Heterocyclic compounds and pharmaceutical compositions as cathepsin s transportation inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

,

where R1 is selected from formulae

, and ,

n equals 0; R6 and R7 are independently selected from hydrogen, C1-C6alkyl, cyanoC1-C6alkyl, C3-C6cycloalkylC0-C4alkyl and C6arylC0-C4alkyl; or R6 and R7 together with a carbon atom to which they are bonded form a 6-member heterocycloalkyl with one nitrogen atom; wherein any alkyl in R6 and R7 can optionally contain a methylene group substituted with an O atom; wherein any aryl in R6 and R7 or formed by a combination of R6 and R7 can be optionally substituted with one radical independently selected from: halide, C1-C6alkyl, -XC(O)OR10; where X denotes a bond; R10 is independently selected from C1-C6alkyl; R8 is selected from C5-C9heteroarylC0-C4alkyl containing 2-3 heteroatoms independently selected from N, O and S; wherein any heteroaryl in R8 can be optionally substituted with one radical independently selected from: halide, C1-C6alkyl, C3-C6cycloalkyl; R2 denotes hydrogen; R3 and R4 are independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkylC0-C4alkyl and C6arylC0-C4alkyl; wherein any alkyl in R3 and R4 can optionally contain a methylene group substituted with a S(O)2 group; R5 is selected from C5-C6heterocycloalkyl with 1-2 heteroatoms selected from N and O, and NR12R13; where R12 and R13 are independently selected from C1-C6alkyl; as well as pharmaceutically acceptable salts and isomers thereof. The invention also relates to use of compounds of formula (I) in preparing a medicinal agent, and to a pharmaceutical composition having cathepsin S inhibiting properties, which contains a therapeutically effective amount of the compound of formula (I) in combination with a pharmaceutically acceptable filler.

EFFECT: obtaining compounds which can be used as cathepsin S inhibitors.

10 cl, 12 dwg, 2 tbl, 9 ex

 

This application claims priority to patent application U.S. 60/566990 of April 30, 2004, which in full and all of the stated purposes included in the present invention by reference.

A PREREQUISITE for CREATING INVENTIONS

The scope of the invention

The invention describes compounds, pharmaceutical compositions comprising these compounds, and methods of using these compounds for treating or preventing diseases or disorders mediated by the activity of cathepsin S.

Prerequisite

Cysteine proteases represent enzymatic class of proteins that catalyze the hydrolysis of peptide bonds at the expense of the nucleophilic sulfhydryl group of the cysteine residue in the active site of the enzyme.

Cathepsins are a subclass of cysteine proteases that play a major role in lysosomal, endosomal and extracellular protein degradation and, thus, involved in many disease processes. It was shown that cathepsin S [EU 3.4.22.27] need for proper presentation of antigens on MHC class II. As a result of its prominent role in the presentation of antigens on MHC class II cathepsin S associated with certain normal and painful processes in mammals. These diseases or disorders include, but are not limited to, osteoporosis, osteoarthritis, muscular dystrophy, waspa the group the tumor invasion, glomerulonephritis, malaria, periodontal disease, the metachromatic leukodystrophy, periodontal disease, Paget's disease, atherosclerosis, multiple sclerosis, rheumatoid arthritis, juvenile initial diabetes, lupus, asthma, tissue rejection, Alzheimer's disease, Parkinson's disease, neuronal degeneration, shock, cancer, neuropathic pain, chronic obstructive pulmonary disease, inflammatory bowel disease, allergies, Chagas disease, leishmaniasis, schistosomiasis, and African sleeping sickness (trypanosomiasis).

The new compounds of the invention inhibit the activity of cathepsin S, and therefore it is assumed that they will be applicable in the treatment of diseases mediated by cathepsin S.

A BRIEF DESCRIPTION of the INVENTION

In one part of the invention provides compounds of formula I

in which

R1choose from formulas (a) (b) or (C)

where n means an integer of 0, 1 and 2;

R6and R7independently selected from hydrogen, C1-C6of alkyl, tsianos0-C6of alkyl, C3-C12cycloalkyl0-C4the alkyl and C6-C10arils0-C4of alkyl; or R6and R7together with at the IOM carbon to which R6and R7attached, form a3-C8heteroseksualci or3-C12cycloalkyl;

however, any alkyl, R6and R7can optionally have a methylene group is replaced by an atom or group selected from O or S(O)0-2; any aryl, heteroseksualci or cycloalkyl R6and R7or formed by the combination of R6and R7may be optionally substituted by 1-3 radicals independently selected from the group: halogen, hydroxy, nitro, cyano, C1-C6alkyl, C1-C6alkoxy, galijasevic C1-C6alkyl, galijasevic C1-C6alkoxy, -XC(O)OR10, -XS(O)0-2R10, -XNRS(O)0-2R10and-XS(O)0-2NR10R10; X is a bond or C1-C4alkylene; and R10independently selected from hydrogen and C1-C6of alkyl;

R8selected from hydrogen, C6-C10arils0-C4of alkyl, C5-C10heteroaryl0-C4of alkyl, -C(O)OR10and-C(0)NR10R11; R10selected from hydrogen and C1-C6of alkyl; and R11selected from hydrogen, C1-C6the alkyl and -[CR12R13]m- R14; m is chosen from 0, 1, and 2; R12and R13independently selected from hydrogen and C1-C6alkyl is; and R14choose from C6-C10aryl, C5-C10heteroaryl,3-C12cycloalkyl and C3-C8geterotsiklicheskie;

however, any aryl, heteroaryl, cycloalkyl or heteroseksualci R8and R14may be optionally substituted by 1-3 radicals independently selected from the group: halogen, hydroxy, nitro, cyano, C1-C6alkyl, C1-C6alkoxy, galijasevic C1-C6alkyl, galijasevic C1-C6alkoxy, C6-C10aryl, C5-C10heteroaryl,3-C12cycloalkyl and C3-C8heteroseksualci; and

R9selected from C1-C6of alkyl, C6-C10arils0-C4the alkyl and C3-C12cycloalkyl0-C4of alkyl;

R2selected from hydrogen and C1-C6of alkyl;

R3and R4independently selected from hydrogen, C1-C6of alkyl, C3-C12cycloalkyl0-C4of alkyl; and (C6-C10arils0-C4of alkyl, where any alkyl, R3and R4can optionally have a methylene group is replaced by an atom or group selected from O and S(O)0-2while any aryl or cycloalkyl R3and R4may optionally be substituted by 1-3 radicals independently selected from the group: halogen, Hydra is XI, nitro, cyano, C1-C6alkyl, C1-C6alkoxy, galijasevic C1-C6alkyl and galijasevic C1-C6alkoxy;

R5choose from C3-C8geterotsiklicheskie and NR12R13where R12and R13independently selected from hydrogen and C1-C6of alkyl; however, any heteroseksualci R5may optionally be substituted by 1-3 radicals independently selected from the group: halogen, hydroxy, nitro, cyano, C1-C6alkyl, C1-C6alkoxy, galijasevic1-C6alkyl and galijasevic1-C6alkoxy, XC(O)OR10, -XS(O)0-2R10, -XNR10S(O)0-2R10and-XS(O)0-2NR10R10; X is a bond or C1-C4alkylene; and R10independently selected from hydrogen and C1-C6of alkyl;

and their N-oxide derivatives, proletarienne derivatives, protected derivatives, individual isomers and mixtures of isomers; and pharmaceutically acceptable salt and solvate (e.g., hydrates) of such compounds.

The second aspect of the present invention provides a pharmaceutical composition which contains a compound of the formula I or an N-oxide derivative, individual isomers and mixtures of isomers and pharmaceutically acceptable salt in a mixture with one or bol is e filler.

The third aspect of the present invention provides a method of treating disease in an animal in which inhibition of the activity of cathepsin S can prevent, inhibit or weaken the pathology and/or symptomatology of the disease; this method includes the introduction of the animal a therapeutically effective amount of the compounds of formula I or a N-oxide derivative, individual isomers and mixtures of isomers and pharmaceutically acceptable salts.

A fourth aspect of the present invention provides the use of compounds of formula I in the preparation of drugs for treating disease in an animal in which the activity of cathepsin S contributes to the pathology and/or symptomatology of the disease.

In the fifth aspect of the present invention the compounds of formula I selectively inhibit cathepsin's about cathepsins K, L, or combinations thereof.

The sixth aspect of the present invention provides a method of producing compounds of the formula I and their N-oxide derivatives, proletarienne derivatives, protected derivatives, individual isomers and mixtures of isomers and their pharmaceutically acceptable salts.

A DETAILED DESCRIPTION of the INVENTION

Definition.

"Alkyl" means a group or a structural element of other groups, for example, Alojamientos of alkyl or alkoxy groups, and may or premazepam Il is branched. C1-C6alkoxy includes methoxy, ethoxy groups and so on. Galijasevic alkyl includes trifluoromethyl, pentafluoroethyl and so on.

"Aryl" means a monocyclic or articulated bicyclic aromatic ring ensemble comprising six to ten carbon atoms in the ring. Aryl may mean, for example, phenyl or naphthyl, preferably phenyl. "Allen" means the divalent radical produced from aryl groups. "Heteroaryl" means the same as defined for aryl, and one or two atoms in the ring are heteroatoms. Heteroaryl includes, for example, pyridyl, indolyl, indazoles, honokalani, chinoline, benzofuranyl, benzopyranyl, benzothiophene, benzo[1,3]dioxol, imidazolyl, benzimidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl and so on. "C6-C10arils0-C4alkyl" means aryl, as defined above, attached via alkylenes grouping. With6-C10arils0-C4alkyl includes, for example, phenethyl, benzyl, and so forth. "Cycloalkyl" means a saturated or partially unsaturated monocyclic, articulated bicyclic, bridged polycyclic ring group or a spiral ring ensemble (where two rings are connected through a common atom, the example, Spiro[5.5]undecane, and the like)containing a specified number of atoms in the ring. For example, With3-C10cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

"Heteroseksualci" means cycloalkyl, as defined above, in which one or more of these ring atoms are replaced by groups selected from-O-, -N=, -NR-, -C(O)-, -S-, -S(O)- or-S(O)2-, where R is hydrogen, C1-C4alkyl or a nitrogen protective group. For example, the term3-C8heteroseksualci used to describe the compounds of the present invention includes a group of morpholino, pyrrolidinyl, piperazinil, piperidinyl, piperidinyl, 1,4-dioxa-8 azaspiro[4.5]Dec-8-yl, etc.

"Halogen (or halo) is preferably represented by chlorine or fluorine, but it can also mean bromine or iodine.

The terms "treat", "treatment" refer to methods of reducing or mitigating the disease and/or its accompanying symptoms.

DESCRIPTION of the PREFERRED PARTS of the INVENTION

The present invention provides compounds, compositions and methods of treating diseases in which inhibition of the activity of cathepsin S can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease; the method includes the introduction of the animal a therapeutically effective amount of the compounds of formula I.

On the part of the invention is the compounds of formula Ia

in which R1chosen from compounds of formulas (a), (b) or (C)

in which n stands for an integer 0, 1 or 2;

R6selected from hydrogen, C1-C6of alkyl, tsianos0-C6of alkyl, C3-C12cycloalkyl0-C4the alkyl and C6-C10arils0-C4of alkyl;

however, any alkyl of R6can optionally have a methylene group is replaced by an atom or group selected from O and S(O)0-2; any aryl or cycloalkyl of R6may be optionally substituted by 1-3 radicals independently selected from the group: halogen, hydroxy, nitro, cyano, C1-C6alkyl, C1-C6alkoxy, galijasevic C1-C6alkyl and galijasevic C1-C6alkoxy, -XC(O)OR10, -XS(O)0-2R10, -XNRS(O)0-2R10and-XS(O)0-2NR10R10; X is a bond or C1-C4alkylene; and R10independently selected from hydrogen and C1-C6of alkyl;

R8selected from hydrogen, C6-C10arils0-C4of alkyl, C5-C10heteroaryl0-C4of alkyl, -C(O)OR10and-C(O)NR10R11; R10selected from hydrogen and C1-C6 of alkyl; and R11selected from hydrogen, C1-C6the alkyl and -[CR12R13]m-R14; m is chosen from 0, 1, and 2; R12and R13independently selected from hydrogen and C1-C6of alkyl; and R14choose from C6-C10aryl, C5-C10heteroaryl,3-C12cycloalkyl and C3-C8geterotsiklicheskie;

however, any aryl, heteroaryl, cycloalkyl or heteroseksualci R8and R14may be optionally substituted by 1-3 radicals independently selected from the group: halogen, hydroxy, nitro, cyano, C1-C6alkyl, C1-C6alkoxy, galijasevic C1-C6alkyl, galijasevic C1-C6alkoxy, C6-C10aryl, C5-C10heteroaryl,3-C12cycloalkyl and C3-C8heteroseksualci; and

R9selected from C1-C6of alkyl, C6-C10arils0-C4the alkyl and C3-C12cycloalkyl0-C4of alkyl;

R3selected from hydrogen, C1-C6of alkyl, C3-C12cycloalkyl0-C4the alkyl and C6-C10arils0-C4of alkyl; any alkyl of R3may not necessarily have a methylene replaced by an atom or group selected from O and S(O)0-2; any aryl or cycloalkyl and the R 3may be optionally substituted by 1-3 radicals independently selected from the group: halogen, hydroxy, nitro, cyano, C1-C6alkyl, C1-C6alkoxy, galijasevic C1-C6alkyl and galijasevic C1-C6alkoxy;

R5choose from C3-C8geterotsiklicheskie and NR12R13while R12and R13independently selected from hydrogen and C1-C6of alkyl; however, any heteroseksualci of R5may be optionally substituted by 1-3 radicals independently selected from the group: halogen, hydroxy, nitro, cyano, C1-C6alkyl, C1-C6alkoxy, galijasevic C1-C6alkyl and galijasevic1-C6alkoxy, -XC(O)OR10, -XS(O)0-2R10, -XNR10S(O)0-2R10and-XS(O)0-2NR10R10; X is a bond or C1-C4alkylene; and R10independently selected from hydrogen and C1-C6the alkyl.

