Claims
- 1. A compound of the formula:
- 2. A compound according to claim 1, wherein R2 and R3 together represent —CH═CR8—CH═CH—.
- 3. A compound according to claim 2, wherein R8 is hydrogen or C1-C6 alkyl.
- 4. A compound according to claim 1, wherein Ar is phenyl mono-, di-, or trisubstituted with halogen, trifluoromethyl, hydroxy, amino, cyano, carboxamide, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or amino(C1-C6)alkyl with the proviso that at least one of the ortho positions of Ar is substituted.
- 5. A compound according to claim 4, wherein Ar is phenyl substituted in the 2 and 4 positions with methyl, fluoro or chloro.
- 6. A compound according to claim 3, wherein Ar is 2,4,6-trimethylphenyl.
- 7. A compound according to claim 6, wherein R4 and R5 independently represent hydrogen, C1-C6 alkoxy(C1-C6) alkyl, C3-C7 cycloalkyl, or C1-C6 alkyl.
- 8. A compound according to claim 2, wherein R8 is —NR9R9′.
- 9. A compound according to claim 2, wherein R8 is —(C1-C6 alkyl)—NR9R9′.
- 11. A compound according to claim 8, wherein Ar is 2,4,6-trimethylphenyl.
- 10. A compound according to claim 8, wherein R4 and R5 independently represent hydrogen, C1-C6 alkoxy(C1-C6) alkyl, C3-C7 cycloalkyl, or C1-C6 alkyl.
- 12. A compound according to claim 1, wherein R2 and R3 together represent —(C0-C2)CH2(C2-C4)—.
- 13. A compound according to claim 12, wherein Ar is 2,4,6-trimethylphenyl.
- 14. A compound according to claim 13, wherein R4 and R5 independently represent hydrogen, C1-C6 alkoxy(C1-C6) alkyl, C3-C7 cycloalkyl, or C1-C6 alkyl.
- 15. A compound according to claim 1 which is 4-(N-Cyclopropylmethyl-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole.
- 16. A compound according to claim 1 which is 4-(N,N-Dipropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole.
- 17. A compound according to claim 1 which is 4-(N-Propyl-N-methyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole.
- 18. A compound according to claim 1 which is 4-(N-Cyclopropylmethyl-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole.
- 19. A compound according to claim 1 which 4-(N,N-Dipropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole.
- 20. A compound according to claim 1 which is 4-(N,N-Dipropyl)amino-6-ethylamino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole.
- 21. A compound according to claim 1 which is 4-(N,N-Dipropyl)amino-6-diethylamino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole.
- 22. A compound according to claim 1 which is 4-Bis(2-methoxyethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole.
- 23. A compound according to claim 1 which is 4-(N,N-Dipropyl)amino-2-methyl-9-(4-bromo-2,6-dimethylphenyl)-9H-pyrimidino[4,5-b]indole.
- 24. A compound according to claim 1 which is 4-Bis(2-methoxyethyl)amino-2-methyl-9-(4-bromo-2,6-dimethylphenyl)-9H-pyrimidino[4,5-b]indole.
- 25. A compound according to claim 1 which is 4-(N,N-Dipropyl)amino-2-methyl-9-(4-chloro-2-methylphenyl)-9H-pyrimidino [4,5-b]l indole.
- 26. A compound according to claim 1 which is 4-(N,N-Dipropyl)amino-2-methyl-9-(4-cyano-2,6-dimethylphenyl)-9H-pyrimidino [4,5-b]indole.
- 27. A compound according to claim 1 which is 4-Bis(2-methoxyethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole.
- 28. A compound according to claim 1 which is 4-(N-Cyclopropylmethyl-N-propyl)amino-6-ethylamino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole.
- 29. A compound according to claim 1 which is 4-(N-(2-Hydroxyethyl)-N-Cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole.
- 30. A compound according to claim 1 which is 4-(N-(2-Hydroxyethyl)-N-Cyclopropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole.
- 31. A compound according to claim 1 which is 4-(N,N-Dipropyl)amino-2-methyl-(2,4,6-trimethylphenyl)-5,6,7-trihydrocyclopenta[2,1-d]-8H-pyrimidino[4,5-b]indole
- 32. A compound according to claim 1 which is 4-(N,N-Dipropyl)amino-2-methyl-9-(2,6-dimethylphenyl)-9H-pyrimidino[4,5-b]indole.
- 33. A compound according to claim 1 which is 4-(N,N-Dipropyl)amino-2-methyl-9-(4-aminomethyl-2,6-dimethylphenyl)-9H-pyrimidino[4,5-b]indole.
- 34. A compound according to claim 1 which is 4-(N,N-Dipropyl)amino-2-methyl-9-(2,6-dimethyl-4-(methylaminomethyl)phenyl)-9H-pyrimidino [4,5-b]indole.
- 35. A compound according to claim 1 which is 4-(N-Cyclopropylmethyl-N-propyl)amino-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole.
