3-oxo-1,4-benzothiazine derivatives

Details 3-oxo-1,4-benzothiazine derivatives 3-oxo-1,4-benzothiazine derivatives

1994-04-22

1996-03-05

Ford, John M.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

544 52, 514 63, C07D27916, A61K 3154

Patent

active

054968178

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP93/01190, filed Aug. 25, 1993.


TECHNICAL FIELD

This invention relates to novel 3-oxo-1,4-benzothiazine derivatives which have protein stabilizing effect and suppressive effect on lipid peroxide formation, and are useful for treatment of cataract etc.


BACKGROUND OF THE INVENTION

Cataract is an intractable eye disease where an opacification of lens is caused and results in a loss of visual acuity. Various studies on a causal factor and mechanism of cataract, and a treatment method therefor have been made. But at present, there is very few medical substances which are effective for cataract.
It is reported that an increase of peroxide in lens is related to a cause of cataract and a chemical substance having suppressive effect on lipid peroxide formation is effective on treatment of cataract (Current Eye Res., 5, 37 (1986)). It is also reported that protein denaturation is observed in lenses of cataract patients (Ophthalmology, 19, 1283 (1977)).
From the reports, a chemical substance which has suppressive effect on lipid peroxide formation in combination with protein stabilizing effect can be presumed to be especially useful for treatment of cataract. A compound having the above both effects, however, has not been studied and a development of such compound has been desired.
As the result of our precise study to find a compound having suppressive effect on lipid peroxide formation in combination with protein stabilizing effect, the inventors found that 3-oxo-1,4-benzothiazine derivatives, in which the 2nd-position was substituted by a benzylidene group and the 4th-position was substituted by a carboxyalkyl group, and the phenyl ring of the said benzylidene group was further substituted by hydroxy and lower alkyl groups, had the both effects.
3-Oxo-1,4-benzothiazine derivatives having benzylidene substituent at the 2nd-position, the chemical structure is common to the basic structure of the compound of this invention, were reported to be applicable to a herbicide (U.S. Pat. No. 3,923,709), a tranquilizer (Japanese Patent Publication No. 10671/1974) or a synthetic intermediate of benzothiazepine derivatives (Japanese Unexamined Patent Publication No. 72875/1985). The chemical structure of the compound of this invention is of course different from the compounds disclosed in the above prior arts. Further the prior arts disclose neither protein stabilizing effect nor suppressive effect on lipid peroxide formation.
Japanese Unexamined Patent Publication No. 287077/1989 discloses2-benzylidene-3-oxo-1,4-benzothiazine derivatives which have active oxygen elimination effect or suppressive effect on lipid peroxide formation. In the publication, however, a substituent at the 4th-position is limited to lower alkyl group and protein stabilizing effect is not disclosed at all.
In the meantime, recently an utility of aldose reductase inhibitors for treatment of cataract attracts attention. The compound of this invention has also aldose reductase inhibiting effect and is very useful for treatment of cataract.


DISCLOSURE OF THE INVENTION

This invention relates to the compounds of the formula [I] and salts thereof, ##STR2## wherein R.sup.1 is hydroxy which can be protected by a protective group; protective group, or lower alkoxy, and the said lower alkyl can be substituted by hydroxy, which can be protected by a protective group, amino or lower alkylamino;
The terms defined above are explained as follows in more detail.
The term "lower alkyl" intends to designate straight or branched alkyl having 1 to 6 carbon atoms exemplified by methyl, ethyl, propyl, hexyl, isopropyl, tert.-butyl and (dimethyl)ethyl.
The term "lower alkoxy" intends to designate straight or branched alkoxy having 1 to 6 carbon atoms exemplified by methoxy, ethoxy, propoxy, hexyloxy, isopropoxy and tert.-butoxy.
The term "alkylene" intends to designate alkylene having 1 to 10 carbon atoms exemplified by methylene, ethylene, propylene, tetramethylene, heptamethylene, decamethylene, (dimethyl)methylene and (diethyl)methy

REFERENCES:
patent: 3923709 (1975-12-01), Worley
J. W. Worley et al, "2-Dialkylphosphonyl-and 2-alkylidene-3,4-dihydro-3-oxo-2H-1,4-benzothiazines", Journal of Organic Chemistry, vol. 40, No. 12, 13 Jun. 1975, Easton US, pp., 1731-1734.

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