Compounds and compositions as protein kinase inhibitors

FIELD: chemistry.

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

EFFECT: more effective treatment.

4 cl, 1 tbl, 3 ex

 

Cross references to related applications

In this application claims the priority in connection with the temporary application for the grant of U.S. patent No. 60/647606, registered on January 25, 2005 this application are included in this description in full by reference.

Background of invention

The technical field

The present invention relates to a new class of compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders associated with abnormal activation of the Abl kinase, Bcr-Abl, FGFR3, PDGFRβ, Flt3 and b-Raf.

Background of invention

Protein kinases belong to the numerous family of proteins, which play a major role in the regulation of many cellular phenomena and support the functioning of the cells. Such kinases include, without limitation, receptor tyrosine kinase, such as receptor kinase platelet growth factor (PDGF-R) and the receptor fibroblast growth factor, FGFR3, preceptories tyrosine kinase like kinase Abl and hybrid kinase BCR-Abl, and sprintringtones, such as kinase b-RAF, SGK, MAP (for example, MCC, MCC etc) and SAPK2α and SAPK2β. Abnormal activity of the kinase on udaetsya in many pathological conditions, such as benign and malignant proliferative disorders and diseases associated with abnormal activation of the immune and nervous system.

The new compounds of the present invention inhibit the activity of one or more protein kinases, and thus, it is expected that such compounds can be used for treatment-related kinases diseases.

A brief description of the invention

One object of the present invention relates to compounds of formula I,

where

n is 0, 1, 2, 3 and 4

R1selected from the group including hydrogen, C1-C6alkyl, C6-C10aryl(C0-C4)alkyl, C5-C10heteroaryl(C0-C4)alkyl, C3-C12cycloalkyl(C0-C4)alkyl, C3-C8heteroseksualci(C0-C4)alkyl and-XNR7R8,

and any aryl, heteroaryl, cycloalkyl or heteroseksualci in the composition of R1optionally substituted by 1-3 radicals independently selected from the group comprising halogen, C1-C6alkyl, halogen-substituted C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkoxy, C1-C6alkylthio, halogen-substituted C1-C6alkylthio, -XNR7R8, -XNR7XNR7R8, -XNR7 R9With6-C10arils0-C4alkyl, C5-C10heteroaryl(C0-C4)alkyl, C3-C12cycloalkyl(C0-C4)alkyl and C3-C8heteroseksualci(C0-C4)alkyl and any aryl, heteroaryl, cycloalkyl or heteroseksualci in the composition of R1optionally substituted by 1-3 radicals independently selected from the group comprising halogen, C1-C6alkyl, halogen-substituted C1-C6alkyl, replacement C1-C6alkyl, C1-C6alkoxy and halogen-substituted C1-C6alkoxy, and any alkyl at R1optionally includes a methylene replaced by an atom Of, where

X each independently selected from the group comprising a chemical bond and C1-C6alkylene, R7and R8independently selected from the group including hydrogen, C1-C6alkyl, and R7and R8optionally includes a methylene replaced by an atom O, a R9selected from the group including6-C10aryl(C0-C4)alkyl, C5-C10heteroaryl(C0-C4)alkyl, C3-C12cycloalkyl(C0-C4)alkyl and C3-C8heteroseksualci(C0-C4)alkyl,

R2selected from the group including hydrogen, C1-C6alkyl,

R 3selected from the group including hydrogen, C1-C6alkyl,

R4selected from the group including halogen, C1-C6alkyl, halogen-substituted C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkoxy, C1-C6alkylthio and halogen-substituted C1-C6alkylthio,

R15selected from the group including-NR5Y(O)R6and-Y(O)NR5R6where

Y is chosen from the group comprising S, S, S(O)p and P(O)

R5selected from the group including hydrogen, C1-C6alkyl, and

R6selected from the group including6-C10aryl, C5-C10heteroaryl,3-C12cycloalkyl and C3-C8heteroseksualci, and specified aryl, heteroaryl, cycloalkyl or heteroseksualci in the composition of R6optionally substituted by 1-3 radicals independently selected from the group comprising halogen, C1-C6alkyl, halogen-substituted C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkoxy, C1-C6alkylthio, halogen-substituted C1-C6alkylthio,6-C10aryl(C0-C4)alkyl, C5-C10heteroaryl(C0-C4)alkyl, C3-C12cycloalkyl(C0-C4)alkyl, C3-C8heteroseksualci(the 0-C4)alkoxy and C3-C8heteroseksualci(C0-C4)alkyl, or aryl, heteroaryl, cycloalkyl or heteroseksualci in the composition of R6optionally substituted by 1-3 radicals independently selected from the group comprising hydroxy, halogen, C1-C6alkyl, halogen-substituted C1-C6alkyl, replacement With1-C6alkyl, C1-C6alkoxy and halogen-substituted C1-C6alkoxy, N-oxides, prodrugs, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts and solvate (e.g., hydrates) of such compounds.

