U.S. patent application number 11/351118 was filed with the patent office on 2006-08-03 for proline derivatives and use thereof as drugs.
Invention is credited to Fumihiko Akahoshi, Yoshiharu Hayashi, Hiroshi Kitajima, Hiroshi Sakashita.
Application Number | 20060173056 11/351118 |
Document ID | / |
Family ID | 26597757 |
Filed Date | 2006-08-03 |
United States Patent
Application |
20060173056 |
Kind Code |
A1 |
Kitajima; Hiroshi ; et
al. |
August 3, 2006 |
Proline derivatives and use thereof as drugs
Abstract
The present invention aims at providing compounds having
therapeutic effects due to a DPP-IV inhibitory action, and
satisfactory as pharmaceutical products. The present inventors have
found that derivatives having a substituent introduced into the
.gamma.-position of proline represented by the formula (I) ##STR1##
wherein each symbol is as defined in the specification, have a
potent DPP-IV inhibitory activity, and completed the present
invention by increasing the stability.
Inventors: |
Kitajima; Hiroshi; (Tokyo,
JP) ; Sakashita; Hiroshi; (Tokyo, JP) ;
Akahoshi; Fumihiko; (Tokyo, JP) ; Hayashi;
Yoshiharu; (Tokyo, JP) |
Correspondence
Address: |
WENDEROTH, LIND & PONACK, L.L.P.
2033 K STREET N. W.
SUITE 800
WASHINGTON
DC
20006-1021
US
|
Family ID: |
26597757 |
Appl. No.: |
11/351118 |
Filed: |
February 10, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11142523 |
Jun 2, 2005 |
7060722 |
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11351118 |
Feb 10, 2006 |
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10344255 |
Feb 10, 2003 |
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PCT/JP01/06906 |
Aug 10, 2001 |
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11142523 |
Jun 2, 2005 |
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Current U.S.
Class: |
514/365 ;
514/422; 548/200; 548/518 |
Current CPC
Class: |
C07D 417/04 20130101;
A61P 1/02 20180101; C07D 413/14 20130101; C07D 401/14 20130101;
A61P 17/00 20180101; A61P 5/48 20180101; A61P 3/10 20180101; C07D
403/14 20130101; C07D 417/06 20130101; A61P 7/00 20180101; C07D
207/16 20130101; A61P 43/00 20180101; C07D 417/14 20130101; C07D
405/14 20130101; A61P 3/00 20180101; C07D 409/14 20130101; C07D
471/10 20130101; A61P 35/04 20180101; C07D 487/04 20130101; A61P
13/08 20180101; A61P 3/04 20180101; A61P 37/06 20180101; A61P 31/18
20180101; C07D 413/04 20130101 |
Class at
Publication: |
514/365 ;
548/200; 548/518; 514/422 |
International
Class: |
A61K 31/427 20060101
A61K031/427; A61K 31/4025 20060101 A61K031/4025; C07D 417/02
20060101 C07D417/02; C07D 403/02 20060101 C07D403/02 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 10, 2000 |
JP |
243217/2000 |
Dec 28, 2000 |
JP |
400296/2000 |
Claims
1-11. (canceled)
12. A method for treating a disease involving DPP-IV, comprising
administering to a mammal in need thereof a therapeutically
effective amount of an L-proline derivative of the formula (I)
##STR377## wherein X is --NR.sup.1R.sup.2 wherein one of R.sup.1
and R.sup.2 is a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl,
aryl, arylalkyl, heteroaryl or heteroarylalkyl, and the other is a
hydrogen atom, alkyl, cycloalkyl or aryl, Y is CH.sub.2, CH--OH, S,
S.dbd.O or SO.sub.2, Z is a hydrogen atom or a cyano, and of the
above-mentioned groups, alkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl and cycloalkylalkyl each optionally
have substituents, or a pharmaceutically acceptable salt
thereof.
13. The method of claim 12, wherein X is a group of the formula
(IV) or (V): ##STR378## wherein R.sup.22 is a hydrogen atom, alkyl,
cycloalkyl, or aryl, R.sup.23 and R.sup.24 are the same or
different and each is independently a hydrogen atom, alkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, halogen, haloalkyl, cyano,
nitro, --NR.sup.25R.sup.26, --NHSO.sub.2R.sup.27, OR.sup.28,
--COOR.sup.29, --CONHSO.sub.2R.sup.30, --SO.sub.2 OR.sup.31,
--SO.sub.2R.sup.32 or --CONR.sup.33R.sup.34 wherein R.sup.25,
R.sup.26, R.sup.27, R.sup.28, R.sup.29, R.sup.30, R.sup.31,
R.sup.32, R.sup.33 and R.sup.34 are the same or different and each
is independently a hydrogen atom, alkyl, cycloalkyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or
haloalkyl, or R.sup.25 and R.sup.26, and R.sup.33 and R.sup.34 may
be bonded to each other to form heterocycles each optionally
containing 1 or 2 nitrogen atoms or oxygen atoms, said heterocycle
optionally being condensed with an aromatic ring optionally having
substituents, a, b, c, d, e, f and g are all carbon atoms, or any
one or two thereof is(are) nitrogen atom(s) and the rest is a
carbon atom, n is 0, 1, 2 or 3, and of the above-mentioned groups,
alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl,
cycloalkylalkyl and heterocycle each optionally have substituents,
or a pharmaceutically acceptable salt thereof.
14. The method of claim 12, wherein X is phenylamino optionally
having substituents, 2-pyridylamino optionally having substituents,
3-pyridazinylamino optionally having substituents or
2-pyrimidinylamino optionally having substituents, and the
asymmetric carbon, to which X is bonded, is expressed by an S
configuration, or a pharmaceutically acceptable salt thereof.
15. A method for treating a disease involving DPP-IV, comprising
administering to a mammal in need thereof a therapeutically
effective amount of an L-proline derivative of the formula (I)
##STR379## wherein X is a group of the formula (III) ##STR380##
wherein R.sup.12 is alkyl, cycloalkyl, cycloalkylalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, --NR.sup.14R.sup.15,
--OR.sup.16, --COR.sup.17, --CO.sub.2R.sup.18,
--CONR.sup.19R.sup.20 or --SO.sub.2R.sup.21 wherein R.sup.14,
R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20 and
R.sup.21 are the same or different and each is independently a
hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl or haloalkyl, or R.sup.14 and R.sup.15,
and R.sup.19 and R.sup.20 may be bonded to each other to form
heterocycles each optionally containing 1 or 2 nitrogen atoms or
oxygen atoms, said heterocycle optionally being condensed with an
aromatic ring optionally having substituents, and R.sup.13 is a
hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heteroaryl or heteroarylalkyl, Y is CH.sub.2, CH--OH, S, S.dbd.O or
SO.sub.2, Z is a hydrogen atom or a cyano, and of the
above-mentioned groups, alkyl, cycloalkyl, cycloalkylalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl and heterocycle each
optionally have substituents, or a pharmaceutically acceptable salt
thereof.
16. A method for treating a disease involving DPP-IV, comprising
administering to a mammal in need thereof a therapeutically
effective amount of an L-proline derivative of the formula (I)
##STR381## wherein X is --NR.sup.1R.sup.2 wherein R.sup.1 and
R.sup.2 may be the same or different and each is independently
cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl, or may
be bonded to each other to form a heterocycle optionally containing
1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally
being condensed with an aromatic ring optionally having
substituents, and the heterocycle optionally being a spiro ring,
--NR.sup.3 COR.sup.4 wherein R.sup.3 and R.sup.4 are the same or
different and each is independently a hydrogen atom, alkyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl,
heteroaryl or heteroarylalkyl, --NR.sup.5 CONR.sup.6R.sup.7 or
--NR.sup.5 CH.sub.2CH.sub.2NR.sup.6R.sup.7 wherein R.sup.5, R.sup.6
and R.sup.7 are the same or different and each is independently
hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl,
arylalkyl, heteroaryl or heteroarylalkyl, or R.sup.6 and R.sup.7
may be bonded to each other to form a heterocycle optionally
containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle
optionally being condensed with an aromatic ring optionally having
substituents, --NR.sup.8SO.sub.2R.sup.9 wherein R.sup.8 and R.sup.9
are the same or different and each is independently a hydrogen
atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heteroaryl or heteroarylalkyl, or --OR.sup.10 or --OCOR.sup.11
wherein R.sup.10 and R.sup.11 are each a hydrogen atom, alkyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or
heteroarylalkyl, Y is CH.sub.2, CH--OH, S, S.dbd.O or SO.sub.2, Z
is a hydrogen atom or a cyano, and of the above-mentioned groups,
alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl,
cycloalkyl, cycloalkylalkyl and heterocycle each optionally have
substituents, or a pharmaceutically acceptable salt thereof.
17. The method of claim 16, wherein X of the formula (I) is a group
of the formula (II): ##STR382## wherein ##STR383## is a single bond
or a double bond, R.sup.12 is alkyl, cycloalkyl, cycloalkylalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, --NR.sup.14R.sup.15,
--OR.sup.16, --COR.sup.17, --CO.sub.2R.sup.18,
--CONR.sup.19R.sup.20 or --SO.sub.2R.sup.21 wherein R.sup.14,
R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20 and
R.sup.21 are the same or different and each is independently a
hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl or haloalkyl, or R.sup.14 and R.sup.15,
and R.sup.19 and R.sup.20 may be bonded to each other to form
heterocycles each optionally containing 1 or 2 nitrogen atoms or
oxygen atoms, said heterocycle optionally being condensed with an
aromatic ring optionally having substituents, m is 1 or 2, and A is
a carbon atom or a nitrogen atom, provided that i) when A is a
carbon atom, A may be substituted by a hydroxyl group, carboxyl or
alkoxycarbonyl, and ii) when A is a nitrogen atom, ##STR384## is a
single bond, of the above-mentioned groups, alkyl, cycloalkyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and
heterocycle each optionally have substituents, or a
pharmaceutically acceptable salt thereof.
18. The method of claim 16, wherein X of the formula (I) is a group
of the formula (VI) or (VII): ##STR385## wherein R.sup.23 and
R.sup.24 are the same or different and each is independently a
hydrogen atom, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
halogen, haloalkyl, cyano, nitro, --NR.sup.25R.sup.26,
--NHSO.sub.2R.sup.27, --OR.sup.28, --COOR.sup.29,
--CONHSO.sub.2R.sup.30, --SO.sub.2OR.sup.31, --SO.sub.2R.sup.32 or
--CONR.sup.33R.sup.34 wherein R.sup.25, R.sup.26, R.sup.27,
R.sup.28, R.sup.29, R.sup.30, R.sup.31, R.sup.32, R.sup.33 and
R.sup.34 are the same or different and each is independently a
hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl or haloalkyl, or R.sup.25 and R.sup.26,
and R.sup.33 and R.sup.34 may be bonded to each other to form
heterocycles each optionally containing 1 or 2 nitrogen atoms or
oxygen atoms, said heterocycle optionally being condensed with an
aromatic ring optionally having substituents, a, b, c, d, e, f and
g are all carbon atoms, or any one or two thereof is(are) nitrogen
atom(s) and the rest is a carbon atom, and A is a carbon atom or a
nitrogen atom, provided that when A is a carbon atom, A may be
substituted by a hydroxyl group, carboxyl or alkoxycarbonyl, and of
the above-mentioned groups, alkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each
optionally have substituents, or a pharmaceutically acceptable salt
thereof.
19. The method of claim 18, wherein, in the formula (I), the
asymmetric carbon, to which X is bonded, is expressed by an S
configuration, X is a group of the formula (VI) or (VII), R.sup.23
and R.sup.24 are the same or different and each is nitro, cyano,
C.sub.1-6alkyl, C.sub.1-6alkyloxy, halogen or haloalkyl, Y is a
sulfur atom and Z is a hydrogen atom, or a pharmaceutically
acceptable salt thereof.
20. The method of claim 16, wherein the L-proline derivative is
3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-5-pyrazolyl)-1-piperazinyl]-2-pyrrolid-
inylcarbonyl}-1,3-thiazolidine trihydrochloride.
21. The method of claim 16, wherein the L-proline derivative is
3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-5-pyrazolyl)-1-piperazinyl]-2-pyrrolid-
inylcarbonyl}-1,3-thiazolidine or a salt thereof.
Description
TECHNICAL FIELD
[0001] The present invention relates to a proline derivative
showing a dipeptidyl peptidase IV (DPP-IV) inhibitory activity,
which is useful for the treatment or prophylaxis of diabetes,
obesity, HIV infection, cancer metastasis, dermopathy, prostatic
hyperplasia, periodontitis, autoimmune disease and the like, and a
salt thereof.
BACKGROUND ART
[0002] DPP-IV is a serine protease, which recognizes an amino acid
sequence having proline (or alanine or hydroxyproline) the
penultimate position from the N-terminal and produces dipeptide
Xaa-Pro (Xaa shows an optional amino acid and Pro shows L-proline).
DPP-IV is widely distributed in mammalian tissues and is known to
be present particularly in blood, kidney, intestinal epithelium and
placenta.
[0003] While the physiological role of DPP-IV in mammal has not
been completely elucidated, its involvement in a broad range of
functions of living organisms such as degradation of neuropeptide
[Heymann et al., FEBS Letters vol. 91, 360-364 (1978)], activation
of T cell [Schon et al., Biomedica Biochimica Acta vol. 44, K9-K15
(1985)], adhesion of metastatic tumor cell to endothelium [Johnson
et al., Journal of Cell Biology, vol. 121, 1423-1432 (1993)],
invasion of HIV virus into lymphocytes [Callebaut et al., Science
vol. 262, 2045-2050 (1993)] and the like is being clarified. Of
these, the role of DPP-IV as an enzyme that inactivates
glucagon-like peptide (GLP-1), which is a biogenic substance having
a strong insulin secretion ability and controls postprandial blood
glucose level, as been drawing attention [Deacon et al., Journal of
Clinical Endocrinology and Metabolism, vol. 80, 952-957
(1995)].
[0004] GLP-1 is known to be metabolized in several minutes in a
living organism. In the metabolism, that by DPP-IV is particularly
important, because it quickly cleaves GLP-1 and produces inert
GLP-1 [Deacon et al., American Journal of Physiology, vol. 271,
E458-E464 (1996)]. In addition, it is considered that physiological
action of GLP-1 becomes attenuated further because this inert GLP-1
shows an antagonistic action on GLP-1 receptor [Knudsen et al.,
European Journal of Pharmacology, vol. 318, 429-435 (1996)].
Therefore, a method for suppressing cleavage of GLP-1 by inhibition
of DPP-IV is considered to be the most superior approach for
reinforcing GLP-1 action. That is, a DPP-IV inhibitor is expected
to be a superior treatment method of curing postprandial
hyperglycemia without side effects, such as prolonged hypoglycemia
and the like, for non insulin-dependent diabetic (type II diabetes)
patients.
[0005] Patent applications relating to DPP-IV inhibitors include
the following.
[0006] Japanese Patent Application under PCT laid-open under kohyo
No. 9-509921 discloses (S)-2-cyano-1-L-prolinepyrrolidine
derivative. The L-.alpha.-amino acid corresponding to the L-proline
moiety of the compound disclosed therein characteristically has a
lipophilic side chain.
[0007] In addition, WO99/61431 describes DPP-IV inhibitory
activities of a compound consisting of natural amino acid and
thiazolidine or pyrrolidine.
DISCLOSURE OF THE INVENTION
[0008] While there have been reported many DPP-IV inhibitors till
date [Augustyns et al., Current Medicinal Chemistry, vol. 6,
311-327 (1999)], none of the compounds shows sufficient inhibitory
activity or sufficient stability and safety in living organisms,
and they are unsatisfactory as a pharmaceutical product. Therefore,
the development of a compound which exhibits a therapeutic effect
through the inhibition of DPP-IV action and satisfactory as a
pharmaceutical product has been demanded.
[0009] In view of the above-mentioned points, the present inventors
have conducted intensive studies with the aim of developing a novel
DPP-IV inhibitor. As a result, the present inventors have found
that a derivative having a substituent introduced into the
.gamma.-position of proline has a potent DPP-IV inhibitory
activity, and made the stability higher, which resulted in the
completion of the present invention.
[0010] Accordingly, the present invention relates to the following
compounds. (1) An L-proline derivative of the formula (I) ##STR2##
wherein [0011] x shows --NR.sup.1R.sup.2 wherein R.sup.1 and
R.sup.2 may be the same or different and each is independently a
hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heteroaryl or heteroarylalkyl, or may be bonded to each other to
form a heterocycle optionally containing 1 or 2 nitrogen atoms or
oxygen atoms, the heterocycle optionally being condensed with an
aromatic ring optionally having substituents, and the heterocycle
optionally being a Spiro ring, [0012] --NR.sup.3COR.sup.4 wherein
R.sup.3 and R.sup.4 are the same or different and each is
independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl,
aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl, [0013]
--NR.sup.5CONR.sup.6R.sup.7 or
--NR.sup.5CH.sub.2CH.sub.2NR.sup.6R.sup.7 wherein R.sup.5, R.sup.6
and R.sup.7 are the same or different and each is independently
hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl,
arylalkyl, heteroaryl or heteroarylalkyl, or R.sup.6 and R.sup.7
may be bonded to each other to form a heterocycle optionally
containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle
optionally being condensed with an aromatic ring optionally having
substituents, [0014] --NR.sup.8SO.sub.2R.sup.9 wherein R.sup.8 and
R.sup.9 are the same or different and each is independently a
hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heteroaryl or heteroarylalkyl, or [0015] --OR.sup.10 or
--OCOR.sup.11 wherein R.sup.10 and R.sup.11 are each a hydrogen
atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heteroaryl or heteroarylalkyl, [0016] Y is CH.sub.2, CH--OH, S,
S.dbd.O or SO.sub.2, [0017] Z is a hydrogen atom or a cyano, and of
the above-mentioned groups, alkyl, aryl, arylalkyl, arylalkenyl,
heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and
heterocycle each optionally have substituents, or a
pharmaceutically acceptable salt thereof (2) The L-proline
derivative described in the aforementioned (1), wherein X of the
formula (I) is a substituent selected from the formulas ##STR3##
wherein ##STR4## is a single bond or a double bond, [0018] R.sup.12
is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, --NR.sup.14R.sup.15, --OR.sup.16, --COR17
--CO.sub.2R.sup.18, --CONR.sup.19R.sup.20 or
--SO.sub.2R.sup.21CH.sub.2 wherein R.sup.14, R.sup.15, R.sup.16,
R.sup.17, R.sup.18, R.sup.19, R.sup.20 and R.sup.21 are the same or
different and each is independently a hydrogen atom, alkyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl or haloalkyl, or R.sup.14 and R.sup.15, and
R.sup.19 and R.sup.20 may be bonded to each other to form
heterocycles each optionally containing 1 or 2 nitrogen atoms or
oxygen atoms, said heterocycle optionally being condensed with an
aromatic ring optionally having substituents, [0019] R.sup.13 is a
hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heteroaryl or heteroarylalkyl, [0020] m is 1 or 2, and [0021] A is
a carbon atom or a nitrogen atom, provided that i) when A is a
carbon atom, A may be substituted by a hydroxyl group, carboxyl or
alkoxycarbonyl, and ii) when A is a nitrogen atom, ##STR5## is a
single bond, of the above-mentioned groups, alkyl, cycloalkyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and
heterocycle each optionally have substituents, or a
pharmaceutically acceptable salt thereof. (3) The L-proline
derivative described in the aforementioned (1) or (2), wherein X of
the formula (I) is a substituent selected from the formulas
##STR6## wherein [0022] R.sup.22 is a hydrogen atom, alkyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or
heteroarylalkyl, [0023] R.sup.23 and R.sup.24 are the same or
different and each is independently a hydrogen atom, alkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, halogen, haloalkyl, cyano,
nitro, --NR.sup.25R.sup.26, --NHSO.sub.2R.sup.27, --OR.sup.28,
--COOR.sup.29, --CONHSO.sub.2R.sup.30, --SO.sub.2OR.sup.31,
--SO.sub.2R.sup.32 or --CONR.sup.33R.sup.34 wherein R.sup.25,
R.sup.26, R.sup.27, R.sup.28, R.sup.29, R.sup.30, R.sup.31,
R.sup.32, R.sup.33 and R.sup.34 are the same or different and each
is independently a hydrogen atom, alkyl, cycloalkyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or
haloalkyl, or R.sup.25 and R.sup.26, and R.sup.33 and R.sup.34 may
be bonded to each other to form heterocycles each optionally
containing 1 or 2 nitrogen atoms or oxygen atoms, said heterocycle
optionally being condensed with an aromatic ring optionally having
substituents, [0024] a, b, c, d, e, f and g are all carbon atoms,
or any one or two thereof is(are) nitrogen atom(s) and the rest is
a carbon atom, [0025] n is 0, 1, 2 or 3, and [0026] A is a carbon
atom or a nitrogen atom, provided that when A is a carbon atom, A
may be substituted by a hydroxyl group, carboxyl or alkoxycarbonyl,
and of the above-mentioned groups, alkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and
heterocycle each optionally have substituents, or a
pharmaceutically acceptable salt thereof. (4) The L-proline
derivative of any of the aforementioned (1) to (3), wherein, in the
formula (I), the asymmetric carbon, to which X is bonded, is
expressed by an S configuration, X is a group of the formula (VI)
or (VII), R.sup.23 and R.sup.24 are the same or different and each
is nitro, cyano, C.sub.1-6alkyl, C.sub.1-6alkyloxy, halogen or
haloalkyl, Y is a sulfur atom and Z is a hydrogen atom, or a
pharmaceutically acceptable salt thereof. (5) The L-proline
derivative of the aforementioned (1), wherein, in the formula (I),
X is a hydroxyl group, phenylamino optionally having substituents,
2-pyridylamino optionally having substituents, 3-pyridazinylamino
optionally having substituents or 2-pyrimidinylamino optionally
having substituents, and the asymmetric carbon, to which X is
bonded, is expressed by an S configuration, or a pharmaceutically
acceptable salt thereof. (6) A compound of the formula (I-a)
##STR7## wherein [0027] X shows --NR.sup.1R.sup.2 wherein R.sup.1
and R.sup.2 may be the same or different and each is independently
a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl,
arylalkyl, heteroaryl or heteroarylalkyl, or may be bonded to each
other to form a heterocycle optionally containing 1 or 2 nitrogen
atoms or oxygen atoms, the heterocycle optionally being condensed
with an aromatic ring optionally having substituents, and the
heterocycle optionally being a spiro ring, [0028]
--NR.sup.3COR.sup.4 wherein R.sup.3 and R.sup.4 are the same or
different and each is independently a hydrogen atom, alkyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl,
heteroaryl or heteroarylalkyl, [0029] --NR.sup.5CONR.sup.6R.sup.7
or --NR.sup.5CH.sub.2CH.sub.2NR.sup.6R.sup.7 wherein R.sup.5,
R.sup.6 and R.sup.7 are the same or different and each is
independently a hydrogen atom, alkyl, acyl, cycloalkyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or
R.sup.6 and R.sup.7 may be bonded to each other to form a
heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen
atoms, said heterocycle optionally being condensed with an aromatic
ring optionally having substituents, or [0030]
--NR.sup.8SO.sub.2R.sup.9 wherein R.sup.8 and R.sup.9 are the same
or different and each is independently a hydrogen atom, alkyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or
heteroarylalkyl, [0031] Y is CH.sub.2, CH--OH, S, S.dbd.O or
SO.sub.2, [0032] Z is a hydrogen atom or a cyano, [0033] R.sup.35
is --COR.sup.41 wherein R.sup.41 is a hydrogen atom, alkyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or
heteroarylalkyl, or --COOR.sup.42 wherein R.sup.42 is alkyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or
heteroarylalkyl, and of the above-mentioned groups, alkyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl,
heteroaryl, heteroarylalkyl and heterocycle each optionally have
substituents. (7) A compound of the formula (I-b) ##STR8## wherein
[0034] Z is a hydrogen atom or a cyano, and [0035] R.sup.35 is
--COR.sup.41 wherein R.sup.41 is a hydrogen atom, alkyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or
heteroarylalkyl, or --COOR.sup.42 wherein R.sup.42 is alkyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or
heteroarylalkyl, and of the above-mentioned groups, alkyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and
heteroarylalkyl each optionally have substituents.
[0036] The present invention further relates to the following
compositions for pharmaceutical agents.
(8) A pharmaceutical composition containing an L-proline derivative
of any of the aforementioned (1)-(5) or a pharmaceutically
acceptable salt thereof, and a pharmacologically acceptable
carrier.
(9) A DPP-IV inhibitor containing an L-proline derivative of any of
the aforementioned (1)-(5) or a pharmaceutically acceptable salt
thereof as an active ingredient.
(10) A therapeutic agent for the disease where DPP-IV is involved,
which contains an L-proline derivative of any of the aforementioned
(1)-(5) or a pharmaceutically acceptable salt thereof as an active
ingredient.
(11) The therapeutic agent of the aforementioned (10), wherein the
aforementioned disease is diabetes, obesity, HIV infection, cancer
metastasis, dermopathy, prostatic hyperplasia, periodontitis or
autoimmune disease.
[0037] The symbols used in the present specification are explained
in the following.
[0038] Alkyl is preferably linear or branched alkyl having 1 to 8
carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, tert-butyl, pentyl, hexyl, octyl and the like.
[0039] Acyl is preferably linear or branched and has 1 to 8 carbon
atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl,
valeryl, isovaleryl, hexanoyl and the like.
[0040] Cycloalkyl preferably has 3 to 7 carbon atoms, and is
exemplified by cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl
and the like.
[0041] Cycloalkylalkyl has a cycloalkyl moiety, which is equivalent
to that mentioned above, and an alkyl moiety which is preferably
linear or branched and has 1 to 3 carbon atoms. Examples thereof
include cyclopropylmethyl, 2-cyclobutylethyl, 3-cyclopentylpropyl,
cyclohexylmethyl, 2-cyclohexylethyl, cycloheptylmethyl and the
like.
[0042] Aryl is preferably phenyl, naphthyl or ortho fused bicyclic
group having 8 to 10 ring atoms wherein at least one ring is an
aromatic ring (e.g., indenyl) and the like.
[0043] Arylalkyl has an aryl moiety, which is equivalent to that
mentioned above, and an alkyl moiety which is preferably linear or
branched and has 1 to 3 carbon atoms. Examples thereof include
benzyl, benzhydryl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl,
2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl, 3-(2-naphthyl)propyl and
the like.
[0044] Arylalkenyl has an aryl moiety, which is equivalent to that
mentioned above, and an alkenyl moiety which has 2 or 3 carbon
atoms and is linear or branched. Examples thereof include styryl
and the like.
[0045] Heteroaryl is preferably a 5 or 6-membered ring group having
carbon and 1-4 hetero atoms (oxygen, sulfur or nitrogen), an ortho
fused bicyclic heteroaryl having 8 to 10 ring atoms, which is
derived therefrom, particularly a benz derivative, those derived
from fusing a propenylene, trimethylene or tetramethylene group
therewith, stable N-oxide thereof and the like. Examples thereof
include pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl,
thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl,
1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,
1,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, benzoxazolyl,
benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzimidazolyl,
oxazolopyridyl, imidazopyridazinyl, thianaphthenyl,
isothianaphthenyl, benzofuranyl, isobenzofuranyl, benzothienyl,
chromenyl, isoindolyl, indolyl, indolinyl, indazolyl, isoquinolyl,
quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl,
2,1,3-benzoxadiazolyl, benzoxazinyl and the like.
[0046] Heteroarylalkyl has a heteroaryl moiety, which is equivalent
to that mentioned above, and an alkyl moiety which is preferably
has 1 to 3 carbon atoms and linear or branched. Examples thereof
include 2-pyrrolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl,
4-pyridylmethyl, 2-thienylmethyl, 2-(2-pyridyl)ethyl,
2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, 3-(2-pyrrolyl)propyl,
4-imidazolylmethyl and the like.
[0047] Heterocycle is a saturated or unsaturated monocyclic 4 to
7-membered ring group or 10 or 11-membered ring group, which is a
spiro ring, having carbon and at least one nitrogen, and optionally
other hetero atom (oxygen or sulfur). Examples thereof include
azetidinyl, pyrrolidinyl, piperidino, piperazinyl, morpholino,
1,4-diazepanyl, 1,2,5,6-tetrahydropyridyl, thiomorpholino,
oxothiomorpholino, dioxothiomorpholino, 3-azaspiro[5,5]undecyl,
1,3,8-triazaspiro[4,5]decyl and the like.
[0048] Moreover, the above-mentioned heterocycle may be condensed
with an aromatic ring (e.g., benzene ring, pyridine ring and the
like) optionally having substituents. Examples thereof include
indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl,
1,2,3,4-tetrahydroisoquinolyl, phthalimido, indolyl and the
like.
[0049] Halogen is exemplified by chlorine, bromine, fluorine and
iodine.
[0050] Haloalkyl is exemplified by trifluoromethyl,
2,2,2-trifluoroethyl, pentafluoroethyl and the like.
[0051] Of the above-mentioned substituents, alkyl, cycloalkyl,
cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl,
heteroarylalkyl and heterocycle are optionally substituted by the
following 1 or more substituents.
[0052] The substituents may be, for example, halogen, hydroxyl
group, nitro, cyano, trifluoromethyl, alkyl, alkoxy, alkylthio,
formyl, acyloxy, oxo, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
4-piperidinyl, 2-morpholinoethyl, 3-picolyl, arylalkyl,
--COOR.sub.a, --CH.sub.2 COOR.sub.a, --OCH.sub.2 COOR.sub.a,
--CONR.sub.bR.sub.c, --CH.sub.2 CQNR.sub.bR.sub.c (Q is .dbd.O or
.dbd.S), --OCH.sub.2CONR.sub.bR.sub.c,
--COO(CH.sub.2).sub.2NR.sub.eR.sub.f, --SO.sub.2T.sub.1,
--CONR.sub.sSO.sub.2T.sub.1, --NR.sub.eR.sub.f, --NR.sub.gCHO,
--NR.sub.gCOT.sub.2, --NR.sub.gCOOT.sub.2,
--NR.sub.9CONR.sub.iR.sub.j, --NR.sub.kSO.sub.2T.sub.3,
--SO.sub.2NR.sub.1R.sub.m, --SO.sub.2NR.sub.nCOT.sub.4,
methylenedioxy, ethyleneoxy and the like.
[0053] These substituents may have substituents, and phenyl,
2-pyridyl and 4-piperidinyl having substituents are exemplified by
4-cyanophenyl, 4-chlorophenyl, 4-methoxyphenyl, 5-cyano-2-pyridyl,
1-ethoxycarbonyl-4-piperidinyl and the like.
[0054] In the above-mentioned substituents of the substituents,
halogen, alkyl and arylalkyl are exemplified by those mentioned
above.
[0055] Alkoxy is linear or branched and preferably has 1 to 8
carbon atoms. Examples thereof include methoxy, ethoxy, propoxy,
butoxy, pentyloxy, hexyloxy, octyloxy and the like. Alkylthio is
linear or branched and preferably has 1 to 8 carbon atoms. Examples
thereof include methylthio, ethylthio, propylthio, butylthio,
pentylthio, hexylthio, octylthio and the like. Acyloxy is linear or
branched and preferably has 1 to 8 carbon atoms. Examples thereof
include formyloxy, acetyloxy, propionyloxy, butyryloxy, valeryloxy,
pivaloyloxy, hexanoyloxy, benzoyloxy and the like.
[0056] R.sub.a-R.sub.n show hydrogen, alkyl (as defined above) or
arylalkyl (as defined above). R.sub.b and R.sub.c, R.sub.e and
R.sub.f, R.sub.i and R.sub.j, and R.sub.l and R.sub.m, of
--NR.sub.bR.sub.c, --NR.sub.eR.sub.f, --NR.sub.iR.sub.j and
--NR.sub.lR.sub.m may be respectively bonded to each other to form
heterocycles each optionally having 1 or 2 nitrogen atoms or oxygen
atoms, and the heterocycle may be condensed with an aromatic ring
optionally having substituents (as defined above, and optionally
substituted by the aforementioned substituents). Moreover,
--NR.sub.eR.sub.f may show a heteroaryl having .dbd.O (e.g.,
2-pyrrolidinon-1-yl, succinimido, oxazolidin-2-on-3-yl,
2-benzoxazolinon-3-yl, phthalimido, cis-hexahydrophthalimido and
the like). T.sub.1-T.sub.4 show hydrogen atom, alkyl, cycloalkyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or
haloalkyl, which may be substituted by the aforementioned
substituents.
[0057] Due to the asymmetric carbon, to which X is bonded, in
compound (I), compound (I) can be present as an optically active
compound or a diastereomer mixture, and the diastereomer mixture
can be separated into each optically active compound by a known
method.
[0058] The compound (I) can show polymorphism, and can be present
as two or more tautomers.
[0059] Therefore, the present invention encompasses any of the
above-mentioned stereoisomers, optical isomers, polymorphs,
tautomers, optional mixtures thereof and the like.
[0060] The pharmaceutically acceptable salt of compound (I)
includes, for example, inorganic acid addition salts (e.g., salts
with hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric
acid, nitric acid, phosphoric acid and the like), organic acid
addition salts (e.g., salts with methanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic
acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid,
fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric
acid, succinic acid, mandelic acid, malic acid, pantothenic acid,
methylsulfuric acid and the like), salts with amino acids (e.g.,
salts with glutamic acid, aspartic acid and the like), and the
like.
[0061] The L-proline derivative of the present invention can be
produced by the following method.
[0062] Scheme 1 shows a production method of a compound of the
formula (I) wherein X is --OR.sup.10 or --OCOR.sup.11. ##STR9##
wherein R.sup.35 is an amino acid-protecting group (e.g.,
tert-butoxycarbonyl (Boc) and benzyloxycarbonyl (Cbz)), R.sup.36 is
a hydroxyl-protecting group (e.g., tert-butyldimethylmethylsilyl,
triisopropylsilyl and tert-butyldiphenylsilyl), A' is R.sup.10 or
COR.sup.11 and other symbols are as defined above.
[0063] When Z of a compound of the formula (VIII) is cyano, this
compound can be prepared by a method described in a reference
[Ashworth et al., Bioorganic & Medicainal Chemistry Letters,
vol. 6, 1163-1166 (1996)] or a conventional method based on such
reference. A compound of the formula (IX') [hereinafter to be
referred to as compound (IX')] can be prepared by silylation of
hydroxyl group of hydroxyproline derivative by a conventional
method.
Step a: Compound (VIII) is Reacted with Compound (IX) to Give Amide
Compound (XI), or Compound (VIII) is Reacted with Compound (IX') to
Give Amide Compound (X).
[0064] As a condensation agent for activating carboxylic acid of
compound (IX) or (IX'), there are recited, for example,
dicyclohexylcarbodiimide (DCC),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), hydrochloride
thereof, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroxyquinoline (EEDQ),
carbodiimidazole (CDI), diethylphosphoryl cyanide,
benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate
(PyBOP), diphenylphosphoryl azide (DPPA), isobutyl chloroformate,
diethylacetyl chloride, trimethylacetyl chloride and the like.
These condensation agent may be used alone, or an additive such as
N-hydroxysuccinimide (HONSu), hydroxybenzotriazole (HOBT) or
3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBT),
4-dimethylaminopyridine (DMAP) and the like is used in
combination.
[0065] This reaction is generally carried out in an inert solvent
and the inert solvent to be used may be any as long as it is
aprotic. Preferable examples include acetonitrile, tetrahydrofuran,
dichloromethane, chloroform, N,N-dimethylformamide (DMF) and the
like. This condensation is carried out generally at a temperature
of from -30.degree. C. to 80.degree. C., preferably from
-10.degree. C. to 25.degree. C.
Step b: Compound (X) is Deprotected to Give Compound (XI').
[0066] This reaction can be carried out in an inert solvent such as
tetrahydrofuran and the like, using tetrabutylammonium fluoride and
the like. The reaction mixture is preferably buffered with an acid
such as acetic acid and the like generally at a temperature of from
-30.degree. C. to 70.degree. C. for 10 min to 24 hr.
Step c: Compound (XI) is Reacted to Give Compound (XII), or
Compound (XI') is Reacted to Give Compound (XII').
[0067] By acylation of hydroxyl group of compound (XI) or (XI') by
a general method, a compound of the formula (XII) or (XII'),
wherein A' is COR.sup.11, can be obtained. The synthetic method of
compound (XII) or (XII'), wherein R.sup.11 is alkyl, cycloalkyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, is
exemplified by a method including use of an active carboxylic acid
derivative such as acid halide, a method including use of a
carboxylic acid and a coupling agent, and the like.
[0068] A compound of the formula (XII) or (XII') wherein A' is
R.sup.10 can be obtained by converting hydroxyl group of compound
(XI) or (XI') to alcoholate, which is followed by nucleophilic
substitution of alkyl halide and the like. The reaction is carried
out in the presence of a base such as sodium hydride and the like,
using alkyl halide and the like in an inert solvent such as
tetrahydrofuran and the like, generally at a temperature of from
-80.degree. C. to 60.degree. C., preferably from -50.degree. C. to
25.degree. C.
Step d: Compound (XI) is Reacted to Give Compound (XII'), or
Compound (XI') is Reacted to Give Compound (XII).
[0069] The reaction is carried out in the presence of phosphines
such as triphenylphosphine, tributylphosphine and the like and
diazodicarboxylic acid diester, using R.sup.11COOH or aryl or
heteroaryl having a hydroxyl group, and the like in an inert
solvent such as toluene, tetrahydrofuran and the like, generally at
a temperature of from -30.degree. C. to 110.degree. C., preferably
from 0.degree. C. to 25.degree. C.
[0070] A compound of the formula (XII') or (XII), wherein A' is
COR.sup.11, can be obtained by sulfonylation of hydroxyl group of
compound (XI) or (XI'), and reacting the compound with carboxylic
acid salt. The sulfonylation is carried out in the presence of a
base such as pyridine, triethylamine and the like using
p-toluenesulfonyl chloride, methanesulfonyl chloride,
trifluoromethanesulfonyl chloride and the like, in an inert solvent
such as dichloromethane, 1,2-dichloroethane and the like generally
from -30.degree. C. to 60.degree. C. for 10 min to 24 hr. The
subsequent reaction with carboxylic acid salt is carried out in the
presence of an inorganic base such as potassium carbonate, sodium
carbonate and the like using R.sup.11COOH in an inert solvent such
as acetone, hexamethylphosphoramide and the like generally from
0.degree. C. to 120.degree. C. for 10 min to 24 hr.
Step e: Compound (XII) is Deprotected to Give Compound (XIII), or
compound (XII') is deprotected to give compound (XIII').
[0071] When, in this reaction, the protecting group is Boc group,
for example, the compound is reacted in a solvent such as
acetonitrile, tetrahydrofuran, 1,4-dioxane, ethyl acetate,
methanol, ethanol, chloroform and the like, using an acid such as
hydrogen chloride, trifluoroacetic acid and the like generally from
-30.degree. C. to 60.degree. C. for 10 min to 24 hr for
deprotection.
[0072] Scheme 2 shows a production method of a compound of the
formula (I) wherein X is --NR.sup.1R.sup.2. ##STR10## wherein
OSO.sub.2R.sup.37 is a leaving group (e.g., tosylate (OTs),
mesylate (OMs) or triflate (OTf)), Hal is halogen, R.sup.38 and
R.sup.39 are the same or different and each is independently
hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heteroaryl or heteroarylalkyl, or may be bonded to each other to
form a heterocycle optionally containing 1 or 2 nitrogen atoms or
oxygen atoms, or the heterocycle may be condensed with an aromatic
ring optionally having substituents, and other symbols are as
defined above. Step f: Hydroxyl Group of Compound (XI) is
Sulfonylated to Give Compound (XIV).
[0073] This reaction is carried out in the presence of a base such
as pyridine, triethylamine and the like, using p-toluenesulfonyl
chloride, methanesulfonyl chloride, trifluoromethanesulfonyl
chloride and the like in an inert solvent such as dichloromethane,
1,2-dichloroethane and the like generally at a temperature of from
-30.degree. C. to 60.degree. C. for 10 min to 24 hr.
Step g: Compound (XIV) is Subjected to Azidation to Give Compound
(XV).
[0074] The reaction is carried out using a metal azide, such as
sodium azide, in a solvent such as N,N-dimethylformamide and the
like generally at a temperature of from 0.degree. C. to 120.degree.
C. for 30 min to 24 hr.
Step h: Compound (XV) is Directly Obtained from Compound (XI).
[0075] The reaction is carried out in the presence of phosphines
such as triphenylphosphine, tributylphosphine and the like, and
diazodicarboxylic acid diester using hydrogen azide, DPPA, zinc
azide bispyridine complex salt and the like in an inert solvent
such as toluene, tetrahydrofuran and the like generally at a
reaction temperature of from -30.degree. C. to 100.degree. C.
Step i: Compound (XV) is Reduced to Give Compound (XVI).
[0076] For this reaction, catalytic reduction using palladium,
platinum, nickel and the like, reduction by metalhydride, reduction
by triphenylphosphine, thiol, sulfide, diborane, or transition
metal and the like are mentioned.
Step j: Compound (XVI) is Reacted with Compound (XVII) or (XVII')
to Give Compound (XIX).
[0077] The reaction is carried out in the presence of a base such
as triethylamine, diisopropylethylamine and the like in an inert
solvent such as N-methyl-2-pyrrolidone, N,N-dimethylformamide,
tetrahydrofuran and the like at a temperature of from 0.degree. C.
to near boiling point of solvent, preferably from 0.degree. C. to
80.degree. C.
Step k: Compound (XVI) is Reacted with Compound (XVIII), which is
Followed by Reduction to Give Compound (XIX).
[0078] This reaction is carried out in the presence of sodium
borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride
and the like in an inert solvent such as methanol, ethanol,
dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile,
1,4-dioxane and the like, and using, where necessary, an acid
catalyst such as acetic acid, p-toluenesulfonic acid, boron
trifluoride diethylether complex and the like, generally at a
temperature of from 0.degree. C. to 100.degree. C. for 10 min to 20
hr.
[0079] By repeating Step j or k as necessary, compound (XIX)
wherein R.sup.1 and R.sup.2 may be the same or different can be
obtained.
Step l: Compound (XIX) is Directly Obtained from Compound (XI).
[0080] The reaction is carried out in the presence of phosphines
such as triphenylphosphine, tributylphosphine and the like and
diazodicarboxylic acid diester using iminodicarbonates,
sulfonamides, a nitrogen-containing compound having N--H hydrogen
and having high acidity, and the like in an inert solvent such as
toluene, tetrahydrofuran and the like.
Step m: Compound (XI) is Oxidized to Give (XX).
[0081] This reaction is carried out by, for example, a method using
pyridine sulfur trioxide complex and dimethyl sulfoxide at room
temperature. Examples of useful other methods include a method
using alkaline potassium permanganate solution; a method using
oxalyl chloride, dimethyl sulfoxide and tertiary amine; a method
using acetic anhydride and dimethyl sulfoxide; a method using EDC
and dimethyl sulfoxide with dichloroacetic acid as a catalyst; a
method using chromium oxide (XI) pyridine complex in
dichloromethane; a method using aqueous sodium hypochlorite
solution with TEMPO free radical as a catalyst in the presence of
sodium bromide in ethyl acetate and toluene, and the like.
Step n: Compound (XX) is Reacted with Compound (XXI), Which is
Followed by Reduction to Give Compound (XIX).
[0082] This reaction is carried out in the presence of sodium
borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride
and the like, in an inert solvent such as methanol, ethanol,
dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile,
1,4-dioxane and the like, and using as necessary an acidic
catalyst, such as acetic acid, p-toluenesulfonic acid, boron
trifluoride diethyl ether complex and the like generally at a
temperature of from 0.degree. C. to 100.degree. C. for 10 min to 20
hr.
[0083] The compound (XXI) can be synthesized by a known method.
Step o is the Same as Step e of Scheme 1.
[0084] The production method of a compound of the formula (I)
wherein X is --NR.sup.3COR.sup.4 is shown in Scheme 3. ##STR11##
wherein each symbol in the formula is as defined above.
[0085] The compound (XXIII) is the same as compound (XVI) obtained
in Scheme 2 or a compound (XIX) wherein one of R.sup.1 and R.sup.2
is hydrogen atom.
Step p: Compound (XXIII) is Reacted to Give Amide Compound
(XXIV).
[0086] The reaction is carried out using R.sup.4COCl or
R.sup.4CO.sub.2H after conversion to an acid halide with thionyl
chloride, thionyl bromide and the like or conversion to a mixed
acid anhydride with pivaloyl chloride, isobutyl chloroformate and
the like, in the presence of a tertiary base such as triethylamine,
pyridine, N,N-dimethylaniline and the like, in an inert solvent
such as toluene, hexane, tetrahydrofuran, 1,4-dioxane, ethyl
acetate, chloroform, N,N-dimethylformamide, dimethyl sulfoxide,
hexamethylphosphoramide and the like, generally from 0.degree. C.
to 120.degree. C. for 10 min to 10 hr.
[0087] For the reaction with R.sup.4CO.sub.2H, a condensation agent
shown in Step a can be also used and the reaction is carried out in
an inert solvent such as acetonitrile, tetrahydrofuran,
dichloromethane, chloroform, N,N-dimethylformamide and the like
generally at a temperature of from -30.degree. C. to 80.degree. C.,
preferably from -10.degree. C. to 25.degree. C.
[0088] Step q is the same as Step e of Scheme 1.
[0089] The production method of a compound of the formula (I)
wherein X is --NR.sup.5CONR.sup.6R.sup.7 is shown in Scheme 4.
##STR12## wherein each symbol in the formula is as defined
above.
[0090] The compound (XXVI) is the same as compound (XVI) obtained
in Scheme 2 or a compound (XIX) wherein one of R.sup.1 and R.sup.2
is hydrogen atom.
Step r: Compound (XXVI) is Reacted to Give Urea Compound
(XXVII).
[0091] The reaction is carried out using isocyanate such as
R.sup.6--NCO and the like in an inert solvent such as toluene,
chloroform, dichloromethane, tetrahydrofuran and the like generally
at a temperature of from -20.degree. C. to 80.degree. C.,
preferably from 0.degree. C. to 25.degree. C.
[0092] Alternatively, there is a method using, for example,
carbodiimidazole, phosgene, diphosgene (trichloromethyl
chloroformate), triphosgene [bis(trichloromethyl)carbonate] and the
like, together with an amine represented by R.sup.6R.sup.7NH and a
tertiary base such as triethylamine and the like.
[0093] Step s is the same as Step e of Scheme 1.
[0094] The production method of a compound of the formula (I)
wherein X is --NR.sup.8SO.sub.2R.sup.9 is shown in Scheme 5.
##STR13## wherein each symbol in the formula is as defined
above.
[0095] The compound (XXIX) is the same as compound (XVI) obtained
in Scheme 2 or a compound (XIX) wherein one of R.sup.1 and R.sup.2
is hydrogen atom.
Step t: Compound (XXIX) is Reacted to Give Sulfonamide Compound
(XXX).
[0096] The reaction is carried out using sulfonyl chloride such as
R.sup.9--SO.sub.2Cl and the like in the presence of an organic base
such as triethylamine, pyridine and the like or an inorganic base
such as sodium carbonate, potassium carbonate, sodium hydroxide and
the like, in a solvent such as water, toluene, chloroform,
dichloromethane, tetrahydrofuran and the like generally at a
temperature of from -20.degree. C. to 80.degree. C.
[0097] Alternatively, there is a method wherein compound (XXIX) and
sulfuryl chloride are reacted in the presence of a tertiary base
such as triethylamine and the like in an inert solvent such as
chloroform, dichloromethane, tetrahydrofuran and the like to give
sulfamyl chloride, which is reacted with aryl compound in the
presence of a Lewis acid such as aluminum chloride and the
like.
[0098] Step u is the Same as Step e of Scheme 1.
[0099] A different production method of compound (XXII) is shown in
Scheme 6. This production method is useful when both R.sup.1 and
R.sup.2 are not hydrogen atoms. ##STR14## wherein R.sup.40 is alkyl
such as methyl, ethyl and the like, benzyl and the like, and other
symbols are as defined above.
[0100] Step v is the same as the method for conversion of compound
(XI) to compound (XIX) shown in Scheme 2.
Step w: Ester-Protected Carboxyl Group of Compound (XXXIII) is
Deprotected to Give Compound (XXXIV).
[0101] For reaction, general deprotection can be used. For example,
sodium hydroxide, potassium hydroxide, sodium carbonate, potassium
carbonate and the like are hydrolyzed under alkali conditions, or
when R.sup.40 is benzyl, catalytic hydrogenation and the like are
conducted in the presence of platinum, palladium and the like, in
an inert solvent such as methanol, ethanol and the like for
deprotection.
Step x: Compound (VIII) and Compound (XXXIV) are Reacted to Give
Amide Compound (XIX).
[0102] The reaction is carried out using a condensation agent shown
in Step a, in an inert solvent such as acetonitrile,
tetrahydrofuran, dichloromethane, chloroform, N,N-dimethylformamide
and the like generally at a temperature of from -30.degree. C. to
80.degree. C., preferably from -10.degree. C. to 25.degree. C.
[0103] The compound of the formula (XXIV) shown in Scheme 3, the
compound of the formula (XXVII) shown in Scheme 4 and the compound
of the formula (XXX) shown in Scheme 5 can be produced by the
routes shown in Scheme 6.
[0104] The production method of compound (XXII), wherein the
asymmetric carbon, to which NR.sup.1R.sup.2 is bonded, is shown by
S configuration, is shown in Scheme 2 using the compound of the
formula (XI) as a starting material, and in Scheme 6, using the
compound of the formula (XXXII) as a starting material.
[0105] Besides the above-mentioned, a compound (XXII'), wherein the
asymmetric carbon, to which NR.sup.1R.sup.2 is bonded, is shown by
R configuration, ##STR15## wherein each symbol in the formula is as
defined above, can be also produced by a method similar to the one
mentioned above using compound (XI') ##STR16## wherein each symbol
in the formula is as defined above, or a compound (XXXII')
##STR17## wherein each symbol in the formula is as defined above,
as a starting material.
[0106] When Z in each formula shows cyano, each compound up to an
intermediate is produced with Z of the formula as a carbamoyl group
and dehydrated by a known method for conversion thereof to cyano
group.
[0107] This reaction is carried out using diphosphorus pentaoxide,
phosphorus oxychloride-imidazole, trifluoroacetic acid anhydride,
p-toluenesulfonyl chloride-pyridine and the like as a dehydrating
agent in an inert solvent such as dichloromethane, pyridine and the
like.
[0108] The L-proline derivative of the formula (I) of the present
invention produced in this manner can be obtained at an optional
purity by applying a known separation and purification means as
necessary, such as concentration, extraction, chromatography,
reprecipitation, recrystallization and the like.
[0109] The L-proline derivative of the formula (I) can be prepared
into an acid addition salt as necessary with an inorganic acid such
as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric
acid, nitric acid, phosphoric acid and the like or an organic acid
such as methanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic
acid, oxalic acid, citric acid, malonic acid, fumaric acid,
glutaric acid, adipic acid, maleic acid, tartaric acid, succinic
acid, mandelic acid, malic acid, pantothenic acid, methylsulfuric
acid and the like. In addition, it is also present as a solvate
such as hydrate and the like.
[0110] The compound of the formula (I) or a pharmacologically
acceptable salt of the present invention has a superior DPP-IV
inhibitory activity in mammals (e.g., human, dog, cat, rat and the
like).
[0111] Therefore, the compound of the present invention (I) or a
pharmacologically acceptable salt thereof is useful as a DPP-IV
inhibitor and useful for the prophylaxis or treatment of various
diseases considered to be caused by DPP-IV, for example, for the
prophylaxis or treatment of diseases where GLP-1 is considered to
be involved (e.g., diabetes, obesity and the like), and the
like.
[0112] The compound (I) of the present invention can be
administered to a same subject with other therapeutic drug for
diabetes, therapeutic drug for diabetic complications,
anti-hyperlipidemic agent, antihypertensive agent and the like at
the same time or timelag. As used herein, examples of the
therapeutic drug for diabetes include insulin sensitivity
increasing agent, .alpha.-glucosidase inhibitor, biguanide agent
and the like. Examples of the therapeutic drug for diabetic
complications include aldose reductase inhibitor. As the
anti-hyperlipidemic agent, statin compound, which is a cholesterol
synthetase inhibitor, squalene synthetase inhibitor, fibrates
having triglyceride lowering effect, and the like can be mentioned.
As the antihypertensive agent, calcium antagonist, angiotensin
converting enzyme inhibitor, angiotensin II antagonist and the like
can be mentioned. When the compound of the present invention is
used on combination with multiple agents, the mixing ratio thereof
can be appropriately determined depending on the subject of
administration, age and body weight of the administration subject,
symptom, administration time, dosage form, administration method,
combination and the like.
[0113] When the compound (I) of the present invention or an acid
addition salt thereof is used as the aforementioned pharmaceutical
agent, it is used on its own or admixed with an appropriate
pharmacologically acceptable carrier, an excipient, a diluent and
the like in the form of powder, granule, tablet, capsule, injection
and the like, and administered orally or parenterally. The
above-mentioned preparation contains an effective amount of
compound (I) or a pharmacologically acceptable salt thereof.
[0114] While the dose of the compound (I) or a pharmacologically
acceptable salt thereof varies depending on the administration
route, target disease, symptom, body weight and age of patients,
and the compound to be used, it can be determined as appropriately
according to the administration object. Generally, when orally
administered to an adult, 0.01-1000 mg/kg body weight/day,
preferably 0.05-500 mg/kg body weight/day, is preferably
administered once a day or in several doses a day.
EXAMPLES
[0115] The present invention is explained in detail by referring to
Reference Examples and Examples, which are not to be construed as
limitative.
[0116] .sup.1H-NMR was measured at 300 MHz unless particularly
indicated. The chemical shift of .sup.1H-NMR relative delta
(.delta.) value was expressed in parts per million (ppm) using
tetramethylsilane (TMS) as the internal standard. For the coupling
constant, obvious multiplicity is shown in hertz (Hz) using s
(singlet), d (doublet), t (triplet), q (quartet), quint (quintet),
m (multiplet), dd (doublet of doublets), td (triplet of doublets),
brs (broad singlet) and the like. Thin-layer chromatography used
was manufactured by Merck, and column chromatography was performed
using silica gel manufactured by Fuji silysia chemical.
[0117] For drying organic solutions in extraction, anhydrous sodium
sulfate or anhydrous magnesium sulfate was used, unless
particularly indicated.
Reference Example 1
Synthesis of
(S)-1-((2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl)-2--
cyanopyrrolidine
[0118] (1) N-tert-Butoxycarbonyl-L-cis-4-hydroxyproline (23.1 g)
and imidazole (30.0 g) were dissolved in DMF (300 mL).
tert-Butyldimethylsilyl chloride (33.3 g) was added thereto. After
stirring at room temperature for 16 hr, water (300 mL) was
gradually added under ice-cooling. The reaction solution was
acidified with 10% aqueous citric acid solution and extracted with
ethyl acetate. The extract was washed 3 times with water and with
brine, and dried. The solvent was distilled away under reduced
pressure. The residue was purified by silica gel chromatography to
give
N-tert-butoxycarbonyl-L-cis-4-tert-butyldimethylsilyloxyproline
(27.4 g) as a white solid.
[0119] (2) The above-mentioned compound (27.4 g) and
(S)-2-cyanopyrrolidine hydrochloride (10.4 g) were dissolved in DMF
(250 mL), and triethylamine (10.9 mL), HOBT (14.3 g) and EDC
hydrochloride (18.0 g) were added successively. The mixture was
stirred at room temperature for 15 hr. The reaction mixture was
added to saturated aqueous sodium hydrogencarbonate solution, and
extracted with ethyl acetate. The extract was washed with water and
brine, and dried. The solvent was evaporated under reduced
pressure. The residue was purified by silica gel chromatography to
give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-tert-butyldimethylsilyloxy-2-pyrro-
lidinylcarbonyl]-2-cyanopyrrolidine (25.3 g) as a slightly yellow
oil.
[0120] (3) The above-mentioned compound (25.3 g) was dissolved in
tetrahydrofuran (300 mL), and a 1.0 mol/L solution (60 mL) of
tetrabutylammonium fluoride in tetrahydrofuran was added dropwise
under ice-cooling. The mixture was stirred at room temperature for
3 hr, and the solvent was evaporated under reduced pressure. The
residue was added to brine, and extracted with ethyl acetate. The
extract was dried, and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel chromatography to
give the title compound (20.6 g) as a white solid.
[0121] .sup.1H-NMR(DMSO-d.sub.6).delta.1.25-1.45(9H,m),
1.50-1.64(1H,m), 1.95-2.30(4H,m), 2.98-3.13(1H,m), 3.30-3.67(4H,m),
4.13-4.26(1H,m), 4.30-4.42(1H,m), 4.77-4.88(1H,m), 5.16(1H,d,J=6.5
Hz).
Reference Example 2
Synthesis of
(S)-1-((2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl)-2--
cyanopyrrolidine
[0122] N-tert-Butoxycarbonyl-L-trans-4-hydroxyproline (68.4 g) and
(S)-2-cyanopyrrolidine hydrochloride (39.2 g) were dissolved in DMF
(350 mL), and triethylamine (41.4 mL), HOBT (49.9 g), and EDC
hydrochloride (62.5 g) were successively added. The mixture was
stirred at room temperature for 15 hr. The reaction mixture was
concentrated and brine and saturated aqueous sodium
hydrogencarbonate solution were added to the residue. The
precipitated crystals were collected by filtration. The filtrate
was extracted with ethyl acetate and the extract was dried. The
solvent was evaporated under reduced pressure. The residue and the
crystals were combined and washed with ethyl acetate to give the
title compound (60.7 g) as a white solid.
[0123] .sup.1H-NMR(CDCl.sub.3).delta.1.30-1.45(9H,m),
1.54-2.38(5H,m), 3.30-3.93(5H,m), 4.49-4.89(3H,m).
Reference Example 3
Synthesis of
(S)-1-((2S,4S)-4-amino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-2-cy-
anopyrrolidine
[0124] (1)
(S)-1-((2S,4R)-1-tert-Butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl)-2--
cyanopyrrolidine (title compound of Reference Example 2, 60.7 g)
and triethylamine (30.1 mL) were dissolved in DMF (300 mL).
Methanesulfonyl chloride (16 mL) was added thereto under
ice-cooling. After stirring at room temperature for 3 hr, the
reaction mixture was washed with water and dried. The solvent was
evaporated under reduced pressure. Ethanol was added to the residue
to give
(S)-1-((2S,4R)-1-tert-butoxycarbonyl-4-methanesulfonyloxy-2-pyrrolidinylc-
arbonyl)-2-cyanopyrrolidine (64.1 g) as a white solid.
[0125] (2) The above-mentioned compound (64.1 g) and sodium azide
(11.8 g) were dissolved in DMF (250 mL), and the mixture was
stirred at 85.degree. C. for 5 hr. The reaction mixture was added
to water and the precipitated crystals were collected by filtration
to give
(S)-1-((2S,4S)-4-azido-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-2-cy-
anopyrrolidine (50.1 g) as a white solid.
[0126] (3) The above-mentioned compound (50.1 g) was dissolved in
ethanol (500 mL). The mixture was stirred under a hydrogen
atomosphere (1 atm) in the presence of 5% palladium/barium sulfate
(5.9 g). The reaction mixture was filtrated and the filtrate was
concentrated under reduced pressure. Diethyl ether was added
thereto and the precipitated solid was collected by filtration to
give the title compound (45.5 g) as a white solid.
[0127] .sup.1H-NMR(CDCl.sub.3).delta.1.23-1.52(10H,m),
1.60-2.47(8H,m), 2.86-3.00(1H,m), 3.43-3.65(3H,m), 4.25-4.40(1H,m),
4.75-5.02(1H,m).
Reference Example 4
Synthesis of
(2S,4R)-1-tert-butoxycarbonyl-4-(5-cyano-2-pyridyl)aminopyrrolidine-2-car-
boxylic acid
[0128] (1) N-tert-Butoxycarbonyl-L-cis-4-hydroxyproline (24.5 g)
and triethylamine (15.4 mL) were dissolved in dichloromethane (500
mL). Methanesulfonyl chloride (8.1 mL) was added thereto under
ice-cooling. After stirring at room temperature for 3 hr, the
reaction mixture was washed with water and dried. The solvent was
evaporated under reduced pressure. The residue was dissolved in DMF
(250 mL) and sodium azide (7.15 g) was added. The mixture was
stirred at 80.degree. C. for 3 hr, added to water and extracted
with ethyl acetate. The extract was dried, and the solvent was
evaporated under reduced pressure. The residue was purified by
silica gel chromatography to give methyl
(2S,4R)-4-azido-1-tert-butoxycarbonylpyrrolidine-2-carboxylate
(18.4 g) as an oil.
[0129] (2) The above-mentioned compound (18.3 g) was dissolved in
methanol (200 mL), and the mixture was stirred under a hydrogen
atomosphere (1 atm) in the presence of 5% palladium/carbon (5.9 g).
The reaction mixture was filtrated and the filtrate was
concentrated under reduced pressure to give methyl
(2S,4R)-4-amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate
(16.6 g) as an oil.
[0130] (3) The above-mentioned compound (3.32 g) and triethylamine
(1.4 mL) were dissolved in tetrahydrofuran (20 mL), and
2-chloro-5-cyanopyridine (1.0 g) was added thereto. The mixture was
stirred at 80.degree. C. for 4 hr. The reaction mixture was added
to water and extracted with ethyl acetate. The extract was washed
with saturated aqueous sodium hydrogencarbonate solution and brine,
and dried. The solvent was evaporated under reduced pressure, and
the residue was purified by silica gel chromatography to give
methyl
(2S,4R)-1-tert-butoxycarbonyl-4-(5-cyano-2-pyridylamino)pyrrolidine-2-car-
boxylate (1.2 g) as a white solid.
[0131] (4) The above-mentioned compound (0.94 g) was dissolved in
methanol (30 mL), and 1 mol/L aqueous sodium hydroxide solution
(3.0 mL) was added thereto. The mixture was stirred at room
temperature for 15 hr. The reaction mixture was concentrated and 5%
aqueous citric acid solution was added to the residue. The mixture
was extracted with ethyl acetate, and the extract was washed with
brine and dried. The solvent was evaporated under reduced pressure
to give the title compound (0.75 g) as amorphous.
[0132] .sup.1H-NMR(CDCl.sub.3).delta.1.33-1.57(9H,m),
2.14-2.68(2H,m), 3.27-3.55(1H,m), 3.82-4.00(1H,m), 4.33-4.57(2H,m),
6.23(1H,brs), 6.50(1H,d,J=8.7 Hz), 7.64(1H,dd,J=8.7, 2.1 Hz)
8.33(1H,d,J=2.1 Hz).
Reference Example 5
Synthesis of
(2S,4S)-4-(2-benzoxazolyl)amino-1-tert-butoxycarbonylpyrrolidine-2-carbox-
ylic acid
[0133] (1) N-tert-Butoxycarbonyl-L-trans-4-hydroxyproline (20.7 g)
and triethylamine (15.4 mL) were dissolved in dichloromethane (400
mL). p-Toluenesulfonic acid chloride (16.8 g) was added thereto
under ice-cooling. After stirring at room temperature for 15 hr,
the reaction mixture was washed with water and dried. The solvent
was evaporated under reduced pressure and the residue was purified
by silica gel chromatography to give methyl
(2S,4R)-1-tert-butoxycarbonyl-4-(p-toluenesulfonyloxy)pyrrolidine-2-carbo-
xylate (11.7 g).
[0134] (2) The above-mentioned compound (11.7 g) was dissolved in
DMF (100 mL), and sodium azide (1.95 g) was added thereto. The
mixture was stirred at 80.degree. C. for 3 hr. The reaction mixture
was added to water, and extracted with ethyl acetate. The extract
was dried, and the solvent was evaporated under reduced pressure.
The residue was purified by silica gel chromatography to give
methyl
(2S,4S)-4-azide-1-tert-butoxycarbonylpyrrolidine-2-carboxylate
(7.99 g) as an oil.
[0135] (3) The above-mentioned compound (7.99 g) was dissolved in
methanol (150 mL). The mixture was stirred under a hydrogen
atomosphere (1 atm) in the presence of 10% palladium/carbon (2 g).
The reaction mixture was filtrated and the filtrate was
concentrated under reduced pressure to give methyl
(2S,4S)-4-amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate
(7.23 g) as an oil.
[0136] (4) The above-mentioned compound (2.4 g) and triethylamine
(1.4 mL) were dissolved in tetrahydrofuran (20 mL), and
2-chlorobenzoxazole (0.82 .mu.L) was added thereto. The mixture was
stirred at 60.degree. C. for 3 hr. The reaction mixture was added
to water, and extracted with ethyl acetate. The extract was washed
with saturated aqueous sodium hydrogencarbonate solution and dried.
The solvent was evaporated under reduced pressure and the residue
was purified by silica gel chromatography to give methyl
(2S,4S)-4-(2-benzoxazolyl)amino-1-tert-butoxycarbonylpyrrolidine-2-carbox-
ylate (1.49 g) as amorphous.
[0137] (5) The above-mentioned compound (1.49 g) was dissolved in
methanol (50 mL), and 1 mol/L aqueous sodium hydroxide solution
(5.0 mL) was added thereto. The mixture was stirred for 15 hr and
concentrated. The residue was extracted with water and the extract
was washed with ethyl acetate. 5% Aqueous citric acid solution was
added thereto to give the title compound (1.39 g) as a white
solid.
[0138] .sup.1H-NMR(DMSO-d.sub.6).delta.1.28-1.50(9H,m),
1.93-2.08(1H,m), 2.53-2.75(1H,m), 3.18-3.30(1H,m), 3.77-4.33(2H,m),
6.97-7.40(4H,m), 8.06-8.16(1H,m), 12.63(1H,brs).
Reference Example 6
Synthesis of
(2S,4R)-4-(2-benzoxazolyl)amino-1-tert-butoxycarbonylpyrrolidine-2-carbox-
ylic acid
[0139] (1) Methyl
(2S,4R)-4-amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate
[product of Reference Example 4 (2), 3.32 g] and triethylamine (1.4
mL) were dissolved in tetrahydrofuran (20 mL). 2-Chlorobenzoxazole
(0.86 mL) was added thereto and the mixture was stirred at room
temperature for 48 hr. The reaction mixture was added to water and
extracted with ethyl acetate. The extract was washed with saturated
aqueous sodium hydrogencarbonate solution and brine, and dried. The
solvent was evaporated under reduced pressure and the residue was
purified by silica gel chromatography to give methyl
(2S,4R)-4-(2-benzoxazolyl)amino-1-tert-butoxycarbonylpyrrolidine-2-carbox-
ylate (1.48 g) as a white solid.
[0140] (2) The above-mentioned compound (1.31 g) was dissolved in
methanol (30 mL) and 1 mol/L aqueous sodium hydroxide solution (4.4
mL) was added thereto. The mixture was stirred at room temperature
for 15 hr and the reaction mixture was concentrated. To the residue
was added 5% aqueous citric acid solution and the mixture was
extracted with ethyl acetate. The extract was washed with brine and
dried. The solvent was evaporated under reduced pressure to give
the title compound (1.11 g) as a white solid.
[0141] .sup.1H-NMR(CDCl.sub.3).delta.1.32-1.68(9H,m),
2.20-2.80(2H,m), 3.37-3.62(1H,m), 3.88-4.10(1H,m), 4.37-4.68(2H,m),
7.01-7.43(4H,m).
Reference Example 7
Synthesis of
(2S,4S)-4-benzoylamino-1-tert-butoxycarbonylpyrrolidine-2-carboxylic
acid
[0142] (1) Methyl
(2S,4S)-4-amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate
[product of Reference Example 5 (3), 2.4 g] and triethylamine (2.0
mL) were dissolved in tetrahydrofuran (20 mL), and benzoyl chloride
(1.1 mL) was added thereto. The mixture was stirred for 1 hr. The
reaction mixture was added to water and extracted with ethyl
acetate. The extract was washed with saturated aqueous sodium
hydrogencarbonate solution and dried. The solvent was evaporated
under reduced pressure and the residue was purified by silica gel
chromatography to give methyl
(2S,4S)-4-benzoylamino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate
(1.63 g) as a white solid.
[0143] (2) The above-mentioned compound (1.5 g) was dissolved in
methanol (50 mL) and 1 mol/L aqueous sodium hydroxide solution (4.7
mL) was added thereto. The mixture was stirred for 15 hr. The
reaction mixture was concentrated and 5% aqueous citric acid
solution was added to the residue. The mixture was extracted with
ethyl acetate, and the extract was washed with brine and dried. The
solvent was evaporated under reduced pressure to give the title
compound (1.1 g) as amorphous.
Reference Example 8
Synthesis of
(2S,4R)-4-benzoylamino-1-tert-butoxycarbonylpyrrolidine-2-carboxylic
acid
[0144] (1) The product (3.32 g) of Reference Example 4 (2) and
triethylamine (1.4 mL) were dissolved in tetrahydrofuran (20 mL),
and benzoyl chloride (0.87 mL) was added thereto. The mixture was
stirred for 1 hr. The reaction mixture was added to water and
extracted with ethyl acetate. The extract was washed with saturated
aqueous sodium hydrogencarbonate solution and dried. The solvent
was evaporated under reduced pressure and the residue was purified
by silica gel chromatography to give methyl
(2S,4R)-4-benzoylamino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate
(2.4 g) as amorphous.
[0145] (2) The above-mentioned compound (2.4 g) was dissolved in
methanol (80 mL), and 1 mol/L aqueous sodium hydroxide solution
(8.2 mL) was added thereto. The mixture was stirred for 15 hr. The
reaction mixture was concentrated and 5% aqueous citric acid
solution was added to the residue. The mixture was extracted with
ethyl acetate, and the extract was washed with brine and dried. The
solvent was evaporated under reduced pressure to give the title
compound (1.9 g) as a white solid.
[0146] .sup.1H-NMR(CDCl.sub.3).delta.1.33-1.55(9H,m),
2.12-2.75(2H,m), 3.31-3.60(1H,m), 3.84-4.00(1H,m), 4.30-4.81(2H,m),
6.16-6.55(4H,m), 7.38-7.80(5H,m).
Reference Example 9
Synthesis of
3-[((2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-t-
hiazolidine
[0147] N-tert-Butoxycarbonyl-L-trans-4-hydroxyproline (69.4 g) and
thiazolidine (29.4 g) were dissolved in DMF (300 mL), and HOBT
(50.5 g) and EDC hydrochloride (63.3 g) were successively added
thereto. The mixture was stirred at room temperature for 18 hr and
the reaction mixture was concentrated. To the concentrate were
added brine and saturated aqueous sodium hydrogencarbonate
solution, and the mixture was extracted with ethyl acetate. The
extract was dried, and the solvent was evaporated under reduced
pressure to give the title compound (56.3 g) as a colorless
transparent oil.
[0148] .sup.1H-NMR(CDCl.sub.3).delta.1.41-1.45(9H,m),
1.95-2.34(2H,m) 2.62-3.25(2H,m), 3.40-3.98(4H,m),
4.40-4.90(4H,m).
Reference Example 10
Synthesis of
3-((2S,4S)-4-amino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-1,3-thia-
zolidine
[0149] (1)
3-((2S,4R)-1-tert-Butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl)-1,3-th-
iazolidine (title compound of Reference Example 9, 56.3 g) and
triethylamine (28.5 mL) were dissolved in dichloromethane (1.0 l),
and methanesulfonyl chloride (15.1 mL) was added thereto under
ice-cooling. After stirring under ice-cooling for 1 hr, the
reaction mixture was washed with water and dried. The solvent was
evaporated under reduced pressure to give
3-((2S,4R)-1-tert-butoxycarbonyl-4-methanesulfonyloxy-2-pyrrolidinylcarbo-
nyl)-1,3-thiazolidine (70.5 g) as an oil.
[0150] (2) The above-mentioned compound (70.5 g) and sodium azide
(13.3 g) were dissolved in DMF (500 mL), and the mixture was
stirred at 80.degree. C. for 5 hr. The reaction mixture was
concentrated under reduced pressure and water was added thereto.
The mixture was extracted with ethyl acetate, and the organic layer
was dried and concentrated. The residue was purified by silica gel
chromatography to give
3-((2S,4S)-4-azido-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-1,3-thia-
zolidine (39.5 g) as a white solid.
[0151] (3) The above-mentioned compound (26.7 g) was dissolved in
ethanol (270 mL) and the mixture was stirred under a hydrogen
atomosphere (1 atm) for 18 hr in the presence of 10% palladium
carbon catalyst (13.4 g). The reaction mixture was filtrated and
the filtrate was concentrated under reduced pressure to give the
title compound (24.5 g) as a black solid.
[0152] .sup.1H-NMR(CDCl.sub.3).delta.1.40-1.45(9H,m),
1.70-1.83(1H,m), 2.07(2H,brs), 2.32-2.56(1H,m), 2.90-3.19(2H,m),
3.25-3.58(2H,m), 3.60-4.14(3H,m), 4.31-4.80(3H,m).
Reference Example 11
Synthesis of
3-((2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl)-1,3-th-
iazolidine
[0153] (1)
N-tert-Butoxycarbonyl-L-cis-4-tert-butyldimethylsilyloxyproline
[product of Reference Example 1 (1), 5.55 g] and thiazolidine (1.4
mL) were dissolved in DMF (55 mL), and triethylamine (2.24 mL),
HOBT (2.96 g) and EDC hydrochloride (3.70 g) were successively
added thereto. The mixture was stirred at room temperature for 13
hr. The reaction mixture was added to saturated aqueous sodium
hydrogencarbonate solution, and extracted with ethyl acetate. The
extract was washed with water and brine and dried. The solvent was
evaporated under reduced pressure and the residue was purified by
silica gel chromatography to give
3-[(2S,4S)-1-tert-butoxycarbonyl-4-tert-butyldimethylsilyloxy-2-pyrrolidi-
nylcarbonyl]-1,3-thiazolidine (3.41 g) as a white solid.
[0154] (2) The above-mentioned compound (3.36 g) was dissolved in
tetrahydrofuran (50 mL), and a 1.0 mol/L solution (9 mL)
tetrabutylammonium fluoride in tetrahydrofuran was added dropwise
under ice-cooling. The mixture was stirred at room temperature for
18 hr, and the solvent was evaporated under reduced pressure. The
residue was added to brine and extracted with ethyl acetate. The
extract was dried and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel chromatography to
give the title compound (2.44 g) as a white solid.
[0155] .sup.1H-NMR(DMSO-d.sub.6).delta.1.25-1.45(9H,m),
1.52-1.70(1H,m), 2.35-2.50(1H,m), 2.95-3.20(3H,m), 3.50-3.80(3H,m),
4.10-4.25(1H,m), 4.37-4.78(3H,m), 5.18(1H,brs).
Reference Example 12
Synthesis of
3-((S)-1-tert-butoxycarbonyl-4-oxo-2-pyrrolidinylcarbonyl)-1,3-thiazolidi-
ne
[0156] The title compound (55.4 g) of Reference Example 9 and
triethylamine (46 mL) were dissolved in dichloromethane (350 mL). A
solution of sulfur trioxide pyridine complex (52.4 g) in dimethyl
sulfoxide (150 mL) was added thereto under ice-cooling, and the
mixture was stirred for 2 hr. Saturated aqueous sodium
hydrogencarbonate solution was added to the reaction mixture, and
the mixture was extracted with ethyl acetate. The extract was
washed with brine and dried. The solvent was evaporated under
reduced pressure and the residue was purified by silica gel
chromatography to give the title compound (30.3 g) as a white
solid.
[0157] .sup.1H-NMR(CDCl.sub.3).delta.1.47(9H,s), 2.45-2.57(1H,m),
2.70-2.93(1H,m), 2.97-3.22(2H,m), 3.66-3.78(0.6H,m),
3.80-4.10(3H,m), 4.28-4.38(0.4H,m), 4.45-5.08(3H,m).
Reference Example 13
Synthesis of
(2S,4S)-1-tert-butoxycarbonyl-4-(1-indolyl)pyrrolidine-2-carboxylic
acid
[0158] (1) N-tert-Butoxycarbonyl-L-trans-4-hydroxyproline benzyl
ester (20.3 g) and triethylamine (17.6 mL) were dissolved in
dichloromethane (120 mL), and a solution of sulfur trioxide
pyridine complex (25.1 g) in dimethyl sulfoxide (60 mL) was added
thereto under ice-cooling, and the mixture was stirred for 5 hr.
Saturated aqueous sodium hydrogencarbonate solution was added to
the reaction mixture, and the mixture was extracted with ethyl
acetate. The extract was washed with brine and dried. The solvent
was evaporated under reduced pressure and the residue was purified
by silica gel chromatography to give benzyl
(S)-1-tert-butoxycarbonyl-4-oxopyrrolidine-2-carboxylate (9.76 g)
as an oil.
