IP Library › Granted Patent US 8,501,736

Granted Patent B2

US 8,501,736 · App. 11/961,193 · Granted Aug 6, 2013

Isoquinoline derivatives

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Patent No.: US 8,501,736
App. No.: 11/961,193
Granted: Aug 6, 2013
Kind: B2

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Abstract

The invention relates to 6-piperidinyl-substituted 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 (194)

1. A compound of the formula (I)

wherein

R 1 is

(C 1 -C 6 )alkyl,

R′,

NH—(C 1 -C 6 )alkyl,

NHR′, or

N[(C 1 -C 6 )alkyl] 2 ;

R 2 is

halogen,

or (C 1 -C 6 )alkyl;

R 3 is

halogen,

(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

halogen,

hydroxy,

CN,

(C 1 -C 6 )alkyl,

R′,

(C 1 -C 6 )alkylene-R′;

R 5 is

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,

CH(OH)—(C 1 -C 6 )alkyl,

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 is

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 is

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′,

CH(OH)—(C 1 -C 6 )alkyl,

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 8 is

halogen,

or (C 1 -C 6 )alkyl;

n is 1, 2, 3 or 4; and

L is

O or

O—(C 1 -C 6 )alkylene;

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 ; and

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

wherein in residues R 4 , R 5 , R 7 and R 8 one alkyl or alkylene hydrogen atom can be optionally 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 , and in any residue one or more alkyl or alkylene hydrogen atoms can optionally be substituted by F;

or a pharmaceutically acceptable salt thereof, a physiologically functional derivative thereof, or a pharmaceutically acceptable salt and physiologically functional derivative thereof.

2. A compound according to claim 1 , wherein R 1 is H, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, NH—(C 1 -C 6 )alkyl, NH—(C 6 -C 10 )aryl N[(C 1 -C 6 )alkyl] 2 .

3. A compound according to claim 2 , wherein R 1 is H, (C 1 -C 4 )alkyl, NH—(C 1 -C 4 )alkyl, N[(C 1 -C 4 )alkyl] 2 or NH-phenyl.

4. A compound according to claim 3 , wherein R 1 is H, (C 1 -C 2 )alkyl or NH—(C 1 -C 2 )alkyl.

5. A compound according to claim 4 , wherein R 1 is H.

6. A compound according to claim 1 , wherein R 3 is H, halogen, (C 1 -C 4 )alkylene-R′, O—R″ or NHR″, and wherein R′ and R″ are defined as in claim 1 .

7. A compound according to claim 6 , wherein R 3 is H or NHR″.

8. A compound according to claim 7 , wherein R 3 is H or NH—(C 5 -C 6 )heterocyclyl, or NH-phenyl.

9. A compound according to claim 8 , wherein R 3 is NH—(C 5 -C 6 )heteroaryl containing one or more N atoms.

10. A compound according to claim 1 , wherein R 8 is H, halogen or (C 1 -C 4 )alkyl.

11. A compound according to claim 10 , wherein R 8 is H, Cl, F, methyl or ethyl.

12. A compound according to claim 1 , wherein R 4 is H, halogen or (C 1 -C 4 )alkyl.

13. A compound according to claim 12 , wherein R 4 is H.

14. A compound according to claim 13 , wherein R 4 is H.

15. A 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.

16. A compound according to claim 15 , wherein R 5 is H, halogen, (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.

17. A compound according to claim 16 , wherein R 5 is H, halogen, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, NH—(C 6 -C 10 )aryl, (C 1 -C 2 )alkyl-(C 6 -C 10 )aryl or (C 5 -C 10 )heteroaryl.

18. A compound according to claim 1 , wherein R 7 is H, halogen, CN, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, R′ or (C 1 -C 6 )alkylene-(C 3 -C 8 )cycloalkyl.

19. A compound according to claim 1 , wherein R 7 is H, halogen, CN, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkenyl, phenyl, cyclopropyl or (C 5 -C 6 )heteroaryl.

20. A compound according to claim 1 , wherein R 7 is H, fluoro, chloro, bromo, methyl, ethyl, phenyl, nitrile, cyclopropyl, thienyl or vinyl.

21. A compound according to claim 1 , wherein n is 1, 2 or 3.

22. A compound according to claim 21 , wherein n is 1.

23. A compound according to claim 1 , wherein R 2 is H, halogen or (C 1 -C 4 )alkyl.

24. A compound according to claim 23 , wherein R 2 is H, (C 1 -C 2 )alkyl.

25. A compound according to claim 24 , wherein R 2 is H or (C 1 -C 2 )alkyl.

26. A compound according to claim 1 , wherein R 6 is 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.

27. A compound according to claim 26 , wherein R 6 is H, (C 1 -C 6 )alkyl, (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.

28. A compound according to claim 1 , wherein L is attached to the 3-position or to the 4-position of the piperidine ring.

