Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-06-25
2003-08-19
Davis, Zinna Northington (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C564S155000
Reexamination Certificate
active
06608218
ABSTRACT:
BACKGROUND OF THE INVENTION
This application is relevant to U.S. Ser. No. 09/526,143, filed Mar. 15, 2000 (now U.S. Pat. No. 6,320,050) and U.S. Ser. No. 09/532,506, filed Mar. 21, 2000.
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 an amide selected from the group consisting of a compound of the formula:
wherein R
1
and R
2
are independently hydrogen, halo, cyano, nitro, loweralkylthio, perfluoro lower alkylthio, lower alkyl sulfonyl, or perfluoro-lower alkyl sulfonyl, R
3
is lower alkyl having from 2 to 4 carbon atoms or a 5 to 7-membered ring which is cycloalkyl, cycloalkenyl, or heterocycloalkyl having one heteroatom selected from oxygen and sulfur, R
4
is —C(O)NHR
5
, or is R
6
, which is an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amide 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; with 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 lower alkyl, halo, nitro, cyano, —(CH
2
)
n
—OR
9
, —(CH
2
)
n
—C(O)—OR
10
, —(CH
2
)
n
—C(O)—NH—R
11
, —C(O)—C(O)—OR
12
, —(CH
2
)
n
—NHR
13
; n is 0, 1, 2, 3 or 4; R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
are independently hydrogen or lower alkyl, R
5
is hydrogen, lower alky, lower alkenyl, hydroxy lower alkyl, halo lower alkyl, —(CH
2
)
n
—C(O)—OR
7
, —C(O)—(CH
2
)
n
—C(O)—OR
8
, X is oxygen, sulfur, sulfonyl, or carbonyl; the * indicates an asymmetric carbon atom; and its pharmaceutically acceptable salts.
Preferably, the compound of formula I is in the “R” configuration at the asymmetric carbon, shown except in the case where X is carbonyl (C═O), when the preferred enantiomer is “S”.
The compounds of formula I have been found to activate glucokinase. Glucokinase activators are useful in the treatment of type II diabetes.
DETAILED DESCRIPTION OF THE INVENTION
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting.
In one embodiment, this invention provides amides of formula I, comprising compounds of formulae II and III as follows:
wherein R
1
and R
2
are independently hydrogen, halo, cyano, nitro, lower alkylthio, perfluoro lower alkylthio, lower alkyl sulfonyl, or perfluoro-lower alkyl sulfonyl, (preferably hydrogen, halo, lower alkyl sulfonyl, or perfluoro lower alkyl sulfonyl) R
3
is a 5 to 7-membered ring which is cycloalkyl, cycloalkenyl, or heterocycloalkyl having one heteroatom selected from oxygen and sulfur, R
5
is lower alkyl, X is oxygen, sulfur, sulfonyl or carbonyl, the * indicates an asymmetric carbon atom and
wherein R
1
and R
2
are independently hydrogen, halo, cyano, nitro, lower alkylthio, perfluoro lower alkyl thio, lower alkyl sulfonyl, or perfluoro-lower alkyl sulfonyl, (preferably hydrogen, halo, lower alkyl sulfonyl, or perfluoro lower alkyl sulfonyl) R
3
is a 5 to 7-membered ring which is cycloalkyl, cycloalkenyl, or heterocycloalkyl having one heteroatom selected from oxygen and sulfur, R
6
is an unsubstituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amide 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, X is oxygen, sulfur, sulfonyl or carbonyl, and the * indicates an asymmetric carbon atom
Preferably, the compounds of formulae II and III are in the “R” configuration at the asymmetric carbon shown except in the case where X is carbonyl (C═O), when the preferred enantiomer is “S”. The pharmaceutically acceptable salts of each amide of this invention are compounds of this invention.
In preferred amides of formula II, R
1
and R
2
are independently halo or lower alkyl sulfonyl, R
3
is a 5 to 7-membered ring which is cyclopentyl, cyclohexyl, cyclohexenyl, or heterocycloalkyl having one heteroatom selected from oxygen and sulfur (preferably oxygen) (Compound A).
In certain amides of Compound A, R
5
is methyl, and X is oxygen. More preferably R
1
and R
2
are independently chloro or methyl sulfonyl (which means R
1
and R
2
may each be chloro or methyl sulfonyl, or one is chloro while the other is methyl sulfonyl) (compound A-1). Examples of such compounds where R
1
and R
2
are c
Kester Robert Francis
Sarabu Ramakanth
Davis Zinna Northington
Hoffmann-La Roche Inc.
Johnston George W.
Parise John P.
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