[0159] (2) The above-mentioned compound (2.50 g), indoline (1.05
mL) and acetic acid (0.45 mL) were dissolved in 1,2-dichloroethane
(40 mL), and sodium triacetoxyborohydride (3.32 g) was added
thereto. The mixture was stirred at room temperature for 6 hr and
saturated aqueous sodium hydrogencarbonate solution was added to
the reaction mixture. The mixture was extracted with ethyl acetate,
and the extract was washed with brine and dried. The solvent was
evaporated under reduced pressure and the residue was purified by
silica gel chromatography to give benzyl
(2S,4S)-1-tert-butoxycarbonyl-4-(1-indolinyl)pyrrolidine-2-carboxylate
(2.59 g) as an oil.
[0160] (3) The above-mentioned compound (2.53 g) was dissolved in
acetone (50 mL) and manganese dioxide (7.51 g) was added thereto.
The mixture was stirred at room temperature for 12 hr and the
reaction mixture was filtrated. The filtrate was concentrated under
reduced pressure and the residue was purified by silica gel
chromatography to give benzyl
(2S,4S)-1-tert-butoxycarbonyl-4-(1-indolyl)pyrrolidine-2-carboxylate
(2.43 g) as an oil.
[0161] (4) The above-mentioned compound (2.42 g) was dissolved in
methanol (50 mL) and the mixture was stirred under a hydrogen
atomosphere (1 atm) for 20 hr in the presence of 10%
palladium/carbon (0.25 g). The reaction mixture was filtrated and
the filtrate was concentrated under reduced pressure to give the
title compound (1.91 g) as a pale-green solid.
[0162] .sup.1H-NMR(CDCl.sub.3).delta.1.49(9H,s), 2.37-3.00(2H,m),
3.60-3.85(1H,m), 4.05-4.25(1H,m), 4.40-4.60(1H,m), 4.95-5.10(1H,m),
6.54(1H,s), 7.13(1H,t,J=7.7 Hz), 7.18-7.28(2H,m), 7.38(1H,d,J=8.2
Hz), 7.62(1H,d,J=7.7 Hz).
Reference Example 14
Synthesis of
1-((S)-1-tert-butoxycarbonyl-4-oxo-2-pyrrolidinylcarbonyl)pyrrolidine
[0163] (1) N-tert-Butoxycarbonyl-L-trans-4-hydroxyproline (46.25 g)
and pyrrolidine (18 mL) were dissolved in DMF (200 mL), and HOBT
(45.5 g) and EDC hydrochloride (46.0 g) were successively added
thereto. The mixture was stirred at room temperature for 13 hr, and
the solvent was evaporated under reduced pressure. Saturated
aqueous sodium hydrogencarbonate solution was added to the residue,
and the mixture was extracted with ethyl acetate. The extract was
dried and the solvent was evaporated under reduced pressure to give
1-((2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl)pyrroli-
dine (59.3 g) as an oil.
[0164] (2) The above-mentioned compound (59.3 g) and triethylamine
(41 mL) were dissolved in dichloromethane (350 mL), and a solution
of sulfur trioxide pyridine complex (46.5 g) in dimethyl sulfoxide
(100 mL) was added thereto under ice-cooling. The mixture was
stirred for 2 hr and saturated aqueous sodium hydrogencarbonate
solution was added to the reaction mixture. The mixture was
extracted with ethyl acetate, and the extract was washed with brine
and dried. The solvent was evaporated under reduced pressure. The
residue was purified by silica gel chromatography to give the title
compound (11.9 g) as a white solid.
[0165] .sup.1H-NMR(CDCl.sub.3).delta.1.47(9H,s), 1.80-2.08(4H,m),
2.42-2.53(1H,m), 2.68-2.88(1H,m), 3.35-3.58(3H,m), 3.62-4.13(3H,m),
4.85(0.4H,d,J=9.0 Hz), 4.99(0.6H,d,J=8.7 Hz).
Reference Example 15
Synthesis of
3-((2S,4R)-4-amino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-1,3-thia-
zolidine
[0166] (1) The title compound (13.6 g) of Reference Example 11 was
dissolved in dichloromethane (250 mL), and triethylamine (7 mL) was
added thereto. Methanesulfonyl chloride (3.64 mL) was added to the
reaction mixture under ice-cooling, and the mixture was stirred for
1 hr. Water was added to the reaction mixture and the organic layer
was separated. The solvent was evaporated under reduced pressure
and the residue was dissolved in DMF (200 mL). Sodium azide (3.25
g) was added thereto and the mixture was stirred at 85.degree. C.
for 3 hr with heating. The reaction mixture was concentrated under
reduced pressure and water was added to the residue. The mixture
was extracted with ethyl acetate and the extract was concentrated
under reduced pressure. The residue was purified by silica gel
chromatography to give
3-((2S,4R)-4-azido-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-1,3-thia-
zolidine (9.9 g).
[0167] (2) The above-mentioned compound (9.9 g) was dissolved in
ethanol (150 mL) and the mixture was stirred at room temperature
for 18 hr under a hydrogen atomosphere (1 atm) in the presence of
10% palladium/carbon (10 g). The reaction mixture was filtrated and
the filtrate was concentrated under reduced pressure to give the
title compound (10.1 g) as a black solid.
[0168] .sup.1H-NMR(500 MHz, DMSO-d.sub.6).delta.1.30(4.5H,s),
1.38(4.5H,s), 1.42-1.52(1H,m), 2.05(2H,brs), 2.33-2.45(1H,m),
2.92-3.88(7H,m), 4.37-4.72(3H,m).
Example 1
Synthesis of
(S)-2-cyano-1-((2S,4S)-4-hydroxy-2-pyrrolidinylcarbonyl)pyrrolidine
trifluoroacetate
[0169]
(S)-1-((2S,4S)-1-tert-Butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbo-
nyl)-2-cyanopyrrolidine (title compound of Reference Example 1, 544
mg) was dissolved in dichloromethane (18 mL), and trifluoroacetic
acid (1.8 mL) was added thereto. The mixture was stirred at room
temperature for 18 hr, and the solvent was evaporated under reduced
pressure. Ethanol and diethyl ether were added to the residue and
the precipitated powder was collected by filtration to give the
title compound (350 mg) as powdery white crystals.
[0170] .sup.1H-NMR(DMSO-d.sub.6).delta.1.68-2.85(6H,m),
3.10-3.30(2H,m), 3.44-3.70(2H,m), 4.30-4.60(2H,m), 4.78-5.09(1H,m),
5.35-5.50(1H,m), 9.18(2H,brs).
Example 2
Synthesis of
(S)-2-cyano-1-((2S,4R)-4-hydroxy-2-pyrrolidinylcarbonyl)pyrrolidine
hydrochloride
[0171] The title compound (309 mg) of Reference Example 2 was
dissolved in 4 mol/L hydrochloric acid-1,4-dioxane (2 mL), and the
mixture was stirred at room temperature for 18 hr. The solvent was
evaporated under reduced pressure and the residue was purified by
HPLC to give the title compound (36 mg) as powdery white
crystals.
[0172] .sup.1H-NMR(DMSO-d.sub.6).delta.1.85-2.44(6H,m),
3.05-3.72(4H,m), 4.41-4.60(2H,m), 4.78-5.16(1H,m),
5.55-5.70(1H,m).
Example 3
Synthesis of
(S)-1-((2S,4S)-4-amino-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine
dihydrochloride
[0173]
(S)-1-((2S,4S)-4-Amino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbony-
l)-2-cyanopyrrolidine (title compound of Reference Example 3, 308
mg) was dissolved in 4 mol/L hydrochloric acid-1,4-dioxane (1.25
mL), and the mixture was stirred at room temperature for 27 hr. The
solvent was evaporated under reduced pressure and tetrahydrofuran
was added thereto. The precipitated solid was collected by
filtration to give the title compound (214 mg).
[0174] .sup.1H-NMR(DMSO-d.sub.6).delta.1.85-2.35(5H,m),
2.80-2.93(1H,m), 3.27-3.68(4H,m), 3.83-3.98(1H,m), 4.52-4.64(1H,m),
4.84(1H,d,J=4.5, 7.8 Hz), 8.81(3H,brs).
Example 4
Synthesis of
(S)-1-((2S,4S)-4-anilino-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine
trifluoroacetate
[0175] (1) The title compound (6.18 g) of Reference Example 2 and
triethylamine (8.4 mL) were dissolved in dimethyl sulfoxide (15
mL). Sulfur trioxide pyridine complex (9.54 g) was added thereto.
After stirring at room temperature for 1 hr, water was added to the
reaction mixture, and the mixture was extracted with ethyl acetate.
The extract was washed with water and dried. The solvent was
evaporated under reduced pressure and the residue was purified by
silica gel chromatography to give
(S)-1-((2S)-1-tert-butoxycarbonyl-4-oxo-2-pyrrolidinylcarbonyl)-2-cy-
anopyrrolidine (6.0 g) as an oil.
[0176] (2) The above-mentioned compound (1.5 g) and aniline (0.43
mL) were dissolved in methanol (25 mL), and the mixture was stirred
at room temperature for 6 hr in the presence of molecular sieve 3A
(1.5 g). Sodium cyanoborohydride (0.315 g) and acetic acid (0.4 mL)
were added to the reaction mixture, and the mixture was stirred for
1 hr. The reaction mixture was filtrated and the filtrate was
evaporated under reduced pressure. Saturated aqueous sodium
hydrogencarbonate solution was added to the residue, and the
mixture was extracted with ethyl acetate. The extract was dried,
and the solvent was evaporated under reduced pressure. The residue
was purified by silica gel chromatography to give
(S)-1-((2S,4S)-4-anilino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-2--
cyanopyrrolidine (0.74 g) as amorphous.
[0177] (3) The above-mentioned compound (0.82 g) was dissolved in
dichloromethane (21 mL) and trifluoroacetic acid (2.1 mL) was added
thereto. The mixture was stood at room temperature for 15 hr, and
the solvent was evaporated under reduced pressure. The residue was
purified by HPLC and freeze-dried to give the title compound (0.246
g) as amorphous.
[0178] .sup.1H-NMR (DMSO-d.sub.6).delta.1.52-2.33(5H,m),
2.87-3.22(2H,m), 3.75-5.13(8H,m), 6.50-6.67(3H,m), 7.03-7.20(2H,m),
8.91(1H,brs), 9.88(1H,brs).
Example 5
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(4-nitrophenyl)amino-2-pyrrolidinylcarbonyl]pyrr-
olidine hydrochloride
[0179] (1) The title compound (0.924 g) of Reference Example 3,
diisopropylethylamine (1.7 mL) and 4-fluoronitrobenzene (0.53 mL)
were dissolved in N-methyl-2-pyrrolidone (10 mL), and the mixture
was stirred at 80.degree. C. for 15 hr. Water was added to the
reaction mixture and the mixture was extracted with ethyl acetate.
The extract was dried, and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel chromatography to
give
(S)-1-[((2S,4S)-1-tert-butoxycarbonyl-4-(4-nitrophenyl)amino-2-pyrrolidin-
ylcarbonyl]-2-cyanopyrrolidine (1.14 g) as amorphous.
[0180] (2) The above-mentioned compound (1.13 g) was dissolved in
ethyl acetate (3.5 mL), and 4 mol/L hydrochloric acid-ethyl acetate
(3.4 mL) was added thereto. The mixture was stood at room
temperature for 15 hr. The precipitated solid was collected by
filtration to give the title compound (0.67 g).
[0181] .sup.1H-NMR(DMSO-d.sub.6).delta.1.74-2.37(6H,m),
2.90-3.10(1H,m), 3.27-3.97(3H,m), 4.37-4.70(2H,m), 4.80-5.20(1H,m),
6.90-7.34(2H,m), 7.88-8.03(2H,m), 9.09(1H,brs), 10.98(1H,brs).
Example 6
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(4-cyanophenyl)amino-2-pyrrolidinylcarbonyl]pyrr-
olidine hydrochloride
[0182] (1) The title compound (924 mg) of Reference Example 3,
diisopropylethylamine (1.7 mL) and 4-fluorobenzonitrile (606 mg)
were dissolved in N-methyl-2-pyrrolidone (10 mL), and the mixture
was stirred at 100.degree. C. for 15 hr. Water was added to the
reaction mixture, and the mixture was extracted with ethyl acetate.
The extract was dried and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel chromatography to
give
(S)-2-cyano-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-cyanophenyl)amino-2-pyr-
rolidinylcarbonyl]pyrrolidine (340 mg) as amorphous.
[0183] (2) The above-mentioned compound (420 mg) was dissolved in
ethyl acetate (1.2 mL), and 4 mol/L hydrochloric acid-ethyl acetate
(1.2 mL) was added thereto. The mixture was stood at room
temperature for 15 hr and the precipitated solid was collected by
filtration to give the title compound (289 mg).
[0184] .sup.1H-NMR(DMSO-d.sub.6).delta.1.62-1.80(1H,m),
1.97-2.33(4H,m), 2.90-3.24(2H,m), 3.64-3.96(3H,m), 4.20-4.63(2H,m),
4.80-5.13(1H,m), 6.70(2H,d,J=8.7 Hz), 7.53(2H,d,J=8.7 Hz),
9.00(1H,brs), 10.50(1H,brs).
Example 7
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(2-cyanophenyl)amino-2-pyrrolidinylcarbonyl]pyrr-
olidine hydrochloride
[0185] (1) The title compound (924 mg) of Reference Example 3,
diisopropylethylamine (1.7 mL) and 2-fluorobenzonitrile (0.54 mL)
were dissolved in N-methyl-2-pyrrolidone (10 mL), and the mixture
was stirred at 100.degree. C. for 15 hr. Water was added to the
reaction mixture, and the mixture was extracted with ethyl acetate.
The extract was dried and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel chromatography to
give
(S)-1-[((2S,4S)-1-tert-butoxycarbonyl-4-(2-cyanophenyl)amino-2-pyrrolidin-
ylcarbonyl]-2-cyanopyrrolidine (177 mg) as amorphous.
[0186] (2) The above-mentioned compound (115 mg) was dissolved in
ethyl acetate (0.5 mL), and 4 mol/L hydrochloric acid-ethyl acetate
(0.35 mL) was added thereto. The mixture was stood at room
temperature for 15 hr. The precipitated solid was collected by
filtration to give the title compound (46 mg).
[0187] .sup.1H-NMR(DMSO-d.sub.6).delta.1.70-2.36(6H,m),
2.93-3.74(3H,m), 4.28-4.66(2H,m), 4.81-5.15(1H,m), 6.33(1H,d,J=8.1
Hz), 6.77(1H,dd,J=8.4, 8.1 Hz), 6.90(1H,d,J=8.4 Hz),
7.39-7.60(2H,m).
Example 8
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(2-fluoro-4-nitrophenyl)amino-2-pyrrolidinylcarb-
onyl]pyrrolidine hydrochloride
[0188] (1) The title compound (0.924 g) of Reference Example 3,
diisopropylethylamine (1.7 mL) and 3,4-difluoronitrobenzene (0.55
mL) were dissolved in N-methyl-2-pyrrolidone (10 mL), and the
mixture was stirred at 80.degree. C. for 15 hr. Water was added to
the reaction mixture and the mixture was extracted with ethyl
acetate. The extract was dried and the solvent was evaporated under
reduced pressure. The residue was purified by silica gel
chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(2-fluoro-4-nitrophenyl)amino-2-py-
rrolidinylcarbonyl]-2-cyanopyrrolidine (0.95 g) as amorphous.
[0189] (2) The above-mentioned compound (0.95 g) was dissolved in
ethyl acetate (3 mL), and 4 mol/L hydrochloric acid-ethyl acetate
(2.65 mL) was added thereto. The mixture was stood at room
temperature for 15 hr and the precipitated solid was collected by
filtration to give the title compound (0.63 g).
[0190] .sup.1H-NMR(DMSO-d.sub.6).delta.1.74-2.37(6H,m),
2.90-3.10(1H,m), 3.27-3.97(3H,m), 4.37-4.70(2H,m), 4.80-5.20(1H,m),
6.90-7.34(2H,m), 7.88-8.03(2H,m), 9.09(1H,brs), 10.98(1H,brs).
Example 9
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(4-cyano-2-fluorophenyl)amino-2-pyrrolidinylcarb-
onyl]pyrrolidine hydrochloride
[0191] (1) The title compound (924 mg) of Reference Example 3,
diisopropylethylamine (1.7 mL) and 3,4-difluorobenzonitrile (700
mg) were dissolved in N-methyl-2-pyrrolidone (10 mL), and the
mixture was stirred at 80.degree. C. for 15 hr. Water was added to
the reaction mixture and the mixture was extracted with ethyl
acetate. The extract was dried and the solvent was evaporated under
reduced pressure. The residue was purified by silica gel
chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-cyano-2-fluorophenyl)amino-2-py-
rrolidinylcarbonyl]-2-cyanopyrrolidine (920 mg) as amorphous.
[0192] (2) The above-mentioned compound (920 mg) was dissolved in
ethyl acetate (2.5 mL), and 4 mol/L hydrochloric acid-ethyl acetate
(2.2 mL) was added thereto. The mixture was stood at room
temperature for 15 hr and the precipitated solid was collected by
filtration to give the title compound (756 mg).
[0193] .sup.1H-NMR(DMSO-d.sub.6).delta.1.67-2.35(6H,m),
2.88-3.06(1H,m), 3.22-3.73(3H,m), 4.27-4.64(2H,m), 4.86-5.13(1H,m),
6.73(1H,d,J=6.3 Hz), 7.82-7.92(1H,m), 7.51(1H,dd,J=8.4, 1.5 Hz),
7.61(1H,dd,J=12.0, 1.5 Hz), 8.98(1H,brs), 10.75(1H,brs).
Example 10
Synthesis of
(S)-1-[(2S,4S)-4-(4-bromo-2-cyanophenyl)amino-2-pyrrolidinylcarbonyl]-2-c-
yanopyrrolidine hydrochloride
[0194] (1) The title compound (924 mg) of Reference Example 3,
diisopropylethylamine (1.7 mL) and 3-bromo-6-fluorobenzonitrile
(1000 mg) were dissolved in N-methyl-2-pyrrolidone (10 mL) and the
mixture was stirred at 80.degree. C. for 5 hr. Water was added to
the reaction mixture and the mixture was extracted with ethyl
acetate. The extract was dried and the solvent was evaporated under
reduced pressure. The residue was purified by silica gel
chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-bromo-2-cyanophenyl)amino-2-pyr-
rolidinylcarbonyl]-2-cyanopyrrolidine (904 mg) as amorphous.
[0195] (2) The above-mentioned compound (900 mg) was dissolved in
ethyl acetate (2 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(1.8 mL) was added thereto. The mixture was stood at room
temperature for 15 hr and the precipitated solid was collected by
filtration to give the title compound (501 mg).
[0196] H-NMR(DMSO-d.sub.6).delta.1.70-2.34(4H,m), 2.93-3.07(1H,m),
3.42-3.65(3H,m), 4.33-4.61(2H,m), 4.82-5.10(1H,m), 6.56(1H,d,J=8.7
Hz), 6.94(1H,dd,J=8.1, 1.8 Hz), 7.12(1H,d,J=1.8 Hz),
7.49(1H,d,J=8.1 Hz), 8.96(1H,brs), 10.02(1H,brs).
Example 11
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(3,4-dicyanophenyl)amino-2-pyrrolidinylcarbonyl]-
pyrrolidine hydrochloride
[0197] (1) The title compound (0.924 g) of Reference Example 3,
diisopropylethylamine (1.7 mL) and 3-fluorophthalonitrile (0.73 g)
were dissolved in N-methyl-2-pyrrolidone (10 mL), and the mixture
was stirred at 80.degree. C. for 4 hr. Water was added to the
reaction mixture and the mixture was extracted with ethyl acetate.
The extract was dried and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel chromatography to
give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(3,4-dicyanophenyl)amino-2-pyrroli-
dinylcarbonyl]-2-cyanopyrrolidine (1.05 g) as amorphous.
[0198] (2) The above-mentioned compound (1.04 g) was dissolved in
ethyl acetate (5 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(3.0 mL) was added thereto. The mixture was stood at room
temperature for 15 hr and the precipitated solid was collected by
filtration to give the title compound (0.794 g).
[0199] .sup.1H-NMR(DMSO-d.sub.6).delta.1.62-1.79(1H,m),
1.95-2.35(3H,m), 2.90-3.28(2H,m), 3.53-3.71(2H,m), 4.23-4.64(2H,m),
4.80-5.13(1H,m), 7.01(1H,dd,J=9.0, 2.4 Hz), 7.24(1H,d,J=2.4 Hz),
7.65(1H,d,J=6.3 Hz), 7.78(1H,d,J=9.0 Hz), 9.06(1H,brs),
10.62(1H,brs).
Example 12
Synthesis of
(S)-1-[(2S,4S)-4-(3-chloro-4-cyanophenyl)amino-2-pyrrolidinylcarbonyl]-2--
cyanopyrrolidine hydrochloride
[0200] (1) The title compound (0.924 g) of Reference Example 3,
diisopropylethylamine (1.7 mL) and 2-chloro-4-fluorobenzonitrile
(0.78 g) were dissolved in N-methyl-2-pyrrolidone (10 mL), and the
mixture was stirred at 80.degree. C. for 4 hr. Water was added to
the reaction mixture and the mixture was extracted with ethyl
acetate. The extract was dried and the solvent was evaporated under
reduced pressure. The residue was purified by silica gel
chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(3-chloro-4-cyanophenyl)amino-2-py-
rrolidinylcarbonyl]-2-cyanopyrrolidine (0.94 g) as amorphous.
[0201] (2) The above-mentioned compound (0.93 g) was dissolved in
ethyl acetate (3 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(2.6 mL) was added thereto. The mixture was stood at room
temperature for 15 hr and the precipitated solid was collected by
filtration to give the title compound (0.73 g).
[0202] .sup.1H-NMR(DMSO-d.sub.6).delta.1.58-1.80(1H,m),
1.96-2.37(3H,m), 2.92-3.22(2H,m), 3.53-3.67(2H,m), 4.22-4.60(2H,m),
4.80-5.10(1H,m), 6.67(1H,dd,J=8.7, 2.4 Hz), 6.84(1H,d,J=2.4 Hz),
7.24(1H,d,J=6.9 Hz), 7.61(1H,d,J=8.7 Hz), 9.02(1H,brs),
9.97(1H,brs).
Example 13
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(4-cyano-2,6-difluorophenyl)amino-2-pyrrolidinyl-
carbonyl]pyrrolidine hydrochloride
[0203] (1) The title compound (0.924 g) of Reference Example 3,
diisopropylethylamine (1.7 mL) and 3,4,5-trifluorobenzonitrile
(0.79 g) were dissolved in N-methyl-2-pyrrolidone (10 mL), and the
mixture was stirred at 80.degree. C. for 3 hr. Water was added to
the reaction mixture and the mixture was extracted with ethyl
acetate. The extract was dried and the solvent was evaporated under
reduced pressure. The residue was purified by silica gel
chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-cyano-2,6-difluorophenyl)amino--
2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine (1.08 g) as
amorphous.
[0204] (2) The above-mentioned compound (1.08 g) was dissolved in
ethyl acetate (3 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(2.4 mL) was added thereto. The mixture was stood at room
temperature for 15 hr and the precipitated solid was collected by
filtration to give the title compound (0.706 g).
[0205] .sup.1H-NMR(DMSO-d.sub.6).delta.1.72-2.33(6H,m),
2.77-2.92(1H,m), 3.20-3.70(3H,m), 4.42-5.09(3H,m), 6.38(1H,d,J=8.4
Hz), 7.51-7.70(2H,m), 8.97(1H,brs), 10.73(1H,brs).
Example 14
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(3-trifluoromethyl-2-pyridyl)amino-2-pyrrolidiny-
lcarbonyl]pyrrolidine trifluoroacetate
[0206] (1) The title compound (1.86 g) of Reference Example 3,
diisopropylethylamine (3.14 mL) and
2-chloro-3-trifluoromethylpyridine (1.09 g) were dissolved in
N-methyl-2-pyrrolidone (36 mL), and the mixture was stirred at
120.degree. C. for 8 hr. The reaction mixture was added to
saturated aqueous sodium hydrogencarbonate solution, and the
mixture was extracted with ethyl acetate. The extract was dried and
the solvent was evaporated under reduced pressure. The residue was
purified by silica gel chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(3-trifluoromethyl-2-pyridyl)amino-
-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine (0.099 g).
[0207] (2) The above-mentioned compound (99 mg) was dissolved in
dichloromethane (2.2 mL) and trifluoroacetic acid (0.2 mL) was
added thereto. The mixture was stood at room temperature for 18 hr.
The reaction mixture was concentrated under reduced pressure and
purified by HPLC to give the title compound (3.2 mg) as
amorphous.
[0208] .sup.1H-NMR(DMSO-d.sub.6).delta.1.80-2.40(5H,m),
2.80-2.98(1H,m), 3.30-3.65(4H,m), 4.40-4.78(1H,m), 4.80-4.89(1H,m),
4.90-5.10(1H,m), 6.58(1H,d,J=7.8 Hz), 6.73-6.89(1H,m),
7.86(1H,d,J=6.6 Hz), 8.33(1H,d,J=3.9 Hz), 8.84(1H,brs),
9.56(1H,brs).
Example 15
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(3-nitro-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-
pyrrolidine trifluoroacetate
[0209] (1) The title compound (928 mg) of Reference Example 3,
diisopropylethylamine (1.57 mL) and 2-chloro-3-nitropyridine (476
mg) were dissolved in N-methyl-2-pyrrolidone (18 mL), and the
mixture was stirred at 80.degree. C. for 3 hr. The reaction mixture
was added to saturated aqueous sodium hydrogencarbonate solution,
and the mixture was extracted with ethyl acetate. The extract was
dried and the solvent was evaporated under reduced pressure. The
residue was purified by silica gel chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(3-nitro-2-pyridyl)amino-2-pyrroli-
dinylcarbonyl]-2-cyanopyrrolidine (851 mg) as a yellow oil.
[0210] (2) The above-mentioned compound (851 mg) was dissolved in
dichloromethane (20 mL) and trifluoroacetic acid (2.0 mL) was added
thereto. The mixture was stood at room temperature for 18 hr. The
reaction mixture was concentrated under reduced pressure and
diethyl ether was added to the residue. The precipitated product
was collected by filtration to give a yellow powder (677 mg). This
powder (257 mg) was purified by HPLC to give the title compound
(152 mg) as a yellow powder.
[0211] .sup.1H-NMR(DMSO-d.sub.6).delta.1.89-2.37(5H,m),
2.86-3.04(1H,m), 3.38-3.65(4H,m), 4.49-4.70(1H,m), 4.79-4.90(1H,m),
5.00-5.22(1H,m), 6.88(1H,dd,J=8.4, 4.8 Hz), 8.38-8.60(3H,m),
9.03(1H,brs), 9.73(1H,brs).
Example 16
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(3-cyano-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-
pyrrolidine hydrochloride
[0212] (1) The title compound (1.86 g) of Reference Example 3,
diisopropylethylamine (3.14 mL) and 2-chloro-3-cyanopyridine (0.831
g) were dissolved in N-methyl-2-pyrrolidone (36 mL), and the
mixture was stirred at 100.degree. C. for 9 hr. The reaction
mixture was added to saturated aqueous sodium hydrogencarbonate
solution, and the mixture was extracted with ethyl acetate. The
extract was dried and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel chromatography to
give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(3-cyano-2-pyridyl)amino-2-pyrroli-
dinylcarbonyl]-2-cyanopyrrolidine (0.487 g).
[0213] (2) The above-mentioned compound (0.464 g) was dissolved in
ethyl acetate (1.13 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(1.41 mL) was added thereto. The mixture was stood at room
temperature for 3 hr. The precipitated solid was collected by
filtration to give the title compound (0.370 g) as a pale-brown
powder.
[0214] .sup.1H-NMR(DMSO-d.sub.6).delta.1.72-2.31(5H,m),
2.81-2.98(1H,m), 3.20-3.36(1H,m), 3.40-3.69(3H,m), 4.45-4.67(1H,m),
4.75-5.11(1H,m), 6.78(1H,dd,J=7.5, 4.8 Hz), 7.35(1H,d,J=7.5 Hz),
7.99(1H,dd,J=7.5, 1.8 Hz), 8.33(1H,dd,J=5.1, 1.8 Hz), 8.88(1H,brs),
10.50(1H,brs).
Example 17
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(4-cyano-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-
pyrrolidine trifluoroacetate
[0215] (1) The title compound (928 mg) of Reference Example 3,
diisopropylethylamine (1.57 mL) and 2-chloro-4-cyanopyridine (416
mg) were dissolved in N-methyl-2-pyrrolidone (18 mL), and the
mixture was stirred at 120.degree. C. for 18 hr. The reaction
mixture was added to saturated aqueous sodium hydrogencarbonate
solution, and extracted with ethyl acetate. The extract was dried
and the solvent was evaporated under reduced pressure. The residue
was purified by silica gel chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-cyano-2-pyridyl)amino-2-
-pyrrolidinylcarbonyl]-2-cyanopyrrolidine (134 mg).
[0216] (2) The above-mentioned compound (134 mg) was dissolved in
dichloromethane (3.3 mL) and trifluoroacetic acid (0.3 mL) was
added thereto. The mixture was stirred at room temperature for 18
hr. The reaction mixture was concentrated under reduced pressure
and diethyl ether was added to the residue. The precipitated
product was collected by filtration to give a pale-brown powder (64
mg). This powder (64 mg) was purified by HPLC to give the title
compound (8 mg) as a white solid.
[0217] .sup.1H-NMR(DMSO-d.sub.6).delta.1.64-1.86(1H,m),
1.86-2.37(4H,m), 2.80-3.00(1H,m), 3.06-3.28(1H,m), 3.42-3.69(3H,m),
4.42-4.70(2H,m), 4.75-5.10(1H,m), 6.89(1H,s), 6.93(1H,d,J=5.2 Hz),
7.44(1H,d,J=6.2 Hz), 8.23(1H,d,J=4.7 Hz), 8.96(1H,brs),
9.81(1H,brs).
Example 18
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(5-cyano-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-
pyrrolidine dihydrochloride
[0218] (1) The title compound (462 mg) of Reference Example 3,
triethylamine (0.42 mL) and 2-chloro-5-cyanopyridine (210 mg) were
dissolved in DMF (10 mL), and the mixture was stirred at 90.degree.
C. for 24 hr. Water was added to the reaction mixture and the
mixture was extracted with ethyl acetate. The extract was dried and
the solvent was evaporated under reduced pressure. The residue was
purified by silica gel chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-cyano-2-pyridyl)amino-2-pyrroli-
dinylcarbonyl]-2-cyanopyrrolidine (310 mg) as amorphous.
[0219] (2) The above-mentioned compound (310 mg) was dissolved in
tetrahydrofuran (3 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(2 mL) was added thereto. The mixture was stood at room temperature
for 15 hr and the solvent was evaporated under reduced pressure.
The residue was purified by HPLC and freeze-dried to give the title
compound (150 mg) as amorphous.
[0220] .sup.1H-NMR(DMSO-d.sub.6).delta.1.77-2.33(2.81-3.23(2H,m),
4.00-5.15(6H,m), 6.61(1H,d,J=8.7 Hz), 7.77(1H,d,J=8.7 Hz),
7.91(1H,d,J=6.0 Hz), 8.46(1H,s), 8.98(1H,brs), 9.91(1H,brs).
Example 19
Synthesis of
(S)-1-[(2S,4R)-4-(5-cyano-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-2-cyano-
pyrrolidine dihydrochloride
[0221] (1)
(2S,4R)-1-tert-Butoxycarbonyl-4-(5-cyano-2-pyridyl)aminopyrrolidine-2-car-
boxylic acid (title compound of Reference Example 4, 0.73 g) and
(S)-2-cyanopyrrolidine hydrochloride (0.29 g) were dissolved in DMF
(10 mL), and triethylamine (0.62 mL), HOBT (0.34 g) and EDC
hydrochloride (0.42 g) were successively added thereto. The mixture
was stirred at room temperature for 15 hr. Water was added to the
reaction mixture and the mixture was extracted with ethyl acetate.
The extract was dried and evaporated under reduced pressure. The
residue was purified by silica gel chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-cyano-2-pyridyl)amino-2-pyrroli-
dinylcarbonyl]-2-cyanopyrrolidine (0.58 g) as amorphous.
[0222] (2) The above-mentioned compound (0.57 g) was dissolved in 4
mol/L hydrochloric acid-1,4-dioxane (4 mL), and the mixture was
stood at room temperature for 15 hr. The solvent was evaporated
under reduced pressure, and the residue was purified by HPLC and
freeze dried to give the title compound (0.181 g) as amorphous.
[0223] .sup.1H-NMR(DMSO-d.sub.6).delta.1.93-2.68(6H,m),
3.13-3.70(4H,m), 4.58-5.10(3H,m), 6.61(1H,d,J=8.7 Hz),
7.79(1H,dd,J=8.7, 1.8 Hz), 7.98(1H,brs), 8.48(1H,d,J=1.8 Hz),
8.87(1H,brs), 9.78(1H,brs).
Example 20
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(5-trifluoromethyl-2-pyridyl)amino-2-pyrrolidiny-
lcarbonyl]pyrrolidine 2 trifluoroacetate
[0224] (1) The title compound (0.924 g) of Reference Example 3,
diisopropylethylamine (1.7 mL) and
2-chloro-5-trifluoromethylpyridine (0.54 g) were dissolved in
N-methyl-2-pyrrolidone (10 mL), and the mixture was stirred at
120.degree. C. for 8 hr. Water was added to the reaction mixture
and the mixture was extracted with ethyl acetate. The extract was
dried and the solvent was evaporated under reduced pressure. The
residue was purified by silica gel chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-trifluoromethyl-2-pyridyl)amino-
-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine (0.40 g) as
amorphous.
[0225] (2) The above-mentioned compound (0.40 g) was dissolved in
dichloromethane (9 mL) and trifluoroacetic acid (0.9 mL) was added
thereto. The mixture was stood at room temperature for 15 hr, and
the solvent was evaporated under reduced pressure. The residue was
purified by HPLC and freeze-dried to give the title compound (0.163
g) as amorphous.
[0226] .sup.1H-NMR(DMSO-d.sub.6).delta.1.68-2.32(5H,m),
2.85-3.26(2H,m), 4.38-5.12(8H,m), 6.65(1H,d,J=9.0 Hz),
7.66(1H,d,J=6.3 Hz), 7.72(1H,dd,J=9.0, 2.4 Hz), 8.35(1H,s),
8.96(1H,brs), 9.80(1H,brs).
Example 21
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(5-nitro-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-
pyrrolidine dihydrochloride
[0227] (1) The title compound (0.462 g) of Reference Example 3,
triethylamine (0.42 mL) and 2-chloro-5-nitropyridine (0.24 g) were
dissolved in DMF (6 mL), and the mixture was stirred at 100.degree.
C. for 8 hr. Water was added to the reaction mixture and the
mixture was extracted with ethyl acetate. The extract was dried and
the solvent was evaporated under reduced pressure. The residue was
purified by silica gel chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-nitro-2-pyridyl)amino-2-pyrroli-
dinylcarbonyl]-2-cyanopyrrolidine (0.50 g) as amorphous.
[0228] (2) The above-mentioned compound (0.50 g) was dissolved in
tetrahydrofuran (3 mL) and 4 mol/L hydrochloric acid-1,4-dioxane (3
mL) was added thereto. The mixture was stood at room temperature
for 15 hr and the precipitated solid was collected by filtration to
give the title compound (0.445 g).
[0229] .sup.1H-NMR(DMSO-d.sub.6).delta.1.69-2.37(5H,m),
2.80-3.26(2H,m), 3.47-3.76(3H,m), 4.50-5.15(3H,m), 6.67(1H,d,J=9.3
Hz), 8.18(1H,dd,J=9.3, 3.0 Hz), 8.58(1H,s), 8.90-9.12(2H,m),
10.65(1H,brs).
Example 22
Synthesis of
(S)-2-cyano-1-[((2S,4S)-4-(3,5-dinitro-2-pyridyl)amino-2-pyrrolidinylcarb-
onyl]pyrrolidine trifluoroacetate
[0230] (1) The title compound (0.928 g) of Reference Example 3,
diisopropylethylamine (1.57 mL) and 2-chloro-3,5-dinitropyridine
(0.611 g) were dissolved in N-methyl-2-pyrrolidone (18 mL), and the
mixture was stirred at room temperature for 2 hr. The reaction
mixture was added to saturated aqueous sodium hydrogencarbonate
solution, and the mixture was extracted with ethyl acetate. The
extract was dried and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel chromatography to
give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(3,5-dinitro-2-pyridyl)amino-2-pyr-
rolidinylcarbonyl]-2-cyanopyrrolidine (1.21 g) as a yellow oil.
[0231] (2) The above-mentioned compound (1.18 g) was dissolved in
dichloromethane (25 mL) and trifluoroacetic acid (2.5 mL) was added
thereto. The mixture was stirred at room temperature for 18 hr. The
reaction mixture was concentrated under reduced pressure and
diethyl ether was added to the residue. The precipitated yellow
powder was collected by filtration to give the title compound (1.12
g).
[0232] .sup.1H-NMR(DMSO-d.sub.6).delta.1.68-2.33(5H,m),
2.84-3.08(1H,m), 3.32-3.68(4H,m), 4.49-4.70(1H,m), 4.76-4.90(1H,m),
5.11-5.37(1H,m), 9.01(1H,s), 9.04(1H,brs), 9.25(1H,brs),
9.28(1H,s), 9.84(1H,brs).
Example 23
Synthesis of
(S)-1-[(2S,4S)-4-(6-chloro-3-pyridazinyl)amino-2-pyrrolidinylcarbonyl]-2--
cyanopyrrolidine hydrochloride
[0233] (1) The title compound (928 mg) of Reference Example 3,
diisopropylethylamine (1.57 mL) and 2,6-dichloropyridazine (447 mg)
were dissolved in N-methyl-2-pyrrolidone (18 mL), and the mixture
was stirred at 120.degree. C. for 5 hr. The reaction mixture was
added to saturated aqueous sodium hydrogencarbonate solution, and
the mixture was extracted with ethyl acetate. The extract was dried
and the solvent was evaporated under reduced pressure. The residue
was purified by silica gel chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(6-chloro-3-pyridazinyl)amino-2-py-
rrolidinylcarbonyl]-2-cyanopyrrolidine (58 mg).
[0234] (2) The above-mentioned compound (57 mg) was dissolved in
ethyl acetate (1.0 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(0.2 mL) was added thereto. The mixture was stood at room
temperature for 4 hr and the precipitated solid was collected by
filtration to give the title compound (31 mg).
[0235] .sup.1H-NMR(DMSO-d.sub.6).delta.11.69-2.35(5H,m),
2.88-3.01(1H,m), 3.09-3.29(1H,m), 3.50-3.70(3H,m), 4.50-4.72(2H,m),
4.76-5.15(1H,m), 7.00(1H,d,J=9.3 Hz), 7.48(1H,d,J=9.3 Hz),
7.71(1H,brs), 9.00(1H,brs), 10.31(1H,brs).
Example 24
Synthesis of (S)-2-cyano-1-[(2S,4S)-4-(2-pyrimidinyl)amino-2-o
pyrrolidinylcarbonyl]pyrrolidine hydrochloride
[0236] (1) The title compound (1.85 g) of Reference Example 3,
diisopropylethylamine (3.14 mL) and 2-chloropyrimidine (0.687 g)
were dissolved in N-methyl-2-pyrrolidone (30 mL), and the mixture
was stirred at 100.degree. C. for 24 hr. The reaction mixture was
added to saturated aqueous sodium hydrogencarbonate solution, and
extracted with ethyl acetate. The extract was dried and the solvent
was evaporated under reduced pressure. The residue was purified by
silica gel chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(2-pyrimidinyl)amino-2-pyr-
rolidinylcarbonyl]-2-cyanopyrrolidine (0.950 g) as a pale-brown
powder.
[0237] (2) The above-mentioned compound (0.833 g) was dissolved in
ethyl acetate (2.16 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(2.69 mL) was added thereto. The mixture was stood at room
temperature for 18 hr. The precipitated solid was collected by
filtration to give the title compound (0.626 g).
[0238] .sup.1H-NMR(DMSO-d.sub.6).delta.1.70-2.35(5H,m),
2.80-2.95(1H,m), 3.10-3.30(1H,m), 3.42-3.90(3H,m), 4.49-4.73(2H,m),
4.80-5.14(1H,m), 6.74(1H,t,J=5.1 Hz), 7.67(1H,brs), 8.38(2H,d,J=5.1
Hz), 8.89(1H,brs), 10.37(1H,brs).
Example 25
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(4-trifluoromethyl-2-pyrimidinyl)amino-2-pyrroli-
dinylcarbonyl]pyrrolidine hydrochloride
[0239] (1) The title compound (1.85 g) of Reference Example 3,
diisopropylethylamine (3.14 mL) and
2-chloro-4-trifluoromethylpyrimidine (1.10 g) were dissolved in
N-methyl-2-pyrrolidone (30 mL), and the mixture was stirred at room
temperature for 18 hr. The reaction mixture was added to saturated
aqueous sodium hydrogencarbonate solution, and the mixture was
extracted with ethyl acetate. The extract was dried and the solvent
was evaporated under reduced pressure. The residue was purified by
silica gel chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-trifluoromethyl-2-pyrimidinyl)a-
mino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine (2.44 g).
[0240] (2) The above-mentioned compound (2.27 g) was dissolved in
ethyl acetate (4.99 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(6.24 mL) was added thereto. The mixture was stood at room
temperature for 4 hr. The precipitated solid was collected by
filtration to give the title compound (1.94 g).
[0241] .sup.1H-NMR(DMSO-d.sub.6).delta.1.72-2.35(5H,m),
2.78-2.99(1H,m), 3.10-3.30(1H,m), 3.36-3.88(3H,m), 4.47-4.72(2H,m),
4.79-5.13(1H,m), 7.11(1H,d,J=5.1 Hz), 8.20(1H,brs), 8.69(1H,d,J=4.2
Hz), 8.94(1H,brs), 10.73(1H,brs).
Example 26
Synthesis of
(S)-1-[(2S,4S)-4-(2-benzoxazolyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyr-
rolidine hydrochloride
[0242] (1)
(2S,4S)-4-(2-Benzoxazolyl)amino-1-tert-butoxycarbonylpyrrolidine-2-carbox-
ylic acid (title compound of Reference Example 5, 1.04 g) and
(s)-2-cyanopyrrolidine hydrochloride (0.40 g) were dissolved in DMF
(5 mL), and triethylamine (0.84 mL), HOBT (0.51 g) and EDC
hydrochloride (0.63 g) were successively added thereto. The mixture
was stirred at room temperature for 15 hr. Water was added to the
reaction mixture, and the mixture was extracted with ethyl acetate.
The extract was dried and evaporated under reduced pressure. The
residue was purified by silica gel chromatography to give
(S)-1-[(2S,4S)-4-(2-benzoxazolyl)amino-1-tert-butoxycarbonyl-2-pyrrolidin-
ylcarbonyl]-2-cyanopyrrolidine (0.86 g) as amorphous.
[0243] (2) The above-mentioned compound (0.86 g) was dissolved in 4
mol/L hydrochloric acid-1,4-dioxane (6 mL), and the mixture was
stood at room temperature for 15 hr. The precipitated white solid
was collected by filtration to give the title compound (0.828
g).
[0244] .sup.1H-NMR(DMSO-d.sub.6).delta.1.70-2.36(5H,m),
2.87-3.50(2H,m), 4.20-5.15(3H,m), 7.00-7.49(4H,m), 8.24-8.38(1H,m),
8.97(1H,brs), 10.26(1H,brs).
Example 27
Synthesis of
(S)-1-[((2S,4R)-4-(2-benzoxazolyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopy-
rrolidine hydrochloride
[0245] (1)
(2S,4R)-4-(2-Benzoxazolyl)amino-1-tert-butoxycarbonylpyrrolidine-2-carbox-
ylic acid (title compound of Reference Example 6, 1.0 g) and
(S)-2-cyanopyrrolidine hydrochloride (0.38 g) were dissolved in DMF
(10 mL), and triethylamine (0.81 mL), HOBT (0.49 g) and EDC
hydrochloride (0.61 g) were successively added thereto. The mixture
was stirred at room temperature for 15 hr. Water was added to the
reaction mixture, and mixture was extracted with ethyl acetate. The
extract was dried and the residue was evaporated under reduced
pressure. The residue was purified by silica gel chromatography to
give
(S)-1-[(2S,4R)-4-(2-benzoxazolyl)amino-1-tert-butoxycarbonyl-2-pyrrolidin-
ylcarbonyl]-2-cyanopyrrolidine (0.91 g) as amorphous.
[0246] (2) The above-mentioned compound (0.91 g) was dissolved in 4
mol/L hydrochloric acid-1,4-dioxane (6 mL), and the mixture was
stood at room temperature for 15 hr. The precipitated white solid
was collected by filtration to give the title compound (0.841
g).
[0247] .sup.1H-NMR(DMSO-d.sub.6).delta.1.93-2.73(6H,m),
3.30-3.94(4H,m), 4.36-5.18(3H,m), 6.96-7.50(4H,m), 8.42-9.05(2H,m),
10.17(1H,brs).
Example 28
Synthesis of
(S)-1-[(2S,4S)-4-(4-chlorophenylmethyl)amino-2-pyrrolidinylcarbonyl]-2-cy-
anopyrrolidine dihydrochloride
[0248] (1) The title compound (1.54 g) of Reference Example 3 and
4-chlorobenzaldehyde (0.703 g) were dissolved in methanol (15 mL),
and the mixture was stirred at room temperature for 1 hr. Sodium
cyanoborohydride (0.315 g) and acetic acid (0.4 mL) were added to
the reaction mixture, and the mixture was stirred for 1 hr. The
reaction mixture was filtrated and the filtrate was evaporated
under reduced pressure. Saturated aqueous sodium hydrogencarbonate
solution was added to the residue, and the mixture was extracted
with ethyl acetate. The extract was dried and the solvent was
evaporated under reduced pressure. The residue was purified by
silica gel chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-chlorophenylmethyl)amino-2-pyrr-
olidinylcarbonyl]-2-cyanopyrrolidine (1.67 g) as amorphous.
[0249] (2) The above-mentioned compound (0.643 g) was dissolved in
ethyl acetate (1.9 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(1.9 mL) was added thereto. The mixture was stood at room
temperature for 15 hr. The precipitated solid was collected by
filtration to give the title compound (0.62 g).
[0250] .sup.1H-NMR(DMSO-d.sub.6).delta.2.00-2.37(5H,m),
2.90-3.05(1H,m), 3.52-3.73(4H,m), 3.86-4.04(1H,m), 4.24(2H,s),
4.48-4.54(1H,m), 4.80-5.17(1H,m), 7.53(2H,d,J=8.4 Hz),
7.66(2H,d,J=8.4 Hz), 9.07(1H,brs), 10.20(2H,brs),
10.72(1H,brs).
Example 29
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(4-nitrophenylmethyl)amino-2-pyrrolidinylcarbony-
l]pyrrolidine dihydrochloride
[0251] (1) The title compound (1.54 g) of Reference Example 3 and
4-nitrobenzaldehyde (6.801 g) were dissolved in methanol (15 mL),
and the mixture was stirred at room temperature for 1 hr. Sodium
cyanoborohydride (0.315 g) and acetic acid (0.4 mL) were added to
the reaction mixture, and the mixture was stirred for 1 hr. The
reaction mixture was filtrated and the filtrate was evaporated
under reduced pressure. Saturated aqueous sodium hydrogencarbonate
solution was added to the residue and the mixture was extracted
with chloroform. The extract was dried and the solvent was
evaporated under reduced pressure. The residue was purified by
silica gel chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-nitrophenylmethyl)amino-2-pyrro-
lidinylcarbonyl]-2-cyanopyrrolidine (1.15 g) as amorphous.
[0252] (2) The above-mentioned compound (1.15 g) was dissolved in
ethyl acetate (3 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(3.3 mL) was added thereto. The mixture was stood at room
temperature for 15 hr. The precipitated solid was collected by
filtration to give the title compound (0.975 g).
[0253] .sup.1H-NMR(DMSO-d.sub.6).delta.1.96-2.37(5H,m),
2.93-3.07(1H,m), 3.66-3.75(3H,m), 3.93-4.10(1H,m), 4.40(2H,s),
4.50-4.67(1H,m), 4.80-5.17(1H,m), 7.92(2H,d,J=8.7 Hz),
8.31(2H,d,J=8.7 Hz), 9.10(1H,brs), 10.10-11.30(2H,m).
Example 30
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(4-phenoxyphenylmethyl)amino-2-pyrrolidinylcarbo-
nyl]pyrrolidine dihydrochloride
[0254] (1) The title compound (0.924 g) of Reference Example 3 and
4-phenoxybenzaldehyde (0.594 g) were dissolved in methanol (15 mL),
and the mixture was stirred at room temperature for 1 hr. Sodium
cyanoborohydride (0.189 g) and acetic acid (0.2 mL) were added to
the reaction mixture, and the mixture was stirred for 1 hr. The
reaction mixture was evaporated under reduced pressure. Saturated
aqueous sodium hydrogencarbonate solution was added to the residue
and the mixture was extracted with ethyl acetate. The extract was
dried and the solvent was evaporated under reduced pressure. The
residue was purified by silica gel chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-phenoxyphenylmethyl)amino-2-pyr-
rolidinylcarbonyl]-2-cyanopyrrolidine (0.99 g) as amorphous.
[0255] (2) The above-mentioned compound (0.99 g) was dissolved in
ethyl acetate (2 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(2.5 mL) was added thereto. The mixture was stood at room
temperature for 15 hr. The precipitated solid was collected by
filtration to give the title compound (0.95 g).
[0256] .sup.1H-NMR(DMSO-d.sub.6).delta.1.95-2.38(5H,m),
2.90-3.16(1H,m), 3.40-3.70(4H,m), 3.89-4.03(1H,m), 4.21(2H,s),
4.50-4.67(1H,m), 4.80-5.17(1H,m), 6.94-7.22(5H,m), 7.34-7.48(2H,m),
7.64(2H,d,J=8.4 Hz), 9.10(1H,brs), 10.17(2H,brs),
10.90(1H,brs).
Example 31
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(4-cyanophenylmethyl)amino-2-pyrrolidinylcarbony-
l]pyrrolidine dihydrochloride
[0257] (1) The title compound (924 mg) of Reference Example 3 and
4-cyanobenzaldehyde (589 mg) were dissolved in methanol (15 mL),
and the mixture was stirred at room temperature for 1 hr. Sodium
cyanoborohydride (283 mg) and acetic acid (0.4 mL) were added to
the reaction mixture, and the mixture was stirred for 1 hr. The
reaction mixture was filtrated and the filtrate was evaporated
under reduced pressure. Saturated aqueous sodium hydrogencarbonate
solution was added to the residue and the mixture was extracted
with ethyl acetate. The extract was dried and the solvent was
evaporated under reduced pressure. The residue was purified by
silica gel chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-cyanophenylmethyl)amino-2-pyrro-
lidinylcarbonyl]-2-cyanopyrrolidine (940 mg) as amorphous.
[0258] (2) The above-mentioned compound (940 mg) was dissolved in
ethyl acetate (3.0 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(2.8 mL) was added thereto. The mixture was stood at room
temperature for 15 hr. The precipitated solid was collected by
filtration to give the title compound (655 mg).
[0259] .sup.1H-NMR(DMSO-d.sub.6).delta.1.94-2.37(6H,m),
2.89-3.09(1H,m), 3.27-3.80(3H,m), 3.90-4.10(1H,m), 4.23-4.44(2H,s),
4.53-4.69(1H,m), 4.80-5.20(1H,m), 7.87(2H,d,J=8.4 Hz),
7.94(2H,d,J=8.4 Hz), 9.18(1H,brs), 10.60(2H,brs).
Example 32
Synthesis of
(S)-1-{(2S,4S)-4-[N-(4-cyanophenylmethyl)-N-methylamino]-2-pyrrolidinylca-
rbonyl}-2-cyanopyrrolidine dihydrochloride
[0260] (1)
(S)-1-[(2S,4S)-1-tert-Butoxycarbonyl-4-(4-cyanophenylmethyl)amino-2-pyrro-
lidinylcarbonyl]-2-cyanopyrrolidine [product of Example 31 (1),
1.04 g] and 37% formaldehyde solution (0.7 mL) were dissolved in
acetonitrile (15 mL), and the mixture was stirred at room
temperature for 1 hr. Sodium cyanoborohydride (0.240 g) and acetic
acid (0.4 mL) were added to the reaction mixture, and the mixture
was stirred for 1 hr. The reaction mixture was evaporated under
reduced pressure. Saturated aqueous sodium hydrogencarbonate
solution was added to the residue and the mixture was extracted
with chloroform. The extract was dried and the solvent was
evaporated under reduced pressure. The residue was purified by
silica gel chromatography to give
(S)-1-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(4-cyanophenylmethyl)-N-methyla-
mino]-2-pyrrolidinylcarbonyl}-2-cyanopyrrolidine (0.71 g) as
amorphous.
[0261] (2) The above-mentioned-compound (0.70 g) was dissolved in
ethyl acetate (2.0 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(2.0 mL) was added thereto. The mixture was stood at room
temperature for 15 hr. The precipitated solid was collected by
filtration to give the title compound (0.548 g).
[0262] .sup.1H-NMR(DMSO-d.sub.6).delta.2.00-2.42(5H,m), 2.59(3H,s),
2.88-3.18(1H,m), 3.50-5.20(9H,m), 7.89(2H,d,J=8.1 Hz),
7.97(2H,d,J=8.1 Hz), 9.26(1H,brs), 10.96(1H,brs),
12.42(1H,brs).
Example 33
Synthesis of
(S)-2-cyano-1-{(2S,4S)-4-[N,N-bis(4-cyanophenylmethyl)amino]-2-pyrrolidin-
ylcarbonyl}pyrrolidine dihydrochloride
[0263] (1) The title compound (0.924 g) of Reference Example 3,
4-cyanobenzyl bromide (1.27 g) and diisopropylethylamine (1.6 mL)
were dissolved in N-methyl-2-pyrrolidone (10 mL), and the mixture
was stirred at room temperature for 15 hr. Water was added to the
reaction mixture and the mixture was extracted with ethyl acetate.
The extract was dried and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel chromatography to
give
(S)-1-{(2S,4S)-1-tert-butoxycarbonyl-4-[N,N-bis(4-cyanophenylmethyl)amino-
]-2-pyrrolidinylcarbonyl}-2-cyanopyrrolidine (1.11 g) as a white
solid.
[0264] (2) The above-mentioned compound (0.95 g) was dissolved in
ethyl acetate (2.2 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(2.2 mL) was added thereto. The mixture was stood at room
temperature for 15 hr. The precipitated solid was collected by
filtration to give the title compound (0.85 g).
[0265] .sup.1H-NMR(DMSO-d.sub.6).delta.1.72-2.37(5H,m),
2.62-2.79(1H,m), 3.06-3.43(2H,m), 3.53-4.50(8H,m), 4.80-5.14(1H,m),
7.55(4H,d,J=8.1 Hz), 7.79(4H,d,J=8.1 Hz), 8.90(1H,brs),
10.10(1H,brs).
Example 34
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(3-pyridylmethyl)amino-2-pyrrolidinylcarbonyl]py-
rrolidine 3 trifluoroacetate
[0266] (1) The title compound (928 mg) of Reference Example 3 and
nicotinaldehyde (321 mg) were dissolved in methanol (16 mL), and
the mixture was stirred at room temperature for 30 min. Sodium
cyanoborohydride (189 mg) and several drops of acetic acid were
added to the reaction mixture, and the mixture was stirred at room
temperature for 18 hr. The reaction mixture was filtrated and the
filtrate was evaporated under reduced pressure. Saturated aqueous
sodium hydrogencarbonate solution was added to the residue and the
mixture was extracted with ethyl acetate. The extract was dried and
the solvent was evaporated under reduced pressure. The residue was
purified by silica gel chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(3-pyridylmethyl)amino-2-p-
yrrolidinylcarbonyl]-2-cyanopyrrolidine (591 mg).
[0267] (2) The above-mentioned compound (557 mg) was dissolved in
dichloromethane (14 mL) and trifluoroacetic acid (1.4 mL) was added
thereto. The mixture was stood at room temperature for 18 hr. The
reaction solvent was concentrated under reduced pressure, and
diethyl ether was added to the residue. The precipitated solid was
collected by filtration to give the title compound (704 mg).
[0268] .sup.1H-NMR(DMSO-d.sub.6).delta.1.70-2.40(5H,m),
2.91-3.14(1H,m), 3.29-3.73(5H,m), 4.31(2H,s), 4.52-4.70(1H,m),
4.78-5.15(1H,m), 7.58(1H,dd,J=7.8, 5.0 Hz), 8.02(1H,d,J=7.9 Hz),
8.68(1H,dd,J=4.9, 1.4 Hz), 8.75(1H,d,J=1.7 Hz).
Example 35
Synthesis of
(S)-2-cyano-1-((2S,4S)-4-phenethylamino-2-pyrrolidinylcarbonyl)pyrrolidin-
e 2 trifluoroacetate
[0269] (1) The title compound (462 mg) of Reference Example 3 and
phenylacetaldehyde (0.18 mL) were dissolved in methanol (15 mL),
and the mixture was stirred at room temperature for 1 hr. Sodium
cyanoborohydride (94 mg) and acetic acid (0.1 mL) were added to the
reaction mixture, and the mixture was stirred for 15 hr. The
reaction mixture was filtrated and the filtrate was evaporated
under reduced pressure. Saturated aqueous sodium hydrogencarbonate
solution was added to the residue and the mixture was extracted
with ethyl acetate. The extract was dried and the solvent was
evaporated under reduced pressure. The residue was purified by
silica gel chromatography to give
(S)-1-((2S,4S)-1-tert-butoxycarbonyl-4-phenethylamino-2-pyrrolidinylcarbo-
nyl)-2-cyanopyrrolidine (300 mg) as amorphous.
[0270] (2) The above-mentioned compound (300 mg) was dissolved in
dichloromethane (7.3 mL) and trifluoroacetic acid (0.73 mL) was
added thereto. The mixture was stood at room temperature for 15 hr.
The solvent was evaporated under reduced pressure, and the residue
was purified by HPLC and freeze-dried to give the title compound
(150 mg) as amorphous.
[0271] .sup.1H-NMR(DMSO-d.sub.6).delta.1.85-2.38(5H,m),
2.83-3.08(3H,m), 3.15-3.74(4H,m), 3.75-5.18(5H,m),
7.17-7.40(5H,m).
Example 36
Synthesis of
(S)-2-cyano-1-((2S,4S)-4-cyclohexylamino-2-pyrrolidinylcarbonyl)pyrrolidi-
ne dihydrochloride
[0272] (1) The title compound (924 mg) of Reference Example 3 and
cyclohexanone (0.34 mL) were dissolved in methanol (15 mL), and the
mixture was stirred at room temperature for 1 hr. Sodium
cyanoborohydride (200 mg) and acetic acid (0.4 mL) were added to
the reaction mixture, and the mixture was stirred for 15 hr. The
reaction mixture was evaporated under reduced pressure. Saturated
aqueous sodium hydrogencarbonate solution was added to the residue
and the mixture was extracted with ethyl acetate. The extract was
dried and the solvent was evaporated under reduced pressure. The
residue was purified by silica gel chromatography to give
(S)-1-(2S,4S)-1-tert-butoxycarbonyl-4-cyclohexylamino-2-pyrrolidi-
nylcarbonyl)-2-cyanopyrrolidine (440 mg) as amorphous.
[0273] (2) The above-mentioned compound (430 mg) was dissolved in
ethyl acetate (1.5 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(1.4 mL) was added thereto. The mixture was stood at room
temperature for 15 hr. The precipitated solid was collected by
filtration to give the title compound (338 mg).
[0274] .sup.1H-HMR(DMSO-d.sub.6).delta.1.01-1.47(5H,m),
1.54-2.38(10H,m), 2.88-3.07(2H,m), 3.38-3.70(4H,m),
3.95-4.13(1H,m), 4.40-4.61(1H,m), 4.80-5.14(1H,m), 9.68(1H,brs),
9.89(1H,brs).
Example 37
Synthesis of
(S)-2-cyano-1-((2S,4S)-4-diethylamino-2-pyrrolidinylcarbonyl)pyrrolidine
dihydrochloride
[0275] (1) The title compound (924 mg) of Reference Example 3 and
90% aqueous acetaldehyde solution (1.7 mL) were dissolved in
methanol (15 mL), and the mixture was stirred at room temperature
for 3 hr. Sodium cyanoborohydride (440 mg) and acetic acid (0.4 mL)
were added to the reaction mixture, and the mixture was stirred for
1 hr. The reaction mixture was evaporated under reduced pressure.
Saturated aqueous sodium hydrogencarbonate solution was added to
the residue and the mixture was extracted with ethyl acetate. The
extract was dried and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel chromatography to
give
(S)-1-((2S,4S)-1-tert-butoxycarbonyl-4-diethylamino-2-pyrrolidinylcarbony-
l)-2-cyanopyrrolidine (720 mg) as amorphous.
[0276] (2) The above-mentioned compound (720 mg) was dissolved in
ethyl acetate (2 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(2.5 mL) was added thereto. The mixture was stood at room
temperature for 15 hr. The precipitated solid was collected by
filtration to give the title compound (713 mg).
[0277] .sup.1H-NMR(DMSO-d.sub.6).delta.1.20-1.30(6H,m),
1.94-2.36(1H,m), 2.87-3.38(6H,m), 3.52-4.18(8H,m), 4.45-4.64(1H,m),
4.82-4.90(1H,m), 9.38(1H,brs), 11.30(1H,brs), 11.82(1H,brs).
Example 38
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(1-piperidino)-2-pyrrolidinylcarbonyl]pyrrolidin-
e dihydrochloride
[0278] (1) The title compound (924 mg) of Reference Example 3 and
50% aqueous glutaraldehyde solution (0.8 mL) were dissolved in
methanol (15 mL), and the mixture was stirred at room temperature
for 3 hr. Sodium cyanoborohydride (630 mg) and acetic acid (0.4 mL)
were added the reaction mixture and the mixture was stirred for 1
hr. The reaction mixture was evaporated under reduced pressure.
Saturated aqueous sodium hydrogencarbonate solution was added to
the residue and the mixture was extracted with ethyl acetate. The
extract was dried and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel chromatography to
give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(1-piperidino)-2-pyrrolidinylcarbo-
nyl]-2-cyanopyrrolidine (480 mg) as amorphous.
[0279] (2) The above-mentioned compound (470 mg) was dissolved in
ethyl acetate (2 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(1.6 mL) was added thereto. The mixture was stood at room
temperature for 15 hr. The precipitated solid was collected by
filtration to give the title compound (485 mg).
[0280] .sup.1H-NMR(DMSO-d.sub.6).delta.1.30-1.50(1H,m),
1.61-1.90(5H,m), 1.99-2.32(3H,m), 2.83-3.09(2H,m), 3.31-3.80(8H,m),
3.90-4.07(1H,m), 4.40-4.62(1H,m), 4.80-5.20(1H,m), 9.27(1H,brs),
11.10(1H,brs), 11.64(1H,brs).
Example 39
Synthesis of
(S)-2-cyano-1-{(2S,4S)-4-[N,N-bis(ethoxycarbonylmethyl)amino]-2-pyrrolidi-
nylcarbonyl}pyrrolidine dihydrochloride
[0281] (1) The title compound (0.924 g) of Reference Example 3,
ethyl bromoacetate (0.73 mL) and diisopropylethylamine (1.6 mL)
were dissolved in N-methyl-2-pyrrolidone (10 mL), and the mixture
was stirred at room temperature for 15 hr. Water was added to the
reaction mixture and the mixture was extracted with ethyl acetate.
The extract was dried and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel chromatography to
give
(S)-1-{(2S,4S)-1-tert-butoxycarbonyl-4-[N,N-bis(ethoxycarbonylmethyl)amin-
o]-2-pyrrolidinylcarbonyl}-2-cyanopyrrolidine (0.95 g) as a white
solid.
[0282] (2) The above-mentioned compound (0.80 g) was dissolved in
ethyl acetate (2 mL) and 4 mol/L hydrochloric acid-ethyl acetate (2
mL) was added thereto. The mixture was stood at room temperature
for 15 hr. The precipitated solid was collected by filtration to
give the title compound (0.65 g).
[0283] .sup.1H-NMR(DMSO-d.sub.6).delta.1.19(6H,t,J=7.2 Hz),
1.57-1.74(1H,m), 1.93-2.34(4H,m), 2.96-3.42(2H,m),
3.75-4.50(12H,m), 4.78-5.12(1H,m), 8.80(1H,brs), 10.19(1H,brs).
Example 40
Synthesis of
(S)-1-((2S,4S)-4-benzoylamino-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine
hydrochloride
[0284] (1)
(2S,4S)-4-Benzoylamino-1-tert-butoxycarbonylpyrrolidine-2-carboxylic
acid (title compound of Reference Example 7, 1.1 g) and
(S)-2-cyanopyrrolidine hydrochloride (0.44 g) were dissolved in DMF
(10 mL), and triethylamine (0.98 mL), HOBT (0.54 g) and EDC
hydrochloride (0.67 g) were successively added. The mixture was
stirred at room temperature for 15 hr. Water was added to the
reaction mixture and the mixture was extracted with ethyl acetate.
The extract was dried and evaporated under reduced pressure. The
residue was purified by silica gel chromatography to give
(S)-1-((2S,4R)-4-benzoylamino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbony-
l)-2-cyanopyrrolidine (1.0 g) as a white solid.
[0285] (2) The above-mentioned compound (0.91 g) was dissolved in
tetrahydrofuran (3 mL) and 4 mol/L hydrochloric acid-1,4-dioxane (6
mL) was added thereto. The mixture was stood at room temperature
for 15 hr. The precipitated white solid was collected by filtration
to give the title compound (541 mg).
[0286] .sup.1H-NMR(DMSO-d.sub.6).delta.1.63-2.36(5H,m),
2.75-2.93((1H,m), 3.21-3.80(4H,m), 4.51-5.13(3H,m),
7.40-7.90(2H,m), 8.52-9.00(2H,m), 10.06(1H,brs).
Example 41
Synthesis of
(S)-1-((2S,4R)-4-benzoylamino-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine
hydrochloride
[0287] (1)
(2S,4R)-4-Benzoylamino-1-tert-butoxycarbonylpyrrolidine-2-carboxylic
acid (title compound of Reference Example 8, 1.6 g) and
(S)-2-cyanopyrrolidine hydrochloride (0.63 g) were dissolved in DMF
(10 mL), and triethylamine (1.32 mL), HOBT (0.79 g) and EDC
hydrochloride (0.99 g) were successively added. The mixture was
stirred at room temperature for 15 hr. Water was added to the
reaction mixture and the mixture was extracted with ethyl acetate.
The extract was dried and evaporated under reduced pressure. The
residue was purified by silica gel chromatography to give
(S)-1-((2S,4R)-4-benzoylamino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbony-
l)-2-cyanopyrrolidine (1.2 g) as a white solid.
[0288] (2) The above-mentioned compound (0.97 g) was dissolved in 4
mol/L hydrochloric acid-1,4-dioxane (6 mL). The mixture was stood
at room temperature for 15 hr. The precipitated white solid was
collected by filtration to give the title compound (0.814 g).
[0289] .sup.1H-NMR(DMSO-d.sub.6).delta.1.96-2.65(6H,m),
3.23-3.71(4H,m), 4.42-5.15(3H,m), 7.51-7.97(5H,m), 8.67-9.03(2H,m),
9.92(1H,brs).
Example 42
Synthesis of
(S)-1-[(2S,4S)-4-(4-chlorobenzoyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopy-
rrolidine hydrochloride
[0290] (1) The title compound (462 mg) of Reference Example 3 and
triethylamine (0.42 mL) were dissolved in dichloromethane (30 mL),
and 4-chlorobenzoyl chloride (0.19 mL) was added under ice-cooling.
The mixture was stirred at room temperature for 24 hr. Water was
added to the reaction mixture and the mixture was extracted with
dichloromethane. The extract was dried and evaporated under reduced
pressure. The residue was purified by silica gel chromatography to
give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-chlorobenzoyl)amino-2-pyrrolidi-
nylcarbonyl]-2-cyanopyrrolidine (617 mg) as amorphous.
[0291] (2) The above-mentioned compound (610 mg) was dissolved in
tetrahydrofuran (4 mL) and 4 mol/L hydrochloric acid-1,4-dioxane
(3.4 mL) was added thereto. The mixture was stirred at room
temperature for 24 hr. The solvent was evaporated under reduced
pressure, and the concentrate was purified by HPLC and freeze-dried
to give the title compound (340 mg) as amorphous.
[0292] .sup.1H-NMR(DMSO-d.sub.6).delta.1.87-2.34(5H,m),
2.78-2.93(1H,m), 3.20-3.75(4H,m), 4.54-4.72(2H,m),
4.85(1H,dd,J=7.8, 4.7 Hz), 7.58(2H,d,J=8.5 Hz), 7.86(2H,d,J=8.5
Hz), 8.70(1H,d,J=6.8 Hz), 8.88(1H,brs), 9.74(1H,brs).
Example 43
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(4-trifluoromethylbenzoyl)amino-2-pyrrolidinylca-
rbonyl]pyrrolidine hydrochloride
[0293] (1) The title compound (462 mg) of Reference Example 3,
4-trifluoromethylbenzoic acid (285 mg) and triethylamine (0.42 mL)
were dissolved in DMF (30 mL), and HOBT (241 mg) and EDC
hydrochloride (302 mg) were successively added under ice-cooling.
The mixture was stirred at room temperature for 22 hr. The solvent
was evaporated under reduced pressure, and saturated aqueous sodium
hydrogencarbonate solution was added to the concentrate. The
mixture was extracted with ethyl acetate. The extract was washed
with brine, dried and evaporated under reduced pressure. The
residue was purified by silica gel chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-trifluoromethylbenzoyl)amino-2--
pyrrolidinylcarbonyl]-2-cyanopyrrolidine (640 mg) as a colorless
oil.
[0294] (2) The above-mentioned compound (640 mg) was dissolved in
tetrahydrofuran (15 mL) and 4 mol/L hydrochloric acid-1,4-dioxane
(3.3 mL) was added thereto. The mixture was stirred at room
temperature for 24 hr. The solvent was evaporated under reduced
pressure and the concentrate was purified by HPLC and freeze-dried
to give the title compound (163 mg) as amorphous.
[0295] .sup.1H-NMR(DMSO-d.sub.6).delta.1.92-2.37(5H,m),
2.82-2.96(1H,m), 3.24-3.65(4H,m), 4.67-4.76(2H,m),
4.89(1H,dd,J=7.8, 4.7), 7.90(2H,d,J=8.2 Hz), 8.06(2H,d,J=8.2 Hz),
8.90(1H,d,J=6.7 Hz), 9.0-10.0(2H,m).
Example 44
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(4-cyanobenzoyl)amino-2-pyrrolidinylcarbonyl]pyr-
rolidine hydrochloride
[0296] (1) The title compound (462 mg) of Reference Example 3,
4-cyanobenzoic acid (221 mg) and triethylamine (0.42 mL) were
dissolved in DMF (30 mL), HOBT (241 mg) and EDC hydrochloride (302
mg) were successively added under ice-cooling. The mixture was
stirred at room temperature for 21 hr. The solvent was evaporated
under reduced pressure, and saturated aqueous sodium
hydrogencarbonate solution was added to the concentrate. The
mixture was extracted with ethyl acetate. The extract was washed
with brine, dried and evaporated under reduced pressure. The
residue was purified by silica gel chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-cyanobenzoyl)amino-2-pyrrolidin-
ylcarbonyl]-2-cyanopyrrolidine (548 mg) as amorphous.
[0297] (2) The above-mentioned compound (548 mg) was dissolved in
tetrahydrofuran (15 mL) and 4 mol/L hydrochloric acid-1,4-dioxane
(3.1 mL) was added thereto. The mixture was stirred at room
temperature for 5 days. The solvent was evaporated under reduced
pressure, and the concentrate was purified by HPLC and freeze-dried
to give the title compound (177 mg) as amorphous.
[0298] .sup.1H-NMR(DMSO-d.sub.6).delta.1.93-2.36(5H,m),
2.80-2.96(1H,m), 3.26-3.68(4H,m), 4.58-4.76(2H,m),
4.88(1H,dd,J=7.7, 4.8 Hz), 8.00(4H,s), 8.93(1H,d,J=6.6 Hz),
9.0-10.0(2H,m).
Example 45
Synthesis of
(S)-2-cyano-1-((2S,4S)-4-nicotinoylamino-2-pyrrolidinylcarbonyl)pyrrolidi-
ne 2 trifluoroacetate
[0299] (1) The title compound (462 mg) of Reference Example 3 and
triethylamine (0.63 mL) were dissolved in tetrahydrofuran (10 mL),
and nicotinoyl chloride hydrochloride (285 mg) was added thereto.
The mixture was stirred at room temperature for 15 hr. Water was
added to the reaction mixture and the mixture was extracted with
ethyl acetate. The extract was dried and the solvent was evaporated
under reduced pressure. The residue was purified by silica gel
chromatography to give
(S)-1-((2S,4S)-1-tert-butoxycarbonyl-4-nicotinoylamino-2-pyrrolidinylcarb-
onyl)-2-cyanopyrrolidine (190 mg) as amorphous.
[0300] (2) The above-mentioned compound (180 mg) was dissolved in
dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was added
thereto. The mixture was stood at room temperature for 15 hr. The
solvent was evaporated under reduced pressure, and the residue was
purified by HPLC and freeze-dried to give the title compound (96
mg) as amorphous.
[0301] .sup.1H-NMR(DMSO-d.sub.6).delta.1.86-2.36(5H,m),
2.80-2.97(1H,m), 3.24-3.68(4H,m), 4.49-5.13(3H,m),
7.58(1H,dd,J=7.8, 4.8 Hz), 8.24(1H,d,J=7.8 Hz), 8.76(1H,d,J=4.8
Hz), 8.87(1H,d,J=6.6 Hz), 9.03(1H,s), 9.93(1H,brs).
Example 46
Synthesis of
(S)-2-cyano-1-((2S,4S)-4-isonicotinoylamino-2-pyrrolidinylcarbonyl)pyrrol-
idine 2 trifluoroacetate
[0302] (1) The title compound (462 mg) of Reference Example 3 and
triethylamine (0.63 mL) were dissolved in tetrahydrofuran (10 mL),
and isonicotinoyl chloride hydrochloride (285 mg) was added
thereto. The mixture was stirred at room temperature for 15 hr.
Water was added to the reaction mixture and the mixture was
extracted with ethyl acetate. The extract was dried and the solvent
was evaporated under reduced pressure. The residue was purified by
silica gel chromatography to give
(S)-1-((2S,4S)-1-tert-butoxycarbonyl-4-isonicotinoylamino-2-pyrrolidinylc-
arbonyl)-2-cyanopyrrolidine (670 mg) as amorphous.
[0303] (2) The above-mentioned compound (650 mg) was dissolved in
dichloromethane (16 mL) and trifluoroacetic acid (1.6 mL) was added
thereto. The mixture was stood at room temperature for 15 hr. The
solvent was evaporated under reduced pressure, and the residue was
purified by HPLC and freeze-dried to give the title compound (412
mg) as amorphous.
[0304] .sup.1H-NMR(DMSO-d.sub.6).delta.1.87-2.36(5H,m),
2.79-2.96(1H,m), 3.20-3.68(4H,m), 4.48-5.15(3H,m), 7.80(2H,d,J=6.0
Hz), 8.70-9.13(4H,m), 9.93(1H,brs).
Example 47
Synthesis of
(S)-2-cyano-1-((2S,4S)-4-glycylamino-2-pyrrolidinylcarbonyl)pyrrolidine
dihydrochloride
[0305] (1) The title compound (464 mg) of Reference Example 3 and
N-methylmorpholine (0.16 mL) were dissolved in tetrahydrofuran (10
mL), and isobutyl chloroformate (0.19 mL) was added thereto at
-20.degree. C. The mixture was stirred for 30 min, and a solution
of N-tert-butoxycarbonylglycine (463 mg) and triethylamine (0.21
mL) in DMF (3 mL) was added thereto at -20.degree. C. The mixture
was stirred at room temperature for 20 hr. Saturated aqueous sodium
hydrogencarbonate solution was added to the reaction mixture and
the mixture was extracted with ethyl acetate. The extract was
washed with brine, dried and evaporated under reduced pressure. The
residue was purified by silica gel chromatography to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(N-tert-butoxycarbonylglycyl)amino-
-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine (680 mg) as
amorphous.
[0306] (2) The above-mentioned compound (360 mg) was dissolved in
1,4-dioxane (1 mL) and 4 mol/L hydrochloric acid-1,4-dioxane (4 mL)
was added thereto. The mixture was stirred at room temperature for
4 hr. The precipitated solid was collected by filtration to give
the title compound (262 mg) as a white solid.
[0307] .sup.1H-NMR(DMSO-d.sub.6).delta.1.7-2.3(5H,m), 2.78(1H,m),
3.5(2H,m), 4.26-4.60(2H,m), 4.84(1H,dd,J=7.9, 4.6 Hz),
8.24(3H,brs), 8.7-9.1(2H,m), 10.71(1H,brs).
