Trans olefinic glucokinase activators

Details Trans olefinic glucokinase activators Trans olefinic glucokinase activators

2000-12-01

2002-03-05

Davis, Zinna Northington (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C560S024000, C560S038000, C562S443000, C564S155000

Reexamination Certificate

active

06353111

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, perfluoro-lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl, lower alkyl sulfonyl methyl or lower alkyl sulfinyl;
R is —(CH
2
)
m
—R
3
or lower alkyl containing from 2 to 4 carbon atoms;
R
3
is cycloalkyl having from 3 to 8 carbon atoms;
R
4
is
or an unsubstituted or a 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 2 heteroatoms selected from the group consisting of sulfur, 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 halo or
m is 0 or 1;
n is 0, 1, 2, 3 or 4;
R
7
is hydrogen or lower alkyl; and
&Dgr; denotes a trans configuration across the double bond;
or a pharmaceutically acceptable salt thereof.
The compounds of formula I are 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 formula:
wherein R
1
and R
2
are independently hydrogen, halo, amino, nitro, perfluoro-lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfinyl, lower alkyl sulfonyl, lower alkyl sulfonyl methyl or perfluoro-lower alkyl sulfonyl;
R is —(CH
2
)
m
—R
3
or lower alkyl containing from 2 to 4 carbon atoms;
R
3
is cycloalkyl having from 3 to 8 carbon atoms;
R
4
is
or an unsubstituted or a 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 2 heteroatoms selected from the group consisting of sulfur 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 halo or
m is 0 or 1;
n is 0, 1, 2, 3 or 4;
R
7
is hydrogen or lower alkyl;
&Dgr; denotes a
trans
configuration across the double bond;
or a pharmaceutically acceptable salt thereof which are useful as glucokinase activators for increasing insulin secretion in the treatment of type II diabetes. In accordance with this invention, it has been found that the compounds of formula I having the
trans
configuration across the double bond have this glucokinase activity. On the other hand, the compounds of formula I which have a
cis
configuration across the double bond do not have this glucokinase activity.
When the term “
cis
” is utilized in this application, it designates that the two largest substituents attached across the double bond are on the same side of the double bond. The term “
trans
” as utilized in this application, designates that the largest substituents attached across the double bond are on opposite sides of the double bond and have the “E”-configuration.
As used throughout this application, the term “lower alkyl” includes both straight chain and branched chain alkyl groups having from 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, preferably methyl and ethyl, most preferably methyl. As used herein, the term “halogen or halo” unless otherwise stated, designates all four halogens, i.e. fluorine, chlorine, bromine and iodine. As used herein, “perfluoro-lower alkyl” means any lower alkyl group wherein all of the hydrogens of the lower alkyl group are substituted or replaced by fluoro. Among the preferred perfluoro-lower alkyl groups are trifluoromethyl, pentafluoroethyl, heptafluoropropyl, etc., most preferred is trifluoromethyl.
As used herein the term “aryl” signifies mononuclear aromatic hydrocarbon groups such as phenyl, tolyl, etc. which can be unsubstituted or substituted in one or more positions with halogen, nitro, lower alkyl, or lower alkoxy substituents and polynuclear aryl groups, such as naphthyl, anthryl, and phenanthryl, which can be unsubstituted or substituted with one or more of the aforementioned groups. Preferred aryl groups are the substituted and unsubstituted mononuclear aryl groups, particularly phenyl. As used herein, the term “lower al

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