Hydantoin derivative compounds, pharmace utical compositions, and methods of using same

• US 20020058685A1
• Filed: 12/21/2000
• Published: 05/16/2002
• Est. Priority Date: 12/21/1999
• Status: Active Grant

• Current Assignee: GliaMed, Inc.
• Original Assignee: GPI NIL Holdings Incorporated
• Inventors: Hamilton, Gregory S.
• Granted Patent: US 6,974,823 B2
• Time in Patent Office: Days
• US Class Current: 514/389
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present invention relates generally to novel hydantoin derivative compounds, pharmaceutical compositions containing such compounds, and methods for their use in preventing and/or 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; for treating memory impairment and/or enhancing memory performance; and for treating sensorineural hearing loss by administering such compounds.

Claims

1. A compound of the formula:

2. The compound according to claim 1 that is selected from the group consisting of:

(7aS)-2-(1-Naphthyl)perhydropyrrolo[1,2-c]imidazole-1,3-dione,

(7aS)-2-(2′

-Phenyl)phenylperhydropyrrolo[1,2-c]imidazole-1,3-dione,

(7aS)-2-(4-(Trifluoromethyl)phenyl)perhydropyrrolo [1,2-c]imidazole-1,3-dione,

2-benzyl-3-thioxo-2,5,6,7,7a-pentahydro-2-azapyrrolizin-1-one,

2-hexyl-2,5,6,7,7a-pentahydro-2-azapyrrolizine-1,3-dione,

2-(2-ethyl)phenyl-2,5,6,7,7a-pentahydro-2-azapyrrolizin-1,3-dione,

2-(3-phenylpropyl)-3-thioxo-2,5,6,7,7a-pentahydro-2-azapyrrolizin-l-one, and

2-(2-phenylethyl)-3-thioxo-2,5,6,7,7a-pentahydro-2-azapyrrolizin-1-one.

3. A pharmaceutical composition comprising an effective amount of a compound and a pharmaceutically acceptable carrier, wherein the compound is of the formula:

4. The pharmaceutical composition of claim 3, further comprising an additional neurotrophic factor.

5. The pharmaceutical composition of claim 4, wherein the additional neurotrophic factor 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-⅘

.

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

administering to the animal an effective amount of a compound to stimulate growth of damaged peripheral nerves or to promote neuronal regeneration, wherein the compound is of the formula;

where

each X independently is O, S, or NR₂;

R₂ is selected from the group consisting of cyano, nitro, hydrogen, C₁-C₄ alkyl, hydroxy, and C₁-C₄ alkoxy;

D is a direct bond or C₁-C₈ alkyl or alkenyl;

R is hydrogen, or an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring;

wherein R is optionally substituted with one substituent selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenyl, phenoxy, benzyloxy, and amino;

or a pharmaceutically acceptable salt, ester, or solvate thereof.

7. The method of claim 6, wherein the neurological disorder is selected from the group consisting of peripheral neuropathies caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorders relating to neurodegeneration.

8. The method of claim 6, wherein the neurological disorder is selected from the group consisting of Alzheimer'"'"'s Disease, Parkinson'"'"'s Disease, amyotrophic lateral sclerosis, and Huntington'"'"'s Disease.

9. The method of claim 6, wherein the neurological disorder is Alzheimer'"'"'s Disease.

10. The method of claim 6, wherein the neurological disorder is Parkinson'"'"'s Disease.

11. The method of claim 6, wherein the neurological disorder is amyotrophic lateral sclerosis.

12. The method of claim 6, wherein the neurological disorder is Huntington'"'"'s Disease.

13. The method of claim 6, wherein the compound is non-immunosuppressive.

14. The method of claim 6, further comprising administrating an additional neurotrophic factor.

15. The method of claim 14, wherein the additional neurotrophic factor 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-⅘

.

17. The method of claim 16, wherein the compound is non-immunosuppressive.

18. The method of claim 16, further comprising administrating an additional neurotrophic factor.

19. The method of claim 18, wherein the additional neurotrophic factor 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-⅘

.

