IP Library › Granted Patent US 8,609,691

Granted Patent B2

US 8,609,691 · App. 12/019,799 · Granted Dec 17, 2013

Cyclohexylamin isoquinolone derivatives

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Patent No.: US 8,609,691
App. No.: 12/019,799
Granted: Dec 17, 2013
Kind: B2

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Abstract

The invention relates to 6-cyclohexylamine-substituted isoquinolone derivatives of the formula (I) or isoquinoline derivatives of the formula (I′) useful for the treatment and/or prevention of diseases associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase, and compositions containing such compounds.

Claims (109)

1. A compound of the formula (I)

or of the formula (I′)

wherein

R 1 is H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, [(C 1 -C 6 )alkylene] 0-1 -(C 3 -C 8 )cycloalkyl, [(C 1 -C 6 )alkylene] 0-1 -(C 5 -C 10 )heterocyclyl, [(C 1 -C 6 )alkylene] 0-1 -(C 6 -C 10 )aryl, C(O)—(C 1 -C 6 )alkyl, C(O)(C 2 -C 6 )alkenyl, C(O)—(C 2 -C 6 )alkynyl, C(O)-[(C 1 -C 6 )alkylene] 0-1 -(C 3 -C 8 )cycloalkyl, C(O)-[(C 1 -C 6 )alkylene] 0-1 -(C 5 -C 10 )heterocyclyl, or C(O)-[(C 1 -C 6 )alkylene] 0-1 -(C 6 -C 10 )aryl;

R 2 is H, (C 1 -C 6 )alkyl, [(C 1 -C 6 )alkylene] 0-1 -R′, [(C 1 -C 6 )alkylene] 0-1 -O—(C 1 -C 6 )alkyl, [(C 1 -C 6 )alkylene] 0-1 -O—R′, [(C 1 -C 6 )alkylene] 0-1 -NH 2 , [(C 1 -C 6 )alkylene] 0-1 -NH(C 1 -C 6 )alkyl, [(C 1 -C 6 )alkylene] 0-1 -N[(C 1 -C 6 )alkyl] 2 , [(C 1 -C 6 )alkylene] 0-1 -CH[R′] 2 , [(C 1 -C 6 )alkylene] 0-1 -C(O)—R′, [(C 1 -C 6 )alkylene] 0-1 -C(O)NH 2 , [(C 1 -C 6 )alkylene] 0-1 -C(O)NH—R′, or [(C 1 -C 6 )alkylene] 0-1 -C(O)N[R′] 2 ;

R 3 is H, halogen, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylene-R′, OH, O—R″, NH 2 , NHR″, NR″R″, or NH—C(O)—R″;

R 4 is H, halogen, OH, CN, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, NH—(C 6 -C 10 )aryl, or (C 1 -C 6 )alkylene-R′;

R 5 is H, halogen, CN, NO 2 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, R′, (C 2 -C 6 )alkenylene-(C 6 -C 10 )aryl, (C 1 -C 6 )alkylene-R′, NH 2 , NH—R′, NH—SO 2 H, NH—SO 2 —(C 1 -C 6 )alkyl, NH—SO 2 —R′, NH—C(O)—(C 1 -C 6 )alkyl, NH—C(O)—R′, C(O)N[(C 1 -C 6 )alkyl] 2 , C(O)OH or C(O)O—(C 1 -C 6 )alkyl;

R 6 and R 6 ′ are independently of each other H, R′, (C 1 -C 8 )alkyl, (C 1 -C 6 )alkylene-R′, (C 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylene-O—R′, (C 1 -C 6 )alkylene-CH[R′] 2 , (C 1 -C 6 )alkylene-C(O)—R′, (C 1 -C 6 )alkylene-C(O)NH 2 , (C 1 -C 6 )alkylene-C(O)NH—R′, or (C 1 -C 6 )alkylene-C(O)N[R′] 2 ;

