RU2273632C2 - Bis-(3-guanidinopropyl)dodecylamine salts - Google Patents

Abstract

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new compounds representing bis-(3-guanidinopropyl)dodecylamine salts of the following formula:

,

wherein A means chlorine atom (Cl), HPO^2- ₄, citrate, lactate, acetate, benzoate. These compounds can be used in preparing medicinal preparations for treatment of infectious diseases, in particular, tuberculosis and for preparing disinfectants for prevention of tuberculosis infection propagation.

EFFECT: valuable medicinal properties of compounds.

1 tbl, 1 dwg, 6 ex

Description

The invention relates to medicine, namely to drugs for the treatment of infectious diseases, in particular tuberculosis, as well as to disinfectants to prevent the spread of tuberculosis infection. The invention can also be used in veterinary medicine for the treatment of infectious diseases of animals.

The amine-type anti-tuberculosis drug is known, namely bis (3-aminopropyl) -n-dodecylamine of the following formula:

,

,

representing a white crystalline powder. A commercially available form of the drug is a 30% aqueous solution ["Some aspects of creating effective disinfectants based on a tertiary amine - Lonzabac 2100." GG Kardash and others. "Medical alphabet." Alfmed. No. 11, 2003, pp. 22-23].

The disadvantages of this tool are amine odor, strongly alkaline reaction, allergic activity, irritating properties, as well as a relatively low tuberculocidal activity.

An effective anti-tuberculosis drug is the antibiotic streptomycin, the molecule of which is a tricyclic carbohydrate containing two guanidine groups in one of the cycles [Drug Encyclopedia. 8th ed., Ed. Yu.F. Krylova, M., "Radar", 2001, p. 813].

The structural formula of streptomycin has the following form:

Streptomycin is quite toxic and with prolonged use affects the auditory nerve.

Also known anti-TB drug - p-aminosalicylic acid (PASK) and its sodium salt [Encyclopedia of drugs. 8th ed., Ed. Yu.F. Krylova, M., "Radar", 2001, p. 76]. The disadvantages of this drug, selected for the prototype, is the rather high toxicity characteristic of aromatic amino compounds, the lack of hydrophobicity of the molecule necessary for the effective penetration of the tuberculosis mycobacteria through the wax membrane.

An object of the invention is to reduce toxicity and increase the effectiveness of the drug in the fight against infection.

To solve the technical problem synthesized bis (3-guanidinopropyl) -n-dodecylamine dihydrochloride of the following structure:

where A = Cl, NRA ₄ ^- , citrate, lactate, acetate, benzoate.

Gross formula: C ₂₀ H ₄₇ N ₇ A ₂ , М≅400.

The drug is synthesized by a simple chemical conversion based on the available bis (3-aminopropyl) -n-dodecylamine:

Bis (3-guanidinopropyl) -n-dodecylamine dihydrochloride preserves the physiologically active skeleton of bis (3-aminopropyl) -n-dodecylamine and at the same time does not contain primary amine groups that are alkaline and prone to light oxidation by air. In addition, like streptomycin, bis (3-guanidinopropyl) n-dodecylamine dihydrochloride contains two active guanidine groups in a molecule in a stable and physiologically safe form of hydrochloride. The long-chain hydrophobic dodecyl group is the most active hydrocarbon radical of physiologically active drugs: HOURs, guanidines, amines. It provides effective penetration through the wax membrane of mycobacterium tuberculosis. Bis (3-guanidinopropyl) -n-dodecylamine dihydrochloride purified by crystallization was tested according to the general procedure [Test methods for disinfectants to assess their safety and effectiveness. Moscow, 1998] on a standard strain of Pseudomonas aeruginosa and on anti-tuberculosis activity (at the All-Russian Research Institute of Disinfection) in vitro on a saprophytic strain of Mycobacterium M-5 tuberculosis and Micobacterium terrae. To verify the effectiveness of disinfecting the drug after a certain time, control flushes were made from the surface. For the cultivation of mycobacteria, potato-glycerin agar or Petraniani medium was used. To eliminate the static effect in the experiments, neutralizers were used: tween 80, saponin, cysteine and histidine. The criterion for a complete 99.9-100% disinfection of surfaces was crops from objects treated with tap water.

