IP Library › Granted Patent US 8,796,458
Granted Patent B2
US 8,796,458 · App. 13/161,003 · Granted Aug 5, 2014

Cyclohexylamine isoquinolone derivatives

View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 8,796,458
App. No.
13/161,003
Granted
Aug 5, 2014
Kind
B2
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 (84)

1. A method of treating pulmonary hypertension, glaucoma, neuronal degeneration or Alzheimer's disease in a patient comprising administering to said patient an effective amount of at least one compound of the formulae (I) or (I′):

wherein

R 1 is H;

R 2 is H;

R 3 is H;

R 4 is H, halogen, OH, CN, (C 1 -C 6 )alkyl;

R 5 is H, halogen, CN, NO 2 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, —NH 2 , NH—SO 2 H, NH—SO 2 —(C 1 -C 6 )alkyl, NH—C(O)—(C 1 -C 6 )alkyl, 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, (C 2 -C 6 )alkenyl, NH 2 , NH—SO 2 H, NH—SO 2 —(C 1 -C 6 )alkyl, SO 2 —NH 2 , NH—C(O)—(C 1 -C 6 )alkyl, 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;

n is 0; 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 a pharmaceutically acceptable salt thereof, or a stereoisomeric form thereof, or a pharmaceutically acceptable salt of a stereoisomeric form thereof.

2. The method according to claim 1 wherein in formulae (I) and (I′),

R 4 is H, halogen, OH, CN, (C 1 -C 6 )alkyl;

or a pharmaceutically acceptable salt thereof, or a stereoisomeric form thereof, or a pharmaceutically acceptable salt of a stereoisomeric form thereof.

3. The method according to claim 1 wherein the formula (I) is:

4. The method according to claim 1 , wherein in the formula (I′) R 1 is H:

5. The method according to claim 1 , wherein in formulae (I) and (I′), 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 method according to claim 1 , wherein in formulae (I) and (I′), R 6 and R 6 ′ are independently of each other H, (C 1 -C 6 )alkyl, (C 5 -C 10 )heterocyclyl, (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 or (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl.

7. The method according to claim 1 , wherein in formulae (I) and (I′), 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 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.

8. The method according to claim 1 , wherein in formulae (I) and (I′), 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 method according to claim 1 , wherein in formulae (I) and (I′),

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 method according to claim 1 , wherein in formulae (I) and (I′), 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 method according to claim 1 , wherein in formulae (I) and (I′), R 6 is H; and R 6 ′ is H, (C 1 -C 6 )alkyl, or (C 3 -C 8 )cycloalkyl.

12. The method according to claim 1 , wherein in formulae (I) and (I′), R 6 and R 6 ′ are H.

13. The method according to claim 1 , wherein in formulae (I) and (I′), R 5 is H, halogen, CN, (C 1 -C 6 )alkyl.

14. The method according to claim 1 , wherein in formulae (I) and (I′), R 5 is H, halogen, (C 1 -C 6 )alkyl.

15. The method according to claim 1 , wherein in formulae (I) and (I′), R 5 is H or halogen.

16. The method according to claim 1 , wherein in formulae (I) and (I′), R 5 is H.

17. The method according to claim 1 , wherein in formulae (I) and (I′), R 4 is H, halogen, CN, (C 1 -C 6 )alkyl, NH—(C 6 -C 10 )aryl, or (C 1 -C 6 )alkylene-R′.

18. The method according to claim 1 , wherein in formulae (I) and (I′), R 4 is H, halogen, or (C 1 -C 6 )alkyl.

19. The method according to claim 1 , wherein in formulae (I) and (I′), R 4 is H or (C 1 -C 6 )alkyl.

20. The method according to claim 1 , wherein in formulae (I) and (I′), R 4 is H.

21. The method according to claim 1 , wherein in formulae (I) and (I′), R 7 and R 8 are independently of each other H, halogen, CN, (C 1 -C 6 )alkyl, O—(C 1 -C 6 )alkyl, or (C 2 -C 6 )alkenyl.

22. The method according to claim 1 , wherein in formulae (I) and (I′), 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, or (C 3 -C 6 )cycloalkyl.

23. The method according to claim 1 , wherein in formulae (I) and (I′), R 7 and R 8 are independently of each other H, halogen, (C 1 -C 4 )alkyl, or O—(C 1 -C 4 )alkyl.

24. The method according to claim 1 , wherein in formulae (I) and (I′), R 7 is H, halogen, or (C 1 -C 4 )alkyl, and R 8 is H.

25. The method according to claim 1 , wherein in formulae (I) and (I′), R 7 and R 8 are H.

26. The method according to claim 1 , wherein in formulae (I) and (I′), R 9 is halogen or (C 1 -C 4 )alkyl.

27. The method according to claim 1 , wherein in formulae (I) and (I′), R 9 is Cl, F, methyl or ethyl.

28. The method according to claim 1 , wherein in formulae (I) and (I′), 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

29. The method according to claim 1 , wherein in formulae (I) and (I′), L is attached to the 4-position of the cyclohexyl ring relative to the NR 6 R 6′ moiety substituted thereon.

30. The method according to claim 1 , wherein in formulae (I) and (I′), L is O-methylene, O-ethylene or O.

31. The method according to claim 1 , wherein in formulae (I) and (I′), 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.

32. The method according to claim 1 , wherein in formulae (I) and (I′), L is O.

33. The method according to claim 1 , wherein in formulae (I) and (I′),

R 3 is H;

R 4 is H, halogen, OH, CN, (C 1 -C 6 )alkyl;

R 5 is H, halogen, CN, NO 2 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, NH—SO 2 H, NH—SO 2 —(C 1 -C 6 )alkyl, NH—C(O)—(C 1 -C 6 )alkyl, 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, NO2, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, NH—SO 2 —(C 1 -C 6 )alkyl, or SO 2 —NH 2 ;

n is 0; and

L is O or O—(C 1 -C 3 )alkylene.

34. The method according to claim 1 , wherein in formulae (I) and (I′),

R 3 is H;

R 4 is H, halogen, CN, (C 1 -C 6 )alkyl;

R 5 is H, halogen, CN, NO 2 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, NH 2 , 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, NO2, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, NH—SO 2 —(C 1 -C 6 )alkyl, or SO 2 —NH 2 ;

n is 0; and

L is O or O-methylene.

35. The method according to claim 1 , wherein in formulae (I) and (I′),

R 3 is H;

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

R 5 is H, halogen, CN, NO 2 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl;

R 6 is H, (C 2 -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, NO2, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, 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.

Assignments (1)
CHANGE OF NAME Recorded Jun 20, 2012
From: SANOFI-AVENTIS
To: SANOFI
Reel/Frame 028413/0927 →