U.S. patent application number 12/137267 was filed with the patent office on 2008-10-23 for fused pyridazine derivative compounds and drugs containing these compounds as the active ingredient.
This patent application is currently assigned to ONO PHARMACEUTICAL CO., LTD.. Invention is credited to Yoshihisa Kamanaka, Wataru Kamoshima, Takuya Seko, Shinya Takahashi, Jun Takeuchi.
Application Number | 20080261947 12/137267 |
Document ID | / |
Family ID | 27759644 |
Filed Date | 2008-10-23 |
United States Patent
Application |
20080261947 |
Kind Code |
A1 |
Seko; Takuya ; et
al. |
October 23, 2008 |
FUSED PYRIDAZINE DERIVATIVE COMPOUNDS AND DRUGS CONTAINING THESE
COMPOUNDS AS THE ACTIVE INGREDIENT
Abstract
Fused pyridazine derivatives represented by formula (I) or
pharmaceutically acceptable salts thereof (wherein each symbol has
the meaning as defined in the specification.). ##STR00001## Because
of inhibiting poly(ADP-ribose)polymerase, the compounds represented
by formula (I) are useful as preventives and/or remedies for
various ischemic diseases (in brain, cord, heart, digestive tract,
skeletal muscle, retina, etc.), inflammatory diseases (inflammatory
bowel disease, multiple cerebrosclerosis, arthritis, etc.),
neurodegenerative diseases (extrapyramidal disorder, Alzheimer's
disease, muscular dystrophy, lumbar spinal canal stenosis, etc.),
diabetes, shock, head trauma, renal failure, hyperalgesia, etc.
Moreover, these compounds are useful as agents against retroviruses
(HIV etc.), sensitizers in treating cancer and
immunosuppressants.
Inventors: |
Seko; Takuya; (Osaka-shi,
JP) ; Takeuchi; Jun; (Mishima-gun, JP) ;
Takahashi; Shinya; (Mishima-gun, JP) ; Kamanaka;
Yoshihisa; (Mishima-gun, JP) ; Kamoshima; Wataru;
(Mishima-gun, JP) |
Correspondence
Address: |
SUGHRUE MION, PLLC
2100 PENNSYLVANIA AVENUE, N.W., SUITE 800
WASHINGTON
DC
20037
US
|
Assignee: |
ONO PHARMACEUTICAL CO.,
LTD.
|
Family ID: |
27759644 |
Appl. No.: |
12/137267 |
Filed: |
June 11, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10505012 |
Aug 18, 2004 |
7402580 |
|
|
PCT/JP2003/001694 |
Feb 18, 2003 |
|
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12137267 |
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Current U.S.
Class: |
514/210.21 ;
514/217.05; 514/233.8; 514/234.2; 514/248; 540/599; 544/117;
544/119; 544/236; 544/237 |
Current CPC
Class: |
C07D 403/06 20130101;
A61P 9/10 20180101; A61P 43/00 20180101; A61P 11/00 20180101; A61P
19/02 20180101; A61P 35/00 20180101; C07D 403/12 20130101; A61P
25/16 20180101; A61P 3/10 20180101; A61P 31/14 20180101; A61P 9/00
20180101; A61P 37/06 20180101; C07D 487/04 20130101; C07D 401/12
20130101; A61P 37/00 20180101; A61P 29/00 20180101; A61P 13/12
20180101; C07D 401/06 20130101; A61P 7/08 20180101; A61P 31/12
20180101; C07D 409/12 20130101; A61P 31/18 20180101; C07D 417/12
20130101; C07D 237/32 20130101; A61P 25/00 20180101; A61P 25/02
20180101; C07D 237/26 20130101; C07D 405/06 20130101; C07D 405/12
20130101; C07D 471/04 20130101; A61P 1/04 20180101; C07D 513/04
20130101; A61P 21/04 20180101; A61P 25/28 20180101; A61P 27/06
20180101 |
Class at
Publication: |
514/210.21 ;
544/237; 544/119; 514/233.8; 514/248; 514/234.2; 544/117; 544/236;
540/599; 514/217.05 |
International
Class: |
A61K 31/501 20060101
A61K031/501; C07D 237/32 20060101 C07D237/32; C07D 401/12 20060101
C07D401/12; C07D 403/12 20060101 C07D403/12; A61K 31/55 20060101
A61K031/55; A61P 29/00 20060101 A61P029/00; A61P 3/10 20060101
A61P003/10; A61P 27/06 20060101 A61P027/06; A61P 25/00 20060101
A61P025/00; A61P 9/00 20060101 A61P009/00; C07D 471/04 20060101
C07D471/04; C07D 413/14 20060101 C07D413/14; A61K 31/5377 20060101
A61K031/5377 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 19, 2002 |
JP |
P.2002-42259 |
Jul 9, 2002 |
JP |
P.2002-199673 |
Claims
1. A fused pyridazine derivative compound represented by formula
(I) ##STR02077## wherein R.sup.1 is (1) a hydrogen atom, (2) C1-8
alkyl, (3) C1-8 alkoxy, (4) hydroxy, (5) halogen atom, (6) nitro,
(7) NR.sup.2R.sup.3, (8) C2-8 acyl, (9) C1-8 alkoxy substituted by
phenyl or (10) C2-8 acyl substituted by NR.sup.2R.sup.3, R.sup.2
and R.sup.3 are each independently (1) a hydrogen atom or (2) C1-8
alkyl, X and Y are each independently (1) C, (2) CH or (3) N, is
(1) a single bond or (2) a double bond, ##STR02078## (1) partially
or fully saturated C3-10 mono-carbocyclic aryl or (2) partially or
fully saturated 3-10 membered mono-hetero aryl containing 1 to 4
hetero atom(s) selected from oxygen, nitrogen and sulfur atoms, A
is (1) A.sup.1, (2) A.sup.2, (3) A.sup.3, (4) A.sup.4 or (5)
A.sup.5, A.sup.1 is ##STR02079## A.sup.2 is
-E.sup.1-E.sup.2-E.sup.3-E.sup.4 A.sup.3 is ##STR02080## A.sup.4 is
##STR02081## A.sup.5 is ##STR02082## D.sup.1 is (1)
--NR.sup.6C(O)--, (2) --NR.sup.6C(S)--, (3) --NR.sup.6SO.sub.2--,
(4) --CH.sub.2--NR.sup.6--, (5) --CH.sub.2--O--, (6) --OC(O)--, (7)
--CH.sub.2--NR.sup.6C(O)--, (8) --NR.sup.6C(O)NR.sup.7--, (9)
--NR.sup.6C(O)O--, (10) --NR.sup.6C(S)NR.sup.7--, (11) --NR.sup.6--
or (12) --NR.sup.6C(.dbd.NR.sup.7)--, R.sup.6 and R.sup.7 are each
independently (1) a hydrogen atom, (2) C1-8 alkyl, (3) phenyl or
(4) C1-8 alkyl substituted by phenyl, D2 is (1) C1-8 alkylene, (2)
C2-8 alkenylene, (3) Cyc2, (4) --(C1-4 alkylene)-O--(C1-4
alkylene)-, (5) --(C1-4 alkylene)-S--(C1-4 alkylene)-, (6) --(C1-4
alkylene)-NR.sup.8--(C1-4 alkylene)-, (7)-(Cyc2)-(C1-8 alkylene)-,
(8) --(C1-8 alkylene)-(Cyc2)- or (9) --(C1-4 alkylene)-(Cyc2)-(C1-4
alkylene)-, R.sup.8 is (1) a hydrogen atom, (2) C1-8 alkyl, (3)
C1-8 alkoxycarbonyl, (4) phenyl or (5) C1-8 alkyl substituted by
phenyl, D.sup.3 is (1) a hydrogen atom, (2) --NR.sup.9R.sup.10, (3)
Cyc3, (4) --OR.sup.11, (5) COOR.sup.12, (6) CONR.sup.13R.sup.14,
(7) cyano, (8) a halogen atom, (9)
--C(.dbd.CR.sup.15)NR.sup.16R.sup.17 or (10)
--NR.sup.18C(.dbd.NR.sup.19)NR.sup.20R.sup.21, R.sup.9 and R.sup.13
are each independently (1) a hydrogen atom, (2) C1-8 alkyl, (3)
C2-8 alkenyl, (4) C2-8 alkynyl, (5) Cyc3, (6) C1-8 alkoxy, (7) C2-8
alkenyloxy, (8) C2-8 alkynyloxy or (9) C1-8 alkyl substituted by
Cyc3, C1-8 alkoxy, C1-8 alkylthio, cyano, hydroxy or 1 to 3 halogen
atom(s), R.sup.10 and R.sup.14 are each independently (1) a
hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl,
(5) C1-8 alkoxycarbonyl, (6) C2-8 acyl, (7) C3-8 cycloalkyl, (8)
C1-8 alkoxycarbonyl substituted by Cyc4 or 1 to 3 halogen atom(s),
or (9) C1-8 alkyl substituted by C1-8 alkoxy, R.sup.11 and R.sup.12
are each independently (1) a hydrogen atom or (2) C1-8 alkyl,
R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20 and
R.sup.21 are each independently (1) a hydrogen atom, (2) C1-8
alkyl, (3) C1-8 alkoxycarbonyl, (4) phenyl or (5) C1-8 alkyl
substituted by phenyl, R.sup.4 is (1) a hydrogen atom, (2) C1-8
alkyl, (3) C1-8 alkoxy, (4) hydroxy, (5) halogen atom, (6) nitro or
(7) NR.sup.22R.sup.23, R.sup.22 and R.sup.23 are each independently
(1) a hydrogen atom or (2) C1-8 alkyl, E.sup.1 is C1-4 alkylene,
E.sup.2 is (1) --C(O)NR.sup.24--, (2) --NR.sup.24C(O)--, (3)
--NR.sup.24--, (4) --C(O)O-- or (5) --S--, R.sup.24 is (1) a
hydrogen atom, (2) C1-8 alkyl or (3) C1-8 alkyl substituted by
phenyl, E.sup.3 is (1) a bond or (2) C1-8 alkylene, E.sup.4 is (1)
C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) Cyc5, (5)
NR.sup.25R.sup.26, (6) OR.sup.27, (7) SR.sup.27, (8) COOR.sup.27,
(9) C1-8 alkyl substituted by two of OR.sup.25, (10) C1-8 alkyl
substituted by 1 to 3 halogen atom(s), (11) cyano or (12) C2-8
acyl, R.sup.25 is (1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8
alkenyl, (4) C2-8 alkynyl, (5) Cyc5 or (6) C1-8 alkyl substituted
by Cyc5 or OR.sup.28, R.sup.26 is (1) a hydrogen atom, (2) C1-8
alkyl, (3) C1-8 alkoxycarbonyl, (4) phenyl or (5) C1-8 alkyl
substituted by phenyl, R.sup.27 is (1) a hydrogen atom, (2) C1-8
alkyl, (3) Cyc5 or (4) C1-8 alkyl substituted by Cyc5, R.sup.28 is
(1) a hydrogen atom or (2) C1-8 alkyl, G.sup.1 is C1-8 alkylene,
Cyc1 is (1) partially or fully saturated C3-10 mono- or
bi-carbocyclic aryl, or (2) partially or fully saturated 3-10
membered mono- or bi-hetero aryl containing 1 to 4 hetero atom(s)
selected from oxygen, nitrogen and sulfur atoms, G.sup.2 is (1) a
hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) C2-8
acyl, (5) Cyc6, (6) C1-8 alkyl or C2-8 alkenyl substituted by 1 to
2 substituent(s) selected from Cyc6, hydroxy and C1-8 alkoxy, (7)
C1-8 alkoxycarbonyl substituted by Cyc6, (8) --C(O)-Cyc6, (9)
nitro, (10) NR.sup.41R.sup.42, (11) C1-8 alkoxy or (12) C1-8 alkyl
substituted by NR.sup.41R.sup.42, R.sup.41 and R.sup.42 are each
dependently (1) a hydrogen atom or (2) C1-8 alkyl, R.sup.5 is (1) a
hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) hydroxy, (5)
nitro, (6) NR.sup.29R.sup.30, (7) C1-8 alkyl substituted by
NR.sup.29R.sup.30, (8) NHSO.sub.2OH, (9) amidino, (10) cyano, (11)
a halogen atom, (12) Cyc8 or (13) C1-8 alkyl substituted by Cyc8,
R.sup.29 and R.sup.30 are each independently (1) a hydrogen atom or
(2) C1-8 alkyl, Cyc2, Cyc3, Cyc4, Cyc5, Cyc6 and Cyc8 are each
independently (1) partially or fully saturated C3-10 mono- or
bi-carbocyclic aryl, or (2) partially or fully saturated 3-10
membered mono- or bi-hetero aryl containing 1 to 4 hetero atom(s)
selected from oxygen, nitrogen and sulfur atoms, Cyc7 is (1)
partially or fully saturated C3-10 mono- or bi-carbocyclic aryl, or
(2) partially or fully saturated 3-10 membered mono- or bi-hetero
aryl containing 1 to 4 hetero atom(s) selected from oxygen,
nitrogen and sulfur atoms, with proviso that Cyc7 is not benzene,
Cyc2, Cyc3, Cyc4, Cyc5, Cyc6 and Cyc8 are optionally substituted by
1 to 3 substituent(s) selected from (1) C1-8 alkyl, (2) C2-8
alkenyl, (3) C1-8 alkoxy, (4) halogen atom, (5) trihalomethyl, (6)
trihalomethoxy, (7) C1-8 alkoxycarbonyl, (8) oxo, (9) C1-8 alkyl
substituted by C1-8 alkoxy or phenyl, (10) hydroxy and (11)
NR.sup.29R.sup.30; m and n are each independently 1 or 2, wherein
(i) when A is A.sup.1 or A.sup.2, then ##STR02083## is not
##STR02084## (ii) when A is A.sup.4 and ##STR02085## then R.sup.5
is not hydroxy or C1-8 alkoxy, (iii) when A is A.sup.5, then
##STR02086## is not ##STR02087## (iv) following compounds of (1) to
(13) are excepted; (1)
4-(3-chloro-4-methoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one,
(2) 4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,
(3)
4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)-one,
(4) 4-phenyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (5)
4-(4-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (6)
4-(4-fluorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (7)
4-(4-chlorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (8)
4-(4-bromophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (9)
7-hydroxy-4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)--
one, (10)
4-phenyl-8,8a-dihydro[1,3]thiazolo[3,4-d][1,2,4]triazin-1(2H)-on-
e, (11)
4-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (12)
4-t-butoxycarbonylmethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one,
(13) 4-ethoxycarbonylmethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one,
or a pharmaceutically acceptable salt thereof.
2. The compound represented by formula (I) according to claim 1,
wherein ##STR02088## is partially or fully saturated C3-7
mono-carbocyclic aryl and A is A.sup.1, or a pharmaceutically
acceptable salt thereof.
3. The compound represented by formula (I) according to claim 1,
wherein ##STR02089## is partially or fully saturated C3-7
mono-carbocyclic aryl and A is A.sup.2, or a pharmaceutically
acceptable salt thereof.
4. The compound represented by formula (I) according to claim 1,
wherein ##STR02090## is partially or fully saturated C3-7
mono-carbocyclic aryl and A is A.sup.3, or a pharmaceutically
acceptable salt thereof
5. The compound represented by formula (I) according to claim 1,
wherein ##STR02091## is partially or fully saturated C3-7
mono-carbocyclic aryl and A is A.sup.4 or A.sup.5, or a
pharmaceutically acceptable salt thereof.
6. The compound represented by formula (I) according to claim 1,
wherein ##STR02092## is partially or fully saturated 3-7 membered
mono-hetero aryl containing 1 to 2 hetero atom(s) selected from
oxygen, nitrogen and sulfur atoms and A is A.sup.1, or a
pharmaceutically acceptable salt thereof.
7. The compound represented by formula (I) according to claim 1,
wherein ##STR02093## is partially or fully saturated 3-7 membered
mono-hetero aryl containing 1 to 2 hetero atom(s) selected from
oxygen, nitrogen and sulfur atoms and A is A.sup.2, or a
pharmaceutically acceptable salt thereof.
8. The compound represented by formula (I) according to claim 1,
wherein ##STR02094## is partially or fully saturated 3-7 membered
mono-hetero aryl containing 1 to 2 hetero atom(s) selected from
oxygen, nitrogen and sulfur atoms and A is A.sup.3, or a
pharmaceutically acceptable salt thereof.
9. The compound represented by formula (I) according to claim 1,
wherein ##STR02095## is partially or fully saturated 3-7 membered
mono-hetero aryl containing 1 to 2 hetero atom(s) selected from
oxygen, nitrogen and sulfur atoms and A is A.sup.4 or A.sup.5, or a
pharmaceutically acceptable salt thereof.
10. The compound represented by formula (I) according to claim 1,
wherein ##STR02096##
11. A poly(ADP-ribose)polymerase inhibitor comprising, as an active
ingredient, the compound represented by formula (I) according to
claim 1 or a pharmaceutically acceptable salt thereof.
12. A preventive and/or treatment agent for ischemic diseases,
inflammatory diseases, neurodegenerative diseases, glaucoma,
diabetes, diabetic complication, shock, head trauma, spinal cord
injury, renal failure or hyperalgesia comprising, as an active
ingredient, the compound represented by formula (I) according to
claim 1 or a pharmaceutically acceptable salt thereof.
13. An antiretroviral drug comprising, as an active ingredient, the
compound represented by formula (I) according to claim 1 or a
pharmaceutically acceptable salt thereof.
14. A sensitizer of anticancer therapy comprising, as an active
ingredient, the compound represented by formula (I) according to
claim 1 or a pharmaceutically acceptable salt thereof.
15. An immunosuppressant comprising, as an active ingredient, the
compound represented by formula (I) according to claim 1 or a
pharmaceutically acceptable salt thereof.
16. The preventive and/or treatment agent according to claim 12,
wherein the ischemic disease is cerebral infarction.
17. The compound or the pharmaceutically acceptable salt according
to claim 1, which is described in any one of Example 1 to 62.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a Divisional of U.S. application Ser. No. 10/505,012
filed Aug. 18, 2004, which is a 371 of PCT Application No.
PCT/JP03/01694, Feb. 18, 2003, which claims priority from Japanese
Application No. 2002-42259 filed on Feb. 19, 2002 and 2002-199673
filed on Jul. 9, 2002. The above-noted applications are
incorporated herein by reference in their entirety.
TECHNICAL FIELD
[0002] The present invention relates to fused pyridazine derivative
compounds.
[0003] More particularly, the present invention relates to
(1) pyridazine derivative compounds represented by formula (I)
##STR00002##
(wherein all symbols have the same meanings as described below), or
pharmaceutically acceptable salts thereof, (2) a process for
preparing thereof, and (3) an agent comprising the same as an
active ingredient.
BACKGROUND ART
[0004] Poly(ADP-ribose)polymerase (abbreviated as PARP
hereinafter), which is a nuclear enzyme activated by DNA strand
breaks, plays a role in the transfer reaction of ADP-ribose moiety
from nicotinamide adenine dinucleotide (abbreviated as NAD.sup.+
hereinafter) to various proteins such as histones, DNA-polymerases
and DNA-topoisomerases, etc.
[0005] DNA strand breaks caused by Peroxynitrite (ONOO.sup.-) and
oxygen radicals lead to overactivation of PARP (PARP is activated
up to 100 times when Zn finger domain of PARP binds to DNA with
nicks.). It is thought that overactivation of PARP causes depletion
of NAD.sup.+, which is essential for electron transport system, and
consequently depletion of ATP, leading to energy failure,
ultimately resulting in cell death. (The suicide hypothesis of PARP
activation: Free Radic. Biol Med., 21, 855 (1996); TIPS., 19, 287
(1998)). Therefore, it is considered that PARP inhibitor is useful
as inhibitor of cell death.
[0006] Since caspase-3, which is one of
interleukin-1.beta.-converting enzyme family, specifically cleaves
PARP as the substrate (Cell., 81, 801 (1995)), it is suggested PARP
is associated with apoptosis.
[0007] It is reported that 3-aminobenzamide and nicotinamide
generally known as inhibitors of PARP are useful for inhibition of
cell death and improvement of diseases on various models of
ischemic diseases (cerebral, myocardial, intestinal, skeletal
muscular or retinal ischemia etc.), inflammatory diseases
(arthritis, inflammatory bowel disease or multiple sclerosis etc.),
diabetes, shock, extrapyramidal disease (TIPS., 19, 287 (1998); Eur
J. Pharmacol., 350, 1 (1998)) and hyperalgesia (Pain, 72, 355
(1997)) in vitro, in vivo and in PARP knockout mouse. And it is
reported that PARP inhibitor is useful as an antiretroviral drug
such as an anti HIV drug (Biochem. Biophys. Res. Commum., 180, 504
(1991)), a sensitizer of anticancer therapy (Radiat. Res., 126, 367
(1991); Br. J. Cancer., 72, 849 (1995)) or an immunosuppressant
(Int. J. Immunopharmac., 17, 265 (1995)).
[0008] PARP inhibitor is useful for prevention and/or treatment of
various diseases, for example, ischemic diseases (cerebral
infarction, myocardial infarction, reperfusion injury or
postoperative injury etc.), inflammatory diseases (inflammatory
bowel disease, multiple sclerosis, arthritis or lung injury etc.),
neurodegenerative disorders (extrapyramidal disease, Parkinson's
disease, Alzheimer's disease, muscular dystrophy or lumbar spinal
canal stenosis etc.), glaucoma, diabetes, diabetic complication,
shock, head trauma, spinal cord injury, renal failure, hyperalgesia
or blood flow obstruction etc. And it is useful as an
antiretroviral drug such as an anti HIV drug, a sensitizer of
anticancer therapy or an immunosuppressant.
[0009] As PARP inhibitor, for example, in the specification of
WO00/44726, it is described that 2H-phthalazin-1-one derivatives
represented by formula (A)
##STR00003##
(wherein R.sup.1A is (i) C1-4 alkyl substituted by hydroxy or
amino, or
(ii) -A.sup.1A-A.sup.2A-A.sup.3A,
[0010] in which A.sup.1A is --NR.sup.3AC(O)-- etc. wherein R.sup.3A
is hydrogen or C1-4 alkyl etc., A.sup.2A is C1-8 alkylene etc.,
A.sup.3A is (i) hydrogen, (ii) --NR.sup.17AR.sup.18A or (iii)
Cyc.sup.2A etc. wherein R.sup.17A is (i) hydrogen, (ii) C1-8 alkyl
etc., and R.sup.18A is (i) hydrogen or (ii) C1-8 alkyl etc.,
Cyc.sup.2A is 3-10 membered mono- or bi-heterocyclic ring
containing 1-4 of nitrogen atoms, 1-2 of oxygen atoms and/or one
sulfur atom, R.sup.2A is hydrogen or halogen etc. Necessary parts
were extracted from the description of groups.) have PARP
inhibitory activity.
[0011] In the specification of DE3302021, it is described that
compounds represented by formula (B)
##STR00004##
(wherein R.sup.1B is hydrogen or C1-3 alkyl, R.sup.2B is hydrogen,
R.sup.1B and R.sup.2B, taken together, are C1-4 alkylene, R.sup.3B
is hydrogen or methyl, nB is 0-3, R.sup.4B is 1-pyrrolyl. Necessary
parts were extracted from the description of groups.) have
inhibitory activity of platelet aggregation.
[0012] In the specification of WO98/31674, it is described that
compounds represented by formula (C)
##STR00005##
(wherein R.sup.1C is C1-4 alkoxy etc., R.sup.2C is C1-8 alkoxy
etc., R.sup.3C and R.sup.4C is hydrogen or R.sup.3C and R.sup.4C,
taken together, are bond, R.sup.5C is hydrogen etc. Necessary parts
were extracted from the description of groups.) have
phosphodiesterase inhibitory activity.
[0013] In Journal of Medicinal Chemistry., 44(16), 2511-2522 and
2523-2535 (2001), it is described that
4-(3-chloro-4-methoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
(CAS Registry No. 244077-36-9) and
4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS
Registry No. 358368-98-6) have phosphodiesterase inhibitory
activity.
[0014] In Tetrahedron., 39(20), 3419-27 (1983),
4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)-one
(CAS Registry No. 89311-30-8) is described as synthetic
intermediate.
[0015] In Synthesis., 240-242 (1995),
4-phenyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS Registry No.
154810-22-7),
4-(4-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS
Registry No. 154810-23-8),
4-(4-fluorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS
Registry No. 154810-24-9),
4-(4-chlorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS
Registry No. 154810-25-0), and
4-(4-bromophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS
Registry No. 154810-26-1) are described as synthetic
intermediate.
[0016] In Bioorganic and Medicinal Chemistry., 6, 349-454 (1998),
7-hydroxy-4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)--
one (CAS Registry No. 206126-90-1) and
4-phenyl-8,8a-dihydro[1,3]thiazolo[3,4-d][1,2,4]triazin-1(2H)-one
(CAS Registry No. 206126-96-7) are described as synthetic
intermediate.
[0017] In Journal of Medicinal Chemistry., 43(12), 2310-2323
(2000),
4-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS
Registry No. 212142-89-7) is described as synthetic
intermediate.
[0018] In the specification of FR2647676,
4-t-butoxycarbonylmethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one
(CAS Registry No. 134972-12-6) and
4-ethoxycarbonylmethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS
Registry No. 134973-24-3) are described as synthetic
intermediate.
DISCLOSURE OF THE INVENTION
[0019] In order to find a compound having
poly(ADP-ribose)polymerase activity, the present inventors have
conducted intensive studies and found, as a result, that the
objects can be accomplished by the pyridazine derivative
represented by formula (I), and thus the present invention has been
accomplished.
[0020] The present invention relates to
(1) a fused pyridazine derivative compound represented by formula
(I)
##STR00006##
[0021] wherein R.sup.1 is
(1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) hydroxy,
(5) halogen atom, (6) nitro, (7) NR.sup.2R.sup.3, (8) C2-8 acyl,
(9) C1-8 alkoxy substituted by phenyl or (10) C2-8 acyl substituted
by NR.sup.2R.sup.3,
[0022] R.sup.2 and R.sup.3 are each independently
(1) a hydrogen atom or (2) C1-8 alkyl,
[0023] X and Y are each independently
(1) C, (2) CH or (3) N,
[0024] is
(1) a single bond or (2) a double bond,
##STR00007##
(1) partially or fully saturated C3-10 mono-carbocyclic aryl or (2)
partially or fully saturated 3-10 membered mono-hetero aryl
containing 1 to 4 hetero atom(s) selected from oxygen, nitrogen and
sulfur atoms,
[0025] A is (1) A.sup.1, (2) A.sup.2, (3) A.sup.3, (4) A.sup.4 or
(5) A.sup.5,
[0026] A.sup.1 is
##STR00008##
[0027] A.sup.2 is -E.sup.1-E.sup.2-E.sup.3-E.sup.4,
[0028] A.sup.3 is
##STR00009##
[0029] A.sup.4 is
##STR00010##
[0030] A.sup.5 is
##STR00011##
[0031] D.sup.1 is
(1) --NR.sup.6C(O)--, (2) --NR.sup.6C(S)--, (3)
--NR.sup.6SO.sub.2--, (4) --CH.sub.2--NR.sup.6--, (5)
--CH.sub.2--O--, (6) --OC(O)--, (7) --CH.sub.2--NR.sup.6C(O)--, (8)
--NR.sup.6C(O)NR.sup.7--, (9) --NR.sup.6C(O)O--, (10)
--NR.sup.6C(S)NR.sup.7--, (11) --NR.sup.6-- or (12)
--NR.sup.6C(.dbd.NR.sup.7)--,
[0032] R.sup.6 and R.sup.7 are each independently
(1) a hydrogen atom, (2) C1-8 alkyl, (3) phenyl or (4) C1-8 alkyl
substituted by phenyl,
[0033] D2 is
(1) C1-8 alkylene, (2) C2-8 alkenylene, (3) Cyc2, (4) --(C1-4
alkylene)-O--(C1-4 alkylene)-, (5) --(C1-4 alkylene)-S--(C1-4
alkylene)-, (6) --(C1-4 alkylene)-NR.sup.8--(C1-4 alkylene)-,
(7)-(Cyc2)-(C1-8 alkylene)-, (8) --(C1-8 alkylene)-(Cyc2)- or (9)
--(C1-4 alkylene)-(Cyc2)-(C1-4 alkylene)-,
[0034] R.sup.8 is
(1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4)
phenyl or (5) C1-8 alkyl substituted by phenyl,
[0035] D.sup.3 is
(1) a hydrogen atom, (2) --NR.sup.9R.sup.10, (3) Cyc3, (4)
--OR.sup.11, (5) COOR, (6) CONR.sup.13R.sup.14, (7) cyano, (8) a
halogen atom, (9) --C(.dbd.CR.sup.15)NR.sup.16R.sup.17 or (10)
--NR.sup.18C(.dbd.NR.sup.19)NR.sup.20R.sup.21,
[0036] R.sup.9 and R.sup.13 are each independently
(1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8
alkynyl, (5) Cyc3, (6) C1-8 alkoxy, (7) C2-8 alkenyloxy, (8) C2-8
alkynyloxy or (9) C1-8 alkyl substituted by Cyc3, C1-8 alkoxy, C1-8
alkylthio, cyano, hydroxy or 1 to 3 halogen atom(s),
[0037] R.sup.10 and R.sup.14 are each independently
(1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8
alkynyl, (5) C1-8 alkoxycarbonyl, (6) C2-8 acyl, (7) C3-8
cycloalkyl, (8) C1-8 alkoxycarbonyl substituted by Cyc4 or 1 to 3
halogen atom(s), or (9) C1-8 alkyl substituted by C1-8 alkoxy,
[0038] R.sup.11 and R.sup.12 are each independently
(1) a hydrogen atom or (2) C1-8 alkyl,
[0039] R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20
and R.sup.21 are each independently
(1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4)
phenyl or (5) C1-8 alkyl substituted by phenyl,
[0040] R.sup.4 is
(1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) hydroxy,
(5) halogen atom, (6) nitro or (7) NR.sup.22R.sup.23,
[0041] R.sup.22 and R.sup.23 are each independently
(1) a hydrogen atom or (2) C1-8 alkyl,
[0042] E.sup.1 is C1-4 alkylene,
[0043] E.sup.2 is
(1) --C(O)NR.sup.24--, (2) --NR.sup.24C(O)--, (3) --NR.sup.24--,
(4) --C(O)O-- or (5) --S--,
[0044] R.sup.24 is
(1) a hydrogen atom, (2) C1-8 alkyl or (3) C1-8 alkyl substituted
by phenyl,
[0045] E.sup.3 is
(1) a bond or (2) C1-8 alkylene,
[0046] E.sup.4 is
(1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) Cyc5, (5)
NR.sup.25R.sup.26, (6) OR.sup.27, (7) SR.sup.27, (8) COOR.sup.27,
(9) C1-8 alkyl substituted by two of OR.sup.25, (10) C1-8 alkyl
substituted by 1 to 3 halogen atom(s), (11) cyano or (12) C2-8
acyl,
[0047] R.sup.25 is
(1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8
alkynyl, (5) Cyc5 or (6) C1-8 alkyl substituted by Cyc5 or
OR.sup.28,
[0048] R.sup.26 is
(1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4)
phenyl or (5) C1-8 alkyl substituted by phenyl,
[0049] R.sup.27 is
(1) a hydrogen atom, (2) C1-8 alkyl, (3) Cyc5 or (4) C1-8 alkyl
substituted by Cyc5,
[0050] R.sup.28 is
(1) a hydrogen atom or (2) C1-8 alkyl,
[0051] G.sup.1 is C1-8 alkylene,
[0052] Cyc1 is
(1) partially or fully saturated C3-10 mono- or bi-carbocyclic
aryl, or (2) partially or fully saturated 3-10 membered mono- or
bi-hetero aryl containing 1 to 4 hetero atom(s) selected from
oxygen, nitrogen and sulfur atoms,
[0053] G.sup.2 is
(1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4)
C2-8 acyl, (5) Cyc6, (6) C1-8 alkyl or C2-8 alkenyl substituted by
1 to 2 substituent(s) selected from Cyc6, hydroxy and C1-8 alkoxy,
(7) C1-8 alkoxycarbonyl substituted by Cyc6, (8) --C(O)-Cyc6, (9)
nitro, (10) NR.sup.41R.sup.42, (11) C1-8 alkoxy or (12) C1-8 alkyl
substituted by NR.sup.41R.sup.42,
[0054] R.sup.41 and R.sup.42 are each dependently
(1) a hydrogen atom or (2) C1-8 alkyl, R.sup.5 is (1) a hydrogen
atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) hydroxy, (5) nitro, (6)
NR.sup.29R.sup.30, (7) C1-8 alkyl substituted by NR.sup.29R.sup.30,
(8) NHSO.sub.2OH, (9) amidino, (10) cyano, (11) a halogen atom,
(12) Cyc8 or (13) C1-8 alkyl substituted by Cyc8,
[0055] R.sup.29 and R.sup.30 are each independently
(1) a hydrogen atom or (2) C1-8 alkyl,
[0056] Cyc2, Cyc3, Cyc4, Cyc5, Cyc6 and Cyc8 are each
independently
(1) partially or fully saturated C3-10 mono- or bi-carbocyclic
aryl, or (2) partially or fully saturated 3-10 membered mono- or
bi-hetero aryl containing 1 to 4 hetero atom(s) selected from
oxygen, nitrogen and sulfur atoms,
[0057] Cyc7 is
(1) partially or fully saturated C3-10 mono- or bi-carbocyclic
aryl, or (2) partially or fully saturated 3-10 membered mono- or
bi-hetero aryl containing 1 to 4 hetero atom(s) selected from
oxygen, nitrogen and sulfur atoms, with proviso that Cyc7 is not
benzene,
[0058] Cyc2, Cyc3, Cyc4, Cyc5, Cyc6 and Cyc8 are optionally
substituted by 1 to 3 substituent(s) selected from (1) C1-8 alkyl,
(2) C2-8 alkenyl, (3) C1-8 alkoxy, (4) halogen atom, (5)
trihalomethyl, (6) trihalomethoxy, (7) C1-8 alkoxycarbonyl, (8)
oxo, (9) C1-8 alkyl substituted by C1-8 alkoxy or phenyl, (10)
hydroxy and (11) NR.sup.29R.sup.30;
m and n are each independently 1 or 2,
[0059] wherein
(i) when A is A.sup.1 or A.sup.2, then
##STR00012##
is not
##STR00013##
(ii) when A is A.sup.4 and
##STR00014##
then
[0060] R.sup.5 is not hydroxy or C1-8 alkoxy,
(iii) when A is A.sup.5, then
##STR00015##
is not
##STR00016##
[0061] and
[0062] (iv) following compounds of (1) to (13) are excepted; [0063]
(1)
4-(3-chloro-4-methoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one,
[0064] (2)
4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,
[0065] (3)
4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)-one,
[0066] (4) 4-phenyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one, [0067]
(5) 4-(4-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,
[0068] (6)
4-(4-fluorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, [0069]
(7) 4-(4-chlorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,
[0070] (8)
4-(4-bromophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, [0071]
(9)
7-hydroxy-4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)--
one, [0072] (10)
4-phenyl-8,8a-dihydro[1,3]thiazolo[3,4-d][1,2,4]triazin-1(2H)-one,
[0073] (11)
4-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,
[0074] (12)
4-t-butoxycarbonylmethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one,
[0075] (13)
4-ethoxycarbonylmethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one,
or
[0076] a pharmaceutically acceptable salt thereof,
(2) a process for preparing thereof, and (3) an agent comprising
the same as an active ingredient.
[0077] In the specification, C1-8 alkyl means methyl, ethyl,
propyl, butyl, pentyl, hexyl, heptyl, octyl or isomeric groups
thereof.
[0078] In the specification, C2-8 alkenyl means ethenyl, propenyl,
butenyl, pentenyl, hexenyl, heptenyl, octenyl or isomeric groups
thereof.
[0079] In the specification, C2-8 alkynyl means ethynyl, propynyl,
butynyl, pentynyl, hexynyl, heptynyl, octynyl or isomeric groups
thereof.
[0080] In the specification, C1-8 alkoxy means methoxy, ethoxy,
propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy or
isomeric groups thereof.
[0081] In the specification, C2-8 alkenyloxy means ethenyloxy,
propenyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy,
octenyloxy or isomeric groups thereof.
[0082] In the specification, C2-8 alkynyloxy means ethynyloxy,
propynyloxy, butynyloxy, pentynyloxy, hexynyloxy, heptynyloxy,
octynyloxy or isomeric groups thereof.
[0083] In the specification, C1-8 alkylthio means methylthio,
ethylthio, propylthio, butylthio, pentylthio, hexylthio,
heptylthio, octylthio or isomeric groups thereof.
[0084] In the specification, C1-4 alkylene means methylene,
ethylene, trimethylene, tetramethylene or isomeric groups
thereof.
[0085] In the specification, C1-8 alkylene means methylene,
ethylene, trimethylene, tetramethylene, pentamethylene,
hexamethylene, heptamethylene, octamethylene or isomeric groups
thereof.
[0086] In the specification, C2-8 alkenylene means ethenylene,
propenylene, butenylene, pentenylene, hexenylene, heptenylene,
octenylene or isomeric groups thereof.
[0087] In the specification, C1-8 alkoxycarbonyl means
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,
pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl,
octyloxycarbonyl or isomeric groups thereof.
[0088] In the specification, trihalomethyl is methyl substituted by
three halogen atoms.
[0089] In the specification, trihalomethoxy is methoxyl substituted
by three halogen atoms.
[0090] In the specification, C2-8 acyl means ethanoyl (acethyl),
propanoyl (propionyl), butanoyl (butyryl), pentanoyl (valeryl),
hexanoyl, heptanoyl, octanoyl or isomeric groups thereof.
[0091] In the specification, C3-8 cycloalkyl means cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
[0092] In the specification, halogen means chlorine, bromine,
fluorine or iodine.
[0093] In the specification, partially or fully saturated C3-10
mono-carbocyclic aryl represented by
##STR00017##
is cyclopropane, cyclobutane, cyclopentane, cyclohexane,
cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene,
cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene,
cyclononene, cyclodecene, cyclohexadiene, cycloheptadiene,
cyclooctadiene etc.
[0094] In the specification, partially or fully saturated 3-10
membered mono-hetero aryl containing 1 to 4 hetero atom(s) selected
from oxygen, nitrogen and sulfur atoms represented by
##STR00018##
means aziridine, azetidine, pyrroline, pyrrolidine, imidazoline,
imidazolidine, triazoline, triazolidine, tetrazoline,
tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine,
tetrahydropyridine, piperidine, dihydropyrazine,
tetrahydropyrazine, piperazine, dihydropyrimidine,
tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine,
tetrahydropyridazine, perhydropyridazine, dihydroazepine,
tetrahydroazepine, perhydroazepine, dihydrodiazepine,
tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane,
dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran,
dihydrooxepine, tetrahydrooxepine, perhydrooxepine, thiirane,
thietane, dihydrothiophene, tetrahydrothiophene, dihydrothiaine
(dihydrothiopyran), tetrahydrothiaine (tetrahydrothiopyran),
dihydrothiepine, tetrahydrothiepine, perhydrothiepine,
dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole,
tetrahydroisoxazole (isoxazolidine), dihydrothiazole,
tetrahydrothiazole (thiazolidine), dihydroisothiazole,
tetrahydroisothiazole (isothiazolidine), dihydrofurazan,
tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole
(oxadiazolidine), dihydrooxazine, tetrahydrooxazine,
dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine,
tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine,
tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole,
tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine,
tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine,
dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine,
dihydrothiadiazepine, tetrahydrothiadiazepine,
perhydrothiadiazepine, morpholine, thiomorpholine, oxathiane,
dioxolane, dioxane, dithiolane, dithiane etc.
[0095] In the specification, among partially or fully saturated
3-10 membered mono- or bi-hetero aryl containing 1 to 4 hetero
atoms selected from oxygen, nitrogen or sulfur atom represented by
Cyc1, Cyc2, Cyc3, Cyc4, Cyc5, Cyc6, Cyc7 and Cyc8, 3-10 membered
mono- or bi-hetero aryl containing 1 to 4 hetero atoms selected
from oxygen, nitrogen or sulfur atom means, for example, pyrrole,
imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,
pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine,
thiophene, thiaine, thiepine, oxazole, isoxazole, thiazole,
isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine,
oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,
thiadiazepine, indole, isoindole, indolizine, benzofuran,
isobenzofuran, benzothiophene, isobenzothiophene,
dithianaphthalene, indazole, quinoline, isoquinoline, quinolizine,
purine, phthalazine, pteridine, naphthyridine, quinoxaline,
quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole,
chromene, benzofurazan, benzothiadiazole, benzotriazole etc.
[0096] Also, partially or fully saturated 3-10 membered mono- or
bi-hetero aryl containing 1-4 hetero atoms selected from oxygen,
nitrogen or sulfur atom, means aziridine, azetidine, pyrroline,
pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine,
tetrazoline, tetrazolidine, pyrazoline, pyrazolidine,
dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine,
tetrahydropyrazine, piperazine, dihydropyrimidine,
tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine,
tetrahydropyridazine, perhydropyridazine, dihydroazepine,
tetrahydroazepine, perhydroazepine, dihydrodiazepine,
tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane,
dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran,
dihydrooxepine, tetrahydrooxepine, perhydrooxepine, thiirane,
thietane, dihydrothiophene, tetrahydrothiophene, dihydrothiaine
(dihydrothiopyran), tetrahydrothiaine (tetrahydrothiopyran),
dihydrothiepine, tetrahydrothiepine, perhydrothiepine,
dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole,
tetrahydroisoxazole (isoxazolidine), dihydrothiazole,
tetrahydrothiazole (thiazolidine), dihydroisothiazole,
tetrahydroisothiazole (isothiazolidine), dihydrofurazan,
tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole
(oxadiazolidine), dihydrooxazine, tetrahydrooxazine,
dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine,
tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine,
tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole,
tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine,
tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine,
dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine,
dihydrothiadiazepine, tetrahydrothiadiazepine,
perhydrothiadiazepine, morpholine, thiomorpholine, oxathiane,
indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran,
dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene,
perhydrobenzothiophene, dihydroisobenzothiophene,
perhydroisobenzothiophene, dihydroindazole, perhydroindazole,
dihydro quinoline, tetrahydroquinoline, perhydroquinoline,
dihydroisoquinoline, tetrahydro isoquinoline, perhydroisoquinoline,
dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,
dihydronaphthyridine, tetrahydronaphthyridine,
perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline,
perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline,
perhydroquinazoline, dihydrocinnoline, tetrahydro cinnoline,
perhydrocinnoline, benzoxathiane, dihydrobenzoxazine,
dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole,
perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole,
dihydrobenzimidazole, perhydrobenzimidazole, dioxolane, dioxane,
dithiolane, dithiane, dioxaindan, benzodioxane, chroman,
benzodithiolane, benzodithiane etc.
[0097] The above hetero ring includes N-oxide which is the compound
where nitrogen is oxidized.
[0098] In the specification, partially or fully saturated C3-10
mono- or bi-carbocyclic aryl represented by Cyc1, Cyc2, Cyc3, Cyc4,
Cyc5, Cyc6, Cyc7 and Cyc8 is cyclopropane, cyclobutane,
cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane,
cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene,
cycloheptene, cyclooctene, cyclononene, cyclodecene,
cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene,
benzene, pentalene, azulene, perhydroazulene, perhydropentalene,
indene, perhydroindene, indan, naphthalene, teterahydronaphthalene
or perhydronaphthalene etc.
[0099] Unless otherwise specified, all isomers are included in the
present invention. For example, alkyl, alkenyl, alkynyl, alkylene
and alkoxy group includes straight or branched ones. In addition,
isomers on double bond, ring, fused ring (E-, Z-, cis-,
trans-isomer), isomers generated from asymmetric carbon atom(s)
(R--, S--, .alpha.-, .beta.-isomer, enantiomer, diastereomer),
optically active isomers (D-, L-, d-, l-isomer), polar compounds
generated by chromatographic separation (more polar compound, less
polar compound), equilibrium compounds, mixtures thereof at
voluntary ratios and racemic mixtures are also included in the
present invention.
[0100] According to the present invention, unless otherwise
indicated and as is apparent for those skilled in the art, symbol
indicates that it is bound to the opposite side of the sheet
(namely .alpha.-configuration), symbol indicates that it is bound
to the front side of the sheet (namely .beta.-configuration),
symbol indicates that it is .alpha.-, .beta.- or a mixture thereof,
and symbol indicates that it is a mixture of .alpha.-configuration
and .beta.-configuration.
[0101] The compound of the present invention can be converted into
a pharmaceutically acceptable salt by known methods.
[0102] The pharmaceutically acceptable salt is preferably
water-soluble.
[0103] The pharmaceutically acceptable salt means, for example,
salts of alkali metals (potassium, sodium, lithium, etc.), salts of
alkaline earth metals (calcium, magnesium, etc.), ammonium salts
(tetramethylammonium, tetrabutylammonium, etc.), salts of organic
amines (triethylamine, methylamine, dimethylamine,
cyclopentylamine, benzylamine, phenethylamine, piperidine,
monoethanolamine, diethanolamine, tris(hydroxymethyl)methylamine,
lysine, arginine, N-methyl-D-glucamine, etc.), acid-addition salts
(inorganic acid salts (hydrochloride, hydrobromate, hydroiodate,
sulfate, phosphate, nitrate, etc.), organic acid salts (acetate,
trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate,
benzoate, citrate, methanesulfonate, ethanesulfonate,
benzenesulfonate, toluenesulfonate, isethionate, glucuronate,
gluconate, etc.), etc.
[0104] Furthermore, solvates or solvates of the above alkai (earth)
metals, ammonium, organic amines and acid-addition salts of the
compound of the present invention are included in the
pharmaceutically acceptable salt of the present invention.
[0105] The solvate is preferably nontoxic and water-soluble.
Appropriate solvate means, for example, solvates such as water, an
alcohol solvent (ethanol etc.), etc.
[0106] In the specification,
##STR00019##
is preferably partially or fully saturated C3-7 mono-carbocyclic
aryl, or partially or fully saturated 3-7 membered mono-hetero aryl
containing 1 to 2 hetero atom(s) selected from oxygen, nitrogen and
sulfur atom. Moreover, partially or fully saturated C3-7
mono-carbocyclic aryl, or partially or fully saturated 3-7 membered
mono-hetero aryl is preferably following compounds;
##STR00020##
[0107] Partially or fully saturated 3-7 membered mono-hetero aryl
containing 1 to 2 hetero atom(s) selected from oxygen, nitrogen and
sulfur atoms is preferably following compounds;
##STR00021##
[0108] In the specification, A is preferably A.sup.1, A.sup.2 or
A.sup.3.
[0109] In the specification, D.sup.1 is preferably
--NR.sup.6C(O)--, --NR.sup.6C(S)--, --NR.sup.6SO.sub.2-- or
--CH.sub.2--NR.sup.6--, and more preferably --NR.sup.6C(O)--.
[0110] In the specification, D.sup.2 is preferably C1-8 alkylene,
C2-8 alkenylene, --(C1-4 alkylene)-O--(C1-4 alkylene)-, --(C1-4
alkylene)-S--(C1-4 alkylene)-, --(C1-4 alkylene)-NR.sup.8--(C1-4
alkylene)- or --(C1-8 alkylene)-(Cyc2)-, and more preferably C1-8
alkylene.
[0111] In the specification, D.sup.3 is preferably
--NR.sup.9R.sup.10 or Cyc3.
[0112] In the specification, E.sup.1 is preferably C1-4
alkylene.
[0113] In the specification, E.sup.2 is preferably
--C(O)NR.sup.24--, --NR.sup.24C(O)--, --NR.sup.24-- or --S--
[0114] In the specification, E.sup.3 is preferably bond or C1-8
alkylene.
[0115] In the specification, E.sup.4 is preferably Cyc5 or
NR.sup.25R.sup.26.
[0116] In the specification, Cyc1 is preferably partially or fully
saturated 3-10 membered mono-hetero aryl containing 1 to 2 hetero
atom(s) selected from oxygen, nitrogen and sulfur atom.
[0117] In the specification, when A is A.sup.3 or A.sup.4, at least
one of X and Y is preferably N.
[0118] In the specification, when A is A.sup.3 or A.sup.4,
##STR00022##
is preferably
##STR00023##
[0119] Among the compounds of the present invention represented by
formula (I), preferred compounds are compounds represented by
formula (I-A-1)
##STR00024##
(wherein all symbols have the same meanings as described above.),
compounds represented by formula (I-A-2)
##STR00025##
(wherein all symbols have the same meanings as described above.),
compounds represented by formula (I-B-1)
##STR00026##
(wherein all symbols have the same meanings as described above.),
compounds represented by formula (I-B-2)
##STR00027##
(wherein all symbols have the same meanings as described above.),
compounds represented by formula (I-C-1)
##STR00028##
(wherein all symbols have the same meanings as described above.),
and compounds represented by formula (I-C-2)
##STR00029##
(wherein all symbols have the same meanings as described
above.).
[0120] Concrete compounds of the present invention include
compounds shown in Tables 1 to 90, compounds described in Examples,
and pharmaceutically acceptable salts thereof.
[0121] In each Table, Me represents methyl group, Et represents
ethyl group, Pr represents propyl group, i-Pr represents isopropyl
group, Bu represents butyl group, c-Pr represents cyclopropyl
group, c-Bu represents cyclobutyl group, c-Pen represents
cyclopentyl group, c-Hex represents cyclohexyl group, Ph represents
phenyl group, Bn represents benzyl group, and other symbols have
the same meanings as described above.
TABLE-US-00001 TABLE 1 (I-A-1-1) ##STR00030## No -D.sup.2-D.sup.3 1
Me 2 Pr 3 Bu 4 --CH.sub.2--Cl 5 --(CH.sub.2).sub.3--OH 6
--(CH.sub.2).sub.4--OH 7 --(CH.sub.2).sub.3--CO.sub.2H 8
--(CH.sub.2).sub.3--CO.sub.2Me 9 ##STR00031## 10 ##STR00032## 11
--(CH.sub.2).sub.3--NH.sub.2 12 --(CH.sub.2).sub.4--NH.sub.2 13
--(CH.sub.2).sub.5--NH.sub.2 14 --(CH.sub.2).sub.3--NHMe 15
--(CH.sub.2).sub.4--NHMe 16 --CH.sub.2--NMe.sub.2 17
--(CH.sub.2).sub.3--NMe.sub.2 18 --(CH.sub.2).sub.4--NMe.sub.2 19
--(CH.sub.2).sub.4--NH-c-Pr 20 --CH.sub.2--NH-c-Bu 21 ##STR00033##
22 ##STR00034## 23 ##STR00035## 24 ##STR00036## 25 ##STR00037## 26
##STR00038## 27 ##STR00039## 28 ##STR00040## 29 ##STR00041## 30
##STR00042##
TABLE-US-00002 TABLE 2 (I-A-1-1) ##STR00043## No -D.sup.2-D.sup.3
31 ##STR00044## 32 ##STR00045## 33 ##STR00046## 34 ##STR00047## 35
##STR00048## 36 ##STR00049## 37 ##STR00050## 38 ##STR00051## 39
##STR00052## 40 ##STR00053## 41 ##STR00054## 42 ##STR00055## 43
##STR00056## 44 ##STR00057## 45 ##STR00058## 46 ##STR00059## 47
##STR00060## 48 ##STR00061## 49 ##STR00062## 50 ##STR00063## 51
##STR00064## 52 ##STR00065## 53 ##STR00066## 54 ##STR00067## 55
##STR00068## 56 ##STR00069## 57 ##STR00070## 58 ##STR00071## 59
##STR00072## 60 ##STR00073##
TABLE-US-00003 TABLE 3 (I-A-1-1) ##STR00074## No -D.sup.2-D.sup.3
61 ##STR00075## 62 ##STR00076## 63 ##STR00077## 64 ##STR00078## 65
##STR00079## 66 ##STR00080## 67 ##STR00081## 68 ##STR00082## 69
##STR00083## 70 ##STR00084## 71 ##STR00085## 72 ##STR00086## 73
##STR00087## 74 ##STR00088## 75 ##STR00089## 76 ##STR00090## 77
##STR00091## 78 ##STR00092## 79 ##STR00093## 80 ##STR00094## 81
##STR00095## 82 ##STR00096## 83 ##STR00097## 84 ##STR00098## 85
##STR00099## 86 ##STR00100## 87 ##STR00101## 88 ##STR00102##
TABLE-US-00004 TABLE 4 (I-A-1-2) ##STR00103## No -D.sup.2-D.sup.3 1
Me 2 Pr 3 Bu 4 --CH.sub.2--Cl 5 --(CH.sub.2).sub.3--OH 6
--(CH.sub.2).sub.4--OH 7 --(CH.sub.2).sub.3--CO.sub.2H 8
--(CH.sub.2).sub.3--CO.sub.2Me 9 ##STR00104## 10 ##STR00105## 11
--(CH.sub.2).sub.3--NH.sub.2 12 --(CH.sub.2).sub.4--NH.sub.2 13
--(CH.sub.2).sub.5--NH.sub.2 14 --(CH.sub.2).sub.3--NHMe 15
--(CH.sub.2).sub.4--NHMe 16 --CH.sub.2--NMe.sub.2 17
--(CH.sub.2).sub.3--NMe.sub.2 18 --(CH.sub.2).sub.4--NMe.sub.2 19
--(CH.sub.2).sub.4--NH-c-Pr 20 --CH.sub.2--NH-c-Bu 21 ##STR00106##
22 ##STR00107## 23 ##STR00108## 24 ##STR00109## 25 ##STR00110## 26
##STR00111## 27 ##STR00112## 28 ##STR00113## 29 ##STR00114## 30
##STR00115##
TABLE-US-00005 TABLE 5 (I-A-1-2) ##STR00116## No -D.sup.2-D.sup.3
31 ##STR00117## 32 ##STR00118## 33 ##STR00119## 34 ##STR00120## 35
##STR00121## 36 ##STR00122## 37 ##STR00123## 38 ##STR00124## 39
##STR00125## 40 ##STR00126## 41 ##STR00127## 42 ##STR00128## 43
##STR00129## 44 ##STR00130## 45 ##STR00131## 46 ##STR00132## 47
##STR00133## 48 ##STR00134## 49 ##STR00135## 50 ##STR00136## 51
##STR00137## 52 ##STR00138## 53 ##STR00139## 54 ##STR00140## 55
##STR00141## 56 ##STR00142## 57 ##STR00143## 58 ##STR00144## 59
##STR00145## 60 ##STR00146##
TABLE-US-00006 TABLE 6 (I-A-1-2) ##STR00147## No -D.sup.2-D.sup.3
61 ##STR00148## 62 ##STR00149## 63 ##STR00150## 64 ##STR00151## 65
##STR00152## 66 ##STR00153## 67 ##STR00154## 68 ##STR00155## 69
##STR00156## 70 ##STR00157## 71 ##STR00158## 72 ##STR00159## 73
##STR00160## 74 ##STR00161## 75 ##STR00162## 76 ##STR00163## 77
##STR00164## 78 ##STR00165## 79 ##STR00166## 80 ##STR00167## 81
##STR00168## 82 ##STR00169## 83 ##STR00170## 84 ##STR00171## 85
##STR00172## 86 ##STR00173## 87 ##STR00174## 88 ##STR00175##
TABLE-US-00007 TABLE 7 (I-A-1-3) ##STR00176## No -D.sup.2-D.sup.3 1
Me 2 Pr 3 Bu 4 --CH.sub.2--Cl 5 --(CH.sub.2).sub.3--OH 6
--(CH.sub.2).sub.4--OH 7 --(CH.sub.2).sub.3--CO.sub.2H 8
--(CH.sub.2).sub.3--CO.sub.2Me 9 ##STR00177## 10 ##STR00178## 11
--(CH.sub.2).sub.3--NH.sub.2 12 --(CH.sub.2).sub.4--NH.sub.2 13
--(CH.sub.2).sub.5--NH.sub.2 14 --(CH.sub.2).sub.3--NHMe 15
--(CH.sub.2).sub.4--NHMe 16 --CH.sub.2--NMe.sub.2 17
--(CH.sub.2).sub.3--NMe.sub.2 18 --(CH.sub.2).sub.4--NMe.sub.2 19
--(CH.sub.2).sub.4--NH-c-Pr 20 --CH.sub.2--NH-c-Bu 21 ##STR00179##
22 ##STR00180## 23 ##STR00181## 24 ##STR00182## 25 ##STR00183## 26
##STR00184## 27 ##STR00185## 28 ##STR00186## 29 ##STR00187## 30
##STR00188##
TABLE-US-00008 TABLE 8 (I-A-1-3) ##STR00189## No -D.sup.2-D.sup.3
31 ##STR00190## 32 ##STR00191## 33 ##STR00192## 34 ##STR00193## 35
##STR00194## 36 ##STR00195## 37 ##STR00196## 38 ##STR00197## 39
##STR00198## 40 ##STR00199## 41 ##STR00200## 42 ##STR00201## 43
##STR00202## 44 ##STR00203## 45 ##STR00204## 46 ##STR00205## 47
##STR00206## 48 ##STR00207## 49 ##STR00208## 50 ##STR00209## 51
##STR00210## 52 ##STR00211## 53 ##STR00212## 54 ##STR00213## 55
##STR00214## 56 ##STR00215## 57 ##STR00216## 58 ##STR00217## 59
##STR00218## 60 ##STR00219##
TABLE-US-00009 TABLE 9 (I-A-1-3) ##STR00220## No -D.sup.2-D.sup.3
61 ##STR00221## 62 ##STR00222## 63 ##STR00223## 64 ##STR00224## 65
##STR00225## 66 ##STR00226## 67 ##STR00227## 68 ##STR00228## 69
##STR00229## 70 ##STR00230## 71 ##STR00231## 72 ##STR00232## 73
##STR00233## 74 ##STR00234## 75 ##STR00235## 76 ##STR00236## 77
##STR00237## 78 ##STR00238## 79 ##STR00239## 80 ##STR00240## 81
##STR00241## 82 ##STR00242## 83 ##STR00243## 84 ##STR00244## 85
##STR00245## 86 ##STR00246## 87 ##STR00247## 88 ##STR00248##
TABLE-US-00010 TABLE 10 (I-A-1-4) ##STR00249## No -D.sup.2-D.sup.3
1 Me 2 Pr 3 Bu 4 --CH.sub.2--Cl 5 --(CH.sub.2).sub.3--OH 6
--(CH.sub.2).sub.4--OH 7 --(CH.sub.2).sub.3--CO.sub.2H 8
--(CH.sub.2).sub.3--CO.sub.2Me 9 ##STR00250## 10 ##STR00251## 11
--(CH.sub.2).sub.3--NH.sub.2 12 --(CH.sub.2).sub.4--NH.sub.2 13
--(CH.sub.2).sub.5--NH.sub.2 14 --(CH.sub.2).sub.3--NHMe 15
--(CH.sub.2).sub.4--NHMe 16 --CH.sub.2--NMe.sub.2 17
--(CH.sub.2).sub.3--NMe.sub.2 18 --(CH.sub.2).sub.4--NMe.sub.2 19
--(CH.sub.2).sub.4--NH-c-Pr 20 --CH.sub.2--NH-c-Bu 21 ##STR00252##
22 ##STR00253## 23 ##STR00254## 24 ##STR00255## 25 ##STR00256## 26
##STR00257## 27 ##STR00258## 28 ##STR00259## 29 ##STR00260## 30
##STR00261##
TABLE-US-00011 TABLE 11 (I-A-1-4) ##STR00262## No -D.sup.2-D.sup.3
31 ##STR00263## 32 ##STR00264## 33 ##STR00265## 34 ##STR00266## 35
##STR00267## 36 ##STR00268## 37 ##STR00269## 38 ##STR00270## 39
##STR00271## 40 ##STR00272## 41 ##STR00273## 42 ##STR00274## 43
##STR00275## 44 ##STR00276## 45 ##STR00277## 46 ##STR00278## 47
##STR00279## 48 ##STR00280## 49 ##STR00281## 50 ##STR00282## 51
##STR00283## 52 ##STR00284## 53 ##STR00285## 54 ##STR00286## 55
##STR00287## 56 ##STR00288## 57 ##STR00289## 58 ##STR00290## 59
##STR00291## 60 ##STR00292##
