Agonists of receptor of peptide-1, similar to glucagone, their obtaining and application

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to agonist of receptor of glucagone-like peptide-1, which can be applied for treatment of diseases, caused by disturbance of glycometabolism, such as type II diabetes, insensibility to insulin or obesity. In structural formula each of Ar1 and Ar2 independently represents substituted phenyl, and group-substituents represent one, two or three groups selected from C1-C6alkoxyl, C1-C6-alkanoylamino, which is substituted with hydroxyl (which contains groups-substituents, including hydroxyl); C3-C6-cyclolkanoylamino, C2-C6-lkenoylamino; banzoylamino, banzyloxy C1-C6-alkanoylamino, thenoyloxy, tret-butoxyformamido, adamantanformamido; and mandeloylamino; X represents O; Y represents O. Invention also relates to method of obtaining agonist, and to its application for obtaining medication for treatment of diseases caused by disturbance of glycometabolism.

EFFECT: obtaining medication for treatment of diseases caused by disturbance of glycometabolism.

8 cl, 4 ex, 2 tbl, 2 dwg

 

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to a group of agonists of the receptor peptide-1, glucagon-like (GLP-1R). In particular, the present invention relates to a group of organic compounds from a small molecule having a substituted five-membered heterocyclic ring, which can be used as repetidly agonists of the GLP-1R. Compounds of the present invention can be used as medicines for the treatment of diseases associated with disorders glycometabolism, such as type II diabetes, insensitivity to insulin, obesity, etc. Present invention relates also to method of obtaining the above agonists of the GLP-1R.

The LEVEL of TECHNOLOGY

Diabetes mellitus (DM) is a common endocrine metabolic disease with a genetic tendency. He is called in the main an absolute or relative hypersecretion of insulin and causes a disturbance of the metabolism of sugars, fats, proteins and then vitamins, water and electrolytes. Manifestations of his include improving glycemia and glucose in the urine, and patients have symptoms of polydipsia, polyphagia, polyuria, xerostomia and General weakness. The prevalence of diabetes is 1-5% and tends to gradually increase. Diabetes, cancer and cardiovascular for the of Alemania call three common all over the world serious diseases. The aim of diabetes treatment is the correction of metabolic disorders of carbohydrates in order to eliminate these symptoms, to enable the restoration of the function of pancreatic islets, increase insulin resistance, to maintain the best state of health and physical strength and to prevent and treat various complications.

Diabetes mellitus is usually divided into two types: insulin-dependent diabetes mellitus (type I, IDDM) and non-insulin dependent diabetes mellitus (type II, NIDDM). Because the pathogenesis for these two types of diabetes are different, medicines to treat them vary considerably and are respectively as follows.

Diabetes type I is caused by a viral infection in hereditary susceptible person who induces paradoxical reaction islet cells through immunogenity, so pancreatic islets begin to be damaged and even completely lose its function. Approximately 5% of diabetes is type I. At present, medicines for the treatment of diabetes mellitus type I mainly include exogenous insulin (including insulin human and animal insulin), medications with insulin action, insulin-like factor-1 growth (IGF-1), a new, long-acting PR the preparations of insulin, hypoglycemic tablets Jin Qi, etc.

Diabetes mellitus type II is very rarely called direct damage β-islet cells, which reduce insulin secretion. Most cases of diabetes mellitus type II is caused by a combination of factors, which may include genetic traits, lifestyle, promoting environmental, metabolic disorders, obesity and so on. This pathological condition of muscle, liver and adipose tissue are resistant to insulin, thereby reducing the absorption of glucose. The majority of patients with diabetes suffer from diabetes type II. Currently, drugs for clinical treatment of NIDDM mainly include sulfonylureas, biguanides, other hypoglycemic drugs and adjuvants, etc.

Hypoglycemic drugs of the type of the sulfonylureas bind to receptors on the cell membrane β-islet cells with the closing of the channels potassium ions, thereby blocking the leakage of potassium ions and inducyruya depolarization of cell membranes, so that the ions calcium channels open, allowing intracellular calcium ions to flow inside. Increasing the concentration of intracellular calcium ions triggers the release of insulin. Hypoglycemic drug typeconversion can be divided into two generations in accordance with the time of their emergence in practice. The first generation includes Taprobane and second generation includes glibenclamide (Anglican), gliclazide (diamikron), glipizide, glikvidon etc.

Biguanide hypoglycemic drugs inhibit the appetite, increase insulin binding to receptors, activate anaerobic glycolysis in cells, inhibits respiration and inhibits hepatic gluconeogenesis. Biguanide hypoglycemic drugs mainly include Metformin, phenformin and buformin.

Other hypoglycemic drugs mainly include thiazolidinedione medicines (such as troglitazone, rosiglitazone, pioglitazone, and so on), β3-adrenoretseptory regulators, agonists of the glucagon receptor, agents that prevent the metabolism of fatty acids, inhibitors α-glycosidase (such as acarbose, voglibose, miglitol) and inhibitors aldozoreduktaza etc.

Recently, the development of research associated with glycometabolism endogenous peptide hormone led to the emergence of new ideas for the treatment of diabetes. When the human body consumes nutritious materials, enteroendocrine cells release enteropeptidase hormone, which mainly includes glucagon-like peptide-1 (GLP-1) and glucosidation insolent opny peptide (GIP), and regulates metabolism through effects on the generation of insulin, gastrointestinal perestaltic and proliferation of islet cells. GLP-1 is secreted enteropancreatic cells and activates adenylate cyclase for the synthesis of camp by a very specific binding with receptor for GLP-1β-islet cells, to further activate the protein kinase. Metabolic signal (glycometabolism) and kinase signal (linking GLP-1) are working together at the level of the cell membrane, eventually causing the opening of channels of CA2+and the flow of calcium ions inside, so that further stimulated insulin secretion while inhibiting generation of glucagon, whereby decreases occur after ingestion of glucose in the blood and is supported by the concentration of glucose in the blood at a constant level. In addition, GLP-1 has the function of neuroregulation and may slow gastric emptying and reduces appetite. They are all very useful to eliminate diabetes. Usually GLP-1 stimulates insulin secretion depending on the concentration of glucose in the blood. When the concentration of glucose in the blood decreases, the action of GLP-1 to stimulate insulin secretion decreases. Therefore, the action of GLP-1 to reduce blood glucose is self-limited and may not cause GI is glycemia. Thus, drugs with GLP-1-like activity are highly desirable for the treatment of diabetes. Agonists of GLP-1 R are one research focus of international organizations on the development of medicines. Currently, studies on GLP-1R mainly focused on the polypeptide regulators. For example, AC 2993 Amylin Corporation used for clinical trials in the US (IND). AC 2993 is a polypeptide of 39 amino acids and has an effect on the activation of insulin secretion, as GLP-1. Because of polypeptide drugs are unsuitable for oral administration and are easily destroyed, ones regulator GLP-1R is a new research direction currently.

DISCLOSURE of the INVENTION

The aim of the present invention is to develop a group of organic compounds from a small molecule derived from five-membered heterocyclic compounds which can be used as agonists of the receptor for glucagon-like peptide-1 (GLP-1R)to confirm the search path leading compounds or drugs for drugs for the treatment of diabetes. Another objective of the present invention is the method of obtaining these compounds.

Agonists of the receptor of podobn is the glucagon peptide-1 according to the present invention have the following structural formula:

where each Ar1and Ar2independently represents a substituted phenyl, and substituted groups represent one, two or three groups selected from C1-C6alkoxyl; C1-C6-alkanolamine, which is substituted by hydroxyl containing group, the substituents including hydroxyl);3-C6cycloalkanones; C2-C6alkanolamine; benzoylamine; benzyloxy1-C6alkanolamine; Tenojoki; tert-butoxyphenyl; adamantane, formamido, mandelamine;

X represents O;

Y represents O.

When Ar1represents,

R5is tenor and R6represents a C1-C6alkyl; X1is About; X2is O,

Ar2represents,

where R2is any one of the following groups:1-C6alkanoyl; substituted C1-C6alkanoyl, which is substituted by hydroxyl containing group, the substituents including hydroxyl);2-C6alkanoyl; C3-C6-cycloalkenyl; benzoyl; benzyloxy1-C6alkanoyl; tert-butoxycarbonyl; the adamantane formail; and Mandalay; and X2is NH.

Obtaining the dinani of the present invention carried out through the following stages according to the chemical equation:

where each Ar1and Ar2independently represents a substituted phenyl groups and the substituents are one, two or three groups selected from the following group: tert-butoxypropyl, Tenojoki; X represents O and Y represents Oh,

or according to the following chemical equation:

where R1, R2and R3are any of the following substituted groups: C1-C6alkyl, C1-C6alkanoyl; substituted C1-C6alkanoyl, which is substituted by hydroxyl; C2-C6alkanoyl; C3-C6cycloalkenyl; benzoyl; benzyloxy1-C6alkanoyl; tert-butoxycarbonyl; thenoyl; adamantaimai and Mandalay; X represents O; Y represents O; X1and X3is O; X2this is NH and X4this is Cl or HE.

Compound III is obtained by condensation of compounds I with compounds II. The condensation is carried out in the following solvents: dichloromethane, acetic anhydride, tetrahydrofuran, dimethylfuran, dichloroethane, toluene, benzene, water, dioxane or mixtures of the above solvents. If necessary, the reaction mixture you can add some activators, such as pyridine, N-methylmorpholine, isobutylparaben, triethylamine, diethylpropane the ylamine or DMAP, etc. According to the reaction conditions compounds the reaction temperature is usually from -78°C to room temperature (for example, to connect Wang 462 and so on) or from 50 to 230°With heating (for example, to connect Wang 520 etc). The reaction time is determined in accordance with certain reagents. The development of the reaction is usually determined by TLC analysis. After completion of the reaction the common methods of treatment include filtration with use of the pump, the concentration of the reaction solution to remove solvent, the extraction and isolation of the product column chromatography, etc. of the Final product III is confirmed with NMR detection.

The method of synthesis of the structural element substituted five-membered heterocyclic ring of the present invention relates to methods Organic Syntheses, CV 2, 55.

In the present invention is designed and synthesized new agonists of the receptor for glucagon-like peptide-1 (GLP-1R). Agonists of GLP-1R of the present invention have a good ability to bind to the GLP-1R, activate the synthesis of camp, they can be used for getting medicines for the treatment of diseases associated with disorders glycometabolism, such as type II diabetes, insensitivity to insulin, obesity, etc. They allow to overcome the disadvantage of the known prior art, namely, that paliperidonesee medicines are unsuitable for oral administration and are easily decomposed. Compounds of the present invention have a relatively simple structure and can easily be obtained.

