Substituted arylalkane acid derivatives as pan agonists rapp with high antihyperglycemic and antihyperlipidemic activity

FIELD: chemistry.

SUBSTANCE: described is obtaining and pharmaceutical application of substituted derivatives of arylalkane acid of formula I , where ring A, ring B, R1, R2, R3, R4, R5, X, Alk1, Alk2, Ar1 and Ar2 are such as determined in said description. Said compounds, as selective agonists activating (RAPPs) receptors, activated by peroximal proliferator, in particular, RXRs/RAPPs-alfa, RXRs/RAPPs-gamma and RXRs/RAPPs-delta heterodimers, are applied in treatment and/or prevention of type 2 diabetes and connected with it metabolic syndrome, such as hypertension, obesity, insulin-resistence, hyperlipidemia, hyperglycemia, hyperolesterinemia, artheriaslerosis, coronary artery disease, and other cardio-vascular disorders, and possess improved profile of side effects, connected with common RAPPs-gamma agonists.

EFFECT: obtaining compunds, which possess improved profile of side effects, connected with common RAPPs-gamma agonists.

22 cl, 38 ex, 2 tbl, 10 dwg

 

Priority for this application is sought on the provisional application U.S. No. 60/429221, filed November 26, 2002; and at the request of the U.S. No. 60/469368, filed may 9, 2003.

The technical field to which the invention relates.

This invention relates to receiving and pharmaceutical application of new substituted derivatives arylalkenes acid. In particular, this invention relates to new compounds of the formula (I), methods for their preparation, their pharmaceutical compositions and their use in the treatment and/or prevention of conditions associated with nuclear receptors, in particular, with RCR and RAPP-heterodimers.

These compounds applicable in the treatment and/or prevention of diabetes of the 2nd type and associated metabolic syndromes such as hypertension, obesity, insulin resistance, hyperlipidemia, hyperglycemia, hypercholesterolemia, atherosclerosis, coronary artery disease and other cardiovascular disorders, and have a better side effect profile, usually associated with normal Rapgame agonists.

The prior art inventions

Metabolic syndrome, including type 2 diabetes type and its associated complications, such as obesity, cardiovascular symptoms, and dyslipidemia, are the main high social and economic importance. the I et, what anti-diabetic drugs increase insulin resistance, they provide little protection from pronounced cardiovascular risk associated with diabetes of the 2nd type.

Therefore, in General, an interesting development of new patterns of treatment effects of reducing insulin resistance and the ratio of cholesterol/triglycerides.

Diabetes mellitus is a polygenic violation affecting in the world, a significant number of people. This disease is divided into two types. When type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM)patients producing little or no insulin is produced, a hormone that regulates the absorption of glucose.

When type 2 diabetes or non-insulin dependent diabetes mellitus (NIDDM), often in patients insulin levels in the blood plasma is the same as in people without diabetes; however, patients develop resistance to glucose and fat metabolism in the main insulinchuvstvitelnyh tissue, i.e. muscle, liver and adipose tissue, and insulin levels in the plasma is sufficient to overcome the pronounced insulin resistance.

Diabetes of the 2nd type is more than 90% of all forms of diabetes. This violation of metabolism characterized by hyperglycemia, leading to secondary complications such as neuropathy, nephropathy, retinopathy, hypersizer the Academy, obesity, and other cardiovascular diseases, mainly described as the metabolic syndrome.

When type 2 diabetes type treatment, which mainly prescribe, is a combination of diet, exercise and oral hyperglycemic agents, mainly sulfonylureas and biguanides. However, the sulfonylurea therapy has many problems associated with primary and secondary loss of efficiency, the occurrence of hypoglycemia and obesity. Therapy with biguanides can induce lactic acidosis, nausea, and diarrhea. Therefore, the drug being able to control the level of glucose in plasma without any significant side effects would be an important addition to dietoterapia. Recently, it was shown that a class of compounds called "preparations of thiazolidinediones", reduces hyperglycemia by stimulating insulin without additional insulin secretion and without calling unwanted hypoglycemia even at high doses. It is assumed that their effect is the result of the initiation and modulation of differentiation of adipocytes agonistic activity of Rapgame.

This class of compounds able to activate Rapgame, has demonstrated clinical efficacy in the treatment of type 2 diabetes type (from AVANDIA GSK ACTOS from Lilly/Tekada). However, a direct link between the asset is of Rapgame and changes in glucose metabolism, the most significant reduction in insulin resistance in muscle has not been established. This communication is performed by means of free fatty acids in such a way that activation of Rapgame induces lipoprotein lipase, protein transport of free fatty acids and acyl-COA-synthetase in adipose tissue but not in muscle cells. This effect, in turn, dramatically reduces the concentration of free fatty acids in plasma, leading to the final switch from fatty acid oxidation in the oxidation of glucose in tissues of high metabolic level, for example in skeletal muscle and other tissues, resulting in substrate competition and compensation of metabolic processes.

This leads to reduced insulin resistance in these tissues. In addition, activation of Rapgame regulates the activity of genes that control glucose metabolism and energy homeostasis, which leads to lowering the level of glucose in the blood (T. M. Wilson and others, "The PPARs: from orphan receptors to drug discovery," J. Med. Chem. 2000 43: 527-50; A. Chawla and other Nuclear receptors and lipid discrimination: Opening the X-files", Science 2001 294: 1866-70).

Despite the advantages achieved by the class of preparations of thiazolidinediones as antidiabetic agents, their clinical application is limited to serious unacceptable side effects, including cardiac hypertrophy, blood-thinning and toxicity of pécs is neither. In the United States and Japan have observed several cases of liver damage and death from drug-related liver damage. In addition, Rapgame-selective ligands induce differentiation of adipocytes and the accumulation of white fat, leading to obesity, an important factor, directly related to the beginning or the consequence of diabetes of the 2nd type. Such undesirable effects completely negate insulinsensitizing favor of the ligands Rapgame. Therefore, there is a need for safe and effective agent for the treatment of patients with diabetes of the 2nd type, which can be double the activity in insulinsensitizing and reducing the delay of white fat by regulating the content of free fatty acids and triglycerides.

Rapgame is a member of the superfamily of ligand-activated nuclear hormone receptors and is expressed mainly in adipose tissue. Class of ligands, called fibrates which, as you know, has the triglyceride - and holesterin lowering activity and activates another member of this family, Rapala, which is mainly expressed in such tissues as the liver. Rapala stimulates peroxisomal proliferation, increasing fatty acid oxidation, resulting in reduced levels of fatty acids in the blood (Keller and Wahli: Trends Endocrin Metab 1993, : 291-296). Recently it was found that Appdelete regulates lipid metabolism, in which Appdelete serves as a widespread regulator of fat burning. In vitro activation Appdelete in adipocytes and skeletal muscle cells provides oxidation and fatty acid. Directional activation Appdelete in the adipose tissue of animals, where Rapala is expressed in a much smaller number of specific induces the expression of genes required for fatty acid oxidation and energy distribution, which, in turn, leads to improved lipid profiles and reduced obesity.

It is important that these animals (Lepr (db/db) is completely resistant to both types of obesity induced by diet with high fat content and genetic predisposition.

Acute administration to mice of Lepr (db/db) agonists, Appdelete prevents the accumulation of fats. In parallel, mice with deficiency of Appdelete consuming food with high fat content, demonstrate reduced energy splitting and predisposed to obesity (Wang YX, etc.. Cell 2003 Apr 18; 113 (2): 159-70). Was also described in the transcriptional repression of atherogenic inflammation through landcruising Appdelete that, in addition, shows the importance of Appdelete in resistance to the development of cardiovascular disease (Lee, CH, etc., Science 302: 43-457, 2003).

Rapala, gamma, and Delta form heterodimer with retinoid-X-receptor (RCR). Heterodimer RCR/RAPP play thus an important role in monitoring and regulation of cellular processes, such as homeostasis of fat (lipid) and glucose and differentiation of adipocytes. It was found that some new chemical compounds have or Rapgame activity or double Rapala - and gamma activity used in the treatment and/or prevention of metabolic syndromes in animals and humans (WO 00/08002, WO 01/57001A1, U.S. patent No. 6054453, EP V, WO 97/25042, WO 02/26729 A2 and U.S. patent No. V). New pan-agonists that activate Rapala, gamma, and Delta must be, therefore, a very important addition in the comprehensive management of syndrome X, such as diabetes, hypertension, obesity, insulin resistance, hyperlipidemia, hyperglycemia, hypercholesterolemia, atherosclerosis, a disease of the coronary arteries and other cardiovascular disorders.

The invention

One aspect of this invention provides compounds of formula I:

where ring a and ring condensed with the ring containing X and N, independently from each other represent a 5-6-membered ring which may optionally contain one or more heteroatoms selected from oxygen, sulfur is whether nitrogen, and optionally can be substituted by one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, askaninja, aralkyl, heteroallyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, alcoxialchil, hydroxyalkyl, thioalkyl, heterocyclyl, alkoxy, aryl, aryloxy, Alcoxy, heteroaryl, heteroaromatic, heteroaromatic, acyl, acyloxy, amino, alkylamino, arylamino, or aralkylamines; ring a and ring b may be saturated or contain one or more double bonds or may be aromatic;

X is a valence bond, CH2CH2, CH=CH, O, S, or NR6where R6represents H, alkyl, alkenyl, alkenyl, aralkyl, heteroaromatic, heterocyclic, aryl or heteroaryl;

R1represents H, alkyl, alkenyl, alkenyl, aralkyl, heteroaromatic, aminoalkyl, alkoxyalkyl, aryloxyalkyl, alcoxialchil, hydroxyalkyl, thioalkyl, heterocyclyl, HE, halogen, alkoxy, aryl, aryloxy, Alcoxy, heteroaryl, heteroaromatic, heteroaromatic, acyl, acyloxy, amino, alkylamino, arylamino or aralkylamines;

R2represents H, alkyl, alkenyl, alkenyl, aralkyl, heteroaromatic, heterocyclic, aryl or heteroaryl;

R3represents H, alkyl, alkenyl, alkenyl, aralkyl, heteroaromatic, heterocyclic, aryl or g is tetraaryl;

R4and R5independently represent H, alkyl, alkenyl, alkenyl, aralkyl, heteroaromatic, aminoalkyl, alkoxyalkyl, aryloxyalkyl, alcoxialchil, hydroxyalkyl, thioalkyl, heterocyclyl, HE, halogen, alkoxy, aryl, aryloxy, Alcoxy, heteroaryl, heteroaromatic, heteroaromatic, acyl, acyloxy, amino, alkylamino, arylamino or aralkylamines;

R4and R5may form a 5 or 6-membered ring, optionally substituted by one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, askaninja, aralkyl, heteroallyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, alcoxialchil, hydroxyalkyl, thioalkyl, heterocyclyl, alkoxy, aryl, aryloxy, Alcoxy, heteroaryl, heteroaromatic, heteroaromatic, acyl, acyloxy, amino, alkylamino, arylamino or aralkylamines;

Alk1represents a C1-6alkylen;

Alk2represents a C1-6alkylen;

Ar1represents Allen, heteroaryl or divalent heterocyclic group, optionally substituted by one or more halogen, C1-6the alkyl, amino, hydroxy, C1-6alkoxyl or aryl;

Ar2represents an aryl group, optionally substituted by one or more halogen, C1-6the alkyl, amino, hydroxy, C1-6alkoxy is or aryl; heteroaryl or heterocyclyl group, optionally substituted by one or more halogen, C1-6the alkyl, amino, hydroxy, C1-6alkoxy or aryl.

