N-substituted dioxothiazolidylbenzamide derivatives and process

Details N-substituted dioxothiazolidylbenzamide derivatives and process N-substituted dioxothiazolidylbenzamide derivatives and process

1998-06-16

1999-09-07

Morris, Patricia L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

548183, A61K 31425, C07D27734

Patent

active

059488034

DESCRIPTION:

BRIEF SUMMARY
TITLE OF THE INVENTION

N-substituted dioxothiazolidylbenzamide derivatives and the process for preparing the same


TECHNICAL FIELD

The present invention relates to novel N-substituted dioxothiazolidylbenzamide derivatives that improve the diabetes mellitus and hyperlipidemia, and the process for preparing the same.


BACKGROUND TECHNOLOGIES

So far, as oral therapeutic drugs for diabetes mellitus, biguanide type and sulfonylurea type compounds have been used. However, with biguanide type compounds, lactic acidosis or hypoglycemia is caused and, with sulfonylurea type compounds, serious and prolonged hypoglycemia is caused, and the adverse effect thereof is posing a problem. Therefore, the appearance of new therapeutic agent without such defect is desired.
Moreover, it is known that some of the 2,4-dioxothiazolidine derivatives exhibit hypoglycemic and lipid-lowering effects (Journal of Medicinal Chemistry, vol. 35, P. 1853 (1992) and Japanese Unexamined Patent Publication No. Hei 1-272573), but, in all of these compounds, the position of substitution on middle benzene ring that connects with 2,4-dioxothiazolidine ring and aromatic ring is p-position; the former has oxazole ring for the aromatic ring and the latter has sulfonylamide for the linkage. In addition, both have a carbon chain between middle benzene ring and thiazolidine-2,4-dione ring, structurally different from N-substituted dioxothiazolidylbenzamide derivatives of the present invention.
On the other hand, it has been clear that aldose reductase takes part in the crisis of diabetic complication (Journal of American Medical Association, vol. 246, p. 257 (1981)).
Moreover, it is known that some of the 2,4-dioxothiazolidines exhibit aldose reductase inhibitory activity (Chemical and Pharmaceutical Bulletin, vol. 30, p. 3601 (1982) and Japanese Unexamined Patent Publication No. Hei 5-92960). In the former, the 2,4-dioxothiazolidine ring and the carboxyl group are p-substituted via middle benzene ring and in the latter, the bonding mode to middle benzene ring is acylamino, and the like. Therefore they are sturcturally different from N-substituted dioxothiazolidylbenzamide derivatives of the present invention, and additionally they have only weak hypoglycemic effect.
For the non-insulin dependent diabetes mellitus (NIDDM) that accounts for the majority of diabetic patients, an effective blood sugar-lowering drug with high safety that allows to prevent or cure the complications together with ability for improving insulin resistance and lowering blood sugar is desired.


DISCLOSURE OF THE INVENTION

As a result of diligent studies on a drug with high safety that improves the insulin resistance and has more potent hypoglycemic effect, the inventors have found that novel N-substituted dioxothiazolidylbenzamide derivatives represented by a following general formula (1) exhibit not only potent hypoglycemic and lipid-lowering effects but also aldose reductase inhibitory activity, leading to the completion of the invention.
Namely, the invention provides N-substituted dioxothiazolidylbenzamide derivatives represented by the general formula (1) ##STR2## atoms, lower alkyl groups with carbon atoms of 1 to 4, lower alkoxy groups with carbon atoms of 1 to 3, lower haloalkyl groups with carbon atoms of 1 to 3, lower haloalkoxy groups with carbon atoms of 1 to 3, halogen atoms or hydroxyl groups, or R.sup.1 and R.sup.2 combine to form a methylenedioxy group, R.sup.3 denotes a hydrogen atom, lower alkoxy group with carbon atoms of 1 to 3, hydroxyl group or halogen atom, R.sup.4 denotes a hydrogen atom or lower alkyl group with carbon atoms of 1 to 3, n denotes an integer of 0 to 2, and X denotes N or CH!, and their pharmacologically acceptable salts.
The salts of the compounds represented by the general formula (1) in the invention are of common use, and metal salts, for example, pharmacologically acceptable salts such as alkali metal salts (e.g. sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g. calcium salt, magnesium salt, etc.) and aluminum

REFERENCES:
patent: 5308856 (1994-05-01), Ohnota et al.
patent: 5342850 (1994-08-01), Ohnota et al.

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