TABLE-US-00012 TABLE 12 (I-A-1-4) ##STR00293## No -D.sup.2-D.sup.3
61 ##STR00294## 62 ##STR00295## 63 ##STR00296## 64 ##STR00297## 65
##STR00298## 66 ##STR00299## 67 ##STR00300## 68 ##STR00301## 69
##STR00302## 70 ##STR00303## 71 ##STR00304## 72 ##STR00305## 73
##STR00306## 74 ##STR00307## 75 ##STR00308## 76 ##STR00309## 77
##STR00310## 78 ##STR00311## 79 ##STR00312## 80 ##STR00313## 81
##STR00314## 82 ##STR00315## 83 ##STR00316## 84 ##STR00317## 85
##STR00318## 86 ##STR00319## 87 ##STR00320## 88 ##STR00321##
TABLE-US-00013 TABLE 13 (I-A-1-5) ##STR00322## No -D.sup.2-D.sup.3
1 Me 2 Pr 3 Bu 4 --CH.sub.2--Cl 5 --(CH.sub.2).sub.3--OH 6
--(CH.sub.2).sub.4--OH 7 --(CH.sub.2).sub.3--CO.sub.2H 8
--(CH.sub.2).sub.3--CO.sub.2Me 9 ##STR00323## 10 ##STR00324## 11
--(CH.sub.2).sub.3--NH.sub.2 12 --(CH.sub.2).sub.4--NH.sub.2 13
--(CH.sub.2).sub.5--NH.sub.2 14 --(CH.sub.2).sub.3--NHMe 15
--(CH.sub.2).sub.4--NHMe 16 --CH.sub.2--NMe.sub.2 17
--(CH.sub.2).sub.3--NMe.sub.2 18 --(CH.sub.2).sub.4--NMe.sub.2 19
--(CH.sub.2).sub.4--NH-c-Pr 20 --CH.sub.2--NH-c-Bu 21 ##STR00325##
22 ##STR00326## 23 ##STR00327## 24 ##STR00328## 25 ##STR00329## 26
##STR00330## 27 ##STR00331## 28 ##STR00332## 29 ##STR00333## 30
##STR00334##
TABLE-US-00014 TABLE 14 (I-A-1-5) ##STR00335## No -D.sup.2-D.sup.3
31 ##STR00336## 32 ##STR00337## 33 ##STR00338## 34 ##STR00339## 35
##STR00340## 36 ##STR00341## 37 ##STR00342## 38 ##STR00343## 39
##STR00344## 40 ##STR00345## 41 ##STR00346## 42 ##STR00347## 43
##STR00348## 44 ##STR00349## 45 ##STR00350## 46 ##STR00351## 47
##STR00352## 48 ##STR00353## 49 ##STR00354## 50 ##STR00355## 51
##STR00356## 52 ##STR00357## 53 ##STR00358## 54 ##STR00359## 55
##STR00360## 56 ##STR00361## 57 ##STR00362## 58 ##STR00363## 59
##STR00364## 60 ##STR00365##
TABLE-US-00015 TABLE 15 (I-A-1-5) ##STR00366## No -D.sup.2-D.sup.3
61 ##STR00367## 62 ##STR00368## 63 ##STR00369## 64 ##STR00370## 65
##STR00371## 66 ##STR00372## 67 ##STR00373## 68 ##STR00374## 69
##STR00375## 70 ##STR00376## 71 ##STR00377## 72 ##STR00378## 73
##STR00379## 74 ##STR00380## 75 ##STR00381## 76 ##STR00382## 77
##STR00383## 78 ##STR00384## 79 ##STR00385## 80 ##STR00386## 81
##STR00387## 82 ##STR00388## 83 ##STR00389## 84 ##STR00390## 85
##STR00391## 86 ##STR00392## 87 ##STR00393## 88 ##STR00394##
TABLE-US-00016 TABLE 16 (I-A-1-6) ##STR00395## No -D.sup.2-D.sup.3
1 Me 2 Pr 3 Bu 4 --CH.sub.2--Cl 5 --(CH.sub.2).sub.3--OH 6
--(CH.sub.2).sub.4--OH 7 --(CH.sub.2).sub.3--CO.sub.2H 8
--(CH.sub.2).sub.3--CO.sub.2Me 9 ##STR00396## 10 ##STR00397## 11
--(CH.sub.2).sub.3--NH.sub.2 12 --(CH.sub.2).sub.4--NH.sub.2 13
--(CH.sub.2).sub.5--NH.sub.2 14 --(CH.sub.2).sub.3--NHMe 15
--(CH.sub.2).sub.4--NHMe 16 --CH.sub.2--NMe.sub.2 17
--(CH.sub.2).sub.3--NMe.sub.2 18 --(CH.sub.2).sub.4--NMe.sub.2 19
--(CH.sub.2).sub.4--NH-c-Pr 20 --CH.sub.2--NH-c-Bu 21 ##STR00398##
22 ##STR00399## 23 ##STR00400## 24 ##STR00401## 25 ##STR00402## 26
##STR00403## 27 ##STR00404## 28 ##STR00405## 29 ##STR00406## 30
##STR00407##
TABLE-US-00017 TABLE 17 (I-A-1-6) ##STR00408## No -D.sup.2-D.sup.3
31 ##STR00409## 32 ##STR00410## 33 ##STR00411## 34 ##STR00412## 35
##STR00413## 36 ##STR00414## 37 ##STR00415## 38 ##STR00416## 39
##STR00417## 40 ##STR00418## 41 ##STR00419## 42 ##STR00420## 43
##STR00421## 44 ##STR00422## 45 ##STR00423## 46 ##STR00424## 47
##STR00425## 48 ##STR00426## 49 ##STR00427## 50 ##STR00428## 51
##STR00429## 52 ##STR00430## 53 ##STR00431## 54 ##STR00432## 55
##STR00433## 56 ##STR00434## 57 ##STR00435## 58 ##STR00436## 59
##STR00437## 60 ##STR00438##
TABLE-US-00018 TABLE 18 (I-A-1-6) ##STR00439## No -D.sup.2-D.sup.3
61 ##STR00440## 62 ##STR00441## 63 ##STR00442## 64 ##STR00443## 65
##STR00444## 66 ##STR00445## 67 ##STR00446## 68 ##STR00447## 69
##STR00448## 70 ##STR00449## 71 ##STR00450## 72 ##STR00451## 73
##STR00452## 74 ##STR00453## 75 ##STR00454## 76 ##STR00455## 77
##STR00456## 78 ##STR00457## 79 ##STR00458## 80 ##STR00459## 81
##STR00460## 82 ##STR00461## 83 ##STR00462## 84 ##STR00463## 85
##STR00464## 86 ##STR00465## 87 ##STR00466## 88 ##STR00467##
TABLE-US-00019 TABLE 19 (I-A-1-7) ##STR00468## No -D.sup.2-D.sup.3
1 Me 2 Pr 3 Bu 4 --CH.sub.2--Cl 5 --(CH.sub.2).sub.3--OH 6
--(CH.sub.2).sub.4--OH 7 --(CH.sub.2).sub.3--CO.sub.2H 8
--(CH.sub.2).sub.3--CO.sub.2Me 9 ##STR00469## 10 ##STR00470## 11
--(CH.sub.2).sub.3--NH.sub.2 12 --(CH.sub.2).sub.4--NH.sub.2 13
--(CH.sub.2).sub.5--NH.sub.2 14 --(CH.sub.2).sub.3--NHMe 15
--(CH.sub.2).sub.4--NHMe 16 --CH.sub.2--NMe.sub.2 17
--(CH.sub.2).sub.3--NMe.sub.2 18 --(CH.sub.2).sub.4--NMe.sub.2 19
--(CH.sub.2).sub.4--NH-c-Pr 20 --CH.sub.2--NH-c-Bu 21 ##STR00471##
22 ##STR00472## 23 ##STR00473## 24 ##STR00474## 25 ##STR00475## 26
##STR00476## 27 ##STR00477## 28 ##STR00478## 29 ##STR00479## 30
##STR00480##
TABLE-US-00020 TABLE 20 (I-A-1-7) ##STR00481## No -D.sup.2-D.sup.3
31 ##STR00482## 32 ##STR00483## 33 ##STR00484## 34 ##STR00485## 35
##STR00486## 36 ##STR00487## 37 ##STR00488## 38 ##STR00489## 39
##STR00490## 40 ##STR00491## 41 ##STR00492## 42 ##STR00493## 43
##STR00494## 44 ##STR00495## 45 ##STR00496## 46 ##STR00497## 47
##STR00498## 48 ##STR00499## 49 ##STR00500## 50 ##STR00501## 51
##STR00502## 52 ##STR00503## 53 ##STR00504## 54 ##STR00505## 55
##STR00506## 56 ##STR00507## 57 ##STR00508## 58 ##STR00509## 59
##STR00510## 60 ##STR00511##
TABLE-US-00021 TABLE 21 (I-A-1-7) ##STR00512## No -D.sup.2-D.sup.3
61 ##STR00513## 62 ##STR00514## 63 ##STR00515## 64 ##STR00516## 65
##STR00517## 66 ##STR00518## 67 ##STR00519## 68 ##STR00520## 69
##STR00521## 70 ##STR00522## 71 ##STR00523## 72 ##STR00524## 73
##STR00525## 74 ##STR00526## 75 ##STR00527## 76 ##STR00528## 77
##STR00529## 78 ##STR00530## 79 ##STR00531## 80 ##STR00532## 81
##STR00533## 82 ##STR00534## 83 ##STR00535## 84 ##STR00536## 85
##STR00537## 86 ##STR00538## 87 ##STR00539## 88 ##STR00540##
TABLE-US-00022 TABLE 22 (I-A-1-8) ##STR00541## No -D.sup.2-D.sup.3
1 Me 2 Pr 3 Bu 4 --CH.sub.2--Cl 5 --(CH.sub.2).sub.3--OH 6
--(CH.sub.2).sub.4--OH 7 --(CH.sub.2).sub.3--CO.sub.2H 8
--(CH.sub.2).sub.3--CO.sub.2Me 9 ##STR00542## 10 ##STR00543## 11
--(CH.sub.2).sub.3--NH.sub.2 12 --(CH.sub.2).sub.4--NH.sub.2 13
--(CH.sub.2).sub.5--NH.sub.2 14 --(CH.sub.2).sub.3--NHMe 15
--(CH.sub.2).sub.4--NHMe 16 --CH.sub.2--NMe.sub.2 17
--(CH.sub.2).sub.3--NMe.sub.2 18 --(CH.sub.2).sub.4--NMe.sub.2 19
--(CH.sub.2).sub.4--NH-c-Pr 20 --CH.sub.2--NH-c-Bu 21 ##STR00544##
22 ##STR00545## 23 ##STR00546## 24 ##STR00547## 25 ##STR00548## 26
##STR00549## 27 ##STR00550## 28 ##STR00551## 29 ##STR00552## 30
##STR00553##
TABLE-US-00023 TABLE 23 (I-A-1-8) ##STR00554## No -D.sup.2-D.sup.3
31 ##STR00555## 32 ##STR00556## 33 ##STR00557## 34 ##STR00558## 35
##STR00559## 36 ##STR00560## 37 ##STR00561## 38 ##STR00562## 39
##STR00563## 40 ##STR00564## 41 ##STR00565## 42 ##STR00566## 43
##STR00567## 44 ##STR00568## 45 ##STR00569## 46 ##STR00570## 47
##STR00571## 48 ##STR00572## 49 ##STR00573## 50 ##STR00574## 51
##STR00575## 52 ##STR00576## 53 ##STR00577## 54 ##STR00578## 55
##STR00579## 56 ##STR00580## 57 ##STR00581## 58 ##STR00582## 59
##STR00583## 60 ##STR00584##
TABLE-US-00024 TABLE 24 (I-A-1-8) ##STR00585## No -D.sup.2-D.sup.3
61 ##STR00586## 62 ##STR00587## 63 ##STR00588## 64 ##STR00589## 65
##STR00590## 66 ##STR00591## 67 ##STR00592## 68 ##STR00593## 69
##STR00594## 70 ##STR00595## 71 ##STR00596## 72 ##STR00597## 73
##STR00598## 74 ##STR00599## 75 ##STR00600## 76 ##STR00601## 77
##STR00602## 78 ##STR00603## 79 ##STR00604## 80 ##STR00605## 81
##STR00606## 82 ##STR00607## 83 ##STR00608## 84 ##STR00609## 85
##STR00610## 86 ##STR00611## 87 ##STR00612## 88 ##STR00613##
TABLE-US-00025 TABLE 25 (I-A-1-9) ##STR00614## No -D.sup.2-D.sup.3
1 Me 2 Pr 3 Bu 4 --CH.sub.2--Cl 5 --(CH.sub.2).sub.3--OH 6
--(CH.sub.2).sub.4--OH 7 --(CH.sub.2).sub.3--CO.sub.2H 8
--(CH.sub.2).sub.3--CO.sub.2Me 9 ##STR00615## 10 ##STR00616## 11
--(CH.sub.2).sub.3--NH.sub.2 12 --(CH.sub.2).sub.4--NH.sub.2 13
--(CH.sub.2).sub.5--NH.sub.2 14 --(CH.sub.2).sub.3--NHMe 15
--(CH.sub.2).sub.4--NHMe 16 --CH.sub.2--NMe.sub.2 17
--(CH.sub.2).sub.3--NMe.sub.2 18 --(CH.sub.2).sub.4--NMe.sub.2 19
--(CH.sub.2).sub.4--NH-c-Pr 20 --CH.sub.2--NH-c-Bu 21 ##STR00617##
22 ##STR00618## 23 ##STR00619## 24 ##STR00620## 25 ##STR00621## 26
##STR00622## 27 ##STR00623## 28 ##STR00624## 29 ##STR00625## 30
##STR00626##
TABLE-US-00026 TABLE 26 (I-A-1-9) ##STR00627## No -D.sup.2-D.sup.3
31 ##STR00628## 32 ##STR00629## 33 ##STR00630## 34 ##STR00631## 35
##STR00632## 36 ##STR00633## 37 ##STR00634## 38 ##STR00635## 39
##STR00636## 40 ##STR00637## 41 ##STR00638## 42 ##STR00639## 43
##STR00640## 44 ##STR00641## 45 ##STR00642## 46 ##STR00643## 47
##STR00644## 48 ##STR00645## 49 ##STR00646## 50 ##STR00647## 51
##STR00648## 52 ##STR00649## 53 ##STR00650## 54 ##STR00651## 55
##STR00652## 56 ##STR00653## 57 ##STR00654## 58 ##STR00655## 59
##STR00656## 60 ##STR00657##
TABLE-US-00027 TABLE 27 (I-A-1-9) ##STR00658## No -D.sup.2-D.sup.3
61 ##STR00659## 62 ##STR00660## 63 ##STR00661## 64 ##STR00662## 65
##STR00663## 66 ##STR00664## 67 ##STR00665## 68 ##STR00666## 69
##STR00667## 70 ##STR00668## 71 ##STR00669## 72 ##STR00670## 73
##STR00671## 74 ##STR00672## 75 ##STR00673## 76 ##STR00674## 77
##STR00675## 78 ##STR00676## 79 ##STR00677## 80 ##STR00678## 81
##STR00679## 82 ##STR00680## 83 ##STR00681## 84 ##STR00682## 85
##STR00683## 86 ##STR00684## 87 ##STR00685## 88 ##STR00686##
TABLE-US-00028 TABLE 28 (I-A-2-1) ##STR00687## No -D.sup.2-D.sup.3
1 Me 2 Pr 3 Bu 4 --CH.sub.2--Cl 5 --(CH.sub.2).sub.3--OH 6
--(CH.sub.2).sub.4--OH 7 --(CH.sub.2).sub.3--CO.sub.2H 8
--(CH.sub.2).sub.3--CO.sub.2Me 9 ##STR00688## 10 ##STR00689## 11
--(CH.sub.2).sub.3--NH.sub.2 12 --(CH.sub.2).sub.4--NH.sub.2 13
--(CH.sub.2).sub.5--NH.sub.2 14 --(CH.sub.2).sub.3--NHMe 15
--(CH.sub.2).sub.4--NHMe 16 --CH.sub.2--NMe.sub.2 17
--(CH.sub.2).sub.3--NMe.sub.2 18 --(CH.sub.2).sub.4--NMe.sub.2 19
--(CH.sub.2).sub.4--NH-c-Pr 20 --CH.sub.2--NH-c-Bu 21 ##STR00690##
22 ##STR00691## 23 ##STR00692## 24 ##STR00693## 25 ##STR00694## 26
##STR00695## 27 ##STR00696## 28 ##STR00697## 29 ##STR00698## 30
##STR00699##
TABLE-US-00029 TABLE 29 (I-A-2-1) ##STR00700## No -D.sup.2-D.sup.3
31 ##STR00701## 32 ##STR00702## 33 ##STR00703## 34 ##STR00704## 35
##STR00705## 36 ##STR00706## 37 ##STR00707## 38 ##STR00708## 39
##STR00709## 40 ##STR00710## 41 ##STR00711## 42 ##STR00712## 43
##STR00713## 44 ##STR00714## 45 ##STR00715## 46 ##STR00716## 47
##STR00717## 48 ##STR00718## 49 ##STR00719## 50 ##STR00720## 51
##STR00721## 52 ##STR00722## 53 ##STR00723## 54 ##STR00724## 55
##STR00725## 56 ##STR00726## 57 ##STR00727## 58 ##STR00728## 59
##STR00729## 60 ##STR00730##
TABLE-US-00030 TABLE 30 (I-A-2-1) ##STR00731## No -D.sup.2-D.sup.3
61 ##STR00732## 62 ##STR00733## 63 ##STR00734## 64 ##STR00735## 65
##STR00736## 66 ##STR00737## 67 ##STR00738## 68 ##STR00739## 69
##STR00740## 70 ##STR00741## 71 ##STR00742## 72 ##STR00743## 73
##STR00744## 74 ##STR00745## 75 ##STR00746## 76 ##STR00747## 77
##STR00748## 78 ##STR00749## 79 ##STR00750## 80 ##STR00751## 81
##STR00752## 82 ##STR00753## 83 ##STR00754## 84 ##STR00755## 85
##STR00756## 86 ##STR00757## 87 ##STR00758## 88 ##STR00759##
TABLE-US-00031 TABLE 31 (I-A-2-2) ##STR00760## No
--D.sup.2--D.sup.3 1 Me 2 Pr 3 Bu 4 --CH.sub.2--Cl 5
--(CH.sub.2).sub.3--OH 6 --(CH.sub.2).sub.4--OH 7
--(CH.sub.2).sub.3--CO.sub.2H 8 --(CH.sub.2).sub.3--CO.sub.2Me 9
##STR00761## 10 ##STR00762## 11 --(CH.sub.2).sub.3--NH.sub.2 12
--(CH.sub.2).sub.4--NH.sub.2 13 --(CH.sub.2).sub.5--NH.sub.2 14
--(CH.sub.2).sub.3--NHMe 15 --(CH.sub.2).sub.4--NHMe 16
--CH.sub.2--NMe.sub.2 17 --(CH.sub.2).sub.3--NMe.sub.2 18
--(CH.sub.2).sub.4--NMe.sub.2 19 --(CH.sub.2).sub.4--NH-c-Pr 20
--CH.sub.2--NH-c-Bu 21 ##STR00763## 22 ##STR00764## 23 ##STR00765##
24 ##STR00766## 25 ##STR00767## 26 ##STR00768## 27 ##STR00769## 28
##STR00770## 29 ##STR00771## 30 ##STR00772##
TABLE-US-00032 TABLE 32 (I-A-2-2) ##STR00773## No
--D.sup.2--D.sup.3 31 ##STR00774## 32 ##STR00775## 33 ##STR00776##
34 ##STR00777## 35 ##STR00778## 36 ##STR00779## 37 ##STR00780## 38
##STR00781## 39 ##STR00782## 40 ##STR00783## 41 ##STR00784## 42
##STR00785## 43 ##STR00786## 44 ##STR00787## 45 ##STR00788## 46
##STR00789## 47 ##STR00790## 48 ##STR00791## 49 ##STR00792## 50
##STR00793## 51 ##STR00794## 52 ##STR00795## 53 ##STR00796## 54
##STR00797## 55 ##STR00798## 56 ##STR00799## 57 ##STR00800## 58
##STR00801## 59 ##STR00802## 60 ##STR00803##
TABLE-US-00033 TABLE 33 (I-A-2-2) ##STR00804## No
--D.sup.2--D.sup.3 61 ##STR00805## 62 ##STR00806## 63 ##STR00807##
64 ##STR00808## 65 ##STR00809## 66 ##STR00810## 67 ##STR00811## 68
##STR00812## 69 ##STR00813## 70 ##STR00814## 71 ##STR00815## 72
##STR00816## 73 ##STR00817## 74 ##STR00818## 75 ##STR00819## 76
##STR00820## 77 ##STR00821## 78 ##STR00822## 79 ##STR00823## 80
##STR00824## 81 ##STR00825## 82 ##STR00826## 83 ##STR00827## 84
##STR00828## 85 ##STR00829## 86 ##STR00830## 87 ##STR00831## 88
##STR00832##
TABLE-US-00034 TABLE 34 (I-A-2-3) ##STR00833## No
--D.sup.2--D.sup.3 1 Me 2 Pr 3 Bu 4 --CH.sub.2--Cl 5
--(CH.sub.2).sub.3--OH 6 --(CH.sub.2).sub.4--OH 7
--(CH.sub.2).sub.3--CO.sub.2H 8 --(CH.sub.2).sub.3--CO.sub.2Me 9
##STR00834## 10 ##STR00835## 11 --(CH.sub.2).sub.3--NH.sub.2 12
--(CH.sub.2).sub.4--NH.sub.2 13 --(CH.sub.2).sub.5--NH.sub.2 14
--(CH.sub.2).sub.3--NHMe 15 --(CH.sub.2).sub.4--NHMe 16
--CH.sub.2--NMe.sub.2 17 --(CH.sub.2).sub.3--NMe.sub.2 18
--(CH.sub.2).sub.4--NMe.sub.2 19 --(CH.sub.2).sub.4--NH-c-Pr 20
--CH.sub.2--NH-c-Bu 21 ##STR00836## 22 ##STR00837## 23 ##STR00838##
24 ##STR00839## 25 ##STR00840## 26 ##STR00841## 27 ##STR00842## 28
##STR00843## 29 ##STR00844## 30 ##STR00845##
TABLE-US-00035 TABLE 35 (I-A-2-3) ##STR00846## No
--D.sup.2--D.sup.3 31 ##STR00847## 32 ##STR00848## 33 ##STR00849##
34 ##STR00850## 35 ##STR00851## 36 ##STR00852## 37 ##STR00853## 38
##STR00854## 39 ##STR00855## 40 ##STR00856## 41 ##STR00857## 42
##STR00858## 43 ##STR00859## 44 ##STR00860## 45 ##STR00861## 46
##STR00862## 47 ##STR00863## 48 ##STR00864## 49 ##STR00865## 50
##STR00866## 51 ##STR00867## 52 ##STR00868## 53 ##STR00869## 54
##STR00870## 55 ##STR00871## 56 ##STR00872## 57 ##STR00873## 58
##STR00874## 59 ##STR00875## 60 ##STR00876##
TABLE-US-00036 TABLE 36 (I-A-2-3) ##STR00877## No
--D.sup.2--D.sup.3 61 ##STR00878## 62 ##STR00879## 63 ##STR00880##
64 ##STR00881## 65 ##STR00882## 66 ##STR00883## 67 ##STR00884## 68
##STR00885## 69 ##STR00886## 70 ##STR00887## 71 ##STR00888## 72
##STR00889## 73 ##STR00890## 74 ##STR00891## 75 ##STR00892## 76
##STR00893## 77 ##STR00894## 78 ##STR00895## 79 ##STR00896## 80
##STR00897## 81 ##STR00898## 82 ##STR00899## 83 ##STR00900## 84
##STR00901## 85 ##STR00902## 86 ##STR00903## 87 ##STR00904## 88
##STR00905##
TABLE-US-00037 TABLE 37 (I-A-2-4) ##STR00906## No
--D.sup.2--D.sup.3 1 Me 2 Pr 3 Bu 4 --CH.sub.2--Cl 5
--(CH.sub.2).sub.3--OH 6 --(CH.sub.2).sub.4--OH 7
--(CH.sub.2).sub.3--CO.sub.2H 8 --(CH.sub.2).sub.3--CO.sub.2Me 9
##STR00907## 10 ##STR00908## 11 --(CH.sub.2).sub.3--NH.sub.2 12
--(CH.sub.2).sub.4--NH.sub.2 13 --(CH.sub.2).sub.5--NH.sub.2 14
--(CH.sub.2).sub.3--NHMe 15 --(CH.sub.2).sub.4--NHMe 16
--CH.sub.2--NMe.sub.2 17 --(CH.sub.2).sub.3--NMe.sub.2 18
--(CH.sub.2).sub.4--NMe.sub.2 19 --(CH.sub.2).sub.4--NH-c-Pr 20
--CH.sub.2--NH-c-Bu 21 ##STR00909## 22 ##STR00910## 23 ##STR00911##
24 ##STR00912## 25 ##STR00913## 26 ##STR00914## 27 ##STR00915## 28
##STR00916## 29 ##STR00917## 30 ##STR00918##
TABLE-US-00038 TABLE 38 (I-A-2-4) ##STR00919## No
--D.sup.2--D.sup.3 31 ##STR00920## 32 ##STR00921## 33 ##STR00922##
34 ##STR00923## 35 ##STR00924## 36 ##STR00925## 37 ##STR00926## 38
##STR00927## 39 ##STR00928## 40 ##STR00929## 41 ##STR00930## 42
##STR00931## 43 ##STR00932## 44 ##STR00933## 45 ##STR00934## 46
##STR00935## 47 ##STR00936## 48 ##STR00937## 49 ##STR00938## 50
##STR00939## 51 ##STR00940## 52 ##STR00941## 53 ##STR00942## 54
##STR00943## 55 ##STR00944## 56 ##STR00945## 57 ##STR00946## 58
##STR00947## 59 ##STR00948## 60 ##STR00949##
TABLE-US-00039 TABLE 39 (I-A-2-4) ##STR00950## No
--D.sup.2--D.sup.3 61 ##STR00951## 62 ##STR00952## 63 ##STR00953##
64 ##STR00954## 65 ##STR00955## 66 ##STR00956## 67 ##STR00957## 68
##STR00958## 69 ##STR00959## 70 ##STR00960## 71 ##STR00961## 72
##STR00962## 73 ##STR00963## 74 ##STR00964## 75 ##STR00965## 76
##STR00966## 77 ##STR00967## 78 ##STR00968## 79 ##STR00969## 80
##STR00970## 81 ##STR00971## 82 ##STR00972## 83 ##STR00973## 84
##STR00974## 85 ##STR00975## 86 ##STR00976## 87 ##STR00977## 88
##STR00978##
TABLE-US-00040 TABLE 40 (I-A-2-5) ##STR00979## No
--D.sup.2--D.sup.3 1 Me 2 Pr 3 Bu 4 --CH.sub.2--Cl 5
--(CH.sub.2).sub.3--OH 6 --(CH.sub.2).sub.4--OH 7
--(CH.sub.2).sub.3--CO.sub.2H 8 --(CH.sub.2).sub.3--CO.sub.2Me 9
##STR00980## 10 ##STR00981## 11 --(CH.sub.2).sub.3--NH.sub.2 12
--(CH.sub.2).sub.4--NH.sub.2 13 --(CH.sub.2).sub.5--NH.sub.2 14
--(CH.sub.2).sub.3--NHMe 15 --(CH.sub.2).sub.4--NHMe 16
--CH.sub.2--NMe.sub.2 17 --(CH.sub.2).sub.3--NMe.sub.2 18
--(CH.sub.2).sub.4--NMe.sub.2 19 --(CH.sub.2).sub.4--NH-c-Pr 20
--CH.sub.2--NH-c-Bu 21 ##STR00982## 22 ##STR00983## 23 ##STR00984##
24 ##STR00985## 25 ##STR00986## 26 ##STR00987## 27 ##STR00988## 28
##STR00989## 29 ##STR00990## 30 ##STR00991##
TABLE-US-00041 TABLE 41 (I-A-2-5) ##STR00992## No
--D.sup.2--D.sup.3 31 ##STR00993## 32 ##STR00994## 33 ##STR00995##
34 ##STR00996## 35 ##STR00997## 36 ##STR00998## 37 ##STR00999## 38
##STR01000## 39 ##STR01001## 40 ##STR01002## 41 ##STR01003## 42
##STR01004## 43 ##STR01005## 44 ##STR01006## 45 ##STR01007## 46
##STR01008## 47 ##STR01009## 48 ##STR01010## 49 ##STR01011## 50
##STR01012## 51 ##STR01013## 52 ##STR01014## 53 ##STR01015## 54
##STR01016## 55 ##STR01017## 56 ##STR01018## 57 ##STR01019## 58
##STR01020## 59 ##STR01021## 60 ##STR01022##
TABLE-US-00042 TABLE 42 (I-A-2-5) ##STR01023## No
--D.sup.2--D.sup.3 61 ##STR01024## 62 ##STR01025## 63 ##STR01026##
64 ##STR01027## 65 ##STR01028## 66 ##STR01029## 67 ##STR01030## 68
##STR01031## 69 ##STR01032## 70 ##STR01033## 71 ##STR01034## 72
##STR01035## 73 ##STR01036## 74 ##STR01037## 75 ##STR01038## 76
##STR01039## 77 ##STR01040## 78 ##STR01041## 79 ##STR01042## 80
##STR01043## 81 ##STR01044## 82 ##STR01045## 83 ##STR01046## 84
##STR01047## 85 ##STR01048## 86 ##STR01049## 87 ##STR01050## 88
##STR01051##
TABLE-US-00043 TABLE 43 (I-A-2-6) ##STR01052## No
--D.sup.2--D.sup.3 1 Me 2 Pr 3 Bu 4 --CH.sub.2--Cl 5
--(CH.sub.2).sub.3--OH 6 --(CH.sub.2).sub.4--OH 7
--(CH.sub.2).sub.3--CO.sub.2H 8 --(CH.sub.2).sub.3--CO.sub.2Me 9
##STR01053## 10 ##STR01054## 11 --(CH.sub.2).sub.3--NH.sub.2 12
--(CH.sub.2).sub.4--NH.sub.2 13 --(CH.sub.2).sub.5--NH.sub.2 14
--(CH.sub.2).sub.3--NHMe 15 --(CH.sub.2).sub.4--NHMe 16
--CH.sub.2--NMe.sub.2 17 --(CH.sub.2).sub.3--NMe.sub.2 18
--(CH.sub.2).sub.4--NMe.sub.2 19 --(CH.sub.2).sub.4--NH-c-Pr 20
--CH.sub.2--NH-c-Bu 21 ##STR01055## 22 ##STR01056## 23 ##STR01057##
24 ##STR01058## 25 ##STR01059## 26 ##STR01060## 27 ##STR01061## 28
##STR01062## 29 ##STR01063## 30 ##STR01064##
TABLE-US-00044 TABLE 44 (I-A-2-6) ##STR01065## No
--D.sup.2--D.sup.3 31 ##STR01066## 32 ##STR01067## 33 ##STR01068##
34 ##STR01069## 35 ##STR01070## 36 ##STR01071## 37 ##STR01072## 38
##STR01073## 39 ##STR01074## 40 ##STR01075## 41 ##STR01076## 42
##STR01077## 43 ##STR01078## 44 ##STR01079## 45 ##STR01080## 46
##STR01081## 47 ##STR01082## 48 ##STR01083## 49 ##STR01084## 50
##STR01085## 51 ##STR01086## 52 ##STR01087## 53 ##STR01088## 54
##STR01089## 55 ##STR01090## 56 ##STR01091## 57 ##STR01092## 58
##STR01093## 59 ##STR01094## 60 ##STR01095##
TABLE-US-00045 TABLE 45 (I-A-2-6) ##STR01096## No
--D.sup.2--D.sup.3 61 ##STR01097## 62 ##STR01098## 63 ##STR01099##
64 ##STR01100## 65 ##STR01101## 66 ##STR01102## 67 ##STR01103## 68
##STR01104## 69 ##STR01105## 70 ##STR01106## 71 ##STR01107## 72
##STR01108## 73 ##STR01109## 74 ##STR01110## 75 ##STR01111## 76
##STR01112## 77 ##STR01113## 78 ##STR01114## 79 ##STR01115## 80
##STR01116## 81 ##STR01117## 82 ##STR01118## 83 ##STR01119## 84
##STR01120## 85 ##STR01121## 86 ##STR01122## 87 ##STR01123## 88
##STR01124##
TABLE-US-00046 TABLE 46 (I-A-2-7) ##STR01125## No -D.sup.2-D.sup.3
1 Me 2 Pr 3 Bu 4 --CH.sub.2--Cl 5 --(CH.sub.2).sub.3--OH 6
--(CH.sub.2).sub.4--OH 7 --(CH.sub.2).sub.3--CO.sub.2H 8
--(CH.sub.2).sub.3--CO.sub.2Me 9 ##STR01126## 10 ##STR01127## 11
--(CH.sub.2).sub.3--NH.sub.2 12 --(CH.sub.2).sub.4--NH.sub.2 13
--(CH.sub.2).sub.5--NH.sub.2 14 --(CH.sub.2).sub.3--NHMe 15
--(CH.sub.2).sub.4--NHMe 16 --CH.sub.2--NMe.sub.2 17
--(CH.sub.2).sub.3--NMe.sub.2 18 --(CH.sub.2).sub.4--NMe.sub.2 19
--(CH.sub.2).sub.4--NH-c-Pr 20 --CH.sub.2--NH-c-Bu 21 ##STR01128##
22 ##STR01129## 23 ##STR01130## 24 ##STR01131## 25 ##STR01132## 26
##STR01133## 27 ##STR01134## 28 ##STR01135## 29 ##STR01136## 30
##STR01137##
TABLE-US-00047 TABLE 47 (I-A-2-7) ##STR01138## No -D.sup.2-D.sup.3
31 ##STR01139## 32 ##STR01140## 33 ##STR01141## 34 ##STR01142## 35
##STR01143## 36 ##STR01144## 37 ##STR01145## 38 ##STR01146## 39
##STR01147## 40 ##STR01148## 41 ##STR01149## 42 ##STR01150## 43
##STR01151## 44 ##STR01152## 45 ##STR01153## 46 ##STR01154## 47
##STR01155## 48 ##STR01156## 49 ##STR01157## 50 ##STR01158## 51
##STR01159## 52 ##STR01160## 53 ##STR01161## 54 ##STR01162## 55
##STR01163## 56 ##STR01164## 57 ##STR01165## 58 ##STR01166## 59
##STR01167## 60 ##STR01168##
TABLE-US-00048 TABLE 48 (I-A-2-7) ##STR01169## No -D.sup.2-D.sup.3
61 ##STR01170## 62 ##STR01171## 63 ##STR01172## 64 ##STR01173## 65
##STR01174## 66 ##STR01175## 67 ##STR01176## 68 ##STR01177## 69
##STR01178## 70 ##STR01179## 71 ##STR01180## 72 ##STR01181## 73
##STR01182## 74 ##STR01183## 75 ##STR01184## 76 ##STR01185## 77
##STR01186## 78 ##STR01187## 79 ##STR01188## 80 ##STR01189## 81
##STR01190## 82 ##STR01191## 83 ##STR01192## 84 ##STR01193## 85
##STR01194## 86 ##STR01195## 87 ##STR01196## 88 ##STR01197##
TABLE-US-00049 TABLE 49 (I-A-2-8) ##STR01198## No -D.sup.2-D.sup.3
1 Me 2 Pr 3 Bu 4 --CH.sub.2--Cl 5 --(CH.sub.2).sub.3--OH 6
--(CH.sub.2).sub.4--OH 7 --(CH.sub.2).sub.3--CO.sub.2H 8
--(CH.sub.2).sub.3--CO.sub.2Me 9 ##STR01199## 10 ##STR01200## 11
--(CH.sub.2).sub.3--NH.sub.2 12 --(CH.sub.2).sub.4--NH.sub.2 13
--(CH.sub.2).sub.5--NH.sub.2 14 --(CH.sub.2).sub.3--NHMe 15
--(CH.sub.2).sub.4--NHMe 16 --CH.sub.2--NMe.sub.2 17
--(CH.sub.2).sub.3--NMe.sub.2 18 --(CH.sub.2).sub.4--NMe.sub.2 19
--(CH.sub.2).sub.4--NH-c-Pr 20 --CH.sub.2--NH-c-Bu 21 ##STR01201##
22 ##STR01202## 23 ##STR01203## 24 ##STR01204## 25 ##STR01205## 26
##STR01206## 27 ##STR01207## 28 ##STR01208## 29 ##STR01209## 30
##STR01210##
TABLE-US-00050 TABLE 50 (I-A-2-8) ##STR01211## No -D.sup.2-D.sup.3
31 ##STR01212## 32 ##STR01213## 33 ##STR01214## 34 ##STR01215## 35
##STR01216## 36 ##STR01217## 37 ##STR01218## 38 ##STR01219## 39
##STR01220## 40 ##STR01221## 41 ##STR01222## 42 ##STR01223## 43
##STR01224## 44 ##STR01225## 45 ##STR01226## 46 ##STR01227## 47
##STR01228## 48 ##STR01229## 49 ##STR01230## 50 ##STR01231## 51
##STR01232## 52 ##STR01233## 53 ##STR01234## 54 ##STR01235## 55
##STR01236## 56 ##STR01237## 57 ##STR01238## 58 ##STR01239## 59
##STR01240## 60 ##STR01241##
TABLE-US-00051 TABLE 51 (I-A-2-8) ##STR01242## No -D.sup.2-D.sup.3
61 ##STR01243## 62 ##STR01244## 63 ##STR01245## 64 ##STR01246## 65
##STR01247## 66 ##STR01248## 67 ##STR01249## 68 ##STR01250## 69
##STR01251## 70 ##STR01252## 71 ##STR01253## 72 ##STR01254## 73
##STR01255## 74 ##STR01256## 75 ##STR01257## 76 ##STR01258## 77
##STR01259## 78 ##STR01260## 79 ##STR01261## 80 ##STR01262## 81
##STR01263## 82 ##STR01264## 83 ##STR01265## 84 ##STR01266## 85
##STR01267## 86 ##STR01268## 87 ##STR01269## 88 ##STR01270##
TABLE-US-00052 TABLE 52 (I-A-2-9) ##STR01271## No -D.sup.2-D.sup.3
1 Me 2 Pr 3 Bu 4 --CH.sub.2--Cl 5 --(CH.sub.2).sub.3--OH 6
--(CH.sub.2).sub.4--OH 7 --(CH.sub.2).sub.3--CO.sub.2H 8
--(CH.sub.2).sub.3--CO.sub.2Me 9 ##STR01272## 10 ##STR01273## 11
--(CH.sub.2).sub.3--NH.sub.2 12 --(CH.sub.2).sub.4--NH.sub.2 13
--(CH.sub.2).sub.5--NH.sub.2 14 --(CH.sub.2).sub.3--NHMe 15
--(CH.sub.2).sub.4--NHMe 16 --CH.sub.2--NMe.sub.2 17
--(CH.sub.2).sub.3--NMe.sub.2 18 --(CH.sub.2).sub.4--NMe.sub.2 19
--(CH.sub.2).sub.4--NH-c-Pr 20 --CH.sub.2--NH-c-Bu 21 ##STR01274##
22 ##STR01275## 23 ##STR01276## 24 ##STR01277## 25 ##STR01278## 26
##STR01279## 27 ##STR01280## 28 ##STR01281## 29 ##STR01282## 30
##STR01283##
TABLE-US-00053 TABLE 53 (I-A-2-9) ##STR01284## No -D.sup.2-D.sup.3
31 ##STR01285## 32 ##STR01286## 33 ##STR01287## 34 ##STR01288## 35
##STR01289## 36 ##STR01290## 37 ##STR01291## 38 ##STR01292## 39
##STR01293## 40 ##STR01294## 41 ##STR01295## 42 ##STR01296## 43
##STR01297## 44 ##STR01298## 45 ##STR01299## 46 ##STR01300## 47
##STR01301## 48 ##STR01302## 49 ##STR01303## 50 ##STR01304## 51
##STR01305## 52 ##STR01306## 53 ##STR01307## 54 ##STR01308## 55
##STR01309## 56 ##STR01310## 57 ##STR01311## 58 ##STR01312## 59
##STR01313## 60 ##STR01314##
TABLE-US-00054 TABLE 54 (I-A-2-9) ##STR01315## No -D.sup.2-D.sup.3
61 ##STR01316## 62 ##STR01317## 63 ##STR01318## 64 ##STR01319## 65
##STR01320## 66 ##STR01321## 67 ##STR01322## 68 ##STR01323## 69
##STR01324## 70 ##STR01325## 71 ##STR01326## 72 ##STR01327## 73
##STR01328## 74 ##STR01329## 75 ##STR01330## 76 ##STR01331## 77
##STR01332## 78 ##STR01333## 79 ##STR01334## 80 ##STR01335## 81
##STR01336## 82 ##STR01337## 83 ##STR01338## 84 ##STR01339## 85
##STR01340## 86 ##STR01341## 87 ##STR01342## 88 ##STR01343##
TABLE-US-00055 TABLE 55 (I-B-1-1) ##STR01344## No -E.sup.3-
-E.sup.4 1 --(CH.sub.2).sub.2-- --OH 2 --(CH.sub.2).sub.2-- --OMe 3
--(CH.sub.2).sub.2-- --NH.sub.2 4 --(CH.sub.2).sub.2-- --NHMe 5
--(CH.sub.2).sub.2-- --NHEt 6 --(CH.sub.2).sub.2-- --NHPr 7
--(CH.sub.2).sub.2-- --NH-i-Pr 8 --(CH.sub.2).sub.2-- --NMe.sub.2 9
--(CH.sub.2).sub.2-- --NEt.sub.2 10 --(CH.sub.2).sub.2--
--NPr.sub.2 11 --(CH.sub.2).sub.2-- --N(i-Pr).sub.2 12
--(CH.sub.2).sub.2-- --NHPh 13 --(CH.sub.2).sub.2-- --NHBn 14
--(CH.sub.2).sub.2-- --NH-c-Pr 15 --(CH.sub.2).sub.2-- --NH-c-Bu 16
--(CH.sub.2).sub.2-- --NH-c-Pen 17 --(CH.sub.2).sub.2-- --NH-c-Hex
18 --(CH.sub.2).sub.2-- --NH--(CH.sub.2).sub.2--OH 19
--(CH.sub.2).sub.2-- --NHCH(Me)(OH) 20 --(CH.sub.2).sub.2--
--N(Me)(c-Pen) 21 --(CH.sub.2).sub.2-- --N(Me)(c-Hex) 22
--(CH.sub.2).sub.2-- --N(Me)(Ph) 23 --(CH.sub.2).sub.2--
##STR01345## 24 --(CH.sub.2).sub.2-- ##STR01346## 25
--(CH.sub.2).sub.2-- ##STR01347## 26 --(CH.sub.2).sub.2--
##STR01348## 27 --(CH.sub.2).sub.2-- ##STR01349## 28
--(CH.sub.2).sub.2-- ##STR01350## 29 --(CH.sub.2).sub.3-- --OH 30
--(CH.sub.2).sub.3-- --OMe 31 --(CH.sub.2).sub.3-- --NH.sub.2 32
--(CH.sub.2).sub.3-- --NHMe 33 --(CH.sub.2).sub.3-- --NHEt 34
--(CH.sub.2).sub.3-- --NHPr 35 --(CH.sub.2).sub.3-- --NH-i-Pr 36
--(CH.sub.2).sub.3-- --NMe.sub.2 37 --(CH.sub.2).sub.3--
--NEt.sub.2 38 --(CH.sub.2).sub.3-- --NPr.sub.2 39
--(CH.sub.2).sub.3-- --N(i-Pr).sub.2 40 --(CH.sub.2).sub.3-- --NHPh
41 --(CH.sub.2).sub.3-- --NHBn 42 --(CH.sub.2).sub.3-- --NH-c-Pr 43
--(CH.sub.2).sub.3-- --NH-c-Bu 44 --(CH.sub.2).sub.3-- --NH-c-Pen
45 --(CH.sub.2).sub.3-- --NH-c-Hex 46 --(CH.sub.2).sub.3--
--NH--(CH.sub.2).sub.2--OH 47 --(CH.sub.2).sub.3-- --NHCH(Me)(OH)
48 --(CH.sub.2).sub.3-- --N(Me)(c-Pen) 49 --(CH.sub.2).sub.3--
--N(Me)(c-Hex) 50 --(CH.sub.2).sub.3-- --N(Me)(Ph) 51
--(CH.sub.2).sub.3-- ##STR01351## 52 --(CH.sub.2).sub.3--
##STR01352## 53 --(CH.sub.2).sub.3-- ##STR01353## 54
--(CH.sub.2).sub.3-- ##STR01354## 55 --(CH.sub.2).sub.3--
##STR01355## 56 --(CH.sub.2).sub.3-- ##STR01356## 57
--(CH.sub.2).sub.4-- --OH 58 --(CH.sub.2).sub.4-- --OMe 59
--(CH.sub.2).sub.4-- --NH.sub.2 60 --(CH.sub.2).sub.4-- --NHMe 61
--(CH.sub.2).sub.4-- --NHEt 62 --(CH.sub.2).sub.4-- --NHPr 63
--(CH.sub.2).sub.4-- --NH-i-Pr 64 --(CH.sub.2).sub.4-- --NMe.sub.2
65 --(CH.sub.2).sub.4-- --NEt.sub.2 66 --(CH.sub.2).sub.4--
--NPr.sub.2 67 --(CH.sub.2).sub.4-- --N(i-Pr).sub.2 68
--(CH.sub.2).sub.4-- --NHPh 69 --(CH.sub.2).sub.4-- --NHBn 70
--(CH.sub.2).sub.4-- --NH-c-Pr 71 --(CH.sub.2).sub.4-- --NH-c-Bu 72
--(CH.sub.2).sub.4-- --NH-c-Pen 73 --(CH.sub.2).sub.4-- --NH-c-Hex
74 --(CH.sub.2).sub.4-- --NH--(CH.sub.2).sub.2--OH 75
--(CH.sub.2).sub.4-- --NHCH(Me)(OH) 76 --(CH.sub.2).sub.4--
--N(Me)(c-Pen) 77 --(CH.sub.2).sub.4-- --N(Me)(c-Hex) 78
--(CH.sub.2).sub.4-- --N(Me)(Ph) 79 --(CH.sub.2).sub.4--
##STR01357## 80 --(CH.sub.2).sub.4-- ##STR01358## 81
--(CH.sub.2).sub.4-- ##STR01359## 82 --(CH.sub.2).sub.4--
##STR01360## 83 --(CH.sub.2).sub.4-- ##STR01361## 84
--(CH.sub.2).sub.4-- ##STR01362##
TABLE-US-00056 TABLE 56 (I-B-1-2) ##STR01363## No -E.sup.3-
-E.sup.4 1 --(CH.sub.2).sub.2-- --OH 2 --(CH.sub.2).sub.2-- --OMe 3
--(CH.sub.2).sub.2-- --NH.sub.2 4 --(CH.sub.2).sub.2-- --NHMe 5
--(CH.sub.2).sub.2-- --NHEt 6 --(CH.sub.2).sub.2-- --NHPr 7
--(CH.sub.2).sub.2-- --NH-i-Pr 8 --(CH.sub.2).sub.2-- --NMe.sub.2 9
--(CH.sub.2).sub.2-- --NEt.sub.2 10 --(CH.sub.2).sub.2--
--NPr.sub.2 11 --(CH.sub.2).sub.2-- --N(i-Pr).sub.2 12
--(CH.sub.2).sub.2-- --NHPh 13 --(CH.sub.2).sub.2-- --NHBn 14
--(CH.sub.2).sub.2-- --NH-c-Pr 15 --(CH.sub.2).sub.2-- --NH-c-Bu 16
--(CH.sub.2).sub.2-- --NH-c-Pen 17 --(CH.sub.2).sub.2-- --NH-c-Hex
18 --(CH.sub.2).sub.2-- --NH--(CH.sub.2).sub.2--OH 19
--(CH.sub.2).sub.2-- --NHCH(Me)(OH) 20 --(CH.sub.2).sub.2--
--N(Me)(c-Pen) 21 --(CH.sub.2).sub.2-- --N(Me)(c-Hex) 22
--(CH.sub.2).sub.2-- --N(Me)(Ph) 23 --(CH.sub.2).sub.2--
##STR01364## 24 --(CH.sub.2).sub.2-- ##STR01365## 25
--(CH.sub.2).sub.2-- ##STR01366## 26 --(CH.sub.2).sub.2--
##STR01367## 27 --(CH.sub.2).sub.2-- ##STR01368## 28
--(CH.sub.2).sub.2-- ##STR01369## 29 --(CH.sub.2).sub.3-- --OH 30
--(CH.sub.2).sub.3-- --OMe 31 --(CH.sub.2).sub.3-- --NH.sub.2 32
--(CH.sub.2).sub.3-- --NHMe 33 --(CH.sub.2).sub.3-- --NHEt 34
--(CH.sub.2).sub.3-- --NHPr 35 --(CH.sub.2).sub.3-- --NH-i-Pr 36
--(CH.sub.2).sub.3-- --NMe.sub.2 37 --(CH.sub.2).sub.3--
--NEt.sub.2 38 --(CH.sub.2).sub.3-- --NPr.sub.2 39
--(CH.sub.2).sub.3-- --N(i-Pr).sub.2 40 --(CH.sub.2).sub.3-- --NHPh
41 --(CH.sub.2).sub.3-- --NHBn 42 --(CH.sub.2).sub.3-- --NH-c-Pr 43
--(CH.sub.2).sub.3-- --NH-c-Bu 44 --(CH.sub.2).sub.3-- --NH-c-Pen
45 --(CH.sub.2).sub.3-- --NH-c-Hex 46 --(CH.sub.2).sub.3--
--NH--(CH.sub.2).sub.2--OH 47 --(CH.sub.2).sub.3-- --NHCH(Me)(OH)
48 --(CH.sub.2).sub.3-- --N(Me)(c-Pen) 49 --(CH.sub.2).sub.3--
--N(Me)(c-Hex) 50 --(CH.sub.2).sub.3-- --N(Me)(Ph) 51
--(CH.sub.2).sub.3-- ##STR01370## 52 --(CH.sub.2).sub.3--
##STR01371## 53 --(CH.sub.2).sub.3-- ##STR01372## 54
--(CH.sub.2).sub.3-- ##STR01373## 55 --(CH.sub.2).sub.3--
##STR01374## 56 --(CH.sub.2).sub.3-- ##STR01375## 57
--(CH.sub.2).sub.4-- --OH 58 --(CH.sub.2).sub.4-- --OMe 59
--(CH.sub.2).sub.4-- --NH.sub.2 60 --(CH.sub.2).sub.4-- --NHMe 61
--(CH.sub.2).sub.4-- --NHEt 62 --(CH.sub.2).sub.4-- --NHPr 63
--(CH.sub.2).sub.4-- --NH-i-Pr 64 --(CH.sub.2).sub.4-- --NMe.sub.2
65 --(CH.sub.2).sub.4-- --NEt.sub.2 66 --(CH.sub.2).sub.4--
--NPr.sub.2 67 --(CH.sub.2).sub.4-- --N(i-Pr).sub.2 68
--(CH.sub.2).sub.4-- --NHPh 69 --(CH.sub.2).sub.4-- --NHBn 70
--(CH.sub.2).sub.4-- --NH-c-Pr 71 --(CH.sub.2).sub.4-- --NH-c-Bu 72
--(CH.sub.2).sub.4-- --NH-c-Pen 73 --(CH.sub.2).sub.4-- --NH-c-Hex
74 --(CH.sub.2).sub.4-- --NH--(CH.sub.2).sub.2--OH 75
--(CH.sub.2).sub.4-- --NHCH(Me)(OH) 76 --(CH.sub.2).sub.4--
--N(Me)(c-Pen) 77 --(CH.sub.2).sub.4-- --N(Me)(c-Hex) 78
--(CH.sub.2).sub.4-- --N(Me)(Ph) 79 --(CH.sub.2).sub.4--
##STR01376## 80 --(CH.sub.2).sub.4-- ##STR01377## 81
--(CH.sub.2).sub.4-- ##STR01378## 82 --(CH.sub.2).sub.4--
##STR01379## 83 --(CH.sub.2).sub.4-- ##STR01380## 84
--(CH.sub.2).sub.4-- ##STR01381##
TABLE-US-00057 TABLE 57 (I-B-1-3) ##STR01382## No -E.sup.3-
-E.sup.4 1 --(CH.sub.2).sub.2-- --OH 2 --(CH.sub.2).sub.2-- --OMe 3
--(CH.sub.2).sub.2-- --NH.sub.2 4 --(CH.sub.2).sub.2-- --NHMe 5
--(CH.sub.2).sub.2-- --NHEt 6 --(CH.sub.2).sub.2-- --NHPr 7
--(CH.sub.2).sub.2-- --NH-i-Pr 8 --(CH.sub.2).sub.2-- --NMe.sub.2 9
--(CH.sub.2).sub.2-- --NEt.sub.2 10 --(CH.sub.2).sub.2--
--NPr.sub.2 11 --(CH.sub.2).sub.2-- --N(i-Pr).sub.2 12
--(CH.sub.2).sub.2-- --NHPh 13 --(CH.sub.2).sub.2-- --NHBn 14
--(CH.sub.2).sub.2-- --NH-c-Pr 15 --(CH.sub.2).sub.2-- --NH-c-Bu 16
--(CH.sub.2).sub.2-- --NH-c-Pen 17 --(CH.sub.2).sub.2-- --NH-c-Hex
18 --(CH.sub.2).sub.2-- --NH--(CH.sub.2).sub.2--OH 19
--(CH.sub.2).sub.2-- --NHCH(Me)(OH) 20 --(CH.sub.2).sub.2--
--N(Me)(c-Pen) 21 --(CH.sub.2).sub.2-- --N(Me)(c-Hex) 22
--(CH.sub.2).sub.2-- --N(Me)(Ph) 23 --(CH.sub.2).sub.2--
##STR01383## 24 --(CH.sub.2).sub.2-- ##STR01384## 25
--(CH.sub.2).sub.2-- ##STR01385## 26 --(CH.sub.2).sub.2--
##STR01386## 27 --(CH.sub.2).sub.2-- ##STR01387## 28
--(CH.sub.2).sub.2-- ##STR01388## 29 --(CH.sub.2).sub.3-- --OH 30
--(CH.sub.2).sub.3-- --OMe 31 --(CH.sub.2).sub.3-- --NH.sub.2 32
--(CH.sub.2).sub.3-- --NHMe 33 --(CH.sub.2).sub.3-- --NHEt 34
--(CH.sub.2).sub.3-- --NHPr 35 --(CH.sub.2).sub.3-- --NH-i-Pr 36
--(CH.sub.2).sub.3-- --NMe.sub.2 37 --(CH.sub.2).sub.3--
--NEt.sub.2 38 --(CH.sub.2).sub.3-- --NPr.sub.2 39
--(CH.sub.2).sub.3-- --N(i-Pr).sub.2 40 --(CH.sub.2).sub.3-- --NHPh
41 --(CH.sub.2).sub.3-- --NHBn 42 --(CH.sub.2).sub.3-- --NH-c-Pr 43
--(CH.sub.2).sub.3-- --NH-c-Bu 44 --(CH.sub.2).sub.3-- --NH-c-Pen
45 --(CH.sub.2).sub.3-- --NH-c-Hex 46 --(CH.sub.2).sub.3--
--NH--(CH.sub.2).sub.2--OH 47 --(CH.sub.2).sub.3-- --NHCH(Me)(OH)
48 --(CH.sub.2).sub.3-- --N(Me)(c-Pen) 49 --(CH.sub.2).sub.3--
--N(Me)(c-Hex) 50 --(CH.sub.2).sub.3-- --N(Me)(Ph) 51
--(CH.sub.2).sub.3-- ##STR01389## 52 --(CH.sub.2).sub.3--
##STR01390## 53 --(CH.sub.2).sub.3-- ##STR01391## 54
--(CH.sub.2).sub.3-- ##STR01392## 55 --(CH.sub.2).sub.3--
##STR01393## 56 --(CH.sub.2).sub.3-- ##STR01394## 57
--(CH.sub.2).sub.4-- --OH 58 --(CH.sub.2).sub.4-- --OMe 59
--(CH.sub.2).sub.4-- --NH.sub.2 60 --(CH.sub.2).sub.4-- --NHMe 61
--(CH.sub.2).sub.4-- --NHEt 62 --(CH.sub.2).sub.4-- --NHPr 63
--(CH.sub.2).sub.4-- --NH-i-Pr 64 --(CH.sub.2).sub.4-- --NMe.sub.2
65 --(CH.sub.2).sub.4-- --NEt.sub.2 66 --(CH.sub.2).sub.4--
--NPr.sub.2 67 --(CH.sub.2).sub.4-- --N(i-Pr).sub.2 68
--(CH.sub.2).sub.4-- --NHPh 69 --(CH.sub.2).sub.4-- --NHBn 70
--(CH.sub.2).sub.4-- --NH-c-Pr 71 --(CH.sub.2).sub.4-- --NH-c-Bu 72
--(CH.sub.2).sub.4-- --NH-c-Pen 73 --(CH.sub.2).sub.4-- --NH-c-Hex
74 --(CH.sub.2).sub.4-- --NH--(CH.sub.2).sub.2--OH 75
--(CH.sub.2).sub.4-- --NHCH(Me)(OH) 76 --(CH.sub.2).sub.4--
--N(Me)(c-Pen) 77 --(CH.sub.2).sub.4-- --N(Me)(c-Hex) 78
--(CH.sub.2).sub.4-- --N(Me)(Ph) 79 --(CH.sub.2).sub.4--
##STR01395## 80 --(CH.sub.2).sub.4-- ##STR01396## 81
--(CH.sub.2).sub.4-- ##STR01397## 82 --(CH.sub.2).sub.4--
##STR01398## 83 --(CH.sub.2).sub.4-- ##STR01399## 84
--(CH.sub.2).sub.4-- ##STR01400##
TABLE-US-00058 TABLE 58 (I-B-1-4) ##STR01401## No -E.sup.3-
-E.sup.4 1 --(CH.sub.2).sub.2-- --OH 2 --(CH.sub.2).sub.2-- --OMe 3
--(CH.sub.2).sub.2-- --NH.sub.2 4 --(CH.sub.2).sub.2-- --NHMe 5
--(CH.sub.2).sub.2-- --NHEt 6 --(CH.sub.2).sub.2-- --NHPr 7
--(CH.sub.2).sub.2-- --NH-i-Pr 8 --(CH.sub.2).sub.2-- --NMe.sub.2 9
--(CH.sub.2).sub.2-- --NEt.sub.2 10 --(CH.sub.2).sub.2--
--NPr.sub.2 11 --(CH.sub.2).sub.2-- --N(i-Pr).sub.2 12
--(CH.sub.2).sub.2-- --NHPh 13 --(CH.sub.2).sub.2-- --NHBn 14
--(CH.sub.2).sub.2-- --NH-c-Pr 15 --(CH.sub.2).sub.2-- --NH-c-Bu 16
--(CH.sub.2).sub.2-- --NH-c-Pen 17 --(CH.sub.2).sub.2-- --NH-c-Hex
18 --(CH.sub.2).sub.2-- --NH--(CH.sub.2).sub.2--OH 19
--(CH.sub.2).sub.2-- --NHCH(Me)(OH) 20 --(CH.sub.2).sub.2--
--N(Me)(c-Pen) 21 --(CH.sub.2).sub.2-- --N(Me)(c-Hex) 22
--(CH.sub.2).sub.2-- --N(Me)(Ph) 23 --(CH.sub.2).sub.2--
##STR01402## 24 --(CH.sub.2).sub.2-- ##STR01403## 25
--(CH.sub.2).sub.2-- ##STR01404## 26 --(CH.sub.2).sub.2--
##STR01405## 27 --(CH.sub.2).sub.2-- ##STR01406## 28
--(CH.sub.2).sub.2-- ##STR01407## 29 --(CH.sub.2).sub.3-- --OH 30
--(CH.sub.2).sub.3-- --OMe 31 --(CH.sub.2).sub.3-- --NH.sub.2 32
--(CH.sub.2).sub.3-- --NHMe 33 --(CH.sub.2).sub.3-- --NHEt 34
--(CH.sub.2).sub.3-- --NHPr 35 --(CH.sub.2).sub.3-- --NH-i-Pr 36
--(CH.sub.2).sub.3-- --NMe.sub.2 37 --(CH.sub.2).sub.3--
--NEt.sub.2 38 --(CH.sub.2).sub.3-- --NPr.sub.2 39
--(CH.sub.2).sub.3-- --N(i-Pr).sub.2 40 --(CH.sub.2).sub.3-- --NHPh
41 --(CH.sub.2).sub.3-- --NHBn 42 --(CH.sub.2).sub.3-- --NH-c-Pr 43
--(CH.sub.2).sub.3-- --NH-c-Bu 44 --(CH.sub.2).sub.3-- --NH-c-Pen
45 --(CH.sub.2).sub.3-- --NH-c-Hex 46 --(CH.sub.2).sub.3--
--NH--(CH.sub.2).sub.2--OH 47 --(CH.sub.2).sub.3-- --NHCH(Me)(OH)
48 --(CH.sub.2).sub.3-- --N(Me)(c-Pen) 49 --(CH.sub.2).sub.3--
--N(Me)(c-Hex) 50 --(CH.sub.2).sub.3-- --N(Me)(Ph) 51
--(CH.sub.2).sub.3-- ##STR01408## 52 --(CH.sub.2).sub.3--
##STR01409## 53 --(CH.sub.2).sub.3-- ##STR01410## 54
--(CH.sub.2).sub.3-- ##STR01411## 55 --(CH.sub.2).sub.3--
##STR01412## 56 --(CH.sub.2).sub.3-- ##STR01413## 57
--(CH.sub.2).sub.4-- --OH 58 --(CH.sub.2).sub.4-- --OMe 59
--(CH.sub.2).sub.4-- --NH.sub.2 60 --(CH.sub.2).sub.4-- --NHMe 61
--(CH.sub.2).sub.4-- --NHEt 62 --(CH.sub.2).sub.4-- --NHPr 63
--(CH.sub.2).sub.4-- --NH-i-Pr 64 --(CH.sub.2).sub.4-- --NMe.sub.2
65 --(CH.sub.2).sub.4-- --NEt.sub.2 66 --(CH.sub.2).sub.4--
--NPr.sub.2 67 --(CH.sub.2).sub.4-- --N(i-Pr).sub.2 68
--(CH.sub.2).sub.4-- --NHPh 69 --(CH.sub.2).sub.4-- --NHBn 70
--(CH.sub.2).sub.4-- --NH-c-Pr 71 --(CH.sub.2).sub.4-- --NH-c-Bu 72
--(CH.sub.2).sub.4-- --NH-c-Pen 73 --(CH.sub.2).sub.4-- --NH-c-Hex
74 --(CH.sub.2).sub.4-- --NH--(CH.sub.2).sub.2--OH 75
--(CH.sub.2).sub.4-- --NHCH(Me)(OH) 76 --(CH.sub.2).sub.4--
--N(Me)(c-Pen) 77 --(CH.sub.2).sub.4-- --N(Me)(c-Hex) 78
--(CH.sub.2).sub.4-- --N(Me)(Ph) 79 --(CH.sub.2).sub.4--
##STR01414## 80 --(CH.sub.2).sub.4-- ##STR01415## 81
--(CH.sub.2).sub.4-- ##STR01416## 82 --(CH.sub.2).sub.4--
##STR01417## 83 --(CH.sub.2).sub.4-- ##STR01418## 84
--(CH.sub.2).sub.4-- ##STR01419##
TABLE-US-00059 TABLE 59 (I-B-1-5) ##STR01420## No -E.sup.3-
-E.sup.4 1 --(CH.sub.2).sub.2-- --OH 2 --(CH.sub.2).sub.2-- --OMe 3
--(CH.sub.2).sub.2-- --NH.sub.2 4 --(CH.sub.2).sub.2-- --NHMe 5
--(CH.sub.2).sub.2-- --NHEt 6 --(CH.sub.2).sub.2-- --NHPr 7
--(CH.sub.2).sub.2-- --NH-i-Pr 8 --(CH.sub.2).sub.2-- --NMe.sub.2 9
--(CH.sub.2).sub.2-- --NEt.sub.2 10 --(CH.sub.2).sub.2--
--NPr.sub.2 11 --(CH.sub.2).sub.2-- --N(i-Pr).sub.2 12
--(CH.sub.2).sub.2-- --NHPh 13 --(CH.sub.2).sub.2-- --NHBn 14
--(CH.sub.2).sub.2-- --NH-c-Pr 15 --(CH.sub.2).sub.2-- --NH-c-Bu 16
--(CH.sub.2).sub.2-- --NH-c-Pen 17 --(CH.sub.2).sub.2-- --NH-c-Hex
18 --(CH.sub.2).sub.2-- --NH--(CH.sub.2).sub.2--OH 19
--(CH.sub.2).sub.2-- --NHCH(Me)(OH) 20 --(CH.sub.2).sub.2--
--N(Me)(c-Pen) 21 --(CH.sub.2).sub.2-- --N(Me)(c-Hex) 22
--(CH.sub.2).sub.2-- --N(Me)(Ph) 23 --(CH.sub.2).sub.2--
##STR01421## 24 --(CH.sub.2).sub.2-- ##STR01422## 25
--(CH.sub.2).sub.2-- ##STR01423## 26 --(CH.sub.2).sub.2--
##STR01424## 27 --(CH.sub.2).sub.2-- ##STR01425## 28
--(CH.sub.2).sub.2-- ##STR01426## 29 --(CH.sub.2).sub.3-- --OH 30
--(CH.sub.2).sub.3-- --OMe 31 --(CH.sub.2).sub.3-- --NH.sub.2 32
--(CH.sub.2).sub.3-- --NHMe 33 --(CH.sub.2).sub.3-- --NHEt 34
--(CH.sub.2).sub.3-- --NHPr 35 --(CH.sub.2).sub.3-- --NH-i-Pr 36
--(CH.sub.2).sub.3-- --NMe.sub.2 37 --(CH.sub.2).sub.3--
--NEt.sub.2 38 --(CH.sub.2).sub.3-- --NPr.sub.2 39
--(CH.sub.2).sub.3-- --N(i-Pr).sub.2 40 --(CH.sub.2).sub.3-- --NHPh
41 --(CH.sub.2).sub.3-- --NHBn 42 --(CH.sub.2).sub.3-- --NH-c-Pr 43
--(CH.sub.2).sub.3-- --NH-c-Bu 44 --(CH.sub.2).sub.3-- --NH-c-Pen
45 --(CH.sub.2).sub.3-- --NH-c-Hex 46 --(CH.sub.2).sub.3--
--NH--(CH.sub.2).sub.2--OH 47 --(CH.sub.2).sub.3-- --NHCH(Me)(OH)
48 --(CH.sub.2).sub.3-- --N(Me)(c-Pen) 49 --(CH.sub.2).sub.3--
--N(Me)(c-Hex) 50 --(CH.sub.2).sub.3-- --N(Me)(Ph) 51
--(CH.sub.2).sub.3-- ##STR01427## 52 --(CH.sub.2).sub.3--
##STR01428## 53 --(CH.sub.2).sub.3-- ##STR01429## 54
--(CH.sub.2).sub.3-- ##STR01430## 55 --(CH.sub.2).sub.3--
##STR01431## 56 --(CH.sub.2).sub.3-- ##STR01432## 57
--(CH.sub.2).sub.4-- --OH 58 --(CH.sub.2).sub.4-- --OMe 59
--(CH.sub.2).sub.4-- --NH.sub.2 60 --(CH.sub.2).sub.4-- --NHMe 61
--(CH.sub.2).sub.4-- --NHEt 62 --(CH.sub.2).sub.4-- --NHPr 63
--(CH.sub.2).sub.4-- --NH-i-Pr 64 --(CH.sub.2).sub.4-- --NMe.sub.2
65 --(CH.sub.2).sub.4-- --NEt.sub.2 66 --(CH.sub.2).sub.4--
--NPr.sub.2 67 --(CH.sub.2).sub.4-- --N(i-Pr).sub.2 68
--(CH.sub.2).sub.4-- --NHPh 69 --(CH.sub.2).sub.4-- --NHBn 70
--(CH.sub.2).sub.4-- --NH-c-Pr 71 --(CH.sub.2).sub.4-- --NH-c-Bu 72
--(CH.sub.2).sub.4-- --NH-c-Pen 73 --(CH.sub.2).sub.4-- --NH-c-Hex
74 --(CH.sub.2).sub.4-- --NH--(CH.sub.2).sub.2--OH 75
--(CH.sub.2).sub.4-- --NHCH(Me)(OH) 76 --(CH.sub.2).sub.4--
--N(Me)(c-Pen) 77 --(CH.sub.2).sub.4-- --N(Me)(c-Hex) 78
--(CH.sub.2).sub.4-- --N(Me)(Ph) 79 --(CH.sub.2).sub.4--
##STR01433## 80 --(CH.sub.2).sub.4-- ##STR01434## 81
--(CH.sub.2).sub.4-- ##STR01435## 82 --(CH.sub.2).sub.4--
##STR01436## 83 --(CH.sub.2).sub.4-- ##STR01437## 84
--(CH.sub.2).sub.4-- ##STR01438##
TABLE-US-00060 TABLE 60 (I-B-1-6) ##STR01439## No -E.sup.1-
-E.sup.3-E.sup.4 1 --CH.sub.2-- Me 2 --CH.sub.2-- Et 3 --CH.sub.2--
Pr 4 --CH.sub.2-- i-Pr 5 --CH.sub.2-- Ph 6 --CH.sub.2-- Bn 7
--CH.sub.2-- c-Pr 8 --CH.sub.2-- c-Bu 9 --CH.sub.2-- c-Pen 10
--CH.sub.2-- c-Hex 11 --CH.sub.2-- ##STR01440## 12 --CH.sub.2--
##STR01441## 13 --CH.sub.2-- ##STR01442## 14 --CH.sub.2--
##STR01443## 15 --CH.sub.2-- ##STR01444## 16 --CH.sub.2--
##STR01445## 17 --(CH.sub.2).sub.2-- Me 18 --(CH.sub.2).sub.2-- Et
19 --(CH.sub.2).sub.2-- Pr 20 --(CH.sub.2).sub.2-- i-Pr 21
--(CH.sub.2).sub.2-- Ph 22 --(CH.sub.2).sub.2-- Bn 23
--(CH.sub.2).sub.2-- c-Pr 24 --(CH.sub.2).sub.2-- c-Bu 25
--(CH.sub.2).sub.2-- c-Pen 26 --(CH.sub.2).sub.2-- c-Hex 27
--(CH.sub.2).sub.2-- ##STR01446## 28 --(CH.sub.2).sub.2--
##STR01447## 29 --(CH.sub.2).sub.2-- ##STR01448## 30
--(CH.sub.2).sub.2-- ##STR01449## 31 --(CH.sub.2).sub.2--
##STR01450## 32 --(CH.sub.2).sub.2-- ##STR01451##
TABLE-US-00061 TABLE 61 (I-B-1-7) ##STR01452## No -E.sup.1-
-E.sup.3-E.sup.4 1 --CH.sub.2-- Me 2 --CH.sub.2-- Et 3 --CH.sub.2--
Pr 4 --CH.sub.2-- i-Pr 5 --CH.sub.2-- Ph 6 --CH.sub.2-- Bn 7
--CH.sub.2-- c-Pr 8 --CH.sub.2-- c-Bu 9 --CH.sub.2-- c-Pen 10
--CH.sub.2-- c-Hex 11 --CH.sub.2-- ##STR01453## 12 --CH.sub.2--
##STR01454## 13 --CH.sub.2-- ##STR01455## 14 --CH.sub.2--
##STR01456## 15 --CH.sub.2-- ##STR01457## 16 --CH.sub.2--
##STR01458## 17 --(CH.sub.2).sub.2-- Me 18 --(CH.sub.2).sub.2-- Et
19 --(CH.sub.2).sub.2-- Pr 20 --(CH.sub.2).sub.2-- i-Pr 21
--(CH.sub.2).sub.2-- Ph 22 --(CH.sub.2).sub.2-- Bn 23
--(CH.sub.2).sub.2-- c-Pr 24 --(CH.sub.2).sub.2-- c-Bu 25
--(CH.sub.2).sub.2-- c-Pen 26 --(CH.sub.2).sub.2-- c-Hex 27
--(CH.sub.2).sub.2-- ##STR01459## 28 --(CH.sub.2).sub.2--
##STR01460## 29 --(CH.sub.2).sub.2-- ##STR01461## 30
--(CH.sub.2).sub.2-- ##STR01462## 31 --(CH.sub.2).sub.2--
##STR01463## 32 --(CH.sub.2).sub.2-- ##STR01464##
TABLE-US-00062 TABLE 62 (I-B-1-8) ##STR01465## No -E.sup.3-
-E.sup.4 1 --(CH.sub.2).sub.2-- --OH 2 --(CH.sub.2).sub.2-- --OMe 3
--(CH.sub.2).sub.2-- --NH.sub.2 4 --(CH.sub.2).sub.2-- --NHMe 5
--(CH.sub.2).sub.2-- --NHEt 6 --(CH.sub.2).sub.2-- --NHPr 7
--(CH.sub.2).sub.2-- --NH-i-Pr 8 --(CH.sub.2).sub.2-- --NMe.sub.2 9
--(CH.sub.2).sub.2-- --NEt.sub.2 10 --(CH.sub.2).sub.2--
--NPr.sub.2 11 --(CH.sub.2).sub.2-- --N(i-Pr).sub.2 12
--(CH.sub.2).sub.2-- --NHPh 13 --(CH.sub.2).sub.2-- --NHBn 14
--(CH.sub.2).sub.2-- --NH-c-Pr 15 --(CH.sub.2).sub.2-- --NH-c-Bu 16
--(CH.sub.2).sub.2-- --NH-c-Pen 17 --(CH.sub.2).sub.2-- --NH-c-Hex
18 --(CH.sub.2).sub.2-- --NH--(CH.sub.2).sub.2--OH 19
--(CH.sub.2).sub.2-- --NHCH(Me)(OH) 20 --(CH.sub.2).sub.2--
--N(Me)(c-Pen) 21 --(CH.sub.2).sub.2-- --N(Me)(c-Hex) 22
--(CH.sub.2).sub.2-- --N(Me)(Ph) 23 --(CH.sub.2).sub.2--
##STR01466## 24 --(CH.sub.2).sub.2-- ##STR01467## 25
--(CH.sub.2).sub.2-- ##STR01468## 26 --(CH.sub.2).sub.2--
##STR01469## 27 --(CH.sub.2).sub.2-- ##STR01470## 28
--(CH.sub.2).sub.2-- ##STR01471## 29 --(CH.sub.2).sub.3-- --OH 30
--(CH.sub.2).sub.3-- --OMe 31 --(CH.sub.2).sub.3-- --NH.sub.2 32
--(CH.sub.2).sub.3-- --NHMe 33 --(CH.sub.2).sub.3-- --NHEt 34
--(CH.sub.2).sub.3-- --NHPr 35 --(CH.sub.2).sub.3-- --NH-i-Pr 36
--(CH.sub.2).sub.3-- --NMe.sub.2 37 --(CH.sub.2).sub.3--
--NEt.sub.2 38 --(CH.sub.2).sub.3-- --NPr.sub.2 39
--(CH.sub.2).sub.3-- --N(i-Pr).sub.2 40 --(CH.sub.2).sub.3-- --NHPh
41 --(CH.sub.2).sub.3-- --NHBn 42 --(CH.sub.2).sub.3-- --NH-c-Pr 43
--(CH.sub.2).sub.3-- --NH-c-Bu 44 --(CH.sub.2).sub.3-- --NH-c-Pen
45 --(CH.sub.2).sub.3-- --NH-c-Hex 46 --(CH.sub.2).sub.3--
--NH--(CH.sub.2).sub.2--OH 47 --(CH.sub.2).sub.3-- --NHCH(Me)(OH)
48 --(CH.sub.2).sub.3-- --N(Me)(c-Pen) 49 --(CH.sub.2).sub.3--
--N(Me)(c-Hex) 50 --(CH.sub.2).sub.3-- --N(Me)(Ph) 51
--(CH.sub.2).sub.3-- ##STR01472## 52 --(CH.sub.2).sub.3--
##STR01473## 53 --(CH.sub.2).sub.3-- ##STR01474## 54
--(CH.sub.2).sub.3-- ##STR01475## 55 --(CH.sub.2).sub.3--
##STR01476## 56 --(CH.sub.2).sub.3-- ##STR01477## 57
--(CH.sub.2).sub.4-- --OH 58 --(CH.sub.2).sub.4-- --OMe 59
--(CH.sub.2).sub.4-- --NH.sub.2 60 --(CH.sub.2).sub.4-- --NHMe 61
--(CH.sub.2).sub.4-- --NHEt 62 --(CH.sub.2).sub.4-- --NHPr 63
--(CH.sub.2).sub.4-- --NH-i-Pr 64 --(CH.sub.2).sub.4-- --NMe.sub.2
65 --(CH.sub.2).sub.4-- --NEt.sub.2 66 --(CH.sub.2).sub.4--
--NPr.sub.2 67 --(CH.sub.2).sub.4-- --N(i-Pr).sub.2 68
--(CH.sub.2).sub.4-- --NHPh 69 --(CH.sub.2).sub.4-- --NHBn 70
--(CH.sub.2).sub.4-- --NH-c-Pr 71 --(CH.sub.2).sub.4-- --NH-c-Bu 72
--(CH.sub.2).sub.4-- --NH-c-Pen 73 --(CH.sub.2).sub.4-- --NH-c-Hex
74 --(CH.sub.2).sub.4-- --NH--(CH.sub.2).sub.2--OH 75
--(CH.sub.2).sub.4-- --NHCH(Me)(OH) 76 --(CH.sub.2).sub.4--
--N(Me)(c-Pen) 77 --(CH.sub.2).sub.4-- --N(Me)(c-Hex) 78
--(CH.sub.2).sub.4-- --N(Me)(Ph) 79 --(CH.sub.2).sub.4--
##STR01478## 80 --(CH.sub.2).sub.4-- ##STR01479## 81
--(CH.sub.2).sub.4-- ##STR01480## 82 --(CH.sub.2).sub.4--
##STR01481## 83 --(CH.sub.2).sub.4-- ##STR01482## 84
--(CH.sub.2).sub.4-- ##STR01483##
TABLE-US-00063 TABLE 63 (I-B-1-9) ##STR01484## No -E.sup.1-
-E.sup.3-E.sup.4 1 --CH.sub.2-- Me 2 --CH.sub.2-- Et 3 --CH.sub.2--
Pr 4 --CH.sub.2-- i-Pr 5 --CH.sub.2-- Ph 6 --CH.sub.2-- Bn 7
--CH.sub.2-- c-Pr 8 --CH.sub.2-- c-Bu 9 --CH.sub.2-- c-Pen 10
--CH.sub.2-- c-Hex 11 --CH.sub.2-- ##STR01485## 12 --CH.sub.2--
##STR01486## 13 --CH.sub.2-- ##STR01487## 14 --CH.sub.2--
##STR01488## 15 --CH.sub.2-- ##STR01489## 16 --CH.sub.2--
##STR01490## 17 --(CH.sub.2).sub.2-- Me 18 --(CH.sub.2).sub.2-- Et
19 --(CH.sub.2).sub.2-- Pr 20 --(CH.sub.2).sub.2-- i-Pr 21
--(CH.sub.2).sub.2-- Ph 22 --(CH.sub.2).sub.2-- Bn 23
--(CH.sub.2).sub.2-- c-Pr 24 --(CH.sub.2).sub.2-- c-Bu 25
--(CH.sub.2).sub.2-- c-Pen 26 --(CH.sub.2).sub.2-- c-Hex 27
--(CH.sub.2).sub.2-- ##STR01491## 28 --(CH.sub.2).sub.2--
##STR01492## 29 --(CH.sub.2).sub.2-- ##STR01493## 30
--(CH.sub.2).sub.2-- ##STR01494## 31 --(CH.sub.2).sub.2--
##STR01495## 32 --(CH.sub.2).sub.2-- ##STR01496##
TABLE-US-00064 TABLE 64 (I-B-1-10) ##STR01497## No -E.sup.3-
-E.sup.4 1 --(CH.sub.2).sub.2-- --OH 2 --(CH.sub.2).sub.2-- --OMe 3
--(CH.sub.2).sub.2-- --NH.sub.2 4 --(CH.sub.2).sub.2-- --NHMe 5
--(CH.sub.2).sub.2-- --NHEt 6 --(CH.sub.2).sub.2-- --NHPr 7
--(CH.sub.2).sub.2-- --NH-i-Pr 8 --(CH.sub.2).sub.2-- --NMe.sub.2 9
--(CH.sub.2).sub.2-- --NEt.sub.2 10 --(CH.sub.2).sub.2--
--NPr.sub.2 11 --(CH.sub.2).sub.2-- --N(i-Pr).sub.2 12
--(CH.sub.2).sub.2-- --NHPh 13 --(CH.sub.2).sub.2-- --NHBn 14
--(CH.sub.2).sub.2-- --NH-c-Pr 15 --(CH.sub.2).sub.2-- --NH-c-Bu 16
--(CH.sub.2).sub.2-- --NH-c-Pen 17 --(CH.sub.2).sub.2-- --NH-c-Hex
18 --(CH.sub.2).sub.2-- --NH--(CH.sub.2).sub.2--OH 19
--(CH.sub.2).sub.2-- --NHCH(Me)(OH) 20 --(CH.sub.2).sub.2--
--N(Me)(c-Pen) 21 --(CH.sub.2).sub.2-- --N(Me)(c-Hex) 22
--(CH.sub.2).sub.2-- --N(Me)(Ph) 23 --(CH.sub.2).sub.2--
##STR01498## 24 --(CH.sub.2).sub.2-- ##STR01499## 25
--(CH.sub.2).sub.2-- ##STR01500## 26 --(CH.sub.2).sub.2--
##STR01501## 27 --(CH.sub.2).sub.2-- ##STR01502## 28
--(CH.sub.2).sub.2-- ##STR01503## 29 --(CH.sub.2).sub.3-- --OH 30
--(CH.sub.2).sub.3-- --OMe 31 --(CH.sub.2).sub.3-- --NH.sub.2 32
--(CH.sub.2).sub.3-- --NHMe 33 --(CH.sub.2).sub.3-- --NHEt 34
--(CH.sub.2).sub.3-- --NHPr 35 --(CH.sub.2).sub.3-- --NH-i-Pr 36
--(CH.sub.2).sub.3-- --NMe.sub.2 37 --(CH.sub.2).sub.3--
--NEt.sub.2 38 --(CH.sub.2).sub.3-- --NPr.sub.2 39
--(CH.sub.2).sub.3-- --N(i-Pr).sub.2 40 --(CH.sub.2).sub.3-- --NHPh
41 --(CH.sub.2).sub.3-- --NHBn 42 --(CH.sub.2).sub.3-- --NH-c-Pr 43
--(CH.sub.2).sub.3-- --NH-c-Bu 44 --(CH.sub.2).sub.3-- --NH-c-Pen
45 --(CH.sub.2).sub.3-- --NH-c-Hex 46 --(CH.sub.2).sub.3--
--NH--(CH.sub.2).sub.2--OH 47 --(CH.sub.2).sub.3-- --NHCH(Me)(OH)
48 --(CH.sub.2).sub.3-- --N(Me)(c-Pen) 49 --(CH.sub.2).sub.3--
--N(Me)(c-Hex) 50 --(CH.sub.2).sub.3-- --N(Me)(Ph) 51
--(CH.sub.2).sub.3-- ##STR01504## 52 --(CH.sub.2).sub.3--
##STR01505## 53 --(CH.sub.2).sub.3-- ##STR01506## 54
--(CH.sub.2).sub.3-- ##STR01507## 55 --(CH.sub.2).sub.3--
##STR01508## 56 --(CH.sub.2).sub.3-- ##STR01509## 57
--(CH.sub.2).sub.4-- --OH 58 --(CH.sub.2).sub.4-- --OMe 59
--(CH.sub.2).sub.4-- --NH.sub.2 60 --(CH.sub.2).sub.4-- --NHMe 61
--(CH.sub.2).sub.4-- --NHEt 62 --(CH.sub.2).sub.4-- --NHPr 63
--(CH.sub.2).sub.4-- --NH-i-Pr 64 --(CH.sub.2).sub.4-- --NMe.sub.2
65 --(CH.sub.2).sub.4-- --NEt.sub.2 66 --(CH.sub.2).sub.4--
--NPr.sub.2 67 --(CH.sub.2).sub.4-- --N(i-Pr).sub.2 68
--(CH.sub.2).sub.4-- --NHPh 69 --(CH.sub.2).sub.4-- --NHBn 70
--(CH.sub.2).sub.4-- --NH-c-Pr 71 --(CH.sub.2).sub.4-- --NH-c-Bu 72
--(CH.sub.2).sub.4-- --NH-c-Pen 73 --(CH.sub.2).sub.4-- --NH-c-Hex
74 --(CH.sub.2).sub.4-- --NH--(CH.sub.2).sub.2--OH 75
--(CH.sub.2).sub.4-- --NHCH(Me)(OH) 76 --(CH.sub.2).sub.4--
--N(Me)(c-Pen) 77 --(CH.sub.2).sub.4-- --N(Me)(c-Hex) 78
--(CH.sub.2).sub.4-- --N(Me)(Ph) 79 --(CH.sub.2).sub.4--
##STR01510## 80 --(CH.sub.2).sub.4-- ##STR01511## 81
--(CH.sub.2).sub.4-- ##STR01512## 82 --(CH.sub.2).sub.4--
##STR01513## 83 --(CH.sub.2).sub.4-- ##STR01514## 84
--(CH.sub.2).sub.4-- ##STR01515##
TABLE-US-00065 TABLE 65 (I-B-1-11) ##STR01516## No -E.sup.3-
-E.sup.4 1 --(CH.sub.2).sub.2-- --OH 2 --(CH.sub.2).sub.2-- --OMe 3
--(CH.sub.2).sub.2-- --NH.sub.2 4 --(CH.sub.2).sub.2-- --NHMe 5
--(CH.sub.2).sub.2-- --NHEt 6 --(CH.sub.2).sub.2-- --NHPr 7
--(CH.sub.2).sub.2-- --NH-i-Pr 8 --(CH.sub.2).sub.2-- --NMe.sub.2 9
--(CH.sub.2).sub.2-- --NEt.sub.2 10 --(CH.sub.2).sub.2--
--NPr.sub.2 11 --(CH.sub.2).sub.2-- --N(i-Pr).sub.2 12
--(CH.sub.2).sub.2-- --NHPh 13 --(CH.sub.2).sub.2-- --NHBn 14
--(CH.sub.2).sub.2-- --NH-c-Pr 15 --(CH.sub.2).sub.2-- --NH-c-Bu 16
--(CH.sub.2).sub.2-- --NH-c-Pen 17 --(CH.sub.2).sub.2-- --NH-c-Hex
18 --(CH.sub.2).sub.2-- --NH--(CH.sub.2).sub.2--OH 19
--(CH.sub.2).sub.2-- --NHCH(Me)(OH) 20 --(CH.sub.2).sub.2--
--N(Me)(c-Pen) 21 --(CH.sub.2).sub.2-- --N(Me)(c-Hex) 22
--(CH.sub.2).sub.2-- --N(Me)(Ph) 23 --(CH.sub.2).sub.2--
##STR01517## 24 --(CH.sub.2).sub.2-- ##STR01518## 25
--(CH.sub.2).sub.2-- ##STR01519## 26 --(CH.sub.2).sub.2--
##STR01520## 27 --(CH.sub.2).sub.2-- ##STR01521## 28
--(CH.sub.2).sub.2-- ##STR01522## 29 --(CH.sub.2).sub.3-- --OH 30
--(CH.sub.2).sub.3-- --OMe 31 --(CH.sub.2).sub.3-- --NH.sub.2 32
--(CH.sub.2).sub.3-- --NHMe 33 --(CH.sub.2).sub.3-- --NHEt 34
--(CH.sub.2).sub.3-- --NHPr 35 --(CH.sub.2).sub.3-- --NH-i-Pr 36
--(CH.sub.2).sub.3-- --NMe.sub.2 37 --(CH.sub.2).sub.3--
--NEt.sub.2 38 --(CH.sub.2).sub.3-- --NPr.sub.2 39
--(CH.sub.2).sub.3-- --N(i-Pr).sub.2 40 --(CH.sub.2).sub.3-- --NHPh
41 --(CH.sub.2).sub.3-- --NHBn 42 --(CH.sub.2).sub.3-- --NH-c-Pr 43
--(CH.sub.2).sub.3-- --NH-c-Bu 44 --(CH.sub.2).sub.3-- --NH-c-Pen
45 --(CH.sub.2).sub.3-- --NH-c-Hex 46 --(CH.sub.2).sub.3--
--NH--(CH.sub.2).sub.2--OH 47 --(CH.sub.2).sub.3-- --NHCH(Me)(OH)
48 --(CH.sub.2).sub.3-- --N(Me)(c-Pen) 49 --(CH.sub.2).sub.3--
--N(Me)(c-Hex) 50 --(CH.sub.2).sub.3-- --N(Me)(Ph) 51
--(CH.sub.2).sub.3-- ##STR01523## 52 --(CH.sub.2).sub.3--
##STR01524## 53 --(CH.sub.2).sub.3-- ##STR01525## 54
--(CH.sub.2).sub.3-- ##STR01526## 55 --(CH.sub.2).sub.3--
##STR01527## 56 --(CH.sub.2).sub.3-- ##STR01528## 57