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

administering to damaged peripheral nerves an effective amount of a compound to stimulate or promote growth of the damaged peripheral nerves, wherein the compound is of the formula;

where

each X independently is O, S, or NR₂;

R₂ is selected from the group consisting of cyano, nitro, hydrogen, C₁-C₄ alkyl, hydroxy, and C₁-C₄ alkoxy;

D is a direct bond or C₁-C₈ alkyl or alkenyl;

R is hydrogen, or an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring;

wherein R is optionally substituted with one substituent selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenyl, phenoxy, benzyloxy, and amino;

or a pharmaceutically acceptable salt, ester, or solvate thereof.

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

administering to an animal an effective amount of a compound to promote neuronal regeneration, wherein the compound is of the formula;

where

each X independently is O, S, or NR₂;

R₂ is selected from the group consisting of cyano, nitro, hydrogen, C₁-C₄ alkyl, hydroxy, and C₁-C₄ alkoxy;

D is a direct bond or C₁-C₈ alkyl or alkenyl;

R is hydrogen, or an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring;

wherein R is optionally substituted with one substituent selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenyl, phenoxy, benzyloxy, and amino;

or a pharmaceutically acceptable salt, ester, or solvate thereof.

21. The method of claim 20, wherein the compound is non-immunosuppressive.

22. The method of claim 20, further comprising administrating an additional neurotrophic factor.

23. The method of claim 22, wherein the additional neurotrophic factor 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-⅘

.

25. The method of claim 24, wherein the neurodegeneration is Alzheimer'"'"'s Disease.

26. The method of claim 24, wherein the neurodegeneration is Parkinson'"'"'s Disease.

27. The method of claim 24, wherein the neurodegeneration is amyotrophic lateral sclerosis.

28. The method of claim 24, wherein the neurodegeneration is Huntington'"'"'s Disease.

29. The method of claim 24, wherein the compound is non-immunosuppressive.

30. The method of claim 24, further comprising administrating an additional neurotrophic factor.

31. The method of claim 30, wherein the additional neurotrophic factor 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-⅘

.

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

administering to an animal an effective amount of a compound to prevent neurodegeneration, wherein the compound is of the formula;

where

each X independently is O, S, or NR₂;

R₂ is selected from the group consisting of cyano, nitro, hydrogen, C₁-C₄ alkyl, hydroxy, and C₁-C₄ alkoxy;

D is a direct bond or C₁-C₈ alkyl or alkenyl;

R is hydrogen, or an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring;

wherein R is optionally substituted with one substituent selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenyl, phenoxy, benzyloxy, and amino;

or a pharmaceutically acceptable salt, ester, or solvate thereof.

32. A compound of the formula:

33. The compound according to claim 32 that is selected from the group consisting of:

2-Benzyl-2,5,6,7,8,8a-hexahydro-2-azaindolizine-1,3-dione,

2-benzyl-3-thioxo-2,5,6,7,8,8a-hexahydro-2-azaindolizin-1-one,

2-(2-phenylethyl)-3-thioxo-2,5,6,7,8,8a-hexahydro-

2-azaindolizin-1-one, 2-Heptyl-2,5,6,7,8,8a-hexahydro-2-azaindolizine-1,3-dione,

2-Octyl-2,5,6,7,8,8a-hexahydro-2-azaindolizine-1,3-dione,

2-(3-phenylpropyl)-3-thioxo-2,5,6,7,8,8a-hexahydro-2-azaindolizin-1-one,

2-hexyl-2,5,6,7,8,8a-hexahydro-2-azaindolizine-1,3-dione, and

2-Cyclohexyl-2,5,6,7,8,8a-hexahydro-2-azaindolizine-1,3-dione.

35. The pharmaceutical composition of claim 34, further comprising an additional neurotrophic factor.

36. The pharmaceutical composition of claim 35, wherein the additional neurotrophic factor 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-⅘

.

38. The method of claim 37, wherein the neurological disorder is selected from the group consisting of peripheral neuropathies caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorders relating to neurodegeneration.

39. The method of claim 37, wherein the neurological disorder is selected from the group consisting of Alzheimer'"'"'s Disease, Parkinson'"'"'s Disease, amyotrophic lateral sclerosis, and Huntington'"'"'s Disease.

