N-(2-benzothiazolyl)amide 2-hydroxy-4-oxo-4-(4-chlorophenyl)-2-butenoic acid having antimicrobial and anti-inflammatory activity

FIELD: chemistry.

SUBSTANCE: invention relates to N-(2-benzothiazolyl)amide 2-hydroxy-4-oxo-4-(4-chlorophenyl)-2-butenoic acid of formula: , which has antimicrobial and anti-inflammatory activity along with low toxicity.

EFFECT: obtaining a compound which can be used to treat diseases associated with pathogenic microorganisms and inflammation.

1 cl, 2 tbl, 1 ex

 

The invention relates to the field of organic chemistry, new biologically active substances of class N-heterylamides 4-aryl-2,4-dioxobutane acids, namely N-(2-benzothiazolyl)amide 2-hydroxy-4-oxo-4-(4-chlorophenyl)-2-butenova acid (1) formula

possessing antimicrobial and anti-inflammatory activity, suggesting its use in medicine as a medicinal antimicrobial and anti-inflammatory agents. The closest analogue to the structure and action of the present compound is N-(2-thiazolyl)amide and 2-hydroxy-4-oxo-4-(4-chlorophenyl)-2-butenova acid (2) [andrejchikov US, Milutin A.V., I. Krylov, etc. Synthesis and biological activity of heterylamides aroylpropionic and 5-arylpyrazole-3-carboxylic acid // Chem.-Pharm. Journe. - 1990. No. 7. - Pp.33-35]

Structural analogue of 2 does not possess anti-inflammatory activity. Data on antimicrobial activity of the structural analogue of 2 in the literature are missing.

The standards of comparison are the following:

1) an antimicrobial agent chlorhexidine [1,6-di-(4-chlorophenylurea)-hexane] (3)widely used in medical practice and are similar in action [Mashkovsky PPM Medicines. - 15-ed., Rev., Corr. and extra - M.: OOO "Publishing The New wave", 2005. - S-936];

2) anti-inflammatory drug diclofenac (sodium salt of 2-[(2,6-dichlorophenyl)amino]phenylacetic acid) (4)widely used in medical practice and are similar in action [Mashkovsky PPM Medicines. - 15-ed., Rev., Corr. and extra - M.: OOO "Publishing house New wave", 2005. - S].

Object of the invention is the finding in a series of N-heterylamides 4-aryl-2,4-dioxobutane acid substances with strong antimicrobial and anti-inflammatory activity and low toxicity.

This object is achieved by obtaining N-(2-benzothiazolyl)amide 2-hydroxy-4-oxo-4-(4-chlorophenyl)-2-butenova acid (1), which has antimicrobial and anti-inflammatory activity.

The claimed compound 1 synthesized by the interaction of 5-(4-chlorophenyl)-2,3-dihydrofuran-2,3-dione with 2-aminobenzothiazole at equimolar ratio of reactants in the medium of anhydrous chloroform at room temperature, followed by separation of the target product with known methods using the pattern

Example 1 to obtain compound 1. To a solution of 2.09 g (0.01 mol) of 5-(4-chlorophenyl)-2,3-dihydrofuran-2,3-dione in 30 ml of anhydrous chloroform is added a solution of 1.50 g (0.01 mol) of 2-aminobenzothiazole in 20 ml of anhydrous chloroform, incubated at room temperature for 24 hours. The reaction mixture is cooled is about 0°C, the precipitation is filtered off, recrystallized from toluene and dried. Yield 3.4 g (95%). TPL 210-212°C. Found, %: C 57.08; N, 3.12; N, 7.92. C17H11ClN2O3S. Calculated, %: C 56.91; N, 3.09; N, 7.81.

IR-spectrum (Specord M80, liquid paraffin, v, cm-1): 3280 (NH), 1710 (CONH), 1640, 1610 (C4=O, C=C, C=N). An NMR spectrum1N (Bruker DRX 500, DMSO-d6, GMDS, δ, ppm): 7.22 (1H, CH), 7.33-7.99 m (10H,6H5With6H4) NH).

The claimed compound 1 is a yellow crystalline substance, soluble in toluene, dioxane, dimethylsulfoxide, and insoluble in water and alkanes.

