Compounds possessing acivating action on peroxisome proliferator activated receptor subtypes (ppars), and method for producing and using above compounds

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to a compound of formula (I) or its pharmaceutically acceptable salts of formula (I), wherein X represents O, S; Y represents O, S; R1 independently represents H, alkyl; G1 represents ethyl; each G2 and G3 are independently specified in H, alkyl, trifluoromethyl, halogen, nitro, amido, cyano and tetrazolyl. The invention also refers to a pharmaceutical composition possessing activating action on peroxisome proliferator activated receptors subtype α, subtype δ and subtype γ and containing an effective amount of the compound of formula (I) or its pharmaceutically acceptable salts. The compounds of formula (I) are applicable for treating or producing a drug preparation for treating or preventing the diseases associated with peroxisome proliferator activated receptors subtype α, subtype δ and subtype γ. The compounds of formula (I) are produced by a reaction of the compound of formula (III) and the compound of formula (IV) when heated in acetonitrile under reflux in the presence of potassium carbonate to produce the compound of formula (II), to saponify the compound of formula (II) in alcoholic solution in the presence of alkali and to acidify the reaction mixture to produce the compound of formula (I). X, Y, R1, G1, G2 and G3 have the above values; R3 represents a leaving group specified in OH, Cl, Br, I, OTs, OMs.

EFFECT: compounds of phenylpropionic acid possessing the activating action on peroxisome proliferator activated receptors (PPARα, δ, γ).

15 cl, 2 ex

 

Area of technology

The present invention relates to new compounds having an activating effect on the α-subtype, δ-and γ subtype-the subtype of receptor proliferator-activated the peroxisome (PPARs), process for their preparation and medicines containing these compounds, for the treatment of diabetes and cardiovascular disease. The present invention also relates to new intermediate compounds of the compounds and the way they are received.

The level of technology

With the development of production and improve the quality of life metabolic syndrome, characterized by obesity, insulin-independent diabetes (type II diabetes), impaired lipid metabolism and hypertension, occurs worldwide and threaten the health of people largely due to excessive consumption of fats and proteins. Metabolic syndrome not only is associated with genetic characteristics, age, sex, physiological characteristics, nutritional status, food habits, etc. of individuals, but also involved in the violation of the balance of lipid metabolism, energy and carbohydrate metabolism in vivo. Therefore, therapeutic regimen aimed at maintaining a balance of energy, fats and carbohydrates in vivo, it becomes an effective way to treat metabolic syndrome. Nuclear receptors (NR) are in the focus of research�, because they play an important role in maintaining energy balance and balances fats and carbohydrates in the cells, even just the individual. Nuclear receptors can regulate the transcription system dependent genes and thus to show its physiological activity only after the activation of various physiological ligands (for example, saturated and unsaturated fatty acids, metabolites and various synthetic compounds) (Kasuga, J. et al., Bioorg. Med. Chem. 2007, 15, 5177-5190).

In the family of nuclear receptors, receptors proliferator-activated the peroxisome (PPARs), nuclear transcription factors activated by ligands, attract the attention of researchers for over a decade and represent an important regulatory factors in metabolic syndrome (Guan, Y. J. Am. Soc. Nephrol, 2004, 15, 2801-2815). Thus, receptors PPARs play an important role in the pathogenesis, development, treatment and prevention of diseases such as insulin resistance, disorders of glucose tolerance, type II diabetes, obesity, hyperlipidemia, hypertension, cardiovascular diseases, atherosclerosis, etc.

Receptors PPARs are classified into three subtypes: PPARα, PPARδ and PPARγ, which regulate gene expression by binding to specific DNA sequences (Berger, J. et al., The Journal of Biological Chemistry, 1999, 274 (10), 6718-6725). Recepto� PPARα is expressed mainly in the liver, heart, intestine, kidney, and macrophages and can accelerate the metabolism of fatty acids, partially to remove the inflammatory response of macrophages and lower the level of cholesterol low density lipoprotein after activation; receptor PPARγ is expressed in adipocytes, choriocarcinoma and other tissues and not only can lower the blood glucose level and increase insulin sensitivity, but also plays an important role in lipid metabolism, inhibition of cytokines, inflammatory response, regulation of immune response, blood pressure regulation, etc. after activation (Kasuga, J. et al., Bioorg. Med. Chem. 2007, 15, 5177-5190). Compared to the other two subtypes, the physiological function of PPARδ receptor is still unknown. However, recent studies in animal models for pharmacological experiments show that the PPARδ receptor can accelerate the catabolism of fatty acids and increase the uncoupling of oxidation and phosphorylation in adipose tissue and muscle and inhibit inflammation mediated by macrophages. By controlling the increase of body weight, increase the tolerance of the human body, increasing insulin sensitivity and improving the condition of atherosclerosis in various aspects ligands of PPARδ receptor may thus be an effective drug for the treatment of hyperlipidemia, obesity, Insa�norethisterone and atherosclerosis.

Currently none of the "three-channel" agonists affecting all receptors PPARα, PPARδ and PPARγ, is not commercially available as a therapeutic agent anywhere in the world. "Three-band" the agonist receptor PPARα, PPARδ, and PPARγ, was developed by the inventors, can be applied for the treatment of metabolic syndrome, which is mainly characterized by diabetes. The agonist has a function similar to the function glitazones or other agents that increase sensitivity to insulin, but can be applied more widely. Although agonists of the PPARγ receptor, glitazone, can increase insulin sensitivity, a recent clinical results indicate that these agonists can increase the risk of cardiovascular disease. In addition, glitazone have an additional common side effects include increased body weight, and hepatotoxicity. Thus, the inventors have made strenuous efforts to find a new drug which not only can cure diabetes, but also has some protective action on the cardiovascular system.

Research and development of new medicines for the treatment of metabolic syndrome is the focus of many pharmaceutical comp�tions. Chinese pharmaceutical companies are also on the competitive basis, focusing their research on new targets in drug development for the treatment of diabetes. Thus, it is of great clinical importance will be the provision of new compounds having activating effect on the receptor proliferator-activated the peroxisome (PPARα, PPARδ and PPARγ).

Brief description of the invention

One object of the present invention is the provision of a compound of formula I or its pharmaceutically acceptable salts:

where

X represents O, S, NR11or (CR11Rn11,)nwhere n is an integer selected from 1, 2, 3 and 4;

Y is O, S, NR11or (CR11R11,)m, where m is an integer selected from 1, 2, 3 and 4;

R1independently represents H, alkyl or cycloalkyl;

G1independently represents an alkyl or cycloalkyl;

G2and G3each independently selected from H, alkyl, alkoxy, trifloromethyl, halogen (F, Cl, Br), nitro, NR11R11,alkylthio, amido, cyano, carboxyl and tetrazolyl;

R11and R11each independently selected from H and C1-C6of alkyl.

In a preferred compound of formula I X represents S, O Il� NR 11, Y represents O and the other substituents have the meaning defined above. In another preferred compound of formula I, R1independently represents H or C1-C6alkyl and the other substituents have the meaning defined above. In another preferred compound of formula I (G1selected from C1-C6the alkyl and the other substituents have the meaning defined above.

In another preferred compound of formula I (G2and G3each independently selected from H, C1-C6alkyl, C1-C6alkoxy, trifloromethyl, F, Cl, Br, nitro, NR11R11,, C1-C6alkylthio, amido, cyano, carboxyl and tetrazolyl, and the other substituents have the meaning defined above.

In another preferred compound of formula I (G1represents ethyl; G2, G3represents F, CF3or methyl and the other substituents have the meaning defined above.

In another preferred compound of formula I, R1is methyl or H and the other substituents have the meaning defined above.

The following compounds of formula I or their pharmaceutically acceptable salts are preferred:

In the present application the term "alkyl" refers to monovalent linear or branched saturated aliphatic hydrocarbon group containing carbon atoms within a certain range. So, for example, "C1-6and alkyl" (or "C1-C6alkyl") refers to any isomer of hexyl and pantile; n-butyl, ISO-butyl, sec-butyl and tert-butyl; n-propyl and ISO-propyl; ethyl; and bromide. As an additional example, "C1-4alkyl" refers to n-butyl, ISO-butyl, sec-butyl and tert-butyl; n-propyl and ISO-propyl; ethyl; and bromide.

The term "alkenyl" refers to monovalent linear or branched aliphatic hydrocarbon group containing one carbon-carbon double bond and containing carbon atoms within a certain range. So, for example, "C2-C6the alkenyl" (or "C2-6the alkenyl" refers to all isomers hexenyl and pentenyl; 1-butenyl, 2-butenyl, 3-butenyl, ISO-butenyl; 1-propene�, 2-propenyl; and Attila. With regard to the present invention, the alkenyl preferably has the formula-CH=CH-(CH2)1-3CH3.

The term "alkynyl" refers to a monovalent linear or branched aliphatic hydrocarbon group containing one carbon-carbon triple bond and containing carbon atoms within a certain range. So, for example, "C2-C6alkinyl" (or "C2-6alkynyl") applies to all isomers of hexenyl and pentenyl; 1-butenyl, 2-butenyl, 3-butenyl; 1-PROPYNYL, 2-PROPYNYL; and etinil.

The term "alkylene" refers to divalent linear or branched aliphatic hydrocarbon group containing carbon atoms within a certain range. For example, "- C1-6alkylene-" refers to any C1-C6linear or branched alkylene, and "-C1-4alkylene-" refers to any C1-C4linear or branched alkylene. With regard to the present invention, alkylene preferably represents -(CH2)1-6. More preferably, alkylene includes -(CH2)1-4-, -(CH2)2-4-, -(CH2)1-3-, -(CH2)2-3-, -(CH2)1-2- and-CH2-. Also preferably, alkylene selected from-CH2-, -CH(CH3)- and-C(CH3)2-.

