Tetrazolyl-phenyl acetamide glucokinase activators

Details Tetrazolyl-phenyl acetamide glucokinase activators Tetrazolyl-phenyl acetamide glucokinase activators

2001-08-08

2002-04-09

Higel, Floyd D. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S190000, C548S195000, C548S202000, C548S253000, C548S254000, C514S381000

Reexamination Certificate

active

06369232

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 are useful for treating type II diabetes.
SUMMARY OF THE INVENTION
This invention provides a tetrazole selected from the group consisting of a compound of the formula:
where one of R
1
or R
2
is
(this tetrazole is linked to the remainder of the molecule by the N, as represented here) and the other is hydrogen, halogen, lower alkyl sulfonyl, perfluoro-lower alkyl, cyano, or nitro; R
3
is cycloalkyl; R
4
is —C(O)NHR
6
or a five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amide group shown, 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 with halogen at a position on a ring carbon atom other than that adjacent to said connecting carbon atom; n is 0 or 1; R
5
is lower alkyl, or perfluoro lower alkyl; R
6
is hydrogen or lower alkyl; and pharmaceutically acceptable salts of the tetrazole.
Formula I-A depicts the isomeric bond when it is not hydrogenated. Formula I-B depicts the bond when it is hydrogenated. Accordingly the A denotes a trans configuration across the double bond in formula I-A, and the * represents the asymmetric carbon atom in formula I-B. Tetrazoles which are compounds of formula I-B are preferably in the R configuration.
The compounds of formula IA or IB are glucokinase activators useful for increasing insulin secretion in the treatment of type II diabetes.
DETAILED DESCRIPTION OF THE INVENTION
One embodiment of formula I-A or of formula I-B is a tetrazole where R
4
is a five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amide group shown, 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 with halogen at a position on a ring carbon atom other than that adjacent to said connecting carbon atom. Formula I-A1 represents this embodiment as a compound of formula I-A, and Formula I-B1 represents this embodiment as a compound of formula I-B.
Another embodiment of formula I-A or formula I-B is a tetrazole where R
4
is —C(O)—NHR
6
where R
6
is hydrogen or lower alkyl. Formula I-A2 represents this embodiment as a compound of formula I-A. Formula I-B2 represents this embodiment as a compound of iz formula I-B.
In most tetrazoles of this invention, it is preferred that R
1
be
It is also preferred that R
5
be lower alkyl (such as methyl). It is further preferred that R
3
be cyclopentyl, although cyclohexyl and cycloheptyl are also possible. When R
4
is a six-membered heteroaromatic ring, it is preferably substituted or unsubstituted pyridine. When R
4
is a 5-membered heteroaromatic ring, it is preferably substituted or unsubstituted thiazole. When substituted, either ring is preferably monosubstituted, and the preferred substituent is halogen such as bromo. R
2
is preferably halogen (such as fluoro or chloro) or perfluoro lower alkyl (such as trifluoromethyl) and R
6
is preferably methyl. Thus, a tetrazole of formula IA or IB may include any one or more of these conditions in any selected combination. In addition, any one or more of these conditions may be applied to any tetrazole of this invention as described herein. For example, in any tetrazole of this invention with substituted pyridine, the preferred substituent is bromo.
In particular, in tetrazoles of formula I-A1, R
1
is
R
5
is lower alkyl, and R
3
is cyclopentyl (formula I-A1a). In one embodiment of formula I-A1a, R
4
is a six-membered heteroaromatic ring, in particular substituted or unsubstituted pyridine. In such a tetrazole, R
2
may be halogen. An example is:
(E)-N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylamide
In another embodiment of formula I-A1a, R
4
is a 5-membered heteroaromatic ring, in particular substituted or unsubstituted thiazole. In such a tetrazole, R
2
may be halogen or perfluoro lower alkyl, or R
2
may be lower alkyl sulfonyl. Examples of the former tetrazoles are
(E)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl-]-N-thiazol-2-yl-acrylamide
(E)-4-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl-]-but-2-enoic acid-thiazol-2-ylamide
(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-acrylamide
(E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-acrylamid

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