Benzothiazole compound, production thereof and use thereof

Details Benzothiazole compound, production thereof and use thereof Benzothiazole compound, production thereof and use thereof

1994-11-25

1996-07-02

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

548180, A61K 31425, C07D27764

Patent

active

055322573

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP94/00490 filed Mar. 25, 1994.


TECHNICAL FIELD

The present invention relates to a novel benzothiazole compound having superior aldose reductase inhibitory activity and a pharmaceutically acceptable salt thereof (hereinafter generally referred to as "compound of the invention"); an intermediate for producing the compound of the invention; production thereof; and pharmaceutical compositions containing the compound of the invention.
The aforementioned compound of the invention is useful as an aldose reductase inhibitor, as well as 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

Traditionally, blood sugar regulators such as insulin and synthetic hypoglycemic agents have been widely used for treating diabetes. 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, retinopathy, nephropathy and neurosis [see J. H. Kinoshita et al. Biochem. Biophys. Acta, 158, 472 (1968), Richard Poulson et al, Biochem. Pharmacol., 32, 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.
Japanese Patent Unexamined Publication Nos. 40478/1982 and 107970/1988 describe that various compounds synthesized for this end have aldose reductase inhibitory action. 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 benzothiazole compounds of the following formula (I) ##STR2## wherein R.sup.1 is a halogen atom, R.sup.2 and R.sup.3 may be the same or different and each is a hydrogen atom or a halogen atom, R.sup.4 is a hydrogen atom, a halogen atom, a lower alkyl, an alkoxy or an alkyl mercapto and R.sup.5 is a hydrogen atom or a lower alkyl, and pharmaceutically acceptable salts thereof can achieve the object and established a method for the efficient production of said compounds, which resulted in the completion of the invention.
That is, the present invention provides the benzothiazole compounds of the above-mentioned formula (I) and pharmaceutically acceptable salts thereof; a method for producing benzothiazole compounds of the above formula (I) and pharmaceutically acceptable salts thereof, comprising reacting a compound of the formula (II) ##STR3## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined above, or a salt thereof, with a compound of the formula (III) ##STR4## wherein X is a halogen atom and R.sup.5a is a lower alkyl, followed by hydrolysis on demand, or reacting a compound of the formula (IV) ##STR5## wherein R.sup.4 and R.sup.5a are as defined above, or a salt thereof, with a compound of the formula (V) ##STR6## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above, or an acid addition salt thereof, followed by hydrolysis on demand; and pharmaceutical comp

REFERENCES:
J. Med. Chem., 15(5), 1972, 523-29.
Chem. Pharm. Bull., 21(1), 1973, 184-90.
Reddy et al., Synth. Comm., 21(2), 173-181, (1991).

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