Bis-(3-guanidinopropyl)dodecylamine salts

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), HPO2-4, 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.

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

Known anti-tuberculosis drug amine type, namely bis(3-aminopropyl)-n-dodecylamine the following formula:

,

representing a white crystalline powder. Commercially available form of the drug is 30% aqueous solution ["Some aspects of creating effective disinfectants on the basis of tertiary amine - lonzabac 2100". God and other Medical alphabet". Alfmed. No. 11, 2003, p.22-23].

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

Effective antituberculous substances is the antibiotic streptomycin, which molecule is a tricyclic carbohydrate containing one of the two cycles guanidine groups [encyclopedia of medicine. 8th ed., edited Ufraw, M., "radar", 2001, str].

The structural formula of streptomycin who meet the following form:

Streptomycin is toxic enough and with long-term use affects the auditory nerve.

Also known antituberculosis drug - p-aminosalicylic acid (PAS) and its sodium salt [encyclopedia of medicine. 8th ed., edited Ufraw, M., "radar", 2001, p.76]. The disadvantages of this drug is chosen for the prototype is sufficiently high toxicity characteristic for aromatic amino compounds, the absence of hydrophobicity of the molecules required for efficient penetration through the wax membrane of Mycobacterium tuberculosis.

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

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

where A=Cl, NRA4--, citrate, lactate, acetate, benzoate.

Brutto-formula: C20H47N7A2, M≅400.

The drug is synthesized by simple chemical transformation on the basis of available bis(3-aminopropyl)-n-dodecylamine:

The dihydrochloride of bis(3-guanidinopropionic)-n-dodecylamine saves physiologically active skeleton(3-aminopropyl)-n-dodecylamine and at the same time does not contain in its composition alkaline and tend to be easily oxidized by oxygen in the air pervichnovodnyh groups. In addition, like streptomycin, the dihydrochloride of bis(3-guanidinopropionic)-n-dodecylamine contains in the molecule two active guanidine groups in stable and physiologically safe form of the hydrochloride. Long-chain hydrophobic Godzilla group is most active hydrocarbon radical physiologically active drugs: HOUR, guanidines, amines. It ensures effective penetration through the wax membrane of Mycobacterium tuberculosis. Purified by crystallization of the hydrochloride of bis-(3-guanidinopropionic)-n-dodecylamine were tested according to the General method [Methods of testing disinfectants for evaluation of their safety and efficacy. Moscow, 1998] on a standard strain of Pseudomonas aeruginosa and anti-TB activity (at the research Institute of disinfection) in vitro saprophytic strain of M. tuberculosis Micobacterium M-5 and Micobacterium terrae. To verify the effectiveness of decontamination of the drug after a certain time has made the control swabs from the surface. For cultivation of mycobacteria used potato-glycerol agar or medium Petrignani. For exceptions static actions in the experiments used neutralizers: tween 80, saponin, cysteine and histidine. Criterion full of 99.9-100% disinfection of surfaces as well as crops with objects, treated water is roodney water.

With regard to the toxicity of the salts of bis(3-guanidinopropionic)-n-dodecylamine, we proceeded from the data allowed for the initial substance - known drug company Lonza - Lonzabac 100 - bis (3 aminopropyl)-n-dodecylamine - moving research to reduce its toxicity. First, two PERVICHNAYA highly alkaline and can be readily oxidized by the oxygen of the amino groups have been replaced by stable saltlike guanidine group. Thus, due to the close vicinity of two strong ion centers dramatically decreases the basicity of the tertiary aminopropionic. Thus, the alkaline properties known antituberculosis drug Lonzabac 100 are minimized. The increase in molecular weight of the drug in 1,5 times in comparison with Lonzabac to 456 is also a positive factor, since it is known that through intact cell membranes freely pass only drugs with a molecular weight less than 400.

They are not dangerous as the alkaline agent. The molecular weight of the dihydrochloride of bis(3-guanidinopropionic)-n-dodecylamine, comprising 456, 1.5 times the molecular weight of the original bis(3-aminopropyl)-n-dodecylamine and 3.5 times the molecular weight of p-aminosalicylic acid. This fact indirectly indicates lower toxicity ven the rata. The contribution to the reduced toxicity of the drug puts hydrophobic n-Godzilla grouping. It is known that the HOUR containing the grouping in their composition, have a maximum microbial activity and minimal toxicity.

Thus, drugs are the salts of bis(3-guanidinopropionic)-n-dodecylamine - match III class hazardous drugs.

The product can be purified by recrystallization from ethanol and has the form of a white powder with bitter taste and a melting point of 192°C.

To prove the above structure of the drug studied the infrared spectrum. In the drawing range of the dihydrochloride of bis(3-guanidinopropionic)dodecylamine (spectrum 1) is depicted on the background of the infrared spectrum of the original bis(3-aminopropyl)dodecylamine (spectrum 2). Here, first of all, attention is drawn to two very intense dual-band (νC=Nand νNH)characteristic guanidino connections: 3470-3200 cm-1and 1700-1555 cm-1. In another known guanidine connection - polyhexamethylene guanidine - these bands are located respectively at 3380-3180 cm-1and 1665-1560 cm-1. Both of these polyguanidine, in addition, there is a band at 515-520 cm-1related to angular deformation CNH-guanidine.

In the original Amina (spectrum 2) fluctuations νNHmanifested in the higher frequency is blasti: 3450 and 1610 cm -1and have 3 times less intensity.

Accordingly, similar to the structure of the skeleton of the molecules of the original amine and end-methylene-guanidine frequency are located in the same spectral regions: 2930, 2860, 1480 and 720 cm-1and Amina in their intensity even higher than in guanidine, respectively, a larger proportion of the hydrocarbon part of the molecule.