The term "cycloalkyl" refers to Liu�WMD monocyclic alkane, containing the number of carbon atoms within a certain range. For example, "C3-8cycloalkyl" (or "C3-C8cycloalkyl") refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term "cycloalkenyl" refers to any monocyclic an alkene containing a number of carbon atoms within a certain range. For example, "C5-8cycloalkenyl" (or "C5-C8cycloalkenyl") refers to cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctanol.

The term "halogen" (or "halo") refers to fluorine, chlorine, bromine and iodine.

The term "haloalkyl" refers to alkyl, as defined above in which one or more hydrogen atom has been substituted by halogen atom (i.e., F, Cl, Br and/or I). For example, "C1-6halogenated" (or "C1-C6halogenated alkyl" refers to C1-C6linear or branched alkyl, as defined above, containing one or more halogen atoms as substituents. The term "foralkyl" has a definition similar to the one above, except that the halogen Deputy identified as fluoride. Suitable foralkyl comprises a group of (CH2)0-4CF3(i.e. triptoreline, 2,2,2-triptoreline, 3,3,3-Cryptor-n-propyl, etc.). More preferably, foralkyl is �Wallpaper CF 3.

The compound can be administered in the form of its pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to salt that has the effectiveness of the parental compounds, but does not exhibit undesirable biological properties or undesirable properties in other aspects (i.e. which is non-toxic and safe for the subject). Suitable salts include acid additive salts, which can be, for example, formed by mixing a solution of the compounds according to the present invention and a solution of pharmaceutically acceptable acids (such as hydrochloric acid, sulfuric acid, acetic acid or benzoic acid). In the case where the compound used according to the present invention contains acid fragment (such as-COOH or a phenolic group), a suitable pharmaceutically acceptable salt may include alkali metal salts (such as sodium salts or potassium salts), salts of alkaline earth metals (such as calcium salts or magnesium salts), and salts formed from the compounds and suitable organic ligands such as Quaternary ammonium salts). In addition, in the presence of acid groups (-COOH) or alcohol group can be used pharmaceutically acceptable ester to improve the solubility or hydrolysis properties with�in the connection.

Another object of the present invention is to provide pharmaceutical compositions containing a compound of formula (I). Thus, a dosage form of the pharmaceutical composition is selected from the following pharmaceutical forms: tablets, tablets, film-coated, tablets coated with sugar-coated, tablets with enteric coated, dispersible tablets, capsules, granules, solutions for oral administration and suspensions for oral administration.

Another object of the present invention is to provide a method for the treatment of diseases associated with α-subtype, δ-and γ subtype-the subtype of receptor proliferator-activated the peroxisome (PPARα, PPARδ and PPARγ). Thus, the diseases associated with α-subtype, δ-and γ subtype-the subtype of receptor proliferator-activated the peroxisome (PPARα, PPARδ and PPARγ), selected from hyperglycemia, insulin resistance, hyperlipidemia, obesity, etc.

In accordance with the method of treatment according to the present invention, the compound of formula I, perhaps in the form of its salt or prodrug, may be administered as the sole therapeutic agent or combination of therapeutic agents by any applicable traditional method of administration. Although the compound can be administered separately, usually it�t in combination with transporting pharmaceutical environments which is selected in accordance with the selected by administration and standard pharmaceutical practice. The connection according to the present invention may be, for example, introduced orally, parenterally (including subcutaneous injections, intravenous injection, intramuscular injection, intramammary injection or infusion), by inhalation spray, or rectally, in the form of a unit dose of a medicinal product containing an effective amount of a compound traditional and non-toxic pharmaceutically acceptable carrying environment, adjuvants and excipients. Liquid dosage forms suitable for oral administration such as suspensions, syrups, elixir, etc.), can be prepared according to any method known in the art, using any traditional medium, such as water, glycols, oils, alcohols, etc. Solid compositions suitable for oral administration such as powders, pills, capsules and tablets) can be prepared according to the method known in the art, with the use of solid excipients, such as starch, sugar, kaolin, lubricants, binders, disintegrant etc Parenteral compositions can be prepared according to the method known in this field those�IKI, traditionally with the use of sterilized water as a transporting medium and possibly other components, such as co-solvents. Solutions for injections may be prepared according to the method known in the art, according to which carrying media include saline solutions, glucose solutions or solutions containing a mixture of saline and glucose. Additional description of a method suitable for obtaining the pharmaceutical composition according to the present invention and of ingredients suitable for use in the compositions, can be found in Remington's Pharmaceutical Sciences, 18th Edition, Edited by A. R. Gennaro, Mack Publishing Co., 1990 and in Remington - The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, 2005.

Another object of the present invention is to provide a method for obtaining compounds of formula (I) with reference to the following schema.

where

X, Y, R1, G1, G2and G3have the meanings defined for compounds of formula I, R3is a leaving group selected from HE, Cl, Br, I, OTs, OMs, etc.

Preferably, alkyl, alkoxyl and alkylthio in accordance with the present invention contain 1-6 carbon atoms; and cycloalkyl contains 3-8 carbon atoms.

In a preferred embodiment of the present invention a method of producing includes: n�GREVENA compound III and compound IV in acetonitrile to reflux in the presence of potassium carbonate for the purpose of obtaining the compound II; saponification of compound II in an alcoholic solution in the presence of alkali; and acidification of the reaction mixture after completion of the reaction in order to obtain the target compound I.

Thus, compound IV can be obtained in accordance with the description in reference to the patent WO/2005/054176 using the following schema:

Another objective of the present invention is to provide a method for obtaining a compound of formula III using the following schema:

where R1= Η or C1-C6alkyl; X = a leaving group selected from Cl, Br, I, OTs, OMs, etc.; R2= hydroxyamides group; R3= a leaving group selected from Cl, Br, 1, OTs, OMs, etc.

Compound XII, acting as the initial substance, is subjected to protection of hydroxyl group, and then a halogen or hydroxyl (can be converted to sulfonate) is introduced into the molecule of the compounds in α-position to the acyl Deputy to the leaving group. Next, the obtained product is subjected to reaction with NaN3with the formation of the azide. Azide is subjected to hydrogenation to obtain the amine and then subjected to reaction with a suitable acylchlorides for the purpose of obtaining an amide. Amide is treated with phosphorus oxychloride with the aim of producing a product of cyclization. Hydroxyamides group is removed from the product �clitatii, and unprotected hydroxyl is converted into a halogen or sulfate for the purpose of obtaining compound III.

Model drug screening

Experimental procedure the model drug screening is carried out as follows:

1) a Brief description of the model of screening associated with nuclear receptors

By applying the gene-reporter, create a model of screening for screening for agonists of nuclear receptors in living cells based on the principle that nuclear receptor after activation, can activate the transcription of the regulated gene they. Construct the plasmid containing the gene-reporter, in which a DNA sequence that binds to a nuclear receptor (nuclear receptor element, NRE), inserted before luciferase gene so that expression of the luciferase gene is regulated by nuclear receptor. The plasmid containing the gene is a reporter, is transferred into the cell simultaneously with the nuclear receptor. Nuclear receptor will be activated when the agonist of the nuclear receptor will be present in the culture medium for the cells. Activated receptor may induce the expression of luciferase gene, while the amount of generated luciferase can be determined using its fluorescent substrate. Thus, the intensity of activation of the nuclear receptor compound can be determined PU�eat the observation of luminescence intensity. To check the errors of the experiment, caused by factors such as transfection efficiency, the number of seeded cells, toxic compounds, etc., the cells simultaneously cotransfected the plasmid with the gene of green fluorescent protein (green fluorescent protein, GFP) as an internal measure. When analyzing the results of the experiment, the luminescence intensity determined for all wells, verify the values for GFP. The experimental results are expressed as the relative ratio for activation for 1 take control of the solvent. The higher the ratio, the greater the ability to activation.

2) Procedure of the experiment

The detailed Protocol for the experiment on the model of screening can be found at the following link: "Design, synthesis and evaluation of a new class of noncyclic 1,3-dicarbonyl compounds as selective PPARa activators" Bioorg Med Chem Lett. 2004; 14 (13): 3507-11. The detailed procedure is described as follows: Required reagents: compounds to be tested (in DMSO).

(1) Day 1: the Cultivation and seeding of cells

Cell hepatocarcinoma HepG2 (from ATS, American Type Culture Collection) were cultured in culture medium DMEM (motivirovannoe by way of Dulbecco the medium eagle) with 10% inactivated by heating fetal bovine serum (FBS, Invitogen, Grand Island, NY, USA) in the culture flask T-75 (Greiner, Germany), placed in an incubator with 5% CO2at 37°C and for the relative�Noah humidity of 100%. When the cells in the culture flask reached 80-90% of confluence, they were treated with 0.25% solution of pancreatic enzyme (EDTA) for 3 min and were sown in 96-well culture tablet to cell seeding density, component of 2000 cells/100 μl/ well.

(2) Day 2: Transfection of cells

The next day, when cells in 96-well culture tablet has grown to 50-80% confluence, transfection of cells. System cotransfection cells contained agent for transfection FuGene6 (Roche Molecular Biochemicals, Indianapolis, IN, U. S. A.) and 60 ng of DNA (10 ng retinoid X receptor (hRXR), 10 ng plasmid pCMV βGal, 10 ng of plasmid for expression of the nuclear receptors RXR/PPARα, δ, γ, and 30 ng of plasmid containing the gene is a reporter gene of the fluorescent protein GFP, respectively).

