Fused heteroaromatic glucokinase activators

Details Fused heteroaromatic glucokinase activators Fused heteroaromatic glucokinase activators

2001-12-04

2003-04-08

Spivack, Phyllis G. (Department: 1614)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S162000, C544S183000, C544S253000, C544S292000, C544S356000

Reexamination Certificate

active

06545155

ABSTRACT:

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 &bgr;-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 (≈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 &bgr;-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 &bgr;-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 &bgr;-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:
wherein R
1
is an alkyl having from 1 to 3 carbon atoms; R
2
is hydrogen, halo, nitro, cyano, or perfluoro-methyl; R
3
is a cycloalkyl having from 4 to 7 carbon atoms or 2-propyl; Z is —CH
2
—CH
2
—CH
2
—CH
2
— or —CH═CR
4
—CH═CH—, wherein R
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
wherein R
3
is a cycloalkyl having from 4 to 7 carbon atoms or 2-propyl; R
5
is a halogen, preferably Cl or F; R
6
is a halogen, preferably Cl or F; Z is —CH
2
—CH
2
H
2
—CH
2
— or —CH═CR
4
—H═CH—, wherein R
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
wherein R
1
is an alkyl having from 1 to 3 carbon atoms; R
2
is hydrogen, halo, nitro, cyano, or perfluoro-methyl; R
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
wherein R
3
is a cycloalkyl having from 4 to 7 carbon atoms or 2-propyl; R
5
is a halogen, preferably Cl or F; R
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.
DETAILED DESCRIPTION OF THE INVENTION
This invention provides a compound, comprising an amide of the formulae Ia, Ib, IIa or IIb:
wherein R
1
is an alkyl having from 1 to 3 carbon atoms; R
2
is hydrogen, halo, nitro, cyano, or perfluoro-methyl; R
3
is a cycloalkyl having from 4 to 7 carbon atoms or 2-propyl; Z is —CH
2
—CH
2
—CH
2
—CH
2
— or —CH═CR
4
—CH═CH—, wherein R
4
is hydrogen, halo, or an alkyl sulfone having from 1 to 3 carbon atoms; and W is O, S or NH; or a pharmaceutically acceptable salt thereof; or
wherein R
3
is a cycloalkyl having from 4 to 7 carbon atoms or 2-propyl; R
5
is Cl or F; R
6
is Cl or F; Z is —CH
2
—CH
2
—CH
2
—CH
2
— or —CH═CR
4
—CH═CH—, wherein R
4
is hydrogen, halo, or an alkyl sulfone having from 1 to 3 carbon atoms; and W is O, S or NH; or a pharmaceutically acceptable salt thereof; or
wherein R
1
is an alkyl having from 1 to 3 carbon atoms; R
2
is hydrogen, halo, nitro, cyano, or perfluoro-methyl; R
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; or a pharmaceutically acceptable salt thereof; or
wherein R
3
is a cycloalkyl having from 4 to 7 carbon atoms or 2-propyl; R
5
is Cl or F; R
6
is Cl or F; each Y is independently CH or N; and dotted lines collectively represent 0 or 2 additional double bonds in the heterocyclic ring structure; or a pharmaceutically acceptable salt thereof.
In formulae Ia, Ib, IIa and IIb, * indicates an asymmetric carbon. A compound of formulae Ia, Ib, IIa or IIb may be present either as a racemate or in the “R” configuration at the asymmetric carbon shown. Compounds which are isolated “R” enantiomers are preferred.
In further preferred embodiments of formulae Ia, Ib, Ia and IIb, R
3
is a cyclopentyl group.
In formulae IIa and IIb, the dotted lines collectively represent zero or two, preferably two additional double bonds in the heterocyclic ring. As an example, in 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-quinolin-2-yl-propionamide, there are two additional double bonds in the heterocyclic ring.
In certain preferred amides of formulae Ia and Ia, R′ is CH
3
and R
2
is H. Examples of such amides are N-benzothiazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide and 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-quinolin-2-yl-propionamide.
In further preferred amides of formulae Ia and IIa, R′ is SO
2
CH
3
and R
2
is halo. Examples of such amides are N-benzooxazol-2-yl-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide; 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-quinolin-2-yl-propionamide;

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