In another part of the invention R2and R4both signify hydrogen; R6selected from hydrogen, C1-C6of alkyl, tsianos0-C6of alkyl, C3-C12cycloalkyl0-C4the alkyl and C6-C10arils0-C4of alkyl; any alkyl of R6can optionally have a methylene group is replaced by an atom Il the group, selected from O and S(O)0-2; any aryl or cycloalkyl of R6may be optionally substituted by 1-3 radicals independently selected from halides;

R7means hydrogen;

R8means5-C10heteroaryl, optionally substituted by 1-3 radicals independently selected from the group: halogen, C1-C6alkyl, galijasevic C1-C6alkyl, C6-C10aryl, C5-C10heteroaryl,3-C12cycloalkyl and C3-C8heteroseksualci; and

R9means C1-C6alkyl;

R3selected from C1-C6of alkyl, C3-C12cycloalkyl0-C4the alkyl and C6-C10arils0-C4of alkyl; any alkyl of R3can optionally have a methylene group is replaced by an atom or group selected from O and S(O)0-2;

R5choose from C3-C8geterotsiklicheskie and NR12R13while R12and R13independently selected from hydrogen and C1-C6the alkyl.

In the next part of this invention R6choose from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyanomethyl, 2-chlorobenzonitrile, benzoyloxymethyl, benzyloxyethyl, Venetia and benzyl.

In another part of the invention R8means benzoxazol-2-yl, benzodiaz the l-2-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]oxadiazol-5-yl and oxazol[5,4-b]pyridine-2-yl; however, any heteroaryl of R8optionally substituted by 1-3 radicals independently selected from halogen, ethyl, phenyl, cyclopropyl and trifloromethyl.

In another part of the invention R3choose from cyclohexylmethyl, cyclopentylmethyl, benzylmethylamine, cyclohexylethyl, phenyl, isobutyl, tert-butylmethyl, cyclohexyl, benzyl and Venetia; and R5selected from the group: morpholino, dimethylamino, piperidinyl and pyrrolidinyl.

Preferred compounds of formula I are detailed in the examples and in table I and are selected from 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of 2-(benzoxazol-2-yl)-(1S)-cyclopropyl-2-oxoethylidene acid, 2-phenylmethanesulfonyl-(1R)-(morpholine-4-carbonyl)ethyl ester of 2-(benzoxazol-2-yl)-(1S)-methyl-2-oxoethylidene acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(5-ethyl[1,2,4]oxadiazol-3-carbonyl)propellerbuying acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(5-phenyl[1,2,4]oxadiazol-3-carbonyl)propellerbuying acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester 4-oxitetraciclina-(3S)-ylcarbamate acid, (S)-1-tert-butoxycarbonyl-4-cyano-4-(1-cyclohexylmethyl-2-morpholine-4-yl-2-exoelectrogenic)piperidine, (S)-4-cyano-4-(1-cyclohexa the methyl-2-morpholine-4-yl-2-exoelectrogenic)-1-methylpiperidine, (1S)-cyclohexylmethyl-2-morpholine-4-yl-2-xoetrope ether 2-(2-chlorobenzoyloxy)-(1R)-cyanoethylidene acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of 2-(benzoxazol-2-yl)-(1S)-methyl-2-oxoethylidene acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(benzoxazol-2-carbonyl)propellerbuying acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(benzoxazol-2-carbonyl)BUTYLCARBAMATE acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of 2-(5-perbenzoate-2-yl)-(1S)-methyl-2-oxoethylidene acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of 2-(6-perbenzoate-2-yl)-(1S)-methyl-2-oxoethylidene acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(benzoxazol-2-carbonyl)-2-methylpropionamidine acid, 2-cyclopentyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(benzoxazol-2-carbonyl)propellerbuying acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(benzothiazole-2-carbonyl)propellerbuying acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(benzothiazole-2-carbonyl)ethylcarbamate acid, 2-phenylmethanesulfonyl-(1R)-(morpholine-4-carbonyl)ethyl ester of (1S)-(benzoxazol-2-carbonyl)propellerbuying acid, 3-cyclohexyl-(1S)-(morpholine-4-carbonyl)propyl ester (1S)-(benzoxazol-2-carbonyl) - Christ.tickerbar.info acid, 3-cyclohexyl-(1S)-(morpholine-4-carbonyl)propyl ester (1S)-(benzoxazol-2-carbonyl)propellerbuying acid, (1S)-(morpholine-4-carbonyl)-1-phenylmethylene ether (1S)-(benzoxazol-2-carbonyl)propellerbuying acid, 3,3-dimethyl-(1S)-(morpholine-4-carbonyl)butyl ether (1S)-(benzoxazol-2-carbonyl)propellerbuying acid, (1S)-cyclohexyl-1-(morpholine-4-carbonyl)methyl ester (1S)-(benzoxazol-2-carbonyl)propellerbuying acid, (1S)-cyclohexylmethyl-2-oxo-2-(piperidine-1-yl)ethyl ester (1S)-(benzoxazol-2-carbonyl)ethylcarbamate acid, (1S)-cyclohexylmethyl-2-oxo-2-(pyrrolidin-1-yl)ethyl ester of 2-(benzoxazol-2-yl)-(1S)-cyclopropyl-2-oxoethylidene acid, (1S)-cyclohexylmethyl-2-oxo-2-(pyrrolidin-1-yl)ethyl ester (1S)-(benzoxazol-2-carbonyl)propellerbuying acid, (1S)-cyclohexylmethyl-2-oxo-2-(pyrrolidin-1-yl)ethyl ester (1S)-(benzoxazol-2-carbonyl)BUTYLCARBAMATE acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester 4-oxitetraciclina-(3R)-ylcarbamate acid, (1S-cyclohexylmethyl-2-(morpholine-4-yl)-2-xoetrope ether (1S)-cyano-2-methylpropiophenone acid, (1S)-cyclohexylmethyl-2-(morpholine-4-yl)-2-xoetrope ether (1S)-cyanopropionic acid, (1S)-cyclohexylmethyl-2-(morpholine-4-yl)-2-xoetrope ether 2-benzyloxy-(1R)-cyanoethylidene acid, (1S)-cyclohe Silmaril-2-(morpholine-4-yl)-2-xoetrope ester 3-benzyloxy-(1S)-cyanopropionic acid, (1S)-cyclohexylmethyl-2-(morpholine-4-yl)-2-xoetrope ether (1S)-cyano-3-phenylpropionylamino acid, (1S)-cyclohexylmethyl-2-(morpholine-4-yl)-2-xoetrope ether (1S)-2-dicyanomethylene acid, (1S)-cyclohexylmethyl-2-(morpholine-4-yl)-2-xoetrope ether (1S)-cyano-2-phenylethylamines acid, (1S)-cyclohexylmethyl-2-(morpholine-4-yl)-2-xoetrope ether cyanomethylene acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(6-perbenzoate-2-carbonyl)propellerbuying acid, 2-cyclopentyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(6-perbenzoate-2-carbonyl)propellerbuying acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester (1S)-(oxazolo[5,4-b]pyridine-2-carbonyl)propellerbuying acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-cyclopropyl-2-(6-perbenzoate-2-yl)-2-oxoethylidene acid, (1S)-cyclohexyl-1-(morpholine-4-carbonyl)methyl ester (1S)-(6-perbenzoate-2-carbonyl)ethylcarbamate acid, (1S)-cyclohexyl-1-(morpholine-4-carbonyl)methyl ester (1S)-(6-perbenzoate-2-carbonyl)propellerbuying acid, 2-cyclohexyl-(1S)-dimethylcarbamodithioato ether (1S)-(benzoxazol-2-carbonyl)propellerbuying acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(6-perbenzoate-2-carbonyl)BUTYLCARBAMATE acid, 2-cyclog the KSIL-(1S)-(morpholine-4-carbonyl)ethyl ester (1S)-(5-cyclopropyl[1,2,4]oxadiazol-3-carbonyl)propellerbuying acid, (1S)-cyclohexyl-1-(morpholine-4-carbonyl)methyl ester (1S)-(benzoxazol-2-carbonyl)BUTYLCARBAMATE acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(6-methylbenzothiazol-2-carbonyl)propellerbuying acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(5-chlorobenzoxazol-2-carbonyl)propellerbuying acid, (1S)-(morpholine-4-carbonyl)-2-phenethyl ester (1S)-(benzoxazol-2-carbonyl)propellerbuying acid, (1S)-(morpholine-4-carbonyl)-3-phenethyl ester (1S)-(benzoxazol-2-carbonyl)propellerbuying acid, (1S)-cyclohexylmethyl-2-oxo-2-(pyrrolidin-1-yl)ethyl ester (1S)-(7-perbenzoate-2-carbonyl)propellerbuying acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(5-trifluoromethyl[1,2,4]oxadiazol-3-carbonyl)propellerbuying acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(7-perbenzoate-2-carbonyl)propellerbuying acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(5-perbenzoate-2-carbonyl)BUTYLCARBAMATE acid; (1S)-cyclohexylmethyl-2-oxo-2-(pyrrolidin-1-yl)ethyl ester (1S)-(6-perbenzoate-2-carbonyl)propellerbuying acid; 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(3-cyclopropyl[1,2,4]oxadiazol-5-carbonyl)propellerbuying acid; 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester (1R-(5-cyclopropyl[1,2,4]oxadiazol-3-carbonyl)propellerbuying acid; 3-methyl-1-(morpholine-4-carbonyl)butyl ether (S,S)-[1-(benzoxazol-2-carbonyl)propyl]carbamino acid; 3-methyl-1-(morpholine-4-carbonyl)butyl ether (S,S)-(2-benzoxazol-2-yl-1-methyl-2-oxoethyl)carbamino acid; 3,3-dimethyl-1-(pyrrolidin-1-carbonyl)butyl ether (S,S)-[1-(5-cyclopropyl[1,2,4]oxadiazol-3-carbonyl)propyl]carbamino acid; 3,3-dimethyl-1-(morpholine-4-carbonyl)butyl ether (S,S)-[1-(5-cyclopropyl[1,2,4]oxadiazol-3-carbonyl)propellerbuying acid.

Pharmacology and usefulness

Compounds of the invention inhibit the activity of cathepsin S, and is therefore useful for treating diseases or disorders in which cathepsin S contributes to the pathology and/or symptomatology of the disease. The invention further provides compounds of this invention for use in medicine for the treatment of diseases or disorders in which cathepsin S contributes to the pathology and/or symptomatology of the disease. Mediated by cathepsin S disease or condition include, but are not limited to: muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, periodontal disease, neuropathic pain, chronic obstructive pneumonia, inflammatory bowel disease, allergies, the metachromatic leukodystrophy, osteoporosis, osteoarthritis (Inui T., O. Ishibshi, J. Biol. Chem., 1997, 272, No. 13, cc.8109-8112; Saftig P., E. Hunziker, and others, Adv. Exp. Med. Biol., 2000 + ADs 2000, 477, cc.293-303; Saftig P., E. Hunziker, and others, Proc. Natl. Acad. Sci. USA, 1998, 95, No. 23, s-1358), periodontal disease, Paget's disease, atherosclerosis (Jormsjo S., D..Wuttge, and others, Am. J. Pathol., 2002, 161, No. 3, cc.939-945), multiple sclerosis (Beck H., G. Schwarz, and others, Eur. J. Immunol., 2001, 31, No. 12, SS-3736), rheumatoid arthritis (Nakagawa M.S., W.H.Brissette, and others, Immunity, 1999, 10, No. 2, cc.207-217; W.S. Hou, Z.Li, and others, Am. J. Pathol., 2001, 159, No. 6, s-2177), Junior primary diabetes, lupus, asthma (Cimerman N., ..Brguljan, and others, Pflugers Arch., 2001, 442, No. 6, Suppl. 1, SS-206), tissue rejection, Alzheimer's disease (Lemere S.A., J.S.Munger, and others, Am. J. Pathol., 1995, 146, No. 4, SS-860), Parkinson's disease (Liu Y., L. Fallon, and others, Cell, 2002, 111, No. 2, SS-18), neuronal degeneration, shock (Jaeschke H., .A.Fisher, etc., J. Immunol., 1998, 160, No. 7, s-3486), cancer (P.L. Fernandez, X.Farre, etc., Int. J. Cancer, 2001, 95, No. 1, SS-55), malaria (Malhotra R., .V.Dasaradhi, and others, Mol. Environ., 2002, 45, No. 5, cc.1245-1254), Chagas disease (Eakin, A.E., A.A.Mills, etc., J. Biol. Chem., 1992, 267, No. 11, SS-20), leishmaniasis, schistosomiasis, and African sleeping sickness (trypanosomiasis) (Caffrey .R., S.Scory, and others, Curr. Drug Targets, 2000, 1, No. 2, SS-162; G. Lalmanach, A.Boulange, and others, Biol. Chem., 2002, 383, No. 5, SS-749).

As mentioned above, the present invention provides a method of preventing or treating any of the diseases or disorders described above in a patient in need of such treatment; this method includes the introduction of the indicated patient a therapeutically effective the number (see following the Introduction section and pharmaceutical compositions") the compounds of formula I or its pharmaceutically acceptable salt. For any application specified above, the required dose varies depending on the method of administration, the individual condition of the patient and the desired effect.

Introduction and pharmaceutical compositions

In General, the compounds of the invention are introduced in therapeutically effective quantities of any of the usual and acceptable methods known in this field, or by themselves or in combination with one or more therapeutic agents. therapeutically effective amount can vary widely depending on the severity of the disease, the age and General health of the patient, of the capabilities of the connection and other factors. In General satisfactory results are obtained systematically in daily doses of about 0.03 to 10.0 mg/kg of body weight. Shows daily dose for large mammals, e.g. humans, is in the range from about 0.5 mg to about 100 mg, administered in the usual way, for example in fractional doses up to four times per day, or in the form of an extended action. Suitable single dose forms for oral administration contain from about 1 to 50 mg of the active component.