R 7 and R 8 are independently of each other H, halogen, CN, NO 2 , (C 1 -C 6 )alkyl, O—(C 1 -C 6 )alkyl, O—[(C 1 -C 6 )alkylene] 0-1 -R′, (C 2 -C 6 )alkenyl, R′, (C 2 -C 6 )alkenylene-(C 6 -C 10 )aryl, (C 1 -C 6 )alkylene-R′, NH 2 , NH—R′, NH—SO 2 H, NH—SO 2 —(C 1 -C 6 )alkyl, NH—SO 2 —R′, SO 2 —NH 2 , SO 2 —NHR′, NH—C(O)—(C 1 -C 6 )alkyl, NH—C(O)—R′, C(O)N[(C 1 -C 6 )alkyl] 2 , C(O)OH, or C(O)O—(C 1 -C 6 )alkyl;

R 9 is halogen or (C 1 -C 6 )alkyl;

R′ is (C 3 -C 8 )cycloalkyl, (C 5 -C 10 )heterocyclyl or (C 6 -C 10 )aryl;

R″ is (C 3 -C 8 )cycloalkyl, (C 5 -C 10 )heterocyclyl, (C 6 -C 10 )aryl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylene-R′, (C 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylene-O—R′, or (C 1 -C 6 )alkylene-NR x R y ;

R x and R y are independently of each other (C 1 -C 6 )alkyl, (C 5 -C 10 )heterocyclyl, (C 6 -C 10 )aryl, (C 1 -C 4 )alkylene-(C 5 -C 10 )heterocyclyl, (C 1 -C 4 )alkylene-(C 6 -C 10 )aryl, (C 1 -C 4 )alkylene-NH(C 1 -C 6 )alkyl, (C 1 -C 4 )alkylene-N[(C 1 -C 6 )alkyl] 2 , (C 1 -C 4 )alkylene-N[(C 6 -C 10 )aryl] 2 , or (C 1 -C 4 )alkylene-N[(C 5 -C 10 )heterocyclyl] 2 ; and

n is 0, 1, 2, 3 or 4; and

L is O or O—(C 1 -C 6 )alkylene;

wherein

in residues R 4 , R 5 , R 7 and R 8 one alkyl or alkylene hydrogen atom can optionally be substituted by OH, OCH 3 , COOH, COOCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCH 3 or CON(CH 3 ) 2 , or

an alkyl or alkylene may be halogenated once or more;

or a pharmaceutically acceptable salt thereof, stereoisomeric form thereof or physiologically functional derivative thereof, pharmaceutically acceptable salt of a stereoisomeric form thereof or physiologically functional derivative thereof, or stereoisomeric form of a physiologically functional derivative thereof.

2. The compound according to claim 1 wherein

R 4 is H, halogen, OH, CN, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 1 -C 6 )alkylene-R′;

R 5 is H, halogen, CN, NO 2 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, R′, (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, (C 2 -C 6 )alkenylene-(C 6 -C 10 )aryl, (C 1 -C 6 )alkylene-(C 5 -C 11 )heterocyclyl, (C 1 -C 6 )alkylene-R′, NH 2 , NH—R′, NH—SO 2 H, NH—SO 2 —(C 1 -C 6 )alkyl, NH—SO 2 —R′, NH—C(O)—(C 1 -C 6 )alkyl, NH—C(O)—R′, C(O)N[(C 1 -C 6 )alkyl] 2 , C(O)OH or C(O)O—(C 1 -C 6 )alkyl;

3. The compound according to claim 1 of the formula (I)

4. The compound according to claim 1 of the formula (I′) wherein R 1 is H

5. The compound according to claim 1 , wherein R 6 and R 6 ′ are independently of each other H, (C 1 -C 6 )alkyl, R′, (C 1 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl, (C 1 -C 4 )alkylene-(C 5 -C 10 )heterocyclyl, (C 1 -C 4 )alkylene-C(O)—(C 5 -C 10 )heterocyclyl, (C 1 -C 4 )alkylene-C(O)—(C 6 -C 10 )aryl or (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl.

6. The compound according to claim 1 , wherein R 6 and R 6 ′ are independently of each other H, (C 1 -C 6 )alkyl, (C 5 -C 10 )heterocyclyl, (C 3 -C 9 )cycloalkyl, (C 1 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl, (C 1 -C 4 )alkylene-(C 5 -C 11 )heterocyclyl or (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl.

