Compounds and compositions as modulators of hedgehog pathway

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula I: where Y1 and Y2 are independently selected from N and CR10, where R10 is selected from group, including hydrogen, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, R1 is selected from group, including hydrogen, cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, dimethylamino, C1-C6alkylsulfanyl, dimethylaminoethoxy and pyperasinyl, substituted up to 2 radicals C1-C6alkyl, R2 and R5 are independently selected from group, including hydrogen, cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy and dimethylamino, R3 and R4 are independently selected from group, including hydrogen, halogen, cyano, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, or R1 and R5 with phenyl, to which they are bound, form C5-C10heteroaryl, R6 and R7 are independently selected from group, including hydrogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkyl, on condition that R6 and R7 both do not represent hydrogen, R8 is selected from group, including hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkoxy, R9 is selected from -S(O)2R11, -C(O)R11, -NR12aR12b and -R11, where R11 is selected from group, including aryl, cycloalkyl and heterocycloalkyl, R12a and R12b are independently selected from (C1-C6)alkyl and hydroxy(C1-C6)alkyl, and said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in composition of R9 optionally contain as substituents from 1 to 3 radicals, independently selected from group, including (C1-C6)alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, C6-C10aryl(C0-C4)alkyl, C5-C10heteroaryl(C0-C4)alkyl, C3-C12cycloalkyl and C3-C8heterocycloalkyl, where said arylalkyl substituent in composition of R9 optionally contains as substituents from 1 to 3 radicals, independently selected from group, including halogen, cyano, (C1-C6)alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, dimethylamino and methyl-pyperasinyl, as well as to its pharmaceutically acceptable salts, hydrates, solvates and isomers. In addition, invention relates to method of inhibiting hedgehog pathway in cell and to method of inhibiting undesirable cell proliferation, when cell contacts with compound described above.

EFFECT: obtained and described are novel compounds, which can be applied in medicine.

13 cl, 153 ex, 1 tbl

 

Cross-reference to related application

In the present application claims the priority in connection with the preliminary application US No. 60/797949, filed may 5, 2006, the Contents of the specified application in full included in the present description by reference.

The scope of the invention

The present invention features a method of modulating the activity of the hedgehog signaling pathway. First of all, in the present invention proposes a method of suppressing aberrant States of growth-mediated phenotypes, such as the phenotype with the lost function of Ptc phenotype with acquired function hedgehog, the phenotype with the acquired function or smoothened phenotype with acquired Gli function, and this method lies in the fact that the cell is in contact with a sufficient quantity of the compounds of formula I.

The background to the present invention

During embryonic development of the hedgehog signaling pathway plays a significant role in many processes, such as control of cell proliferation, cell differentiation and tissue formation. However, the aberrant activity of the hedgehog signaling pathway, for example, as a result of increased activation may lead to the development of pathological conditions. In this regard, activation of the hedgehog pathway in tissues in adult subjects leads to the development of specific types of cancer, which include, but are not limited to the texts listed, cancer of the brain, muscles and skin, prostate cancer, medulloblastoma, pancreatic adenocarcinoma and small cell lung cancer. Increased activation of the hedgehog signaling pathway contributes to the pathology and/or symptomology of diseases. Accordingly, compounds that modulate the activity of the hedgehog signaling pathway, can be used as therapeutic agents for the treatment of these diseases.

Summary of the invention

The first object of the present invention provides compounds of formula I:

where

Y1and Y2independently selected from N and CR10where R10selected from the group comprising hydrogen, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy and-OXNR10aR10b, a R10aand R10bindependently selected from hydrogen and C1-C6of alkyl,

R1selected from the group consisting of cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, C6-C10aryl, dimethylamino, C1-C6alkylsulfanyl and C3-C8heteroseksualci, optionally containing as substituents up to 2 radicals C1-C6 alkyl,

R2and R5independently selected from the group including hydrogen, cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy and dimethylamino,

R3and R4independently selected from the group comprising hydrogen, halogen, cyano, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy and halogen(C1-C6)alkoxy, or R1and R2or R1and R5together with the phenyl to which they are attached, form a5-C10heteroaryl,

R6and R7independently selected from the group including hydrogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy and halogen(C1-C6)alkoxy, provided that R6and R7both signify hydrogen,

R8selected from the group comprising hydrogen, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy and halogen(C1-C6)alkoxy,

R9selected from-S(O)2R11, -C(O)R11, -OR11, -NR12aR12band R11where R11selected from the group including aryl, heteroaryl, cycloalkyl and heteroseksualci, R12aand R12bindependently selected from C1-C6of alkyl and hydroxy(C1-C6)alkyl,

while specified aryl, heteroaryl, cycloalkyl and heteroseksualci in the composition of R9not necessarily contain as substituents of 1 to 3 radicals independently selected from the group comprising C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, C6-C10aryl(C0-C4)alkyl, C5-C10heteroaryl(C0-C4)alkyl, C3-C12cycloalkyl and C3-C8heteroseksualci,

where specified killkenny Deputy in the composition of R9not necessarily contain as substituents of 1 to 3 radicals independently selected from the group comprising halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy and methylpiperazine,

and derivatives, N-oxides, prodrugs, protected derivatives, individual isomers and mixtures of isomers of these compounds and their pharmaceutically acceptable salt and solvate (e.g. hydrate).

The second object of the present invention features a pharmaceutical composition that includes a compound of formula I or a derivative thereof, N-oxides, individual isomers and mixtures of isomers of the compounds or its pharmaceutically acceptable salt in a mixture with one or more suitable table of what is not clear.

The third object of the present invention features a method of treating disease in an animal in which modulation of the activity of the hedgehog pathway prevents, inhibits or reduces the pathology and/or symptomology of the diseases, and this method lies in the fact that the animal is administered a therapeutically effective amount of the compounds of formula I or its derivative N-oxides, individual isomers and mixtures of isomers of the compounds or its pharmaceutically acceptable salt.

The fourth object of the present invention features the use of the compounds of formula I to obtain a medicinal product intended for the treatment of a disease in an animal in which the activity of the hedgehog pathway contributes to the pathology and/or symptomology disease.

The fifth object of the present invention proposes a method of producing compounds of formula I and derivatives, N-oxides, prodrugs, protected derivatives, individual isomers and mixtures of isomers of these compounds and their pharmaceutically acceptable salts.

Definition

The term "alkyl" alone or as part of other groups, for example, halogenoalkane and alkoxy means a radical with a straight or branched chain. With1-C4aloxi includes methoxy, ethoxy etc. Halogenated includes trifluoromethyl, pentafluoroethyl and so what.

The term "aryl" means a monocyclic or condensed bicyclic aromatic cyclic system containing from six to ten carbon atoms. For example, aryl means phenyl or naphthyl, preferably phenyl. The term "Allen" means a divalent radical derived from an aryl group.

The term "heteroaryl" means aryl, as defined above, where one or more atoms in the cycle are the heteroatom. For example, With5-C10heteroaryl includes at least 5 atoms, for example the specified number of carbon atoms, but these atoms can be replaced by a heteroatom.

Therefore, With5-C10heteroaryl includes pyridyl, indolyl, indazoles, honokalani, chinoline, benzofuranyl, benzopyranyl, benzothiophene, benzo[1,3]dioxol, imidazolyl, benzimidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl etc.

The term "cycloalkyl" means a saturated or partially unsaturated monocyclic, condensed bicyclic or bridged polycyclic system containing the specified number of atoms in the cycle. For example, With3-C10cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

The term "heteroseksualci" means cycloalkyl, as defined in this context in terms of the AI, that one or more of these carbon atoms in the cycle is replaced by a fragment selected from-O-, -N=, -NR-, -C(O)-, -S-, -S(O)- or-S(O)2-, where R is hydrogen, C1-C4alkyl or azatadine group. For example, With3-C8heteroseksualci used in this context to describe the compounds of the present invention, includes morpholino, pyrrolidinyl, pyrrolidinyl-2-it, piperazinil, piperidinyl, piperidinyl, 1,4-dioxa-8 azaspiro[4.5]Dec-8-yl, thiomorpholine, alfanumerajn, sulfonating etc.

The term "halogen" preferably means chlorine or fluorine, but also means bromine or iodine.

The term "acquired function hedgehog" means aberrant modification or mutation of a gene Ptc gene hedgehog or smoothened gene, or a decrease (or no) level of expression of the indicated gene that causes a phenotype, i.e. a phenomenon which usually occurs after contacting the cell with a hedgehog protein, such as aberrant activation of the hedgehog pathway. The term "acquired function" means the inability of the resulting Ptc gene to regulate the level of expression of Gli genes, such as Gli1, Gli2 and Gli3. The term "acquired function hedgehog"used in this context, also means any similar cellular phenotype (e.g., showing a surplus proliferation), which occurs due to edit the deposits in any part of the transmission signal hedgehog, including, without limitation, modification or mutation of the gene hedgehog. For example, the tumor cell with an abnormally high rate of cell proliferation due to activation of the hedgehog signaling pathway, characterized by the phenotype with the acquired function hedgehog, even if hedgehog gene in a given cell is neutrogenas form.

The term "lost function patched" means aberrant modification or mutation of a gene Ptc or decrease the level of expression of a specified gene that causes a phenotype, i.e. a phenomenon which usually occurs after contacting the cell with a hedgehog protein, such as aberrant activation of the hedgehog pathway. The term "lost function" means the inability of the resulting Ptc gene to regulate the level of expression of Gli genes, such as Gli1, Gli2 and Gli3.

The term "purchased Gli function" means aberrant modification or mutation of a gene Gli or increased level of expression of a specified gene that causes a phenotype, i.e. a phenomenon which usually occurs after contacting the cell with a hedgehog protein, such as aberrant activation of the hedgehog pathway.

The term "purchased smoothened function" means aberrant modification or mutation of a gene Smo or the increased expression of a specified gene that causes a phenotype, i.e. a phenomenon which usually prospect who comes after contacting the cell with a hedgehog protein, for example to aberrant activation of the hedgehog pathway.

The term "treatment" means a method of suppressing or reducing the intensity of the disease and/or related symptoms.

The present invention relates also to the opening, there is proposed a method of modulation of the transmission signal-regulated genes hedgehog, patched (Ptc), Gli and/or smoothened, in the presence of compounds of formula I.

Description of the preferred embodiments of the invention

In one embodiment, in compounds of formula I Y1and Y2selected from N and CR10where R10selected from the group comprising hydrogen, methyl, fluorine, chlorine, bromine, dimethylaminoethoxy and trifluoromethyl, R6and R7independently selected from the group comprising hydrogen, methyl, chlorine, fluorine, bromine, trifluoromethyl and methoxy, provided that R6and R7both signify hydrogen, a R8selected from the group comprising hydrogen, fluorine, chlorine, methyl and trifluoromethyl.

In another embodiment, R1selected from the group consisting of cyano, chlorine, fluorine, methyl, ethyl, tert-butyl, propyl, isobutyl, isopropyl, isopropoxy, butoxy, methoxy, dimethylamino, ethoxy, methylsulfonyl, phenyl, trifluoromethyl, triptoreline and piperazinil, optionally containing as substituents up to 2 radicals methyl, R2and R5independently selected from the group comprising hydrogen, chlorine, FPO is, cyano, methyl, trifluoromethyl, isopropoxy, methoxy, ethoxy, triptoreline and dimethylamino, a R3and R4independently selected from the group comprising hydrogen, chlorine, methyl, methoxy and cyano, or R1and R2or R1and R5together with the phenyl to which they are attached, form honokalani.

In another embodiment, R9selected from the group including-S(O)2R11, -OR11, -C(O)R11, -NR12aR12band R11where R11choose from a group that includes thiomorpholine, sulforophane, alfanumerajn, morpholine, cyclohexyl, phenyl, azepin-1-yl, 2-oxopiperidin-1-yl, 1,4-oxazepan-4-yl, piperidine-1-yl, tetrahydro-2H-Piran-4-yl, piperidine-3-yl, piperazinil, pyrrolidinyl and 1,4-diazepan-1-yl, R12aand R12bindependently selected from isobutyl and hydroxyethyl where specified thiomorpholine, sulforophane, alfanumerajn, morpholine, cyclohexyl, phenyl, azepin-1-yl, 2-oxopiperidin-1-yl, 1,4-oxazepan-4-yl, piperidine-1-yl, tetrahydro-2H-Piran-4-yl, piperidine-3-yl, piperazinil, pyrrolidinyl or 1,4-diazepan-1-yl at R9not necessarily contain as substituents of 1 to 3 radicals independently selected from the group comprising methyl, ethyl, methoxy, benzyl, thienylmethyl, pyridinylmethyl, benzo[d][1,3]dioxol-6-yl and 2,3-dihydrobenzo[b][1,4]dioxin-7-yl, where the specified phenyl Il the benzyl substituent R 9not necessarily contain as substituents of 1 to 3 radicals independently selected from the group comprising methoxy, ethoxy, methylpiperazine, methyl, triptoreline, chlorine, fluorine and trifluoromethyl.