--(CH.sub.2).sub.4-- --OH 58 --(CH.sub.2).sub.4-- --OMe 59
--(CH.sub.2).sub.4-- --NH.sub.2 60 --(CH.sub.2).sub.4-- --NHMe 61
--(CH.sub.2).sub.4-- --NHEt 62 --(CH.sub.2).sub.4-- --NHPr 63
--(CH.sub.2).sub.4-- --NH-i-Pr 64 --(CH.sub.2).sub.4-- --NMe.sub.2
65 --(CH.sub.2).sub.4-- --NEt.sub.2 66 --(CH.sub.2).sub.4--
--NPr.sub.2 67 --(CH.sub.2).sub.4-- --N(i-Pr).sub.2 68
--(CH.sub.2).sub.4-- --NHPh 69 --(CH.sub.2).sub.4-- --NHBn 70
--(CH.sub.2).sub.4-- --NH-c-Pr 71 --(CH.sub.2).sub.4-- --NH-c-Bu 72
--(CH.sub.2).sub.4-- --NH-c-Pen 73 --(CH.sub.2).sub.4-- --NH-c-Hex
74 --(CH.sub.2).sub.4-- --NH--(CH.sub.2).sub.2--OH 75
--(CH.sub.2).sub.4-- --NHCH(Me)(OH) 76 --(CH.sub.2).sub.4--
--N(Me)(c-Pen) 77 --(CH.sub.2).sub.4-- --N(Me)(c-Hex) 78
--(CH.sub.2).sub.4-- --N(Me)(Ph) 79 --(CH.sub.2).sub.4--
##STR01529## 80 --(CH.sub.2).sub.4-- ##STR01530## 81
--(CH.sub.2).sub.4-- ##STR01531## 82 --(CH.sub.2).sub.4--
##STR01532## 83 --(CH.sub.2).sub.4-- ##STR01533## 84
--(CH.sub.2).sub.4-- ##STR01534##
TABLE-US-00066 TABLE 66 (I-B-1-12) ##STR01535## No -E.sup.3-
-E.sup.4 1 --(CH.sub.2).sub.2-- --OH 2 --(CH.sub.2).sub.2-- --OMe 3
--(CH.sub.2).sub.2-- --NH.sub.2 4 --(CH.sub.2).sub.2-- --NHMe 5
--(CH.sub.2).sub.2-- --NHEt 6 --(CH.sub.2).sub.2-- --NHPr 7
--(CH.sub.2).sub.2-- --NH-i-Pr 8 --(CH.sub.2).sub.2-- --NMe.sub.2 9
--(CH.sub.2).sub.2-- --NEt.sub.2 10 --(CH.sub.2).sub.2--
--NPr.sub.2 11 --(CH.sub.2).sub.2-- --N(i-Pr).sub.2 12
--(CH.sub.2).sub.2-- --NHPh 13 --(CH.sub.2).sub.2-- --NHBn 14
--(CH.sub.2).sub.2-- --NH-c-Pr 15 --(CH.sub.2).sub.2-- --NH-c-Bu 16
--(CH.sub.2).sub.2-- --NH-c-Pen 17 --(CH.sub.2).sub.2-- --NH-c-Hex
18 --(CH.sub.2).sub.2-- --NH--(CH.sub.2).sub.2--OH 19
--(CH.sub.2).sub.2-- --NHCH(Me)(OH) 20 --(CH.sub.2).sub.2--
--N(Me)(c-Pen) 21 --(CH.sub.2).sub.2-- --N(Me)(c-Hex) 22
--(CH.sub.2).sub.2-- --N(Me)(Ph) 23 --(CH.sub.2).sub.2--
##STR01536## 24 --(CH.sub.2).sub.2-- ##STR01537## 25
--(CH.sub.2).sub.2-- ##STR01538## 26 --(CH.sub.2).sub.2--
##STR01539## 27 --(CH.sub.2).sub.2-- ##STR01540## 28
--(CH.sub.2).sub.2-- ##STR01541## 29 --(CH.sub.2).sub.3-- --OH 30
--(CH.sub.2).sub.3-- --OMe 31 --(CH.sub.2).sub.3-- --NH.sub.2 32
--(CH.sub.2).sub.3-- --NHMe 33 --(CH.sub.2).sub.3-- --NHEt 34
--(CH.sub.2).sub.3-- --NHPr 35 --(CH.sub.2).sub.3-- --NH-i-Pr 36
--(CH.sub.2).sub.3-- --NMe.sub.2 37 --(CH.sub.2).sub.3--
--NEt.sub.2 38 --(CH.sub.2).sub.3-- --NPr.sub.2 39
--(CH.sub.2).sub.3-- --N(i-Pr).sub.2 40 --(CH.sub.2).sub.3-- --NHPh
41 --(CH.sub.2).sub.3-- --NHBn 42 --(CH.sub.2).sub.3-- --NH-c-Pr 43
--(CH.sub.2).sub.3-- --NH-c-Bu 44 --(CH.sub.2).sub.3-- --NH-c-Pen
45 --(CH.sub.2).sub.3-- --NH-c-Hex 46 --(CH.sub.2).sub.3--
--NH--(CH.sub.2).sub.2--OH 47 --(CH.sub.2).sub.3-- --NHCH(Me)(OH)
48 --(CH.sub.2).sub.3-- --N(Me)(c-Pen) 49 --(CH.sub.2).sub.3--
--N(Me)(c-Hex) 50 --(CH.sub.2).sub.3-- --N(Me)(Ph) 51
--(CH.sub.2).sub.3-- ##STR01542## 52 --(CH.sub.2).sub.3--
##STR01543## 53 --(CH.sub.2).sub.3-- ##STR01544## 54
--(CH.sub.2).sub.3-- ##STR01545## 55 --(CH.sub.2).sub.3--
##STR01546## 56 --(CH.sub.2).sub.3-- ##STR01547## 57
--(CH.sub.2).sub.4-- --OH 58 --(CH.sub.2).sub.4-- --OMe 59
--(CH.sub.2).sub.4-- --NH.sub.2 60 --(CH.sub.2).sub.4-- --NHMe 61
--(CH.sub.2).sub.4-- --NHEt 62 --(CH.sub.2).sub.4-- --NHPr 63
--(CH.sub.2).sub.4-- --NH-i-Pr 64 --(CH.sub.2).sub.4-- --NMe.sub.2
65 --(CH.sub.2).sub.4-- --NEt.sub.2 66 --(CH.sub.2).sub.4--
--NPr.sub.2 67 --(CH.sub.2).sub.4-- --N(i-Pr).sub.2 68
--(CH.sub.2).sub.4-- --NHPh 69 --(CH.sub.2).sub.4-- --NHBn 70
--(CH.sub.2).sub.4-- --NH-c-Pr 71 --(CH.sub.2).sub.4-- --NH-c-Bu 72
--(CH.sub.2).sub.4-- --NH-c-Pen 73 --(CH.sub.2).sub.4-- --NH-c-Hex
74 --(CH.sub.2).sub.4-- --NH--(CH.sub.2).sub.2--OH 75
--(CH.sub.2).sub.4-- --NHCH(Me)(OH) 76 --(CH.sub.2).sub.4--
--N(Me)(c-Pen) 77 --(CH.sub.2).sub.4-- --N(Me)(c-Hex) 78
--(CH.sub.2).sub.4-- --N(Me)(Ph) 79 --(CH.sub.2).sub.4--
##STR01548## 80 --(CH.sub.2).sub.4-- ##STR01549## 81
--(CH.sub.2).sub.4-- ##STR01550## 82 --(CH.sub.2).sub.4--
##STR01551## 83 --(CH.sub.2).sub.4-- ##STR01552## 84
--(CH.sub.2).sub.4-- ##STR01553##
TABLE-US-00067 TABLE 67 (I-B-1-13) ##STR01554## No -E.sup.1-
-E.sup.3-E.sup.4 1 --CH.sub.2-- Me 2 --CH.sub.2-- Et 3 --CH.sub.2--
Pr 4 --CH.sub.2-- i-Pr 5 --CH.sub.2-- Ph 6 --CH.sub.2-- Bn 7
--CH.sub.2-- c-Pr 8 --CH.sub.2-- c-Bu 9 --CH.sub.2-- c-Pen 10
--CH.sub.2-- c-Hex 11 --CH.sub.2-- ##STR01555## 12 --CH.sub.2--
##STR01556## 13 --CH.sub.2-- ##STR01557## 14 --CH.sub.2--
##STR01558## 15 --CH.sub.2-- ##STR01559## 16 --CH.sub.2--
##STR01560## 17 --(CH.sub.2).sub.2-- Me 18 --(CH.sub.2).sub.2-- Et
19 --(CH.sub.2).sub.2-- Pr 20 --(CH.sub.2).sub.2-- i-Pr 21
--(CH.sub.2).sub.2-- Ph 22 --(CH.sub.2).sub.2-- Bn 23
--(CH.sub.2).sub.2-- c-Pr 24 --(CH.sub.2).sub.2-- c-Bu 25
--(CH.sub.2).sub.2-- c-Pen 26 --(CH.sub.2).sub.2-- c-Hex 27
--(CH.sub.2).sub.2-- ##STR01561## 28 --(CH.sub.2).sub.2--
##STR01562## 29 --(CH.sub.2).sub.2-- ##STR01563## 30
--(CH.sub.2).sub.2-- ##STR01564## 31 --(CH.sub.2).sub.2--
##STR01565## 32 --(CH.sub.2).sub.2-- ##STR01566## 33
--(CH.sub.2).sub.3-- Me 34 --(CH.sub.2).sub.3-- Et 35
--(CH.sub.2).sub.3-- Pr 36 --(CH.sub.2).sub.3-- i-Pr 37
--(CH.sub.2).sub.3-- Ph 38 --(CH.sub.2).sub.3-- Bn 39
--(CH.sub.2).sub.3-- c-Pr 40 --(CH.sub.2).sub.3-- c-Bu 41
--(CH.sub.2).sub.3-- c-Pen 42 --(CH.sub.2).sub.3-- c-Hex 43
--(CH.sub.2).sub.3-- ##STR01567## 44 --(CH.sub.2).sub.3--
##STR01568## 45 --(CH.sub.2).sub.3-- ##STR01569## 46
--(CH.sub.2).sub.3-- ##STR01570## 47 --(CH.sub.2).sub.3--
##STR01571## 48 --(CH.sub.2).sub.3-- ##STR01572##
TABLE-US-00068 TABLE 68 (I-B-1-14) ##STR01573## No -E.sup.1-
-E.sup.3-E.sup.4 1 --CH.sub.2-- Me 2 --CH.sub.2-- Et 3 --CH.sub.2--
Pr 4 --CH.sub.2-- i-Pr 5 --CH.sub.2-- Ph 6 --CH.sub.2-- Bn 7
--CH.sub.2-- c-Pr 8 --CH.sub.2-- c-Bu 9 --CH.sub.2-- c-Pen 10
--CH.sub.2-- c-Hex 11 --CH.sub.2-- ##STR01574## 12 --CH.sub.2--
##STR01575## 13 --CH.sub.2-- ##STR01576## 14 --CH.sub.2--
##STR01577## 15 --CH.sub.2-- ##STR01578## 16 --CH.sub.2--
##STR01579## 17 --(CH.sub.2).sub.2-- Me 18 --(CH.sub.2).sub.2-- Et
19 --(CH.sub.2).sub.2-- Pr 20 --(CH.sub.2).sub.2-- i-Pr 21
--(CH.sub.2).sub.2-- Ph 22 --(CH.sub.2).sub.2-- Bn 23
--(CH.sub.2).sub.2-- c-Pr 24 --(CH.sub.2).sub.2-- c-Bu 25
--(CH.sub.2).sub.2-- c-Pen 26 --(CH.sub.2).sub.2-- c-Hex 27
--(CH.sub.2).sub.2-- ##STR01580## 28 --(CH.sub.2).sub.2--
##STR01581## 29 --(CH.sub.2).sub.2-- ##STR01582## 30
--(CH.sub.2).sub.2-- ##STR01583## 31 --(CH.sub.2).sub.2--
##STR01584## 32 --(CH.sub.2).sub.2-- ##STR01585## 33
--(CH.sub.2).sub.3-- Me 34 --(CH.sub.2).sub.3-- Et 35
--(CH.sub.2).sub.3-- Pr 36 --(CH.sub.2).sub.3-- i-Pr 37
--(CH.sub.2).sub.3-- Ph 38 --(CH.sub.2).sub.3-- Bn 39
--(CH.sub.2).sub.3-- c-Pr 40 --(CH.sub.2).sub.3-- c-Bu 41
--(CH.sub.2).sub.3-- c-Pen 42 --(CH.sub.2).sub.3-- c-Hex 43
--(CH.sub.2).sub.3-- ##STR01586## 44 --(CH.sub.2).sub.3--
##STR01587## 45 --(CH.sub.2).sub.3-- ##STR01588## 46
--(CH.sub.2).sub.3-- ##STR01589## 47 --(CH.sub.2).sub.3--
##STR01590## 48 --(CH.sub.2).sub.3-- ##STR01591##
TABLE-US-00069 TABLE 69 (I-B-1-15) ##STR01592## No -E.sup.1-
-E.sup.3-E.sup.4 1 --CH.sub.2-- Me 2 --CH.sub.2-- Et 3 --CH.sub.2--
Pr 4 --CH.sub.2-- i-Pr 5 --CH.sub.2-- Ph 6 --CH.sub.2-- Bn 7
--CH.sub.2-- c-Pr 8 --CH.sub.2-- c-Bu 9 --CH.sub.2-- c-Pen 10
--CH.sub.2-- c-Hex 11 --CH.sub.2-- ##STR01593## 12 --CH.sub.2--
##STR01594## 13 --CH.sub.2-- ##STR01595## 14 --CH.sub.2--
##STR01596## 15 --CH.sub.2-- ##STR01597## 16 --CH.sub.2--
##STR01598## 17 --(CH.sub.2).sub.2-- Me 18 --(CH.sub.2).sub.2-- Et
19 --(CH.sub.2).sub.2-- Pr 20 --(CH.sub.2).sub.2-- i-Pr 21
--(CH.sub.2).sub.2-- Ph 22 --(CH.sub.2).sub.2-- Bn 23
--(CH.sub.2).sub.2-- c-Pr 24 --(CH.sub.2).sub.2-- c-Bu 25
--(CH.sub.2).sub.2-- c-Pen 26 --(CH.sub.2).sub.2-- c-Hex 27
--(CH.sub.2).sub.2-- ##STR01599## 28 --(CH.sub.2).sub.2--
##STR01600## 29 --(CH.sub.2).sub.2-- ##STR01601## 30
--(CH.sub.2).sub.2-- ##STR01602## 31 --(CH.sub.2).sub.2--
##STR01603## 32 --(CH.sub.2).sub.2-- ##STR01604## 33
--(CH.sub.2).sub.3-- Me 34 --(CH.sub.2).sub.3-- Et 35
--(CH.sub.2).sub.3-- Pr 36 --(CH.sub.2).sub.3-- i-Pr 37
--(CH.sub.2).sub.3-- Ph 38 --(CH.sub.2).sub.3-- Bn 39
--(CH.sub.2).sub.3-- c-Pr 40 --(CH.sub.2).sub.3-- c-Bu 41
--(CH.sub.2).sub.3-- c-Pen 42 --(CH.sub.2).sub.3-- c-Hex 43
--(CH.sub.2).sub.3-- ##STR01605## 44 --(CH.sub.2).sub.3--
##STR01606## 45 --(CH.sub.2).sub.3-- ##STR01607## 46
--(CH.sub.2).sub.3-- ##STR01608## 47 --(CH.sub.2).sub.3--
##STR01609## 48 --(CH.sub.2).sub.3-- ##STR01610##
TABLE-US-00070 TABLE 70 (I-B-2-1) ##STR01611## No -E.sup.3-
-E.sup.4 1 --(CH.sub.2).sub.2-- --OH 2 --(CH.sub.2).sub.2-- --OMe 3
--(CH.sub.2).sub.2-- --NH.sub.2 4 --(CH.sub.2).sub.2-- --NHMe 5
--(CH.sub.2).sub.2-- --NHEt 6 --(CH.sub.2).sub.2-- --NHPr 7
--(CH.sub.2).sub.2-- --NH-i-Pr 8 --(CH.sub.2).sub.2-- --NMe.sub.2 9
--(CH.sub.2).sub.2-- --NEt.sub.2 10 --(CH.sub.2).sub.2--
--NPr.sub.2 11 --(CH.sub.2).sub.2-- --N(i-Pr).sub.2 12
--(CH.sub.2).sub.2-- --NHPh 13 --(CH.sub.2).sub.2-- --NHBn 14
--(CH.sub.2).sub.2-- --NH-c-Pr 15 --(CH.sub.2).sub.2-- --NH-c-Bu 16
--(CH.sub.2).sub.2-- --NH-c-Pen 17 --(CH.sub.2).sub.2-- --NH-c-Hex
18 --(CH.sub.2).sub.2-- --NH--(CH.sub.2).sub.2--OH 19
--(CH.sub.2).sub.2-- --NHCH(Me)(OH) 20 --(CH.sub.2).sub.2--
--N(Me)(c-Pen) 21 --(CH.sub.2).sub.2-- --N(Me)(c-Hex) 22
--(CH.sub.2).sub.2-- --N(Me)(Ph) 23 --(CH.sub.2).sub.2--
##STR01612## 24 --(CH.sub.2).sub.2-- ##STR01613## 25
--(CH.sub.2).sub.2-- ##STR01614## 26 --(CH.sub.2).sub.2--
##STR01615## 27 --(CH.sub.2).sub.2-- ##STR01616## 28
--(CH.sub.2).sub.2-- ##STR01617## 29 --(CH.sub.2).sub.3-- --OH 30
--(CH.sub.2).sub.3-- --OMe 31 --(CH.sub.2).sub.3-- --NH.sub.2 32
--(CH.sub.2).sub.3-- --NHMe 33 --(CH.sub.2).sub.3-- --NHEt 34
--(CH.sub.2).sub.3-- --NHPr 35 --(CH.sub.2).sub.3-- --NH-i-Pr 36
--(CH.sub.2).sub.3-- --NMe.sub.2 37 --(CH.sub.2).sub.3--
--NEt.sub.2 38 --(CH.sub.2).sub.3-- --NPr.sub.2 39
--(CH.sub.2).sub.3-- --N(i-Pr).sub.2 40 --(CH.sub.2).sub.3-- --NHPh
41 --(CH.sub.2).sub.3-- --NHBn 42 --(CH.sub.2).sub.3-- --NH-c-Pr 43
--(CH.sub.2).sub.3-- --NH-c-Bu 44 --(CH.sub.2).sub.3-- --NH-c-Pen
45 --(CH.sub.2).sub.3-- --NH-c-Hex 46 --(CH.sub.2).sub.3--
--NH--(CH.sub.2).sub.2--OH 47 --(CH.sub.2).sub.3-- --NHCH(Me)(OH)
48 --(CH.sub.2).sub.3-- --N(Me)(c-Pen) 49 --(CH.sub.2).sub.3--
--N(Me)(c-Hex) 50 --(CH.sub.2).sub.3-- --N(Me)(Ph) 51
--(CH.sub.2).sub.3-- ##STR01618## 52 --(CH.sub.2).sub.3--
##STR01619## 53 --(CH.sub.2).sub.3-- ##STR01620## 54
--(CH.sub.2).sub.3-- ##STR01621## 55 --(CH.sub.2).sub.3--
##STR01622## 56 --(CH.sub.2).sub.3-- ##STR01623## 57
--(CH.sub.2).sub.4-- --OH 58 --(CH.sub.2).sub.4-- --OMe 59
--(CH.sub.2).sub.4-- --NH.sub.2 60 --(CH.sub.2).sub.4-- --NHMe 61
--(CH.sub.2).sub.4-- --NHEt 62 --(CH.sub.2).sub.4-- --NHPr 63
--(CH.sub.2).sub.4-- --NH-i-Pr 64 --(CH.sub.2).sub.4-- --NMe.sub.2
65 --(CH.sub.2).sub.4-- --NEt.sub.2 66 --(CH.sub.2).sub.4--
--NPr.sub.2 67 --(CH.sub.2).sub.4-- --N(i-Pr).sub.2 68
--(CH.sub.2).sub.4-- --NHPh 69 --(CH.sub.2).sub.4-- --NHBn 70
--(CH.sub.2).sub.4-- --NH-c-Pr 71 --(CH.sub.2).sub.4-- --NH-c-Bu 72
--(CH.sub.2).sub.4-- --NH-c-Pen 73 --(CH.sub.2).sub.4-- --NH-c-Hex
74 --(CH.sub.2).sub.4-- --NH--(CH.sub.2).sub.2--OH 75
--(CH.sub.2).sub.4-- --NHCH(Me)(OH) 76 --(CH.sub.2).sub.4--
--N(Me)(c-Pen) 77 --(CH.sub.2).sub.4-- --N(Me)(c-Hex) 78
--(CH.sub.2).sub.4-- --N(Me)(Ph) 79 --(CH.sub.2).sub.4--
##STR01624## 80 --(CH.sub.2).sub.4-- ##STR01625## 81
--(CH.sub.2).sub.4-- ##STR01626## 82 --(CH.sub.2).sub.4--
##STR01627## 83 --(CH.sub.2).sub.4-- ##STR01628## 84
--(CH.sub.2).sub.4-- ##STR01629##
TABLE-US-00071 TABLE 71 (I-B-2-2) ##STR01630## No -E.sup.3-
-E.sup.4 1 --(CH.sub.2).sub.2-- --OH 2 --(CH.sub.2).sub.2-- --OMe 3
--(CH.sub.2).sub.2-- --NH.sub.2 4 --(CH.sub.2).sub.2-- --NHMe 5
--(CH.sub.2).sub.2-- --NHEt 6 --(CH.sub.2).sub.2-- --NHPr 7
--(CH.sub.2).sub.2-- --NH-i-Pr 8 --(CH.sub.2).sub.2-- --NMe.sub.2 9
--(CH.sub.2).sub.2-- --NEt.sub.2 10 --(CH.sub.2).sub.2--
--NPr.sub.2 11 --(CH.sub.2).sub.2-- --N(i-Pr).sub.2 12
--(CH.sub.2).sub.2-- --NHPh 13 --(CH.sub.2).sub.2-- --NHBn 14
--(CH.sub.2).sub.2-- --NH-c-Pr 15 --(CH.sub.2).sub.2-- --NH-c-Bu 16
--(CH.sub.2).sub.2-- --NH-c-Pen 17 --(CH.sub.2).sub.2-- --NH-c-Hex
18 --(CH.sub.2).sub.2-- --NH--(CH.sub.2).sub.2--OH 19
--(CH.sub.2).sub.2-- --NHCH(Me)(OH) 20 --(CH.sub.2).sub.2--
--N(Me)(c-Pen) 21 --(CH.sub.2).sub.2-- --N(Me)(c-Hex) 22
--(CH.sub.2).sub.2-- --N(Me)(Ph) 23 --(CH.sub.2).sub.2--
##STR01631## 24 --(CH.sub.2).sub.2-- ##STR01632## 25
--(CH.sub.2).sub.2-- ##STR01633## 26 --(CH.sub.2).sub.2--
##STR01634## 27 --(CH.sub.2).sub.2-- ##STR01635## 28
--(CH.sub.2).sub.2-- ##STR01636## 29 --(CH.sub.2).sub.3-- --OH 30
--(CH.sub.2).sub.3-- --OMe 31 --(CH.sub.2).sub.3-- --NH.sub.2 32
--(CH.sub.2).sub.3-- --NHMe 33 --(CH.sub.2).sub.3-- --NHEt 34
--(CH.sub.2).sub.3-- --NHPr 35 --(CH.sub.2).sub.3-- --NH-i-Pr 36
--(CH.sub.2).sub.3-- --NMe.sub.2 37 --(CH.sub.2).sub.3--
--NEt.sub.2 38 --(CH.sub.2).sub.3-- --NPr.sub.2 39
--(CH.sub.2).sub.3-- --N(i-Pr).sub.2 40 --(CH.sub.2).sub.3-- --NHPh
41 --(CH.sub.2).sub.3-- --NHBn 42 --(CH.sub.2).sub.3-- --NH-c-Pr 43
--(CH.sub.2).sub.3-- --NH-c-Bu 44 --(CH.sub.2).sub.3-- --NH-c-Pen
45 --(CH.sub.2).sub.3-- --NH-c-Hex 46 --(CH.sub.2).sub.3--
--NH--(CH.sub.2).sub.2--OH 47 --(CH.sub.2).sub.3-- --NHCH(Me)(OH)
48 --(CH.sub.2).sub.3-- --N(Me)(c-Pen) 49 --(CH.sub.2).sub.3--
--N(Me)(c-Hex) 50 --(CH.sub.2).sub.3-- --N(Me)(Ph) 51
--(CH.sub.2).sub.3-- ##STR01637## 52 --(CH.sub.2).sub.3--
##STR01638## 53 --(CH.sub.2).sub.3-- ##STR01639## 54
--(CH.sub.2).sub.3-- ##STR01640## 55 --(CH.sub.2).sub.3--
##STR01641## 56 --(CH.sub.2).sub.3-- ##STR01642## 57
--(CH.sub.2).sub.4-- --OH 58 --(CH.sub.2).sub.4-- --OMe 59
--(CH.sub.2).sub.4-- --NH.sub.2 60 --(CH.sub.2).sub.4-- --NHMe 61
--(CH.sub.2).sub.4-- --NHEt 62 --(CH.sub.2).sub.4-- --NHPr 63
--(CH.sub.2).sub.4-- --NH-i-Pr 64 --(CH.sub.2).sub.4-- --NMe.sub.2
65 --(CH.sub.2).sub.4-- --NEt.sub.2 66 --(CH.sub.2).sub.4--
--NPr.sub.2 67 --(CH.sub.2).sub.4-- --N(i-Pr).sub.2 68
--(CH.sub.2).sub.4-- --NHPh 69 --(CH.sub.2).sub.4-- --NHBn 70
--(CH.sub.2).sub.4-- --NH-c-Pr 71 --(CH.sub.2).sub.4-- --NH-c-Bu 72
--(CH.sub.2).sub.4-- --NH-c-Pen 73 --(CH.sub.2).sub.4-- --NH-c-Hex
74 --(CH.sub.2).sub.4-- --NH--(CH.sub.2).sub.2--OH 75
--(CH.sub.2).sub.4-- --NHCH(Me)(OH) 76 --(CH.sub.2).sub.4--
--N(Me)(c-Pen) 77 --(CH.sub.2).sub.4-- --N(Me)(c-Hex) 78
--(CH.sub.2).sub.4-- --N(Me)(Ph) 79 --(CH.sub.2).sub.4--
##STR01643## 80 --(CH.sub.2).sub.4-- ##STR01644## 81
--(CH.sub.2).sub.4-- ##STR01645## 82 --(CH.sub.2).sub.4--
##STR01646## 83 --(CH.sub.2).sub.4-- ##STR01647## 84
--(CH.sub.2).sub.4-- ##STR01648##
TABLE-US-00072 TABLE 72 (I-B-2-3) ##STR01649## No -E.sup.3-
-E.sup.4 1 --(CH.sub.2).sub.2-- --OH 2 --(CH.sub.2).sub.2-- --OMe 3
--(CH.sub.2).sub.2-- --NH.sub.2 4 --(CH.sub.2).sub.2-- --NHMe 5
--(CH.sub.2).sub.2-- --NHEt 6 --(CH.sub.2).sub.2-- --NHPr 7
--(CH.sub.2).sub.2-- --NH-i-Pr 8 --(CH.sub.2).sub.2-- --NMe.sub.2 9
--(CH.sub.2).sub.2-- --NEt.sub.2 10 --(CH.sub.2).sub.2--
--NPr.sub.2 11 --(CH.sub.2).sub.2-- --N(i-Pr).sub.2 12
--(CH.sub.2).sub.2-- --NHPh 13 --(CH.sub.2).sub.2-- --NHBn 14
--(CH.sub.2).sub.2-- --NH-c-Pr 15 --(CH.sub.2).sub.2-- --NH-c-Bu 16
--(CH.sub.2).sub.2-- --NH-c-Pen 17 --(CH.sub.2).sub.2-- --NH-c-Hex
18 --(CH.sub.2).sub.2-- --NH--(CH.sub.2).sub.2--OH 19
--(CH.sub.2).sub.2-- --NHCH(Me)(OH) 20 --(CH.sub.2).sub.2--
--N(Me)(c-Pen) 21 --(CH.sub.2).sub.2-- --N(Me)(c-Hex) 22
--(CH.sub.2).sub.2-- --N(Me)(Ph) 23 --(CH.sub.2).sub.2--
##STR01650## 24 --(CH.sub.2).sub.2-- ##STR01651## 25
--(CH.sub.2).sub.2-- ##STR01652## 26 --(CH.sub.2).sub.2--
##STR01653## 27 --(CH.sub.2).sub.2-- ##STR01654## 28
--(CH.sub.2).sub.2-- ##STR01655## 29 --(CH.sub.2).sub.3-- --OH 30
--(CH.sub.2).sub.3-- --OMe 31 --(CH.sub.2).sub.3-- --NH.sub.2 32
--(CH.sub.2).sub.3-- --NHMe 33 --(CH.sub.2).sub.3-- --NHEt 34
--(CH.sub.2).sub.3-- --NHPr 35 --(CH.sub.2).sub.3-- --NH-i-Pr 36
--(CH.sub.2).sub.3-- --NMe.sub.2 37 --(CH.sub.2).sub.3--
--NEt.sub.2 38 --(CH.sub.2).sub.3-- --NPr.sub.2 39
--(CH.sub.2).sub.3-- --N(i-Pr).sub.2 40 --(CH.sub.2).sub.3-- --NHPh
41 --(CH.sub.2).sub.3-- --NHBn 42 --(CH.sub.2).sub.3-- --NH-c-Pr 43
--(CH.sub.2).sub.3-- --NH-c-Bu 44 --(CH.sub.2).sub.3-- --NH-c-Pen
45 --(CH.sub.2).sub.3-- --NH-c-Hex 46 --(CH.sub.2).sub.3--
--NH--(CH.sub.2).sub.2--OH 47 --(CH.sub.2).sub.3-- --NHCH(Me)(OH)
48 --(CH.sub.2).sub.3-- --N(Me)(c-Pen) 49 --(CH.sub.2).sub.3--
--N(Me)(c-Hex) 50 --(CH.sub.2).sub.3-- --N(Me)(Ph) 51
--(CH.sub.2).sub.3-- ##STR01656## 52 --(CH.sub.2).sub.3--
##STR01657## 53 --(CH.sub.2).sub.3-- ##STR01658## 54
--(CH.sub.2).sub.3-- ##STR01659## 55 --(CH.sub.2).sub.3--
##STR01660## 56 --(CH.sub.2).sub.3-- ##STR01661## 57
--(CH.sub.2).sub.4-- --OH 58 --(CH.sub.2).sub.4-- --OMe 59
--(CH.sub.2).sub.4-- --NH.sub.2 60 --(CH.sub.2).sub.4-- --NHMe 61
--(CH.sub.2).sub.4-- --NHEt 62 --(CH.sub.2).sub.4-- --NHPr 63
--(CH.sub.2).sub.4-- --NH-i-Pr 64 --(CH.sub.2).sub.4-- --NMe.sub.2
65 --(CH.sub.2).sub.4-- --NEt.sub.2 66 --(CH.sub.2).sub.4--
--NPr.sub.2 67 --(CH.sub.2).sub.4-- --N(i-Pr).sub.2 68
--(CH.sub.2).sub.4-- --NHPh 69 --(CH.sub.2).sub.4-- --NHBn 70
--(CH.sub.2).sub.4-- --NH-c-Pr 71 --(CH.sub.2).sub.4-- --NH-c-Bu 72
--(CH.sub.2).sub.4-- --NH-c-Pen 73 --(CH.sub.2).sub.4-- --NH-c-Hex
74 --(CH.sub.2).sub.4-- --NH--(CH.sub.2).sub.2--OH 75
--(CH.sub.2).sub.4-- --NHCH(Me)(OH) 76 --(CH.sub.2).sub.4--
--N(Me)(c-Pen) 77 --(CH.sub.2).sub.4-- --N(Me)(c-Hex) 78
--(CH.sub.2).sub.4-- --N(Me)(Ph) 79 --(CH.sub.2).sub.4--
##STR01662## 80 --(CH.sub.2).sub.4-- ##STR01663## 81
--(CH.sub.2).sub.4-- ##STR01664## 82 --(CH.sub.2).sub.4--
##STR01665## 83 --(CH.sub.2).sub.4-- ##STR01666## 84
--(CH.sub.2).sub.4-- ##STR01667##
TABLE-US-00073 TABLE 73 (I-B-2-4) ##STR01668## No -E.sup.3-
-E.sup.4 1 --(CH.sub.2).sub.2-- --OH 2 --(CH.sub.2).sub.2-- --OMe 3
--(CH.sub.2).sub.2-- --NH.sub.2 4 --(CH.sub.2).sub.2-- --NHMe 5
--(CH.sub.2).sub.2-- --NHEt 6 --(CH.sub.2).sub.2-- --NHPr 7
--(CH.sub.2).sub.2-- --NH-i-Pr 8 --(CH.sub.2).sub.2-- --NMe.sub.2 9
--(CH.sub.2).sub.2-- --NEt.sub.2 10 --(CH.sub.2).sub.2--
--NPr.sub.2 11 --(CH.sub.2).sub.2-- --N(i-Pr).sub.2 12
--(CH.sub.2).sub.2-- --NHPh 13 --(CH.sub.2).sub.2-- --NHBn 14
--(CH.sub.2).sub.2-- --NH-c-Pr 15 --(CH.sub.2).sub.2-- --NH-c-Bu 16
--(CH.sub.2).sub.2-- --NH-c-Pen 17 --(CH.sub.2).sub.2-- --NH-c-Hex
18 --(CH.sub.2).sub.2-- --NH--(CH.sub.2).sub.2--OH 19
--(CH.sub.2).sub.2-- --NHCH(Me)(OH) 20 --(CH.sub.2).sub.2--
--N(Me)(c-Pen) 21 --(CH.sub.2).sub.2-- --N(Me)(c-Hex) 22
--(CH.sub.2).sub.2-- --N(Me)(Ph) 23 --(CH.sub.2).sub.2--
##STR01669## 24 --(CH.sub.2).sub.2-- ##STR01670## 25
--(CH.sub.2).sub.2-- ##STR01671## 26 --(CH.sub.2).sub.2--
##STR01672## 27 --(CH.sub.2).sub.2-- ##STR01673## 28
--(CH.sub.2).sub.2-- ##STR01674## 29 --(CH.sub.2).sub.3-- --OH 30
--(CH.sub.2).sub.3-- --OMe 31 --(CH.sub.2).sub.3-- --NH.sub.2 32
--(CH.sub.2).sub.3-- --NHMe 33 --(CH.sub.2).sub.3-- --NHEt 34
--(CH.sub.2).sub.3-- --NHPr 35 --(CH.sub.2).sub.3-- --NH-i-Pr 36
--(CH.sub.2).sub.3-- --NMe.sub.2 37 --(CH.sub.2).sub.3--
--NEt.sub.2 38 --(CH.sub.2).sub.3-- --NPr.sub.2 39
--(CH.sub.2).sub.3-- --N(i-Pr).sub.2 40 --(CH.sub.2).sub.3-- --NHPh
41 --(CH.sub.2).sub.3-- --NHBn 42 --(CH.sub.2).sub.3-- --NH-c-Pr 43
--(CH.sub.2).sub.3-- --NH-c-Bu 44 --(CH.sub.2).sub.3-- --NH-c-Pen
45 --(CH.sub.2).sub.3-- --NH-c-Hex 46 --(CH.sub.2).sub.3--
--NH--(CH.sub.2).sub.2--OH 47 --(CH.sub.2).sub.3-- --NHCH(Me)(OH)
48 --(CH.sub.2).sub.3-- --N(Me)(c-Pen) 49 --(CH.sub.2).sub.3--
--N(Me)(c-Hex) 50 --(CH.sub.2).sub.3-- --N(Me)(Ph) 51
--(CH.sub.2).sub.3-- ##STR01675## 52 --(CH.sub.2).sub.3--
##STR01676## 53 --(CH.sub.2).sub.3-- ##STR01677## 54
--(CH.sub.2).sub.3-- ##STR01678## 55 --(CH.sub.2).sub.3--
##STR01679## 56 --(CH.sub.2).sub.3-- ##STR01680## 57
--(CH.sub.2).sub.4-- --OH 58 --(CH.sub.2).sub.4-- --OMe 59
--(CH.sub.2).sub.4-- --NH.sub.2 60 --(CH.sub.2).sub.4-- --NHMe 61
--(CH.sub.2).sub.4-- --NHEt 62 --(CH.sub.2).sub.4-- --NHPr 63
--(CH.sub.2).sub.4-- --NH-i-Pr 64 --(CH.sub.2).sub.4-- --NMe.sub.2
65 --(CH.sub.2).sub.4-- --NEt.sub.2 66 --(CH.sub.2).sub.4--
--NPr.sub.2 67 --(CH.sub.2).sub.4-- --N(i-Pr).sub.2 68
--(CH.sub.2).sub.4-- --NHPh 69 --(CH.sub.2).sub.4-- --NHBn 70
--(CH.sub.2).sub.4-- --NH-c-Pr 71 --(CH.sub.2).sub.4-- --NH-c-Bu 72
--(CH.sub.2).sub.4-- --NH-c-Pen 73 --(CH.sub.2).sub.4-- --NH-c-Hex
74 --(CH.sub.2).sub.4-- --NH--(CH.sub.2).sub.2--OH 75
--(CH.sub.2).sub.4-- --NHCH(Me)(OH) 76 --(CH.sub.2).sub.4--
--N(Me)(c-Pen) 77 --(CH.sub.2).sub.4-- --N(Me)(c-Hex) 78
--(CH.sub.2).sub.4-- --N(Me)(Ph) 79 --(CH.sub.2).sub.4--
##STR01681## 80 --(CH.sub.2).sub.4-- ##STR01682## 81
--(CH.sub.2).sub.4-- ##STR01683## 82 --(CH.sub.2).sub.4--
##STR01684## 83 --(CH.sub.2).sub.4-- ##STR01685## 84
--(CH.sub.2).sub.4-- ##STR01686##
TABLE-US-00074 TABLE 74 (I-B-2-5) ##STR01687## No -E.sup.3-
-E.sup.4 1 --(CH.sub.2).sub.2-- --OH 2 --(CH.sub.2).sub.2-- --OMe 3
--(CH.sub.2).sub.2-- --NH.sub.2 4 --(CH.sub.2).sub.2-- --NHMe 5
--(CH.sub.2).sub.2-- --NHEt 6 --(CH.sub.2).sub.2-- --NHPr 7
--(CH.sub.2).sub.2-- --NH-i-Pr 8 --(CH.sub.2).sub.2-- --NMe.sub.2 9
--(CH.sub.2).sub.2-- --NEt.sub.2 10 --(CH.sub.2).sub.2--
--NPr.sub.2 11 --(CH.sub.2).sub.2-- --N(i-Pr).sub.2 12
--(CH.sub.2).sub.2-- --NHPh 13 --(CH.sub.2).sub.2-- --NHBn 14
--(CH.sub.2).sub.2-- --NH-c-Pr 15 --(CH.sub.2).sub.2-- --NH-c-Bu 16
--(CH.sub.2).sub.2-- --NH-c-Pen 17 --(CH.sub.2).sub.2-- --NH-c-Hex
18 --(CH.sub.2).sub.2-- --NH--(CH.sub.2).sub.2--OH 19
--(CH.sub.2).sub.2-- --NHCH(Me)(OH) 20 --(CH.sub.2).sub.2--
--N(Me)(c-Pen) 21 --(CH.sub.2).sub.2-- --N(Me)(c-Hex) 22
--(CH.sub.2).sub.2-- --N(Me)(Ph) 23 --(CH.sub.2).sub.2--
##STR01688## 24 --(CH.sub.2).sub.2-- ##STR01689## 25
--(CH.sub.2).sub.2-- ##STR01690## 26 --(CH.sub.2).sub.2--
##STR01691## 27 --(CH.sub.2).sub.2-- ##STR01692## 28
--(CH.sub.2).sub.2-- ##STR01693## 29 --(CH.sub.2).sub.3-- --OH 30
--(CH.sub.2).sub.3-- --OMe 31 --(CH.sub.2).sub.3-- --NH.sub.2 32
--(CH.sub.2).sub.3-- --NHMe 33 --(CH.sub.2).sub.3-- --NHEt 34
--(CH.sub.2).sub.3-- --NHPr 35 --(CH.sub.2).sub.3-- --NH-i-Pr 36
--(CH.sub.2).sub.3-- --NMe.sub.2 37 --(CH.sub.2).sub.3--
--NEt.sub.2 38 --(CH.sub.2).sub.3-- --NPr.sub.2 39
--(CH.sub.2).sub.3-- --N(i-Pr).sub.2 40 --(CH.sub.2).sub.3-- --NHPh
41 --(CH.sub.2).sub.3-- --NHBn 42 --(CH.sub.2).sub.3-- --NH-c-Pr 43
--(CH.sub.2).sub.3-- --NH-c-Bu 44 --(CH.sub.2).sub.3-- --NH-c-Pen
45 --(CH.sub.2).sub.3-- --NH-c-Hex 46 --(CH.sub.2).sub.3--
--NH--(CH.sub.2).sub.2--OH 47 --(CH.sub.2).sub.3-- --NHCH(Me)(OH)
48 --(CH.sub.2).sub.3-- --N(Me)(c-Pen) 49 --(CH.sub.2).sub.3--
--N(Me)(c-Hex) 50 --(CH.sub.2).sub.3-- --N(Me)(Ph) 51
--(CH.sub.2).sub.3-- ##STR01694## 52 --(CH.sub.2).sub.3--
##STR01695## 53 --(CH.sub.2).sub.3-- ##STR01696## 54
--(CH.sub.2).sub.3-- ##STR01697## 55 --(CH.sub.2).sub.3--
##STR01698## 56 --(CH.sub.2).sub.3-- ##STR01699## 57
--(CH.sub.2).sub.4-- --OH 58 --(CH.sub.2).sub.4-- --OMe 59
--(CH.sub.2).sub.4-- --NH.sub.2 60 --(CH.sub.2).sub.4-- --NHMe 61
--(CH.sub.2).sub.4-- --NHEt 62 --(CH.sub.2).sub.4-- --NHPr 63
--(CH.sub.2).sub.4-- --NH-i-Pr 64 --(CH.sub.2).sub.4-- --NMe.sub.2
65 --(CH.sub.2).sub.4-- --NEt.sub.2 66 --(CH.sub.2).sub.4--
--NPr.sub.2 67 --(CH.sub.2).sub.4-- --N(i-Pr).sub.2 68
--(CH.sub.2).sub.4-- --NHPh 69 --(CH.sub.2).sub.4-- --NHBn 70
--(CH.sub.2).sub.4-- --NH-c-Pr 71 --(CH.sub.2).sub.4-- --NH-c-Bu 72
--(CH.sub.2).sub.4-- --NH-c-Pen 73 --(CH.sub.2).sub.4-- --NH-c-Hex
74 --(CH.sub.2).sub.4-- --NH--(CH.sub.2).sub.2--OH 75
--(CH.sub.2).sub.4-- --NHCH(Me)(OH) 76 --(CH.sub.2).sub.4--
--N(Me)(c-Pen) 77 --(CH.sub.2).sub.4-- --N(Me)(c-Hex) 78
--(CH.sub.2).sub.4-- --N(Me)(Ph) 79 --(CH.sub.2).sub.4--
##STR01700## 80 --(CH.sub.2).sub.4-- ##STR01701## 81
--(CH.sub.2).sub.4-- ##STR01702## 82 --(CH.sub.2).sub.4--
##STR01703## 83 --(CH.sub.2).sub.4-- ##STR01704## 84
--(CH.sub.2).sub.4-- ##STR01705##
TABLE-US-00075 TABLE 75 (I-B-2-6) ##STR01706## No -E.sup.1-
-E.sup.3-E.sup.4 1 --CH.sub.2-- Me 2 --CH.sub.2-- Et 3 --CH.sub.2--
Pr 4 --CH.sub.2-- i-Pr 5 --CH.sub.2-- Ph 6 --CH.sub.2-- Bn 7
--CH.sub.2-- c-Pr 8 --CH.sub.2-- c-Bu 9 --CH.sub.2-- c-Pen 10
--CH.sub.2-- c-Hex 11 --CH.sub.2-- ##STR01707## 12 --CH.sub.2--
##STR01708## 13 --CH.sub.2-- ##STR01709## 14 --CH.sub.2--
##STR01710## 15 --CH.sub.2-- ##STR01711## 16 --CH.sub.2--
##STR01712## 17 --(CH.sub.2).sub.2-- Me 18 --(CH.sub.2).sub.2-- Et
19 --(CH.sub.2).sub.2-- Pr 20 --(CH.sub.2).sub.2-- i-Pr 21
--(CH.sub.2).sub.2-- Ph 22 --(CH.sub.2).sub.2-- Bn 23
--(CH.sub.2).sub.2-- c-Pr 24 --(CH.sub.2).sub.2-- c-Bu 25
--(CH.sub.2).sub.2-- c-Pen 26 --(CH.sub.2).sub.2-- c-Hex 27
--(CH.sub.2).sub.2-- ##STR01713## 28 --(CH.sub.2).sub.2--
##STR01714## 29 --(CH.sub.2).sub.2-- ##STR01715## 30
--(CH.sub.2).sub.2-- ##STR01716## 31 --(CH.sub.2).sub.2--
##STR01717## 32 --(CH.sub.2).sub.2-- ##STR01718##
TABLE-US-00076 TABLE 76 (I-B-2-7) ##STR01719## No -E.sup.1-
-E.sup.3-E.sup.4 1 --CH.sub.2-- Me 2 --CH.sub.2-- Et 3 --CH.sub.2--
Pr 4 --CH.sub.2-- i-Pr 5 --CH.sub.2-- Ph 6 --CH.sub.2-- Bn 7
--CH.sub.2-- c-Pr 8 --CH.sub.2-- c-Bu 9 --CH.sub.2-- c-Pen 10
--CH.sub.2-- c-Hex 11 --CH.sub.2-- ##STR01720## 12 --CH.sub.2--
##STR01721## 13 --CH.sub.2-- ##STR01722## 14 --CH.sub.2--
##STR01723## 15 --CH.sub.2-- ##STR01724## 16 --CH.sub.2--
##STR01725## 17 --(CH.sub.2).sub.2-- Me 18 --(CH.sub.2).sub.2-- Et
19 --(CH.sub.2).sub.2-- Pr 20 --(CH.sub.2).sub.2-- i-Pr 21
--(CH.sub.2).sub.2-- Ph 22 --(CH.sub.2).sub.2-- Bn 23
--(CH.sub.2).sub.2-- c-Pr 24 --(CH.sub.2).sub.2-- c-Bu 25
--(CH.sub.2).sub.2-- c-Pen 26 --(CH.sub.2).sub.2-- c-Hex 27
--(CH.sub.2).sub.2-- ##STR01726## 28 --(CH.sub.2).sub.2--
##STR01727## 29 --(CH.sub.2).sub.2-- ##STR01728## 30
--(CH.sub.2).sub.2-- ##STR01729## 31 --(CH.sub.2).sub.2--
##STR01730## 32 --(CH.sub.2).sub.2-- ##STR01731##
TABLE-US-00077 TABLE 77 (I-B-2-8) ##STR01732## No -E.sup.3-
-E.sup.4 1 --(CH.sub.2).sub.2-- --OH 2 --(CH.sub.2).sub.2-- --OMe 3
--(CH.sub.2).sub.2-- --NH.sub.2 4 --(CH.sub.2).sub.2-- --NHMe 5
--(CH.sub.2).sub.2-- --NHEt 6 --(CH.sub.2).sub.2-- --NHPr 7
--(CH.sub.2).sub.2-- --NH-i-Pr 8 --(CH.sub.2).sub.2-- --NMe.sub.2 9
--(CH.sub.2).sub.2-- --NEt.sub.2 10 --(CH.sub.2).sub.2--
--NPr.sub.2 11 --(CH.sub.2).sub.2-- --N(i-Pr).sub.2 12
--(CH.sub.2).sub.2-- --NHPh 13 --(CH.sub.2).sub.2-- --NHBn 14
--(CH.sub.2).sub.2-- --NH-c-Pr 15 --(CH.sub.2).sub.2-- --NH-c-Bu 16
--(CH.sub.2).sub.2-- --NH-c-Pen 17 --(CH.sub.2).sub.2-- --NH-c-Hex
18 --(CH.sub.2).sub.2-- --NH--(CH.sub.2).sub.2--OH 19
--(CH.sub.2).sub.2-- --NHCH(Me)(OH) 20 --(CH.sub.2).sub.2--
--N(Me)(c-Pen) 21 --(CH.sub.2).sub.2-- --N(Me)(c-Hex) 22
--(CH.sub.2).sub.2-- --N(Me)(Ph) 23 --(CH.sub.2).sub.2--
##STR01733## 24 --(CH.sub.2).sub.2-- ##STR01734## 25
--(CH.sub.2).sub.2-- ##STR01735## 26 --(CH.sub.2).sub.2--
##STR01736## 27 --(CH.sub.2).sub.2-- ##STR01737## 28
--(CH.sub.2).sub.2-- ##STR01738## 29 --(CH.sub.2).sub.3-- --OH 30
--(CH.sub.2).sub.3-- --OMe 31 --(CH.sub.2).sub.3-- --NH.sub.2 32
--(CH.sub.2).sub.3-- --NHMe 33 --(CH.sub.2).sub.3-- --NHEt 34
--(CH.sub.2).sub.3-- --NHPr 35 --(CH.sub.2).sub.3-- --NH-i-Pr 36
--(CH.sub.2).sub.3-- --NMe.sub.2 37 --(CH.sub.2).sub.3--
--NEt.sub.2 38 --(CH.sub.2).sub.3-- --NPr.sub.2 39
--(CH.sub.2).sub.3-- --N(i-Pr).sub.2 40 --(CH.sub.2).sub.3-- --NHPh
41 --(CH.sub.2).sub.3-- --NHBn 42 --(CH.sub.2).sub.3-- --NH-c-Pr 43
--(CH.sub.2).sub.3-- --NH-c-Bu 44 --(CH.sub.2).sub.3-- --NH-c-Pen
45 --(CH.sub.2).sub.3-- --NH-c-Hex 46 --(CH.sub.2).sub.3--
--NH--(CH.sub.2).sub.2--OH 47 --(CH.sub.2).sub.3-- --NHCH(Me)(OH)
48 --(CH.sub.2).sub.3-- --N(Me)(c-Pen) 49 --(CH.sub.2).sub.3--
--N(Me)(c-Hex) 50 --(CH.sub.2).sub.3-- --N(Me)(Ph) 51
--(CH.sub.2).sub.3-- ##STR01739## 52 --(CH.sub.2).sub.3--
##STR01740## 53 --(CH.sub.2).sub.3-- ##STR01741## 54
--(CH.sub.2).sub.3-- ##STR01742## 55 --(CH.sub.2).sub.3--
##STR01743## 56 --(CH.sub.2).sub.3-- ##STR01744## 57
--(CH.sub.2).sub.4-- --OH 58 --(CH.sub.2).sub.4-- --OMe 59
--(CH.sub.2).sub.4-- --NH.sub.2 60 --(CH.sub.2).sub.4-- --NHMe 61
--(CH.sub.2).sub.4-- --NHEt 62 --(CH.sub.2).sub.4-- --NHPr 63
--(CH.sub.2).sub.4-- --NH-i-Pr 64 --(CH.sub.2).sub.4-- --NMe.sub.2
65 --(CH.sub.2).sub.4-- --NEt.sub.2 66 --(CH.sub.2).sub.4--
--NPr.sub.2 67 --(CH.sub.2).sub.4-- --N(i-Pr).sub.2 68
--(CH.sub.2).sub.4-- --NHPh 69 --(CH.sub.2).sub.4-- --NHBn 70
--(CH.sub.2).sub.4-- --NH-c-Pr 71 --(CH.sub.2).sub.4-- --NH-c-Bu 72
--(CH.sub.2).sub.4-- --NH-c-Pen 73 --(CH.sub.2).sub.4-- --NH-c-Hex
74 --(CH.sub.2).sub.4-- --NH--(CH.sub.2).sub.2--OH 75
--(CH.sub.2).sub.4-- --NHCH(Me)(OH) 76 --(CH.sub.2).sub.4--
--N(Me)(c-Pen) 77 --(CH.sub.2).sub.4-- --N(Me)(c-Hex) 78
--(CH.sub.2).sub.4-- --N(Me)(Ph) 79 --(CH.sub.2).sub.4--
##STR01745## 80 --(CH.sub.2).sub.4-- ##STR01746## 81
--(CH.sub.2).sub.4-- ##STR01747## 82 --(CH.sub.2).sub.4--
##STR01748## 83 --(CH.sub.2).sub.4-- ##STR01749## 84
--(CH.sub.2).sub.4-- ##STR01750##
TABLE-US-00078 TABLE 78 (I-B-2-9) ##STR01751## No -E.sup.1-
-E.sup.3-E.sup.4 1 --CH.sub.2-- Me 2 --CH.sub.2-- Et 3 --CH.sub.2--
Pr 4 --CH.sub.2-- i-Pr 5 --CH.sub.2-- Ph 6 --CH.sub.2-- Bn 7
--CH.sub.2-- c-Pr 8 --CH.sub.2-- c-Bu 9 --CH.sub.2-- c-Pen 10
--CH.sub.2-- c-Hex 11 --CH.sub.2-- ##STR01752## 12 --CH.sub.2--
##STR01753## 13 --CH.sub.2-- ##STR01754## 14 --CH.sub.2--
##STR01755## 15 --CH.sub.2-- ##STR01756## 16 --CH.sub.2--
##STR01757## 17 --(CH.sub.2).sub.2-- Me 18 --(CH.sub.2).sub.2-- Et
19 --(CH.sub.2).sub.2-- Pr 20 --(CH.sub.2).sub.2-- i-Pr 21
--(CH.sub.2).sub.2-- Ph 22 --(CH.sub.2).sub.2-- Bn 23
--(CH.sub.2).sub.2-- c-Pr 24 --(CH.sub.2).sub.2-- c-Bu 25
--(CH.sub.2).sub.2-- c-Pen 26 --(CH.sub.2).sub.2-- c-Hex 27
--(CH.sub.2).sub.2-- ##STR01758## 28 --(CH.sub.2).sub.2--
##STR01759## 29 --(CH.sub.2).sub.2-- ##STR01760## 30
--(CH.sub.2).sub.2-- ##STR01761## 31 --(CH.sub.2).sub.2--
##STR01762## 32 --(CH.sub.2).sub.2-- ##STR01763##
TABLE-US-00079 TABLE 79 (I-B-2-10) ##STR01764## No -E.sup.3-
-E.sup.4 1 --(CH.sub.2).sub.2-- --OH 2 --(CH.sub.2).sub.2-- --OMe 3
--(CH.sub.2).sub.2-- --NH.sub.2 4 --(CH.sub.2).sub.2-- --NHMe 5
--(CH.sub.2).sub.2-- --NHEt 6 --(CH.sub.2).sub.2-- --NHPr 7
--(CH.sub.2).sub.2-- --NH-i-Pr 8 --(CH.sub.2).sub.2-- --NMe.sub.2 9
--(CH.sub.2).sub.2-- --NEt.sub.2 10 --(CH.sub.2).sub.2--
--NPr.sub.2 11 --(CH.sub.2).sub.2-- --N(i-Pr).sub.2 12
--(CH.sub.2).sub.2-- --NHPh 13 --(CH.sub.2).sub.2-- --NHBn 14
--(CH.sub.2).sub.2-- --NH-c-Pr 15 --(CH.sub.2).sub.2-- --NH-c-Bu 16
--(CH.sub.2).sub.2-- --NH-c-Pen 17 --(CH.sub.2).sub.2-- --NH-c-Hex
18 --(CH.sub.2).sub.2-- --NH--(CH.sub.2).sub.2--OH 19
--(CH.sub.2).sub.2-- --NHCH(Me)(OH) 20 --(CH.sub.2).sub.2--
--N(Me)(c-Pen) 21 --(CH.sub.2).sub.2-- --N(Me)(c-Hex) 22
--(CH.sub.2).sub.2-- --N(Me)(Ph) 23 --(CH.sub.2).sub.2--
##STR01765## 24 --(CH.sub.2).sub.2-- ##STR01766## 25
--(CH.sub.2).sub.2-- ##STR01767## 26 --(CH.sub.2).sub.2--
##STR01768## 27 --(CH.sub.2).sub.2-- ##STR01769## 28
--(CH.sub.2).sub.2-- ##STR01770## 29 --(CH.sub.2).sub.3-- --OH 30
--(CH.sub.2).sub.3-- --OMe 31 --(CH.sub.2).sub.3-- --NH.sub.2 32
--(CH.sub.2).sub.3-- --NHMe 33 --(CH.sub.2).sub.3-- --NHEt 34
--(CH.sub.2).sub.3-- --NHPr 35 --(CH.sub.2).sub.3-- --NH-i-Pr 36
--(CH.sub.2).sub.3-- --NMe.sub.2 37 --(CH.sub.2).sub.3--
--NEt.sub.2 38 --(CH.sub.2).sub.3-- --NPr.sub.2 39
--(CH.sub.2).sub.3-- --N(i-Pr).sub.2 40 --(CH.sub.2).sub.3-- --NHPh
41 --(CH.sub.2).sub.3-- --NHBn 42 --(CH.sub.2).sub.3-- --NH-c-Pr 43
--(CH.sub.2).sub.3-- --NH-c-Bu 44 --(CH.sub.2).sub.3-- --NH-c-Pen
45 --(CH.sub.2).sub.3-- --NH-c-Hex 46 --(CH.sub.2).sub.3--
--NH--(CH.sub.2).sub.2--OH 47 --(CH.sub.2).sub.3-- --NHCH(Me)(OH)
48 --(CH.sub.2).sub.3-- --N(Me)(c-Pen) 49 --(CH.sub.2).sub.3--
--N(Me)(c-Hex) 50 --(CH.sub.2).sub.3-- --N(Me)(Ph) 51
--(CH.sub.2).sub.3-- ##STR01771## 52 --(CH.sub.2).sub.3--
##STR01772## 53 --(CH.sub.2).sub.3-- ##STR01773## 54
--(CH.sub.2).sub.3-- ##STR01774## 55 --(CH.sub.2).sub.3--
##STR01775## 56 --(CH.sub.2).sub.3-- ##STR01776## 57
--(CH.sub.2).sub.4-- --OH 58 --(CH.sub.2).sub.4-- --OMe 59
--(CH.sub.2).sub.4-- --NH.sub.2 60 --(CH.sub.2).sub.4-- --NHMe 61
--(CH.sub.2).sub.4-- --NHEt 62 --(CH.sub.2).sub.4-- --NHPr 63
--(CH.sub.2).sub.4-- --NH-i-Pr 64 --(CH.sub.2).sub.4-- --NMe.sub.2
65 --(CH.sub.2).sub.4-- --NEt.sub.2 66 --(CH.sub.2).sub.4--
--NPr.sub.2 67 --(CH.sub.2).sub.4-- --N(i-Pr).sub.2 68
--(CH.sub.2).sub.4-- --NHPh 69 --(CH.sub.2).sub.4-- --NHBn 70
--(CH.sub.2).sub.4-- --NH-c-Pr 71 --(CH.sub.2).sub.4-- --NH-c-Bu 72
--(CH.sub.2).sub.4-- --NH-c-Pen 73 --(CH.sub.2).sub.4-- --NH-c-Hex
74 --(CH.sub.2).sub.4-- --NH--(CH.sub.2).sub.2--OH 75
--(CH.sub.2).sub.4-- --NHCH(Me)(OH) 76 --(CH.sub.2).sub.4--
--N(Me)(c-Pen) 77 --(CH.sub.2).sub.4-- --N(Me)(c-Hex) 78
--(CH.sub.2).sub.4-- --N(Me)(Ph) 79 --(CH.sub.2).sub.4--
##STR01777## 80 --(CH.sub.2).sub.4-- ##STR01778## 81
--(CH.sub.2).sub.4-- ##STR01779## 82 --(CH.sub.2).sub.4--
##STR01780## 83 --(CH.sub.2).sub.4-- ##STR01781## 84
--(CH.sub.2).sub.4-- ##STR01782##
TABLE-US-00080 TABLE 80 (I-B-2-11) ##STR01783## No -E.sup.3-
-E.sup.4 1 --(CH.sub.2).sub.2-- --OH 2 --(CH.sub.2).sub.2-- --OMe 3
--(CH.sub.2).sub.2-- --NH.sub.2 4 --(CH.sub.2).sub.2-- --NHMe 5
--(CH.sub.2).sub.2-- --NHEt 6 --(CH.sub.2).sub.2-- --NHPr 7
--(CH.sub.2).sub.2-- --NH-i-Pr 8 --(CH.sub.2).sub.2-- --NMe.sub.2 9
--(CH.sub.2).sub.2-- --NEt.sub.2 10 --(CH.sub.2).sub.2--
--NPr.sub.2 11 --(CH.sub.2).sub.2-- --N(i-Pr).sub.2 12
--(CH.sub.2).sub.2-- --NHPh 13 --(CH.sub.2).sub.2-- --NHBn 14
--(CH.sub.2).sub.2-- --NH-c-Pr 15 --(CH.sub.2).sub.2-- --NH-c-Bu 16
--(CH.sub.2).sub.2-- --NH-c-Pen 17 --(CH.sub.2).sub.2-- --NH-c-Hex
18 --(CH.sub.2).sub.2-- --NH--(CH.sub.2).sub.2--OH 19
--(CH.sub.2).sub.2-- --NHCH(Me)(OH) 20 --(CH.sub.2).sub.2--
--N(Me)(c-Pen) 21 --(CH.sub.2).sub.2-- --N(Me)(c-Hex) 22
--(CH.sub.2).sub.2-- --N(Me)(Ph) 23 --(CH.sub.2).sub.2--
##STR01784## 24 --(CH.sub.2).sub.2-- ##STR01785## 25
--(CH.sub.2).sub.2-- ##STR01786## 26 --(CH.sub.2).sub.2--
##STR01787## 27 --(CH.sub.2).sub.2-- ##STR01788## 28
--(CH.sub.2).sub.2-- ##STR01789## 29 --(CH.sub.2).sub.3-- --OH 30
--(CH.sub.2).sub.3-- --OMe 31 --(CH.sub.2).sub.3-- --NH.sub.2 32
--(CH.sub.2).sub.3-- --NHMe 33 --(CH.sub.2).sub.3-- --NHEt 34
--(CH.sub.2).sub.3-- --NHPr 35 --(CH.sub.2).sub.3-- --NH-i-Pr 36
--(CH.sub.2).sub.3-- --NMe.sub.2 37 --(CH.sub.2).sub.3--
--NEt.sub.2 38 --(CH.sub.2).sub.3-- --NPr.sub.2 39
--(CH.sub.2).sub.3-- --N(i-Pr).sub.2 40 --(CH.sub.2).sub.3-- --NHPh
41 --(CH.sub.2).sub.3-- --NHBn 42 --(CH.sub.2).sub.3-- --NH-c-Pr 43
--(CH.sub.2).sub.3-- --NH-c-Bu 44 --(CH.sub.2).sub.3-- --NH-c-Pen
45 --(CH.sub.2).sub.3-- --NH-c-Hex 46 --(CH.sub.2).sub.3--
--NH--(CH.sub.2).sub.2--OH 47 --(CH.sub.2).sub.3-- --NHCH(Me)(OH)
48 --(CH.sub.2).sub.3-- --N(Me)(c-Pen) 49 --(CH.sub.2).sub.3--
--N(Me)(c-Hex) 50 --(CH.sub.2).sub.3-- --N(Me)(Ph) 51
--(CH.sub.2).sub.3-- ##STR01790## 52 --(CH.sub.2).sub.3--
##STR01791## 53 --(CH.sub.2).sub.3-- ##STR01792## 54
--(CH.sub.2).sub.3-- ##STR01793## 55 --(CH.sub.2).sub.3--
##STR01794## 56 --(CH.sub.2).sub.3-- ##STR01795## 57
--(CH.sub.2).sub.4-- --OH 58 --(CH.sub.2).sub.4-- --OMe 59
--(CH.sub.2).sub.4-- --NH.sub.2 60 --(CH.sub.2).sub.4-- --NHMe 61
--(CH.sub.2).sub.4-- --NHEt 62 --(CH.sub.2).sub.4-- --NHPr 63
--(CH.sub.2).sub.4-- --NH-i-Pr 64 --(CH.sub.2).sub.4-- --NMe.sub.2
65 --(CH.sub.2).sub.4-- --NEt.sub.2 66 --(CH.sub.2).sub.4--
--NPr.sub.2 67 --(CH.sub.2).sub.4-- --N(i-Pr).sub.2 68
--(CH.sub.2).sub.4-- --NHPh 69 --(CH.sub.2).sub.4-- --NHBn 70
--(CH.sub.2).sub.4-- --NH-c-Pr 71 --(CH.sub.2).sub.4-- --NH-c-Bu 72
--(CH.sub.2).sub.4-- --NH-c-Pen 73 --(CH.sub.2).sub.4-- --NH-c-Hex
74 --(CH.sub.2).sub.4-- --NH--(CH.sub.2).sub.2--OH 75
--(CH.sub.2).sub.4-- --NHCH(Me)(OH) 76 --(CH.sub.2).sub.4--
--N(Me)(c-Pen) 77 --(CH.sub.2).sub.4-- --N(Me)(c-Hex) 78
--(CH.sub.2).sub.4-- --N(Me)(Ph) 79 --(CH.sub.2).sub.4--
##STR01796## 80 --(CH.sub.2).sub.4-- ##STR01797## 81
--(CH.sub.2).sub.4-- ##STR01798## 82 --(CH.sub.2).sub.4--
##STR01799## 83 --(CH.sub.2).sub.4-- ##STR01800## 84
--(CH.sub.2).sub.4-- ##STR01801##
TABLE-US-00081 TABLE 81 (I-B-2-12) ##STR01802## No -E.sup.3-
-E.sup.4 1 --(CH.sub.2).sub.2-- --OH 2 --(CH.sub.2).sub.2-- --OMe 3
--(CH.sub.2).sub.2-- --NH.sub.2 4 --(CH.sub.2).sub.2-- --NHMe 5
--(CH.sub.2).sub.2-- --NHEt 6 --(CH.sub.2).sub.2-- --NHPr 7
--(CH.sub.2).sub.2-- --NH-i-Pr 8 --(CH.sub.2).sub.2-- --NMe.sub.2 9
--(CH.sub.2).sub.2-- --NEt.sub.2 10 --(CH.sub.2).sub.2--
--NPr.sub.2 11 --(CH.sub.2).sub.2-- --N(i-Pr).sub.2 12
--(CH.sub.2).sub.2-- --NHPh 13 --(CH.sub.2).sub.2-- --NHBn 14
--(CH.sub.2).sub.2-- --NH-c-Pr 15 --(CH.sub.2).sub.2-- --NH-c-Bu 16
--(CH.sub.2).sub.2-- --NH-c-Pen 17 --(CH.sub.2).sub.2-- --NH-c-Hex
18 --(CH.sub.2).sub.2-- --NH--(CH.sub.2).sub.2--OH 19
--(CH.sub.2).sub.2-- --NHCH(Me)(OH) 20 --(CH.sub.2).sub.2--
--N(Me)(c-Pen) 21 --(CH.sub.2).sub.2-- --N(Me)(c-Hex) 22
--(CH.sub.2).sub.2-- --N(Me)(Ph) 23 --(CH.sub.2).sub.2--
##STR01803## 24 --(CH.sub.2).sub.2-- ##STR01804## 25
--(CH.sub.2).sub.2-- ##STR01805## 26 --(CH.sub.2).sub.2--
##STR01806## 27 --(CH.sub.2).sub.2-- ##STR01807## 28
--(CH.sub.2).sub.2-- ##STR01808## 29 --(CH.sub.2).sub.3-- --OH 30
--(CH.sub.2).sub.3-- --OMe 31 --(CH.sub.2).sub.3-- --NH.sub.2 32
--(CH.sub.2).sub.3-- --NHMe 33 --(CH.sub.2).sub.3-- --NHEt 34
--(CH.sub.2).sub.3-- --NHPr 35 --(CH.sub.2).sub.3-- --NH-i-Pr 36
--(CH.sub.2).sub.3-- --NMe.sub.2 37 --(CH.sub.2).sub.3--
--NEt.sub.2 38 --(CH.sub.2).sub.3-- --NPr.sub.2 39
--(CH.sub.2).sub.3-- --N(i-Pr).sub.2 40 --(CH.sub.2).sub.3-- --NHPh
41 --(CH.sub.2).sub.3-- --NHBn 42 --(CH.sub.2).sub.3-- --NH-c-Pr 43
--(CH.sub.2).sub.3-- --NH-c-Bu 44 --(CH.sub.2).sub.3-- --NH-c-Pen
45 --(CH.sub.2).sub.3-- --NH-c-Hex 46 --(CH.sub.2).sub.3--
--NH--(CH.sub.2).sub.2--OH 47 --(CH.sub.2).sub.3-- --NHCH(Me)(OH)
48 --(CH.sub.2).sub.3-- --N(Me)(c-Pen) 49 --(CH.sub.2).sub.3--
--N(Me)(c-Hex) 50 --(CH.sub.2).sub.3-- --N(Me)(Ph) 51
--(CH.sub.2).sub.3-- ##STR01809## 52 --(CH.sub.2).sub.3--
##STR01810## 53 --(CH.sub.2).sub.3-- ##STR01811## 54
--(CH.sub.2).sub.3-- ##STR01812## 55 --(CH.sub.2).sub.3--
##STR01813## 56 --(CH.sub.2).sub.3-- ##STR01814## 57
--(CH.sub.2).sub.4-- --OH 58 --(CH.sub.2).sub.4-- --OMe 59
--(CH.sub.2).sub.4-- --NH.sub.2 60 --(CH.sub.2).sub.4-- --NHMe 61
--(CH.sub.2).sub.4-- --NHEt 62 --(CH.sub.2).sub.4-- --NHPr 63
--(CH.sub.2).sub.4-- --NH-i-Pr 64 --(CH.sub.2).sub.4-- --NMe.sub.2
65 --(CH.sub.2).sub.4-- --NEt.sub.2 66 --(CH.sub.2).sub.4--
--NPr.sub.2 67 --(CH.sub.2).sub.4-- --N(i-Pr).sub.2 68
--(CH.sub.2).sub.4-- --NHPh 69 --(CH.sub.2).sub.4-- --NHBn 70
--(CH.sub.2).sub.4-- --NH-c-Pr 71 --(CH.sub.2).sub.4-- --NH-c-Bu 72
--(CH.sub.2).sub.4-- --NH-c-Pen 73 --(CH.sub.2).sub.4-- --NH-c-Hex
74 --(CH.sub.2).sub.4-- --NH--(CH.sub.2).sub.2--OH 75
--(CH.sub.2).sub.4-- --NHCH(Me)(OH) 76 --(CH.sub.2).sub.4--
--N(Me)(c-Pen) 77 --(CH.sub.2).sub.4-- --N(Me)(c-Hex) 78
--(CH.sub.2).sub.4-- --N(Me)(Ph) 79 --(CH.sub.2).sub.4--
##STR01815## 80 --(CH.sub.2).sub.4-- ##STR01816## 81
--(CH.sub.2).sub.4-- ##STR01817## 82 --(CH.sub.2).sub.4--
##STR01818## 83 --(CH.sub.2).sub.4-- ##STR01819## 84
--(CH.sub.2).sub.4-- ##STR01820##
TABLE-US-00082 TABLE 82 (I-B-2-13) ##STR01821## No -E.sup.1-
-E.sup.3-E.sup.4 1 --CH.sub.2-- Me 2 --CH.sub.2-- Et 3 --CH.sub.2--
Pr 4 --CH.sub.2-- i-Pr 5 --CH.sub.2-- Ph 6 --CH.sub.2-- Bn 7
--CH.sub.2-- c-Pr 8 --CH.sub.2-- c-Bu 9 --CH.sub.2-- c-Pen 10
--CH.sub.2-- c-Hex 11 --CH.sub.2-- ##STR01822## 12 --CH.sub.2--
##STR01823## 13 --CH.sub.2-- ##STR01824## 14 --CH.sub.2--
##STR01825## 15 --CH.sub.2-- ##STR01826## 16 --CH.sub.2--
##STR01827## 17 --(CH.sub.2).sub.2-- Me 18 --(CH.sub.2).sub.2-- Et
19 --(CH.sub.2).sub.2-- Pr 20 --(CH.sub.2).sub.2-- i-Pr 21
--(CH.sub.2).sub.2-- Ph 22 --(CH.sub.2).sub.2-- Bn 23
--(CH.sub.2).sub.2-- c-Pr 24 --(CH.sub.2).sub.2-- c-Bu 25
--(CH.sub.2).sub.2-- c-Pen 26 --(CH.sub.2).sub.2-- c-Hex 27
--(CH.sub.2).sub.2-- ##STR01828## 28 --(CH.sub.2).sub.2--
##STR01829## 29 --(CH.sub.2).sub.2-- ##STR01830## 30
--(CH.sub.2).sub.2-- ##STR01831## 31 --(CH.sub.2).sub.2--
##STR01832## 32 --(CH.sub.2).sub.2-- ##STR01833## 33
--(CH.sub.2).sub.3-- Me 34 --(CH.sub.2).sub.3-- Et 35
--(CH.sub.2).sub.3-- Pr 36 --(CH.sub.2).sub.3-- i-Pr 37
--(CH.sub.2).sub.3-- Ph 38 --(CH.sub.2).sub.3-- Bn 39
--(CH.sub.2).sub.3-- c-Pr 40 --(CH.sub.2).sub.3-- c-Bu 41
--(CH.sub.2).sub.3-- c-Pen 42 --(CH.sub.2).sub.3-- c-Hex 43
--(CH.sub.2).sub.3-- ##STR01834## 44 --(CH.sub.2).sub.3--
##STR01835## 45 --(CH.sub.2).sub.3-- ##STR01836## 46
--(CH.sub.2).sub.3-- ##STR01837## 47 --(CH.sub.2).sub.3--
##STR01838## 48 --(CH.sub.2).sub.3-- ##STR01839##
TABLE-US-00083 TABLE 83 (I-B-2-14) ##STR01840## No -E.sup.1-
-E.sup.3-E.sup.4 1 --CH.sub.2-- Me 2 --CH.sub.2-- Et 3 --CH.sub.2--
Pr 4 --CH.sub.2-- i-Pr 5 --CH.sub.2-- Ph 6 --CH.sub.2-- Bn 7
--CH.sub.2-- c-Pr 8 --CH.sub.2-- c-Bu 9 --CH.sub.2-- c-Pen 10
--CH.sub.2-- c-Hex 11 --CH.sub.2-- ##STR01841## 12 --CH.sub.2--
##STR01842## 13 --CH.sub.2-- ##STR01843## 14 --CH.sub.2--
##STR01844## 15 --CH.sub.2-- ##STR01845## 16 --CH.sub.2--
##STR01846## 17 --(CH.sub.2).sub.2-- Me 18 --(CH.sub.2).sub.2-- Et
19 --(CH.sub.2).sub.2-- Pr 20 --(CH.sub.2).sub.2-- i-Pr 21
--(CH.sub.2).sub.2-- Ph 22 --(CH.sub.2).sub.2-- Bn 23
--(CH.sub.2).sub.2-- c-Pr 24 --(CH.sub.2).sub.2-- c-Bu 25
--(CH.sub.2).sub.2-- c-Pen 26 --(CH.sub.2).sub.2-- c-Hex 27
--(CH.sub.2).sub.2-- ##STR01847## 28 --(CH.sub.2).sub.2--
##STR01848## 29 --(CH.sub.2).sub.2-- ##STR01849## 30
--(CH.sub.2).sub.2-- ##STR01850## 31 --(CH.sub.2).sub.2--
##STR01851## 32 --(CH.sub.2).sub.2-- ##STR01852## 33
--(CH.sub.2).sub.3-- Me 34 --(CH.sub.2).sub.3-- Et 35
--(CH.sub.2).sub.3-- Pr 36 --(CH.sub.2).sub.3-- i-Pr 37
--(CH.sub.2).sub.3-- Ph 38 --(CH.sub.2).sub.3-- Bn 39
--(CH.sub.2).sub.3-- c-Pr 40 --(CH.sub.2).sub.3-- c-Bu 41
--(CH.sub.2).sub.3-- c-Pen 42 --(CH.sub.2).sub.3-- c-Hex 43
--(CH.sub.2).sub.3-- ##STR01853## 44 --(CH.sub.2).sub.3--
##STR01854## 45 --(CH.sub.2).sub.3-- ##STR01855## 46
--(CH.sub.2).sub.3-- ##STR01856## 47 --(CH.sub.2).sub.3--
##STR01857## 48 --(CH.sub.2).sub.3-- ##STR01858##
TABLE-US-00084 TABLE 84 (I-B-2-15) ##STR01859## No -E.sup.1-
-E.sup.3-E.sup.4 1 --CH.sub.2-- Me 2 --CH.sub.2-- Et 3 --CH.sub.2--
Pr 4 --CH.sub.2-- i-Pr 5 --CH.sub.2-- Ph 6 --CH.sub.2-- Bn 7
--CH.sub.2-- c-Pr 8 --CH.sub.2-- c-Bu 9 --CH.sub.2-- c-Pen 10
--CH.sub.2-- c-Hex 11 --CH.sub.2-- ##STR01860## 12 --CH.sub.2--
##STR01861## 13 --CH.sub.2-- ##STR01862## 14 --CH.sub.2--
##STR01863## 15 --CH.sub.2-- ##STR01864## 16 --CH.sub.2--
##STR01865## 17 --(CH.sub.2).sub.2-- Me 18 --(CH.sub.2).sub.2-- Et
19 --(CH.sub.2).sub.2-- Pr 20 --(CH.sub.2).sub.2-- i-Pr 21
--(CH.sub.2).sub.2-- Ph 22 --(CH.sub.2).sub.2-- Bn 23
--(CH.sub.2).sub.2-- c-Pr 24 --(CH.sub.2).sub.2-- c-Bu 25
--(CH.sub.2).sub.2-- c-Pen 26 --(CH.sub.2).sub.2-- c-Hex 27
--(CH.sub.2).sub.2-- ##STR01866## 28 --(CH.sub.2).sub.2--
##STR01867## 29 --(CH.sub.2).sub.2-- ##STR01868## 30
--(CH.sub.2).sub.2-- ##STR01869## 31 --(CH.sub.2).sub.2--
##STR01870## 32 --(CH.sub.2).sub.2-- ##STR01871## 33
--(CH.sub.2).sub.3-- Me 34 --(CH.sub.2).sub.3-- Et 35
--(CH.sub.2).sub.3-- Pr 36 --(CH.sub.2).sub.3-- i-Pr 37
--(CH.sub.2).sub.3-- Ph 38 --(CH.sub.2).sub.3-- Bn 39
--(CH.sub.2).sub.3-- c-Pr 40 --(CH.sub.2).sub.3-- c-Bu 41
--(CH.sub.2).sub.3-- c-Pen 42 --(CH.sub.2).sub.3-- c-Hex 43
--(CH.sub.2).sub.3-- ##STR01872## 44 --(CH.sub.2).sub.3--
##STR01873## 45 --(CH.sub.2).sub.3-- ##STR01874## 46
--(CH.sub.2).sub.3-- ##STR01875## 47 --(CH.sub.2).sub.3--
##STR01876## 48 --(CH.sub.2).sub.3-- ##STR01877##
TABLE-US-00085 TABLE 85 (I-C-1-1) ##STR01878## No -Cyc1-G.sup.2 1
##STR01879## 2 ##STR01880## 3 ##STR01881## 4 ##STR01882## 5
##STR01883## 6 ##STR01884## 7 ##STR01885## 8 ##STR01886## 9
##STR01887## 10 ##STR01888## 11 ##STR01889## 12 ##STR01890## 13
##STR01891## 14 ##STR01892## 15 ##STR01893## 16 ##STR01894## 17
##STR01895## 18 ##STR01896## 19 ##STR01897## 20 ##STR01898##
TABLE-US-00086 TABLE 86 (I-C-1-2) ##STR01899## No -Cyc1-G.sup.2 1
##STR01900## 2 ##STR01901## 3 ##STR01902## 4 ##STR01903## 5
##STR01904## 6 ##STR01905## 7 ##STR01906## 8 ##STR01907## 9
##STR01908## 10 ##STR01909## 11 ##STR01910## 12 ##STR01911## 13
##STR01912## 14 ##STR01913## 15 ##STR01914## 16 ##STR01915## 17
##STR01916## 18 ##STR01917## 19 ##STR01918## 20 ##STR01919##
TABLE-US-00087 TABLE 87 (I-C-1-3) ##STR01920## No -Cyc1-G.sup.2 1
##STR01921## 2 ##STR01922## 3 ##STR01923## 4 ##STR01924## 5
##STR01925## 6 ##STR01926## 7 ##STR01927## 8 ##STR01928## 9
##STR01929## 10 ##STR01930## 11 ##STR01931## 12 ##STR01932## 13
##STR01933## 14 ##STR01934## 15 ##STR01935## 16 ##STR01936## 17
##STR01937## 18 ##STR01938## 19 ##STR01939## 20 ##STR01940##
TABLE-US-00088 TABLE 88 (I-C-2-1) ##STR01941## No -Cyc1-G.sup.2 1
##STR01942## 2 ##STR01943## 3 ##STR01944## 4 ##STR01945## 5
##STR01946## 6 ##STR01947## 7 ##STR01948## 8 ##STR01949## 9
##STR01950## 10 ##STR01951## 11 ##STR01952## 12 ##STR01953## 13
##STR01954## 14 ##STR01955## 15 ##STR01956## 16 ##STR01957## 17
##STR01958## 18 ##STR01959## 19 ##STR01960## 20 ##STR01961##
TABLE-US-00089 TABLE 89 (I-C-2-2) ##STR01962## No -Cyc1-G.sup.2 1
##STR01963## 2 ##STR01964## 3 ##STR01965## 4 ##STR01966## 5
##STR01967## 6 ##STR01968## 7 ##STR01969## 8 ##STR01970## 9
##STR01971## 10 ##STR01972## 11 ##STR01973## 12 ##STR01974## 13
##STR01975## 14 ##STR01976## 15 ##STR01977## 16 ##STR01978## 17
##STR01979## 18 ##STR01980## 19 ##STR01981## 20 ##STR01982##
TABLE-US-00090 TABLE 90 (I-C-2-3) ##STR01983## No -Cyc1-G.sup.2 1
##STR01984## 2 ##STR01985## 3 ##STR01986## 4 ##STR01987## 5
##STR01988## 6 ##STR01989## 7 ##STR01990## 8 ##STR01991## 9
##STR01992## 10 ##STR01993## 11 ##STR01994## 12 ##STR01995## 13
##STR01996## 14 ##STR01997## 15 ##STR01998## 16 ##STR01999## 17
##STR02000## 18 ##STR02001## 19 ##STR02002## 20 ##STR02003##
Processes for the Preparation of the Compound of the Present
Invention:
[0122] The compound represented by formula (I) can be prepared by
the following method or the method described in Example.
(1) Among the compounds of the present invention represented by
formula (I), a compound in which A represents A.sup.1, and D.sup.1
represents --NR.sup.6C(O)-- or --CH.sub.2--NR.sup.6C(O)--, i.e., a
compound represented by formula (IA-1)
##STR02004##
(wherein D.sup.1-1 is --NR.sup.6C(O)-- or
--CH.sub.2--NR.sup.6C(O)--, and other symbols have the same
meanings as described above.) can be prepared by the following
method.
[0123] The compound represented by formula (IA-1) can be prepared
by the amidation of the compounds of formula (II)
##STR02005##
(wherein R.sup.31 is --NHR.sup.6 or --CH.sub.2--NHR.sup.6, and
R.sup.1-1, R.sup.4-1 and
##STR02006##
are R.sup.1, R.sup.4 and
##STR02007##
[0124] respectively. With proviso that, hydroxyl or amino in the
group represented by R.sup.1-1, hydroxyl or amino represented by
R.sup.4-1, and amino in the group represented by
##STR02008##
may be protected, if necessary. Other symbols have the same
meanings as defined above.) and a compound represented by formula
(III)
HOOC-D.sup.2-1-D.sup.3-1 (III)
(wherein D.sup.2-1 and D.sup.3-1 are D.sup.2 and D.sup.3
respectively. With proviso that, amino in the group represented by
D.sup.2-1, and carboxy, hydroxy, amino, amidino or guanidino in
D.sup.3-1 may be protected, if necessary.), if necessary, followed
by removal of the protective group from the resulting product.
[0125] The method of amidation is known. For example, it includes
the method
[0126] (1) an acyl halide,
[0127] (2) via a mixed acid anhydride,
[0128] (3) using a condensing agent.
[0129] These methods are explained as follows.
[0130] (1) The method via an acyl halide may be carried out, for
example, by reacting carboxylic acid with an acyl halide (e.g.,
oxalyl chloride or thionyl chloride etc.) in an organic solvent
(e.g., chloroform, methylene chloride, diethyl ether or
tetrahydrofuran) or without a solvent at -20.degree. C. to reflux
temperature. And then the obtained acyl halide derivative may be
reacted with amine in an inert organic solvent (e.g., chloroform,
methylene chloride, diethyl ether or tetrahydrofuran) in the
presence of tertiary amine (e.g., pyridine, triethylamine,
dimethylaniline or dimethylaminopyridine etc.) at 0 to 40.degree.
C. As an alternative, the obtained acyl halide derivative may be
reacted in an organic solvent (dioxane, tetrahydrofuran) using an
alkaline aqueous solution (e.g., sodium bicarbonate, sodium
hydroxide) at 0 to 40.degree. C.
[0131] (2) The method via a mixed acid anhydride may be carried
out, for example, by reacting carboxylic acid with an acyl halide
(e.g., pivaloyl chloride, tosyl chloride or mesyl chloride) or an
acid derivative (ethyl chloroformate or isobutyl chloroformate) in
an organic solvent (e.g., chloroform, methylene chloride, diethyl
ether, tetrahydrofuran) or without a solvent, in the presence of
tertiary amine (e.g., pyridine, triethylamine, dimethylaniline or
dimethylaminopyridine) at 0 to 40.degree. C. And then the obtained
mixed acid anhydride derivative may be reacted with amine in an
organic solvent (e.g., chloroform, methylene chloride, diethyl
ether or tetrahydrofuran), at 0 to 40.degree. C.
[0132] (3) The method using a condensing agent may be carried out,
for example, by reacting carboxylic acid with amine in an organic
solvent (e.g., chloroform, methylene chloride, dimethylformamide,
diethyl ether or tetrahydrofuran) or without a solvent, in the
presence or absence of tertiary amine (e.g., pyridine,
triethylamine, dimethylaniline or dimethylaminopyridine), using a
condensing agent (e.g., 1,3-dicyclohexyl carbodiimide (DCC),
1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC),
1,1'-carbodiimidazole (CDI), 2-chloro-1-methylpyridinium iodide, or
1-propanephosphonic acid cyclic anhydride (PPA)), in the presence
or absence of 1-hydroxybenzothiazole (HOBt), at 0 to 40.degree.
C.
[0133] The reaction described in (1), (2) and (3) may be carried
out under an inert gas (e.g., argon, nitrogen) to avoid water in
order to obtain a preferable result.
[0134] The removal of the protective group may be carried out by
following method.
[0135] The reaction for removing the protective group for carboxyl,
hydroxyl, amino, amidino or guanidino is well known, including, for
example, the following:
[0136] (1) alkali hydrolysis,
[0137] (2) deprotection under acidic condition,
[0138] (3) deprotection through hydrogenolysis,
[0139] (4) silyl deprotection.
[0140] These methods are explained as follows.
[0141] (1) The deprotection through alkali hydrolysis may be
effected, for example, in an organic solvent (e.g., methanol,
tetrahydrofuran, dioxane) by the use of an alkali metal hydroxide
(e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide),
an alkaline earth metal hydroxide (e.g., barium hydroxide, calcium
hydroxide) or a carbonate (e.g., sodium carbonate, potassium
carbonate), or an aqueous solution thereof or their mixture, at 0
to 40.degree. C.
[0142] (2) The deprotection under acidic condition may be effected,
for example, in an organic solvent (e.g., dichloromethane,
chloroform, dioxane, ethyl acetate, anisole) with an organic
solvent (e.g., acetic acid, trifluoroacetic acid, methanesulfonic
acid, p-toluenesulfonic acid) or an inorganic acid (e.g.,
hydrochloric acid, sulfuric acid) or their mixture (hydrogen
bromide/acetic acid), at 0 to 100.degree. C.
[0143] (3) The deprotection through hydrogenolysis may be effected,
for example, in a solvent (e.g., ether-type (e.g., tetrahydrofuran,
dioxane, dimethoxyethane, diethyl ether), alcohol-type (e.g.,
methanol, ethanol), benzene-type (e.g., benzene, toluene),
ketone-type (e.g., acetone, methyl ethyl ketone), nitrile-type
(e.g., acetonitrile), amide-type (e.g., dimethylformamide), water,
ethyl acetate, acetic acid, or mixed solvent of two or more of
these), in the presence of a catalyst (e.g., palladium-carbon,
palladium-black, palladium hydroxide, platinum oxide, Raney
nickel), in a normal-pressure or increased-pressure hydrogen
atmosphere or in the presence of ammonium formate, at 0 to
200.degree. C.
