Hydantoin-containing glucokinase activators

Details Hydantoin-containing glucokinase activators Hydantoin-containing glucokinase activators

2001-04-26

2003-06-24

Fan, Jane (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S015000, C548S195000, C548S214000

Reexamination Certificate

active

06583288

ABSTRACT:

BACKGROUND OF THE INVENTION
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 &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 a substituted hydantoin of the formula:
wherein
R
1
is a five- or six-membered aromatic heterocyclic ring having one to three heteroatoms selected from nitrogen, oxygen, and sulfur, which ring is unsubstituted or substituted with halo, amino, hydroxylamino, nitro, cyano, sulfonamido, lower alkyl, perfluoro lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl, lower alkyl sulfinyl, or —(R
5
)
n
—C(O)—OR
6
;
R
2
is a cycloalkyl ring containing from 5 to 7 carbon atoms;
R
3
is hydrogen, lower alkyl, a cycloalkyl ring containing from 5 to 7 carbon atoms, unsubstituted aryl, aryl substituted with halo or hydroxy, or an unsubstituted five- or six-membered aromatic heterocyclic ring having one or two heteroatoms selected from nitrogen, oxygen, and sulfur;
R
4
is hydrogen, lower alkyl, or R
3
and R
4
together with the carbon atom to which they are attached form a cycloalkyl ring containing 5 to 7 carbon atoms;
R
5
is —C(O)— or lower alkyl;
R
6
is lower alkyl;
n is 0 or 1; * and ** each designate an asymmetric centers,
and pharmaceutically acceptable salts thereof.
The compounds of Formula I have been found to activate glucokinase. Glucokinase activators are useful for increasing insulin secretion in the treatment of type II diabetes. Therefore compounds of this invention are useful to increase insulin secretion in view of their activity as glucokinase activators.
DETAILED DESCRIPTION OF THE INVENTION
This invention is directed to compounds of Formula I above. The invention is particularly directed to compounds as follows, where:
R
2
and R
3
are both cyclohexyl, or
R
3
, when it is lower alkyl, is methyl, ethyl, propyl, or butyl, or
R
4
, when it is lower alkyl, is methyl or ethyl (especially compounds where R
3
and R
4
are both so defined), or
R
1
, when substituted, is substituted with halo, lower alkyl, or —(R
5
)
n
—C(O)—OR
6
, or compounds where any two or more, or all, of these conditions are met. For any compound of this invention where R
1
, R
2
, or R
3
are not specified, it is preferred that the variable is as described in this paragraph.
Certain preferred compounds of Formula I include a compound where R
1
is substituted or unsubstituted thiazolyl (Compound A). Among the embodiments of Compound A are those compounds where R
1
is thiazolyl substituted with halo, lower alkyl, or —(R
5
)
n
—C(O)—OR
6
, and especially with —(R
5
)
n
—C(O)—OR
6
. (Compound A-1). In Compound A-1, it is preferred that R
2
is cyclopentyl or cyclohexyl. It is also preferred that R
3
is cyclopentyl or cyclohexyl. It is preferred that R
4
is hydrogen. It is especially preferred that R
2
and R
3
are cyclohexyl.
In preferred embodiments of Compound A-1, R
2
and R
3
are cyclopentyl or cyclohexyl, and R
4
is hydrogen (Compound A-1a). In one embodiment of Compound A-1 a, n is 0 (e.g., the thiazolyl is substituted with —C(O)—OR
6
). Examples of such compounds are
(S,S)-2-[[3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidin-1-yl]propanoyl]amino]thiazole-4-carboxylic acid methyl ester.
(S,S)-2-[[2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidin-1-yl)-3-cyclopentylpropanoyl]amino]thiazole-4-carboxylic acid methyl ester.
(S,S)-2-[[3-cyclopentyl-2-[4-(cyclopentyl)methyl-2,5-dioxoimidazolidin-1-yl]propanoyl]amino]thiazole-4-carboxylic acid methyl ester.
(S,S)-2-[[3-cyclohexyl-2-[4-(cyclopentyl)methyl-2,5-dioxoimidazolidin-1-yl]propanoyl]amino]thiazole-4-carboxylic acid methyl ester.
In such a compound, R
2
and R
3
may both be cyclohexyl, for example (S,S)-2-[[3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidin-1-yl]propanoyl]amino] thiazole-4-carboxylic acid methyl ester.
In another embodiment of Compound A-1a, R
5
is —C(O)— or lower alkyl (e.g., the thiazolyl is substituted with —C(O)—C(O)—OR
6
or -lower alkyl-C(O)—OR
6
). In addition, in such compounds R
2
and R
3
may be cyclohexyl. Examples of such compounds are
(S,S)-[2-[[3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidin-1-yl]propanoyl]amino]thiazole-4-yl]oxoacetic acid ethyl ester and
(S,S)-[2-[[3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidin-1-yl]propanoyl]amino]thiazole-4-yl]acetic acid ethyl ester.
In another embodiment of Compound A1, R
2
is cyclopentyl or cyclohexyl (Compound A-1b). In one embodiment of Compound A-1b, R
3
is substituted or unsubstituted phenyl and R
4

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