Claims
- 1. A compound of the formula
- 2. A compound according to claim 1 wherein R1 is hydrogen; R2 is phenyl unsubstituted or substituted by halogen or lower alkyl; R3 and n are as defined above.
- 3. A compound according to claim 2 wherein R2 is p-tolyl and n is 3.
- 4. A compound according to claim 3 wherein R3 is N(R′)—C(O)—R4, or a 5- or 6-membered heteroaryl ring containing from 1 to 4 N or O heteroatoms, said ring being unsubstituted or substituted by lower alkyl or cycloalkyl, and R4 is as defined above.
- 5. The compound of claim 4, which is (RS)-N-{3-[1-(Toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-acetamide.
- 6. The compound of claim 4, which is (RS)-Cyclopropanecarboxylic acid {3-[1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-amide.
- 7. The compound of claim 4, which is (RS)-1-{3-[1-(Toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-[1,2,4]triazole.
- 8. A compound according to claim 1 wherein R1 is phenyl or halo substituted phenyl and R2 is phenyl, or halo substituted phenyl or lower alkyl substituted phenyl.
- 9. A compound according to claim 1 having the structure
- 10. A compound according to claim 9 wherein R3 is —OR′, N-hydroxy-amidino, —C(O)NR′R″ or —N(R′)—C(O)—R4; R5 is halogen and n is 2 or 3.
- 11. The compound of claim 10, which is (2RS,5SR)-N-{2-[1-(4-Chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-ethyl}-acetamide.
- 12. The compound of claim 10, which is (2RS,5SR)-Cyclopropanecarboxylic acid {2-[1-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-ethyl}-amide.
- 13. The compound of claim 10, which is (2RS,5SR)-3-[1-(4-Chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-propionamide.
- 14. The compound of claim 10, which is (2RS,5RS)-N-{3-[1-(4-Chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-propyl}-acetamide.
- 15. The compound of claim 10, which is (2RS,5SR)-3-[1-(4-Chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-propan-1-ol.
- 16. The compound of claim 10, which is (2RS,5SR)-5-{2-[1-(4-Chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-ethyl}-2-methyl-2H-tetrazole.
- 17. A compound according to claim 9 wherein R3 is OR′, R5 is ethyl, R′ is as defined above and n is 1.
- 18. The compound of claim 17, which is (2RS,5SR)-[1-(4-Ethyl-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-methanol.
- 19. A compound according to claim 9 having the structure
- 20. A compound according to claim 19 wherein R3 is an unsubstituted 5-membered heteroaryl ring containing 1 to 4 from N or O heteroatoms.
- 21. A compound according to claim 20 wherein said unsubstituted 5-membered heteroaryl ring contains from 1 to 4 nitrogen atoms and n is 0, 1 or 2.
- 22. The compound of claim 21, which is (2RS,5SR)-1-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-imidazole.
- 23. The compound of claim 21, which is (2RS,5SR)-1-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-pyrazole.
- 24. The compound of claim 21, which is (2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-2H-tetrazole.
- 25. The compound of claim 21, which is (2RS,5SR)-1-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-tetrazole.
- 26. The compound of claim 21, which is (2RS,5SR)-1-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-[1,2,4]triazole.
- 27. A compound according to claim 20 wherein said heteroaryl ring includes at least one oxygen atom and n is 0, 1 or 2.
- 28. The compound of claim 27, which is (2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-[1,2,4]oxadiazole.
- 29. The compound of claim 27, which is (2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-5-methyl-[1,3,4]oxadiazole.
- 30. The compound of claim 27, which is (2RS,5SR)-5-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-oxazole.
- 31. The compound of claim 27, which is (2RS,5SR)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-ylmethyl]-oxazole.
- 32. The compound of claim 27, which is (2RS,5SR)-2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-[1,3,4]oxadiazole.
