6-CYCLOAMINO-3-(1H-PYRROLO[2,3-b]PYRIDIN-4-YL)IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVES, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF

• US 20120010208A1
• Filed: 11/30/2009
• Published: 01/12/2012
• Est. Priority Date: 12/01/2008
• Status: Active Grant

• Current Assignee: Sanofi
• Original Assignee: Sanofi
• Inventors: Pacaud, Christophe, Puech, Frederic
• Granted Patent: US 8,546,395 B2
• Time in Patent Office: Days
• US Class Current: 514/248
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 25/34 Tobacco-abuse
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention relates to 6-cycloamino-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine derivatives corresponding to the general formula (I) in which R₂ represents an aryl group optionally substituted with one or more halogen atoms or C_1-6-alkyl, C_1-6-alkyloxy, C_1-6-alkylthio, C_1-6-fluoroalkyl, C_1-6-fluoroalkyloxy and —CN groups or R₂ represents a group chosen from C_1-6-alkyl, C_1-6-fluoroalkyl, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-6-alkyl groups; A represents a C_1-7-alkylene group; B represents a C_1-7-alkylene group; L represents either a nitrogen atom optionally substituted with an R_c or R_d group, or a carbon atom substituted with an R_e1 group and an R_d group or two R_e2 groups; the carbon atoms of A and of B being optionally substituted with one or more R_f groups, which may be identical to or different from one another. Preparation process and therapeutic use.

Claims

1. A compound of general formula (I):

2. The compound according to claim 1, wherein:

R₂ represents a phenyl optionally substituted with one or more halogen atoms or C_1-6-alkyl or C_1-6-fluoroalkyl groups.

3. The compound according to claim 1, wherein:

R₂ represents a group chosen from C_1-6-alkyl, C_1-6-fluoroalkyl, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-6-alkyl groups.

4. The compound according to claim 1, wherein:

R₇ and R₈ represent, independently of each other, a hydrogen atom or a methyl group.

5. The compound according to claim 1, wherein:

A represents a C_1-7-alkylene group optionally substituted with one or two R_a groups;

B represents a C_1-7-alkylene group optionally substituted with an R_b group;

L represents a nitrogen atom optionally substituted with an R_c or R_d group;

the carbon atoms of A and of B being optionally substituted with one or more R_f groups, which may be identical to or different from each other;

two R_a groups may together form a C_1-6-alkylene group;

R_a and R_b may together form a bond or a C_1-6-alkylene group;

R_a and R_c may together form a bond or a C_1-6-alkylene group;

R_b and R_c may together form a bond or a C_1-6-alkylene group;

—

R_d represents a group chosen from a hydrogen atom and C_1-6-alkyl, C_3-7-cycloalkyl, C_3-7-cycloalkyl-C_1-6-alkyl, hydroxy-C_1-6-alkyl, C_1-6-alkyloxy-C_1-6-alkyl, C_1-6-alkylthio-C_1-6-alkyl, C_1-6-fluoroalkyl or benzyl groups; and

R_f represents a C_1-6-alkyl, C_3-7-cycloalkyl, C_3-7-cycloalkyl-C_1-6-alkyl, C_1-6-alkyloxy-C_1-6-alkyl, hydroxy-C_1-6-alkyl, C_1-6-fluoroalkyl or phenyl group.

6. The compound according to claim 1, wherein:

A represents a C_1-7-alkylene group optionally substituted with one or two R_a groups;

B represents a C_1-7-alkylene group optionally substituted with an R_b group;

L represents a carbon atom optionally substituted with two R_e2 groups;

the carbon atoms of A and of B being optionally substituted with one or more R_f groups, which may be identical to or different from each other;

two R_e2 groups form, with the carbon atom that bears them, a cyclic monoamine optionally comprising an oxygen atom, this cyclic monoamine being optionally substituted with one or more R_f groups, which may be identical to or different from one another; and

R_f represents a C_1-6-alkyl group.

7. The compound according to claim 1, wherein:

A represents a C_1-7-alkylene group;

B represents a C_1-7-alkylene group;

L represents a carbon atom substituted with an R_e1 group and an R_d group;

R_d represents a hydrogen atom;

R_e1 represents an —

NR₄R₅ group or a cyclic monoamine optionally comprising an oxygen atom, the cyclic monoamine being optionally substituted with one or more R_f groups, which may be identical to or different from one another; and

R_f represents a C_1-6-alkyl, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-6-alkyl group.

8. The compound according to claim 1, wherein:

R₂ represents a methyl group;

the cyclic amine formed by —

N-A-L-B—

represents an (R)-3-methylpiperazin-1-yl, 3,3-dimethylpiperazin-1-yl, (cis)-3,5-dimethylpiperazin-1-yl, 4-isopropylpiperazin-1-yl or (cis)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl group; and

R₇ and R₈ represent a hydrogen atom.

