NMR(CDCl.sub.3).delta.:1.36(3H, t, J=7.1 Hz),
1.55-1.71(1H, m), 1.73-2.05(3H, m), 2.05-2.35(2H, m), 2.52(3H, s),
2.75-3.05(5H, m), 2.97(3H, s), 3.11(3H, s), 3.67-3.80(2H, m),
4.10-4.35(3H, m), 4.55-4.67(1H, m), 7.09(1H, br.s), 7.40-7.60(2H,
m), 7.94(1H, d, J=6.1 Hz), 8.03(1H, d, J=7.8 Hz), 8.16(1H, d, J=7.8
Hz), 8.27(1H, s), 9.68(1H, br.s).
[4140] MS(ESI)m/z:584(M+H).sup.+.
Example 370
N-[(1R,2S,5S)-5-[(dimethylamino)carbonyl]-2-({3-[imino(methylamino)methyl]-
benzoyl}amino)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridi-
ne-2-carboxamide formic acid salt D22-9226
##STR01036##
[4142] Saturated HCl in ethanol (30 mL) was added to the compound
obtained in Example 367 (400 mg) at room temperature. The mixture
was stirred for 2 days and then condensed under reduced pressure,
thereby yielding a white solid. The solid was dissolved in methanol
(10 mL). To the solution, methylamine (2.0M tetrahydrofuran
solution) (30 mL) was added at room temperature. The mixture was
stirred for 2 hours and then concentrated under reduced pressure,
and the residue was purified sequentially through fractional
reversed phase high performance liquid chromatography
(acetonitrile-water-formic acid) and a sephadex column (methanol),
to thereby yield the title compound (152 mg) as a white solid.
[4143] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.40-1.54(1H, m),
1.57-1.71(2H, m), 1.71-1.80(1H, m), 1.90-2.06(2H, m), 2.32(3H, s),
2.45(3H, s), 2.68(2H, d, J=5.6 Hz), 2.75(3H, s), 2.75-2.85(2H, m),
2.91(3H, s), 2.91-3.00(1H, m), 3.42(3H, br.s), 3.59(2H, s),
4.00-4.12(1H, m), 4.43-4.52(1H, m), 7.59(1H, t, J=7.8 Hz), 7.81(1H,
d, J=7.8 Hz), 7.96(1H, d, J=7.8 Hz), 8.15(1H, s), 8.34-8.47(2H, m),
8.89(1H, d, J=7.6 Hz).
[4144] MS(ESI)m/z:526(M+H).sup.+.
Example 371
N-{(1R,2S,5S)-2-({3-[amino(methoxyimino)methyl]benzoyl}amino)-5-[(dimethyl-
amino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyrid-
ine-2-carboxamide hydrochloride
##STR01037##
[4146] Saturated HCl in ethanol (30 mL) was added to the compound
obtained in Example 367 (300 mg) at room temperature. The mixture
was stirred for 2 days and then concentrated under reduced
pressure, thereby yielding a pale yellow solid. The solid was
dissolved in methanol (10 mL). O-Methylhydroxylamine hydrochloride
(1.01 g) and triethylamine (1.69 mL) were added to the solution at
room temperature. The mixture was stirred for 2 hours, and
methylene chloride and saturated aqueous sodium hydrogencarbonate
were added to the reaction mixture to partition the mixture,
followed by extracting the aqueous layer with methylene chloride.
The extract was combined with the organic layer and then dried over
sodium sulfate anhydrate, and the solvent was removed under reduced
pressure. The residue was purified sequentially through silica gel
medium-pressure chromatography (methylene
chloride:methanol=20:1.fwdarw.7:1) and fractional reversed phase
high performance liquid chromatography (acetonitrile-water-formic
acid), and the product was treated with 1N HCl, to thereby yield
the title compound (51.8 mg) as a white solid.
[4147] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.44-1.57(1H, m),
1.63-1.88(3H, m), 1.88-2.05(2H, m), 2.79(3H, s), 2.85-3.85(5H, m),
2.90(3H, s), 2.96(3H, s), 3.73(3H, s), 4.04-4.13(1H, m), 4.42(1H,
br.s), 4.50-4.60(1H, m), 4.67(1H, br.s), 6.22(2H, br.s), 7. 44(1H,
t, J=7.8 Hz), 7.75(2H, d, J=7.8 Hz), 7.99(1H, s), 8.33-8.50(2H, m),
11.20-11.60(1H, br).
[4148] MS(ESI)m/z:542(M+H).sup.+.
Example 372
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)
-4-[(dimethylamino)carbonyl]-2-{[4-(3-oxomorpholin-4-yl)benzoyl]amino)cyc-
lohexyl)ethanediamide
##STR01038##
[4150] In a manner similar to that employed in Example 2, the
compound obtained in Referential Example 531 was condensed with the
compound obtained in Referential Example 420, to thereby give the
title compound.
[4151] .sup.1H-NMR(CDCl.sub.3).delta.:1.72-2.16(6H, m),
2.78-2.88(1H, m), 2.95(3H, s), 3.02(3H, s), 3.76-3.80(2H, m),
4.01-4.08(3H, m), 4.32(2H, s), 4.59-4.65(1H, m), 7.07(1H, d, J=6.9
Hz), 7.38(2H, dt, J=8.6, 2.2 Hz), 7.70(1H, dd, J=8.8, 2.5 Hz),
7.78(2H, dt, J=8.6, 2.2 Hz), 8.16(1H, d, J=8.8 Hz), 8.28-8.31(2H,
m), 9.73(1H, s).
[4152] MS(FAB)m/z:571(M+H).sup.+.
Example 373
N-{(1R,2S,5S)-2-{[(Z)-3-(5-chlorothien-2-yl)-2-fluoro-2-propenoyl]amino)-5-
-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[-
5,4-c]pyridine-2-carboxamide hydrochloride
##STR01039##
[4154] In a manner similar to that described in Example 49, the
compound obtained in Referential Example 519 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 534,
and the product was again treated with hydrochloric acid, whereby
the title compound was obtained.
[4155] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.42-2.01(6H, m), 2.79(3H,
s), 2.91-3.02(7H, m), 3.19(1H, br.s), 3.25(1H, br.s), 3.49(1H,
br.s), 3.70(1H, br.s), 3.98-4.05(1H, m), 4.39-4.50(2H, m), 4.70(1H,
br.s), 7.19(1H, dd, J=3.9, 1.7 Hz), 7.22(1H, d, J=37.6 Hz),
7.37(1H, d, J=3.9 Hz), 8.50(1H, d, J=7.3 Hz), 8.57(1H, br.s),
11.38-11.53(1H, m).
[4156] MS(FAB)m/z:554(M+H).sup.+.
Example 374
N-{(1R,2S,5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoethanethioyl}amino)-
-5-[(dimethylamino)carbonyl]cyclohexyl}-6-methyl-5,6,7,8-tetrahydro-4H-thi-
azolo[5,4-d]azepine-2-carboxamide hydrochloride
##STR01040##
[4158] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 428 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 537,
and the product was again treated with hydrochloric acid, whereby
the title compound was obtained.
[4159] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.44-1.58(1H, m),
1.62-1.74(1H, m), 1.74-1.88(2H, m), 1.95-2.07(1H, m), 2.15-2.30(1H,
m), 2.45-2.65(1H, m), 2.79(3H, s), 2.84-3.08(7H, m), 3.16-3.72(7H,
m), 4.45-4.55(1H, m), 4.61-4.70(1H, m), 8.02(1H, dd, J=8.8, 2.4
Hz), 8.07(1H, d, J=8.8 Hz), 8.46(1H, d, J=2.4 Hz), 8.59-8.68(1H,
m), 10.56(1H, d, J=4.0 Hz), 10.85(1H, br.s), 11.00-11.09(1H,
m).
[4160] MSm/z:578(M+H).sup.+.
Example 375
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-{(1S,2R,4S)
-2-[(6,7-dihydro-4H-pyrano[4,
3-d]thiazol-2-ylcarbonyl)amino]-4-[(dimethylamino)carbonyl]cyclohexyl}eth-
anediamide
##STR01041##
[4162] In a manner similar to that employed in Example 2, the
compound obtained in Referential Example 26 was condensed with the
compound obtained in Referential Example 420, to thereby give the
title compound.
[4163] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.39-1.56(1H, m),
1.58-1.80(3H, m), 1.97-2.13(2H, m), 2.77(3H, s), 2.92(6H, br.s),
3.90-4.06(3H, m), 4.35-4.45(1H, m), 4.83(2H, s), 7.96-8.06(2H, m),
8.44(1H, br.s), 8.61(1H, d, J=7.3 Hz), 9.22(1H, d, J=8.1 Hz),
10.25(1H, br.s).
