U.S. patent application number 13/920846 was filed with the patent office on 2013-10-24 for jnk inhibitors for the treatment of endometriosis.
The applicant listed for this patent is Merck Serono SA. Invention is credited to Selvaraj Nataraja, Stephen S. Palmer.
Application Number | 20130281447 13/920846 |
Document ID | / |
Family ID | 37076303 |
Filed Date | 2013-10-24 |
United States Patent
Application |
20130281447 |
Kind Code |
A1 |
Palmer; Stephen S. ; et
al. |
October 24, 2013 |
JNK INHIBITORS FOR THE TREATMENT OF ENDOMETRIOSIS
Abstract
This invention relates to a method of treating and/or preventing
endometriosis comprising administering a JNK inhibitor. The JNK
inhibitor can also be administered combined with a hormonal
suppressor. The invention further relates to the treatment of
endometriosis.
Inventors: |
Palmer; Stephen S.;
(Plympton, MA) ; Nataraja; Selvaraj; (Randolph,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Merck Serono SA |
Vaud |
|
CH |
|
|
Family ID: |
37076303 |
Appl. No.: |
13/920846 |
Filed: |
June 18, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11988572 |
Apr 23, 2008 |
|
|
|
PCT/US2006/027455 |
Jul 12, 2006 |
|
|
|
13920846 |
|
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|
|
60699658 |
Jul 15, 2005 |
|
|
|
Current U.S.
Class: |
514/233.8 ;
514/252.19; 514/256 |
Current CPC
Class: |
A61K 31/5377 20130101;
A61K 31/506 20130101; A61P 15/00 20180101; A61K 45/06 20130101;
A61K 31/00 20130101; A61P 43/00 20180101; A61P 15/08 20180101; C07D
417/14 20130101 |
Class at
Publication: |
514/233.8 ;
514/256; 514/252.19 |
International
Class: |
A61K 31/506 20060101
A61K031/506; A61K 31/5377 20060101 A61K031/5377; A61K 45/06
20060101 A61K045/06 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 11, 2005 |
EP |
05109447.2 |
Claims
1. A method of treating endometriosis in an individual consisting
essentially of administering a therapeutically effective amount of
a JNK inhibitor; wherein the JNK inhibitor is a benzothiazole
derivative according to any of formulae (Ia), (Ia') or (Ia''):
##STR00017## as well as its tautomers, its geometrical isomers, its
optically active forms as enantiomers, diastereomers and its
racemate forms, as well as pharmaceutically acceptable salts
thereof, wherein: R.sup.1 is selected from the group consisting of
hydrogen, sulfonyl, amino, C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl or
C.sub.1-C.sub.6-alkoxy, aryl, halogen, cyano and hydroxy; L is an
amino group of the formula --NR.sup.3R.sup.4 wherein R.sup.3 and
R.sup.4 are each independently from each other H,
C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy, aryl, heteroaryl,
saturated or unsaturated 3-8-membered cycloalkyl, 3-8-membered
heterocycloalkyl, (wherein said cycloalkyl, heterocycloalkyl, aryl
or heteroaryl groups may be fused with 1-2 further cycloalkyl,
heterocycloalkyl, aryl or heteroaryl group), C.sub.1-C.sub.6-alkyl
aryl, C.sub.1-C.sub.6-alkyl heteroaryl, C.sub.2-C.sub.6-alkenyl
aryl, C.sub.2-C.sub.6-alkenyl heteroaryl, C.sub.2-C.sub.6-alkynyl
aryl, C.sub.2-C.sub.6-alkynyl heteroaryl, C.sub.1-C.sub.6-alkyl
cycloalkyl, C.sub.1-C.sub.6-alkyl heterocycloalkyl,
C.sub.2-C.sub.6-alkenyl cycloalkyl, C.sub.2-C.sub.6-alkenyl
heterocycloalkyl, C.sub.2-C.sub.6-alkynyl cycloalkyl,
C.sub.2-C.sub.6-alkynyl heterocycloalkyl, or R.sup.3 and R.sup.4
may form a ring together with the nitrogen to which they are
bound.
2. The method according to claim 1, wherein R.sup.3 is hydrogen or
a methyl or ethyl or propyl group and R.sup.4 is selected from the
group consisting of (C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.6
alkyl-aryl, C.sub.1-C.sub.6-alkyl-heteroaryl, cycloalkyl,
heterocycloalkyl, aryl or heteroaryl and 4-8 membered saturated or
unsaturated cycloalkyl.
3. The method according to claim 1, wherein R.sup.3 and R.sup.4
form an optionally substituted piperazine or a piperidine or a
morpholine or a pyrrolidine ring together with the nitrogen to
which they are bound, whereby said optional substituent is selected
from the group consisting of C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl,
C.sub.1-C.sub.6-alkoxy, aryl, heteroaryl, saturated or unsaturated
3-8-membered cycloalkyl, 3-8-membered heterocycloalkyl, (wherein
said cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups may be
fused with 1-2 further cycloalkyl, heterocycloalkyl, aryl or
heteroaryl group), C.sub.1-C.sub.6-alkyl aryl,
C.sub.1-C.sub.6-alkyl heteroaryl, C.sub.2-C.sub.6-alkenyl aryl,
C.sub.2-C.sub.6-alkenyl heteroaryl, C.sub.2-C.sub.6-alkynyl aryl,
C.sub.2-C.sub.6-alkynyl heteroaryl, C.sub.1-C.sub.6-alkyl
cycloalkyl, C.sub.1-C.sub.6-alkyl heterocycloalkyl,
C.sub.2-C.sub.6-alkenyl cycloalkyl, C.sub.2-C.sub.6-alkenyl
heterocycloalkyl, C.sub.2-C.sub.6-alkynyl cycloalkyl,
C.sub.2-C.sub.6-alkynyl heterocycloalkyl.
4. The method according to claim 1, wherein L is selected from:
##STR00018## wherein n is 1 to 10; and R.sup.5 and R.sup.5' are
independently selected from each other from the group consisting of
H, C.sub.1-C.sub.10 alkyl, aryl or hetero-aryl, C.sub.1-C.sub.6
alkyl-aryl and C.sub.1-C.sub.6-alkyl-heteroaryl.
5. The method according to claim 1, wherein the JNK inhibitor is
1,3-benzothiazol-2-yl(2-{[2-(3-pyridinyl)ethyl]amino}-4-pyrimidinyl)aceto-
nitrile, or a pharmaceutically acceptable salt thereof.
6. A method of treating endometriosis in an individual in need
thereof consisting essentially of administering a therapeutically
effective amount of a compound selected from the group consisting
of:
1,3-benzothiazol-2-yl(2-{[2-(1H-imidazol-5-yl)ethyl]amino}-4-pyrimidinyl)-
acetonitrile,
1,3-benzothiazol-2-yl[2-(1-piperazinyl)-4-pyrimidinyl]acetonitrile,
1,3-benzothiazol-2-yl[2-(4-benzyl-1-piperidinyl)-4-pyrimidinyl]acetonitri-
le,
1,3-benzothiazol-2-yl[2-(4-methyl-1-piperazinyl)-4-pyrimidinyl]acetoni-
trile,
1,3-benzothiazol-2-yl[2-(4-morpholinyl)-4-pyrimidinyl]acetonitrile,
1,3-benzothiazol-2-yl[2-(methylamino)-4-pyrimidinyl]acetonitrile,
1,3-benzothiazol-2-yl(2-{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}-4-pyri-
midinyl)-acetonitrile,
1,3-benzothiazol-2-yl{2-[4-(benzyloxy)-1-piperidinyl]-4-pyrimidinyl}aceto-
nitrile,
1,3-benzothiazol-2-yl[2-(4-hydroxy-1-piperidinyl)-4-pyrimidinyl]a-
cetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(dimethylamino)ethyl]amino}-4-pyrimidinyl)ace-
tonitrile,
1,3-benzothiazol-2-yl[2-(dimethylamino)-4-pyrimidinyl]acetonitr-
ile,
1,3-benzothiazol-2-yl{2-[(2-methoxyethyl)amino]-4-pyrimidinyl}acetoni-
trile,
1,3-benzothiazol-2-yl{2-[(2-hydroxyethyl)amino]-4-pyrimidinyl}aceto-
nitrile,
1,3-benzothiazol-2-yl[2-(propylamino)-4-pyrimidinyl]acetonitrile,
1,3-benzothiazol-2-yl(2-{[3-(1H-imidazol-1-yl)propyl]amino}-4-pyrimidinyl-
)acetonitrile,
1,3-benzothiazol-2-yl[2-(1-pyrrolidinyl)-4-pyrimidinyl]acetonitrile,
1,3-benzothiazol-2-yl{2-[(2-phenylethyl)amino]-4-pyrimidinyl}acetonitrile-
,
1,3-benzothiazol-2-yl(2-{[2-(2-pyridinyl)ethyl]amino}-4-pyrimidinyl)acet-
onitrile,
1,3-benzothiazol-2-yl{2-[(2-pyridinylmethyl)amino]-4-pyrimidinyl-
}acetonitrile,
1,3-benzothiazol-2-yl{2-[4-(1H-1,2,3-benzotriazol-1-yl)-1-piperidinyl]-4--
pyrimidinyl}acetonitrile,
1,3-benzothiazol-2-yl{2-[4-(2-pyrazinyl)-1-piperazinyl]-4-pyrimidinyl}ace-
tonitrile,
1,3-benzothiazol-2-yl{2-[4-(2-pyrimidinyl)-1-piperazinyl]-4-pyr-
imidinyl}acetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(3-pyridinyl)ethyl]amino}-4-pyrimidinyl)aceto-
nitrile,
1,3-benzothiazol-2-yl(5-bromo-2-{[2-(dimethylamino)ethyl]amino}-4-
-pyrimidinyl)-acetonitrile,
1,3-benzothiazol-2-yl{2-[(2-morpholin-4-ylethyl)amino]pyrimidin-4-yl}acet-
onitrile,
1,3-benzothiazol-2-yl[2-(4-{3-[(trifluoromethyl)sulfonyl]anilino-
}piperidin-1-yl)pyrimidin-4-yl]acetonitrile,
1,3-benzothiazol-2-yl(2-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}pyrimidin--
4-yl)-acetonitrile,
1,3-benzothiazol-2-yl(2-{methyl[3-(methylamino)propyl]amino}pyrimidin-4-y-
l)acetonitrile,
1,3-benzothiazol-2-yl(2-{[3-(4-methylpiperazin-1-yl)propyl]amino}pyrimidi-
n-4-yl)-acetonitrile,
1,3-benzothiazol-2-yl{2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-4-yl}ace-
tonitrile,
1,3-benzothiazol-2-yl(2-{[2-(1-methyl-1H-imidazol-4-yl)ethyl]am-
ino}pyrimidin-4-yl)acetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(1H-indol-3-yl)ethyl]amino}pyrimidin-4-yl)ace-
tonitrile,
1,3-benzothiazol-2-yl(2-{[2-(4-hydroxyphenyl)ethyl]amino}pyrimi-
din-4-yl)acetonitrile
tert-butyl({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}amino)ac-
etate,
{2-[(3-aminopropyl)amino]pyrimidin-4-yl}(1,3-benzothiazol-2-yl)acet-
onitrile,
{2-[(2-aminoethyl)amino]pyrimidin-4-yl}(1,3-benzothiazol-2-yl)ac-
etonitrile,
1,3-benzothiazol-2-yl(2-{[3-(dimethylamino)propyl]amino}pyrimidin-4-yl)ac-
etonitrile,
1,3-benzothiazol-2-yl{2-[(2-piperidin-1-ylethyl)amino]pyrimidin-4-yl}acet-
onitrile,
1,3-benzothiazol-2-yl(2-{[2-(1-methyl-1H-imidazol-5-yl)ethyl]ami-
no}pyrimidin-4-yl)acetonitrile,
1,3-benzothiazol-2-yl[2-(benzylamino)pyrimidin-4-yl]acetonitrile,
isopropyl
3-({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}amino)-
propanoate,
1,3-benzothiazol-2-yl{2-[(3-hydroxypropyl)amino]pyrimidin-4-yl}acetonitri-
le,
1,3-benzothiazol-2-yl{2-[(pyridin-3-ylmethyl)amino]pyrimidin-4-yl}acet-
onitrile,
1,3-benzothiazol-2-yl{2-[(pyridin-4-ylmethyl)amino]pyrimidin-4-y-
l}acetonitrile, tert-butyl
4-[2-({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}amino)-ethyl]-
phenylcarbamate,
(2-{[2-(4-aminophenyl)ethyl]amino}pyrimidin-4-yl)(1,3-benzothiazol-2-yl)a-
cetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(3,4-dimethoxyphenyl)ethyl]amino}pyrimidin-4--
yl)acetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(3-methoxyphenyl)ethyl]amino}pyrimidin-4-yl)a-
cetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(2-fluorophenyl)ethyl]amino}pyrimidin-4-yl)ac-
etonitrile,
1,3-benzothiazol-2-yl[2-({2-[3-(trifluoromethyl)phenyl]ethyl}amino)pyrimi-
din-4-yl]acetonitrile,
1,3-benzothiazol-2-yl{2-[(2-hydroxy-2-phenylethyl)amino]pyrimidin-4-yl}ac-
etonitrile,
1,3-benzothiazol-2-yl{2-[(2-{[3-(trifluoromethyl)pyridin-2-yl]amino}ethyl-
)amino]-pyrimidin-4-yl}acetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(3-chlorophenyl)ethyl]amino}pyrimidin-4-yl)ac-
etonitrile,
1,3-benzothiazol-2-yl(2-{[2-(3,4-dichlorophenyl)ethyl]amino}pyrimidin-4-y-
l)acetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(4-methoxyphenyl)ethyl]amino}pyrimidin-4-yl)a-
cetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(4-methylphenyl)ethyl]amino}pyrimidin-4-yl)ac-
etonitrile,
1,3-benzothiazol-2-yl(2-{[2-(3-fluorophenyl)ethyl]amino}pyrimidin-4-yl)ac-
etonitrile,
1,3-benzothiazol-2-yl(2-{[2-(4-phenoxyphenyl)ethyl]amino}pyrimidin-4-yl)a-
cetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(2-phenoxyphenyl)ethyl]amino}pyrimidin-4-yl)a-
cetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(4-bromophenyl)ethyl]amino}pyrimidin-4-yl)ace-
tonitrile,
1,3-benzothiazol-2-yl(2-{[2-(4-fluorophenyl)ethyl]amino}pyrimid-
in-4-yl)acetonitrile,
1,3-benzothiazol-2-yl{2-[(2-[1,1'-biphenyl]-4-ylethyl)amino]pyrimidin-4-y-
l}acetonitrile,
1,3-benzothiazol-2-yl{2-[(2-{4-[hydroxy(oxido)amino]phenyl}ethyl)amino]py-
rimidin-4-yl}acetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(1H-1,2,4-triazol-1-yl)ethyl]amino}pyrimidin--
4-yl)acetonitrile,
1,3-benzothiazol-2-yl(2-{[3-(1H-pyrazol-1-yl)propyl]amino}pyrimidin-4-yl)-
acetonitrile,
4-[2-({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}amino)ethyl]b-
enzene-sulfonamide,
{2-[(2-pyridin-3-ylethyl)amino]pyrimidin-4-yl}[5-(trifluoromethyl)-1,3-be-
nzothiazol-2-yl]acetonitrile,
1,3-benzothiazol-2-yl{2-[(1H-tetrazol-5-ylmethyl)amino]pyrimidin-4-yl}ace-
tonitrile,
N-[2-({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}ami-
no)ethyl]-4-chlorobenzamide; and pharmaceutically acceptable salts
thereof.
7. A method of treating endometriosis in an individual in need
thereof consisting essentially of sequentially or simultaneously
administering a therapeutically effective amount of a JNK inhibitor
in combination with a hormonal suppressor or fertility drugs,
wherein the JNK inhibitor is a compound selected from the group
consisting of:
1,3-benzothiazol-2-yl(2-{[2-(1H-imidazol-5-yl)ethyl]amino}-4-pyrimidinyl)-
acetonitrile,
1,3-benzothiazol-2-yl[2-(1-piperazinyl)-4-pyrimidinyl]acetonitrile,
1,3-benzothiazol-2-yl[2-(4-benzyl-1-piperidinyl)-4-pyrimidinyl]acetonitri-
le,
1,3-benzothiazol-2-yl[2-(4-methyl-1-pip)-4-pyrimidinyl]acetonitrile,
1,3-benzothiazol-2-yl[2-(4-morpholinyl)-4-pyrimidinyl]acetonitrile,
1,3-benzothiazol-2-yl[2-(methylamino)-4-pyrimidinyl]acetonitrile,
1,3-benzothiazol-2-yl(2-{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}-4-pyri-
midinyl)-acetonitrile,
1,3-benzothiazol-2-yl{2-[4-(benzyloxy)-1-piperidinyl]-4-pyrimidinyl}aceto-
nitrile,
1,3-benzothiazol-2-yl[2-(4-hydroxy-1-piperidinyl)-4-pyrimidinyl]a-
cetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(dimethylamino)ethyl]amino}-4-pyrimidinyl)ace-
tonitrile,
1,3-benzothiazol-2-yl[2-(dimethylamino)-4-pyrimidinyl]acetonitr-
ile,
1,3-benzothiazol-2-yl{2-[(2-methoxyethyl)amino]-4-pyrimidinyl}acetoni-
trile,
1,3-benzothiazol-2-yl{2-[(2-hydroxyethyl)amino]-4-pyrimidinyl}aceto-
nitrile,
1,3-benzothiazol-2-yl[2-(propylamino)-4-pyrimidinyl]acetonitrile,
1,3-benzothiazol-2-yl(2-{[3-(1H-imidazol-1-yl)propyl]amino}-4-pyrimidinyl-
)acetonitrile,
1,3-benzothiazol-2-yl[2-(1-pyrrolidinyl)-4-pyrimidinyl]acetonitrile,
1,3-benzothiazol-2-yl{2-[(2-phenylethyl)amino]-4-pyrimidinyl}acetonitrile-
,
1,3-benzothiazol-2-yl(2-{[2-(2-pyridinyl)ethyl]amino}-4-pyrimidinyl)acet-
onitrile,
1,3-benzothiazol-2-yl{2-[(2-pyridinylmethyl)amino]-4-pyrimidinyl-
}acetonitrile,
1,3-benzothiazol-2-yl{2-[4-(1H-1,2,3-benzotriazol-1-yl)-1-piperidinyl]-4--
pyrimidinyl}acetonitrile,
1,3-benzothiazol-2-yl{2-[4-(2-pyrazinyl)-1-piperazinyl]-4-pyrimidinyl}ace-
tonitrile,
1,3-benzothiazol-2-yl{2-[4-(2-pyrimidinyl)-1-piperazinyl]-4-pyr-
imidinyl}acetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(3-pyridinyl)ethyl]amino}-4-pyrimidinyl)aceto-
nitrile,
1,3-benzothiazol-2-yl(5-bromo-2-{[2-(dimethylamino)ethyl]amino}-4-
-pyrimidinyl)-acetonitrile,
1,3-benzothiazol-2-yl{2-[(2-morpholin-4-ylethyl)amino]pyrimidin-4-yl}acet-
onitrile,
1,3-benzothiazol-2-yl[2-(4-{3-[(trifluoromethyl)sulfonyl]anilino-
}piperidin-1-yl)pyrimidin-4-yl]acetonitrile,
1,3-benzothiazol-2-yl(2-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}pyrimidin--
4-yl)-acetonitrile,
1,3-benzothiazol-2-yl(2-{methyl[3-(methylamino)propyl]amino}pyrimidin-4-y-
l)acetonitrile,
1,3-benzothiazol-2-yl(2-{[3-(4-methylpiperazin-1-yl)propyl]amino}pyrimidi-
n-4-yl)-acetonitrile,
1,3-benzothiazol-2-yl{2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-4-yl}ace-
tonitrile,
1,3-benzothiazol-2-yl(2-{[2-(1-methyl-1H-imidazol-4-yl)ethyl]am-
ino}pyrimidin-4-yl)acetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(1H-indol-3-yl)ethyl]amino}pyrimidin-4-yl)ace-
tonitrile,
1,3-benzothiazol-2-yl(2-{[2-(4-hydroxyphenyl)ethyl]amino}pyrimi-
din-4-yl)acetonitrile
tert-butyl({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}amino)ac-
etate,
{2-[(3-aminopropyl)amino]pyrimidin-4-yl}(1,3-benzothiazol-2-yl)acet-
onitrile,
{2-[(2-aminoethyl)amino]pyrimidin-4-yl}(1,3-benzothiazol-2-yl)ac-
etonitrile,
1,3-benzothiazol-2-yl(2-{[3-(dimethylamino)propyl]amino}pyrimidin-4-yl)ac-
etonitrile,
1,3-benzothiazol-2-yl{2-[(2-piperidin-1-ylethyl)amino]pyrimidin-4-yl}acet-
onitrile,
1,3-benzothiazol-2-yl(2-{[2-(1-methyl-1H-imidazol-5-yl)ethyl]ami-
no}pyrimidin-4-yl)acetonitrile,
1,3-benzothiazol-2-yl[2-(benzylamino)pyrimidin-4-yl]acetonitrile,
isopropyl
3-({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}amino)-
propanoate,
1,3-benzothiazol-2-yl{2-[(3-hydroxypropyl)amino]pyrimidin-4-yl}acetonitri-
le,
1,3-benzothiazol-2-yl{2-[(pyridin-3-ylmethyl)amino]pyrimidin-4-yl}acet-
onitrile,
1,3-benzothiazol-2-yl{2-[(pyridin-4-ylmethyl)amino]pyrimidin-4-y-
l}acetonitrile, tert-butyl
4-[2-({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}amino)-ethyl]-
phenylcarbamate,
(2-{[2-(4-aminophenyl)ethyl]amino}pyrimidin-4-yl)(1,3-benzothiazol-2-yl)a-
cetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(3,4-dimethoxyphenyl)ethyl]amino}pyrimidin-4--
yl)acetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(3-methoxyphenyl)ethyl]amino}pyrimidin-4-yl)a-
cetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(2-fluorophenyl)ethyl]amino}pyrimidin-4-yl)ac-
etonitrile,
1,3-benzothiazol-2-yl[2-({2-[3-(trifluoromethyl)phenyl]ethyl}amino)pyrimi-
din-4-yl]acetonitrile,
1,3-benzothiazol-2-yl{2-[(2-hydroxy-2-phenylethyl)amino]pyrimidin-4-yl}ac-
etonitrile,
1,3-benzothiazol-2-yl{2-[(2-{[3-(trifluoromethyl)pyridin-2-yl]amino}ethyl-
)amino]-pyrimidin-4-yl}acetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(3-chlorophenyl)ethyl]amino}pyrimidin-4-yl)ac-
etonitrile,
1,3-benzothiazol-2-yl(2-{[2-(3,4-dichlorophenyl)ethyl]amino}pyrimidin-4-y-
l)acetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(4-methoxyphenyl)ethyl]amino}pyrimidin-4-yl)a-
cetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(4-methylphenyl)ethyl]amino}pyrimidin-4-yl)ac-
etonitrile,
1,3-benzothiazol-2-yl(2-{[2-(3-fluorophenyl)ethyl]amino}pyrimidin-4-yl)ac-
etonitrile,
1,3-benzothiazol-2-yl(2-{[2-(4-phenoxyphenyl)ethyl]amino}pyrimidin-4-yl)a-
cetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(2-phenoxyphenyl)ethyl]amino}pyrimidin-4-yl)a-
cetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(4-bromophenyl)ethyl]amino}pyrimidin-4-yl)ace-
tonitrile,
1,3-benzothiazol-2-yl(2-{[2-(4-fluorophenyl)ethyl]amino}pyrimid-
in-4-yl)acetonitrile,
1,3-benzothiazol-2-yl{2-[(2-[1,1'-biphenyl]-4-ylethyl)amino]pyrimidin-4-y-
l}acetonitrile,
1,3-benzothiazol-2-yl{2-[(2-{4-[hydroxy(oxido)amino]phenyl}ethyl)amino]py-
rimidin-4-yl}acetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(1H-1,2,4-triazol-1-yl)ethyl]amino}pyrimidin--
4-yl)acetonitrile,
1,3-benzothiazol-2-yl(2-{[3-(1H-pyrazol-1-yl)propyl]amino}pyrimidin-4-yl)-
acetonitrile,
4-[2-({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}amino)ethyl]b-
enzene-sulfonamide,
{2-[(2-pyridin-3-ylethyl)amino]pyrimidin-4-yl}[5-(trifluoromethyl)-1,3-be-
nzothiazol-2-yl]acetonitrile,
1,3-benzothiazol-2-yl{2-[(1H-tetrazol-5-ylmethyl)amino]pyrimidin-4-yl}ace-
tonitrile,
N-[2-({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}ami-
no)ethyl]-4-chlorobenzamide; and pharmaceutically acceptable salts
thereof.
8. The method according to claim 7, wherein the hormonal suppressor
is selected from the group consisting of a GnRH antagonist, GnRH
agonist, aromatase inhibitor, progesterone receptor modulator and
an estrogen receptor modulator.
