New derivatives of 3-phenylpropionic acid

FIELD: chemistry.

SUBSTANCE: compounds of the invention can be used for treating or preventing diseases and conditions, mediated by peroxisome proliferator activated gamma receptor (PPARγ). In formula (I) W represents a COOH group or -COOC-C1-C4alkyl; Y represents NH; Z represents S or O; X represents O; R1-R6 each independently represents a hydrogen atom or substitute, chosen from a group consisting of: C1-C4-alkyl, thienyl or phenyl, where phenyl is optionally substituted with one or more substitutes, independently chosen from a group consisting of C1-C4-alkyl, C1-C4-alkoxy, a halogen atom; -NO2 and -CN; A represents C1-C4-alkyl, -N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl, aryl, chosen from a group consisting of phenyl, naphthyl, or heteroaryl, chosen from a group consisting of oxazolyl, isoxazolyl, thienyl, pyridyl, thiazolyl, thiadiazolyl, benzo[b]thienyl, imidazolyl, indolyl and carbazolyl, where aryl and heteroaryl are substituted or not substituted with one or more substitutes, independently chosen from a group consisting of C1-C4-alkyl, C1-C4-alkoxy, phenyl and a halogen atom; and n is an integer from 0 to 4. The invention also relates to a pharmaceutical composition, containing the invented compound as an active component, use of the compounds to make a medicinal agent, and method of treatment.

EFFECT: obtaining new biologically active compounds.

22 cl, 6 ex

 

The scope of the invention

The present invention relates to new compounds which are derivatives of 3-phenylpropionic acid, containing their pharmaceutical compositions and to their use for the treatment and/or prophylaxis of diseases and conditions mediated by activated proliferation peroxisomes gamma receptor (PPARγ). These compounds show the ability to bind to the receptor PPARγ and modify its activity.

The state of the art

More than 20 years ago, was discovered by a group thiazolidinedione compounds showing activity in rodent models of type 2 diabetes and insulin resistance. Although their mechanism of action was not known, the connection was successfully used in the treatment of type 2 diabetes. Publication demonstrating that they act through the nuclear receptor PPAR gamma, were published only in the mid-90s. It is now known that intracellular receptor proteins of the family of PPAR control the expression of genes involved in the regulation of lipid-carbohydrate metabolism.

Diseases such as hyperlipidemia, atherosclerosis, obesity and type 2 diabetes become a serious problem not only for the population of industrialized countries. It is estimated that more than 150 million people worldwide suffer from type 2 diabetes, and this number is expected to double by 2025. The Poland currently, approximately 2 million people suffer from this disease, and the same number of people at risk of its development. The medical costs of patients with diabetes reach 6-8 percent of the total budgets on health care. In the initial stage of diabetes may be asymptomatic and may begin at any age; however, most often it occurs in middle age and the elderly. The progression of type 2 diabetes is the result of the superposition of physiological disorders, such as tissue resistance to insulin, insufficient insulin production in the pancreas, increased insulin production after enhanced gluconeogenesis. The most frequent diabetic complications are capillary changes in the retina, kidney and nervous system, which leads to an increased risk of blindness, kidney failure and neuropathy. Diabetes is also a major causal factor for myocardial infarction and cerebral stroke.

The PPARγ receptors belonging to the family of nuclear receptors that play a role in the regulation of metabolism and deposition of lipids. They are expressed in adipose tissue and colon, and participate in the process of lipogenesis. The ligand that activates the receptor PPARγ, can enhance the effect of insulin to lower plasma glucose levels. They can also be useful in the management and treatment of disorders of energy balance and metabolic the ISM lipids.

Known compounds, which are derivatives or analogs of L-tyrosine, which act through the modulation of the response of the receptor PPARγ, thereby affecting glucose metabolism, hemostasis, lipids and energy balance.

In the international patent application WO03/011834 and WO03/011814 disclosed derivatives of N-(2-benzoylphenyl)-L-tyrosine, which have partial activity of the PPARγ agonist and can be used in the treatment and prevention of, inter alia, reducing the portability of insulin, diabetes both type 1 and type 2, dyslipidemia, disorders related to syndrome X such as hypertension, obesity, insulin resistance, hyperglycemia, atherosclerosis, myocardial ischemia, coronary artery disease, kidney disease, and to improve cognitive functions and for the treatment of diabetic complications. Disclosed compounds are derivatives of L-tyrosine, in which the hydroxyl group of tyrosine substituted vinyl group, and the nitrogen in the amino group of tyrosine substituted 2-benzoylphenyl group.

In the international patent application WO01/17994 disclosed oxazoline compounds as antagonists of PPARγ, which can be used in the treatment of diabetes, obesity, metabolic syndrome, reducing the portability of insulin, syndrome X and cardiovascular diseases, including dyslipidemia. These compounds p is establet a derivative of L-tyrosine, in which the carboxyl group of tyrosine substituted 5-membered heterocyclic group, a hydroxyl group of tyrosine substituted (5-methyl-2-phenyloxazol-4-yl)ethyl group, and the nitrogen in the amino group of tyrosine substituted 2-benzoylphenyl group.

In the international patent application WO97/31907 disclosed derivatives of 4-hydroxyphenylacetic acid with agonistic activity towards PPARγ. Among other disclosed derivatives of L-tyrosine, in which the hydroxyl group of tyrosine substituted 5-membered heterocyclic group, which itself may be substituted, and the nitrogen in the amino group of tyrosine substituted 2-substituted phenyl group, including 2-benzoylphenyl group.

In this area there is still a need for new compounds - PPARγ ligands, which could be used in the treatment and/or prevention of diabetes and complications resulting from or associated with diabetes, especially lipid metabolism disorders and cardiovascular diseases.

The invention

The present invention relates to derivatives of 3-phenylpropionic acid of the formula (I)

in which:

W denotes a group COOH or its bioisostere, or-COO-C1-C4-alkyl;

Y represents NH, N-C1-C10-alkyl, O or S;

Z represents NH, N-C1-C10-alkyl, N-aryl, N-heteroaryl, S and O;

X denotes O, S, NH, N-C1-C10-alkyl, N-aryl, NSO2-C1-C10-alkyl, N-SO2-aryl, or N-SO2-heteroaryl;

R1- R6each independently represents a hydrogen atom or a Deputy selected from the group consisting of the following compounds:

C1-C4-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl, C3-C7-cycloalkane, C1-C4-dialkoxy, C3-C7-cyclotourism, halogen atom, substituted with halogen

C1-C4-alkyl substituted by halogen, C3-C7-cycloalkyl, -NO2, -CN, -SO2-NH2,

-SO2-NH-(C1-C4)-alkyl, -SO2-N(C1-C4-alkyl)2, -CO-(C1-C4)-alkyl, -O-CO-(C1-C4)-alkyl, -CO-O-(C1-C4)-alkyl, CO-aryl, -CO-NH2, -CO-NH-(C1-C4)-alkyl, -CO-N(C1-C4-alkyl)2, aryl and heteroaryl, and these aryl and heteroaryl can be substituted by one or more substituents independently selected from the group consisting of C1-C4-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl, C3-C7-cycloalkane, C1-C4-dialkoxy, C3-C7-cyclotourism, halogen atom; substituted by halogen, C1-C4-alkyl substituted by halogen, C3-C7-cycloalkyl, -NO2 , -CN, -SO2-NH2, -SO2-NH-(C1-C4)-alkyl, -SO2-N(C1-C4-alkyl)2, -CO-(C1-C4)-alkyl, -O-CO-(C1-C4)-alkyl, -CO-O-(C1-C4)-alkyl, CO-aryl, -CO-NH2, -CO-NH-(C1-C4)-alkyl, -CO-N(C1-C4-alkyl)2;

And represents C1-C4-alkyl, C3-C7-cycloalkyl, substituted with halogen, C1-C4-alkyl substituted by halogen, C3-C7-cycloalkyl, aryl, heteroaryl, heterocyclyl, -NH-CO-(C1-C4)-alkyl, -N(C1-C4-alkyl)-CO-(C1-C4)-alkyl, -NH-CO-aryl, -N(C1-C4-alkyl)-CO-aryl, -N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl, -NH-CO-NH2, -NH-CO-NH-(C1-C4)-alkyl, -NH-CS-NH-(C1-C4)-alkyl, -NH-CO-NH-aryl, -NH-CS-NH-aryl, -SO2-(C1-C4)-alkyl, -SO2-aryl, or-SO2-heteroaryl, and aryl, heteroaryl and heterocyclyl can be substituted by one or more substituents independently selected from the group consisting of C1-C4-alkyl, C1-C4-alkoxy and halogen atom; and

n denotes an integer from 0 to 4, inclusive;

and their pharmaceutically acceptable salts.

One group of compounds according to the invention includes compounds in which W represents COOH.

Another group of compounds according to the invention includes compounds in which W convoy is ACHAT-COO-C 1-C4-alkyl, preferably, the group-COO-CH3.

Another group of compounds according to the invention includes compounds in which Y represents NH.

Another group of compounds according to the invention includes compounds in which Y represents O.

Another group of compounds according to the invention includes compounds in which Y denotes N-C1-C4-alkyl, preferably N-CH3.

Another group of compounds according to the invention includes compounds in which Z represents O.

Another group of compounds according to the invention includes compounds in which Z represents S.

Another group of compounds according to the invention includes compounds in which Z denotes N-C1-C4-alkyl, especially N-CH3.

Another group of compounds according to the invention includes compounds in which Z denotes N-phenyl.

Another group of compounds according to the invention includes compounds in which X is O.

Another group of compounds according to the invention includes compounds in which X is S.

Another group of compounds according to the invention includes compounds in which X denotes NSO2-C1-C4-alkyl, especially NSO2-CH3.

Another group of compounds according to the invention includes compounds in which W represents COOH, Y represents NH, Z represents S, and X is O.

Another group of compounds is about the invention includes compounds in which W represents-COO-C1-C4-alkyl, especially-COO-CH3, Y represents NH, Z represents S, and X is O.

Another group of compounds according to the invention includes compounds in which W represents COOH, Y represents NH, Z represents O and X is O.

