RU2529790C2 - Method for preparing alkylbenzyldimethylammoniumfluorides possessing antiviral and antibacterial action - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to preparing alkylbenzyldimethylammoniumfluorides possessing antiviral and antibacterial action. The declared method consists in a reaction of a mixture of 1.5 M alkyl iodide of formula RJ, wherein R represents alkyl C₈H₁₇-C₁₈H₃₇, in absolute alcohol with dimethylbenzylamine at boiling; that is followed by a sequential ethanol stripping in vacuum, resolution of a residue in ethyl acetate, drying in diethyl ester, separation of an oil-precipitated intermediate product and residual ester stripping. The intermediate product is resolved in mixed ethanol and water in volume ratio 1:1 and titred in 10% aqueous AgF until iodide ions disappear from the solution; the solution is filtered, and the filter is boiled down, and crystallised from mixed methanol and hexane.

EFFECT: method provides preparing effective low-toxic therapeutic agent.

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Description

The present invention to medicine and can be used to treat viral and other infectious diseases, including tuberculosis.

The purpose of the invention is the synthesis of an effective drug with low toxicity.

Known composition, created on the basis of benzalkonium fluoride, which has a fairly wide spectrum of action and is able to suppress the activity of retroviruses, especially the herpes simplex virus and the LVA virus, responsible for the development of AIDS [1].

The proposed method differs from the method for producing the specified composition in that when reacted with an alkylpodide under the conditions specified in the claims, dimethylbenzylammonium alkyl diode is obtained, from which then titrated with an AgF solution gives the corresponding dimethylbenzylammonium alkyl fluoride.

In addition, the disadvantage of the composition [1] is its complex chemical synthesis and high toxicity, including hemolytic, difficulties in selecting an individual dose of the administered drug.

A known method for producing dimethylbenzylammonium alkyl iodite, in particular dimethylbenzylammonium nonyl iodite by reacting benzylnonylamine with MeJ [2]. Known methods for producing ammonium fluoride by the exchange reaction in the Quaternary ammonium salts of one halogen to another [3, 4, 5].

So, when AgF is added to laurylbenzyldimethylammonium bromide in aqueous medium, followed by separation of AgBr and the filtrate is condensed in vacuo, laurylbenzyldimethylammonium fluoride is obtained.

Known methods for producing alkylbenzyldimethylammonium fluoride [2] does not possess the combination of distinctive features of the proposed method for their preparation - the creation of a new effective drug with low toxicity, with antiviral and antibacterial effects.

Thus, the proposed technical solution does not follow from the level of modern technology and meets the criteria of "novelty" and "inventive step" of the invention.

This goal is achieved by synthesis of compounds, the starting products of which are alkyl iodide and dimethylbenzylamine mixture, 1.5 M of alkyl iodide and dimethylbenzylamine are boiled in absolute alcohol (I). Ethanol is then distilled off in vacuo. The residue was dissolved in ethyl acetate and dried (II) with diethyl ether. The settled oil is separated, and the remaining ether is distilled off in vacuo. Next, the exact sample (II) is dissolved in a mixture (ethanol-water) in a volume ratio of I: I and titrated with a 10% aqueous AgF solution until the iodide ions disappear from the solution. The solution was filtered, and the filtrate was evaporated and crystallized from methanol-hexane.

,

,

where R-CH ₈ H ₁₇ -CH ₁₈ H _37.

Compounds with all alkyl values, from C ₈ H ₁₇ to C ₁₈ H _37, were prepared and tested.

The synthesized compound with an alkyl value of C ₉ H ₁₉ has the formula:

, Mc 281,3-бензилдиметил-н-нониламмония фторид. Температура плавления - 119,5-121,5°C.

, Mc 281,3-benzyldimethyl-n-nonylammonium fluoride. Melting point - 119.5-121.5 ° C.

It is soluble in water.

Elemental analysis of the synthesized compound:

C - 76.81%; H - 11.45%; F - 6.73%; N - 5.01%.

PMR spectrum, (b, w, d): 3.01 C (6H, N (CH ₃ ) ₂ ;

4.72 ^C (2H, CH ₂ Ph); 6 · 99 ^T (1H, N _arom - 4);

7.21t (2H, Harom - 3.5); 7.72d (2H, Narom - 2.6);

3.37 ^d (2H, H-1), 0-87 ^d (3H, H-9), 1.25-1.39 m (12H, H-2/8).

IR spectrum recorded on the IKS-29 device (in the EHF tables)

3063 ^CM-1 (SNar)

2920 ^CM-1 (CH ₂ )

2872 ^CM-1 (CH ₃ )

1678 ^CM-1 ( ^- C = C, arom).

