The present invention relates to novel hydantoin derivatives, processes for producing hydantoin derivatives, pharmaceutical compositions containing at least one of said hydantoin derivatives as aldose reductase inhibitors and novel intermediate compounds in the synthesis of said hydantoin derivatives.
The present invention further relates to pharmaceutical compositions containing at least one of hydantoin derivatives as hypoglycemic agents.
Cataract, peripheral neuropathy, retinopathy and nephropathy associated with diabetes mellitus result from abnormal accumulation of polyol metabolites converted from sugars by aldose reductase. For example, sugar cataract results from damage of lens provoked by change in osmotic pressure induced by abnormal accumulation of polyol metabolites converted from glucose or galactose by aldose reductase in lens. [see J. H. Kinoshita et al., Biochim. Biophys. Acta, 158, 472 (1968) and cited references in the report]. And some reports were submitted about undesirable effect of abnormal accumulation of polyol metabolites in lens, peripheral nerve cord and kidney of the diabetic animals [see A. Pirie et al. Exp. Eye Res., 3, 124 (1964) ; L. T. Chylack Jr. et al., Invest. Ophthal., 8, 401 (1969) J. D. Ward et al., Diabetologia, 6, 531 (1970)]. Consequently, it is important to inhibit aldose reductase as strongly as possible for treating and/or preventing diabetic complications mentioned above. Although several compounds have been offered as aldose reductase inhibitors, none of them is fully sufficient in inhibitory activity against the enzyme. Therefore, it has been desired to develop new compounds having a stronger inhibitory activity against aldose reductase.
In spite of the early discovery of insulin and its subsequent wide-spread use in the treatment of diabetes mellitus, and the later discovery and use of sulfonylureas (e.g. chlorpropamide, tolbutamide) and biguanides (e.g. phenformin) as oral hypoglycemic agents, the treatment of diabetes mellitus remains less than satisfactory. Insulin can only be administered intravenously due to its chemical nature, and therefore, is troublesome and inconvenient to use. Oral hypoglycemic agents tend to promote side effects such as excessive hypoglycemia or lactic acidosis. A continuing need for potent hypoglycemic agents, which may be less toxic, is clearly evident.
Recently, developments of the aldose reductase (AR) inhibitors as agents for diabetic complications are in progress. AR inhibitors will not be agents for diabetes mellitus, but symptomatic agents for diabetic complications, so they are expected to be little effective against diabetes mellitus itself.
Diabetes mellitus should be treated by hypoglycemic agents, and preferably, by the hypoglycemic agents with AR inhibiting activity, so such agents having both hypoglycemic and AR inhibiting activities have been desired.
Further, diabetes mellitus is usually accompanied by cardiovascular disease due to atherosclerosis, so the hypoglycemic agents with hypolipidemic activities have also been desired.