Another aspect of this invention relates to pharmaceutical compositions containing the active ingredient, at least one of the compounds of General formula (I), and/or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent for the treatment and/or prevention of type 2 diabetes type and the associated metabolic syndrome, such as hypertension, obesity, insulin resistance, hyperlipidemia, hyperglycemia, hypercholesterolemia, atherosclerosis, a disease of the coronary arteries and other cardiovascular disorders.

It has been unexpectedly found that the compounds of formula I are able to reduce hyperglycemia and hypertriglyceridemia associated with diabetes of the 2nd type. Also unexpectedly found that the compounds of formula I can be used as a pan-agonist for RCR/Rapala, RCR/Rapgame and RCR/Appdelete of heterodimers, and also as agents for lowering levels of glucose and triglycerides for the treatment and/or prevention of type 2 diabetes type and the associated metabolic syndrome. The content of the cited here of patents and publications and content of the documents cited in these Pat the tah and publications included in this description as references in the permitted volume.

Brief description of drawings

Figure 1 graphically illustrates the relative activation RCR/Rappala of heterodimeric compounds of this invention (Example 30).

Figure 2 shows comparative activation RCR/Rapgame of heterodimeric compounds of this invention (Example 31).

Figure 3 shows comparative activation RCR/Appdelete of heterodimeric compounds of this invention (Example 32).

Figure 4 shows comparative activation RCR/Rappala of heterodimeric compounds of this invention (Example 33).

Figure 5 shows comparative activation RCR/Rapgame of heterodimeric compounds of this invention (Example 33).

6 shows comparative activation RCR/Appdelete of heterodimeric compounds of this invention (Example 33).

7 graphically illustrates the reduction in vivo glucose in the blood caused by the connection of the present invention (Example 34).

Fig graphically illustrates the increased sensitivity to insulin induced in vivo compound of this invention (Example 35).

Figure 9 graphically illustrates the increased glucose tolerance induced in vivo compound of this invention (Example 36).

Detailed description of the invention

If not defined otherwise, all technical and N. the scientific terms used herein shall have the meaning usually mean the person skilled in the art to which this description is relevant.

All publications and patents referenced in this description is included here as a reference.

In the preferred embodiment of the compounds of this

the invention is represented by formula I, are compounds where

ring a is a 6-membered aromatic ring;

ring b is a 6-membered aromatic ring;

X is a valence bond, CH2CH2, CH=CH, O or S;

R1represents H or alkyl;

R2represents H or alkyl;

R3represents H or alkyl;

R4and R5are independently H or alkyl;

Alk1represents a C2-3alkylen;

Alk2represents a C1-6alkylen;

Ar1represents Allenova group;

Ar2represents a substituted aryl group.

In another preferred embodiment, compounds of this

inventions are the compounds of formula I, where

ring a is a 6-membered aromatic ring;

ring b is a 6-membered aromatic ring;

X is a valence bond, CH2CH2, CH=CH, O or S;

R1represents H or alkyl;

R2the stand is made by an H or alkyl;

R3represents H or alkyl;

R4and R5form a 6-membered aromatic ring;

Alk1represents a C2-3alkylen;

Alk2represents a C1-6alkylen;

Ar1is a 6-membered aromatic ring;

Ar2is a substituted aryl group.

In another preferred embodiment, the compounds of this invention are compounds of formula I, where

ring a is a benzene ring;

ring b is a benzene ring;

X is a valence bond, CH2CH2, CH=CH, O or S;

R1represents N;

R2represents N;

R3represents N;

R4represents methyl; R5is N;

Alk1represents CH2CH2;

Alk2represents CH2;

Ar1represents a benzene ring;

Ar2represents a benzene ring, optionally substituted by one or more fluorine atom.

In another preferred embodiment, the compounds of this invention are compounds of formula I, where

ring a is a benzene ring;

ring b is a benzene ring;

X is a valence bond, CH2CH2CH=CH, O or S;

R1represents N;

2represents N;

R3represents N;

R4and R5represent a benzene ring;

Alk1represents CH2CH2;

Alk2represents CH2;

Ar1represents a benzene ring;

Ar2represents a benzene ring, optionally substituted by one or more fluorine atom.

In an additional preferred embodiment of the compounds of this invention are compounds of formula I, where

ring a is a benzene ring;

ring b is a benzene ring;

X is a valence bond, CH2CH2, CH=CH, O or S;

R1represents N;

R2represents N;

R3represents N;

R4represents methyl; R5represents N;

Alk1represents CH2CH2;

Alk2represents CH2;

Ar1represents a benzene ring;

Ar2represents a pyridine ring, optionally substituted by one or more halogen atom.

In another preferred embodiment of the compounds of this invention are compounds of formula I, where

ring a is a benzene ring;

ring b is a benzene ring;

X is Val is nteu communication, CH2CH2, CH=CH, O or S;

R1represents N;

R2represents N;

R3represents N;

R4and R5form a benzene ring;

Alk1represents CH2CH2;

Alk2represents CH2;

Ar1represents a benzene ring

Ar2represents a pyridine ring, optionally substituted by one or more fluorine atom.

The following terms used herein have the specified meaning: refers to that used here, the term "alkyl" includes alkyl groups, linear or branched configuration. Typical alkyl groups include, but are not limited to methyl, ethyl, n-sawn, ISO-propyl, butilkoi, isobutylene, terbutaline, tertbutylphenol, Pintilei, isopentyl, hexylene, isohexyl, cyclopropenes, cyclobutenes, cyclopentyloxy, tsiklogeksilnogo and similar groups.

Used herein, the term "aralkyl" refers to a straight or branched saturated carbon chain containing from 1 to 6 carbon atoms, substituted aromatic carbohidratos, for example benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl and the like.

Used herein, the term "heteroalkyl" refers to a straight or branched saturated carbon is native circuit, containing from 1 to 6 carbon atoms, substituted defined here heteroaryl, for example, (2-furyl)methyl, (3-furyl)methyl, (2-pyridyl)methyl and the like.

Used herein, the term "aminoalkyl" refers to alkyl as defined here, is attached to the amino group, for example aminoethyl, 1-aminopropyl, 2-aminopropyl, and the like.

Used herein, the term "alkoxyalkyl" refers to alkyl as defined here, is attached to some here alkoxygroup, such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like.

Used herein, the term "aryloxyalkyl" refers to alkyl as defined here, is attached to some here alloctype, such as phenoxymethyl, fenoxedil, 1-naphthylacetyl and the like.

Used herein, the term "alcoxialchil" refers to alkyl as defined here, is attached to some here urlcategory, such as benzoyloxymethyl, 3-phenylpropoxy and the like.

Used herein, the term "hydroxyalkyl" refers to alkyl as defined here, is attached to some here, the hydroxy-group, such as hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, and the like.

Used herein, the term "thioalkyl" refers to alkyl as defined here, to the mu joined the group of the formula-SR', where R' is H, alkyl or aryl, such as thiomethyl, methylthiomethyl, phenylthiomethyl and the like.

Used herein, the term "heterocyclyl" means a monovalent saturated or unsaturated adnakolava group containing one or more heteroatoms, such as pyrrolidine, pyrrolin, pyrazoline, imidazolidine, imidazoline, piperidine, morpholine and the like.

Used herein, the term "halogen" means fluorine, chlorine, bromine or iodine.

It is implied that used here, the term "alkoxy" includes alkyl groups are linear, branched or cyclic configuration, connected by oxygen of the ether group having a free valence bond from the ether oxygen groups, such as methoxy, ethoxy, propoxy, butoxy, pentox, isopropoxy, secretaxy, cyclopropylamine, cyclohexyloxy and the like.

Used herein, the term "aryl", as implied, includes an aromatic ring, optionally substituted with halogen, amino, hydroxy, alkyl or alkoxy, for example phenyl, naphthyl and the like.

Used herein, the term "aryloxy" refers to phenoxy, 1 naphthyloxy, 2-naphthyloxy and the like.

Used herein, the term "arakaki" refers to alkyl as defined here, a substituted aromatic carbohidratos, for example benzyloxy, venetucci, 1-is teletaxi and the like.

Used herein, the term "heteroaryl" refers to monovalent Deputy containing 5-6-membered monocyclic aromatic system or a 9-10-membered bicycling system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, such as furan, thiophene, pyrrole, imidazole, triazole, pyridine, pyrazin, pyrimidine, oxazole, quinoline, indole, benzimidazole, and the like.

Used herein, the term "heteroaromatic" refers to heteroaryl defined here, is associated with the oxygen atom having a free valence bond from the oxygen atom, for example, pyrrole, imidazole, triazole, pyridine, pyrazin, pyrimidine, oxazole, quinoline, indole, benzimidazole, associated with oxygen.

Used herein, the term "heteroaromatic" refers to heteroalkyl defined here, is associated with the oxygen atom having a free valence bond from the oxygen atom, such as (2-furyl)methyl, (3-furyl)methyl, (2-pyridyl)methyl associated with the oxygen atom.

