Non-peptidic cyclophilin binding compounds and their use

• US 20030232815A1
• Filed: 06/11/2003
• Published: 12/18/2003
• Est. Priority Date: 09/08/1999
• Status: Abandoned Application

• Current Assignee: Chi Choi, Gregory S. Hamilton, Joseph P. Steiner, Mark Vaal, Wei Ling
• Original Assignee: Chi Choi, Gregory S. Hamilton, Joseph P. Steiner, Mark Vaal, Wei Ling
• Inventors: Choi, Chi, Steiner, Joseph P., Hamilton, Gregory S., Wei, Ling, Vaal, Mark
• Application Number:
  US10/458,677
• Publication Number:
  US 20030232815A1
• Time in Patent Office: Days
• US Class Current: 514/227.8
• CPC Class Codes: A61K 31/17 having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 275/28 having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
• CPC Class Codes: C07C 275/30 being further substituted by halogen atoms, or by nitro or nitroso groups
• CPC Class Codes: C07C 275/40 being further substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 275/42 being further substituted by carboxyl groups
• CPC Class Codes: C07C 311/21 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 323/62 having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton

Abstract

The invention relates to non-peptidic compounds that possess bioactive properties, such as the ability to protect neuronal cells from otherwise lethal treatments or the ability to promote the growth or regeneration of neuronal cells. In part, the invention provides compounds that interact with or bind to a cyclophilin and compounds that have activity towards neuronal cells. Methods for using the compounds, such as administering them to cells or animals or using them to treat neurodegenerative conditions, are specifically included.

Claims

1. A method of using a compound to bind a cyclophilin-type immunophilin protein, comprising contacting the compound with a cyclophilin, wherein the compound has the following formula:

2. The method of claim 1, wherein the compound inhibits cyclophilin rotamase activity with an IC₅₀ of 1 μ

M or less.

3. The method of claim 2, wherein the compound inhibits FKBP rotamase activity with an IC₅₀ of 10 μ

M or more.

4. The method of claim 1, wherein contacting the compound with a cyclophilin occurs in vivo.

5. The method of claim 1, wherein contacting the compound with a cyclophilin occurs within a cell or in a cell culture.

6. The method of claim 1, wherein the cyclophilin protein is a human cyclophilin.

7. The method of claim 1, wherein contacting the compound with a cyclophilin occurs after administering the compound to an animal.

8. The method of claim 7, wherein the animal is a human.

9. The method of claim 8, wherein the human is diagnosed with, is predisposed to, or is suspected of having a neurodegenerative condition, a neuropathic condition, or a peripheral neuropathy.

10. The method of claim 8, wherein the human has Parkinson'"'"'s disease, Alzheimer'"'"'s disease, ALS, memory loss, hair loss, hearing loss, vision loss, stroke, peripheral neuropathy including diabetic neuropathy, mitochondrial disorder, viral infection, traumatic brain injury, or a spinal cord injury.

11. A complex comprising a compound of Formula I of claim 1 and a cyclophilin.

12. The complex of claim 11, wherein the cyclophilin is a human cyclophilin.

13. A composition comprising a compound of Formula I of claim 1, further comprising a pharmaceutically acceptable carrier, diluent, or excipient.

14. A method of using a compound of Formula I of claim 1, comprising administering a pharmaceutically effective amount of the compound to an animal.

15. The method of claim 14, wherein the animal is a human.

16. The method of claim 15, wherein the human is diagnosed with, is predisposed to, or is suspected of having a neurodegenerative condition, a neuropathic condition, or a peripheral neuropathy.

17. The method of claim 15, wherein the human has Parkinson'"'"'s disease, Alzheimer'"'"'s disease, ALS, memory loss, hair loss, hearing loss, vision loss, stroke, peripheral neuropathy including diabetic neuropathy, mitochondrial disorder, viral infection, traumatic brain injury, or a spinal cord injury.

18. A method of preventing a neurodegenerative condition comprising administering to an animal an effective amount of the composition of claim 13.

19. A method of stimulating the growth of or regenerating damaged nerves comprising administering to an animal an effective amount of the composition of claim 13.

20. A method of protecting nerves from damage comprising administering to an animal an effective amount of the composition of claim 13.

21. A method of using a compound to bind a cyclophilin-type immunophilin protein, comprising contacting the compound with a cyclophilin, wherein the compound has the following formula:

22. The method of claim 21, wherein the compound inhibits cyclophilin rotamase activity with an IC₅₀ of 1 μ

M or less.