Connection offer izobreteny may be introduced in the form of pharmaceutical compositions in any suitable way, in particular enterline, for example, orally, for example in the form of tablets or capsules, or parenteral, for example, in the form of solutions or suspensions for injection, topicaine, for example, in the form of lotions, gels, ointments or creams, or in the nose, or in the form of a suppository. Pharmaceutical compositions containing a compound of the invention in free form or in the form of pharmaceutically acceptable salts, in Association with at least one pharmaceutically acceptable carrier or diluent can be obtained suitable means of mixing, granulating or coating. Oral compositions, for example, can be tablets or gelatin capsules containing the active ingredient together with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g. silica, talc, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also C) binders, for example, manuallyselected, starch paste, gelatin, Astragalus, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if you want to e) dezinfeciruyuhimi substances such as starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, Otus the AMI and softeners. Compositions for injection may be aqueous isotonic solutions or suspensions, and suppositories can be obtained from fatty emulsions or suspensions. Composie can be sterilized and/or contain auxiliary substances, such as preserving, stabilizing, moisture or emulsifying agents, activators solution, salts for regulating osmotic pressure and/or buffers. In addition, they can also contain other therapeutically suitable substances. Suitable compositions for transdermal application include an effective amount of the compounds of the present invention with the carrier. The media may include absorbable pharmacologically acceptable solvents that promote penetration through the skin of the host. For example, a device for percutaneous introduction exists in the form of a bandage containing a detail of the support, a reservoir containing the compound optionally with a carrier, not necessarily the device that controls the speed of the connection to the skin of the host with a controlled and predetermined rate over a prolonged period of time, and means of securing the device to the skin. Matrix form percutaneous injection can also be used. Suitable forms for topical application, for example, on the skin and eyes, preferably are water RA the works, ointments, creams or gels, are well known in the art. They may contain soljubilizatory, stabilizers, agents that enhance the tone, buffers and preservatives.

Compounds of the invention can be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combination). For example, synergistic effects can be achieved with other substances used in the treatment of osteoporosis, osteoarthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromatic leukodystrophy, periodontal disease, Paget's disease, atherosclerosis, multiple sclerosis, rheumatoid arthritis, juvenile initial diabetes, lupus, asthma, tissue rejection, Alzheimer's disease, Parkinson's disease, neurodegeneration, shock, cancer, malaria, neuropathic pain, chronic obstructive pneumonia, inflammatory bowel disease, allergies, Chagas disease, leishmaniasis, shistosomiasis, and/or African trypanosomiasis (sleeping sickness). In cases where compounds of the invention are administered together with other therapies, dose together input connections, of course, can vary depending on the type together PR is changing drugs the specificity of the drugs, from the conditions of use and so on.

The invention also provides a pharmaceutical combination, e.g. a kit containing a first agent which is a compound of the invention as here disclosed, in free form or in the form of pharmaceutically acceptable salts, and b) at least one co-agent. The kit may contain instructions for its introduction.

The terms "introduction" or "co-administration" or the like, as used here, means the introduction of selected therapeutic agents to the individual patient and use treatment regimens in which the agents are administered not necessarily one and the same way of introducing or not necessarily at the same time.

The term "pharmaceutical combination", as used here, means a product obtained from a mixture or combination of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound of formula I and a co-agent, are administered to a patient simultaneously in the form of a single dose. The term "non-fixed combination" means that the active ingredients, e.g. a compound of formula I and a co-agent, are administered to a patient as separate agents or simultaneously, or the settlement of adavale without a specific time limit, while this introduction provides therapeutically effective levels of both compounds in the body of the patient. The latter also offers a "cocktail"therapy, such as the introduction of 3 or more active ingredients.

Methods for obtaining compounds of the invention

The present invention also includes methods of making compounds of the invention. In the described reactions may be necessary to protect reactive functional groups, for example, hydroxy-, amino-, imino-, thio - or carboxyl groups desired in the final product, to avoid their unwanted participation in the reactions. This can be used a conventional protective group, a standard in the practice of the synthesis, see, for example, T.W.Greene and P.G.M.Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991.

The following diagrams illustrate some of the ways to obtain the compounds of the present invention. Professionals should be clear that these methods are merely representative and in any case do not cover all methods of producing compounds of the present invention. Radicals in the schemes described in formula I.

Scheme 1

Scheme 1 illustrates the synthesis of compounds of the present invention, in which R1means-CR7R6C(=O)R8, a R2, R4and R7osakeyhtio. W.Kelly and others, Org. Lett., 2004, 6, s, give an overview of different methods of synthesis of α-hydroxyacids. α-Gidrokshikislotu 1A enter into reaction with the amine R5H in normal conditions of formation of amide (e.g., DIC/HOBt, HATU, Rumor etc., DIC - ?, HOBt is 1-hydroxybenzotriazole, HATU - hexaphosphate o-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium, PyBOP - hexaphosphate benzotriazol-1-yl-extraparliamentary)to give compound 1b. Reviews reactions combination amides described in Chamberlin and others, Chem. Rev., 1997, 97, s and M.Bodanszky and others, The practice of peptide synthesis, 2nd ed., Springer-Verlag 1994. Compound 1b is treated with p-nitrophenylphosphate in the environment Foundation, receiving mixed carbonate 1C. The reaction of 1C with NH2CHR6CH(OH)R8leads to carbamate 1E, which oxidizes to 1f in the standard oxidation conditions. Preferred methods for the oxidation of secondary alcohols to the corresponding ketones include, but are not limited to, peridinin dessa-Martin (D..Dess etc., J. Am. Chem. Soc., 1991, 113, s and J. Org. Chem., 1983, 48, c.4155), oxidation by Svernu and its modifications (D.Swern etc., J. Org. Chem., 1978, 43, s; ..Tidwell, Org. React., 1990, 39, c.297; M. Hudlicky, Oxidations in Organic Chemistry; ACS: Washington, DC, 1990), PCC (E.J.Corey and others, Tetrahedron Lett, 1975, c.2647; G. Piancatelli, Synthesis, 1982, c.245), PDC (E.J.Corey and others, Tetrahedron Lett., 1979, s) and catalyzed TRAR (perruthenate Tetra-n-Propylamine) oxidation (S.V.Ley etc., Synthesis, 1994, s).

Scheme 2

P the torching of the vicinal amerosport NH 2CHR6CH(OH)R8in which R8means optionally substituted 0-3 X benzoxazol, where X means the substituents in the R8as specified in claim 1, are given by way of example in scheme 2. N-substituted amino acid restores using or NR3or the restoration of its mixed anhydride with isobutylparaben action NaBH4[see R..Larock, A guide to functional group preparations, cc.548-552, Wiley-VCH, 1989] to obtain a compound 2b (Scheme 2). The resulting alcohol 2b can then be oxidized to the aldehyde 2C. Preferred methods for the oxidation of alcohols to the corresponding aldehydes include, but are not limited to, peridinin dessa-Martin (D..Dess etc., J. Am. Chem. Soc., 1991, 113, s and J. Org. Chem., 1983, 48, c.4155), oxidation by Svernu and its modifications (D.Swern etc., J. Org. Chem., 1978, 43, s; ..Tidwell, Org. React, 1990, 39, c.297; M.Hudlicky, Oxidations in Organic Chemistry; ACS: Washington, DC, 1990), AMRO/trichloroisocyanurate acid (TEMPO - 2,2,6,6-tetramethyl-1-piperidinyloxy) (L. De Luca and others, Org. Lett, 2001, 3, s), TRAR catalyzed oxidation (S.V.Ley etc., Synthesis, 1994, s). The addition of the Grignard reagent derived from benzoxazole, connection 2 connects the 2-d, which after removal of protection gives amerosport 2-E.

The preferred method of obtaining substituted benzoxazoles used in the present invention and which are not commercial products, is cyclocondensation about-is aminophenol with triethylorthoformate. See the links A.R.Katritzky and others, Heterocycles, 1995, 41, s; J.H.Musser etc., J. Med. Chem., 1985, 28, c.1255; and K.R.Kunz and others, OPPI, 1990, 22, s.

Scheme 3

Alternatively, amerosport 2-d can be obtained by consecutive reactions described in scheme 3 (see ..McGrath and others, Biochemistry, 2003, 42, s). Aminoaldehyde 2-turn in cyanidin 3-a (..Heathcock and others, Org. Synth. Coll., v.7, s), which is then treated with anhydrous ethanol and acetyl chloride, receiving the broadcast imidate 3-b. The condensation of 3-b with o-aminophenol leads to aminopyrido 2-d.

Scheme 4

Getting the vicinal amerosporttBOCNHCHR6CH(OH)R8where R8means 1,2,4-oxadiazol, optionally substituted 0-1 X, where X means the substituents at R8as defined in claim 1, shown in figure 4. Hydroxylamine is added to cyanhydrin 3-but in the main environment, getting hydroxyamide 4-a, which acelerou using SOON (or equivalent acylchlorides or anhydride)to give 4-b, 4-b is heated in a microwave oven, where he cyclized in oxidiazol 4-c.

Scheme 5

Illustration of the synthesis of compounds of the present invention, in which R1means-CHR6CN, and R2and R4both signify hydrogen, is given in scheme 5. α-Aminoamide 5-and add to mixed carbonate 1-c. The product 5-b dehydrate the comfort of the cyanuric chloride, receiving 5-S. For detailed discussions of obtaining commercially available α-aminoamides and their transformation into the corresponding α-aminonitriles see Y.D.Ward etc., J. Med. Chem., 2002, 45, c.5471; P.D.Greenspan etc., J. Med. Chem., 2001, 44, s.

Additional methods of producing compounds of the present invention.

The compound of the present invention can be obtained in the form of a pharmaceutically acceptable acid additive salts by reaction of the free basic form compounds with pharmaceutically acceptable inorganic or organic acid. Alternatively, the pharmaceutically acceptable basic additive salts of the compounds of the present invention can be obtained by reaction of the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Alternatively, compounds of the invention in the form of salts can be obtained with the use of salts of starting materials or intermediate products.

Free acid or base forms of the compounds of the present invention can be obtained from the corresponding primary additive salt or acid salt additive, respectively. For example, the compound of the present invention in the form of an acid additive salt may be converted into the corresponding free basic form by treatment with a suitable base is receiving (for example, a solution of ammonium hydroxide, sodium hydroxide and the like). The compound of the present invention in the form of a basic additive salts can be converted into the corresponding acid free form by treatment with a suitable acid (e.g. hydrochloric acid, etc).

Compounds of the invention in unoxidized form can be obtained from N-oxides of the compounds of the present invention, the processing of regenerating agent (for example, sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide phosphorus or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane or these solvents at temperatures from 0°C to 80°C.

Proletarienne derivatives of the compounds of the present invention can be obtained by methods known to experts in this field (for details see, for example, Saulnier and others, Bioorganic and Medicinal Chemistry Letters, 1994, 4, s). For example, appropriate prodrugs can be prepared by the reaction noderivatives compounds of the present invention with a suitable carbamimidoyl agent (for example, 1,1-aryloxyalkanoic, para-nitrophenylarsonic or similar).

Protected derivatives of compounds offer from the retene can be obtained by means well-known experts in this field. A detailed description of the equipment used for the introduction of protective groups and their removal can be found in .W.Greene, "Protecting Groups in Organic Chemistry", 3rd ed., John Wiley and Sons, Inc., 1999.

Compounds of the invention can be easily obtained or can be formed during the processes described in the present invention, in the form of a solvate (e.g. hydrate). Hydrates of the compounds of the present invention can be easily obtained by recrystallization from a mixture of water/organic solvent when using such organic solvents as dioxane, tetrahydrofuran or methanol.

Compounds of the invention can be obtained in the form of their individual stereoisomers by reaction of the racemic mixture of compounds with optically active separating agent for forming a pair of diastereoisomeric compounds, separating the diastereomers and the allocation of optically pure enantiomers. Since the separation of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the present invention, preferred are dissociable complexes (e.g., crystalline diastereomeric salt). The diastereomers differ in their physical properties (e.g. melting points, boiling points, solubility,reactivity, etc. and, with such differences, can be easily separated. The diastereomers can be separated by chromatographic or, preferably, a separation technique based upon differences in solubility. Optically pure enantiomer then allocate together with the separating agent in practical ways, which do not cause racemization. A more detailed description of the equipment, suitable to the separation of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen "Enantiomers, Racemates and Resolutions", John Wiley and Sons, Inc., 1981.

In sum, we can say that the compounds of formula I can be prepared according to the scheme, including:

(a) the reaction indicated in schemes 1, 2, 3, 4 and 5 and

(b) optional conversion of a compound of the invention in pharmaceutically acceptable salt;

(c) optional conversion of the salt form of the compounds of the present invention in the non-salt form;

(d) an optional transformation of the oxidized form of the compounds of the invention in pharmaceutically acceptable N-oxide;

(e) optional conversion of the N-oxide forms of the compounds of the present invention in its unoxidized form;

(f) optional selection of individual isomers of compounds of the invention from a mixture of isomers;

(g) optional conversion of rederivation the th compounds of the invention in pharmaceutically acceptable proletarienne derived; and

(h) an optional transformation procarcinogen derived compounds of the present invention in rederivation form.

Where the preparation of starting materials is not described specifically, the compounds are well-known compounds or can be obtained analogously to known methods or in accordance with the described herein in the Examples.

Professionals understand that the above transformations are only representative methods of preparing compounds of the present invention, and can also be used other well known methods.

Examples

The present invention further includes examples that do not limit the entire volume, and illustrate obtaining intermediates (note 1) and compounds of the present invention (note 2).

Instructions 1

Obtaining α-hydroxy acids via diazotization of chiral amino acids (representative procedure)

To a stirred suspension of L-cyclohexylamine (4,00 g and 23.4 mmol) in 0.5m H2SO4(120 ml) at 0°C. is slowly added dropwise an aqueous solution of NaNO2(12.1 g in 40 ml of N2About). Adding complete after about 1 hour, and the solution is allowed to warm to room temperature. After 16 h, the reaction mixture was extracted with ether (3×100 ml)and the combined organic extracts washed with 1M NaHSO (1×200 ml), saturated brine (1×100) and then dried over anhydrous Na2SO4. The solvent is removed in vacuo, and the crude product is crystallized from a mixture of Et2O/pentane (10 ml/100 ml)to give 2.1 g (52% yield) of (S)-2-hydroxy-3-cyclohexylpropionic acid in the form of a brilliant white needles.