[0144] (4) The silyl deprotection may be effected, for example, in
a water-miscible organic solvent (e.g., tetrahydrofuran,
acetonitrile) by the use of tetrabutylammonium fluoride, at 0 to
40.degree. C.
[0145] The carboxyl-protective group includes, for example, methyl,
ethyl, t-butyl and benzyl.
[0146] The hydroxyl-protective group includes, for example,
methoxymethyl, 2-tetrahydropyranyl, t-butyldimethylsilyl,
t-butyldiphenylsilyl, acetyl and benzyl.
[0147] The amino, amidino and guanidino-protective group includes,
for example, benzyloxycarbonyl, t-butoxycarbonyl, trifluoroacetyl,
9-fluorenylmethoxycarbonyl and trimethylsilyl.
[0148] The carboxyl, hydroxyl, amino, amidino or
guanidino-protective group may be any others than those mentioned
above, capable of being readily and selectively removed, and are
not specifically defined. For example, those described in T. W.
Greene, Protective Groups in Organic Synthesis, 3rd edition, Wiley,
New York, 1999 may be used.
[0149] The intended compounds of the invention may be readily
produced through selective use of the deprotecting reaction, which
could be readily understood by anyone skilled in the art.
(2) Among the compounds of the present invention represented by
formula (I), a compound in which A represents A.sup.1, and D.sup.1
represents --NR.sup.6SO.sub.2--, i.e., a compound represented by
formula (IA-2)
##STR02009##
(wherein all symbols have the same meanings as described above.)
can be prepared by the following method.
[0150] The compound represented by formula (IA-2) can be prepared
by the sulfonamidation of the compounds of formula (II-1)
##STR02010##
(wherein all symbols have the same meanings as defined above.) and
a compound represented by formula (IV)
##STR02011##
(wherein R.sup.32 is halogen atom and other symbols have the same
meanings as defined above.), if necessary, followed by removal of
the protective group from the resulting product.
[0151] This sulfonamidation is known. For example, it is carried
out at 0 to 40.degree. C. in an inert organic solvent (e.g.,
chloroform, methylene chloride, diethyl ether or tetrahydrofuran)
in the presence of tertiary amine (e.g., pyridine, triethylamine,
dimethylaniline or dimethylaminopyridine).
[0152] The removal of the protective group may be carried out by
the above method.
(3) Among the compounds of the present invention represented by
formula (I), a compound in which A represents A.sup.1, and D.sup.1
represents --OC(O)--, i.e., a compound represented by formula
(IA-3)
##STR02012##
(wherein all symbols have the same meanings as described above.)
can be prepared by the following method.
[0153] The compound represented by formula (IA-3) can be prepared
by esterifying the compounds of formula (V)
##STR02013##
(wherein all symbols have the same meanings as defined above.) with
the above compound represented by formula (III)
HOOC-D.sup.2-1-D.sup.3-1 (III)
(wherein all symbols have the same meanings as defined above.), if
necessary, followed by removal of the protective group from the
resulting product.
[0154] The method of esterification is known. For example, it
includes the method
[0155] (1) via an acyl halide,
[0156] (2) via a mixed acid anhydride,
[0157] (3) using a condensing agent.
[0158] These methods are explained as follows.
[0159] (1) The method via an acyl halide may be carried out, for
example, by reacting carboxylic acid with an acyl halide (e.g.,
oxalyl chloride or thionyl chloride etc.) in an inert organic
solvent (e.g., chloroform, methylene chloride, diethyl ether or
tetrahydrofuran) or without a solvent at -20.degree. C. to reflux
temperature. And then the obtained acyl halide derivative may be
reacted with alcohol in an inert organic solvent (e.g., chloroform,
methylene chloride, diethyl ether or tetrahydrofuran) in the
presence of tertiary amine (e.g., pyridine, triethylamine,
dimethylaniline or dimethylaminopyridine etc.) at 0 to 40.degree.
C.
[0160] (2) The method via a mixed acid anhydride may be carried
out, for example, by reacting carboxylic acid with an acyl halide
(e.g., pivaloyl chloride, tosyl chloride or mesyl chloride) or an
acid derivative (ethyl chloroformate or isobutyl chloroformate) in
an inert organic solvent (e.g., chloroform, methylene chloride,
diethyl ether, tetrahydrofuran) or without a solvent, in the
presence of tertiary amine (e.g., pyridine, triethylamine,
dimethylaniline or dimethylaminopyridine) at 0 to 40.degree. C. And
then the obtained mixed acid anhydride derivative may be reacted
with alcohol in an inert organic solvent (e.g., chloroform,
methylene chloride, diethyl ether or tetrahydrofuran), at 0 to
40.degree. C.
[0161] (3) The method using a condensing agent may be carried out,
for example, by reacting carboxylic acid with alcohol in an organic
solvent (e.g., chloroform, methylene chloride, dimethylformamide,
diethyl ether or tetrahydrofuran) or without a solvent, in the
presence or absence of tertiary amine (e.g., pyridine,
triethylamine, dimethylaniline or dimethylaminopyridine), using a
condensing agent (e.g., 1,3-dicyclohexyl carbodiimide (DCC),
1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC),
1,1'-carbodiimidazole (CDI) or 2-chloro-1-methylpyridinium iodide),
in the presence or absence of 1-hydroxybenzothiazole (HOBt), at 0
to 40.degree. C.
[0162] The reaction described in (1), (2) and (3) may be carried
out under an inert gas (e.g., argon, nitrogen) to avoid water in
order to obtain a preferable result.
[0163] The removal of the protective group may be carried out by
the above method.
[0164] (4) Among the compounds of the present invention represented
by formula (I), a compound in which A represents A.sup.1, and
D.sup.1 represents --CH.sub.2--O--, i.e., a compound represented by
formula (IA-4)
##STR02014##
(wherein all symbols have the same meanings as described above.)
can be prepared by the following method.
[0165] The compound represented by formula (IA-4) can be prepared
by the etherification of the compounds of formula (VI-1)
##STR02015##
(wherein all symbols have the same meanings as described above.)
and the compound of formula (VII-1)
R.sup.33-D.sup.2-1-D.sup.3-1 (VII-1)
(wherein R.sup.33 is a leaving group (halogen atom, mesyloxy or
tosyloxy, etc.) and other symbols have the same meanings as
described above.), if necessary, followed by removal of the
protective group, by the etherification of the compounds of formula
(VI-2)
##STR02016##
(wherein all symbols have the same meanings as described above.)
and the compound of formula (VII-2)
HO-D.sup.2-1-D.sup.3-1 (VII-2)
(wherein all symbols have the same meanings as described above.),
if necessary, followed by removal of the protective group, or by
the etherification of the above compounds of formula (VI-1)
##STR02017##
(wherein all symbols have the same meanings as described above.)
and the compound of formula (VII-2)
HO-D.sup.2-1-D.sup.3-1 (VII-2)
(wherein all symbols have the same meanings as described above.),
if necessary, followed by removal of the protective group.
[0166] This etherification of the compound of formula (VI-1) and
the compound of formula (VII-1), and the compound of formula (VI-2)
and the compound of formula (VII-2) is known. For example, it is
carried out at 0 to 100.degree. C. in an inert organic solvent
(e.g., dimethylformamide, dimethylsulfoxide, chloroform, methylene
chloride, diethyl ether or tetrahydrofuran) in the presence of an
alkali metal hydroxide (e.g., sodium hydroxide, potassium
hydroxide, lithium hydroxide), an alkaline earth metal hydroxide
(e.g., barium hydroxide, calcium hydroxide) or a carbonate (e.g.,
sodium carbonate, potassium carbonate), or an aqueous solution
thereof or their mixture.
[0167] This etherification of the compound of formula (VI-1) and
the compound of formula (VII-2) is known. For example, it is
carried out at 0 to 60.degree. C. by reacting with a corresponding
alcohol compound in an organic solvent (dichloromethane, diethyl
ether, tetrahydrofuran, acetonitrile, benzene, toluene, etc.) in
the presence of an azo compound (diethyl azodicarboxylate,
diisopropyl azodicarboxylate, 1,1'-(azodicarbonyl)dipiperidine,
1,1'-azobis(N,N-dimethylformamide), etc.) and a phosphine compound
(triphenylphosphine, tributylphosphine, trimethylphosphine,
etc.).
[0168] The deprotection reaction of the protective group may be
carried out by the methods described above.
(5) Among the compounds of the present invention represented by
formula (I), a compound in which A represents A.sup.1, and D.sup.1
represents --NR.sup.6--, i.e., a compound represented by formula
(IA-5)
##STR02018##
(wherein all symbols have the same meanings as described above.)
can be prepared by the following method.
[0169] The compound represented by formula (IA-5) can be prepared
by reacting the above compound of formula (II-1)
##STR02019##
(wherein all symbols have the same meanings as described above.)
with the compound of formula (VIII-1)
R.sup.32-D.sup.2-1-D.sup.3-1 (VIII-1)
(wherein all symbols have the same meanings as described above.),
if necessary, followed by removal of the protecting group, or by
reacting the compound of formula (IX)
##STR02020##
(wherein all symbols have the same meanings as described above.)
with the compound of formula (VIII-2)
R.sup.6HN-D.sup.2-1-D.sup.3-1 (VIII-2)
(wherein all symbols have the same meanings as described above.),
if necessary, followed by removal of the protecting group.
[0170] This reaction of the compound of formula (II) and the
compound of formula (VIII-1), and the compound of formula (IX) and
the compound of formula (VIII-2) is known. For example, it is
carried out at 0 to 100.degree. C. in an inert organic solvent
(e.g., dimethylformamide, dimethylsulfoxide, chloroform, methylene
chloride, diethyl ether, tetrahydrofuran or acetonitrile) in the
presence or absence of a base (e.g., triethylamine, pyridine).
[0171] The deprotection reaction of the protective group may be
carried out by the methods described above.
[0172] Among the compounds of the present invention represented by
formula (IA-5), a compound in which D.sup.2 is C1-8 alkylene, C2-8
alkenylene, --(C1-4 alkylene)-O--(C1-4 alkylene)-, --(C1-4
alkylene)-S--(C1-4 alkylene)-, --(C1-4 alkylene)-NR.sup.8--(C1-4
alkylene)-, --(C1-8 alkylene)-(Cyc2)- or --(C1-4
alkylene)-(Cyc2)-(C1-4 alkylene)-, i.e., a compound represented by
formula (IA-5-1)
##STR02021##
(wherein D.sup.2' is C1-8 alkylene, C2-8 alkenylene, --(C1-4
alkylene)-O--(C1-4 alkylene)-, --(C1-4 alkylene)-S--(C1-4
alkylene)-, --(C1-4 alkylene)-NR.sup.8--(C1-4 alkylene)-, --(C1-8
alkylene)-(Cyc2)- or --(C1-4 alkylene)-(Cyc2)-(C1-4 alkylene)- and
other symbols have the same meanings as described above.) can be
prepared by reductive amination of the above compound of formula
(II-1)
##STR02022##
(wherein all symbols have the same meanings as described above.)
and the compound of formula (VIII-3)
OHC-D.sup.2''-D.sup.3-1 (VIII-3)
(wherein D.sup.2'' is C1-7 alkylene, C2-7 alkenylene, --(C1-3
alkylene)-O--(C1-4 alkylene)-, --(C1-3 alkylene)-S--(C1-4
alkylene)-, --(C1-3 alkylene)-NR.sup.8--(C1-4 alkylene)-, --(C1-7
alkylene)-(Cyc2)- or --(C1-3 alkylene)-(Cyc2)-(C1-4 alkylene)- and
other symbols have the same meanings as described above.), if
necessary, followed by removal of the protecting group.
[0173] The reductive amination is well known. For example, it may
be carried out in an organic solvent (e.g., methanol, ethanol) in
the presence of reducing agent (e.g., sodium cyanoborohydride,
sodium borohydride, sodium triacetoxyborohydride) and, if
necessary, in the presence of an acid (e.g., acetic acid, hydrogen
chloride) at -20 to 60.degree. C.
[0174] The removal of the protective group may be carried out by
the methods described above.
(6) Among the compounds of the present invention represent by
formula (I), a compound in which A is A.sup.1 and D.sup.1 is
--CH.sub.2--NR.sup.6--, i.e., a compound of formula (IA-6)
##STR02023##
(wherein all symbols have the same meanings as described above.)
can be prepared by the following method.
[0175] The compound represented by formula (IA-6) can be prepared
by reacting the compound of formula (X)
##STR02024##
(wherein all symbols have the same meanings as described above.)
with the above compound of formula (VIII-1)
R.sup.32-D.sup.2-1-D.sup.3-1 (VIII-1)
(wherein all symbols have the same meanings as described above.),
if necessary, followed by removal of the protecting group, or by
reductive amination of the compound of formula (XI)
##STR02025##
(wherein all symbols have the same meanings as described above.)
with the above compound of formula (VIII-2)
R.sup.6HN-D.sup.2-1-D.sup.3-1 (VIII-2)
(wherein all symbols have the same meanings as described above.),
if necessary, followed by removal of the protecting group.
[0176] The reaction of the compound of formula (X) and the compound
of formula (VIII-1) may be carried out by the same method as the
above reaction of the compound of formula (IX) and the compound of
formula (VIII-2).
[0177] The reaction of the compound of formula (XI) and the
compound of formula (VIII-2) may be carried out by the same method
as the above reaction of the compound of formula (II-1) and the
compound of formula (VIII-3).
[0178] The removal of the protective group may be carried out by
the methods described above.
(7) Among the compounds represented by formula (I), a compound in
which A is A.sup.1 and D.sup.1 is --NR.sup.6C(O)NR.sup.7--, i.e., a
compound (IA-7)
##STR02026##
(wherein all symbols have the same meanings as described above.)
can be prepared by the following method.
[0179] The compound represented by formula (IA-7) can be prepared
by reacting the above compound of formula (II-1)
##STR02027##
(wherein all symbols have the same meanings as described above.)
with the compound of formula (XII)
O.dbd.C.dbd.N-D.sup.2-1-D.sup.3-1 (XII)
(wherein all symbols have the same meanings as described above.),
if necessary, followed by removal of the protecting group.
[0180] The reaction is known. It may be carried out in organic
solvent (e.g., tetrahydrofuran, methylene chloride, diethyl ether)
at 0 to 100.degree. C.
[0181] The removal of the protective group may be carried out by
the methods described above.
(8) Among the compounds represented by formula (I), a compound in
which A is A.sup.1 and D.sup.1 is --NR.sup.6C(S)NR.sup.7--, i.e., a
compound of formula (IA-8)
##STR02028##
(wherein all symbols have the same meanings as described above.)
can be prepared by the following method.
[0182] The compound represented by formula (IA-8) can be prepared
by reacting the above compound of formula (II-1)
##STR02029##
(wherein all symbols have the same meanings as described above.)
with the compound of formula (XIII)
S.dbd.C.dbd.N-D.sup.2-1-D.sup.3-1 (XIII)
(wherein all symbols have the same meanings as described above.),
if necessary, followed by removal of the protecting group.
[0183] The reaction is known. It may be carried out in an organic
solvent (tetrahydro furan, methylene chloride, diethyl ether) at 0
to 100.degree. C.
[0184] The removal of the protective group may be carried out by
the methods described above.
(9) Among the compound of the present invention represented by
formula (I), a compound in which A is A.sup.1 and D.sup.1 is
--NR.sup.6C(O)O--, i.e., a compound of formula (IA-9)
##STR02030##
(wherein all symbols have the same meanings as described above.)
can be prepared by the following method.
[0185] The compound represented by formula (IA-9) can be prepared
by reacting the above compound of formula (II-1)
##STR02031##
(wherein all symbols have the same meanings as described above.)
with the compound of formula (XIV)
##STR02032##
(wherein all symbols have the same meanings as described above.),
if necessary, followed by removal of the protecting group.
[0186] The reaction is known. It may be carried out in an organic
solvent (e.g., tetrahydrofuran, methylene chloride, diethyl ether)
at -78 to 40.degree. C.
[0187] The removal of the protective group may be carried out by
the methods described above.
(10) Among the compounds of the present invention represented by
formula (I), a compound in which A is A.sup.1 and D.sup.1 is
--NR.sup.6C(S)--, i.e., a compound of formula (IA-10)
##STR02033##
(wherein all symbols have the same meanings as described above.)
can be prepared by the following method.
[0188] The compound represented by formula (IA-10) can be prepared
by thiocarbonylation of the compound of formula (XV)
##STR02034##
(wherein all symbols have the same meanings as described above.),
if necessary, followed by removal of the protecting group.
[0189] The reaction is known. It may be carried out in an organic
solvent (e.g., dioxane, benzene, toluene, xylene, tetrahydrofuran),
using Lawesson reagent
(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)
at 20 to 150.degree. C.
[0190] The removal of the protective group may be carried out by
the methods described above.
(11) Among the compound of the present invention represented by
formula (I), a compound in which A is A.sup.1 and D.sup.1 is
--NR.sup.6C(.dbd.NR.sup.7)--, i.e., a compound of formula
(IA-11)
##STR02035##
(wherein all symbols have the same meanings as described above.)
can be prepared by the following method.
[0191] The compound of formula (IA-11) can be prepared by reacting
the above compound of formula (II-1)
##STR02036##
(wherein all symbols have the same meanings as described above.)
with the compound of formula (XVI)
##STR02037##
(wherein R.sup.34 is C1-4 alkyl and other symbols have the same
meanings as described above.), if necessary, followed by removal of
the protecting group.
[0192] The reaction is known. For example, it may be carried out in
an organic solvent (e.g., methanol, ethanol) at 0 to 50.degree.
C.
[0193] The removal of the protective group may be carried out by
the methods described above.
(12) Among the compound of the present invention represented by
formula (I), a compound in which A is A.sup.1 and D.sup.3 is
--NR.sup.9R.sup.10 or hetero ring represented by
##STR02038##
(among Cyc2, the hetero ring is a hetero ring having at least one
nitrogen atom which binds to D.sup.2), i.e., a compound of formula
(IA-12)
##STR02039##
(wherein D.sup.3-2 is --NR.sup.9R.sup.10 or hetero ring represented
by
##STR02040##
(among Cyc2, the hetero ring is a hetero ring having at least one
nitrogen atom which binds to D.sup.2 and other symbols have the
same meanings as described above.) can be prepared by the following
method.
[0194] The compound represented by formula (IA-12) can be prepared
by reacting a compound of formula (XVII)
##STR02041##
(wherein all symbols have the same meanings as described above.)
with a compound of formula (XVIII)
H--NR.sup.9R.sup.10 (XVIII)
(wherein all symbols have the same meanings as described above.) or
a compound of formula (XIX)
##STR02042##
(wherein all symbols have the same meanings as described above.),
if necessary, followed by removal of the protecting group.
[0195] The reaction of the compound of formula (XVII) and the
compound of formula (XVIII) or (XIX) may be carried out by the same
method as the above reaction of the compound of formula (IX) and
the compound of formula (VIII-2).
[0196] The removal of the protective group may be carried out by
the methods described above.
(13) Among the compounds of the present invention represented
formula (I), a compound in which A is A.sup.2, and E.sup.2 is
--C(O)NR.sup.24--, i.e., a compound of formula (IB-1)
##STR02043##
(wherein all symbols have the same meanings as described above.)
can be prepared by the following method.
[0197] The compound of formula (IB-1) can be prepared by amidation
of a compound of formula (XX)
##STR02044##
(wherein all symbols have the same meanings as described above.)
and the compound of formula (XXI)
##STR02045##
(wherein E.sup.4-1 is E.sup.4. With proviso that, hydroxyl, amino
or carboxyl in the group represented by E.sup.4-1 may be protected,
if necessary. Other symbols have the same meanings as defined
above.), if necessary, followed by removal of the protecting
group.
[0198] The amidation and the removal of the protective group may be
carried out by the methods described above.
(14) Among the compounds of the present invention represented by
formula (I), a compound in which A is A.sup.2 and E.sup.2 is
--NR.sup.24C(O)--, i.e., a compound of formula (IB-2)
##STR02046##
(wherein all symbols have the same meanings as described above.)
can be prepared by the following method.
[0199] The compound of formula (IB-2) can be prepared by amidation
of a compound of formula (XXII)
##STR02047##
(wherein all symbols have the same meanings as described above.)
and a compound of formula (XXIII)
HOOC-E.sup.3-E.sup.4-1 (XXIII)
(wherein all symbols have the same meanings as described above.),
if necessary, followed by removal of the protecting group.
[0200] The amidation and the removal of the protective group may be
carried out by the methods described above.
(15) Among the compounds of the present invention represented by
formula (I), a compound in which A is A.sup.2 and E.sup.2 is
--NR.sup.24--, i.e., a compound of formula (IB-3)
##STR02048##
(wherein all symbols have the same meanings as described above.)
can be prepared by the following method.
[0201] The compound of formula (IB-3) can be prepared by reacting a
compound of formula (XXIV)
##STR02049##
(wherein all symbols have the same meanings as described above.)
with the above compound of formula (XXI)
##STR02050##
(wherein all symbols have the same meanings as described above.),
if necessary, followed by removal of the protecting group.
[0202] The reaction of the compound of formula (XXIV) and the
compound of formula (XXI) may be carried out by the same method as
the above reaction of the compound of formula (IX) and the compound
formula (VIII-2).
[0203] The removal of the protective group may be carried out by
the methods described above.
(16) Among the compound of the present invention represented by
formula (I), a compound in which A is A.sup.2, and E.sup.2 is
--C(O)O--, i.e., a compound of formula (IB-4)
##STR02051##
(wherein all symbols have the same meanings as described above.)
can be prepared by the following method.
[0204] The compound of formula (IB-4) can be prepared by
esterifying the compound of formula (XX)
##STR02052##
(wherein all symbols have the same meanings as described above.)
with a compound of formula (XXV)
HO-E.sup.3-E.sup.4-1 (XXV)
(wherein all symbols have the same meanings as described above.),
if necessary, followed by removal of the protecting group.
[0205] The esterifying and the removal of the protective group may
be carried out by the methods described above.
(17) Among the compounds of the present invention represented by
formula (I), a compound in which A is A.sup.2, and E.sup.2 is
--S--, i.e., a compound of formula (IB-5)
##STR02053##
(wherein all symbols have the same meanings as described above.)
can be prepared by the following method.
[0206] The compound of formula (IB-5) can be prepared by reacting a
compound of formula (XXVI)
##STR02054##
(wherein all symbols have the same meanings as described above.)
with a compound of formula (XXVII)
R.sup.32-E.sup.3-E.sup.4-1 (XXVII)
(wherein all symbols have the same meanings as described above.),
if necessary, followed by removal of the protecting group.
[0207] The reaction is known. For example, it may be carried out in
an inert organic solvent (e.g., dimethylformamide,
dimethylsulfoxide, chloroform, methylene chloride, diethyl ether,
tetrahydrofuran, acetonitrile) in the presence or absence of a base
(e.g., triethylamine, pyridine) at 0 to 100.degree. C.
[0208] The removal of the protective group may be carried out by
the methods described above.
(18) Among the compounds of the present invention represented by
formula (I), a compound in which A is A.sup.2, and E.sup.4 is
--NR.sup.25R.sup.26 or hetero ring represented by
##STR02055##
(The hetero ring is a hetero ring having at least one nitrogen atom
(The nitrogen atom binds to E.sup.3.) in Cyc5.), i.e., a compound
of formula (IB-6)
##STR02056##
(wherein E.sup.4-2 is --NR.sup.25R.sup.26 or hetero ring
represented by
##STR02057##
(The hetero ring is a hetero ring having at least one nitrogen atom
(The nitrogen atom binds to E.sup.3.) in Cyc5.) and other symbols
have the same meanings as described above.) can be prepared by the
following method.
[0209] The compound of formula (IB-6) can be prepared by reacting a
compound of formula (XXVIII)
##STR02058##
(wherein all symbols have the same meanings as described above.)
with a compound of formula (XXIX)
H--NR.sup.25R.sup.26 (XXIX)
(wherein all symbols have the same meanings as described above.) or
a compound of formula (XXX)
##STR02059##
(wherein all symbols have the same meanings as described above.),
if necessary, followed by removal of the protecting group.
[0210] The reaction of the compound of formula (XXVIII) and the
compound of formula (XXIX) or (XXX) may be carried out by the same
method as the above reaction of the compound of formula (IX) and
the compound of formula (VIII-2).
[0211] The removal of the protective group may be carried out by
the methods described above.
(19) Among the compounds of the present invention represented by
formula (I), a compound in which A is A.sup.3, i.e., a compound of
formula (IC-1)
##STR02060##
(wherein all symbols have the same meanings as described above.)
can be prepared by the following method.
[0212] The compound of formula (IC-1) can be prepared by reacting a
compound of formula (XXXI)
##STR02061##
(wherein G.sup.1-1 is bond or C1-7 alkylene, Cyc1' and G.sup.2-1
are Cyc1 and G.sup.2 respectively. With proviso that amino in the
group represented by Cyc1, and hydroxy and amino in the group
represented by G.sup.2-1 may be protected, if necessary. Other
symbols have the same meanings as described above.) with hydrazine
or a salt thereof (e.g., hydride, chloride), if necessary, followed
by removal the protecting group.
[0213] The reaction is known. For example, it may be carried out in
an organic solvent (e.g., methanol, ethanol, propanol, isopropanol,
butanol, acetic acid, tetrahydrofuran) at 50.degree. C. to reflux
temperature.
[0214] The removal of the protective group may be carried out by
the methods described above.
[0215] Moreover, among the compounds of the present invention
represented by formula (IC-1), a compound in which Cyc1 is hetero
ring represented by
##STR02062##
(The hetero ring is a hetero ring having at least one nitrogen atom
(The nitrogen atom binds to G.sup.1.) in Cyc1.), i.e., a compound
of formula (IC-1-1)
##STR02063##
is a hetero ring having at least one nitrogen atom (The nitrogen
atom binds to G.sup.1.) in Cyc1 and other symbols have the same
meanings as described above.) can be prepared by following
method.
[0216] The compound of formula (IC-1-1) can be prepared by reacting
a compound of formula (XXXII)
##STR02064##
(wherein all symbols have the same meanings as described above.)
with a compound of formula (XXXIII)
##STR02065##
(wherein all symbols have the same meanings as described above.),
if necessary, followed by removal the protecting group.
[0217] The reaction of the compound of formula (XXXII) and the
compound of formula (XXXIII) may be carried out by the same method
as the above reaction of the compound of formula (IX) and the
compound of formula (VIII-2).
[0218] The removal of the protective group may be carried out by
the methods described above.
(20) Among the compounds of the present invention represented by
formula (I), a compound in which A is A.sup.4 or A.sup.5, i.e., a
compound of (ID-1)
##STR02066##
(wherein A.sup.6 is A.sup.4 or A.sup.5 and other symbols have the
same meanings as described above.) can be prepared by the following
a) to b). a) The compound of formula (ID-1) can be prepared by
reacting a compound of formula (XXXIV-1)
##STR02067##
(wherein R.sup.35 is C1-8 alkyl, and A.sup.6-1 is A.sup.6. With
proviso that hydroxy or amino in the group represented by A.sup.6-1
may be protected, if necessary. Other symbols have the same
meanings as described above.) or a compound of formula
(XXXIV-2)
##STR02068##
(wherein all symbols have the same meanings as described above.)
with hydrazine or a salt thereof (e.g., hydride, chloride), if
necessary, followed by removal the protecting group.
[0219] The reaction is known. For example, it may be carried out in
an organic solvent (e.g., methanol, ethanol, propanol, isopropanol,
butanol, acetic acid, tetrahydrofuran) at 50.degree. C. to reflux
temperature.
[0220] The removal of the protective group may be carried out by
the methods described above.
b) The compound of formula (ID-1) can be prepared by reacting a
compound of formula (XXXV)
##STR02069##
(wherein all symbols have the same meanings as described above.)
with hydrazine and a salt thereof (e.g., hydride, chloride), if
necessary, followed by removal the protecting group.
[0221] The reaction is known. For example, it may be carried out in
an organic solvent (e.g., methanol, ethanol, propanol, isopropanol,
butanol, acetic acid, tetrahydrofuran) at 50.degree. C. to reflux
temperature.
[0222] The removal of the protective group may be carried out by
the methods described above.
[0223] Moreover, among the compound of formula (ID-1), a compound
in which X is N,
is single bond, i.e., a compound of formula (ID-1-1)
##STR02070##
(wherein all symbols have the same meanings as described above.)
can be prepared by the following method.
[0224] The compound of formula (ID-1-1) can be prepared by reacting
a compound of formula (XXXVI)
##STR02071##
(wherein all symbols have the same meanings as described above.)
with a compound of formula (XXXVII)
##STR02072##
(wherein R.sup.35 has the same meaning as described above.), if
necessary, followed by removal of the protecting group.
[0225] The reaction may be carried out, for example, in an organic
solvent (e.g., toluene, tetrahydrofuran, chloroform, methylene
chloride) in the presence or absence of catalyst (e.g.,
p-toluenesulfonic acid, pyridine) at 50.degree. C. to reflux
temperature.
[0226] The removal of the protective group may be carried out by
the methods described above.
[0227] The compounds represented by formulae (II), (II-1), (III),
(IV), (V), (VI-1), (VI-2), (VII-1), (VII-2), (VIII-1), (VIII-2),
(VIII-3), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI),
(XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV),
(XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII),
(XXXIII), (XXXIV-1), (XXXIV-2), (XXXV), (XXXVI) and (XXXVII) are
known compounds or can be prepared by known methods or methods as
described in Examples.
[0228] For example the compounds of formulae (II), (II-1), (V),
(VI-1), (VI-2), (IX), (X), (XI), (XX), (XXII), (XXIV), (XXVI),
(XXXI), (XXXIV-1), (XXXIV-2), (XXXV) and (XXXVI) can be prepared by
the method described in reaction scheme 1, 2, 3 and 4.
[0229] In each reaction scheme, R.sup.36 is --NHR.sup.6,
--CH.sub.2--NHR.sup.6, --OH, --CH.sub.2--OH, --CH.sub.2--R.sup.33
or halogen atom. With proviso that hydroxy and amino in the group
represented by R.sup.36 may be protected, if necessary. R.sup.37 is
the protecting group of amino, R.sup.38 is --NHR.sup.6,
--CH.sub.2--NHR.sup.6, --OH, --CH.sub.2--OH, --CH.sub.2--R.sup.33
or halogen atom, BOP is
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate, Me is methyl, Et is ethyl, E.sup.1-1 is bond
or C1-3 alkylene, Ph is phenyl, TBAF is tetrabutylammonium
fluoride, TMSN.sub.3 is trimethylsilylazide, and R.sup.39 is COOH,
--NHR.sup.24, halogen atom or --SCOCH.sub.3. With proviso that
amino or carboxy in the group represented by R.sup.39 may be
protected, if necessary. R.sup.40 is COOH, --NHR.sup.24, halogen
atom or --SCOCH.sub.3, and other symbols have the same meanings as
described above. The compound represented by formulae (XXXIX) and
(XXXXXV) with bromo instead of chloro may be used, which could be
readily understood by anyone skilled in the art.
##STR02073##
##STR02074##
##STR02075##
##STR02076##
[0230] In Reaction Schemes 1, 2, 3 and 4, the compounds used as the
starting materials are known compounds or can be prepared easily by
known methods.
[0231] In each reaction described herein, the reaction product can
be purified by general purification techniques such as distillation
under ordinary pressure or a reduced pressure, high performance
liquid chromatography, thin layer chromatography or column
chromatography using silica gel or magnesium silicate, washing and
recrystallization. Purification may be carried out in each reaction
or after completion of several reactions.
Pharmacological Activities:
[0232] It has been confirmed that the compounds of the present
invention of formula (I) have PARP inhibitory activity by the
following experimental results.
1) Enzyme Assay In Vitro
Methods
[0233] The below procedure was carried out with 96 well plate at
room temperature. In a final volume of 80 .mu.L, the reaction
mixture contained each 10 .mu.L of 500 mM Tris/HCl (pH 8.0, WAKO),
100 mM MgCl.sub.2, 50 mM dithiothreitol (sigma), 1 mg/mL activated
DNA and 1 mM NAD (containing .sup.3H-NAD). The 10 .mu.L of test
compound was added to the reaction mixture and the reaction was
started by addition of 10 .mu.L of 0.1 U/.mu.L PARP (TREVIGEN). The
reaction was terminated at 10 minutes by addition of 100 .mu.L of
20% trichloroacetic acid. Poly(ADP-ribose), which is the reaction
product, was collected on a glass fiber filter (GF/C, PACKARD). The
radioactivity was measured by topcount (PACKARD). Inhibitory
activity of the compound was represented by 50% inhibitory
concentration calculated as 100% of control (distilled water). The
results were shown in Table 91.
TABLE-US-00091 TABLE 91 Example No. IC.sub.50(.mu.M) 6 (9) 0.61 11
(4) 0.10 30 (4) 0.29
2) Ischemia-Reperfusion Injury Model (Brain and Heart)
[0234] Model of cerebral or coronary ischemia-reperfusion was
prepared according to procedures described previously (Jpn. J.
Stroke, 8, 1 (1986), Stroke, 27, 1624-1628 (1996) and Eur. J.
Pharmacol., 270, 45 (1994)). The compounds of the present invention
were improvement effective of these diseases.
Toxicity:
[0235] The toxicity of the compounds of the present invention
represented by formula (I) is very low (For example, as a result of
administering the compounds of the present invention to rats, they
did not affect circulatory parameters, such as blood pressure, an
electrocardiogram, and heart rate.) and therefore the compounds may
be considered safe for pharmaceutical use.
INDUSTRIAL APPLICABILITY
Application to Pharmaceutical
[0236] Since the compound of the present invention represented by
formula (I) has PARP inhibitory activity, it is useful for
prevention and/or treatment of various diseases, for example,
ischemic diseases (cerebral infarction, myocardial infarction,
reperfusion injury or postoperative injury etc.), inflammatory
diseases (inflammatory bowel disease, multiple sclerosis, arthritis
or lung injury etc.), neurodegenerative disorders (extrapyramidal
disease, Parkinson's disease, Alzheimer's disease, muscular
dystrophy or lumbar spinal canal stenosis etc.), glaucoma,
diabetes, diabetic complication, shock, head trauma, spinal cord
injury, renal failure or hyperalgesia etc. Moreover, it is useful
as an antiretroviral drug such as an anti HIV drug, a sensitizer of
anticancer therapy or an immunosuppressant.
[0237] The compound represented by formula (I) or pharmaceutically
acceptable salt thereof may be administered in combination with
other pharmaceutical preparations to accomplish the following
purposes:
1) To complement for and/or enhance the preventive and/or treatment
effect of the compound to be combined; 2) To improve the
kinetics/absorption of the compound to be combined and reduce the
dose of the compound; and/or 3) To eliminate the side effect of the
compound to be combined
[0238] The compound represented by formula (I) and other
pharmaceutical preparations may be administered in the form of
formulation having these components incorporated in one preparation
or may be administered in separate preparations. In the case where
these pharmaceutical preparations are administered in separate
preparations, they may be administered simultaneously or at
different times. In the latter case, the compound represented by
formula (I) may be administered before the other pharmaceutical
preparations. Alternatively, the other pharmaceutical preparations
may be administered before the compound represented by formula (I).
The method for the administration of these pharmaceutical
preparations may be the same or different.
[0239] The diseases on which the preventive and/or treatment effect
of the aforementioned combined preparations works are not
specifically limited but may be those for which the preventive
and/or treatment effect of the compound represented by formula (I)
is complemented and/or enhanced.
[0240] Examples of the other pharmaceutical preparations for
complementing and/or enhancing the preventive and/or treatment
effect of the compound represented by formula (I) on ischemic
diseases include radical scavenger, astrocyto modulator,
N-methyl-D-aspartate (NMDA) antagonist,
alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)
antagonist, antithrombotic agent, thrombolytic agent,
immunosuppressive agent, cell adhesion molecules inhibitor,
nitrogen oxide synthase (NOS) inhibitor, neurotrophic factor and
interleukin-8 inhibitor etc.
[0241] Examples of the other pharmaceutical preparations for
complementing and/or enhancing the preventive and/or treatment
effect of the compound represented by formula (I) on lumbar spinal
canal stenosis include nitrogen oxide synthase (NOS) inhibitor,
aldose reductase (AR) inhibitor, radical scavenger,
N-methyl-D-aspartate (NMDA) antagonist,
alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)
antagonist, neurotrophic factor and interleukin-8 inhibitor
etc.
[0242] Examples of the radical scavenger include, for example,
edaravone and ebselen (DR-3305) etc.
[0243] Examples of the astrocyto modulator include, for example,
ONO-2506 etc.
[0244] Examples of the antithrombotic agent include, for example,
sodium ozagrel, argatroban and aspirin etc.
[0245] Examples of the thrombolytic agent include, for example,
tissue plasminogen activator (t-PA), urokinase and heparin etc.
[0246] Examples of the immunosuppressive agent include, for
example, cyclosporin A, cyclophosphamide and tacrolimus etc.
[0247] Examples of the NOS inhibitor include, for example, L-NMMA
and ONO-1714 etc.
[0248] Examples of the AR inhibitor include, for example,
epalrestat, zenarestat, fidarestat, zopolrestat and AS-3201
etc.
[0249] The weight proportion of the compound represented by formula
(I) and the other pharmaceutical preparations is not specifically
limited.
[0250] Arbitrary two or more of the other pharmaceutical
preparations may be administered in combination.
[0251] Examples of the other pharmaceutical preparations for
complementing and/or enhancing the preventive and/or treatment
effect of the compound represented by formula (I) include not only
those which have so far been found but also those which will be
found on the basis of the aforementioned mechanism.
[0252] In order to use the compound of the present invention
represented by formula (I) or the pharmaceutically acceptable salt
thereof, or the compound represented by formula (I) in combination
with the other pharmaceutical preparations, these compounds are
normally administered to the entire or local part of human body
orally or parenterally.
[0253] The doses to be administered are determined depending upon,
for example, age, body weight, symptom, the desired therapeutic
effect, the route of administration, and the duration of the
treatment. In the human adult, the doses per person are generally
from 1 mg to 1000 mg, by oral administration, up to several times
per day, and from 1 mg to 100 mg, by parenteral administration
(preferably intravenous administration), up to several times per
day, or continuous administration from 1 to 24 hours per day from
vein.
[0254] As mentioned above, the doses to be used depend upon various
conditions. Therefore, there are cases in which doses lower than or
greater than the ranges specified above may be used.
[0255] The compound represented by formula (I) or the
pharmaceutically acceptable salt thereof, or the concomitant drug
combined the compound represented by formula (I) with
pharmaceutical preparations may be administered in the form of, for
example, solid compositions, liquid compositions or other
compositions each for oral administration, or injections,
preparations for external use or suppositories, each for parenteral
administration.
[0256] Solid compositions for oral administration include
compressed tablets, pills, capsules, powders, and granules.
[0257] Capsules include hard capsules and soft capsules.
[0258] In such solid compositions, one or more of the active
substance(s) may be admixed with at least one inert diluent such as
lactose, mannitol, glucose, hydroxypropyl cellulose,
microcrystalline cellulose, starch, polyvinylpyrrolidone or
magnesium aluminometasilicate. The compositions may comprise, in
accordance with the conventional process, additives other than the
inert diluent, for example, lubricants such as magnesium stearate,
disintegrants such as cellulose calcium glycolate, stabilizer such
as lactose, and solubilizing agent such as glutamic acid or
aspartic acid. Tablets or pills may be coated with a film of a
gastric soluble or enteric substance such as sucrose, gelatin,
hydroxypropyl cellulose or hydroxypropyl methylcellulose phthalate,
or with two or more layers, if necessary. Furthermore, capsules
made of a substance which can be absorbed in the body, for example,
gelatin, are included.
[0259] Liquid compositions for oral administration include
pharmaceutically acceptable emulsions, solutions, syrups and
elixirs etc. Such liquid compositions comprise one or more of the
active substance(s) and an ordinarily employed inert diluent(s)
(for example, purified water or ethanol) dissolving the
substance(s) therein. The compositions may comprise, in addition to
the inert diluent, an adjuvant such as humectants or suspending
agents, sweetening agents, flavoring agents, aromatic agents and
antiseptics.
[0260] The other compositions for oral administration include
sprays which comprise one or more active substance(s) and are
formulated in a manner known per se in the art. The compositions
may comprise, in addition to an inert diluent, a stabilizer such as
sodium bisulfite and an isotonization buffer such as sodium
chloride, sodium citrate or citric acid. The preparation process of
sprays is described in detail in, for example, U.S. Pat. Nos.
2,868,691 and 3,095,355.
[0261] In the present invention, injections for parenteral
administration include sterile aqueous and/or non-aqueous
solutions, suspensions and emulsions. The aqueous solutions or
suspensions include, for example, distilled water for injection and
saline. The non-aqueous solutions or suspensions include propylene
glycol, polyethylene glycol, vegetable oils such as olive oil,
alcohol such as ethanol and Polysorbate 80 (trade mark).
Furthermore, sterile aqueous and non-aqueous solutions,
suspensions, and emulsions may be used in combination. Such
compositions may additionally comprise adjuvants such as
antisaptic, humectant, emulsfier, dispersant, stabilizer (such as
lactose) and solubilizing agent (such as glutamic acid and aspartic
acid). They are sterilized by filtration through a bacteria
retaining filter, the addition of a sterilizer, or irradiation.
Also, a sterile solid composition is prepared and then, for
example, a freeze-dried product may be dissolved in sterilized or
sterile distilled water for injection or another sterile solvent
before use.
[0262] The other compositions for parenteral administration include
liquids for external use, ointments, endermic liniments,
suppositories for intrarectal administration and pessaries for
vaginal administration which comprise one or more of the active
substance(s) and may be prepared by methods known per se.
BEST MODE FOR CARRYING OUT THE INVENTION
[0263] The present invention is explained below in detail based on
Reference Examples and Examples, however, the present invention is
not limited thereto.
[0264] The solvents in the parentheses show the developing or
eluting solvents and the ratios of the solvents used are by volume
in chromatographic separations or TLC. The solvents in the
parentheses in NMR show the solvents for measurement.
REFERENCE EXAMPLE 1
3-(3-aminophenyl)-3-methoxy-4,5,6,7-tetrahydro-2-benzofuran-1(3H)-one
[0265] To a solution of 3,4,5,6-tetrahydrophthalic acid anhydride
(3.04 g) in tetrahydrofuran (40.0 mL) was added a solution of
3-(bis(trimethylsilyl)amino)phenylmagnesium chloride in
tetrahydrofuran (1M, 20.0 mL) at -78.degree. C. The mixture was
stirred for 1.5 hours. A saturated aqueous ammonium chloride
solution was added to the reaction mixture, which was stirred at
room temperature for 30 minutes. Anhydrous magnesium sulfate was
added to the reaction mixture, which was filtrated. The filtrate
was concentrated to give an oily product. Thionyl chloride (5.20
mL) was added dropwise to methanol (20.0 mL) at -10.degree. C. and
then the solution was stirred at 0.degree. C. for 15 minutes. To
the solution was added the oily product obtained previously and the
solution was stirred at room temperature for 18 hours. The reaction
mixture was concentrated. The obtained residue was dissolved in
methylene chloride (20 mL) and thereto was added triethylamine
(2.79 mL) at 0.degree. C. Water was added to the reaction solution,
which was extracted with methylene chloride. The extract was washed
with water, a saturated aqueous sodium hydrogen carbonate solution
and brine sequentially, dried over anhydrous magnesium sulfate and
concentrated. The residue was purified by column chromatography on
silica gel (ethyl acetate:hexane=3:7) to give the title compound
(2.56 g) having the following physical data.
[0266] NMR (DMSO-d.sub.6): .delta. 7.03 (t, J=7.8 Hz, 1H),
6.60-6.47 (m, 3H), 5.21 (brs, 2H), 3.20 (s, 3H), 2.17-1.60 (m,
8H).
EXAMPLE 1
4-(3-aminophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0267] A solution of the compound prepared in Reference example 1
(2.56 g) and hydrazine monohydrate (503 mg) in ethanol (30.0 mL)
was refluxed for 18 hours. After cooling the reaction mixture to
room temperature, the deposited crystal was collected by
filtration. It was washed with hexane and dried under reduced
pressure. 4N hydrogen chloride in dioxane (0.10 mL) was added
dropwise to a suspension of the obtained solid (32.0 mg) in
methanol (1.00 mL) and the mixture was stirred at room temperature
for 30 minutes. The reaction mixture was concentrated. The obtained
crystal was dried under reduced pressure to give the compound of
the present invention (36.2 mg) having the following physical data.
Moreover, the compound was converted to methanesulfonate thereof by
conventional method.
Hydrochloride:
[0268] TLC: Rf 0.27 (ethyl acetate:hexane=2:1);
[0269] NMR (DMSO-d.sub.6): .delta. 12.95 (s, 1H), 9.40 (brs, 3H),
7.47 (t, J=8.1 Hz, 1H), 7.32-7.26 (m, 3H), 2.43-1.59 (m, 8H).
Methanesulfonate:
[0270] TLC: Rf 0.55 (methanol:methylene chloride=1:9);
[0271] NMR (DMSO-d.sub.6): .delta. 12.94 (s, 1H), 8.31 (s, 1H),
7.44 (t, J=7.8 Hz, 1H), 7.26-7.21 (m, 2H), 7.18 (s, 1H), 2.48-2.34
(m, 4H), 2.31 (s, 3H), 1.71-1.60 (m, 4H).
EXAMPLE 2 TO EXAMPLE 2(2)
[0272] By the same procedure as described in Reference Example
1.fwdarw.Example 1, if necessary, by converting to corresponding
salts by conventional method, using 3,4,5,6-tetrahydrophthalic acid
anhydride in tetrahydrofuran or a corresponding derivative, and
3-(bis(trimethylsilyl)amino)phenylmagnesium chloride or a
corresponding derivative, the following compounds of the present
invention were obtained.
EXAMPLE 2
4-(3-aminophenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
methanesulfonate
[0273] TLC: Rf 0.50 (methanol:methylene chloride=1:9);
[0274] NMR (CD.sub.3OD): .delta. 7.66-7.58 (m, 2H), 7.51-7.44 (m,
2H), 5.82 (m, 1H), 5.73 (m, 1H), 3.21 (m, 1H), 2.74 (s, 3H),
2.72-2.47 (m, 3H), 2.27 (m, 1H), 1.92 (m, 1H).
EXAMPLE 2(1)
4-(3-aminophenyl)-2,5,6,7,8,9-hexahydro-1H-cyclohepta[d]pyridazin-1-one
Methanesulfonate
[0275] TLC: Rf 0.47 (chloroform:methanol=9:1);
[0276] NMR (DMSO-d.sub.6): .delta. 13.01 (br-s, 1H), 7.45 (m, 1H),
7.20-7.09 (m, 3H), 2.86-2.80 (m, 2H), 2.58-2.52 (m, 2H), 2.31 (s,
3H), 1.86-1.76 (m, 2H), 1.58-1.46 (m, 4H).
EXAMPLE 2(2)
4-(3-nitro-4-chlorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0277] TLC: Rf 0.24 (ethyl acetate:hexane=1:1);
[0278] NMR (DMSO-d.sub.6): .delta. 13.07 (s, 1H), 8.17 (d, J=1.5
Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.80 (dd, J=8.4, 1.5 Hz, 1H),
2.48-2.38 (m, 4H), 1.71-1.58 (m, 4H).
REFERENCE EXAMPLE 2
4-(3-nitrobenzoyl)thiomorpholine-3-carboxylic acid ethyl ester
[0279] To a solution of thiomorpholin-3-ylcarboxylic acid ethyl
ester (5.05 g) in methylene chloride (120 mL) were added
dimethylaminopyridine (352 mg), triethylamine (4.9 mL) and
3-nitrobenzoyl chloride (5.62 g) in ice bath and then the mixture
was stirred at room temperature overnight. 2N hydrochloric acid was
added to the reaction mixture, which was extracted with methylene
chloride. The extract was wash with a saturated aqueous sodium
hydrogen carbonate solution and brine sequentially, dried over
anhydrous magnesium sulfate and concentrated. The residue was
purified by column chromatography on silica gel (hexane:ethyl
acetate=2:1) to give the title compound (5.91 g) having the
following physical data.
[0280] TLC: Rf 0.23 (hexane:ethyl acetate=2:1);
[0281] NMR (CDCl.sub.3): .delta. 8.32-8.30 (m, 2H), 7.79-7.62 (m,
2H), 5.78 and 4.57 (m, 1H), 4.98-4.93 and 3.84-3.79 (m, 1H), 4.23
(q, J=7.2 Hz, 2H), 3.71-3.63 and 3.28-3.02 and 2.91-2.70 (m, 4H),
2.61-2.57 and 2.43-2.39 (m, 1H), 1.36 (t, J=7.2 Hz, 3H).
REFERENCE EXAMPLE 3
4-((3-nitrophenyl)carbonothioyl)thiomorpholine-3-carboxylic acid
ethyl ester
[0282] To a solution of the compound prepared in Reference example
2 (5.88 g) in toluene (90 mL) was added Lawesson's reagent
(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)
(8.62 g) and the mixture was refluxed for 2 hours. After cooling to
room temperature, the reaction mixture was filtrated and
concentrated. The residue was purified by column chromatography on
silica gel (hexane:ethyl acetate=4:1) to give the title compound
(6.16 g) having the following physical data.
[0283] TLC: Rf 0.27 (hexane:ethyl acetate=4:1);
[0284] NMR (CDCl.sub.3): .delta. 8.24-8.17 (m, 2H), 7.66-7.55 (m,
2H), 6.96-6.93 and 4.88-4.86 (m, 1H), 5.96-5.90 and 4.13-4.06 (m,
1H), 4.39-4.32 (m, 2H), 3.83-3.73 and 3.59-3.50 (m, 1H), 3.37-3.30
and 3.12-3.07 (m, 1H), 3.20-3.14 and 3.02-2.94 (m, 1H), 2.94-2.88
and 2.80-2.71 (m, 1H), 2.72-2.64 and 2.49-2.41 (m, 1H), 1.40-1.28
(m, 3H).
EXAMPLE 3
4-(3-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(-
2H)-one
[0285] To a solution of the compound prepared in Reference example
3 (4.78 g) in ethanol (50 mL) was added hydrazine monohydrate (2.0
mL) and the mixture was refluxed overnight. The reaction mixture
was cooled to room temperature and the precipitate was collected by
filtration to give the compound of the present invention (2.30 g)
having the following physical data.
[0286] TLC: Rf 0.45 (chloroform:methanol=19:1);
[0287] NMR (DMSO-d.sub.6): .delta. 10.65 (s, 1H), 8.30-8.27 (m,
2H), 7.89-7.86 (m, 1H), 7.76-7.70 (m, 1H), 4.24 (dd, J=10.8, 2.7
Hz, 1H), 3.49 (dt, J=13.8, 2.7 Hz, 1H), 3.17-3.08 (m, 1H), 2.97
(dd, J=13.2, 10.8 Hz, 1H), 2.88-2.82 (m, 1H), 2.71 (dt, J=12.6, 2.7
Hz, 1H), 2.32-2.27 (m, 1H).
EXAMPLE 4 TO EXAMPLE 4(32)
[0288] By the same procedure as described in Reference example
2.fwdarw.Reference example 3.fwdarw.Example 3, using
thiomorpholin-3-ylcarboxylic acid ethyl ester or a corresponding
derivative, and 3-nitrobenzoyl chloride or a corresponding
derivative, the following compounds of the present invention were
obtained.
EXAMPLE 4
4-(3-nitrophenyl)-7,8,9,9a-tetrahydro-2H-pyrido[1,2-d][1,2,4]triazin-1(6H)-
-one
[0289] TLC: Rf 0.50 (chloroform:methanol=9:1);
[0290] NMR (DMSO-d.sub.6): .delta. 10.48 (s, 1H), 8.28 (d, J=8.1
Hz, 1H), 8.22 (s, 1H), 7.86 (d, J=8.1 Hz, 1H), 7.73 (t, J=8.1 Hz,
1H), 3.91 (m, 1H), 3.17 (m, 1H), 2.87 (m, 1H), 2.10 (m, 1H), 1.86
(m, 1H), 1.43 (m, 4H).
EXAMPLE 4(1)
4-phenyl-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one
[0291] TLC: Rf 0.18 (hexane:ethyl acetate=2:1);
[0292] NMR (DMSO-d.sub.6): .delta. 10.53 (s, 1H), 7.50-7.38 (m,
5H), 4.23 (dd, J=9.6, 3.6 Hz, 1H), 3.52 (m, 1H), 3.08 (m, 1H),
2.94-2.80 (m, 2H), 2.68 (m, 1H), 2.30 (d, J=10.5 Hz, 1H).
EXAMPLE 4(2)
(9aR)-4-(3-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]tria-
zin-1(2H)-one
[0293] TLC: Rf 0.18 (hexane:ethyl acetate=1:1);
[0294] NMR (CDCl.sub.3): .delta. 8.32 (dd, J=8.1, 1.5 Hz, 1H), 8.27
(s, 1H), 8.14 (br, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.66 (t, J=8.1 Hz,
1H), 4.39 (dd, J=10.8, 2.7 Hz, 1H), 3.72 (dt, J=14.1, 2.7 Hz, 1H),
3.24 (m, 1H), 3.13 (m, 1H), 2.99 (dd, J=14.1, 10.8 Hz, 1H), 2.77
(m, 1H), 2.32 (m, 1H);
[0295] [.alpha.].sub.D=-71.9 (c, 0.16, MeOH).
EXAMPLE 4(3)
4-(4-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(-
2H)-one
[0296] TLC: Rf 0.28 (ethyl acetate:hexane=1:1);
[0297] NMR (DMSO-d.sub.6): .delta. 10.69 (s, 1H), 8.28 (d, J=8.4
Hz, 2H), 7.73 (d, J=8.4 Hz, 2H), 4.26 (dd, J=10.2, 3.0 Hz, 1H),
3.48 (d, J=14.4 Hz, 1H), 3.17-2.29 (m, 5H).
EXAMPLE 4(4)
4-(3-methoxyphenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin--
1(2H)-one
[0298] TLC: Rf 0.17 (hexane:ethyl acetate=1:1);
[0299] NMR (DMSO-d.sub.6): .delta. 10.50 (s, 1H), 7.33 (t, J=8.1
Hz, 1H), 7.00-6.93 (m, 3H), 4.20 (dd, J=10.5, 3.0 Hz, 1H), 3.76 (s,
3H), 3.53 (dt, J=13.8, 3.0 Hz, 1H), 3.10-3.01 (m, 1H), 2.93-2.78
(m, 2H) 2.73-2.63 (m, 1H), 2.32-2.27 (m, 1H).
EXAMPLE 4(5)
4-(4-methoxyphenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin--
1(2H)-one
[0300] TLC: Rf 0.50 (chloroform:methanol=8:1);
[0301] NMR (DMSO-d.sub.6): .delta. 7.40-7.26 (m, 2H), 7.04-6.92 (m,
2H), 4.20 (dd, J=9.3, 4.2 Hz, 1H), 3.77 (s, 3H), 3.57 (dt, J=14.1,
2.7 Hz, 1H), 3.06 (m, 1H), 2.94-2.78 (m, 2H), 2.68 (m, 1H), 2.30
(m, 1H).
EXAMPLE 4(6)
4-(2-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(-
2H)-one
[0302] TLC: Rf 0.50 (methylene chloride:methanol=10:1);
[0303] NMR (CDCl.sub.3): .delta. 8.14 (br, 1H), 7.21 (ddd, J=8.4,
7.5, 2.1 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H), 6.80 (td, J=7.5, 1.2 Hz,
1H), 6.74 (dd, J=8.4, 1.2 Hz, 1H), 4.35 (dd, J=10.5, 3.0 Hz, 1H),
3.72 (dt, J=13.8, 3.0 Hz, 1H), 3.14 (m, 1H), 3.08-2.90 (m, 2H),
2.79 (m, 1H), 2.21 (dd, J=13.8, 1.2 Hz, 1H).
EXAMPLE 4(7)
4-(3-nitrophenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one
[0304] TLC: Rf 0.27 (methylene chloride:methanol=20:1);
[0305] NMR (DMSO-d.sub.6): .delta. 11.02 (brs, 1H), 8.32 (d, J=8.1
Hz, 1H), 8.28 (s, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.76 (t, J=8.1 Hz,
1H), 6.28 (s, 1H), 3.61 (m, 2H), 3.16 (m, 2H).
EXAMPLE 4(8)
4-phenyl-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one
[0306] TLC: Rf 0.51 (methanol:methylene chloride=1:10);
[0307] NMR (DMSO-d.sub.6): .delta. 10.89 (s, 1H), 7.45 (m, 5H),
6.24 (s, 1H), 3.60 (m, 2H), 3.14 (m, 2H).
EXAMPLE 4(9)
4-phenyl-7,8,10,10a-tetrahydro-6H-[1,2,4]triazino[5,4-c][1,4]thiazepin-1(2-
H)-one
[0308] TLC: Rf 0.53 (chloroform:methanol=9:1);
[0309] NMR (DMSO-d.sub.6): .delta. 10.57 (br-s, 1H), 7.50-7.40 (m,
5H), 4.29 (dd, J=6.9, 4.5 Hz, 1H), 3.44-3.36 (m, 1H), 3.16-3.00 (m,
3H), 2.78-2.70 (m, 2H), 1.80-1.64 (m, 1H), 1.55-1.40 (m, 1H).
EXAMPLE 4(10)
4-(3-nitrophenyl)-7,8,10,10a-tetrahydro-6H-[1,2,4]triazino[5,4-c][1,4]thia-
zepin-1(2H)-one
[0310] TLC: Rf 0.60 (chloroform:methanol=9:1).
EXAMPLE 4(11)
4-(3-dimethylaminophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]tr-
iazin-1(2H)-one
[0311] TLC: Rf 0.50 (chloroform:methanol=8:1);
[0312] NMR (DMSO-d.sub.6): .delta. 7.21 (dd, J=8.1, 7.2 Hz, 1H),
6.75 (m, 1H), 6.72-6.58 (m, 2H), 4.20 (dd, J=10.5, 3.0 Hz, 1H),
3.58 (dt, J=13.8, 2.7 Hz, 1H), 3.04 (m, 1H), 2.98-2.76 (m, 2H),
2.90 (s, 6H), 2.68 (m, 1H), 2.30 (m, 1H).
EXAMPLE 4(12)
(8aR)-4-(3-nitrophenyl)-8,8a-dihydro[1,3]thiazolo[3,4-d][1,2,4]triazin-1(2-
H)-one
[0313] TLC: Rf 0.39 (methylene chloride:methanol=10:1);
[0314] NMR (DMSO-d.sub.6): .delta. 11.07 (s, 1H), 8.33 (m, 2H),
8.02 (d, J=7.8 Hz, 1H), 7.76 (t, J=7.8 Hz, 1H), 4.53 (m, 2H), 4.28
(m, 1H), 3.46 (m, 2H).
EXAMPLE 4(13)
4-(3-amino-5-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]tr-
iazin-1(2H)-one
[0315] TLC: Rf 0.44 (chloroform:methanol=8:1);
[0316] NMR (DMSO-d.sub.6): .delta. 7.41 (dd, J=2.1, 2.1 Hz, 1H),
7.32 (dd, J=2.1, 1.2 Hz, 1H), 6.94 (dd, J=2.1, 1.2 Hz, 1H), 6.52
(brs, 1H), 6.01 (brs, 2H), 4.23 (dd, J=7.5, 3.0 Hz, 1H), 3.57 (m,
1H), 3.10 (m, 1H), 3.00-2.76 (m, 2H), 2.68 (m, 1H), 2.33 (m,
1H).
EXAMPLE 4(14)
(9aS)-4-(3-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]tria-
zin-1(2H)-one
[0317] TLC: Rf 0.51 (methylene chloride:methanol=10:1).
EXAMPLE 4(15)
(7R,8aS)-7-benzyloxy-4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]tria-
zin-1(2H)-one
[0318] TLC: Rf 0.26 (hexane:ethyl acetate=1:1);
[0319] NMR (DMSO-d.sub.6): .delta. 10.55 (s, 1H), 7.50-7.24 (m,
10H), 4.53 (d, J=12.3 Hz, 1H), 4.48 (d, J=12.3 Hz, 1H), 4.16 (dd,
J=8.7, 7.2 Hz, 1H), 4.09-4.03 (m, 1H), 3.54 (dd, J=10.8, 3.0 Hz,
1H), 3.44 (dd, J=10.8, 4.8 Hz, 1H), 2.39-2.31 (m, 1H), 2.24-2.15
(m, 1H).
EXAMPLE 4(16a)
(7R,8aS)-7-benzyloxy-4-(3-nitrophenyl)-6,7,8,8a-tetrahydropyrrolo[1,2-d][1-
,2,4]triazin-1(2H)-one
[0320] TLC: Rf 0.10 (hexane:ethyl acetate=1:1);
[0321] NMR (DMSO-d.sub.6): .delta. 10.73 (s, 1H), 8.31-8.27 (m,
2H), 7.95 (dt, J=7.5, 1.5 Hz, 1H), 7.75-7.69 (m, 1H), 7.34-7.24 (m,
5H), 4.53 (d, J=12.0 Hz, 1H), 4.50 (d, J=12.0 Hz, 1H), 4.24-4.19
(m, 1H), 4.11-4.04 (m, 1H), 3.57 (dd, J=10.5, 3.0 Hz, 1H), 3.50
(dd, J=10.5, 5.1 Hz, 1H), 2.41-2.33 (m, 1H), 2.28-2.19 (m, 1H).
EXAMPLE 4(16b)
(7R,8aS)-7-benzyloxy-4-(3-aminophenyl)-6,7,8,8a-tetrahydropyrrolo[1,2-d][1-
,2,4]triazin-1(2H)-one
[0322] TLC: Rf 0.51 (chloroform:methanol=9:1);
[0323] NMR (DMSO-d.sub.6): .delta. 10.45 (s, 1H), 7.34-7.24 (m,
5H), 7.03 (t, J=7.8 Hz, 1H), 6.72 (t, J=1.8 Hz, 1H), 6.60 (dd,
J=7.8, 1.8 Hz, 1H), 5.19 (s, 2H), 4.53 (d, J=12.0 Hz, 1H), 4.48 (d,
J=12.0 Hz, 1H), 4.14-4.01 (m, 2H), 3.54 (dd, J=10.8, 2.4 Hz, 1H),
3.46 (dd, J=10.8, 4.8 Hz, 1H), 2.38-2.30 (m, 1H), 2.22-2.13 (m,
1H).
EXAMPLE 4(17)
4-phenyl-9,9a-dihydro-2H-[1,3]thiazino[3,4-d][1,2,4]triazin-1(8H)-one
[0324] TLC: Rf 0.55 (chloroform:methanol=9:1);
[0325] NMR (DMSO-d.sub.6): .delta. 10.55 (br-s, 1H), 7.53-7.43 (m,
5H), 4.43 (d, J=13.8 Hz, 1H), 4.20 (dd, J=12.0, 2.4 Hz, 1H), 4.06
(dd, J=13.8, 2.4 Hz, 1H), 3.21 (m, 1H), 2.88 (m, 1H), 2.07 (m, 1H),
1.80 (m, 1H).
EXAMPLE 4(18)
4-(3-nitrophenyl)-9,9a-dihydro-2H-[1,3]thiazino[3,4-d][1,2,4]triazin-1(8H)-
-one
[0326] TLC: Rf 0.55 (chloroform:methanol=9:1);
[0327] NMR (DMSO-d.sub.6): .delta. 10.70 (br-s, 1H), 8.40 (m, 1H),
8.33 (m, 1H), 7.96 (m, 1H), 7.75 (m, 1H), 4.48 (d, J=14.1 Hz, 1H),
4.24 (dd, J=12.0, 2.1 Hz, 1H), 4.14 (dd, J=14.1, 2.1 Hz, 1H), 3.23
(m, 1H), 2.91 (m, 1H), 2.08 (m, 1H), 1.86 (m, 1H).
EXAMPLE 4(19)
4-(3-nitro-4-methylphenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1-
(2H)-one
[0328] TLC: Rf 0.33 (methylene chloride:methanol=20:1);
[0329] NMR (DMSO-d.sub.6): .delta. 10.97 (brs, 1H), 8.04 (d, J=1.8
Hz, 1H), 7.70 (dd, J=7.8, 1.8 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 6.27
(s, 1H), 3.61 (m, 2H), 3.14 (m, 2H), 2.55 (s, 3H).
EXAMPLE 4(20)
4-(3-cyanophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(-
2H)-one
[0330] TLC: Rf 0.20 (hexane:ethyl acetate=1:1);
[0331] NMR (CDCl.sub.3): .delta. 8.10 (br, 1H), 7.75 (dt, J=6.9,
1.8 Hz, 1H), 7.68 (m, 1H), 7.62-7.55 (m, 2H), 4.36 (dd, J=11.1, 2.7
Hz, 1H), 3.69 (dt, J=11.1, 2.7 Hz, 1H), 3.21 (ddd, J=14.1, 12.0,
2.7 Hz, 1H), 3.12 (dt, J=10.8, 2.4 Hz, 1H), 2.96 (dd, J=14.1, 11.1
Hz, 1H), 2.74 (m, 1H), 2.32 (ddd, J=11.1, 4.5, 2.4 Hz, 1H).
EXAMPLE 4(21)
4-(3-nitro-4-methylphenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]t-
riazin-1(2H)-one
[0332] TLC: Rf 0.59 (chloroform:methanol=9:1).
EXAMPLE 4(22)
4-(3-fluorophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1-
(2H)-one
[0333] TLC: Rf 0.63 (chloroform:methanol=9:1);
[0334] NMR (DMSO-d.sub.6): .delta. 7.56-7.46 (m, 1H), 7.36-7.24 (m,
3H), 4.20 (dd, J=10.2, 3.6 Hz, 1H), 3.54-3.44 (m, 1H), 3.16-3.02
(m, 1H), 2.96-2.78 (m, 2H), 2.76-2.64 (m, 1H), 2.36-2.24 (m,
1H).
EXAMPLE 4(23)
4-(3-nitro-5-fluorophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]t-
riazin-1(2H)-one
[0335] TLC: Rf 0.66 (chloroform:methanol=9:1).
EXAMPLE 4(24)
4-(2-methyl-5-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]t-
riazin-1(2H)-one
[0336] TLC: Rf 0.59 (chloroform:methanol=9:1).
EXAMPLE 4(25)
4-(4-nitrophenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one
[0337] TLC: Rf 0.54 (chloroform:methanol=9:1);
[0338] NMR (DMSO-d.sub.6): .delta. 11.03 (brs, 1H), 8.32-8.25 (m,
2H), 7.77-7.70 (m, 2H), 6.29 (s, 1H), 3.64-3.54 (m, 2H), 3.20-3.12
(m, 2H).
EXAMPLE 4(26)
4-(2-methyl-3-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]t-
riazin-1(2H)-one
[0339] TLC: Rf 0.49 (chloroform:methanol=9:1);
[0340] NMR (CDCl.sub.3): .delta. 8.64 (s, 1H), 7.93 (dd, J=7.8, 1.5
Hz, 1H), 7.50-7.40 (m, 2H), 4.34 (dd, J=11.1, 2.4 Hz, 1H), 3.41
(dt, J=11.1, 2.7 Hz, 1H), 3.24-3.00 (m, 2H), 2.91 (dd, J=13.5, 11.1
Hz, 1H), 2.70-2.40 (m, 4H), 2.30-2.26 (m, 1H).
EXAMPLE 4(27)
4-(3-methoxyphenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-on-
e
[0341] TLC: Rf 0.46 (hexane:ethyl acetate=1:1);
[0342] NMR (DMSO-d.sub.6): .delta. 10.85 (s, 1H), 7.37 (t, J=7.6
Hz, 1H), 7.08-6.96 (m, 3H), 6.23 (s, 1H), 3.77 (s, 3H), 3.64-3.56
(m, 2H), 3.16-3.08 (m, 2H).
EXAMPLE 4(28)
4-(3-nitro-4-methoxyphenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin--
1(2H)-one
[0343] TLC: Rf 0.30 (chloroform:methanol=9:1);
[0344] NMR (DMSO-d.sub.6): .delta. 10.92 (s, 1H), 7.95 (d, J=2.1
Hz, 1H), 7.73 (dd, J=8.7, 2.1 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 6.25
(s, 1H), 3.96 (s, 3H), 3.65-3.60 (m, 2H), 3.20-3.15 (m, 2H).
EXAMPLE 4(29)
4-benzyl-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one
[0345] TLC: Rf 0.37 (methylene chloride:methanol=10:1);
[0346] NMR (CDCl.sub.3): .delta. 8.03 (br, 1H), 7.39-7.24 (m, 5H),
4.17 (dd, J=10.8, 2.7 Hz, 1H), 3.93 (dt, J=14.4, 2.7 Hz, 1H), 3.06
(ddd, J=14.4, 12.0, 2.7 Hz, 1H), 2.89 (dt, J=13.5, 2.7 Hz, 1H),
2.78 (dd, J=13.5, 10.8 Hz, 1H), 2.21 (ddd, J=14.4, 12.0, 2.7 Hz,
1H), 2.06 (dq, J=14.4, 2.7 Hz, 1H).
EXAMPLE 4(30)
4-3-nitrobenzyl-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one
[0347] TLC: Rf 0.60 (chloroform:methanol=9:1);
[0348] NMR (CDCl.sub.3): .delta. 8.61 (s, 1H), 8.20-8.10 (m, 2H),
7.64-7.54 (m, 2H), 6.39 (s, 1H), 3.82 (s, 2H), 3.80-3.74 (m, 2H),
2.76-2.72 (m, 2H).
EXAMPLE 4(31)
4-phenyl-7,8,9,9a-tetrahydro-2H-pyrido[1,2-d][1,2,4]triazin-1(6H)-one
[0349] TLC: Rf 0.67 (methanol:methylene chloride=1:10);
[0350] NMR (DMSO-d.sub.6): .delta. 10.34 (s, 1H), 7.44-7.34 (m,
5H), 3.86 (dd, J=11.1, 3.0 Hz, 1H), 3.20 (dt, J=13.2, 2.1 Hz, 1H),
2.77 (td, J=13.2, 2.1 Hz, 1H), 2.06 (m, 1H), 1.85 (m, 1H),
1.49-1.26 (m, 4H).
EXAMPLE 4(32)
5-phenyl-2,3-dihydro-7H-[1,3]thiazolo[3,2-d][1,2,4]triazin-8(8aH)-one
[0351] TLC: Rf 0.30 (ethyl acetate:hexane=1:1);
[0352] NMR (DMSO-d.sub.6): .delta. 10.99 (s, 1H), 7.48 (m, 5H),
5.39 (s, 1H), 3.97 (ddd, J=12.0, 6.3, 1.2 Hz, 1H), 3.35-3.25 (m,
1H), 2.92 (ddd, J=10.0, 6.3, 1.2 Hz, 1H), 2.59-2.48 (m, 1H).
EXAMPLE 5
4-(3-nitro-4-hydroxyphenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin--
1(2H)-one
[0353] The compound prepared in Example 4(28) (150 mg) and lithium
chloride (59 mg) were dissolved in dimethylformamide (2.0 mL) and
the mixture was refluxed for 16 hours. After cooling to room
temperature, to the reaction mixture was added 1N hydrochloric
acid. The precipitate was collected by filtration. It was dried to
give the compound of the present invention (126 mg) having the
following physical data.
[0354] TLC: Rf 0.19 (hexane:ethyl acetate=1:1);
[0355] NMR (DMSO-d.sub.6): .delta. 11.45 (brs, 1H), 10.89 (s, 1H),
7.92 (d, J=2.4 Hz, 1H), 7.58 (dd, J=9.0, 2.4 Hz, 1H), 7.16 (d,
J=9.0 Hz, 1H), 6.24 (s, 1H), 3.65-3.60 (m, 2H), 3.20-3.15 (m,
2H).
EXAMPLE 6
4-(3-aminophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(-
2H)-one
[0356] To a solution of the compound prepared in Example 3 (537 mg)
in ethanol (4 mL) was added tin chloride dihydrate (2.07 g) and the
mixture was refluxed for 30 minutes. After cooling to room
temperature, a saturated aqueous sodium hydrogen carbonate solution
was added to the reaction mixture, which was extracted with ethyl
acetate. The extract was washed with brine, dried over anhydrous
magnesium sulfate and concentrated. To methanol (2 mL) was added
the obtained solid (137 mg) and then 4N hydrogen chloride in
dioxane (0.26 mL) was added to the mixture, which was stirred at
room temperature for 3 hours. The reaction mixture was
concentrated. The residue was recrystallized from a mixture solvent
(isopropanol:ethanol=4:1) to give the compound of the present
invention (144 mg) having the following physical data. Moreover,
the compound was converted to methanesulfonate thereof by
conventional method.
Hydrochloride:
[0357] TLC: Rf 0.42 (chloroform:methanol=9:1);
[0358] NMR (DMSO-d.sub.6): .delta. 10.90-10.70 (br, 1H), 7.51 (t,
J=7.8 Hz, 1H), 7.40-7.36 (m, 3H), 4.25 (dd, J=10.2, 3.0 Hz, 1H),
3.58-3.49 (m, 1H), 3.14-3.06 (m, 1H), 2.96-2.82 (m, 2H), 2.77-2.67
(m, 1H), 2.34-2.30 (m, 1H).
Methanesulfonate:
[0359] TLC: Rf 0.36 (chloroform:methanol=9:1);
[0360] NMR (DMSO-d.sub.6): .delta. 10.84-10.48 (br, 1H), 7.44 (t,
J=7.8 Hz, 1H), 7.25-7.18 (m, 3H), 4.24 (dd, J=9.9, 3.3 Hz, 1H),
3.56-3.49 (m, 1H), 3.15-3.05 (m, 1H), 2.95-2.81 (m, 2H), 2.75-2.65
(m, 1H), 2.33-2.30 (m, 4H).
EXAMPLE 6(1) TO EXAMPLE 6(19)
[0361] By the same procedure as described in Example 6, if
necessary, by converting to corresponding salts by conventional
method, using the compounds prepared in Example 4, 4(2), 4(3),
4(6), 4(7), 4(10), 4(12), 4(14), 4(13), 4(18), 4(19), 4(21),
4(23)-4(26), 4(28), 4(30) or 5 instead of the compound prepared in
Example 3, the following compounds of the present invention were
obtained.
EXAMPLE 6(1)
4-(3-aminophenyl)-7,8,9,9a-tetrahydro-2H-pyrido[1,2-d][1,2,4]triazin-1(6H)-
-one methanesulfonate
[0362] TLC: Rf 0.44 (methanol:methylene chloride=1:9);
[0363] NMR (DMSO-d.sub.6): .delta. 10.65 (brs, 1H), 7.38 (t, J=7.8
Hz, 1H), 7.13-7.04 (m, 3H), 3.93 (m, 1H), 3.26 (d, J=13.2 Hz, 1H),
2.82 (m, 1H), 2.31 (s, 3H), 2.07 (m, 1H), 1.86 (m, 1H), 1.46 (m,
4H).
EXAMPLE 6(2)
(9aR)-4-(3-aminophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]tria-
zin-1(2H)-one
[0364] TLC: Rf 0.27 (methylene chloride:methanol=10:1);
[0365] NMR (DMSO-d.sub.6): .delta. 10.44 (s, 1H), 7.04 (t, J=7.5
Hz, 1H), 6.57 (d, J=7.5 Hz, 1H), 6.53 (s, 1H), 6.47 (d, J=7.5 Hz,
1H), 5.23 (s, 2H), 4.19 (t, J=6.6 Hz, 1H), 3.62 (m, 1H), 3.03 (m,
1H), 2.84-2.80 (m, 2H), 2.66 (m, 1H), 2.31 (d, J=13.2 Hz, 1H).
EXAMPLE 6(3)
4-(4-aminophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(-
2H)-one methanesulfonate
[0366] TLC: Rf 0.39 (methanol:methylene chloride=1:10);
[0367] NMR (DMSO-d.sub.6): .delta. 10.87 (brs, 1H), 7.24 (d, J=8.4
Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 4.26 (dd, J=10.6, 3.0 Hz, 1H),
3.66 (brd, J=14.1 Hz, 1H), 3.16-2.35 (m, 5H), 2.30 (s, 3H).
EXAMPLE 6(4)
4-(2-aminophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(-
2H)-one
[0368] TLC: Rf 0.22 (methylene chloride:methanol=10:1);
[0369] NMR (CDCl.sub.3): .delta. 8.24 (brs, 1H), 7.21 (t, J=7.5 Hz,
1H), 7.09 (d, J=7.5 Hz, 1H), 6.80 (t, J=7.5 Hz, 1H), 6.74 (d, J=7.5
Hz, 1H), 4.34 (dd, J=11.7, 2.7 Hz, 1H), 3.95 (brs, 2H), 3.72 (m,
1H), 3.13 (m, 1H), 3.08-2.92 (m, 2H), 2.80 (m, 1H), 2.21 (m,
1H).
EXAMPLE 6(5)
4-(3-aminophenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one
Free Form:
[0370] TLC: Rf 0.31 (methanol:methylene chloride=1:10);
[0371] NMR (DMSO-d.sub.6): .delta. 10.81 (s, 1H), 7.07 (t, J=7.8
Hz, 1H), 6.63 (d, J=7.8 Hz, 1H), 6.56 (s, 1H), 6.50 (d, J=7.8 Hz,
1H), 6.21 (s, 1H), 5.28 (s, 2H), 3.62 (m, 2H), 3.14 (m, 2H).
Methanesulfonate:
[0372] TLC: Rf 0.48 (methanol:methylene chloride=1:9);
[0373] NMR (DMSO-d.sub.6): .delta. 10.93 (s, 1H), 7.44 (t, J=7.8
Hz, 1H), 7.19 (m, 3H), 6.26 (s, 1H), 3.60 (m, 2H), 3.15 (m, 2H),
2.33 (s, 3H).
EXAMPLE 6(6)
4-(3-aminophenyl)-7,8,10,10a-tetrahydro-6H-[1,2,4]triazino[5,4-c][1,4]thia-
zepin-1(2H)-one
[0374] TLC: Rf 0.44 (chloroform:methanol=9:1);
[0375] NMR (DMSO-d.sub.6): .delta. 10.47 (br-s, 1H), 7.04 (m, 1H),
6.62-6.52 (m, 3H), 5.21 (br-s, 2H), 4.25 (dd, J=6.9, 4.5 Hz, 1H),
3.52-3.42 (m, 1H), 3.14-2.96 (m, 3H), 2.76-2.60 (m, 2H), 1.82-1.56
(m, 2H).
EXAMPLE 6(7)
(8aR)-4-(3-aminophenyl)-8,8a-dihydro[1,3]thiazolo[3,4-d][1,2,4]triazin-1(2-
H)-one
[0376] TLC: Rf 0.56 (methanol:methylene chloride=1:9);
[0377] NMR (DMSO-d.sub.6): .delta. 10.81 (s, 1H), 7.07 (t, J=7.8
Hz, 1H), 6.72 (s, 1H), 6.63 (m, 2H), 5.25 (s, 2H), 4.50 (d, J=9.3
Hz, 1H), 4.41 (d, J=9.3 Hz, 1H), 4.16 (t, J=7.2 Hz, 1H), 3.36 (m,
2H).
EXAMPLE 6(8)
(9aS)-4-(3-aminophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]tria-
zin-1(2H)-one
[0378] TLC: Rf 0.44 (methylene chloride:methanol=10:1);
[0379] NMR (CDCl.sub.3): .delta. 8.01 (br, 1H), 7.20 (t, J=8.1 Hz,
1H), 6.76-6.69 (m, 2H), 6.64 (t, J=1.8 Hz, 1H), 4.33 (dd, J=10.8,
3.0 Hz, 1H), 3.85 (dt, J=10.8, 3.0 Hz, 1H), 3.78 (br, 2H), 3.11 (m,
1H), 3.05 (m, 1H), 2.94 (dd, J=13.5, 10.8 Hz, 1H), 2.74 (m, 1H),
2.25 (m, 1H).