7. The compound according to claim 1 , wherein R 6 is H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl or (C 1 -C 4 )alkylene-(C 3 -C 6 )cycloalkyl; and R 6 ′ is H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 4 )alkylene-(C 3 -C 9 )cycloalkyl, (C 5 -C 10 )heterocyclyl, (C 1 -C 4 )alkylene-(C 5 -C 10 )heterocyclyl or (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl.

8. The compound according to claim 1 , wherein R 6 is H, or (C 1 -C 6 )alkyl and R 6 ′ is H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl, (C 5 -C 10 )heterocyclyl, (C 1 -C 4 )alkylene-(C 5 -C 10 )heterocyclyl or (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl.

9. The compound according to claim 1 ,

R 6 is H, or (C 1 -C 6 )alkyl; and

R 6 ′ is H,

(C 1 -C 6 )alkyl,

(C 3 -C 8 )cycloalkyl,

(C 1 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl,

(C 1 -C 4 )alkylene-(C 5 -C 10 )heterocyclyl, which heterocyclyl is unsubstituted or substituted by (C 1 -C 4 )alkyl or halogen, or (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, which aryl is unsubstituted or substituted by halogen, (C 1 -C 4 )alkyl, O—(C 1 -C 4 )alkyl or SO 2 —(C 1 -C 4 )alkyl.

10. The compound according to claim 1 , wherein R 6 is H, or (C 1 -C 6 )alkyl; and R 6 ′ is H, (C 1 -C 6 )alkyl, or (C 3 -C 8 )cycloalkyl.

11. The compound according to claim 1 , wherein R 6 is H; and R 6 ′ is H, (C 1 -C 6 )alkyl, or (C 3 -C 8 )cycloalkyl.

12. The compound according to claim 1 , wherein R 6 and R 6 ′ are H.

13. The compound according to claim 1 , wherein R 5 is H, halogen, CN, (C 1 -C 6 )alkyl, R′, NH—(C 6 -C 10 )aryl, or (C 1 -C 6 )alkylene-R′.

14. The compound according to claim 1 , wherein R 5 is H, halogen, CN, (C 1 -C 6 )alkyl, R′, NH—(C 6 -C 10 )aryl, C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, or (C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl.

15. The compound according to claim 1 , wherein R 5 is H, halogen, (C 1 -C 6 )alkyl, R′, NH—(C 6 -C 10 )aryl or (C 1 -C 6 )alkylene-R′.

16. The compound according to claim 1 , wherein R 5 is H, halogen, (C 1 -C 6 )alkyl, R′, NH—(C 6 -C 11 )aryl, C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, or (C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl.

17. The compound according to claim 1 , wherein R 5 is H, halogen, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 5 -C 10 )heteroaryl, NH—(C 6 -C 10 )aryl or (C 1 -C 2 )alkylene-(C 6 -C 10 )aryl.

18. The compound according to claim 1 , wherein R 5 is H, halogen, (C 1 -C 6 )alkyl, phenyl or (C 5 -C 6 )heteroaryl.

19. The compound according to claim 1 , wherein R 5 is H, halogen or (C 1 -C 6 )alkyl.

20. The compound according to claim 1 , wherein R 5 is H or halogen.

21. The compound according to claim 1 , wherein R 5 is H.

22. The compound according to claim 1 , wherein R 4 is H, halogen, CN, (C 1 -C 6 )alkyl, NH—(C 6 -C 10 )aryl, or (C 1 -C 6 )alkylene-R′.

23. The compound according to claim 1 , wherein R 4 is H, halogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylene-R′.

24. The compound according to claim 1 , wherein R 4 is H, halogen, (C 1 -C 6 )alkyl, NH—(C 6 -C 10 )aryl, or (C 1 -C 6 )alkylene-R′.

25. The compound according to claim 1 , wherein R 4 is H, halogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylene-R′.

26. The compound according to claim 1 , wherein R 4 is H, halogen, (C 1 -C 6 )alkyl, NH—(C 6 -C 10 )aryl, or (C 1 -C 2 )alkylene-(C 6 -C 10 )aryl.

