IP Library › Granted Patent US 8,188,117
Granted Patent B2
US 8,188,117 · App. 12/019,866 · Granted May 29, 2012

Piperidinyl-substituted isoquinolone derivatives

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Quick Facts
Patent No.
US 8,188,117
App. No.
12/019,866
Granted
May 29, 2012
Kind
B2
Abstract

The invention relates to 6-piperidinyl-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 (232)

1. A compound of the formula (I)

or of the formula (I′)

wherein

R1 is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, [(C1-C6)alkylene]0-1-(C3-C8)cycloalkyl, [(C1-C6)alkylene]0-1-(C5-C10)heterocyclyl, [(C1-C6)alkylene]0-1-(C6-C10)aryl, C(O)—(C1-C6)alkyl, C(O)(C2-C6)alkenyl, C(O)—(C2-C6)alkynyl, C(O)—[(C1-C6)alkylene]0-1-(C3-C8)cycloalkyl, C(O)—[(C1-C6)alkylene]0-1-(C5-C10)heterocyclyl, or C(O)—[(C1-C6)alkylene]0-1-(C6-C10)aryl;

R2 is H, (C1-C6)alkyl, [(C1-C6)alkylene]0-1-R′, [(1-C6)alkylene]0-1-O—(C1-C6)alkyl, [(C1-C6)alkylene]0-1-O—R′, [(C1-C6)alkylene]0-1-NH2, [(C1-C6)alkylene]0-1-NH(C1-C6)alkyl, [(C1-C6)alkylene]0-1-N[(C1-C6)alkyl] 2, [(C 1-C6)alkylene]0-1-CH[R′] 2, [(C 1-C6)alkylene]0-1-C(O)—R′, [(C1-C6)alkylene]0-1-C(O)NH 2, [(C 1-C6)alkylene]0-1-C(O)NH—R′, or [(C1-C6)alkylene]0-1-C(O)N[R′]2 ;

R3 is H, halogen, CN, (C1-C6)alkyl, (C1-C6)alkylene-R′, OH, O—R″, NH2, NHR″, NR″R″ or NH—C(O)—R″;

R4 is H, halogen, OH, CN, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkylene-R′ or NH—(C6-C10)aryl;

R5 is H, halogen, CN, NO2, (C1-C6)alkyl, (C2-C6)alkenyl, R′, (C1-C6)alkylene-R′, (C1-C6)alkylene-(C6-C10)aryl, (C2-C6)alkenylene-(C6-C10)aryl, (C1-C6)alkylene-(C5-C10)heterocyclyl, NH2, NH—R′, NH—SO2H, NH—SO2-(C1-C6)alkyl, NH—SO2-R′, NH—C(O)—(C1-C6)alkyl, NH—C(O)—R′, C(O)N[(C1-C6)alkyl]2, C(O)OH or C(O)O—(C1-C6)alkyl;

R6 is H, R′, (C1-C8)alkyl, (C1-C6)alkylene-R′, (C1-C6)alkylene-O—(C1-C6)alkyl, (C1-C6)alkylene-O—R′, (C1-C6)alkylene-CH[R′]2, (C1-C6)alkylene-C(O)—R′, (C1-C6)alkylene-C(O)NH2, (C1-C6)alkylene-C(O)NH—R′, or (C1-C6)alkylene-C(O)N[R′]2;

R7 and R8 are independently of each other H, halogen, CN, NO2, (C1-C6)alkyl, O—(C1-C6)alkyl, O—[(C1-C6)alkylene]0-1-R′, (C2-C6)alkenyl, R′, (C2-C6)alkenylene-(C6-C10)aryl, (C1-C6)alkylene-R′, NH2, NH—R′, NH—SO2H, NH—SO2-(C1-C6)alkyl, NH—SO2-R′, SO2-NH2, SO2-NHR′, NH—C(O)—(C1-C6)alkyl, NH—C(O)—R′, C(O)N[(C1-C6)alkyl]2, C(O)OH or C(O)O—(C1-C6)alkyl;