Preferred compounds of formula I are selected from the group comprising [4-(morpholine-4-sulfonyl)phenyl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid [6-(2,6-dimethylmorpholine-4-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 4'-cyano-2-methylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 4'-methoxy-2-methylbiphenyl-3-carboxylic acid (4-cyclohexylphenol)amide 4'-methoxy-2-methylbiphenyl-3-carboxylic acid [6-(2-methylmorpholin-4-yl)pyridine-3-yl]amide 4'-methoxy-2-methylbiphenyl-3-carboxylic acid (4-cyclohexylphenol)amide 4'-dimethylamino-2-methylbiphenyl-3-carboxylic acid (4-morpholine-4-ylphenyl)amide 4'-dimethylamino-2-methylbiphenyl-3-carboxylic acid (6-[1,4]oxazepan-4-espiridion-3-yl)amide 6-chloro-4'-dimethylaminophenyl-3-carboxylic acid (6-morpholine-4-espiridion-3-yl)amide 6-chloro-4'-dimethylaminophenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 6-chloro-4'dimethylaminophenyl-3-carboxylic acid [6-(2-methylmorpholin-4-yl)pyridine-3-yl]amide of 6-chloro-4'-methoxybiphenyl-3-carboxylic acid (6-[1,4]oxazepan-4-espiridion-3-yl)amide 6-chloro-4'-methoxybiphenyl-3-carboxylic acid (6-azepin-lipiridy-3-yl)amide 6-chloro-4'-methoxybiphenyl-3-carboxylic acid, (6-morpholine-4-espiridion-3-yl)amide 6-chloro-4'-methoxybiphenyl-3-carboxylic acid (6-morpholine-4-espiridion-3-yl)amide 4'-methoxy-6-methylbiphenyl-3-carboxylic acid (6-[1,4]oxazepan-4-espiridion-3-yl)amide 4'-methoxy-6-methylbiphenyl-3-carboxylic acid [6-(2-methylmorpholin-4-yl)pyridine-3-yl]amide 4'-methoxy-6-methylbiphenyl-3-carboxylic acid [6-(2-methylmorpholin-4-yl)pyridine-3-yl]amide 4'-dimethylamino-6-methylbiphenyl-3-carboxylic acid (6-[1,4]oxazepan-4-espiridion-3-yl)amide 4'-dimethylamino-6-methylbiphenyl-3-carboxylic acid (6-morpholine-4-espiridion-3-yl)amide 4'-dimethylamino-6-methylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 4'-methoxy-6-methylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 4'-ethoxy-6-methylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 6-methyl-4'-methylsulfinylphenyl-3-carboxylic acid (6-ASEAN-1-espiridion-3-yl)amide 4'-dimethylamino-6-methylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 6-methyl[1,1';4',1"]terphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 3'-chloro-6-methylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 2',4'-dichloro-6-methylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 2'-chloro-6-methylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 3'-chloro-6-methylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 3',4'-dichloro-6-methylbiphenyl-3 car is about acid, (6-azepin-1-espiridion-3-yl)amide 3'-chloro-6-methyl-4'-triptorelin-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 6,4'-dimethylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 4'-ethyl-6-methylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide of 4'-tert-butyl-6-methylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 6-methyl-4'-propylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 4'-isobutyl-6-methylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 4'-isopropyl-6-methylbiphenyl-3-carboxylic acid, (6-azepin-1-espiridion-3-yl)amide 6,2',6'-trimethylphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 6,2',3'-trimethylphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 6-methyl-4'-triptorelin-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 6-methyl-3'trifloromethyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 6-methyl-3',5'-bis-triptorelin-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 3'-isopropoxy-6-methylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 3'-ethoxy-6-methylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 2',6'-dimethoxy-6-methylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 6-methyl-4'-cryptomaterial-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 6-methyl-3'-cryptomaterial-3-carboxylic KIS is the notes, (4-morpholine-4-ylphenyl)amide 6-methylbiphenyl-3-carboxylic acid (4-morpholine-4-ylphenyl)amide 4'-methoxy-6-methylbiphenyl-3-carboxylic acid (4-morpholine-4-ylphenyl)amide 3'-methoxy-6-methylbiphenyl-3-carboxylic acid (4-morpholine-4-ylphenyl)amide 4'-(2-dimethylaminoethoxy)-6-methylbiphenyl-3-carboxylic acid (4-morpholine-4-ylphenyl)amide 3'-dimethylamino-6-methylbiphenyl-3-carboxylic acid (4-morpholine-4-ylphenyl)amide 4'-fluoro-6-methylbiphenyl-3-carboxylic acid (4-morpholine-4-ylphenyl)amide 3'-fluoro-6-methylbiphenyl-3-carboxylic acid (4-morpholine-4-ylphenyl)amide 2'-fluoro-6-methylbiphenyl-3-carboxylic acid, 4-methyl-N-(4-morpholine-4-ylphenyl)-3-cinoxacin-6-ylbenzene, (4-morpholine-4-ylphenyl)amide 6-methyl-4'-(4-methylpiperazin-1-yl) - biphenyl-3-carboxylic acid (4-morpholine-4-ylphenyl)amide 2'-cyano-6-methylbiphenyl-3-carboxylic acid (4-morpholine-4-ylphenyl)amide 3'-cyano-6-methylbiphenyl-3-carboxylic acid (6-[1,4]oxazepan-4-espiridion-3-yl)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid [6-(2-methylmorpholin-4-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid (3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid (6-morpholine-4-elpidia-3-yl)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid [6-(4-methylpiperazin-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carbon is howling acid, (4-morpholine-4-ylphenyl)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid (3-fluoro-4-morpholine-4-ylphenyl)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid (3-chloro-4-morpholine-4-ylphenyl)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid (3-bromo-4-morpholine-4-ylphenyl)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid (3-methyl-4-morpholine-4-ylphenyl)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid (4-morpholine-4-yl-3-triptoreline)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid (4-cyclohexylphenol)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid, biphenyl-4-alamid 4'-cyano-6-methylbiphenyl-3-carboxylic acid (4'-methoxybiphenyl-4-yl)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid, [4-(4-benzylpiperazine-1-yl)phenyl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid, [4-(piperidine-1-sulfonyl)phenyl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid, [4-(pyrrolidin-1-sulfonyl)phenyl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 4'-cyano-6-methoxybiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 4'-cyano-2-methoxybiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 4'-cyano-2-methylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 3'-fluoro-4'-methoxy-6-methylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 4'-isopropoxy-6-methylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 4'-butoxy-methylbiphenyl-3-carboxylic acid, (6-azepin-1-espiridion-3-yl)amide 3'-chloro-4'-methoxy-6-methylbiphenyl-3-carboxylic acid (6-azepin-1-espiridion-3-yl)amide 4'-methoxy-6,3'-dimethylbiphenyl-3-carboxylic acid, [4-(piperidine-1-sulfonyl)phenyl]amide 4'-cyano-2-methylbiphenyl-3-carboxylic acid, [4-(piperidine-1-sulfonyl)phenyl]amide 4'-cyano-6-forbiden-3-carboxylic acid, [4-(piperidine-1-sulfonyl)phenyl]amide of 6-bromo-4'-cyanobiphenyl-3-carboxylic acid [6-(4-benzyl[1,4]diazepan-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid [6-(4-thiophene-3-ylmethyl[1,4]diazepan-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid [6-(2,6-dimethylmorpholine-4-yl)pyridine-3-yl]amide 4'-cyano-2-methylbiphenyl-3-carboxylic acid [6-(2,6-dimethylmorpholine-4-yl)pyridine-3-yl]amide 4'-methoxy-2-methylbiphenyl-3-carboxylic acid [6-(2,6-dimethylmorpholine-4-yl)pyridine-3-yl]amide of 2-methyl-4'-triptorelin-3-carboxylic acid [6-(2,6-dimethylmorpholine-4-yl)pyridine-3-yl]amide of 2-methyl-4'-cryptomaterial-3-carboxylic acid [6-(2-methylmorpholin-4-yl)pyridine-3-yl]amide 4'-cyano-2-methylbiphenyl-3-carboxylic acid, [4-(piperidine-1-sulfonyl)phenyl]amide 4'-cyano-2-forbiden-3-carboxylic acid, [4-(piperidine-1-sulfonyl)phenyl]amide 4'-cyano-6-triptorelin-3-carboxylic acid [6-(4-pyridin-4-ylmethyl[1,4]diazepan-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid [6-(4-pyridine-3-ylmethyl[1,4]diazep the n-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid, {6-[4-(2,6-dimethoxybenzyl)[1,4]diazepan-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid {6-[4-(2-ethoxybenzyl)[1,4]diazepan-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid (6-{4-[2-(4-methylpiperazin-1-yl)benzyl][1,4]diazepan-1-yl}pyridine-3-yl)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid {6-[4-(4-methoxy-2,3-dimethylbenzyl)[1,4]diazepan-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid {6-[4-(2,3-dihydrobenzo[1,4] dioxin-6-ylmethyl)[1,4] diazepan-1-yl]pyridine-3-yl} amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid [6-(4-pyridine-2-ylmethyl[1,4]diazepan-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid [6-(4-benzo[1,3]dioxol-4-ylmethyl[1,4]diazepan-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid {6-[4-(2-cryptomaterial)[1,4] diazepan-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid {6-[4-(2-dimethylaminobenzoyl)[1,4]diazepan-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid {6-[4-(2-chloro-5-trifloromethyl)[1,4]diazepan-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid {6-[4-(2,3-diferensial)[1,4]diazepan-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid {6-[4-(2-chloro-4-terbisil)[1,4]diazepan-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid {6-[4-(2,6-diferensial)[1,4]diazepan-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbutan the l-3-carboxylic acid, [4-(piperidine-1-sulfonyl)phenyl]amide of 2-chloro-4'-cyanobiphenyl-3-carboxylic acid [6-(2,6-dimethylmorpholine-4-yl)pyridine-3-yl]amide 4'-cyano-6-triptorelin-3-carboxylic acid [6-(2,6-dimethylmorpholine-4-yl)pyridine-3-yl]amide of 2-chloro-4'-cyanobiphenyl-3-carboxylic acid [6-(2,6-dimethylmorpholine-4-yl)pyridine-3-yl]amide 4'-cyano-6-ethylbiphenyl-3-carboxylic acid {6-[4-(3-terbisil)piperazine-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid {6-[4-(2-cryptomaterial)piperazine-1-yl]pyridine-3-yl} amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid, {6-[4-(3-Chlorobenzyl)piperazine-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid {6-[4-(4-isobutylphenyl)piperazine-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid {6-[4-(4-tert-butylbenzyl)piperazine-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid {6-[4-(7-methoxybenzo[1,3]dioxol-5-ylmethyl)piperazine-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid [6-(4-benzylpiperazine-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid, [6-(4-pyridine-3-iletileri-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid {6-[4-(4-deformational)piperazine-1-yl] pyridine-3-yl} amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid {6-[4-(4-cyanobenzyl)piperazine-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid [6-(4-x is the nolin-5-iletileri-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid, [6-(4-pyridin-4-iletileri-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid [6-(4-pyridine-2-iletileri-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid {6-[4-(4-imidazol-1-ylbenzyl)piperazine-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid {6-[4-(3-cyanobenzyl)piperazine-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid [6-(4-isoquinoline-5-iletileri-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid, (R)-2-methyl-N-(6-(2-methylmorpholine)pyridine-3-yl)-4'-(triptoreline)biphenyl-3-carboxamide, 4'-cyano-2-methyl-N-(6-sulfonilmorpholid-3-yl)biphenyl-3-carboxamide, (S)-4'-cyano-2-methyl-N-(6-(2-methylmorpholine)pyridine-3-yl)biphenyl-3-carboxamide, (R)-6-chloro-N-(6-(2 methylmorpholine)pyridine-3-yl)-4'-(triptoreline)biphenyl-3-carboxamide, 4'-cyano-2-methyl-N-(6-sulfidecontaining-3-yl)biphenyl-3-carboxamide, 4'-cyano-N-(6-(diisobutylamine)pyridine-3-yl)-2-methylbiphenyl-3-carboxamide, 4'-cyano-N-(2-((2S,6R)-2,6-dimethylmorpholine)pyrimidine-5-yl)-2-methylbiphenyl-3-carboxamide, N-(2-((2S,6R)-2,6-dimethylmorpholine)pyrimidine-5-yl)-2-methyl-4'-(trifluoromethyl)biphenyl-3-carboxamide, N-(2-((2S,6R)-2,6-dimethylmorpholine)pyrimidine-5-yl)-2-methyl-4'-(triptoreline)biphenyl-3-carboxamide, N-(2-(bis(2-hydroxyethyl)amino)pyrimidine-5-yl)-2-methyl-4'-(triptoreline)biphenyl-3-carboxamide, 2-methyl-N-(6-(tetrahydro-2H-Piran-4-ilok and)pyridine-3-yl)-4'-(triptoreline)biphenyl-3-carboxamide, N-(5-chloro-6-((2S,6R)-2,6-dimethylmorpholine)pyridine-3-yl)-2-methyl-4'-(triptoreline)biphenyl-3-carboxamide, N-(6-((2R,6S)-2,6-dimethylether-2H-Piran-4-yl)pyridine-3-yl)-2-methyl-4'-(triptoreline)biphenyl-3-carboxamide, N-(6-(4-ethylpiperazin-1-carbonyl)pyridin-3-yl)-2-methyl-4'-(triptoreline)biphenyl-3-carboxamide, 2-methyl-N-(6-(2-oxopiperidin-1-yl)pyridine-3-yl)-4'-(triptoreline)biphenyl-3-carboxamide, 2-methyl-N-(6-(1-(pyridine-4-ylmethyl)piperidine-4-yl)pyridine-3-yl)-4'-(triptoreline)biphenyl-3-carboxamide, 2-methyl-N-(6-(2-oxo-4-(pyridine-4-ylmethyl)piperazine-1-yl)pyridine-3-yl)-4'-(triptoreline)biphenyl-3-carboxamide, 2-methyl-R-(6-(1-(pyridine-4-ylmethyl)piperidine-3-yl)pyridine-3-yl)-4'-(triptoreline)biphenyl-3-carboxamide, N-(6-(1-ethylpiperidine-3-yl)pyridine-3-yl)-2-methyl-4'-(triptoreline)biphenyl-3-carboxamide and N-(6-((2R,6S)-2,6-dimethylmorpholine)pyridine-3-yl)-2-methyl-4'-(triptoreline)biphenyl-3-carboxamide.

