Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-03-24
1998-03-17
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514269, 544242, 544322, 544333, 544329, A71K 31505, C07D40104
Patent
active
057287040
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel pyrimidine derivatives and to the use of such derivatives and related compounds to inhibit sorbitol dehydrogenase, lower fructose levels, or treat or prevent diabetic complications such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic microangiopathy and diabetic macroangiopathy in mammals. This invention also relates to pharmaceutical compositions containing such pyrimidine derivatives and related compounds.
S. Ao et al., Metabolism, 40, 77-87 (1991) have shown that significant functional improvement in the nerves of diabetic rats (based on nerve conduction velocity) occurs when nerve fructose levels are pharmacologically lowered, and that such improvement correlates more closely with the lowering of nerve fructose than the lowering of nerve sorbitol. Similar results were reported by N. E. Cameron and M. A. Cotter, Diabetic Medicine, 8, Suppl. 1, 35A-36A (1991). In both of these cases, lowering of nerve fructose was achieved using relatively high does of aldose reductase inhibitors, which inhibit the formation of sorbitol, a precursor of fructose, from glucose via the enzyme aldose reductase.
We have found that pyrimidine derivatives of the formula I, as defined below, and their pharmaceutically acceptable salts, lower fructose levels in the tissues of mammals affected by diabetes (e.g., nerve, kidney and retina tissue) and are useful in the treatment and prevention of the diabetic complications referred to above. These compounds, or their metabolites in vivo, are inhibitors of the enzyme sorbitol dehydrogenase, which catalyzes the oxidation of sorbitol to fructose.
SUMMARY OF THE INVENTION
The present invention also relates to the use of substituted pyrimidines of the formula I, as defined below, to treat or prevent diabetic complications in mammals, and to pharmaceutical compositions containing such pyrimidines.
Compounds of the formula I are those having the formula ##STR1## wherein R.sup.1 is hydrogen, CF.sub.3, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl--S--(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl--SO--(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl--SO.sub.2 --(C.sub.1 -C.sub.6)alkyl, hydroxy-(C.sub.1 -C.sub.6)alkyl, dihydroxy-(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, (C.sub.1 -C.sub.6)alkoxycarbonyl-(C.sub.1 -C.sub.6)alkyl, aryl selected from phenyl and naphthyl, aryl-(C.sub.1 -C.sub.6)alkyl wherein the aryl moiety is selected from phenyl and naphthyl, (C.sub.1 -C.sub.6)alkoxycarbonylaryl wherein the aryl moiety is selected from phenyl and naphthyl, aryl-(C.sub.1 -C.sub.6)alkyl wherein the aryl moiety is selected from phenyl and naphthyl, aryl-(C.sub.1 -C.sub.6)alkyloxy wherein the aryl moiety is selected from phenyl and naphthyl, heteroaryl selected from pyridyl, furyl, tetrahydrofuryl, thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, benzothiazolyl, benzofuranyl, and benzothienyl; heteroaryl-(C.sub.1 -C.sub.6)alkyl wherein heteroaryl is defined as above, or heteroaryl-(C.sub.1 -C.sub.6)alkyloxy wherein heteroaryl is defined as above, and wherein said aryl and heteroaryl groups, the aryl moieties of said aryl-(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxycarbonylaryl and aryl-(C.sub.1 -C.sub.6)alkyloxy and the heteroaryl moiety of said heteroaryl-(C.sub.1 -C.sub.6)alkyl may optionally be substituted with one or more substituents independently selected from chloro, bromo, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, --S--(C.sub.1 -C.sub.6)alkyl, --SO--(C.sub.1 -C.sub.6)alkyl, --SO.sub.2 --(C.sub.1 -C.sub.6)alkyl, hydroxy-(C.sub.1 -C.sub.6)alkyl and trifluoromethyl;
or R.sup.1 is a group of the formula ##STR2## wherein the dotted line represents an optional double bond, W, Q and Z are independently selected from hydrogen, (C.sub.1 -C.sub.6)alkyl and trifluoromethyl, phenyl, furyl, triazolyl, thiazolyl and thienyl, wherein said phenyl, furyl, triazolyl, thiazolyl and thienyl may optionally be substituted with one or more-substituents independently selected from (C.sub.1 -C.sub.6)alkyl
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Mylari Banavara L.
Oates Peter J.
Siegel Todd W.
Zembrowski William J.
Butterfield Garth
Ginsbury Paul H.
Pfizer Inc.
Richardson Peter C.
Shah Mukund J.
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