JPS5938227B2 - 2-substituted-1,3-diazacycloalkane compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 2-substituted -1,3
This invention relates to a -diazacycloalkane compound and a hypoglycemic agent containing this compound as an active ingredient, and this compound is represented by the following general formula (1).

▲VO4V In the formula, R1 is hydrogen, halogen or alkyl, R2 is cycloalkyl, pyridyl or phenyl which may be substituted with halogen, alkyl or alkoxy, R3 is hydrogen, alkyl, hydroxyalkyl or aralkyl, R
4 means hydrogen, alkyl or phenyl, and n means 1-3.

This compound is called 2-benzuhydrylimino-1,3-diazacycloalkane or 2-(α-R2-substituted benzyl)imino-1,3-diazacycloalkane.
Its tautomer, 2-benzhydrylamino-1,3-diazacycloalkene or 2-(α-R
Also represented as (2-substituted benzyl)amino-1,3-diazacycloalkenes.

In this specification, for convenience, it is expressed as formula (1),
To call.

The 2-monosubstituted-1,3-diazacycloalkane compound or salt thereof of the present invention has a strong hypoglycemic effect and is useful as an oral antidiabetic agent.

This blood sugar lowering effect can be achieved by oral administration of 25~/kg to hungry rats.
Or, the following table shows the results measured by intraperitoneal administration of 10 K9 immediately. There are various methods for producing the compound of the present invention, examples of which are as follows.

However, in the formula, X is a halogen, Y is a group that can be substituted with an amine,
For example, it represents halogen, alkylmercapto, nitroamino, etc., Z means a group active in alkylation, such as halogen, alkyl sulfate group, etc., R represents hydrogen or alkyl, and Q represents benzhydryl group, α-monosubstituted benzyl group, etc. etc. Further, R3, R4 and n have the same meanings as above. /a) An isocyanide halide represented by the formula Q-N=C3 is subjected to a dithimine leakage Σ reaction represented by the formula NH-CH-(CH2)11-NH2.

b) I0 [
V Sotiuronium halide is reacted with the same diamines as in a).

c) Amines of formula Q-NH2 and formula Y (.-ゞ11.22
) React with the compound represented by 1.

d) The reaction of formula a) or b) on a compound of formula Q-N:
It is appropriate to carry out the reaction at a temperature of ~200°C, and ethers, alcohols, etc. are preferable as the solvent.

The reaction c) is carried out in a solvent or without a solvent at room temperature or under heating, preferably external heating to increase the reaction rate. The reaction d) is suitably carried out in a suitable solvent at room temperature or under heating, and it is preferable to use a deoxidizing reagent generally used in alkylation, such as an alkali hydride or an alkali alcoholade. In this reaction, the position to be alkylated was confirmed because it coincided with the target product of the reaction in b). Compounds produced by the methods described above can be converted into their physiologically acceptable acid addition salts.

Acids suitable for salt formation are, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid or acetic acid, propionic acid, oxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, benzoic acid, salicylic acid,
Organic acids such as methanesulfonic acid. The compound of the present invention has pharmacological activities such as hypoglycemic action and platelet aggregation inhibiting action, and is useful as a medicine.

In addition, acute toxicity was observed in rats with 1-methyl-2-benzhydryl iminoimidazolidine hydrochloride.
3η/Kg, and 276.3~/Kg for mice orally.
To use the compound of the present invention as a hypoglycemic agent, it can be made into tablets, capsules, powders, etc. for oral administration using appropriate excipients, disintegrants, lubricants, binders, etc.

Other liquids, syrups, injections, etc. can also be produced as appropriate depending on the purpose. A dosage of 100 to 750 doses per day is usually sufficient for humans. A manufacturing example will be described below.

Example 1 7.3f7 of benzhydrylamine and 4.8899 of 2-methylmercabuto-2-imidazoline hydroiodide are mixed in 10 ml of methanol and heated under reflux for 3 hours.

