US 2001/0044545 A1Published application

Substituted thiazoles and the use thereof as inhibitors of plasminogen activator inhibitor-1

Assignee3-Dimensional Pharmaceuticals, Inc.

InventorsDale S. Dhanoa, Declan E. Ryan, Ingrid Deckman, Anthony Sapienza

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Abstract

The present invention relates to the use of aminothiazole derivatives of Formula I of as inhibitors of PAI-1, and to novel classes of aminothiazole derivatives, their synthesis and their use as inhibitors of PAI-1. It has been discovered that compounds of Formula I: 1 or a solvate, hydrate or a pharmaceutically acceptable salt thereof, wherein Y, Ar1, Ar2, R1, R2, Z, m and n are described in the specification, inhibit plasminogen activator inhibitor-1 (PAI-1). These compounds can be used in the prophylaxis or for the treatment of thrombosis, angina pectoris, cerebral infarction, myocardial infarction, pulmonary infarction, intra-atrial thrombus in atrial fibrillation, deep venous thrombus, disseminated intravascular coagulation syndrome, diabetic complications, restenosis and stroke.

Claims35

Dependent claims

A method of inhibiting plasminogen activator inhibitor-1, comprising administering to a mammal in need thereof an effective amount of a compound of Formula I:

15
or a solvate, hydrate or a pharmaceutically acceptable salt thereof, wherein
Y is —N—, —C(R3)— or —CH(R3)—, wherein
R3 is selected from the group consisting of hydrogen, cyano, C(CN)3, N(CN)2, trifluoromethyl, halogen, alkyl, cycloalkyl, aryl and heteroaryl radical, all of which can be optionally substituted;
Ar1 and Ar2, which can be the same or different, are an optionally substituted aryl or heteroaryl radical;
m is 0 or 1, provided that when Y is —N— or —C(R3)—, then m is 1 and when Y is —CH(R3)—, then m is 0;
R1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl or heteroaryl radical, all of which can be optionally substituted;
and
R2 is hydrogen, or an optionally substituted aryl or an optionally substituted heteroaryl radical;
with the provisos that
when Y is N, R1 and R2 are hydrogen and Ar2 is an optionally substituted phenyl, then Ar1 is other than a phenyl group substituted with carboxyalkyl or an alkyl ester of carboxyalkyloxy;
when Y is N, R1 is hydrogen, and Ar2 and R2 are both a phenyl group, then Ar1 is other than a phenyl group substituted with carboxyalkyl;
or
when Y is N, R1 and R2 are hydrogen and Ar2 is naphthyl, then Ar1 is other than a phenyl group substituted with carboxyalkyl.

11 more elements

A compound having the Formula II:

23
or a solvate, hydrate or a pharmaceutically acceptable salt thereof, wherein
Ar21 is an optionally substituted aryl or an optionally substituted heteroaryl radical;
Ar22 is a substituted aryl or an optionally substituted heteroaryl radical;
R21 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl or heteroaryl radical, all of which can be optionally substituted;
R22 is hydrogen, or an optionally substituted aryl or an optionally substituted heteroaryl radical,
with the provisos that
when R21 and R22 are hydrogen and Ar22 is substituted phenyl, then Ar21 is other than a phenyl group substituted with carboxyalkyl;
when R21 is hydrogen, and Ar22 and R22 are both a phenyl group, then Ar21 is other than a phenyl group substituted with carboxyalkyl;
when R21 and R22 are hydrogen and Ar22 is naphthyl, then Ar21 is other than a phenyl group substituted with carboxyalkyl;
when Ar21 an unsubstituted naphthyl or a naphthyl substituted with halogen, R21 and R22 are both hydrogen and Ar22 is a substituted phenyl group, then the substituents in Ar22 are not selected from the group consisting of alkyl, haloalkyl, halogen, thiol, and nitro;
or
when Ar21 is a phenyl group substituted only with trifluoro(C1-6)alkyl, R21 and R22 are both hydrogen, and Ar22 is a phenyl group substituted with halogen or trifluoromethyl, then Ar22 has another substituent other than hydrogen.

