Compounds producing stimulating effect on subtype b receptor of peroxisome proliferation activator, method of obtaining and application thereof

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a novel compound of formula I

,

where X and Y stand for O or S, R, R3, G1- G3 stand for H or C1-9alkyl; R1 and R2 is H or C1-4alkyl; R4 is H or phenyl; G4- G6 and G8- G9 are H; G7 is trifluoromethyl, a pharmaceutical composition containing it, methods of obtaining, an initial compound in methods described and a method of obtaining the initial compound and application of the formula I compound for treatment or prevention of a disease by activation of receptor δ(PPARδ); the said disease represents metabolic syndrome, obesity, dyslipidemia, pathological glycemia, insulin resistance, senile dementia and tumours.

EFFECT: obtaining the formula I compounds for treatment or prevention of the disease by activation of receptor δ(PPARδ).

20 cl, 47 ex, 3 dwg, 5 tbl

 

The technical field

The present invention relates to new compounds that have a stimulating effect on the receptor peroxisome proliferator-activated subtype δ (PPAR δ), the method of production of these compounds to medicines containing these compounds and to the use of these compounds for the treatment and prevention of cardiovascular diseases and the like, the Present invention also relates to new intermediate connection of new compounds and to a method for the specified intermediate.

The level of technology

Currently, along with the high speed development and growth of living standards of people consume excessive amounts of fats and proteins, which leads to widespread metabolic syndrome, characterized by obesity, insulin resistance (type II diabetes), disorder of lipid metabolism and hypertension. This represents a significant threat to human health. In addition to the genetic characteristics of the individual, age, sex, physiological characteristics, nutritional status, addiction to food, etc., metabolic syndrome is associated with an imbalance of lipid metabolism, exchange of energy and carbohydrates in vivo. Thus, an effective method for the treatment of metabolic syndrome is therapeuti the mini-mode, aimed at maintaining or restoring the balance of lipids, carbohydrates and energy in vivo. As nuclear receptors (NRs) play a key role in maintaining energy balance, lipids and carbohydrates in the cell in vivo, as well as in the human body in General, these receptors have been the focus of researchers. Only after activation of various physiological ligands (e.g., saturated fatty acids and their metabolites and various synthetic compounds) nuclear receptors are able to exert a regulatory effect on the transcription system sensitive genes, thereby affecting physiological activity (Kasuga, J. et al., Bioorg. Med. hem. 2007, 15, 5177-5190).

Among families of nuclear receptors increased attention for more than a decade attract receptors peroxisome proliferator-activated (PPARs)are nuclear transcription factors that are activated by ligands, and act as key regulatory factors in the metabolic syndrome (Guan, Y. J. Am. Soc. Nephrol, 2004, 15, 2801-2815). Therefore, PPARs play an important role in the emergence, development and control of diseases such as insulin resistance, impaired glucose tolerance, type II diabetes, obesity, hyperlipidemia, hypertension, angiocardiopathy, atherosclerosis, etc.

PPARs are divided into three subtypes: PPARα, PPARδ and PPARγ, which is haunted regulate gene expression by binding to specific DNA sequence (Berger, J. et al., The Journal of Biological Chemistry, 1999, 274 (10), 6718-6725). PPARα is mainly expressed in liver, heart, gastrointestinal tract, kidneys and macrophages after activation can enhance the metabolism of fatty acids, reduce inflammatory response in macrophages and reduced cholesterol in low-density lipoprotein; PPARγ is expressed in adipocytes, placentae and other tissues and after activation may not only reduce the level of blood glucose and increase insulin sensitivity, but also plays a key role in lipid metabolism, anti-cytokines, anti-inflammatory processes, immune regulation, and the regulation of blood pressure, etc. (Kasuga, J. et al., Bioorg. Med. Chem. 2007, 15, 5177-5190). In contrast to the other two subtypes, the physiological function of PPARδ is still not clear. However, recent studies in the course of pharmacological experiments in animal models it was shown that PPARδ may enhance the separation of the catabolism of fatty acids and energy in adipose tissue and muscles and can suppress inflammation, mediated by macrophages. Due to the different functions in the control of gain in body weight, increase endurance, increase insulin sensitivity and ameliorate atherosclerosis, PPARδ ligands may be effective drugs for the treatment of hyperlipidemia is, obesity, insulin resistance and atherosclerosis.

Currently, none of the agonists of PPARδ receptors is not commercially available as a drug. Among modern studies of PPARδ agonists clinical research GW501516, developed by GlaxoSmithKline, showed that GW501516 can increase the level of cholesterol in high density lipoprotein (HDL) levels up to 80%, reduce the level of cholesterol in low-density lipoprotein (LDL) to 29%, to reduce the level of triglycerides (TG) to 56%, reduce insulin levels to 48% (Oliver, W.; Jr.; Shenk, J. L. et al, Natl. Acad. Sci. U.S.A. 2001, 98, 5306-5311). Thus, I believe that GW501516 can be an effective drug for the treatment of obesity and cardiovascular disease (WO01/00603A1, Bioord. Med. Chem. Lett. 2003, 13, 1517). However, the project GW501516 is currently suspended due to unfavorable results obtained at the second stage of its clinical trials.

Thus, there is an urgent need for a new connection, which has an agonistic effect on the receptor peroxisome proliferator-activated subtype δ (PPARδ) and a much better ability to regulate the content of lipids in the blood than GW501516.

The invention

One of the objectives of the present invention is to provide compounds of formula (I) and/or pharmaceutically who priemlimyh salt and/or solvate specified connection:

Where

1) X represents O, S, N or (CH2)nin which n is an integer from 1 to 4, X preferably represents O, S or CH2;

2) Y represents O, S or N, preferably O or S;

3) R represents H or C1-C9 alkyl, preferably H, methyl or ethyl;

4) R1and R2independently of one another represent H or C1-C4 alkyl, and at least one of R1and R2represents H; preferably, R1and R2independently of one another represent methyl, ethyl or N;

5) R3represents H, C1-C9 alkyl, preferably H or C1-C4 alkyl, for example methyl, ethyl, isopropyl, more preferably methyl;

6) R4represents H, C1-C9 alkyl, C3-C7 cycloalkyl, phenyl or substituted phenyl, and the group is the substituent in the substituted phenyl is selected from C1-C9 of alkyl, hydroxyl, C1-C9 alkoxy, mercapto, C1-C9, alkylthio, trifloromethyl, F, CI, Br, nitro, NR5R6, COOR5, NR5COR6or CONR5R6; R5and R6independently of one another represent H or C1-C9 alkyl, and when R4is a substituted phenyl, the group-Deputy preferably represents 4-methoxy or 4-methyl;

7) G1and G4separately represent H, C1-C9 alkyl, g is droxyl, C1-C9 alkoxy, mercapto, C1-C9, alkylthio, trifluoromethyl, F, CI, Br, nitro, NR5R6, COOR5, NR5COR6or CONR5R6; R5and R6independently of one another represent H or C1-C9 alkyl; preferably, G1and G4individually represent methyl or ethyl;

8) G2and G3separately represent H, C1-C9 alkyl, hydroxyl, C1-C9 alkoxy, mercapto, C1-C9, alkylthio, trifluoromethyl, F, CI, Br, nitro, NR5R6, COOR5, NR5COR6or CONR5R6; R5and R6independently of one another represent H or C1-C9 alkyl; preferably, G2and G3individually represent methyl, ethyl or N;

9) G5, G6, G8and G9separately represent H, C1-C9 alkyl, hydroxyl, C1-C9 alkoxy, mercapto, C1-C9, alkylthio, trifluoromethyl, F, CI, Br, nitro, NR5R6, COOR5, NR5COR6or CONR5R6; R5and R6independently of one another represent H or C1-C9 alkyl; preferably, G5, G6, G8and G9separately represent H, F, Cl, Br, methyl, ethyl or methoxy; and

10) G7represents H, C1-C9 alkyl, hydroxyl, C1-C9 alkoxy, mercapto, C1-C9, alkylthio, trifluoromethyl, F, CI, Br, nitro, NR5R6, COOR5, NR5COR6or CONR 5R6; R5and R6independently of one another represent H or C1-C9 alkyl; preferably, G7represents trifluoromethyl, isopropyl, ethyl, methyl, or Cl; more preferably, G7represents trifluoromethyl.

When the connection according to the present invention is in the form of ether, the connection specified hereinafter in the description of the invention designated "compound I (ether)". The preferred compound I (ether) according to the present invention includes the following compounds:

Ethyl-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenoxy)-acetate (hereinafter referred to as "E-1");

Ethyl-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetate (hereinafter referred to as "E-2");

Ethyl-2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetate (hereinafter referred to as "E-3");

Ethyl-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate (hereinafter referred to as "E-4");

Ethyl-2-(2-ethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenoxy)-acetate (hereinafter referred to as "E-5");

Ethyl-2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenoxy)-setat (hereinafter referred to as "E-6");

Ethyl-2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate (hereinafter referred to as "E-7");

Ethyl-2-(2-methyl-4-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl)-methylthio)-phenoxy)-acetate (hereinafter referred to as "E-8");

Ethyl-2-(2-methyl-4-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl)-methoxy)-phenoxy)-acetate (hereinafter referred to as "E-9");

Ethyl-2-(2,5-dimethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate (hereinafter referred to as "E-10");

Ethyl-2-(2,5-dimethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetate (hereinafter referred to as "E-11");

Ethyl-2-(3-methyl-4-(3-(4-methyl-5-oxo-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-1,2,4-triazolyl)-methoxy)-phenylthio)-acetate (hereinafter referred to as "E-12");

Methyl-2-methyl-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate (hereinafter referred to as "E-13");

Ethyl-2-(2-ethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate (hereinafter referred to as "E-14");

Ethyl-2,2-dimethyl-2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetate (hereinafter referred to as "E-15");

Ethyl-2,2-dimethyl-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-trifluoromethyl-phenyl)-4,dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate (hereinafter referred to as "E-16");

Ethyl-2-(3-methyl-4-(1-(3-(4-n-butyl-5-oxo-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetate (hereinafter referred to as "E-17");

Ethyl-2,2-dimethyl-2-(2-methyl-4-(1-(3-(4-n-butyl-5-oxo-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate (hereinafter referred to as "E-18");

Ethyl-2-(2,5-dimethyl-4-(1-(3-(4-n-butyl-5-oxo-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate (hereinafter referred to as "E-19").

Compound I (ether) can be hydrolyzed under alkaline conditions to receive it in the form of acid, hereinafter in the description of the invention called "compound I (acid)". Preferably, the alkaline conditions form with alkali, which is the hydroxides of alkali metals including sodium hydroxide, lithium hydroxide, potassium hydroxide and the like, but not limited to; the solvent used in the hydrolysis represents a C1-C4 alcohol (e.g. methanol, ethanol, propanol, butanol and the like) - water (ratio of alcohol:water=9-1:1 (vol./vol.), tetrahydrofuran (THF) - water (ratio of THF:water=9-1:1 (vol./vol.), or alcohol-dichloromethane-water (ratio of alcohol:dichloromethane:water=9-1:9-1:1 (vol./about.)); the reaction temperature is 0-80°C., preferably 20-40°C.; the reaction time is 1-12 hours, preferably 2-4 hours.

The preferred compound I (acid) of the present invention including the AET following connections:

2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenoxy)-acetic acid (hereinafter referred to as "a-1");

2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptorelin yl)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid (hereinafter referred to as "a-2");

2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid (hereinafter referred to as "a-3");

2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid (hereinafter referred to as "a-4");

2-(2-ethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenoxy)-acetic acid (hereinafter referred to as "A-5);

2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenoxy)-acetic acid (hereinafter referred to as "A-6);

2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid (hereinafter referred to as "a-7");

2-(2-methyl-4-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl)-methylthio)-phenoxy)-acetic acid (hereinafter referred to as "a-8");

2-(2-methyl-4-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl)-methoxy)-phenoxy)-acetic acid (hereinafter referred to as "A-9");

2-(2,5-dimethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptime fenil)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid (hereinafter referred to as "A-10");

2-(2,5-dimethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid (hereinafter referred to as "A-11");

2-(3-methyl-4-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl)-methoxy)-phenylthio)-acetic acid (hereinafter referred to as "A-12");

2-methyl-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid (hereinafter referred to as "A-13");

2-(2-ethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid (hereinafter referred to as "A-14");

2,2-dimethyl-2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid (hereinafter referred to as "a-15");

2,2-dimethyl-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid(hereinafter referred to as "A-16");

2-(3-methyl-4-(1-(3-(4-n-butyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid (hereinafter referred to as "A-17");

2,2-dimethyl-2-(2-methyl-4-(1-(3-(4-n-butyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid(hereinafter referred to as "A-18");

2-(2,5-dimethyl-4-(1-(3-(4-n-butyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid (hereinafter called the th "A-19").

The most preferred compound I (acid) according to the present invention includes the following compounds:

2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid (a-3);

2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid (a-4);

2-(2,5-dimethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid (A-11);

2-(2-ethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid (A-14);

2,2-dimethyl-2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid (a-15);

2,2-dimethyl-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid (A-16);

2-(3-methyl-4-(1-(3-(4-n-butyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid(A-17);

2,2-dimethyl-2-(2-methyl-4-(1-(3-(4-n-butyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid (A-18);

2-(2,5-dimethyl-4-(1-(3-(4-n-butyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid (A-19).

Pharmaceutically acceptable salt of the value of the formula I according to the present invention relates to salts of the compounds, educated alkaline or alkaline earth metals. Preferred are salts of potassium, sodium and calcium.

MES the compounds of formula 1 according to the present invention relates to a hydrate of the compounds or organic MES, preferably the hydrate or alcoholate. The hydrate may contain 1-4 water molecules. The alcoholate may include alcoholate formed by methanol, ethanol and propanol.

Another aim of the invention is to provide new compounds, i.e. compounds III:

in which

Z represents Cl or Br;

R3represents H or C1-C9 alkyl;

R4represents H, C1-C9 alkyl, C3-C7 cycloalkyl, phenyl or substituted phenyl; a group-Deputy phenyl selected from C1-C9 of alkyl, hydroxyl, C1-C9 alkoxy, mercapto, C1-C9, alkylthio, trifloromethyl, F, CI, Br, nitro, NR5R6, COOR5, NR5COR6or CONR5R6; and

G5, G6, G7, G8and G9independently of one another represent H, C1-C9 alkyl, hydroxyl, C1-C9 alkoxy, mercapto, C1-C9, alkylthio, trifluoromethyl, F, Cl, Br, nitro, NR5R6, COOR5, NR5COR6or CONR5R6; R5and R6independently of one another represent H or C1-C9 alkyl.

The preferred compound III according to astasia invention includes the following compounds:

3-(1'-bromobenzyl)-4-methyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-triazole-5(4H)-he (hereinafter referred to as "III-1")

3-(1'-bromobenzyl)-4-n-butyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-triazole-5(4H)-he (hereinafter referred to as "III-2");

3-methyl bromide-4-methyl-1-(4-triptoreline)-1,4-dihydro-1,2,4-triazole-5-he (hereinafter referred to as "III-3").

Compound III according to the present invention can be used as intermediate compounds for obtaining the compounds of formula 1 according to the present invention.

Another objective of the invention is the provision of a method of obtaining the compounds of formula III.

The compound of formula III according to the present invention can be synthesized in the reaction of compounds of formula VI with glorieuses or brainwashin reagent:

where

Z represents CL or Br; R3, R4, G5-G9are as defined for compounds of formula III.

Gloriouse or pomeroyi reagent chosen from:

(1) N-bromosuccinimide (NS)/triphenylphosphine (PH3R);

(2) thionyl chloride (Sl2or thienylboronic (SOBr2);

(3) N-chlorosuccinimide (NCS)/triphenylphosphine (PH3R);

(4) carbon tetrachloride (CCL4or tetrabromomethane (GVS4)/triphenylphosphine (PH3R);

(5) pentachloride phosphorus (PCl5or pentabromide phosphorus (PBr5);

(6) oxychlorination (l 3or oxybromide phosphorus (Ravg3); and

(7) trichloride phosphorus (l3or tribromide phosphorus (RVG3).

The solvent is selected from dichloromethane, chloroform, carbon tetrachloride, and any mixtures thereof; the reaction temperature is 10-80°C; reaction time is 2-8 hours.

The compound of formula III is preferably synthesized according to the following scheme:

The above chart includes the following steps:

1) using tetrahydrofuran (THF) as solvent and sodium hydride (NaH) as the alkali benzyl alcohol 1 reacts with bromide 2, forming ether 3;

2) when using ethanol (tO) as solvent ether 3 miniroot the amine 4 with the formation of amide 5;

3) when using toluene (h3) as solvent amide 5 reacts with phenylhydrazine 6 under the action of phosphorus oxychloride (l3), forming a hydrazone 7;

4) using tetrahydrofuran (THF) as solvent hydrazone 7 reacts with carbonyl diimidazol (CDI)to form compound 8;

5) when using ethanol (tO) as solvent and palladium carbon (Pd/C) as a catalyst benzyl otscheplaut from compound 8 by gidrogenizirovanii at normal pressure with the formation of alcohol 9;

6) using dichloromethane (DHM) in to the amount of solvent alcohol 9 was converted into compound III under the action of glorieuses or brainwashes reagent.

For example, if R4, G5, G6, G8, G9represent H, R3represents methyl, and G7represents a trifluoromethyl, a scheme of the synthesis is as follows:

The above chart includes the following steps:

1) using tetrahydrofuran (THF) as solvent and sodium hydride (NaH) as alkali when heated under reflux benzyl alcohol 1 reacts with ethylbromoacetate, forming ethylbenzylamine 10;

2) when using ethanol (tO) as solvent ethylbenzylamine 10 miniroot the methylamine 11 at room temperature with the formation of benzyloxyacetophenone 12;

3) when using toluene (h3as the solvent benzyloxyacetophenone 12 reacts with ρ-triftormetilfullerenov 13 at 80°C under the action of phosphorus oxychloride (l3), forming a hydrazone 14;

4) using tetrahydrofuran (THF) as solvent hydrazone 14 reacts with carbonyl diimidazol (CDI), forming a connection 15;

5) when using ethanol (tO) as solvent and palladium carbon (Pd/C) as a catalyst benzyl otscheplaut from connection 15 at room temperature by gidrogenizirovanii at normal pressure with the formation of the alcohol 16;

6) using dichloromethane (DHM) as solvent and N-bromosuccinimide (NBS) as brainwashes reagent alcohol 16 is converted into a compound III-3 under the action of triphenylphosphine (PH3R.).

The compound of the formula III can also be synthesized in the reaction of compounds of formula VI with glorieuses or brainwashin agent; the solvent is a chloroform or carbon tetrachloride, pomeroyi agent is N-bromosuccinimide (NBS), gloriouse agent - N-chlorosuccinimide (NCS), the catalyst is Dibenzoyl peroxide, the reaction temperature is 40 to 80°C. the reaction time is 2-8 hours.

where

Z represents CL or Br;

R3, G5-G9are as defined for compounds of formula III;

G10-G14independently of one another or simultaneously with each other represent H, C1-C9 alkyl, hydroxyl, C1-C9 alkoxy, mercapto, C1-C9, alkylthio, trifluoromethyl, F, Cl, Br, nitro, NR5R6, COOR5, NR5COR6or CONR5R6;

R5and R6independently of one another represent H or C1-C9 alkyl.

The compound of formula III preferably receive according to the following scheme:

The above chart includes the following steps:

1) when using methanol (Meon) as Rast is rites and sulfuric acid as the acid catalyst 17 is subjected to esterification to obtain the ester 18;

2) when using methanol (Meon) as solvent ether 18 miniroot Amin 19 with the formation of amide 20;

3) when using toluene (h3) as solvent amide 20 reacts with phenylhydrazine 6 under the action of phosphorus oxychloride (hl3), forming a hydrazone 22;

4) using tetrahydrofuran (THF) as solvent hydrazone 22 reacts with carbonyl diimidazol (CDI), forming a connection 23;

5) using chloroform as solvent, N-bromosuccinimide (NBS) as brainwashes reagent (or N-chlorosuccinimide (NCS) as glorieuses reagent) and dibenzoylperoxide as a catalyst compound 23 bromilow (or glorious) with the formation of compound III.