Example 1

2-Cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of 2-(benzoxazol-2-yl)-(1S)-cyclopropyl-2-oxoethylidene acid

Scheme 6

Stage A: (S)-3-phenylalanyl acid (1,21 g, 126 mmol) dissolved in dichloromethane (300 ml) and treated with morpholine (55 g, 631 mmol). The reaction is cooled in a bath of ice/water and added dropwise a solution of PyBOP (72 g, 139 mmol) in dichloromethane (200 ml) through equalizing pressure funnel. The reaction mixture was stirred overnight and allowed to warm to room temperature. After adding 110 ml of 4M HCl the reaction mixture was filtered, and the organic phase is separated. The aqueous layer was twice extracted with dichloromethane. The combined organic solutions dried over MgSO4and remove the solvent. The resulting substance chromatographic on silica gel and elute with ethyl acetate, getting 20,65 g (68% yield) of (S)-2-hydroxy-1-morpholine-4-yl-3-phenylpropane-1-it (2) in the form of oil; HPLC-MS calculated for C13H17NO3(M+N+) 236,1; on the Albanian 236,4.

Stage C. a Solution of compound 2 (20.5 g, is 87.1 mmol) in ethanol (80 ml), water (10 ml) and acetic acid (10 ml) is placed in the container Parra and treated with 2 g of 10% Rh/C. the Cylinder spin, vacuum and filled with hydrogen to a pressure of 1000 psi. Then the reaction mixture is heated under stirring at 50°C during the night. After cooling to room temperature and pressure relief tank pumped and twice again filled with nitrogen. The reaction mixture was filtered through a layer of celite, and the solvent is removed, releasing of 18.6 g (88,5%) (S)-3-cyclohexyl-2-hydroxy-1-morpholine-4-improper-1-it (3) in the form of oil; HPLC-MS calculated for C13H23NO3(M+N+) 242,2 found 242,4.

Stage C. a Solution of 4-nitrophenylphosphate (20,55 g, 102 mmol) in dioxane (150 ml) is treated with pyridine (50 ml)to give a suspension, which is heated up to 70°C, then for ~5 min added through an addition funnel with pressure solution of compound 3 (12,30 g, 51,0 mmol) in dioxane (50 ml). After stirring for a further 5 min the reaction is allowed to cool to room temperature, and the solvent is removed by evaporation on the rotor. The remaining mass is distributed between ethyl acetate and water. The organic layer is collected, the aqueous phase is again extracted with ethyl acetate and remove. The combined organic layers dried over MgSO4and the solvent is removed. Received TV is RDY the residue is dissolved in a minimum quantity of hot dichloroethane and treated with dichloromethane. The mixture is then placed overnight in a refrigerator at -4°C, then filtered. The mother liquid is concentrated and purified using a 330 g silica gel with a gradient of ethyl acetate in hexane from 0 to 100%, highlighting 15.2 g (yield 73%) of (S)-2-cyclohexyl-1-(morpholine-4-carbonyl)ethyl ester 4-nitrophenylarsonic acid (4) in the form of a slightly yellowish oil;1H NMR (CDCl3, 400 MHz) δ 0,97-1,08 (m, 2H), 1,09-of 1.36 (m, 3H), 1,48-to 4.62 (m, 2H), 1,65 by 1.68 (m, 4H), 1,82-of 1.97 (m, 2H), 3,41-of 3.60 (m, 3H), 3,64-of 3.80 (m, 5H), of 5.29 and 5.36 (m, 1H), 7,38-7,44 (m, 2H), 8,24-8,30 (M, 2H); HPLC-MS calculated for C20H26N2O7(M+H+) 407,2 found 407,4.

Scheme 7

Benzyl ether of (S)-(1-cyclopropyl-2-hydroxyethyl)carbamino acid (5)as outlined in scheme 7, was prepared as follows:

(i) a Sample of (S)-phenethyl-(S)-cyclopropylamine (16,8 g, 76,7 mmol, obtained from cyclopropanecarboxaldehyde, cyanide and potassium (S)-(-)-α-methylbenzylamine, using a modified technique described in Daniel J. Bayson and others, U.S. patent 6191306) is treated with THF (200 ml), water (100 ml) and 10% Pd/C (4,76 g). To a stirred mixture of formic acid (17 ml) and stirred over night. The catalyst was then removed by filtration through a layer of celite, and the solvent is removed by evaporation on the rotor. The remainder of the process several times with methanol, evaporated, and the residue is dried in vacuum, highlighting of 4.75 g (Ihad 54%) of (S)-aminocyclopropane acid in the form of solids, used without further purification.

(ii) the Product of the previous stage and 4.75 g, 41 mmol) was dissolved in 130 ml of 1N. NaOH and treated under intensive stirring benzylchloride (of 5.92 g, a 49.5 mmol). The reaction mixture was stirred over night, then twice extracted with dichloromethane. The organic layers are removed, the aqueous phase is acidified with concentrated HCl and extracted three times with dichloromethane. The combined organic layers dried over MgSO4and the solvent is removed, releasing 7,38 g (yield 72%) of (S)-benzyloxycarbonylamino acid as a white solid.

(iii) a Solution of (S)-benzyloxycarbonylamino acid (3.2 g, 12.8 mmol) in THF (20 ml) is cooled in a bath of ice/water and treated with 1M solution NR3in THF (16,7 ml of 16.7 mmol). The reaction mixture is stirred for 4 h and then treated with 1M HCl until the termination of allocation of bubbles. The mixture is stirred overnight, after which the organic solvent is evaporated on the rotor. The residue is treated with ethyl acetate and transferred into a separating funnel. The aqueous phase is discarded, the organic phase is twice washed with 1M NaOH, dried over MgSO4and the solvent is removed. The residue is purified by passing through silica gel, using ethyl acetate in hexane with gradient from 0%to 100%, and allocate 1.5 g (yield 50%) of the alcohol as a white solid .sup> 1H NMR (CDCl3, 400 MHz) δ 0,26 is 0.37 (m, 1H), 0,34 to 0.44 (m, 1H), 0,47-and 0.61 (m, 2H), 0,83-0,94 (m, 1H), 2.95 and totaling 3.04 (m, 1H), 3,70 (DD 1H, J1=5,8, h=11,1), 3,79-3,88 (m, 1H), 5,00-5,12 (m, 1H), 5,10 (s, 2H), 7,29-7,31 (m, 5H); HPLC-MS calculated for C13H17NO3(M+H+) 236,1 found 236,3.

Synthesis of 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of 2-(benzoxazol-2-yl)-(1S)-cyclopropyl-2-oxoethylidene acid (Scheme 7).

Stage A. the Transformation is carried out in accordance with the procedures described in .Graupe and others, WO 02098850, reference Example 17(a), except that used periodinane dessa-Martin for the conversion of compound 5 to the corresponding aldehyde, getting benzyl ester 1-(S)-cyclopropyl-2-(benzoxazol-2-yl)-2-gidroksietilirovannogo acid (6) with a total yield 45%; HPLC-MS calculated for C20H20N2O4(M+H+) 353,1; found 353,4.

Stages b, C and D. a Solution of compound 6 (269 mg, 0,763 mmol) in methanol (8 ml) was treated with 20% Pd(OH)2coal (34 mg). Replace the atmosphere of the reaction into hydrogen by injecting 3 min the solution using a long syringe, and then the reaction mixture is stirred for 2 hours under a pressure of 1 atmosphere of hydrogen. Replace the atmosphere again on nitrogen, again injecting the solution through the long syringe over 3 minutes, the Reaction mixture was filtered through celite and remove the solvent. The oil obtained is treated with a solution of compound 4 (310 m is, 0,763 mmol) in ethyl acetate, and the solvent is removed. The mixture is then dissolved in isopropyl alcohol (10 ml) and treated with diisopropylethylamine (148 mg, 1.15 mmol). The reaction is maintained at a temperature of 50°C during the night. Volatiles are removed in vacuo and the resulting residue is dissolved in ethyl acetate and washed with 5% solution of NaHSO4. The organic phase is dried over MgSO4and the solvent is removed. The oil obtained is dissolved in dichloromethane (10 ml) and treated with periodinane dessa-Martin (937 mg, 2.21 mmol). After stirring over night the reaction is treated with saturated aqueous NaHCO3(~15 ml) and 1M Na2S2O3(~15 ml) and stirred for 20 minutes the Mixture was then transferred into a separating funnel and selected organic layer. The aqueous layer was twice extracted with dichloromethane and drop. The combined organic extracts dried over MgSO4and remove the solvent. The residue is purified on silica gel using a gradient from 0 to 100% ethyl acetate in hexane, getting 114 mg (31%) of 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of 2-(benzoxazol-2-yl)-(1S)-cyclopropyl-2-oxoethylidene acid in the form of a solid after lyophilization.1H NMR (CDCl3, 400 MHz) δ 0,51 is 0.65 (m, 3H), 0,73 of 1.00 (m, 3H), 1.04 million-of 1.29 (m, 4H), of 1.35 to 1.47 (m, 2H), 1,58-of 1.84 (m, 6N), 3,37 is 3.76 (m, 8H), 4,88-is 4.93 (m, 1H), from 5.29 (DD, 1H, J1=2,7, h=10,1), of 5.82 (d, 1H, J=7,1), 7,44 is 7.50 (m, 1H), 7,527,58 (m, 1H), to 7.67(d, 1H, J=8,3), of 7.90 (d, 1H, J=8,0); HPLC-MS calculated for C26H33N3O6(M+H+) 484,2 found 484,5.

Example 2

2-Phenylmethanesulfonyl-(1R)-(morpholine-4-carbonyl)ethyl ester of 2-(benzoxazol-2-yl)-(1S)-methyl-2-oxoethylidene acid

Scheme 8

Stage A: This reaction is carried out as described in Deechongkit, S.; You, S.-L.; Kelly, J. W., Org. Lett, 2004, 6, s, using (S)-methyl ester of glycine acid 1 and benzylmercaptan. Methyl ester of (R)-3-benzylmethyl-2-hydroxypropionic acid 2 (7,41 g, 31,41 mmol, 92%) was isolated as a viscous oil: MS calculated for C11H14O3S (M+N+) 227,1 found 227,3.

Stage: This reaction is carried out, as previously described in Deechongkit, S.; You, S.-L.; Kelly, J. W., Org. Lett., 2004, 6, s using methyl ester of (R)-3-benzylmethyl-2-hydroxypropionic acid 2 and lithium hydroxide. (R)-3-benzylmethyl-2-hydroxypropionic acid 3 (is 3.08 g, 14,51 mmol, 46%) was isolated as a viscous oil: MS calculated for C10H12O3S (M+Na+) 235,1 found 235,3.

Stage C: the reaction is carried out as described in example 1 using (R)-3-benzylmethyl-2-hydroxypropionic acid 3. (R)-3-benzylmethyl-2-hydroxy-1-morpholine-4-improper-1-4 (3,41 g, 11.87 per mmol, 67%) was isolated as a viscous oil: MS calculated for C14H19NO3S (M+N+) 282,, found 282,4.

Stage D: Oxon (2KHSO5×KHSO4×K2SO4, 10,55 g, 17,17 mmol, 3.0 EQ) was dissolved in H2O (25 ml, 0.7 M) and added to a solution of (R)-3-benzylmethyl-2-hydroxy-1-morpholine-4-improper-1-she 4 (1,61 g, 5,73 mmol, 1.0 EQ) in Meon (25 ml, 0.3 M) for 30 min at 0°C. the reaction Monitoring is performed by methods LC/MS. After the reaction takes place completely (about 12 hours), Meon removed in vacuum. The resulting solution was diluted with water (30 ml) and extracted with CH2Cl2(3×50 ml). The organic extracts are combined, washed with water (75 ml) and saturated NaCl solution (50 ml). The organic layer is dried over MgSO4and filtered. The organic solvent is removed in vacuum, obtaining (R)-2-hydroxy-1-morpholine-4-yl-3-phenylmethanesulfonyl-1-he (5) in the form of a viscous oil (1.60 g, 5,11 mmol, 89%), which is used directly without further purification: MS calculated for C14H19NO5S (M+N+) 314,1 found 314,3.

Stage E. This reaction is carried out as described in example 1 using (R)-2-hydroxy-1-morpholine-4-yl-3-phenylmethanesulfonyl-1-he (5). (R)-1-(morpholine-4-carbonyl)-2-phenylmethanesulfonyl(4-nitrophenyl)carbonate 6 (1.98 g, 4.14 mmol, 81%) was isolated as a white solid after chromatography on a column. MS calculated for C21H22N2O9S (M+N+) 479,1; found 479,3.

This substance is the ZAT is used to synthesize the titled compound, using a procedure similar to that described in example 1.1H NMR (CD3OD, 600 MHz) δ and 1.54 (d, 3H, J=6.6 Hz), 3,51 at 3.69 (m, 10H), 4,51-4,58 (m, 2H), 5.08 to 5,10 (m, 1H), 5,74 is 5.77 (m, 1H), 6,94-7,01 (m, 1H), 7,28-7,58 (m, 6N), 7,72-7,79 (m, 1H), to 7.93 (d, 1H, J=8,4 Hz); HPLC-MS calculated for C25H27N3O8S (M+N+) 530,2; found 530,4.

Example 3

2-Cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(5-ethyl-[1,2,4]oxadiazol-3-carbonyl)propellerbuying acid

This product is obtained with a yield of 49% using (S)-2-amino-1-(5-ethyl-1,2,4-oxadiazol-3-yl)butane-1-ol and (S)-2-cyclohexyl-1-(morpholine-4-carbonyl)ethyl(4-nitrophenyl)carbonate as described in example 1.1H NMR (CDCl3, 400 MHz) δ 0,78 with 0.93 (m, 2H), 0,97 (DD, 3H, J1=J2=7,4), 1,05-1,30 (m, 3H), 1,33-1,44 (m, 1H), USD 1.43 (DD, 3H, J1=J2=7,6), 1,60 of-1.83 (m, 8H), 1,98-2,11 (m, 1H), 3.00 and (q, 2H, J=7,6), 3,38-of 3.48 (m, 1H), 3,50-to 3.58 (m, 2H), 3,60 is 3.76 (m, 5H), 5,18 (DD 1H, J1=4,8, J2=7,8, J3=12,6), 5,26-5,32 (m, 1H), 5,67 (d, 1H, J=8,2); HPLC-MS calculated for C22H34N4O6(M+H+) 451,3 found of 451.5.

Example 4

2-Cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(5-phenyl-[1,2,4]oxadiazol-3-carbonyl)propellerbuying acid.