23. The method of claim 21, wherein each R of R⁴ and R⁵ in said compound of Formula II may independently be

hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q;

where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.

24. The method of claim 23, wherein the compound inhibits cyclophilin rotamase activity with an IC₅₀ of 1 μ

M or less.

25. The method of claim 21, wherein the compound inhibits FKBP rotamase activity with an IC₅₀ of 10 μ

M or more.

26. The method of claim 23, wherein the compound inhibits FKBP rotamase activity with an IC₅₀ of 10 μ

M or more.

27. The method of claim 21, wherein contacting the compound with a cyclophilin occurs in vivo.

28. The method of claim 23, wherein contacting the compound with a cyclophilin occurs in vivo.

29. The method of claim 21, wherein contacting the compound with a cyclophilin occurs within a cell.

30. The method of claim 23, wherein contacting the compound with a cyclophilin occurs within a cell.

31. The method of claim 21, wherein the cyclophilin is a human cyclophilin.

32. The method of claim 23, wherein the cyclophilin is a human cyclophilin.

33. The method of claim 21, wherein contacting the compound with a cyclophilin occurs after administering the compound to an animal.

34. The method of claim 23, wherein contacting the compound with a cyclophilin occurs after administering the compound to an animal.

35. The method of claim 33, wherein the animal is human

36. The method of claim 34, wherein the animal is human.

37. The method of claim 35, wherein the human is diagnosed with, is predisposed to, or is suspected of having a neurodegenerative condition, a neuropathic condition, or a peripheral neuropathy.

38. The method of claim 36, wherein the human is diagnosed with, is predisposed to, or is suspected of having a neurodegenerative condition, a neuropathic condition, or a peripheral neuropathy.

39. The method of claim 35, wherein the human has Parkinson'"'"'s disease, Alzheimer'"'"'s disease, ALS, memory loss, hair loss, hearing loss, vision loss, stroke, peripheral neuropathy including diabetic neuropathy, mitochondrial disorder, viral infection, traumatic brain injury, or a spinal cord injury.

40. The method of claim 36, wherein the human has Parkinson'"'"'s disease, Alzheimer'"'"'s disease, ALS, memory loss, hair loss, hearing loss, vision loss, stroke, peripheral neuropathy including diabetic neuropathy, mitochondrial disorder, viral infection, traumatic brain injury, or a spinal cord injury.

41. A complex comprising a compound of Formula II of claim 21 and a cyclophilin.

42. The complex of claim 41 wherein each R of R⁴ and R⁵ in said compound of Formula II may independently be

hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q;

where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.

43. The complex of claim 41, wherein the cyclophilin is a human cyclophilin.

44. The complex of claim 42, wherein the cyclophilin is a human cyclophilin.

45. A composition comprising a compound of Formula II of claim 21, further comprising a pharmaceutically acceptable carrier, diluent, or excipient.

46. The composition of claim 45, wherein each R of R⁴ and R⁵ in said compound of Formula II may independently be

hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q;

where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.

47. A method of using a compound of Formula II of claim 21, comprising administering a pharmaceutically effective amount of the compound to an animal.

48. The method of claim 47, wherein each R of R⁴ and R⁵ in said compound of Formula II may independently be

hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q;

where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.

49. The method of claim 47, wherein the animal is human.

50. The method of claim 48, wherein the animal is human.

51. The method of claim 49, wherein the human is diagnosed with, is predisposed to, or is suspected of having a neurodegenerative condition, a neuropathic condition, or a peripheral neuropathy.

52. The method of claim 50, wherein the human is diagnosed with, is predisposed to, or is suspected of having a neurodegenerative condition, a neuropathic condition, or a peripheral neuropathy.

53. The method of claim 49, wherein the human has Parkinson'"'"'s disease, Alzheimer'"'"'s disease, ALS, memory loss, hair loss, hearing loss, vision loss, stroke, peripheral neuropathy including diabetic neuropathy, mitochondrial disorder, viral infection, traumatic brain injury, or a spinal cord injury.

54. The method of claim 50, wherein the human has Parkinson'"'"'s disease, Alzheimer'"'"'s disease, ALS, memory loss, hair loss, hearing loss, vision loss, stroke, peripheral neuropathy including diabetic neuropathy, mitochondrial disorder, viral infection, traumatic brain injury, or a spinal cord injury.

