Derivatives of 2-[1-(1,1-dioxothietanyl-3)-1,2,4-triasolyl-5-thio]acetic acid, possessing hemorrheologic activity

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 2-[1-(1,1-dioxothietanyl-3)-1,2,4-triasolyl-5-thio]acetic acid of formula I , where R=H2N+(CH2CH2OH)2 (Ia); R=H3N+CH2CH2OH (Ib).

EFFECT: increased hemorrheologic activity and possibility to apply for reduction of blood viscosity.

4 cl, 2 tbl, 2 ex

 

The invention relates to medicine, namely to pharmaceutical chemistry and pharmacology, and can be used to create new offsets hemorheological disorders.

The objective of the invention is to expand the Arsenal of biologically active substances with hemorheological activity.

The technical result - obtaining substances with pronounced hemorheological activity.

The essence of the invention: derivatives of 2-[1-(1,1-dissociator-3)-1,2,4-triazolyl-5-thio] acetic acid (Ia, b), General formula

where R=H2N+(CH2CH2OH)2(Ia); R=N3N+CH2CH2HE (Ib),

with hemorheological activity.

As the comparison drug taken pentoxifylline (3,7-dihydro-3,7-dimethyl-1- (5-oxohexyl)-1H-purine-2,6-dione, Aventis, Germany), which for a long time used in the clinic as a corrector of rheological disorders (Hikiami H., Goto, H., Sekiya, N. [et al.] // Phytomedecine. - 2003. - Vol.10, No. 6-7. - P.459-466).

The claimed compounds are synthesized as follows.

The interaction of 3,5-dibromo-1 -(1,1-dissociator-3)-1,2,4-triazole (Iskhakov GF Synthesis of 3,5-dibromo-1-(1,1-dissociator-3)-1,2,4-triazole (Iskhakov GF, Maple EA, Khaliullin FA // the human Sciences: papers of the Third international Congress of young scientists and specialists. - Tomsk, 2002. S-218) with thioglycolic acid in the presence of potassium hydroxide in ethanol medium synthesize 2-[3-bromo-1-(1,1-dissociator-3)-1,2,4-triazolyl-5-thio] acetic acid, the reaction which monoethanolamine or diethanolamine in ethanol medium at boiling for 0.5 hours to obtain the corresponding salt of 2-[3-bromo-1-(1,1-dissociator-3)-1,2,4-triazolyl-5-thio] acetic acid.

Example 1. The synthesis of compounds Ia.

A mixture of 1.65 g (5 mmol) of 3,5-dibromo-1-(1,1-dissociator-3)-1,2,4-triazole, 0,92 g (10 mmol) of thioglycolic and 0.84 g (15 mmol) of potassium hydroxide is boiled in 50 ml of ethanol for 1 hour. The solution is evaporated to a dry residue. The residue is dissolved in water. To the solution add diluted sulfuric acid to pH=3. The residue is filtered off, washed with water. Dried. Gain of 0.91 g (53%) of 2-[3-bromo-1-(1,1-dissociator-3)-1,2,4-triazolyl-5-thio] acetic acid, with TPL214-216°C. Purify by crystallization from ethanol.

Elemental analysis.

Found, %: From 24.8; H 2,6; 12,5 N; S 18,9. C7H8BrN3O4S2.

Calculated, %: C 24,5; N 2,4; N 12,3; S 18,7.

An NMR spectrum1H (DMSO - D6), δ, ppm: of 4.05 (2H, s, SCH2); 4,60-to 4.73 (2H, m, S(CH)2);

4,78 to 4.92 (2H, m, S(CH)2); 5,34-vs. 5.47 (1H, m, NCH).

The solution 1,71 g (5 mmol) 2-[3-bromo-1-(1,1-dissociator-3)-1,2,4-triazolyl-5-thio] acetic acid and 0.68 g (6.5 mmol) of diethanolamine in 50 ml of ethanol is boiled for 0.5 hour. The solution is evaporated to a dry residue. The residue is washed with acetone, filtered. Dried. Obtain 1.39 g (62%) diethanolammonium salt of 2-[3-bromo-1-(1,1-dissociator-3)-1,2,4-triazolyl-5-thio]vinegar is Oh acid with T PL227-230°C. Purify by crystallization from ethanol.