For example, if R4represents phenyl, G5, G6, G8, G9represent H, R3represents methyl, and G7represents a trifluoromethyl, a scheme of the synthesis is as follows:

The above chart includes the following steps:

1) when using methanol (Meon) as solvent and sulfuric acid as catalyst, at reflux acid 24 is subjected to esterification with the formation of ether 25;

2) when using methanol (Meon) as solvent EPE is 25 miniroot Amin 11 at room temperature with the formation of amide 26;

3) when using toluene (h3) as solvent amide 26 reacts with ρ-triftormetilfullerenov 13 under the action of phosphorus oxychloride (l3) at 80°C, forming a hydrazone 27;

4) using tetrahydrofuran (THF) as solvent hydrazone 27 reacts with carbonyl diimidazol (CDI) at room temperature, forming a connection 28;

5) using chloroform as solvent, N-bromosuccinimide (NBS) as brainwashes reagent and dibenzoylperoxide as a catalyst, at reflux connection 28 bromilow with the formation of compound III-1.

Another objective of the invention is the provision of a method of obtaining the compounds of formula (I).

The compound of formula (I) according to the invention obtained by the method described below in Scheme 1 or Scheme 2:

Scheme 1:

Where:

X, Y, R1-R4, G1-G9are as defined for compounds of formula I, R represents H or C1-C9 alkyl, preferably methyl or ethyl.

Scheme 1 intermediate compounds II and III are subjected to interaction under the action of the alkali with the formation of compound I (ether). The alkali is an organic or inorganic alkali, and inorganic alkali may include carbonates of Molochny the metals, soluble carbonates of alkaline earth metals, ammonium carbonate, etc. or any mixture; examples of the inorganic alkali include sodium carbonate, potassium carbonate, strontium carbonate, ammonium carbonate, etc. and the organic alkali may be triethylamine and the like; the solution is preferably selected from acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dioxane, etc. or any mixtures of these substances. Preferably, the reaction temperature is 0-100°C., preferably 40-80°C.; the reaction time is 1-12 hours, preferably 4-8 hours.

In the diagram above, the compound of formula II may be obtained commercially or synthesized according to the standard method described in the prior art (for example, the method described in M. L. Sznaidman, Curt D. Haffner, Patric R. et al., Bioorg. Med. Chem. Lett. 2003, 13, 1517-1521; Zhi-liang wei et al., J. Org. Chem. 2003, 68, 9116-9118; Org. Syn. Coll. Vol 1, 102, 1941; Org. Syn. Coll. Vol 2, 290, 1943; Handbook of Fine Organic Chemical Raw Materials and Intermediate. XU Ke-xun (Eds), Scientific & Technological Industry Press, 3-426-3-584).

The compound of formula II includes, but is not limited to the following compounds:

Ethyl-2-(2-methyl-4-hydroxy)-phenoxyacetate (hereinafter referred to as "II-1");

Ethyl-2-(3-methyl-4-hydroxy)-phenoxyacetate (hereinafter referred to as "II-2");

Ethyl-2-(2-ethyl-4-hydroxy)-phenoxyacetate (hereinafter referred to as "II-3");

Ethyl-2-(3-methyl-4-hydroxy)-phenylthio the Etat (hereinafter referred to as "II-4");

Ethyl-2-(2-methyl-4-hydroxy)-phenylthiourea (hereinafter referred to as "II-5");

Ethyl-2-(2,5-dimethyl-4-hydroxy)-phenylthiourea (hereinafter referred to as "II-6").

Scheme 2:

Where:

X, Y, Z, R1-R4, G1-G9are as defined for compounds of formula I;

R represents H or C1-C9 alkyl, preferably methyl or ethyl.

Figure 2 during continuous reaction with carbonate as the alkali compound III is first reacted with compound IV, and then with the compound V, without separation of the intermediate compounds during the reaction. Addition of acetonitrile as a solvent can be used tetrahydrofuran (THF), dioxane, etc. or any mixture of these substances.

Addition of potassium carbonate as a carbonate can be used sodium carbonate, strontium carbonate, ammonium carbonate, etc. or any mixture. And the intermediate compound IV, and an intermediate connection V commercially available.

In Scheme 2, the compound I (ether) may be subjected to hydrolysis under alkaline conditions, to form compound I (acid), if R is a C1-C9 alkyl, these alkaline conditions can be obtained by using alkali, such as alkali metal hydroxide, including, but not limited to, sodium hydroxide, lithium hydroxide, potassium hydroxide and the like, or any see the camping of these compounds; the system solvent used in the hydrolysis represents a C1-C4 alcohol (e.g. methanol, ethanol, propanol, butanol and the like) - water (ethanol: water=9-1:1 (vol./vol.), THF-water (THF: water=9-1:1 (vol./about.)) or alcohol-dichloromethane-water (ethanol: dichloromethane: water=9-1:9-1:1 (vol./about.)); the reaction temperature is 0-80°C., preferably 20-40°C.; the reaction time is 1-12 hours, preferably 2-4 hours.

Where:

X, Y, Z, R1-R4, G1-G9are as defined for compounds of formula I;

R represents H or C1-C9 alkyl, preferably methyl or ethyl.

Another objective of the invention to provide pharmaceutical compositions containing the aforementioned compound of formula (I) as an active ingredient.

The pharmaceutical composition according to the present invention containing the aforementioned compound of formula (I) as the active ingredient, contains a compound of the formula (I) and conventional excipients used to prepare pharmaceutical compositions.

Common excipients used to prepare pharmaceutical compositions, are approved by the competent authority for administering drugs and meet the criteria for pharmaceutical excipients. Their is divided into two groups based on their differing functionality: one group of auxiliary substances required for the processing and production of pharmaceutical formulations and include diluents, binding agents, glidant, suspendresume agents, lubricants, etc.; the function of another group of auxiliary substances, including leavening agents, co-solvents, etc. is to stimulate digestion and absorption of drugs in vivo. They do not have activity in vivo in the human body and do not show any therapeutic or toxic effect.

Among the above-mentioned auxiliary substances, diluents can be selected from any mixture of any two or more of the following substances: starch, modified starch, sucrose, lactose monohydrate, anhydrous lactose, glucose, mannitol and various microcrystalline modification of cellulose.

Among the above-mentioned auxiliary substances binding agents may be selected from any mixture of any two or more of the following substances: hypromellose, pregelatinized starch, polyvidone (polyvinylpyrrolidone), carboxymethylcellulose and derivatives thereof, methyl cellulose, ethylcellulose, starch, carbohydrates and the like; preferably from hydroxypropylmethylcellulose, pregelatinization starch and polyvidone.

Among the above-mentioned auxiliary substances sliding substances can be selected from any mixture of any two or more of the following substances: magnesium stearate, powder, talc and gidrogenit rowanne vegetable oil type I.

Among the above-mentioned auxiliary substances suspendresume agents can be selected from any mixture of any two or more of the following ingredients: gelatin, pectin, gum Arabic, sodium alginate, methylcellulose, ethylcellulose, hydroxypropylcellulose, carboxymethylcellulose and methylcellulose.

Among the above-mentioned auxiliary substances leavening agents can be selected from any mixture of any two or more of the following substances: starch, hydroxypropylcellulose with a low degree of substitution, sodium carboximetilkrahmal, calcium carboxymethylcellulose, cross stitched polyvidone, cross stitched cellulose and transverse cross-linked sodium carboxymethylcellulose.

Among the above-mentioned auxiliary substances, the cosolvent may be selected from any mixture of any two or more of the following substances: a series of Span, series twin, series glycol, soy lecithin, etc.

The above-mentioned pharmaceutical composition can be provided in any form of the following dosage forms for oral administration: 1, smooth tablets; 2 tablets, film coated liner; 3, dragee; 4 tablets with intersolubility coating; 5, dispersible tablets; 6 capsules; 7, granules; 8, suspensions; and 9 solutions.

The above dosage forms can be manufactured according to the conventional technology n the production of a medicinal product.

Another aim of the invention is the use of compounds of formula (I) for the preparation of drugs for treatment or prevention of diseases which can be treated or prevented by activation of receptor peroxisome proliferator-activated subtype δ (PPARδ). The disease includes metabolic syndrome, obesity, dyslipidemia, abnormal glycemia, insulin resistance, senile dementia or tumor, etc.

According to the invention provides the use of compounds of formula (I) for the preparation of drugs for treatment or prevention of diseases which can be treated or prevented by activation of receptor peroxisome proliferator-activated subtype δ (PPARδ) δ (PPARδ), and the disease is chosen from one or more of the following diseases: metabolic syndrome, obesity, dyslipidemia, abnormal glycemia, insulin resistance, senile dementia or tumor, etc.

According to the invention, provided is a method of treatment or prevention of diseases which can be treated or prevented by activation of receptor peroxisome proliferator-activated subtype δ (PPARδ), and the method includes the step of introducing the patient a therapeutically or prophylactically effective kolichestvennie formula (I), and the disease is chosen from one or more of the following diseases: metabolic syndrome, obesity, dyslipidemia, abnormal glycemia, insulin resistance, senile dementia or tumors, etc.

After reading the description of the invention to a person skilled in the field of technology will be obvious other advantages and applications of the present invention.

DESCRIPTION of FIGURES

Figure 1 represents a curve of the changes in animal body weight over time, which demonstrates the effect of drugs on the body weight of the animal and food consumption. On the x-axis shows the time of weighing (weighing every 2 days); on the y-axis shows the body weight of the animal. The positive control represents orlistat (two groups treated with the drug in doses of 30 mg/kg and 10 mg/kg). In the present invention the animals treated with the compositions of the medicinal product (a-3 and a-11), were divided into two groups according to the dose (10 mg/kg and 3.3 mg/kg).

Figure 2 is a curve of change of the glucose level in the blood of animals, which shows the results of oral tolerance test glucose. On the x-axis shows the time of sampling blood samples at 0 min, 30 min, 60 min, 120 min after oral administration of glucose; on the y-axis presents the corresponding level of blood glucose (mmol/l).

<> Figure 3 is a curve medicine-a time for a-3 (HS060098) and a-1 (HS060001) according to the present invention. On the x-axis shows time (h) sampling of blood; on the ordinate axis shows the concentration (μg/ml) of the drug in the plasma of animals at different times.

The embodiments of the INVENTION

The present invention is described below with reference to specific examples. It should be understood that in light of the description of the invention in this application, specialists in the field of technology can make various changes and improve the present invention, without leaving the scope of the present invention defined by the attached claims. In addition, it should be understood that the examples given in this application are intended only for illustrative purposes and should not be interpreted as limiting the present invention in any way.

In this application the radical C1-C9 (alkyl, alkoxy, alkylthio etc.) includes C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, C1-C7, C1-C8 and C1-C9 radical (alkyl, alkoxy, alkylthio and the like), etc.

Model for screening drugs

The screening agent that activates the nuclear receptor in vitro

Experimental procedure in the framework of the model of screening is as follows.

1. A brief description of the model of screening associated with nuclear recipe for the rum

The screening model to study agonist of the nuclear receptor in living cells has been developed using experimental techniques with reporter genes based on the idea that the activated nuclear receptor is able to activate transcription of a gene located to the right from its site of initiation. Constructed a plasmid with a reporter gene in which a DNA sequence that binds a nuclear receptor (oil and gas prospecting expedition), inserted to the left of luciferase gene, so that expression of the luciferase gene is under the control of a nuclear receptor. Then in the cell at the same time introduced a plasmid with a reporter gene and a nuclear receptor; activation of nuclear receptor occurred in the presence of an agonist of the nuclear receptor in the culture medium. The activated receptor was able to induce the expression of the luciferase gene, despite the fact that the amount of luciferase can be detected by its glowing substrate. Thus it was possible to determine the intensity of activation of the nuclear receptor connection, registering the intensity of the luminescence. To determine the error of the study, caused by such factors as the efficiency of transfection, the number of inoculated cells, toxic compounds, etc. as internal standard cells at the same time transfusional a plasmid expressing GFP, and analysis of the results of the experiment luminescence values in all tested wells were calibrated by the values of GFP. The experimental results were expressed in relative units activation, where a value of 1 corresponded to the control with the solvent, and the increase in relative unit meant increased ability to activate.

2. Experimental procedure

The detailed procedure of the experiment in the framework of the model of screening can be found in the following publications: "Design, synthesis and evaluation of a new class of noncyclic 1,3-dicarbonyl compounds as PPARa selective activators", Bioorg Med Chem Lett. 2004; 14(13): 3507-11. Specific description of the experiment is as follows:

Reagents for the experiment: the compounds (20 mm solutions in DMSO, stored at -80°C).

(1) Day 1: Cultivation and seeding of cells

Cell hepatocarcinoma HepG2 (obtained from the American type culture collection ATSS) were cultured in DMEM enriched with 10% fetal bovine serum inactivated by heating (FBs, Invitogen, Grand island, NY, USA) in the culture vessels T-75 (Greiner, Germany) in an incubator at 37°C, 100% relative humidity and 5% CO2. When cell culture in a culture vessel reached 80-90% confluently, its hydrolyzed in 0.25% trypsin (EDTA) for 3 min and sown in 96-well culture plate with a planting density of 2000 cells/100 μl/well.

(2) Day 2: Transfection of cells

On the following day, when the growth of cells on 96-well culture square is hetah reached 50-80% of confluently, carried out the transfection of cells. The co-transfection of cells includes transfiziologii agent FuGene6 (Roche Molecular Biochemicals, Indianapolis, Indiana, USA) and 60 ng DNA (10 ng hRXR, 10 ng pCMV βGal, 10 ng plasmid expressing the nuclear receptor RXR/PPARδ, 30 ng of plasmid bearing the reporter gene GFP, respectively).

(3) Processing of the medicinal product

Culture medium was removed 24 hours after transfection and replaced with 200 μl of fresh DMEM medium containing the investigational medicinal product (with 10% FBS, treated with activated charcoal). The final concentrations of the investigational medicinal product was 10, 5, 1, 0,1, 0,01, 0,001 and 0 μm, the positive control consisted of 0.05 μm 2-posterino acid (purchased in Sigma, USA) with DMSO in each well (final concentration was 0.1%).

(4) Analysis of kinase activity

After 24 h after treatment and drug cells were literally in lyse solution (buffer lizirovania cell cultures, Promega), centrifuged and collected the supernatant. The supernatant was treated with reagents of the kit for detection of fluorescence (Promega), was detected fluorescence on fluorimeter (Fluoroskan Ascent FL reader, Thermo Labsystems, Finland) and determined the relative luciferase activity. To analyze the activity of β-galactosidase, used in the xperimenta as internal standard (calibration by internal standard for assessing the efficiency of transfection), 50 μl of supernatant was transferred into a clean microplate, were treated with reagents from Promega kit and read at a wavelength of 405 nm on a tablet reader (Bio-tech Instruments Inc., Winooski, Vermont, USA) (Sauerberg, P.; Olsen, G. S.; Jeppesen, L; Mogensen, J. P. et al., J. Med. Chem., 2007, 50, 1495-1503).

3. Analysis:

The median effective concentration (EC50) sample represents the concentration at which the sample has 50% of the pharmacological effect. This value represents one of the important parameters to evaluate the pharmacological effect of the compounds. In this research process EU50the sample was calculated in accordance with activation of the receptor by the sample at six different concentrations.

4. The screening result

There was obtained compound of formula I, are able to activate the receptor PPARδ.

Data on the activity of the compounds of formula I (acid) in vitro

The activity of the compounds of formula I (acid) in vitro was measured according to the following methods: a sample of the compounds of formula (I) (acid) was dissolved and diluted to different concentrations, the activity of the sample in relation to the activation of PPARδ receptor was tested at various concentrations, obtained according to the concentration and effect and to calculate the corresponding value for the median effective concentration (EC50). The results of the study shown in ablaze 1.

Table 1
Data on the activity of the compounds of formula I (acid) in vitro
Code connectionPPARδ EU50(nm)
A-1468
A-2100
A-310
A-410
A-5340
A-62090
A-7380
A-83020
A-96610
A-10100
A-11<1
A-12650
A-1320
A-14<1
A-1520
A-16 1
A-17<1
A-18<1
A-19<1

Note: the lower the value EC50(nm), the higher the activity.

Based on the data in Table 1 one can see that all connections according to the present invention have agonistic activity against PPARδ.

SCREENING PHARMACODYNAMIC ACTIVITY of the COMPOUNDS IN VIVO

1. The screening activity in the control of blood lipids

Analysis of the activity part of the compounds of formula I (acid) of the present invention in vivo:

From a-1 - A-19 selected four compounds and subjected them to analysis on activity in vivo. The interaction effects of drugs observed in rats Sprague, doli, mice, APOE, Mesocricetus auratus, and other models with hyperlipidemia caused by food high in fat. The results are shown in Table 2.

Table 2
Activity of compounds of the formula I (acid) in vivo
CodeOHTGLDLHDL
GW501516↓22%↓53%↓40%↑23%
A-1↓40%↓55%↓57%↑25%
A-3↓65%↓51%↓40%↑43%
A-16↓60%↓41%↓36%↑12%
A-11↓58%↓58%↓28%↑46%
Note: ↓ means decrease, ↑ indicates increase.

From Table 2 one can see that the four compounds that were selected and analyzed activity in vivo, is capable of reducing cholesterol (TC), triglyceride (TG) and low density lipoprotein (LDL)and increase high density lipoprotein (HDL), which indicates the exceptional action of the compounds according to the invention for the regulation of blood lipids. At the same time, the four with the organisations also had a similar pharmacological action models based on the rat line Sprague, doli and mouse APOE and had the best effect on the regulation of blood lipids compared with GW501516.

In particular, compound a-3 is able not only to lower cholesterol (OH) up to 40%, triglycerides (TG) up to 65% and low-density lipoprotein (LDL) to 51%, but also increase the level of high density lipoprotein (HDL) levels up to 43%.

Subsequently, the effectiveness of drug a-3 confirmed on the model of hyperlipidemia on the basis of Massa rhesus. Three months later the introduction of the femoral vein was collected blood samples for determination of hematological parameters, and determination of insulin, apolipoprotein a-1 (area-1) and apolipoprotein b-100 (Ares-100) using a solid-phase ELISA. The results showed that, compared with the control group models of hyperlipidemia, serum of animals exposed to introduction a-3, the content of total cholesterol (TC) decreased by 45%, the content of low-density lipoprotein (LDL) decreased by 38%, and the content of high density lipoprotein (HDL) increased by 67%. While using solid-phase ELISA was found that the concentration of insulin increased significantly; the concentration of area-1 significantly increased the concentration of Ares-100 decreased significantly, and the ratio of area-1 and Ares-100 has reached a level characteristic of normal animals that were fully consistent with the results of hematological determine LDL and HDL. The above results showed that after tog is how animals suffering from hyperlipidemia, were injected drug a-3, all the indicators are defined with hematological analysis and solid phase ELISA, was significantly changed in the direction of norms that, in turn, demonstrated that therapeutic effect of this medication was much larger than that of GW501516.

2. Screening for pharmacological activity towards the reduction of body weight

The experimental technique

As the experimental animals were selected male mice C57BL/6J age 3 weeks, 15 of them were randomly selected for feeding standard food, and the rest were fed food high in fat, and each of the mice was marked by a cut on the ear. Body weight and feed derived mice were weighed every week. After feeding for 15 weeks in the mouse group treated with food high in fat, weighed on average, 42 g, the mouse group treated with standard food, weighed on average 28, further mice and from the model group and the group treated with the drugs that were fed food high in fat. After administration of the compounds according to the invention within four weeks observed the effect of drugs on lipid levels and blood glucose, body weight and feed intake by the animals, while for the study of drug action among the STV on glucose tolerance in animals performed the analysis of glucose tolerance.

(1) the Effect of drugs on the levels of lipids and glucose in the blood of animals

As shown in Table 3, a-3 and a-11 is able to significantly reduce the levels of triglycerides and glucose in the serum of animal models, demonstrating better effect than orlistat.

