Pyrido[1,2-a]benzimidazole derivatives having antibacterial activity and method of producing said derivatives

FIELD: chemistry.

SUBSTANCE: present invention relates to pyrido[1,2-a]benzimidazole derivatives of general formula I, where R=alkyl; R1=alkyl, aryl; R2=alkyl. The invention also relates to a method of producing formula I compounds.

EFFECT: novel to pyrido[1,2-a]benzimidazole derivatives with antibacterial activity are obtained.

2 cl, 2 tbl

 

The invention relates to agriculture and medical chemistry, namely, drugs to fight infectious diseases of plants and animals.

Known synthetic derivatives of 6-aminopenicillanic acid, which has antibacterial activity (Mashkovsky PPM Medicines. The Handbook. - M, "Medicine", 1993, Vol.2, s-258; Navashin S.M., Fomin I.P. Rational antibiotic therapy. The Handbook. - M, "Medicine", 1982, p.93-112).

Known derivatives of 4-quinolones, have antibacterial properties and are widely used in veterinary and medical practice (Mashkovsky PPM Medicines. The Handbook. - M, "Medicine", 1993, Vol.2, s-353).

Long-term use of antibiotics leads to the development of resistant strains of microorganisms that causes the update range of the drugs used.

The purpose of this invention is the synthesis of new antibacterial compounds and expanding Arsenal of substances that affect a living organism.

This goal is achieved by the fact that we synthesized the compounds of formula I, have antibacterial properties, and developed a convenient method for their synthesis.

where R=alkyl;

R1=alkyl, aryl;

R2=alkyl.

The compounds of formula I are synthesized according to the following scheme:

2-Chloromethylthiazole (II) react with mercaptans (III) in alkaline conditions with the formation of thioesters (IV). Oxidation of the latter with hydrogen peroxide obtained sulfones (V), the interaction of which with ethoxymethylenemalonic (VI) leads to the desired product I.

Source 1-R-2-chloromethylthiazole (II) described in the literature (Zubenko A.A. Synthesis and transformations of 2-etinilestradiolo. Diss. Kida. chem. Sciences. - Rostov n/D - 1977).

Examples of syntheses.

1-Methyl-2-(methylthio)-methyl-benzimidazole (IVa, R=CH3, R1=CH3).

To the alcoholic solution ethylate sodium (prepared from 2.3 g of Na (0.1 mol) in 100 ml of C2H5OH) was added at room temperature, 4.8 g of methylmercaptan III (0.1 mol; R1=CH3), stirred for 5 minutes and make of 19.2 g of 1-methyl-2-chloromethylthiazole (II; R=CH3, 0.1 mol). Stirred for 30 minutes, poured into 400 ml of water, filtered off the precipitation. Output 21,28 g (95%), colorless oil.

Similarly receive: 1-methyl-2-(ethylthio)-methyl-benzimidazole IV (R=CH3, R1=C2H5), yield 92%, oil;

1-methyl-2-(phenylthio)-methyl-benzimidazole IVB (R=CH3, R1=phenyl), yield 90%, TPL 96-98°C (petroleum ether). Compounds IV and used without further purification in the next stage.

1-Methyl-2-(methylsulphonyl)-methyl-benzimidazole V (R=CH3, R1=CH3).

Restore the t of 19.2 g of IVa (0.1 mol) in 75 ml of glacial acetic acid, add 0.2 g of Na2WO42H2O, pre-dissolved in 5 ml of water, and then with stirring and cooling, add 60 ml of perhydrol, maintaining the temperature of 40-45°C. Then keep the temperature 40-45°C for 3 hours. Leave overnight at room temperature. Neutralize the aqueous ammonia, the precipitate is filtered off, washed with water. The output of 17.4 g (78%), TPL 155-157°C.

Similarly receive 1-methyl-2-(ethylsulfonyl)-methyl-benzimidazole V (R=CH3, R1=C2H5), yield 75%, TPL 146-148°C;

1-methyl-2-(phenylsulfonyl)-methyl-benzimidazole Vin(R=CH3, R1=phenyl), yield 75%, TPL 176-178°C (ethyl acetate).

5-Methyl-4-(methylsulphonyl)-1-oxo-1,5-dihydropyrido[1,2-a]-benzimidazole-2-ethylcarboxylate Ia (R=CH3, R1=CH3, R2=C2H5).

