| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | November 20, 2001 |
| PATENT TITLE |
Heteroaromatic glucokinase activators |
| PATENT ABSTRACT | 2,3-Di-substituted N-heteroaromatic propionamides with said substitution at the 2-position being a substituted phenyl group and at the 3-position being a cycloalkyl ring, said propionamides being glucokinase activators which increase insulin secretion in the treatment of type II diabetes |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | March 15, 2000 |
| PATENT REFERENCES CITED |
Mndzhoyan, A. L. et al., Effect of Organic Acids of Pyridyl and Thiazolylamides on Certain Members of Coli-Typhosal, Staphylococcal, Streptococcal Groups and on Acid-Resistant Mycobacteria, Biol. Svoistva Khim. Soedin., Akad. Nauk Arm. SSR, Inst. Tonkoi O, 1962.* Speilman et al., Journal of American Chemical Society, vol. 70, pp. 4189-4191 (1948). Rodier et al., Acta Crystallogr., C46, pp. 154-156 (1990). Robert et al., Eur. J. Med. Chem., 29, pp. 841-854 (1994). Spickett et al., Eur. J. Med. Chem. -Chimica Therapeutica, 11(1), pp. 7-12 (1976). Bhat et al., J. Inst. Chemists (India), 61, pp. 134-136 (1989). |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A compound selected from the group consisting of an amide of the formula: ##STR139## wherein, the * indicates an asymmetric carbon atom, R.sup.1 and R.sup.2 are independently hydrogen, halo, amino, hydroxyamino, cyano, nitro, lower alkyl, --OR.sup.5, ##STR140## perfluoro-lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl, lower alkyl sulfinyl, or sulfonamido, R.sup.3 is cycloalkyl having from 3 to 7 carbon atoms; R.sup.4 is an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amine group shown, which five- or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur, oxygen or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom; said mono-substituted heteroaromatic ring being monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of lower alkyl, halo, nitro, cyano, --(CH.sub.2).sub.n -OR.sup.6, ##STR141## --(CH.sub.2).sub.n -NHR.sup.6 n is 0, 1, 2, 3 or 4; R.sup.5 is hydrogen, lower alkyl, or perfluoro-lower alkyl and R.sup.6, R.sup.7 and R.sup.8 are independently hydrogen or lower alkyl; and a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein R.sup.3 is cyclopentyl. 3. The compound of claim 2, wherein R.sup.4 is unsubstituted thiazole. 4. The compound of claim 3, wherein the amide is the R configuration at the asymmetric carbon shown. 5. The compound of claim 3, wherein one of R.sup.1 and R.sup.2 is hydrogen, halogen, perfluoro-lower alkyl and the other of said R.sup.1 and R.sup.2 is halo, nitro or perfluoro-lower alkyl. 6. The compound of claim 5, wherein said amide is 2-(3-chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide. 7. The compound of claim 5, wherein said amide is 2-(4-bromo-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide. 8. The compound of claim 5, wherein said amide is 2-(4-chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide. 9. The compound of claim 5, wherein said amide is 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-yl-propionamide. 10. The compound of claim 5, wherein said amide is 3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethyl-phenyl)-propionamide. 11. The compound of claim 5, wherein said amide is 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-thiazol-2-yl-propion amide. 12. The compound of claim 5, wherein said amide is 3-cyclopentyl-2-(4--fluoro-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propio namide. 13. The compound of claim 5, wherein said amide is 3-cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethyl-phenyl)-propionamide. 14. The compound of claim 9, wherein said amide is 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-thiazol-2-yl-propionamide. 15. The compound of claim 5, wherein one of R.sup.1 and R.sup.2 is amino, nitro, halo or hydrogen and the other of said R.sup.1 and R.sup.2 is amino, cyano or nitro. 16. The compound of claim 15, wherein said amide is 3-cyclopentyl-2-(4-nitrophenyl)-N-thiazol-2-yl-propionamide. 17. The compound of claim 15, wherein said amide is 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide. 18. The compound of claim 15, wherein said amide is 2-(3-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide. 19. The compound of claim 15, wherein said amide is 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide. 20. The compound of claim 15, wherein said amide is 2-(4-cyano-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide. 21. The compound of claim 3, wherein one of R.sup.1 and R.sup.2 is lower alkylthio, perfluoro-lower alkyl thio, halo or hydrogen and the other is perfluoro-lower alkylthio, lower alkylsulfinyl or lower alkylthio. 