JPS6047263B2 - Biguanide derivative hetero5-membered ring carboxylic acid salt and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to a novel five-membered heterocyclic carboxylate of a biguanide derivative and a method for producing the same.

Background of the Invention Diabetes is currently generally understood to be a metabolic disorder caused by insufficient insulin action, but traditionally the metabolic abnormalities in diabetes were mainly disorders of carbohydrate metabolism, with other disorders being secondary. In some ways, it has been thought that

However, in recent years, Randle and Weber et al. have clarified the interaction between carbohydrate metabolism and lipid metabolism (Randle P.
J. , Llncet. L785 (1963), Web
rG. , Scier] Ce Takumi (1357 (1966))
The important role that lipid metabolism plays in diabetes has been recognized. Today, phenethylbiquanide, butylbiquanide, and dimethylbiquanide are used clinically as hydrochlorides as biquanide antidiabetic drugs, but these biquanide derivative hydrochlorides are relatively toxic. It is also known that its effect on lipids is very weak.

The present inventor conducted research based on the knowledge that biquanide derivatives have a remarkable hypoglycemic effect as well as an effect on lipids, and that if a compound with lower toxicity could be obtained, an extremely advantageous antidiabetic drug could be obtained. As a result of repeating
It has been discovered that this objective can be achieved by combining a biquanide derivative with a five-membered heterocyclic carbonic acid. DISCLOSURE OF THE INVENTION The biguanide derivative heterofive-membered carboxylic acid salt of the present invention has the general formula (wherein one of R1 and R2 represents a hydrogen atom, a lower alkyl group, or an aralkyl group, and the other represents a lower alkyl group or an aralkyl group). This is a compound represented by

Examples of lower alkyl groups represented by R1 and R2 in the formula include methyl, ethyl, propyl, and butyl groups, and examples of aralkyl groups include benzyl and phenethyl groups. The above compound of the present invention is a new compound and has excellent hypoglycemic and free fatty acid lowering effects.

In addition, its efficacy remains unchanged even after continuous administration, making it useful as a therapeutic agent for diabetes. General formula of the present invention [
1] can be produced by reacting a compound represented by the general formula (in which R1 and R2 are the same as above) and a compound represented by the general formula.

For detailed explanation of the present invention, compound [2] and compound [3] used as raw materials of the present invention are known compounds, and examples of compound [2] include dimethyl biguanide, butyl biguanide, phenethyl biguanide, etc. Examples of compound [3] include 3-methylisoxazole-5-carboxylic acid and 5-methylisoxazole-3-carboxylic acid.

Compound [2] is usually preferably used in its free form during the reaction, but its mineral acid salt can also be used. When using the latter mineral salt, for example, the mineral salt can be added to an equimolar amount of sodium metal dissolved in anhydrous alcohol, and the precipitated inorganic salt can be filtered and used afterward.
It is not necessarily necessary to isolate during the reaction. Compound〔
2] and compound [3] is usually preferably carried out in a solvent.

The solvent is not particularly limited as long as it does not participate in the reaction, but methanol, ethanol, acetone, etc. are generally preferably used. Although the ratio of compound [2] and compound [3] may be selected as appropriate, it is generally advantageous to use equimolar amounts. Although the reaction temperature may be selected appropriately, the reaction generally proceeds advantageously at room temperature to 100°C. The above reaction produces a new compound [1], which can be isolated by conventional separation means such as distillation, chromatography, recrystallization, etc. The toxicity, blood sugar lowering effect, and free fatty acid lowering effect of representative compounds of the present invention will be shown below.

1 Acutely toxic Wistar rats (male), 5 weeks old, were raised for 1 week, and 16
~1? After intermittent fasting, the compound of Example 4 described below was orally administered.

LD5O was calculated by the conventional up-down method. The results are shown in Table 1. 2 Blood sugar lowering effect and free fatty acid lowering effect Wistar rat (male) 5 weeks old, (body weight 140-15
A 5% physiological saline solution of alloxan monohydrate was intravenously injected into the mice (50 m9/K9), and after 2 weeks, those showing good body weight and high blood sugar levels (>400 mg/d1) were selected and used in the test. .