Another group of compounds according to the invention includes compounds in which W represents COOH, Y represents NH, Z represents O, and X denotes NSO2-C1-C4-alkyl, especially NSO2-CH3.

Another group of compounds according to the invention includes compounds in which W represents COOH, Y represents NH, Z represents S, and X denotes NSO2-C1-C4-alkyl, especially NSO2-CH3.

A particular variant of compounds of formula (I), defined above, are compounds in which each of R1- R6denotes a hydrogen atom.

Another particular variant of compounds of formula (I), defined above, are compounds in which n is 1 or 2.

Another group of compounds according to the invention includes compounds in which A represents aryl or heteroaryl, and specified aryl or heteroaryl may be substituted by one or more substituents independently selected from the group consisting of C1-C4-alkyl, C1-C4-alkoxy, C1-C4-dialkoxy, CN, halogen atom and phenyl.

Within this group, And the site is preferably denotes isoxazolyl, if necessary substituted by one or more substituents, independently selected from C1-C4-alkyl, especially-CH3.

Also preferably, A represents phenyl, with the specified phenyl may be substituted by one or more substituents independently selected from the group consisting of C1-C4-alkyl, C1-C4-alkoxy, C1-C4-dialkoxy, CN, halogen atom and phenyl, preferably CN or-CH3.

The next group of compounds according to the invention includes compounds in which A represents-N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl, especially N(CH3)-CO-cyclohexyl.

The next group of compounds according to the invention includes compounds in which one of R5and R6denotes phenyl, if necessary, replaced by Deputy selected from the group consisting of C1-C4-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl, C3-C7-cycloalkane, C1-C4-dialkoxy, C3-C7-cyclotourism, halogen atom, substituted by halogen, C1-C4-alkyl substituted by halogen, C3-C7-cycloalkyl, -NO2, -CN, -SO2-NH2, -SO2-NH-C1-C4-alkyl, -SO2-N(C1-C4-alkyl)2, -CO-C1-C4-alkyl, -O-CO-C1-C4-alkyl, -CO-O-C1-C4and the Qila, -CO-aryl, -CO-NH2, -CO-NH-C1-C4-alkyl,- CO-N(C1-C4-alkyl)2and the other of R5and R6denotes a hydrogen atom.

Preferably, one of R5and R6denotes phenyl, if necessary, replaced by Deputy selected from CN and C1-C4-alkyl, especially CH3.

As examples of private compounds according to the invention can be named the following:

methyl (2S)-3-{4-[(3,5-dimethylisoxazol-4-yl)metalinox] phenyl}-2-[(4-phenyl-1,3-thiazol-2-yl)amino]propionate,

(2S)-3-{4-[(3,5-dimethylisoxazol-4-yl)metalinox]phenyl}-2-[(4-phenyl-1,3-thiazol-2-yl)amino]propionic acid,

methyl (2S)-3-(4-{2-[(cyclohexylcarbonyl)(methyl)amino] ethoxy}phenyl)-2-[(4-phenyl-1,3-thiazol-2-yl)amino]propionate,

(2S)-3-(4-{2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy} phenyl)-2-[(4-phenyl-1,3-thiazol-2-yl)amino]propionic acid,

Methyl (2S)-3-(4-{2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-[4-(4-cyanophenyl-1,3-thiazol-2-yl)amino]propionate,

(2S)-3-(4-{2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy} phenyl)-2-[4-(4-cyanophenyl-1,3-thiazol-2-yl)amino]propionic acid,

methyl (2S)-3-(4-{2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-[4-(4-were-1,3-thiazol-2-yl)amino]propionate,

(2S)-3-(4-{2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy} phenyl)-2-[4-(4-were-1,3-thiazol-2-yl)amino]propionic acid,

methyl 3-(4-{2-[(cyclohexylcarbonyl the)(methyl)amino]ethoxy} phenyl)-2-[4-(5-phenyl-1,3-oxazol-2-yl)oxy]propionate,

3-(4-{2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-[4-(5-phenyl-1,3-oxazol-2-yl)oxy]propionic acid,

methyl 3-[4-(benzyloxy)phenyl]-2-(5-phenyl-1H-imidazol-2-ylthio) propionate, and

3-[4-(benzyloxy)phenyl]-2-(5-phenyl-1H-imidazol-2-ylthio)propionic acid

and their pharmaceutically acceptable salts.

Compounds according to the invention have a high affinity for activated proliferation peroxisomes gamma receptor (PPARγ). Thus, the compounds exhibit the ability to bind to PPARγ and modulate its activity.

Compounds according to the invention, in which W represents-COO-C1-C4-alkyl, are prodrugs of the compounds according to the invention, in which W represents COOH group.

The invention relates also to pharmaceutical compositions comprising at least one compound of formula (I)as defined above, or its pharmaceutically acceptable salt, in combination with possible other pharmacologically active ingredients with one or more pharmaceutically acceptable carriers and/or excipients.

The invention relates also to the compound of formula (I)as defined above, for use as pharmaceuticals.

The invention also relates to the use of compounds of formula (I)as defined above, or its pharmaceutically acceptable salt for a drug the CSO funds for the treatment and/or prophylaxis of diseases and conditions, mediated activated proliferation peroxisomes gamma receptors (PPARγ).

These PPARγ-mediated diseases and conditions include, in particular, reduced tolerance to insulin, insulin resistance, diabetes type 1 and type 2 complications resulting from or associated with diabetes, such as peripheral neuropathy, renal failure, retinopathy, dyslipidemia, diseases related to syndrome X such as hypertension, obesity, hyperglycemia, atherosclerosis, myocardial ischemia, coronary artery disease of the heart and other cardiovascular diseases, and diseases of the kidney.

Compounds according to the invention can also be used to improve cognitive functions, for example, in the case of dementia.

Detailed description of the invention

Definitions

The term "bioisostere" in the context of the invention refers to a chemical group that replaces another group in the molecule of the active compounds, without exerting a significant impact on its biological activity. Other properties of active compounds such as, for example, its stability as a medicinal product, therefore, can be changed.

As bioisosteric groups to carboxyl (COOH) groups may be especially named 5-membered heterocyclic group containing from 1 to heteroatoms, selected from nitrogen, oxygen and sulfur, such as, for example, 1,3,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazole and N-substituted tetrazolyl. 5-membered heterocyclic group may be substituted by 1 or 2 substituents selected from the group comprising phenyl, pyridinyl, straight or branched alkyl, amino group, hydroxyl group, fluorine, chlorine, bromine, iodine, trifluoromethyl, triptoreline, cryptorchidectomy, alkoxy, dialkoxy.

As bioisostere group for carboxyl (COOH) groups can be also referred to as phenyl and 6-membered heterocyclic group containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, such as, for example, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, tetrazines and others. Phenyl and 6-membered heterocyclic group may be substituted by 1 or 2 substituents selected from the group comprising phenyl, pyridinyl, straight or branched alkyl, amino group, hydroxyl group, fluorine, chlorine, bromine, iodine, trifluoromethyl, triptoreline, cryptorchidectomy, alkoxy, dialkoxy.

The term "halogen" refers to an atom selected from F, Cl, Br and I.

The term "alkyl" refers to saturated, straight or branched pleva orodno group, having the specified number of carbon atoms. As examples of alkyl substituents may be named the following: methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3,3-dimethylbutyl, heptyl, 1-ethylphenyl, octyl, nonyl and decyl.

The term "aryl" refers to mono - or bicyclic aromatic radical having from 6 to 14 carbon atoms. Examples of aryl groups are phenyl, tolyl, xylyl, naphthyl, such as naphthas-1-yl, naphthas-2-yl, 1,2,3,4-tetrahydronaphtyl-5-yl, and 1,2,3,4-tetrahydronaphtyl-6-yl.

The term "heteroaryl" refers to mono - or bicyclic heteroaromatic group having from 5 to 13 carbon atoms and from 1 to 4 heteroatoms selected from N, O and S. Examples of heteroaryl groups are pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, 1,3,5-triazinyl, indolyl, benzo[b]furyl, benzo[b]thienyl, indazoles, benzimidazoles, isoindolyl, cannoli, ethenolysis and carbazolyl.

The term "cycloalkyl" refers to saturated or partially unsaturated cyclic hydrocarbon group having about the 3 to 7 carbon atoms. Examples cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl and cycloheptyl.

The term "heterocyclyl" refers to saturated or partially unsaturated 5 - or 6-membered cyclic hydrocarbon group having from 1 to 4 heteroatoms selected from N, O and S. Preferred saturated or partially unsaturated cyclic hydrocarbon is a monocyclic and contains 4 or 5 carbon atoms and 1 to 3 heteroatoms. Examples heterocyclyl groups are piperidinyl, piperazinil, morpholinyl and pyrrolidinyl.

Compounds according to the invention have a chiral center at the carbon atom bearing the group W, and can exist in the form of the corresponding enantiomers, enantiomeric mixtures and racemic mixtures.

Therefore, the enantiomers R and S enantiomeric mixtures and racemic mixtures of compounds of formula (I) are part of the invention.

Thus, in a particular embodiment, the invention relates to compounds of formula (I)having a stereochemical configuration, such as shown in formula (IA):

in which W, X, Y, Z, A, n and R1-R6have the same meanings as defined above for formula (I),

and their pharmaceutically acceptable salts.

In the second cast the m embodiment, the invention relates to compounds of formula (I), having the stereochemical configuration, such as shown in formula (IB):

in which W, X, Y, Z, A, n and R1-R6have the same meanings as defined above for formula (I),

and their pharmaceutically acceptable salts.