This product is obtained with a yield of 49% using (S)-2-amino-1-(5-phenyl-1,2,4-oxadiazol-3-yl)butane-1-ol and (S)-2-cyclohexyl-1-(morpholine-4-carbonyl)ethyl(4-nitro the Nile)carbonate, as described in example 1.1H NMR (CDCl3, 400 MHz) δ 0,80-of 1.03 (m, 2H), 1,01 (DD, 3H, J1=J2=7,4), the 1.06-1.32 to (m, 2H), 1,39-1,89 (m, N), 2,04-2,17 (m, 1H), 3,39-of 3.78 (m, 8H), 5,27 (DDD, 1H, J1=4,9, J2=7,7, J3=12,6), from 5.29-of 5.34 (m, 1H), of 5.68 (d, 1H, J=8,2), 7,54-of 7.60 (m, 2H), 7,62-to 7.68 (m, 1H), 8,18-8,24 (m, 2H); HPLC-MS calculated for C26H34N4O6(M+N+) 499,3 found 499,4.

Example 5

2-Cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of 4-oxitetraciclina-(3S)-ylcarbamate acid

Used (4S)-aminotetrahydrofuran-(3R)-ol gain, as described by E.N. Jacobsen and others, J. Am. Chem. Soc., 1995, 117, cc.5897-5898.

2-Cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester (4R)-hydroxymitragynine-(3S)-ylcarbamate acid get, as described in example 1.

Scheme 9

Stage A: 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester (4R)-hydroxymitragynine-(3S)-ylcarbamate acid (40 mg, 0,1079 mmol) dissolved in dry dichloromethane (5 ml) and cooled to 0°C, then add periodinane dessa-Martina dry and stirred at this temperature for half an hour before giving to warm to room temperature for 1.5 hour. Volatile components of the reaction are removed by evaporation on a rotary evaporator, the crude product is purified using preparative HPLC, receiving 15 mg to 37.5%. HPLC-MS calculated DL is C 18H28N2O6(M+H+) 369,2 found 369,4.

Example 6

(S)-1-tert-butoxycarbonyl-4-cyano-4-(1-cyclohexylmethyl-2-morpholine-4-yl-2-exoelectrogenic)piperidine

Scheme 10

Stage A: 1-BOC-4-piperidone 1 (2 g, 10 mmol) is added to the flask containing KCN (3,256 g, 50 mmol) and ammonium acetate (7.7 g, 100 mmol). In the flask, closed with a rubber stopper, is added through a syringe dry methanol (50 ml). The reaction mixture was homogenized with ultrasound for 15 min to break down the salts and then stirred at room temperature overnight. Volatiles are removed by evaporation on a rotary evaporator, the residue is neutralized with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layers dried over MgSO4the solvent is removed, highlighting exit 98% of 2.21 g of pure tert-butyl ester 4-amino-4-cyanopiperidine-1-carboxylic acid 2.1H NMR (CDCl3, 400 MHz) δ of 3.95 (s, 2H), 3,18 (so J=11.3 Hz, 2H), 1,96 (d, J=13,2 Hz, 2H), 1,82 (s, 2H), and 1.63 (t, J=12 Hz, 2H), 1,45 (s, N).

Stage b: Sample 2 (192 mg, 0,852 mmol) and lutidine (for 91.3 mg, 0,852 mmol) dissolved in dry DHM, is added dropwise to a solution of triphosgene (278 mg, of 2.81 mmol) in dry DHM and stirred for 1.5 hours at room temperature. A solution of (S)-3-cyclohexyl-2-hydroxy-1-morpholine-4-improper-1-it (p is obtained, as described in example 1, 205 mg, 0,852 mmol) and lutidine (for 91.3 mg, 0,852 mmol) is added dropwise to the reaction mixture over 10 min and stirred for 3 hours. Volatile products are removed under vacuum. The resulting residue is purified preparative HPLC, highlighting 150 mg of (S)-1-tert-butoxycarbonyl-4-cyano-4-(1-cyclohexylmethyl-2-morpholine-4-yl-2-exoelectrogenic)piperidine.1H NMR (CD3OD, 400 MHz) δ to 5.35 (d, J=9,2 Hz, 1H), 3,81 (d, J=10.5 Hz, 2H), 3,74-3,62 (m, 6N), 3,56-of 3.48 (m, 2H), 3,32 (m, 4H), of 2.23 (d, J=11.2 Hz, 2H), 1,87 (m, 3H), 1,71 (m, 5H), 1,52 of 1.46 (m, 11N), 1,29-1,20 (m, 3H), 1,03 is-0.97 (m, 2H). HPLC-MS calculated for C25H40H4O6(M+N+) 493,3 found 493,3.

Example 7

(S)-4-Cyano-4-(1-cyclohexylmethyl-2-morpholine-4-yl-2-exoelectrogenic)-1-methylpiperidin

The title compound of example 6 (125 mg, 0,254 mmol) dissolved in DHM (1 ml) and TFU (1 ml) and stirred for 1 hour, the volatile products are removed by evaporation on a rotary evaporator and produce (S)-4-cyano-4-(1-cyclohexylmethyl-2-morpholine-4-yl-2-exoelectrogenic)piperidine with a quantitative yield in the form of a salt TFU. The corresponding free amine is obtained by adding 1M NaOH and extraction DHM with subsequent drying and evaporation of the organic layer on a rotary evaporator. HPLC-MS calculated for C20H32N4O4(M+H+) 393,2 found to 393.3.

Sample free is mine, obtained in the previous stage (40 mg, is 0.102 mmol), dissolved in Meon (1 ml) and add a solution of formaldehyde (6,06 mg, 0,202 mmol) in methanol (2 ml) with one drop of acetic acid. Then the reaction mixture was added solid cyanoborohydride sodium (2.1 mg, 0,034 mmol) and stirred for half an hour. The solvent is removed in vacuo, the product was then purified preparative HPLC, highlighting the title product, 29,8 mg, yield 72%. HPLC-MS C21H34N4O4(M+H+) 407,3 found 407,3.

Example 8

(1S)-Cyclohexylmethyl-2-morpholine-4-yl-2-oksietilnye ether 2-(2-chlorobenzoyloxy)-(1R)-cyanoethylidene acid

Scheme 11

(S)-2-Amino-3-(2-chlorobenzoyloxy)propionamide receive, as described in P.D.Greenspan etc., J. Med. Chem., 2001, 44, SS-4534.

Stage A: (S)-2-Cyclohexyl-1-(morpholine-4-carbonyl)ethyl(4-nitrophenyl)carbonate (getting in example 1 to 132.8 mg, 0,326 mmol) and (S)-2-amino-3-(2-chlorobenzoyloxy)propionamide (89,7 mg, 0,392 mmol) is placed in a dry flask with 2 ml of anhydrous DMF, add DMAP (4-dimethylamino)pyridine) (159 mg, 1.3 mmol) in 0.5 ml of dry DMF and the reaction mixture stirred for night. After processing, the product is obtained by purification using preparative HPLC to yield 39% in the form of amorphous solids. HPLC-MS for C24H34ClN3O6(M+1)=496,9.

Stage b: the Product of stage A (61 mg, 0,122 mmol) dissolve Aut in 0.5 ml of dry DMF and added to a solution of cyanuric chloride (67 mg, 0,369 mmol) in dry DMF. The reaction mixture is stirred for 2 hours, then the solvent is removed by evaporation on a rotary evaporator, the crude product is purified using preparative HPLC, getting 14,66 mg of pure amorphous solid.1H NMR (CD3OD, 400 MHz) δ to 7.59 (d, J=7,1 Hz, 1H), 7,42 (d, J=7,3 Hz, 1H), 7,34 (m, 2H), 5,38 (d, J=9.8 Hz, 1H), a 4.86 (t, J=5.7 Hz, 1H), and 4.75 (d, J=1.8 Hz, 2H), 3,83 (d, J=5.6 Hz, 2H), 3,7-to 3.67 (m, 6N), 3,6-to 3.49 (m, 2H), to 1.87 (d, J=a 12.7 Hz, 1H), 1.77 in-1,72 (m, 5H), 1,58-1,49 (m, 2H), 1,37-of 1.18 (m, 3H), 1,09 to 0.92 (m, 2H). HPLC-MS for C24H32ClN3O5(M+1)=479,2.

Example 45

2-Cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(5-cyclopropyl-[1,2,4]oxadiazol-3-carbonyl)propellerbuying acid

Scheme 12

Stage A: Intermediate product 2 is obtained from commercially available (S)-2-aminobutane-1-ol (1): compound 1 (10.0 g, 112 mmol, 1.0 EQ) was dissolved in 500 ml of dry DHM, BOC-anhydride (26,93 g, 123,4 mmol, 1.1 EQ) is dissolved in 200 ml of dry DHM and add to the connection 1 via an addition funnel at 0°C for 1 hour. After stirring the reaction mixture overnight process it 25% NH4OH. The organic layer is separated and dried over MgSO4After evaporation of the solvent to get pure compound 2 with a quantitative yield.

Stage: Product 2 (1,02 g of 5.39 mmol, 1 EQ) is dissolved in 60 m in the dry DHM and cooled to 0°C, add trichloroisocyanurate acid (1,32 g, the 5.65 mmol, of 1.05 EQ) and stirred for 10 min, obtaining a white suspension. TEMPO (8,8 mg, 0,056 mmol, 0.01 EQ) are added to the cooled reaction mixture, which immediately becomes orange, and is the formation of additional precipitate. The reaction vessel is removed from the cooling bath, the reaction mixture is stirred for further 45 min, then filtered through a layer of celite, washed with 5% citric acid, then with a saturated solution of bicarbonate, dried over MgSO4filter and excrete pure product 3 (0,979 g, yield 97%), which is immediately used in the next stage C.

Stage C: the Product of 3 (0,99 g, 5,28 mmol, 1 EQ) was dissolved in 20 ml of dioxane for 10 minutes and cooled to 0°C, then add NaHSO3(2,75 g, 21.1 mmol, 4 equiv, dissolved in 10 ml of water). The reaction mixture was stirred 10 min at 0°C and added KCN (1,37 g, 21.1 mmol, 4 EQ, 10 ml of water), and then stirred over night. The reaction mixture is treated by adding 150 ml of ethyl acetate and washing the organic layer with three portions of saturated sodium bicarbonate solution. The organic layer is dried over sodium sulfate, filtered and concentrated to dryness, obtaining pure cyanhydrin with quantitative yield.

Stage D: the Product 4 (of 5.68 g of 26.5 mmol, 1 EQ) is dissolved in 60 ml of ethanol and added to a solution of hydroxylamine (50% weight/volume) in water (2,44 ml, 39,7 m is ol, 1.5 EQ). The reaction mixture is heated for 2 hours at 60°C, then remove volatile products, the remaining white foam is kept in a high vacuum for 18 hours, getting with a quantitative yield of pure product 5 in the form of an amorphous white solid.

Stage E: 5 Product (9.7 g, 39,23 mmol, 1 EQ) is dissolved in 50 ml of dry DMF, and thereto with vigorous stirring anhydride cyclopropanecarbonyl acid (6,148 g, 39,23 mmol, 1 EQ). The resulting solution was divided into five vessels in 20 ml microwave oven, equipped with agitators. The vessels closed, each individually heated at 200°C for 75 C. the Contents of the vessels then combine, diluted with 250 ml ethyl acetate, washed with water, bicarbonate and saline. The organic layer is dried over magnesium sulfate, filtered and concentrated to dryness. The oil obtained chromatographic on a column with ISCO silica gel with gradient ethyl acetate/hexane 20% to 80% within 40 minutes Yield of 8.2 g (70%).

Stage F and G: 7 Product (8 g, 26.9 mmol, 1 EQ) is dissolved in 50 ml DHM, and slowly over 15 min to a stirred solution add 50 ml of TFU. The reaction mixture is stirred for 2 hours, then evaporated to dryness. The obtained viscous oil is dissolved in 40 ml of dry DMF, there is added DIPEA (diisopropylethylamine) (of 17.35 g, 134,5 mmol, 5 EQ), then a solution of compound (9) in 40 ml of dry DMF. The floor is built yellow solution is stirred over night. By evaporation on a rotary evaporator partially remove DMF) to ~ 35 ml, and the residue is diluted with 500 ml ethyl acetate, washed with portions of 4×200 ml of 25% Na2CO3. The organic layer was washed with brine, concentrated to dryness and placed in methanol. The resulting mixture was purified using shirokozonnoj reversible-phase preparative HPLC, the fractions are combined to remove the acetonitrile and extracted with ethyl acetate, dried over MgSO4, filtered and evaporated, obtaining the pure product 10 (11.5g, to 24.7 mmol, yield 92%).

Stage N: Product 10 (8.8 g, 18,94 mmol, 1 EQ) is dissolved in 500 ml of dry DHM and cooled to 0°C. thereto at the same temperature is added in solid form periodinane dessa-Martin (24,1 g of 56.8 mmol, 3 EQ)and the reaction mass allowed to warm to room temperature, then stirred overnight and treated with a saturated solution of Na2S2O3(400 ml), then saturated sodium bicarbonate solution. The organic layer is dried over MgSO4, filtered and concentrated to 40 ml, the Suspension is filtered, the solution chromatographic two 110 g ISCO column with a gradient of ethyl acetate from 0 to 100% over 30 min, then washed with 100% etiracetam for 15 min to ensure that the output from the column of the entire product. HPLC captures the mixture of hydrate, methylketone (sample was obtained in methanol and the desired product. The special is Tr 1H NMR clear and defined.

Getting 6: Cyclopropanecarbonyl acid (29 g, 336,9 mmol, 1 EQ) is dissolved in 500 ml of dry DHM, to the solution is added at 0°C dropwise over 0.5 hours BCA (34,75 g, 168,5 mmol, 0.5 EQ) in solution in 100 ml DHM. The reaction mixture is allowed to warm to room temperature and stirred over night. The resulting suspension is filtered through a layer of celite, evaporated and dissolved in 500 ml of hexane, then filtered through a layer of celite to remove residual by-products, and evaporated. The oil obtained is distilled in vacuum, obtaining the pure anhydride.

By repeating the processes described in the above examples, using appropriate starting materials the following compounds of formula I listed in table 1.