Used herein, the term "acyl" refers to a monovalent Deputy containing alkyl group linked to a carbonyl group, for example acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl and the like.

Used herein, the term "acyloxy" refers to acyl defined here, which is linked to the oxygen atom is within its free valence bond from the oxygen atom, for example, atomic charges, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy, valerianic and the like.

Used herein, the term "alkylamino" refers to a straight or branched or cyclic monovalent Deputy containing alkyl group associated with amino having a free valence bond from the nitrogen atom, such as methylamine, ethylamine, Propylamine, butylamine, cyclopropylamino, cyclopentylamine, cyclohexylamine and the like.

Used herein, the term "arylamino" refers to aryl as defined here, is associated with the amino group having a free valence bond from the nitrogen atom, for example, phenylamino, naphthylamine and the like.

Used herein, the term "aralkylamines" refers to aralkyl defined here, is associated with the amino group having a free valence bond from the nitrogen atom, for example, benzylamino, phenethylamine, 3 phenylpropylamine, 1 naphthylenediamine and the like.

The compounds of formula (1) can be obtained by synthesis shown in scheme 1:

Connection 1 when interacting with β-diketone 2 gives analogues of amides of the vinyl series 3 with the release of 95-98%. O-alkylation of compound 3 in the usual way by treatment of the CON and the corresponding dibromethane in ethanol gives the ester 4 with the release of 15-20%. N-al is iliriana compounds 4 processing NaOH and compound 5 in the presence of tetrabutylammonium gives substituted derivatives arylalkenes acid 6 with the release of 20-25%.

The synthetic path shown in scheme 1, also suitable for producing compounds of formula (1), where Ar2is a benzene ring.

The pharmaceutical composition may be in a commonly used forms, such as tablets, capsules, powders, syrups, solutions, suspensions, aerosols, and the like, may contain flavoring agents, sweeteners, etc. in suitable solid or liquid carriers or diluents, or in suitable sterile environment with the formation of injection solutions and suspensions. In the preferred embodiment, the pharmaceutical composition contains up to about 65% of the compounds of formula I by weight, preferably from about 0.5 to about 40%, more preferably from about 1 to about 20%, and most preferably, from about 1 to 10%, with the remaining composition is a pharmaceutically acceptable carriers, diluents or solvents or salt solutions.

Used herein, the term "pharmaceutically acceptable carrier or diluent" includes, but is not limited to those described in "Handbook of Pharmaceutical Excipients, published in October 1986 the American Pharmaceutical Association, the content of which, to the extent possible, incorporated herein by reference.

The compounds of formula (I)as defined above, clinically administered to mammals, including the friends of man and animals, oral, intranasal, transdermal, intra-lungs (inhalation), or parenteral. Oral administration is preferred, it is more convenient and avoids the potential for pain and irritation in the introduction. In the preferred embodiment, the dosage ranges from about 0.01 to about 200 mg/kg of body weight per day administered once or in divided doses, preferably from about 0.01 to about 100 mg/kg and more preferably from about 0.1 to about 50 mg/kg But the optimal dose for the individual subject is determined by the expert responsible for the treatment, mainly at first enter a lower dose and then increase the dose to determine the most appropriate. Without intending to communicate with a specific theory of efficiency, probably, the introduction of compounds of formula I to a patient cures diabetes and its associated complications by lowering levels of glucose and triglycerides in a patient. Such dual activity, for example, help the patient to eliminate hyperglycemia and hypertriglyceridemia associated with diabetes of the 2nd type. It is also believed that the treatment of patients with 2nd type of diabetes and its associated complications, it may be more efficient and desirable if it can be reduced in glucose and triglyceride levels with treatment.

The following examples danyale a specific illustration of the present invention. However, it should be understood that the invention is not limited by the specific details presented in the examples. All parts and percentages in the examples as well as in the remaining description, are given by weight, unless otherwise specified.

In addition, any number of values cited in this description, or sections, hereinafter describing or addressing various aspects of the present invention, such as those that represent a private set of properties, units of measure, conditions, physical States or percentages, is intended for complete and accurate coverage in the form of links or in any other manner, any number falling within this interval, including any set of numbers or values within the specified interval.

The term "about" when used to define or due to the magnitude implies that the values and ranges described herein are flexible, and the application of this invention by the person skilled in the art using temperatures, concentrations, amounts, contents, number of carbon atoms and the properties that are outside of the range or different from a single value, will achieve the desired result.

Example 1

Obtain methyl ester of 2-(1-methyl-3-oxo-3-phenyl-propylamino)-3-(4-hydroxyphenyl)-propionic acid.

To a solution of methyl ester of L-tyrosine (4,00 g, 20,51 mmol) in methanol (150 ml) was added 1-benzoylacetone (3,66 g, 22,56 mmol), the mixture is then heated in a flask at a temperature of flameworthy (under reflux) within 24 hours

The solvent is evaporated in vacuum. To the residue is added ethanol (50 ml), then the ethanol is distilled off at atmospheric pressure. The crude product is purified by chromatography on silica gel, using as eluent hexane/EtOAc (4:1), with the connection specified in the header (to 6.80 g, 98%).

Example 2

Obtain methyl ester of 2-(1-methyl-3-oxo-3-phenyl-propylamino)-3-[4-(2-bromoethoxy)-phenyl]-propionic acid.

To a solution of potassium hydroxide (0.17 g, 2,95 mmol) in ethanol (20 ml) is added methyl ether 2- (1-methyl-3-oxo-3-phenyl-propylamino)-3-(4-hydroxyphenyl)-propionic acid (1,00 g, 2,95 mmol) and 1,2-dibromethane (5,54 g, 29,50 mmol). Then the mixture is heated in a flask under reflux for 8 hours. After cooling, the reaction mixture was filtered to remove solids, and then the filtrate is evaporated in vacuum. The crude product is purified by chromatography on silica gel, using as eluent hexane/EtOAc (4:1), with the connection specified in the header (0,22 g, 17%).

Example 3

Getting 2-(1-methyl-3-oxo-3-phenyl-propylamino)-3-[4-(2-carbazolyl the toxi)-phenyl]-propionic acid (compound CS023)

To a solution of methyl ester of 2-(1-methyl-3-oxo-3-phenyl-propylamino)-3-[4-(2-bromoethoxy)-phenyl]-propionic acid (0,22 g, 0.49 mmol) and carbazole (0,082 g, 0.49 mmol) in benzene (10 ml) add tetrabutylammonium (0.08 g) and an aqueous solution of 50% NaOH (0,084 g at 1.08 mmol), the mixture is then heated in a flask under reflux for 10 hours After cooling, add benzene (30 ml) and the mixture washed with water (3×30 ml). Then the solvent is evaporated in vacuum. The crude product is purified by chromatography on silica gel, using as eluent CHCl3/Meon (4:1), with the connection specified in the header (0.05 g, 20%).

Msvr calculated for C33H30N2O4: 518,6123. Found: 518,6125. MA calculated for C33H30N2O4: 76,43%; N OF 5.83%; N OF 5.40%.

Found, %: C 76,21; N. Of 5.85; N 5,39.

Example 4

Obtaining methyl ester 2-[1-methyl-3-oxo-3-(4-forfinal)propylamino]-3-(4-hydroxyphenyl)-propionic acid.

To a solution of methyl ester of L-tyrosine (4,00 g, 20,51 mmol) in methanol (150 ml) was added 1-(4-perbenzoic)acetone (4,06 g, 22,56 mmol), the mixture is then heated in a flask under reflux for 24 hours the Solvent is evaporated in vacuum. To the residue is added ethanol (50 ml), then the ethanol is distilled off at atmospheric pressure. The crude product PTS who participate chromatography on silica gel, using as eluent hexane/EtOAc (4:1), with the connection specified in the header (7,03 g, 96%).

Example 5

Obtaining methyl ester 2-[1-methyl-3-oxo-3-(4-forfinal)propylamino]-3-[4-(2-bromoethoxy)phenyl]-propionic acid.

To a solution of potassium hydroxide (0.17 g, 2,95 mmol) in ethanol (20 ml) is added methyl ether 2-[1-methyl-3-oxo-3-(4-forfinal)-propylamino]-3-(4-hydroxyphenyl)-propionic acid (1,05 g, 2,95 mmol) and 1,2-dibromethane (5,54 g, 29,50 mmol). Then the mixture is heated in a flask under reflux for 8 hours. After cooling, the reaction mixture is filtered to remove the formed solid particles, and then the filtrate is evaporated in vacuum. The crude product is purified by chromatography on silica gel, using as eluent hexane/EtOAc (4:1), with the connection specified in the header (0,37 g, 27%).

Example 6

Getting 2-[1-methyl-3-oxo-3-(4-forfinal)-propylamino]-3-[4-(2-carbasalate)-phenyl]-propionic acid

To a solution of methyl ester 2-[1-methyl-3-oxo-3-(4-forfinal) -propylamino]-3-[4-(2-bromoethoxy)-phenyl]-propionic acid (to 0.23 g, 0.49 mmol) and carbazole (0,082 g, 0.49 mmol) in benzene (10 ml) add tetrabutylammonium (0.08 g) and an aqueous solution of 50% NaOH (0,084 g at 1.08 mmol), the mixture is then heated in a flask with a return was built in the ICOM for 10 hours After cooling, add benzene (30 ml) and the mixture washed with water (3×30 ml). Then the solvent is evaporated in vacuum. The crude product is purified by chromatography on silica gel, using as eluent CHCl3/Meon (4:1), with the connection specified in the header (0.06 g, 23%).

Msvr calculated for C33H29FN2O4: 536,6027. Found: 536,6025. MA calculated for C33H29FN2O4: 73,86%; H 5.45 PER CENT; N 5,22%.

Found, %: C 73,63; N 5,46; N 5,20.

Example 7

Obtaining methyl ester 2-[1-methyl-3-oxo-3-(3-pyridyl) propylamino]-3-[4-hydroxyphenyl]-propionic acid.

To a solution of methyl ester of L-tyrosine (4,00 g, 20,51 mmol) in methanol (150 ml) was added 1-nicotinoylureas (3,68 g, 22,56 mmol), the mixture is then heated in a flask under reflux for 24 hours the Solvent is evaporated in vacuum. To the residue is added ethanol (50 ml), then the ethanol is distilled off at atmospheric pressure. The crude product is purified by chromatography on silica gel, using as eluent hexane/EtOAc (4:1), with the connection specified in the header (5,51 g, 79%).

