Triiodide 1,2,3-substituted benzimidazole and methods for their production

 

(57) Abstract:

The invention relates to the field of organic chemistry and relates to new triiodide 1,2,3-substituted benzimidazole with antimicrobial and anti-tumor activity, which may find application in medicine, as well as methods for their preparation. Compounds have high activity. 3 C. p. F.-ly, 4 PL.

The invention relates to medicinal preparations containing biologically active ingredients, and methods for their preparation and can be used in medicine and veterinary medicine to combat infectious and oncological diseases of humans and animals.

Known iodoform ZN3- crystalline substance yellow, antiseptic action, was previously used to disinfect wounds (Akhmetov N. With. General and inorganic chemistry. M.: Higher school, 1981).

A disadvantage of the known chemical compounds is inconvenient form application in the form of powder and high toxicity when applied to the wound surfaces that may cause a General poisoning.

Known antimicrobial agent is a tetracycline, a commonly used broad-spectrum antibiotic (M. D. Mashkovsky. Drug the spine of microorganisms, and nephro - and hepatotoxicity.

A method of obtaining substances with antimicrobial and antitumor action of antibiotics, which consists in the production of these substances by microorganisms, followed by separation from biomass (Shemyakin, M. M. et al. Chemistry of antibiotics. M, an SSSR, 1961, 2 h, S. 675).

However, the known method requires sophisticated equipment, and multi-nutrient environments, strictly sterile conditions, time-consuming process of excretion of the antibiotic biomass.

Most loved ones chemical compounds of the same purpose to the declared triiodide 1,2,3-substituted benzimidazole in the group of inventions on a set of attributes are based on the technical solution to the patent of the Russian Federation "Triiodide Quaternary nitrogen bases and their water-soluble composition" (the description of the invention to the patent of the Russian Federation 2154053, 7 C 07 C 211/63, 209/74, C 07 D 295/037, 487/18, 487/04, 213/20, 215/10, a 61 K 31/14, a 61 P 31/00).

A disadvantage of the known chemical compounds is the fact that significantly narrowed the number of members of the class of triiodide Quaternary nitrogen bases are not covered by derivatives of 1,2,3-substituted benzimidazole.

Closest to the claimed spot of triiodide Quaternary nitrogen bases on the patent of the Russian Federation 2154053 (see above).

The disadvantage of this method is the impossibility of obtaining in this way triiodide 1,2,3-substituted benzimidazole.

The problem to which this invention is directed, is expanding the selection of compounds with antimicrobial and antitumor activity, and methods for their preparation.

A single technical result that can be achieved with the implementation of a group of inventions is the creation of a new members class triiodide 1,2,3-substituted benzimidazole, each of whom must possess antimicrobial, including TB, and antitumor action.

This technical result is achieved by the fact that to obtain triiodide 1,2,3-substituted benzimidazole the benzimidazole or 1,2-derivative is subjected to alkylation by the corresponding iodide Akilov in the presence of a base or diallylsulfide and then adding to the reaction mixture crystal of iodine.

Paragraph 1. The essence of the invention is possessing antimicrobial and antitumor activity of a substance (chemical compound) obtained by chemical means, achieved a new connection is k.

Nomenclature triiodide 1,2,3-substituted benzimidazole reflected in: 1. Banks, J. Names of organic compounds. M, Chemistry, 1980; 2. Vasilieva N. C. the IUPAC Nomenclature of organic compounds. M., 1975; 3. Chemist's Handbook. So 2. Ed. "PI". M.-L. 1963.

Contained in the molecules of triiodide 1,2,3-substituted benzimidazole triode-anion I3-not only provides antimicrobial activity of the claimed compounds, but the lack of resistance of microorganisms.

Paragraph 2. The essence of the invention is a method of producing triiodide 1,2,3-substituted benzimidazole (method A) is that the benzimidazole or 1,2-derived enter into reaction with the corresponding iodide alkilani in the presence of a base and then adding to the reaction mixture of crystalline iodine according to the scheme:

< / BR>
where-- base; R1=Alk, Ph; R2=H, Alk; R3=Alk.

