IP Library › Granted Patent US 6,838,484
Granted Patent B2
US 6,838,484 · App. 10/270,232 · Granted Jan 4, 2005

Formulations comprising selective androgen receptor modulators

Assignee: University of Tennessee Research Foundation
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Quick Facts
Patent No.
US 6,838,484
App. No.
10/270,232
Granted
Jan 4, 2005
Kind
B2
Abstract

The present invention relates to pharmaceutical compositions and formulations comprising a novel class of androgen receptor targeting agents (ARTA) which demonstrate androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor. The agents define a new subclass of compounds which are selective androgen receptor modulators (SARM) which are useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia,osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and/or prevention of chronic muscular wasting; and/or e) decreasing the incidence of, halting or causing a regression of prostate cancer. The present invention provides pharmaceutical compositions comprising the selective androgen receptor modulator compounds, together with pharmaceutically acceptable excipients.

Claims (120)

1. A pharmaceutical composition comprising:

a selective androgen receptor modulator (SARM) compound having in-vivo androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor, said compound represented by the structure of formula I:

wherein

X is O, CH 2 , NH, Se, PR, NO or NR;

T is OH, OR, —NHCOCH 3 , or NHCOR;

Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;

Y is CF 3 , F, I, Br, Cl, CN, CR 3 or SnR 3 ;

Q is alkyl, halogen, CF 3 , CN CR 3 , SnR 3 , NR 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH; and

R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;

and a pharmaceutically acceptable carrier or diluent.

2. The composition according to claim 1 , comprising an analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, N-oxide, hydrate or any combination thereof of the compound of formula I.

3. The composition according to claim 1 , wherein X is O.

4. The composition according to claim 1 , wherein Z is NO 2 .

5. The composition according to claim 1 , wherein Z is CN.

6. The composition according to claim 1 , wherein Y is CF 3 .

7. The composition according to claim 1 , wherein Q is NHCOCH 3 .

8. The composition according to claim 1 , wherein Q is F.

9. The composition according to claim 1 , wherein T is OH.

10. The composition according to claim 1 , wherein R 1 is CH 3 .

11. The composition according to claim 1 , wherein Q is in the para position.

12. The composition according to claim 1 , wherein Z is in the para position.

13. The composition according to claim 1 , wherein Y is in the meta position.

14. The composition according to claim 1 , wherein said selective androgen receptor modulator compound is represented by the structure of formula II:

15. The composition according to claim 1 , wherein said selective androgen receptor modulator compound is represented by the structure of formula III:

16. The composition according to claim 1 , wherein said selective androgen receptor modulator compound is represented by the structure of formula IV:

17. The composition according to claim 1 , wherein said carrier or diluent is a gum, a starch, a sugar, a cellulosic material, an acrylate, calcium carbonate, magnesium oxide, talc, or mixtures thereof.

18. The composition according to claim 1 , wherein said carrier or diluent is lactose monohydrate, microcrystalline cellulose, or a mixture thereof.

19. The composition according to claim 1 , further comprising a lubricant.

20. The composition of claim 19 , wherein said lubricant is magnesium stearate.

21. The composition according to claim 1 , further comprising a flow-aid.

22. The composition according to claim 21 , wherein said flow aid is colloidal silicon dioxide.

23. The composition according to claim 1 , further comprising one or more additives selected from a binder, a disintegrant, a buffer, a protease inhibitor, a surfactant, a solubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, a viscosity increasing agent, a sweetner, a film forming agent, or any combination thereof.

24. The composition according to claim 1 , wherein said composition is in the form of a pellet, a tablet, a capsule, a solution, a suspension, a dispersion, an emulsion, an elixir, a gel, an ointment, a cream, a powder or a suppository.

25. The composition according to claim 1 , wherein said composition is in the form of a capsule.

26. The composition according to claim 1 , wherein said composition is in a form suitable for oral, intravenous, intraarterial, intramuscular, subcutaneous, parenteral, transmucosal, transdermal, intravaginal or topical administration.

27. The composition according to claim 1 , wherein said composition is in a form suitable for oral administration.

28. The composition according to claim 1 , wherein said composition is a controlled release composition.

29. The composition according to claim 1 , wherein said composition is an immediate release composition.

30. The composition according to claim 1 , wherein said composition is a liquid dosage form.

31. The composition according to claim 1 , wherein said composition is a solid dosage form.

32. A pharmaceutical composition comprising:

a selective androgen receptor modulator (SARM) compound having in-vivo androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor, said compound represented by the structure of formula I:

wherein

X is O, CH 2 , NH, Se, PR, NO or NR;

T is OH, OR, —NHCOCH 3 , or NHCOR;

Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;

Y is CF 3 , F, I, Br, Cl, CN, CR 3 or SnR 3 ;

Q is alkyl, halogen, CF 3 , CN CR 3 , SnR 3 , NR 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH; and

R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;

a pharmaceutically acceptable carrier or diluent;

a flow-aid; and

a lubricant.

33. The composition according to claim 32 , comprising an analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, N-oxide, hydrate or any combination thereof of the compound of formula I.