[4164] MS(FAB)m/z:535(M+H).sup.+.
Example 376
N-{(1R,2S,5S)-2-((2-[(5-chloropyridin-2-yl)amino]-2-oxoethanethioyl}amino)-
-5-[(dimethylamino)carbonyl]cyclohexyl}-6-methyl-5,6,7,8-tetrahydro[1,6]na-
phthyridine-2-carboxamide
##STR01042##
[4166] In a manner similar to that described in Example 219, the
compound obtained in Referential Example 428 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 540,
whereby the title compound was obtained.
[4167] .sup.1H-NMR(CDCl.sub.3).delta.:1.50-1.75(2H, m),
1.80-2.10(3H, m), 2.10-2.20(1H, m), 2.30-2.45(1H, m), 2.52(3H, s),
2.75-2.85(2H, m), 2.98(3H, s), 2.95-3.10(2H, m), 3.11(3H, s),
3.66(2H, s), 4.45-4.55(1H, m), 4.65-4.80(1H, m), 7.52(1H, d, J=7.8
Hz), 7.67(1H, dd, J=8.8, 2.4 Hz), 8.05(1H, d, J=7.8 Hz), 8.21(1H,
d, J=8.8 Hz), 8.31(1H, d, J=2.7 Hz), 8.50(1H, d, J=7.5 Hz),
10.49(1H, d, J=7.3 Hz), 10.60(1H, s).
[4168] MS(ESI)m/z:558(M+H).sup.+.
Example 377
(1S,3R,4S)-4-({2-[(5-chloropyridin-2-yl)amino]-2-oxoethanethioyl}amino)-3--
{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}c-
yclohexanecarboxylic acid tert-butyl ester
##STR01043##
[4170] In a manner similar to that employed in Example 2, the
compound obtained in Referential Example 543 was condensed with the
compound obtained in Referential Example 10, to thereby give the
title compound.
[4171] .sup.1H-NMR(CDCl.sub.3).delta.:1.46(9H, s), 1.58-1.78(2H,
m), 1.95-2.33(4H, m), 2.49-2.61(1H, m), 2.52(3H, s), 2.80-2.88(2H,
m), 2.93-3.00(2H, m), 3.66-3.79(2H, m), 4.40-4.54(1H, m),
4.71-4.84(1H, m), 7.43(1H, d, J=8.3 Hz), 7.68(1H, dd, J=8.8, 2.4
Hz), 8.19(1H, d, J=8.8 Hz), 8.31(1H, d, J=2.4 Hz), 10.13(1H, d,
J=7.6 Hz), 10.55(1H, s).
[4172] MS(ESI)m/z:593(M+H).sup.+.
Example 378
(1S,3R,4S)-4-({2-[(5-chloro-2-pyridinyl)amino]-2-oxoethanethioyl}amino)-3--
{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}c-
yclohexanecarboxylic acid hydrochloride
##STR01044##
[4174] 4N HCl in dioxane (10 mL) was added to a solution of the
compound obtained in Example 377 (293 mg) in dioxane (8.0 mL), and
the mixture was stirred for 16 hours at room temperature. The
reaction mixture was concentrated under reduced mixture, and the
residue was suspended in diisopropyl ether and then collected
through filtration. The collected powder was dissolved in water and
then neutralized with saturated aqueous sodium bicarbonate. The
aqueous solution was extracted with methylene chloride, and the
formed organic layer was washed with saturated brine and dried over
sodium sulfate anhydrate, followed by concentration under reduced
pressure. 1N HCl in ethanol (0.50 mL) was added to the residue, and
the mixture was subjected to concentration under reduced pressure.
The residue was dissolved in water, followed by freeze-drying, to
thereby yield the title compound (242 mg).
[4175] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.50-1.64 (1H, m),
1.66-1.86(2H, m), 1.89-2.04(1H, m), 2.16-2.32(2H, m), 2.51-2.64(1H,
m), 2.93(3H, s), 3.12-3.58(3H, m), 3.64-3.80(1H, m), 4.36-4.80(4H,
m), 8.03(1H, dd, J=8.8, 2.7 Hz), 8.08(1H, d, J=8.8 Hz), 8.46(1H, d,
J=2.7 Hz), 8.73(1H, br.s), 10.57(1H, s), 10.94-11.45(2H, m).
[4176] MS(ESI)m/z:537(M+H).sup.+.
Example 379
(1S,3R,4S)-4-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-3-[(6,7--
dihydro-4H-pyrano[4,3-d]thiazol-2-ylcarbonyl)amino]cyclohexanecarboxylic
acid tert-butyl ester
##STR01045##
[4178] 1N HCl-ethyl acetate (3.09 mL) was added to the compound
obtained in Referential Example 544 (307 mg), and the resultant
suspension was stirred for 7 hours at room temperature. 2N
HCl-ethyl acetate (40 mL) was further added to the suspension, and
the mixture was stirred for 2 hours at room temperature. The
solvent was removed under reduced pressure, and diethyl ether was
added to the residue. The precipitated solid was collected through
filtration and dried under reduced pressure. The resultant solid
was dissolved in N,N-dimethylformamide (10 mL). The compound
obtained in Referential Example 26 (191 mg),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (288
mg), and 1-hydroxybenzotriazole (135 mg) were added to the
solution, and the resultant mixture was stirred for 4 days at room
temperature. The solvent was reduced under reduced pressure,
methylene chloride and a saturated aqueous solution of sodium
hydrogencarbonate were added to the residue to partition the
mixture, and the formed organic layer was washed with saturated
brine. The organic layer was dried over sodium sulfate anhydrate
and then concentrated under reduced pressure, and the residue was
purified through silica gel flash column chromatography
(methanol:methylene chloride=1:49), to thereby yield the title
compound (124 mg).
[4179] .sup.1H-NMR(CDCl.sub.3).delta.:1.46(9H, s), 1.58-1.76(2H,
m), 1.90-2.21(4H, m), 2.45-2.55(1H, m), 2.97(2H, t, J=5.6 Hz),
3.99-4.14(3H, m), 4.62-4.71(1H, m), 4.88(2H, br.s), 7.35(1H, d,
J=8.8 Hz), 7.69(1H, dd, J=8.8, 2.7 Hz), 7.99(1H, d, J=8.1 Hz),
8.17(1H, d, J=8.8 Hz), 8.30(1H, d, J=2.7 Hz), 9.70(1H, br.s).
[4180] MS(ESI)m/z:564(M+H).sup.+.
Example 380
(1S,3R,4S)-4-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-3-[(6,7--
dihydro-4H-pyrano[4,
3-d]thiazol-2-ylcarbonyl)amino]cyclohexanecarboxylic acid
##STR01046##
[4182] In a manner similar to that employed in Example 378, the
title compound was prepared from the compound obtained in Example
379.
[4183] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.44-1.80(3H, m),
1.83-2.11(2H, m), 2.17-2.27(1H, m), 2.45-2.54(1H, m), 2.92(2H,
br.s), 3.90-4.10(3H, m), 4.33(1H, br.s), 4.84(2H, br.s),
7.98-8.07(2H, m), 8.45(1H, d, J=2.2 Hz), 8.59(1H, d, J=7.4 Hz),
9.19(1H, d, J=8.1 Hz), 10.27(1H, s), 12.23(1H, s).
[4184] MS(FAB)m/z:508(M+H).sup.+.
Example 381
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-[(dimethylamino)carbo-
nyl]-2-{[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)carbonyl]amino}cyclo-
hexyl)ethanediamide hydrochloride
##STR01047##
[4186] In a manner similar to that described in Example 2, a
lithium salt of a carboxylic acid prepared through hydrolyzing the
compound obtained in Referential Example 545 was condensed with the
compound obtained in Referential Example 420, and the product was
treated with hydrochloric acid, whereby the title compound was
obtained.
[4187] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.31-1.46(1H, m),
1.49-1.72(3H, m), 1.75-2.01(2H, m), 2.68(3H, s), 2.80(3H, s),
2.86(3H, s), 2.90-3.06(1H, m), 3.05-3.42(3H, m), 3.49-3.61(1H, m),
3.80-3.92(1H, m), 4.13-4.48(3H, m), 7.20(1H, d, J=8.0 Hz), 7.62(1H,
d, J=8.0 Hz), 7.64(1H, s), 7.85-7.95(2H, m), 7.95-8.05(1H, m),
8.34(1H, s), 8.84-8.96(1H, m), 10.16(1H, s), 11.10(1H, br.s).
[4188] MSm/z:541(M+H).sup.+.
