RU2570896C2 - (4-fluoro-benzyl)-ethyl-(2-tetrazol-1-yl-phenyl)-amine and method for production thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

having anti-infection activity and to a method of producing said compound.

EFFECT: obtaining a novel compound having improved anti-infection activity.

2 cl, 3 tbl, 4 ex

Description

The invention relates to synthetic biologically active substances of the heterocyclic series having anti-infective activity, and is a new compound (4-fluoro-benzyl) -ethyl- (2-tetrazol-1-yl-phenyl) -amine. The invention can be used in the treatment of diseases caused by infections, as well as for similar purposes in veterinary medicine.

It is known that structures containing aminophenyl-1-tetrazole are described as substances having various kinds of physiological activity: antifungal [T. Ichikawa, M. Yamada, M. Yamaguchi, and others. Chem. Pharm. Bull., 2001, vol. 49, Issue 9, p.1110-1119)], antibacterial [K. Kariyone, H. Harada, M. Kurita, T. Takano. J. Antibiot, 1970, vol. 23, Issue 3, p. 131-136; Genin M.J., Allwine D.A., Anderson D.J. and others. J. Med. Chem., 2000, vol. 43, issue 5, p.953-970], anti-tumor [W.V Curran., A.S. Tomcufcik. US Pat. 4010179. 1977. Chem. Abstr. 1977. V. 87. P. 23287]. However, these substances are characterized by an insufficiently wide spectrum of action. In addition, there is the formation of resistance and a decrease in the sensitivity of strains of pathogens to the action of these substances.

The objective of the invention is to create a fully synthetic biologically active substance with high anti-infective activity and a wide spectrum of action for the development on its basis of an active pharmaceutical substance, which is the starting material for a highly effective anti-infectious drug, to which there is no resistance of infection pathogens.

The problem is solved by synthesizing an anti-infectious substance that effectively acts on microorganisms located in human cells, indicated by formula (I).

The inventive substance indicated by formula (I) can be used in the form of a neutral form or in the form of pharmacologically acceptable salts (chlorides, phosphates, sulfates, formates, acetates, oxalates, sulfamates).

The applicant has not identified sources containing information on the methods of synthesis of substances identical to the present invention, which allows us to conclude that it meets the criterion of "Novelty."

A method of obtaining a compound of formula (I) (Scheme 1) includes the steps of:

1) cyclization of 2-nitroaniline (II) with sodium azide and triethyl orthoformate in acetic acid;

2) reduction of the nitro group of 2-nitrophenyl-1H-tetrazole (III);

3) reductive amination with 2-tetrazol-1-yl-phenylamine (IV) 4-fluoro-benzaldehyde;

4) alkylation of (4-fluoro-benzyl) - (2-tetrazol-1-yl-phenyl) -amine (V) with ethyl bromide.

The invention is illustrated by the following examples of the synthesis of intermediates and the claimed substance, physico-chemical characteristics of the claimed substance (examples 1-4), anti-infective activity of the substance (table 3).

Example 1. An embodiment of the 1st stage of the synthesis of the claimed substance (obtaining 2-nitrophenyl-1H-tetrazole).

To a suspension of 0.05 mol of 2-nitro-phenylamine (II) and 0.05 sodium azide in 0.25 mol of triethylorthoformate, heated to 50-60 ° C, 0.5 mol of acetic acid is quickly added with stirring and incubated for 10 hours at boiling point . The precipitate formed during the reaction is filtered, recrystallized from a mixture of water - propanol-2 and dried in air. The product yield is 94%.

Example 2. An embodiment of the 2nd stage of the synthesis of the claimed substance (obtaining 2-tetrazol-1-yl-phenylamine).

7.0 g of Nickel-aluminum alloy is stirred up in 100 ml of water and mixed with 13.5 g of sodium hydroxide without cooling. After the induction period, the mixture is heated for 30 minutes at 70 ° C. The spongy precipitate is separated from the solution by decantation and washed with water and then ethanol.

A solution of 0.15 mol of 2-nitrophenyl-1H-tetrazole (III) and 0.37 mol of hydrazine hydrate in 300 ml of 95% ethanol is heated to 30-40 ° C. A suspension of prepared Raney nickel of 30 ml is added in portions in ethanol. At the end of the mixture is boiled for 3 hours under reflux. Then the reaction mixture was filtered, the filtrate was evaporated to dryness and the residue was recrystallized from water-propanol-2 mixture and dried in air. The product yield is 98%.

Example 3. An embodiment of the 3rd stage of the synthesis of the claimed substance (obtaining (4-fluoro-benzyl) - (2-tetrazol-1-yl-phenyl) -amine).

A hydrogenation unit with a hydrogen burette, a three-way valve and a vacuum nozzle are used.

200 mg of 5% Pd / C in 150 ml of anhydrous methanol are placed in a 250 ml two-necked flask with a baffle and a gas passage nozzle. The installation is evacuated three times and filled with hydrogen. Then, with vigorous stirring, the reaction mixture is saturated with hydrogen until gas absorption ceases (about 30 min), 0.05 mol of 4-fluoro-benzaldehyde and 0.05 mol of 2-nitrophenyl-1H-tetrazole (IV) are added, the gas volume in the burette is fixed, and the mixture is stirred vigorously with room temperature. After absorbing the calculated amount of hydrogen (1.12 L, ~ 6 h), the catalyst was filtered off, the filtrate was evaporated to dryness, and the residue was recrystallized from water-propanol-2 mixture and dried in air. The product yield is 98%

Example 4. An embodiment of the 4th stage of the synthesis of the claimed substances (obtaining (4-fluoro-benzyl) -ethyl- (2-tetrazol-1-yl-phenyl) -amine).

To a solution of 0.005 mol of (4-fluoro-benzyl) - (2-tetrazol-1-yl-phenyl) -amine (V) in 50 ml of benzene, 0.005 mol of ethyl bromide and 0.005 mol of triethylamine are dosed. The reaction mass is heated for 4 hours at boiling point. The solvent is distilled off under vacuum, the residue is recrystallized from a mixture of water - propanol-2 and dried in air. The product yield is 96%.

Anti-infective activity of (4-fluorobenzyl) -ethyl- (2-tetrazol-1-yl-phenyl) -amine.

The determination of the sensitivity of microorganisms to (4-fluorobenzyl) -ethyl- (2-tetrazol-1-yl-phenyl) -amine (compounds of formula (I)) is carried out by the method of serial dilutions of it in liquid or solid media. The criteria for antimicrobial activity (I) is the minimum inhibitory concentration (MIC).

As cultures of microorganisms, the corresponding control strains of Enterobacteriaceae - E. coli ATCC 25922 are used.

As a nutrient medium, nutrient agar is used for the cultivation of microorganisms (GMF agar). Composition of dry nutrient agar: enzymatic meat hydrolyzate (GMF) dry - 15 g, sodium chloride - 9 g, microbiological agar - 12-15 g.

This experiment is carried out simultaneously on 4 cups and is repeated 3 times. The number of seeding per cup 10. The average values of these experiments are shown in Table 3.

Claims (2)

1. The compound of formula (I)

2. A method of obtaining a compound of formula (I), comprising the steps

1) cyclization of 2-nitroaniline (II) with sodium azide and triethyl orthoformate in acetic acid;
2) reduction of the nitro group of 2-nitrophenyl-1H-tetrazole (III);
3) reductive amination with 2-tetrazol-1-yl-phenylamine (IV) 4-fluoro-benzaldehyde;
4) alkylation of (4-fluoro-benzyl) - (2-tetrazol-1-yl-phenyl) -amine (V) with ethyl bromide.