Potassium salt of 2-[1-(1,1 dissociator-3) benzimidazolyl-2 - thio]-acetic acid, showing immunotropic activity

 

(57) Abstract:

The invention relates to chemistry, namely the synthesis of biologically active compounds. The aim of the invention is the expansion of the means of influence on a living organism. The essence of the invention: a new chemical compound potassium salt of 2-[1-(1,1-dissociator-3) benzimidazolyl-2-thio-acetic acid (N-state registration 9393889) of the formula (I), which has immunomodulatory activity. 10 table.

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The invention relates to new chemical compound, which can be used as a means of manifesting immunotropic activity.

Known reference synthetic immunomodulator azole structure levamisole (hydrochloride 2,3,5,6-tetrahydro-6-imidazo[2,1-b] thiazole), immunotropic activity described in numerous original and review papers [1-3].

New chemical compound potassium salt of 2-[1-(1,1-dissociator-3)benzimidazolyl-2-thio]acetic acid (N registration 9393889) formula

< / BR>
has more immunomodulatory activity than levamisole at a lower 46.5 times of toxicity.

The inventive compound is synthesized as follows.

It is up 2-[1-(1,1-dissociator-3)benzimidazolyl-2-thio] acetic acid, passing by interaction with sodium hydroxide in ethanol in the target salt.

Example 1. The synthesis of the claimed compounds (N registration 9393889).

Synthesis of 1-(1,1-dissociator-3)-2-chlorobenzimidazole carried out according to the method described in [6]. To a solution of 1.84 g (20 mmol) of thioglycolic in 150 ml of ethanol is added 1.68 g (30 mmol) of sodium hydroxide in 10 ml of water and 2.57 g (10 mmol) of 1-(1,1-dissociator-3)-2-chlorobenzimidazole. The mixture is boiled for 5 h, cooled to 5 to 10oC. the precipitation is filtered off, dissolved in water, insoluble impurities are filtered off, the filtrate is added a solution of diluted acetic acid to slightly acid reaction medium. The precipitation is filtered off, washed with water, dried. Get 2,71 g(87%) 2-[1-(1,1-dissociator-3)benzimida-Salil-2-thio]acetic acid, crystallized from ethanol.

IR spectrum, cm-1(vaseline oil): 3400 (OH), 1700(C=O), 1150 and 1310 (SO2), 750-770(CH arene.)

Elemental analysis.

Found,%: C 46,3 H 4,1 N 8,8 S 20,35 - C12H12N2O4S2.

Calculated,%: C 46,1 H 3,9 9,0 N S 20,2.

To a solution of 3.12 g (10 mmol) 2-[1-(1,1-dissociator-3)benzimidazolyl-2 - thio] acetic acid in 200 ml ethanol add to 0.67 g (12 mmol) of sodium hydroxide. See the eve salts of 2-[1-(1,1-dissociator-3)benzimidazolyl-2-thio]-acetic acid.

An NMR spectrum1H (D2O), M. D. : of 3.77 (s, SCH2); 4,55-4,74 (m, S(CH2)2); 5,42-5.56mm (m, NCH); 6,86-7,02 (m, 2 CH arene.); 7,22-7,44 (m, 2 CH arene).

An NMR spectrum13C (D2O), M. D.: 38,24 (NCH); 40,69 (SCH2); 72,04 (S(CH2)2); 112,56 (C arene); 120,41 (C arene); 125,24 (C arene); 125,38 (C arene); 135,03 (C arene); 144,88 (C arene); 154,96 (C arene); b (CO).

Elemental analysis.

Found,%: C 41,3 H 3,4 7,8 N S 18,5 - C12H11KN2O4S2.

Calculated,%: C 41,1 H 3,2 8,0 N S 18,3.

The inventive compound is a white crystalline powder, soluble in water, hot ethanol, insoluble in acetone, ether.

Example 2. The effect of the claimed compounds N 9393889 and levamisole on anti-infective drug resistance was studied on the model of lethal Pseudomonas aeruginosa infections caused by intraperitoneal introduction of the daily culture of Pseudomonas aeruginosa. The causative agent was administered in doses of 1.25 to 2.0 from DL50that was 40 - 90 million microbial cells in the mouse.

The claimed compound was injected into the muscle using intermittent preventive scheme introduction (last injection the day before inoculation of the pathogen) in a dose equal to 1/10 of DL50. Levamisole was administered in a similar way and in equitoxic the lifespan - the student criterion. The difference was considered significant when P< 0,05.

Thus, the claimed compound N 9393889 stimulated nonspecific anti-infective resistance. With the introduction of a moderate dose of the pathogen (from 1,25 DL50the connection was slightly surpassed by the effect of levamisole. In "hard" flow conditions infectious-toxic process (introduction of 2.0 DL50exciter) connection N 9393889 provided statistically significant protection, levamisole was ineffective.

