Isoindolin-1-one glucokinase activators

Details Isoindolin-1-one glucokinase activators Isoindolin-1-one glucokinase activators

2001-12-06

2002-11-19

Chang, Ceila (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C544S328000, C544S405000, C546S163000, C546S277100, C548S195000, C548S222000, C548S233000, C548S305100, C548S312100, C548S472000, C548S484000

Reexamination Certificate

active

06482951

ABSTRACT:

BACKGROUND OF THE INVENTION
Glucokinase (GK) is one of four exokinases 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
A is unsubstituted phenyl or phenyl which is mono- or di-substituted with halo or mono-substituted with lower alkyl sulfonyl, lower alkyl thio or nitro; p
1
R
1
is cycloalkyl having from 3 to 9 carbon atoms or lower alkyl having from 2 to 4 carbon atoms;
R
2
is an unsubstituted or 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 3 heteroatoms selected from sulfur, oxygen or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom, which ring may be monocyclic or fused with phenyl at two of its ring carbons, said monosubstituted 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, lower alkyl, nitro, cyano, perfluoro-lower alkyl; hydroxy, —(CH
2
)
n
—OR
3
, —(CH
2
)
n
—C(O)—OR
3
, —(CH
2
)
n
—C(O)—NH—R
3
, —C(O)C(O)—OR
3
, or —(CH
2
)
n
—NHR
3
; where R
3
is hydrogen or lower alkyl; and n is 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salts or N-oxides thereof.
Preferably R
2
is a five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amine group shown in formula I, which five- or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur, oxygen or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom. This ring may be monocyclic or may be fused with phenyl at two of its ring carbons. In accordance with an embodiment of this invention, the adjacent nitrogen in the nitrogen containing heteroaromatic rings may be in the form of an N-oxide where the nitrogen adjacent to the ring carbon atom is converted to an N-oxide. On the other hand, compounds of formula I can be in the form of pharmaceutically acceptable salts.
The compounds of formula I 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 formula I above or a pharmaceutically acceptable salt thereof.
In the compound of formula I, the “.” illustrates the asymmetric carbon atom in this compound. The compound of formula I may be present as a racemate at the asymmetric carbon shown. However, the “S” enantiomers, where the amide is in the “S” configuration at the asymmetric carbon, is preferred. When the phenyl ring A is monosubstituted with lower alkyl sulfonyl, nitro or lower alkyl thio, it is preferred that it is substituted at the 5- or 6-position as indicated in formula I. Thus, when A is phenyl substituted with nitro, it is preferred that this substitution be at positions 5 or 6 such as 5-nitro phenyl and 6 nitro phenyl.
In one embodiment of formula I, the R
2
ring as described above is a single, or monocyclic (unfused) ring. When R
2
is a monocyclic ring, it is preferably substituted or unsubstituted pyridine. In another embodiment of formula I, the R
2
ring as described above is a bicyclic ring, i.e. is fused with a phenyl.
As used throughout this application, the term “lower alkyl” includes both straight chain and branched chain alkyl groups having from 1 to 10 and preferably 3 to 9 carbon atoms, such as propyl, isopropyl, heptyl, and especially 2 to 4 carbon atoms.
As used herein, the term “cycloalkyl” signifies a 3- to 9-membered cycloalkyl ring, preferably 5- to 8-membered, for example cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.
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, “lower alkyl thio” means a lower alkyl group as defined above bound to the rest of the molecule through the sulfur atom in a thio group.
As used herein, “lower alkyl sulfonyl” means a lower alkyl group as defined above bound to the rest of the molecule through the sulfur atom in a sulfonyl group.
As used herein, the term “halogen” is used interchangeably with the word “halo”, and, unless otherwise stated, designates all four halogens, i.e. fluorine, chlorine, bromine, and iodine.
As used herein, the term “N-oxide” means a negatively charged oxygen atom which is covalently linked to a nitrogen which is po

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