Therefore, it should be noted that the compounds of formula I, which affect the activity of the transmission path of the signal hedgehog, Ptc, or smoothened, similarly, can inhibit the proliferation (or other biological phenomena) in normal cells and/or cells containing the phenotype with the lost patched function, the phenotype with the acquired function hedgehog, the phenotype with the acquired function or smoothened phenotype with acquired Gli function. In this regard, in certain embodiments is sushestvennee of the present invention, these compounds can be used for inhibiting the activity of hedgehog in normal cells, in which, for example, is not a genetic mutation, an activating path hedgehog. In preferred embodiments, the compounds inhibit at least some types of biological activity of hedgehog proteins, i.e. preferably exhibit specificity in target cells.

In this regard, the methods of the present invention include the use of compounds of the formula I, which exhibit agonistic activity against inhibition of Ptc in signaling pathways hedgehog, for example, by inhibiting the activation of components or smoothened the following components of the cascade hedgehog signaling pathway in the regulation of regeneration and/or functional efficiency of many types of cells, tissues and organs, including normal cells, tissues and organs, and cells, tissues and organs containing the phenotype with the lost function of Ptc phenotype with acquired function hedgehog, the phenotype with the acquired function or smoothened phenotype with acquired Gli function. For example, the method object of the present invention can be used in therapeutic and cosmetic purposes that include the regulation of formation and capacity nerve, bone and cartilage tissues, regulation of spermatogenesis, regulation of smooth muscle, regulation of lung, liver and other organs originating from archenteron, regulation of hematopoietic function, regulation of growth of skin and hair, etc. is moreover, ways objects can be accomplished with the use of cell cultures in vitro or animal cells in the body (in vivo).

In another embodiment, the method object of the present invention is that the process of epithelial cells containing the phenotype with the lost function of Ptc phenotype with acquired function hedgehog, the phenotype with the acquired function or smoothened phenotype with acquired Gli function. For example, the method consists in the fact that they are carrying out the treatment or prevention of basal-cell cancer or other disorders associated with by hedgehog.

In some embodiments, the compound of formula I inhibits the activation of the hedgehog pathway by binding to protein smoothened or with the following proteins of the cascade of signaling pathways hedgehog. In some embodiments, the analyzed antagonist inhibits the activation of the hedgehog pathway by binding to protein patched.

In another preferred variant of the method, the object can be used to treat malignant Protocol and other primary malignant neuroectodermal tumors of the Central nervous system as one of the courses of treatment.

Another object of the present invention offers pharmaceutical preparations comprising as active ingredient a modulator of hedgehog signaling pathway, such as the compound of formula I, the Ptc agonist, antagonist or smoothened antagonist of the following proteins is asked signaling pathways hedgehog, as described in this context, in an amount sufficient for inhibition of in vivo proliferation or other biological effects associated with the phenotype with the lost function of Ptc phenotype with acquired function hedgehog, the phenotype with the acquired function or smoothened phenotype with acquired Gli function.

The claimed methods of treatment using the compounds of formula I, agonists patched, smoothened antagonists or antagonists of the following components of the cascade of signaling pathways hedgehog are effective against humans and animals. Animals that can be treated by the methods of the present invention, include Pets and farm animals. Examples include dogs, cats, cattle, horses, sheep, pigs and goats.

Pharmacology and industrial applicability

The present invention provides methods and compounds designed for inhibiting activation of the hedgehog signaling pathway, for example, to suppress aberrant state growth-related phenotypes, such as the phenotype with the lost function of Ptc phenotype with acquired function hedgehog, the phenotype with the acquired function or smoothened phenotype with acquired Gli function, and these methods lies in the fact that the cell is in contact with a number of the compounds of formula I sufficient to agonistic actions agains the normal activity of the Ptc, antagonistic action with respect to the normal activity of the hedgehog, smoothened activity or activity of Gli, for example, for a full treatment or control the aberrant state of growth.

Members of the family of molecules signal Hedgehog mediates many important short-term and long-term processes in the formation of tissues and organs in vertebrate development. The formation of tissues and organs associated with the activity, which contributes to the development of organized space structures of differentiated tissue from embryonic cells. Complex physical higher organisms develop during embryogenesis in the process of interaction of the sequence of cell generations with extracellular signals. Induction interactions play an important role in the process of tissue formation during vertebrate development, starting from the early stages of forming a circuit of the body prior to the formation of organ systems, the formation of various cell types during differentiation of tissues. The influence of interactions of developing cell changes: reactive cells are switched from one path cell differentiation on a different path due to induction of the cells, a condition which differs from reinducing and induced States of reactive cells (stage induction). In some cases, the cells induce differentiation neighbouring the x cells, similar self-differentiation (golograficheskaya induction), in other cases, the cell inhibits the differentiation of neighboring cells, similar to their own. Interaction of cells at early stages of development can be consistent, for example, the initial induction between the two cell types leads to progressive amplification varieties. In addition, induction interactions occur not only in the embryo, but also in cells of the adult subjects and may contribute to the development and maintenance of morphogenetic types, as well as to induce differentiation.

The family of hedgehog genes of vertebrates consists of three known mammalian gene: genes Desert (Dhh) hedgehog, Sonic (Shh) hedgehog and Indian (Ihh) hedgehog encoding secreted proteins. These various hedgehog proteins consist of a signal peptide, a highly conservative N-terminal domain and a more variable C-terminal domain. Biochemical tests indicate that autoproteolytic the decomposition of the protein-predecessor hedgehog occurs when the formation of an intermediate internal tiefer, which is then cleaved in nucleophilic substitution. Assume that the nucleophile is a low molecular weight lipophilic molecule, which forms a covalent bond with the C-terminal fragment of N-peptide and attaches it to a surface the STI cell, which leads to significant biological consequences. As a result of this joining surface of the cells that produce the hedgehog, increases the local concentration of the N-terminal peptide hedgehog, which is necessary and sufficient for short-term and long-term activity of the hedgehog signaling pathway.

Inactivation of signaling pathways hedgehog occurs when the receptor is a transmembrane protein Patched (Ptc) inhibits the activity of protein Smoothened (Smo), the seventh transmembrane protein. The penetration of the transcription factor Gli, the next component in the cascade of signaling pathways hedgehog, the core is prevented through interactions with cytoplasmic proteins, including hybrid protein and suppressor hybrid protein (Sufu). In the inhibited transcriptional activation of target genes hedgehog. Activation of the pathway is initiated by binding of Ptc protein of any of the three ligands mammals (Dhh, Shh or Ihh). The binding of the ligand leads to suppression of Smo, this activates a cascade of reactions leading to the displacement of the active form of the transcription factor Gli in the core. Nuclear Gli activates expression of target genes, including genes Ptc and Gli.

Elevated levels of signal transmission hedgehog are sufficient to initiate cancer development and are necessary for survival of the tumor. These cancers is clucalc, without limitation, prostate cancer (Karhadkar, S. S., Bova, G. S., Abdallah n, Dhara, S., Gardner D., Maitra, A., Isaacs, J. T., D. M. Berman, P. A. Beachy, "Hedgehog signalling in prostate regeneration, neoplasia and metastasis", Nature, 431 (7009), cc. 707-712 (7 October 2004); P. Sanchez, A. M. Hernandez, Stecca C., Kahler, A. J., DeGueme A. M., Barrett, A., Beyna, M., Datta, M. W., Datta, S., Ruiz i Altaba A., "Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling", Proc. Natl. Acad. Sci USA, 101 (34), cc. 12561-12566 (24 August 2004)), breast cancer (Kubo M, Nakamura M, Tasaki, A., Yamanaka N., Nakashima, H., Nomura, M., Kuroki, S., Katano M., "Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer", Cancer Res., 64 (17), cc. 6071-6074 (1 September 2004)), medulloblastoma (Berman D. M., S. Karhadkar, S., Hallahan, A. R., Pritchard, J. I., Eberhart, C. G., Watkins, D. N., Chen, J. K., Cooper, M. K., Taipale J., Olson J. M., Beachy, P. A., "Medulloblastoma growth inhibition by hedgehog pathway blockade", Science, 297 (5586), 1559-1561 (30 August 2002)), basal cell carcinoma (Williams J. A., Guicherit, O. M, Zaharian C. I., Xu Y., Chai L., Wichterle, H., C. Kop, C. Gatchalian, Porter J. A., Rubin L. L., Wang F.Y., "Identification of a small molecule inhibitor of the hedgehog signaling pathway: effects on basal cell carcinoma-like lesions", Proc. Natl. Acad. Sci USA, 100 (8), cc. 4616-4621 (15 April 2003); Xie j, Murone m, Luoh, S. M., Ryan, A., Gu q, Zhang C, Bonifas, J. M., Lam, C. W., Hynes m, Goddard a, Rosenthal A., Epstein, E. H. Jr, de Sauvage F. J., "Activating Smoothened mutations in sporadic basal-cell carcinoma", Nature, 391 (6662), cc. 90-92 (1 January 1998)), pancreatic cancer (Thayer S. P., di Magliano, M. P., Heiser, P. W., Nielsen, C. M., Roberts D. J., Lauwers, G. Y., Qi Y. P., Gysin, S., Fernandez-del Castillo C, Yajnik V, Antoniu Century, McMahon m, Warshaw, A. L., Hebrok M., "Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis", Nature, 425 (6960), cc. 851-856 (23 October 2003); D. M. Berman, S. Karhadkar, S., Maitra, A., Montes De Oca, R., M. erstenblith R., Briggs K., Parker, A. R., Shimada Y., Eshleman, J. R., Watkins, D. N., P. A. Beachy, "Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours", Nature, 425 (6960), cc. 846-851 (23 October 2003)and small cell lung cancer (Watkins D. N., Berman, D. M., Burkholder, S. G., Wang C., Beachy, P. A., Baylin, S. C., "Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer" Nature, 422 (6929), cc. 313-317(20 March 2003)).

In accordance with the foregoing the present invention also proposes a method of prevention or treatment of any of the above diseases or disorders in a subject in need of such treatment, and this method lies in the fact that the specified subject is administered a therapeutically effective amount (see "Introduction and pharmaceutical compositions" below) the compounds of formula I or its pharmaceutically acceptable salt. For any of the above apply to the desired dosage change depending on the method of administration, the particular condition to be treated, and the desired action.

Introduction and pharmaceutical compositions

Mainly compounds of the present invention is administered in therapeutically effective amounts by any known standard and suitable ways, separately or in combination with one or more therapeutic agents. A therapeutically effective amount varies widely depending on the severity of the disease, age and individualno the health of the subject, the efficiency of the used connections and other factors. Basically found that satisfactory results are obtained with the systematic introduction of daily doses of from about 0.03 to 2.5 mg/kg of body weight. The specified daily dose for larger mammal, e.g. humans, is a value in the range from approximately 0.5 mg to approximately 100 mg, which is usually injected, for example, in divided doses up to four times per day, or in the form of delayed release. Suitable standard dosage forms for oral administration comprise from about 1 to 50 mg of active ingredient.

Compounds of the present invention is administered as pharmaceutical compositions by any standard method, first of all enteral, e.g. oral, for example, in the form of tablets or capsules, or parenterally way, for example, in the form of solutions or suspensions for injection, local way, for example, in the form of lotions, gels, ointments or creams, or in a nasal form or in the form of suppositories. Pharmaceutical compositions comprising the compound of the present invention in free form or in the form of pharmaceutically acceptable salts in the mixture, at least one pharmaceutically acceptable carrier or diluent, get a standard method of mixing, the pellet is tion or coating. For example, oral compositions receive in the form of tablets or gelatin capsules comprising the active ingredient in the mixture of a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, (b) oiling agents, for example silica, talc, stearic acid, magnesium stearate or calcium and/or polyethylene glycol, in the case of tablets also along with binders, such as magnesium aluminosilicate, starch paste, gelatin, tragakant, methylcellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone, if necessary g) with dezinfeciruyuhimi agents for example starches, agar, alginic acid or sodium alginate, or effervescent mixtures and/or e) absorbents, colorants, flavors and sweeteners. Compositions for injection include aqueous isotonic solutions or suspensions, and suppositories are obtained from emulsions or suspensions fats. The composition is sterilized and/or they include adjuvants, such as preservatives, stabilizing, wetting or emulsifying agents, agents to increase the solubility, salts for regulating osmotic pressure and/or buffer substances. In addition, these compositions also include other therapeutically valuable compounds. Suitable formulations for transdermal application include an effective amount of the compounds is of the present invention in a mixture with a carrier. The media contains absorbable pharmacologically acceptable solvents that increase the permeability through the skin of the host. For example, a device for percutaneous delivery is presented in the form of a bandage comprising a protective layer, a reservoir containing the compound optionally in a mixture with the media, optional layer that controls the delivery rate of the compound to the skin of the host-controlled and certain speed for a long period of time, as well as a layer for bonding the device to the skin. You can also use matrix percutaneous formulations. Suitable formulations for topical application, for example to the skin and eyes, preferably include known aqueous solutions, ointments, creams or gels. These compositions include soljubilizatory, stabilizers, agents for increasing toychest, buffering agents and preservatives.

Compounds of the present invention can be introduced in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combination). For example, a synergistic effect is achieved in the mixture with immunomodulatory or anti-inflammatory compounds or other cancer therapeutic agents. If the compounds of the present invention is administered along with other drugs, dosiro and together input connections change depending on the type jointly used drugs, specificity of action of the applied drugs, the condition to be treated, etc.

In the present invention are also pharmaceutical combination, e.g. a kit, comprising a) a first agent which is a compound of the present invention, as described in this context, in free form or in the form of pharmaceutically acceptable salts and b) at least one joint agent. The set includes instructions for implementation.