EXAMPLE 6(9)
4-(3,5-diaminophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazi-
n-1(2H)-one
[0380] TLC: Rf 0.25 (chloroform:methanol=8:1);
[0381] NMR (DMSO-d.sub.6): .delta. 5.82 (t, J=1.8 Hz, 1H), 5.75 (d,
J=1.8 Hz, 2H), 4.86 (brs, 4H), 4.15 (dd, J=9.3, 4.2 Hz, 1H), 3.72
(m, 1H), 3.00 (m, 1H), 2.84-2.50 (m, 3H), 2.32 (m, 1H).
EXAMPLE 6(10)
4-(3-aminophenyl)-9,9a-dihydro-2H-[1,3]thiazino[3,4-d][1,2,4]triazin-1(8H)-
-one methanesulfonate
[0382] TLC: Rf 0.40 (chloroform:methanol=9:1);
[0383] NMR (DMSO-d.sub.6): .delta. 10.61 (br-s, 1H), 7.42 (m, 1H),
7.29-7.16 (m, 3H), 4.45 (d, J=13.8 Hz, 1H), 4.21 (dd, J=12.0, 2.4
Hz, 1H), 4.11 (dd, J=13.8, 2.4 Hz, 1H), 3.21 (m, 1H), 2.88 (m, 1H),
2.32 (s, 3H), 2.08 (m, 1H), 1.78 (m, 1H).
EXAMPLE 6(11)
4-(3-amino-4-methylphenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1-
(2H)-one methanesulfonate
[0384] TLC: Rf 0.38 (methanol:methylene chloride=1:10);
[0385] NMR (DMSO-d.sub.6): .delta. 10.88 (s, 1H), 8.30 (s, 1H),
7.26 (d, J=7.8 Hz, 1H), 7.09 (s, 1H), 7.04 (d, J=7.8 Hz, 1H), 6.25
(s, 1H), 3.61 (m, 2H), 3.16 (m, 2H), 2.32 (s, 3H), 2.24 (s,
3H).
EXAMPLE 6(12)
4-(3-amino-4-methylphenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]t-
riazin-1(2H)-one methanesulfonate
[0386] TLC: Rf 0.42 (chloroform:methanol=9:1);
[0387] NMR (DMSO-d.sub.6): .delta. 7.40-7.35 (m, 1H), 7.30-7.25 (m,
2H), 4.25 (dd, J=10.2, 3.6 Hz, 1H), 3.60-3.50 (m, 1H), 3.20-3.05
(m, 1H), 2.95-2.80 (m, 2H), 2.80-2.65 (m, 1H), 2.40-2.25 (m,
7H).
EXAMPLE 6(13)
4-(3-amino-5-fluorophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]t-
riazin-1(2H)-one methanesulfonate
[0388] TLC: Rf 0.37 (chloroform:methanol=9:1);
[0389] NMR (DMSO-d.sub.6): .delta. 10.65 (brs, 1H), 6.55-6.40 (m,
3H), 4.21 (dd, J=10.2, 3.3 Hz, 1H), 3.64-3.54 (m, 1H), 3.14-3.02
(m, 1H), 2.94-2.78 (m, 2H), 2.76-2.64 (m, 1H), 2.40-2.30 (m,
4H).
EXAMPLE 6(14)
4-(2-methyl-5-aminophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]t-
riazin-1(2H)-one
[0390] TLC: Rf 0.40 (chloroform:methanol=9:1);
[0391] NMR (DMSO-d.sub.6): .delta. 10.43 (s, 1H), 6.88 (d, J=8.1
Hz, 1H), 6.51 (dd, J=8.1, 2.4 Hz, 1H), 6.45 (brs, 1H), 4.20-4.12
(m, 1H), 3.40-3.26 (m, 1H), 3.06-2.94 (m, 1H), 2.90-2.70 (m, 2H),
2.58-2.46 (m, 1H), 2.34-2.22 (m, 1H), 2.02 (s, 3H).
EXAMPLE 6(15)
4-(4-aminophenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one
methanesulfonate
[0392] TLC: Rf 0.39 (chloroform:methanol=9:1);
[0393] NMR (DMSO-d.sub.6): .delta. 10.85 (brs, 1H), 7.40-7.32 (d,
J=8.4 Hz, 2H), 7.12-7.05 (d, J=8.4 Hz, 2H), 6.24 (s, 1H), 3.64-3.58
(m, 2H), 3.20-3.12 (m, 2H), 2.34 (s, 3H).
EXAMPLE 6(16)
4-(2-methyl-3-aminophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]t-
riazin-1(2H)-one methanesulfonate
[0394] TLC: Rf 0.41 (chloroform:methanol=9:1);
[0395] NMR (DMSO-d.sub.6): .delta. 7.35-7.27 (m, 2H), 7.20 (brs,
1H), 4.34-4.21 (m, 1H), 3.26-3.16 (m, 1H), 3.10-2.98 (m, 1H),
2.96-2.78 (m, 2H), 2.58-2.48 (m, 1H), 2.34 (s, 3H), 2.32-2.22 (m,
1H), 2.17 (s, 3H).
EXAMPLE 6(17)
4-(3-amino-4-methoxyphenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin--
1(2H)-one methanesulfonate
[0396] TLC: Rf 0.53 (chloroform:methanol=9:1);
[0397] NMR (DMSO-d.sub.6): .delta. 10.86 (s, 1H), 7.24-7.10 (m,
3H), 6.25 (s, 1H), 3.90 (s, 3H), 3.65-3.58 (m, 2H), 3.20-3.13 (m,
2H), 2.32 (s, 3H).
EXAMPLE 6(18)
4-(3-amino-4-hydroxyphenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin--
1(2H)-one
[0398] TLC: Rf 0.14 (chloroform:methanol=9:1);
[0399] NMR (DMSO-d.sub.6): .delta. 10.72 (s, 1H), 9.45 (brs, 1H),
6.66 (d, J=7.5 Hz, 1H), 6.60 (d, J=2.1 Hz, 1H), 6.42 (dd, J=7.5,
2.1 Hz, 1H), 6.19 (s, 1H), 4.70 (brs, 2H), 3.70-3.60 (m, 2H),
3.20-3.10 (m, 2H).
EXAMPLE 6(19)
4-3-aminobenzyl-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one
[0400] TLC: Rf 0.29 (chloroform:methanol=9:1);
[0401] NMR (DMSO-d.sub.6): .delta. 10.69 (s, 1H), 6.95 (dt, J=1.2,
7.2 Hz, 1H), 6.44-6.32 (m, 3H), 6.06 (s, 1H), 5.08 (s, 2H),
3.72-3.64 (m, 2H), 3.58 (s, 2H), 2.76-2.66 (m, 2H).
EXAMPLE 7
(7R,8aS)-7-hydroxy-4-(3-nitrophenyl)-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2-
,4]triazin-1(2H)-one
[0402] To a solution of the compound prepared in Example 4(16a) (76
mg) in methylene chloride (0.5 mL) was added boron tribromide (2
mL; 1.0 M in methylene chloride) at -40.degree. C. and the mixture
was stirred for 1.5 hours. To the reaction mixture was added sodium
hydrogen carbonate (ca 1 g). The reaction mixture was allowed to
return to room temperature slowly and then brine was added to the
reaction mixture, which was extracted with methylene chloride. The
extract was dried over anhydrous magnesium sulfate and
concentrated. The residue was purified by column chromatography on
silica gel (chloroform:methanol=19:1.fwdarw.9:1) to give the
compound of the present invention (57 mg) having the following
physical data.
[0403] TLC: Rf 0.37 (chloroform:methanol=9:1);
[0404] NMR (DMSO-d.sub.6): .delta. 10.69 (s, 1H), 8.30-8.27 (m,
2H), 7.99-7.96 (m, 1H), 7.76-7.71 (m, 1H), 5.21 (d, J=3.6 Hz, 1H),
4.22-4.13 (m, 2H), 3.40 (d, J=3.6 Hz, 2H), 2.17-2.12 (m, 2H).
EXAMPLE 8
(7R,8aS)-7-hydroxy-4-(3-aminophenyl)-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2-
,4]triazin-1(2H)-one methanesulfonate
[0405] To a solution of the compound prepared in Example 4(16b)
(188 mg) in methylene chloride (2 mL) was added aluminum
trichloride (153 mg) and the mixture was stirred at room
temperature overnight. Moreover, aluminum trichloride (151 mg) was
added to the reaction mixture, which was stirred at room
temperature for 7 hours. Sodium hydrogen carbonate (ca 1 g), small
amount of water and methanol were added, sequentially, to the
reaction mixture, which was stirred for 30 minutes. The reaction
mixture was filtrated through Celite. The filtrate was
concentrated. The residue was purified by column chromatography on
silica gel (chloroform:methanol=19:1.fwdarw.9:1.fwdarw.4:1). To
methanol (1 mL) was added the obtained solid and thereto was added
a solution of methanesulfonic acid (42 mg) in methanol (1 mL). The
mixture was stirred at room temperature for 10 minutes. The
reaction mixture was concentrated to give the compound of the
present invention (147 mg) having the following physical data.
[0406] TLC: Rf 0.17 (chloroform:methanol=9:1);
[0407] NMR (DMSO-d.sub.6): .delta. 10.90-10.62 (br, 1H), 7.44 (t,
J=7.8 Hz, 1H), 7.34-7.21 (m, 3H), 4.24-4.16 (m, 2H), 3.44 (dd,
J=10.5, 2.4 Hz, 1H), 3.39 (dd, J=10.5, 4.8 Hz, 1H), 2.32 (s, 3H),
2.16-2.12 (m, 2H).
EXAMPLE 9
4-(3-aminomethylphenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]tria-
zin-1(2H)-one methanesulfonate
[0408] To a solution of
4-((3-chloromethylphenyl)carbonothioyl)thiomorpholine-3-carboxylic
acid ethyl ester (131 mg; It was prepared by the same procedure as
described in Reference example 2.fwdarw.Reference example 3, using
3-chloromethylbenzoyl chloride instead of 3-nitrobenzoyl chloride)
in dimethylformamide (1.5 mL) was added phthalimide potassium salt
(70 mg) and the mixture was stirred at room temperature overnight.
Water was added to the reaction mixture, which was extracted with a
mixed solvent (hexane:ethyl acetate=1:1). The extract was washed
with water and brine sequentially, dried over anhydrous sodium
sulfate and concentrated. To a solution of the obtained solid in
ethanol (2 mL) was added hydrazine monohydrate (92 .mu.L) and the
mixture was refluxed for 1 hour. After cooling the reaction mixture
to room temperature, the precipitate was separated by filtration
and the filtrate was concentrated. The precipitate and the residue
were purified by column chromatography on silica gel
(chloroform:methanol:water=8:2:0.2), respectively. To the obtained
solid was added a solution of methanesulfonic acid in methanol (1M,
0.11 mL) and the mixture was concentrated. To the obtained residue
was added ethyl acetate and the precipitate was separated by
filtration. The precipitate was dried under reduced pressure to
give the compound of the present invention (40 mg) having the
following physical data.
[0409] TLC: Rf 0.11 (methylene chloride:methanol=10:1);
[0410] NMR (DMSO-d.sub.6): .delta. 10.59 (s, 1H), 8.14 (br, 3H),
7.60-7.40 (m, 4H), 4.25 (t, J=6.6 Hz, 1H), 4.12-4.02 (m, 2H), 3.52
(m, 1H), 3.12 (m, 1H), 2.88-2.83 (m, 2H), 2.72 (m, 1H), 2.30 (m,
1H), 2.28 (s, 3H).
EXAMPLE 10
4-(3-amino-4-fluorophenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1-
(2H)-one
[0411] By the same procedure as described in Reference example
2.fwdarw.Example 6.fwdarw.Reference example 3 Example 3 using
3,4-dihydro-2H-1,4-thiazine-5-carboxylic acid ethyl ester instead
of thiomorpholin-3-ylcarboxylic acid ethyl ester, and
3-nitro-4-fluorobenzoyl chloride instead of 3-nitrobenzoyl
chloride, the compound of the present invention having the
following physical data.
[0412] TLC: Rf 0.41 (methanol:methylene chloride=1:10);
[0413] NMR (DMSO-d.sub.6): .delta. 10.81 (s, 1H), 7.04 (dd, J=11.4,
7.8 Hz, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.55 (m, 1H), 6.22 (s, 1H),
5.34 (s, 2H), 3.61 (m, 2H), 3.12 (m, 2H).
EXAMPLE 11
8-phenyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one
[0414] Under an atmosphere of hydrogen, a mixture of
8-phenylpyrido[2,3-d]pyridazin-5(6H)-one (100 mg; It was prepared
by the same procedure as described in Reference example
1.fwdarw.Example 1 using furo[3,4-b]pyridine-5,7-dione instead of
4,5,6,7-tetrahydro-2-benzofuran-1,3-dione, and phenylmagnesium
chloride instead of 3-(bis(trimethylsilyl)amino)phenylmagnesium
chloride), platinum(IV) oxide (10 mg), 1N hydrochloric acid (0.5
mL) and dimethylformamide (5 mL) was stirred at room temperature
for 6 hours. The reaction mixture was filtrated through Celite. The
filtrate was concentrated. The residue was diluted with ethyl
acetate. The diluted solution was washed with a saturated aqueous
sodium hydrogen carbonate solution and brine sequentially, dried
over anhydrous sodium sulfate and concentrated. The residue was
recrystallized from ethanol to give the compound of the present
invention (42 mg) having the following physical data. Moreover, the
compound was converted to a corresponding salt thereof by
conventional method.
Free Form:
[0415] TLC: Rf 0.43 (chloroform:methanol=9:1);
[0416] NMR (DMSO-d.sub.6): .delta. 12.11 (br-s, 1H), 7.52-7.40 (m,
5H), 5.72 (br-s, 1H), 3.13 (m, 2H), 2.39 (t, J=6.6 Hz, 2H), 1.72
(m, 2H).
Hydrochloride:
[0417] TLC: Rf 0.40 (chloroform:methanol=8:1);
[0418] NMR (DMSO-d.sub.6): .delta. 12.41 (brs, 1H), 7.52-7.40 (m,
5H), 5.88 (brs, 2H), 3.16 (t, J=5.4 Hz, 2H), 2.43 (t, J=6.3 Hz,
2H), 1.73 (tt, J=6.3, 5.4 Hz, 2H).
Methanesulfonate:
[0419] TLC: Rf 0.39 (chloroform:methanol=8:1);
[0420] NMR (DMSO-d.sub.6): .delta. 12.37 (s, 1H), 7.54-7.40 (m,
5H), 4.53 (brs, 2H), 3.22-3.08 (m, 2H), 2.42 (t, J=6.0 Hz, 2H),
2.35 (s, 3H), 1.82-1.64 (m, 2H).
EXAMPLE 11(1) TO EXAMPLE 11(4)
[0421] By the same procedure as described in Example 11, if
necessary, by converting to corresponding salts by conventional
method, using a corresponding derivative instead of
8-phenylpyrido[2,3-d]pyridazin-5(6H)-one, the following compounds
of the present invention were obtained.
EXAMPLE 11(1)
4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-one
methanesulfonate
[0422] TLC: Rf 0.30 (chloroform:methanol=9:1);
[0423] NMR (DMSO-d.sub.6): .delta. 13.30 (s, 1H), 8.94 (br-s, 2H),
7.55-7.43 (m, 5H), 4.00 (s, 2H), 3.37 (t, J=6.0 Hz, 2H), 2.74 (t,
J=6.0 Hz, 2H), 2.30 (s, 3H).
EXAMPLE 11(2)
1-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-4(3H)-one
[0424] TLC: Rf 0.29 (chloroform:methanol=9:1);
[0425] NMR (DMSO-d.sub.6): .delta. 12.93 (br-s, 1H), 7.52-7.40 (m,
5H), 3.61 (br-s, 2H), 2.79 (t, J=5.7 Hz, 2H), 2.32 (m, 2H).
EXAMPLE 11(3)
5-phenyl-1,3,4,7-tetrahydropyrido[2,3-d]pyridazin-8(2H)-one
[0426] TLC: Rf 0.49 (chloroform:methanol=9:1);
[0427] NMR (DMSO-d.sub.6): .delta. 12.51 (br-s, 1H), 7.50-7.36 (m,
5H), 6.69 (br-s, 1H), 3.27 (m, 2H), 2.39 (t, J=5.7 Hz, 2H), 1.67
(m, 2H).
EXAMPLE 11(4)
8-(3-aminophenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one
Hydrochloride:
[0428] TLC: Rf 0.40 (methylene chloride:methanol=9:1);
[0429] NMR (DMSO-d.sub.6): .delta. 1.73 (m, 2H) 2.41 (t, J=6.04 Hz,
2H) 3.14 (m, 2H) 5.92 (br. s., 1H) 7.37 (m, 3H) 7.52 (m, 1H) 12.23
(br. s., 1H).
Dihydrochloride:
[0430] TLC: Rf 0.33 (chloroform:methanol=8:1);
[0431] NMR (DMSO-d.sub.6): .delta. 12.60 (brs, 1H), 7.64-7.42 (m,
4H), 6.07 (br, 4H), 3.24-3.08 (m, 2H), 2.44 (t, J=6.0 Hz, 2H),
1.84-1.64 (m, 2H).
REFERENCE EXAMPLE 4
6-methoxymethyl-8-phenylpyrido[2,3-d]pyridazin-5(6H)-one
[0432] After washing sodium hydride (103 mg; 62.6% in oil) with
hexane, the mixture was suspended in dimethylformamide (1.5 mL). A
solution of 8-phenylpyrido[2,3-d]pyridazin-5(6H)-one (200 mg; It
was prepared by the same procedure as described in Reference
example 1.fwdarw.Example 1 using furo[3,4-b]pyridine-5,7-dione
instead of 4,5,6,7-tetrahydro-2-benzofuran-1,3-dione, and
phenylmagnesium chloride instead of
3-(bis(trimethylsilyl)amino)phenylmagnesium chloride) in
dimethylformamide (5.7 mL) was added dropwise to the suspension at
0.degree. C. The mixture was stirred at room temperature for 40
minutes. Methoxymethyl chloride (0.27 mL) was added dropwise to the
reaction mixture, which was stirred at room temperature overnight.
The reaction mixture was concentrated. The obtained residue was
diluted in a mixed solvent of water and ethyl acetate. The mixture
was poured in a saturated aqueous sodium hydrogen carbonate
solution and extracted with ethyl acetate. The extract was washed
with brine, dried over anhydrous magnesium sulfate and concentrated
to give the title compound (269 mg) having the following physical
data. The obtained compound was used in next reaction without
purification.
[0433] TLC: Rf 0.78 (chloroform:methanol=8:1).
REFERENCE EXAMPLE 5
6-methoxymethyl-8-phenyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-on-
e
[0434] Under an atmosphere of argon, to platinum oxide (70 mg) was
added dimethylformamide (1.0 mL). A solution of the compound
prepared in Reference example 4 (269 mg) in dimethylformamide (8.0
mL) was added dropwise to the reaction mixture and 1N hydrochloric
acid (0.9 mL) was added thereto. Under an atmosphere of hydrogen,
the mixture was stirred at room temperature for 4 hours. Under an
atmosphere of argon, the reaction mixture was filtrated through
Celite. The filtrate was concentrated. The residue was purified by
column chromatography on silica gel (methylene
chloride:methanol=40:1.fwdarw.30:1) to give the title compound (224
mg) having the following physical data.
[0435] TLC: Rf 0.16 (hexane:ethyl acetate=1:1);
[0436] NMR (DMSO-d.sub.6): .delta. 7.56-7.40 (m, 5H), 5.92 (brs,
1H), 5.23 (s, 2H), 3.29 (s, 3H), 3.20-3.06 (m, 2H), 2.43 (t, J=6.0
Hz, 2H), 1.84-1.64 (m, 2H).
REFERENCE EXAMPLE 6
6-methoxymethyl-1-methyl-8-phenyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-
-5(1H)-one
[0437] After washing sodium hydride (141 mg; 62.6% in oil) with
hexane, the mixture was suspended in dimethylformamide (1.0 mL). A
solution of the compound prepared in Reference example 5 (200 mg)
in dimethylformamide (6.4 mL) was added dropwise thereto at
0.degree. C. and the mixture was stirred at room temperature for 1
hour. Methyl iodide (0.37 mL) was added dropwise to the reaction
mixture, which was stirred at room temperature overnight. After
adding water to the reaction mixture, it was poured in ice water
and extracted with ethyl acetate. The extract was washed with
brine, dried over anhydrous magnesium sulfate and concentrated. The
residue was purified by column chromatography on silica gel
(methylene chloride:methanol=100:1.fwdarw.50:1) to give the title
compound (116 mg) having the following physical data.
[0438] TLC: Rf 0.23 (hexane:ethyl acetate=1:1).
EXAMPLE 12
1-methyl-8-phenyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one
[0439] 6N hydrochloric acid (2.4 mL) was added dropwise to a
solution of the compound prepared in Reference example 6 (110 mg)
in methanol (1.2 mL), which was stirred at room temperature
overnight. 6N hydrochloric acid (2.4 mL) was added dropwise to the
reaction mixture, which was stirred at 110.degree. C. overnight.
After cooling the reaction mixture to room temperature, it was
poured in cold water. After neutralizing with 5N sodium hydroxide
solution, the solution was extracted with ethyl acetate. The
extract was washed with brine, dried over anhydrous magnesium
sulfate and concentrated. The residue was washed with ethyl acetate
to give the compound of the present invention (39 mg) having the
following physical data.
[0440] TLC: Rf 0.44 (chloroform:methanol=4:1);
[0441] NMR (DMSO-d.sub.6): .delta. 12.50 (s, 1H), 7.58-7.34 (m,
5H), 3.12-3.00 (m, 2H), 2.41 (t, J=6.0 Hz, 2H), 2.27 (s, 3H),
1.84-1.66 (m, 2H).
REFERENCE EXAMPLE 7
N-methyl-N-methoxy-1-t-butoxycarbonylpiperidine-2-carboxamide
[0442] To a solution of 1-t-butoxycarbonylpiperidine-2-carboxylic
acid (2.29 g) in methylene chloride (30 mL) were added
N,O-dimethylhydroxyamine hydrochloride (1.17 g),
benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate
(4.87 g, BOP reagent) and triethylamine (4.88 mL) and the mixture
was stirred at room temperature overnight. The reaction mixture was
concentrated. The residue was diluted with ethyl acetate. The
diluted solution was washed water, 1N hydrochloric acid, water, a
saturated aqueous sodium hydrogen carbonate solution and brine
sequentially, dried over anhydrous sodium sulfate and concentrated
to give the title compound (2.59 g) having the following physical
data.
[0443] TLC: Rf 0.54 (hexane:ethyl acetate=3:1);
[0444] NMR (CDCl.sub.3): .delta. 5.30-4.86 (m, 1H), 4.06-3.84 (m,
1H), 3.77 (br-s, 3H), 3.56-3.36 (m, 1H), 3.19 (s, 3H), 2.04-1.96
(m, 1H), 1.76-1.32 (m, 14H).
REFERENCE EXAMPLE 8
2-benzoylpiperidine-1-carboxylic acid t-butyl ester
[0445] A solution of phenyllithium in cyclohexane-ether (1.06 M,
6.23 mL) was added dropwise to a solution of the compound prepared
in Reference example 7 (1.63 g) in tetrahydrofuran (30 mL) at
-25.degree. C. and the mixture was stirred at -25.degree. C. for 3
hours. The reaction mixture was poured in 1M sodium dihydrogen
phosphate solution and extracted with ethyl acetate. The extract
was washed with water and brine sequentially, dried over anhydrous
sodium sulfate and concentrated. The residue was purified by column
chromatography on silica gel (hexane:ethyl acetate=9:1) to give the
title compound (850 mg) having the following physical data.
[0446] TLC: Rf 0.56 (hexane:ethyl acetate=4:1);
[0447] NMR (CDCl.sub.3): .delta. 7.96-7.84 (m, 2H), 7.66-7.40 (m,
3H), 5.70-5.44 (m, 1H), 4.04-3.86 (m, 1H), 3.30-3.08 (m, 1H),
2.20-1.98 (m, 1H), 1.92-1.76 (m, 1H), 1.74-1.20 (m, 13H).
REFERENCE EXAMPLE 9
2-benzoylpiperidine hydrochloride
[0448] To the compound prepared in Reference example 8 (270 mg) was
added 4N hydrogen chloride-ethyl acetate solution (4 mL) and the
mixture was stirred at room temperature for 15 minutes. The
reaction mixture was concentrated to give the title compound (211
mg) having the following physical data.
[0449] TLC: Rf 0.48 (chloroform:methanol:acetic acid=40:10:1);
[0450] NMR (DMSO-d.sub.6): .delta. 9.02 (br-s, 2H), 8.05 (m, 2H),
7.75 (m, 1H), 7.61 (m, 2H), 5.09 (dd, J=12.0, 3.0 Hz, 1H), 2.97 (m,
1H), 2.09 (m, 1H), 1.82-1.58 (m, 4H), 1.44 (m, 1H).
EXAMPLE 13
1-phenyl-3,6,7,8,9,9a-hexahydro-4H-pyrido[1,2-d][1,2,4]triazin-4-one
(compound a) and
1-phenyl-3,6,7,8-tetrahydro-4H-pyrido[1,2-d][1,2,4]triazin-4-one
(compound b)
[0451] The compound prepared in Reference example (199 mg) was
separated with ethyl acetate and a saturated aqueous sodium
hydrogen carbonate solution and the water layer was extracted with
ethyl acetate. The combined organic layer was washed with brine,
dried over anhydrous sodium sulfate and concentrated. The obtained
powder was dissolved in toluene (10 mL). Thereto were added
hydrazine carboxylic acid ethyl ester (184 mg) and
p-toluenesulfonic acid monohydrate (8.4 mg) and the mixture was
refluxed overnight. After cooling the reaction mixture to room
temperature, it was diluted in ethyl acetate. The diluted solution
was washed with 1N hydrochloric acid, water and brine sequentially,
dried over anhydrous sodium sulfate and concentrated. The residue
was purified by column chromatography on silica gel (hexane:ethyl
acetate=2:1.fwdarw.1:1). The more polar fraction was recrystallized
from ethyl acetate to give the compound a (16.3 mg) having the
following physical data. The less polar fraction was recrystallized
from a mixed solution of ethyl acetate and hexane (1:1) to give the
compound b (13.6 mg) having the following physical data.
Compound a:
[0452] TLC: Rf 0.30 (hexane:ethyl acetate=1:1);
[0453] NMR (DMSO-d.sub.6): .delta. 10.14 (s, 1H), 7.76-7.66 (m,
2H), 7.46-7.34 (m, 3H), 4.77 (dd, J=11.7, 2.7 Hz, 1H), 4.18 (m,
1H), 2.72 (m, 1H), 1.88-1.34 (m, 6H).
Compound b:
[0454] TLC: Rf 0.46 (hexane:ethyl acetate=1:1);
[0455] NMR (DMSO-d.sub.6): .delta. 10.74 (s, 1H), 7.56-7.34 (m,
5H), 4.82 (t, J=4.5 Hz, 1H), 3.64 (m, 2H), 2.10 (m, 2H), 1.71 (m,
2H).
EXAMPLE 14
1-phenyl-3,8,9,9a-tetrahydro-4H-[1,3]thiazino[3,4-d][1,2,4]triazin-4-one
[0456] By the same procedure as described in Reference example
7.fwdarw.Reference example 8.fwdarw.Reference example
9.fwdarw.Example 13 using
3-t-butoxycarbonyl-1,3-thiazinane-4-carboxylic acid instead of
1-t-butoxycarbonylpiperidine-2-carboxylic acid, the compound of the
present invention having the following physical data was
obtained.
[0457] TLC: Rf 0.48 (hexane:ethyl acetate=1:1);
[0458] NMR (DMSO-d.sub.6): .delta. 10.42 (s, 1H), 7.75-7.70 (m,
2H), 7.46-7.38 (m, 3H), 5.10 (dd, J=11.4, 2.7 Hz, 1H), 4.90 (dd,
J=13.2, 2.7 Hz, 1H), 4.34 (d, J=13.2 Hz, 1H), 3.36 (m, 1H), 2.75
(m, 1H), 1.88-1.62 (m, 2H).
REFERENCE EXAMPLE 10
((E)-3-oxo-4,5,6,7-tetrahydro-2-benzofuran-1(3H)-ylidene)acetic
acid methyl ester
[0459] A solution of 3,4,5,6-tetrahydrophthalic acid anhydride
(3.04 g) and (triphenylphosphoranylidene)acetic acid methyl ester
(6.69 g) in chloroform (50.0 mL) was refluxed for 3 hours. After
cooling the reaction mixture to room temperature, it was
concentrated. The residue was purified by column chromatography on
silica gel (ethyl acetate:hexane=1:9.fwdarw.3:7) to give the title
compound (1.93 g) having the following physical data.
[0460] TLC: Rf 0.71 (ethyl acetate:hexane=1:1);
[0461] NMR (CDCl.sub.3): .delta. 5.92 (s, 1H), 3.76 (s, 3H), 2.81
(m, 2H), 2.38 (m, 2H), 1.76 (m, 4H).
EXAMPLE 15
4-methoxycarbonylmethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0462] A solution of the compound prepared in Reference example 10
(1.04 g) and hydrazine monohydrate (250 mg) in ethanol (10.0 mL)
was refluxed for 18 hours. After cooling the reaction mixture to
room temperature, it was concentrated. The obtained crystal was
washed with ethanol and ethyl acetate, and dried under reduced
pressure to give the compound of the present invention (672 mg)
having the following physical data.
[0463] TLC: Rf 0.45 (methanol:methylene chloride=1:9);
[0464] NMR (DMSO-d.sub.6): .delta. 12.66 (brs, 1H), 3.65 (s, 2H),
3.63 (s, 3H), 2.38 (m, 4H), 1.64 (m, 4H).
EXAMPLE 16
4-(1-ethoxycarbonylethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0465] By the same procedure as described in Reference example
10.fwdarw.Example 15 using 2-(triphenylphosphoranylidene)propanoic
acid ethyl ester instead of (triphenylphosphoranylidene)acetic acid
methyl ester, the compound of the present invention having the
following physical data was obtained.
[0466] TLC: Rf 0.56 (methanol:methylene chloride=1:10);
[0467] NMR (DMSO-d.sub.6): .delta. 12.67 (brs, 1H), 4.07 (q, J=6.9
Hz, 2H), 3.91 (q, J=6.9 Hz, 1H), 2.48-2.33 (m, 4H), 1.65 (m, 4H),
1.33 (d, J=6.9 Hz, 3H), 1.13 (t, J=6.9 Hz, 3H).
REFERENCE EXAMPLE 11
4-carboxymethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0468] 5N sodium hydroxide solution (1.72 mL) was added dropwise to
a suspension of the compound prepared in Example 15 (635 mg) in
methanol (10.0 mL) in ice bath and the mixture was stirred at room
temperature for 3 hours. The reaction mixture was concentrate. 2N
hydrochloric acid was added to the residue, which was adjusted to
pH 2. The deposited crystal was collected by filtration. It was
washed with hexane and dried under reduced pressure to give the
title compound (478 mg) having the following physical data.
[0469] TLC: Rf 0.62 (methanol:methylene chloride:acetic
acid=2:8:0.1);
[0470] NMR (DMSO-d.sub.6): .delta. 12.62 (brs, 2H), 3.54 (s, 2H),
2.39 (m, 4H), 1.64 (m, 4H).
REFERENCE EXAMPLE 11(1)
4-(1-carboxyethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0471] By the same procedure as described in Reference example 11
using the compound prepared in Example 16 instead of the compound
prepared in Example 15, the title compound having the following
physical data was obtained.
[0472] TLC: Rf 0.28 (methanol:methylene chloride=1:4);
[0473] NMR (DMSO-d.sub.6): .delta. 12.64 (s, 1H), 12.48 (brs, 1H),
3.81 (q, J=7.5 Hz, 1H), 2.48-2.37 (m, 4H), 1.65 (brs, 4H), 1.32 (d,
J=7.5 Hz, 3H).
EXAMPLE 17 TO EXAMPLE 17(1)
[0474] By the same procedure as described in Reference example
10.fwdarw.Example 15.fwdarw.Example 11, if necessary, by converting
to corresponding salts by conventional method, using a
corresponding derivative instead of
4,5,6,7-tetrahydro-2-benzofuran-1,3-dione, and
(triphenylphosphoranylidene)acetic acid ethyl ester instead of
(triphenylphosphoranylidene)acetic acid methyl ester, the following
compounds of the present invention were obtained.
EXAMPLE 17
8-ethoxycarbonylmethyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one
[0475] TLC: Rf 0.46 (chloroform:methanol=9:1);
[0476] NMR (DMSO-d.sub.6): .delta. 11.88 (br-s, 1H), 6.32 (br-s,
1H), 4.07 (q, J=7.2 Hz, 2H), 3.54 (s, 2H), 3.15 (m, 2H), 2.33 (t,
J=6.3 Hz, 2H), 1.69 (m, 2H), 1.18 (t, J=7.2 Hz, 3H).
EXAMPLE 17(1)
5-ethoxycarbonylmethyl-1,3,4,7-tetrahydropyrido[2,3-d]pyridazin-8(2H)-one
hydrochloride
[0477] TLC: Rf 0.48 (chloroform:methanol=9:1);
[0478] NMR (DMSO-d.sub.6): .delta. 12.60 (br-s, 1H), 4.10 (q, J=7.2
Hz, 2H), 3.75 (br-s, 2H), 3.28 (m, 2H), 2.45 (m, 2H), 1.77 (m, 2H),
1.18 (t, J=7.2 Hz, 3H).
REFERENCE EXAMPLE 12
4-(2-hydroxyethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0479] The compound prepared in Example 15 (350 mg) was dissolved
in tetrahydrofuran (8.0 mL). Under an atmosphere of argon, sodium
borohydride (239 mg) was added thereto at 0.degree. C. and the
mixture was refluxed for 13 hours. After cooling to 0.degree. C.,
1N hydrochloric acid was added to the reaction mixture, which was
adjusted to pH 5. The deposited solid was collected by filtration.
The filtrate was concentrated and extracted with chloroform. The
extract was dried over anhydrous magnesium sulfate and concentrated
to give the title compound having the following physical data.
[0480] TLC: Rf 0.32 (chloroform:methanol=9:1);
[0481] NMR (CD.sub.3OD): .delta. 3.87 (t, J=6.6 Hz, 2H), 2.80 (t,
J=6.6 Hz, 2H), 2.64-2.58 (m, 2H), 2.54-2.48 (m, 2H), 1.88-1.70 (m,
4H).
REFERENCE EXAMPLE 13
4-(2-chloroethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0482] To a solution of the compound prepared in Reference example
12 g (2.47 g) and pyridine (201 mg) in methylene chloride (60 mL)
was added thionyl chloride (2.25 g) and the mixture was stirred at
room temperature for 20 hours. Chloroform and a saturated aqueous
sodium hydrogen carbonate solution were added to the reaction
mixture, which was separated. The organic layer was washed with a
saturated aqueous sodium hydrogen carbonate solution, water and
brine sequentially, dried over anhydrous magnesium sulfate and
concentrated to give the title compound (2.58 g) having the
following physical data.
[0483] TLC: Rf 0.52 (chloroform:methanol=9:1);
[0484] NMR (CD.sub.3OD): .delta. 3.88 (t, J=7.2 Hz, 2H), 3.05 (t,
J=7.2 Hz, 2H), 2.60-2.50 (m, 4H), 1.85-1.70 (m, 4H).
REFERENCE EXAMPLE 14
4-(2-azidoethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0485] A solution of the compound prepared in Reference example 13
(106 mg), trimethylsilylazide (86.4 mg) and tetrabutylammonium
fluoride (237 mg) in tetrahydrofuran (2.00 mL) was refluxed for 24
hours. The reaction mixture was concentrated. The residue was
purified by column chromatography on silica gel (ethyl
acetate:hexane=1:1) to give the title compound (85.0 mg) having the
following physical data.
[0486] TLC: Rf 0.52 (ethyl acetate:hexane=4:1);
[0487] NMR (DMSO-d.sub.6): .delta. 12.62 (brs, 1H), 3.63 (t, J=6.9
Hz, 2H), 2.79 (t, J=6.9 Hz, 2H), 2.48-2.37 (m, 4H), 1.67 (m,
4H).
REFERENCE EXAMPLE 15
4-(2-aminoethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
hydrochloride
[0488] Under an atmosphere of hydrogen, a suspension of the
compound prepared in Reference example 14 (50.0 mg) and 5%
palladium on calcium carbonate (20.0 mg) in ethanol (3.0 mL) was
stirred at room temperature for 6 hours. The reaction mixture was
filtrated through Celite. The filtrate was concentrated. 4N
hydrogen chloride-ethyl acetate solution (0.5 mL) was added
dropwise to a solution of the obtained solid (44.0 mg) in methanol
(3.0 mL) and the mixture was stirred at room temperature for 1
hour. The reaction mixture was concentrated. The residue was
recrystallized from a mixed solvent of methanol and ethyl acetate
to give the title compound (45.9 mg) having the following physical
data.
[0489] TLC: Rf 0.39 (methanol:methylene chloride:saturated aqueous
ammonia=1:4:0.1);
[0490] NMR (DMSO-d.sub.6): .delta. 12.65 (s, 1H), 8.07 (brs, 3H),
3.07 (m, 2H), 2.83 (t, J=7.2 Hz, 2H), 2.44 (m, 2H), 2.38 (m, 2H),
1.66 (m, 4H).
REFERENCE EXAMPLE 16
4-(2-cyanoethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0491] To a suspension of the compound prepared in Reference
example 13 (500 mg) in tetrahydrofuran (12 mL) were added
trimethylsilyl cyanide (0.94 mL) and tetrabutylammonium fluoride
(1.84 g) and the mixture was stirred at 80.degree. C. overnight.
After cooling to room temperature, the reaction mixture was poured
in a cold saturated aqueous ammonium chloride solution and
extracted with ethyl acetate. The extracted was washed with brine,
dried over anhydrous magnesium sulfate and concentrated. The
residue was purified by column chromatography on silica gel
(methylene chloride:methanol=20:1). The obtained solid was washed
with t-butyl methyl ether to give the title compound (249 mg)
having the following physical data.
[0492] TLC: Rf 0.52 (chloroform:methanol=8:1);
[0493] NMR (DMSO-d.sub.6): .delta. 12.66 (s, 1H), 2.94-2.72 (m,
4H), 2.60-2.26 (m, 4H), 1.78-1.54 (m, 4H).
REFERENCE EXAMPLE 17
4-(2-carboxyethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0494] To a suspension of the compound prepared in Reference
example 16 (130 mg) in ethanol (3.2 mL) was added 5N sodium
hydroxide solution (0.64 mL) and the mixture was stirred at
90.degree. C. for 1 day. After cooling to 0.degree. C., the
reaction mixture was poured in cold water and washed with ethyl
acetate. The water layer was neutralized with 2N hydrochloric acid
and concentrated. The residue was washed with water. The solid was
washed water and ether to give the title compound (131 mg) having
the following physical data.
[0495] TLC: Rf 0.36 (chloroform:methanol=4:1);
[0496] NMR (DMSO-d.sub.6): .delta. 12.51 (s, 1H), 12.08 (brs, 1H),
2.71 (t, J=6.9 Hz, 2H), 2.56 (t, J=6.9 Hz, 2H), 2.54-2.26 (m, 4H),
1.78-1.54 (m, 4H).
EXAMPLE 18
3-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)phenylsulfamic acid
pyridine salt
[0497] To a suspension of the compound prepared in Example 1 (100
mg) in methylene chloride (1.5 mL) and dimethylformamide (1.5 mL)
was added sulfur trioxide pyridine complex (144 mg) and the mixture
was stirred at room temperature for 4 hours. The reaction mixture
was concentrated. The residue was washed with ethyl acetate to give
the compound of the present invention (160 mg) having the following
physical data.
[0498] TLC: Rf 0.17 (chloroform:methanol=4:1);
[0499] NMR (CD.sub.3OD): .delta. 8.90-8.78 (m, 2H), 8.59 (dddd,
J=7.8, 7.8, 1.5, 1.5 Hz, 1H), 8.12-7.98 (m, 2H), 7.48-7.14 (m, 3H),
6.89 (m, 1H), 2.66-2.52 (m, 2H), 2.52-2.38 (m, 2H), 1.90-1.60 (m,
4H).
EXAMPLE 19
4-(3-amidinophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin--
1(2H)-one methanesulfonate
[0500] To a solution of the compound prepared in Example 4(20) (127
mg) in dimethylformamide (3 mL) were added sodium hydrosulfide (215
mg) and magnesium chloride hexahydrate (474 mg) and the mixture was
stirred at room temperature for 3 hours under an atmosphere of
argon. To the reaction mixture was added ethyl acetate and the
precipitate was separated by filtration. The filtrate was wash with
water and brine sequentially, dried over anhydrous sodium sulfate
and concentrated. To a solution of the obtained solid (277 mg) in
acetone (2 mL) was added methyl iodide (0.15 mL) and the mixture
was stirred at room temperature for 3 hours. The reaction mixture
was concentrated. To the residue were added methanol (2 mL) and
ammonium acetate (43 mg) and the mixture was refluxed for 2 hours.
The reaction mixture was concentrated. The residue was purified by
column chromatography on silica gel
(chloroform:methanol:water=9:1:0.1.fwdarw.8:2:0.2). The obtained
solid was washed with a mixed solvent of methanol, ethyl acetate
and hexane and converted to methanesulfonate thereof by
conventional method to give the compound of the present invention
(149 mg) having the following physical data.
[0501] TLC: Rf 0.22 (methylene chloride:methanol=10:1);
[0502] NMR (DMSO-d.sub.6): .delta. 10.68 (s, 1H), 9.36 (s, 2H),
9.02 (s, 2H), 7.86 (d, J=7.8 Hz, 1H), 7.84-7.77 (m, 2H), 7.69 (t,
J=7.8 Hz, 1H), 4.26 (dd, J=8.7, 4.8 Hz, 1H), 3.50 (m, 1H), 3.16 (m,
1H), 2.95-2.84 (m, 2H), 2.71 (m, 1H), 2.366 and 2.362 (s, 3H), 2.30
(d, J=13.8 Hz, 1H).
EXAMPLE 20
4-(3-hydroxyphenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin--
1(2H)-one
[0503] To a solution of the compound prepared in Example 4(4) (175
mg) in methylene chloride (1.3 mL) was added boron tribromide (1.3
mL; 1.0 M in methylene chloride) in ice bath and the mixture was
stirred at room temperature for 5 hours. To the reaction mixture
was added boron tribromide (1.3 mL; 1.0 M in methylene chloride)
and the mixture was stirred at room temperature overnight. Methanol
was added to the reaction mixture, which was concentrated. The
residue was washed with methylene chloride. Water was added thereto
and the mixture was extracted with ethyl acetate. The extract was
washed with brine, dried over anhydrous magnesium sulfate and
concentrated. The residue was recrystallized from acetonitrile to
give the compound of the present invention (73 mg) having the
following physical data.
[0504] TLC: Rf 0.43 (chloroform:methanol=9:1);
[0505] NMR (DMSO-d.sub.6): .delta. 10.47 (s, 1H), 9.67 (bs, 1H),
7.20 (t, J=7.8 Hz, 1H), 6.81-6.73 (m, 3H), 4.19 (dd, J=9.3, 3.9 Hz,
1H), 3.56 (dt, J=14.1, 3.0 Hz, 1H), 3.09-2.99 (m, 1H), 2.90-2.79
(m, 2H) 2.69-2.60 (m, 1H), 2.33-2.28 (m, 1H).
EXAMPLE 20(1) TO EXAMPLE 20(2)
[0506] By the same procedure as described in Example 20 using the
compound prepared in Example 4(5) or 4(27) instead of the compound
prepared in Example 4(4), the following compounds of the present
invention were obtained.
EXAMPLE 20(1)
4-(4-hydroxyphenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin--
1(2H)-one
[0507] TLC: Rf 0.32 (chloroform:methanol=8:1);
[0508] NMR (DMSO-d.sub.6): .delta. 9.74 (brs, 1H), 7.24-7.14 (m,
2H), 6.84-6.74 (m, 2H), 4.18 (dd, J=8.1, 5.1 Hz, 1H), 3.60 (dt,
J=14.1, 2.7 Hz, 1H), 3.05 (m, 1H), 2.92-2.78 (m, 2H), 2.68 (m, 1H),
2.31 (m, 1H).
EXAMPLE 20(2)
4-(3-hydroxyphenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-on-
e
[0509] TLC: Rf 0.40 (chloroform:methanol=9:1);
[0510] NMR (DMSO-d.sub.6): .delta. 10.83 (s, 1H), 9.70 (s, 1H),
7.24 (t, J=7.8 Hz, 1H), 6.88-6.75 (m, 3H), 6.22 (s, 1H), 3.66-3.56
(m, 2H), 3.16-3.06 (m, 2H).
EXAMPLE 21
N-(3-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)phenyl)ethanimidamide
hydrobromide
[0511] To a suspension of the compound prepared in Example 1 (60
mg) in ethanol (2.5 mL) was added 2-naphthylmethylethanimidothioate
(74 mg) and the mixture was stirred at room temperature for 4
hours. Methanol (1.5 mL) and 2-naphthylmethylethanimidothioate (222
mg) were added to the reaction mixture, which was stirred at
75.degree. C. overnight. After cooling to room temperature, the
reaction mixture was concentrated. The residue was purified by
column chromatography on silica gel (methylene
chloride:methanol=20:1.fwdarw.6:1) to give the compound of the
present invention (84 mg) having the following physical data.
[0512] TLC: Rf 0.24 (chloroform:methanol=4:1);
[0513] NMR (DMSO-d.sub.6): .delta. 12.97 (s, 1H), 7.59 (dd, J=8.1,
8.1 Hz, 1H), 7.50 (m, 1H), 7.44-7.34 (m, 2H), 2.54-2.32 (m, 4H),
2.34 (s, 3H), 1.80-1.50 (m, 4H).
EXAMPLE 21(1) TO EXAMPLE 21(3)
[0514] By the same procedure as described in Example 21 using the
compound prepared in Example 6, 6(5) or 11(4) instead of the
compound prepared in Example 1, the following compounds of the
present invention were obtained.
EXAMPLE 21(1)
N-(3-(1-oxo-1,2,6,7,9,9a-hexahydro[1,4]thiazino[4,3-d][1,2,4]triazin-4-yl)-
phenyl)ethanimidamide hydrobromide
[0515] TLC: Rf 0.25 (chloroform:methanol:water=8:2:0.2);
[0516] NMR (DMSO-d.sub.6): .delta. 11.13 (br, 1H), 10.60 (s, 1H),
9.43 (br, 1H), 8.56 (br, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.47 (d,
J=7.8 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.36 (s, 1H), 4.24 (dd,
J=9.6, 3.9 Hz, 1H), 3.63 (d, J=13.8 Hz, 1H), 3.10 (d, J=12.0 Hz,
1H), 2.96-2.82 (m, 2H), 2.72 (m, 1H), 2.32 (s, 3H), 2.29 (m,
1H).
EXAMPLE 21(2)
N-(3-(1-oxo-1,2,6,7-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-4-yl)phen-
yl)ethanimidamide hydrobromide
[0517] TLC: Rf 0.24 (chloroform:methanol:water=8:2:0.2);
[0518] NMR (DMSO-d.sub.6): .delta. 10.95 (s, 1H), 9.30 (br, 1H),
8.87 (br, 1H), 8.35 (br, 1H), 7.60 (m, 1H), 7.48 (m, 1H), 7.42-7.36
(m, 2H), 6.28 (s, 1H), 3.72-3.64 (m, 2H), 3.20-3.12 (m, 2H), 2.30
(brs, 3H).
EXAMPLE 21(3)
N-(3-(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)phenyl)ethani-
midamide
[0519] TLC: Rf 0.14 (chloroform:methanol=4:1).
EXAMPLE 22
4-(3-methylaminophenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H-
)-one
[0520] To a suspension of the compound prepared in Example 6(5)
(100 mg) in methanol (1.1 mL) were added a solution of sodium
methylate in methanol (0.5 mL; 28% solution) and paraformaldehyde
(32 mg) and the mixture was stirred at room temperature for 3
hours. Methanol (1.1 mL) and sodium borohydride (22 mg) were added
to the reaction mixture, which was stirred at 75.degree. C. for 1
hour. After cooling to room temperature, water was added to the
reaction mixture, which was poured in cold water. The solution was
concentrated. The residue was washed with a mixed solvent of
methanol and methylene chloride and filtrated through Celite. The
filtrate was concentrated. The residue was purified by column
chromatography on silica gel (methylene chloride:methanol=15:1) to
give the compound of the present invention (15 mg) having the
following physical data.
[0521] TLC: Rf 0.44 (chloroform:methanol=8:1);
[0522] NMR (DMSO-d.sub.6): .delta. 10.80 (s, 1H), 7.15 (dd, J=7.5,
7.5 Hz, 1H), 6.66-6.46 (m, 3H), 6.21 (s, 1H), 5.86 (q, J=4.8 Hz,
1H), 3.68-3.56 (m, 2H), 3.20-3.06 (m, 2H), 2.67 (d, J=4.8 Hz,
3H).
EXAMPLE 23
4-(N-(2-(N'-t-butoxycarbonylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydr-
ophthalazin-1(2H)-one
[0523] The mixture of the compound prepared in Reference example 11
(183 mg), triethylamine (178 mg), N-(2-aminoethyl)carbamic acid
t-butyl ester (160 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (338
mg), 1-hydroxybenzotriazol (238 mg) and dimethylformamide (3.00 mL)
was stirred at room temperature for 16 hours. The reaction mixture
was concentrated. To the residue was added water and the deposited
crystal was collected by filtration. It was washed with ethyl
acetate and dried under reduced pressure to give the compound of
the present invention (189 mg) having the following physical
data.
[0524] TLC: Rf 0.50 (methylene chloride:methanol=9:1);
[0525] NMR (DMSO-d.sub.6): .delta. 12.56 (s, 1H), 8.01 (brs, 1H),
6.77 (brs, 1H), 3.39 (s, 2H), 3.08-2.95 (m, 4H), 2.38 (m, 4H), 2.25
(m, 4H), 1.37 (s, 9H).
EXAMPLE 23(1) TO EXAMPLE 23(37)
[0526] By the same procedure as described in Example 23, if
necessary, by converting to corresponding salts by conventional
method, using the compound prepared in Example 11 or a
corresponding carboxylic acid derivative, and
N-(2-aminoethyl)carbamic acid t-butyl ester or a corresponding
derivative, the following compounds of the present invention were
obtained.
EXAMPLE 23(1)
4-(N-(2-(morpholin-4-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazi-
n-1(2H)-one
[0527] TLC: Rf 0.37 (methanol:methylene chloride=1:9);
[0528] NMR (DMSO-d.sub.6): .delta. 12.60 (brs, 1H), 11.06 (brs,
1H), 8.45 (t, J=5.7 Hz, 1H), 3.95-3.77 (m, 4H), 3.47 (s, 2H), 3.43
(m, 4H), 3.18-3.02 (m, 4H), 2.37 (m, 4H), 1.64 (brs, 4H).
EXAMPLE 23(2)
4-(N-(2-(N',N'-dimethylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophth-
alazin-1(2H)-one
Free Form:
[0529] TLC: Rf 0.60 (methanol:methylene chloride:saturated aqueous
ammonia=1:4:0.1);
[0530] NMR (DMSO-d.sub.6): .delta. 12.56 (brs, 1H), 7.94 (brt,
J=6.2 Hz, 1H), 3.40 (s, 2H), 3.13 (td, J=6.2, 6.2 Hz, 2H), 2.43
(brs, 2H), 2.36 (brs, 2H), 2.26 (t, J=6.2 Hz, 2H), 2.12 (s, 6H),
1.63 (brs, 4H).
Hydrochloride:
[0531] TLC: Rf 0.69 (methanol:methylene chloride:saturated aqueous
ammonia=2:8:0.1);
[0532] NMR (DMSO-d.sub.6): .delta. 12.60 (s, 1H), 10.22 (brs, 1H),
8.39 (t, J=5.7 Hz, 1H), 3.41-2.98 (m, 4H), 2.24 (m, 8H), 2.48-2.36
(m, 4H), 1.64 (brs, 4H).
EXAMPLE 23(3)
4-(N-(3-(N'-t-butoxycarbonylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahyd-
rophthalazin-1(2H)-one
[0533] NMR (DMSO-d.sub.6): .delta. 12.56 (s, 1H), 7.97 (t, J=5.1
Hz, 1H), 6.75 (m, 1H), 3.39 (s, 2H), 3.02 (q, J=6.6 Hz, 2H), 2.90
(q, J=6.6 Hz, 2H), 2.46-2.33 (m, 4H), 1.68-1.58 (m, 4H), 1.55-1.44
(m, 2H), 1.36 (s, 9H).
EXAMPLE 23(4)
4-(N-(2-(N'-t-butoxycarbonyl-N'-methylamino)ethyl)carbamoylmethyl)-5,6,7,8-
-tetrahydrophthalazin-1(2H)-one
[0534] TLC: Rf 0.59 (chloroform:methanol:water=8:2:0.2);
[0535] NMR (CDCl.sub.3): .delta. 10.69 (br, 1H), 6.88 (br, 1H),
3.49 (s, 2H), 3.45-3.32 (m, 4H), 2.86 (s, 3H), 2.60-2.48 (m, 4H),
1.90-1.80 (m, 4H), 1.45 (s, 9H).
EXAMPLE 23(5)
4-(N-(2-(pyrrolidin-1-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalaz-
in-1(2H)-one hydrochloride
[0536] TLC: Rf 0.24 (ethyl acetate:acetic acid:water=3:3:1);
[0537] NMR (DMSO-d.sub.6): .delta. 12.60 (s, 1H), 10.46 (br, 1H),
8.39 (m, 1H), 3.61-3.50 (m, 2H), 3.47 (s, 2H), 3.40 (q, J=6.0 Hz,
2H), 3.17 (q, J=6.0 Hz, 2H), 3.04-2.90 (m, 2H), 2.50-2.34 (m, 4H),
2.04-1.90 (m, 2H), 1.90-1.80 (m, 2H), 1.70-1.60 (m, 4H).
EXAMPLE 23(6)
4-(2-hydroxyethoxycarbonylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0538] TLC: Rf 0.60 (chloroform:methanol:water=8:2:0.2);
[0539] NMR (DMSO-d.sub.6): .delta. 12.66 (s, 1H), 4.80 (t, J=5.1
Hz, 1H), 4.07 (t, J=5.1 Hz, 2H), 3.66 (s, 2H), 3.55 (q, J=5.1 Hz,
2H), 2.45-2.34 (m, 4H), 1.70-1.60 (m, 4H).
EXAMPLE 23(7)
4-(N-(3-(N',N'-dimethylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropht-
halazin-1(2H)-one hydrochloride
[0540] TLC: Rf 0.12 (chloroform:methanol:water=7:3:0.3);
[0541] NMR (DMSO-d.sub.6): .delta. 12.60 (s, 1H), 10.43 (br, 1H),
8.28 (m, 1H), 3.42 (s, 2H), 3.11 (q, J=6.0 Hz, 2H), 3.04-2.96 (m,
2H), 2.71 (s, 3H), 2.69 (s, 3H), 2.46-2.34 (m, 4H), 1.84-1.74 (m,
2H), 1.68-1.48 (m, 4H).
EXAMPLE 23(8)
4-(N-(3-(imidazol-1-yl)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazi-
n-1(2H)-one hydrochloride
[0542] TLC: Rf 0.82 (chloroform:methanol:water=7:3:0.3);
[0543] NMR (DMSO-d.sub.6): .delta. 14.64 (br, 1H), 12.60 (s, 1H),
9.17 (m, 1H), 8.39 (m, 1H), 7.81 (d, J=1.5 Hz, 1H), 7.68 (d, J=1.5
Hz, 1H), 4.22 (t, J=6.6 Hz, 2H), 3.44 (s, 2H), 3.03 (q, J=6.6 Hz,
2H), 2.46-2.32 (m, 4H), 1.93 (quin, J=6.6 Hz, 2H), 1.68-1.46 (m,
4H).
EXAMPLE 23(9)
4-(1-(N-(2-(N'-t-butoxycarbonylamino)ethyl)carbamoyl)ethyl)-5,6,7,8-tetrah-
ydrophthalazin-1(2H)-one
[0544] TLC: Rf 0.44 (methanol:methylene chloride=1:10);
[0545] NMR (DMSO-d.sub.6): .delta. 12.60 (s, 1H), 7.93 (t, J=5.1
Hz, 1H), 6.74 (brs, 1H), 3.66 (q, J=7.2 Hz, 1H), 3.05 (m, 2H), 2.96
(m, 2H), 2.48-2.30 (m, 4H), 1.63 (m, 4H), 1.36 (s, 9H), 1.30 (d,
J=7.2 Hz, 3H).
EXAMPLE 23(10)
4-(N-(1-ethylpyrrolidin-2-ylmethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophth-
alazin-1(2H)-one hydrochloride
[0546] TLC: Rf 0.59 (methanol:methylene chloride:saturated aqueous
ammonia=2:8:0.1);
[0547] NMR (DMSO-d.sub.6): .delta. 12.61 (s, 1H), 10.42 (brs, 1H),
8.56 (m, 1H), 3.58-2.96 (m, 9H), 2.42-2.36 (m, 4H), 2.08-1.64 (m,
8H), 1.24 (t, J=6.9 Hz, 3H).
EXAMPLE 23(11)
4-(N-(3-(morpholin-4-yl)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalaz-
in-1(2H)-one
[0548] TLC: Rf 0.48 (chloroform:methanol=4:1);
[0549] NMR (DMSO-d.sub.6): .delta. 12.57 (s, 1H), 8.00 (brt, 1H),
3.64-3.48 (m, 4H), 3.46-3.18 (m, 6H), 3.14-2.96 (m, 2H), 2.50-2.14
(m, 6H), 1.74-1.44 (m, 6H).
EXAMPLE 23(12)
4-(N-(3-(pyrrolidin-1-yl)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthala-
zin-1(2H)-one hydrochloride
[0550] TLC: Rf 0.25 (chloroform:methanol:water=7:3:0.3);
[0551] NMR (DMSO-d.sub.6): .delta. 12.59 (s, 1H), 10.59 (br, 1H),
8.25 (br, 1H), 3.52-3.38 (m, 4H), 3.17-3.00 (m, 4H), 2.98-2.84 (m,
2H), 2.46-2.32 (m, 4H), 2.00-1.75 (m, 6H), 1.69-1.58 (m, 4H).
EXAMPLE 23(13)
4-(N-(pyridin-3-yl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
hydrochloride
[0552] TLC: Rf 0.47 (methanol:methylene chloride=1:9);
[0553] NMR (DMSO-d.sub.6): .delta. 12.67 (s, 1H), 11.31 (s, 1H),
9.12 (d, J=2.1 Hz, 1H), 8.55 (d, J=4.8 Hz, 1H), 8.43 (d, J=8.7 Hz,
1H), 7.86 (dd, J=8.7, 4.8 Hz, 1H), 3.78 (s, 2H), 2.48-2.39 (m, 4H),
1.65 (brs, 4H).
EXAMPLE 23(14)
4-(N-(2-(piperidin-1-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazi-
n-1(2H)-one hydrochloride
[0554] TLC: Rf 0.53 (chloroform:methanol:water=7:3:0.3);
[0555] NMR (DMSO-d.sub.6): .delta. 12.60 (s, 1H), 10.30 (br, 1H),
8.44 (br, 1H), 3.50-3.34 (m, 2H), 3.31 (s, 2H), 3.10-2.96 (br, 2H),
2.90-2.72 (br, 2H), 2.48-2.32 (m, 4H), 1.80-1.68 (br, 4H),
1.68-1.56 (br, 6H), 1.50-1.40 (br, 2H).
EXAMPLE 23(15)
4-(N-(2-(N',N'-dimethylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropht-
halazin-1(2H)-one hydrochloride
[0556] TLC: Rf 0.26 (chloroform:methanol:water=7:3:0.3);
[0557] NMR (DMSO-d.sub.6): .delta. 12.60 (s, 1H), 10.40 (br, 1H),
8.32 (br, 1H), 3.48 (s, 2H), 3.42-3.12 (m, 3H), 2.58 (s, 6H),
2.46-2.32 (m, 4H), 1.68-1.58 (m, 4H), 1.12 (d, J=6.0 Hz, 3H).
EXAMPLE 23(16)
4-(N-(4-(N'-t-butoxycarbonylamino)butyl)carbamoylmethyl)-5,6,7,8-tetrahydr-
ophthalazin-1(2H)-one
[0558] NMR (CD.sub.3OD): .delta. 8.12 (br, 1H), 6.59 (br, 1H), 3.54
(s, 2H), 3.23-3.15 (m, 2H), 3.08-2.98 (m, 2H), 2.56-2.47 (m, 4H),
1.82-1.74 (m, 4H), 1.56-1.46 (m, 4H), 1.42 (s, 9H).
EXAMPLE 23(17)
4-(N-(pyridin-2-yl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
hydrochloride
[0559] TLC: Rf 0.51 (methanol:methylene chloride=1:10);
[0560] NMR (DMSO-d.sub.6): .delta. 12.64 (s, 1H), 11.08 (s, 1H),
8.33 (m, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.87 (m, 1H), 7.18 (m, 1H),
3.77 (s, 2H), 2.45-2.38 (m, 4H), 1.65 (brs, 4H).
EXAMPLE 23(18)
4-(2-(N',N'-dimethylamino)ethoxycarbonylmethyl)-5,6,7,8-tetrahydrophthalaz-
in-1(2H)-one
Free Form:
[0561] TLC: Rf 0.51 (methylene
chloride:methanol:water=8:2:0.2);
[0562] NMR (DMSO-d.sub.6): .delta. 12.66 (s, 1H), 4.13 (t, J=5.7
Hz, 2H), 3.64 (s, 2H), 2.44 (t, J=5.7 Hz, 2H), 2.44-2.35 (m, 4H),
2.12 (s, 6H), 1.72-1.58 (m, 4H).
Hydrochloride:
[0563] TLC: Rf 0.51 (chloroform:methanol:water=8:2:0.2);
[0564] NMR (DMSO-d.sub.6): .delta. 12.70 (s, 1H), 10.72 (br, 1H),
4.44-4.36 (m, 2H), 3.74 (s, 2H), 3.40-3.32 (m, 2H), 2.75 (s, 6H),
2.46-2.32 (m, 4H), 1.72-1.60 (m, 4H).
EXAMPLE 23(19)
4-(N-(2-(pyrrol-1-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1-
(2H)-one
[0565] TLC: Rf 0.60 (chloroform:methanol:water=8:2:0.2);
[0566] NMR (DMSO-d.sub.6): .delta. 12.57 (s, 1H), 8.11 (m, 1H),
6.69 (d, J=1.2 Hz, 2H), 5.96 (d, J=1.2 Hz, 2H), 3.92 (t, J=6.0 Hz,
2H), 3.38 (s, 2H), 3.35 (t, J=6.0 Hz, 2H), 2.40-2.24 (m, 4H),
1.68-1.58 (m, 4H).
EXAMPLE 23(20)
4-(N-(2-(imidazol-4-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-
-1(2H)-one hydrochloride
[0567] TLC: Rf 0.56 (chloroform:methanol:water=7:3:0.3);
[0568] NMR (DMSO-d.sub.6): .delta. 12.56 (s, 1H), 8.10 (m, 1H),
7.73 (br, 1H), 6.86 (s, 1H), 3.39 (s, 2H), 3.34-3.23 (m, 2H),
2.74-2.62 (m, 2H), 2.40-2.30 (m, 4H), 1.66-1.56 (m, 4H).
EXAMPLE 23(21)
4-(1-(N-(4-(N'-t-butoxycarbonylamino)butyl)carbamoyl)ethyl)-5,6,7,8-tetrah-
ydrophthalazin-1(2H)-one
[0569] TLC: Rf 0.38 (methanol:methylene chloride=1:10);
[0570] NMR (DMSO-d.sub.6): .delta. 12.59 (s, 1H), 7.93 (t, J=5.7
Hz, 1H), 6.77 (m, 1H), 3.66 (q, J=7.0 Hz, 1H), 3.01 (m, 2H), 2.88
(m, 2H), 2.48-2.26 (m, 4H), 1.63 (brs, 4H), 1.42-1.28 (m, 16H).
EXAMPLE 23(22)
4-(N-(pyridin-2-ylmethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2-
H)-one
[0571] TLC: Rf 0.85 (chloroform:methanol:water=8:2:0.2);
[0572] NMR (DMSO-d.sub.6): .delta. 12.60 (s, 1H), 8.62 (t, J=6.0
Hz, 1H), 8.49 (m, 1H), 7.75 (dt, J=7.5, 1.8 Hz, 1H), 7.29 (m, 1H),
7.25 (m, 1H), 4.35 (d, J=6.0 Hz, 2H), 3.51 (s, 2H), 2.48-2.34 (m,
4H), 1.70-1.58 (m, 4H).
EXAMPLE 23(23)
4-(N-(2-bromoethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0573] TLC: Rf 0.64 (methylene chloride:methanol=10:1);
[0574] NMR (DMSO-d.sub.6): .delta. 12.59 (s, 1H), 8.32 (m, 1H)
3.52-3.44 (m, 2H), 3.43 (s, 2H), 3.42-3.33 (m, 2H), 2.48-2.33 (m,
4H), 2.70-1.60 (m, 4H).
EXAMPLE 23(24)
4-(N-(3-bromopropyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-on-
e
[0575] TLC: Rf 0.60 (methylene chloride:methanol=10:1);
[0576] NMR (DMSO-d.sub.6): .delta. 12.58 (s, 1H), 8.10 (t, J=6.0
Hz, 1H), 3.51 (t, J=6.0 Hz, 2H), 3.40 (s, 2H), 3.15 (q, J=6.0 Hz,
2H), 2.45-2.33 (m, 4H), 1.93 (quin, J=6.0 Hz, 2H), 1.68-1.59 (m,
4H).
EXAMPLE 23(25)
4-(N-(5-(N'-t-butoxycarbonylamino)pentyl)carbamoylmethyl)-5,6,7,8-tetrahyd-
rophthalazin-1(2H)-one
[0577] NMR (DMSO-d.sub.6): .delta. 12.56 (s, 1H), 7.99 (t, J=6.0
Hz, 1H), 6.75 (t, J=6.0 Hz, 1H), 3.38 (s, 2H), 3.10 (q, J=6.0 Hz,
2H), 2.86 (q, J=6.0 Hz, 2H), 2.45-2.33 (m, 4H), 1.69-1.62 (m, 4H),
1.44-1.29 (m, 4H), 1.36 (s, 9H), 1.28-1.18 (m, 2H).
EXAMPLE 23(26)
4-(N-(5-methylthiazol-2-yl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1-
(2H)-one
[0578] TLC: Rf 0.57 (methanol:methylene chloride=1:10);
[0579] NMR (DMSO-d.sub.6): .delta. 12.65 (brs, 1H), 12.12 (brs,
1H), 7.12 (s, 1H), 3.73 (s, 2H), 2.39 (m, 4H), 2.32 (s, 3H), 1.65
(brs, 4H).
EXAMPLE 23(27)
4-(N-(3-(N',N'-dimethylamino)propyl)-N-methylcarbamoylmethyl)-5,6,7,8-tetr-
ahydrophthalazin-1(2H)-one hydrochloride
[0580] TLC: Rf 0.11 (methylene
chloride:methanol:water=7:3:0.3);
[0581] NMR (DMSO-d.sub.6): .delta. 12.59 (s, 1H), 10.92 and 10.51
(br, 1H), 3.68 and 3.66 (s, 2H), 3.43 and 3.36 (t, J=6.6 Hz, 2H),
3.80-2.90 (m, 2H), 3.01 and 2.82 (s, 3H), 2.73 and 2.71 and 2.69
(s, 6H), 2.42-2.32 (m, 4H), 2.02-1.82 (m, 2H), 1.67-1.58 (m,
4H).
EXAMPLE 23(28)
4-(N-(2-(N',N'-dimethylamino)ethyl)-N-methylcarbamoylmethyl)-5,6,7,8-tetra-
hydrophthalazin-1(2H)-one hydrochloride
[0582] TLC: Rf 0.21 (methylene
chloride:methanol:water=7:3:0.3);
[0583] NMR (DMSO-d.sub.6): .delta. 12.59 (s, 1H), 10.69 and 9.93
(br, 1H), 3.75 and 3.68 (s, 2H), 3.64 (t, J=6.0 Hz, 2H), 3.20 (q,
J=6.0 Hz, 2H), 3.04 and 2.84 (s, 3H), 2.79 and 2.77 and 2.76 (s,
6H), 2.42-2.33 (m, 4H), 1.68-1.60 (m, 4H).
EXAMPLE 23(29)
4-(N-(4-bromobutyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0584] TLC: Rf 0.65 (methylene chloride:methanol=10:1);
[0585] NMR (DMSO-d.sub.6): .delta. 12.56 (s, 1H), 8.02 (t, J=6.3
Hz, 1H), 3.52 (t, J=6.3 Hz, 2H), 3.39 (s, 2H), 3.06 (q, J=6.3 Hz,
2H), 2.45-2.33 (m, 4H), 1.82-1.73 (m, 2H), 1.67-1.58 (m, 4H),
1.58-1.48 (m, 2H).
EXAMPLE 23(30)
4-(2-(N-t-butoxycarbonylamino)ethoxycarbonylmethyl)-5,6,7,8-tetrahydrophth-
alazin-1(2H)-one
[0586] NMR (CD.sub.3OD): .delta. 4.15 (t, J=5.7 Hz, 1H), 3.71 (m,
2H), 3.54 (t, J=5.7 Hz, 2H), 3.29 (t, J=5.7 Hz, 1H), 3.14 (t, J=5.7
Hz, 1H), 2.56-2.47 (m, 4H), 1.91-1.84 (m, 4H), 1.43 (s, 9H).
EXAMPLE 23(31)
4-(N-(4-oxo-4,5-dihydro-1,3-thiazol-2-yl)carbamoylmethyl)-5,6,7,8-tetrahyd-
rophthalazin-1(2H)-one
[0587] NMR (DMSO-d.sub.6): .delta. 12.73 (brs, 1H), 12.67 (s, 1H),
3.88 (s, 2H), 3.80 (s, 2H), 2.38 (brs, 4H), 1.65 (brs, 4H).
EXAMPLE 23(32)
4-(N-(1-methyl-4-oxo-1,5-dihydro-4H-imidazol-2-yl)carbamoylmethyl)-5,6,7,8-
-tetrahydrophthalazin-1(2H)-one
[0588] TLC: Rf 0.49 (methanol:methylene chloride=1:10);
[0589] NMR (DMSO-d.sub.6): .delta. 12.52 (brs, 1H), 11.03 (brs,
1H), 4.00 (s, 2H), 3.58 (s, 2H), 2.90 (s, 3H), 2.41 (m, 4H), 1.63
(brs, 4H).
EXAMPLE 23(33)
4-(2-(N-(2-(N'-t-butoxycarbonylamino)ethyl)carbamoyl)ethyl)-5,6,7,8-tetrah-
ydrophthalazin-1(2H)-one
[0590] TLC: Rf 0.66 (chloroform:methanol=4:1);
[0591] NMR (DMSO-d.sub.6): .delta. 12.50 (s, 1H), 7.87 (brt, 1H),
6.78 (brt, 1H), 3.12-2.84 (m, 4H), 2.78-2.62 (m, 2H), 2.56-2.26 (m,
6H), 1.76-1.54 (m, 4H), 1.36 (s, 9H).
EXAMPLE 23(34)
4-(N-(2-cyanoethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0592] TLC: Rf 0.79 (methylene
chloride:methanol:water=8:2:0.2);
[0593] NMR (DMSO-d.sub.6): .delta. 12.59 (s, 1H), 8.39 (t, J=5.7
Hz, 1H), 3.43 (s, 2H), 3.32-3.23 (m, 2H), 2.64 (t, J=6.3 Hz, 2H),
2.45-2.33 (m, 4H), 1.68-1.60 (m, 4H).
EXAMPLE 23(35)
4-(N-(4-(imidazol-1-yl)butyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-
-1(2H)-one
[0594] TLC: Rf 0.75 (methylene chloride:methanol:saturated aqueous
ammonia=8:2:0.2);
[0595] NMR (DMSO-d.sub.6): .delta. 12.57 (s 1H), 8.03 (m, 1H), 7.60
(s, 1H), 7.13 (s, 1H), 6.87 (s, 1H), 3.94 (t, J=6.6 Hz, 2H), 3.38
(s, 2H), 3.05 (q, J=6.6 Hz, 2H), 2.46-2.33 (m, 4H), 1.74-1.60 (m,
6H), 1.31 (quin, J=6.6 Hz, 2H).
EXAMPLE 23(36)
4-(N-(2-methoxycarbonylethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-
-1(2H)-one
[0596] TLC: Rf 0.83 (methylene
chloride:methanol:water=8:2:0.2);
[0597] NMR (DMSO-d.sub.6): .delta. 12.57 (s 1H), 8.13 (m, 1H), 3.58
(s, 3H), 3.38 (s, 2H), 3.32-3.24 (m, 2H), 2.50-2.43 (m, 2H),
2.42-2.32 (m, 4H), 1.68-1.60 (m, 4H).
EXAMPLE 23(37)
4-(N-methyl-N-(3-chloropropyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazi-
n-1(2H)-one
[0598] TLC: Rf 0.81 (methylene
chloride:methanol:water=8:2:0.2);
[0599] NMR (DMSO-d.sub.6): .delta. 12.56 (s, 1H), 3.68 and 3.60 (m,
2H), 3.63 and 3.31 (s, 2H), 3.45 and 3.41 (t, J=6.3 Hz, 2H), 3.02
and 2.81 (s, 3H), 2.41-2.33 (m, 4H), 2.01 and 1.90 (m, 2H),
1.70-1.60 (m, 4H).
EXAMPLE 24
4-(N-(2-hydroxyethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-o-
ne
[0600] A mixture of the compound prepared in Example 15 (222 mg)
and 2-aminoethanol (305 mg) was stirred at 100.degree. C. for 1
hour. After cooling the reaction mixture to room temperature, the
deposited crystal was washed with ethyl acetate. The obtained
crystal was recrystallized from a mixed solvent methanol and ethyl
acetate to give the compound of the present invention (190 mg)
having the following physical data.
[0601] TLC: Rf 0.23 (methanol:methylene chloride=1:10);
[0602] NMR (DMSO-d.sub.6): .delta. 12.55 (brs, 1H), 8.03 (t, J=5.4
Hz, 1H), 4.66 (t, J=5.4 Hz, 1H), 3.41 (s, 2H), 3.38 (m, 2H), 3.11
(m, 2H), 2.42 (brs, 2H), 2.36 (brs, 2H), 1.63 (brs, 4H).
EXAMPLE 24(1) TO EXAMPLE 24(48)
[0603] By the same procedure as described in Example 24, if
necessary, by converting to corresponding salts by conventional
method, using the compound prepared in Example 15 or a
corresponding ester derivative, and a corresponding derivative
instead of 2-aminoethanol, the following compounds of the present
invention were obtained.
EXAMPLE 24(1)
8-(N-(2-aminoethyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridaz-
in-5(1H)-one dihydrochloride
[0604] TLC: Rf 0.36 (chloroform:methanol:28% ammonia
water=15:5:1);
[0605] NMR (DMSO-d.sub.6): .delta. 12.32 (br-s, 1H), 8.41 (t, J=5.4
Hz, 1H), 8.06 (br-s, 3H), 3.49 (s, 2H), 3.30 (m, 2H), 3.20 (m, 2H),
2.86 (m, 2H), 2.38 (t, J=6.0 Hz, 2H), 1.70 (m, 2H).
EXAMPLE 24(2)
4-(N-(2-methoxyethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-o-
ne
[0606] TLC: Rf 0.53 (methanol:methylene chloride=1:10);
[0607] NMR (DMSO-d.sub.6): .delta. 12.56 (brs, 1H), 8.11 (t, J=5.4
Hz, 1H), 3.41 (s, 2H), 3.32 (m, 2H), 3.23 (s, 3H), 3.19 (m, 2H),
2.41-2.36 (m, 4H), 1.63 (brs, 4H).
EXAMPLE 24(3)
4-(N-(2-(N',N'-diethylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophtha-
lazin-1(2H)-one
[0608] TLC: Rf 0.35 (chloroform:methanol:water=8:2:0.2);
[0609] NMR (DMSO-d.sub.6): .delta. 12.57 (s, 1H), 7.85 (t, J=5.4
Hz, 1H), 3.39 (s, 2H), 3.09 (q, J=6.6 Hz, 2H), 2.48-2.32 (m, 10H),
1.67-1.58 (m, 4H), 0.91 (t, J=7.2 Hz, 6H).
EXAMPLE 24(4)
4-(N-propylcarbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0610] TLC: Rf 0.60 (chloroform:methanol:water=8:2:0.2);
[0611] NMR (DMSO-d.sub.6): .delta. 12.56 (s, 1H), 8.00 (t, J=6.9
Hz, 1H), 3.39 (s, 2H), 2.99 (q, J=6.9 Hz, 2H), 2.46-2.32 (m, 4H),
1.68-1.58 (m, 4H), 1.39 (sextet, J=6.9 Hz, 2H), 0.83 (t, J=6.9 Hz,
3H).
EXAMPLE 24(5)
4-(N-(4-hydroxybutyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-o-
ne
[0612] TLC: Rf 0.68 (methanol:methylene chloride=1:4);
[0613] NMR (DMSO-d.sub.6): .delta. 12.54 (brs, 1H), 8.00 (t, J=5.6
Hz, 1H), 4.37 (t, J=5.1 Hz, 1H), 3.38 (s, 2H), 3.36 (m, 2H), 3.02
(m, 2H), 2.42-2.36 (m, 4H), 1.63 (brs, 4H), 1.38 (m, 4H).
EXAMPLE 24(6)
4-(N-(furan-2-ylmethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-
-one
[0614] TLC: Rf 0.37 (methanol:methylene chloride=1:10);
[0615] NMR (DMSO-d.sub.6): .delta. 12.58 (brs, 1H), 8.51 (t, J=5.4
Hz, 1H), 7.56 (m, 1H), 6.38 (m, 1H), 6.22 (m, 1H), 4.25 (d, J=5.4
Hz, 2H), 3.44 (s, 2H), 2.37 (m, 4H), 1.62 (brs, 4H).
EXAMPLE 24(7)
4-(N-(piperidin-4-ylmethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1-
(2H)-one hydrochloride
[0616] TLC: Rf 0.21 (methanol:methylene chloride:saturated aqueous
ammonia=1:4:0.2);
[0617] NMR (DMSO-d.sub.6): .delta. 12.59 (s, 1H), 8.92 (m, 1H),
8.63 (m, 1H), 8.19 (t, J=5.4 Hz, 1H), 3.42 (s, 2H), 3.21 (m, 2H),
2.97-2.72 (m, 4H), 2.38 (m, 4H), 1.76-1.26 (m, 9H).
EXAMPLE 24(8)
4-(N-(2,3,4,5-tetrahydrofuran-2-ylmethyl)carbamoylmethyl)-5,6,7,8-tetrahyd-
rophthalazin-1(2H)-one
[0618] TLC: Rf 0.45 (methanol:methylene chloride=1:10);
[0619] NMR (DMSO-d.sub.6): .delta. 12.56 (brs, 1H), 8.10 (t, J=5.7
Hz, 1H), 3.85-3.56 (m, 3H), 3.42 (s, 2H), 3.18-3.04 (m, 2H),
2.41-2.36 (m, 4H), 1.90-1.42 (m, 8H).