BRIEF DESCRIPTION of DRAWINGS

Figure 1 shows the result of detection of the expression of the reporter gene for compounds of the present invention, which is used to assess activity of these compounds stimulus for GLP-1R. Figure 1 relative luciferase activity induced by 30 nm positive GLP-1, is taken as 100%.

Figure 2 shows the effect of compound 2f concentration camp in 293/GLP-1R cells.

Embodiments of the PRESENT INVENTION

The present invention will next be explained with reference to the following specific examples, but they in no way limit the present invention.

The method of obtaining the compounds in the following examples of the preparation 1-3 mainly includes the following three methods of conducting reactions.

Method 1

The compounds I and II, sodium acetate and acetic anhydride are mixed, the mixture is heated to melting (150-230° (C) and kept in a molten condition within 1 hour. Then to the reaction mixture add the ethanol and the mixture is cooled. The product is separated by crystallization, followed by filtration. The liquid residue is concentrated to remove solvents and the product vydelyayushchei chromatography.

Method 2

Compound I is dissolved in dichloromethane and the solution is cooled to a low temperature bath at -20°then add triperoxonane acid and raising the temperature to room temperature. The reaction mixture was analyzed TLC until then, until the connection I will not react completely. After concentration of the reaction system and remove completely triperoxonane acid substrate is dissolved in dichloromethane and the solution is cooled to a low temperature bath at -20°C. Then, in order, add pyridine and acylchlorides, the temperature was raised to room temperature and the reaction mixture is analyzed TLC. The reaction solution is concentrated and the product emit column chromatography.

Method 3

Compound I is dissolved in dichloromethane and the solution is cooled to a low temperature bath at -20°then add triperoxonane acid and raising the temperature to room temperature. The reaction mixture was analyzed TLC until then, until the connection I will not react completely with the subsequent concentration of the reaction system and completely remove triperoxonane acid. Then compound II is dissolved in tetrahydrofuran (THF) and the solution is cooled to low temperature is ane at -20° C. Then, in order to add N-methylmorpholine (NMM) and CICOOiBu. The reaction product of compound I with triperoxonane acid is dissolved in tetrahydrofuran and then transferred into the above mixture by syringe to the reaction mixture at room temperature. Analysis of the reaction mixture is conducted TLC. After completion of the reaction, the reaction solution is concentrated and the product emit column chromatography.

Join wang 520, wang 337, wang 405, wang 450, wang 520-1 and wang 462-1 get the technique of reaction 1, the compounds wang 420, wang 462, wang 524, wang 516, 488 wang, wang 568, wang 502, wang 530, wang 504, wang 866, 2f, wang 582, wang 538 and wang 496 receive method reaction 2 using join wang 520 and connections wang 516-1 and wang 591 obtained by method 3 using join wang 520.

In the following examples, obtaining the NMR measuring device of Mercury-Vx 300M, manufactured by Varian cooperation. Indicators NMR are δ N/a With 7,26/to 7.77 ppm (CDCl3); δ N/s 2,50/39,51 ppm (DMSO-d6and δ N/a With 3,31/49,15 ppm (methyl-d3marketing alcohol-d). Agents provided Changhai Chemistry Agents Cooperation. The products are cleaned in the main column chromatography. To separate the used silica gel 200-300 mesh, silica gel for column chromatography is dense and hollow model (ZLX-11)received branch factory of Qingdao Haiyang Chemical plant.

Example 1

Compound II (466 mg, 1.78 mmol), compound I (576 mg, a 1.96 mmol), ACE is at sodium (146 mg, 1.78 mmol) and 2 ml of acetic anhydride are mixed at room temperature followed by heating the mixture to 170°until then, until the mixture is melted and the mixture remain in the molten condition within 1 hour. Then, the resulting mixture was added 2 ml of ethanol and cooled it to room temperature. Thus formed yellow solid was separated and filtered. The liquid residue is concentrated and the solvent is completely removed, thus obtaining the crude product. The crude product chromatografic on a column of silica gel using a mixture of petroleum ether/ethyl acetate (5:1, vol/vol.), while receiving 556 mg of the product compound wang 520 (yield 60%).

1H NMR (300 MHz, CDCl3) δ and 1.54 (s, N), of 3.95 (s, 3H), 6,79 (user., 1H), 7,16 (s, 1H), 7,20 (DD, J=4,8 Hz, 3.9 Hz, 1H), 7,25 (d, J=9.9 Hz, 1H), 7,53 (d, J=9.0 Hz, 2H), 7,63 (DD, J=8.4 Hz and 2.1 Hz, 1H), 7,69 (DD, J=4,8 Hz, 1.2 Hz, 1H), 8,02 (DD, J=3,9 Hz, 1.2 Hz, 1H), of 8.06 (d, J=to 8.7 Hz, 2H), 8,17 (d, J=1.5 Hz, IH).

13C NMR (75 MHz, CDCl3) δ 28,17, 55,79, 81,23, 115,28, 117,92, 119,11, 123,09, 125,74, 128,02, 129,29, 129,41, 132,18, 132,75, 133,29, 133,71, 134,99, 141,57, 143,46, 151,37, 152,08, 159,93, 163,13, 167,46.

Compound II (466 mg, 1.78 mmol), compound I (576 mg, a 1.96 mmol), sodium acetate (146 mg, 1.78 mmol) and 2 ml of acetic anhydride are mixed at room temperature followed by heating the mixture to 200°until then, until the mixture is melted, and the feature remain in the molten condition within 1 hour. Then, the resulting mixture was added 2 ml of ethanol and cooled it to room temperature. The liquid concentrate and the solvent is completely removed, thus obtaining the crude product. The crude product chromatografic on a column of silica gel using a mixture of petroleum ether/ethyl acetate (1:1, vol/vol.), while receiving 158 mg of the compound wang 462-1.

1H NMR (300 MHz, CDCl3, wang 520-1) δ 1,50 (s, N), 3,88 (s, 3H), 7,27 (s, IH), 7,33-7,37 (2N), of 7.69 (d, J=8.7 Hz, 2H), 8,01 (d, J=8.7 Hz, 2H), 8,07 (d, J=3,9 Hz, 1H), 8,13 (d, J=4.8 Hz, 1H), they were 8.22 compared to 8.26 (2H), to 9.93 (s, 1H).

1H NMR (300 MHz, CDCl3, wang 462-1) δ 2,22 (s, 3H), 3,91 (s, 3H), 7,07 (d, J=8.7 Hz, 1H), 7,14 (s, 1H), 7,21 (m, 1H), 7,42 (m, 1H), 7,66 (d, J=8.1 Hz, 2H), 7,71 (d, J=4,8 Hz, 1H), to 7.99 (d, J=8.7 Hz, 1H), with 8.05 (m, 1H), 8,10 (d, J=8,4 Hz, 2H), 8,19 (m, 1H).

Compound II (1,46 g, 9.6 mmol), compound I (1.9 grams, of 10.7 mmol), sodium acetate (0.8 g 9.8 mmol) and 2.8 ml of acetic anhydride are mixed at room temperature followed by heating the mixture to 170°until then, until the mixture is melted and the mixture remain in the molten condition within 1 hour. Then, the resulting mixture was added 5 ml of ethanol and cooled it to room temperature. Thus formed yellow solid was separated and filtered, thus obtaining 2.0 g of the product compound wang 337 (yield 62%).

1H NMR (300 MHz, CDCl3) δ to 2.35 (s, 3H), of 3.97 (s, MN),7,13 (d, J=8,4 Hz, 1H), 7,20 (s, 1H), 7,50-7,56 (2N), TO 7.59-THE 7.65 (2H), 8,12-8,15 (3H).

Compound II (262 mg, 1.0 mmol), compound I (200 mg, 1.1 mmol), sodium acetate (82 mg, 1.0 mmol) and 1 ml of acetic anhydride are mixed at room temperature followed by heating the mixture to 170°until then, until the mixture is melted and the mixture remain in the molten condition within 1 hour. Then, the resulting mixture was added 5 ml of ethanol and cooled it to room temperature. Thus formed yellow solid was separated and filtered. The liquid residue is concentrated and the solvent is completely removed, thus obtaining the crude product. The crude product chromatografic on a column of silica gel using a mixture of petroleum ether/ethyl acetate (6:1, about./vol.), while receiving 235 mg of the product compound wang 405 (yield 58%).

1H NMR (300 MHz, CDCl3) δ of 3.97 (s, 3H), 7,20 (DD, J=4,8 Hz, 3.9 Hz, 1H), 7,24 (s, 1H), 7,26 (d, J=7.8 Hz, 1H), 7,51-EUR 7.57 (2H), 7,60-OF 7.70 (3H), 8,02 (DD, J=3,6 Hz, 0.9 Hz, 1H), 8,14-8,19 (3H).

Compound II (262 mg, 1.0 mmol), compound I (250 mg, 1.1 mmol), sodium acetate (82 mg, 1.0 mmol) and 4 ml of acetic anhydride are mixed at room temperature followed by heating and curing the mixture at 210-230°C for 1 hour. Then, the resulting mixture was added 5 ml of ethanol and cooled her decanates temperature. Thus formed yellow solid was separated and filtered, while receiving 100 mg of the product compound wang 450 (yield 22%).

1H NMR (300 MHz, CDCl3) δ of 3.97 (s, 3H), 7,21 (DD, J=4,8 Hz, 3.9 Hz, 1H), 7,30 (d, J=8,1 Hz, 1H), 7,37 (s, 1H), of 7.70 (d, J=5,1 Hz, 1H), 7,73 (DD, J=9.9 Hz, 1.5 Hz, 1H), 8,02 (d, J=3,9 Hz, 1H), of 8.09 (d, J=1.8 Hz, 1H), 8,33 (d, J=9.0 Hz, 2H), 8,40 (d, J=9,3 Hz, 2H).

Example 2

Compound I (50 mg, 0.1 mmol) dissolved in 2 ml of dichloromethane and the solution is cooled to a low temperature bath at -20°C, followed by addition of 1 ml triperoxonane acid and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC until then, until the connection I will not react completely. After concentrating the reaction mixture and remove completely triperoxonane acid intermediate connection of the reaction is dissolved in 2 ml of dichloromethane and the mixture is cooled to a low temperature bath at -20°C, followed by addition of 40 μl (0.6 mmol) of pyridine and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC. The reaction solution is concentrated and the solvent is removed, thus obtaining the crude product. The crude product chromatografic on a column of silica gel using a mixture of petroleum ether/ethyl acetate (2:1, vol/vol.), while receiving 38 m the product, join wang 420 (yield 90%).

