Quinoline-3-acetic acid derivative, process for production there

Details Quinoline-3-acetic acid derivative, process for production there Quinoline-3-acetic acid derivative, process for production there

1994-11-01

1996-08-06

Ivy, C. Warren

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

546157, 546158, C07D41706, C07D215227, A61K 3147, A61K 31425

Patent

active

055434207

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP94/00007, filed 6 Jan. 1996.


TECHNICAL FIELD

The present invention relates to a novel quinoline-3-acetic acid derivative having a superior aldose reductase inhibitory activity, a pharmaceutically acceptable salt thereof, a process for the production thereof and a pharmaceutical agent containing said compound.
The compounds of the present invention mentioned above (which include the above-mentioned derivative and a pharmaceutically acceptable salt thereof, hereinafter the same) are useful as aldose reductase inhibitors and for the prevention and/or treatment of the complications of diabetes, such as faulty union of corneal injury, diabetic cataract, retinopathy, nephropathy and neurosis.


BACKGROUND ART

For treating diabetes, blood sugar regulators such as insulin and synthetic hypoglycemic agents have been conventionally used widely. Diabetes is a disease which accompanies various complications which are hardly prevented from developing by a mere control of the blood sugar, and a new therapeutic agent for the complications of diabetes has been demanded. Accumulation of and increase in sorbitol and galactitol in tissues which are caused by chronic hyperglycemia have recently been drawing attention as the mechanism of the onset of the complications of diabetes.
Some literatures suggest that a compound having an inhibitory action on the activity of aldose reductase, which is an enzyme capable of converting aldose such as glucose or galactose into sorbitol or galactitol, is useful for the treatment of the complications of diabetes, such as faulty union of corneal injury, cataract, neurosis, nephropathy and retinopathy [see J. H. Kinoshita et al., Biochem. Biophys, Acta, 158, 472 (1968), Richard Poulson et al. Biochem. Pharmacol., 2, 1495 (1983) and D. Dvornik et al., Science, 182, 1145 (1973)].
Based on the foregoing, the study is directed to the prevention and treatment of the complications of diabetes by the inhibition of aldose reductase activity to ultimately inhibit accumulation of polyols such as sorbitol and galactitol.
Of the compounds synthesized for this end, various 1,4-benzothiazine-4-acetic acid derivatives have aldose reductase inhibitory action as reported in Japanese Patent Unexamined Publication Nos. 40264/1986 and 107970/1988. Yet, the development of a therapeutic agent for the complications of diabetes, which has a still more excellent aldose reductase inhibitory action, is desired.


DISCLOSURE OF THE INVENTION

In view of the above, the present inventors have conducted intensive studies with the aim of developing a therapeutic agent for the complications of diabetes, which has an aldose reductase inhibitory action, and found that a certain quinoline derivative can achieve the object, which resulted in the completion of the invention.
That is, the present invention provides a quinoline-3-acetic acid derivative of the formula (I) ##STR2## wherein R.sup.1, R.sup.2 and R.sup.3 are the same or different and each is a hydrogen atom or a halogen atom, R.sup.4 is a hydrogen atom, a halogen atom or a substituted or unsubstituted lower alkyl, R.sup.5 is an optionally esterified carboxyl and the broken line means an optional presence of a double bond, or a pharmaceutically acceptable salt thereof; a process for producing the aforementioned quinoline-3-acetic acid derivative or a pharmaceutically acceptable salt thereof, comprising reacting a compound of the formula (II) ##STR3## wherein R.sup.4, R.sup.5 and the broken line are as defined above, or a salt thereof with a compound of the formula (III) ##STR4## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above, or an acid addition salt thereof and hydrolysis where necessary; and a composition containing the compound as an active ingredient.
The compound of the formula (I) of the present invention has a novel structure essentially comprising a quinoline-3-acetic acid moiety as the basic structure.
Examples of the halogen atom include fluorine atom, chlorine atom, bromine atom and iodine atom. The substituted

REFERENCES:
patent: 5143930 (1992-09-01), Yoshioka
patent: 5258382 (1993-11-01), Negoro
patent: 5262433 (1993-11-01), Horio
Elgemeie, "Nitriles in Heterocyclic Synthesis . . .", Heterocycles, vol. 24, No. 2, pp. 349-353, 1986.
Fathy, "Nitriles in Heterocylic Synthesis . . .", Arch Pharm (Weinhiem), vol. 321, pp. 509-512, 1988.

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