Example 48
Synthesis of
(S)-2-cyano-1-[((2S,4S)-4-(ethoxyoxalyl)amino-2-pyrrolidinylcarbonyl]pyrr-
olidine trifluoroacetate
[0308] (1) The title compound (464 mg) of Reference Example 3 and
triethylamine (0.63 mL) were dissolved in tetrahydrofuran (10 mL),
and ethyl chloroglyoxylate (0.18 mL) was added thereto under
ice-cooling. The mixture was stirred for 2 hr and the solvent was
evaporated under reduced pressure. Saturated aqueous sodium
hydrogencarbonate solution was added to the concentrate and the
mixture was extracted with ethyl acetate. The extract was washed
with brine and dried. The solvent was evaporated under reduced
pressure and the residue was purified by silica gel chromatography
to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(ethoxyoxalyl)amino-2-pyrrolidinyl-
carbonyl]-2-cyanopyrrolidine (615 mg) as amorphous.
[0309] (2) The above-mentioned compound (492 mg) was dissolved in
acetonitrile (10 mL), and trifluoroacetic acid (2 mL) was added
thereto under ice-cooling. The mixture was stood at room
temperature for 28 hr. The solvent was evaporated under reduced
pressure, and the residue was purified by HPLC and freeze-dried to
give the title compound (168 mg) as amorphous.
[0310] .sup.1H-NMR(DMSO-d.sub.6).delta.1.27(3H,t,J=7.1 Hz),
1.82-2.35(5H,m), 2.82(1H,m), 3.26(1H,dd,J=11.5, 7.1 Hz),
3.45(1H,dd,J=11.5, 7.1 Hz), 3.5(2H,m), 4.24(2H,q,J=7.1 Hz),
4.43-4.62(2H,m), 4.85(1H,dd,J=7.8, 4.8 Hz), 8.89(1H,brs),
9.18(1H,d,J=7.8 Hz), 9.78(1H,brs).
Example 49
Synthesis of
(S)-2-cyano-1-[(2S,4S)-4-(4-pyridyl)oxy-2-pyrrolidinylcarbonyl]pyrrolidin-
e dihydrochloride
[0311] (1) The title compound (464 mg) of Reference Example 2,
4-hydroxypyridine (144 mg) and triphenylphosphine (393 mg) were
dissolved in tetrahydrofuran (20 mL), and 40% toluene solution
(0.71 mL) of diethyl diazodicarboxylate was added thereto. The
mixture was stirred for 9 days. The solvent was evaporated under
reduced pressure, and the concentrate was purified by HPLC and
freeze-dried to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-pyridyl)oxy-2-pyrrolidinylcarbo-
nyl]-2-cyanopyrrolidine (178 mg) as amorphous.
[0312] (2) The above-mentioned compound (173 mg) was dissolved in
ethyl acetate (1.0 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(0.6 mL) was added thereto. The mixture was stood at room
temperature for 5 hr. The precipitated white solid was collected by
filtration to give the title compound (159 mg).
[0313] .sup.1H-NMR(DMSO-d.sub.6).delta.1.73-2.42(5H,m),
2.87-3.03(1H,m), 3.2-3.8(4H,m), 4.66-4.87(2H,m), 5.53-5.67(m,1H),
7.52(1H,d,J=7.2 Hz), 8.78(1H,d,J=7.2 Hz), 8.81(1H,d,J=7.2 Hz),
8.96(1H,brs), 10.86(1H,brs).
Example 50
Synthesis of
(S)-1-[(2S,4S)-4-(4-aminobenzoyl)oxy-2-pyrrolidinylcarbonyl]-2-cyanopyrro-
lidine dihydrochloride
[0314] (1) The title compound (619 mg) of Reference Example 1 and
triethylamine (0.84 mL) were dissolved in dichloromethane (10 mL),
and 4-nitrobenzoyl chloride (557 mg) and 4-dimethylaminopyridine
(24 mg) were added thereto. The mixture was stirred at room
temperature for 14 hr. Saturated aqueous sodium hydrogencarbonate
solution was added to the reaction mixture and the mixture was
extracted with chloroform. The extract was washed with brine and
dried. The solvent was evaporated under reduced pressure, and the
residue was purified by silica gel chromatography and
recrystallized from ethyl acetate-hexane to give
(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-nitrobenzoyl)oxy-2-pyrrolidinyl-
carbonyl]-2-cyanopyrrolidine (800 mg) as pale-brown crystals.
[0315] (2) The above-mentioned compound (600 mg) was dissolved in
ethyl acetate (15 mL), and the mixture was stirred under a hydrogen
atomosphere (1 atm) in the presence of 10% palladium/carbon (123
mg) for 3 hr. The reaction mixture was filtrated and the filtrate
was concentrated under reduced pressure. The residue was
crystallized from ethyl acetate-hexane to give
(S)-1-[(2S,4S)-4-(4-aminobenzoyl)oxy-1-tert-butoxycarbonyl-2-pyrr-
olidinylcarbonyl]-2-cyanopyrrolidine (96 mg) as white crystals.
[0316] (3) The above-mentioned compound (518 mg) was dissolved in
ethyl acetate (1.2 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(1.5 mL) was added thereto. The mixture was stood at room
temperature for 15 hr. The precipitated pale-brown solid was
collected by filtration to give the title compound (378 mg).
[0317] .sup.1H-NMR(DMSO-d.sub.6).delta.1.97-2.38(5H,m),
2.76-2.88(1H,m), 3.40-3.70(4H,m), 4.63-4.76(1H,m),
4.88(1H,dd,J=7.9, 5.3 Hz), 5.42-5.50(m,1H), 6.71(1H,d,J=8.7 Hz),
7.72(1H,d,J=8.7 Hz), 8.88(1H,brs), 10.84(1H,brs).
Example 51
Synthesis of
(S)-2-cyano-1-((2S,4S)-4-nicotinoyloxy-2-pyrrolidinylcarbonyl)pyrrolidine
dihydrochloride
[0318] (1) The title compound (619 mg) of Reference Example 1 and
triethylamine (0.84 mL) were dissolved in dichloromethane (10 mL),
and nicotinoyl chloride hydrochloride (534 mg) and
4-dimethylaminopyridine (23 mg) were added thereto. The mixture was
stirred at room temperature for 15 hr. Saturated aqueous sodium
hydrogencarbonate solution was added to the reaction mixture and
the mixture was extracted with chloroform. The extract was washed
with brine and dried. The solvent was evaporated under reduced
pressure and the residue was purified by silica gel chromatography
and recrystallized from ethyl acetate-hexane to give
(S)-1-((2S,4S)-1-tert-butoxycarbonyl-4-nicotinoyloxy-2-pyrrolidinylcarbon-
yl)-2-cyanopyrrolidine (731 mg) as pale-yellow crystals.
[0319] (2) The above-mentioned compound (414 mg) was dissolved in
ethyl acetate (2 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(1.25 mL) was added thereto. The mixture was stood at room
temperature for 18 hr. The precipitated white solid was collected
by filtration to give the title compound (524 mg).
[0320] .sup.1H-NMR(DMSO-d.sub.6).delta.1.97-2.45(5H,m),
2.81-2.96(1H,m), 3.45-3.85(4H,m), 4.67-4.78(1H,m),
4.86(1H,dd,J=7.9, 5.0 Hz), 5.60-5.67(m,1H), 7.65(1H,dd,J=8.0, 5.1
Hz), 8.40-8.47(1H,m), 8.88(1H,dd,J=5.0, 1.6 Hz), 9.02(1H,brs),
9.17(1H,d,J=1.8 Hz), 10.94(1H,brs).
Example 52
Synthesis of
(S)-2-cyano-1-((2S,4S)-4-isonicotinoyloxy-2-pyrrolidinylcarbonyl)pyrrolid-
ine dihydrochloride
[0321] (1) The title compound (752 mg) of Reference Example 1 and
triethylamine (0.84 mL) were dissolved in dichloromethane (10 mL),
and isonicotinoyl chloride hydrochloride (712 mg) and
4-dimethylaminopyridine (40 mg) were added thereto. The mixture was
stirred at room temperature for 22 hr. Saturated aqueous sodium
hydrogencarbonate solution was added to the reaction mixture, and
the mixture was extracted with chloroform. The extract was washed
with brine and dried. The solvent was evaporated under reduced
pressure. The residue was purified by silica gel chromatography and
crystallized from diethyl ether to give
(S)-1-((2S,4S)-1-tert-butoxycarbonyl-4-isonicotinoyloxy-2-pyrrolidinylcar-
bonyl)-2-cyanopyrrolidine (576 mg) as white crystals.
[0322] (2) The above-mentioned compound (414 mg) was dissolved in
ethyl acetate (1.0 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(1.25 mL) was added thereto. The mixture was stood at room
temperature for 18 hr. The precipitated white solid was collected
by filtration to give the title compound (458 mg).
[0323] .sup.1H-NMR(DMSO-d.sub.6).delta.1.97-2.47(5H,m),
2.79-2.92(1H,m), 3.5-3.8(4H,m), 4.68-4.81(1H,m), 4.87(1H,dd,J=7.9,
5.3 Hz), 5.60-5.67(m,1H), 7.97(2H,d,J=6.0 Hz), 8.83(2H,d,J=6.0 Hz),
8.97(1H,brs), 10.98(1H,brs)
Example 53
Synthesis of
3-((2S,4S)-4-amino-2-pyrrolidinylcarbonyl)-1,3-thiazolidine
dihydrochloride
[0324]
3-((2S,4S)-4-Amino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-1-
,3-thiazolidine (title compound of Reference Example 10, 400 mg)
was dissolved in ethyl acetate (3.0 mL), and 4 mol/L hydrochloric
acid-ethyl acetate (3.75 mL) was added thereto. The mixture was
stood at room temperature for 3 hr. The reaction mixture was
concentrated under reduced pressure, and the residue was dissolved
in ethanol (100 mL). Activated carbon (0.4 g) was added thereto and
the activated carbon was filtered off. The filtrate was
concentrated and diethyl ether was added thereto. The precipitated
solid was collected by filtration to give the title compound (28.8
mg) as a white powder.
[0325] .sup.1H-NMR(DMSO-d.sub.6).delta.1.85-2.06(1H,m),
2.71-2.93(1H,m), 2.99-3.20(2H,m), 3.40-3.98(5H,m), 4.37-4.78(3H,m),
8.86(5H,brs).
Example 54
Synthesis of
3-[(2S,4S)-4-(4-cyanophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidin-
e hydrochloride
[0326] (1) The title compound (1810 mg) of Reference Example 10,
diisopropylethylamine (3.14 mL) and 4-fluorobenzonitrile (727 mg)
were dissolved in N-methyl-2-pyrrolidone (18 mL), and the mixture
was stirred at 100.degree. C. for 24 hr. The reaction mixture was
poured into saturated aqueous sodium hydrogencarbonate solution,
and the mixture was extracted with ethyl acetate. The extract was
dried and the solvent was evaporated under reduced pressure. The
residue was purified by silica gel chromatography to give
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-cyanophenyl)amino-2-pyrrolidinylcar-
bonyl]-1,3-thiazolidine (170 mg) as a pale-brown oil.
[0327] (2) The above-mentioned compound (170 mg) was dissolved in
ethyl acetate (0.42 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(0.53 mL) was added thereto. The mixture was stirred at room
temperature for 18 hr. The precipitated solid was collected by
filtration to give the title compound (69.3 mg) as a pale-brown
powder.
[0328] .sup.1H-NMR(DMSO-d.sub.6).delta.1.64-1.80(1H,m),
2.84-3.20(4H,m), 3.45-3.96(3H,m), 4.15-4.34(1H,m), 4.39-4.78(3H,m),
6.70(2H,d,J=8.8 Hz), 6.85-7.01(1H,m), 7.52(1H,d,J=8.7 Hz),
9.45(2H,brs).
Example 55
Synthesis of
3-[(2S,4S)-4-(4-nitrophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidin-
e hydrochloride
[0329] (1) The title compound (904 mg) of Reference Example 10,
diisopropylethylamine (1.57 mL) and 4-fluoronitrobenzene (423 mg)
were dissolved in N-methyl-2-pyrrolidone (9 mL), and the mixture
was stirred at 80.degree. C. for 24 hr. The reaction mixture was
poured into saturated aqueous sodium hydrogencarbonate solution,
and the mixture was extracted with ethyl acetate. The extract was
dried and the solvent was evaporated under reduced pressure. The
residue was purified by silica gel chromatography to give
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-nitrophenyl)amino-2-pyrrolidinylcar-
bonyl]-1,3-thiazolidine (919 mg) as yellow amorphous.
[0330] (2) The above-mentioned compound (795 mg) was dissolved in
ethyl acetate (3.8 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(2.4 mL) was added thereto. The mixture was stirred at room
temperature for 18 hr. The precipitated solid was collected by
filtration to give the title compound (647 mg) as a yellow
powder.
[0331] .sup.1H-NMR(DMSO-d.sub.6).delta.1.68-1.87(1H,m),
2.88-3.30(4H,m), 3.48-3.98(3H,m), 4.24-4.80(4H,m), 6.72(2H,d,J=9.3
Hz), 7.40-7.56(1H,m), 8.04(2H,d,J=7.5 Hz), 9.51(2H,brs).
Example 56
Synthesis of
3-[(2S,4S)-4-(4-methanesulfonylphenyl)amino-2-pyrrolidinylcarbonyl]-1,3-t-
hiazolidine hydrochloride
[0332] (1) The title compound (904 mg) of Reference Example 10,
diisopropylethylamine (1.57 mL) and 4-fluorophenyl methyl sulfone
(523 mg) were dissolved in N-methyl-2-pyrrolidone (9 mL), and the
mixture was stirred at 100.degree. C. for 18 hr. The reaction
mixture was poured into saturated aqueous sodium hydrogencarbonate
solution, and the mixture was extracted with ethyl acetate. The
extract was dried and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel chromatography to
give
3-[((2S,4S)-1-tert-butoxycarbonyl-4-(4-methanesulfonylphenyl)amino-2-pyrr-
olidinylcarbonyl]-1,3-thiazolidine (27 mg).
[0333] (2) The above-mentioned compound (27 mg) was dissolved in
ethyl acetate (0.2 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(0.1 mL) was added thereto. The mixture was stirred at room
temperature for 18 hr. The precipitated solid was collected by
filtration to give the title compound (19.4 mg).
[0334] .sup.1H-NMR(DMSO-d.sub.6).delta.1.65-1.82(1H,m),
2.89-3.23(7H,m), 3.49-3.98(3H,m), 4.18-4.78(4H,m), 6.74(2H,d,J=9.0
Hz), 6.80-6.92(1H,m), 6.63(2H,d,J=9.0 Hz), 9.30(2H,brs).
Example 57
Synthesis of
3-[(2S,4S)-4-(2-cyanophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidin-
e hydrochloride
[0335] (1) The title compound (1810 mg) of Reference Example 10,
diisopropylethylamine (3.14 mL) and 2-fluorobenzonitrile (727 mg)
were dissolved in N-methyl-2-pyrrolidone (18 mL), and the mixture
was stirred at 80.degree. C. for 32 hr. The reaction mixture was
poured into saturated aqueous sodium hydrogencarbonate solution,
and the mixture was extracted with ethyl acetate. The extract was
dried and the solvent was evaporated under reduced pressure. The
residue was purified by silica gel chromatography to give
3-[((2S,4S)-1-tert-butoxycarbonyl-4-(2-cyanophenyl)amino-2-pyrrolidinylca-
rbonyl]-1,3-thiazolidine (88 mg).
[0336] (2) The above-mentioned compound (88 mg) was dissolved in
ethyl acetate (0.4 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(0.3 mL) was added thereto. The mixture was stirred at room
temperature for 18 hr. The precipitated solid was collected by
filtration to give the title compound (25 mg).
[0337] .sup.1H-NMR(DMSO-d.sub.6).delta.1.74-1.95(1H,m),
2.85-3.16(3H,m), 3.30-3.92(4H,m), 4.27-4.79(4H,m), 6.15-6.27(1H,m),
6.77(1H,t,J=7.5 Hz), 6.87(1H,d,J=8.4 Hz), 7.38-7.59(2H,m),
8.90(1H,brs), 10.80(1H,brs).
Example 58
Synthesis of
3-[(2S,4S)-4-(5-cyano-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazol-
idine dihydrochloride
[0338] (1) The title compound (904 mg) of Reference Example 10,
diisopropylethylamine (1.57 mL) and 2-chloro-5-cyanopyridine (416
mg) were dissolved in N-methyl-2-pyrrolidone (9 mL), and the
mixture was stirred at 80.degree. C. for 18 hr. The reaction
mixture was added to saturated aqueous sodium hydrogencarbonate
solution, and the mixture was extracted with ethyl acetate. The
extract was dried and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel chromatography to
give
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-cyano-2-pyridyl)amino-2-pyrrolidiny-
lcarbonyl]-1,3-thiazolidine (807 mg) as white amorphous.
[0339] (2) The above-mentioned compound (711 mg) was dissolved in
ethyl acetate (1.76 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(2.20 mL) was added thereto. The mixture was stood at room
temperature for 18 hr. The precipitated solid was collected by
filtration to give the title compound (709 mg) as a white
powder.
[0340] .sup.1H-NMR(DMSO-d.sub.6).delta.1.74-1.94(1H,m),
2.78-2.94(1H,m), 2.97-3.26(3H,m), 3.40-3.77(3H,m), 4.40-4.80(4H,m),
6.64(1H,d,J=9.0 Hz), 7.77(1H,dd,J=8.7, 2.4 Hz), 8.08(1H,brs),
8.46(1H,d,J=1.8 Hz), 8.86(1H,brs), 10.37(1H,brs).
Example 59
Synthesis of
3-[(2S,4S)-4-(3,4-dicyanophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazol-
idine hydrochloride
[0341] (1) The title compound (0.904 g) of Reference Example 10,
diisopropylethylamine (1.57 mL) and 4-fluorophthalonitrile (0.438
g) were dissolved in N-methyl-2-pyrrolidone (9 mL), and the mixture
was stirred at 80.degree. C. for 4 hr. The reaction mixture was
poured into saturated aqueous sodium hydrogencarbonate solution,
and the mixture was extracted with ethyl acetate. The extract was
dried and the solvent was evaporated under reduced pressure. The
residue was purified by silica gel chromatography to give
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(3,4-dicyanophenyl)amino-2-pyrrolidiny-
lcarbonyl]-1,3-thiazolidine (1.08 g) as white amorphous.
[0342] (2) The above-mentioned compound (0.924 g) was dissolved in
ethyl acetate (2.16 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(2.70 mL) was added thereto. The mixture was stirred at room
temperature for 18 hr. The precipitated solid was collected by
filtration to give the title compound (0.782 g) as a yellow
powder.
[0343] .sup.1H-NMR(DMSO-d.sub.6).delta.1.66-1.84(1H,m),
2.90-3.27(4H,m), 3.49-3.95(3H,m), 4.20-4.40(1H,m), 4.40-5.79(3H,m),
7.00(1H,dd,J=8.7, 2.4 Hz), 7.22(1H,s), 7.52-7.67(1H,m),
7.76(1H,d,J=9.0 Hz).
Example 60
Synthesis of
3-[(2S,4S)-4-(3-chloro-4-cyanophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-th-
iazolidine hydrochloride
[0344] (1) The title compound (0.904 g) of Reference Example 10,
diisopropylethylamine (1.57 mL) and 2-chloro-4-fluorobenzonitrile
(0.467 g) were dissolved in N-methyl-2-pyrrolidone 9 mL), and the
mixture was stirred at 80.degree. C. for 8 hr. The reaction mixture
was poured into saturated aqueous sodium hydrogencarbonate
solution, and the mixture was extracted with ethyl acetate. The
extract was dried and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel chromatography to
give
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(3-chloro-4-cyanophenyl)amino-2-pyrrol-
idinylcarbonyl]-1,3-thiazolidine (0.630 g) as a colorless
transparent oil.
[0345] (2) The above-mentioned compound (0.630 g) was dissolved in
ethyl acetate (2.88 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(1.80 mL) was added thereto. The mixture was stirred at room
temperature for 18 hr, and the precipitated solid was collected by
filtration to give the title compound (0.465 g) as a white
powder.
[0346] .sup.1H-NMR(DMSO-d.sub.6).delta.1.65-1.81(1H,m),
2.84-2.99(1H,m), 2.99-3.22(3H,m), 3.48-3.95(3H,m), 4.16-4.37(1H,m),
4.39-4.78(3H,m), 6.68(1H,dd,J=8.7, 2.1 Hz), 6.85(1H,d,J=1.8 Hz),
7.30-7.45(1H,m), 7.60(1H,d,J=8.7 Hz), 9.60(2H,brs).
Example 61
Synthesis of
3-[(2S,4S)-4-(2-benzoxazolyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidi-
ne hydrochloride
[0347] (1) The title compound (904 mg) of Reference Example 10,
diisopropylethylamine (1.57 mL) and 2-chlorobenzoxazole (461 mg)
were dissolved in N-methyl-2-pyrrolidone (9 mL), and the mixture
was stirred at room temperature for 1 hr. The reaction mixture was
poured into saturated aqueous sodium hydrogencarbonate solution,
and the mixture was extracted with ethyl acetate. The extract was
dried and the solvent was evaporated under reduced pressure. The
residue was purified by silica gel chromatography to give
3-[(2S,4S)-4-(2-enzoxazolyl)amino-1-tert-butoxycarbonyl-2-pyrrolidinylcar-
bonyl]-1,3-thiazolidine (975 mg) as white morphous.
[0348] (2) The above-mentioned compound (862 mg) was dissolved in
ethyl acetate (4.1 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(2.6 mL) was added thereto. The mixture was stirred at room
temperature for 8 hr. The precipitated solid was collected by
filtration to give the title compound (656 mg) as a white
powder.
[0349] .sup.1H-NMR(DMSO-d.sub.6).delta.1.94-2.13(1H,m),
2.85-2.99(1H,m), 3.00-3.20(2H,m), 3.31-4.00(4H,m), 4.40-4.82(4H,m),
7.07(1H,td,J=7.8, 1.2 Hz), 7.18(1H,td,J=7.8, 1.2 Hz),
7.33(1H,d,J=7.2 Hz), 7.42(1H,d,J=7.5 Hz), 8.61(1H,brs), 8.89(1
Hbrs), 10.59(1H,brs).
Example 62
Synthesis of
3-((2S,4S)-4-benzylamino-2-pyrrolidinylcarbonyl)-1,3-thiazolidine
dihydrochloride
[0350] (1) The title compound (904 mg) of Reference Example 10 and
benzaldehyde (318 mg) were dissolved in methanol (16 mL), and the
mixture was stirred at room temperature for 30 min. Sodium
cyanoborohydride (189 mg) and several drops of acetic acid were
added to the reaction mixture, and the mixture was stirred for 6
hr. The reaction mixture was evaporated under reduced pressure.
Saturated aqueous sodium hydrogencarbonate solution was added to
the residue and the mixture was extracted with ethyl acetate. The
extract was dried and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel chromatography to
give
3-[((2S,4S)-4-benzylamino-1-tert-butoxycarbonyl-2-pyrrolidinylcar-
bonyl]-1,3-thiazolidine (742 mg) as a colorless transparent
oil.
[0351] (2) The above-mentioned compound (742 mg) was dissolved in
ethyl acetate (3.8 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(2.4 mL) was added thereto. The mixture was stirred at room
temperature for 18 hr and the precipitated solid was collected by
filtration to give the title compound (540 mg) as a white
powder.
[0352] .sup.1H-NMR(DMSO-d.sub.6).delta.2.10-2.32(1H,m),
2.86-3.20(3H,m), 3.49-4.03(5H,m), 4.21(2H,s), 4.39-4.80(3H,m),
7.31-7.52(3H,m), 7.52-7.72(2H,m), 10.17(4H,brs).
Example 63
Synthesis of
3-[(2S,4S)-4-(4-cyanophenylmethyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiaz-
olidine dihydrochloride
[0353] (1) The title compound (904 mg) of Reference Example 10 and
4-cyanobenzaldehyde (393 mg) were dissolved in methanol (16 mL),
and the mixture was stirred at room temperature for 30 min. Sodium
cyanoborohydride (189 mg) and several drops of acetic acid were
added to the reaction mixture, and the mixture was stirred for 18
hr. The reaction mixture was evaporated under reduced pressure.
Saturated aqueous sodium hydrogencarbonate solution was added to
the residue and the mixture was extracted with ethyl acetate. The
extract was dried and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel chromatography to
give
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-cyanophenylmethyl)amino-2-pyrrolidi-
nylcarbonyl]-1,3-thiazolidine (389 mg) as a colorless transparent
oil.
[0354] (2) The above-mentioned compound (389 mg) was dissolved in
ethyl acetate (0.9 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(1.2 mL) was added thereto. The mixture was stood at room
temperature for 18 hr. The precipitated solid was collected by
filtration to give the title compound (286 mg) as a white
powder.
[0355] .sup.1H-NMR(DMSO-d.sub.6).delta.2.06-2.34(1H,m),
2.85-3.01(1H,m), 3.01-3.20(2H,m), 3.50-4.06(5H,m), 4.30(2H,s),
4.41-4.79(3H,m), 7.80(2H,d,J=8.1 Hz), 7.95(2H,d,J=8.4 Hz),
9.05(1H,brs), 10.30(3H,brs).
Example 64
Synthesis of
3-{(2S,4S)-4-[N-(4-cyanophenylmethyl)-N-methylamino]-2-pyrrolidinylcarbon-
yl}-1,3-thiazolidine dihydrochloride
[0356] (1)
3-[(2S,4S)-1-tert-Butoxycarbonyl-4-(4-cyanophenylmethyl)amino-2-pyrrolidi-
nylcarbonyl]-1,3-thiazolidine [product of Example 63 (1), 1.35 g]
and 37% formaldehyde solution (0.788 mL) were dissolved in
acetonitrile (20 mL), and the mixture was stirred at room
temperature for 30 min. Sodium cyanoborohydride (0.305 g) and
several drops of acetic acid were added to the reaction mixture,
and the reaction mixture was stirred for 1 hr. The reaction mixture
was evaporated under reduced pressure. Saturated aqueous sodium
hydrogencarbonate solution was added to the residue and the mixture
was extracted with ethyl acetate. The extract was dried and the
solvent was evaporated under reduced pressure. The residue was
purified by silica gel chromatography to give
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[(N-(4-cyanophenylmethyl)-N-methylamin-
o]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (0.953 g) as white
amorphous.
[0357] (2) The above-mentioned compound (0.818 g) was dissolved in
ethyl acetate (3.8 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(2.4 mL) was added thereto. The mixture was stirred at room
temperature for 5 hr. The precipitated solid was collected by
filtration to give the title compound (0.683 g) as a white
powder.
[0358] .sup.1H-NMR(DMSO-d.sub.6).delta.2.20-2.48(1H,m), 2.57(3H,s),
2.80-3.20(3H,m), 3.57-4.17(5H,m), 4.20-4.85(5H,m), 7.88(2H,d,J=7.8
Hz), 7.96(2H,d,J=8.4 Hz), 9.12(1H,brs), 10.95(1H,brs),
12.50(1H,brs).
Example 65
Synthesis of
3-[((2S,4R)-4-(7-methoxy-2-phenyl-4-quinolyl)oxy-2-pyrrolidinylcarbonyl]--
1,3-thiazolidine trihydrochloride
[0359] (1) N-tert-Butoxycarbonyl-L-trans-hydroxyproline (5.67 g)
was dissolved in dimethyl sulfoxide (70 mL), and potassium
tert-butoxide (6.88 g) was gradually added thereto at room
temperature. The mixture was stirred for 1.5 hr.
4-Chloro-7-methoxy-2-phenylquinoline (7.28 g) was gradually added
to this solution, and the mixture was stirred for 17 hr. Water was
added to the reaction mixture and the mixture was washed with ethyl
acetate/hexane (1/1). The aqueous layer was adjusted to pH 4 with 1
mol/L hydrochloric acid, and the precipitate was collected by
filtration to give
(2S,4R)-1-tert-butoxycarbonyl-4-(7-methoxy-2-phenyl-4-quinolyl)ox-
y-2-pyrrolidine-2-carboxylic acid (8.00 g) as a white solid.
[0360] (2) Using the above-mentioned compound (546 mg) and in the
same manner as in Reference Example 9,
3-[(2S,4R)-1-tert-butoxycarbonyl-4-(7-methoxy-2-phenyl-4-quinolyl)oxy-2-p-
yrrolidinylcarbonyl]-1,3-thiazolidine (568 mg) was obtained as a
white solid.
[0361] (3) Using the above-mentioned compound (554 mg) and in the
same manner as in Example 5 (2), the title compound (521 mg) was
obtained as a white powder.
[0362] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.40-2.50(1H,m),
2.96-3.12(3H,m), 3.68-3.97(4H,m), 3.99(3H,s), 4.48-4.94(3H,m),
4.98(1H,brs), 7.43(1H,d,J=8.1 Hz), 7.69-7.70(4H,m), 7.91(1H,brs),
8.26(2H,d,J=7.4 Hz), 8.57(1H,brs), 9.10(1H,brs), 11.00(1H,brs).
Example 66
Synthesis of
3-((2S,4S)-4-benzoyloxy-2-pyrrolidinylcarbonyl)-1,3-thiazolidine
[0363] (1) Using the title compound (643 mg) of Reference Example
11 and benzoyl chloride (0.44 mL), and in the same manner as in
Example 50 (1),
3-((2S,4S)-4-benzoyloxy-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-1,3-
-thiazolidine (515 mg) was obtained as an oil.
[0364] (2) The above-mentioned compound (413 mg) was dissolved in
ethyl acetate (4 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(1.3 mL) was added thereto. The mixture was stirred at room
temperature for 14 hr and the solvent was evaporated under reduced
pressure. The residue was added to aqueous sodium hydrogencarbonate
solution and extracted with ethyl acetate. The extract was washed
with brine and dried. The solvent was evaporated under reduced
pressure and the residue was purified by silica gel chromatography
to give the title compound (315 mg) as an oil.
[0365] .sup.1H-NMR(DMSO-d.sub.6).delta.1.83-1.93(1H,m),
2.45-2.57(1H,m), 2.87(1H,dd,J=12.8, 4.2 Hz), 2.99(1H,t,J=6.3 Hz),
3.08(1H,t,J=6.3 Hz), 3.19(1H,d,J=12.8 Hz), 3.57-3.77(1.5H,m),
3.83-3.98(1.5H,m), 4.42(0.5H,d,J=9.5 Hz), 4.48-4.58(1H,m),
4.72(0.5H,d,J=9.5 Hz), 5.28-5.36(1H,m), 7.52(2H,t,J=7.4 Hz),
7.65(1H,t,J=7.4 Hz), 7.93(2H,d,J=7.4 Hz).
Example 67
Synthesis of
3-[(2S,4S)-4-(4-cyanobenzoyl)oxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine
[0366] (1) Using the title compound (445 mg) of Reference Example
11 and 4-cyanobenzoyl chloride (371 mg), and in the same manner as
in Example 50 (1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-cyanobenzoyl)oxy-2-pyrrolidiny-
lcarbonyl]-1,3-thiazolidine (519 mg) was obtained as a pale-brown
solid.
[0367] (2) Using the above-mentioned compound (386 mg), and in the
same manner as in Example 66 (2), the title compound (280 mg) was
obtained as a pale-yellow solid.
[0368] .sup.1H-NMR(DMSO-d.sub.6).delta.1.88-1.97(1H,m),
2.46-2.58(1H,m), 2.88(1H,dd,J=12.9, 4.0 Hz), 2.99(1H,t,J=6.3 Hz),
3.09(1H,t,J=6.3 Hz), 3.23(1H,d,J=12.9 Hz), 3.57-3.76(1.5H,m),
3.84-3.99(1.5H,m), 4.42(0.5H,d,J=9.5 Hz), 4.48-4.57(1H,m),
4.72(0.5H,d,J=9.5 Hz), 5.33-5.38(1H,m), 8.01(2H,d,J=8.3 Hz),
8.07(2H,d,J=8.3 Hz).
Example 68
Synthesis of
3-((2S,4S)-4-anilino-2-pyrrolidinylcarbonyl)-1,3-thiazolidine
dihydrochloride
[0369] (1) The title compound (501 mg) of Reference Example 12,
aniline (0.20 mL) and acetic acid (0.10 mL) were dissolved in
methanol (10 mL), and the mixture was stirred at room temperature
for 1.5 hr. Sodium cyanoborohydride (145 mg) was added to the
reaction mixture and the mixture was stirred for 2 hr. The reaction
mixture was evaporated under reduced pressure. Saturated aqueous
sodium hydrogencarbonate solution was added to the residue and the
mixture was extracted with ethyl acetate. The extract was washed
with brine and dried. The solvent was evaporated under reduced
pressure, and the residue was purified by silica gel chromatography
and crystallized from diethyl ether to give
3-((2S,4S)-4-anilino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-1,3-th-
iazolidine (156 mg) as white crystals.
[0370] (2) The above-mentioned compound (142 mg) was dissolved in
ethyl acetate (2 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(0.5 mL) was added thereto. The mixture was stirred at room
temperature for 12 hr. The precipitated solid was collected by
filtration to give the title compound (89 mg) as a white
powder.
[0371] .sup.1H-NMR(DMSO-d.sub.6).delta.1.64-1.78(1H,m),
2.84-2.97(1H,m), 3.00-3.19(3H,m), 3.43-3.55(1H,m), 3.60-4.20(5H,m),
4.41-4.76(3H,m), 6.56-6.67(3H,m), 7.13(2H,t,J=7.2 Hz),
8.79(1H,brs), 10.29(1H,brs).
Example 69
Synthesis of
3-[((2S,4S)-4-(4-aminophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidi-
ne hydrochloride
[0372] The title compound (200 mg) of Example 55 was dissolved in
ethanol (10 mL), and 4 mol/L hydrochloric acid-1,4-dioxane (0.28
mL) and 10% palladium/carbon (100 mg) were added. The mixture was
stirred under a hydrogen atomosphere (1 atm) at room temperature
for 18 hr. The reaction mixture was filtrated and the filtrate was
concentrated under reduced pressure, and the obtained solid was
washed with ethanol to give the title compound (13 mg) as a white
powder.
[0373] .sup.1H-NMR(DMSO-d.sub.6).delta.1.58-1.80(1H,m),
2.83-3.00(1H,m), 3.00-3.20(3H,m), 3.60-3.90(3H,m), 4.08-4.25(1H,m),
4.39-4.79(3H,m), 6.67(2H,d,J=8.7 Hz), 7.15(2H,d,J=8.7 Hz),
8.81(1H,brs), 10.00(3H,brs), 10.25(1H,brs).
Example 70
Synthesis of
3-[(2S,4S)-4-(p-anisidino)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine
dihydrochloride
[0374] (1) The title compound (450 mg) of Reference Example 12,
p-anisidine (222 mg) and acetic acid (0.09 mL) were dissolved in
1,2-dichloroethane (8 mL), and sodium triacetoxyborohydride (636
mg) was added thereto. The mixture was stirred at room temperature
for 3 hr. Saturated aqueous sodium hydrogencarbonate solution was
added to the reaction mixture, and the mixture was extracted with
ethyl acetate. The extract was washed with brine and dried. The
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel chromatography to give
3-[(2S,4S)-4-(p-anisidino)-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]--
1,3-thiazolidine (515 mg) as a white solid.
[0375] (2) The above-mentioned compound (448 mg) was dissolved in
ethyl acetate (10 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(1.4 mL) was added thereto. The mixture was stirred at room
temperature for 13 hr. The precipitated solid was collected by
filtration to give the title compound (223 mg) as a white
powder.
[0376] .sup.1H-NMR(DMSO-d.sub.6).delta.1.77-1.90(1H,m),
2.77-2.89(1H,m), 3.00-3.14(3H,m), 3.20-4.20(1H,m), 3.60-4.20(6H,m),
4.40-4.72(3H,m), 6.87(4H,s), 8.84(1H,brs), 10.33(1H,brs).
Example 71
Synthesis of
3-[(2S,4S)-4-(4-chlorophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidi-
ne dihydrochloride
[0377] (1) Using the title compound (450 mg) of Reference Example
12 and p-chloroaniline (230 mg), and in the same manner as in
Example 70 (1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-chlorophenyl)amino-2-pyrrolidinylca-
rbonyl]-1,3-thiazolidine (415 mg) was obtained as an oil.
[0378] (2) Using the above-mentioned compound (412 mg), and in the
same manner as in Example 70 (2) the title compound (297 mg) was
obtained as a white powder.
[0379] .sup.1H-NMR(DMSO-d.sub.6).delta.1.63-1.78(1H,m),
2.84-2.97(1H,m), 3.00-3.17(3H,m), 3.5-3.92(3H,m), 4.07-4.18(1H,m),
4.40-4.73(3H,m), 6.62(2H,d,J=8.8 Hz), 7.15(2H,d,J=8.8 Hz),
8.86(1H,brs), 10.23(1H,brs).
Example 72
Synthesis of
3-[(2S,4S)-4-(2-chloro-4-cyanophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-th-
iazolidine hydrochloride
[0380] (1) The title compound (904 mg) of Reference Example 10,
diisopropylethylamine (1.57 mL) and 3-chloro-4-fluorobenzonitrile
(467 mg) were dissolved in N-methyl-2-pyrrolidone (9 mL), and the
mixture was stirred at 80.degree. C. for 8 hr. The reaction
solution was added to saturated aqueous sodium hydrogencarbonate
solution, extracted with ethyl acetate. The extract was dried and
the solvent was evaporated under reduced pressure. The residue was
purified by silica gel chromatography to give
3-[((2S,4S)-1-tert-butoxycarbonyl-4-(2-chloro-4-cyanophenyl)amino-
-2-pyrrolidinylcarbonyl]-1,3-thiazolidine (460 mg) as a white
solid.
[0381] (2) The above-mentioned compound (395 mg) was dissolved in
ethyl acetate (1.8 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(1.13 mL) was added thereto. The mixture was stirred at room
temperature for 4 hr, and the precipitated solid was collected by
filtration to give the title compound (177 mg) as a white
powder.
[0382] .sup.1H-NMR(DMSO-d.sub.6).delta.1.80-1.99(1H,m),
2.82-3.17(3H,m), 3.25-3.94(4H,m), 4.36-4.54(2H,m), 4.54-4.80(2H,m),
6.42(1H,d,J=7.8 Hz), 6.93(1H,d,J=8.7 Hz), 7.64(1H,dd,J=8.4, 1.8
Hz), 7.82(d,J=1.8 Hz).
Example 73
Synthesis of
3-[(2S,4S)-4-(3-chloro-4-methoxyphenyl)amino-2-pyrrolidinylcarbonyl]-1,3--
thiazolidine dihydrochloride
[0383] (1) Using the title compound (450 mg) of Reference Example
12 and 3-chloro-4-methoxyaniline (284 mg), and in the same manner
as in Example 70 (1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(3-chloro-4-methoxyphenyl)amin-
o-2-pyrrolidinylcarbonyl]-1,3-thiazolidine (569 mg) was obtained as
an oil.
[0384] (2) Using the above-mentioned compound (561 mg), and in the
same manner as in Example 70 (2), the title compound (429 mg) was
obtained as a pale-brown powder.
[0385] .sup.1H-NMR(DMSO-d.sub.6).delta.1.62-1.76(1H,m),
2.82-2.95(1H,m), 3.00-3.18(3H,m), 3.5-3.92(6H,m), 4.07-4.18(1H,m),
4.40-4.73(3H,m), 6.61(1H,dd,J=8.8, 2.7 Hz), 6.75(1H,d,J=2.7 Hz),
6.98(1H,d,J=8.8 Hz), 8.80(1H,brs), 10.15(1H,brs).
Example 74
Synthesis of
3-[((2S,4S)-4-(3,4-methylenedioxyphenyl)amino-2-pyrrolidinylcarbonyl]-1,3-
-thiazolidine dihydrochloride
[0386] (1) Using the title compound (450 mg) of Reference Example
12 and 3,4-methylenedioxyaniline (249 mg), and in the same manner
as in Example 70 (1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(3,4-methylenedioxyphenyl)amin-
o-2-pyrrolidinylcarbonyl]-1,3-thiazolidine (553 mg) was obtained as
a pale-brown-reddish solid.
[0387] (2) Using the above-mentioned compound (549 mg), and in the
same manner as in Example 70 (2), the title compound (457 mg) was
obtained as a pale-brown-reddish powder.
[0388] .sup.1H-NMR(DMSO-d.sub.6).delta.1.72-1.85(1H,m),
2.820-2.93(1H,m), 3.00-3.28(3H,m), 3.45-3.57(1H,m),
3.60-3.95(2H,m), 4.08-4.20(1H,m), 4.42-4.75(3H,m), 5.92(2H,s),
6.25-6.32(1H,m), 6.53(1H,s), 6.76-6.83(1H,m), 8.89(1H,brs),
10.36(1H,brs).
Example 75
Synthesis of
3-[(2S,4S)-4-(5-trifluoromethyl-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-1-
,3-thiazolidine dihydrochloride
[0389] (1) The title compound (904 mg) of Reference Example 10,
diisopropylethylamine (1.57 mL) and
2-chloro-5-trifluoromethylpyridine (545 mg) were dissolved in
N-methyl-2-pyrrolidone (9 mL), and the mixture was stirred at
80.degree. C. for 18 hr. The reaction solution was added to
saturated aqueous sodium hydrogencarbonate solution, and extracted
with ethyl acetate. The extract was dried and the solvent was
evaporated under reduced pressure. The residue was purified by
silica gel chromatography to give
3-[((2S,4S)-1-tert-butoxycarbonyl-4-(5-trifluoromethyl-2-pyridyl)amino-2--
pyrrolidinylcarbonyl]-1,3-thiazolidine (143 mg).
[0390] (2) The above-mentioned compound (143 mg) was dissolved in
ethyl acetate (0.64 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(0.32 mL) was added thereto. The mixture was stirred at room
temperature for 18 hr. The precipitated solid was collected by
filtration to give the title compound (65 mg) as a brown
powder.
[0391] .sup.1H-NMR(DMSO-d.sub.6).delta.1.71-1.93(1H,m),
2.80-2.98(1H,m), 3.00-3.28(3H,m), 3.34-3.99(3H,m), 4.40-4.80(4H,m),
6.68(1H,d,J=9.0 Hz), 7.74(1H,dd,J=8.7, 2.4 Hz), 7.83(1H,brs),
8.35(1H,d,J=1.2 Hz), 8.91(1H,brs), 10.22(1H,brs).
Example 76
Synthesis of
3-[(2S,4S)-4-(6-cyano-5-trifluoromethyl-2-pyridyl)amino-2-pyrrolidinylcar-
bonyl]-1,3-thiazolidine hydrochloride
[0392] (1) 2-Chloro-5-trifluoromethylpyridine (5 g) was dissolved
in chloroform (150 mL) and m-chloroperbenzoic acid (14.3 g) was
added thereto. The mixture was stirred at 60.degree. C. for 30 hr.
Aqueous sodium thiosulfate solution and saturated aqueous sodium
hydrogencarbonate solution were added to the reaction mixture, and
after stirring, the mixture was extracted with chloroform. The
extract was washed successively with saturated aqueous sodium
hydrogencarbonate solution and brine, and dried. The solvent was
evaporated under reduced pressure and the residue was purified by
silica gel chromatography to give
2-chloro-5-trifluoromethylpyridine 1-oxide (0.64 g).
[0393] (2) The above-mentioned compound (610 mg) was dissolved in
acetonitrile (5 mL), and triethylamine (0.861 mL) and
trimethylsilyl cyanide (1.16 mL) were added thereto. The mixture
was refluxed for 4 hr. Saturated aqueous sodium hydrogencarbonate
solution was added to the reaction mixture, and the mixture was
extracted with ethyl acetate. The extract was washed with brine and
the solvent was evaporated under reduced pressure. The residue was
purified by silica gel chromatography to give
6-chloro-3-trifluoromethylpyridine-2-carbonitrile (401 mg) as a red
oil.
[0394] (3) The above-mentioned compound (381 mg), the title
compound (556 mg) of Reference Example 10 and diisopropylethylamine
(0.96 mL) were dissolved in N-methyl-2-pyrrolidone (6 mL), and the
mixture was stirred at room temperature for 18 hr. The reaction
solution was added to saturated aqueous sodium hydrogencarbonate
solution and extracted with ethyl acetate. The extract was dried
and the solvent was evaporated under reduced pressure. The residue
was purified by silica gel chromatography to give
3-[((2S,4S)-1-tert-butoxycarbonyl-4-(6-cyano-5-trifluoromethyl-2--
pyridyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine (509 mg) as
a colorless transparent oil.
[0395] (4) The above-mentioned compound (481 mg) was dissolved in
ethyl acetate (2.04 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(1.02 mL) was added thereto. The mixture was stirred at room
temperature for 8 hr. The reaction solvent was evaporated under
reduced pressure, and the obtained solid was washed with ethyl
acetate to give the title compound (272 mg) as a white powder.
[0396] .sup.1H-NMR(DMSO-d.sub.6).delta.1.71-1.95(1H,m),
2.77-2.98(1H,m), 2.99-3.27(3H,m), 3.48-3.99(3H,m), 4.40-4.80(4H,m),
6.96(1H,d,J=9.0 Hz), 7.93(1H,d,J=9.0 Hz), 8.40(1H,t,J=6.0 Hz),
9.55(1H,brs).
Example 77
Synthesis of
3-[(2S,4S)-4-(5,6-dicyano-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-1,3-thi-
azolidine hydrochloride
[0397] (1) 2-Chloropyridine-5-carbonitrile (7.01 g) was dissolved
in acetonitrile (70 mL), and urea hydrogen peroxide addition
compound (10 g) was added. Trifluoroacetic anhydride was added
dropwise to the reaction mixture under ice-cooling and the mixture
was stirred at room temperature for 18 hr. The reaction mixture was
added to aqueous sodium thiosulfate solution and the mixture was
extracted with chloroform. The extract was washed successively with
saturated aqueous sodium hydrogencarbonate solution and brine and
dried. The solvent was evaporated under reduced pressure and the
residue was purified by silica gel chromatography to give
2-chloro-5-cyanopyridine 1-oxide (0.779 g) as a white solid.
[0398] (2) Using the above-mentioned compound (7-79 mg), and in the
same manner as in Example 76 (2), 6-chloro-2,3-dicyanopyridine (198
mg) was obtained as a brown solid.
[0399] (3) Using the above-mentioned compound (196 mg) and the
title compound (361 mg) of Reference Example 10, and in the same
manner as in Example 76 (3),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5,6-dicyano-2-pyridyl)amino-2-pyrroli-
dinylcarbonyl]-3-1,3-thiazolidine (338 mg) was obtained as a white
solid.
[0400] (4) The above-mentioned compound (338 mg) was dissolved in
ethyl acetate (1.58 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(0.79 mL) was added thereto. The mixture was stirred at room
temperature for 6 hr. The precipitated solid was collected by
filtration to give the title compound (178 mg) as a pale-yellow
powder.
[0401] .sup.1H-NMR(DMSO-d.sub.6).delta.1.71-1.98(1H,m),
2.80-3.00(1H,m), 3.00-3.24(3H,m), 3.49-4.00(3H,m), 4.39-4.90(3H,m),
6.94(1H,d,J=9.0 Hz), 7.97(1H,d,J=8.7 Hz), 8.70(1H,brs),
9.55(2H,brs).
Example 78
Synthesis of
3-[(2S,4S)-4-(3-cyanophenylmethyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiaz-
olidine dihydrochloride
[0402] (1) Using the title compound (3.62 g) of Reference Example
10 and 3-cyanobenzaldehyde (1.57 g), and in the same manner as in
Example 63 (1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(3-cyanophenylmethyl)amino-2-pyrr-
olidinylcarbonyl]-1,3-thiazolidine (2.01 g) was obtained.
[0403] (2) The above-mentioned compound (313 mg) was dissolved in
ethyl acetate (1.50 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(0.94 mL) was added thereto. The mixture was stirred at room
temperature for 18 hr. The precipitated solid was collected by
filtration to give the title compound (217 mg) as a white
powder.
[0404] .sup.1H-NMR(DMSO-d.sub.6).delta.2.09-2.30(1H,m),
2.87-3.01(1H,m), 3.07(1H,t,J=6.3 Hz), 3.15(1H,t,J=6.0 Hz),
3.50-4.05(5H,m), 4.27(2H,s), 4.40-4.78(3H,m), 7.67(1H,t,J=7.8 Hz),
7.84-8.00(2H,m), 8.10(1H,s), 10.28(3H,brs).
Example 79
Synthesis of
3-[(2S,4S)-4-(4-trifluoromethylphenylmethyl)amino-2-pyrrolidinylcarbonyl]-
-1,3-thiazolidine dihydrochloride
[0405] (1) Using the title compound (1.81 g) of Reference Example
10 and 4-(trifluoromethyl)benzaldehyde (1.05 g), and in the same
manner as in Example 63 (1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-trifluoromethylphenylmethyl)amino-2-
-pyrrolidinylcarbonyl]-1,3-thiazolidine (1.69 g) was obtained.
[0406] (2) The above-mentioned compound (488 mg) was dissolved in
ethyl acetate (2.12 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(1.33 mL) was added thereto. The mixture was stirred at room
temperature for 18 hr and the precipitated solid was collected by
filtration to give the title compound (375 mg) as a white
powder.
[0407] .sup.1H-NMR(DMSO-d.sub.6).delta.2.10-2.32(1H,m),
2.86-3.00(1H,m), 2.50(1H,t,J=1.8 Hz), 2.51(1H,t,J=1.8 Hz),
3.50-4.02(5H,m), 4.32(2H,s), 4.41-4.80(3H,m), 7.78-7.92(4H,m),
10.35(3H,brs).
Example 80
Synthesis of
3-{(2S,4S)-4-[bis(4-cyanophenylmethyl)]amino-2-pyrrolidinylcarbonyl}-1,3--
thiazolidine dihydrochloride
[0408] (1) The title compound (0.904 g) of Reference Example 10,
4-cyanobenzyl bromide (1.29 g) and diisopropylethylamine (1.57 mL)
were dissolved in N-methyl-2-pyrrolidone (9 mL), and the mixture
was stirred at room temperature for 18 hr. The reaction mixture was
added to saturated aqueous sodium hydrogencarbonate solution, and
the mixture was extracted with ethyl acetate. The extract was dried
and the solvent was evaporated under reduced pressure. The residue
was purified by silica gel chromatography to give
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[bis(4-cyanophenylmethyl)]amino-2-pyrr-
olidinylcarbonyl}-1,3-thiazolidine (1.27 g).
[0409] (2) The above-mentioned compound (1.13 g) was dissolved in
ethyl acetate (4.24 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(2.65 mL) was added thereto. The mixture was stirred at room
temperature for 18 hr and the precipitated solid was collected by
filtration to give the title compound (444 mg) as a white
powder.
[0410] .sup.1H-NMR(DMSO-d.sub.6).delta.1.81-1.94(1H,m),
2.57-2.79(1H,m), 3.00-3.95(11H,m), 4.39-4.75(3H,m), 7.55(4H,d,J=8.1
Hz), 7.79(4H,d,J=8.1 Hz), 8.78(1H,brs), 10.19(1H,brs).
Example 81
Synthesis of
3-[(2S,4S)-4-(4-imidazolylmethyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazo-
lidine trihydrochloride
[0411] (1) Using the title compound (904 mg) of Reference Example
10 and 4-imidazolecarboxyaldehyde (288 mg), and in the same manner
as in Example 63 (1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-imidazolylmethyl)amino-2-py-
rrolidinylcarbonyl]-1,3-thiazolidine (221 mg) was obtained.
[0412] (2) The above-mentioned compound (221 mg) was dissolved in
ethyl acetate (1.16 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(0.72 mL) was added thereto. The mixture was stirred at room
temperature for 18 hr. The precipitated solid was collected by
filtration, and washed with ethanol to give the title compound (7.7
mg) as a white powder.
[0413] .sup.1H-NMR(DMSO-d.sub.6).delta.2.04-2.26(1H,m),
2.88-4.10(8H,m), 4.25-4.80(5H,m), 7.82(1H,s), 9.07(1H,s).
Example 82
Synthesis of
3-{(2S,4S)-4-[N-benzyl-N-(5-cyano-2-pyridyl)amino]-2-pyrrolidinylcarbonyl-
}-1,3-thiazolidine hydrochloride
[0414] (1)
3-[(2S,4S)-1-tert-Butoxycarbonyl-4-(5-cyano-2-pyridyl)amino-2-pyrrolidiny-
lcarbonyl]-1,3-thiazolidine [product of Example 58 (1)] (305 mg)
was dissolved in DMF (10 mL), and potassium tert-butoxide (93 mg)
was added under ice cooling. After stirring the mixture for 10 min,
benzyl bromide (94 .mu.l) was added, and the mixture was stirred at
room temperature for 3 days. 10% citric acid solution was added to
the reaction mixture, and the mixture was extracted with ethyl
acetate. The extract was washed successively with saturated aqueous
sodium hydrogencarbonate solution and brine, and dried. The solvent
was evaporated under reduced pressure and the residue was purified
by silica gel chromatography to give
3-{(2S,4S)-4-[N-benzyl-N-(5-cyano-2-pyridyl)amino]-1-tert-butoxycarbonyl--
2-pyrrolidinylcarbonyl}-1,3-thiazolidine (202 mg) as a pale-yellow
solid.
[0415] (2) The above-mentioned compound (196 mg) was dissolved in
ethyl acetate (2 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(0.5 mL) was added thereto. The mixture was stirred at room
temperature for 17 hr. The precipitated solid was collected by
filtration to give the title compound (112 mg) as a pale-yellow
powder.
[0416] .sup.1H-NMR(DMSO-d.sub.6).delta.1.91-1.99(1H,m),
2.69-2.76(1H,m), 3.00-3.11(2H,m), 3.28-3.34(1H,m), 3.41-3.48(1H,m),
3.58-3.90(2H,m), 4.41-4.47(1H,m), 4.58-4.81(4H,m), 5.43-5.48(1H,m),
6.65(1H,d,J=9.0 Hz), 7.17-7.38(5H,m), 7.88(1H,dd,J=9.0, 2.1 Hz),
8.54(1H,d,J=2.1 Hz), 8.84(1H,brs), 10.21(1H,brs).
Example 83
Synthesis of
3-[(2S,4S)-4-(1-indolyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine
hydrochloride
[0417] (1) The title compound (950 mg) of Reference Example 13 and
thiazolidine (0.27 mL) were dissolved in DMF (20 mL), and HOBT (666
mg) and EDC hydrochloride (666 mg) were added successively. The
mixture was stirred at room temperature for 4 hr. The reaction
mixture was added to saturated aqueous sodium hydrogencarbonate
solution, and extracted with ethyl acetate. The extract was washed
with brine and dried. The solvent was evaporated under reduced
pressure and the residue was purified by silica gel chromatography
to give
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(1'-indolyl)-2-pyrrolidinylcarbonyl]-1-
,3-thiazolidine (978 mg) as a white solid.
[0418] (2) using the above-mentioned compound (665 mg), and in the
same manner as in Example 68 (2), the title compound (486 mg) was
obtained as a red powder.
[0419] .sup.1H-NMR(DMSO-d.sub.6).delta.2.14-2.28(1H,m),
2.98-3.18(4H,m), 3.4-3.97(3H,m), 4.43-4.87(3H,m), 5.38-5.55(1H,m),
6.55(1H,d,J=3.3 Hz), 7.07(1H,t,J=7.1 Hz), 7.20(1H,d,J=7.1 Hz),
7.48-7.63(3H,m), 9.25(1H,brs), 10.45(1H,brs).
Example 84
Synthesis of 3-[((2S,4S)-4-(1-indolinyl)-2-102'
pyrrolidinylcarbonyl]-1,3-thiazolidine dihydrochloride
[0420] (1) Using the title compound (601 mg) of Reference Example
12 and indoline (0.27 mL), and in the same manner as in Example 70
(1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(1-indolinyl)-2-pyrrolidinylcarbonyl]--
1,3-thiazolidine (460 mg) was obtained as a white solid.
[0421] (2) Using the above-mentioned compound (436 mg), and in the
same manner as in Example 70 (2), the title compound (373 mg) was
obtained as a white powder.
[0422] .sup.1H-NMR(DMSO-d.sub.6).delta.1.83-1.97(1H,m),
2.62-2.77(1H,m), 2.88(2H,t,J=8.2 Hz), 3.04(1H,t,J=7.0 Hz),
3.12(1H,t,J=6.2 Hz), 3.20-3.95(6H,m), 4.40-4.78(4H,m),
6.55-6.68(2H,m), 6.98-7.09(2H,m), 8.84(1H,brs), 10.31(1H,brs).
Example 85
Synthesis of
1-[(2S,4S)-4-(1-indolinyl)-2-pyrrolidinylcarbonyl]pyrrolidine
dihydrochloride
[0423] (1) Using the title compound (565 mg) of Reference Example
14 and indoline (0.27 mL), and in the same manner as in Example 70
(1),
1-[(2S,4S)-1-tert-butoxycarbonyl-4-(1-indolinyl)-2-pyrrolidinylcarbonyl]p-
yrrolidine (653 mg) was obtained as a white solid.
[0424] (2) Using the above-mentioned compound (648 mg), and in the
same manner as in Example 70 (2), the title compound (491 mg) was
obtained as a white powder.
[0425] .sup.1H-NMR(DMSO-d.sub.6).delta.1.75-1.97(5H,m),
2.60-2.72(1H,m), 2.88(2H,t,J=8.2 Hz), 3.218-3.60(8H,m),
4.40-4.55(2H,m), 6.56-6.67(2H,m), 6.98-7.09(2H,m), 8.75(1H,brs),
10.41(1H,brs).
Example 86
Synthesis of
3-[(2S,4S)-4-(5-nitro-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidi-
ne hydrochloride
[0426] (1) Using the title compound (450 mg) of Reference Example
12 and 5-nitroindoline (295 mg), and in the same manner as in
Example 70 (1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-nitro-1-indolinyl)-2-pyrrolidinylca-
rbonyl]-1,3-thiazolidine (153 mg) was obtained as an oil.
[0427] (2) Using the above-mentioned compound (153 mg), and in the
same manner as in Example 70 (2), the title compound (116 mg) was
obtained as a yellow powder.
[0428] .sup.1H-NMR(DMSO-d.sub.6).delta.1.92-2.06(1H,m),
2.67-2.80(1H,m), 3.00-3.17(4H,m), 3.27-3.94(6H,m), 4.42-4.78(4H,m),
6.62(1H,d,J=8.9 Hz), 7.87(1H,d,J=2.3 Hz), 8.04(1H,dd,J=8.9, 2.3
Hz), 9.1(1H,brs), 10.2(1H,brs).
Example 87
Synthesis of
3-[(2S,4S)-4-(6-nitro-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidi-
ne dihydrochloride
[0429] (1) Using the title compound (450 mg) of Reference Example
12 and 6-nitroindoline (296 mg), and in the same manner as in
Example 70 (1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(6-nitro-1-indolinyl)-2-pyrrolidinylca-
rbonyl]-1,3-thiazolidine (188 mg) was obtained as an oil.
[0430] (2) Using the above-mentioned compound (188 mg), and in the
same manner as in Example 70 (2), the title compound (80 mg) was
obtained as a brown-reddish powder.
[0431] .sup.1H-NMR(DMSO-d.sub.6).delta.1.84-2.00(1H,m),
2.64-2.77(1H,m), 3.00-3.17(4H,m), 3.22-3.92(6H,m), 4.41-4.77(4H,m),
7.22-7.32(2H,m), 7.51(1H,dd,J=7.9, 1.9 Hz), 8.94(1H,brs),
10.12(1H,brs).
Example 88
Synthesis of
3-[(2S,4S)-4-(5-methoxy-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazoli-
dine dihydrochloride
[0432] (1) Using the title compound (751 mg) of Reference Example
12 and 5-methoxyindoline (410 mg), and in the same manner as in
Example 70 (1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-methoxy-1-indolinyl)-2-pyrrolidinyl-
carbonyl]-1,3-thiazolidine (1010 mg) was obtained as a white
solid.
[0433] (2) Using the above-mentioned compound (326 mg), and in the
same manner as in Example 70 (2), the title compound (262 mg) was
obtained as a white powder.
[0434] .sup.1H-NMR(DMSO-d.sub.6).delta.1.80-1.95(1H,m),
2.62-2.75(1H,m), 2.86(2H,t,J=7.9 Hz), 3.04(1H,t,J=7.0 Hz),
3.12(1H,t,J=6.2 Hz), 3.17-3.52(4H,m), 3.65(3H,s), 3.66-4.08(6H,m),
4.28-4.77(4H,m), 6.54(1H,d,J=8.5 Hz), 6.63(1H,dd,J=8.5, 2.4 Hz),
6.75(1H,d,J=2.4 Hz), 8.83(1H,brs), 10.40(1H,brs).
Example 89
Synthesis of
3-[(2S,4S)-4-(5-hydroxy-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazoli-
dine dihydrochloride
[0435] (1) Using the title compound (872 mg) of Reference Example
12 and 5-hydroxyindoline (390 mg), and in the same manner as in
Example 70 (1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-hydroxy-1-indolinyl)-2-pyrrolidinyl-
carbonyl]-1,3-thiazolidine (538 mg) was obtained as a pale-brown
solid
[0436] (2) Using the above-mentioned compound (163 mg), and in the
same manner as in Example 70 (2), the title compound (101 mg) was
obtained as a white powder.
[0437] .sup.1H-NMR(DMSO-d.sub.6).delta.1.85-2.00(1H,m),
2.63-2.78(1H,m), 2.88(2H,t,J=7.7 Hz), 3.04(1H,t,J=6.6 Hz),
3.12(1H,t,J=6.2 Hz), 3.24-3.95(6H,m), 4.27-4.76(4H,m),
6.51-6.68(3H,m), 8.96(1H,brs), 10.43(1H,brs).
Example 90
Synthesis of
3-[(2S,4S)-4-(5-acetoxy-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazoli-
dine dihydrochloride
[0438] (1) Using
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-hydroxy-1-indolinyl)-2-pyrrolidinyl-
carbonyl]-1,3-thiazolidine [product of Example 89 (1), 174 mg] and
acetyl chloride (50 .mu.L), and in the same manner as in Example 50
(1),
3-[(2S,4S)-4-(5-acetoxy-1-indolinyl)-1-tert-butoxycarbonyl-2-pyrrolidinyl-
carbonyl]-1,3-thiazolidine (136 mg) was obtained as an oil.
[0439] (2) Using the above-mentioned compound (136 mg), and in the
same manner as in Example 70 (2), the title compound (77 mg) was
obtained as a pale-brown powder.
[0440] .sup.1H-NMR(DMSO-d.sub.6).delta.1.83-1.96(1H,m), 2.20(3H,s),
2.63-2.77(1H,m), 2.89(2H,t,J=8.1 Hz), 3.05(1H,t,J=6.8 Hz),
3.12(1H,t,J=6.2 Hz), 3.18-3.53(4H,m), 3.61-3.93(2H,m),
4.36-4.77(4H,m), 6.56(1H,d,J=8.4 Hz), 6.76(1H,dd,J=8.4, 2.3 Hz),
6.83(1H,d,J=2.3 Hz), 8.91(1H,brs), 10.19(1H,brs).
Example 91
Synthesis of
3-[(2S,4S)-4-(5-benzoyloxy-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiaz-
olidine dihydrochloride
[0441] (1) Using the product (199 mg) of Example 89 (1) and benzoyl
chloride (83 .mu.L), and in the same manner as in Example 50 (1),
3-[(2S,4S)-4-(5-benzoyloxy-1-indolinyl)-1-tert-butoxycarbonyl-2-pyrrolidi-
nylcarbonyl]-1,3-thiazolidine (173 mg) was obtained as a pale-brown
solid.
[0442] (2) Using the above-mentioned compound (173 mg), and in the
same manner as in Example 70 (2), the title compound (116 mg) was
obtained as a pale-brown-powder.
[0443] .sup.1H-NMR(DMSO-d.sub.6).delta.1.84-1.98(1H,m),
2.66-2.78(1H,m), 2.93(2H,t,J=8.3 Hz), 3.05(1H,t,J=6.7 Hz),
3.13(1H,t,J=6.2 Hz), 3.23-3.56(4H,m), 3.6-3.95(2H,m),
4.42-4.78(4H,m), 6.62(1H,d,J=8.4 Hz), 6.93(1H,dd,J=8.4, 2.2 Hz),
6.99(1H,d,J=2.2 Hz), 7.60(2H,t,J=7.5 Hz), 7.74(1H,t,J=7.5 Hz),
8.10(2H,d,J=7.5 Hz), 8.93(1H,brs), 10.37(1H,brs).
Example 92
Synthesis of
3-[(2S,4S)-4-(5-fluoro-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolid-
ine dihydrochloride
[0444] (1) Using the title compound (496 mg) of Reference Example
12 and 5-fluoroindoline (200 mg), and in the same manner as in
Example 70 (1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-fluoro-1-indolinyl)-2-pyrrolidinylc-
arbonyl]-1,3-thiazolidine (492 mg) was obtained as a pale-brown
solid (2) Using the above-mentioned compound (487 mg), and in the
same manner as in Example 70 (2), the title compound (357 mg) was
obtained as a white powder.
[0445] .sup.1H-NMR(DMSO-d.sub.6).delta.1.80-1.95(1H,m),
2.62-2.75(1H,m), 2.88(2H,t,J=8.2 Hz), 3.04(1H,t,J=7.0 Hz),
3.11(1H,t,J=6.2 Hz), 3.18-3.52(4H,m), 3.60-3.94(2H,m),
4.35-4.78(4H,m), 6.55(1H,dd,J=8.8, 4.3 Hz), 6.85(1H,td,J=8.8, 2.6
Hz), 6.94(1H,dd,J=8.5, 2.6 Hz), 8.90(1H,brs), 10.44(1H,brs).
Example 93
Synthesis of
3-[(2S,4S)-4-(5-chloro-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolid-
ine hydrochloride
[0446] (1) Using the title compound (665 mg) of Reference Example
12 and 5-chloroindoline (340 mg), and in the same manner as in
Example 70 (1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-chloro-1-indolinyl)-2-pyrrolidinylc-
arbonyl]-1,3-thiazolidine (393 mg) was obtained as a white
solid.
[0447] (2) Using the above-mentioned compound (389 mg), and in the
same manner as in Example 70 (2), the title compound (242 mg) was
obtained as a white powder.
[0448] .sup.1H-NMR(DMSO-d.sub.6).delta.1.81-1.95(1H,m),
2.62-2.74(1H,m), 2.90(2H,t,J=8.3 Hz), 3.04(1H,t,J=7.1 Hz),
3.12(1H,t,J=6.2 Hz), 3.18-3.52(4H,m), 3.60-3.94(2H,m),
4.38-4.77(4H,m), 6.57(1H,d,J=8.3 Hz), 7.03-7.11(2H,m),
8.86(1H,brs), 10.38(1H,brs).
Example 94
Synthesis of
3-[(2S,4S)-4-(5-bromo-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidi-
ne hydrochloride
[0449] (1) Using the title compound (0.901 g) of Reference Example
12 and 5-bromoindoline (0.713 g), and in the same manner as in
Example 70 (1),
3-[(2S,4S)-4-(5-bromo-1-indolinyl)-1-tert-butoxycarbonyl-2-pyrrolidinylca-
rbonyl]-1,3-thiazolidine (1.31 g) was obtained as a white
solid.
[0450] (2) Using the above-mentioned compound (340 mg), and in the
same manner as in Example 70 (2), the title compound (251 mg) was
obtained as a pale-red powder.
[0451] H-NMR(DMSO-d.sub.6).delta.1.82-1.96(1H,m), 2.62-2.74(1H,m),
2.91(2H,t,J=8.3 Hz), 3.04(1H,t,J=7.0 Hz), 3.12(1H,t,J=6.2 Hz),
3.18-3.54(4H,m), 3.62-3.93(2H,m), 4.37-4.77(4H,m), 6.53(1H,d,J=8.1
Hz), 7.15-7.24(2H,m), 8.91(1H,brs), 10.27(1H,brs).
Example 95
Synthesis of
3-[(2S,4S)-4-(1,2,3,4-tetrahydro-1-quinolyl)-2-pyrrolidinylcarbonyl]-1,3--
thiazolidine hydrochloride
[0452] (1) Using the title compound (450 mg) of Reference Example
12 and 1,2,3,4-tetrahydroquinoline (0.23 mL), and in the same
manner as in Example 70 (1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(1,2,3,4-tetrahydro-1-quinolyl)-2-pyrr-
olidinylcarbonyl]-1,3-thiazolidine (-100 mg) was obtained as an
oil.
[0453] (2) Using the above-mentioned compound (100 mg), and in the
same manner as in Example 70 (2), the title compound (60 mg) was
obtained as a pale-brown-reddish powder.
[0454] .sup.1H-NMR(DMSO-d.sub.6).delta.1.76-1.97(3H,m),
2.59-2.73(3H,m), 3.02-3.5(6H,m), 3.62-3.94(2H,m), 4.42-4.86(4H,m),
6.57(1H,d,J=7.2 Hz), 6.80(1H,d,J=8.3 Hz), 6.92(1H,d,J=7.2 Hz),
6.97-7.07(1H,m), 8.84(1H,brs), 10.04(1H,brs).
Example 96
Synthesis of
3-[(2S,4S)-4-(2-isoindolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine
2 trifluoroacetate
[0455] (1) The title compound (1.49 g) of Reference Example 10 was
dissolved in DMF (50 mL), and potassium carbonate (2.04 g) and
.alpha.,.alpha.'-dibromo-o-xylene (1.37 g) were added thereto. The
mixture was stirred at room temperature for 18 hr. Water was added
to the reaction mixture and the mixture was extracted with
chloroform. The extract was washed with brine and dried. The
solvent was evaporated under reduced pressure. The residue was
purified by silica gel chromatography to give
3-[((2S,4S)-1-tert-butoxycarbonyl-4-(2-isoindolinyl)-2-pyrrolidin-
ylcarbonyl]-1,3-thiazolidine (1.26 g) as a pale-brown solid
[0456] (2) Using the above-mentioned compound (910 mg), and in the
same manner as in Example 1, the title compound (730 mg) was
obtained as a brown powder.
[0457] .sup.1H-NMR(DMSO-d.sub.6).delta.2.05-2.14(1H,m),
2.88-2.96(1H,m), 3.05-3.17(2H,m), 3.42-4.02(5H,m), 4.44-4.75(7H,m),
7.31-7.37(4H,m).
Example 97
Synthesis of
3-[(2S,4S)-4-(N-methylanilino)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine
dihydrochloride
[0458] (1) Using the title compound (450 mg) of Reference Example
12 and N-methylaniline (0.22 mL), and in the same manner as in
Example 70 (1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(N-methylanilino)-2-pyrrolidinylcarbon-
yl]-1,3-thiazolidine (274 mg) was obtained as a white solid.
[0459] (2) Using the above-mentioned compound (216 mg), and in the
same manner as in Example 70 (2), the title compound (149 mg) was
obtained as a white powder.
[0460] .sup.1H-NMR(DMSO-d.sub.6).delta.1.83-1.98(1H,m),
2.56-2.69(1H,m), 2.82(3H,s), 3.05(1H,t,J=6.9 Hz), 3.11(1H,t,J=6.2
Hz), 3.20-3.32(1H,m), 3.36-3.50(1,m), 3.62-4.0(4H,m),
4.43-4.82(4H,m), 6.85(1H,t,J=7.5 Hz), 7.02(1H,d,J=7.5 Hz),
7.27(1H,t,J=7.5 Hz), 8.89(1H,brs), 10.44(1H,brs).
Example 98
Synthesis of
3-{(2S,4S)-4-[N-(5-cyano-2-pyridyl)-N-methylamino]-2-pyrrolidinylcarbonyl-
}-1,3-thiazolidine hydrochloride
[0461] (1) Using the product (313 mg) of Example 58 (1) and methyl
iodide 53 .mu.L, and in the same manner as in Example 82 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(5-cyano-2-pyridyl)-N-methylamino]--
2-pyrrolidinylcarbonyl}-1,3-thiazolidine (200 mg) was obtained as a
white powder.
[0462] (2) Using the above-mentioned compound (198 mg), and in the
same manner as in Example 5 (2), the title compound (165 mg) was
obtained as a white powder.
[0463] .sup.1H-NMR(DMSO-d.sub.6).delta.1.91-1.99(1H,m),
2.62-2.70(1H,m), 2.98(3H,s), 3.00-3.13(2H,m), 3.30-3.34(2H,m),
3.65-3.93(2H,m), 4.45-4.77(3H,m), 5.51-5.57(1H,m), 6.84(1H,d,J=9.0
Hz), 7.94(1H,dd,J=9.0, 2.4 Hz), 8.52(1H,d,J=2.4 Hz), 8.93(1H,brs),
10.22(1H,brs).
Example 99
Synthesis of
3-{(2S,4S)-4-[N-(3-cyanophenylmethyl)-N-methylamino]-2-pyrrolidinylcarbon-
yl}-1,3-thiazolidine dihydrochloride
[0464] (1) Using
3-[((2S,4S)-1-tert-butoxycarbonyl-4-(3-cyanophenylmethyl)amino-2-pyrrolid-
inylcarbonyl]-1,3-thiazolidine [product of Example 78 (1), 313 mg],
and in the same manner as in Example 64 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(3-cyanophenylmethyl)-N-methylamino-
]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (598 mg) was obtained as
an oil.
[0465] (2) The above-mentioned compound (571 mg) was dissolved in
ethyl acetate (2.65 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(1.66 mL) was added thereto. The mixture was stirred at room
temperature for 18 hr. The precipitated solid was collected by
filtration to give the title compound (377 mg) as a white
powder.
[0466] .sup.1H-NMR(DMSO-d.sub.6).delta.2.20-2.42(1H,m),
2.57(3H,brs), 2.80-3.20(3H,m), 3.55-4.10(5H,m), 4.20-4.85(5H,m),
7.68(1H,t,J=7.8 Hz), 7.88-8.05(2H,m), 8.14(1H,brs), 9.12(1H,brs),
10:70(1H,brs).
Example 100
Synthesis of
3-{(2S,4S)-4-[N-(4-cyanophenylmethyl)-N-(2-propyl)amino]-2-pyrrolidinylca-
rbonyl}-1,3-thiazolidine dihydrochloride
[0467] (1) Using the product (833 mg) of Example 63 (1) and
acetone, and in the same manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(4-cyanophenylmethyl)-N-(2-propyl)a-
mino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (818 m) was
obtained.
[0468] (2) The above-mentioned compound (792 mg) was dissolved in
ethyl acetate (3.47 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(2.16 mL) was added thereto. The mixture was stirred at room
temperature for 18 hr and the precipitated solid was collected by
filtration to give the title compound (637 mg) as a white
powder.
[0469] .sup.1H-NMR(DMSO-d.sub.6).delta.0.90-1.60(6H,m),
1.95-2.45(1H,m), 2.65-3.20(3H,m), 3.40-4.90(11H,m),
7.50-8.30(4H,m).
Example 101
Synthesis of
3-{(2S,4S)-4-[N-butyl-N-(4-cyanophenylmethyl)amino]-2-pyrrolidinylcarbony-
l}-1,3-thiazolidine dihydrochloride
[0470] (1) Using the product (833 mg) of Example 63 (1) and
n-butyraldehyde (216 mg), and in the same manner as in Example 70
(1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-butyl-N-(4-cyanophenylmethyl)amino]-
-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (837 mg) was
obtained.
[0471] (2) The above-mentioned compound-(830 mg) was dissolved in
ethyl acetate (3.51 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(2.20 mL) was added thereto. The mixture was stirred at room
temperature for 18 hr and the precipitated solid was collected by
filtration to give the title compound (607 mg) as a pale-yellow
powder.
[0472] .sup.1H-NMR(DMSO-d.sub.6).delta.0.80(3H,t,J=7.2 Hz),
1.18(2H,quint,J=6.9 Hz), 1.30-1.90(2H,m), 2.10-2.50(1H,m),
2.60-3.24(5H,m), 3.54-4.87(9H,m), 7.60-8.20(4H,m).
Example 102
Synthesis of
3-{(2S,4S)-4-[N-(4-cyanophenylmethyl)-N-(2-hydroxyethyl)amino]-2-pyrrolid-
inylcarbonyl}-1,3-thiazolidine dihydrochloride
[0473] (1) The product (1.67 g) of Example 63 (1) was dissolved in
N-methyl-2-pyrrolidone (12 mL), and 2-bromoethanol (1.42 mL) and
diisopropylethylamine (2.09 mL) were added thereto. The mixture was
stirred at 80.degree. C. for 2 days. The reaction mixture was added
to saturated aqueous sodium hydrogencarbonate solution and the
mixture was extracted with ethyl acetate. The extract was dried and
the solvent was evaporated under reduced pressure. The residue was
purified by silica gel chromatography to give
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N
(4-cyanophenylmethyl)-N-(2-hydroxyethyl)amino]-2-pyrrolidinylcarbonyl}-1,-
3-thiazolidine (0.480 g).