22. The compound of claim 21, wherein said amide is 3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethylsulfanyl-phenyl)-propiona mide. 23. The compound of claim 21, wherein said amide is 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide. 24. The compound of claim 21, wherein said amide is 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl -propionamide. 25. The compound of claim 21, wherein said amide is 3-cyclopentyl-2-(4-methanesulfinyl-phenyl)-N-thiazol-2-yl-propionamide. 26. The compound of claim 3, wherein one of R.sup.1 and R.sup.2 is lower alkyl sulfonyl, hydrogen, nitro, amino, cyano, hydroxylamino, sulfonamido or halo, and the other of said R.sup.1 and R.sup.2 is lower alkyl sulfonyl. 27. The compound of claim 26, wherein said amide is 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide. 28. The compound of claim 26, wherein said amide is 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)N-thiazol-2-yl-propionami de. 29. The compound of claim 26, wherein said amide is 2-(3-amino-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propiona mide. 30. The compound of claim 26, wherein said amide is 3-cyclopentyl-2-(3-hydroxyamino-4-methanesulfonyl-phenyl)-N-thiazol-2-yl-p ropionamide. 31. The compound of claim 26, wherein said amide is 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propiona mide. 32. The compound of claim 26, wherein said amide is 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide. 33. The compound of claim 26, wherein said amide is 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionami de. 34. The compound of claim 26, wherein said amide is 3-cyclopentyl-2-(4-sulfamoyl-phenyl)-N-thiazol-2-yl-propionamide. 35. The compound of claim 26, wherein said amide is 2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide . 36. The compound of claim 26, wherein said amide is 3-cyclopentyl-2-[4-(propane-1-sulfonyl)-phenyl]-N-thiazol-2-yl-propionamid e. 37. The compound of claim 3, wherein one of R.sup.1 and R.sup.2 is lower alkyl sulfonyl, and the other is halo or perfluoro-lower alkyl. 38. The compound of claim 37, wherein said amide is 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-y l-propionamide. 39. The compound of claim 37, wherein said amide is 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-prop ionamide. 40. The compound of claim 37, wherein said amide is 2-[3-chloro-4-methanesulfonyl-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propion amide. 41. The compound of claim 37, wherein said amide is 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propiona mide. 42. The compound of claim 3, wherein one of R.sup.1 and R.sup.2 is perfluoro-lower alkyl sulfonyl or hydrogen and the other is perfluoro-lower alkyl sulfonyl. 43. The compound of claim 42, wherein said amide is 3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propion amide. 44. The compound of claim 42, wherein said amide is 3-cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethanesulfonyl-phenyl)-propion amide. 45. The compound of claim 3, wherein one of R.sup.1 and R.sup.2 is --OR.sup.5, or ##STR142## and the other of said R.sup.1 and R.sup.2 is hydrogen or --OR.sup.5 ; and R.sup.5 is as above. 46. The compound of claim 45, wherein said amide is 3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethoxy-phenyl)-propionamide. 47. The compound of claim 45, wherein said amide is 3-cyclopentyl-2-(3-methoxy-phenyl)-N-thiazol-2-yl-propionamide. 48. The compound of claim 45, wherein said amide is 3-cyclopentyl-2-(3-hydroxy-phenyl)-N-thiazol-2-yl-propionamide. 49. The compound of claim 45, wherein said amide is 3-cyclopentyl-2-(3,4-dimethoxy-phenyl)-N-thiazol-2-yl-propionamide. 50. The compound of claim 45, wherein said amide is 3-cyclopentyl-2-(3,4-dihydroxy-phenyl)-N-thiazol-2-yl-propionamide. 51. The compound of claim 45, wherein said amide is 3-cyclopentyl-2-(4-methoxy-phenyl)-N-thiazol-2-yl-propionamide. 52. The compound of claim 45, wherein said amide is 3-cyclopentyl-2-(4-hydroxy-phenyl)-N-thiazol-2-yl-propionamide. 53. The compound of claim 45, wherein said amide is 4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-benzoic acid methyl ester. 