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: ##STR1## wherein A, Q, R.sub.1, R.sub.2, R.sub.3a, R.sub.3b, R.sub.4, R.sub.5, R.sub.6 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):	Zhu; Yun-Fei (San Diego, CA), Chen; Chen (San Diego, CA), Tucci; Fabio C. (San Diego, CA), Guo; Zhiqiang (San Diego, CA), Gross; Timothy D. (San Diego, CA), Rowbottom; Martin (La Jolla, CA), Struthers; R. Scott (Encinitas, CA)
Assignee:	Neurocrine Biosciences, Inc. (San Diego, CA)
Application Number:	10/361,144
Patent Claims:	1. A compound having the following structure: ##STR2976## or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: Q is a direct bond; A is O; n is 2, 3 or 4; R.sub.1 and R.sub.2 are the same or different and independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, --C(R.sub.1a)(.dbd.NR.sub.1b), or --C(NR.sub.1a R.sub.1c)(.dbd.NR.sub.1b); or R.sub.1 and R.sub.2 taken together with the nitrogen atom to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R.sub.3a and R.sub.3b 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, --COOR.sub.14 or --CONR.sub.14 R.sub.15 ; or R.sub.3a and R.sub.3b 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 R.sub.3a and R.sub.3b taken together form .dbd.NR.sub.3c ; or R.sub.3a and the carbon to which it is attached taken together with R.sub.1 and the nitrogen to which it is attached form a heterocyclic ring or substituted heterocyclic ring; R.sub.4 is aryl, substituted aryl, heteroaryl or substituted heteroaryl; R.sub.5 is hydrogen, halogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, alkoxy, alkylthio, alkylamino, cyano or nitro; R.sub.6 is higher alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R.sub.7 is hydrogen, --SO.sub.2 R.sub.11, cyano, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroalkyl or substituted heteroarylalkyl; and R.sub.1a, R.sub.1b, R.sub.1c, R.sub.3c, R.sub.11, R.sub.12, R.sub.13, R.sub.14 and R.sub.15 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 R.sub.1a and R.sub.1b, R.sub.12 and R.sub.13, or R.sub.14 and R.sub.15 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) R.sub.1 and R.sub.2 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 R.sub.1 and R.sub.2 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 R.sub.1 is aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl. 3. The compound of claim 2 wherein as applied to R.sub.1 heterocycle is heteroaryl, substituted heterocycle is substituted heteroaryl, heterocyclealkyl is heteroarylalkyl, and substituted heterocyclealkyl is substituted heteroarylalkyl. 4. The compound of claim 3 wherein R.sub.1 is heteroarylalkyl or substituted heteroarylalkyl. 5. The compound of claim 1 wherein R.sub.1 is phenylalkyl or substituted phenylalkyl. 6. The compound of claim 1 wherein R.sub.1 is benzyl. 7. The compound of claim 1 wherein R.sub.1 is hydrogen or lower alkyl. 8. The compound of claim 1 wherein R.sub.2 is hydrogen, alkyl or substituted alkyl. 9. The compound of claim 1 wherein R.sub.2 is hydrogen or methyl. 10. The compound of claim 1 wherein R.sub.3a and R.sub.3b are, at each occurrence, hydrogen. 11. The compound of claim 1 wherein R.sub.3a is hydrogen, alkyl, aryl or arylalkyl. 12. The compound of claim 1 wherein R.sub.3a is hydrogen, methyl, isobutyl, cyclohexyl, phenyl or benzyl. 13. The compound of claim 1 wherein R.sub.3b 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 --(R.sub.3a R.sub.3b C).sub.n -- has the structure --C(R.sub.3a)(R.sub.3b)CH.sub.2 --. 17. The compound of claim 16 wherein R.sub.3a is benzyl. 18. The compound of claim 16 wherein R.sub.3a is alkyl. 