[0474] (2) The above-mentioned compound (480 mg) was dissolved in
ethyl acetate (2.08 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(1.04 mL) was added thereto. The mixture was stirred at room
temperature for 18 hr and the precipitated solid was collected by
filtration to give the title compound (351 mg) as a brown
powder.
[0475] .sup.1H-NMR(DMSO-d.sub.6).delta.1.85-1.97(1H,m),
2.02-2.33(2H,m), 2.70-4.80(14H,m), 7.60-8.00(4H,m), 9.00(1H,brs),
10.50(1H,brs).
Example 103
Synthesis of
3-{(2S,4S)-4-[N-(carboxymethyl)-N-(5-cyano-2-pyridyl)amino]-2-pyrrolidiny-
lcarbonyl]-1,3-thiazolidine trifluoroacetate
[0476] (1) Using the product (461 mg) of Example 58 (1) and
tert-butyl bromoacetate (202 .mu.L), and in the same manner as in
Example 82 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(tert-butoxycarbonylmethyl)-N-(5-cy-
ano-2-pyridyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (344
mg) was obtained as a pale-yellow powder.
[0477] (2) Using the above-mentioned compound (340 mg), and by the
synthesis in the same manner as in Example 1 and purification by
HPLC, the title compound (118 mg) was obtained as a white
solid.
[0478] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.93-1.98(1H,m),
2.66-2.69(1H,m), 3.04-3.12(2H,m), 3.27-3.31(1H,m), 3.40-3.45(1H,m),
3.62-3.87(2H,m), 4.32(2H,s), 4.44-4.71(3H,m), 5.23(1H,m),
6.81(1H,d,J=7.3 Hz), 7.95(1H,dd,J=7.3, 2.3 Hz), 8.51(1H,d,J=2.3
Hz).
Example 104
Synthesis of
3-{(2S,4S)-4-[N-(4-cyanophenylmethyl)-N-(ethoxycarbonylmethyl)amino]-2-py-
rrolidinylcarbonyl}-1,3-thiazolidine dihydrochloride
[0479] (1) The product (0.833 g) of Example 63 (1) was dissolved in
N-methyl-2-pyrrolidone (6 mL), and ethyl bromoacetate (0.333 mL)
and diisopropylethylamine (1.05 mL) were added thereto. The mixture
was stirred at room temperature for 18 hr. The reaction mixture was
added to saturated aqueous sodium hydrogencarbonate solution, and
the mixture was extracted with ethyl acetate. The extract was
dried, and the solvent was evaporated under reduced pressure. The
residue was purified by silica gel chromatography to give
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(4-cyanophenylmethyl)-N-(ethoxycarb-
onylmethyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.01 g)
as an oil.
[0480] (2) The above-mentioned compound (976 mg) was dissolved in
ethyl acetate (3.88 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(2.43 mL) was added thereto. The mixture was stirred at room
temperature for 18 hr and the precipitated solid was collected by
filtration to give the title compound (630 mg) as a white
powder.
[0481] .sup.1H-NMR(DMSO-d.sub.6).delta.1.18-(3H,t,J=7.1 Hz),
1.67-1.90(1H,m), 2.56-2.75(1H,m), 2.94-3.22(3H,m), 3.25-4.00(8H,m),
4.07(2H,q,J=7.1 Hz), 4.34-4.78(3H,m), 7.54(2H,d,J=8.2 Hz),
7.81(2H,d,J=8.2 Hz), 8.80(1H,brs), 10.40(1H,brs).
Example 105
Synthesis of
3-{(2S,4S)-4-[N-(4-cyanophenylmethyl)-N-(isopropoxycarbonylmethyl)amino]--
2-pyrrolidinylcarbonyl}-1,3-thiazolidine dihydrochloride
[0482] (1) Using the product (0.833 g) of Example 63 (1) and
isopropyl bromoacetate (0.259 mL), and in the same manner as in
Example 104(1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(4-cyanophenylmethyl)-N-(isopropoxy-
carbonylmethyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine
(0.967 g) was obtained as an oil.
[0483] (2) The above-mentioned compound (966 mg) was dissolved in
ethyl acetate (3.74 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(1.87 mL) was added thereto. The mixture was stirred at room
temperature for 8 hr. The precipitated solid was collected by
filtration to give the title compound (641 mg) as a
white-powder.
[0484] .sup.1H-NMR(DMSO-d.sub.6).delta.1.18(6H,d,J=6.0 Hz),
1.65-1.84(1H,m), 2.55-2.74(1H,m), 2.95-3.16(3H,m), 3.22-3.47(3H,m),
3.50-3.98(5H,m), 4.39-4.80(3H,m), 4.91(1H,quint,J=6.3 Hz),
7.53(2H,d,J=8.1 Hz), 7.81(2H,d,J=8.4 Hz), 8.70(1H,brs),
10.25(1H,brs).
Example 106
Synthesis of
3-{(2S,4S)-4-[N-(benzyloxycarbonylmethyl)-N-(4-cyanophenylmethyl)amino}-2-
-pyrrolidinylcarbonyl]-1,3-thiazolidine dihydrochloride
[0485] (1) using the product (0.833 g) of Example 63 (1) and benzyl
bromoacetate (0.317 mL), and in the same manner as in Example
104(1),
3-{(2S,4S)-4-[N-(benzyloxycarbonylmethyl)-N-(4-cyanophenylmethyl)amino]-1-
-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl}-1,3-thiazolidine
(0.992 g) was obtained as an oil.
[0486] (2) The above-mentioned compound (992 mg) was dissolved in
ethyl acetate (3.51 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(1.76 mL) was added thereto. The mixture was stirred at room
temperature for 8 hr and the precipitated solid was collected by
filtration to give the title compound (680 mg) as a white
powder.
[0487] .sup.1H-NMR(DMSO-d.sub.6).delta.1.67-1.85(1H,m),
2.53-2.71(1H,m), 2.94-3.20(3H,m), 3.20-4.00(8H,m), 4.37-4.80(3H,m),
5.11(2H,s), 7.29-7.45(5H,m), 7.50(2H,d,J=8.1 Hz), 7.78(2H,d,J=8.4
Hz), 8.75(1H,brs), 10.15(1H,brs).
Example 107
Synthesis of
3-{(2S,4S)-4-[N-(carboxymethyl)-N-(4-cyanophenylmethyl)amino]-2-pyrrolidi-
nylcarbonyl}-1,3-thiazolidine 2 trifluoroacetate
[0488] (1) Using the product (0.833 g) of Example 63 (1) and
tert-butyl bromoacetate (0.443 mL), and in the same manner as in
Example 104 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(tert-butoxycarbonylmethyl)-N-(4-cy-
anophenylmethyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine
(0.990 g) was obtained.
[0489] (2) The above-mentioned compound (881 mg) was dissolved in
ethyl acetate (3.06 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(6.91 mL) was added thereto. The mixture was stirred at room
temperature for 3 days. The precipitated solid was purified by HPLC
to give the title compound (141 mg) as a white powder.
[0490] .sup.1H-NMR(DMSO-d.sub.6).delta.1.65-1.84(1H,m),
2.57-2.74(1H,m), 2.96-3.19(3H,m), 3.22-4.00(8H,m), 4.37-4.72(3H,m),
7.53(2H,d,J=8.4 Hz), 7.81(2H,d,J=8.1 Hz), 8.77(1H,brs),
9.63(1H,brs).
Example 108
Synthesis of
3-{(2S,4S)-4-[N-(4-carbamoylphenylmethyl)-N-(carboxymethyl)amino]-2-pyrro-
lidinylcarbonyl}-1,3-thiazolidine 2 trifluoroacetate
[0491] The title compound (41 mg) was obtained as a pale-yellow
powder by purification of Example 107 (2) by HPLC.
[0492] .sup.1H-NMR(DMSO-d.sub.6).delta.1.67-1.90(1H,m),
2.56-2.79(1H,m), 2.90-4.20(11H,m), 4.36-4.74(3H,m), 7.34(1H,brs),
7.56(2H,d,J=8.1 Hz), 7.84(2H,d,J=8.4 Hz), 7.96(1H,brs),
8.80(1H,brs), 9.60(1H,brs).
Example 109
Synthesis of
3-{(2S,4S)-4-[N-(carbamoylmethyl)-N-(4-cyanophenylmethyl)amino]-2-pyrroli-
dinylcarbonyl}-1,3-thiazolidine dihydrochloride
[0493] (1) Using the product (0.833 g) of Example 63 (1) and
2-bromoacetamide (0.276 mL), and in the same manner as in Example
104(1),
3-[((2S,4S)-1-tert-butoxycarbonyl-4-[N-(carbamoylmethyl)-N-(4-cyanophenyl-
methyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (0.599 g)
was obtained.
[0494] (2) The above-mentioned compound (599 mg) was dissolved in
ethyl acetate (2.53 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(1.27 mL) was added thereto. The mixture was stirred at room
temperature for 6 hr and the precipitated solid was collected by
filtration to give the title compound (416 mg) as a white
powder.
[0495] .sup.1H-NMR(DMSO-d.sub.6).delta.1.76-1.99(1H,m),
2.62-2.83(1H,m), 2.90-4.10(11H,m), 4.25-4.80(3H,m), 7.22(1H,brs),
7.44(1H,brs), 7.64(2H,d,J=8.1 Hz), 7.84(2H,d,J=8.4 Hz),
8.82(1H,brs), 10.35(1H,brs).
Example 110
Synthesis of
3-((2S,4S)-4-benzoylamino-2-pyrrolidinylcarbonyl)-1,3-thiazolidine
[0496] (1) Using the title compound (499 mg) of Reference Example
10 and benzoyl chloride (202 .mu.L), and in the same manner as in
Reference Example
7,3-((2S,4S)-4-benzoylamino-1-tert-butoxycarbonyl-2-pyrrolidinylc-
arbonyl)-1,3-thiazolidine (652 mg) was obtained as a white
powder.
[0497] (2) Using the above-mentioned compound (648 mg), and in the
same manner as in Example 5 (2), the title compound (250 mg) was
obtained as a white powder.
[0498] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.76-1.81(1H,m),
2.33-2.39(1H,m), 2.91-3.09(5H,m), 3.63-3.95(3H,m), 4.34-4.70(3H,m),
7.44-7.53(3H,m), 7.80-7.82(2H,m), 8.38(1H,brs).
Example 111
Synthesis of
3-[((2S,4S)-4-(4-cyanobenzoyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolid-
ine hydrochloride
[0499] (1) Using the title compound (543 mg) of Reference Example
10 and 4-cyanobenzoyl chloride (313 mg), and in the same manner as
in Reference Example 7,
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-cyanobenzoyl)amino-2-pyrrolidinylca-
rbonyl]-1,3-thiazolidine (804 mg) was obtained as a white
powder.
[0500] (2) Using the above-mentioned compound (798 mg), and in the
same manner as in Example 5 (2), the title compound (513 mg) was
obtained as a white powder.
[0501] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.01-2.06(1H,m),
2.81-2.86(1H,m), 3.03-3.14(2H,m), 3.36-3.50(2H,m), 3.65-3.94(2H,m),
4.45-4.75(4H,m), 7.98-8.06(4H,m), 8.86(1H,brs), 9.07-9.12(1H,m),
10.49(1H,brs).
Example 112
Synthesis of
3-[(2S,4S)-4-(5-chloro-2-nitrobenzoyl)amino-2-pyrrolidinylcarbonyl]-1,3-t-
hiazolidine hydrochloride
[0502] (1) Using the title compound (495 mg) of Reference Example
10 and 5-chloro-2-nitrobenzoic acid (300 mg), and in the same
manner as in Reference Example 9,
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-chloro-2-nitrobenzoyl)amino-2-pyrro-
lidinylcarbonyl]-1,3-thiazolidine (340 mg) was obtained as a white
powder.
[0503] (2) Using the above-mentioned compound (338 mg), and in the
same manner as in Example 5 (2), the title compound (272 mg) was
obtained as a white powder.
[0504] .sup.1H-NMR(DMSO-d.sub.6).delta.1.88-1.99(1H,m),
2.79-2.88(1H,m), 3.04-3.15(2H,m), 3.26-3.36(1H,m), 3.47-3.94(3H,m),
4.44-4.75(4H,m), 7.80-7.84(2H,m), 8.11-8.14(1H,m), 9.09-9.12(1H,m),
9.50(2H,brs).
Example 113
Synthesis of
3-[(2S,4S)-4-(2,4-dichlorobenzoyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiaz-
olidine hydrochloride
[0505] (1) using the title compound (440 mg) of Reference Example
10 and 2,4-dichlorobenzoic acid (254 mg), and in the same manner as
in Reference Example 9,
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(2,4-dichlorobenzoyl)amino-2-pyrrolidi-
nylcarbonyl]-1,3-thiazolidine (356 mg) was obtained as a white
powder.
[0506] (2) Using the above-mentioned compound (356 mg), and in the
same manner as in Example 5 (2), the title compound (211 mg) was
obtained as a white powder.
[0507] .sup.1H-NMR(DMSO-d.sub.6).delta.1.86-1.99(1H,m),
2.79-2.88(1H,m), 3.04-3.14(2H,m), 3.26-3.31(1H,m), 3.47-3.95(3H,m),
4.43-4.75(4H,m), 7.50-7.56(2H,m), 7.71(1H,s), 8.84-8.88(1H,m),
9.70(2H,brs).
Example 114
Synthesis of
3-{(2S,4S)-4-[(3-nitrophenyl)acetyl]amino-2-pyrrolidinylcarbonyl}-1,3-thi-
azolidine hydrochloride
[0508] (1) Using the title compound (370 mg) of Reference Example
10 and 3-nitrophenylacetic acid (201 mg), and in the same manner as
in Reference Example 9,
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[(3-nitrophenyl)acetyl]amino-2-pyrroli-
dinylcarbonyl}-1,3-thiazolidine (516 mg) was obtained as a white
powder.
[0509] (2) Using the above-mentioned compound (515 mg), and in the
same manner as in Example 5 (2), the title compound (427 mg) was
obtained as a white powder.
[0510] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.86-1.93(1H,m),
2.74-2.78(1H,m), 3.04-3.14(3H,m), 3.40-3.44(1H,m), 3.63(2H,s),
3.63-3.89(2H,m), 4.36-4.70(4H,m), 7.60-7.63(1H,m), 7.72(1H,d,J=7.7
Hz), 8.12(1H,d,J=8.2 Hz), 8.15(1H,s), 8.65-8.68(1H,m).
Example 115
Synthesis of
3-[((2S,4S)-4-(trans-3-trifluoromethylcinnamoyl)amino-2-pyrrolidinylcarbo-
nyl]-1,3-thiazolidine hydrochloride
[0511] (1) Using the compound (338 mg) of Reference Example 10 and
3-trifluoromethylcinnamoyl chloride (201 .mu.L), and in the same
manner as in Reference Example 7,
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(trans-3-trifluoromethylcinnamoyl)amin-
o-2-pyrrolidinylcarbonyl]-1,3-thiazolidine (274 mg) was obtained as
a white powder.
[0512] (2) Using the above-mentioned compound (270 mg), and in the
same manner as in Example 5 (2), the title compound (230 mg) was
obtained as a white powder.
[0513] .sup.1H-NMR(DMSO-d.sub.6).delta.1.78-1.88(1H,m),
2.79-2.87(1H,m), 3.04-3.22(3H,m), 3.46-3.52(1H,m), 3.64-3.94(2H,m),
4.46-4.75(4H,m), 6.76(1H,d,J=15.9 Hz), 7.57(1H,d,J=15.9 Hz),
7.64-7.76(2H,m), 7.89-8.03(2H,m), 8.70-8.75(1H,m),
9.60(2H,brs).
Example 116
Synthesis of
3-{(2S,4S)-4-[N-(4-cyanobenzoyl)-N-(4-cyanophenylmethyl)amino]-2-pyrrolid-
inylcarbonyl}-1,3-thiazolidine hydrochloride
[0514] (1) The product (0.833 g) of Example 63 (1) was dissolved in
dichloromethane (10 mL), and triethylamine (0.418 mL) and
4-cyanobenzoyl chloride (0.331 g) were added thereto. The mixture
was stirred at room temperature for 18 hr. The reaction mixture was
added to saturated aqueous sodium hydrogencarbonate solution, and
the mixture was extracted with ethyl acetate. The extract was dried
and the solvent was evaporated under reduced pressure. The residue
was purified by silica gel chromatography to give
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(4-cyanobenzoyl)-N-(4-cyanophenylme-
thyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (0.956 g).
[0515] (2) The above-mentioned compound (514 mg) was dissolved in
ethyl acetate (1.88 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(1.18 mL) was added thereto. The mixture was stirred at room
temperature for 18 hr and the precipitated solid was collected by
filtration to give the title compound (320 g) as a white
powder.
[0516] .sup.1H-NMR(DMSO-d.sub.6).delta.1.62-2.39(1H,m),
2.45-2.82(1H,m), 2.90-3.25(2H,m), 3.30-3.95(4H,m), 4.25-5.00(6H,m),
7.30-8.20(8H,m).
Example 117
Synthesis of
3-{(2S,4S)-4-[N-acetyl-N-(5-cyano-2-pyridyl)amino]-2-pyrrolidinylcarbonyl-
}-1,3-thiazolidine hydrochloride
[0517] (1) Using the product (340 mg) of Example 58 (1) and acetyl
chloride (72 .mu.L), and in the same manner as in Example 82 (1),
3-{(2S,4S)-4-[N-acetyl-N-(5-cyano-2-pyridyl)amino]-1-tert-butoxycarbonyl--
2-pyrrolidinylcarbonyl}-1,3-thiazolidine (188 mg) was obtained.
[0518] (2) Using the above-mentioned compound (186 mg), and in the
same manner as in Example 82 (2), the title compound (121 mg) was
obtained as a white powder.
[0519] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.90-1.95(1H,m),
1.91(3H,s), 2.75-2.80(1H,m), 3.03-3.11(2H,m), 3.40-3.44(1H,m),
3.50-3.54(1H,m), 3.59-3.63(1H,m), 3.71-3.85(1H,m), 4.39-4.44(1H,m),
4.56-4.69(2H,m), 5.04-5.08(1H,m), 7.75(1H,d,J=8.3 Hz),
8.50(1H,dd,J=8.3, 2.1 Hz), 9.01(1H,d,J=2.1 Hz).
Example 118
Synthesis of
3-((2S,4S)-4-phthalimido-2-pyrrolidinylcarbonyl)-1,3-thiazolidine
trifluoroacetate
[0520] (1) The title compound (1.23 g) of Reference Example 10 was
suspended in toluene (20 mL), and phthalic anhydride (632 mg) and
triethylamine (60 .mu.L) were added thereto. The mixture was
refluxed for 5 hr. To the reaction mixture was added 10% citric
acid solution and the mixture was extracted with ethyl acetate. The
extract was washed successively with saturated aqueous sodium
hydrogencarbonate solution and brine, and dried. The solvent was
evaporated under reduced pressure. The residue was purified by
silica gel chromatography to give
3-((2S,4S)-1-tert-butoxycarbonyl-4-phthalimido-2-pyrrolidinylcarbonyl)-1,-
3-thiazolidine (1.21 g) as a white solid.
[0521] (2) The above-mentioned compound (362 mg) was dissolved in
dichloromethane (4 mL) and trifluoroacetic acid (2 mL) was added
thereto. The mixture was stirred at room temperature for 20 hr. The
solvent was evaporated under reduced pressure to give the title
compound (374 mg) as a pale-yellow solid.
[0522] H-NMR(500 MHz,DMSO-d.sub.6).delta.2.38-2.44(1H,m),
2.80-2.84(1H,m), 3.07-3.13(2H,m), 3.50-3.54(1H,m), 3.60-3.89(3H,m),
4.46-4.50(1H,m), 4.62-4.78(2H,m), 4.97-5.00(1H,m), 7.86-7.90(4H,m),
8.74(1H,brs), 9.90(1H,brs).
Example 119
Synthesis of
3-[((2S,4S)-4-(4-nitrophthalimido)-2-pyrrolidinylcarbonyl]-1,3-thiazolidi-
ne trifluoroacetate
[0523] (1) Using the title compound (2.31 g) of Reference Example
10 and 4-nitrophthalic anhydride (1.16 g), and in the same manner
as in Example 118 (1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-nitrophthalimido)-2-pyrrol-
idinylcarbonyl]-1,3-thiazolidine (1.42 g) was obtained as a white
solid.
[0524] (2) Using the above-mentioned compound (355 mg), and in the
same manner as in Example 118 (2), the title compound (298 mg) was
obtained as a white powder.
[0525] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.40-2.45(1H,m),
2.82-2.88(1H,m), 3.06-3.14(2H,m), 3.52-3.56(1H,m), 3.62-3.89(3H,m),
4.47-4.50(1H,m), 4.62-4.78(2H,m), 5.01-5.07(1H,m), 8.15(1H,d,J=8.2
Hz), 8.51(1H,d,J=1.9 Hz), 8.65(1H,dd,J=8.2, 1.9 Hz),
9.24(2H,brs).
Example 120
Synthesis of
3-[(2S,4S)-4-(3-phenylureido)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine
trifluoroacetate
[0526] (1) The title compound (401 mg) of Reference Example 10 was
dissolved in tetrahydrofuran (10 mL), and phenyl isocyanate (167
mg) was added thereto at room temperature. The mixture was stirred
for 18 hr. To the reaction mixture was added 10% citric acid
solution and the mixture was extracted with ethyl acetate. The
extract was washed successively with saturated aqueous sodium
hydrogencarbonate solution and brine, and dried. The solvent was
evaporated under reduced pressure to give
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(3-phenylureido)-2-pyrrolidinylcarbony-
l]-1,3-thiazolidine (560 mg) as a white solid.
[0527] (2) The above-mentioned compound (532 mg) was dissolved in
trifluoroacetic acid (2 mL) and the mixture was stirred at room
temperature for 3 hr. The solvent was evaporated under reduced
pressure to give the title compound (363 mg) as a brown powder.
[0528] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.75-1.80(1H,m),
2.75-2.80(1H,m), 3.04-3.20(3H,m), 3.43-3.47(1H,m), 3.68-3.89(2H,m),
4.40-4.71(4H,m), 6.72-6.75(1H,m), 6.91(1H,t,J=7.4 Hz),
7.21-7.24(2H,m), 7.39(2H,d,J=7.8 Hz), 8.85(1H,brs),
8.89-8.90(1H,m), 9.60(1H,brs).
Example 121
Synthesis of
3-{(2S,4S)-4-[3-(4-cyanophenyl)ureido]-2-pyrrolidinylcarbonyl}-1,3-thiazo-
lidine
[0529] (1) Using the title compound (640 mg) of Reference Example
10 and 4-cyanophenyl isocyanate (321 mg), and in the same manner as
in Example 120 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[3-(4-cyanophenyl)ureido]-2-p-
yrrolidinylcarbonyl}-1,3-thiazolidine (992 mg) was obtained as a
white powder.
[0530] (2) The above-mentioned compound (978 mg) was dissolved in
chloroform (5 mL), and then dissolved in trifluoroacetic acid (3
mL), and the mixture was stirred at room temperature for 8 hr. The
solvent was evaporated under reduced pressure and saturated aqueous
sodium hydrogencarbonate solution was added to the residue. The
mixture was extracted with chloroform. The extract was concentrated
under reduced pressure to give the title compound (140 mg) as a
white powder.
[0531] .sup.1H-NMR(DMSO-d.sub.6).delta.1.60-1.68(1H,m),
2.22-2.32(1H,m), 2.67-2.72(1H,m), 2.91-3.11(4H,m), 3.65-3.93(3H,m),
4.13-4.16(1H,m), 4.43-4.72(2H,m), 6.47(1H,d,J=7.2 Hz),
7.56(2H,d,J=8.7 Hz), 7.65(2H,d,J=8.7 Hz), 9.11(1H,s).
Example 122
Synthesis of
3-((2S,4S)-4-phenylsulfonylamino-2-pyrrolidinylcarbonyl)-1,
3-thiazolidine hydrochloride
[0532] (1) The title compound (543 mg) of Reference Example 10 was
dissolved in dichloromethane (10 mL), and 4-methylmorpholine (240
.mu.L) and benzenesulfonyl chloride (240 .mu.L) were added thereto
at room temperature. The mixture was stirred for 17 hr.
[0533] To the reaction mixture was added 10% citric acid solution,
and the mixture was extracted with ethyl acetate. The extract was
washed successively with saturated aqueous sodium hydrogencarbonate
solution and brine, and dried. The solvent was evaporated under
reduced pressure to give
3-((2S,4S)-1-tert-butoxycarbonyl-4-phenylsulfonylamino-2-pyrrolidiny-
lcarbonyl)-1,3-thiazolidine (644 mg) as a white powder.
[0534] (2) The above-mentioned compound (634 mg) was dissolved in
ethyl acetate (4 mL) and 4 mol/L hydrochloric acid-ethyl acetate
(1.8 mL) was added thereto. The mixture was stirred at room
temperature for 67 hr. The precipitate was collected by filtration
to give the title compound (437 mg) as a pale-yellow powder.
[0535] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.68-1.74(1H,m),
2.50-2.58(1H,m), 3.00-3.08(3H,m), 3.17-3.20(1H,m), 3.53-3.87(3H,m),
4.38-4.63(3H,m), 7.62-7.71(3H,m), 7.84-7.85(2H,m), 8.24-8.27(1H,m),
9.50(2H,brs).
Example 123
Synthesis of
3-[((2S,4S)-4-(4-cyanophenylsulfonyl)amino-2-pyrrolidinylcarbonyl]-1,3-th-
iazolidine hydrochloride
[0536] (1) Using the title compound (1.09 g) of Reference Example
10 and 4-cyanobenzenesulfonyl chloride (0.780 g), and in the same
manner as in Example 122 (1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-cyanophenylsulfonyl)amino-2-pyrroli-
dinylcarbonyl]-1,3-thiazolidine (1.67 g) was obtained as a white
powder.
[0537] (2) Using the above-mentioned compound (798 mg), and in the
same manner as in Example 122 (2), the title compound (544 mg) was
obtained as a pale-yellow powder.
[0538] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.68-1.75(1H,m),
2.53-2.59(1H,m), 3.02-3.09(3H,m), 3.23-3.28(1H,m), 3.54-3.90(3H,m),
4.40-4.64(3H,m), 8.01(2H,d,J=8.4 Hz), 8.13(2H,d,J=8.4 Hz),
8.62-8.65(1H,m), 9.93(2H,brs).
Example 124
Synthesis of 3-{(2S,4S)-4-[N-(4-cyanophenylmethyl)-N-(4
cyanophenylsulfonyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine
hydrochloride
[0539] (1)
3-[(2S,4S)-1-tert-Butoxycarbonyl-4-(4-cyanophenylsulfonyl)amino-2-pyrroli-
dinylcarbonyl]-1,3-thiazolidine [product of Example 123 (1), 856
mg] was dissolved in DMF (20 mL), and potassium carbonate (380 mg)
and 4-cyanobenzyl bromide (400 mg) were added thereto at room
temperature. The mixture was stirred for 4 hr. To the reaction
mixture was added 10% citric acid solution, and the precipitate was
collected by filtration to give
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(4-cyanophenylmethyl)-N-(4-cya-
nophenylsulfonyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine
(900 mg) as a pale-yellow solid.
[0540] (2) Using the above-mentioned compound (900 mg), and in the
same manner as in Example 122 (2), the title compound (800 mg) was
obtained as a pale-yellow powder.
[0541] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.54-1.60(1H,m),
2.45-2.50(1H,m), 2.79(1H,dd,J=8.7, 1.6 Hz), 3.00-3.20(3H,m),
3.55-3.58(1H,m), 3.68-3.82(1H,m), 4.34-4.63(3H,m), 4.65(2H,s),
4.87-4.93(1H,m), 7.51(2H,d,J=8.2 Hz), 7.86(2H,d,J=8.2 Hz),
8.11(2H,d,J=8.4 Hz), 8.16(2H,d,J=8.4 Hz), 8.85(1H,brs),
9.91(1H,brs).
Example 125
Synthesis of
3-[(2S,4S)-4-(1-pyrrolidinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine
dihydrochloride
[0542] (1) Using the title compound (1.00 g) of Reference Example
12 and pyrrolidine (0.274 g), and in the same manner as in Example
70(1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(1-pyrrolidinyl)-2-pyrrolidinylcarbony-
l]-1,3-thiazolidine (0.793 g) was obtained as a white solid.
[0543] (2) Using the above-mentioned compound (791 mg), and in the
same manner as in Example 70 (2), the title-compound (626 mg) was
obtained as a white powder.
[0544] .sup.1H-NMR(DMSO-d.sub.6).delta.1.80-2.15(6H,m),
2.16-2.28(2H,m), 2.95-3.25(3H,m), 3.50-3.95(3H,m), 4.02-4.15(2H,m),
4.45-4.75(4H,m).
Example 126
Synthesis of
3-((2S,4S)-4-morpholino-2-pyrrolidinylcarbonyl)-1,3-thiazolidine
dihydrochloride
[0545] (1) Using the title compound (1.00 g) of Reference Example
12 and morpholine (0.319 g), and in the same manner as in Example
70(1),
3-((2S,4S)-1-tert-butoxycarbonyl-4-morpholino-2-pyrrolidinylcarbonyl)-1,3-
-thiazolidine (0.987 g) was obtained as a white solid.
[0546] (2) Using the above-mentioned compound (985 mg), and in the
same manner as in Example 70 (2), the title compound (746 mg) was
obtained as a white powder.
[0547] .sup.1H-NMR(DMSO-d.sub.6).delta.2.22-2.35(2H,m),
2.90-3.50(7H,m), 3.70-4.20(5H,m), 4.46-4.83(6H,m),
9.30(1H,brs).
Example 127
Synthesis of
3-((2S,4S)-4-piperidino-2-pyrrolidinylcarbonyl)-1,3-thiazolidine
dihydrochloride
[0548] (1) Using the title compound (1.00 g) of Reference Example
12 and piperidine (0.318 g), and in the same manner as in Example
70(1),
3-((2S,4S)-1-tert-butoxycarbonyl-4-piperidino-2-pyrrolidinylcarbonyl)-1,3-
-thiazolidine (0.908 g) was obtained as a white solid.
[0549] (2) Using the above-mentioned compound (906 mg), and in the
same manner as in Example 70 (2), the title compound (705 mg) was
obtained as a white powder.
[0550] .sup.1H-NMR(DMSO-d.sub.6).delta.1.65-1.90(6H,m),
2.18-2.34(2H,m), 2.85-3.20(4H,m), 3.30-3.50(2H,m), 3.55-4.05(2H,m),
4.50-4.82(6H,m).
Example 128
Synthesis of
3-[(2S,4S)-4-(4-hydroxypiperidino)-2-pyrrolidinylcarbonyl]-1,3-thiazolidi-
ne trihydrochloride
[0551] (1) Using the title compound (988 mg) of Reference Example
12 and 4-hydroxypiperidine (867 mg), and in the same manner as in
Example 70 (1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-hydroxypiperidino)-2-pyrrolidi-
nylcarbonyl]-1,3-thiazolidine (408 mg) was obtained as a white
solid.
[0552] (2) Using the above-mentioned compound (408 mg), and in the
same manner as in Example 70 (2), the title compound (250 mg) was
obtained as a white powder.
[0553] .sup.1H-NMR(DMSO-d.sub.6).delta.1.60-1.82(2H,m),
.delta.1.84-2.05(2H,m), 2.12-2.33(2H,m), 2.85-3.55(6H,m),
3.59-4.10(6H,m), 4.45-4.78(3H,m).
Example 129
Synthesis of
3-[(2S,4S)-4-(3-azaspiro[5.5]undec-3-yl)-2-pyrrolidinylcarbonyl]-1,3-thia-
zolidine 2 trifluoroacetate
[0554] (1) The title compound (340 mg) of Reference Example 12,
3-azaspiro[5.5]undecene (210 mg) and acetic acid (0.066 mL) were
dissolved in 1,2-dichloroethane (10 mL), and sodium
triacetoxyborohydride (485 mg) was added thereto. The mixture was
stirred at room temperature for 17 hr. The reaction mixture was
added to and the mixture was extracted with chloroform. The extract
was washed with brine and dried. The solvent was evaporated under
reduced pressure. Ethyl acetate was added to the residue, and the
precipitate was collected by filtration to give
3-[(2S,4S)-4-(3-azaspiro[5.5]undec-3-yl)-1-tert-butoxycarbonyl-2-pyr-
rolidinylcarbonyl]-1,3-thiazolidine (141 mg) as a white solid.
[0555] (2) The above-mentioned compound (140 mg) was dissolved in
methanol (3 mL) and chloroform (3 mL) and 4 mol/L hydrochloric
acid-1,4-dioxane (1 mL) were added thereto. The mixture was stirred
at room temperature for 18 hr. The solvent was evaporated under
reduced pressure and the residue was purified by HPLC to give the
title compound (52 mg) as a white solid.
[0556] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.39-1.75(14H,m),
2.08-2.14(1H,m), 2.96-3.30(8H,m), 3.64-3.89(3H,m), 4.05-4.10(1H,m),
4.44-4.69(3H,m), 9.84(2H,brs).
Example 130
Synthesis of
3-[(2S,4S)-4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)-2-pyrrolidin-
ylcarbonyl]-1,3-thiazolidine dihydrochloride
[0557] (1) Using the title compound (1.00 g) of Reference Example
12 and 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane (0.81 g), and in
the same manner as in Example 70 (1),
3-[((2S,4S)-1-tert-butoxycarbonyl-4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5-
]dec-8-yl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine (1.64 g) was
obtained as a white solid powder.
[0558] (2) Using the above-mentioned compound (1.64 g), and in the
same manner as in Example 70 (2), the title compound (0.900 g) was
obtained as a white powder.
[0559] .sup.1H-NMR(DMSO-d.sub.6).delta.1.50-2.16(6H,m),
2.80-3.30(5H,m), 3.40-3.95(6H,m), 4.45-4.80(5H,m), 6.75-6.85(1H,m),
6.90-7.05(2H,m), 7.21-7.30(2H,m).
Example 131
Synthesis of
3-[(2S,4S)-4-(4-phenyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine
dihydrochloride
[0560] (1) Using the title compound (461 mg) of Reference Example
12 and 4-phenylpiperidine (300 mg), and in the same manner as in
Example 129 (1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-phenylpiperidi)-2-pyrrolidinyl-
carbonyl]-1,3-thiazolidine (118 mg) was obtained as a white
solid.
[0561] (2) Using the above-mentioned compound (116 mg), and in the
same manner as in Example 129 (2), the title compound (78 mg) was
obtained as a white powder.
[0562] .sup.1H-NMR(DMSO-d.sub.6).delta.1.98-2.06(4H,m),
2.22-2.33(1H,m), 2.84-2.90(1H,m), 3.00-3.20(5H,m), 3.53-4.04(7H,m),
4.47-4.74(3H,m), 7.23-7.38(5H,m).
Example 132
Synthesis of
3-[(2S,4S)-4-(1,2,3,6-tetrahydro-4-phenyl-1-pyridyl)-2-pyrrolidinylcarbon-
yl]-1,3-thiazolidine dihydrochloride
[0563] (1) Using the title compound (236 mg) of Reference Example
12 and 1,2,3,6-tetrahydro-4-phenyl-1-pyridine (150 mg), and in the
same manner as in Example 70 (1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(1,2,3,6-tetrahydro-4-phenyl-1-pyridyl-
)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine (227 mg) was obtained as
a white solid.
[0564] (2) The above-mentioned compound (225 mg) was dissolved in
dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added
thereto at room temperature. The mixture was stirred for 16 hr. The
solvent was evaporated under reduced pressure, and saturated
aqueous sodium hydrogencarbonate solution was added to the residue.
The mixture was extracted with chloroform. The extract was washed
with brine and dried. The solvent was evaporated under reduced
pressure. The residue was dissolved in ethyl acetate and 4 mol/L
hydrochloric acid-ethyl acetate was added and the precipitate was
collected by filtration to give the title compound (158 mg) as a
white powder.
[0565] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.27-2.32(1H,m),
2.83(2H,brs), 3.03-3.16(4H,m), 3.68-4.15(8H,m), 4.48-4.75(3H,m),
6.19(1H,s), 7.32-7.41(3H,m), 7.49-7.51(2H,m).
Example 133
Synthesis of
3-{(2S,4S)-4-[4-(p-tolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazoli-
dine dihydrochloride
[0566] (1) The title compound (504 mg) of Reference Example 12,
4-(p-tolyl)piperidine (353 mg) and acetic acid (0.096 mL) were
dissolved in 1,2-dichloroethane (10 mL), and sodium
triacetoxyborohydride (710 mg) was added thereto. The mixture was
stirred at room temperature for 18 hr. The reaction mixture was
added to water and the mixture was extracted with chloroform. The
extract was washed with brine and dried. The solvent was evaporated
under reduced pressure to give
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[(4-(p-tolyl)piperidino]-2-pyrrolidiny-
lcarbonyl}-1,3-thiazolidine (115 mg) as a white solid.
[0567] (2) The above-mentioned compound (114 mg) was dissolved in
methanol (3 mL), and chloroform (3 mL) and 4 mol/L hydrochloric
acid-1,4-dioxane (1 mL) were added thereto. The mixture was stirred
at room temperature for 18 hr. The solvent was evaporated under
reduced pressure to give the title compound (84 mg) as a white
powder.
[0568] .sup.1H-NMR(DMSO-d.sub.6).delta.1.97-2.06(4H,m),
2.25-2.35(1H,m), 2.27(3H,s), 2.78-2.85(1H,m), 3.00-3.17(5H,m),
3.50-4.05(7H,m), 4.47-4.74(3H,m), 7.10-7.17(4H,m).
Example 134
Synthesis of
3-{(2S,4S)-4-[4-(3,4-xylyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazo-
lidine dihydrochloride
[0569] (1) Using the title compound (450 mg) of Reference Example
12 and 4-(3,4-xylyl)piperidine (312 mg), and in the same manner as
in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3,4-xylyl)piperidino]-2-pyrro-
lidinylcarbonyl}-1,3-thiazolidine 618 mg) was obtained as a white
solid.
[0570] (2) Using the above-mentioned compound (613 mg), and in the
same manner as in Example 70 (2), the title compound (374 mg) was
obtained as a white powder.
[0571] .sup.1H-NMR(DMSO-d.sub.6).delta.1.86-2.15(4H,m), 2.18(3H,s),
2.20(3H,s), 2.22-2.37(1H,m), 2.68-2.74(1H,m), 2.93-3.25(5H,m),
3.42-4.07(7H,m), 4.44-4.77(3H,m), 6.88-7.04(2H,m), 7.09(1H,d,J=7.8
Hz), 10.1(1H,brs), 11.91(1H,brs).
Example 135
Synthesis of
3-{(2S,4S)-4-[4-(2,4-dimethoxyphenyl)piperidino]-2-pyrrolidinylcarbonyl}--
1,3-thiazolidine dihydrochloride
[0572] (1) Using the title compound (487 mg) of Reference Example
12 and 4-(2,4-dimethoxyphenyl)piperidine (430 mg), and in the same
manner as in Example 133 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2,4-dimethoxyphenyl)piperidino]-2--
pyrrolidinylcarbonyl}-1,3-thiazolidine (82 mg) was obtained as a
pale-brown solid
[0573] (2) Using the above-mentioned compound (82 mg), and in the
same manner as in Example 133 (2), the title compound (61 mg) was
obtained as a brown powder.
[0574] .sup.1H-NMR(DMSO-d.sub.6).delta.1.99-2.08(4H,m),
2.25-2.35(1H,m), 2.78-3.17(6H,m), 3.53-4.06(7H,m), 3.72(3H,s),
3.75(3H,s), 4.47-4.75(3H,m), 6.74(1H,d,J=8.1 Hz), 6.83(1H,s),
6.91(1H,d,J=8.1 Hz).
Example 136
Synthesis of
3-{(2S,4S)-4-[4-(2,3-dihydrobenzo[b]furan-5-yl)piperidino]-2-pyrrolidinyl-
carbonyl}-1,3-thiazolidine dihydrochloride
[0575] (1) Using the title compound (450 mg) of Reference Example
12 and 4-(2,3-dihydrobenzo[b]furan-5-yl)piperidine (335 mg), and in
the same manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2,3-dihydrobenzo[b]furan-5-yl)pipe-
ridino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (494 mg) was
obtained as a white solid.
[0576] (2) Using the above-mentioned compound (489 mg), and in the
same manner as in Example 70 (2), the title compound (330 mg) was
obtained as a white powder.
[0577] .sup.1H-NMR(DMSO-d.sub.6).delta.1.84-2.14(4H,m),
2.21-2.37(1H,m), 2.72-2.86(1H,m), 2.96-3.26(7H,m), 3.47-4.07(7H,m),
4.44-4.77(5H,m), 6.71(1H,d,J=8.1 Hz), 6.94(1H,d,J=8.1 Hz),
7.09(1H,s), 9.9(1H,brs), 11.89(1H,brs).
Example 137
Synthesis of
3-{(2S,4S)-4-[4-(3,4-methylenedioxyphenyl)piperidino]-2-pyrrolidinylcarbo-
nyl}-1,3-thiazolidine dihydrochloride
[0578] (1) Using the title compound (505 mg) of Reference Example
12 and 4-(3,4-methylenedioxyphenyl)piperidine (414 mg), and in the
same manner as in Example 133 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3,4-methylenedioxyphenyl)piperidin-
o]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (105 mg) was obtained
as a white solid.
[0579] (2) Using the above-mentioned compound (105 mg), and in the
same manner as in Example 133 (2), the title compound (61 mg) was
obtained as a white powder.
[0580] .sup.1H-NMR(DMSO-d.sub.6).delta.1.97-2.04(4H,m),
2.25-2.35(1H,m), 2.78-2.82(1H,m), 3.00-3.17(5H,m), 3.50-4.03(7H,m),
4.47-4.76(3H,m), 5.98(2H,s), 6.70(1H,d,J=8.1 Hz), 6.82(1H,s),
6.87(1H,d,J=8.1 Hz).
Example 138
Synthesis of
3-{(2S,4S)-4-[4-(4-fluoro-3-methylphenyl)piperidino]-2-pyrrolidinylcarbon-
yl}-1,3-thiazolidine dihydrochloride
[0581] (1) Using the title compound (450 mg) of Reference Example
12 and 4-(4-fluoro-3-methylphenyl)piperidine (326 mg), and in the
same manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[(4-(4-fluoro-3-methylphenyl)piperidin-
o]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (603 mg) was obtained
as a white solid.
[0582] (2) Using the above-mentioned compound (597 mg), and in the
same manner as in Example 70 (2), the title compound (441 mg) was
obtained as a white powder.
[0583] .sup.1H-NMR(DMSO-d.sub.6).delta.1.90-2.16(4H,m), 2.23(3H,s),
2.25-2.38(1H,m), 2.77-2.92(1H,m), 2.96-3.26(5H,m), 3.48-4.07(7H,m),
4.46-4.78(3H,m), 7.04-7.19(3H,m), 10.5(1H,brs), 11.94(1H,brs).
Example 139
Synthesis of
3-{(2S,4S)-4-[(4-(3,4-dichlorophenyl)piperidino]-2-pyrrolidinylcarbonyl}--
1,3-thiazolidine dihydrochloride
[0584] (1) Using the title compound (480 mg) of Reference Example
12 and 4-(3,4-dichlorophenyl)piperidine (442 mg), and in the same
manner as in Example 133 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3,4-dichlorophenyl)piperidino]-2-p-
yrrolidinylcarbonyl}-1,3-thiazolidine (820 mg) was obtained as a
white powder.
[0585] (2) Using the above-mentioned compound (820 mg), and in the
same manner as in Example 133 (2), the title compound (654 mg) was
obtained as a white powder.
[0586] .sup.1H-NMR(DMSO-d.sub.6).delta.1.99-2.10(4H,m),
2.25-2.35(1H,m), 2.89-3.20(6H,m), 3.53-4.06(7H,m), 4.47-4.77(3H,m),
7.26(1H,d,J=8.1 Hz), 7.50(1H,d,J=3.3 Hz), 7.61(1H,dd,J=8.1, 3.3
Hz).
Example 140
Synthesis of
3-{(2S,4S)-4-[4-(4-chloro-3-trifluoromethylphenyl)piperidino]-2-pyrrolidi-
nylcarbonyl}-1,3-thiazolidine dihydrochloride
[0587] (1) Using the title compound (503 mg) of Reference Example
12 and 4-(4-chloro-3-trifluoromethylphenyl)piperidine (530 mg), and
in the same manner as in Example 133 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-chloro-3-trifluoromethylphenyl)p-
iperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (189 mg) was
obtained as a white solid.
[0588] (2) Using the above-mentioned compound (189 mg), and in the
same manner as in Example 133 (2), the title compound (116 mg) was
obtained as a white powder.
[0589] .sup.1H-NMR(DMSO-d.sub.6).delta.2.07-2.12(4H,m),
2.25-2.35(1H,m), 3.00-3.17(6H,m), 3.59-4.10(7H,m), 4.47-4.76(3H,m),
7.57-7.74(3H,m).
Example 141
Synthesis of
3-{(2S,4S)-4-[4-(1-naphthyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiaz-
olidine dihydrochloride
[0590] (1) Using the title compound (601 mg) of Reference Example
12 and 4-(1-naphthyl)piperidine (630 mg), and in the same manner as
in Example 133 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(1-naphthyl)piperidinol-2--
pyrrolidinylcarbonyl}-1,3-thiazolidine (130 mg) as a pale-brown
solid
[0591] (2) Using the above-mentioned compound (129 mg), and in the
same manner as in Example 133 (2), the title compound (72 mg) was
obtained as a brown powder.
[0592] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.99-2.35(5H,m),
3.05-3.41(5H,m), 3.63-4.06(8H,m), 4.49-4.75(3H,m), 7.38-7.39(1H,m),
7.45-7.61(3H,m), 7.83-7.84(1H,m), 7.95-7.97(1H,m),
8.21-8.23(1H,m).
Example 142
Synthesis of
3-{(2S,4S)-4-[4-(2-naphthyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiaz-
olidine dihydrochloride
[0593] (1) Using the title compound (450 mg) of Reference Example
12 and 4-(2-naphthyl)piperidine (349 mg), and in the same manner as
in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-naphthyl)piperidino]-2-p-
yrrolidinylcarbonyl}-1,3-thiazolidine (721 mg) was obtained as a
white solid.
[0594] (2). Using the above-mentioned compound (616 mg), and in the
same manner as in Example 70 (2), the title compound (206 mg) was
obtained as a white powder.
[0595] .sup.1H-NMR(DMSO-d.sub.6).delta.2.03-2.40(5H,m),
2.97-3.35(6H,m), 3.54-4.15(7H,m), 4.47-4.80(3H,m), 7.40-7.57(3H,m),
7.73(1H,s), 7.86-7.97(3H,m), 10.1(1H,brs), 11.95(1H,brs).
Example 143
Synthesis of
3-{(2S,4S)-4-[4-(2-benzo[b]thienyl)piperidino]-2-pyrrolidinylcarbonyl}-1,-
3-thiazolidine dihydrochloride
[0596] (1) Using the title compound (450 mg) of Reference Example
12 and 4-(2-benzo[b]thienyl)piperidine (330 mg), and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-benzo[b]thienyl)piperidino]-2-py-
rrolidinylcarbonyl}-1,3-thiazolidine (531 mg) was obtained as a
white solid.
[0597] (2) Using the above-mentioned compound (447 mg), and in the
same manner as in Example 70 (2), the title compound (258 mg) was
obtained as a white powder.
[0598] .sup.1H-NMR(DMSO-d.sub.6).delta.2.03-2.40(5H,m),
2.96-4.10(13H,m), 4.46-4.77(3H,m), 7.23-7.42(3H,m), 7.78(1H,d,J=7.2
Hz), 7.92(1H,d,J=7.5 Hz), 10.3(1H,brs), 11.95(1H,brs).
Example 144
Synthesis of
3-{(2S,4S)-4-[4-(1-indolinyl)piperidinol-2-pyrrolidinylcarbonyl}-1,3-thia-
zolidine trihydrochloride
[0599] (1) 1-tert-Butoxycarbonylpiperidin-4-one (2.50 g), indoline
(1.50 g) and acetic acid (0.73 mL) were dissolved in
1,2-dichloroethane (75 mL), and sodium triacetoxyborohydride (5.32
g) was added thereto. The mixture was stirred at room temperature
for 12 hr. The reaction mixture was added to iced water and the
mixture was extracted with chloroform. The extract was dried and
the solvent was evaporated under reduced pressure. The residue was
purified by silica gel chromatography to give
1-tert-butoxycarbonyl-4-(1-indolinyl)piperidine (2.82 g).
[0600] (2) The above-mentioned compound (2.82 g) was dissolved in
methanol (20 mL) and 4 mol/L hydrochloric acid-1,4-dioxane (20 mL)
was added thereto. The mixture was stirred at room temperature for
12 hr. The reaction mixture was added to aqueous sodium
hydrogencarbonate solution, and the mixture was extracted with
chloroform. The extract was dried and the solvent was evaporated
under reduced pressure to give 4-(1-indolinyl)piperidine (0.60
g).
[0601] (3) Using the above-mentioned compound (470 mg) and the
title compound (700 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(1-indolinyl)piperidino]-2-pyrrolid-
inylcarbonyl]-1,3-thiazolidine (449 mg) was obtained as a white
solid.
[0602] (4) Using the above-mentioned compound (448 mg), and in the
same manner as in Example 70 (2), the title compound (350 mg) was
obtained as a white powder.
[0603] .sup.1H-NMR(DMSO-d.sub.6).delta.1.85-2.30(5H,m),
2.85-3.25(9H,m), 3.50-4.02(8H,m), 4.52-4.81(3H,m), 6.51-6.60(2H,m),
6.98-7.05(2H,m).
Example 145
Synthesis of
3-{(2S,4S)-4-[4-(1-indolyl)piperidinol-2-pyrrolidinylcarbonyl}-1,3-thiazo-
lidine dihydrochloride
[0604] (1) Using the title compound (604 mg) of Reference Example
12 and 4-(1-indolyl)piperidine (403 mg), and in the same manner as
in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(1-indolyl)piperidino]-2-pyrro-
lidinylcarbonyl}-1,3-thiazolidine (868 mg) was obtained as a white
solid.
[0605] (2) Using the above-mentioned compound (868 mg), and in the
same manner as in Example 70 (2), the title compound (642 mg) was
obtained as a white powder.
[0606] .sup.1H-NMR(DMSO-d.sub.6).delta.2.05-2.60(6H,m),
2.99-3.18(4H,m), 3.55-4.20(6H,m), 4.30-4.90(5H,m), 6.50(1H,d,J=3.0
Hz), 7.05(1H, dd,J=8.2, 3.0 Hz), 7.16(1H,dd,J=8.1, 3.0 Hz),
7.35(1H,d,J=3.0 Hz), 7.57(1H,d,J=8.1 Hz), 7.61(1H,d,J=8.1 Hz),
9.30(1H,brs), 10.00(1H,brs).
Example 146
Synthesis of
3-{(2S,4S)-4-[4-(5-bromo-1-indolinyl)piperidino]-2-pyrrolidinylcarbonyl}--
1,3-thiazolidine trihydrochloride
[0607] (1) Using 1-tert-butoxycarbonylpiperidin-4-one (2.81 g) and
5-bromo-1-indoline (3.00 g), and in the same manner as in Example
144 (1), 1-tert-butoxycarbonyl-4-(5-bromo-1-indolinyl)piperidine
(3.34 g) was obtained.
[0608] (2) Using the above-mentioned compound (3.34 g), and in the
same manner as in Example 144 (2),
4-(5-bromo-1-indolinyl)piperidine (1.79 g) was obtained.
[0609] (3) Using the above-mentioned compound (1.12 g) and the
title compound (1.20 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-4-[4-(5-bromo-1-indolinyl)piperidino]-1-tert-butoxycarbonyl-2--
pyrrolidinylcarbonyl}-1,3-thiazolidine (1.27 g) was obtained as a
white powder.
[0610] (4) Using the above-mentioned compound (1.27 g), and in the
same manner as in Example 70 (2), the title compound (0.850 g) was
obtained as a white powder.
[0611] .sup.1H-NMR(DMSO-d.sub.6).delta.1.76-1.98(2H,m),
2.01-2.20(2H,m), 2.21-2.35(2H,m), 2.85-3.30(9H,m), 3.11-3.45(2H,m),
3.55-4.10(5H,m), 4.55-4.85(3H,m), 6.49(1H,d,J=8.4 Hz),
7.13(1H,d,J=1.8 Hz), 7.15(1H,dd,J=8.4, 1.8 Hz), 9.25(1H,brs).
Example 147
Synthesis of
3-{(2S,4S)-4-(4-(2-oxo-1-benzimidazolinyl)piperidino]-2-pyrrolidinylcarbo-
nyl}-1,3-thiazolidine dihydrochloride
[0612] (1) Using the title compound (450 mg) of Reference Example
12 and 4-(2-oxo-1-benzimidazolinyl)piperidine (358 mg), and in the
same manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[(4-(2-oxo-1-benzimidazolinyl)piperidi-
no]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (752 mg) was obtained
as a white solid.
[0613] (2) The above-mentioned compound (635 mg) was dissolved in
1.5 mol/L hydrochloric acid-methanol (5 mL), and the mixture was
stirred at room temperature for 36 hr. The reaction mixture was
concentrated under reduced pressure and ethanol (10 mL) was added
to the residue. The precipitate was collected by filtration to give
the title compound (352 mg) as a pale-brown powder.
[0614] .sup.1H-NMR(DMSO-d.sub.6).delta.1.83-1.98(2H,m),
2.20-2.37(1H,m), 2.72-2.93(2H,m), 2.96-3.45(5H,m), 3.52-4.10(7H,m),
4.46-4.77(4H,m), 7.00(3H,brs), 7.58(1H,brs), 10.97(1H,brs),
12.23(1H,brs).
Example 148
Synthesis of
3-[(2S,4S)-4-(4-anilinopiperidino)-2-pyrrolidinylcarbonyl]-1,3-thiazolidi-
ne trihydrochloride
[0615] (1) Using 1-tert-butoxycarbonylpiperidin-4-one (2.50 g) and
aniline (1.24 g), and in the same manner as in Example 144 (1),
4-anilino-1-tert-butoxycarbonylpiperidine (2.35 g) was
obtained.
[0616] (2) Using the above-mentioned compound (2.34 g), and in the
same manner as in Example 144 (2), 4-anilinopiperidine (0.88 g) was
obtained.
[0617] (3) using the above-mentioned compound (320 mg) and the
title compound (500 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-[(2S,4S)-4-(4-anilinopiperidino)-1-tert-butoxycarbonyl-2-pyrrolidinylca-
rbonyl]-1,3-thiazolidine (679 mg) was obtained as a white
solid.
[0618] (4) Using the above-mentioned compound (678 mg), and in the
same manner as in Example 70 (2), the title compound (469 mg) was
obtained as a white powder.
[0619] .sup.1H-NMR(DMSO-d.sub.6).delta.1.98-2.45(6H,m),
2.90-325(6H,m), 3.30-4.25(5H,m), 4.50-4.85(4H,m), 6.95-7.50(5H,m),
9.22(1H,brs).
Example 149
Synthesis of
3-{(2S,4S)-4-[4-(4-nitrophenyl)aminopiperidino]-2-pyrrolidinylcarbonyl]-1-
,3-thiazolidine trihydrochloride
[0620] (1) 4-Amino-1-tert-butoxycarbonylpiperazine (3.00 g),
4-fluoronitrobenzene (2.54 g) and N,N-diisopropylethylamine (8.82
g) were dissolved in N-methyl-2-pyrrolidone (30 mL), and the
mixture was stirred at 80.degree. C. for 18 hr. The reaction
mixture was added to water and the mixture was extracted with ethyl
acetate. The extract was washed with brine and dried. The solvent
was evaporated under reduced pressure. The residue was purified by
silica gel column chromatography to give
1-tert-butoxycarbonyl-4-(4-nitrophenyl)aminopiperidine (2.55 g) as
a white solid.
[0621] (2) Using the above-mentioned compound (1.00 g), and in the
same manner as in Example 144 (2), 4-(4-nitrophenyl)aminopiperidine
(0.563 g) was obtained.
[0622] (3) Using the above-mentioned compound (562 mg) and the
title compound (761 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-nitrophenyl)aminopiperidino]-2-p-
yrrolidinylcarbonyl}-1,3-thiazolidine (780 mg) was obtained as a
yellow solid.
[0623] (4) Using the above-mentioned compound (778 mg), and in the
same manner as in Example 70 (2), the title compound (575 mg) was
obtained as a yellow powder.
[0624] .sup.1H-NMR(DMSO-d.sub.6).delta.1.85-2.01(2H,m),
2.05-2.24(2H,m), 2.25-2.45(2H,m), 3.00-3.21(5H,m), 3.50-4.20(7H,m),
4.48-4.85(3H,m), 6.72(2H,d,J=9.3 Hz), 8.00(2H,d,J=9.3 Hz),
9.21(1H,brs).
Example 150
Synthesis of
3-{(2S,4S)-4-[4-(4-trifluoromethylphenyl)aminopiperidino]-2-pyrrolidinylc-
arbonyl}-1,3-thiazolidine trihydrochloride
[0625] (1) Using 1-tert-butoxycarbonylpiperidin-4-one (2.50 g) and
4-trifluoromethylaniline (2.12 g), and in the same manner as in
Example 144 (1),
1-tert-butoxycarbonyl-4-(4-trifluoromethylphenyl)aminopiperidine
(2.23 g) was obtained.
[0626] (2) Using the above-mentioned compound (2.23 g), and in the
same manner as in Example 144 (2),
4-(4-trifluoromethylphenyl)aminopiperidine (1.36 g) was
obtained.
[0627] (3) Using the above-mentioned compound (447 mg) and the
title compound (500 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-trifluoromethylphenyl)aminopiper-
idino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (775 mg) was
obtained as a white solid.
[0628] (4) Using the above-mentioned compound (774 mg), and in the
same manner as in Example 70 (2), the title compound (514 mg) was
obtained as a white powder.
[0629] .sup.1H-NMR(DMSO-d.sub.6).delta.1.75-1.95(2H,m),
2.05-2.30(2H,m), 2.25-2.55(2H,m), 2.95-3.30(6H,m), 3.40-4.15(5H,m),
4.50-4.80(4H,m), 6.72(2H,d,J=8.7 Hz), 7.38(2H,d,J=8.7 Hz),
9.21(1H,brs).
Example 151
Synthesis of
3-{(2S,4S)-4-[(4-(4-chlorophenyl)aminopiperidino]-2-pyrrolidinylcarbonyl}-
-1,3-thiazolidine trihydrochloride
[0630] (1) Using 1-tert-butoxycarbonylpiperidin-4-one (3.00 g) and
4-chloroaniline (1.92 g), and in the same manner as in Example 144
(1), 1-tert-butoxycarbonyl-4-(4-chlorophenyl)aminopiperidine (2.77
g) was obtained.
[0631] (2) Using the above-mentioned compound (2.76 g), and in the
same manner as in Example 144 (2),
4-(4-chlorophenyl)aminopiperidine (1.07 g) was obtained.
[0632] (3) Using the above-mentioned compound (725 mg) and the
title compound (500 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-((2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-chlorophenyl)aminopiperidino]-2--
pyrrolidinylcarbonyl}-1,3-thiazolidine (553 mg) was obtained as an
oil.
[0633] (4) Using the above-mentioned compound (550 mg), and in the
same manner as in Example 70 (2), the title compound (416 mg) was
obtained as a white powder.
[0634] .sup.1H-NMR(DMSO-d.sub.6).delta.1.65-1.99(2H,m),
2.05-2.35(3H,m), 2.95-3.25(5H,m), 3.26-4.15(8H,m), 4.48-4.82(3H,m),
6.58-6.85(2H,m), 7.08-7.20(2H,m), 9.22(1H,brs).
Example 152
Synthesis of
3-{(2S,4S)-4-[(4-(5-cyano-2-pyridyl)aminopiperidino]-2-pyrrolidinylcarbon-
yl}-1,3-thiazolidine trihydrochloride
[0635] (1) Using the title compound (254 mg) of Reference Example
12 and 4-(5-cyano-2-pyridyl)aminopiperidine (155 mg), and in the
same manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-cyano-2-pyridyl)aminopiperidino]-
-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (225 mg) was obtained as
a white solid.
[0636] (2) Using the above-mentioned compound (224 mg), and in the
same manner as in Example 70 (2), the title compound (219 mg) was
obtained as a white powder.
[0637] .sup.1H-NMR(DMSO-d.sub.6).delta.1.80-1.99(2H,m),
2.02-2.20(2H,m), 2.21-2.45(2H,m), 2.98-3.23(5H,m), 3.75-4.20(7H,m),
4.55-4.86(3H,m), 6.55-6.62(1H,m), 7.72(1H,d,J=9.0 Hz), 8.42(1H,s),
9.22(1H,brs).
Example 153
Synthesis of
3-{(2S,4S)-4-[4-(N-methylanilino)piperidino]-2-pyrrolidinylcarbonyl}-1,3--
thiazolidine trihydrochloride
[0638] (1)
3-[(2S,4S)-4-(4-Anilinopiperidino)-1-tert-butoxycarbonyl-2-pyrrolidinylca-
rbonyl]-1,3-thiazolidine [product of Example 148 (3), 1.18 g] was
dissolved in 1,2-dichloroethane (75 mL), and sodium
triacetoxyborohydride (5.32 g), acetic acid (0.73 mL) and 37%
formaldehyde solution (5.0 mL) were added thereto. The mixture was
stirred at room temperature for 12 hr. The reaction mixture was
added to water, and the mixture was extracted with chloroform. The
extract was dried and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel column
chromatography to give
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(N-methylanilino)piperidino]-2-pyrr-
olidinylcarbonyl}-1,3-thiazolinine (967 mg).
[0639] (2) Using the above-mentioned compound (965 mg), and in the
same manner as in Example 70 (2), the title compound (618 mg) was
obtained as a white powder.
[0640] .sup.1H-NMR(DMSO-d.sub.6).delta.1.75-2.35(6H,m),
2.78-3.28(9H,m), 3.40-4.15(6H,m), 4.48-4.85(3H,m), 7.20-7.75(5H,m),
9.22(1H,brs), 9.22(1H,brs).
Example 154
Synthesis of
3-{(2S,4S)-4-[4-(4-chlorophenyl)-4-hydroxypiperidino]-2-pyrrolidinylcarbo-
nyl}-1,3-thiazolidine 2 trifluoroacetate
[0641] (1) The title compound (593 mg) of Reference Example 12 was
dissolved in methanol (10 mL), and
4-(4-chlorophenyl)-4-hydroxypiperidine (500 mg), acetic acid (113
.mu.L) and sodium cyanoborohydride (124 mg) were added thereto at
room temperature. The mixture was stirred for 21 hr. Water was
added to the reaction mixture, and the mixture was extracted with
chloroform. The extract was washed with brine and dried. The
solvent was evaporated under reduced pressure to give
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-chlorophenyl)-4-hydroxypiperidin-
o]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (428 mg) as a white
solid.
[0642] (2) Formic acid (10 mL) was added to the above-mentioned
compound (427 mg). The mixture was stirred at room temperature for
21 hr. The solvent was evaporated under reduced pressure and the
residue was purified by HPLC to give the title compound (78 mg) as
a white powder.
[0643] .sup.1H-NMR(DMSO-d.sub.6).delta.1.81-1.85(2H,m),
2.05-2.19(3H,m), 3.00-4.06(12H,m), 4.45-4.71(3H,m), 5.60(1H,brs),
7.42-7.50(4H,m).
Example 155
Synthesis of
3-{(2S,4S)-4-[4-ethoxycarbonyl-4-(4-fluorophenyl)piperidino]-2-pyrrolidin-
ylcarbonyl}-1,3-thiazolidine dihydrochloride
[0644] (1) Using the title compound (450 mg) of Reference Example
12 and 4-ethoxycarbonyl-4-(4-fluorophenyl)piperidine (414 mg), and
in the same manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[(4-ethoxycarbonyl-4-(4-fluorophenyl)p-
iperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (742 mg) was
obtained as a white solid.
[0645] (2) The above-mentioned compound (321 mg) was dissolved in
ethanol (4 mL), and 4.6 mol/L hydrochloric acid-ethanol (1 mL) was
added thereto. The mixture was stirred at room temperature for 18
hr. The precipitate was collected by filtration to give the title
compound (218 mg) as a white powder.
[0646] .sup.1H-NMR(DMSO-d.sub.6).delta.1.14(3H,t,J=6.8 Hz),
2.05-2.28(2H,m), 2.58-2.67(2H,m), 2.83-3.16(5H,m), 3.5-4.15(10H,m),
4.42-4.73(3H,m), 7.24(2H,t,J=8.8 Hz), 7.34(2H,brs), 9.1(1H,brs),
10.35(1H,brs), 11.95(1H,brs).
Example 156
Synthesis of
3-{(2S,4S)-4-[1-(4-nitrophenyl)-4-piperidinyl]amino-2-pyrrolidinylcarbony-
l}-1,3-thiazolidine trihydrochloride
[0647] (1) 1,4-Dioxa-8-azaspiro[4,5]decane (7.88 g) was dissolved
in N-methyl-2-pyrrolidine (50 mL), and diisopropylethylamine (9.58
mL) and 4-fluoronitrobenzene (7.06 g) were successively added. The
mixture was stirred at room temperature for 2 hr. The reaction
mixture was added to iced water, and the precipitated solid was
collected by filtration to give N-(4-nitrophenyl)-4-piperidone
ethylene ketal (10.6 g) as a yellow powder.
[0648] (2) The above-mentioned compound (9.25 g) was suspended in
acetone (100 mL), and p-toluenesulfonic acid monohydrate (7.32 g)
and hydrochloric acid (20 mL) were successively added. The mixture
was stirred at room temperature for 18 hr. Aqueous sodium hydroxide
solution was added to the reaction mixture and the precipitate was
collected by filtration to give
[1-(4-nitrophenyl)-4-piperidinyl]amine (6.48 g) as a yellow
powder.
[0649] (3) Using the above-mentioned compound (6.17 g) and the
title compound (4.22 g) of Reference Example 10, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[1-(4-nitrophenyl)-4-piperidinyl]amino-
-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (7.26 g) was
obtained.
[0650] (4) The above-mentioned compound (524 mg) was dissolved in
ethyl acetate (2.07 mL), and 4 mol/L hydrochloric acid-ethyl
acetate (1.04 mL) was added thereto. The mixture was stirred at
room temperature for 18 hr. The precipitate was collected by
filtration to give the title compound (406 mg) as a yellow
powder.
[0651] .sup.1H-NMR(DMSO-d.sub.6).delta.1.53-1.79(2H,m),
2.02-2.25(3H,m), 2.88-3.01(5H,m), 3.35-3.96(5H,m), 3.96-4.28(3H,m),
4.39-4.78(3H,m), 7.08(2H,d,J=9.6 Hz), 8.07(2H,d,J=9.3 Hz).
Example 157
Synthesis of
3-{(2S,4S)-4-{N-methyl-N-[1-(4-nitrophenyl)-4-piperidinyl]amino}-2-pyrrol-
idinylcarbonyl}-1,3-thiazolidine dihydrochloride
[0652] (1) Using
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[1-(4-nitrophenyl)-4-piperidinyl]amino-
-2-pyrrolidinylcarbonyl}-1,3-thiazolidine [product of Example 156
(3), 1.01 g], and in the same manner as in Example 64 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-{N-methyl-N-[1-(4-nitrophenyl)-4-piper-
idinyl]amino}-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.04 g) was
obtained.
[0653] (2) The above-mentioned compound (1.04 g) was dissolved in
methanol (4 mL), and 4 mol/L hydrochloric acid-1,4-dioxane (2 mL)
was added thereto. The mixture was stirred at room temperature for
18 hr. The reaction mixture was concentrated under reduced pressure
and the obtained solid was washed with ethanol to give the title
compound (0.555 g) as a yellow powder.
[0654] .sup.1H-NMR(DMSO-d.sub.4).delta.1.50-1.90(2H,m),
1.95-2.40(3H,m), 2.68(3H,s), 2.80-3.25(5H,m), 3.25-3.98(5H,m),
4.02-4.37(3H,m), 4.40-4.75(3H,m), 7.09(2H,d,J=9.6 Hz),
8.07(2H,d,J=9.3 Hz).
Example 158
Synthesis of
3-{(2S,4S)-4-{N-(4-cyanophenylmethyl)-N-[1-(4-nitrophenyl)-4-piperidinyl]-
amino}-2-pyrrolidinylcarbonyl}-1,3-thiazolidine dihydrochloride
[0655] (1) The product (1.01 g) of Example 156 (3) was dissolved in
N-methyl-2-pyrrolidone (6 mL), and 4-cyanobenzyl bromide (0.392 g)
and disopropylethylamine (1.05 mL) were added thereto. The mixture
was stirred at 80.degree. C. for 8 hr with heating. The reaction
mixture was added to saturated aqueous sodium hydrogencarbonate
solution and the mixture was extracted with ethyl acetate. The
extract was dried and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel chromatography to
give
3-{(2S,4S)-1-tert-butoxycarbonyl-4-{N-(4-cyanophenylmethyl)-N-[1-(4-nitro-
phenyl)-4-piperidinyl]amino}-2-pyrrolidinylcarbonyl}-1,3-thiazolidine
(0.685 g) as a yellow oil.
[0656] (2) The above-mentioned compound (1.04 g) was dissolved in
ethyl acetate (4.41 mL), and 4 mol/L hydrochloric acid-ethyl
acetate (2.20 mL) was added thereto. The mixture was stirred at
room temperature for 18 hr. The reaction mixture was added to
saturated aqueous sodium hydrogencarbonate solution and the mixture
was extracted with chloroform. The extract was dried and
concentrated under reduced pressure. The residue was purified by
silica gel chromatography and was dissolved in chloroform. 4 mol/L
Hydrochloric acid-ethyl acetate (0.309 mL) was added and the
precipitate was collected by filtration to give the title compound
(0.249 g) as a yellow powder.
[0657] .sup.1H-NMR(DMSO-d.sub.6).delta.1.34-2.35(5H,m),
2.45-3.20(7H,m), 3.20-4.25(8H,m), 4.35-4.80(3H,m), 7.01(2H,d,J=9.6
Hz), 7.50-7.90(4H,m), 8.03(2H,d,J=9.3 Hz), 8.87(1H,brs),
10.24(1H,brs).
Example 159
Synthesis of
3-[(2S,4S)-4-(4-methyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazol-
idine trihydrochloride
[0658] The title compound (450 mg) of Reference Example 12,
1-methylpiperazine (0.20 mL) and acetic acid (0.09 mL) were
dissolved in 1,2-dichloroethane (8 mL), and sodium
triacetoxyborohydride (636 mg) was added thereto. The mixture was
stirred at room temperature for 30 hr. Saturated aqueous sodium
hydrogencarbonate solution was added to the reaction mixture and
the mixture was extracted with ethyl acetate. The extract was
washed with brine and dried. The solvent was evaporated under
reduced pressure and the residue was purified by silica gel
chromatography to give
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-methyl-1-piperazinyl)-2-pyrrolidiny-
lcarbonyl]-1,3-thiazolidine (526 mg) as a white solid.
[0659] (2) The above-mentioned compound (522 mg) was dissolved in
methanol (25 mL), and 1.5 mol/L hydrochloric acid-methanol (25 mL)
was added thereto. The mixture was stirred at room temperature for
38 hr. The reaction mixture was concentrated under reduced pressure
and ethyl acetate was added to the residue. The precipitate was
collected by filtration to give the title compound (355 mg) as a
white powder.
[0660] .sup.1H-NMR(DMSO-d.sub.6).delta.1.88-2.03(1H,m), 2.79(3H,s),
2.80-2.94(1H,m), 2.98-3.93(15H,m), 4.43-4.77(3H,m), 9.10(1H,brs),
10.78(1H,brs), 11.5(1H,brs).
Example 160
Synthesis of
3-[(2S,4S)-4-(4-phenyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazol-
idine trihydrochloride
[0661] (1) Using the title compound (450 mg) and 1-phenylpiperazine
(0.27 mL), and in the same manner as in Example 70 (1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-phenyl-1-piperazinyl)-2-pyrrolidiny-
lcarbonyl]-1,3-thiazolidine (566 mg) was obtained as a white
solid.
[0662] (2) The above-mentioned compound (442 mg) was dissolved in
1.5 mol/L hydrochloric acid-methanol (10 mL), and the mixture was
stirred at room temperature for 20 hr. the reaction mixture was
concentrated under reduced pressure and ethyl acetate was added to
the residue. The precipitate was collected by filtration to give
the title compound (418 mg) as a white powder.
[0663] .sup.1H-NMR(DMSO-d.sub.6).delta.2.35(1H,q,J=11.2 Hz),
2.94-3.95(15H,m), 4.03-4.18(1H,m), 4.44-4.77(3H,m), 6.89(1H,t,J=7.3
Hz), 7.03(2H,d,J=8.0 Hz), 7.28(2H,dd,J=8.0, 7.3 Hz), 9.23(1H,brs),
10.94(1H,brs).
Example 161
Synthesis of
1-[(2S,4S)-4-(4-phenyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]pyrrolidine
trihydrochloride
[0664] (1) Using the title compound (565 mg) of Reference Example
14 and 1-phenylpiperazine (0.37 mL), and in the same manner as in
Example 70 (1),
1-[((2S,4S)-1-tert-butoxycarbonyl-4-(4-phenyl-1-piperazinyl)-2-pyrro-
lidinylcarbonyl]pyrrolidine (832 mg) was obtained as a white
solid.
[0665] (2) The above-mentioned compound (700 mg) was dissolved in
methanol (50 mL) and chloroform (50 mL), and 1.5 mol/L hydrochloric
acid-methanol (50 mL) was added thereto. The mixture was stirred at
room temperature for 5 days. The reaction mixture was concentrated
under reduced pressure and methanol was added to the residue. The
precipitated solid was collected by filtration to give the title
compound (632 mg) as a white powder.
[0666] .sup.1H-NMR(DMSO-d.sub.6).delta.1.73-1.98(4H,m),
2.29(1H,q,J=11.6 Hz), 2.93-4.18(16H,m), 4.45-4.57(1H,m),
6.89(1H,t,J=8.0 Hz), 7.03(2H,d,J=8.0 Hz), 7.28(2H,t,J=8.0 Hz),
9.13(1H,brs), 10.89(1H,brs).
Example 162
Synthesis of
3-[(2S,4S)-4-(4-benzyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazol-
idine trihydrochloride
[0667] (1) The title compound (437 mg) of Reference Example 12,
1-benzylpiperazine (303 mg) and acetic acid (0.085 mL) were
dissolved in 1,2-dichloroethane (6 mL), and sodium
triacetoxyborohydride (650 mg) was added thereto. The mixture is
was stirred at room temperature for 5 hr. Saturated aqueous sodium
hydrogencarbonate solution was added to the reaction mixture and
the mixture was extracted with ethyl acetate. The extract was
washed with brine and dried. The solvent was evaporated under
reduced pressure and the residue was purified by silica gel
chromatography to give
3-[(2S,4S)-4-(4-benzyl-1-piperazinyl)-1-tert-butoxycarbonyl-2-pyrrolidiny-
lcarbonyl]-1,3-thiazolidine (556 mg) as a white solid.
[0668] (2) The above-mentioned compound (546 mg) was dissolved in
methanol (16 mL), and 4 mol/L hydrochloric acid-1,4-dioxane (8 mL)
was added thereto. The mixture was stirred at room temperature for
15 hr. The precipitate was collected by filtration to give the
title compound (412 mg) as a white powder.
[0669] .sup.1H-NMR(DMSO-d.sub.6).delta.1.79-1.89(1H,m),
2.76-2.84(1H,m), 2.90-3.90(15H,m), 4.35(2H,s), 4.45-4.73(3H,m),
7.45-7.47(3H,m), 7.62-7.65(2H,m), 8.99(1H,brs), 10.45(1H,brs).
Example 163
Synthesis of
3-{(2S,4S)-4-[4-(diphenylmethyl)-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1-
,3-thiazolidine trihydrochloride
[0670] (1) Using the title compound (402 mg) of Reference Example
12 and 1-diphenylmethylpiperazine (405 mg), and in the same manner
as in Example 162 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(diphenylmethyl)-1-piperaz-
inyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (470 mg) was
obtained as a white powder.
[0671] (2) Using the above-mentioned compound (470 mg), and in the
same manner as in Example 162 (2), the title compound (449 mg) was
obtained as a white powder.
[0672] .sup.1H-NMR(DMSO-d.sub.6).delta.1.94-2.01(1H,m),
2.79-2.85(1H,m), 3.03-3.92(15H,m), 4.43-4.73(3H,m), 4.48(1H,brs),
7.30-7.44(6H,m), 7.88(4H,brs), 9.09(1H,brs), 10.50(1H,brs).