1H NMR (300 MHz, CDCl3) δ of 3.94 (s, 3H), 7,20-7,24 (m, 2H), 7,27 (d, J=1.8 Hz, 1H), 7,66 (DD, J=8,1 Hz, 1.5 Hz, 1H), 7,71 (DD, J=4,8 Hz, 0.9 Hz, 1H), 7,76 (d, J=9.0 Hz, 2H), 8,03 (DD, J=3,6 Hz, 0.9 Hz, 1H), 8,07 (d, J=1.5 Hz, 1H), to 8.14 (d, J=8.7 Hz, 2H), 8,20 (user., 2H).

Compound I (50 mg, 0.1 mmol) dissolved in 2 ml of dichloromethane and the solution is cooled to a low temperature bath at -20°C, followed by addition of 1 ml triperoxonane acid and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC until then, until the connection I will not react completely. After concentrating the reaction mixture and remove completely triperoxonane acid intermediate connection of the reaction is dissolved in 2 ml of dichloromethane and the mixture is cooled to a low temperature bath at -20°C, followed by addition of 40 μl (0.6 mmol) of pyridine, the addition of compound II (27 μl, 0,39 mmol) and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC. The reaction solution is concentrated and the solvent is removed, thus obtaining the crude product. The crude product chromatografic on a column of silica gel using a mixture of petroleum ether/ethyl acetate (1,5:1, vol/vol.), while receiving 26 mg of the product compound wang 462 (yield 56%).

1H NMR (300 MHz, CDCl3 ) δ 2,19 (s, 3H), 3,88 (s, 3H), 7,12 (s, 1H), 7,20-7,24 (m, 2H), 7,55 (d, J=1.5 Hz, 1H), 7,60 (d, J=9.0 Hz, 2H), 7,71 (DD, J=4,8 Hz, 0.9 Hz, 1H), to 7.77 (user., 1H), of 7.97 (d, J=8.7 Hz, 2H), 8,03 (DD, J=3,9 Hz, 0.9 Hz, 1H), 8,07 (d, J=1.5 Hz, 1H).

13With NMR (75 MHz, CDCl3) δ 24,66, 55,84, 155,64, 119,55, 120,54, 123,35, 126,15, 128,43, 129,59, 129,87, 132,37, 133,12, 133,52, 134,26, 135,41, 141,85, 143,13, 151,63, 160,63, 163,28, 167,60, 168,99.

Compound I (40 mg, 0.08 mmol) dissolved in 2 ml of dichloromethane and the solution is cooled to a low temperature bath at -20°C, followed by addition of 1 ml triperoxonane acid and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC until then, until the connection I will not react completely. After concentrating the reaction mixture and remove completely triperoxonane acid intermediate connection of the reaction is dissolved in 2 ml of dichloromethane and the mixture is cooled to a low temperature bath at -20°C, followed by addition of 40 μl (0.6 mmol) of pyridine, the addition of compound II (23 μl, 0.2 mmol) and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC. The reaction solution is concentrated and the solvent is removed, thus obtaining the crude product. The crude product chromatografic on a column of silica gel using a mixture of petroleum ether/ethyl acetate (5:1, vol/vol.), while receiving 1 mg of product, join wang 524 (yield 36%).

1H NMR (300 MHz, DMSO-d6) δ are 3.90 (s, 3H), 7,22 (d, J=5.4 Hz, 1H), 7,33, (d, J=8,4 Hz, 2H), 7,39-7,44 (1H), 7,50-7,58 (2N), 7,83 (d, J=8,4 Hz), 7,98 (d, J=8.7 Hz, 2H), 8,04 IS 8.22 (7H), a 10.74 (s, 1H).

Compound I (40 mg, 0.08 mmol) dissolved in 2 ml of dichloromethane and the solution is cooled to a low temperature bath at -20°C, followed by addition of 1 ml triperoxonane acid and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC until then, until the connection I will not react completely. After concentrating the reaction mixture and remove completely triperoxonane acid intermediate connection of the reaction is dissolved in 2 ml of dichloromethane and the mixture is cooled to a low temperature bath at -20°C, followed by addition of 40 μl (0.6 mmol) of pyridine, the addition of compound II (25 μl, 0.2 mmol) and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC. The reaction solution is concentrated and the solvent is removed, thus obtaining the crude product. The crude product chromatografic on a column of silica gel using a mixture of petroleum ether/ethyl acetate (4:1, vol/vol.), while receiving 25 mg of the product compound wang 516 (output 62,5%).

1H NMR (300 MHz, DMSO-d6) δ of 1.57 (m, 2H), and 1.63-1.77 in (m, 4H), 1,80-1,89 (m, 2H), 2,84 (m, 1 is), the 3.89 (s, 3H), 7,31 (m, 2H), 7,40 (d, J=8,4 Hz,1H), 7,86 (d, J=9.0 Hz, 2H), 7,94 (DD, J=8,4 Hz, 1.8 Hz, 1H), 8,03 (DD, J=3,9 Hz, 1.2 Hz, 1H), 8,07 (d, J=9.0 Hz, 2H), 8,10 (DD, J=4,8 Hz, 1.2 Hz, 1H), 8,18 (d, J=1.8 Hz, 1H), 10,35 (s, 1H).

13With NMR (75 MHz, DMSO-d6) δ 25,62, 30,00, 55,97, 115,74, 118,71, 119,04, 123,52, 125,27, 128,51, 128,77, 129,24, 131,19, 132,78, 133,34, 135,43, 135,50, 140,86, 144,42, 151,04, 159,24, 162,91, 166,93, 175,11.

Compound I (40 mg, 0.08 mmol) dissolved in 2 ml of dichloromethane and the solution is cooled to a low temperature bath at -20°C, followed by addition of 1 ml triperoxonane acid and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC until then, until the connection I will not react completely. After concentrating the reaction mixture and remove completely triperoxonane acid intermediate connection of the reaction is dissolved in 2 ml of dichloromethane and the mixture is cooled to a low temperature bath at -20°C, followed by addition of 40 μl (0.6 mmol) of pyridine, the addition of compound II (23 μl, 0.2 mmol) and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC. The reaction solution is concentrated and the solvent is removed, thus obtaining the crude product. The crude product chromatografic on a column of silica gel using a mixture of petroleum ether/ethyl acetate (4:1, vol/vol.), while receiving 25 m the product, join wang 488 (yield 64%).

1H NMR (300 MHz, DMSO-d6) δ to 0.80 (m, 2H), 0,85 (m, 2H), of 1.84 (m, 1H), 3.88 (s, 3H), 7,28 (s, 1H), 7,32 (DD, J=5,1 Hz, 3.9 Hz, 1H), 7,39 (d, J=8,1 Hz, 1H), a 7.85 (d, J=8.7 Hz, 2H), 7,92 (DD, J=8,4 Hz, 1.5 Hz, 1H), 8,04 (m, 1H), with 8.05 (d, J=8.7 Hz, 2H), 8,11 (DD, J=4,8 Hz, 1.2 Hz, 1H), 8,18 (d, J=1.8 Hz, 1H), is 10.68 (s, 1H).

13With NMR (75 MHz, DMSO-d6) δ 7,78, 14,83, 55,97, 115,71, 118,73, 118,93, 123,53, 125,32, 128,54, 128,81, 129,32, 131,22, 132,80, 133,36, 135,46, 135,53, 140,88, 144,24, 151,05, 159,29, 162,91, 166,96, 172,44.

Compound I (40 mg, 0.08 mmol) dissolved in 2 ml of dichloromethane and the solution is cooled to a low temperature bath at -20°C, followed by addition of 1 ml triperoxonane acid and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC until then, until the connection I will not react completely. After concentrating the reaction mixture and remove completely triperoxonane acid intermediate connection of the reaction is dissolved in 2 ml of dichloromethane and the mixture is cooled to a low temperature bath at -20°C, followed by addition of 40 μl (0.6 mmol) of pyridine, the addition of compound II (23 μl, 0.2 mmol) and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC. The reaction solution is concentrated and the solvent is removed, thus obtaining the crude product. The crude product chromatographically column of silica gel using a mixture of petroleum ether/ethyl acetate (4:1, about./vol.), while receiving 26 mg of the product compound wang 568 (yield 57%).

1H NMR (300 MHz, CDCl3) δ of 3.95 (s, 3H), of 4.13 (s, 2H), and 4.68 (s, 2H), 7,18 (s, 1H), 7,19-7,26 (m, 2H), 7,39-to 7.50 (m, 5H), 7,63 (DD, J=6,9 Hz, 0.9 Hz, 1H), 7,69 (DD, J=4,8 Hz, 0.9 Hz, 1H), 7,74 (d, J=9.0 Hz, 2H), 8,01 (DD, J=3,6 Hz, 1.2 Hz, 1H), 8,10 (d, J=8.7 Hz, 2H), 8,16 (d, J=1.5 Hz, 1H), 8,56 (s, 1H).

Compound I (40 mg, 0.08 mmol) dissolved in 2 ml of dichloromethane and the solution is cooled to a low temperature bath at -20°C, followed by addition of 1 ml triperoxonane acid and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC until then, until the connection I will not react completely. After concentrating the reaction mixture and remove completely triperoxonane acid intermediate connection of the reaction is dissolved in 2 ml of dichloromethane and the mixture is cooled to a low temperature bath at -20°C, followed by addition of 40 μl (0.6 mmol) of pyridine, the addition of compound II (23 μl, 0.2 mmol) and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC. The reaction solution is concentrated and the solvent is removed, thus obtaining the crude product. The crude product chromatografic on a column of silica gel using a mixture of petroleum ether/ethyl acetate (4:1, vol/vol.), while receiving 22 mg of product, with the unity wang 502 (yield 56%).

1H NMR (300 MHz, DMSO-d6) δ 1,81-of 1.94 (m, 2H), 2,12-of 2.28 (m, 4H), 3,29 (m, 1H), with 3.89 (s, 3H), 7,31 (s, 1H), 7,33 (m, 1H), 7,40 (d, J=7.5 Hz, 1H), 7,87 (d, J=8.1 Hz, 2H), 7,94 (d, J=8.1 Hz, 2H), 8,04-8,08 (2N), to 8.12 (d, J=a 5.1 Hz, 1H), 8,19 (s,1H), and 10.20 (s, 1H).

