JPS61268182A - Aldose reductase inhibitor - Google Patents

Abstract

PURPOSE:To provide the titled inhibitor composed of 3-methylglutaconic acid or its nontoxic salt, useful for the remedy or prevention of complication of diabetes, and easily producible in the form of injection, etc. CONSTITUTION:It has been found that 3-methylglutaconic acid of formula or its nontoxic salt (e.g. sodium salt) has aldose reductase inhibiting activity, and that the sodium salt (E-type) gives no toxic symptoms when administered to a mouse at a dose of 400mg/kg by intravenous injection. An aldose reductase inhibitor useful for the remedy or prevention of complication of diabetes can be produced by forming the above agent in the form of tablet, injection, etc. The inhibitor is administered orally or parenterally at a dose of 0.2-1,000mg daily for adult.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to an aldose reductase inhibitor that is expected to be used as a reagent and as a preventive and therapeutic agent for diabetic complications.

[Conventional technology]

In recent years, it has become clear that diabetic complications, particularly diabetic neuropathy, are due to the abnormal accumulation of nrubitol in the body due to the abnormal inhibition of aldose reductase. Tests and clinical trials are underway (Pharmasha, Volume 19 rh1 (19
83) Pages 43-47, Diabetes, Volume 28, Volume 2 (1
985) pages 89-98).

[Problems to be solved by the invention]

Aldose reductase inhibitors are highly water-soluble because it is becoming clear that they are useful as therapeutic agents for diabetic complications. Furthermore, it is expected that new aldose reductase inhibitors with various characteristics such as low toxicity will emerge.

[Means for solving problems]

Therefore, the present inventors conducted various studies and found that 3-methyl glutaconic acid (3-methyl glutaconic acid) expressed by the formula (1)
) was found to have an aldose reductase inhibitory effect.

The present invention has been completed based on the above findings.

3-Methylglutaconic acid of formula (I) used in the present invention is produced by the Journal Oporganic Chemistry (J.
Org, Chem, ), volume 33, page 1284 (
(1968) is a known compound that has been described.

Examples of the non-toxic salts include sodium salts, potassium salts, calcium salts, and ammonium salts.

The toxicity of 3-methylglutaconic acid used in the present invention is low; for example, its sodium salt (E type) was administered to mice for 400 min.
No signs of toxicity were observed even after intravenous administration of Ag.

When the aldose reductase inhibitor of the present invention is used for the treatment or prevention of complications of diabetes, solid preparations such as tablets, tablets, powders, capsules, and solutions such as injections and eye drops can be used. or in the form of a suspension;
Administered orally, parenterally or topically.

The dosage is usually 0.2 to 1000 doses per adult person per day.
It is appropriate to administer the drug orally or parenterally in 1 to 4 divided doses. For eye drops, it is desirable to instill one to several drops of the solution as an eye drop solution of 0001 to 1%, 3 to 5 times a day.

〔effect〕

Next, it will be explained using experimental examples that 3-methylglutaconic acid has aldose reductase inhibitory activity and suppresses the production of sorbitol in tissues.

Experimental Example 1 Various concentrations of 3-methylglutaconic acid (EW) were administered to aldose reductase, and the enzyme activity at each concentration was measured using Methods in Enzymeology.
Enzymology), Volume 41 (1975) 159
Measurement was performed according to the method described on the page, and the enzyme activity inhibition rate (value and 50% inhibitory concentration) at each concentration was determined.

The results are shown in Table 1.

In addition, the aldose reductase for measuring inhibitory activity is
Biochemical and Biophysical Research Communication (Biocien, Biophy
s, Res, Commun,) vol. 47 (1972
(2013) A sample collected from human placenta was used according to the method described on page 1473.

Table 1゜Experimental example 2゜Washed red blood cells derived from rats were mixed with 50 mmol of glucose and 3-methylglutaconic acid (EW, 2Na salt),
After incubating for 3 hours at 37°C, the total amount of sorbitol in red blood cells was determined by
It was measured according to the method described in Vol. 1980, pages 861-864, and the sorbitol production inhibition rate (regret) and 50% inhibitory concentration (IC50) were calculated.

The results are shown in Table 2.

Table 2 As is clear from Table 1 above, 3-methylglutaconic acid used in the present invention has aldose reductase inhibitory activity. Therefore, 3-methylglutaconic acid can be used as an aldose reductase inhibitor and is useful as a reagent.

Further, as is clear from Table 2 above, the aldose reductase inhibitor of the present invention exhibits the effect of suppressing sorbitol in red blood cells, and is therefore useful as an agent for treating or preventing complications of diabetes.

Since this substance (Na salt) has extremely high solubility in water, it has the effect of facilitating the production of aqueous preparations such as injections.

〔Example〕

1.3-methylglutaconic acid was dissolved in water containing 2 mol of sodium hydroxide and lyophilized.
-Methylglutaconic acid disodium salt is obtained.

Other non-toxic salts are obtained in a similar manner.

2. Formulation Example (1) Tablets containing 100,119 disodium 3-methylglutaconate per tablet were obtained using a rotary tablet press using a composition consisting of the following ingredients.

3-methylglutaconic acid disodium salt 100g milk
Sugar 200g Corn starch 10゜02 Polyvinylpyrrolidone 1oy Hydroxyglobil cellulose 80g Magnesium stearate 10g (2) Dissolve a composition consisting of the following ingredients in distilled water for injection, and adjust H to 6.8 with sodium hydroxide. After that, the total amount is set to 1 rnl. This solution was sterilized and filtered, and then sealed in 1 ml ampoules to obtain an injection.

Claims (1)

[Claims] Aldose reductase inhibitor containing 3-methylglutaconic acid or its non-toxic salt as an active ingredient