Example 3. Evaluation of the effect of the claimed compounds N 9393889 in comparison with levamisole on the growth of transplanted tumors in mice was conducted on the model inoculated with sarcoma S-180 (ainbridge mouse-males) and melanoma B-16 (mice male C57BL/6). Tumor strains obtained from Bank WANTS RAMS. Implantation of tumor material and assessment of the dynamics of tumor growth was performed according to a standard method. The target compound N 9393889 and levamisole was administered in doses of from 1/20 DL50intraperitoneally with +1 day after implantation of tumor material by intermittently scheme - 1 every 3 days. The results illustrates the table. 2.

The claimed connection N 9393889 by the ability to inhibit the growth of grafted sarcoma S-180 and melanoma B-16 delici is. the and model vaccinated melanoma B-16 connection N 9393889 surpassed levamisole 1.3 times.

Example 4. Assessing the impact of the proposed connection N 9393889 and levamisole on the course of experimental autoimmune process was performed on the model of experimental autoimmune hemolytic anemia (EGO), called in female mice of line SN weekly (within 3 weeks) intraperitoneal sensitization xenogeneic erythrocytes in a dose of 2108erythrocytes per mouse. As a donor erythrocytes were used Wistar rats. Assessment of the severity of the process was carried out for 4 weeks from the start of the course immunization by determining the level of hemoglobin standard method. The claimed connection N 9393889 and levamisole was administered into the muscle at a dose of from 1/10 DL50+1-th day after immunization by intermittently scheme - 1 every three days. All animals received 7 injections connection or levamisole. The results illustrates the table.3.

Thus the claimed compound N 9393889 restored the levels of hemoglobin sensitized xenogeneic erythrocytes of mice, indicating that the suppression of the formation of the EGO. Levamisole in terms of this model did not show activity.

Example 5. The effect of this Declaration is transplantatio skin flap in historicalmystery system mouse C57BL/6 (donor) - mouse strain CBA (the recipient). Grafting of the skin flap was performed by standard method. The claimed connection N 9393889 and levamisole was administered in equitoxic doses (1/10 from DL50in muscle every day to +1 day after allotransplantation. Based on average day of transplant rejection, excluding animals whose rejection occurred in the first 3 days (non-immunological mechanisms). The results illustrates the table. 4.

Thus the claimed connection statistically significantly increased the lifespan of skin allograft, excelling on the effectiveness of levamisole 1.4 times.

Example 6. Assessing the impact of the proposed connection N 9393889 and levamisole on the humoral immune response to thymusdependent antigen sheep erythrocytes was made by determining the amount of antibody productive cells (AFC) in the spleen of mice +5 days after intraperitoneal immunization with sheep erythrocytes. The number of KLA was determined by slide method (Cunnengham A. et al., 1966). To evaluate the activity of regulatory cells immunization produced immunogenic dose of erythrocytes (2108/mouse) and tolerogenic doses: hyperimmune (2109/mouse) and suboptimal (2107/mouse). The compounds and levamisole BBO what you're illustrates a table. 5.

Thus, immunization with immunogenic antigen dose of the inventive connection N 9393889 inhibited the humoral response; levamisole was ineffective. On the background of induction vysokogornoi tolerance hyperimmune dose of antigen declare connection, and to a lesser extent levamisole, increased the intensity of the humoral response. On the background of suboptimal doses of antigen declare connection N 9393889 most effectively restored immunoreactivity. Levamisole was inactive.

Example 7. The effect of the studied compounds and levamisole on the formation of delayed-type hypersensitivity (GST) was studied on the model of formation GST caused by 2,4-dinitrofluorobenzene (DNFB). Animals were senzibilizirani by a double application (0 and +1 day) 25 ál of a 0.5% aqueous solution DNFB (Serva) in acetone-olive oil (4:1) on pilirovanny abdominal surface area of 3 cm2. Later, 4 days after the last sensitization on the dorsal surface of the ears was applied allowing dose DNFB (0,2% solution, 25 μl). After 24 h the thickness of the ears was measured engineering micrometer MK-0-25 and the result was expressed as the increase in the thickness of the ears in comparison with the original, %. State vysokogornoi tolerance created hyperimmune connection and levamisole was administered in equitoxic doses (1/20 from DL50) intraperitoneally on the first day of sensitization and two days later. The results illustrates the table. 6.

Thus the claimed compound N 9393889 by the ability to inhibit the formation of GST on the background immunogenic dose of antigen surpassed levamisole 1.5 times. The ability to restore reactivity with sensitization hyperimmune dose DNFB the claimed connection exceeded levamisole 1.2 times.

Example 8. The effect of the claimed compounds N 9393889 and levamisole on the adsorption activity of macrophages was evaluated in the test clearance was introduced intravenously colloidal coal. The experiments were carried out on weinbrenner mice-males weighing 18 to 20 g of the Studied compounds and levamisole were injected daily intraperitoneally in equitoxic doses (1/20 from DL50within 4 days and a day after the last injection conducted an assessment of the absorptive activity of the reticulo-endothelial system (RES) by intravenous injection of colloidal carbon (160 mg/kg) and determine the elimination rate of coal from the blood spectrophotometrically. The results are shown in table. 7.