9. A pharmaceutical composition consisting essentially of a JNK
inhibitor, a hormonal suppressor and a pharmaceutically acceptable
carrier, wherein the JNK inhibitor is a compound selected from the
group consisting of:
1,3-benzothiazol-2-yl(2-{[2-(1H-imidazol-5-yl)ethyl]amino}-4-pyrimidinyl)-
acetonitrile,
1,3-benzothiazol-2-yl[2-(1-piperazinyl)-4-pyrimidinyl]acetonitrile,
1,3-benzothiazol-2-yl[2-(4-benzyl-1-piperidinyl)-4-pyrimidinyl]acetonitri-
le,
1,3-benzothiazol-2-yl[2-(4-methyl-1-piperazinyl)-4-pyrimidinyl]acetoni-
trile,
1,3-benzothiazol-2-yl[2-(4-morpholinyl)-4-pyrimidinyl]acetonitrile,
1,3-benzothiazol-2-yl[2-(methylamino)-4-pyrimidinyl]acetonitrile,
1,3-benzothiazol-2-yl(2-{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}-4-pyri-
midinyl)-acetonitrile,
1,3-benzothiazol-2-yl{2-[4-(benzyloxy)-1-piperidinyl]-4-pyrimidinyl}aceto-
nitrile,
1,3-benzothiazol-2-yl[2-(4-hydroxy-1-piperidinyl)-4-pyrimidinyl]a-
cetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(dimethylamino)ethyl]amino}-4-pyrimidinyl)ace-
tonitrile,
1,3-benzothiazol-2-yl[2-(dimethylamino)-4-pyrimidinyl]acetonitr-
ile,
1,3-benzothiazol-2-yl{2-[(2-methoxyethyl)amino]-4-pyrimidinyl}acetoni-
trile,
1,3-benzothiazol-2-yl{2-[(2-hydroxyethyl)amino]-4-pyrimidinyl}aceto-
nitrile,
1,3-benzothiazol-2-yl[2-(propylamino)-4-pyrimidinyl]acetonitrile,
1,3-benzothiazol-2-yl(2-{[3-(1H-imidazol-1-yl)propyl]amino}-4-pyrimidinyl-
)acetonitrile,
1,3-benzothiazol-2-yl[2-(1-pyrrolidinyl)-4-pyrimidinyl]acetonitrile,
1,3-benzothiazol-2-yl{2-[(2-phenylethyl)amino]-4-pyrimidinyl}acetonitrile-
,
1,3-benzothiazol-2-yl(2-{[2-(2-pyridinyl)ethyl]amino}-4-pyrimidinyl)acet-
onitrile,
1,3-benzothiazol-2-yl{2-[(2-pyridinylmethyl)amino]-4-pyrimidinyl-
}acetonitrile,
1,3-benzothiazol-2-yl{2-[4-(1H-1,2,3-benzotriazol-1-yl)-1-piperidinyl]-4--
pyrimidinyl}acetonitrile,
1,3-benzothiazol-2-yl{2-[4-(2-pyrazinyl)-1-piperazinyl]-4-pyrimidinyl}ace-
tonitrile,
1,3-benzothiazol-2-yl{2-[4-(2-pyrimidinyl)-1-piperazinyl]-4-pyr-
imidinyl}acetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(3-pyridinyl)ethyl]amino}-4-pyrimidinyl)aceto-
nitrile,
1,3-benzothiazol-2-yl(5-bromo-2-{[2-(dimethylamino)ethyl]amino}-4-
-pyrimidinyl)-acetonitrile,
1,3-benzothiazol-2-yl{2-[(2-morpholin-4-ylethyl)amino]pyrimidin-4-yl}acet-
onitrile,
1,3-benzothiazol-2-yl[2-(4-{3-[(trifluoromethyl)sulfonyl]anilino-
}piperidin-1-yl)pyrimidin-4-yl]acetonitrile,
1,3-benzothiazol-2-yl(2-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}pyrimidin--
4-yl)-acetonitrile,
1,3-benzothiazol-2-yl(2-{methyl[3-(methylamino)propyl]amino}pyrimidin-4-y-
l)acetonitrile,
1,3-benzothiazol-2-yl(2-{[3-(4-methylpiperazin-1-yl)propyl]amino}pyrimidi-
n-4-yl)-acetonitrile,
1,3-benzothiazol-2-yl{2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-4-yl}ace-
tonitrile,
1,3-benzothiazol-2-yl(2-{[2-(1-methyl-1H-imidazol-4-yl)ethyl]am-
ino}pyrimidin-4-yl)acetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(1H-indol-3-yl)ethyl]amino}pyrimidin-4-yl)ace-
tonitrile,
1,3-benzothiazol-2-yl(2-{[2-(4-hydroxyphenyl)ethyl]amino}pyrimi-
din-4-yl)acetonitrile
tert-butyl({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}amino)ac-
etate,
{2-[(3-aminopropyl)amino]pyrimidin-4-yl}(1,3-benzothiazol-2-yl)acet-
onitrile,
{2-[(2-aminoethyl)amino]pyrimidin-4-yl}(1,3-benzothiazol-2-yl)ac-
etonitrile,
1,3-benzothiazol-2-yl(2-{[3-(dimethylamino)propyl]amino}pyrimidin-4-yl)ac-
etonitrile,
1,3-benzothiazol-2-yl{2-[(2-piperidin-1-ylethyl)amino]pyrimidin-4-yl}acet-
onitrile,
1,3-benzothiazol-2-yl(2-{[2-(1-methyl-1H-imidazol-5-yl)ethyl]ami-
no}pyrimidin-4-yl)acetonitrile,
1,3-benzothiazol-2-yl[2-(benzylamino)pyrimidin-4-yl]acetonitrile,
isopropyl
3-({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}amino)-
propanoate,
1,3-benzothiazol-2-yl{2-[(3-hydroxypropyl)amino]pyrimidin-4-yl}acetonitri-
le,
1,3-benzothiazol-2-yl{2-[(pyridin-3-ylmethyl)amino]pyrimidin-4-yl}acet-
onitrile,
1,3-benzothiazol-2-yl{2-[(pyridin-4-ylmethyl)amino]pyrimidin-4-y-
l}acetonitrile, tert-butyl
4-[2-({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}amino)-ethyl]-
phenylcarbamate,
(2-{[2-(4-aminophenyl)ethyl]amino}pyrimidin-4-yl)(1,3-benzothiazol-2-yl)a-
cetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(3,4-dimethoxyphenyl)ethyl]amino}pyrimidin-4--
yl)acetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(3-methoxyphenyl)ethyl]amino}pyrimidin-4-yl)a-
cetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(2-fluorophenyl)ethyl]amino}pyrimidin-4-yl)ac-
etonitrile,
1,3-benzothiazol-2-yl[2-({2-[3-(trifluoromethyl)phenyl]ethyl}amino)pyrimi-
din-4-yl]acetonitrile,
1,3-benzothiazol-2-yl{2-[(2-hydroxy-2-phenylethyl)amino]pyrimidin-4-yl}ac-
etonitrile,
1,3-benzothiazol-2-yl{2-[(2-{[3-(trifluoromethyl)pyridin-2-yl]amino}ethyl-
)amino]-pyrimidin-4-yl}acetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(3-chlorophenyl)ethyl]amino}pyrimidin-4-yl)ac-
etonitrile,
1,3-benzothiazol-2-yl(2-{[2-(3,4-dichlorophenyl)ethyl]amino}pyrimidin-4-y-
l)acetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(4-methoxyphenyl)ethyl]amino}pyrimidin-4-yl)a-
cetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(4-methylphenyl)ethyl]amino}pyrimidin-4-yl)ac-
etonitrile,
1,3-benzothiazol-2-yl(2-{[2-(3-fluorophenyl)ethyl]amino}pyrimidin-4-yl)ac-
etonitrile,
1,3-benzothiazol-2-yl(2-{[2-(4-phenoxyphenyl)ethyl]amino}pyrimidin-4-yl)a-
cetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(2-phenoxyphenyl)ethyl]amino}pyrimidin-4-yl)a-
cetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(4-bromophenyl)ethyl]amino}pyrimidin-4-yl)ace-
tonitrile,
1,3-benzothiazol-2-yl(2-{[2-(4-fluorophenyl)ethyl]amino}pyrimid-
in-4-yl)acetonitrile,
1,3-benzothiazol-2-yl{2-[(2-[1,1'-biphenyl]-4-ylethyl)amino]pyrimidin-4-y-
l}acetonitrile,
1,3-benzothiazol-2-yl{2-[(2-{4-[hydroxy(oxido)amino]phenyl}ethyl)amino]py-
rimidin-4-yl}acetonitrile,
1,3-benzothiazol-2-yl(2-{[2-(1H-1,2,4-triazol-1-yl)ethyl]amino}pyrimidin--
4-yl)acetonitrile,
1,3-benzothiazol-2-yl(2-{[3-(1H-pyrazol-1-yl)propyl]amino}pyrimidin-4-yl)-
acetonitrile,
4-[2-({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}amino)ethyl]b-
enzene-sulfonamide,
{2-[(2-pyridin-3-ylethyl)amino]pyrimidin-4-yl}[5-(trifluoromethyl)-1,3-be-
nzothiazol-2-yl]acetonitrile,
1,3-benzothiazol-2-yl{2-[(1H-tetrazol-5-ylmethyl)amino]pyrimidin-4-yl}ace-
tonitrile,
N-[2-({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}ami-
no)ethyl]-4-chlorobenzamide; and pharmaceutically acceptable salts
thereof.
10. The pharmaceutical composition according to claim 9, wherein
the hormonal suppressor is selected from the group consisting of a
GnRH antagonist, GnRH agonist, aromatase inhibitor, progesterone
receptor modulator and an estrogen receptor modulator.
Description
RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 11/988,572, filed Apr. 23, 2008, which is the U.S. National
Stage of International Application No. PCT/US2006/027455, filed
Jul. 12, 2006, published in English, which claims priority under 35
U.S.C. .sctn.119 or 365 to European Application No. 05109447.2,
filed Oct. 11, 2005 and U.S. Provisional Application No.
60/699,658, filed Jul. 15, 2005. The entire teachings of the above
applications are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Endometriosis is one of the most frequent diseases of women
in their reproductive lifespan. It is characterized by the presence
of endometrial tissue outside the uterine cavity, consisting
histological of glands and stroma. The anatomical sites most often
affected are the ovaries, uterosacral ligaments, pelvic peritoneum,
rectovaginal septum, cervix, vagina, the fallopian tubes and
vulva.
[0003] Endometriosis is considered to be a benign disease, but
endometriotic lesions occasionally become malignant. As in other
kind of malignancies, the development of endometriosis-derived
neoplasms is due to concurrent events, involving alterations in
growth factors and/or oncogenes regulation (Kyama et al. 2003).
Further, endometriosis is considered as a major cause of
infertility (Giudice et al. 2004).
[0004] The current treatment of endometriosis consists of hormonal
therapy and/or surgery. Hormonal therapies include high dose of
progestogens, progestins, oral contraceptives (combinations of
estrogen and progesterone), Danazol (an androgenic derivative of
ethisterone) and more recently GnRH agonists. These hormonal
therapies are effective on pelvic pain and may induce an objective
regression of lesions, but have several caveats. Estrogen may
stimulate and cause proliferation of endometriotic tissue since it
may be unable to respond to progesterone (Dawood et al, 1993).
Progestational agents can provoke irregular bleeding along with
depression, weight gain, and fluid retention. Danazol can improve
symptoms in approximately 66-100% of the patients suffering from
pain, but recurrence rates after up to 4 years are approximately
40%-50%. Other drawbacks of Danazol therapy are weight gain and
androgenic side effects. GnRH analogs are more potent and long
acting than native GnRH, which act by removing the estrogenic
stimulus for the growth of all estrogen sensitive tissues. Side
effects of GnRH analogs are mainly secondary to the profound
hypoestrogenemia, like decreased bone density, and recurrence rate
are up to 50% after 5 years (Waller et al., 1993). Further
complicating treatment is the observation that endometriotic
lesions in many patients either are or become resistant to the
effects of progesterone and/or progestins. (Bulun et al. 2006).
[0005] Surgical intervention can be conservative, if fertility is
desired, or can lead to the removal of the uterus, tubes and
ovaries in case of severe disease. In any case, even limited
surgical treatment leads to a significant decrease in
fertility.
[0006] Although endometriosis stands as one of the most
investigated disorders of gynecology, the current understanding of
pathophysiology of the disease remains elusive. According to a
favored theory, endometriotic lesions develop by eutopic
endometrical cells leaving their primary site, possibly by
retrograde menstruation, and implant at distant sites, followed by
invasion of host tissue and proliferation. Furthermore, it appears
that endometriosis is an invasive and metastasizing disease. Though
endometriotic cells proliferate to a certain extent, they are not
neoplastic as typically found in carcinomas. Apparently,
endometriotic cells become senescent, apoptotic and necrotic.
Inflammatory responses that are induced or accompanied by lesion
formation finally lead to fibrosis and the formation of scars.
[0007] It has been speculated whether tumor or metastasis
suppressor genes (e.g. E-cadherin) are associated with
endometriosis. E-cadherin is a metastasis suppressor molecule, its
down-regulation or functional inactivation is a prerequisite for
invasion and metastasis (Frixen et al, 1991). Zeitvogel et al.
(2001) showed that E-cadherin is absent and N-cadherin is present
in endometriotic cells. N-cadherin is suggested to be the
path-finding molecule that allows cells to be invasive and
migratory in normal development and pathological processes.
[0008] Recently, it has been demonstrated that recombinant human
TNF.alpha. binding protein (rh-TBP-1) is effective in reducing the
size and severity of endometriotic lesions in an experimental model
of endometriosis (D'Hooghe et al. 2001). These results were the
first to demonstrate that an anti-inflammatory molecule (r-hTBP-1)
that targeted the TNF.alpha.--pathway provided effective medical
treatment for patients with endometriosis that did not inhibit
ovulation.
[0009] Yoshino et al. (2004) showed that mitogen-activated protein
kinases (MAPKs), which are intracellular signal transducers,
mediate some of the effects exerted by proinflammatory cytokines
Yoshino et al. further showed the presence of MAPks (e.g. ERK, JNK
and p38) in endometriotic cells and their phosphorylation under
inflammatory stimulation by IL-1.beta., TNF.alpha. and
H.sub.2O.sub.2. MAPKs are serine/threonine kinases that are
activated by dual phosphorylation on threonine and tyrosine
residues. In mammalian cells, there are at least three separate but
parallel pathways that convey information generated by
extra-cellular stimuli to the MAPKs. Said pathways consist of
kinase cascades leading to activation of the ERKs (extracellular
regulated kinases), the JNKs (c-Jun N-terminal kinases), and the
p38/CSBP kinases (Dent et al 2003). c-Jun is a protein that forms
homodimers and heterodimers (with e.g. c-Fos) to produce the
transactivating complex AP-1, which is required for the activation
of many genes (e.g. matrix metalloproteinases) involved in the
inflammatory response.
[0010] The invention described herein clearly shows the unexpected
result that inhibiting JNK, by means of a JNK inhibitor, reduces
endometriotic-like foci in a rat and in nude mouse experimental
models. A rat model also demonstrates that such effect is obtained
by inhibiting the Natural Killer cells activity associated with the
disease as well as reducing several cytokines found elevated in
endometriosis. These cytokines are among others, IL-6 and IL-8 that
are suggested to play a key role (Barcz et al., 2000). The JNK
inhibitors described herein restore the sensitivity of endometrial
cells and lesions to progesterone. Furthermore, the JNK inhibitors
described herein used in combination with a SPRM or progestin can
prevent re-establishment of endometriosis. The reduction of
endometriotic lesions using JNK inhibitors can also improve
fertility rates, since the normalization of genital structure has a
positive effect on the implantation rate.
[0011] Several small molecules have been proposed as modulators of
the JNK pathway. Aryl-oxindole derivatives of respectively the
generic formula (A) (WO 00/35909; WO 00/35906; WO 00/35920) and
formula (B) (WO 00/64872) have been developed for the treatment of
neurodegenerative diseases, inflammation and solid tumors for
formula (A) and for the treatment of a broad range of disorders
including, neurodegenerative diseases, inflammatory and autoimmune
diseases, cardiovascular and bone disorders for formula (B).
##STR00001##
[0012] Pyrazoloanthrones derivatives of formula (C) have been
reported to inhibit JNK for the treatment of neurological
degenerative diseases, inflammatory and autoimmune disorders as
well as cardiovascular pathologies (WO 01/12609).
##STR00002##
[0013] Tetrahydro-pyrimidine derivatives of formula (D) were
reported to be JNK inhibitors useful in the treatment of a wide
range of diseases including neurodegenerative diseases,
inflammatory and autoimmune disorders, cardiac and destructive bone
pathologies (WO 00/75118).
##STR00003##
[0014] Other heterocyclic compounds of formula (E) have been
proposed to inhibit protein kinases and especially c-un-N-Terminal
kinases (WO 01/12621) for treating "JNK-mediated conditions"
including proliferative diseases, neurodegenerative disorders,
inflammatory and autoimmune disorders.
##STR00004##
[0015] Benzazoles derivatives such as represented by formula (F)
(WO 01/47920) have been described as modulators of the JNK pathway
for the treatment of neuronal disorders, autoimmune diseases,
cancers and cardiovascular diseases.
##STR00005##
[0016] Several sulfonamide derivatives of formula (G) (WO
01/23378), sulfonyl amino acid derivatives of formula (H) (WO
01/23379) and sulfonyl hydrazide derivatives of formula (J) (WO
01/23382), were also developed to inhibit JNKs for treating
neurodegenerative diseases, auto-immune disorders, cancers and
cardiovascular diseases.
##STR00006##
SUMMARY OF THE INVENTION
[0017] The present invention relates to a method of treating and/or
preventing endometriosis in an individual comprising administering
a therapeutically effective amount of a JNK inhibitor.
[0018] The invention further relates to a method of treating and/or
preventing endometriosis by combined treatment of hormonal
suppressor (e.g. GnRH antagonists, GnRH agonists, aromatase
inhibitors, progesterone receptor modulators, estrogen receptor
modulators) along with a JNK inhibitor.
[0019] The invention also relates to a method of treating
endometriosis-related infertility in a female comprising the
administration of a therapeutically effective amount of a JNK
inhibitor, alone or in combination with other fertility drugs.
[0020] The invention finally relates to a pharmaceutical
composition comprising a JNK inhibitor, a hormal suppressor and a
pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] FIG. 1: Expression of N-cadherin and cytokeratin in
endometriotic cells (12Z). Cells treated with JNK inhibitor were
fixed with paraformaldehyde and stained for N-cadherin and
cytokeratin. Cells were observed under fluorescent microscope
(phase contrast and fluorescence pictures). Treating cells with a
JNK inhibitor decreased the expression of N-cadherin. The
expression of cytokeratin was not altered after treatment with the
JNK inhibitor.
[0022] FIG. 2: Effect of a JNK inhibitor on the growth of
endometriotic-like foci in experimentally induced endometriosis in
rats. The effect of the JNK inhibitor given at a dose of 10 mg/kg
was not different from the vehicle. 30 mg/kg and 60 mg/kg doses
showed a significant regression of established endometriotic
lesions.
[0023] FIG. 3: Effect of JNK inhibitor on cytokines in
endometriotic-like foci in the rat endometriosis model. The JNK
inhibitor reduced the levels of inflammatory cytokines, IL-12,
INF-.gamma., IL-10 and MCP-1 in the endometriotic foci.
[0024] FIG. 4: Effect of JNK inhibitor on cytokines in the
contralateral horn in experimentally induced endometriosis in rats.
No effect of the JNK inhibitor on cytokine expression was
observed.
[0025] FIG. 5: Effect of JNK inhibitor on NK-cell activity in the
rat endometriosis model. Treatment with a JNK inhibitor increased
NK cell activity compared to the vehicle treated group.
DESCRIPTION OF THE INVENTION
[0026] The following paragraphs provide definitions of the various
chemical moieties that make up the compounds according to the
invention and are intended to apply uniformly throughout the
specification and claims unless an otherwise expressly set out
definition provides a broader definition.
[0027] "C.sub.1-C.sub.6-alkyl" refers to alkyl groups having 1 to 6
carbon atoms. This term is exemplified by groups such as methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-butyl,
n-pentyl, n-hexyl and the like.
[0028] "Aryl" refers to an unsaturated aromatic carbocyclic group
of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or
multiple condensed rings (e.g., naphthyl). Preferred aryl include
phenyl, naphthyl, phenantrenyl and the like.
[0029] "C.sub.1-C.sub.6-alkyl aryl" refers to C.sub.1-C.sub.6-alkyl
groups having an aryl substituent, including benzyl, phenethyl and
the like.
[0030] "Heteroaryl" refers to a monocyclic heteroaromatic, or a
bicyclic or a tricyclic fused-ring heteroaromatic group. Particular
examples of heteroaromatic groups include optionally substituted
pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadia-zolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,3,4-triazinyl,
1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl,
isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl,
indolyl, isoindolyl, 3H-indolyl, benzimidazolyl,
imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxa-zolyl, quinolizinyl,
quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl,
pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl,
quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl,
5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl,
xanthenyl or benzoquinolyl.
[0031] "C.sub.1-C.sub.6-alkyl heteroaryl" refers to
C.sub.1-C.sub.6-alkyl groups having a heteroaryl substituent,
including 2-furylmethyl, 2-thienylmethyl, 2-(1H-indol-3-yl)ethyl
and the like.
[0032] "C.sub.2-C.sub.6-alkenyl" refers to alkenyl groups
preferably having from 2 to 6 carbon atoms and having at least 1 or
2 sites of alkenyl unsaturation. Preferable alkenyl groups include
ethenyl (--CH.dbd.CH.sub.2), n-2-propenyl (allyl,
--CH.sub.2CH.dbd.CH.sub.2) and the like.
[0033] "C.sub.2-C.sub.6-alkenyl aryl" refers to
C.sub.2-C.sub.6-alkenyl groups having an aryl substituent,
including 2-phenylvinyl and the like.
[0034] "C.sub.2-C.sub.6-alkenyl heteroaryl" refers to
C.sub.2-C.sub.6-alkenyl groups having a heteroaryl substituent,
including 2-(3-pyridinyl)vinyl and the like.
[0035] "C.sub.2-C.sub.6-alkynyl" refers to alkynyl groups
preferably having from 2 to 6 carbon atoms and having at least 1-2
sites of alkynyl unsaturation, preferred alkynyl groups include
ethynyl (--C.ident.CH), propargyl (--CH.sub.2C.ident.CH), and the
like.
[0036] "C.sub.2-C.sub.6-alkynyl aryl" refers to
C.sub.2-C.sub.6-alkynyl groups having an aryl substituent,
including phenylethynyl and the like.
[0037] "C.sub.2-C.sub.6-alkynyl heteroaryl" refers to
C.sub.2-C.sub.6-alkynyl groups having a heteroaryl substituent,
including 2-thienylethynyl and the like.
[0038] "C.sub.3-C.sub.8-cycloalkyl" refers to a saturated
carbocyclic group of from 3 to 8 carbon atoms having a single ring
(e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl).
Preferred cycloalkyl include cyclopentyl, cyclohexyl, norbornyl and
the like.
[0039] "C.sub.1-C.sub.6-alkyl cycloalkyl" refers to
C.sub.1-C.sub.6-alkyl groups having a cycloalkyl substituent,
including cyclohexylmethyl, cyclopentylpropyl, and the like.
[0040] "Heterocycloalkyl" refers to a C.sub.3-C.sub.8-cycloalkyl
group according to the definition above, in which 1 to 3 carbon
atoms are replaced by hetero atoms chosen from the group consisting
of O, S, NR, R being defined as hydrogen or C.sub.1-C.sub.6 alkyl.
Preferred heterocycloalkyl include pyrrolidine, piperidine,
piperazine, 1-methylpiperazine, morpholine, and the like.
[0041] "C.sub.1-C.sub.6-alkyl heterocycloalkyl" refers to
C.sub.1-C.sub.6-alkyl groups having a heterocycloalkyl substituent,
including 2-(1-pyrrolidinyl)ethyl, 4-morpholinylmethyl,
(1-methyl-4-piperidinyl)methyl and the like.
[0042] "Carboxy" refers to the group --C(O)OH.
[0043] "C.sub.1-C.sub.6-alkyl carboxy" refers to
C.sub.1-C.sub.6-alkyl groups having a carboxy substituent,
including 2-carboxyethyl and the like.
[0044] "Acyl" refers to the group --C(O)R where R includes H,
"C.sub.1-C.sub.6-alkyl", "C.sub.2-C.sub.6-alkenyl",
"C.sub.2-C.sub.6-alkynyl", "C.sub.3-C.sub.8-cycloalkyl",
""heterocycloalkyl", "aryl", "heteroaryl", "C.sub.1-C.sub.6-alkyl
aryl" or "C.sub.1-C.sub.6-alkyl heteroaryl",
"C.sub.2-C.sub.6-alkenyl aryl", "C.sub.2-C.sub.6-alkenyl
heteroaryl", "C.sub.2-C.sub.6-alkynyl aryl",
"C.sub.2-C.sub.6-alkynylheteroaryl", "C.sub.1-C.sub.6-alkyl
cycloalkyl", "C.sub.1-C.sub.6-alkyl heterocycloalkyl".
[0045] "C.sub.1-C.sub.6-alkyl acyl" refers to C.sub.1-C.sub.6-alkyl
groups having an acyl substituent, including 2-acetylethyl and the
like.
[0046] "Acyloxy" refers to the group --OC(O)R where R includes H,
"C.sub.1-C.sub.6-alkyl", "C.sub.2-C.sub.6-alkenyl",
"C.sub.2-C.sub.6-alkynyl", "C.sub.3-C.sub.8-cycloalkyl",
"heterocycloalkyl", "aryl", "heteroaryl", "C.sub.1-C.sub.6-alkyl
aryl" or "C.sub.1-C.sub.6-alkyl heteroaryl",
"C.sub.2-C.sub.6-alkenyl aryl", "C.sub.2-C.sub.6-alkenyl
heteroaryl", "C.sub.2-C.sub.6-alkynyl aryl",
"C.sub.2-C.sub.6-alkynylheteroaryl", "C.sub.1-C.sub.6-alkyl
cycloalkyl", "C.sub.1-C.sub.6-alkyl heterocycloalkyl".
[0047] "C.sub.1-C.sub.6-alkyl acyloxy" refers to
C.sub.1-C.sub.6-alkyl groups having an acyloxy substituent,
including 2-(acetyloxy)ethyl and the like.
[0048] "Alkoxy" refers to the group --O--R where R includes
"C.sub.1-C.sub.6-alkyl", "C.sub.2-C.sub.6-alkenyl",
"C.sub.2-C.sub.6-alkynyl", "C.sub.3-C.sub.8-cycloalkyl",
"Heterocycloalkyl", "aryl", "heteroaryl", "C.sub.1-C.sub.6-alkyl
aryl" or "C.sub.1-C.sub.6-alkyl heteroaryl",
"C.sub.2-C.sub.6-alkenyl aryl", "C.sub.2-C.sub.6-alkenyl
heteroaryl", "C.sub.2-C.sub.6-alkynyl aryl",
"C.sub.2-C.sub.6-alkynylheteroaryl", "C.sub.1-C.sub.6-alkyl
cycloalkyl", "C.sub.1-C.sub.6-alkyl heterocycloalkyl".
[0049] "C.sub.1-C.sub.6-alkyl alkoxy" refers to
C.sub.1-C.sub.6-alkyl groups having an alkoxy substituent,
including 2-ethoxyethyl and the like.
[0050] "Alkoxycarbonyl" refers to the group --C(O)OR where R
includes "C.sub.1-C.sub.6-alkyl", "C.sub.2-C.sub.6-alkenyl",
"C.sub.2-C.sub.6-alkynyl", "C.sub.3-C.sub.8-cycloalkyl",
"Heterocycloalkyl", "aryl", "heteroaryl", "C.sub.1-C.sub.6-alkyl
aryl" or "C.sub.1-C.sub.6-alkyl heteroaryl",
"C.sub.2-C.sub.6-alkenyl aryl", "C.sub.2-C.sub.6-alkenyl
heteroaryl", "C.sub.2-C.sub.6-alkynyl aryl",
"C.sub.2-C.sub.6-alkynylheteroaryl", "C.sub.1-C.sub.6-alkyl
cycloalkyl", "C.sub.1-C.sub.6-alkyl heterocycloalkyl".
[0051] "C.sub.1-C.sub.6-alkyl alkoxycarbonyl" refers to
C.sub.1-C.sub.6-alkyl groups having an alkoxycarbonyl substituent,
including 2-(benzyloxycarbonyl)ethyl and the like.
[0052] "Aminocarbonyl" refers to the group --C(O)NRR' where each R,
R' includes independently hydrogen, "C.sub.1-C.sub.6-alkyl",
"C.sub.2-C.sub.6-alkenyl", "C.sub.2-C.sub.6-alkynyl",
"C.sub.3-C.sub.8-cycloalkyl", "Heterocycloalkyl", "aryl",
"heteroaryl", "C.sub.1-C.sub.6-alkyl aryl" or
"C.sub.1-C.sub.6-alkyl heteroaryl", "C.sub.2-C.sub.6-alkenyl aryl",
"C.sub.2-C.sub.6-alkenyl heteroaryl", "C.sub.2-C.sub.6-alkynyl
aryl", "C.sub.2-C.sub.6-alkynylheteroaryl", "C.sub.1-C.sub.6-alkyl
cycloalkyl", "C.sub.1-C.sub.6-alkyl heterocycloalkyl".
[0053] "C.sub.1-C.sub.6-alkyl aminocarbonyl" refers to
C.sub.1-C.sub.6-alkyl groups having an aminocarbonyl substituent,
including 2-(dimethylaminocarbonyl)ethyl and the like.
[0054] "Acylamino" refers to the group --NRC(O)R' where each R, R'
is independently hydrogen, "C.sub.1-C.sub.6-alkyl",
"C.sub.2-C.sub.6-alkenyl", "C.sub.2-C.sub.6-alkynyl",
"C.sub.3-C.sub.8-cycloalkyl", "Heterocycloalkyl", "aryl",
"heteroaryl", "C.sub.1-C.sub.6-alkyl aryl" or
"C.sub.1-C.sub.6-alkyl heteroaryl", "C.sub.2-C.sub.6-alkenyl aryl",
"C.sub.2-C.sub.6-alkenyl heteroaryl", "C.sub.2-C.sub.6-alkynyl
aryl", "C.sub.2-C.sub.6-alkynylheteroaryl", "C.sub.1-C.sub.6-alkyl
cycloalkyl", "C.sub.1-C.sub.6-alkyl heterocycloalkyl".
[0055] "C.sub.1-C.sub.6-alkyl acylamino" refers to
C.sub.1-C.sub.6-alkyl groups having an acylamino substituent,
including 2-(propionylamino)ethyl and the like.