Example 8

Obtaining methyl ester 2-[1-methyl-3-oxo-3-(3-pyridyl)-propylamino]-3-[4-(2-bromoethoxy)-phenyl]-propionic acid.

To a solution of potassium hydroxide (0.17 g, 2,95 mmol) in it the OLE (20 ml) is added methyl ether 2-[1-methyl-3-oxo-3-(3-pyridyl)-propylamino]-3-(4-hydroxyphenyl)-propionic acid (1,00 g, 2,95 mmol) and 1,2-dibromethane (5,54 g, 29,50 mmol).

Then the mixture is heated in a flask under reflux for 8 hours. After cooling, the reaction mixture is filtered to remove the formed solid particles, and then the filtrate is evaporated in vacuum. The crude product is purified by chromatography on silica gel, using as eluent hexane/EtOAc (4:1), with the connection specified in the header (0.20 g, 15%).

Example 9

Getting 2-[1-methyl-3-oxo-3-(3-pyridyl)-propylamino]-3-[4-(2-carbasalate)-phenyl]-propionic acid

To a solution of methyl ester 2-[1-methyl-3-oxo-3-(3-pyridyl)-propylamino]-3-[4-(2-bromoethoxy)-phenyl]-propionic acid (0,22 g, 0.49 mmol) and carbazole (0,082 g, 0.49 mmol) in benzene (10 ml) add tetrabutylammonium (0.08 g) and an aqueous solution of 50% NaOH (0,084 g at 1.08 mmol), the mixture is then heated in a flask under reflux for 10 hours After cooling, add benzene (30 ml) and the mixture washed with water (3×30 ml). Then the solvent is evaporated in vacuum. The crude product is purified by chromatography on silica gel, using as eluent CHCl3/Meon (4:1), with the connection specified in the header (0.04 g, 16%).

Msvr calculated for C32H29N3O4: 519,6001. Found: 519,6003. MA calculated for C32H29N3O4: 73,97%; N, 5.6 PERCENT; N of 8.09%.

Found, %: C 73,84; N The 5.65; N 8,11.

Example 10

Obtain methyl ester of 2-((2-benzoylphenyl)amino)-3-(4-hydroxyphenyl)-propionic acid.

To a mixture of 2-benzoylecognine (90.9 g, 0.45 mol), methyl ester of L-tyrosine (78.0 g, 0.40 mol) in anisole (1000 ml) is added 5% palladium on coal (20 g), then the mixture is heated in a flask under reflux for 2 h, the resulting water is removed through the nozzle (apparatus) Dean-stark. The mixture is cooled to 80°C and Pd/C was filtered and washed with anisole (3×60 ml). The mixture is cooled to 40°add hexane (1000 ml) and the mixture maintained at -20°C for 48 hours the Solids filtered and washed with hexane (5×200 ml) to give the crude methyl ester of 2-((2-benzoylphenyl)-amino)-3-(4-hydroxyphenyl)-propionic acid. The crude product is mixed with 250 ml of methanol and then heated in a flask under reflux for 30 minutes After cooling to 0°the product is filtered, washed with methanol (2×50 ml) and dried in vacuum to obtain compound indicated in heading (60,2 g, 40.1 per cent).

Example 11

Obtain methyl ester of 2-((2-benzoylphenyl)amino)-3-[4-(2-bromoethoxy)-phenyl]-propionic acid.

To a solution of potassium hydroxide (0.17 g, 2,95 mmol) in ethanol (20 ml) is added methyl EF the R 2-((2-benzoylphenyl)amino)-3-(4-hydroxyphenyl)-propionic acid (1,11 g, 2,95 mmol) and 1,2-dibromethane (5,54 g, 29,50 mmol). Then the mixture is heated in a flask under reflux for 8 hours. After cooling, the reaction mixture was filtered to remove solids, and then the filtrate is evaporated in vacuum. The crude product is purified by chromatography on silica gel, using as eluent hexane/EtOAc (4:1), with the connection specified in the header (0,30 g, 21%).

Example 12

Getting 2-((2-benzoylphenyl)amino)-3-[4-(2-carbasalate)-phenyl]-propionic acid (compound CS0381)

To a solution of methyl ester of 2-((2-benzoylphenyl)amino)-3-[4-(2-bromoethoxy)-phenyl]-propionic acid (0.24 g, 0.49 mmol) and carbazole (0,082 g, 0.49 mmol) in benzene (10 ml) add tetrabutylammonium (0.08 g) and an aqueous solution of 50% NaOH (0,084 g at 1.08 mmol), the mixture is then heated in a flask under reflux for 10 hours After cooling, add benzene (30 ml) and the mixture washed with water (3×30 ml). Then the solvent is evaporated in vacuum. The crude product is purified by chromatography on silica gel, using as eluent CHCl3/Meon (4:1), with the connection specified in the header (0.06 g, 22%).

Msvr calculated for C36H30N2O4: 554,6453. Found: 554,6451. MA calculated for C36H30N2O4: 77,96%; H 5.45 PER CENT; N OF 5.05%.

Found, %: C 77,83; N 5,46; N 5,07.

Example 13

Obtaining methyl ester 2-[(2-perbenzoic)phenyl)amino]-3-(4-hydroxyphenyl)-propionic acid

To a mixture of 2-(4-perbenzoic)cyclohexanone (99,0 g, 0.45 mol), methyl ester of L-tyrosine (78.0 g, 0.40 mol) in anisole (1000 ml) is added 5% palladium on coal (20 g), then the mixture is heated in a flask under reflux for 2 h, the resulting water is removed by the apparatus of the Dean-stark. The mixture is cooled to 80°C and Pd/C was filtered and washed with anisole (3×60 ml). The mixture is cooled to 40°add hexane (1000 ml) and the mixture maintained at -20°C for 48 hours the Solids filtered and washed with hexane (5×200 ml) to give the crude methyl ester 2-[(2-(4-perbenzoic)phenyl)-amino]-3-(4-hydroxyphenyl)-propionic acid. The crude product is mixed with 250 ml of methanol and then heated in a flask under reflux for 30 minutes After cooling to 0°the product is filtered, washed with methanol (2×50 ml) and dried in vacuum to obtain compound indicated in heading (75,6 g, 48.1 percent).

Example 14

Obtaining methyl ester 2-[(2-(4-perbenzoic)phenyl)amino]-3-[4-(2-bromoethoxy)-phenyl]-propionic acid

To a solution of potassium hydroxide (0.17 g, 2,95 mmol) in ethanol (20 ml) is added methyl ether 2-[(2-(4-perbenzoic)phenyl)amino]-3-(hydroxyphenyl)-propionic acid (1,16 g, 2,95 mmol) and 1,2-dibromethane (5,54 g, 29,50 mmol). Then the mixture is heated in a flask under reflux for 8 hours. After cooling, the reaction mixture is filtered to remove the formed solid particles, and then the filtrate is evaporated in vacuum. The crude product is purified by chromatography on silica gel, using as eluent hexane/EtOAc (4:1), with the connection specified in the header (0.56 g, 38%).

Example 15

Getting 2-[(2-(4-perbenzoic)phenyl)amino]-3-[4-(2-carbasalate)-phenyl]-propionic acid (compound CS038)

To a solution of methyl ester 2-[(2-(4-perbenzoic)phenyl)amino]-3-[4-(2-bromoethoxy)-phenyl]-propionic acid (0.25 g, 0.49 mmol) and carbazole (0,082 g, 0.49 mmol) in benzene (10 ml) add tetrabutylammonium (0.08 g) and an aqueous solution of 50% NaOH (0,084 g at 1.08 mmol), the mixture is then heated in a flask under reflux for 10 hours After cooling, add benzene (30 ml) and the mixture washed with water (3×30 ml). Then the solvent is evaporated in vacuum. The crude product is purified by chromatography on silica gel, using as eluent CHCl3/Meon (4:1), with the connection specified in the header (0.10 g, 36%).

Msvr calculated for C36H29FN2O2: 572,6357. Found: 572,6354. MA calculated for C36H29FN2O4: 75,51%; N 5,11%; N 4,89%. Nai is prohibited, %75,83; N 5,10; N 4,90.

Example 16

Obtain methyl ester of 2-((2-nicotinoyl)amino)-3-(4-hydroxyphenyl)-propionic acid

To a mixture of 2-nicotinereplacement (914,0 g, 0.45 mol), methyl ester of L-tyrosine (78.0 g, 0.40 mol) in anisole (1000 ml) is added 5% palladium on coal (20 g), then the mixture is heated in a flask under reflux for 2 h, the resulting water is removed by the apparatus of the Dean-stark. The mixture is cooled to 80°C and Pd/C was filtered and washed with anisole (3×60 ml). The mixture is cooled to 40°add hexane (1000 ml) and the mixture maintained at -20°C for 48 hours the Solids filtered and washed with hexane (5×200 ml) to give the crude methyl ester of 2-((2-nicotinoyl)amino)-3-(4-hydroxyphenyl)-propionic acid. The crude product is mixed with 250 ml of methanol and then heated in a flask under reflux for 30 minutes After cooling to 0°the product is filtered, washed with methanol (2×50 ml) and dried in vacuum to obtain compound indicated in heading (58,6 g, 39.0 per cent).

Example 17

Obtain methyl ester of 2-((2-nicotinoyl)amino)-3-[4-(2-bromoethoxy)-phenyl)-propionic acid

To a solution of potassium hydroxide (0.17 g, 2,95 mmol) in ethanol (20 ml) is added methyl ether 2-((2-nicotine is phenyl)amino]-3-(4-hydroxyphenyl)-propionic acid (1.10 g, 2,95 mmol) and 1,2-dibromethane (5,54 g, 29,50 mmol). Then the mixture is heated in a flask under reflux for 8 hours. After cooling, the reaction mixture is filtered to remove the formed solid particles, and then the filtrate is evaporated in vacuum. The crude product is purified by chromatography on silica gel, using as eluent hexane/EtOAc (4:1), with the connection specified in the header (0.40 g, 28.2 per cent).