40. The method of claim 37, wherein the neurological disorder is Alzheimer'"'"'s Disease.

41. The method of claim 37, wherein the neurological disorder is Parkinson'"'"'s Disease.

42. The method of claim 37, wherein the neurological disorder is amyotrophic lateral sclerosis.

43. The method of claim 37, wherein the neurological disorder is Huntington'"'"'s Disease.

44. The method of claim 37, wherein the compound is non-immunosuppressive.

45. The method of claim 37, further comprising administrating an additional neurotrophic factor.

46. The method of claim 45, wherein the additional neurotrophic factor 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-⅘

.

48. The method of claim 47, wherein the compound is non-immunosuppressive.

49. The method of claim 47, further comprising administrating an additional neurotrophic factor.

50. The method of claim 49, wherein the additional neurotrophic factor 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-⅘

.

34. A pharmaceutical composition comprising an effective amount of a compound and a pharmaceutically acceptable carrier, wherein the compound is of the formula:

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

administering to the animal an effective amount of a compound to stimulate growth of damaged peripheral nerves or to promote neuronal regeneration, wherein the compound is of the formula;

where

each X independently is O, S, or NR₂;

R₂ is selected from the group consisting of cyano, nitro, hydrogen, C₁-C₄ alkyl, hydroxy, and C₁-C₄ alkoxy;

D is a direct bond or C₁-C₈ alkyl or alkenyl;

R is hydrogen, or an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring;

wherein R is optionally substituted with one substituent selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenyl, phenoxy, benzyloxy, and amino;

or a pharmaceutically acceptable salt, ester, or solvate thereof.

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

administering to damaged peripheral nerves an effective amount of a compound to stimulate or promote growth of the damaged peripheral nerves, wherein the compound is of the formula;

where

each X independently is O, S, or NR₂;

R₂ is selected from the group consisting of cyano, nitro, hydrogen, C₁-C₄ alkyl, hydroxy, and C₁-C₄ alkoxy;

D is a direct bond or C₁-C₈ alkyl or alkenyl;

R is hydrogen, or an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring;

wherein R is optionally substituted with one substituent selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenyl, phenoxy, benzyloxy, and amino;

or a pharmaceutically acceptable salt, ester, or solvate thereof.

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

administering to an animal an effective amount of a compound to promote neuronal regeneration, wherein the compound is of the formula;

where

each X independently is O, S, or NR₂;

R₂ is selected from the group consisting of cyano, nitro, hydrogen, C₁-C₄ alkyl, hydroxy, and C₁-C₄ alkoxy;

D is a direct bond or C₁-C₈ alkyl or alkenyl;

R is hydrogen, or an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring;

wherein R is optionally substituted with one substituent selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenyl, phenoxy, benzyloxy, and amino;

or a pharmaceutically acceptable salt, ester, or solvate thereof.

52. The method of claim 51, wherein the compound is non-immunosuppressive.

53. The method of claim 51, further comprising administrating an additional neurotrophic factor.

54. The method of claim 53, wherein the additional neurotrophic factor 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-⅘

.

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

administering to an animal an effective amount of a compound to prevent neurodegeneration, wherein the compound is of the formula;

where

each X independently is O, S, or NR₂;

R₂ is selected from the group consisting of cyano, nitro, hydrogen, C₁-C₄ alkyl, hydroxy, and C₁-C₄ alkoxy;

D is a direct bond or C₁-C₈, alkyl or alkenyl;

R is hydrogen, or an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring;

wherein R is optionally substituted with one substituent selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenyl, phenoxy, benzyloxy, and amino;

or a pharmaceutically acceptable salt, ester, or solvate thereof.

56. The method of claim 55, wherein the neurodegeneration is Alzheimer'"'"'s Disease.

57. The method of claim 55, wherein the neurodegeneration is Parkinson'"'"'s Disease.

58. The method of claim 55, wherein the neurodegeneration is amyotrophic lateral sclerosis.

59. The method of claim 55, wherein the neurodegeneration is Huntington'"'"'s Disease.

60. The method of claim 55, wherein the compound is non-immunosuppressive.

61. The method of claim 55, further comprising administrating an additional neurotrophic factor.

62. The method of claim 61, wherein the additional neurotrophic factor 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-⅘

.