[0056] "Ureido" refers to the group --NRC(O)NR'R'' where each R,
R', R'' is independently hydrogen, "C.sub.1-C.sub.6-alkyl",
"C.sub.2-C.sub.6-alkenyl", "C.sub.2-C.sub.6-alkynyl",
"C.sub.3-C.sub.8-cycloalkyl", "Heterocycloalkyl", "aryl",
"heteroaryl", "C.sub.1-C.sub.6-alkyl aryl" or
"C.sub.1-C.sub.6-alkyl heteroaryl", "C.sub.2-C.sub.6-alkenyl aryl",
"C.sub.2-C.sub.6-alkenyl heteroaryl", "C.sub.2-C.sub.6-alkynyl
aryl", "C.sub.2-C.sub.6-alkynylheteroaryl", "C.sub.1-C.sub.6-alkyl
cycloalkyl", "C.sub.1-C.sub.6-alkyl heterocycloalkyl", and where R'
and R'', together with the nitrogen atom to which they are
attached, can optionally form a 3-8-membered heterocycloalkyl
ring.
[0057] "C.sub.1-C.sub.6-alkyl ureido" refers to
C.sub.1-C.sub.6-alkyl groups having an ureido substituent,
including 2-(N'-methylureido)ethyl and the like.
[0058] "Amino" refers to the group --NRR' where each R, R' is
independently hydrogen, "C.sub.1-C.sub.6-alkyl",
"C.sub.2-C.sub.6-alkenyl", "C.sub.2-C.sub.6-alkynyl",
"C.sub.3-C.sub.8-cycloalkyl", "Heterocycloalkyl", "aryl",
"heteroaryl", "C.sub.1-C.sub.6-alkyl aryl" or
"C.sub.1-C.sub.6-alkyl heteroaryl", "C.sub.2-C.sub.6-alkenyl aryl",
"C.sub.2-C.sub.6-alkenyl heteroaryl", "C.sub.2-C.sub.6-alkynyl
aryl", "C.sub.2-C.sub.6-alkynylheteroaryl", "C.sub.1-C.sub.6-alkyl
cycloalkyl", "C.sub.1-C.sub.6-alkyl heterocycloalkyl", and where R
and R', together with the nitrogen atom to which they are attached,
can optionally form a 3-8-membered hetero-cycloalkyl ring.
[0059] "C.sub.1-C.sub.6-alkyl amino" refers to
C.sub.1-C.sub.6-alkyl groups having an amino substituent, including
2-(1-pyrrolidinyl)ethyl and the like.
[0060] "Cyclic amino" refers to piperazinyl, piperidinyl,
imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, isoindolinyl,
pyrazolidinyl, pyrrolidinyl "Acyclic amino" refers to the group
--NRR' where each R, R' is independently hydrogen or
"C.sub.1-C.sub.6-alkyl" or "aryl" or "heteroaryl" or
"C.sub.1-C.sub.6-alkyl aryl" or "C.sub.1-C.sub.6-alkyl heteroaryl",
or "cycloalkyl", or "heterocycloalkyl" and also refers to the
ammonium group --N'RR'R'' such as defined hereinafter.
[0061] "Ammonium" refers to a positively charged group --N'RR'R'',
where each R, R',R'' is independently, "C.sub.1-C.sub.6-alkyl",
"C.sub.2-C.sub.6-alkenyl", "C.sub.2-C.sub.6-alkynyl",
"C.sub.3-C.sub.8-cycloalkyl", "Heterocycloalkyl",
"C.sub.1-C.sub.6-alkyl aryl" or "C.sub.1-C.sub.6-alkyl heteroaryl",
"C.sub.2-C.sub.6-alkenyl aryl", "C.sub.2-C.sub.6-alkenyl
heteroaryl", "C.sub.2-C.sub.6-alkynyl aryl",
"C.sub.2-C.sub.6-alkynylheteroaryl", "C.sub.1-C.sub.6-alkyl
cycloalkyl", "C.sub.1-C.sub.6-alkyl heterocycloalkyl", and where R
and R', together with the nitrogen atom to which they are attached,
can optionally form a 3-8-membered heterocycloalkyl ring.
[0062] "C.sub.1-C.sub.6-alkyl ammonium" refers to
C.sub.1-C.sub.6-alkyl groups having an ammonium substituent,
including 2-(1-pyrrolidinyl)ethyl and the like.
[0063] "Halogen" refers to fluoro, chloro, bromo and iodo
atoms.
[0064] "Sulfonyloxy" refers to a group --OSO.sub.2--R wherein R is
selected from H, "C.sub.1-C.sub.6-alkyl", "C.sub.1-C.sub.6-alkyl"
substituted with halogens, e.g., an --OSO.sub.2--CF.sub.3 group,
"C.sub.2-C.sub.6-alkenyl", "C.sub.2-C.sub.6-alkynyl",
"C.sub.3-C.sub.8-cycloalkyl", "heterocycloalkyl", "aryl",
"heteroaryl", "C.sub.1-C.sub.6-alkyl aryl" or
"C.sub.1-C.sub.6-alkyl heteroaryl", "C.sub.2-C.sub.6-alkenyl aryl",
"C.sub.2-C.sub.6-alkenyl heteroaryl", "C.sub.2-C.sub.6-alkynyl
aryl", "C.sub.2-C.sub.6-alkynylheteroaryl", "C.sub.1-C.sub.6-alkyl
cycloalkyl", "C.sub.1-C.sub.6-alkyl heterocycloalkyl".
[0065] "C.sub.1-C.sub.6-alkyl sulfonyloxy" refers to
C.sub.1-C.sub.6-alkyl groups having a sulfonyloxy substituent,
including 2-(methylsulfonyloxy)ethyl and the like.
[0066] "Sulfonyl" refers to group "--SO.sub.2--R" wherein R is
selected from H, "aryl", "heteroaryl", "C.sub.1-C.sub.6-alkyl",
"C.sub.1-C.sub.6-alkyl" substituted halogens, e.g., an
--SO.sub.2--CF.sub.3 group, "C.sub.2-C.sub.6-alkenyl",
"C.sub.2-C.sub.6-alkynyl", "C.sub.3-C.sub.8-cycloalkyl",
"heterocycloalkyl", "aryl", "heteroaryl", "C.sub.1-C.sub.6-alkyl
aryl" or "C.sub.1-C.sub.6-alkyl heteroaryl",
"C.sub.2-C.sub.6-alkenyl aryl", "C.sub.2-C.sub.6-alkenyl
heteroaryl", "C.sub.2-C.sub.6-alkynyl aryl",
"C.sub.2-C.sub.6-alkynylheteroaryl", "C.sub.1-C.sub.6-alkyl
cycloalkyl", "C.sub.1-C.sub.6-alkyl heterocycloalkyl".
[0067] "C.sub.1-C.sub.6-alkyl sulfonyl" refers to
C.sub.1-C.sub.6-alkyl groups having a sulfonyl substituent,
including 2-(methylsulfonyl)ethyl and the like.
[0068] "Sulfinyl" refers to a group "--S(O)--R" wherein R is
selected from H, "C.sub.1-C.sub.6-alkyl", "C.sub.1-C.sub.6-alkyl"
substituted with halogens, e.g., an --SO--CF.sub.3 group,
"C.sub.2-C.sub.6-alkenyl", "C.sub.2-C.sub.6-alkynyl",
"C.sub.3-C.sub.8-cycloalkyl", "heterocycloalkyl", "aryl",
"heteroaryl", "C.sub.1-C.sub.6-alkyl aryl" or
"C.sub.1-C.sub.6-alkyl heteroaryl", "C.sub.2-C.sub.6-alkenyl aryl",
"C.sub.2-C.sub.6-alkenyl heteroaryl", "C.sub.2-C.sub.6-alkynyl
aryl", "C.sub.2-C.sub.6-alkynylheteroaryl", "C.sub.1-C.sub.6-alkyl
cycloalkyl", "C.sub.1-C.sub.6-alkyl heterocycloalkyl".
[0069] "C.sub.1-C.sub.6-alkyl sulfinyl" refers to
C.sub.1-C.sub.6-alkyl groups having a sulfinyl substituent,
including 2-(methylsulfinyl)ethyl and the like.
[0070] "Sulfanyl" refers to groups --S--R where R includes H,
"C.sub.1-C.sub.6-alkyl", "C.sub.1-C.sub.6-alkyl" substituted with
halogens, e.g., an --SO--CF.sub.3 group, "C.sub.2-C.sub.6-alkenyl",
"C.sub.2-C.sub.6-alkynyl", "C.sub.3-C.sub.8-cycloalkyl",
"heterocycloalkyl", "aryl", "heteroaryl", "C.sub.1-C.sub.6-alkyl
aryl" or "C.sub.1-C.sub.6-alkyl heteroaryl",
"C.sub.2-C.sub.6-alkenyl aryl", "C.sub.2-C.sub.6-alkenyl
heteroaryl", "C.sub.2-C.sub.6-alkynyl aryl",
"C.sub.2-C.sub.6-alkynylheteroaryl", "C.sub.1-C.sub.6-alkyl
cycloalkyl", "C.sub.1-C.sub.6-alkyl heterocycloalkyl". Preferred
sulfanyl groups include methylsulfanyl, ethylsulfanyl, and the
like.
[0071] "C.sub.1-C.sub.6-alkyl sulfanyl" refers to
C.sub.1-C.sub.6-alkyl groups having a sulfanyl substituent,
including 2-(ethylsulfanyl)ethyl and the like.
[0072] "Sulfonylamino" refers to a group --NRSO.sub.2--R' where
each R, R' includes independently hydrogen,
"C.sub.1-C.sub.6-alkyl", "C.sub.2-C.sub.6-alkenyl",
"C.sub.2-C.sub.6-alkynyl", "C.sub.3-C.sub.8-cycloalkyl",
"heterocycloalkyl", "aryl", "heteroaryl", "C.sub.1-C.sub.6-alkyl
aryl" or "C.sub.1-C.sub.6-alkyl heteroaryl",
"C.sub.2-C.sub.6-alkenyl aryl", "C.sub.2-C.sub.6-alkenyl
heteroaryl", "C.sub.2-C.sub.6-alkynyl aryl",
"C.sub.2-C.sub.6-alkynylheteroaryl", "C.sub.1-C.sub.6-alkyl
cycloalkyl", "C.sub.1-C.sub.6-alkyl heterocycloalkyl".
[0073] "C.sub.1-C.sub.6-alkyl sulfonylamino" refers to
C.sub.1-C.sub.6-alkyl groups having a sulfonylamino substituent,
including 2-(ethylsulfonylamino)ethyl and the like.
[0074] "Aminosulfonyl" refers to a group --SO.sub.2--NRR' where
each R, R' includes independently hydrogen,
"C.sub.1-C.sub.6-alkyl", "C.sub.2-C.sub.6-alkenyl",
"C.sub.2-C.sub.6-alkynyl", "C.sub.3-C.sub.8-cycloalkyl",
"heterocycloalkyl", "aryl", "heteroaryl", "C.sub.1-C.sub.6-alkyl
aryl" or "C.sub.1-C.sub.6-alkyl heteroaryl",
"C.sub.2-C.sub.6-alkenyl aryl", "C.sub.2-C.sub.6-alkenyl
heteroaryl", "C.sub.2-C.sub.6-alkynyl aryl",
"C.sub.2-C.sub.6-alkynylheteroaryl", "C.sub.1-C.sub.6-alkyl
cycloalkyl", "C.sub.1-C.sub.6-alkyl heterocycloalkyl".
[0075] "C.sub.1-C.sub.6-alkyl aminosulfonyl" refers to
C.sub.1-C.sub.6-alkyl groups having an aminosulfonyl substituent,
including 2-(cyclohexylaminosulfonyl)ethyl and the like.
[0076] "Substituted or unsubstituted": Unless otherwise constrained
by the definition of the indi-vidual substituent, the above set out
groups, like "alkyl", "alkenyl", "alkynyl", "aryl" and "heteroaryl"
etc. groups can optionally be substituted with from 1 to 5
substituents selected from the group consisting of
"C.sub.1-C.sub.6-alkyl", "C.sub.2-C.sub.6-alkenyl",
"C.sub.2-C.sub.6-alkynyl", "cycloalkyl", "heterocycloalkyl",
"C.sub.1-C.sub.6-alkyl aryl", "C.sub.1-C.sub.6-alkyl heteroaryl",
"C.sub.1-C.sub.6-alkyl cycloalkyl", "C.sub.1-C.sub.6-alkyl
heterocycloalkyl", "amino", "ammonium", "acyl", "acyloxy",
"acylamino", "aminocarbonyl", "alkoxycarbonyl", "ureido", "aryl",
"heteroaryl", "sulfinyl", "sulfonyl", "alkoxy", "sulfanyl",
"halogen", "carboxy", trihalomethyl, cyano, hydroxy, mercapto,
nitro, and the like. Alternatively said substitution could also
comprise situations where neighbouring substituents have undergone
ring closure, notably when vicinal functional substituents are
involved, thus forming, e.g., lactams, lactons, cyclic anhydrides,
but also acetals, thioacetals, aminals formed by ring closure for
instance in an effort to obtain a protective group.
[0077] "Pharmaceutically acceptable salts or complexes" refers to
salts or complexes that retain the desired biological activity of
the below-identified compounds of formula I and exhibit minor or no
undesired toxicological effects. Examples of such salts include,
but are not restricted to acid addition salts formed with inorganic
acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid,
phosphoric acid, nitric acid, and the like), and salts formed with
organic acids such as acetic acid, oxalic acid, tartaric acid,
succinic acid, malic acid, fumaric acid, maleic acid, ascorbic
acid, benzoic acid, tannic acid, pamoic acid, alginic acid,
polyglutamic acid, naphthalene sulfonic acid, naphthalene
disulfonic acid, and poly-galacturonic acid. Said compounds can
also be administered as pharmaceutically acceptable quaternary
salts known by a person skilled in the art, which specifically
include the quarter-nary ammonium salt of the formula
--NR,R',R''.sup.+ Z.sup.-, wherein R, R', R'' is independently
hydrogen, alkyl, or benzyl, and Z is a counterion, including
chloride, bromide, iodide, --O-alkyl, toluenesulfonate,
methylsulfonate, sulfonate, phosphate, or carboxylate (such as
benzoate, succinate, acetate, glycolate, maleate, malate, fumarate,
citrate, tartrate, ascor-bate, cinnamoate, mandeloate, and
diphenylacetate).
[0078] "Pharmaceutically active derivative" refers to any compound
that upon administration to the recipient, is capable of providing
directly or indirectly, the activity disclosed herein.
[0079] The "tautomers" of the compounds according to formula I are
only those wherein R.sup.2 and/or R.sup.0 are hydrogen and which
display the formulae (Ia) and (Ib).
[0080] "Enantiomeric excess" (ee) refers to the products that are
obtained by an asymmetric synthesis, i.e. a synthesis involving
non-racemic starting materials and/or reagents or a synthesis
comprising at least one enantioselective step, whereby a surplus of
one enantiomer in the order of at least about 52% ee is
yielded.
[0081] "Aromatase Inhibitors" refers to drugs that inhibit the
enzyme aromatase and by that lowers the level of the estradiol.
Preferred aromatase inhibitors include by way of example
anastrozole, letrozole, vorozole and exemestane.
[0082] "Estrogen receptor modulators (SERM)" refers to drugs that
block the actions of estrogen by occupying the estrogen receptors
on cells. SERMS also include estrogen receptor beta antagonists and
estrogen receptor beta agonists. Preferred SERMs include by way of
example Tamoxifen, Raloxifen.
[0083] "GnRH antagonists" refers to synthetic GnRH analogues, which
are drugs that competitively block the pituitary GnRH receptor,
which is located on the plasma membrane of gonadotrophs, inducing a
rapid, reversible suppression of gonadotrophin secretion. Preferred
GnRH antagonists include by way of example Cetrorelix,
Ganirelix.
[0084] "GnRH agonists" refers to decapeptide modifications of the
natural hormone GnRH, which are drugs that desensitize GnRH
receptors of the pituitary gland at continued exposure, which
causes an initial stimulation of the pituitary-ovarian axis,
followed by a reduction in circulating serum gonadotrophin
concentration and inhibition of ovarian function. Preferred GnRH
agonists include by way of example Buserelin acetate, Nafarelin,
Leuprolide, Triptorelin, Goserelin.
[0085] "JNK" means a protein or an isoform thereof expressed by a
JNK 1, JNK 2, or JNK 3 gene (Gupta et al. 1996).
[0086] "JNK-inhibitor" refers to a compound, a peptide or a protein
that inhibits c-jun amino terminal kinase (JNK) phosphorylation of
a JNK targeted transcription factor. The JNK-inhibitor is an agent
capable of inhibiting the activity of JNK in vitro or in vivo. Such
inhibitory activity can be determined by an assay or animal model
well-known in the art.
[0087] "Progesterone receptor modulators (SPRMs)": The progesterone
receptor, a member of the superfamily of nuclear receptors, is the
receptor for progesterone that plays a pivotal role in female
reproduction. Selective progesterone receptor modulators are drugs
that can have agonist, antagonist or partial (mixed)
agonist/antagonist activities depending upon the site of action. A
preferred SPRM includes by way of example asoprisnil.
[0088] One embodiment of the present invention is to provide a
method of treating and/or preventing endometriosis in an individual
comprising administering a therapeutically effective amount of a
JNK inhibitor.
[0089] Another embodiment of the present invention relates to a
method of treating and/or preventing endometriosis by sequential or
combined treatment of a hormonal suppressor (e.g. GnRH antagonists,
GnRH agonists, aromatase inhibitors, progesterone receptor
modulators, estrogen receptor modulators) along with a JNK
inhibitor.
[0090] Second or subsequent administrations of therapeutically
effective amounts can be performed at a dosage which is the same,
less than or greater than the initial or previous dose administered
to the individual. Second or subsequent administrations can be
administered during or prior to relapse of the endometriosis or the
related symptoms. The terms "relapse" or "reoccurrence" are defined
to encompass the appearance of one or more of symptoms of
endometriosis.
[0091] In another embodiment, the invention relates to a method of
treating endometriosis-related infertility in a female comprising
the administration of a therapeutically effective amount of a JNK
inhibitor, alone or in combination with other fertility drugs.
[0092] In a further embodiment, the sequential or combined
treatment regimen minimizes the disease by suppressing
endocrine-dependent cells.
[0093] Another embodiment of the present invention consists of a
pharmaceutical composition comprising a JNK inhibitor, a hormal
suppressor (e.g. GnRH antagonists, GnRH agonists, aromatase
inhibitors, progesterone receptor modulators, estrogen receptor
modulators) and a pharmaceutically acceptable excipient.
[0094] Another embodiment of the present invention consists of the
use of a JNK inhibitor in the manufacture of a medicament for the
treatment and/or prevention of endometriosis.
[0095] The term "preventing", as used herein, should be understood
as partially or totally preventing, inhibiting, alleviating, or
reversing one or more symptoms or cause(s) of endometriosis.
[0096] A proposed model for progression of endometriotic disease
predicts that lesions progress from benign inflammatory lesions
responsive to endocrine intervention to partially or completely
hormonally unresponsive lesions that involve upregulated survival
pathways in addition to inflammatory pathways.
[0097] Therefore, in one embodiment, the JNK inhibitor may
interfere with survival pathways in endometriosis.
[0098] Another embodiment of the invention relates to the use of a
JNK inhibitor together with a hormal suppressor (e.g. GnRH
antagonists, GnRH agonists, aromatase inhibitors, progesterone
receptor modulators, estrogen receptor modulators) and a
pharmaceutically acceptable carrier in the manufacture of a
medicament for the treatment and/or prevention of
endometriosis.
[0099] The use of a JNK inhibitor together with a hormal suppressor
(e.g. GnRH antagonists, GnRH agonists, aromatase inhibitors,
progesterone receptor modulators, estrogen receptor modulators) can
be a sequential or a combined use of the JNK inhibitor and the
hormal suppressor.
[0100] Another embodiment of the invention, relates to the use of a
JNK inhibitor, alone or in combination with other drugs, in the
manufacture of a medicament for the treatment of
endometriosis-related infertility.
[0101] In particular, when endometriosis-related infertility is
intended to be treated or cured, biologically active human
chorionic gonadotrophin (hCG), luteinizing hormone (LH) or follicle
stimulating hormone (FSH), either in a natural highly purified or
in a recombinant form, can be administered. Such molecules and
methods of their production have been described in the European
Patent Applications EP 160,699, EP 211,894 and EP 322,438.
[0102] The pharmaceutical compositions of the present invention can
be administered by a variety of routes including oral, rectal,
transdermal, subcutaneous, intravenous, intramuscular and
intranasal. The compositions for oral administration can take the
form of bulk liquid solutions or suspensions, or bulk powders. More
commonly, however, the compositions are presented in unit dosage
forms to facilitate accurate dosing. The term "unit dosage forms"
refers to physically discrete units suitable as unitary dosages for
human subjects and other mammals, each unit containing a
predetermined quantity of active material calculated to produce the
desired therapeutic effect, in association with a suitable
pharmaceutical excipient. Typical unit dosage forms include
prefilled, premeasured ampoules or syringes of the liquid
compositions or pills, tablets, capsules or the like in the case of
solid compositions. In such compositions, the JNK inhibitor is
usually a minor component (from about 0.1 to about 50% by weight or
preferably from about 1 to about 40% by weight) with the remainder
being various vehicles or carriers and processing aids helpful for
forming the desired dosing form.
[0103] Liquid forms suitable for oral administration may include a
suitable aqueous or nonaqueous vehicle with buffers, suspending and
dispensing agents, colorants, flavors and the like.
[0104] Solid forms may include, for example, any of the following
ingredients, or compounds of a similar nature: a binder such as
microcrystalline cellulose, gum tragacanth or gelatine; an
excipient such as starch or lactose, a disintegrating agent such as
alginic acid, Primogel, or corn starch; a lubricant such as
magnesium stearate; a glidant such as colloidal silicon dioxide; a
sweetening agent such as sucrose or saccharin; or a flavoring agent
such as pepper-mint, methyl salicylate, or orange flavoring.
[0105] Injectable compositions are typically based upon injectable
sterile saline or phosphate-buffered saline or other injectable
carriers known in the art. As above-mentioned, the JNK inhibitor in
such compositions is typically a minor component, frequently
ranging between 0.05 to 10% by weight with the remainder being the
injectable carrier and the like.
[0106] The above-described components for orally administered or
injectable compositions are merely representative. Further
materials as well as processing techniques and the like are set out
in Part 5 of Remington's Pharmaceutical Sciences, 20.sup.t1
Edition, 2000, Marck Publishing Company, Easton, Pa., which is
incorporated herein by reference.
[0107] The compounds of this invention can also be administered in
sustained release forms or from sustained release drug delivery
systems. A description of representative sustained release
materials can also be found in the incorporated materials in
Remington's Pharmaceutical Sciences.
[0108] The definition of "pharmaceutically acceptable" is meant to
encompass any carrier, which does not interfere with effectiveness
of the biological activity of the active ingredient and that is not
toxic to the host to which it is administered. For example, for
parenteral administration, JNK inhibitor may be formulated in a
unit dosage form for injection in vehicles such as saline, dextrose
solution, serum albumin and Ringer's solution.
[0109] For parenteral (e.g. intravenous, subcutaneous,
intramuscular) administration, JNK inhibitors can be formulated as
a solution, suspension, emulsion or lyophilized powder in
association with a pharmaceutically acceptable parenteral vehicle
(e.g. water, saline, dextrose solution) and additives that maintain
isotonicity (e.g. mannitol) or chemical stability (e.g.
preservatives and buffers). The formulation is sterilized by
commonly used techniques.
[0110] The therapeutically effective amounts of a JNK inhibitor
will be a function of many variables, including the type of
inhibitor, the affinity of the inhibitor for JNK, any residual
cytotoxic activity exhibited by the JNK inhibitor, the route of
administration or the clinical condition of the patient.
[0111] A "therapeutically effective amount" is such that when
administered, the JNK inhibitor results in inhibition of the
biological activity of JNK. The dosage administered, as single or
multiple doses, to an individual will vary depending upon a variety
of factor, including JNK inhibitor pharmacokinetic properties, the
route of administration, patient conditions and characteristics
(sex, age, body weight, health, size), extent of symptoms,
concurrent treatments, frequency of treatment and the effect
desired. Adjustment and manipulation of established dosage ranges
are well within the ability of those skilled, as well as in vitro
and in vivo methods of determining the inhibition of JNK in an
individual.
[0112] The JNK inhibitors may be of formula (I)
##STR00007##
[0113] Said compounds are disclosed in WO 01/47920 (Applied
Research Systems ARS Holding NV) in which benzazoles derivatives of
formula (A) are described in particular for the treatment of
neuronal disorders, autoimmune diseases, cancer and cardiovascular
diseases:
[0114] In the compounds according to formula (I):
[0115] G is an unsubstituted or substituted pyrimidinyl group.
[0116] L is an unsubstituted or substituted C.sub.1-C.sub.6-alkoxy,
or an amino group, or an unsubstituted or a substituted 3-8
membered heterocycloalkyl, containing at least one heteroatom
selected from N, O, S (e.g. a piperazine, a piperidine, a
morpholine, a pyrrolidine).
[0117] R.sup.1 is selected from the group comprising or consisting
of hydrogen, sulfonyl, amino, unsubstituted or substituted
C.sub.1-C.sub.6-alkyl, unsubstituted or substituted
C.sub.2-C.sub.6-alkenyl, unsubstituted or substituted
C.sub.2-C.sub.6-alkynyl or C.sub.1-C.sub.6-alkoxy, unsubstituted or
substituted aryl (e.g. phenyl), halogen, cyano or hydroxy.
[0118] Preferably R.sup.1 is H or C.sub.1-C.sub.3 alkyl (e.g. a
methyl or ethyl group).
[0119] Formula (I) also comprises its tautomers, its geometrical
isomers, its optically active forms as enantiomers, diastereomers
and its racemate forms, as well as pharmaceutically acceptable
salts thereof. Preferred pharmaceutically acceptable salts of the
formula (I) are acid addition salts formed with pharmaceutically
acceptable acids like hydrochloride, hydrobromide, sulfate or
bisulfate, phosphate or hydrogen phosphate, acetate, benzoate,
succinate, fumarate, maleate, lactate, citrate, tartrate,
gluconate, methanesulfonate, benzenesulfonate, and
para-toluenesulfonate salts.
[0120] More specifically, the benzothiazole acetonitriles of
formula (I) comprise the tautomeric forms, e.g. the below ones:
##STR00008##
[0121] A specific embodiment of the present invention consists in
benzothiazole acetonitriles of formula (Ia) in its tautomeric
forms, e.g. the below ones:
##STR00009##
[0122] R.sup.1 and L are as defined for formula (I).
[0123] According to a specific embodiment, the moiety L is an amino
group of the formula --NR.sup.3R.sup.4 wherein R.sup.3 and R.sup.4
are each independently from each other H, unsubstituted or
substituted C.sub.1-C.sub.6-alkyl, unsubstituted or substituted
C.sub.2-C.sub.6-alkenyl, unsubstituted or substituted
C.sub.2-C.sub.6-alkynyl, unsubstituted or substituted
C.sub.1-C.sub.6-alkoxy, unsubstituted or substituted aryl,
unsubstituted or substituted heteroaryl, unsubstituted or
substituted saturated or unsaturated 3-8-membered cycloalkyl,
unsubstituted or substituted 3-8-membered heterocycloalkyl,
(wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl
groups may be fused with 1-2 further cycloalkyl, heterocycloalkyl,
aryl or heteroaryl group), unsubstituted or substituted
C.sub.1-C.sub.6-alkyl aryl, unsubstituted or substituted
C.sub.1-C.sub.6-alkyl heteroaryl, unsubstituted or substituted
C.sub.2-C.sub.6-alkenyl aryl, unsubstituted or substituted
C.sub.2-C.sub.6-alkenyl heteroaryl, unsubstituted or substituted
C.sub.2-C.sub.6-alkynyl aryl, unsubstituted or substituted
C.sub.2-C.sub.6-alkynyl heteroaryl, unsubstituted or substituted
C.sub.1-C.sub.6-alkyl cycloalkyl, unsubstituted or substituted
C.sub.1-C.sub.6-alkyl heterocycloalkyl, unsubstituted or
substituted C.sub.2-C.sub.6-alkenyl cycloalkyl, unsubstituted or
substituted C.sub.2-C.sub.6-alkenyl heterocycloalkyl, unsubstituted
or substituted C.sub.2-C.sub.6-alkynyl cycloalkyl, unsubstituted or
substituted C.sub.2-C.sub.6-alkynyl heterocycloalkyl.