Compound I (40 mg, 0.08 mmol) dissolved in 2 ml of dichloromethane and the solution is cooled to a low temperature bath at -20°C, followed by addition of 1 ml triperoxonane acid and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC until then, until the connection I will not react completely. After concentrating the reaction mixture and remove completely triperoxonane acid intermediate connection of the reaction is dissolved in 2 ml of dichloromethane and the mixture is cooled to a low temperature bath at -20°C, followed by addition of 40 μl (0.6 mmol) of pyridine, the addition of compound II (23 μl, 0.2 mmol) and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC. The reaction solution is concentrated and the solvent is removed, thus obtaining the crude product. The crude product chromatografic on a column of silica gel using a mixture of petroleum ether/ethyl acetate (4:1, vol/about that), while receiving 24 mg of the product compound wang 530 (yield 57%).

1H NMR (300 MHz, DMSO-d6) δ of 1.20 to 1.48 (6N), 1,65-OF 1.81 (4H), 2,39 (m, 1H),with 3.89 (s, 3H), 7,32 (s, 1H), 7,34 (m, 1H), 7,41 (d, J=8,4 Hz, 1H), 7,87 (d, J=8.1 Hz, 2H), 7,95 (d, J=8,1 Hz, 1H), 8,04 (m,1H), 8,08 (d, J=8.7 Hz, 2H), 8,12 (d, J=4,8 Hz, 1H), to 8.20 (m, 1H), 10,31 (s, 1H).

Compound I (40 mg, 0.08 mmol) dissolved in 2 ml of dichloromethane and the solution is cooled to a low temperature bath at -20°C, followed by addition of 1 ml triperoxonane acid and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC until then, until the connection I will not react completely. After concentrating the reaction mixture and remove completely triperoxonane acid intermediate connection of the reaction is dissolved in 2 ml of dichloromethane and the mixture is cooled to a low temperature bath at -20°C, followed by addition of 40 μl (0.6 mmol) of pyridine, the addition of compound II (23 μl, 0.2 mmol) and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC. The reaction solution is concentrated and the solvent is removed, thus obtaining the crude product. The crude product chromatografic on a column of silica gel using a mixture of petroleum ether/ethyl acetate (6:1, about./vol.), while receiving 4 mg of the product compound wang 504 (yield 10%).

1H NMR (300 MHz, CDCl3) δ of 1.34 (s, N), of 3.94 (s, 3H), 7,15 (s, 1H), 7,20 (DD, J=4,8 Hz, 3.6 Hz, 1H), 7.23 percent (s, 1H), 7,58 (user., 1H), OF 7.64-OF 7.69 (2H), 7,72 (d, J=8.7 Hz, 2H), and 8.0 (DD, J=3,6 Hz, 1.5 Hz, 1H), 8,08 (d, J=9.0 Hz, 2H), 8,11 (d, J=1.8 Hz, 1H).

Compound I (40 mg, 0.08 mmol) dissolved in 2 ml of dichloromethane and the solution is cooled to a low temperature bath at -20°C, followed by addition of 1 ml triperoxonane acid and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC until then, until the connection I will not react completely. After concentrating the reaction mixture and remove completely triperoxonane acid intermediate connection of the reaction is dissolved in 2 ml of dichloromethane and the mixture is cooled to a low temperature bath at -20°C, followed by addition of 40 μl (0.6 mmol) of pyridine, the addition of compound II (27 μl, 0.2 mmol) and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC. The reaction solution is concentrated and the solvent is removed, thus obtaining the crude product. The crude product chromatografic on a column of silica gel using CH2Cl2while receiving 40 mg of the product compound wang 554 (yield 89%).

1H NMR (300 MHz, CDCl3) δ a 3.83 (s, 3H), 6,28 (s, 1H), 7,05 (s, 1H), 7,16 (d, J=8,1 Hz, 1H), 7,20 (DD, J=5,1 Hz, 3.6 Hz, 1H), 7,39-7,41 (2N), 7,50-OF 7.55 (3H), 7,60 (d, J=9.0 Hz, 2H), 7,71 (DD, J=5,1 Hz, 1.2 Hz, 1H), 7,92 (d, J=an 8.4 Hz, 2H), to 7.99 (d, J=1.2 Hz), 8,03 (DD, J=3,6 Hz, 0.9 Hz, 2H), 8,24 (s, 1H), 8,42 (s, 1H).

Compound I (52 mg, 0.1 mmol) dissolved in 2 ml of dichloromethane and the solution is cooled to a low temperature bath at -20°C, followed by addition of 1 ml triperoxonane acid and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC until then, until the connection I will not react completely. After concentrating the reaction mixture and remove completely triperoxonane acid intermediate connection of the reaction is dissolved in 2 ml of dichloromethane and the mixture is cooled to a low temperature bath at -20°C, followed by addition of 40 μl (0.6 mmol) of pyridine, the addition of compound II (10 μl, 0.03 mmol) and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC. The reaction solution is concentrated and the solvent is removed, thus obtaining the crude product. The crude product chromatografic on a column of silica gel using CH2Cl2while receiving 19 mg of the product compound wang 866 (yield 44%).

1H NMR (300 MHz, DMSO-d6) δ the 3.89 (s, 6N), 7,33 (DD, J=4,8 Hz, 3.9 Hz, 2H), was 7.36 (s, 2H), 7,41 (d, J=8,4 Hz, 2H), 7,93-OF 7.96 (2H), of 7.96 (d, J=8.7 Hz, 4H), of 8.04 (DD, J=3.3 Hz, 0.9 Hz, 2H), 8,12 (DD, J=4,8 Hz, 0.9 Hz, 2H), 8,17(d, J=8,7 Hz, 4H), to 8.20 (d, J=1.8 Hz, 2H), 11,66 (s, 2H).

According to the same method compound 2f is received with the application of a CR is the product of reaction of 1 EQ. connection

with triperoxonane acid and 1.5 EQ. acetylchloride (yield 56%).

1H NMR (300 MHz, CDCl3) δ of 1.41 (t, J=6.9 Hz, 3H), 2,24 (s, 3H), 4,18 (sq, J=6,9 Hz, 2H), 7,11 (s, 1H), 7,19 (m, 1H), 7,45 (m, 2H), 7,62-OF 7.70 (4H), 8,02 (m, 1H), 8,08 (d, J=9.0 Hz, 2H).

According to the same method of connection wang 582 receive with the use of the reaction product of 1 EQ. join wang 520 with triperoxonane acid and 1.5 EQ. Diamantopoulou (yield 38%).

1H NMR (300 MHz, CDCl3) δ 1,76 (6N), 1,99 (6N), 2,12 (3H), of 3.95 (s, 3H), 7,14-OF 7.23 (2H), 7,54 (s, 1H), TO 7.61-OF 7.70 (2H), 7,73 (d, J=9.0 Hz, 2H), 8,02 (DD, J=3,9 Hz, 1H), of 8.09 (d, J=9.0 Hz, 2H), 8,12 (d, J=1.8 Hz, 1H).

According to the same method of connection wang 538 receive with the use of the reaction product of 1 EQ. join wang 520 with triperoxonane acid and 1.5 EQ. benzylacrylamide (yield 58%).

1H NMR (300 MHz, CDCl3) δ of 3.78 (s, 2H), 3,92 (s, 3H), 7,16 (s, 1H), 7,19-7,24 (2N), 7,34-7,74 (6N), to 7.59 (d, J=8.7 Hz, 2H), 7.62mm (m, 1H), of 7.70 (d, J=4,8 Hz, 1H), 8,02 (d, J=8.7 Hz, 2H), 8,13 (m, 1H).

According to the same method of connection wang 496 receive with the use of the reaction product of 1 EQ. join wang 520 with triperoxonane acid and 1.5 EQ. chloroacetanilide (yield 70%).

1H NMR (300 MHz, DMSO-d6) δ the 3.89 (s, 3H), 4,36 (s, 2H), 7,34 (s, 1H), 7,41 (d, J=8,1 Hz, 1H), 7,88 (d, J=9.0 Hz, 2H), 7,93-7,98 (2N), 8,05 (who, 1H), 8,12 (d, J=7.5 Hz, 2H), by 8.22 (m, 1H), 8,89 (m, 1H), 10,95 (s, 1H).

Example 3

Compound I (40 mg, 0.08 mmol) dissolved in 2 ml of dichloromethane and the solution is cooled to a low temperature bath at -20°C, followed by addition of 1 ml triperoxonane acid and gradual temperature increase to room temperature. The reaction mixture was analyzed TLC until then, until the connection I will not react completely. After concentrating the reaction mixture and remove completely triperoxonane acid compound II (19 μl, 0.16 mmol) dissolved in 2 ml of tetrahydrofuran and the solution is cooled to a low temperature bath at -20°With stirring for 10 min at this temperature. Then in order to add N-methylmorpholine (NMM) (53 μl, 0.48 mmol) and CICOOiBu (21 μl, 0.16 mmol) with stirring for 0.5 hour at -20°C. the reaction Product of compound I with triperoxonane acid dissolved in 1 ml of tetrahydrofuran and then transferred by syringe into the above mixture to reaction at room temperature for about 15 hours. The reaction solution is concentrated and the solvent is completely removed, thus obtaining the crude product. The crude product chromatografic on a column of silica gel using a mixture of petroleum ether/ethyl acetate (5:1, vol/vol.), while receiving 12 mg of the product compound wang 516-1 (30%yield).

1H NMR (300 MHz, CDCl3) δ of 1.74 (s, 3H), of 1.87 (s, 3H), 3,18 (d, J=7.8 Hz, 2H), 3,95 (s, 3H), 5,42 (m, 1H), 7,19 (s, 1H), 7,20-7,27 (2N), 7,63 (2N), the 7.65 (d, J=1.8 Hz, 1H), of 7.70 (d, J=8,4 Hz, 2H), 8,02 (DD, J=3,6 Hz, 0.9 Hz, 1H), 8,09 (doctor J=9.0 Hz, 2H), 8,16 (d, J=2.1 Hz, 1H).

According to the same method of connection wang 591 receive with the use of the reaction product of 1 EQ. join wang 520 with triperoxonane acid and 2.0 EQ. connection Boc-Ala-OH (yield 18%).