- 33. A compound according to claim 20 wherein said unsubstituted 5-membered heteroaryl ring contains from 1 to 4 nitrogen atoms and n is 3, 4 or 5.
- 34. The compound of claim 33, which is (2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-[1,2,4]triazole.
- 35. The compound of claim 33, which is (2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-imidazole.
- 36. The compound of claim 33, which is (2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-pyrazole.
- 37. The compound of claim 33, which is (2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-2H-tetrazole.
- 38. The compound of claim 33, which is (2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-tetrazole.
- 39. The compound of claim 33, which is (2RS,5RS)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-pyrazole.
- 40. The compound of claim 33, which is (2RS,5RS)-2-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-2H-tetrazole.
- 41. The compound of claim 33, which is (2RS,5RS)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-tetrazole.
- 42. The compound of claim 33, which is (2RS,5RS)-1-{5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentyl}-1H-imidazole.
- 43. The compound of claim 33, which is (2RS,5RS)-1-{5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentyl}-1H-[1,2,4]triazole.
- 44. The compound of claim 33, which is (2RS,5RS)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-imidazole.
- 45. The compound of claim 33, which is (2RS,5RS)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene 4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-[1,2,4]triazole.
- 46. A compound according to claim 19 wherein R3 is a substituted 5-membered heteroaryl ring containing from 1 to 4 N or O heteroatoms.
- 47. A compound according to claim 46 wherein said substituted 5-membered heteroaryl ring contains from 1 to 4 nitrogen atoms and n is 0, 1 or 2.
- 48. The compound of claim 47, which is (2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-1-methyl-1H-[1,2,4]triazole.
- 49. The compound of claim 47, which is (2RS,5SR)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-2-methyl-2H-tetrazole.
- 50. The compound of claim 47, which is (2RS,5SR)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-2-methyl-2H-tetrazole.
- 51. The compound of claim 47, which is (2RS,5SR)-5-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-2-methyl-2H-tetrazole.
- 52. The compound of claim 47, which is (2RS,5SR)-5-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1-methyl-1H-[1,2,4]triazole.
- 53. The compound of claim 47, which is (2RS,5SR)-3-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1-methyl-1H-[1,2,4]triazole.
- 54. The compound of claim 47, which is (2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-ylmethyl]-1-methyl-1H-[1,2,4]triazole.
- 55. The compound of claim 47, which is (2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-5-methyl-2H-tetrazole.
- 56. The compound of claim 47, which is (2RS,5SR)-1-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-5-methyl-1H-tetrazole.
- 57. The compound of claim 47, which is (2RS,5SR)-1-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-4-methyl-1H-imidazole.
- 58. The compound of claim 47, which is (2RS,5SR)-1-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-2-methyl-1H-imidazole.
- 59. A compound according to claim 46 wherein said substituted 5-membered heteroaryl ring contains from 1 to 4 nitrogen atoms and n is 3, 4 or 5.
- 60. The compound of claim 59, which is (2RS,5RS)-5-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-2-methyl-2H-tetrazole.
- 61. The compound of claim 59, which is (2RS,5RS)-5-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1-methyl-1H-tetrazole.
- 62. The compound of claim 59, which is (2RS,5RS)-5-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1-methyl-1H-tetrazole.
- 63. The compound of claim 59, which is (2RS,5RS)-5-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1-methyl-1H-[1,2,4]triazole.
- 64. The compound of claim 59, which is (2RS,5RS)-3-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1-methyl-1H-[1,2,4]triazole.
- 65. The compound of claim 59, which is (2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-4-methyl-1H-imidazole.
- 66. The compound of claim 59, which is (2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-2-methyl-1H-imidazole.
- 67. The compound of claim 59, which is (2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-5-methyl-2H-tetrazole.
- 68. The compound of claim 59, which is (2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-5-methyl-1H-tetrazole.
- 69. The compound of claim 59, which is (2RS,5RS)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-4-methyl-1H-imidazole.
