Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-03-21
2003-03-04
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S522000, C514S530000, C514S542000, C514S595000, C558S413000, C558S417000, C560S009000, C560S013000, C564S047000, C564S056000
Reexamination Certificate
active
06528543
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 the formula
wherein R
1
and R
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
3
is cycloalkyl having from 3 to 7 carbon atoms or lower alkyl having from 2 to 4 carbon atoms; R
4
is hydrogen, lower alkyl, lower alkenyl, hydroxy lower alkyl, halo lower alkyl;
R
5
and R
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.
DETAILED DESCRIPTION OF THE INVENTION
This invention provides a compound, comprising an amide of the formula
wherein R
1
and R
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
3
is cycloalkyl having from 3 to 7 carbon atoms or lower alkyl having from 2 to 4 carbon atoms; R
4
is hydrogen, lower alkyl, lower alkenyl, hydroxy lower alkyl, halo lower alkyl,
R
5
and R
6
are hydrogen or lower alkyl; and n is 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof. In preferred compounds, the amide is in the “R” configuration at the asymmetric carbon shown.
In certain compounds of this invention, R
4
of the amide is hydrogen, lower alkyl, or lower alkenyl. Such amides are preferred when R
3
is cyclopentyl, especially when the amide is in the “R” configuration at the asymmetric carbon shown.
In certain amides of the above compound, R
1
and R
2
of the amide are hydrogen. Such an amide is 1-(3-cyclopentyl-2-phenyl-propionyl)-3-methyl-urea. In other of the above compounds, one of R
1
and R
2
is hydrogen and the other is cyano or halo.
Examples of Such Amides Are
1-[2-(3-chloro-phenyl)-3cyclopentyl-propionyl]-3-methyl-urea;
1-[2-(4-chloro-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea;
1-[2-(4-cyano-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea;
1-[2-(4-bromo-phenyl)-3-cyclopentyl-propionyl]-3-methyl urea.
In other amides of the above compound, R
1
and R
2
of the amide are each independently halo (preferably chloro). Examples of such amides are [3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-urea;
1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-methyl-urea;
1-[3-cyclopentyl-2R)-(3,4-dichloro-phenyl)-propionyl]-3-ethyl-urea;
1-allyl-3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl]-urea;
1-allyl-3-[3-cyclopentyl-2R)-(3,4-dichloro-phenyl)-proprionyl]-urea;
1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-ethyl-urea;
1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-3-methyl-urea;
1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-isopropyl-urea;
1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-propyl-urea;
1-[3-cyclopentyl-2-(3,4-difluoro-phenyl)-propionyl]-3-methyl-urea.
In yet other amides of the above compound, one of R
1
and R
2
of the amide is hydrogen or halo and the other is nitro. Examples of such amides are
1-[2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-proprionyl]-3-methyl-urea.
1-[3-cyclopentyl-2-(4-nitro-phenyl)-propionyl]-3-methyl-urea.
In further amides of the above compound, one of R
1
and R
2
is hydrogen, lower alkyl thio or perfluoro-lower alkyl thio and the other is lower alkyl thio or perfluoro-lower alkyl thio. Examples of such amides are
1-[3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)-propionyl]-3-methyl urea;
1-[3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-propionyl]-3-methyl urea.
In yet further amides of the above compound, one of R
1
and R
2
is hydrogen or perfluoro-lower alkyl sulfonyl and the other is perfluoro-lower alkyl sulfonyl. Examples of such amides are
1-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionyl]-3-methyl urea;
1-[3-cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionyl]-3-methyl urea.
In certain amides of the above compound, at least one of R
1
and R
2
is lower alkyl sulfonyl. Preferably one of R
1
and R
2
is hydrogen or lower alkyl sulfonyl and the other is lower alkyl sulfonyl, and more preferably R
2
is lower alkyl sulfonyl. Examples of such amides are
1-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionyl]-3-methyl urea;
1-{2-[4-(butane-1-sulf
Bizzarro Fred Thomas
Corbett Wendy Lea
Focella Antonio
Grippo Joseph Francis
Haynes Nancy-Ellen
Hoffman-La Roche Inc.
Johnston George W.
O'Sullivan Peter
Tramaloni Dennis P.
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