| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | March 4, 2003 |
| PATENT TITLE |
Urea derivatives |
| PATENT ABSTRACT | Glucokinase activating compounds of the formula ##STR1## wherein R.sup.1 and R.sup.2 are independently hydrogen, halo, amino, nitro, cyano, sulfonamido, lower alkyl, perfluoro-lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl, or perfluoro-lower alkyl sulfonyl; R.sup.3 is cycloalkyl having from 3 to 7 carbon atoms or lower alkyl having from 2 to 4 carbon atoms; R.sup.4 is hydrogen, lower alkyl, lower alkenyl, hydroxy lower alkyl, halo lower alkyl, ##STR2## R.sup.5 and R.sup.6 are hydrogen or lower alkyl; and n is 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | March 21, 2000 |
| PATENT REFERENCES CITED |
Speilman et al., Journal of American Chemical Society, vol. 70, pps. 4189-4191 (1948). Ribalta et al., Arzneim.-Forsch, 31(10A), p. 1782-1786 (1981). Spickett et al., Eur. J. Med. Chem.--Chim. Ther., 11(1), p. 7-12 (1976). Ruettinger et al., Biochimica et Biophysica Acta, 801, p. 372-380 (1984). M. Rautio, Farm. Aikak, 84(4), p. 143-153 (1975). Jimenez et al., J. Indian Chem. Soc., 65, p. 725-728 (1988). Selvi et al., Tetrahedron Lett., 38, p. 6263-6266 (1997). Kitagawa et al., Kuromatogurafi, 15, p. 17-20 (1994). Chemical Abstract for B2 (1981) 95:1329162. Abstract for B1 (1978) WPI (Derwent) Acc. No. 1980-09606C/198006 |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A compound comprising an amide of the formula ##STR54## wherein R.sup.1 and R.sup.2 are independently hydrogen, halo, amino, nitro, cyano, sulfonamido, lower alkyl, perfluoro-lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl, or perfluoro-lower alkyl sulfonyl; R.sup.3 is cycloallyl having from 3 to 7 carbon atoms; R.sup.4 is hydrogen, lower allyl, lower alkenyl, hydroxy lower alkyl halo lower alkyl; ##STR55## R.sup.5 and R.sup.6 are hydrogen or lower alkyl; and n is 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein the amide is in the "R" configuration at the asymmetric carbon shown. 3. The compound of claim 1 wherein R.sup.4 is hydrogen, lower alkyl, or lower alkenyl. 4. The compound of claim 3 wherein R.sup.3 is cyclopentyl. 5. The compound of claim 4, wherein R.sup.1 and R.sup.2 are hydrogen. 6. The compound of claim 5, wherein said amide is 1-(3-cyclopentyl-2-phenyl propionyl)-3-methyl-urea. 7. The compound of claim 4, wherein one of R.sup.1 and R.sup.2 is hydrogen and the other is cyano or halo. 8. The compound of claim 7, wherein said amide is 1-[2-(3-chloro-phenyl)-3cyclopentyl-propionyl]-3-methyl-urea. 9. The compound of claim 7, wherein said amide is 1-[2-(4-chloro-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea. 10. The compound of claim 7, wherein said amide is 1-[2-(4-cyano-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea. 11. The compound of claim 7, wherein said amide is 1-[2-(4-bromo-phenyl)-3-cyclopentyl-propionyl]-3-methyl urea. 12. The compound of claim 4, wherein R.sup.1 and R.sup.2 are each independently halo. 13. The compound of claim 12, wherein said amide is [3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-urea. 14. The compound of claim 12, wherein said amide is 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-methyl-urea. 15. The compound of claim 12, wherein said amide is 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-3-ethyl-urea. 16. The compound of claim 12, wherein said amide is 1-allyl-3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl]-urea. 17. The compound of claim 12, wherein said amide is 1-allyl-3-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-proprionyl]-urea. 18. The compound of claim 12, wherein said amide is 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-ethyl-urea. 19. The compound of claim 12, wherein said amide is 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-3-methyl-urea. 20. The compound of claim 12, wherein said amide is 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-isopropyl-urea. 21. The compound of claim 12, wherein said amide is 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-propyl-urea. 22. The compound of claim 12, wherein said amide is 1-[3-cyclopentyl-2-(3,4-difluoro-phenyl)-propionyl]-3-methyl-urea. 23. The compound of claim 4, wherein one of R.sub.1 and R.sup.2 is hydrogen or halo and the other is nitro. 