JPS6024790B2 - biguanide derivatives - Google Patents

Description

[Detailed description of the invention] The present invention is based on the general formula (In the formula, n represents an integer 1 or 2) The present invention relates to a novel piguanide derivative represented by

The compound [1] of the present invention has a blood sugar-lowering effect and a free fatty acid-lowering effect, and is useful as a therapeutic agent for diabetes. Compound [1] of the present invention is produced by the following reaction formula (in the formula, n
is the same as above).

To explain the present invention in detail, the compounds represented by the general formula [2] used as the raw material of the present invention include, for example, 3-aminomethyl-5-methylisoxazole, 3-aminoethyl-5-methylisoxazole, 5-amino/methyl-3- Methyl isoxazole, 5-aminoethyl-3
-methylisoxazole, etc.

These compounds are generally known compounds or can be easily obtained by known methods. In the present invention, the reaction between compound [2] and dicyandiamide [3] is carried out without using a solvent or in a suitable solvent under heating.

Solvents are alcohols such as ethanol, propanol, buta/ol, hydrocarbons such as benzene, toluene and xylene, ethers such as methylcellosolve, ethylcellosolve, diglyme, and are inert to the starting materials such as water. , and solvents that do not decompose the product can be used. Compound [2] and dicyandiamide [
3] is usually used in equimolar proportions, and the reaction temperature may be selected appropriately, but generally 80 to 18,000 molar.
It progresses in an advantageous manner. The above reaction produces a new compound [1
], which can be isolated by conventional separation means. Specific examples of the compound represented by the general formula [1] include those shown in Table 1 below.

Table 1 The compound of general formula [1] of the present invention can be used as a free base or in the form of a salt by reacting the free base with various acids.

Such acids include pharmaceutically acceptable acids, such as mineral acids such as hydrochloric acid, sulfuric acid and nitric acid, and organic acids such as acetic acid, oxalic acid and methanesulfonic acid. The toxicity, blood plasma 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
Used for testing after ~1 hour fast.

The LD arc was calculated by the conventional up-down method. The results are shown in Table 2. 2 Alloxan Hypoglycemic and Free Fatty Acid Lowering Effects in Diabetic Rats A 5% saline solution of alloxan monohydrate was intravenously injected at 50 o/kg to male Wistar rats (body weight 140-150 kg) at 5 weeks of age. However, after 2 weeks, the weight was good and the blood sugar level was high (>400/9).
/d') were selected and used for the test.

The compound used was prepared as a 0.5% carboxymethyl cellulose aqueous solution or suspension and was orally administered at a ratio of 1/100 days.

Blood was collected from the tail vein at 0, 2, 4, and 6 hours after administration, and a blood sample was used for measurement. Glucose in blood counts was measured by the glucose oxidase method, and free fatty acids were measured by the Itaya-Wi method.

Effect evaluation was expressed as a reduction rate (%) relative to the control. The results are shown in Table 3. In the table, OLG indicates glucose in blood count, and NEFA indicates free fatty acid in blood count. Table 2 Table 3 Diabetes is currently generally understood to be a metabolic disorder caused by insufficient insulin action, but traditionally the metabolic abnormalities in diabetes were primarily disorders of carbohydrate metabolism, with other disorders secondary to In some ways, it has been thought of as a target.

However, in recent years, Randie and Weber et al. have clarified the interrelationship between lipid metabolism and carbohydrate metabolism (Randie P.J.
Helincet1 785 (1963), Webe rank,
, Science 154 1357 (1966)), the great role that lipid metabolism plays in diabetes has been recognized. Conventionally, phenethyl biguanide, butylpiguanide, and dimethyl biguanide have been clinically used as biguanide antidiabetic drugs, but these have very weak effects on lipids. As shown in Tables 2 and 3, the compounds of the present invention have very low toxicity and also have a blood sugar lowering effect and a lipid metabolism improving effect, making them useful as therapeutic agents for diabetes.

Examples of the present invention will be described below. Example 1 7.4 hours of 5-aminomethyl-3-methylisoxazole hydrochloride and 4.2 hours of dicyandiamide were thoroughly mixed and then heated to 130 qo.

After melting, heat at 150qC for 1 hour. After cooling, dissolve in methanol, add an equal amount of diluted hydrochloric acid, and concentrate under reduced pressure. Recrystallized from methanol-isopropanol to obtain mp181~
9.8 hours of 1-(3-methyl-5-isoxazolylmethyl)piguanide dihydrochloride (yield 73%) was obtained at 190°C. Elemental analysis layer (C7 days, 2N60 as CI)
C day N calculation value (%) 31.24 5.24 31.2
3 Actual value (%) 31.51 5.46 31.05 Example 4.5 hours of 23-aminomethyl-5methylisoxazole hydrochloride and 2.5 hours of dicyandiamide are thoroughly mixed and then heated to 140oC.

After melting, heat at 140-1500C for 1 hour. After cooling, dissolve in ethanol, add an equal amount of diluted hydrochloric acid, and concentrate under reduced pressure. Recrystallized from ethanol water to mpl98-203q○
5.4 volumes of (5-methyl-3-isoxazolylmethyl) biguanide dihydrochloride (yield 68%) were obtained. Elemental analysis layer (C7 day, as 2N60/2HCI) C day N
Calculated value (%) 31.24 5.24 31.23 Actual value (%) 31.14 5.30 31.06 Example
After thoroughly mixing 8.1 parts of 35-8-aminomethyl-3-methylisoxazole hydrochloride and 4.2 parts of dicyandiamide, the mixture was heated to 13,000 ℃ and melted.

Claims (1)

[Claims] 1. A piganide derivative represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, n represents an integer 1 or 2). 2. The piganide derivative according to claim 1, which is represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, n represents an integer 1 or 2). 3. The piganide derivative according to claim 1, which is represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, n represents an integer 1 or 2). 4. The piganide derivative according to claim 2, which is represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼. 5. The piganide derivative according to claim 3, which is represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼.