Carboxylic acids and carboxylic acid isosteres of N-heterocyclic compounds

• US 20030186961A1
• Filed: 08/02/2001
• Published: 10/02/2003
• Est. Priority Date: 06/03/1998
• Status: Active Grant

• Current Assignee: GliaMed, Inc.
• Original Assignee: Guilford Pharmaceuticals Inc. (Eisai Medical Research Incorporated)
• Inventors: Norman, Mark H., Hamilton, Gregory S., Wu, Yong-Qian
• Granted Patent: US 7,153,883 B2
• Time in Patent Office: Days
• US Class Current: 514/215
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4525 containing a five-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/4535 containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• 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 27/00 Drugs for disorders of the senses
• CPC Class Codes: C07D 207/09 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 207/12 Oxygen or sulfur atoms
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/34 with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond

Abstract

This invention relates to novel N-heterocyclic carboxylic acids and carboxylic acid isosteres, their preparation and use for treating neurological disorders including physically damaged nerves and neurodegenerative diseases, for treating alopecia and promoting hair growth, for treating vision disorders and/or improving vision, and for treating memory impairment and/or enhancing memory performance by administering such compounds.

Claims

1. A compound having the formula (I):

2. The compound of claim 1, wherein R₂ is a carbocycle or heterocycle containing any combination of CH₂, O, S, or N in any chemically stable oxidation state, wherein any of the atoms of said ring structure are optionally substituted in one or more positions with R₃.

3. The compound of claim 1, wherein R₂ is selected from the group consisting of:

4. The compound of claim 1, wherein R₂ is selected from the group consisting of:

—

COOH;

—

SO₃H,;

—

SO₂HNR³;

—

PO₂(R³)₂;

—

CN;

—

PO₃(R³)₂;

—

OR³;

—

SR³;

—

NHCOR³;

—

N(R³)₂;

—

CONZ(R³);

—

CONH(O)R³;

—

CONHNHSO₂R³;

—

COHNSO₂R³; and

—

CONR³CN.

5. The compounds, (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-hydroxymethylpyrrolidine;

(2S)-1-(1,2-dioxo-3,3-dimethyl pentyl)-2-pyrrolidinetetrazole;

(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarbonitrile; and

(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-aminocarbonyl piperidine; and

compounds 1-25, 27, 28, 31-33, and 35-136 of Tables I, II, and III.

6. The compound 1-{2-[3-(4-Fluorophenyl)(1,2,4-oxadiazol-5-yl)]pyrrolidinyl}-3,3-di-methylpentane-1,2-dione.

7. The compound 3,3-Dimehyl-1-[2-(3-methyl(1,2,4-oxadiazol-5-yl))pyrrolidinyl]pentane-1,2-dione.

8. A pharmaceutical composition, comprising:

a) an effective amount of an N-heterocyclic carboxylic acid or carboxylic acid isostere; and

b) a pharmaceutically acceptable carrier.

9. The pharmaceutical composition of claim 8, wherein the N-heterocyclic carboxylic acid or carboxylic acid isostere comprises a compound of formula (I):

10. The pharmaceutical composition of claim 9, wherein R₂ is a carbocycle or heterocycle containing any combination of CH₂, O, S, or N in any chemically stable oxidation state, wherein any of the atoms of said ring structure are optionally substituted in one or more positions with R³.

11. The pharmaceutical composition of claim 9, wherein R₂ is selected from the following group:

12. The pharmaceutical composition of claim 9, wherein R₂ is selected from the group consisting of:

—

COOH;

—

SO₃H,;

—

SO₂HNR³;

—

PO₂(R³)₂;

—

CN;

—

PO₃(R³)₂;

—

OR³;

—

SR³;

—

NHCOR³;

—

N(R³)₂;

—

CON(R³)₂;

—

CONH(O)R³;

—

CONHNHSO₂R³;

—

COHNSO₂R³; and

—

CONR³CN.

13. The pharmaceutical composition of claim 9, wherein the N-heterocyclic carboxylic acid or carboxylic acid isostere compound is selected from the group consisting of compounds 1-139.

14. The pharmaceutical composition of claim 8, further comprising a neurotrophic factor different from formula (I)

15. The pharmaceutial composition of claim 14, wherein said neurotrophic factor different from formula (I) is selected from neurotrophic growth factor, brain derived growth factor, glial derived growth factor, cilial neurotrophic factor, insulin growth factor and active truncated derivatives thereof, acidic fibroblast growth factor, basic fibroblast growth factor, platelet-derived growth factors, neurotropin-3 and neurotropin 4/5.

16. A method of treating a neurological disorder in an animal, comprising:

administering to the animal an effective amount of an N-heterocyclic carboxylic acid or carboxylic acid isostere to stimulate growth of damaged peripheral nerves or to promote neuronal regeneration.

17. The method of claim 16, wherein the neurological disorder is selected from the group consisting of peripheral neuropathies cause by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, seroke associated with brain damage, and neurological disorders relating to neurodegeneration.

18. The method of claim 16, wherein the neurological disorder is selected from the group consisting of Alzheimer'"'"'s Disease, Parkinson'"'"'s Disease, amyotrophic lateral sclerosis, and Huntington'"'"'s Disease.

19. The method of claim 16, wherein the neurological disorder is Alzheimer'"'"'s disease.

20. The method of claim 16, wherein the neurological is disorder is Parkinson'"'"'s disease.

21. The method of claim 16, wherein the neurological disorder is aryotrophic lateral sclerosis.

22. The method of claim 16, wherein the neurological disorder is Huntington'"'"'s disease.

23. The method of claim 16, wherein the N-heterocyclic carboxylic acid or carboxylic acid isostere is non-immunosuppressive.

24. The method of claim 16, wherein the N-heterocyclic carboxylic acid or carboxylic acid isostere comprises a compound of formula (I):

25. The method of claim 24, wherein R₂ is a carbocycle or heterocycle containing any combination of CH₂, O, S, or N in any chemically stable oxidation state, wherein any of the atoms of said ring structure are optionally substituted in one or more positions with R³.

26. The method of claim 24, wherein R₂ is selected from the following group:

27. The method of claim 24, wherein R, is selected from the group consisting of:

—

COOH;

—

SO₃H,;

—

SO₂HNR³;

—

PO₂(R³)₂;

—

CN;

—

PO₂(R³)₂;

—

OR³;

—

SR³;

—

NHCOR³;

—

N(R³)₂;

—

CON(R³)₂;

—

CONH(O)R³;

—

CONHNHSO₂R³;

—

COHNSO₂R³; and

—

CONR³CN.

28. The method of claim 16, wherein the N-heterocyclic carboxylic acid or caroboxylic acid isostere compound is selected from the group consisting of compounds 1-139.

29. The method of claim 16, further comprising administering a neurotrophic factor different from formula (I).

30. The method of claim 29, wherein said neurotrophic factor different from formula (I) is selected from the group consisting of neurotrophic growth factor, brain derived growth factor, glial derived growth factor, cilial neurotrophic factor, insulin growth factor and active truncated derivatives thereof, acidic fibroblast growth factor, basic fibroblast growth factor, platelet-derived growth factors, neurotropin-3, and neurotropin 4/5.

31. A method of stimulating growth of damaged peripheral nerves, comprising:

administering to damaged peripheral nerves an effective amount of an N-heterocyclic carboxylic acid or carboxylic acid isostere to stimulate or promote growth of the damaged peripheral nerves.

32. The method of claim 31, wherein the N-heterocyclic carboxylic acid or carboxylic acid isostere is non-immunosuppressive.

33. The method of claim 31, wherein the N-heterocyclic carboxylic acid or carboxylic acid isostere comprises a compound of formula (I):

34. The method of claim 33, wherein R₂ is a carbocycle or heterocycle containing any combination of CH₂, O, S, or N in any chemically stable oxidation state, wherein any of the atoms of said ring structure are optionally substituted in one or more positions with R³.

35. The method of claim 33, wherein R₂ is selected from the following group:

36. The method of claim 33, wherein R₂ is selected from the group consisting of:

—

COOH;

—

SO₃H,;

—

SO₂HN³;

—

PO₂(R³)₂;

—

CN;

—

PO₃(R³)₂;

—

OR³;

—

SR³;

—

NHCOR³;

—

N(R³)₂;

—

CON(R³)₂;

—

CONH(O)R³;

—

CONHNHSO₂R³;

—

COHNSO₂R³; and

—

CONR³CN.

37. The method of claim 31, wherein the N-heterocyclic carboxylic acid or carboxylic acid isostere compound is selected from the group consisting of compounds 1-139.