The proposed technical solution, the method of producing triiodide 1,2,3-substituted benzimidazole, allows you to choose the optimal variant of the synthesis of compounds on p. 1, both in terms of substituents in the 1,2,3-positions, and the initial reagents.

Item 3. The essence of the invention is a method pohodnye enter into reaction with the appropriate diallylsulfide in the presence of a base and then adding to the reaction mixture of crystalline iodine according to the scheme:

< / BR>
where-- base; R1, R3=Alk; Ph, R2=H, Alk.

The proposed technical solution, the method of producing triiodide 1,2,3-substituted benzimidazole gives you more choices for the synthesis of compounds on p. 1, both in terms of substituents in the 1,2,3-positions, and the initial reagents.

This invention covers compounds containing organic cation derived 1,2,3-substituted benzimidazole and biologically active anion I3-(triode-anion), which are interconnected electrostatic forces. Triode-anion contained in the composition of triiodide 1,2,3-substituted benzimidazole, provides their biological, in particular antimicrobial and antitumor activity, and the absence of the claimed compounds of resistance of microorganisms. Thus, the proposed solution allows you to expand the selection of antimicrobial agents for infectious diseases of humans and animals.

Conducted by the applicant's analysis of the level of technology has allowed to establish that the analogues, characterized by a set of characteristics is identical for all features of the declared ttsutsumi. Therefore, each of the claimed invention meets the condition of patentability "novelty."

The results of the search of solutions in this and related areas of technology in order to identify matching the distinctive features of the prototypes of the characteristics of each of the claimed invention, have shown that they do not follow explicitly from the prior art. Of certain of applicant's prior art there have been no known impact provided the essential features of each of the claimed inventions transformations on the achievement of the technical result. Therefore, each of the claimed invention meets the condition of patentability "inventive step".

In the present application for patent complied with the requirement of unity of invention, since substances - triiodide 1,2,3-substituted benzimidazole, methods a and B are designed to receive a single technical result - getting new members class triiodide 1,2,3-substituted benzimidazole possessing antimicrobial and antitumor activity.

The claimed group of inventions to meet the requirement of unity of invention, since the group single object of the invention is formed by idle manufacturing third of the declared object group - triiodide 1,2,3-substituted benzimidazole possessing antimicrobial and antitumor activity. We offer chemical compounds can be used for the manufacture of various drugs, including parenteral forms for medical and veterinary purposes.

Expansion of functional capabilities antimicrobial and antitumor effects on a living organism is dictated by the peculiarities of higher organisms (e.g., individual sensitivity), contraindications of the drugs used. Proposed connection eliminates the need for determining the sensitivity of pathogenic microflora, since there is no resistance of microorganisms. This is particularly important in the context of the liquidation of the consequences of mass lesions.

The possibility of carrying out the invention is confirmed by the following information. The structural formula of triiodide 1,2,3-substituted benzimidazole:

< / BR>
where R1, R3=Alk, Ph; R3=H, lk.

Ways of getting triiodide 1,2,3-substituted benzimidazole not described in literature. The proposed connection can be derived from benzimidazole and its derivatives one of the following ways.


< / BR>
where-= Foundation; R1=Alk, Ph; R2=H, Alk; R3=Alk.

Method B. These compounds may be obtained by alkylation of benzimidazole and its derivatives by diallylsulfide and then adding to the reaction mixture of crystalline iodine with potassium iodide. The quantitative limits of reagents used are determined by the equation the corresponding chemical reactions scheme:

< / BR>
where-= Foundation; R1=Alk, Ph; R2=H, Alk; R3=Alk.

The following are specific examples of the preparation of the proposed connections.

Example 1 (method A).

