JP2906513B2 - Hypoglycemic inhibitor - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to 1-phenyl-3-methyl-2-pyrazolin-5-one for the purpose of preventing or treating progression of blood glucose elevation due to pancreatic dysfunction. The present invention relates to a blood glucose elevation inhibitor as an active ingredient.

[Prior art and its problems] Diabetes is one of the modern diseases which is increasing year by year, and the development of an effective therapeutic agent which has few side effects, is easily legalized and is effective is being actively conducted.

On the other hand, much modern research has been conducted on the relationship between the onset of diabetes and active oxygen, and it has been revealed that there is a close relationship between the two. That is, one of the onset mechanisms of diabetes is cell destruction of pancreatic islets of Langerhans, which produces and secretes an important insulin as a blood sugar level (representing blood glucose level) as a depressor. The cause of this cell destruction is that superoxide (O ₂ ⁻ ), which is a metabolite in the body and externally derived active oxygen, or a hydroxyl radical (OH ゜) in which O ₂ ^- has a more oxidizing power, It is thought that lipid peroxidation is important (Japanese clinical study, 4
6 , 120 (1988)). As this diabetes progresses and becomes chronic,
It causes arteriosclerosis and may be accompanied by severe circulatory disorders such as cerebral infarction and myocardial infarction (Japanese clinical study, 46 , 113
(1988)).

From these facts, it is expected that suppressing lipid peroxidation of membranes by active oxygen and preventing cell destruction of pancreatic islets of Langerhans can prevent the progression and chronicity of diabetes or complications based on this disease. However, nothing has been put into practical use.

The present inventors have previously made the following formula (II) (Wherein, R ¹ represents a hydrogen atom, an aryl group, an alkyl group having 1 to 5 carbon atoms or an alkoxycarbonylalkyl group having 3 to 6 carbon atoms; R ² represents a hydrogen atom, an aryloxy group, an arylmercapto group, Represents an alkyl group having 1 to 5 carbon atoms or a hydroxyalkyl group having 1 to 3 carbon atoms;
Alternatively, R ¹ and R ² together represent an alkylene group having 3 to 5 carbon atoms; R ³ is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or a cycloalkyl group having 5 to 7 carbon atoms,
A hydroxyalkyl group, a benzyl group, a naphthyl group or an unsubstituted or C1-C5 alkyl group,
An alkoxy group having 1 to 5 carbon atoms, a hydroxyalkyl group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, an alkylmercapto group having 1 to 3 carbon atoms,
4 alkylamino groups, dialkylamino groups having 2 to 8 carbon atoms, halogen atoms, trifluoromethyl groups, carbonyl groups, cyano groups, hydroxyl groups, nitro groups, amino groups and acetamido groups Represents a phenyl group substituted with 1 to 3 substituents. ) Were found to have a potent lipid peroxidation inhibitory action and to show a protective action against ischemic cerebral dysfunction mainly caused by active oxygen-induced lipid peroxidation by using an actual disease state model ( JP 61
-263917 and JP-A-62-108814).

Furthermore, the present inventors have studied the protective effect of pyrazolone derivatives on blood glucose elevation due to cell destruction of pancreatic islets of Langerhans by active oxygen OH ゜, using an alloxan blood glucose elevation model (Biochemical Pharmacology (Biochemical Pharmacology)).
Pharmacology), 25 , 1085 (1976)), the following formula (I): 1-methyl-3-phenyl-2-pyrazolin-5-one represented by the formula (II) exhibits the most potent anti-hyperglycemic effect among the pyrazolone derivatives represented by the formula (II), and is a typical OH ゜ scavenger. Was found to be superior to mannitol, and the present invention was completed.

[Constitution of the Invention] The blood glucose elevation inhibitor of the present invention is 1-phenyl-3-methyl-2-pyrazolin-5-one (hereinafter sometimes abbreviated as “the present compound”) or a pharmaceutically acceptable salt thereof. It is characterized by using the salt as an active ingredient.

Pharmaceutically acceptable salts of the compound used in the present invention include those described in JP-A-62-108814. That is, salts with mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, and phosphoric acid; methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, acetic acid, glycolic acid, glucuronic acid, maleic acid, fumaric acid, and oxalic acid. Salts with organic acids such as acid, ascorbic acid, citric acid, salicylic acid, nicotinic acid, 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-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine,
And salts with amines such as L-glucamine.

