Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-03-14
1997-11-18
Grumbling, Matthew V.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548180, C07D27762, C07D27764
Patent
active
056888180
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/JP 94/01266 (Aug. 1, 1994).
TECHNICAL FIELD
The present invention relates to novel succinamic acid compounds having superior aldose reductase activity-inhibitory action, pharmaceutically acceptable salts thereof (hereinafter also generally referred to as the compound of the present invention), production thereof and pharmaceutical compositions containing the compound of the present invention.
The above-mentioned compound of the present invention is useful as an aldose reductase inhibitor and as an agent for the prophylaxis and/or treatment of the complications of diabetes, such as faulty union of corneal injury, diabetic cataract, retinopathy, nephropathy and neurosis.
1. Background Art
There have been conventionally known many compounds having an aldose reductase activity-inhibitory action and some of them have been found to be useful as pharmaceuticals. However, the succinamic acid compound of the formula (1) of the present invention has not been known. The present invention has been made in an attempt to develop a more superior pharmaceutical product.
2. Disclosure of the Invention
In view of the present situation, the present inventors have conducted intensive studies for the purpose of developing a therapeutic agent for the complications of diabetes, which has an aldose reductase activity-inhibitory action, and found that a certain succinamic acid compound can accomplish the object, which resulted in the completion of the present invention.
That is, the present invention relates to succinamic acid compounds of the following formula (1) ##STR2## wherein R.sup.1 is an alkyl or a lower alkenyl and R.sup.2 is an optionally esterified carboxyl, pharmaceutically acceptable salts thereof, agents for the prophylaxis and/or treatment of the complications of diabetes which contain said succinamic acid compound or a pharmaceutically acceptable salt thereof as an active ingredient, and aldose reductase inhibitors containing, as an active ingredient, said succinamic acid compound or a pharmaceutically acceptable salt thereof, methods for producing the above-mentioned compounds of the formula (1) and pharmaceutically acceptable salts thereof, which comprise reacting a compound of the formula (2) ##STR3## wherein R.sup.1 is as defined above and R.sup.2A is an esterified carboxyl, or an acid addition salt thereof with 2-amino-3,4,6-trifluorothiophenol or an acid addition salt thereof, which is followed by, on demand, hydrolysis of said compound, and methods for producing the above-mentioned compounds of the formula (1) and pharmaceutically acceptable salts thereof, which comprise reacting a compound of the formula (3) ##STR4## wherein R.sup.1 is as defined above, with a compound of the formula (4) ##STR5## wherein R.sup.2A is as defined above and X is a halogen atom, or an acid addition salt thereof, which is followed by, on demand, hydrolysis of said compound.
The compound of the present invention which is represented by the formula (1) above has a novel structure essentially including a succinamic acid moiety as a basic structure.
The respective terms used in the present specification are defined in the following.
In the above-mentioned formula (1), esterified carboxyl is exemplified by lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl and tert-butoxycarbonyl, and aryloxycarbonyl and benzyloxycarbonyl both of which may have a substituent on the benzene ring, with preference given to ethoxycarbonyl.
Alkyl means linear, branched or cyclic alkyl having 1 to 16 carbon atoms, such as methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, amyl, isoamyl, sec-amyl, tert-amyl, cyclopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl and hexadecyl, with preference given to methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, butyl, cyclobutyl, amyl, cyclopentyl, hexyl, cyclohexyl, octyl and hexadecyl.
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Katritzy et. al., "A Novel Synthesis of Benzothiazoles.", Synth. Commun., vol. 18, No. 7 (1988), pp. 651-658.
Minisci et. al., "Amidomethylation of Basic Heterocyclic . . . ", Chemical Abstract, vol. 84 (1976), p. 501, ABS#59237v.
Francesco et al., Chemical Abstract, vol. 84, 1976, p. 59237.
Hosono Hiroshi
Ishikawa Hiromichi
Matsui Tetsuo
Nakamura Yoshiyuki
Nishio Toshiyuki
Grumbling Matthew V.
Ngo Tamthom T.
Senju Pharmaceutical Co. Ltd.
The Green Cross Corporation
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