[0124] Alternatively, R.sup.3 and R.sup.4 may form a ring together
with the nitrogen to which they are attached.
[0125] In a specific embodiment, R.sup.3 is hydrogen or a methyl or
ethyl or propyl group and R.sup.4 is selected from the group
consisting of unsubstituted or substituted (C.sub.1-C.sub.6)-alkyl,
unsubstituted or substituted C.sub.1-C.sub.6 alkyl-aryl,
unsubstituted or substituted C.sub.1-C.sub.6-alkyl-heteroaryl,
unsubstituted or substituted cycloalkyl, unsubstituted or
substituted heterocycloalkyl, unsubstituted or substituted aryl or
heteroaryl and unsubstituted or substituted 4-8 membered saturated
or unsaturated cycloalkyl.
[0126] In a further specific embodiment, R.sup.3 and R.sup.4 form a
substituted or unsubstituted piperazine or a piperidine or a
morpholine or a pyrrolidine ring together with the nitrogen to
which they are bound, whereby said optional substituent is selected
from the group consisting of unsubstituted or substituted
C.sub.1-C.sub.6-alkyl, unsubstituted or substituted
C.sub.2-C.sub.6-alkenyl, unsubstituted or substituted
C.sub.2-C.sub.6-alkynyl, unsubstituted or substituted
C.sub.1-C.sub.6-alkoxy, unsubstituted or substituted aryl,
unsubstituted or substituted heteroaryl, unsubstituted or
substituted saturated or unsaturated 3-8-membered cycloalkyl,
unsubstituted or substituted 3-8-membered heterocycloalkyl,
(wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl
groups may be fused with 1-2 further cycloalkyl, heterocycloalkyl,
aryl or heteroaryl group), unsubstituted or substituted
C.sub.1-C.sub.6-alkyl aryl, unsubstituted or substituted
C.sub.1-C.sub.6-alkyl heteroaryl, unsubstituted or substituted
C.sub.2-C.sub.6-alkenyl aryl, unsubstituted or substituted
C.sub.2-C.sub.6-alkenyl heteroaryl, unsubstituted or substituted
C.sub.2-C.sub.6-alkynyl aryl, unsubstituted or substituted
C.sub.2-C.sub.6-alkynyl heteroaryl, unsubstituted or substituted
C.sub.1-C.sub.6-alkyl cycloalkyl, unsubstituted or substituted
C.sub.1-C.sub.6-alkyl heterocycloalkyl, unsubstituted or
substituted C.sub.2-C.sub.6-alkenyl cycloalkyl, unsubstituted or
substituted C.sub.2-C.sub.6-alkenyl heterocycloalkyl, unsubstituted
or substituted C.sub.2-C.sub.6-alkynyl cycloalkyl, unsubstituted or
substituted C.sub.2-C.sub.6-alkynyl heterocycloalkyl.
[0127] In a specific embodiment L is selected from:
##STR00010##
wherein n is 1 to 3, preferably 1 or 2.
[0128] R.sup.5 and R.sup.5' are independently selected from each
other from the group consisting of H, substituted or unsubstituted
C.sub.1-C.sub.6 alkyl, substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl, substituted or
unsubstituted C.sub.1-C.sub.6 alkyl-aryl and substituted or
unsubstituted C.sub.1-C.sub.6-alkyl-heteroaryl.
[0129] Compounds wherein L is moiety (d) are particularly
preferred.
[0130] Specific examples of compounds of formula (I) include the
following: [0131]
1,3-benzothiazol-2-yl(2,6-dimethoxy-4-pyrimidinyl)acetonitrile
[0132]
1,3-benzothiazol-2-yl(2-{[2-(1H-imidazol-5-yl)ethyl]amino}-4-pyrimidinyl)-
acetonitrile [0133]
1,3-benzothiazol-2-yl[2-(1-piperazinyl)-4-pyrimidinyl]acetonitrile
[0134]
1,3-benzothiazol-2-yl[2-(4-benzyl-1-piperidinyl)-4-pyrimidinyl]acetonitri-
le [0135]
1,3-benzothiazol-2-yl[2-(4-methyl-1-piperazinyl)-4-pyrimidinyl]a-
cetonitrile [0136]
1,3-benzothiazol-2-yl[2-(4-morpholinyl)-4-pyrimidinyl]acetonitrile
[0137]
1,3-benzothiazol-2-yl[2-(methylamino)-4-pyrimidinyl]acetonitrile
[0138]
1,3-benzothiazol-2-yl(2-{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}-4-pyri-
midinyl)-acetonitrile [0139]
1,3-benzothiazol-2-yl{2-[4-(benzyloxy)-1-piperidinyl]-4-pyrimidinyl}aceto-
nitrile [0140]
1,3-benzothiazol-2-yl[2-(4-hydroxy-1-piperidinyl)-4-pyrimidinyl]acetonitr-
ile [0141]
1,3-benzothiazol-2-yl(2-{[2-(dimethylamino)ethyl]amino}-4-pyrim-
idinyl)acetonitrile [0142]
1,3-benzothiazol-2-yl[2-(dimethylamino)-4-pyrimidinyl]acetonitrile
[0143]
1,3-benzothiazol-2-yl{2-[(2-methoxyethyl)amino]-4-pyrimidinyl}acetonitril-
e [0144]
1,3-benzothiazol-2-yl{2-[(2-hydroxyethyl)amino]-4-pyrimidinyl}ace-
tonitrile [0145]
1,3-benzothiazol-2-yl[2-(propylamino)-4-pyrimidinyl]acetonitrile
[0146]
1,3-benzothiazol-2-yl(2-{[3-(1H-imidazol-1-yl)propyl]amino}-4-pyrimidinyl-
)acetonitrile [0147]
1,3-benzothiazol-2-yl[2-(1-pyrrolidinyl)-4-pyrimidinyl]acetonitrile
[0148]
1,3-benzothiazol-2-yl{2-[(2-phenylethyl)amino]-4-pyrimidinyl}aceto-
nitrile [0149]
1,3-benzothiazol-2-yl(2-{[2-(2-pyridinyl)ethyl]amino}-4-pyrimidinyl)aceto-
nitrile [0150]
1,3-benzothiazol-2-yl{2-[(2-pyridinylmethyl)amino]-4-pyrimidinyl}acetonit-
rile [0151]
1,3-benzothiazol-2-yl{2-[4-(1H-1,2,3-benzotriazol-1-yl)-1-piperidinyl]-4--
pyrimidinyl}acetonitrile [0152]
1,3-benzothiazol-2-yl{2-[4-(2-pyrazinyl)-1-piperazinyl]-4-pyrimidinyl}ace-
tonitrile [0153]
1,3-benzothiazol-2-yl{2-[4-(2-pyrimidinyl)-1-piperazinyl]-4-pyrimidinyl}a-
cetonitrile [0154]
1,3-benzothiazol-2-yl(2-{[2-(3-pyridinyl)ethyl]amino}-4-pyrimidinyl)aceto-
nitrile [0155]
1,3-benzothiazol-2-yl(5-bromo-2-{[2-(dimethylamino)ethyl]amino}-4-pyrimid-
inyl)-acetonitrile [0156]
1,3-benzothiazol-2-yl{2-[(2-morpholin-4-ylethyl)amino]pyrimidin-4-yl}acet-
onitrile [0157]
1,3-benzothiazol-2-yl[2-(4-{3-[(trifluoromethyl)sulfonyl]anilino}piperidi-
n-1-yl)pyrimidin-4-yl]acetonitrile [0158]
1,3-benzothiazol-2-yl(2-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}pyrimidin--
4-yl)-acetonitrile [0159]
1,3-benzothiazol-2-yl(2-{methyl[3-(methylamino)propyl]amino}pyrimidin-4-y-
l)acetonitrile [0160]
1,3-benzothiazol-2-yl(2-{[3-(4-methylpiperazin-1-yl)propyl]amino}pyrimidi-
n-4-yl)-acetonitrile [0161]
1,3-benzothiazol-2-yl{2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-4-yl}ace-
tonitrile [0162]
1,3-benzothiazol-2-yl(2-{[2-(1-methyl-1H-imidazol-4-yl)ethyl]amino}pyrimi-
din-4-yl)acetonitrile [0163]
1,3-benzothiazol-2-yl(2-{[2-(1H-indol-3-yl)ethyl]amino}pyrimidin-4-yl)ace-
tonitrile [0164]
1,3-benzothiazol-2-yl(2-{[2-(4-hydroxyphenyl)ethyl]amino}pyrimidin-4-yl)a-
cetonitrile [0165]
tert-butyl({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}amino)ac-
etate [0166]
{2-[(3-aminopropyl)amino]pyrimidin-4-yl}(1,3-benzothiazol-2-yl)acetonitri-
le [0167]
{2-[(2-aminoethyl)amino]pyrimidin-4-yl}(1,3-benzothiazol-2-yl)ac-
etonitrile [0168]
1,3-benzothiazol-2-yl(2-{[3-(dimethylamino)propyl]amino}pyrimidin-4-yl)ac-
etonitrile [0169]
1,3-benzothiazol-2-yl{2-[(2-piperidin-1-ylethyl)amino]pyrimidin-4-yl}acet-
onitrile [0170]
1,3-benzothiazol-2-yl(2-{[2-(1-methyl-1H-imidazol-5-yl)ethyl]amino}pyrimi-
din-4-yl)acetonitrile [0171]
1,3-benzothiazol-2-yl[2-(benzylamino)pyrimidin-4-yl]acetonitrile
isopropyl
3-({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}amino)-
propanoate [0172]
1,3-benzothiazol-2-yl{2-[(3-hydroxypropyl)amino]pyrimidin-4-yl}acetonitri-
le [0173]
1,3-benzothiazol-2-yl{2-[(pyridin-3-ylmethyl)amino]pyrimidin-4-y-
l}acetonitrile [0174]
1,3-benzothiazol-2-yl{2-[(pyridin-4-ylmethyl)amino]pyrimidin-4-yl}acetoni-
trile [0175] tert-butyl
4-[2-({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}amino)-ethyl]-
phenylcarbamate [0176]
(2-{[2-(4-aminophenyl)ethyl]amino}pyrimidin-4-yl)(1,3-benzothiazol-2-yl)a-
cetonitrile [0177]
1,3-benzothiazol-2-yl(2-{[2-(3,4-dimethoxyphenyl)ethyl]amino}pyrimidin-4--
yl)acetonitrile [0178]
1,3-benzothiazol-2-yl(2-{[2-(3-methoxyphenyl)ethyl]amino}pyrimidin-4-yl)a-
cetonitrile [0179]
1,3-benzothiazol-2-yl(2-{[2-(2-fluorophenyl)ethyl]amino}pyrimidin-4-yl)ac-
etonitrile [0180]
1,3-benzothiazol-2-yl[2-({2-[3-(trifluoromethyl)phenyl]ethyl}amino)pyrimi-
din-4-yl]acetonitrile [0181]
1,3-benzothiazol-2-yl{2-[(2-hydroxy-2-phenylethyl)amino]pyrimidin-4-yl}ac-
etonitrile [0182]
1,3-benzothiazol-2-yl{2-[(2-{[3-(trifluoromethyl)pyridin-2-yl]amino}ethyl-
)amino]-pyrimidin-4-yl}acetonitrile [0183]
1,3-benzothiazol-2-yl(2-{[2-(3-chlorophenyl)ethyl]amino}pyrimidin-4-yl)ac-
etonitrile [0184]
1,3-benzothiazol-2-yl(2-{[2-(3,4-dichlorophenyl)ethyl]amino}pyrimidin-4-y-
l)acetonitrile [0185]
1,3-benzothiazol-2-yl(2-{[2-(4-methoxyphenyl)ethyl]amino}pyrimidin-4-yl)a-
cetonitrile [0186]
1,3-benzothiazol-2-yl(2-{[2-(4-methylphenyl)ethyl]amino}pyrimidin-4-yl)ac-
etonitrile [0187]
1,3-benzothiazol-2-yl(2-{[2-(3-fluorophenyl)ethyl]amino}pyrimidin-4-yl)ac-
etonitrile [0188]
1,3-benzothiazol-2-yl(2-{[2-(4-phenoxyphenyl)ethyl]amino}pyrimidin-4-yl)a-
cetonitrile [0189]
1,3-benzothiazol-2-yl(2-{[2-(2-phenoxyphenyl)ethyl]amino}pyrimidin-4-yl)a-
cetonitrile [0190]
1,3-benzothiazol-2-yl(2-{[2-(4-bromophenyl)ethyl]amino}pyrimidin-4-yl)ace-
tonitrile [0191]
1,3-benzothiazol-2-yl(2-{[2-(4-fluorophenyl)ethyl]amino}pyrimidin-4-yl)ac-
etonitrile [0192]
1,3-benzothiazol-2-yl{2-[(2-[1,1'-biphenyl]-4-ylethyl)amino]pyrimidin-4-y-
l}acetonitrile [0193]
1,3-benzothiazol-2-yl{2-[(2-{4-[hydroxy(oxido)amino]phenyl}ethyl)amino]py-
rimidin-4-yl}acetonitrile [0194]
1,3-benzothiazol-2-yl(2-{[2-(1H-1,2,4-triazol-1-yl)ethyl]amino}pyrimidin--
4-yl)acetonitrile [0195]
1,3-benzothiazol-2-yl(2-{[3-(1H-pyrazol-1-yl)propyl]amino}pyrimidin-4-yl)-
acetonitrile [0196]
4-[2-({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}amino)ethyl]b-
enzene-sulfonamide [0197]
{2-[(2-pyridin-3-ylethyl)amino]pyrimidin-4-yl}[5-(trifluoromethyl)-1,3-be-
nzothiazol-2-yl]acetonitrile [0198]
1,3-benzothiazol-2-yl{2-[(1H-tetrazol-5-ylmethyl)amino]pyrimidin-4-yl}ace-
tonitrile [0199]
1,3-benzothiazol-2-yl[2-(benzyloxy)pyrimidin-4-yl]acetonitrile
[0200]
1,3-benzothiazol-2-yl{2-[(4-pyridin-3-ylbenzyl)oxy]pyrimidin-4-yl}acetoni-
trile [0201]
1,3-benzothiazol-2-yl[2-(pyridin-4-ylmethoxy)pyrimidin-4-yl]acetonitrile
[0202]
1,3-benzothiazol-2-yl[2-(pyridin-2-ylmethoxy)pyrimidin-4-yl]aceton-
itrile [0203]
1,3-benzothiazol-2-yl[2-(3-pyridin-2-ylpropoxy)pyrimidin-4-yl]acetonitril-
e [0204]
1,3-benzothiazol-2-yl{2-[(4-methoxybenzyl)oxy]pyrimidin-4-yl}acet-
onitrile [0205]
1,3-benzothiazol-2-yl[2-(pyridin-3-ylmethoxy)pyrimidin-4-yl]acetonitrile
[0206]
1,3-benzothiazol-2-yl{2-[2-(4-methoxyphenyl)ethoxy]pyrimidin-4-yl}-
acetonitrile [0207]
1,3-benzothiazol-2-yl[2-([1,1'-biphenyl]-3-ylmethoxy)pyrimidin-4-yl]aceto-
nitrile [0208]
1,3-benzothiazol-2-yl{2-[(3,4,5-trimethoxybenzyl)oxy]pyrimidin-4-yl}aceto-
nitrile [0209]
1,3-benzothiazol-2-yl{2-[(3,4-dichlorobenzyl)oxy]pyrimidin-4-yl}acetonitr-
ile [0210]
1,3-benzothiazol-2-yl[2-({3-[(dimethylamino)methyl]benzyl}oxy)p-
yrimidin-4-yl]acetonitrile [0211]
1,3-benzothiazol-2-yl{2-[(1-oxidopyridin-3-yl)methoxy]pyrimidin-4-yl}acet-
onitrile [0212]
1,3-benzothiazol-2-yl(2-{[4-(morpholin-4-ylmethyl)benzyl]oxy}pyrimidin-4--
yl)acetonitrile [0213]
1,3-benzothiazol-2-yl{2-[(4-pyridin-2-ylbenzyl)oxy]pyrimidin-4-yl}acetoni-
trile [0214]
1,3-benzothiazol-2-yl(2-{[4-(piperidin-1-ylmethyl)benzyl]oxy}pyrimidin-4--
yl)acetonitrile [0215]
1,3-benzothiazol-2-yl[2-(4-methoxyphenoxy)pyrimidin-4-yl]acetonitrile
[0216]
1,3-benzothiazol-2-yl[2-(4-butoxyphenoxy)pyrimidin-4-yl]acetonitri-
le [0217]
{2-[4-(4-acetylpiperazin-1-yl)phenoxy]pyrimidin-4-yl}(1,3-benzot-
hiazol-2-yl)acetonitrile [0218]
[2-(4-methoxyphenoxy)pyrimidin-4-yl][5-(trifluoromethyl)-1,3-benzothiazol-
-2-yl]acetonitrile [0219]
N-[2-({4-[1,3-benzothiazol-2-yl(cyano)methyl]pyrimidin-2-yl}amino)ethyl]--
4-chlorobenzamide [0220]
1,3-benzothiazol-2-yl(2-methoxy-4-pyrimidinyl)acetonitrile [0221]
1,3-benzothiazol-2-yl[2-({4-[(4-methylpiperazin-1-yl)methyl]benzyl}oxy)py-
rimidin-4-yl]acetonitrile [0222]
1,3-benzothiazol-2-yl[2-({4-[(4-benzyl-piperazin-1-yl)methyl]-benzyl}oxy)-
pyrimidin-4-yl]acetonitrile [0223]
1,3-benzothiazol-2-yl(2-{[4-(piperazin-1-ylmethyl)benzyl]oxy}pyrimidin-4--
yl)acetonitrile [0224]
1,3-benzothiazol-2-yl[2-({4-[(4-formylpiperazin-1-yl)methyl]benzyl}oxy)py-
rimidin-4-yl]acetonitrile [0225]
[2-({4-[(4-acetylpiperazin-1-yl)methyl]benzyl}oxy)pyrimidin-4-yl](1,3-ben-
zothiazol-2-yl)acetonitrile [0226]
(3H-Benzothiazol-2-ylidene)-{2-[4-(4-[1,2,4]oxadiazol-3-ylmethyl-piperazi-
n-1-ylmethyl)-benzyloxy]-pyrimidin-4-yl}-acetonitrile [0227]
4-(4-{4-[(3H-Benzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxymethy-
l}-benzyl)-piperazine-1-carboxylic acid methyl ester [0228]
2-[4-(4-{4-[(3H-Benzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxyme-
thyl}-benzyl)-piperazin-1-yl]-acetamide [0229]
(2-{4-[4-(2-Amino-acetyl)-piperazin-1-ylmethyl]-benzyloxy}-pyrimidin-4-yl-
)-(3H-benzothiazol-2-ylidene)-acetonitrile [0230]
[4-(4-{4-[(3H-Benzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxymeth-
yl}-benzyl)-piperazin-1-yl]-acetic acid methyl ester [0231]
(3H-Benzothiazol-2-ylidene)-(2-{4-[4-(2-methoxy-ethyl)-piperazin-1-ylmeth-
yl]-benzyloxy}-pyrimidin-4-yl)-acetonitrile [0232]
4-(4-{4-[(3H-Benzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxymethy-
l}-benzyl)-piperazine-1-carboxylic acid dimethylamide [0233]
(3H-Benzothiazol-2-ylidene)-{2-[4-(4-ethyl-piperazin-1-ylmethyl)-benzylox-
y]-pyrimidin-4-yl}-acetonitrile [0234]
(3H-Benzothiazol-2-ylidene)-(2-{4-[4-(2-hydroxy-ethyl)-piperazin-1-ylmeth-
yl]-benzyloxy}-pyrimidin-4-yl)-acetonitrile
[0235] The compounds of formula (I) may be obtained according to
methods described in WO 01/47920.
[0236] In a further embodiment, the compounds of formula (I), are
of sub-structure (II) and corresponding tautomers thereof
##STR00011##
[0237] wherein R in formula (II) is selected from the group
comprising or consisting of hydrogen, substituted or unsubstituted
C.sub.1-C.sub.6-alkyl, substituted or unsubstituted
C.sub.1-C.sub.6-alkyl aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted C.sub.1-C.sub.6-alkyl
heteroaryl, substituted or unsubstituted C.sub.2-C.sub.6-alkenyl,
substituted or unsubstituted C.sub.2-C.sub.6-alkenyl aryl,
substituted or unsubstituted C.sub.2-C.sub.6-alkenyl heteroaryl,
substituted or unsubstituted C.sub.2-C.sub.6-alkynyl, substituted
or unsubstituted C.sub.2-C.sub.6-alkynyl aryl, substituted or
unsubstituted C.sub.2-C.sub.6-alkynyl heteroaryl, substituted or
unsubstituted C.sub.3-C.sub.8-cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted
C.sub.1-C.sub.6-alkyl cycloalkyl, substituted or unsubstituted
C.sub.1-C.sub.6-alkyl heterocycloalkyl, substituted or
unsubstituted C.sub.1-C.sub.6-alkyl carboxy, acyl, substituted or
unsubstituted C.sub.1-C.sub.6-alkyl acyl, acyloxy, substituted or
unsubstituted C.sub.1-C.sub.6-alkyl acyloxy, substituted or
unsubstituted C.sub.1-C.sub.6-alkyl alkoxy, alkoxycarbonyl,
substituted or unsubstituted C.sub.1-C.sub.6-alkyl alkoxycarbonyl,
aminocarbonyl, substituted or unsubstituted C.sub.1-C.sub.6-alkyl
aminocarbonyl, acylamino, substituted or unsubstituted
C.sub.1-C.sub.6-alkyl acylamino, ureido, substituted or
unsubstituted C.sub.1-C.sub.6-alkyl ureido, amino, substituted or
unsubstituted C.sub.1-C.sub.6-alkyl amino, sulfonyloxy, substituted
or unsubstituted C.sub.1-C.sub.6-alkyl sulfonyloxy, sulfonyl,
substituted or unsubstituted C.sub.1-C.sub.6-alkyl sulfonyl,
sulfinyl, substituted or unsubstituted C.sub.1-C.sub.6-alkyl
sulfinyl, sulfanyl, substituted or unsubstituted
C.sub.1-C.sub.6-alkyl sulfanyl, sulfonylamino, substituted or
unsubstituted C.sub.1-C.sub.6-alkyl sulfonylamino.
[0238] R.sup.1 is selected from the group comprising or consisting
of H, halogen, cyano, nitro, amino, substituted or unsubstituted
C.sub.1-C.sub.6-alkyl, in particular C.sub.1-C.sub.3 alkyl, like
methyl or ethyl or --CF.sub.3, substituted or unsubstituted
C.sub.2-C.sub.6-alkenyl, substituted or unsubstituted
C.sub.2-C.sub.6-alkynyl, substituted or unsubstituted
C.sub.1-C.sub.6-alkyl-aryl, substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl, substituted or
unsubstituted C.sub.1-C.sub.6-alkyl-heteroaryl, --C(O)--OR.sup.2,
--C(O)--R.sup.2, --C(O)--NR.sup.2R.sup.2', --(SO.sub.2)R.sup.2,
with R.sup.2 and R.sup.2' being independently selected from the
group comprising or consisting of hydrogen, unsubstituted or
substituted C.sub.1-C.sub.6 alkyl, unsubstituted or substituted
C.sub.2-C.sub.6 alkenyl, unsubstituted or substituted
C.sub.2-C.sub.6 alkynyl, unsubstituted or substituted aryl,
unsubstituted or substituted heteroaryl, unsubstituted or
substituted C.sub.1-C.sub.6-alkyl aryl, unsubstituted or
substituted C.sub.1-C.sub.6-alkyl heteroaryl. Preferably R.sup.1 is
H n is an integer from 0 to 3, more preferred is 1.
[0239] Specific piperazine benzothiazole derivatives according to
the present invention are selected from the following group: [0240]
1,3-benzothiazol-2-yl[2-({4-[(4-methylpiperazin-1-yl)methyl]benzyl}oxy)py-
rimidin-4-yl]acetonitrile [0241]
1,3-benzothiazol-2-yl[2-({4-[(4-benzyl-piperazin-1-yl)methyl]-benzyl}oxy)-
pyrimidin-4-yl]acetonitrile [0242]
1,3-benzothiazol-2-yl(2-{[4-(piperazin-1-ylmethyl)benzyl]oxy}pyrimidin-4--
yl)acetonitrile [0243]
1,3-benzothiazol-2-yl[2-({4-[(4-formylpiperazin-1-yl)methyl]benzyl}oxy)py-
rimidin-4-yl]acetonitrile [0244]
[2-({4-[(4-acetylpiperazin-1-yl)methyl]benzyl}oxy)pyrimidin-4-yl](1,3-ben-
zothiazol-2-yl)acetonitrile [0245]
(3H-Benzothiazol-2-ylidene)-{2-[4-(4-[1,2,4]oxadiazol-3-ylmethyl-piperazi-
n-1-ylmethyl)-benzyloxy]-pyrimidin-4-yl}-acetonitrile [0246]
4-(4-{4-[(3H-Benzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxymethy-
l}-benzyl)-piperazine-1-carboxylic acid methyl ester [0247]
2-[4-(4-{4-[(3H-Benzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxyme-
thyl}-benzyl)-piperazin-1-yl]-acetamide [0248]
(2-{4-[4-(2-Amino-acetyl)-piperazin-1-ylmethyl]-benzyloxy}-pyrimidin-4-yl-
)-(3H-benzothiazol-2-ylidene)-acetonitrile [0249]
[4-(4-{4-[(3H-Benzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxymeth-
yl}-benzyl)-piperazin-1-yl]-acetic acid methyl ester [0250]
(3H-Benzothiazol-2-ylidene)-(2-{4-[4-(2-methoxy-ethyl)-piperazin-1-ylmeth-
yl]-benzyloxy}-pyrimidin-4-yl)-acetonitrile [0251]
4-(4-{4-[(3H-Benzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxymethy-
l}-benzyl)-piperazine-1-carboxylic acid dimethylamide [0252]
(3H-Benzothiazol-2-ylidene)-{2-[4-(4-ethyl-piperazin-1-ylmethyl)-benzylox-
y]-pyrimidin-4-yl}-acetonitrile [0253]
(3H-Benzothiazol-2-ylidene)-(2-{4-[4-(2-hydroxy-ethyl)-piperazin-1-ylmeth-
yl]-benzyloxy}-pyrimidin-4-yl)-acetonitrile.
[0254] The compounds of formula (II) may be obtained according to
the methods described in WO 03/091249.
[0255] In a further embodiment the JNK inhibitors may have the
formula (III):
##STR00012##
[0256] Y is an unsubstituted or a substituted 4-12-membered
saturated cyclic or bicyclic alkyl ring containing at least one
nitrogen atom (heterocycle), whereby one nitrogen atom within said
ring is forming a bond with the sulfonyl group of formula III, thus
providing a sulfonamide.
[0257] R.sup.1 is selected from the group comprising or consisting
of hydrogen, unsubstituted or a substituted C.sub.1-C.sub.6-alkoxy,
unsubstituted or a substituted C.sub.1-C.sub.6-alkyl, unsubstituted
or a substituted C.sub.2-C.sub.6-alkenyl, unsubstituted or a
substituted C.sub.2-C.sub.6-alkynyl, amino, sulfanyl, sulfinyl,
sulfonyl, sulfonyloxy, sulfonamide, acylamino, aminocarbonyl,
unsubstituted or a substituted C.sub.1-C.sub.6 alkoxycarbonyl,
unsubstituted or a substituted aryl, unsubstituted or a substituted
heteroaryl, carboxy, cyano, halogen, hydroxy, nitro, hydrazide.