54. The compound of claim 3, wherein one of R.sup.1 and R.sup.2 is --OR.sup.5 and the other is halo. 55. The compound of claim 54, wherein said amide is 3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-N-thiazol-2-yl-propionamide. 56. The compound of claim 54, wherein said amide is 3-cyclopentyl-2-(3-fluoro-4-hydroxy-phenyl)-N-thiazol-2-yl-propionamide. 57. The compound of claim 3, wherein R.sup.4 is a mono-substituted thiazole with said substituent. 58. The compound of claim 57, wherein said substituent is --(CH.sub.2).sub.n -OR.sup.6 and n and R.sup.6 are as above. 59. The compound of claim 58, wherein one of R.sup.1 and R.sup.2 is halo and the other of said R.sup.1 and R.sup.2 is hydrogen or halo. 60. The compound of claim 59, wherein said amide is 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-hydroxymethyl-thiazol-2-yl)-prop ionamide. 61. The compound of claim 59, wherein said amide is 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[4-(2-hydroxyethyl)-thiazol-2-yl]-p ropionamide. 62. The compound of claim 59, wherein said amide is 2-(4-chloro-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-thiazol-2-yl)-propion amide. 63. The compound of claim 59, wherein said amide is 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-hydroxymethyl-thiazol-2-yl)-prop ionamide. 64. The compound of claim 58, wherein one of R.sup.1 and R.sup.2 is lower alkyl sulfonyl, and the other of said R.sup.1 and R.sup.2 is lower alkyl sulfonyl or hydrogen. 65. The compound of claim 64, wherein said amide is 3-cyclopentyl-N-(4-hydroxymethyl-thiazol-2-yl)-2-(4-methanesulfonyl-phenyl )-propionamide. 66. The compound of claim 64 wherein said amide is 3-cyclopentyl-N-[4-(2-hydroxyethyl)-thiazol-2-yl]-2-(4-methanesulfonyl-phe nyl)-propionamide. 67. The compound of claim 57, wherein said substituent is lower alkyl, one of R.sup.1 and R.sup.2 is hydrogen or halogen and the other of said R.sup.1 and R.sup.2 is halogen. 68. The compound of claim 67, wherein said amide is 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-methyl-thiazol-2-yl)-propionamid e. 69. The compound of claim 67, wherein said amide is 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methyl-thiazol-2-yl)-propionamid e. 70. The compound of claim 57, wherein said substituent is ##STR143## wherein n is 0 or 1 and R.sup.7 is hydrogen, or lower alkyl. 71. The compound of claim 70, wherein one of R.sup.1 and R.sup.2 is hydrogen and the other is halo. 72. The compound of claim 71, wherein said amide is {2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester. 73. The compound of claim 71, wherein said amide is {2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-acetic acid methyl ester. 74. The compound of claim 71, wherein said amide is 2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4carboxylic acid methyl ester. 75. The compound of claim 71, wherein said amide is 2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid ethyl ester. 76. The compound of claim 71, wherein said amide is {2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester. 77. The compound of claim 71, wherein said amide is 2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid methyl ester. 78. The compound of claim 71, wherein said amide is 2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid ethyl ester. 79. The compound of claim 71, wherein said amide is {2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-acetic acid methyl ester. 80. The compound of claim 70, wherein R.sup.1 and R.sup.2 are each independently halo. 81. The compound of claim 80, wherein said amide is {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-ace tic acid. 82. The compound of claim 80, wherein said amide is {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-ace tic acid ethyl ester. 83. The compound of claim 80, wherein said amide is 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carboxy lic acid. 84. The compound of claim 80, wherein said amide is 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-4-carboxy lic acid. 85. The compound of claim 80, wherein said amide is {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-ace tic acid methyl ester. 86. The compound of claim 80, wherein said amide is (2R)-2-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-thiazole-4-c arboxylic acid methyl ester. 