Novel heterocyclic amide derivatives and their use as dopamine D3 receptor ligands

• US 20040030137A1
• Filed: 02/19/2002
• Published: 02/12/2004
• Est. Priority Date: 02/16/2001
• Status: Abandoned Application

• Current Assignee: Aventis Pharma Deutschland GmbH (Sanofi )
• Original Assignee: Aventis Pharmaceuticals Incorporated (Sanofi-Aventis U.S., LLC)
• Inventors: Urmann, Matthias, Shutske, Gregory, Bordeau, Kenneth J., Zhao, Xu-Yang, Hemmerle, Horst, Jurcak, John G., Hendrix, James A., Nieduzak, Thaddeus R., Strupczewski, Joseph T., Mueller, Paul Justin, Gill, Harpal, Jackson, Sharon Anne, Weiberth, Franz J.
• Application Number:
  US10/078,206
• Publication Number:
  US 20040030137A1
• Time in Patent Office: Days
• US Class Current: 546/13
• CPC Class Codes: A61K 31/33 Heterocyclic compounds
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 333/58 Radicals substituted by nitrogen atoms
• CPC Class Codes: C07D 333/66 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 333/68 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 451/02 : containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems

Abstract

The invention relates to heterocyclic substituted amide derivatives that display selective binding to dopamine D₃ receptors. In another aspect, the invention relates to a method for treating central nervous system disorders associated with the dopamine D₃ receptor activity in a patient in need of such treatment comprising administering to the subject a therapeutically effective amount of said compounds for alleviation of such disorder. The central nervous system disorders that may be treated with these compounds include Psychotic Disorders, Substance Dependence, Substance Abuse, Dyskinetic Disorders (e.g. Parkinson'"'"'s Disease, Parkinsonism, Neuroleptic-Induced Tardive Dyskinesia, Gilles de la Tourette Syndrome and Huntington'"'"'s Disease), Dementia, Anxiety Disorders, Sleep Disorders, Circadian Rhythm Disorders and Mood Disorders. The subject invention is also directed towards processes for the preparation of the compounds described herein as well as methods for making and using the compounds as imaging agents for dopamine D₃ receptors.

Claims

1. A compound of the formula (I):

2. A compound according to claim 1 wherein Y is carbonyl, R is group (a) wherein R₄ is hydrogen and Q is CF₃, or group (b) wherein Q is hydrogen, C₁-C₆alkyl, or —

CH₂OC₁-C₆alkyl.

3. A compound according to claim 2 wherein B is group (a).

4. A compound according to claim 2 wherein B is group (b).

5. A compound according to claim 3 wherein z is 4.

6. A compound according to claim 4 wherein R₅, R₆, R₇ and R₈ are hydrogen.

7. A compound according to claim 3 wherein R₂ is group (a), (b), (l), (s), (n) or (ll).

8. A compound according to claim 4 wherein R₂ is group (a), (b), (l), (s), (n) or (ll).

9. A compound according to claim 7 wherein R₂ is group (a).

10. A compound according to claim 9 wherein R₂ is group (a) wherein y is 0 or 1 and e is 5.

11. A compound according to claim 7 wherein R₂ is group (b).

12. A compound according to claim 11 wherein M is hydrogen, C₁-C₆alkoxy, C₁-C₆alkyl or group (15);

and D is

group (a) wherein each R₁₃ and R₁₄ is independently hydrogen, halogen or C₁-C₃ linear alkyl; and

u is 0 or 1;

or

group (b) wherein R₁₅ and R₁₆ are hydrogen.

13. A compound according to claim 7 wherein R₂ is group (l).

14. A compound according to claim 13 wherein g is 0 or 1 and R₃₁ is hydrogen.

15. A compound according to claim 7 wherein R₂ is group (s).

16. A compound according to claim 15 wherein R₆₁ is hydrogen, C₁-C₆alkyl or halogen.

17. A compound according to claim 7 wherein R₂ is group (n).

18. A compound according to claim 17 wherein R₃₃ is hydrogen, C₁-C₆alkyl, or C₁-C₆alkoxy and R₃₄ is hydrogen or C₁-C₆alkyl.

19. A compound according to claim 7 wherein R₂ is group (ll).

20. A compound according to claim 19 wherein R₆₆ is hydrogen, C₁-C₆alkyl or halogen.

21. A compound according to claim 8 wherein R₂ is group (a).

22. A compound according to claim 21 wherein R₂ is group (a) wherein y is 0 or 1 and e is 5.

23. A compound according to claim 8 wherein R₂ is group (b).

24. A compound according to claim 23 wherein M is hydrogen, C₁-C₆alkoxy, C₁-C₆alkyl or group (15);

and D is

group (a) wherein each R₁₃ and R₁₄ is independently hydrogen, halogen or C₁-C₃ linear alkyl; and

u is 0 or 1;

or

group (b) wherein R₁₅ and R₁₆ are hydrogen.

25. A compound according to claim 8 wherein R₂ is group (I).

26. A compound according to claim 25 wherein g is 0 or 1 and R₃₁ is hydrogen.

27. A compound according to claim 8 wherein R₂ is group (s).

28. A compound according to claim 27 wherein R₆₁ is hydrogen, C₁-C₆alkyl or halogen.

29. A compound according to claim 8 wherein R₂ is group (n).

30. A compound according to claim 29 wherein R₃₃ is hydrogen, C₁-C₆alkyl, or C₁-C₆alkoxy and R₃₄ is hydrogen or C₁-C₆alkyl.

31. A compound according to claim 8 wherein R₂ is group (II).

32. A compound according to claim 31 wherein R₆₆ is hydrogen, C₁-C₆alkyl or halogen.

33. The compound of claim 1 which is benzo[b]thiophene-2-carboxylic acid {4-[4-s (6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-yl]-butyl}-amide.

