Claims for Patent: 6,872,728

Summary for Patent: 6,872,728

Title:	Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
Abstract:	GnRH receptor antagonists are disclosed which have utility in the treatment of a variety of sex-hormone related conditions in both men and women. The compounds of this invention have the structure: wherein A, Q, R1, R2, R3a, R3b, R4, R5, R6 and n are as defined herein, including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for antagonizing gonadotropin-releasing hormone in a subject in need thereof.
Inventor(s):	Yun-Fei Zhu, Chen Chen, Fabio C. Tucci, Zhiqiang Guo, Timothy D. Gross, Martin Rowbottom, R. Scott Struthers
Assignee:	Neurocrine Biosciences Inc
Application Number:	US10/361,144
Patent Claims:	1. A compound having the following structure: or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: Q is a direct bond; A is O; n is 2, 3 or 4; R1 and R2 are the same or different and independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, —C(R1a)(═NR1b), or —C(NR1aR1c)(═NR1b); or R1 and R2 taken together with the nitrogen atom to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R3a and R3b are the same or different and, at each occurrence, independently hydrogen, alkyl, substituted alkyl, alkoxy, alkylthio, alkylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, —COOR14 or —CONR14R15; or R3a and R3b taken together with the carbon atom to which they are attached form a homocyclic ring, substituted homocyclic ring, heterocyclic ring or substituted heterocyclic ring; or R3a and R3b taken together form ═NR3c; or R3a and the carbon to which it is attached taken together with R1 and the nitrogen to which it is attached form a heterocyclic ring or substituted heterocyclic ring; R4 is aryl, substituted aryl, heteroaryl or substituted heteroaryl; R5 is hydrogen, halogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, alkoxy, alkylthio, alkylamino, cyano or nitro; R6 is higher alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R7 is hydrogen, —SO2R11, cyano, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroalkyl or substituted heteroarylalkyl; and R1a, R1b, R1c, R3c, R11, R12, R13, R14 and R15 are the same or different and, at each occurrence, independently hydrogen, acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl; or R1a and R1b, R12 and R13, or R14 and R15 taken together with the atom or atoms to which they are attached form a homocyclic ring, substituted homocyclic ring, heterocyclic ring or substituted heterocyclic ring; with the provisos that: (a) R1 and R2 is not (1) cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl substituted with phenyl, pyridyl or thienyl, or (2) a 4-, 5-, 6-, or 7-membered nonaromatic heterocyclic ring containing one ring nitrogen atom and 3, 4, 5, or 6 ring carbon atoms substituted with phenyl, pyridyl or thienyl; and (b) when R1 and R2 taken together with the nitrogen atom to which they are attached form a substituted heterocyclic ring, said substituted heterocyclic ring is not (1) a 4-, 5-, 6- or 7-membered nonaromatic heterocyclic ring containing one ring nitrogen atom and 3, 4, 5, or 6 ring carbon atoms substituted with phenyl, pyridyl or thienyl, or (2) piperazin-1-yl substituted at the 4 position with phenyl. 2. The compound of claim 1 wherein R1 is aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl. 3. The compound of claim 2 wherein as applied to R1 heterocycle is heteroaryl, substituted heterocycle is substituted heteroaryl, heterocyclealkyl is heteroarylalkyl, and substituted heterocyclealkyl is substituted heteroarylalkyl. 4. The compound of claim 3 wherein R1 is heteroarylalkyl or substituted heteroarylalkyl. 5. The compound of claim 1 wherein R1 is phenylalkyl or substituted phenylalkyl. 6. The compound of claim 1 wherein R1 is benzyl. 7. The compound of claim 1 wherein R1 is hydrogen or lower alkyl. 8. The compound of claim 1 wherein R2 is hydrogen, alkyl or substituted alkyl. 9. The compound of claim 1 wherein R2 is hydrogen or methyl. 