29. A compound according to claim 1 , wherein L is attached to the 4-position of the piperidine ring.

30. A compound according to claim 1 , wherein L is O-methylene, O-ethylene or O.

31. A compound according to claim 30 , wherein L is O.

32. A compound according to claim 1 , wherein

R 1 is H, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, NH—(C 1 -C 6 )alkyl, NH—(C 6 -C 10 )aryl, or N[(C 1 -C 6 )alkyl] 2 ;

R 2 is hydrogen, halogen, or (C 1 -C 6 )alkyl;

R 3 is H, halogen, (C 1 -C 4 )alkylene-R′, O—R″ or NHR″;

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

R 5 is H, (C 1 -C 6 )alkyl, halogen, CN, (C 6 -C 10 )aryl, NH—(C 6 -C 10 )aryl, (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, (C 5 -C 10 )heterocyclyl or (C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl;

R 6 is H, (C 1 -C 6 )alkyl, R′, (C 1 -C 4 )alkylene-(C 5 -C 10 )heterocyclyl, (C 1 -C 6 )alkylene-C(O)—(C 6 -C 10 )aryl, (C 1 -C 4 )alkylene-C(O)—(C 5 -C 10 )heterocyclyl, or (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl;

R 7 is H, halogen, CN, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl or R′;

n is 1, 2 or 3, and

L is O, O-methylene or O-ethylene.

33. A compound according to claim 1 , wherein

R 1 is H, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, NH—(C 1 -C 6 )alkyl, NH—(C 6 -C 10 )aryl, or N[(C 1 -C 6 )alkyl] 2 ;

R 2 is H or (C 1 -C 4 )alkyl;

R 3 is H, halogen or NHR″;

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

R 5 is H, (C 1 -C 6 )alkyl, halogen, (C 6 -C 10 )aryl, NH—(C 6 -C 10 )aryl, (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl or (C 5 -C 10 )heterocyclyl;

R 6 is H, (C 1 -C 6 )alkyl, R′, (C 1 -C 4 )alkylene-(C 5 -C 10 )heterocyclyl or (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl;

R 7 is H, halogen, CN, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl or R′;

n is 1, 2 or 3; and

L is O.

34. A compound according to claim 1 , wherein

R 1 is H, (C 1 -C 4 )alkyl, NH—(C 1 -C 4 )alkyl, N[(C 1 -C 4 )alkyl] 2 or NH-phenyl;

R 2 is H or (C 1 -C 4 )alkyl;

R 3 is H, NH—(C 5 -C 6 )heteroaryl or NH-phenyl;

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

R 5 is H, (C 1 -C 4 )alkyl, halogen, (C 6 -C 10 )aryl, NH—(C 6 -C 10 )aryl, (C 1 -C 2 )alkyl-(C 6 -C 10 )aryl or (C 5 -C 10 )heteroaryl;

R 6 is H, (C 1 -C 6 )alkyl, (C 5 -C 10 )heterocyclyl, (C 1 -C 4 )alkylene-(C 5 -C 10 )heterocyclyl, (C 6 -C 10 )aryl or (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl;

R 7 is H, halogen, CN, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, phenyl, cyclopropyl, (C 5 -C 6 )heteroaryl;

R 8 is H, halogen or (C 1 -C 4 )alkyl;

n is 1; and

L is O.