34. The compound of claim 1 which is 4-ethoxy-N-{4-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-yl]-butyl}-benzamide.

35. The compound of claim 1 which is biphenyl-4-carboxylic acid {4-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-yl]-butyl}-amide.

36. The compound of claim 1 which is N-{4-[4-(fluoro-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-yl]-butyl}-trifluoromethyl-benzamide.

37. The compound of claim 1 which is thiophene-2-carboxylic acid {6-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-yl]-hexyl}-amide.

38. The compound of claim 1 which is biphenyl-4-carboxylic acid [4-(4-thieno[2,3-d]isoxazol-3-yl-piperazin-1-yl)-butyl]-amide.

39. The compound of claim 1 which is benzo[b]thiophene-2-carboxylic acid {4-[4-(6-fluoro-benzo[b]thiophen-3-yl)-[1,4]diazepan-1-yl]-butyl}-amide.

40. The compound of claim 1 which is 1H-indole-2-carboxylic acid {4-[4-(6-fluorobenzo[b]thiophen-3-yl)-[1,4]diazepan-1-yl]-butyl}-amide.

41. The compound of claim 1 which is naphthalene-2-carboxylic acid {4-[4-(6-fluoro-benzo[b]thiophen-3-yl)-[1,4]diazepan-1-yl]-butyl}-amide.

42. The compound of claim 1 which is 2-methyl-5-phenyl-furan-3-carboxylic acid {4-[4-(6-fluoro-benzo[b]thiophen-3-yl)-[1,4]diazepan-1-yl]-butyl}-amide.

43. The compound of claim 1 which is (E)-N-{4-[4-(6-fluoro-benzo[b]thiophen-3-yl)-[1,4]diazepan-1-yl]-butyl}-3-phenyl-acrylamide.

44. The compound of claim 1 which is 5-hydroxy-1H-indole-2-carboxylic acid {4-[4-(6-fluoro-benzo[b]thiophen-3-yl)-[1,4]diazepan-1-yl]-butyl}-amide.

45. The compound of claim 1 which is 4-Fluoro-N-{2R-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmenthyl]-1 R-cyclopropylmethyl}-benzenesulfonamide.

46. The compound of claim 1 which is (3-Imidazol-1-yl-propyl)-{(1R,2R)-2-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropylmethyl}-amine.

52. A pharmaceutical composition comprising an effective amount of a compound of claim 1 with a pharmaceutically-acceptable carrier or diluent.

53. A pharmaceutical composition comprising an effective amount of a compound of claim 1 with a pharmaceutically-acceptable carrier or diluent in conjunction with one or more dopamine D₁, D₂, D₄, D₅ or 5HT₃ receptor antagonists.

54. A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1, wherein the compound contains an acylated hydroxy group, or an acylated amino group.

55. The depot pharmaceutical composition of claim 54, wherein the hydroxy group is acylated, or the amino group is acylated with (C₄-C₁₈)alkanoyl group or a (C₄-C₁₈)alkoxycarbonyl group.

56. The composition of claim 54 which contains a pharmaceutically acceptable oil.

57. The composition of claim 56 wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cotton seed oil, corn oil, soybean oil, olive oil, and synthetic esters of fatty acids and polyfunctional alcohols.

58. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 54 sufficient to produce a long acting antipsychotic effect.

59. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 55 sufficient to product a long acting antipsychotic effect.

60. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 56 sufficient to produce a long acting antipsychotic effect.

61. The compound of claim 1 wherein one or more of the atoms contained therein is a radionuclide.

62. A compound according to claim 61 wherein R is group (a), Y is carbonyl;

Q is trifluromethyl, p is 1, R₃ is H, R₄ is H, n is 1, k is 0, A is N, and the carbon atom of R that is bonded to A is the radionuclide ¹⁴C.

63. A diagnostic method for monitoring neuronal functions in a mammal comprising:

(a) introducing into a mammal a radiolabeled compound according to claim 61.

64. The method of claim 63 wherein said diagnostic method is performed using single photon emission computed tomography.

65. A process for preparing a compound of claim 1 which comprises reacting a compound of formula (II):

66. A process for preparing a compound of claim 1 which comprises reacting a compound of formula (IV):

67. A process for preparing a compound of formula (VI)

69. A method of treating renal dysfunction comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1.

70. A compound according to claim 1 wherein R is group (b).

71. A compound according to claim 1 wherein R is group (c).

72. A compound according to claim 1 wherein R is group (d).

73. A compound according to claim 1 wherein R is group (e).

47. A method of modulating the activity of dopamine D₃ receptors, said method comprising:

contacting cell-associated dopamine D₃ receptors with a concentration of a compound of formula IA, or a physiologically acceptable salt thereof, sufficient to modulate the activity of said dopamine D₃ receptor wherein said compound of formula IA has the structure;

48. A method of treating conditions or disorders of the central nervous system comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula IB, or a pharmaceutically acceptable salt thereof wherein said compound of formula IB has the structure:

49. The method of claim 48 wherein the central nervous system disorder is selected from Psychotic Disorders, Substance Dependence, Subsance Abuse, Dyskinetic Disorders, Dementia, Anxiety Disorders, Sleep Disorders, Mood Disorders and Nausea.

50. The method of claim 49 wherein the Psychotic Disorder is Schizophrenia.

51. The method of claim 48 wherein the compound of formula IB or the pharmaceutically acceptable salt thereof, is admininstered in conjunction with one or more dopamine D₁, D₂, D₄, D₅, or 5HT₃ receptor antagonists.

68. A compound of formula