JPH11130671A - Aldose reductase inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an aldose reductase having excellent inhibitory effect against aldose reductase, and useful as a preventive and/or therapeutic agent for diabetic complications such as diabetic neuropathy, retinopathy, cataract and nephropathy, or as a medicine or food additive. SOLUTION: This aldose reductase inhibitor contains, as active ingredient, compound(s) having aurone skeleton, specifically, maritimein of formula I and/or sulfuretin of formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an aldose reductase inhibitor, and more particularly to an aldose reductase inhibitor containing a compound having an aurone skeleton as an active ingredient. The drug of the present invention shows excellent inhibitory activity against aldose reductase, diabetic neuropathy, retinopathy, cataract,
As a preventive and / or therapeutic agent for diabetic complications such as nephropathy,
It is useful as a pharmaceutical or food additive.

[0002]

2. Description of the Related Art Diabetic complications are caused by metabolic abnormalities caused by prolonged hyperglycemia, and the hypothesis of increased polyol metabolism is widely accepted as one of the causes. Aldose reductase is an enzyme that converts glucose into sorbitol. When the glucose concentration in cells increases, the activity of the enzyme increases, and sorbitol is produced in large amounts and accumulates in tissues. It is said that cell dysfunction due to this sorbitol accumulation causes various complications. Therefore, the inhibitor of the present enzyme is useful as an agent for preventing and treating diabetic complications such as diabetic neuropathy, retinopathy, cataract and nephropathy.

[0003] Examples of applications of aldose reductase inhibitors as preventive or therapeutic agents for diabetic complications include:
Kinedak (registered trademark, generic name: Epalrestat, Ono Pharmaceutical Company Limited) is only on the market. However, as a preventive or therapeutic drug for diabetic complications using an aldose reductase inhibitor, a drug having a satisfactory effect cannot be said to be sufficiently provided, and a new drug has been desired.

[0004]

DISCLOSURE OF THE INVENTION In view of the above situation, the present inventors have conducted intensive searches for a substance having an aldose reductase inhibitory effect on a natural product. As a result, a compound having an aurone skeleton has an aldose reductase inhibitory activity. This led to the completion of the present invention. That is, the present invention comprises a compound having an aurone skeleton as an active ingredient,
It is an object to provide an aldose reductase inhibitor.

[0005]

The aldose reductase inhibitor of the present invention comprises a compound having an aurone skeleton as an active ingredient. The preventive or therapeutic agent for diabetic complications of the present invention is characterized in that a compound having an aurone skeleton and having aldose reductase inhibitory activity is used as an active ingredient.

[0006] The fact that compounds having aldose reductase inhibitory activity are effective as preventive or therapeutic agents for diabetic complications is disclosed, for example, in "Ayumi of Medicine", Vol.
13 (1991).

[0007] The compound having an aurone skeleton used in the present invention has good aldose reductase inhibitory activity and is useful as a preventive or therapeutic drug for diabetic complications.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION A compound used as an active ingredient of an aldose reductase inhibitor in the present invention is represented by the following formula (1):

[0009]

Embedded image Is a compound having an auron skeleton having a structure represented by
That is, the active ingredient of the aldose reductase inhibitor of the present invention may be any as long as it has the above-mentioned aurone skeleton and has aldose reductase inhibitory activity. Further, the compounds can be utilized in the form of a pharmaceutically acceptable salt. Bases used to obtain pharmaceutically acceptable salts include inorganic bases such as sodium, potassium, magnesium, calcium, aluminum;
Organic bases such as lower alkylamines and lower alcoholamines; basic amino acids such as lysine, arginine and ornithine; and ammonia can be mentioned, and salts can be formed by known methods.

The preferred compound having an auron skeleton is, for example, the following formula (2):

[0011]

Embedded image And pharmaceutically acceptable salts thereof, and the following formula (3):

[0012]

Embedded image Or a pharmaceutically acceptable salt thereof. Maritimine and sulfretin are known substances, are generally commercially available (Extra Syntheses) and are available compounds. Extraction and purification from plants (J. Am. Chem. Soc., 7
5, 1900 (1953)) or organic synthesis (Ber., 92, 2847)
(1959)).