24. The compound of claim 23 wherein said amide is 1-[2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-proprionyl]-3-methyl-urea. 25. The compound of claim 23, wherein said amide is 1-[3-cyclopentyl-2-(4-nitro-phenyl)-propionyl]-3-methyl-urea. 26. The compound of claim 4, wherein one of R.sup.1 and R.sup.2 is hydrogen, lower alkyl thio or perfluoro-lower alkyl thio and the other is lower alkyl thio or perfluoro-lower alkyl thio. 27. The compound of claim 26, wherein said amide is 1-[3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)-propionyl]-3-methyl urea. 28. The compound of claim 26, wherein said amide is 1-[3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-propionyl]-3-methyl urea. 29. The compound of claim 4, wherein one of R.sup.1 and R.sup.2 is hydrogen or perfluoro-lower alkyl sulfonyl and the other is perfluoro-lower alkyl sulfonyl. 30. The compound of claim 29, wherein said amide is 1-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionyl]-3-methyl urea. 31. The compound of claim 29, wherein said amide is 1-[3-cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionyl]-3-methyl urea. 32. The compound of claim 4 wherein at least one of R.sup.1 and R.sup.2 is lower alkyl sulfonyl. 33. The compound of claim 32 wherein one of R.sup.1 and R.sup.2 is hydrogen or lower alkyl sulfonyl and the other is lower alkyl sulfonyl. 34. The compound of claim 33 wherein R.sup.2 is lower alkyl sulfonyl. 35. The compound of claim 34, wherein said amide is 1-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionyl]-3-methyl urea. 36. The compound of claim 34 wherein said amide is 1-{2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-proprionyl}-3-methyl-ure a. 37. The compound of claim 34 wherein said amide is 1-[3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-proprionyl]-3-methyl-urea. 38. The compound of claim 34 wherein said amide is 1-[2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-methyl-u rea. 39. The compound of claim 32 wherein one of R.sup.1 and R.sup.2 is cyano or halo and the other is lower alkyl sulfonyl. 40. The compound of claim 39 wherein R.sup.2 is lower alkyl sulfonyl. 41. The compound of claim 40, wherein said amide is 1-[2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-methyl -urea. 42. The compound of claim 40, wherein said amide is 1-[3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-proprionyl]-3-methy l-urea. 43. The compound of claim 40, wherein said amide is 1-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-methy l-urea. 44. The compound of claim 40, wherein said amide is 1-[2(R)-(3-chloro4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-met hyl-urea. 45. The compound of claim 40, wherein said amide is 1-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-ethyl -urea. 46. The compound of claim 40, wherein said amide is 1-[2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-methyl -urea. 47. The compound of claim 32, wherein one of R.sup.1 and R.sup.2 is perfluoro-lower alkyl and the other is lower alkyl sulfonyl. 48. The compound of claim 47 wherein R.sup.2 is lower alkyl sulfonyl. 49. The compound of claim 48, wherein said amide is 1-[3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-proprionyl ]-3-methyl-urea. 50. The compound of claim 4, wherein one of R.sup.1 and R.sup.2 is perfluoro-lower alkyl and the other is halo. 51. The compound of claim 50 wherein said amide is 1-[3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionyl]-3-methyl urea. 52. The compound of claim 50 wherein said amide is 1-[3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionyl]-3-methyl urea. 53. The compound of claim 32, wherein one of R.sup.1 and R.sup.2 is nitro and the other is lower alkyl sulfonyl. 54. The compound of claim 53, wherein said amide is 1-[3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionyl]-3-methyl-u rea. 55. The compound of claim 3 wherein one of R.sup.1 and R.sup.2 is halo or hydrogen and the other is hydrogen. 56. The compound of claim 55 wherein said amide is [2-(4-chloro-phenyl)-4-methyl-pentanoyl]-urea. 57. The compound of claim 55 wherein R.sup.1 and R.sup.2 are each chlorine. 