35. The compound of claim 1 wherein (C 6 -C 10 )aryl and (C 5 -C 10 )heterocyclyl groups are unsubstituted or substituted one or more times by suitable groups independently selected from halogen, CF 3 , NO 2 , N 3 , CN, C(O)—(C 1 -C 6 )alkyl, C(O)—(C 6 -C 10 )aryl, COOH, COO(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, CON[(C 1 -C 6 )alkyl] 2 , (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylene-OH, (C 1 -C 6 )alkylene-NH 2 , (C 1 -C 6 )alkylene-NH(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylene-N[(C 1 -C 6 )alkyl] 2 , (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, O—(C 1 -C 6 )alkyl, O—C(O)—(C 1 -C 6 )alkyl, O—C(O)—(C 6 -C 10 )aryl, O—C(O)—(C 5 -C 10 )heterocyclyl, PO 3 H 2 , SO 3 H, SO 2 —NH 2 , SO 2 NH(C 1 -C 6 )alkyl, SO 2 [(C 1 -C 6 )alkyl] 2 , S—(C 1 -C 6 )alkyl; S—(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, S—(C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl, SO—(C 1 -C 6 )alkyl, SO—(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, SO—(C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl, SO 2 —(C 1 -C 6 )alkyl, SO 2 —(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, SO 2 —(C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl, SO 2 —NH(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, SO 2 —NH(C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl, SO 2 —N[(C 1 -C 6 )alkyl][(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl], SO 2 —N[(C 1 -C 6 )alkyl][(C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl], SO 2 —N[(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl] 2 , SO 2 —N[(C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl] 2 , C(NH)(NH 2 ), NH 2 , NH—(C 1 -C 6 )alkyl, N[(C 1 -C 6 )alkyl] 2 , NH—C(O)—(C 1 -C 6 )alkyl, NH—C(O)O—(C 1 -C 6 )alkyl, NH—C(O)—(C 6 -C 10 )aryl, NH—C(O)—(C 5 -C 10 )heterocyclyl, NH—C(O)O—(C 6 -C 10 )aryl, NH—C(O)O—(C 5 -C 10 )heterocyclyl, NH—C(O)—NH—(C 1 -C 6 )alkyl, NH—C(O)—NH—(C 6 -C 10 )aryl, NH—C(O)—NH—(C 5 -C 10 )heterocyclyl, NH—SO 2 —(C 1 -C 6 )alkyl, NH—SO 2 —(C 6 -C 10 )aryl, NH—SO 2 —(C 5 -C 10 )heterocyclyl, N(C 1 -C 6 )alkyl-C(O)—(C 1 -C 6 )alkyl, N(C 1 -C 6 )alkyl-C(O)O—(C 1 -C 6 )alkyl, N(C 1 -C 6 )alkyl-C(O)—(C 6 -C 10 )aryl, N(C 1 -C 6 )alkyl-C(O)-heterocyclyl, N(C 1 -C 6 )alkyl-C(O)O—(C 6 -C 10 )aryl, N(C 1 -C 6 )alkyl-C(O)O—(C 5 -C 10 )heterocyclyl, N(C 1 -C 6 )alkyl-C(O)—NH—(C 1 -C 6 )alkyl], N(C 1 -C 6 )alkyl-C(O)—NH—(C 6 -C 10 )aryl, N(C 1 -C 6 )alkyl-C(O)—NH—(C 5 -C 10 )heterocyclyl, N[(C 1 -C 6 )alkyl]-C(O)—N[(C 1 -C 6 )alkyl] 2 , N[(C 1 -C 6 )alkyl]-C(O)—N[(C 1 -C 6 )alkyl]-(C 6 -C 10 )aryl, N[(C 1 -C 6 )alkyl]-C(O)—N[(C 1 -C 6 )alkyl]-(C 5 -C 10 )heterocyclyl, N[(C 1 -C 6 )alkyl]-C(O)—N[(C 6 -C 10 )aryl] 2 , N[(C 1 -C 6 )alkyl]-C(O)—N[(C 5 -C 10 )heterocyclyl] 2 , N[(C 6 -C 10 )aryl]-C(O)—(C 1 -C 6 )alkyl, N[(C 5 -C 10 )heterocyclyl]-C(O)—(C 1 -C 6 )alkyl, N[(C 6 -C 10 )aryl]-C(O)O—(C 1 -C 6 )alkyl, N[(C 5 -C 10 )heterocyclyl]-C(O)O—(C 1 -C 6 )alkyl, N(aryl)-C(O)—(C 6 -C 10 )aryl, N[(C 5 -C 10 )heterocyclyl]-C(O)—(C 6 -C 10 )aryl, N[(C 6 -C 10 )aryl]-C(O)O—(C 6 -C 10 )aryl, N[(C 5 -C 10 )heterocyclyl]-C(O)O—(C 6 -C 10 )aryl, N[(C 6 -C 10 )aryl]-C(O)—NH—(C 1 -C 6 )alkyl, N[(C 5 -C 10 )heterocyclyl]-C(O)—NH—(C 1 -C 6 )alkyl, N(aryl)-C(O)—NH—(C 6 -C 10 )aryl, N[(C 5 -C 10 )heterocyclyl]-C(O)—NH—(C 6 -C 10 )aryl, N[(C 6 -C 10 )aryl]-C(O)—N[(C 1 -C 6 )alkyl] 2 , N[(C 5 -C 10 )heterocyclyl]-C(O)—N[(C 1 -C 6 )alkyl] 2 , N[(C 6 -C 10 )aryl]-C(O)—N[(C 1 -C 6 )alkyl]-(C 6 -C 10 )aryl, N[(C 5 -C 10 )heterocyclyl]-C(O)—N[(C 1 -C 6 )alkyl]-(C 6 -C 10 )aryl, N[(C 6 -C 10 )aryl]-C(O)—N[(C 6 -C 10 )aryl] 2 , N[(C 5 -C 10 )heterocyclyl]-C(O)—N[(C 6 -C 10 )aryl] 2 , (C 6 -C 10 )aryl, (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, O—(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, (C 5 -C 10 )heterocyclyl, (C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl, O—(C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl, wherein the (C 6 -C 10 )aryl or (C 5 -C 10 )heterocyclyl may be substituted one to 3 times by halogen, OH, NO 2 , CN, O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, NH 2 , NH(C 1 -C 6 )alkyl, N[(C 1 -C 6 )alkyl] 2 , SO 2 CH 3 , COOH, C(O)O—(C 1 -C 6 )alkyl, CONH 2 , (C 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylene-O—(C 6 -C 10 )aryl, O—(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl; or wherein (C 6 -C 10 )aryl is vicinal substituted by a O—(C 1 -C 4 )alkylene-O group whereby a 5-8-membered ring is formed together with the carbon atoms to which the oxygen atoms are attached; and wherein the aryl or heterocyclyl substituents of (C 6 -C 10 )aryl and (C 5 -C 10 )heterocyclyl groups may not be further substituted by an aryl or heterocyclyl containing group.