Example 1

The antiviral activity of benzyldimethyl nonylammonium fluoride was tested against herpes simplex virus in 30 outbred white rats, weighing 180-200 g, aged 14-16 months. The work was carried out in the State institution "Samara Regional Veterinary Laboratory".

The experiments were carried out in accordance with the "Rules for the use of experimental animals" (Order of the Ministry of Higher Education of 13.11.84, No. 724). The herpes virus was introduced intradermally into the animals (HSV-1 strain Tu1og-0.2 ^ml (10 ⁴ TTCP ₅₀ ). This strain is known to cause herpetic viremia.

Before the experiment, the acute toxicity of benzyl-dimethyl-n-nonylammonium fluoride was determined by a single administration to mice (n = 15) and guinea pigs (n = 15) according to the Behrers-Karbel method. The solution at a concentration of 3 g / l in a sterile isotonic sodium chloride solution was administered to mice intravenously, intraperitoneally. Guinea pigs - intraperitoneally and intrapericardially.

Animals were observed for 14 days. Daily weighing and thermometry. The LD _{50 was} determined. The synthesized compound is low toxic: LD ₅₀ for mice was from 54.7 to 56.9 mg / kg of body weight, for guinea pigs - from 28.6 to 37.9 mg / kg of body weight.

In experiments on white rats (n = 17) infected with herpes simplex virus, a concentration of benzyldimethyl n-nonylammonium fluoride solution from 10 to 20 mg / kg was used.

All animals of the experimental group, to which benzyldimethyl-n-nonylammonium fluoride was administered once on the 7th day after infection, remained alive in the presence of clinical symptoms of herpetic viremia. Their condition quickly returned to normal, and 5 days after the injection they became almost healthy: they were active, they ate food with pleasure.

Rats in the control group (n = 9) infected with herpes simplex virus but not treated with benzyldimethyl n-nonylammonium fluoride died on days 14, 21, 30, 32, 36.

Example 2

The synthesized compound was used to treat guinea pigs infected with human mycobacterium tuberculosis isolated from a patient with pulmonary tuberculosis. For animals (n = 25), mycobacteria were administered intraperitoneally (0.001 mg in 1.0 ml of physiological saline). After 15-20 days, all infected animals showed clinical signs of the tuberculosis process: lethargy, weight loss, partial baldness. Three times with an interval of 5 days, benzyl-n-nonylammonium fluoride was administered intrapleurally at a dose of 20 mg / kg body weight in 5.0 ml of isotonic sodium chloride solution. All animals remained alive and were observed for a year after clinical recovery. Animals of the control group (n = 15), which were not given benzyl dimethyl-n-nonylammonium fluoride, died on the 38th day (n = 7), the 45th day (n = 5) and on the 48th day (n = 3 ) after infection with mycobacteria of the human type.

Thus, an effective agent with low toxicity, with antiviral and antibacterial effects, has been synthesized.

Cited documents

1. Arofarm Limited, Pierre Bourbon, Pierre Lagney. A solution for vascular administration, a method of combating viral and infectious diseases, a method of combating AIDS, a method of combating tuberculosis // RF Patent, No. 2128507 from 01.24.94.

2. King N. Antiplasmodial action and chemical constitution. V. Carbinolamines derived from 6-methooxyguinoline // J. Chemical soc. 1942, v. 79, p. 401-404.

3. Weigand-Hilgemag K. Methods of experiment in organic chemistry / M. Chemistry, 1969, p.192-194.

4. Patent US 164744 A. 11/18/1965.

5. Patent BE 621086. 11/30/1962.

Claims (1)

A method of producing alkylbenzyldimethylammonium fluorides having antiviral and antibacterial action, characterized in that in order to synthesize an effective drug with low toxicity, by reacting a mixture of 1.5 M alkyl iodide of the formula RJ, where RC ₈ H ₁₇ -C ₁₈ H ₃₇ alkyl, in absolute alcohol with dimethylbenzylamine at a boil, followed by successive distillation of ethanol in vacuo, dissolving the residue in ethyl acetate, drying in diethyl ether, and separating the resulting intermediate product which had settled as oil with distillation of the remaining ether, dissolution of the intermediate in an ethanol-water mixture in a volume ratio of 1: 1, followed by titration with a 10% aqueous AgF solution until the iodide ions disappeared from the solution, after which the solution was filtered, and the filtrate was evaporated and crystallized from methanol - hexane.