Example 18

Getting 2-((2-nicotinoyl)amino)-3-[4-(2-carbasalate)-phenyl]-propionic acid

To a solution of methyl ester of 2-((2-nicotinoyl)amino)-3-[4-(2-bromoethoxy)-phenyl]-propionic acid (0.24 g, 0.49 mmol) and carbazole (0,082 g, 0.49 mmol) in benzene (10 ml) add tetrabutylammonium (0.08 g) and an aqueous solution of 50% NaOH (0,084 g at 1.08 mmol), the mixture is then heated in a flask under reflux for 10 hours After cooling, add benzene (30 ml) and the mixture washed with water (3×30 ml). Then the solvent is evaporated in vacuum. The crude product is purified by chromatography on silica gel, using as eluent CHCl3/Meon (4:1), with the connection specified in the header (0.05 g, 18%).

Msvr calculated for C35H29N3O4: 555,6331. Found: 555,6329. MA calculated for C35H29N3O4: 75,66%; N 5,26%; N 7,56%.

Found, %: C 75,42; N At 5.27; N ,53.

Example 19

The method of obtaining 2-((2-benzoylphenyl)amino)-3-[4-(2-carbasalate)-phenyl]-propionic acid on an industrial scale.

To a solution of potassium carbonate (2 kg) in acetonitrile (5000 ml) is added methyl ether 2-((2-benzoylphenyl)amino]-3-(4-hydroxyphenyl)-propionic acid (555 g, 1.48 mol) and 1,2-dibromethane (1000 ml). The mixture is then stirred at room temperature for 24 hours. After that the reaction mixture is filtered and the filtrate evaporated in vacuum. The crude product is purified by chromatography on silica gel, using as eluent hexane/EtOAc (4:1), to obtain the methyl ester of 2-((2-benzoylphenyl)amino)-3-[4-(2-bromoethoxy)-phenyl]-propionic acid (442 g, 62%).

To a solution of methyl ester of 2-((2-benzoylphenyl)amino)-3-[4-(2-bromoethoxy)-phenyl]-propionic acid (240 g, 0.49 mol) and carbazole (82 g, 0.49 mol) in benzene (3000 ml) add tetrabutylammonium (80 g) and an aqueous solution of 40% NaOH (105 g, 1.05 mol), the mixture is then heated in a flask under reflux for 10 hours After cooling, the upper organic layer is evaporated in a vacuum. The crude product is purified by chromatography on silica gel, using as eluent CHCl3/Meon (8:1), with the connection specified in the header (78 g, 28.7 percent).

Example 20

The method of obtaining 2-[(2-(4-perbenzoic)phenyl)amino)-3-[4-(2-carbazole is LaTeXe)-phenyl]-propionic acid on an industrial scale

To a solution of potassium carbonate (2 kg) in acetonitrile (5000 ml) is added methyl ether 2-[(2-(4-perbenzoic)phenyl)amino]-3-(4-hydroxyphenyl)-propionic acid (581 g, 1.48 mol) and 1,2-dibromethane (1000 ml). The mixture is then stirred at room temperature for 24 hours. After that the reaction mixture is filtered and the filtrate evaporated in vacuum. The crude product is purified by chromatography on silica gel, using as eluent hexane/EtOAc (4:1), to obtain the methyl ester of 2-[(2-(4-perbenzoic)phenyl)amino]-3-[4-(2-bromoethoxy)-phenyl]-propionic acid (429 g, 58%).

To a solution of methyl ester 2-[(2-(4-perbenzoic)phenyl)amino]-3-[4-(2-bromoethoxy)-phenyl]-propionic acid (250 g, 0.50 mol) and carbazole (83,5 g, 0.50 mmol) in benzene (3000 ml) add tetrabutylammonium (80 g) and an aqueous solution of 40% NaOH (108 g, a 1.08 mol), the mixture is then heated in a flask under reflux for 10 hours After cooling, the upper organic layer is evaporated in a vacuum. The crude product is purified by chromatography on silica gel, using as eluent CHCl3/Meon (8:1), with the connection specified in the header (91,52 g, 32%).

Example 21

Obtaining methyl ester 2-[(2-(4-tert-butylbenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)-propionic acid

To a mixture of 2- (4-tert-butylbenzoyl)C is clohexane (116,1 g, 0.45 mol), methyl ester of L-tyrosine (78.0 g, 0.40 mol) in anisole (1000 ml) is added 5% palladium on coal (20 g), then the mixture is heated in a flask under reflux for 2 h, the resulting water is removed by the apparatus of the Dean-stark. The mixture is cooled to 80°C and Pd/C was filtered and washed with anisole (3×60 ml). The mixture is cooled to 40°add hexane (1000 ml) and the mixture maintained at -20°C for 48 hours the Solids filtered and washed with hexane (5×200 ml) to give the crude methyl ester 2-[(2-(4-tert-butylbenzoyl) phenyl)amino]-3-(4-hydroxyphenyl)-propionic acid. The crude product is mixed with 250 ml of methanol and then heated in a flask under reflux for 30 minutes After cooling to 0°the product is filtered, washed with methanol (2×50 ml) and dried in vacuum to obtain compound indicated in heading (70,7 g, 41,0%).

Example 22

Obtaining methyl ester 2- [(2-(4-tert-butylbenzoyl)phenyl)amino]-3-[4-(2-bromoethoxy)-phenyl]-propionic acid

To a solution of potassium hydroxide (0.17 g, 2,95 mmol) in ethanol (20 ml) is added methyl ether 2-[(2-(4-tert-butylbenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)-propionic acid (1.27 g, 2,95 mmol) and 1,2-dibromethane (5,54 g, 29,50 mmol). Then the mixture is heated in a flask under reflux for 8 hours. After about what ladenia the reaction mixture was filtered to remove the formed solid particles, and then the filtrate is evaporated in vacuum. The crude product is purified by chromatography on silica gel, using as eluent hexane/EtOAc (4:1), with the connection specified in the header (0,67 g, 42%).

Example 23

Getting 2-[(2-(4-tert-butylbenzoyl)phenyl)amino]-3-[4-(2-carbasalate)phenyl]-propionic acid (Laboratory code CS0130090)

To a solution of methyl ester 2-[(2-(4-tert-butylbenzoyl)phenyl)amino]-3-[4-(2-bromoethoxy)-phenyl]-propionic acid (0.26 g, 0.49 mmol) and carbazole (0,082 g, 0.49 mmol) in benzene (10 ml) add tetrabutylammonium (0.08 g) and an aqueous solution of 50% NaOH (0,084 g at 1.08 mmol), the mixture is then heated in a flask under reflux for 10 hours After cooling, add benzene (30 ml) and the mixture washed with water (3×30 ml). Then the solvent is evaporated in vacuum. The crude product is purified by chromatography on silica gel, using as eluent CHCl3/Meon (4:1), with the connection specified in the header (0.14 g, 47%).

Msvr calculated for C40H38N2O4: 610,7496. Found: 610,7493. MA calculated for C40H38N2O4: 78,66%; N 6,27%; N 4,59%.

Found: 78,85; N 6,24; N Br4.61.

Example 24

Obtaining methyl ester 2-[(2-(4-methylbenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)-propionic acid

To a mixture of 2- (4-methylbenzoyl)cyclohexanone (97,2 is, 0.45 mol), methyl ester of L-tyrosine (78.0 g, 0.40 mol) in anisole (1000 ml) is added 5% palladium on coal (20 g), then the mixture is heated in a flask under reflux for 2 h, the resulting water is removed by the apparatus of the Dean-stark. The mixture is cooled to 80°C and Pd/C was filtered and washed with anisole (3×60 ml). The mixture is cooled to 40°add hexane (1000 ml) and the mixture maintained at -20°C for 48 hours the Solids filtered and washed with hexane (5×200 ml) to give the crude methyl ester 2-[(2-(4-methylbenzoyl) phenyl)amino]-3-(4-hydroxyphenyl)-propionic acid. The crude product is mixed with 250 ml of methanol and then heated in a flask under reflux for 30 minutes After cooling to 0°the product is filtered, washed with methanol (2×50 ml) and dried in vacuum to obtain compound indicated in heading (59,1 g, 38%).

Example 25

Obtaining methyl ester 2-[(2-(4-methylbenzoyl)phenyl)amino]-3-[4-(2-bromoethoxy)-phenyl]-propionic acid

To a solution of potassium hydroxide (0.17 g, 2,95 mmol) in ethanol (20 ml) is added methyl ether 2-[(2-(4-methylbenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)-propionic acid (1,15 g, 2,95 mmol) and 1,2-dibromethane (5,54 g, 29,50 mmol). Then the mixture is heated in a flask under reflux for 8 hours. After cooling the reactions is nnow the mixture is filtered to remove the formed solid particles, and then the filtrate is evaporated in vacuum. The crude product is purified by chromatography on silica gel, using as eluent hexane/EtOAc (4:1), with the connection specified in the header (0,78 g, 53%).

Example 26

Getting 2-[(2-(4-methylbenzoyl)phenyl)amino]-3-[4-(2-carbasalate)-phenyl]-propionic acid (Laboratory code CS0130080)

To a solution of methyl ester 2-[(2-(4-methylbenzoyl)phenyl)amino]-3-[4-(2-bromoethoxy)-phenyl]-propionic acid (0.24 g, 0.49 mmol) and carbazole (0,082 g, 0.49 mmol) in benzene (10 ml) add tetrabutylammonium (0.08 g) and an aqueous solution of 50% NaOH (0,084 g at 1.08 mmol), the mixture is then heated in a flask under reflux for 10 hours After cooling, add benzene (30 ml) and the mixture washed with water (3×30 ml). Then the solvent is evaporated in vacuum. The crude product is purified by chromatography on silica gel, using as eluent CHCl3/Meon (4:1), with the connection specified in the header (0.15 g, 54%).

Msvr calculated for C37H32N2O4: 568,6692. Found: 568,6693. MA calculated for C37H32N2O4: 78,15%; N 5,67%; N, 4.93 PER CENT.

Found, %: C 78,36; N 5,64; N 4,91.