- 70. The compound of claim 59, which is (2RS,5RS)-2-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-5-methyl-2H-tetrazole.
- 71. The compound of claim 59, which is (2RS,5RS)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-5-methyl-1H-tetrazole.
- 72. A compound according to claim 19 wherein R3 is a substituted 5-membered heteroaryl ring containing from 1 to 4 N or O heteroatoms and containing at least one N atom and at least one O atom.
- 73. A compound according to claim 72 wherein n is 0, 1 or 2.
- 74. The compound of claim 73, which is (2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-5-methyl-[1,2,4]oxadiazole.
- 75. The compound of claim 73, which is (2RS,5SR)-5-Phenyl-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid amide.
- 76. The compound of claim 73, which is (2RS,5SR)-5-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-3-methyl-[1,2,4]oxadiazole.
- 77. The compound of claim 73, which is (2RS,5SR)-5-Cyclopropyl-3-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-[1,2,4]oxadiazole.
- 78. The compound of claim 73, which is (2RS,5SR)-3-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-5-methyl-[1,2,4]oxadiazole.
- 79. The compound of claim 73, which is (2RS,5SR)-3-Cyclopropyl-5-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-[1,2,4]oxadiazole.
- 80. The compound of claim 73, which is (2RS,5SR)-3-Cyclopropyl-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-ylmethyl]-[1,2,4]oxadiazole.
- 81. The compound of claim 73, which is (2RS,5SR)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-ylmethyl]-3-methyl-[1,2,4]oxadiazole.
- 82. The compound of claim 73, which is (2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-5-methyl-[1,3,4]oxadiazole.
- 83. The compound of claim 73, which is (2RS,5SR)-2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-5-methyl-[1,3,4]oxadiazole.
- 84. A compound according to claim 72 wherein n is 3, 4 or 5.
- 85. The compound of claim 84, which is (2RS,5RS)-5-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-3-methyl-[1,2,4]oxadiazole.
- 86. The compound of claim 84, which is (2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-5-methyl-[1,3,4]oxadiazole.
- 87. A compound according to claim 19 wherein R3 is an unsubstituted 5-membered heteroaryl ring containing from 1 to 4 N or O heteroatoms and containing at least one N atom and one O atom and wherein n is 3, 4 or 5.
- 88. The compound of claim 87, which is (2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-[1,3,4]oxadiazole.
- 89. A compound according to claim 19 wherein R3 is —C(O)—OR.
- 90. The compound of claim 89, which is (2RS,5SR)-5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester.
- 91. A compound according to claim 19 wherein R3 is —OR′.
- 92. The compound of claim 91, which is (2RS,5SR)-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methanol.
- 93. The compound of claim 91, which is (2RS,5SR)-2-(4-Fluoro-phenyl)-5-methoxymethyl-1-(toluene-4-sulfonyl)-pyrrolidine.
- 94. The compound of claim 91, which is (2RS,5RS)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propan-1-ol.
- 95. The compound of claim 91, which is (2RS,5SR)-2-(4-Fluoro-phenyl)-5-(2-methoxy-ethyl)-1-(toluene-4-sulfonyl)-pyrrolidine.
- 96. The compound of claim 91, which is (2RS,5RS)-2-(4-Fluoro-phenyl)-5-(3-methoxy-propyl)-1-(toluene-4-sulfonyl)-pyrrolidine.
- 97. The compound of claim 91, which is (2RS,5SR)-2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethanol.
- 98. The compound of claim 91, which is (2RS,5RS)-2-(4-Fluoro-phenyl)-5-(4-methoxy-butyl)-1-(toluene-4-sulfonyl)-pyrrolidine.
- 99. The compound of claim 91, which is (2RS,5RS)-2-(4-Ethoxy-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine.
- 100. The compound of claim 91, which is (2RS,5RS)-4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butan-1-ol.
- 101. The compound of claim 91, which is (2RS,5RS)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentan-1-ol.