Triode 1,3-dimethylbenzimidazole. To a solution of 59 g (0.5 mol) benzimidazole in 300 ml of ethyl alcohol add 142 g (61,8 ml, 1 mol) methyl iodide, 68 g (0.5 mol) of three-hydrate of sodium acetate and heated the reaction mixture for 2-3 hours. Cool and under vigorous stirring contribute small portions 127 g (0.5 mole) of crystalline iodine. Stirred until the disappearance of iodine crystals and deposition of the reaction product. Diluted three times with water and filtered product. H is Tim analysis molecular weight and range of the PMR. Found, %: N 5,20; I 47,10. WITH9H11N2I3. Calculated, %: N 5.3; I 48,1, M m RUR 527.9. Range of PMR, DMSO-d6, . memorial plaques : 4,1 (6N, s, 2 N-CH3), and 7.7 (2H, m, H5,6); TO 8.0 (2H, M, H4,7); and 9.6 (1H, s, H2).

Example 2 (method A).

Triode 1,2,3-trimethylsilylimidazole. Get similar to triiodide 1,3-dimethylbenzimidazole (example 1) from 2-methylbenzimidazole, iodine bromide, sodium acetate and a crystal of iodine in a ratio of moles of 1:2:1:1 respectively. Dark brown crystalline substance with so pl. 160-161oC. The Yield Of 55%. The structure of the obtained compounds was confirmed by elemental analysis, molecular weight and range of the PMR. Found,%: N 4,9; I 46,8. C10H13N2I3. Calculated, %: N 5,0; I 47,7. M m 541,9. Range of PMR, DMSO-d6, . memorial plaques: 2,9 (3H, s, CH3); 4,0 (6N, s, 2 N-CH3); and 7.6 (2H, m, H5; N6); to 7.9 (2H, m, H4; N7).

Example 3 (method B).

Triode 1,3-diethylbenzamide. A mixture of 14.2 g (0.12 mol) benzimidazole, 4.9 g (0.12 mol) of caustic soda (NaOH) and 25 ml of water is stirred for 10-15 minutes until complete dissolution of alkali. The mixture is heated to 50oC. Portions add to 18.7 g (0.12 mol, 16 ml) diethylsulfate with such IC is eshivot 2-3 hours at 50-60oWith, then within hours add to 18.7 g (0.12 mol, 16 ml) diethylsulfate. The mixture is stirred for 1.5-2 hours at 50-60oWith, then another 2 hours at 70-75oC.

To the thus obtained aqueous solution of ethyl sulfate 1,3-diethylbenzamide poured 25 ml of water and 50 ml of alcohol and with stirring, heated to 70-75oTo make 20 g (0.12 mol) of potassium iodide, mix until it dissolves and portions contribute 27 g (0.11 mol) of crystalline iodine. Under vigorous stirring, the reaction mixture was maintained at 65-70oC for 30-40 minutes. After that, stirring, cooled to room temperature. The precipitated product is filtered, washed on the filter with ethanol (2 times 25 ml) and then water (4 times 50 ml of the Crude product is recrystallized from alcohol. Dark brown crystals with so pl. 84-85oC. The Yield Of 88%. The structure of the obtained compounds was confirmed by elemental analysis, molecular weight, range of PMR. Found, %: N 5,1; I 46,2. C11H15N2I3. Calculated, %: N 5,0; I 45,6. M m 556,0. Range of PMR, DMSO-d6, . memorial plaques: 1,6 (6N, m, 2 of CH3); 4,5 [4H, kV 2 (N-CH2-)]; and 7.7 (2H, m, H5; H6); to 8.0 (2H, m, H4N7); and 9.8 (1H, s, H2).

Example 4 (method B).

Criodrilidae, caustic soda, diethylsulfate, potassium iodide and a crystal of iodine in a ratio of moles of 1: 1:2:1:0.9 respectively. Red-brown crystalline substance with so pl. 122-123oC. The Yield Was 73%. The structure of the obtained compounds was confirmed by elemental analysis, molecular weight, range of PMR. Found,%: N 4,8; I 46,0. C12H17N2I3. Calculated, %: N 4,9; I 44,5. M m 570,0. Range of PMR, DMSO-d6, . memorial plaques : 1,5 (6N, m, 2 of CH3); 3,0 (3H, s, CH3); 4,6 [4H, kV 2 (N-CH2-)]; and 7.6 (2H, m, H5N6); to 7.95 (2H, m, H4N7).

Example 5 (method B).

