Para-amine substituted phenylamide glucokinase activators

Details Para-amine substituted phenylamide glucokinase activators Para-amine substituted phenylamide glucokinase activators

2001-05-01

2002-12-03

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06489485

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 be 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 an amide selected from the group consisting of a compound of the formula:
wherein X is
R is perfluoro-lower alkyl, lower alkyl,
 lower alkoxycarbonyl, a heteroaromatic ring, connected by a ring carbon atom, containing from 5 to 6 ring members with from 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, unsubstituted aryl containing 6 or 10 ring carbon atoms, a nitro or a lower alkyl substituted aryl, which aryl contains 6 or 10 ring carbon atoms, a saturated 5- to 6-membered cycloheteroalkyl ring, connected by a ring carbon atom, containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, or a cycloalkyl ring having 5 or 6 carbon atoms; R
1
is a cycloalkyl having 5 or 6 carbon atoms; R
2
is a five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amide group in the remainder of the compound, which heteroaromatic ring contains from 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen with a first heteroatom being nitrogen adjacent to the connecting ring carbon atom, said heteroaromatic ring being unsubstituted or 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 lower alkyl, or
n and y independently are an integer of from 1 to 4, R
4
, R
5
and R
7
are independently hydrogen or lower alkyl, and * denotes the asymmetric carbon atom and a pharmaceutically acceptable salt thereof.
The compounds of formula I are glucokinase activators useful for increasing insulin secretion in the treatment of type II diabetes.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of formula I have the following embodiments
wherein R, R
1
, R
2
, * and y are as above;
In the compound of formulae I, IA and IB, the “*” designates that the asymmetric carbon atom in the compounds with the R optical configuration being preferred. The compounds of formula I may be present in the R or as a racemic or other mixtures of compounds having the R and S optical configuration at the asymmetric carbon shown. The pure R enantiomers are preferred.
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. 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.
As used herein, the term “aryl” signifies “polynuclear” and mononuclear unsubstituted aromatic hydrocarbon groups such as phenyl, naphthy containing either 6 or 10 carbon atoms which aryl groups in the compounds of formulae I, IA and IB are either phenyl and naphthyl. The aryl substituent can be unsubstituted or substituted, preferably monosubstituted with a nitro or lower alkyl substituted.
R can be any five- or six-membered saturated cycloheteroalkyl ring containing from 1 to 2 heteroatoms selected from the group consisting of sulfur, oxygen or nitrogen. Any such five- or six-membered saturated heterocyclic ring can be used in accordance with this invention. Among the preferred rings are morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, etc. When R is a saturated cyclic heteroacetyl ring, it is connected to the remainder of the molecule of formula I through a ring carbon atom.
The heteroaromatic ring defined by R and R
2
can be five- or six-membered heteroaromatic ring having from 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur which is connected by a ring carbon to the remainder of the molecule as shown. The heteroaromatic ring defined by R
2
contains a first nitrogen heteroatom adjacent to the connecting ring carbon atom and if present, the other heteroatoms can be oxygen, sulfur, or nitrogen. Among the preferred heteroaromatic rings include pyridinyl, pyrimidinyl and thiazolyl. These heteroaromatic rings which constitute R are connected via a ring carbon atom to the amide group to form the amides of formula I. The ring carbon atom of the heteroaromatic ring which is connected to the amide to form the compound of formula I does not contain any substituent. When R
2
is an unsubstituted or mono-substituted five- or six-membered he

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