The compounds of formula (I)bearing the main group, can be converted to salts with inorganic or organic acids conventional and known manner by treatment with an appropriate acid in an organic solvent, such as alcohol, ketone, simple ether or a chlorinated solvent, and obtaining salt in the usual way. Examples of such salts are salts with pharmaceutically acceptable inorganic or organic acids. As examples of salts with inorganic acid can be named as the hydrochloride, hydrobromide, nitrate, sulfate, hydrosulfate, persulfate, sulfite, pyrosulfite, phosphate, monohydratefast, dihydrophosphate, metaphosphate and pyrophosphate. As examples of salts with organic acid can be called the acetate, propionate, acrylate, 4-hydroxybutyrate, kaprilat, kapronat, decanoate, oxalate, malonate, succinate, glutarate, adipate, pimelate, maleate, fumarate, citrate, tartrate, lactate, phenylacetate, mandelate, sebacina, suberate, benzoate, phthalate, alkyl - and arylsulfonate, such as methanesulfonate, propanesulfonate, p-toluene is ulpanat, ecological, salicylate, cinnamate, glutamate, aspartate, glucuronate and galacturonic.

The compounds of formula (I)bearing an acid group can be converted to salts with inorganic or organic basis of usual and known manner by reaction of the compound of formula (I) with a suitable organic or inorganic base. Salts with pharmaceutically acceptable bases include salts of alkaline or alkaline earth metal, such as salts of Li, Na, K, Mg or Ca, ammonium salts and salts with basic organic compounds, such as, for example, arginine, histidine, piperidine, tetrahydrooxazolo, piperazine, Ethylenediamine or triethylamine and salts of Quaternary ammonium bases.

The present invention relates also to pharmaceutical compositions comprising a compound of formula (I) with pharmaceutical excipients, depending on the selected route of administration.

One of the embodiments of the invention are pharmaceutical compositions suitable for oral administration. Pharmaceutical compositions suitable for oral administration may be in the form of tablets, capsules, pills, lozenges, powders or granules, or solutions, or dispersions in liquids, etc. Each of these forms includes a predefined number of compounds according to the invention as active and is gradient. Composition in the form of tablets can be obtained using any pharmaceutical excipients known in this regard, in the prior art and is traditionally used for producing solid pharmaceutical compositions. Examples of such excipients include starch, lactose, microcrystalline cellulose, magnesium stearate and binders, such as polyvinylpyrrolidone. In addition, the active compound may be made in the form of controlled drug release, such as tablets, including hydrophilic or hydrophobic matrix.

Pharmaceutical composition in the form of capsules you can make using conventional procedures, for example the inclusion of a mixture of the active compounds and excipients in hard gelatin capsules. Alternatively, a semi-solid matrix of the active compounds and high molecular weight polyethylene glycol can be formed and filled in hard gelatin capsules or soft gelatin capsules can be filled with a solution of active compound in polyethylene glycol or its dispersion in food oil. Powder form for recovery before use (e.g., lyophilized) can also be considered. Alternatively, you can also use oil carriers for formulations for injection.

Liquid form for parenteral administration can be prepared the forms for administration by injection or continuous infusion.

Acceptable routes of administration by injection is intravenous, intraperitoneal, intramuscular and subcutaneous, and intravenous injections are usually preferred. A typical composition for intravenous injection include sterile isotonic aqueous solution or dispersion containing(th), for example, the active connection and dextrose or sodium chloride. Other examples of suitable excipients are lactosidase ringer's solution for injection, lactacidemia ringer's solution for injection with dextrose, Normosol-M and dextrose, acylated ringer's solution for injection. The composition for injection can, if necessary, to include a co-solvent, such as glycol, chelating agent, such as ethylenediaminetetraacetic acid; stabilizer, such as cyclodextrin, and the antioxidant, for example, persulfate sodium.

Enter the dose depends on the patient's condition and the chosen route of administration and appointed by the doctor.

Compounds according to the invention can be obtained using the processes described below and illustrated with Examples.

Compounds according to the invention of formula (I)in which W represents-COOH or-COO-C1-C4-alkyl, and X, Y, Z, A, n and R1-R6have the meanings given above for formula (I)can be obtained:

a) substitution of a hydrogen atom when X is a group (CH2)n- soedinenii formula (II)

in which R represents a C1-C4-alkyl and X, Y, Z, and R1-R6have the meanings given above for formula (I), to obtain the compounds of formula (II)in which R represents a C1-C4alkyl and X, Y, Z, and R1-R6have the meanings given above for formula (I), and then

b) if necessary, by hydrolysis in the alkaline environment of the ester group-COOR to group-COOH with obtaining the compounds of formula (I)in which W represents-COOH.

The specified substitution at the stage a) can be performed by a Mitsunobu reaction of the compounds of formula (II)in which R represents a C1-C4alkyl and X, Y, Z, and R1-R6have the meanings given above for formula (I)with the compound of the formula(CH2)nOH, in which A and n have the meanings given above for formula (I)according to scheme 1:

Scheme 1

The Mitsunobu reaction can be carried out in anhydrous solvents, such as simple ether or halogenated alkane in the presence of diazo compounds, such as DEAD, DIAD, ADDP and triphenylphosphine, usually at a temperature of from -20 to 20°C.

Alternatively, the specified substitution of a hydrogen atom when X can be carried out by alkylation of compounds of formula (II)in which R represents a C1-C4alkyl and X, Y, Z, and R1-R6have the meanings set is installed above for formula (I), with the compound of the formula(CH2)n-V, where A(CH2)n- shall have the meaning given above for formula (I), and V denotes the deleted group selected from halogen and alkylsulfonyl or arylsulfonyl groups, in the presence of a strong base capable of generating an anion of the compound (II), such as sodium hydride, according to the scheme 2:

Scheme 2

The alkylation reaction can be carried out in an inert organic solvent, such as anhydrous DMF, THF, dimethylsulfoxide. A strong base capable of generating an anion, which may be a sodium hydride. Sodium hydride can be used in dry form or in the form of suspension in mineral oil. The generation of the anion is carried out at room temperature until the evolution of hydrogen. Then in the second stage adds an alkylating agent And(CH2)n-V in pure form or in the form of a solution in an inert organic solvent such as DMF, THF, dimethylsulfoxide. The second stage alkylation can be performed at a temperature of from 0 to 100°C.

Hydrolysis of the ester group at the stage b) can be carried out in basic conditions thus, as is known in the prior art. As examples of bases are the alkali metal hydroxides such as hydroxides of sodium,potassium and lithium. To obtain the individual enantiomers of the compounds of formula (I) is preferably carried out by hydrolysis with lithium hydroxide, which allows you to set the configuration.

Hydrolysis in an alkaline environment at the stage b) can be, for example, performed in a system with three solvents consisting of THF (tetrahydrofuran), methanol and water, which allows to obtain a homogeneous reaction mixture. At the end of the hydrolysis reaction mixture may be neutralized with hydrochloric acid, and, if desired, the free acid product may be extracted, for example, ethyl acetate, according to scheme 3 below:

Scheme 3

The compounds of formula (I)in which Y=S and X, W, Z, A, n and R1-R6have the meanings given above, can be obtained by reaction of compounds of formula (IV)in which W, X, A, n and R1-R4have the meanings given above for formula (I)with the compound of the formula (V)in which Z and R5-R6have the meanings given above for formula (I), in the presence of a base in an alcohol solution according to the scheme 4.

Scheme 4

In the case of preparing compounds of formula (I)in which W represents COOH, the original connection in the specified process is a compound of formula (V), where W denotes a secure complex ester group COOH. At the end of the reaction scrappy COOH remove the protection by hydrolysis in an alkaline environment.

The compounds of formula (I) can be obtained in racemic form and in the form of an individual enantiomer, based on optically active materials. Alternatively, racemic compounds of formula (I) can be divided into enantiomers using conventional techniques known in the art.

Starting materials of the formula (II)in which Y=NH, can be obtained from the use or adaptation of the method described in Joachim Rudolph,Facile access to N-Thiazolyl α-Amino Acids from a-bromo ketones and α-Amino Acids, Tetrahedron, 56 (2000) 3161-3165, according to scheme 5, below.

Scheme 5

Source derivatives of ethyl 2-chloro-3-phenylpropionate of formula IV can be obtained by using or adapting the method described in Y.Kawamatsu, H. Asakawa, T. Saraie, E. Imamiya, K. Nishikawa, Y. Hamuro, Arzneim. Forsch. Drug Res., 30 (I), 4, 1980, 585-589. The method is illustrated in scheme 6. According to the scheme 6 complex glorify obtained in the Meerwein reaction, is introduced into reaction with 1,3-thiazole-2-thiol derivative in the presence of a base in an alcohol solution to obtain the corresponding complex of α-(1,3-thiazol-2-ylthio) ethyl ester. This ester hydrolyzing in aqueous-alcoholic NaOH or KOH. Free acids free from salts with dilute hydrochloric acid.

Scheme 6

Thus were obtained the following compounds.

Source derivatives of tyrosine of the formula (II)in which X=O, Y=NH, and Z=O, were obtained according to Shyam B. Advani, Joseph Sam, Journal of Pharmaceutical Sciences, Vol. 57, 10, 1968. For example, according to scheme 7 hydrochloride difficult methyl ester of L-tyrosine was obtained by the esterification of L-tyrosine with methanol in the presence of chloride tonila, followed by reaction of the hydrochloride difficult methyl ester of L-tyrosine with 2-chloro-5-phenyl-1,3-oxazole in benzene in the presence of triethylamine. Similar procedures were used in the case of D-tyrosine and D,L-tyrosine.

Scheme 7

Connection tyrosine of the formula (II)in which X=O, Y=NH, and Z=NH, N-alkyl, N-aryl, N-heteroaryl or S, can be obtained by adaptation of the method Shyam B. Advani, Joseph Sam, Journal of Pharmaceutical Sciences, Vol. 57, 10, 1968, described above.

Derivatives of tyrosine of the formula (II)in which X=O, Y=NH, and Z=S, can be obtained according to the method described in Edward S. Lazer, Clara K. Miao, Hin Wong Chor, Rondla Sorcek, Denice M. Spero, Alex Galman, Kollol Pal, Mark Behnke, Anne G. Graham, Jane M. Watrous, Carol A. Homon, Juergen Nagle, Arvind Shah, Yvan Guindon, Peter R. Farina, Julian Adams, J.Med.Chem., 1994,37,913-923, according to scheme 8.