87. The compound of claim 80, wherein said amide is 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carboxy lic acid methyl ester. 88. The compound of claim 80, wherein said amide is 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carboxy lic acid ethyl ester. 89. The compound of claim 70, wherein one of R.sup.1 or R.sup.2 is nitro, amino or hydrogen and the other of said R.sup.1 and R.sup.2 is nitro or amino. 90. The compound of claim 89, wherein said amide is {2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester. 91. The compound of claim 89, wherein said amide is {2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid methyl ester. 92. The compound of claim 89, wherein said amide is 2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester. 93. The compound of claim 89, wherein said amide is 2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylic acid ethyl ester. 94. The compound of claim 89, wherein said amide is {2-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-acetic acid methyl ester. 95. The compound of claim 89, wherein said amide is 2-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid methyl ester. 96. The compound of claim 70, wherein one of R.sup.1 and R.sup.2 is lower alkyl sulfonyl, perfluoro-lower alkyl, halogen or hydrogen and the other of said R.sup.1 and R.sup.2 is lower alkyl sulfonyl. 97. The compound of claim 96, wherein said amide is {2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-4- carboxylic acid ethyl ester. 98. The compound of claim 96, wherein said amide is {2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-4-y l}-4-acetic acid methyl ester. 99. The compound of claim 96, wherein said amide is {2-[3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionyl amino]-thiazol-4-yl}-acetic acid methyl ester. 100. The compound of claim 96, wherein said amide is 2-[3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionyla mino]-thiazole-4-carboxylic acid methyl ester. 101. The compound of claim 57, wherein said substituent is ##STR144## wherein R.sup.8 is as above. 102. The compound of claim 101, wherein one of R.sup.1 and R.sup.2 are hydrogen and the other of said R.sup.1 and R.sup.2 is nitro or amino. 103. The compound of claim 102, wherein said amide is {2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-oxo-ace tic acid ethyl ester. 104. The compound of claim 101, wherein one of R.sup.1 and R.sup.2 is halo or perfluoro-lower alkyl and the other of said R.sup.1 and R.sup.2 is perfluoro-lower alkyl, halogen or hydrogen. 105. The compound of claim 104, wherein said amide is {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]thiazol-5-yl}-oxo- acetic ethyl ester. 106. The compound of claim 104, wherein said amide is {2-[3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionylamino]-th iazol-4-yl}-oxo-acetic acid ethyl ester. 107. The compound of claim 101, wherein said one of R.sup.1 and R.sup.2 is hydrogen or halogen and the other of said R.sup.1 and R.sup.2 is lower alkyl sulfonyl. 108. The compound of claim 107, wherein said compound is {2-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-th iazol-4-yl}-oxo-acetic acid ethyl ester. 109. The compound of claim 57, wherein said substitutent is nitro. 110. The compound of claim 109, wherein said amide is 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-nitro-thiazol-2-yl)-propionamide . 111. The compound of claim 2, wherein R.sup.4 is unsubstituted pyridine. 112. The compound of claim 111, wherein one of R.sup.1 and R.sup.2 are halo, perfluoro-lower alkyl or hydrogen and the other of said R.sup.1 and R.sup.2 is halo, perfluoro-lower alkyl, amino, cyano or nitro. 113. The compound of claim 112, wherein said amide is 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-pyridin-2-yl-propion amide. 114. The compound of claim 112, wherein said amide is 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-pyridin-2-yl-propionamide. 115. The compound of claim 112, wherein said amide is 3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethyl-phenyl)-2-propionamide. 116. The compound of claim 112, wherein said amide is 3-cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethyl-phenyl)-propionamide. 