(3) Treatment drugs

Culture medium for the cells was removed immediately after 24 hours after transfection and replaced by 200 μl of fresh DMEM containing the investigational medicinal product (with 10% FBS, treated with activated charcoal). The final concentration gradients of the studied drugs was 10 μm, 5 μm, 1 μm, 0.1 μm, and 0.01 μm, about 0.001 μm and 0 μm. 0.05 to 2 μm, posterino acid (purchased from Sigma, USA) was used as positive control. The final concentration of DMSO in each well was 0.1%.

(4) Analysis of the kinase activity of�

After 24 h after treatment with drugs, cells were literally using lysing solution (Cell Culture Lysis buffer, Promega) and centrifuged, and supernatant was collected.The supernatant was subjected to interaction with the reagent kit for analysis of fluorescence (Promega), and calculated fluorescence using a fluorimeter (Fluoroskan Ascent FL reader, Thermo Labsystems, Finland) and determined the relative intensity of luciferase. To analyze the activity of β-galactosidase used in the experiment as an internal measures (internal measure to check the transfection efficiency), 50 µl of the supernatant was transferred to a new microplate, and treated with the Promega kit and read the values with a spectrophotometer for reading the microplates at a wavelength of 405 nm (Bio-tech Instruments Inc., Winooski, VT, USA) (Sauerberg, P.; Olsen, G. S.; Jeppesen, L.; Mogensen, J. P. et al., J. Med. Chem., 2007, 50, 1495-1503).

3) Analysis:

The average effective concentration (EC50) the sample represents the concentration at which the sample exhibits a 50% pharmacological effect, and is one of the important parameters for the evaluation of pharmacological effects of the compounds. In this Protocol screening this concentration was calculated in accordance with activation of the receptor by a sample with 6 different concentrations of the latter.

4) the screening test Results

The results of the screening test show that the compounds of formula I according to the present invention activate receptors α, δ and γ proliferator-activated the peroxisome.

1) the activity of the compounds of formula I in vitro

The activity of compounds of formula I in vitro was investigated in accordance with the following procedure:

a sample (a compound of the formula (I) was dissolved and diluted in various concentrations, the activity of the sample by activation of receptors PPARα, δ, γ were investigated on the basis of concentration gradients, obtained the dependence between concentration and activity and the corresponding expected value of the mean effective concentration (EC50).

Results:

The lower the value of the EC50the higher activity in vitro shows the connection.

Analysis:

The average effective concentration (EC50) is one of the important parameters for the evaluation of pharmacological effects of the compounds. In the Protocol of the present model screening watched the activating effect of the sample on the receptor, with 6 different concentrations, and this may give a General idea for the pharmacological characteristics of the compounds. The profile of the concentration-activity effects the connection was picked up by performing iterative calculations in accordance with the following formula, were calculated and the relevant EU50:

<> As can be seen from the results of the screening of the studied compounds 1, 3 and 5 have the best trigger action on the receptor PPARα, PPARδ receptor and the receptor PPARγ.

The relationship between concentration and activity
Sample # DeputyEC50(μm)
G3R1PPARαPPARγPPARδ
Connection 1F-CH3-0,0290,0130,029
Compound 2F3C-H-5,4950,692<0,001
Union 3F3C-CH3-0,0040,005<0,001
Connect 4But/sup> -CH3-5,4950,0890,851
Connection 5SN3-CH3-1,1750,0040,007
Compound 6CH3-2,6306,7616,761
Connection 7NO2-CH3-2,8840,0250,003
Compound 8NC-CH3-5,2480,0220,006
Connection 9CH3-1,1480,0470,331
Rosiglitazone On0,0015,248
On: not enabled

As can be seen from the above table: with respect to compounds of formula I, compounds in which the Deputy G3represents an electrophilic group, have significantly better EU50for receptors PPARα, PPARγ and PPARδ than compounds in which the Deputy G3represents an electron-donor group, moreover, EC50largely related to the size of the Deputy G3. More than the under, the more the EU50. Among other things, the most affected EU50for receptor PPARα. In addition, compounds in which the substituent R1is methyl, have significantly higher activity in vitro than the compounds in which R1represents N.

2) Screening of part of the compounds of formula (I) according to the present invention on the activity in vivo

Compounds that showed relatively high activity in in vitro screening, were tested for activity in vivo. Applied animal models such as rats line ZDF diabetic mice with genotype db/db mouse lines DIO with obesity induced by diet, etc., for the purpose of determining the effects of drugs.

At present invent�teli completed pharmacodynamic studies in 3 animal models of diabetes, i.e., DB/DB, DIO and ZDF. As for the key indicators in type II diabetes, including tolerance to sugar, plasma insulin, plasma triglycerides, etc., some compounds have similar or better pharmacological effects on reduction of blood sugar levels compared with rosiglitazone. Compounds developed by the inventors, also have a better effect on lowering cholesterol and to reduce the effect of body weight than rosiglitazone, which is exclusively agonist of the PPARγ receptor. The inventors also studied the security taken for screening compounds.

As for LD50, the main indicator for assessing the acute toxicity of the drug, the majority of the compounds are close to rosiglitazone (3-4 g/kg, oral). The autopsy was not found obvious visible damage to major internal organs, and there was statistical difference in the change of the coefficients of bodies.

According to pharmacodynamic studies in combination with verification of toxicity, the inventors hypothesized that the compounds of the formula have the potential to be developed into new medicines for the treatment of type II diabetes.

Examples

The present invention will be explained with reference to the following examples. Specialists in the art will understand that the examples do not exhaust�anywayt method of receiving according to the present invention.

Example 1: Obtain 3-(2-ethyl-4-{2-[2-(4-fluorophenyl)-5-methoxazole-4-yl]ethoxy} phenyl)propionic acid (compound 1)

Connection 1

a) preparation of 2-[2-(4-fluorophenyl)-5-methoxazole-4-yl]ethylmethanesulfonate

Stage 1: Obtain 4-carbonintensity

5-Hydroxy-2-pentanon (0,647 mol) was dissolved in dichloromethane (400 ml), then added 104 ml (1,294 mol) of pyridine. The mixture is cooled to a temperature below 10°C in an ice-water bath and then slowly added dropwise, the benzoyl chloride (90,15 ml, 0,076 mol), maintaining the temperature of the reaction mixture below 10°C. After the addition was complete, the mixture was warmed to room temperature and stirred for 2 days for the reaction. After completion of the reaction, the reaction mixture was washed with water and was extracted with dichloromethane. The organic phase was dried with anhydrous magnesium sulfate, dichloro methane concentrated. The product was distilled under reduced pressure from an oil pump to obtain the intermediate compounds, i.e. 4-carbonintensity, with a yield of 75%.

1H NMR (400 MHz, CDCl3) δ: 2,04-of 2.06 (m, 2H, CH2), of 2.15 (s, 3H, CH3), 2,58-2,61 (m, 2H, CH2), 4,29-of 4.33(m, 2H, och2), 7,41-7,44(m, 2H, ArH), 7,53-to 7.55 (m, H, ArH), 8,00-8,02 (m, 2H, ArH);

13With NMR (75 MHz, CDCl3) δ: 22,9, 30,0, 39,9, 64,1, 128,4, 129,5, 130,2, 133,0, 166,5, 207,6;

MS (+ES): M=206, found 20 (M+1).

Stage 2: Obtain 3-bromo-4-carbonintensity

Intermediate compound, 4-carbonintensity (72 mmol), was dissolved in 75 ml of dichloromethane. The system temperature was maintained below 5°C, then slowly added dropwise bromine (3.7 ml, 72 mmol). After the addition was complete, continued the stirring for half an hour to until the coloration of the reaction system did not disappear. Then the product was washed with water, dried with anhydrous magnesium sulfate and concentrated to give intermediate compounds, i.e. 3-bromo-4-carbonintensity, which was directly used for next step without further purification.

Stage 3: preparation of 3-azido-4-carbonintensity

The intermediate compound, 3-bromo-4-carbonintensity (the product obtained according to the previous stage), was dissolved in 100 ml of DMF and then added 9.3 g (143 mmol) of NaN3. The mixture was stirred over night at room temperature. After completion of the reaction the product was extracted with ethyl acetate, washed with water, dried with anhydrous magnesium sulfate and then concentrated to give intermediate compounds, i.e. 3-azido-4-carbonintensity, which was directly used for next step without further purification. Stage 4: Obtain 3-(4-perbenzoic)-4-carbonylative�ATA

The intermediate compound, 3-azido-4-carbonintensity (the product obtained according to the previous step) was dissolved in 200 ml of methanol was added 2 g of catalyst for the hydrogenation of palladium on charcoal and then run the hydrogen through the solution. Once the reaction was filtered palladium on charcoal, and the product concentrated to give intermediate compounds, i.e. 3-amino-4-carbonintensity. The intermediate compound, 3-amino-4-carbonintensity, was dissolved in 200 ml of ethyl acetate, cooled to 0°C, was added potassium carbonate (30 g, 216 mmol) and added dropwise and tormentilla (72 mmol), maintaining the temperature below 5°C. After completion of the reaction the product was washed with water and was extracted with ethyl acetate. The organic phase was dried with anhydrous magnesium sulfate and concentrated to give the intermediate, i.e. the crude 3-(4-perbenzoic)-4-carbonintensity. The crude product was separated and purified with the receipt of 16.1 g of the intermediate compound with a yield of 65% (overall yield on 3 stages, i.e., stage 2, stage 3 and stage 4).