55. A method of preventing a neurodegenerative condition comprising administering to an animal an effective amount of the composition of claim 45.

56. A method of preventing a neurodegenerative condition comprising administering to an animal an effective amount of the composition of claim 46.

57. A method of protecting nerves from damage comprising administering to an animal an effective amount of the composition of claim 45.

58. A method of protecting nerves from damage comprising administering to an animal an effective amount of the composition of claim 46.

59. A method of stimulating the growth of or regenerating damaged nerves comprising administering to an animal an effective amount of the composition of claim 45.

60. A method of stimulating the growth of or regenerating damaged nerves comprising administering to an animal an effective amount of the composition of claim 46.

61. A method of identifying a cyclophilin binding compound, comprising selecting one or more R^1-5, X, and Y groups of Formula I or II, selecting a value for n, modifying the remaining R, X, or Y groups, and detecting the capability of one or more of the following:

binding to a CyP;

inhibition of rotamase activity;

in vitro or in vivo neurotrophic, neuroregenerative, or neuroprotectant activity;

cell growth promoting activity on neuronal or nervous system cells;

or promoting neurite extension.

62. A cyclophilin binding compound identified by the method of claim 61.

63. The method of claim 61, wherein each R of R⁴ and R⁵ in said compound of Formula II may independently be

hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q;

where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.

64. A cyclophilin binding compound identified by the method of claim 63.

65. A compound of the following formula

66. A compound of claim 65, wherein the compound inhibits cyclophilin rotamase activity with an IC₅₀ of 1 μ

M or less.

67. A compound claim 66, wherein the compound inhibits FKBP rotamase activity with an IC₅₀ of 10 μ

M or more.

68. A compound of claim 65, wherein X and Y are N or NH.

69. A compound of claim 65, wherein X and Y are O.

70. A compound of claim 65, wherein n is 0.

71. A composition comprising a compound of claim 65 and a pharmaceutically acceptable carrier, diluent, or excipient.

72. A compound of the following formula

73. A compound of claim 72, wherein the compound inhibits cyclophilin rotamase activity with an IC₅₀ of 1 μ

M or less.

74. A compound of claim 73, wherein the compound inhibits FKBP rotamase activity with an IC₅₀ of 10 μ

M or more.

75. A compound of claim 72, wherein n is 0.

76. A composition comprising a compound of claim 72 and a pharmaceutically acceptable carrier, diluent, or excipient.

77. A compound of the following formula

78. A compound of claim 77, wherein the compound inhibits cyclophilin rotamase activity with an IC₅₀ of 1 μ

M or less.

79. A compound of claim 77, wherein the compound inhibits FKBP rotamase activity with an IC₅₀ of 10 μ

M or more.

80. A compound of the following formula

81. A compound of claim 80, wherein the compound inhibits cyclophilin rotamase activity with an IC₅₀ of 1 μ

M or less.

82. A compound of claim 81, wherein the compound inhibits FKBP rotamase activity with an IC₅₀ of 10 μ

M or more.

83. A compound of the following formula:

84. The compound of claim 83, wherein each R of R⁴ and R⁵ may independently be

hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q;

where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.

85. A compound of claim 83, wherein the compound inhibits cyclophilin rotamase activity with an IC₅₀ of 1 μ

M or less.

86. A compound of claim 84, wherein the compound inhibits cyclophilin rotamase activity with an IC₅₀ of 1 μ

M or less.

87. A compound of claim 85, wherein the compound inhibits FKBP rotamase activity with an IC₅₀ of 10 μ

M or more.

88. A compound of claim 86, wherein the compound inhibits FKBP rotamase activity with an IC₅₀ of 10 μ

M or more.

89. A compound of claim 83, wherein either or both of R⁴ and R⁵ is N—

SO₂—

R.

90. The compound of claim 89, wherein each R of R⁴ and R⁵ may independently be hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q;

where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.

91. A compound of claim 83, wherein either or both of R⁴ and R⁵ is O—

R.

92. The compound of claim 91, wherein each R of R⁴ and R⁵ may independently be hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q;

where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.

93. A compound of claim 83, wherein either or both of R⁴ and R⁵ is N—

CO—

R.

94. The compound of claim 93, wherein each R of R⁴ and R⁵ may independently be hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q;

where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.