Example 4

Connection wang 568 (11 mg, 0.02 mmol) dissolved in 2 ml dichloromethane and cooled at -78°C for 10 minutes followed by the addition of 0.2 ml BCl3/n-hexane (1 M) to continue the reaction for 30 minutes at -78°C. Then the temperature was raised to -18°for reaction for 4 hours. Add 2 ml of ether for quenching the reaction with stirring for 30 minutes at room temperature, followed by adding 5 ml of water. The aqueous phase and the organic phase separated. The aqueous phase is extracted with dichloromethane and the combined organic phases, dried with anhydrous MgSO4and concentrate. The crude product subjected to column chromatography using a mixture of petroleum ether/ethyl acetate (1/2,./vol.), while receiving the connection wang 477 (1.5 mg, yield 17%).

1H NMR (300 MHz, CDCl3) δ 1,86 (user., 1H), 3,95 (s, 3H), 4.26 deaths (s, 2H), 7,18 (s, 1H), 7,20 (dd. J=8.7 Hz, 4.8 Hz, 1H),7.23 percent (d, J=3.3 Hz, 1H), 7,63 (d, J=8,1 Hz, 1H), 7,71 (DD, J=5,1 Hz, 1.5 Hz, 1H), of 7.75 (d, J=8.7 Hz, 2H), 8,02 (d, J=3.6 Hz, 1H), 8,08 (d, J=8.7 Hz, 2H), 8,14 (m, 1H), 8,57 (user., 1H).

Connection wang 591 (3 mg) was dissolved in 1.5 ml dichloromethane and cooled in an ice bath for 5 minutes followed by the addition of 0.15 ml of trichloroacetic acid. Then the temperature was gradually increased to room temperature and analysis of the reaction mixture is conducted TLC. After the disappearance of the original substance solvent and triperoxonane acid is removed by pumping, while receiving 2 mg of the product compound wang 605 (yield 65%).

1H NMR (300 MHz, methyl-d3marketing alcohol-d) δ and 1.63 (d, J=7.2 Hz, 3H), of 3.95 (s, 3H), 4.09 to (m, 1H), 7,265 (s, 1H), 7,267 (d, J=8.7 Hz, 1H), 7,29 (d, J=8,1 Hz, 1H), 7,81 (DD, J=8.7 Hz and 2.1 Hz, 1H), 7,87 (d, J=9.0 Hz, 2H), to $ 7.91 (DD, J=5,1 Hz, 1.2 Hz,1H), 8,01 (DD, J=3,6 Hz, 0.9 Hz, 1H), 8,16 (d, J=9,3 Hz, 2H), of 8.25 (d, J=2.1 Hz, 1H).

Example 4. Experiments testing the biological activity

1. The test reporter gene expression

After GLP-1R is associated with GLP-1 or agonist, its link Gasubunt is activated for the stimulation of adenylate cyclase, which makes it possible to increase the concentration of intracellular camp. Because the promotor region of the gene of proinsulin has a cyclic amp-responsive element, after binding of camp to its item the susceptibility of proinsulin gene transcription is activated, so in order to increase the susceptibility β -islet cells to glucose and increased the expression and secretion of insulin (Diabetes, 2000, vol. 49:1156-1164). In the model of screening applied strain embryonic kidney cells, which stably conspicious vector gene expression of GLP-1R and expression vector reporter gene luciferase under the regulation of an element of camp-sensitivity for detection of its susceptibility to the connection candidate (Cell Biology, 1992, Vol.89:8641-8645; Proc. Natl. Acad. Sci. U.S.A. 1987, Vol.84: 3434-3438). When screening candidate compounds compound that can induce reporter gene luciferase to expression, has a activity by activation of GLP-1.

1.1. Experimental material and tools

Cell strain: strain SOME 293/GLP-IR+Luc, which stably expresses the GLP-1R and the luciferase (National New Medicaments Screening Center).

Fetal bovine serum (GIBCO/BRL Cooperation).

System analysis of luciferase Steady-glo™ (Promega Cooperation).

Standard GLP-1 (Sigma Cooperation).

G418 (Invitrogen Cooperation).

Incubator with carbon dioxide Forma (Forma Cooperation).

The unit of count Victor 2 (Wallac Cooperation).

The connection candidate: connection wang 524, wang 520, wang 462, 2f, wang 516, wang 516-2, wang 502 and wang 504.

1.2 Experimental method

Cells of SOME 293/GLP-IR+Luc in the amount of 20,000 cells/100 µl/well inoculant in 96-well plate and cultured at 37°during the night from the culture medium DMEM containing 10% fetal bovine is ikorodu and 500 μg/ml G418. Candidate connections wang 516-2, wang 502 and wang 504, respectively, was diluted to 2 mm, 1 mm, 0.3 mm, 0.1 mm, 0.03 mm, 0.01 mm and 0.003 mm and other compounds-candidates bred gradually from 30 mm for 8 times by using the relationship 1:3 to obtain a concentration gradient (i.e. 30 mm, 10 mm, 3 mm, 1 mm, 0.3 mm, 0.1 mm, 0.03 mm and 0.01 mm) and then adding them to the above 96-well plate at a rate of 1 µl/well. The cells are then cultivated at 37°C in an atmosphere with 5% CO2within 6 hours. The luciferase activity detected according to the description set system for analysis of luciferase Steady-glo™ and the calculation carried out by the device for counting Victor 2. For the positive control select 30 nm standard GLP-1.

1.3 Experimental result

The experimental result of reporter gene for candidate compounds is as shown in figure 1 and in table 1.

Figure 1 shows that the compound wang 520 at a final concentration of 30 μm has the best relative activity (94%), which significantly increased compared with the potency of the compound 2f.

In addition, compounds as shown in table 1, have the dose dependence of the activity of GLP-1R, where the average effective dose (EU50) compounds wang 520, wang 516, wang 554, 488 wang, wang 516-2, wang 502 and wang 504 is less than 10 μm. This result gives orientation to determine the best structure for interaction the connection with the GLP-1R.

Table 1
The connection numberEC50/mcm
wang 52446,5
wang 5204,6
wang 462the 11.6
wang 5166,85
2f13,0
wang 86654,41
wang 5545,24
wang 488of 6.73
wang 516-2the 6.06
wang 5023,31
wang 5044,87

2. Determining the concentration of intracellular camp

Since the determination of the concentration of intracellular camp indirect detection of the expression of the reporter gene is an indirect method, functional re-screening directly conduct set for camp-detection in order to ensure that the connection can certainly increase the concentration of intracellular camp.

2.1 Experimental materials and tools

Kit for detection of camp (Applied Biosystems Cooperation).

Incubator with carbon dioxide Forma (Forma Cooperation).

The unit of count Victor 2 (Wallac Cooperation).

Strain SOME 293/GLP-IR+Luc, which stably expresses the GLP-1R and the luciferase (National new medicaments screening center).

Connected to the e-candidate: compound 2f.

Standard camp (provided in the kit, Applied Biosystems Cooperation).

2.2 Experimental method

Cells of SOME 293 inoculant in 96-well plate in the amount of 20,000 cells/100 µl/well and cultured at 37°With during the night. Compound 2f was diluted to 1,E-03M, 1,E-04M, 1,E-05M, 1,E-06M 1,E-07M dimethylsulfoxide followed by inoculation in the above 96-tablet amount 1 μl/well and cultivated at 37°C in an atmosphere with 5% CO2within 1 hour. The concentration of intracellular C-AMP detects according to the description of the set of c-AMP-Direct Screen TM system kit.

2.3 Experimental result

The result of the determination of the concentration of intracellular camp is shown in figure 2. As shown in figure 2, with increasing concentration of the compound 2f concentration camp, which is produced when this stimulation, shows an exponential increase. This indicates that the connection 2f has some effect on the signal transfer GLP-1R as an agonist of the GLP-1R. When the concentration of compound 2f is raised to 30 μm and 100 μm, concentration camp tends to decrease, which is caused by cytotoxic action of high concentration of the compound 2f.

Test landscapelaumu activity

For determining the activity of compounds on the binding of ligand receive cells, which have high expre is this GLP-1R, as a ligand is used GLP-1R, labeled125I, adding to the compound-ligand. When the connection-candidate competition between125I-labeled GLP-1, isotope labels on the cell membrane are reduced. In accordance with this it is possible to evaluate the affinity of compounds of the candidate to ligand (J. Mol. Endocrinol. 2000 Vol.25:321-35; J. Biomol Screen, 2000 Vol. 5:377-84).

3.1 Experimental material and tools

Cell strain SOME 293/GLP-IR+Luc (National New Medicaments Screening Center).

Labeled connection:125I-labeled GLP-1 (Amersham Biosciences Cooperation).

Workstation Wallac MicroBata (Perkin Elmer Cooperation).

The collector cells TomTech (TomTec Cooperation).

Buffer solution for testing: 20 mm Tris-HCI (pH 7.4) (Shanghai Shenggong biological engineering technology co. LTD.), 100 mm NaCl (Shanghai Chemical agents Cooperation), 15 mm NaF (Shanghai Chemical agents Cooperation), 2 mm deoxypyridoxine (Sigma Cooperation), 0.2 mm phenylmethylsulfonyl (Sigma Cooperation), Aprotinin (Shanghai Chemical agents Cooperation) (1 μg/ml) and leupeptin (Shanghai chemical agents Cooperation) (1 μg/ml).

Wash solution: 20 mm Tris-HCl (pH 7.4), 100 mm NaCl and 15 mm NaF.

Scintillation fluid (Wallac Cooperation).

Connection-candidate diluted with dimethylsulfoxide at a concentration gradient of 0.1 nm, 1 nm, 10 nm, 100 nm, 1000 nm, 10000 nm and 100,000 nm.

3.2 Experimental method

105cells of SOME 293/GLP-IR+Luc in logarithmic growth phase are incubated together with125I-labeled GLP-1-positive peptide (final concentrat the I 40 PM) in 200 μl of buffer solution for testing at 25° C for 4 hours when added to unlabeled positive peptide or compound candidate. Cells are collected by the collector cells, followed by washing three times with wash solution. To add scintillation fluid and the cells of each well positivt counter Microbata.

3.3 Experimental result

The result of the experiment, the binding of the receptor are shown in table 2. As shown in table 2, compound 21 has a better affinity for the GLP-1 R, and the affinity of the compounds wang 520 and wang 516 are a bit weaker and other compounds essentially does not bind the receptor in the range of test concentrations.