- 102. A compound according to claim 19 wherein R3 is —C(O)NR′R″.
- 103. The compound of claim 102, which is (2RS,5SR)-5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid amide.
- 104. The compound of claim 102, which is (2RS,5SR)-5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (pyridin-3-yl-methyl)-amide hydrochloride.
- 105. The compound of claim 102, which is (2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionamide.
- 106. The compound of claim 102, which is (2RS,5RS)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentanoic acid amide.
- 107. The compound of claim 102, which is (2RS,5RS)-4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyramide.
- 108. A compound according to claim 19 wherein R3 is N-hydroxy-amidino.
- 109. The compound of claim 108, which is (2RS,5SR)-5-(4-Fluoro-phenyl)-N-hydroxy-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxamidine.
- 110. The compound of claim 108, which is (2RS,5SR)-2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-acetamidine.
- 111. The compound of claim 108, which is (2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-propionamidine.
- 112. The compound of claim 108, which is (2RS,5RS)-4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-butyramidine.
- 113. The compound of claim 108, which is (2RS,5RS)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-pentanamidine.
- 114. A compound according to claim 19 wherein R3 is —N(R′)—C(O)—R4.
- 115. The compound of claim 114, which is (2RS,5SR)-N-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-propionamide.
- 116. The compound of claim 114, which is (2RS,5SR)-Cyclopropanecarboxylic acid [5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-amide.
- 117. The compound of claim 114, which is (2SR,5SR)-N-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-acetamide.
- 118. The compound of claim 114, which is (2SR,5SR)-Cyclopropanecarboxylic acid {3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-amide.
- 119. The compound of claim 114, which is (2RS,5RS)-N-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-propionamide.
- 120. The compound of claim 114, which is (2RS,5RS)-N-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-2,2-dimethyl-propionamide.
- 121. The compound of claim 114, which is (2RS,5RS)-Cyclopentanecarboxylic acid {3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-amide.
- 122. The compound of claim 114, which is (2RS,5RS)-N-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-acetamide.
- 123. The compound of claim 114, which is (2RS,5RS)-Cyclopropanecarboxylic acid {4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-amide.
- 124. The compound of claim 114, which is (2RS,5RS)-N-{5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentyl}-acetamide.
- 125. The compound of claim 114, which is (2RS,5RS)-N-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-benzamide.
- 126. The compound of claim 114, which is (2RS,5RS)-2,2,2-Trifluoro-N-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-acetamide.
- 127. The compound of claim 114, which is (2RS,5RS)-N-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-isobutyramide.
- 128. The compound of claim 114, which is (2RS,5SR)-N-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-acetamide.
- 129. A compound according to claim 19 wherein R3 is —C(O)—OR.
- 130. The compound of claim 129, which is (2RS,5SR)-5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester.
- 131. A compound according to claim 19 wherein R3 is —N(R′)—C(S)—NR′R″ and R′ and R′″ are as defined above.
- 132. The compound of claim 131, which is (2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-3-methyl-thiourea.
- 133. A compound according to claim 19 wherein R3 is an unsubstituted 6-membered heteroaryl ring containing 2 nitrogen atoms.
- 134. The compound of claim 133, which is (2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-pyrimidine.
- 135. The compound of claim 133, which is (2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-pyrimidine.
- 136. A compound according to claim 19 wherein R3 is a substituted 6-membered heteroaryl ring containing 2 nitrogen atoms.
- 137. The compound of claim 136, which is (2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-4,6-dimethyl-pyrimidine.
- 138. The compound of claim 136, which is (2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-4,6-dimethyl-pyrimidine.
- 139. A compound according to claim 9 wherein R3 is a dihydro derivative of a 5- or 6-membered heteroaryl ring containing from 1 to 4 N or O heteroatoms, which are unsubsituted or substituted by lower alkyl or cycloalkyl; and n is an integer from 0 to 5.