We studied the connection and levamisole increased adsorption activity of the RES, indicating that the activating villaume connection N 9393889, which surpassed levamisole 1.13 times.

Example 9. The influence of the connection 9393889 and levamisole on the production of cytokines was studied in cultures of mononuclear cells from peripheral blood of healthy donors. Mononuclear cells were isolated from the blood by the method of gradient centrifugation, washed three times with medium 199 and were cultured for 24 h in medium 199 supplemented with 10% fetal calf serum and 50 μg/ml gentamicin. In the experimental culture was added to 100 μl of the diluted saline solution of the investigated compounds in equimolar concentration of 10-4M (final concentration) in the control culture - equivalent amount of saline. After 24 h in supernatant crops in enzyme-linked immunosorbent analysis determined the level of interleukin-1b and interferon - using ready ELISA test system ProCon-IL1b and ProConIFN-plus (NII OCP, S.-Pb.). The results are presented in table. 8.

Levamisole caused a trend towards increased production of interleukin-1b (difference not statistically significant) and increased production of interferon- . Connection N9393889 used in equimolar concentrations, significantly increased the production of interleukin-1b, surpassing levamisole 1.2 times and increased production online is ity of liver microsomal enzymes was studied on white weinbrenner male mice weighing 18-20 g The compound N 9393889 was administered daily inside for 7 days at a dose of from 1/100 DL50(entering into) that was 64 mg/kg Levamisole was administered in equitoxic the dose of 2.5 mg/kg in the same mode of administration.

A day after the last injection, animals were scored, was isolated microsomal fraction of the liver standard method by differential centrifugation and determined the level of cytochromes P-450 and b5 [4], amidopyrine N-demethylase and aniline p-hydroxylase activity [5]. The level of protein in microsomal fractions was determined by the method of Lowry. The results are presented in table. 9.

The compound N 9393889 used in injection mode, increased the level of cytochrome P-450 in the liver by 39%, the level of cytochrome b5 remained virtually unchanged, the activity aminopyrine-N-demethylase was increased by 31%, p-aniline hydroxylase - 40%, stimulating, thus, metabolic and antitoxic function of the liver. Levamisole in similar mode of administration and equitoxic dose was ineffective.

Example 11. Acute toxicity of the claimed compounds was studied on weinbrenner mice-males weighing 14-16 g according to the method of Litchfield and Wilcoxon signed intraperitoneal injection. Results Illus is and levamisole.

Thus, the claimed compound N 9393889 showed distinct immunotropic activity, surpassing efficiency "reference" azole immunomodulator levamisole. The claimed compound was characterized as the least toxic. In the study of immunotropic activity revealed that on the model of lethal infection (example 2) in the conditions of introduction of 1.25 LD50infectious agent activity of the claimed compounds is higher than the activity of levamisole. However, with the introduction of 2.0 LD50pathogen declare the connection is active, and levamisole in these conditions is ineffective. Immunotropic activity of the claimed compounds N 9393889 model inoculated with sarcoma S-180 (example 3) is superior to the activity of levamisole 2.1 times (table. 2). On the model of melanoma B-16 connection N 9393889 exceeds the activity of levamisole 1.3 times.

On the model of autoimmune hemolytic anemia activity of the claimed compounds N 9393889 exceeds levamisole 1.2 times (table. 4). The claimed connection provides a statistically significant suppression of transplantation immunity (table. 3) that outperforms the activity of levamisole 1.4 times.

The claimed connection N 9393889 on the model se the Finance and exceeds levamisole 2.6 times.

On the background of immunization "hyperimmune" dose of antigen activity of the claimed compounds is similar to that of levamisole. On the background of immunization suboptimal dose of antigen declare connection N 9393889 increased immunoreactivity. Levamisole is ineffective.

On the model of contact hypersensitivity of the delayed type (example 7) on the background of sensitization immunogenic dose inhibited the formation of reaction 1.5 stronger than levamisole.

On the background sensitization "hyperimmune dose" of the inventive compound on the ability to recover immunoreactivity was surpassed levamisole 1.3 times.

When evaluating the effect of compounds on the activity of macrophages revealed that the claimed compound has expressed immunotropic activity and increases the absorptive activity of macrophages 1.13 stronger than levamisole (example 8). In the in vitro system (example 9) connection N 9393889 on the ability to enhance the production of interleukin-1 exceeded levamisole 1.2 times, and interferonogenna activity exceeded levamisole 1.8 times. Interferonogenna effect is a valuable component of immunotropic activity.

The compound N 9393889 has the ability to usilivat activity (example 10). Levamisole in equitoxic dose was ineffective.

Potassium salt of 2-[1-(1,1-dissociator-3) benzimidazolyl-2-thio]-acetic acid formula

< / BR>
showing immunotropic activity.

 

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