EXAMPLE 24(9)
4-(1-(N-(2-(piperidin-1-yl)ethyl)carbamoyl)ethyl)-5,6,7,8-tetrahydrophthal-
azin-1(2H)-one
[0620] TLC: Rf 0.20 (methanol:methylene chloride=1:4);
[0621] NMR (DMSO-d.sub.6): .delta. 12.60 (brs, 1H), 7.80 (t, J=5.7
Hz, 1H), 3.69 (q, J=6.9 Hz, 1H), 3.20-3.05 (m, 2H), 2.48-2.25 (m,
10H), 1.65-1.34 (m, 10H), 1.30 (d, J=6.9 Hz, 3H).
EXAMPLE 24(10)
4-(N-(2-(pyridin-4-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin--
1(2H)-one
[0622] TLC: Rf 0.37 (methanol:methylene chloride=1:10);
[0623] NMR (DMSO-d.sub.6): .delta. 12.53 (brs, 1H), 8.44 (d, J=6.3
Hz, 2H), 8.10 (t, J=5.7 Hz, 1H), 7.22 (d, J=6.3 Hz, 2H), 3.35 (m,
4H), 2.84-2.63 (m, 2H), 2.34-2.27 (m, 4H), 1.59 (brs, 4H).
EXAMPLE 24(11)
4-(N-(2-(pyridin-2-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin--
1(2H)-one
[0624] TLC: Rf 0.36 (methanol:methylene chloride=1:10);
[0625] NMR (DMSO-d.sub.6): .delta. 12.57 (s, 1H), 8.48 (d, J=3.9
Hz, 1H), 8.09 (t, J=5.4 Hz, 1H), 7.70 (m, 1H), 7.23 (m, 2H), 3.42
(td, J=6.9, 5.4 Hz, 2H), 3.36 (s, 2H), 2.87 (t, J=6.9 Hz, 2H), 2.33
(m, 4H), 1.60 (brs, 4H).
EXAMPLE 24(12)
4-(N-(2,2-dimethyl-3-(N',N'-dimethylamino)propyl)carbamoylmethyl)-5,6,7,8--
tetrahydrophthalazin-1(2H)-one
[0626] TLC: Rf 0.24 (methanol:methylene chloride=1:4);
[0627] NMR (DMSO-d.sub.6): .delta. 12.61 (s, 1H), 7.89 (t, J=6.0
Hz, 1H), 3.44 (s, 2H), 2.95 (d, J=6.0 Hz, 2H), 2.43 (m, 2H), 2.36
(m, 2H), 2.15 (s, 6H), 2.05 (s, 2H), 1.63 (brs, 4H), 0.78 (s,
6H).
EXAMPLE 24(13)
4-(N-(2-(N'-isopropylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthal-
azin-1(2H)-one
[0628] TLC: Rf 0.27 (ethyl acetate:acetic acid:water=3:1:1);
[0629] NMR (DMSO-d.sub.6): .delta. 12.57 (br, 1H), 7.96 (m, 1H),
3.40 (s, 2H), 3.09 (q, J=6.0 Hz, 2H), 2.66 (m, 1H), 2.58-2.48 (m,
2H), 2.45-2.32 (m, 4H), 1.68-1.59 (m, 4H), 0.93 (d, J=6.0 Hz,
6H).
EXAMPLE 24(14)
4-(N-(2-(N'-ethylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-
-1(2H)-one
[0630] TLC: Rf 0.22 (ethyl acetate:acetic acid:water=3:1:1);
[0631] NMR (DMSO-d.sub.6): .delta. 12.53 (br, 1H), 7.96 (m, 1H),
3.40 (s, 2H), 3.10 (q, J=6.0 Hz, 2H), 2.57-2.45 (m, 4H), 2.45-2.34
(m, 4H), 1.68-1.58 (m, 4H), 0.97 (t, J=6.9 Hz, 3H).
EXAMPLE 24(15)
4-(N-(3-(N'-methylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalaz-
in-1(2H)-one
[0632] TLC: Rf 0.20 (ethyl acetate:acetic acid:water=3:1:1);
[0633] NMR (DMSO-d.sub.6): .delta. 8.01 (t, J=6.9 Hz, 1H), 3.38 (s,
2H), 3.07 (q, J=6.9 Hz, 2H), 2.41 (t, J=6.9 Hz, 2H), 2.45-2.33 (m,
4H), 2.21 (s, 3H), 1.70-1.60 (m, 4H), 1.52 (quin, J=6.9 Hz,
2H).
EXAMPLE 24(16)
4-(N-(2-(pyridin-3-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin--
1(2H)-one
[0634] TLC: Rf 0.47 (methanol:methylene chloride=1:10);
[0635] NMR (DMSO-d.sub.6): .delta. 12.56 (brs, 1H), 8.40 (m, 2H),
8.10 (t, J=5.7 Hz, 1H), 7.61 (m, 1H), 7.30 (m, 1H), 3.36 (s, 2H),
3.31 (m, 2H), 2.73 (t, J=6.9 Hz, 2H), 2.31 (m, 4H), 1.60 (brs,
4H).
EXAMPLE 24(17)
4-(N-(1-benzylpiperidin-4-yl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-
-1(2H)-one
Free Form:
[0636] TLC: Rf 0.38 (methanol:methylene chloride=1:10);
[0637] NMR (CD.sub.3OD): .delta. 7.36 (m, 5H), 3.76 (m, 1H), 3.69
(s, 2H), 3.59 (s, 2H), 3.01 (m, 2H), 2.56 (brs, 4H), 2.33 (m, 2H),
1.97-1.61 (m, 8H).
Hydrochloride:
[0638] TLC: Rf 0.49 (methanol:methylene chloride:saturated aqueous
ammonia=1:9:0.1);
[0639] NMR (DMSO-d.sub.6): .delta. 12.58 (s, 1H), 10.63 (brs, 1H),
8.33 (d, J=7.2 Hz, 1H), 7.58 (m, 2H), 7.44 (m, 3H), 4.29-2.92 (m,
9H), 2.38 (m, 4H), 1.94-1.70 (m, 4H), 1.62 (brs, 4H).
EXAMPLE 24(18)
4-(N-(2-(N'-phenylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazi-
n-1(2H)-one
Free Form:
[0640] TLC: Rf 0.47 (methanol:methylene chloride=1:10);
[0641] NMR (DMSO-d.sub.6): .delta. 12.58 (brs, 1H), 8.12 (t, J=5.7
Hz, 1H), 7.05 (dd, J=8.4, 7.2 Hz, 2H), 6.52 (m, 3H), 5.55 (t, J=5.7
Hz, 1H), 3.42 (s, 2H), 3.22 (m, 2H), 3.06 (m, 2H), 2.38 (m, 4H),
1.60 (brs, 4H).
Hydrochloride:
[0642] TLC: Rf 0.57 (methanol:methylene chloride=1:10);
[0643] NMR (DMSO-d.sub.6): .delta. 12.60 (s, 1H), 8.31 (m, 1H),
7.35-7.04 (m, 5H), 3.44 (s, 2H), 3.33-3.23 (m, 4H), 2.38 (m, 4H),
1.62 (brs, 4H).
EXAMPLE 24(19)
4-(N-(2-(1-methylpyrrol-2-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophth-
alazin-1(2H)-one
[0644] TLC: Rf 0.47 (methanol:methylene chloride=1:10);
[0645] NMR (DMSO-d.sub.6): .delta. 12.57 (brs, 1H), 8.13 (t, J=5.7
Hz, 1H), 6.58 (t, J=2.4 Hz, 1H), 5.84 (t, J=2.4 Hz, 1H), 5.76 (brs,
1H), 3.49 (s, 3H), 3.39 (s, 2H), 3.24 (m, 2H), 2.64 (t, J=7.2 Hz,
2H), 2.37 (m, 4H), 1.63 (brs, 4H).
EXAMPLE 24(20)
4-(N-(5-hydroxypentyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)--
one
[0646] TLC: Rf 0.29 (methanol:methylene chloride=1:10);
[0647] NMR (DMSO-d.sub.6): .delta. 12.56 (brs, 1H), 7.99 (t, J=5.4
Hz, 1H), 4.33 (t, J=5.4 Hz, 1H), 3.38 (s, 2H), 3.35 (m, 2H), 3.02
(td, J=6.3, 5.4 Hz, 2H), 2.39 (m, 4H), 1.63 (brs, 4H), 1.41-1.22
(m, 6H).
EXAMPLE 24(21)
4-(N-(2-(N'-benzylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazi-
n-1(2H)-one
[0648] TLC: Rf 0.15 (methanol:methylene chloride=1:9);
[0649] NMR (DMSO-d.sub.6): .delta. 12.55 (brs, 1H), 7.97 (t, J=6.0
Hz, 1H), 7.30-7.17 (m, 5H), 3.67 (s, 2H), 3.40 (s, 2H), 3.15 (q,
J=6.0 Hz, 2H), 2.56-2.35 (m, 6H), 1.61 (brs, 4H).
EXAMPLE 24(22)
4-(N-(2-(furan-2-ylmethylthio)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropht-
halazin-1(2H)-one
[0650] TLC: Rf 0.38 (methanol:methylene chloride=1:10);
[0651] NMR (DMSO-d.sub.6): .delta. 12.57 (brs, 1H), 8.16 (t, J=5.7
Hz, 1H), 7.56 (t, J=1.5 Hz, 1H), 6.37 (dd, J=3.0, 1.5 Hz, 1H), 6.26
(d, J=3.0 Hz, 1H), 3.77 (s, 2H), 3.40 (s, 2H), 3.22 (m, 2H),
2.53-2.36 (m, 6H), 1.63 (brs, 4H).
EXAMPLE 24(23)
4-(N-(3-(2-methylpiperidin-1-yl)propyl)carbamoylmethyl)-5,6,7,8-tetrahydro-
phthalazin-1(2H)-one
[0652] TLC: Rf 0.43 (methanol:methylene chloride:saturated aqueous
ammonia=2:8:0.1);
[0653] NMR (DMSO-d.sub.6): .delta. 12.57 (brs, 1H), 8.00 (t, J=5.7
Hz, 1H), 3.38 (s, 2H), 3.03 (m, 2H), 2.73-1.96 (m, 11H), 1.63-1.13
(m, 10H), 0.94 (d, J=6.3 Hz, 3H).
EXAMPLE 24(24)
4-(N-(3-(N'-cyclohexylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophth-
alazin-1(2H)-one
[0654] TLC: Rf 0.41 (methanol:methylene chloride:saturated aqueous
ammonia=2:8:0.1);
[0655] NMR (DMSO-d.sub.6): .delta. 12.58 (brs, 1H), 8.01 (t, J=5.1
Hz, 1H), 3.38 (s, 2H), 3.08 (m, 2H), 2.51-2.25 (m, 7H), 1.77-0.92
(m, 16H).
EXAMPLE 24(25)
4-(N-(2-(N'-butylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-
-1(2H)-one
[0656] TLC: Rf 0.66 (methanol:methylene chloride:saturated aqueous
ammonia=2:8:0.1);
[0657] NMR (DMSO-d.sub.6): .delta. 12.58 (brs, 1H), 7.95 (t, J=5.4
Hz, 1H), 3.40 (s, 2H), 3.11 (m, 2H), 2.55-2.36 (m, 8H), 1.63 (brs,
4H), 1.31 (m, 4H), 0.85 (t, J=6.9 Hz, 3H).
EXAMPLE 24(26)
4-(N-(2-(N'-(2-hydroxypropyl)amino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahyd-
rophthalazin-1(2H)-one
[0658] TLC: Rf 0.51 (methanol:methylene chloride:saturated aqueous
ammonia=1:10:0.1);
[0659] NMR (DMSO-d.sub.6): .delta. 7.99 (t, J=5.1 Hz, 1H), 4.44
(brs, 1H), 3.62 (m, 1H), 3.40 (s, 2H), 3.11 (m, 2H), 2.57-2.37 (m,
8H), 1.63 (brs, 4H), 1.01 (d, J=6.3 Hz, 3H).
EXAMPLE 24(27)
4-(N-(3-(N'-methyl-N'-phenylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahyd-
rophthalazin-1(2H)-one
[0660] TLC: Rf 0.58 (methanol:methylene chloride=1:10);
[0661] NMR (DMSO-d.sub.6): .delta. 12.58 (brs, 1H), 8.07 (t, J=5.4
Hz, 1H), 7.14 (t, J=7.5 Hz, 2H), 6.61 (m, 3H), 3.41 (s, 2H), 3.29
(m, 2H), 3.08 (m, 2H), 2.83 (s, 3H), 2.39 (m, 4H), 1.62 (m,
6H).
EXAMPLE 24(28)
4-(N-(3-hydroxypropyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)--
one
[0662] TLC: Rf 0.26 (methanol:methylene chloride=1:10);
[0663] NMR (DMSO-d.sub.6): .delta. 12.54 (brs, 1H), 7.99 (t, J=5.4
Hz, 1H), 4.41 (t, J=5.4 Hz, 1H), 3.40 (m, 2H), 3.39 (s, 2H), 3.09
(m, 2H), 2.39 (m, 4H), 1.63 (brs, 4H), 1.58-1.49 (m, 2H).
EXAMPLE 24(29)
4-(N-(2-(thiophen-2-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-
-1(2H)-one
[0664] TLC: Rf 0.48 (methanol:methylene chloride=1:10);
[0665] NMR (DMSO-d.sub.6): .delta. 12.57 (brs, 1H), 8.16 (t, J=5.7
Hz, 1H), 7.32 (d, J=5.1 Hz, 1H), 6.94 (dd, J=5.1, 3.3 Hz, 1H), 6.67
(d, J=3.3 Hz, 1H), 3.39 (s, 2H), 3.30 (m, 2H), 2.92 (t, J=6.9 Hz,
2H), 2.35 (brs, 4H), 1.62 (brs, 4H).
EXAMPLE 24(30)
4-(N-(2-(1-methylpyrrolidin-2-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydro-
phthalazin-1(2H)-one
[0666] TLC: Rf 0.30 (methanol:methylene chloride:saturated aqueous
ammonia=2:8:0.1);
[0667] NMR (DMSO-d.sub.6): .delta. 12.58 (brs, 1H), 8.01 (t, J=5.4
Hz, 1H), 3.38 (s, 2H), 3.07 (m, 2H), 2.88 (m, 1H), 2.38 (m, 4H),
2.15 (s, 3H), 2.03-1.24 (m, 12H).
EXAMPLE 24(31)
4-(N-(2-(1-benzylpiperidin-4-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrop-
hthalazin-1(2H)-one
Free Form:
[0668] TLC: Rf 0.44 (methanol:methylene chloride:saturated aqueous
ammonia=2:8:0.1);
[0669] NMR (DMSO-d.sub.6): .delta. 12.56 (brs, 1H), 7.96 (t, J=5.4
Hz, 1H), 7.32-7.19 (m, 5H), 3.40 (s, 2H), 3.37 (s, 2H), 3.06 (m,
2H), 2.75 (m, 2H), 2.31 (m, 4H), 1.87-1.03 (m, 13H).
Hydrochloride:
[0670] TLC: Rf 0.48 (methanol:methylene chloride:saturated aqueous
ammonia=1:9:0.1);
[0671] NMR (DMSO-d.sub.6): .delta. 12.58 (s, 1H), 10.21 (brs, 1H),
8.05 (t, J=5.4 Hz, 1H), 7.56 (m, 2H), 7.45 (m, 3H), 4.24 (m, 2H),
3.38-2.78 (m, 8H), 2.37 (m, 4H), 1.83-1.31 (m, 11H).
EXAMPLE 24(32)
4-(N-(2-(N'-(2-hydroxyethyl)amino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydr-
ophthalazin-1(2H)-one
[0672] TLC: Rf 0.18 (ethyl acetate:acetic acid:water=3:1:1);
[0673] NMR (DMSO-d.sub.6): .delta. 12.55 (br, 1H), 7.99 (t, J=6.0
Hz, 1H), 4.43 (m, 1H), 3.44-3.37 (m, 2H), 3.40 (s, 2H), 3.11 (q,
J=6.0 Hz, 2H), 2.59-2.52 (m, 4H), 2.45-2.33 (m, 4H), 1.68-1.60 (m,
4H).
EXAMPLE 24(33)
4-(N-(3-methylthiopropyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2-
H)-one
[0674] TLC: Rf 0.60 (methanol:methylene chloride=1:10);
[0675] NMR (DMSO-d.sub.6): .delta. 12.57 (brs, 1H), 8.05 (t, J=5.4
Hz, 1H), 3.39 (s, 2H), 3.11 (m, 2H), 2.44-2.36 (m, 6H), 2.02 (s,
3H), 1.66 (m, 6H).
EXAMPLE 24(34)
4-(N-(2-(N'-ethyl-N'-(3-methylphenyl)amino)ethyl)carbamoylmethyl)-5,6,7,8--
tetrahydrophthalazin-1(2H)-one
[0676] TLC: Rf 0.63 (methanol:methylene chloride=1:10);
[0677] NMR (DMSO-d.sub.6): .delta. 12.59 (brs, 1H), 8.12 (t, J=5.4
Hz, 1H), 7.00 (dd, J=7.2, 7.2 Hz, 1H), 6.50 (m, 2H), 6.37 (d, J=7.2
Hz, 1H), 3.40 (s, 2H), 3.33-3.18 (m, 6H), 2.38 (m, 4H), 2.20 (s,
3H), 1.62 (brs, 4H), 1.04 (t, J=6.9 Hz, 3H).
EXAMPLE 24(35)
4-(N-(4,4-dimethoxybutyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2-
H)-one
[0678] TLC: Rf 0.34 (methanol:methylene chloride=1:10);
[0679] NMR (DMSO-d.sub.6): .delta. 12.56 (brs, 1H), 8.01 (t, J=5.4
Hz, 1H), 4.31 (t, J=5.4 Hz, 1H), 3.39 (s, 2H), 3.19 (s, 6H), 3.01
(m, 2H), 2.39 (m, 4H), 1.63 (brs, 4H), 1.52-1.34 (m, 4H).
EXAMPLE 24(36)
4-(N-(3-(N',N'-diethylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophth-
alazin-1(2H)-one
[0680] TLC: Rf 0.34 (methylene chloride:methanol:saturated aqueous
ammonia=8:2:0.2);
[0681] NMR (DMSO-d.sub.6): .delta. 12.57 (s, 1H), 7.99 (t, J=5.7
Hz, 1H), 3.38 (s, 2H), 3.05 (q, J=5.7 Hz, 2H), 2.44-2.29 (m, 10H),
1.66-1.59 (m, 4H), 1.49 (quin, J=5.7 Hz, 2H), 0.91 (t, J=6.9 Hz,
6H).
EXAMPLE 24(37)
4-(N-(3-(N'-isopropylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophtha-
lazin-1(2H)-one
[0682] TLC: Rf 0.18 (methylene chloride:methanol:saturated aqueous
ammonia=8:2:0.2);
[0683] NMR (DMSO-d.sub.6): .delta. 12.52 (br, 1H), 8.00 (m, 1H),
3.38 (s, 2H), 3.08 (q, J=6.0 Hz, 2H), 2.62 (sep, J=6.0 Hz, 1H),
2.48-2.32 (m, 6H), 1.68-1.60 (m, 4H), 1.49 (quin, J=6.0 Hz, 2H),
0.92 (d, J=6.0 Hz, 6H).
EXAMPLE 24(38)
4-(N-(2-(1,3-dioxolan-2-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthal-
azin-1(2H)-one
[0684] TLC: Rf 0.41 (methanol:methylene chloride=1:10);
[0685] NMR (DMSO-d.sub.6): .delta. 12.57 (brs, 1H), 8.01 (t, J=5.7
Hz, 1H), 4.79 (t, J=4.8 Hz, 1H), 3.89-3.71 (m, 4H), 3.38 (s, 2H),
3.13 (m, 2H), 2.38 (m, 4H), 1.70 (m, 2H), 1.63 (brs, 4H).
EXAMPLE 24(39)
4-(N-(3-(N'-propylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalaz-
in-1(2H)-one
[0686] TLC: Rf 0.14 (methylene chloride:methanol:saturated aqueous
ammonia=8:2:0.2);
[0687] NMR (DMSO-d.sub.6): .delta. 12.60 (br, 1H), 8.00 (m, 1H),
3.38 (s, 2H), 3.08 (q, J=6.6 Hz, 2H), 2.47-2.34 (m, 8H), 1.70-1.60
(m, 4H), 1.50 (quin, J=6.6 Hz, 2H), 1.38 (sex, J=6.6 Hz, 2H), 0.83
(t, J=6.6 Hz, 3H).
EXAMPLE 24(40)
4-(N-(2-(N'-propylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazi-
n-1(2H)-one
[0688] TLC: Rf 0.31 (methylene chloride:methanol:saturated aqueous
ammonia=8:2:0.2);
[0689] NMR (DMSO-d.sub.6): .delta. 12.59 (br, 1H), 7.96 (m, 1H),
3.40 (s, 2H), 3.11 (q, J=6.3 Hz, 2H), 2.57-2.47 (m, 2H), 2.45-2.33
(m, 6H), 1.70-1.60 (m, 4H), 1.37 (sex, J=7.2 Hz, 2H), 0.84 (t,
J=7.2 Hz, 3H).
EXAMPLE 24(41)
4-(N-(2-(4-methoxyphenyl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalaz-
in-1(2H)-one
[0690] TLC: Rf 0.47 (methanol:methylene chloride=1:10);
[0691] NMR (DMSO-d.sub.6): .delta. 12.56 (brs, 1H), 8.04 (t, J=5.7
Hz, 1H), 7.10 (d, J=8.7 Hz, 2H), 6.83 (d, J=8.7 Hz, 2H), 3.70 (s,
3H), 3.36 (s, 2H), 3.24 (m, 2H), 2.63 (t, J=7.2 Hz, 2H), 2.33 (m,
4H), 1.60 (brs, 4H).
EXAMPLE 24(42)
4-(N-(2-(4-aminophenyl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-
-1(2H)-one hydrochloride
[0692] TLC: Rf 0.39 (methanol:methylene chloride=1:10);
[0693] NMR (DMSO-d.sub.6): .delta. 12.58 (brs, 1H), 10.38 (brs,
3H), 8.19 (t, J=5.4 Hz, 1H), 7.31 (m, 4H), 3.37 (s, 2H), 3.29 (q,
J=6.9 Hz, 2H), 2.73 (t, J=6.9 Hz, 2H), 2.35 (brs, 4H), 1.61 (brs,
4H).
EXAMPLE 24(43)
8-(N-(2-(N'-phenylamino)ethyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,-
3-d]pyridazin-5(1H)-one dihydro chloride
[0694] TLC: Rf 0.40 (methanol:methylene chloride=1:10);
[0695] NMR (DMSO-d.sub.6): .delta. 12.27 (brs, 1H), 8.36 (m, 1H),
7.31 (t, J=7.8 Hz, 2H), 7.10-6.00 (m, 7H), 3.46 (s, 2H), 3.24 (m,
6H), 2.38 (t, J=6.3 Hz, 2H), 1.70 (m, 2H).
EXAMPLE 24(44)
8-(N-(2-(1-benzylpiperidin-4-yl)ethyl)carbamoylmethyl)-2,3,4,6-tetrahydrop-
yrido[2,3-d]pyridazin-5(1H)-one methanesulfonate
[0696] TLC: Rf 0.36 (methanol:methylene chloride:saturated aqueous
ammonia=1:10:0.1);
[0697] NMR (DMSO-d.sub.6): .delta. 11.87 (s, 1H), 9.20 (brs, 1H),
8.05 (t, J=5.1 Hz, 1H), 7.48 (m, 5H), 6.38 (brs, 1H), 4.27 (m, 2H),
3.33-3.06 (m, 8H), 2.83 (m, 2H), 2.33 (m, 2H), 2.30 (s, 3H),
1.87-1.22 (m, 9H).
EXAMPLE 24(45)
8-(N-(3-(morpholin-4-yl)propyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2-
,3-d]pyridazin-5(1H)-one
[0698] TLC: Rf 0.31 (methanol:methylene chloride=1:4);
[0699] NMR (DMSO-d.sub.6): .delta. 11.85 (s, 1H), 8.05 (t, J=5.4
Hz, 1H), 6.41 (s, 1H), 3.54 (m, 4H), 3.29 (m, 2H), 3.17 (brs, 2H),
3.06 (q, J=6.6 Hz, 2H), 2.28 (m, 8H), 1.69 (m, 2H), 1.53 (m,
2H).
EXAMPLE 24(46)
8-(N-(2-(piperidin-1-yl)ethyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,-
3-d]pyridazin-5(1H)-one methanesulfonate
[0700] TLC: Rf 0.14 (methanol:methylene chloride:acetic
acid=1:4:0.2);
[0701] NMR (DMSO-d.sub.6): .delta. 11.91 (s, 1H), 8.94 (brs, 1H),
8.29 (t, J=5.4 Hz, 1H), 6.30 (brs, 1H), 3.50-3.38 (m, 6H), 3.12 (m,
4H), 2.90 (m, 2H), 2.35 (m, 2H), 2.32 (s, 3H), 1.98-1.33 (m,
8H).
EXAMPLE 24(47)
8-(N-(2-(morpholin-4-yl)ethyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,-
3-d]pyridazin-5(1H)-one
[0702] TLC: Rf 0.29 (methanol:methylene chloride=1:4);
[0703] NMR (DMSO-d.sub.6): .delta. 11.85 (s, 1H), 7.99 (t, J=5.4
Hz, 1H), 6.40 (s, 1H), 3.53 (m, 4H), 3.34 (s, 2H), 3.16 (m, 4H),
2.30 (m, 8H), 1.70 (m, 2H).
EXAMPLE 24(48)
8-(N-(3-(N'-t-butoxycarbonylamino)propyl)carbamoylmethyl)-2,3,4,6-tetrahyd-
ropyrido[2,3-d]pyridazin-5(1H)-one
[0704] TLC: Rf 0.35 (methanol:methylene chloride=1:9);
[0705] NMR (DMSO-d.sub.6): .delta. 11.84 (s, 1H), 8.02 (t, J=5.4
Hz, 1H), 6.76 (t, J=5.4 Hz, 1H), 6.38 (s, 1H), 3.31 (m, 2H), 3.18
(brs, 2H), 2.98 (td, J=6.6, 5.4 Hz, 2H), 2.90 (td, J=6.6, 5.4 Hz,
2H), 2.32 (t, J=6.3 Hz, 2H), 1.69 (m, 2H), 1.47 (m, 2H), 1.36 (s,
9H).
EXAMPLE 25
4-(3-(N-(5-chloropentanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H-
)-one
[0706] 5-chloropentanoyl chloride (171 mg) was added dropwise to a
mixed solution of the compound prepared in Example 1 (241 mg) and
potassium carbonate (89.8 mg) in tetrahydrofuran (3.00 mL) and
water (1.00 mL) in ice bath and the mixture was stirred for 30
minutes. Moreover, potassium carbonate (45.0 mg) and
5-chloropentanoyl chloride (85.5 mg) was added the reaction
mixture, which was stirred for 30 minutes. 1N hydrochloric acid was
added to the reaction mixture, which was adjusted to pH 2. Water
was added thereto and the deposited crystal was collected by
filtration. It was washed with water and hexane sequentially and
dried under reduced pressure to give the compound of the present
invention (347 mg) having the following physical data.
[0707] NMR (DMSO-d.sub.6): .delta. 12.88 (s, 1H), 10.00 (s, 1H),
7.69 (s, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.08
(d, J=7.8 Hz, 1H), 3.65 (t, J=6.0 Hz, 2H), 2.56-2.32 (m, 6H),
1.75-1.59 (m, 8H).
EXAMPLE 25(1) TO EXAMPLE 25(13)
[0708] By the same procedure as described in Example 25 using a
corresponding derivative instead of the compound prepared in
Example 1, and a corresponding derivative instead of
5-chloropentanoyl chloride, the following compounds of the present
invention were obtained.
EXAMPLE 25(1)
4-(3-(N-(5-bromopentanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-
-one
[0709] TLC: Rf 0.28 (methanol:methylene chloride=1:20);
[0710] NMR (DMSO-d.sub.6): .delta. 12.88 (s, 1H), 10.00 (s, 1H),
7.69 (t, J=1.2 Hz, 1H), 7.59 (dd, J=7.8, 1.2 Hz, 1H), 7.35 (t,
J=7.8 Hz, 1H), 7.09 (dd, J=7.8, 1.2 Hz, 1H), 3.55 (t, J=6.6 Hz,
2H), 2.48-2.32 (m, 6H), 1.86-1.59 (m, 8H).
EXAMPLE 25(2)
4-(3-(N-(4-chlorobutanoyl)amino)phenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4-
,3-d][1,2,4]triazin-1(2H)-one
[0711] TLC: Rf 0.50 (chloroform:methanol=9:1);
[0712] NMR (CDCl.sub.3): .delta. 8.47-8.28 (br, 1H), 7.69 (bs, 1H),
7.62 (bs, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.09
(d, J=7.8 Hz, 1H), 4.35 (dd, J=10.5, 2.7 Hz, 1H), 3.85 (dt, J=13.5,
2.7 Hz, 1H), 3.67 (t, J=6.3 Hz, 2H), 3.21-3.11 (m, 1H), 3.08-3.02
(m, 1H), 2.94 (dd, J=13.5, 10.5 Hz, 1H), 2.86-2.76 (m, 1H), 2.56
(t, J=7.2 Hz, 2H), 2.32-2.16 (m, 3H).
EXAMPLE 25(3)
4-(3-(N-acetylamino)phenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]-
triazin-1(2H)-one
[0713] TLC: Rf 0.40 (methylene chloride:methanol=10:1);
[0714] NMR (DMSO-d.sub.6): .delta. 10.52 (s, 1H), 10.05 (s, 1H),
7.67 (s, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.34 (t, J=8.1 Hz, 1H), 7.06
(d, J=8.1 Hz, 1H), 4.23 (dd, J=8.7, 4.8 Hz, 1H), 3.56 (m, 1H), 3.08
(m, 1H), 2.89-2.83 (m, 2H), 2.70 (m, 1H), 2.32 (m, 1H), 2.04 (s,
3H).
EXAMPLE 25(4)
4-(3-(N-acetylamino)phenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin--
1(2H)-one
[0715] TLC: Rf 0.51 (methanol:methylene chloride=1:10);
[0716] NMR (DMSO-d.sub.6): .delta. 10.88 (s, 1H), 10.08 (s, 1H),
7.70 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.09
(d, J=7.8 Hz, 1H), 6.26 (s, 1H), 3.61 (m, 2H), 3.15 (m, 2H), 2.05
(s, 3H).
EXAMPLE 25(5)
4-(3-(N-acetylamino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0717] TLC: Rf 0.45 (methanol:methylene chloride=1:10);
[0718] NMR (DMSO-d.sub.6): .delta. 12.87 (s, 1H), 10.02 (s, 1H),
7.67 (s, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.08
(d, J=7.8 Hz, 1H), 2.39 (m, 4H), 2.04 (s, 3H), 1.64 (m, 4H).
EXAMPLE 25(6)
4-(3-(N-(4-chlorobutanoyl)amino)phenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,-
2,4]triazin-1(2H)-one
[0719] NMR (DMSO-d.sub.6): .delta. 10.89 (s, 1H), 10.12 (s, 1H),
7.71 (t, J=1.5 Hz, 1H), 7.62 (m, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.10
(dt, J=7.8, 1.5 Hz, 1H), 6.26 (s, 1H), 3.70 (t, J=6.9 Hz, 2H),
3.64-3.58 (m, 2H), 3.18-3.13 (m, 2H), 2.35 (t, J=6.9 Hz, 2H), 2.03
(quin, J=6.9 Hz, 2H).
EXAMPLE 25(7)
4-(3-(N-(2-chloroacetyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-o-
ne
[0720] TLC: Rf 0.27 (methanol:methylene chloride=1:20);
[0721] NMR (DMSO-d.sub.6): .delta. 12.90 (s, 1H), 10.40 (s, 1H),
7.68 (s, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.15
(d, J=7.8 Hz, 1H), 4.25 (s, 2H), 2.39 (m, 4H), 1.68 (m, 2H), 1.59
(m, 2H).
EXAMPLE 25(8)
4-(3-(N-(3-bromopropanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-
-one
[0722] TLC: Rf 0.20 (methanol:methylene chloride=1:20);
[0723] NMR (DMSO-d.sub.6): .delta. 12.88 (s, 1H), 10.15 (s, 1H),
7.70 (s, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.12
(d, J=7.8 Hz, 1H), 3.72 (t, J=6.3 Hz, 2H), 2.95 (t, J=6.3 Hz, 2H),
2.48-2.34 (m, 4H), 1.70 (m, 2H), 1.60 (m, 2H).
EXAMPLE 25(9)
8-(3-(N-acetylamino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-
-one
Free Form:
[0724] TLC: Rf 0.31 (chloroform:methanol=8:1);
[0725] NMR (DMSO-d.sub.6): .delta. 12.11 (s, 1H), 10.06 (s, 1H),
7.70 (m, 1H), 7.61 (m, 1H), 7.37 (dd, J=7.8, 7.8 Hz, 1H), 7.09 (m,
1H), 5.37 (s, 1H), 3.20-3.06 (m, 2H), 2.39 (t, J=6.3 Hz, 2H), 2.04
(s, 3H), 1.82-1.60 (m, 2H).
Methanesulfonate:
[0726] TLC: Rf 0.31 (methylene chloride:methanol=9:1);
[0727] NMR (DMSO-d.sub.6): .delta. 12.31 (s, 1H), 10.06 (s, 1H),
7.70 (m, 1H), 7.62 (m, 1H), 7.38 (t, J=7.9 Hz, 1H), 7.09 (m, 1H),
3.14 (m, 2H), 2.41 (t, J=6.2 Hz, 2H), 2.33 (s, 3H), 2.04 (s, 3H),
1.73 (m, 2H).
EXAMPLE 25(10)
4-(3-(N-mesylamino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0728] TLC: Rf 0.56 (methanol:methylene chloride=1:10);
[0729] NMR (DMSO-d.sub.6): .delta. 12.89 (s, 1H), 9.86 (brs, 1H),
7.39 (t, J=7.8 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.23 (s, 1H), 7.16
(d, J=7.8 Hz, 1H), 3.00 (s, 3H), 2.48-2.34 (m, 4H), 1.69 (m, 2H),
1.59 (m, 2H).
EXAMPLE 25(11)
8-(3-(N-(4-chlorobutanoyl)amino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyr-
idazin-5(1H)-one
[0730] TLC: Rf 0.41 (chloroform:methanol=8:1);
[0731] NMR (DMSO-d.sub.6): .delta. 12.11 (s, 1H), 10.09 (s, 1H),
7.72 (m, 1H), 7.63 (s, 1H), 7.38 (dd, J=7.8, 7.8 Hz, 1H), 7.09 (m,
1H), 5.74 (s, 1H), 3.69 (t, J=6.3 Hz, 2H), 3.22-3.04 (m, 2H),
2.60-2.32 (m, 4H), 2.12-1.94 (m, 2H), 1.82-1.64 (m, 2H).
EXAMPLE 25(12)
4-(2-(N-(2-bromoacetyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0732] TLC: Rf 0.68 (chloroform:methanol=4:1);
[0733] NMR (DMSO-d.sub.6): .delta. 12.56 (s, 1H), 8.33 (brt, J=5.1
Hz, 1H), 3.82 (s, 2H), 3.44-3.26 (m, 2H), 2.64 (t, J=6.9 Hz, 2H),
2.54-2.28 (m, 4H), 1.78-1.52 (m, 4H).
EXAMPLE 25(13)
4-(2-(N-(3-bromopropanoyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)--
one
[0734] TLC: Rf 0.71 (chloroform:methanol=4:1);
[0735] NMR (DMSO-d.sub.6): .delta. 12.55 (brs, 1H), 8.07 (brt,
J=6.0 Hz, 1H), 3.61 (t, J=6.0 Hz, 2H), 3.44-3.24 (m, 2H), 2.72-2.28
(m, 8H), 1.78-1.54 (m, 4H).
EXAMPLE 26
4-(3-(N-(5-(N'-methyl-N'-t-butoxycarbonylamino)pentanoyl)amino)phenyl)-5,6-
,7,8-tetrahydrophthalazin-1(2H)-one
[0736] A mixture of the compound prepared in Example 1 (277 mg),
triethylamine (223 mg),
5-(N-methyl-N-t-butoxycarbonylamino)pentanoic acid (277 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230
mg), 1-hydroxybenzotriazole (184 mg) and dimethylformamide (3.00
mL) was stirred at room temperature for 18 hours. The reaction
mixture was concentrated. Water was added to the residue, which was
extracted with ethyl acetate. The extract was washed with 1N
hydrochloric acid, water, a saturated aqueous sodium hydrogen
carbonate solution and brine sequentially, dried over anhydrous
magnesium sulfate and concentrated. The residue was recrystallized
from a mixed solvent of ethyl acetate and hexane to give the
compound of the present invention (298 mg) having the following
physical data.
[0737] TLC: Rf 0.49 (methylene chloride:methanol=9:1);
[0738] NMR (DMSO-d.sub.6): .delta. 12.88 (s, 1H), 9.97 (s, 1H),
7.69 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.35 (t, J=8.1 Hz, 1H), 7.08
(d, J=8.1 Hz, 1H), 3.15 (t, J=6.8 Hz, 2H), 2.74 (s, 3H), 2.48-2.30
(m, 6H), 1.70-1.50 (m, 8H), 1.36 (s, 9H).
EXAMPLE 26(1) TO EXAMPLE 26(19)
[0739] By the same procedure as described in Example 26, if
necessary, by converting to corresponding salts by conventional
method, using the compound prepared in Example 1 or a corresponding
derivative, and (N-methyl-N-t-butoxycarbonylamino)pentanoic acid or
a corresponding derivative, the following compounds of the present
invention were obtained.
EXAMPLE 26(1)
4-(3-(N-(5-(N'-methyl-N'-benzyloxycarbonylamino)pentanoyl)amino)phenyl)-5,-
6,7,8-tetrahydrophthalazin-1(2H)-one
[0740] TLC: Rf 0.29 (methanol:methylene chloride=1:20);
[0741] NMR (DMSO-d.sub.6): .delta. 12.88 (s, 1H), 9.98 (s, 1H),
7.70 (s, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.32 (m, 6H), 7.08 (d, J=7.8
Hz, 1H), 5.04 (s, 2H), 3.28-2.33 (m, 11H), 1.69-1.51 (m, 8H).
EXAMPLE 26(2)
4-(3-(N-(4-chlorobutanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-
-one
[0742] TLC: Rf 0.48 (methanol:methylene chloride=1:20);
[0743] NMR (DMSO-d.sub.6): .delta. 12.88 (s, 1H), 10.07 (s, 1H),
7.69 (s, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.09
(d, J=7.8 Hz, 1H), 3.69 (t, J=6.3 Hz, 2H), 2.46-1.59 (m, 12H).
EXAMPLE 26(3)
4-(3-(N-(5-(N',N'-dimethylamino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydro-
phthalazin-1(2H)-one methanesulfonate
[0744] TLC: Rf 0.30 (methanol:methylene chloride:saturated aqueous
ammonia=2:8:0.1);
[0745] NMR (CD.sub.3OD): .delta. 7.75 (t, J=1.8 Hz, 1H), 7.63 (brd,
J=8.1 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H), 7.20 (brd, J=8.1 Hz, 1H),
3.16 (m, 2H), 2.89 (s, 6H), 2.74 (s, 3H), 2.66-2.50 (m, 6H), 1.81
(m, 8H).
EXAMPLE 26(4)
4-(3-(N-(5-(N'-benzyloxycarbonylamino)pentanoyl)amino)phenyl)-5,6,7,8-tetr-
ahydrophthalazin-1(2H)-one
[0746] TLC: Rf 0.79 (methanol:methylene chloride=1:4);
[0747] NMR (DMSO-d.sub.6): .delta. 12.88 (s, 1H), 9.97 (s, 1H),
7.69 (s, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.37-7.26 (m, 6H), 7.08 (d,
J=7.8 Hz, 1H), 4.99 (s, 2H), 3.00 (m, 2H), 2.48-2.28 (m, 6H),
1.69-1.42 (m, 8H).
EXAMPLE 26(5)
4-(3-(N-(2-(2-chloroethoxy)acetyl)amino)phenyl)-5,6,7,8-tetrahydrophthalaz-
in-1(2H)-one
[0748] TLC: Rf 0.41 (methanol:methylene chloride=1:20);
[0749] NMR (DMSO-d.sub.6): .delta. 12.89 (s, 1H), 9.81 (s, 1H),
7.73 (s, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.13
(d, J=7.8 Hz, 1H), 4.14 (s, 2H), 3.81 (s, 4H), 2.48-2.34 (m, 4H),
1.70-1.59 (m, 4H).
EXAMPLE 26(6)
4-(3-(N-(5-(N'-methyl-N'-benzyloxycarbonylamino)pentanoyl)amino)phenyl)-7,-
8,9,9a-tetrahydro-2H-pyrido[1,2-d][1,2,4]triazin-1(6H)-one
[0750] TLC: Rf 0.28 (methanol:methylene chloride=1:20);
[0751] NMR (DMSO-d.sub.6): .delta. 10.34 (s, 1H), 9.98 (s, 1H),
7.68 (s, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.33 (m, 6H), 7.01 (d, J=7.8
Hz, 1H), 5.04 (s, 2H), 3.86 (m, 1H), 3.25-1.42 (m, 19H).
EXAMPLE 26(7)
4-(3-(5-(N'-methyl-N'-benzyloxycarbonylamino)pentanoyl)aminophenyl)-6,7,9,-
9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one
[0752] TLC: Rf 0.24 (methanol:chloroform=1:10);
[0753] NMR (DMSO-d.sub.6): .delta. 10.53 (s, 1H), 10.01 (s, 1H),
7.67 (t, J=1.5 Hz, 1H), 7.58 (m, 1H), 7.34 (m, 6H), 7.06 (m, 1H),
5.04 (s, 2H), 4.23 (dd, J=8.6, 4.8 Hz, 1H), 3.57 (brd, J=13.8 Hz,
1H), 3.28 (m, 3H), 3.07 (t, J=12.0 Hz, 1H), 2.88-2.65 (m, 5H), 2.33
(m, 3H), 1.52 (m, 4H).
EXAMPLE 26(8)
4-(3-(N-(5-(N'-methyl-N'-benzyloxycarbonylamino)pentanoyl)amino)phenyl)-2,-
5,6,7,8,9-hexahydro-1H-cyclohepta[d]pyridazin-1-one
[0754] TLC: Rf 0.54 (chloroform:methanol=9:1);
[0755] NMR (CDCl.sub.3): .delta. 10.58 (br-s, 1H), 8.21 (br-s, 1H),
7.69 (br-s, 1H), 7.60 (m, 1H), 7.40-7.28 (m, 6H), 7.04 (m, 1H),
5.13 (s, 2H), 3.42-3.28 (m, 2H), 3.00-2.86 (m, 5H), 2.70-2.64 (m,
2H), 2.46-2.30 (m, 2H), 1.94-1.84 (m, 2H), 1.80-1.60 (m, 8H).
EXAMPLE 26(9)
4-(3-(N-(4-(N'-methyl-N'-t-butoxycarbonylamino)butanoyl)amino)phenyl)-6,7,-
9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one
[0756] TLC: Rf 0.35 (methylene chloride:methanol=10:1).
EXAMPLE 26(10)
4-(3-(N-(6-(N'-methyl-N'-t-butoxycarbonylamino)hexanoyl)amino)phenyl)-6,7,-
9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one
[0757] TLC: Rf 0.35 (methylene chloride:methanol=10:1).
EXAMPLE 26(11)
4-(3-(N-(5-(N'-(3-methyl-2-butenyl)-N'-t-butoxycarbonylamino)pentanoyl)ami-
no)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0758] TLC: Rf 0.31 (hexane:ethyl acetate=1:3);
[0759] NMR (DMSO-d.sub.6): .delta. 12.87 (s, 1H), 9.95 (s, 1H),
7.68 (m, 1H), 7.58 (m, 1H), 7.34 (dd, J=7.8, 7.8 Hz, 1H), 7.07 (m,
1H), 5.10 (m, 1H), 3.72 (d, J=6.6 Hz, 2H), 3.16-3.00 (m, 2H),
2.62-2.40 (m, 2H), 2.40-2.22 (m, 4H), 1.78-1.30 (m, 8H), 1.64 (s,
3H), 1.60 (s, 3H), 1.36 (s, 9H).
EXAMPLE 26(12)
4-(3-(N-(5-(N'-methyl-N'-benzyloxycarbonylamino)pentanoyl)amino)phenyl)-6,-
7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one
[0760] TLC: Rf 0.63 (chloroform:methanol:water=8:2:0.2);
[0761] NMR (CD.sub.3OD): .delta. 7.74 (s, 1H), 7.57 (d, J=7.8 Hz,
1H), 7.41 (t, J=7.8 Hz, 1H), 7.35-7.20 (m, 5H), 7.14 (d, J=7.8 Hz,
1H), 6.39 (s, 1H), 5.08 (s, 2H), 3.73-3.68 (m, 2H), 3.38-3.28 (m,
2H), 3.16-3.10 (m, 2H), 2.91 (brs, 3H), 2.44-2.25 (m, 2H),
1.78-1.50 (m, 4H).
EXAMPLE 26(13)
4-(3-(N-(2-(N',N'-dimethylamino)acetyl)amino)phenyl)-5,6,7,8-tetrahydropht-
halazin-1(2H)-one hydrochloride
[0762] TLC: Rf 0.27 (chloroform:methanol=8:1);
[0763] NMR (DMSO-d.sub.6): .delta. 12.92 (s, 1H), 10.97 (s, 1H),
9.96 (brs, 1H), 7.72 (m, 1H), 7.65 (m, 1H), 7.43 (dd, J=7.8, 7.8
Hz, 1H), 7.20 (m, 1H), 4.16 (s, 2H), 2.87 (s, 6H), 2.60-2.24 (m,
4H), 1.80-1.50 (m, 4H).
EXAMPLE 26(14)
4-(3-(N-(1-t-butoxycarbonylazetidin-3-ylcarbonyl)amino)phenyl)-5,6,7,8-tet-
rahydrophthalazin-1(2H)-one
[0764] TLC: Rf 0.27 (chloroform:methanol=8:1);
[0765] NMR (DMSO-d.sub.6): .delta. 12.88 (s, 1H), 10.13 (s, 1H),
7.71 (m, 1H), 7.60 (m, 1H), 7.37 (dd, J=7.5, 7.5 Hz, 1H), 7.12 (m,
1H), 4.08-3.84 (m, 4H), 3.46 (m, 1H), 2.54-2.28 (m, 4H), 1.78-1.52
(m, 4H), 1.38 (s, 9H).
EXAMPLE 26(15)
4-(3-(N-(1-t-butoxycarbonylpyrrolidin-2-ylcarbonyl)amino)phenyl)-5,6,7,8-t-
etrahydrophthalazin-1(2H)-one
[0766] NMR (DMSO-d.sub.6): .delta. 12.88 (s, 1H), 10.07 (s, 1H),
7.71 (s, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.10
(d, J=7.8 Hz, 1H), 4.17 (m, 1H), 3.38-2.34 (m, 8H), 1.98-1.60 (m,
6H), 1.38 (s, 9H.times.1/3), 1.26 (s, 9H.times.2/3).
EXAMPLE 26(16)
4-(2-(N-(2-(N'-t-butoxycarbonylamino)acetyl)amino)ethyl)-5,6,7,8-tetrahydr-
ophthalazin-1(2H)-one
[0767] TLC: Rf 0.31 (chloroform:methanol=8:1);
[0768] NMR (DMSO-d.sub.6): .delta. 12.54 (s, 1H), 7.82 (brt, 1H),
6.91 (brt, 1H), 3.47 (d, J=6.3 Hz, 2H), 3.40-3.26 (m, 2H), 2.61 (t,
J=7.2 Hz, 2H), 2.56-2.30 (m, 4H), 1.76-1.54 (m, 4H), 1.36 (s,
9H).
EXAMPLE 26(17)
4-(2-(N-(3-(N'-t-butoxycarbonylamino)propanoyl)amino)ethyl)-5,6,7,8-tetrah-
ydrophthalazin-1(2H)-one
[0769] TLC: Rf 0.44 (chloroform:methanol=4:1);
[0770] NMR (DMSO-d.sub.6): .delta. 12.54 (s, 1H), 7.92 (t, J=6.0
Hz, 1H), 6.72 (brt, 1H), 3.42-3.18 (m, 2H), 3.16-3.02 (m, 2H),
2.68-2.28 (m, 6H), 2.18 (t, J=7.2 Hz, 2H), 1.78-1.52 (m, 4H), 1.36
(s, 9H).
EXAMPLE 26(18)
4-(2-(N-(2-(N',N'-dimethylamino)acetyl)amino)ethyl)-5,6,7,8-tetrahydrophth-
alazin-1(2H)-one
[0771] TLC: Rf 0.62 (chloroform:methanol=4:1);
[0772] NMR (DMSO-d.sub.6): .delta. 12.54 (brs, 1H), 7.80 (t, J=5.7
Hz, 1H), 3.44-3.24 (m, 2H), 2.80 (s, 2H), 2.64 (t, J=7.2 Hz, 2H),
2.54-2.26 (m, 4H), 2.16 (s, 6H), 1.76-1.52 (m, 4H).
EXAMPLE 26(19)
4-(2-(N-(4-(N'-t-butoxycarbonylamino)butanoyl)amino)ethyl)-5,6,7,8-tetrahy-
drophthalazin-1(2H)-one
[0773] TLC: Rf 0.67 (chloroform:methanol=4:1);
[0774] NMR (DMSO-d.sub.6): .delta. 12.53 (s, 1H), 7.85 (t, J=5.4
Hz, 1H), 6.78 (t, J=5.7 Hz, 1H), 3.40-3.20 (m, 2H), 2.94-2.80 (m,
2H), 2.60 (t, J=7.2 Hz, 2H), 2.56-2.28 (m, 4H), 2.01 (t, J=7.2 Hz,
2H), 1.78-1.46 (m, 6H), 1.36 (s, 9H).
EXAMPLE 27
4-(2-(N-benzylamino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0775] The compound prepared in Reference example 13 (40 mg),
sodium iodide (8.4 mg) and benzylamine (0.21 mL) were stirred at
room temperature for 10 hours. Methylene chloride and a saturated
aqueous sodium hydrogen carbonate solution were added to the
reaction mixture, which was separated. The organic layer was dried
over anhydrous magnesium sulfate and concentrated. The residue was
purified by column chromatography on silica gel
(chloroform:methanol=50:1) to give the compound of the present
invention (18 mg) having the following physical data.
[0776] TLC: Rf 0.29 (chloroform:methanol=9:1);
[0777] NMR (DMSO-d.sub.6): .delta. 12.46 (s, 1H), 7.40-7.15 (m,
5H), 3.69 (s, 2H), 2.80-2.60 (m, 4H), 2.50-2.30 (m, 4H), 1.63 (brs,
4H).
EXAMPLE 27(1) TO EXAMPLE 27(80)
[0778] By the same procedure as described in Example 27, if
necessary, by converting to corresponding salts by conventional
method, using the compound prepared in Reference example 13 or a
corresponding derivative, and a corresponding derivative instead of
benzylamine, the following compounds of the present invention were
obtained.
EXAMPLE 27(1)
4-(2-(morpholin-4-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
Free Form:
[0779] TLC: Rf 0.38 (chloroform:methanol:acetic acid=90:10:1);
[0780] NMR (CD.sub.3OD): .delta. 3.74-3.66 (m, 4H), 2.84-2.77 (m,
2H), 2.75-2.66 (m, 2H), 2.64-2.48 (m, 8H), 1.88-1.72 (m, 4H).
Hydrochloride:
[0781] TLC: Rf 0.24 (chloroform:methanol=9:1);
[0782] NMR (DMSO-d.sub.6): .delta. 12.68 (s, 1H), 10.85 (brs, 1H),
4.02-3.92 (m, 2H), 3.82-3.70 (m, 2H), 3.54-3.44 (m, 2H), 3.44-3.32
(m, 2H), 3.15-3.05 (m, 2H), 3.05-2.96 (m, 2H), 2.53-2.33 (m, 4H),
1.76-1.58 (m, 4H).
EXAMPLE 27(2)
4-(2-(pyrrolidin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
hydrochloride
[0783] TLC: Rf 0.12 (chloroform:methanol=9:1);
[0784] NMR (CD.sub.3OD): .delta. 3.78-3.66 (m, 2H), 3.63 (t, J=8.1
Hz, 2H), 3.26-3.10 (m, 2H), 3.06 (t, J=8.1 Hz, 2H), 2.62-2.48 (m,
4H), 2.26-1.96 (m, 4H), 1.90-1.72 (m, 4H).
EXAMPLE 27(3)
4-(2-(4-methylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
dihydrochloride
[0785] TLC: Rf 0.32 (chloroform:methanol=9:1);
[0786] NMR (DMSO-d.sub.6): .delta. 12.68 (s, 1H), 11.80 (brs, 2H),
4.00-3.20 (m, 10H), 3.10-2.95 (m, 2H), 2.80 (s, 3H), 2.50-2.30 (m,
4H), 1.75-1.55 (m, 4H).
EXAMPLE 27(4)
4-(2-(piperidin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
hydrochloride
[0787] TLC: Rf 0.34 (chloroform:methanol=9:1);
[0788] NMR (DMSO-d.sub.6): .delta. 12.66 (s, 1H), 10.45 (brs, 1H),
3.52-3.42 (m, 2H), 3.34-3.22 (m, 2H), 3.06-2.96 (m, 2H), 2.96-2.80
(m, 2H), 2.54-2.32 (m, 4H), 1.84-1.56 (m, 9H), 1.46-1.26 (m,
1H).
EXAMPLE 27(5)
4-(2-(N-cyclohexylamino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
hydrochloride
[0789] TLC: Rf 0.34 (chloroform:methanol=9:1);
[0790] NMR (DMSO-d.sub.6): .delta. 12.65 (s, 1H), 8.85 (brs, 2H),
3.26-3.10 (m, 2H), 3.10-2.96 (m, 1H), 2.90 (t, J=7.2 Hz, 2H),
2.50-2.36 (m, 4H), 2.06-1.98 (m, 2H), 1.80-1.54 (m, 7H), 1.40-1.00
(m, 5H).
EXAMPLE 27(6)
4-(2-(azepan-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
hydrochloride
[0791] TLC: Rf 0.28 (chloroform:methanol=9:1);
[0792] NMR (DMSO-d.sub.6): .delta. 12.66 (s, 1H), 10.55 (s, 1H),
3.46-3.28 (m, 4H), 3.20-3.06 (m, 2H), 3.06-2.98 (m, 2H), 2.56-2.46
(m, 2H), 2.44-2.34 (m, 2H), 1.90-1.50 (m, 12H).
EXAMPLE 27(7)
4-(2-(4-t-butoxycarbonylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-
-1(2H)-one
[0793] TLC: Rf 0.29 (chloroform:methanol=9:1);
[0794] NMR (DMSO-d.sub.6): .delta. 12.51 (s, 1H), 3.32-3.24 (m,
6H), 2.70-2.60 (m, 2H), 2.60-2.50 (m, 2H), 2.40-2.30 (m, 6H),
1.72-1.56 (m, 4H), 1.37 (s, 9H).
EXAMPLE 27(8)
4-(2-(thiomorpholin-4-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
hydrochloride
[0795] TLC: Rf 0.40 (chloroform:methanol=9:1);
[0796] NMR (DMSO-d.sub.6): .delta. 12.67 (s, 1H), 10.90 (brs, 1H),
3.84-3.70 (m, 2H), 3.44-3.30 (m, 2H), 3.24-3.10 (m, 4H), 3.08-2.98
(m, 2H), 2.90-2.76 (m, 2H), 2.52-2.44 (m, 2H), 2.42-2.34 (m, 2H),
1.76-1.58 (m, 4H).
EXAMPLE 27(9)
4-(2-(N-(2-propynyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
hydrochloride
[0797] TLC: Rf 0.28 (chloroform:methanol=9:1);
[0798] NMR (DMSO-d.sub.6): .delta. 12.66 (s, 1H), 9.70-9.45 (m,
2H), 3.98-3.88 (m, 2H), 3.70 (t, J=2.4 Hz, 1H), 3.30-3.18 (m, 2H),
2.91 (t, J=7.8 Hz, 2H), 2.48-2.32 (m, 4H), 1.76-1.58 (m, 4H).
EXAMPLE 27(10)
4-(2-(4-ethylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0799] TLC: Rf 0.19 (chloroform:methanol=5:1);
[0800] NMR (CD.sub.3OD): .delta. 2.84-2.76 (m, 2H), 2.75-2.67 (m,
2H), 2.67-2.47 (m, 12H), 2.44 (q, J=7.5H, 2H), 1.79 (m, 4H), 1.10
(t, J=7.5 Hz, 3H).
EXAMPLE 27(11)
4-(2-(N-cyclohexylmethylamino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-on-
e hydrochloride
[0801] TLC: Rf 0.49 (chloroform:methanol=4:1);
[0802] NMR (DMSO-d.sub.6): .delta. 12.66 (s, 1H), 8.86 (brs, 2H),
3.26-3.08 (m, 2H), 3.02-2.88 (m, 2H), 2.86-2.70 (m, 2H), 2.58-2.30
(m, 4H), 1.88-1.50 (m, 10H), 1.32-0.82 (m, 5H).
EXAMPLE 27(12)
4-(2-(azocan-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0803] TLC: Rf 0.41 (chloroform:methanol=5:1);
[0804] NMR (CD.sub.3OD): .delta. 3.61 (t, J=6.6 Hz, 2H), 3.58-3.30
(m, 4H), 3.08 (t, J=6.6 Hz, 2H), 2.62-2.50 (m, 4H), 2.12-1.60 (m,
14H).
EXAMPLE 27(13)
4-(2-(4-methyl-1,4-diazepan-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-
-one
[0805] TLC: Rf 0.29 (chloroform:methanol:saturated aqueous
ammonia=5:1:0.1);
[0806] NMR (CD.sub.3OD): .delta. 3.26 (m, 4H), 3.08-3.01 (m, 4H),
2.96 (t, J=6.0 Hz, 2H), 2.84 (m, 2H), 2.81 (s, 3H), 2.60 (m, 2H),
2.52 (m, 2H), 2.03 (m, 2H), 1.80 (m, 4H).
EXAMPLE 27(14)
4-(2-(N-(2-(N'-t-butoxycarbonylamino)ethyl)amino)ethyl)-5,6,7,8-tetrahydro-
phthalazin-1(2H)-one
[0807] TLC: Rf 0.47 (chloroform:methanol=8:1);
[0808] NMR (DMSO-d.sub.6): .delta. 12.52 (brs, 1H), 6.73 (brt, 1H),
3.34 (br, 1H), 3.06-2.94 (m, 2H), 2.80 (t, J=7.2 Hz, 2H), 2.70-2.54
(m, 4H), 2.54-2.28 (m, 4H), 1.76-1.54 (m, 4H), 1.36 (s, 9H).
EXAMPLE 27(15)
4-(2-(4-phenylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0809] TLC: Rf 0.50 (chloroform:methanol=9:1);
[0810] NMR (CD.sub.3OD): .delta. 7.23 (dd, J=7.5, 7.5 Hz, 2H), 6.97
(d, J=7.5 Hz, 2H), 6.83 (dd, J=7.5, 7.5 Hz, 1H), 3.20 (m, 4H),
2.90-2.70 (m, 8H), 2.62 (m, 2H), 2.52 (m, 2H), 1.80 (m, 4H).
EXAMPLE 27(16)
4-(2-(4-(2-chlorophenyl)piperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-
-1(2H)-one
[0811] TLC: Rf 0.44 (chloroform:methanol=9:1);
[0812] NMR (CDCl.sub.3): .delta. 10.61 (s, 1H), 7.36 (d, J=7.8 Hz,
1H), 7.22 (dd, J=7.8, 7.8 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 6.98
(dd, J=7.8, 7.8 Hz, 1H), 3.11 (m, 4H), 2.78 (s, 4H), 2.74 (m, 4H),
2.59 (m, 2H), 2.53 (m, 2H), 1.78 (m, 4H).
EXAMPLE 27(17)
4-(2-(4-benzylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0813] TLC: Rf 0.43 (chloroform:methanol=9:1);
[0814] NMR (CD.sub.3OD): .delta. 7.36-7.22 (m, 5H), 3.54 (s, 2H),
2.84-2.64 (m, 4H), 2.64-2.45 (m, 12H), 1.86-1.72 (m, 4H).
EXAMPLE 27(18)
4-(2-(N-(4-trifluoromethylbenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-
-1(2H)-one
[0815] TLC: Rf 0.33 (chloroform:methanol=9:1);
[0816] NMR (CD.sub.3OD): .delta. 7.63 (d, J=8.4 Hz, 2H), 7.54 (d,
J=8.4 Hz, 2H), 3.90 (s, 2H), 2.96 (t, J=6.9 Hz, 2H), 2.80 (t, J=6.9
Hz, 2H), 2.52 (m, 4H), 1.77 (m, 4H).
EXAMPLE 27(19)
4-(2-(N-methyl-N-benzylamino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
Free Form:
[0817] TLC: Rf 0.32 (chloroform:methanol=9:1);
[0818] NMR (CD.sub.3OD): .delta. 7.28 (m, 5H), 3.56 (s, 2H),
2.83-2.65 (m, 4H), 2.49 (m, 4H), 2.31 (s, 3H), 1.73 (m, 4H).
Methanesulfonate:
[0819] TLC: Rf 0.44 (methylene chloride:methanol=9:1);
[0820] NMR (DMSO-d.sub.6): .delta. 12.69 (s, 1H), 9.42 (m, 1H),
7.49 (m, 5H), 4.48 (m, 1H), 4.31 (m, 1H), 3.50-3.25 (m, 2H), 2.98
(m, 2H), 2.75 (m, 3H), 2.38 (m, 4H), 2.29 (s, 3H), 1.68 (m,
4H).
EXAMPLE 27(20)
4-(2-(N-(2-phenylethyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0821] TLC: Rf 0.41 (methanol:methylene chloride=1:10);
[0822] NMR (CD.sub.3OD): .delta. 7.37 (m, 5H), 3.52 (t, J=6.8 Hz,
2H), 3.38 (m, 2H), 3.07 (m, 4H), 2.60 (m, 4H), 1.85 (m, 4H).
EXAMPLE 27(21)
4-(2-(N-(4-trifluoromethoxybenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazi-
n-1(2H)-one
[0823] TLC: Rf 0.37 (chloroform:methanol=9:1);
[0824] NMR (CD.sub.3OD): .delta. 7.44 (d, J=7.5 Hz, 2H), 7.23 (d,
J=7.5 Hz, 2H), 3.82 (s, 2H), 2.93 (t, J=6.9 Hz, 2H), 2.79 (t, J=6.9
Hz, 2H), 2.59-2.49 (m, 4H), 1.77 (m, 4H).
EXAMPLE 27(22)
4-(2-(4-(pyridin-2-yl)piperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1-
(2H)-one
[0825] TLC: Rf 0.55 (chloroform:methanol=9:1);
[0826] NMR (CD.sub.3OD): .delta. 8.08 (m, 1H), 7.56 (m, 1H), 6.82
(d, J=8.4 Hz, 1H), 6.68 (dd, J=6.3, 4.8 Hz, 1H), 3.54 (t, J=5.1 Hz,
4H), 2.90-2.74 (m, 4H), 2.68 (t, J=5.1 Hz, 4H), 2.62 (m, 2H), 2.52
(m, 2H), 1.79 (m, 4H).
EXAMPLE 27(23)
4-(2-(N-(2-(N'-phenylamino)ethyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-
-1(2H)-one
[0827] TLC: Rf 0.26 (chloroform:methanol=9:1);
[0828] NMR (CD.sub.3OD): .delta. 7.18-7.08 (m, 2H), 6.74-6.64 (m,
3H), 3.48-3.36 (m, 4H), 3.22 (t, J=6.0 Hz, 2H), 2.95 (t, J=6.6 Hz,
2H), 2.51 (m, 4H), 1.78 (m, 4H).
EXAMPLE 27(24)
4-(2-(4-acetylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0829] TLC: Rf 0.21 (chloroform:methanol=9:1);
[0830] NMR (CD.sub.3OD): .delta. 3.62-3.52 (m, 4H), 2.85-2.70 (m,
4H), 2.64-2.48 (m, 8H), 2.09 (s, 3H), 1.79 (m, 4H).
EXAMPLE 27(25)
4-(2-(N-(naphthalen-1-ylmethyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1-
(2H)-one
[0831] TLC: Rf 0.45 (methanol:methylene chloride=1:9);
[0832] NMR (DMSO-d.sub.6): .delta. 12.49 (brs, 1H), 8.15 (m, 1H),
7.89 (m, 1H), 7.79 (d, J=7.2 Hz, 1H), 7.53-7.40 (m, 4H), 4.15 (s,
2H), 2.87 (t, J=7.2 Hz, 2H), 2.69 (t, J=7.2 Hz, 2H), 2.35 (m, 4H),
1.62 (brs, 4H).
EXAMPLE 27(26)
4-(2-(N-ethyl-N-benzylamino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0833] TLC: Rf 0.41 (chloroform:methanol=9:1);
[0834] NMR (CD.sub.3OD): .delta. 7.30-7.20 (m, 5H), 3.60 (s, 2H),
2.72 (s, 4H), 2.62 (q, J=7.2 Hz, 2H), 2.48 (m, 2H), 2.40 (m, 2H),
1.70 (m, 4H), 1.10 (t, J=7.2 Hz, 3H).
EXAMPLE 27(27)
4-(2-(N-(1-benzylpiperidin-4-yl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin--
1(2H)-one
[0835] TLC: Rf 0.17 (methylene
chloride:methanol:water=9:1:0.1);
[0836] NMR (CD.sub.3OD): .delta. 7.43-7.23 (m, 5H), 3.60 (s, 2H),
3.41 (t, J=6.6 Hz, 2H), 3.14 (m, 1H), 3.06-2.98 (m, 2H), 2.95 (t,
J=6.6 Hz, 2H), 2.60-2.50 (m, 4H), 2.22-2.06 (m, 4H), 1.86-1.60 (m,
6H).
EXAMPLE 27(28)
4-(2-(N-(2-hydroxyethyl)-N-benzylamino)ethyl)-5,6,7,8-tetrahydrophthalazin-
-1(2H)-one
[0837] TLC: Rf 0.44 (methylene chloride:methanol=9:1);
[0838] NMR (CD.sub.3OD): .delta. 7.19 (m, 5H), 3.65 (t, J=8.7 Hz,
2H), 3.61 (s, 2H), 2.78-2.67 (m, 6H), 2.43 (m, 2H), 2.30 (m, 2H),
1.64 (m, 4H).
EXAMPLE 27(29)
4-(2-(4-cyclohexylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-
-one
[0839] TLC: Rf 0.55 (methylene chloride:methanol=9:1);
[0840] NMR (CD.sub.3OD): .delta. 3.30-2.70 (m, 13H), 2.59 (m, 2H),
2.51 (m, 2H), 2.05 (m, 2H), 1.91 (m, 2H), 1.86-1.65 (m, 6H),
1.44-1.20 (m, 4H).
EXAMPLE 27(30)
4-(2-(N-(4-fluorobenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-on-
e
Free Form:
[0841] TLC: Rf 0.50 (methylene chloride:methanol=4:1);
[0842] NMR (CD.sub.3OD): .delta. 7.41 (m, 2H), 7.10 (dd, J=8.7, 8.7
Hz, 2H), 3.94 (s, 2H), 3.10 (t, J=6.9 Hz, 2H), 2.85 (t, J=6.9 Hz,
2H), 2.52 (m, 4H), 1.78 (m, 4H).
Hydrochloride:
[0843] TLC: Rf 0.43 (methylene chloride:methanol=4:1);
[0844] NMR (DMSO-d.sub.6): .delta. 12.68 (s, 1H), 9.00 (s, 2H),
7.57 (m, 2H), 7.29 (m, 2H), 4.20 (m, 2H), 3.21 (m, 2H), 2.90 (m,
2H), 2.58-2.38 (m, 4H), 1.67 (m, 4H).
EXAMPLE 27(31)
4-(2-(N-(4-methoxybenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-o-
ne
[0845] TLC: Rf 0.39 (methylene chloride:methanol:saturated aqueous
ammonia=4:1:0.3);
[0846] NMR (CD.sub.3OD): .delta. 7.40 (d, J=8.7 Hz, 2H), 6.99 (d,
J=8.7 Hz, 2H), 4.15 (s, 2H), 3.81 (s, 3H), 3.37 (t, J=6.9 Hz, 2H),
2.95 (t, J=6.9 Hz, 2H), 2.53 (m, 4H), 1.78 (m, 4H).
EXAMPLE 27(32)
4-(2-(N-(1-phenylethyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0847] TLC: Rf 0.38 (methylene chloride:methanol=9:1);
[0848] NMR (CD.sub.3OD): .delta. 7.50 (m, 5H), 4.48 (q, J=6.9 Hz,
1H), 3.29 (m, 2H), 2.92 (t, J=6.6 Hz, 2H), 2.51 (m, 4H), 1.78 (m,
4H), 1.70 (d, J=6.9 Hz, 3H).
EXAMPLE 27(33)
4-(2-(N-(3-fluorobenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-on-
e
[0849] TLC: Rf 0.39 (methylene chloride:methanol=9:1);
[0850] NMR (CD.sub.3OD): .delta. 7.48-7.06 (m, 4H), 4.06 (s, 2H),
3.20 (t, J=6.9 Hz, 2H), 2.90 (t, J=6.9 Hz, 2H), 2.53 (m, 4H), 1.77
(m, 4H).
EXAMPLE 27(34)
4-(2-(4-diphenylmethylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1-
(2H)-one
[0851] TLC: Rf 0.48 (methylene chloride:methanol=9:1);
[0852] NMR (CD.sub.3OD): .delta. 7.48-7.40 (m, 4H), 7.32-7.13 (m,
6H), 4.25 (s, 1H), 3.16 (t, J=5.1 Hz, 2H), 2.81-2.40 (m, 14H), 1.78
(m, 4H).
EXAMPLE 27(35)
4-(2-(N-(3-methoxybenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-o-
ne
[0853] TLC: Rf 0.44 (methylene chloride:methanol=9:1);
[0854] NMR (CD.sub.3OD): .delta. 7.32 (dd, J=8.1, 8.1 Hz, 1H),
7.02-6.90 (m, 3H), 4.05 (s, 2H), 3.81 (s, 3H), 3.24 (t, J=6.9 Hz,
2H), 2.90 (t, J=6.9 Hz, 2H), 2.51 (m, 4H), 1.77 (m, 4H).
EXAMPLE 27(36)
8-(2-(piperidin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-
-one hydrochloride
[0855] TLC: Rf 0.26 (chloroform:methanol=4:1);
[0856] NMR (DMSO-d.sub.6): .delta. 11.94 (s, 1H), 9.31 (brs, 1H),
6.39 (brs, 1H), 3.60-3.10 (m, 6H), 3.06-2.74 (m, 4H), 2.34 (t,
J=6.6 Hz, 2H), 1.94-1.50 (m, 7H), 1.38 (m, 1H).
EXAMPLE 27(37)
4-(2-(N-(2-phenoxyethyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-on-
e
[0857] TLC: Rf 0.62 (methylene
chloride:methanol:water=4:1:0.2);
[0858] NMR (CD.sub.3OD): .delta. 7.26 (dd, J=8.1, 8.1 Hz, 2H),
6.98-6.88 (m, 3H), 4.11 (t, J=5.1 Hz, 2H), 3.14-3.05 (m, 4H), 2.84
(t, J=6.6 Hz, 2H), 2.60-2.50 (m, 4H), 1.78 (m, 4H).
EXAMPLE 27(38)
4-(2-(4-benzyloxycarbonyl-1,4-diazepan-1-yl)ethyl)-5,6,7,8-tetrahydrophtha-
lazin-1(2H)-one
Free Form:
[0859] TLC: Rf 0.67 (methylene chloride:methanol:saturated aqueous
ammonia=4:1:0.3);
[0860] NMR (CD.sub.3OD): .delta. 7.34 (m, 5H), 5.11 (s, 2H), 3.54
(m, 4H), 2.82-2.70 (m, 8H), 2.60 (m, 2H), 2.52 (m, 2H), 1.90-1.72
(m, 6H).
Methanesulfonate:
[0861] TLC: Rf 0.64 (methylene chloride:methanol=9:1);
[0862] NMR (DMSO-d.sub.6): .delta. 12.7 (s, 1H), 9.35 (s, 1H),
7.40-7.30 (m, 5H), 5.11 (s, 2H), 3.89 (m, 1H), 3.72-3.40 (m, 7H),
3.35-3.16 (m, 2H), 2.95 (t, J=7.2 Hz, 2H), 2.65-2.50 (m, 4H), 2.30
(s, 3H), 1.85 (m, 2H), 1.67 (m, 4H).
EXAMPLE 27(39)
4-(2-(4-cyclopentylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H-
)-one dihydrochloride
[0863] TLC: Rf 0.14 (methylene chloride:methanol=9:1);
[0864] NMR (CD.sub.3OD): .delta. 4.00-3.40 (m, 11H), 3.12 (t, J=7.5
Hz, 2H), 2.62-2.50 (m, 4H), 2.22-2.15 (m, 2H), 1.92-1.68 (m,
10H).
EXAMPLE 27(40)
4-(2-(4-butylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
dihydrochloride
[0865] TLC: Rf 0.16 (methylene chloride:methanol=9:1);
[0866] NMR (CD.sub.3OD): .delta. 4.10-3.45 (m, 8H), 3.74 (t, J=7.2
Hz, 2H), 3.30 (m, 2H), 3.16 (t, J=7.2 Hz, 2H), 2.60 (m, 2H), 2.53
(m, 2H), 1.90-1.75 (m, 6H), 1.45 (m, 2H), 1.01 (t, J=7.2 Hz,
3H).
EXAMPLE 27(41)
8-(2-(4-cyclohexylpiperazin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyr-
idazin-5(1H)-one trihydrochloride
[0867] TLC: Rf 0.36 (chloroform:methanol=4:1);
[0868] NMR (DMSO-d.sub.6): .delta. 12.17 (s, 1H), 11.85 (brs, 1H),
5.09 (br, 3H), 3.98-3.08 (m, 11H), 2.96 (m, 2H), 2.36 (t, J=6.0 Hz,
2H), 2.10 (m, 2H), 1.94-0.98 (m, 12H).
EXAMPLE 27(42)
4-(2-(N-(4-chlorobenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-on-
e hydrochloride
[0869] TLC: Rf 0.75 (methanol:methylene chloride=1:4);
[0870] NMR (DMSO-d.sub.6): .delta. 12.66 (s, 1H), 9.39 (brs, 2H),
7.59 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 4.19 (m, 2H), 3.18
(m, 2H), 2.94 (t, J=7.5 Hz, 2H), 2.40 (m, 4H), 1.66 (m, 4H).
EXAMPLE 27(43)
4-(2-(4-hexylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
dihydrochloride
[0871] TLC: Rf 0.68 (methylene chloride:methanol=4:1);
[0872] NMR (CD.sub.3OD): .delta. 4.04-3.45 (m, 8H), 3.71 (t, J=7.2
Hz, 2H), 3.26 (m, 2H), 3.15 (t, J=7.2 Hz, 2H), 2.59 (m, 2H), 2.53
(m, 2H), 1.80 (m, 6H), 1.39 (m, 6H), 0.93 (t, J=6.9 Hz, 3H).
EXAMPLE 27(44)
4-(2-(4-isopropylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)--
one dihydrochloride
[0873] TLC: Rf 0.25 (methylene chloride:methanol=4:1);
[0874] NMR (CD.sub.3OD): .delta. 4.12-3.58 (m, 11H), 3.18 (t, J=6.9
Hz, 2H), 2.60 (m, 2H), 2.53 (m, 2H), 1.80 (m, 4H), 1.44 (d, J=6.9
Hz, 6H).
EXAMPLE 27(45)
4-(2-(N-(2-fluorobenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-on-
e hydrochloride
[0875] TLC: Rf 0.65 (methylene chloride:methanol=4:1);
[0876] NMR (CD.sub.3OD): .delta. 7.61-7.50 (m, 2H), 7.32-7.20 (m,
2H), 4.39 (s, 2H), 3.51 (t, J=6.9 Hz, 2H), 3.02 (t, J=6.9 Hz, 2H),
2.52 (m, 4H), 1.79 (m, 4H).
EXAMPLE 27(46)
4-(2-(N-(3-methoxypropyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-o-
ne hydrochloride
[0877] TLC: Rf 0.42 (methylene chloride:methanol=4:1);
[0878] NMR (CD.sub.3OD): .delta. 3.55 (t, J=6.6 Hz, 2H), 3.45 (t,
J=6.9 Hz, 2H), 3.35 (s, 3H), 3.21 (t, J=6.9 Hz, 2H), 2.99 (t, J=6.6
Hz, 2H), 2.54 (m, 4H), 1.97 (m, 2H), 1.79 (m, 4H).
EXAMPLE 27(47)
8-(2-(N-(4-fluorobenzyl)amino)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyrida-
zin-5(1H)-one dihydrochloride
[0879] TLC: Rf 0.30 (chloroform:methanol=4:1);
[0880] NMR (DMSO-d.sub.6): .delta. 12.41 (brs, 1H), 9.60 (brs, 2H),
7.65 (dd, J=8.4, 5.7 Hz, 2H), 7.27 (dd, J=8.4, 8.4 Hz, 2H), 6.00
(brs, 2H), 4.16 (m, 2H), 3.34-3.06 (m, 4H), 2.95 (t, J=7.2 Hz, 2H),
2.39 (t, J=6.0 Hz, 2H), 1.71 (m, 2H).
EXAMPLE 27(48)
4-(2-(N-(furan-2-ylmethyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)--
one hydrochloride
[0881] TLC: Rf 0.32 (methanol:methylene chloride=1:10);
[0882] NMR (DMSO-d.sub.6): .delta. 12.66 (s, 1H), 9.33 (brs, 2H),
7.78 (d, J=1.5 Hz, 1H), 6.65 (d, J=3.3 Hz, 1H), 6.53 (dd, J=3.3,
1.5 Hz, 1H), 4.27 (m, 2H), 3.18 (m, 2H), 2.90 (t, J=7.6 Hz, 2H),
2.40 (m, 4H), 1.66 (m, 4H).
EXAMPLE 27(49)
4-(2-(N-(4-methylbenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-on-
e hydrochloride
[0883] TLC: Rf 0.16 (methanol:methylene chloride=1:10);
[0884] NMR (DMSO-d.sub.6): .delta. 12.66 (s, 1H), 9.23 (brs, 2H),
7.43 (d, J=7.8 Hz, 2H), 7.24 (d, J=7.8 Hz, 2H), 4.13 (m, 2H), 3.16
(m, 2H), 2.92 (t, J=7.2 Hz, 2H), 2.40 (m, 4H), 2.31 (s, 3H), 1.66
(m, 4H).
EXAMPLE 27(50)
4-(2-(N-(2-methoxybenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-o-
ne hydrochloride
[0885] TLC: Rf 0.34 (methylene chloride:methanol=4:1);
[0886] NMR (CD.sub.3OD): .delta. 7.50-7.42 (m, 2H), 7.15-7.00 (m,
2H), 4.29 (s, 2H), 3.92 (s, 3H), 3.48 (t, J=6.6 Hz, 2H), 3.00 (t,
J=6.6 Hz, 2H), 2.53 (m, 4H), 1.78 (m, 4H).