Example 164
Synthesis of
3-{(2S,4S)-4-[4-(4-cyanophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,-
3-thiazolidine trihydrochloride
[0673] (1) Using the title compound (485 mg) of Reference Example
12 and 1-(4-cyanophenyl)piperazine (335 mg), and in the same manner
as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-cyanophenyl)-1-piperazinyl]-2-py-
rrolidinylcarbonyl}-1,3-thiazolidine (492 mg) was obtained as a
white powder.
[0674] (2) Formic acid (8 mL) was added to the above-mentioned
compound (492 mg). The mixture was stirred at room temperature for
2 days. The solvent was evaporated under reduced pressure, and
saturated aqueous sodium hydrogencarbonate solution was added to
the residue. The mixture was extracted with chloroform. The extract
was washed with brine and dried. The solvent was evaporated under
reduced pressure, and the residue was purified by silica gel
chromatography. 4 mol/L Hydrochloric acid-ethyl acetate was added
and the precipitate was collected by filtration to give the title
compound (78 mg) as a white powder.
[0675] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.20-2.27(1H,m),
2.95-3.16(3H,m), 3.10-4.05(13H,m), 4.47-4.74(3H,m), 7.13(1H,d,J=8.8
Hz), 7.65(1H,d,J=8.8 Hz), 9.13(1H,brs), 10.61(1H,brs).
Example 165
Synthesis of
3-{(2S,4S)-4-[4-(3-trifluoromethylphenyl)-1-piperazinyl]-2-pyrrolidinylca-
rbonyl}-1,3-thiazolidine trihydrochloride
[0676] (1) Using the title compound (411 mg) of Reference Example
12 and 1-(3-trifluoromethylphenyl)piperazine (378 mg), and in the
same manner as in Example 162 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3-trifluoromethylphenyl)-1-piperaz-
inyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (700 mg) was
obtained as a white powder.
[0677] (2) Using the above-mentioned compound (700 mg), and in the
same manner as in Example 162 (2), the title compound (553 mg) was
obtained as a white powder.
[0678] .sup.1H-NMR(DMSO-d.sub.6).delta.2.25-2.36(1H,m),
3.00-4.10(16H,m), 4.47-4.77(3H,m), 7.17(1H,d,J=7.8 Hz),
7.26-7.33(2H,m), 7.48(1H,t,J=7.8 Hz), 9.25(1H,brs),
10.82(1H,brs).
Example 166
Synthesis of
3-{(2S,4S)-4-[4-(4-methoxyphenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}--
1,3-thiazolidine trihydrochloride
[0679] (1) Using the title compound (513 mg) of Reference Example
12 and 1-(4-methoxyphenyl)piperazine (394 mg), and in the same
manner as in Example 162 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-methoxyphenyl)-1-piperazinyl]-2--
pyrrolidinylcarbonyl}-1,3-thiazolidine (536 mg) was obtained as a
white powder.
[0680] (2) Using the above-mentioned compound (530 mg), and in the
same manner as in Example 162 (2), the title compound (567 mg) was
obtained as a white powder.
[0681] .sup.1H-NMR(DMSO-d.sub.6).delta.2.28-2.39(1H,m),
3.00-3.17(3H,m), 3.68-4.12(13H,m), 3.71(3H,s), 4.47-4.77(3H,m),
6.89(2H,d,J=9.0 Hz), 7.05(2H,d,J=9.0 Hz), 9.22(1H,brs),
11.00(1H,brs).
Example 167
Synthesis of
3-{(2S,4S)-4-[(4-(4-hydroxyphenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-
-1,3-thiazolidine trihydrochloride
[0682] (1) Using the title compound (515 mg) of Reference Example
12 and 1-(4-hydroxyphenyl)piperazine (366 mg) and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-hydroxyphenyl)-1-piperazinyl]-2--
pyrrolidinylcarbonyl}-1,3-thiazolidine (260 mg) was obtained as a
pale-brown solid.
[0683] (2) The above-mentioned compound (259 mg) was dissolved in
dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added
thereto. The mixture was stirred at room temperature for 16 hr. The
reaction mixture was added to saturated aqueous sodium
hydrogencarbonate solution, and the mixture was extracted with
chloroform. The extract was washed with brine and dried. The
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel column chromatography. Thereto was added 4
mol/L hydrochloric acid-ethyl acetate and the precipitate was
collected by filtration to give the title compound (15 mg) as a
brown powder.
[0684] .sup.1H-NMR(DMSO-d.sub.6).delta.2.18-2.28(1H,m),
2.97-4.00(16H,m), 4.46-4.75(3H,m), 6.73(2H,d,J=8.7 Hz),
6.96-6.99(2H,m), 9.18(1H,brs), 10.51(1H,brs).
Example 168
Synthesis of
3-{(2S,4S)-4-[4-(2-nitrophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,-
3-thiazolidine dihydrochloride
[0685] (1) piperazine (12.9 g) was dissolved in DMF (100 mL), and a
solution of 2-fluoronitrobenzene (7.06 g) in DMF (30 mL) was added
dropwise. The mixture was stirred at room temperature for 3 hr. The
reaction mixture was added to water and the mixture was extracted
with ethyl acetate. The extract was washed with water and dried.
The solvent was evaporated to give 1-(2-nitrophenyl)piperazine (7.7
g) as a red oil.
[0686] (2) Using the above-mentioned compound (414 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-nitrophenyl)-1-piperazinyl]-2-py-
rrolidinylcarbonyl}-1,3-thiazolidine (690 mg) was obtained as a red
oil.
[0687] (3) Using the above-mentioned compound (690 mg) and in the
same manner as in Example 161 (2), the title compound (433 mg) was
obtained as a yellow powder.
[0688] .sup.1H-NMR(DMSO-d.sub.6).delta.2.19-2.40(1H,m),
2.90-4.24(16H,m), 4.44-4.80(3H,m), 7.27(1H,t,J=7.5 Hz),
7.41(1H,d,J=7.8 Hz), 7.68(1H,t,J=7.2 Hz), 7.92(1H,d,J=8.1 Hz).
Example 169
Synthesis of
3-[((2S,4S)-4-[4-(4-nitrophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1-
,3-thiazolidine trihydrochloride
[0689] (1) Using the title compound (465 mg) of Reference Example
12 and 1-(4-nitrophenyl)piperazine (385 mg), and in the same manner
as in Example 162 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-nitrophenyl)-1-piperazinyl]-2-py-
rrolidinylcarbonyl}-1,3-thiazolidine (688 mg) was obtained as a
yellow powder: .sup.1H-NMR(CDCl.sub.3).delta.1.41(4.5H,s),
1.46(4.5H,s), 1.79-1.99(1H,m), 2.38-2.52(1H,m), 2.52-2.74(4H,m),
2.75-3.22(3H,m), 3.25-3.50(5H,m), 3.60-4.20(3H,m), 4.36-4.82(3H,m),
6.82(2H,d,J=9.4 Hz), 8.12(2H,d,J=9.4 Hz).
[0690] (2) Using the above-mentioned compound (560 mg), and in the
same manner as in Example 162 (2), the title compound (511 mg) was
obtained as a yellow powder.
[0691] .sup.1H-NMR(DMSO-d.sub.6).delta.2.23-2.32(1H,m),
2.95-3.17(3H,m), 3.57-4.04(13H,m), 4.47-4.76(3H,m), 7.15(2H,d,J=9.3
Hz), 8.12(2H,d,J=9.3 Hz), 9.19(1H,brs), 10.68(1H,brs);
[.].sub.D.sup.24-35 (c1.0,H.sub.2O).
Example 170
Synthesis of
3-[(2S,4S)-4-[4-(4-fluorophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1-
,3-thiazolidine trihydrochloride
[0692] (1) Using the title compound (409 mg) of Reference Example
12 and 1-(4-fluorophenyl)piperazine (300 mg), and in the same
manner as in Example 162 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-fluorophenyl)-1-piperazinyl]-2-p-
yrrolidinylcarbonyl}-1,3-thiazolidine (404 mg) was obtained as a
white solid.
[0693] (2) using the above-mentioned compound (402 mg), and in the
same manner as in Example 162 (2), the title compound (371 mg) was
obtained as a white powder.
[0694] .sup.1H-NMR(DMSO-d.sub.6).delta.2.28-2.39(1H,m),
3.00-4.10(16H,m), 4.47-4.76(3H,m), 7.02-7.14(4H,m), 9.20(1H,brs),
10.79(1H,brs).
Example 171
Synthesis of
3-{(2S,4S)-4-[4-(2-chlorophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1-
,3-thiazolidine dihydrochloride
[0695] (1) Using the title compound (430 mg) of Reference Example
12 and 1-(2-chlorophenyl)piperazine (338 mg), and in the same
manner as in Example 162 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-chlorophenyl)-1-piperazinyl]-2-p-
yrrolidinylcarbonyl}-1,3-thiazolidine (687 mg) was obtained as a
white powder.
[0696] (2) Using the above-mentioned compound (687 mg), and in the
same manner as in Example 162 (2), the title compound (531 mg) was
obtained as a white powder.
[0697] .sup.1H-NMR(DMSO-d.sub.6).delta.2.28-2.38(1H,m),
2.97-4.15(16H,m), 4.47-4.77(3H,m), 7.12(1H,td,J=4.8, 1.5 Hz),
7.21(1H,dd,J=4.8, 1.5 Hz), 7.35(1H,td,J=8.1, 1.5 Hz),
7.46(1H,dd,J=8.1, 1.5 Hz), 9.30(1H,brs), 10.15(1H,brs).
Example 172
Synthesis of
3-{(2S,4S)-4-[4-(3-chlorophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1-
,3-thiazolidine trihydrochloride
[0698] (1) Using the title compound (476 mg) of Reference Example
12 and 1-(3-chlorophenyl)piperazine (374 mg), and in the same
manner as in Example 162 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3-chlorophenyl)-1-piperazinyl]-2-p-
yrrolidinylcarbonyl}-1,3-thiazolidine (495 mg) was obtained as a
white solid.
[0699] (2) Using the above-mentioned compound (494 mg), and in the
same manner as in Example 162 (2), the title compound (426 mg) was
obtained as a white powder.
[0700] .sup.1H-NMR(DMSO-d.sub.6).delta.2.22-2.32(1H,m),
2.97-4.06(16H,m), 4.47-4.76(3H,m), 6.88(1H,dd,J=8.1, 1.8 Hz),
6.98(1H,dd,J=8.1, 1.8 Hz), 7.07(1H,d,J=1.8 Hz), 7.27(1H,t,J=8.1
Hz), 9.24(2H,brs).
Example 173
Synthesis of
3-{(2S,4S)-4-[4-(4-chlorophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1-
,3-thiazolidine trihydrochloride
[0701] (1) Using the title compound (473 mg) of Reference Example
12 and 1-(4-chlorophenyl)piperazine (372 mg), and in the same
manner as in Example 162 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-chlorophenyl)-1-piperazinyl]-2-p-
yrrolidinylcarbonyl}-1,3-thiazolidine (564 mg) was obtained as a
white solid.
[0702] (2) Using the above-mentioned compound (554 mg), and in the
same manner as in Example 162 (2), the title compound (533 mg) was
obtained as a white powder.
[0703] .sup.1H-NMR(DMSO-d.sub.6).delta.2.25-2.35(1H,m),
2.98-3.94(15H,m), 4.04-4.10(1H,m), 4.45-4.75(3H,m), 7.05(2H,d,J=9.0
Hz), 7.30(2H,d,J=9.0 Hz), 9.19(1H,brs), 10.63(1H,brs).
Example 174
Synthesis of
3-{(2S,4S)-4-[(4-(4-bromophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1-
,3-thiazolidine trihydrochloride
[0704] (1) Using the title compound (332 mg) of Reference Example
12 and 1-(4-bromophenyl)piperazine (300 mg), and in the same manner
as in Example 162 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-bromophenyl)-1-piperazinyl]-2-py-
rrolidinylcarbonyl}-1,3-thiazolidine (390 mg) was obtained as a
white solid.
[0705] (2) Using the above-mentioned compound (388 mg), and in the
same manner as in Example 162 (2), the title compound (341 mg) was
obtained as a white powder.
[0706] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.18-2.27(1H,m),
2.95-4.06(16H,m), 4.47-4.74(3H,m), 6.98(2H,d,J=8.8 Hz),
7.40(2H,d,J=8.8 Hz), 9.15(1H,brs), 10.50(1H,brs).
Example 175
Synthesis of
3-{(2S,4S)-4-[4-(3,4-dicyanophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl-
}-1,3-thiazolidine trihydrochloride
[0707] (1) Using the title compound (561 mg) of Reference Example
12 and 1-(3,4-dicyanophenyl)piperazine (475 mg), and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3,4-dicyanophenyl)-1-piperazinyl]--
2-pyrrolidinylcarbonyl}-1,3-thiazolidine (945 mg) was obtained as a
pale-yellow powder.
[0708] (2) Using the above-mentioned compound (935 mg), and in the
same manner as in Example 167 (2), the title compound (508 mg) was
obtained as a pale-yellow powder.
[0709] .sup.1H-NMR(DMSO-d.sub.6).delta.2.18-2.28(1H,m),
2.93-3.90(16H,m), 4.46-4.75(3H,m), 7.41(1H,dd,J=9.0, 2.7 Hz),
7.72(1H,d,J=2.7 Hz), 7.90(1H,d,J=9.0 Hz), 9.19(1H,brs),
10.63(1H,brs).
Example 176
Synthesis of
3-{(2S,4S)-4-[4-(3,4-dichlorophenyl)-1-piperazinyl]-2-pyrrolidinylcarbony-
l}-1,3-thiazolidine trihydrochloride
[0710] (1) Using the title compound (540 mg) of Reference Example
12 and 1-(3,4-dichlorophenyl)piperazine (500 mg), and in the same
manner as in Example 162 (1),
3-3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3,4-dichlorophenyl)-1-piperaziny-
l]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (540 mg) was obtained
as a white solid.
[0711] (2) Using the above-mentioned compound (540 mg), and in the
same manner as in Example 162 (2), the title compound (503 mg) was
obtained as a white solid.
[0712] .sup.1H-NMR(DMSO-d.sub.6).delta.2.22-2.32(1H,m),
2.97-4.06(16H,m), 4.47-4.76(3H,m), 7.03(1H,dd,J=9.0, 2.7 Hz),
7.27(1H,d,J=2.7 Hz), 7.46(1H,d,J=9.0 Hz), 9.20(1H,brs),
10.70(1H,brs).
Example 177
Synthesis of
3-{(2S,4S)-4-[4-(3,5-dichlorophenyl)-1-piperazinyl]-2-pyrrolidinylcarbony-
l}-1,3-thiazolidine trihydrochloride
[0713] (1) Using the title compound (481 mg) of Reference Example
12 and 1-(3,5-dichlorophenyl)piperazine (444 mg), and in the same
manner as in Example 162 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3,5-dichlorophenyl)-1-piperazinyl]-
-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (523 mg) was obtained as
a white solid.
[0714] (2) Using the above-mentioned compound (520 mg), and in the
same manner as in Example 162 (2), the title compound (442 mg) was
obtained as a white powder.
[0715] .sup.1H-NMR(DMSO-d.sub.6).delta.2.20-2.30(1H,m),
2.97-4.06(16H,m), 4.47-4.75(3H,m), 6.97(1H,s), 7.07(2H,s),
9.20(1H,brs), 10.60(1H,brs).
Example 178
Synthesis of
3-{(2S,4S)-4-[4-(4-nitro-1-naphthyl)-1-piperazinyl]-2-pyrrolidinylcarbony-
l}-1,3-thiazolidine dihydrochloride
[0716] (1) Using the title compound (400 mg) of Reference Example
12 and 1-(4-nitro-1-naphthyl)piperazine (414 mg), and in the same
manner as in Example 162 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-nitro-1-naphthyl)-1-piperazinyl]-
-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (600 mg) was obtained as
a yellow powder.
[0717] (2) Using the above-mentioned compound (596 mg), and in the
same manner as in Example 162 (2), the title compound (449 mg) was
obtained as a pale-yellow powder.
[0718] .sup.1H-NMR(DMSO-d.sub.6).delta.2.29-2.39(1H,m),
3.00-3.18(3H,m), 3.57-4.17(13H,m), 4.48-4.78(3H,m), 7.29(1H,d,J=8.7
Hz), 7.73(1H,t,J=7.8 Hz), 7.83(1H,t,J=7.8 Hz), 8.27(1H,d,J=8.4 Hz),
8.36(1H,d,J=8.4 Hz), 8.52(1H,d,J=8.7 Hz), 9.20(1H,brs),
10.60(1H,brs).
Example 179
Synthesis of
3-{(2S,4S)-4-[4-(2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-th-
iazolidine trihydrochloride
[0719] (1) Using the title compound (426 mg) of Reference Example
12 and 1-(2-pyridyl)piperazine (0.26 mL), and in the same manner as
in Example 162 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-pyridyl)-1-piperazinyl]-
-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (375 mg) was obtained as
a white solid.
[0720] (2) Using the above-mentioned compound (374 mg), and in the
same manner as in Example 162 (2), the title compound (466 mg) was
obtained as a white powder.
[0721] .sup.1H-NMR(DMSO-d.sub.6).delta.2.26-2.37(1H,m),
3.00-3.16(3H,m), 3.43-4.06(13H,m), 4.47-4.78(3H,m), 6.98(1H,t,J=6.0
Hz), 7.35(1H,d,J=9.0 Hz), 7.96(1H,td,J=9.0, 1.5 Hz),
8.13(1H,dd,J=6.0, 1.5 Hz), 9.23(1H,brs), 10.98(1H,brs).
Example 180
Synthesis of
3-{(2S,4S)-4-[4-(4-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-th-
iazolidine trihydrochloride
[0722] (1) Using the title compound (601 mg) of Reference Example
12 and 1-(4-pyridyl)piperazine (326 mg), and in the same manner as
in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-pyridyl)-1-piperazinyl]-2-p-
yrrolidinylcarbonyl}-1,3-thiazolidine (366 mg) was obtained.
[0723] (2) Using the above-mentioned compound (366 mg), and in the
same manner as in Example 161 (2), the title compound (133 mg) was
obtained as a white powder.
[0724] .sup.1H-NMR(DMSO-d.sub.6).delta.2.03-2.30(1H,m),
2.79-4.30(16H,m), 4.40-4.80(3H,m), 7.32(2H,d,J=7.5 Hz),
8.34(2H,d,J=7.2 Hz), 9.15(1H,brs), 10.80(1H,brs),
14.00(1H,brs).
Example 181
Synthesis of
3-{(2S,4S)-4-[4-(4-cyano-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl-
}-1,3-thiazolidine trihydrochloride
[0725] (1) Using the title compound (494 mg) of Reference Example
12 and 1-(4-cyano-2-pyridyl)piperazine (371 mg), and in the same
manner as in Example 154 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-cyano-2-pyridyl)-1-piperazinyl]--
2-pyrrolidinylcarbonyl}-1,3-thiazolidine (431 mg) was obtained as a
white solid.
[0726] (2) Using the above-mentioned compound (424 mg), and in the
same manner as in Example 167 (2), the title compound (194 mg) was
obtained as a pale-yellow powder.
[0727] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.32-2.39(1H,m),
3.00-3.16(3H,m), 3.25-4.07(13H,m), 4.48-4.75(3H,m),
7.10(1H,dd,J=5.1, 0.8 Hz), 7.50(1H,d,J=0.8 Hz), 8.36(1H,d,J=5.1
Hz), 9.22(1H,brs), 10.91(1H,brs).
Example 182
Synthesis of 1-{(2S
4S)-4-[4-(4-cyano-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}pyrrol-
idine trihydrochloride
[0728] (1) Using the title compound (527 mg) of Reference Example
14 and 1-(4-cyano-2-pyridyl)piperazine (422 mg), and in the same
manner as in Example 70 (1),
1-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-cyano-2-pyridyl)-1-piperazinyl]--
2-pyrrolidinylcarbonyl}pyrrolidine (502 mg) was obtained as a
pale-yellow solid.
[0729] (2) Using the above-mentioned compound (491 mg), and in the
same manner as in Example 167 (2), the title compound (134 mg) was
obtained as a pale-yellow powder.
[0730] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.83-1.96(4H,m),
2.25-2.30(1H,m), 2.98-3.02(1H,m), 3.20-3.56(10H,m),
3.70-3.72(2H,m), 4.04-4.08(1H,m), 4.30-4.54(2H,m), 4.50-4.54(1H,m),
7.10(1H,dd,J=5.1, 0.8 Hz), 7.50(1H,d,J=0.8 Hz), 8.36(1H,d,J=5.1
Hz), 9.12(1H,brs), 10.73(1H,brs).
Example 183
Synthesis of
3-{(2S,4S)-4-[4-(5-cyano-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl-
}-1,3-thiazolidine trihydrochloride
[0731] (1) Using the title compound (740 mg) of Reference Example
12 and 1-(5-cyano-2-pyridyl)piperazine (516 mg), and in the same
manner as in Example 154 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-cyano-2-pyridyl)-1-piperazinyl]--
2-pyrrolidinylcarbonyl}-1,3-thiazolidine (772 mg) was obtained as a
white powder.
[0732] .sup.1H-NMR(CDCl.sub.3).delta.1.41(4.5H,s), 1.46(4.5H,s),
1.86-1.98(1H,m), 2.45-2.60(5H,m), 2.83-3.25(3H,m), 3.31-3.39(1H,m),
3.60-3.79(5H,m), 3.81-3.99(2H,m), 4.40-4.85(3H,m), 6.58(1H,d,J=9.0
Hz), 7.61(1H,dd,J=9.0, 2.1 Hz), 8.40(1H,d,J=2.1 Hz).
[0733] (2) Using the above-mentioned compound (744 mg), and in the
same manner as in Example 167 (2), the title compound (202 mg) was
obtained as a pale-yellow powder.
[0734] .sup.1H-NMR(DMSO-d.sub.6).delta.2.28-2.39(1H,m),
2.97-3.16(3H,m), 3.35-4.10(13H,m), 4.47-4.76(3H,m), 7.11(1H,d,J=9.3
Hz), 7.98(1H,dd,J=9.3, 2.1 Hz), 8.57(1H,d,J=2.1 Hz), 9.25(1H,brs),
10.91(1H,brs); [.].sub.D.sup.23-32(c1.0,H.sub.2O).
Example 184
Synthesis of
3-{(2S,4S)-4-[4-(5-trifluoromethyl-2-pyridyl)-1-piperazinyl]-2-pyrrolidin-
ylcarbonyl}-1,3-thiazolidine dihydrochloride
[0735] (1) Piperazine (12.9 g) was suspended in
N-methyl-2-pyrrolidone (130 mL), and a solution of
2-chloro-5-trifluoromethylpyridine (9.08 g) in
N-methyl-2-pyrrolidone (30 mL) was added dropwise. The mixture was
stirred at room temperature for 18 hr. The reaction mixture was
added to water and the mixture was extracted with ethyl acetate.
The extract was washed with water and dried. The solvent was
evaporated under reduced pressure to give
1-(5-trifluoromethyl-2-pyridyl)piperazine (11.5 g) as a white
solid.
[0736] (2) Using the above-mentioned compound (462 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-trifluoromethyl-2-pyridyl)-1-pip-
erazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (379 mg) as an
oil.
[0737] (3) Using the above-mentioned compound (368 mg), and in the
same manner as in Example 161 (2), the title compound (276 mg) was
obtained as a white powder.
[0738] .sup.1H-NMR(DMSO-d.sub.6).delta.2.20-2.48(1H,m),
2.87-5.00(19H,m), 7.14(1H,d,J=9.0 Hz), 7.92(1H,dd,J=9.3, 2.4 Hz),
8.49(1H,d,J=0.6 Hz).
Example 185
Synthesis of
3-{(2S,4S)-4-[4-(5-nitro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl-
}-1,3-thiazolidine dihydrochloride
[0739] (1) Using 2-chloro-5-nitropyridine (7.93 g), and in the same
manner as in Example 184 (1), 1-(5-nitro-2-pyridyl)piperazine (9.3
g) was obtained as a yellow powder.
[0740] (2) Using the above-mentioned compound (416 mg) and the
title is compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-nitro-2-pyridyl)-1-piperazinyl]--
2-pyrrolidinylcarbonyl}-1,3-thiazolidine (754 mg) was obtained as a
yellow powder.
[0741] (3) Using the above-mentioned compound (693 mg), and in the
same manner as in Example 161 (2), the title compound (475 mg) was
obtained as a yellow powder.
[0742] .sup.1H-NMR(DMSO-d.sub.6).delta.2.00-2.34(1H,m),
2.75-4.10(16H,m), 4.40-4.80(3H,m), 7.09(1H,d,J=9.6 Hz),
8.32(1H,dd,J=9.6, 3.0 Hz), 9.01(1H,d,J=3.0 Hz), 9.18(1H,brs),
10.50(1H,brs).
Example 186
Synthesis of
1-{(2S,4S)-4-[4-(5-nitro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl-
}pyrrolidine trihydrochloride
[0743] (1) Using 1-(5-nitro-2-pyridyl)piperazine [product of
Example 185(1), 625 mg] and the title compound (565 mg) of
Reference Example 14, and in the same manner as in Example 70 (1),
1-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-nitro-2-pyridyl)-1-piperazinyl]--
2-pyrrolidinylcarbonyl}pyrrolidine (632 mg) was obtained as a
yellow powder.
[0744] (2) The above-mentioned compound (522 mg) was dissolved in
methanol (10 mL) and chloroform (2.5 mL), and 4 mol/L hydrochloric
acid-ethyl acetate (5 mL) was added thereto. The mixture was
stirred at room temperature for 18 hr. The reaction mixture was
concentrated under reduced pressure, and the residue was washed
with ethanol to give the title compound (395 mg) as a yellow
powder.
[0745] .sup.1H-NMR(DMSO-d.sub.6).delta.1.70-2.04(4H,m),
2.09-2.36(1H,m), 2.86-3.07(1H,m), 3.20-5.00(14H,m), 7.11(1H,d,J=9.6
Hz), 8.33(1H,dd,J=9.6, 3.0 Hz), 9.02(1H,d,J=2.7 Hz), 9.11(1H,brs),
10.80(1H,brs).
Example 187
Synthesis of
3-{(2S,4S)-4-[4-(5-chloro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbony-
l}-1,3-thiazolidine trihydrochloride
[0746] (1) Using the title compound (340 mg) of Reference Example
12 and 1-(5-chloro-2-pyridyl)piperazine (268 mg), and in the same
manner as in Example 162 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-chloro-2-pyridyl)-1-piperazinyl]-
-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (421 mg) was obtained as
a white solid.
[0747] (2) Using the above-mentioned compound (418 mg), and in the
same manner as in Example 162 (2), the title compound (262 mg) was
obtained as a white powder.
[0748] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.26-2.31(1H,m),
2.97-4.40(16H,m), 4.47-4.73(3H,m), 7.03(1H,d,J=9.1 Hz),
7.71(1H,dd,J=9.1, 2.5 Hz), 8.18(1H,d,J=2.5 Hz), 9.18(1H,brs),
10.57(1H,brs).
Example 188
Synthesis of
3-{(2S,4S)-4-[4-(2-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-t-
hiazolidine trihydrochloride
[0749] (1) Using the title compound (488 mg) of Reference Example
12 and 1-(2-quinolyl)piperazine (416 mg), and in the same manner as
in Example 162 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-quinolyl)-1-piperazinyl-
]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (724 mg) was obtained as
a white solid.
[0750] (2) Using the above-mentioned compound (720 mg), and in the
same manner as in Example 162 (2), the title compound (560 mg) was
obtained as a white powder.
[0751] .sup.1H-NMR(DMSO-d.sub.6).delta.2.20-2.30(1H,m),
2.96-3.17(3H,m), 3.64-4.40(13H,m), 4.47-4.76(3H,m), 7.50(1H,t,J=7.5
Hz), 7.60(1H,d,J=9.6 Hz), 7.77(1H,t,J=7.8 Hz), 7.93(1H,d,J=7.5 Hz),
8.15-8.20(1H,m), 8.44(1H,d,J=9.6 Hz), 9.21(1H,brs),
10.68(1H,brs).
Example 189
Synthesis of
3-{(2S,4S)-4-[4-(4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-t-
hiazolidine trihydrochloride
[0752] (1) piperazine (13.2 g) was melted by heating at 140.degree.
C., and 4-chloroquinoline (2.5 g) was added thereto. The mixture
was stirred at 140.degree. C. for 30 min. The reaction mixture was
added to iced water, and the mixture was extracted with chloroform
to give 1-(4-quinolyl)piperazine (3.45 g) as a pale-yellow oil.
[0753] (2) Using the above-mentioned compound (469 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-quinolyl)-1-piperazinyl]-2-pyrro-
lidinylcarbonyl}-1,3-thiazolidine (995 mg) was obtained.
[0754] (3) Using the above-mentioned compound (995 mg), and in the
same manner as in Example 186 (2), the title compound (392 mg) was
obtained as a white powder.
[0755] .sup.1H-NMR(DMSO-d.sub.6).delta.2.16-2.40(1H,m),
2.70-4.30(16H,m), 4.40-4.80(3H,m), 7.37(1H,d,J=6.9 Hz),
7.77(1H,t,J=8.1 Hz), 8.04(1H,t,J=8.4 Hz), 8.21(1H,d,J=8.7 Hz),
8.85(1H,d,J=6.9 Hz).
Example 190
Synthesis of
3-{(2S,4S)-4-[4-(1-isoquinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,-
3-thiazolidine trihydrochloride
[0756] (1) Using the title compound (606 mg) of Reference Example
12 and 1-(1-isoquinolyl)piperazine (692 mg), and in the same manner
as in Example 162 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(1-isoquinolyl)-1-piperazinyl]-2-py-
rrolidinylcarbonyl}-1,3-thiazolidine (216 mg) was obtained as a
white solid.
[0757] (2) Using the above-mentioned compound (215 mg), and in the
same manner as in Example 162 (2), the title compound (99 mg) was
obtained as a pale-yellow powder.
[0758] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.25-2.30(1H,m),
3.00-3.17(3H,m), 3.59-3.95(12H,m), 4.13-4.18(1H,m),
4.49-4.77(3H,m), 7.59(1H,d,J=6.1 Hz), 7.71-7.74(1H,m),
7.86-7.89(1H,m), 8.02(1H,d,J=8.2 Hz), 8.08(1H,d,J=6.1 Hz),
8.21(1H,d,J=8.5 Hz), 9.25(1H,brs), 10.89(1H,brs).
Example 191
Synthesis of
3-{(2S,4S)-4-[4-(2-trifluoromethyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidi-
nylcarbonyl}-1,3-thiazolidine dihydrochloride
[0759] (1) Using the title compound (0.655 g) of Reference Example
12 and 1-(2-trifluoromethyl-4-quinolyl)piperazine (0.735 g), and in
the same manner as in Example 162 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-trifluoromethyl-4-quinolyl)-1-pi-
perazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.23 g) was
obtained as a pale-yellow powder:
.sup.1H-NMR(DMSO-d.sub.6).delta.1.33(4.5H,s), 1.41(4.5H,s),
1.55-1.64(1H,m), 2.60-2.78(5H,n), 2.90-3.15(4H,m), 3.33-3.38(4H,m),
3.67-3.85(3H,m), 4.04-4.69(3H,m), 7.25(1H,s), 7.70(1H,t,J=8.1 Hz),
7.81-7.87(1H,m), 8.07(2H,d,J=8.4 Hz).
[0760] (2) Using the above-mentioned compound (1.23 g), and in the
same manner as in Example 162 (2), the title compound (1.06 g) was
obtained as a pale-yellow powder.
[0761] .sup.1H-NMR(DMSO-d.sub.6).delta.2.28-2.38(1H,m),
3.00-3.18(3H,m), 3.48-4.15(13H,m), 4.48-4.78(3H,m), 7.39(1H,s),
7.75(1H,t,J=7.5 Hz), 7.89(1H,t,J=7.5 Hz), 8.11-8.16(2H,m),
9.23(1H,brs), 10.68(1H,brs);
[.].sub.D.sup.24-32(c1.0,H.sub.2O).
Example 192
Synthesis of
3-{(2S,4S)-4-[4-(2-benzoxazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1-
,3-thiazolidine trihydrochloride
[0762] (1) Using 2-chlorobenzoxazole (7.68 g) and piperazine (12.9
g), and in the same manner as in Example 168 (1),
1-(2-benzoxazolyl)piperazine (2.4 g) was obtained as a white
solid.
[0763] (2) Using the above-mentioned compound (610 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-4-[4-(2-benzoxazolyl)-1-tert-butoxycarbonyl-1-piperazinyl]-2-p-
yrrolidinylcarbonyl}-1,3-thiazolidine (526 mg) was obtained as a
white powder.
[0764] (3) Using the above-mentioned compound (416 mg), and in the
same manner as in Example 186 (2), the title compound (286 mg) was
obtained as a white powder.
[0765] .sup.1H-NMR(DMSO-d.sub.6).delta.2.20-2.42(1H,m),
2.89-3.20(3H,m), 3.25-4.35(13H,m), 4.40-4.80(3H,m),
7.10(1H,td,J=7.5, 1.2 Hz), 7.22(1H,td,J=7.8, 1.2 Hz),
7.37(1H,dd,J=7.8, 0.6 Hz), 7.47(1H,d,J=7.8 Hz), 9.25(1H,brs),
11.00(1H,brs).
Example 193
Synthesis of
3-{(2S,4S)-4-t4-(2-benzothiazolyl)-1-piperazinyl]2-pyrrolidinylcarbonyl}--
1,3-thiazolidine trihydrochloride
[0766] (1) Using 2-chlorobenzothiazole (8.48 g) and piperazine
(43.1 g), and in the same manner as in Example 189 (1),
1-(2-benzothiazolyl)piperazine (10.9 g) was obtained.
[0767] (2) Using the above-mentioned compound (482 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-4-[(4-(2-benzothiazolyl)-1-piperazinyl]-1-tert-butoxycarbonyl--
2-pyrrolidinylcarbonyl}-1,3-thiazolidine (798 mg) was obtained as a
white powder.
[0768] (3) Using the above-mentioned compound (606 mg), and in the
same manner as in Example 186 (2), the title compound (591 mg) was
obtained as a white powder.
[0769] .sup.1H-NMR(DMSO-d.sub.6).delta.2.20-2.44(1H,m),
2.90-3.20(3H,m), 3.35-4.30(13H,m), 4.42-4.82(3H,m), 7.16(1H,t,J=7.2
Hz), 7.35(1H,t,J=7.2 Hz), 7.55(1H,d,J=7.8 Hz), 7.86(1H,d,J=7.5 Hz),
9.25(1H,brs), 10.90(1H,brs).
Example 194
Synthesis of
3-{(2S,4S)-4-[4-(benz-2-oxa-1,3-diazol-5-yl)-1-piperazinyl]-2-pyrrolidiny-
lcarbonyl}-1,3-thiazolidine dihydrochloride
[0770] (1) Using 5-chlorobenzofurazan (0.500 g) and piperazine
(2.79 g), and in the same manner as in Example 189 (1),
1-(benz-2-oxa-1,3-diazol-5-yl)piperazine (0.433 g) was
obtained.
[0771] (2) Using the above-mentioned compound (433 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-4-[4-(benz-2-oxa-1,3-diazol-5-yl)-1-tert-butoxycarbonyl-1-pipe-
razinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (500 mg) was
obtained as a yellow powder.
[0772] (3) Using the above-mentioned compound (438 mg), and in the
same manner as in Example 186 (2), the title compound (409 mg) was
obtained as a yellow powder.
[0773] .sup.1H-NMR(DMSO-d.sub.6).delta.2.10-2.40(1H,m),
2.80-4.30(16H,m), 4.40-4.80(3H,m), 7.02(1H,s), 7.72(1H,dd,J=9.9,
1.5 Hz), 7.94(1H,d,J=9.9 Hz).
Example 195
Synthesis of
3-{(2S,4S)-4-[4-(4-nitrobenzoyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1-
,3-thiazolidine dihydrochloride
[0774] (1) Using the title compound (454 mg) of Reference Example
12 and 1-(4-nitrobenzoyl)piperazine (426 mg), and in the same
manner as in Example 162 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-nitrobenzoyl)-1-piperazinyl]-2-p-
yrrolidinylcarbonyl}-1,3-thiazolidine (500 mg) was obtained as a
white solid.
[0775] (2) Using the above-mentioned compound (496 mg), and in the
same manner as in Example 162 (2), the title compound (242 mg) was
obtained as a white powder.
[0776] .sup.1H-NMR(DMSO-d.sub.6).delta.2.15-2.22(1H,m),
2.90-2.94(1H,m), 3.07-3.93(15H,m), 4.46-4.73(3H,m), 7.75(2H,d,J=8.6
Hz), 8.32(2H,d,J=8.6 Hz), 9.15(1H,brs), 10.63(1H,brs).
Example 196
Synthesis of
3-{(2S,4S)-4-[4-(4-nitrophenyl)-1,4-diazepam-1-yl]-2-pyrrolidinylcarbonyl-
}-1,3-thiazolidine dihydrochloride
[0777] (1) Homopiperazine (15.0 g) was dissolved in
N-methyl-2-pyrrolidine (50 mL), and 4-fluoronitrobenzene (7.06 g)
was added thereto. The mixture was stirred at room temperature for
30 min. The reaction mixture was added to iced water, and the
precipitate was collected by filtration to give
N-(4-nitrophenyl)-1,4-diazepam (10.9 g) as a yellow powder.
[0778] (2) Using the above-mentioned compound (443 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert.butoxycarbonyl-4-[4-(4-nitrophenyl)-1,4-diazepam-1-yl]--
2-pyrrolidinylcarbonyl}-1,3-thiazolidine (429 mg) was obtained as a
yellow powder.
[0779] (3) Using the above-mentioned compound (398 mg), and in the
same manner as in Example 161 (2), the title compound (118 mg) was
obtained as a yellow powder.
[0780] .sup.1H-NMR(DMSO-d.sub.6).delta.1.80-2.60(3H,m),
2.70-4.20(12H,m), 4.38-4.78(3H,m), 6.89(2H,d,J=9.3 Hz),
8.09(2H,d,J=9.3 Hz).
Example 197
Synthesis of
3-{(2S,4S)-4-[4-(2-trifluoromethyl-4-quinolyl)-1,4-diazepam-1-yl]-2-pyrro-
lidinylcarbonyl}-1,3-thiazolidine trihydrochloride
[0781] (1) Using 4-chloro-2-trifluoromethylquinoline (5.00 g) and
homopiperazine (20.7 g), and by reaction in the same manner as in
Example 196 (1) at 60.degree. C.,
N-(2-trifluoromethyl-4-quinolyl)-1,4-diazepam (6.11 g) was obtained
as a yellow solid.
[0782] (2) Using the above-mentioned compound (0.83 g) and the
title compound (0.703 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-trifluoromethyl-4-quinolyl)-1,4--
diazepam-1-yl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.35 g)
was obtained as a white powder.
[0783] (3) Using the above-mentioned compound (1.35 g), and in the
same manner as in Example 133 (2), the title compound (1.21 g) was
obtained as a pale-yellow powder.
[0784] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.19-2.49(3H,m),
2.96-3.19(3H,m), 3.30-4.28(13H,m), 4.48-4.76(3H,m), 7.17(1H,s),
7.67(1H,t,J=7.6 Hz), 7.83(1H,t,J=7.6 Hz), 8.05-8.10(2H,m),
9.14(1H,brs), 10.91(1H,brs), 12.51(1H,brs)
Example 198
Synthesis of
3-{(2S,4S)-4-[(4-(2-hydroxyethyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}--
1,3-thiazolidine trihydrochloride
[0785] (1) Using 1-piperazineethanol (147 mg) and the title
compound (307 mg) of Reference Example 12, and in the same manner
as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-hydroxyethyl)-1-piperazinyl]-2-p-
yrrolidinylcarbonyl}-1,3-thiazolidine (354 mg) was obtained as an
oil.
[0786] (2) Using the above-mentioned compound (350 mg), and in the
same manner as in Example 132 (2), deprotection was conducted. The
solvent was evaporated under reduced pressure, and the residue was
dissolved in ethyl acetate (5 mL). 4 mol/L Hydrochloric acid-ethyl
acetate (1.0 mL) was added thereto, and the precipitated solid was
collected by filtration to give the title compound (158 mg) as a
white powder.
[0787] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.91(1H,m),
2.78-3.93(20H,m), 4.46-4.74(3H,m), 8.97(1H,brs), 10.80(1H,brs),
11.97(1H,brs).
Example 199
Synthesis of
3-[(2S,4S)-4-(4-pivaloyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiaz-
olidine dihydrochloride
[0788] (1) using N-benzyloxycarbonyl-L-trans-4-hydroxyproline (25.0
g), and in the same manner as in Reference Examples 9 and 12,
3-((2S)-1-benzyloxycarbonyl-4-oxo-2-pyrrolidinylcarbonyl)-1,3-thiazolidin-
e (10.9 g) was obtained as white crystals.
[0789] (2) Using the above-mentioned compound (4.05 g) and
1-tert-butoxycarbonylpiperazine (2.48 g), and in the same manner as
in Example 70 (1),
3-[(2S,4S)-1-benzyloxycarbonyl-4-(4-tert-butoxycarbonyl-1-piperazinyl)-2--
pyrrolidinylcarbonyl]-1,3-thiazolidine (4.64 g) was obtained as a
white powder.
[0790] (3) The above-mentioned compound (4.04 g) was deprotected in
the same manner as in Example 132 (2). The solvent was evaporated
under reduced pressure, and saturated aqueous sodium
hydrogencarbonate solution was added to the residue. The mixture
was extracted with chloroform, and the extract was dried and
concentrated under reduced pressure to give
3-(2S,4S)-1-benzyloxycarbonyl-4-(1-piperazinyl)-2-pyrrolidinylcarbonyl]-1-
,3-thiazolidine (3.10 g) as a white powder.
[0791] (4) The above-mentioned compound (405 mg) and triethylamine
(170 .mu.L) were dissolved in chloroform (4 mL), and pivaloyl
chloride (126 .mu.L) was added thereto at room temperature. The
mixture was stirred for 3 hr. Water was added to the reaction
mixture and the mixture was extracted with chloroform. The extract
was dried and the mixture was concentrated under reduced pressure
to give
3-[((2S,4S)-1-benzyloxycarbonyl-4-(4-pivaloyl-1-piperazinyl)-2-pyrrolidin-
ylcarbonyl]-1,3-thiazolidine (430 mg) as a white solid.
[0792] (5) The above-mentioned compound (423 mg) was dissolved in
trifluoroacetic acid, and thioanisole (0.6 mL) was added thereto.
The mixture was stirred at room temperature for 21 hr. Diethyl
ether was added to the reaction mixture, and the precipitated solid
was collected by filtration and purified by HPLC. This was
converted to hydrochloride with 4 mol/L hydrochloric acid-ethyl
acetate to give the title compound (95 mg) as a white powder.
[0793] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.20(9H,s),
2.12-2.33(1H,m), 2.85-4.05(16H,m), 4.48-4.73(3H,m), 9.08(1H,brs),
10.73(1H,brs).
Example 200
Synthesis of
3-[(2S,4S)-4-(4-methoxycarbonyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,-
3-thiazolidine dihydrochloride
[0794] (1) Using
3-[(2S,4S)-1-benzyloxycarbonyl-4-(1-piperazinyl)-2-pyrrolidinylcarbonyl]--
1,3-thiazolidine [product of Example 199 (3), 405 mg] and methyl
chlorocarbonate (79 .mu.L), and in the same manner as in Example
199 (4),
3-[(2S,4S)-1-benzyloxycarbonyl-4-(4-methoxycarbonyl-1-piperazinyl)-2-pyrr-
olidinylcarbonyl]-1,3-thiazolidine (413 mg) was obtained as a white
solid.
[0795] (2) Using the above-mentioned compound (407 mg), and in the
same manner as in Example 199 (5), the title compound (43 mg) was
obtained as a brown powder.
[0796] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.13-2.43(1H,m),
2.85-4.05(16H,m), 3.63(3H,s), 4.47-4.74(3H,m), 9.08(1H,brs),
10.73(1H,brs).
Example 201
Synthesis of
3-[(2S,4S)-4-(4-isobutyloxycarbonyl-1-piperazinyl)-2-pyrrolidinylcarbonyl-
]-1,3-thiazolidine dihydrochloride
[0797] (1) Using the product (405 mg) of Example 199 (3) and
isobutyl chlorocarbonate (133 .mu.L), and in the same manner as in
Example 199 (4),
3-[(2S,4S)-1-benzyloxycarbonyl-4-(4-isobutyloxycarbonyl-1-piperaziny-
l)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine (421 mg) was obtained
as a white solid.
[0798] (2) Using the above-mentioned compound (416 mg), and in the
same manner as in Example 199 (5), the title compound (59 mg) was
obtained as a white powder.
[0799] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.0.90(6H,d,J=6.8 Hz),
1.81-1.97(1H,m), 2.19-2.39(1H,m), 2.90-4.20(16H,m), 3.83(2H,d,J=6.5
Hz), 4.47-4.74(3H,m), 9.12(1H,brs), 11.07(1H,brs).
Example 202
Synthesis of
3-[(2S,4S)-4-(4-benzyloxycarbonyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]--
1,3-thiazolidine dihydrochloride
[0800] (1) using 1-benzyloxcarbonylpiperazine (217 mg) and the
title compound (307 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-((2S,4S)-4-(4-benzyloxycarbonyl-1-piperazinyl)-1-tert-butoxycarbonyl-2--
pyrrolidinylcarbonyl]-1,3-thiazolidine (500 mg) was obtained as a
white powder.
[0801] (2) Using the above-mentioned compound (490 mg), and in the
same manner as in Example 133 (2), the title compound (399 mg) was
obtained as a white powder.
[0802] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.10-2.30(1H,m),
1.70-4.20(16H,m), 4.46-4.73(3H,m), 5.11(2H,s), 7.31-7.42(5H,m),
9.06(1H,brs), 10.67(1H,brs), 12.50(1H,brs).
Example 203
Synthesis of
3-[(2S,4S)-4-(4-cyclohexylaminocarbonyl-1-piperazinyl)-2-pyrrolidinylcarb-
onyl]-1,3-thiazolidine dihydrochloride
[0803] (1) Using the product (405 mg) of Example 199 (3) and
cyclohexyl isocyanate (127 .mu.L), and in the same manner as in
Example 199 (4),
3-[(2S,4S)-1-benzyloxycarbonyl-4-(4-cyclohexylaminocarbonyl-1-piperazinyl-
)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine (296 mg) was obtained as
a white solid.
[0804] (2) Using the above-mentioned compound (296 mg), and in the
same manner as in Example 199 (5), the title compound (85 mg) was
obtained as a white powder.
[0805] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.00-1.29(5H,m),
1.53-1.80(5H,m), 2.12-2.32(1H,m), 2.80-4.20(17H,m),
4.47-4.73(3H,m), 6.48(1H,brs), 9.09(1H,brs), 10.65(1H,brs),
12.18(1H,brs).
Example 204
Synthesis of
3-{(2S,4S)-4-[(4-(2,6-dimethylphenyl)aminocarbonyl-1-piperazinyl]-2-pyrro-
lidinylcarbonyl}-1,3-thiazolidine dihydrochloride
[0806] (1) Using the product (405 mg) of Example 199 (3) and
2,6-dimethylphenyl isocyanate (142 .mu.L), and in the same manner
as in Example 199 (4),
3-{(2S,4S)-1-benzyloxycarbonyl-4-[4-(2,6-dimethylphenyl)aminocarbonyl-1-p-
iperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (517 mg) was
obtained as a white powder.
[0807] (2) Using the above-mentioned compound (503 mg), and in the
same manner as in Example 199 (5), the title compound (166 mg) was
obtained as a white powder.
[0808] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.15(6H,s),
2.09-2.29(1H,m), 2.85-4.20(16H,m), 4.48-4.73(3H,m), 7.04(3H,m),
8.16(1H,s), 9.07(1H,brs), 10.61(1H,brs).
Example 205
Synthesis of
3-{(2S,4S)-4-[4-(8-quinolinesulfonyl)-1-piperazinyl]-2-pyrrolidinylcarbon-
yl}-1,3-thiazolidine trihydrochloride
[0809] (1) 1-tert-Butoxycarbonylpiperazine (2.22 g) and
triethylamine (2.0 mL) were dissolved in dichloromethane (100 mL),
and 8-quinolinesulfonyl chloride (2.71 g) was added thereto. The
mixture was stirred at room temperature for 14 hr. 10% citric acid
solution was added to the reaction mixture and the mixture was
extracted with chloroform. The extract was washed with brine, dried
and concentrated under reduced pressure. The residue was dissolved
in dichloromethane (20 mL), and trifluoroacetic acid (5 mL) was
added thereto. The mixture was stirred at room temperature for 1.5
hr. The reaction mixture was concentrated under reduced pressure,
and saturated aqueous sodium hydrogencarbonate solution was added
to the residue. The mixture was extracted with chloroform, and the
extract was dried and concentrated under reduced pressure to give
1-(8-quinolinesulfonyl)piperazine (0.73 g) as a white solid.
[0810] (2) Using the above-mentioned compound (0.725 g) and the
title compound (0.714 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(8-quinolinesulfonyl)-1-piperazinyl-
]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.34 g) was obtained as
a white powder.
[0811] (3) Using the above-mentioned compound (1.34 g), and in the
same manner as in Example 133 (2), the title compound (0.56 g) was
obtained as a pale-yellow powder.
[0812] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.01-2.21(1H,m),
2.80-3.95(16H,m), 4.43-4.72(3H,m), 7.74(1H,dd,J=8.3, 4.2 Hz),
7.79(1H,t,J=7.9 Hz), 8.35-8.40(2H,m), 8.58(1H,dd,J=8.3, 1.7 Hz),
9.00(1H,brs), 9.06(1H,dd,J=4.2, 1.7 Hz), 10.60(1H,brs).
Example 206
Synthesis of
3-{(2S,4S)-4-[4-(1-ethoxycarbonyl-4-piperidinyl)-1-piperazinyl]-2-pyrroli-
dinylcarbonyl}-1,3-thiazolidine tetrahydrochloride
[0813] (1) Using 1-(9-fluorenylmethoxycarbonyl)piperazine (1.47 g)
and the title compound (1.30 g) of Reference Example 12, and in the
same manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(9-fluorenylmethoxycarbonyl)-1-pipe-
razinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.68 g) was
obtained as a white powder.
[0814] (2) The above-mentioned compound (1.68 g) was dissolved in
dichloromethane (30 mL), and piperidine (1.5 mL) was added thereto
at room temperature. The mixture was stirred for 4 hr. The solvent
was evaporated under reduced pressure, and the residue was purified
by silica gel chromatography to give
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(1-piperazinyl)-2-pyrrolidinylcarbonyl-
]-1,3-thiazolidine (206 mg) as a white solid.
[0815] (3) Using the above-mentioned compound (202 mg) and
1-ethoxycarbonyl-4-piperidone (90 .mu.L), and in the same manner as
in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(1-ethoxycarbonyl-4-piperidinyl)-1--
piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (168 mg) was
obtained as a white powder.
[0816] (4) Using the above-mentioned compound (168 mg), and in the
same manner as in Example 133 (2), the title compound (113 mg) was
obtained as a white powder.
[0817] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.18(3H,t,J=7.1 Hz),
1.53-1.65(2H,m), 1.81-1.95(1H,m), 2.01-2.21(2H,m),
2.70-4.20(21H,m), 4.04(2H,q,J=7.1 Hz), 4.47-4.73(3H,m),
8.89(1H,brs), 10.39(1H,brs), 11.46(1H,brs).
Example 207
Synthesis of
3-{(2S,4R)-4-[4-(4-nitrophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,-
3-thiazolidine dihydrochloride
[0818] (1)
3-((2S,4R)-4-Amino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-1,3-thia-
zolidine (title compound of Reference Example 15, 1 g) was
dissolved in N-methyl-2-pyrrolidone (20 mL), and
N,N-bis{2-[(methylsulfonyl)oxy]ethyl}-4-nitroaniline (1.27 g) and
N,N-diisopropylethylamine (1.73 mL) were added thereto. The mixture
was stirred at 80.degree. C. for 24 hr with heating. The reaction
mixture was added to saturated aqueous sodium hydrogencarbonate
solution, and the mixture was extracted with ethyl acetate. The
extract was washed with brine and the solvent was evaporated under
reduced pressure. The residue was purified by silica gel
chromatography to give
3-{(2S,4R)-1-tert-butoxycarbonyl-4-[4-(4-nitrophenyl)-1-piperazinyl]-2-py-
rrolidinylcarbonyl}-1,3-thiazolidine.
[0819] (2) This was dissolved in methanol (20 mL) and chloroform
(10 mL), and 4 mol/L hydrochloric acid-ethyl acetate (10 mL) was
added thereto. The mixture was stirred for 2 hr. The reaction
mixture was concentrated under reduced pressure, and saturated
aqueous sodium hydrogencarbonate solution was added to the residue.
The mixture was extracted with chloroform and the extract was
concentrated under reduced pressure. The residue was purified by
silica gel chromatography to give a free base (161 mg) of the title
compound. This was dissolved in ethanol (5 mL), and 4 mol/L
hydrochloric acid-ethyl acetate (0.21 mL) was added thereto. The
solvent was evaporated under reduced pressure to give the title
compound (128 mg) as a yellow powder.
[0820] .sup.1H-NMR(DMSO-d.sub.6).delta.2.22-2.46(1H,m),
2.75-2.99(1H,m), 3.00-3.20(2H,m), 3.20-4.30(13H,m),
4.40-5.07(3H,m), 7.16(2H,d,J=9.3 Hz), 8.12(2H,d,J=9.3 Hz).
Example 208
Synthesis of
3-{(2S,4S)-4-[4-(4-trifluoromethylphenyl)-1-piperazinyl]-2-pyrrolidinylca-
rbonyl}-1,3-thiazolidine trihydrochloride
[0821] (1) Using the title compound (450 mg) of Reference Example
12 and 1-(4-trifluoromethylphenyl)piperazine (414 mg), and in the
same manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[(4-(4-trifluoromethylphenyl)-1-pipera-
zinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (772 mg) was
obtained as a white solid.
[0822] (2) The above-mentioned compound (766 mg) was dissolved in
methanol (5 mL), and 1.1 mol/L hydrochloric acid-methanol (14 mL)
was added thereto. The mixture was stirred at room temperature for
4 days. The reaction mixture was concentrated under reduced
pressure, and ethyl acetate was added to the residue. The
precipitated solid was collected by filtration to give the title
compound (680 mg) as a pale-brown powder.
[0823] .sup.1H-NMR(DMSO-d.sub.6).delta.2.27-2.40(1H,m),
2.96-4.16(16H,m), 4.46-4.77(3H,m), 7.18(2H,d,J=8.8),
7.58(2H,d,J=8.8), 9.22(1H,brs), 10.73(1H,brs).
Example 209
Synthesis of
3-{(2S,4S)-4-[4-(3-cyano-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl-
}-1,3-thiazolidine trihydrochloride
[0824] (1) piperazine (125 g) was melted by heating at 150.degree.
C. and 2-chloro-3-cyanopyridine (20.0 g) was added thereto. The
mixture was stirred at 110.degree. C. for 2 hr. Water was added to
the reaction mixture and the mixture was extracted with chloroform.
The extract was washed with brine, dried and concentrated under
reduced pressure to give 1-(3-cyano-2-pyridyl)piperazine (24.2 g)
as a brown solid.
[0825] (2) Using the above-mentioned compound (0.621 g) and the
title compound (0.901 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3-cyano-2-pyridyl)-1-piperazinyl]--
2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.42 g) was obtained as a
white solid.
[0826] .sup.1H-NMR(CDCl.sub.3).delta.1.41(4.5H,s), 1.46(4.5H,s),
1.83-1.97(1H,m), 2.40-2.51(1H,m), 2.53-2.72(4H,m), 2.82-3.22(3H,m),
3.33(1H,t,J=9.9 Hz), 3.35-4.14(7H,m), 4.38-4.79(3H,m),
6.76(1H,dd,J=7.6, 4.7 Hz), 7.77(1H,dd,J=7.6, 1.7 Hz),
8.34(1H,dd,J=4.7, 1.7 Hz).
[0827] (3) The above-mentioned compound (1.42 g) was dissolved in
ethyl acetate (7.5 mL), and 4 mol/L hydrochloric acid-ethyl acetate
(7.5 mL) was added thereto. The mixture was stirred at room
temperature for 12 hr. The precipitated solid was collected by
filtration to give the title compound (1.00 g) as a white
powder.
[0828] .sup.1H-NMR(DMSO-d.sub.6).delta.2.26-2.40(1H,m),
2.93-3.18(3H,m), 3.2-4.8(16H,m), 7.09(1H,dd,J=7.7, 4.8),
8.19(1H,dd,J=7.7, 1.9), 8.49(1H,dd,J=4.8, 1.9), 9.16(1H,brs),
11.02(1H,brs), 12.7(1H,brs).
Example 210
Synthesis of
3-{(2S,4S)-4-[4-(3-chloro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbony-
l}-1,3-thiazolidine trihydrochloride
[0829] (1) piperazine (20.0 g) was melted by heating at 140.degree.
C. and 2,3-dichloropyridine (3.42 g) was added thereto. The mixture
was stirred at 120.degree. C. for 2 hr. Water was added to the
reaction mixture and the mixture was extracted with chloroform. The
extract was washed with brine, dried and concentrated under reduced
pressure to give 1-(3-chloro-2-pyridyl)piperazine (4.68 g) as a
dark-brown oil.
[0830] (2) Using the above-mentioned compound (0.712 g) and the
title compound (0.901 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3-chloro-2-pyridyl)-1-piperazinyl]-
-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.41 g) was obtained as
a white solid.
[0831] .sup.1H-NMR(CDCl.sub.3).delta.1.41(4.5H,s), 1.46(4.5H,s),
1.84-1.99(1H,m), 2.40-2.51(1H,m), 2.53-2.73(4H,m), 2.79-3.18(3H,m),
3.28-3.45(5H,m), 3.58-4.12(3H,m), 4.38-4.78(3H,m),
6.84(1H,dd,J=7.7, 4.7 Hz), 7.58(1H,dd,J=7.7, 1.5 Hz),
8.18(1H,dd,J=4.7, 1.5 Hz).
[0832] (3) The above-mentioned compound (1.40 g) was dissolved in
ethanol (4 mL), and 4.1 mol/L hydrochloric acid-ethanol (4 mL) was
added thereto. The mixture was stirred at room temperature for 14
hr. The precipitated solid was collected by filtration to give the
title compound (1.14 g) as a white powder.
[0833] .sup.1H-NMR(DMSO-d.sub.6).delta.2.30-2.43(1H,m),
2.95-3.18(3H,m), 3.2-4.2(13H,m), 4.45-4.80(3H,m), 7.12(1H,dd,J=7.8,
4.7 Hz), 7.89(1H,dd,J=7.8, 1.5 Hz), 8.28(1H,dd,J=4.7, 1.5 Hz),
9.16(1H,brs), 10.96(1H,brs), 12.55(1H,brs).
Example 211
Synthesis of
3-{(2S,4S)-4-[4-(5-ethoxycarbonyl-2-pyridyl)-1-piperazinyl]-2-pyrrolidiny-
lcarbonyl}-1,3-thiazolidine trihydrochloride
[0834] (1) Ethyl 6-chloronicotinate (1.12 g) was dissolved in DMF
(30 mL), and 1-tert-butoxycarbonylpiperazine (1.24 g) and potassium
carbonate (1.00 g) were added thereto. The mixture was stirred at
80.degree. C. for 18 hr. Water (100 mL) was added to the reaction
mixture and the mixture was extracted with ethyl acetate. The
extract was washed successively with saturated aqueous sodium
hydrogencarbonate solution and brine and dried. The solvent was
evaporated under reduced pressure. The residue was dissolved in
dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added
thereto at room temperature. The mixture was stirred for 2 hr and
the reaction mixture was concentrated under reduced pressure. Water
(50 mL) was added to the residue, and the mixture was washed with
diethyl ether. The aqueous layer was basified with aqueous sodium
hydrogen carbonate solution. The mixture was extracted with
chloroform. The extract was dried and the mixture was concentrated
under reduced pressure to give
1-(5-ethoxycarbonyl-2-pyridyl)piperazine (1.17 g) as an oil.
[0835] (2) Using the above-mentioned compound (1.17 g) and the
title compound (1.47 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-ethoxycarbonyl-2-pyridyl)-1-pipe-
razinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (2.07 g) as a
white solid.
[0836] (3) Using the above-mentioned compound (1.06 g), and in the
same manner as in Example 133 (2), the title compound (1.06 g) was
obtained as a white powder.
[0837] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.30(3H,t,J=7.1 Hz),
2.23-2.43(1H,m), 2.92-4.90(19H,m), 4.28(2H,q,J=7.1 Hz),
7.05(1H,d,J=9.1 Hz), 8.04(1H,dd,J=9.1, 2.3 Hz), 8.69(1H,d,J=2.3
Hz), 9.13(1H,brs), 10.91(1H,brs), 12.58(1H,brs).
Example 212
Synthesis of
3-{(2S,4S)-4-[4-(5-carboxy-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbon-
yl}-1,3-thiazolidine trihydrochloride
[0838] 6 mol/L Hydrochloric acid was added to
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[(4-(5-ethoxycarbonyl-2-pyridyl)-1-pip-
erazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine trihydrochloride
[product of Example 211 (2), 1.00 g] and the mixture was refluxed
for 2 hr. The solvent was evaporated under reduced pressure, and
the residue was purified by HPLC. This was converted to
hydrochloride with 4 mol/L hydrochloric acid-1,4-dioxane to give
the title compound (158 mg) as a white powder.
[0839] .sup.1H-HMR(500 MHz,DMSO-d.sub.6).delta.2.21-2.41(1H,m),
2.90-4.90(19H,m), 7.04(1H,d,J=9.0 Hz), 8.03(1H,dd,J=9.0, 2.2 Hz),
8.67(1H,d,J=2.2 Hz), 9.12(1H,brs), 10.80(1H,brs),
12.50(1H,brs).
Example 213
Synthesis of
3-{(2S,4S)-4-[(4-(5-carbamoyl-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcar-
bonyl}-1,3-thiazolidine trihydrochloride
[0840] (1) Using 6-chloronicotinamide (5.00 g) and piperazine (27.6
g), and by reaction in the same manner as in Example 196 (1) at
100.degree. C., 1-(5-carbamoyl-2-pyridyl)piperazine (0.41 g) was
obtained as a yellow powder.
[0841] (2) Using the above-mentioned compound (370 mg) and the
title compound (450 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-carbamoyl-2-pyridyl)-1-piperazin-
yl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (350 mg) was obtained
as a white solid.
[0842] (3) Using the above-mentioned compound (347 mg), and in the
same manner as in Example 133 (2), the title compound (332 mg) was
obtained as a white powder.
[0843] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.81-2.01(1H,m),
2.93-4.10(14H,m), 4.28-4.75(5H,m), 7.08(1H,d,J=9.0 Hz),
7.26(1H,brs), 7.91(1H,brs), 8.10(1H,dd,J=9.0, 2.3 Hz),
8.66(1H,d,J=2.3 Hz), 9.12(1H,brs), 10.87(1H,brs),
12.51(1H,brs).
Example 214
Synthesis of
3-{(2S,4R)-4-[4-(5-cyano-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl-
}-1,3-thiazolidine trihydrochloride
[0844] (1) The title compound (1.74 g) of Reference Example 11 and
triethylamine (1.0 mL) were dissolved in dichloromethane (35 mL),
and methanesulfonyl chloride (0.49 mL) was added dropwise under
ice-cooling. The mixture was stirred for 3 hr. Iced water was added
to the reaction mixture and the mixture was extracted with
dichloromethane. The extract was washed with brine, dried and
concentrated under reduced pressure to give
3-{(2S,4S)-1-tert-butoxycarbonyl-4-methanesulfonyloxy-2-pyrrolidinyl-
carbonyl}-1,3-thiazolidine (2.03 g) as a pale-brown solid.
[0845] (2) The above-mentioned compound (1.10 g) and
1-(5-cyano-2-pyridyl)piperazine (1.12 g) were dissolved in
1-methyl-2-pyrrolidone (20 mL), and the mixture was stirred at
90.degree. C. for 12 hr. The reaction mixture was added to water
and the mixture was extracted with ethyl acetate. The extract was
concentrated under reduced pressure and the residue was purified by
column chromatography to give
3-{(2S,4R)-1-tert-butoxycarbonyl-4-[4-(5-cyano-2-pyridyl)-1-piperazinyl]--
2-pyrrolidinylcarbonyl}-1,3-thiazolidine (170 mg).
[0846] .sup.1H-NMR(CDCl.sub.3).delta.1.41(4.5H,s), 1.46(4.5H,s),
2.07-2.20(2H,m), 2.45-2.65(4H,m), 3.00-3.40(4H,m), 3.57-3.79(5H,m),
3.81-4.00(2H,m), 4.45-4.83(3H,m), 6.59(1H,d,J=9.3 Hz),
7.61(1H,dd,J=9.3, 1.9 Hz), 8.40(1H,d,J=1.9 Hz).
[0847] (3) The above-mentioned compound (150 mg) was suspended in
tetrahydrofuran (40 mL), and 4 mol/L hydrochloric acid-ethyl
acetate (40 mL) was added thereto. The mixture was stirred at
55.degree. C. for 5 hr. After allowing to cool, the precipitated
solid was collected by filtration to give the title compound (130
mg) as a white powder.
[0848] .sup.1H-NMR(DMSO-d.sub.6).delta.2.26-2.45(1H,m),
2.80-3.00(1H,m), 3.01-3.27(3H,m), 3.28-3.94(8H,m), 3.95-4.15(3H,m),
4.38-4.77(3H,m), 4.84-5.01(1H,m), 7.12(1H,d,J=9.3 Hz),
8.00(1H,dd,J=9.3, 2.1 Hz), 8.58(1H,d,J=2.1 Hz), 9.22(1H,brs).
Example 215
Synthesis of
3-{(2S,4S)-4-[(4-(3-chloro-5-trifluoromethyl-2-pyridyl)-1-piperazinyl]-2--
pyrrolidinylcarbonyl}-1,3-thiazolidine trihydrochloride
[0849] (1) piperazine (40 g) was melted by heating at 140.degree.
C. and 2,3-dichloro-5-trifluoromethylpyridine (10 g) was added
thereto.
[0850] The mixture was stirred at 120.degree. C. for 2 hr. Water
was added to the reaction mixture and the mixture was extracted
with chloroform. The extract was washed with brine, dried and
concentrated under reduced pressure to give
1-(3-chloro-5-trifluoromethyl-2-pyridyl)piperazine (12.8 g) as a
brown solid.
[0851] (2) Using the above-mentioned compound (0.956 g) and the
title compound (0.901 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3-chloro-5-trifluoromethyl-2-pyrid-
yl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.64
g) was obtained as a white solid.
[0852] .sup.1H-NMR(CDCl.sub.3).delta.1.41(4.5H,s), 1.46(4.5H,s),
1.83-1.98(1H,m), 2.38-2.50(1H,m), 2.52-2.70(4H,m), 2.78-3.19(3H,m),
3.33(1H,t,J=10.1 Hz), 3.47-4.13(7H,m), 4.37-4.81(3H,m), 7.75(1H,s),
8.38(1H,s).
[0853] (3) The above-mentioned compound (1.64 g) was dissolved in
ethanol (4 mL), and 4.1 mol/L hydrochloric acid-ethanol (4 mL) was
added thereto. The mixture was stirred at room temperature for 5
days. The precipitated solid was collected by filtration to give
the title compound (1.20 g) as a white powder.
[0854] H-NMR(DMSO-d.sub.6).delta.2.30-2.47(1H,m), 2.92-4.2(16H,m),
4.45-4.78(3H,m), 8.31(1H,d,J=1.9 Hz), 8.63(1H,d,J=1.9 Hz),
9.15(1H,brs), 10.77(1H,brs), 12.6(1H,brs).
Example 216
Synthesis of
3-{(2S,4S)-4-[4-(3-chloro-5-ethoxycarbonyl-2-pyridyl)-1-piperazinyl]-2-py-
rrolidinylcarbonyl}-1,3-thiazolidine trihydrochloride
[0855] (1) 5,6-Dichloronicotinic acid (4.90 g) was dissolved in
ethanol (40 mL), and thionyl chloride (2.0 mL) was added thereto
under ice-cooling. The mixture was refluxed for 1.5 hr. The
reaction mixture was concentrated under reduced pressure, and
saturated aqueous sodium hydrogencarbonate solution was added to
the residue. The mixture was extracted with ethyl acetate. The
extract was dried and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel chromatography to
give ethyl 5,6-dichloronicotinate (4.85 g) as a white solid.
[0856] (2) piperazine (19.0 g) was melted by heating at 140.degree.
C. and the above-mentioned compound (4.80 g) was added thereto. The
mixture was stirred at 120.degree. C. for 2 hr. Water was added to
the reaction mixture and the mixture was extracted with chloroform.
The extract was washed with brine, dried and concentrated under
reduced pressure to give
1-(3-chloro-5-ethoxycarbonyl-2-pyridyl)piperazine (5.64 g) as a
dark brown solid.
[0857] (3) Using the above-mentioned compound (5.12 g) and the
title compound (4.75 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3-chloro-5-ethoxycarbonyl-2-pyridy-
l)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (7.53 g)
was obtained as a white solid.
[0858] .sup.1H-NMR(CDCl.sub.3).delta.1.38(3H,t,J=7.1 Hz),
1.41(4.5H,s), 1.46(4.5H,s), 1.83-1.98(1H,m), 2.38-2.50(1H,m),
2.53-2.73(4H,m), 2.78-3.20(3H,m), 3.33(1H,t,J=10.3 Hz),
3.45-4.13(7H,m), 4.36(2H,q,J=7.1 Hz), 4.32-4.78(3H,m),
8.11(1H,d,J=1.8 Hz), 8.74(1H,d,J=1.8 Hz).
[0859] (4) The above-mentioned compound (1.00 g) was dissolved in
dichloroethane (10 mL) and trifluoroacetic acid (5 mL) was added
thereto. The mixture was stirred at room temperature for 3 hr. The
reaction mixture was concentrated under reduced pressure, and the
residue was dissolved in ethyl acetate (10 mL). 4 mol/L
Hydrochloric acid-ethyl acetate (2.25 mL) was added thereto, and
the mixture was stirred at room temperature for 1 hr. The
precipitated solid was collected by filtration to give the title
compound (0.82 g) as a white powder.
[0860] .sup.1H-NMR(DMSO-d.sub.6).delta.1.32(3H,t,J=7.1 Hz),
2.26-2.40(1H,m), 2.93-3.18(3H,m), 3.25-4.15(13H,m), 4.32(2H,q,J=7.1
Hz), 4.4-4.78(3H,m), 8.19(1H,d,J=2.0 Hz), 8.73(1H,d,J=2.0 Hz),
9.16(1H,brs), 10.78(1H,brs), 12.5(1H,brs).
Example 217
Synthesis of
3-{(2S,4S)-4-[(4-(5-carboxy-3-chloro-2-pyridyl)-1-piperazinyl]-2-pyrrolid-
inylcarbonyl}-1,3-thiazolidine trihydrochloride
[0861] (1)
3-{(2S,4S)-1-tert-Butoxycarbonyl-4-[4-(3-chloro-5-ethoxycarbonyl-2-pyridy-
l)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine [product
of Example 216 (3), 6.49 g] was dissolved in ethanol (30 mL), and
aqueous solution (30 mL) of lithium hydroxide (0.59 g) was added
thereto. The mixture was stirred at room temperature for 19 hr and
ethanol was evaporated under reduced pressure. The concentrate was
washed with ethyl acetate, and 1 mol/L hydrochloric acid was added
thereto. The precipitated solid was collected by filtration to give
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-carboxy-3-chloro-2-pyridyl)-1-pi-
perazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (2.64 g) as a
white solid.
[0862] .sup.1H-NMR(DMSO-d.sub.6).delta.1.33(4.5H,s), 1.41(4.5H,s),
1.97-2.15(1H,m), 2.77-2.87(1H,m), 2.95-4.25(15H,m),
4.40-4.76(3H,m), 8.16(1H,d,J=2.0 Hz), 8.71(1H,d,J=2.0 Hz),
11.40(1H,brs).
[0863] (2) Using the above-mentioned compound (500 mg), and in the
same manner as in Example 216 (4), the title compound (437 mg) was
obtained as a white powder.
[0864] .sup.1H-NMR(DMSO-d.sub.6).delta.2.27-2.42(1H,m),
2.94-3.18(3H,m), 3.2-4.8(16H,m), 8.17(1H,d,J=2.0 Hz),
8.71(1H,d,J=2.0 Hz), 9.16(1H,brs), 10.95(1H,brs), 12.60(1H,brs)
Example 218
Synthesis of
3-{(2S,4S)-4-[4-(5-carbamoyl-3-chloro-2-pyridyl)-1-piperazinyl]-2-pyrroli-
dinylcarbonyl}-1,3-thiazolidine trihydrochloride
[0865] (1)
3-{(2S,4S)-1-tert-Butoxycarbonyl-4-[4-(5-carboxy-3-chloro-2-pyridyl)-1-pi-
perazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine [product of
Example 217 (1), 2.63 g] and ammonium chloride (0.54 g) were
dissolved in DMF (30 mL), and N-methylmorpholine (1.1 mL), HOBT
(1.53 g) and EDC hydrochloride (1.15 g) were successively added
thereto. The mixture was stirred at room temperature for 4 hr. The
reaction mixture was concentrated under reduced pressure, and
saturated aqueous sodium hydrogencarbonate solution was added to
the residue. The mixture was extracted with ethyl acetate. The
extract washed with brine and dried. The solvent was evaporated
under reduced pressure to give
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-carbamoyl-3-chloro-2-pyridyl)-1--
piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (2.50 g) as a
white solid.
[0866] .sup.1H-NMR(CDCl.sub.3).delta.1.41(4.5H,s), 1.45(4.5H,s),
1.84-1.98(1H,m), 2.39-2.52(-1H,m), 2.53-2.73(4H,m),
2.78-3.18(3H,m), 3.34(1H,t,J=10.0 Hz), 3.45-4.13(7H,m),
4.38-4.78(3H,m), 5.87(1H,brs), 6.17(1H,brs), 8.07(1H,d,J=2.0 Hz),
8.56(1H,d,J=2.0 Hz).
[0867] (2) The above-mentioned compound (683 mg) was dissolved in
ethanol (2 mL), and 4.1 mol/L hydrochloric acid-ethanol (2 mL) was
added thereto. The mixture was stirred at room temperature for 22
hr. The precipitated solid was collected by filtration to give the
title compound (616 mg) as a white powder.
[0868] .sup.1H-NMR(DMSO-d.sub.6).delta.2.26-2.42(1H,m),
2.92-4.3(16H,m), 4.46-4.78(3H,m), 7.56(1H,brs), 8.12(1H,brs),
8.26(1H,s), 8.73(1H,s), 9.15(1H,brs), 10.83(1H,brs),
12.52(1H,brs).
Example 219
Synthesis of
3-{(2S,4S)-4-[4-(3-chloro-5-cyano-2-pyridyl)-1-piperazinyl]-2-pyrrolidiny-
lcarbonyl}-1,3-thiazolidine trihydrochloride
[0869] (1)
3-{(2S,4S)-1-tert-Butoxycarbonyl-4-[4-(5-carbamoyl-3-chloro-2-pyridyl)-1--
piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine [product of
Example 218 (1), 1000 mg] and imidazole (195 mg) were dissolved in
pyridine (10 mL), and phosphorus oxychloride (0.35 mL) was added
thereto under ice-cooling. The mixture was stirred at room
temperature for 13 hr and saturated aqueous sodium
hydrogencarbonate solution was added to the reaction mixture. The
mixture was extracted with chloroform. The extract was washed with
brine, dried and concentrated under reduced pressure. The residue
was purified by silica gel chromatography to give
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[(4-(3-chloro-5-cyano-2-2-pyridyl)-1-p-
iperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (628 mg) as a
white solid.
[0870] .sup.1H-NMR(CDCl.sub.3).delta.1.41(4.5H,s), 1.45(4.5H,s),
1.83-1.98(1H,m), 2.38-2.70(5H,m), 2.80-3.20(3H,m), 3.33(1H,t,J=10.0
Hz), 3.53-4.13(7H,m), 4.37-4.82(3H,m), 7.73(1H,d,J=1.9 Hz),
8.37(1H,d,J=1.9 Hz).
[0871] (2) The above-mentioned compound (622 mg) was dissolved in
ethyl acetate (1.5 mL), and 4 mol/L hydrochloric acid-ethyl acetate
(1.5 mL) was added thereto. The mixture was stirred at room
temperature for 14 hr. The reaction mixture was concentrated under
reduced pressure, and saturated aqueous sodium hydrogencarbonate
solution was added to the residue. The mixture was extracted with
chloroform. The extract was dried and concentrated under reduced
pressure. The residue was purified by silica gel chromatography to
give a white solid. This was dissolved in ethyl acetate (6 mL) and
4 mol/L hydrochloric acid-ethyl acetate (0.9 mL) was added thereto.