After cooling, methanol is distilled off, and the residue is made alkaline with 10% sodium hydroxide, and then the soluble content is extracted with 200 ml of chloroform, washed with water, and dried. After removing chloroform under reduced pressure, unreacted benzhydrylamine was further removed under reduced pressure, and the residue was treated with a small amount of acetone to obtain 2-benzhydryl imino imidazolidine in crystal form. Melting point 189-191 diC0 Example 2 Benzhydrylamine 229 and 2-nitroamino-2-
Mix 5.29 of imidazoline and heat to 180-200℃ for 3
Heat and react for 0 minutes.

After cooling, unreacted benzhydrylamine is removed under reduced pressure, and 2-benzhydryliminoimidazolidine is obtained in the same manner as in Example 1. Example 3 2.26 g of benzhydrylamine are left at room temperature for 2 days with 30 d of an ether solution containing 2.59 g of 2-chloro-2-imidazoline.

Thereafter, 2-benzhydryliminoimidazolidine was obtained in the same manner as in Example 1. This product was dissolved in methanol, an equimolar amount of concentrated hydrochloric acid was added, and the solution was dried under reduced pressure to obtain its hydrochloride. Melting point 207-209°C o Example 4 Benzhydrylamine 1.89 (!: 1-methyl-2-
3.4 fl of methylmercapto-2-imidazoline hydroiodide is dissolved in 30 ml of chloroform and left at room temperature for 2 days.

When chloroform is distilled off, 1-methyl-2-benzhydryliminoimidazolidine hydroiodide is obtained. Melting point: 254-256°C. Example 5 α-(p-chlorophenyl)benzylamine 3.379
and 4.549 g of 2-methylmercapto-2-imidazoline hydroiodide and heated to 150 to 160°C for 20 minutes.

After cooling, it was dissolved in methanol and added as a free base with sodium hydroxide to obtain 2-(α-(p-chlorophenyl)benzyl)imino-imidazoline. Melting point: 187-189 C0 Example 6 5.649 g of N-benzhydryl-S-methylisothiuronium iodide and 8.539 g of ethylenediamine were added to 40 ml of methanol and heated under reflux for 15 hours.

After cooling, methanol and excess ethylenediamine are removed under reduced pressure, and the residue is dissolved in 30 ml of ethanol, made alkaline with sodium hydroxide, extracted with chloroform, washed with water, and dried. When the chloroform is distilled off, the residue crystallizes. Recrystallized from isopropyl alcohol, melting point 1
2.709 of 2-benzhydryl iminoimidazolidine was obtained at 89-190°C. Example 7 N-benzhydryl-S-methylisothiuronium iodide 3.849 and 1,3-propanediamine 7.59
was added to 25 ml of methanol and heated under reflux for 16 hours.

Thereafter, the same procedure as in Example 6 was carried out to obtain a free base, which was then added with hydrochloric acid in methanol to obtain 2-benzhydrylimino-1,3-diazacyclohexane hydrochloride. Melting point 238-2420C0N-benzhydryl-S-methylisothiuronium iodide 5,099 and 1,4-diaminobutane 1.39 are mixed and heated to 185-190°C for 15 minutes.

After preparing the free base in the same manner as in Example 7,
2-benzhydryl imino-1 at 27-229.5°C,
3-diazacycloheptane hydrochloride. Example 9 0.429 of N-α-(0-chlorophenyl)benzyl-S-methylisothiuronium iodide and 0.609 of ethylenediamine were heated and reacted in methanol for 15 hours. α-(0-chlorophenyl)benzyl)imino-imidazolidine hydrochloride was obtained.

Melting point 205-207 da C0 Example 10 N-α-(p-chlorophenyl)benzyl-S-methylisothiuronium iodide 0.849 and ethylenediamine 1.209 were reacted by heating in methanol for 15 hours. Similarly, 2-(α-(p-chlorophenyl)benzyl)iminoimidazolidine was obtained.