Elemental analysis.

Found, %: C 29,2; N 4,2; N 12,6; S 14,6. C11H19BrN4O6S2.

Calculated, %: From 29.5; H 4,3; 12,5 N; S 14,3.

An NMR spectrum1H (DMSO - D6), δ, ppm: 3,38-3,62 (8H, m, N(CH2CH2O)2); 3,68 (2H, s, SCH2); 4,56-4,70 (2H, m, S(CH)2); 4.75 V-a 4.86 (2H, m, S(CH)2); 5,32-5,46 (1H, m, NCH).

The inventive compound is a white powder, soluble in water, dimethylformamide, when heated in ethanol.

Example 2. Synthesis of compound Ib.

The solution 1,71 g (5 mmol) 2-[3-bromo-1-(1,1-dissociator-3)-1,2,4-triazolyl-5-thio]acetic acid and 0.40 g (6.5 mmol) of monoethanolamine in 50 ml of ethanol is boiled for 0.5 hour. Cooled to room temperature, the precipitation is filtered off, washed with ethanol and dried. Get 0,94 g (47%) monoethanolammonium salt of 2-[3-bromo-1-(1,1-dissociator-3)-1,2,4-triazolyl-5-thio]acetic acid, with TPL251-251,5°C. Purify by crystallization from ethanol.

Elemental analysis.

Found, %: 26.6; H 3,4; N 13,7; S Of 16.2. C9H15BrN4O5S2.

Calculated, %: From 26.8; H 3,7; N 13,9; S 15,9.

An NMR spectrum1H (DMSO - D6), δ, ppm: 3,39 (4H, ush. s, NCH2CH2O); to 3.67 (2H, s, SCH2); 4,57-4,88 (4H, m, 2S(CH)2); 5,32-of 5.48 (1H, m, NCH).

The inventive compound is a white powder, soluble in water, dimethylformamide, under load, is the so called all - in ethanol.

Acute toxicity of the claimed compounds.

Acute toxicity was determined on rats when administered intravenously. The death of animals were recorded for two weeks. The calculation of LD50produced according to the method of Prozorovsky (Prozorovsky V.B. have been et al. // Pharmacol. and toxicol. - 1978. No. 4. - S-502). The results are presented in table 1.

Hemorheological activity.

Hemorheological activity of the claimed compounds was studied using playback violations of rheological properties of blood in vitro. The syndrome of increased blood viscosity was modeled using hyperthermia (MB carpenters Koltunov, A., Aliev I. // bull. exp. Biol. and the honey. - 1996. No. 9. - S-275), using the blood of rabbits. Compounds Ia, Ib and pentoxifylline at concentrations of 10, 50, 100 and 500 µmol/l was added to the blood samples for 10 minutes before incubation. In the control samples were added to 10 μl of warm (37° (C) saline (0,89%solution of sodium chloride). The viscosity of the blood samples was measured in centipoise (SDR) before and after incubation in the viscometer ACRE-2 (Ruscan Reaseach Ltd., Russia), the principle is based on the method of rotational viscometry free floating front rotor (Dobrovolsky N.A., Lopukhin, Y.M., Parfenov A.S. [and other] // Rheological studies in medicine: collected scientific articles. Tr. - M.: NCH Russian Academy of medical Sciences, 1998. - C.45-5L). Effect ve the EU ETS on the aggregation of erythrocytes was estimated by the index of aggregation, calculated as the ratio of blood viscosity at the shear rate of 3-1to blood viscosity at 100 C-1(Dinten L. // Aging. - 1989. No. 1. - R-125). The calculation of the inhibition effect of the inventive compounds on erythrocyte aggregation was carried out according to the formula:

INAA=100-(V/a)*100%,

where Inae - the index of inhibition of aggregation of erythrocytes;

A - index of aggregation of erythrocytes without the studied compounds;

In the index of aggregation of the erythrocytes after incubation of the suspension with the target connection.

