JPH03215426A - Agent for suppressing increase of blood sugar - Google Patents

Abstract

PURPOSE:To obtain an agent for suppressing the increase of blood sugar containing 1-phenyl-3-methyl-2-pyrazoline-5-one as an active ingredient, having excellent suppressing action on the increase of blood sugar caused by functional disorders of spleen and useful for preventing the occurrence of diabetes mellitus and preventing from becoming chronic diabetes. CONSTITUTION:The objective agent containing 1-phenyl-3-methyl-2-pyrazoline-5- one expressed by the formula or salt thereof as an active ingredient and obtained by properly blending the above-mentioned compound with carrier for preparation, vehicle, other additives ordinarily used and formulating according to ordinary method. The agent can be prepared in the form of tablet, soft gelatin capsule, injection, suspension, etc. The daily dose of the compound expressed by the formula is 1-100mg once to divided into 3 times/adult in the case of oral administration, 0.01-10mg divided into 2 to 5 times/adult in the case of intravenous injection and 1-100mg once to divided into 3 times/adult in the case of intrarectal administration.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention uses 1-phenyl-3-methyl-2-virazolin-5-one to effectively prevent or treat hyperglycemia caused by pancreatic dysfunction. This relates to a blood sugar rise suppressant as a component.

[Prior art and its problems] Diabetes is one of the modern diseases that continues to increase year by year, and efforts are being made to develop effective therapeutic agents that have few side effects, are easy to administer, and are effective.

On the other hand, much research has progressed in recent years on the relationship between the onset of diabetes and active oxygen, and it is becoming clear that there is a close relationship between the two. That is, one of the onset mechanisms of diabetes is cell destruction of the pancreatic islets of Langerhans, which produce and secrete insulin, which is an important factor for lowering blood sugar levels (representing blood glucose concentration). The cause of this cell destruction is lipid peroxidation of the membrane due to in-vivo metabolites and externally derived active oxygen superoxide (02 or hydroxyl radical (OH'), which is an even more oxidizing form of 02-). Tamoto clinical practice is considered to be important.
46, 120 (1988)). When this diabetes progresses and becomes chronic, it can lead to arteriosclerosis, which can lead to serious circulatory disorders such as cerebral infarction and myocardial infarction.
Japan Clinical Journal, 46, 113 (1988)).

Based on these facts, it is expected that suppressing membrane lipid peroxidation caused by active oxygen and preventing cell destruction of pancreatic islets of Langerhans will be able to prevent the progression and chronicity of diabetes and complications caused by this disease. However, nothing has been put into practical use yet.

The present inventors previously found that the following formula (II) ; R2 represents a hydrogen atom, an anoloxy group, an arylmercabuto group, an alkyl group having 1 to 5 carbon atoms, or a hydroxyalkyl group having 1 to 3 carbon atoms; or R1 and R2 jointly represent a group having 3 to 5 carbon atoms; represents an alkylene group; R3 is a hydrogen atom, and has 1 to 5 carbon atoms.
an alkyl group or a cycloalkyl group having 5 to 7 carbon atoms,
A hydroxyalkyl group having 1 to 3 carbon atoms, a benzyl group, a naphthyl group, or an unsubstituted alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a hydroxyalkyl group having 1 to 3 carbon atoms, Alkoxycarbonyl group having 2 to 5 carbon atoms in total, alkylmerkabuto group having 1 to 3 carbon atoms, alkylamino group having 1 to 4 carbon atoms, dialkylamino group having 2 to 8 total carbon atoms, halogen atom, trifluoromethyl represents a phenyl group substituted with 1 to 3 same or different substituents selected from the group consisting of a carbonyl group, a cyano group, a hydroxyl group, a nitro group, an amine group, and an acetamido group. ) was found to have a strong ability to inhibit lipid peroxidation, and to exhibit protective effects against ischemic brain dysfunction, which is mainly caused by lipid peroxidation caused by active oxygen, using an actual pathological model. (JP-A-61-263917 and JP-A-62-1088
Publication No. 14).

Furthermore, the present inventors investigated the protective effect of pyrazolone derivatives on blood sugar rise due to cell destruction of pancreatic islets of Langerhans by active oxygen OH' using an alloxan blood sugar rise model (Biochemical Pharmacology).
ical Pharmacology), 25. 1
085 (1976)), the following formula (
1-methyl-3-phenyl-2-virazolin-5-one represented by I): exhibits the most potent hypoglycemic inhibitory effect among the pyrazolone derivatives represented by formula (II), and furthermore, the representative OH' They discovered that it is superior to mannitol, which is a scavenger, and completed the present invention.

[Configuration of the Invention] The hypoglycemic agent of the present invention is 1-phenyl-3-methyl-
It is characterized in that it contains 2-Virazoline-5-one (hereinafter sometimes abbreviated as "F compound") or a pharmaceutically acceptable salt thereof as an active ingredient.

Among the salts of the present compound used in the present invention, pharmaceutically acceptable salts include those described in JP-A-62-108814. Namely, salts with mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid; methanesulfonic acid,
p-Toluenesulfonic acid, benzenesulfonic acid, acetic acid, glycolic acid, glucuronic acid, maleic acid, fumaric acid, oxalic acid, ascorbic acid, citric acid, salicylic acid,
Salts with organic acids such as nicotinic acid and tartaric acid; Salts with alkali metals such as sodium and potassium; Salts with alkaline earth metals such as magnesium and calcium; ammonia, tris(hydroxymethyl)aminomethane, N, N- Screw(
Examples include salts with amines such as hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, and L-glucamine.