Example 382
N.sup.1-(5-chloropyridin-2-yl) -N.sup.2-[(1S,2R,4R)
-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]ami-
no}-4-(thiazol-2-yl)cyclohexyl]ethanediamide hydrochloride and
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-[(1S,2R,4S)-2-{[(5-methyl-4,5,6,7--
tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(thiazol-2-yl)cycl-
ohexyl]ethanediamide hydrochloride
##STR01048##
[4190] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 549 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 10, and
the resultant two stereoisomers were treated with hydrochloric
acid, whereby the title compounds were obtained.
[4191] Low-polar compound:
.sup.1H-NMR(DMSO-d.sub.6).delta.:1.60-1.84 (2H, m), 1.86-1.97(1H,
m), 2.00-2.14(2H, m), 2.21-2.34(1H, m), 2.89(3H, br.s),
3.01-3.52(4H, m), 3.61-3.74(1H, m), 4.06-4.49(3H, m), 4.63-4.75(1H,
m), 7.63(1H, d, J=3.2 Hz), 7.75(1H, d, J=3.2 Hz), 7.98-8.10(2H, m),
8.44(1H, br.s), 8.78-8.87(1H, m), 9.13-9.29(1H, m), 10.34-10.42(1H,
m), 11.66(1H, br.s).
[4192] MS(FAB)m/z:560(M+H).sup.+.
[4193] High-polar
compound:.sup.1H-NMR(DMSO-d.sub.6).delta.:1.67-1.80(2H, m),
1.89-1.99(1H, m), 2.10-2.25(2H, m), 2.30-2.46(1H, m), 2.90(3H,
br.s), 3.08-3.53(4H, m), 3.65-3.76(1H, m), 4.05-4.53(3H, m),
4.64-4.75(1H, m), 7.62(1H, br.s), 7.73(1H, br.s), 7.97-8.10(2H, m),
8.44(1H, br.s), 8.69-8.81(1H, m), 9.18-9.34(1H, m), 10.20-10.35(1H,
m), 11.48-11.92(1H, m).
[4194] MS(FAB)m/z:560(M+H).sup.+.
Example 383
N.sup.1-(5-chloropyridin-2-yl) -N.sup.2-[(1S,2R,4S)
-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]ami-
no}-4-(1,2,4-oxadiazol-3-yl)cyclohexyl]ethanediamide
hydrochloride
##STR01049##
[4196] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 550 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 10, and
the product was again treated with hydrochloric acid, whereby the
title compound was obtained.
[4197] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.64-1.79(2H, m),
1.84-1.95(1H, m), 2.01-2.22(2H, m), 2.30-2.43(1H, m), 2.91(4H,
br.s), 3.19(2H, br.s), 3.34-3.79(2H, m), 4.06-4.17(1H, m),
4.35-4.75(3H, m), 7.97-8.06(2H, m), 8.42(1H, s), 8.81(1H, d, J=7.1
Hz), 9.21(1H, br.s), 9.51(1H, s), 10.28(1H, s).
[4198] MS(FAB)m/z:545(M+H).sup.+.
Example 384
N.sup.1-(5-chloropyridin-2-yl) -N.sup.2-[(1S,2R,4S)
-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]ami-
no}-4-(5-methyl-1,3,4-oxadiazol-2-yl)cyclohexyl]ethanediamide
hydrochloride
##STR01050##
[4200] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 552 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 10, and
the product was again treated with hydrochloric acid, whereby the
title compound was obtained.
[4201] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.66-1.80(2H, m),
1.87-1.96(1H, m), 2.04-2.20(2H, m), 2.35-2.43(1H, m), 2.45(3H, s),
2.93(3H, s), 3.16-3.31(2H, m), 3.43-3.57(2H, m), 3.63-3.80(1H, m),
4.08-4.19(1H, m), 4.37-4.52(2H, m), 4.65-4.82(1H, m), 7.99-8.08(2H,
m), 8.44-8.48(1H, m), 8.84(1H, d, J=6.8 Hz), 9.22(1H, br.s),
10.30(1H, s), 10.96-11.25(1H, m).
[4202] MS(EI)m/z:558(M.sup.+).
Example 385
N.sup.1-(5-chloropyridin-2-yl)
-N.sup.2-[(1S,2R,4S)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyrid-
in-2-yl)carbonyl]amino}-4-(1,3,4-oxadiazol-2-yl)cyclohexyl]ethanediamide
##STR01051##
[4204] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 554 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 10,
whereby the title compound was obtained.
[4205] .sup.1H-NMR(CDCl.sub.3).delta.:1.72-2.00(2H, m),
2.13-2.23(2H, m), 2.28-2.36(1H, m), 2.39-2.46(1H, m), 2.53(3H, s),
2.80-2.91(2H, m), 2.93-3.00(2H, m), 3.28-3.38(1H, m), 3.69-3.79(2H,
m), 4.14-4.24(1H, m), 4.68-4.77(1H, m), 7.51(1H, d, J=8.3 Hz),
7.70(1H, dd, J=8.8, 2.5 Hz), 8.14(1H, d, J=7.8 Hz), 8.18(1H, d,
J=8.8 Hz), 8.31(1H, d, J=2.5 Hz), 8.38(1H, s), 9.72(1H, s).
[4206] MS(FAB)m/z:545(M+H).sup.+.
Example 386
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-[(1S,2R,4S)
-2-}[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]ami-
no)-4-(1, 3-oxazol-2-yl)cyclohexyl]ethanediamide hydrochloride
##STR01052##
[4208] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 556 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 10,
whereby the title compound was obtained.
[4209] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.65-1.82 (2H, m),
1.85-2.00(1H, m), 2.01-2.22(2H, m), 2.31-2.48(1H, m), 2.94(3H, s),
3.08-3.74(4H, m), 3.65-3.83(1H, m), 4.06-4.20(1H, m), 4.36-4.55(2H,
m), 4.65-4.82(1H, m), 7.14(1H, s), 8.00-8.17(3H, m), 8.48(1H, s),
8.77-8.90(1H, m), 9.14-9.34(1H, m), 10.25-10.40(1H, m),
11.35-11.68(1H, m).
[4210] MSm/z:544(M+H).sup.+.
Example 387
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-(5-methyl-1,3,4-oxadi-
azol-2-yl)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)car-
bonyl]amino}cyclohexyl)ethanediamide hydrochloride
##STR01053##
[4212] The compound obtained in Referential Example 560 (110 mg)
was dissolved in methylene chloride (5 mL), and 4N HCl in dioxane
(5 mL) was added to the solution, followed by stirring for 3 hours
at room temperature. The solvent was removed under reduced
pressure, and the obtained yellow solid was dissolved in
N,N-dimethylformamide (5 mL). To the solution, sequentially added
were the compound obtained in Referential Example 266 (71.1 mg),
1-hydroxybenzotriazole (42.7 mg), and
1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80.9
mg), and the mixture was stirred overnight at room temperature. The
reaction mixture was concentrated under reduced pressure, and
methylene chloride and aqueous sodium hydrogencarbonate were added
to the residue to partition the mixture. The formed organic layer
was dried over sodium sulfate anhydrate. The solvent was removed
under reduced pressure, and the residue was purified through
chromatography (methanol:methylene chloride=1:19). 1N HCl in
ethanol was added to the thus-obtained free form, and the mixture
was concentrated. Diethyl ether was added to the residue, and the
precipitated colorless powder was collected through filtration, to
thereby yield the title compound (69.8 mg).
[4213] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.65-1.85(2H, m),
1.89-1.92(1H, m), 2.05-2.22(2H, m), 2.32(3H, s), 2.35-2.46(1H, m),
2.93(3H, br.s), 3.05-3.56(4H, m), 3.65-3.78(1H, m), 4.05-4.18(1H,
m), 4.35-4.53(2H, m), 4.65-4.83(1H, m), 7.97-8.10(2H, m), 8.46(1H,
br.s), 8.78-8.90(1H, m), 9.15-9.32(1H, m), 10.30(1H, br.s),
10.90-11.30(1H, m). MS(FAB)m/z:559(M+H).sup.+.
Example 388
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-[(1S,2R,4S)
-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]ami-
no}-4-(1,3,4-thiadiazol-2-yl)cyclohexyl]ethanediamide
hydrochloride
##STR01054##
[4215] In a manner similar to that described in Example 387, the
compound obtained in Referential Example 562 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 266,
and the product was again treated with hydrochloric acid, whereby
the title compound was obtained.