38. The method of claim 31, further comprising administering a neurotrophic factor different from formula (I)

39. The method of claim 38, wherein said neurotrophic factor different from formula (I) is selected from the group consisting of neurotrophic growth factor, brain derived growth factor, glial derived growth factor, cilial neurotrophic factor, insulin growth factor and active truncated derivatives thereof, acidic fibroblast growth factor, basic fibroblast growth factor, platelet-derived growth factors, neurotropin-3, and neurotropin 4/5.

40. A method for promoting neuronal regeneration and growth in animals, comprising:

administering to an animal an effective amount of a N-heterocyclic carboxylic acid or carboxylic acid isostere to promote neuronal regeneration.

41. The method of claim 40, wherein the N-heterocyclic carboxylic acid or carboxylic acid isostere is non-immunosuppressive.

42. The method of claim 40, wherein the N-heterocyclic carboxylic acid or carboxylic acid isostere comprises a compound of formula (I):

43. The method of claim 42, wherein R₂ is a carbocycle or heterocycle containing any combination of CH₂, O, S, or N in any chemically stable oxidation state, wherein any of the atoms of said ring structure are optionally substituted in one or more positions with R³.

44. The method of claim 42, wherein R₂ is selected from the following group:

45. The method of claim 42, wherein R₂ is selected from the group consisting of:

—

COOH;

—

SO₃H, ;

—

SO₂HNR³;

—

PO₂(R³)₂;

—

CN;

—

PO₃(R³)₂;

—

OR³;

—

SR³;

—

NHCOR³;

—

N(R³)₂;

—

CON(R³)₂;

—

CONH(O)R³;

—

CONHNHSO₂R³;

—

COHNSO₂R³; and

—

CONR³CN.

46. The method of claim 40, wherein the N-heterocyclic carboxylic acid or carboxylic, acid isostere compound is selected from the group consisting of compounds 1-139.

47. The method of claim 40, further comprising administering a neurotrophic factor different from formula (I).

48. The method of claim 47, wherein said neurotrophic factor different from formula (I) is selected from the group consisting of neurotrophic growth factor, brain derived growth factor, glial derived growth factor, cilial neurotrophic factor, insulin growth factor and active truncated derivatives thereof, acidic fibroblast growth factor, basic fibroblast growth factor, platelet-derived growth factors, neurotropin-3, and neurotropin 4/5.

49. A method for preventing neurodegeneration in an animal, comprising:

administering to an animal an effective amount of a N-heterocyclic carboxylic acid or carboxylic acid isostere to prevent neurodegeneration.

50. The method of claim 49, wherein the neurodegeneration is Alzheimer'"'"'s disease.

51. The method of claim 49, wherein the neurodegeneration is Parkinson'"'"'s disease.

52. The method of claim 49, wherein the neurodegeneration is amyotrophic lateral sclerosis.

53. The method of claim 49,wherein the neurodegeneration is Huntington'"'"'s Disease.

54. The method of claim 49, wherein the N-heterocyclic carboxylic acid or carboxylic acid isostere is non-immunosuppressive.

55. The method of claim 49, wherein the N-heterocyclic carboxylic acid or carboxylic acid isostere comprises a compound of formula (I):

56. The method of claim 55, wherein R₂ is a carbocycle or heterocycle containing any combination of CH₂, O, S, or N in any chemically stable oxidation state, wherein any of the atoms of said ring structure are optionally substituted in one or more positions with R³.

57. The method of claim 55, wherein R₂ is selected from the following group:

58. The method of claim 55, wherein R₂ is selected from the group consisting of:

—

COOH;

—

SO₃H,;

—

SO₂HNR³;

—

PO₂(R³)₂;

—

CN;

—

PO₃(R³)₂;

—

OR³;

—

SR³;

—

NHCOR³;

—

N(R³)₂;

—

CON(R³)₂;

—

CONH(O)R³;

—

CONHNHSO₂R³;

—

COHNSO₂R³; and

—

CONR³CN.

59. The method of claim 49, wherein the N-heterocyclic carboxylic acid or carboxylic acid isostere compound is selected from the group consisting of compounds 1-139.

60. The method of claim 49, further comprising administering a neurotrophic factor different from formula (I).

61. The method of claim 60, wherein said neurotrophic factor different from formula (I) is selected from the group consisting of neurotrophic growth factor, brain derived growth factor, glial derived growth factor, cilial neurotrophic factor, insulin growth factor and active truncated derivatives thereof, acidic fibroblast growth factor, basic fibroblast growth factor, platelet-derived growth factors, neurotropin-3, and neurotropin 4/5.

