3-heteroaryl-3,5-dihydro-4-oxo-4H-pyridazino[4,5-b] indole-1-acetamide derivatives, preparation and use thereof in medicaments

1. A compound of the formula (I)

in which

X represents a hydrogen or halogen atom,

R 1 represents a hydrogen atom or a (C 1 -C 4 )alkyl group,

R 2 and R 3 each independently of one another represent a hydrogen atom or a (C 1 -C 4 )alkyl group, or else R 2 and R 3 , together with the nitrogen atom bearing them, form a pyrrolidinyl, piperidinyl, morpholinyl or 4-(C 1 -C 4 )alkylpiperazinyl group, and

Het represents a heteroaromatic group of pyridinyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrazinyl or pyridazinyl type which may carry one or more halogen atoms and/or one or more (C 1 -C 4 )alkyl and/or (C 1 -C 4 )alkoxy groups,

in the form of the base or an addition salt with acids.

2. The compound according to claim 1 wherein X represents a halogen atom.

3. The compound according to claim 1 wherein R 1 represents a (C 1 -C 4 ) alkyl.

4. The compound according to claim 1 wherein R 2 and R 3 , each independently of one another, represent a (C 1 -C 4 )alkyl group or else R 2 and R 3 , together with the nitrogen atom bearing them, form a pyrrolidinyl or 4-(C 1 -C 4 )alkylpiperazinyl group.

5. The compound according to claim 1 wherein Het represents a heteroaromatic group of pyridinyl type which may carry one or more halogen atoms and/or one or more (C 1 -C 4 )alkyl and/or (C 1 -C 4 )alkoxy groups.

6. The compound according to claim 1 wherein X represents a chlorine atom and R 1 represents a methyl group.

7. A process for preparing a compound of formula (I),

in which

X represents a hydrogen or halogen atom,

R 1 represents a hydrogen atom or a (C 1 -C 4 )alkyl group,

R 2 and R 3 each independently of one another represent a hydrogen atom or a (C 1 -C 4 )alkyl group, or else R 2 and R 3 , together with the nitrogen atom bearing them, form a pyrrolidinyl, piperidinyl, morpholinyl or 4-(C 1 -C 4 )alkylpiperazinyl group, and

Het represents a heteroaromatic group of pyildinyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrazinyl or pyridazinyl type which may carry one or more halogen atoms and/or one or more (C 1 -C 4 )alkyl and/or (C 1 -C 4 )alkoxy groups,

wherein the compound of formula (IV),

in which

X, R 1 , R 2 and R 3 are as defined above,

R′ represents a (C 1 -C 4 )alkyl group,

is reacted, in a polar solvent in the presence of an acid, with a heteroarylhydrazine.

8. The process according to claim 7 wherein the compound of formula (IV),

in which

X, R 1 , R 2 , R 3 and R′ are as defined claim 7 ,

is prepared by reacting a compound of formula (III),

in which

X, R 1 and R′ are as defined above,

R″ represents a (C 1 -C 4 )alkyl group,

with an amine of formula HNR 2 R 3 , in which R 2 and R 3 are as defined in claim 7 , in the presence of a catalyst, 4-(dimethylamino)pyridine.

9. A process for preparing a compound of formula (I),

in which

X represents a hydrogen or halogen atom,

R 1 represents a hydrogen atom or a (C 1 -C 4 )alkyl group,

R 2 and R 3 each independently of one another represent a hydrogen atom or a (C 1 -C 4 )alkyl group, or else R 2 and R 3 , together with the nitrogen atom bearing them, form a pyrrolidinyl, piperidinyl, morpholinyl or 4-(C 1 -C 4 )alkylpiperazinyl group, and

Het represents a heteroaromatic group of pyridinyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrazinyl or pyridazinyl type which may carry one or more halogen atoms and/or one or more (C 1 -C 4 )alkyl and/or (C 1 -C 4 )alkoxy groups,

comprising the step consisting in

carrying out an N-heteroarylation reaction on a compound of formula (V),

in which

X, R 1 , R 2 and R 3 are as defined above,

in the presence of a heteroaryl halide, or else of a heteroarylboronic acid derivative and of a metal salt, a copper salt.