1H NMR (400 MHz, CDCl3) δ: 2,32-2,41 (m, 4H, CH3and CH2), 2,58-to 2.65 (m, H, CH2), 4,30 (t, J=6,0 Hz, 2H, och2), to 4.92 (m, 1H, NCH), 7,08-7,12 (m, 2H, ArH), 7,27 (s, nl, N, NH), 7,41 was 7.45 (m, 2H, ArH), 7,53-members, 7.59 (m, H, ArH), a 7.85 (d, J=8.4 Hz, 2H, ArH), 7,95 (d, J=8.4 Hz, 2H, ArH);

MS (+ES): M=343, found 344 (M+1).

p> Stage 5: Obtain 2-[2-(4-fluorophenyl)-5-methoxazole-4-yl]ethylbenzoic

The intermediate compound, 3-(4-perbenzoic)-4-carbonintensity (15,4 g, 45 mmol), obtained according to the previous step, was dissolved in 350 ml of toluene and slowly added dropwise to the phosphorus oxychloride (8.5 ml, 90 mmol) at room temperature. After the addition was complete, the mixture was heated for 2.5 hours to reflux. After completion of the reaction, the reaction solution was poured into a mixture of ice water, was extracted with toluene, concentrated and then separated and purified to obtain the intermediate compounds, i.e. 2-[2-(4-fluorophenyl)-5-methoxazole-4-yl]ethylbenzoic (13.2 g, yield 90%).

1H NMR (400 MHz, CDCl3) δ: 2,33 (s, 3H, CH3), 2,96 (t, J=6,4 Hz, 2H, CH2), 4,59 (t, J=6,4 Hz, 2H, och2), between 7.09-7.13 (m, 2H, ArH), 7,41-7,44 (m, 2H, ArH), 7,53-to 7.55 (m, H, ArH), 7,95-8,03 (m, 4H, ArH);

13With NMR (75 MHz, CDCl3) δ: 10,2, 25,8, 63,7, 115,7, 115,9, 124,1, 124,2, 127,9, 128,0, 128,4, 129,6, 130,3, 132,5, 132,9, 144,9, 158,8, 162,5, 165,0, 166,5;

MS (+ES): M=325, found 326 (M+1).

Stage 6: Getting 2-[2-(4-fluorophenyl)-5-methoxazole-4-yl]ethanol

The intermediate compound, 2-[2-(4-fluorophenyl)-5-methoxazole-4-yl] ethylbenzoic is (19.5 g, 60 mmol) was dissolved in 70 ml of ethanol and stirred. Slowly added dropwise 10% sodium hydroxide solution (NaOH: 4.8 g, 120 mmol) and the mixture was stirred over night at room temperature.After completion of the reaction the ethanol was concentrated, and the product was extracted with toluene, and then sequentially washed with water and brine, dried with anhydrous magnesium sulfate and concentrated to give intermediate compounds, i.e. 2-[2-(4-fluorophenyl)-5-methoxazole-4-yl]ethanol, which was directly used for next step without further purification.

Step 7: Obtain 2-[2-(4-fluorophenyl)-5-metrocast-4-yl] ethylmethanesulfonate

The intermediate compound, 2-[2-(4-fluorophenyl)-5-methoxazole-4-yl]ethanol (the product obtained according to the previous step) was dissolved in 200 ml of dichloromethane and then cooled to 0°C. Added triethylamine (100 mmol) at this temperature, and slowly added dropwise MsCl (60 mmol). After the addition was complete, the mixture was warmed to room temperature and stirred over night. After completion of the reaction the product was washed with water, was extracted with dichloromethane, dried with anhydrous magnesium sulfate, concentrated, separated and was purified by preparation of the compound 2-[2-(4-fluorophenyl)-5-metrocast-4-yl]ethylmethanesulfonate (15.6 g, yield 87% over 2 stages).

1H NMR (400 MHz, CDCl3) δ: 2,32 (s, 3H, CH3), 2,91-2,96 (m, 5H, CH2and SO2CH3), 4,51 (t, 2H, och2), between 7.09-7.13 (m, 2H, ArH), 7,92-7,94 (m, H, ArH);

13SAMR (75 MHz, CDCl3) δ: 10,1, 26,2, 37,2, 116,0, 123,9, 128,0, 131,1, 145,5, 158,9, 162,5, 162,6, 165,0;

MS (+C, �C): M=299, found 300 (M+1).

b) the production of ethyl-3-(2-ethyl-4-hydroxyphenyl)propionate

The connection can be obtained in accordance with the description in reference to the patent WO/2005/054176.

b) Obtaining ethyl-3-(2-ethyl-4-{2-[2-(4-fluorophenyl)-5-methoxazole-4-yl]ethoxy} phenyl)propionate and 3-(2-ethyl-4-{2-[2-(4-fluorophenyl)-5-methoxazole-4-yl]ethoxy}phenyl)propionic acid

Original phenolic compound, ethyl-3-(2-ethyl-4-hydroxyphenyl)propionate (10.4 g, 50 mmol) and 120 ml of acetonitrile was added to odnogolosy flask with a volume of 250 ml and stirred. Then added the source of the sulfonate compound, 2-[2-(4-fluorophenyl)-5-methoxazole-4-yl]ethylmethanesulfonate (15 g, 50 mmol) and potassium carbonate (K2CO3) (100 mmol). The mixture was heated for 16 hours to reflux. After completion of the reaction the product was filtered. The filter cake was washed with ethyl acetate (3×50 ml) and then removed. The filtrates were combined and the solvent drove under reduced pressure to obtain crude ethyl-3-(2-ethyl-4-{2-[2-(4-fluorophenyl)-5-methoxazole-4-yl]ethoxy}phenyl)propionate. Crude ethyl-3-(2-ethyl-4-{2-[2-(4-fluorophenyl)-5-methoxazole-4-yl]ethoxy}phenyl)propionate, without purification, was dissolved in 120 ml of ethanol. Added 10% NaOH (30 ml) at room temperature, and continued stirring for 3 hours at room temperature. After completion of the reaction the product was acidified with addition of 10% of thei�branched hydrochloric acid to obtain a solid precipitate. The precipitate was filtered by filtration with suction to obtain crude 3-(2-ethyl-4-{2-[2-(4-fluorophenyl)-5-methoxazole-4-yl]ethoxy}phenyl)propionic acid. The crude product was crystallisable from a mixture of ethyl acetate-petroleum ether to obtain 12.3 g of a white solid with a yield of 62% over 2 stages.

1H NMR (400 MHz, CDCl3) δ: 1,22 (t, J=7,6 Hz, 3H, CH3), is 2.37 (s, 3H, CH3), to 2.59-2.65 (m, 4H, 2CH2), 2,90-to 2.94 (m, 2H, CH2), of 2.97 (t, J=6,4 Hz, 2H, CH2), 4,22 (t, J=6,4 Hz, 2H, OCH2), 6,69-6,76 (m, 2H, ArH), 7,05-7,15 (m, 3H, ArH), 7,96-7,98 (m, 2H, ArH);

13C NMR (75 MHz, CDCl3) δ: 10,2, 15,1, 25,7, 26,3, 26,7, 35,4, 66,6, 111,7, 114,9, 115,0, 115,7, 115,9, 124,0, 128,1, 130,0, 132,7, 143,3, 145,1, 157,5, 158,8, 162,5, 165,0, 179,1;

MS (+ES): M=397, found 398 (M+1), 420 (M+Na).

Example 2:

The following compounds were obtained by the application of appropriate starting materials in accordance with the method according to example 1.

Compound 2, a white solid, yield: 63%

1H NMR (400 MHz, CDCl3) δ: 1,22 (t, J=7,6 Hz, 3H, CH3), 2,59-to 2.65 (m, 4H, 2CH2), 2,89-of 2.93 (m, 2H, CH2), 3,09 (t, J=6,4 Hz, 2H, CH2), 4,27 (t, J=6,4 Hz, 2H, OCH2), 6,70-6,73 (m, 2H, ArH), was 6.77 (d, J=2.4 Hz, 1H, ArH), 7,07 (d, J=8.4 Hz, 1H, ArH), 7.62 mm (s, 1H, OCH=), of 7.70 (d, J=8.4 Hz, 2H, ArH), 8,13 (d, J=8.4 Hz, 2H, ArH);

13C NMR (75 MHz, CDCl3) δ: 15,1, 25,7, 26,7, 26,9, 35,2, 66,0, 111,7, 115,1, 125,7, 125,8, 126,7, 129,4, 130,2, 130,6, 136,1, 139,4, 143,4, 157,4, 178,0;

MS (+ES): M=433, found 438 (M+1), 456 (M+a).

Compound 3, a white solid, yield: 58%

1H NMR (400 MHz, CDCl3) δ: of 1.20 (t, J=7,6 Hz, 3H, CH3), is 2.40 (s, 3H, CH3), 2,57-of 2.64 (m, 4H, 2CH2), 2,88-of 2.92 (m, 2H, CH2), 2,98 (t, J=6,4 Hz, 2H, CH2), 4,22 (t, J=6,4 Hz, 2H, OCH2), 6,67-6,74 (m, 2H, ArH), 6,73 (d, J=2.4 Hz, 1H, ArH), 7,67 (d, J=8.4 Hz, 2H, ARH), 8,08 (d, J=8.4 Hz, 2H, ArH);

13C NMR (75 MHz, CDCl3) δ: 10,3, 15,2, 25,7, 26,3, 26,7, 35,5, 66,5, 111,7, 115,0, 125,6, 125,7, 126,1, 129,7, 130,0, 130,8, 131,2, 133,5, 143,3, 146,1, 157,4, 158,2, 178,7;

MS (+ES): M=447, found 448 (M+1), 470 (M+Na).