The mixture was stirred at room temperature for 1 hr. The
precipitated solid was collected by filtration to give the title
compound (388 mg) as a white powder.
[0872] .sup.1H-NMR(DMSO-d.sub.6).delta.2.10-2.26(1H,m),
2.90-4.2(16H,m), 4.47-4.78(3H,m), 8.41(1H,d,J=1.9 Hz),
8.69(1H,d,J=1.9 Hz), 9.13(1H,brs), 10.81(1H,brs),
12.57(1H,brs).
Example 220
Synthesis of
3-{(2S,4S)-4-[4-(3,5-dichloro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcar-
bonyl}-1,3-thiazolidine trihydrochloride
[0873] (1) piperazine (24.0 g) was melted by heating at 140.degree.
C. and 2,3,5-trichloropyridine (5.00 g) was added thereto. The
mixture was stirred at 120.degree. C. for 2 hr. Water was added to
the reaction mixture and the mixture was extracted with chloroform.
The extract was washed with brine, dried and concentrated under
reduced pressure to give 1-(3,5-dichloro-2-pyridyl)piperazine (6.43
g) as a brown solid.
[0874] (2) Using the above-mentioned compound (0.832 g) and the
title compound (0.901 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3,5-dichloro-2-pyridyl)-1-piperazi-
nyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.35 g) was obtained
as a white solid.
[0875] .sup.1H-NMR(CDCl.sub.3).delta.1.41(4.5H,s), 1.46(4.5H,s),
1.82-1.98(1H,m), 2.38-2.50(1H,m), 2.53-2.73(4H,m), 2.78-3.22(3H,m),
3.28-3.44(5H,m), 3.62-4.14(3H,m), 4.38-4.80(3H,m), 7.59(1H,d,J=2.2
Hz), 8.12(1H,d,J=2.2 Hz).
[0876] (3) The above-mentioned compound (1.34 g) was dissolved in
ethanol (3.5 mL), and 4.1 mol/L hydrochloric acid-ethanol (3.5 mL)
was added thereto. The mixture was stirred at room temperature for
15 hr. The precipitated solid was collected by filtration to give
the title compound (1.10 g) as a white powder.
[0877] .sup.1H-NMR(DMSO-d.sub.6).delta.2.20-2.38(1H,m),
2.90-4.15(16H,m), 4.46-4.78(3H,m), 8.15(1H,d,J=2.3 Hz),
8.73(1H,d,J=2.3 Hz), 9.13(1H,brs), 10.84(1H,brs),
12.55(1H,brs).
Example 221
Synthesis of
3-{(2S,4S)-4-[(4-(3,5-dichloro-4-pyridyl)-1-piperazinyl]-2-pyrrolidinylca-
rbonyl}-1,3-thiazolidine trihydrochloride
[0878] (1) Using 1-(3,5-dichloro-4-pyridyl)piperazine (0.766 g) and
the title compound (0.901 g) of Reference Example 12, and in the
same manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[(4-(3,5-dichloro-4-pyridyl)-1-piperaz-
inyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.53 g) was
obtained as a white solid.
[0879] .sup.1H-NMR(CDCl.sub.3).delta.1.41(4.5H,s), 1.46(4.5H,s),
1.82-1.98(1H,m), 2.40-2.52(1H,m), 2.55-2.72(4H,m), 2.83-3.21(3H,m),
3.28-3.45(5H,m), 3.62-4.14(3H,m), 4.38-4.81(3H,m), 8.33(2H,s).
[0880] (2) The above-mentioned compound (1.53 g) was dissolved in
ethyl acetate (7.5 mL), and 4 mol/L hydrochloric acid-ethyl acetate
(7.5 mL) was added thereto. The mixture was stirred at room
temperature for 13 hr. The precipitated solid was collected by
filtration to give the title compound (1.64 g) as a white
powder.
[0881] .sup.1H-NMR(DMSO-d.sub.6).delta.2.27-2.43(1H,m),
2.95-4.2(16H,m), 4.45-4.78(3H,m), 8.52(2H,s), 9.14(1H,brs),
10.97(1H,brs), 12.6(1H,brs).
Example 222
Synthesis of
3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-5-pyrazolyl)-1-piperazinyl]-2-pyrrolid-
inylcarbonyl}-1,3-thiazolidine trihydrochloride
[0882] (1) 1-tert-Butoxycarbonylpiperazine (5.02 g) was dissolved
in DMF (90 mL), and diketene (2.50 mL) was added thereto at room
temperature. The mixture was stirred for 1.5 hr and the solvent was
evaporated under reduced pressure. Water was added to the residue,
and the mixture was extracted with ethyl acetate. The extract was
washed with brine and dried. The solvent was evaporated under
reduced pressure to give
1-acetoacetyl-4-tert-butoxycarbonylpiperazine (6.26 g) as a
pale-brown powder.
[0883] (2) The above-mentioned compound (6.24 g) was dissolved in
ethanol (500 mL), and phenylhydrazine (2.27 mL) and methanesulfonic
acid (350 .mu.L) were added at room temperature. The mixture was
stirred for 14 hr and pyridine (6 mL) was added to the reaction
mixture. The solvent was evaporated under reduced pressure and the
residue was dissolved in pyridine (250 mL). Phosphorus oxychloride
(5.0 mL) was added thereto at room temperature and the mixture was
stirred for 20 hr. The solvent was evaporated under reduced
pressure, the residue was acidified with dilute hydrochloric acid
to pH 3. The mixture was extracted with ethyl acetate. The extract
was washed successively with saturated aqueous sodium
hydrogencarbonate solution and brine and dried. The solvent was
evaporated under reduced pressure and the residue was purified by
silica gel chromatography to give
1-tert-butoxycarbonyl-4-(3-methyl-1-phenyl-5-pyrazolyl)piperazine
(935 mg) as an oil.
[0884] (3) The above-mentioned compound (935 mg) was dissolved in
dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added
thereto at room temperature. The mixture was stirred for 1.5 hr.
The solvent was evaporated under reduced pressure, and water (50
mL) was added to the residue. The mixture was washed with diethyl
ether. The aqueous layer was basified with aqueous sodium hydrogen
carbonate solution, and the mixture was extracted with chloroform.
The extract was dried, and evaporated under reduced pressure to
give 1-(3-methyl-1-phenyl-5-pyrazolyl)piperazine (584 mg) as a
brown powder.
[0885] (4) Using the above-mentioned compound (584 mg) and the
title compound (604 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3-methyl-1-phenyl-5-pyrazolyl)-1-p-
iperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (846 mg) was
obtained as a pale-yellow powder.
[0886] (5) Using the above-mentioned compound (844 mg), and in the
same manner as in Example 133 (2), the title compound (751 mg) was
obtained as a white solid.
[0887] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.17(3H,s),
2.18-2.38(1H,m), 2.90-4.10(16H,m), 4.46-4.74(3H,m), 5.93(1H,s),
7.31(1H,m), 7.47(2H,m), 7.79(2H,m), 9.09(1H,brs), 10.91(1H,brs),
12.40(1H,brs).
Example 223
Synthesis of
3-{(2S,4S)-4-[4-(1-tert-butyl-3-methyl-5-pyrazolyl)-1-piperazinyl]-2-pyrr-
olidinylcarbonyl}-1,3-thiazolidine trihydrochloride
[0888] (1) 1-Acetoacetyl-4-tert-butoxycarbonylpiperazine [product
of Example 222 (1), 3.92 g] was dissolved in ethanol (300 ml), and
tert-butylhydrazine hydrochloride (1.81 g) and molecular sieves 3A
(10 g) were added thereto at room temperature. The mixture was
stirred for 15 hr. The reaction mixture was filtrated and the
filtrate was concentrated under reduced pressure. The residue was
dissolved in pyridine (200 mL), and phosphorus oxychloride (3.0 mL)
was added thereto at room temperature. The mixture was stirred for
24 hr. The reaction mixture was concentrated under reduced
pressure, the residue was acidified with dilute hydrochloric acid
to pH 3. The mixture was extracted with ethyl acetate. The extract
was washed successively with saturated aqueous sodium
hydrogencarbonate solution and brine and dried. The solvent was
evaporated under reduced pressure and the residue was purified by
silica gel chromatography to give
1-tert-butoxycarbonyl-4-(1-tert-butyl-3-methyl-5-pyrazolyl)piperazine
(886 mg) as an oil.
[0889] (2) Using the above-mentioned compound (880 mg), and in the
same manner as in Example 222 (3),
1-(3-methyl-1-tert-butyl-5-pyrazolyl)piperazine (607 mg) was
obtained as a pale-yellow powder.
[0890] (3) Using the above-mentioned compound (0.607 g) and the
title compound (0.781 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3-methyl-1-tert-butyl-5-pyrazolyl)-
-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.17 g)
was obtained as a white powder.
[0891] (4) Using the above-mentioned compound (1.17 g), and in the
same manner as in Example 133 (2), the title compound (0.902 g) was
obtained as a white solid.
[0892] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.56(9H,s),
2.09(3H,s), 2.27-2.47(1H,m), 2.90-4.20(16H,m), 4.48-4.78(3H,m),
6.00(1H,s), 9.12(1H,brs), 11.12(1H,brs), 12.49(1H,brs).
Example 224
Synthesis of
3-{(2S,4S)-4-[4-(1-phenyl-2-imidazolyl)-1-piperazinyl]-2-pyrrolidinylcarb-
onyl}-1,3-thiazolidine trihydrochloride
[0893] (1) 1-Benzyloxycarbonylpiperazine (5.00 g) was dissolved in
acetone (50 mL), and phenyl isothiocyanate (2.9 mL) was added
thereto under ice-cooling. The mixture was stirred at room
temperature for 1 hr. The precipitated solid was collected by
filtration to give
1-(anilinocarbothioyl)-4-(benzyloxycarbonyl)piperazine (5.08 g) as
a white powder.
[0894] (2) The above-mentioned compound (5.07 g) was dissolved in
methanol (100 mL) and dichloromethane (20 mL), methyl iodide (1.4
mL) were added thereto. The mixture was stirred at room temperature
for 17 hr. The reaction mixture was concentrated under reduced
pressure, and saturated aqueous sodium hydrogencarbonate solution
was added to the residue. The mixture was extracted with
dichloromethane, and the extract was washed with brine, dried and
concentrated under reduced pressure to give
1-benzyloxycarbonyl-4-[(methylthio)phenyliminomethyl]piperazine
(5.71 g) as a slightly yellow oil.
[0895] (3) The above-mentioned compound (3.00 g) and
aminoacetaldehyde dimethyl acetal (1.8 mL) were dissolved in
pyridine (15 mL), and the mixture was stirred at 100.degree. C. for
2 days with heating. The reaction mixture was concentrated under
reduced pressure, and saturated aqueous sodium hydrogencarbonate
solution was added to the residue. The mixture was extracted with
chloroform and the extract was washed with brine, dried and
concentrated under reduced pressure. The residue was dissolved in 2
mol/L hydrochloric acid (30 mL), and heated at 100.degree. C. for 2
hr. Saturated aqueous sodium hydrogencarbonate solution was added
to the reaction mixture, and the mixture was extracted with
chloroform. The extract was washed with brine, dried and
concentrated under reduced pressure. The residue was purified by
silica gel chromatography to give
1-benzyloxycarbonyl-4-(1-phenyl-2-imidazolyl)piperazine (1.16 g) as
a brown oil.
[0896] (4) The above-mentioned compound (1.16 g) was dissolved in
methanol (30 mL). The solution was stirred in the presence of 10%
palladium/carbon (232 mg) under a hydrogen atomosphere (1 atm) at
room temperature for 20 hr. The reaction mixture was filtrated and
the filtrate was concentrated under reduced pressure to give
1-(1-phenyl-2-imidazolyl)piperazine (0.742 g) as a white solid.
[0897] (5) Using the above-mentioned compound (0.740 g) and the
title compound (0.901 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(1-phenyl-2-imidazolyl)-1-piperazin-
yl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.30 g) was obtained
as a white solid.
[0898] .sup.1H-NMR(CDCl.sub.3).delta.1.39(4.5H,s), 1.44(4.5H,s),
1.75-1.92(1H,m), 2.36-2.57(5H,m), 2.74-2.89(1H,m), 2.93-3.17(6H,m),
3.25(1H,t,J=10.0 Hz), 3.60-4.08(3H,m), 4.34-4.77(3H,m),
6.83-6.88(2H,m), 7.34(1H,t,J=7.1 Hz), 7.43-7.54(4H,m).
[0899] (6) The above-mentioned compound (1.30 g) was dissolved in
ethanol (3 ml), and 4.1 mol/L hydrochloric acid-ethanol (3 mL) was
added thereto. The mixture was stirred at room temperature for 18
hr. The precipitated solid was collected by filtration to give the
title compound (1.15 g) as a white powder.
[0900] .sup.1H-NMR(DMSO-d.sub.6).delta.2.10-2.26(1H,m),
2.83-4.05(16H,m), 4.43-4.77(3H,m), 7.48(1H,d,J=2.3 Hz),
7.53(1H,d,J=2.3 Hz), 7.54-7.72(5H,m), 9.07(1H,brs),
10.98(1H,brs).
Example 225
Synthesis of
3-{(2S,4S)-4-[4-(5-methyl-1-phenyl-2-imidazolyl)-1-piperazinyl]-2-pyrroli-
dinylcarbonyl}-1,3-thiazolidine trihydrochloride
[0901] (1)
1-Benzyloxycarbonyl-4-[(methylthio)phenyliminomethyl]piperazine
[product of Example 224 (2), 2.70 g] and propargylamine (2.3 mL)
were dissolved in 1-butanol (25 mL), and p-toluenesulfonic acid
monohydrate (156 mg) was added thereto. The mixture was refluxed
for 20 hr. The reaction mixture was concentrated under reduced
pressure, and saturated aqueous sodium hydrogencarbonate solution
was added to the residue. The mixture was extracted with
chloroform, and the extract was washed with brine, dried and
concentrated under reduced pressure. The residue was purified by
silica gel chromatography to give
1-benzyloxycarbonyl-4-(5-methyl-1-phenyl-2-imidazolyl)piperazine
(1.82 g) as a brown oil.
[0902] (2) Using the above-mentioned compound (1.16 g), and in the
same manner as in Example 224 (4),
1-(5-methyl-1-phenyl-2-imidazolyl)piperazine (1.23 q) was obtained
as a brown solid.
[0903] (3) Using the above-mentioned compound (0.800 g) and the
title compound (0.901 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-methyl-1-phenyl-2-imidazolyl)-1--
piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.20 g) was
obtained as a white solid.
[0904] .sup.1H-NMR(CDCl.sub.3).delta.1.38(4.5H,s), 1.43(4.5H,s),
1.75-1.88(1H,m), 1.99(3H,s), 2.28-2.46(5H,m), 2.68-2.83(1H,m),
2.90-3.16(6H,m), 3.22(1H,t,J=10.1 Hz), 3.57-4.07(3H,m),
4.32-4.75(3H,m), 6.57(1H,s), 7.27-7.53(5H,m).
[0905] (4) The above-mentioned compound (1.19 g) was dissolved in
ethanol (3 mL), and 4.1 mol/L hydrochloric acid-ethanol (3 mL) was
added thereto. The mixture was stirred at room temperature for 13
hr. The precipitated solid was collected by filtration to give the
title compound (0.913 g) as a white powder.
[0906] .sup.1H-NMR(DMSO-d.sub.6).delta.2.00-2.18(1H,m),
2.79-3.93(16H,m), 4.42-4.76(3H,m), 7.23(1H,s), 7.58-7.72(5H,m),
9.02(1H,brs), 10.86(1H,brs), 14.01(1H,brs).
Example 226
Synthesis of
3-{(2S,4S)-4-[4-(4-phenyl-2-thiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbo-
nyl}-1,3-thiazolidine trihydrochloride
[0907] (1) Phenacyl bromide (4 g) was dissolved in acetonitrile (30
mL), and sodium thiocyanate (1.8 g) was added at room temperature
with stirring. The reaction mixture was concentrated under reduced
pressure, and brine was added to the residue. The mixture was
extracted with ethyl acetate. The extract was dried, and the
solvent was evaporated under reduced pressure to give
2-isocyanatoacetophenone (3.53 g) as white crystals.
[0908] (2) piperazine (3.8 g) was dissolved in ethanol (40 mL), and
a solution of the above-mentioned compound (3.53 g) in ethyl
acetate (10 mL) was added thereto. The mixture was heated at
70.degree. C. for 1 hr. The reaction mixture was concentrated under
reduced pressure, and brine was added to the residue. The mixture
was extracted with ethyl acetate, and the extract was dried and
concentrated under reduced pressure. The residue was purified by
silica gel chromatography to give
4-phenyl-2-(1-piperazinyl)thiazole (2.38 g) as a yellow oil.
[0909] (3) Using the above-mentioned compound (0.810 g) and the
title compound (0.901 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-phenyl-2-thiazolyl)-1-piperaziny-
l]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.59 g) was obtained
as a pale-yellow solid.
[0910] .sup.1H-NMR(CDCl.sub.3).delta.1.41(4.5H,s), 1.46(4.5H,s),
1.84-1.98(1H,m), 2.40-2.72(5H,m), 2.80-3.18(3H,m), 3.34(1H,t,J=9.9
Hz), 3.49-4.15(7H,m), 4.38-4.80(3H,m), 6.78(1H,s),
7.26-7.46(13H,m), 7.83(2H,d,J=7.1 Hz).
[0911] (4) The above-mentioned compound (1.59 g) was dissolved in
ethanol (6 mL), and 4.1 mol/L hydrochloric acid-ethanol (6 mL) was
added thereto. The mixture was stirred at room temperature for 12
hr. The precipitated solid was collected by filtration to give the
title compound (1.41 g) as a pale-brown powder.
[0912] .sup.1H-NMR(DMSO-d.sub.6).delta.2.27-2.42(1H,m),
2.95-3.18(3H,m), 3.37-4.18(16H,m), 4.47-4.78(3H,m), 7.30(1H,t,J=7.3
Hz), 7.37-7.45(3H,s), 7.87(2H,d,J=7.1 Hz), 9.17(1H,brs),
10.93(1H,brs).
Example 227
Synthesis of
3-((2S,4S)-4-{4-[4-(4-cyanophenyl)-2-thiazolyl]-1-piperazinyl}-2-pyrrolid-
inylcarbonyl)-1,3-thiazolidine trihydrochloride
[0913] (1) 4-Acetylbenzonitrile (4.35 g) was dissolved in
chloroform (40 mL), and a solution of bromine (1.7 mL) in
chloroform (10 mL) was added dropwise. The mixture was stirred at
room temperature. The reaction mixture was washed with saturated
aqueous sodium hydrogencarbonate solution, dried and concentrated
under reduced pressure. The residue was dissolved in acetonitrile
(40 mL), and sodium thiocyanate (2.4 g) was added thereto. The
mixture was stirred at room temperature and concentrated under
reduced pressure. Brine was added to the residue, and the mixture
was extracted with ethyl acetate. The extract was dried and the
solvent was evaporated under reduced pressure. The residue was
purified by silica gel chromatography to give
4-(2-isocyanatoacetyl)benzonitrile (4.39 g) as yellow crystals.
[0914] (2) The above-mentioned compound (4.39 g) and piperazine
(4.15 g) were dissolved in ethanol (70 mL), and the mixture was
stirred at 80.degree. C. for 1 hr with heating. The reaction
mixture was concentrated under reduced pressure, and brine was
added to the residue. The mixture was extracted with ethyl acetate.
The extract was dried and concentrated under reduced pressure. The
residue was purified by silica gel chromatography to give
1-[4-(4-cyanophenyl)-2-thiazolyl]piperazine (1.83 g) as a yellow
solid.
[0915] (3) Using the above-mentioned compound (0.892 g) and the
title compound (0.901 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-((2S,4S)-1-tert-butoxycarbonyl-4-{4-[4-(4-cyanophenyl)-2-thiazolyl]-1-p-
iperazinyl}-2-pyrrolidinylcarbonyl)-1,3-thiazolidine (1.40 g) was
obtained as a brown solid.
[0916] .sup.1H-NMR(CDCl.sub.3).delta.1.41(4.5H,s), 1.46(4.5H,s),
1.83-1.98(1H,m), 2.38-2.75(5H,m), 2.82-3.22(3H,m), 3.34(1H,t,J=9.9
Hz), 3.48-4.15(7H,m), 4.38-4.81(3H,m), 6.93(1H,s), 7.65(2H,d,J=8.3
Hz), 8.34(2H,d,J=8.3 Hz).
[0917] (4) The above-mentioned compound (1.39 g) was dissolved in
ethyl acetate (3 mL), and 4 mol/L hydrochloric acid-ethyl acetate
(6 mL) was added thereto. The mixture was stirred at room
temperature for 4 days. The precipitated solid was collected by
filtration to give the title compound (1.23 g) as a pale-yellow
powder.
[0918] .sup.1H-NMR(DMSO-d.sub.6).delta.2.24-2.38(1H,m),
2.94-3.18(3H,m), 3.35-4.14(16H,m), 4.46-4.78(3H,m), 7.73(1H,s),
7.87(2H,d,J=8.5 Hz), 8.07(2H,d,J=8.5 Hz), 9.16(1H,brs),
10.83(1H,brs).
Example 228
Synthesis of
3-{(2S,4S)-4-[4-(1-phenyl-1H-tetrazol-5-yl)-1-piperazinyl]-2-pyrrolidinyl-
carbonyl}-1,3-thiazolidine trihydrochloride
[0919] (1) Using 5-chloro-1-phenyl-1H-tetrazol (2.10 g) and
piperazine (10.0 g), and reaction at 100.degree. C. in the same
manner as in Example 196 (1),
1-(1-phenyl-1H-tetrazol-5-yl)piperazine (2.67 g) was obtained as a
pale-yellow powder.
[0920] (2) Using the above-mentioned compound (0.59 g) and the
title compound (0.696 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(1-phenyl-1H-tetrazol-5-yl)-1-piper-
azinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.19 g) was
obtained as a white powder.
[0921] (3) Using the above-mentioned compound (1.19 g), and in the
same manner as in Example 133 (2), the title compound (0.863 g) was
obtained as a white powder.
[0922] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.02-2.22(1H,m),
2.80-3.95(16H,m), 4.45-4.73(3H,m), 7.57-7.73(5H,m), 9.04(1H,brs),
10.61(1H,brs).
Example 229
Synthesis of
3-{(2S,4S)-4-[4-(1-cyclohexyl-1H-tetrazol-5-yl)-1-piperazinyl]-2-pyrrolid-
inylcarbonyl}-1,3-thiazolidine trihydrochloride
[0923] (1) 1-Benzyloxycarbonylpiperazine (2.07 g) was dissolved in
dichloromethane (50 mL), and cyclohexyl isocyanate (1.20 mL) was
added thereto at room temperature. The mixture was stirred for 1
hr. The solvent was evaporated under reduced pressure, and the
residue was dissolved in tetrahydrofuran (100 mL). Phosphorus
oxychloride (8.8 mL) was added thereto, and the mixture was
refluxed for 18 hr. The reaction mixture was concentrated under
reduced pressure, and a 0.5 mol/L solution of triazole in
acetonitrile (100 mL) was added to the residue. The mixture was
stirred at room temperature for 3 hr. The solvent was evaporated
under reduced pressure, and saturated aqueous sodium
hydrogencarbonate solution was added to the residue. The mixture
was extracted with ethyl acetate, and the extract was washed with
brine and dried. The solvent was distilled away under reduced
pressure, and the residue was dissolved in methanol (100 mL). An
aqueous solution (20 mL) of sodium azide (6.50 g) was added
thereto. The mixture was stirred at 70.degree. C. for 3 hr and the
reaction mixture was concentrated under reduced pressure. Water was
added to the residue, and the mixture was extracted with ethyl
acetate. The extract was washed with brine and dried. The solvent
was evaporated under reduced pressure and the residue was purified
by silica gel chromatography to give
1-benzyloxycarbonyl-4-(1-cyclohexyl-1H-tetrazol-5-yl)piperazine
(390 mg) as a white powder.
[0924] (2) The above-mentioned compound (388 mg) was dissolved in
ethanol (10 mL) and ethyl acetate (10 mL). The mixture was stirred
in the presence of 10% palladium/carbon (140 mg) under a hydrogen
atomosphere (1 atm) for 2 hr. The reaction mixture was filtrated
and the filtrate was concentrated under reduced pressure to give
1-(1-cyclohexyl-1H-tetrazol-5-yl)piperazine (248 mg) as a white
powder.
[0925] (3) Using the above-mentioned compound (248 mg) and the
title compound (290 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(1-cyclohexyl-1H-tetrazol-5-yl)-1-p-
iperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (502 mg) was
obtained as a white powder.
[0926] (4) Using the above-mentioned compound (502 mg), and in the
same manner as in Example 133 (2), the title compound (302 mg) was
obtained as a white powder.
[0927] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.20-1.34(1H,m),
1.40-1.50(2H,m), 1.64-1.88(5H,m), 1.97-2.03(2H,m), 2.12-2.32(1H,m),
2.90-4.05(16H,m), 4.25(1H,m), 4.48-4.75(3H,m), 9.10(1H,brs),
10.67(1H,brs).
Example 230
Synthesis of
3-{(2S,4S)-4-[4-(2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-
-1,3-thiazolidine dihydrochloride
[0928] (1) Using 2-chlorobenzimidazole (0.500 g) and piperazine
(8.47 g), and in the same manner as in Example 189 (1),
1-(2-benzimidazolyl)piperazine (0.086 g) was obtained as a white
powder.
[0929] (2) Using the above-mentioned compound (86 mg) of Reference
Example 12 and the title compound (128 mg), and in the same manner
as in Example 70 (1),
3-{(2S,4S)-4-[4-(2-benzimidazolyl)-1-piperazinyl]-1-tert-butoxycarbonyl-2-
-pyrrolidinylcarbonyl}-1,3-thiazolidine (203 mg) was obtained as a
white solid.
[0930] (3) Using the above-mentioned compound (203 mg), and in the
same manner as in Example 186 (2), the title compound (94 mg) was
obtained as a white powder.
[0931] .sup.1H-NMR(DMSO-d.sub.6).delta.1.72-2.16(1H,m),
2.65-4.30(16H,m), 4.40-4.80(3H,m), 7.18-7.33(2H,m),
7.36-7.51(2H,m), 8.95(1H,brs), 9.70(1H,brs), 10.50(1H,brs),
13.71(2H,brs).
Example 231
Synthesis of
3-{(2S,4S)-4-[4-(5-cyano-2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinylc-
arbonyl}-1,3-thiazolidine trihydrochloride
[0932] (1) 4-Amino-3-nitrobenzonitrile (25 g) was dissolved in
methanol (200 mL) and tetrahydrofuran (200 mL). The mixture was
stirred in the presence of 10% palladium/carbon (3.0 g) under a
hydrogen atomosphere (0.1 atm) for 20 hr. The reaction mixture was
filtrated and the filtrate was concentrated under reduced pressure
to give 3,4-diaminobenzonitrile (20 g) as a charcoal brown
solid.
[0933] (2) The above-mentioned compound (2.60 g) was dissolved in
DMF (20 mL) and pyridine (2 mL), and a solution of triphosgene
(2.12 g) in tetrahydrofuran (20 mL) was added dropwise under
ice-cooling. The mixture was stirred at room temperature for 18 hr.
Dilute hydrochloric acid was added to the reaction mixture, and the
mixture was extracted with ethyl acetate. The extract was washed
with brine and dried. The solvent was evaporated under reduced
pressure and ethyl acetate was added to the residue. The
precipitated solid was collected by filtration to give
2-hydroxybenzimidazole-5-carbonitrile (896 mg) as a purple
solid.
[0934] (3) The above-mentioned compound (894 mg) was dissolved in
phosphorus oxychloride (12 mL), and the solution was refluxed for 3
hr. The reaction mixture was added to ice, and extracted with ethyl
acetate. The extract was washed with brine, dried and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography to give 2-chlorobenzimidazole-5-carbonitrile (322
mg) as a white powder.
[0935] (4) The product (345 mg) of Example 199 (3) was dissolved in
N-methyl-2-pyrrolidone (6 mL), and the above-mentioned compound
(182 mg) and N,N-diisopropylethylamine (180 .mu.L) were added
thereto. The mixture was stirred at 100.degree. C. for 17 hr. The
reaction mixture was added to water, and the mixture was extracted
with ethyl acetate. The extract was washed with brine, dried and
concentrated under reduced pressure. The residue was purified by
HPLC to give
3-{(2S,4S)-1-benzyloxycarbonyl-4-[4-(5-cyano-2-benzimidazolyl)-1-piperazi-
nyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (250 mg) as a white
solid.
[0936] (5) Using the above-mentioned compound (200 mg), and in the
same manner as in Example 199 (5), the title compound (50 mg) was
obtained as a white powder.
[0937] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.89-2.09(1H,m),
2.78-4.20(16H,m), 4.47-4.82(3H,m), 7.51(1H,d,J=8.2 Hz),
7.61(1H,d,J=8.2 Hz), 7.81(1H,s), 8.97(1H,brs), 10.28(1H,brs).
Example 232
Synthesis of
3-{(2S,4S)-4-[4-(5-trifluoromethyl-2-benzimidazolyl)-1-piperazinyl]-2-pyr-
rolidinylcarbonyl}-1,3-thiazolidine trihydrobromide
[0938] (1) Using 4-trifluoromethyl-2-nitroaniline (25.0 g), and in
the same manner as in Example 231 (1),
4-trifluoromethyl-1,2-phenylenediamine (21.3 g) was obtained as a
white solid.
[0939] (2) Using the above-mentioned compound (10.2 g) and in the
same manner as in Example 231 (2), the reaction mixture was added
to water. The precipitated solid was collected by filtration to
give 5-trifluoromethyl-2-hydroxybenzimidazole (3.28 g) as a white
solid.
[0940] (3) Using the above-mentioned compound (3.27 g), and in the
same manner as in Example 231 (3),
2-chloro-5-trifluoromethylbenzimidazole (2.48 g) was obtained as a
white powder.
[0941] (4) Using the above-mentioned compound (226 mg) and the
product (345 mg) of Example 199 (3), and in the same manner as in
Example 231 (4),
3-{(2S,4S)-1-benzyloxycarbonyl-4-[4-(5-trifluoromethyl-2-benzimidazo-
lyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (192
mg) was obtained as a white solid.
[0942] (5) 30% Hydrogen bromide-acetic acid solution (10 mL) was
added to the above-mentioned compound (190 mg), and the mixture was
stirred at room temperature for 6 hr. Diethyl ether was added to
the reaction mixture, and the precipitated solid was collected by
filtration and washed with ethanol. The title compound (101 mg) was
obtained as a white powder.
[0943] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.761.96(1H,m),
2.75-4.80(16H,m), 4.46-4.74(3H,m), 7.60(2H,s), 7.67(1H,s),
8.96(1H,brs), 9.59(1H,brs), 13.02(1H,brs).
Example 233
Synthesis of
3-{(2S,4S)-4-[4-(5-fluoro-2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinyl-
carbonyl}-1,3-thiazolidine trihydrobromide
[0944] (1) Using 4-fluoro-2-nitroaniline (25.0 g), and in the same
manner as in Example 231 (1), 4-fluoro-1,2-phenylenediamine (20.1
g) was obtained as a charcoal brown solid.
[0945] (2) Using the above-mentioned compound (10.0 g), and in the
same manner as in Example 231 (2), the reaction mixture was added
to water. The precipitated solid was collected by filtration to
give 5-fluoro-2-hydroxybenzimidazole (2.14 g) as a brown solid.
[0946] (3) Using the above-mentioned compound (2.13 g), and in the
same manner as in Example 231 (3), 2-chloro-5-fluorobenzimidazole
(1.44 g) was obtained as a brown solid.
[0947] (4) Using the above-mentioned compound (174 mg) and the
product (345 mg) of Example 199 (3), and in the same manner as in
Example 231 (4),
3-{(2S,4S)-1-benzyloxycarbonyl-4-[4-(5-fluoro-2-benzimidazolyl)-1-pi-
perazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (66 mg) was
obtained as a white solid.
[0948] (5) Using the above-mentioned compound (66 mg), and in the
same manner as in Example 232 (5), the title compound (20 mg) was
obtained as a white powder.
[0949] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.77-1.97(1H,m),
2.88-4.20(16H,m), 4.46-4.76(3H,m), 7.12-7.16(1H,m),
7.32(1H,dd,J=8.5, 2.2 Hz), 7.44(1H,dd,J=8.7, 4.5 Hz), 8.97(1H,brs),
9.61(1H,brs), 13.16(1H,brs).
Example 234
Synthesis of
3-{(2S,4S)-4-[4-(5-chloro-2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinyl-
carbonyl}-1,3-thiazolidine trihydrobromide
[0950] (1) 2-Chlorobenzimidazole (1.05 g) was dissolved in DMF (10
mL), and N-chlorosuccinimide (1.01 g) was added thereto. The
mixture was stirred at 60.degree. C. for 30 min and the reaction
mixture was added to water. The precipitated solid was collected by
filtration to give 2,5-dichlorobenzimidazole (0.480 g) as a white
solid.
[0951] (2)-Using the above-mentioned compound (191 mg) and the
product (345 mg) of Example 199 (3), and in the same manner as in
Example 231 (4),
3-{(2S,4S)-1-benzyloxycarbonyl-4-[4-(5-chloro-2-benzimidazolyl)-1-pi-
perazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (122 mg) was
obtained as a pale-yellow solid.
[0952] (3) Using the above-mentioned compound (110 mg), and in the
same manner as in Example 232 (5), the title compound (56 mg) was
obtained as a white powder.
[0953] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.76-1.96(1H,m),
2.70-4.87(16H,m), 4.46-4.74(3H,m), 7.32(1H,dd,J=8.5, 1.7 Hz),
7.44(1H,d,J=8.5 Hz), 7.48(1H,d,J=1.7 Hz), 8.96(1H,brs),
9.59(1H,brs), 13.15(1H,brs).
Example 235
Synthesis of
3-{(2S,4S)-4-[4-(5-nitro-2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinylc-
arbonyl}-1,3-thiazolidine trihydrochloride
[0954] (1) Using 4-nitro-1,2-phenylenediamine (9.12 g), and in the
same manner as in Example 231 (2), the reaction mixture was added
to water. The precipitated solid was collected by filtration to
give 5-nitro-2-hydroxyxisobenzimidazole (5.69 g) as an yellow
solid.
[0955] (2) Using the above-mentioned compound (5.69 g), and in the
same manner as in Example 231 (3), 2-chloro-5-nitrobenzimidazole
(2.41 g) was obtained as a yellow solid.
[0956] (3) Using the above-mentioned compound (1.00 g) and
piperazine (4.70 g), and by a reaction at 100.degree. C. in the
same manner as in Example 196 (1),
1-(5-nitro-2-benzimidazolyl)piperazine (0.16 g) was obtained as an
orange solid.
[0957] (4) Using the above-mentioned compound (160 mg) and the
title compound (162 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-nitro-2-benzimidazolyl)-1-pipera-
zinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (172 mg) was
obtained as a yellow solid.
[0958] (5) Using the above-mentioned compound (172 mg), and in the
same manner as in Example 133 (2), the title compound (138 mg) was
obtained as a yellow powder.
[0959] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.08-2.24(1H,m),
2.78-4.03(16H,m), 4.48-4.75(3H,m), 7.52(2H,d,J=8.6 Hz),
8.11(2H,dd,J=8.6, 2.0 Hz), 8.12(1H,d,J=2.0 Hz), 9.06(1H,brs),
10.59(1H,brs).
Example 236
Synthesis of
3-{(2S,4S)-4-[4-(1-methyl-2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinyl-
carbonyl}-1,3-thiazolidine trihydrochloride
[0960] (1) Sodium hydride (contained by 60%, 0.288 g) was suspended
in DMF (10 mL), and 2-chlorobenzimidazole (1 q) was added thereto.
The mixture was stirred at room temperature for 30 min and methyl
iodide (0.61 mL) was added thereto. After stirring at room
temperature for 1 hr, water was added to the reaction mixture. The
mixture was extracted with ethyl acetate, and the extract was
washed with brine and concentrated under reduced pressure to give
2-chloro-1-methylbenzimidazole (0.928 g) as a white powder.
[0961] (2) Using the above-mentioned compound (0.928 g) and
piperazine (9.60 g), and in the same manner as in Example 189 (1),
1-(1-methyl-2-benzimidazolyl)piperazine (1.18 g) was obtained as a
pale-yellow solid.
[0962] (3) Using the above-mentioned compound (476 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(1-methyl-2-benzimidazolyl)-1-piper-
azinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (947 mg) was
obtained as a white solid.
[0963] (4) Using the above-mentioned compound (857 mg), and in the
same manner as in Example 186 (2), the title compound (532 mg) was
obtained as a white powder.
[0964] .sup.1H-NMR(DMSO-d.sub.6).delta.2.19-2.38(1H,m),
2.89-3.20(3H,m), 3.30-4.30(13H,m), 3.79(3H,s), 4.42-4.85(3H,m),
7.34-7.47(2H,m), 7.53-7.63(1H,m), 7.64-7.76(1H,m), 9.15(1H,brs),
11.08(1H,brs).
Example 237
Synthesis of
3-{(2S,4S)-4-[4-(5-trifluoromethyl-1-methyl-2-benzimidazolyl)-1-piperazin-
yl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine trihydrochloride
[0965] (1) 4-Fluoro-3-nitrobenzotrifluoride (25 g) was dissolved in
ethanol (50 mL), and 30% methylamine-ethanol solution (97.9 g) was
gradually added dropwise under ice-cooling, and the mixture was
stirred at room temperature for 40 min. The reaction mixture was
added to water, and the precipitated solid was collected by
filtration to give 4-methylamino-3-nitrobenzotrifluoride (25.5 g)
as yellow crystals.
[0966] (2) Using the above-mentioned compound (25.3 g), and in the
same manner as in Example 231 (1),
4-trifluoromethyl-N1-methyl-1,2-phenylenediamine (21.9 g) was
obtained as a pale-yellow solid.
[0967] (3) The above-mentioned compound (21.9 g) was subjected to
the reaction in the same manner as in Example 231 (2), and water
was added to the reaction mixture. The precipitated solid was
collected by filtration to give
5-trifluoromethyl-2-hydroxy-1-methylbenzimidazole (23.8 g) as a
white solid.
[0968] (4) Using the above-mentioned compound (10.1 g), and in the
same manner as in Example 231 (3),
2-chloro-5-trifluoromethyl-1-methylbenzimidazole (10.5 g) was
obtained as a white solid.
[0969] (5) Using the above-mentioned compound (5.07 g) and
piperazine (18.6 g), and by a reaction at 100.degree. C. in the
same manner as in Example 196 (1),
1-(5-trifluoromethyl-1-methyl-2-benzimidazolyl)piperazine (4.87 g)
was obtained as a white solid.
[0970] (6) Using the above-mentioned compound (485 mg) and the
title compound (518 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-trifluoromethyl-1-methyl-2-benzi-
midazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine
(978 mg) was obtained as a white powder.
[0971] (7) Using the above-mentioned compound (978 mg), and in the
same manner as in Example 133 (2), the title compound (483 mg) was
obtained as a white powder.
[0972] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.23-2.43(1H,m),
2.97-4.15(16H,m), 3.76(3H,s), 4.49-4.77(3H,m), 7.61(1H,d,J=8.4 Hz),
7.74(1H,d,J=8.4 Hz), 7.80(1H,s), 9.14(1H,brs), 10.94(1H,brs).
Example 238
Synthesis of
3-{(2S,4S)-4-[4-(5-fluoro-1-methyl-2-benzimidazolyl)-1-piperazinyl]-2-pyr-
rolidinylcarbonyl}-1,3-thiazolidine trihydrochloride
[0973] (1) Using 2,5-difluoronitrobenzene (25.4 g), and in the same
manner as in Example 237 (1), 5-fluoro-2-(methylamino)nitrobenzene
(27.2 g) was obtained as an orange solid.
[0974] (2) Using the above-mentioned compound (27.2 g), and in the
same manner as in Example 231 (1),
4-fluoro-N1-methyl-1,2-phenylenediamine (20.9 g) was obtained as an
orange solid.
[0975] (3) Using the above-mentioned compound (18.1 g), and in the
same manner as in Example 231 (2),
5-fluoro-2-hydroxy-1-methylbenzimidazole (0.682 g) was obtained as
a pale-yellow solid.
[0976] (4) Using the above-mentioned compound (675 mg), and in the
same manner as in Example 231 (3),
2-chloro-5-fluoro-1-methylbenzimidazole (647 mg) was obtained as a
white solid.
[0977] (5) Using the above-mentioned compound (0.633 g) and
piperazine (3.2 g), and by a reaction at 100.degree. C. in the same
manner as in Example 196 (1),
1-(5-fluoro-1-methyl-2-benzimidazolyl)piperazine (0.77 g) was
obtained as a pale-yellow solid.
[0978] (6) Using the above-mentioned compound (0.76 g) and the
title compound (0.80 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-fluoro-1-methyl-2-benzimidazolyl-
)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.40 g)
was obtained as a white powder.
[0979] (7) Using the above-mentioned compound (1.40 g), and in the
same manner as in Example 133 (2), the title compound (0.676 g) was
obtained as a white powder.
[0980] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.20-2.40(1H,m),
2.85-4.14(16H,m), 3.76(3H,s), 4.49-4.76(3H,m), 7.23(1H,m),
7.38(1H,dd,J=8.6, 2.1 Hz), 7.65(1H,dd,J=8.7, 4.3 Hz), 9.13(1H,brs),
11.03(1H,brs).
Example 239
Synthesis of
3-{(2S,4S)-4-[4-(5-cyano-2-benzoxazolyl)-1-piperazinyl]-2-pyrrolidinylcar-
bonyl}-1,3-thiazolidine dihydrochloride
[0981] (1) 3-Amino-4-cyanophenol (6.71 g) was dissolved in pyridine
(100 mL), and potassium ethylxanthate (8.82 g) was added thereto.
The mixture was refluxed for 2 hr. After allowing to cool, iced
water (200 mL) was added to the reaction mixture, and conc.
hydrochloric acid (40 mL) was added thereto. The precipitated solid
was collected by filtration to give 5-cyano-2-mescaptobenzoxazole
(5.62 g) as a gray powder.
[0982] (2) The above-mentioned compound (5 g) and two drops of DMF
were added to thionyl chloride (20 mL), and the mixture was
refluxed for 1 hr. The reaction mixture was concentrated under
reduced pressure to give 2-chloro-5-cyanobenzoxazole (5.06 g);
[0983] (3) piperazine (4.29 g) was dissolved in DMF (40 mL), and
the above-mentioned compound (2.96 g) was added thereto. The
mixture was stirred at room temperature for 3 hr. The reaction
mixture was added to water, and the mixture was extracted with
chloroform. 1 mol/L Hydrochloric acid was added to the extract, and
the aqueous layer was separated. Aqueous sodium hydroxide solution
was added thereto, and the mixture was extracted with chloroform.
The extract was concentrated under reduced pressure to give
1-(5-cyano-2-benzoxazolyl)piperazine (0.933 g) as a pale-yellow
powder.
[0984] (4) Using the above-mentioned compound (502 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-cyano-2-benzoxazolyl)-1-piperazi-
nyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (428 mg) was obtained
as a white powder.
[0985] (5) The above-mentioned compound (424 mg) was dissolved in
chloroform (10 mL), and 5 mol/L hydrochloric acid-ethyl acetate (5
mL) was added thereto. The mixture was stirred at room temperature
for 18 hr and the reaction mixture was concentrated under reduced
pressure. The residue was washed with ethanol to give the title
compound (302 mg) as a white powder.
[0986] .sup.1H-NMR(DMSO-d.sub.6).delta.1.94-2.26(1H,m),
2.80-3.00(1H,m), 3.00-4.30(15H,m), 4.45-4.78(3H,m),
7.56(1H,dd,J=8.4, 1.8 Hz), 7.66(1H,d,J=8.4 Hz), 7.83(1H,d,J=1.5
Hz), 9.05(1H,brs), 10.43(1H,brs).
Example 240
Synthesis of
3-{(2S,4S)-4-[4-(5-cyano-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylc-
arbonyl}-1,3-thiazolidine dihydrochloride
[0987] (1) 2-Bromo-5-nitroaniline (10 g) was dissolved in
N-methyl-2-pyrrolidone (50 mL), and potassium ethylxanthate (14.8
g) was added thereto. The mixture was stirred at 140.degree. C.
with heating. The reaction mixture was concentrated under reduced
pressure, and water (300 mL) and conc. hydrochloric acid (10 mL)
were added to the residue. The precipitated solid was collected by
filtration, which was then dissolved in 1 mol/L aqueous sodium
hydroxide solution (80 mL). After washing with chloroform, 1 mol/L
hydrochloric acid was added thereto, and the precipitated solid was
collected by filtration to give 2-mercapto-5-nitrobenzothiazole
(8.43 g) as an orange powder.
[0988] (2) Sodium hydride (contained by 60%, 1.05 g) was suspended
in DMF (50 mL) and the above-mentioned compound (8.43 g) was added
thereto under ice-cooling. After the mixture was stirred for 30
min, methyl iodide (2.72 mL) was added thereto under ice-cooling.
The mixture was stirred at room temperature for 2 hr. The reaction
mixture was added to water, and the mixture was extracted with
ethyl acetate (insoluble material was removed by filtration). The
extract was washed successively with water and brine and
concentrated under reduced pressure to give
2-methylthio-5-nitrobenzothiazole (4.82 g) as a pale-brown
powder.
[0989] (3) The above-mentioned compound (3.33 g) was dissolved in
ethanol (70 mL), and chloride dihydrate (II) (14.0 g) was added
thereto. The mixture was refluxed for 1 hr. The reaction mixture
was concentrated under reduced pressure, and saturated aqueous
sodium hydrogencarbonate solution was added to the residue. The
mixture was extracted with chloroform (insoluble material was
filtered off). The extract was washed with brine and concentrated
under reduced pressure to give 5-amino-2-methylthiobenzothiazole
(2.54 g) as a red-orange solid.
[0990] (4) The above-mentioned compound (2.54 g) was suspended in
water (40 mL) and conc. hydrochloric acid (3.75 mL) was added
thereto under ice-cooling. Thereto was added dropwise a solution of
sodium nitrite (1.00 g) in water (10 mL) under ice-cooling. After
stirring the reaction mixture for 20 min, 5% aqueous potassium
carbonate solution (20 mL) was added dropwise under ice-cooling.
This reaction mixture was added dropwise under ice-cooling to a
solution of copper cyanide (2.35 g) and potassium cyanide (3.44 g)
in water (40 mL) prepared separately. After stirring under
ice-cooling for 1 hr, the mixture was stirred at 50.degree. C. for
10 min with heating. The reaction mixture was added to water (50
mL), and the mixture was extracted with ethyl acetate (insoluble
material was filtered off). The extract was washed with brine, and
concentrated under reduced pressure to give
5-cyano-2-methylthiobenzothiazole (1.96 g).
[0991] (5) Using the above-mentioned compound (0.645 g) and
piperazine (8.08 g), and in the same manner as in Example 189 (1),
1-(5-cyano-2-benzothiazolyl)piperazine (0.601 g) was obtained as a
brown solid.
[0992] (6) Using the above-mentioned compound (601 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-cyano-2-benzothiazolyl)-1-pipera-
zinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (649 mg) was
obtained as a pale-orange powder.
[0993] (7) Using the above-mentioned compound (649 mg), and in the
same manner as in Example 239 (5), the title compound (500 mg) was
obtained as a white powder.
[0994] .sup.1H-NMR(DMSO-d.sub.6).delta.2.04-2.28(1H,m),
2.82-3.00(1H,m), 3.00-4.30(15H,m), 4.43-4.80(3H,m),
7.53(1H,dd,J=8.2, 1.5 Hz), 7.93(1H,d,J=1.5 Hz), 8.07(1H,d,J=8.2
Hz), 9.08(1H,brs), 10.51(1H,brs).
Example 241
Synthesis of
3-{(2S,4S)-4-[4-(6-cyano-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylc-
arbonyl}-1,3-thiazolidine dihydrochloride
[0995] (1) Sodium hydride (containing by 60%, 6.15 g) was suspended
in DMF (120 mL) and 2-mercapto-6-nitrobenzothiazole (20 g) was
added thereto under ice-cooling. After completion of bubbling,
methyl iodide (26.4 mL) was added thereto. The mixture was stirred
at room temperature for 18 hr. Water (800 mL) was added to the
reaction mixture, and the precipitated solid was collected by
filtration to give 2-methylthio-6-nitrobenzothiazole (21.2 g) as a
pale-yellow powder.
[0996] (2) Using the above-mentioned compound (10 g) and tin(II)
chloride (41.9 g), and in the same manner as in Example 240 (3),
6-amino-2-methylthiobenzothiazole (7.75 g) was obtained as a white
solid.
[0997] (3) Using the above-mentioned compound (2.59 g), sodium
nitrite (1.00 g), copper cyanide (2.35 g) and potassium cyanide
(3.44 g), and in the same manner as in Example 240 (4),
6-cyano-2-mercaptobenzothiazole (2.22 g) was obtained as a brown
solid.
[0998] (4) Using the above-mentioned compound (2.04 g) and
piperazine (8.82 g), and in the same manner as in Example 189 (1),
1-(6-cyano-2-benzothiazolyl)piperazine (2.02 mg) was obtained as a
brown-reddish solid.
[0999] (5) Using the above-mentioned compound (538 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(6-cyano-2-benzothiazolyl)-1-pipera-
zinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (526 mg) was
obtained as an orange powder.
[1000] (6) Using the above-mentioned compound (526 mg), and in the
same manner as in Example 239 (5), the title compound (394 mg) was
obtained as a white powder.
[1001] .sup.1H-NMR(DMSO-d.sub.6).delta.2.00-2.30(1H,m),
2.80-3.00(1H,m), 3.00-4.30(15H,m), 4.42-4.80(3H,m), 7.59(1H,d,J=8.4
Hz), 7.72(1H,dd,J=8.1, 1.5 Hz), 8.39(1H,d,J=1.5 Hz), 9.06(1H,brs),
10.58(1H,brs).
Example 242
Synthesis of
3-{(2S,4S)-4-[4-(6-trofluoromethyl-2-benzothiazolyl)-1-piperazinyl]-2-pyr-
rolidinylcarbonyl}-1,3-thiazolidine dihydrochloride
[1002] (1) 4-Amino-3-bromobenzotrifluoride (2.40 g) was dissolved
in N-methyl-2-pyrrolidone (10 mL), and potassium ethylxanthate
(3.52 g) was added thereto. The mixture was stirred at 160.degree.
C. for 3 hr with heating. Water (300 mL) was added to the reaction
mixture, and the mixture was extracted with ethyl acetate. The
extract was washed successively with water and brine, and
concentrated under reduced pressure to give
6-trifluoromethyl-2-mercaptobenzothiazole (607 mg) as an orange
powder.
[1003] (2) Using the above-mentioned compound (607 mg), sodium
hydride (containing by 60%, 155 mg) and methyl iodide (241 mL), and
in the same manner as in Example 236 (1),
6-trifluoromethyl-2-methylthiobenzothiazole (665 mg) was obtained
as a brown solid.
[1004] (3) Using the above-mentioned compound (0.665 g) and
piperazine (11.5 g), and in the same manner as in Example 189 (1),
1-(6-trifluoromethylbenzothiazolyl)piperazine (0.56 g) was obtained
as a white powder.
[1005] (4) Using the above-mentioned compound (560 mg) and the
title compound (532 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(6-trifluoromethyl-2-benzothiazolyl-
)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (477 mg)
was obtained as a white powder.
[1006] (5) Using the above-mentioned compound (477 mg), and in the
same manner as in Example 186 (2), the title compound (403 mg) was
obtained as a white powder.
[1007] .sup.1H-NMR(DMSO-d.sub.6).delta.2.05-2.33(1H,m),
2.79-3.00(1H,m), 3.00-3.29(2H,m), 3.29-4.30(13H,m),
4.45-4.80(3H,m), 7.58-7.70(2H,m), 8.34(1H,s), 9.10(1H,brs),
10.72(1H,brs).
Example 243
Synthesis of
3-{(2S,4S)-4-[4-(6-methoxy-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidiny-
lcarbonyl}-1,3-thiazolidine trihydrochloride
[1008] (1) Using 2-chloro-6-methoxybenzothiazole (1 g) and
piperazine (8.63 g), and in the same manner as in Example 189 (1),
1-(6-methoxybenzothiazolyl)piperazine (1.22 g) was obtained as a
pale-brown powder.
[1009] (5) Using the above-mentioned compound (549 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(6-methoxy-2-benzothiazolyl)-1-pipe-
razinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (420 mg) was
obtained as a white powder.
[1010] (6) Using the above-mentioned compound (420 mg), and in the
same manner as in Example 186 (2), the title compound (393 mg) was
obtained as a white powder.
[1011] .sup.1H-NMR(DMSO-d.sub.6).delta.2.22-2.41(1H,m),
2.90-3.20(3H,m), 3.25-4.20(13H,m), 3.77(3H,s), 4.42-4.81(3H,m),
6.96(1H,dd,J=8.9, 2.6 Hz), 7.47(1H,d,J=8.8 Hz), 7.50(1H,d,J=2.6
Hz).
Example 244
Synthesis of
3-{(2S,4S)-4-[4-(6-isopropoxy-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolid-
inylcarbonyl}-1,3-thiazolidine trihydrochloride
[1012] (1) 4-Isopropoxyaniline (24.2 g) was dissolved in acetic
acid (300 mL), and a mixture of bromine (8.25 mL) and acetic acid
(80 mL) was added dropwise. After stirring at room temperature for
2 hr, the reaction mixture was concentrated under reduced pressure.
Water was added to residue, and the mixture was extracted with
diethylether. The extract was washed successively with aqueous
sodium thiosulfate solution and brine, and concentrated under
reduced pressure. The residue was purified by silica gel
chromatography to give 2-bromo-4-isopropoxyaniline (10.2 g) as a
black brown oil.
[1013] (2) The above-mentioned compound (10.2 g) was dissolved in
N-methyl-2-pyrrolidone (50 mL), and potassium ethylxanthate (14.2
g) was added thereto. The mixture was stirred at 140.degree. C. for
6 hr with heating. The reaction mixture was concentrated under
reduced pressure, and 1 mol/L aqueous sodium hydroxide solution (50
mL) was added to the residue. The mixture was washed with
chloroform, and conc. hydrochloric acid (30 mL) was added thereto.
The mixture was extracted with chloroform. The extract was
concentrated under reduced pressure to give
6-isopropoxy-2-mercaptobenzothiazole (12.6 g) as a black brown
oil.
[1014] (3) The above-mentioned compound (11.6 g) and 2 drops of DMF
were added to thionyl chloride (30 mL), and the mixture was stirred
at room temperature for 18 hr. The reaction mixture was
concentrated under reduced pressure, and saturated aqueous sodium
hydrogencarbonate solution was added to the residue. The mixture
was extracted with chloroform. The extract was concentrated under
reduced pressure and the residue was purified by silica gel
chromatography to give 2-chloro-6-isopropoxybenzothiazole (9.37 g)
as a black oil.
[1015] (4) Using the above-mentioned compound (9.37 g) and
piperazine (35.4 g), and in the same manner as in Example 189 (1),
1-(6-isopropoxy-2-benzothiazolyl)piperazine (2.8 g) was obtained as
a black powder.
[1016] (5) Using the above-mentioned compound (1.25 g) and the
title compound (0.901 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(6-isopropoxy-2-benzothiazolyl)-1-p-
iperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (0.993 g) was
obtained as a pale-brown powder.
[1017] (6) Using the above-mentioned compound (933 mg), and in the
same manner as in Example 186 (2), the title compound (749 mg) was
obtained as a white powder.
[1018] .sup.1H-NMR(DMSO-d.sub.6).delta.1.26(6H,d,J=6.0 Hz),
2.20-2.40(1H,m), 2.90-3.20(3H,m), 3.28-4.12(14H,m),
4.39-4.80(3H,m), 6.92(1H,dd,J=8.8, 2.6 Hz), 7.44(1H,d,J=8.8 Hz),
7.48(1H,d,J=2.6 Hz), 9.18(1H,brs), 10.90(1H,brs).
Example 245
Synthesis of
3-{(2S,4S)-4-[4-(5-nitro-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylc-
arbonyl}-1,3-thiazolidine dihydrochloride
[1019] (1) Using 2-methylthio-5-nitrobenzothiazole [product of
Example 240(2), 1.5 g] and piperazine (11.4 g), and in the same
manner as in Example 189 (1),
1-(5-nitro-2-benzothiazolyl)piperazine (1.55 g) was obtained as a
yellow powder.
[1020] (2) Using the above-mentioned compound (581 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-nitro-2-benzothiazolyl)-1-pipera-
zinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (507 mg) was
obtained as a yellow powder.
[1021] (3) Using the above-mentioned compound (507 mg), and in the
same manner as in Example 186 (2), the title compound (243 mg) was
obtained as a yellow powder.
.sup.1H-NMR(DMSO-d.sub.6).delta.2.00-2.22(1H,m), 2.79-3.00(1H,m),
3.00-4.30(15H,m), 4.42-4.80(3H,m), 7.98(1H,dd,J=8.7, 2.2 Hz),
8.13(1H,d,J=8.7 Hz), 8.21(1H,d,J=2.2 Hz), 9.05(1H,brs),
10.40(1H,brs).
Example 246
Synthesis of
3-{(2S,4S)-4-[4-(6-nitro-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylc-
arbonyl}-1,3-thiazolidine dihydrochloride
[1022] (1) Conc. sulfuric acid (50 mL) was added to
2-chlorobenzothiazole (10 g) under ice-cooling, and conc. nitric
acid (5 mL) was added dropwise under ice-cooling. The mixture was
stirred under ice-cooling for 1 hr, and iced water (600 mL) was
added to the reaction mixture. The precipitated solid was collected
by filtration, which was then recrystallized from acetone to give
2-chloro-6-nitrobenzothiazole (6.36 g) as a pale-yellow powder.
[1023] (2) Using the above-mentioned compound (6.36 g) and
piperazine (25.8 g), and in the same manner as in Example 189 (1),
1-(6-nitro-2-benzothiazolyl)piperazine (1.84 g) was obtained as a
yellow powder.
[1024] (3) Using the above-mentioned compound (581 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(6-nitro-2-benzothiazolyl)-1-pipera-
zinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (664 mg) was
obtained as a yellow powder.
[1025] (4) Using the above-mentioned compound (588 mg), and in the
same manner as in Example 186 (2), the title compound (495 mg) was
obtained as a yellow powder.
[1026] .sup.1H-NMR(DMSO-d.sub.6).delta.2.00-2.26(1H,m),
2.83-3.00(1H,m), 3.01-4.30(15H,m), 4.43-4.80(3H,m), 7.60(1H,d,J=9.0
Hz), 8.19(1H,dd,J=9.0, 2.4 Hz), 8.89(1H,d,J=2.4 Hz), 9.16(1H,brs),
10.45(1H,brs).
Example 247
Synthesis of
3-{(2S,4S)-4-[4-(6-fluoro-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinyl-
carbonyl}-1,3-thiazolidine dihydrochloride
[1027] (1) Using 2-bromo-4-fluoroaniline (25 g) and potassium
ethylxanthate (42.2 g), and in the same manner as in Example
244(2), 6-fluoro-2-mercaptobenzothiazole (1.01 g) was obtained as a
white powder.
[1028] (2) Using the above-mentioned compound (1.01 g), sodium
hydride (containing by 60%, 0.24 g), and methyl iodide (373 mL),
and in the same manner as in Example 236 (1),
6-fluoro-2-methylthiobenzothiazole (0.928 g) was obtained as a
pale-yellow solid.
[1029] (3) Using the above-mentioned compound (0.928 g) and
piperazine (8.02 g), and in the same manner as in Example 189 (1),
1-(6-fluoro-2-benzothiazolyl)piperazine (0.627 g) was obtained as a
pale-yellow oil.
[1030] (4) Using the above-mentioned compound (627 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(6-fluoro-2-benzothiazolyl)-1-piper-
azinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (535 mg) was
obtained as a white powder.
[1031] (5) Using the above-mentioned compound (535 mg), and in the
same manner as in Example 186 (2), the title compound (441 mg) was
obtained as a white powder.
[1032] .sup.1H-NMR(DMSO-d.sub.6).delta.2.05-2.38(1H,m),
2.82-4.30(16H,m), 4.42-4.80(3H,m), 7.17(1H,td,J=9.0, 2.7 Hz),
7.52(1H,dd,J=9.0, 4.8 Hz), 7.79(1H,dd,J=8.7, 2.7 Hz), 9.09(1H,brs),
10.72(1H,brs).
Example 248
Synthesis of
3-{(2S,4S)-4-[(4-(5-chloro-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidiny-
lcarbonyl}-1,3-thiazolidine trihydrochloride
[1033] (1) Using 5-chloro-2-mercaptobenzothiazole (25 g), sodium
hydride (containing by 60%, 5.45 g) and methyl iodide (8.49 mL),
and in the same manner as in Example 241 (1),
5-chloro-2-methylthiobenzothiazole (26.7 g) was obtained as a white
powder.
[1034] (2) Using the above-mentioned compound (10.8 g) and
piperazine (43.1 g), and in the same manner as in Example 189 (1),
1-(6-chloro-2-benzothiazolyl)piperazine (10.9 g) was obtained as a
white powder.
[1035] (3) Using the above-mentioned compound (558 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-chloro-2-benzothiazolyl)-1-piper-
azinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (834 mg) was
obtained as a white powder.
[1036] (4) Using the above-mentioned compound (834 mg), and in the
same manner as in Example 186 (2), the title compound (735 mg) was
obtained as a white powder.
.sup.1H-NMR(DMSO-d).delta.2.20-2.40(1H,m), 2.89-3.20(3H,m),
3.23-3.60(4H,m), 3.60-4.85(12H,m), 7.18(1H,dd,J=8.4, 2.1 Hz),
7.56(1H,d,J=2.1 Hz), 7.88(1H,d,J=8.4 Hz), 9.15(1H,brs),
10.86(1H,brs).
Example 249
Synthesis of
3-{(2S,4S)-4-[4-(6-chloro-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinyl-
carbonyl}-1,3-thiazolidine trihydrochloride
[1037] (1) Using 2,6-dichlorobenzothiazole (1 g) and piperazine
(8.44 g), and in the same manner as in Example 189 (1),
1-(6-chloro-2-benzothiazolyl)piperazine (1.24 g) was obtained as a
pale-brown solid.
[1038] (2) Using the above-mentioned compound (558 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(6-chloro-2-benzothiazolyl)-1-piper-
azinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (740 mg) was
obtained as a white powder.
[1039] (3) Using the above-mentioned compound (647 mg), and in the
same manner as in Example 186 (2), the title compound (603 mg) was
obtained as a white powder.
[1040] .sup.1H-NMR(DMSO-d.sub.6).delta.2.22-2.42(1H,m),
2.90-3.21(3H,m), 3.30-4.20(13H,m), 4.43-4.81(3H,m),
7.36(1H,dd,J=8.5, 2.2 Hz), 7.52(1H,d,J=8.5 Hz), 8.01(1H,d,J=2.2
Hz), 9.25(1H,brs), 11.10(1H,brs).
Example 250
Synthesis of
3-{(2S,4S)-4-[4-(1-methyl-1H-indazol-3-yl)-1-piperazinyl]-2-pyrrolidinylc-
arbonyl}-1,3-thiazolidine trihydrochloride
[1041] (1) using 1-(1-methyl-1H-indazol-3-yl)piperazine (0.714 g)
and the title compound (0.901 g) of Reference Example 12, and in
the same manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(1-methyl-1H-indazol-3-yl)-1-pipera-
zinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.37 g) was
obtained as a pale-yellow solid.
[1042] .sup.1H-NMR(CDCl.sub.3).delta.1.41(4.5H,s), 1.46(4.5H,s),
1.85-2.00(1H,m), 2.42-2.55(1H,m), 2.62-2.80(4H,m), 2.83-3.22(3H,m),
3.35(1H,t,J=10.1 Hz), 3.40-3.52(4H,m), 3.63-4.14(6H,m),
4.39-4.81(3H,m), 7.01(1H,t,J=7.6 Hz), 7.23-7.38(2H,m),
7.67(1H,d,J=8.2 Hz).
[1043] (2) The above-mentioned compound (1.36 g) was dissolved in
ethanol (3.5 mL), and 4.1 mol/L hydrochloric acid-ethanol (3.5 mL)
was added thereto. The mixture was stirred at room temperature for
15 hr. The reaction mixture was concentrated under reduced
pressure, and the obtained crystal was recrystallized from ethanol
to give the title compound (0.985 g) as a white powder.
[1044] .sup.1H-NMR(DMSO-d.sub.6).delta.2.30-2.42(1H,m),
2.95-3.17(3H,m), 3.2-4.2(16H,m), 4.46-4.78(3H,m), 7.02-7.08(1H,m),
7.35-7.42(1H,m), 7.51(1H,d,J=8.6 Hz), 7.81(1H,d,J=8.2 Hz),
9.17(1H,brs), 10.86(1H,brs), 12.40(1H,brs).
Example 251
Synthesis of
3-{(2S,4S)-4-[4-(1-phenyl-1H-indazol-3-yl)-1-piperazinyl]-2-pyrrolidinylc-
arbonyl}-1,3-thiazolidine trihydrochloride
[1045] (1) Using 1-(1-phenyl-1H-indazol-3-yl)piperazine (0.918 g)
and the title compound (0.901 g) of Reference Example 12, and in
the same manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(1-phenyl-1H-indazol-3-yl)-1-pipera-
zinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.23 g) was
obtained as a white solid.
[1046] .sup.1H-NMR(CDCl.sub.3).delta.1.41(4.5H,s), 1.47(4.5H,s),
1.88-2.04(1H,m), 2.45-2.57(1H,m), 2.66-3.18(7H,m), 3.38(1H,t,J=9.9
Hz), 3.50-4.15(7H,m), 4.39-4.80(3H,m), 7.11(1H,t,J=7.5 Hz),
7.24-7.32(1H,m), 7.40(1H,t,J=7.6 Hz), 7.49(2H,t,J=7.5 Hz),
7.66-7.78(4H,m).
[1047] (2) The above-mentioned compound (1.22 g) was dissolved in
ethanol (3 mL), and 4.1 mol/L hydrochloric acid-ethanol (6 mL) was
added thereto. The mixture was stirred at room temperature for 14
hr. The precipitated solid was collected by filtration to give the
title compound (0.823 g) as a white powder.
[1048] .sup.1H-NMR(DMSO-d.sub.6).delta.2.30-2.46(1H,m),
2.96-3.18(3H,m), 3.3-4.2(13H,m), 4.46-4.79(3H,m), 7.17-7.25(1H,m),
7.33(1H,t,J=7.4 Hz), 7.46-7.58(3H,m), 7.74(2H,d,J=7.6 Hz),
7.81(1H,d,J=8.6 Hz), 7.98(1H,d,J=8.2 Hz), 9.18(1H,brs),
10.94(1H,brs), 12.50(1H,brs).
Example 252
Synthesis of
3-{(2S,4S)-4-[4-(3-benz[d]isoxazolyl)-1-piperazinyl]-2-pyrrolidinylcarbon-
yl}-1,3-thiazolidine trihydrochloride
[1049] (1) Hydroxylammonium hydrochloride (15 g) was dissolved in
10% aqueous sodium hydroxide solution (220 mL), and a solution of
ethyl salicylate (24 g) in 1,4-dioxane (70 mL) was gradually added,
and the mixture was stirred at room temperature for 5 hr. The
reaction mixture was concentrated until the amount thereof became
almost the half, and acidified with conc. hydrochloric acid. The
precipitated solid was collected by filtration, which was then
recrystallized from methanol to give salicylhydroxamic acid (12 g)
as white crystals.
[1050] (2) The above-mentioned compound (12 g) was suspended in
tetrahydrofuran (30 mL) and thionyl chloride (13 mL) was added
thereto. The mixture was stirred at room temperature for 1 hr. The
reaction mixture was concentrated under reduced pressure, and the
residue was dissolved in 1,4-dioxane (30 mL). To this solution was
gradually added triethylamine (33 mL), and the mixture was stirred
at room temperature for 2 hr. The reaction mixture was acidified
with conc. hydrochloric acid, extracted with toluene. The extract
was washed successively with water and brine, dried and
concentrated under reduced pressure. The residue was washed with
diisopropyl ether to give 3-hydroxybenz[d]isoxazole (3.7 g) as a
pale-brown powder.
[1051] (3) Pyridine (1.2 mL) and phosphorus oxychloride (2.1 mL)
were added to the above-mentioned compound (2.0 g), and the mixture
was stirred at 125.degree. C. for 5 hr. Ice was added to the
reaction mixture, and the mixture was extracted with chloroform.
The extract was washed with water, dried and concentrated under
reduced pressure to give 3-chlorobenz[d]isoxazole (1.7 g) as a
brown solid.
[1052] (4) Using the above-mentioned compound (1.7 g) and
piperazine (7.6 g), and in the same manner as in Example 189 (1),
4-(3-benz[d]isoxazolyl)piperazine (0.944 g) was obtained as a gray
powder.
[1053] (5) Using the title compound (0.900 g) of Reference Example
12 and the above-mentioned compound (0.734 g), and in the same
manner as in Example 70 (1),
3-{(2S,4S)-4-[4-(3-benz[d]isoxazolyl)-1-piperazinyl]-1-tert-butoxycarbony-
l-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.5 g) was obtained as
a white solid.
[1054] (6) Using the above-mentioned compound (1.0 g), and in the
same manner as in Example 70 (2), the title compound (0.978 g) was
obtained as a white powder.
[1055] .sup.1H-NMR(DMSO-d.sub.6).delta.2.19-2.35(1H,m),
2.90-3.16(3H,m), 3.25-3.55(4H,m), 3.60-4.15(10H,m),
4.47-4.75(4H,m), 7.06-7.12(1H,m), 7.18-7.23(1H,m), 7.36(1H,d,J=7.5
Hz), 7.46(1H,d,J=7.8 Hz), 9.13(1H,brs), 10.86(1H,brs)
Example 253
Synthesis of
3-{(2S,4S)-4-[4-(5-cyano-3-benz[d]isoxazolyl)-1-piperazinyl]-2-pyrrolidin-
ylcarbonyl}-1,3-thiazolidine trihydrochloride
[1056] (1) Methyl salicylate (149 g) was dissolved in acetic acid
(900 mL), and bromine (50 mL) was added thereto. The mixture was
stirred at room temperature for 21 hr. Water (10 L) was added to
the reaction mixture, and the precipitated solid was collected by
filtration, which was then recrystallized from methanol to give
methyl 5-bromosalicylate (175 g) as white crystals.
[1057] (2) Using the above-mentioned compound (30 g), and in the
same manner as in Example 252 (1), 5-bromosalicylhydroxamic acid
(24 g) was obtained as white crystals.
[1058] (3) Using the above-mentioned compound (10 g), and in the
same manner as in Example 252 (2),
5-bromo-3-hydroxybenz[d]isoxazole (8.6 g) was obtained as a white
powder.
[1059] (4) Using the above-mentioned compound (8.6 g), and in the
same manner as in Example 252 (3), 5-bromo-3-chlorobenz[d]isoxazole
(7.4 g) was obtained as a white powder.
[1060] (5) Using the above-mentioned compound (7.4 g) and
piperazine (21 g), and in the same manner as in Example 189 (1),
4-(5-bromo-3-benz[d]isoxazolyl)piperazine (6.5 g) was obtained as a
gray powder.
[1061] (6) The above-mentioned compound (6.5 g) was dissolved in a
solution of tetrahydrofuran (100 mL) and sodium hydroxide (1.0 g)
in water (125 mL) and benzyl chloroformate (3.9 mL) was gradually
added under ice-cooling. The mixture was stirred at room
temperature for 2 hr. The precipitated solid was collected by
filtration, and washed with diisopropyl ether to give
1-benzyloxycarbonyl-4-(5-bromo-3-benz[d]isoxazolyl)piperazine (8.3
g) as a pale-brown powder.
[1062] (7) The above-mentioned compound (3.0 g) and zinc cyanide
(1.1 g) was dissolved in DMF (15 mL), and
tetrakistriphenylphosphinepalladium (0.633 g) was added thereto.
The mixture was stirred at 85.degree. C. for 18 hr under a nitrogen
atmosphere. The reaction mixture was added to 2 mol/L aqueous
ammonia and extracted with ethyl acetate. The extract was washed
successively with water and brine, dried and concentrated under
reduced pressure. The residue was purified by silica gel
chromatography to give
1-benzyloxycarbonyl-4-(5-cyano-3-benz[d]isoxazolyl)piperazine (2.1
g) as a white solid.
[1063] (8) The above-mentioned compound (1.5 g) was suspended in
methanol (60 mL), and ammonium formate (1.8 g) and 5% palladium
carbon (0.230 g) were added thereto. The mixture was refluxed for
0.5 hr. The reaction mixture was filtrated and the filtrate was
concentrated under reduced pressure. Saturated aqueous sodium
hydrogencarbonate solution was added to the residue, and the
mixture was extracted with chloroform. The extract was dried and
concentrated under reduced pressure to give a mixture (1.1 g)
containing 4-(5-cyano-3-benz[d]isoxazolyl)piperazine as a white
solid.
[1064] (9) Using the title compound (904 mg) and the
above-mentioned compound (681 mg), and in the same manner as in
Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-cyano-3-benz[d]isoxazolyl)-1-pip-
erazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (778 mg) was
obtained as a white solid.
[1065] (10) Using the above-mentioned compound (778 mg), and in the
same manner as in Example 70 (2), the title compound (349 mg) was
obtained as a white powder.
[1066] .sup.1H-NMR(DMSO-d.sub.6).delta.2.15-2.40(1H,m),
2.90-3.20(3H,m), 3.25-4.20(14H,m), 4.47-4.77(4H,m), 7.86(1H,d,J=8.7
Hz), 8.06(1H,dd,J=8.7, 1.2 Hz), 8.81(1H,brs), 9.11(1H,brs),
10.65(1H,brs).
Example 254
Synthesis of
3-{(2S,4S)-4-[4-(5-methoxy-3-benz[d]isoxazolyl)-1-piperazinyl]-2-pyrrolid-
inylcarbonyl}-1,3-thiazolidine trihydrochloride
[1067] (1) 5-Methoxysalicylic acid (41 g) was dissolved in
acetonitrile (500 mL), and ethyl iodide (20 mL) and DBU (38 mL)
were added thereto. The mixture was refluxed for 6 hr. The reaction
mixture was concentrated under reduced pressure, and 1 mol/L
hydrochloric acid was added to the residue. The mixture was
extracted with ethyl acetate. The extract was washed successively
with saturated aqueous sodium hydrogencarbonate solution and brine,
dried and concentrated under reduced pressure to give a mixture (44
g) containing ethyl 5-methoxysalicylate as a brown oil.
[1068] (2) Using the above-mentioned compound (44 g), and in the
same manner as in Example 252 (1), 5-methoxysalicylhydroxamic acid
(33 g) was obtained as white crystals.
[1069] (3) Using the above-mentioned compound (33 g), and in the
same manner as in Example 252 (2),
3-hydroxy-5-methoxybenz[d]isoxazole (5.9 g) was obtained as a
pale-brown powder.
[1070] (4) Using the above-mentioned compound (5.9 g), and in the
same manner as in Example 252 (3), a mixture (4.2 g) containing
3-chloro-5-hydroxybenz[d]isoxazole was obtained as a black oil.
[1071] (5) piperazine (19 g) was melted by heating at 140.degree.
C., and the above-mentioned title compound (4.2 g) was added
thereto. After stirring at 140.degree. C. for 1 hr, the mixture was
poured into iced water and extracted with chloroform. After drying,
the solvent was evaporated under reduced pressure, and the residue
was diluted with ethyl acetate and extracted with 1 mol/L
hydrochloric acid. The aqueous layer was basified with 2 mol/L
aqueous sodium hydroxide solution and extracted with chloroform.
After drying, the solvent was evaporated under reduced pressure to
give 4-(5-methoxy-3-benz[d]isoxazolyl)piperazine (804 mg) as a
black solid.
[1072] (6) Using the title compound (0.900 g) of Reference Example
12 and the above-mentioned compound (0.804 g), and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-methoxy-3-benz[d]isoxazolyl)-1-p-
iperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.0 g) was
obtained as white amorphous.
[1073] (7) Using the above-mentioned compound (1.0 g), and in the
same manner as in Example 70 (2), the title compound (0.693 g) was
obtained as a white powder.
[1074] .sup.1H-NMR(DMSO-d.sub.6).delta.2.20-2.40(1H,m),
2.90-3.19(3H,m), 3.30-3.60(4H,m), 3.65-4.15(13H,m),
4.30-4.76(4H,m), 6.65(1H,dd,J=8.7, 2.4 Hz), 6.97(1H,d,J=2.4 Hz),
7.35(1H,d,J=8.7 Hz), 10.15(1H,brs), 10.95(1H,brs).