Furthermore, the present compound used in the present invention can be synthesized by any method suitable for the purpose, and one of the preferred methods is the method described in JP-A-62-108814. It will be done.

When applying this compound clinically, when using it orally, it is preferable to administer 1 to 100 mg of this compound 1 to 3 times a day to adults, and once when administering intravenously. , 0.01 to 10 mg of this compound 2 times a day
It is preferable to administer the compound up to 5 times or by continuous infusion of these doses. In the case of rectal administration, it is preferable to administer 1 to 100 mg of the compound at a time, 1 to 3 times a day. Further, it is more preferable that the above dosage is adjusted as appropriate depending on the age, pathological condition, and symptoms.

Furthermore, in the case of oral or rectal administration, it may be used as a sustained release preparation.

Regarding formulation, it is common to use one or more of the present compound or its pharmaceutically acceptable salts as a composition containing commonly used pharmaceutical carriers, excipients, and other additives. . Pharmaceutical carriers may be solid or liquid; examples of solid carriers include lactose, kaolin, sucrose, crystalline cellulose, cornstarch, talc, agar, pectin, acacia, stearic acid, magnesium stearate, lecithin, and chloride. Examples include sodium.

Examples of liquid carriers include syrup, glycerin, peanut oil, polyvinylpyrrolidone, olive oil, ethanol, benzyl alcohol, propylene glycol, water, and the like.

Various dosage forms can be taken, and when a solid carrier is used, tablets, powders, granules, hard gelatin capsules, suppositories, or troches can be used. The amount of solid carrier can vary widely but is preferably from about 1 mg to about 1 g.
shall be.

If a liquid carrier is used, it can be a syrup, emulsion, gelatin capsule, sterile injectable solution such as an ampoule, or an aqueous or non-aqueous suspension.

Further, the present compound can also be used by inserting it into a cyclodextrin clathrate or liposome.

[Effects of the Invention] 1-Phenyl-3-methyl-2-virazolin-5-one of the present invention has an excellent effect of suppressing blood sugar rise, preventing the progression and chronicity of diabetes, and preventing circulatory disorders (arteriosclerosis) associated with this. , cerebral infarction, myocardial infarction).

[Examples of the Invention] Hereinafter, the present invention will be explained in more detail based on Examples, but these are not intended to limit the scope of the present invention in any way.

Synthesis Example 1 - Synthesis of Phenyl-3-Methyl-2-Virazolin-5 One 13.0 g of ethyl acetoacetate and 10.8 g of phenylhydrazine were added to 50 ml of ethanol, and the mixture was stirred under reflux for 3 hours. After cooling, the precipitated crystals were collected and recrystallized from ethanol to obtain 11.3 g of the title compound as colorless crystals.

Melting point. 127.5-128.5°C Example 1 After fasting male Wistar rats weighing approximately 300 g for 18 hours, alloxan was administered at 40 mg/k.
g was administered intravenously. At this time, 1-phenyl-3-methyl-2-birazolin-5-one of the present compound is 10 to 10
0mg/kg (after dissolving in 1N sodium hydroxide,
Neutralize with an equal volume of 1N hydrochloric acid, and add 1 ml of physiological saline.
kg) or 100 and 300 mg/kg (100 and 300 mg/kg) of mannitol, which has a lipid peroxidation inhibitory effect.
(adjusted to 1 ml/kg with physiological saline) was administered intravenously immediately before administration of alloxan. 1, 3 and 7 days after administration of alloxan, 50% blood was collected from the tail vein, respectively. 1 and 3000 r. p. m. At 10
After centrifugation for a minute, take 20p1 of the supernatant and use the enzyme method (Glucomesser Direct: Sinotest Shoji Co., Ltd.).
Colorimetric determination (Shimadzu UV
-730, measurement wavelength 5000 nm) L, blood sugar level was calculated according to the following formula.

As a control, a system in which only 1 ml/kg of physiological saline was administered intravenously was used.

The above results are shown in Table 1 below.

The blood glucose concentration of the rats treated with alloxan was approximately 430 to 460 mg/dl, which was approximately 3.7 times higher than that of the control group, but in the case where the compound was administered immediately before the administration of alloxan. , the increase in blood glucose concentration is suppressed, especially when this compound is administered at 30 to 100 mg/kg.
When administered, blood sugar rise was suppressed to the same extent as in the control group.

On the other hand, in the system in which mannitol, which is known as a lipid peroxidation inhibitor, was administered, no inhibitory effect on blood sugar rise was observed.

From the above results, the present compound had a large blood sugar increase suppressing effect on the alloxan blood sugar increase model, and its effect was far superior to that of mannitol, which is known to have a lipid peroxidation suppressing effect like the present compound.

Formulation Example 1 (1) Tablet The following ingredients were mixed according to a conventional method and tableted using a conventional device.

Active ingredients of this compound: 10 mg crystalline cellulose 21 mg cornstarch 33 mg lactose
65 mg Magnesium stearate 1.3 mg (2) Soft capsules The following ingredients were mixed in a conventional manner and filled into soft capsules.

Active ingredients of this compound: 10 mg olive oil 105 mg lecithin
6.5 mg (3) The following components were mixed according to a conventional method to prepare a 1 ml ampoule.

Claims (1)

[Claims] (1) The following formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼1-phenyl-3-methyl-2-pyrazolin-5-one represented by (I) or a pharmaceutically acceptable salt thereof A blood sugar rise suppressant as an active ingredient.