Further, regarding the method for synthesizing the present compound used in the present invention,
It can be synthesized by any suitable method, and one of the preferable methods is described in JP-A-62-108814.

In the case of oral use of the present compound in clinical applications, 1 to 100 mg of the present compound is administered once per adult.
It is preferably administered 1 to 3 times a day, and in the case of intravenous injection, it is preferable to administer 0.01 to 10 mg of the present compound 2 to 5 times a day or continuously instill these doses once a day,
In the case of rectal administration, the compound of the present invention may be administered once.
Preferably, 投 与 100 mg is administered one to three times a day. Also,
It is more preferable that the above dosage be appropriately increased or decreased depending on the age, disease state and symptoms.

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

With regard to formulation, it is common to use one or more of the present compound or a pharmaceutically acceptable salt thereof as a composition containing commonly used pharmaceutical carriers, excipients and other additives. . Pharmaceutical carriers may be solid or liquid, and examples of solid carriers include lactose, white clay (kaolin),
Sucrose, crystalline cellulose, corn starch, talc, agar, pectin, acacia, stearic acid, magnesium stearate, lecithin, sodium chloride and the like.

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

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

In addition, the compound can be used after being put into a cyclodextrin clathrate or liposome.

[Effects of the Invention] The 1-phenyl-3-methyl-2-pyrazolin-5-one of the present invention has an excellent blood glucose elevation inhibitory effect, prevents the progression and chronicity of diabetes, or circulatory disorders (arteries) associated therewith. Sclerosis, cerebral infarction, myocardial infarction).

[Examples of the Invention] Hereinafter, the present invention will be described in more detail based on examples, but this does not limit the scope of the present invention at all.

Synthesis Example 1 Synthesis of 1-phenyl-3-methyl-2-pyrazolin-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 refluxed and stirred for 3 hours. After allowing to cool, 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 Male Wistar rats weighing about 300 g
After fasting for an hour, alloxan 40 mg / kg was administered intravenously. At this time, 1-phenyl-3-methyl-2 of the present compound
-Pyrazolin-5-one 10 to 100 mg / kg (dissolved in 1N sodium hydroxide, neutralized with an equal volume of 1N hydrochloric acid, and adjusted to 1 ml / kg with physiological saline) or lipid extract Mannitol having an antioxidant action was administered intravenously at 100 and 300 mg / kg (prepared at 1 ml / kg with physiological saline) immediately before administration of alloxan. On days 1, 3 and 7 after alloxan administration, 50 μl of blood was collected from the tail vein and centrifuged at 3000 rpm for 10 minutes.
The μl was taken, and the glucose content in the sample was colorimetrically determined (Shimadzu UV-730, measurement wavelength 5000 nm) by an enzyme method (Glucomesser Direct: Sinotest Shoji Co., Ltd.), and the blood sugar level was calculated according to the following equation.

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

 The above results are shown in Table 1 below.

The blood glucose concentration of rats to which alloxan was administered was about 430 to 460 mg / dl, which was about 3.7 times higher than that of the control group. The rise in glucose concentration is suppressed,
In particular, when the present compound was administered at a dose of 30 to 100 mg / kg, the increase in blood glucose was suppressed to the same extent as that of the control group.

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

Based on the above results, the compound of the present invention has a large blood glucose elevation inhibitory effect on the alloxan hyperglycemic model, and the effect was much superior to that of mannitol, which is known to have a lipid peroxidation inhibitory effect similarly to the present compound.

Formulation Example 1 (1) Tablet The following components were mixed according to a conventional method, and tableted with a conventional device.

Active ingredient of this compound 10 mg Crystalline cellulose 21 mg Corn starch 33 mg Lactose 65 mg Magnesium stearate 1.3 mg (2) Soft capsule The following ingredients were mixed according to a conventional method, and filled in a soft capsule.

Active ingredient of this compound 10 mg Olive oil 105 mg Lecithin 6.5 mg (3) The following ingredients were mixed in a conventional manner to prepare a 1 ml ampule.

Active ingredient of this compound 0.7mg Sodium chloride 3.5mg Distilled water for injection 1.0ml

──────────────────────────────────────────────────続 き Continued on front page (58) Field surveyed (Int.Cl. ⁶ , DB name) A61K 31/415 C07D 231/120 CA (STN)

Claims (1)

(57) [Claims] 1. The following formula (I): 1-phenyl-3-methyl-2-pyrazolin-5-one represented by the formula: or a pharmaceutically acceptable salt thereof as an active ingredient.