JPS5936629B2 - 1,3-disubstituted-2-imidazolidines - Google Patents

Description

[Detailed description of the invention] The present invention relates to general formula (I) □CH-Hibiki-C-R3(I) R.

Y11 (In the formula, R is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group, or a halogen atom, R2 is a hydrogen atom or a phenyl group, and R3 is a lower alkyl group, a lower alkoxy group, an amino group, or a lower alkylamino group. 1,3-disubstituted-2-iminoimidazolidine or its acid addition salt, the compound of formula (I) has a strong Exhibits a hypoglycemic effect.

The compound of formula 1) can be produced by the following method.

(In the above formula, Q is an oxygen atom or an imino group, X is a halogen atom, R4 is a lower alkyl group, z is an oxygen atom or a sulfur atom, R5 is a lower alkyl group or a lower alkoxy group, M is an alkali metal In other words, according to Method 4, an amine represented by formula (3) may be reacted with a halogen cyanide in the presence of a base such as sodium hydroxide in an aqueous solution. However, it is more advantageous to react the hydrochloride of the compound of formula (9) hot with potassium cyanate to give benzhydryl mono- or benzyl-aminoethyl urea and then to react with the halogen cyanide.

It can also be obtained by reacting a product obtained by reacting the compound of formula (3) with S-methylisothiourea sulfate and a halogen cyanide. According to Method 8, the hydrohalide salt of the starting compound of formula (1!) may be reacted with potassium cyanate or sodium cyanate in dimethyl sulfoxide at room temperature.

The raw material compound used here, for example, 1-benzyl-2-
Imino-imidazolidine hydrobromide can be obtained quantitatively by adding benzylaminoethylamine to a benzene solution of bromine cyanide. According to Method 8, a compound of formula (sub) may be heated to about 50 to 80° C. in silicon thiocyanide and an inert solvent such as benzene or chloroform.

The target compound can also be obtained by heating the compound of formula (2) and an alkyl isocyanate or an alkyl isothiocyanate in an alcohol such as methanol or ethanol or an inert solvent such as chloroform or benzene from room temperature to about 100°C. can be obtained. Furthermore, the compound of formula (2) and acetyl halide or methoxycarbonyl chloride may be mixed at o°C in an inert solvent such as chloroform, benzene or dimethylformamide, preferably in the presence of a deoxidizing agent such as sodium hydride or triethylamine. ~The reaction may be carried out at room temperature.

or? What is the law? This is a modification of the method and uses a lower alcohol as a solvent. For example, when N-benzylaminoethylenediamine and bromine cyanide are reacted in methanol, 1-benzyl-2-imino-3-(1-methoxy-
1-imino)methylimidazolidine can be obtained.

The compound of the present invention thus produced has the above-mentioned substituents at the 1st and 3rd positions of the imidazolidine ring, and has structural specificity that is fundamentally different from that of conventional hypoglycemic drugs. It also has a strong hypoglycemic effect.

More specifically, the compounds of the present invention exhibit superior effects in normal fasting animals compared to sulfonylurea and biguanide compounds, which are conventionally frequently used hypoglycemic drugs.

The results of comparing the hypoglycemic effects of several examples of the compounds of the present invention with those of commercially available tolbutamide and fenformin are shown below. Preparation Example by Method 8 Example 1 1-benzylamino-2-aminoethane hydrochloride 1.86
y and 0.88 y of potassium cyanate in 8 ml of dimethyl sulfoxide are heated to 100-110 DEG C. for 1 hour.

After the reaction, the mixture was dried under reduced pressure, and 50 g of water and 0.8 y of sodium hydroxide were added to dissolve the residue, and 1.5 y of bromine cyanide was added. When stirring at room temperature, 1-benzyl-2-imino-
Crystals of 3-carbamoylimidazolidine begin to precipitate, and after 30 minutes, they are collected by filtration, thoroughly washed with water, and dried. The compounds shown in Table 2 were obtained in the same manner.

Example 62 1-(p-methoxybenzyl)-2 obtained in Example 5
-Imino-3-carbamoylimidazolidine 3.0P was suspended in methylene chloride 150d, -50 to -60'
C, IIC. Cooling.

Add 9.0f of boron tribromide to this. Gradually warm to room temperature and continue stirring overnight. Then ice water 1001Rt
The aqueous layer is separated, made alkaline with sodium hydroxide, and thoroughly washed with chloroform to remove unreacted raw materials. The remaining aqueous layer is again adjusted to pH 3 with hydrochloric acid and then concentrated under reduced pressure to precipitate crystals, which are then filtered off. This was dissolved in 307711 water at a warm temperature, and purified by passing it through a 75 ml column of Dowex 2×8 (Kroll type). The effluent was collected and concentrated under reduced pressure to yield 1-(p-hydroxybenzyl).
2.25f7 (70%) of the hydrochloride of -2-imino-3-carbamoylimidazolidine is obtained. Melting point 203-5
℃. Example 7 1-Benzylamino-2-guanidinoethane sulfate 4.
Add and dissolve 8f in 60d of 1N sodium monohydroxide, and add 2.3V of bromine cyanide.

After stirring at room temperature for 1 hour, the precipitated crystals were collected by filtration, treated with 50 ml of hot water to remove insoluble materials, and concentrated under reduced pressure to obtain 1.507 g of crude crystals.

This was dissolved in methanol, concentrated hydrochloric acid was added to adjust the pH to 4, and the solution was concentrated to dryness under reduced pressure to obtain 1-benzyl-2-iminoamidinoimidazolidine hydrochloride. Melting point 178-1
Preparation Example 1-Benzyl-2-iminoimidazolidine hydrochloride 0.8 by 79°C Method 5
4y and 0.32V of potassium cyanate were added and dissolved in 4ml of dimethyl sulfoxide, and the mixture was stirred at room temperature for 4 hours.

After adding 0.5 ml of concentrated hydrochloric acid to adjust the pH to 3, dimethyl sulfoxide was removed under reduced pressure. Water is added to the residue, made alkaline with sodium hydroxide, extracted with chloroform, washed with water, dried, and then chloroform is distilled off to obtain 1-benzy-2-imino-3-carbamoylimidazolidine. Method? Example 9 Silicon tetraisothiocyanate (0.90 V) was dissolved in 30 g of dry benzene, 2.10 g of 1-benzyl-2-imino-imidazolidine was added thereto, and the mixture was stirred for 45 minutes.

Concentrate to dryness under reduced pressure and add 10% water-isopropanol 2
After adding 0ml, heat and stir for 10 minutes. After that, it was concentrated to dryness under reduced pressure, 30 ml of chloroform was added to the residue, and the insoluble matter was filtered out. 0.24 V of carbamoylimidazolidine was obtained. Melting point 147-148°C. The compounds shown in Table 3 were obtained by the same reaction.

Claims (1)

[Claims] 1 ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_1 is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group, or a halogen atom, R_2 is a hydrogen atom or a phenyl group, R_3 represents an alkyl group, an alkoxy group, an amino group, or an alkylamino group, and Y represents an oxygen atom, a sulfur atom, or an imino group).
-Disubstituted-2-iminoimidazolidines or acid addition salts thereof. 2. The compound according to claim 1, which is 1-benzhydryl-2-imino-3-carbamoylimidazolidine. 3. The compound according to claim 1, which is 1-benzhydryl-2-imino-3-acetylimidazolidine. 4. The compound according to claim 1, which is 1-benzhydryl-2-imino-3-methoxycarbonylimidazolidine.