Example 27

Obtaining methyl ester 2-[(2-(2-methylbenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)-propionic acid

To a mixture of 2-(2-methylbenzoyl)cyclohexanone (97,2 g of 0.45 mol is), methyl ester of L-tyrosine (78.0 g, 0.40 mol) in anisole (1000 ml) is added 5% palladium on coal (20 g), then the mixture is heated in a flask under reflux for 2 h, the resulting water is removed by the apparatus of the Dean-stark. The mixture is cooled to 80°C and Pd/C was filtered and washed with anisole (3×60 ml). The mixture is cooled to 40°add hexane (1000 ml) and the mixture maintained at -20°C for 48 hours the Solids filtered and washed with hexane (5×200 ml) to give the crude methyl ester 2-[(2-(2-methylbenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)-propionic acid. The crude product is mixed with 250 ml of methanol and then heated in a flask under reflux for 30 minutes After cooling to 0°the product is filtered, washed with methanol (2×50 ml) and dried in vacuum to obtain compound indicated in heading (52,9 g, 34%).

Example 28

Obtaining methyl ester 2-[(2-(2-methylbenzoyl)phenyl)amino]-3-[4-(2-bromoethoxy)-phenyl)-propionic acid

To a solution of potassium hydroxide (0.17 g, 2,95 mmol) in ethanol (20 ml) is added methyl ether 2-[(2-(2-methylbenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)-propionic acid (1,15 g, 2,95 mmol) and 1,2-dibromethane (5,54 g, 29,50 mmol). Then the mixture is heated in a flask under reflux for 8 hours. After cooling, the reaction to shift the ü is filtered to remove the formed solid particles, and then the filtrate is evaporated in vacuum. The crude product is purified by chromatography on silica gel, using as eluent hexane/EtOAc (4:1), with the connection specified in the header (0,83 g, 57%).

Example 29

Getting 2-[(2-(2-methylbenzoyl)phenyl)amino]-3-[4-(2-carbasalate)-phenyl]-propionic acid (Laboratory code CS01300110)

To a solution of methyl ester 2-[(2-(2-methylbenzoyl)phenyl)amino]-3-[4-(2-bromoethoxy)-phenyl]-propionic acid (0.24 g, 0.49 mmol) and carbazole (0,082 g, 0.49 mmol) in benzene (10 ml) add tetrabutylammonium (0.08 g) and an aqueous solution of 50% NaOH (0,084 g at 1.08 mmol), the mixture is then heated in a flask under reflux for 10 hours After cooling, add benzene (30 ml) and the mixture washed with water (3×30 ml). Then the solvent is evaporated in vacuum. The crude product is purified by chromatography on silica gel, using as eluent CHCl3/Meon (4:1), with the connection specified in the header (0.11 g, 39%).

Msvr calculated for C37H32N2O4: 568,6692. Found: 568,6689. MA calculated for C37H32N2O4: 78,15%; N 5,67%; N, 4.93 PER CENT.

Found, %: C 77,96; N. Of 5.68; N 4,90.

Example 30

Compounds 2-(1-methyl-3-oxo-3-phenyl-propylamino)-3-[4-(2-carbasalate)-phenyl]-propionic acid (compound CS-023), 2-((2-benzoylphenyl)amino)-3-[4-(2-carbasalate)-phenyl]-propionic acid the (CS-0381), and 2-[(2-(4-perbenzoic)phenyl)amino]-3-[4-(2-carbasalate)-phenyl]-propionic acid (CS-038) act as agonists RCR/Rappala of heterodimer in vitro. Cm. figure 1.

Activation RCR/Rappala of heterodimer these compounds is measured by the test of the reporter luciferase. In short, the entire sequence Rapala clone by PCR using oligonucleotide primers (5'-acgtgcttcctgcttcataga-3' (SEQ ID NO: 1) and 5'-cctgagattagccacctccc-3' (SEQ ID NO: 2)) from HepG2 cells. Amplified cDNA clone in the expression vector and a is sequenced. The reporter construct by inserting the annealed oligonucleotide containing three copies of the corresponding element RAPP (5'-gatcctctcctttgacctattgaactattacctacatttga-3' (SEQ ID NO: 3)) above sequence luciferase gene in the vector pHD(X3)Luc. Cells CV-1 transferout in 96-well tablets RCR and Rapala expression vectors together with a reporter construct. Cells cultivated in a medium containing delipidation serum within 24 hours after transfection, then add test compounds and the positive control WY(WY14643)dissolved in DMSO. The final concentration of DMSO in culture medium (200 μl) is 0.5%. Cells treated with the different compounds at various concentrations, as indicated above, within 24 hours, followed by analysis of luciferase reporter in tablet analyzer (Fluoroscan, Thermo Life Scieces).

Example 31

Compounds 2-(1-methyl-3-oxo-3-phenyl-propylamino)-3-[4-(2-carbasalate)-phenyl]-propionic acid (compound CS-023), 2-((2-benzoylphenyl)amino)-3-[4-(2-carbasalate)-phenyl]-propionic acid (CS-0381), and 2-[(2-(4-perbenzoic)phenyl)amino]-3-[4-(2-carbasalate)-phenyl]-propionic acid (CS-038) act as agonists RCR/Rapgame of heterodimer in vitro. Cm. figure 2.

Activation RCR/Rapgame of heterodimer measured by the test of the reporter luciferase. In short, the entire sequence of Rapgame clone by PCR using oligonucleotide primers (5'- ggggtacctgcttcagcagcgtgttcga-3' (SEQ ID NO: 4) and 5'- gctctagatgttggcagtggctcaggac-3' (SEQ ID NO: 5)) from the adipose tissue. Amplified cDNA clone in the expression vector and a is sequenced. The reporter construct by inserting the annealed oligonucleotide containing a single copy of the corresponding element RAPP (5'-cgcgttcctttccgaacgtgacctttgtcctggtccccttttgct-3' (SEQ ID NO: 6)) above sequence of a gene luciferase. Cells CV-1 transferout in 96-well tablets RCR and Rapgame expression vectors together with a reporter construct. Cells cultivated in a medium containing delipidation serum within 24 hours after transfection, then add test compounds and the positive control of the Roses (Rosiglitazone), dissolved in DMSO. The final concentration of DMSO in culture medium (200 μl) is 5%. Cells treated with the different compounds at various concentrations, as indicated above, within 24 hours, followed by analysis of luciferase reporter in tablet analyzer (Fluoroscan, Thermo Life Sciences).

Example 32

Compounds 2-(1-methyl-3-oxo-3-phenyl-propylamino)-3-[4-(2-carbasalate)-phenyl]-propionic acid (compound CS-023), 2-((2-benzoylphenyl)amino)-3-[4-(2-carbasalate)-phenyl]-propionic acid (CS-0381), and 2-[(2-(4-perbenzoic)phenyl)amino]-3-[4-(2-carbasalate)-phenyl]-propionic acid (CS-038) act as agonists RCR/Appdelete of heterodimer in vitro. Cm. figure 3.

Activation RCR/Appdelete of heterodimer measured by the test of the reporter luciferase. In short, the entire sequence of Appdelete clone by PCR using oligonucleotide primers (5'-ggggtacctgcttcagcagcgtgttcga-3' (SEQ ID NO: 4) and 5'- gctctagatgttggcagtggctcaggac-3' (SEQ ID NO: 5)) from the adipose tissue. Amplified cDNA clone in the expression vector and a is sequenced. The reporter construct by inserting the annealed oligonucleotide containing a single copy of the corresponding element RAPP (5'-cgcgttcctttccgaacgtgacctttgtcctggtccccttttgct-3' (SEQ ID NO: 6)) above sequence of a gene luciferase. Cells CV-1 transferout in 96-well tablets RCR and Appdelete expression vectors together with a reporter construct. Cells cultivated in a medium containing delipidation serum than is their 24 hours after transfection, then add test compounds and the positive control 2-D (2-bromohexadecane acid)dissolved in DMSO. The final concentration of DMSO in culture medium (200 μl) is 0.5%. Cells treated with the different compounds at various concentrations, as indicated above, within 24 hours, followed by analysis of luciferase reporter in tablet analyzer (Fluoroscan, Thermo Life Sciences).

Example 33

Compounds 2-[(2-(4-methylbenzoyl)phenyl)amino]-3-[4-(2-carbasalate)-phenyl]-propionic acid (Laboratory code CS0130080), and 2-[(2-(4-tert-butylbenzoyl)phenyl)amino]-3-[4-(2-carbasalate)-phenyl]-propionic acid (Laboratory code CS0130090) act as agonists RCR/RAPP of heterodimers in vitro. Cm. figure 4. (RCR/Rapala), 5 (RCR/Rapgame) and 6 (RCR/AppData).

Example 34

Compounds 2-(1-methyl-3-oxo-3-phenyl-propylamino)-3-[4-(2-carbasalate)-phenyl]-propionic acid (compound CS-023, also named 7 CS-98), and 2-[(2-(4-perbenzoic)phenyl)amino]-3-[4-(2-carbasalate)-phenyl]-propionic acid (CS-038 at 30 mg/kg/body weight and Rosiglitazone 4 mg/kg/body weight) reduces the level of glucose in db/db mice (number of animals 10). Cm. Fig.7.

Example 35

Treatment models of obesity in rats the compound 2-[(2-(4-perbenzoic)phenyl)amino]-3-[4-(2-carbasalate)-phenyl]-propionic acid (CS-038) increases insulinomas the required test insulintreated after 13 days of exposure to the drug (doses indicated in Fig. mg/kg/body weight, Roses means Rosiglitazone at a dose of 4 mg/kg/body weight, CS-4 CS means-038 dose of 4 mg/kg/body weight and CS-30 CS means-038 at a dose of 30 mg/kg/body weight; norm means hungry rat. Control is a rat with obesity and all the experiments were carried out on rats with obesity; the number of animals 10). Cm. Fig.

Example 36

Treatment in an experimental model of obesity in rats the compound 2-[(2-(4-perbenzoic)phenyl)amino]-3-[4-(2-carbasalate)-phenyl]-propionic acid (CS-038) improves glucose tolerance test oral glucose tolerance following a 13-day treatment drug (doses indicated in the following figure in mg/kg/body weight. Roses means Rosiglitazone at a dose of 4 mg/kg/body weight, CS-4 CS means-038 dose of 4 mg/kg/body weight and CS-30 CS means-038 at a dose of 30 mg/kg/body weight; norm means hungry rat. Control is a rat with obesity and all the experiments were carried out on rats with obesity; the number of animals 10). Cm. Fig.9.

