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-9808473-B2
Application number	US-201414912315-A
Country	US
Kind code	B2
Filing date	Aug 18, 2014
Priority date	Aug 22, 2013
Publication date	Nov 7, 2017
Grant date	Nov 7, 2017

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

We 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 selected from the group consisting of: aspirin, seratrodast, picotamide, ramatroban, clopidogrel, meloxicam, rofecoxib, celecoxib, valsartan, telmisartan, candesartran, irbesartran, losartan, eprosartan, tezosentan, milrinoone, enoximone, captopril, enalapril, enaliprilat, spirapril, quinapril, perindopril, ramipril, fosinopril, trandolapril, lisinopril, moexipril, benazepril, candoxatril, ecadotril, ximelagatran, fondaparin, enoxaparin, chlorothiazide, hydrochlorothiazide, ethacrynic acid, furosemide, amiloride, abciximab and eptifibatide.

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 selected from the group consisting of: aspirin, seratrodast, picotamide, ramatroban, clopidogrel, meloxicam, rofecoxib, celecoxib, valsartan, telmisartan, candesartran, irbesartran, losartan, eprosartan, tezosentan, milrinoone, enoximone, captopril, enalapril, enaliprilat, spirapril, quinapril, perindopril, ramipril, fosinopril, trandolapril, lisinopril, moexipril, benazepril, candoxatril, ecadotril, ximelagatran, fondaparin, enoxaparin, chlorothiazide, hydrochlorothiazide, ethacrynic acid, furosemide, amiloride, abciximab and eptifibatide.

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 compound as defined in claim 3 or a pharmaceutically acceptable salt thereof.

Assignees

• Merck Sharp & Dohme

Inventors

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

Classifications

• A61K31/4365

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07D409/04

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

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title