10. The compound of claim 1 wherein R3a and R3b are, at each occurrence, hydrogen. 11. The compound of claim 1 wherein R3a is hydrogen, alkyl, aryl or arylalkyl. 12. The compound of claim 1 wherein R3a is hydrogen, methyl, isobutyl, cyclohexyl, phenyl or benzyl. 13. The compound of claim 1 wherein R3b is, at each occurrence, hydrogen. 14. The compound of claim 1 wherein n is 3. 15. The compound of claim 1 wherein n is 2. 16. The compound of claim 15 wherein —(R3aR3bC)n— has the structure —C(R3a)(R3b)CH2—. 17. The compound of claim 16 wherein R3a is benzyl. 18. The compound of claim 16 wherein R3a is alkyl. 19. The compound of claim 18 wherein R3a is isobutyl or cyclohexyl. 20. The compound of claim 16 wherein R3b is hydrogen or methyl. 21. The compound of claim 1 wherein R4 is substituted aryl or substituted heteroaryl. 22. The compound of claim 1 wherein R4 is substituted phenyl. 23. The compound of claim 22 wherein R4 is phenyl substituted with halogen, alkoxy, or both halogen and alkoxy. 24. The compound of claim 1 wherein R5 is H, lower alkyl or substituted lower alkyl. 25. The compound of claim 1 wherein R5 is hydrogen or methyl. 26. The compound of claim 1 wherein R6 is aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl. 27. The compound of claim 1 wherein R6 is arylalkyl, substituted arylalkyl, heteroarylalkyl or substituted heteroarylalkyl. 28. The compounds of claim 1 wherein R6 is benzyl or substituted benzyl. 29. The compound of claim 1 wherein R6 is benzyl substituted with two halogens. 30. The compound of claim 1 wherein R1 is —CH2(heteroaryl) or —CH2CH2(heteroaryl). 31. The compound of claim 1 wherein R1 and R2 taken together with the nitrogen atom to which they are attached form a heterocyclic ring or substituted heterocyclic ring. 32. The compound of claim 8 wherein R1 is hydrogen. 33. The compound of claim 32 wherein R6 is arylalkyl, substituted arylalkyl, heteroarylalkyl or substituted heteroarylalkyl. 34. The compound of claim 33 wherein R6 is substituted arylalkyl. 35. The compound of claim 34 wherein R6 is substituted benzyl. 36. The compound of claim 35 wherein R4 is substituted aryl. 37. The compound of claim 36 wherein R5 is hydrogen or methyl. 38. The compound of claim 37 wherein n is 2. 39. The compound of claim 38 wherein —(R3aR3bC)n— has the structure —C(R3a)(R3b)CH2—. 40. The compound of claim 39 wherein R3a is hydrogen, alkyl or aryl. 41. The compound of claim 40 wherein R3a is phenyl. 42. The compound of claim 39 wherein R3b is hydrogen. 43. A compound having the following structure: or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: Q is a direct bond; A is O; n is 2, 3 or 4; R1 and R2 are the same or different and independently hydrogen, straight chain or branched alkyl, substituted straight chain or branched alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heterocyclealkyl, substituted heterocyclealkyl, —C(R1a)(═NR1b), or —C(NR1aR1c)(═NR1b); or R1 and R2 taken together with the nitrogen atom to which they are attached form heteroaryl or substituted heteroaryl; R3a and R3b are the same or different and, at each occurrence, independently hydrogen, alkyl, substituted alkyl, alkoxy, alkylthio, alkylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, —COOR14 or —CONR14R15; or R3a and R3b taken together with the carbon atom to which they are attached form a homocyclic ring, substituted homocyclic ring, heterocyclic ring or substituted heterocyclic ring; or R3a and R3b taken together form ═NR3c; or R3a and the carbon to which it is attached taken together with R1 and the nitrogen to which it is attached form a heterocyclic ring or substituted heterocyclic ring; R4 is aryl, substituted aryl, heteroaryl or substituted heteroaryl; R5 is hydrogen, halogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, alkoxy, alkylthio, alkylamino, cyano or nitro; R6 is higher alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R7 is hydrogen, —SO2R11, cyano, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroalkyl or substituted heteroarylalkyl; and R1a, R1b, R1c, R3c, R11, R12, R13, R14 and R15 are the same or different and, at each occurrence, independently hydrogen, acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl; or R1a and R1b, R12 and R13, or R14 and R15 taken together with the atom or atoms to which they are attached form a homocyclic ring, substituted homocyclic ring, heterocyclic ring or substituted heterocyclic ring. 44. The compound of claim 43 wherein, as applied to R1 and R2, the straight chain or branched portion of the alkyl moiety is saturated. 