Connect 4, a white solid, yield: 72%

1H NMR (400 MHz, CDCl3) δ: 1.17 (t, J=7,6 Hz, 3H, CH3), of 1.27 (s, 9H, C(CH3)3), of 2.35 (s, 3H, CH3), of 2.57 (m, 4H, 2CH2), 2,86 (m, 2H, CH2), 2,96 (t, J=6,4 Hz, 2H, CH2), 4,17 (t, J=6,4 Hz, 2H, -OCH2), 6,67 (m, 2H, ArH), 7,02 (d, J=4.0 Hz, 1H, ArH), 7,43 (d, J=4.4 Hz, 2H, ArH), to 7.89 (d, J=4.4 Hz, 2H, ArH);

13C NMR (100 MHz, CDCl3) 5: 10,2, 15,1, 25,6, 26,2, 26,8, 31,1 (3C), 34,8, 35,6, 66,5, 111,5, 114,8, 124,6, 125,6 (2C), INCLUDING 125.7 (2C), 129,6, 130,0, 132,3, 143,2, 144,7, 153,1, 157,3, 159,6, 178,5;

MS (+ES): M=435, found 436 (M+1).

Compound 5, a white solid, yield: 71%

1H NMR (400 MHz, CDCl3) δ:1,19 (t, J=7,6 Hz, 3H, CH3), of 2.35 (s, 3H, CH3), is 2.37 (s, 3H, CH3), 2,59 (m, 4H, 2CH2), 2,88 (t, J=7,6 Hz, 2H, CH2), 2,96 (t, J=6,4 Hz, 2H, CH2), 4,18 (t, J=6,4 Hz, 2H, CH2), 6,68 (m, 2H, ArH), 7,03 (d, J=8,0 Hz, 1H, ArH), 7.23 percent (d, J=8,0 Hz, 2H, ArH), a 7.85 (d, J=7,6 Hz, H, ARH);

13C NMR (100 MHz, CDCl3) δ: 10,3, 15,2, 21,5, 25,7, 26,2, 26,9, 35,7, 66,6, 111,6, 114,9, 124,7, 126,0 (2C), 129.4 DEATHS (2C), 129,7, 130,1, 132,3, 140,2, 143,3, 144,8, 157,4, 159,8, 178,3;

MS (+ES): M=393, found 394 (M+1).

Compound 6, a white solid, yield: 62%

1H NMR (400 MHz, d-DMSO) δ of 1.11 (t, J=7,6 Hz, 3H, CH3), of 2.35 (s, 3H, CH3), 2,43-2,63 (m, 4H, 2CH2), 2,74 (t, J=6,4 Hz, 2H, CH2), 2,90 (t, J=6,4 Hz, 2H, CH2), 4,17 (t, J=6,4 Hz, 2H, OCH2), 6,61-6,68 (m, 2H, ArH), 6,70 (d, J=2.4 Hz, 1H, ArH), 7,67 (d, J=8.4 Hz, 2H, ArH), 8,08 (d, J=8.4 Hz, 2H, ArH);

13C NMR (100 MHz, d-DMSO) δ: 9,8, 15,1, 25,0, 25,6, 26,2, 35,0, 65,9, 111,5, 114,4, 126,1, 127,3, 128,7, 129,5, 130,2, 133,2, 142,8, 145,6, 155,6, 156,7, 157,5, 173,8;

MS (+ES): M=447, found 448 (M+1), 470 (M+Na).

Compound 7, a white solid, yield: 70%

1H NMR (400 MHz, d-DMSO) δ: of 1.20 (t, J=7,6 Hz, 3H, CH3), 2,42 (s, 3H, CH3), 2,57-2,61 (m, 4H, 2CH2), 2,89 (t, J=7,6 Hz, 2H, CH2), 2,99 (t, J=6,4 Hz, 2H, CH2), 4,21 (t, J=6,4 Hz, 2H, OCH2), 6,67-6,73 (m, 2H, ArH), 7,05 (d, J=8,0 Hz, 1H, ARH), 8,13 (d, J=8,0 Hz, 2H, ArH), 8,29 (d, J=7,6 Hz, 2H, ArH);

13With NMR (100 MHz, d-DMSO) δ: 9,8, 15,0, 25,0, 25,5, 26,2, 35,0, 65,7, 111,4, 114,3, 124,1, 126,2, 129,4, 130,2, 132,2, 134,0, 142,7 146,9, 147,5, 156,4, 156,6, 173,9;

MS (+ES): M=424, found 425 (M+1), 447 (M+Na).

Compound 8, a white solid, yield: 52%

1H NMR (400 MHz, CDCl3) 5: of 0.87 (t, J=7,6 Hz, 3H, CH3), is 2.40 (s, 3H, CH3), 2,59-2,61 (m, 4H, 2CH2), 2,74-2,98 (m, 4H, 2CH2), 4,20 (t, J=6,4 �C, 2H, OCH2), 6,66-6,72 (m, 2H, ArH), 7,05 (d, J=2.4 Hz, 1H, ArH), of 7.70 (d, J=8.4 Hz, 2H, ArH), 8,06 (d, J=8.4 Hz, 2H, ArH);

13C NMR (100 MHz, CDCl3) δ: 10,3, 15,2, 25,6, 26,3, 26,7, 35,4, 66,4, 111,6, 112,9, 114,9, 118,5, 126,2, 129,7, 130,0, 131,3, 132,5, 133,9, 143,3, 146,7, 157,3, 157,6, 178,5;

MC (+C, ES): M=404, found 405 (M+1), 427 (M+Na).

Connection 9, a white solid, yield: 64%

1H NMR (400 MHz, CDCl3) δ: of 1.12 (t, J=7,2 Hz, 3H, CH3), is 2.37 (s, 3H, CH3), 2,43 (t, J=7,2 Hz, 2H, CH2), 2,51-2,56 (m, 4H, 2CH2), of 2.72 (t, J=7,2 Hz, 2H, CH2) or 2.91 (m, 2H, CH2), 4,17 (t, J=7,2 Hz, 2H, OCH2), 6,68-6,70 (m, 2H, ArH), to 7.04 (d, J=7,6 Hz, 1H, ArH), 7,51 (s, br, 1H, ArH), 7,93-and 8.04 (m, 4H, ArH), 8,12 (s, br, 1H, ArH);

13C NMR (100 MHz, CDCl3) δ: 9,8, 15,2, 25,0, 25,6, 26,3, 35,1, 65,9, 111,6, 114,5, 125,2, 128,2, 129,2, 129,6, 130,3, 133,0, 135,2, 142,8, 145,7, 156,7, 157,7, 167,2, 173,9;

MC (+C, ES): M=422, found 423 (M+1), 445 (M+Na).

Connection 10, a white solid, yield: 65%

1H NMR (400 MHz, CDCl3) δ: to 1.21 (t, J=7,6 Hz, 3H, CH3), 2,58-of 2.64 (m, 4H, 2CH2), 2,89-of 2.93 (m, 2H, CH2), of 3.07 (t, J=6,4 Hz, 2H, CH2), 4,25 (t, J=6,4 Hz, 2H, OCH2), 6,69-was 6.77 (m, 2H, ArH), 7,06-7,15 (m, 3H, ArH), 7,55 (s, 1H, OCH=), 7,98-8,02 (m, 2H, ArH);

13C NMR (75 MHz, CDCl3) δ: 15,2, 25,7, 26,7, 26,8, 35,4, 66,1, 111,7, 115,0, 115,8, 116,1, 123,8, 128,5, 129,7, 130,2, 135,3, 138,9, 143,4, 157,4, 160,8, 162,8, 165,3, 178,5;

MC (+C, ES): M=383, found 384 (M+1).

Connection 11, a white solid, yield: 54%

1H NMR (400 MHz, CDCl3) δ: 1,22 (t, J=7,6 Hz, 3H,CH 3), of 1.33 (t, J=7,6 Hz, 3H, CH3), 2,59-of 2.66 (m, 4H, 2CH2), 2,79 (K, J=7,6 Hz, 2H, CH2), 2,90-to 2.94 (m, 2H, CH2), 3,01 (t, J=6,4 Hz, 2H, CH2), 4,23 (t, J=6,4 Hz, 2H, OCH2), 6,69 to 6.75 (m, 2H, ArH), 7,07 (d, J=7,2 Hz, 1H, ArH), of 7.70 (d, J=8,0 Hz, 2H, ArH), 8,11 (d, 7=8,0 Hz, 2H, ArH);

MC (+S, ES): M=461, found 462 (M+1), 484 (M+Na).

1. The compound of formula (I) or its pharmaceutically acceptable salt:

where
X is O, S;
Υ is O, S;
R1independently represents H, alkyl;
G1represents ethyl;
G2and G3each independently selected from H, alkyl, trifloromethyl, halogen, nitro, amido, cyano and tetrazolyl.

2. The compound according to claim 1, characterized in that X represents S or O, Υ represents O.

3. The compound according to claim 1, characterized in that R1independently represents Η or C1-C6alkyl.

4. The compound according to claim 3, characterized in that R1is methyl or N.

5. The compound according to claim 1, characterized in that G2and G3each independently selected from H, C1-C6of alkyl, trifloromethyl, F, Cl, Sh, nitro, amido, cyano and tetrazolyl.

6. The compound according to claim 5, characterized in that G1represents ethyl; G2and G3represents F, CF3or methyl.

7. The compound according to claim 1, selected from:


or its pharmaceutically acceptable salt.