The claimed compounds in the tested concentrations caused statistically significant compared to control reduction of the index of inhibition of aggregation of erythrocytes (table 2). As can be seen from the table, hemorheological activity of the claimed substances exceeds that of pentoxifylline. The largest effect sizes observed for compounds Ia at a concentration of 100 µmol/L.

When determining the value of the effective concentration (EC20), which causes a decrease in the aggregation of erythrocytes by 20% (table 2) (Dukhanin A.S., Gubaev FR // Experimental. and clinically. pharmacology. - 1998. No. 4. - P.66 - 71), it is established that the claimed compounds Ia, Ib superior in hemorheological activity pentoxifylline 3.1 and 1.7 times, respectively

As an objective indicator of the conditional breadth of therapeutic action used conditional therapist is economic index (UTI), which was calculated by dividing the index of acute toxicity LD50to measure the effective concentration EC20. OOTY to connect Ia equal 13,30, compounds Ib 103,82, and for pentoxifylline 1,92. Largest OOTY claimed compounds Ia, Ib exceeds the reference product in 6,93 and 54,07 times, respectively.

Accordingly, the chemical compounds (Ia, Ib) have hemorheological activity, significantly exceed pentoxifylline therapeutic breadth and compares favorably to more low toxicity.

DERIVATIVES of 2-[1-(1,1-DISSOCIATOR-3)-1,2,4-TRIAZOLYL-5-thio]ACETIC ACID, WITH HEMORHEOLOGICAL ACTIVITY

Table 1
Acute toxicity of the claimed compounds and the comparison drug
ConnectionIndicator of acute toxicity LD50rats/
mmol/kgmg/kg
Ia0,838374,86
Ib>14,956029,0
Pentoxifylline0,379105,48
Table 2
Hemorheological effects of the inventive compounds and drug comparisons in experiments in vitro
ConnectionThe index of inhibition of aggregation of erythrocytes (%) at a concentration of connectionsEU20, umol/l
1050100500
Ia-11,59±1,81**-15,26±3,91**-22,22±6,57*-63,0
1b-10,79±2,33*-15,37±1,97*-19,98±4,82*-29,48±5,41*114,0
Pentoxifylline-6,00±1,54*-14,56±3,71**-18,59±3,66**-28,13±2,84***197,4
Note * - the difference from the control was significantly (p<0,05);
** - the difference from the control was significantly (p<0,01);
*** the difference from the control was significantly (p<0,001).

1. Derivatives of 2-[1-(1,1-dissociator-3)-1,2,4-triazolyl-5-thio]acetic acid of General formula

where R=H2 N+(CH2CH2OH)2(Ia); R=H3N+CH2CH2OH (Ib).

2. The compound according to claim 1, which represents diethanolammonium salt of 2-[3-bromo-1-(1,1-dissociator-3)-1,2,4-triazolyl-5-thio]acetic acid.

3. The compound according to claim 1, which represents monoethanolammonium salt of 2-[3-bromo-1-(1,1-dissociator-3)-1,2,4-triazolyl-5-thio]acetic acid.

4. Derivative according to claim 1, having hemorheological activity.



 

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4 cl, 5 tbl, 5 ex

FIELD: medicine.

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20 cl, 2 dwg, 8 ex

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1 ex

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FIELD: chemistry.

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23 cl, 1 dwg, 1 tbl, 13 ex

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1 ex

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FIELD: pharmaceutical chemistry.

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14 cl, 4 dwg, 3 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

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EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 70 ex

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17 cl, 3 ex, 3 dwg

FIELD: chemico-pharmaceutical industry.

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EFFECT: higher efficiency.