Determination of the bacteriostatic activity was performed by the method of twofold serial dilutions in liquid nutrient medium [Manual on experimental (preclinical) study of new pharmacological substances / Fisenko VP (as amended). - M.: JJA Remedium, 2000. - S-273]. For all the studied compounds were determined IPC in respect of pharmacopoeial strains: S.aureus was ATSS 6538-P and E.coli was ATSS 25922. The results of the tests are presented in table 1. Crops produced in mesopotania broth, pH 7.0 with different concentrations of the tested compounds. The cultures were grown in test tubes on a beveled apparitional environment (mastopathy agar). To determine the antimicrobial activity was used 18-20-hour culture. For preparation of the working ot the art of microbes produced washout grown culture isotonic sodium chloride solution, and set the density of the microbial suspension according to the turbidity standard 5 units. Next, from the obtained microbial suspension (500 million M.L./ml) were prepared working solution of bacteria with a concentration of 5 million M.L./ml of This suspension of microbes was made in the amount of 0.1 ml in tubes with serial dilutions of study drug. Thus, microbial load when determining the ACA was 250000 M.L./ml of the Studied compound in the amount of 0.05 g was dissolved in 5 ml of dimethylformamide and 1 ml of the prepared dilution of 1:100 was combined with 4 ml mycopathologia broth (1:500). Next was preparing a series of serial dilutions of the compounds twice with decreasing concentration. Records of the results produced after 18-20 hours of exposure control and experimental tubes in the incubator at 37°C. the Minimum inhibitory concentration (MIC) was determined by the absence of signs of growth on nutrient medium: the last tube of stunting (clear broth) corresponds to the IPC of the drug in relation to this strain. Bacteriostatic effect of the studied compounds was compared with the action of chlorhexidine.

Anti-inflammatory activity was studied in experiments on 30 outbred rats of both sexes weighing 220-260 g Compound 1 was administered orally at a dose of 50 mg/kg as a suspension in 2% starch solution for an hour before modeling acute carragenine inflammation. Carrageenophyte swelling caused subplantar injection of 0.1 ml of 1% solution Flo is ogena in hind paw of the rat. About anti-inflammatory activity was assessed by the change in the severity of inflammation in the dynamics, which were recorded ecometrics after 1, 3 and 5 hours after modeling inflammation [Methodical recommendations for a pilot study of non-steroidal anti-inflammatory chemical/ Pharmacological Committee of Ministry of health USSR, Protocol No. 22 dated 11 November 1982. - Moscow, 1982. - 47 S.]. Control animals were injected equiano amount of 2% starch solution. Drug comparison served diclofenac at a dose of 10 mg/kg the Results were processed statistically using Excel 2003 and are presented in table 2.

Acute toxicity (LD50) the claimed compound 1 was determined on 24 outbred mice of both sexes weighing 18-22 g oral route of administration as a suspension in 2% starch solution on an Express method Webprotector [Prozorovsky V.B. have been, Prozorovsky BTW, Demchenko V.M. rapid method for determination of the average effective dose and its errors. // Pharmacology and toxicology. - 1978. No. 4. - S-502]. Found that LD50connection 1 is 5800 mg/kg According to the classification of the toxicity of preparations of compound 1 belongs to the class of practically non-toxic substances [Izmerov IVAN, Sanotski I., Sidorov, K.K. Settings toxicometric industrial poisons. - M.: Medicine, 1977. - S-197]. It is 1.45 times less toxic than large Sedin, and 7,44 times less toxic than diclofenac.

Table 1
Antimicrobial activity and acute toxicity of compounds 1
ConnectionLD50mg/kgIPC mg/mlIPC/LD50
St.aureusE. coliSt.aureusE. coli
158002,0a 3.90,00030,0007
Chlorhexidine40001251250,03130,0313

As can be seen from table 1, compound 1 exceeds antimicrobial activity of chlorhexidine against Golden staph in 62.5 times and to Escherichia coli - 32 times. The ratio of MBC (μg/ml) toxicity LD50(mg/kg) compound 1 is for Staphylococcus 0,0003 and for Escherichia coli 0,0007, while the chlorhexidine is minute rates are significantly inferior.

Table 2
Anti-inflammatory activity and acute toxicity of compounds 1
ConnectionDose, mg/kgLD50mg/kg% inhibition carragenine edema
1 hour3 hours5 hours
Control--0,0±0,00,0±0,00,0±0,0
150580039,7±2,1**164,2±3,2***1of 56.4±3,3***1
*2*2
Diclofenac1078040,2±4,865,6±4,3***160,1±4,7***1
*=p<0,05,**=p<0,01,***=p<0,001.
1, compared with control; 2 - compared with diclofenac.

As can be seen from table 2, compound 1 showed a pronounced anti-inflammatory activity throughout the observation period, and at the peak of inflammation, it is not inferior to diclofenac. It should be noted that the effective dose of diclofenac is 0,013 from his LD50and the claimed compounds 0,008 from his LD50, indicating that certain advantages of the connection 1 before diclofenac in terms of its safety and effectiveness.

Thus, N-(2-benzothiazolyl)amide and 2-hydroxy-4-oxo-4-(4-chlorophenyl)-2-butenova acid (1) has higher antimicrobial and anti-inflammatory activity in comparison with the structural analogue and standards of comparison, and is practically non-toxic, which makes it possible to use it to create new medicines, which have antimicrobial and anti-inflammatory activity.

Literature

1. Andrejchikov US, Milutin AV, Krylova, I. V. and other Synthesis and biological activity of heterylamides aroylpropionic and 5-arylpyrazole-3-carboxylic acid // Chem.-Pharm. Journe. - 1990. No. 7. - Pp.33-35.