27. The compound according to claim 1 , wherein R 4 is H, halogen, (C 1 -C 6 )alkyl, or (C 1 -C 2 )alkylene-(C 6 -C 10 )aryl.

28. The compound according to claim 1 , wherein R 4 is H, halogen, or (C 1 -C 6 )alkyl.

29. The compound according to claim 1 , wherein R 4 is H or (C 1 -C 6 )alkyl.

30. The compound according to claim 1 , wherein R 4 is H.

31. The compound according to claim 1 , wherein R 7 and R 8 are independently of each other H, halogen, CN, (C 1 -C 6 )alkyl, O—(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, R′, or (C 1 -C 6 )alkylene-(C 3 -C 8 )cycloalkyl.

32. The compound according to claim 1 , wherein R 7 and R 8 are independently of each other H, halogen, CN, (C 1 -C 4 )alkyl, O—(C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, phenyl, (C 5 -C 6 )heteroaryl, (C 3 -C 6 )cycloalkyl, or (C 1 -C 4 )alkylene-(C 3 -C 6 )cycloalkyl.

33. The compound according to claim 1 , wherein R 7 and R 8 are independently of each other H, halogen, (C 1 -C 4 )alkyl, O—(C 1 -C 4 )alkyl or (C 3 -C 6 )cycloalkyl.

34. The compound according to claim 1 , wherein R 7 is H, halogen, (C 1 -C 4 )alkyl, or (C 3 -C 6 )cycloalkyl; and R 8 is H.

35. The compound according to claim 1 , wherein R 7 and R 8 are H.

36. The compound according to claim 1 , wherein R 9 is halogen or (C 1 -C 4 )alkyl.

37. The compound according to claim 1 , wherein R 9 is Cl, F, methyl or ethyl.

38. The compound according to claim 1 , wherein n is 0, 1, 2 or 3.

39. The compound according to claim 1 , wherein n is 0 or 1.

40. The compound according to claim 1 , wherein n is 0.

41. The compound according to claim 1 , wherein R 3 is H, halogen, (C 1 -C 6 )alkyl, (C 1 -C 4 )alkylene-R′, O—R″ or NHR″.

42. The compound according to claim 1 , wherein R 3 is H, (C 1 -C 6 )alkyl or NHR″.

43. The compound according to claim 1 , wherein R 3 is H, (C 1 -C 4 )alkyl, NH—(C 5 -C 6 )heterocyclyl or NH-phenyl.

44. The compound according to claim 1 , wherein R 3 is H, (C 1 -C 4 )alkyl, NH-phenyl, or NH—(C 5 -C 6 )heteroaryl containing one or more N atoms.

45. The compound according to claim 1 , wherein R 3 is H.

46. The compound according to claim 1 , wherein L is attached as shown in the following figure to the 4-position of the cyclohexyl ring relative to the NR 6 R 6 ′ moiety substituted thereon

L is attached as shown in the following figure to the 3-position of the cyclohexyl ring relative to the NR 6 R 6 ′ moiety substituted thereon

47. The compound according to claim 1 , wherein L is attached to the 4-position of the cyclohexyl ring relative to the NR 6 R 6 ′ moiety substituted thereon.

48. The compound according to claim 1 , wherein L is O-methylene, O-ethylene or O.

49. The compound according to claim 1 , wherein L is O-methylene, O-ethylene or O attached to the 4-position of the cyclohexyl ring relative to the NR 6 R 6 ′ moiety substituted thereon.

50. The compound according to claim 1 , wherein L is O.

51. The compound according to claim 1 , wherein

R 3 is H, halogen, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylene-R′, OH, O—R″, NH 2 , or NHR″;

R 4 is H, halogen, OH, CN, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 1 -C 6 )alkylene-R′;

R 5 is H, halogen, CN, NO 2 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, R′, (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, (C 2 -C 6 )alkenylene-(C 6 -C 10 )aryl, (C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl, NH 2 , NH—R′, NH—SO 2 H, NH—SO 2 —(C 1 -C 6 )alkyl, NH—SO 2 —R′, NH—C(O)—(C 1 -C 6 )alkyl, NH—C(O)—R′, C(O)N[(C 1 -C 6 )alkyl] 2 , C(O)OH or C(O)O—(C 1 -C 6 )alkyl;

