Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-07-03
1997-06-03
Datlow, Philip I.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544105, A61K 31535, C07D41706
Patent
active
056355050
DESCRIPTION:
BRIEF SUMMARY
This is a 35USC371 National Stage of International Application PCT/JP94/00005, filed Jan. 6, 1994.
TECHNICAL FIELD
The present invention relates to novel 1,4-benzoxazine-2-acetic acid compounds having superior aldose reductase inhibitory activity, pharmaceutically acceptable salts thereof, methods for production thereof, and pharmaceutical use thereof. The compounds of the present invention and pharmaceutically acceptable salts thereof are useful as agents for the prevention and treatment of the complications of diabetes, such as 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 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 been recently 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 cataract, neurosis, nephropathy and retinopathy [J. H. Kinoshita et al. Biochem. Biophys. Acta, 158, 472 (968), 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.
Of the compounds synthesized for this end, Japanese Patent Unexamined Publication Nos. 40264/1986 and 107970/1988 describe that various 1,4-benzothiazine-4-acetic acid compounds have aldose reductase inhibitory action. Yet, the development of an agent for the prophylaxis and treatment of 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 certain benzoxazine compounds can accomplish such object and completed the present invention.
Accordingly, the present invention relates to a 1,4-benzoxazine-2-acetic acid compound of the following formula (I) ##STR2## wherein R.sup.1, R.sup.2 and R.sup.3 may be the same or different and each is a hydrogen atom, a lower alkyl, an alkoxy, a halogen atom or a hydroxy, R.sup.4 is a hydrogen atom, a halogen atom, a lower alkyl or an alkoxy and R.sup.5 is an optionally esterified carboxyl, and pharmaceutically acceptable salts thereof.
The present invention also relates to methods for producing 1,4-benzoxazine-2-acetic acid compounds of the above formula (I) and pharmaceutically acceptable salts thereof, comprising (a) reacting a compound of the formula (II) ##STR3## wherein R.sup.4 and R.sup.5 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, and Y is a halogen atom or --OSO.sub.2 R.sup.6 wherein R.sup.6 is lower alkyl, trifluoromethyl or optionally substituted phenyl, or (b) reacting a compound of the formula (IV) ##STR5## wherein R.sup.4 and R.sup.5 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, on demand, hydrolysis of the compound obtained in the above (a) or (b).
The present invention also provides a pharmaceutical composition containing the ab
REFERENCES:
patent: 4824833 (1989-04-01), Iijima et al.
patent: 4962200 (1990-10-01), Kihara et al.
Aotsuka Tomoji
Hase Takema
Ishikawa Hiromichi
Kobayashi Fujio
Kumonaka Takahiro
Datlow Philip I.
Qazi Sabiha N.
Senju Pharmaceutical Co. Ltd.
The Green Cross Corporation
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