9. The compound according to claim 1, wherein:

R₂ represents a 3-fluorophenyl or a 4-fluorophenyl group;

the cyclic amine formed by —

N-A-L-B—

represents an (R)-3-methylpiperazin-1-yl, 3,3-dimethylpiperazin-1-yl, (cis)-3,5-dimethylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, 6,9-diazaspiro[4.5]dec-9-yl, 3-phenylpiperazin-1-yl, 4-benzylpiperazin-1-yl, 3-hydroxymethylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, (R)-4-(2-hydroxypropyl)piperazin-1-yl, (S)-4-(2-hydroxypropyl)piperazin-1-yl, 4-(1-hydroxy-2-methylpropan-2-yl)piperazin-1-yl, 4-(2-hydroxy-2-methylpropyl)piperazin-1-yl, 4-(3-hydroxy-3-methylbutyl)piperazin-1-yl, (R)-3-phenylpiperazin-1-yl, (S)-3-phenylpiperazin-1-yl, 4-benzylpiperazin-1-yl, (cis)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, (cis)-5-(2-hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, (4aR,7aR)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (4aS,7aS)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, or (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl group; and

R₇ and R₈ represent, independently of each other, a hydrogen atom or a methyl group.

10. The compound according to claim 1, wherein:

R₂ represents a 4-fluorophenyl group;

the cyclic amine formed by —

N-A-L-B—

represents a 2,9-diazaspiro[5.5]undec-9-yl group; and

R₇ and R₈ represent a hydrogen atom.

11. The compound according to claim 1, wherein:

R₂ represents a 4-fluorophenyl group;

the cyclic amine formed by —

N-A-L-B—

represents a 4-(pyrrolidin-1-yl)-piperidin-1-yl group;

R₇ and R₈ represent a hydrogen atom.

12. The compound according to claim 1, chosen from:

1. 2-Methyl-6-[(R)-3-methylpiperazin-1-yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

2. 6-(3,3-Dimethylpiperazin-1-yl)-2-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine and the trihydrochloride thereof;

3. 6-[(cis)-3,5-Dimethylpiperazin-1-yl]-2-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-imidazo[1,2-b]pyridazine and the trihydrochloride thereof;

4. 6-(4-Isopropylpiperazin-1-yl)-2-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine and the trihydrochloride thereof;

5. 2-Methyl-6-[(cis)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine and the trihydrochloride thereof;

6. 2-(4-Fluorophenyl)-6-[(3R)-3-methylpiperazin-1-yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-imidazo[1,2-b]pyridazine;

7. {4-[2-(4-Fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]-piperazin-2-yl}methanol;

8. 6-(3,3-Dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-imidazo[1,2-b]pyridazine;

9. 6-(3,3-Dimethylpiperazin-1-yl)-2-(3-fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

10. 6-(3,3-Dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

11. 6-[(cis)-3,5-Dimethylpiperazin-1-yl]-2-(4-fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

12. 2-{4-[2-(3-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol;

13. 2-{4-[2-(4-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol;

14. 2-(4-Fluorophenyl)-6-(4-isopropylpiperazin-1-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-imidazo[1,2-b]pyridazine;

15. 2-(4-Fluorophenyl)-6-(4-isopropylpiperazin-1-yl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

16. (R)-1-{4-[2-(4-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}propan-2-ol;

17. (S)-1-{4-[2-(4-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}propan-2-ol;

18. 6-(6,9-Diazaspiro[4.5]dec-9-yl)-2-(4-fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

19. 2-{4-[2-(4-Fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-1-ol;

20. 1-{-4-[2-(4-Fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-2-ol;

21. 1-{4-[2-(3-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-2-ol;

22. 1-{4-[2-(4-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-2-ol;

23. 4-{4-[2-(4-Fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylbutan-2-ol;

24. (R)-2-(4-Fluorophenyl)-6-[3-phenylpiperazin-1-yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-imidazo[1,2-b]pyridazine and the trihydrochloride thereof;

25. (S)-2-(4-Fluorophenyl)-6-[3-phenylpiperazin-1-yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-imidazo[1,2-b]pyridazine and the trihydrochloride thereof;

26. 2-(4-Fluorophenyl)-8-methyl-6-[3-phenylpiperazin-1-yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

27. 6-(4-Benzylpiperazin-1-yl)-2-(4-fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-imidazo[1,2-b]pyridazine;

28. (cis)-2-(4-Fluorophenyl)-6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

29. (cis)-2-(4-Fluorophenyl)-8-methyl-6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

30. (cis)-2-{5-[2-(4-Fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}ethanol;

31. (cis)-2-{5-[2-(4-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}ethanol;

32. 2-(4-Fluorophenyl)-8-methyl-6-((4aR,7aR)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

33. 2-(4-Fluorophenyl)-8-methyl-6-((4aS,7aS)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

34. 2-(4-Fluorophenyl)-64(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

35. 9-[2-(4-Fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane;

36. 2-(4-Fluorophenyl)-6-(4-pyrrolidin-1-ylpiperidin-1-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine.

13. A process for preparing the compound according to claim 1, wherein a compound of general formula (II):

14. A process for preparing the compound according to claim 1, wherein a compound of general formula (V):

15. A pharmaceutical composition comprising the compound according to claim 1, in the form of a base or an addition salt with a pharmaceutically acceptable acid.

16. The pharmaceutical composition according to claim 15 further comprising, at least one pharmaceutically acceptable excipient.

17. A method for preventing or treating sleep disorders, circadian rhythm disorders, mood disorders, anxiety and depressives disorders, diseases associated with a dependence on abuse substances, diseases related to hyperphosphorylation of the tau protein, diseases caused or exacerbated by cell proliferation or inflammatory diseases in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of claim 15.