Example 37

Treatment models of obesity in rats the compound 2-[(2-(4-perbenzoic)phenyl)amino]-3-[4-(2-carbasalate)-phenyl]-propionic acid (CS-038) reduces the level of triglycerides in the blood after a 13-day treatment drug (doses indicated in figure 9 mg/kg/body weight. Norm means hungry rat. Control is rat obesity, and all the experiments were carried out on rats with what geranium; the number of animals 10).

Table 1

The group of animalsDose (mg/kg)Triglycerides (mg/DL)Cholesterol (mg/DL)
Norma-149,6±39,8*73,1±7,8**
Control-233,9±101,6109,4±26,7
CS0384150,3±52,I*98,4±29,4
CS03830143,2±61,8*86,6±37,7
Roses4273,3+87,4112,7±25,5
In comparison with normal group: *P<0,05, **P<0,01

Example 38

Treatment in an experimental model of obesity in rats the compound 2-[(2-(4-perbenzoic)phenyl)amino]-3-[4-(2-carbasalate)-phenyl]-propionic acid (CS-038) does not affect the body weight, and the content of fat in the abdominal cavity is increased after 15 days of drug treatment (dose indicated in mg/kg body weight; Control is rat obesity, and all the experiments were carried out on rats with obesity; the number of animals 10).

Table 2
The group of animalsDose (mg/is d) Body weight (g)The fat of the abdominal cavity (g)
0 days6 days9 days15 days
Control-576,5±138,0569,4±142,1568,5±145,3562,7±136,560,4±21,0
CS0384591,5±130,0580,8±130,2575,2±to 130.6569,4±122,955,8±16,8
CS03830580,5±134,9586,1±143,2586,5±144,2578,3±176,856,6±21,1
Roses4594,9±169,3604,5±181,4601,6±183,9596,4±176,863,1±31,4

All publications and patents mentioned in the above document, included in this description by reference.

Various modifications and variations of the described compositions and methods of the invention are obvious to those skilled in the art within the scope and essence of the invention. Although the invention is described in connection with certain preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such determi is lennemi incarnations. In fact, it is understood that various modifications of the described compositions and methods for the embodiment of the invention which are obvious to a person skilled in this field or related areas, are within the scope of the following claims.

1. The compound of the formula I

or its pharmaceutically acceptable salt, where ring a and ring condensed with the ring containing X and N are, each independently from each other represents a 5-6 membered cyclic aromatic ring;

X represents a valence bond;

R1represents N;

R2represents N;

R3represents N;

R4and R5independently represent H, C1-6alkyl; or

R4and R5may form an aromatic 5 - or 6-membered ring;

Alk1represents a C1-6alkylen;

Alk2represents a C1-6alkylen;

Ar1represents an aromatic 6-membered ring;

Ar2represents an aromatic 6-membered ring, optionally substituted by one or more halogen, C1-6by alkyl; or is a 5-6-membered monocyclic aromatic ring containing one nitrogen heteroatom.

2. The compound according to claim 1, where

ring a is a 6-membered aromatic ring;

ring b is a 6-membered aromatic ring;

X is a valence bond;

R1is N;

R2is N;

R3is N;

R4and R5independently are H or alkyl;

Alk1is2-3alkylene;

Alk2is1-2alkylene;

Ar1is a group of arylene;

Ar2is a substituted aryl group.

3. The compound according to claim 1, where

ring a is a 6-membered aromatic ring;

ring b is a 6-membered aromatic ring;

X is a valence bond;

R1is N;

R2is N;

R3is N;

R4and R5form a 6-membered aromatic ring;

Alk1is2-3alkylene;

Alk2is1-2alkylene;

Ar1is a 6-membered aromatic ring;

Ar2is a substituted aryl group.

4. The compound according to claim 1, where

ring a is a benzene ring;

ring b is a benzene ring;

X is a valence bond;

R1is N;

R is N;

R3is N;

R4is stands; R5is N;

Alk1is CH2CH2;

Alk2is CH2;

Ar1is a benzene ring;

Ar2is a benzene ring, optionally substituted by one or more fluorine.

5. The compound according to claim 1, where

ring a is a benzene ring;

ring b is a benzene ring;

X is a valence bond;

R1is N;

R2is N;

R3is N;

R4and R5form a benzene ring;

Alk1is CH2CH2;

Alk2is CH2;

Ar1is a benzene ring;

Ar2is a benzene ring, optionally substituted by one or more fluorine.

6. The compound according to claim 1, where

ring a is a benzene ring;

ring b is a benzene ring;

X is a valence bond;

R1is N;

R2is N;

R3is N;

R4is stands; R5is N;

Alk1is CH2CH2;

Alk2is CH2;

Ar1is Ben the Aulnay ring;

Ar2is a pyridine ring, optionally substituted by one or more halogen.

7. The compound according to claim 1, where

ring a is a benzene ring;

ring b is a benzene ring;

X is a valence bond;

R1is N;

R2is N;

R3is N;

R4and R5form a benzene ring;

Alk1is CH2CH2;

Alk2is CH2;

Ar1is a benzene ring;

Ar2is a pyridine ring, optionally substituted by one or more fluorine.

8. The method of obtaining the compounds of formula I

or its pharmaceutically acceptable salts, where ring a and ring condensed with the ring containing X and N are, each independently from each other represents a 5-6 membered cyclic aromatic ring;

X represents a valence bond;

R1represents N;

R2represents N;

R3represents N;

R4and R5independently represent H, C1-6by alkyl; or

R4and R5may form an aromatic 5 - or 6-membered ring;

Alk1 1-6alkylen;

Alk2represents a C1-2alkylen;

Ar1represents an aromatic 6-membered ring;

Ar2represents an aromatic 6-membered ring, optionally substituted by one or more halogen, C1-6by alkyl; or is a 5-6-membered monocyclic aromatic ring containing one heteroatom of nitrogen, including stages:

a) initiate the condensation reaction between compound 1 and β-diketone 2 with obtaining amide analogues vinylogous number 3;

b) implementation 0-alkylation of compound 3 to obtain compound 4;

(C) the implementation of the N-alkylation of compound 4 with obtaining substituted derivatives arylalkenes acid 6.

9. The method of obtaining of claim 8, in which:

(a) the condensation reaction is conducted in ethanol at a temperature of education phlegmy;

(b) O-alkylation is achieved by treating compound 3 CON and dibromethane in ethanol;

(c) N-alkylation is achieved by treating compound 4 NaOH and compound 5 in the presence of tetrabutylammonium.

10. The compound according to claim 1, where the specified connection is RAPP pan-agonist, activating RCR/Rapala, R Is R/Rapgame and RCR/AppData heterodimer.

11. The connection of claim 10, where the specified connection is a partial RAPP pan-agonist, activating RCR/Rapala, RCR/Rapgame and RCR/AppData heterodimer in varying degrees.

12. Pharmaceutical composition for the activation of nuclear receptors, including Retinoic X Receptor (RCR) and the receptors activated peroxisomal proliferation (RAPP), comprising an effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt with at least one pharmaceutically acceptable carrier or diluent.

13. The pharmaceutical composition according to item 12 in the standard (dose) dosage form containing from about 0.05 to about 200 mg of a compound according to claim 1.

14. The pharmaceutical composition according to item 13, standard (dose) dosage form containing from about 0.1 to about 100 mg of the compound according to claim 1.

15. The pharmaceutical composition according to item 12, which is suitable for oral, intranasal, transdermal, pulmonary (inhalation), or parenteral administration.

16. Activation of nuclear receptors, including Retinoic X Receptor (RCR) and the receptors activated peroxisomal proliferation (RAPP), including introduction to the needy in this subject an effective amount of the compounds of formula I

or is farmacevtichesky acceptable salts, where ring a and ring condensed with the ring containing X and N are, each independently from each other represents a 5-6 membered cyclic aromatic ring;

X represents a valence bond;

R1represents N;

R2represents N;

R3represents N;

R4and R5independently represent H, C1-6alkyl; or

R4and R5may form an aromatic 5 - or 6-membered ring;

Alk1represents a C1-6alkylen;

Alk2represents a C1-2alkylen;

Ar1represents an aromatic 6-membered ring;

Ar2represents an aromatic 6-membered ring, optionally substituted by one or more halogen, C1-6by alkyl; or is a 5-6-membered monocyclic aromatic ring containing a heteroatom of nitrogen.

17. A method of treating or preventing conditions caused by reduced activity of at least one of the nuclear receptors, including Retinoic X Receptor (RCR) and the receptors activated peroxisomal proliferation (RAPP), including introduction to the needy in this subject an effective amount of the compounds of formula I

or its pharmaceutically acceptable salt, where ring a and ring condensed with the ring containing X and N are, each independently from each other represents a 5-6 membered cyclic aromatic ring;

X represents a valence bond;

R1represents N;

R2represents N;

R3represents N;

R4and R5independently represent H, C1-6alkyl; or

R4and R5may form a 5 - or 6-membered ring;

Alk1represents a C1-6alkylen;

Alk2represents a C1-2alkylen;

Ar1represents an aromatic 6-membered ring;

Ar represents an aromatic 6-membered ring, optionally substituted by one or more halogen, C1-6by alkyl; or is a 5-6-membered monocyclic aromatic ring containing one heteroatom of nitrogen.

18. The method according to 17, treatment or prevention of a condition selected from the group consisting of type 1 diabetes type 2 diabetes type, dyslipidemia, syndrome X, cardiovascular disease, atherosclerosis, hypercholesterolemia and obesity.

19. The method according to p, treat, cure or prevent type 2 diabetes type.

20. The method according to p, where the effective amount of the compound n is located in the range of from about 0.05 to about 200 mg/kg of body weight per day.

21. The method according to claim 20, where the effective amount of the compound is in the range from about 0.1 to about 100 mg/kg of body weight per day.