10
Table 3.
The action of drugs on the levels of lipids and glucose in the blood of animals (x±s)
groupnDosage (mg/kg)Introduction for 2 weeksIntroduction for 4 weeks
GlucoseOHTGHDLGlucoseOXTGHDL
Normal5-3,61±0,721,87±0,350,17±0,051,34 is 0,2 2,9±0,862,59±0,350,21±0,091,5±0,64
Modal510,12±0,8Δ4,4±0,48Δ0,53±0,143,05±0,3110,16±0,7of 5.05±0,430,42±0,132,96±0,46
ΔΔΔΔΔΔΔΔΔΔ7ΔΔΔΔΔΔΔΔΔΔΔΔ
Orlistat5308,81±2,163,89±0,440,45±0,092,72±0,39,84±1,833,48±0,54*0,41±0,042,79±0,35
Orlistat510to 11.11±1,083,81±2,56*0,36±0,093,29±0,2711,05±1,094,24±0,33**0,28±0,03*2,63±1,27
A-35106,54±1,04***5,12±0,650,18±0,02***2,94±0,426,6±1,15***4,75±0,570,11±0,07***2,89±0,28
A-353,39,52±1,713,25±was 2.760,19±0,12**3,31±0,219,54±0,715,11±0,310,07±0,01***3,1±0,59
A-1156,51±1,61***4,51±0,370,16±0,06***2,39±1,366,93±0,3***5,28±0,480,15±0,05**2,84±1,09
A-1153,3cent to 8.85±2,13534±0,850,21±0,08**3,25±1,29to 7.61±0,5***of 5.84±0,210,12±0,05***3,83±0,1*
ΔΔΔ P<0,001 compared with normal group;
*P<0,05, **P<0,01, ***P<0,001 compared with model group

(2) the Effect of drugs on body weight and food consumption of animals

As shown in Table 4 and in Fig,1, a-3 and a-11 is able to significantly reduce the body weight of animals and do not have a significant impact on the consumption of food animals, which indicates the exceptional action of the medicinal product in relation to stimulating weight loss.

Table 4
The effect of drugs on food intake in animals
groupFood consumption (g)
12345
Normal7,88,38,587,9812,78
Model13,345,946,647,27,12
Orlistat 30 mg/kg6,04of 4.665,527,78a 7.92
Orlistat 10 mg/kg5,885,426,76,646,4
A-3 to 10 mg/kg5,464,844,945,285,9
A3 - 3,3 mg/kg5,225,04the 6.065,16,275
A-11 - 10 mg/kg7,25,26,0of 5.46,9
A-11 and 3.3 mg/kg6,05,05,85,26,9

(3) Oral test for glucose tolerance

The results are shown in figure 2, i.e. the initial glucose level cannot be restored within 2 hours in animal models suffering from obesity, the curve of glucose tolerance does not correspond to the normal and glucose tolerance decreased, while the a-3 and a-11 is able to significantly improve glucose tolerance in animals suffering from obesity.

3. Pharmacokinetic study

1. The curve "concentration - time"

Experimental technique:

Took 36 rats Sprague, doli weighing in the range of 150-170 g when the sex ratio is 1:1, divided them into two experimental groups and introduced them to the a-1 and a-3, respectively; in each experimental group was allocated 3 experimental Podger PPy six animals in each when the sex ratio is 1:1, receiving the drug concentration of 50, 10 and 2 mg/kg, All rats within 12 hours he was kept without food and with unlimited access to water. The amount of dose was 10 ml/kg, the blood samples volume of 0.4-0.5 ml were taken from the back of the ophthalmic veins awake animals at different time points after gastric lavage and centrifuged at 5000 rpm for 10 minutes Accurately measured 200 μl of plasma sample was added to 200 μl of acetonitrile, was shaken until uniform, left to stand for 5 min and centrifuged (14000 rpm, 5 min). The supernatant was collected and again centrifuged (14000 rpm, 5 min). The obtained supernatant was collected and subjected to HPLC. Blood samples were collected at time points corresponding to 0, 0,5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48 and 72 h, the peak area for each time point were averaged for samples taken from 6 rats in the same time. Expected plasma concentrations and amounted to graph the drug concentration - time".

The results are shown in Figure 3.

The results show that t1/2for the a-3 was 10-12 h, t1/2for A-1 was 26-28 h, the bioavailability of a-3 was 86%, whereas the bioavailability of a-1 was 15%.

2. Tissue distribution

18 rats Sprague, doli for 16 h were kept without food with free access to water, distributed them n the 3 groups of 6 animals/group at ratios 1:1 and injected them HS060098 (10 mg/kg), then after 1, 10 and 24 h after injection, animals were killed and quickly removed from each animal heart, liver, spleen, lungs, kidneys. From the surface of each body immediately washed away the blood with saline. The tissues of the body cut out, thoroughly washed, removed from them liquid, weighed, added saline solution in 400 mg/ml, homogenized in an ice bath for 1 min and centrifuged at 3750 rpm for 20 minutes was Collected by pipette exactly 400 ál of supernatant was then added to 40 ál of internal standard (as internal standard used HS060001 in molar concentration of 5 mmol/l)was diluted in 3 ml of purified water were mixed to homogeneity and was loaded onto a column (column C18 SPE initially washed with 3 ml of purified water, and then 3 ml of 10% methanol to activate). The column was washed 3 ml of purified water at a speed of 1 ml/min and was suirable 3 ml of an eluting agent (methanol: purified water=9:1). The eluate was collected and dried in a stream of nitrogen at 45°C. the Residue was dissolved in 100 μl of acetonitrile were placed in a HPLC injector and then injected with a sample.

The results are shown in Table 5. The results indicate that a-3 and a-1 are distributed mainly in the liver, and a-3 is distributed relatively evenly.

the figure 5
The main distribution of a-3 and a-1 in organs
MedicationLiver(%)Heart (%)Spleen (%)Light (%)Kidney(%)
A-3362613169
A-13589119

EXAMPLE

Obtain the intermediate compound (II):

Example 1: obtaining a compound (II-1

Getting ethyl-2-(2-methyl-4-hydroxy)-phenoxyacetate (II-1)

In odnogolosy flask 500 ml) was sequentially added with stirring 3-methyl-4-hydroxyacetophenone (25 g, KZT 166.5 mmol), 250 ml of acetonitrile and potassium carbonate (K2CO3, 26 g, 188,2 mmol). Then was added dropwise ethylbromoacetate (20 ml, 172,2 mmol) in acetonitrile (50 ml). The reaction mixture was stirred at room temperature for 8 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (200 ml), filtered and evaporated who, getting a yellow oil.

In another odnogolosy flask 500 ml to a stirred solution of the above yellow oil in dichloromethane (CH2Cl2, 300 ml) was added 3-chlormadinone acid (46 g, of 199, 9 mmol) and catalytic amount of 4-methylbenzenesulfonic acid. The resulting mixture was stirred over night at room temperature. After completion of the reaction, the reaction mixture was filtered and washed obtained filter cake with 100 ml of dichloromethane. The combined filtrate was washed with a saturated aqueous solution of hyposulphite of sodium (Na2S2SO4) and sodium bicarbonate (Panso3) and then evaporated, obtaining a pale yellow oil.

The crude product obtained in the above reaction, was transferred into another odnogolosy flask 500 ml and was added 80 ml of ethanol and a catalytic amount of 4-methylbenzenesulfonic acid. The solution was heated under reflux for 6 h and then evaporated in vacuum, obtaining a pale yellow solid. Specified pale yellow solid is recrystallized from petroleum ether/ethyl acetate (2:1 vol./vol.), getting ethyl-2-(2-methyl-4-hyroxy)-phenoxyacetate (16 g, 45.8% in three stages) in the form of a white solid.

The structure of the obtained compounds were described on the basis of the following data, obtained when amodu spectroscopy nuclear magnetic resonance:

1H NMR (400 MHz, CDCl3) δ of 1.34 (t, J=7,14 Hz, 3H), and 2.27 (s, 3H), 4,30 (q, J=7,14 Hz, 2H), br4.61 (s, 2H), 6,61-6,63 (m, 1H), 6,65 (s, 1H), 6,67 of 6.68 (m, 1H), 7,31 (s, 1H).

Example 2: Obtain the compound (II-2

Using 3-methyl-4-hydroxyacetophenone as starting material, was obtained ethyl-2-(3-methyl-4-hydroxy)-phenoxyacetate (II-2) according to the method similar to the method described in Example 1, in the form of a white solid with a yield of 40.2 per cent.

The structure of the obtained compounds were described on the basis of the following data, obtained using spectroscopy nuclear magnetic resonance:

1H NMR (400 MHz, DMSO) δ of 1.23 (t, J=7,12 Hz, 3H), to 2.29 (s, 3H), 4,18 (q, J=7,14 Hz, 2H), with 4.64 (s, 2H), 6,57-6,60 (m, 1H), of 6.68 (s, 1H), 6,69-6,70 (m, 1H), 8,87 (s, 1H);13With NMR (100 MHz, DMSO) δ 14,5, 16,6, 60,9, 65,9, 112,2, 112,8, 115,4, 117,6, 125,2, 150,2, 150,8, 169,6.

Example 3: Obtaining the compound (II-3

Using 3-ethyl-4-hydroxyacetophenone as starting material, was obtained ethyl-2-(2-ethyl-4-hydroxy)-phenoxyacetate (11-3) according to the method similar to the method described in Example 1, in the form of a pale yellow solid with a yield of 74.5%.

The structure of the obtained compounds were described on the basis of the following data, obtained using spectroscopy nuclear magnetic resonance:

1H NMR (400 MHz, Dl3) δ of 1.23 (t, J=7,53 Hz, 3H), of 1.34 (t, J=7,12 Hz, 3H), 2,69 (q, J=7,52 Hz, 2H), 4,30 (q, J=7,14 Hz, 2H), br4.61(s, 2H), 5,35 (s, 1H), 6,6 (dd, J=8,65 Hz, 2,84 Hz, 1H), 6,65 (d, J=8,63 Hz, 1H), 6,72 (d, J=2,84 Hz, 1H);13With NMR (100 MHz, CDCI3) δ 14,0, 14,1, 23,1, 61,3, 66,7, 112,6, 113,1, 116,5, 134,9, 149,9, 150,4, 169,8.

Example 4: Obtaining the compound (II-4

Getting ethyl-2-(3-methyl-4-hydroxy)-phenylthiourea (II-4)

In a three-neck flask with a volume of 500 ml was sequentially added with stirring o-cresol (15 g, 138, 7mm mmol), sodium thiocyanate (NaSCN, 34 g, 419,3 mmol), sodium bromide (NaBr, 16 g, 155,5 mmol) and methanol (200 ml). The mixture was cooled to 0°C. and was added dropwise a solution of bromine (8.6 ml, 167 mmol) in methanol (30 ml). After 1 hour stirring at 0°C. the mixture was heated to room temperature and stirred over the next 4 hours at room temperature. After completion of the reaction, to the reaction mixture were added 200 ml of a saturated aqueous solution of sodium bicarbonate (NaHC3) and was stirred for 10 minutes the Mixture was extracted with ethyl acetate (2 X 500 ml). The combined organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, obtaining a yellow oil. Performed cleaning method column chromatography on silica gel (silica gel H: 300-400 mesh; petroleum ether/ethyl acetate=8:1 vol./vol.), getting 3-methyl-4-hydroxy-phenylthieno acid as a white solid (16 g, yield: 69,8%).

The structure of the obtained compounds is s described on the basis of the following data, obtained using spectroscopy nuclear magnetic resonance:

1H NMR (400 MHz, DMSO) δ 2,17 (s, 3H), 6,92(d, J=8,4 Hz, 1H), 7,37 (dd, J=8,4 Hz, 2,48 HZ, 1 H), 7,44 (d,J=2,48 HZ, 1H), 10,1 (s, 1H);13With NMR (100 MHz, DMSO) δ 16,2, 111,1, 113,1, 116,8, 127,3, 132,2, 135,4, 158,3.

In a three-neck flask of 500 ml to stir the mixture of allotetraploid lithium (LiAlH4, 3.5 g, 92,2 mmol) and tetrahydrofuran (THF, 50 ml) was added dropwise a solution of 3-methyl-4-hydroxyphenylethylamine acid (6,13 g, 37,1 mmol) in tetrahydrofuran (THF, 30 ml) at 0°C. After 30 min stirring at 0°C. the mixture was heated to room temperature and then was stirred for 1 hour at room temperature. The reaction was stopped by adding ethanol (10 ml). The pH value of the mixture was brought up to 3-4 by addition of 6 M hydrochloric acid at Toledano bath. Then the aqueous layer was extracted with ethyl acetate (3 X 100 ml). The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuum, obtaining the crude product 4-hydroxy-3-methyl thiophenol in the form of a yellow oil.

In odnogolosy flask of 250 ml to a solution of the above crude product 4-hydroxy-3-methylthiophenol in acetonitrile (80 ml) under stirring was added ethyl-2-bromoacetate (4.3 ml, 37 mmol), followed by the addition of potassium carbonate (5.1 g, 36,9 mmol). The resulting mixture was stirred for 8 hours is at room temperature. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (80 ml), filtered and evaporated, receiving the remainder. The residue was purified by the method of column chromatography on silica gel (silica gel H:300-400 mesh; petroleum ether/ethyl acetate=8:1 vol./vol.), getting 6,38 g ethyl-2-(3-methyl-4-hydroxy)-phenylthioureido in the form of a yellow oil (yield: 76%).

The structure of the obtained compounds were described on the basis of the following data, obtained using spectroscopy nuclear magnetic resonance:

1H NMR (400 MHz, CDCl3) δ 1,24 (t, J=7.2 Hz, 3H), of 2.18 (s, 3H), 3,49 (s, 2H), 4,15 (q, J=7,14 Hz, 2H), 5,74 (s, 1H), 6,63 (d, J=8,27 Hz, 1H), 7,17 (dd, J=8,16 Hz, 2,28 HZ, 1H), 7,25 (d, J=2,28 Hz, 1H);13With NMR (100 MHz, Dl3) δ 14,1, 15,7, 38,8, 61,6, 115,6, 124,1, 125,1, 131,9,135,7, 154,5, 170,6.

Example 5: Obtain compound II-5

Using m-cresol as a starting material, was obtained ethyl 2-(2-methyl-4-hydroxy)-phenylthiourea (II-5) according to the method similar to the method described in Example 4 in the form of a yellow oil with a yield of 63%.

The structure of the obtained compounds were described on the basis of the following data, obtained using spectroscopy nuclear magnetic resonance:

1H NMR (400 MHz, DCl3) δ of 1.23 (t, J=7,1 Hz, 3H), 2,39 (s, 3H), 3,44 (s, 2H), 4,14 (q, J=7,11 Hz, 2H), 6,38 (s, 1H), is 6.54 (dd, J=at 8.36 Hz, 2,72 Hz, 1H), only 6.64 (d, J=2,71 Hz, 1H), 7,31 (d, J=8,37H4, 1H).

Example 6: Obtain compound II-6

Using 2.5-DIMET phenol as source material, was obtained ethyl 2-(2,5-dimethyl-4-hydroxy)-phenylthiourea (II-6) according to the method similar to the method described in Example 4 as a white solid with a yield of 72%.

The structure of the obtained compounds were described on the basis of the following data, obtained using spectroscopy nuclear magnetic resonance:

1H NMR (400 MHz, CDCI3) δ of 1.23 (t, J=7,16 Hz, 3H), of 2.16 (s, 3H), of 2.38 (s, 3H), 3.43 points (s, 2H), 4,13 (q, J=7,13 Hz, 2H), 5,19 (s, 1H), return of 6.58 (s, 1H), 7.23 percent (s, 1H);13With NMR (100 MHz, CDCl3) δ 14,1, 15,1, 20,2, 37,9, 61,4, 116,9, 122,1, 123,3, 136,9, 140,0, 154,3, 170,3.

Obtaining an intermediate compound III:

Example 7: Obtain compound III-1

3-(1'-bromobenzyl)-4-methyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-triazole-5(4H)-he (connection 111-1) can be obtained according to the following reaction scheme:

Receiving the N-methyl phenylacetamide

Phenylacetic acid (10 g, of 73.5 mmol) and methanol (60 ml) was added to the three-neck flask with a volume of 250 ml, followed by adding 10 drops of concentrated sulfuric acid. The resulting solution was heated under reflux for 2 hours. Then the solution was cooled to room temperature, then added 25-30% aqueous solution of methylamine (50 ml, approximately 403 mmol) and was heated under reflux for 3 hours. After completed the I reaction mixture was cooled to room temperature. A large part of the solvent was removed on a rotary vacuum evaporator, was added 30 ml of water and was extracted with a mixture of ethyl acetate (3 X 80 ml). The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, obtaining a 10.1 g of N-methylformamide (white solid, yield: 91,8%).

The structure of the obtained compounds were described on the basis of the following data, obtained using spectroscopy nuclear magnetic resonance:

1H NMR (400 MHz, CDCl3) δ 2,69 (d, J=4,84 Hz, 3H), 3,51 (s, 3H), 5,95 (wide, 1H), 7,21-7,24 (m, 3H), 7,28-to 7.32 (m, 3H);13With NMR (100 MHz, CDCl3) δ 26,4, 43,6, 127,2, 128,9, 129,4, 135,1, 171,8.

Obtain 3-benzyl-4-methyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-triazole-5(4H)-it

In a three-neck flask with a volume of 1000 ml to a stirred solution of N-methylformamide (25 g, 167,7 mmol) and (4-trifluoromethyl)phenylhydrazine (30 g, 170 mmol) in toluene (250 ml) at 80-90°C was added dropwise a solution of phosphorus oxychloride (POCl315 ml, 180 mmol) in toluene (50 ml). After complete addition, the mixture was stirred for 5 hours at 80-90°C, and then, after completion of the reaction, cooled to room temperature and filtered. The remaining filter cake was washed with ethyl acetate until he acquired a yellowish-brown color. The filtrate was washed with saturated in the s ' solution of sodium bicarbonate, was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and re-filtered. The filter cake was washed with ethyl acetate. The filtered precipitates were mixed and dried under vacuum. The result has been to 43.5 g of N-methyl-2-phenyl-n-(4-trifluoromethyl)-phenylacetamido hydrazone (yellowish-brown solid, yield: 84.4 per cent).

In a three-neck flask with a volume of 1000 ml to a stirred mixture of N-methyl-2-phenyl-n-(4-trifluoromethyl)-phenylacetamido hydrazone (58,6 g, 190,9 mmol) and N,N-dimethylaminopyridine (DMAP, 0.5 g, 4.0 mmol) in tetrahydrofuran (THF, 500 ml) was slowly added carbonyldiimidazole (CDI, 46,43 g, 286,4 mmol). The resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction the mixture was transferred into a beaker with a volume of 2000 ml containing 300 ml of water, brought the pH to 2-4 6 N. hydrochloric acid with stirring and filtered. The filtered precipitate was washed with distilled water and dried in vacuum, obtaining 56.7 g of 3-benzyl-4-methyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-triazole-5(4H)-she (pale yellow solid, yield: 89.2%of).

The structure of the obtained compounds were described on the basis of the following data, obtained using spectroscopy nuclear magnetic resonance:

1H NMR (400 MHz, CDCl3) δ 3,11 (s, 3H), 4,0 (s, 2H), 7,25-7,38 (m, 5H), to 7.67 (d, J=8,68 Hz, 2H), 8,18 (d, J=8,68 Hz, 2H);13C NMR (100 MHz, CDCI 3) δ 27,6, 32,7, 118,0, 122,8, 125,5, 126,6, 127,7, 128,4, 129,1, 133,6, 140,7, 146,8, 152,6.