8. Pharmaceutical composition having an activating effect on the α-subtype, δ-and γ subtype-the subtype of receptor proliferator-activated the peroxisome that contains an effective amount of a compound according to any one of claims.1 to 7 or its pharmaceutically acceptable salt.

9. Pharmaceutical composition according to claim 8 with a dosage form selected from
tablets, tablets, film-coated, tablets coated with sugar-coated, tablets with enteric coated, dispersible tablets, capsules, granules, solutions for oral administration and suspensions for oral administration.

10. Use of a compound according to any one of claims.1-7 to obtain drugs for treatment or prevention of diseases associated with α-subtype, δ-and γ subtype-the subtype of receptor proliferator-activated the peroxisome.

11. The use according to claim 10, characterized in that the diseases associated with α-subtype, δ-and γ subtype-the subtype of receptor proliferator-activated the peroxisome selected from hyperglycemia, insulin resistance, hyperlipidemia and obesity.

12. Use of a compound according to any one of claims. 1-7 for the treatment and prevention of diseases associated with α-subtype, δ-and γ subtype-the subtype of receptor proliferator-activated perk of�ICOM.

13. The method of obtaining compounds of formula (I) according to claim 1, including

where
Χ, Υ, R1, G1, G2and G3have the meanings defined in claim 1, R3is a leaving group selected from HE, Cl, Br, I, OTs, OMs.

14. A method according to claim 13, comprising heating a compound of formula (III) and compounds of formula (IV) in acetonitrile to reflux in the presence of potassium carbonate to produce a compound of formula (II); saponification of a compound of formula (II) in alcoholic solution in the presence of alkali; and acidification of the reaction mixture after completion of reaction to give the desired compounds of formula (I).

15. A method according to claim 13 or 14, characterized in that the compound (III) is prepared in accordance with the following method:

where
R1represents Η or C1-C6alkyl;
X is a leaving group selected from Cl, Br, I, OTs and OMs;
R2is hydroxyamides group;
R3is a leaving group selected from Cl, Br, I, OTs, OMs;
Y, R1, G2and G3have the meanings given in claim 1.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and their pharmaceutically acceptable salts, wherein A is thiazolyl, oxazolyl, thienyl, furyl, imidazolyl, pyrazolyl or oxadiazolyl (structures of which are presented in cl.1 of the patent claim), R1 represents C1-6alkyl; R2 represents (i) phenyl substituted by halogen; C1-6alkyl optionally substituted by morpholine or C1-6dialkylamino; C1-6alkoxy optionally substituted by halogen; or heterocyclyl, wherein a heterocyclyl substitute is specified in morpholine; pyrazolyl optionally substituted by C1-6alkyl; piperidinyl; pyrrolidinyl; oxadiazolyl substituted by C1-6alkyl; furyl substituted by C1-6alkyl; dioxydoisothiazolidinyl; triazolyl; tetrazolyl substituted by C1-6alkyl, tridiazolyl substituted by C1-6alkyl; thiazolyl substituted by C1-6alkyl; pyridyl; or pyrazinyl; (ii) substituted or unsubstituted heterocyclyl specified in quinolinyl; pyridyl substituted by C1-6alkoxy or morpholinyl; or benzo [d] [1, 2, 3] triazolyl substituted by C1-6alkyl; R3 represents phenyl substituted by 2 or 3 substitutes specified in halogen; C1-6alkyl; C1-6alkoxy optionally substituted by halogen; hydroxy group; cyano; or -C(=O)ORa, wherein Ra represents phenyl; R4 represents hydrogen, C1-6alkyl or C1-6halogenalkyl. The invention also refers to a pharmaceutical composition containing the compounds of formula (I), a method for PDE10 inhibition, a method of treating neurological disorders, and to intermediate compounds: 2-(4-chlor-3,5-dimethoxyphenyl)furan and 4-(5-methyl-1,3,4-thiadiazol-2-yl)benzaldehyde.

EFFECT: compounds of formula (I) as PDE10 inhibitors.

39 cl, 13 ex, 2 tbl, 77 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula (I), which possess the properties of HCV polymerase inhibitors. In formula , is specified in a group consisting of a single carbon-carbon bond and a double carbon-carbon bond; R1 and R3 are specified in hydrogen and methyl; R2 represents hydrogen; R5 is specified in a group consisting of hydrogen, hydroxy, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C2-C6alkenyloxy, C3-C6alkynyloxy and halo; L represents a bond, and R6 represents a condensed 2-ring carbocyclyl, wherein each substitute is optionally substituted by one or more substitutes independently specified in a group consisting of RE, RF, RG, RH, RI, RJ and RK; or L is specified in a group consisting of a bond, C≡C, C(O)N(RC), N(RD)C(O), C1-C2-alkylene, C(H)2O, OC(H)2, cyclopropyl-1,2-ene, C(H)2N(RL), N(RM)C(H)2, C(O)CH2 and CH2C(O), and R6 is specified in a group consisting of C5-C6-carbocyclyk and 5-6-merous heterocyclyl, wherein each substitute is optionally substituted by one or more substitutes independently specified in a group consisting of RE, RF, RG, RH, RI, RJ, RK, RL and RM; the R4, RE, RF, RG, RH, RI, RJ, RK, RL and RM values are presented in the patent claim.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, to using the compounds for producing a drug preparation for HCV RNA polymerase inhibition and hepatitis C treatment, and to a method for preparing the above compounds.

21 cl, 46 dwg, 42 tbl, 140 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula I, their pharmaceutically acceptable salts and crystalline forms, which possess the properties of HCV polymerase inhibitor. In formula I is specified in a group consisting of a single carbon-carbon bond and a double carbon-carbon bond; R1 represents hydrogen; R2 is specified in a group consisting of hydrogen and halo; R3 represents hydrogen; R4 is specified in a group consisting of halo, C1-C6alkyl, C1-C6alkylsulphonyl and 5-6-merous heteroaryl containing heteroatom specified in N, O and S, wherein alkyl is optionally substituted by one or more hydroxy; R5 is specified in a group consisting of hygrogen, hydroxy, C1-C6alkyloxy and halo; L is specified in a group consisting of C(RA)=C(RB), ethylene and cyclopropyl-1,2-ene; RA and RB are independently specified in a group consisting of hydrogen, C1-C6alkyl, C1-C6alkyloxy and halo; R6 represents C6aryl optionally substituted by one or more substitutes independently specified in a group consisting of RE, RF, RG, RH, RI and RJ; the substitutes RE, RF, RG, RH, RI and RJ are presented in the patent claim.

EFFECT: invention refers to the pharmaceutical composition containing the above compounds, to using the compounds for inhibiting HCV RNA-polymerase and treating hepatitis C and to a method of preparing the above compounds.

40 cl, 23 dwg, 7 tbl, 40 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula (Ip1) or (Ip3) or its pharmaceutically acceptable salt, where G1 represents (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)halogenalkyl, (C1-C4)halogenalkoxy, halogen, cyano or nitro; n equals 0; G2a represents (C3-C4)cycloalkyl or (C3-C4)cycloalkyl(C1-C2)alkyl; G2b represents hydrogen; R1 represents methyl or ethyl; R2 represents phenyl or fluorophenyl; and R3 represents 2-hydroxy-2-methylpropyl or 2-methyl-2-cyanopropyl.

EFFECT: invention relates to application of compound of formula (Ip1 and Ip3) for manufacturing medication or pharmaceutical composition, intended for treating a person with disease or state, selected from type II diabetes mellitus, obesity, glucose intolerance, hyperglycemias, hyperlipidemis, insulin resistance, decrease of cognitive functions and dyslipidemia.

5 cl, 6 tbl, 107 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyrimidine derivatives of structural formula (I-L0) and their crystalline forms possessing the inhibitory activity on the hepatitis C virus (HCV) polymerase. In formula is specified in a single or double carbon-carbon bond; R1, R2 and R3 represent hydrogen; R4 is specified in halo, C1-C6alkyl, C2-C6alkinyl, amino, C1-C6alkylsulphonyl, C3-C10carbocyclyl and 5-6-merous heterocyclyl having a heteroatom specified in a group consisting of O and S, wherein amino is optionally substituted by one or two C1-C6alkylsulphonyls, and C1-C6alkyl and C2-C6alkynyl are optionally substituted by one or more substitutes optionally specified in a group consisting of halo, oxo, hydroxy, C1-C6alkyloxy and trimethylsilyl, and C3-C10carbocyclyl and 5-6-merous heterocyclyl are optionally substituted by substitutes specified in C1-C6alkyl, halo and amino, wherein amino is optionally substituted by one or two C1-C6alkylsulphonyls; R5 is specified in a group consisting of hydrogen, hydroxy, C1-C6alkyloxy and halo; R6 represents a condensed 2-ring C3-C10carbocyclyl optionally substituted by substitutes specified in RE, RF, RG, RH, RI, RJ and RK, the values of which are specified in the patent claim.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, to using the compounds for producing a therapeutic agent for hepatitis C, to an intermediate compound for producing the compound of structural formula (I-L0) and to a method for preparing the above compounds and their crystalline forms.