The second object of the present invention relates to a pharmaceutical composition that includes a compound of formula I or a N-oxide, individual isomers, mixtures of isomers, or pharmaceutically acceptable salts of these compounds in a mixture with one or more suitable of excipients.

A third object of the present invention relates to a method of treatment of a mammal, which is sensitive to inhibition of kinase activity, primarily to inhibition of the activity of Abl kinase, Bcr-Abl, FGFR3, PDGFRβ, Flt3 and b-Raf, which in turn leads to the prevention, suppression or reduction of the intensity of the pathology and/or symptoms of diseases, and this method includes the introduction of m is capitalsim therapeutically effective amount of the compounds of formula I or its N-oxide derivative, individual isomers, mixtures of isomers, or pharmaceutically acceptable salts of such compounds.

The fourth object of the present invention relates to the use of compounds of formula I to obtain a medicinal product intended for the treatment of animal diseases, which is associated with kinase activity, primarily with the activity of Abl kinase, Bcr-Abl, FGFR3, PDGFRβ, Flt3 and b-Raf, and the activity of these kinases causes the development of the pathology and/or symptoms.

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

Description of the preferred embodiments of the invention

Definition

The term "alkyl" means a group or a structural element of other groups, such as, for example, halogen-substituted alkyl, alkoxy, straight or branched chain. With1-C4alkoxy includes methoxy, ethoxy and other halogen-substituted alkyl includes trifluoromethyl, pentafluoroethyl etc.

The term "aryl" means a monocyclic or condensed bicyclic aromatic ring containing from 6 to 10 carbon atoms in the cycle. For example, aryl includes phenyl or naphthyl, preferably is phenyl. The term "Allen" means the divalent radical aryl group.

The term "heteroaryl" means aryl, as defined above, which contains one or more heteroatoms in the loop. For example, heteroaryl 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 defined above in which one or more carbon atoms in the cycle is replaced by a residue selected from the group comprising-O-, -N=, -NR-, -C(O)-, -S-, -S(O)- or-S(O)2-, where R is hydrogen,

With1-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, etc.

T is pmin "halogen" preferably means chlorine or fluorine, as well as bromine or iodine.

The term "panel of kinases" means a group of kinases, including Abl kinase (human), Abl(T315I), JAK2, JAK3, ALK, JNK1α1, ALK4, KDR, Aurora-A, Lck, Blk, MAPK1, Bmx, MAPKAP-K2, BR, MEK1, CaMKII (rats), Met, CDKl/Cycling, p70S6K, CHK2, PAK2, CK1, PDGFRα, CK2, PDK1, c-kit, Pim-2, c-RAF, PKA(h), CSK, PKBα, cSrc, PKCα, DYRK2, Plk3, EGFR, ROCK-I, Fes, Ron, FGFR3, Ros, Flt3, SAPK2α, Fms, SGK, Fyn, SIK, GSK3β, Syk, IGF-1R, Tie-2, IKKβ, TrKB, IR, WNK3, IRAK4, ZAP-70, ITK, AMPK (rats), LIMK1, Rsk2, Axl, LKB1, SAPK2β, BrSK2, Lyn (h), SAPK3, CPD, MARGAR-K3, SAPK4, CaMKIV, MARK1, Snk, CD2/cyclina, MINK, SRPK1, CD3/cyclin, MKK4(m), TAK1, CDK5/p25, MKK6(h), TBK1, CDK6/D3, MLCK, TrkA, CD7/cyclin/MAT, MRCKβ, TSSK1, CHK1, MSK1, Yes, CKld, MST2, ZIPK, c-Kit (D816V), MuSK, DAPK2, NEK2, DDR2, NEK6, DMPK, PAK4, DRAK1, PAR-1Bα, EphAl, PDGFRβ, EphA2, Pim-1, EphA5, PKBβ, EphB2, PKCβI, EphB4, PKCδ, FGFR1, PKCη, FGFR2, θ, FGFR4, PKD2, Fgr, PKG1β, Flt1, PRK2, Hck, PYK2, HIPK2, Ret, IKKα, RIPK2, IRR, ROCK-II (human), JNK2α2, Rse, JNK3, Rsk1(h), PI3-Kγ, PI3-δ and P13-β. The action of the compounds of the present invention evaluated for a panel of kinases (wild type and/or mutant forms), and found that they inhibit the activity of at least one kinase from the specified panel of kinases.