Scheme 8

Source derivatives of 4-mercaptoethylamine formula (II)in which Y=NH, Z=O and X=S, were obtained according to scheme 9 from 4-mercaptoethylamine, which was obtained according to Helen S.M. Lu, Martin Volk, Yuriy Kholodenko, Edward Gooding, Robin M. Hochstrasser, William F. DeGrado, Journal of the American Chemical Society, 119,31,1997,71737180. Mercapto (SH) group 4-mercaptoethylamine was protected by a group of trityl with subsequent substitution of one hydrogen atom in α-amino-nitrogen atom of the 5-phenyl-1,3-oxazol-2-yl. The final stage of the synthesis is the removal of the protection group SH.

Scheme 9

Derivatives of 4-aminophenylalanine formula (II)in which Y=NH, Z=O and X=NSO2-CH3were obtained according to scheme 10 from the complicated methyl ester 4-nitro-N-caloifornia. The first stage of the synthesis was carried out according to F. Bergel, J.A. Stock, Journal of Organic Chemistry, 1956, 90-96. Thus, the obtained methyl ester 4-amino-N-caloifornia was metilirovanie chloride methylsulfonyl in pyridine in the presence of catalytic amounts of DMAP. The next stage was to remove falorni group by heating with 6 M aqueous HCl solution. Thus, the obtained 4-methanesulfonylaminoethyl was converted into a hydrochloride difficult methyl ester by the esterification in methanol in the presence of thionyl chloride. The next stage was the implementation of the reaction of the hydrochloride difficult methyl ester 4-methanesulfonylaminoethyl with 2-chloro-5-phenyl-1,3-oxazole in the presence of triethylamine in benzene.

Scheme 10

The initial compounds of the formula (V)in which Z=O, i.e. substituted 1-oxazol-2(3 H)-thioketone, can be obtained as described in G. Kjellin, J. Sandstroem Acta.Chem.Scand. 23, 2879, 1969 by reaction of the compound of formula (VI)in which R5and R6have the meanings as in formula (I)according to scheme 11.

Scheme 11

The initial compounds of the formula (VII), i.e. substituted 2-chloro-1,3-oksazolov can be obtained with the use or adaptation of procedures described in Roger Garick Harrison, FR 2313372, the reaction of the compound of formula (V)in which Z=O and R5and R6have the meanings as in formula (I), with phosphorus pentoxide according to scheme 11.

Scheme 11

Complex ethyl ester 3-[4-(Benzyloxy)phenyl]-2-hydroxypropionic acid was obtained according to Makoto Takamura, Hiroaki Yanagisawa, Kanai Motoru, Masakatsu Shibasaki, Efficient Synthesis of Antihyperglycemic (S)-α-Aryloxy-β-phenylpropionic Amides Using a Bifunctional Asymmetric Catalyst,Chem.Pharm.Bull., 50, 8, 2002,1118-1121. Then ester was treated with sodium hydride and then 2-chloro-5-phenyl-1,3-oxazole according to scheme 12.

Scheme 12

The following abbreviations are used:

DIAD: aminobutiramida azodicarboxylate

DEAD: diethyl-azodicarboxylate

ADDP: azodicarbonamide

EXAMPLES

Example 1

(2S)-3-{4-[(3,5-Dimethylisoxazol-4-yl)methoxy]phenyl}-2-[(4-phenyl-1,3-thiazol-2-yl)amino] propionic acid and its methyl ester

R1-R5=N, R =C6H5, W=COOH/COOCH3X=O, Z=S, Y=NH, n=1, A=3.5 dimethylisoxazol-4-yl

Stage A: methyl(2S)-3-(4-hydroxyphenyl)-2-[(4-phenyl-1,3-thiazol-2-yl)amino]propionate

15,40 g (0.1 mol) of chloride Fenella and 8.66 g (0.107 mol) of dry sodium thiocyanate in ethanol (200 ml) was stirred for 3 h at 50°C. the Solution 19,51 g (0.1 mol) of a compound methyl ester (S)-tyrosine in ethanol (100 ml) was added in one portion and the reaction mixture was stirred for 12 hours. After removal of ethanol by distillation was added water and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over sodium sulfate, and the solvent evaporated. The product was purified by chromatography. The output was 20,54 g (58%). MS (ES) 354 (M+, 100%)

Stage B: Methyl(2S)-3-{4-[(3,5-dimethylisoxazol-4-yl)methoxy]phenyl}-2-[(4-phenyl-1,3-thiazol-2-yl)amino]propionate

(3,5-Dimethylisoxazol-4-yl)methanol (0.28 g, 1.5 mmol), methyl(2S)-3-(4-hydroxyphenyl)-2-[(4-phenyl-1,3-thiazol-2-yl)amino]propionate from step A (0.35 g, 1 mmol) and triphenylphosphine (0,79 g, 3 mmol) was dissolved in tetrahydrofuran (THF). After cooling the reaction mixture to 5°C, was added DEAD (0.52 g, 3 mmol). The reaction mixture was stirred at room temperature for 18-24 hours. THF is evaporated to obtain crude methyl(2S)-3-{4-[(3,5-dimethylisoxazol-4-yl)methoxy]phenyl}-2-[(4-phenyl-1,3-thiazol-2-yl)AMI is about]propionate.

Stage C:(2S)-3-{4-[(3,5-Dimethylisoxazol-4-yl)methoxy]phenyl}-2-[(4-phenyl-1,3-thiazol-2-yl)amino]propionic acid

The crude product from step B was dissolved in a mixture of THF/MeOH/H2O (6:0,1:1,2 ml). Was added aqueous 1M LiOH solution (1.6 ml) and the mixture was stirred for 3 days at room temperature. Then neutralize the reaction mixture with 1M HCl was added a small amount of water and the mixture was extracted with ethyl acetate. The solvent is evaporated. The product was purified by chromatography (SiO2, ethyl acetate/hexane), yield was 35%. MS(ES) 463 (M+, 100%)

Example 2

(2S)-3-(4-{2-[(Cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-[(4-phenyl-1,3-thiazol-2-yl)amino]propionic acid and its methyl ester

R1-R5=N, R6=C6H5, W=COOH/COOCH3Y=NH, X=O, Z=S, n=1, A=(cyclohexylcarbonyl)(methyl)amino of the formula:

Stage A: Methyl(2S)-3-{4-[(methylsulphonyl)amino]phenyl}-2-[(4-phenyl-1,3-thiazol-2-yl)amino]propionate

of 29.1 g (0.1 mol)N[4-(2-bromoacetyl)phenyl]methanesulfonamide and 8,66 g (0,107 mol) of dry sodium thiocyanate in ethanol (200 ml) was stirred for 3 h at 50°C. the Solution 19,51 g (0.1 mol) of a compound methyl ester (S)-tyrosine in ethanol (100 ml) was added in one portion and the reaction mixture was stirred for 12 hours. After removal of ethanol by distillation was added water and atilas the tat. The aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over sodium sulfate, and the solvent evaporated. The product was purified by chromatography (SiO2, ethyl acetate/hexane). The output was 20,12 g (45%). MS (ES) 447 (M+, 100%)

Stage B: Methyl(2S)-3-(4-{2-[(cyclohexylcarbonyl) (methyl)amino]ethoxy}phenyl)-2-[(4-phenyl-1,3-thiazol-2-yl)amino]propionate

N(2-hydroxyethyl)-Nmethylcyclohexanecarboxylic (0,19 g, 1.5 mmol), methyl(2S)-3-(4-hydroxyphenyl)-2-[(4-phenyl-1,3-thiazol-2-yl)amino]propionate from step (0.35 g, 1 mmol) and triphenylphosphine (0,79 g, 3 mmol) was dissolved in tetrahydrofuran (THF). After cooling the reaction mixture to 5°C was added ADDP (0,76 g, 3 mmol). The reaction mixture was stirred at room temperature for 18-24 hours. THF is evaporated to obtain crude methyl(2S)-3-(4-{2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-[(4-phenyl-1,3-thiazol-2-yl)amino]propionate.

Stage C:(2S)-3-(4-{2-[(Cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-[(4-phenyl-1,3-thiazol-2-yl)amino]propionic acid

The crude product from step B was dissolved in a mixture of THF/MeOH/H2O (6:0,1:1,2 ml). Was added aqueous 1M LiOH solution (1.6 ml)and the mixture was stirred for 3 days at room temperature. Then neutralize the reaction mixture with 1M HCl was added a small amount of water, and the mixture was extracted with ethylacetoacetate evaporated. The product was purified by chromatography (SiO2, ethyl acetate/hexane). The yield was 42%.

MS (ES) 507 (M+, 100%)

Example 3

(2S)-3-(4-{2-[(Cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-[4-(4-cyanophenyl-1,3-thiazol-2-yl)amino]propionic acid and its methyl ester

R1-R5=N, R6=4-CN-C6H5, W=COOH/COOCH3X=O, Z=S, Y=NH, n=2, A=(cyclohexylcarbonyl)(methyl)amino of the formula:

Stage A: Methyl(2S)-2-{[4-(4-cyanophenyl)-1,3-thiazol-2-yl]amino}-3-(4-hydroxyphenyl)propionate

of 22.3 g (0.1 mol) 4-(bromoacetyl)benzonitrile and 8,66 g (0,107 mol) of dry sodium thiocyanate in ethanol (200 ml) was stirred for 3 h at 50°C. Then 19,51 g (0.1 mol) of a compound methyl ester (S)-tyrosine in ethanol (100 ml) was added in one portion and the reaction mixture was stirred for 12 hours. After removal of ethanol by distillation was added water and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over sodium sulfate, and the solvent evaporated. The product was purified by chromatography (SiO2, ethyl acetate/hexane). The yield was 53%. MS (ES) 379 (M+, 100%)

Stage B: Methyl(2S)-3-(4-{2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-[4-(4-cyanophenyl-1,3-thiazol-2-yl)amino]propionate

N(Hydroxyethyl)-Nmethylcyclohexanecarboxylic (0,19 g, 1.5 mmol), ethyl (2S)-2-{[4-(4-cyanophenyl)-1,3-thiazol-2-yl]amino}-3-(4-hydroxyphenyl)propionate from step A (0.35 g, 1 mmol) and triphenylphosphine (0.79 g, 3 mmol) was dissolved in tetrahydrofuran (THF). After cooling the reaction mixture to 5°C, was added ADDP (0,76 g, 3 mmol). The reaction mixture was stirred at room temperature for 18-24 hours. THF is evaporated to obtain crude methyl(2S)-3-(4-{2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-{[4-(4-cyanophenyl-1,3-thiazol-2-yl)amino]}propionate.