To a solution of 2.24 g VA (0.01 mol) and 2.16 g VI (0.01 mol) in 20 ml of chlorobenzene was added 0.05 g of 60%sodium hydride and boil the mixture for 1 hour with distillation of the volatile products. Cooled, diluted with petroleum ether (20 ml), the precipitate is filtered off and recrystallized from dimethylformamide. Yield 2.4 g (69%), TPL 259-260°C.

Similarly receive 5-methyl-4-(etiology)-1-oxo-1,5-dihydropyrido[1,2-a]-benzimidazole-2-ethylcarboxylate IB (R=CH3, R1=C2H5, R2=C2H5), yield 70%, TPL 240-243°C;

5-methyl-4-(phenylsulfonyl)-1-oxo-1,dihydropyrido[1,2-a]-benzimidazole-2-ethylcarboxylate IB (R=CH 3, R1=phenyl, R2=C2H5), yield 75%, TPL than 300°C.

An NMR spectrum1H compounds (DMSO d6, 300 MHz) IB (BMD): 8.89-8.86(1H), 8.68 (1H), 7.82-7.46 (3H), 4.32-4.25 (2H,), 4.28 (3H, N-CH3), 3.48-3.41 (2H, SO2-CH2), 1.40-1.28 (6H).

Examples of tests of antibacterial activity of the proposed connections.

Antimicrobial activity of the proposed substances for the first time studied in the sector synthesis wildebeest, SCRIVI. Previously they have never been used.

Study of antimicrobial properties of the proposed compounds were carried out by the method of Milovanovi S.N. (Methods of experimental chemotherapy.- M, "Medicine", 1971, S. 100-106) method twofold serial dilutions in liquid nutrient medium. Bacterial load was 500 thousand microbial cells in 1 ml of Prepared suspension of bacteria was added 2 ml (equal volume) in tubes with different dilutions of the substance. Incubated in an incubator for 18 hours at 37°C served as Control tubes containing 2 ml of medium used for cultivation of substances and 2 ml suspension of bacteria (500 thousand to 1 ml). As the test organisms used the following strains of bacteria E. coli O78, Staph.aureus P-209. The results of the tests are presented in table 1. The data in table 1 show significant antimicrobial activity proposed connections.

The comparison is given in tab is itzá 2 data shows that the proposed activity of the compounds is superior to the activity of Iodinol, iodine solution, polymyxin b, chloramphenicol and tetracycline against St.aureus, and also surpasses the activity of the iodine solution, kanamycin, chloramphenicol and catapilla against E.coli.

+
Table 1
The bacteriostatic activity of the proposed compounds (exposure time of 18 hours, the bacterial load of 0.5 million/ml)
MedicationThe test-cultureConcentration, mg/mlThe control cultureControl environment
50025012562,531,2the 15.67,8
IaE.coli o-----+++-
-----+++-
-----+++-
St.aureus P-209------++-
------++-
--- ---++-
IBE.coli o-----+++-
-----+++-
-----+++-
St.aureus P-209------+-
------++-
------++-
Legend: "-" no culture growth of bacteria
"+" growth of bacterial cultures

Table 2
Comparative antimicrobial activity of the proposed compounds known drugs and some antibiotics
MedicationThe minimum inhibitory concentration, μg/ml
E.coliSt.aureus
Ia1,2 the 15.6
IB31,2the 15.6
Idina*16,016-32
A solution of iodine*16-6464,0
Kanamycin sulfate**100,03-6
Polymyxin**0,19100,0
Chloramphenicol* *100,01,5-50
Oxytetracycline hydrochloride100,0the 1.6-100
Oxytetracycline hydrochloride100,0the 1.6-100
* According to Monaca V.O. in kN.: "Iodine and problems of life." - HP - Nauka, 1974. - S.89-90.
** According to guide "Rational pharmacotherapy". Navashin S.M., Fomin I.P., M, Medicine. - 1982. - 496 S.

Acute toxicity of the proposed compounds were studied in laboratory rats when injected into the stomach. The dose of 0.5 g/kg body weight does not cause the death of laboratory animals (observation period of 10 days). Therefore, the toxicity of the compounds Ia and IB can be attributed to secondary hazard class.

1. Derivatives of pyrido[1,2-a]benzimidazole of formula I:

where R is alkyl;
R1- alkyl, aryl;
R2- alkyl,
possessing antibacterial activity.