Experience with cathepsin S.

Kinetic measurements were performed in a total reaction volume of 30 μl for 384-hole microtiter dies. Cathepsin S with a final concentration of 0.3-3 nm (active center) incubated with the connection of the proposed image is etenia at twelve varying concentrations in the buffer, containing 100 mm NaAc (pH 5.5), 1 mm EDTA, 100 mm NaCl. of 0.01% Brij-35 (ethoxylated lauric alcohol) at room temperature for 20 minutes Control reactions in the absence of inhibitor is carried out in 24 iterations. The reaction initiated by addition of substrate - acetyl-histidine-Proline-valine-lysine-aminocarbonylmethyl to a final concentration of 50 µl. The rate of hydrolysis of the substrate define locking the increase of fluorescence at the wavelength of excitation 380 nm and the wavelength of emission of 450 nm, which occurs in the decomposition of aniline connection in the substrate under the action of the enzyme. Apparent inhibition constants for compounds determined by curve enzymatic development and then used to calculate the competitive inhibition constants.

Experience with cathepsin K.

Kinetic measurements were performed in a total reaction volume of 30 μl for 384-hole microtiter dies. Catepsin To the final concentration of 3.5 nm (active center) incubated with the compound of the present invention when the twelve varying concentrations in a buffer containing 100 mm NaAc (pH 5.5), 1 mm EDTA, 100 mm NaCl. of 0.01% Brij-35 at room temperature for 20 minutes Control reactions in the absence of inhibitor is carried out in 24 iterations. The reaction initiated by addition of substrate - acetyl-lysine-histidine-Proline-lysine-aminocarbonylmethyl to the con who offered concentration of 40 ál. The rate of hydrolysis of the substrate define locking the increase of fluorescence at the wavelength of excitation 380 nm and the wavelength of emission of 450 nm, which occurs in the decomposition of aniline connection in the substrate under the action of the enzyme. Apparent inhibition constants for compounds determined by curve enzymatic development and then used to calculate the competitive inhibition constants.

Experience with cathepsin C.

Kinetic measurements were performed in a total reaction volume of 30 μl for 384-hole microtiter dies. Cathepsin In with a final concentration of 1.5 nm (active center) incubated with the compound of the present invention when the twelve varying concentrations in a buffer containing 100 mm NaAc (pH 5.5), 1 mm EDTA, 100 mm NaCl. of 0.01% Brij-35 at room temperature for 20 minutes Control reactions in the absence of inhibitor is carried out in 24 iterations. The reaction initiated by addition of substrate - acetyl-histidine-Proline-valine-lysine-aminocarbonylmethyl to a final concentration of 10 μl. The rate of hydrolysis of the substrate determine monitorina increased fluorescence at the wavelength of excitation 380 nm and the wavelength of emission of 450 nm, which occurs in the decomposition of aniline connection in the substrate under the action of the enzyme. Apparent inhibition constants for compounds determined by the curve of the enzyme is practical development and then used to calculate the competitive inhibition constants.

Experience with cathepsin L.

Kinetic measurements were performed in a total reaction volume of 30 μl for 384-hole microtiter dies. Cathepsin L with a final concentration of 0.1 nm (active center) incubated with the compound of the present invention when the twelve varying concentrations in a buffer containing 100 mm NaAc (pH 5.5), 1 mm EDTA, 100 mm NaCl. of 0.01% Brij-35 at room temperature for 20 minutes Control reactions in the absence of inhibitor is carried out in 24 iterations. The reaction initiated by addition of substrate - acetyl-histidine-lysine-phenylalanine-aminocarbonylmethyl to a final concentration of 20 µl. The rate of hydrolysis of the substrate determine monitorina increased fluorescence at the wavelength of excitation 380 nm and the wavelength of emission of 450 nm, which occurs in the decomposition of aniline connection in the substrate under the action of the enzyme. Apparent inhibition constants for compounds determined by curve enzymatic development and then used to calculate the competitive inhibition constants.

The compounds of formula I in free form or in the form of pharmaceutically acceptable salts exhibit valuable pharmacological properties, for example, as shown in the in vitro tests described in the invention. Preferred constants of inhibition of cathepsin S for the compounds of the invention are less than the 10 μm. More preferred the inhibition constants for the compounds of the present invention comprise less than 1.0 μm. Most preferred the inhibition constants for the compounds of the present invention comprise less than 0.1 μm. Selectivity for cathepsin S in the presence of cathepsin isozyme is defined as the ratio of the constants of inhibition of cathepsin isozyme for compounds of the present invention to constant inhibition of cathepsin S for the same connection. Preferred compounds of the invention are selective for cathepsin S have values of this ratio greater than 10. More preferred compounds of the invention are selective for cathepsin S have values of this ratio greater than 100. The most preferred compounds of the invention are selective for cathepsin S have values of this ratio greater than 1000.

So, for example, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of 2-(benzooxazol-2-yl)-(1S)-cyclopropyl-2-oxoethylidene acid (Example 1) has a value of IC50 of 6.6 nm, and at least 100-fold greater selectivity for cathepsin S than for cathepsin K, and L. the Following examples of activity and selectivity of the compounds of the invention are detailed in Table 2.

Table 2
Number exampleCathepsin S Ki (μm)Catepsin To Ki (μm)Cathepsin L Ki (μm)Cathepsin In Ki (μm)
10.00665.163>23.32>47.5
20.4878>100>100>100
50.8921>30>100>100
80.031413.790>22.63>30
270.00080.2112.035.70
390.00040.2601.315.22
400.00212.13015.27 >30
420.00460.2789.5016.72
430.00360.2504.6516.00
440.00050.4833.619.70
460.00160.1132.214.04
470.00110.2052.17>30
480.00280.4812.751.88
540.00180.4822.314.36
550.00090.1883.979.09

It is obvious that the described examples and sections of the service is t only for illustrative purposes, and specialists may be offered various modifications or changes, which are also included in the invention and the claims. All publications, patents and patent applications cited in the text, incorporated by reference in its entirety.

1. The compound of the formula I

in which R1choose from formulas (a), (b) and (C),

in which n denotes 0;
R6and R7independently selected from hydrogen, C1-C6of alkyl, tsianos1-C6of alkyl, C3-C6cycloalkyl0-C4the alkyl and C6arils0-C4of alkyl; or R6and R7together with the carbon atom to which R6and R7attached, form a 6-membered heteroseksualci with one nitrogen atom;
however, any alkyl, R6and R7may not necessarily include a methylene group substituted by an atom Of; any aryl in R6and R7or formed by the combination of R6and R7may be optionally substituted 1 radical independently selected from the group: halogen, C1-C6alkyl, -XC(O)OR10; X is a bond; and R10independently selected from C1-C6of alkyl;
R8choose from C5-C9heteroaryl0 -C4of alkyl containing 2-3 heteroatoms independently selected from N, O and S; any heteroaryl R8may be optionally substituted 1 radical independently selected from the group: halogen, C1-C6alkyl, C3-C6cycloalkyl; and R2denotes hydrogen;
R3and R4independently selected from hydrogen, C1-C6of alkyl, C3-C6cycloalkyl0-C4the alkyl and C6arils0-C4of alkyl; any alkyl, R3and R4may not necessarily include a methylene group substituted by a group S(O)2;
R5choose from C5-C6geterotsiklicheskie with 1-2 heteroatoms, selected from N and O, and NR12R13; where R12and R13independently selected from C1-C6of alkyl;
and their pharmaceutically acceptable salts, and isomers.

2. The compound according to claim 1 of formula Ia

in which R1choose from formulas (a), (b) and (C)

in which n denotes 0;
R6selected from hydrogen, C1-C6of alkyl, cyano-C1-C6of alkyl, C3-C6cycloalkyl0-C4the alkyl and C6arils0-C4of alkyl;
however, any alkyl of R6may not necessarily include methylene, y is the SCP, replaced by atom On; aryl in R6may be optionally substituted 1 radical independently selected from the group: halogen, C1-C6alkyl, -XC(O)OR10; X is a bond; and R10independently selected from C1-C6of alkyl;
R8choose from C5-C9heteroaryl0-C4of alkyl containing 2-3 heteroatoms independently selected from N, O and S; any heteroaryl R8may be optionally substituted 1 radical independently selected from the group: halogen, C1-C6alkyl, C3-C6cycloalkyl; and
R3selected from hydrogen, C1-C6of alkyl, C3-C6cycloalkyl0-C4the alkyl and C6arils0-C4of alkyl; any alkyl of R3may not necessarily include a methylene group substituted by a group S(O)2;
R5choose from C5-Cbgeterotsiklicheskie with 1-2 heteroatoms, selected from N and O, and NR12R13while R12and R13independently selected from C1-C6the alkyl.

3. The compound according to claim 1, in which
R3and R4both signify hydrogen;
R6selected from hydrogen, C1-C6of alkyl, tsianos1-C6of alkyl, C3-C6cycloalkyl0-C4the alkyl and C6arils0-C4of alkyl, with lubojacky of R 6may not necessarily include a methylene group substituted by an atom Of; any aryl in R6may be optionally substituted 1 radical independently selected from the group of halides;
R7means hydrogen;
R8choose from C5-C9heteroaryl0-C4of alkyl containing 2-3 heteroatoms independently selected from N, O and S; any heteroaryl R8may be optionally substituted 1 radical independently selected from the group: halogen, C1-C6alkyl, C3-C6cycloalkyl; and
R3selected from C1-C6of alkyl, C3-C6cycloalkyl0-C4the alkyl and C6arils0-C4of alkyl; any alkyl, R3may not necessarily include a methylene group substituted by a group S(O)2;
R5choose from C5-C6geterotsiklicheskie with 1-2 heteroatoms, selected from N and O, and NR12R13while R12and R13independently choose
from C1-C6the alkyl.

4. The compound according to claim 3 in which R6selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyanomethyl, 2-chlorobenzonitrile, benzoyloxymethyl, Venetia and benzyl.

5. The compound according to claim 3 in which R8means benzoxazol-2-yl, benzothiazol-2-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]oxadiazol-5-yl and OK the Asolo[5,4-b]pyridine-2-yl; however, any heteroaryl R8optionally substituted 1 radical independently selected from halogen, ethyl and cyclopropyl.

6. The compound according to claim 3 in which R3choose from cyclohexylmethyl, cyclopentylmethyl, benzylmethylamine, cyclohexylethyl, phenyl, isobutyl, tert-butylmethyl, cyclohexyl, benzyl and Venetia; and R5choose from groups: morpholino-, dimethylamino-, piperidinyl and pyrrolidinyl.

