Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-06-26
2000-05-09
Higel, Floyd D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514399, 5483415, A61K 31415, C07D23360, C07D233101
Patent
active
060604964
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to an agent for the prophylaxis and treatment of diabetic complications, namely, to an agent for the prophylaxis and treatment of diabetic neuropathy, nephropathy, ophthalmopathy and arteriosclerosis. More particularly, the present invention relates to an agent for the prophylaxis and treatment of diabetic complications comprising, as an active ingredient, 4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoic acid, an optically active compound thereof or a pharmaceutically acceptable salt thereof. The present invention further relates to a method for the prophylaxis and treatment of diabetic complications.
BACKGROUND ART
The discovery of insulin and its clinical application resulted in drastic progress in the treatment of diabetes. Life sustention of the patients with diabetes--which had been a deadly disease until then--was strikingly improved. However, the therapy of chronic complications of diabetes has become a new problem.
The therapy of diabetes aims at prevention of such chronic complications, and essentially consists of a further control of blood glucose and a direct therapy of complications. The major chronic complications of diabetes are known to be neuropathy, nephropathy, ophthalmopathy, arteriosclerosis and the like (David M. et al., N. Engl. J. Med., 328, p. 1676-1685(1993)).
Various factors have been considered to be responsible for the onset and progression of chronic complications of diabetes. For example, there are known an abnormal sorbitol metabolism theory wherein activity promotion of sorbitol-producing polyol metabolitic pathway is the cause (Gabbay K. H. et al., N. Engl. J. Med. 288, p. 831-837(1973)), a circulatory disorder theory wherein a causative factor is a decreased blood flow due to angiopathy (Dyck P. J. et al, Proc. Natl. Acad. Sci. USA, 82, p. 2513-2517 (1985)), a theory attributing the disease to a compound produced by non enzymatic binding reaction of protein and reducing glucose (AGE: advanced glycation endproduct) (Brownlee M. et al., N. Engl. J. Med. 318, p. 1315-1321 (1988)) and the like. Based on each hypothesis, an aldose reductase inhibitor and lipoprostaglandin E1have been developed, and an AGE production inhibitor is under development.
The diabetic patients show promoted platelet aggregation, and the mechanism thereof has been known to be the promotion of biosynthesis of thromboxane (hereinafter abbreviated as TX) A2 due to hyperglycemia. This is considered to be one of the pathogens of diabetic chronic complications (Giovanni Davi M. D. et al., N. Engl. J. Med. 322, p. 1769-1774 (1990)). Thus, lipoprostaglandin E1 (hereafter sometimes to be referred to as Lipo PGE 1) having peripheral circulation improving action or platelet aggregation inhibitory action, 6-[4-(1 -cyclohexyl-1,2,3,4-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyryl(cilostazo l) and 6-[4-(R)-chlorophenylsulfonamido]-1-(3pyridylmethyl)pyrrolidin-2(S)-yl)-5- (Z)-hexenoic acid.hydrochloride (investigational numer: KDI-792) having TXA2 receptor antagonistic/synthesis inhibitory activity have been under development as agents for the prophylaxis and treatment of diabetic complications.
On the other hand, Japanese Patent Examined Publication No. 41143/1993 discloses 4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoic acid having pharmacological activities such as strong TXA2 biosynthesis inhibitory activity, platelet aggregation inhibitory action, vasodilating action and the like, which is useful for the prophylaxis and treatment of thrombosis, cerebral hemorrhage, myocardial infarction, acute cardiac death, angina pectoris, hypertension, asthma, nephritis and the like, an optically active compound and a pharmaceutically acceptable salt thereof. Nevertheless, it is not known that these compounds act as agents for the prophylaxis and treatment of diabetic complications.
Under the circumstances, the development of a new therapeutic agent that acts directly on chronic complications of diabetes for the prophylaxis and treat
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Goto Nobuharu
Hayashi Yoshiharu
Higel Floyd D.
Yoshitomi Pharmaceutical Industires, Ltd.
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