117. The compound of claim 112, wherein said amide is 2-(3-chloro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide. 118. The compound of claim 112, wherein said amide is 2-(4-amino-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide. 119. The compound of claim 112, wherein said amide is 2-(4-cyano-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide. 120. The compound of claim 112, wherein said amide is 2-(4-chloro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide. 121. The compound of claim 112, wherein said amide is 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide. 122. The compound of claim 112, wherein said amide is 3-cyclopentyl-2-(4-nitro-phenyl)-N-pyridin-2-yl-propionamide. 123. The compound of claim 111, wherein one of R.sup.1 and R.sup.2 is lower alkyl thio, perfluoro-lower alkyl thio or cyano, and the other is hydrogen. 124. The compound of claim 123, wherein said amide is 2-(4-cyano-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide. 125. The compound of claim 123, wherein said amide is 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-pyridin-2-yl-propionamide. 126. The compound of claim 123, wherein said amide is 3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethylsulfanyl-phenyl)-propiona mide. 127. The compound of claim 111, wherein one of R.sup.1 and R.sup.2 is lower alkyl sulfonyl, halo, cyano, nitro or hydrogen and the other is lower alkyl sulfonyl. 128. The compound of claim 127, wherein said amide is 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-pyridin-2-yl-propionam ide. 129. The compound of claim 127, wherein said amide is 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide. 130. The compound of claim 127, wherein said amide is 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propiona mide. 131. The compound of claim 127, wherein said amide is 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl- propionamide. 132. The compound of claim 127, wherein said amide is 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide. 133. The compound of claim 127, wherein said amide is 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionami de. 134. The compound of claim 127, wherein said amide is 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propion amide. 135. The compound of claim 111, wherein one of R.sup.1 and R.sup.2 is perfluoro-lower-alkyl sulfonyl, lower alkyl sulfonyl or hydrogen and the other is perfluoro-lower alkyl sulfonyl, or perfluro-lower alkyl. 136. The compound of claim 135, wherein said amide is 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyridin-2-y l-propionamide. 137. The compound of claim 135, wherein said amide is 3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)propiona mide. 138. The compound of claim 2, wherein R.sup.4 is a pyridine ring mono-substituted with one of said substituents. 139. The compound of claim 138, wherein said substitutent is ##STR145## wherein n and R.sup.7 are as above. 140. The compound of claim 139, wherein R.sup.1 and R.sup.2 are each independently halo. 141. The compound of claim 140, wherein said amide is 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-carboxymethylpyridin)-2-yl-prop ionamide. 142. The compound of claim 140, wherein said amide is 6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid methyl ester. 143. The compound of claim 139, wherein one of R.sup.1 and R.sup.2 is hydrogen and the other is halo, amino, cyano or nitro. 144. The compound of claim 143, wherein said amide is 6-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid. 145. The compound of claim 143, wherein said amide is 6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester. 146. The compound of claim 143, wherein said amide is 6-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester. 147. The compound of claim 143, wherein said amide is 6-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-nicotinic acid methyl ester. 148. The compound of claim 143, wherein said amide is 6-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester. 149. The compound of claim 143, wherein said amide is 6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid. 150. The compound of claim 143, wherein said amide is 6-[2-(4-cyano-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid. 151. The compound of claim 139, wherein one of R.sup.1 and R.sup.2 is perfluoro-lower alkyl sulfonyl, lower alkyl sulfonyl or hydrogen and the other is perfluoro-lower alkyl sulfonyl or lower alkyl sulfonyl. 152. The compound of claim 151, wherein said amide is 6-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-nic otinic acid methyl ester. 