[4216] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.68-1.86(2H, m),
1.96-2.08(1H, m), 2.11-2.28(2H, m), 2.38-2.47(1H, m), 2.94(3H, s),
3.10-3.30(1H, m), 3.37-3.62(2H, m), 3.63-3.80(1H, m), 4.11-4.23(1H,
m), 4.38-4.51(2H, m), 4.65-4.81(1H, m), 7.99-8.08(2H, m),
8.44-8.48(1H, m), 8.76-8.84(1H, m), 9.20-9.34(1H, m), 9.52(1H, s),
10.29(1H, br.s), 10.99-11.33(1H, m).
[4217] MS(ESI)m/z:561(M+H).sup.+.
Example 389
N-[(1R,2S,5S)-5-[(dimethylamino)carbonyl]-2-({2-[(5-fluoropyridin-2-yl)ami-
no]-2-oxoethanethioyl}amino)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazol-
o[5,4-c]pyridine-2-carboxamide
##STR01055##
[4219] To a solution of the compound obtained in Referential
Example 563 (76.3 g) in N,N-dimethylformamide (1.0 L), were added
the compound obtained in Referential Example 10 (38.4 g),
1-hydroxybenzotriazole monohydrate (28.8 g),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (37.6
g), and diisopropylethylamine (35 mL), and the mixture was stirred
for 63 hours at room temperature. The reaction mixture was
concentrated under reduced pressure, and methylene chloride (1.2 L)
and saturated aqueous sodium hydrogencarbonate (500 mL) were added
to the residue. The aqueous layer was extracted with methylene
chloride, and the organic layer was washed with saturated aqueous
sodium hydrogencarbonate and saturated aqueous sodium chloride and
then dried over sodium sulfate anhydrate, followed by concentration
under reduced pressure. The residue was purified through silica gel
column chromatography (methylene chloride:methanol=50:1 10:1), and
the obtained powder (77.2 g) was dissolved in methylene chloride
(500 mL). The insoluble substances were removed through filtration,
and the filtrate was concentrated under reduced pressure. Methylene
chloride (250 mL) was added to the residue, and diethyl ether (1 L)
was added dropwise thereto. The mixture was stirred for 30 minutes
at 0.degree. C., followed by filtration, to thereby yield the title
compound (71.5 g).
[4220] .sup.1H-NMR(CDCl.sub.3).delta.:1.61-1.75(1H, m),
1.78-2.21(5H, m), 2.19(3H, s), 2.27-2.37(1H, m), 2.52(3H, s),
2.77-2.95(4H, m), 2.96(3H, s), 3.70(1H, d, J=15.4 Hz), 3.75(1H, d,
J=15.6 Hz), 4.48-4.57(1H, m), 4.76-4.85(1H, m), 7.40-7.49(2H, m),
8.21(2H, dd, J=8.2, 4.8 Hz), 10.06(1H, br.d, J=7.6 Hz), 10.55(1H,
br.s).
[4221] MS(ESI)m/z:548(M+H).sup.+.
Example 390
N-[(1R,2S,5S)-5-[(dimethylamino)carbonyl]-2-({2-[(5-fluoropyridin-2-yl)ami-
no]-2-oxoethanethioyl}amino)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazol-
o[5,4-c]pyridine-2-carboxamide citric acid monohydrate
##STR01056##
[4223] The compound obtained in Example 389 (6.26 g) was suspended
in 20% hydrous ethanol (100 mL), and 1M aqueous citric acid (11.4
mL) was added to the suspension. Under stirring at 60.degree. C.,
20% hydrous ethanol was gradually added thereto to dissolve the
suspension. After filtration with heating, the solution was allowed
to cool to room temperature under stirring and then was left to
stand for 1 day. The precipitated crystals were collected through
filtration and then dried for 2 hours at room temperature under
reduced pressure, and the residue was left to stand for 1 day, to
thereby yield the title compound (6.95 g).
[4224] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.44-1.56(1H, m),
1.64-1.72(1H, m), 1.74-1.84(2H, m), 2.05(1H, d, J=14.2 Hz),
2.21-2.32(1H, m), 2.47-2.53(1H, m), 2.50(3H, s), 2.71(2H, d, J=15.1
Hz), 2.62(2H, d, J=15.6 Hz), 2.79(3H, s), 2.94-3.01(2H, m),
2.94(3H, s), 4.48-4.56(1H, m), 4.62-4.68(1H, m), 7.86-7.90(1H, dt,
J=8.2 Hz), 8.10(1H, dd, J=9.2, 3.7 Hz), 8.42(1H, d, J=2.7 Hz),
8.72(1H, d, J=6.9 Hz), 10.53(1H, s), 11.11(1H, d, J=7.8 Hz).
[4225] Element
analysis:C.sub.24H.sub.30AN.sub.7O.sub.3S.sub.2.C.sub.6H.sub.8O.sub.7.H.s-
ub.2O
[4226] Calculated:C;47.55, H;5.32, N;12.94, F;2.51, S;8.46
[4227] Found:C;47.48, H;5.10, N;13.05, F;2.55, S;8.61 mp
(decomposed):176 to 179.degree. C.
Example 391
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-[(1S,2R,4S)
-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]ami-
no}-4-(5-methyl-1,3,4-thiadiazol-2-yl)cyclohexyl]ethanediamide
hydrochloride
##STR01057##
[4229] In a manner similar to that described in Example 387, the
compound obtained in Referential Example 566 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 266,
and the product was again treated with hydrochloric acid, whereby
the title compound was obtained.
[4230] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.67-1.82(2H, m),
1.92-2.03(1H, m), 2.06-2.26(2H, m), 2.35-2.44(1H, m), 2.68(3H, s),
2.94(3H, s), 3.13-3.27(2H, m), 3.40-3.56(2H, m), 3.66-3.80(1H, m),
4.09-4.22(1H, m), 4.37-4.51(2H, m), 4.64-4.82(1H, m), 7.98-8.07(2H,
m), 8.44-8.48(1H, m), 8.79(1H, br.s), 9.16-9.34(1H, m), 10.29(1H,
s).
[4231] MS(ESI)m/z:575(M+H).sup.+.
Example 392
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-[(1S,2R,4S)
-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]ami-
no}-4-(1,3-oxazol-5-yl)cyclohexyl]ethanediamide hydrochloride
##STR01058##
[4233] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 568 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 10, and
the product was again treated with hydrochloric acid, whereby the
title compound was obtained.
[4234] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.50-1.87 (3H, m),
1.97-2.40(3H, m), 2.93(3H, s), 2.96-3.83(5H, m), 4.04-4.16(1H, m),
4.30-4.53(2H, m), 4.62-4.80(1H, m), 6.93(1H, s), 7.96-8.10(2H, m),
8.22(1H, s), 8.45(1H, s), 8.66-8.80(1H, m), 9.17-9.37(1H, m),
10.24-10.37(1H, m), 11.20-11.54(1H, m).
[4235] MS(ESI)m/z:544(M+H).sup.+.
Example 393
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-(5-methyl-1,2,4-oxadi-
azol-3-yl)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)car-
bonyl]amino}cyclohexyl)ethanediamide hydrochloride
##STR01059##
[4237] In a manner similar to that described in Example 387, the
compound obtained in Referential Example 572 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 266,
and the product was again treated with hydrochloric acid, whereby
the title compound was obtained.
[4238] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.63-1.79(2H, m),
1.80-1.94(1H, m), 1.98-2.24(2H, m), 2.27-2.41(1H, m), 2.56(3H, s),
2.83(3H, s), 3.04-3.88(6H, m), 4.06-4.18(1H, m), 4.29-4.53(2H, m),
7.98-8.10(2H, m), 8.46(1H, d, J=2.4 Hz), 8.79(1H, d, J=6.8 Hz),
9.23(1H, d, J=8.0 Hz), 10.31(1H, s).
[4239] MS(ESI)m/z:559(M+H).sup.+.
Example 394
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-2-{[(5-methyl-4,5,6,7-t-
etrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino)}-4-(4H-1,2,4-triazol--
4-yl)cyclohexyl)ethanediamide hydrochloride
##STR01060##
[4241] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 576 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 564,
and the product was again treated with hydrochloric acid, whereby
the title compound was obtained.
[4242] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.69-1.79(1H, m),
1.87-2.00(1H, m), 2.04-2.14(1H, m), 2.17-2.40(3H, m), 2.92(3H, s),
3.02-3.84(4H, m), 4.13-4.22(1H, m), 4.35-4.83(4H, m), 7.99-8.05(2H,
m), 8.45-8.47(1H, m), 8.65(2H, s), 8.69-8.76(1H, m), 9.39(1H, d,
J=8.1 Hz), 10.29(1H, s), 11.49(1H, br.s).
[4243] MS(ESI)m/z:544(M+H).sup.+.