62. A method for treating alopecia or promoting hair growth in an animal, which comprises administering to said animal an effective amount of an N-heterocyclic carboxylic acid or carboxylic acid isostere.

63. The method of claim 62, wherein the N-heterocyclic carboxylic acid or carboxylic acid isostere is non-immunosuppressive.

64. The method of claim 62, wherein the N-heterocyclic carboxylic acid or carboxylic acid isostere is a compound of formula (I):

65. The method of claim 64, wherein R₂ is a carbocycle or heterocycle containing any combination of CH₂, O, S, or N in any chemically stable oxidation state, wherein any of the atoms of said ring structure are optionally substituted in one or more positions with R³.

66. The method of claim 64, wherein R₂ is selected from the following group:

67. The method of claim 64, wherein R₂ is selected from the group consisting of

—

COOH;

—

SO₃H,;

—

SO₂HNR³;

—

PO₂(R³)₂;

—

CN;

—

PO₃(R³)₂;

—

OR³;

—

SR³;

—

NHCOR³;

—

N(R³)₂;

—

CON(R³)₂;

—

CONH(O)R³;

—

CONHNHSO₂R³;

—

COHNSO₂R³; and

—

CONR³CN.

68. The method of claim 62, wherein the carboxylic acid or carboxylic acid isostere is selected from the group consisting of compounds 1-139.

69. A pharmaceutical composition comprising:

(i) an effective amount of a N-heterocyclic carboxylic acid or carboxylic acid isostere for treating alopecia or promoting hair growth in an animal; and

(ii) a pharmaceutically acceptable carrier.

70. The pharmaceutical composition of claim 69, wherein the N-heterocyclic carboxylic acid or carboxylic acid isostere is non-immunosuppressive.

71. The composition of claim 69, wherein the carboxylic acid or carboxylic acid isostere is a compound of formula (I):

72. The composition of claim 71, wherein R₂ is a carbocycle or heterocycle containing any combination of CH₂, O, S, or N in any chemically stable oxidation state, wherein any of the atoms of said ring structure are optionally substituted in one or more positions with R³.

73. The composition of claim 71, wherein R₂ is selected from the following group:

74. The composition of claim 71, wherein R₂ is selected from the group consisting of:

—

COOH;

—

SO₃H,;

—

SO₂HNR³;

—

PO₂(R³)₂;

—

CN;

—

PO₃(R³)₂;

—

OR³;

—

SR³;

—

NHCOR³;

—

N(R³)₂;

—

CON(R³)₂;

—

CONH(O)R³;

—

CONHNHSO₂R³;

—

COHNSO₂R³; and

—

CONR³CN.

75. The composition of claim 69, wherein the carboxylic acid or carboxylic acid isostere is selected from the group consisting of compounds 1-139.

76. A method for treating a vision disorder, improving vision, treating memory impairment, or enhancing memory performance in an animal, which comprises administering to said animal an effective amount of an N-heterocyclic carboxylic acid or carboxylic acid isostere.

77. The method of claim 76, wherein the N-heterocyclic carboxylic acid or carboxylic acid isostere is non-immunosuppressive.

78. The method of claim 76, wherein the N-heterocyclic carboxylic acid or carboxylic acid isostere is a compound of formula (I):

79. The method of claim 78, wherein R₂ is a carbocycle or heterocycle containing any combination of CH₂, O, S, or N in any chemically stable oxidation state, wherein any of the atoms of said ring structure are optionally substituted in one or more positions with R³.

80. The method of claim 78, wherein R₂ is selected from the following group:

81. The method of claim 78, wherein R2 is selected from the group consisting of

—

COOH;

—

SO₃H, ;

—

SO₂HNR³;

—

PO₂(R³)₂;

—

CN;

—

PO₃ (R³)₂;

—

OR³;

—

SR³;

—

NHCOR³;

—

N(R³)₂;

—

CON(R³)₂;

—

CONH(O)R³;

—

CONHNHSO₂R³;

—

COHNSO₂R³; and

—

CONR³CN.

82. The method of claim 76, wherein the carboxylic acid or carboxylic acid isostere is selected from the group consisting of compounds 1-139.