Triode 1-benzyl-3-ethylbenzothiazoline. To a solution of 12.5 g (0.06 mol) of 1-benzylbenzimidazole in 50 ml of ethanol is added 9.4 g (0.06 mol, 8 ml) diethylsulfate and refluxed for 3 hours, then add 50 ml of water and at a temperature of 50-60oTo make 10 g (0.06 mol) of potassium iodide. The mixture is stirred until complete dissolution of KI and then portions contribute 13.5 g (0.05 mol) of crystalline iodine and with vigorous stirring the mixture is maintained at 65-70oC for 30-40 minutes. After that, the mixture is cooled to room temperature. The precipitated product is filtered, washed on the filter with ethanol (2 times 25 ml) and then water portions 50 12-113oC. The Yield 84%. The structure of the obtained compounds was confirmed by elemental analysis, molecular weight, range of PMR. Found, %: N 4,4; I 40,1. WITH16H17N2I3. Calculated, %: N 4,5; I 41,0. M m 618,1. Range of PMR, DMSO-d6, . memorial plaques: 1,6 (3H, t, CH3); and 4.6 (2H, q, N-CH2-); of 5.75 (2H, s, N-CH2-Ph); 7,4-7,6 (7H, m, H5H6C6H5); to 7.9 and 8.1 (2H, m, H4N7); 9,9 (1H, s, H2).

Examples of the compounds shown in table 1.

Study of the antimicrobial action of the proposed compounds listed in table. 1, was performed ten-fold serial dilutions in saline solution with successive planting in appropriate nutrient medium (Lewicki C. I. et al. Clinical laboratory diagnostics. 1998. 1. S. 44). As test objects used the following microorganisms: Escherichia coli; Pseudomonas aeruginosa; Staphylococcus aureus; Clostridium perfringens. The test results are summarized in table 2.

In table 2 data show that the proposed compounds for antimicrobial activity are not inferior to widely used antibiotics.

Some biological activity in inflammatory processes accompanying, for example, syphilis, have a p is th sodium, that is explained by the presence in the body of iodinated translating anion iodine (I-in biologically active form, containing iodine in the oxidation state +1 (I+), which has a therapeutic effect (Mochnacz C. O. Theoretical foundations of the biological effect of halide compounds. The science. L. 1968).

The proposed triiodide 1,2,3-substituted benzimidazole allow you to enter into the body iodine directly to the biologically active form, thereby strengthening its action, while reducing toxicity.

As follows from the data of tables 3 and 4 triiodide 1,2,3-substituted benzimidazole have significant antitumor activity in the treatment of mice with melanoma b-16. Antitumor effect of their stable and does not decrease on day 7 after stopping treatment. The reduction effect is observed only on day 10 after stopping treatment.

Proof of compliance of the claimed invention, the condition of "industrial applicability" is as follows.

When using the claimed group of inventions made the following sets of conditions:

1. The substance obtained by chemical means one of the following methods, intended for use VI humans and animals.

2. For the claimed group of inventions, as described in independent clauses set forth in the claims, confirmed the possibility of their implementation using the above in the application of tools and techniques.

The invention in its implementation ensures the achievement of the envisaged in the application of a single technical solution, consisting in the creation of new members number of triiodide 1,2,3-substituted benzimidazole, each of whom must possess antimicrobial activity.

Therefore, the claimed group of inventions meets the condition of "industrial applicability".

1. Triiodide 1,2,3-substituted benzimidazole possessing antimicrobial and antitumor activity, of General formula:

< / BR>
where R1, R3= Alk, PH;

R2= N, lk,

moreover, when R2=lk, R1and R3at the same time cannot be lk.

2. The method of producing triiodide 1,2,3-substituted benzimidazole, wherein the benzimidazole or 1,2-derivative is introduced into reaction with iodine alkilani in the presence of base, followed by ladirovannye formed iodide 1,2,3-substituted benzimidazole.

3. The way the floor is W ill result in reaction with diallylsulfide with subsequent ladirovannye sulfate 1,2,3-substituted benzimidazole.

 

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< / BR>
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