34. The composition according to claim 32 , wherein X is O.

35. The composition according to claim 32 , wherein Z is NO 2 .

36. The composition according to claim 32 , wherein Z is CN.

37. The composition according to claim 32 , wherein Y is CF 3 .

38. The composition according to claim 32 , wherein Q is NHCOCH 3 .

39. The composition according to claim 32 , wherein Q is F.

40. The composition according to claim 32 , wherein T is OH.

41. The composition according to claim 32 , wherein R 1 is CH 3 .

42. The composition according to claim 32 , wherein Q is in the para position.

43. The composition according to claim 32 , wherein Z is in the para position.

44. The composition according to claim 32 , wherein Y is in the meta position.

45. The composition according to claim 32 , wherein said selective androgen receptor modulator compound is represented by the structure of formula II:

46. The composition according to claim 32 , wherein said selective androgen receptor modulator compound is represented by the structure of formula III:

47. The composition according to claim 32 , wherein said selective androgen receptor modulator compound is represented by the structure of formula IV:

48. The composition according to claim 32 , wherein said carrier or diluent is a gum, a starch, a sugar, a cellulosic material, an acrylate, calcium carbonate, magnesium oxide, talc, or mixtures thereof.

49. The composition according to claim 32 , wherein said carrier or diluent is lactose monohydrate, microcrystalline cellulose, or a mixture thereof.

50. The composition of claim 32 , wherein said lubricant is magnesium stearate.

51. The composition according to claim 32 , wherein said flow aid is colloidal silicon dioxide.

52. The composition according to claim 32 , further comprising one or more additives selected from a binder, a disintegrant, a buffer, a protease inhibitor, a surfactant, a solubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, a viscosity increasing agent, a sweetner, a film forming agent, or any combination thereof.

53. The composition according to claim 32 , wherein said composition is in the form of a pellet, a tablet, a capsule, a solution, a suspension, a dispersion, an emulsion, an elixir, a gel, an ointment, a cream, a powder or a suppository.

54. The composition according to claim 32 , wherein said composition is in the form of a capsule.

55. The composition according to claim 32 , wherein said composition is in a form suitable for oral, intravenous, intraarterial, intramuscular, subcutaneous, parenteral, transmucosal, transdermal, intravaginal or topical administration.

56. The composition according to claim 32 , wherein said composition is in a form suitable for oral administration.

57. The composition according to claim 32 , wherein said composition is a controlled release composition.

58. The composition according to claim 32 , wherein said composition is an immediate release composition.

59. The composition according to claim 32 , wherein said composition is a liquid dosage form.

60. The composition according to claim 32 , wherein said composition is a solid dosage form.

61. A pharmaceutical composition comprising:

a selective androgen receptor modulator (SARM) compound having in-vivo androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor, said compound represented by the structure of formula I:

wherein

X is O, CH 2 , NH, Se, PR, NO or NR;

T is OH, OR, —NHCOCH 3 , or NHCOR;

Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;

Y is CF 3 , F, I, Br, Cl, CN, CR 3 or SnR 3 ;

Q is alkyl, halogen, CF 3 , CN CR 3 , SnR 3 , NR 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH; and

R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;

lactose monohydrate;

microcrystalline cellulose;

magnesium stearate; and

silicon dioxide.

62. The composition according to claim 61 , comprising an analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, N-oxide, hydrate or any combination thereof of the compound of formula I.

63. The composition according to claim 61 , wherein X is O.

64. The composition according to claim 61 , wherein Z is NO 2 .

65. The composition according to claim 61 , wherein Z is CN.

66. The composition according to claim 61 , wherein Y is CF 3 .

67. The composition according to claim 61 , wherein Q is NHCOCH 3 .

68. The composition according to claim 61 , wherein Q is F.

69. The composition according to claim 61 , wherein T is OH.

70. The composition according to claim 61 , wherein R 1 is CH 3 .

71. The composition according to claim 61 , wherein Q is in the para position.

72. The composition according to claim 61 , wherein Z is in the para position.

73. The composition according to claim 61 , wherein Y is in the meta position.

74. The composition according to claim 32 , wherein said selective androgen receptor modulator compound is represented by the structure of formula II:

75. The composition according to claim 61 , wherein said selective androgen receptor modulator compound is represented by the structure of formula III:

76. The composition according to claim 61 , wherein said selective androgen receptor modulator compound is represented by the structure of formula IV:

77. The composition according to claim 61 , further comprising one or more additives selected from a binder, a disintegrant, a buffer, a protease inhibitor, a surfactant, a solubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, a viscosity increasing agent, a sweetner, a film forming agent, or any combination thereof.

78. The composition according to claim 61 , wherein said composition is in the form of a pellet, a tablet, a capsule, a solution, a suspension, a dispersion, an emulsion, an elixir, a gel, an ointment, a cream, a powder or a suppository.

79. The composition according to claim 61 , wherein said composition is in the form of a capsule.

80. The composition according to claim 61 , wherein said composition is in a form suitable for oral, intravenous, intraarterial, intramuscular, subcutaneous, parenteral, transmucosal, transdermal, intravaginal or topical administration.

81. The composition according to claim 61 , wherein said composition is in a form suitable for oral administration.

82. The composition according to claim 61 , wherein said composition is a controlled release composition.

83. The composition according to claim 61 , wherein said composition is an immediate release composition.

84. The composition according to claim 61 , wherein said composition is a liquid dosage form.

85. The composition according to claim 32 , wherein said composition is a solid dosage form.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 2, 2003
From: YIN, DONGHUA; HE, YALI; STEINER, MITCHELL S.; DALTON, JAMES T.; VERVERKA, KAREN A.; MILLER, DUANE D.
To: UNIVERSITY OF TENNESSEE RESEARCH FOUNDATION, THE
Reel/Frame 014453/0132 →
Continuity (5)
Continuation In Part 0993504400 · Aug 23, 2001
Continuation In Part 0993504500 · Aug 23, 2001
Provisional Application 6036735500 · Aug 24, 2000
Provisional Application 6030008300 · Jun 25, 2001
Related Publication 20030162761A1 · Aug 28, 2003