R9 is halogen or (C1-C6)alkyl;

R′ is (C3-C8)cycloalkyl, (C5-C10)heterocyclyl or (C6-C10)aryl;

R″ is (C3-C8)cycloalkyl, (C5-C10)heterocyclyl, (C6-C10)aryl, (C1-C6)alkyl, (C1-C6)alkylene-R′, (C1-C6)alkylene-O—(C1-C6)alkyl, (C1-C6)alkylene-O—R′, or (C1-C6)alkylene-NRxRy;

Rx and Ry are independently of each other (C1-C6)alkyl, (C5-C10)heterocyclyl, (C6-C10)aryl, (C1-C4)alkylene-(C5-C10)heterocyclyl, (C1-C4)alkylene-(C6-C10)aryl, (C1-C4)alkylene-NH(C1-C6)alkyl, (C1-C4)alkylene-N[(C1-C6)alkyl]2, (C1-C4)alkylene-N [(C6-C10)aryl]2, or (C1-C4)alkylene-N[(C5-C10)heterocyclyl]2;

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

L is O or O—(C1-C6)alkylene;

wherein in

residues R4, R5, R7 and R8 one alkyl or alkylene hydrogen atom can optionally be substituted by OH, OCH3, COOH, COOCH3, NH2, NHCH3, N(CH3)2, CONH2, CONHCH3 or CON(CH3)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

R4 is H, halogen, OH, CN, (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C1-C6)alkylene-R′;

R5 is H, halogen, CN, NO2, (C1-C6)alkyl, (C2-C6)alkenyl, R′,

(C1-C6)alkylene-(C6-C10)aryl, (C2-C6)alkenylene-(C6-C10)aryl,

(C1-C6)alkylene-(C5-C10)heterocyclyl, NH2, NH—R′, NH—SO2H, NH—SO2-(C1-C6)alkyl,

NH—SO2-R′, NH—C(O)—(C1-C6)alkyl, NH—C(O)—R′, C(O)N[(C1-C6)alkyl]2, C(O)OH or

C(O)O—(C1-C6)alkyl;

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.

3. The compound according to claim 1

wherein

R4 is H, halogen, OH, CN, (C1-C6)alkyl, (C3-C8)cycloalkyl, or (Cl-C6)alkylene-R′;

R5 is H, halogen, CN, NO2, (C1-C6)alkyl, (C2-C6)alkenyl, R′,

(C1-C6)alkylene-(C6-C10)aryl, (C2-C6)alkenylene-(C6-C10)aryl,

(C1-C6)alkylene-(C5-C10)heterocyclyl, NH2, NH—R′, NH—SO2H, NH—SO2-(C1-C6)alkyl,

NH—SO2-R′, NH—C(O)—(C1-C6)alkyl, NH—C(O)—R′, C(O)N[(C1-C6)alkyl]2, C(O)OH or

C(O)O—(C1-C6)alkyl;

wherein in

residues R4, R5, R7 and R8 one alkyl or alkylene hydrogen atom can optionally be substituted by OH, F, OCH3, COOH, COOCH3, NH2, NHCH3, N(CH3)2, CONH2, CONHCH3 or CON(CH3)2,

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.

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

5. The compound according to claim 1 of the formula (I′) wherein R1 is hydrogen.

6. The compound according to claim 1 , wherein R6 is H, (C1-C6)alkyl, R′,

(C1-C4)alkylene-(C3 -C8)cycloalkyl, (C1-C4)alkylene-(C5-C10)heterocyclyl,

(C1-C4)alkylene-C(O)—(C5-C10)heterocyclyl, (C1-C4)alkylene-C(O)—(C6-C10)aryl or

(C1-C6)alkylene-(C6-C10)aryl.

7. The compound according to claim 1 , wherein R6 is H, (C1-C6)alkyl, (C5-C10)heterocyclyl, (C3-C8)cycloalkyl, (C1-C4)alkylene-(C3-C8)cycloalkyl,

(C1-C4)alkylene-(C5-C10)heterocyclyl or (C1-C6)alkylene-(C6-C10)aryl.