Stage C:(2S)-3-(4-{2-[(Cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-{[4-(4-cyanophenyl-1,3-thiazol-2-yl)amino]}propionic acid

The crude product from step B was dissolved in a mixture of THF/MeOH/H2O (6:0.1:1; 2 ml). Was added aqueous 1M LiOH solution (1.6 ml)and the mixture was stirred for 3 days at room temperature. Then neutralize the reaction mixture with 1M HCl was added a small amount of water, and the mixture was extracted with ethyl acetate. The solvent is evaporated. The product was purified by chromatography (SiO2, ethyl acetate/hexane). The yield was 38%.

MS (ES) 532 (M+, 100%)

Example 4

(2S)-3-(4-{2-[(Cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-[4-(4-were-1,3-thiazol-2-yl)amino]propionic acid and its methyl ester

R1-R5=N, R6=4-CH3-C6H5, W=COOH/COOCH3X=O, Z=S, Y=NH, n=2, A=(cyclohexylcarbonyl)(methyl)amino form is s:

Stage A: Methyl(2S)-2-{[4-(4-were)-1,3-thiazol-2-yl] amino}-3-(4-hydroxyphenyl)propionate

of 21.2 g (0.1 mol) of 2-bromo-1-(4-were)ethanol and 8,66 g (0,107 mol) of dry sodium thiocyanate in ethanol (200 ml) was stirred for 3 h at 50°C. the Solution 19,51 g (0.1 mol) of a compound methyl ester (S)-tyrosine in ethanol (100 ml) was added in one portion and the reaction mixture was stirred for 12 hours. After removal of ethanol by distillation was added water and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over sodium sulfate, and the solvent evaporated. The product was purified by chromatography (SiO2, ethyl acetate/hexane). The output was 17,67 g (48%). MS (ES) 368 (M+, 100%)

Stage B: 2-[(Cyclohexylcarbonyl)(methyl)amino] ethyl 4-toluensulfonate

4-Toluensulfonate (1.9 g, 10 mmol) was added in portions to a solution ofN(Hydroxyethyl)-Nmethylcyclohexanecarboxylic (1.85 g, 10 mmol) in pyridine (30 ml) at room temperature. After stirring at room temperature for 5 h, the reaction mixture was poured into 200 ml of water and was extracted three times with 50 ml dichloromethane. The combined extracts were washed with 1M HCl, aqueous sodium bicarbonate solution and saline. The aqueous phase was dried over anhydrous magnesium sulfate, and the solvent Lipari is Ali, to get the product 2-[(cyclohexylcarbonyl)(methyl)amino]ethyl, 4-toluensulfonate with the release of approximately 87%.

Stage C: Methyl(2S)-3-(4-{2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-[4-(4-were-1,3-thiazol-2-yl)amino]propionate

To a solution 3,68 g methyl(2S)-2-{[4-(4-were)-1,3-thiazol-2-yl]amino}-3-(4-hydroxyphenyl)propionate from the Stage And in dimethylformamide (50 ml) at room temperature in an argon atmosphere was added in portions with stirring NaH (0.4 g, 60%dispersion in mineral oil). After cessation of gas evolution was added dropwise a solution of 2-[(cyclohexylcarbonyl)(methyl)amino] ethyl, 4-toluensulfonate with Stage B (3,39 g, 10 mmol) in dimethylformamide (10 ml). The mixture was heated under stirring at 80°C. After cooling, the mixture was poured into 1 l of water and was extracted several times with ethyl acetate. The combined extracts were washed with saline, dried over magnesium sulfate, and the solvent evaporated to obtain crude methyl(2S)-3-(4-{2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-[4-(4-were-1,3-thiazol-2-yl)amino]propionate.

Stage D:(2S)-3-(4-{2-[(Cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-[4-(4-were-1,3-thiazol-2-yl)amino]propionic acid

1 g of the crude product from step C was dissolved in a mixture of THF/MeOH/H2O (6:0,1:1; 2 ml). Added a 1M aqueous solution of LiOH (8 ml), and the mixture peremeci the Ali for 3 days at room temperature. Then neutralize the reaction mixture with 1M HCl was added a small amount of water, and the mixture was extracted with ethyl acetate. The solvent is evaporated. The product was purified by chromatography (SiO2, ethyl acetate/hexane). The yield was 35%.

MS (ES) 521 (M+, 100%)

Example 5

3-(4-{2-[(Cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-[4-(5-phenyl-1,3-oxazol-2-yl)oxy]propionic acid and its methyl ester

R1-R4and R6=N, R5=C6H5, W=COOH/COOCH3X=O, Z=O, Y=O, n=2, A=(cyclohexylcarbonyl)(methyl) amino of the formula:

Stage A: Methyl 3-(4-{2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-{[4-(5-phenyl-1,3-oxazol-2-yl)oxy]propionate

N(Hydroxyethyl)-Nmethylcyclohexanecarboxylic (0,19 g, 1.5 mmol), methyl 3-(4-hydroxyphenyl)-2-[(5-phenyl-1,3-oxazol-2-yl)oxy]propionate (0.35 g, 1 mmol) and triphenylphosphine (0,79 g, 3 mmol) was dissolved in tetrahydrofuran (THF). Reaktsionnuyu the mixture was cooled to 5°C and was added DEAD (0.52 g, 3 mmol). The reaction mixture was stirred at room temperature for 18-24 hours. THF is evaporated to obtain crude methyl 3-(4-{2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-[4-(5-phenyl-1,3-oxazol-2-yl)oxy]propionate.

Stage B: 3-(4-{2-[(Cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-[4-(5-phenyl-1,3-oxazol-2-yl)oxy]propionic acid

The crude product is CT from step B was dissolved in a mixture of THF/MeOH/H 2O (6:0,1:1; 2 ml). Was added aqueous 1M LiOH solution (1.6 ml) and the mixture was stirred for 3 days at room temperature. Then neutralize the reaction mixture with 1M HCl was added a small amount of water, and the mixture was extracted with ethyl acetate. The solvent is evaporated. The product was purified by chromatography (SiO2; ethyl acetate/hexane). The yield was 41%.

MS (ES) 492 (M+, 100%)

Example 6

3-[4-(Benzyloxy)phenyl]-2-(5-phenyl-1N-imidazol-2-ylthio)propionic acid and its methyl ester

R1-R4and R6=N, R5=C6H5, W=COOH/COOCH3X=O, Z=N, Y=S, n=1, A=phenyl

Stage A: Methyl 3-[4-(benzyloxy)phenyl]-2-(5-phenyl-1Nimidazol-2-ylthio)propionate

A solution of 0.3 g (0.001 mol) of methyl 3-[4-(benzyloxy)phenyl]-2-chloropropionate in methanol (2 ml) was added dropwise to a solution of 0.18 g (0.001 mol) of 5-phenyl-1H-imidazole-2-thiol and 0.04 g (0.001 mol) of NaOH in methanol (3 ml). The solution was heated under reflux for 5 hours the Crude product obtained after removal of solvent, was used without purification in the next stage of the synthesis.

Stage B: 3-[4-(benzyloxy)phenyl]-2-(5-phenyl-1H-imidazol-2-ylthio)propionic acid

The crude product from step A was dissolved in a mixture of MeOH/H2O (2:1,4 ml). To the solution was added 0.7 g of KOH and the mixture was heated under reflux for 2 hours Then the reaction mixture neutralize with HCl 1, added small amounts of water, and the mixture was extracted with ethyl acetate. The solvent is evaporated. The product was purified by chromatography (SiO2; ethyl acetate). The yield was 42%.

MS (ES) 430 (M+, 100%)

Biological tests

The ability of compounds according to the invention to contact the receptor PPAR gamma and modify its activity was determined using the following methods.

Binding in vitro

The ability of compounds to contact the receptor PPAR gammain vitrodetermined according to the procedure described below, using the method of the competitive displacement of the labeled ligand from the complex ligand-receptor. The PPAR agonist3H-rosiglitazone at a final concentration of 10 nm was used as the labeled ligand. Excess of its test compounds at a final concentration of 20 μm was added to the reaction medium. Source receptor in the tests was a human recombinant protein containing the LBD (ligand binding domain) PPAR gamma. Separation of labeled ligand, non-receptor was performed using the methods using activated charcoal coated with dextran. Radioactivity was measured using a scintillation counter LS 6500-Beckman Coulter. Obtained values of the scintillation counts were compared with the values obtained for the samples inkubiruemykh with labeled ligand (presumably the offset 0%), and with the values obtained for samples containing as the labeled ligand, and the excess is not labeled with isotope rosiglitazone (estimated 100%offset). The obtained values fall in the range 0-130%.

Bibliography

1. ADD1/SREBP1 activates PPAR gamma through the production of endogenous ligand. Proc. Natl. Acad. Sci. USA. 1998 Apr 14; 95(8):4333-7.

2. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J. Biol. Chem. 1995 Jun 2;270(22):12953-6.

3. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc. Natl. Acad. Sci. U S A. 1997 Apr. 29; 94(9):4318-23.

Binding in adipocytes

To confirm the ability of test molecules to contact thein vivoconducted similar experiments using the cell line of mouse fibroblasts 3T3-L1 differentiated adipocytes. Differentiation of fibroblasts was performed on tablets with 12 holes during the period of 10 days. On the day of the experiment cells were washed twice with a solution of PBS before incubation for 1 h in DMEM containing tritium-labeled control connection (rosiglitazone) at a concentration of 30 PM and various concentrations of test compounds (in the range of concentrati from 100 PM to 20 μm) at 37°C. Then cells were washed three times with PBS solution and solubilizers in 1M NaOH solution. The lysate obtained as described above was measured both radioactivity (using the m scintillation counter LS 6500 Beckman Coulter) and protein concentration (using the method of Bradford). Nonspecific binding was assessed in the presence of unlabeled control connection (at a concentration of 20 μm).