153. The compound of claim 151, wherein said amide is 6-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-nic otinic acid. 154. The compound of claim 151, wherein said amide is 6-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-nicotinic acid methyl ester. 155. The compound of claim 138, wherein said substituent is --(CH.sub.2).sub.n -OR.sup.6 wherein n and R.sup.6 are as above. 156. The compound of claim 155, wherein one of R.sup.1 and R.sup.2 are halo and the other is hydrogen or halo. 157. The compound of claim 156, wherein said amide is 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-(5-hydroxymethyl-pyridin-2-yl) propionamide. 158. The compound of claim 156, wherein said amide is 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-hydroxy-pyridin-2-yl)-propionam ide. 159. The compound of claim 156, wherein said amide is 2-(4-chloro-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-propion amide. 160. The compound of claim 155, wherein one of R.sup.1 and R.sup.2 is lower alkyl sulfonyl or hydrogen and the other is lower alkyl sulfonyl. 161. The compound of claim 160, wherein said amide is 3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-2-(4-methanesulfonyl-phenyl )-propionamide. 162. The compound of claim 138, wherein said substituent is halo or perfluoro-lower alkyl. 163. The compound of claim 162, wherein one of R.sup.1 and R.sup.2 is halo or hydrogen and the other is halo. 164. The compound of claim 163, wherein said amide is N-(5-chloro-pyridin-2-yl)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionami de. 165. The compound of claim 163, wherein said amide is 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-brompyridin)-2-yl-propionamide. 166. The compound of claim 163, wherein said amide is 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-(5-trifluoromethyl-pyridin-2-yl )-propionamide. 167. The compound of claim 163, wherein said amide is N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propiona mide. 168. The compound of claim 162, wherein one of R.sup.1 and R.sup.2 is halo, nitro or hydrogen and the other is perfluoro-lower alkyl sulfonyl or lower alkyl sulfonyl. 169. The compound of claim 168, wherein said amide is N-(5-chloro-pyridin-2-yl)-3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phen yl)-propionamide. 170. The compound of claim 168, wherein said amide is N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-trifluoromethanesulfonyl-pheny l)-propionamide. 171. The compound of claim 168, wherein said amide is N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl )-propionamide. 172. The compound of claim 168, wherein said amide is 2-(3-bromo-4-methanesulfonyl-phenyl)-N-(5-bromo-pyridin-2-yl)-3-cyclopenty l-propionamide. 173. The compound of claim 168, wherein said amide is N-(5-bromo-pyridin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopent yl-propionamide. 174. The compound of claim 168, wherein said amide is 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-trifluoromethyl-p yridin-2-yl)-propionamide. 175. The compound of claim 168, wherein said amide is N-(5-chloro-pyridin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopen tyl-propionamide. 176. The compound of claim 138, wherein said substituent is nitro. 177. The compound of claim 176, wherein said amide is 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-nitropyridin)-2-yl-propionamide . 178. The compound of claim 138, wherein said substituent is lower alkyl. 179. The compound of claim 178, wherein one of R.sup.1 and R.sup.2 is halo or hydrogen and the other of said R.sup.1 and R.sup.2 is halo, perfluoro-lower alkyl or perfluoro-lower alkyl sulfonyl. 180. The compound of claim 179, wherein said substituent is 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-methylpyridin)-2-yl-propionamid e. 181. The compound of claim 179, wherein said amide is 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(4-methylpyridin)-2-yl-propionamid e. 182. The compound of claim 179, wherein said amide is 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(6-methylpyridin)-2-yl-propionamid e. 183. The compound of claim 179, wherein said amide is 3-cyclopentyl-N-(5-methyl-pyridin-2-yl)-2-(4-trifluoromethanesulfonyl-phen yl)-propionamide. 184. The compound of claim 179, wherein said amide is 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-(5-methyl-pyridin-2- yl)-propionamide. 185. The compound of claim 138, wherein said substituent is ##STR146## wherein n and R.sup.6 are as above. 