8. The compound according to claim 1 , wherein R6 is H,

(C1-C6)alkyl,

(C3-C8)cycloalkyl,

(C1-C4)alkylene-(C3-C8)cycloalkyl,

(C1-C4)alkylene-(C5-C10)heterocyclyl in which heterocyclyl is unsubstituted or substituted by (C1-C4)alkyl, or

(C1-C4)alkylene-(C6-C10)aryl in which aryl is unsubstituted or substituted by halogen, (C1-C4)alkyl, O—(C1-C4)alkyl, SO2-(C1-C4)alkyl, or N[(C1-C4)alkyl]2.

9. The compound according to claim 1 , wherein R6 is H, (C1-C6)alkyl, (C3-C6)cycloalkyl or (C1-C4)alkylene-(C3-C6)cycloalkyl.

10. The compound according to claim 1 , wherein R6 is H or (C1-C6)alkyl.

11. The compound according to claim 1 , wherein R6 is H.

12. The compound according to claim 1 , wherein R5 is H, halogen, CN, (C1-C6)alkyl, R′, NH—(C6-C10)aryl, (C1-C6)alkylene-(C6-C10)aryl, or (C1-C6)alkylene-(C5-C10)heterocyclyl.

13. The compound according to claim 1 , wherein R5 is H, halogen, (C1-C6)alkyl, R′, NH—(C6-C10)aryl or (C1-C6)alkylene-(C6-C10)aryl, or (C1-C6)alkylene-(C5-C10)heterocyclyl.

14. The compound according to claim 1 , wherein R5 is H, halogen, (C1-C6)alkyl, (C6-C10)aryl, (C5-C10)heteroaryl, NH—(C6-C10)aryl or (C1-C2)alkylene-(C6-C10)aryl.

15. The compound according to claim 1 , wherein R5 is H, halogen, (C1-C6)alkyl, phenyl or (C5-C6)heteroaryl.

16. The compound according to claim 1 , wherein R5 is H, halogen or (C1-C6)alkyl.

17. The compound according to claim 1 , wherein R5 is H or halogen.

18. The compound according to claim 1 , wherein R5 is H.

19. The compound according to claim 1 , wherein R4 is H, halogen, CN, (C1-C6)alkyl, or (C1-C6)alkylene-R′.

20. The compound according to claim 1 , wherein R4 is H, halogen, (C1-C6)alkyl, or (C1-C6)alkylene-R′.

21. The compound according to claim 1 , wherein R4 is H, halogen, (C1-C6)alkyl, or (C1-C2)alkylene-(C6-C10)aryl.

22. The compound according to claim 1 , wherein R4 is H, halogen, or (C1-C6)alkyl.

23. The compound according to claim 1 , wherein R4 is H.

24. The compound according to claim 1 , wherein R7 and R8 are independently of each other H, halogen, CN, (C1-C6)alkyl, O—(C1-C6)alkyl, (C2-C6)alkenyl, R′ or (C1-C6)alkylene-(C3-C8)cycloalkyl.

25. The compound according to claim 1 , wherein R7 and R8 are independently of each other H, halogen, CN, (C1-C4)alkyl, O—(C1-C4)alkyl, (C2-C4)alkenyl, phenyl, (C5-C6)heteroaryl, (C3-C6)cycloalkyl or (C1-C4)alkylene-(C3-C6)cycloalkyl.

26. The compound according to claim 1 , wherein R7 and R8 are independently of each other H, halogen, (C1-C4)alkyl, O—(C1-C4)alkyl or phenyl.

27. The compound according to claim 1 , wherein R7 and R8 are H.

28. The compound according to claim 1 , wherein R9 is halogen or (C1-C4)alkyl.

29. The compound according to claim 1 , wherein R9 is Cl, F, methyl or ethyl.

30. The compound according to claim 1 , wherein R9 is methyl.

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

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

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

34. The compound according to claim 1 , wherein R3 is H, halogen, (C1-C6)alkyl, (C1-C4)alkylene-R′, O—R″ or NHR″.

35. The compound according to claim 1 , wherein R3 is H, (C1-C6)alkyl or NHR″.

36. The compound according to claim 1 , wherein R3 is H, (C1-C4)alkyl, NH—(C5-C6)heterocyclyl or NH-phenyl.

37. The compound according to claim 1 , wherein R3 is H, (C1-C4)alkyl, NH—(C5-C6)heteroaryl containing one or more N atoms or NH-phenyl.