EXAMPLE 27(51)
4-(2-(N-(3-methylthiopropyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H-
)-one hydrochloride
[0887] TLC: Rf 0.069 (methylene chloride:methanol=4:1);
[0888] NMR (CD.sub.3OD): .delta. 3.47 (t, J=6.6 Hz, 2H), 3.20 (t,
J=7.2 Hz, 2H), 3.00 (t, J=6.6 Hz, 2H), 2.62 (t, J=7.2 Hz, 2H),
2.63-2.50 (m, 4H), 2.12 (s, 3H), 2.01 (m, 2H), 1.90-1.75 (m,
4H).
EXAMPLE 27(52)
4-(2-(N-(pyridin-4-ylmethyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H-
)-one
[0889] TLC: Rf 0.39 (methylene chloride:methanol=4:1);
[0890] NMR (CD.sub.3OD): .delta. 8.53 (d, J=6.0 Hz, 2H), 7.48 (d,
J=6.0 Hz, 2H), 4.06 (s, 2H), 3.15 (t, J=6.9 Hz, 2H), 2.89 (t, J=6.9
Hz, 2H), 2.60-2.45 (m, 4H), 1.88-1.72 (m, 4H).
EXAMPLE 27(53)
8-(2-(4-ethylpiperazin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazi-
n-5(1H)-one trihydrochloride
[0891] TLC: Rf 0.26 (chloroform:methanol=4:1);
[0892] NMR (DMSO-d.sub.6): .delta. 12.24 (s, 1H), 11.73 (brs, 1H),
5.59 (br, 3H), 4.00-3.06 (m, 14H), 2.97 (t, J=8.1 Hz, 2H), 2.37 (t,
J=6.0 Hz, 2H), 1.73 (m, 2H), 1.26 (t, J=6.9 Hz, 3H).
EXAMPLE 27(54)
4-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-
-1(2H)-one dihydrochloride
[0893] TLC: Rf 0.60 (methylene chloride:methanol=9:1);
[0894] NMR (CD.sub.3OD): .delta. 7.10-7.00 (m, 4H), 3.82-3.72 (m,
4H), 3.67 (t, J=7.2 Hz, 2H), 3.42-3.30 (m, 4H), 3.15 (t, J=7.2 Hz,
2H), 2.65-2.50 (m, 4H), 1.82 (m, 4H).
EXAMPLE 27(55)
4-(2-(4-(pyridin-4-yl)piperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1-
(2H)-one trihydrochloride
[0895] TLC: Rf 0.14 (methylene chloride:methanol=4:1);
[0896] NMR (CD.sub.3OD): .delta. 8.28 (d, J=8.1 Hz, 2H), 7.33 (d,
J=8.1 Hz, 2H), 4.50 (m, 2H), 3.95-3.30 (m, 6H), 3.71 (t, J=6.9 Hz,
2H), 3.18 (t, J=6.9 Hz, 2H), 2.62 (m, 2H), 2.53 (m, 2H), 1.81 (m,
4H).
EXAMPLE 27(56)
8-(2-(4-cyclopentylpiperazin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]py-
ridazin-5(1H)-one trihydrochloride
[0897] TLC: Rf 0.45 (chloroform:methanol=4:1);
[0898] NMR (DMSO-d.sub.6): .delta. 12.23 (s, 1H), 12.22 (brs, 1H),
4.66 (br, 3H), 4.00-3.30 (m, 11H), 3.23 (m, 2H), 2.98 (m, 2H), 2.37
(t, J=6.0 Hz, 2H), 2.00 (m, 2H), 1.92-1.40 (m, 8H).
EXAMPLE 27(57)
8-(2-(4-isopropylpiperazin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyri-
dazin-5(1H)-one trihydrochloride
[0899] TLC: Rf 0.26 (chloroform:methanol=4:1);
[0900] NMR (DMSO-d.sub.6): .delta. 12.18 (s, 1H), 11.86 (brs, 1H),
4.55 (br, 3H), 3.98-3.30 (m, 11H), 3.22 (m, 2H), 2.97 (m, 2H), 2.37
(t, J=6.3 Hz, 2H), 1.72 (m, 2H), 1.30 (d, J=6.3 Hz, 6H).
EXAMPLE 27(58)
4-(2-(N-(thiophen-2-ylmethyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2-
H)-one hydrochloride
[0901] TLC: Rf 0.32 (methanol:methylene chloride=1:10);
[0902] NMR (DMSO-d.sub.6): .delta. 12.65 (s, 1H), 9.59 (brs, 2H),
7.62 (d, J=5.1 Hz, 1H), 7.37 (d, J=2.7 Hz, 1H), 7.09 (dd, J=5.1,
2.7 Hz, 1H), 4.41 (s, 2H), 3.18 (m, 2H), 2.96 (t, J=7.8 Hz, 2H),
2.40 (m, 4H), 1.66 (m, 4H).
EXAMPLE 27(59)
4-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazi-
n-1(2H)-one dihydrochloride
[0903] TLC: Rf 0.72 (methylene chloride:methanol=9:1);
[0904] NMR (CD.sub.3OD): .delta. 7.15-6.90 (m, 4H), 3.87 (s, 3H),
3.82-3.05 (m, 8H), 3.67 (t, J=6.9 Hz, 2H), 3.13 (t, J=6.9 Hz, 2H),
2.62-2.50 (m, 4H), 1.80 (m, 4H).
EXAMPLE 27(60)
4-(2-(N-methyl-N-(2-(N',N'-dimethylamino)ethyl)amino)ethyl)-5,6,7,8-tetrah-
ydrophthalazin-1(2H)-one
[0905] TLC: Rf 0.13 (methylene chloride:methanol:saturated aqueous
ammonia=4:1:0.5);
[0906] NMR (CD.sub.3OD): .delta. 3.16 (t, J=6.3 Hz, 2H), 3.00 (t,
J=6.9 Hz, 2H), 2.94-2.83 (m, 4H), 2.78 (s, 6H) 2.61 (m, 2H), 2.52
(m, 2H), 2.48 (s, 3H), 1.80 (m, 4H).
EXAMPLE 27(61)
4-(2-(4-(3-methoxyphenyl)piperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazi-
n-1(2H)-one dihydrochloride
[0907] TLC: Rf 0.54 (methylene chloride:methanol=9:1);
[0908] NMR (CD.sub.3OD): .delta. 7.20 (dd, J=8.4, 8.4 Hz, 1H),
6.66-6.52 (m, 3H), 3.90-3.08 (m, 8H), 3.77 (s, 3H), 3.67 (t, J=7.2
Hz, 2H), 3.14 (t, J=7.2 Hz, 2H), 2.61 (m, 2H), 2.54 (m, 2H), 1.81
(m, 4H).
EXAMPLE 27(62)
4-(2-(4-((2E)-3-phenyl-2-propenyl)piperazin-1-yl)ethyl)-5,6,7,8-tetrahydro-
phthalazin-1(2H)-one dihydrochloride
[0909] TLC: Rf 0.53 (methylene chloride:methanol=9:1);
[0910] NMR (CD.sub.3OD): .delta. 7.52 (m, 2H), 7.42-7.32 (m, 3H),
6.96 (d, J=16.2 Hz, 1H), 6.36 (dt, J=16.2, 7.2 Hz, 1H), 4.04 (d,
J=7.2 Hz, 2H), 3.90-3.45 (m, 10H), 3.13 (t, J=7.2 Hz, 2H), 2.59 (m,
2H), 2.53 (m, 2H), 1.79 (m, 4H).
EXAMPLE 27(63)
4-(2-(4-(1-methylpropyl)piperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-
-1(2H)-one dihydrochloride
[0911] TLC: Rf 0.13 (methylene chloride:methanol=9:1);
[0912] NMR (CD.sub.3OD): .delta. 4.15-3.40 (m, 11H), 3.15 (t, J=6.9
Hz, 2H), 2.60 (m, 2H), 2.53 (m, 2H), 2.02-1.58 (m, 6H), 1.41 (d,
J=6.6 Hz, 3H), 1.06 (t, J=7.5 Hz, 3H).
EXAMPLE 27(64)
4-(2-(4-(furan-2-ylcarbonyl)piperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthal-
azin-1(2H)-one hydrochloride
[0913] TLC: Rf 0.42 (methylene chloride:methanol=9:1);
[0914] NMR (CD.sub.3OD): .delta. 7.73 (dd, J=1.8, 0.9 Hz, 1H), 7.17
(dd, J=2.4, 0.9 Hz, 1H), 6.63 (dd, J=2.4, 1.8 Hz, 1H), 4.80-4.65
(m, 2H), 3.90-3.25 (m, 6H), 3.66 (t, J=7.2 Hz, 2H), 3.13 (t, J=7.2
Hz, 2H), 2.60 (m, 2H), 2.53 (m, 2H), 1.80 (m, 4H).
EXAMPLE 27(65)
4-(2-(N-(3-chlorobenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-on-
e methanesulfonate
[0915] TLC: Rf 0.38 (methylene chloride:methanol=9:1);
[0916] NMR (CD.sub.3OD): .delta. 7.60 (s, 1H), 7.47 (s, 3H), 4.31
(s, 2H), 3.49 (t, J=6.9 Hz, 2H), 3.02 (t, J=6.9 Hz, 2H), 2.72 (s,
3H), 2.54 (m, 4H), 1.79 (m, 4H).
EXAMPLE 27(66)
8-(2-(N-benzylamino)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)--
one
[0917] TLC: Rf 0.42 (methylene chloride:methanol=4:1);
[0918] NMR (CD.sub.3OD): .delta. 7.58-7.45 (m, 5H), 4.28 (s, 2H),
3.47 (t, J=6.6 Hz, 2H), 3.34 (m, 2H), 2.89 (t, J=6.6 Hz, 2H), 2.52
(t, J=6.6 Hz, 2H), 1.86 (m, 2H).
EXAMPLE 27(67)
8-(2-(N-(2-(N'-phenylamino)ethyl)amino)ethyl)-2,3,4,6-tetrahydropyrido[2,3-
-d]pyridazin-5(1H)-one
[0919] TLC: Rf 0.23 (methylene chloride:methanol=4:1);
[0920] NMR (CD.sub.3OD): .delta. 7.15 (m, 2H), 6.69 (m, 3H), 3.50
(m, 4H), 3.32 (m, 4H), 2.89 (t, J=6.6 Hz, 2H), 2.51 (t, J=6.6 Hz,
2H), 1.84 (m, 2H).
EXAMPLE 27(68)
8-(2-(4-hexylpiperazin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazi-
n-5(1H)-one trihydrochloride
[0921] TLC: Rf 0.51 (methylene chloride:methanol=4:1);
[0922] NMR (CD.sub.3OD): .delta. 4.10-3.55 (m, 10H), 3.47 (t, J=5.7
Hz, 2H), 3.30 (m, 2H), 3.18 (t, J=7.2 Hz, 2H), 2.63 (t, J=6.3 Hz,
2H), 1.92 (m, 2H), 1.81 (m, 2H), 1.39 (m, 6H), 0.93 (m, 3H).
EXAMPLE 27(69)
4-(2-(N-(2,4-difluorobenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H-
)-one
[0923] TLC: Rf 0.15 (methanol:methylene chloride=1:10).
EXAMPLE 27(70)
4-(2-(4-(2-methylpropyl)piperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-
-1(2H)-one dihydrochloride
[0924] TLC: Rf 0.63 (methylene chloride:methanol=4:1);
[0925] NMR (CD.sub.3OD): .delta. 4.05-3.50 (m, 8H), 3.78 (t, J=7.2
Hz, 2H), 3.24-3.15 (m, 4H), 2.60 (m, 2H), 2.53 (m, 2H), 2.20 (m,
1H), 1.80 (m, 4H), 1.10 (d, J=6.6 Hz, 6H).
EXAMPLE 27(71)
8-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-
-d]pyridazin-5(1H)-one trihydrochloride
[0926] TLC: Rf 0.69 (methylene chloride:methanol=9:1);
[0927] NMR (CD.sub.3OD): .delta. 7.12-7.00 (m, 4H), 3.85-3.70 (m,
6H), 3.51 (t, J=5.7 Hz, 2H), 3.50-3.18 (m, 6H), 2.67 (t, J=6.3 Hz,
2H), 1.95 (m, 2H).
EXAMPLE 27(72)
8-(2-(4-(pyridin-4-yl)piperazin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d-
]pyridazin-5(1H)-one methanesulfonate
[0928] TLC: Rf 0.12 (methylene chloride:methanol=4:1);
[0929] NMR (CD.sub.3OD): .delta. 8.15 (d, J=7.8 Hz, 2H), 7.20 (d,
J=7.8 Hz, 2H), 3.90-3.75 (m, 4H), 3.35 (m, 2H), 3.05-2.78 (m, 8H),
2.69 (s, 3H), 2.52 (t, J=6.3 Hz, 2H), 1.86 (m, 2H).
EXAMPLE 27(73)
8-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,-
3-d]pyridazin-5(1H)-one methanesulfonate
[0930] TLC: Rf 0.65 (methylene chloride:methanol=9:1);
[0931] NMR (DMSO-d.sub.6): .delta. 12.0 (s, 1H), 9.53 (brs, 1H),
6.97 (d, J=9.0 Hz, 2H), 6.85 (d, J=9.0 Hz, 2H), 6.42 (s, 1H),
3.80-3.60 (m, 4H), 3.69 (s, 3H), 3.50 (m, 2H), 3.30-3.18 (m, 4H),
2.98-2.80 (m, 4H), 2.35 (m, 2H), 2.32 (s, 3H), 1.73 (m, 2H).
EXAMPLE 27(74)
4-(2-(N-methyl-N-(3-(N',N'-dimethylamino)propyl)amino)ethyl)-5,6,7,8-tetra-
hydrophthalazin-1(2H)-one
[0932] TLC: Rf 0.10 (methylene chloride:methanol:saturated aqueous
ammonia=4:1:0.5%);
[0933] NMR (CD.sub.3OD): .delta. 2.77 (m, 4H), 2.64-2.45 (m, 6H),
2.36 (m, 2H), 2.33 (s, 3H), 2.26 (s, 6H), 1.85-1.65 (m, 6H).
EXAMPLE 27(75)
4-(2-(N-(2-(N',N'-diethylamino)ethyl)amino)ethyl)-5,6,7,8-tetrahydrophthal-
azin-1(2H)-one
[0934] TLC: Rf 0.13 (methylene chloride:methanol:saturated aqueous
ammonia=4:1:0.5%);
[0935] NMR (CD.sub.3OD): .delta. 3.38 (t, J=6.6H, 2H), 3.24 (m,
2H), 3.10 (m, 2H), 3.05-2.92 (m, 6H), 2.62-2.48 (m, 4H), 1.80 (m,
4H), 1.21 (t, J=7.2H, 6H).
EXAMPLE 27(76)
8-(2-(morpholin-4-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-
-one
Free Form:
[0936] TLC: Rf 0.60 (methanol:methylene chloride=1:4);
[0937] NMR (DMSO-d.sub.6): .delta. 11.73 (s, 1H), 6.58 (s, 1H),
3.58-3.55 (m, 4H), 3.17 (m, 2H), 2.58 (m, 4H), 2.41 (m, 4H), 2.32
(t, J=6.0 Hz, 2H), 1.71-1.67 (m, 2H).
Methanesulfonate:
[0938] TLC: Rf 0.52 (methanol:methylene chloride=1:4);
[0939] NMR (DMSO-d.sub.6): .delta. 11.96 (s, 1H), 9.65 (brs, 1H),
6.36 (s, 1H), 4.01 (m, 2H), 3.65 (t, J=11.7 Hz, 2H), 3.45 (m, 4H),
3.16 (m, 4H), 2.83 (t, J=7.8 Hz, 2H), 2.35 (m, 2H), 2.31 (s, 3H),
1.72 (m, 2H).
EXAMPLE 27(77)
8-(2-(4-methyl-1,4-diazepan-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyr-
idazin-5(1H)-one methanesulfonate
[0940] TLC: Rf 0.41 (methanol:methylene chloride:saturated aqueous
ammonia=1:4:0.1);
[0941] NMR (DMSO-d.sub.6): .delta. 11.85 (s, 1H), 10.28 (brs, 1H),
6.41 (s, 1H), 3.32-2.78 (m, 16H), 2.42-2.20 (m, 6H), 2.12 (m, 2H),
1.71 (m, 2H).
EXAMPLE 27(78)
4-(2-(4-cyclohexylmethylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-
-1(2H)-one dihydrochloride
[0942] TLC: Rf 0.52 (methylene chloride:methanol=4:1);
[0943] NMR (CD.sub.3OD): .delta. 4.10-3.50 (m, 8H), 3.76 (t,
J=6.9H, 2H), 3.20-3.12 (m, 4H), 2.65-2.48 (m, 4H), 1.98-1.65 (m,
12H), 1.48-1.00 (m, 3H).
EXAMPLE 27(79)
8-(2-(4-butylpiperazin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazi-
n-5(1H)-one trihydrochloride
[0944] TLC: Rf 0.28 (methylene chloride:methanol=4:1);
[0945] NMR (CD.sub.3OD): .delta. 4.15-3.60 (m, 8H), 3.80 (t, J=7.2
Hz, 2H), 3.48 (t, J=5.7 Hz, 2H), 3.28 (m, 2H), 3.19 (t, J=7.2 Hz,
2H), 2.65 (t, J=6.6 Hz, 2H), 1.94 (m, 2H), 1.80 (m, 2H), 1.45 (m,
2H), 1.01 (t, J=7.2 Hz, 3H).
EXAMPLE 27(80)
4-(5-(morpholin-4-yl)pentyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[0946] TLC: Rf 0.43 (methylene chloride:methanol=10:1);
[0947] NMR (DMSO-d.sub.6): .delta. 12.48 (s, 1H), 3.54 (t, J=7.5
Hz, 4H), 2.54-2.43 (m, 4H), 2.40-2.28 (m, 6H), 2.22 (t, J=7.5 Hz,
2H), 1.74-1.60 (m, 4H), 1.64-1.48 (m, 2H), 1.50-1.37 (m, 2H),
1.40-1.26 (m, 2H).
EXAMPLE 28
4-(3-(N-(5-(morpholin-4-yl)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydrophtha-
lazin-1(2H)-one methanesulfonate
[0948] A mixture of the compound prepared in Example 25(1) (115 mg)
and morpholine (0.5 mL) was refluxed for 3 hours. The reaction
mixture was concentrated. Water was added to the residue, which was
extracted with ethyl acetate. The extract was washed with a
saturated aqueous sodium hydrogen carbonate solution and brine
sequentially, dried over anhydrous magnesium sulfate and
concentrated. The residue was recrystallized from a mixed solvent
of isopropanol and hexane. A solution of the obtained solid (56.2
mg) and methanesulfonic acid (13.2 mg) in methanol (3.0 mL) was
stirred at room temperature for 1 hour. The reaction mixture was
concentrated to give the compound of the present invention (67.9
mg) having the following physical data.
[0949] TLC: Rf 0.41 (methanol:methylene chloride=1:4);
[0950] NMR (DMSO-d.sub.6): .delta. 12.90 (s, 1H), 10.04 (s, 1H),
9.42 (brs, 1H), 7.70 (s, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.36 (t,
J=8.1 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 3.96 (m, 2H), 3.61 (t,
J=11.4 Hz, 2H), 3.43-2.30 (m, 12H), 2.29 (s, 3H), 1.63 (m, 8H).
EXAMPLE 28(1) TO EXAMPLE 28(42)
[0951] By the same procedure as described in Example 28, if
necessary, by converting to corresponding salts by conventional
method, using the compound prepared in Example 25(1) or the
compound prepared in Example 23(23), 23(24), 23(29), 23(37), 25,
25(2), 25(6) to 25(8), 25(11) to 25(13), 26(2) or 26(5), and
morpholine or a corresponding derivative, the following compounds
of the present invention were obtained.
EXAMPLE 28(1)
4-(3-(N-(4-(morpholin-4-yl)butanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthal-
azin-1(2H)-one methanesulfonate
[0952] TLC: Rf 0.22 (methanol:methylene chloride=1:9);
[0953] NMR (DMSO-d.sub.6): .delta. 12.90 (s, 1H), 10.12 (s, 1H),
9.54 (brs, 1H), 7.70 (s, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.37 (t,
J=7.8 Hz, 1H), 7.11 (d, J=7.8 Hz, 1H), 3.98 (m, 2H), 3.63 (t,
J=11.6 Hz, 2H), 3.43-2.32 (m, 12H), 2.30 (s, 3H), 1.95 (m, 2H),
1.64 (m, 4H).
EXAMPLE 28(2)
4-(3-(N-(5-(4-methoxypiperidin-1-yl)pentanoyl)amino)phenyl)-5,6,7,8-tetrah-
ydrophthalazin-1(2H)-one methanesulfonate
[0954] TLC: Rf 0.29 (methanol:methylene chloride=2:3);
[0955] NMR (DMSO-d.sub.6): .delta. 12.89 (s, 1H), 10.04 (s, 1H),
8.95 (brs, 1H), 7.70 (s, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.36 (t,
J=7.8 Hz, 1H), 7.10 (d, J=7.8 Hz, 1H), 3.52-2.33 (m, 13H), 3.24 (s,
3H), 2.29 (s, 3H), 2.15-1.46 (m, 12H).
EXAMPLE 28(3)
4-(3-(N-(2-(2-(morpholin-4-yl)ethoxy)acetyl)amino)phenyl)-5,6,7,8-tetrahyd-
rophthalazin-1(2H)-one methanesulfonate
[0956] TLC: Rf 0.50 (methanol:methylene chloride=1:9);
[0957] NMR (DMSO-d.sub.6): .delta. 12.91 (s, 1H), 10.00 (s, 1H),
9.78 (brs, 1H), 7.70 (s, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.40 (t,
J=7.8 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 4.20 (s, 2H), 4.05-3.40 (m,
10H), 3.16 (m, 2H), 2.56-2.33 (m, 4H), 2.31 (s, 3H), 1.70-1.59 (m,
4H).
EXAMPLE 28(4)
4-(3-(N-(4-(morpholin-4-yl)butanoyl)amino)phenyl)-6,7,9,9a-tetrahydro[1,4]-
thiazino[4,3-d][1,2,4]triazin-1(2H)-one methanesulfonate
[0958] TLC: Rf 0.16 (chloroform:methanol=9:1);
[0959] NMR (DMSO-d.sub.6): .delta. 10.53 (s, 1H), 10.15 (s, 1H),
9.59 (bs, 1H), 7.70 (s, 1H), 7.58-7.55 (m, 1H), 7.35 (t, J=7.8 Hz,
1H), 7.07 (d, J=7.8 Hz, 1H), 4.28-4.18 (m, 1H), 3.99-3.94 (m, 2H),
3.68-3.42 (m, 5H), 3.17-3.00 (m, 5H), 2.90-2.80 (m, 2H), 2.74-2.64
(m, 1H), 2.43 (t, J=6.9 Hz, 2H), 2.33-2.26 (m, 4H), 2.00-1.90 (m,
2H).
EXAMPLE 28(5)
4-(3-(N-(5-(N'-(2-propynyl)amino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydr-
ophthalazin-1(2H)-one methanesulfonate
[0960] TLC: Rf 0.30 (methanol:methylene chloride=1:9);
[0961] NMR (DMSO-d.sub.6): .delta. 12.88 (s, 1H), 10.03 (s, 1H),
8.93 (brs, 2H), 7.70 (s, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.36 (t,
J=7.8 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 3.92 (m, 2H), 3.72 (t, J=2.4
Hz, 1H), 2.96 (m, 2H), 2.48-2.32 (m, 6H), 2.31 (s, 3H), 1.65 (m,
8H).
EXAMPLE 28(6)
4-(3-(N-(5-(N'-(2-methyl-2-propenyl)amino)pentanoyl)amino)phenyl)-5,6,7,8--
tetrahydrophthalazin-1(2H)-one methanesulfonate
[0962] TLC: Rf 0.36 (methanol:methylene chloride:saturated aqueous
ammonia=1:9:0.1);
[0963] NMR (DMSO-d.sub.6): .delta. 12.88 (brs, 1H), 10.07 (s, 1H),
8.54 (brs, 2H), 7.71 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.35 (t,
J=7.8 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 5.08 (s, 1H), 5.07 (s, 1H),
3.51 (t, J=6.0 Hz, 2H), 2.89 (m, 2H), 2.48-2.34 (m, 9H), 1.77 (s,
3H), 1.69-1.59 (m, 8H).
EXAMPLE 28(7)
4-(3-(N-(5-(1,2,3,6-tetrahydropyridin-1-yl)pentanoyl)amino)phenyl)-5,6,7,8-
-tetrahydrophthalazin-1(2H)-one methanesulfonate
[0964] TLC: Rf 0.48 (chloroform:methanol=4:1);
[0965] NMR (DMSO-d.sub.6): .delta. 12.88 (s, 1H), 10.05 (s, 1H),
9.43 (brs, 1H), 7.70 (s, 1H), 7.60 (m, 1H), 7.36 (dd, J=7.8, 7.8
Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 5.90 (m, 1H), 5.70 (m, 1H), 3.80
(m, 1H), 3.54 (m, 1H), 3.22-2.98 (m, 4H), 2.60-2.18 (m, 8H), 2.50
(s, 3H), 1.82-1.50 (m, 8H).
EXAMPLE 28(8)
4-(3-(N-(5-(N'-cyclopropylamino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydro-
phthalazin-1(2H)-one methanesulfonate
[0966] TLC: Rf 0.35 (chloroform:methanol=4:1);
[0967] NMR (DMSO-d.sub.6): .delta. 12.88 (s, 1H), 10.06 (s, 1H),
8.56 (brs, 2H), 7.70 (s, 1H), 7.60 (m, 1H), 7.36 (dd, J=7.8, 7.8
Hz, 1H), 7.09 (m, 1H), 3.08-2.90 (m, 2H), 2.69 (m, 1H), 2.56-2.20
(m, 6H), 2.34 (s, 3H), 1.80-1.46 (m, 8H), 0.84-0.64 (m, 4H).
EXAMPLE 28(9)
4-(3-(N-(4-(morpholin-4-yl)butanoyl)amino)phenyl)-6,7-dihydro[1,4]thiazino-
[4,3-d][1,2,4]triazin-1(2H)-one methanesulfonate
[0968] TLC: Rf 0.69 (chloroform:methanol:water=8:2:0.2);
[0969] NMR (DMSO-d.sub.6): .delta. 10.89 (s, 1H), 10.16 (s, 1H),
9.52 (br, 1H), 7.74 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.40 (t, J=7.8
Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 6.27 (s, 1H), 4.02-3.94 (m, 2H),
3.69-3.58 (m, 4H), 3.50-3.42 (m, 2H), 3.20-3.01 (m, 6H), 2.48-2.42
(m, 2H), 2.02-1.92 (m, 2H).
EXAMPLE 28(10)
4-(3-(N-(2-(2-(piperidin-1-yl)ethoxy)acetyl)amino)phenyl)-5,6,7,8-tetrahyd-
rophthalazin-1(2H)-one hydrochloride
[0970] TLC: Rf 0.30 (methanol:methylene chloride=1:9);
[0971] NMR (DMSO-d.sub.6): .delta. 12.89 (s, 1H), 10.19 (s, 2H),
7.83 (s, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.38 (t, J=8.1 Hz, 1H), 7.13
(d, J=8.1 Hz, 1H), 4.16 (s, 2H), 3.85 (t, J=5.1 Hz, 2H), 3.28 (m,
2H), 2.58 (m, 2H), 2.48-2.35 (m, 6H), 1.82-1.59 (m, 10H).
EXAMPLE 28(11)
4-(3-(N-(2-(2-(pyrrolidin-1-yl)ethoxy)acetyl)amino)phenyl)-5,6,7,8-tetrahy-
drophthalazin-1(2H)-one hydrochloride
[0972] TLC: Rf 0.55 (methanol:methylene chloride:saturated aqueous
ammonia=1:9:0.1);
[0973] NMR (DMSO-d.sub.6): .delta. 12.88 (s, 1H), 10.66 (brs, 1H),
10.17 (s, 1H), 7.86 (s, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.37 (t, J=7.8
Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 4.16 (s, 2H), 3.82-3.55 (m, 4H),
3.38 (m, 2H), 3.03 (m, 2H), 2.48-2.36 (m, 4H), 1.99-1.59 (m,
8H).
EXAMPLE 28(12)
4-(3-(N-(5-(3-methoxypiperidin-1-yl)pentanoyl)amino)phenyl)-5,6,7,8-tetrah-
ydrophthalazin-1(2H)-one hydrochloride
[0974] TLC: Rf 0.45 (chloroform:methanol=4:1);
[0975] NMR (DMSO-d.sub.6): .delta. 12.88 (s, 1H), 10.51 (brs,
1/2H), 10.24 (s, 1/2H), 10.20 (s, 1/2H), 9.11 (brs, 1/2H), 7.73 (s,
1H), 7.64 (m, 1H), 7.35 (dd, J=7.8, 7.8 Hz, 1H), 7.09 (m, 1H),
3.74-3.20 (m, 8H), 3.14-2.94 (m, 2H), 2.80-2.24 (m, 8H), 2.16-1.10
(m, 10H).
EXAMPLE 28(13)
4-(3-(N-(2-(morpholin-4-yl)acetyl)amino)phenyl)-5,6,7,8-tetrahydrophthalaz-
in-1(2H)-one hydrochloride
[0976] TLC: Rf 0.44 (methanol:methylene chloride=1:10);
[0977] NMR (DMSO-d.sub.6): .delta. 12.92 (s, 1H), 10.92 (brs, 1H),
10.52 (brs, 1H), 7.71 (s, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.43 (t,
J=7.8 Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 4.20-2.27 (m, 14H), 1.69 (m,
2H), 1.60 (m, 2H).
EXAMPLE 28(14)
4-(3-(N-(2-(N'-(2-propynyl)amino)acetyl)amino)phenyl)-5,6,7,8-tetrahydroph-
thalazin-1(2H)-one hydrochloride
[0978] TLC: Rf 0.43 (methanol:methylene chloride=1:10);
[0979] NMR (DMSO-d.sub.6): .delta. 12.92 (s, 1H), 10.88 (s, 1H),
9.64 (brs, 2H), 7.69 (s, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.43 (t,
J=7.8 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 4.02 (s, 2H), 3.97 (s, 2H),
3.76 (t, J=2.1 Hz, 1H), 2.48-2.35 (m, 4H), 1.69 (m, 2H), 1.60 (m,
2H).
EXAMPLE 28(15)
4-(3-(N-(2-(N'-cyclobutylamino)acetyl)amino)phenyl)-5,6,7,8-tetrahydrophth-
alazin-1(2H)-one hydrochloride
[0980] TLC: Rf 0.40 (methanol:methylene chloride=1:10);
[0981] NMR (DMSO-d.sub.6): .delta. 12.92 (s, 1H), 10.81 (s, 1H),
9.29 (m, 2H), 7.69 (s, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.43 (t, J=7.8
Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 3.85-3.71 (m, 3H), 2.45-2.13 (m,
8H), 1.80-1.61 (m, 6H).
EXAMPLE 28(16)
4-(3-(N-(3-(morpholin-4-yl)propanoyl)amino)phenyl)-5,6,7,8-tetrahydrophtha-
lazin-1(2H)-one hydrochloride
[0982] TLC: Rf 0.41 (methanol:methylene chloride=1:10);
[0983] NMR (DMSO-d.sub.6): .delta. 12.89 (s, 1H), 10.57 (brs, 1H),
10.42 (s, 1H), 7.70 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.38 (t, J=7.8
Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 3.96 (m, 2H), 3.74 (t, J=11.5 Hz,
2H), 3.42-3.33 (m, 4H), 3.09 (m, 2H), 2.92 (t, J=7.5 Hz, 2H),
2.48-2.34 (m, 4H), 1.69 (m, 2H), 1.60 (m, 2H).
EXAMPLE 28(17)
4-(3-(N-(3-(N'-(2-propynyl)amino)propanoyl)amino)phenyl)-5,6,7,8-tetrahydr-
ophthalazin-1(2H)-one hydrochloride
[0984] TLC: Rf 0.40 (methanol:methylene chloride=1:10);
[0985] NMR (DMSO-d.sub.6): .delta. 12.89 (s, 1H), 10.43 (s, 1H),
9.37 (brs, 2H), 7.72 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.38 (t,
J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 3.93-3.71 (m, 3H), 3.25 (m,
2H), 2.83 (t, J=6.9 Hz, 2H), 2.48-2.34 (m, 4H), 1.69 (m, 2H), 1.59
(m, 2H).
EXAMPLE 28(18)
4-(3-(N-(4-(N'-(2-propynyl)amino)butanoyl)amino)phenyl)-5,6,7,8-tetrahydro-
phthalazin-1(2H)-one hydrochloride
[0986] TLC: Rf 0.25 (methanol:methylene chloride=1:10);
[0987] NMR (DMSO-d.sub.6): .delta. 12.89 (s, 1H), 10.24 (s, 1H),
9.35 (brs, 2H), 7.70 (s, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.36 (t,
J=8.1 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 3.91 (d, J=2.7 Hz, 2H), 3.70
(t, J=2.7 Hz, 1H), 3.00 (m, 2H), 2.44 (m, 4H), 2.34 (m, 2H), 1.92
(m, 2H), 1.69 (m, 2H), 1.60 (m, 2H).
EXAMPLE 28(19)
8-(3-(N-(4-(morpholin-4-yl)butanoyl)amino)phenyl)-2,3,4,6-tetrahydropyrido-
[2,3-d]pyridazin-5(1H)-one dihydro chloride
[0988] TLC: Rf 0.54 (chloroform:methanol=4:1);
[0989] NMR (DMSO-d.sub.6): .delta. 12.34 (brs, 1H), 11.04 (brs,
1H), 10.31 (s, 1H), 7.78-7.64 (m, 2H), 7.39 (dd, J=7.8, 7.8 Hz,
1H), 7.11 (m, 1H), 4.02-3.70 (m, 4H), 3.50-3.32 (m, 2H), 3.24-2.90
(m, 6H), 2.60-2.34 (m, 4H), 2.12-1.90 (m, 2H), 1.82-1.62 (m,
2H).
EXAMPLE 28(20)
4-(2-(N-(2-(pyrrolidin-1-yl)acetyl)amino)ethyl)-5,6,7,8-tetrahydrophthalaz-
in-1(2H)-one
[0990] TLC: Rf 0.43 (chloroform:methanol=4:1);
[0991] NMR (DMSO-d.sub.6): .delta. 12.56 (s, 1H), 7.77 (t, J=5.7
Hz, 1H), 3.42-3.26 (m, 2H), 2.97 (s, 2H), 2.63 (t, J=6.9 Hz, 2H),
2.54-2.28 (m, 8H), 1.76-1.52 (m, 8H).
EXAMPLE 28(21)
4-(N-(2-(N'-cyclobutylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophtha-
lazin-1(2H)-one
[0992] TLC: Rf 0.21 (chloroform:methanol:water=8:2:0.2);
[0993] NMR (DMSO-d.sub.6): .delta. 12.57 (br, 1H), 7.97 (t, J=6.0
Hz, 1H), 3.40 (s, 2H), 3.18-3.03 (m, 3H), 2.52-2.45 (m, 2H),
2.44-2.32 (m, 4H), 2.12-2.02 (m, 2H), 1.78-1.56 (m, 8H).
EXAMPLE 28(22)
4-(N-(2-(azepan-1-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1-
(2H)-one
Free Form:
[0994] TLC: Rf 0.29 (chloroform:methanol:water=8:2:0.2);
[0995] NMR (DMSO-d.sub.6): .delta. 12.58 (br, 1H), 7.82 (t, J=6.0
Hz, 1H), 3.39 (s, 2H), 3.10 (q, J=6.0 Hz, 2H), 2.60-2.52 (m, 4H),
2.52-2.45 (m, 2H), 2.44-2.33 (m, 4H), 1.68-1.60 (m, 4H), 1.58-1.46
(m, 8H).
Hydrochloride:
[0996] TLC: Rf 0.34 (methylene
chloride:methanol:water=8:2:0.2);
[0997] NMR (DMSO-d.sub.6): .delta. 12.61 (s, 1H), 10.44 (br, 1H),
8.49 (m, 1H), 3.51-3.42 (m, 2H), 3.47 (s, 2H), 3.42-3.31 (m, 2H),
3.18-3.03 (m, 4H), 2.46-2.34 (m, 4H), 1.88-1.76 (m, 4H), 1.72-1.50
(m, 8H).
EXAMPLE 28(23)
4-(2-(N-(3-(N'-cyclobutylamino)propanoyl)amino)ethyl)-5,6,7,8-tetrahydroph-
thalazin-1(2H)-one
[0998] TLC: Rf 0.17 (chloroform:methanol=4:1);
[0999] NMR (DMSO-d.sub.6): .delta. 12.55 (brs, 1H), 7.99 (t, J=5.4
Hz, 1H), 4.08 (br, 1H), 3.46-3.20 (m, 2H), 3.09 (m, 1H), 2.68-2.28
(m, 8H), 2.13 (t, J=6.9 Hz, 2H), 2.04 (m, 2H), 1.80-1.40 (m,
8H).
EXAMPLE 28(24)
4-(2-(N-(3-(piperidin-1-yl)propanoyl)amino)ethyl)-5,6,7,8-tetrahydrophthal-
azin-1(2H)-one
[1000] TLC: Rf 0.26 (chloroform:methanol=4:1);
[1001] NMR (DMSO-d.sub.6): .delta. 12.55 (s, 1H), 8.05 (t, J=5.4
Hz, 1H), 3.42-3.24 (m, 4H), 2.60 (t, J=7.2 Hz, 2H), 2.56-2.22 (m,
8H), 2.18 (t, J=7.2 Hz, 2H), 1.76-1.54 (m, 4H), 1.52-1.24 (m,
6H).
EXAMPLE 28(25)
4-(N-(2-(N'-methyl-N'-isopropylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrah-
ydrophthalazin-1(2H)-one
[1002] TLC: Rf 0.25 (chloroform:methanol:water=8:2:0.2);
[1003] NMR (DMSO-d.sub.6): .delta. 12.57 (s, 1H), 7.84 (m, 1H),
3.39 (s, 2H), 3.09 (q, J=6.0 Hz, 2H), 2.72 (m, 1H), 2.46-2.30 (m,
6H), 2.10 (s, 3H), 1.66-1.60 (m, 4H), 0.89 (d, J=6.6 Hz, 6H).
EXAMPLE 28(26)
4-(N-(2-(N'-cyclopropylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophth-
alazin-1(2H)-one
[1004] TLC: Rf 0.43 (chloroform:methanol:water=8:2:0.2);
[1005] NMR (DMSO-d.sub.6): .delta. 12.56 (s, 1H), 7.93 (m, 1H),
3.40 (s, 2H), 3.12 (q, J=6.0 Hz, 2H), 2.61 (t, J=6.0 Hz, 2H),
2.44-2.32 (m, 2H), 2.04 (m, 1H), 1.68-1.60 (m, 4H), 0.37-0.30 (m,
2H), 0.20-0.14 (m, 2H).
EXAMPLE 28(27)
4-(N-(3-(piperidin-1-yl)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalaz-
in-1(2H)-one
[1006] TLC: Rf 0.20 (chloroform:methanol:water=8:2:0.2);
[1007] NMR (DMSO-d.sub.6): .delta. 12.70 (s, 1H), 8.00 (m, 1H),
3.38 (s, 2H), 3.04 (q, J=6.3 Hz, 2H), 2.46-2.33 (m, 4H), 2.32-2.16
(m, 6H), 1.68-1.60 (m, 4H), 1.59-1.42 (m, 6H), 1.41-1.30 (m,
2H).
EXAMPLE 28(28)
4-(N-(2-(N'-cyclopentylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophth-
alazin-1(2H)-one hydrobromide
[1008] TLC: Rf 0.35 (ethyl acetate:acetic acid:water=3:1:1);
[1009] NMR (DMSO-d.sub.6): .delta. 12.62 (s, 1H), 8.44 (m, 2H),
8.21 (t, J=6.0 Hz, 1H), 3.46 (m, 1H), 3.46 (s, 2H), 3.38-3.26 (m,
2H), 300-2.92 (m, 2H), 2.45-2.34 (m, 4H), 2.00-1.86 (m, 2H),
1.74-1.60 (m, 6H), 1.60-1.48 (m, 4H).
EXAMPLE 28(29)
4-(N-(3-(N'-cyclobutylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophth-
alazin-1(2H)-one hydrobromide
[1010] TLC: Rf 0.30 (ethyl acetate:acetic acid:water=3:1:1);
[1011] NMR (DMSO-d.sub.6): .delta. 12.61 (s, 1H), 8.53 (m, 2H),
8.19 (t, J=6.0 Hz, 1H), 3.65 (quin, J=7.8 Hz, 1H), 3.42 (s, 2H),
3.12 (q, J=6.0 Hz, 2H), 2.80-2.70 (m, 2H), 2.45-2.36 (m, 4H),
2.20-2.00 (m, 4H), 1.84-1.60 (m, 8H).
EXAMPLE 28(30)
4-(N-(4-(N'-cyclobutylamino)butyl)carbamoylmethyl)-5,6,7,8-tetrahydrophtha-
lazin-1(2H)-one hydrobromide
[1012] TLC: Rf 0.26 (ethyl acetate:acetic acid:water=3:1:1);
[1013] NMR (DMSO-d.sub.6): .delta. 12.58 (s, 1H), 8.53 (br, 2H),
8.09 (t, J=6.0 Hz, 1H), 3.64 (quin, J=6.0 Hz, 1H), 3.40 (s, 2H),
3.06, (q, J=6.0 Hz, 2H), 2.82-2.70 (m, 2H), 2.46-2.33 (m, 4H),
2.22-2.02 (m, 4H), 1.84-1.72 (m, 2H), 1.70-1.60 (m, 4H), 1.60-1.38
(m, 4H).
EXAMPLE 28(31)
4-(N-(2-(N'-cyclohexylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophtha-
lazin-1(2H)-one hydrobromide
[1014] TLC: Rf 0.18 (ethyl acetate:acetic acid:water=3:1:1);
[1015] NMR (DMSO-d.sub.6): .delta. 12.62 (br, 1H), 8.40-8.20 (m,
2H), 8.22 (m, 1H), 3.45 (s, 2H), 3.30 (m, 1H), 3.03-2.90 (m, 2H),
2.43-2.32 (m, 4H), 2.00-1.90 (m, 2H), 1.78-1.54 (m, 8H), 1.28-1.00
(m, 6H).
EXAMPLE 28(32)
4-(N-(4-(N'-methylamino)butyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazi-
n-1(2H)-one hydrobromide
[1016] TLC: Rf 0.063 (methylene chloride:methanol:saturated aqueous
ammonia=8:2:0.2);
[1017] NMR (DMSO-d.sub.6): .delta. 12.58 (brs, 1H), 8.28-8.00 (br,
2H), 8.10 (m, 1H), 3.40 (s, 2H), 3.05 (q, J=6.0 Hz, 2H), 2.86 (t,
J=7.2 Hz, 2H), 2.52 (s, 3H), 2.48-2.32 (m, 4H), 1.70-1.60 (m, 4H),
1.60-1.36 (m, 4H).
EXAMPLE 28(33)
4-(N-(4-(N'-cyclopentylamino)butyl)carbamoylmethyl)-5,6,7,8-tetrahydrophth-
alazin-1(2H)-one hydrobromide
[1018] TLC: Rf 0.28 (methylene chloride:methanol:saturated aqueous
ammonia=8:2:0.2);
[1019] NMR (DMSO-d.sub.6): .delta. 12.58 (s 1H), 8.37 (br, 2H),
8.11 (m, 1H), 3.43 (m, 1H), 3.41 (s, 2H), 3.07 (q, J=6.0 Hz, 2H),
2.92-2.83 (m, 2H), 2.46-2.33 (m, 4H), 2.00-1.88 (m, 2H), 1.74-1.40
(m, 14H).
EXAMPLE 28(34)
4-(N-(3-(N'-cyclopentylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropht-
halazin-1(2H)-one hydrobromide
[1020] TLC: Rf 0.56 (methylene chloride:methanol:saturated aqueous
ammonia=8:2:0.2);
[1021] NMR (DMSO-d.sub.6): .delta. 12.61 (s 1H), 8.30-8.00 (br,
2H), 8.22 (m, 1H), 3.43 (s, 2H), 3.43 (m, 1H), 3.14 (q, J=6.6 Hz,
2H), 2.86 (t, J=7.5 Hz, 2H), 2.46-2.34 (m, 4H), 1.96-1.84 (m, 2H),
1.80-1.46 (m, 12H).
EXAMPLE 28(35)
4-(N-(4-(N'-cyclohexylamino)butyl)carbamoylmethyl)-5,6,7,8-tetrahydrophtha-
lazin-1(2H)-one hydrobromide
[1022] TLC: Rf 0.56 (methylene chloride:methanol:saturated aqueous
ammonia=8:2:0.2);
[1023] NMR (DMSO-d.sub.6): .delta. 12.58 (s 1H), 8.24 (br, 2H),
8.10 (m, 1H), 3.40 (s, 2H), 3.07 (q, J=6.3 Hz, 2H), 3.00-2.84 (m,
3H), 2.46-2.34 (m, 4H), 2.04-1.95 (m, 2H), 1.80-1.40 (m, 11H),
1.28-1.10 (m, 5H).
EXAMPLE 28(36)
4-(N-(3-(N'-cyclopropylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropht-
halazin-1(2H)-one
[1024] TLC: Rf 0.44 (methylene chloride:methanol:saturated aqueous
ammonia=8:2:0.2);
[1025] NMR (DMSO-d.sub.6): .delta. 12.59 (s 1H), 8.09 (t, J=6.0 Hz,
1H), 3.40 (s, 2H), 3.09 (q, J=6.0 Hz, 2H), 2.74 (t, J=5.2 Hz, 2H),
2.46-2.25 (m, 5H), 1.70-1.55 (m, 6H), 0.58-0.50 (m, 2H), 0.50-0.40
(m, 2H).
EXAMPLE 28(37)
4-(N-(4-(N'-cyclopropylamino)butyl)carbamoylmethyl)-5,6,7,8-tetrahydrophth-
alazin-1(2H)-one
[1026] TLC: Rf 0.44 (methylene chloride:methanol:saturated aqueous
ammonia=8:2:0.2);
[1027] NMR (DMSO-d.sub.6): .delta. 12.56 (brs 1H), 8.01 (t, J=6.0
Hz, 1H), 3.38 (s, 2H), 3.18-2.98 (m, 2H), 2.60-2.52 (m, 2H),
2.46-2.32 (m, 4H), 2.06 (m, 1H), 1.70-1.60 (m, 4H), 1.44-1.35 (m,
4H), 0.40-0.34 (m, 2H), 0.26-0.18 (m, 2H).
EXAMPLE 28(38)
4-(N-methyl-N-(3-(N'-cyclohexylamino)propyl)carbamoylmethyl)-5,6,7,8-tetra-
hydrophthalazin-1(2H)-one hydrochloride
[1028] TLC: Rf 0.20 (methylene chloride:methanol:saturated aqueous
ammonia=8:2:0.2);
[1029] NMR (DMSO-d.sub.6): .delta. 12.60 (s, 1H), 8.62 and 8.42
(br, 2H), 3.68 (s, 2H), 3.43-3.34 (m, 2H), 3.02 and 2.82 (s, 3H),
3.00-2.78 (m, 3H), 2.42-2.32 (m, 4H), 2.02-1.54 (m, 12H), 1.32-1.17
(m, 4H).
EXAMPLE 28(39)
4-(N-methyl-N-(3-(N'-cyclopentylamino)propyl)carbamoylmethyl)-5,6,7,8-tetr-
ahydrophthalazin-1(2H)-one hydrochloride
[1030] TLC: Rf 0.20 (methylene chloride:methanol:saturated aqueous
ammonia=8:2:0.2);
[1031] NMR (DMSO-d.sub.6): .delta. 12.60 (s, 1H), 8.73 and 8.49
(br, 2H), 3.68 and 3.67 (s, 2H), 3.46-3.36 (m, 3H), 3.01 and 2.82
(s, 3H), 2.98-2.78 (m, 2H), 2.42-2.34 (m, 4H), 1.98-1.76 (m, 4H),
1.70-1.44 (m, 10H).
EXAMPLE 28(40)
4-(N-methyl-N-(3-(N'-cyclobutylamino)propyl)carbamoylmethyl)-5,6,7,8-tetra-
hydrophthalazin-1(2H)-one hydrochloride
[1032] TLC: Rf 0.24 (methylene
chloride:methanol:water=8:2:0.2);
[1033] NMR (DMSO-d.sub.6): .delta. 12.59 (s, 1H), 8.63 (br, 2H),
3.67 and 3.65 (s, 2H), 3.62 (m, 1H), 3.44-3.30 (m, 2H), 3.00 and
2.81 (s, 3H), 2.82-2.67 (m, 2H), 2.41-2.32 (m, 4H), 2.20-2.04 (m,
4H), 1.90-1.70 (m, 4H), 1.70-1.60 (m, 4H).
EXAMPLE 28(41)
4-(N-methyl-N-(3-(N'-cyclopropylamino)propyl)carbamoylmethyl)-5,6,7,8-tetr-
ahydrophthalazin-1(2H)-one hydrochloride
[1034] TLC: Rf 0.24 (methylene
chloride:methanol:water=8:2:0.2);
[1035] NMR (DMSO-d.sub.6): .delta. 12.59 and 12.57 (s, 1H), 8.57
(br, 2H), 3.67 (s, 2H), 3.46-3.30 (m, 2H), 3.01 and 2.81 (s, 3H),
2.95-2.82 (m, 2H), 2.57 (m, 1H), 2.41-2.33 (m, 4H), 1.95-1.75 (m,
2H), 1.70-1.58 (m, 4H), 0.81-0.72 (m, 2H), 0.72-0.64 (m, 2H).
EXAMPLE 28(42)
4-(N-(4-(morpholin-4-yl)butyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazi-
n-1(2H)-one
Free Form:
[1036] TLC: Rf 0.38 (methanol:methylene chloride=1:4);
[1037] NMR (DMSO-d.sub.6): .delta. 12.57 (s, 1H), 8.00 (t, J=5.4
Hz, 1H), 3.55 (m, 4H), 3.39 (s, 2H), 3.29-2.20 (m, 12H), 1.63 (brs,
4H), 1.40 (brs, 4H).
Hydrochloride:
[1038] TLC: Rf 0.37 (methanol:methylene chloride:saturated aqueous
ammonia=1:9:0.1);
[1039] NMR (DMSO-d.sub.6): .delta. 12.59 (s, 1H), 10.34 (brs, 1H),
8.13 (t, J=5.4 Hz, 1H), 3.94 (m, 2H), 3.72 (t, J=11.4 Hz, 2H), 3.41
(s, 2H), 3.38 (m, 2H), 3.07 (m, 6H), 2.39 (m, 4H), 1.63-1.40 (m,
8H).
Methanesulfonate:
[1040] TLC: Rf 0.34 (methanol:methylene chloride:28% ammonia
water=1:9:0.1);
[1041] NMR (DMSO-d.sub.6): .delta. 12.58 (s, 1H), 9.54 (brs, 1H),
8.10 (t, J=5.4 Hz, 1H), 4.00-3.94 (m, 2H), 3.69-3.61 (m, 2H), 3.41
(s, 2H), 3.36 (m, 2H), 3.11-2.97 (m, 6H), 2.42-2.33 (m, 4H), 2.34
(s, 3H), 1.63 (m, 6H), 1.48-1.38 (m, 2H).
EXAMPLE 29
4-(3-(N-(5-aminopentanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-
-one methanesulfonate
[1042] Under an atmosphere of hydrogen, a mixture of the compound
prepared in Example 26(4) (430 mg) and 10% palladium on carbon
(86.0 mg) in methanol (5.0 mL) was stirred at room temperature for
10 hours. The reaction mixture was filtrated through Celite. The
filtrate was concentrated. The obtained powder was recrystallized
from ethyl acetate to give a free form of the title compound (268
mg). A suspension of the obtained free form (264 mg) and
methanesulfonate (74.6 mg) in methanol (3.0 mL) was stirred at room
temperature for 1 hour. The reaction mixture was concentrated to
give the compound of the present invention (307 mg) having the
following physical data.
[1043] TLC: Rf 0.28 (methanol:methylene chloride:saturated aqueous
ammonia=4:8:0.1);
[1044] NMR (CD.sub.3OD): .delta. 7.80 (s, 1H), 7.66 (m, 1H), 7.47
(t, J=7.8 Hz, 1H), 7.22 (m, 1H), 3.01 (brt, J=6.8 Hz, 2H), 2.75 (s,
3H), 2.68 (brt, J=6.0 Hz, 2H), 2.53 (m, 4H), 1.90-1.74 (m, 8H).
EXAMPLE 29(1) TO EXAMPLE 29(6)
[1045] By the same procedure as described in Example 29, if
necessary, by converting to corresponding salts by conventional
method, using the compound prepared in Example 26(6) to 26(8),
26(12), 24(31) or 27(38) instead of the compound prepared in
Example 26(4), the following compounds of the present invention
were obtained.
EXAMPLE 29(1)
4-(3-(N-(5-(N'-methylamino)pentanoyl)amino)phenyl)-7,8,9,9a-tetrahydro-2H--
pyrido[1,2-d][1,2,4]triazin-1(6H)-one methanesulfonate
[1046] TLC: Rf 0.34 (methanol:methylene chloride:saturated aqueous
ammonia=1:4:0.2);
[1047] NMR (CD.sub.3OD): .delta. 10.02 (brs, 1H), 7.78 (s, 1H),
7.65 (d, J=7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.17 (d, J=7.8 Hz,
1H), 4.07 (m, 1H), 3.47 (m, 1H), 3.07 (t, J=6.9 Hz, 2H), 2.91 (m,
1H), 2.75 (s, 6H), 2.53 (t, J=6.6 Hz, 2H), 2.29-1.52 (m, 10H).
EXAMPLE 29(2)
4-(3-(N-(5-(N'-methylamino)pentanoyl)amino)phenyl)-6,7,9,9a-tetrahydro[1,4-
]thiazino[4,3-d][1,2,4]triazin-1(2H)-one methanesulfonate
[1048] TLC: Rf 0.26 (methanol:methylene chloride:saturated aqueous
ammonia=1:4:0.2);
[1049] NMR (CD.sub.3OD): .delta. 8.14 (t, J=1.8 Hz, 1H), 7.78 (m,
1H), 7.64 (t, J=7.8 Hz, 1H), 7.39 (m, 1H), 4.68 (dd, J=11.1, 2.4
Hz, 1H), 4.00 (dt, J=14.1, 3.0 Hz, 1H), 3.53-3.34 (m, 2H), 3.10 (m,
4H), 2.76 (s, 6H), 2.57 (m, 3H), 1.84 (m, 4H).
EXAMPLE 29(3)
4-(3-(N-(5-(N'-methylamino)pentanoyl)amino)phenyl)-2,5,6,7,8,9-hexahydro-1-
H-cyclohepta[d]pyridazin-1-one methanesulfonate
[1050] TLC: Rf 0.29 (chloroform:methanol:28% ammonia
water=40:10:1);
[1051] NMR (DMSO-d.sub.6): .delta. 12.96 (br-s, 1H), 10.05 (s, 1H),
8.22 (br-s, 2H), 7.69 (m, 1H), 7.57 (m, 1H), 7.37 (m, 1H), 7.00 (m,
1H), 2.92-2.78 (m, 4H), 2.58-2.52 (m, 5H), 2.40-2.32 (m, 2H), 2.30
(s, 3H), 1.86-1.76 (m, 2H), 1.66-1.46 (m, 8H).
EXAMPLE 29(4)
4-(3-(N-(5-(N'-methylamino)pentanoyl)amino)phenyl)-6,7-dihydro[1,4]thiazin-
o[4,3-d][1,2,4]triazin-1(2H)-one hydrochloride
[1052] TLC: Rf 0.34 (chloroform:methanol:water=8:2:0.2);
[1053] NMR (DMSO-d.sub.6): .delta. 10.89 (s, 1H), 10.37 (br, 1H),
8.83 (br, 2H), 7.76 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.38 (t, J=7.8
Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 6.26 (s, 1H), 3.64-3.58 (m, 2H),
3.20-3.14 (m, 2H), 2.94-2.84 (m, 2H), 2.54-2.30 (m, 5H), 1.70-1.60
(m, 4H).
EXAMPLE 29(5)
4-(N-(2-(piperidin-4-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazi-
n-1(2H)-one
Free Form:
[1054] TLC: Rf 0.14 (methanol:methylene chloride:saturated aqueous
ammonia=1:4:0.1);
[1055] NMR (DMSO-d.sub.6): .delta. 12.54 (brs, 1H), 8.44 (s, 1H),
8.01 (t, J=5.4 Hz, 1H), 3.38 (s, 2H), 3.08-2.26 (m, 12H), 1.63
(brs, 4H), 1.34-1.00 (m, 5H).
Methanesulfonate:
[1056] TLC: Rf 0.43 (methylene chloride:methanol:28% ammonia
water=6:3:1);
[1057] NMR (DMSO-d.sub.6): .delta. 12.58 (brs, 1H), 8.18 (brs, 2H),
8.02 (t, J=5.4 Hz, 1H), 3.38 (s, 2H), 3.22 (m, 2H), 3.08 (m, 2H),
2.76 (m, 2H), 2.46-2.34 (m, 4H), 2.30 (s, 3H), 1.77 (m, 2H), 1.63
(m, 4H), 1.50 (m, 1H), 1.40-1.24 (m, 4H).
EXAMPLE 29(6)
4-(2-(1,4-diazepan-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[1058] TLC: Rf 0.083 (methylene chloride:methanol=4:1);
[1059] NMR (DMSO-d.sub.6): .delta. 12.5 (brs, 1H), 2.80-2.55 (m,
12H), 2.49 (m, 2H), 2.35 (m, 2H), 1.75-1.68 (m, 6H).
EXAMPLE 30
4-(3-(N-(5-(N'-methylamino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydrophtha-
lazin-1(2H)-one methanesulfonate
[1060] 4N hydrogen chloride in dioxane (2.50 mL) was added dropwise
to a solution of the compound prepared in Example 26 (290 mg) in
methanol (3.0 mL) in ice bath, the mixture was stirred at room
temperature for 2 hours. The reaction mixture was concentrated. The
residue was purified by column chromatography on silica gel
(methanol:methylene chloride=1:9.fwdarw.methanol:methylene
chloride:saturated aqueous ammonia=2:8:0.1). 1N sodium hydroxide
solution (0.34 mL) was added dropwise to a suspension of the
obtained solid (134 mg) in methanol (1.0 mL) and the mixture was
stirred at room temperature for 30 minutes. A saturated aqueous
ammonium chloride solution was added to the reaction mixture, which
was extracted with methylene chloride. The extract was washed with
brine, dried over anhydrous magnesium sulfate and concentrated. A
solution of the obtained solid (64.8 mg) and methanesulfonate (17.6
mg) in methanol (3.0 mL) was stirred at room temperature for 30
minutes. The reaction mixture was concentrated to give the compound
of the present invention (82.4 mg) having the following physical
data.
[1061] TLC: Rf 0.27 (methanol:methylene chloride:saturated aqueous
ammonia=2:8:0.5);
[1062] NMR (CD.sub.3OD): .delta. 10.00 (brs, 1H), 7.75 (d, J=1.2
Hz, 1H), 7.63 (dd, J=8.1, 1.2 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H), 7.21
(d, J=8.1 Hz, 1H), 3.07 (brt, J=7.2 Hz, 2H), 2.74 (s, 6H), 2.65
(brt, J=6.3 Hz, 2H), 2.52 (m, 4H), 1.82 (m, 8H).
EXAMPLE 30(1) TO EXAMPLE 30(19)
[1063] By the same procedure as described in Example 30, if
necessary, by converting to corresponding salts by conventional
method, using the compound prepared in Example 26(9), 26(10),
26(11), 23, 26(14), 26(15), 23(3), 23(4), 23(9), 23(16), 26(16),
27(7), 23(21), 26(17), 27(14), 26(19), 23(25), 23(33) or 24(48)
instead of the compound prepared in Example 26, the following
compounds of the present invention were obtained.
EXAMPLE 30(1)
4-(3-(N-(4-(N'-methylamino)butanoyl)amino)phenyl)-6,7,9,9a-tetrahydro[1,4]-
thiazino[4,3-d][1,2,4]triazin-1(2H)-one methanesulfonate
[1064] TLC: Rf 0.20 (chloroform:methanol:water=8:2:0.2);
[1065] NMR (DMSO-d.sub.6): .delta. 10.56 (s, 1H), 10.17 (s, 1H),
8.45 (br, 2H), 7.71 (s, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.36 (t, J=7.8
Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 4.24 (dd, J=8.4, 4.5 Hz, 1H), 3.56
(m, 1H), 3.09 (m, 1H), 2.98-2.90 (m, 2H), 2.88-2.84 (m, 2H), 2.71
(m, 1H), 2.56 (t, J=6.0 Hz, 3H), 2.44 (t, J=6.0 Hz, 2H), 2.31 (s,
3H), 2.31 (m, 1H), 1.94-1.86 (m, 2H).
EXAMPLE 30(2)
4-(3-(N-(6-(N'-methylamino)hexanoyl)amino)phenyl)-6,7,9,9a-tetrahydro[1,4]-
thiazino[4,3-d][1,2,4]triazin-1(2H)-one methanesulfonate
[1066] TLC: Rf 0.17 (chloroform:methanol:water=8:2:0.2);
[1067] NMR (DMSO-d.sub.6): .delta. 10.54 (s, 1H), 10.05 (s, 3H),
8.36 (br, 2H), 7.71 (s, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.35 (t, J=7.5
Hz, 1H), 7.06 (d, J=7.5 Hz, 1H), 4.24 (m, 1H), 3.59 (m, 1H), 3.08
(m, 1H), 2.92-2.82 (m, 2H), 2.71 (m, 1H), 2.60-2.40 (m, 3H), 2.31
(m, 1H), 2.293 (s, 3H), 2.289 (s, 3H), 1.68-1.55 (m, 4H), 1.40-1.30
(m, 2H).
EXAMPLE 30(3)
4-(3-(N-(5-(N'-(3-methyl-2-butenyl)amino)pentanoyl)amino)phenyl)-5,6,7,8-t-
etrahydrophthalazin-1(2H)-one hydrochloride
[1068] TLC: Rf 0.34 (chloroform:methanol=4:1);
[1069] NMR (DMSO-d.sub.6): .delta. 12.88 (s, 1H), 10.24 (s, 1H),
8.84 (s, 2H), 7.73 (s, 1H), 7.64 (m, 1H), 7.35 (dd, J=7.8, 7.8 Hz,
1H), 7.08 (m, 1H), 5.25 (t, J=7.2 Hz, 1H), 3.56-3.40 (m, 2H),
2.98-2.72 (m, 2H), 2.60-2.24 (m, 6H), 1.80-1.50 (m, 14H).
EXAMPLE 30(4)
4-(N-(2-aminoethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
Free Form:
[1070] TLC: Rf 0.19 (methylene chloride:methanol:ammonia
water=8:2:0.2);
[1071] NMR (DMSO-d.sub.6): .delta. 7.98 (m, 1H), 3.41 (s, 2H), 3.03
(q, J=6.6 Hz, 2H), 2.55 (t, J=6.6 Hz, 2H), 2.46-2.33 (m, 4H),
1.70-1.60 (m, 4H).
Hydrochloride:
[1072] TLC: Rf 0.44 (methanol:methylene chloride:saturated aqueous
ammonia=1:4:0.2);
[1073] NMR (DMSO-d.sub.6): .delta. 12.60 (brs, 1H), 8.42 (t, J=6.0
Hz, 1H), 8.11 (brs, 3H), 3.46 (s, 2H), 3.31 (q, J=6.0 Hz, 2H), 2.84
(q, J=6.0 Hz, 2H), 2.39 (m, 4H), 1.63 (m, 4H).
EXAMPLE 30(5)
4-(3-(N-(azetidin-3-ylcarbonyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin--
1(2H)-one hydrochloride
[1074] TLC: Rf 0.18 (chloroform:methanol=4:1);
[1075] NMR (DMSO-d.sub.6): .delta. 10.43 (s, 1H), 9.10 (brs, 1H),
8.82 (brs, 1H), 7.73 (m, 1H), 7.64 (m, 1H), 7.39 (dd, J=7.8, 7.8
Hz, 1H), 7.14 (m, 1H), 4.20-3.92 (m, 4H), 3.79 (m, 1H), 2.62-2.20
(m, 4H), 1.78-1.50 (m, 4H).
EXAMPLE 30(6)
4-(3-(N-(pyrrolidin-2-ylcarbonyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazi-
n-1(2H)-one hydrochloride
[1076] TLC: Rf 0.53 (methanol:methylene chloride=1:4);
[1077] NMR (DMSO-d.sub.6): .delta. 12.91 (s, 1H), 10.86 (s, 1H),
9.65 (brs, 1H), 8.67 (brs, 1H), 7.71 (s, 1H), 7.64 (d, J=7.8 Hz,
1H), 7.43 (t, J=7.8 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 4.37 (m, 1H),
3.27-2.26 (m, 6H), 1.94 (m, 4H), 1.70-1.59 (m, 4H).
EXAMPLE 30(7)
4-(N-(3-aminopropyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-on-
e hydrochloride
[1078] TLC: Rf 0.41 (ethyl acetate:acetic acid:water=3:3:1);
[1079] NMR (DMSO-d.sub.6): .delta. 12.59 (s, 1H), 8.23 (br, 1H),
7.88 (br, 3H), 3.42 (s, 2H), 3.11 (q, J=6.6 Hz, 2H), 2.76 (q, J=6.6
Hz, 2H), 2.50-2.32 (m, 4H), 1.76-1.60 (m, 6H).
EXAMPLE 30(8)
4-(N-(2-(N'-methylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazi-
n-1(2H)-one hydrochloride
[1080] TLC: Rf 0.29 (ethyl acetate:acetic acid:water=3:3:1);
[1081] NMR (DMSO-d.sub.6): .delta. 12.60 (brs, 1H), 8.86 (br, 2H),
8.38 (br, 1H), 3.47 (s, 2H), 3.35 (q, J=6.0 Hz, 2H), 2.94 (quin,
J=6.0 Hz, 2H), 2.53 (t, J=5.4 Hz, 3H), 2.50-2.34 (m, 4H), 1.70-1.60
(m, 4H).
EXAMPLE 30(9)
4-(1-(N-(2-aminoethyl)carbamoyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)--
one hydrochloride
[1082] TLC: Rf 0.62 (methanol:methylene chloride:saturated aqueous
ammonia=1:4:0.2);
[1083] NMR (DMSO-d.sub.6): .delta. 12.62 (s, 1H), 8.25 (t, J=5.4
Hz, 1H), 8.00 (brs, 3H), 3.73 (q, J=6.9 Hz, 1H), 3.26 (m, 2H), 2.83
(m, 2H), 2.48-2.30 (m, 4H), 1.64 (m, 4H), 1.31 (d, J=6.9 Hz,
3H).
EXAMPLE 30(10)
4-(N-(4-aminobutyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
hydrochloride
[1084] TLC: Rf 0.15 (ethyl acetate:acetic acid:water=3:1:1);
[1085] NMR (DMSO-d.sub.6): .delta. 12.58 (s, 1H), 8.17 (t, J=6.3
Hz, 1H), 7.95 (br, 3H), 3.41 (s, 2H), 3.05 (q, J=6.3 Hz, 2H), 2.75
(m, 2H), 2.46-2.33 (m, 4H), 1.68-1.60 (m, 4H), 1.60-1.40 (m,
4H).
EXAMPLE 30(11)
4-(2-(N-(2-aminoacetyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
hydrochloride
[1086] TLC: Rf 0.11 (chloroform:methanol=4:1);
[1087] NMR (DMSO-d.sub.6): .delta. 12.58 (brs, 1H), 8.59 (t, J=5.7
Hz, 1H), 8.19 (brs, 3H), 3.56-3.28 (m, 4H), 2.65 (t, J=7.2 Hz, 2H),
2.54-2.28 (m, 4H), 1.76-1.54 (m, 4H).
EXAMPLE 30(12)
4-(2-(piperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
dihydrochloride
[1088] TLC: Rf 0.15 (chloroform:methanol=9:1);
[1089] NMR (CD.sub.3OD): .delta. 3.80-3.50 (m, 10H), 3.14 (t, J=7.5
Hz, 2H), 2.64-2.50 (m, 4H), 1.90-1.74 (m, 4H).
EXAMPLE 30(13)
4-(1-(N-(4-aminobutyl)carbamoyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)--
one hydrochloride
[1090] TLC: Rf 0.19 (methanol:methylene chloride:saturated aqueous
ammonia=1:4:0.1);
[1091] NMR (DMSO-d.sub.6): .delta. 12.60 (s, 1H), 8.04 (t, J=5.4
Hz, 1H), 7.83 (brs, 3H), 3.69 (q, J=7.2 Hz, 1H), 3.09 (m, 2H), 2.74
(m, 2H), 2.48-2.25 (m, 4H), 1.64-1.42 (m, 8H), 1.31 (d, J=7.2 Hz,
3H).
EXAMPLE 30(14)
4-(2-(N-(3-aminopropanoyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)--
one hydrochloride
[1092] TLC: Rf 0.11 (chloroform:methanol=4:1);
[1093] NMR (DMSO-d.sub.6): .delta. 12.56 (brs, 1H), 8.24 (t, J=5.7
Hz, 1H), 7.94 (brs, 3H), 3.42-3.24 (m, 2H), 3.04-2.84 (m, 2H), 2.63
(t, J=7.2 Hz, 2H), 2.56-2.28 (m, 6H), 1.76-1.52 (m, 4H).
EXAMPLE 30(15)
4-(2-(N-(2-aminoethyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
dihydrochloride
[1094] TLC: Rf 0.10 (methylene chloride:methanol:saturated aqueous
ammonia=8:2:0.1);
[1095] NMR (DMSO-d.sub.6): .delta. 12.69 (s, 1H), 9.63 (brs, 2H),
8.41 (brs, 3H), 3.78-3.06 (m, 6H), 2.94 (t, J=7.5 Hz, 2H),
2.58-2.30 (m, 4H), 1.78-1.54 (m, 4H).
EXAMPLE 30(16)
4-(2-(N-(4-aminobutanoyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-o-
ne hydrochloride
[1096] TLC: Rf 0.10 (chloroform:methanol=4:1);
[1097] NMR (DMSO-d.sub.6): .delta. 12.56 (brs, 1H), 8.09 (m, 4H),
3.36-3.20 (m, 2H), 2.82-2.66 (m, 2H), 2.61 (t, J=7.2 Hz, 2H),
2.54-2.28 (m, 4H), 2.15 (t, J=7.2 Hz, 2H), 1.84-1.52 (m, 6H).
EXAMPLE 30(17)
4-(N-(5-aminopentyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-on-
e hydrochloride
[1098] TLC: Rf 0.34 (chloroform:methanol:water=8:2:0.2);
[1099] NMR (DMSO-d.sub.6): .delta. 12.57 (br, 1H), 8.09 (m, 1H),
7.87 (br, 2H), 3.40 (s, 2H), 3.03 (q, J=6.0 Hz, 2H), 2.80-2.66 (m,
2H), 2.46-2.33 (m, 4H), 1.70-1.60 (m, 4H), 1.60-1.49 (m, 2H),
1.48-1.36 (m, 2H), 1.36-1.26 (m, 2H).
EXAMPLE 30(18)
4-(2-(N-(2-aminoethyl)carbamoyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)--
one hydrochloride
[1100] TLC: Rf 0.18 (chloroform:methanol=4:1);
[1101] NMR (DMSO-d.sub.6): .delta. 12.52 (s, 1H), 8.20 (t, J=5.4
Hz, 1H), 8.02 (brs, 3H), 3.36-3.20 (m, 2H), 2.92-2.76 (m, 2H), 2.73
(t, J=7.5 Hz, 2H), 2.54-2.28 (m, 6H), 1.76-1.54 (m, 4H).
EXAMPLE 30(19)
8-(N-(3-aminopropyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyrida-
zin-5(1H)-one dihydrochloride
[1102] TLC: Rf 0.25 (methanol:acetic acid=5:1);
[1103] NMR (DMSO-d.sub.6): .delta. 12.24 (s, 1H), 8.41 (t, J=5.4
Hz, 1H), 7.94 (brs, 5H), 3.42 (s, 2H), 3.20 (t, J=5.4 Hz, 2H), 3.12
(m, 2H), 2.78 (m, 2H), 2.37 (t, J=6.0 Hz, 2H), 1.69 (m, 4H).
EXAMPLE 31
4-(2-acetylthioethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[1104] To a solution of the compound prepared in Reference example
13 (650 mg) in dimethylformamide (15 mL) were added potassium
thioacetate (698 mg) and potassium carbonate (422 mg) and the
mixture was stirred at 50.degree. C. for 2 hours. After cooling to
room temperature, the reaction mixture was poured in cold water and
extracted with ethyl acetate. The extract was washed with water and
brine sequentially, dried over anhydrous magnesium sulfate and
concentrated to give the compound of the present invention (688 mg)
having the following physical data.
[1105] TLC: Rf 0.40 (chloroform:methanol=8:1);
[1106] NMR (DMSO-d.sub.6): .delta. 12.60 (s, 1H), 3.11 (t, J=7.2
Hz, 2H), 2.75 (t, J=7.2 Hz, 2H), 2.56-2.28 (m, 4H), 2.31 (s, 3H),
1.76-1.54 (m, 4H).
EXAMPLE 31(1)
8-(2-acetylthioethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one
[1107] By the same procedure as described in Example 31 using a
corresponding derivative instead of the compound prepared in
Reference example 13, the compound of the present invention having
the following physical data was obtained.
[1108] TLC: Rf 0.43 (chloroform:methanol=8:1);
[1109] NMR (DMSO-d.sub.6): .delta. 11.82 (s, 1H), 6.32 (s, 1H),
3.16 (m, 2H), 3.09 (t, J=7.2 Hz, 2H), 2.66 (t, J=7.2 Hz, 2H), 2.32
(t, J=6.3 Hz, 2H), 2.31 (s, 3H), 1.69 (m, 2H).
EXAMPLE 32
4-(2-benzylthioethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[1110] To a suspension of the compound prepared in Example 31 (100
mg) in methanol (4.0 mL) were added benzyl bromide (0.06 mL) and
potassium carbonate (82 mg) and the mixture was stirred at room
temperature for 2 hours. The reaction mixture was poured in cold
0.5N hydrochloric acid and extracted with ethyl acetate. The
extract was washed with brine, dried over anhydrous magnesium
sulfate and concentrated. The residue was purified by column
chromatography on silica gel (methylene
chloride:methanol=70:1.fwdarw.30:1) to give the compound of the
present invention (47 mg) having the following physical data.
[1111] TLC: Rf 0.42 (chloroform:methanol=8:1);
[1112] NMR (DMSO-d.sub.6): .delta. 12.54 (s, 1H), 7.38-7.16 (m,
5H), 3.77 (s, 2H), 2.80-2.58 (m, 4H), 2.50-2.26 (m, 4H), 1.76-1.52
(m, 4H).
EXAMPLE 32(1) TO EXAMPLE 32(2)
[1113] By the same procedure as described in Example 32, if
necessary, by converting to corresponding salts by conventional
method, using a corresponding derivative instead of benzyl bromide,
the following compounds of the present invention were obtained.
EXAMPLE 32(1)
4-(2-(3-(piperidin-1-yl)propylthio)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2-
H)-one
[1114] TLC: Rf 0.57 (chloroform:methanol=4:1);
[1115] NMR (DMSO-d.sub.6): .delta. 12.56 (s, 1H), 2.78-2.70 (m,
4H), 2.58-2.20 (m, 12H), 1.76-1.56 (m, 6H), 1.54-1.26 (m, 6H).
EXAMPLE 32(2)
4-(2-(2-(piperidin-1-yl)ethylthio)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H-
)-one
Free Form:
[1116] TLC: Rf 0.28 (chloroform:methanol=8:1);
[1117] NMR (DMSO-d.sub.6): .delta. 12.56 (s, 1H), 2.82-2.70 (m,
4H), 2.68-2.56 (m, 2H), 2.54-2.22 (m, 10H), 1.76-1.55 (m, 4H),
1.54-1.26 (m, 6H).
Hydrochloride:
[1118] TLC: Rf 0.28 (chloroform:methanol=8:1);
[1119] NMR (DMSO-d.sub.6): .delta. 12.61 (s, 1H), 10.22 (brs, 1H),
3.44 (m, 2H), 3.19 (m, 2H), 3.04-2.68 (m, 8H), 2.62-2.28 (m, 4H),
1.90-1.54 (m, 9H), 1.35 (m, 1H).
EXAMPLE 33
4-(2-(2-hydroxyethylthio)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[1120] To a solution of
4-(2-(2-t-butyldimethylsilyloxyethylthio)ethyl)-5,6,7,8-tetrahydrophthala-
zin-1(2H)-one (300 mg; It was prepared by the same procedure as
described in Example 32 using
1-t-butyldimethylsilyloxy-2-iodoethane instead of benzyl bromide.)
in tetrahydrofuran (4.0 mL) was added tetrabutylammonium fluoride
(638 mg) and the mixture was stirred at room temperature overnight.
The reaction mixture was poured in a cold saturated aqueous
ammonium chloride solution and extracted with ethyl acetate. The
extract was washed with brine, dried over magnesium sulfate and
concentrated. The residue was washed with t-butyl methyl ether to
give the compound of the present invention (191 mg) having the
following physical data.
[1121] TLC: Rf 0.36 (chloroform:methanol=8:1);
[1122] NMR (DMSO-d.sub.6): .delta. 12.56 (s, 1H), 4.77 (t, J=5.4
Hz, 1H), 3.53 (dt, J=5.4, 6.6 Hz, 2H), 2.84-2.72 (m, 4H), 2.59 (t,
J=6.6 Hz, 2H), 2.56-2.28 (m, 4H), 1.76-1.54 (m, 4H).
EXAMPLE 33(1) TO EXAMPLE 33(3)
[1123] By the same procedure as described in Example 33 using
4-(2-(3-t-butyldimethylsilyloxypropylthio)ethyl)-5,6,7,8-tetrahydrophthal-
azin-1(2H)-one,
8-(2-(2-t-butyldimethylsilyloxyethylthio)ethyl)-2,3,4,6-tetrahydropyrido[-
2,3-d]pyridazin-5(1H)-one or
8-(2-(3-t-butyldimethylsilyloxypropylthio)ethyl)-2,3,4,6-tetrahydropyrido-
[2,3-d]pyridazin-5(1H)-one instead of
4-(2-(2-t-butyldimethylsilyloxyethylthio)ethyl)-5,6,7,8-tetrahydrophthala-
zin-1(2H)-one, the following compounds of the present invention
were obtained.
EXAMPLE 33(1)
4-(2-(3-hydroxypropylthio)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[1124] TLC: Rf 0.37 (chloroform:methanol=8:1);
[1125] NMR (DMSO-d.sub.6): .delta. 12.56 (s, 1H), 4.46 (t, J=5.1
Hz, 1H), 3.44 (dt, J=5.1, 6.9 Hz, 2H), 2.80-2.68 (m, 4H), 2.56 (t,
J=7.2 Hz, 2H), 2.54-2.30 (m, 4H), 1.76-1.54 (m, 6H).
EXAMPLE 33(2)
8-(2-(2-hydroxyethylthio)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5-
(1H)-one
[1126] TLC: Rf 0.31 (chloroform:methanol=8:1);
[1127] NMR (DMSO-d.sub.6): .delta. 11.78 (s, 1H), 6.33 (s, 1H),
4.78 (t, J=5.4 Hz, 1H), 3.53 (dt, J=5.4, 6.6 Hz, 2H), 3.17 (m, 2H),
2.84-2.60 (m, 4H), 2.59 (t, J=6.6 Hz, 2H), 2.32 (t, J=6.3 Hz, 2H),
1.69 (m, 2H).
