Preparation and use of 3-pyridyl substituted- 6,6-difluoro bicyclic himbacine derivatives as par-1 receptor antagonists

Patent metadata

Field	Value
Publication number	US-2016200713-A1
Application number	US-201414912315-A
Country	US
Kind code	A1
Filing date	Aug 18, 2014
Priority date	Aug 22, 2013
Publication date	Jul 14, 2016
Grant date	—

Abstract

The present invention relates to bicyclic himbacine derivatives of the formula

or a pharmaceutically acceptable salt thereof

wherein:
R 1 is halo; —CN; alkyl; cycloalkyl; alkoxy; phenyl, which is optionally substituted one or twice independently by alkyl, halo, or —CN; or a thiophene ring, which is optionally substituted once or twice independently by alkyl.

The compounds of the invention are effective inhibitors of the PAR-1 receptor. The inventive compounds may be used for the treatment or prophylaxis of disease states such as ASC, secondary prevention of myocardial infarction or stroke, or PAD.

First claim

1 . A compound of the formula

or a pharmaceutically acceptable salt thereof

wherein:
R 1 is halo; —CN; alkyl; cycloalkyl; alkoxy; phenyl, which is optionally substituted one or twice independently by alkyl, halo, or —CN; or a thiophene ring, which is optionally substituted once or twice independently by alkyl.

2 . The compound as defined in claim 1 or a pharmaceutically acceptable salt thereof wherein R 1 is methoxy, —CN, —F, —Cl, or cyclopropyl.

3 . A compound as defined in claim 1 , which is:
6′-((E)-2-((3R,3aR,4R,5S,7aS)-6,6-difluoro-7a-hydroxy-3,5-dimethyl-1-oxooctahydro isobenzofuran-4-yl)vinyl)[3,3′-bipyridine]-2-carbonitrile; (3R,3aR,4R,5S,7aS)-6,6-difluoro-7a-hydroxy-3,5-dimethyl-4-((E)-2-(2′-phenyl-[3,3′-bipyridin]-6-yl)vinyl)hexahydroisobenzofuran-1(3H)-one; (3R,3aR,4R,5S,7aS)-6,6-difluoro-7a-hydroxy-4-((E)-2-(2′-methoxy-[3,3′-bipyridin]-6-yl)vinyl)-3,5-dimethylhexahydroisobenzofuran-1(3H)-one; (3R,3aR,4R,5S,7aS)-4-((E)-2-(2′-chloro-[3,3′-bipyridin]-6-yl)vinyl)-6,6-difluoro-7a-hydroxy-3,5-dimethylhexahydroisobenzofuran-1(3H)-one; (3R,3aR,4R,5S,7aS)-4-((E)-2-(2′-fluoro-[3,3′-bipyridin]-6-yl)vinyl)-7a-hydroxy-3,5-dimethylhexahydroisobenzofuran-1(3H)-one; (3R,3aR,4R,5S,7aS)-4-((E)-2-(2′-cyclopropyl-[3,3′-bipyridin]-6-yl)vinyl)-6,6-difluoro-7a-hydroxy-3,5-dimethylhexahydroisobenzofuran-1(3H)-one; 3R,3aR,4R,5S,7aS)-6,6-difluoro-7a-hydroxy-3,5-dimethyl-4-((E)-2-(2′-(5-methylthiophen-2-yl)-[3,3′-bipyridin]-6-yl)vinyl)hexahydroisobenzofuran-1(3H)-one; or a pharmaceutically acceptable salt thereof.

4 . A pharmaceutical composition comprising an effective amount of a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

5 . The pharmaceutical composition as defined in claim 4 , which further comprises a therapeutically effective amount of at least one additional cardiovascular agent.

6 . The pharmaceutical composition as defined in claim 5 , wherein the at least one additional cardiovascular agent is aspirin or clopidogrel, wherein clopidogrel is a free base or pharmaceutically acceptable salt.

7 . A pharmaceutical composition comprising an effective amount of a compound as defined in claim 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

8 . The pharmaceutical composition as defined in claim 7 , which further comprises a therapeutically effective amount of at least one additional cardiovascular agent.

9 . The pharmaceutical composition as defined in claim 8 , wherein the at least one additional cardiovascular agent is aspirin or clopidogrel, wherein clopidogrel is a free base or pharmaceutically acceptable salt.

10 . A method for treating acute coronary syndrome or peripheral artery disease by administering a compound as defined in claim 1 to a mammal in need of such treatment.

11 . A method of inhibiting platelet aggregation comprising administering to a mammal an effective amount of a compound as defined in claim 1 .

12 . A method for treating acute coronary syndrome or peripheral artery disease by administering a compound as defined in claim 3 or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment.

13 . A method of inhibiting platelet aggregation comprising administering to a mammal an effective amount of a compound as defined in claim 3 or a pharmaceutically acceptable salt thereof.

Assignees

• Dropinski James Francis
• Maletic Milana
• Kim Jae-Hun
• Sha Deyou
• Merck Sharp & Dohme

Inventors

• Dropinski James Francis
• Maletic Milana
• Kim Jae-Hun
• Sha Deyou

Classifications

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/60 Primary

  Salicylic acid; Derivatives thereof · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/4365

  the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine · CPC title