Example 395
N.sup.1-(5-chloro-2-thienyl)-N.sup.2-((1S,2R,4S)-4-(5-methyl-1,3,4-oxadiaz-
ol-2-yl)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbo-
nyl]amino}cyclohexyl)ethanediamide citric acid salt
##STR01061##
[4245] The compound obtained in Referential Example 577 (317 mg)
and a lithium salt (249 mg) of a carboxylic acid obtained through
hydrolyzing the compound obtained in Referential Example 356 was
dissolved in N,N-dimethylformamide (8 mL), and
1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (308 mg)
and 1-hydroxybenzotriazole(159 mg) were added to the solution at
0.degree. C., followed by stirring for 11 hours at room
temperature. The reaction mixture was diluted with ethyl acetate,
and then washed sequentially with 10% aqueous citric acid,
saturated aqueous sodium hydrogencarbonate, and saturated brine,
followed by drying over sodium sulfate anhydrate. The residue was
concentrated under reduced pressure, and the produced solid was
dissolved in methylene chloride (10 mL). 4N HCl in dioxane (10 mL)
was added to the solution, and the mixture was stirred for 1 hour
at room temperature. The reaction mixture was concentrated under
reduced pressure, and the residue was dissolved in
N,N-dimethylformamide (8 mL). The compound obtained in Referential
Example 10 (262 mg), 1-hydroxybenzotriazole(174 mg),
1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (308 mg),
and triethylamine (149 .mu.L) were added to the solution at room
temperature. The reaction mixture was stirred for 19 hours, diluted
with methylene chloride, washed with saturated aqueous sodium
hydrogencarbonate, and dried over sodium sulfate anhydrate. The
residue was concentrated under reduced pressure, and the
concentrated product was purified through silica gel thin layer
chromatography (methylene chloride:methanol=10:1). The
thus-obtained compound was dissolved in ethanol, and hexane was
added to the solution, and the precipitated solid was collected
through filtration. Ethanol (15 mL) and citric acid monohydrate
(138 mg) were added to the solid (371 mg) to dissolve the solid
therein, and the solution was concentrated under reduced pressure,
followed by co-boiling three times with water and then drying, to
thereby yield the title compound (503 mg).
[4246] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.69-1.84 (2H, m),
1.87-1.99(1H, m), 2.05-2.22(2H, m), 2.35-2.52(1H, m), 2.48(3H, s),
2.65(2H, d, J=15.4 Hz), 2.75(2H, d, J=15.4 Hz), 2.98(3H, s),
3.03-3.84(5H, m), 3.84-3.95(2H, m), 4.10-4.21(1H, m), 4.38-4.48(1H,
m), 6.93(1H, d, J=4.4 Hz), 6.98(1H, d, J=4.4 Hz), 8.77(1H, d, J=7.6
Hz), 9.22(1H, d, J=8.4 Hz), 12.34(1H, s).
[4247] MS(ESI)m/z:564(M+H).sup.+.
Example 396
N.sup.1-(5-bromo-2-pyridinyl)-N.sup.2-((1S,2R,4S)-4-(5-methyl-1,3,4-oxadia-
zol-2-yl)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carb-
onyl]amino}cyclohexyl)ethanediamide hydrochloride.
##STR01062##
[4249] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 579 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 564,
and the product was treated with hydrochloric acid, whereby the
title compound was obtained.
[4250] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.70-2.15(5H, m),
2.32-2.43(1H, m), 2.45(3H, s), 2.92(3H, s), 3.10-3.30(3H, m),
3.49(1H, br.s), 3.70(1H, br.s), 4.09-4.17(1H, m), 4.38-4.52(2H, m),
4.69(1H, br.s), 7.99(1H, d, J=8.8 Hz), 8.13(1H, dd, J=8.8, 2.5 Hz),
8.53(1H, d, J=2.5 Hz), 8.83(1H, br.s), 9.22(1H, br.s), 10.28(1H,
s), 11.43(1H, br.s).
[4251] MS(FAB)m/z:603(M+H).sup.+.
Example 397
N.sup.1-(4-chlorophenyl)-N.sup.2-((1S,2R,4S)-4-(5-methyl-1,3,4-oxadiazol-2-
-yl)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-
amino}cyclohexyl)ethanediamide citric acid salt
##STR01063##
[4253] In a manner similar to that described in Example 395, the
compound obtained in Referential Example 577 was condensed with the
compound obtained in Referential Example 374, and the condensed
product was treated with hydrochloric acid for deprotection. The
deprotected compound was condensed with the compound obtained in
Referential Example 10, and the product was treated with citric
acid, whereby the title compound was obtained.
[4254] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.66-1.82(2H, m),
1.85-1.97(1H, m), 2.02-2.23(2H, m), 2.34-2.48(1H, m), 2.46(3H, s),
2.63(2H, d, J=15.4 Hz), 2.72(2H, d, J=15.4 Hz), 2.95(3H, s),
3.03-3.82(5H, m), 3.84-3.92(2H, m), 4.07-4.20(1H, m), 4.37-4.46(1H,
m), 7.42(2H, d, J=8.8 Hz), 7.84(2H, d, J=8.8 Hz), 8.78(1H, d, J=7.3
Hz), 9.13(1H, d, J=8.1 Hz), 10.83(1H, s).
[4255] MS(ESI)m/z:558(M+H).sup.+.
Example 398
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-(5-methyl-1,3,4-oxadi-
azol-2-yl)-2-{[(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-2-yl)carbonyl-
]amino}cyclohexyl)ethanediamide citric acid salt
##STR01064##
[4257] In a manner similar to that described in Example 395, the
compound obtained in Referential Example 577 was condensed with the
compound obtained in Referential Example 266, and the condensed
product was treated with hydrochloric acid for deprotection. The
deprotected compound was condensed with the compound obtained in
Referential Example 540, and the product was treated with citric
acid, whereby the title compound was obtained.
[4258] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.70-1.87 (2H, m),
1.90-2.21(3H, m), 2.29-2.40(1H, m), 2.47(3H, s), 2.59(3H, s),
2.62(2H, d, J=15.4 Hz), 2.71(2H, d, J=15.4 Hz), 2.90-3.80(5H, m),
3.87-3.95(2H, m), 4.08-4.19(1H, m), 4.48-4.58(1H, m), 7.74(1H, d,
J=8.1 Hz), 7.84(1H, d, J=8.1 Hz), 7.98-8.07(2H, m), 8.44-8.48(1H,
m), 8.59(1H, d, J=8.1 Hz), 9.21(1H, d, J=7.8 Hz), 10.31(1H, s).
[4259] MS(ESI)m/z:553(M+H).sup.+.
Example 399
N-[(1R,2S,5S)-2-{[(5-chloro-1H-indol-2-yl)carbonyl]amino}-5-(5-methyl-1,3,-
4-oxadiazol-2-yl)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyr-
idine-2-carboxamide citric acid salt
##STR01065##
[4261] In a manner similar to that described in Example 395, the
compound obtained in Referential Example 577 was condensed with
5-chloroindole-2-carboxylic acid, and the condensed product was
treated with hydrochloric acid for deprotection. The deprotected
compound was condensed with the compound obtained in Referential
Example 10, and the product was treated with citric acid, whereby
the title compound was obtained.
[4262] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.71-1.85(2H, m),
1.90-2.21(3H, m), 2.31-2.43(1H, m), 2.47(3H, s), 2.63(2H, d, J=15.2
Hz), 2.72(2H, d, J=15.2 Hz), 2.94(3H, s), 3.05-3.95(7H, m),
4.20-4.31(1H, m), 4.49-4.58(1H, m), 7.10(1H, d, J=1.6 Hz), 7.19(1H,
dd, J=8.8, 2.0 Hz), 7.44(1H, d, J=8.8 Hz), 7.70(1H, d, J=2.0 Hz),
8.40(1H, d, J=7.6 Hz), 8.44(1H, d, J=7.6 Hz), 11.79(1H, s).
[4263] MS(ESI)m/z:554(M+H).sup.+.
Example 400
N.sup.1-(5-chloro-2-thienyl)-N.sup.2-((1S,2R,4S)
-4-(5-methyl-1,3,4-oxadiazol-2-yl)-2-{[(6-methyl-5,6,7,8-tetrahydro[1,6]n-
aphthyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide citric
acid salt
##STR01066##
[4265] In a manner similar to that described in Example 395, a
lithium salt of a carboxylic acid prepared through hydrolyzing the
compound obtained in Referential Example 356 was condensed with the
compound obtained in Referential Example 577, and the condensed
product was treated with hydrochloric acid for deprotection. The
deprotected compound was condensed with the compound obtained in
Referential Example 540, and the product was treated with citric
acid, whereby the title compound was obtained.
