Stable radicals having bactericidal and fungicidal activity

FIELD: chemistry.

SUBSTANCE: invention relates to novel heterocyclic radicals of formulae and , having bactericidal and fungicidal properties, which can be used in veterinary and medicine, as well as labels when investigating metabolic routes of medications in living organisms.

EFFECT: novel, unparalleled bactericidal and fungicidal compounds are disclosed.

1 cl, 1 tbl, 3 ex, 2 dwg

 

The invention relates to the field of organic chemistry, in particular phosphorylated nitrogen and the oxygen-containing heterocycles - benzofuroxan and-furazan, namely stable NH-radicals of General formula I and II:

having high bactericidal and fungicidal activity at low concentrations, which can find application in the field of veterinary medicine and agriculture as drugs and disinfectants and as labels in the study of pathways of drug metabolism in liquor living organisms.

Development of new domestic drugs currently delivered by the state to the rank of the main priority areas of socio-economic development and national security. The fundamental task of biomolecular and pharmaceutical and medicinal chemistry is the development of new methods of synthesis, it provides a systematic way to design new effective drugs having high physiological activity and minimal toxicity. For the successful implementation of this task, you must resolve the issues that are at the intersection of many fields of science - organic, Organoelement, physical, pharmaceutical chemistry,physics and medicine. However, the absence to date of a single satisfactory theory linking chemical structure to biological activity, significantly slows down the emergence of new domestic pharmaceuticals.

The applicant claimed a new class of compounds not previously known from the prior art, which has no analogues in the world and is not described in the literature. After conducting biological tests on pathogens of humans and animals by the applicant were received high antibacterial and antifungal results. In addition, the claimed compounds according to the method of EPR (electron paramagnetic resonance) are stable NH-radicals, which can be used as labels for the study of the metabolism and distribution of drugs in liquor (biological liquids of an organism.

Structural tax as drug labels of the investigated prior art and literary sources are not identified. However, there are structural analogues in the series of substituted benzofuroxans on Antitrypanosomal, anticancer and antibacterial activity in the works of foreign authors [Porcal W., Herrandes P., Boiani M., Aguirre, G., Boiani L., ets. In vivo anti-Chahas vinilthio-, and vinylsulfonylbenzofuroxan derivatives. J.Med.Chem. 2007, 50 (24), P. 6004-6015.; Aguirre G., Boiani M., H. Cerecetto, ets. Furoxan derivatives as cytotoxic agents: preliminary in vivo antitumoral activity studes. Pharmazie, 2005, 61 (10, P.54-59].

Known functional analogue of the biological activity of the inventive compounds on purpose - the active ingredient of many domestic and foreign (France, Germany, the Netherlands) antibacterial, antiseptic drugs - benzalconi chloride (Benzalkonium chloride), which is a chloride of benzylacrylamide where the alkyl is a mixture of the higher halide Akilov with radical length from C8 to C18 [Jansson P.M. Medical encyclopedic dictionary (Collins), Moscow: Astrel, 2006, 1375 S.].

The disadvantage of this drug is benzalkonium chloride is its high working concentration (1% solution), at low temperatures, precipitates, has a low thermal stability up to 100°C, as all ammonium salts, which when heated, decompose to the original connection and lose their therapeutic activity. In connection with this difficult sterilization of these drugs (100°C), autoclaving (200°C). In addition, all products containing benzalconi chloride, dissolved soap, as stated in the instructions for their use [Burbelo A.T., V. Shabrov Modern medicines. - M.: OLMA Media Group, 2007, - S].

Object of the present invention are new stable up to 200°C according to the method TG-DSC) radical system (I) and (II)that has more bio is esteem - simultaneous and bactericidal, and fungicidal activity at low concentrations (0.1 to 0.01%), in contrast to benzalkonium chloride, which has a bactericidal action, thus the claimed technical solution significantly extends the range of known means specified destination with the possibility of their use as labels in the metabolism of drugs in various liquor living organism.

The technical result is achieved by obtaining a robust NH-radicals (I) and (II) in ether-alcohol medium 1:1 at room temperature by the reaction of triphenylphosphine (V) with 5,7-dinitrobenzofuroxan formula (III) and 4-chloro-5-nitrobenzofurazan formula (IV), which has antibacterial and antifungal properties.

The claimed technical solution is illustrated by the following materials. Figure 1 shows the EPR spectra of the heterocycle (I) or heterocycle (II). Figure 2 presents the molecular structure of the crystals stable NH-radicals (I) and (II)obtained by the method of x-ray analysis (PCA).