58. The compound of claim 57, wherein said amide is [3-cyclopropyl-2-(3,4-dichloro-phenyl)-propionyl]-urea. 59. The compound of claim 57, wherein said amide is [3-cyclobutyl-2-(3,4-dichloro-phenyl)-propionyl]-urea. 60. The compound of claim 57 wherein said amide is R-[2-(3,4-dichloro-phenyl)-4-methyl-pentanoyl]-urea. 61. The compound of claim 57, wherein said amide is 1-[2-(3,4-dichloro-phenyl)-4-methyl-pentanoyl]-3-methyl-urea. 62. The compound of claim 57, wherein said amide is 1-[2-(3,4-dichloro-phenyl)-hexanoyl]-3-methyl-urea. 63. The compound of claim 3, wherein R.sup.1 is cyclohexyl. 64. The compound of claim 63, when one of R.sup.1 and R.sup.2 is halo or hydrogen and the other is halo. 65. The compound of claim 64, wherein said amide is 3-[cyclohexyl-2-(3,4-dichloro-phenyl)-propionyl]-urea. 66. The compound of claim 64, wherein said amide is [3-cyclohexyl-2-(3,4-dichloro phenyl)-propionyl]-3-methyl-urea. 67. The compound of claim 3, wherein R.sup.3 is cycloheptyl. 68. The compound of claim 67, when one of R.sup.1 and R.sup.2 is halo or hydrogen and the other is halo. 69. The compound of claim 68, wherein said amide is [3-cycloheptyl-2-(3,4-dichloro-phenyl)-propionyl]-urea. 70. A compound of claim 1 wherein R.sup.4 is ##STR56## 71. The compound of claim 70 wherein R.sup.3 is cyclopentyl. 72. The compound of claim 71 wherein R.sup.1 and R.sup.2 are independently halo. 73. The compound of claim 72, wherein said amide is 3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-propionic acid ethyl ester. 74. The compound of claim 72, wherein said amide is {3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-acetic acid ethyl ester. 75. The compound of claim 72, wherein said amide is {3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-acetic acid methyl ester. 76. The compound of claim 72, wherein said amide is 3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-propionic acid methyl ester. 77. The compound of claim 72, wherein said amide is {3-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-ureido}-acetic acid ethyl ester. 78. The compound of claim 72 wherein said amide is 3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-3-oxo-propi onic acid ethyl ester. 79. A compound of claim 1 wherein R.sup.4 is hydroxy lower alkyl, or halo lower alkyl. 80. A compound of claim 79 wherein R.sup.3 is cyclopentyl. 81. A compound of claim 80 wherein R.sup.1 and R.sup.2 are independently halo. 82. A compound of claim 81 wherein the amide is 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl]-3-(2-hydroxy-ethyl)-u rea. 83. A compound of claim 81 wherein the amide is 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl]-3-(2-hydroxy-propyl)- urea. 84. A compound of claim 81 wherein the amide is 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl]-3-(3-hydroxy-propyl)- urea. 85. A compound of claim 81 wherein the amide is 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-proprionyl]-3-(2-hydroxy-propy l)-urea. 86. A compound of claim 81 wherein the amide is 1-(2-chloro-ethyl)-3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl]-ur ea. 87. A compound of claim 81 wherein the amide is 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-proprionyl]-3-(3-hydroxy-propy l)-urea. -------------------------------------------------------------------------------- |
| 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 ##STR3## wherein R.sup.1 and R.sup.2 are independently hydrogen, halo, amino, nitro, cyano, sulfonamido, lower alkyl, perfluoro-lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl, or perfluoro-lower alkyl sulfonyl; R.sup.3 is cycloalkyl having from 3 to 7 carbon atoms or lower alkyl having from 2 to 4 carbon atoms; R.sup.4 is hydrogen, lower alkyl, lower alkenyl, hydroxy lower alkyl, halo lower alkyl; ##STR4## R.sup.5 and R.sup.6 are hydrogen or lower alkyl; and n is 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof. The compounds of formula I have been found to activate glucokinase in vitro. Glucokinase activators are useful in the treatment of type II diabetes. |
| PATENT PHOTOCOPY | Available on request |
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