EXAMPLE 33(3)
8-(2-(3-hydroxypropylthio)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin--
5(1H)-one
[1128] TLC: Rf 0.32 (chloroform:methanol=8:1);
[1129] NMR (DMSO-d.sub.6): .delta. 11.77 (s, 1H), 6.33 (s, 1H),
4.46 (t, J=5.1 Hz, 1H), 3.44 (dt, J=5.1, 5.7 Hz, 2H), 3.16 (m, 2H),
2.80-2.60 (m, 4H), 2.55 (t, J=7.2 Hz, 2H), 2.32 (t, J=6.3 Hz, 2H),
1.78-1.50 (m, 4H).
EXAMPLE 34
4-(2-(2-bromoethylthio)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[1130] To a solution of the compound prepared in Example 33 (160
mg) in chloroform (5.0 mL) were added triphenylphosphine (248 mg)
and carbon tetrabromide (313 mg), and the mixture was stirred at
room temperature for 2 hours. Methanol (1.0 mL) was added dropwise
to the reaction mixture, which was stirred for 5 minutes and
concentrated. The residue was purified by column chromatography on
silica gel (methylene chloride:methanol=80:1.fwdarw.50:1) to give a
crude compound of the present invention (598 mg) having the
following physical data. The obtained compound was used in next
reaction without purifying.
[1131] TLC: Rf 0.49 (chloroform:methanol=8:1);
[1132] NMR (CD.sub.3OD): .delta. 3.55 (t, J=6.3 Hz, 2H), 2.96-2.82
(m, 4H), 2.72 (t, J=6.3 Hz, 2H), 2.64-2.44 (m, 4H), 1.86-1.70 (m,
4H).
EXAMPLE 35
4-(2-(3-chloropropylthio)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[1133] To a suspension of the compound prepared in Example 33(1)
(110 mg) in methylene chloride (2.1 mL) were added thionyl chloride
(0.08 mL) and pyridine (0.01 mL), and the mixture was stirred at
room temperature for 1 day. The reaction mixture was poured in cold
water and extracted with methylene chloride. The extract was washed
with a saturated aqueous sodium hydrogen carbonate solution and
brine sequentially, dried over anhydrous magnesium sulfate and
concentrated to give the compound of the present invention (109 mg)
having the following physical data.
[1134] TLC: Rf 0.49 (chloroform:methanol=8:1);
[1135] NMR (DMSO-d.sub.6): .delta. 12.57 (s, 1H), 3.70 (t, J=6.3
Hz, 2H), 2.82-2.72 (m, 4H), 2.64 (t, J=6.9 Hz, 2H), 2.54-2.30 (m,
4H), 1.95 (tt, J=6.9, 6.3 Hz, 2H), 1.76-1.54 (m, 4H).
EXAMPLE 36 TO EXAMPLE 36(1)
[1136] By the same procedure as described in Example 28, if
necessary, by converting to corresponding salts by conventional
method, using the compound prepared in Example 34 or 35 instead of
the compound prepared in Example 25(1) and cyclopentylamine instead
of morpholine, the following compounds of the present invention
were obtained.
EXAMPLE 36
4-(2-(2-(N-cyclopentylamino)ethylthio)ethyl)-5,6,7,8-tetrahydrophthalazin--
1(2H)-one
[1137] TLC: Rf 0.36 (chloroform:methanol=4:1);
[1138] NMR (DMSO-d.sub.6): .delta. 12.56 (brs, 1H), 3.00 (quint,
J=6.3 Hz, 1H), 2.82-2.72 (m, 4H), 2.71-2.28 (m, 8H), 1.80-1.16 (m,
12H).
EXAMPLE 36(1)
4-(2-(3-(N-cyclopentylamino)propylthio)ethyl)-5,6,7,8-tetrahydrophthalazin-
-1(2H)-one hydrochloride
[1139] TLC: Rf 0.38 (chloroform:methanol=4:1);
[1140] NMR (DMSO-d.sub.6): .delta. 12.59 (s, 1H), 8.99 (brs, 2H),
3.41 (m, 1H), 2.92 (m, 2H), 2.84-2.70 (m, 4H), 2.63 (t, J=7.2 Hz,
2H), 2.58-2.28 (m, 4H), 2.06-1.38 (m, 14H).
EXAMPLE 37
8-(3-(N-(5-(N'-methylamino)pentanoyl)amino)phenyl)-2,3,4,6-tetrahydropyraz-
ino[2,3-d]pyridazin-5(1H)-one methanesulfonate
[1141] By the same procedure as described in Reference example
1.fwdarw.Example 1.fwdarw.Example 26.fwdarw.Example 29 using
furo[3,4-d]pyrazine-5,7-dione instead of
4,5,6,7-tetrahydro-2-benzofuran-1,3-dione, the compound of the
present invention having the following physical data was
obtained.
[1142] TLC: Rf 0.17 (methanol:methylene chloride:saturated aqueous
ammonia=1:4:0.2);
[1143] NMR (CD.sub.3OD): .delta. 7.81 (s, 1H), 7.69 (d, J=7.8 Hz,
1H), 7.49 (t, J=7.8 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 3.50 (m, 2H),
3.39 (m, 2H), 3.08 (m, 2H), 2.75 (s, 3H), 2.74 (s, 3H), 2.53 (m,
2H), 1.81 (m, 4H).
EXAMPLE 38
4-(N-(2-(1H-tetrazol-5-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthala-
zin-1(2H)-one
[1144] A mixture of the compound prepared in Example 23(34) (180
mg), trimethyltin azide (285 mg) and toluene (1.5 mL) was refluxed
overnight. The reaction mixture was concentrated. The residue was
washed with ethyl acetate and hot methanol sequentially to give the
compound of the present invention (113 mg) having the following
physical data.
[1145] TLC: Rf 0.14 (methylene chloride:methanol:saturated aqueous
ammonia=8:2:0.2);
[1146] NMR (DMSO-d.sub.6): .delta. 12.57 (s, 1H), 8.19 (t, J=6.0
Hz, 1H), 3.44 (q, J=6.0 Hz, 2H), 3.37 (s, 2H), 3.02 (t, J=6.0 Hz,
2H), 2.40-2.24 (m, 4H), 1.67-1.58 (m, 4H).
EXAMPLE 39
6-acetyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-one
[1147] To a suspension of the compound prepared in Example 11(1)
(150 mg) in tetrahydrofuran (2.9 mL) was added an aqueous solution
(1.1 mL) of potassium carbonate (157 mg) and then thereto was added
acetyl chloride (0.05 mL) at 0.degree. C., and the mixture was
stirred at room temperature for 4 hours. The reaction mixture was
diluted with water and 1N hydrochloric acid was added thereto. The
mixture was extracted with ethyl acetate. The extract was washed
with brine, dried over anhydrous magnesium sulfate and
concentrated. The residue was washed with ether to give the
compound of the present invention (131 mg) having the following
physical data.
[1148] TLC: Rf 0.36 (chloroform:methanol=8:1);
[1149] NMR (DMSO-d.sub.6): .delta. 13.08 (s, 1H), 7.60-7.40 (m,
5H), 4.28 (s, 2H), 3.66 (t, J=5.7 Hz, 2H), 2.63 (t, J=5.7 Hz, 2H),
2.04 (s, 3H).
EXAMPLE 39(1)
6-(2-(N,N-dimethylamino)acetyl)-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]py-
ridazin-1(2H)-one hydrochloride
[1150] By the same procedure as described in Example 39 and then by
converting to a corresponding salt by conventional method, using
2-dimethylaminoacetyl chloride instead of acetyl chloride, the
compound of the present invention having the following physical
data was obtained.
[1151] TLC: Rf 0.57 (chloroform:methanol=4:1);
[1152] NMR (DMSO-d.sub.6): .delta. 13.17 (s, 1H), 9.75 (brs, 1H),
7.64-7.36 (m, 5H), 4.48-4.30 (m, 3H), 4.21 (m, 1H), 3.96-3.52 (m,
8H), 2.86-2.64 (m, 2H).
EXAMPLE 40
4-(N-(2-carboxyethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-o-
ne
[1153] By the same procedure as described in Reference example 11
using the compound prepared in Example 23(36) instead of the
compound prepared in Example 15, the compound of the present
invention having the following physical data was obtained.
[1154] TLC: Rf 0.26 (methylene
chloride:methanol:water=8:2:0.2);
[1155] NMR (DMSO-d.sub.6): .delta. 12.57 (s, 1H), 8.15 (m, 1H),
4.11 (m, 1H), 3.39 (s, 2H), 3.23 (q, J=6.0 Hz, 2H), 2.58-2.35 (m,
2H), 2.42-2.32 (m, 4H), 1.66-1.58 (m, 4H).
EXAMPLE 41
4-(N-(2-(4-hydroxyphenyl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalaz-
in-1(2H)-one
[1156] By the same procedure as described in Example 20 using the
compound prepared in Example 24(41) instead of the compound
prepared in Example 4(4), the compound of the present invention
having the following physical data was obtained.
[1157] TLC: Rf 0.35 (methanol:methylene chloride=1:10);
[1158] NMR (DMSO-d.sub.6): .delta. 12.57 (s, 1H), 9.15 (s, 1H),
8.04 (t, J=5.7 Hz, 1H), 6.96 (d, J=8.4 Hz, 2H), 6.65 (d, J=8.4 Hz,
2H), 3.36 (s, 2H), 3.22 (m, 2H), 2.58 (t, J=7.5 Hz, 2H), 2.33 (m,
4H), 1.61 (brs, 4H).
REFERENCE EXAMPLE 18
3-hydroxy-4,5,6,7-tetrahydro-2-benzofuran-1(3H)-one
[1159] To a solution of 3,4,5,6-tetrahydrophthalic acid anhydride
(10.0 g) in tetrahydrofuran (50.0 mL) was added sodium borohydride
(600 mg) in ice bath. The mixture was stirred at room temperature
for 30 minutes and refluxed for 5 hours. After cooling to room
temperature, 1N hydrochloric acid (10.0 mL) was added to the
reaction mixture, which was concentrated. Water was added to the
residue, which was extracted with ethyl acetate. The extract was
washed with water and brine sequentially, dried over anhydrous
magnesium sulfate and concentrated. The residue was purified by
column chromatography on silica gel (ethyl acetate:hexane=1:4) to
give the title compound (5.40 g) having the following physical
data.
[1160] TLC: Rf 0.64 (ethyl acetate:hexane=1:1);
[1161] NMR (CDCl.sub.3): .delta. 5.98 (brs, 1H), 4.90-4.50 (m, 1H),
2.52-2.40 (m, 1H), 2.32-2.16 (m, 3H), 1.86-1.60 (m, 4H).
REFERENCE EXAMPLE 19
Tributyl(3-oxo-1,3,4,5,6,7-hexahydro-2-benzofuran-1-yl)phosphonium
bromide
[1162] A mixed solution of the compound prepared in Reference
example 18 (1.54 g), tri-n-butylphosphine (2.02 g) and hydrogen
bromide acetic acid solution (47%, 1.20 mL) in acetic acid (0.700
mL) was refluxed for 21 hours. After cooling to room temperature,
the reaction mixture was concentrated. The residue was purified by
column chromatography on silica gel (methylene
chloride:methanol=20:1) to give the title compound (3.56 g) having
the following physical data.
[1163] TLC: Rf 0.51 (methanol:methylene chloride=1:10).
REFERENCE EXAMPLE 20
3-benzylidene-4,5,6,7-tetrahydro-2-benzofuran-1(3H)-one
[1164] To a solution of the compound prepared in Reference example
19 (419 mg) and benzaldehyde (106 mg) in methylene chloride (4.00
mL) was added triethylamine (0.130 mL) and the mixture was stirred
at room temperature for 3 hours. Water was added to the reaction
mixture, which was extracted with ethyl acetate. The extract was
washed with water and brine sequentially, dried over anhydrous
magnesium sulfate and concentrated. The residue was purified by
column chromatography on silica gel (ethyl acetate:hexane=1:8) to
give the title compound (206 mg) having the following physical
data.
[1165] TLC: Rf 0.83 (hexane:ethyl acetate=2:1).
EXAMPLE 42
4-benzyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[1166] A solution of the compound prepared in Reference example 20
(206 mg) and hydrazine monohydrate (49.0 .mu.L) in ethanol (4.00
mL) was refluxed for 1 hour. Hydrazine monohydrate (49.0 .mu.L) was
added to the reaction mixture, which was refluxed for 1 hour. After
cooling the reaction mixture to room temperature, the deposited
crystal was collected by filtration. It was washed with ethanol and
hexane, and dried under reduced pressure to give the compound of
the present invention (152 mg) having the following physical
data.
[1167] TLC: Rf 0.63 (methylene chloride:methanol=10:1);
[1168] NMR (DMSO-d.sub.6): .delta. 12.61 (s, 1H), 7.32-7.24 (m,
2H), 7.23-7.13 (m, 3H), 3.88 (s, 2H), 2.44-2.25 (m, 4H), 1.65-1.54
(m, 4H).
EXAMPLE 43 TO EXAMPLE 43(6)
[1169] By the same procedure as described in Reference example
20.fwdarw.Example 42 using a corresponding derivative instead of
benzaldehyde, the following compounds of the present invention were
obtained.
EXAMPLE 43
4-(2-phenylethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[1170] TLC: Rf 0.51 (methylene chloride:methanol=10:1);
[1171] NMR (DMSO-d.sub.6): .delta. 12.54 (s, 1H), 7.35-7.15 (m,
5H), 2.90-2.82 (m, 2H), 2.81-2.72 (m, 2H), 2.52-2.42 (m, 2H),
2.41-2.32 (m, 2H), 1.70-1.58 (m, 4H).
EXAMPLE 43(1)
4-(pyridin-3-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[1172] TLC: Rf 0.42 (methylene chloride:methanol=10:1);
[1173] NMR (DMSO-d.sub.6): .delta. 12.59 (s, 1H), 8.45-8.39 (m,
2H), 7.56 (m, 1H), 7.31 (dd, J=7.5, 4.8 Hz, 1H), 3.92 (s, 2H),
2.46-2.33 (m, 4H), 1.72-1.56 (m, 4H).
EXAMPLE 43(2)
4-(pyridin-2-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[1174] TLC: Rf 0.59 (methylene chloride:methanol=10:1);
[1175] NMR (DMSO-d.sub.6): .delta. 12.58 (s, 1H), 8.45 (d, J=4.5
Hz, 1H), 7.71 (t, J=7.8 Hz, 1H), 7.28-7.18 (m, 2H), 4.04 (s, 2H),
2.44-2.32 (m, 4H), 1.68-1.56 (m, 4H).
EXAMPLE 43(3)
4-(5-methylfuran-2-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[1176] TLC: Rf 0.68 (methylene chloride:methanol=10:1);
[1177] NMR (DMSO-d.sub.6): .delta. 12.60 (s, 1H), 5.95 (m, 2H),
3.84 (s, 2H), 2.50-2.35 (m, 4H), 2.18 (s, 3H), 1.70-1.58 (m,
4H).
EXAMPLE 43(4)
4-(2-nitrobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[1178] TLC: Rf 0.59 (methanol:methylene chloride=1:10);
[1179] NMR (DMSO-d.sub.6): .delta. 12.40 (s, 1H), 8.03 (dd, J=7.8,
1.2 Hz, 1H), 7.68 (dt, J=1.2, 7.8 Hz, 1H), 7.53 (m, 1H), 7.46 (d,
J=7.8 Hz, 1H), 4.24 (s, 2H), 2.56-2.46 (m, 2H), 2.44-2.35 (m, 2H),
1.78-1.62 (m, 4H).
EXAMPLE 43(5)
4-(3-nitrobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[1180] NMR (DMSO-d.sub.6): .delta. 12.61 (s, 1H), 8.15-8.06 (m,
2H), 7.68-7.57 (m, 2H), 4.06 (s, 2H), 2.47-2.34 (m, 4H), 1.70-1.56
(m, 4H).
EXAMPLE 43(6)
4-(4-nitrobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[1181] TLC: Rf 0.60 (methanol:methylene chloride=1:10);
[1182] NMR (DMSO-d.sub.6): .delta. 12.65 (s, 1H), 8.16 (dt, J=6.9,
1.8 Hz, 2H), 7.46 (dt, J=6.9, 1.8 Hz, 2H), 4.05 (s, 2H), 2.42-2.33
(m, 4H), 1.70-1.55 (m, 4H).
EXAMPLE 44
4-(2-aminobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[1183] Under an atmosphere of hydrogen, a mixed solution of the
compound prepared in Example 43(4) (145 mg) and 10% palladium on
carbon (30.0 mg) in methanol (15.0 mL) was stirred at room
temperature for 30 minutes. The reaction mixture was filtrated
through Celite. The filtrate was concentrated to give the compound
of the present invention (129 mg) having the following physical
data.
[1184] TLC: Rf 0.42 (methylene chloride:methanol=10:1);
[1185] NMR (DMSO-d.sub.6): .delta. 12.57 (s, 1H), 6.91 (dt, J=1.2,
7.8 Hz, 1H), 6.72 (dd, J=7.8, 1.2 Hz, 1H), 6.61 (dd, J=7.8, 1.2 Hz,
1H), 6.46 (dt, J=1.2, 7.8 Hz, 1H), 4.97 (s, 2H), 3.66 (s, 2H),
2.50-2.30 (m, 4H), 1.70-1.57 (m, 4H).
EXAMPLE 44(1) TO EXAMPLE 44(2)
[1186] By the same procedure as described in Example 44 using the
compound prepared in Example 43(5) or 43(6) instead of the compound
prepared in Example 43(4), the following compounds of the present
invention were obtained.
EXAMPLE 44(1)
4-(3-aminobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
Free Form:
[1187] TLC: Rf 0.38 (methylene chloride:methanol=10:1);
[1188] NMR (DMSO-d.sub.6): .delta. 12.60 (s, 1H), 6.91 (t, J=8.1
Hz, 1H), 6.37 (d, J=8.1 Hz, 1H), 6.31 (s, 1H), 6.29 (d, J=8.1 Hz,
1H), 5.00 (s, 2H), 3.71 (s, 2H), 2.45-2.30 (m, 4H), 1.70-1.50 (m,
4H).
Methanesulfonate:
[1189] TLC: Rf 0.53 (methylene chloride:methanol=10:1);
[1190] NMR (DMSO-d.sub.6): .delta. 12.67 (s, 1H), 9.60 (br, 3H),
7.41 (t, J=7.8 Hz, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.16 (d, J=7.8 Hz,
1H), 7.06 (s, 1H), 3.93 (s, 2H), 2.43-2.28 (m, 4H), 2.33 (s, 3H),
1.67-1.54 (m, 4H).
EXAMPLE 44(2)
4-(4-aminobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[1191] TLC: Rf 0.44 (methylene chloride:methanol=10:1);
[1192] NMR (DMSO-d.sub.6): .delta. 12.55 (s, 1H), 6.78 (d, J=8.1
Hz, 2H), 6.47 (d, J=8.1 Hz, 2H), 4.90 (s, 2H), 3.68 (s, 2H),
2.42-2.25 (m, 4H), 1.70-1.50 (m, 4H).
EXAMPLE 45
4-phenyl-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-1-one
[1193] A solution of
(4aS,7aR)-4-phenyl-2,4a,5,6,7,7a-hexahydro-1H-cyclopenta[d]pyridazin-1-on-
e (210 mg; It was prepared by the same procedure as described in
Example 1 using (1R,2S)-2-benzoylcyclopentanecarboxylic acid
instead of the compound prepared in Reference example 1.) and
thionyl chloride (0.500 mL) in benzene (3.00 mL) was refluxed for
18 hours. After cooling to room temperature, the reaction mixture
was concentrated. The residue was recrystallized from ethyl acetate
to give the compound of the present invention (154 mg) having the
following physical data.
[1194] TLC: Rf 0.21 (methanol:methylene chloride=1:20);
[1195] NMR (DMSO-d.sub.6): .delta. 13.02 (s, 1H), 7.62-7.58 (m,
2H), 7.50-7.42 (m, 3H), 2.99 (t, J=7.5 Hz, 2H), 2.76 (t, J=7.5 Hz,
2H), 2.06-1.96 (m, 2H).
REFERENCE EXAMPLE 21
6-phenyl-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione
[1196] To a solution of 2,3-pyridinedicarboxylic acid anhydride
(19.4 g) in tetrahydrofuran (260 mL) was added aniline (11.8 mL)
and the mixture was refluxed 2 hours. The reaction mixture was
concentrated. Acetic anhydride (65 mL) was added to the reaction
mixture, which was refluxed for 1.5 hours. After cooling in ice
bath, the reaction mixture was poured in ice water (200 mL) and
stirred for 1 hours. The precipitate was collected by filtration.
It was washed with water and then washed with ethanol on heating to
give the title compound (20.9 g) having the following physical
data.
[1197] TLC: Rf 0.31 (hexane:ethyl acetate=1:1);
[1198] NMR (CDCl.sub.3): .delta. 7.48 (m, 5H) 7.70 (dd, J=7.69,
4.94 Hz, 1H) 8.28 (dd, J=7.69, 1.65 Hz, 1H) 9.06 (dd, J=4.94, 1.65
Hz, 1H).
REFERENCE EXAMPLE 22
7-(3-aminophenyl)-7-hydroxy-6-phenyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin--
5-one
[1199] A solution of 3-(bis(trimethylsilyl)amino)phenylmagnesium
chloride in tetrahydrofuran (5.50 mL, 1.0M) was added dropwise to a
suspension of the compound prepared in Reference example 21 (1.12
g) in tetrahydrofuran (20 mL) in ice bath and the mixture was
stirred for 1 hour. 1N hydrochloric acid (10 mL) was added dropwise
to the reaction mixture, which was stirred for 30 minutes. A
saturated aqueous sodium hydrogen carbonate solution (10 mL) was
added to the reaction mixture, which was extracted with ethyl
acetate. The extract was washed with brine, dried over anhydrous
sodium sulfate and concentrated. The residue was washed with ethyl
acetate on heating to give the title compound (1.35 g) having the
following physical data.
[1200] TLC: Rf 0.52 (methylene chloride:methanol=9:1);
[1201] NMR (DMSO-d.sub.6): .delta. 5.02 (s, 2H) 6.36 (m, 1H) 6.47
(m, 1H) 6.62 (t, J=1.92 Hz, 1H) 6.86 (t, J=7.83 Hz, 1H) 7.14 (m,
1H) 7.28 (m, 2H) 7.54 (m, 4H) 8.20 (dd, J=7.69, 1.65 Hz, 1H) 8.70
(dd, J=4.94, 1.65 Hz, 1H).
REFERENCE EXAMPLE 23
2-(3-aminobenzoyl)nicotinic acid
[1202] To the compound prepared in Reference example 22 (3.17 g)
was added 6N hydrochloric acid (20 mL) and the mixture was refluxed
overnight. The reaction mixture was cooled in ice bath, adjusted to
pH 5 with 5N sodium hydroxide solution (24 mL) and concentrated.
The residue was azeotroped with ethanol and suspended in ethanol
(50 mL) with refluxing. Unnecessary sodium chloride was separated
by filtration. The filtrate was concentrated. The residue was
washed with isopropanol (15 mL) on heating to give the title
compound (2.13 g) having the following physical data.
[1203] TLC: Rf 0.49 (methylene chloride:methanol:acetic
acid=8:1:1);
[1204] NMR (DMSO-d.sub.6): .delta. 6.74 (m, 2H) 6.85 (t, J=2.00 Hz,
1H) 7.09 (t, J=7.87 Hz, 1H) 7.63 (dd, J=7.97, 4.76 Hz, 1H) 8.33
(dd, J=7.97, 1.55 Hz, 1H) 8.77 (dd, J=4.76, 1.55 Hz, 1H).
REFERENCE EXAMPLE 24
8-(3-aminophenyl)pyrido[2,3-d]pyridazin-5(6H)-one
[1205] To a suspension of the compound prepared in Reference
example 23 (1.94 g) in ethanol (40 mL) was added hydrazine
monohydrate (400 mg) and the mixture was refluxed overnight. After
cooling the reaction mixture to room temperature, the precipitate
was collected by filtration. It was washed with ethanol to give the
title compound (1.70 g) having the following physical data.
[1206] TLC: Rf 0.54 (methylene chloride:methanol=9:1);
[1207] NMR (DMSO-d.sub.6): .delta. 5.14 (s, 2H) 6.64 (m, 1H) 6.94
(m, 1H) 6.99 (m, 1H) 7.09 (t, J=7.69 Hz, 1H) 7.84 (dd, J=8.06, 4.39
Hz, 1H) 8.63 (dd, J=8.06, 1.83 Hz, 1H) 9.12 (dd, J=4.39, 1.83 Hz,
1H) 13.00 (s, 1H).
EXAMPLE 46
8-(3-aminophenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one
[1208] To a suspension of the compound prepared in Reference
example 24 (1.67 g) and platinum oxide (83 mg) in dimethylformamide
(35 mL) was added 6N hydrochloric acid (2.5 mL) and the mixture was
stirred 8 hours under an atmosphere of hydrogen. The reaction
mixture was filtrated through Celite. The filtrate was
concentrated. A saturated aqueous sodium hydrogen carbonate
solution was added to the residue, which was extracted with
tetrahydrofuran three times. The combined organic layer was washed
with brine, dried over anhydrous sodium sulfate and concentrated.
The residue was dissolved in methanol (35 mL) on heating. Activated
carbon (340 mg) was added to the mixture, which was stirred for 15
minutes. Activated carbon was filtrated through Celite. The
filtrate was concentrated. The residue was washed with isopropanol
on heating to give the compound of the present invention (1.25 g;
free form) having the following physical data. The obtained
compound (242 mg) was suspended in methanol (4 mL). A solution of
methanesulfonic acid (96 mg) in methanol (1 mL) was added to the
mixture, which was stirred. The deposited crystal was collected by
filtration. It was washed with methanol to give the compound of the
present invention (258 mg; methanesulfonate) having the following
physical data.
Free Form:
[1209] TLC: Rf 0.40 (methylene chloride:methanol=9:1);
[1210] NMR (DMSO-d.sub.6): .delta. 12.00 (s, 1H), 7.07 (m, 1H),
6.64-6.60 (m, 2H), 6.53 (d, J=7.3 Hz, 1H), 5.60 (s, 1H), 5.21 (s,
2H), 3.15 (m, 2H), 2.38 (t, J=6.2 Hz, 2H), 1.71 (m, 2H).
Methanesulfonate:
[1211] TLC: Rf 0.40 (methylene chloride:methanol=9:1);
[1212] NMR (DMSO-d.sub.6): .delta. 12.28 (s, 1H), 7.53 (m, 1H),
7.40-7.30 (m, 3H) 3.13 (m, 2H), 2.40 (t, J=6.0 Hz, 2H), 2.35 (s,
3H), 1.73 (m, 2H).
EXAMPLE 47 TO EXAMPLE 47(13)
[1213] By the same procedure as described in Reference example
21.fwdarw.Reference example 22.fwdarw.Reference example
23.fwdarw.Reference example 24.fwdarw.Example 46, if necessary, by
converting to corresponding salts by conventional method, using
furo[3,4-b]pyridine-5,7-dione or a corresponding derivative, and a
corresponding derivative instead of
3-(bis(trimethylsilyl)amino)phenylmagnesium chloride, the following
compounds of the present invention were obtained.
EXAMPLE 47
8-(3-(N,N-dimethylamino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5-
(1H)-one methanesulfonate
[1214] TLC: Rf 0.56 (methylene chloride:methanol=9:1);
[1215] NMR (DMSO-d.sub.6): .delta. 12.29 (s, 1H), 7.39 (t, J=8.1
Hz, 1H), 7.22-6.78 (m, 3H), 3.15 (m, 2H), 3.01 (s, 6H), 2.41 (t,
J=6.0 Hz, 2H), 2.33 (s, 3H), 1.73 (m, 2H).
EXAMPLE 47(1)
8-benzyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one
methanesulfonate
[1216] TLC: Rf 0.51 (methanol:methylene chloride=1:10);
[1217] NMR (DMSO-d.sub.6): .delta. 12.13 (s, 1H), 7.31-7.16 (m,
5H), 6.22 (brs, 2H), 3.83 (s, 2H), 3.19 (t, J=6.0 Hz, 2H), 2.36 (t,
J=6.0 Hz, 2H), 2.32 (s, 3H), 1.73-1.65 (m, 2H).
EXAMPLE 47(2)
8-(3-methoxyphenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one
methanesulfonate
[1218] TLC: Rf 0.50 (methanol:methylene chloride=1:10);
[1219] NMR (DMSO-d.sub.6): .delta. 12.27 (s, 1H), 7.38 (t, J=7.8
Hz, 1H), 7.03-6.96 (m, 3H), 6.21 (m, 2H), 3.78 (s, 3H), 3.16-3.13
(m, 2H), 2.41 (t, J=6.0 Hz, 2H), 2.32 (s, 3H), 1.76-1.71 (m,
2H).
EXAMPLE 47(3)
8-(4-aminophenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one
methanesulfonate
[1220] TLC: Rf 0.25 (methylene chloride:methanol=19:1);
[1221] NMR (DMSO-d.sub.6): .delta. 12.2 (brs, 1H), 7.42 (d, J=8.1
Hz, 2H), 7.16 (d, J=8.1 Hz, 2H), 3.14 (m, 2H), 2.40 (t, J=6.3 Hz,
2H), 2.33 (s, 3H), 1.73 (m, 2H).
EXAMPLE 47(4)
8-(3-(morpholin-4-ylmethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazi-
n-5(1H)-one methanesulfonate
[1222] TLC: Rf 0.49 (methylene chloride:methanol=9:1);
[1223] NMR (DMSO-d.sub.6): .delta. 12.21 (s, 1H), 9.79 (br-s, 1H),
7.80-7.37 (m, 4H), 5.83 (s, 1H), 4.40 (d, J=4.0 Hz, 2H), 3.96 (d,
J=12.1 Hz, 2H), 3.62 (t, J=11.7 Hz, 2H), 3.30 (d, J=12.1 Hz, 2H),
3.20-3.06 (m, 4H), 2.40 (t, J=6.0 Hz, 2H), 2.30 (s, 3H), 1.73 (m,
2H).
EXAMPLE 47(5)
8-(4-(N,N-dimethylamino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5-
(1H)-one methanesulfonate
[1224] TLC: Rf 0.50 (methylene chloride:methanol=9:1);
[1225] NMR (DMSO-d.sub.6): .delta. 12.38 (s, 1H), 7.34 (d, J=8.1
Hz, 2H), 6.95 (m, 2H), 3.15 (m, 2H), 2.99 (s, 6H), 2.42 (m, 2H),
2.34 (s, 3H), 1.73 (m, 2H).
EXAMPLE 47(6)
8-(4-(morpholin-4-ylmethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazi-
n-5(1H)-one dimethanesulfonate
[1226] TLC: Rf 0.51 (methylene chloride:methanol=10:1);
[1227] NMR (CD.sub.3OD): .delta. 7.72 (d, J=8.1 Hz, 2H), 7.66 (d,
J=8.1 Hz, 2H), 4.46 (s, 2H), 4.11-4.02 (m, 2H), 3.80 (t, J=12.6 Hz,
2H), 3.42 (d, J=12.6 Hz, 2H), 3.40-3.18 (m, 4H), 2.69 (s, 6H),
2.72-2.64 (m, 2H), 2.00-1.89 (m, 2H).
EXAMPLE 47(7)
8-(2-(morpholin-4-ylmethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazi-
n-5(1H)-one methanesulfonate
[1228] TLC: Rf 0.54 (methylene chloride:methanol=10:1);
[1229] NMR (DMSO-d.sub.6): .delta. 12.32 (s, 1H), 9.45 (br, 1H),
7.76 (m, 1H), 7.64-7.53 (m, 2H), 7.43 (m, 1H), 5.64 (br, 1H), 4.25
(s, 2H), 3.87 (d, J=12.0 Hz, 2H), 3.67 (t, J=12.0 Hz, 2H), 3.25 (d,
J=12.0 Hz, 2H), 3.16-3.00 (m, 4H), 2.42 (t, J=6.0 Hz, 2H), 2.33 (s,
3H), 1.79-1.66 (m, 2H).
EXAMPLE 47(8)
8-(3-(4-ethylpiperazin-1-ylmethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]p-
yridazin-5(1H)-one trihydrochloride
[1230] TLC: Rf 0.42 (methylene
chloride:methanol:water=8:2:0.2);
[1231] NMR (DMSO-d.sub.6): .delta. 12.40 (br, 1H), 11.99 (br, 1H),
7.77-7.69 (m, 2H), 7.62-7.48 (m, 2H), 6.30-5.30 (br, 3H), 4.45 (s,
2H), 3.80-3.50 (m, 4H), 3.70-3.40 (m, 4H), 3.30-3.00 (m, 4H), 2.42
(t, J=6.3 Hz, 2H), 1.80-1.66 (m, 2H), 1.24 (t, J=7.2 Hz, 3H).
EXAMPLE 47(9)
8-(3-(N,N-dimethylaminomethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyrid-
azin-5(1H)-one methanesulfonate
[1232] TLC: Rf 0.27 (methylene
chloride:methanol:water=8:2:0.2);
[1233] NMR (DMSO-d.sub.6): .delta. 12.21 (s, 1H), 9.59 (br, 1H),
7.62-7.52 (m, 4H), 5.82 (s, 1H), 4.35-4.31 (m, 2H), 3.20-3.12 (m,
2H), 2.76 (s, 3H), 2.75 (s, 3H), 2.41 (t, J=6.3 Hz, 2H), 2.30 (s,
3H), 1.81-1.68 (m, 2H).
EXAMPLE 47(10)
8-(4-(N,N-dimethylaminomethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyrid-
azin-5(1H)-one methanesulfonate
[1234] TLC: Rf 0.82 (methylene chloride:methanol:ammonia
water=8:2:0.2);
[1235] NMR (DMSO-d.sub.6): .delta. 12.19 (s, 1H), 9.68 (br, 1H),
7.57 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 5.76 (s, 1H), 4.34
(s, 2H), 3.18-3.10 (m, 2H), 2.76 (s, 6H), 2.40 (t, J=6.0 Hz, 2H),
2.31 (s, 3H), 1.80-1.68 (m, 2H).
EXAMPLE 47(11)
8-(4-(N,N-diethylaminomethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyrida-
zin-5(1H)-one methanesulfonate
[1236] TLC: Rf 0.38 (methylene chloride:methanol:ammonia
water=8:2:0.2);
[1237] NMR (DMSO-d.sub.6): .delta. 12.20 (s, 1H), 9.34 (br, 1H),
7.60 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 5.77 (s, 1H), 4.36
(d, J=4.8 Hz, 2H), 3.12-3.02 (m, 6H), 2.40 (t, J=6.0 Hz, 2H), 2.30
(s, 3H), 1.80-1.68 (m, 2H), 1.24 (t, J=7.2 Hz, 6H).
EXAMPLE 47(12)
4-(4-(N,N-dimethylaminomethyl)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-o-
ne methanesulfonate
[1238] TLC: Rf 0.49 (methylene
chloride:methanol:water=8:2:0.2);
[1239] NMR (DMSO-d.sub.6): .delta. 12.95 (s, 1H), 9.64 (br, 1H),
7.60-7.52 (m, 4H), 4.33 (s, 2H), 2.76 (s, 6H), 2.50-2.40 (m, 2H),
2.40-2.32 (m, 2H), 2.30 (s, 3H), 1.76-1.66 (m, 2H), 1.66-1.55 (m,
2H).
EXAMPLE 47(13)
8-(4-(2-(N,N-dimethylamino)ethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]py-
ridazin-5(1H)-one methanesulfonate
[1240] TLC: Rf 0.50 (methylene chloride:methanol:ammonia
water=8:2:0.2);
[1241] NMR (DMSO-d.sub.6): .delta. 12.12 (s, 1H), 9.41 (br, 1H),
7.42 (d, J=8.1 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 5.70 (s, 1H),
3.35-3.25 (m, 2H), 3.18-3.09 (m, 2H), 3.05-2.96 (m, 2H), 2.83 (s,
6H), 2.39 (t, J=6.3 Hz, 2H), 2.30 (s, 3H), 1.80-1.68 (m, 2H).
REFERENCE EXAMPLE 25
2-(3-aminobenzoyl)nicotinic acid methyl ester
[1242] After cooling methanol (5 mL) to -15.degree. C., thionyl
chloride (1.3 mL) was added dropwise thereto and the solution was
stirred for 15 minutes. To the solution was added the compound
prepared in Reference example 23 (1.21 g). The solution was allowed
to return to room temperature and then refluxed overnight. The
reaction mixture was concentrated. To the residue were added a
saturated aqueous sodium hydrogen carbonate solution and ethyl
acetate. The organic layer was washed with brine, dried over
anhydrous sodium sulfate and concentrated. The residue was
recrystallized from isopropanol (5 mL) to give the title compound
(815 mg) having the following physical data.
[1243] TLC: Rf 0.37 (hexane:ethyl acetate=1:3);
[1244] NMR (DMSO-d.sub.6): .delta. 3.69 (s, 3H) 5.36 (s, 2H) 6.79
(m, 2H) 6.89 (m, 1H) 7.12 (t, J=7.83 Hz, 1H) 7.70 (dd, J=8.04, 4.81
Hz, 1H) 8.39 (dd, J=8.04, 1.65 Hz, 1H) 8.83 (dd, J=4.74, 1.65 Hz,
1H).
REFERENCE EXAMPLE 26
2-(3-(trifluoroacetyl)aminobenzoyl)nicotinic acid methyl ester
[1245] To a solution of the compound prepared in Reference example
25 (800 mg) in methylene chloride (15 mL) were added pyridine (505
.mu.L) and trifluoroacetic acid anhydride (529 .mu.L) sequentially
in ice bath, and the mixture was stirred for 30 minutes. The
reaction mixture was diluted with methylene chloride and washed
with 1N hydrochloric acid and water sequentially. The organic layer
was dried over anhydrous sodium sulfate and concentrated. The
residue was purified by column chromatography on silica gel
(hexane:ethyl acetate=1:1) to give the title compound (1.10 g)
having the following physical data.
[1246] TLC: Rf 0.48 (hexane:ethyl acetate=1:1);
[1247] NMR (CDCl.sub.3): .delta. 3.79 (s, 3H) 7.49 (t, J=7.97 Hz,
1H) 7.56 (dd, J=8.11, 4.81 Hz, 1H) 7.63 (m, 1H) 7.99 (m, 2H) 8.28
(s, 1H) 8.39 (dd, J=8.11, 1.65 Hz, 1H) 8.82 (dd, J=4.81, 1.65 Hz,
1H).
REFERENCE EXAMPLE 27
2-(3-(N-methyl-N-(trifluoroacetyl)amino)benzoyl)nicotinic acid
methyl ester
[1248] To a solution of the compound prepared in Reference example
26 (1.06 g) in dimethylformamide (12 mL) was added sodium hydride
(127 mg) in ice bath and the mixture was stirred for 30 minutes.
Methyl iodide (224 .mu.L) was added to the reaction mixture, which
was stirred at 0.degree. C. for 1 hour and subsequently at room
temperature for 6 hours. The reaction mixture was poured in ice
water and extracted with a mixed solvent (ethyl acetate:hexane=1:1)
twice. The combined organic layer was washed with water and brine
sequentially, dried over anhydrous sodium sulfate and concentrated.
The residue was recrystallized from a mixed solvent
(isopropanol:hexane=1:1) to give the title compound (892 mg) having
the following physical data.
[1249] TLC: Rf 0.31 (hexane:ethyl acetate=1:1);
[1250] NMR (CDCl.sub.3): .delta. 3.37 (s, 3H) 3.76 (s, 3H) 7.55 (m,
3H) 7.71 (s, 1H) 7.87 (d, J=7.69 Hz, 1H) 8.40 (dd, J=7.97, 1.65 Hz,
1H) 8.83 (dd, J=4.94, 1.65 Hz, 1H).
REFERENCE EXAMPLE 28
8-(3-(N-methylamino)phenyl)pyrido[2,3-d]pyridazin-5(6H)-one
[1251] To a solution of the compound prepared in Reference example
27 (880 mg) in ethanol (12 mL) was added a solution of hydrazine
monohydrate (240 mg) in ethanol (3 mL) and the mixture was refluxed
overnight. 1N sodium hydroxide solution (5 mL) was added to the
reaction mixture, which was refluxed for 1 hour. The reaction
mixture was cooled in ice bath and 1N hydrochloric acid (5 mL) was
added thereto. The precipitate was collected by filtration. It was
washed with water and then washed with ethanol on heating to give
the title compound (581 mg) having the following physical data.
[1252] TLC: Rf 0.39 (methylene chloride:methanol=19:1);
[1253] NMR (DMSO-d.sub.6): .delta. 2.69 (d, J=5.13 Hz, 3H) 5.73 (q,
J=5.13 Hz, 1H) 6.62 (m, 1H) 6.97 (m, 2H) 7.18 (t, J=7.69 Hz, 1H)
7.85 (dd, J=8.06, 4.39 Hz, 1H) 8.64 (dd, J=8.06, 1.83 Hz, 1H) 9.13
(dd, J=4.39, 1.83 Hz, 1H) 13.02 (s, 1H).
EXAMPLE 48
8-(3-(N-methylamino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-
-one methanesulfonate
[1254] By the same procedure as described in Example 46 using the
compound prepared in Reference example 28 instead of the compound
prepared in Reference example 24, the compounds of the present
invention having the following physical data was obtained.
[1255] TLC: Rf 0.49 (methylene chloride:methanol=9:1);
[1256] NMR (DMSO-d.sub.6): .delta. 12.31 (s, 1H), 7.36 (t, J=7.9
Hz, 1H), 7.18-6.85 (m, 3H), 3.16 (m, 2H), 2.83 (s, 3H), 2.41 (t,
J=6.0 Hz, 2H), 2.34 (s, 3H), 1.73 (m, 2H).
EXAMPLE 49
8-(4-(N-methylamino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-
-one methanesulfonate
[1257] By the same procedure as described in Reference example
25.fwdarw.Reference example 26.fwdarw.Reference example
27.fwdarw.Reference example 28.fwdarw.Example 46 using a
corresponding derivative instead of the compound prepared in
Reference example 23, the compounds of the present invention having
the following physical data was obtained.
[1258] TLC: Rf 0.39 (methanol:methylene chloride=1:9);
[1259] NMR (DMSO-d.sub.6): .delta. 12.26 (brs, 1H), 7.27 (d, J=7.8
Hz, 2H), 6.79 (d, J=7.8 Hz, 2H), 5.96 (brs, 3H), 3.16 (m, 2H), 2.76
(s, 3H), 2.41 (m, 2H), 2.32 (s, 3H), 1.72 (m, 2H).
EXAMPLE 50 TO EXAMPLE 50(4)
[1260] By the same procedure as described in Reference example
20.fwdarw.Example 42 using a corresponding derivative instead of
benzaldehyde, the compounds of the present invention having the
following physical data was obtained.
EXAMPLE 50
4-(2-phenoxyethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[1261] TLC: Rf 0.41 (methylene chloride:methanol=19:1);
[1262] NMR (DMSO-d.sub.6): .delta. 12.6 (s, 1H), 7.30-7.22 (m, 2H),
6.95-6.90 (m, 3H), 4.26 (t, J=6.9 Hz, 2H), 2.97 (t, J=6.9 Hz, 2H),
2.60-2.35 (m, 4H), 1.66 (m, 4H).
EXAMPLE 50(1)
4-(3-phenoxypropyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[1263] TLC: Rf 0.40 (methylene chloride:methanol=19:1);
[1264] NMR (DMSO-d.sub.6): .delta. 12.52 (s, 1H), 7.26 (m, 2H),
6.90 (m, 3H), 4.01 (t, J=6.3 Hz, 2H), 2.65 (t, J=7.5 Hz, 2H),
2.55-2.30 (m, 4H), 2.01 (m, 2H), 1.64 (m, 4H).
EXAMPLE 50(2)
4-(4-(3-(N,N-dimethylamino)propoxy)benzyl)-5,6,7,8-tetrahydrophthalazin-1(-
2H)-one hydrochloride
[1265] TLC: Rf 0.37 (methylene chloride:methanol:ammonia
water=8:2:0.2);
[1266] NMR (DMSO-d.sub.6): .delta. 12.60 (s, 1H), 9.32 (brs, 1H),
7.08 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 3.99 (t, J=6.0 Hz,
2H), 3.81 (s, 2H), 3.24-3.16 (m, 2H), 2.79 (s, 6H), 2.40-2.28 (m,
4H), 2.14-2.02 (m, 2H), 1.64-1.54 (m, 4H).
EXAMPLE 50(3)
4-(2-benzyloxyethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[1267] TLC: Rf 0.54 (methylene chloride:methanol=19:1);
[1268] NMR (DMSO-d.sub.6): .delta. 12.5 (s, 1H), 7.35-7.22 (m, 5H),
4.47 (s, 2H), 3.69 (t, J=7.2 Hz, 2H), 2.78 (t, J=7.2 Hz, 2H),
2.50-2.36 (m, 4H), 1.63 (m, 4H).
EXAMPLE 50(4)
4-(quinolin-3-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[1269] TLC: Rf 0.53 (methylene chloride:methanol=10:1);
[1270] NMR (DMSO-d.sub.6): .delta. 12.60 (s, 1H), 8.79 (d, J=1.8
Hz, 1H), 8.08 (d, J=1.8 Hz, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.92 (dd,
J=8.1, 1.5 Hz, 1H), 7.70 (ddd, J=8.1, 6.9, 1.5 Hz, 1H), 7.57 (ddd,
J=8.1, 6.9, 1.5 Hz, 1H), 4.12 (s, 2H), 2.54-2.40 (m, 2H), 2.46-2.30
(m, 2H), 1.70-1.55 (m, 4H).
EXAMPLE 51 TO EXAMPLE 51(3)
[1271] By the same procedure as described in Example 27, if
necessary, by converting to corresponding salts by conventional
method, using a corresponding derivative instead of the compound
prepared in Reference example 13 and a corresponding derivative
instead of benzylamine, the following compounds of the present
invention were obtained.
EXAMPLE 51
4-(5-(piperidin-1-yl)pentyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
hydrochloride
[1272] TLC: Rf 0.83 (methylene chloride:methanol:ammonia
water=8:2:0.2);
[1273] NMR (DMSO-d.sub.6): .delta. 12.51 (s, 1H), 9.96 (br, 1H),
3.46-3.28 (m, 2H), 3.02-2.84 (m, 2H), 2.95-2.65 (m, 2H), 2.54-2.44
(m, 2H), 2.42-2.32 (m, 2H), 1.84-1.54 (m, 14H), 1.44-1.26 (m,
4H).
EXAMPLE 51(1)
8-(2-(4-(2-(morpholin-4-yl)ethyl)piperazin-1-yl)ethyl)-2,3,4,6-tetrahydrop-
yrido[2,3,d]pyridazin-5(1H)-one
[1274] TLC: Rf 0.15 (methylene chloride:methanol:saturated aqueous
ammonia=4:1:0.5%);
[1275] NMR (CD.sub.3OD): .delta. 3.69 (m, 4H), 3.33 (m, 2H),
2.78-2.42 (m, 22H), 1.85 (m, 2H).
EXAMPLE 51(2)
8-(2-(4-benzyloxycarbonyl-1,4-diazepan-1-yl)ethyl)-2,3,4,6-tetrahydropyrid-
o[2,3,d]pyridazin-5(1H)-one methanesulfonate
[1276] TLC: Rf 0.19 (methylene chloride:methanol=19:1);
[1277] NMR (DMSO-d.sub.6): .delta. 11.97 (s, 1H), 9.39 (s, 1H),
7.41-7.30 (m, 5H), 6.38 (brs, 1H), 5.11 (s, 2H), 4.32 (brs, 2H),
3.87 (m, 1H), 3.70-3.40 (m, 7H), 3.30-3.15 (m, 2H), 2.84 (t, J=7.5
Hz, 2H), 2.35 (t, J=6.3 Hz, 2H), 2.31 (s, 3H), 2.07 (m, 2H), 1.72
(m, 2H).
EXAMPLE 51(3)
4-(4-(morpholin-4-yl)butyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
Hydrochloride:
[1278] TLC: Rf 0.29 (methylene chloride:methanol=10:1);
[1279] NMR (300 MHz, CD.sub.3OD) 3.10-3.00 (m, 4H), 2.37-2.26 (m,
4H), 2.25-2.16 (m, 2H), 1.85 (t, J=6.9 Hz, 2H), 1.83-1.75 (m, 2H),
1.75-1.67 (m, 2H), 1.08-0.88 (m, 8H).
Methanesulfonate:
[1280] TLC: Rf 0.25 (methylene chloride:methanol=10:1);
[1281] NMR (DMSO-d.sub.6): .delta. 12.55 (s, 1H), 9.52 (br, 1H),
4.01-3.92 (m, 2H), 3.64 (t, J=11.4 Hz, 2H), 3.45-3.36 (m, 2H),
3.17-2.95 (m, 4H), 2.58-2.43 (m, 4H), 2.43-2.34 (m, 2H), 2.31 (s,
3H), 1.77-1.54 (m, 8H).
EXAMPLE 52 TO EXAMPLE 52(3)
[1282] By the same procedure as described in Example 24, if
necessary, by converting to corresponding salts by conventional
method, using a corresponding ester derivative instead of the
compound prepared in Example 15 and a corresponding derivative
instead of 2-aminoethanol, the following compounds of the present
invention were obtained.
EXAMPLE 52
8-(N-(4-hydroxybutyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3,d]pyrid-
azin-5(1H)-one
[1283] TLC: Rf 0.54 (methanol:methylene chloride=1:4);
[1284] NMR (DMSO-d.sub.6): .delta. 11.84 (s, 1H), 8.06 (t, J=5.7
Hz, 1H), 6.42 (s, 1H), 4.37 (t, J=4.8 Hz, 1H), 3.35 (m, 4H), 3.18
(m, 2H), 3.03 (td, J=6.6, 5.7 Hz, 2H), 2.32 (t, J=6.3 Hz, 2H), 1.69
(m, 2H), 1.41 (m, 4H).
EXAMPLE 52(1)
8-(N-(4-(morpholin-4-yl)butyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,-
3,d]pyridazin-5(1H)-one
[1285] TLC: Rf 0.22 (methanol:methylene chloride=1:4);
[1286] NMR (DMSO-d.sub.6): .delta. 11.84 (s, 1H), 8.06 (t, J=5.4
Hz, 1H), 6.43 (s, 1H), 3.55-3.52 (m, 4H), 3.32-3.31 (m, 2H), 3.18
(brs, 2H), 3.04 (m, 2H), 2.34-2.19 (m, 8H), 1.71-1.68 (m, 2H),
1.40-1.36 (m, 4H).
EXAMPLE 52(2)
8-(N-(2-(azepan-1-yl)ethyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3,d-
]pyridazin-5(1H)-one methanesulfonate
[1287] TLC: Rf 0.39 (methanol:methylene chloride:saturated aqueous
ammonia=2:8:0.1);
[1288] NMR (DMSO-d.sub.6): .delta. 11.90 (s, 1H), 9.13 (brs, 1H),
8.30 (t, J=5.4 Hz, 1H), 6.30 (brs, 1H), 3.45-3.35 (m, 6H),
3.19-3.08 (m, 6H), 2.40-2.29 (m, 2H), 2.33 (s, 3H), 1.80-1.52 (m,
10H).
EXAMPLE 52(3)
4-(N-(6-hydroxyhexyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-o-
ne
[1289] TLC: Rf 0.23 (methanol:methylene chloride=1:10);
[1290] NMR (DMSO-d.sub.6): .delta. 12.56 (s, 1H), 7.99 (t, J=5.7
Hz, 1H), 4.32 (t, J=5.1 Hz, 1H), 3.38 (s, 2H), 3.37-3.33 (m, 2H),
3.05-2.99 (m, 2H), 2.41-2.36 (m, 4H), 1.63 (m, 4H), 1.40-1.23 (m,
8H).
EXAMPLE 53 TO EXAMPLE 53(1)
[1291] By the same procedure as described in Example 34 using a
corresponding derivative instead of the compound prepared in
Example 33, the following compounds of the present invention were
obtained.
EXAMPLE 53
4-(N-(5-bromopentyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-on-
e
[1292] TLC: Rf 0.53 (methylene chloride:methanol=10:1);
[1293] NMR (DMSO-d.sub.6): .delta. 12.57 (s, 1H), 8.02 (t, J=5.1
Hz, 1H), 3.51 (t, J=6.3 Hz, 2H), 3.39 (s, 2H), 3.04 (q, J=6.3 Hz,
2H), 2.46-2.33 (m, 4H), 1.78 (quin, J=6.3 Hz, 2H), 1.70-1.58 (m,
4H), 1.48-1.30 (m, 4H).
EXAMPLE 53(1)
4-(N-(6-bromohexyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
[1294] TLC: Rf 0.37 (methanol:methylene chloride=1:10);
[1295] NMR (DMSO-d.sub.6): .delta. 12.57 (s, 1H), 7.99 (t, J=5.4
Hz, 1H), 3.51 (t, J=6.6 Hz, 2H), 3.38 (s, 2H), 3.06-3.00 (m, 2H),
2.41-2.36 (m, 4H), 1.82-1.75 (m, 2H), 1.64 (m, 4H), 1.41-1.16 (m,
6H).
EXAMPLE 54 TO EXAMPLE 54(2)
[1296] By the same procedure as described in Example 28, if
necessary, by converting to corresponding salts by conventional
method, using the compound prepared in Example 53, 23(23) or 53(1)
instead of the compound prepared in Example 25(1), the following
compounds of the present invention were obtained.
EXAMPLE 54
4-(N-(5-(morpholin-4-yl)pentyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalaz-
in-1(2H)-one
[1297] TLC: Rf 0.57 (methylene
chloride:methanol:water=8:2:0.2);
[1298] NMR (DMSO-d.sub.6): .delta. 12.57 (s, 1H), 7.99 (t, J=5.7
Hz, 1H), 3.54 (t, J=4.8 Hz, 4H), 3.38 (s, 2H), 3.02 (q, J=6.9 Hz,
2H), 2.46-2.33 (m, 4H), 2.33-2.25 (m, 4H), 2.21 (t, J=6.9 Hz, 2H),
1.68-1.58 (m, 4H), 1.39 (quin, J=6.9 Hz, 4H), 1.31-1.19 (m,
2H).
EXAMPLE 54(1)
4-(N-(2-(azocan-1-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1-
(2H)-one methanesulfonate
[1299] TLC: Rf 0.67 (methanol:methylene chloride:28% ammonia
water=2:8:0.1);
[1300] NMR (DMSO-d.sub.6): .delta. 12.63 (s, 1H), 9.37 (brs, 1H),
8.36 (t, J=5.7 Hz, 1H), 3.46 (s, 2H), 3.43-3.34 (m, 4H), 3.16-3.12
(m, 4H), 2.42-2.37 (m, 4H), 2.29 (s, 3H), 1.84-1.49 (m, 14H).
EXAMPLE 54(2)
4-(N-(6-(morpholin-4-yl)hexyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazi-
n-1(2H)-one methanesulfonate
[1301] TLC: Rf 0.22 (methanol:methylene chloride=1:9);
[1302] NMR (DMSO-d.sub.6): .delta. 12.58 (s, 1H), 9.48 (brs, 1H),
8.03 (t, J=5.4 Hz, 1H), 3.98-3.94 (m, 2H), 3.67-3.39 (m, 6H),
3.07-3.01 (m, 6H), 2.48-2.36 (m, 7H), 1.63-1.27 (m, 12H).
EXAMPLE 55 TO EXAMPLE 55(2)
[1303] By the same procedure as described in Reference example
22.fwdarw.Reference example 24.fwdarw.Example 20.fwdarw.Example 46,
if necessary, by converting to corresponding salts by conventional
method, using a corresponding derivative instead of
4-(bis(trimethylsilyl)amino)phenylmagnesium bromide, the following
compounds of the present invention were obtained.
EXAMPLE 55
8-(3,4-dihydroxyphenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one
[1304] TLC: Rf 0.59 (methylene
chloride:methanol:water=8:2:0.2);
[1305] NMR (DMSO-d.sub.6): .delta. 11.94 (s, 1H), 9.14 (br, 2H),
6.80 (s, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.68 (m, 1H), 5.65 (s, 1H),
3.16-3.08 (m, 2H), 2.37 (t, J=6.0 Hz, 2H), 1.77-1.65 (m, 2H).
EXAMPLE 55(1)
8-(4-hydroxyphenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one
methanesulfonate
[1306] TLC: Rf 0.29 (methanol:methylene chloride=1:10);
[1307] NMR (DMSO-d.sub.6): .delta. 12.40 (brs, 1H), 9.20 (brs, 1H),
7.26 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 3.16 (t, J=5.1 Hz,
2H), 2.42 (t, J=6.0 Hz, 2H), 2.34 (s, 3H), 1.71 (m, 2H).
EXAMPLE 55(2)
8-(2-hydroxyphenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one
[1308] TLC: Rf 0.4 (methylene chloride:methanol=10:1);
[1309] NMR (DMSO-d.sub.6): .delta. 12.58 (br, 1H), 9.58 (br, 1H),
7.29 (t, J=7.5 Hz, 1H), 7.12 (d, J=7.5 Hz, 1H), 6.93 (d, J=7.5 Hz,
1H), 6.88 (t, J=7.5 Hz, 1H), 5.96 (br, 1H), 3.23-3.12 (m, 2H),
2.54-2.4- (m, 2H), 1.82-1.64 (m, 2H).
EXAMPLE 56 TO EXAMPLE 56(6)
[1310] By the same procedure as described in Example 46, if
necessary, by converting to corresponding salts by conventional
method, using the compound prepared in Example 43(1), Example
43(2), 23(17), 23(22), 24(11) or 24(16), or
4-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
instead of the compound prepared in Reference example 24 and, the
following compounds of the present invention were obtained.
EXAMPLE 56
4-(piperidin-3-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
acetate
[1311] TLC: Rf 0.21 (methylene chloride:methanol:ammonia
water=8:2:0.2);
[1312] NMR (DMSO-d.sub.6): .delta. 12.49 (br, 1H), 2.97-2.84 (m,
2H), 2.53-2.42 (m, 5H), 2.41-2.31 (m, 4H), 2.26 (m, 1H), 1.84 (m,
1H), 1.82 (s, 3H), 1.77-1.53 (m, 6H), 1.40 (m, 1H), 1.09 (m,
1H).
EXAMPLE 56(1)
4-(piperidin-4-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
acetate
[1313] TLC: Rf 0.16 (methylene chloride:methanol:ammonia
water=8:2:0.2);
[1314] NMR (DMSO-d): .delta. 12.51 (br, 1H), 2.90 (m, 1H), 2.78 (m,
1H), 2.58-2.40 (m, 7H), 2.40-2.32 (m, 2H), 1.86 (s, 3H), 1.74-1.45
(m, 7H), 1.38-1.20 (m, 2H), 1.10 (m, 1H).
EXAMPLE 56(2)
4-(piperidin-2-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
acetate
[1315] TLC: Rf 0.58 (methylene chloride:methanol:ammonia
water=8:2:0.2);
[1316] NMR (DMSO-d.sub.6): .delta. 12.47 (br, 1H), 3.01-2.91 (m,
2H), 2.56-2.42 (m, 6H), 2.41-2.32 (m, 4H), 1.81 (s, 3H), 1.80 (m,
1H), 1.70-1.55 (m, 6H), 1.22-1.07 (m, 2H).
EXAMPLE 56(3)
4-(N-(piperidin-2-yl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-o-
ne methanesulfonate
[1317] TLC: Rf 0.27 (methylene
chloride:methanol:water=8:2:0.2);
[1318] NMR (DMSO-d.sub.6): .delta. 12.64 (s, 1H), 9.22 (d, J=7.5
Hz, 1H), 8.77 (br, 2H), 4.83 (m, 1H), 3.55 (s, 2H), 3.10 (m, 1H),
2.97 (m, 1H), 2.55-2.35 (m, 4H), 2.34 (s, 3H), 1.94-1.50 (m,
10H).
EXAMPLE 56(4)
4-(N-(piperidin-2-ylmethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1-
(2H)-one methanesulfonate
[1319] TLC: Rf 0.55 (methylene chloride:methanol:28% ammonia
water=15:5:1);
[1320] NMR (DMSO-d.sub.6): .delta. 12.62 (s, 1H), 8.50 (m, 1H),
8.30-8.10 (m, 2H), 3.48 (s, 2H), 3.40-3.00 (m, 4H), 2.84 (m, 1H),
2.46-2.34 (m, 4H), 2.32 (s, 3H), 1.82-1.20 (m, 10H).
EXAMPLE 56(5)
4-(N-(2-(piperidin-2-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazi-
n-1(2H)-one methanesulfonate
[1321] TLC: Rf 0.40 (methylene chloride:methanol:28% ammonia
water=15:5:1);
[1322] NMR (DMSO-d.sub.6): .delta. 12.61 (s, 1H), 8.41 (m, 1H),
8.30-8.16 (m, 2H), 3.42 (s, 2H), 3.30-2.70 (m, 5H), 2.46-2.32 (m,
4H), 2.31 (s, 3H), 1.92-1.20 (m, 12H).
EXAMPLE 56(6)
4-(N-(2-(piperidin-3-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazi-
n-1(2H)-one methanesulfonate
[1323] TLC: Rf 0.28 (methylene chloride:methanol:28% ammonia
water=15:5:1);
[1324] NMR (DMSO-d.sub.6): .delta. 12.57 (brs, 1H), 8.26 (brs, 2H),
8.06 (t, J=5.5 Hz, 1H), 3.39 (s, 2H), 3.24-3.02 (m, 4H), 2.73 (m,
1H), 2.46-2.32 (m, 4H), 2.30 (s, 3H), 1.80-1.04 (m, 12H).
EXAMPLE 57
8-(3-hydroxyphenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one
[1325] By the same procedure as described in Example 20, if
necessary, by converting to corresponding salts by conventional
method, using the compound prepared in Example 47(2) instead of the
compound prepared in Example 4(4), the compounds of the present
invention having the following data were obtained.
Free Form:
[1326] TLC: Rf 0.33 (methanol:methylene chloride=1:20);
[1327] NMR (DMSO-d.sub.6): .delta. 12.06 (s, 1H), 9.60 (s, 1H),
7.25 (t, J=8.1 Hz, 1H), 6.81 (m, 3H), 5.71 (s, 1H), 3.13 (m, 2H),
2.36 (m, 2H), 1.71 (m, 2H).
Sodium Salt:
[1328] TLC: Rf 0.43 (methanol:methylene chloride=1:9);
[1329] NMR (DMSO-d.sub.6): .delta. 11.85 (brs, 1H), 6.92 (t, J=7.8
Hz, 1H), 6.36 (brs, 2H), 6.17 (brs, 1H), 5.40 (s, 1H), 3.13 (m,
2H), 2.36 (m, 2H), 1.68 (m, 2H).
EXAMPLE 58
8-(N-(2-(piperidin-4-yl)ethyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,-
3-d]pyridazin-5(1H)-one
[1330] A mixed solution of the compound prepared in Example 24(44)
(307 mg), 10% palladium on carbon (307 mg) and ammonium formate
(236 mg) in methanol (3.00 mL) was refluxed for 30 minutes. After
cooling to room temperature, the reaction mixture was filtrated
through Celite. The filtrate was concentrated. The residue was
washed with a mixed solution of methanol and ethyl acetate and
dried under reduced pressure to give the compound of the present
invention (187 mg) having the following physical data.
[1331] TLC: Rf 0.13 (methanol:methylene chloride:acetic
acid=1:4:1);
[1332] NMR (DMSO-d.sub.6): .delta. 11.83 (brs, 1H), 8.06 (t, J=5.1
Hz, 1H), 6.44 (s, 1H), 3.18-2.09 (m, 13H), 1.69 (m, 2H), 1.52 (m,
2H), 1.29 (m, 3H), 0.94 (m, 2H).
EXAMPLE 59
8-(pyridin-2-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one
(compound A) and
8-(piperidin-2-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one
(compound B)
[1333] Under an atmosphere of argon, to
8-(pyridin-2-yl)pyrido[2,3-d]pyridazin-5(6H)-one (118 mg; It was
prepared by the same procedure as described in Reference example
22.fwdarw.Reference example 23.fwdarw.Reference example 24 using
pyridin-2-ylmagnesium bromide instead of
3-(bis(trimethylsilyl)amino)phenylmagnesium chloride.) were added
methanol (6 mL), methanesulfonate (51 mg) and platinum oxide (12
mg) sequentially. Under an atmosphere of hydrogen, the reaction
mixture was stirred at room temperature for 5.5 hours. The reaction
mixture was filtrated through Celite. The filtrate was
concentrated. The residue was purified by column chromatography on
silica gel (methylene chloride:methanol=20:1 methylene
chloride:methanol:water=8:2:0.2) to give free form of the compound
A (14 mg) and methanesulfonate of the compound B (77 mg) having the
following physical data. The obtained compound A and B were
converted to corresponding salts or free form by conventional
method to give the compound of the present invention having the
following physical data.
Free Form of the Compound A:
[1334] TLC: Rf 0.51 (methylene chloride:methanol=10:1).
[1335] NMR (DMSO-d.sub.6): .delta. 12.39 (br, 1H), 8.88 (br, 1H),
8.59 (m, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.93 (m, 1H), 7.44 (m, 1H),
3.40-3.25 (m, 2H), 2.43 (t, J=6.3 Hz, 2H), 1.85-1.74 (m, 2H).
Methanesulfonate of the Compound B:
[1336] TLC: Rf 0.15 (methylene
chloride:methanol:water=8:2:0.2);
[1337] NMR (DMSO-d.sub.6): .delta. 12.36 (s, 1H), 8.76 (br, 2H),
6.63 (s, 1H), 4.21 (d, J=9.9 Hz, 1H), 3.30 (m, 1H), 3.28-3.16 (m,
2H), 2.89 (m, 1H), 2.36 (t, J=6.0 Hz, 2H), 2.29 (s, 3H), 2.03 (d,
J=12.3 Hz, 1H), 1.84-1.60 (m, 6H), 1.43 (m, 1H).
Free Form of the Compound B:
[1338] TLC: Rf 0.14 (methylene
chloride:methanol:water=8:2:0.2);
[1339] NMR (DMSO-d.sub.6): .delta. 11.74 (s, 1H), 7.36 (s, 1H),
3.54 (dd, J=9.6, 3.9 Hz, 1H), 3.26-3.16 (m, 2H), 2.94 (d, J=12.0
Hz, 1H), 2.65-2.50 (m, 1H), 2.32 (t, J=6.3 Hz, 2H), 1.79 (m, 1H),
1.76-1.26 (m, 7H).
Methanesulfonate of the Compound A:
[1340] TLC: Rf 0.50 (methylene chloride:methanol=10:1);
[1341] NMR (DMSO-d.sub.6): .delta. 12.63 (br, 1H), 9.45 (br, 2H),
8.60 (d, J=4.5 Hz, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.97 (t, J=8.4 Hz,
1H), 7.48 (m, 1H), 3.40-3.33 (m, 2H), 2.52-2.42 (m, 2H), 2.36 (s,
3H), 1.84-1.73 (m, 2H).
Dimethanesulfonate of the Compound B:
[1342] TLC: Rf 0.66 (methylene chloride:methanol:ammonia
water=8:2:0.2);
[1343] NMR (DMSO-d.sub.6): .delta. 1.45 (m, 1H) 1.72 (m, 6H) 2.04
(d, J=12.82 Hz, 1H) 2.37 (m, 8H) 2.94 (s, 1H) 3.25 (m, 3H) 4.26 (t,
J=10.44 Hz, 1H) 7.21 (m, 1H) 8.71 (m, 1H) 8.89 (m, 1H) 12.48 (s,
1H).
EXAMPLE 59(1) TO EXAMPLE 59(3)
[1344] By the same procedure as described in Example 59, if
necessary, by converting to corresponding salts by conventional
method, using 8-(pyridin-3-yl)pyrido[2,3-d]pyridazin-5(6H)-one,
8-(pyridin-4-yl)pyrido[2,3-d]pyridazin-5(6H)-one or
8-(1-benzylpyridin-4-yl)pyrido[2,3-d]pyridazin-5(6H)-one instead of
8-(pyridin-2-yl)pyrido[2,3-d]pyridazin-5(6H)-one, the following
compounds of the present invention were obtained.
EXAMPLE 59(1)
8-(pyridin-3-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one
methanesulfonate (compound A) and
8-(piperidin-3-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one
acetate (compound B)
Compound A:
[1345] TLC: Rf 0.66 (methylene chloride:methanol=4:1);
[1346] NMR (DMSO-d.sub.6): .delta. 12.46 (s, 1H), 8.92 (s, 1H),
8.86 (d, J=5.1 Hz, 1H), 8.37 (d, J=7.5 Hz, 1H), 7.91 (dd, J=7.5,
5.1 Hz, 1H), 6.20 (brs, 1H), 3.13 (m, 2H), 2.41 (m, 2H), 2.31 (s,
3H), 1.75 (m, 2H).
Compound B:
[1347] TLC: Rf 0.12 (methylene chloride:methanol:acetic
acid=4:1:2%);
[1348] NMR (DMSO-d.sub.6): .delta. 11.75 (s, 1H), 6.48 (s, 1H),
3.18 (m, 2H), 2.98 (m, 2H), 2.71 (m, 1H), 2.44 (m, 2H), 2.32 (m,
2H), 1.86 (s, 3H), 1.83 (m, 1H), 1.74-1.43 (m, 5H).
EXAMPLE 59(2)
8-(pyridin-4-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one
methanesulfonate (compound A) and
8-(piperidin-4-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one
(compound B)
Compound A:
[1349] TLC: Rf 0.28 (methylene chloride:methanol=10:1);
[1350] NMR (DMSO-d.sub.6): .delta. 12.63 (br, 1H), 8.90 (d, J=6.0
Hz, 2H), 8.00 (d, J=6.0 Hz, 2H), 6.23 (br, 1H), 3.18-3.10 (m, 2H),
2.42 (t, J=6.0 Hz, 2H), 2.31 (s, 3H), 1.82-1.70 (m, 2H).
Free Form of Compound B:
[1351] TLC: Rf 0.053 (methylene chloride:methanol:acetic
acid=4:1:2%);
[1352] NMR (DMSO-d.sub.6): .delta. 11.71 (s, 1H), 6.33 (s, 1H),
3.16 (m, 2H), 2.94 (m, 2H), 2.74-2.38 (m, 3H), 2.32 (m, 2H),
1.75-1.32 (m, 6H).
Dimethanesulfonate of Compound B:
[1353] TLC: Rf 0.86 (methylene
chloride:methanol:water=8:2:0.2);
[1354] NMR (DMSO-d.sub.6): .delta. 11.79 (br, 1H), 8.13 (br, 3H),
6.40 (s, 1H), 3.23-3.15 (m, 2H), 3.15-3.04 (m, 2H), 2.81-2.64 (m,
3H), 2.33 (t, J=6.3 Hz, 2H), 1.82 (s, 6H), 1.80-1.65 (m, 4H),
1.64-1.46 (m, 2H).
EXAMPLE 59(3)
8-(1-cyclohexylmethylpiperidin-4-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyrida-
zin-5(1H)-one
[1355] TLC: Rf 0.41 (methylene chloride:methanol:acetic
acid=4:1:2%).
EXAMPLE 60 TO EXAMPLE 60(7)
[1356] By the same procedure as described in Reference example
2.fwdarw.Reference example 3.fwdarw.Example 3 using
thiomorpholin-3-ylcarboxylic acid ethyl ester or a corresponding
derivative, and a corresponding derivative instead of
3-nitrobenzoyl chloride, the following compounds of the present
invention were obtained.
EXAMPLE 60
4-cyclohexenyl-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-
-one
[1357] TLC: Rf 0.18 (hexane:ethyl acetate=2:1);
[1358] NMR (DMSO-d.sub.6): .delta. 10.27 (s, 1H), 5.79 (m, 1H),
4.03 (dd, J=10.3, 3.0 Hz, 1H), 3.82 (dt, J=13.8, 3.0 Hz, 1H), 3.06
(ddd, J=13.8, 11.7, 2.1 Hz, 1H), 2.77 (m, 1H), 2.74-2.58 (m, 2H),
2.42 (m, 1H), 2.10-2.00 (m, 4H), 1.68-1.50 (m, 4H).
EXAMPLE 60(1)
4-(furan-2-yl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-
-one
[1359] TLC: Rf 0.37 (hexane:ethyl acetate=1:1);
[1360] NMR (DMSO-d.sub.6): .delta. 10.66 (s, 1H) 7.80 (m, 1H), 6.72
(d, J=3.3 Hz, 1H), 6.58 (m, 1H), 4.22 (dd, J=10.2, 3.0 Hz, 1H),
3.73 (dt, J=14.1, 3.0 Hz, 1H), 3.22 (m, 1H), 2.94-2.72 (m, 3H),
2.49 (m, 1H).
EXAMPLE 60(2)
4-(thiophen-2-yl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(-
2H)-one
[1361] TLC: Rf 0.37 (hexane:ethyl acetate=1:1);
[1362] NMR (DMSO-d.sub.6): .delta. 10.62 (s, 1H), 7.65 (dd, J=5.1,
1.2 Hz, 1H), 7.30 (dd, J=3.6, 1.2 Hz, 1H), 7.11 (dd, J=5.1, 3.6 Hz,
1H), 4.24 (dd, J=8.1, 3.3 Hz, 1H), 3.96 (dt, J=13.8, 3.3 z, 1H),
3.20 (m, 1H), 2.92-2.76 (m, 3H), 2.49 (m, 1H).
EXAMPLE 60(3)
4-(thiazol-2-yl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2-
H)-one
[1363] TLC: Rf 0.53 (hexane:ethyl acetate=1:1);
[1364] NMR (CDCl.sub.3): .delta. 8.24 (br, 1H), 7.85 (d, J=3.3 Hz,
1H), 7.42 (d, J=3.3 Hz, 1H), 5.15 (m, 1H), 4.20 (dd, J=11.1, 3.0
Hz, 1H), 3.36-3.20 (m, 2H), 3.03-2.83 (m, 2H), 2.41 (m, 1H).
EXAMPLE 60(4)
4-(pyridin-3-yl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2-
H)-one
[1365] TLC: Rf 0.32 (methylene chloride:methanol=10:1);
[1366] NMR (CDCl.sub.3): .delta. 8.70 (dd, J=4.8, 1.8 Hz, 1H), 8.66
(d, J=1.8 Hz, 1H), 8.13 (br, 1H), 7.71 (dt, J=8.1, 1.8 Hz, 1H),
7.39 (dd, J=8.1, 4.8 Hz, 1H), 4.38 (dd, J=11.1, 2.7 Hz, 1H), 3.75
(dt, J=14.1, 2.7 Hz, 1H), 3.21 (ddd, J=14.1, 12.0, 2.7 Hz, 1H),
3.11 (m, 1H), 2.98 (dd, J=14.1, 10.8 Hz, 1H), 2.76 (m, 1H), 2.31
(m, 1H).
EXAMPLE 60(5)
4-(1,3-dioxaindan-5-yl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]tria-
zin-1(2H)-one
[1367] TLC: Rf 0.30 (chloroform:methanol=9:1);
[1368] NMR (CD.sub.3OD): .delta. 8.10-8.00 (brs, 1H), 6.85-6.83 (m,
2H), 6.82-6.80 (m, 1H), 6.01 (s, 2H), 4.33 (dd, J=10.8, 2.4 Hz,
1H), 3.83 (dt, J=13.5, 2.7 Hz, 1H), 3.20-3.02 (m, 2H), 3.00-2.88
(m, 1H), 2.80-2.68 (m, 1H), 2.32-2.22 (m, 1H).
EXAMPLE 60(6)
4-(pyridin-3-yl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one
[1369] TLC: Rf 0.36 (methanol:methylene chloride=1:10);
[1370] NMR (DMSO-d.sub.6): .delta. 10.99 (s, 1H), 8.66 (m, 2H),
7.90 (dt, J=7.8, 2.1 Hz, 1H), 7.50 (dd, J=7.8, 4.8 Hz, 1H), 6.27
(s, 1H), 3.62 (m, 2H), 3.16 (m, 2H).
EXAMPLE 60(7)
4-(naphthalen-2-yl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-on-
e
[1371] TLC: Rf 0.54 (methylene chloride:methanol=10:1);
[1372] NMR (DMSO-d.sub.6): .delta. 10.96 (s, 1H), 8.04-7.95 (m,
4H), 7.62-7.53 (m, 3H), 6.28 (s, 1H), 3.69-3.64 (m, 2H), 3.24-3.16
(m, 2H).
EXAMPLE 61
4-(piperazin-1-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one
hydrochloride
[1373] To a suspension of
4-chloro-5,6,7,8-tetrahydrophthalazin-1(2H)-one (150 mg; CAS
Registry No. 89981-21-5; the compound described in Yakugaku Zassi.,
82, 302-303 (1962)) in ethylene glycol (1.6 mL) was added
piperazine (420 mg) and the mixture was stirred at 200.degree. C.
for 7 hours. After cooling to room temperature, the reaction
mixture was poured in a cold saturated aqueous sodium hydrogen
carbonate solution and extracted with chloroform. The extract was
washed brine, dried over anhydrous magnesium sulfate and
concentrated. The residue was purified by column chromatography on
silica gel (methylene chloride:methanol=20:1.fwdarw.10:1) to give
free form of the title compound (64 mg). To a solution of the
obtained free form in methanol (2.0 mL) was added 4N hydrogen
chloride-ethyl acetate solution (1 mL). The mixture was stirred at
room temperature and concentrated. The residue was recrystallized
from a mixed solution of methanol and ethyl acetate to give the
compound of the present invention (21 mg) having the following
physical data.
[1374] TLC: Rf 0.46 (methylene chloride:methanol:acetic
acid=20:5:2);
[1375] NMR (DMSO-d.sub.6): .delta. 12.31 (s, 1H), 8.98 (brs, 2H),
3.24-3.02 (m, 8H), 2.58-2.30 (m, 4H), 1.78-1.50 (m, 4H).
EXAMPLE 62
8-(piperazin-1-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one
[1376] By the same procedure as described in Example
60.fwdarw.Example 59 using 8-chloropyrido[2,3-d]pyridazin-5(6H)-one
(the compound described in Chem. Pharm. Bull., 13(5), 586-593
(1965)) instead of 4-chloro-5,6,7,8-tetrahydrophthalazin-1(2H)-one,
the compound of the present invention having the following physical
data was obtained.
[1377] TLC: Rf 0.18 (methylene chloride:methanol:acetic
acid=20:5:2);
[1378] NMR (DMSO-d.sub.6): .delta. 11.51 (s, 1H), 6.12 (s, 1H),
3.26-3.04 (m, 8H), 3.02-2.88 (m, 3H), 2.31 (t, J=6.0 Hz, 2H), 1.71
(m, 2H).
FORMULATION EXAMPLE 1
[1379] The following components were admixed in conventional method
and punched out to obtain 100 tablets each containing 50 mg of
active ingredient.
TABLE-US-00092 4-(N-(2-aminoethyl)carbamoylmethyl)-5,6,7,8- 5.0 g
tetrahydrophthalazin-1(2H)-one carboxymethyl cellulose calcium
(disintegrating agent) 0.2 g magnesium stearate (lubricating agent)
0.1 g microcrystalline cellulose 4.7 g
FORMULATION EXAMPLE 2
[1380] After mixing the following components by a conventional
method, the resulting solution was sterilized by a conventional
method and 5 ml portions thereof were filled in amples,
respectively, and freeze-dried by a conventional method to obtain
100 amples of injection containing each 20 mg of the active
ingredient.
TABLE-US-00093 4-(N-(2-aminoethyl)carbamoylmethyl)-5,6,7,8- 2.0 g
tetrahydrophthalazin-1(2H)-one mannitol 20 g distilled water 1000
mL
* * * * *