According to the EPR spectra of the products monophosphorylation - 6-nitro-7-oxo-4-(triphenylphosphonio)-4,7-dihydro-2,1,3-benzoxadiazole-1-imil - (I, 1) and 5-nitro-4-oxo-7-(triphenyltetrazolium)-4,7-dihydro-2,1,3-benzoxadiazole-1-yumil (II, who IG) are stable NH-radicals and open a new class of previously undescribed connection:

Source triphenylphosphine (V) chloronitrobenzenes (IV) are commercially available drugs.

4.6-Dinitrobenzofuroxan (III) are readily available in synthetic terms of the reagent obtained by the method described in the work of German authors [R. Nietski, R. Dietschy. Ber., N.34. - S.55 (1901)]:

Methods of obtaining NH-stable radicals on the basis of substituted benzofuroxan and benzofurazan are illustrated by the following examples.

Example 1. The method of obtaining a stable radical (I):

To a solution of 2.26 g (0.01 mol) 4.6-dinitrobenzofuroxan (III) in 25 ml of abs. solvent mixture of ethanol and diethyl ether was added a solution 2,62 g (0.01 mol) of triphenylphosphine in 25 ml of the same solvent. The reaction mixture was kept at room temperature (18-20°C) for 72 hours, then cooled and stored in a refrigerator at 0°C. until a crystalline product.

Two weeks from the reaction mass crystallized Druze needle-shaped crystals of a dark red color, which according to the RBA have the structure of complex Pospolita (I), representing according to EPR stable free radical.

The precipitate was separated, washed with ether from the parent compounds, dried. Output 2,78 g (57%), Tpl.177.7°C. IR: 3290 cm-1(NH), 1620 cm-1(C=N), 980 cm-1(N-O). Found, % 65.54; N, 4.03; N, 9.77 C24H17N3O4P. Calculated, %: C 65.16; N, 3.85; N, 9.50.

Method PCA established the final structure of the heterocycle (I) and shown in figure 2(1).

Example 2. The method of obtaining a stable radical (II):

To a solution of 2.00 g (0.01 mol) 4-chloro-5-nitrobenzofurazan (IV) in 25 ml of abs. solvent mixture of ethanol and diethyl ether was added a solution 2,62 g (0.01 mol) of triphenylphosphine in 25 ml of the same solvent.

The reaction mixture was kept at room temperature (18-20 C) for 72 hours, then cooled and stored in a refrigerator at 0°C. until a crystalline product.

Two weeks from the reaction mass crystallized plate crystals of dark green, which according to the RBA have the structure of complex Pospolita (II)representing according to EPR stable free radical.

The precipitate was separated, washed with ether from the parent compounds, dried. Output 3,19 g (69%), Tpl.291.2°C. IR: 3290 cm-1(NH), 1620 cm-1(C=N). Found, %: C 65.05; N, 3.47; N, 9.19 C24H17N3O4P. Calculated, %: C 65.16; N, 3.85; N, 9.50. Method PCA established the final structure of the heterocycle (II) and shown in figure 2 (II).

Example 3. Study of biological activity

Fungicidal and bactericidal activity of phosphorylated heterocycles is ormula (I) and (II) investigated the test-cultures: Candida Albicans, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis [Pershin GN. Methods of experimental chemotherapy. - M.: Medicine, 1971. - 245 C.]. For evaluation of biocidal activity of the investigated substance of the formula (I) and (II) in a 1% solution in DMSO (dimethyl sulfoxide) were introduced into the wells apparitional nutrient medium. Of bactericidal and fungicidal activity was judged by the presence of zone of inhibition of growth of the test cultures, which is formed around the hole with the test substance. The results of the study fungicidal and bactericidal activity of the compounds of formula (I) shown in table 1.

Table 1
Fungicidal and bactericidal activity of heterocyclic compounds (I) and (II)
ConnectionThe zone of inhibition of growth of bacteria and fungi, R (mm)
Staphylococcus aureusEscherichia coliPseudomonas aeruginozaProteus MirabilisCandida Albicans
211791330
1711171728

Advantages of the claimed compounds is that they have a higher bactericidal and high fungicidal activity at low concentrations (0.1 to 0.01%), against a higher working concentration (1% solution) at the closest functional equivalent of the biological activity of benzalkonium chloride. In addition, the claimed NH-radicals showed a high thermal stability (according to the method of thermogravimetry and scanning calorimetry) up to 200°C, which makes possible their use (sterilization, autoclaving) in pharmacology, in the creation of advanced domestic medicines and disinfectants in medicine and veterinary medicine.

Stable phosphorylated NH-benzofurazan radicals of the formula (I) and (II):

having bactericidal and fungicidal activity.



 

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