Obtaining 3-(1'-bromobenzyl)-4-methyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-triazole-5(4H)-she (III-1)

In a three-neck flask with a volume of 500 ml with stirring was added 3-benzyl-4-methyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-triazole-5(4H)-one (15 g, 45 mmol) and chloroform (l3250 ml). To the stirred solution was added N-bromosuccinimide (NBS, 12 g, 68 mmol) and benzoyl peroxide (0.5 g, 2.25 mmol). The mixture was carefully heated under reflux for 12 hours. After completion of the reaction the mixture was filtered. The filtrate was concentrated under reduced pressure, obtaining a residue that was purified by the method of flash-chromatography on a column of silica gel (silica gel H:300-400 mesh; petroleum ether/ethyl acetate=8:1 vol./vol.), receiving 14.6 g of 3-(1'-bromobenzyl)-4-methyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-triazole-5(4H)-it is in the form of a reddish-brown oil (yield: 79.7 per cent).

The structure of the obtained compounds were described on the basis of the following data, obtained using spectroscopy nuclear magnetic resonance:

1H NMR (400 MHz, DCl3) δ of 3.28 (s, 3H), 6,07 (s, 1H), 7,25-7,58 (m, 5H), 7,66 (d, J=8,68 Hz, 2H), 8,13 (d, J=8,68 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 28,4, 42,1, 69,6, 118,3, 126,2, 126,8, 127,3, 129,1, 129,9 133,9, 140,3, 145,7, 152,4.

Example 8: Obtain compound III-2

The compound 3-(1'-bromobenzyl)-4-n-butyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-resol-5(4H)-she (compound III-2) can be obtained in accordance with the following reaction scheme

Obtaining N-n-butylferrocene

Phenylacetic acid (16 g, of 117.6 mmol) and methanol (60 ml) was added to the three-neck flask with a volume of 250 ml, followed by adding 5 drops of concentrated sulfuric acid. The resulting solution was heated under reflux for 6 hours. Then the mixture was cooled to room temperature, followed by addition of n-butylamine (12 ml, 121,4 mmol) and was heated under reflux for 3 hours. After completion of the reaction the mixture was cooled to room temperature. A large part of the solvent was removed with a rotary vacuum evaporator, was added 30 ml of water and was extracted with a mixture of ethyl acetate (3 X 80 ml). Mixed organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, obtaining 15.9 g of N-n-butylferrocene (white solid, yield: 70,4%).

The structure of the obtained compounds were described on the basis of the following data, obtained using spectroscopy nuclear magnetic resonance:

1H NMR (400 MHz, DCl3) δ 0,86 (t, J=7,28 Hz, 3H), 1,21-of 1.29 (m, 2H), 1,36-of 1.44 (m, 2H), 3,2 (q, J=? 7.04 baby mortality Hz, 2H), 5,62 (wide, 1H), 7.24 to 7,29 (m, 3H), to 7.32 and 7.36 (m, 2H);13With NMR (100 MHz, CDCl3) δ 13,7, 19,9, 31,5, 39,4, 43,8, 127,2, 128,9, 129,4, 135,1, 170,9.

Obtain 3-benzyl-4-n-butyl-1-(trifloromethyl)-Fe the Il-1H-1,2,4-triazole-5(4H)-it

In a three-neck flask of 500 ml to mix a solution of N-n-butylferrocene (11 g, 57.5 mmol) in toluene (150 ml) at 80-90°C was added dropwise a solution of phosphorus oxychloride (l3, 17 ml of 75.1 mmol) in toluene (20 ml). After complete addition, the mixture was stirred for 5 hours at 80-90°C and then cooled to room temperature after completion of the reaction and was filtered. The obtained filter cake was washed with ethyl acetate until he acquired a yellowish-brown color. The filtrate was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and re-filtered. The filter cake was re-washed with ethyl acetate. The obtained filtered precipitates were mixed and dried under vacuum. At the end of the treatment received 15.7 g of N-n-butyl-2-phenyl-n-(4-trifluoromethyl)-phenylacetamide hydrazone (yellowish-brown solid).

In a three-neck flask with a volume of 500 ml to stir a mixture of N-n-butyl-2-phenyl-n-(4-trifluoromethyl)-phenylacetamido hydrazone (15.7 g) and N,N-dimethylaminopyridine (DMAP, 0.5 g, 4.0 mmol) in tetrahydrofurane (THF, 250 ml) was slowly added carbonyldiimidazole (CDI, the 7.43 g of 45.8 mmol) at room temperature. The reaction mixture was stirred at room temp is the temperature in 12 hours. After completion of the reaction the mixture was poured into a beaker with a volume of 500 ml containing 100 ml of water, brought the pH to 2-4 6 N. hydrochloric acid with stirring and was filtered. The filtered precipitate was washed with distilled water and then dried in vacuum, obtaining 6,28 g 3-benzyl-4-n-butyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-triazole-5(4H)-she (pale yellow solid, yield in two stages: 29,2%).

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) 6 0,86 (t, J=7,3 Hz, 3H), 1,22-of 1.29 (m, 2H), 1,37-of 1.44 (m, 2H), 3,49 (q, J=7,6 Hz, 2H), 4,0 (s, 2H), 7,26-7,38 (m, 5H), to 7.67 (d, J=to 8.70 Hz, 2H), 8,19 (d, J=8,65 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 13,5, 19,8, 30,6, 32,8, 41,7, 117,9, 126,1, 126,9, 127,2, 127,8, 128,6, 129,1, 134,0, 140,7, 146,6, 152,5; MS (ESI) m/z 376,29 (M+1)+.

Obtaining 3-(1'-bromobenzyl)-4-n-butyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-triazole-5(4H)-she (III-2)

In a three-neck flask with a volume of 250 ml was added 3-benzyl-4-n-butyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-triazole-5(4H)-he (3.75 g, 10 mmol) and chloroform (100 ml). To the stirred solution was added N-bromosuccinimide (NBS, of 3.56 g, 20 mmol) and benzoyl peroxide (0.4 g, of 1.65 mmol). The resulting mixture was gently heated under reflux for 6 hours. After completion of the reaction the solvent was removed with rotary in chumnogo evaporator and the residue was subjected to column chromatography (silica gel 1-1:300-400 mesh; petroleum ether/ethyl acetate=8:1 vol./vol.), receiving of 3.9 g of 3-(1'-bromo-benzyl)-4-n-butyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-triazole-5(4H)-she (III-2) (reddish-brown viscous liquid, yield: 85,9%).

The structure of the obtained compounds were described on the basis of the following data, obtained using spectroscopy nuclear magnetic resonance:

1H NMR (400 MHz, CDCl3) δ of 0.90 (t, J=of 7.36 Hz, 3H), of 1.27 and 1.35 (m, 2H), 1,47-of 1.53 (m, 1H), 1,63-of 1.66 (m, 1H), 3,66-and 3.72 (m, 2H), 6,00 (s, 1H), 7,41-7,46 (m, 3H), to 7.61 (dd, J=7,99 Hz and 1.83 Hz, 2H) 7,66 (d, J=8,69 Hz, 2H), 8,15 (d, J=8,57 Hz, 2H);13With NMR (100 MHz, Dl3) δ 13,5, 19,9, 30,3, 41,5, 42,4, 118,2, 126,2, 126,8, 127,3, 128,6, 128,9, 129,5, 134,8, 140,4, 145,6, 152,2.

Example 9: Obtain compound III-3

The compound III-3 can be obtained in accordance with the following reaction scheme:

Obtaining N-methylbenzoxazolium

60% sodium hydride (3.7 g, of 92.5 mmol) and tetrahydrofuran (20 ml) was added to the three-neck flask with a volume of 250 ml, followed by heating and adding dropwise 20 ml of a solution of benzyl alcohol (10 g, for 96.1 mmol) in tetrahydrofuran. After complete addition, the reaction mixture was heated under reflux for 1 hour. Then add ethylbromoacetate (11 ml, or 94.8 mmol) and stirred the reaction mixture for the next 4 hours while heating under reflux. After cooling to room temperaturedisplay 25 ml of an aqueous solution of methylamine and carried out the reaction by heating under reflux in the course of the next 6 hours. After completion of the reaction the mixture was concentrated under reduced pressure and subjected to column chromatography (silica gel H: 300-400 mesh; petroleum ether/ethyl acetate=4:1 vol./vol.), getting to 5.3 g of N-methylbenzeneethanamine (white solid, yield in two stages: 32%).

The structure of the obtained compounds were described on the basis of the following data, obtained using spectroscopy nuclear magnetic resonance:

1H NMR (400 MHz, CDCl3) δ and 2.83 (d, J=5,16 Hz, 3H), 3,98 (s, 2H), 4,55 (S, 2h), is 6.61 (s, 1H), 7,30-7,39 (m,5H).

Obtaining 3-benzocoumarin-4-methyl-1-(4-triptoreline)-1,4-dihydro-1,2,4-triazole-5-she

In a three-neck flask with a volume of 250 ml to a mixed solution of N-methylbenzeneethanamine (6.4 g, of 3.57 mmol) in toluene (40 ml) at 80-90°C was added dropwise phosphorus oxychloride (3.6 ml, of 38.5 mmol) in toluene (20 ml). The resulting reaction mixture was stirred at 80-90°C for 5 hours. After completion of the reaction the mixture was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate, to obtain the red color. The filtrate was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and re-filtered. The filter cake was re-washed with ethyl acetate. The resulting tfilter the bathrooms sediments were mixed and dried under vacuum. At the end of the treatment received 4.5 g red solid.

The above red solid in the amount of 4.5 g was transferred into another three-neck flask with a volume of 500 ml, were added 200 ml of tetrahydrofuran (THF)were mixed and slowly added carbonyldiimidazole (CDI) (5 g, for 30.8 mmol). The reaction mixture after the addition was stirred at room temperature for 12 hours. After completion of the reaction the mixture was concentrated under reduced pressure and subjected to column chromatography (silica gel H: 300-400 mesh; petroleum ether/ethyl acetate=4:1 vol./vol.), receiving 3 g of 3-benzocoumarin-4-methyl-1-(4-triptoreline)-1,4-dihydro-1,2,4-triazole-5-on (light-brown gel-like substance, out in two stages: 23%).

The structure of the obtained compounds were described on the basis of the following data, obtained using spectroscopy nuclear magnetic resonance:

1H NMR (400 MHz, CDCl3) δ at 3.35 (s, 3H), 4,50 (s, 2H), 4,59 (s, 2H), 7,32-7,37 (m, 5H), 7,66 (d, J=8,46 Hz, 2H), 8,14 (d, J=8,46 Hz, 2H);13With NMR (100 MHz, CDCl3) 5 26,9, 27,8, 62,8, 72,9, 118,1, 126,1, 126,2, 126,3, 128,3, 128,5, 136,6, 140,5, 144,7, 152,5.

Obtaining 3-hydroxymethyl-4-methyl-1 -(4-triptoreline)-1,4-dihydro-1,2,4-triazole-5-she

In a three-neck flask with a volume of 250 ml to mix the solution of the above product 3-benzocoumarin-4-methyl-1-(4-triptoreline)-1,4-dihydro-1,2,4-triazole-5-she (3.0 g, 8.3 m is ol) in ethanol (60 ml) was added 1 g of 10% palladium charcoal. 1 g of 10% palladium charcoal in the flask was replaced by N2and then introduced hydrogen gas. The reaction mixture was stirred at room temperature for 24 hours. After completion of the reaction the mixture was filtered and concentrated in vacuum, obtaining 2.1 g of 3-hydroxymethyl-4-methyl-1-(4-triptoreline)-1,4-dihydro-1,2,4-triazole-5-it (white solid, yield: 93%).

The structure of the obtained compounds were described on the basis of the following data, obtained using spectroscopy nuclear magnetic resonance:

1H NMR (400 MHz, CDCl3) δ to 3.34 (s, 3H), to 4.52 (d, J=of 5.84 Hz, 2H), 5,77 {t, J=of 5.84 Hz, 1H), a 7.85 (d, J=8,59 Hz, 2H), 8,17 (d, J=8,59 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 27,9, 55,2, 118,0, 125,2, 125,5, 126,0, 141,3, 149,0, 152,5.

Obtaining 3-methyl bromide-4-methyl-1-(4-triptoreline)-1,4-dihydro-1,2,4-triazole-5-she (III-3)

In a three-neck flask with a volume of 250 ml to mix the solution of the above product (2.1 g, to 7.77 mmol) in dichloromethane (100 ml) was added N-bromosuccinimide (NBS, 1.8 g, 10.1 mmol) followed by slow addition of triphenylphosphine (2.4 g, to 9.15 mmol). The reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction the mixture was subjected to column chromatography (silica gel H: 300-400 mesh; petroleum ether/ethyl acetate=5:1 vol./vol.), obtaining 2.3 g of 3-methyl bromide-4-methyl-1-(4-triptoreline)-1,4-dihydro-1,2,4-three is evil-5-it (pale yellow solid, yield: 89%).

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ of 3.42 (s, 3H), 4,34 (s, 2H), to 7.67 (d, J=8,63 Hz, 2H), 8,12 (d, J=8,63 Hz, 2H);13C NMR (100 MHz, CDCl3) δ 19,1, 26,9, 27,9, 118,2, 126,2, 140,2, 143,5, 152,1; MS (ESI) m/z 332,27 (M-4)+.

Obtaining the compound (I) (ether):

Example 10: the connection is E-1

Obtain ethyl 2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenoxy)-acetate (E-1)

In odnogolosy flask with a volume of 150 ml to stir a solution of 3-(1-bromobenzyl)-4-methyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-triazole-5(4H)-she (111-1) (36,3 g, at 88.1 mmol) in acetonitrile (150 ml) was added ethyl-(2-methyl-4-hydroxy)-phenoxyacetate (11-1) (17.5 g, and 83.3 mmol), N,N-dimethylaminopyridine (DMAP, 0.5 g, 4.09 to mmol) and sodium carbonate potassium (K2CO3for 13.8 g of 99.9 mmol). The reaction mixture was stirred at room temperature for 8 hours. After completion of the reaction the mixture was filtered. The filter cake was washed with ethyl acetate (CH ml), then was thrown out. The filtrates were mixed, the solvent was removed on a rotary vacuum evaporator and then subjected to column chromatography (silica gel H: 300-400 mesh; petroleum ether/ethyl acetate=8:1 vol./vol.), receiving a colorless gel-like substance (to the which gradually became white solid storage) (33,5 g, output: 74,3%).

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, Dl3) δ of 1.28 (t, J=7,11 Hz, 3H), and 2.26 (s, 3H), 3,20 (s, 3H), 4.26 deaths {q, J=7,11 Hz, 2H), br4.61 (s, 2H), 6,28 (s, 1H), 6,65 (d, J=8,8 Hz, 1H), for 6.81 (d, J=8,75 Hz, 1H), 6,93 (d, J=3.0 Hz, 1 H), 7,25 was 7.45 (m, 3H), to 7.50 (d, J=7,32, 2H), to 7.67 (d, J=8,48 Hz, 2H), 8,14 (d, J=8,48 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 14,1, 16,7, 28,2, 61,3, 65,9, 75,1, 112,8, 113,2, 118,3, 119,3, 122,7, 125,8, 126,2, 127,1, 128,9, 129,0, 129,4, 135,1, 140,4, 146,3, 151,5,152,8, 169,1; MS (ESI)m/z 558,9 (M+NH4+).

Example 11: the connection is E-2

Using compound III-1 and II-5 as a starting material, was obtained ethyl-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetate (E-2) according to the chemical method similar to the method described in Example 9. The compound obtained was a white solid with a yield of 60%.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ 1,19 (t, J=7,12 Hz, 3H), of 2.45 (s, 3H), 3,21 (s, 3H), 3,50 (s, 2H), 4,12 (q, J=7,12 Hz, 2H), to 6.39 (s, 1H), 6,92 (dd, J=8,59 Hz, 2,82 Hz, 1H), 7,0, d, J=2,82 Hz, 1 H), 7,40-7,53(m, 3H), 7,52 (d, J=of 7.48 Hz, 2H), 7,69 (d, J=8,76 Hz, 2H), 8,18 (d, J=8,76 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 14,1, 20,9, 28,3, 37,1, 61,4, 74,6, 13,6, 117,9, 118,2, 125,4, 125,8, 126,2, 126,9, 127,3, 128,96, 129,1, 134,2, 134,7, 140,5, 142,2, 145,9, 152,6, 169,7; MS (ESI) m/z 558,01 (M+H)+.

Example 12: the connection is E-3

Using compound III-1 and II-4 as a starting material, was obtained ethyl-2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1 -(4-triptoreline)-4,5-dihydro-1 H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetate (E-3) according to the chemical method similar to the method described in Example 9. The compound obtained was a white solid with a yield of 71%.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ of 1.20 (t, J=7,10 Hz, 3H), is 2.37 (s, 3H), 3,19 (s, 3H), 3,53 (s, 2H), 4,14 (q, J=7,10 Hz, 2H), to 6.39 (s, 1H), 6,94 (d, J=8,58 Hz, 1H), 7,24 (dd, J=8,58 Hz, 2.4 Hz, 1H), 7,34 (d, J=2.4 Hz, 1H), 7,40-7,46 (m, 3H), to 7.50 (d, J=7,52 Hz, 2H), 7,69 (d, J=8,84 Hz, 2H), 8,17 (d, J=8,84 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 14,1, 16,5, 28,2, 38,0, 61,4, 74,5, 113,1, 118,2, 122,7, 125,4, 125,8, 126,2, 126,3, 127,1, 127,4, 128,0, 128,96, 129,1, 130,8, 134,8, 140,4, 145,9, 152,6, 169,8; MS (ESI) m/z 557,97 (M+N)+.

Example 13: Getting connection E-4

Getting ethyl-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate (E-4)

In a three-neck flask with a volume of 250 ml addition funnel constant pressure to stir the mixture of allotetraploid lithium (LiAl 4with 1.0 g of 26.3 mmol) and tetrahydrofuran (30 ml) at 0°C was added dropwise a solution of 3-methyl-4-hydroxyphenylethylamine acid (1.7 g, or 10.3 mmol) in tetrahydrofuran (THF, 30 ml). After 30 min stirring at 0°C and following 2 hours of stirring at room temperature the reaction was stopped by addition of crushed ice in vodoledyanym bath. The pH value of the mixture was brought up to 3-4 by adding 6 M hydrochloric acid, and then extracted the aqueous phase with ethyl acetate (3 X 100 ml). The combined organic layer was washed with a saturated solution of sodium chloride (2 X 100 ml), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuum, obtaining the crude product 3-methyl-4-hydroxybenzothiazole (yellow liquid).

In odnogolosy flask with a volume of 150 ml to stir a solution of 3-(1'-bromobenzyl)-4-methyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-triazole-5(4H)-she (4,01 g, 9.73 mmol) in acetonitrile (30 ml) was added their crude product 3-methyl-4-hydroxybenzothiazole in acetonitrile (30 ml), N,N-dimethylaminopyridine (DMAP, 0.07 g of 0.57 mmol) and potassium carbonate (K2CO3, 1.28 g, 9,27 mmol). After stirring the reaction mixture at room temperature for 4 hours was added potassium carbonate (K2CO3, 1.4 g, 10.1 mmol) and ethylbromoacetate (1.1 ml, 9.5 mmol). The reaction mixture was stirred for next 8 hours. PEFC the completion of the reaction the mixture was filtered. The filter cake was washed with ethyl acetate (3 X 30 ml), then was thrown out. The filtrates were mixed, the solvent was removed on a rotary vacuum evaporator and then subjected to column chromatography (silica gel H: 300-400 mesh; petroleum ether/ethyl acetate=5:1 vol./vol.), obtaining 4.4 g of white solid (yield: 81%).

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, Dl3) δ of 1.26 (t, J=7,14 Hz, 3H), 2,19 (s, 3H), 3.15 in (s, 3H), 4,23 (q, J=7,14 Hz, 2H), 4,58 (s, 2H), 5,17 (s, 1H), is 6.54 (d, J=8,44 Hz, 1H), 7,11 (dd, J=8,32 Hz, 2,28 Hz, 1H), 7,17 (d, J=2,28 Hz, 1H), 7,33-7,38 (m, 5H), 7,66 (d, J=8,56 Hz, 2H), 8,10 (d, J=8,56 Hz, 2H);13C NMR (100 MHz, CDCl3) δ 14,1, 16,1, 28,0, 50,6, 61,4, 65,4, 113,6, 118,2, 122,8, 125,5, 126,2, 126,8, 127,1, 128,2, 128,5, 128,9, 133,8, 135,2, 137,8, 140,5, 146,5, 152,6, 157,1, 168,5; MS (ESI) m/z 558,03(M+H)+.