19. The compound of claim 18 wherein R.sub.3a is isobutyl or cyclohexyl. 20. The compound of claim 16 wherein R.sub.3b is hydrogen or methyl. 21. The compound of claim 1 wherein R.sub.4 is substituted aryl or substituted heteroaryl. 22. The compound of claim 1 wherein R.sub.4 is substituted phenyl. 23. The compound of claim 22 wherein R.sub.4 is phenyl substituted with halogen, alkoxy, or both halogen and alkoxy. 24. The compound of claim 1 wherein R.sub.5 is H, lower alkyl or substituted lower alkyl. 25. The compound of claim 1 wherein R.sub.5 is hydrogen or methyl. 26. The compound of claim 1 wherein R.sub.6 is aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl. 27. The compound of claim 1 wherein R.sub.6 is arylalkyl, substituted arylalkyl, heteroarylalkyl or substituted heteroarylalkyl. 28. The compounds of claim 1 wherein R.sub.6 is benzyl or substituted benzyl. 29. The compound of claim 1 wherein R.sub.6 is benzyl substituted with two halogens. 30. The compound of claim 1 wherein R.sub.1 is --CH.sub.2 (heteroaryl) or --CH.sub.2 CH.sub.2 (heteroaryl). 31. The compound of claim 1 wherein R.sub.1 and R.sub.2 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 R.sub.1 is hydrogen. 33. The compound of claim 32 wherein R.sub.6 is arylalkyl, substituted arylalkyl, heteroarylalkyl or substituted heteroarylalkyl. 34. The compound of claim 33 wherein R.sub.6 is substituted arylalkyl. 35. The compound of claim 34 wherein R.sub.6 is substituted benzyl. 36. The compound of claim 35 wherein R.sub.4 is substituted aryl. 37. The compound of claim 36 wherein R.sub.5 is hydrogen or methyl. 38. The compound of claim 37 wherein n is 2. 39. The compound of claim 38 wherein --(R.sub.3a R.sub.3b C).sub.n -- has the structure --C(R.sub.3a)(R.sub.3b)CH.sub.2 --. 40. The compound of claim 39 wherein R.sub.3a is hydrogen, alkyl or aryl. 41. The compound of claim 40 wherein R.sub.3a is phenyl. 42. The compound of claim 39 wherein R.sub.3b is hydrogen. 43. A compound having the following structure: ##STR2977## or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: Q is a direct bond; A is O; n is 2, 3 or 4; R.sub.1 and R.sub.2 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(R.sub.1a)(.dbd.NR.sub.1b), or --C(NR.sub.1a R.sub.1c)(.dbd.NR.sub.1b); or R.sub.1 and R.sub.2 taken together with the nitrogen atom to which they are attached form heteroaryl or substituted heteroaryl; R.sub.3a and R.sub.3b 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, --COOR.sub.14 or --CONR.sub.14 R.sub.15 ; or R.sub.3a and R.sub.3b 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 R.sub.3a and R.sub.3b taken together form .dbd.NR.sub.3c ; or R.sub.3a and the carbon to which it is attached taken together with R.sub.1 and the nitrogen to which it is attached form a heterocyclic ring or substituted heterocyclic ring; R.sub.4 is aryl, substituted aryl, heteroaryl or substituted heteroaryl; R.sub.5 is hydrogen, halogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, alkoxy, alkylthio, alkylamino, cyano or nitro; R.sub.6 is higher alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R.sub.7 is hydrogen, --SO.sub.2 R.sub.11, cyano, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroalkyl or substituted heteroarylalkyl; and R.sub.1a, R.sub.1b, R.sub.1c, R.sub.3c, R.sub.11, R.sub.12, R.sub.13, R.sub.14 and R.sub.15 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 R.sub.1a and R.sub.1b, R.sub.12 and R.sub.13, or R.sub.14 and R.sub.15 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 R.sub.1 and R.sub.2, the straight chain or branched portion of the alkyl moiety is saturated. 