[0258] More specifically, R.sup.1 is selected from the group
consisting of hydrogen, halogen (e.g. chlorine), C.sub.1-C.sub.6
alkyl (e.g. methyl or ethyl) or C.sub.1-C.sub.6 alkoxy (e.g.
methoxy or ethoxy). Most preferred is halogen, in particular
chlorine.
[0259] R.sup.2 is selected from the group comprising or consisting
of hydrogen, COOR.sup.3, --CONR.sup.3R.sup.3', OH, a
C.sub.1-C.sub.4 alkyl substituted with an OH or amino group, a
hydrazido carbonyl group, a sulfate, a sulfonate, an amine or an
ammonium salt. Thereby, R.sup.3, R.sup.3' are independently
selected from the group consisting of H, C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl, aryl, heteroaryl,
aryl-C.sub.1-C.sub.6-alkyl, heteroaryl-C.sub.1-C.sub.6-alkyl.
[0260] According to one embodiment the cyclic amines Y have either
of the general formulae (a) to (d):
##STR00013##
[0261] Thereby, L.sup.1 and L.sup.2 are independently selected from
each other from the group consisting of unsubstituted or a
substituted C.sub.1-C.sub.6-alkyl, unsubstituted or a substituted
C.sub.2-C.sub.6-alkenyl, unsubstituted or a substituted
C.sub.2-C.sub.6-alkynyl, unsubstituted or a substituted
C.sub.4-C.sub.8-cycloalkyl optionally containing 1-3 heteroatoms
and optionally fused with aryl or heteroaryl.
[0262] Alternatively, L.sup.1 and L.sup.2 are independently
selected from the group consisting of unsubstituted or a
substituted aryl, unsubstituted or a substituted heteroaryl,
unsubstituted or a substituted aryl-C.sub.1-C.sub.6-alkyl,
unsubstituted or a substituted heteroaryl-C.sub.1-C.sub.6-alkyl,
--C(O)--OR.sup.3, --C(O)--R.sup.3, --C(O)--NR.sup.3'R.sup.3,
--NR.sup.3'R.sup.3, --NR.sup.3'C(O)R.sup.3,
--NR.sup.3'C(O)NR.sup.3'R.sup.3, --(SO)R.sup.3,
--(SO.sub.2)R.sup.3, --NSO.sub.2R.sup.3,
--SO.sub.2NR.sup.3'R.sup.3.
[0263] Alternatively, L.sup.1 and L.sup.2 taken together may form a
4-8-membered, unsubstituted or a substituted saturated cyclic alkyl
or heteroalkyl ring.
[0264] R.sup.3, R.sup.3' are independently selected from the group
consisting of H, unsubstituted or a substituted
C.sub.1-C.sub.6-alkyl, unsubstituted or a substituted
C.sub.2-C.sub.6-alkenyl, unsubstituted or a substituted aryl,
unsubstituted or a substituted heteroaryl, unsubstituted or a
substituted aryl-C.sub.1-C.sub.6-alkyl, unsubstituted or a
substituted heteroaryl-C.sub.1-C.sub.6-alkyl.
[0265] R.sup.6 is selected from the group consisting of hydrogen,
unsubstituted or a substituted C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkoxy, OH, halogen, nitro, cyano, sulfonyl, oxo
(.dbd.O), and n' is an integer from 0 to 4, preferably 1 or 2. In
one embodiment R.sup.6 is hydrogen.
[0266] In a further specific embodiment R.sup.6 is H, L.sup.2 is H,
L.sup.1 is --NR.sup.3'R.sup.3; where at least one of R.sup.3' and
R.sup.3 is not hydrogen, but a substituent selected from the group
consisting of straight or branched C.sub.4-C.sub.18-alkyl,
aryl-C.sub.1-C.sub.18-alkyl, heteroaryl-C.sub.2-C.sub.18-alkyl,
C.sub.1-C.sub.14-alkyl substituted with a
C.sub.3-C.sub.12-cycloalkyl or -bicyclo or -tricyloalkyl, and
whereby said alkyl chain may contain 1-3 O or S atoms.
[0267] In a more specific embodiment L.sup.1 is --NHR.sup.3; where
R.sup.3 is a straight or branched C.sub.4-C.sub.12-alkyl,
preferably a C.sub.6-C.sub.12-alkyl, optionally substituted with a
cyclohexyl group or a benzyl group.
[0268] In an even more specific embodiment Y is a piperidine
group
##STR00014##
[0269] L.sup.1 is --NHR.sup.3; where R.sup.3 is a straight or
branched C.sub.4-C.sub.12-alkyl, preferably a
C.sub.8-C.sub.12-alkyl, or a benzyl group.
[0270] Specific examples of compounds of formula (III) include the
following: [0271]
4-chloro-N-[5-(piperazine-1-sulfonyl)-thiophen-2-yl-methyl]-benzamide
[0272]
4-Chloro-N-{5-[4-(3-trifluoromethanesulfonyl-phenylamino)-piperidi-
ne-1-sulfonyl]-thiophen-2-ylmethyl}-benzamide [0273]
4-chloro-N-({5-[(4-pyridin-2-ylpiperazin-1-yl)sulfonyl]thien-2-yl}methyl)-
benzamide [0274]
4-chloro-N-[(5-{[4-(4-fluorobenzoyl)piperidin-1-yl]sulfonyl}thien-2-yl)me-
thyl]benzamide [0275]
4-chloro-N-{[5-({4-[4-(trifluoromethyl)phenyl]piperazin-1-yl}sulfonyl)thi-
en-2-yl]methyl}benzamide [0276]
4-chloro-N-({5-[(4-{2-nitrophenyl}piperazin-1-yl)sulfonyl]thien-2-yl}meth-
yl)benzamide [0277]
4-chloro-N-({5-[(4-{4-nitrophenyl}piperazin-1-yl)sulfonyl]thien-2-yl}meth-
yl)benzamide [0278]
4-chloro-N-[(5-{[4-(2-furoyl)piperazin-1-yl]sulfonyl}thien-2-yl)methyl]be-
nzamide [0279]
4-chloro-N-[(5-{[4-(4-hydroxyphenyl)piperazin-1-yl]sulfonyl}thien-2-yl)me-
thyl]benzamide [0280]
4-chloro-N-[(5-{[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]sulfonyl}-
thien-2-yl)methyl]benzamide [0281]
4-chloro-N-[(5-{[4-(2-morpholin-4-yl-2-oxoethyl)piperazin-1-yl]sulfonyl}t-
hien-2-yl)methyl]benzamide [0282]
4-chloro-N-[(5-{[4-(pyridin-4-ylmethyl)piperazin-1-yl]sulfonyl}thien-2-yl-
)methyl]benzamide [0283]
4-chloro-N-[(5-{[4-(2-thien-2-ylethyl)piperazin-1-yl]sulfonyl}thien-2-yl)-
methyl]benzamide [0284]
4-chloro-N-[(5-{[4-(3,5-dimethoxyphenyl)piperazin-1-yl]sulfonyl}thien-2-y-
l)methyl]benzamide [0285]
4-chloro-N-[(5-{[4-(cyclohexylmethyl)piperazin-1-yl]sulfonyl}thien-2-yl)m-
ethyl]benzamide [0286]
4-chloro-N-[(5-{[4-(2-methoxyphenyl)piperazin-1-yl]sulfonyl}thien-2-yl)me-
thyl]benzamide [0287]
N-({5-[(4-benzylpiperazin-1-yl)sulfonyl]thien-2-yl}methyl)-4-chlorobenzam-
ide [0288]
4-chloro-N-[(5-{[4-(2-phenylethyl)piperazin-1-yl]sulfonyl}thien-
-2-yl)methyl]benzamide [0289]
4-chloro-N-[(5-{[4-(4-fluorobenzyl)piperazin-1-yl]sulfonyl}thien-2-yl)met-
hyl]benzamide [0290]
4-chloro-N-[(5-{[4-(2-cyanophenyl)piperazin-1-yl]sulfonyl}thien-2-yl)meth-
yl]benzamide [0291]
4-chloro-N-{[5-({4-[4-chloro-3-(trifluoromethyl)phenyl]piperazin-1-yl}sul-
fonyl)thien-2-yl]methyl}benzamide [0292]
4-chloro-N-[(5-{[4-(3-piperidin-1-ylpropyl)piperazin-1-yl]sulfonyl}thien--
2-yl)methyl]benzamide [0293]
4-chloro-N-({5-[(4-{4-chloro-2-nitrophenyl}piperazin-1-yl)sulfonyl]thien--
2-yl}methyl)benzamide [0294]
4-chloro-N-[(5-{[4-(6-methylpyridin-2-yl)piperazin-1-yl]sulfonyl}thien-2--
yl)methyl]benzamide [0295]
4-chloro-N-({5-[(4-hydroxy-4-phenylpiperidin-1-yl)sulfonyl]thien-2-yl}met-
hyl)benzamide [0296]
N-({5-[(4-benzoylpiperidin-1-yl)sulfonyl]thien-2-yl}methyl)-4-chlorobenza-
mide [0297]
4-chloro-N-[(5-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl-
]sulfonyl}thien-2-yl)methyl]benzamide [0298]
N-({5-[(4-benzylpiperidin-1-yl)sulfonyl]thien-2-yl}methyl)-4-chlorobenzam-
ide [0299]
4-chloro-N-({5-[(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)-
sulfonyl]thien-2-yl}methyl)benzamide [0300]
4-chloro-N-{[5-({4-[2-(methylanilino)-2-oxoethyl]piperazin-1-yl}sulfonyl)-
thien-2-yl]methyl}benzamide [0301]
4-chloro-N-{[5-({4-[hydroxy(diphenyl)methyl]piperidin-1-yl}sulfonyl)thien-
-2-yl]methyl}benzamide [0302]
4-chloro-N-[(5-{[4-(3-cyanopyrazin-2-yl)piperazin-1-yl]sulfonyl}thien-2-y-
l)methyl]benzamide [0303]
4-chloro-N-({5-[(4-{5-nitropyridin-2-yl}piperazin-1-yl)sulfonyl]thien-2-y-
l}methyl)benzamide [0304]
4-chloro-N-{[5-({4-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]piperazin-1--
yl}sulfonyl)thien-2-yl]methyl}benzamide [0305]
4-chloro-N-{[5-({4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}sulfon-
yl)thien-2-yl]methyl}benzamide [0306]
4-chloro-N-{[5-({4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}sulfon-
yl)thien-2-yl]methyl}benzamide [0307]
4-chloro-N-[(5-{[4-(2,4-difluorobenzoyl)piperidin-1-yl]sulfonyl}thien-2-y-
l)methyl]benzamide [0308] methyl
5-{4-[(5-{[(4-chlorobenzoyl)amino]methyl}thien-2-yl)sulfonyl]piperazin-1--
yl}-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate [0309]
ethyl
2-{4-[(5-{[(4-chlorobenzoyl)amino]methyl}thien-2-yl)sulfonyl]piperazin-1--
yl}-5-cyano-6-methylnicotinate [0310]
4-chloro-N-{[5-({4-[5-cyano-4,6-bis(dimethylamino)pyridin-2-yl]piperazin--
1-yl}sulfonyl)thien-2-yl]methyl}benzamide [0311]
4-chloro-N-{[5-({4-[6-methyl-2-(trifluoromethyl)quinolin-4-yl]piperazin-1-
-yl}sulfonyl)thien-2-yl]methyl}benzamide [0312] tert-butyl
4-[(5-{[(4-chlorobenzoyl)amino]methyl}thien-2-yl)sulfonyl]piperazine-1-ca-
rboxylate [0313]
2-{4-[(5-{[(4-chlorobenzoyl)amino]methyl}thien-2-yl)sulfonyl]piperazin-1--
yl}-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylic
acid [0314]
7-{4-[(5-{[(4-chlorobenzoyl)amino]methyl}thien-2-yl)sulfonyl]piper-
azin-1-yl}-1-ethyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxyl-
ic acid [0315]
7-{4-[(5-{[(4-chlorobenzoyl)amino]methyl}thien-2-yl)sulfonyl]piperazin-1--
yl}-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
[0316]
4-chloro-N-[(5-{[4-(2,3-dihydro-1,4-benzodioxin-2-ylcarbonyl)piperazin-1--
yl]sulfonyl}thien-2-yl)methyl]benzamide [0317]
4-chloro-N-{[5-({4-[(2E)-3-phenylprop-2-enyl]piperazin-1-yl}sulfonyl)thie-
n-2-yl]methyl}benzamide [0318]
4-chloro-N-[(5-{[4-(3-phenylpropyl)piperazin-1-yl]sulfonyl}thien-2-yl)met-
hyl]benzamide [0319]
4-chloro-N-[(5-{[4-(3,4,5-trimethoxyphenyl)piperazin-1-yl]sulfonyl}thien--
2-yl)methyl]benzamide [0320]
N-[(5-{[4-(4-tert-butylbenzyl)piperazin-1-yl]sulfonyl}thien-2-yl)methyl]--
4-chlorobenzamide [0321]
4-chloro-N-[(5-{[4-(4-fluorophenyl)piperazin-1-yl]sulfonyl}thien-2-yl)met-
hyl]benzamide [0322]
4-chloro-N-[(5-{[4-(2-hydroxyphenyl)piperazin-1-yl]sulfonyl}thien-2-yl)me-
thyl]benzamide [0323]
4-chloro-N-{[5-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}sulfon-
yl)thien-2-yl]methyl}benzamide [0324]
4-chloro-N-[(5-{[4-(5-cyanopyridin-2-yl)piperazin-1-yl]sulfonyl}thien-2-y-
l)methyl]benzamide [0325] tert-butyl
1-[(5-{[(4-chlorobenzoyl)amino]methyl}thien-2-yl)sulfonyl]piperidin-4-ylc-
arbamate [0326]
4-chloro-N-({5-[(4-phenylpiperazin-1-yl)sulfonyl]thien-2-yl}methyl)benzam-
ide [0327]
4-chloro-N-{[5-(piperidin-1-ylsulfonyl)thien-2-yl]methyl}benzam-
ide [0328]
4-chloro-N-[(5-{[4-(1-naphthyl)piperazin-1-yl]sulfonyl}thien-2--
yl)methyl]benzamide [0329]
4-chloro-N-[(5-{[4-(3,4-dichlorophenyl)piperazin-1-yl]sulfonyl}thien-2-yl-
)methyl]benzamide [0330]
4-chloro-N-{[5-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}sulfonyl)thi-
en-2-yl]methyl}benzamide [0331]
4-chloro-N-{[5-({3-hydroxy-4-[3-(trifluoromethyl)phenyl]piperidin-1-yl}su-
lfonyl)thien-2-yl]methyl}benzamide [0332]
4-chloro-N-[(5-{[4-(2-methylphenyl)piperazin-1-yl]sulfonyl}thien-2-yl)met-
hyl]benzamide [0333]
N-[(5-{[(1R,4R)-5-benzyl-2,5-diazabicyclo[2.2.1]hept-2-yl]sulfonyl}thien--
2-yl)methyl]-4-chlorobenzamide [0334]
N-[(5-{[4-(benzyloxy)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-4-chlorob-
enzamide [0335]
4-chloro-N-[(5-{[4-(2-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-1-y-
l]sulfonyl}thien-2-yl)methyl]benzamide [0336]
N-(4-chlorophenyl)-2-(5-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piper-
idin-1-yl]sulfonyl}thien-2-yl)acetamide [0337]
4-chloro-N-({5-[(4-hydroxypiperidin-1-yl)sulfonyl]thien-2-yl}methyl)benza-
mide [0338]
N-[(5-{[4-(4-acetylphenyl)piperazin-1-yl]sulfonyl}thien-2-yl)methyl]-4-ch-
lorobenzamide [0339]
4-chloro-N-[(5-{[4-(3,5-dichloropyridin-4-yl)piperazin-1-yl]sulfonyl}thie-
n-2-yl)methyl]benzamide [0340]
4-chloro-N-[(5-{[4-(3-methoxyphenyl)piperazin-1-yl]sulfonyl}thien-2-yl)me-
thyl]benzamide [0341]
N-({5-[(4-benzyl-4-hydroxypiperidin-1-yl)sulfonyl]thien-2-yl}methyl)-4-ch-
lorobenzamide [0342]
N-{[5-({4-[(2-tert-butyl-1H-indol-5-yl)amino]piperidin-1-yl}sulfonyl)thie-
n-2-yl]methyl}-4-chlorobenzamide [0343]
4-chloro-N-{[5-({4-[(phenylacetyl)amino]piperidin-1-yl}sulfonyl)thien-2-y-
l]methyl}benzamide [0344]
4-chloro-N-[(5-{[4-(tetrahydrofuran-2-ylcarbonyl)piperazin-1-yl]sulfonyl}-
thien-2-yl)methyl]benzamide [0345]
4-chloro-N-[(5-{[4-(6-chloropyridin-2-yl)piperazin-1-yl]sulfonyl}thien-2--
yl)methyl]benzamide [0346]
4-chloro-N-[(5-{[4-(4-chlorophenyl)piperazin-1-yl]sulfonyl}thien-2-yl)met-
hyl]benzamide [0347]
N-[(5-{[4-(2H-1,2,3-benzotriazol-2-yl)piperidin-1-yl]sulfonyl}thien-2-yl)-
methyl]-4-chlorobenzamide [0348]
4-chloro-N-[(5-{[4-(4-chlorobenzoyl)piperidin-1-yl]sulfonyl}thien-2-yl)me-
thyl]benzamide [0349]
4-chloro-N-({5-[(4-phenoxypiperidin-1-yl)sulfonyl]thien-2-yl}methyl)benza-
mide [0350]
N-{[5-({4-[benzyl(methyl)amino]piperidin-1-yl}sulfonyl)thien-2-yl]methyl}-
-4-chlorobenzamide [0351]
4-chloro-N-{[5-({4-[3-(2,4-dichlorophenyl)-1H-pyrazol-5-yl]piperidin-1-yl-
}sulfonyl)thien-2-yl]methyl}benzamide [0352]
4-chloro-N-[(5-{[4-(5-thien-2-yl-1H-pyrazol-3-yl)piperidin-1-yl]sulfonyl}-
thien-2-yl)methyl]benzamide [0353]
4-chloro-N-[(5-{[4-(2,3,4,5,6-pentamethylbenzoyl)piperidin-1-yl]sulfonyl}-
thien-2-yl)methyl]benzamide [0354]
4-chloro-N-[(5-{[4-(phenylacetyl)-1,4-diazepan-1-yl]sulfonyl}thien-2-yl)m-
ethyl]benzamide [0355]
4-chloro-N-{[5-({4-[5-(4-methoxyphenyl)-1H-pyrazol-3-yl]piperidin-1-yl}su-
lfonyl)thien-2-yl]methyl}benzamide [0356]
N-({5-[(4-anilinopiperidin-1-yl)sulfonyl]thien-2-yl}methyl)-4-chlorobenza-
mide [0357]
4-chloro-N-[(5-{[4-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazin-1-yl]sulfony-
l}thien-2-yl)methyl]benzamide [0358]
4-chloro-N-[(5-{[4-(2-phenylethyl)piperidin-1-yl]sulfonyl}thien-2-yl)meth-
yl]benzamide [0359]
4-chloro-N-({5-[(4-heptylpiperazin-1-yl)sulfonyl]thien-2-yl}methyl)benzam-
ide [0360]
4-chloro-N-({5-[(4-octylpiperazin-1-yl)sulfonyl]thien-2-yl}meth-
yl)benzamide [0361]
N-[(5-{[4-(1H-1,2,3-benzotriazol-1-yl)piperidin-1-yl]sulfonyl}thien-2-yl)-
methyl]-4-chlorobenzamide [0362]
2-(5-{[4-(1H-1,2,3-benzotriazol-1-yl)piperidin-1-yl]sulfonyl}thien-2-yl)--
N-(4-chlorophenyl)acetamide [0363]
2-{1-[(5-{[(4-chlorobenzoyl)amino]methyl}thien-2-yl)sulfonyl]piperidin-4--
yl}-2H-1,2,3-benzotriazole-5-carboxylic acid [0364]
4-chloro-N-[(5-{[4-(5-chloro-1H-1,2,3-benzotriazol-1-yl)piperidin-1-yl]su-
lfonyl}thien-2-yl)methyl]benzamide [0365] methyl
1-{1-[(5-{[(4-chlorobenzoyl)amino]methyl}thien-2-yl)sulfonyl]piperidin-4--
yl}-1H-1,2,3-benzotriazole-5-carboxylate [0366] methyl
1-{1-[(5-{[(4-chlorobenzoyl)amino]methyl}thien-2-yl)sulfonyl]piperidin-4--
yl}-1H-1,2,3-benzotriazole-6-carboxylate [0367] methyl
2-{1-[(5-{[(4-chlorobenzoyl)amino]methyl}thien-2-yl)sulfonyl]piperidin-4--
yl}-2H-1,2,3-benzotriazole-5-carboxylate [0368]
4-chloro-N-[(5-{[4-(6-chloro-1H-1,2,3-benzotriazol-1-yl)piperidin-1-yl]su-
lfonyl}thien-2-yl)methyl]benzamide [0369]
4-chloro-N-{[5-({4-[5-(trifluoromethyl)-1H-1,2,3-benzotriazol-1-yl]piperi-
din-1-yl}sulfonyl)thien-2-yl]methyl}benzamide [0370]
N-[(5-{[4-(7-aza-1H-benzimidazol-1-yl)piperidin-1-yl]sulfonyl}thien-2-yl)-
methyl]-4-chlorobenzamide [0371]
1-{1-[(5-{[(4-chlorobenzoyl)amino]methyl}thien-2-yl)sulfonyl]piperidin-4--
yl}-1H-1,2,3-benzotriazole-5-carboxylic acid [0372]
1-{1-[(5-{[(4-chlorobenzoyl)amino]methyl}thien-2-yl)sulfonyl]piperidin-4--
yl}-1H-1,2,3-benzotriazole-6-carboxylic acid [0373]
N-[(5-{[4-(2-amino-9H-purin-9-yl)piperidin-1-yl]sulfonyl}thien-2-yl)methy-
l]-4-chlorobenzamide [0374]
4-chloro-N-[(5-{[4-(9H-purin-9-yl)piperidin-1-yl]sulfonyl}thien-2-yl)meth-
yl]benzamide [0375]
N-[(5-{[4-(6-amino-9H-purin-9-yl)piperidin-1-yl]sulfonyl}thien-2-yl)methy-
l]-4-chlorobenzamide [0376]
4-chloro-N-({5-[(4-{6-nitro-1H-benzimidazol-1-yl}piperidin-1-yl)sulfonyl]-
thien-2-yl}methyl)benzamide [0377]
4-chloro-N-({5-[(4-{5-nitro-1H-benzimidazol-1-yl}piperidin-1-yl)sulfonyl]-
thien-2-yl}methyl)benzamide [0378]
4-chloro-N-[(5-{[4-(2H-1,2,3-triazol-2-yl)piperidin-1-yl]sulfonyl}thien-2-
-yl)methyl]benzamide [0379]
N-[(5-{[4-(1H-benzimidazol-1-yl)piperidin-1-yl]sulfonyl}thien-2-yl)methyl-
]-4-chlorobenzamide [0380]
4-chloro-N-{[5-({4-[3-propylanilino]piperidin-1-yl}sulfonyl)thien-2-yl]me-
thyl}benzamide [0381]
4-chloro-N-{[5-({4-[3-(trifluoromethyl)anilino]piperidin-1-yl}sulfonyl)th-
ien-2-yl]methyl}benzamide [0382]
4-chloro-N-{[5-({4-[3-(dimethylamino)anilino]piperidin-1-yl}sulfonyl)thie-
n-2-yl]methyl}benzamide [0383] methyl
3-({1-[(5-{[(4-chlorobenzoyl)amino]-methyl}thien-2-yl)sulfonyl]-piperidin-
-4-yl}amino)-benzoate [0384]
4-chloro-N-{[5-({4-[3-(methylsulfanyl)anilino]piperidin-1-yl}sulfonyl)thi-
en-2-yl]methyl}benzamide [0385]
4-chloro-N-({5-[(4-{3-nitroanilino}piperidin-1-yl)sulfonyl]thien-2-yl}met-
hyl)benzamide [0386]
4-chloro-N-[(5-{[4-(2-methoxyanilino)piperidin-1-yl]sulfonyl}thien-2-yl)m-
ethyl]benzamide [0387]
3-({1-[(5-{[(4-chlorobenzoyl)amino]methyl}thien-2-yl)sulfonyl]piperidin-4-
-yl}amino)benzamide [0388]
4-chloro-N-{[5-({4-[2-(trifluoromethyl)anilino]piperidin-1-yl}sulfonyl)th-
ien-2-yl]methyl}benzamide [0389]
4-chloro-N-({5-[(4-{2-nitro-4-[(trifluoromethyl)sulfonyl]anilino}piperidi-
n-1-yl)sulfonyl]thien-2-yl}methyl)benzamide [0390]
4-chloro-N-[(5-{[4-(4-chloroanilino)piperidin-1-yl]sulfonyl}thien-2-yl)me-
thyl]benzamide [0391]
4-chloro-N-{[5-({4-[4-(trifluoromethyl)anilino]piperidin-1-yl}sulfonyl)th-
ien-2-yl]methyl}benzamide [0392]
4-chloro-N-({5-[(4-{4-[(trifluoromethyl)sulfonyl]anilino}piperidin-1-yl)s-
ulfonyl]thien-2-yl}methyl)benzamide [0393]
4-chloro-N-({5-[(4-{2-nitroanilino}piperidin-1-yl)sulfonyl]thien-2-yl}met-
hyl)benzamide [0394]
N-{[5-({4-[4-(aminocarbonyl)anilino]piperidin-1-yl}sulfonyl)thien-2-yl]me-
thyl}-4-chlorobenzamide [0395]
4-chloro-N-{[5-({4-[4-(1,3-dithiolan-2-yl)anilino]piperidin-1-yl}sulfonyl-
)thien-2-yl]methyl}benzamide [0396]
N-[(5-{[4-(3-chloroanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-3-n-
itrobenzamide [0397]
4-chloro-N-[(5-{[4-(3-chloroanilino)piperidin-1-yl]sulfonyl}thien-2-yl)me-
thyl]benzamide [0398]
4-chloro-N-[(5-{[4-(3-methoxyanilino)piperidin-1-yl]sulfonyl}thien-2-yl)m-
ethyl]benzamide [0399]
4-chloro-N-{[5-({4-[3-(methylsulfonyl)anilino]piperidin-1-yl}sulfonyl)thi-
en-2-yl]methyl}benzamide [0400]
N-({5-[(4-{3-[amino(imino)methyl]anilino}piperidin-1-yl)sulfonyl]thien-2--
yl}methyl)-4-chlorobenz amide [0401]
4-chloro-N-({5-[(4-{3-[(2-hydroxyethyl)sulfonyl]anilino}piperidin-1-yl)su-
lfonyl]thien-2-yl}methyl)benzamide [0402]
N-[(5-{[4-(2-aminoanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-4-ch-
lorobenzamide [0403]
4-chloro-N-[(5-{[4-(2-hydroxyanilino)piperidin-1-yl]sulfonyl}thien-2-yl)m-
ethyl]benzamide [0404]
4-chloro-N-[(5-{[4-(4-hydroxyanilino)piperidin-1-yl]sulfonyl}thien-2-yl)m-
ethyl]benzamide [0405]
4-chloro-N-({5-[(4-{3-[(trifluoromethyl)sulfanyl]anilino}piperidin-1-yl)s-
ulfonyl]thien-2-yl}methyl)benzamide [0406]
4-chloro-N-[(5-{[4-(3-toluidino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl-
]benzamide [0407]
4-chloro-N-({5-[(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}piper-
idin-1-yl)sulfonyl]thien-2-yl}methyl)benzamide [0408]
4-chloro-N-{[5-({4-[3-(1,3-oxazol-5-yl)anilino]piperidin-1-yl}sulfonyl)th-
ien-2-yl]methyl}benzamide [0409]
N-[(5-{[4-(3-tert-butylanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-
-4-chlorobenzamide [0410]
4-chloro-N-[(5-{[4-(2-propylanilino)piperidin-1-yl]sulfonyl}thien-2-yl)me-
thyl]benzamide [0411]
4-chloro-N-{[5-({4-[(2,2-dioxido-1,3-dihydro-2-benzothien-5-yl)amino]pipe-
ridin-1-yl}sulfonyl)thien-2-yl]methyl}benzamide [0412]
4-chloro-N-[(5-{[4-(2,3-dihydro-1H-inden-5-ylamino)piperidin-1-yl]sulfony-
l}thien-2-yl)methyl]benzamide [0413]
4-chloro-N-[(5-{[4-(4-propylanilino)piperidin-1-yl]sulfonyl}thien-2-yl)me-
thyl]benzamide [0414]
4-chloro-N-[(5-{[4-({3-nitropyridin-2-yl}amino)piperidin-1-yl]sulfonyl}th-
ien-2-yl)methyl]benzamide
[0415]