[4266] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.70-1.86(2H, m),
1.90-2.21(3H, m), 2.27-2.39(1H, m), 2.46(3H, s), 2.58(3H, s),
2.61(2H, d, J=15.4 Hz), 2.71(2H, d, J=15.4 Hz), 2.98-3.95(7H, m),
4.09-4.19(1H, m), 4.47-4.56(1H, m), 6.90(1H, d, J=4.2 Hz), 6.95(1H,
d, J=4.2 Hz), 7.74(1H, d, J=7.8 Hz), 7.83(1H, d, J=7.8 Hz),
8.58(1H, d, J=8.0 Hz), 9.15(1H, d, J=8.0 Hz), 12.32(1H, s).
[4267] MS(ESI)m/z:558(M+H).sup.+.
Example 401
N.sup.1-((1S,2R,4S)-4-(5-methyl-1,3,4-oxadiazol-2-yl)-2-{[(5-methyl-4,5,6,-
7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N.sup.2-
-{5-[2-(trimethylsilyl)ethynyl]pyridin-2-yl}ethanediamide
##STR01067##
[4269] In a manner similar to that employed in Referential Example
455, the title compound was prepared from the compound obtained in
Example 396.
[4270] .sup.1H-NMR(CDCl.sub.3).delta.:0.26(9H, s), 1.77-1.92(2H,
m), 2.08-2.43(4H, m), 2.52(6H, s), 2.81-2.89(2H, m), 2.93-2.98(2H,
m), 3.19-3.28(1H, m), 3.68-3.77(2H, m), 4.13-4.22(1H, m),
4.68-4.74(1H, m), 7.48(1H, d, J=8.4 Hz), 7.78(1H, dd, J=8.4, 2.3
Hz), 8.11-8.17(2H, m), 8.44(1H, d, J=2.3 Hz), 9.73(1H, s).
[4271] MS(FAB)m/z:621(M+H).sup.+.
Example 402
N.sup.1-(5-ethynylpyridin-2-yl)-N.sup.2-((1S,2R,4S)-4-(5-methyl-1,3,4-oxad-
iazol-2-yl)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)ca-
rbonyl]amino}cyclohexyl)ethanediamide
##STR01068##
[4273] Potassium fluoride (116 mg) was added to a solution of the
compound obtained in Example 401 (617 mg) in methanol (30 mL), and
the mixture was stirred for 7 hours at room temperature. The
solvent was removed under reduced pressure, and methylene chloride
and water were added to the residue to partition the mixture. The
organic layer was dried over sodium sulfate anhydrate, and the
solvent was removed under reduced pressure. The residue was
purified through silica gel flash column chromatography (methylene
chloride:methanol=93:7). The thus-obtained solid was dissolved in
methanol, water was added thereto, and the solvent was removed
under reduced pressure, to thereby yield the title compound (287
mg).
[4274] .sup.1H-NMR(CDCl.sub.3).delta.:1.81-1.96(2H, m),
2.07-2.19(2H, m), 2.27(1H, br.s), 2.41(1H, d, J=13.2 Hz), 2.52(3H,
s), 2.58(3H, s), 2.88-3.07(4H, m), 3.22(1H, s), 3.27(1H, br.s),
3.76-3.92(2H, m), 4.20(1H, s), 4.71-4.76(1H, m), 7.60(1H, d, J=8.3
Hz), 7.79(1H, d, J=8.3 Hz), 8.14(1H, d, J=8.3 Hz), 8.23(1H, d,
J=7.4 Hz), 8.45(1H, s), 9.81(1H, s).
[4275] MS(FAB)m/z:549(M+H).sup.+.
Example 403
7-chloro-N-((1S,2R,4S)-4-(5-methyl-1,3,4-oxadiazol-2-yl)-2-{[(5-methyl-4,5-
,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-3-ci-
nnolinecarboxamide citric acid salt
##STR01069##
[4277] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 580 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 10, and
the product was treated with citric acid, whereby the title
compound was obtained.
[4278] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.75-1.90(2H, m),
1.91-2.03(1H, m), 2.10-2.22(1H, m), 2.25-2.52(2H, m), 2.47(3H, s),
2.63(2H, d, J=15.4 Hz), 2.73(2H, d, J=15.4 Hz), 2.96(3H, s),
3.00-3.95(7H, m), 4.41-4.58(2H, m), 8.02(1H, ddd, J=8.8, 2.0, 2.0
Hz), 8.39(1H, dd, J=8.8, 1.6 Hz), 8.65-8.70(1H, m), 8.90-8.94(1H,
m), 9.00(1H, d, J=6.8 Hz), 9.66(1H, d, J=8.4 Hz).
[4279] MS(ESI)m/z:567(M+H).sup.+.
Example 404
N-[(1R,2S,5S)-2-{[(Z)-3-(4-chlorophenyl)-2-fluoroacryloyl]amino}-5-(5-meth-
yl-1,3,4-oxadiazol-2-yl)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,-
4-c]pyridine-2-carboxamide citric acid salt
##STR01070##
[4281] In a manner similar to that described in Example 395, the
compound obtained in Referential Example 577 was condensed with the
compound obtained in Referential Example 516, and the condensed
product was treated with hydrochloric acid for deprotection. The
deprotected compound was condensed with the compound obtained in
Referential Example 10, and the product was treated with citric
acid, whereby the title compound was obtained.
[4282] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.66-1.80(2H, m),
1.85-1.96(1H, m), 2.00-2.16(2H, m), 2.30-2.41(1H, m), 2.46(3H, s),
2.63(2H, d, J=15.6 Hz), 2.72(2H, d, J=15.6 Hz), 2.96(3H, s),
3.10-3.95(7H, m), 4.11-4.22(1H, m), 4.40-4.50(1H, m), 6.90(1H, d,
J=38.8 Hz), 7.51(2H, d, J=8.4 Hz), 7.68(2H, d, J=8.4 Hz), 8.54(1H,
d, J=7.2 Hz), 8.62(1H, d, J=7.6 Hz).
[4283] MS(ESI)m/z:559(M+H).sup.+.
Example 405
7-chloro-N-((1S,2R,4S)-4-(5-methyl-1,3,4-oxadiazol-2-yl)-2-{[(5-methyl-4,5-
,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-3-is-
oquinolinecarboxamide citric acid salt
##STR01071##
[4285] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 581 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 10, and
the product was treated with citric acid, whereby the title
compound was obtained.
[4286] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.69-1.86(2H, m),
1.89-2.03(1H, m), 2.05-2.19(1H, m), 2.20-2.34(1H, m), 2.34-2.49(1H,
m), 2.47(3H, s), 2.63(2H, d, J=15.4 Hz), 2.72(2H, d, J=15.4 Hz),
2.96(3H, s), 3.00-3.80(5H, m), 3.84-3.91(2H, m), 4.30-4.42(1H, m),
4.47-4.56(1H, m), 7.91(1H, dd, J=8.8, 2.2 Hz), 8.27(1H, d, J=8.8
Hz), 8.37-8.41(1H, m), 8.61(1H, s), 8.95(1H, d, J=7.3 Hz), 9.08(1H,
d, J=8.3 Hz), 9.36(1H, s).
[4287] MS(ESI)m/z:566(M+H).sup.+.
Example 406
6-chloro-N-((1S,2R,4S)-4-(5-methyl-1,3,4-oxadiazol-2-yl)-2-{[(5-methyl-4,5-
,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-4-ox-
o-1,4-dihydro-2-quinazolinecarboxamide citric acid salt
##STR01072##
[4289] In a manner similar to that described in Example 395, the
compound obtained in Referential Example 577 was condensed with the
compound obtained in Referential Example 349, and the condensed
product was treated with hydrochloric acid for deprotection. The
deprotected compound was condensed with the compound obtained in
Referential Example 10, and the product was treated with citric
acid, whereby the title compound was obtained.
[4290] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.71-1.88(2H, m),
1.90-2.02(1H, m), 2.07-2.26(2H, m), 2.34-2.44(1H, m), 2.47(3H, s),
2.63(2H, d, J=15.4 Hz), 2.73(2H, d, J=15.4 Hz), 2.95(3H, s),
3.17-3.94(7H, m), 4.18-4.30(1H, m), 4.46-4.56(1H, m), 7.76(1H, d,
J=8.8 Hz), 7.89-7.94(1H, m), 8.08-8.13(1H, m), 8.76-8.85(1H, m),
8.96-9.06(1H, m).
[4291] MS(ESI)m/z:583(M+H).sup.+.