Used in this context, the terms "co-administration" or "combined introduction" or the like mean the introduction of selected therapeutic agents to a single patient and include treatments in which agents do not necessarily impose the same method of administration or at the same time.

Used in this context, the term "pharmaceutical combination" means a product that is obtained by mixing or combining 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 joint agent, is administered to a patient simultaneously in the form of one form or dosage. The term "non-fixed combination" means that the active ingredients, for example link the formula I and joint agent, administered to a patient as separate forms together, simultaneously or sequentially without any special time constraints, and this introduction provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to the combined treatment, for example the introduction of three or more active ingredients.

Methods for obtaining compounds of the present invention

The present invention also includes methods of making compounds of the present invention. In the above reactions it is necessary to protect reactive functional groups, for example hydroxy group, amino, imino, thio or carboxy, if the presence of these groups is required in the final product, in order to exclude unwanted participation of these groups in the reactions. Standard protective groups used in accordance with standard practice, for example, see Greene, T. W. and Wuts P. G. M., "Protective Groups in Organic Chemistry", John Wiley and Sons (1991).

The compounds of formula I get reactions presented in scheme I:

where Y1, Y2, R1, R2, R3, R4, R5, R6, R7, R8and R9have the meanings as defined for formula I in the section "Summary of the invention". The compound of formula I receive when interacting with the organisations of the formula 2 (or 2') with the compound of the formula 3 in the presence of a suitable solvent (for example, dichloromethane, N,N-dimethylformamide or the like) at a temperature of from about -20°to about 100°C. To complete the reaction takes approximately 20 hours

Detailed examples of methods for producing compounds of formula I are given in the "Examples" section below.

Additional methods of producing compounds of the present invention

The compound of the present invention receive in the form of a pharmaceutically acceptable acid salt additive in the interaction of the compounds in free base form with a pharmaceutically acceptable inorganic or organic acid. In another embodiment, a pharmaceutically acceptable basic additive salt of the compound of the present invention receive when interacting compounds in the form of the free acid with a pharmaceutically acceptable inorganic or organic base.

In another embodiment, the salts of the compounds of the present invention is obtained using salts of the source or intermediate compounds.

Compounds of the present invention in the form of free acid or free base form is obtained from the compounds in the form of a basic additive salt or acid salt additive, respectively. For example, the compound of the present invention in the form of an acid additive salt is converted into the corresponding compound in the form of free is th reason when processing suitable base (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 salt is converted into the corresponding compound in the form of the free acid in the processing of suitable acid (e.g. hydrochloric acid, and the like).

Compounds of the present invention in non-oxidized form is obtained from N-oxides of the compounds of the present invention when processing a reducing agent (for example, sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, trichloride phosphorus, tribromide phosphorus or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at a temperature of from 0 to 80°C.

Derivative prodrugs of the compounds of the present invention receive by known methods (for more information, see, for example, article Saulnier and others, Bioorganic and Medicinal Chemistry Letters, v.4, s (1994)). For example, appropriate prodrugs get in the interaction of the initial compounds of the present invention with suitable carbamimidoyl agent (for example, 1,1-aryloxyalkanoic, para-nitrophenylarsonic or the like).

Protected derivatives of compounds of the present invention receive by known methods. Detailed description of methods suitable for introducing protective groups and their removal are listed in the CED is E. T. Greene W., "Protecting Groups in Organic Chemistry", 3eed., John Wiley and Sons, Inc. (1999).

Compounds of the present invention receive the standard ways or methods of the present invention in the form of a solvate (e.g. hydrate). Hydrates of the compounds of the present invention are usually obtained by recrystallization from a mixture of water/organic solvent with the use of organic solvents, such as dioxane, tetrahydrofuran or methanol.

Compounds of the present invention obtained as individual stereoisomers in the interaction of racemic mixtures of compounds with optically active permissive agent with the formation of a pair of diastereomers, separating the diastereomers and the allocation of optically pure enantiomers. Although the separation of enantiomers carried out using covalent diastereomeric derivatives of the compounds of the present invention, the preferred dissociable complexes (for example, a crystalline salt of diastereomers). The diastereomers are characterized by different physical properties (e.g. melting point, boiling point, solubility, reactivity, and so on), and they can be divided in accordance with these differences. The diastereomers can be separated by chromatography or preferably by the method of separation according to differences in Rast is ariosti. Then produce optically pure enantiomer, along with the allow agent by any known method which does not cause racemization. A more detailed description of methods suitable for separation of the stereoisomers of the compounds of the present invention from a racemic mixture, given in the book Jacques, J., Collet, A., Wilen, S. H., "Enantiomers, Racemates and Resolutions)), John Wiley and Sons, Inc. (1981).

Basically, the compounds of formula I get way, which is that:

(a) carry out the reaction presented in scheme I, and

(b) does not necessarily make the connection according to the present invention in pharmaceutically acceptable salt,

(in) does not necessarily make the connection according to the present invention in the form of a salt compound according to the present invention in mesolevel form

(g) does not necessarily make the connection according to the present invention in non-oxidized form, pharmaceutically acceptable N-oxide,

(d) does not necessarily make the connection according to the present invention in the form of N-oxide in the compound of the present invention in non-oxidized form,

(e) optional allocate individual isomer of the compounds of the present invention from a mixture of isomers.

Examples

The present invention is illustrated, without limitation, the following examples, which describe the formation of compounds of the formula I according to present the invention.

Example 1

[4-(Morpholine-4-sulfonyl)phenyl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid

Stage 1

To a solution of 3-iodine-4-methylbenzoic acid (10.0 g, 38.2 mmole) in methanol (70 ml) was added concentrated sulfuric acid (0.5 in). The reaction mixture was heated at 70°C for 48 hours, cooled to CT and concentrated. Then to the residue was added ethyl acetate (100 ml) and an aqueous solution of NaHCO3(feast upon., 100 ml). The organic layer was separated and washed again in an aqueous solution of NaHCO3(feast upon., 100 ml). The organic layer was separated, dried over anhydrous Na2SO4and concentrated, to receive the methyl ester of 3-iodine-4-methylbenzoic acid 1, which was used in the next stage without additional purification.

1H NMR (400 MHz, DMSO-d6): δ (ppm million) 8,31 (s, 1H), 7,87 (d, 1H, J 8,4 Hz), of 7.48 (d, 1H, J 8,4 Hz), 3,85 (s, 3H), at 3.35 (s, 3H). LC-MS: (m/z) 277,0 (M+1).

Stage 2

In a round bottom flask containing methyl ester of 3-iodine-4-methylbenzoic acid (1,38 g, 5,00 mmole), 4-cyanoaniline acid (1.10 g, of 7.48 mmole), palladium acetate (168 mg, 0,748 mmole), 2-(dicyclohexylphosphino)biphenyl (0,526 g, 1.50 mmole) and potassium fluoride (0,870 g of 15.0 mmole), was added anhydrous 1,4-dioxane (15 ml). The flask was purged with argon and closed. The mixture was stirred at 130°C for 18 h, cooled to CT and was added water (20 ml) and ethyl acetate (20 ml)Tordue substance was removed by filtration under vacuum. The filtrate was extracted with EtOAc (20 ml × 2). The organic layers were combined, washed with aqueous solution of Hcl (5%, 20 ml) and a saturated solution of NaHCO3(20 ml), dried over MgSO4and concentrated. The residue was purified column chromatography on silica gel (eluent: gradient EtOAc/hexane), thus instructed methyl ether 4'-cyano-6-methylbiphenyl-3-carboxylic acid 2, LC-MS: m/z 252,1 (M+1).

Stage 3

To a solution of methyl ester 4'-cyano-6-methylbiphenyl-3-carboxylic acid 2 (2,56 g, 10.3 mmole) in 1,4-dioxane/N2About (1:1, 20 ml) was added NaOH (1.22 g, 30.2 mmole). The reaction mixture was stirred at RT for 24 h, then was added an aqueous solution of HCl (1N., 36 ml) and was extracted with ethyl acetate (40 ml × 3). The organic layers were combined and dried over anhydrous Na2SO4the solvent was removed. The obtained solid substance was washed with a small amount of acetonitrile and dried in the air, it was obtained 4'-cyano-6-methylbiphenyl-3-carboxylic acid 3.

1H NMR (DMSO-d6): δ (ppm million) 7,94 (d, 2 H, J 8.0 Hz), to 7.84 (dd, 1 H, J, and 8.4 Hz, J21.2 Hz), of 7.75 (d, 1 H, J 1.2 Hz), to 7.61 (d, 2 H, J 8.0 Hz), of 7.48 (d, 1 H, J 8,4 Hz)to 2.29 (s, 3 H). LC-MS: m/z 238,1 (M+1).

Stage 4

To a suspension of 4'-cyano-6-methylbiphenyl-3-carboxylic acid 3 (40 mg, 0.17-mmole) in anhydrous methylene chloride (5 ml) was added 2 drops of DMF and oxalicacid (32 mg, 22 μl, 0.25 mmole). The mixture was stirred at RT before the formation of transp is knogo solution. Then the mixture was concentrated again was dissolved in anhydrous methylene chloride (3 ml) and added to a solution of 4-(morpholine-4-sulfonyl)phenylamine (61 mg, 0.25 mmole) and triethylamine (34 mg, 47 μl, of 0.33 mmole) in methylene chloride (2 ml). The mixture was stirred for 2 h, concentrated and the residue was purified preparative MS-GHUR (column18, eluent: CH3CN/H2O, containing 0.05% TFU), it was received [4-(morpholine-4-sulfonyl)phenyl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid.

1H NMR (DMSO-d6): δ (ppm million) at 10.64 (s, 1H), 8,07 (d, 2H, J is 8.8 Hz), of 7.97 (d, 2H, J 8,4 Hz), 7,95 (d, 1H, J is 8.8 Hz), 7,89 (s, 1H), 7,43 (d, 2H, J 8,4 Hz), to 7.67 (d, 2H, J is 8.8 Hz), 7,53 (d, 2H, J is 8.8 Hz), 3,63 (m, 4H), 2,84 (m, 4H) 2,32 (s, 3H)). LC-MS: m/z 462,1 (M+1).

Example 2

[6-(2,6-Dimethylmorpholine-4-yl)pyridine-3-yl]amide of 4,-cyano-6-methylbiphenyl-3-carboxylic acid

Stage 1

To a solution of 2-chloro-5-nitropyridine 4 (2.38 g, 15 mmol) and CIS-2,6-dimethylmorpholine (1.73 g, 15 mmol) was added To a2CO3(to 4.14 g, 30 mmol). The mixture was heated at 50°C during the night. After concentration the residue was distributed between EtOAc and water. The EtOAc layer was dried over anhydrous Na2SO4and concentrated, to receive the crude product 6 in the form of a solid yellow color. The crude product was used in the next stage without additional purification. LC-MS: m/z 238,1 (M+1).

Stage 2

Obtained in the previous phase of the crude product 6 was first made in the presence of Pd/C (0.2 g) in Meon (100 ml) in an atmosphere of hydrogen for 10 hours, the Suspension was filtered through celite and the filtrate was concentrated, it was obtained the crude product 7 in the form of oil, dark brown color, which is used in the next stage without additional purification. LC-MS: m/z 208,1 (M+1).

Stage 3

To a solution of 3-bromo-4-methylbenzoic acid (108 mg, 0.5 mmole), 6-(2,6-dimethylmorpholine-4-yl)pyridine-3-ylamine 7 (104 mg, 0.5 mmole) and HATU (190 mg, 0.5 mmole) in dry DMF (5 ml) was dropwise added triethylamine (139 μl, 1.0 mmole). The resulting mixture was stirred at RT for 2 h, after concentration the residue was distributed between EtOAc and water. The organic layer was dried and concentrated, to receive the crude product. The target compound was purified column Express chromatography, eluent: 50% EtOAc in hexane, to receive the connection 8 in a solid white color. LC-MS: m/z 404,1 (M+1).

Stage 4

A mixture of 4-cyanophenylacetic acid (18 mg, 0.12 mmole), 3-bromo-N-[6-(2,6-dimethylmorpholine-4-yl)pyridine-3-yl]-4-methylbenzamide 8 (40 mg, 0.1 mmole), Pd(PPh3)4(11 mg, 0.01 mmole) and Na2CO3(42 mg, 0.4 mmole) in a mixture of toluene (0.2 ml), water (0.2 ml) and ethanol (0.05 ml) was heated at 140°C. in a microwave reactor for 30 minutes, the Reaction mixture was diluted EOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layer was washed brine, and concentrated, to receive the crude product, which was purified preparative MS/GHUR (column18, eluent: CH3CN/H2O, containing 0.05% TFU), were obtained [6-(2,6-dimethylmorpholine-4-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid. LC-MS: m/z 427,2 (M+1).

The compounds of formula I, shown in the table were obtained as described above, but using the appropriate starting compounds.

Compounds of the present invention were analyzed and evaluated their ability to inhibit signaling pathway heghehog.

Determination of inhibitory activity against the way Hh using Porterage gene Gli-Luc

Cells of mice TM (American Type Culture Collection, ATSS, Manassas, VA) were maintained in DMEM/F12 (Gibco/Invitrogen, Carlsbad, CA)containing 5% horse serum, inactivated by heating, 2.5% ETS (Gibco/Invitrogen, Carlsbad, CA), 50 U./ml penicillin and 50 µg/ml streptomycin (Gibco/Invitrogen, Carlsbad, CA) at 37°C in an atmosphere of 5% CO2. Cells TMZ has transfectional reporter plasmid pTA-8xGli-Luc. Selected stable transfectional clone TMHh-12 with high response to the stimulation of Shh-n To determine the value of the IC50for antagonists, 8000 cells TMHh-12 was placed in each well of 384-well tablet containing environment 50% DMEM/F12 containing 2% ETS. After 12 h activated path Hh the addition of recombinant Shh protein mouse (expressed in E.coli, 8 µg/ml) or the addition of agonists (Smo). The investigated compounds were added to the plate at various concentrations. After 48 h, the luciferase activity of the fireflies was determined using the Bright-Glo™ for determining the activity of luciferase (Promega, Madison, WI). The value of the IC50was calculated by the concentration of the compound at which there is a decrease in fluorescent signal by 50%. The toxicity of these compounds was evaluated using cells to TMZ and reagent CellTiter Glo or cell line TM-Luc (cells TMZ, stable transfection constitutive expression vector luciferase).