45. The compound of claim 43 wherein, as applied to R1 and R2, the straight chain or branched portion of the alkyl moiety is unsaturated. 46. The compound of claim 43 wherein R1 is aryl or substituted aryl. 47. The compound of claim 43 wherein R1 is hydrogen. 48. The compound of claim 43 wherein R1 is heteroarylalkyl or substituted heteroarylalkyl. 49. The compound of claim 48 wherein R1 is phenylalkyl or substituted phenylalkyl. 50. The compound of claim 49 wherein R1 is benzyl. 51. The compound of claim 43 wherein R1 is hydrogen, straight chain or branched alkyl or substituted straight chain or branched alkyl. 52. The compound of claim 43 wherein R2 is hydrogen, straight chain or branched alkyl or substituted straight chain or branched alkyl. 53. The compound of claim 43 wherein R2 is hydrogen or methyl. 54. The compound of claim 43 wherein R3a and R3b are, at each occurrence, hydrogen. 55. The compound of claim 43 wherein R3a is hydrogen, alkyl, aryl or arylalkyl. 56. The compound of claim 43 wherein R3a is hydrogen, methyl, isobutyl, cyclohexyl, phenyl or benzyl. 57. The compound of claim 43 wherein R3b is, at each occurrence, hydrogen. 58. The compound of claim 43 wherein n is 3. 59. The compound of claim 43 wherein n is 2. 60. The compound of claim 59 wherein —(R3aR3bC)n— has the structure —C(R3a)(R3b)CH2—. 61. The compound of claim 60 wherein R3a is benzyl. 62. The compound of claim 60 wherein R3a is alkyl. 63. The compound of claim 60 wherein R3a is isobutyl or cyclohexyl. 64. The compound of claim 60 wherein R3b is hydrogen or methyl. 65. The compound of claim 43 wherein R4 is substituted aryl or substituted heteroaryl. 66. The compound of claim 43 wherein R4 is substituted phenyl. 67. The compound of claim 43 wherein R4 is phenyl substituted with halogen, alkoxy, or both halogen and alkoxy. 68. The compound of claim 43 wherein R5 is hydrogen, lower alkyl or substituted lower alkyl. 69. The compound of claim 43 wherein R5 is hydrogen or methyl. 70. The compound of claim 43 wherein R6 is aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl. 71. The compound of claim 43 wherein R6 is arylalkyl, substituted arylalkyl, heteroarylalkyl or substituted heteroarylalkyl. 72. The compounds of claim 43 wherein R6 is benzyl or substituted benzyl. 73. The compound of claim 43 wherein R6 is benzyl substituted with two halogens. 74. The compound of claim 43 wherein R1 is —CH2(heteroaryl) or —CH2CH2(heteroaryl). 75. The compound of claim 43 wherein R6 is arylalkyl, substituted arylalkyl, heteroarylalkyl or substituted heteroarylalkyl. 76. The compound of claim 75 wherein R6 is substituted arylalkyl. 77. The compound of claim 76 wherein R6 is substituted benzyl. 78. The compound of claim 77 wherein R4 is substituted aryl. 79. The compound of claim 78 wherein R5 is hydrogen or methyl. 80. The compound of claim 79 wherein n is 2. 81. The compound of claim 80 wherein —(R3aR3bC)n— has the structure —C(R3a)(R3b)CH2—. 82. The compound of claim 81 wherein R3a is hydrogen, alkyl or aryl. 83. The compound of claim 82 wherein R3b is hydrogen. 84. The compound of claim 83 wherein R1 is hydrogen, straight chain or branched alkyl, or substituted straight chain or branched alkyl. 85. The compound of claim 84 wherein R2 is hydrogen. 86. A pharmaceutical composition comprising a compound of any one of claim 1 or 43 and a pharmaceutically acceptable carrier or diluent.