- 140. The compound of claim 139, which is 3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-5-methyl-4,5-dihydro-[1,2,4]oxadiazole.
- 141. A compound according to claim 1 having the structure
- 142. A compound according to claim 141 wherein R3 is —N(R′)—C(O)—R4, R4 and R′ are as defined above, and n is 0, 1 or 2.
- 143. The compound of claim 142, which is (2RS,5SR)-N-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-propionamide.
- 144. The compound of claim 142, which is (2RS,5SR)-N-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-benzamide.
- 145. The compound of claim 142, which is (2RS,5SR)-Cyclopropanecarboxylic acid {2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-amide.
- 146. The compound of claim 142, which is (2RS,5SR)-N-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-acetamide.
- 147. The compound of claim 142, which is (2RS,5SR)-Cyclopentanecarboxylic acid [5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-amide.
- 148. The compound of claim 142, which is (2RS,5SR)-N-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-2,2-dimethyl-propionamide.
- 149. The compound of claim 142, which is (2R,5S)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionamide.
- 150. A compound according to claim 141 wherein R3 is —N(R′)—C(O)—R4; wherein R4 and R′ are as defined above; and wherein n is 3, 4 or 5.
- 151. The compound of claim 150, which is (2S,5S)-N-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-acetamide.
- 152. The compound of claim 150, which is (2S,5S)-Cyclopropane-carboxylic acid {3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-amide.
- 153. A compound according to claim 151 wherein R3 is —C(O)NR′R″ and R′ and R″ are as defined above.
- 154. The compound of claim 153, which is (2RS,5SR)-5-Phenyl-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid amide.
- 155. The compound of claim 153, which is (2R,5S)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionamide.
- 156. A compound according to claim 141 wherein R3 is a 5- or 6-membered heteroaryl ring containing from 1 to 4 N or O heteroatoms, said ring being unsubstituted or substituted by lower alkyl or cycloalkyl.
- 157. A compound according to claim 156 wherein R3 is a substituted 5-membered heteroaryl ring and n is 0, 1 or 2.
- 158. The compound of claim 157, which is (2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-5-methyl-[1,2,4]oxadiazole.
- 159. The compound of claim 157, which is (2RS,5SR)-5-Cyclopropyl-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-[1,2,4]oxadiazole.
- 160. The compound of claim 157, which is (2R,5S)-5-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-2-methyl-2H-tetrazole.
- 161. The compound of claim 157, which is (2R,5S)-5-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1-methyl-1H-tetrazole.
- 162. The compound of claim 157, which is (2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-11-methyl-1H-imidazole.
- 163. The compound of claim 157, which is (2R,5S)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1-methyl-1H-imidazole.
- 164. A compound according to claim 156 wherein R3 is a substituted 5-membered heteroaryl ring and n is 3, 4 or 5.
- 165. The compound of claim 164, which is (2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1-methyl-1H-imidazole.
- 166. The compound of claim 164, which is (2S,5S)-5-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1-methyl-1H-[1,2,4]triazole.
- 167. The compound of claim 164, which is (2S,5R)-3-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1-methyl-1H-[1,2,4]triazole.
- 168. A compound according to claim 156 wherein R3 is an unsubstituted 5-membered heteroaryl ring and n is 0, 1 or 2.
- 169. The compound of claim 168, which is (2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-[1,2,4]oxadiazole.
- 170. The compound of claim 168, which is (2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-imidazole.
- 171. The compound of claim 168, which is (2R,5S)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-imidazole.
- 172. The compound of claim 168, which is (2R,5S)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-[1,3,4]oxadiazole.
- 173. A compound according to claim 156 wherein R3 is an unsubstituted 5-membered heteroaryl ring and n is 3, 4 or 5.
- 174. The compound of claim 173, which is (2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-imidazole.
- 175. The compound of claim 173, which is (2R,5S)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-[1,2,4]triazole.
- 176. The compound of claim 173, which is (2S,5S)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-imidazole.