Obtained values of the scintillation counts were compared with the values obtained for the samples inkubiruemykh with labeled ligand (estimated offset 0%), and with values obtained for samples containing as the labeled ligand, and the excess is not labeled with isotope rosiglitazone (estimated 100%offset). The obtained values fall in the range 0-130%.

Bibliography

1. Identification of high-affinity binding sites for the insulin sensitizer rosiglitazone (BRL-49653) in rodent and human adipocytes using a radioiodinated ligand for peroxisomal proliferator-activated receptor gamma. J. Pharmacol. Exp. Ther. 1998 Feb;284(2):751-9.

2. Differential regulation of the stearoyl-CoA desaturase genes by thiazolidinediones in 3T3-L1 adipocytes. J. Lipid Res. 2000 Aug;.41(8):1310-6.

3. Distinct stages in adipogenesis revealed by retinoid inhibition of differentiation after induction of PPARgamma. Mol Cell Biol. 1996 Apr;16(4):1567-75.

4. The Differentiation Kinetics ofin vitro3T3-L1 Preadipocyte Cultures. Tissue Eng. 2002 Dec;8(6):1071-1081.

5. Role of PPARgamma in regulating a cascade expression of cyclin-dependent kinase inhibitors, p18(INK4c) and p21(Waf1/Cip1), during adipogenesis. J. Biol. Chem. 1999 Jun 11;274(24):17088-97.

Adipokines

Cell line 3T3-L1 (ATCC) contained in the modified according Dulbecco environment, Needle, supplemented with 10%Fetal Bovine serum and antibiotics. Two days before the experiment the cells were passively on microplate with 12 holes (30×104cells/well) and maintained within posleduiuscih days before fusion. After that, the medium was replaced with DMEM+FBS+antibiotics and the cells were added to the test compound at a final concentration of 50 μm. Under these conditions, the cells were kept for 14 days, replacing the medium with test compounds every 2 days. After 10-14 days, the differentiated cells were stained with Oil Red O before photographing.

Bibliography

1. Differential regulation of the stearoyl-CoA desaturase genes by thiazolidinediones in 3T3-L1 adipocytes. J. Lipid Res. 2000 Aug;41(8):1310-6.

The seizure of glucose

Differentiated fibroblasts 3T3-L1 cells were then incubated in DMEM, supplemented with 10%FBS and antibiotics with test compounds (concentration 20 μm) for 48 hours. After that, cells were washed in PBS and then the cells were added to serum-free DMEM. Cells were kept in an incubator for 3 h (37°C/5% CO2), and then the medium was replaced with buffer KHR (25 mm HEPES-NaOH; pH 7.4; 125 mm NaCl; 5 mm KCl; 1.2 mm MgSO4; 1.3 mm CaCl2; 1.3 mm KH2PO4), and cells were incubated for 30 minutes at 37°C. the Seizure of glucose was initiated by adding to each test well 50 μl KRH buffer containing 0.5 mm 2-deoxy-D-[1,2-3H]glucose (0.5 to MCs) and 100 nm insulin. After 10 minutes incubation at 37°C the medium was aspirated and cells were washed three times with ice-cold KRH buffer. Then the cells were dissolved in 1M NaOH. The lysate obtained as described above was measured both radioactivity (using scintillation the CSOs counter LS 6500 Beckman Coulter) and protein concentration (using the method of Bradford). Nonspecific binding was assessed in the presence of its control connection (at a concentration of 20 μm).

Bibliography

1. Role of peroxisome proliferator-activated receptor-gamma in maintenance of the characteristics of mature 3T3-L1 adipocytes. Diabetes. 2002 Jul; 51(7):2045-55.

2. Identification of high-affinity binding sites for the insulin sensitizer rosiglitazone (BRL-49653) in rodent and human adipocytes using a radioiodinated ligand for peroxisomal proliferator-activated receptor gamma. J. Pharmacol. Exp. Ther. 1998 Feb; 284(2):751-9.

3. Identification of bioactive molecules by adipogenesis profiling of organic compounds. J. Biol. Chem. 2003 Feb 28;278(9):7320-4. Epub 2002 Dec 19.

4. Evidence for the involvement of vicinal sulfhydryl groups in insulin-activated hexose transport by 3T3-L1 adipocytes. J. Biol. Chem. 1985 Mar 10;260(5):2646-52.

1. Derivatives of 3-phenylpropionic acid of the formula (I):

in which:
W denotes a group COOH or-COO-C1-C4-alkyl;
Y represents NH;
Z represents S or O;
X denotes O;
R1-R6each independently represents a hydrogen atom or a Deputy selected from the group consisting of:
With1-C4-alkyl, tanila and phenyl, where phenyl optionally substituted by one or more substituents independently selected from the group consisting of C1-C4-alkyl, C1-C4-alkoxy, halogen atom; -NO2and-CN;
And represents C1-C4-alkyl, -N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl, aryl selected from the group consisting of phenyl and naphthyl, or heteroaryl, vybrannyi group, consisting of oxazolyl, isoxazolyl, teinila, pyridyl, thiazolyl, thiadiazolyl, benzo[b]teenie, imidazolyl, indolyl and carbazolyl, where aryl and heteroaryl substituted or unsubstituted by one or more substituents independently selected from the group consisting of C1-C4-alkyl, C1-C4-alkoxy, phenyl and halogen atom; and
n denotes an integer from 0 to 4, inclusive;
and their pharmaceutically acceptable salts.

2. The compound according to claim 1, in which W represents COOH.

3. The connection of claim 1, wherein W represents-COO-C1-C4-alkyl.

4. The compound according to claim 1, in which Y represents NH.

5. The compound according to claim 1, in which Z represents O.

6. The compound according to claim 1, in which Z represents S.

7. The compound according to claim 1, in which W represents COOH, and Z represents S.

8. The compound according to any one of claims 1 to 7, in which each of R1-R6denotes a hydrogen atom.

9. The compound according to any one of claims 1 to 7, in which n is 1 or 2.

10. The compound according to any one of claims 1 to 7, where And denotes isoxazolyl, optionally substituted by one or more substituents, independently selected from C1-C4-alkyl, especially-CH3.

11. The compound according to any one of claims 1 to 7, where And denotes phenyl.

12. The compound according to any one of claims 1 to 7, where And denotes-N(C1-C4-alkyl)-CO-C 3-C7-cycloalkyl.

13. The connection section 12, where And denotes the-N(CH3)-CO-cyclohexyl.

14. The compound according to any one of claims 1 to 7, having the stereochemical configuration as shown in formula (IA):

and its pharmaceutically acceptable salts.

15. The compound according to any one of claims 1 to 7, having the stereochemical configuration as shown in formula (IB):

and its pharmaceutically acceptable salts.

16. The compound according to claim 1, with the specified connection is selected from the following compounds: methyl (2S)-3-{4-[(3,5-dimethylisoxazol-4-yl)metalinox]phenyl}-2-[(4-phenyl-1,3-thiazol-2-yl)amino]propionate;
(2S)-3-{4-[(3,5-dimethylisoxazol-4-yl)metalinox]phenyl}-2-[(4-phenyl-1,3-thiazol-2-yl)amino]propionic acid;
methyl (2S)-3-(4-{2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-[(4-phenyl-1,3-thiazol-2-yl)amino]propionate;
(2S)-3-(4-{2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-[(4-phenyl-1,3-thiazol-2-yl)amino]propionic acid;
methyl (2S)-3-(4-{2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-[4-(4-cyanophenyl-1,3-thiazol-2-yl)amino]propionate;
(2S)-3-(4-{2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-[4-(4-cyanophenyl-1,3-thiazol-2-yl)amino]propionic acid;
methyl (2S)-3-(4-{2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy}phenyl)-2-[4-(4-were-1,3-thiazol-2-yl)amino]propionate;
(2S)-3-(4-{2-[(qi is logicalchannel)(methyl)amino]ethoxy}phenyl)-2-[4-(4-were-1,3-thiazol-2-yl)amino]propionic acid
and their pharmaceutically acceptable salts.

17. Pharmaceutical composition having the properties of PPARγ ligand, comprising as an active ingredient the compound according to any one of claims 1 to 16 or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier and/or excipients.

18. The compound according to any one of claims 1 to 16 for use in preparation of medicines for the treatment and/or prophylaxis of diseases and conditions mediated by activated proliferate peroxisomes gamma receptor (PPARγ).

19. The use of compounds according to any one of claims 1 to 16, to obtain drugs for the treatment and/or prophylaxis of diseases and conditions mediated by activated proliferate peroxisomes gamma receptor (PPARγ).

20. The application of claim 19, in which the disease or condition selected from the group consisting of type 2 diabetes, insulin resistance, metabolic syndrome, complications resulting from or associated with diabetes, cardiovascular disorders, atherosclerosis, obesity, cognitive disorders, and disorders of lipid metabolism.

21. The method of treatment and/or prophylaxis of diseases and conditions mediated by activated proliferation peroxisomes gamma receptor (PPARγ), a mammal, comprising an introduction to the specified mammal, the compound is of any one of claims 1 to 16, in therapeutically or prophylactically effective amount.

