Cyclic peptides and use as medicines

Patent metadata

Field	Value
Publication number	US-9566312-B2
Application number	US-201514717872-A
Country	US
Kind code	B2
Filing date	May 20, 2015
Priority date	Sep 29, 2012
Publication date	Feb 14, 2017
Grant date	Feb 14, 2017

Abstract

The present invention provides a compound of formula I;

or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , and A-B are as defined herein, which are non-immunosuppressive, cyclophilin-binding, mPTP blockers and are therefore useful for the prevention or treatment of diseases or disorders such as HCV infection, stroke, multiple sclerosis, HBV infection, HPV infection, asthma, cancer, muscular dystrophy, sepsis, ischemia/reperfusion injury, and heart failure.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein
A-B is —CH═CH or CH 2 CH 2 ;
R 1 is C 1 -C 4 alkoxy or C 1 -C 4 alkyl;
R 2 is —OR 1a , or a 4 to 8 membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, wherein said heterocycle is optionally substituted with at least one substituent selected from the group consisting of halogen, —OH, CN, —O(C 1 -C 4 )alkyl, oxo (═O), —S(O) 2 (C 1 -C 4 )alkyl, —C(O)(C 1 -C 4 )alkyl, —C(O) 2 (C 1 -C 4 )alkyl, C 1 -C 4 haloalkyl, C 3 -C 7 cycloalkyl, and C 1 -C 4 alkyl optionally substituted with C 1 -C 4 alkoxy;
R 1a is C 1 -C 4 alkyl, (C 1 -C 4 )alkyl-OH, (C 1 -C 4 )alkyl-C 1 -C 4 alkoxy, (C 2 -C 4 )alkyl-NR 9 R 10 , a 4 to 8 membered heterocycle containing 1 to 3 heteroatom selected from N, S, and O, or a (C 1 -C 4 )alkyl-4 to 8 membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, wherein said heterocycles are optionally substituted with at least one substituent selected from the group consisting of halogen, —OH, CN, —O(C 1 -C 4 )alkyl, oxo (═O), —S(O) 2 (C 1 -C 4 )alkyl, —C(O)(C 1 -C 4 )alkyl, —C(O) 2 (C 1 -C 4 )alkyl, C 1 -C 4 haloalkyl, C 3 -C 7 cycloalkyl, and C 1 -C 4 alkyl optionally substituted with C 1 -C 4 alkoxy;
R 3 is C 1 -C 6 alkyl optionally substituted with at least one substituent selected from the group consisting of OH, O(C 1 -C 4 alkyl), —NR 7 R 8 , and S(C 1 -C 6 alkyl);
R 4 is C 1 -C 4 alkyl;
R 5 is H, (C 1 -C 6 )alkyl;
R 7 is H or C 1 -C 4 alkyl;
R 8 is H or C 1 -C 4 alkyl; or
R 7 and R 8 taken together with the nitrogen to which they are attached form a 4 to 8 membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, wherein said heterocycle is optionally substituted with at least one substituent selected from the group consisting of halogen and C 1 -C 4 alkyl;
R 9 is H, C 1 -C 4 alkyl optionally substituted with one or more halogen, one or more hydroxy, C 1 -C 4 alkoxy, 5 to 6 membered heteroaryl or 5 to 6 membered heterocycle; and
R 10 is H, C 1 -C 4 alkyl optionally substituted with one or more halogen, C 1 -C 4 alkoxy or one or more hydroxy.

2. The compound or a pharmaceutically acceptable salt thereof of claim 1 having the following Formula II:

or a pharmaceutically acceptable salt thereof,

wherein
R 1 , R 2 , R 3 and R 4 are defined in claim 1 .

3. The compound or a pharmaceutically acceptable salt thereof according to claim 2 ,
wherein R 2 is —OR 1a .

4. The compound or a pharmaceutically acceptable salt thereof according to claim 2 , wherein
R 2 is a 4 to 8 membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, wherein said heterocycle is optionally substituted with at least one substituent selected from the group consisting of halogen, —OH, CN, —O(C 1 -C 4 )alkyl, oxo (═O), —S(O) 2 (C 1 -C 4 )alkyl, —C(O)(C 1 -C 4 )alkyl, —C(O) 2 (C 1 -C 4 )alkyl, C 1 -C 4 haloalkyl, C 3 -C 7 cycloalkyl, and C 1 -C 4 alkyl optionally substituted with C 1 -C 4 alkoxy; and
R 4 is methyl.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 2 , wherein
R 4 is methyl.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 5 , wherein R 1 is C 1 -C 4 alkyl.

7. The compound according to claim 3 , wherein the compound is represented by formula IIIa:

or a pharmaceutically acceptable salt thereof.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 7 , wherein R 1a is —CH 3 , —CH 2 CH 3 ,

9. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is

10. The compound according to claim 1 , wherein,
R 2 is

11. The compound according to claim 1 , wherein R 3 is methyl, ethyl, isopropyl,

12. The compound according to claim 1 , wherein A-B is —CH═CH.

13. The compound according to claim 1 , wherein A-B is CH 2 CH 2 .

14. The compound of claim 1 , which is:
1-dihydro-3-[D-Ala]-4-[(2S,3S)-3-methyl-2-(methylamino)-4-(2-morpholinoethoxy)butanoyl]-cyclosporin,
or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 , which is
1-dihydro-3-[D-Ala]-4[(2S,3S)-2-Amino-3-methyl-4-morpholin-4-yl-butanoyl]-cyclosporin
or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , which is
3-[D-Ala]-4[(2S,3R)-2-Amino-4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-3-methyl-butanoyl]-cyclosporin or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 , which is
1-dihydro-3-[D-Ala]-4[(2S,3R)-2-Amino-4-(4-cyclobutyl-piperazin-1-yl)-butanoyl]-cyclosporin
or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1 , which is
3-[D-Ala]-4-[(2S,3R)-4-(3,3-difluoropyrrolidin-1-yl)-3-methyl-2-(methylamino)butanoyl]-cyclosporin
or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1 , which is
3-[D-Ala]-4-[(2S,3S)-3-methyl-2-(methylamino)-4-(2-((S)-3-methylmorpholino)ethoxy)-butanoyl]-cyclosporin
or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition, comprising:
the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21. A pharmaceutical combination composition, comprising:
a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and
one or more therapeutically active agents selected from Interferons, ribavirin and ribavirin analogs, HCV NS3 protease inhibitors, HCV NS5a inhibitors, nucleoside and non-nucleoside NS5b inhibitors, HCV NS4a antagonists, TLR-7 agonists, HCV IRES inhibitors, pharmacokinetic enhancers, anti-fibrotic agents, or mixtures thereof.

22. A method of treating a disorder or a disease selected from HCV infection, stroke, multiple sclerosis, HBV infection, HPV infection, asthma, muscular dystrophy, sepsis, ischemia/reperfusion injury, and heart failure in a subject, which comprises administering to the subject a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

Assignees

• Novartis Ag

Inventors

• Fu Jiping
• Karur Subramanian
• Li Xiaolin
• Lu Peichao
• Mergo Wosenu
• Rivkin Alexey
• Sweeney Zachary Kevin
• Tjandra Meiliana
• Weiss Andrew
• Yifru Aregahegn

Classifications

• A61P31/20

  for DNA viruses · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title