Example 14: the connection is E-5

Using compound III-1 and II-3 as a starting material, was obtained ethyl-2-(2-ethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenyloxy)-acetate (E-5) according to the chemical method similar to the method described in Example 9. The compound obtained was a white solid with a yield of 87.3%.

The structure of the obtained compounds were described on the basis of the following data, obtained using spectroscopy the nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, DCl3) δ 1,19 {t, J=7,24 Hz, 3H), of 1.27 (t, J=7,24 Hz, 3H), to 2.67 (m, 2H), 3,20 (s, 3H), 4,24 (q, J=7.24 to Hz, 2H), 4,57 (s, 2H), 6,29 (s, 1H), for 6.81 (dd, J=8,88 Hz, is 3.08 Hz, 1H), 6,95 (d, J=is 3.08 Hz, 1H), of 7.36 was 7.45 (m, 3H), 7,52 (d, J=7,60, 2H), to 7.67 (d, J=8,76 Hz, 2H), 8,16 (d, J=8,76 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 13,9, 14,1, 23,2, 23,3, 28,3, 61,3, 66,3, 75,3, 112,5, 112,6, 112,96, 113,2, 116,5, 117,6, 118,2, 125,4, 125,9, 126,2, 127,3, 128,8, 128,96, 135,2, 135,3, 140,5, 146,4, 150,6, 151,3, 151,6, 152,8, 169,2; MS (ESI) m/z 556,29(M+H)+.

Example 15: the connection is E-6

Using compound III-1 and II-2 as a starting material, was obtained ethyl-2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenoxy)-acetate (E-6) according to the chemical method similar to the method described in Example 9. The compound obtained was a white solid with a yield of 98%.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ of 1.32 (t, J=7,02 Hz, 3H), 2,24 (s, 3H), of 3.25 (s, 3H), 4,29 (q, J=7,02 Hz, 2H), 4,59 (s, 2H), 6.35mm (s, 1H), 6,56 to 6.75 (m, 1H), to 6.88 (d, J=2,95 Hz, 1H), 6,95 (d, J=8,94 Hz, 1H), 7,42-of 7.55(m, 3H), 7,58 (d, J=7,49 Hz, 2H), 7,72 (d, J=8,69 Hz, 2H), 8,23 (d, J=8,56 Hz, 2H);13With NMR (100 MHz, DCl3) δ 14,1, 16,7, 28,2, 61,3,65,96,75,1, 112,1, 112,8, 113,9, 115,4, 117,8, 118,2, 118,5, 125,5, 125,8, 126,2, 126,9, 127,2, 128,8, 129,0, 135,3, 140,5, 146,4, 149,9, 152,7, 169,1; MS (ESI) m/z 541,9(M+H+); 558,9 (M+NH4+).

Example 16: Getting the connections-7

Getting ethyl-2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1 H-L,2,4-triazolyl))-benzylthio)-phenoxy)-acetate (E-7)

In a three-neck flask with a volume of 250 ml to stir the mixture of allotetraploid lithium (LiAlH4, 0.8 g, 21 mmol) and tetrahydrofuran (30 ml) at 0°C. (cooling with cold water) was added dropwise a solution of 3-methyl-4-hydroxyphenylethylamine acid (1.1 g, 6.6 mmol) in tetrahydrofuran (THF 30 ml). After 30 min stirring at 0°C and following 2 hours of stirring at room temperature the reaction was stopped by addition of crushed ice in vodoledyanym bath. The pH value of the mixture was brought up to 3-4 by adding 6 N. hydrochloric acid, and then extracted the aqueous phase with ethyl acetate. The combined organic layer was washed with a saturated solution of sodium chloride (2 X 100 ml), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuum, obtaining the crude product 3-methyl-4-hydroxybenzothiazole (yellow liquid).

In another odnogolosy flask of 250 ml to a mixed solution of the obtained 3-methyl-4-hydroxybenzothiazole in acetonitrile (30 ml) was added 3-(1'-bromobenzyl)-4-methyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-triazole-5(4H)-he (III-1, 2.5 g, the 6.06 mmol), acetonitrile (30 ml), N,N-dimethylaminopyridine (DMAP, 0.1 g, 0.82 mmol) and potassium carbonate (K2CO3, 0.5 g, x 6.15 mmol). After stirring the reaction mixture at room temperature for 5 hours was added potassium carbonate (K2CO3, 1.6 g, 11.6 mmol) and ethylbromoacetate (1.2 ml, or 10.3 mmol) and the reaction mixture was stirred at room temperature over the next 8 hours. After completion of the reaction the mixture was filtered. The filter cake was washed with ethyl acetate (3 X 50 ml), then was thrown out. The filtrates were mixed, the solvent was removed on a rotary vacuum evaporator and then subjected to column chromatography (silica gel H: 300-400 mesh; petroleum ether/ethyl acetate=8:1-5:1.vol.), obtaining 2.0 g of a white solid substance (yield: 59%).

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ of 1.27 (t, J=7.18 in Hz, 3H), 2,31 (s, 3H), of 3.13 (s, 3H), 4,24 (q, J=7.18 in Hz, 2H), 4,55 (s, 2H), 5,09 (s, 1H), 6,59 (dd, J=8,56 Hz, 2,88 Hz, 1H), 6,78, (d, J=2,88 Hz, 1 H), 7,24 (d, J=8,68 Hz, 1H), 7,30-7,34 (m, 4H), 7,66 (d, J=8,66 Hz, 2H), 8,10 (d, J=8,66 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 14,1, 20,9, 28,1, 49,8, 61,5, 65,2, 112,6, 117,0, 118,2, 123,1, 125,5, 126,2, 126,8, 127,1, 128,0, 128,5, 128,9, 135,1, 137,9, 140,5, 144,5, 146,4, 152,5, 168,5; MS (ESI) m/z 558,05 (M+H)+.

Example 17: Getting connection E-8

Obtain ethyl 2-(2-methyl-4-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl)-methylthio)-phenoxy)-acetate (E-8)

In a three-neck flask with a volume of 250 ml to stir the mixture of allotetraploid lithium (LiAlH4with 1.0 g of 26.3 mmol) and tetrahydrofuran (30 ml) at 0°C was added dropwise a solution of 3-methyl-4-hydroxyphenylethylamine acid (1,38 g, 8,35 mmol) in tetrahydrofuran (20 ml). After 30 min stirring at 0°C. the reaction mixture was allowed to warm to room temperature and was stirred for the next 2 hours at room temperature. Then the reaction was stopped by adding ethanol (10 ml). The pH value of the mixture was brought up to 3-4 by adding 6 M hydrochloric acid at Toledano bath, and then the aqueous phase is extracted with ethyl acetate (3 X 80 ml). The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, leaving the air during the day and was purified by the method of column chromatography (silica gel H: 300-400 mesh; petroleum ether/ethyl acetate=5:1 vol./vol.), obtaining 1.6 g associated connection 3-methyl-4-hydroxybenzothiazole (yellow gel-like liquid, yield: 68.8 per cent).

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ 2,2 (s, 3H), to 5.35 (s, 1H), 6,69 (d, J=8,28 Hz, 1H), 7,18 (dd, J=8,23 Hz, of 2.23 Hz, 1H), 7,24 (d, J=2,24 Hz, 1H);13C NMR (100 MHz, CDCl3) δ 15,7,115,5, 125,0, 128,3, 130,2, 134,0, 154,4; MS (ESI) m/z 278,33 (M+H+).

In odnogolosy flask with a volume of 150 ml to stir a solution of 3-methyl-4-hydroxybenzothiazole (1.6 g, USD 5.76 mmol) in acetonitrile (60 ml) was added ethylbromoacetate (1,4 ml of 60.7 mmol) and potassium carbonate (K2CO3, 1.6 g, 11.6 mmol). After stirring the reaction mixture at room temperature for 12 hours, the reaction mixture was diluted by adding 60 ml of ethyl acetate, filtered and evaporated, receiving the remainder. This residue was purified by the method of column chromatography (silica gel H: 300-400 mesh; petroleum ether/ethyl acetate=5:1 vol./vol.), obtaining 2.0 g of pale yellow gel-like liquid (yield: 77.5%of).

In a three-neck flask with a volume of 150 ml to mix the solution of the above product (2.0 g, of 4.44 mmol) in ethanol (15 ml) was added water (15 ml) and concentrated hydrochloride (7 ml). Slowly add the powdered zinc (10 g, 153 mmol) under stirring. After the addition the reaction mixture was stirred at room temperature for 30 min and then was extracted with dichloromethane (3 X 60 ml). The organic phases were mixed, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, obtaining a pale yellow liquid.

In odnogolosy flask with a volume of 150 ml to mix the solution of the above crude product in 30 ml of acetonitrile was added 30 is l 3-(1-bromobenzyl)-4-methyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-triazole-5(4H)-it III-3 (1.3 g, 3.9 mmol) and potassium carbonate (K2CO3, 3.4 g, 24.6 mmol). The resulting reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was diluted by adding 50 ml of ethyl acetate and filtered. The filtrate was concentrated under reduced pressure and subjected to column chromatography (silica gel H: 300-400 mesh; petroleum ether/ethyl acetate=3:1 vol./vol.), obtaining 1.7 g of white solids (yield: 91%).

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, DCl3) δ 1,25 (t, J=7,12 Hz, 3H), 2,22 (s, 3H), 3,3 7 (s, 3H), a 3.87 (s, 2H), is 4.21 (q, J=7,12 Hz, 2H), 4,58 (s, 2H), return of 6.58 (d, J=of 8.37 Hz, 1H), 7,16 (dd, J=of 8.37 Hz, of 2.34 Hz, 1H), 7.23 percent (d, J=2,34 Hz, 1H), 7,63 (d, J=to 8.57 Hz, 2H), 7,98 (d, J=to 8.57 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 14,1, 16,1, 27,8, 31,3, 61,3, 65,5, 111,6, 118,1, 122,7, 123,5, 125,4, 126,1, 128,1, 128,6, 132,4, 136,3, 140,5, 144,6, 152,4, 156,8, 168,5; MS (ESI) m/z 482,49 (M+N)+.

Example 18: the connection F-9

Using the compound III-3 and II-2 as a starting material, was obtained ethyl-2-(2-methyl-4-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl)-methoxy)-phenoxy)-acetate (E-9) according to the chemical method similar to the method described in Example 9. The compound obtained was a white solid with a yield of 73.5%.

is the structure of the obtained compound was described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, DCl3) δ of 1.32 (t, J=7,14 Hz, 3H), of 2.33 (s, 3H), of 3.45 (s, 3H), 4,28 (q, J=7,14 Hz, 2H), 4,63 (s, 2H), free 5.01 (s, 2H), of 6.71 (d, J=cent to 8.85 Hz, 1 H), 6,8 (dd, J=cent to 8.85 Hz, is 3.08 Hz, 1H), to 6.88 (d, J=is 3.08 Hz, 1H), of 7.70 (d, J=8,56 Hz, 2H), 8,17 (d, J=8,55 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 14,1, 16,2, 61,2, 61,9, 66,4, 112,0, 112,7, 117,7, 118,2, 118,3, 126,2, 126,3, 129,3, 140,5, 143,9, 151,6, 151,8, 152,4, 169,1; MS (ESI) m/z 464,39 (M-1), 466,48 (M+H)+.

Example 19: Obtaining connection E-10

Using compound III-1 and II-6 as a starting material, was obtained ethyl-2-(2,5-dimethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetate (E-10) according to the chemical method similar to the method described in Example 9. The compound obtained was a yellow gel-like liquid with access to 72.2%.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ of 1.29 (t, J=7,16 Hz, 3H), 2,32 (s, 3H), is 2.37 (s, 3H), 3,18 (s, 3H), 3,51 (s, 2H), 4,25 (q, J=7,16 Hz, 2H), to 6.39 (s, 1H), to 6.88 (s, 1H), 7,31 (s, 1H), 7,39-7,52 (m, 5H), of 7.69 (d, J=8,67 Hz, 2H), 8,16 (d, J=8,67 Hz, 2H);13C NMR (100 MHz, CDCl3) δ 16,0, 20,7, 28,2, 37,2, 74,4, 114,7, 118,2, 125,4, 125,6, 125,7, 126,3, 128,9, 129,1, 134,9, 135,7, 139,5, 140,4, 146,1, 152,7, 155,0, 168,7; MS (ESI) m/z 573,07 (M+H)+.

Example 20: Obtaining connection F-11

Using with the organisations III-3 and II-4 as starting materials, received ethyl-2-(3-methyl-4-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl)-methoxy)-phenylthio)-acetate (E-11) according to the chemical method similar to the method described in Example 9. The compound obtained was a pale yellow solid with a yield of 69.7 percent.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, DCl3) δ of 1.32 (t, J=7,14 Hz, 3H), 2,19 (s, 3H), 3.43 points (s, 3H), 3,55 (s, 2H), 4,28 (q, J=7,14 Hz, 2H), to 5.03 (s, 2H), 6,91 (d, J=8,77 Hz, 3H), 7,29-to 7.32 (m, 2H), to 7.67 (d, J=8,66 Hz, 2H), 8,12 (d, J=8,66 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 16,1, 28,1, 38,1, 61,4, 111,8, 118,3, 126,2, 126,3, 127,2, 127,5, 127,9, 130,8, 134,8, 140,3, 143,6, 152,5, 155,4, 169,2; MS (ESI) m/z 481,23 (M-1)-, 482,34 (M)-, 483,35 (M+H)-.

Example 21: the connection F-12

Obtain ethyl 2-(2,5-dimethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate(E-12)

In a three-neck flask with a volume of 250 ml to stir the mixture of allotetraploid lithium (LiAlH4with 1.0 g of 26.3 mmol) and tetrahydrofuran (40 ml) at 0°C was added dropwise a solution of 2,5-dimethyl-4-hydroxyphenylethylamine acid (1.2 g, 6.7 mmol) in 20 ml of tetrahydrofuran. After 30 min stirring at 0°C. the mixture was allowed to warm to room temperature and stirred is in the next 1 hour at room temperature. The reaction was stopped by adding ethanol (10 ml). The pH value of the mixture was brought up to 3-4 by adding 6 M hydrochloric acid at Toledano bath, and then the aqueous phase is extracted with ethyl acetate (3 X 60 ml). The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuum, obtaining the crude product is 2,5-dimethyl-4-hydroxybenzothiazole (yellow liquid).

In another odnogolosy flask of 250 ml to a mixed solution of the obtained crude product of 2,5-dimethyl-4-hydroxybenzothiazole in acetonitrile (60 ml) was added 3-(1-bromobenzyl)-4-methyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-triazole-5(4H)-he (111-1) (1.6 g, 3.88 mmol) and potassium carbonate (K2CO3, 0.54 g, 3.9 mmol). After stirring the reaction mixture at room temperature for 4 hours was added ethylbromoacetate (1.8 ml, of 15.5 mmol) and potassium carbonate (K2CO3, 0.54 g, 3.9 mmol). The mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was diluted with 200 ml ethyl acetate and filtered. The filtrate is evaporated, obtaining a residue that was purified by the method of column chromatography (silica gel H: 300-400 mesh; petroleum ether/ethyl acetate=5:1 vol./vol.), obtaining 1.1 g of a yellow gel-like fluid (output in three stages: 50%).

The structure of the obtained compounds were described on the basis of the following the data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, DCl3) δ 1.28 (in t J=7,16 Hz, 3H), 2,12 (s, 3H), of 2.25 (s, 3H), of 3.13 (s, 3H), 4,25 (J=7,16 Hz, 2H), 4,59 (s, 2H), 5,08 (s, 1H), 6,51 (s, 1H), 7,13 (s, 1H), 7,27-35 (m, 5H), 7,66 (d, J=8,75 Hz, 2H), 8,10 (d, J=rate of 8.75 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 14,1, 15,5, 20,7, 28,0, 50,0, 61,3, 65,5, 113,1, 117,9, 118,2, 122,4, 125,9, 126,1, 126,2, 126,8, 128,1, 128,4, 128,8, 129,1, 135,2, 138,9, 140,5, 141,5, 146,5, 152,6, 157,0, 168,6; MS (ESI) m/z 588,31 (M+NH4+).

Example 22: connection F-13

Getting ethyl-2-methyl-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1 -(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate (E-13)

In a three-neck flask with a volume of 250 ml to stir the mixture of allotetraploid lithium (LiAlH4, 1.0 g of 26.4 mmol) and tetrahydrofuran (THF 30 ml) was added dropwise a solution of 3-methyl-4-hydroxyphenylethylamine acid (1,38 g, 8,35 mmol) in 20 ml of tetrahydrofuran at 0°C. After 30 min stirring at 0°C. the reaction mixture was allowed to warm to room temperature and was stirred for the next 2 hours at room temperature. Then the reaction was stopped by adding ethanol (10 ml). The pH value of the mixture was brought up to 3-4 by adding 6 N. hydrochloric acid on Toledano bath, and then the aqueous phase is extracted with ethyl acetate (3 X 80 ml). The combined organic layer was dried over anhydrous self the volume of magnesium, was filtered, concentrated under reduced pressure and was purified by the method of column chromatography (silica gel H: 300-400 mesh; petroleum ether/ethyl acetate=5:1 vol./vol.), getting 1.44 g of the disulfide (yellow gel-like liquid, yield: 62%).

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ 2,2 (s, 3H), to 5.35 (s, 1H), 6,69 (d, J=8,28 Hz, 1H), 7,18 (dd, J=8,23 Hz, of 2.23 Hz, 1H), 7,24 (d, J=2,24 Hz, 1H);13With NMR (100 MHz, CDCl3) δ 15,7, 115,5, 125,0, 128,3, 130,2, 134,0, 154,4; MS (ESI) m/z 278,33 (M+H)+.

In odnogolosy flask of 250 ml to a mixed solution of the obtained crude product (0.7 g, at 2.59 mmol) in acetonitrile (60 ml) was added methyl-2-bromopropionate (0.7 ml, 6.0 mmol) and potassium carbonate (K2CO3, 2 g, 14.5 mmol). The resulting mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (100 ml) and filtered. The combined solution is evaporated under reduced pressure, obtaining a residue that was purified by chromatography (silica gel H: 300-400 mesh; petroleum spir/ethyl acetate=5:1 vol./vol.), receiving 1.0 g of a yellow gel-like liquid (yield: 86%).

The structure of the obtained compounds were described on the basis of the following data, obtained using a spectroscope and nuclear magnetic resonance:

1H NMR (400 MHz, CDCl3) δ and 1.63 (d, J=6,84 Hz, 1H); of 2.34 (s, 3H), of 3.75 (s, 3H), 4,73 (d, J=6,84 Hz, 1H), 6,57-of 6.61 (m, 1H), 7,19-7,27 (m, 2H).

In odnogolosy flask of 250 ml to mix the solution of the above product(1.0 g, 2.22 mmol) in ethanol (15 ml) was added 15 ml of water and 5 ml of concentrated hydrochloric acid. Slowly add the powdered zinc (10 g, 153 mmol). After the addition the reaction mixture was stirred at room temperature for 30 min and then was extracted with dichloromethane (3 X 50 ml). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, obtaining a pale yellow liquid.

In odnogolosy flask with a volume of 150 ml to mix the solution of the above crude product in 30 ml of acetonitrile was added a solution of 3-(1-bromobenzyl)-4-methyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-triazole-5(4H)-she (111-1) (1.8 g, 4,36 mmol) in acetonitrile (30 ml) and potassium carbonate (K2CO3, 2.5 g of 18.1 mmol). The reaction mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was diluted by adding 100 ml of ethyl acetate, filtered, concentrated under reduced pressure and subjected to column chromatography (silica gel H:300-400 mesh; petroleum ether/ethyl acetate=5:1 vol./vol.), receiving 1.2 g E-13 (a couple of diastereoisomers) (pale yellow heliobar is knowing the liquid, yield: 50%).