When the aldose reductase inhibitor of the present invention is administered to humans and animals as pharmaceuticals, oral and parenteral administration methods can be used. Parenteral administration includes, for example, intravenous injection,
Intramuscular injection, subcutaneous injection, intraperitoneal injection, transdermal administration, pulmonary administration, nasal administration, enteral administration, buccal administration, transmucosal administration, etc., and formulation into a form suitable for these administration methods It is used. Examples of the formulation include injections, suppositories, aerosols, transdermal absorption tapes, eye drops, nasal drops and the like. Examples of oral administration preparations include tablets (including sugar-coated tablets, coated tablets and buccal tablets), powders, capsules (including soft capsules), granules (including coated ones), pills, troches, liquids,
Or, a pharmaceutically acceptable sustained-release preparation and the like can be mentioned. Liquid preparations for oral administration include suspensions, emulsions, syrups (including dry syrups), elixirs and the like. These preparations are administered as a pharmaceutical composition together with pharmacologically acceptable carriers, excipients, disintegrants, lubricants, coloring agents, etc., according to known pharmaceutical manufacturing methods. As carriers and excipients used in these preparations, for example, lactose, glucose, sucrose, mannitol, potato starch, corn starch, calcium carbonate, calcium phosphate, calcium sulfate, crystalline cellulose, licorice powder, gentian powder, etc. For example, starch, tragacanth, gelatin, syrup, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, hydroxypropylcellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, etc. Lubricants such as crystalline cellulose, calcium carbonate, sodium bicarbonate, and sodium alginate Magnesium stearate, talc, hydrogenated vegetable oil, macrogol, those which are allowed to added to pharmaceuticals as coloring agents, can be used respectively. Tablets and granules are sucrose, gelatin, hydroxypropylcellulose, purified shellac, gelatin, glycerin, sorbitol, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, cellulose phthalate acetate, hydroxypropylmethylcellulose phthalate, methyl methacrylate as required. And a film of methacrylic acid polymer or two or more layers. Further, capsules made of a substance such as ethyl cellulose or gelatin may be used. or,
When preparing injections, a pH adjuster, a buffer, a stabilizer, a solubilizer, and the like are added to the main drug, if necessary, and each injection is prepared by a conventional method. The drug of the present invention may be blended in a nutritional composition, food or the like.

The diseases targeted by the aldose reductase inhibitor in the present invention include diabetic complications such as diabetic neuropathy, retinopathy, cataract and nephropathy. When the aldose reductase inhibitor of the present invention is administered to a patient, it varies depending on conditions such as the degree of symptoms, age of the patient, health condition, and body weight, and is not particularly limited. However, about 10 mg to 10 g per day of an adult is orally or parenterally administered. 1 day a day
It may be administered one or more times. In the case of eye drops,
Adults several times a day, 1 drop, concentration 0.003-5 (W /
V) It is sufficient to administer about%. In addition, the toxicity of the drug of the present invention is very low. For example, 300 mg / kg body weight of this drug (malitimein or sulphletin) at 4 weeks of age (body weight of 100 to
Oral administration to 120 g) SD male rats showed no toxicity, and eye irritation was observed when 0.1 ml of a 1 (W / V)% solution was administered to the eyes of young adult rabbits. Not a very safe drug.

For use as a food additive, a body weight of 1 k
It can be mixed and used in foods so as to be 0.1 to 100 mg per g.