Is EU50for connection of the Affairs of the formula I is preferably less than 500 nm, more preferably less than 200 nm.

Determination of cytotoxicity

Determination of cytotoxicity was performed to compare the activity of a compound of the present invention on the cells Protocol (Daoy cells), cells of the basal cell carcinoma (cell TECH) and control cells (normal human fibroblasts) using the following methods:

Daoy cells (cell line Protocol, ATSS) were cultured in medium Minimum essential medium (Eagle)containing 2 mm L-glutamine and environment Earle BSS, containing 1.5 g/l sodium bicarbonate, 0.1 mm nonessential amino acids, 1.0 mm sodium pyruvate and 10% ETS at 37°C in an atmosphere of 5% CO2.

Cells THAT ATSS) were cultured in medium Dulbecco modified medium Eagle containing 4 mm L-glutamine in ETS and 10% ETS.

Normal fibroblast cells of human skin (Clonetics) were cultured in medium Fibroblast Growth Medium (Clonetics).

Each of the above cell lines independently were cultivated in 96-well plates and cultured to a density of 5000-10000 cells in the well. The compound of the present invention at various concentrations was added to the cell culture. After 2 days, cell viability was evaluated using a set of reagents Cell Titer-Glo fluorescent assess the viability of the cells (Promega) according to the method of the manufacturer. Cell viability was evaluated directly when measure the fluorescent signal, an EC50was calculated by the concentration of the compound at which there is a decrease of the signal by 50%.

Is EU50for compounds of formula I is preferably less than 500 nm, more preferably less than 200 nm.

The person skilled in the art it is obvious that the examples and embodiments of the present invention described in this context, are presented only to illustrate the invention, and various modifications or changes that are included in the scope of the present invention. All references, patents and applications for patents, cited herein, are included in this description as a reference.

1. The compound of formula I:

where Y1and Y2independently selected from N and CR10where R10selected from the group comprising hydrogen, halogen, C1-C6alkyl, halogen(C1-C6)alkyl,
R1selected from the group including hydrogen, cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, dimethylamino, C1-C6alkylsulfanyl, dimethylaminoethoxy and piperazinil, substituted by up to 2 radicals C1-C6alkyl,
R2and R5independently selected from the group including hydrogen, cyano, Galaga is, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy and dimethylamino,
R3and R4independently selected from the group comprising hydrogen, halogen, cyano, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy,
or R1and R5together with the phenyl to which they are attached, form a C5-C10heteroaryl,
R6and R7independently selected from the group including hydrogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkyl, provided that R6and R7both signify hydrogen,
R8selected from the group comprising hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkoxy,
R9selected from-S(O)2R11, -C(O)R11, -NR12aR12band R11where R11selected from the group including aryl, cycloalkyl and heteroseksualci, R12aand R12bindependently selected from C1-C6of alkyl and hydroxy(C1-C6)alkyl,
while specified aryl, heteroaryl, cycloalkyl and heteroseksualci in the composition of R9not necessarily contain as substituents of 1 to 3 radicals independently selected from the group comprising C1-C6alkyl, halogen(C1-C6)and the keel, With1-C6alkoxy, halogen(C1-C6)alkoxy, C6-C10aryl(C0-C4)alkyl, C5-C10heteroaryl(C0-C4)alkyl, C3-C12cycloalkyl and C3-C8heteroseksualci,
where specified killkenny Deputy in the composition of R9not necessarily contain as substituents of 1 to 3 radicals independently selected from the group comprising halogen, cyano, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, dimethylamino and methylpiperazine,
as well as pharmaceutically acceptable salts, hydrates, solvate and isomers of the compounds.

2. The compound according to claim 1, where
Y1and Y2selected from N and CR10where R10selected from the group comprising hydrogen, methyl, chlorine, fluorine, bromine and trifluoromethyl,
R6and R7independently selected from the group comprising hydrogen, methyl, chlorine, fluorine, bromine, trifluoromethyl and methoxy, provided that R6and R7both signify hydrogen, and
R8selected from the group comprising hydrogen, fluorine, chlorine, methyl.

3. The compound according to claim 2, where R1selected from the group consisting of cyano, chlorine, fluorine, methyl, ethyl, tert-butyl, propyl, isobutyl, isopropyl, isopropoxy, butoxy, methoxy, dimethylamino, ethoxy, methylsulfonyl, trifluoromethyl, Tr is formatosi and piperazinil, containing as substituents up to 2 radicals methyl,
R2and R5independently selected from the group comprising hydrogen, chlorine, fluorine, cyano, methyl, trifluoromethyl, isopropoxy, methoxy, ethoxy, triptoreline and dimethylamino, and
R3and R4independently selected from the group comprising hydrogen, chlorine, methyl, methoxy and cyano, or R1and R5together with the phenyl to which they are attached, form honokalani.

4. The compound according to claim 3, where R9choose from a group that includes
-S(O)2R11, -C(O)R11, -NR12aR12band R11where R11choose from a group that includes thiomorpholine, sulforophane, alfanumerajn, morpholine, cyclohexyl, phenyl, azepin-1-yl, 2-oxopiperidin-1-yl, 1,4-oxazepan-4-yl, piperidine-1-yl, tetrahydro-2H-Piran-4-yl, piperidine-3-yl, piperazinil, pyrrolidinyl and 1,4-diazepan-1-yl, a R12aand R12bindependently selected from isobutyl, hydroxyethyl,
where specified thiomorpholine, sulforophane, alfanumerajn, morpholine, cyclohexyl, phenyl, azepin-1-yl, 2-oxopiperidin-1-yl, 1,4-oxazepan-4-yl, piperidine-1-yl, tetrahydro-2H-Piran-4-yl, piperidine-3-yl, piperazinil, pyrrolidinyl or 1,4-diazepan-1-yl at R9not necessarily contain as substituents of 1 to 3 radicals independently selected from the group comprising methyl, ethyl, met the XI, benzyl, thienylmethyl, pyridinylmethyl, benzo[d][1,3]dioxol-6-yl and 2,3-dihydrobenzo[b][1,4]dioxin-7-yl,
where specified phenyl or benzyl substituent in the R9not necessarily contain as substituents of 1 to 3 radicals independently selected from the group comprising methoxy, ethoxy, methylpiperazine, methyl, triptoreline, chlorine, fluorine and trifluoromethyl.

