Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1992-04-30
1994-04-19
Berch, Mark L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514249, 514403, 544236, 544237, 5483625, C07D23156, C07D40306, C07D47104, A61K 31415
Patent
active
053045572
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to novel substituted oxophthalazinyl acetic acids having aldose reductase inhibitory activity useful in the treatment of chronic complications arising from diabetes mellitus, such as diabetic cataracts, retinopathy and neuropathy, to pharmaceutical compositions containing such compounds and to a method of using such compounds.
The use of aldose reductase inhibitors in the treatment of complications of diabetes is known from European Patent Publication No. 222,576,published May 20, 1987, disclosing heterocyclic oxophthalazinyl acetic acids.
SUMMARY OF THE INVENTION
According to the invention, a compound is provided having the formula ##STR3## wherein A.sup.1 and A.sup.2 are independently N or CH; B is a covalent bond or C.dbd.O; R.sup.1 is hydrogen or C.sub.1 `-C.sub.6 alkyl; R.sup.2 is hydrogen, fluorine, chlorine, bromine, trifluoromethyl, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, or C.sub.1 -C.sub.4 alkylthio;
R.sup.3 is ##STR4## wherein R.sup.4 is phenyl optionally independently substituted by one or two of fluoro, chloro, bromo, trifluoromethyl, trifluoromethylthio, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, or nitro; with the proviso that when R.sup.4 is disubstituted phenyl, the substitution is at the 3 and 4, or the 3 and 5, or the 2 and 5 positions in the phenyl moiety; X is oxygen or sulphur; Y is hydrogen; or Y forms an indole group with the carbon on the ortho position of the phenyl moiety in R.sup.4 ; or a pharmaceutically acceptable base salt thereof when R.sup.1 is hydrogen; with the proviso that when B is a covalent bond, A.sup.1 and A.sup.2 are each CH.
In a preferred embodiment of the invention, A.sup.1 and A.sup.2 are each CH. In another preferred embodiment, B is C.dbd.O. In yet another preferred embodiment, R.sup.4 is phenyl substituted by at least one of chloro, bromo, or trifluoromethyl.
The present invention also relates to a composition for inhibition of aldose reductase activity comprising a compound of formula I in an amount effective in the inhibition of aldose reductase activity, in admixture with a pharmaceutically acceptable carrier. Preferred compositions contain the preferred compounds of formula I as described above.
The invention further comprises a method of treating a diabetic host such as an animal or a human for diabetes-associated complications, which comprises administering to the host an effective amount of a compound of formula I. Preferred methods comprise administering the preferred compound of formula I as described above.
DETAILED DESCRIPTION OF THE INVENTION
The term "alkyl" whenever used in the definitions of R.sup.1, R.sup.2, R.sup.3, etc., denotes saturated monovalent straight or branched aliphatic hydrocarbon radicals, such as methyl, ethyl, propyl, t-butyl, etc.
The compounds of formula I wherein R.sup.3 is --C(.dbd.X)--NYR.sup.4 may be prepared by reacting a compound of the formula ##STR5## wherein A.sup.1, A.sup.2, B and R.sup.2 are as defined above with reference to formula I, and R.sup.1 is C.sub.1 -C.sub.6 alkyl, with a compound of the formula ##STR6## wherein R.sup.6 is one or two of fluoro, chloro, bromo, trifluoromethyl, trifluoromethylthio, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, or nitro, with the proviso that when R.sup.6 is a disubstituent, the substitution is at the 3 and 4, or the 3 and 5, or the 2 and 5 positions in the aniline derivative of formula III. This condensation reaction proceeds under process conditions conventional for the formation of peptide bonds by coupling of a carboxylic acid and an amine. Thus, the reaction is generally conducted in the presence of a coupling agent such as isobutylchloroformate, dicyclohexylcarbodiimide or anhydroxy succinimide. The reaction is conveniently carried out in a reaction inert solvent. Suitable solvents are halocarbon solvents such as
REFERENCES:
patent: 4251528 (1981-02-01), Brittain et al.
patent: 4868301 (1989-09-01), Mylari et al.
patent: 4904478 (1990-02-01), Sinay, Jr. et al.
patent: 4939140 (1990-07-01), Larson
Berch Mark L.
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
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