Synthesis of dihydrochloride of bis(3-guanidinopropionic)dodecylamine as follows.

First, to a solution of bis(3-aminopropyl)-n-dodecylamine is added 2 moles of hydrochloric acid per 1 mol of the analogue. The resulting solution of the dihydrochloride of bis(3-aminopropyl)-n-dodecylamine evaporated on a water bath to dryness. The dihydrochloride analogue mixed with dicyandiamide in equimole proportions and heated to melt at a temperature of ˜200°C.

The resulting melt dihydrochloride of bis(3-guanidinopropionic)-n-dodecylamine purify by crystallization and experience on the anti-TB activity in vitro on the strain of Mycobacterium tuberculosis M-5.

Example 1

In the beaker of 200 ml to 125 ml of 30% aqueous solution of bis(3-aminopropyl)dodecylamine is added dropwise with stirring 26 ml of concentrated hydrochloric acid. The solution may fall precipitate salt - dihydrochloride of bis(3-aminopropyl)-n-dodecylamine. The reaction mixture is dehydrated n the water bath to dryness and obtain 47 g of the dihydrochloride of bis(3-aminopropyl)-n-dodecylamine in the form of a wax-like mass of pinkish color.

To the resulting dihydrochloride of bis(3-aminopropyl)-n-dodecylamine add 11 g of powdered dicyandiamide and mix thoroughly. The mixture is melted in the glass at a temperature of 200°C. the Melt is cooled to room temperature and get a glass-like transparent light yellow salt is the dihydrochloride of bis(3-guanidinopropionic)-n-dodecylamine.

Portion 10 g of the crude dihydrochloride of bis(3-guanidinopropionic)-n-dodecylamine dissolved by heating in 50 ml of ethanol, cooled to -4°and filtered off the precipitated crystals of salt that dried and analyzed.

Brutto-formula: C20H47N7C12. Calculated, %: 52,85; H 10,30; N 21,50; Cl 15,70. Found, %: C 52,50; N 10,10; N To 21.15; Cl 15,85.

The results of determination of the anti-TB activity of the drug is presented in the table.

Example 2

Portion 10 g of the crude dihydrochloride of bis(3-guanidinopropionic)-n-dodecylamine dissolved in 25 ml of water and add 3 ml of 50% aqueous sodium hydroxide solution. Separate pop-up base bis(3-guanidinopropionic)dodecylamine, washed twice with 10 ml of water and added with stirring dropwise 0.75 ml of concentrated (85%) phosphoric acid. Get ˜10 g of virtually anhydrous disubstituted phosphate bis(3-guanidinopropionic)-n-dodecylamine.

Brutto-formula: C26H48N7PO4. Calculated, % 56,42; N 8,68; N 17,72; P THE CEILING OF 5.60. Found, %: C 56,04; N 7,01; N 17,53; P 5,91.

Melting point 212°C.

Example 3

To a water solution of 10 g of the crude dihydrochloride of bis(3-guanidinopropionic)dodecylamine, obtained by the method of example 2, add an aqueous solution of 3 g of sodium benzoate. Separate dibenzoate bis(3-guanidinopropionic)dodecylamine from aqueous NaCl solution, washed with water and dried.

Brutto-formula: C40H57N7O4. Calculated, %: C 68,60; N 8,14; N 14,00. Found, %: C 67,90; N. Of 8.25; N 13,78.

Melting point 137°C.

Example 4

To the alcoholic solution of 9 g of the Foundation of the bis(3-guanidinopropionic)dodecylamine, obtained according to example 2, was added 1 g of dihydrate citric acid. The resulting solution was dried and receive ˜10 g of citrate bis(3-guanidinopropionic)-dodecylamine.

Brutto-formula: C30H51N7About4,7. Calculated, %: C 61,64; N 8,73; N 16.78 In. Found, %: C 60,98; N 9,07; N 15,71.

Melting point 172°C.

Example 5

To the alcoholic solution of 9 g of the Foundation of the bis(3-guanidinopropionic)dodecylamine according to example 2 add 1.2 g of glacial acetic acid. Remove the solvent and obtain diacetate bis(3-guanidinopropionic)dodecylamine.

Brutto-formula: C30H53N7O4. Calculated, %: C 62,60; N Which 9.22; N 17,00. Found, %: C 61,75; N 9,37; N 16,59.

Melting point 153°C.

Example 6

The agreement is but example 5 synthesize delectat bis(3-guanidinopropionic)dodecylamine mixing alcohol solution 10 g base bis(3-guanidinopropionic)dodecylamine and 5 ml of 40% aqueous solution of lactic acid. Remove the solvents and get delectat bis(3-guanidinopropionic)-n-dodecylamine.

Brutto-formula: C32H57N7O6. Calculated,%: C 61,08; N 8,83; N 15,20. Found, %: C 60,58; N 8,97; N 14,59.

Melting point 148°C.

The table below shows comparative data on anti-TB activity of the dihydrochloride of bis(3-guanidinopropionic)-n-dodecylamine in comparison with the known drugs. The table shows that the dihydrochloride of bis(3-guanidinopropionic)dodecylamine than the known drugs: bis (3-aminopropyl)-n-dodecylamine and p-aminosalicylic acid.

td align="left" morerows="1"> n-Aminosalicylic acid
Antituberculosis activity of the dihydrochloride of bis(3-guanidinopropionic)dodecylamine
MedicationDose, %Duration
10 min30 min1 hour
The dihydrochloride of bis(3-guanidinopropionic)-n-dodecylamine0,25---
0,15+--
Bis(3-aminopropyl)-n-dodecylamine0,50---
0,15++-
0,50++-
0,15+++

Salt bis(3-guanidinopropionic)dodecylamine the following structure:

where A =Cl, HPO4--, citrate, lactate, acetate, benzoate.



 

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