5. The compound according to claim 4, which is chosen from the group comprising N-(6-((2R,6S)-2,6-dimethylmorpholine)pyridine-3-yl)-2-methyl-4'-(triptoreline)biphenyl-3-carboxamide, [4-(morpholine-4-sulfonyl)phenyl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
[6-(2,6-dimethylmorpholine-4-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 4'-cyano-2-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 4'-methoxy-2-methylbiphenyl-3-carboxylic acid,
(4-cyclohexylphenol)amide 4'-methoxy-2-methylbiphenyl-3-carboxylic acid,
[6-(2-methylmorpholin-4-yl)pyridine-3-yl]amide 4'-methoxy-2-methylbiphenyl-3-carboxylic acid,
(4-cyclohexylphenol)amide 4'-dimethylamino-2-methylbiphenyl-3-carboxylic acid,
(4-morpholine-4-ylphenyl)amide 4'-dimethylamino-2-methylbiphenyl-3-carboxylic acid,
(6-[1,4]oxazepan-4-espiridion-3-yl)amide 6-chloro-4'-dimethylaminophenyl-3-carboxylic acid,
(6-morpholine-4-espiridion-3-yl)amide 6-chloro-4'-dimethylaminophenyl-3-carbon is th acid,
(6-azepin-1-espiridion-3-yl)amide 6-chloro-4'-dimethylaminophenyl-3-carboxylic acid,
[6-(2-methylmorpholin-4-yl)pyridine-3-yl]amide of 6-chloro-4'-methoxybiphenyl-3-carboxylic acid,
(6-[1,4]oxazepan-4-espiridion-3-yl)amide 6-chloro-4'-methoxybiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 6-chloro-4'-methoxybiphenyl-3-carboxylic acid,
(6-morpholine-4-espiridion-3-yl)amide 6-chloro-4'-methoxybiphenyl-3-carboxylic acid,
(6-morpholine-4-espiridion-3-yl)amide 4'-methoxy-6-methylbiphenyl-3-carboxylic acid,
(6-[1,4]oxazepan-4-espiridion-3-yl)amide 4'-methoxy-6-methylbiphenyl-3-carboxylic acid,
[6-(2-methylmorpholin-4-yl)pyridine-3-yl]amide 4'-methoxy-6-methylbiphenyl-3-carboxylic acid,
[6-(2-methylmorpholin-4-yl)pyridine-3-yl]amide 4'-dimethylamino-6-methylbiphenyl-3-carboxylic acid,
(6-[1,4]oxazepan-4-espiridion-3-yl)amide 4'-dimethylamino-6-methylbiphenyl-3-carboxylic acid,
(6-morpholine-4-espiridion-3-yl)amide 4'-dimethylamino-6-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 4'-methoxy-6-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 4'-ethoxy-6-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 6-methyl-4'-methylsulfinylphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 4'-dimethylamino-6-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 3'-chloro-6-methylbiphenyl-3-carboxylic to the slots,
(6-azepin-1-espiridion-3-yl)amide 2',4'-dichloro-6-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 2'-chloro-6-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 3'-chloro-6-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 3',4'-dichloro-6-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 3'-chloro-6-methyl-4'-triptorelin-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 6,4'-dimethylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 4'-ethyl-6-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 4'-tert-butyl-6-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 6-methyl-4'-propylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 4'-isobutyl-6-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 4'-isopropyl-6-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 6,2',6'-trimethylphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 6,2',3'-trimethylphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 6-methyl-4'-triptorelin-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 6-methyl-3'-trifloromethyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 6-methyl-3',5'-bistrifluormethylbenzene-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 3'-isopropoxy-6-methylbut the Nile-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 3'-ethoxy-6-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 2',6'-dimethoxy-6-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 6-methyl-4'-cryptomaterial-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 6-methyl-3'-cryptomaterial-3-carboxylic acid,
(4-morpholine-4-ylphenyl)amide 6-methylbiphenyl-3-carboxylic acid,
(4-morpholine-4-ylphenyl)amide 4'-methoxy-6-methylbiphenyl-3-carboxylic acid,
(4-morpholine-4-ylphenyl)amide 3'-methoxy-6-methylbiphenyl-3-carboxylic acid,
(4-morpholine-4-ylphenyl)amide 4'-(2-dimethylaminoethoxy)-6-methylbiphenyl-3-carboxylic acid,
(4-morpholine-4-ylphenyl)amide 3'-dimethylamino-6-methylbiphenyl-3-carboxylic acid,
(4-morpholine-4-ylphenyl)amide 4'-fluoro-6-methylbiphenyl-3-carboxylic acid,
(4-morpholine-4-ylphenyl)amide 3'-fluoro-6-methylbiphenyl-3-carboxylic acid,
(4-morpholine-4-ylphenyl)amide 2' -fluoro-6-methylbiphenyl-3-carboxylic acid,
4-methyl-N-(4-(morpholine-4-ylphenyl)-3-cinoxacin-6-ylbenzene,
(4-morpholine-4-ylphenyl)amide 6-methyl-4'-(4-methylpiperazin-1-yl) - biphenyl-3-carboxylic acid,
(4-morpholine-4-ylphenyl)amide 2' -cyano-6-methylbiphenyl-3-carboxylic acid,
(4-morpholine-4-ylphenyl)amide 3'-cyano-6-methylbiphenyl-3-carboxylic acid,
(6-[1,4]oxazepan-4-espiridion-3-yl)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-the l)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
[6-(2-methylmorpholin-4-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
(3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
(6-morpholine-4-espiridion-3-yl)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
[6-(4-methylpiperazin-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
(4-morpholine-4-ylphenyl)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
(3-fluoro-4-morpholine-4-ylphenyl)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
(3-chloro-4-morpholine-4-ylphenyl)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
(3-bromo-4-morpholine-4-ylphenyl)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
(3-methyl-4-morpholine-4-ylphenyl)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
(4-morpholine-4-yl-3-triptoreline)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
(4-cyclohexylphenol)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
biphenyl-4-alamid 4'-cyano-6-methylbiphenyl-3-carboxylic acid (4'-methoxybiphenyl-4-yl)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
[4-(4-benzylpiperazine-1-yl)phenyl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
[4-(piperidine-1-sulfonyl)phenyl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
[4-(pyrrolidin-1-sulfonyl)phenyl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 4'-cyano-6-methoxybiphenyl the-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 4'-cyano-2-methoxybiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 4'-cyano-2-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 3'-fluoro-4'-methoxy-6-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 4'-isopropoxy-6-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 4'-butoxy-6-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 3'-chloro-4'-methoxy-6-methylbiphenyl-3-carboxylic acid,
(6-azepin-1-espiridion-3-yl)amide 4'-methoxy-6,3'-dimethylbiphenyl-3-carboxylic acid,
[4-(piperidine-1-sulfonyl)phenyl]amide 4'-cyano-2-methylbiphenyl-3-carboxylic acid,
[4-(piperidine-1-sulfonyl)phenyl]amide 4'-cyano-6-forbiden-3-carboxylic acid,
[4-(piperidine-1-sulfonyl)phenyl]amide of 6-bromo-4'-cyanobiphenyl-3-carboxylic acid,
[6-(4-benzyl[1,4]diazepan-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
[6-(4-thiophene-3-ylmethyl [1,4]diazepan-1-yl)pyridine-3-yl] amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
[6-(2,6-dimethylmorpholine-4-yl)pyridine-3-yl]amide 4'-cyano-2-methylbiphenyl-3-carboxylic acid,
[6-(2,6-dimethylmorpholine-4-yl)pyridine-3-yl]amide 4'-methoxy-2-methylbiphenyl-3-carboxylic acid,
[6-(2,6-dimethylmorpholine-4-yl)pyridine-3-yl]amide of 2-methyl-4'-triptorelin-3-carboxylic acid,
[6-(2,6-dimethylmorpholine-4-yl)pyridine-3-yl]amide methyl-4'-cryptomaterial-3-carboxylic acid,
[6-(2-methylmorpholin-4-yl)pyridine-3-yl]amide 4'-cyano-2-methylbiphenyl-3-carboxylic acid,
[4-(piperidine-1-sulfonyl)phenyl]amide 4'-cyano-2-forbiden-3-carboxylic acid,
[4-(piperidine-1-sulfonyl)phenyl]amide 4'-cyano-6-triptorelin-3-carboxylic acid,
[6-(4-pyridin-4-ylmethyl[1,4]diazepan-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
[6-(4-pyridine-3-ylmethyl[1,4]diazepan-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
{6- [4-(2,6-dimethoxybenzyl)[1,4]diazepan-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
{6-[4-(2-ethoxybenzyl)-[1,4]diazepan-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
(6-{4-[2-(4-methylpiperazin-1-yl)benzyl][1,4]diazepan-1-yl)pyridine-3-yl)amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
{6-[4-(4-methoxy-2,3-dimethylbenzyl)[1,4]diazepan-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
{6-[4-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)[1,4]diazepan-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
[6-(4-pyridine-2-ylmethyl[1,4]diazepan-1-yl)pyridine-3-yl] amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
[6-(4-benzo[1,3]dioxol-4-ylmethyl[1,4]diazepan-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
{6-[4-(2-cryptomaterial)[1,4]diazepan-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
{6-4-(2-dimethylaminobenzoyl)[1,4]diazepan-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
{6-[4-(2-chloro-5-trifloromethyl)[1,4]diazepan-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
{6-[4-(2,3-diferensial)-[1,4]diazepan-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
{6-[4-(2-chloro-4-terbisil)[1,4]diazepan-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
{6-[4-(2,6-diferensial)[1,4]diazepan-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
[4-(piperidine-1-sulfonyl)phenyl]amide of 2-chloro-4'-cyanobiphenyl-3-carboxylic acid,
[6-(2,6-dimethylmorpholine-4-yl)pyridine-3-yl]amide 4'-cyano-6-triptorelin-3-carboxylic acid,
[6-(2,6-dimethylmorpholine-4-yl)pyridine-3-yl]amide of 2-chloro-4'-cyanobiphenyl-3-carboxylic acid,
[6-(2,6-dimethylmorpholine-4-yl)pyridine-3-yl]amide 4'-cyano-6-ethylbiphenyl-3-carboxylic acid,
{6-[4-(3-terbisil)piperazine-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
{6-[4-(2-cryptomaterial)piperazine-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
{6-[4-(3-Chlorobenzyl)piperazine-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
{6-[4-(4-isobutylphenyl)piperazine-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
[6-[4-(4-tert-butylbenzyl)piperazine-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
{6-[4-(7-methoxybenzo [1,3]dioxol-5-ylmethyl)piperazine-1-yl]Piri is INF-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
[6-(4-benzylpiperazine-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
[6-(4-pyridine-3-iletileri-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
{6-[4-(4-deformational)piperazine-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
{6-[4-(4-cyanobenzyl)piperazine-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
[6-(4-(quinoline-5-iletileri-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
[6-(4-pyridin-4-iletileri-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
[6-(4-pyridine-2-eletrophoresis-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
{6-[4-(4-imidazol-1-ylbenzyl)piperazine-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
{6-[4-(3-cyanobenzyl)piperazine-1-yl]pyridine-3-yl}amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
[6-(4-isoquinoline-5-iletileri-1-yl)pyridine-3-yl]amide 4'-cyano-6-methylbiphenyl-3-carboxylic acid,
(R)-2-methyl-N-(6-(2-methylmorpholine)pyridine-3-yl)-4'-(triptoreline)biphenyl-3-carboxamide,
4'-cyano-2-methyl-N-(6-sulfonilmorpholid-3-yl)biphenyl-3-carboxamide,
(S)-4'-cyano-2-methyl-N-(6-(2-methylmorpholine)pyridine-3-yl)biphenyl-3-carboxamide,
(R)-6-chloro-N-(6-(2-methylmorpholine)pyridine-3-yl)-4'-(triptoreline)biphenyl-3-carboxamide,
4'-cyano-2-methyl-N-6-sulfidecontaining-3-yl)biphenyl-3-carboxamide,
4'-cyano-N-(6-(diisobutylamine)pyridine-3-yl)-2-methylbiphenyl-3-carboxamide,
4'-cyano-N-(2-((2S,6R)-2,6-dimethylmorpholine)pyrimidine-5-yl)-2-methylbiphenyl-3-carboxamide,
N-(2-((2S,6R)-2,6-dimethylmorpholine)pyrimidine-5-yl)-2-methyl-4'-(trifluoromethyl)biphenyl-3-carboxamide,
N-(2-((2S,6R)-2,6-dimethylmorpholine)pyrimidine-5-yl)-2-methyl-4'-(triptoreline)biphenyl-3-carboxamide,
N-(2-(bis(2-hydroxyethyl)amino)pyrimidine-5-yl)-2-methyl-4'-(triptoreline)biphenyl-3-carboxamide,
2-methyl-N-(6-(tetrahydro-2H-Piran-4-yloxy)pyridine-3-yl)-4'-(triptoreline)biphenyl-3-carboxamide,
N-(5-chloro-6-((2S,6R)-2,6-dimethylmorpholine)pyridine-3-yl)-2-methyl-4'-(triptoreline)biphenyl-3-carboxamide,
N-(6-((2R,6S)-2,6-dimethylether-2H-Piran-4-yl)pyridine-3-yl)-2-methyl-4'-(triptoreline)biphenyl-3-carboxamide,
N-(6-(4-ethylpiperazin-1-carbonyl)pyridin-3-yl)-2-methyl-4'-(triptoreline)biphenyl-3-carboxamide,
2-methyl-N-(6-(2-oxopiperidin-1-yl)pyridine-3-yl)-4'-(triptoreline)biphenyl-3-carboxamide,
2-methyl-N-(6-(1-(pyridine-4-ylmethyl)piperidine-4-yl)pyridine-3-yl)-4'-(triptoreline)biphenyl-3-carboxamide,
2-methyl-N-(6-(2-oxo-4-(pyridine-4-ylmethyl)piperazine-1-yl)pyridine-3-yl)-4'-(triptoreline)biphenyl-3-carboxamide,
2-methyl-N-(6-(1-(pyridine-4-ylmethyl)piperidine-3-yl)pyridine-3-yl)-4'-(triptoreline)biphenyl-3-carboxamide and
N-(6-(1-ethylpiperidine-3-yl)pyridine-3-yl)-2-methyl-4'-(triptoreline)biphenyl-3-carboxamide.

6. (6-azepin-1-yl-is iridin-3-yl)amide 6-methyl-[1,1'; 4',1"]terphenyl-3-carboxylic acid.

7. A method of inhibiting the hedgehog pathway in a cell, which lies in the fact that the cell is in contact with the connection according to claim 1.

8. The method according to claim 7, where the cell is characterized by the phenotype with the lost function of Ptc phenotype with acquired function hedgehog, the phenotype with the acquired function or smoothened phenotype with acquired Gli function.

9. The method according to claim 7, where the cell is in contact with a hedgehog antagonist in vivo or in vitro.

10. The method according to claim 9, where the compound is administered to the animal as one of the components of the combined treatment.

11. The method according to claim 10, where the disease intended for treatment, selected from the group including pancreatic cancer, prostate cancer, medulloblastoma, basal cell carcinoma and small cell lung cancer.

12. The method of suppressing unwanted cell proliferation, which is that the cell is in contact with the connection according to claim 1.

13. The method according to item 12, where the cell is selected from a cell pancreatic cancer, prostate cancer, Protocol, basal cell carcinoma and small cell lung cancer.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of general formula (I-B), where values of radicals are described in formula of invention, or to its pharmaceutically acceptable salts, which possess activity of inhibiting cholesterol ester transfer protein, due to which said compounds or salts can be used for prevention and/or treatment of arteriosclerotic diseases, hyperlipemia or dislipidemia or similar diseases.

EFFECT: obtaining pharmaceutical compositions for prevention and treatment of arteriosclerosis, as well as application of formula I-B compounds for manufacturing of medication.

15 cl, 36 tbl, 252 ex

FIELD: chemistry.

SUBSTANCE: invention relates to thiophene derivatives of formula (I):

where A denotes -CONH-CH2-, -CO-CH=CH-, -CO-CH2CH2-, -CO-CH2-O-, -CO-CH2-NH-, or ; R1 denotes hydrogen, C1-5-alkyl or C1-5-alkoxy; R2 denotes hydrogen, C1-2-alkyl, C1-5-alkoxy, trifluoromethyl or halogen, R3, R31, R32, R33, R34, R4, R5, R6, R7, k, m, n are described in claim 1. The invention also relates to a pharmaceutical composition for preventing or treating diseases and disorders associated with an activated immune system, based on said compounds and to use thereof as therapeutically active compounds for preventing or treating diseases or disorders such as graft rejection, graft versus host reaction and autoimmune syndromes.

EFFECT: improved properties of the compound.

27 cl, 2 tbl, 525 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds can be used as a medicinal agent which modulates PPARδ (peroxisome proliferator-activated receptor δ). In formula I

, p is equal to 1; L2 is selected from a group which includes -XOX- and -XSX-, where X is independently selected from a group which includes a bond and C1-C4alkylene; R13 is selected from a group which includes halogen, C1-C6alkyl; R14 is selected from a group which includes -XOXC(O)OR17 and -XC(O)OR17, where X denotes a bond or C1-C4alkylene and R17 denotes hydrogen; R15 and R16 are independently selected from a group which includes -R18 and -YR18, where Y is selected from a group which includes C2-C6alkenylene, and R18 is selected from a group which includes C6-C10aryl, pyridinyl, pyrimidinyl, quinolinyl, benzo[b]furanyl, benzoxazolyl, 1,5-benzodioxanyl, 1,4-benzodioxanyl and 3,4-dihydro-2H-benzo[b][1,4]dioxepin; where any of phenyl, pyridinyl, pyrimidinyl, benzoxazolyl in R18 is independently substituted with 1-2 radicals, independently selected from a group which includes halogen, C1-C6alkyl, C2-C7alkenyl, C1-C6alkoxy group, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxy group, C3-C12cycloalkyl, phenyl, morpholinyl, pyrrolidinyl, piperidinyl, -XNR17R17, -XC(O)NR17R17, -XC(O)R19 and -XOXR19, where X denotes a bond or C1-C4alkylene; R17 is selected from a group which includes C1-C6alkyl, and R19 is selected from a group which includes C3-C12cycloalkyl, piperidinyl and phenyl. The invention also relates to use of the disclosed compounds to prepare a medicinal agent which modulates PPARδ activity, a pharmaceutical composition having PPARδ activity modulating properties, which contains a therapeutically effective amount of the disclosed compound and to use of the pharmaceutical composition in preparing a medicinal agent which modulates PPARδ activity.

EFFECT: improved properties of compounds.

