3-aryl-3-hydroxy-2-amino-propionic acid amides, 3-heteroaryl-3-hydroxy-2-amino-propionic acid amides and related compounds having analgesic and/or immuno stimulant activity

• US 8,288,556 B2
• Filed: 01/25/2006
• Issued: 10/16/2012
• Est. Priority Date: 01/26/2005
• Status: Active Grant

• Current Assignee: Allergan, Inc. (Canada) (Abbvie Incorporated), Exonhit Therapeutics SA (Eurobio-Scientific SA)
• Original Assignee: Allergan, Inc. (Canada) (Abbvie Incorporated), Exonhit Therapeutics SA (Eurobio-Scientific SA)
• Inventors: Leblond, Bertrand, Beausoleil, Eric, Taverne, Thierry, Donello, John E.
• Primary Examiner(s): McKane, Joseph K.
• Assistant Examiner(s): Grazier, Nyeemah A
• Application Number:
  US11/814,598
• Publication Number:
  US 20090036436A1
• Time in Patent Office: 2,456 Days
• Field of Search: None
• US Class Current: 546/279.1
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/4409 only substituted in position 4, e.g. isoniazid, iproniazid
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/541 Non-condensed thiazines containing further heterocyclic rings
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• 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 29/02 without antiinflammatory effect
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: C07D 207/09 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 265/30 not condensed with other rings
• CPC Class Codes: C07D 295/12 substituted by singly or doubly bound nitrogen atoms nitro radicals C07D295/06
• CPC Class Codes: C07D 295/13 : to an acyclic saturated chain
• CPC Class Codes: C07D 295/15 : to an acyclic saturated chain
• CPC Class Codes: C07D 319/18 : Ethylenedioxybenzenes, not substituted on the hetero ring
• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms

Abstract

Compounds of Formulas 1 and 2

where the variables have the meaning disclosed in the specification, have analgesic and in some cases immunostimulant activity.

Claims

1. A compound of the formula

2. A compound in accordance with claim 1 where R₄ is H.

3. A compound in accordance with claim 2 where both R₃ groups are H.

4. A compound in accordance with claim 2 where one R₃ group is H and the other R₃ group is CO—

R₇ or alkyl of 1 to 20 carbons.

5. A compound in accordance with claim 2 where R₃ is independently selected from the group consisting of H and alkyl of 1 to 10 carbons.

6. A compound in accordance with claim 1 where R₄ is CO—

R₈.

7. A compound in accordance with claim 1 where R₁ and R₂ together with the nitrogen form a 4, 5, 6 or 7 membered ring.

8. A compound in accordance with claim 7 where R₁ and R₂ together with the nitrogen form a 5 membered ring.

9. A compound in accordance with claim 7 where R₁ and R₂ together with the nitrogen form a 6 membered ring.

10. A compound in accordance with claim 1 where both R₅ and R₆ are hydrogen.

40. A method of treating pain in a mammal in need of such treatment, comprising administering to said mammal at least one compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof.

42. A pharmaceutical composition comprising at least one compound of claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

56. The method of claim 40, wherein said pain is chronic pain.

11. A compound of the formula

12. A compound in accordance with claim 11 where R₄ is H.

13. A compound in accordance with claim 11 where both R₃ groups are H.

14. A compound in accordance with claim 11 where both R₅ and R₆ are hydrogen.

30. A compound in accordance with claim 11 having the formula

31. A compound in accordance with claim 11 having the formula

32. A compound in accordance with claim 11 having the formula

33. A compound in accordance with claim 11 having the formula

34. A compound in accordance with claim 11 having the formula

35. A compound in accordance with claim 11 having the formula

36. A compound in accordance with claim 11 having the formula

37. A compound in accordance with claim 11 having the formula

38. A compound in accordance with claim 37 having the formula

39. A compound in accordance with claim 37 having the formula

43. A pharmaceutical composition comprising at least one compound of claim 11 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

52. A method of treating pain in a mammal in need of such treatment, comprising administering to said mammal at least one compound in accordance with claim 11 or a pharmaceutically acceptable salt thereof.

57. The method of claim 52, wherein said pain is chronic pain.

15. A compound of the formula

16. A compound in accordance with claim 15 where R₄ is H.

17. A compound in accordance with claim 15 where both R₃ groups are H.

20. A compound in accordance with claim 15 having the formula

21. A compound in accordance with claim 15 having the formula

22. A compound in accordance with claim 15 having the formula

23. A compound in accordance with claim 15 having the formula

24. A compound in accordance with claim 15 having the formula

25. A compound in accordance with claim 15 having the formula

44. A pharmaceutical composition comprising at least one compound of claim 15 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

53. A method of treating pain in a mammal in need of such treatment, comprising administering to said mammal at least one compound in accordance with claim 15 or a pharmaceutically acceptable salt thereof.

58. The method of claim 53, wherein said pain is chronic pain.

18. A compound of the formula

45. A pharmaceutical composition comprising the compound of claim 18 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

19. A compound of formula

46. A pharmaceutical composition comprising the compound of claim 19 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

26. A compound of the formula

47. A pharmaceutical composition comprising at least one compound of claim 26, and at least one pharmaceutically acceptable excipient.

27. A compound of the formula

48. A pharmaceutical composition comprising at least one compound of claim 27, and at least one pharmaceutically acceptable excipient.

28. A compound of the formula

49. A pharmaceutical composition comprising at least one compound of claim 28, and at least one pharmaceutically acceptable excipient.

54. A method of treating pain in a mammal in need of such treatment, comprising administering to said mammal at least one compound in accordance with claim 28.

59. The method of claim 54, wherein said pain is chronic pain.

29. A compound of the formula

50. A pharmaceutical composition comprising at least one compound of claim 29, and at least one pharmaceutically acceptable excipient.

41. A compound of the formula

51. A pharmaceutical composition comprising the compound of claim 41 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

55. A method of treating pain in a mammal in need of such treatment, comprising administering to said mammal the compound in accordance with claim 41 or a pharmaceutically acceptable salt thereof.

60. The method of claim 55, wherein said pain is chronic pain.