22. The method according to item 21, in which the disease or condition selected from the group consisting of type 2 diabetes, insulin resistance, metabolic syndrome, complications resulting from or associated with diabetes, cardiovascular disorders, atherosclerosis, obesity, cognitive disorders, and disorders of lipid metabolism.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invented compounds have inhibitory activity towards protein kinase. In formula 1a m lies between 0 and 1, R1 is chosen from a group which includes hydrogen, methyl, isopropyl, imidazolylpropyl, piperazinylpropyl, pyridinyl, diethylaminopropyl, hydroxyethyl, pyrimidinyl, morpholinopropyl, phenyl, cyclopropyl, morpholinoethyl, benzyl and morpholino, where any of pyridinyl, imidazolyl, piperazinyl or pyrimidinyl in R1 are optionally substituted with 1-3 radicals, independently chosen from a group, which includes methyl, methylamine, dimethylaminomethyl, cycloproylamine, hydroxyethylamine, diethylaminopropylamine, pyrrolydinylmethyl, morpholino, morpholinomethyl, piperazinylmethyl and piperazinyl, where any of morpholino and piperazinyl in R1 are optionally further substituted with a radical, chosen from a group which includes methyl, hydroxyethyl and ethyl, R2, R3 and R5 each represents hydrogen, R4 represents methyl, L is chosen from a group which includes -NR5C(O)- and -C(O)NR5-, R10 represents trifluoromethyl, and R11 is chosen from a group which includes halogen, morpholinomethyl, piperazinyl, optionally substituted with a methyl, ethyl or hydroxyethyl group; piperazinylmethyl, optionally substituted with a methyl or ethyl group, imidazolyl, optionally substituted with methyl, pyrrolidinylmethoxy and piperidinyl, optionally substituted with a hydroxy group.

EFFECT: more effective treatment.

4 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: in formula (1) compound, cysteinprotease is cathepsin K, cathepsin S, cathepsin L or cathepsin B. In formula (I) R is , AA1 is a bond, AA2 is a bond, R7 and R8 each independently represents hydrogen, C1-8 alkyl, CycA or C1-8 alkyl, substituted CycA, R9 is hydrogen, values of the rest of the radicals are given in the formula of invention. The invention also relates to a pharmaceutical composition, containing a formula (I) compound as an active ingredient, to a cysteinprotease inhibitor, method of inhibiting cysteinprotease, use of formula (I) compound in obtaining cysteinprotease inhibitor.

EFFECT: compound has inhibitory activity towards cysteinprotease.

10 cl, 16 tbl, 8 dwg, 224 ex

FIELD: chemistry.

SUBSTANCE: described are derivatives of 1,3,4-oxadiazol-2-on of formula (I) , where ARYL represents phenyl; Z represents -O(CH2)n- and n represents independent integer number from 1 to 5; X represents S; R1 represents C1-6alkyl; R2 represents phenyl, substituted with C1-6perfluoralkyl; or its pharmaceutically acceptable salt; based on it pharmaceutical composition; and method of disease treatment, where disease can be modulated by activity of PPAR-delta binding.

EFFECT: obtaining compounds which possess agonistic or antagonistic activity.

7 cl, 5 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

SUBSTANCE: invented compounds have antagonist properties towards CB1 receptors. In formula (I) , R1 is a lower alkoxy, (lower alkyl amino)-(lower alkoxy) or -N(Ra)Rb; Ra is hydrogen, lower alkyl, carbamoyl-(lower alkyl), hydroxy-(lower alkyl), dihydroxy-(lower alkyl), lower alkynyl, lower alkoxy, (lower alkoxy)-(lower alkyl), di-(lower alkylamino)-(lower alkyl), C3-6cycloalkyl; or Ra is a phenyl-(lower alkyl) group, where the phenyl fragment can be optionally mono-substituted, independently, by lower alkyl, lower alkoxy or halogen; or Ra is a 5- or 6-member heteroaromatic ring system, containing one or two nitrogen atoms in the ring, where the said heteroaromatic ring system is bonded to the remaining part of the molecule by lower alkylene; or Ra is a 5-, 6- or 7-member saturated heterocyclic ring system, containing one nitrogen heteroatom, where the said heterocyclic ring system is optionally mono-substituted by lower alkyl; Rb is hydrogen, lower alkyl or (lower alkoxy)-(lower alkyl); or Ra and Rb together with a nitrogen atom to which they are bonded, for a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring system, optionally containing an extra heteroatom, which is chosen from nitrogen, oxygen or sulphur, where the said heterocyclic ring system is optionally mono- or disubstituted, independently, by lower alkyl, hydroxy group, hydroxy-(lower alkyl), lower alkoxy, (lower alkoxy)-(lower alkyl) group, cyano group, halogen, phenyl and/or benzyl; R2 is hydrogen or lower alkyl; R3 is phenyl, mono- or disubstituted, independently, by lower alkoxy, halogen, or perfluoro-(low alkoxy) group; and R4 is phenyl, which is mono- or disubstituted with a halogen.

EFFECT: new compounds have useful biological properties.

18 cl, 195 ex

FIELD: chemistry, medicine.

SUBSTANCE: in the general formula (I): X is oxygen atom; R1 is C1-10-alkyl , substituted if necessary by phenyl or thienyl group; or R1 is C3-7-cycloalkyl, thienyl, pyridinyl; the thienyl groups can be substituted if necessary by 1-2 C1-3-alkyl groups; phenyl can be substituted if necessary by 1-2 halogen atoms; R2 is C1-6-alkyl; or R2 is C3-7-cycloalkyl, phenyl or pyridinyl; phenyl if necessary can be substituted by one or more halogen atoms or by the CN, C1-3-alkyl, C1-3-alkoxyl, C1-3-fluoroalkyl groups; R3 is C1-6-alkyl; R4 is hydrogen atom or C1-6-alkyl; R5 and R5' are independently of each other the hydrogen atom, hydroxyl; or R5 and R5' form together the oxo-group; n is integer value in the range from 0 to 3; R6 is independently of each other hydrogen atom, halogen atom, C1-3-alkyl, C1-3-alkoxyl.

EFFECT: compounds of present invention can find application as pharmaceutical for pathology treatment where the inhibitor of β-amiloyd peptide β-A4 is useful.

8 cl, 1 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention is related to compounds of formula (II) as inhibitor of leukotriene A4-hydrolase (LTA4H) and their enantiomers, racemic compounds and pharmaceutically acceptable salts, and also to treatment methods, method inhibition and pharmaceutical composition on their basis. In general formula (II) , X is selected from group that consists of O and S; Y is selected from group that consists of CH2 and O; R4 represents H; R6 represents H or F; and R2' is determined as R2, and R3' is determined as R3, as follows: R2 and R3, each, is independently selected from group that consists of A) H, C1-7alkyl, C3-7cycloalkyl, where each of substitutes of A) is independently substituted with 0 or 1 RQ, and each of mentioned RQ is substitute at carbon, which is distanced from nitrogen at least by one carbon atom; alternatively, R2 and R3, taken together with nitrogen, to which they are connected, create heterocyclic ring, which contains at least one heteroatom, which is specified nitrogen of connection, and specified heterocyclic ring is selected from group that consists of i) (4-7)-member heterocyclic ring HetRb, where specified (4-7)-member heterocyclic ring HetRb has single heteroatom, which is specified nitrogen of connection, and 0, 1 or 2 are substituted by substitutes at the same or different substituted atoms, at that specified substitutes are selected from group that consists of -RY, -C(O)RY, -C0-4alkylCO2RY, -C0-4alkylC(O)NRYRZ, -C0-4alkylNRYC(O)Rz, -C0-4alkylNRYC(O)CH2ORY, -C0-4alkylNRYCO2RY, -C0-4alkylNRYC(O)NRYRz, -C0-4alkylNRyC(S)NRyRz, -NRyC(O)CO2Ry, -C0-4alkylNRwSO2RY, tetrazol-5-yl, -C0-4alkylN(RY)(SO2)NRYRY, -C0-4alkylN(RY)(SO2)NRYCO2RY, ii) (5-7)-member heterocyclic ring HetRc, where specified (5-7)-member heterocyclic ring has single additional heteroatom distanced from specified nitrogen of connection at least by one carbon atom, thereat the specified additional heteroatom is selected from group that consists of O, S(=O)0-2 and >NRM, and where mentioned (5-7)-member heterocyclic ring HetRc has 0 or 1 carbonyl group; iv) one of 2,8-diazaspyro[4.5]decan-1-on-8-yl, 4-{[(2-tret- butoxycarbonylaminocyclobutancarbonyl)amino]methyl}-piperidine-1-yl, 4-{[(2-aminocyclobutancarbonyl)amino]methyl}piperidine-1-yl, tret-butyl ether of 3,9-diazaspyro [5.5]undecan-3-carbonic acid-9-yl; where RK is selected from group that consists of H, -C1-4alkyl, each not necessarily substituted by 1 substitute RN; RM is selected from group that consists of -SO2RY, -C(O)RY, -C(O)C1-4alkylORY, each not necessarily substituted by 1 substitute RN; RN is selected from group that consists of OH, NH2, CF3; RQ is selected from group that consists of -C0-4alkylRAr', -C0-4alkylCO2RY, -C0-4alkylNRYRz, -C0-4alkylNRYCORY, -C0-4alkylNRyCONRyRz; Rw is selected from group that consists of RY and -C3-7cycloalkyl; RY is selected from group that consists of H, -C1-4alkyl, -C0-4alkylRAr and -C0-4alkylRAr', each not necessarily substituted by 1 substitute RN; Rz is selected from group that consists of RY, -C1-2alkylCO2RY; RAr represents fragment connected via carbon atom, and specified fragment is selected from phenyl, pyridyl; RAr' represents (5-6)-member cyclic ring, having 1 or 2 heteroatoms selected from group that consists of O, N and >NRY, having 0 unsaturated connections, having 0 or 1 carbonyl group, where each atom, when allows for valency, in every of mentioned cyclic rings is independently substituted by 0 or 1 RK; provided that (a) specified R2' and R3', moreover, satisfy the following requirements: (e1): specified R2' and R3', both, are not H, when Y represents O and X represents S; (e3): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperazine group, when X represents O and Y is one of O and CH2; (e4): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperidine group, which is mono-substituted by 6-member cyclic group, when X represents O and Y is one of O and CH2; and (e5): specified R2' and R3', taken together with nitrogen, with which they are connected, create neither substituted piperidine group or substituted piperazine group, where specified substituted piperidine group or specified substituted piperazine group is substituted in position 4 by substitute XG, at that specified XG has structure , where n=0, 1, and when ne=1, then XL represents C1-6alkyl, OSG represents O or S, and XR1 and XR2, taken together with nitrogen, with which they are connected, create one of piperidine group, piperazine group, morpholine group, thiomorpholine group and pyrrolidine group, or each of XR1 and XR2, taken independently, represent one of H, C1-6alkyl, aryl, aralkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, heteroalkyl, heteroaryl-C1-6alkyl, heterocycloalkyl and heterocycloalkyl-C1-6alkyl; where aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be not necessarily substituted by one or several substitutes, independently selected from halogen, hydroxy, C1-6alkyl, C1-6alkoxy, halogenated C1-6alkyl, halogenated C1-6alkoxy, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, heteroaryl or heterocycloalkyl; and (b) further provided that when X represents S and Y represents O, then one of R2' and R3' is not XCG, while the other represents C1-6alkyl, where XCG represents group , where HC16 represents one of H, C1-6alkyl, halogenC1-6alkyl, allyl and C1-6alcoxymethyl, and GO represents group connected to carbon atom, which has substitute =0, creating amido group with nitrogen, with which all mentioned GO group is connected.

