| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | November 26, 2002 |
| PATENT TITLE |
.alpha.-acyl- and .alpha.-heteroatom-substituted benzene acetamide glucokinase activators |
| PATENT ABSTRACT |
Substituted benzene acetamide compounds which are glucokinase activators and pharmaceutically acceptable salts thereof. -------------------------------------------------------------------------------- |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | July 13, 2001 |
| PATENT REFERENCES CITED |
Teijin Ltd., Chemical Abstracts, JP 55 064592 (1980). Asthana T. et al., Chemical Abstracts, 74, No. 21, pp. 256 (1971). Asthana T. et al, Chemical Abstracts, Indian J. Chem., 8 No. 12, pp. 1086-1095 (1970). |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. An amide selected from the group consisting of a compound of the formula: ##STR39## wherein R.sup.1 and R.sup.2 are independently hydrogen, halo, cyano, nitro, lower alkylthio, perfluoro loweralkylthio, lower alkyl sulfonyl, or perfluoro-lower alkyl sulfonyl; R.sup.3 a 5 to 7-membered ring which is cycloalkyl, cycloalkenyl, or heterocycloalkyl having one heteroatom selected from oxygen and sulfur; R.sup.6 is an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amide 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; with 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.9, --(CH.sub.2).sub.n --C(O)--OR.sup.10, --(CH.sub.2).sub.n --C(O)--NH--R.sup.11, --C(O)--C(O)--OR.sup.12, --(CH.sub.2).sub.n --NHR.sup.13 ; n is 0, 1, 2, 3 or 4; R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 are independently hydrogen or lower alkyl; X is oxygen, sulfur, sulfonyl or carbonyl; the * indicates an asymmetric carbon atom; and its pharmaceutically acceptable salts. 2. The amide of claim 1 wherein said compound is ##STR40## wherein R.sup.1 and R.sup.2 are independently hydrogen, halo, lower alkyl sulfonyl, or perfluoro-lower alkyl sulfonyl; R.sup.3 is a 5 to 7-membered ring which is cycloalkyl, cycloalkenyl, or heterocycloalkyl having one heteroatom selected from oxygen and sulfur; R.sup.6 is an unsubstituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amide 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 X is oxygen, sulfur, sulfonyl or carbonyl; the * indicates an asymmetric carbon atom; and its pharmaceutically acceptable salts. 3. The amide of claim 2 wherein R.sup.1 and R.sup.2 are independently halo or lower alkyl sulfonyl, and R.sup.3 is a 5 to 7-membered ring which is cyclopentyl, cyclohexyl, cyclohexenyl, or a six-membered heterocycloalkyl having one heteroatom selected from oxygen and sulfur. 4. The amide of claim 3 wherein the heteroatom is oxygen. 5. The amide of claim 4 wherein R.sup.6 is thiazolyl or pyridinyl. 6. The amide of claim 19 wherein R.sup.1 and R.sup.2 are independently chloro or methyl sulfonyl. 7. The amide of claim 6 where X is oxygen. 8. The amide of claim 7 wherein R.sup.1 and R.sup.2 are chloro. 9. The amide of claim 8 wherein R.sup.6 is thiazolyl. 10. The amide of claim 9 which is 2-(3,4-dichloro-phenyl)-2-(tetrahydro-pyran-4-yloxy)-N-thiazol-2-yl-acetam ide. 11. The amide of claim 9 which is 2-cyclopentyloxy-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide. 12. The amide of claim 9 which is 2-cyclohexyloxy-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide. 13. The amide of claim 9 which is 2-(cyclohex-2-enyloxy)-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide. 14. The amide of claim 8 wherein R.sup.6 is pyridinyl. 15. The amide of claim 14 which is 2-cyclopentyloxy-2-(3,4-dichloro-phenyl)-N-pyridin-2-yl-acetamide. 16. The amide of claim 7 wherein R.sup.1 is chloro and R.sup.2 is methyl sulfonyl. 17. The amide of claim 16 which is 2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxy-N-thiazol-2-yl-acet amide. 18. The amide of claim 16 which is 2-(3-chloro-4-methanesulfonyl-phenyl)-2-(cyclohex-2-enyloxy)-N- thiazol-2-yl-acetamide. 19. The amide of claim 6 wherein X is sulfur, sulfonyl or carbonyl. 20. The amide of claim 19 wherein R.sup.1 and R.sup.2 are chloro. 21. The amide of claim 20 wherein R.sup.3 is cyclopentyl. 22. The amide of claim 21 which is 3-cyclopentyl-2-(3,4-dichloro-phenyl)-3-oxo-N-thiazol-2-yl-propionamide. 23. The amide of claim 21 which is 2-cyclopentanesulfonyl-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide. 24. The amide of claim 21 which is 2-cyclopentylsulfanyl-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
Glucokinase (GK) is one of four hexokinases 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 an amide selected from the group consisting of a compound of the formula: ##STR1## wherein R.sup.1 and R.sup.2 are independently hydrogen, halo, cyano, nitro, lower alkylthio, perfluoro lower alkylthio, lower alkyl sulfonyl, or perfluoro-lower alkyl sulfonyl, R.sup.3 is lower alkyl having from 2 to 4 carbon atoms or a 5 to 7-membered ring which is cycloalkyl, cycloalkenyl, or heterocycloalkyl having one heteroatom selected from oxygen and sulfur, R.sup.4 is --C(O)NHR.sup.5, or is R.sup.6, which is an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amide 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; with 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.9, --(CH.sub.2).sub.n --C(O)--OR.sup.10, --(CH.sub.2).sub.n --C(O)--NH--R.sup.11, --C(O)--C(O)--OR.sup.12, --(CH.sub.2).sub.n --NHR.sup.13 ; n is 0, 1, 2, 3 or 4; R.sup.7, R.sup.8, R.sup.9, R.sub.10, R.sup.11, R.sup.12, R.sup.13 are independently hydrogen or lower alkyl, R.sup.5 is hydrogen, lower alkyl, lower alkenyl, hydroxy lower alkyl, halo lower alkyl, --(CH.sub.2).sub.n --C(O)--OR.sup.7, --C(O)--(CH.sub.2).sub.n --C(O)--OR.sup.8, X is oxygen, sulfur, sulfonyl, or carbonyl; the * indicates an asymmetric carbon atom; and its pharmaceutically acceptable salts. Preferably, the compound of formula I is in the "R" configuration at the asymmetric carbon, shown except in the case where X is carbonyl (C.dbd.O), when the preferred enantiomer is "S". The compounds of formula I have been found to activate glucokinase. Glucokinase activators are useful in the treatment of type II diabetes. |
| PATENT PHOTOCOPY | Available on request |
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