3 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to new compounds of formula

,

wherein A and B are independently CH or CR3; X is C=O or (CR4aR4b)m, (m = 1 or 2); Y is S(O)n-R2 (n = 1 or 2), S(O)n-NR2R2, or S(O)n-OR2; N1 and N2 are nitrogen atoms; Q and R1 are independently 1) optionally substituted C1-C10-alkyl; 2) optionally substituted aralkyl containing C6-C10-aryl, attached to C1-C10-alkyl; 3) optionally substituted aralkenyl containing C5-C10-aryl, attached to C1-C10-alkenyl; 4) optionally substituted C6-C10-aryl; 5) optionally substituted aryl, containing 5-10 ring atoms, selected from carbon and sulfur; each R2 and R3 are hydrogen; R4a, R4b, R5, and R6, are independently hydrogen; R2 and R3 are independently hydrogen or C1-C6-alkyl; as well as acid and base additive salts thereof. Also disclosed are method for production of claimed compounds, pharmaceutical composition inhibiting serine protease enzymes and therapeutic method based thereon.

EFFECT: new compounds and pharmaceutical composition for thrombosis preventing or abnormal thrombosis treatment.

11 cl, 7 tbl, 15 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to compounds of formula I , wherein A, L, Y, and k are as defined in specification. Compounds of formula I have value pharmacological activity, in particular potent antithrombosis action and are useful in treatment and prophylaxis of cardiovascular diseases such as thromboembolia. They represent also reversible inhibitors of factor X and factor VIIa (blood coagulation enzymes). Also disclosed are methods for production of compounds I, uses thereof, in particular as active ingredients in pharmaceutical compositions, as well as medicines containing the same.

EFFECT: new pharmaceutical compositions for treatment and prophylaxis of cardiovascular diseases.

10 cl, 50 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.

26 cl, 2 tbl, 253 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to biologically active compounds, in particular, to substituted 5R1,6R2-thiadiazine-2-amines and pharmaceutical compositions comprising thereof that can be used in medicine as potential pharmacologically active substances eliciting the unique combination of properties: expressed anticoagulant activity in combination with capacity to inhibit aggregation of platelets. Effect of these substances differ from preparations used in medicinal practice and they can be used therefore in treatment of such diseases as myocardium infarction, disturbance in cerebral circulation, rejection of transplanted organs and tissues and so on. Indicated compounds correspond to the formula (I):

wherein values of radicals R1, R2 and R3 are given in the invention claim.

EFFECT: valuable medicinal properties of compounds.

4 cl, 2 tbl, 7 dwg, 33 ex

FIELD: medicine, hematology, cardiology, endocrinology.

SUBSTANCE: invention relates to a method for correction of disturbances at thrombocyte hemostasis in patients with metabolic syndrome. Method involves prescription of hypocaloric diet and lovastatin in the dose 20 mg before sleeping. Method provides normalization of primary hemostasis in these patients.

EFFECT: improved treatment method.

2 ex

FIELD: biotechnology, microbiology, medicine.

SUBSTANCE: method involves selection of signal sequence suitable for the effective expression of Leu-hirudine in E. coli cells by the polymerase chain reaction-screening method. Method involves construction of a protein as a precursor of hirudine based on the selected signal sequence of surface membrane protein from Serratia marcescens, oprF protein from Pseudomonas fluorescens or fumarate reductase from Shewanella putrifaciens by joining the Leu-hirudine amino acid sequence with C-end of selected signal sequence. Prepared precursor of Leu-hirudine is used in a method for preparing Leu-hirudine. Invention provides preparing Leu-hirudine by the direct secretion in E. coli cells with the high yield. Invention can be used in preparing the hirudine precursor.

EFFECT: improved preparing method.

4 cl, 1 dwg, 2 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 2-[1-(1,1-dioxothietanyl-3)-1,2,4-triasolyl-5-thio]acetic acid of formula I , where R=H2N+(CH2CH2OH)2 (Ia); R=H3N+CH2CH2OH (Ib).

EFFECT: increased hemorrheologic activity and possibility to apply for reduction of blood viscosity.

4 cl, 2 tbl, 2 ex

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