- 36. A compound according to claim 1 which is 4-(N,N-Dipropyl)amino-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole.
- 37. A compound according to claim 1 which is 4-(N-Butyl-N-methyl)amino-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole.
- 38. A compound according to claim 1 which is 4-(N-Propyl)amino-8-(2,4,6-trimethylphenyl)-5,6,7-trihydrocyclopenta[2,1-d]-8H-pyrimidino[4,5-b]indole.
- 39. A compound according to claim 1 which is 4-(N,N-Dipropyl)amino-8-(2,4,6-trimethylphenyl)-5,6,7-trihydrocyclopenta[2,1-d]-8H-pyrimidino[4,5-b]indole.
- 40. A compound according to claim 1 which is Ethyl 4-(dipropylamino)-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydropyrimidino[4,5-b]indole-2-carboxylate.
- 41. A compound according to claim 1 which is 4-(N,N-Dipropyl)amino-2-carboxyamido-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole.
- 42. A compound according to claim 1 which is 4-(N,N-Dipropyl)amino-2-aminomethyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole.
- 43. A compound according to claim 1 which is 4-(N-Cyclopropylmethylamino)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole.
- 44. 4-(N,N-Dibutylamino)-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole.
- 45. 4-(N,N-Dibutylamino)-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole.
- 46. A compound according to claim 1 which is 4-(N-(2-(4-Chlorophenyl)ethyl)amino)-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole.
- 47. A compound according to claim 1 which is 4-(N-(2-(4-Chlorophenyl)ethyl)amino)-2-methyl-9-(2,4-dimethylphenyl)-5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole.
- 48. A compound according to claim 1 which is 4-(N-(4-Chlorophenyl)methylamino)-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole.
- 49. A compound according to claim 1 which is 4-(N-(2-Methylphenyl)methylamino)-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole.
- 50. A compound according to claim 1 which is 4-(N-(3-Trifluromethylphenyl)methylamino)-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole.
- 51. A compound according to claim 1 which is (N,N-Dipropylamino)-2-methyl-6-dimethylamino-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole.
- 52. A compound according to claim 1, which is 4-(N-Butyl-N-methyl)amino-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole.
- 53. A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable carrier or excipient.
- 54. A process for preparing a compound according to claim 1.
- 55. A packaged pharmaceutical composition comprising the pharmaceutical composition of claim 53 in a container and instructions for using the composition to treat a patient in need thereof.
- 56. The packaged pharmaceutical composition of claim 55, wherein said patient is suffering from stress, posttraumatic stress disorder, anxiety, depression, cardiovascular disease, headache, obesity or an eating disorder.
- 57. A method for localizing CRF receptors in tissue section samples comprising:
contacting with a sample of tissue a detectably-labelled compound of claim 1 under conditions that permit binding of the compound to the sample of tissue; washing the tissue sample to remove unbound compound; and detecting the bound compound.
- 58. A method for the treatment or prevention of physiological disorders associated with excess of or insufficient amount of CRF, which method comprises administration to a patient in need thereof an effect amount of a compound according to claim 1.
- 59. A method of inhibiting the binding of CRF to the CRF1 receptor, which method comprises contacting, in the presence of CRF, a solution comprising a compound of claim 1, with cells expressing the CRF1 receptor, wherein the compound is present in the solution at a concentration sufficient to reduce levels of CRF binding to IMR32 cells in vitro.
- 60. A method for altering the signal-transducing activity of a cell surface CRF1 receptor, said method comprising contacting cells expressing such a receptor with a solution comprising a compound according to claim 1, wherein the compound is present in the solution at a concentration sufficient to reduce levels of CRF binding to IMR32 cells in vitro.
- 61. A compound according to claim 1 wherein in a standard assay of CRF binding the compound exhibits an IC50 of 1 micromolar or less.
- 62. A compound according to claim 1 wherein in a standard assay of CRF binding the compound exhibits an IC50 of 100 nanomolar or less.
- 63. A compound according to claim 1 wherein in a standard assay of CRF binding the compound exhibits an IC50 of 10 nanomolar or less.
- 64. A method for treating stress, posttraumatic stress disorder, anxiety or depression which comprises administering an effective amount of a compound according to claim 1 to a patient in need thereof.
- 65. A method for treating obesity or eating disorders which comprises administering an effective amount of a compound according to claim 1 to a patient in need thereof.
- 66. A method for treating cardiovascular disorders which comprises administering an effective amount of a compound according to claim 1 to a patient in need thereof.
- 67. A method for treating headache which comprises administering an effective amount of a compound according to claim 1 to a patient in need thereof.
Parent Case Info
[0001] This application claims priority from provisional application no. 60/131,719, filed Apr. 30, 1999, which is incorporated herein by reference in its entirety.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60131719 |
Apr 1999 |
US |
Continuations (1)
|
Number |
Date |
Country |
Parent |
09561569 |
Apr 2000 |
US |
Child |
09930734 |
Aug 2001 |
US |