7. The connection according to claim 6, selected from 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of 2-(benzoxazol-2-yl)-(1S)-cyclopropyl-2-oxoethylidene acid, 2-phenylmethanesulfonyl-(1R)-(morpholine-4-carbonyl)ethyl ester of 2-(benzoxazol-2-yl)-(1S)-methyl-2-oxoethylidene acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester (1S)-(5-ethyl[1,2,4]oxadiazol-3-carbonyl)propellerbuying acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester 4-oxitetraciclina-(3S)-ylcarbamate acid, (S)-1-tert-butoxycarbonyl-4-cyano-4-(1-cyclohexylmethyl-2-morpholine-4-yl-2-exoelectrogenic)piperidine, (S)-4-cyano-4-(1-cyclohexylmethyl-2-morpholine-4-yl-2-exoelectrogenic)-1-methylpiperidine, (1S)-cyclohexylmethyl-2-morpholine-4-yl-2-xoetrope ether 2-(2-chlorobenzoyloxy)-(1R)-cyanoethylidene acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of 2-(benzoxazol-2-yl)-(1S)-methyl-2-oxoethyl raminosoa acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(benzoxazol-2-carbonyl)propellerbuying acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(benzoxazol-2-carbonyl)BUTYLCARBAMATE acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of 2-(5-perbenzoate-2-yl)-(1S)-methyl-2-oxoethylidene acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of 2-(6-perbenzoate-2-yl)-(1S)-methyl-2-oxoethylidene acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(benzoxazol-2-carbonyl)-2-methylpropionamidine acid, 2-cyclopentyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(benzoxazol-2-carbonyl)propellerbuying acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(benzothiazole-2-carbonyl)propellerbuying acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(benzothiazole-2-carbonyl)ethylcarbamate acid, 2-phenylmethanesulfonyl-(1R)-(morpholine-4-carbonyl)ethyl ester of (1S)-(benzoxazol-2-carbonyl)propellerbuying acid, 3-cyclohexyl-(1S)-(morpholine-4-carbonyl)propyl ester (1S)-(benzoxazol-2-carbonyl)ethylcarbamate acid, 3-cyclohexyl-(1S)-(morpholine-4-carbonyl)propyl ester (1S)-(benzoxazol-2-carbonyl)propellerbuying acid, (1S)-(morpholine-4-carbonyl)-1-phenylmethylene ether (1S)-(benzoxazol-2-carbonyl)propilkki inovas acid, 3,3-dimethyl-(1S)-(morpholine-4-carbonyl)butyl ether (1S)-(benzoxazol-2-carbonyl)propellerbuying acid, (1S)-cyclohexyl-1-(morpholine-4-carbonyl)methyl ester (1S)-(benzoxazol-2-carbonyl)propellerbuying acid, (1S)-cyclohexylmethyl-2-oxo-2-(piperidine-1-yl)ethyl ester (1S)-(benzoxazol-2-carbonyl)ethylcarbamate acid, (1S)-cyclohexylmethyl-2-oxo-2-(pyrrolidin-1-yl)ethyl ester of 2-(benzoxazol-2-yl)-(1S)-cyclopropyl-2-oxoethylidene acid, (1S)-cyclohexylmethyl-2-oxo-2-(pyrrolidin-1-yl)ethyl ester (1S)-(benzoxazol-2-carbonyl)propellerbuying acid, (1S)-cyclohexylmethyl-2-oxo-2-(pyrrolidin-1-yl)ethyl ester (1S)-(benzoxazol-2-carbonyl)BUTYLCARBAMATE acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester 4-oxitetraciclina-(3R)-ylcarbamate acid, (1S)-cyclohexylmethyl-2-(morpholine-4-yl)-2-xoetrope ether (1S)-cyano-2-methylpropiophenone acid, (1S)-cyclohexylmethyl-2-(morpholine-4-yl)-2-xoetrope ether (1S)-cyanopropionic acid, (1S)-cyclohexylmethyl-2-(morpholine-4-yl)-2-xoetrope ether 2-benzyloxy-(1R)-cyanoethylidene acid, (1S)-cyclohexylmethyl-2-(morpholine-4-yl)-2-xoetrope ester 3-benzyloxy-(1S)-cyanopropionic acid, (1S)-cyclohexylmethyl-2-(morpholine-4-yl)-2-xoetrope ether (1S)-cyano-3-phenylpropionylamino acid, (1S)-cyclohex metil-2-(morpholine-4-yl)-2-xoetrope ether (1S)-2-dicyanomethylene acid, (1S)-cyclohexylmethyl-2-(morpholine-4-yl)-2-xoetrope ether (1S)-cyano-2-phenylethylamines acid, (1S)-cyclohexylmethyl-2-(morpholine-4-yl)-2-xoetrope ether cyanomethylene acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(6-perbenzoate-2-carbonyl)propellerbuying acid, 2-cyclopentyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(6-perbenzoate-2-carbonyl)propellerbuying acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(oxazolo[5,4-b]pyridine-2-carbonyl)propellerbuying acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-cyclopropyl-2-(6-perbenzoate-2-yl)-2-oxoethylidene acid, (1S)-cyclohexyl-1-(morpholine-4-carbonyl)methyl ester (1S)-(6-perbenzoate-2-carbonyl)ethylcarbamate acid, (1S)-cyclohexyl-1-(morpholine-4-carbonyl)methyl ester (1S)-(6-perbenzoate-2-carbonyl)propellerbuying acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(6-perbenzoate-2-carbonyl)BUTYLCARBAMATE acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(5-cyclopropyl[1,2,4]oxadiazol-3-carbonyl)propellerbuying acid, (1S)-cyclohexyl-1-(morpholine-4-carbonyl)methyl ester (1S)-(benzoxazol-2-carbonyl)BUTYLCARBAMATE acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(6-methylbenzothiazol-2-ka is bonyl)propellerbuying acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(5-chlorobenzoxazol-2-carbonyl)propellerbuying acid, (1S)-(morpholine-4-carbonyl)-2-phenethyl ester (1S)-(benzoxazol-2-carbonyl)propellerbuying acid, (1S)-(morpholine-4-carbonyl)-3-phenethyl ester (1S)-(benzoxazol-2-carbonyl)propellerbuying acid, (1S)-cyclohexylmethyl-2-oxo-2-(pyrrolidin-1-yl)ethyl ester (1S)-(7-perbenzoate-2-carbonyl)propellerbuying acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(7-perbenzoate-2-carbonyl)propellerbuying acid, 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(5-perbenzoate-2-carbonyl)BUTYLCARBAMATE acid; (1S)-cyclohexylmethyl-2-oxo-2-(pyrrolidin-1-yl)ethyl ester (1S)-(6-perbenzoate-2-carbonyl)propellerbuying acid; 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester of (1S)-(3-cyclopropyl[1,2,4]oxadiazol-5-carbonyl)propellerbuying acid; 2-cyclohexyl-(1S)-(morpholine-4-carbonyl)ethyl ester (1R)-(5-cyclopropyl[1,2,4]oxadiazol-3-carbonyl)propellerbuying acid; 3-methyl-1-(morpholine-4-carbonyl)butyl ether (S,S)-[1-(benzoxazol-2-carbonyl)propyl]carbamino acid; 3-methyl-1-(morpholine-4-carbonyl)butyl ether (S,S)-(2-benzoxazol-2-yl-1-methyl-2-oxoethyl)carbamino acid; 3,3-dimethyl-1-(pyrrolidin-1-carbonyl)butyl ether (S,S)-[1-(5-cycloprop the l[1,2,4]oxadiazol-3-carbonyl)propyl]carbamino acid; 3,3-dimethyl-1-(morpholine-4-carbonyl)butyl ether (S,S)-[1-(5-cyclopropyl[1,2,4]oxadiazol-3-carbonyl)propyl]carbamino acid.

8. The compound according to claim 1, represented by formula

and its pharmaceutically acceptable salts.

9. Pharmaceutical composition having the property of an inhibitor of cathepsin S, containing a therapeutically effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable filler.

10. The use of compounds according to claim 1 when getting medicines with the property inhibitor of cathepsin S.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to oxazolidinone derivatives covered by general graphic formula (I) and to their pharmaceutically acceptable salts. In formula (I) R1, R2, R3 and R4 are independently chosen from a group including -H and halogen; A is chosen from a group including R5 and R6 are independently chosen from a group including -H, -F, -CI, -Br, -OH, alkyl(C1-C6), haloalkyl(C1-C6), alkoxygroup(C1-C6); R7 is chosen from a group including -H, alkyl(C1-C6); either R7 and R5 or R6 taken together form a cycle of 2 carbon atoms and include 1 group chosen from O which in turn can be substituted by one substitute chosen from alkyl(C1-C6); R12 is chosen from a group including -H, -COR14, -CSR14, -COOR14; R14 is chosen from a group including alkyl (C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), R16, R17 and R18 represent -H; R21 is chosen from a group including -H, alkyl(C1-C6); X is chosen from a group including O, S, and Y is chosen from a group including O, S, SO, SO2, and NR12; and optional substitutes of alkyl(C1-C6) groups can represent one or two groups chosen from the following: -OR21, -CN.

EFFECT: invention refers to methods for preparing the compounds of the invention, to application of oxazolidinone derivatives for preparing a drug for treating bacterial infections and to a pharmaceutical composition for treating bacterial infections, including a therapeutically effective amount of the compound of the invention.

36 cl, 10 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to (5H-pyrazolo[1,5-c][1,3]benzoxazin-5-yl)phenylmethanone derivatives (I), useful as HIV viral replication inhibitors, as well as pharmaceutical compositions, use thereof as medicinal agents.

EFFECT: disclosed compounds are meant for preventing or treating HIV infection and treating AIDS.

7 cl, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula I and to their physiologically compatible salts. In general formula I , X denotes identical or different groups =C(-R)- or =N-, wherein at least one =C(-R-)- is substituted by =N-; Y is -O-; R denotes identical or different hydrogen, halogen, (C1-C6)-alkyl; R1 denoes (C4-C16-alkyl, (C1-C4)-alkylene-(C6-C10)-aryl, (C1-C4)-alkylene-(C3-C12)-cycloalkyl, (C9-C10)-bicyclic ring, wherein the aryl can be singly or multiply substituted with (C1-C6)-alkyl; R2 denotes hydrogen; or R1 and R2 together with the nitrogen atom which it is bonded form a monocyclic, saturated 6-member ring in which separate members of the ring system can be substituted with -CHR4-; R4 denotes (C1-C6)-alkyl. The invention also relates to a pharmaceutical composition having inhibiting action on endothelial lipase (EL) and containing one or more compounds of formula I, to use of the disclosed compounds to prepare a medicinal agent and to methods of producing compounds of formula I.

EFFECT: high effectiveness of derivatives.

11 cl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to azole derivatives of formula I , where: A denotes S, O; W denotes -(C=O)-; X are identical or different and denote =C(-R)- or =N-; Y denotes -O- or -NR1-; R denotes hydrogen, halogen, (C1-C6)-alkyl, nitro; R1 denotes hydrogen; R2 denotes (C5-C16)-alkyl, (C1-C4)alkyl-phenyl, where phenyl can be optionally mono- or poly-substituted with (C1-C6)-alkyl; R3 denotes hydrogen; or R2 and R3 together with the nitrogen atom bearing them can form a monocyclic saturated 6-member ring system, where separate members of this ring system can be substituted with 1 group selected from the following: -CHR5-, -NR5-; R5 denotes (C1-C6)-alkyl, trifluoromethyl; and physiologically acceptable salts thereof. The invention also pertains to methods of producing said compounds and a medicinal agent based on said compounds.

EFFECT: novel compounds and a medicinal agent based on said compounds are obtained, which can be used as hormone-sensitive lipase (HSL) or endothelial lipase (EL) inhibitors.

12 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of tetrahydrobenzoxazines

in which substitute R1 denotes a hydrocarbyl residue having 1-3000 carbon atoms, and substitutes R2, R3, R4 and R5 independently denote hydrogen atoms, hydroxyl groups or hydrocarbyl residues, having 1-3000 carbon atoms, respectively, and in which substitutes R3 and R4 or R4 and R5 with a partial structure -O-CH2-NR7-CH2-, bonded to the benzene ring, can also form a second tetrahydrooxazine ring, where R7 denotes hydrocarbyl residues having 1-3000 carbon atoms, provided that at least one of substitutes R1, R2, R3, R4, R5 or R7 are polyisobutenyl, having 3000 carbon atoms and the rest of the substitutes from the group R1, R2, R3, R4, R5 or R7, if they denote hydrocarbyl residues, have 1-20 carbon atoms, respectively, as anti-oxidants for stabilising mineral oil and fuel products against the effect of light, oxygen and heat. The invention also describes jet fuel and jet fuel additive concentrate containing tetrahydrobenzoxazine of formula (I).

EFFECT: preparation of stabilisers having improved stabilisation of nonliving organic material, particularly jet fuel against the effect of light, oxygen and heat.

9 cl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to methods for synthesis of compounds of formula (A), where R1 denotes halogen, C1-C6halogenalkyl, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2 denotes halogen, C1-C4alkyl or C1-C4alkoxy; R3 and R4 independently denote a branched C3-C6alkyl; and R5 denotes C3-C12cycloalkyl, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxy(C1-C6)alkyl, C1-C6alkanoyloxy(C1-C6)alkyl, C1-C6aminoalkyl, C1-C6alkylamino(C1-C6)alkyl, C1-C6dialkylamino(C1-C6)alkyl, C1-C6alkanoylamino(C1-C6)alkyl, HO(O)C-(C1-C6)alkyl, C1-C6alkyl-O-(O)C-(C1-C6)alkyl, H2N-C(O)-(C1-C6)alkyl, C1-C6alkyl-HNC(O)-(C1-C6)alkyl or (C1-C6alkyl)2N-C(O)-(C1-C6)alkyl, or their pharmaceutically acceptable salts which have renin inhibiting activity, as well as to basic intermediate compounds obtained during steps for synthesis of the desired compounds and to methods for synthesis of said intermediate compounds.

EFFECT: alternative synthesis method.

43 cl, 8 dwg, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula pharmaceutically acceptable salts thereof, where ---- independently denotes a single or double bond; ring Q is imidazole, triazole (for example 1,2,3-triazole or 1,3,4-triazole), tetrazole or oxadiazole; B denotes C(R7)(R8) or C(R7), where if the bond between B and Y is a single bond, B denotes C(R7)(R8), and when the bond between B and Y is a double bond, B denotes C(R7); Y denotes C(R7), C(R7)(R8) or O, where if the bond between B and Y is a single bond, Y denotes C(R7)(R8) or O, and when the bond between B and Y is a double bond, B denotes C(R7); Z1 denotes -CH2-, -(CH2)2-, -CH2CH-CH3-, where Z1 is bonded on the left side to a nitrogen atom or -(CH2)3-; X denotes C(R1) or N; A denotes quinolyl, quinazolinyl or benzofuranyl, any of which is optionally substituted with 1-4 substitutes, which can be identical or different and are selected from a group comprising halogen, cyano, C1-6-alkyl, halogen-C1-6-alkyl, C(O)N(R3)(R4), 5-member heterocyclic ring containing 1-3 heteroatoms selected from N or O. The heterocyclic ring is optionally substituted with C1-6-alkyl; when R is present, each independently denotes halogen, C1-6-alkyl; each R1 denotes hydrogen or methyl; each R2 denotes cyano, C1-6-alkyl, C1-6-alkoxy, halogen-C1-6-alkyl, =O, -C(O)N(R3)(R4), -C(O)N(R3)-C1-6-alkoxy, -C(NOR5)R6, -C(O)R6, -C(O)OR7, -C(O)NHNHC(O)R6, 5-member heterocyclic ring containing 1-3 heteroatoms selected from N or O. The heterocyclic ring is optionally substituted with C1-6-alkyl; R3 and R4 independently denote hydrogen; C1-6-alkyl; C3-7-cycloalkyl; C3-7-cycloalkyl-C1-6-alkyl; or when R3 and R4 are bonded to the same nitrogen atom, they, together with the nitrogen atom, they form a 4-, 5- or 6-member ring which optionally contains one extra O atom in the ring; R5 denotes C1-4-alkyl; R6 denotes C3-7-cycloalkyl or C1-6-alkyl; R7 and R8 independently denote hydrogen or C1-6-alkyl; p equals 0, 1 or 2; r equals 0, 1, 2 or 3; s equals 0, 1, 2 or 3. The invention also relates to 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide, 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperidinyl]ethyl}imidazo-[1,5-a]quinoline-3-carboxamide, dihydrochloride 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperidinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxamide, 7-methyl-6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide, to use of the compound in any of claims 1-16, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, having 5-HT1 receptor mediated activity.

23 cl, 195 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of a compound of formula , where R1 is an alkyl or aryl group, or a pharmaceutically acceptable salt or solvate thereof, including hydrate, involving reaction of a compound of formula with a Grignard reagent of formula , where X is a halogen selected from Cl, Br and I, and R1 is an alkyl or aryl group; and optional conversion of the obtained free base compound of formula (I) to a pharmaceutically acceptable salt. The invention also relates to a compound of formula II; a compound of formula , where X is a halogen selected from O, Br and I and to use of formula II and IIIA compounds in synthesis of delmopinol and a derivative of the formula I compound.

EFFECT: novel method for synthesis of a compound of formula I using novel intermediate compounds of formulae II and IIIA.

18 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula I or its pharmaceutically acceptable salt , where R, R9, Z, X, Q and Y are defined in the formula of invention. The compounds are chemokine receptor 2 and chemokine receptor 5 antagonists and can be used as a medicinal agent for preventing, relieving or treating autoimmune or inflammatory diseases or conditions.

EFFECT: obtaining a formula (I) compound, a pharmaceutical composition based on the formula (I) compound, use of the compound in paragraph 1 to prepare a medicinal agent for treating an autoimmune or inflammatory disease or condition, as well as use of the compound in paragraph 1 to prepare a medicinal agent for treating HIV infection or AIDS.