[0016]

The present invention will be described in more detail with reference to the following examples, which are merely illustrative, and do not limit the present invention. In the examples, "malitimein / sulfretin" means maritimine or sulfretin. Example 1 (Production of Injection) Injection composition: maritimine / sulfretin (Na salt): 1.5 g physiological saline: 100 ml (total: 1.5 g / 100 ml) Was dissolved in physiological saline, filled into a vial, and sterilized by heating to give an injection for intravenous injection. Example 2 (Production of tablets) Tablet composition: Malitime / sulfretin: 20 g Potato starch: 6 g Talc stearate: 4 g 6% HPC lactose: 170 g (Total: 200 g) To make 400 tablets of 500 mg each containing 50 mg of maritimine / sulfretin. Example 3 (Production of granules) Granule composition: maritimine / sulfretin 10 g lactose 187 g magnesium stearate 3 g (total: 200 g) After mixing the above components with the above composition, compression was performed. The mixture was molded, pulverized, and sized to prepare 20% to 50 mesh 5% granules. Example 4 (Manufacture of Capsule) Capsule composition: maritimine / sulfretin 5 g lactose 40 g potato starch 50 g hydroxypropyl methylcellulose 3.5 g magnesium stearate 1.5 g ( (Total: 100 g) The above components were mixed well with the above composition and filled in No. 1 capsule to produce 300 pieces. Example 5 (Manufacture of eye drops) Eye drop composition: maritimine / sulfretin 0.1 g sodium chloride 0.9 g benzalkonium chloride ... trace amount 1N sodium hydroxide ... appropriate amount 1N hydrochloric acid -Appropriate amount of sterilized purified water ... 100 ml Each of the above components was dissolved in sterilized purified water with the above composition and used as an eye drop by a conventional method. Test Example 1 Inukai.S et al.'S method (Jpn. J. Pharmacol., 61, 221-227)
(1993)), a crude enzyme of aldose reductase was prepared from a porcine lens. 0.4 M lithium sulfate, 150 μM NA
The test substance solution was added to 0.1 M phosphate buffer (pH 6.2) containing DPH and 10 mM glyceraldehyde, and then preincubated at 30 ° C. for 3 minutes. Add crude enzyme solution (5%, v / v
) Was added and the change with time in the absorbance at 340 nm at 30 ° C. was measured. The inhibition rate (%) was calculated by (1−change in absorbance for 1 minute in the system containing the test substance / change in absorbance for 1 minute in the control) × 100. The control is a system using distilled water instead of the test substance solution, that is, a system containing no test substance. Table 1 shows the results. As a result, the active ingredients of the present invention, sulfretin and malitime,
It was confirmed that tea catechin (Sanphenone, Taiyo Kagaku), which is a positive control, had an excellent aldose reductase inhibitory activity over that of tea catechin.

[0017]

[Table 1] (The numbers in the table represent inhibition (%))

[0018]

Industrial Applicability According to the present invention, there is provided an aldose reductase inhibitor comprising a compound having an aurone skeleton, particularly preferably maritimine and sulfretin as active ingredients. Due to its excellent activity, the drug of the present invention is useful as an agent for preventing and / or treating diabetic complications such as diabetic neuropathy, retinopathy, cataract and nephropathy, and as a pharmaceutical or a food additive.

Continued on the front page (51) Int.Cl. ⁶ Identification code FI // C07D 307/83 C07D 307/83 C07H 17/04 C07H 17/04 (72) Inventor Makoto Yoshihama 1400-8 Esojimacho, Utsunomiya City, Tochigi Prefecture ( 72) Inventor Kazuma Shioda 773-3 Ishibashi, Ishibashi-cho, Shimotsuga-gun, Tochigi SK Mansion 3-B (72) Inventor Kazuko Sanai 2-263-4-502 Mukogane, Nagareyama-shi, Chiba (72) Inventor Masae Ichikawa Chiba 179 Otaniguchi, Matsudo, Japan (72) Inventor Keinori Negishi 470-2-203, Hikawa-cho, Soka, Saitama (72) Kenji Seri 5-502, Yashio Danchi, Yashio, Saitama

Claims (3)

[Claims] An aldose reductase inhibitor comprising as an active ingredient a compound having an aurone skeleton. 2. The aldose reductase inhibitor according to claim 1, wherein the compound having an aurone skeleton is maritimine or a pharmaceutically acceptable salt thereof. 3. The aldose reductase inhibitor according to claim 1, wherein the compound having an aurone skeleton is sulfretin or a pharmaceutically acceptable salt thereof.