Table 2
The connection numberEU50/mcm
Wang 524>100 mm
Wang 450>100 mm
Wang 405>100 mm
Wang 327>100 mm
Wang 52060-100 microns
Wang 462>100 mm
Wang 866>100 mm
Wang 51640-80 microns
Wang 420>100 mm
2f31 mcm

1. Agonist receptor glucagon-like peptide-1 having the following structure is ing the formula:

where each Ar1and Ar2independently represents a substituted phenyl, and the group substituents specified substituted phenyl are one, two or three groups selected from C1-C6alkoxy, C1-C6-alkanolamine, which is substituted by hydroxyl containing group, the substituents including hydroxyl);3-C6-cycloalkanones,2-C6-alkanolamine; benzoylamine, benzyloxy1-C6alkanolamine; Tenojoki, tert-butoxyphenyl, adamantanamine; and mandelamine; X represents O; Y represents O.

2. Agonist receptor glucagon-like peptide-1 according to claim 1, characterized in that when Ar1represents,

R5is tenor, and R6represents a C1-C6alkyl; and X1represents Oh, and

X2represents Oh,

Ar2represents,

where R2is any one of the following groups of substituents: C1-C6alkanoyl; substituted C1-C6alkanoyl, which contains group-substituents including hydroxyl; C2-C6-alkanoyl; C3-C6-kloeckener; benzoyl; benzyloxy1-C6alkanoyl; tert-butoxycarbonyl; adamantaimai and Mandalay; and X2represents NH.

3. Receptor antagonist glucagon-like peptide-1 according to claim 1, having the following structural formula:

4. The method of obtaining agonist receptor glucagon-like peptide-1 according to claim 1, characterized in that the specified connectionget a substitution reaction product of compoundsand triperoxonane acid with the compound R1COX4where R1, R2and R3this is one of the following groups of substituents: C1-C6alkyl, C1-C6alkanoyl; substituted C1-C6alkanoyl, which contains group-substituents including hydroxyl; C2-C6-alkanoyl; C3-C6-cycloalkenyl; benzoyl; benzyloxy1-C6alkanoyl; tert-butoxycarbonyl; thenoyl; adamantaimai; and Mandalay;

X is O;

Y is O;

X1and X3this is About;

and X2this is NH;

and X4this is Cl or HE.

5. The method of obtaining agonist receptor glucagon-like peptide-1 according to claim 4, characterized in that the solvent used in the reaction is AI substitution is dichloromethane, tetrahydrofuran, dimethylfuran, dichloroethane, toluene, benzene, water, dioxane or a mixture.

6. The method of obtaining agonist receptor glucagon-like peptide-1 according to claim 4, characterized in that the reaction temperature is a temperature from -78°C to room temperature.

7. The method of obtaining agonist receptor glucagon-like peptide-1 according to claim 4, characterized in that as activator in substitution reactions used pyridine, triethylamine, diethylproprion, DMAP, N-methylmorpholine or isobutylparaben.

8. The use of compounds according to claim 1 as an agonist of the receptor for glucagon-like peptide-1 to obtain drugs for the treatment of diseases associated with the violation of glycometabolism, such as type II diabetes, insensitivity to insulin or obese, etc.



 

Same patents:

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to novel compounds of formula (I), its pharmaceutically acceptable salts, possessing qualities of chemokine receptor modulators. Compounds can be applied for asthma, allergic rhinitis, COLD, inflammatory intestinal disease, irritated intestine syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis or cancer. In compound of formula (I) , R1 represents group selected from C1-8alkyl, said group is possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4 , -NR5R6 , phenyl, phenyl is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4,-NR5R6,-SR10,C1-6alkyl and trifluoromethyl; R2 represents group selected from C1-8alkyl, said group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-(C1-6alkyl)-N-(phenyl)amino; R3 represents hydrogen, R4 represents hydrogen or group selected from C1-6alkyl and phenyl, R5 and R6, independently, represent hydrogen or group selected from C1-6alkyl and phenyl, said group being probably substituted with 1, 2 or 3 substituents, independently selected from -OR14, -NR15R16, -COOR14,-CONR15R16, or R5 and R6 together with nitrogen atom, to which they are bound, form 4-7-member saturated heterocyclic ring system, possibly containing additional heteroatom, selected from oxygen and nitrogen atoms, ring possibly being substituted with 1, 2 or 3 substituents, independently selected from -OR14, -COOR14,-NR15R16,CONR15R16 and C1-6alkyl; R10 represents hydrogen or group selected from C1-6alkyl or phenyl; and each from R7, R8, R9, R14, R15, R16 independently represents hydrogen, C1-6alkyl or phenyl; X represents hydrogen, halogeno; Rx represents trifluoromethyl, -NR5 R6 , phenyl, naphtyl, heteroaryl, heteroring can be partly or fully saturated, and one or more ring carbon atoms can form carbonyl group, each phenyl or heteroaryl group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR4, -NR5R6, -CONR5R6, -COR7, -COOR7, -NR8COR9, -SR10, -SO2R10, -SO2NR5R6, -NR8SO2R9, C1-6alkyl or trifluoromethyl; or Rx represents group selected from C1-6alkyl, said group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6, phenyl or heteroaryl, where heteroaryl represents monocyclic or bicyclic aryl ring, containing from 5 to 10 ring atoms, from which 1, 2 or 3 ring atoms are selected from nitrogen, sulfur or oxygen. Invention also relates to methods of obtaining compounds, versions, pharmaceutical composition and application for manufacturing medications using compounds of invention.

EFFECT: obtaining novel compounds of formula (I), its pharmaceutically acceptable salts, possessing properties of chemokine receptor moduators.

25 cl, 138 ex

FIELD: medicine; pharmacology.

SUBSTANCE: in formula (I) V represents -N (R1) (R2) or OR4; R4 represents H, C1-6alkyl, C1-6halogenalkyl or (C1-6alkylen)0-1R4' R4' represents C3-7cycloalkyl, phenyl, pyridyl, piperidinyl; and R4' is optionally substituted with 1 or 2 identical or different substitutes chosen from group consisting of C1-4alkyl, amino, C1-3alkylamino, C1-3dialkylamino, phenyl and benzyl; and each R1 and R2 independently represents L1, where L1 is chosen from group consisting from H, C1-6alkyl, C2-6alkenyl, C2-6alkinyl, - adamantyl, pyrrolidinyl, pyridyl, or R1 and R2 together with nitrogen atom to which attached, form X, where X represents pyrrolidinyl, piperazinyl, piperidinyl, morpholino; where X is optionally substituted with Y, where Y represents dioxolanyl, C1-9alkyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrrolidinyl; and where X and Y are optionally split with Z, where Z represents -C1-3alkylen-, C1-3alkylen-. Other radical values are specified in formula of invention.

EFFECT: effective application for treatment of migraine and other headache mediated by action of CGRP-receptors.

34 cl, 11 dwg, 6 tbl, 201 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

Crystal form // 2339634

FIELD: chemistry.

SUBSTANCE: (E)-2-(5-Chlorothiene-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl} ethensulfonamide in essentially crystal form has powder radiograph, expressed in angle values 20, and obtained by means of difractometer, including peaks, located in the following positions expressed in angles 2θ: 9.1-9.2 (±0.1), 16.0-16.1(±0.1), 18.0-18.2 (±0.1) and 18.3-18.4 (±0.1) degrees, and term "essentially crystal form" means that said form is mainly free from amorphous form of (E)-2-(5-Chlorothiene-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl} ethensulfonamide, and by term "mainly free from" content of amorphous form less than 50% is meant.

EFFECT: increased activity.

15 cl, 2 dwg, 5 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new derivatives of 2-pyridinecarboxamide and their pharmaceutical salts, which have glucokinase activating properties. In formula (I): D represents O or S; R2 and R3 each represents a hydrogen atom; formula (II) represents triazole group, imidazole group, thiazole group and pyridine group, which can have in the ring, 1 or 2 substitutes; formula (III) represents a thiazole group, thiadiazole group, isoxazolyl group, pyrazine group, pyridothiazolyl group or pyridyl group, ring B can have 1 or 2 substitutes. The invention also relates to pharmaceutical compositions based on the invented compounds.

EFFECT: new derivatives can be used for treating such diseases as sugar diabetes.

19 cl, 5 tbl, 165 ex

FIELD: chemistry.

SUBSTANCE: new compounds with formula Ia are proposed, where: P represents pyridine or pyrimidine; R1 represents hydrogen; R2 is chosen from halogen, nitro, C0-6alkylheteroaryl, (CO)OR4, trifluoromethyl, C0-6alkylcyano, C0-6alkylNR4R5, OC1-6alkylNR4R5, C0-6alkylCONR4R5, C0-6alkyl(SO2)NR4R5 and X1R6 group, where X1 represents a direct link; R6 represents a 5- or 6-member heterocyclic group, containing one or two heteroatoms, independently chosen from N, O, and S, for which the given heterocyclic group can be unsaturated and can be substituted with by one substitute, chosen from W; m equals 0, 1, or 2; R3 is chosen from CO(OR4), C0-6alkylNR4R5, C0.6alkylCONR4R5, OC1-6alkylNR4R5 C1-6alkyl(SO2)NR4R5; n equals 1 or 2; R4 is chosen from hydrogen, C1-6alkyl; R5 is chosen from hydrogen, C1-6 alkyl, C0-6 alkyl C3-6 cycloalkyl, C0-6 alkylaryl, C0-6alkylheteroaryl and C1-6alkylNR14R15 or R4 and R5 together can form a 4-, 5-, 6- or 7-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O, where the given heterocyclic group can be substituted by group Y; and where any C1-6alkyl, indicated in defining R2-R5, can be substituted with one or more one Z group; R14 and R15 together can form a 5-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O; W and Z are independently chosen from halogen, CN, OR16, C1-6alkyl, trifluoromethyl, trifluoromethoxy, 5-member heterocyclic group, containing one heteroatom, independently chosen from N, for which the given heterocyclic group can be substituted with group Y; Y is chosen from oxo, halogen, C1-6alkyl, C0-6alkylaryl, NR16R17, phenyl, C0-6alkylaryl, where the phenyl and C0-6alkylaryl groups can be substituted with nitro, trifluoromethyl; R16 and R17 are independently chosen from hydrogen and C1-6alkyl, or where R16 and R17 together can form a 5-member heterocyclic group, containing one heteroatom, chosen from N; in form of a free base or pharmaceutical salt. Formula Ia compounds have inhibiting effect to glycogen-synthase-kinase-3 (GSK3). The invention also relates to the method of obtaining the proposed compounds and to new intermediate compounds, used in them, pharmaceutical compositions, containing the given therapeutically active compounds, and use of the given active compounds in therapy for treating conditions, related to GSK3.