38. The compound according to claim 1 , wherein R3 is H.

39. The compound according to claim 1 , wherein L is attached to the 4-position of the piperdinyl ring as follows

L is attached to the 3-position of the piperdinyl ring as follows

40. The compound according to claim 1 , wherein L is attached to the 4-position of the piperdinyl ring.

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

42. The compound according to claim 1 , wherein L is O-methylene, O-ethylene or O attached to the 4-position of the piperdinyl ring.

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

44. The compound according to claim 1 , wherein

R3 is H, halogen, CN, (C1-C6)alkyl, (C1-C6)alkylene-R′, OH, O—R″, NH2, or NHR″;

R6 is H, (C3-C8)cycloalkyl, (C1-C8)alkyl, (C1-C6)alkylene-R′, (C1-C6)alkylene-O—(C1-C6)alkyl, (C1-C6)alkylene-O—R′, (C1-C6)alkylene-CH[R′]2, (C1-C6)alkylene-C(O)NH2, (C1-C6)alkylene-C(O)NH—R′, or (C1-C6)alkylene-C(O)N[R′]2;

R7 and R8 are independently of each other H, halogen, CN, NO2, (C1-C6)alkyl, (C2-C6)alkenyl, R′, (C2-C6)alkenylene-(C6-C10)aryl, (C1-C6)alkylene-R′, NH2, NH—R′, NH—SO2-(C1-C6)alkyl, NH—SO2-R′, SO2-NH2, SO2-NHR′, NH—C(O)—(C1-C6)alkyl, NH—C(O)—R′, C(O)N[(C1-C6)alkyl]2, C(O)OH or C(O)O—(C1-C6)alkyl;

n is 0, 1, 2; and

L is O or O—(C1-C3)alkylene; or

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.

45. The compound according to claim 1 , wherein

R3 is H, halogen, CN, (C1-C6)alkyl, (C1-C2)alkylene-R′ or NHR″;

R4 is H, halogen, CN, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C2)alkylene-R′;

R5 is H, halogen, CN, NO2, (C1-C6)alkyl, (C2-C6)alkenyl, R′,

(C1-C6)alkylene-(C6-C10)aryl, (C2-C6)alkenylene-(C6-C10)aryl,

(C1-C6)alkylene-(C5-C10)heterocyclyl, NH2, NH—R′, NH—C(O)—(C1-C6)alkyl, or

C(O)N[(C1-C6)alkyl]2;

R6 is H, (C3-C8)cycloalkyl, (C1-C8)alkyl, or (C1-C3)alkylene-R′;

R7 and R8 are independently of each other H, halogen, CN, NO2, (C1-C6)alkyl, (C2-C6)alkenyl, R′, (C2-C3)alkenylene-(C6-C10)aryl, (C1-C3)alkylene-R′, NH—R′, NH—SO2-(C1-C6)alkyl, or SO2-NH2;

n is 0 or 1; and

L is O or O-methylene;

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.

46. The compound according to claim 1 , wherein

R3 is H, halogen, CN, (C1-C6)alkyl, (C1-C2)alkylene-R′ or NHR″;

R4 is H, halogen, CN, (C1-C4)alkyl, (C3-C6)cycloalkyl, or (C1-C2)alkylene-R′;

R5 is H, halogen, CN, NO2, (C1-C6)alkyl, (C2-C6)alkenyl, R′,

(C1-C6)alkylene-(C6-C10)aryl, (C2-C6)alkenylene-(C6-C10)aryl,

(C1-C6)alkylene-(C5 -C1 0)heterocyclyl, or NH—R′;

R6 is H, (C3-C6)cycloalkyl or (C1-C4)alkyl;

R7 and R8 are independently of each other H, halogen, CN, NO2, (C1-C6)alkyl,

(C2-C6)alkenyl, R′, (C2-C3)alkenylene-(C6-C10)aryl, (C1-C3)alkylene-R′, NH—SO2-(C1-C6)alkyl, or SO2-NH2;

R9 is halogen or (C1-C4)alkyl;

n is 0 or 1; and

L is O;

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.