186. The compound of claim 185, wherein one of R.sup.1 and R.sup.2 are independently selected from the group consisting of halo or hydrogen and the other of said R.sup.1 and R.sup.2 is halo, or lower alkyl sulfonyl. 187. The compound of claim 186, wherein said amide is 6-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-N-methyl-nicotina mide. 188. The compound of claim 2, wherein R.sup.4 is unsubstituted imidazolyl. 189. The compound of claim 188, wherein one of R.sup.1 and R.sup.2 is selected from the group consisting of halo and hydrogen and the other of said R.sup.1 and R.sup.2 is halo, or lower alkyl sulfonyl. 190. The compound of claim 189, wherein said amide is 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(1H-imidazol-2-yl)-propionamide. 191. The compound of claim 2, wherein R.sup.4 is an isoxazolyl ring. 192. The compound of claim 191, wherein said ring is substituted with a lower alkyl substituent. 193. The compound of claim 192, wherein one of R.sup.1 or R.sup.2 is halo, nitro or perfluoro-lower alkyl, or lower alkyl sulfonyl and the other of said R.sup.1 or R.sup.2 is hydrogen or halo. 194. The compound of claim 193, wherein said amide is 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methyl-isoxazol-3-yl)-propionami de. 195. The compound of claim 2, wherein R.sup.4 is unsubstituted oxazolyl. 196. The compound of claim 195, wherein one of R.sup.1 or R.sup.2 is halo, nitro or perfluoro-lower alkyl or lower alkyl sulfonyl and the other of said R.sup.1 or R.sup.2 is hydrogen or halo. 197. The compound of claim 196, wherein said amide is 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-oxazol-2-yl-propionamide. 198. The compound of claim 2, wherein R.sup.3 is cyclopentyl and R.sup.4 is unsubstituted pyridazinyl ring. 199. The compound of claim 198, wherein one of R.sup.1 or R.sup.2 is halo, nitro or perfluoro-lower alkyl or lower alkyl sulfonyl and the other of said R.sup.1 or R.sup.2 is hydrogen or halo. 200. The compound of claim 199, wherein said amide is 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyridazin-3-yl-propionamide. 201. The compound of claim 2, wherein R.sup.4 is unsubstituted pyrimidinyl. 202. The compound of claim 201, wherein one of R.sup.1 or R.sup.2 is halo, nitro or perfluoro-lower alkyl or lower alkyl sulfonyl and the other is hydrogen or halo. 203. The compound of claim 202, wherein said amide is 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidin-2-yl-propionamide. 204. The compound of claim 202, wherein said amide is 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidin-6-yl-propionamide. 205. The compound of claim 202, wherein said amide is 3-cyclopentyl-2-(4-nitro-phenyl)-N-pyrimidin-4-yl-propionamide. 206. The compound of claim 2, wherein R.sup.4 is an unsubstituted thiadiazolyl ring. 207. The compound of claim 206, wherein one of R.sup.1 or R.sup.2 is halo, nitro or perfluoro-lower alkyl or lower alkyl sulfonyl and the other of said R.sup.1 and R.sup.2 is hydrogen or halo. 208. The compound of claim 207, wherein said amide is 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,3,4]thiadiazol-2-yl-propionamide . 209. The compound of claim 1, wherein R.sup.3 is cyclohexyl. 210. The compound of claim 209, wherein R.sup.4 is unsubstituted thiazolyl. 211. The compound of claim 210, wherein one of R.sup.1 and R.sup.2 is halo, lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl, perfluoro-lower alkyl, and the other of said R.sup.1 and R.sup.2 is halo, perfluoro-lower alkyl or hydrogen. 212. The compound of claim 211, wherein said amide is 2-[4-methanesulfonyl phenyl]-3-cyclohexyl N-thiazol-2-yl-propionamide. 213. The compound of claim 1, wherein R.sup.3 is cycloheptyl. 214. The compound of claim 213, wherein R.sup.4 is unsubstituted thiazolyl. 215. The compound of claim 214, wherein one of R.sup.1 and R.sup.2 is halo, lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl, perfluoro-lower alkyl, and the other of said R.sup.1 and R.sup.2 is halo, perfluoro-lower alkyl or hydrogen. 216. The compound of claim 215, wherein said amide is 2-[4-methanesulfonyl phenyl]-3-cycloheptyl N-thiazol-2-yl-propionamide. |
| PATENT DESCRIPTION |