EFFECT: new method of obtaining indole derivatives.

33 cl, 1 tbl, 112 ex

Carbonyl compounds // 2337099

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to novel compounds of general formula(I) , where D represents phenyl, pyridyl or tienyl, each of which is single-substituted or double-substituted with Hal; R1 represents H, =O, COOR3, OH, OA, NH2, alkyl, which has 1, 2, 3, 4, 5 or 6 carbon atoms, N3, ethinyl, vinyl, allyloxy, -OCOR3, NHCOA or NHSO2A; R2 represents H, =O, OH, OA or alkyl, which has 1, 2, 3, 4, 5 or 6 carbon atoms; R1 and R2 together alternatively represent spirocyclically linked 3-6-member carbocyclic ring, R3 represents H or A, R4 represents H or A; represents pyrrolidine-1,2-diyl, piperidine-1,2-diyl, oxazolidine-3,4 or 3,5-diyl, thiazolidine-3,4-diyl, 2,5-dihydro-1H-pyrrol-1,5-diyl, 1,3-dioxolane-4,5-diyl; G represents (CH2)n or (CH2)nNH-; X represents CONH; Y represents 1,3- or 1,4-phenylene, which is not substituted or is single-substituted with methyl, trifluoromethyl, ethyl, propyl, Cl or F; T represents morpholine-4-yl, which is single-substituted or double-substituted with carbonyl oxygen; A represents non-branched or branched alkyl, which has 1-10 carbon atoms and in which 1-7 hydrogen atoms can be substituted with F; Hal represents F, CI, Br or I, n represents 0, 1 or 2; and their pharmaceutically acceptable derivatives, solvates, salts or sterioisomers, including their mixtures in all ratios. Invention also relates to method of obtaining formula I compounds, to medication based on formula I compound and application of formula I compounds for preparation of medication, which has inhibiting activity with respect to coagulation factors Xa and VIla.

EFFECT: obtained novel compounds have inhibiting activity with respect to said coagulation factors.

11 cl, 1 tbl, 14 ex

Amid derivative // 2336273

FIELD: chemistry.

SUBSTANCE: invention relates to amid derivatives of formula (I), method of disease treatment and pharmaceutical composition based on them. Compounds can be applied in treatment of different herpes virus infections. In general formula (I) , Z: 1,2,4-oxydiazol-3-yl, 4-oxazolyl, 1,2,3-triazol-2-yl or 2-pyridyl, A: phenyl, which can have a substitute (substitutes) selected from group, including lower alkyl, halogen, halogen-substituted lower alkyl, O-lower alkyl, O-lower alkylene -OH, CN, OH, O-lower alkylene-phenyl, O-lower alkylene-O-lower alkyl, NH2, NH-lower alkyl, N-(lower alkyl)2 ,NH-lower alkylene-OH, NH-lower alkylene-O-lower alkyl, O-lower alkylene- NH2, O-lower alkylene-NH-lower alkyl and O-lower alkylene-N(lower alkyl)2; heteroaryl, representing monocyclic 6-member ring, which contains nitrogen atom as heteroatom or bicyclic 9-member ring, containing 1-2 heteroatoms selected from nitrogen and/or sulfur, which can have a substitute (substitutes), selected from lower alkyl; or phenyl group, condensed with saturated 5-member hydrocarbon cycle; or phenyl group, condensed with saturated 5-member heterocyclic cycle, which contains 1-2 heteroatoms, selected from nitrogen and/or oxygen, which can have a substitute (substitutes), selected from group, including lower alkyl, halogen, -C(O)-lower alkyl, lower alkylene-O-lower alkyl, on condition, that aryl group, condensed with saturated hydrocarbon cycle or aryl group, condensed with saturated heterocyclic cycle is bound with nitrogen atom through carbon atom in aromatic cycle, X: CO, R3: C3-C6cycloalkyl, which can have a substitute (substitutes), selected from group, which includes oxo, OH, halogen, CN, O-lower alkyl, -C(O)-NH2, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)2, lower alkylene-OH, lower alkylene-O-lower alkyl; aryl, selected from phenyl, naphtyl, which can have a substitute (substitutes), selected from halogen; pyridyl; 9-member bicyclic heteroaryl, containing 1-3 heteroatoms, selected from S, N, O; or saturated heterocyclic group, representing monocyclic 6-member group, which contains 1-2 heteroatoms selected from S, SO, SO2, N, O, which can have a substitute (substitutes), selected from halogen.

EFFECT: obtaining amid derivatives that can be applied for treating various herpes virus infections.

17 cl, 26 tbl, 125 ex

FIELD: chemistry.

SUBSTANCE: invention refers to benzothiazole derivatives of general formula I and to their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands and based medicinal product. Compounds can be applied for treatment and prevention of diseases mediated by adenosine receptors, e.g., epilepsy, depressions, narcomania, Parkinson's disease. In general formula I R denotes phenyl unsubstituted or substituted with halogen or -SN2N(CH3) (CH2)nOCH3, or denotes benzyl, lower alkyl, lower alkoxy-group, - (CH2)nOCH3, or denotes pyridine-3- or -4-yl unsubstituted or substituted with lower alkyl, halogen, morpholinyl, - (CH2)n-halogen, - (CH2)nOCH3, - (CH2)n-diethylene-imide oxide-4-yl, or (CH2)n-tetrahydropyrrole-1-yl; R1 denotes phenyl unsubstituted or substituted with halogen tetrahydropyran-4-yl, 3,6-2H-2n-pyran-4-yl or morpholine-4-yl; n denotes mutually independent 1 or 2.

EFFECT: production of benzothiazole derivatives which can be applied for treatment and prevention of diseases mediated by adenosine receptors.

9 cl, 4 dwg, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new compounds presented by the following formula (I), or to the pharmaceutically acceptable salts: , where R1 and R2 represent substitutes, adjoining with each other and with two carbonic atoms, to each of which they are adjoined forming the group presented by the following formula: 1) , or

2) , , , , , , , , or

3) or

4) , , or

where hydrogen atom in each cyclic group can be substituted bi 1-4 substitutes selected fro the following group of substitutes B1, R3 represents hydrogen atom or methyl group; and R6 represents substitute selected from the following group of A1 substitutes, the group of A1 substitutes: (1) hydrogen atom, (2) C1-C6 alkoxy group; substitute B1 group: (1) hydrogen atom, (2) hydroxyl group, (3) oxo group, (4) C1-C6 alkanoyl group, (5) C3-C8 cycloalkyl group, (6) C1-C6 alkyl group (where C1-C6 alkyl group can be substituted by C1-C6 alkoxy group), (7) C1-C6 alkoxy group, (8) C1-C6 alkoxyimino group, (9) C5-C6 cycloalkyl group, derived by two C1-C3 alkyl groups joined to the same carbonic atom with hydrogen atom and the carbons. The invention is also relates to the pharmaceutical composition.

EFFECT: production of the new biologically active compounds and pharmaceutical compositions on their basis having inhibitor potency towards to serotonine1A receptor.

34 cl, 73 ex, 12 tbl, 4 dwg

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to novel compounds of formula (I), its pharmaceutically acceptable salts, possessing qualities of chemokine receptor modulators. Compounds can be applied for asthma, allergic rhinitis, COLD, inflammatory intestinal disease, irritated intestine syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis or cancer. In compound of formula (I) , R1 represents group selected from C1-8alkyl, said group is possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4 , -NR5R6 , phenyl, phenyl is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4,-NR5R6,-SR10,C1-6alkyl and trifluoromethyl; R2 represents group selected from C1-8alkyl, said group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-(C1-6alkyl)-N-(phenyl)amino; R3 represents hydrogen, R4 represents hydrogen or group selected from C1-6alkyl and phenyl, R5 and R6, independently, represent hydrogen or group selected from C1-6alkyl and phenyl, said group being probably substituted with 1, 2 or 3 substituents, independently selected from -OR14, -NR15R16, -COOR14,-CONR15R16, or R5 and R6 together with nitrogen atom, to which they are bound, form 4-7-member saturated heterocyclic ring system, possibly containing additional heteroatom, selected from oxygen and nitrogen atoms, ring possibly being substituted with 1, 2 or 3 substituents, independently selected from -OR14, -COOR14,-NR15R16,CONR15R16 and C1-6alkyl; R10 represents hydrogen or group selected from C1-6alkyl or phenyl; and each from R7, R8, R9, R14, R15, R16 independently represents hydrogen, C1-6alkyl or phenyl; X represents hydrogen, halogeno; Rx represents trifluoromethyl, -NR5 R6 , phenyl, naphtyl, heteroaryl, heteroring can be partly or fully saturated, and one or more ring carbon atoms can form carbonyl group, each phenyl or heteroaryl group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR4, -NR5R6, -CONR5R6, -COR7, -COOR7, -NR8COR9, -SR10, -SO2R10, -SO2NR5R6, -NR8SO2R9, C1-6alkyl or trifluoromethyl; or Rx represents group selected from C1-6alkyl, said group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6, phenyl or heteroaryl, where heteroaryl represents monocyclic or bicyclic aryl ring, containing from 5 to 10 ring atoms, from which 1, 2 or 3 ring atoms are selected from nitrogen, sulfur or oxygen. Invention also relates to methods of obtaining compounds, versions, pharmaceutical composition and application for manufacturing medications using compounds of invention.

EFFECT: obtaining novel compounds of formula (I), its pharmaceutically acceptable salts, possessing properties of chemokine receptor moduators.

25 cl, 138 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to compounds of formula (I) or their pharmaceutically acceptable salts, where Q represents optionally substituted with 1-3 substituents, determined in formula, phenyl or pyridyl or pyrodazinyl; R2 represents C1-6alkyl or aminogroup, determined in item 1 of formula or C1-6alkyl, substituted with said aminogroup; bond between oxygen atom O* and adjacent carbon atom C1 or (i) is double bond, which determines carbonyl group [C(=O)], where R6 represents C1-6alkyl or cyclopropyl; or (ii) represents simple bond, where, in case of simple bond, said oxygen atom O*, is in addition bound to group R6 and, taken together with R6 and with adjacent nitrogen atom, determines optionally substituted with C1-6alkyl, oxadiazolyl ring, bond between C1 and adjacent nitrogen atom being double bond.

EFFECT: obtaining medications which are useful in obtaining medications for treatment of conditions connected with p38 kinase and/or in obtaining medications for treatment of inflammatory diseases or conditions in patient.