47. The compound of claim 1 wherein R1, R3, R4, R5, and R9 are H; R7 is H, methyl or halogen; R6 is H, (C1-C4)alkyl, phenyl or (C5-C10)heteroaryl, which phenyl or (C5-C10)heteroaryl are unsubstituted or substituted by one or more (C1-C4)alkyl, O—(C1-C6)alkyl, and halogen.

48. The compound according to claim 1 selected from the group consisting of

or tautomeric form thereof,

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.

49. A compound of one of the following formula A1 or A2 or A3 or A4:

wherein

R 4 is H, (C 1 -C 4 )alkyl, or halogen

R 5 is H or halogen;

R 7 is H, (C 1 -C 4 )alkyl, or halogen;

R 6 is H,

(C 1 -C 8 )alkyl,

(C 1 -C 6 )alkylene-O—(C 1 -C 4 )alkyl,

(C 1 -C 6 )alkylene-O—R′ wherein R′ is (C 6 -C 10 )aryl, or

(C 1 -C 6 )alkylene-R′ wherein R′ is (C 3 -C 8 )cycloalkyl, (C 5 -C 10 )heterocyclyl,

or (C 6 -C 10 )aryl,

wherein each (C 6 -C 10 )aryl or (C 5 -C 10 )heterocyclyl is optionally substituted with 1-3 substituents selected from ( C 1 -C 4 )alkyl, O—(C 1 -C 4 )alkyl, SO 2 —(C 1 -C 4 )alkyl, and halogen;

or a pharmaceutically acceptable salt thereof.

50. The compound according to claim 49 wherein

R 6 is H, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylene-R′ wherein R′ is (C 3 -C 8 )cycloalkyl, (C 5 -C 10 )heterocyclyl, or (C 6 -C 10 )aryl,

wherein each (C 6 -C 10 )aryl or (C 5 -C 10 )heterocyclyl is optionally substituted with 1-3 substituents selected from (C 1 -C 4 )alkyl, SO 2 —(C 1 -C 4 )alkyl, and halogen;

or a pharmaceutically acceptable salt thereof.

51. A compound of one of the following formula A5 or A6 or A7 or A8:

wherein

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

R 5 is H or halogen;

R 7 is H, (C 1 -C 4 )alkyl, or halogen;

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

R′ is (C 3 -C 8 )cycloalkyl;

(C 5 -C 10 )heterocyclyl wherein the (C 5 -C 10 )heterocyclyl is furanyl, piperidinyl, pyrrolidinyl, pyrazolyl, pyridinyl, pyrrolyl, tetrahydrofuranyl, or thienyl wherein pyrazolyl or pyrrolyl is optionally substituted by (C 1 -C 4 )alkyl; or

(C 6 -C 10 )aryl wherein the (C 6 -C 10 )aryl is naphthyl or phenyl wherein the phenyl is optionally substituted with 1 or 2 substituents independently selected from halogen, (C 1 -C 4 )alkyl, O—(C 1 -C 4 )alkyl, and SO 2 —(C 1 -C 4 )alkyl;

or a pharmaceutically acceptable salt thereof.

52. The compound according to claim 51 wherein

R 4 is H, methyl, ethyl, or Br;

R 5 is H or F; and

R 7 is H, methyl, Br, Cl, or F;

or a pharmaceutically acceptable salt thereof.