Example 407
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-[(1S,2R,4S)-2-{[(5-methyl-4,5,6,7-t-
etrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(1,2,4-oxadiazol-5--
yl)cyclohexyl]ethanediamide hydrochloride
##STR01073##
[4293] In a manner similar to that described in Example 387, the
compound obtained in Referential Example 583 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 266,
and the product was treated with hydrochloric acid, whereby the
title compound was obtained.
[4294] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.65-1.85(2H, m),
1.92-2.05(1H, m), 2.09-2.23(2H, m), 2.37-2.50(1H, m), 2.92(3H, s),
3.11-3.57(4H, m), 3.71(1H, br.s), 4.14(1H, br.s), 4.44(2H, br.s),
4.64-4.79(1H, m), 7.98-8.09(2H, m), 8.46(1H, br.s), 8.84(1H, br.s),
8.91(1H, br.s), 9.15-9.33(1H, m), 10.29(1H, br.s), 11.36-11.67(1H,
m).
[4295] MS(FAB)m/z:545(M+H).sup.+.
Example 408
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-{(1S,2R,4S)-2-{[(5-methyl-4,5,6,7-t-
etrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-[5-(trifluoromethyl-
)-1,3,4-oxadiazol-2-yl]cyclohexyl}ethanediamide hydrochloride
##STR01074##
[4297] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 586 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 10, and
the product was treated with hydrochloric acid, whereby the title
compound was obtained.
[4298] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.70-1.88(2H, m),
1.95-2.06(1H, m), 2.10-2.23(2H, m), 2.42-2.49(1H, m), 2.92(3H, s),
3.09-3.81(5H, m), 4.15(1H, br.s), 4.33-4.56(2H, m), 4.57-4.79(1H,
m), 7.99-8.08(2H, m), 8.46(1H, br.s), 8.86(1H, d, J=7.1 Hz),
9.24(1H, br.s), 10.30(1H, s), 11.48(1H, br.s).
[4299] MS(ESI)m/z:613(M+H).sup.+.
Example 409
N.sup.1-(5-chloro-2-thienyl)-N.sup.2-((1S,2R,4S)-4-(3-methyl-1,2,4-oxadiaz-
ol-5-yl)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbo-
nyl]amino}cyclohexyl)ethanediamide hydrochloride
##STR01075##
[4301] In a manner similar to that described in Example 387, the
compound obtained in Referential Example 560 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with a lithium salt of a carboxylic acid prepared through
hydrolyzing the compound obtained in Referential Example 356, and
the product was again treated with hydrochloric acid, whereby the
title compound was obtained.
[4302] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.65-1.82 (2H, m),
1.90-1.99(1H, m), 2.06-2.18(2H, m), 2.31(3H, s), 2.36-2.46(1H, m),
2.92(3H, s), 3.21(2H, br.s), 3.32-3.38(1H, m), 3.50(1H, br.s),
3.68(1H, br.s), 4.08-4.16(1H, m), 4.37-4.74(3H, m), 6.91(1H, d,
J=4.2 Hz), 6.94(1H, d, J=4.2 Hz), 8.83(1H, d, J=6.9 Hz), 9.15(1H,
br.s), 11.43(1H, br.s), 12.31(1H, s).
[4303] MS(FAB)m/z:564(M+H).sup.+.
Example 410
N.sup.1-(6-chloropyridazin-3-yl)-N.sup.2-((1S,2R,4S)-4-(3-methyl-1,2,4-oxa-
diazol-5-yl)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)c-
arbonyl]amino}cyclohexyl)ethanediamide hydrochloride
##STR01076##
[4305] In a manner similar to that described in Example 387, the
compound obtained in Referential Example 560 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with a lithium salt of a carboxylic acid prepared through
hydrolyzing the compound obtained in Referential Example 264, and
the product was again treated with hydrochloric acid, whereby the
title compound was obtained.
[4306] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.69-1.82(2H, m),
1.97-2.03(1H, m), 2.08-2.20(2H, m), 2.32(3H, s), 2.39-2.45(1H, m),
2.81-2.83(4H, m), 3.10-3.53(3H, m), 4.10-4.18(1H, m), 4.36-4.46(4H,
m), 7.98(1H, d, J=9.2 Hz), 8.29(1H, d, J=9.2 Hz), 8.79(1H, d, J=7.1
Hz), 9.27(1H, d, J=7.8 Hz), 11.06(1H, s).
[4307] MS(FAB)m/z:560(M+H).sup.+.
Example 411
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-[(1S,2R,4S)-2-{[(5-methyl-4,5,6,7-t-
etrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(2-oxo-1,3-oxazolid-
in-3-yl)cyclohexyl]ethanediamide
##STR01077##
[4309] p-Toluenesufonic acid monohydrate (301 mg) was added to a
solution of the compound obtained in Referential Example 589 (696
mg) in methanol (70 mL), and the mixture was heated under reflux
overnight. p-Toluenesulfonic acid monohydrate (82 mg) was further
added to the reaction mixture, and the resultant mixture was heated
under reflux for two hours. The solvent was removed under reduced
pressure, and the residue was dissolved in N,N-dimethylformamide
(50 mL). The compound obtained in Referential Example 564 (338 mg),
3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (552
mg), and 1-hydroxybenzotriazole (97 mg) were added to the solution,
and the mixture was stirred overnight at room temperature.
Triethylamine (599 .mu.L) was added to the reaction mixture, and
the resultant mixture was stirred overnight at 45.degree. C. Water
and ethyl acetate were added to the reaction mixture to partition
the mixture, and the organic layer was washed with water and
saturated brine. The organic layer was dried over sodium sulfate
anhydrate, and the solvent was removed under reduced pressure. The
residue was purified through silica gel flash column chromatography
(methylene chloride:methanol=93:7). A fraction of interest was
concentrated, and diethyl ether was added to the residue. The
thus-precipitated solid was collected through filtration, to
thereby yield the title compound (83 mg).
[4310] .sup.1H-NMR(CDCl.sub.3).delta.:1.46(9H, s), 1.58-1.65(2H,
m), 1.79-2.05(4H, m), 3.47-3.55(2H, m), 3.84-3.93(2H, m), 4.29(1H,
br.s), 4.33-4.39(2H, m), 5.08(1H, br.s), 7.70(1H, dd, J=8.8, 2.5
Hz), 8.10(1H, br.s), 8.19(1H, dd, J=8.8, 0.7 Hz), 8.31(1H, dd,
J=2.5, 0.7 Hz), 9.71(1H, s).
[4311] MS(ESI)m/z:562(M+H).sup.+.
Example 412
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-[(1S,2R,4S)-2-{[(5-methyl-4,5,6,7-t-
etrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(tetrazol-1-yl)cycl-
ohexyl]ethanediamide
##STR01078##
[4313] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 592 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 10,
whereby the title compound was obtained.
[4314] .sup.1H-NMR(CDCl.sub.3).delta.:1.90-2.02(1H, m),
2.16-2.29(2H, m), 2.40-2.52(2H, m), 2.52(3H, s), 2.59-2.66(1H, m),
2.80-2.91(2H, m), 2.94-2.98(2H, m), 3.68-3.78(2H, m), 4.23-4.32(1H,
m), 4.78-4.92(2H, m), 7.55(1H, d, J=8.1 Hz), 7.70(1H, dd, J=8.9,
2.6 Hz), 8.05(1H, d, J=7.6 Hz), 8.16(1H, dd, J=8.9, 0.6 Hz),
8.32(1H, dd, J=2.6, 0.6 Hz), 8.72(1H, s), 9.72(1H, s).
[4315] MS(ESI)m/z:545(M+H).sup.+.
Example 413
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-[(1S,2R,4S)
-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]ami-
no}-4-(1H-pyrrol-1-yl)cyclohexyl]ethanediamide hydrochloride
##STR01079##
[4317] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 594 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 564,
and the product was again treated with hydrochloric acid, whereby
the title compound was obtained.
[4318] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.67-1.78 (1H, m),
1.82-1.95(1H, m), 1.97-2.06(1H, m), 2.13-2.31(3H, m), 2.94(3H, s),
3.29-3.39(2H, m), 3.51(1H, br.s), 3.73(1H, br.s), 4.12-4.30(2H, m),
4.43(2H, br.s), 4.66-4.80(1H, m), 5.96(2H, br.s), 6.85(2H, br.s),
7.98-8.06(2H, m), 8.46(1H, br.s), 8.72(1H, br.s), 9.36(1H, br.s),
10.28(1H, br.s), 11.20-11.48(1H, m).
[4319] MS(FAB)m/z:542(M+H).sup.+.
Example 414
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-[(1S,2R,4S)
-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]ami-
no}-4-(1,2,4-triazol-5-yl)cyclohexyl]ethanediamide
hydrochloride
##STR01080##
[4321] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 597 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 564,
and the product was again treated with hydrochloric acid, whereby
the title compound was obtained.