Melting point 187-189°C oExample 11N-benzhydryl-S-methylisothiuronium iodide 3.849
and 7.49 g of N-methylethylenediamine were heated and reacted in methanol for 15 hours, and the same procedure as in Example 7 was carried out to obtain 1-methyl-2-benzhydryl imino imidazolidine hydrochloride.

Melting point: 254-256°C. Example 12 N-benzhydryl-S-methylitiuronium iodide 3.8411::. 2.659 g of N-ethylethylenediamine was heated and reacted in methanol for 16 hours, and the same procedure as in Example 7 was carried out to obtain 1-ethyl-2-benzhydryl imino imidazolidine hydrochloride.

Melting point 274-276mm C0 Example 13 N-benzhydryl-S-methylisothiuronium iodide 3,849 and N-n-butylethylenediamine 7
．． 59 was heated and reacted in methanol for 13 hours, and the same procedure as in Example 7 was carried out to obtain 1-n-butyl-2-benzhydryl imino imidazolidine hydrochloride.

Melting point 240-242°C o Example 14 N-benzhydryl-S-methyl-isothiuronium iodide 3.849 and N-benzylethylenediamine 1
59 was heated and reacted in methanol for 16 hours, and the same procedure as in Example 7 was carried out to obtain 1-benzyl-2-benzhydryl iminoimidazolidine hydrochloride.

Melting point 237-239°C. Example 15 7.689 of N-benzhydryl-S-methylisothiuronium iodide was heated to react with 17.69 of N-methyl-1,3-diaminopropane in ethanol for 20 hours.
Thereafter, in the same manner as in Example 7, 1-methyl-2-benzhydrylimino-1,3-diazacyclohexane hydrochloride was obtained.

Melting point 219-221 C0 Example 16 N-benzhydryl-S-methylisothiuronium iodide 3.849 and 1,2-diaminopropane 7.49
The mixture was heated and reacted in methanol for 16 hours, and the same procedure as in Example 7 was carried out to obtain 4-methyl-2-benzhydryl imino imidazolidine hydrochloride.

Melting point: 225-227C Example 17 N-benzhydryl-S-methylisothiuronium iodide 1.09 and 2-phenylethylenediamine 2.1
39 in methanol] for 5 hours, and then in the same manner as in Example 7, 4-phenyl-2-benzhydryliminoimidazolidine hydrochloride was obtained.

Melting point: 155-157°C. Example 18 2-Benzhydryl iminoimidazolidine 1.259
and 0.169 ml of sodium hydride were added to 7 ml of dry dimethylformamide and stirred for 20 minutes.

Add 1.009 g of iodomethyl to this and stir at room temperature for 1 to 2 hours. After the reaction, dimethylformamide was removed under reduced pressure.
After adding water, extract the soluble content with chloroform, wash with water,
After drying, chloroform is distilled off. The residue was dissolved in a small amount of methanol, and hydrochloric acid was added to form the hydrochloride. Methanol was distilled off to obtain 1-methyl-2-benzhydryl imino imidazolidine hydrochloride. Melting point: 254-256°C. Example
19 2-benzhydryl iminoimidazolidine 1.259
and sodium hydride 0.169 and ethyl iodide 1.
109, the reaction was carried out in the same manner as in Example 18,
1-Ethyl-2-benzhydryl iminoimidazolidine hydrochloride was obtained.

Melting point 274-276°C o Example 20 2 Benzhydryl iminoimidazolidine 2.519
was reacted with sodium hydride (50%) 0.609 and n-propyl iodide 2.049, and the following Example 1
1-n-propyl-2-benzhydryliminoimidazolidine hydrochloride was obtained in the same manner as in 8.

Melting point: 261-263°C. Example 21 2-benzhydryl iminoimidazolidine 2.519
was reacted with 0.349 of sodium hydride and 2.589 of n-butyl iodide, and in the same manner as in Example 18, 1-n-butyl-2-benzhydryl iminoimidazolidine hydrochloride was obtained.

Melting point 240-242C0 Example 22 2-benzhydryl imino-1,3-diazacyclohexane 2.