53. The compound according to claim 51 wherein

R 6 is H methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 3-methylbutyl, cyclopropylmethyl, cyclohexylmethyl, benzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2,4-dichlorobenzyl, 3,5-dichlorobenzyl, 4-methylbenzyl, 4-methylsulfonylbenzyl, 5-fluoro-2-methylsulfonylbenzyl, 5-fluoro-3-methylsulfonylbenzyl, naphth-l-ylmethyl, naphth-2-ylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, thien-3-ylmethyl, piperidin-4-ylmethyl, 2-(piperidin-4-yl)ethyl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, furan-3-ylmethyl, 1-methylpyrrol-3-ylmethyl, 1-methylpyrazol-3-ylmethyl, 1-methylpyrazol-4-ylmethyl, or tetrahydrofuran-3-ylmethyl;

or a pharmaceutically acceptable salt thereof.

54. A compound of the following formula B1 or B2

wherein

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

R 7 is H or halogen,

or a pharmaceutically acceptable salt thereof.

55. The compound according to claim 54 wherein

R 6 is H or isopropyl; and

R 7 is H or Cl

or a pharmaceutically acceptable salt thereof.

56. A compound of formula

or a pharmaceutically acceptable salt thereof.

57. A compound of formula

or a pharmaceutically acceptable salt thereof.

58. A compound of formula

or a pharmaceutically acceptable salt thereof.

59. A compound of formula (I)

or a pharmaceutically acceptable salt thereof.

60. A compound of formula

or a pharmaceutically acceptable salt thereof.

61. A compound of formula (I)

or a pharmaceutically acceptable salt thereof.

62. A compound of formula

or a pharmaceutically acceptable salt thereof.

63. A compound of formula

or a pharmaceutically acceptable salt thereof.

64. A compound of formula

or a pharmaceutically acceptable salt thereof.

65. A compound of formula

or a pharmaceutically acceptable salt thereof.

66. A pharmaceutical composition comprising an effective amount of at least one compound of the formulae (I) and (I′), or a pharmaceutically acceptable salt thereof, or stereoisomeric form thereof, or pharmaceutically acceptable salt of a stereoisomeric form as claimed in 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.

67. A method of treating or preventing in a patient a disease associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase comprising administering an effective amount of at least one compound of the formulae (I) and (I′),

wherein

R1 is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,

[(C1-C6)alkylene]0-1-(C3-C8)cycloalkyl, [(C1-C6)alkylene]0-1-(C5-C10)heterocyclyl,

[(C1-C6)alkylene]0-1-(C6-C10)aryl,

C(O)—(C1-C6)alkyl, C(O)(C2-C6)alkenyl, C(O)—(C2-C6)alkynyl,

C(O)-[(C1-C6)alkylene]0-1-(C3-C8)cycloalkyl,

C(O)-[(C1-C6)alkylene]0-1-(C5-C10)heterocyclyl, or

C(O)-[(C1-C6)alkylene]0-1-(C6-C10)aryl;

R2 is H, (C1-C6)alkyl, [(C1-C6)alkylene]0-1-R′,

[(C1-C6)alkylene]0-1-O—(C1-C6)alkyl, [(C1-C6)alkylene]0-1-O—R′, [(C1-C6)alkylene]0-1-NH2, [(C1-C6)alkylene]0-1-NH(C1-C6)alkyl, [(C1-C6)alkylene]0-1-N[(C1-C6)alkyl]2,

[(C1-C6)alkylene]0-1-CH[R′]2,

[(C1-C6)alkylene]0-1-C(O)—R′, [(C1-C6)alkylene]0-1-C(O)NH2,

[(C1-C6)alkylene]0-1-C(O)NH—R′, or [(C1-C6)alkylene]0-1-C(O)N[R′]2 ;

R3 is H, halogen, CN, (C1-C6)alkyl, (C1-C6)alkylene-R′, OH, O—R″, NH2, NHR″, NR″R″ or NH—C(O)—R″;

R4 is H, halogen, OH, CN, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkylene-R′ or NH—(C6-C10)aryl;

R5 is H, halogen, CN, NO2, (C1-C6)alkyl, (C2-C6)alkenyl, R′, (C1-C6)alkylene-R′,

(C1-C6)alkylene-(C6-C10)aryl, (C2-C6)alkenylene-(C6-C10)aryl,

(C1-C6)alkylene-(C5-C10)heterocyclyl, NH2, NH—R′, NH—SO2H, NH—SO2-(C1-C6)alkyl,

NH—SO2-R′, NH—C(O)—(C1-C6)alkyl, NH—C(O)—R′, C(O)N[(C1-C6)alkyl]2, C(O)OH or

C(O)O—(C1-C6)alkyl;

R6 is H, R′, (C1-C8)alkyl, (C1-C6)alkylene-R′, (C1-C6)alkylene-O—(C1-C6)alkyl, (C1-C6)alkylene-O—R′, (C1-C6)alkylene-CH[R′]2, (C1-C6)alkylene-C(O)—R′,

(C1-C6)alkylene-C(O)NH2, (C1-C6)alkylene-C(O)NH—R′, or (C1-C6)alkylene-C(O)N[R′]2;

R7 and R8 are independently of each other H, halogen, CN, NO2, (C1-C6)alkyl, O—(C1C6)alkyl, O—[(C1-C6)alkylene]0-1-R′, (C2-C6)alkenyl, R′, (C2-C6)alkenylene-(C6-C10)aryl, (C1-C6)alkylene-R′, NH2, NH—R′, NH—SO2H, NH—SO2-(C1-C6)alkyl, NH—SO2-R′, SO2-NH2, SO2-NHR′, NH—C(O)—(C1-C6)alkyl, NH—C(O)—R′, C(O)N[(C1-C6)alkyl]2, C(O)OH or C(O)O—(C1-C6)alkyl;

R9 is halogen or (C1-C6)alkyl;

R′ is (C3-C8)cycloalkyl, (C5-C10)heterocyclyl or (C6-C10)aryl;

R″ is (C3-C8)cycloalkyl, (C5-C10)heterocyclyl, (C6-C10)aryl, (C1-C6)alkyl,

(C1-C6)alkylene-R′, (C1-C6)alkylene-O—(C1-C6)alkyl, (C1-C6)alkylene-O—R′ , or (C1-C6)alkylene-NRxRy;

Rx and Ry are independently of each other (C1-C6)alkyl, (C5-C10)heterocyclyl, (C6-C10)aryl, (C1-C4)alkylene-(C5-C10)heterocyclyl,

(C1-C4)alkylene-(C6-C10)aryl, (C1-C4)alkylene-NH(C1-C6)alkyl,

(C1-C4)alkylene-N[(C1-C6)alkyl]2, (C1-C4)alkylene-N[(C6-C10)aryl]2, or

(C1-C4)alkylene-N[(C5-C10)heterocyclyl]2;

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

L is O or O—(C1-C6)alkylene;

wherein in

residues R4, R5, R7 and R8 one alkyl or alkylene hydrogen atom can optionally be substituted by OH, OCH3, COOH, COOCH3, NH2, NHCH3, N(CH3)2, CONH2, CONHCH3 or

CON(CH3)2, or

an alkyl or alkylene may be halogenated once or more;

or its physiologically 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 wherein the disease is hypertension, glaucoma, nephropathy, renal failure, and atherosclerosis.

68. A method of treating Rho-kinase associated disorders consisting of hypertension, atherosclerosis and glaucoma comprising administering an effective amount of a compound of claim 49 , 51 , or 54 to a patient in need thereof.

69. A method of treating Rho-kinase associated disorders consisting of hypertension, atherosclerosis and glaucoma comprising administering an effective amount of a compound as in any one of claims 56 - 65 to a patient in need thereof.

Assignments (2)
CHANGE OF NAME Recorded Jun 20, 2012
From: SANOFI-AVENTIS
To: SANOFI
Reel/Frame 028413/0927 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 5, 2008
From: PLETTENBURG, OLIVER; HOFMEISTER, ARMIN; KADEREIT, DIETER; BRENDEL, JOACHIM; LOEHN, MATTHIAS
To: SANOFI-AVENTIS
Reel/Frame 021337/0948 →