| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | August 26, 2003 |
| PATENT TITLE |
Heteroaromatic glucokinase activators |
| PATENT ABSTRACT | 2,3-Di-substituted N-heteroaromatic propionamides with said substitution at the 3-position being a substituted phenyl group and at the 2-position being a methyl 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 | September 28, 2000 |
| PATENT REFERENCES CITED |
Rodier et al., Acta Crystallogr., C46, p. 154-156 (1990). Robert et al., Eur. J. Med. Chem., vol. 29, pp. 841-854 (1994). Spickett et al., Eur. J. Med. Chem.--Chimica Therapeutica, vol. 11(1), pp. 7-12 (1976). Bhat et al., Inst. Chemists (India), vol. 61, pp. 134-136 (1989). Spielman, M.A., et al., J. Am. Chem. Soc., 70, pp. 4189-4191 (1948). |
| 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 amides of the formula: ##STR174## 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, --C(O)OR.sup.6, perfluoro-lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl, lower alkoxy lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl, lower alkyl sulfinyl, or sulfonamido; 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 an unsubstituted or mono-substituted triazine, pyrazine or pyridazine connected by a ring carbon atom to the amide group shown, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom; said mono-substituted triazine, pyrazine or pyridazine 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, perfluoro-lower alkyl, oxo, --(CH.sub.2).sub.n --OR.sup.7, --(CH.sub.2).sub.n --C(O)--OR.sup.7, --(CH.sub.2).sub.n --C(O)--NH--R.sup.7, --C(O)C(O)--OR.sup.7, or --(CH.sub.2).sub.n --NHR.sup.7 ; n is 0, 1, 2, 3 or 4; R.sup.5 is hydrogen, lower alkyl, or perfluoro-lower alkyl; R.sup.6 is lower alkyl; and R.sup.7 is hydrogen or lower alkyl; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein the amide is the R configuration at the asymmetric carbon shown. 3. The compound of claim 1, wherein R.sup.3 is cycloalkyl having from 3 to 7 carbon atoms. 4. The compound of claim 3, wherein R.sup.3 is cyclopentyl. 5. The compound of claim 4 wherein R.sup.4 is unsubstituted pyridazinyl ring. 6. The compound of claim 5, 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. 7. The compound of claim 6, wherein said amide is 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyridazin-3-yl-propionamide. 8. The compound of claim 1, wherein R.sup.3 is cyclohexyl. 9. The compound of claim 1, wherein R.sup.3 is cycloheptyl. 10. The compound of claim 4 wherein R.sup.4 is unsubstituted pyrazinyl. 11. The compound of claim 10 wherein one of R.sup.1 or R.sup.2 is lower alkyl sulfonyl, halo, or perfluoro-lower alkyl and the other is hydrogen, halo, cyano, nitro, or perfluoro-lower alkyl. 12. The compound of claim 11, wherein said amide is 3-cyclopentyl-2(R)-(4-methylsulfanyl-phenyl)-N-pyrazin-2-yl-propionamide. 13. The compound of claim 11, wherein said amide is 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-pyrazin-2-yl-propionamide. 14. The compound of claim 11, wherein said amide is 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-pyrazin-2-yl-propionamide. 15. The compound of claim 10 wherein one of R.sup.1 or R.sup.2 is perfluoro-lower alkyl or lower alkyl sulfonyl and the other is hydrogen, cyano, or nitro. 16. The compound of claim 15, wherein said amide is 3-cyclopentyl-2(R)-(4-methylsulfonyl-phenyl)-N-pyrazin-2-yl-propionamide. 17. The compound of claim 15, wherein said amide is 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propiona mide. 18. The compound of claim 15, wherein said amide is 3-cyclopentyl-N-pyrazin-2-yl-2-(3-trifluoromethyl-phenyl)-propionamide. 19. The compound of claim 15, wherein said amide is 3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-pyrazin-2-yl-propiona mide. 20. The compound of claim 10 wherein one of R.sup.1 or R.sup.2 is lower alkyl sulfonyl and the other is perfluoro-lower alkyl or halo. 21. The compound of claim 20, wherein said amide is 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propion amide. 22. The compound of claim 20, wherein said amide is 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-prop ionamide. 23. The compound of claim 20, wherein said amide is 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propiona mide. 24. The compound of claim 20, wherein said amide is 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyrazin-2-y l-propionamide. 25. The compound of claim 20, wherein said amide is 3-cyclopentyl-2(R)-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyrazin- 2-yl-propionamide. 26. The compound of claim 4 wherein R4 is unsubstituted triazinyl. 27. The compound of claim 26 wherein R1 and R2 are each independently halo. 28. The compound of claim 27, wherein said amide is 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrazin-3-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, --C(O)OR.sup.6, perfluoro-lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl, lower alkoxy lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl, lower alkyl sulfinyl, or sulfonamido; 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 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, perfluoro-lower alkyl; oxo, --(CH.sub.2).sub.n --OR.sup.7, --(CH.sub.2).sub.n --C(O)--OR.sup.7, --(CH.sub.2).sub.n --C(O)--NH--R.sup.7, --C(O)C(O)--OR.sup.7, or --(CH.sub.2).sub.n --NHR.sup.7 ; n is 0, 1, 2, 3 or 4; R.sup.5 is hydrogen, lower alkyl, or perfluoro-lower alkyl; R.sup.6 is lower alkyl; and R.sup.7 is 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 |
|
Want more information ? Interested in the hidden information ? Click here and do your request. |