36. A compound according to claim 1 wherein (C 6 -C 10 )aryl is substituted by (C 1 -C 4 )alkyl, O—(C 1 -C 4 )alkyl, O-phenyl, C(O)O—(C 1 -C 6 )alkyl, C(O)OH, C(O)—(C 1 -C 4 )alkyl, halogen, NO 2 , SO 2 NH 2 , CN, SO 2 —(C 1 -C 4 )alkyl, NH—SO 2 —(C 1 -C 4 )alkyl, NH 2 , NH—C(O)—(C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 4 )alkyl-OH, C(O)N[(C 1 -C 4 )alkyl] 2 , C(O)NH 2 , N[(C 1 -C 4 )alkyl] 2 , (C 2 -C 4 )alkenylene —(C 6 -C 10 )aryl, wherein the (C 6 -C 10 )aryl may be further substituted by (C 1 -C 4 )alkyl, (C 1 -C 4 )alkylene-O—(C 1 -C 6 )alkyl, O—(C 1 -C 6 )alkyl-(C 6 -C 10 )aryl, or may be vicinal substituted by a O—(C 1 -C 4 )alkylene-O group whereby a 5-8-membered ring is formed together with the carbon atoms to which the oxygen atoms are attached.

37. A compound according to claim 1 wherein (C 5 -C 10 )heterocyclyl is substituted by

(C 1 -C 4 )alkyl, O—(C 1 -C 4 )alkyl, (C 1 -C 4 )alkylene-phenyl, halogen, (C 1 -C 4 )alkylene-O—(C 1 -C 4 )alkyl, (C 5 -C 10 )heterocyclyl, (C 1 -C 4 )alkylene-N[(C 1 -C 4 )alkyl] 2 , or (C 6 -C 10 )aryl, wherein the (C 6 -C 10 )aryl may be further substituted by (C 1 -C 4 )alkyl, (C 1 -C 4 )alkylene-O—(C 1 -C 6 )alkyl, O—(C 1 -C 6 )alkyl-(C 6 -C 10 )aryl, or may be vicinal substituted by a O—(C 1 -C 4 )alkylene-O group whereby a 5-8-membered ring is formed together with the carbon atoms to which the oxygen atoms are attached.

38. A compound according to claim 1 , wherein R 3 is

39. A compound according to claim 1 , wherein

R 5 is hydrogen, fluoro, chloro, bromo, iodo, nitrile, nitro, (p-methoxy)-phenyl, N-aniline, phenyl, benzyl, methyl, ethyl, vinyl, 2-propenyl, s-butenyl, cyclopropyl, thienyl, tetrazol, amino, 4-methoxy-anilin, N-acetyl or a substituent of the group consisting of

40. A compound according to claim 1 wherein

R 6 are H, methyl, ethyl, propyl, butyl, s-butyl, pentyl, 3-methyl-butyl, isopropyl, trifluoromethyl, 3,3,3-trifluorobutyl, cyclopropyl, methylene cyclopropyl, 2-pyrimidinyl, benzyl or a substituent of the group consisting of

41. A pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound according to claim 1 , or a pharmaceutically acceptable salt thereof, a physiologically functional derivative thereof, or a pharmaceutically acceptable salt and physiologically functional derivative thereof, and physiologically tolerated excipients and carriers.

42. The pharmaceutical composition according to claim 41 further comprising additional additives or other active ingredients, or additional additives and other active ingredients.

Assignments (2)

CHANGE OF NAME Recorded Jun 20, 2012

From: SANOFI-AVENTIS

To: SANOFI

Reel/Frame 028413/0927 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 3, 2008

From: PLETTENBURG, OLIVER; HOFMEISTER, ARMIN; KADEREIT, DIETER; PEUKERT, STEFAN; RUF, SVEN; RITTER, KURT; LOHN, MATTHIAS; IVASHCHENKO, YURI; MONECKE, PETER; DREYER, MATTHIAS; KANNT, AIMO

To: SANOFI-AVENTIS

Reel/Frame 021042/0996 →