-------------------------------------------------------------------------------- BACKGROUND OF THE INVENTION Glucokinase (GK) is one of four hexokinases that are found in mammals [Colowick, S. P., in The Enzymes, Vol. 9 (P. Boyer, ed.) Academic Press, New York, N.Y., pages 1-48, 1973]. The hexokinases catalyze the first step in the metabolism of glucose, i.e., the conversion of glucose to glucose-6-phosphate. Glucokinase has a limited cellular distribution, being found principally in pancreatic .beta.-cells and liver parenchymal cells. In addition, GK is a rate-controlling enzyme for glucose metabolism in these two cell types that are known to play critical roles in whole-body glucose homeostasis [Chipkin, S. R., Kelly, K. L., and Ruderman, N. B. in Joslin's Diabetes (C. R. Khan and G. C. Wier, eds.), Lea and Febiger, Philadelphia, Pa., pages 97-115, 1994]. The concentration of glucose at which GK demonstrates half-maximal activity is approximately 8 mM. The other three hexokinases are saturated with glucose at much lower concentrations (<1 mM). Therefore, the flux of glucose through the GK pathway rises as the concentration of glucose in the blood increases from fasting (5 mM) to postprandial (.apprxeq.10-15 mM) levels following a carbohydrate-containing meal [Printz, R. G., Magnuson, M. A., and Granner, D. K. in Ann. Rev. Nutrition Vol. 13 (R. E. Olson, D. M. Bier, and D. B. McCormick, eds.), Annual Review, Inc., Palo Alto, Calif., pages 463-496, 1993]. These findings contributed over a decade ago to the hypothesis that GK functions as a glucose sensor in .beta.-cells and hepatocytes (Meglasson, M. D. and Matschinsky, F. M. Amer. J Physiol. 246, E1-E13, 1984). In recent years, studies in transgenic animals have confirmed that GK does indeed play a critical role in whole-body glucose homeostasis. Animals that do not express GK die within days of birth with severe diabetes while animals overexpressing GK have improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. et al., Cell 83, 69-78, 1995; Ferrie, T., Riu, E., Bosch, F. et al., FASEB J., 10, 1213-1218, 1996). An increase in glucose exposure is coupled through GK in .beta.-cells to increased insulin secretion and in hepatocytes to increased glycogen deposition and perhaps decreased glucose production. The finding that type II maturity-onset diabetes of the young (MODY-2) is caused by loss of function mutations in the GK gene suggests that GK also functions as a glucose sensor in humans (Liang, Y., Kesavan, P., Wang, L. et al., Biochem. J 309, 167-173, 1995). Additional evidence supporting an important role for GK in the regulation of glucose metabolism in humans was provided by the identification of patients that express a mutant form of GK with increased enzymatic activity. These patients exhibit a fasting hypoglycemia associated with an inappropriately elevated level of plasma insulin (Glaser, B., Kesavan, P., Heyman, M. et al., New England J Med. 338, 226-230, 1998). While mutations of the GK gene are not found in the majority of patients with type II diabetes, compounds that activate GK and, thereby, increase the sensitivity of the GK sensor system will still be useful in the treatment of the hyperglycemia characteristic of all type II diabetes. Glucokinase activators will increase the flux of glucose metabolism in .beta.-cells and hepatocytes, which will be coupled to increased insulin secretion. Such agents would be useful for treating type II diabetes. SUMMARY OF THE INVENTION This invention provides a compound, comprising an amide of the formula: ##STR1## wherein R.sup.1 and R.sup.2 are independently hydrogen, halo, amino, hydroxyamino, cyano, nitro, lower alkyl, --OR.sup.5, ##STR2## perfluoro-lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl, lower alkyl sulfinyl, or sulfonamido; R.sup.3 is cycloalkyl having from 3 to 7 carbon atoms; R.sup.4 is an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amine group shown, which five- or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur, oxygen or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom; said mono-substituted heteroaromatic ring being monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of lower alkyl, halo, nitro, cyano, ##STR3## --(CH.sub.2).sub.n --NHR.sup.6 n is 0, 1, 2, 3 or 4; R.sup.5 is hydrogen, lower alkyl, or perfluoro-lower alkyl and R.sup.6, R.sup.7 and R.sup.8 are independently hydrogen or lower alkyl; or a pharmaceutically acceptable salt thereof. The compounds of formula I have been found to activate glucokinase in vitro. Glucokinase activators are useful for increasing insulin secretion in the treatment of type II diabetes. |
| PATENT PHOTOCOPY | Available on request |
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