Example 255
Synthesis of
3-{(2S,4S)-4-[4-(3-benz[d]isothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarb-
onyl}-1,3-thiazolidine 1.5 oxalate
[1075] (1) Using 1-(3-benz[d]isothiazolyl)piperazine (385 mg) and
the title compound (500 mg) of Reference Example 12, and in the
same manner as in Example 70 (1),
3-{(2S,4S)-4-[4-(3-benz[d]isothiazolyl)-1-piperazinyl]-1-tert-butoxycarbo-
nyl-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (716 mg) was obtained
as a white powder.
[1076] (2) The above-mentioned compound (709 mg) was dissolved in
methanol (10 mL), and 4 mol/L hydrochloric acid-ethyl acetate (10
mL) was added thereto. The mixture was stirred at room temperature
for 19 hr. The precipitated solid was collected by filtration, and
saturated aqueous sodium hydrogencarbonate solution was added
thereto. The mixture was extracted with chloroform. The extract was
concentrated under reduced pressure, and the residue was dissolved
in ethanol (10 mL), and oxalic acid (130 mg) was added thereto. The
precipitated solid was collected by filtration to give the title
compound (150 mg) as a white powder.
[1077] .sup.1H-NMR(DMSO-d.sub.6).delta.1.60-1.81(1H,m),
2.78-2.85(4H,m), 2.89-3.24(4H,m), 3.52-3.99(7H,m), 4.43-4.74(4H,m),
7.39-7.48(1H,m), 7.53-7.60(1H,m), 8.01-8.09(2H,m).
Example 256
Synthesis of
3-{(2S,4S)-4-[4-(2-oxazolo[4,5-b]pyridyl)-1-piperazinyl]-2-pyrrolidinylca-
rbonyl}-1,3-thiazolidine trihydrochloride
[1078] (1) 2-Amino-3-hydroxypyridine (5.51 g) was dissolved in
pyridine (100 mL), and potassium ethylxanthate (8.82 g) was added
thereto. The mixture was refluxed for 2 hr. Iced water (400 mL) was
added to the reaction mixture, and concentrated hydrochloric acid
(40 mL) was added thereto. The mixture was extracted with
chloroform and the extract was washed with brine and concentrated
under reduced pressure to give 1,3-oxazolo[4,5-b]pyridine-2-thiol
(5.13 g) as a pale-brown powder.
[1079] (2) The above-mentioned compound (5 g) and 2 drops of DMF
were added to thionyl chloride (20 mL). The mixture was refluxed
for 1 hr. The reaction mixture was concentrated under reduced
pressure to give 2-chloro-1,3-oxazolo[4,5-b]-pyridine (5.08 g) as a
pale-brown powder.
[1080] (3) Using the above-mentioned compound (3.09 g) and
piperazine (5.17 g), and in the same manner as in Example 239 (3),
1-(2-oxazolo[4,5-b]pyridyl)piperazine (1.15 g) was obtained as a
yellowish brown powder.
[1081] (4) Using the above-mentioned compound (1.15 g) and the
title compound (0.601 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-oxazolo[4,5-b]pyridyl)-1-piperaz-
inyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (0.635 g) was
obtained as a white solid.
[1082] (5) Using the above-mentioned compound (635 mg), and in the
same manner as in Example 186 (2), the title compound (293 mg) was
obtained as a white powder.
[1083] .sup.1H-NMR(DMSO-d.sub.6).delta.2.02-2.30(1H,m),
2.83-3.00(1H,m), 3.00-3.20(2H,m), 3.20-3.48(4H,m), 3.48-4.30(9H,m),
4.40-4.80(3H,m), 7.16(1H,dd,J=7.8, 5.4 Hz), 7.95(1H,d,J=7.8 Hz),
8.22(1H,d,J=5.4 Hz), 9.09(1H,brs), 10.59(1H,brs)
Example 257
Synthesis of
3-((2S,4S)-4-{4-[2-(1-ethoxycarbonyl-1-methylethyl)-6-imidazo[1,2-b]pyrid-
azinyl]-1-piperazinyl}-2-pyrrolidinylcarbonyl)-1,3-thiazolidine
trihydrochloride
[1084] (1) Using ethyl
2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate (2.00
g) and piperazine (19.7 g), and by a reaction at 100.degree. C. in
the same manner as in Example 196 (1),
1-[(2-(1-ethoxycarbonyl-1-methylethyl)-6-imidazo[1,2-b]pyridazinyl]pipera-
zine (2.37 g) was obtained as an oil.
[1085] (2) Using the above-mentioned compound (2.37 g) and the
title compound (1.87 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-((2S,4S)-1-tert-butoxycarbonyl-4-{4-[2-(1-ethoxycarbonyl-1-methylethyl)-
-6-imidazo[1,2-b]pyridazinyl]-1-piperazinyl}-2-pyrrolidinylcarbonyl)-1,3-t-
hiazolidine (3.29 g) was obtained as a pale-yellow solid.
[1086] (3) The above-mentioned compound (1.10 g) was dissolved in
dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added
thereto. The mixture was stirred at room temperature for 1.5 hr.
The solvent was evaporated under reduced pressure, and the residue
was dissolved in ethyl acetate. 4 mol/L Hydrochloric acid-ethyl
acetate solution (1 mL) was added thereto, and the precipitated
solid was collected by filtration to give the title compound (1.05
g) as a white powder.
[1087] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.15(3H,t,J=7.1 Hz),
1.61(6H,s), 2.16-2.36(1H,m), 2.90-4.80(19H,m), 4.10(2H,q,J=7.1 Hz),
7.64(1H,d,J=10 Hz), 8.10(1H,d,J=10 Hz), 8.22(1H,s), 9.11(1H,brs),
10.85(1H,brs).
Example 258
Synthesis of
3-((2S,4S)-4-{4-[2-(1-carboxy-1-methylethyl)-6-imidazo[1,2-b]pyridazinyl]-
-1-piperazinyl}-2-pyrrolidinylcarbonyl)-1,3-thiazolidine
trihydrochloride
[1088] (1)
3-((2S,4S)-1-tert-Butoxycarbonyl-4-{4-[2-(1-ethoxycarbonyl-1-methylethyl)-
-6-imidazo[1,2-b]pyridazinyl]-1-piperazinyl}-2-pyrrolidinylcarbonyl)-1,3-t-
hiazolidine [product of Example 257 (2), 608 mg] was dissolved in
ethanol (2 mL). A solution of lithium hydroxide monohydrate (85 mg)
in water (1 mL) was added, and the mixture was stirred at
60.degree. C. for 2 hr. Dilute hydrochloric acid was added to the
reaction mixture to make the pH 6. The mixture was extracted with
chloroform. The extract was dried and concentrated under reduced
pressure to give
3-((2S,4S)-1-tert-butoxycarbonyl-4-{4-[2-(1-carboxy-1-methylethyl)-6-imid-
azo[1,2-b]pyridazinyl]-1-piperazinyl}-2-pyrrolidinylcarbonyl)-1,3-thiazoli-
dine (580 mg) as a pale-yellow powder.
[1089] (2) Using the above-mentioned compound (579 mg), and in the
same manner as in Example 257 (3), the title compound (477 mg) was
obtained as a white powder.
[1090] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.59(6H,s),
2.11-2.31(1H,m), 2.82-4.20(16H,m), 4.47-4.74(3H,m).sub.1,
7.64(1H,d,J=10 Hz), 8.09(1H,d,J=10 Hz), 8.22(1H,s), 9.07(1H,brs),
10.68(1H,brs), 12.85(1H,brs).
Example 259
Synthesis of
3-{(2S,4S)-4-[4-(2-methyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbon-
yl}-1,3-thiazolidine trihydrochloride
[1091] (1) Phosphorus oxychloride (30 mL) was added to
4-hydroxy-2-methylquinoline (10 g), and the mixture was stirred at
room temperature for 30 min. The reaction mixture was concentrated
under reduced pressure, and saturated aqueous sodium carbonate
solution was added to the residue under ice-cooling. The mixture
was extracted with ethyl acetate. The extract was washed with
brine, and concentrated under reduced pressure to give
4-chloro-2-methylquinoline (11.2 g) as a black oil.
[1092] (2) Using the above-mentioned compound (5.33 g) and
piperazine (25.8 g), and in the same manner as in Example 189 (1),
1-(2-methyl-4-quinolyl)piperazine (4.19 g).
[1093] (3) Using the above-mentioned compound (500 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-methyl-4-quinolyl)-1-piperazinyl-
]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.15 g) was obtained as
a pale-yellow oil.
[1094] (4) Using the above-mentioned compound (1.15 g), and in the
same manner as in Example 186 (2), the title compound (0.863 g) was
obtained as a pale-brown powder.
[1095] .sup.1H-NMR(DMSO-d.sub.6).delta.2.20-2.42(1H,m), 2.81(3H,s),
2.91-3.20(3H,m), 3.30-4.26(13H,m), 4.44-4.87(3H,m), 7.35(1H,s),
7.73(1H,t,J=7.6 Hz), 8.00(1H,t,J=7.6 Hz), 8.16(1H,d,J=8.4 Hz),
8.24(1H,d,J=8.4 Hz)
Example 260
Synthesis of
3-{(2S,4R)-4-[4-(2-trifluoromethyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidi-
nylcarbonyl}-1,3-thiazolidine dihydrochloride
[1096] (1) Diethanolamine (20 mL) was added to
4-chloro-2-trifluoromethylquinoline (5.04 g), and the mixture was
stirred at 80.degree. C. for 19 hr. Brine was added to the reaction
mixture, and the mixture was extracted with ethyl acetate. The
extract was dried and concentrated under reduced pressure. The
residue was purified by silica gel chromatography to give
4-[(N,N-bis(2-hydroxyethyl)amino]-2-trifluoromethylquinoline (3.40
g) as a white powder.
[1097] (2) The above-mentioned compound (1.77 g) and triethylamine
(2.63 mL) were dissolved in ethyl acetate (100 mL), and
methanesulfonyl chloride (1.28 mL) was added under ice-cooling. The
mixture was stirred at room temperature for 30 min. The
precipitated solid was collected by filtration, and the filtrate
was concentrated under reduced pressure to give dimesylate as an
oil. This was dissolved in N-methyl-2-pyrrolidone (100 mL), and the
title compound (2.02 g) of Reference Example 15 and
N,N-diisopropylethylamine (3.10 mL) were added thereto. The mixture
was stirred at 100.degree. C. for 15 hr. 10% Aqueous citric acid
solution was added to the reaction mixture, and the mixture was
extracted with ethyl acetate. The extract was washed successively
with saturated aqueous sodium hydrogencarbonate solution and brine,
dried and concentrated under reduced pressure. The residue was
purified by silica gel chromatography to give
3-{(2S,4R)-1-tert-butoxycarbonyl-4-[4-(2-trifluoromethyl-4-quinol-
yl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (0.248
g) as a pale-brown powder.
[1098] (3) Using the above-mentioned compound (246 mg), and in the
same manner as in Example 133 (2), the title compound (101 mg) was
obtained as a white powder.
[1099] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.40-2.50(1H,m),
3.00-3.18(3H,m), 3.59-3.95(12H,m), 4.12-4.22(1H,m),
4.47-5.03(3H,m), 7.39(1H,s), 7.75(1H,t,J=7.9 Hz), 7.88-7.91(1H,m),
8.12-8.14(2H,m), 9.30(1H,brs), 10.75(1H,brs).
Example 261
Synthesis of
3-{(2S,4S)-4-[4-(7-trifluoromethyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidi-
nylcarbonyl}-1,3-thiazolidine trihydrochloride
[1100] (1) Using 4-chloro-7-(trifluoromethyl)quinoline (2.5 g) and
piperazine (9.30 g), and in the same manner as in Example 189 (1),
1-(7-trifluoromethyl-4-quinolyl)piperazine (3.04 g) was obtained as
a pale-brown solid.
[1101] (2) Using the above-mentioned compound (619 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(7-trifluoromethyl-4-quinolyl)-1-pi-
perazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (458 mg) was
obtained as a pale-yellow oil.
[1102] (3) Using the above-mentioned compound (458 mg), and in the
same manner as in Example 186 (2), the title compound (282 mg) was
obtained as a brown powder.
[1103] .sup.1H-NMR(DMSO-d.sub.6).delta.2.20-2.47(1H,m),
2.90-3.20(3H,m), 3.30-4.30(13H,m), 4.45-4.85(3H,m), 7.46(1H,d,J=6.7
Hz), 7.98(1H,dd,J=9.0, 1.5 Hz), 8.43(1H,d,J=8.9 Hz), 8.62(1H,s),
8.96(1H,d,J=6.7 Hz).
Example 262
Synthesis of
3-{(2S,4S)-4-[4-(2-methoxycarbonyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidi-
nylcarbonyl}-1,3-thiazolidine trihydrochloride
[1104] (1) Phosphorus oxychloride (100 mL) was added to kynurenic
acid (25 g). The mixture was refluxed for 6 hr. The reaction
mixture was concentrated under reduced pressure, and the residue
was dissolved in 1,4-dioxane (100 mL). Aqueous ammonia (400 mL) was
dropwise added thereto under ice-cooling. Water (500 mL) was added
thereto, and the mixture was extracted with chloroform. The extract
was washed with brine and concentrated under reduced pressure to
give 4-chloroquinoline-2-carboxamide (27.3 g) as a black purple
solid.
[1105] (2) piperazine (12.9 g) was suspended in
N-methyl-2-pyrrolidone (170 mL) and the above-mentioned compound
(10.3 g) was added thereto. The mixture was stirred at 80.degree.
C. with heating. The reaction mixture was concentrated under
reduced pressure, and the residue was added to 1 mol/L hydrochloric
acid (150 mL), and the mixture was washed with chloroform. The
mixture was basified with aqueous sodium hydroxide solution, and
the mixture was extracted with chloroform. The extract was
concentrated under reduced pressure to give
1-(2-carbamoyl-4-quinolyl)piperazine (35.18 g) as a pale-yellow
powder.
[1106] (3) Using the above-mentioned compound (2.54 g) and the
title compound (1.26 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-carbamoyl-4-quinolyl)-1-piperazi-
nyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (2.19 g).
[1107] (4) The above-mentioned compound (2.19 g) and imidazole
(0.551 g) were dissolved in pyridine (20 mL), and phosphorus
oxychloride (1.51 mL) was dropwise added to the reaction mixture
under ice-cooling. The mixture was stirred under ice-cooling for 1
hr. Saturated aqueous sodium hydrogencarbonate solution was added
to the reaction mixture, and the mixture was extracted with
chloroform. The extract was concentrated under reduced pressure and
the residue was purified by silica gel chromatography to give
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-cyano-4-quinolyl)-1-piperazinyl]-
-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (0.658 g) as a red orange
solid.
[1108] (5) 5.6 mol/L Hydrochloric acid-methanol (30 mL) was added
to the above-mentioned compound (992 mg), and the mixture was
stirred at room temperature for 24 hr. The reaction mixture was
concentrated under reduced pressure, and saturated aqueous sodium
hydrogencarbonate solution was added to the residue. The mixture
was extracted with chloroform and the extract was concentrated
under reduced pressure. The residue was purified by silica gel
chromatography to give a free base (670 mg) of the title compound
as a pale-yellow oil. This was dissolved in methanol (10 mL), and
5.6 mol/L hydrochloric acid-methanol (0.79 mL) was added thereto.
The mixture was concentrated under reduced pressure to give the
title compound (615 mg) as a pale-yellow powder.
[1109] .sup.1H-NMR(DMSO-d.sub.6).delta.2.20-2.56(1H,m),
2.82-3.20(3H,m), 3.40-4.30(13H,m), 4.00(3H,s), 4.41-4.82(3H,m),
7.63(1H,s), 7.75(1H,t,J=7.8 Hz), 7.93(1H,t,J=7.8 Hz),
8.17(1H,d,J=7.8 Hz), 8.24(1H,d,J=7.8 Hz), 9.20(1H,brs),
11.05(1H,brs).
Example 263
Synthesis of
3-{(2S,4S)-4-[4-(2-carbamoyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcar-
bonyl}-1,3-thiazolidine trihydrochloride
[1110] Using
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-carbamoyl-4-quinolyl)-1-piperazi-
nyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine [product of Example
262 (3), 1.05 g], and in the same manner as in Example 186 (2), the
title compound (696 mg) was obtained as a brown powder.
[1111] .sup.1H-NMR(DMSO-d.sub.6).delta.2.20-2.42(1H,m),
2.89-3.20(3H,m), 3.30-4.30(13H,m), 4.44-4.83(3H,m), 7.73(1H,t,J=8.0
Hz), 7.87(1H,s), 7.95(1H,t,J=8.0 Hz), 8.17(1H,d,J=8.0 Hz),
8.24(1H,brs), 8.28(1H,d,J=8.0 Hz), 8.86(1H,brs), 9.18(1H,brs),
10.89(1H,brs).
Example 264
Synthesis of
3-{(2S,4S)-4-[4-(3-exycarbonyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylc-
arbonyl}-1,3-thiazolidine trihydrochloride
[1112] (1) Diethyl ethoxymethylenemalonate (115 g) was dropwise
added to aniline (50 g), and the mixture was refluxed for 1 hr. The
resulting ethanol was evaporated under atmospheric pressure, and
the residue was heated at 200.degree. C. and poured into diphenyl
ether (750 mL). The mixture was stirred at 220-250.degree. C. for 2
hr with heating. The resulting ethanol was again evaporated under
atmospheric pressure, and the reaction mixture was allowed to cool
to room temperature. The precipitated solid was collected by
filtration and washed with hexane to give ethyl
4-hydroxyquinoline-3-carboxylate (51.0 g) as a white powder.
[1113] (2) The above-mentioned compound (51.0 g) was added to
phosphorus oxychloride (121 mL), and the mixture was stirred at
60-70.degree. C. for 2 hr with heating. The reaction mixture was
concentrated under reduced pressure, and the residue was added to
iced water (1 L). The mixture was basified with 1 mol/L aqueous
sodium hydroxide solution (500 mL) and sodium hydrogencarbonate.
The mixture was extracted with ethyl acetate, washed with brine and
concentrated under reduced pressure to give ethyl
4-chloroquinoline-3-carboxylate (54.2 g) as a pale-brown solid.
[1114] (3) piperazine (12.9 g) was dissolved in DMF (100 mL), and a
solution of the above-mentioned compound (11.8 g) in DMF (100 mL)
was added thereto. The mixture was stirred at room temperature for
1 hr. The reaction mixture was added to iced water (500 mL), and
the mixture was extracted with ethyl acetate. The extract was
washed successively with water and brine, and concentrated under
reduced pressure to give 1-(2-ethoxycarbonyl-4-quinolyl)piperazine
(7.92 g) as a pale-yellow solid.
[1115] (4) Using the above-mentioned compound (3.42 g) and the
title compound (2.70 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3-ethoxycarbonyl-4-quinolyl)-1-pip-
erazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (4.57 g) was
obtained as a pale-yellow powder.
[1116] (5) The above-mentioned compound (600 mg) was dissolved in
ethanol (20 mL), and 4.1 mol/L hydrochloric acid-ethanol (10 mL)
was added thereto. The mixture was stirred at room temperature for
24 hr. The reaction mixture was concentrated under reduced
pressure, and saturated aqueous sodium hydrogencarbonate solution
was added to the residue. The mixture was extracted with chloroform
and the extract was concentrated under reduced pressure. The
residue was purified by silica gel chromatography to give a free
base (269 mg) of the title compound. This was dissolved in ethanol
(5 mL) and 4.1 mol/L hydrochloric acid-ethanol(0.42 mL) was added
thereto. The mixture was concentrated under reduced pressure to
give the title compound (253 mg) as a pale-yellow powder.
[1117] .sup.1H-NMR(DMSO-d.sub.6).delta.1.41(3H,t,J=6.9 Hz),
2.22-2.46(1H,m), 2.90-3.20(3H,m), 3.30-4.30(13H,m),
4.33-4.82(5H,m), 7.80(1H,t,J=7.8 Hz), 8.02(1H,t,J=7.8 Hz),
8.19(1H,d,J=7.8 Hz), 8.27(1H,d,J=7.8 Hz), 9.02(1H,s), 9.15(1H,brs),
10.88(1H,brs).
Example 265
Synthesis of
3-{(2S,4S)-4-[4-(2-cyano-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbony-
l}-1,3-thiazolidine trihydrochloride
[1118]
3-{(2S,4S)-1-tert-Butoxycarbonyl-4-[4-(2-cyano-4-quinolyl)-1-piper-
azinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine [product of
Example 262 (4), 658 mg] was dissolved in chloroform (10 mL), and 4
mol/L hydrochloric acid-ethyl acetate (5 mL) was added thereto. The
mixture was stirred at room temperature for 24 hr. The solvent was
evaporated under reduced pressure, and saturated aqueous sodium
hydrogencarbonate solution was added to the residue. The mixture
was extracted with chloroform and the extract was concentrated
under reduced pressure. The residue was purified by silica gel
chromatography to give a free base (435 mg) of the title compound.
This was dissolved in ethanol (20 mL), and 4.1 mol/L hydrochloric
acid-ethanol (0.75 mL) was added thereto. The mixture was
concentrated under reduced pressure to give the title compound (353
mg) as a pale-yellow powder.
[1119] .sup.1H-NMR(DMSO-d.sub.6).delta.2.20-2.45(1H,m),
2.90-3.20(3H,m), 3.30-4.22(13H,m), 4.43-4.80(3H,m), 7.63(1H,s),
7.75(1H,t,J=7.8 Hz), 7.89(1H,t,J=7.8 z), 8.01-8.19(2H,m),
9.17(1H,brs), 10.71(1H,brs).
Example 266
Synthesis of
3-{(2S,4S)-4-[(4-(2-phenyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbo-
nyl}-1,3-thiazolidine trihydrochloride
[1120] (1) Using 4-chloro-2-phenylquinoline (2.50 g) and piperazine
(8.98 g), and in the same manner as in Example 268 (1),
1-(2-phenyl-4-quinolyl)piperazine (2.72 g) was obtained.
[1121] (2) Using the above-mentioned compound (1.01 g) and the
title compound (1.00 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-phenyl-4-quinolyl)-1-piperazinyl-
]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.77 g) was obtained as
a white powder.
[1122] (3) The above-mentioned compound (1.75 g) was dissolved in
methanol (10 mL), and 4 mol/L hydrochloric acid-ethyl acetate (10
mL) was added thereto. The mixture was stirred at room temperature
for 14 hr. The precipitated solid was collected by filtration to
give the title compound (0.970 g) as a white powder.
[1123] .sup.1H-NMR(DMSO-d.sub.6).delta.2.20-2.45(1H,m),
2.90-3.17(3H,m), 3.28-4.00(13H,m), 4.42-4.80(3H,m), 7.57(1H,s),
7.61-7.82(4H,m), 7.95-8.08(1H,m), 8.16-8.31(3H,m), 8.50(1H,d,J=8.7
Hz), 9.15(1H,brs), 11.06(1H,brs).
Example 267
Synthesis of
3-{(2S,4S)-4-[(4-(2-amino-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbon-
yl}-1,3-thiazolidine trihydrochloride
[1124] (1) Bromine (2.32 mL) was dissolved in 5% aqueous potassium
hydroxide solution (190 mL), and a solution of
4-chloroquinoline-2-carboxamide [product of Example 262 (1), 9.80
g] in tetrahydrofuran (190 mL) was dropwise added thereto. The
mixture was stirred at room temperature for 30 min, and the mixture
was stirred at 80.degree. C. for 1 hr with heating. The reaction
mixture was filtrated and the filtrate was added to water. The
mixture was extracted with chloroform, and the extract was washed
with brine and concentrated under reduced pressure. The residue was
purified by silica gel chromatography to give
2-amino-4-chloroquinoline (1.98 g) as a pale-yellow solid.
[1125] (2) using the above-mentioned compound (1.98 g) and
piperazine (19.1 g), and in the same manner as in Example 189 (1),
1-(2-amino-4-quinolyl)piperazine (1.85 g) was obtained as a
pale-brown powder.
[1126] (3) Using the above-mentioned compound (913 mg) and the
title compound (901 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-amino-4-quinolyl)-1-piperazinyl]-
-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (465 mg) was obtained as
a white solid.
[1127] (4) Using the above-mentioned compound (465 mg), and in the
same manner as in Example 186 (2), the title compound (439 mg) was
obtained as a white powder.
[1128] .sup.1H-NMR(DMSO-d.sub.6).delta.2.20-2.42(1H,m),
2.86-3.20(3H,m), 3.30-4.30(13H,m), 4.41-4.84(3H,s), 6.52(1H,s),
7.46(1H,t,J=8.1 Hz), 7.59-7.82(2H,m), 7.91(1H,d,J=8.1 Hz),
8.33(2H,brs), 9.14(1H,brs), 10.85(1H,brs), 13.79(1H,brs)
Example 268
Synthesis of
3-{(2S,4S)-4-[4-(7-chloro-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbon-
yl}-1,3-thiazolidine trihydrochloride
[1129] (1) piperazine (65.2 g) was melted by heating at 120.degree.
C., and 4,7-dichloroquinoline (15.0 g) was added thereto. The
mixture was stirred at 120.degree. C. for 2.5 hr and the reaction
mixture was added to water. The mixture was extracted with
chloroform and concentrated under reduced pressure to give
1-(7-chloro-4-quinolyl)piperazine (7.72 g).
[1130] (2) Using the above-mentioned compound (0.87 g) and the
title compound (1.00 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(7-chloro-4-quinolyl)-1-piperazinyl-
]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.65 g) was obtained as
a white powder.
[1131] (3) The above-mentioned compound (1.64 g) was suspended in
methanol (10 mL), and 4 mol/L hydrochloric acid-ethyl acetate (8.0
mL) was added thereto. The mixture was stirred at room temperature
for 13 hr. The precipitated solid was collected by filtration to
give the title compound (1.04 g) as a white powder.
[1132] .sup.1H-NMR(DMSO-d.sub.6).delta.2.10-2.37(1H,m),
2.84-4.00(16H,m), 4.41-4.82(3H,m), 7.36(1H,d,J=6.9 Hz),
7.77(1H,dd,J=9.0, 1.8 Hz), 8.22(1H,d,J=9.0 Hz), 8.27(1H,d,J=1.8
Hz), 8.85(1H,d,J=6.9 Hz), 9.18(1H,brs), 10.82(1H,brs).
Example 269
Synthesis of
3-{(2S,4S)-4-[(4-(2-trifluoromethyl-8-methyl-4-quinolyl)-1-piperazinyl]-2-
-pyrrolidinylcarbonyl}-1,3-thiazolidine dihydrochloride
[1133] (1) 2-Methylaniline (5.00 g) was dissolved in 75% phosphoric
acid (20 mL), and ethyl trifluoroacetoacetate (8.60 g) was dropwise
added thereto at 105.degree. C. The mixture was stirred at
105.degree. C. for 5.5 hr. After allowing to cool, the reaction
mixture was added to water. The precipitated solid was collected by
filtration to give 2-trifluoromethyl-4-hydroxy-8-methylquinoline
(1.84 g).
[1134] (2) The above-mentioned compound (1.82 g) was dissolved in
phosphorus oxychloride (8.00 mL), and the mixture was stirred at
70.degree. C. for 2.5 hr. The reaction mixture was concentrated
under reduced pressure, and saturated aqueous sodium
hydrogencarbonate solution was added to the residue. The mixture
was extracted with chloroform and the extract was concentrated
under reduced pressure to give
4-chloro-2-trifluoromethyl-8-methylquinoline (1.66 g).
[1135] (3) Using the above-mentioned compound (1.65 g) and
piperazine (4.00 g), and in the same manner as in Example 268 (1),
1-(2-trifluoromethyl-8-methyl-4-quinolyl)piperazine (1.57 g) was
obtained.
[1136] (4) Using the above-mentioned compound (1.03 g) and the
title compound (1.00 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-trifluoromethyl-8-methyl-4-quino-
lyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.81
g) was obtained as a white powder.
[1137] (5) Using the above-mentioned compound (1.80 g), and in the
same manner as in Example 268 (3), the title compound (1.30 g) was
obtained as a white powder.
[1138] .sup.1H-NMR(DMSO-d.sub.6).delta.2.20-2.45(1H,m), 2.72(3H,s),
2.90-3.20(3H,m), 3.25-4.25(13H,m), 4.44-4.82(3H,m), 7.40(1H,s),
7.63(1H,dd,J=8.3, 6.9 Hz), 7.75(1H,d,J=6.9 Hz), 7.93(1H,d,J=8.3
Hz), 9.12(1H,brs), 10.85(1H,brs), 12.65(1H,brs).
Example 270
Synthesis of
3-((2S,4S)-4-{4-[2,6-bis(trifluoromethyl)-4-quinolyl]-1-piperazinyl}-2-py-
rrolidinylcarbonyl)-1,3-thiazolidine dihydrochloride
[1139] (1) 4-Hydroxy-2,6-bis(trifluoromethyl)quinoline (1.28 g) was
dissolved in phosphorus oxychloride (5.0 mL), and the mixture was
stirred at room temperature for 17 hr. The reaction mixture was
concentrated under reduced pressure, and saturated aqueous sodium
hydrogencarbonate solution was added to the residue. The mixture
was extracted with chloroform and concentrated under reduced
pressure to give 4-chloro-2,6-bis(trifluoromethyl)quinoline (1.17
g).
[1140] (2) Using the above-mentioned compound (1.14 g) and
piperazine (3.29 g), and in the same manner as in Example 189 (1),
1-[(2,6-bis(trifluoromethyl)-4-quinolyl]piperazine (870 mg) was
obtained.
[1141] (3) Using the above-mentioned compound (0.860 g) and the
title compound (0.86 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-((2S,4S)-1-tert-butoxycarbonyl-4-{4-[2,6-bis(trifluoromethyl)-4-quinoly-
l]-1-piperazinyl}-2-pyrrolidinylcarbonyl)-1,3-thiazolidine (1.55 g)
was obtained as a white powder.
[1142] (3) Using the above-mentioned compound (1.54 g), and in the
same manner as in Example 268 (3), the title compound (860 mg) was
obtained as a white powder.
[1143] .sup.1H-NMR(DMSO-d.sub.6).delta.2.11-2.46(1H,m),
2.72-4.20(16H,m), 4.35-4.89(3H,m), 7.54(1H,s), 8.14(1H,dd,J=9.0,
1.2 Hz), 8.33(1H,d,J=9.0 Hz), 8.38(1H,d,J=1.2 Hz), 9.24(1H,brs),
10.88(1H,brs).
Example 271
Synthesis of
3-((2S,4S)-4-{4-[2,8-bis(trifluoromethyl)-4-quinolyl]-1-piperazinyl}-2-py-
rrolidinylcarbonyl)-1,3-thiazolidine dihydrochloride
[1144] (1) using 4-chloro-2,8-bis(trifluoromethyl)quinoline (0.500
g) and piperazine (7.19 g), and in the same manner as in Example
189(1), 1-[2,8-bis(trifluoromethyl)-4-quinolyl]piperazine (0.519 g)
was obtained as a pale-brown solid.
[1145] (2) Using the above-mentioned compound (519 mg) and the
title compound (406 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-{4-[2,8-bis(trifluoromethyl)-4-quinoly-
l]-1-piperazinyl}-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (631 mg)
was obtained as a white powder.
[1146] (3) Using the above-mentioned compound (547 mg), and in the
same manner as in Example 186 (2), the title compound (362 mg) was
obtained as a white powder.
[1147] .sup.1H-NMR(DMSO-d.sub.6).delta.2.11-2.45(1H,m),
2.86-3.20(3H,m), 3.30-4.30(13H,m), 4.45-4.86(3H,m), 7.52(1H,s),
7.85(1H,t,J=8.4 Hz), 8.31(1H,d,J=8.4 Hz), 8.42(1H,d,J=8.4 Hz).
Example 272
Synthesis of
3-{(2S,4S)-4-[4-(2-trifluoromethyl-6-methoxy-4-quinolyl)-1-piperazinyl]-2-
-pyrrolidinylcarbonyl}-1,3-thiazolidine trihydrochloride
[1148] (1) 4-Methoxyaniline (5.00 g) was dissolved in 75%
phosphoric acid (20 mL) and ethyl trifluoroacetoacetate (7.48 g)
was dropwise added thereto at 110.degree. C. The mixture was
stirred at 110.degree. C. for 4' hr with heating. After allowing to
cool, the reaction mixture was added to saturated aqueous natrim
hydrogencarbonate solution, and the mixture was extracted with
ethyl acetate. The extract was dried and the solvent was evaporated
under reduced pressure. The residue was purified by silica gel
chromatography to give
2-trifluoromethyl-4-hydroxy-6-methoxyquinoline (0.450 g).
[1149] (2) Using the above-mentioned compound (450 mg), and in the
same manner as in Example 270 (1),
4-chloro-2-trifluoromethyl-6-methoxyquinoline (410 mg) was obtained
as a white powder.
[1150] (3) Using the above-mentioned compound (0.410 g) and
piperazine (1.32 g), and in the same manner as in Example 189 (1),
1-(2-trifluoromethyl-6-methoxy-4-quinolyl)piperazine (0.450 g) was
obtained.
[1151] (4) Using the above-mentioned compound (450 mg) and the
title compound (430 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-trifluoromethyl-6-methoxy-4-quin-
olyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (660
mg) was obtained as a white powder.
[1152] (5) Using the above-mentioned compound (660 mg), and in the
same manner as in Example 268 (3), the title compound (290 mg) was
obtained as a white powder.
[1153] .sup.1H-NMR(DMSO-d.sub.6).delta.2.34-2.54(1H,m),
2.93-3.21(3H,m), 3.31-4.30(13H,m), 3.97(3H,s), 4.45-4.85(3H,m),
7.31(1H,d,J=2.7 Hz), 7.38(1H,s), 7.55(1H,dd,J=9.3, 2.7 Hz),
8.06(1H,d,J=9.3 Hz), 9.18(1H,brs), 11.84(1H,brs),
12.78(1H,brs).
Example 273
Synthesis of
3-{(2S,4S)-4-[(4-(2-trifluoromethyl-7-methoxy-4-quinolyl)-1-piperazinyl]--
2-pyrrolidinylcarbonyl}-1,3-thiazolidine dihydrochloride
[1154] (1) Using 3-methoxyaniline (20.0 g) and ethyl
trifluoroacetoacetate (29.9 g), and in the same manner as in
Example 269 (1), 2-trifluoromethyl-4-hydroxy-7-methoxyquinoline
(860 mg) was obtained.
[1155] (2) Using the above-mentioned compound (850 mg), and in the
same manner as in Example 269 (2),
4-chloro-2-trifluoromethyl-7-methoxyquinoline (820 mg) was obtained
as a white powder.
[1156] (3) Using the above-mentioned compound (0.820 g) and
piperazine (4.00 g), and in the same manner as in Example 189 (1),
1-(2-trifluoromethyl-7-methoxy-4-quinolyl)piperazine (0.840 g) was
obtained.
[1157] (4) Using the above-mentioned compound (0.830 g) and the
title compound (0.800 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-trifluoromethyl-7-methoxy-4-quin-
olyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.25
g) was obtained as a white powder.
[1158] (5) Using the above-mentioned compound (1.24 g), and in the
same manner as in Example 268 (3), the title compound (0.900 g) was
obtained as a white powder.
[1159] .sup.1H-NMR(DMSO-d.sub.6).delta.2.28-2.48(1H,m),
2.95-3.20(3H,m), 3.21-3.97(12H,m), 3.95(3H,s), 4.03-4.24(1H,m),
4.44-4.83(3H,m), 7.25(1H,s), 7.36(1H,dd,J=9.9, 2.6 Hz),
7.51(1H,d,J=2.6 Hz), 8.04(1H,d,J=9.9 Hz), 9.16(1H,brs),
11.69(1H,brs).
Example 274
Synthesis of
3-{(2S,4S)-4-[4-(2-trifluoromethyl-8-methoxy-4-quinolyl)-1-piperazinyl]-2-
-pyrrolidinylcarbonyl}-1,3-thiazolidine dihydrochloride
[1160] (1) Using 2-methoxyaniline (10.0 g) and ethyl
trifluoroacetoacetate (14.5 g), and in the same manner as in
Example 269 (1), 2-trifluoromethyl-4-hydroxy-8-methoxyquinoline
(2.03 g) was obtained.
[1161] (2) Using the above-mentioned compound (2.00 g), and in the
same manner as in Example 269 (2),
4-chloro-2-trifluoromethyl-8-methoxyquinoline (1.95 g) was obtained
as a white powder. Using the above-mentioned compound (1.95 g) and
piperazine (8.00 g), and in the same manner as in Example 189 (1),
1-(2-trifluoromethyl-8-methoxy-4-quinolyl)piperazine (2.14 g) was
obtained.
[1162] (4) Using the above-mentioned compound (1.60 g) and the
title compound (1.01 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-trifluoromethyl-8-methoxy-4-quin-
olyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.01
g) was obtained as a white powder.
[1163] (5) Using the above-mentioned compound (1.01 g), and in the
same manner as in Example 268 (3), the title compound (0.640 g) as
obtained as a white powder.
[1164] .sup.1H-NMR(DMSO-d.sub.6).delta.2.15-2.39(1H,m),
2.80-3.19(3H,m), 3.20-4.18(13H,m), 3.99(3H,s), 4.40-4.78(3H,m),
7.29-7.33(1H,m), 7.35(1H,s), 7.60-7.69(2H,m), 9.14(1H,brs),
10.71(1H,brs), 12.61(1H,brs).
Example 275
Synthesis of
3-{(2S,4S)-4-[4-(8-fluoro-2-trifluoromethyl-4-quinolyl)-1-piperazinyl]-2--
pyrrolidinylcarbonyl}-1,3-thiazolidine dihydrochloride
[1165] (1) 2-Fluoroaniline (10.0 g), ethyl trifluoroacetoacetate
(16.6 g) and concentrated hydrochloric acid (0.1 mL) were dissolved
in benzene (40 mL), and the mixture was refluxed in a reaction
vessel equipped with Dean-Stark trap for 7 hr. The reaction mixture
was concentrated under reduced pressure and 75% phosphoric acid (40
mL) was added thereto. The mixture was stirred at 110.degree. C.
for 5 hr. The reaction mixture was added to water, neutralized with
sodium hydrogencarbonate, and extracted with ethyl acetate. The
extract was concentrated under reduced pressure to give
8-fluoro-4-hydroxy-2-trifluoromethylquinoline (1.77 g).
[1166] (2) Using the above-mentioned compound (1.77 g), and in the
same manner as in Example 269 (2),
4-chloro-8-fluoro-2-trifluoromethylquinoline (1.70 g) was obtained
as a white powder.
[1167] (3) The above-mentioned compound (1.45 g), piperazine (0.5
g) and N,N-diisopropylethylamine (0.751 g) were dissolved in DMF
(25 mL), and the mixture was stirred at 70.degree. C. for 6.5 hr.
The reaction mixture was added to water, and the mixture was
extracted with chloroform. The extract was concentrated under
reduced pressure and the residue was purified by silica gel
chromatography to give
1-(8-fluoro-2-trifluoromethyl-4-quinolyl)piperazine (0.187 g).
[1168] (4) Using the above-mentioned compound (186 mg) and the
title compound (187 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(8-fluoro-2-trifluoromethyl-4-quino-
lyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (302
mg) was obtained as a white powder.
[1169] (5) Using the above-mentioned compound (302 mg), and in the
same manner as in Example 186 (2), the title compound (150 mg) was
obtained as a white powder.
[1170] .sup.1H-NMR(DMSO-d.sub.6).delta.2.23-2.48(1H,m),
2.91-3.20(3H,m), 3.21-3.89(11H,m), 3.90-3.99(1H,m),
4.00-4.22(1H,m), 4.45-4.85(3H,m), 7.46(1H,s), 7.65-7.78(2H,m),
7.89-8.01(1H,m), 9.16(1H,brs), 11.02(1H,brs).
Example 276
Synthesis of
3-{(2S,4S)-4-[4-(6-chloro-2-trifluoromethyl-4-quinolyl)-1-piperazinyl]-2--
pyrrolidinylcarbonyl}-1,3-thiazolidine dihydrochloride
[1171] (1) 4-Chloroaniline (5.00 g) was dissolved in 75% phosphoric
acid (20 mL), and ethyl trifluoroacetoacetate (8.60 g) was dropwise
added thereto at 110.degree. C. The mixture was stirred at
110.degree. C. for 4 hr, and then at 130.degree. C. for 7 hr. After
allowing to cool, water was added thereto. The precipitated solid
was collected by filtration to give
2-trifluoromethyl-4-hydroxy-6-methoxyquinoline (0.800 g).
[1172] (2) Using the above-mentioned compound (800 mg) and in the
same manner as in Example 270 (1),
4,6-dichloro-2-trifluoromethylquinoline (540 mg) was obtained as a
white powder.
[1173] (3) Using the above-mentioned compound (0.54 g) and
piperazine (1.50 g), and in the same manner as in Example 189 (1),
1-(6-chloro-2-trifluoromethyl-4-quinolyl)piperazine (0.490 g) was
obtained.
[1174] (4) Using the above-mentioned compound (480 mg) and the
title compound (460 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(6-chloro-2-trifluoromethyl-4-quino-
lyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (740
mg) was obtained as a white powder.
[1175] (5) Using the above-mentioned compound (730 mg), and in the
same manner as in Example 268 (3), the title compound (550 mg) was
obtained as a white powder.
[1176] .sup.1H-NMR(DMSO-d.sub.6).delta.2.45-2.70(1H,m),
2.80-4.06(14H,m), 4.39-4.78(5H,m), 7.42(1H,s), 7.90(1H,d,J=9.0 Hz),
8.08(1H,d,J=2.7 Hz), 8.14(1H,dd,J=9.0 Hz, 2.7 Hz), 9.10(1H,brs),
10.08(1H,brs).
Example 277
Synthesis of
3-{(2S,4S)-4-[4-(8-chloro-2-trifluoromethyl-4-quinolyl)-1-piperazinyl]-2--
pyrrolidinylcarbonyl}-1,3-thiazolidine dihydrochloride
[1177] (1) Using 2-chloroaniline (20.0 g), and in the same manner
as in Example 275 (1),
8-chloro-4-hydroxy-2-trifluoromethylquinoline (3.20 g) was
obtained.
[1178] (2) Using the above-mentioned compound (3.17 g), and in the
same manner as in Example 269 (2),
4,8-dichloro-2-trifluoromethylquinoline (2.30 g) was obtained as a
white powder.
[1179] (3) Using the above-mentioned compound (2.30 g), and in the
same manner as in Example 275 (3),
1-(8-chloro-2-trifluoromethyl-4-quinolyl)piperazine (0.950 g) was
obtained.
[1180] (4) Using the above-mentioned compound (0.950 g) and the
title compound (0.900 g) of Reference Example 12, and in the same
manner as in Example 70 (1), 3-{(2S,4S)-1-tert-butoxycarbonyl
4-[4-(8-chloro-2-trifluoromethyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidiny-
lcarbonyl}-1,3-thiazolidine (1.20 g) was obtained as a white
powder.
[1181] (5) Using the above-mentioned compound (1.18 g), and in the
same manner as in Example 268 (3), the title compound (0.790 g) was
obtained as a white powder.
[1182] H-NMR(DMSO-d.sub.6).delta.2.22-2.53(1H,m), 2.90-3.23(3H,m),
3.24-3.89(11H,m), 3.90-4.01(1H,m), 4.07-4.22(1H,m),
4.44-4.85(3H,m), 7.49(1H,s), 7.62-7.75(1H,m), 7.99-8.18(2H,m),
9.18(1H,brs), 11.09(1H,brs).
Example 278
Synthesis of
3-{(2S,4S)-4-[4-(4-cyano-1-isoquinolyl)-1-piperazinyl]-2-pyrrolidinylcarb-
onyl}-1,3-thiazolidine trihydrochloride
[1183] (1) 4-Bromo-1-hydroxyisoquinoline (1.56 g) was dissolved in
N-methyl-2-pyrrolidine (25 mL), and copper cyanide (1.56 g) was
added thereto. The mixture was stirred at 180.degree. C. for 4 hr
with heating. The reaction mixture was added to cool to 100.degree.
C. and added to an aqueous solution (125 mL) of sodium cyanide
(31.25 g). The mixture was extracted with dichloromethane and the
extract was dried and concentrated under reduced pressure. The
residue was purified by silica gel chromatography to give
4-cyano-1-hydroxyisoquinoline (0.62 g) as a pale-yellow solid.
[1184] (2) The above-mentioned compound (916 mg) was dissolved in
phosphorus oxychloride (10 mL), and the mixture was stirred at
70.degree. C. for 5 hr with heating. Phosphorus oxychloride was
evaporated under reduced pressure, and saturated aqueous sodium
hydrogencarbonate solution was added to the residue. The mixture
was extracted with ethyl acetate, and the extract was washed with
brine, dried and concentrated under reduced pressure. The residue
was purified by silica gel chromatography to give
1-chloro-4-cyanoisoquinoline (704 mg) as a white solid.
[1185] (3) piperazine (4.6 g) was melted by heating at 140.degree.
C. and the above-mentioned compound (0.500 g) was added thereto.
The mixture was stirred at 140.degree. C. for 2 hr and water was
added to the reaction mixture. The mixture was extracted with
chloroform, and the extract was washed with brine, dried and
concentrated under reduced pressure to give
1-(4-cyano-1-isoquinolyl)piperazine (0.491 g) as a dark brown
solid.
[1186] (4) Using the above-mentioned compound (252 mg) and the
title compound (300 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-cyano-1-isoquinolyl)-1-piperazin-
yl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (494 mg) was obtained
as a pale-yellow solid.
[1187] .sup.1H-NMR(CDCl.sub.3).delta.1.41(4.5H,s), 1.46(4.5H,s),
1.87-2.02(1H,m), 2.41-2.55(1H,m), 2.61-2.80(4H,m), 2.84-3.32(3H,m),
3.35(1H,dt,J=2.7, 10.0 Hz), 3.62-4.16(7H,m), 4.40-4.82(3H,m),
7.59(1H,t,J=8.1 Hz), 7.77(1H,t,J=8.1 Hz), 8.01(1H,d,J=8.1 Hz),
8.07(1H,d,J=8.1 Hz), 8.46(1H,s).
[1188] (5) The above-mentioned compound (490 mg) was dissolved in
tetrahydrofuran (5 mL), and 4 mol/L hydrochloric acid-ethyl acetate
(2.5 mL) was added thereto. The mixture was stirred at room
temperature for 14 hr. The precipitated solid was collected by
filtration and recrystallized from ethanol to give the title
compound (202 mg) as a pale-brown powder.
[1189] .sup.1H-NMR(DMSO-d.sub.6).delta.2.26-2.43(1H,m),
2.93-4.20(16H,m), 4.44-4.78(3H,m), 7.74-7.82(1H,m),
7.75-8.05(2H,m), 8.22(1H,d,J=8.4 Hz), 8.69(1H,s), 9.16(1H,brs),
10.85(1H,brs), 12.65(1H,brs).
Example 279
Synthesis of
3-{(2S,4S)-4-[4-(4-chloro-1-isoquinolyl)-1-piperazinyl]-2-pyrrolidinylcar-
bonyl}-1,3-thiazolidine trihydrochloride
[1190] (1) Using 1-chloro-1-hydroxyisoquinoline (3.63 g), and in
the same manner as in Example 278 (2), 1,4-dichloroisoquinoline
(3.95 g) was obtained as a gray solid.
[1191] (2) piperazine (12.6 g) was melted by heating at 140.degree.
C., and the above-mentioned compound (2.78 g) was added thereto.
The mixture was stirred at 110.degree. C. for 1 hr. The reaction
mixture was added to water and the mixture was extracted with
chloroform. The extract was washed with brine, dried and
concentrated under reduced pressure to give
1-(4-chloro-1-isoquinolyl)piperazine (3.86 g) as a dark brown
solid.
[1192] (3) Using the above-mentioned compound (446 mg) and the
title compound (450 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-chloro-1-isoquinolyl)-1-piperazi-
nyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (596 mg) was obtained
as a white solid.
[1193] (4) The above-mentioned compound (592 mg) was dissolved in
1.1 mol/L hydrochloric acid-methanol (10 mL), and the mixture was
stirred at room temperature for 5 days. The reaction mixture was
concentrated under reduced pressure, and ethanol (5 mL) was added
thereto. The precipitated solid was collected by filtration to give
the title compound (318 mg) as a pale-yellow powder.
[1194] .sup.1H-NMR(DMSO-d.sub.4).delta.2.32-2.46(1H,m),
2.95-4.20(16H,m), 4.43-4.78(3H,m), 7.74-7.82(1H,m),
7.90-7.97(1H,m), 8.14(1H,d,J=8.0 Hz), 8.23(1H,d,J=8.3 Hz),
8.30(1H,s), 9.17(1H,brs), 10.83(1H,brs), 12.53(1H,brs).
Example 280
Synthesis of
3-{(2S,4S)-4-[4-(4-bromo-1-isoquinolyl)-1-piperazinyl]-2-pyrrolidinylcarb-
onyl}-1,3-thiazolidine trihydrochloride
[1195] (1) Using 1-bromo-1-hydroxyisoquinoline (3.11 g), and in the
same manner as in Example 278 (2), 4-bromo-1-chloroisoquinoline
(3.00 g) was obtained as a pale-brown solid.
[1196] (2) piperazine (6.94 g) was melted by heating at 140.degree.
C., and the above-mentioned compound (2.92 g) was added thereto.
The mixture was stirred at 110.degree. C. for 1 hr. Water was added
to the reaction mixture and the mixture was extracted with
chloroform. The extract was dried and concentrated under reduced
pressure to give 1-(4-bromo-1-isoquinolyl)piperazine (2.52 g) as a
dark brown solid.
[1197] (3) Using the above-mentioned compound (488 mg) and the
title compound (450 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-4-[4-(4-bromo-1-isoquinolyl)-1-tert-butoxycarbonyl-1-piperazin-
yl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (753 mg) was obtained
as a pale-yellow solid.
[1198] (4) The above-mentioned compound (749 mg) was dissolved in
1.1 mol/L hydrochloric acid-methanol (6 mL), and the mixture was
stirred at room temperature for 4 days. The precipitated solid was
collected by filtration to give the title compound (135 mg) as a
white powder.
[1199] .sup.1H-NMR(DMSO-d.sub.6).delta.2.32-2.46(1H,m),
2.97-3.19(3H,m), 3.40-3.97(12H,m), 4.06-4.20(1H,m),
4.45-4.78(3H,m), 7.73-7.80(1H,m), 7.89-7.97(1H,m), 8.08(1H,d,J=8.0
Hz), 8.22(1H,d,J=8.3 Hz), 8.40(1H,s), 9.17(1H,brs), 10.94(1H,brs),
12.60(1H,brs).
Example 281
Synthesis of
3-{(2S,4S)-4-[4-(4-quinazolinyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1-
,3-thiazolidine trihydrochloride
[1200] (1) 4-Hydroxyquinazoline (3.76 g) and 2 drops of DMF were
added to thionyl chloride (12 mL), and the mixture was refluxed for
2 hr. The reaction mixture was concentrated under reduced pressure,
and the residue was added by small portions to piperazine (10 g)
melted by heating at 140.degree. C. Water and chloroform were added
to the reaction mixture and an insoluble material was filtered off.
The organic layer of the filtrate was separated and extracted with
1 mol/L hydrochloric acid. The aqueous layer was basified with
aqueous sodium hydroxide solution, and the mixture was extracted
with chloroform and concentrated under reduced pressure to give
1-(4-quinazolinyl)piperazine (1.86 g) as a yellow oil.
[1201] (2) Using the above-mentioned compound (471 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-quinazolinyl)-1-piperazinyl]-2-p-
yrrolidinylcarbonyl}-1,3-thiazolidine (543 mg) was obtained as a
yellow powder.
[1202] (3) Using the above-mentioned compound (543 mg), and in the
same manner as in Example 186 (2), the title compound (40 mg) was
obtained as a white powder.
[1203] .sup.1H-NMR(DMSO-d.sub.6).delta.2.00-2.30(1H,m),
2.80-3.00(1H,m), 3.00-4.85(18H,m), 7.66-7.81(1H,m),
7.93-8.12(2H,m), 8.24(1H,d,J=8.4 Hz), 8.95(1H,brs), 9.09(1H,brs),
10.84(1H,brs).
Example 282
Synthesis of
3-{(2S,4S)-4-[4-(2-trifluoromethyl-4-quinazolinyl)-1-piperazinyl]-2-pyrro-
lidinylcarbonyl}-1,3-thiazolidine
[1204] (1) 2-Amino benzamide (13.6 g) was dissolved in 1,4-dioxane
(50 mL) and trifluoroacetic acid anhydride (16.8 mL) was dropwise
added thereto under ice-cooling. After stirring at room temperature
for 1 hr, the reaction mixture was concentrated under reduced
pressure. Acetic acid (50 mL) was added to the residue and the
mixture was refluxed for 2 hr. After allowing to cool, the
precipitated solid was collected by filtration and washed with
diethyl ether to give 4-hydroxy-2-trifluoromethylquinazoline (11.9
g) as a white powder.
[1205] (2) The above-mentioned compound (5 g) and 2 drops of DMF
were added to thionyl chloride (30 mL), and the mixture was
refluxed for 1 hr. The reaction mixture was concentrated under
reduced pressure, and the residue was added to a solution of
piperazine (6.03 g) in DMF (60 mL). The mixture was stirred at room
temperature for 1 hr and then at 60.degree. C. for 30 min. The
reaction mixture was concentrated under reduced pressure, and water
and chloroform were added thereto. An insoluble material was
filtered off. The organic layer of the filtrate was separated and
extracted with 1 mol/L hydrochloric acid. The aqueous layer was
basified with aqueous sodium hydroxide solution, and the mixture
was extracted with chloroform. The extract was concentrated under
reduced pressure to give
1-(2-trifluoromethyl-4-quinazolinyl)piperazine (3.75 g) as a
pale-yellow solid.
[1206] (3) Using the above-mentioned compound (1.13 g) and the
title compound (0.901 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-trifluoromethyl-4-quinazolinyl)--
1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.51 g)
was obtained as a yellow powder.
[1207] (4) Using the above-mentioned compound (1.51 g), and in the
same manner as in Example 186 (2), hydrochloride of the title
compound was obtained. Aqueous sodium hydroxide solution was added
thereto, and the mixture was extracted with chloroform. The extract
was concentrated under reduced pressure and the residue was
purified by HPLC to give the title compound (450 mg) as a yellow
powder.
[1208] .sup.1H-NMR(CDCl.sub.3).delta.1.68-1.76(1H,m),
2.34-2.49(1H,m), 2.57-2.80(4H,m), 2.91-3.23(5H,m), 3.60-4.07(7H,m),
4.42-4.74(2H,m), 7.54(1H,t,J=7.8 Hz), 7.80(1H,t,J=7.8 Hz),
7.91(1H,dd,J=7.8, 0.8 Hz), 8.01(1H,dd,J=7.8, 0.8 Hz).
Example 283
Synthesis of
3-{(2S,4S)-4-[4-(2-phenyl-4-quinazolinyl)-1-piperazinyl]-2-pyrrolidinylca-
rbonyl}-1,3-thiazolidine trihydrochloride
[1209] (1) piperazine (3.22 g) was dissolved in DMF (830 mL), and
4-chloro-2-phenylquinazoline (3 g) was added thereto. The mixture
was stirred at room temperature for 6 hr. The reaction mixture was
concentrated under reduced pressure, water and chloroform were
added to the residue and an insoluble material as filtered off. The
organic layer of the filtrate was separated and extracted with 1
mol/L hydrochloric acid. The aqueous layer was basified with
aqueous sodium hydroxide solution, and the mixture was extracted
with chloroform. The extract was concentrated under reduced
pressure to give 1-(2-phenyl-4-quinazolinyl)piperazine (2.27 g) as
a white solid.
[1210] (2) Using the above-mentioned compound (1.16 g) and the
title compound (0.901 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-phenyl-4-quinazolinyl)-1-piperaz-
inyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.66 g) was
obtained as a white powder.
[1211] (3) Using the above-mentioned compound (1.66 g), and in the
same manner as in Example 186 (2), the title compound (1.21 g) was
obtained as a white powder.
[1212] .sup.1H-NMR(DMSO-d.sub.6).delta.2.17-2.38(1H,m),
2.85-3.18(3H,m), 3.30-4.90(16H,m), 7.56-7.80(4H,m), 8.04(1H,t,J=8.2
Hz), 8.22(1H,d,J=8.2 Hz), 8.33(1H,d,J=8.2 Hz), 8.53(2H,d,J=8.4 Hz),
9.16(1H,brs).
Example 284
Synthesis of
3-{(2S,4S)-4-[4-(5-cyano-2-pyridyl)-2-oxo-1-piperazinyl]-2-pyrrolidinylca-
rbonyl}-1,3-thiazolidine dihydrochloride
[1213] (1) Using the title compound (2.10 g) of Reference Example
12 and 2-aminoacetaldehyde diethyl acetal 0.984, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2,2-diethoxyethyl)amino]-2-pyrroli-
dinylcarbonyl}-1,3-thiazolidine (3.57 g) was obtained as a
pale-yellow oil.
[1214] (2) The above-mentioned compound (3.56 g) and
N-benzyloxycarbonylglycine (1.54 g) were dissolved in DMF (30 mL),
and HOBT (1.39 g) and EDC hydrochloride (1.61 g) were successively
added thereto. The mixture was stirred at room temperature for 2
days. The reaction mixture was concentrated under reduced pressure,
and 0.5 mol/L hydrochloric acid was added to the residue. The
mixture was extracted with chloroform. The extract was washed with
saturated aqueous sodium hydrogencarbonate solution and brine,
dried and concentrated under reduced pressure. The residue was
purified by silica gel chromatography to give
3-((2S,4S)-4-{N-[2-(1-benzyloxycarbonylamino)acetyl]-N-(2,2-dieth-
oxyethyl)amino}-2-pyrrolidinylcarbonyl)-1-tert-butoxycarbonyl-1,3-thiazoli-
dine (2.77 g) as a pale-brown oil.
[1215] (3) The above-mentioned compound (2.77 g) and
p-toluenesulfonic acid monohydrate (0.164 g) were dissolved in
toluene (100 mL), and the solution was heated at 70.degree. C. for
7 hr. The reaction mixture was added to saturated aqueous sodium
hydrogencarbonate solution, and the mixture was extracted with
ethyl acetate. The extract was dried and concentrated under reduced
pressure. The residue was dissolved in methanol (50 mL), and
ammonium formate (1.44 g) and 10% palladium/carbon (1.93 g) were
added thereto. The mixture was heated at 100.degree. C. for 2 days.
Furthermore, ammonium formate (1.44 g) and 10% palladium/carbon
(1.93 g) were added thereto, and the mixture was stirred at
100.degree. C. for 1 day with heating. The reaction mixture was
filtrated and the filtrate was concentrated under reduced pressure.
Saturated aqueous sodium hydrogencarbonate solution was added to
the residue, and the mixture was extracted with chloroform. The
extract was washed with brine, dried and concentrated under reduced
pressure. The residue was purified by silica gel chromatography to
give
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(2-oxo-1-piperazinyl)-2-pyrrolidinylca-
rbonyl]-1,3-thiazolidine (0.237 g) as a white solid.
[1216] (4) The above-mentioned compound (237 mg) and
N,N-diisopropylethylamine (0.32 mL) were dissolved in
N-methyl-2-pyrrolidone (5 mL), and 2-chloro-5-cyanopyridine (145
mg) was added thereto. The mixture was heated at 80.degree. C. for
4 hr. The reaction mixture was added to saturated aqueous sodium
hydrogencarbonate solution, and the mixture was extracted with
ethyl acetate. The extract was washed with brine, dried and
concentrated under reduced pressure. The residue was purified by
silica gel chromatography to give
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-cyano-2-pyridyl)-2-oxo-1-piperaz-
inyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (425 mg) as a
pale-brown oil.
[1217] .sup.1H-NMR(CDCl.sub.3).delta.1.42(4.5H,s), 1.44(4.5H,s),
1.93-2.10(1H,m), 2.43-2.58(1H,m), 2.94-3.22(2H,m), 3.43-4.06(8H,m),
4.24(2H,s), 4.40-4.92(3H,m), 5.20-5.38(1H,m), 6.52(1H,d,J=8.9 Hz),
7.70(1H,dd,J=8.9, 2.1 Hz), 8.45(1H,d,J=2.1 Hz).
[1218] (5) The above-mentioned compound (422 mg) was dissolved in
ethyl acetate (1 mL), and 4 mol/L hydrochloric acid-ethyl acetate
(1.2 mL) was added thereto. The mixture was stirred at room
temperature for 18 hr. The precipitated solid was collected by
filtration to give the title compound (217 mg) as a white
powder.
[1219] .sup.1H-NMR(DMSO-d.sub.6).delta.1.86-1.96(1H,m),
2.14-2.23(1H,m), 2.60-2.75(1H,m), 3.12(1H,t,J=6.2 Hz),
3.25-4.32(10H,m), 4.47(1H,t,J=10.0 Hz), 4.55-4.77(2H,m),
4.95-5.10(1H,m), 7.93(1H,d,J=9.0 Hz), 7.93(1H,dd,J=9.0, 2.2 Hz),
8.54(1H,d,J=2.2 Hz), 8.79(1H,brs), 10.29(1H,brs).
Example 285
Synthesis of
3-{(2S,4S)-4-[4-(5-cyano-2-pyridyl)-3-oxo-1-piperazinyl]-2-pyrrolidinylca-
rbonyl}-1,3-thiazolidine dihydrochloride
[1220] (1) N-(5-Cyano-2-pyridyl)ethylenediamine (10.0 g) and
triethylamine (9.5 mL) were dissolved in tetrahydrofuran (300 mL),
and ethyl 2-bromoacetate (6.9 mL) was added thereto under
ice-cooling. The mixture was stirred at room temperature for 21 hr.
Di-tert-butyl dicarbonate (14.2 mL) was added to the reaction
mixture, and the mixture was further stirred at room temperature
for 21 hr. The reaction mixture was filtrated and the filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel chromatography to give
N-tert-butoxycarbonyl-N'-(5-cyano-2-pyridyl)-N-(ethoxycarbonylmethyl)ethy-
lenediamine (17.3 g) as a white solid.
[1221] (2) The above-mentioned compound (17.3 g) was dissolved in
1,4-dioxane (220 mL), and 1 mol/L aqueous sodium hydroxide solution
(75 mL) was added thereto. The mixture was stirred at room
temperature for 13 hr. The reaction mixture was concentrated under
reduced pressure, and 10% aqueous citric acid solution was added to
the residue. The mixture was extracted with ethyl acetate. The
extract was washed with brine, dried, concentrated under reduced
pressure and crystallized from diethyl ether-hexane to give
N-tert-butoxycarbonyl-N-(carboxymethyl)-N'-(5-cyano-2-pyridyl)ethylenedia-
mine (11.7 g) as a white solid.
[1222] (3) The above-mentioned compound (3.20 g) and triethylamine
(2.8 mL) were dissolved in tetrahydrofuran (60 mL), and HOBT (1.84
g) and EDC hydrochloride (2.30 g) were successively added. The
mixture was stirred at room temperature for 6 hr. The reaction
mixture was concentrated under reduced pressure, and saturated
aqueous sodium hydrogencarbonate solution was added to the residue.
The mixture was extracted with ethyl acetate. The extract was
washed with brine, dried and concentrated under reduced pressure to
give 4-tert-butoxycarbonyl-1-(5-cyano-2-pyridyl)-2-oxopiperazine
(2.34 g) as a white solid.
[1223] (4) The above-mentioned compound (2.34 g) was dissolved in
dichloromethane (50 mL), and trifluoroacetic acid (25 mL) was added
thereto under ice-cooling. The mixture was stirred for 1 hr. The
reaction mixture was concentrated under reduced pressure, and
saturated aqueous sodium hydrogencarbonate solution was added to
the residue. The mixture was extracted with chloroform. The extract
was washed with brine, dried and concentrated under reduced
pressure to give 1-(5-cyano-2-pyridyl)-2-oxopiperazine (1.02 g) as
a white solid.
[1224] (5) Using the above-mentioned compound (667 mg) and the
title compound (901 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-cyano-2-pyridyl)-3-oxo-1-piperaz-
inyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (976 mg) was
obtained as a white solid.
[1225] .sup.1H-NMR(CDCl.sub.3).delta.1.41(4.5H,s), 1.46(4.5H,s),
1.86-2.02(1H,m), 2.42-2.55(1H,m), 2.78-4.83(16H,m),
7.91(1H,dd,J=8.8, 2.1 Hz), 8.37(1H,d,J=8.8 Hz), 8.68(1H,d,J=2.1
Hz).
[1226] (6) The above-mentioned compound (972 mg) was dissolved in
ethyl acetate (5 mL), and 4 mol/L hydrochloric acid-ethyl acetate
(5 mL) was added thereto. The mixture was stirred at room
temperature for 17 hr. The precipitated solid was collected by
filtration to give the title compound (789 mg) as a white
powder.
[1227] .sup.1H-NMR(DMSO-d.sub.6).delta.1.95-2.10(1H,m),
2.80-2.94(1H,m), 3.02-3.45(5H,m), 3.50-4.15(8H,m), 4.4-4.8(3H,m),
8.21(1H,d,J=8.9 Hz), 8.32(1H,dd,J=8.9, 2.3 Hz), 8.87-9.06(2H,m),
10.61(1H,brs).
Example 286
Synthesis of
3-[(2S,4S)-4-(4-methoxycarbonylpiperidino)-2-pyrrolidinylcarbonyl]-1,3-th-
iazolidine dihydrochloride
[1228] (1) Using methyl isonipecotinate (0.466 g) and the title
compound (0.89 g) of Reference Example 12, and in the same manner
as in Example 70 (1),
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-methoxycarbonylpiperidino)-2-p-
yrrolidinylcarbonyl]-1,3-thiazolidine (1.19 g) was obtained as a
white powder.
[1229] (2) Using the above-mentioned compound (166 mg), and in the
same manner as in Example 133 (2), the title compound (132 mg) was
obtained as a white powder.
[1230] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.88-2.13(4H,m),
2.15-2.35(1H,m), 2.56-2.76(1H,m), 2.85-3.20(5H,m), 3.43-4.00(7H,m),
3.64(3H,s), 4.47-4.73(3H,m), 9.20(1H,brs), 10.70(1H,brs),
11.98(1H,brs).
Example 287
Synthesis of
3-{(2S,4S)-4-[(4-(4-nitrophenyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-t-
hiazolidine dihydrochloride
[1231] (1) Using 4-(4-nitrophenyl)piperidine (625 mg) and the title
compound (606 mg) of Reference Example 12, and in the same manner
as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-nitrophenyl)piperidino]-2-pyrrol-
idinylcarbonyl}-1,3-thiazolidine 387 mg) was obtained as a
pale-yellow solid.
[1232] (2) Using the above-mentioned compound (387 mg), and in the
same manner as in Example 133 (2), the title compound (240 mg) was
obtained as a white powder.
[1233] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.95-2.38(5H,m),
2.90-3.28(6H,m), 3.51-4.08(7H,m), 4.48-4.75(3H,m), 7.54(2H,d,J=8.1
Hz), 8.22(2H,d,J=8.1 Hz), 9.20(1H,brs), 10.60(1H,brs),
12.07(1H,brs).
Example 288
Synthesis of
3-{(2S,4S)-4-[4-(2-pyrimidinyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-th-
iazolidine dihydrochloride
[1234] (1) 4-Cyanopyridine (50.0 g) was suspended in methanol (50
mL), and 28% sodium methoxide-methanol solution (4.14 mL) was added
thereto. After stirring at room temperature for 15 min, ammonium
chloride (25.7 g) was added to the mixture. The mixture was stirred
at room temperature for 24 hr. Acetone (200 mL) was added to the
reaction mixture, and the precipitated solid was collected by
filtration to give 4-amidinopyridine hydrochloride (62.8 g) as a
white solid.
[1235] (2) The above-mentioned compound (5.00 g) and
3-dimethylamino-2-propenal (3.18 g) were suspended in methanol (30
mL), and 28% sodium methoxide-methanol solution (13.8 mL) was added
thereto. The mixture was refluxed for 12 hr. The reaction mixture
was filtrated and the filtrate was concentrated under reduced
pressure. Water was added to the residue, and the mixture was
extracted with chloroform. The extract was washed with brine and
dried, and the solvent was evaporated under reduced pressure. The
residue was purified by silica gel chromatography to give
4-(2-pyrimidiny)pyridine (3.45 g) as a slightly yellow solid.
[1236] (3) The above-mentioned compound (3.14 g) was dissolved in
acetonitrile (50 mL), and benzyl chloride (4.60 mL) was added
thereto. The mixture was refluxed for 16 hr. The reaction mixture
was concentrated to about 10 mL, and diethyl ether (10 mL) was
added thereto. The precipitated solid was collected by filtration
to give 1-benzyl-4-(2-pyrimidinyl)pyridine hydrochloride (5.61 g)
as a white solid.
[1237] (4) The above-mentioned compound (5.50 g) was suspended in
ethanol (20 mL), and sodium borohydride (1.47 g) was added thereto
under ice-cooling. The mixture was stirred at room temperature for
1.5 hr and water was added to the reaction mixture. The mixture was
extracted with ethyl acetate, and the extract was washed
successively with water and brine, and dried. The solvent was
evaporated under reduced pressure. The residue was purified by
silica gel chromatography to give
1-benzyl-4-(2-pyrimidinyl)-1,2,3,6-tetrahydropyridine (4.10 g) as a
slightly yellow solid.
[1238] (5) The above-mentioned compound (4.10 g) was dissolved in
ethanol (100 mL), and the mixture was stirred at room temperature
in the presence of 10% palladium carbon (1.10 g) under a hydrogen
atomosphere (1 atm). The reaction mixture was filtrated and the
filtrate was concentrated under reduced pressure. The residue was
purified by silica gel chromatography to give
1-benzyl-4-(2-pyrimidinyl)piperidine (3.33 g) as a colorless
transparent oil.
[1239] (6) The above-mentioned compound (3.33 g) was dissolved in
dichloromethane (25 mL), and a solution of 1-chloroethyl
chlorocarbonate (1.70 mL) in dichloromethane (5 mL) was added under
ice-cooling. The mixture was refluxed for 30 min. The reaction
mixture was concentrated under reduced pressure, and the residue
was dissolved in methanol (25 mL). The solution was refluxed for 1
hr and 28% sodium methoxide-methanol solution (3.40 mL) was added
to the reaction mixture. After filtration, the filtrate was
concentrated under reduced pressure and the residue was purified by
silica gel chromatography to give 4-(2-pyrimidinyl)piperidine (1.43
g) as a brown oil.
[1240] (7) Using the above-mentioned compound (1.43 g) and the
title compound (2.39 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-pyrimidinyl)piperidino]-2-pyrrol-
idinylcarbonyl}-1,3-thiazolidine (2.30 g) was obtained as a white
solid.
[1241] (8) Using the above-mentioned compound (895 mg), and in the
same manner as in Example 167 (2), the title compound (227 mg) was
obtained as a slightly yellow powder.
[1242] .sup.1H-NMR(DMSO-d.sub.6).delta.2.05-2.46(5H,m),
2.86-3.50(4H,m), 3.52-4.07(7H,m), 4.42-4.79(3H,m), 7.42(1H,t,J=5.1
Hz), 8.82(2H,d,J=5.1 Hz), 9.11(1H,brs), 11.01(1H,brs),
12.03(1H,brs).
Example 289
Synthesis of
3-{(2S,4S)-4-[4-(5-ethyl-1,3,4-oxadiazol-2-yl)piperidino]-2-pyrrolidinylc-
arbonyl}-1,3-thiazolidine dihydrochloride
[1243] (1) Ethyl isonipecotinate (51.5 g) was dissolved in
tetrahydrofuran (400 mL) and pyridine (40 mL), and a solution of
benzyl chlorocarbonate (58.7 g) in tetrahydrofuran (50 mL) was
dropwise added under ice-cooling. After stirring the mixture under
ice-cooling for 1.5 hr, the solvent was evaporated under reduced
pressure. Water was added to the residue, and the mixture was
extracted with ethyl acetate. The extract was washed successively
with dilute hydrochloric acid, saturated aqueous sodium
hydrogencarbonate solution and brine, and dried. The solvent was
evaporated under reduced pressure to give ethyl
1-benzyloxycarbonylisonipecotinate (80.4 g) as an oil.
[1244] (2) The above-mentioned compound (42.8 g) was dissolved in
isopropanol (300 mL), and hydrazine monohydrate (43 mL) was added
thereto. The mixture was refluxed for 10 hr. The solvent was
evaporated under reduced pressure, and the residue was washed with
diisopropyl ether and water to give 1-benzyloxycarbonylisonipecotic
acid hydrazide (23.8 g) as a white solid.
[1245] (3) The above-mentioned compound (3.52 g) was dissolved in
tetrahydrofuran (50 mL) and pyridine (5 mL), and propionyl chloride
(1.21 mL) was added thereto under ice-cooling. The mixture was
stirred for 4 hr. Water was added to the reaction mixture, and the
precipitated solid was collected by filtration. This was suspended
in 1,2-dimethoxyethane (70 mL), and phosphorus oxychloride (1.40
mL) was added thereto. The mixture was refluxed for 4 hr. The
reaction mixture was concentrated under reduced pressure, and
saturated aqueous sodium hydrogencarbonate solution was added to
the residue. The mixture was extracted with chloroform, and the
extract was dried and concentrated under reduced pressure. The
residue was purified by silica gel chromatography to give
1-benzyloxycarbonyl-4-(5-ethyl-1,3,4-oxadiazol-2-yl)piperidine
(2.29 g) as an oil.
[1246] (4) Using the above-mentioned compound (2.29 g), and in the
same manner as in Example 232 (5),
4-(5-ethyl-1,3,4-oxadiazol-2-yl)piperidine hydrobromide (1.90 g)
was obtained as a white solid.
[1247] (5) Using a free base (400 mg) of the above-mentioned
compound and the title compound (553 mg) of Reference Example 12,
and in the same manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[(4-(5-ethyl-1,3,4-oxadiazol-2-yl)pipe-
ridino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (856 mg) was
obtained as a white powder.
[1248] (6) Using the above-mentioned compound (856 mg), and in the
same manner as in Example 257 (3), the title compound (307 mg) was
obtained as a white powder.
[1249] .sup.1H-NMR(DMSO-d.sub.6).delta.1.25(3H,t,J=7.5 Hz),
1.90-2.44(5H,m), 2.84(2H,q,J=7.5 Hz), 2.89-4.20(13H,m),
4.46-4.75(3H,M), 10.10(2H,brs), 12.15(1H,brs).
Example 290
Synthesis of
3-((2S,4S)-4-{4-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidino}-2-py-
rrolidinylcarbonyl)-1,3-thiazolidine dihydrochloride
[1250] (1) Using 4-chlorobenzoyl chloride (1.40 .mu.L) and
1-benzyloxycarbonylisonipecotic acid hydrazide [product of Example
289 (2), 3.00 g], and in the same manner as in Example 289 (3),
1-benzyloxycarbonyl-4-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine
(1.26 g) was obtained as a white solid.
[1251] (2) Using the above-mentioned compound (1.26 g), and in the
same manner as in Example 232 (5),
4-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine hydrobromide
(1.09 g) was obtained as a white solid.
[1252] (3) Using a free base (556 mg) of the above-mentioned
compound and the title compound (530 mg) of Reference Example 12,
and in the same manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-{4-chlorophenyl}-1,3,4-oxadiazol-
-2-yl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (922 mg)
was obtained as a white powder.
[1253] (4) Using the above-mentioned compound (896 mg), and in the
same manner as in Example 257 (3), the title compound (739 mg) was
obtained as a white powder.
[1254] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.06-2.48(5H,m),
2.90-4.15(13H,m), 4.48-4.98(3H,m), 7.69(2H,d,J=7.4 Hz),
8.01(2H,d,J=7.4 Hz), 9.14(1H,brs), 10.92(1H,brs),
12.25(1H,brs).
Example 291
Synthesis of
3-((2S,4S)-4-{4-[5-(3-pyridyl)-1,3,4-oxadiazol-2-yl]piperidino}-2-pyrroli-
dinylcarbonyl)-1,3-thiazolidine trihydrochloride
[1255] (1) Using nicotinoyl chloride (1.40 g) and the product (2.08
g) of Example 289 (2), and in the same manner as in Example 289
(3),
1-benzyloxycarbonyl-4-[5-(3-pyridyl)-1,3,4-oxadiazol-2-yl]piperidine
(0.48 g) was obtained as a white solid.
[1256] (2) Using the above-mentioned compound (477 mg), and in the
same manner as in Example 232 (5),
4-[5-(3-pyridyl)-1,3,4-oxadiazol-2-yl]piperidine hydrobromide (435
mg) was obtained as a white solid.
[1257] (3) Using a free base (256 mg) of the above-mentioned
compound and the title compound (320 mg) of Reference Example 12,
and in the same manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-{3-pyridyl}-1,3,4-oxadiazol-2-yl-
)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (425 mg) was
obtained as a white powder.
[1258] (4) Using the above-mentioned compound (425 mg), and in the
same manner as in Example 257 (3), the title compound (430 mg) was
obtained as a white powder.