2. The method of synthesis of compounds according to claim 1, characterized in that 1-R-2-chloromethylthiazole enter into interaction with the mercaptans R1-SH in alkaline conditions, the resulting sulfides are oxidized by hydrogen peroxide in 1R-2-(R1-sulfonyl)-methylbenzimidazole that react with ethoxymethylenemalonic with the formation of 5-R-4-(R1-sulfonyl)-methyl-1-oxo-1,5-dihydropyrido[1,2-a]-benzimidazol-2-R2-carboxylates of the formula I.



 

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FIELD: medicine.

SUBSTANCE: invention refers to 3 - (2-methoxy-4-pyrazol-1-ilfenil) -2,5-dimethyl-7-(3-methylpyridine-2-yl) pyrazolo [1.5-a] pyrimidine or its pharmaceutically acceptable salts, solvate, stereoisomer, having the following structural formula, which are antagonists of CRF-receptors and can be used in treatment of various disorders that cause hypersecretion of CRF in warm-blooded animals, such as at the sudden attack. Also the invention refers to intermediate compounds, pharmaceutical compositions on the basis of this compound and method of treating disorder causing hypersecretion of CRF in mammals.

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15 cl, 14 tbl, 28 ex

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16 cl, 2 tbl, 21 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. In general formula 1 , R1 and R3 independently denote optionally identical C1-C3 alkyl, and R2 is a -(CH2)nX group or R1 and R3 independently denote different substitutes selected from C1-C3 alkyl or a -(CH2)nX group, and R2 is a hydrogen atom or C1-C3 alkyl; R4 is C1-C3 alkyl; Ri5 is a hydrogen atom, one or two identical or different halogen atoms, C1-C3 alkyl; equals 0, 1 or 2; n equals 0, 1, 2 or 3; X is a carboxyl CO2H, C1-C3 alkyloxycarbonyl, aminocarbonyl CONR6R7 or amino group NR6R7; except compounds in which R3 is a -(CH2)nX group, where X is an amino group NR6R7 and n equals 0; R6 and R7 are optionally identical and denote a hydrogen atom, optionally substituted C1-C5 alkyl or R6 and R7 together with the nitrogen atom with which they are bonded form an optionally substituted 6-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitute is selected from C1-C3 alkyl.

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FIELD: chemistry.

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24 cl, 9 dwg, 4 tbl, 19 ex

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1 cl, 5 tbl, 1 ex

FIELD: chemistry.

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10 cl, 3 tbl, 96 ex

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19 cl, 82 tbl, 500 ex

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21 cl, 10 dwg, 8 tbl, 57 ex

FIELD: chemistry.

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65 cl, 51 tbl, 244 ex

FIELD: medicine.

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3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to pharmaceuticals applied for skin protection against chemical and biological damage factors, bacterial or fungal infections, for prevention of occupational skin diseases, for prevention of contact dermatitis, including allergic dermatitis, and also for first aid and following treatment of wound defects of skin, soft tissues or mucous membranes and can be used in the industry, building, agriculture, medicine and everyday life. Substance of the invention is a therapeutic dermatological composition for local administration which contains an active principle in the form of complex rare-earth salt compounds and a pharmaceutically acceptable carrier.

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6 cl, 10 tbl, 22 ex

FIELD: medicine.

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3 cl, 2 ex

FIELD: medicine.

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3 ex

FIELD: medicine.

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7 cl, 2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention relates to pharmaceutical industry, in particular to composition for prevention and treatment of bacterial infections of oral cavity. Composition for prevention and treatment of bacterial infections of oral cavity, containing anthocyanosides, extracted from Vaccinium myrtillus or Vaccinium myrtillus or procyanides extracted from Vitis vinifera, sanguinarines and heleretrines extracted from Sanguinaria canadensis, Macleaya cordata or Macleaya microcarpa and lypophylic extract of Echinacea angustifolia. Application of said components for production of composition for prevention and treatment of bacterial infections of oral cavity. Application of said components for production of composition for oral cavity hygiene. Application of said composition for oral cavity hygiene.

EFFECT: said composition is efficient for prevention and treatment of bacterial infections of oral cavity.