10 more elements

A compound selected from the group consisting of

3-{[4-(5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}phenol;
4-{[4-(3-ethyl-5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}benzoic acid;
3-{4-(3-ethyl-5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}benzoic acid;
[4-(3-bromophenyl)(1,3-thiazol-2-yl)][3-(trifluoromethyl)phenyl]amine;
(3,5-dichlorophenyl)[4-(4-fluorophenyl)(1,3-thiazol-2-yl)]amine;
[4-(4-bromophenyl)(1,3-thiazol-2-yl)](3-chlorophenyl)amine;
[4-(3,4-dichlorophenyl)(1,3-thiazol-2-yl)](2,5-difluorophenyl)amine;
(3,5-dichlorophenyl){4-[4-(trifluoromethyl)phenyl](1,3-thiazol-2-yl}amine;
2-{[4-(4-phenylphenyl)-1,3-thiazol-2-yl]amino}phenol;
4-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}benzenecarbonitrile;
4-{[4-(4-phenylphenyl)-1,3-thiazol-2-yl]amino}-benzenecarbonitrile;
(2,4-difluorophenyl)[4-(4-chlorophenyl)-5-phenyl-1,3-thiazol-2-yl]amine;
4-{[4-(4-phenylphenyl)-1,3-thiazol-2-yl]amino}-1,2,3-trifluorobenzene;
[4-(3,4-difluorophenyl)(1,3-thiazol-2[-yl) (3,4-dichlorophenyl)-amine;
[4-(4-trifluoromethylphenyl)(1,3-thiazol-2-yl)](4-nitrophenyl)amine;
[4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)](3,5-dichlorophenyl)amine;
[4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)](3-chloro-4-bromophenyl)amine;
[4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)](3-trifluoromethylphenyl)amine;
[4-(2,4-difluorophenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)amine;
4-{4-(3-ethyl-5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}-1-hydroxyethylbenzene;
2-{[4-(5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}phenol;
[4-(4-trifluoromethylphenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)amine;
4-{[4-(2,4-dichlorophenyl)-1,3-thiazol-2-yl]amino}benzenecarbonitrile;
(4-aminophenyl)[4-(4-chlorophenyl)-5-(4-methylphenyl)-1,3-thiazol-2-yl]amine;
[4-(2,4-difluorophenyl)(1,3-thiazol-2-yl)](3,5-dichlorophenyl)amine;
[4-(4-trifluoromethylphenyl)(1,3-thiazol-2-yl)](3-hydroxyphenyl)amine;
[4-(4-tert-butyl-2,6-dimethyl-3,5-dinitrophenyl)(1,3-thiazol-2-yl)](3,4,5-trimethoxyphenyl)amine;
3-[4-(4-tert-butyl-2,6-dimethyl-3,5-dinitrophenyl)(1,3-thiazol-2-yl)amino]benzoic acid;
3-[4-(4-tert-butyl-2,6-dimethyl-3,5-dinitrophenyl)(1,3-thiazol-2-yl)amino]phenol;
[4-(4-nitrophenyl)(1,3-thiazol-2-yl)](2,4-benzyloxyphenyl)amine;
[4-(4-nitrophenyl)(1,3-thiazol-2-yl)](2,4-dimethoxyphenyl)amine;
[4-(4-fluorophenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)amine;
[4-(4-chlorophenyl)(1,3-thiazol-2-yl)](3-hydroxyphenyl)amine;
[4-(3-chloro-4-methylphenyl)-5-methyl-1,3-thiazol-2-yl](3-hydroxyphenyl)amine;
(4-nitrophenyl)[4-(isoxazol-3-yl-5-carboxylic acid ethyl ester)-1,3-thiazol-2-yl]amine;
(2,4,5-trichlorophenyl)[4-(isoxazol-3-yl-5-carboxylic acid ethyl ester)-1,3-thiazol-2-yl]amine;
and
2-cyanomethyl-4-(5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazole;
or a solvate, hydrate or a pharmaceutically acceptable salt thereof.

36 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/822,351Filed 2 Apr 2001
Priority: 3 Apr 2000
Published: 22 Nov 2001
Term ends: Not estimatedThe source records don’t support an estimate.

Classification4 codes

C07D 417/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
C07D 277/38
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
C07D 277/42
Nitrogen atoms: amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
C07D
Heterocyclic compounds