[4322] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.64-1.79(2H, m),
1.83-1.95(1H, m), 1.97-2.08(1H, m), 2.09-2.21(1H, m), 2.28-2.38(1H,
m), 2.89(3H, s), 2.97-3.63(5H, m), 4.04-4.16(1H, m), 4.34-4.62(3H,
m), 7.81(1H, br.s), 8.01(1H, dd, J=8.9, 2.3 Hz), 8.05(1H, d, J=8.9
Hz), 8.46(1H, d, J=2.3 Hz), 8.74(1H, d, J=6. Hz), 9.24(1H, br.s),
10.28(1H, s), 13.67(1H, br.s).
[4323] MS(FAB)m/z:544(M+H).sup.+.
Example 415
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-[(1S,2R,4S)
-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]ami-
no}-4-(1-methyl-1H-1,2,4-triazol-5-yl)cyclohexyl]ethanediamide
hydrochloride
##STR01081##
[4325] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 599 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 564,
and the product was again treated with hydrochloric acid, whereby
the title compound was obtained.
[4326] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.60-1.76(2H, m),
1.77-1.88(1H, m), 1.94-2.04(1H, m), 2.05-2.18(1H, m), 2.25-2.36(1H,
m), 2.85-2.98(4H, m), 3.15-3.67(4H, m), 3.78(3H, s), 4.08(1H,
br.s), 4.31-4.70(3H, m), 7.97-8.08(2H, m), 8.30(1H, s), 8.44(1H,
br.s), 8.71(1H, d, J=6.8 Hz), 9.14-9.26(1H, m), 10.27(1H, s).
[4327] MS(FAB)m/z:558(M+H).sup.+.
[4328] MS(FAB)m/z:544(M+H).sup.+.
Example 416
7-chloro-N-((1S,2R,4S)-4-(3-methyl-1,2,4-oxadiazol-5-yl)-2-{[(5-methyl-4,5-
,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-3-ci-
nnolinecarboxamide hydrochloride
##STR01082##
[4330] In a manner similar to that described in Example 387, the
compound obtained in Referential Example 560 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 298,
and the product was again treated with hydrochloric acid, whereby
the title compound was obtained.
[4331] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.76-1.90(2H, m),
1.97-2.06(1H, m), 2.16-2.23(1H, m), 2.28-2.38(4H, m), 2.44-2.52(1H,
m), 2.88(3H, s), 3.21(2H, br.s), 3.27-3.42(1H, m), 3.55(2H, br.s),
4.41-4.56(4H, m), 8.01(1H, dd, J=8.8, 1.7 Hz), 8.38(1H, d, J=9.1
Hz), 8.67(1H, s), 8.91(1H, s), 9.06(1H, d, J=6.9 Hz), 9.64(1H, d,
J=7.8 Hz).
[4332] MS(ESI)m/z:567(M+H).sup.+.
Example 417
N.sup.1-(5-chloropyridin-2-yl)-N.sup.2-((3R,4S)-3-{[(5-methyl-4,5,6,7-tetr-
ahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-1-(thiazol-2-yl)piperidi-
n-4-yl)ethanediamide hydrochloride
##STR01083##
[4334] In a manner similar to that described in Example 214, the
compound obtained in Referential Example 603 was treated with
hydrochloric acid for deprotection. The deprotected compound was
condensed with the compound obtained in Referential Example 10, and
the product was treated with hydrochloric acid, whereby the title
compound was obtained.
[4335] .sup.1H-NMR(DMSO-d.sub.6).delta.:1.73-1.87(1H, m),
2.21-2.37(1H, m), 2.91(3H, s), 3.03-3.29(2H, m), 3.31-3.52(2H, (2H,
m), 3.84-4.53(5H, m), 4.64-4.76(1H, m), 6.91(1H, br.s), 7.23(1H,
br.s), 8.02(2H, s), 8.46(1H, s), 8.70-8.93(1H, m), 9.28, 9.36(total
1H, each d, J=7.8 Hz), 10.28, 10.33(total 1H, each br.s),
11.30-11.64(1H, br).
[4336] MS(ESI)m/z:561(M+H).sup.+.
Test Example 1
Determination of Human FXa-Inhibiting Effect (IC.sub.50 Value):
[4337] 5% DMSO solutions (10 .mu.l) of each test compound (the
concentrations of which were suitably set stepwise), Tris buffer
(100 mM Tris, 200 mM potassium chloride, 0.2% BSA, pH 7.4) (40
.mu.l), and 0.0625 U/ml human FXa (Enzyme Research Labolatories,
Inc., dissolved and diluted with Tris buffer) (10 .mu.l) were put
in respective wells of a 96-well microplate, and a 750 .mu.M
aqueous solution (40 .mu.l) of S-2222 (Chromogenix Co.) was added
thereto. Absorbance at 405 nm was measured for 10 minutes at room
temperature, and an increase in absorbance (.DELTA.OD/min) was
calculated. As a control, Tris buffer was used in place of the test
compound.
[4338] The percent inhibition (%) calculated using the following
equation at the final concentration of the test compound and the
final concentration of the test compound were plotted on the axis
of ordinate and the axis of abscissa of logarithmic normal
probability paper, respectively, and the 50% inhibition
concentration (IC.sub.50 value) was calculated.
Percent inhibition (%)=[1-(.DELTA.OD/min of test
compound)/(.DELTA.OD/min of control).times.100 (Result)
[4339] As shown in Table 1, the compounds of the present invention
were found to have potent FXa-inhibiting effect.
TABLE-US-00001 TABLE 1 Human FXa- inhibiting effect Compound
(IC.sub.50): nM Ex. 3 86 Ex. 7 83 Ex. 11 92 Ex. 54 4.2 Ex. 62 3.5
Ex. 63 2.5 Ex. 74 1.4 Ex. 101 26 Ex. 130 4.5 Ex. 138 4.4 Ex. 143
5.8 Ex. 164 4.8 Ex. 191 1.2 Ex. 192 2.0 Ex. 194 5.0 Ex. 204 1.5 Ex.
246 3.1 Ex. 247 1.9 Ex. 248 5.4 Ex. 384 1.0 Ex. 385 1.3 Ex. 387 1.2
Ex. 394 1.1 Ex. 395 0.72 Ex. 396 1.1 Ex. 402 1.1 Ex. 413 1.0
Test Example 2
[4340] Determination of Anti-FXa Activity in Rat Plasma after Oral
Administration:
(A) Administration and Blood Collection:
[4341] A drug solution (1 mg/ml) obtained by dissolving or
suspending a test compound (10 mg) in 0.5% methyl cellulose (MC)
was orally administered to rats (10 ml/kg). After 0.5, 1, 2 and 4
hours from the drug administration, the blood (0.5 ml) was
collected through the jugular vein using a syringe containing a
3.13% (w/v) aqueous solution (50 .infin.l) of trisodium citrate
dihydrate (amount of blood collected: 0.45 ml). For rats of a
control group, the same blood collection was conducted after a 0.5%
MC solution was administered. Each blood sample was centrifuged at
1500.times.g for 10 minutes at 4.degree. C. to separate plasma, and
the plasma was preserved at -40.degree. C. until it was used in the
following determination of anti-FXa activity in plasma.
(B) Determination of FXa-Inhibiting Activity in Plasma:
[4342] In the determination of anti-FXa activity in plasma, S-2222
was used as a substrate. Tris buffer (100 mM Tris, 200 mM potassium
chloride, 0.2% BSA, pH 7.4) (5456 .mu.l), human FXa (2.5 U/ml, 44
.mu.l), and water (550 .mu.l) were mixed. The resultant human FXa
solution was used in the following test.
[4343] Rat plasma (5 .mu.l) obtained in accordance with the
procedure (A) described above was put in wells of a 96-well
microplate, and the above-described human FXa solution (55 .mu.l)
and a 750 .mu.M aqueous solution (40 .mu.l) of S-2222 were
sequentially added. Immediately after that, absorbance at 405 nm
was measured at room temperature and a rate of reaction
(.DELTA.OD/min) was calculated with a spectrophotometer SPECTRAmax
340 or 190 (Molecular Devices Co., U.S.A.).
[4344] The anti-FXa activity, i.e., percent inhibition (%) was
calculated in accordance with the following equation:
Percent inhibition (%)=[1-(.DELTA.OD/min of sample)/(average value
of .DELTA.OD/min of the control group)].times.100 (Result)
[4345] The compounds described in Examples 63, 191, 192, 194, and
204 exhibited potent FXa-inhibiting activity in plasma (i.e., 62%
to 96%) at an oral dose of 10 mg/kg.
* * * * *