JPH059114A - Preventive and therapeutic agent for diabetic complication - Google Patents

Abstract

PURPOSE:To obtain a safe preventive and therapeutic agent useful for diabetic complications such as nephritis, retinitis, neuropathy, arteriosclerosis, thrombosis, cataract, iritis and gangrene caused by superpoxide dismutase produced from saccharified proteins in the body of a patient suffering from diabetes. CONSTITUTION:A safe preventive and therapeutic agent for diabetic complications, containing a compound expressed by the formula [R is methyl or methoxy or two groups R are bonded to form one butadienylene; (n) is an integer of 4-22, preferably 7-15, especially 9-13] or its hydroquinone derivative, e.g. idebenone [2, 3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone] as an active ingredient and having low toxicity. The aforementioned compound can orally or parenterally be administered in various dosage forms such as a tablet, a granule, a capsule, an injection or a suppository to patients suffering from diabetes. The normal dose of the aforementioned agent for an adult is 0.1-500mg, preferably 5-200mg per day in the case of oral administration.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a preventive / therapeutic agent for diabetic complications.

[0002]

2. Description of the Related Art Generally, in diabetic patients, non-enzymatic glycation of proteins due to hyperglycemia is accelerated, while arteriosclerosis, nephropathy,
It causes various diabetic complications such as retinopathy. It is considered that these complications may be caused by superoxide-induced vascular endothelial cell damage. However, the relationship between the large amount of glycated proteins and the production of superoxide has not been clarified.

[0003]

From the above viewpoints, the present inventors have earnestly studied the superoxide production mechanism and the superoxide production inhibitor, and as a result,
It was found that superoxide is produced by autoxidation of glycated protein, and that the 1,4-benzoquinones represented by the general formula (I) and their hydroquinone compounds have a superoxide production inhibitory action. .

[0004]

The present invention has the general formula

[Chemical 2] [In the formula, each R represents a methyl group or a methoxy group, or two R are bonded to each other to represent one butadienylene group, and n represents an integer of 4 to 22. ] The preventive / therapeutic agent for diabetic complications caused by superoxide generated from glycated protein in a diabetic patient body, which comprises a compound represented by the formula or a hydroquinone form thereof as an active ingredient.

In the compound represented by the general formula (I), n is preferably 7 to 15, more preferably 9 to 13. Representative examples of the compound represented by the general formula (I) include idebenone [2,3-dimethoxy-5-methyl-6- (10-hydroxydecyl) -1,4-benzoquinone].

The hydroquinone form of the compound represented by the general formula (I) is represented by the general formula

[Chemical 3] (In the formula, each symbol has the same meaning as described above). Since the compound represented by the general formula (I) and its hydroquinone compound (II) can be interconverted under physiological conditions, these compounds are considered to be pharmacologically equivalent to each other. . Generally, the hydroquinone compound (II) is easily chemically oxidized, and thus the quinone compound (I) is easier to handle.

When the compound represented by the general formula (I) is used as a prophylactic / therapeutic agent for diabetic complications as described above, for example, according to a method known per se,
It can be orally or parenterally administered to diabetic patients in various dosage forms such as tablets, granules, capsules, injections and suppositories. The dose varies depending on the type and symptom of the target disease, but in general, in adults, in the case of oral administration, it is generally 0.1 mg to 500 mg, preferably 5 mg to 2 mg per day.
It is 00 mg.

The preventive / therapeutic agent for diabetic complications of the present invention is caused by superoxide generated from glycated protein in diabetic patients such as nephropathy, retinopathy, neuropathy, arteriosclerosis, thrombosis, cataract, iritis, It is used for prevention and treatment of gangrene.

[0009]

EXAMPLES The operation and embodiments of the present invention will be specifically described by the following experimental examples and examples. Experimental Example 1 Purified human fibrinogen was incubated with glucose to prepare saccharified fibrinogen. Idebenone was added thereto, and the change in absorbance at a wavelength of 550 nm, 37 ° C., and 10 minutes was measured by the cytochrome C method in order to check the amount of superoxide produced. As a control, a similar test was conducted without using idebenone and using only non-glycated fibrinogen. The results are as shown in [Table 1].

[Table 1] Glycated fibrinogen produced more superoxide than non-glycated fibrinogen, and the addition of idebenone suppressed the production of superoxide.

Experimental Example 2 4-week-old female KKA ^y mouse ¹⁾ was fed CE-2 powdered feed (CLEA Japan, Inc.) containing 0.05% idebenone for 4 weeks, urine was collected for 24 hours, and excreted in urine. The amount of albumin produced was determined. The results are as shown in [Table 2].

[Table 2] The test compound reduced urinary albumin excretion and urinary albumin / total protein ratio without affecting the onset of hyperglycemia and weight gain in KKA ^y mice.

Formulation Example 1 (1) Idebenone 20 g (2) Lactose 198 g (3) Corn starch 40 g (4) Magnesium stearate 2 g Granulated with a paste made from (1), (2) and 15 g of corn starch, 10 g of corn starch and (4) were added to, and the mixture was compressed by a compression tablet machine to give (1) 20 mg per tablet containing 5 mg in diameter.
1000 tablets of m were produced.

[0012]

The general formula (I) used in the present invention is as follows.
The prophylactic / therapeutic agent for diabetic complications containing the compound represented by the formula or a hydroquinone derivative thereof has low toxicity and is safe, and nephropathy, retinopathy caused by superoxide generated from glycated protein in diabetic patients, It is useful for diabetic complications such as neuropathy, arteriosclerosis, thrombosis, cataract, iritis, and gangrene.

Claims (1)

What is claimed is: 1. A general formula: [In the formula, each R represents a methyl group or a methoxy group, or two R are bonded to each other to represent one butadienylene group, and n represents an integer of 4 to 22. ] A preventive / therapeutic agent for a diabetic complication caused by superoxide generated from a glycated protein in a diabetic patient's body, which comprises a compound represented by the following formula or a hydroquinone derivative thereof as an active ingredient.