659 using 0.349% of sodium hydride and 2.09% of methyl iodide to obtain 1-methyl-2-benzhydrylimino-1,3-diazacyclohexane hydrochloride in the same manner as in Example 18. Ta.

Melting point: 219-221°C. Example 23 2-benzhydrylimino-1,3-diazacyclohexane 2.659 was reacted with 0.349 sodium hydride and 2.209 ethyl iodide, and the following Example 18
In the same manner as above, 1-ethyl-2-benzhydrylimino-1,3-diazacyclohexane hydrochloride was obtained.

Melting point 247-249°C. Example 242-(α-(p-
Chlorpheno(c)benzino(c)imino-imidazolidine 1.409 and sodium hydride (50%) 0.3
09 and methyl iodide, and the same procedure as in Example 18 was carried out to prepare 1-methyl-2-(α-(p
-chlorophenyl)benzyl)imino-imidazolidine sulfate was obtained.

Melting point 206-208 C0 Example 25 Benzhydryl isocyanide dichloride was dissolved in 20 ml of dry ether, methylethylenediamine 2f1 was added at 0-5° C. under ice cooling, and the mixture was stirred overnight at room temperature.

After converting to PHL with 2N monohydrochloric acid, the precipitated crystals were collected and filtered to obtain 1-methyl-2-benzhydryl iminoimidazolidine hydrochloride.

Melting point: 254-256°C. Example 26 Benzhydryl isocyanide dichloride and 4.29 ml of ethylenediamine were mixed in 40 ml of dry ether as shown in Example 25.
The reaction and treatment were carried out in the same manner as above to obtain 2-benzhydryl iminoimidazolidine hydrochloride.

Melting point 207-209 C0 Example 27 Benzhydryl isocyanide dichloride and 1,3-diaminopropane are reacted in the same manner as in Example 25 to obtain 2-benzhydryl imino-1,3-diazacyclohexane hydrochloride. .

Melting point 238-242°C. Example 28 Benzhydryl isocyanide dichloride and 1,4-diaminobutane were reacted and treated in the same manner as in Example 25 to obtain 2.
- Benzhydrylimino-1,3-diazacycloheptane hydrochloride is obtained.

Melting point 227-230°C. Example 29 Benzhydryl isocyanide dichloride and 1,2-diaminopropane were reacted and treated in the same manner as in Example 25 to obtain 2-benzhydryl imino-14methyl-imidazolidine hydrochloride.

Melting point 225-227°C o Example 30 N-benzhydryl-S-methylisothiuronium iodide 7.689 and N-hydroxyethylethylenediamine 10.09 were heated to reflux in 400 ml of methanol for 2 hours, and after cooling, methanol and excess amine were mixed. is removed under reduced pressure.

The residue was dissolved in methanol, made alkaline with 10% caustic soda, extracted with chloroform, washed with water, dried, and the chloroform was distilled off to give 1-(2-hydroxyethyl)-2.
- A benzhydryl iminoimidazolidine is obtained.
Melting point 132-135°C o Example 31 N-α-(2-pyridyl)benzyl-S-methylisothiuronium iodide 5.79 and ethylenediamine 8.
59 with 40 ml of methanol and treated in the same manner as in Example 30 to obtain 2-(α-(2-pyridyl)benzyl)imino-imidazolidine.

Melting point 199-20rC0α-(0-chlorophenyl)benzyl isocyanide dichloride was reacted with ethylenediamine 1.09% in the same manner as in Example 25 to obtain 2-(α-(0-chlorophenyl)benzyl)iminoimidazolidine hydrochloride. Got salt.

Melting point 205-207°C o Example 33 α-(p-chlorophenino(ha)benzylisocyanide dichloride and 1.09 g of ethylenediamine were reacted and treated in the same manner as in Example 25 to produce 2-α-(p-chlorophenyl)
Benzyl)iminoimidazolidine was obtained as the free base.