EFFECT: compounds may find application for treatment and prevention of diseases mediated by LTA4H, for instance, asthma, chronic obstructive lung disease, atherosclerosis, rheumatoid arthritis, disseminated sclerosis, inflammatory disease of bowels and psoriasis.

39 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I) where R1 stands for hydrogen or linear, branched, saturated or unsaturated hydrocarbon radical; D stands for nitrogen atom or C-R2; E stands for nitrogen atom or C-R3; F stands for nitrogen atom or C-R4; G stands for nitrogen atom or C-R5; R2, R3, R4 and R5 are identical or different and individually represent hydrogen, halogen, alkoxy, linear or branched, saturated or unsaturated hydrocarbon radical; W stands for oxygen atom; X stands for radical of formula radical -(CH2)k-C(O)-(CH2)m-, -(CH2)n- or -(CH2)r-O-(CH2)s-, where k, m, r and s are equal to integers 0 to 6, and n is equal to an integer 1 to 6. Said radicals are optionally substituted with one or more substitutes independently chosen from the group consisting of R7; Y stands for radical of formula radical -(CH2)i-NH-C(O)-(CH2)j-, -(CH2)n-, -(CH2)r-O-(CH2)s-, -(CH2)t-NH-(CH2)u-, where i, j, n, r, s, t and u are equal to integers 0 to 6. Said radicals are optionally substituted C1-3alkyl, or C1-3alkyl-C1-3alkylsulphonylamino; radicals R7, B, R8, A, R9 are as it is presented in the patent claim. The invention also describes the pharmaceutical composition possessing inhibitory activity of receptor tyrosine kinase to KDR receptor including described compounds.

EFFECT: compounds possess inhibitory activity of receptor tyrosine kinase to KDR receptor and can be effective in therapy of the diseases associated uncontrolled angiogenesis.

29 cl, 746 ex, 6 tbl

FIELD: pharmacology.

SUBSTANCE: claimed invention relates to novel 2,4-pyridindiamine compounds of formula (1). In structural formula (I) L1 is direct bond; L2 is direct bond; R2 is phenyl group, three times substituted with three groups R8; R4 is X represents N; Y is selected from group consisting of O, NH, S, SO and SO2; Z is selected from group consisting of O, NH; on condition that if Y is selected from group consisting of NH, S, SO and SO2, Z is not the same as Y; R5 is selected from group consisting from R6, halogen; each R6 is independently selected from group consisting of hydrogen, halogen; R8 is selected from group consisting from Ra, Rb, Ra substituted with one or several similar or different groups Ra or Rb, -ORa, -O-CHRaRb; each R35 independently on others is selected from group consisting of hydrogen and R35, or in alternative case, two groups R35, bound to one and the same carbon atom are taken together with formation of oxogroup (=O), and the remaining two groups R35 each independently on each other are selected from group consisting from hydrogen and R8; each Ra is independently selected from group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl; each Rb is suitable group which is independently selected from group consisting of -ORd, halogen, -CF3, -C(O)NRcRc, and -OC(O)ORd; each Rc is independently protective group or Ra; each Rd is independently protective group or Ra; each index m is independently integer number from 1 to 3.

EFFECT: novel compounds can be used for treatment or prevention of autoimmune diseases, for instance such as rheumatoid arthritis and/or related to it symptoms, systemic lupus erythematosus and/or related to it symptoms, as well as and/or related to it symptoms.

41 cl, 14 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of formula (I) and its pharmaceutically acceptable salts and esters. Compounds of the present invention are characterised with properties of DGAT-1 inhibitor. In general formula (I) , Q represents O, S or NR5; A represents a linker chosen from where p is equal to 1 or 2, and , where m is equal to 0, and n is equal to 1, 2, 3 or 4, or m is equal to 1, while n is equal to 1, 2 or 3, where specified linker is optionally substituted with one or two groups R8; R1 and R2 are independently chosen from hydrogen, haloid; R3 is chosen from hydrogen, (C1-C6)alkyl optionally substituted with hydroxyl and phenyl optionally substituted with haloid; R4 is chosen from hydrogen, nitro and (C1-C6)alkyl; or R3 and R4 together with carbon atoms whereto attached, can form benzene ring optionally substituted with 1-2 substitutes. The invention also concerns compounds of formula (Ia) and (Ib) with structural formulas presented in the patent claim, and also to a pharmaceutical composition, a medical product, to application of compounds for making a medical product and compound process.

EFFECT: new compounds possess useful biological activity.

19 cl, 2 tbl, 7 dwg, 215 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts and esters wherein R1 means phenyl, naphthyl, 5-6-membered heterocyclyl comprising oxygen (O), nitrogen (N) or sulfur atom (S) as heteroatoms and wherein phenyl, naphthyl and heterocyclyl are optionally substituted with 1-3 substitutes chosen from halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy, nitro; di-(C1-C6)-alkylamino or (C1-C6)-alkoxy groups; R2 means hydrogen atom; R3 means (C1-C6)-alkyl or trifluoromethyl; A1 means C-R3 or nitrogen atom; A2 means piperidine or pyrrolidine wherein nitrogen atom in piperidine or pyrrolidine ring is added to A3 wherein A3 means -S(O)2- or -C(O)-; n = 0, 1 or 2. Also, invention relates to a pharmaceutical composition based on compounds proposed by the invention. Proposed compounds possess properties of NPY receptors antagonists and can be used in treatment arthritis, diabetes mellitus, nutrition disorders, obesity and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 1 tbl, 1 dwg, 26 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel cyclic compounds of the formula (I) and (II) or tier pharmaceutically acceptable salts wherein radical values given in formula (I) and (II) are indicated in the invention description. Also, invention relates to a pharmaceutical composition containing at least one compound of the formula (I), and to using these compounds for preparing a drug. Invention provides synthesis of novel compounds and preparing a compositions containing hereof that possess inhibitory activity with respect to protein-tyrosine kinase.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

24 cl, 3 tbl, 582 ex

FIELD: organic chemistry, biochemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to novel diaminothiazoles of the formula (I) , their pharmaceutically acceptable salts and esters, and to a pharmaceutical composition based on thereof. Proposed compounds inhibit activity of cyclin-dependent kinase 4 (Cdk4), shows selectivity with respect to Cdk2 and Cdk1 and can be used in treatment against cancer, in particular, against solid tumors. In the general formula (I) R2 and R3 represent hydrogen atom; R4 is chosen from group comprising lower alkyl, (C3-C6)-cycloalkyl, O-lower alkyl, halogen atom, -NO2, S-lower alkyl, -CF3 and -CN; R5 is chosen from group comprising hydrogen atom, O-lower alkyl, lower alkyl, halogen atom and -OH, or, alternatively, R4 and R in common with two carbon atoms and a bond binding them belonging to benzene cycle (C) to which R4 and R5 are bound can form a cycle consisting of 5-6 atoms comprising one or two heteroatoms chosen from oxygen atom and optionally substituted with (C1-C4)-alkyl; R6 and R are chosen independently from group comprising hydrogen atom, lower alkyl and -COOR12, or, alternatively, group -NR6R7 can mean cycle consisting of 5-6 atoms optionally comprising heteroatom chosen from nitrogen or oxygen atoms; R8 and R9 are chosen independently from group comprising hydrogen atom and lower alkyl; R10 is chosen from group comprising hydrogen atom, lower alkyl, lower alkyl substituted with hydroxyl, and -COOR12; R11 is chosen from group comprising hydrogen atom, lower alkyl and -COOR12 wherein R12 means lower alkyl; m can mean 1 or 2; n can mean 0, 1 or 2 under condition that if m means 2 and R4 means fluorine atom then R5 is not hydrogen atom, and under condition if m means 1 and R4 means lower alkyl then R5 is not hydroxyl.

EFFECT: valuable biochemical and medicinal properties of compounds and pharmaceutical compositions.

20 cl, 6 sch, 3 tbl, 153 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to new derivatives of 2-arylimino-2,3-dihydrothiazoles of the general formula (I): wherein radical values R1, R2, R3 and R4 are given in the claim invention. New compounds are useful in treatment of pathological states or diseases wherein one or some somatostatin receptors are implicated, for example, acromegaly, hypophysis adenomas or gastroenteropancreatic endocrine tumors with carcinoid syndrome and gastroenteric bleedings.

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

14 cl, 2825 ex

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

The invention relates to new and nitrate salts of heterocyclic compounds of formulas (a) and (b), where R is hydrogen, alkoxyl, R1- alkyl, alkoxyl, R2is hydrogen, alkyl, R3- alkyl, alkoxyl, X denotes N-R11or oxygen, R11means the free valence, Y represents N-R16, sulfur or alkyl, R16means hydrogen; other values radicals presented in the description of the invention

The invention relates to branched amino-thiazole, methods for their preparation and the pharmaceutical compositions

The invention relates to a new derivative of 2-(3H)-oxazolone formula I, where R1is an alkyl group or a group-NR4R5where each R4and R5independently are hydrogen, alkyl or benzyl group, R2is naftilos, unsubstituted phenyl or a phenyl group substituted by 1 to 3 halogen atoms, alkyl groups, hydroxy, alkoxy or triptorelin group, R3is hydrogen or alkyl group
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