The structure of the obtained compounds were described on the basis of the following data, obtained using spectroscopy nuclear magnetic resonance:

1H NMR (400 MHz, CDCl3) δ of 1.61 (d, J=6,84 Hz, 1H); to 2.18 (s, 3H), 3.15 in (s, 3H), 3,70 (d, J=12,61 Hz, 3H); 4,70 (q, J=6,82 Hz, 1H); by 5.18 (s, 1H); 6,51 (d, J=8,46 Hz, 1H), 7,0-7,11 (m, 1H), 7,10-to 7.15 (m, 1H), 7,34-7,37 (m, 5H), to 7.67 (d, J=a total of 8.74 Hz, 2H), 8,11 (d, J=a total of 8.74 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 16,1, 18,5, 28,1, 50,6, 52,2, 72,7, 112,1, 118,2, 123,0, 125,5, 126,2, 126,8, 127,1, 128,2, 128,5, 128,9, 133,8, 135,2, 137,7, 140,6, 146,5, 152,6, 156,9, 172,2.

Example 23: Obtaining connection E-14

Getting ethyl-2-(2-ethyl-4-(1 -(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate (E-14)

In a three-neck flask with a volume of 500 ml was consistently added about-ethylphenol (5 g, of 40.9 mmol), sodium thiocyanate (10 g, 123,3 mmol), sodium bromide (4.3 g, 41,79 mmol) and methanol (100 ml). The mixture was cooled to 0°C in an ice bath and then was added dropwise a solution of bromine (2.6 ml, and 50.6 mmol) in methanol (50 ml). After 1 hour stirring at 0 °C. the mixture was allowed to warm to room temperature and stirred over the next 4 hours at room temperature. To the reaction mixture was slowly added to 200 ml of a saturated aqueous solution of sodium bicarbonate and stirred for 10 minutes the Mixture was extracted with ethyl acetate (2 X 300 ml). The combined organic layer of vysushivaya anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, obtaining a reddish-brown viscous liquid. Column chromatography was performed (silica gel H: 300-400 mesh; petroleum ether/ethyl acetate=5:1 vol./vol.), obtaining 6.8 g of 3-ethyl-4-hydroxy-phenylthieno acid (reddish-brown viscous liquid, yield: 93%).

The structure of the obtained compounds were described on the basis of the following data, obtained using spectroscopy nuclear magnetic resonance:

1H NMR (400 MHz, DMSO) δ 1,25 (t J=7,28 Hz, 3H), of 2.64 (q, J=7,53 Hz, 2H), 5,46 (s, 1 H), to 6.80 (d, J=at 8.36 Hz, 1 H), 7,28 (dd, J=at 8.36 Hz, 2,52 Hz, 1 H), 7,34 (d, J=2,48,36 Hz, 1 H).

In a three-neck flask with a volume of 150 ml to stir the mixture of allotetraploid lithium (LiAlH4, 1.0 g, 26,2 mmol) and tetrahydrofuran (40 ml) was added dropwise a solution of 3-ethyl-4-hydroxyphenylethylamine acid (1.3 g, of 7.25 mmol) in 20 ml of tetrahydrofuran at 0°C. After 30 min stirring at 0°C. the reaction mixture was allowed to warm to room temperature and was stirred for the next 1 hour at room temperature. The reaction was stopped by adding ethanol (10 ml). The pH value of the mixture was brought up to 3-4 by adding 6 N. hydrochloric acid on Toledano bath, and then the aqueous phase is extracted with ethyl acetate (3 X 60 ml). The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuum, receiving untreated the i.i.d. product 3-ethyl-4-hydroxybenzothiazole (yellow liquid).

In another odnogolosy flask with a volume of 150 ml to a mixed solution of the obtained crude product 3-ethyl-4-hydroxybenzothiazole in acetonitrile (20 ml) was added potassium carbonate (K2CO3with 1.0 g of 7.23 mmol) followed by the addition dropwise of a solution of 3-(1'-bromobenzyl)-4-methyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-triazole-5(4H)-she (111-1) (1.6 g, 3.88 mmol) in 20 ml of acetonitrile. After stirring the mixture for 6 hours at room temperature was added potassium carbonate (K2CO3with 1.0 g of 7.23 mmol) and ethylbromoacetate (1.6 ml, of 13.8 mmol). The mixture was stirred over the next 8 h at the same temperature. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (50 ml) and filtered. The filtrate is evaporated to a residue, which was purified by the method of column chromatography (silica gel H:300-400 mesh; petroleum ether/ethyl acetate=5:1 vol./vol.), receiving 1,3 g E-14 (yellow gel-like substance, out in three stages: 58,6%).

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, DMSO) δ 1,09 (t J=of 7.48 Hz, 3H), 1.26 in (t J=7,28 Hz, 3H), at 2.59 (q, J=7,52 Hz, 2H), 3.15 in (s, 3H), 4,22 (q, J=7,20 Hz, 2H), 4,58 (s, 2H), 5,18 (s, 1H), 6,56 (d, J=to 8.20 Hz, 1H), 7,15 (dd, J=8,32 Hz, 2,28 Hz, 1H), 7,31 and 7.36 (m, 5H), 7,66 (d, J=8,72 Hz, 1H), 8,11 (d, J=charged 8.52 Hz, 1H);13With NMR (100 MHz, CDCl3) δ 13,7, 14,1, 23,0, 28,1, 50,6 61,3, 65,4, 111,5, 118,2, 123,3, 126,1, 126,8, 127,1, 128,2, 128,5, 128,9, 133,8, 134,3, 135,2, 136,2, 140,5, 146,5, 152,6, 156,7, 168,5; MS (ESI) m/z 572,14 (M+H+); 589,1 (M+NH4+).

Example 24: Getting connection E-15

Getting ethyl-2,2-dimethyl-2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1 -(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetate (E-15)

In odnogolosy flask with a volume of 150 ml to stir a solution of 3-methyl-4-hydroxybenzothiazole (0.52 g, of 1.87 mmol) in acetonitrile (30 ml) was added bromide (III-1 (1,53 g, 3,71 mmol) and potassium carbonate (K2CO3, 2.5 g of 18.1 mmol). The mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (100 ml) and filtered. The filtrate is evaporated to a residue, which was subjected to column chromatography (silica gel H:300-400 mesh; petroleum ether/ethyl acetate=5:1 vol./vol.), getting 1.4 g of pale yellow gel-like liquid.

In a three-neck flask with a volume of 150 ml to mix the solution of the above product(1.4 g, 1.48 mmol) in ethanol (15 ml) was added 15 ml of water and 5 ml of concentrated hydrochloric acid. Slowly add the powdered zinc (10 g, 153 mmol). After the addition the reaction mixture was stirred at room temperature for 30 min and then was extracted with dichloromethane (3 X 50 ml). The organic phases were combined, dried over be the water, magnesium sulfate, was filtered and concentrated under reduced pressure, obtaining a pale yellow liquid.

In odnogolosy flask with a volume of 150 ml to mix the solution of the above crude product in acetonitrile (30 ml) was added ethyl-2-polisaprobical (3 ml, a 20.2 mmol) in acetonitrile (30 ml) and potassium carbonate (K2CO3, 2.0 g, 14.4 mmol). The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (100 ml) and filtered. The filtrate is evaporated to a residue, which was purified by the method of column chromatography (silica gel H:300-400 mesh; petroleum ether/ethyl acetate=5:1 vol./vol.), getting 0,58 g E-15 (colorless gel-like substance, out in three stages: 26,6%).

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ 1,19 (t, J=7,20 Hz, 3H), 1,45 (s, 6H), is 2.37 (s, 3H), 3,20 (s, 3H), 4,10 (q, J=7,20 Hz, 2H), 6,41 (s, 1H), 6,94 (d, J=charged 8.52 Hz, 1H), 7,25 (dd, J=charged 8.52 Hz, 1.8 Hz, 1H), 7,32 (d, J=1.8 Hz, 1H), 7,39-7,52 (m, 5H), of 7.69 (d, J=charged 8.52 Hz, 2H), 8,17 (d, J=charged 8.52 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 14,1, 16,4, 25,8, 28,2, 50,9, 61,1, 74,5, 112,4, 118,2, 124,2, 125,7, 126,2, 126,3, 127,4, 129,0, 129,1, 134,7, 136,1, 139,9, 140,4, 145,9, 152,6, 156,2, 173,9; MS (ESI) m/z 584,71 (M-H)-.

Example 25: connection F-16

Getting ethyl-2,2-dimethyl-2-(3-methyl-4-(1-(2-(4-methyl-5-the CSR-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate (E-16)

In a three-neck flask with a volume of 250 ml to stir the mixture of allotetraploid lithium (LiAlH4, 2.0 g, and 52.7 mmol) and tetrahydrofuran (40 ml) was added dropwise a solution of 3-methyl-4-hydroxyphenylethylamine acid (2.5 g, 15,13) in tetrahydrofuran (30 ml) at 0°C. After 30 min stirring at 0°C. the reaction mixture was left to warm to room temperature and was stirred for the next 2 hours at room temperature. Then the reaction was stopped by adding ethanol (10 ml). The pH value of the mixture was brought up to 3-4 by adding 6 M hydrochloric acid at Toledano bath, and then the aqueous phase is extracted with ethyl acetate (3 X 100 ml). The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuum, obtaining a yellow liquid.

In odnogolosy flask of 250 ml to stir the solution obtained yellow liquid in acetonitrile (30 ml) was added bromide (III-1 (3.2 g, 7,76 mmol) and potassium carbonate (K2CO3and 1.15 g, 8,32 mmol). The mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (100 ml) and filtered. The filtrate is evaporated to a residue, which was subjected to column chromatography (silica gel H:300-400 mesh; petroleum ether/ethyl acetate=5:1 vol./vol.), getting 3.6 g yellow Heliodor the second liquid.

In odnogolosy flask of 250 ml to mix the solution of the above product (2.2 g, of 4.67 mmol) in acetonitrile (60 ml) was added ethyl-2-polisaprobical (2 ml, 13.5 mmol) and potassium carbonate (K2CO3) (1.5 g, to 10.8 mmol). The reaction mixture was heated under reflux for 36 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (100 ml) and filtered. The filtrate is evaporated to a residue, which was purified by the method of column chromatography (silica gel H:300-400 mesh; petroleum ether/ethyl acetate=5:1 vol./vol.), getting 1,0 g E-16 (yellow gel-like substance, out in three stages: 44%).

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ of 1.20 (t, J=7,14 Hz, 3H), of 1.55 (d, J=5,76 Hz, 6N)by 2.13 (s, 3H), 3.15 in (s, 3H), 4,18 (q, J=7,14 Hz, 2H), 5,19 (s, 1H), of 6.49 (d, J=8,46 Hz, 1H), 7,03 (dd, J=8,46 Hz, a 2.36 Hz, 1H), 7,16 (d, J=2,36 Hz, 1H), 7,32-7,37 (m, 5H), 7,66 (d, J=a total of 8.74 Hz, 2H), 8,10 (d, J=a total of 8.74 Hz, 2H); MS (ESI) m/z 586,39(M+H+).

Example 26: Obtaining connection E-17

Using the compound (II-1-2 and 11-4 as a starting material, was obtained ethyl-2-(3-methyl-4-(1-(3-(4-n-butyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1 H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetate (E-17) according to the chemical procedure similar to that described in Example 9. The compound obtained before taulealo a pale yellow solid with a yield of 81.2 per cent.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ 0,76 (t, J=7,30 Hz, 3H), 0,92-1,02 (m, 1H), 1,03-of 1.29 (m, 5H), of 1.35 to 1.48(m, 1H), is 2.37 (s, 3H), 3,47 of 3.56 (m, 3H), 3,63-to 3.67 (m, 1H), 4,11-4,16 (m, 2H), 6,38 (s, 1H), 6,97 (d, J=8,59 Hz, 1H), 7,24 (dd, J=to 8.57 Hz, 2.25 Hz, 1H), 7,34 (d, J=2,04 Hz, 1H), 7,39-7,52 (m, 5H), of 7.69 (d, J=8,73 Hz, 2H), 8,19 (d, J=8,56 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 13,5, 14,1, 16,5, 19,9, 30,1, 38,0, 42,4, 61,4, 74,7, 113,1, 118,2, 125,6, 126,2, 126,3, 128,0, 128,9, 129,1, 130,8, 134,9, 135,3, 140,5, 145,9, 152,6, 155,0, 169,8; MS (ESI) m/z 600,0 (M)+, 601,2 (M+1)+, 602,2 (M+2)+, 603,2 (M+3)+.

Example 27: Obtaining connection F-18

Getting ethyl 2,2-dimethyl-2-(3-methyl-4-(1-(2-(4-n-butyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate (E-18)

In a three-neck flask with a volume of 250 ml to stir the mixture of allotetraploid lithium (LiAlH4, 1.2 g, of 31.6 mmol) and tetrahydrofuran (50 ml) was added dropwise a solution of 3-methyl-4-hydroxyphenylethylamine acid (1.4 g of 8.47 mmol) in tetrahydrofuran (20 ml) at 0°C. After 30 min stirring at 0°C. the mixture was left to warm to room temperature and was stirred for the next 2 hours at room temperature. The reaction was stopped by adding ethanol (10 ml). The pH value of the mixture was brought up to 3-4 by adding 6 N. hydrochloric to the slot on Toledano bath, and then the aqueous phase is extracted with ethyl acetate (3 X 100 ml). The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuum, obtaining yellow liquid

In odnogolosy flask of 250 ml to stir the solution obtained yellow liquid in acetonitrile (60 ml) was added bromide (III-2 (1.4 g, is 3.08 mmol) and potassium carbonate (K2CO3, 0,42 g, 3.04 from mmol). After stirring the reaction mixture at room temperature for 6 hours was added ethyl-2-polisaprobical (6 ml, 40,5 mmol) in acetonitrile (10 ml) and potassium carbonate (K2CO3, 2.4 g, to 17.4 mmol). The mixture was heated under reflux for 36 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (100 ml) and filtered. The filtrate is evaporated to a residue, which was subjected to column chromatography (silica gel H:300-400 mesh; petroleum ether/ethyl acetate=10:1 vol./vol.), getting 1.52 g E-18 (yellow gel-like substance, out in three stages: 28,6%).

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ 0,80 {t, J=7,30 Hz, 3H), 1,16-of 1.36(m, 7H), and 1.56 (d, J=2,84 Hz, 6H), 2,12 (s, 3H), 3,48 is 3.57 (m, 2H), 4,17-to 4.23 (m, 2H), 5,10 (s, 1H), 6.48 in (d, J=8,44 Hz, 1H), 7,01 (dd, J=8,46 Hz, 2,28 Hz, 1H), 7,17 (d, J=of 2.08 Hz, 1H), 7,30-to 7.35 (m, 5H), to 7.67 (d, J=8,81 Hz,2H), of 8.15 (d, J=8,66 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 13,5, 14,0, 16,5, 19,8, 25,3, 29,7, 30,4, 41,9, 50,3, 61,5, 79,2, 116,4, 118,1, 124,5, 126,1, 128,4, 128,5, 128,8, 130,3, 133,3, 135,9, 137,8, 140,6, 146,4, 152,3, 154,9, 174,1; MS (ESI) m/z 626,1 (M-2)-, 627,1 (M-1)-, 628,1 (M)-.

Example 28: Obtaining connection E-19

Getting ethyl-2-(2,5-dimethyl-4-(1-(3-(4-n-butyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate(E-19)

In a three-neck flask with a volume of 250 ml to stir the mixture of allotetraploid lithium (LiAlH4with 1.0 g of 26.3 mmol) and tetrahydrofuran (40 ml) was added dropwise a solution of 2,5-dimethyl-4-hydroxyphenylethylamine acid (1,02 g, 5,69 mmol) in tetrahydrofuran (20 ml) at 0°C. After 30 min stirring at 0°C. the reaction mixture was left to warm to room temperature and was stirred for the next 1 hour at room temperature. The reaction was stopped by adding ethanol (10 ml). The pH value of the mixture was brought up to 3-4 by adding 6 M hydrochloric acid at Toledano bath, and then the aqueous phase is extracted with ethyl acetate (3 X 60 ml). The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuum, obtaining the crude product is 2,5-dimethyl-4-hydroxybenzothiazole (yellow liquid).

In odnogolosy flask of 250 ml to stir a solution of the crude about the ukta 2,5-dimethyl-4-hydroxybenzothiazole in acetonitrile (60 ml) was added 3-(1'-bromobenzyl)-4-n-butyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-triazole-5(4H)-III-2 (1.1 g, to 2.42 mmol) and potassium carbonate (K2CO3, 0.35 g, 2,35 mmol). After stirring the reaction mixture at room temperature for 4 hours was added ethylbromoacetate (1.8 ml, of 15.5 mmol) and potassium carbonate (K2CO3, 1.5 g, and 10.8 mmol), and then the reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (200 ml) and filtered. The filtrate is evaporated in vacuo to a residue, which was subjected to column chromatography (silica gel H:300-400 mesh; petroleum ether/ethyl acetate=8:1 vol./vol.), getting 0,8 g E-19 (yellow gel-like substance, out in three stages: 22,9%).

The structure of the obtained compounds were described on the basis of the following data, obtained using spectroscopy nuclear magnetic resonance:

1H NMR (400 MHz, CDCl3) δ 0,80 (t, J=7,26 Hz, 3H), of 1.18 and 1.33 (m, 7H), to 2.13 (s, 3H), 2,22 (s, 3H), 3,50-to 3.52 (m, 2H), 4,23-the 4.29 (m, 2H), 4,59 (s, 2H), free 5.01 (s, 1H), 6,50 (s, 1H), 7,13 (s, 1H), 7,30-to 7.32 (m, 5H), to 7.68 (d, J=8,64 Hz, 2H), 8,16 (d, J=charged 8.52 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 13,5, 14,2, 15,5, 19,8, 20,8, 29,7, 30,4, 41,8, 49,7, 61,4, 65,5, 112,7, 118,1, 122,7, 125,8, 126,2, 128,3, 128,4, 128,8, 135,9, 139,0, 140,6, 141,6, 146,5, 152,3, 156,9, 168,7.

Obtaining the compound (I) (acid):

Example 29: obtain the compounds a-1

Obtaining 2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenoxy)-acetic acid (a-1).

To stir process is the ethyl-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenoxyacetate (28 g, to 51.8 mmol) in dichloromethane (50 ml) and ethanol (50 ml) was added 50 ml of an aqueous solution of sodium hydroxide (10 g, 250 mmol). The reaction mixture was stirred for 12 hours at room temperature. After completion of the reaction the pH value of the mixture was brought up to 2-3 by adding 6 N. hydrochloric acid. The resulting mixture was extracted with dichloromethane (3 X 100 ml). The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to a residue. The residue was purified by the method of column chromatography (silica gel H:300-400 mesh; petroleum ether/ethyl acetate=4:1→1:1 vol./vol.), getting 18,2 m a-1 in the form of a white solid (yield: 68.5 per cent).

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ to 2.29 (s, 3H), of 3.25 (s, 3H), to 4.62 (s, 2H), 6,32 (s, 1H), 6,69 (d, J=8,8 Hz, 1 H)6,86 (d, J=8,75 Hz, 1 H), 6,98 (s, 1 H), 7,43-to 7.50 (m, 3H), 7,55-7,58 (m, 2H), 7,72 (d, J=8,48 Hz, 2H), 8,19 (d, J=8,48 Hz, 2H);13C NMR (100 MHz, CDCl3) δ 16,4, 18,1, 28,3, 58,4, 65,9, 75,3, 112,8, 113,2, 118,3, 119,3, 122,7, 125,8, 126,2, 127,1, 128,9, 129,0, 129,4, 135,1, 140,4, 146,3, 151,5, 152,8, 173,2; MS (ESI) m/z 514,2 (M+H+); 531 (M+NH4+).