N-{[5-({4-[(3-aminopyridin-2-yl)amino]piperidin-1-yl}sulfonyl)thie-
n-2-yl]methyl}-4-chlorobenzamide [0416]
N-[(5-{[4-([1,1'-biphenyl]-3-ylamino)piperidin-1-yl]sulfonyl}thien-2-yl)m-
ethyl]-4-chlorobenzamide [0417]
N-[(5-{[4-(3-benzylanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-4-c-
hlorobenzamide [0418]
4-chloro-N-[(5-{[4-(pyrimidin-2-ylamino)piperidin-1-yl]sulfonyl}thien-2-y-
l)methyl]benzamide [0419]
4-chloro-N-{[5-({4-[4-(morpholin-4-ylsulfonyl)anilino]piperidin-1-yl}sulf-
onyl)thien-2-yl]methyl}benzamide [0420]
4-chloro-N-({5-[(4-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}piperidin-1--
yl)sulfonyl]thien-2-yl}methyl)benzamide [0421]
4-chloro-N-[(5-{[4-(3-cyclohexyl-4-hydroxyanilino)piperidin-1-yl]sulfonyl-
}thien-2-yl)methyl]benzamide [0422]
N-({5-[(4-{3-[(butylamino)sulfonyl]anilino}piperidin-1-yl)sulfonyl]thien--
2-yl}methyl)-4-chlorobenzamide [0423]
4-chloro-N-[(5-{[4-(3-ethylanilino)piperidin-1-yl]sulfonyl}thien-2-yl)met-
hyl]benzamide [0424]
4-chloro-N-[(5-{[4-(5,6,7,8-tetrahydronaphthalen-1-ylamino)piperidin-1-yl-
]sulfonyl}thien-2-yl)methyl]benzamide [0425]
N-{[5-({4-[3-(aminosulfonyl)anilino]piperidin-1-yl}sulfonyl)thien-2-yl]me-
thyl}-4-chlorobenzamide [0426]
4-chloro-N-[(5-{[4-(quinolin-5-ylamino)piperidin-1-yl]sulfonyl}thien-2-yl-
)methyl]benzamide [0427]
4-chloro-N-[(5-{[4-(quinolin-8-ylamino)piperidin-1-yl]sulfonyl}thien-2-yl-
)methyl]benzamide [0428]
4-Chloro-N-[(5-{[4-(3-propylphenoxy)piperidin-1-yl]sulfonyl}thien-2-yl)me-
thyl]benzamide [0429]
4-chloro-N-{[5-({4-[(2E)-3-phenylprop-2-enoyl]piperazin-1-yl}sulfonyl)thi-
en-2-yl]methyl}benzamide [0430]
4-chloro-N-({5-[(4-{4-nitrobenzoyl}piperazin-1-yl)sulfonyl]thien-2-yl}met-
hyl)benzamide [0431]
N-({5-[(4-benzoylpiperazin-1-yl)sulfonyl]thien-2-yl}methyl)-4-chlorobenza-
mide [0432]
4-chloro-N-{[5-({4-[4-(trifluoromethyl)benzoyl]piperazin-1-yl}sulfonyl)th-
ien-2-yl]methyl}benzamide [0433]
4-chloro-N-{[5-({4-[4-(dimethylamino)benzoyl]piperazin-1-yl}sulfonyl)thie-
n-2-yl]methyl}benzamide [0434]
4-chloro-N-[(5-{[4-(2-fluorobenzoyl)piperazin-1-yl]sulfonyl}thien-2-yl)me-
thyl]benzamide [0435]
4-chloro-N-[(5-{[4-(2,6-difluorobenzoyl)piperazin-1-yl]sulfonyl}thien-2-y-
l)methyl]benzamide [0436]
4-chloro-N-[(5-{[4-(3-fluorobenzoyl)piperazin-1-yl]sulfonyl}thien-2-yl)me-
thyl]benzamide [0437]
4-chloro-N-[(5-{[4-(2-naphthoyl)piperazin-1-yl]sulfonyl}thien-2-yl)methyl-
]benzamide [0438]
4-chloro-N-[(5-{[4-(1-naphthoyl)piperazin-1-yl]sulfonyl}thien-2-yl)methyl-
]benzamide [0439]
4-chloro-N-({5-[(4-{2-nitrobenzoyl}piperazin-1-yl)sulfonyl]thien-2-yl}met-
hyl)benzamide [0440]
4-chloro-N-[(5-{[4-(pyridin-3-ylcarbonyl)piperazin-1-yl]sulfonyl}thien-2--
yl)methyl]benzamide [0441]
N-[(5-{[4-(2,1,3-benzoxadiazol-5-ylcarbonyl)piperazin-1-yl]sulfonyl}thien-
-2-yl)methyl]-4-chlorobenzamide [0442]
4-chloro-N-[(5-{[4-(2,4-difluorobenzoyl)piperazin-1-yl]sulfonyl}thien-2-y-
l)methyl]benzamide [0443]
4-chloro-N-[(5-{[4-(2,4,6-trifluorobenzoyl)piperazin-1-yl]sulfonyl}thien--
2-yl)methyl]benzamide [0444]
4-chloro-N-[(5-{[4-(2,6-dichlorobenzoyl)piperazin-1-yl]sulfonyl}thien-2-y-
l)methyl]benzamide [0445]
4-chloro-N-({5-[(4-heptanoylpiperazin-1-yl)sulfonyl]thien-2-yl}methyl)ben-
zamide [0446]
4-chloro-N-[(5-{[4-(quinolin-8-ylsulfonyl)piperazin-1-yl]sulfonyl}thien-2-
-yl)methyl]benzamide [0447]
4-nitro-N-({5-[(4-{3-[(trifluoromethyl)sulfonyl]anilino}piperidin-1-yl)su-
lfonyl]thien-2-yl}methyl)benzamide [0448]
N-[(5-{[4-(1H-1,2,3-benzotriazol-1-yl)piperidin-1-yl]sulfonyl}thien-2-yl)-
methyl]-3-nitrobenzamide [0449]
4-nitro-N-({5-[(4-{3-[(trifluoromethyl)sulfonyl]anilino}piperidin-1-yl)su-
lfonyl]thien-2-yl}methyl)benzamide [0450]
N-[(5-{[4-(2,4-difluorobenzoyl)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-
-4-nitrobenzamide [0451]
N-[(5-{[4-(1H-1,2,3-benzotriazol-1-yl)piperidin-1-yl]sulfonyl}thien-2-yl)-
methyl]-4-nitrobenzamide [0452]
N-[(5-{[4-(1H-1,2,3-benzotriazol-1-yl)piperidin-1-yl]sulfonyl}thien-2-yl)-
methyl]-3-nitrobenzamide [0453]
4-nitro-N-({5-[(4-{3-[(trifluoromethyl)sulfonyl]anilino}piperidin-1-yl)su-
lfonyl]thien-2-yl}methyl)benzamide [0454]
N-[(5-{[4-(2,4-difluorobenzoyl)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-
-4-nitrobenzamide [0455]
N-[(5-{[4-(1H-1,2,3-benzotriazol-1-yl)piperidin-1-yl]sulfonyl}thien-2-yl)-
methyl]-4-nitrobenzamide [0456]
3-nitro-N-[(5-{[4-(3-methoxyanilino)piperidin-1-yl]sulfonyl}thien-2-yl)me-
thyl]benzamide [0457]
3-nitro-N-{[5-({4-[3-(trifluoromethyl)anilino]piperidin-1-yl}sulfonyl)thi-
en-2-yl]methyl}benzamide [0458]
N-{[5-({4-[3-(dimethylamino)anilino]piperidin-1-yl}sulfonyl)thien-2-yl]me-
thyl}-3-nitrobenzamide [0459]
3-nitro-N-{[5-({4-[3-(methylsulfonyl)anilino]piperidin-1-yl}sulfonyl)thie-
n-2-yl]methyl}benzamide [0460]
3-nitro-N-{[5-({4-[3-(methylsulfanyl)anilino]piperidin-1-yl}sulfonyl)thie-
n-2-yl]methyl}benzamide [0461]
N-{[5-({4-[3-(aminosulfonyl)anilino]piperidin-1-yl}sulfonyl)thien-2-yl]me-
thyl}-3-nitrobenzamide [0462] methyl
3-{[1-({5-[({3-nitrobenzoyl}amino)methyl]-thien-2-yl}sulfonyl)-piperidin--
4-yl]amino}benzoate [0463] N-{[5-({4-[3-(amino
carbonyl)anilino]piperidin-1-yl}sulfonyl)thien-2-yl]methyl}-3-nitrobenzam-
ide [0464]
3-nitro-N-({5-[(4-{3-nitroanilino}piperidin-1-yl)sulfonyl]thien-
-2-yl}methyl)benzamide [0465]
3-nitro-N-[(5-{[4-(2-methoxyanilino)piperidin-1-yl]sulfonyl}thien-2-yl)me-
thyl]benzamide [0466]
3-nitro-N-{[5-({4-[2-(trifluoromethyl)anilino]piperidin-1-yl}sulfonyl)thi-
en-2-yl]methyl}benzamide [0467]
3-nitro-N-({5-[(4-{2-nitroanilino}piperidin-1-yl)sulfonyl]thien-2-yl}meth-
yl)benzamide [0468]
N-[(5-{[4-(4-chloroanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-3-n-
itrobenzamide [0469]
3-nitro-N-{[5-({4-[4-(trifluoromethyl)anilino]piperidin-1-yl}sulfonyl)thi-
en-2-yl]methyl}benzamide [0470]
3-nitro-N-({5-[(4-{4-[(trifluoromethyl)sulfonyl]anilino}piperidin-1-yl)su-
lfonyl]thien-2-yl}methyl)benzamide [0471]
N-{[5-({4-[4-(aminocarbonyl)anilino]piperidin-1-yl}sulfonyl)thien-2-yl]me-
thyl}-3-nitrobenzamide [0472]
N-[(5-{[4-(3-propylanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-3-n-
itrobenzamide [0473]
N-[(5-{[4-(3-chloroanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-4-n-
itrobenzamide [0474]
4-nitro-N-[(5-{[4-(3-methoxyanilino)piperidin-1-yl]sulfonyl}thien-2-yl)me-
thyl]benzamide [0475]
4-nitro-N-{[5-({4-[3-(trifluoromethyl)anilino]piperidin-1-yl}sulfonyl)thi-
en-2-yl]methyl}benzamide [0476]
N-{[5-({4-[3-(dimethylamino)anilino]piperidin-1-yl}sulfonyl)thien-2-yl]me-
thyl}-4-nitrobenzamide [0477]
4-nitro-N-[(5-{[4-(3-propylanilino)piperidin-1-yl]sulfonyl}thien-2-yl)met-
hyl]benzamide [0478]
4-nitro-N-{[5-({4-[3-(methylsulfonyl)anilino]piperidin-1-yl}sulfonyl)thie-
n-2-yl]methyl}benzamide [0479]
4-nitro-N-{[5-({4-[3-(methylsulfanyl)anilino]piperidin-1-yl}sulfonyl)thie-
n-2-yl]methyl}benzamide [0480]
N-{[5-({4-[3-(aminosulfonyl)anilino]piperidin-1-yl}sulfonyl)thien-2-yl]me-
thyl}-4-nitrobenzamide [0481]
3-{[1-({5-[({4-nitrobenzoyl}amino)methyl]thien-2-yl}sulfonyl)piperidin-4--
yl]amino}benzamide [0482]
3-{[1-({5-[({4-nitrobenzoyl}amino)methyl]thien-2-yl}sulfonyl)piperidin-4--
yl]amino}benzamide [0483]
4-nitro-N-({5-[(4-{3-nitroanilino}piperidin-1-yl)sulfonyl]thien-2-yl}meth-
yl)benzamide [0484]
4-nitro-N-[(5-{[4-(2-methoxyanilino)piperidin-1-yl]sulfonyl}thien-2-yl)me-
thyl]benzamide [0485]
4-nitro-N-{[5-({4-[2-(trifluoromethyl)anilino]piperidin-1-yl}sulfonyl)thi-
en-2-yl]methyl}benzamide [0486]
4-nitro-N-({5-[(4-{2-nitroanilino}piperidin-1-yl)sulfonyl]thien-2-yl}meth-
yl)benzamide [0487]
N-[(5-{[4-(4-chloroanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-4-n-
itrobenzamide [0488]
4-nitro-N-{[5-({4-[4-(trifluoromethyl)anilino]piperidin-1-yl}sulfonyl)thi-
en-2-yl]methyl}benzamide [0489]
4-nitro-N-({5-[(4-{4-[(trifluoromethyl)sulfonyl]anilino}piperidin-1-yl)su-
lfonyl]thien-2-yl}methyl)benzamide [0490]
N-{[5-({4-[4-(aminocarbonyl)anilino]piperidin-1-yl}sulfonyl)thien-2-yl]me-
thyl}-4-nitrobenzamide [0491]
N-{[5-({4-[4-(1,3-dithiolan-2-yl)anilino]piperidin-1-yl}sulfonyl)thien-2--
yl]methyl}-4-nitrobenzamide [0492]
N-({5-[(4-{3-[amino(imino)methyl]anilino}piperidin-1-yl)sulfonyl]thien-2--
yl}methyl)-3-nitrobenzamide [0493]
N-({5-[(4-{3-[(2-hydroxyethyl)sulfonyl]anilino}piperidin-1-yl)sulfonyl]th-
ien-2-yl}methyl)-3-nitrobenzamide [0494]
N-({5-[(4-anilinopiperidin-1-yl)sulfonyl]thien-2-yl}methyl)-3-nitrobenzam-
ide [0495]
N-({5-[(4-{3-[(2-hydroxyethyl)sulfonyl]anilino}piperidin-1-yl)s-
ulfonyl]thien-2-yl}methyl)-4-nitrobenzamide [0496]
N-({5-[(4-anilinopiperidin-1-yl)sulfonyl]thien-2-yl}methyl)-4-nitrobenzam-
ide [0497]
N-({5-[(4-{3-[amino(imino)methyl]anilino}piperidin-1-yl)sulfony-
l]thien-2-yl}methyl)-4-nitrobenzamide [0498]
3-nitro-N-({5-[(4-{3-[(trifluoromethyl)sulfanyl]anilino}piperidin-1-yl)su-
lfonyl]thien-2-yl}methyl)benzamide [0499]
4-nitro-N-({5-[(4-{3-[(trifluoromethyl)sulfanyl]anilino}piperidin-1-yl)su-
lfonyl]thien-2-yl}methyl)benzamide [0500]
3-nitro-N-[(5-{[4-({3-nitropyridin-2-yl}amino)piperidin-1-yl]sulfonyl}thi-
en-2-yl)methyl]benzamide [0501]
N-{[5-({4-[(2,2-dioxido-1,3-dihydro-2-benzothien-5-yl)amino]piperidin-1-y-
l}sulfonyl)thien-2-yl]methyl}-3-nitrobenzamide [0502]
N-[(5-{[4-(2,3-dihydro-1H-inden-5-ylamino)piperidin-1-yl]sulfonyl}thien-2-
-yl)methyl]-3-nitrobenzamide [0503]
3-nitro-N-[(5-{[4-(2-propylanilino)piperidin-1-yl]sulfonyl}thien-2-yl)met-
hyl]benzamide [0504]
3-nitro-N-[(5-{[4-(4-propylanilino)piperidin-1-yl]sulfonyl}thien-2-yl)met-
hyl]benzamide [0505]
N-[(5-{[4-(3-tert-butylanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-
-3-nitrobenzamide [0506]
3-nitro-N-{[5-({4-[3-(1,3-oxazol-5-yl)anilino]piperidin-1-yl}sulfonyl)thi-
en-2-yl]methyl}benzamide [0507]
3-nitro-N-[(5-{[4-(2-phenylethyl)piperidin-1-yl]sulfonyl}thien-2-yl)methy-
l]benzamide [0508]
N-({5-[(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl-
)sulfonyl]thien-2-yl}methyl)-3-nitrobenzamide [0509]
N-[(5-{[4-([1,1'-biphenyl]-3-ylamino)piperidin-1-yl]sulfonyl}thien-2-yl)m-
ethyl]-3-nitrobenzamide [0510]
N-[(5-{[4-(3-benzylanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-3-n-
itrobenzamide [0511]
3-nitro-N-{[5-({4-[3-(morpholin-4-ylsulfonyl)anilino]piperidin-1-yl}sulfo-
nyl)thien-2-yl]methyl}benzamide [0512]
3-nitro-N-[(5-{[4-(3-propylphenoxy)piperidin-1-yl]sulfonyl}thien-2-yl)met-
hyl]benzamide [0513]
4-nitro-N-[(5-{[4-(pyrimidin-2-ylamino)piperidin-1-yl]sulfonyl}thien-2-yl-
)methyl]benzamide [0514]
N-{[5-({4-[(3-aminopyridin-2-yl)amino]piperidin-1-yl}sulfonyl)thien-2-yl]-
methyl}-4-nitrobenzamide [0515]
4-nitro-N-[(5-{[4-({3-nitropyridin-2-yl}amino)piperidin-1-yl]sulfonyl}thi-
en-2-yl)methyl]benzamide [0516]
N-[(5-{[4-(2,3-dihydro-1H-inden-5-ylamino)piperidin-1-yl]sulfonyl}thien-2-
-yl)methyl]-4-nitrobenzamide [0517]
4-nitro-N-[(5-{[4-(2-propylanilino)piperidin-1-yl]sulfonyl}thien-2-yl)met-
hyl]benzamide [0518]
4-nitro-N-[(5-{[4-(4-propylanilino)piperidin-1-yl]sulfonyl}thien-2-yl)met-
hyl]benzamide [0519]
N-[(5-{[4-(3-tert-butylanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-
-4-nitrobenzamide [0520]
4-nitro-N-{[5-({4-[3-(1,3-oxazol-5-yl)anilino]piperidin-1-yl}sulfonyl)thi-
en-2-yl]methyl}benzamide [0521]
4-nitro-N-[(5-{[4-(2-phenylethyl)piperidin-1-yl]sulfonyl}thien-2-yl)methy-
l]benzamide [0522]
N-({5-[(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl-
)sulfonyl]thien-2-yl}methyl)-4-nitrobenzamide [0523]
N-[(5-{[4-([1,1'-biphenyl]-3-ylamino)piperidin-1-yl]sulfonyl}thien-2-yl)m-
ethyl]-4-nitrobenzamide [0524]
N-[(5-{[4-(3-benzylanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-4-n-
itrobenzamide [0525]
4-nitro-N-{[5-({4-[3-(morpholin-4-ylsulfonyl)anilino]piperidin-1-yl}sulfo-
nyl)thien-2-yl]methyl}benzamide [0526]
N-[(5-{[4-(2-aminoanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-3-ni-
trobenzamide [0527]
3-nitro-N-[(5-{[4-(pyrimidin-2-ylamino)piperidin-1-yl]sulfonyl}thien-2-yl-
)methyl]benzamide [0528]
N-{[5-({4-[(3-aminopyridin-2-yl)amino]piperidin-1-yl}sulfonyl)thien-2-yl]-
methyl}-3-nitrobenzamide [0529]
N-({5-[(4-{2-nitro-4-[(trifluoromethyl)sulfonyl]anilino}piperidin-1-yl)su-
lfonyl]thien-2-yl}methyl)-3-methoxybenzamide [0530]
3-nitro-N-[(5-{[4-(3-phenylpropyl)piperazin-1-yl]sulfonyl}thien-2-yl)meth-
yl]benzamide [0531]
3-nitro-N-({5-[(4-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}piperidin-1-y-
l)sulfonyl]thien-2-yl}methyl)benzamide [0532]
N-[(5-{[4-(3-cyclohexyl-4-hydroxyanilino)piperidin-1-yl]sulfonyl}thien-2--
yl)methyl]-3-nitrobenzamide [0533]
N-({5-[(4-{3-[(butylamino)sulfonyl]anilino}piperidin-1-yl)sulfonyl]thien--
2-yl}methyl)-3-nitrobenzamide [0534]
N-[(5-{[4-(3-ethylanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-3-ni-
trobenzamide [0535]
3-nitro-N-[(5-{[4-(5,6,7,8-tetrahydronaphthalen-1-ylamino)piperidin-1-yl]-
sulfonyl}thien-2-yl)methyl]benzamide [0536]
4-nitro-N-[(5-{[4-(3-propylphenoxy)piperidin-1-yl]sulfonyl}thien-2-yl)met-
hyl]benzamide [0537]
N-[(5-{[4-(2,4-difluorobenzoyl)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-
-3-nitrobenzamide [0538]
N-[(5-{[4-(2,4-difluorobenzoyl)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-
-3-methoxybenzamide [0539]
2-Hydroxy-N-({5-[(4-{3-[(trifluoromethyl)sulfonyl]anilino}piperidin-1-yl)-
sulfonyl]thien-2-yl}methyl)benzamide [0540]
N-[(5-{[4-(1H-1,2,3-benzotriazol-1-yl)piperidin-1-yl]sulfonyl}thien-2-yl)-
methyl]-3-methoxybenzamide [0541]
N-[(5-{[4-(1H-1,2,3-benzotriazol-1-yl)piperidin-1-yl]sulfonyl}thien-2-yl)-
methyl]-2-hydroxybenzamide [0542]
N-{[5-({4-[4-(1,3-dithiolan-2-yl)anilino]piperidin-1-yl}sulfonyl)thien-2--
yl]methyl}-3-nitrobenzamide [0543]
3-methoxy-N-[(5-{[4-(3-methoxyanilino)piperidin-1-yl]sulfonyl}thien-2-yl)-
methyl]benzamide [0544]
3-methoxy-N-{[5-({4-[3-(trifluoromethyl)anilino]piperidin-1-yl}sulfonyl)t-
hien-2-yl]methyl}benzamide [0545]
N-{[5-({4-[3-(dimethylamino)anilino]piperidin-1-yl}sulfonyl)thien-2-yl]me-
thyl}-3-methoxybenzamide [0546]
3-methoxy-N-[(5-{[4-(3-propylanilino)piperidin-1-yl]sulfonyl}thien-2-yl)m-
ethyl]benzamide [0547]
3-methoxy-N-{[5-({4-[3-(methylsulfonyl)anilino]piperidin-1-yl}sulfonyl)th-
ien-2-yl]methyl}benzamide [0548]
3-methoxy-N-{[5-({4-[3-(methylsulfanyl)anilino]piperidin-1-yl}sulfonyl)th-
ien-2-yl]methyl}benzamide [0549]
N-{[5-({4-[3-(aminosulfonyl)anilino]piperidin-1-yl}sulfonyl)thien-2-yl]me-
thyl}-3-methoxybenzamide [0550] methyl
3-({1-[(5-{[(3-methoxybenzoyl)amino]-methyl}thien-2-yl)sulfonyl]-piperidi-
n-4-yl}amino)-benzoate [0551]
N-{[5-({4-[3-(aminocarbonyl)anilino]piperidin-1-yl}sulfonyl)thien-2-yl]me-
thyl}-3-methoxybenzamide [0552]
3-methoxy-N-[(5-{[4-(2-methoxyanilino)piperidin-1-yl]sulfonyl}thien-2-yl)-
methyl]benzamide [0553]
N-({5-[(4-{3-nitroanilino}piperidin-1-yl)sulfonyl]thien-2-yl}methyl)-3-me-
thoxybenzamide [0554]
3-methoxy-N-{[5-({4-[2-(trifluoromethyl)anilino]piperidin-1-yl}sulfonyl)t-
hien-2-yl]methyl}benzamide [0555]
N-({5-[(4-{2-nitroanilino}piperidin-1-yl)sulfonyl]thien-2-yl}methyl)-3-me-
thoxybenzamide [0556]
N-{[5-({4-[4-(aminocarbonyl)anilino]piperidin-1-yl}sulfonyl)thien-2-yl]me-
thyl}-3-methoxybenzamide [0557]
N-{[5-({4-[4-(1,3-dithiolan-2-yl)anilino]piperidin-1-yl}sulfonyl)thien-2--
yl]methyl}-3-methoxybenzamide [0558]
N-[(5-{[4-(3-chloroanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-3-m-
ethoxybenzamide [0559]
N-[(5-{[4-(4-chloroanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-3-m-
ethoxybenzamide [0560]
3-methoxy-N-({5-[(4-{4-[(trifluoromethyl)sulfonyl]anilino}piperidin-1-yl)-
sulfonyl]thien-2-yl}methyl)benzamide [0561]
N-({5-[(4-{3-[amino(imino)methyl]anilino}piperidin-1-yl)sulfonyl]thien-2--
yl}methyl)-3-methoxybenzamide
[0562]
N-({5-[(4-{3-[(2-hydroxyethyl)sulfonyl]anilino}piperidin-1-yl)sulf-
onyl]thien-2-yl}methyl)-3-methoxybenzamide [0563]
3-methoxy-N-({5-[(4-{3-[(trifluoromethyl)sulfonyl]anilino}piperidin-1-yl)-
sulfonyl]thien-2-yl}methyl)benzamide [0564]
N-({5-[(4-anilinopiperidin-1-yl)sulfonyl]thien-2-yl}methyl)-3-methoxybenz-
amide [0565]
3-methoxy-N-({5-[(4-{3-[(trifluoromethyl)sulfanyl]anilino}piperidin-1-yl)-
sulfonyl]thien-2-yl}methyl)benzamide [0566]
N-[(5-{[4-(4-hydroxyanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-3--
methoxybenzamide [0567]
3-nitro-N-({5-[(4-{3-[(trifluoromethyl)sulfanyl]anilino}piperidin-1-yl)su-
lfonyl]thien-2-yl}methyl)benzamide [0568]
4-nitro-N-({5-[(4-{3-[(trifluoromethyl)sulfanyl]anilino}piperidin-1-yl)su-
lfonyl]thien-2-yl}methyl)benzamide [0569]
N-[(5-{[4-(2-hydroxyanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-3--
methoxybenzamide [0570]
3-methoxy-N-[(5-{[4-(pyrimidin-2-ylamino)piperidin-1-yl]sulfonyl}thien-2--
yl)methyl]benzamide [0571]
N-{[5-({4-[(3-aminopyridin-2-yl)amino]piperidin-1-yl}sulfonyl)thien-2-yl]-
methyl}-3-methoxybenzamide [0572]
N-[(5-{[4-({3-nitropyridin-2-yl}amino)piperidin-1-yl]sulfonyl}thien-2-yl)-
methyl]-3-methoxybenzamide [0573]
N-{[5-({4-[(2,2-dioxido-1,3-dihydro-2-benzothien-5-yl)amino]piperidin-1-y-
l}sulfonyl)thien-2-yl]methyl}-3-methoxybenzamide [0574]
N-[(5-{[4-(2,3-dihydro-1H-inden-5-ylamino)piperidin-1-yl]sulfonyl}thien-2-
-yl)methyl]-3-methoxybenzamide [0575]
3-methoxy-N-[(5-{[4-(2-propylanilino)piperidin-1-yl]sulfonyl}thien-2-yl)m-
ethyl]benzamide [0576]
3-methoxy-N-[(5-{[4-(4-propylanilino)piperidin-1-yl]sulfonyl}thien-2-yl)m-
ethyl]benzamide [0577]
N-[(5-{[4-(3-tert-butylanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-
-3-methoxybenzamide [0578]
N-({5-[(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl-
)sulfonyl]thien-2-yl}methyl)-3-methoxybenzamide [0579]
3-methoxy-N-{[5-({4-[3-(1,3-oxazol-5-yl)anilino]piperidin-1-yl}sulfonyl)t-
hien-2-yl]methyl}benzamide [0580]
N-[(5-{[4-([1,1'-biphenyl]-3-ylamino)piperidin-1-yl]sulfonyl}thien-2-yl)m-
ethyl]-3-methoxybenzamide [0581]
3-methoxy-N-[(5-{[4-(3-propylphenoxy)piperidin-1-yl]sulfonyl}thien-2-yl)m-
ethyl]benzamide [0582]
3-methoxy-N-{[5-({4-[3-(morpholin-4-ylsulfonyl)anilino]piperidin-1-yl}sul-
fonyl)thien-2-yl]methyl}benzamide [0583]
3-methoxy-N-[(5-{[4-(2-phenylethyl)piperidin-1-yl]sulfonyl}thien-2-yl)met-
hyl]benzamide [0584]
N-[(5-{[4-(3-benzylanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-3-m-
ethoxybenzamide [0585]
3-methoxy-N-[(5-{[4-(3-phenylpropyl)piperazin-1-yl]sulfonyl}thien-2-yl)me-
thyl]benzamide [0586]
3-methoxy-N-({5-[(4-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}piperidin-1-
-yl)sulfonyl]thien-2-yl}methyl)benzamide [0587]
N-[(5-{[4-(3-cyclohexyl-4-hydroxyanilino)piperidin-1-yl]sulfonyl}thien-2--
yl)methyl]-3-methoxybenzamide [0588]
N-({5-[(4-{3-[(butylamino)sulfonyl]anilino}piperidin-1-yl)sulfonyl]thien--
2-yl}methyl)-3-methoxybenzamide [0589]
N-[(5-{[4-(3-ethylanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-3-me-
thoxybenzamide [0590]
3-methoxy-N-[(5-{[4-(5,6,7,8-tetrahydronaphthalen-1-ylamino)piperidin-1-y-
l]sulfonyl}thien-2-yl)methyl]benzamide [0591]
N-[(5-{[4-(1H-1,2,3-benzotriazol-1-yl)piperidin-1-yl]sulfonyl}thien-2-yl)-
methyl]-5-nitro-1H-pyrazole-3-carboxamide [0592]
N-[(5-{[4-(1H-1,2,3-benzotriazol-1-yl)piperidin-1-yl]sulfonyl}thien-2-yl)-
methyl]-2-oxo-1,2-dihydropyridine-3-carboxamide [0593]
N-[(5-{[4-(1H-1,2,3-benzotriazol-1-yl)piperidin-1-yl]sulfonyl}thien-2-yl)-
methyl]-2-thioxo-1,2-dihydropyridine-3-carboxamide [0594]