22. The method according to item 21, where the effective amount of the compound is in the range from about 0.1 to about 50 mg/kg of body weight per day.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: novel compounds are selected from group, consisting of: 4-(2-cyclopropyl-ethyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 3-fluorine-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-(2-hydroxymethyl-cyclopropylmethyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopentylmethyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 3-chlorine-4-(3-methyl- 4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 3-chlorine-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-(2-cyclopropyl-ethyl)-piperazine-1-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 3-fluorine-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 2-fluorine-4-(3-methyl-4,10-dihudro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 2-fluorine-4-(3-methyl-4,10-dihydro-3H-2,3,4;9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 3-ethyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 2-chlorine-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 2-chlorine-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide and 4-cyclobutylmethyl-piperazine-1-carboxylic acid 3-methoxy-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-benzylamide. Invention also relates to pharmaceutical composition and to application of compounds of general formula 1.

EFFECT: obtaining novel biologically active compounds and based on them pharmaceutical composition, possessing antagonistic activity with respect to vasopressin receptors.

60 cl, 153 ex

FIELD: chemistry.

SUBSTANCE: in general formula I

R1 is phenyl or 5-6-member heterocycle, containing one N atom and/or one O atom; R2 is imidazole or annelated imidazole, selected from group, including a), b), c), d) and e); and R3 stands for hydrogen, phenyl, 2,3-dihydrobenzo[1,4]dioxin-6-yl, benzo[b]thiophen-3-yl, 3-methylbenzo[b] thiophen-2-yl, thiophen-2-yl or thiophen-2-ylmethyl, R4 is hydrogen or lower alkyl, R5 is hydrogen, lower alkyl, halogen, morpholinyl, -NR'R", piperydinyl, optionally substituted with hydroxy-group, or is pyrrolidin-1-yl; R6 is hydrogen or -(CH2)nO-lower alkyl, R7 is hydrogen, -C(O)O-lower alkyl, -C(O)-C6H4-halogen, -C(O)-C6H4-lower alkyl, -C(O)-lower alkyl, -C(O)-cycloalkyl, -C(O)-NR'R", -C(O)-(CH2)nO-lower alkyl, -S(O)2-lower alkyl, -(CH2)nO-lower alkyl, -C(O)-pyridin-4-yl, whose ring can contain as substituents lower alkyl, halogen-lower alkyl or pyrrolidin-1-ylmethyl or is -(CH2)n-C(O)-NR'R"; R'/R" independently on each other stand for hydrogen, lower alkyl or -(CH2)n-tetrahydropyran-4-yl, X is -CH2-, -NR'''- or -O-; R''' is hydrogen, -C(O)-lower alkyl, -C(O)O-lower alkyl, -C(O)-C6H4CH3 or benzyl; n is 1 or 2.

EFFECT: increase of composition and treatment method efficiency.

14 cl, 56 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

FIELD: chemistry.

SUBSTANCE: in substituted with carbamate groups pyrazolpyridines of general formula (I): R1 stands for group -NR3C(=O)OR4, R2 stands for hydrogen atom or NH2, R3 stands for hydrogen atom or alkyl group with number of carbon atoms from one to four, R4 stands for alkyl group with number of carbon atoms from one to six, as well as to their salt, isomers and hydrates; to methods of their obtaining, medication based on them, as well as to application of said compounds for manufacturing medications for cardio-vascular diseases.

EFFECT: useful biological properties of compounds.

13 cl, 9 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns new histamine receptor blockers in the form of 2,3,4,5-tetrahydro-1H-pyrido-[3,4-b]indoles of the general formula 1 , where: R1 is an aminogroup substitute selected out of optionally substituted C1-C5alkyl; R2i is one or several same or different substitutes selected out of hydrogen, halogen, C1-C3 alkyl, CF3; Ar is phenyl or 5-6-member heterocycle containing 1-2 nitrogen or sulphur atoms in the cycle, unsubstituted or substituted by halogen, C1-C5alkyl, C1-C5alkoxy, substituted aminogroup or trifluormethyl; W is CH2 group optionally substituted CH2CH2 group or optionally substituted CH=CH group.

EFFECT: enhanced antiallergic and autoimmune effect.

4 tbl

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula (I) R1 is selected from , R2 stands for hydrogen or (lower) alkoxy; R3, R4, R5 and R6 are selected each independently from hydrogen, (lower) alkyl, halogenated (lower) alkyl, haloid or cycloalkyl; on condition that R2, R3, R4, R5 and R6 do not all stand for hydrogen; R7, R8 and R9 stand each independently for hydrogen, (lower) alkyl, (lower) alkoxy, (lower) hydroxyalkyl or halogenated (lower) alkyl; on condition that R7, R8 and R9 do not all stand for hydrogen; R10 stands for (lower) alkyl or halogenated (lower) alkyl.

EFFECT: obtaining novel biologically active compounds with improved properties.

16 cl, 38 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new substituted 2,3,4,5-tetrahydro-1N-pyrido[4,3-b]indoles with general formula 1.1, 1.2 or 1.3, their pharmaceutical salts and/or hydrates with antihistamine activity. In general formulae 1.1, 1.2 or 1.3 radicals assume values given below . In 1.1 compounds, R1 represents a substitute, chosen from hydrogen or unsubstituted C1-C5 alkyl; R2 represents a hydrogen atom or C1-C4 alkyl; R3i represents one or more single or different substitutes, chosen from hydrogen, halogen, C1-C3 alkyl or CF3; n=0 or 1-3; in 1.2 compounds R1 represents a substitute of an amino group, chosen from hydrogen or optionally substituted C1-C5 alkyl; R3 represents one or more single or different substitutes, chosen from hydrogen, halogen, C1-C3 alkyl or CF3, and Ar1 represents an aryl or heterocyclyl, containing at least one carboxyl and/or alkoxycarboxyl substitute or R3i represents a carboxyl and/or alkyloxycarboxyl substitute, and Ar1 represents optionally substituted aryl or heterocyclyl; in 1.3 compounds, R2 represents a hydrogen atom or C1-C4 alkyl; R3i represents one or more single or different substitutes, chosen from hydrogen, halogen, C1-C3 alkyl or CF3, and Ar2 represents optionally substituted aryl or heterocyclyl; k=0 or 1-4; m=1 or 2.

EFFECT: compounds can be used for making drug formulation for treating allergies, autoimmune diseases such as pollen allergy, urticaria, bronchial asthma etc.

17 cl, 10 dwg, 2 tbl,13 ex

FIELD: chemistry.

SUBSTANCE: invention refers to of serotonin receptor 5-NT6 antagonists, simultaneously regulating calcium ions homeostasis in cells, representing substituted 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole of general formula I, its pharmaceutically acceptable salt and/or hydrate. In general formula I where: R1 is amides substitute selected from optionally substituted C1-C5 alkyl; R2i represents one or number of identical or various substitutes selected from hydrogen, halogen, C1-C3 alkyl, CF3, OCF3; Ar represents halogen unsubstituted or substituted C1-C6 alkyl, C1-C6 alkoxy, phenyl substituted with amides or trifluoromethyl or optionally substituted aromatic hexamerous heterocycle containing 1-2 nitrogen atoms per one cycle, W represents ethyl group-CH2CH2 - vinyl group or ethynyl group. Invention also concerns new compounds selected from group of compounds of formula 1, methods of production thereof, pharmaceutical compositions and methods of their use.

EFFECT: production of composition that simultaneously regulates calcium ions homeostasis in cells.

34 cl, 7 dwg, 4 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: present invention concerns new piperidinyl compounds of the formula (I) and (II) which are selectively binding integrine receptors, pharmaceutical compositions and application of the compositions for obtaining medication with antagonistic effect on integrine receptors, where W, R2, Z and q are described in the claim.

EFFECT: pharmaceutical composition for obtaining medication with antagonistic effect on integrine receptors.

33 cl, 1 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the method of production of analogues of natural alkaloids of harman series (eleagnine) having potential biological activity, namely, to the method of 1-substituted -4phenyl-2,3,4,9-terahydro-1H-beta-carboline of general formula where one of R1 and R2 denotes hydrogen atom, and the other represents alkyl with 1 or 2 hydrogen atoms or aryl, hetaryl, or R1 and R2 together with carbon atom to which they are banded derive optionally substituted indol-3-on. The method is cyclisation of aldehydes by substituted tryptamine with acids, at the same time beta-phenyltryptamine is used as substituted tryptamine, aliphatic or aromatic aldehydes or optionally substituted isatins are used as aldehydes, mineral salts or Lewis catalysts are used as acids.

EFFECT: production of analogues of natural alkaloids of harman series (eleagnine) having potential biological activity.

1 cl, 4 tbl, 14 ex

The invention relates to a method for producing 2-trifluoromethyl-10-[3-(1-methyl-piperazinil-4)-propyl)] -fenotiazina used to treat diseases of the Central nervous system
The invention relates to a method for producing 2-trifluoromethyl-10-(3-chlorpropyl)fenotiazina is a key product in the synthesis of psychopharmacological drugs

The invention relates to organic chemistry, namely the synthesis fenotiazina derivatives of the formula I

< / BR>
Known 2,3-dihydro-3-keto-1H-pyrido[3,2,1]phenothiazines [1] as antioxidants for lubricants

FIELD: chemistry of heterocyclic compounds.

SUBSTANCE: invention relates to preparing new heterocyclic o-dicarbonitrile of the formula: . Ortho-dicarbonitriles can be used for preparing hexazocyclanes-fluorophores, as a donor-fragment for preparing hexazocyclanes-bifluorophores and hexazocyclanes-trifluorophores. Such hexazocyclanes are perspective compounds for their using as active media for liquid and solid lasers, scintillators and especially for indication of rigid radiation, for transformation of short-wave radiation to long-wave radiation in the information transfer by fiber-optics connection lines, for enhancing power of solar batteries, for protection of securities, for making advertising billboards and so on.

EFFECT: valuable properties of compounds.

2 ex

The invention relates to the field of production of new heterocyclic O-dicarbonitriles, which can be used to achieve different hexatriene, useful as active media of liquid and solid lasers, scintillators, for the transformation of shortwave radiation in the long wavelength in the transmission of information through fiber-optic communication lines and so on

The invention relates to a new method of obtaining derivatives of 7-hydroxy-5,6-califonication, which are used in the aniline-dye industry for dyeing different types of fibers

The invention relates to a new method of obtaining derivatives of 7-hydroxy-5,6-califonication General formula (I)

< / BR>
where X is hydrogen or halogen, or lower alkyl, which are used in the aniline-dye industry for dyeing different types of fibers

The invention relates to the derivatives of uracil and their use in agriculture, namely use as herbicides
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