Example 30: Obtaining connection a-2

Using the compound E-2 as a starting material, was obtained 2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-ftilt is about)-acetic acid (a-2) according to the synthesis method, similar to the method described in Example 29. The compound obtained was a pale yellow solid with a yield of 46%.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ to 2.42 (s, 3H), 3,18 (s, 3H), 3,51 (s, 2H), 6,76 (s, 1H), make 6.90 (d, J=8,4 Hz, 1H), 6,98 (d, J=2.76 Hz, 1H), 7,25-7,52 (m, 5H), to 7.67 (d, J=8,67 Hz, 2H), 8,14 (d, J=8,58 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 20,9, 28,3, 36,9, 74,6, 113,7, 118,0, 118,3, 125,8, 126,2, 126,3, 126,6, 127,1, 128,98, 129,01, 134,1, 134,6, 140,4, 142,2, 145,9, 152,6, 156,8, 174,6; MS (ESI) m/z 528 (M-H)-; 529 (M-); 530 1 (M+H)-.

Example 31: the connection a-3

Using the compound E-3 as starting material, was obtained 2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid (a-3) according to the synthesis process similar to that described in Example 29. The compound obtained was a white solid with a yield of 24.2 per cent.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ is 2.41 (s, 3H), 3,24 (s, 3H), 3,61 (s, 2H), to 6.43 (s, 1H), 6,99 (d, J=8,58 Hz, 1H), 7,22-7,29 (m, 1H), 7,38 (d, J=2,28 Hz, 1H), 7,38-7,56 (m, 5H), 7,73 (d, J=8,68 Hz, 2H), 8,21 (d, J=8,68 Hz, 2H);13With NMR (100 MHz, CDCl3 ) δ 16,5, 28,2, 37,8, 74,5, 113,2, 118,2, 125,7, 126,2, 126,6, 127,1, 128,2, 128,99, 129,1, 130,8, 134,7, 140,4, 145,9, 152,7, 155,0, 174,2; MS (ESI) m/z 556,9 (M+CO)+.

Example 32: Obtaining connection a-4

Using the compound E-4 as a starting material, was obtained 2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid (a-4) according to the synthesis method similar to the method described in Example 29. The compound obtained was a white solid with a yield of 52.9%.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ to 2.18 (s, 3H), 3,13, (s, 3H), 4,63 (s, 2H), 5,19 (s, 1H), to 6.57 (d, J=8,43 Hz, 1H), 7,13 (dd, J=6,07 Hz, and 2.26 Hz, 1H), 7,18 (d, J=1.8 Hz, 1H), 7,32 and 7.36 (m, 5H), 7,66 (d, J=8,73 Hz, 2H), 8,10 (d, J=8,69 Hz, 2H);13C NMR (100 MHz, CDCl3) δ 16,0, 28,1, 50,5, 64,9, 118,3, 123,6, 126,1, 126,2, 128,2, 128,4, 128,6, 128,9, 133,9, 135,0, 137,8, 140,4, 146,5, 156,7, 172,6; MS (ESI) m/z 530 (M+H)+, 531 (M+2), 532 (M+3).

Example 33: Obtaining connection A-5

Using the compound E-5 as a starting material, was obtained 2-(2-ethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenoxy)-acetic acid (A-5) according to the synthesis method similar to the method described in Example 29. The compound obtained was a white solid with a yield of 6.8%.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ 1,19 (t, J=at 7.55 Hz, 3H), of 2.66 (q, J=7,51 Hz, 2H), 3,19 (s, 3H), to 4.62 (s, 2H), 6,29 (s, 1H), 6,66 (d, J=8,88 Hz, 1H), 6,83 (dd, J=8,87 Hz, 3,09 Hz, 1H), of 6.96 (d, J=3,09 Hz, 1H), 7,38-7,53 (m, 5H), to 7.67 (d, J=cent to 8.85 Hz, 2H), 8,15 (d, J=8,78 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 13,9, 23,2, 28,3, 65,7, 75,2, 112,6, 113,0, 117,7, 118,2, 125,8, 126,2, 127,0, 127,4, 128,8, 129,01, 135,1, 135,2, 140,4, 146,3, 150,9, 151,8, 152,8, 173,3; MS (ESI) m/z 525,9 (M-1)-, 527 (M)-, 528 (M+1)-.

Example 34: Obtaining connection A-6

Using the compound E-6 as a starting material, was obtained 2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenoxy)-acetic acid (A-6) according to the synthesis method similar to the method described in Example 29. The compound obtained was a pale yellow solid with a yield of 42.4 per cent.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ 2.40 a (s, 3H), of 3.25 (s, 3H)and 4.65 (s, 3H), 6,34 (s, 1H), 6,69 (d, J=8,86 Hz, 3.0 Hz, 1H), to 6.88 (d, J=3.0 Hz, 1H), 6,95 (d, J=8,88 Hz, 2H), 7,43-7,58 (m, 5H), 7,73 (d, J=8,63 Hz, 2H), 8,21 (d, J=8,58 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 16,8, 28,3, 65,4, 75,1, 112,2, 113,8, 118,3, 118,5, 125,7, 126,2, 126,3, 127,1, 128,9, 129,1, 1351, 140,4, 146,3, 150,2, 152,4, 152,8, 173,1; MS (ESI) m/z 513 (M)-, 512 (M-1)-, 514 (M+1)-.

Example 35: Obtaining connection a-7

Using the compound E-7 as a starting material, was obtained 2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid (a-7) according to the synthesis method similar to the method described in Example 29. The compound obtained was a pale yellow solid with a yield of 42%.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, DCl3) δ of 2.33 (s, 3H), 3,11 (s, 3H)and 4.65 (s, 2H), 5,11 (s, 1H), 6,62 (dd, J=8.53 Hz, 2,88 Hz, 1 H), 6,78 (d, J=2,88 Hz, 1 H), 7,27-7,34 (m, 5H), 7,66 (d, J=8,79 Hz, 2H), of 8.09 (d, J=8,71 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 21,0, 28,1, 49,7, 64,6, 112,6, 116,9, 118,3, 123,1, 126,2, 128,1, 128,6, 129,0, 135,0, 137,9, 140,4, 144,6, 146,5, 152,6, 158,3, 172,1; MS (ESI) m/z 530 (M)+, 531 (M+1)+.

Example 36: Obtaining compounds a-8

Using the compound E-8 as starting material, was obtained 2-(2-methyl-4-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl)-methylthio)-phenoxy)-acetic acid (a-8) according to the synthesis method similar to the method described in Example 29. The compound obtained was a white solid with a yield of 76%.

The structure obtained from the organisations described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, DMSO) δ 2,11 (s, 3H), and 3.3 (s, 3H), of 4.13 (s, 2H), and 4.68 (s, 2H), 6,80 (d, J=8,13 Hz, 1H), 7,25-7,27 (m, 2H), 7,80 (d, J=cent to 8.85 Hz, 2H), to 7.99 (d, J=8,68 Hz, 2H);13With NMR (100 MHz, DMSO) δ 16,2, 28,0, 30,4, 62,5, 65,3, 112,5, 118,1, 120,6, 123,3, 123,6, 123,9, 124,9, 125,2, 125,6, 125,9, 126,8, 127,5, 128,7, 132,1, 135,6, 141,1, 146,3, 152,3, 156,6, 170,5; MS (ESI) m/z 452,8 (M).

Example 37: Obtaining connection A-9

Using the compound E-9 as a starting material, was obtained 2-(2-methyl-4-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl)-methoxy)-phenoxy)-acetic acid (A-9) according to the synthesis method similar to the method described in Example 29. The compound obtained was a white solid with a yield of 69.2%.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ of 2.28 (s, 3H), 3.43 points (s, 3H), with 4.64 (s, 2H), 4,99 (s, 2H), 6,69 (d, J=8,40 Hz, 1 H), 6,78 (dd, J=8,82 Hz, a 3.06 Hz, 1 H), 6,85 (dd, J=2,96 Hz, 1 H), to 7.67 (d, J=at 8.60 Hz, 2H), 8,13 (d, J=8,55 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 16,4, 28,1, 61,9, 65,9, 112,1, 112,8, 118,2, 118,3, 118,4, 126,2, 126,3, 129,3, 143,9, 151,2, 152,0, 152,5, 170,4; MS (ESI) m/z 436 (M-1), 437 (M), 438 (M+1).

Example 38: Obtaining connection A-10

Using the compound E-10 as a starting material, was obtained 2-(2,5-dimethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptorelin is)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid (A-10) according to the synthesis method, similar to the method described in Example 29. The compound obtained was a white solid with the yield at 88.9%.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ is 2.09 (s, 3H), of 2.25 (s, 3H), to 3.09 (s, 3H), 4,59 (s, 2H),5,09 (s, 1H), 6,52 ('s. 1H), 7,13 (s, 1H), 7,31-7,37 (m, 5H), the 7.65 (d, J=to 8.70 Hz, 2H), of 8.09 (d, J=to 8.70 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 15,4, 20,7, 28,0, 49,7, 65,2, 113,2, 118,4, 122,7, 126,2, 126,7, 128,2, 128,5, 128,9, 135,1, 139,0, 140,4, 141,6, 146,7, 152,6, 156,8, 173,0; MS (ESI) m/z 542,42 (M-1)-, 543,54 (M)-, 544,43 (M+H)-.

Example 39: Obtaining connection A-11

Using the compound E-11 as starting material, was obtained 2-(2,5-dimethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid (A-11) according to the synthesis method similar to the method described in Example 29. The compound obtained was a white solid with a yield of 70.8%.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ 2,32 (s, 3H), is 2.37 (s, 3H), 3,18 (s, 3H), 3,51 (s, 2H), 6,39 ('s. 1H), to 6.88 (s, 1H), 7,31 (s, 1H), 7,39-7,52 (m, 5H), of 7.69 (d, J=8,67 Hz, 2H), 8,16 (d, J=8,67 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 16,0, 20,7, 282, 37,2, 74,4, 114,7, 118,2, 125,4, 125,6, 125,7, 126,3, 128,9, 129,1, 134,9, 135,7, 139,5, 140,4, 146,1, 152,7, 155,0, 174,7; MS (ESI) m/z 541,96 (M-1)-, 543,04 (M)-, 544,07 (M+H)-.

Example 40: Obtaining connection A-12

Using the compound E-12 as a starting material, was obtained 2-(3-methyl-4-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl)-methoxy)-phenylthio)-acetic acid (A-12) according to the synthesis method similar to the method described in Example 29. The compound obtained was a white solid with a yield of 47.9%.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, DCl3) δ are 2.19 (s, 3H), 3.43 points (s, 3H), 3,55 (s, 2H), to 5.03 (s, 2H), 6,91 (d, J=8,77 Hz, 3H), 7,29-to 7.32 (m, 2H), to 7.67 (d, J=8,66 Hz, 2H), 8,12 (d, J=8,66 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 16,1, 28,1, 38,1, 61,4, 111,8, 118,3, 126,2, 126,3, 127,2, 127,5, 127,9, 130,8, 134,8, 140,3, 143,6, 152,5, 155,4, 174,8; MS (ESI) m/z 452,23 (M-1)-, 453,34 (M)-, 454,35 (M+H)-.

Example 41: Obtaining connection A-13

Using the compound E-13 as a starting material, was obtained 2-methyl-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid (A-13) according to the synthesis method similar to the method described in Example 29. The compound obtained was a white solid matter what with the release of 76.9%.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ of 1.55 (d, J=6,56 Hz, 3H), 2,12 (s, 3H), 3,06 (s, 3H), to 4.62 (q, J=6,56 Hz, 1H), 5,17 (s, 1H), 6,56 (d, J=9,04 Hz, 1H), 7,14-7,17 (m, 2H), 7,31-7,38 (m, 5H), the 7.65 (d, J=8,68 Hz, 2H), of 8.09 (d, J=8,68 Hz, 2H); MS (ESI) m/z 542,24 (M-1)-, 543,26 (M)-, 544,24 (M+H)-.

Example 42: Obtaining compound A-14

Using the compound E-14 as starting material, was obtained 2-(2-ethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid (A-14) according to the synthesis method similar to the method described in Example 29. The compound obtained was a white solid with a yield of 63.1%.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ of 1.07 (t, J=7,56 Hz, 3H), of 2.56 (q, J=7,56 Hz, 2H), to 3.09 (s, 3H), 4,59 (s, 2H), 5,18 (s, 1H), 6,56 (d, J=9,04 Hz, 1H), 7,14-7,17 (m, 2H), 7,31-7,38 (m, 5H), the 7.65 (d, J=8,68 Hz, 2H), of 8.09 (d, J=8,68 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 13,7, 22,9, 28,0, 50,4, 65,0, 111,6, 118,3, 123,6, 125,4, 126,1, 126,2, 127,3, 127,5, 128,3, 128,5, 128,9, 133,9, 134,2, 135,1, 136,3, 140,4, 146,6, 152,5, 156,4, 172,7; MS (ESI) m/z 544,14 (M+H)+, 561,93(M+NH4)+.

Example 43: Obtaining compound a-15

Using the compound E-15 is the quality of the source material, received 2,2-dimethyl-2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid (a-15) according to the synthesis method similar to the method described in Example 29. The compound obtained was a white solid with a yield of 70.6 per cent.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, DCl3) δ of 1.46 (s, 6N), to 2.35 (s, 3H), 3,18 (s, 3H), 6,40 (s, 1H), of 6.96 (d, J=8,56 Hz, 1H), 7,26-7,27 (m, 1H),7,35 is 7.50 (m, 6N), to 7.67 (d, J=8,72 Hz, 2H), 8,15 (d, J=8,64 Hz, 2H);13With NMR (100 MHz, DCl3) δ 16,4, 25,4, 28,2, 50,7, 74,5, 112,6, 118,2, 123,7, 125,7, 126,2, 127,4, 128,1, 128,9, 129,1, 134,7, 136,1, 139,8, 140,4, 145,9, 152,6, 156,4, 179,1; MS (ESI) m/z 556,69 (M)+, 558,04 (M+1)+.

Example 44: Obtaining connection A-16

Using the connection F-16 as starting material, was obtained 2,2-dimethyl-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid (A-16) according to the synthesis method similar to the method described in Example 29. The compound obtained was a white solid with a yield of 52.6%.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, DCl3) δ of 1.57 (d, J=a 5.25 Hz, 6N), 2,12 (s, 3H), 3,10 (s, 3H), to 5.21 (s, 2H), 6,63 (d, J=of 8.47 Hz, 1H),7,05 (dd, J=of 8.47 Hz, to 2.06 Hz, 1H), 7,19 (d, J=1,99 Hz, 1H), 7,25-7,37 (m, 5H), the 7.65 (d, J=8,76 Hz, 2H), of 8.09 (d, J=to 8.62 Hz, 2H);13C NMR (100 MHz, DCl3) δ 16,6, 25,1, 25,3, 28,1, 50,3, 79,4, 117,3, 118,3, 124,1, 126,2, 126,3, 128,2, 128,5, 128,9, 130,8, 133,2, 134,9, 137,8, 140,4, 146,6, 152,6, 154,5, 177,4; MS (ESI) m/z 558,06 (M)+

Example 45: Obtaining connection A-17

Using the compound E-17 as a starting material, was obtained 2-(3-methyl-4-(1-(3-(4-n-butyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid (A-17) according to the synthesis method similar to the method described in Example 29. The compound obtained was a white solid with a yield of 62%.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ of 0.75 (t, J=7.29 trend Hz, 3H), equal to 1.03-1.05 (m, 1H), 1,11-of 1.18(m, 2H),1,19-of 1.26 (m, 1H), of 1.40-1.50 (m, 1H), a 2.36 (s, 3H), 3,47-of 3.53 (m, 1H), of 3.56 (s, 2H), 3,62 at 3.69 (m, 1H), 6,38 (s, 1H), 6,97 (d, J=8,58 Hz, 1H), from 7.24 (dd, J=of 8.47 Hz, with 1.92 Hz, 1H), 7,33 (d, J=1,99 Hz, 1H), 7,39-7,51 (m, 5H), to 7.68 (d, J=a total of 8.74 Hz, 2H), 8,17 (d, J=8,61 Hz, 2H);13C NMR (100 MHz, DCl3) δ 13,5, 16,6, 19,9, 37,8, 42,4, 74,7, 113,2, 118,2, 125,6, 126,2, 126,3, 128,2, 128,9, 129,1, 130,9, 134,8, 135,1, 140,4, 145,9, 152,6, 155,3, 174,4; MS (ESI) m/z 569,93 (M-2)-, 570,9 (M-1)-.

Example 46: Obtaining connection A-18

Using the compound E-18 as a starting material, in which Uchali 2,2-dimethyl-2-(2-methyl-4-(1-(3-(4-n-butyl-5-oxo-1 -(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid (A-18) according to the synthesis method, similar to the method described in Example 29. The compound obtained was a white solid with access to 61.3%.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ of 0.79 (t, J=7,26 Hz, 3H), 1,17-of 1.32(m, 6H), to 1.59 (s, 6H), to 2.13 (s, 3H), 3,48-of 3.53 (m, 2H), 5,13 (s, 1H), 6,63 (d, J=8,44 Hz, 1H), 7,05 (dd, J=of 8.47 Hz, 2,04 Hz, 1H), 7,17 (d, J=2,08 Hz, 1H), 7,31-to 7.35 (m, 5H), to 7.67 (d, J=8,84 Hz, 2H), 8,14 (d, J=at 8.60 Hz, 2H);13C NMR (100 MHz, CDCl3) δ 13,5, 16,6, 19,8, 25,2, 25,3, 29,7, 30,4, 41,8, 50,1, 79,4, 117,3, 118,3, 124,4, 126,1, 128,4, 128,5, 128,8, 130,7, 133,4, 135,7, 137,9, 140,5, 146,5, 152,4, 154,5, 177,9; MS (ESI) m/z 597,96 (M-2)-, 599,0 (M-1)-, 600,0 (M)-.

Example 47: Obtaining compound A-19

Using the compound E-19 as a starting material, was obtained 2-(2,5-dimethyl-4-(1-(3-(4-n-butyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid (A-19) according to the synthesis method similar to the method described in Example 29. The compound obtained was a white solid with a yield of 31.4%.

The structure of the obtained compounds were described on the basis of the following data, obtained using nuclear magnetic resonance and mass spectroscopy:

1H NMR (400 MHz, CDCl3) δ of 0.79 (t, J=7,27 Hz, 3H), 1,13-of 1.23 (m, 2H), 1,28-of 1.36 (m, 2H), 2,12 (s, 3H), of 2.25 (s, 3H), 3,47-3,55 (m, 2H), of 4.66 (s, 2H), to 5.03 (s, 1H) 6,53 (s, 1H), 7,15 (s, 1H), 7.29 trend was 7.36 (m, 5H), to 7.68 (d, J=8,66 Hz, 2H), 8,16 (d, J=8,56 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 13,5, 15,5, 19,8, 20,8, 30,4, 41,9, 49,6, 64,9, 112,9, 118,3, 123,1, 125,7, 126,2, 128,3, 128,5, 128,8, 135,8, 139,1, 140,5, 141,7, 146,5, 152,4, 156,6, 173,2; MS (ESI) m/z 584,03 (M-1)-, 584,98 (M)-.

1. The compound of formula (I) or pharmaceutically acceptable salts of the compounds

where
X represents O or S;
Y represents O or S;
R represents H or C1-C9alkyl;
R1and R2independently of one another represent H or C1-C4alkyl;
R3represents N or C1-C9alkyl;
R4represents H or phenyl;
G1, G2and G3independently of one another represent H or C1-C9alkyl;
G4, G5, G6, G8and G9represent H; and
G7represents trifluoromethyl.