2. Mashkovsky PPM Medicines.- 15th ed., Rev., COI is. and extra - M.: OOO "Publishing house New wave", 2005. - S, 935-936.

3. Manual on experimental (preclinical) study of new pharmacological substances / Fisenko VP (as amended). - M.: JJA Remedium. - 2000. - S-273.

4. Methodological guidelines for experimental study of non-steroidal anti-inflammatory chemical / Pharmacological Committee of Ministry of health USSR, Protocol No. 22 dated 11 November 1982. - Moscow, 1982. - 47 S.

5. Prozorovskiy V.B. have been, Prozorovsky BTW, Demchenko V.M. rapid method for determination of the average effective dose and its errors. // Pharmacology and toxicology. - 1978. No. 4. - S-502.

6. Izmerov IVAN, Sanotski I., Sidorov, K.K. Settings toxicometric industrial poisons. - M.: Medicine, 1977. - S-197.

N-(2-Benzothiazolyl)amide and 2-hydroxy-4-oxo-4-(4-chlorophenyl)-2-butenova acid formula

possessing antimicrobial and anti-inflammatory activity.



 

Same patents:

FIELD: medicine, pharmaceutics.

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1 cl, 1 ex, 1 tbl

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12 cl, 6 tbl, 12 ex

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20 cl, 6 dwg, 8 tbl, 6 ex

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2 cl, 2 tbl

FIELD: medicine.

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3 ex

FIELD: medicine, pharmaceutics.

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6 cl, 10 tbl, 22 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, and can be used for integrated treatment of purulent cholangitis by external percutaneous transhepatic drainage and laser and antibiotic therapy. That is ensured by ultrasound-aided percutaneous transhepatic drainage. Then Cefoperazone 2 g in 100 ml of 0.9% saline solution in a plastic package is exposed to low-intensity infra-red pulse laser light at wave length 0.89 mcm, power 200 mWt and frequency 1500 Hz for 6 minutes. Thereafter, the exposed antibiotic substance is introduced intravenously drop-by-drop for 30 minutes. Simultaneously, blood is exposed intravenously to continuous laser light at wave length 0.63 mcm, power 2 mWt for 30 minutes. The therapeutic course of laser and antibiotic therapy is 5-10 days.

EFFECT: method allows preventing purulent-septic complications represented by hepatic abscesses and hepatic failure.

3 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention belongs to vaccine manufacture for infectious diseases prophylaxis. Salmonella vaccine manufacture includes detoxication of exo- and endotoxins in suspention of autoclaved salmonells consecuently with two detoxicants - 0.2% formalin solution at 40±1 C° during 6-7 days and 0.5±0.1% aethonium solution at 41±1 C° during 7-8 days, followed by sterilisation at 1.0 atm during 20 minutes. Derived anatoxins are sorbed on aluminium hydroxide and sterilised at 1 atm during 20 minutes.

EFFECT: anatoxin-vaccine with enhanced effectivity and safety is used for specific prevention of salmonellosis in piglets, calves, carnivorous and poultry.

3 ex

FIELD: medicine.

SUBSTANCE: invention belongs to medicine, notably to pharmaceutical composition for treatment and prevention of bacterial infections induced by gram-positive bacteria. Composition includes effective doses of cholanic acid or its salt, phosphatidylcholine and neutral lipids. Neutral lipids and phospholipids are associated in lipoprotein-like particles, which does not include proteins or peptides.

EFFECT: composition effectivity is caused by its ability to bind lipoteichoic acid of gram-positive bacteria, neutralising or preventing their pathogenic action.

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: present invention refers to compounds of general formula (I), where R1 - C1-C6alkyl, (C1-C6alkyl)C1-C6alkyl, di(C1-C6)C1-C6alkyl or C3-C6dicloalkyl; each R2 independently represents halogen, C1-C6alkyl, halogen-substituted C1-C6alkyl or cyano; R3 - hydrogen, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkinyl, hydroxyl, hydroxy-substituted C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, cyano, C(=O)H, phenyl, (C3-C6cycloalkyl)C1-C6alkoxy, (C1-C6alkoxycarbonylamino)C1-C6alkoxy or (C1-C6alkylcarbonylamino)C1-C6alkoxy; R4 represents hydroxyl, C1-C6alkoxy, the group -NH(C=O)R4a, where R4a is halogen-substituted C1-C6alkyl, or the group -NH(CH2)2OR4b, where R4b is benzyl or phenyl ethyl; and m = 1 or 2 in a free form or in the form of pharmaceutically acceptable salt. Besides the invention refers to a pharmaceutical composition of the compounds applied for treatment or prevention of a disease or condition wherein vaniloid receptor activation acts the part or participates.

EFFECT: invention refers to application of the named compounds for preparing a drug to be applied for treatment or prevention of pain or gastrointestinal disturbance.

20 cl, 30 ex

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