- 177. The compound of claim 173, which is (2S,5S)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-pyrazole.
- 178. The compound of claim 173, which is (2S,5S)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-imidazole.
- 179. The compound of claim 173, which is (2S,5S)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-[1,2,4]triazole.
- 180. A compound according to claim 141 wherein R3 is —OR′, R′ is as defined above, and n is 0, 1 or 2.
- 181. The compound of claim 180, which is (2R,5S)-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methanol.
- 182. The compound of claim 180, which is (2RS,5SR)-2-(2-Ethoxy-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine.
- 183. The compound of claim 180, which is (2RS,5SR)-2-(2-Cyclopropylmethoxy-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine.
- 184. A compound according to claim 141 wherein R3 is —OR′, R′ is as defined above, and n is 3, 4 or 5.
- 185. The compound of claim 184, which is (2S,5S)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propan-1-ol.
- 186. The compound of claim 184, which is (2R,5S)-2-(4-Fluoro-phenyl)-5-(3-methoxy-propyl)-1-(toluene-4-sulfonyl)-pyrrolidine.
- 187. The compound of claim 184, which is (2S,5S)-4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butan-1-ol.
- 188. The compound of claim 184, which is (2S,5S)-2-(4-Fluoro-phenyl)-5-(4-methoxy-butyl)-1-(toluene-4-sulfonyl)-pyrrolidine.
- 189. A method of treating a person having a disease state treatable by modulation of the metabotropic glutamate receptor comprising administering, to a person in need of such treatment, an effective amount of a compound of the formula
- 190. A method of treatment according to claim 189, further comprising administering a medicament which comprises an effective amount of the compound of formula I in a suitable pharmaceutical vehicle for the control or prevention of acute and/or chronic neurological disorders selected from the group consisting of restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest, hypoglycaemia, Alzheimer's disease, Huntington's chorea, ALS, dementia caused by AIDS, eye injuries, retinopathy, cognitive disorders, memory deficits, acute and chronic pain, schizophrenia, idiopathic parkinsonism or parkinsonism caused by medicaments, and conditions which lead to glutamate deficiency functions.
- 191. A method of treatment according to claim 190 wherein the acute and/or chronic neurological disorder is selected from the group consisting of muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, dyskinesia and depression.
- 192. A method of treatment according to claim 190, further comprising administering to the patient in need of treatment a sufficient amount of said medicament to modulate the metabotropic glutamate receptors mGluR1 and mGluR5, thereby treating the disease state in the patient.
- 193. A medicament comprising a compound of formula I or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient.
- 194. A process for the manufacture of a compound of formula I or a pharmaceutically acceptable salt thereof, which process comprises
reacting a compound of the formula 20with a compound of formula 21to obtain a compound of formula 22or, converting a functional group of R3 in a compound of formula I into another functional group, or, converting a compound of formula I into a pharmaceutically acceptable salt.
- 195. The compound according to claim 1 having the following formula
- 196. A compound according to claim 1 having the following formula
- 197. A compound according to claim 1 having the following formula
- 198. A compound according to claim 1 having the following formula
- 199. A compound according to claim 1 having the following formula
- 200. A compound according to claim 1 having the following formula
- 201. A compound according to claim 1 wherein R3 is imidazole, pyrazole, [1.2.4]triazole, [1.2.4]oxadiazole, tetrazole, [1.3.4]oxadiazole or oxazole.
- 202. A compound according to claim 1 wherein R3 is —N(R′)—C(O)—R4.
Priority Claims (1)
Number |
Date |
Country |
Kind |
00113894.0 |
Jun 2000 |
EP |
|
Parent Case Info
[0001] This application is a divisional of U.S. patent application Ser. No. 09/880,539, filed Jun. 13, 2001.
Divisions (1)
|
Number |
Date |
Country |
Parent |
09880539 |
Jun 2001 |
US |
Child |
10397908 |
Mar 2003 |
US |