R 6 and R 6 ′ are independently of each other H, (C 3 -C 8 )cycloalkyl, (C 1 -C 8 )alkyl, (C 1 -C 6 )alkylene-R′, (C 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylene-O—R′, (C 1 -C 6 )alkylene-CH[R′] 2 , (C 1 -C 6 )alkylene-C(O)NH 2 , (C 1 -C 6 )alkylene-C(O)NH—R′, or (C 1 -C 6 )alkylene-C(O)N[R′] 2 ;

R 7 and R 8 are independently of each other H, halogen, CN, NO 2 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, R′, (C 2 -C 6 )alkenylene-(C 6 -C 10 )aryl, (C 1 -C 6 )alkylene-R′, NH 2 , NH—R′, NH—SO 2 —(C 1 -C 6 )alkyl, NH—SO 2 —R′, SO 2 —NH 2 , SO 2 —NHR′, NH—C(O)—(C 1 -C 6 )alkyl, NH—C(O)—R′, C(O)N[(C 1 -C 6 )alkyl] 2 , C(O)OH, or C(O)O—(C 1 -C 6 )alkyl;

n is 0, 1, 2; and

L is O or O—(C 1 -C 3 )alkylene;

52. The compound according to claim 1 , wherein

R 3 is H, halogen, CN, (C 1 -C 6 )alkyl, (C 1 -C 2 )alkylene-R′ or NHR″;

R 4 is H, halogen, CN, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 2 )alkylene-R′;

R 5 is H, halogen, CN, NO 2 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, R′, (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, (C 2 -C 6 )alkenylene-(C 6 -C 10 )aryl, (C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl, NH 2 , NH—R′, NH—C(O)—(C 1 -C 6 )alkyl, or C(O)N[(C 1 -C 6 )alkyl] 2 ;

R 6 and R 6 ′ are independently of each other H, (C 3 -C 8 )cycloalkyl, (C 1 -C 8 )alkyl, or (C 1 -C 3 )alkylene-R′;

R 7 and R 8 are independently of each other H, halogen, CN, NO 2 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, R′, (C 2 -C 3 )alkenylene-(C 6 -C 10 )aryl, (C 1 -C 3 )alkylene-R′, NH—R′, NH—SO 2 —(C 1 -C 6 )alkyl, or SO 2 —NH 2 ;

n is 0 or 1; and

L is O or O-methylene;

53. The compound according to claim 1 , wherein

R 3 is H, halogen, CN, (C 1 -C 6 )alkyl, (C 1 -C 2 )alkylene-R′ or NHR″;

R 4 is H, halogen, CN, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 2 )alkylene-R′;

R 5 is H, halogen, CN, NO 2 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, R′, (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, (C 2 -C 6 )alkenylene-(C 6 -C 10 )aryl, (C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl, or NH—R′;

R 6 is H, (C 3 -C 6 )cycloalkyl, or (C 1 -C 4 )alkyl;

R 6 ′ is H, (C 3 -C 8 )cycloalkyl, (C 1 -C 8 )alkyl, or (C 1 -C 3 )alkylene-R′;

R 7 and R 8 are independently of each other H, halogen, CN, NO 2 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, R′, (C 2 -C 3 )alkenylene-(C 6 -C 10 )aryl, (C 1 -C 3 )alkylene-R′, NH—SO 2 —(C 1 -C 6 )alkyl, or SO 2 —NH 2 ;

R 9 is halogen or (C 1 -C 4 )alkyl;

n is 0; and

L is O;

54. A pharmaceutical composition comprising an effective amount of at least one compound of the formula (I) and (I′), or a pharmaceutically acceptable salt thereof, or stereoisomeric form thereof, or pharmaceutically acceptable salt of a stereoisomeric form according to claim 1 , and a physiologically tolerated excipient or carrier, or excipient and carrier and, where appropriate, a further additive or other active ingredient, or and additive and other active ingredient.

Assignments (1)

CHANGE OF NAME Recorded Jun 20, 2012

From: SANOFI-AVENTIS

To: SANOFI

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