70 cl, 23 dwg, 9 tbl, 83 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a new compound of formula or its pharmaceutically acceptable salt, wherein R1 represents (C1-C6)alkyl; an oxodihydropyridyl ring in the formula is optionally substituted by 1-3 groups optionally specified in fluorine, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, halo(C1-C6)alkyl and (C1-C6)alkoxy(C1-C6)alkoxy; R2 represents (C1-C6)alkyl, phenyl, or tetrahydropyranyl optionally substituted by a group in the number of up to 1 independently specified in fluorine, hydroxy(C1-C6)alkyl and (C3-C6)cycloalkyl; R3 is specified in (C1-C6)alkyl optionally substituted by groups in the number of up to 3 independently specified in fluorine, cyano, R4, R4O-, (R4)2N-, R4C(=O)NR4-, (R4)2NC(=O)-, R4OC(=O)NR4-, R4S(=O)2NR4- and oxadiazolyl optionally substituted by (C1-C6)alkyl; R4 independently represents H or (C1-C6)alkyl. Also, the invention refers to a method of treating an individual by using the above compound, a method of inhibiting 11β-HSD1, and a compound-based pharmaceutical composition.

EFFECT: there are prepared new compounds effective in treating the diseases related to 11β-HSD1 activity or expression.

15 cl, 6 tbl, 101 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new phenylpyrimidone derivatives of formula I possessing the properties of a phosphodiesterase type 5 (PDE5) inhibitor. The compounds of formula I can be used for treating various vascular disorders, such as erectile dysfunction, pulmonary arterial hypertension, etc. In formula each R1 and R2 independently means H; C1-C10alkyl; halogen; CF3; CN; OR5; NR6R7; NHCOR8; aryl; or C1-C4alkyl optionally substituted by OR5; Z means OR3; R3 means C1-C6alkyl or C1-C3alkyl, substituted by C1-C3alkoxy group; R4 means SO2NR6R7; NR9R10, providing NR9R10 is other than NH2; COR11; OR12; or R4 means 5-6-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of OH and C1-C6 alkyl; or R4 means 5- or 6-merous cyclic monosaccharide group; R5 means C1-C6alkyl; C1-C4alkyl optionally substituted by C1-C4alkoxy group; each R6 and R7 independently means H, OH, C1-C6alkyl, C1-C6alkoxy group, C3-C6alkenyl, C3-C6cycloalkyl, adamantyl, C3-C8lactamyl, aryl, Het or (CH2CH2O)jH, wherein j is 1-3; or each R6 and R7 independently means C1-C6alkyl, optionally substituted by OH, C1-C4alkoxy group, SO3H, SO2NR13R14, SO2R16, NR13R14, aryl, Het or 5-6-merous heterocyclyl; or each R6 and R7 independently means 5-6-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of C1-C6 alkyl and C1-C6alkyl substituted by hydroxyl; or R6 and R7 together with a nitrogen atom attached whereto form 5-7-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of OH, COOR8, (CH2CH2O)jH, wherein j is 1-3, C1-C4alkoxy group, Het and C1-C6alkyl substituted by aryl; or R6 and R7 together with a nitrogen atom attached whereto form a glucosyl amino group, an amino acid residue, a residue of an amino acid ester or an amino amide residue. The other radical values are specified in the patent claim.

EFFECT: invention refers to pharmaceutical compositions based on the above compounds, using them, methods for preparing the compounds, and intermediate products.

18 cl, 2 tbl, 224 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 4-substituted-N-phenyl-1,8-naphthalimides which contain in the N-aryl nucleus a crown ether residue (with a different combination of oxygen, nitrogen and sulphur atoms) of general formula (I) , where R1=NO2, Br, NH2, OCH3, NHCOCH3, Ia: Rl=NO2, X=S, n=1; Ib: R1=NO2, x=NCH3, n=1; Ic: R1=NO2, X=NCH3, n=2; Id: R1=Br, X=NCH3, n=2; Ie: R1=NH2, X=S, n=1; If: R1=NHCOCH3, X=S, n=1; Ig: R1=OMe, X=S, n=1; Ih: R1=OMe, X=NCH3, n=1; Ii: R1=OMe, X=NCH3, n=2, where compounds If-Ii exhibit properties of fluorescent sensors on cations of alkali-earth, transition and heavy metals, and compounds Ia-Ie are intermediate compounds in the process of synthesis of compounds If-Ii. The invention also relates to a method of producing a compound of formula (I) and intermediate compounds of formula (II)

EFFECT: obtaining novel sensors on cations of alkali-earth, transition and heavy metals, novel methods of producing compounds of the given formula.

7 cl, 3 tbl, 7 ex

Cetp inhibitors // 2513107

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I, or its pharmaceutically acceptable salt where: X stands for -O-; Z stands for -C(=O)-; Y stands for -(CRR1)-, where R1 is selected from -C1-C2alkyl; R stands for H or -C1-C5alkyl; R5 stands for H; R2 and B each is selected from A1 and A2, where one of R2 and B stands for A1, and the other from R2 and B stands for A2; where A1 has structure (a); A2 is selected from the group, which includes phenyl, pyridyl, pyrazolyl, thienyl, 1,2,4-triazolyl and imodazolyl; A3 is selected from the group including phenyl, thiazolyl and pyrazolyl; A4 is selected from the group, including phenyl, pyridyl, thiazolyl, pyrazolyl, 1,2,4-triazolyl, pyrimidinyl, piperidinyl, pyrrolidinyl and asetidinyl; A2 is optionally substituted with 1-3 substituents, independently selected from halogen atom, -OCH3 and -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A3 is substituted with one A4 group and is optionally substituted with 1-2 substituents, independently selected from halogen atom, -OH, -OCH3, -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A4 is optionally substituted with 1-3 substituents, independently selected from the group, which includes: (a) -C1-C5alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with group -OH, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) halogen atom, (j) -CN, (k) -NO2, (l) -C(=O)NR3R4, (m) -OC1-C2alkyleneOC1-C2alkyl, (n) -OC1-C3alkyl, optionally substituted with 1-3 halogen atoms, (o) -C(=O)OC1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (q) -NR3R4 and (r) -S(O)xNR3R4, on condition that A4 stands for heterocyclic group, attached to A3 by means of ring carbon atom in A4, at least, one substituent in A4 must be selected from Re, where Re is selected from the group including: (a) -C1-C5alkyl, substituted with -OH group and optionally substituted with 1-3 halogen atoms, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) -CN, (j) -NO2, (k) -C(=O)NR3R4, (l) -OC1-C2alkyleneOC1-C2alkyl, (m) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (n) -NR3R4(=O)OC1-C2alkyl, (o) -NR3R4 and (p) -S(O)xNR3R4; p equals 0, 1 or 2; and Ra is selected from halogen atom, -CH3, -CF3, -OCH3 and -OCF3; R3 and R4 each is independently selected from H and CH3; and x equals 0, 1 or 2.

EFFECT: formula (I) compound is applied for medication, which possesses properties of CETP inhibitor, for increase of HDL-C and for reduction of LDL-C Technical result is compounds, inhibiting cholesterol ether transferring protein (CETP).

10 cl, 140 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel compounds of general formula (A), their stereoisomers or pharmaceutically acceptable salts, possessing ability to inhibit activity of isomerase, taking part in visual cycle. Compounds can be applied for treatment of ophthalmological disease or disorder, such as age-related macular degeneration or Stargardt's macular dystrophy. In general formula (A) Z represents-C(R9)(R10)-C(R1)(R2)-; R1 and R2 each, independently on each other, are selected from hydrogen, halogen, C1-C5alkyl, or -OR6; or R1 and R2 together from oxo; R3 and R4 each, independently on each other, are selected from hydrogen; R6 is selected from a) C5-C15alkyl, optionally substituted with hydroxy, C1-C8alkoxy; or b) C5-C10carbocyclylalkyl, in which carbocycle is 4-, 5-, 6-, 7- or 8-member non-aromatic carbocycle, optionally substituted with hydroxy, halogen or R6CO2-; R9 and R10 each, independently on each other, is selected from hydrogen, halogen, C1-C5alkyl, optionally substituted with hydroxy, or -OR19; or R9 and R10 form oxo; or optionally, R9 and R1 together form direct bond to provide double bond; or optionally, R9 and R1 together form direct bond, and R10 and R2 together form direct bond to provide triple bond; R11 and R12 each, independently on each other, is selected from hydrogen, -C(=O)R23 or -C(NH)NH2, R23 is selected from C1-C8alkyl; R6, R19 and R34 are independently on each other are hydrogen or C1-C8alkyl; each R33 is independently selected from halogen, hydroxyl, C1-C5carboalkoxy, C1-C8alkyl, optionally substituted with hydroxy; and n equals 0 or 1.

EFFECT: compounds inhibit degeneration of retinal cell, in particular neuronal cell, such as photoreceptor cell, in patient's retina.

45 cl, 11 dwg, 11 tbl, 206 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to using compounds of general formula (I) possessing the properties of monoaminoxidase (MAO) and/or lipid peroxidation inhibitors, and/or the properties of sodium channel modulators, as well as to a based therapeutic agent possessing the same properties, more specifically the compounds and therapeutic agent can be used for treating the Parkinson's disease, senile dementia, Alzheimer disease, Huntington's chorea, amyotrophic lateral sclerosis, schizophrenia, depressions, psychosis, pain and epilepsy. In general formula (I) X means S; A means radical (a), wherein Q means OH, two of the radicals R19, R20 and R21 mean alkyl, while the third one means H; B means H, n means 0 or 1, both R1 and R2 mean H, and Ω means: either the radical NR46R47, wherein one of R46 and R47 means H or hydroxyalkyl, alkynyl or cyanoalkyl, while the other one means H or alkyl; or the radical OH.

EFFECT: preparing the compounds of general formula (I) possessing the properties of the monoaminoxidase (MAO) inhibitors.