10 cl, 1 tbl, 69 ex

Organic compounds // 2411239

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I, in which R1 denotes alkyl or cycloalkyl; R2 denotes phenyl-C1-C7-alkyl, di-(phenyl)- C1-C7-alkyl, naphthyl- C1-C7-alkyl, phenyl, naphthyl, pyridyl-C1-C7-alkyl, indolyl- C1-C7-alkyl, 1H-indazolyl- C1-C7-alkyl, quinolyl C1-C7-alkyl, isoquinolyl- C1-C7-alkyl, 1,2,3,4-tetrahydro-1,4-benzoxazinyl- C1-C7-alkyl, 2H-1,4-benzoxazin-3(4H)-onyl-C1-C7-alkyl, 9-xanthenyl-C1-C7-alkyl, 1-benzothiophenyl-C1-C7-alkyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 9-xanthenyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl, where each phenyl, naphthyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl are unsubstituted or contain one or up to 3 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy-C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkoxy-C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkanoyloxy- C1-C7-alkyl, amino- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkylamino- C1-C7-alkyl, C1-C7-alkanoylamino- C1-C7-alkyl, C1-C7-alkylsulphonylamino- C1-C7-alkyl, carboxy- C1-C7-alkyl, C1-C7-alkoxycarbonyl- C1-C7-alkyl, halogen, hydroxy group, C1-C7-alkoxy group, C1-C7-alkoxy- C1-C7-alkoxy group, amino- C1-C7-alkoxy group, N-C1-C7-alkanoylamino-C1-C7-alkoxy group, carbamoyl- C1-C7-alkoxy group, N-C1-C7-alkylcarbamoyl-C1-C7-alkoxy group, C1-C7-alkanoyl, C1-C7-alkoxy-C1-C7-alkanoyl, C1-C7-alkoxy- C1-C7-alkanoyl, carboxyl, carbamoyl and N-C1-C7-alkoxy-C1-C7-alkylcarbamoyl; W denotes a fragment selected from residues of formulae IA, IB and IC, where () indicates the position in which the fragment W is bonded to the carbon atom in position 4 of the piperidine ring in formula I, and where X1, X2, X3, X4 and X5 are independently selected from a group containing carbon and oxygen, where X4 in formula IB and X1 in formula IC can assume one of these values or can be additionally selected from a group comprising S and O, where carbon and nitrogen ring atoms can include a number of hydrogen atoms or substitutes R3 or R4 if contained, taking into account limitations given below, required to bring the number of bonds of the carbon ring atom to 4 and 3 for the nitrogen ring atom; provided that in formula IA at least 2, preferably at least 3 of the atoms X1-X5 denote carbon and in formulae IB and IC at least one of X1-X4 denotes carbon, preferably 2 of the atoms X1-X4 denote carbon; y equals 0 or 1; z equals 0 or 1; R3, which can be bonded with any of the atoms X1, X2, X3 and X4, denotes hydrogen or a C1-C7-alkyloxy-C1-C7-alkyloxy group, phenyloxy-C1-C7-alkyl, phenyl, pyridinyl, phenyl- C1-C7-alkoxy group, phenyloxy group, phenyloxy-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, tetrahydropyranyloxy group, 2H,3H-1,4-benzodioxynyl-C1-C7-alkoxy group, phenylaminocarbonyl or phenylcarbonylamino group, where each phenyl or pyridyl is unsubstituted or contains one or up to 3 substitutes, preferably 1 or 2 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy group, C1-C7-alkoxy group, phenyl-C1-C7-alkoxy group, where phenyl is unsubstituted or substituted with a C1-C7-alkoxy group and/or halogen; carboxy- C1-C7-alkyloxy group, N-mono- or N,N-di-(C1-C7-alkyl)aminocarbonyl-C1-C7-alkyloxy group, halogen, amino group, N-mono- or N,N-di-(C1-C7-alkyl)amino group, C1-C7-alkanoylamino group, morpholino-C1-C7-alkoxy group, thiomorpholino-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, pyrazolyl, 4- C1-C7-alkylpiperidin-1-yl, tetrazolyl, carboxyl, N-mono- or N,N-di-(C1-C7-alkylamino)carbonyl or cyano group; or denotes 2-oxo-3-phenyltetrahydropyrazolidin-1-yl, oxetidin-3-yl-C1-C7-alkyloxy group, 3-C1-C7-alkyloxetidin-3-yl- C1-C7-alkyloxy group or 2-oxotetrahydrofuran-4-yl- C1-C7-alkyloxy group; provided that if R3 denotes hydrogen, then y and z are equal to 0; R4, if contained, denotes a hydroxy group, halogen or C1-C7-alkoxy group; T denotes carbonyl; and R11 denotes hydrogen, or pharmaceutically acceptable salts thereof. The invention also relates to use of formula I compounds, a pharmaceutical composition, as well as a method of treating diseases.

EFFECT: obtaining novel biologically active compounds having activity towards rennin.

11 cl, 338 ex, 1 tbl

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: medicine, pharmaceutics.

SUBSTANCE: invention relates to new derivatives of piperidine of formula I: , in which: R1 and R2 are selected from group, including alkyl, halogenalkyl, alkyl substituted with one or more hydroxy groups, -CN, alkynyl, -N(R6)2, - N(R6)-S(O2)-alkyl, -N(R6)-C(O)-N(R9)2, -alkylene-CN, -cycloalkylene-CN, -alkylene-O-alkyl, -C(O)-alkyl, -C(=N-OR5)-alkyl, -C(O)-O-alkyl, -alkylene-C(O)-alkyl, -alkylene-C(O)-O-alkyl, -alkylene-C(O)-N(R9)2 and group , , , ,

provided that at least one of R1 and R2 stands for -CN or group , , , ,

W stands for =C(R8)- or =N-; X stands for -C(O)- or -S(O2)-; Y is selected from group, including -CH2-, -O- and -N(R6)-C(O)-, provided that: (a) atom of nitrogen of group -N(R6)-C(O)- is linked with X, and (b) if R1 and/or R2 stands for and Y stands for -O-, then X does not stand for -S(O2)-; Z stands for -C(R7)2-, -N(R6)-, or -O-; R3 is selected from group, including H and non-substituted alkyl; R4 stands for H; R5 stands for H or alkyl; R6 is selected from group, including H, alkyl, cycloalkyl and aryl; each R7 independently stands for H or alkyl; or each R7 together with circular atom of carbon, to which they are linked, as indicated, forms cycloalkylene ring; R8 is selected from group including H, alkyl, alkyl substituted with one or large number of hydroxygroups, -N(R6)2, -N(R6)-S(O2)- alkyl, -N(R6)-S(O2)-aryl, -N(R6)-C(O)-alkyl, -N(R6)-C(O)-aryl, alkylene-O-alkyl and -CN; R9 is selected from group including H, alkyl and aryl, or each R9 jointly with atom of nitrogen, to which, as indicated, they are linked, forms heterocycloalkyl ring; Ar1 stands for non-substituted phenyl; Ar2 stands for phenyll substituted with 0-3 substituents, selected from group including halogenalkyl; n equals 0, 1 or 2; and m equals 1, 2 or 3, and to their pharmaceutically acceptance salts and hydrates.

EFFECT: production of new biologically active compounds, having properties of antagonist of neurokinin receptor NK1.

35 cl, 60 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula I and to its pharmaceutically acceptable salts. In formula I R1 is selected from C1-6alkyl, C3-12cycloalkyl, phenyl, furanyl, thienyl, pyridyl, where phenyl of radical R1, is optionally substituted with radical, which is selected from halogen, nitro, C1-6alkyl, C1-6alkoxy, substituted with halogen of C1-6alkyl and -XC(O)YR5; where X represents C1-4alkylene, Y represents O, and R5 represents hydrogen; R2 represents -C(O)NR4XOR5, where X represents C1-4alkylene; R4 is selected from hydrogen and C1-6alkyl; R5 represents phenyl; where any phenyl of radical R2, is optionally substituted with two radicals, which are independently selected from halogen, nitro and halogen-substituted C1-6alkyl; R3 represents phenyl, which is optionally substituted with radicals in number from 1 to 2, which are independently selected from halogen, C1-6alkyl, C1-6alkoxy, -XOXC(O)OR5, -XC(O)OR5, where X is independently selected from simple link and C1-4alkylene; and R5 is selected from hydrogen and C1-6alkyl. Invention also relates to compounds selected from 2-(2-nitro-4-trifluoromethylphenoxy)ethyl ester 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbonic acid, 2-(2,4-dichlorophenoxy)ethyl ester 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbonic acid, 3-(2,6-dichlorophenyl)-5-methyl-4-[2-(2-nitro-4-trifluoromethylphenoxy)ethoxymethyl]isoxazole, other compounds are specified in invention formula.

EFFECT: compounds of present invention may find application as medicinal agent that modulates activity of receptors activated by PPARδ.

7 cl, 2 tbl, 65 ex

FIELD: chemistry.

SUBSTANCE: in compounds of formula:

, A and B denote a pair of condensed saturated or unsaturated 5- or 6-member rings, where the said system of condensed rings A/B contains 0-2 nitrogen atoms, and said rings are further substituted with 0-4 substitutes independently selected from halogen, lower alkyl or oxo; and a and b are bonding positions for residues Y and D, respectively, and these positions a and b are in the peri-position relative each other on the said condensed ring system A/B; d and e are condensed positions between ring A and ring B in the said condensed ring system A/B; D is an aryl or heteroaryl cyclic system which denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S; which can be further substituted with 0-4 substitutes independently selected from lower alkyl and amine; Y is selected from -CH2 and -O-; M is selected from aryl, aryl substituted with a halogen or alkoxy; R1 is selected from aryl, aryl substituted with a halogen, heteroaryl, heteroaryl substituted with a halogen, where heteraryl denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S, and CF3; and if Y denotes -CH2- or -O-, then R1 further denotes a lower alkyl. The invention also pertains to use of compounds in claim 1, a pharmaceutical composition, a screening method on selective ligands of prostanoid receptors, as well as compounds of the formula.

EFFECT: obtaining novel biologically active compounds for inhibiting binding of prostanoid E2 with EP3 receptor.

25 cl, 46 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula where: R1 denotes -OR1', -SR1", 6-member heterocycloalkyl with one O atom and possibly one N atom, phenyl or 5-member heteroaryl with two N atoms, 6-member heteraryl with one N atom; R1'/R1" denote C1-6-alkyl, C1-6-alkyl substituted with a halogen, -(CH2)x-C3-6cycloalkyl or -(CH2)x-phenyl; R2 denotes S(O)2-C1-6-alkyl, -S(O)2NH-C1-6-alkyl, CN; denotes the group: , and where one extra N atom of the nucleus of an aromatic or partially aromatic bicyclic amine may be present in form of its oxide ; R3 - R10 denotes H, halogen, C1-6-alkyl, C3-6cycloalkyl, 4-6-member heterocycloalkyl with one N or O atom, 6-member heterocycloalkyl with two O atoms or two N atoms, 6-8-member heterocycloalkyl containing on N atom or one O or S atom, 5-member heteroaryl with two or three N atoms, 5-member heteroaryl with one S atom, in which one carbon atom may be also substituted with N or O, 6-member heteroaryl with one or two N atoms, C1-6-alkoxy, CN, NO2, NH2, phenyl, -C(O)-5-member cyclic amide, S-C1-6-alkyl, -S(O)2-C1-6-alkyl, C1-6-alkyl substituted with halogen;C1-6-alkoxy substituted with halogen, C1-6-alkyl substituted with OH, -O-(CH2)y-C1-6-alkoxy, -O(CH2)yC(O)N(C1-6-alkyl)2, -C(O)-C1-6-alkyl, -O-(CH2)x-phenyl, -O-(CH2)x-C3-6cycloalkyl, -O-(CH2)x-6-member heterocycloalkyl with one O atom, -C(O)O-C1-6-alkyl, -C(O)-NH-C1-6-alkyl, -C(O)-N(C1-6-alkyl)2, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; R' and R'" in group (e) together with -(CH2)2- with which it is bonded can form a 6-member ring; R, R', R" and R"' independently denote H, C1-6-alkyl; and where all groups - phenyl, cycloalkyl, cyclic amine, heterocycloalkyl or 5- or 6-member heteroaryl, as defined for R1, R1', R1" and R3 - R10, can be unsubstituted or substituted with one or more substitutes selected from OH, =O, halogen, C1-6-alkyl, phenyl, C1-6-alkyl substituted with halogen, or C1-6-alkoxy; n, m o, p, q, r, s and t = 1 , 2; x =0, 1 or 2; y = 1 , 2; and their pharmaceutically acceptable acid addition salts.

EFFECT: compounds have glycine transporter 1 inhibiting activity, which enables their use in a pharmaceutical composition.

20 cl, 2 tbl, 12 dwg, 382 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula: or its pharmaceutically acceptable salts, where Y represents COOR2; A represents -(CH2)6-, cys-CH2CH=CH-(CH2)3-, where 1 carbon atom can be substituted with O; or A represents -(CH2)m-Ar-(CH2)0-, where Ar represents phenylene or 5-member heteroarylene, which contains one heteroatom selected from O or S, sum of m and o constitutes from 1 to 4, and where one of groups CH2 can be substituted with O; and B represents phenyl, which can be substituted with C1-12 alkyl, hydroxy C1-12 alkyl; R2 represents H, C1-6 alkyl.

EFFECT: obtaining compounds for ophthalmological composition.

15 cl, 1 tbl, 16 dwg, 43 ex

FIELD: chemistry.

SUBSTANCE: invention relates to thiophene derivatives of formula (I):

where A denotes -CONH-CH2-, -CO-CH=CH-, -CO-CH2CH2-, -CO-CH2-O-, -CO-CH2-NH-, or ; R1 denotes hydrogen, C1-5-alkyl or C1-5-alkoxy; R2 denotes hydrogen, C1-2-alkyl, C1-5-alkoxy, trifluoromethyl or halogen, R3, R31, R32, R33, R34, R4, R5, R6, R7, k, m, n are described in claim 1. The invention also relates to a pharmaceutical composition for preventing or treating diseases and disorders associated with an activated immune system, based on said compounds and to use thereof as therapeutically active compounds for preventing or treating diseases or disorders such as graft rejection, graft versus host reaction and autoimmune syndromes.

EFFECT: improved properties of the compound.