10. The process according to claim 9 wherein compound of formula (V),

in which

X, R 1 , R 2 and R 3 are as defined in claim 9 ,

is prepared by reacting a compound of formula (IV),

in which

X, R 1 , R 2 , R 3 are as defined in claim 9 ,

R′ represents a (C 1 -C 4 )alkyl group,

with hydrazine by heating in a solvent, toluene and in the presence of a catalytic amount of acid.

11. A compound of the formula (V)

in which

X represents a hydrogen or halogen atom,

R 1 represents a hydrogen atom or a (C 1 -C 4 )alkyl group,

R 2 and R 3 , each independently of one another, represent a hydrogen atom or a (C 1 -C 4 )alkyl group, or else R 2 and R 3 , together with the nitrogen atom hearing them, form a pyrrolidinyl, piperidinyl, morpholinyl or 4-(C 1 -C 4 )alkylpiperazinyl group.

12. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, a hydrate or a solvate of this compound, combined with at least one pharmaceutically acceptable excipient.

13. The compound according to claim 2 wherein R 1 represents a (C 1 -C 4 )alkyl.

14. The compound according to claim 2 wherein R 2 and R 3 , each independently of one another, represent a (C 1 -C 4 )alkyl group or else R 2 and R 3 , together with the nitrogen atom bearing them, form a pyrrolidinyl or 4-(C 1 -C 4 )alkylpiperazinyl group.

15. The compound according to claim 3 wherein R 2 and R 3 , each independently of one another, represent a (C 1 -C 4 )alkyl group or else R 2 and R 3 , together with the nitrogen atom bearing them, form a pyrrolidinyl or 4-(C 1 -C 4 )alkylpiperazinyl group.

16. The compound according to claim 2 wherein Het represents a heteroaromatic group of pyridinyl type which may carry one or more halogen atoms and/or one or more (C 1 -C 4 )alkyl and/or (C 1 -C 4 )alkoxy groups.

17. The compound according to claim 3 wherein Het represents a heteroaromatic group of pyridinyl type which may carry one or more halogen atoms and/or one or more (C 1 -C 4 )alkyl and/or (C 1 -C 4 )alkoxy groups.

18. The compound according to claim 4 wherein Het represents a heteroaromatic group of pyridinyl type which may carry one or more halogen atoms and/or one or more (C 1 -C 4 )alkyl and/or (C 1 -C 4 )alkoxy groups.

19. The compound according to claim 2 wherein X represents a chlorine atom and R 1 represents a methyl group.

20. The compound according to claim 3 wherein X represents a chlorine atom and R 1 represents a methyl group.

21. The compound according to claim 4 wherein X represents a chlorine atom and R 1 represents a methyl group.

22. The compound according to claim 5 wherein X represents a chlorine atom and R 1 represents a methyl group.

23. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 2 or a pharmaceutically acceptable salt, combined with at least one pharmaceutically acceptable excipient.

24. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt, combined with at least one pharmaceutically acceptable excipient.

25. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 4 or a pharmaceutically acceptable salt, combined with at least one pharmaceutically acceptable excipient.

26. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 5 or a pharmaceutically acceptable salt, combined with at least one pharmaceutically acceptable excipient.

27. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 6 or a pharmaceutically acceptable salt, combined with at least one pharmaceutically acceptable excipient.

28. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 13 or a pharmaceutically acceptable salt, combined with at least one pharmaceutically acceptable excipient.

29. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 14 or a pharmaceutically acceptable salt, combined with at least one pharmaceutically acceptable excipient.

30. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 15 or a pharmaceutically acceptable salt, combined with at least one pharmaceutically acceptable excipient.

31. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 16 or a pharmaceutically acceptable salt, combined with at least one pharmaceutically acceptable excipient.

32. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 17 or a pharmaceutically acceptable salt, combined with at least one pharmaceutically acceptable excipient.

33. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 18 or a pharmaceutically acceptable salt, combined with at least one pharmaceutically acceptable excipient.

34. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 19 or a pharmaceutically acceptable salt, combined with at least one pharmaceutically acceptable excipient.

35. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 20 or a pharmaceutically acceptable salt, combined with at least one pharmaceutically acceptable excipient.

36. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 21 or a pharmaceutically acceptable salt, combined with at least one pharmaceutically acceptable excipient.

37. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 22 or a pharmaceutically acceptable salt, combined with at least one pharmaceutically acceptable excipient.