45. The compound of claim 43 wherein, as applied to R.sub.1 and R.sub.2, the straight chain or branched portion of the alkyl moiety is unsaturated. 46. The compound of claim 43 wherein R.sub.1 is aryl or substituted aryl. 47. The compound of claim 43 wherein R.sub.1 is hydrogen. 48. The compound of claim 43 wherein R.sub.1 is heteroarylalkyl or substituted heteroarylalkyl. 49. The compound of claim 48 wherein R.sub.1 is phenylalkyl or substituted phenylalkyl. 50. The compound of claim 49 wherein R.sub.1 is benzyl. 51. The compound of claim 43 wherein R.sub.1 is hydrogen, straight chain or branched alkyl or substituted straight chain or branched alkyl. 52. The compound of claim 43 wherein R.sub.2 is hydrogen, straight chain or branched alkyl or substituted straight chain or branched alkyl. 53. The compound of claim 43 wherein R.sub.2 is hydrogen or methyl. 54. The compound of claim 43 wherein R.sub.3a and R.sub.3b are, at each occurrence, hydrogen. 55. The compound of claim 43 wherein R.sub.3a is hydrogen, alkyl, aryl or arylalkyl. 56. The compound of claim 43 wherein R.sub.3a is hydrogen, methyl, isobutyl, cyclohexyl, phenyl or benzyl. 57. The compound of claim 43 wherein R.sub.3b 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 --(R.sub.3a R.sub.3b C).sub.n -- has the structure --C(R.sub.3a)(R.sub.3b)CH.sub.2 --. 61. The compound of claim 60 wherein R.sub.3a is benzyl. 62. The compound of claim 60 wherein R.sub.3a is alkyl. 63. The compound of claim 60 wherein R.sub.3a is isobutyl or cyclohexyl. 64. The compound of claim 60 wherein R.sub.3b is hydrogen or methyl. 65. The compound of claim 43 wherein R.sub.4 is substituted aryl or substituted heteroaryl. 66. The compound of claim 43 wherein R.sub.4 is substituted phenyl. 67. The compound of claim 43 wherein R.sub.4 is phenyl substituted with halogen, alkoxy, or both halogen and alkoxy. 68. The compound of claim 43 wherein R.sub.5 is hydrogen, lower alkyl or substituted lower alkyl. 69. The compound of claim 43 wherein R.sub.5 is hydrogen or methyl. 70. The compound of claim 43 wherein R.sub.6 is aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl. 71. The compound of claim 43 wherein R.sub.6 is arylalkyl, substituted arylalkyl, heteroarylalkyl or substituted heteroarylalkyl. 72. The compounds of claim 43 wherein R.sub.6 is benzyl or substituted benzyl. 73. The compound of claim 43 wherein R.sub.6 is benzyl substituted with two halogens. 74. The compound of claim 43 wherein R.sub.1 is --CH.sub.2 (heteroaryl) or --CH.sub.2 CH.sub.2 (heteroaryl). 75. The compound of claim 43 wherein R.sub.6 is arylalkyl, substituted arylalkyl, heteroarylalkyl or substituted heteroarylalkyl. 76. The compound of claim 75 wherein R.sub.6 is substituted arylalkyl. 77. The compound of claim 76 wherein R.sub.6 is substituted benzyl. 78. The compound of claim 77 wherein R.sub.4 is substituted aryl. 79. The compound of claim 78 wherein R.sub.5 is hydrogen or methyl. 80. The compound of claim 79 wherein n is 2. 81. The compound of claim 80 wherein --(R.sub.3a R.sub.3b C).sub.n -- has the structure --C(R.sub.3a)(R.sub.3b)CH.sub.2 --. 82. The compound of claim 81 wherein R.sub.3a is hydrogen, alkyl or aryl. 83. The compound of claim 82 wherein R.sub.3b is hydrogen. 84. The compound of claim 83 wherein R.sub.1 is hydrogen, straight chain or branched alkyl, or substituted straight chain or branched alkyl. 85. The compound of claim 84 wherein R.sub.2 is hydrogen. 86. A pharmaceutical composition comprising a compound of any one of claim 1 or 43 and a pharmaceutically acceptable carrier or diluent.