2. The compound according to claim 1, characterized in that R represents H, methyl or ethyl.

3. The compound according to claim 1, wherein R1represents H, methyl or ethyl.

4. The compound according to claim 1, wherein R2represents H, methyl or ethyl.

5. The compound according to claim 1, wherein R3represents H or C1-C4alkyl.

6. The compound according to claim 1 or 5, wherein R3is own the th methyl.

7. The compound according to claim 1, characterized in that G1, G2and G3represent H.

8. The compound according to claim 1, selected from the following compounds:
Ethyl-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenoxy)-acetate;
Ethyl-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetate;
Ethyl-2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetate;
Ethyl-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate;
Ethyl-2-(2-ethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenoxy)-acetate;
Ethyl-2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenoxy)-acetate);
Ethyl-2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate;
Ethyl-2-(2-methyl-4-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl)-methylthio)-phenoxy)-acetate;
Ethyl-2-(2-methyl-4-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl)-methoxy)-phenoxy)-acetate;
Ethyl-2-(2,5-dimethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate;
Ethyl-2-(2,5-dimethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-Tr is formationl)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetate;
Ethyl-2-(3-methyl-4-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl)-methoxy)-phenylthio)-acetate;
Methyl-2-methyl-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate;
Ethyl-2-(2-ethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate;
Ethyl-2,2-dimethyl-2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetate;
Ethyl-2,2-dimethyl-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate;
Ethyl-2-(3-methyl-4-(1-(3-(4-n-butyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetate;
Ethyl-2,2-dimethyl-2-(2-methyl-4-(1-(3-(4-n-butyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate;
Ethyl-2-(2,5-dimethyl-4-(1-(3-(4-n-butyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetate;
2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenoxy)-acetic acid;
2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid;
2-(2-ethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenoxy)-acetic acid;
2-(2-methyl-4-(1-(3-(4-methyl-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid;
2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid;
2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenoxy)-acetic acid;
2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid;
2-(2-methyl-4-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl)-methylthio)-phenoxy)-acetic acid;
2-(2-methyl-4-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl)-methoxy)-phenoxy)-acetic acid;
2-(2,5-dimethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid;
2-(2,5-dimethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid;
2-(3-methyl-4-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl)-methoxy)-phenylthio)-acetic acid;
2-methyl-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid;
2-(2-ethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid;
2,2-dimethyl-2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid;
2,2-dime the Il-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid;
2-(3-methyl-4-(1-(3-(4-n-butyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid;
2,2-dimethyl-2-(2-methyl-4-(1-(3-(4-n-butyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid;
2-(2,5-dimethyl-4-(1-(3-(4-n-butyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid.

9. The compound according to claim 1, selected from the following compounds:
2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid;
2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy-phenylthio)-acetic acid;
2-(2,5-dimethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid;
2-(2-ethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid;
2,2-dimethyl-2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid;
2,2-dimethyl-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid;
2-(3-methyl-4-(1-(3-(4-n-butyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid;
2,2-dimethyl-2-(2-methyl-4-(1-(3-(4-n-bout the l-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid;
2-(2,5-dimethyl-4-(1-(3-(4-n-butyl-5-oxo-1-(4-triptoreline)-4,5-dihydro-1H-1,2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid.

10. Pharmaceutical composition for the activation of the receptor δ-activated proliferation peroxisome (PPARδ)containing the compound according to any one of paragraphs. 1-9 and suitable excipients.

11. The pharmaceutical composition of claim 10, in dosage form selected from the group comprising conventional tablets, pills, coated film-coated, tablets, tablets with intersolubility coated, dispersible tablets, capsules, granules, solutions for oral administration and suspension for oral administration.

12. The use of compounds according to any one of paragraphs. 1-9 for the preparation of drugs for treatment or prevention of diseases which can be treated or prevented by activation of the receptor δ-activated proliferation peroxisome (PPARδ).

13. The application of item 12, wherein the disease is selected from one or more of obesity, dyslipidemia and abnormal glucose.

14. The method of obtaining compounds of General formula I according to claim 1, where R represents a C1-C9alkyl, and other radicals have specified in claim 1 values, including the interaction of the compounds of General formula II, where X, Y, R, R1, R2, G1-G4have specified in claim 1 the values, with a compound of General formula III, where R3-R4and G5-G9have specified in claim 1 values, Z represents Cl or Br,

under the action of an inorganic base such as a carbonate of an alkali metal, in a solvent environment, representing acetonitrile at room temperature for 1-12 hours.

15. The method of obtaining compounds of General formula I according to claim 1, where R represents a C1-C9alkyl, and other radicals have specified in claim 1 values, including during a continuous reaction process of sequential interaction of the compounds of General formula III, where R3, R4, G5-G9have specified in claim 1 values, first with a compound of General formula IV, where X, Y, G1-G4have specified in claim 1 values, and then with a compound of General formula V, where R, R1, R2have specified in claim 1 values, a Z represents Cl or Br, in the presence of carbonate as a base selected from potassium carbonate or sodium carbonate, in an environment of acetonitrile, without the need for separation of intermediates during the reaction

16. The method of obtaining compounds of General formula I according to claim 1, where R represents H and the other radicals have specified in claim 1 values, including the implementation of the alkaline hydrolysis of compounds of General the th formula I according to claim 1, where R represents a C1-C9alkyl, in the presence of a base, representing an alkali metal hydroxide including sodium hydroxide, lithium hydroxide, potassium hydroxide, in a solvent environment, which is a system of C1-C4alcohol - dichloromethane - water ratio in the range of 9-1:9-1:1 (vol./vol.), moreover, the process is carried out at room temperature for 1-12 hours, preferably within 2-4 hours.

17. The compound of formula III:
where
Z represents Cl or Br;
R3represents N or C1-C9alkyl;
R4represents H or phenyl;
G5, G6, G8and G9represent H; and
G7represents trifluoromethyl.

18. The connection 17, selected from the following compounds:
3-(1'-bromobenzyl)-4-methyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-triazole-5(4H)-she;
3-(1'-bromobenzyl)-4-n-butyl-1-(4-trifluoromethyl)-phenyl-1H-1,2,4-triazole-5(4H)-she; and
3-methyl bromide-4-methyl-1-(4-triptoreline)-1,4-dihydro-1,2,4-triazole-5-it.

19. The method of obtaining the compounds of formula III according to 17, comprising the reaction of compounds of formula (VI)

where
Z represents Cl or Br;
R3represents N or C1-C9alkyl;
R4represents H or phenyl;
G5, G6, G8and G9represent H;
G7represents trifluoromethyl;
with glorieuses or brainwashin reagent selected from the group including:
N-bromosuccinimide/triphenylphosphine and N-chlorosuccinimide/triphenylphosphine;
in the solvent, representing dichloromethane at room temperature for 2-8 hours.

20. The method of obtaining the compounds of formula III according to 17, comprising the reaction of compounds of formula (VII)

where
Z represents Cl or Br;
R3represents N or C1-C9alkyl;
G5, G6, G8and G9represent H;
G7represents trifluoromethyl; and
G10-G14represent H;
with glorieuses or brainwashin reagent, such as N-bromosuccinimide or N-chlorosuccinimide, in the environment of the solvent, representing chloroform, in the presence of benzoyl peroxide as a catalyst at the boiling temperature of the reaction mixture within 2-8 hours.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: described are novel 1,2,4-triazolones of general formula (I):

, where A denotes N and values of other radicals are given in the claim, which are vasopressin receptor inhibitors, synthesis method thereof and use thereof to prepare medicinal agents for treating and/or preventing diseases, particularly for treating and/or preventing cardiovascular diseases.

EFFECT: high efficiency of using said derivatives.

6 cl, 512 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

, where radicals are described in the claims, as well as to salts and hydrates of said compound or salts thereof. The invention also relates to pharmaceutical compositions and medicinal agents for treating diseases associated with thrombosis.

EFFECT: highly effective treatment.

35 cl, 1 tbl, 488 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I, where R1 -OH, R2- CONAA', SO2NAA', SO2NA-benzyl, SO2NHAr, SO2NAHet, SO2NHA or S(O)mHet, R3, R5, R6 - H, R4 - H, Hal or A, Y - OH, A, A' denotes a straight or branched C1-C10 alkyl, in which one CH2 group can be substituted with NR8, where R8 denotes a straight or branched C1-C6 alkyl or cycloalkyl, Ar denotes phenyl, Het denotes a saturated C5-C6-heterocyclic ring containing 1-2 nitrogen atoms, which can be substituted with A, m equals 1 or 2, and pharmaceutically suitable salts or tautomers thereof. The invention also relates to a method of producing said compounds and pharmaceutically suitable salts or tautomers thereof. The invention also relates to use of said compounds, salts or tautomers to prepare a medicinal agent for treating and/or preventing diseases affected by HSPS90 inhibition, as well as a medicinal agent based on said active ingredients, having HSP90 inhibiting activity. The invention also relates to an intermediate compound of formula I-1, where Z denotes A, Y - OH, R1 - OCH3, R2 - SO2Het, SO2NHAr or SO2NAA', R3 - H, R4 - Hal or A, R5, R6 - H, Ar - phenyl, Het - saturated C5-C6-heterocyclic ring, containing 1-2 nitrogen atoms which can be substituted with A, A, A' - straight or branched C1-C10 alkyl.

EFFECT: high efficiency of the composition.

6 cl, 1 tbl, 23 ex

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula I where A represents an optionally substituted aryl or heteroaryl, B - a benzene or thiophene cycle, C - a benzene or aliphatic hydrocarbon cycle, while values of other radicals are disclosed in the description. The compound according to the present invention, and the based pharmaceutical compositions exhibit a strong antagonistic effect in relation to GnRH receptor that makes them applicable for treatment of GnRH-related diseases, particularly prostate cancer, benign prostatic hyperplasia, breast cancer, endometriosis and/or uterine fibroid tumour.

EFFECT: improved clinical effectiveness.

11 cl, 70 tbl, 765 ex

FIELD: chemistry.

SUBSTANCE: 3-triazolylphenyl sulphide derivatives have formula (I): , where R is a cyclopropylmethyl group of a trifluoroethyl group, B2 is a hydrogen atom, halogen atom or a methyl group, B4 is a halogen atom, cyano group or C1-C6-alkyl group (which can be poly-substituted with halogen atoms), and each of A1 and A3 are selected from groups I and II given in the formula of invention, n equals 0 or 1. Described also is an aniline derivative which is an intermediate compound for producing formula (I) compounds and an insecticide, acaricide or nematocide based on formula (I) compounds.

EFFECT: obtaining novel 3-triazolylphenyl sulphide derivatives with excellent activity when treating soil as insecticides, acaricides or nematocides for agricultural and garden plants.

10 cl, 18 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I and their pharmaceutically acceptable salts. In formula I R1 is a halide, (C1-C6)alkyl or (C1-C6)alkoxy group; R2 is hydrogen; R3 is phenyl, substituted with one or two substitutes independently selected from a group comprising halide(C1-C6)alkyl, halide and a cyano group; R4 is CH2OH, CH2OC(=O)(CH2)2C(=O)OH or CH2OC(=O)(C1-C6)alkyl; R5 is (C1-C6)alkyl. The invention also relates to use of the compounds to make a medicinal agent, to a pharmaceutical composition containing a therapeutically effective amount of the compound and to a method of obtaining formula I compounds.

EFFECT: obtaining compounds with HIV reverse transcriptase inhibiting properties.

9 cl, 2 tbl,11 ex

Triazole derivative // 2383536

FIELD: chemistry.

SUBSTANCE: described are novel triazole derivatives with general formula where values of radicals are given in the formula of invention, a pharmaceutical composition containing said derivatives, and a method of treating autoimmune diseases. Compounds with general formula (1) and their pharmaceutically acceptable salts have inhibition effect on S1P and its Edg-1 receptor (S1P1).

EFFECT: possibility of use as a pharmaceutical product.

43 cl, 10 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: new method is described for producing new derivatives in the series 5-amino-2,4-dihydro-3N-1,2,4-triazole-3-thiones, and specifically to a method of producing 4,5-disubstituted 2,4-dihydro-3N-1,2,4-triazole-3-thiones with general formula I: , where R1=C1-C6 alkylphenyl, haloid phenyl, thienyl, furanyl or pyrrolyl; R2= phenyl C1-C6 alkyl, naphthyl C1-C6 alkyl, anthryl C1-C6 alkyl, C1-C6 alkoxyphenyl, which involves reaction of corresponding acylisothiocyanates, obtained from acylchlorides R1-C(O)Cl and ammonium rhodanide, with 4-R2- thiosemicarbazides R2-NH-C(S)-NH-NH2 and subsequent cyclisation of N-[2-(R2- carbamothioyl) hydrazinocarbonothioyl]acylamides in a medium of high-boiling aliphatic alcohols.

EFFECT: desired product, which is obtained with high output and purity, can be used in medicine.

1 cl, 8 ex

FIELD: pharmacology.

SUBSTANCE: invention claims novel bioactive compound, lysinium 3-methyl-1,2,4- triasolyl-5-thioacetate.

EFFECT: basis for obtainment of medicines with wide range of bioactivity for treatment of central nervous system diseases, including acute disorders of cerebral blood circulation, and cardiac decompensation.

1 cl, 4 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: new 5-sulphanyl-4H-1,2,4-triazole derivatives of general formula I (meaning of radicals R1-R3 are indicated in the description of the invention), methods of their preparation by liquid-phase parallel synthesis and pharmaceutical composition are claimed.

EFFECT: claimed compounds display high affinity to some subtypes of somostatin receptors of the SST2 and SST5 subtypes and possibility of their usage for treatment of pathological states or diseases involving one or more of the given somostatin receptors

9 cl, 708 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of biotechnology. The claimed invention relates to the field of modulation of enzymatic activity by application of interaction between a molecular chaperone Hsp70 and lysosomal phospholipid bis(monoacylglycero)phosphate (BMP). The invention can be used in medicine.

EFFECT: interaction of Hsp70-BMP modulates activity of lysosomal compartment enzymes, interacting with BMP, therefore the claimed invention represents means of reversing pathology of lysosomal storage diseases.

21 cl, 16 dwg, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, more specifically to a pharmaceutical composition possessing antithrombotic, thrombolytic, immunomodulatory, anti-inflammatory action, normalising lipid and carbohydrate metabolism, more specifically to the pharmaceutical composition of the substance Pijavitum (hereinafter referred to Pijavitum) made from lyophilised medicinal leech. The above pharmaceutical composition is presented in the form of an enteric coated tablet.

EFFECT: coating prevents the active ingredients of Pijavitum from destruction under action of the enzymes and acid medium of the stomach.

FIELD: medicine.

SUBSTANCE: invention relates to a method of treating or reducing insulin resistance in susceptible warm-blooded animals, including people. Method includes introduction of a selective estrogen receptor modulator (SERM).

EFFECT: described is SERM combination with an amount of estrogen or a precursor of a sexual steroid hormone, selected from a group, consisting of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androst-5-en-3b,17b-diol and compounds, converted in vivo into one of the said precursors or estrogen.

2 cl, 13 ex, 13 tbl, 8 dwg

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to medications, capable of inhibiting Na+/H+-exchange (NHE-exchangers, NHE inhibitors).

EFFECT: increased efficiency of inhibitors.

3 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medication for treatment or prevention of disease, which developed on the basis of structural and/or functional, and/or compositional changes of lipids in cell membranes, selected from cancer, vascular diseases, inflammatory diseases, metabolic diseases, obesity and excessive body weight, neurological or neurodegenerative disorders, which represents compound of formula COOR1-CHR2-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3 (I) or its pharmaceutically acceptable salts and derivatives, selected from esters, ethers, alkyl, acyl, phosphate, sulfate, ethyl, methyl or propyl; in which a and c can have independent values from 0 to 7; b can have independent values from 2 to 7, where R1 is selected from the following radicals: H, Na, K, CH3O, CH3-CH2O and OPO(O-CH2-CH3)2, and R2 is selected from the following radicals: OH, OCH3, O-CH3COOH, CH3, Cl, CH2OH, OPO(O-CH2-CH3)2, NOH, F, HCOO and N(OCH2CH3)2.Invention also relates to application of formula (I) compound and pharmaceutical composition, which contains it.

EFFECT: medications, based on claimed compound, are more efficient than medications of preceding level of technology.

22 cl, 7 dwg, 16 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds, represented by formula (I) , where X1 and X2 independently represent CH or N; ring U represents benzene ring, pyrazole ring, 1,2,4-oxadiazole ring, 1,2,4-thiadiazole ring, isothiazole ring, oxazole ring, pyridine ring, thiazole ring or thiophene ring, m represents integer number, which has values from 0 to 1; n represents integer number, which has values from 0 to 3; R1 represents hydroxygroup or C1-6 alkyl; R2 represents any of (1)-(3): (1) halogen atom; (2) hydroxygroup; (3) C1-6 alkyl or C1-6 alkoxy, each of which can independently contain any group, selected from group of substituents α; group of substituents α includes fluorine atom and hydroxygroup, or its pharmaceutically acceptable salt. Invention also relates to pharmaceutical composition, possessing inhibiting activity with respect to xanthenes oxidase, including formula (I) compound or its pharmaceutically acceptable salt as active ingredient.

EFFECT: derivative, which contains condensed ring structure, intended as means for prevention and treatment of disease, associated with abnormal level of uric acid in serum.

15 cl, 11 tbl, 126 ex

FIELD: medicine.

SUBSTANCE: method involves a combination of peloid applications and ultrasonic exposure. Peloid is applied on anterolateral thighs and an anterior abdominal wall. The applications are alternated every second day. Peloid is silt sulphide mud of Melkovodnenskiy deposit. The mud is applied in layer 10 mm thick at temperature 34-36°C. The applications are exposed to ultrasound at frequency 880 kHz in a continuous mode. The applications of the anterior abdominal wall are exposed to ultrasound at intensity 0.2-0.4 Wt/cm2 for 5 - 10 minutes. The anterolateral thighs are exposed to ultrasound at intensity 0.4-0.6 Wt/cm2, for 6-8 minutes for each thigh. Upon the completion of the procedure, the patient is covered with a hydrophobic tissue and left for 10 minutes. The therapeutic course is 10 procedures.

EFFECT: reducing obesity effectively by exposing on the hormonal activity of fat tissue, maintains the results obtained within three months.

2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to versions of a compound of formula where R1 is a hydrogen atom; R2 is a lower alkyl group; P is H; , where P1, P2 and P3 are identical or different and are selected from a hydrogen atom, a lower alkyl group and a C14-C22 alkenyl group substituted with a lower alkyl group; or where P1 is an alkenyl group, and each of P2 and P3 is a hydrogen atom; and Y is a C14-C22 alkenyl group with at least one double bond having a Z-configuration, and having a first double bond at the third carbon-carbon bond from the omega (ω)-end of the carbon chain, capable of lowering the level of triglycerides and cholesterol, a pharmaceutical or lipid composition based on the disclosed compounds, as well as use (versions) of the disclosed compounds.

EFFECT: high efficiency of using compounds.

32 cl, 6 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics, and aims at the prevention and treatment of hypovitaminosis and the normalisation of metabolism. The drug preparation contains vitamin A, vitamin D3, vitamin E, vitamin C; a selenium compound is presented by DAFS-25 in the following ratio of the ingredients in 1 l of the solution: vitamin A - 25.0-35.0 ml, vitamin D3 - 0.03-0.05 ml, vitamin E - 55.0-65.0 g, vitamin C - 90.0-110.0 g, DAFS-25 - 0.2-0.4 g, polysorbate-80 - 190.0-210.0 ml, 2-pyrrolidone 39.0-41.0 ml, distilled water - up to one litre.

EFFECT: using the declared invention enables increasing the immune status in poultry, normalising the antioxidant and detoxifying systems, improving the livability, egg production and meat production along with reducing the feed consumption per a unit of product.

3 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiology, and may be used for treating and preventing arterial hypertension with metabolic syndrome. That is ensured by adding the food ration with the functional foodstuff 'Samarskiy Zdorovyak' No 61 in a min daily dose of 33.3 g per one intake - with breakfast or lunch or dinner with underlying drug-induced therapy.

EFFECT: enabled treatment and prevention of arterial hypertension with metabolic syndrome

FIELD: medicine.

SUBSTANCE: with underlying antituberculous therapy from the first day of treatment, a therapeutic course is added with an oral administration of preparations Wobenzym and Thiotriazoline; Wobenzym is administered for 4 months in a dose of 1 tablet once a day 30 minutes before breakfast, while Thiotriazoline is administered for the first 15 days in a dose of 100 mg 2 times a day, from the 16th to 45th day in a dose of 100 mg 1 time a day, on the 46th day, Thiotriazoline is withdrawn.

EFFECT: method enables higher clinical effectiveness and reduced rate of an adverse hepatotoxic response to the antituberculous preparations due to improving the immune status and peroxidation values.

6 tbl, 2 ex

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