As for the toxicity of salts of bis (3-guanidinopropyl) -n-dodecylamine, we proceeded from the data for the authorized starting material - the well-known drug of the company Lonza - Lonzabac 100 - bis (3 aminopropyl) -n-dodecylamine - following the path of research to reduce its toxicity . Firstly, the two primary amine strongly alkaline and easily oxidized by atmospheric oxygen amino groups were replaced by stable salt-like guanidine groups. Thus, due to the close proximity to two strong ionic centers, the basicity of the tertiary amino group decreases sharply. Thus, the alkaline properties of the well-known anti-TB drug Lonzabac 100 are reduced to a minimum. An increase in the molecular weight of the drug by 1.5 times in comparison with Lonzabac to 456 is also a positive factor, since it is known that only drugs with a molecular weight of less than 400 freely pass through intact cell membranes.

They are not dangerous as an alkaline agent. The molecular weight of bis (3-guanidinopropyl) n-dodecylamine dihydrochloride, which is 456, is 1.5 times the molecular weight of the starting bis (3-aminopropyl) n-dodecylamine and 3.5 times the molecular weight of p-aminosalicylic acid. This circumstance indirectly indicates less toxicity of the drug. A hydrophobic n-dodecyl group contributes to the reduced toxicity of the drug. It is known that HOURs containing this group in their composition have maximum microbial activity and minimal toxicity.

Thus, the preparations - salts of bis (3-guanidinopropyl) -n-dodecylamine - correspond to class III low-hazard drugs.

The preparation can be purified by recrystallization from alcohol and has the appearance of a white powder with a bitter taste and a melting point of 192 ° C.

To prove the structure of the drug, its IR spectrum was studied. In the drawing, the spectrum of bis (3-guanidinopropyl) dodecylamine dihydrochloride (spectrum 1) is shown against the background of the IR spectrum of the starting bis (3-aminopropyl) dodecylamine (spectrum 2). Here, first of all, two extremely intense double bands (ν _{C = N} and ν _NH ), characteristic of guanidine compounds: 3470-3200 cm ^-1 and 1700-1555 cm ^-1, attract attention. In another known guanidine compound - polyhexamethylene guanidine - these bands are located respectively at 3380-3180 cm ^-1 and 1665-1560 cm ^-1 . Both of these polyguanidines also have a band at 515-520 cm ^-1 , which is related to the angular deformations of CNH-guanidinium.

In the starting amine (spectrum 2), ν _NH vibrations manifest themselves in a higher frequency region: 3450 and 1610 cm ^-1 and have a 3 times lower intensity.

According to the similar structure of the skeletons of the molecules of the starting amine and final guanidine, the methylene frequencies in them are located in the same spectral regions: 2930, 2860, 1480, and 720 cm ^-1 , and their intensity in amine is even higher than in guanidine, respectively, a higher proportion of hydrocarbon parts of the molecule.

The synthesis of bis (3-guanidinopropyl) dodecylamine dihydrochloride is carried out as follows.

First, 2 moles of hydrochloric acid per 1 mol of triamine are added to a solution of bis (3-aminopropyl) -n-dodecylamine. The resulting bis (3-aminopropyl) -n-dodecylamine dihydrochloride solution was evaporated to dryness in a water bath. Triamine dihydrochloride is mixed with dicyandiamide in an equimolar proportion and heated until it melts at a temperature of ~ 200 ° C.

The obtained melt of bis (3-guanidinopropyl) -n-dodecylamine dihydrochloride is purified by crystallization and tested for antituberculous activity in vitro on the Mycobacterium tuberculosis strain M-5.

Example 1

In a 200 ml beaker, 125 ml of concentrated hydrochloric acid are added dropwise with stirring to 125 ml of a 30% aqueous solution of bis (3-aminopropyl) dodecylamine. In this case, a salt precipitate of bis (3-aminopropyl) -n-dodecylamine dihydrochloride may precipitate from the solution. The reaction mixture was dehydrated in a water bath to dryness to obtain 47 g of bis (3-aminopropyl) -n-dodecylamine dihydrochloride as a pinkish wax.

To the bis (3-aminopropyl) -n-dodecylamine dihydrochloride obtained, 11 g of powdered dicyandiamide are added and mixed thoroughly. The mixture is melted in a glass at a temperature of 200 ° C. The melt is cooled to room temperature and a glassy, clear, light yellow salt is obtained - bis (3-guanidinopropyl) -n-dodecylamine dihydrochloride.

A portion of 10 g of crude bis (3-guanidinopropyl) -n-dodecylamine dihydrochloride is dissolved by heating in 50 ml of alcohol, cooled to -4 ° C, and the precipitated salt crystals are filtered off, which are dried and analyzed.