5 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns veterinary medicine. A vaccine contains cell suspensions of pure cultures of activators of pseudomonose Pseudomonas aeruginosa and enterococcal infection Enterococcus faecalis prepared by sampling involved organs from dead nutrias of a local epizootic centre, preparation of a suspension, inoculation for differential diagnostic mediums, recovery of pure cultures of activators and their separate cultivation in a plain broth with glucose to concentration of microbial cells 4-5 billion per 1 cm3. The vaccine also contains formalin and aluminium hydroxide in the following ratio, wt %: cell suspensions of pure cultures of the activator of pseudomonose Pseudomonas aeruginosa recovered from involved organs from dead nutrias from the local epizootic centre, in a nutrient medium with titre 4-5 billion of microbial cells per 1 cm3 - 38.0-41.5, cell suspensions of pure cultures of the activator of enterococcal infection Enterococcus faecalis recovered from involved organs from dead nutrias from the local epizootic centre in the nutrient medium with titre of 4-5 billion of microbial cells per 1 cm3 - 38.0-41.5, glucose - 2.0-1.0, formalin - 2.0-1.5, aluminium hydroxide - the rest.

EFFECT: prepared vaccine is safe, specific and immunogenic.

1 tbl, 5 ex

Composition // 2389481

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns pharmacy and medicine and represents an antimicrobial composition containing at least 3 various diols wherein specified diols have general formula (CH2)nH2O2 where n is a number of groups CH2 within 3 to 6, in total approximately 0.1 to approximately 50% vol/vol.

EFFECT: invention provides production of the composition which exhibits improved antimicrobial properties, is highly effective, non-toxic, anallergic, and ecologically safe.

16 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the novel tri-indolylmethane derivatives of general formulae I and II. The compounds can be used during bacterial or fungal infection and for protecting different products from harmful effect of bacteria or fungi, particulary as antiseptics or for disinfection. In general formulae

I

or II , where R1; R7; R13 independently represent hydrogen, alkyl, substituted alkyl, R2; R8; R14 independently represent hydrogen, alkyl, substituted alkyl, -OH, -OR, C1-C4acyl, where R is alkyl or substituted alkyl, R3-R6; R9-R12; R15-R18 independently represent hydrogen, alkyl, substituted alkyl, -OH, -OR, C1-C4acyl, where R represents alkyl or substituted alkyl, Y is an anion of a pharmacologically acceptable organic or inorganic acid; R19 is hydrogen, alkyl, substituted alkyl acyl, metal ion. The invention also relates to methods of obtaining compounds of formulae I and II, a pharmaceutical composition and use. The invention relates to a method for synthesis of tri-indolylmethane of formula III mono-substituted in the methane group which is an intermediate compound.

EFFECT: obtaining tri-indolylmethanes of general formulae I or II having antibacterial and antifungal activity.

17 cl, 4 dwg, 4 tbl, 5 ex

FIELD: medicine, veterinary science.

SUBSTANCE: invention concerns veterinary medicine. vaccine contains inactivated antigen and adjuvant. The antigen contained in the vaccine is cell suspension of germ Pseudomonas aeruginosa pure culture. The culture is obtained by selecting target affected organs of fallen nutrias are taken from a local epizootic nidus, preparing suspension, inoculating in differentially diagnostic media, evolving pure culture of the germ and growing the culture in meat infusion broth until microbe cell concentration of 5-6 milliard per 1 cm3 is achieved. The vaccine also contains formalin and aluminium hydroxide in the following wt % ratio: cell suspension of germ Pseudomonas aeruginosa pure culture evolved from target affected organs of fallen nutria from a local epizootic nidus in meat infusion broth with titre of 5-6 milliard of microbal cells per 1 cm3- 83.0-85.5, formalin - 1.0-2.0, the remainder being aluminium hydroxide.

EFFECT: vaccine is safe, highly immunogenic and stable during storage.

1 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to 3 - (2-methoxy-4-pyrazol-1-ilfenil) -2,5-dimethyl-7-(3-methylpyridine-2-yl) pyrazolo [1.5-a] pyrimidine or its pharmaceutically acceptable salts, solvate, stereoisomer, having the following structural formula, which are antagonists of CRF-receptors and can be used in treatment of various disorders that cause hypersecretion of CRF in warm-blooded animals, such as at the sudden attack. Also the invention refers to intermediate compounds, pharmaceutical compositions on the basis of this compound and method of treating disorder causing hypersecretion of CRF in mammals.

EFFECT: improvement of composition.

15 cl, 14 tbl, 28 ex

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