N-[(5-{[4-(1H-1,2,3-benzotriazol-1-yl)piperidin-1-yl]sulfonyl}thien-2-yl)-
methyl]-3,4-dihydroxybenzamide [0595]
N-[(5-{[4-(1H-1,2,3-benzotriazol-1-yl)piperidin-1-yl]sulfonyl}thien-2-yl)-
methyl]pyridine-2-carboxamide [0596]
N-[(5-{[4-(hexyloxy)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-3-methoxyb-
enzamide [0597]
N-({5-[(4-heptanoylpiperidin-1-yl)sulfonyl]thien-2-yl}methyl)-3-methoxybe-
nzamide [0598]
4-chloro-N-[(5-{[4-(3-propylanilino)piperidin-1-yl]sulfonyl}-2-furyl)meth-
yl]benzamide [0599]
4-chloro-N-[(5-{[4-(3-chloroanilino)piperidin-1-yl]sulfonyl}-2-furyl)meth-
yl]benzamide [0600]
4-chloro-N-[(5-{[4-(3-methoxyanilino)piperidin-1-yl]sulfonyl}-2-furyl)met-
hyl]benzamide [0601]
4-chloro-N-{[5-({4-[3-(trifluoromethyl)anilino]piperidin-1-yl}sulfonyl)-2-
-furyl]methyl}benzamide [0602]
4-chloro-N-{[5-({4-[3-(dimethylamino)anilino]piperidin-1-yl}sulfonyl)-2-f-
uryl]methyl}benzamide [0603]
4-chloro-N-{[5-({4-[3-(methylsulfonyl)anilino]piperidin-1-yl}sulfonyl)-2--
furyl]methyl}benzamide [0604]
4-chloro-N-{[5-({4-[3-(methylsulfanyl)anilino]piperidin-1-yl}sulfonyl)-2--
furyl]methyl}benzamide [0605]
N-{[5-({4-[3-(aminosulfonyl)anilino]piperidin-1-yl}sulfonyl)-2-furyl]meth-
yl}-4-chlorobenzamide [0606] methyl
3-({1-[(5-{[(4-chlorobenzoyl)amino]methyl}-2-furyl)sulfonyl]piperidin-4-y-
l}amino)benzoate [0607]
3-({1-[(5-{[(4-chlorobenzoyl)amino]methyl}-2-furyl)sulfonyl]piperidin-4-y-
l}amino)benzamide [0608]
4-chloro-N-({5-[(4-{3-nitroanilino}piperidin-1-yl)sulfonyl]-2-furyl}methy-
l)benzamide [0609]
4-chloro-N-[(5-{[4-(2-methoxyanilino)piperidin-1-yl]sulfonyl}-2-furyl)met-
hyl]benzamide [0610]
4-chloro-N-{[5-({4-[2-(trifluoromethyl)anilino]piperidin-1-yl}sulfonyl)-2-
-furyl]methyl}benzamide [0611]
4-chloro-N-({5-[(4-{2-nitroanilino}piperidin-1-yl)sulfonyl]-2-furyl}methy-
l)benzamide [0612]
4-chloro-N-[(5-{[4-(4-chloroanilino)piperidin-1-yl]sulfonyl}-2-furyl)meth-
yl]benzamide [0613]
4-chloro-N-{[5-({4-[4-(trifluoromethyl)anilino]piperidin-1-yl}sulfonyl)-2-
-furyl]methyl}benzamide [0614]
4-chloro-N-({5-[(4-{4-[(trifluoromethyl)sulfonyl]anilino}piperidin-1-yl)s-
ulfonyl]-2-furyl}methyl)benzamide [0615]
N-{[5-({4-[4-(aminocarbonyl)anilino]piperidin-1-yl}sulfonyl)-2-furyl]meth-
yl}-4-chlorobenzamide [0616]
4-chloro-N-{[5-({4-[4-(1,3-dithiolan-2-yl)anilino]piperidin-1-yl}sulfonyl-
)-2-furyl]methyl}benzamide [0617]
N-({5-[(4-{3-[amino(imino)methyl]anilino}piperidin-1-yl)sulfonyl]-2-furyl-
}methyl)-4-chlorobenzamide [0618]
4-chloro-N-({5-[(4-{3-[(trifluoromethyl)sulfonyl]anilino}piperidin-1-yl)s-
ulfonyl]-2-furyl}methyl)benzamide [0619]
N-({5-[(4-anilinopiperidin-1-yl)sulfonyl]-2-furyl}methyl)-4-chlorobenzami-
de [0620]
4-nitro-N-({5-[(4-{3-[(trifluoromethyl)sulfanyl]anilino}piperidi-
n-1-yl)sulfonyl]2-furyl}methyl)benzamide [0621]
4-chloro-N-({5-[(3-{3-[(trifluoromethyl)sulfonyl]anilino}pyrrolidin-1-yl)-
sulfonyl]thien-2-yl}methyl)benzamide [0622]
4-chloro-N-({5-[(4-{3-[(trifluoromethyl)sulfonyl]anilino}azepan-1-yl)sulf-
onyl]thien-2-yl}methyl)benzamide [0623]
5-{[(3-methoxybenzoyl)amino]methyl}-2-[(4-{3-[(trifluoromethyl)sulfonyl]--
anilino}piperidin-1-yl)sulfonyl]thiophene-3-carboxylic acid [0624]
5-{[(3-methoxybenzoyl)amino]methyl}-2-{[4-(octylamino)piperidin-1-yl]sulf-
onyl}thiophene-3-carboxylic acid [0625]
N-(2-hydroxyethyl)-5-{[(3-methoxybenzoyl)amino]methyl}-2-[(4-{3-[(trifluo-
ro-methyl)sulfonyl]anilino}piperidin-1-yl)sulfonyl]thiophene-3-carboxamide
[0626]
N-({4-(hydrazinocarbonyl)-5-[(4-{3-[(trifluoromethyl)sulfonyl]anil-
ino}-piperidin-1-yl)sulfonyl]thien-2-yl}methyl)-3-methoxybenzamide
[0627]
5-{[(3-methoxybenzoyl)amino]methyl}-2-[(4-{3-[(trifluoromethyl)sulfonyl]--
anilino}piperidin-1-yl)sulfonyl]thiophene-3-carboxamide [0628]
N-[2-(dimethylamino)ethyl]-5-{[(3-methoxybenzoyl)amino]methyl}-2-[(4-{3-[-
(trifluoromethyl)sulfonyl]anilino}piperidin-1-yl)sulfonyl]thiophene-3-carb-
oxamide [0629]
N-({4-(hydroxymethyl)-5-[(4-{3-[(trifluoromethyl)sulfonyl]anilino}piperid-
in-1-yl)sulfonyl]thien-2-yl}methyl)-3-methoxybenzamide [0630]
4-chloro-N-[(5-{[4-(hexylamino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-
benzamide [0631]
3-Methoxy-N-{[5-({4-[(4-trifluoromethylbenzyl)amino]piperidin-1-yl}sulfon-
yl)thien-2-yl]methyl}benzamide [0632]
4-chloro-N-[(5-{[4-(1,3-thiazol-2-ylamino)piperidin-1-yl]sulfonyl}thien-2-
-yl)methyl]benzamide [0633]
4-chloro-N-[(5-{[4-(heptylamino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl-
]benzamide [0634]
4-chloro-N-[(5-{[4-(pentylamino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl-
]benzamide [0635]
4-chloro-N-[(5-{[4-(butylamino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-
benzamide [0636]
4-chloro-N-[(5-{[4-(dodecylamino)piperidin-1-yl]sulfonyl}thien-2-yl)methy-
l]benzamide [0637]
4-chloro-N-{[5-({4-[(2-cyclohexylethyl)amino]piperidin-1-yl}sulfonyl)thie-
n-2-yl]methyl}benzamide [0638]
4-chloro-N-{[5-({4-[(cyclohexylmethyl)amino]piperidin-1-yl}sulfonyl)thien-
-2-yl]methyl}benzamide [0639]
4-chloro-N-({5-[(4-{[(1R)-1-cyclohexylethyl]amino}piperidin-1-yl)sulfonyl-
]thien-2-yl}methyl)benzamide [0640]
N-{[5-({4-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]piperidin-1-yl}sulfony-
l)thien-2-yl]methyl}-4-chlorobenzamide [0641]
4-chloro-N-{[5-({4-[(2-propoxyethyl)amino]piperidin-1-yl}sulfonyl)thien-2-
-yl]methyl}benzamide [0642]
N-{[5-({4-[(1-adamantylmethyl)amino]piperidin-1-yl}sulfonyl)thien-2-yl]me-
thyl}-4-chlorobenzamide [0643]
4-chloro-N-{[5-({4-[(2-pyridin-2-ylethyl)amino]piperidin-1-yl}sulfonyl)th-
ien-2-yl]methyl}benzamide [0644]
4-chloro-N-{[5-({4-[(2-piperidin-1-ylethyl)amino]piperidin-1-yl}sulfonyl)-
thien-2-yl]methyl}benzamide [0645]
4-chloro-N-{[5-({4-[(2-ethylhexyl)amino]piperidin-1-yl}sulfonyl)thien-2-y-
l]methyl}benzamide [0646]
4-chloro-N-({5-[(4-{[3-(1H-imidazol-1-yl)propyl]amino}piperidin-1-yl)sulf-
onyl]thien-2-yl}methyl)benzamide [0647]
4-chloro-N-[(5-{[4-(octylamino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-
benzamide [0648]
N-[(5-{[4-(heptylamino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-3-metho-
xybenzamide [0649]
3-methoxy-N-[(5-{[4-(octylamino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl-
]benzamide [0650]
3-methoxy-N-[(5-{[4-(pentylamino)piperidin-1-yl]sulfonyl}thien-2-yl)methy-
l]benzamide [0651]
N-[(5-{[4-(butylamino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-3-methox-
ybenzamide [0652]
N-[(5-{[4-(dodecylamino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-3-meth-
oxybenzamide [0653]
N-{[5-({4-[(2-cyclohexylethyl)amino]piperidin-1-yl}sulfonyl)thien-2-yl]me-
thyl}-3-methoxybenzamide [0654]
N-({5-[(4-{[(1R)-1-cyclohexylethyl]amino}piperidin-1-yl)sulfonyl]thien-2--
yl}methyl)-3-methoxybenzamide [0655]
N-{[5-({4-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]piperidin-1-yl}sulfony-
l)thien-2-yl]methyl}-3-methoxybenzamide [0656]
3-methoxy-N-{[5-({4-[(2-propoxyethyl)amino]piperidin-1-yl}sulfonyl)thien--
2-yl]methyl}benzamide [0657]
N-{[5-({4-[(1-adamantylmethyl)amino]piperidin-1-yl}sulfonyl)thien-2-yl]me-
thyl}-3-methoxybenzamide [0658]
N-{[5-({4-[(3,3-diethoxypropyl)amino]piperidin-1-yl}sulfonyl)thien-2-yl]m-
ethyl}-3-methoxybenzamide [0659]
3-methoxy-N-{[5-({4-[(3-morpholin-4-ylpropyl)amino]piperidin-1-yl}sulfony-
l)thien-2-yl]methyl}benzamide [0660]
3-methoxy-N-{[5-({4-[(2-pyridin-2-ylethyl)amino]piperidin-1-yl}sulfonyl)t-
hien-2-yl]methyl}benzamide [0661]
3-methoxy-N-{[5-({4-[(2-piperidin-1-ylethyl)amino]piperidin-1-yl}sulfonyl-
)thien-2-yl]methyl}benzamide [0662]
N-{[5-({4-[(2-ethylhexyl)amino]piperidin-1-yl}sulfonyl)thien-2-yl]methyl}-
-3-methoxybenzamide [0663]
N-({5-[(4-{[3-(1H-imidazol-1-yl)propyl]amino}piperidin-1-yl)sulfonyl]thie-
n-2-yl}methyl)-3-methoxybenzamide [0664]
N-[(5-{[4-(hexylamino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-3-methox-
ybenzamide [0665]
N-[(5-{[4-(heptylamino)azepan-1-yl]sulfonyl}thien-2-yl)methyl]-3-methoxyb-
enzamide [0666]
3-methoxy-N-[(5-{[4-(octylamino)azepan-1-yl]sulfonyl}thien-2-yl)methyl]be-
nzamide [0667]
3-methoxy-N-[(5-{[4-(pentylamino)azepan-1-yl]sulfonyl}thien-2-yl)methyl]b-
enzamide [0668]
N-[(5-{[4-(butylamino)azepan-1-yl]sulfonyl}thien-2-yl)methyl]-3-methoxybe-
nzamide [0669]
N-[(5-{[4-(dodecylamino)azepan-1-yl]sulfonyl}thien-2-yl)methyl]-3-methoxy-
benzamide [0670]
N-{[5-({4-[(2-cyclohexylethyl)amino]azepan-1-yl}sulfonyl)thien-2-yl]methy-
l}-3-methoxybenzamide [0671]
N-({5-[(4-{[(1R)-1-cyclohexylethyl]amino}azepan-1-yl)sulfonyl]thien-2-yl}-
methyl)-3-methoxybenzamide [0672]
N-{[5-({4-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]azepan-1-yl}sulfonyl)t-
hien-2-yl]methyl}-3-methoxybenzamide [0673]
3-methoxy-N-{[5-({4-[(2-propoxyethyl)amino]azepan-1-yl}sulfonyl)thien-2-y-
l]methyl}benzamide [0674]
N-{[5-({4-[(cyclohexylmethyl)amino]azepan-1-yl}sulfonyl)thien-2-yl]methyl-
}-3-methoxybenzamide [0675]
N-{[5-({4-[(1-adamantylmethyl)amino]azepan-1-yl}sulfonyl)thien-2-yl]methy-
l}-3-methoxybenzamide [0676]
3-methoxy-N-{[5-({4-[(3-morpholin-4-ylpropyl)amino]azepan-1-yl}sulfonyl)t-
hien-2-yl]methyl}benzamide [0677]
3-methoxy-N-{[5-({4-[(2-pyridin-2-ylethyl)amino]azepan-1-yl}sulfonyl)thie-
n-2-yl]methyl}benzamide [0678]
3-methoxy-N-{[5-({4-[(2-piperidin-1-ylethyl)amino]azepan-1-yl}sulfonyl)th-
ien-2-yl]methyl}benzamide [0679]
N-{[5-({4-[(2-ethylhexyl)amino]azepan-1-yl}sulfonyl)thien-2-yl]methyl}-3--
methoxybenzamide [0680]
N-({5-[(4-{[3-(1H-imidazol-1-yl)propyl]amino}azepan-1-yl)sulfonyl]thien-2-
-yl}methyl)-3-methoxybenzamide [0681]
4-chloro-N-[(5-{[4-(heptylamino)azepan-1-yl]sulfonyl}thien-2-yl)methyl]be-
nzamide [0682]
4-chloro-N-[(5-{[4-(octylamino)azepan-1-yl]sulfonyl}thien-2-yl)methyl]ben-
zamide [0683]
4-chloro-N-[(5-{[4-(pentylamino)azepan-1-yl]sulfonyl}thien-2-yl)methyl]be-
nzamide [0684]
N-[(5-{[4-(butylamino)azepan-1-yl]sulfonyl}thien-2-yl)methyl]-4-chloroben-
zamide [0685]
4-chloro-N-[(5-{[4-(dodecylamino)azepan-1-yl]sulfonyl}thien-2-yl)methyl]b-
enzamide [0686]
4-chloro-N-{[5-({4-[(2-cyclohexylethyl)amino]azepan-1-yl}sulfonyl)thien-2-
-yl]methyl}benzamide [0687]
N-{[5-({4-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]azepan-1-yl}sulfonyl)t-
hien-2-yl]methyl}-4-chlorobenzamide [0688]
4-chloro-N-{[5-({4-[(2-propoxyethyl)amino]azepan-1-yl}sulfonyl)thien-2-yl-
]methyl}benzamide [0689]
4-chloro-N-{[5-({4-[(2-ethylhexyl)amino]azepan-1-yl}sulfonyl)thien-2-yl]m-
ethyl}benzamide [0690]
4-chloro-N-[(5-{[4-(hexylamino)azepan-1-yl]sulfonyl}thien-2-yl)methyl]ben-
zamide [0691]
N-[(5-{[4-(hexylamino)azepan-1-yl]sulfonyl}thien-2-yl)methyl]-3-methoxybe-
nzamide [0692]
3-methoxy-N-[(5-{[4-({2-[3-(trifluoromethyl)phenyl]ethyl}amino)piperidin--
1-yl]sulfonyl}thien-2-yl)methyl]benzamide [0693]
3-methoxy-N-({5-[(4-{[2-(4-methylphenyl)ethyl]amino}piperidin-1-yl)sulfon-
yl]thien-2-yl}methyl)benzamide [0694]
3-methoxy-N-({5-[(4-{[(1S,2R)-2-phenylcyclopropyl]amino}piperidin-1-yl)su-
lfonyl]thien-2-yl}methyl)benzamide [0695]
3-methoxy-N-{[5-({4-[(1-naphthylmethyl)amino]piperidin-1-yl}sulfonyl)thie-
n-2-yl]methyl}benzamide [0696]
3-methoxy-N-{[5-({4-[(2-phenylpropyl)amino]piperidin-1-yl}sulfonyl)thien--
2-yl]methyl}benzamide [0697]
N-({5-[(4-{[2-(4-hydroxyphenyl)ethyl]amino}piperidin-1-yl)sulfonyl]thien--
2-yl}methyl)-3-methoxybenzamide [0698]
3-methoxy-N-{[5-({4-[(3-phenylpropyl)amino]piperidin-1-yl}sulfonyl)thien--
2-yl]methyl}benzamide [0699]
N-{[5-({4-[(2,3-dihydroxypropyl)amino]piperidin-1-yl}sulfonyl)thien-2-yl]-
methyl}-3-methoxybenzamide [0700]
N-{[5-({4-[(2-hydroxyethyl)amino]piperidin-1-yl}sulfonyl)thien-2-yl]methy-
l}-3-methoxybenzamide [0701]
3-methoxy-N-[(5-{[4-(nonylamino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl-
]benzamide [0702]
3-methoxy-N-[(5-{[4-(decylamino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl-
]benzamide [0703]
3-methoxy-N-[(5-{[4-(ethylamino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl-
]benzamide [0704]
N-{[5-({4-[(2-[1,1'-biphenyl]-4-ylethyl)amino]piperidin-1-yl}sulfonyl)thi-
en-2-yl]methyl}-3-methoxybenzamide [0705]
N-{[5-({4-[([1,1'-biphenyl]-3-ylmethyl)amino]piperidin-1-yl}sulfonyl)thie-
n-2-yl]methyl}-3-methoxybenzamide
[0706]
3-methoxy-N-{[5-({4-[(2-thien-2-ylethyl)amino]piperidin-1-yl}sulfo-
nyl)thien-2-yl]methyl}benzamide [0707]
3-methoxy-N-[(5-{[4-({4-[(trifluoromethyl)sulfonyl]benzyl}amino)piperidin-
-1-yl]sulfonyl}thien-2-yl)methyl]benzamide [0708]
3-methoxy-N-{[5-({4-[(quinolin-4-ylmethyl)amino]piperidin-1-yl}sulfonyl)t-
hien-2-yl]methyl}benzamide [0709]
N-{[5-({4-[([1,1'-biphenyl]-4-ylmethyl)amino]-1-piperidinyl}sulfonyl)-2-t-
hienyl]methyl}-3-methoxybenzamide [0710]
4-chloro-N-{[5-({4-[(2-{[(trifluoromethyl)sulfonyl]amino}ethyl)amino]-1-p-
iperidinyl}sulfonyl)-2-thienyl]methyl}benzamide [0711]
4-chloro-N-[(5-{[4-(propylamino)-1-piperidinyl]sulfonyl}-2-thienyl)methyl-
]benzamide [0712]
4-chloro-N-[(5-{[4-({4-[(trifluoromethyl)sulfonyl]benzyl}amino)-1-piperid-
inyl]sulfonyl}-2-thienyl)methyl]benzamide [0713]
4-chloro-N-{[5-({4-[(3,4-dihydroxybenzyl)amino]-1-piperidinyl}sulfonyl)-2-
-thienyl]methyl}benzamide [0714]
methyl[{1-[(5-{[(4-chlorobenzoyl)amino]methyl}-2-thienyl)sulfonyl]-4-pipe-
ridinyl}(hexyl)amino]acetate [0715]
tert-butyl[{1-[(5-{[(4-chlorobenzoyl)amino]methyl}-2-thienyl)sulfonyl]-4--
piperidinyl}hexyl)amino]acetate [0716]
[{1-[(5-{[(4-chlorobenzoyl)amino]methyl}-2-thienyl)sulfonyl]-4-piperidiny-
l}(hexyl)amino]acetic acid [0717]
N-[(5-{[3-(heptylamino)pyrrolidin-1-yl]sulfonyl}thien-2-yl)methyl]-3-meth-
oxybenzamide [0718]
3-methoxy-N-[(5-{[3-(octylamino)pyrrolidin-1-yl]sulfonyl}thien-2-yl)methy-
l]benzamide [0719]
3-methoxy-N-[(5-{[3-(pentylamino)pyrrolidin-1-yl]sulfonyl}thien-2-yl)meth-
yl]benzamide [0720]
N-[(5-{[3-(butylamino)pyrrolidin-1-yl]sulfonyl}thien-2-yl)methyl]-3-metho-
xybenzamide [0721]
N-[(5-{[3-(dodecylamino)pyrrolidin-1-yl]sulfonyl}thien-2-yl)methyl]-3-met-
hoxybenzamide [0722]
N-{[5-({3-[(2-cyclohexylethyl)amino]pyrrolidin-1-yl}sulfonyl)thien-2-yl]m-
ethyl}-3-methoxybenzamide [0723]
N-({5-[(3-{[(1R)-1-cyclohexylethyl]amino}pyrrolidin-1-yl)sulfonyl]thien-2-
-yl}methyl)-3-methoxybenzamide [0724]
N-{[5-({3-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]pyrrolidin-1-yl}sulfon-
yl)thien-2-yl]methyl}-3-methoxybenzamide [0725]
3-methoxy-N-{[5-({3-[(2-propoxyethyl)amino]pyrrolidin-1-yl}sulfonyl)thien-
-2-yl]methyl}benzamide [0726]
N-{[5-({3-[(cyclohexylmethyl)amino]pyrrolidin-1-yl}sulfonyl)thien-2-yl]me-
thyl}-3-methoxybenzamide [0727]
N-{[5-({3-[(1-adamantylmethyl)amino]pyrrolidin-1-yl}sulfonyl)thien-2-yl]m-
ethyl}-3-methoxybenzamide [0728]
3-methoxy-N-{[5-({3-[(3-morpholin-4-ylpropyl)amino]pyrrolidin-1-yl}sulfon-
yl)thien-2-yl]methyl}benzamide [0729]
3-methoxy-N-{[5-({3-[(2-pyridin-2-ylethyl)amino]pyrrolidin-1-yl}sulfonyl)-
thien-2-yl]methyl}benzamide [0730]
3-methoxy-N-{[5-({3-[(2-piperidin-1-ylethyl)amino]pyrrolidin-1-yl}sulfony-
l)thien-2-yl]methyl}benzamide [0731]
N-{[5-({3-[(2-ethylhexyl)amino]pyrrolidin-1-yl}sulfonyl)thien-2-yl]methyl-
}-3-methoxybenzamide [0732]
N-[(5-{[3-(hexylamino)pyrrolidin-1-yl]sulfonyl}thien-2-yl)methyl]-3-metho-
xybenzamide [0733]
4-chloro-N-[(5-{[3-(heptylamino)pyrrolidin-1-yl]sulfonyl}thien-2-yl)methy-
l]benzamide [0734]
4-chloro-N-[(5-{[3-(hexylamino)pyrrolidin-1-yl]sulfonyl}thien-2-yl)methyl-
]benzamide [0735]
4-chloro-N-[(5-{[3-(pentylamino)pyrrolidin-1-yl]sulfonyl}thien-2-yl)methy-
l]benzamide [0736]
N-[(5-{[3-(butylamino)pyrrolidin-1-yl]sulfonyl}thien-2-yl)methyl]-4-chlor-
obenzamide [0737]
4-chloro-N-{[5-({3-[(2-cyclohexylethyl)amino]pyrrolidin-1-yl}sulfonyl)thi-
en-2-yl]methyl}benzamide [0738]
N-{[5-({3-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]pyrrolidin-1-yl}sulfon-
yl)thien-2-yl]methyl}-4-chlorobenzamide [0739]
4-chloro-N-({5-[(3-{[(1-hydroxycyclohexyl)methyl]amino}pyrrolidin-1-yl)su-
lfonyl]thien-2-yl}methyl)benzamide [0740]
N-{[5-({3-[(1-adamantylmethyl)amino]pyrrolidin-1-yl}sulfonyl)thien-2-yl]m-
ethyl}-4-chlorobenzamide [0741]
4-chloro-N-{[5-({3-[(3-morpholin-4-ylpropyl)amino]pyrrolidin-1-yl}sulfony-
l)thien-2-yl]methyl}benzamide [0742]
4-chloro-N-{[5-({3-[(2-pyridin-2-ylethyl)amino]pyrrolidin-1-yl}sulfonyl)t-
hien-2-yl]methyl}benzamide [0743]
4-chloro-N-{[5-({3-[(2-piperidin-1-ylethyl)amino]pyrrolidin-1-yl}sulfonyl-
)thien-2-yl]methyl}benzamide [0744]
4-chloro-N-{[5-({3-[(2-ethylhexyl)amino]pyrrolidin-1-yl}sulfonyl)thien-2--
yl]methyl}benzamide [0745]
4-chloro-N-[(5-{[3-(octylamino)pyrrolidin-1-yl]sulfonyl}thien-2-yl)methyl-
]benzamide [0746] methyl
(2S)-1-[(5-{[(4-chlorobenzoyl)amino]methyl}-2-thienyl)sulfonyl]-4-(hexyla-
mino)-2-pyrrolidinecarboxylate [0747]
3-methoxy-N-{[5-({4-[(pentylamino)methyl]piperidin-1-yl}sulfonyl)thien-2--
yl]methyl}benzamide [0748]
N-{[5-({4-[2-(butylamino)ethyl]piperidin-1-yl}sulfonyl)thien-2-yl]methyl}-
-3-methoxybenzamide [0749]
N-{[5-({4-[(4-butylanilino)methyl]-1-piperidinyl}sulfonyl)-2-thienyl]meth-
yl}-3-methoxybenzamide [0750]
4-chloro-N-{[5-({4-[hexyl(methyl)amino]piperidin-1-yl}sulfonyl)thien-2-yl-
]methyl}benzamide [0751]
4-chloro-N-{[5-({4-[(cyclohexylmethyl)(hexyl)amino]piperidin-1-yl}sulfony-
l)thien-2-yl]methyl}benzamide [0752]
N-{[5-({4-[benzyl(hexyl)amino]piperidin-1-yl}sulfonyl)thien-2-yl]methyl}--
4-chlorobenzamide [0753]
4-chloro-N-{[5-({4-[hexyl(pyridin-3-ylmethyl)amino]piperidin-1-yl}sulfony-
l)thien-2-yl]methyl}benzamide [0754]
4-chloro-N-{[5-({4-[hexyl(pyridin-4-ylmethyl)amino]piperidin-1-yl}sulfony-
l)thien-2-yl]methyl}benzamide [0755]
4-chloro-N-{[5-({4-[hexyl(pyridin-2-ylmethyl)amino]piperidin-1-yl}sulfony-
l)thien-2-yl]methyl}benzamide [0756]
N-{[5-({4-[butyl(hexyl)amino]piperidin-1-yl}sulfonyl)thien-2-yl]methyl}-4-
-chlorobenzamide [0757]
4-chloro-N-{[5-({4-[hexyl(3-phenylpropyl)amino]piperidin-1-yl}sulfonyl)th-
ien-2-yl]methyl}benzamide [0758]
4-chloro-N-{[5-({4-[hexyl(2-phenylethyl)amino]piperidin-1-yl}sulfonyl)thi-
en-2-yl]methyl}benzamide [0759]
N-{[5-({4-[[(5-bromo-2-furyl)methyl](hexyl)amino]piperidin-1-yl}sulfonyl)-
thien-2-yl]methyl}-4-chlorobenzamide [0760]
3-methoxy-N-({5-[(4-{methyl[4-(trifluoromethyl)benzyl]amino}-1-piperidiny-
l)sulfonyl]-2-thienyl}methyl)benzamide [0761]
4-chloro-N-{[5-({4-[(3-chlorobenzyl)amino]piperidin-1-yl}sulfonyl)thien-2-
-yl]methyl}benzamide [0762]
3-methoxy-N-({5-[(4-{[4-(trifluoromethyl)benzyl]amino}piperidin-1-yl)sulf-
onyl]thien-2-yl}methyl)benzamide [0763]
3-methoxy-N-{[5-({4-[(3-methylbenzyl)amino]piperidin-1-yl}sulfonyl)thien--
2-yl]methyl}benzamide [0764]
3-methoxy-N-{[5-({4-[(4-propylbenzyl)amino]piperidin-1-yl}sulfonyl)thien--
2-yl]methyl}benzamide [0765]
3-methoxy-N-({5-[(4-{[3-(trifluoromethyl)benzyl]amino}piperidin-1-yl)sulf-
onyl]thien-2-yl}methyl)benzamide [0766]
3-methoxy-N-({5-[(4-{[4-(trifluoromethoxy)benzyl]amino}piperidin-1-yl)sul-
fonyl]thien-2-yl}methyl)benzamide [0767]
N-({5-[(4-{[4-(difluoromethoxy)benzyl]amino}piperidin-1-yl)sulfonyl]thien-
-2-yl}methyl)-3-methoxybenzamide [0768]
3-methoxy-N-{[5-({4-[(2,3,4,5,6-pentamethylbenzyl)amino]piperidin-1-yl}su-
lfonyl)thien-2-yl]methyl}benzamide [0769]
3-methoxy-N-{[5-({4-[(4-propoxybenzyl)amino]piperidin-1-yl}sulfonyl)thien-
-2-yl]methyl}benzamide [0770]
N-{[5-({4-[(4-butoxybenzyl)amino]piperidin-1-yl}sulfonyl)thien-2-yl]methy-
l}-3-methoxybenzamide [0771]
3-methoxy-N-{[5-({4-[(4-methoxybenzyl)amino]piperidin-1-yl}sulfonyl)thien-