[1259] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.18-2.45(5H,m),
2.95-4.15(13H,m), 4.48-4.77(3H,m), 7.69(1H,dd,J=8.2, 5.1 Hz),
8.40-8.47(1H,m), 8.82-8.85(1H,m), 9.12(1H,brs), 9.18(1H,s),
10.88(1H,brs), 12.20(1H,brs).
Example 292
Synthesis of
3-((2S,4S)-4-{4-[5-(4-pyridyl)-1,3,4-oxadiazol-2-yl]piperidino}-2-pyrroli-
dinylcarbonyl)-1,3-thiazolidine trihydrochloride
[1260] (1) Using isonicotinic acid chloride (1.36 g) and the
product (2.02 g) of Example 289 (2), and in the same manner as in
Example 289 (3),
1-benzyloxycarbonyl-4-[5-(4-pyridyl)-1,3,4-oxadiazol-2-yl]piperidine
(0.287 g) was obtained as a white solid.
[1261] (2) Using the above-mentioned compound (287 mg), and in the
same manner as in Example 232 (5),
4-[5-(4-pyridyl)-1,3,4-oxadiazol-2-yl]piperidine hydrobromide (211
mg) was obtained as a white solid.
[1262] (3) Using a free base (124 mg) of the above-mentioned
compound and the title compound (157 mg) of Reference Example 12,
and in the same manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-{4-pyridyl}-1,3,4-oxadiazol-2-yl-
)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (269 mg) was
obtained as a white powder.
[1263] (4) Using the above-mentioned compound (268 mg), and in the
same manner as in Example 257 (3), the title compound (242 mg) was
obtained as a white powder.
[1264] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.10-2.46(5H,m),
2.92-4.08(13H,m), 4.48-4.72(3H,m), 7.97(2H,brs), 8.85-8.87(2H,m),
9.13(1H,brs), 10.55(1H,brs), 11.97(1H,brs).
Example 293
Synthesis of
3-{(2S,4S)-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidinol-2-pyr-
rolidinylcarbonyl}-1,3-thiazolidine dihydrochloride
[1265] (1)
3-[(2S,4S)-1-tert-Butoxycarbonyl-4-(4-methoxycarbonylpiperidino)-2-pyrrol-
idinylcarbonyl]-1,3-thiazolidine [product of Example 286 (1), 1.01
g] was dissolved in methanol (10 mL) and water (10 mL), and 1 mol/L
sodium hydroxide (3.54 mL) was added thereto under ice-cooling. The
mixture was stirred at room temperature for 3 hr. Methanol was
evaporated under reduced pressure and dilute hydrochloric acid was
added to the residue to adjust its pH to 7. The precipitated solid
was collected by filtration to give
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-carboxylpiperidino)-2-pyrrolid-
inylcarbonyl]-1,3-thiazolidine (650 mg) as a white powder.
[1266] (2) The above-mentioned compound (650 mg), HOBT (290 mg) and
EDC hydrochloride (362 mg) were suspended in DMF (15 mL), and
hydrazine monohydrate (114 .mu.L) was added thereto. The mixture
was stirred at room temperature for 18 hr. After DMF was evaporated
under reduced pressure, saturated aqueous sodium hydrogencarbonate
solution was added to the residue and the mixture was extracted
with chloroform. The extract was dried and concentrated under
reduced pressure. The residue was dissolved in tetrahydrofuran (50
mL) and pyridine (5 mL), and triphosgene (190 mg) was added thereto
under ice-cooling. The mixture was stirred at room temperature for
2 days. Water was added to the reaction mixture, and the mixture
was extracted with chloroform and dried. The solvent was evaporated
under reduced pressure and the residue was purified by silica gel
chromatography to give
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol--
2-yl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (104 mg)
as a white solid.
[1267] (3) Using the above-mentioned compound (104 mg), and in the
same manner as in Example 257 (3), the title compound (80 mg) was
obtained as a white powder.
[1268] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.82-2.32(5H,m),
2.80-4.10(13H,m), 4.47-4.72(3H,m), 9.10(1H,brs), 10.41(1H,brs),
11.86(1H,brs), 12.21(1H,brs).
Example 294
Synthesis of
3-{(2S,4S)-4-[4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidi-
no]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine dihydrochloride
[1269] (1) The product (7.46 g) of Example 289 (2) was suspended in
tetrahydrofuran (200 mL) and pyridine (20 mL), and tetrahydrofuran
solution (20 mL) of triphosgene (3.0 g) was added thereto under
ice-cooling. The mixture was stirred at room temperature for 18 hr.
The solvent was evaporated under reduced pressure, and water was
added to the residue. The mixture was extracted with ethyl acetate.
The extract was dried and concentrated under reduced pressure. The
residue was purified by silica gel chromatography to give
1-benzyloxycarbonyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine
(5.92 g) as an oil.
[1270] (2) The above-mentioned compound (1.02 g) was dissolved in
DMF (15 mL), and potassium carbonate (0.700 g) and methyl iodide
(320 .mu.L) were added thereto. The mixture was stirred at room
temperature for 15 hr. The reaction mixture was concentrated under
reduced pressure, and water was added to the residue. The mixture
was extracted with ethyl acetate. The extract was washed with
brine, dried and concentrated under reduced pressure to give
1-benzyloxycarbonyl-4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pi-
peridine (0.900 g) as an oil.
[1271] (3) Using the above-mentioned compound (894 mg), and in the
same manner as in Example 232 (5), 1 mol/L aqueous sodium hydroxide
solution was added to the resulting hydrobromide. The mixture was
extracted with chloroform, and concentrated under reduced pressure
to give
4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine (352
mg) as a pale-yellow solid.
[1272] (4) Using the above-mentioned compound (352 mg) and the
title compound (550 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-o-
xadiazol-2-yl)piperidinol-2-pyrrolidinylcarbonyl}-1,3-thiazolidine
(402 mg) was obtained as a white solid.
[1273] (5) Using the above-mentioned compound (402 mg), and in the
same manner as in Example 257 (3), the title compound (375 mg) was
obtained as a white powder.
[1274] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.90-2.32(5H,m),
2.85-4.05(13H,m), 3.29(3H,s), 4.47-4.72(3H,m), 9.10(1H,brs),
10.45(1H,brs), 11.92(1H,brs).
Example 295
Synthesis of
3-{(2S,4S)-4-[4-(4-methoxycarbonylmethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazo-
l-2-yl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine
dihydrochloride
[1275] (1) Using
1-benzyloxycarbonyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine
[product of Example 294 (1), 1.84 g] and methyl bromoacetate (670
.mu.L), and in the same manner as in Example 294 (2),
1-benzyloxycarbonyl-4-(4-methoxycarbonylmethyl-5-oxo-4,5-dihydro-1,3,4-ox-
adiazol-2-yl)piperidine (2.28 g) was obtained as an oil.
[1276] (2) Using the above-mentioned compound (2.26 g), and in the
same manner as in Example 232 (5), 1 mol/L aqueous sodium hydroxide
solution was added to the resulting hydrobromide. The mixture was
extracted with chloroform, and concentrated under reduced pressure
to give
4-(4-methoxycarbonylmethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperid-
ine (1.20 g) as an oil.
[1277] (3) Using the above-mentioned compound (1.20 g) and the
title compound (1.24 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-methoxycarbonylmethyl-5-oxo-4,5--
dihydro-1,3,4-oxadiazol-2-yl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiaz-
olidine (1.41 g) was obtained as a pale-yellow solid.
[1278] (4) Using the above-mentioned compound (904 mg), and in the
same manner as in Example 133 (2), the title compound (877 mg) was
obtained as a white powder.
[1279] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.90-2.32(5H,m),
2.90-4.10(13H,m), 3.57(3H,s), 4.47-4.74(3H,m), 4.64(2H,s),
9.10(1H,brs), 10.73(1H,brs), 12.20(1H,brs).
Example 296
Synthesis of
3-((2S,4S)-4-{4-[4-(2-morpholinoethyl)-5-oxo-4,5-dihydro-1,3,4-oxadiazol--
2-yl]piperidino}-2-pyrrolidinylcarbonyl)-1,3-thiazolidine
trihydrochloride
[1280] (1) Using the product (930 mg) of Example 294 (1) and
4-(2-chloroethyl)morpholine hydrochloride (685 mg), and in the same
manner as in Example 294 (2),
1-benzyloxycarbonyl-4-[4-(2-morpholinoethyl)-5-oxo-4,5-dihydro-1,3,4-oxad-
iazol-2-yl]piperidine (720 mg) was obtained as an oil.
[1281] (2) Using the above-mentioned compound (696 mg), and in the
same manner as in Example 232 (5), 1 mol/L aqueous sodium hydroxide
solution was added to the resulting hydrobromide. The mixture was
extracted with chloroform, and concentrated under reduced pressure
to give
4-[4-(2-morpholinoethyl)-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl]piperidin-
e (328 mg) as an oil.
[1282] (3) Using the above-mentioned compound (318 mg) and the
title compound (322 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-((2S,4S)-1-tert-butoxycarbonyl-4-{4-[4-(2-morpholinoethyl)-5-oxo-4,5-di-
hydro-1,3,4-oxadiazol-2-yl]piperidino}-2-pyrrolidinylcarbonyl)-1,3-thiazol-
idine (606 mg) was obtained as an oil.
[1283] (4) using the above-mentioned compound (606 mg), and in the
same manner as in Example 258 (2), the title compound (522 mg) was
obtained as a white powder.
[1284] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.95-2.36(5H,m),
2.90-4.15(25H,m), 4.47-4.74(3H,m), 9.10(1H,brs), 10.64(1H,brs),
11.54(1H,brs), 11.83(1H,brs), 12.02(1H,brs).
Example 297
Synthesis of
3-((2S,4S)-4-{4-[5-oxo-4-(3-picolyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]pip-
eridino}-2-pyrrolidinylcarbonyl)-1,3-thiazolidine
trihydrochloride
[1285] (1) Using the product (0.932 g) of Example 294 (1) and
3-picolyl chloride hydrochloride (0.605 g), and in the same manner
as in Example 294 (2),
1-benzyloxycarbonyl-4-[5-oxo-4-(3-picolyl)-4,5-dihydro-1,3,4-oxa-
diazol-2-yl]piperidine (1.06 g) was obtained as an oil.
[1286] (2) Using the above-mentioned compound (1.01 g), and in the
same manner as in Example 232 (5), 1 mol/L aqueous sodium hydroxide
solution was added to the resulting hydrobromide. The mixture was
extracted with chloroform, and concentrated under reduced pressure
to give
4-[5-oxo-4-(3-picolyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]piperidine
(0.17 g) as a pale-yellow solid.
[1287] (3) Using the above-mentioned compound (170 mg) and the
title compound (187 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-((2S,4S)-1-tert-butoxycarbonyl-4-{4-[5-oxo-4-(3-picolyl)-4,5-dihydro-1,-
3,4-oxadiazol-2-yl]piperidino}-2-pyrrolidinylcarbonyl)-1,3-thiazolidine
(236 mg) was obtained as a white powder.
[1288] (4) Using the above-mentioned compound (236 mg), and in the
same manner as in Example 257 (3), the title compound (204 mg) was
obtained as a white powder.
[1289] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.98-2.36(5H,m),
2.93-4.05(13H,m), 4.47-4.74(3H,m), 5.08(2H,s), 7.86-7.89(1H,m),
8.30-8.32(1H,m), 8.79(1H,d,J=5.1 Hz), 8.85(1H,s), 9.10(1H,brs),
10.90(1H,brs), 12.22(1H,brs).
Example 298
Synthesis of
3-{(2S,4S)-4-[4-(2-tert-butyl-2H-tetrazol-5-yl)piperidino]-2-pyrrolidinyl-
carbonyl}-1,3-thiazolidine dihydrochloride
[1290] (1) Isonipecotamide (19.4 g) and triethylamine (42 mL) were
dissolved in dichloromethane (500 mL), and benzyloxy
chlorocarbonate (24 mL) was added thereto under ice-cooling. The
mixture was stirred at room temperature for 18 hr. The reaction
mixture was added to saturated aqueous sodium hydrogencarbonate
solution, and the mixture was extracted with chloroform. The
extract was dried and concentrated under reduced pressure to give
1-benzyloxycarbonyl-4-carbamoylpiperidine (33.3 g) as a white
solid.
[1291] (2) The above-mentioned compound (33.3 g) and imidazole
(17.3 g) were dissolved in pyridine (350 mL), and phosphorus
oxychloride (47 mL) was added thereto under ice-cooling. The
mixture was stirred at room temperature for 3 hr. The saturated
aqueous sodium hydrogencarbonate solution was added to the reaction
mixture under ice-cooling, and the mixture was extracted with
chloroform. The extract was washed with brine, dried, and the
solvent was evaporated under reduced pressure. The residue was
purified by silica gel chromatography to give
1-benzyloxycarbonyl-4-cyanopiperidine (20.6 g) as a slightly yellow
oil.
[1292] (3) The above-mentioned compound (1.42 g) was dissolved in
N-methyl-2-pyrrolidone (60 mL), and sodium azide (1.13 g) and
triethylamine hydrochloride (1.24 g) were added thereto. The
mixture was stirred at 150.degree. C. for 6 hr. 1 mol/L
Hydrochloric acid was added to the reaction mixture to adjust its
pH to 1, and the mixture was extracted with ethyl acetate. 10%
Aqueous sodium hydroxide solution was added to the extract, and the
mixture was washed with diethyl ether. The aqueous layer was
adjusted to pH 1 with concentrated hydrochloric acid, and the
mixture was extracted with ethyl acetate. The extract was dried and
concentrated under reduced pressure. Trifluoroacetic acid (6 mL),
tert-butanol (0.900 g) and concentrated sulfuric acid (0.16 mL)
were added to the residue, and the mixture was stirred at room
temperature for 3 days. Water was added to the reaction mixture,
and the mixture was extracted with ethyl acetate. The extract was
washed successively with 2.5 mol/L aqueous sodium hydroxide
solution and brine, dried, and concentrated under reduced pressure.
The residue was purified by HPLC to give
1-benzyloxycarbonyl-4-(2-tert-butyl-2H-tetrazol-5-yl)piperidine
(140 mg) as a white solid.
[1293] (4) The above-mentioned compound (140 mg) was dissolved in
ethanol (10 mL), and the mixture was stirred in the presence of 10%
palladium/carbon (100 mg) at room temperature under a hydrogen
atomosphere (1 atm) for 4 hr. The reaction mixture was filtrated
and the filtrate was concentrated under reduced pressure to give
4-(2-tert-butyl-2H-tetrazol-5-yl)piperidine (85 mg) as a white
solid.
[1294] (5) Using the above-mentioned compound (85 mg) and the title
compound (117 mg) of Reference Example 12, and in the same manner
as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-(4-(2-tert-butyl-2H-tetrazol-5-yl)pipe-
ridino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (192 mg) was
obtained as a white powder.
[1295] (6) Using the above-mentioned compound (192 mg), and in the
same manner as in Example 257 (3), the title compound (113 mg) was
obtained as a white powder.
[1296] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.67(9H,s),
1.95-2.30(5H,m), 2.92-4.10(13H,m), 4.40-4.73(3H,m).
Example 299
Synthesis of
3-((2S,4S)-4-{4-[1-(4-methoxyphenyl)-1H-tetrazol-5-yl]piperidino}-2-pyrro-
lidinylcarbonyl)-1,3-thiazolidine dihydrochloride
[1297] (1) Isonipecotic acid (19.0 g) was dissolved in water (150
mL) and 1,4-dioxane (300 mL), 1 mol/L aqueous sodium hydroxide
solution (150 mL) and di-tert-butyl dicarbonate (35.3 g) were added
thereto under ice-cooling. The mixture was stirred at room
temperature for 3 days. 1,4-Dioxane was evaporated under reduced
pressure, and 5% potassium hydrogen sulfate was added to the
residue. The precipitated solid was collected by filtration to give
1-tert-butoxycarbonylisonipecotic acid (33.0 g) as a white
solid.
[1298] (2) The above-mentioned compound (2.63 g), HOBT (2.11 g) and
EDC hydrochloride (2.64 g) were dissolved in DMF (50 mL), and
p-anisidine (1.41 g) was added thereto. The mixture was stirred at
room temperature for 3 hr. Water was added to the reaction mixture,
and the precipitated solid was collected by filtration to give
1-tert-butoxycarbonylisonipecotic acid 4-methoxyphenylamide (2.84
g) as a white solid.
[1299] (3) The above-mentioned compound (1.06 g) was dissolved in
tetrahydrofuran (30 mL), and trimethylsilylazide (845 .mu.L),
triphenylphosphine (1.66 g) and 40% diisopropyl
azodicarboxylate/toluene solution (3.20 g) was added thereto. The
mixture was stirred at room temperature for 23 hr. Water was added
to the reaction mixture, and the mixture was extracted with ethyl
acetate. The extract was washed with brine, dried, and concentrated
under reduced pressure. The residue was purified by HPLC to give
1-tert-butoxycarbonyl-4-[1-(4-methoxyphenyl)-1H-tetrazol-5-yl]piperidine
(0.514 g) as a white solid.
[1300] (4) The above-mentioned compound (514 mg) was dissolved in
dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added
thereto at room temperature. The mixture was stirred for 5 hr. The
solvent was evaporated under reduced pressure, and saturated
aqueous sodium hydrogencarbonate solution was added to the residue.
The mixture was extracted with chloroform. The extract was dried
and concentrated under reduced pressure to give
4-[1-(4-methoxyphenyl)-1H-tetrazol-5-yl]piperidine (260 mg) as an
oil.
[1301] (5) Using the above-mentioned compound (260 mg) and the
title compound (295 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-((2S,4S)-1-tert-butoxycarbonyl-4-{4-[1-(4-methoxyphenyl)-1H-tetrazol-5--
yl]piperidino}-2-pyrrolidinylcarbonyl)-1,3-thiazolidine (427 mg)
was obtained as a white powder.
[1302] (6) Using the above-mentioned compound (424 mg), and in the
same manner as in Example 133 (2), the title compound (301 mg) was
obtained as a white powder.
[1303] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.1.95-2.35(5H,m),
2.87-3.95(13H,m), 3.87(3H,s), 4.46-4.73(3H,m), 7.19(2H,d,J=8.8 Hz),
7.61(2H,d,J=8.8 Hz), 9.10(1H,brs), 10.70(1H,brs),
12.02(1H,brs).
Example 300
Synthesis of
3-{(2S,4S)-4-[4-(5-chloro-3-benzofuranyl)piperidino]-2-pyrrolidinylcarbon-
yl}-1,3-thiazolidine dihydrochloride
[1304] (1) Using 4-(5-chloro-3-benzofuranyl)piperidine (380 mg) and
the title compound (404 mg) of Reference Example 12, and in the
same manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-chloro-3-benzofuranyl)piperidino-
]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (697 mg) was obtained as
a pale-yellow powder.
[1305] (2) Using the above-mentioned compound (697 mg), and in the
same manner as in Example 133 (2), the title compound (182 mg) was
obtained as a brown powder.
[1306] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.00-2.40(5H,m),
2.90-4.14(13H,m), 4.49-4.74(3H,m), 7.35(1H,dd,J=8.7, 1.8 Hz),
7.61(1H,d,J=8.7 Hz), 7.94(1H,s), 7.99(1H,s), 9.22(1H,brs),
10.71(1H,brs), 12.11(1H,brs).
Example 301
Synthesis of
3-{(2S,4S)-4-[4-(2-benzimidazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-
-thiazolidine trihydrochloride
[1307] (1) Acetyl chloride (180 mL) was dropwise added to a mixture
of ethanol (160 mL) and chloroform (180 mL) under ice-cooling.
After the mixture was stirred for 30 min, a solution of
1-benzyloxycarbonyl-4-cyanopiperidine [product of Example 298 (2),
20.6 g] in chloroform (180 mL) was added thereto under ice-cooling.
The mixture was stirred at room temperature for 18 hr. The reaction
mixture was concentrated under reduced pressure to give
1-benzyloxycarbonyl-4-(ethoxycarbonimidoyl)piperidine hydrochloride
(28.7 g) as a white solid.
[1308] (2) The above-mentioned compound (2.88 g) and
1,2-phenylenediamine (1.19 g) were dissolved in ethanol (50 mL),
and the mixture was refluxed for 4 hr. The reaction mixture was
concentrated under reduced pressure, and 0.5 mol/L aqueous sodium
hydroxide solution was added to the residue. The mixture was
extracted with chloroform. The extract was washed successively with
0.2 mol/L hydrochloric acid, saturated aqueous sodium
hydrogencarbonate solution and brine, and dried. The solvent was
evaporated under reduced pressure and the residue was purified by
silica gel chromatography to give
1-benzyloxycarbonyl-4-(2-benzimidazolyl)piperidine (2.61 g) as a
pale-brown solid.
[1309] (3) The above-mentioned compound (2.50 g) was dissolved in
methanol (50 mL), and the mixture was stirred in the presence of
10% palladium/carbon (500 mg) at room temperature under a hydrogen
atomosphere (1 atm). The reaction mixture was filtrated and the
filtrate was concentrated under reduced pressure to give
4-(2-benzimidazolyl)piperidine (1.50 g) as a pale-brown solid.
[1310] (4) Using the above-mentioned compound (332 mg) and the
title compound (450 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-4-[4-(2-benzimidazolyl)piperidino]-1-tert-butoxycarbonyl-2-pyr-
rolidinylcarbonyl}-1,3-thiazolidine (434 mg) was obtained as a
yellow solid.
[1311] .sup.1H-NMR(CDCl.sub.3).delta.1.36(4.5H,s), 1.40(4.5H,s),
1.75-2.32(7H,m), 2.43-2.56(1H,m), 2.75-4.15(10H,m),
4.38-4.82(3H,m), 7.17-7.25(2H,m), 7.41(1H,brs), 7.68(1H,brs),
10.74(1H,brs).
[1312] (5) The above-mentioned compound (430 mg) was dissolved in
ethanol (4 mL), and 4.1 mol/L hydrochloric acid-ethanol (2.2 mL)
was added thereto. The mixture was stirred at room temperature for
13 hr. The precipitated solid was collected by filtration to give
the title compound (318 mg) as a white powder.
[1313] .sup.1H-NMR(DMSO-d.sub.6).delta.2.20-2.57(5H,m),
2.95-4.07(13H,m), 4.47-4.79(3H,m), 7.48-7.57(2H,m),
7.74-7.83(2H,m), 9.14(1H,brs), 10.91(1H,brs), 12.18(1H,brs).
Example 302
Synthesis of
3-{(2S,4S)-4-[4-(5-cyano-2-benzimidazolyl)piperidino]-2-pyrrolidinylcarbo-
nyl}-1,3-thiazolidine trihydrochloride
[1314] (1) Using
1-benzyloxycarbonyl-4-(ethoxycarbonimidoyl)piperidine hydrochloride
(product of Example 301 (1), 2.87 g] and 3,4-diaminobenzonitrile
[product of Example 231 (1), 1.46 g], and in the same manner as in
Example 301 (2),
1-benzyloxycarbonyl-4-(5-cyano-2-benzimidazolyl)piperidine (2.11 g)
was obtained as a pale-brown solid.
[1315] (2) Using the above-mentioned compound (2.11 g), and in the
same manner as in Example 301 (3),
4-(5-cyano-2-benzimidazolyl)piperidine (1.44 g) was obtained as a
yellow powder.
[1316] (3) Using the above-mentioned compound (498 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-cyano-2-benzimidazolyl)piperidin-
o]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (463 mg) was obtained
as a white solid.
[1317] (4) 4 mol/L Hydrochloric acid-1,4-dioxane (2.5 mL) was added
to the above-mentioned compound (459 mg), and the mixture was
stirred at room temperature for 10 days. The precipitated solid was
collected by filtration to give the title compound (412 mg) as a
white powder.
[1318] .sup.1H-NMR(DMSO-d.sub.6).delta.2.17-2.60(5H,m),
2.95-4.10(13H,m), 4.45-4.79(3H,m), 5.7(1H,brs), 7.73(1H,d,J=8.4
Hz), 7.82(1H,d,J=8.4 Hz), 8.21(1H,s), 9.13(1H,brs), 10.97(1H,brs),
12.14(1H,brs).
Example 303
Synthesis of
3-{(2S,4S)-4-[4-(5-fluoro-2-benzimidazolyl)piperidino]-2-pyrrolidinylcarb-
onyl}-1,3-thiazolidine trihydrochloride
[1319] (2) Using the product (2.87 g) of Example 301 (1) and
4-fluoro-1,2-phenylenediamine [product of Example 233 (1), 1.38 g],
and in the same manner as in Example 301 (2),
1-benzyloxycarbonyl-4-(5-fluoro-2-benzimidazolyl)piperidine (2.72
g) was obtained as a yellow solid.
[1320] (2) Using the above-mentioned compound (2.71 g), and in the
same manner as in Example 301 (3),
4-(5-fluoro-2-benzimidazolyl)piperidine (1.84 g) was obtained as a
brown-dark solid.
[1321] (3) Using the above-mentioned compound (488 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-fluoro-2-benzimidazolyl)piperidi-
no]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (505 mg) was obtained
as a pale-brown solid.
[1322] (4) The above-mentioned compound (501 mg) was dissolved in
ethanol (5.5 mL), and 4.1 mol/L hydrochloric acid-ethanol (3.7 mL)
was added thereto. The mixture was stirred at room temperature for
3 days. The precipitated solid was collected by filtration to give
the title compound (391 mg) as a white powder.
[1323] .sup.1H-NMR(DMSO-d.sub.6).delta.2.17-2.55(5H,m),
2.93-4.10(13H,m), 4.45-4.78(3H,m), 7.30-7.41(1H,m),
7.60(1H,dd,J=8.6, 2.1 Hz), 7.79(1H,dd,J=8.9, 4.5 Hz), 9.14(1H,brs),
10.96(1H,brs), 12.16(1H,brs).
Example 304
Synthesis of
3-{(2S,4S)-4-[4-(5-cyano-1-methyl-2-benzimidazolyl)piperidino]-2-pyrrolid-
inylcarbonyl}-1,3-thiazolidine 3 hydrochloride
[1324] (1) Using the product (1.29 g) of Example 301 (1) and
3-amino-4-methylaminobenzonitrile (0.61 g), and in the same manner
as in Example 301 (2),
1-benzyloxycarbonyl-4-(5-cyano-1-methyl-2-benzimidazolyl)piperidine
(1.03 g) was obtained as a pale-brown solid.
[1325] (2) Using the above-mentioned compound (1.03 g), and in the
same manner as in Example 301 (3),
4-(5-cyano-1-methyl-2-benzimidazolyl)piperidine (0.549 g) was
obtained as a yellow solid.
[1326] (3) Using the above-mentioned compound (396 mg) and the
title compound (450 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-cyano-1-methyl-2-benzimidazolyl)-
piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (316 mg) was
obtained as a white solid.
[1327] (4) The above-mentioned compound (313 mg) was dissolved in
ethyl acetate (1 mL), and 4 mol/L hydrochloric acid-ethyl acetate
(3 mL) was added thereto. The mixture was stirred at
room-temperature for 18 hr. The precipitated solid was collected by
filtration to give the title compound (298 mg) as a white
powder.
[1328] .sup.1H-NMR(DMSO-d.sub.6).delta.2.13-2.43(5H,m),
2.97-3.35(5H,m), 3.42-4.07(13H,m), 4.47-4.90(3H,m), 7.71(1H,d,J=8.4
Hz), 7.84(1H,d,J=8.4 Hz), 8.19(1H,s), 9.14(1H,brs), 10.91(1H,brs),
12.14(1H,brs).
Example 305
Synthesis of
3-{(2S,4S)-4-[4-(5-fluoro-1-methyl-2-benzimidazolyl)piperidino]-2-pyrroli-
dinylcarbonyl}-1,3-thiazolidine trihydrochloride
[1329] (1) Using the product (2.87 g) of Example 301 (1) and
4-fluoro-N1-methyl-1,2-phenylenediamine [product of Example 238
(1), 1.30 g], and in the same manner as in Example 301 (2),
1-benzyloxycarbonyl-4-(5-fluoro-1-methyl-2-benzimidazolyl)piperidine
(2.83 g) was obtained as a brown-dark oil.
[1330] (2) Using the above-mentioned compound (2.83 g), and in the
same manner as in Example 301 (3),
4-(5-fluoro-1-methyl-2-benzimidazolyl)piperidine (1.65 g) was
obtained as a brown solid.
[1331] (3) Using the above-mentioned compound (513 mg) and the
title compound (601 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-fluoro-1-methyl-2-benzimidazolyl-
)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (377 mg) was
obtained as a pale-brown solid.
[1332] (4) The above-mentioned compound (373 mg) was dissolved in
ethyl acetate (1 mL), and 4 mol/L hydrochloric acid-ethyl acetate
(3.8 mL) was added thereto. The mixture was stirred at room
temperature for 12 hr. The precipitated solid was collected by
filtration to give the title compound (226 mg) as a white
powder.
[1333] .sup.1H-NMR(DMSO-d.sub.6).delta.2.18-2.43(5H,m),
2.97-3.37(5H,m), 3.60-4.09(13H,m), 4.47-4.80(4H,m), 7.39(1H,t,J=8.7
Hz), 7.57(1H,dd,J=8.7, 2.0 Hz), 7.83-7.92(1H,m), 9.14(1H,brs),
10.95(1H,brs), 12.14(1H,brs).
Example 306
Synthesis of
3-{(2S,4S)-4-[(4-(5-methyl-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbo-
nyl}-1,3-thiazolidine
[1334] (1) Using the product (2.50 g) of Example 301 (1) and
2-amino-4-methylphenol (1.60 g), and in the same manner as in
Example 301 (2),
1-benzyloxycarbonyl-4-(5-methyl-2-benzoxazolyl)piperidine (2.01 g)
was obtained as a dark brown oil.
[1335] (2) Using the above-mentioned compound (2.00 g), and in the
same manner as in Example 301 (3),
4-(5-methyl-2-benzoxazolyl)piperidine (1.21 g) was obtained as a
green solid.
[1336] (3) Using the above-mentioned compound (0.714 g) and the
title compound (0.901 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-methyl-2-benzoxazolyl)piperidino-
]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.47 g) was obtained as
a pale-green solid.
[1337] (4) The above-mentioned compound (1.47 g) was dissolved in
4.1 mol/L hydrochloric acid-ethanol (7 mL), and the mixture was
stirred at room temperature for 6 hr. The reaction mixture was
concentrated under reduced pressure, and saturated aqueous sodium
hydrogencarbonate solution was added to the residue.
[1338] The mixture was extracted with chloroform. The extract was
dried and concentrated under reduced pressure. The residue was
purified by silica gel chromatography and recrystallized from
diethyl ether to give the title compound (0.601 g) as a white
powder.
[1339] .sup.1H-NMR(DMSO-d.sub.6).delta.1.52-1.65(1H,m),
1.72-1.88(2H,m), 1.98-2.18(4H,m), 2.22-2.33(1H,m), 2.40(3H,s),
2.64-3.03(7H,m), 3.07(1H,t,J=6.2 Hz), 3.58-3.93(3H,m),
4.38-4.68(2H,m), 7.15(1H,dd,J=8.3, 1.3 Hz), 7.48(1H,d,J=1.3 Hz),
7.53(1H,d,J=8.3 Hz).
Example 307
Synthesis of
3-{(2S,4S)-4-[4-(5-trifluoromethyl-2-benzoxazolyl)piperidino]-2-pyrrolidi-
nylcarbonyl}-1,3-thiazolidine
[1340] (1) Using the product (2.96 g) of Example 301 (1) and
2-amino-4-trifluoromethylphenol (2.30 g), and in the same manner as
in Example 301 (2),
1-benzyloxycarbonyl-4-(5-trifluoromethyl-2-benzoxazolyl)piperidine
(2.68 g) was obtained as a brown oil.
[1341] (2) Using the above-mentioned compound (2.68 g), and in the
same manner as in Example 301 (3),
4-(5-trifluoromethyl-2-benzoxazolyl)piperidine (1.74 g) was
obtained as a pale-green oil.
[1342] (3) Using the above-mentioned compound (0.892 g) and the
title compound (0.901 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-trifluoromethyl-2-benzoxazolyl)p-
iperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.56 g) was
obtained as a white solid.
[1343] (4) The above-mentioned compound (1.47 g) was dissolved in
4.1 mol/L hydrochloric acid-ethanol (7 mL), and the mixture was
stirred at room temperature for 16 hr. The reaction mixture was
concentrated under reduced pressure, and saturated aqueous sodium
hydrogencarbonate solution was added to the residue.
[1344] The mixture was extracted with chloroform. The extract was
dried and concentrated under reduced pressure. The residue was
purified by silica gel chromatography and crystallized from diethyl
ether to give the title compound (0.034 g) as a white powder.
[1345] .sup.1H-NMR(DMSO-d.sub.6).delta.1.54-1.65(1H,m),
1.74-1.89(2H,m), 2.03-2.24(4H,m), 2.27-2.38(1H,m), 2.71-3.14(8H,m),
3.58-4.03(3H,m), 4.41-4.72(2H,m), 7.74(1H,d,J=8.5 Hz),
7.92(1H,d,J=8.5 Hz), 8.14(1H,s).
Example 308
Synthesis of
3-{(2S,4S)-4-[4-(5-methoxycarbonyl-2-benzoxazolyl)piperidino]-2-pyrrolidi-
nylcarbonyl}-1,3-thiazolidine
[1346] (1) Using the product (5.92 g) of Example 301 (1) and methyl
3-amino-4-hydroxybenzoate (4.34 g), and in the same manner as in
Example 301 (2),
1-benzyloxycarbonyl-4-(5-methoxycarbonyl-2-benzoxazolyl)piperidi-
ne (5.44 g) was obtained as a slightly red solid.
[1347] (2) Using the above-mentioned compound (2.02 g), and in the
same manner as in Example 301 (3),
4-(5-methoxycarbonyl-2-benzoxazolyl)piperidine (1.40 g) was
obtained as a pale-yellow solid.
[1348] (3) Using the above-mentioned compound (0.858 g) and the
title compound (0.901 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-methoxycarbonyl-2-benzoxazolyl)p-
iperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.48 g) was
obtained as a white solid.
[1349] (4) The above-mentioned compound (1.47 g) was dissolved in
methanol (2 mL), and 5.6 mol/L hydrochloric acid-methanol (2.5 mL)
was added thereto. The mixture was stirred at room temperature for
14 hr. The reaction mixture was concentrated under reduced
pressure, and saturated aqueous sodium hydrogencarbonate solution
was added to the residue. The mixture was extracted with
chloroform. The extract was dried and concentrated under reduced
pressure. The residue was purified by HPLC and crystallized from
diethyl ether to give the title compound (0.080 g) as a white
powder.
[1350] .sup.1H-NMR(DMSO-d.sub.6).delta.1.56-1.67(1H,m),
1.74-1.89(2H,m), 2.03-2.24(4H,m), 2.32-2.43(1H,m), 2.72-3.12(8H,m),
3.48-3.73(1H,m), 3.48-3.73(1H,m), 3.80-3.90(1H,m), 3.88(3H,s),
3.96-4.08(1H,m), 4.42-4.72(2H,m), 5.3(1H,brs), 7.82(1H,d,J=8.5 Hz),
8.00(1H,dd,J=8.5, 1.7 Hz), 8.24(1H,d,J=1.7 Hz).
Example 309
Synthesis of
3-{(2S,4S)-4-[4-(5-ethoxycarbonyl-2-benzoxazolyl)piperidino]-2-pyrrolidin-
ylcarbonyl}-1,3-thiazolidine
[1351] (1) Using the product (25.0 g) of Example 301 (1) and ethyl
3-amino-4-hydroxybenzoate (18.8 g), and in the same manner as in
Example 301 (2),
1-benzyloxycarbonyl-4-(5-ethoxycarbonyl-2-benzoxazolyl)piperidin- e
(20.0 g) was obtained as a white solid.
[1352] (2) Using the above-mentioned compound (10.2 g), and in the
same manner as in Example 301 (3),
4-(5-ethoxycarbonyl-2-benzoxazolyl)piperidine (7.05 g) was obtained
as a white solid.
[1353] (3) Using the above-mentioned compound (4.04 g) and the
title compound (4.03 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-ethoxycarbonyl-2-benzoxazolyl)pi-
peridino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (7.56 g) was
obtained as a white powder.
[1354] (4) The above-mentioned compound (2.24 g) was dissolved in
dichloromethane (4 mL) and trifluoroacetic acid (2 mL), and the
mixture was stirred at room temperature for 15 hr. Saturated
aqueous sodium hydrogencarbonate solution was added to the reaction
mixture, and the mixture was extracted with chloroform. The extract
was dried and the solvent was evaporated under reduced pressure.
The residue was purified by silica gel chromatography and
recrystallized from diethyl ether to give the title compound (1.18
g) as a white powder.
[1355] .sup.1H-NMR(CDCl.sub.3).delta.1.41(3H,t,J=7.2 Hz),
1.65-2.45(8H,m), 2.94-3.16(9H,m), 3.63-3.98(3H,m), 4.40(2H,q,J=7.2
Hz), 4.44-4.68(2H,m), 7.51(1H,d,J=8.7 Hz), 8.07(1H,dd,J=8.7, 1.8
Hz), 8.39(1H,d,J=1.8 Hz).
Example 310
Synthesis of
3-{(2S,4S)-4-[4-(5-carboxy-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbo-
nyl}-1,3-thiazolidine dihydrochloride
[1356] (1)
3-{(2S,4S)-1-tert-Butoxycarbonyl-4-[4-(5-ethoxycarbonyl-2-benzoxazolyl)pi-
peridino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine [product of
Example 309 (3), 4.51 g] was dissolved in ethanol (16 mL) and water
(8 mL), and lithium hydroxide monohydrate (678 mg) was added. The
mixture was stirred at room temperature for 3.5 hr. The reaction
mixture was diluted with water, and 1 mol/L hydrochloric acid was
added to adjust its pH to 7. The mixture was extracted with
chloroform. The extract was dried and concentrated under reduced
pressure to give
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-carboxy-2-benzoxazolyl)piperidin-
o]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (3.45 g) as a white
powder.
[1357] (2) Using the above-mentioned compound (786 mg), and in the
same manner as in Example 167 (2), the title compound (689 mg) was
obtained as a white powder.
[1358] .sup.1H-NMR(DMSO-d.sub.6).delta.2.10-2.45(5H,m),
2.88-4.12(13H,m), 4.45-4.81(3H,m), 7.82(1H,d,J=8.7 Hz),
8.02(1H,dd,J=8.7, 1.5 Hz), 8.24(1H,d,J=1.5 Hz), 9.20(1H,brs),
10.45(1H,brs), 11.90(1H,brs), 13.15(1H,brs).
Example 311
Synthesis of
3-{(2S,4S)-4-[4-(5-carbamoyl-2-benzoxazolyl)piperidino]-2-pyrrolidinylcar-
bonyl}-1,3-thiazolidine
[1359] (1)
3-{(2S,4S)-1-tert-Butoxycarbonyl-4-[4-(5-carboxy-2-benzoxazolyl)piperidin-
o]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine [product of Example 310
(1), 1.06 g] was dissolved in tetrahydrofuran (5 mL), and
triethylamine (0.279 mL) and isobutyl chlorocarbonate (0.263 mL)
were added thereto under ice-cooling. The mixture was stirred at
room temperature for 30 min. A solution of 7 mol/L ammonia-methanol
(1 mL) was added to the reaction mixture, and the mixture was
stirred at room temperature for 15 hr. Water was added to the
reaction mixture, and the mixture was extracted with chloroform.
The extract was dried and concentrated under reduced pressure. The
residue was purified by silica gel chromatography to give
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-carbamoyl-2-benzoxazolyl)piperid-
ino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (345 mg) as a white
powder.
[1360] (2) The above-mentioned compound (335 mg) was dissolved in
dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL), and the
mixture was stirred at room temperature for 7.5 hr. Saturated
aqueous sodium hydrogencarbonate solution was added to the reaction
mixture, and the mixture was extracted with chloroform. The extract
was dried, and concentrated under reduced pressure to give the
title compound (75 mg) as a white powder.
[1361] .sup.1H-NMR(CDCl.sub.3).delta.1.65-1.78(1H,m),
1.95-2.47(8H,m), 2.85-3.19(8H,m), 3.62-3.75(1H,m), 3.77-3.98(2H,m),
4.47-4.67(2H,m), 5.88(1H,brs), 6.18(1H,brs), 7.54(1H,d,J=9.6 Hz),
7.87(1H,dd,J=9.6, 1.5 Hz), 8.11(1H,d,J=1.5 Hz).
Example 312
Synthesis of
3-((2S,4S)-4-{4-[(5-(N-methylcarbamoyl)-2-benzoxazolyl]piperidino}-2-pyrr-
olidinylcarbonyl)-1,3-thiazolidine
[1362] (1) Using the product (1.06 g) of Example 310 (1) and 30%
methylamine-ethanol solution (1 mL), and in the same manner as in
Example 311 (1),
3-((2S,4S)-1-tert-butoxycarbonyl-4-{4-[5-(N-methylcarbamoyl)-2-b-
enzoxazolyl]piperidino}-2-pyrrolidinylcarbonyl)-1,3-thiazolidine
(0.725 g) was obtained as a white powder.
[1363] (2) Using the above-mentioned compound (669 mg), and in the
same manner as in Example 311 (2), the title compound (386 mg) was
obtained as a white powder.
[1364] .sup.1H-NMR(CDCl.sub.3).delta.1.62-1.78(1H,m),
1.92-2.38(8H,m), 2.87-3.20(11H,m), 3.63-3.74(1H,m),
3.75-3.97(2H,m), 4.47-4.67(2H,m), 6.35(1H,brs), 7.51(1H,d,J=8.5
Hz), 7.81(1H,dd,J=8.5, 1.7 Hz), 8.04(1H,d,J=1.7 Hz).
Example 313
Synthesis of
3-((2S,4S)-4-{4-[5-(N,N-dimethylcarbamoyl)-2-benzoxazolyl]piperidino}-2-p-
yrrolidinylcarbonyl)-1,3-thiazolidine dihydrochloride
[1365] (1) The product (1.36 g) of Example 310 (1) and
dimethylamine hydrochloride (0.244 g) were dissolved in DMF, and
triethylamine (0.42 mL), HOBT (0.457 g) and EDC hydrochloride
(0.572 g) were added thereto. The mixture was stirred at room
temperature for 1.5 hr. The saturated aqueous sodium
hydrogencarbonate solution was added to the reaction mixture, and
the mixture was extracted with ethyl acetate. The extract was dried
and concentrated under reduced pressure. The residue was purified
by silica gel chromatography to give
3-((2S,4S)-1-tert-butoxycarbonyl-4-{4-[(5-(N,N-dimethylcarbamoyl)-2-benzo-
xazolyl]piperidino}-2-pyrrolidinylcarbonyl)-1,3-thiazolidine (0.786
g) as a white powder.
[1366] (2) Using the above-mentioned compound (760 mg), and in the
same manner as in Example 167 (2), the title compound (634 mg) was
obtained as a white powder.
[1367] .sup.1H-NMR(DMSO-d.sub.6).delta.2.13-2.46(5H,m),
2.84-4.10(19H,m), 4.41-4.79(3H,m), 7.43(1H,dd,J=1.5, 8.4 Hz),
7.75-7.78(2H,m), 9.18(1H,brs), 10.63(1H,brs), 12.05(1H,brs).
Example 314
Synthesis of
3-{(2S,4S)-4-[4-(5-cyano-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbony-
l}-1,3-thiazolidine
[1368] (1) Using the product (2.88 g) of Example 301 (1) and
3-amino-4-cyanophenol (1.47 g), and in the same manner as in
Example 301 (2),
1-benzyloxycarbonyl-4-(5-cyano-2-benzoxazolyl)piperidine (2.43 g)
was obtained as a pale-brown powder.
[1369] (2) Using the above-mentioned compound (2.43 g), and in the
same manner as in Example 301 (3),
4-(5-cyano-2-benzoxazolyl)piperidine (1.33 g) was obtained as a
brown-dark solid.
[1370] (3) Using the above-mentioned compound (409 mg) and the
title compound (450 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-cyano-2-benzoxazolyl)piperidino]-
-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (230 mg) was obtained as
a white solid.
[1371] (4) The above-mentioned compound (226 mg) was dissolved in
ethyl acetate (1 mL), and 4 mol/L hydrochloric acid-ethyl acetate
(1.1 mL) was added thereto. The mixture was stirred at room
temperature for 18 hr. The reaction mixture was concentrated under
reduced pressure, and saturated aqueous sodium hydrogencarbonate
solution was added to the residue. The mixture was extracted with
chloroform. The extract was dried, and concentrated under reduced
pressure. The residue was purified by silica gel chromatography and
crystallized from ethyl acetate to give the title compound (869 mg)
as a white powder.
[1372] .sup.1H-NMR(DMSO-d.sub.6).delta.1.53-1.65(1H,m),
1.73-1.90(2H,m), 2.04-2.24(4H,m), 2.27-2.37(1H,m), 2.68-3.12(8H,m),
3.60-3.98(3H,m), 4.40-4.69(2H,m), 7.84(1H,dd,J=8.4, 1.4 Hz),
7.92(1H,d,J=8.4 Hz), 8.32(1H,d,J=1.4 Hz).
Example 315
Synthesis of
3-{(2S,4S)-4-[(4-(5-methoxy-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarb-
onyl}-1,3-thiazolidine dihydrochloride
[1373] (1) Using the product (5.11 g) of Example 301 (1) and
3-amino-4-methoxyphenol 2.72 g, and in the same manner as in
Example 301 (2),
1-benzyloxycarbonyl-4-(5-methoxy-2-benzoxazolyl)piperidine (4.35 g)
was obtained as an orange oil.
[1374] (2) Using the above-mentioned compound (4.25 g), and in the
same manner as in Example 301 (3),
4-(5-methoxy-2-benzoxazolyl)piperidine (2.47 g) was obtained as a
red-brown solid.
[1375] (3) Using the above-mentioned compound (0.767 g) and the
title compound (0.901 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-methoxy-2-benzoxazolyl)piperidin-
o]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.38 g) was obtained
as a white solid.
[1376] (4) The above-mentioned compound (1.37 g) was dissolved in
ethanol (4 mL), and 4.1 mol/L hydrochloric acid-ethanol (6.5 mL)
was added thereto. The mixture was stirred at room temperature for
16 hr. The reaction mixture was concentrated under reduced pressure
and the residue was crystallized from ethanol (10 mL) to give the
title compound (0.953 g) as a white powder.
[1377] .sup.1H-NMR(DMSO-d.sub.6).delta.2.12-2.43(5H,m),
2.90-4.07(16H,m), 4.45-4.77(3H,m), 6.97(1H,dd,J=8.9, 2.5 Hz),
7.28(1H,d,J=2.5 Hz), 7.60(1H,d,J=8.9 Hz), 9.14(1H,brs),
10.67(1H,brs), 12.03(1H,brs).
Example 316
Synthesis of
3-{(2S,4S)-4-[(4-(2-benzothiazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,-
3-thiazolidine dihydrochloride
[1378] (1) Using the product (5.74 g) of Example 301 (1) and
2-aminothiophenol (2.3 mL), and in the same manner as in Example
301(2), 4-(2-benzothiazolyl)-1-benzyloxycarbonylpiperidine (3.76 g)
was obtained as a yellow solid.
[1379] (2) The above-mentioned compound (986 mg) and thioanisole
(1.0 mL) were dissolved in trifluoroacetic acid (10 mL), and the
mixture was stirred at room temperature for 11 hr. The reaction
mixture was concentrated under reduced pressure, and saturated
aqueous sodium hydrogencarbonate solution was added to the residue.
The mixture was extracted with chloroform. The extract was dried
and concentrated under reduced pressure to give
4-(2-benzothiazolyl)piperidine (0.299 g) as a white solid.
[1380] (3) Using the above-mentioned compound (297 mg) and the
title compound (409 mg) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-4-[(4-(2-benzothiazolyl)piperidino]-1-tert-butoxycarbonyl-2-py-
rrolidinylcarbonyl}-1,3-thiazolidine (625 mg) was obtained as a
white solid.
[1381] .sup.1H-NMR(CDCl.sub.3).delta.1.41(4.5H,s), 1.46(4.5H,s),
1.82-2.06(3H,m), 2.14-2.32(4H,m), 2.39-2.52(1H,m), 2.78-3.21(6H,m),
3.32(1H,t,J=10.0 Hz), 3.63-4.12(3H,m), 4.37-4.79(3H,m),
7.35(1H,t,J=7.8 Hz), 7.46(1H,t,J=7.8 Hz), 7.86(1H,d,J=7.8 Hz),
7.97(1H,d,J=7.8 Hz).
[1382] (4) The above-mentioned compound (621 mg) was dissolved in
1.1 mol/L hydrochloric acid-methanol (6 mL), and the mixture was
stirred at room temperature for 2 days. The reaction mixture was
concentrated under reduced pressure and the residue was
crystallized from ethanol (6 mL) to give the title compound (423
mg) as a white powder.
[1383] .sup.1H-NMR(DMSO-d.sub.6).delta.2.16-2.46(5H,m),
2.94-3.36(5H,m), 3.40-4.08(8H,m), 4.47-4.78(3H,m), 7.44(1H,t,J=7.8
Hz), 7.52(1H,t,J=7.8 Hz), 7.99(1H,d,J=7.8 Hz), 8.11(1H,d,J=7.8 Hz),
9.13(1H,brs), 10.82(1H,brs), 12.14(1H,brs).
Example 317
Synthesis of
3-{(2S,4S)-4-[(4-(5-trifluoromethyl-2-benzothiazolyl)piperidino]-2-pyrrol-
idinylcarbonyl}-1,3-thiazolidine
[1384] (1) The product (2.96 g) of Example 301 (1),
2-amino-4-trifluoromethylthiophenol hydrochloride (2.99 g) and
triethylamine (1.8 mL) were dissolved in ethanol (60 mL), and the
mixture was refluxed for 4 hr. The reaction mixture was
concentrated under reduced pressure, and 0.5 mol/L aqueous sodium
hydroxide solution was added to the residue. The mixture was
extracted with chloroform. The extract was washed successively with
0.5 mol/L hydrochloric acid, saturated aqueous sodium
hydrogencarbonate solution and brine, and dried. The solvent was
evaporated under reduced pressure and the residue was purified by
silica gel chromatography to give
1-benzyloxycarbonyl-4-(5-trifluoromethyl-2-benzothiazolyl)piperidine
(1.75 g) as a pale-yellow oil.
[1385] (2) The above-mentioned compound (1.74 g) was dissolved in
30% hydrogen bromide-acetic acid solution (8 mL), and the mixture
was stirred at room temperature for 1 hr. Diethyl ether (10 mL) was
added to the reaction mixture, and the precipitated solid was
collected by filtration. The saturated aqueous sodium
hydrogencarbonate solution was added to the precipitated solid, and
the mixture was extracted with chloroform. The extract was dried
and concentrated under reduced pressure to give
4-(5-trifluoromethyl-2-benzothiazolyl)piperidine (0.943 g) as a
pale-yellow solid.
[1386] (3) Using the above-mentioned compound (0.923 g) and the
title compound (0.901 g) of Reference Example 12, and in the same
manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-trifluoromethyl-2-benzothiazolyl-
)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.60 g) was
obtained as a white solid.
[1387] (4) The above-mentioned compound (1.60 g) was dissolved in
4.1 mol/L hydrochloric acid-ethanol (7 mL), and the mixture was
stirred at room temperature for 2 days. The reaction mixture was
concentrated under reduced pressure, and saturated aqueous sodium
hydrogencarbonate solution was added to the residue. The mixture
was extracted with chloroform. The extract was dried and
concentrated under reduced pressure. The residue was purified by
silica gel chromatography and crystallized from diethyl ether to
give the title compound (0.848 g) as a white powder.
[1388] .sup.1H-NMR(DMSO-d.sub.6).delta.1.52-1.65(1H,m),
1.72-1.88(2H,m), 2.04-2.20(4H,m), 2.22-2.33(1H,m), 2.67-3.23(8H,m),
3.58-3.92(3H,m), 4.40-4.70(2H,m), 7.74(1H,dd,J=8.4, 1.5 Hz),
8.31(1H,d,J=1.5 Hz), 8.34(1H,d,J=8.4 Hz).
Example 318
Synthesis of
3-{(2S,4S)-4-[4-(6-fluoro-3-benz[d]isoxazolyl)piperidino]-2-pyrrolidinylc-
arbonyl}-1,3-thiazolidine dihydrochloride
[1389] (1) Using 4-(6-fluoro-3-benz[d]isoxazolyl)piperidine (0.54
g) and the title compound (0.614 g) of Reference Example 12, and in
the same manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(6-fluoro-3-benz[d]isoxazolyl)piper-
idino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.01 g) was
obtained as a white powder.
[1390] (2) Using the above-mentioned compound (1.00 g), and in the
same manner as in Example 133 (2), the title compound (0.38 g) was
obtained as a white powder.
[1391] .sup.1H-NMR(500 MHz,DMSO-d.sub.6).delta.2.05-2.46(5H,m),
2.92-4.20(13H,m), 4.49-4.73(3H,m), 7.32-7.36(1H,m),
7.72-7.74(1H,m), 8.20(1H,brs), 9.10(1H,brs), 10.60(1H,brs),
12.22(1H,brs).
Example 319
Synthesis of
3-{(2S,4S)-4-{2-[(5-cyano-2-pyridyl)amino]ethyl}amino-2-pyrrolidinylcarbo-
nyl}-1,3-s thiazolidine trihydrochloride
[1392] (1) Using N-(5-cyano-2-pyridyl)ethylenediamine (0.656 g) and
the title compound (1.20 g) of Reference Example 12, and in the
same manner as in Example 70 (1),
3-{(2S,4S)-1-tert-butoxycarbonyl-4-{2-[((5-cyano-2-pyridyl)amino]ethyl}am-
ino-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (1.46 g) was obtained
as a white solid.
[1393] (2) The above-mentioned compound (656 mg) was dissolved in
ethyl acetate (4 mL), and 4 mol/L hydrochloric acid-ethyl acetate
(4 mL) was added thereto. The mixture was stirred at room
temperature for 12 hr. The precipitated solid was collected by
filtration to give the title compound (666 mg) as a white
powder.
[1394] .sup.1H-NMR(DMSO-d.sub.6).delta.2.03-2.19(1H,m),
2.87-2.98(1H,m), 3.06(1H,t,J=6.5 Hz), 3.10-3.25(3H,m),
3.45-4.10(7H,m), 4.47-4.74(3H,m), 6.67(1H,d,J=8.9 Hz),
7.76(1H,dd,J=8.9, 2.2 Hz), 8.03(1H,brs), 8.46(1H,d,J=2.2 Hz),
8.96(1H,brs), 9.96(2H,brs), 10.64(1H,brs).
Example 320
Synthesis of
3-[(2S,4S)-4-(N-acetyl-N-{2-[(5-cyano-2-pyridyl)amino]ethyl}amino)-2-pyrr-
olidinylcarbonyl]-1,3-thiazolidine dihydrochloride
[1395] (1)
3-{(2S,4S)-1-tert-Butoxycarbonyl-4-{2-[(5-cyano-2-pyridyl)amino]ethyl}ami-
no-2-pyrrolidinylcarbonyl}-1,3-thiazolidine [product of Example 319
(1), 800 mg] and triethylamine (0.42 mL) were dissolved in
dichloromethane (20 mL), and acetyl chloride (0.18 mL) was added
thereto under ice-cooling. The mixture was stirred at room
temperature for 5 hr. The reaction mixture was added to saturated
aqueous sodium hydrogencarbonate solution and the mixture was
extracted with chloroform. The extract was washed with brine,
dried, and concentrated under reduced pressure. The residue was
purified by silica gel chromatography to give
3-[(2S,4S)-4-(N-acetyl-N-{2-[(5-cyano-2-pyridyl)amino]ethyl}amino)-1-tert-
-butoxycarbonyl-2-pyrrolidinylcarbonyl]-1,3-thiazolidine (786 mg)
as a white solid.
[1396] (2) The above-mentioned compound (380 mg) was dissolved in
ethyl acetate (3 mL), and 4 mol/L hydrochloric acid-ethyl acetate
(1 mL) was added thereto. The mixture was stirred at room
temperature for 3 hr. The precipitated solid was collected by
filtration to give the title compound (314 mg) as a white
powder.
[1397] .sup.1H-NMR(DMSO-d.sub.6).delta.1.95-2.10(4H,m),
2.62-2.80(1H,m), 3.00-3.90(11H,m), 4.28-4.77(4H,m), 6.64(1H,d,J=8.8
Hz), 7.73(1H,dd,J=8.8, 2.2 Hz), 7.95(1H,brs), 8.35(1H,brs),
8.42(1H,d,J=2.2 Hz), 9.96% (1H,brs).
[1398] The structures of the compound obtained in the
above-mentioned Examples are all shown in Tables 1-40.
TABLE-US-00001 TABLE 1 ##STR18## Example No. X Y Z salt 1 ##STR19##
CH.sub.2 CN CF.sub.3CO.sub.2H 2 ##STR20## CH.sub.2 CN HCl 3
##STR21## CH.sub.2 CN 2HCl 4 ##STR22## CH.sub.2 CN
CF.sub.3CO.sub.2H 5 ##STR23## CH.sub.2 CN HCl 6 ##STR24## CH.sub.2
CN HCL 7 ##STR25## CH.sub.2 CN HCl 8 ##STR26## CH.sub.2 CN HCl 9
##STR27## CH.sub.2 CN HCl 10 ##STR28## CH.sub.2 CN HCl 11 ##STR29##
CH.sub.2 CN HCl
[1399] TABLE-US-00002 TABLE 2 ##STR30## Example No. X Y Z salt 12
##STR31## CH.sub.2 CN HCl 13 ##STR32## CH.sub.2 CN HCl 14 ##STR33##
CH.sub.2 CN CF.sub.3CO.sub.2H 15 ##STR34## CH.sub.2 CN
CF.sub.3CO.sub.2H 16 ##STR35## CH.sub.2 CN HCl 17 ##STR36##
CH.sub.2 CN CF.sub.3CO.sub.2H 18 ##STR37## CH.sub.2 CN 2HCl 19
##STR38## CH.sub.2 CN 2HCl 20 ##STR39## CH.sub.2 CN
2CF.sub.3CO.sub.2H 21 ##STR40## CH.sub.2 CN 2HCl
[1400] TABLE-US-00003 TABLE 3 ##STR41## Ex- am- ple No. X Y Z salt
22 ##STR42## CH.sub.2 CN CF.sub.3CO.sub.2H 23 ##STR43## CH.sub.2 CN
HCl 24 ##STR44## CH.sub.2 CN HCl 25 ##STR45## CH.sub.2 CN HCl 26
##STR46## CH.sub.2 CN HCl 27 ##STR47## CH.sub.2 CN HCl 28 ##STR48##
CH.sub.2 CN 2HCl 29 ##STR49## CH.sub.2 CN 2HCl 30 ##STR50##
CH.sub.2 CN 2HCl 31 ##STR51## CH.sub.2 CN 2HCl 32 ##STR52##
CH.sub.2 CN 2HCl
[1401] TABLE-US-00004 TABLE 4 ##STR53## Example No. X Y Z salt 33
##STR54## CH.sub.2 CN 2HCl 34 ##STR55## CH.sub.2 CN
3CF.sub.3CO.sub.2H 35 ##STR56## CH.sub.2 CN 2CF.sub.3CO.sub.2H 36
##STR57## CH.sub.2 CN 2HCl 37 ##STR58## CH.sub.2 CN 2HCl 38
##STR59## CH.sub.2 CN 2HCl 39 ##STR60## CH.sub.2 CN 2HCl 40
##STR61## CH.sub.2 CN HCl 41 ##STR62## CH.sub.2 CN HCl 42 ##STR63##
CH.sub.2 CN HCl 43 ##STR64## CH.sub.2 CN HCl
[1402] TABLE-US-00005 TABLE 5 ##STR65## Example No. X Y Z salt 44
##STR66## CH.sub.2 CN HCl 45 ##STR67## CH.sub.2 CN
2CF.sub.3CO.sub.2H 46 ##STR68## CH.sub.2 CN 2CF.sub.3CO.sub.2H 47
##STR69## CH.sub.2 CN 2HCl 48 ##STR70## CH.sub.2 CN
CF.sub.3CO.sub.2H 49 ##STR71## CH.sub.2 CN 2HCl 50 ##STR72##
CH.sub.2 CN 2HCl 51 ##STR73## CH.sub.2 CN 2HCl 52 ##STR74##
CH.sub.2 CN 2HCl 53 ##STR75## S H 2HCl
[1403] TABLE-US-00006 TABLE 6 ##STR76## Example No. X Y Z salt 54
##STR77## S H HCl 55 ##STR78## S H HCl 56 ##STR79## S H HCl 57
##STR80## S H HCl 58 ##STR81## S H 2HCl 59 ##STR82## S H HCI 60
##STR83## S H HCl 61 ##STR84## S H HCl 62 ##STR85## S H 2HCl 63
##STR86## S H 2HCl 64 ##STR87## S H 2HCl
[1404] TABLE-US-00007 TABLE 7 ##STR88## Example No. X Y Z salt 65
##STR89## S H 3HCl 66 ##STR90## S H -- 67 ##STR91## S H -- 68
##STR92## S H 2HCl 69 ##STR93## S H HCl 70 ##STR94## S H 2HCl 71
##STR95## S H 2HCl 72 ##STR96## S H HCl 73 ##STR97## S H 2HCl
[1405] TABLE-US-00008 TABLE 8 ##STR98## Example No. X Y Z salt 74
##STR99## S H 2HCl 75 ##STR100## S H 2HCl 76 ##STR101## S H HCl 77
##STR102## S H HCl 78 ##STR103## S H 2HCl 79 ##STR104## S H 2HCl 80
##STR105## S H 2HCl 81 ##STR106## S H 3HCl 82 ##STR107## S H HCl 83
##STR108## S H HCl 84 ##STR109## S H 2HCl
[1406] TABLE-US-00009 TABLE 9 ##STR110## Example No. X Y Z salt 85
##STR111## CH.sub.2 H 2HCl 86 ##STR112## S H HCl 87 ##STR113## S H
2HCl 88 ##STR114## S H 2HCl 89 ##STR115## S H 2HCl 90 ##STR116## S
H 2HCl 91 ##STR117## S H 2HCl 92 ##STR118## S H 2HCl 93 ##STR119##
S H HCl 94 ##STR120## S H HCl
[1407] TABLE-US-00010 TABLE 10 ##STR121## Ex- am- ple No. X Y Z
salt 95 ##STR122## S H HCl 96 ##STR123## S H 2CF.sub.3CO.sub.2H 97
##STR124## S H 2HCl 98 ##STR125## S H HCl 99 ##STR126## S H 2HCl
100 ##STR127## S H 2HCl 101 ##STR128## S H 2HCl 102 ##STR129## S H
2HCl 103 ##STR130## S H CF.sub.3CO.sub.2H 104 ##STR131## S H 2HCl
105 ##STR132## S H 2HCl
[1408] TABLE-US-00011 TABLE 11 ##STR133## Example No. X Y Z salt
106 ##STR134## S H 2HCl 107 ##STR135## S H 2CF.sub.3CO.sub.2H 108
##STR136## S H 2CF.sub.3CO.sub.2H 109 ##STR137## S H 2HCl 110
##STR138## S H 111 ##STR139## S H HCl 112 ##STR140## S H HCl 113
##STR141## S H HCl 114 ##STR142## S H HCl 115 ##STR143## S H
HCl
[1409] TABLE-US-00012 TABLE 12 ##STR144## Example No. X Y Z salt
116 ##STR145## S H HCl 117 ##STR146## S H HCl 118 ##STR147## S H
CF3CO2H 119 ##STR148## S H CF3CO2H 120 ##STR149## S H CF3CO2H 121
##STR150## H -- 122 ##STR151## S H HCl 123 ##STR152## S H HCl 124
##STR153## S H HCl 125 ##STR154## S H 2HCl
[1410] TABLE-US-00013 TABLE 13 ##STR155## Example No. X Y Z salt
126 ##STR156## S H 2HCl 127 ##STR157## S H 2HCl 128 ##STR158## S H
3HCl 129 ##STR159## S H 2CF.sub.3CO.sub.2H 130 ##STR160## S H 2HCl
131 ##STR161## S H 2HCl 132 ##STR162## S H 2HCl 133 ##STR163## S H
2HCl 134 ##STR164## S H 2HCl
[1411] TABLE-US-00014 TABLE 14 ##STR165## Example No. X Y Z salt
135 ##STR166## S H 2HCl 136 ##STR167## S H 2HCl 137 ##STR168## S H
2HCl 138 ##STR169## S H 2HCl 139 ##STR170## S H 2HCl 140 ##STR171##
S H 2HCl 141 ##STR172## S H 2HCl 142 ##STR173## S H 2HCl
[1412] TABLE-US-00015 TABLE 15 ##STR174## Example No. X Y Z salt
143 ##STR175## S H 2HCl 144 ##STR176## S H 3HCl 145 ##STR177## S H
2HCl 146 ##STR178## S H 3HCl 147 ##STR179## S H 2HCl 148 ##STR180##
S H 3HCl 149 ##STR181## S H 3HCl 150 ##STR182## S H 3HCl 151
##STR183## S H 3HCl
[1413] TABLE-US-00016 TABLE 16 ##STR184## Ex- am- ple No. X Y Z
salt 152 ##STR185## S H 3HCl 153 ##STR186## S H 3HCl 154 ##STR187##
S H 2CF.sub.3CO.sub.2H 155 ##STR188## S H 2HCl 156 ##STR189## S H
3HCl 157 ##STR190## S H 2HCl 158 ##STR191## S H 2HCl 159 ##STR192##
S H 3HCl
[1414] TABLE-US-00017 TABLE 17 ##STR193## Example No. X Y Z salt
160 ##STR194## S H 3HCl 161 ##STR195## CH.sub.2 H 3HCl 162
##STR196## S H 3HCl 163 ##STR197## S H 3HCl 164 ##STR198## S H 3HCl
165 ##STR199## S H 3HCl 166 ##STR200## S H 3HCl 167 ##STR201## S H
3HCl
[1415] TABLE-US-00018 TABLE 18 ##STR202## Example No. X Y Z salt
168 ##STR203## S H 2HCl 169 ##STR204## S H 3HCl 170 ##STR205## S H
3HCl 171 ##STR206## S H 2HCl 172 ##STR207## S H 3HCl 173 ##STR208##
S H 3HCl 174 ##STR209## S H 3HCl 175 ##STR210## S H 3HCl
[1416] TABLE-US-00019 TABLE 19 ##STR211## Example No. X Y Z salt
176 ##STR212## S H 3HCl 177 ##STR213## S H 3HCl 178 ##STR214## S H
2HCl 179 ##STR215## S H 3HCl 180 ##STR216## S H 3HCl 181 ##STR217##
S H 3HCl 182 ##STR218## CH.sub.2 H 3HCl
[1417] TABLE-US-00020 TABLE 20 ##STR219## Example No. X Y Z salt
183 ##STR220## S H 3HCl 184 ##STR221## S H 2HCl 185 ##STR222## S H
2HCl 186 ##STR223## CH.sub.2 H 3HCl 187 ##STR224## S H 3HCl 188
##STR225## S H 3HCl 189 ##STR226## S H 3HCl 190 ##STR227## S H
3HCl
[1418] TABLE-US-00021 TABLE 21 ##STR228## Example No. X Y Z salt
191 ##STR229## S H 2HC 192 ##STR230## S H 3HCl 193 ##STR231## S H
3HCl 194 ##STR232## S H 2HC 195 ##STR233## S H 2HC 196 ##STR234## S
H 2HCl 197 ##STR235## S H 3HCl
[1419] TABLE-US-00022 TABLE 22 ##STR236## Example No. X Y Z salt
198 ##STR237## S H 3HCl 199 ##STR238## S H 2HCl 200 ##STR239## S H
2HCl 201 ##STR240## S H 2HCl 202 ##STR241## S H 2HCl 203 ##STR242##
S H 2HCl 204 ##STR243## S H 2HCl 205 ##STR244## S H 3HCl
[1420] TABLE-US-00023 TABLE 23 ##STR245## Example No. X Y Z salt
206 ##STR246## S H 4HCl 207 ##STR247## S H 2HCl 208 ##STR248## S H
3HCl 209 ##STR249## S H 3HCl 210 ##STR250## S H 3HCl 211 ##STR251##
S H 3HCl 212 ##STR252## S H 3HCl
[1421] TABLE-US-00024 TABLE 24 ##STR253## Example No. X Y Z salt
213 ##STR254## S H 3HCl 214 ##STR255## S H 3HCl 215 ##STR256## S H
3HCl 216 ##STR257## S H 3HCl 217 ##STR258## S H 3HCl 218 ##STR259##
S H 3HCl 219 ##STR260## S H 3HCl
[1422] TABLE-US-00025 TABLE 25 ##STR261## Example No. X Y Z salt
220 ##STR262## S H 3HCl 221 ##STR263## S H 3HCl 222 ##STR264## S H
3HCl 223 ##STR265## S H 3HCl 224 ##STR266## S H 3HCl 225 ##STR267##
S H 3HCl 226 ##STR268## S H 3HCl
[1423] TABLE-US-00026 TABLE 26 ##STR269## Ex- am- ple No. X Y Z
salt 227 ##STR270## S H 3HCl 228 ##STR271## S H 3HCl 229 ##STR272##
S H 3HCl 230 ##STR273## S H 2HCl 231 ##STR274## S H 3HCl 232
##STR275## S H 3HBr 233 ##STR276## S H 3HBr
[1424] TABLE-US-00027 TABLE 27 ##STR277## Example No. X Y Z salt
234 ##STR278## S H 3HBr 235 ##STR279## S H 3HCl 236 ##STR280## S H
3HCl 237 ##STR281## S H 3HCl 238 ##STR282## S H 3HCl 239 ##STR283##
S H 2HCl
[1425] TABLE-US-00028 TABLE 28 ##STR284## Example No. X Y Z salt
240 ##STR285## S H 2HCl 241 ##STR286## S H 2HCl 242 ##STR287## S H
2HCl 243 ##STR288## S H 3HCl 244 ##STR289## S H 3HCl 245 ##STR290##
S H 2HCl
[1426] TABLE-US-00029 TABLE 29 ##STR291## Example No. X Y Z salt
246 ##STR292## S H 2HCl 247 ##STR293## S H 2HCl 248 ##STR294## S H
3HCl 249 ##STR295## S H 3HCl 250 ##STR296## S H 3HCl 251 ##STR297##
S H 3HCl
[1427] TABLE-US-00030 TABLE 30 ##STR298## Ex- am- ple No. X Y Z
salt 252 ##STR299## S H 3HCl 253 ##STR300## S H 3HCl 254 ##STR301##
S H 3HCl 255 ##STR302## S H 1.5(CO.sub.2H).sub.2 256 ##STR303## S H
3HCl 257 ##STR304## S H 3HCl 258 ##STR305## S H 3HCl
[1428] TABLE-US-00031 TABLE 31 ##STR306## Example No. X Y Z salt
259 ##STR307## S H 3HCl 260 ##STR308## S H 2HCl 261 ##STR309## S H
2HCl 262 ##STR310## S H 3HCl 263 ##STR311## S H 3HCl 264 ##STR312##
S H 3HCl
[1429] TABLE-US-00032 TABLE 32 ##STR313## Example No. X Y Z salt
265 ##STR314## S H 3HCl 266 ##STR315## S H 3HCl 267 ##STR316## S H
3HCl 268 ##STR317## S H 3HCl 269 ##STR318## S H 2HCl 270 ##STR319##
S H 2HCl
[1430] TABLE-US-00033 TABLE 33 ##STR320## Example No. X Y Z salt
271 ##STR321## S H 2HCl 272 ##STR322## S H 3HCl 273 ##STR323## S H
2HCl 274 ##STR324## S H 2HCl 275 ##STR325## S H 2HCl 276 ##STR326##
S H 2HCl
[1431] TABLE-US-00034 TABLE 34 ##STR327## Example No. X Y Z salt
277 ##STR328## S H 2HCl 278 ##STR329## S H 3HCl 279 ##STR330## S H
3HCl 280 ##STR331## S H 3HCl 281 ##STR332## S H 3HCl 282 ##STR333##
S H --
[1432] TABLE-US-00035 TABLE 35 ##STR334## Example No. X Y Z salt
283 ##STR335## S H 3HCl 284 ##STR336## S H 2HCl 285 ##STR337## S H
2HCl 286 ##STR338## S H 2HCl 287 ##STR339## S H 2HCl 288 ##STR340##
S H 2HCl 289 ##STR341## S H 2HCl
[1433] TABLE-US-00036 TABLE 36 ##STR342## Exam- ple No. X Y Z salt
290 ##STR343## S H 2HCl 291 ##STR344## S H 3HCl 292 ##STR345## S H
3HCl 293 ##STR346## S H 2HCl 294 ##STR347## S H 2HCl 295 ##STR348##
S H 2HCl
[1434] TABLE-US-00037 TABLE 37 ##STR349## Ex- ample No. X Y Z salt
296 ##STR350## S H 3HCl 297 ##STR351## S H 3HCl 298 ##STR352## S H
2HCl 299 ##STR353## S H 2HCl 300 ##STR354## S H 2HCl 301 ##STR355##
S H 3HCl
[1435] TABLE-US-00038 TABLE 38 ##STR356## Example No. X Y Z salt
302 ##STR357## S H 3HCl 303 ##STR358## S H 3HCl 304 ##STR359## S H
3HCl 305 ##STR360## S H 3HCl 306 ##STR361## S H -- 307 ##STR362## S
H --
[1436] TABLE-US-00039 TABLE 39 ##STR363## Exam- ple No. X Y Z salt
308 ##STR364## S H -- 309 ##STR365## S H -- 310 ##STR366## S H 2HCl
311 ##STR367## S H -- 312 ##STR368## S H -- 313 ##STR369## S H
2HCl
[1437] TABLE-US-00040 TABLE 40 Exam- ple No. X Y Z salt 314
##STR370## S H -- 315 ##STR371## S H 2HCl 316 ##STR372## S H 2HCl
317 ##STR373## S H -- 318 ##STR374## S H 2HCl 319 ##STR375## S H
3HCl 320 ##STR376## S H 2HCl
[1438] The compound of the present invention showed a potent DPP-IV
inhibitory activity in Experimental Example 1 shown below.
Experimental Example 1
Plasma DPP-IV Inhibitory Activity
[1439] The plasma DPP-IV inhibitory activity of human and rat was
measured by the fluorescence assay method. Using Gly-Pro-MCA
(Peptide Institute Inc.) as a DPP-IV specific fluorescent
substrate, reaction solutions having the following compositions and
containing test substances having various concentrations were
incubated at room temperature for 60 min and the measured (SPECTRA
FLUOR, TECAN) fluorescent intensity (Exitation 360 nm/Emission 465
nm) was taken as the DPP-IV activity. TABLE-US-00041 Rat or human
plasma (10-fold diluted solution) 20 .mu.L/well fluorescent
substrate (100 .mu.mol/L) 20 .mu.L/well test substance 20
.mu.L/well buffer (0.003% Brij-35 containing PBS) 140 .mu.L/well
total amount 200 .mu.L/well
[1440] The inhibitory rate relative to the solvent addition group
was calculated and IC.sub.50 values were determined by logistic
analysis.
[1441] The IC.sub.50 values of the plasma DPP-IV inhibitory
activity of the present invention as determined by the method above
are shown in the following table. TABLE-US-00042 Human plasma
DPP-IV Rat plasma DPP-IV Example compound Inhibitory activity
Inhibitory activity No. IC.sub.50 (nM) IC.sub.50 (nM) 5 0.18 0.17
12 0.13 0.15 20 0.54 0.41 24 0.51 0.64 29 0.30 0.22 39 1.1 0.55 88
4.8 6.1 99 6.8 9.4 143 1.5 2.1 186 3.7 4.2 189 0.95 1.0 212 0.45
0.75 242 0.33 0.34 279 0.73 0.79 296 1.1 1.9 303 0.61 1.1
[1442] As shown in the following, the plasma DPP-IV inhibitory
activity of the compound of Japanese Patent Application under PCT
laid-open under kohyo No. 9-509921 and the compound of WO99/61431
is not sufficient. TABLE-US-00043 Human plasma DPP-IV Inhibitory
activity IC.sub.50 Known compound (nM)
(S)-2-cyano-1-L-prolylpyrrolidine 2.9 hydrochloride
3-L-prolyl-1,3-thiazolidine 538
INDUSTRIAL APPLICABILITY
[1443] From the foregoing Experimental Example and various
pharmacological experiments, the compounds of the present invention
exhibit a potent DPP-IV inhibitory activity and are useful for the
prophylaxis or treatment of diabetes or the prophylaxis or
treatment of obesity or the prophylaxis or treatment of HIV
infection, cancer metastasis, dermopathy, prostatic hyperplasia,
periodontitis or autoimmune disease, and the like.
[1444] This application is based on patent application Nos.
243217/2000 and 400296/2000 filed in Japan, the contents of which
are hereby incorporated by reference.
* * * * *