The compound of Example 4 described later was made into a 0.5% carboxymethylcellulose aqueous solution or suspension, and 1 m1/100y
was administered orally at a rate of Blood was collected from the tail vein at 0, 2, 4, and 6 hours after administration, and plasma was used for measurements. Plasma glucose was measured by the glucose oxidase method, and free fatty acids were measured by the Itaya-Uy method. Efficacy evaluation was expressed as a reduction rate (%) relative to the control. The results are shown in Table 2. EXAMPLES Next, the present invention will be explained in detail by giving examples.

Example 1 After dissolving 1.38 y of metallic sodium in 80 ml of anhydrous methanol, 1,1-dimethyl biguanide sulfate 6
．． Add 81q.

Stir for 1 hour at room temperature and 1 hour under reflux. After removing insoluble materials during cooling, 3.81y of 3-methylisoxazole-5-carboxylic acid is added. The mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The residue is recrystallized from isopropyl alcohol to obtain 5.5y of 3-methylisoxazole-5-carboxylate of 1,1-dimethylbiguanide having an Mpl of 76 to 177°C. (Yield 71.6%) Elemental analysis (C
9Hl6N6O3) Example 2 When 5-methylisoxazole-3-carboxylic acid was used in place of 3-methylisoxazole-5-carboxylic acid in Example 1 and the same operation was performed, Mpl44-1
5.9y of 5-methylisoxazole-3-carboxylate of 1,1-dimethylbiguanide of Encyclopedia 45C is obtained.

(Yield 76.8%) Elemental analysis (C9H, 6N603) Example 3 After dissolving 1.38 da of metallic sodium in 100 ml of anhydrous methanol, 1-n-butyl biguanide sulfate 7
．． Add 66q.

Stir for 1 hour at room temperature and 1 hour under reflux. After removing insoluble materials during cooling, 3.81f of 3-methylisoxazole-5-carboxylic acid is added. The mixture was stirred at 50° C. for 1 hour, and the solvent was distilled off under reduced pressure.

The residue is recrystallized from isopropyl alcohol ether to obtain 6.4q of 3-methylisoxazole-noncarboxylic acid salt of 1-n-butyl biguanide having an Mpl of 42 to 144-C. (Yield 75.1%) Elemental analysis (Cl
lH2ONGO3) Example 4 - 0.69f1 of metallic sodium in 80ml of anhydrous methanol
After dissolving 1-phenethyl biguanide hydrochloride 7
．． Add 25y.

After stirring overnight at room temperature, 3.81y of 3-methylisoxazole-5-carboxylic acid is added. Stir at room temperature for 1 hour to remove insoluble materials. ) When the solution is concentrated under reduced pressure and reconstituted from ethanol-ether-acetone, Mpl33-1 is obtained.
7.4y of 3-methylisoxazole-5-carboxylate of 1-phenethyl biguanide at 35°C is obtained. (Yield 74.3%) Elemental analysis (Cl5H2ON6O3)

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. Biguanide derivative hetero five-membered ring carboxylic acid salt represented by (representing a group). 2. A biguanide derivative hetero5-membered ring carboxylic acid salt according to claim 1, which is represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. 3. A biguanide derivative hetero5-membered ring carboxylic acid salt according to claim 1, which is represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. 4. A biguanide derivative hetero5-membered ring carboxylic acid salt according to claim 1, which is represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. 5. The biguanide derivative hetero5-membered ring carboxylic acid salt according to claim 1, which is represented by the formula: 6. A biguanide derivative hetero5-membered ring carboxylic acid salt according to claim 1, which is represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. 7. A biguanide derivative hetero5-membered ring carboxylic acid salt according to claim 1, which is represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. 8 General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, one of R^1 and R^2 represents a hydrogen atom, a lower alkyl group, or an aralkyl group, and the other represents a lower alkyl group or an aralkyl group.) Compounds and general formula▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ General formulas characterized by reacting the compounds shown in ▲ There are mathematical formulas, chemical formulas, tables, etc.
^2 is the same as above).