4 cl, 349 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to using the compounds of formula (I) wherein R1 is specified in C1-C6 alkyl optionally substituted by cyano, unsubstituted C3-C8cycloalkyl5 phenyl optionally substituted by halogen, and unsubstituted 3-8-members heterocyclyl containing one heteroatom specified in nitrogen and sulphur; R2 is specified in C1-C6alkyl optionally substituted by a 3-member heterocyclyl containing one oxygen heteroatom, and unsubstituted C3-C8cycloalkyl, and R3 represents C1-C6alkyl radical for preparing a therapeutic agent for treating an acute or chronic inflammatory disease by inhibiting the production of at least one anti-inflammatory cytokine specified in TNF-alpha and IFN-gamma, or by immunomodulating chemokine IL-8 and/or regulatory cytokine IL-10. The invention also refers to the compounds of formula (I') and the pharmaceutical composition thereof.

EFFECT: preparing the 5-(4-methanesulphonyl phenyl)thiazole derivatives for treating the acute and chronic inflammatory diseases or conditions.

14 cl, 51 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), where A is C-R1b; R1a, R1b, R1c, R1d, R1e, R2, R3, R4, R5 and n are as described in claim 1 of the invention, as well as pharmaceutically acceptable salts thereof. Described also is a pharmaceutical composition having activity as glucocorticoid receptor modulators.

EFFECT: novel compounds are obtained and described, which are glucocorticoid receptor antagonists and useful for treating and/or preventing diseases such as diabetes, dyslipidaemia, obesity, hyptension, cardiovascular diseases, adrenal gland malfunction or depression.

24 cl, 210 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to cyclohexane derivatives presented by general formula wherein the substitute A is a group of general formula or wherein the radicals and symbols are presented in the patent claim. The compounds of formula (I) possess strong analgesic action both on nociceptive pain, and on neuropathic pain, and to a lesser degree side effects. Their pharmaceutical use is also described.

EFFECT: cyclohexane derivative and its pharmaceutical use is presented.

17 cl, 42 tbl, 7 dwg, 177 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula I and to their pharmaceutically acceptable salts. In formula I p is integer, equal to 0-1; L2 is selected from group including -XOX-, -XSX- and -XSXO-; where X is independently selected from group, including bond and C1-C4alkylene; R13 is selected from group, including halogen, C1-C6alkyl, C1-C6alkoxygroup, -C(O) C1-C6alkyl; R14 is selected from group, including -XOXC(O)OR17 and -C1-C4alkylene-C(O)OR17; where X represents bond or C1-C4alkylene; and R17 is selected from group, including hydrogen and C1-C6alkyl; R15 and R16 are independently selected from group, including -R18 and -YR18; where Y represents C2-C6alkenylene, and R18 is selected from group, including C6-C10aryl, benzo[1,3]dioxolyl, pyridinyl, pyrimidinyl, quinolyl, phenoxatiinyl, benzofuranyl, dibenzofuranyl, benzoxasolyl, 2,3-dihydrobenzofuranyl, 2-oxo-2,3-dihydrobenzooxasolyl, indolyl, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazinyl, 2,3-dihydrobenzo[1,4]dioxinyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, where any C6-C10aryl, pyridinyl, benzoxasolyl, indolyl in R18 is optionally substituted by 1-2 radicals, independently selected from group, including halogen, nitrogroup, cyanogroup, C1-C6alkyl, C1-C6alkoxygroup, C1-C6alkylthiogroup, hydroxy-C1-C6alkyl, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxygroup, piperidinyl, morpholinyl, pyrrolidinyl, phenyl, XS(O)0-2R17, -XNR17R17, -XNR17S(O)2R17, -XNR17C(O)R17, -XC(O)NR17R17, -XC(O)NR17R19, -XC(O)R17, -XC(O)R19 and -XOXR19, where X represents bond; R17 is selected from group, including hydrogen, C1-C6alkyl, halogen-substituted C1-C6alkyl, and R19 is selected from group, including C3-C12cycloalkyl, phenyl, piperidinyl, morpholinyl.

EFFECT: ensuring application of invention compounds for production of medication, modulating activity of activated receptors of peroxisome proliferators δ (ARPPδ), to pharmaceutical composition, possessing properties of ARPPδ activity modulator, including therapeutically efficient quantity of invention compound and to application of pharmaceutical composition for medication manufacturing.

8 cl, 1 tbl, 301 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula , where Qa is phenyl or heteroaryl, and Qa can possibly carry 1 or 2 substitutes selected from hydroxy, halogen, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; R1 and R2 are each independently selected from hydrogen and (1-6C)alkyl; Qb is phenyl or heteroaryl, and Qb can possibly carry 1 or 2 substitutes selected from hydroxy, halogen, (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, (1-6C)alkylthio, (1-6C)alkylsulfinyl and (1-6C)alkylsulfonyl; where any of the substitutes Qa and Qb defined above, containing a CH2 group which is bonded to 2 carbon atoms, or a CH3 group bonded to a carbon atom, can possibly carry on each of the said CH2 or CH3 group one or more substitutes selected from hydroxy, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; where heteroaryl is an aromatic 5- or 6-member monocyclic ring which can contain up to three heteroatoms selected from oxygen, nitrogen and sulphur, and can be condensed with a benzene ring or a five-member nitrogen-containing ring containing 2 nitrogen atoms; as well as pharmaceutically acceptable salts thereof. The invention also relates to a method of producing formula I compounds, a pharmaceutical composition and use of these compounds for treating conditions mediated by effect of TNF cytokines.

EFFECT: more effective treatment.

13 cl, 3 tbl, 46 ex

FIELD: medicine.

SUBSTANCE: in formula (1), R1 is di-C1-6alkoxyphenyl group; A is one of the following groups (i)-(vi); (i) -CO-B-, where B is C1-6alkylene group; (ii) -CO-Ba-, where Ba is C2-6alkenylene group; (iii) -CH(OH)-B-; (iv) -COCH((C)OOR3)-Bb-, where R3 is C1-6alkyl group and Bb is C1-6alkylene group. Values of the other radicals are specified in the patent claim. Invention also concerns the pharmaceutical composition exhibiting properties of a phosphodiesterase PDE4 inhibitor containing the compound under the invention; the phosphodiesterase 4 inhibitor containing as an active component the compound of the invention; preventive or therapeutic preparation for atopic dermatitis containing as an active component the compound of the invention.

EFFECT: higher effectiveness of application of the compound.

8 cl, 24 tbl, 262 ex

FIELD: medicine.

SUBSTANCE: invention covers thaizole derivatives of formula (I) and to their pharmaceutically acceptable salts. In formula I: X1 and X2 differ from each other and represent sulphur atom or carbon atom; R1 represents phenyl group; phenyl group substituted by 1-2 members chosen from the group including halogen atoms, alkoxygroup with 1-6 carbon atoms, hydroxygroup, phenylalkoxygroup with 7-12 carbon atoms; phenyl group fused with 5-7-membered heteroaromatic or nonaromatic ring with at least one heteroatom consisting of N, O and S; pyridyl group; R2 represents hydrogen atom, halogen atom, alkyl group with 1-6 carbon atoms, alkyl group with 1-6 carbon atoms substituted by 1-5 halogen atoms, alkoxygroup with 1-6 carbon atoms, or hydroxyalkyl group with 1-5 carbon atoms; A represents group which is presented by formula or . Also, the invention concerns ALK5 inhibitor containing compound of the invention as an active component, stimulators of hair follicles proliferation and hair growth, and also to thiazole derivative of formula where A1 represents .

EFFECT: higher efficiency.

12 cl, 2 tbl, 50 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention pertains to dimetansulphonate N-hydroxy-4-{5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy}benzamidine, method of producing thereof, pharmaceutical compositions based on the said compound and a peroral pharmaceutical composition.

EFFECT: wider field of use of the compounds.

9 cl, 5 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and their pharmaceutically acceptable salts, wherein A is thiazolyl, oxazolyl, thienyl, furyl, imidazolyl, pyrazolyl or oxadiazolyl (structures of which are presented in cl.1 of the patent claim), R1 represents C1-6alkyl; R2 represents (i) phenyl substituted by halogen; C1-6alkyl optionally substituted by morpholine or C1-6dialkylamino; C1-6alkoxy optionally substituted by halogen; or heterocyclyl, wherein a heterocyclyl substitute is specified in morpholine; pyrazolyl optionally substituted by C1-6alkyl; piperidinyl; pyrrolidinyl; oxadiazolyl substituted by C1-6alkyl; furyl substituted by C1-6alkyl; dioxydoisothiazolidinyl; triazolyl; tetrazolyl substituted by C1-6alkyl, tridiazolyl substituted by C1-6alkyl; thiazolyl substituted by C1-6alkyl; pyridyl; or pyrazinyl; (ii) substituted or unsubstituted heterocyclyl specified in quinolinyl; pyridyl substituted by C1-6alkoxy or morpholinyl; or benzo [d] [1, 2, 3] triazolyl substituted by C1-6alkyl; R3 represents phenyl substituted by 2 or 3 substitutes specified in halogen; C1-6alkyl; C1-6alkoxy optionally substituted by halogen; hydroxy group; cyano; or -C(=O)ORa, wherein Ra represents phenyl; R4 represents hydrogen, C1-6alkyl or C1-6halogenalkyl. The invention also refers to a pharmaceutical composition containing the compounds of formula (I), a method for PDE10 inhibition, a method of treating neurological disorders, and to intermediate compounds: 2-(4-chlor-3,5-dimethoxyphenyl)furan and 4-(5-methyl-1,3,4-thiadiazol-2-yl)benzaldehyde.

EFFECT: compounds of formula (I) as PDE10 inhibitors.

39 cl, 13 ex, 2 tbl, 77 dwg

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