27 cl, 2 tbl, 525 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: invention relates to 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives of formula I

or pharmaceutically acceptable salts thereof, where R1 denotes (1-6C)alkyl; R2, R3 independently denote halogen, (1-4C)alkoxy; R4 denotes phenyl or a 5-6-member heteroaryl, having one or two heteroatoms selected from nitrogen, oxygen or sulphur, phenyl or said heteroaryl, substituted with R7 and optionally substituted on the (hetero)aromatic ring with one or two substitutes selected from halogen, nitro, trifluoromethyl and (1-4C)alkyl; R7 denotes H, (1-4C)alkylthio, (1-4C)alkylsulphonyl, R8R9-amino, R10R11-aminocarbonyl, R12R13-amino(1-4C)alkylcarbonyl-amino, R14R15-amino(1-4C)alkyl, R16-oxy, R17R18-aminocarbonyl (1-4C)alkoxy, R19-oxy(1-4C)alkyl, R19-oxycarbonyl(1-4C)alkyl, R20R21-aminosulphonyl, R20-oxysulphonyl, aminoiminomethyl, (di)(1-4C)alkylaminoiminomethyl, morpholinyliminomethyl, trifluoromethylsulphonyl; R23-oxycarbonyl, or R23R24-aminocarbonyl; R8 denotes H or (1-4C)alkyl; R9 denotes (1-4C)alkylsulphonyl, (1-6C)alkylcarbonyl, (2-6C)alkenylcarbonyl, (3-6C)cycloalkylcarbonyl, (1-4C)alkoxycarbonyl, (3-4C)alkenyloxycarbonyl, (di)(1-4C)alkylaminocarbonyl, piperazinylcarbonyl, (5-8C)alkyl, (3-6C)cycloalkyl(1-4C)alkyl or phenylcarbonyl, furylcarbonyl, thiophenylsulphonyl, 5-member heteraryl(1-4C)alkyl, having one or two nitrogen atoms, optionally substituted on the heteroaromatic ring with one, two or three substitutes selected from hydroxy, amino, halogen, nitro, trifluoromethyl, (1-4C)alkoxy; R10 denotes H or (1-4C)alkyl; R11 denotes hydroxy(2-4C)alkyl, (1-4C)alkoxy(2-4C)alkyl; R12, R13 independently denote H, (1-6C)alkyl, (3-6C)-cycloalkyl, (1-4C)alkoxy(2-4C)alkyl, (3-6C)cycloalkyl-(1-4C)alkyl, pyrrolidinyl(1-4C)alkyl, amino(2-4C)alkyl, (di)(1-4C)-alkylamino(2-4C)alkyl or phenyl(1-4C)alkyl, pyridinyl (1-4C)alkyl; or R12R13 in R12R13-amino(1-4C)alkylcarbonylamino can be bonded together with the nitrogen atom to which they are bonded into a (5-6C)heterocycloalkyl ring, having one or two nitrogen atoms, optionally substituted with hydroxy(1-4C)alkyl; R14, R15 independently denote H, (1-6C)alkyl, (1-6C)alkylcarbonyl, (1-4C)alkoxycarbonyl or pyridinyl(1-4C)alkyl, optionally substituted on the aromatic ring with one substitute selected from halogen; or R16 denotes (di)(1-4C)alkylamino(2-4C)alkyl, hydroxycarbonyl(1-4C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl, phenyl(1-4C)alkyl or pyridinyl(1-4C)alkyl; R17, R18 independently denote H, (1-6C)alkyl, thiophenyl(1-4C)alkyl; or R17R18 in R17R18-aminocarbonyl(1-4C)alkoxy can be bonded into a morpholine or piperazine ring, R19 denotes H or (1-6C)alkyl; R20R21 independently denote H, (1-6C)alkyl or (1-4C)alkoxy(1-4C)alkyl; or R20R21 in R20R21-aminosulphonyl can be bonded into a morpholine ring; X denotes O or N-R22; Y denotes CH2 or C(O); Z denotes CN or NO2; R22 denotes H; R23, R24 independently denotes H; (1-4C)alkyl; or R23R24 in R23R24-aminocarbonyl can be bonded into a dihydropyridine ring; provided that compounds of formula I, in which X denotes O, R4 denotes phenyl and R7 is selected from H, (1-4C)alkylthio, (1-4C)alkylsulphonyl, R23-oxycarbonyl, and R23R24-aminocarbonyl, and compounds of formula I, in which X denotes O, R4 denotes (2-5C)heteroaryl and R7 denotes H are excluded. The invention also relates to use of 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives to prepare a medicinal agent for treating sterility.

EFFECT: improved useful biological properties.

12 cl, 73 ex

Organic compounds // 2411239

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I, in which R1 denotes alkyl or cycloalkyl; R2 denotes phenyl-C1-C7-alkyl, di-(phenyl)- C1-C7-alkyl, naphthyl- C1-C7-alkyl, phenyl, naphthyl, pyridyl-C1-C7-alkyl, indolyl- C1-C7-alkyl, 1H-indazolyl- C1-C7-alkyl, quinolyl C1-C7-alkyl, isoquinolyl- C1-C7-alkyl, 1,2,3,4-tetrahydro-1,4-benzoxazinyl- C1-C7-alkyl, 2H-1,4-benzoxazin-3(4H)-onyl-C1-C7-alkyl, 9-xanthenyl-C1-C7-alkyl, 1-benzothiophenyl-C1-C7-alkyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 9-xanthenyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl, where each phenyl, naphthyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl are unsubstituted or contain one or up to 3 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy-C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkoxy-C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkanoyloxy- C1-C7-alkyl, amino- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkylamino- C1-C7-alkyl, C1-C7-alkanoylamino- C1-C7-alkyl, C1-C7-alkylsulphonylamino- C1-C7-alkyl, carboxy- C1-C7-alkyl, C1-C7-alkoxycarbonyl- C1-C7-alkyl, halogen, hydroxy group, C1-C7-alkoxy group, C1-C7-alkoxy- C1-C7-alkoxy group, amino- C1-C7-alkoxy group, N-C1-C7-alkanoylamino-C1-C7-alkoxy group, carbamoyl- C1-C7-alkoxy group, N-C1-C7-alkylcarbamoyl-C1-C7-alkoxy group, C1-C7-alkanoyl, C1-C7-alkoxy-C1-C7-alkanoyl, C1-C7-alkoxy- C1-C7-alkanoyl, carboxyl, carbamoyl and N-C1-C7-alkoxy-C1-C7-alkylcarbamoyl; W denotes a fragment selected from residues of formulae IA, IB and IC, where () indicates the position in which the fragment W is bonded to the carbon atom in position 4 of the piperidine ring in formula I, and where X1, X2, X3, X4 and X5 are independently selected from a group containing carbon and oxygen, where X4 in formula IB and X1 in formula IC can assume one of these values or can be additionally selected from a group comprising S and O, where carbon and nitrogen ring atoms can include a number of hydrogen atoms or substitutes R3 or R4 if contained, taking into account limitations given below, required to bring the number of bonds of the carbon ring atom to 4 and 3 for the nitrogen ring atom; provided that in formula IA at least 2, preferably at least 3 of the atoms X1-X5 denote carbon and in formulae IB and IC at least one of X1-X4 denotes carbon, preferably 2 of the atoms X1-X4 denote carbon; y equals 0 or 1; z equals 0 or 1; R3, which can be bonded with any of the atoms X1, X2, X3 and X4, denotes hydrogen or a C1-C7-alkyloxy-C1-C7-alkyloxy group, phenyloxy-C1-C7-alkyl, phenyl, pyridinyl, phenyl- C1-C7-alkoxy group, phenyloxy group, phenyloxy-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, tetrahydropyranyloxy group, 2H,3H-1,4-benzodioxynyl-C1-C7-alkoxy group, phenylaminocarbonyl or phenylcarbonylamino group, where each phenyl or pyridyl is unsubstituted or contains one or up to 3 substitutes, preferably 1 or 2 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy group, C1-C7-alkoxy group, phenyl-C1-C7-alkoxy group, where phenyl is unsubstituted or substituted with a C1-C7-alkoxy group and/or halogen; carboxy- C1-C7-alkyloxy group, N-mono- or N,N-di-(C1-C7-alkyl)aminocarbonyl-C1-C7-alkyloxy group, halogen, amino group, N-mono- or N,N-di-(C1-C7-alkyl)amino group, C1-C7-alkanoylamino group, morpholino-C1-C7-alkoxy group, thiomorpholino-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, pyrazolyl, 4- C1-C7-alkylpiperidin-1-yl, tetrazolyl, carboxyl, N-mono- or N,N-di-(C1-C7-alkylamino)carbonyl or cyano group; or denotes 2-oxo-3-phenyltetrahydropyrazolidin-1-yl, oxetidin-3-yl-C1-C7-alkyloxy group, 3-C1-C7-alkyloxetidin-3-yl- C1-C7-alkyloxy group or 2-oxotetrahydrofuran-4-yl- C1-C7-alkyloxy group; provided that if R3 denotes hydrogen, then y and z are equal to 0; R4, if contained, denotes a hydroxy group, halogen or C1-C7-alkoxy group; T denotes carbonyl; and R11 denotes hydrogen, or pharmaceutically acceptable salts thereof. The invention also relates to use of formula I compounds, a pharmaceutical composition, as well as a method of treating diseases.

EFFECT: obtaining novel biologically active compounds having activity towards rennin.

11 cl, 338 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula (Ia) or their pharmaceutically acceptable salts, tautomers, or N-oxides, for use in prevention or treatment of unhealthy conditions or diseases, mediated with cyclin-dependent kinase and glycogen synthase-kinase-3, such as cancerous diseases. In formula (Ia) X stands for group R1-A-NR4; A stands for link, C=O, or NRg(C=O, where R8 stands for hydrogen or C1-3 alkyl; Y stands for link or alkylene chain, made of 1, 2 or 3 atoms of carbon; R1 stands for carbocyclic or heterocyclic group, containing from 3 to 12 circular units; or saturated C1-8hydrocarbyl group, optionally substituted with one or more substituents selected from halogen (for instance, fluorine), hydroxygroups, C1.4alkoxygroups, and carbocyclic or heterocyclic groups, and where 1 or 2 atoms of hydrocarbyl group carbon may be optionally substituted with atom or group selected from O, S, NH, SO, SO2; R2 stands for hydrogen or methyl; R3 is selected from hydrogen and carbocyclic or heterocyclic groups, containing from 3 to 6 circular units; and R4 stands for hydrogen or methyl. Specified carbocyclic and heterocyclic groups are determined in formula of invention and may be optionally substituted with groups specified in invention formula. Objects of invention are also a pharmaceutical composition based on proposed compounds, their application to produce medicinal agents and methods of their application.

EFFECT: production of pharmaceutical composition based on proposed compounds for use in prevention or treatment of unhealthy conditions or diseases, mediated with cyclin-dependent kinase and glycogen synthase-kinase-3, such as cancerous diseases.

48 cl, 6 tbl, 254 ex

FIELD: chemistry.

SUBSTANCE: in compounds of formula:

, A and B denote a pair of condensed saturated or unsaturated 5- or 6-member rings, where the said system of condensed rings A/B contains 0-2 nitrogen atoms, and said rings are further substituted with 0-4 substitutes independently selected from halogen, lower alkyl or oxo; and a and b are bonding positions for residues Y and D, respectively, and these positions a and b are in the peri-position relative each other on the said condensed ring system A/B; d and e are condensed positions between ring A and ring B in the said condensed ring system A/B; D is an aryl or heteroaryl cyclic system which denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S; which can be further substituted with 0-4 substitutes independently selected from lower alkyl and amine; Y is selected from -CH2 and -O-; M is selected from aryl, aryl substituted with a halogen or alkoxy; R1 is selected from aryl, aryl substituted with a halogen, heteroaryl, heteroaryl substituted with a halogen, where heteraryl denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S, and CF3; and if Y denotes -CH2- or -O-, then R1 further denotes a lower alkyl. The invention also pertains to use of compounds in claim 1, a pharmaceutical composition, a screening method on selective ligands of prostanoid receptors, as well as compounds of the formula.

EFFECT: obtaining novel biologically active compounds for inhibiting binding of prostanoid E2 with EP3 receptor.

25 cl, 46 ex

FIELD: medicine.

SUBSTANCE: invention refers to derivatives of 2-pyridylmethylenecarboxamide of formula (I), where: -A represents a substituted or unsubstituted 5-member heterocyclyl group bound with carbonyl through carbon atom; -Z1 and Z2 which can be equal or different, represent hydrogen atom; C1-C5-alkyl; C5-alkoxycarbonyl; -Z3 represents substituted or unsubstituted C3-C7cycloalkyl; -Y represents C1-C5-halogenalkyl, containing to 5 halogen atoms which can be equal or different; X which can be equal or different, represents halogen atom, - n=0, 1, 2 or 3; and to their salts. Besides the invention describes a method of plant pathogenic fungi control with the use of such compounds.

EFFECT: there are prepared and described new derivatives of 2-pyridylmethylenecarboxamide which can be effective as fungicidal active agents.

8 cl, 96 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compound of general formula (I) and its pharmaceutically acceptable salts. In general formula (I) , Y represents group -CONH(Q)- or -NHCONH(Q)-; Q represents 6-member aromatic ring or 5-10-member heteroaromatic ring, containing one or two N heteroatoms or two O heteroatoms; R represents hydrogen, halogen, linear or branched (C1-C6)alkyl; (C1-C6)alkoxy; di-(C1-C6)alkylamino, 5-member heteroaromatic ring, containing one O or S heteroatom; 6- or 9-member heteroaromatic ring, containing one or two N heteroatoms; phenyl, mono- or disubstituted with halogen, (C1-C6)alkyl, halogeno(C1-C6)alkyl, (C1-C6)alkoxy, acyl; hydroxy; piano; di-(C1-C6)alkylamino, acylamino' carbamoyl; X represents group : where Z represents CH2, N or O; m represents integer number from 1 to 3; p is equal 0, 1; R" is selected from group, consisting of di-( C1-C6)alkylaminocarbonyl, (C1-C6)alkyl, acyl. Invention also relates to pharmaceutical composition, containing as active ingredient, invention compound, to application of invention compound for manufacturing pharmaceutical composition, to method of inhibition of nicotinic acetylcholine receptor α7.

EFFECT: obtaining compound, which possesses agonistic activity with respect to nicotinic acetylcholine receptor (nAChR) α7.

7 cl, 2 tbl, 4 dwg, 270 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula: or its pharmaceutically acceptable salts, where Y represents COOR2; A represents -(CH2)6-, cys-CH2CH=CH-(CH2)3-, where 1 carbon atom can be substituted with O; or A represents -(CH2)m-Ar-(CH2)0-, where Ar represents phenylene or 5-member heteroarylene, which contains one heteroatom selected from O or S, sum of m and o constitutes from 1 to 4, and where one of groups CH2 can be substituted with O; and B represents phenyl, which can be substituted with C1-12 alkyl, hydroxy C1-12 alkyl; R2 represents H, C1-6 alkyl.

EFFECT: obtaining compounds for ophthalmological composition.

15 cl, 1 tbl, 16 dwg, 43 ex

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