Gross formula: C ₂₀ H ₄₇ N ₇ C ₁₂ . Calculated,%: C 52.85; H 10.30; N, 21.50; Cl 15.70. Found,%: C 52.50; H 10.10; N, 21.15; Cl 15.85.

The results of determining the anti-tuberculosis activity of the drug are presented in the table.

Example 2

A portion of 10 g of crude bis (3-guanidinopropyl) -n-dodecylamine dihydrochloride is dissolved in 25 ml of water and 3 ml of a 50% aqueous solution of sodium hydroxide are added. The bis (3-guanidinopropyl) dodecylamine pop-up base is separated, washed twice with 10 ml of water each, and 0.75 ml of concentrated (85%) phosphoric acid is added dropwise with stirring. ~ 10 g of practically anhydrous bis (3-guanidinopropyl) -n-dodecylamine phosphate are obtained.

Gross formula: C ₂₆ H ₄₈ N ₇ PO ₄ . Calculated,%: C 56.42; H, 8.68; N, 17.72; P 5.60. Found,%: C 56.04; H 7.01; N, 17.53; P 5.91.

Melting point 212 ° C.

Example 3

To an aqueous solution of 10 g of crude bis (3-guanidinopropyl) dodecylamine dihydrochloride obtained according to the procedure of Example 2, an aqueous solution of 3 g of sodium benzoate is added. Bis (3-guanidinopropyl) dodecylamine dibenzoate is separated from an aqueous NaCl solution, washed with water and dried.

Gross formula: C ₄₀ H ₅₇ N ₇ O ₄ . Calculated,%: C 68.60; H, 8.14; N, 14.00. Found,%: C 67.90; H, 8.25; N, 13.78.

Melting point 137 ° C.

Example 4

To an alcohol solution of 9 g of a bis (3-guanidinopropyl) dodecylamine base prepared according to Example 2, 1 g of citric acid dihydrate was added. Dry the resulting solution and obtain ~ 10 g of bis (3-guanidinopropyl) dodecylamine citrate.

Gross formula: C ₃₀ H ₅₁ N ₇ O _4.7 . Calculated,%: C 61.64; H, 8.73; N, 16.78. Found,%: C 60.98; H, 9.07; N, 15.71.

Melting point 172 ° C.

Example 5

To an alcohol solution of 9 g of a base of bis (3-guanidinopropyl) dodecylamine according to Example 2, 1.2 g of glacial acetic acid was added. The solvent was removed and bis (3-guanidinopropyl) dodecylamine diacetate was obtained.

Gross formula: C ₃₀ H ₅₃ N ₇ O ₄ . Calculated,%: C 62.60; H, 9.22; N, 17.00. Found,%: C 61.75; H 9.37; N, 16.59.

Melting point 153 ° C.

Example 6

According to Example 5, bis (3-guanidinopropyl) dodecylamine dilactate is synthesized by mixing an alcohol solution of 10 g of bis (3-guanidinopropyl) dodecylamine base and 5 ml of a 40% aqueous lactic acid solution. Solvents were removed and bis (3-guanidinopropyl) -n-dodecylamine dilactate was obtained.

Gross formula: C ₃₂ H ₅₇ N ₇ O ₆ . Calculated,%: C 61.08; H, 8.83; N, 15.20. Found,%: C 60.58; H, 8.97; N, 14.59.

Melting point 148 ° C.

The table shows comparative data on the anti-tuberculosis activity of bis (3-guanidinopropyl) -n-dodecylamine dihydrochloride in comparison with known drugs. The table shows that bis (3-guanidinopropyl) dodecylamine dihydrochloride is superior to the known drugs: bis (3-aminopropyl) -n-dodecylamine and p-aminosalicylic acid.

Tuberculosis activity of bis (3-guanidinopropyl) dodecylamine dihydrochloride A drug Dose% Time of action 10 min 30 minutes 1 hour Bis (3-guanidinopropyl) -n-dodecylamine dihydrochloride 0.25 - - - 0.15 + - - Bis (3-aminopropyl) -n-dodecylamine 0.50 - - - 0.15 + + - n-aminosalicylic acid 0.50 + + - 0.15 + + +

Claims (1)

The bis (3-guanidinopropyl) dodecylamine salts of the following structure:

where A = Cl, HPO ₄ ^- , citrate, lactate, acetate, benzoate.