11 cl, 181 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to their pharmaceutically acceptable salts exhibiting P2X3 receptor antagonist activity. In formula (I), X represents -O-; Y represents -NRdRe where one of radicals Rd and Re means hydrogen, and the other means hydrogen; C1-C12alkyl; C5-C7cycloalkyl; C5-C7cycloalky-C1-C12alkyl; hydroxy-C1-C12alkyl; acetyl; aminocarbonyloxy- C1-C12alkyl or heterocyclyl representing a 6-members saturated ring containing heteroatom S substituted by two oxo groups; D represents optional oxygen; R1 represents isopropyl; R2 represents hydrogen; R5 represents hydrogen or C1-C12alkyl; R4 means hydrogen; C1-C12alkyl; halogen; halogen- C1-C12alkyl; C1-C12alkoxy; hydroxy; halogen- C1-C12alkoxy; nitro; amino; hydroxy- C1-C12alkyl; C1-C12alkoxyalkyl; hydroxy- C1-C12alkoxy; C1-C12alkylsulphonyl; cyano; heteroaryl representing a 5-members aromatic ring containing one, two or three heteroatoms selected from O, S and N which can be optionally substituted by a thio group, C1-C12alkyl or C1-C12alkylsulphonyl; heterocyclyl representing a 6-members saturated ring containing two heteroatoms N, one of which is substituted C1-C12alkylsulphonyl; -(CH2)m-(Z)n-(CO)-Rf or -(CH2)m-(Z)n-SO2-(NRg)n-Rf where each m and n independently represents 0 or 1, Z means NR8, Rf means C1-C12alkyl, hydroxy, amino or hydroxy- C1-C12alkyl, and Rg means hydrogen; R3 represents methoxy; R6 represents hydrogen; and one of radicals R7 and R8 represents hydrogen, and the other represents hydrogen, acetyl or phenyl.

EFFECT: also, the invention refers to a pharmaceutical composition and to an application of the compound of formula (I) for preparing a drug.

8 cl, 3 tbl, 70 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel oxadiazole compounds of formula (1) and pharmaceutically acceptable salts thereof, where R1 and R2 assume values given in the description, Y is a single bond. The invention also relates to use of said compounds as DGAT1 inhibitors, for example for treating obesity and diabetes, and a method of inhibiting.

EFFECT: high treatment efficiency.

13 cl, 65 tbl, 712 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R1 is a 3-7-member carbocyclic ring and n is a number ranging from 1 to 8, and the rest of the radicals are described in the claim.

EFFECT: possibility of using such compounds and compositions in therapy as metabotropic glutamate receptor modulators.

33 cl, 367 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula

where there are R3/R3', R4/R4' and R5/R5' where at least one of either R4/R4' or R5/R5' always represents a fluorine atom, and the other radical values are disclosed in the description.

EFFECT: making the compounds which are γ-secretase inhibitors, and can be effective in treating Alzheimer's disease or advanced cancers, including but not limited to carcinoma of uterine cervix and breast carcinoma and malignant tumours of hematopoietic system.

15 cl, 3 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel 3,4-substituted pyrrolidine derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is an acyl selected from values given paragraph 1 of the formula of invention; R2 is unsubstituted C1-C4-alkyl or C3-C7-cycloalkyl; R3 is a fragment selected from a group of fragments of formulae: (a), (b),

(c) and (f), where any of the fragments of formulae given above (a), (b) and (f), the star (*) indicates a bond of the corresponding fragment R3 with the molecule residue in formula I; Ra denotes N-C1-C4-alkylaminocarbonyl, N-phenylaminocarbonyl, N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C1-C4-alkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl- C1-C4-alkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C1-C4-alkyl)-N-(C3-C7-cycloalkyl-C1-C4-alkyl)aminocarbonyl, N,N-di-(C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(tetrahydropyranyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(tetrahydropyranyl)aminocarbonyl or hydrogen; Rb and Rc are independently selected from a group comprising unsubstituted C1-C4-alkyl, unsubstituted monocyclic aryl, unsubstituted monocyclic heterocyclyl, unsubstituted or substituted monocyclic C3-C7-cycloalkyl, unsubstituted aryl- C1-C4-alkyl, usubstituted monocyclic C3-C7-cycloalkyl- C1-C4-alkyl, hydrogen or acyl, where the acyl is selected from values given in paragraph 1 of the formula of invention; or Rb and Rc together may form a 6-member nitrogen-containing ring which may be unsubstituted or disubstituted with =O; Rd in the fragment of formula (c) denotes a phenyl or phenyl-C1-C4-alkyl; Re denotes hydrogen or C1-C4-alkyl; and m equals 2; each of R4 and R5 denotes hydrogen; and T denotes methylene. The invention also relates to the pharmaceutical composition based on the compound of formula I and a method of treating hypertension using the compound of formula I.

EFFECT: novel pyrrolidine derivatives having renin inhibiting activity are obtained.

7 cl, 19 tbl, 37 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to oxazole compound represented by formula (1) and its pharmaceutically acceptable salts. In formula (1) R1 represents phenyl group, which can contain one or two substituents, selected from the following groups (1-1)-(1-11): (1-1) hydroxy groups, (1-2) unsubstituted or halogen-substituted lower alkoxy groups, (1-3) lower alkenyloxy-groups, (1-4) lower alkinyloxy groups, (1-5) cycloC3-8alkyl (lower) alkoxy groups, (1-6) cycloC3-8alkyloxy groups, (1-7) cycloC3-8alkenyloxy groups, (1-8) dihydroindenyloxy groups, (1-9) hydroxyl-(lower)ankoxy groups, (1-10) oxiranyl(lower)alkoxy groups, and (1-11) phenyl(lower)-alkoxy groups; R2 represents phenyl group or heterocyclyl group, selected from pyridine, pyrasine, isoquinoline, pyrrolidine, piperazine, morpholine, each of which can contain one or two substituents, selected from the following groups (2-1)-(2-10):(2-1) hydroxy groups, (2-2) unsubstituted or halogen-substituted lower alkoxy groups, (2-3) unsubstituted or halogen-substituted lower alkyl groups, (2-4) lower alkenyloxy groups, (2-5) halogen atoms, (2-6) lower alkanoyl groups, (2-7) lower alkylthio groups, (2-8) lower alkylsulphonyl groups, (2-9) oxo groups and (2-10) groups lower alkoxy-lower alkoxy; and W represents bivalent group represented by formula (i) or (ii): formula (i) -Y -A -, formula (ii) -Y2-C(=O)-, where A1 represents lower alkenylene group or lower alkylene group, which can contain one substitutent, selected from group, consisting from hydroxy group and lower alkoxicarbonyl group, Y1 represents simple bond, -C(=O)-, -C(=O)-N(R3)-, -N(R4)-C(=O)-, -S(O)m-NH- or -S(O)n-, where R3 and R4, each independently, represent a hydrogen atom or lower alkyl group, and m and n, each independently, represent integer, which has value 2, and Y represents pyperazine-diyl group, or bivalent group, represented by formula (iii) or (iv): formula (iii) -C (=O)-A2-N(R5)-, formula (iv) A3-N(R6)-, where A2 and A3, each independently, represent lower alkylene group, and R5 and R6, each independently, represent a hydrogen atom. Invention also relates to pharmaceutical composition, containing the invention compound as an active ingredient, to pharmaceutical composition for treatment or prevention of atopic dermatitis, which includes the invention compound, to application of the compound as medication, to application of the compound as phosphodiesterase 4 inhibitor and/or as inhibitor of production of tumour necrosis factor α and to method of treatment or prevention of diseases, mediated by phosphodiesterase 4 or mediated by tumour necrosis factor α, including introduction of efficient dose of the compound.

EFFECT: creation of pharmaceutical composition for treatment or prevention of diseases mediated by phosphodiesterase 4 or mediated by tumour necrosis factor, as well as for treatment or prevention of atopic dermatitis.

12 cl, 42 tbl, 486 ex

FIELD: chemistry.

SUBSTANCE: invention relates to (3-trifluromethylphenyl)amide 6-(6-hydroxymethylpyrimidin-4-yloxy)naphthalene-1-carboxylic acid or tautomer or salt thereof. The invention also relates to a pharmaceutical composition which has protein kinase inhibiting activity, based on the said compound and use of the said compound to prepare pharmaceutical compositions for use in treating protein kinase dependent diseases, preferably proliferative diseases, particularly tumorous diseases.

EFFECT: improved properties of compounds.

6 cl, 115 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates or tautomers thereof, where substitute M is selected from groups D1 and D2, having structural formulae given below, and R1, E, A and X are as described in the formula of invention. Disclosed also are pharmaceutical compositions which contain these compounds, methods for synthesis of these compounds, intermediate compounds and synthesis methods thereof, as well as use of compounds of formula (I) in preventing or treating diseases mediated by CDK kinases, GSK-3 kinases or Aurora kinases.

EFFECT: high effectiveness of the compounds.

40 cl, 8 dwg, 18 tbl, 84 ex

Aromatic compound // 2416608

FIELD: chemistry.

SUBSTANCE: invention describes a novel compound of general formula (1), where radicals R1, R2, X1, Y and A are as described in claim 1 of the invention. The invention also describes a method of obtaining compounds of formula (1), as well as a pharmaceutical composition based on said compounds, for treating fibrosis.

EFFECT: novel compounds with excellent collagen formation suppression, cause fewer side-effects and which are safer are obtained.

62 cl, 2717 ex, 432 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzo[d]isoxazol-3-ylamine compounds of formula I in free form or in form of salts with physiologically compatible acids, having antagonistic effect on KCNQ2/3 ion channel. In formula I , R1, R2, R3 and R4 independently denote H, F, CI, Br, I, -NR7R8, -OR9 or C1-C10alkyl, R5 denotes -C(=S)NR21R22 or (CHR6)n-R25, where n equals 1, 2 or 3, R6 denotes H or C1-C6 alkyl, R25 denotes aryl or heteroaryl, R7 and R8 independently denote H or C1-C10 alkyl, R9 denotes H, C1-C10alkyl or -(C1-C5alkylene)aryl, R21 denotes H, R22 denotes C1-C10alkyl, C2-C10alkenyl, C3-C8cycloalkyl, -(C1-C5alkylene)-C3-C8cycloalkyl, -(C1-C3alkylene)heterocycloalkyl, aryl, heteroaryl or -(C1-C5alkylene)aryl, wherein each of the heterocycloalkyl residues has 5-6 members, contains 1 or 2 heteroatoms in the ring, independently selected from oxygen and nitrogen, each of the aryl residues is phenyl, anthracenyl or naphthyl, each of the heteroaryl residues has 5 or 6 members and contains 1 or 2 heteroatoms in the ring, independently selected from oxygen, sulphur and nitrogen.

EFFECT: said compounds can be used to prepare a medicinal agent for curing pain, migraine, anxiety, uroclepsia or epilepsy.

17 cl, 203 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula 1 , where R1, R2, R3, R4, R5, R6, R7 and R8 are independently selected from hydrogen, halogen, alkylcarboxylate, alkyl, alkenyl, cycloalkyl, nitro, sulfonyl chloride, sufonyl hydrazide, alkyl sulfonyl, heterocycylsulfonyl, heteroarylsufonyl, sulfonamide, alkyl-NH-SO2-, cycloalkyl-NH-SO2-, heterocyclyl-NH-SO2-, heteroalkyl-NH-SO2-, heteroarylalkyl-NH-SO2-, heterocyclyl, heteroaryl, guanidinocarbonyl, guanidine, -NR'R" and N=R'"; R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl, halogenalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, aminoalkyl, mono- or dialkyl substituted aminoalkyl, cycloalkylaminoalkyl, aralkylaminoalkyl, alkoxyaralkylaminoalkyl, heterocyclylalkyl, heterocyclylaminoalkyl, heterocyclylalkylaminoalkyl, heterocyclylalkyl-N(alkyl) alkyl, heteroarylalkyl, heteroaralkylaminoalkyl, alkoxyaralkyl-N(alkyl)alkyl, aralkyl-N(alkyl)alkyl, alkoxycarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl alkylcarbonyl; R'" is selected from heterocyclyl, cycloalkyl and alkyl; where the alkyl is unsubstituted or substituted with 1, 2 or 3 identical or different substitutes selected from halogen, halogen alkyl, hydroxy, alkoxy, alkylamino, carbonyl, cycloalkylamino, nitro, cycloalkyl, aryl, heteroaryl and heterocyclyl; aryl is (C6-C10)aryl which is unsubstituted or substituted with 1-2 identical or different substitutes selected from nitro, alkyl, alkoxy, halogen, halogenalkyl, amino and mono or dialkylamino-; heteroaryl is a 5- or 6-member ring system containing 1, 2 or 3 atoms in the ring selected from N, O and S, which is unsubstituted or substituted with 1-2 identical or different groups selected from halogen, nitro, amino, alkylamino, alkyl, alkoxy and cycloalkyl; heterocyclyl is a 5- or 6-member ring system containing 1, 2 or 3 atoms in the ring selected from N, O and S, which is unsubstituted or substituted with 1-2 identical or different groups selected from alkyl, cycloalkyl, hydroxyalkyl, alkylaminoalkyl, cycloalkylalkyl, cycloalkylcarbonyl, heterocyclylalkyl, heteroarylalkyl, heteroarylcarbonyl, arylalkyl and oxo; and guanidino and guanidinocarbonyl are unsubstituted or substituted with 1, 2 or 3 identical or different groups selected from alkyl and alkylcarbonyl; provided that at least one of R1, R2, R3, R4, R5, R6, R7 or R8 is guanidine or guanidine carbonyl; U is C(O), CRaRb, O or NRa; V is CRaRb or NRa; and W is S(O)m; where Ra is H, alkyl, cycloalkyl or alkenyl; Rb is H, alkyl, OH or ORa, and m equals 1 or 2; or to pharmaceutically acceptable salts thereof. The invention also relates to a method of obtaining formula 1 compounds, to a pharmaceutical composition, as well as to use of the said compounds.

EFFECT: obtaining new biologically active compounds which are sodium/proton exchange (Na+/H+) (NHE) inhibitors.

19 cl, 203 ex, 2 tbl

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