-2-yl]methyl}benzamide [0772]
3-methoxy-N-{[5-({4-[(pyridin-4-ylmethyl)amino]piperidin-1-yl}sulfonyl)th-
ien-2-yl]methyl}benzamide [0773]
3-methoxy-N-{[5-({4-[(pyridin-2-ylmethyl)amino]piperidin-1-yl}sulfonyl)th-
ien-2-yl]methyl}benzamide [0774]
3-methoxy-N-{[5-({4-[(pyridin-3-ylmethyl)amino]piperidin-1-yl}sulfonyl)th-
ien-2-yl]methyl}benzamide [0775]
N-{[5-({4-[(4-tert-butylbenzyl)amino]piperidin-1-yl}sulfonyl)thien-2-yl]m-
ethyl}-3-methoxybenzamide [0776]
N-{[5-({4-[(3-ethoxybenzyl)amino]piperidin-1-yl}sulfonyl)thien-2-yl]methy-
l}-3-methoxybenzamide [0777]
3-methoxy-N-{[5-({4-[(4-phenoxybenzyl)amino]piperidin-1-yl}sulfonyl)thien-
-2-yl]methyl}benzamide [0778]
3-methoxy-N-[(5-{[4-({4-[(trifluoromethyl)sulfanyl]benzyl}amino)piperidin-
-1-yl]sulfonyl}thien-2-yl)methyl]benzamide [0779]
3-methoxy-N-({5-[(4-{[4-(methylsulfonyl)benzyl]amino}-1-piperidinyl)sulfo-
nyl]-2-thienyl}methyl)benzamide [0780]
N-({5-[(4-{[3,5-bis(trifluoromethyl)benzyl]amino}-1-piperidinyl)sulfonyl]-
-2-thienyl}methyl)-3-methoxybenzamide [0781]
N-({5-[(4-{[2,5-bis(trifluoromethyl)benzyl]amino}-1-piperidinyl)sulfonyl]-
-2-thienyl}methyl)-3-methoxybenzamide [0782]
N-({5-[(4-{[4-(ethylsulfanyl)benzyl]amino}-1-piperidinyl)sulfonyl]-2-thie-
nyl}methyl)-3-methoxybenzamide [0783]
3-methoxy-N-[(5-{[4-({3-[(trifluoromethyl)sulfanyl]benzyl}amino)-1-piperi-
dinyl]sulfonyl}-2-thienyl)methyl]benzamide [0784]
N-({5-[(4-{[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]amino}-1-piperidiny-
l)sulfonyl]-2-thienyl}methyl)-3-methoxybenzamide [0785]
N-{[5-({4-[(4-iodobenzyl)amino]-1-piperidinyl}sulfonyl)-2-thienyl]methyl}-
-3-methoxybenzamide [0786]
N-({5-[(4-{[4-(benzyloxy)benzyl]amino}-1-piperidinyl)sulfonyl]-2-thienyl}-
methyl)-3-methoxybenzamide [0787]
N-{[5-({4-[(mesitylmethyl)amino]-1-piperidinyl}sulfonyl)-2-thienyl]methyl-
}-3-methoxybenzamide [0788] 5
N-{[5-({4-[(4-chlorobenzyl)amino]-1-piperidinyl}sulfonyl)-2-thienyl]methy-
l}-3-methoxybenzamide [0789]
N-{[5-({4-[(4-ethylbenzyl)amino]-1-piperidinyl}sulfonyl)-2-thienyl]methyl-
}-3-methoxybenzamide [0790]
3-methoxy-N-{[5-({4-[(4-pentylbenzyl)amino]-1-piperidinyl}sulfonyl)-2-thi-
enyl]methyl}benzamide [0791]
3-methoxy-N-[(5-{[4-({1-[4-(trifluoromethyl)phenyl]ethyl}amino)-1-piperid-
inyl]sulfonyl}-2-thienyl)methyl]benzamide [0792]
3-methoxy-N-{[5-({4-[(4-methylbenzyl)amino]-1-piperidinyl}sulfonyl)-2-thi-
enyl]methyl}benzamide [0793]
N-{[5-({4-[(4-butylbenzyl)amino]-1-piperidinyl}sulfonyl)-2-thienyl]methyl-
}-3-methoxybenzamide [0794]
N-{[5-({4-[(4-isopropylbenzyl)amino]-1-piperidinyl}sulfonyl)-2-thienyl]me-
thyl}-3-methoxybenzamide [0795]
N-{[5-({4-[(4-isobutylbenzyl)amino]-1-piperidinyl}sulfonyl)-2-thienyl]met-
hyl}-3-methoxybenzamide [0796]
N-({5-[(4-{[(1-hydroxy-1lambda.about.5.about.pyridin-4-yl)methyl]amino}-1-
-piperidinyl)sulfonyl]-2-thienyl}methyl)-3-methoxybenzamide [0797]
N-{[5-({4-[(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]-1-piperidinyl}s-
ulfonyl)-2-thienyl]methyl}-3-methoxybenzamide [0798]
N-{[5-({4-[(2,3-dihydro-1-benzofuran-5-ylmethyl)amino]-1-piperidinyl}sulf-
onyl)-2-thienyl]methyl}-3-methoxybenzamide [0799]
4-chloro-N-{[5-({4-[(4-propylbenzyl)amino]-1-piperidinyl}sulfonyl)-2-thie-
nyl]methyl}benzamide [0800]
4-chloro-N-({5-[(4-{[4-(trifluoromethoxy)benzyl]amino}-1-piperidinyl)sulf-
onyl]-2-thienyl}methyl)benzamide [0801]
4-chloro-N-({5-[(4-{[4-(difluoromethoxy)benzyl]amino}-1-piperidinyl)sulfo-
nyl]-2-thienyl}methyl)benzamide [0802]
4-chloro-N-{[5-({4-[(4-propoxybenzyl)amino]-1-piperidinyl}sulfonyl)-2-thi-
enyl]methyl}benzamide [0803]
N-{[5-({4-[(4-butoxybenzyl)amino]-1-piperidinyl}sulfonyl)-2-thienyl]methy-
l}-4-chlorobenzamide [0804]
4-chloro-N-{[5-({4-[(4-quinolinylmethyl)amino]-1-piperidinyl}sulfonyl)-2--
thienyl]methyl}benzamide [0805]
N-{[5-({4-[(4-tert-butylbenzyl)amino]-1-piperidinyl}sulfonyl)-2-thienyl]m-
ethyl}-4-chlorobenzamide [0806]
4-chloro-N-{[5-({4-[(4-phenoxybenzyl)amino]-1-piperidinyl}sulfonyl)-2-thi-
enyl]methyl}benzamide [0807]
4-chloro-N-[(5-{[4-({4-[(trifluoromethyl)sulfanyl]benzyl}amino)-1-piperid-
inyl]sulfonyl}-2-thienyl)methyl]benzamide [0808]
4-chloro-N-({5-[(4-{[4-(trifluoromethyl)benzyl]amino}-1-piperidinyl)sulfo-
nyl]-2-thienyl}methyl)benzamide [0809]
3-methoxy-N-({5-[(4-{[2-(trifluoromethyl)benzyl]amino}-1-piperidinyl)sulf-
onyl]-2-thienyl}methyl)benzamide [0810]
3-methoxy-N-[(5-{[4-({[6-(trifluoromethyl)-3-pyridinyl]methyl}amino)-1-pi-
peridinyl]sulfonyl}-2-thienyl)methyl]benzamide [0811]
N-[(5-{[4-(benzylamino)-1-piperidinyl]sulfonyl}-2-thienyl)methyl]-3-metho-
xybenzamide [0812]
3-methoxy-N-[(5-{[4-({1-[4-(trifluoromethyl)phenyl]propyl}amino)-1-piperi-
dinyl]sulfonyl}-2-thienyl)methyl]benzamide [0813]
3-methoxy-N-[(5-{[4-({1-methyl-1-[4-(trifluoromethyl)phenyl]ethyl}amino)--
1-piperidinyl]sulfonyl}-2-thienyl)methyl]benzamide [0814]
4-chloro-N-[(5-{[4-({1-[4-(trifluoromethyl)phenyl]ethyl}amino)-1-piperidi-
nyl]sulfonyl}-2-thienyl)methyl]benzamide [0815]
4-chloro-N-[(5-{[4-({1-methyl-1-[4-(trifluoromethyl)phenyl]ethyl}amino)-1-
-piperidinyl]sulfonyl}-2-thienyl)methyl]benzamide [0816]
4-chloro-N-[(5-{[2-({[4-(trifluoromethyl)benzyl]amino}methyl)-1-pyrrolidi-
nyl]sulfonyl}-2-thienyl)methyl]benzamide [0817]
4-chloro-N-[(5-{[(3R)-3-({[4-(trifluoromethyl)benzyl]amino}methyl)pyrroli-
dinyl]sulfonyl}-2-thienyl)methyl]benzamide [0818]
4-chloro-N-({5-[(3-{[4-(trifluoromethyl)benzyl]amino}-1-piperidinyl)sulfo-
nyl]-2-thienyl}methyl)benzamide [0819]
4-chloro-N-{[5-({3-[(hexylamino)methyl]-1-piperidinyl}sulfonyl)-2-thienyl-
]methyl}benzamide [0820]
4-chloro-N-({5-[(3-{[4-(trifluoromethyl)benzyl]amino}-1-pyrrolidinyl)sulf-
onyl]-2-thienyl}methyl)benzamide [0821]
4-chloro-N-{[5-({(3R)-3-[(hexylamino)methyl]pyrrolidinyl}sulfonyl)-2-thie-
nyl]methyl}benzamide [0822]
4-chloro-N-[(5-{[3-({[4-(trifluoromethyl)benzyl]amino}methyl)-1-piperidin-
yl]sulfonyl}-2-thienyl)methyl]benzamide [0823]
2-oxo-N-({5-[(4-{[4-(trifluoromethyl)benzyl]amino}-1-piperidinyl)sulfonyl-
]-2-thienyl}methyl)-1,2-dihydro-3-pyridinecarboxamide [0824]
N-[(5-{[4-(hexylamino)-1-piperidinyl]sulfonyl}-2-thienyl)methyl]-2-oxo-1,-
2-dihydro-3-pyridinecarboxamide [0825]
N-[(5-{[4-(hexylamino)-1-piperidinyl]sulfonyl}-2-thienyl)methyl]-2-hydrox-
ybenzamide [0826]
2-hydroxy-N-({5-[(4-{[4-(trifluoromethyl)benzyl]amino}-1-piperidinyl)sulf-
onyl]-2-thienyl}methyl)benzamide [0827]
N-[(5-{[4-(hexylamino)-1-piperidinyl]sulfonyl}-2-thienyl)methyl]-2-thioxo-
-1,2-dihydro-3-pyridinecarboxamide [0828]
2-thioxo-N-({5-[(4-{[4-(trifluoromethyl)benzyl]amino}-1-piperidinyl)sulfo-
nyl]-2-thienyl}methyl)-1,2-dihydro-3-pyridinecarboxamide [0829]
N-[(5-{[4-(butylamino)-1-piperidinyl]sulfonyl}-2-thienyl)methyl]-2-oxo-1,-
2-dihydro-3-pyridinecarboxamide [0830]
N-({5-[(4-{ethyl[4-(trifluoromethyl)benzyl]amino}-1-piperidinyl)sulfonyl]-
-2-thienyl}methyl)-3-methoxybenzamide [0831]
4-chloro-N-[(5-{[4-({imino[4-(trifluoromethyl)phenyl]methyl}amino)-1-pipe-
ridinyl]sulfonyl}-2-thienyl)methyl]benzamide [0832]
1-[(5-{[(4-chlorobenzoyl)amino]methyl}-2-thienyl)sulfonyl]-4-(hexylamino)-
proline ethyl
2-{[4-(hexylamino)piperidin-1-yl]sulfonyl}-5-{[(3-methoxybenzoyl)amino]me-
thyl}thiophene-3-carboxylate [0833]
N-{[5-{[4-(hexylamino)piperidin-1-yl]sulfonyl}-4-(trimethylsilyl)thien-2--
yl]methyl}-3-methoxybenzamide [0834]
N-({5-{[4-(hexylamino)piperidin-1-yl]sulfonyl}-4-[hydroxy(phenyl)methyl]t-
hien-2-yl}methyl)-3-methoxybenzamide [0835]
5-[(3-Methoxy-benzoylamino)-methyl]-2-[4-(4-trifluoromethyl-benzylamino)--
piperidine-1-sulfonyl]-thiophene-3-carboxylic acid ethyl ester
[0836]
N-[(4-chloro-5-{[4-(hexylamino)piperidin-1-yl]sulfonyl]thien-2-yl)methyl}-
-3-methoxybenzamide.
[0837] The compounds of formula (III) may be obtained according to
the methods described in any of WO 01/23378, WO 02/28856 and WO
02/26733.
[0838] In a further embodiment the JNK inhibitors may be a
pyrazoloanthrone derivative as shown in formula (C) (WO
01/12609):
##STR00015##
[0839] In a further embodiment the JNK inhibitors may have the
formula (IV) (WO 03/018022):
##STR00016##
[0840] The present invention will now be illustrated by the
example, which is not intended to be limiting in any way.
EXAMPLES
Example 1
Models for Endometriosis
[0841] The effect of the JNK inhibitor was evaluated in both in
vitro and in vivo models of endometriosis. The efficacy of the drug
treatment in inhibiting endometriosis was tested in two in vivo
models, i) nude mouse model and ii) the rat model and an in vitro
proliferative organ culture model.
Example 1.1
N-Cadherin Expression
[0842] For in vitro studies, human endometriotic cells (12Z) were
used (Zeitvogel et al 2001). These cells are invasive and express
N-cadherin, whereas less invasive cells have lower levels of
N-cadherin. These cells were treated with the JNK inhibitor and
cells were fixed with paraformaldehyde. Fixed cells were stained
for N-cadherin and cytokeratin using specific antibodies against
these proteins, followed by second antibody conjugated to
Alexafluor (a fluorochrome). Cells were observed under fluorescent
microscope and both phase contrast and fluorescent pictures were
taken. FIG. 1 represents the expression patterns of cytokeratin and
N-cadherin in these cells. Treating cells with the JNK inhibitor
decreased the expression of N-cadherin (FIG. 1), showing that this
pathway is involved in the regulation of N-cadherin expression and
invasive activity of endometriosis. On the other hand, expression
of cytokeratin, a marker for epithelial cells was not altered
following the treatment with the compound (FIG. 1). This shows that
only endometriotic cells are affected by treatment with the JNK
inhibitor, whereas epithelial cells are not affected. Thus, by
blocking the JNK pathway, the invasive properties associated with
endometriosis can be specifically inhibited and thus be very useful
for treating endometriosis.
Example 1.2
Nude Mouse Model
[0843] Human endometrial tissue was injected in ovarectomized nude
mice to establish the disease (Bruner-Tran et al 2002). In brief,
endometrial biopsies obtained from normal volunteers or from
endometriotic patients were cut into small pieces and cultured in
the presence of estradiol for 24 h. Treated tissues, were injected
either subcutaenously or intraperitoneally into ovarectomized nude
mice with estradiol implant. Within 2-4 days of injection, ectopic
endometriotic lesions developed in animals. Treatment with either
progesterone or a JNK inhibitor was started 10-12 days following
the injection of tissue. The compound was administered at a dose of
10 mg/kg and 30 mg/kg/animal for 30 days. Earlier work using this
model has established that progesterone treatment prevents disease
progression, hence this was used as control. Following the
completion of treatment, animals were sacrificed, lesions developed
from the transplanted tissue found in both subcutaneous and
intraperitoneal sites, were measured (both size and number).
[0844] Table 1 below, illustrates the results of studies carried
out as described above. The JNK inhibitor at a dose of 30 mg/kg was
effective in regressing the established disease in 50% animals
compared to progesterone treatment. The mean lesion size was also
reduced by 20% by the treatment. In another experiment conducted
with TBP, about 60% reduction in number of animals having the
disease was observed compared to the positive control,
progesterone, without any effect on lesion size. These results are
significant, since the model measures the growth/regression of
human endometrial tissue and thus has a direct relevance for
treating the human disease.
TABLE-US-00001 TABLE 1 Effects of JNK inhibitors (a JNK inhibitor
of formula I) and protein immunomodulatory agents on regression of
endometriotic lesions in the nude mouse xenograft model. Lesion (%
Progesterone) Compared to progesterone Treatment treated group
Lesion size JNK inhibitor 50% Decrease 20% Decrease 30 mg/kg
.times. 30 days TBP-1 (control) 60% Decrease No change 5 mg/kg
.times. 30 days
[0845] In another experiment in nude mice, human endometrial tissue
was obtained from endometriotic patients, and cultured in the
presence of either estradiol alone, estradiol plus medroxy
progesterone acetate (MPA) or JNK inhibitor for 24 h. Treated
tisses were then injected either subcutaneously or
intraperitoneally into ovarectomized mice with estradiol implant.
Within 2-4 days of injection, ectopic endometriotic lesions
developed in animals. At 10-12 days following injection of tissue,
treatment was begun with either MPA alone, JNK inhibitor alone or
MPA plus JNK inhibitor. The JNK inhibitor was administered at a
dose of 30/mg/kg/animal for 30 days. Following the completion of
treatment, animals were sacrificed, lesions developed from the
transplanted tissue found in both subcutaneous and intraperitoneal
sites were measured in both size and number. Treatment with a
combination of MPA and JNK inhibitor of formula 1 led to a
reduction in the lesion load of approximately 50% with a reduction
in lesion size of about 15 to 30% as compared to the lesion load
and size of those treated with estradiol alone. These results
indicate that the combination of a JNK inhibitor of formula 1 in
combination with a progestin would be effective in treating and/or
preventing endometriosis.
Example 1.3
Rat Model
[0846] Endometriosis was induced in rats as described earlier
(D'Antonio et al 2000). In brief, autologous uterine horn fragment
was transplanted onto the inner surface of the abdominal wall in
rat. Three weeks following transplantation, the size and the
viability of the engrafted tissue was measured. One week after the
confirmation of the tissue attachment, treatments were started. The
control group received the vehicle only. The JNK inhibitor was
administered orally (po) at doses of 10 mg/kg and 30 mg/kg per day.
Treatment with JNK inhibitor was conducted for nine days, animals
were anaesthetized 2 hr following the last treatment and blood
samples were collected. Surface area of the endometriosis-like foci
was measured, endometriotic-like foci flushed with PBS and
contralateral uterine flushing was also collected for measuring
cytokine. The endometriotic-like foci and spleen was removed for
histology and for NK cell activity measurement respectively. In
this model, the effect of the JNK inhibitor at 10 mg/kg dose was
not different from the vehicle, but at 30 mg/kg and 60 mg/kg a
significant regression of established endometriotic lesions was
observed (FIG. 2). Treatment with antide (for comparison) showed
about 85% regression (data not shown).
Example 1.4
Rat Model/Determination of Cytokine Levels
[0847] Of additional significance from these recent studies are
modifications in cytokine levels measured in either the
endometriotic foci or in the contralateral uterine horn without any
lesion. The effect of the JNK inhibitor on the cytokine levels was
determined in the rat model (see Example 1.3). The results
demonstrate that treatment with the JNK inhibitor reduced the
levels of inflammatory cytokines, IL-12, INF-.gamma., IL-10 and
MCP-1 in the endometriotic foci (FIG. 3). These cytokines have been
previously reported to be elevated in peritoneal fluid of women
with disease. In the contralateral horn, the JNK inhibitor was
without effect on the cytokine expression (FIG. 4). In addition,
inhibitor treatment increased NK cell activity compared to the
vehicle treated group (FIG. 5). A reduced lymphocyte cytolytic
activity has been observed in women with endometriosis. Therefore,
these results suggest that an increase in the NK cell cytolytic
activity due to the JNK inhibitor treatment may contribute to the
elimination of ectopic endometrium. Further, these results with JNK
inhibitors suggest that the effects of the inhibitor may treat the
diseased tissue without affecting portions of the uterus or
peritoneal cavity without disease.
[0848] The immune system of the rat in this model is intact,
suggesting that if molecules had as a primary mechanism to affect
only an immune-modulated pathway of the host, that the effects of
the molecules in this model should have been stronger than observed
in nude mice. In fact, these results from nude mouse and rat models
suggest an important activity of the molecule directly on the
endometriotic tissue or in immune cell populations that remain in
nude mice. Another important distinction of the rat model is that
intact myometrial and endometrial tissues are surgically resected
into experimental animals. Taken together, results from these two
model systems show that kinase inhibitors which target JNK pathway
are involved in endometriosis and can be effective agents for
treatment of disease.
Example 1.5
Proliferative Organ Culture Model
[0849] Normal endometrial tissues were acquired just prior to
ovulation by biopsy from a donor population (no history of
endometriosis) and from women with surgically confirmed
endometriosis. Informed consent was obtained prior to biopsy and
the use of human tissues was approved by Vanderbilt University's
Institutional Review Board and Committee for the Protection of
Human Subjects.
[0850] Endometrial biopsies were dissected into small cubes
(.about.1.times.1 mm.sup.3) and 8-10 pieces of tissue per treatment
group were suspended in tissue culture inserts. Organ cultures were
maintained a total of 72 hrs at 37.degree. C. in DME/F-12 media
with serum supplements. Tissue treatments included
17.beta.-estradiol (E), E plus progesterone (P), or E plus medroxy
progesterone acetate (MPA) with and without the JNK inhibitor.
Cultures were maintained for 24 hours in E only until the
initiation of experimental conditions. JNK inhibitor was used at a
concentration of 5 or 15 .mu.M and MPA was used at a concentration
of 50, 100 or 250 .mu.M.
[0851] Media was collected from organ cultures and secreted
proteins quantified using the Coomassie Plus Protein Assay (Pierce)
and 20 .mu.g total protein subjected to 10% SDS-PAGE. Proteins were
transferred to PVDF membrane and blocked in PBS with 10% non-fat
milk and 0.05% Tween-20. Blots were incubated overnight at
4.degree. C. in PBS/Milk/Tween with a primary antibody recognizing
human MMP-3, which is a marker for endometrial tissue, washed and
incubated with secondary antibody for one hour. Proteins were
visualized by chemiluminesence (Amersham) and autoradiography. As a
negative control, identical blots were incubated without a primary
antibody.
[0852] Results showed that the normal human endometrial cultures
were sensitive to MPA treatment, in contrast to endometrial
cultures obtained from endometriosis patients, which failed to
regress with MPA alone. When a JNK inhibitor of formula 1 was
combined with MPA treatment, the sensitivity to MPA was restored in
the cultures obtained from endometriosis patients and maintained in
the cultures obtained from normal volunteers.
[0853] These results indicate that co-administration of a progestin
with a JNK (inhibitor of formula 1 would treat and prevent the
re-establishment of endometriosis.
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* * * * *