8 cl, 6 tbl, 88 ex

FIELD: medicine; pharmacology.

SUBSTANCE: presented are anilides of nicotinic acid of general formula I , where R means atom of hydrogen, halogen or benzyloxy-group, R' means atom of hydrogen or halogen, X means 2-furyl, 2-pyridyl, 3-pyridyl unsubstituted or substituted with phenyl halogen atom with fungicidal activity.

EFFECT: new compound are effective for hazardous fungi.

3 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: in pyridylmethylanilides of heterocyclic acids of general formula I R stands for atom of hydrogen halogen or benzyloxy-group, R' stands for atom of hydrogen or halogen, X stands for 2-phuryl or 2-pyridyl.

EFFECT: increase of compound efficiency against harmful fungi.

1 cl, 3 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula (I) X stands for C, N; R1 stands for H or (lower) alkyl, R2 stands for 9(lower) alkyl, -(CH2)n-R2a; R2a stands for C3-C8cycloalkyl, optionally and independently mono-, di-, tri- or tetrasubstituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent saturated heterocyclic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent heteroaromatic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, C3-C6cycloalkyl; R3 stands for C3-C6cycloalkyl, being optionally and independently mono-, di- or tri- or tetra-substituted with groups: OH, (lower) alkyl, (lower)alkoxy, phenyl, which optionally and independently is mono-, di- or tri- or tetra-substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; R4 stands for 5- or 6-member single-valent heteroaromatic ring, containing from one to two nitrogen heteroatoms, said heteroaromatic ring being optionally and independently mono-, di- or tri- substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, halogen; naphtyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; or phenyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, nitro, halogenated (lower)alkyl, halogenated (lower)alkoxy, cyano, (lower)alkylsulfonyl, -NR7R8; or two neighbouring substituents in said phenyl residue together represent -O-(CH2)p-O-, -(CH2)2-C(O)NH-; R5 and R6 each independently represent H, (lower)alkyl; R7 and R8 each independently represent hydrogen, (lower)alkyl, or R7 and R8 together with nitrogen atom, to which they are bound, form 5- or 6- member saturated or aromatic heterocyclic ring, which optionally contain nitrogen as additional heteroatom; said saturated or aromatic heterocyclic ring, being optionally substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy; m equals 1 or 2, n equals 0 or 1, p equals 1, 2 or 3; or their pharmaceutically acceptable salts.

EFFECT: increased antagonistic activity of compounds.

19 cl

FIELD: chemistry.

SUBSTANCE: invention pertains to new compounds with general formula: , where R is -(CH2)n-A, where A: where each of B and C independently represent phenyl or phenyl substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl) and -NO2; or n equals an integer from 0 to 3; n1 equals an integer from 1 to 3; n2 equals an integer from 0 to 4; n3 equals an integer from 0 to 3; n4 equals an integer from 0 to 2; X1 is chosen from a chemical bond -S-, -S(O)2-, -NH-, -NHC(O)- and -C=C-, R1 is chosen from C1-C6alkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, tetrahydropyranyl, CN, -N(C1-C6alkyl)2, phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, naphtyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, piperizinyl, thiazolydinyl, thiomopholinyl, tetrazolyl, benzoxazolyl, imidazolidine-2-thionyl, 7,7-dimethylbicyclo[2.2.1]heptane-2-onyl, benzo[1.2.5]oxadiazolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl and pyrrolyl, each of which can be optionally substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NO2, -SO2(C1-C3alkyl), -SO2NH2, -SO2N(C1-C3alkyl)2, -COOH, -CH2-COOH, pyridyl, 2-methylazolyl, morpholino, 1-chloro-2-methylpropyl, phenyl, (optionally substituted with one or more halogens), benzyloxy, and , X2 selected from -O-, -CH2-, -S-, -SO-, -SO2-, -NH- and , R2 represents a ring group, chosen from a phenyl or thienyl group. Each ring group is substituted with a group with formula -(CH2)n4-CO2H; and besides that, the ring group can optionally be substituted with 1 or 2 extra substitutes, independently chosen from halogen, - C1-C6alkyl and -C1-C6alkoxy; R3 is chosen from H, halogen and -NO2; R4 is chosen from H, halogen and morpholino; or its salt form, used in pharmaceuticals. The invention also relates to pharmaceutical compositions, to methods of treatment, and to compounds with formula (A).

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on them, which have inhibiting effect on cytosolic phospholipase A2.

45 cl, 300 ex

FIELD: medicine; pharmacology.

SUBSTANCE: subjects of invention are also pharmaceutical drugs or agents for prophylaxis and treatment of neuropathy, increase of production and treatment of the neurotrophic factor, for pain relief, for nerve protection, for prophylaxis and treatment of the neuropathic pain containing compound of the formula or of the formula . In the compounds of the formulas (I) and (II) symbols and radicals have the meanings mentioned in the invention formula. The specified agents have an excellent effect and low toxicity. There are also proposed ways of treatment and prophylaxis of the abovementioned conditions by means of the compounds of the formula (I) or (II) and application of these compounds for production of the abovementioned agents. Besides, one has proposed methods for production of the specified compounds and intermediate pyrazol compounds.

EFFECT: compound has an effect increasing production and secretion of the neurotrophic factor.

46 cl, 1 tbl, 233 ex

Carbonyl compounds // 2337099

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to novel compounds of general formula(I) , where D represents phenyl, pyridyl or tienyl, each of which is single-substituted or double-substituted with Hal; R1 represents H, =O, COOR3, OH, OA, NH2, alkyl, which has 1, 2, 3, 4, 5 or 6 carbon atoms, N3, ethinyl, vinyl, allyloxy, -OCOR3, NHCOA or NHSO2A; R2 represents H, =O, OH, OA or alkyl, which has 1, 2, 3, 4, 5 or 6 carbon atoms; R1 and R2 together alternatively represent spirocyclically linked 3-6-member carbocyclic ring, R3 represents H or A, R4 represents H or A; represents pyrrolidine-1,2-diyl, piperidine-1,2-diyl, oxazolidine-3,4 or 3,5-diyl, thiazolidine-3,4-diyl, 2,5-dihydro-1H-pyrrol-1,5-diyl, 1,3-dioxolane-4,5-diyl; G represents (CH2)n or (CH2)nNH-; X represents CONH; Y represents 1,3- or 1,4-phenylene, which is not substituted or is single-substituted with methyl, trifluoromethyl, ethyl, propyl, Cl or F; T represents morpholine-4-yl, which is single-substituted or double-substituted with carbonyl oxygen; A represents non-branched or branched alkyl, which has 1-10 carbon atoms and in which 1-7 hydrogen atoms can be substituted with F; Hal represents F, CI, Br or I, n represents 0, 1 or 2; and their pharmaceutically acceptable derivatives, solvates, salts or sterioisomers, including their mixtures in all ratios. Invention also relates to method of obtaining formula I compounds, to medication based on formula I compound and application of formula I compounds for preparation of medication, which has inhibiting activity with respect to coagulation factors Xa and VIla.

EFFECT: obtained novel compounds have inhibiting activity with respect to said coagulation factors.

11 cl, 1 tbl, 14 ex

Amid derivative // 2336273

FIELD: chemistry.

SUBSTANCE: invention relates to amid derivatives of formula (I), method of disease treatment and pharmaceutical composition based on them. Compounds can be applied in treatment of different herpes virus infections. In general formula (I) , Z: 1,2,4-oxydiazol-3-yl, 4-oxazolyl, 1,2,3-triazol-2-yl or 2-pyridyl, A: phenyl, which can have a substitute (substitutes) selected from group, including lower alkyl, halogen, halogen-substituted lower alkyl, O-lower alkyl, O-lower alkylene -OH, CN, OH, O-lower alkylene-phenyl, O-lower alkylene-O-lower alkyl, NH2, NH-lower alkyl, N-(lower alkyl)2 ,NH-lower alkylene-OH, NH-lower alkylene-O-lower alkyl, O-lower alkylene- NH2, O-lower alkylene-NH-lower alkyl and O-lower alkylene-N(lower alkyl)2; heteroaryl, representing monocyclic 6-member ring, which contains nitrogen atom as heteroatom or bicyclic 9-member ring, containing 1-2 heteroatoms selected from nitrogen and/or sulfur, which can have a substitute (substitutes), selected from lower alkyl; or phenyl group, condensed with saturated 5-member hydrocarbon cycle; or phenyl group, condensed with saturated 5-member heterocyclic cycle, which contains 1-2 heteroatoms, selected from nitrogen and/or oxygen, which can have a substitute (substitutes), selected from group, including lower alkyl, halogen, -C(O)-lower alkyl, lower alkylene-O-lower alkyl, on condition, that aryl group, condensed with saturated hydrocarbon cycle or aryl group, condensed with saturated heterocyclic cycle is bound with nitrogen atom through carbon atom in aromatic cycle, X: CO, R3: C3-C6cycloalkyl, which can have a substitute (substitutes), selected from group, which includes oxo, OH, halogen, CN, O-lower alkyl, -C(O)-NH2, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)2, lower alkylene-OH, lower alkylene-O-lower alkyl; aryl, selected from phenyl, naphtyl, which can have a substitute (substitutes), selected from halogen; pyridyl; 9-member bicyclic heteroaryl, containing 1-3 heteroatoms, selected from S, N, O; or saturated heterocyclic group, representing monocyclic 6-member group, which contains 1-2 heteroatoms selected from S, SO, SO2, N, O, which can have a substitute (substitutes), selected from halogen.

EFFECT: obtaining amid derivatives that can be applied for treating various herpes virus infections.

17 cl, 26 tbl, 125 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , where R1 represents phenyl group, containing 1-3 substitutes, selected from halogen and cyano group; R2 represents pyridyl group, which has 1-3 substitutes, selected from monocyclic or polycyclic heterocyclic group, which can have 1-3 substitutes, selected from halogen atoms, cyanogroup, as well as other values of R2 radical, given in formula of invention, R3 represents phenyl group or pyridyl group, which has 1-2 substitutes, selected from halogen and trihalogenmethyl group; R4 represents hydrogen atom; and X represents -SO2-; its salt or its solvate. As well as to medication and pharmaceutical composition, inhibiting production or secretion of β-amyloid protein, and containing compound of formula (I), and to application of compound of pt.1 in order to obtain medication.

EFFECT: obtaining novel compounds, inhibiting production or secretion of β-amyloid protein.

14 cl, 1 tbl, 296 ex

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