Example 34α-(p-chlorophenyl)benzylisocyanide dichloride and methylethylenediamine 1.19% were reacted and treated in the same manner as in Example 25 to obtain 1-methyl-2-(α-(p- (talolophenil)
The benzyl)iminoimidazolidine was isolated as the sulfate salt.

Melting point 206-208 C0 Example 35 4.19 N-α-(p-methoxyphenyl)benzyl S-methylisothiuronium iodide and 3.01 ml of ethylenediamine were reacted and treated in the same manner as in Example 30 with 30 ml of methanol. and 2-(α(p-methoxyphenyl)
Benzino(c)iminoimidazolidine was obtained.

Melting point: 172-174°C. Example 36N-di-(p-trino(ha)methyl-S-methylisothiuronium iodide 4,19 and ethylenediamine 3.09 were reacted and treated in the same manner as in Example 30 with methanol 307TL1 to obtain 2-di-1) Mono(p-tolyl)methyliminoimidazolidine was obtained.

Melting point: 195-197°C. Example 37 3.9f1 of N-(α-cyclohexylbenzyl)-S-methylisothiuronium iodide and 3.09ml of ethylenediamine were reacted and treated in the same manner as in Example 30 with 30ml of methanol to give 2-(α-cyclohexylbenzyl). Benzyl)iminoimidazolidine was obtained.

Melting point 203-205°C.

Elemental analysis Calculated value as Cl6H23N3 C74.66, H9. Ol, Nl6.33 analysis value C74.48, H9. O3, Nl 6.2l example
38 N-(α-(2-pyridyl)benzyl)-S-
5.7f1 of methylisothiuronium iodide and 101ml of N-methylethylenediamine were reacted and treated with 40ml of methanol in the same manner as in Example 30 to obtain 2-(α-(2
-pyridyl)benzyl)iminoimidazolidine was obtained.

Melting point 127-129°C o Elemental analysis Calculated value as Cl6Hl8N4 C72. l5, H6.8l, N2l. O4 analysis value C72.42, H6.83, N2O. 92 examples
39 1.72 f1 of N-benzhydryl-S-methylisothiuronium iodide and 1.9 I of N-isopropylethylenediamine were mixed and reacted by heating for 5 hours. Example 3
1-isopropyl-2-benzhydrinoleiminoimidazolidine hydroiodide was obtained in the same manner as in Example 0.

Melting point 200-202℃o Elemental analysis C,,H24N,I
as

Claims (1)

[Claims] 1. A 2-substituted-1,3-diazacycloalkane compound or a salt thereof represented by the following general formula ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ In the formula, R_1 is hydrogen, halogen, or lower Alkyl, R_
2 is phenyl which may be substituted with cycloalkyl, pyridyl or halogen, lower alkyl or lower alkoxy, R_3 is hydrogen, lower alkyl, hydroxyalkyl or aralkyl, R_4 is hydrogen, lower alkyl or phenyl, n is 1-3 means. 2 In the compound of claim 1, R_1 is hydrogen, R_2 is phenyl, R_3 is hydrogen or lower alkyl,
The compound or salt thereof according to claim 1, wherein R_4 is hydrogen and n is 1. 3. The compound according to claim 1, which is 1-methyl-2-benzhydryl iminoimidazolidine or a salt thereof. 4. A hypoglycemic agent containing a 2-substituted-1,3-diazacycloalkane compound represented by the following general formula or a salt thereof as an active ingredient. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ However, R_1 is hydrogen, halogen, or lower alkyl, and R
_2 is lower alkyl, cycloalkyl, pyridyl, or phenyl which may be substituted with halogen, lower alkyl or lower alkoxy; R_3 is hydrogen, lower alkyl,
hydroxyalkyl or aralkyl, R_4 is hydrogen,
lower alkyl or phenyl; n means 1-3; 5. The hypoglycemic agent according to claim 4, wherein the active ingredient is 1-methyl-2-benzhydryl iminoimidazolidine or a salt thereof.