| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | September 10, 2002 |
| PATENT TITLE |
Fused heteroaromatic glucokinase activators |
| PATENT ABSTRACT | Glucokinase activating amides are useful for increasing 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 | December 4, 2001 |
| PATENT REFERENCES CITED |
Colowick, S.P., The Enzymes, vol. 9 (P. Boyer, ed.) Academic Press, New York, New York, pp. 1-48 (1973). Chipkin et al., Joslin's Diabetes Mellitus (C. R. Kahn and G.C. Wier, eds.) Lea & Febiger, Philiadelphia, PA, pp. 97-115 (1994). Printz et al., Ann. Rev. Nutrition, vol. 13 (R.E. Olson, D. M. Bier and D.B. McCormick, eds.) Annual Review, Inc., Palo Alto, CA, pp. 463-496 (1993). Meglasson et al., Amer. J. Physiol., 246, E1-E13 (1984). Grupe et al., Cell, 83, pp. 69-78 (1995). Ferre et al., FASEB J., 10, pp. 1213-1218 (1996). Liang et al., Biochem. J., 309, pp. 167-173 (1995). Glaser et al., New England J. Med., 338, pp. 226-230 (1998). Skeean et al., Synthesis, pp. 628-630 (1990). Boswell et al., J. Org. Chem., 60, pp. 6592-6594 (1995). Sheikh et al., J. Org. Chem., 47, pp. 4341-4344 (1982). Brown et al., J. Org. Chem., pp. 4707-4708 (1961). Wrobel et al., J. Med. Chem., 32, pp. 2493-2500 (1989). Greenlee et al., J. Org. Chem., 46 pp. 5351-5353 (1981). Testaferri et al., Synthesis, pp. 751-757 (1983). Ulman et al., J. Org. Chem., 54, pp. 4691-4692 (1989). Levine et al., J. Med. Chem., pp. 1029-1032 (1972). D.J. milner, Synthetic Commun., 22, pp. 73-82 (1992). Fukuhara et al., J. Fluorine Chem., pp. 299-304 (1991). Myers et al., J. Am. Chem. Soc., pp. 6496-6511 (1997). Ahmar et al., Tetradron Lett., pp. 7053-7056 (1989). |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A compound of formula ##STR46## or a pharmaceutically acceptable salt thereof; wherein R.sup.3 is a cycloalkyl having from 4 to 7 carbon atoms or 2-propyl; R.sup.5 is Cl or F; R.sup.6 is Cl or F; each Y is independently CH or N; dotted lines collectively represent 0 or 2 additional double bonds in the heterocyclic ring structure; and * denotes an asymmetric carbon atom. 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 both R.sup.5 and R.sup.6 are Cl. 4. The compound of claim 3, wherein R.sup.3 is cyclopentyl. 5. The compound of claim 4, wherein both Y are CH. 6. The compound of claim 5, wherein the amide is 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-quinolin-2-yl-propionamide. 7. The compound of claim 5, wherein the amide is 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-quinolin-2-yl-propionamide. 8. The compound of claim 4, wherein at least one Y is N. 9. The compound of claim 1, wherein R.sup.3 is cyclopentyl. 10. The compound of claim 1, wherein both Y are CH. 11. The compound of claim 9, wherein at least one Y is N. 12. The compound of claim 1, wherein both Y are CH. 13. The compound of claim 12, wherein the dotted lines represent 0 additional double bonds. 14. The compound of claim 12, wherein the dotted lines represent 2 additional double bonds. 15. The compound of claim 1, wherein at least one Y is N. 16. The compound of claim 15, wherein the dotted lines represent 0 additional double bonds. 17. The compound of claim 15, wherein the dotted lines represent 2 additional double bonds. -------------------------------------------------------------------------------- |
| 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 formulae Ia, Ib, IIa or IIb: ##STR1## wherein R.sup.1 is an alkyl having from 1 to 3 carbon atoms; R.sup.2 is hydrogen, halo, nitro, cyano, or perfluoro-methyl; R.sup.3 is a cycloalkyl having from 4 to 7 carbon atoms or 2-propyl; Z is --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --or --CH.dbd.CR.sup.4 --CH.dbd.CH--, wherein R.sup.4 is hydrogen, halo, or an alkyl sulfone having from 1 to 3 carbon atoms; W is O, S or NH; and * denotes an asymmetric carbon atom; or a pharmaceutically acceptable salt thereof; or ##STR2## wherein R.sup.3 is a cycloalkyl having from 4 to 7 carbon atoms or 2-propyl; R.sup.5 is a halogen, preferably Cl or F; R.sup.6 is a halogen, preferably Cl or F; Z is --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --or --CH.dbd.CR.sup.4 --CH.dbd.CH--, wherein R.sup.4 is hydrogen, halo, or an alkyl sulfone having from 1 to 3 carbon atoms; W is O, S or NH; and * denotes an asymmetric carbon atom; or a pharmaceutically acceptable salt thereof; or ##STR3## wherein R.sup.1 is an alkyl having from 1 to 3 carbon atoms; R.sup.2 is hydrogen, halo, nitro, cyano, or perfluoro-methyl; R.sup.3 is a cycloalkyl having from 4 to 7 carbon atoms or 2-propyl; each Y is independently CH or N; dotted lines collectively represent 0 or 2 additional double bonds in the heterocyclic ring structure; and * denotes an asymmetric carbon atom; or a pharmaceutically acceptable salt thereof; or ##STR4## wherein R.sup.3 is a cycloalkyl having from 4 to 7 carbon atoms or 2-propyl; R.sup.5 is a halogen, preferably Cl or F; R.sup.6 is a halogen, preferably Cl or F; each Y is independently CH or N; dotted lines collectively represent 0 or 2 additional double bonds in the heterocyclic ring structure; and * denotes an asymmetric carbon atom; or a pharmaceutically acceptable salt thereof. The compounds of formulae Ia, Ib, IIa and IIb 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. |