38. A method for treating a disease in a patient, said disease selected from the group consisting of spinal amyotrophy; amyotrophic lateral sclerosis; cranial and medullar trauma; multiple sclerosis; and diabetic nephropathy which comprises administering to said patient an effective amount of a compound according to claim 1 .

39. A method for treating a disease in a patient, said disease selected from the group consisting of spinal amyotrophy; amyotrophic lateral sclerosis; cranial and medullar trauma; multiple sclerosis; and diabetic nephropathy which comprises administering to said patient an effective amount of a compound according to claim 2 .

40. A method for treating a disease in a patient, said disease selected from the group consisting of spinal amyotrophy; amyotrophic lateral sclerosis; cranial and medullar trauma; multiple sclerosis; and diabetic nephropathy which comprises administering to said patient an effective amount of a compound according to claim 3 .

41. A method for treating a disease in a patient, said disease selected from the group consisting of spinal amyotrophy; amyotrophic lateral sclerosis; cranial and medullar trauma; multiple sclerosis; and diabetic nephropathy which comprises administering to said patient an effective amount of a compound according to claim 4 .

42. A method for treating a disease in a patient, said disease selected from the group consisting of spinal amyotrophy; amyotrophic lateral sclerosis; cranial and medullar trauma; multiple sclerosis; and diabetic nephropathy which comprises administering to said patient an effective amount of a compound according to claim 5 .

43. A method for treating a disease in a patient, said disease selected from the group consisting of spinal amyotrophy; amyotrophic lateral sclerosis; cranial and medullar trauma; multiple sclerosis; and diabetic nephropathy which comprises administering to said patient an effective amount of a compound according to claim 6 .

44. A method for treating a disease in a patient, said disease selected from the group consisting of spinal amyotrophy; amyotrophic lateral sclerosis; cranial and medullar trauma; multiple sclerosis; and diabetic nephropathy which comprises administering to said patient an effective amount of a compound according to claim 13 .

45. A method for treating a disease in a patient, said disease selected from the group consisting of spinal amyotrophy; amyotrophic lateral sclerosis; cranial and medullar trauma; multiple sclerosis; and diabetic nephropathy which comprises administering to said patient an effective amount of a compound according to claim 14 .

46. A method for treating a disease in a patient, said disease selected from the group consisting of spinal amyotrophy; amyotrophic lateral sclerosis; cranial and medullar trauma; multiple sclerosis; and diabetic nephropathy which comprises administering to said patient an effective amount of a compound according to claim 15 .

47. A method for treating a disease in a patient, said disease selected from the group consisting of spinal amyotrophy; amyotrophic lateral sclerosis; cranial and medullar trauma; multiple sclerosis; and diabetic nephropathy which comprises administering to said patient an effective amount of a compound according to claim 16 .

48. A method for treating a disease in a patient, said disease selected from the group consisting of spinal amyotrophy; amyotrophic lateral sclerosis; cranial and medullar trauma; multiple sclerosis; and diabetic nephropathy which comprises administering to said patient an effective amount of a compound according to claim 17 .

49. A method for treating a disease in a patient, said disease selected from the group consisting of spinal amyotrophy; amyotrophic lateral sclerosis; cranial and medullar trauma; multiple sclerosis; and diabetic nephropathy which comprises administering to said patient an effective amount of a compound according to claim 18 .

50. A method for treating a disease in a patient, said disease selected from the group consisting of spinal amyotrophy; amyotrophic lateral sclerosis; cranial and medullar trauma; multiple sclerosis; and diabetic nephropathy which comprises administering to said patient an effective amount of a compound according to claim 19 .

51. A method for treating a disease in a patient, said disease selected from the group consisting of spinal amyotrophy; amyotrophic lateral sclerosis; cranial and medullar trauma; multiple sclerosis; and diabetic nephropathy which comprises administering to said patient an effective amount of a compound according to claim 20 .

52. A method for treating a disease in a patient, said disease selected from the group consisting of spinal amyotrophy; amyotrophic lateral sclerosis; cranial and medullar trauma; multiple sclerosis; and diabetic nephropathy which comprises administering to said patient an effective amount of a compound according to claim 21 .

53. A method for treating a disease in a patient, said disease selected from the group consisting of spinal amyotrophy; amyotrophic lateral sclerosis; cranial and medullar trauma; multiple sclerosis; and diabetic nephropathy which comprises administering to said patient an effective amount of a compound according to claim 22 .