The term "mutant form of the kinase BCR-Abl" means the form of the kinase, containing one or more substitutions of amino acids compared to the kinase wild-type. Mutations in the sequence of the kinase BCR-Abl leads to changes in the areas contacting the protein and inhibitor (e.g., Gleevec, etc.), in most cases when this occurs the transformation of inactivated in the active state, i.e. formed informacija protein, which is not associated Gleevec. In clinical trials it was found that the set of mutations identified in connection with the resistant phenotype, slowly growing, but continuously over time. Mutations occur in four main areas. One group of mutations (G250E, Q252R, Y253F/H, E255K/V) includes amino acids, which form fasfasfasfasf loop for ATP (also known as P-loop). The second group of mutations (V289A, F311L, T315I, F317L) was discovered in the area, communicating with Gleevec and interact directly with the inhibitor due to the formation of hydrogen bonds or van der Vaal's interactions. The third group of mutations (MT, E355G) is in close proximity to the catalytic domain. The fourth group of mutations (H396R/P) is located in the activation loop, the conformation of which is a "molecular switch", is responsible for the activation/inactivation of the kinase. Point mutations in the kinase BCR-ABL associated with resistance to Gleevec detected in patients of CML and ALL, and include mutations M224V, L248V, G250E, G250R, Q252R, Q252H, Y253H, Y253F, EC, E255V, D276G, TA, V289A, F311L, T315I, T315N, F317L, MT, MT, E355G, F359V, F359A, V379I, F382L, L387M, L387F, NR, H396R, AR, S417Y, EC and F486S (position of the amino acids designated single-letter code according to the information in the database room AAV, and correspond to the ABL kinase 1A, see Martinelli and others, Haematologica/The Hematology Journal, April, 90-4 (2005). If context is not specified, the All-Abl means kinase wild-type and its mutant forms.

The term "treat" and "treatment" means a method of reducing the intensity of the disease and/or its accompanying symptoms.

Description of the preferred embodiments of the present invention

The present invention relates to compounds, compositions and methods for treating diseases associated with protein kinases, especially such as kinases Abl, Bcr-Abl, FGFR3, PDGFRβ, Flt3 and b-Raf. For example, leukemia and other proliferative diseases associated with kinase BCR-Abl, can be treated by inhibiting the kinase BCR-Abl wild type and its mutant forms.

In one embodiment, the present invention provides compounds of formula I, characterized by formula Ia

where

m is 0 and 1,

R1selected from the group including hydrogen, C1-C6alkyl, C6-C10aryl(C0-C4)alkyl, C5-C10heteroaryl(C0-C4)alkyl, C3-C12cycloalkyl(C0-C4)alkyl, C3-C8heteroseksualci(C0-C4)alkyl and-XNR7R8,

where any aryl, heteroaryl, cycloalkyl or heteroseksualci in the composition of R1optionally substituted by 1-3 radicals independently selected from the group comprising From1-C6lcil, -XNR7R8,-XNR7XNR7R8, -XNR7R9With5-C10heteroaryl(C0-C4)alkyl and C3-C8heteroseksualci(C0-C4)alkyl, where any heteroaryl or heteroseksualci in the composition of R1optionally substituted by 1-3 radicals independently selected from the group comprising C1-C6alkyl and replacement C1-C6alkyl, where any alkyl at R1optionally includes a methylene replaced by an atom Of, and each X is independently selected from the group comprising a chemical bond and C1-C6alkylene, R7and R8independently selected from the group including hydrogen, C1-C6alkyl, and any methylene in the composition of R7and

R8optionally substituted on the atom, and R9means3-C12cycloalkyl(C0-C4)alkyl,

R2selected from the group including hydrogen and C1-C6alkyl,

R3selected from the group including hydrogen and C1-C6alkyl,

R4selected from the group including halogen, C1-C6alkyl, halogen-substituted C1-C6alkyl, C1-C6alkoxy and halogen-substituted C1-C6alkoxy,

L is chosen from the group comprising-NR5C(O)- and-C(O)NR5-,

R5selected from the group comprising hydrogen and C 1-C6alkyl,

R10means halogen-substituted C1-C6alkyl and

R11selected from the group comprising hydrogen, halogen, C5-C10heteroaryl and C3-C8heteroseksualci where heteroaryl or heteroseksualci in the composition of R10optionally substituted by 1-3 radicals independently selected from the group comprising hydroxy and C1-C6alkyl.

In another embodiment, the present invention R1selected from the group comprising hydrogen, methyl, isopropyl, imidazolidinyl, piperazinyl, pyridinyl, diethylaminopropyl, hydroxyethyl, pyrimidinyl, morpholinopropan, phenyl, cyclopropyl, morpholinoethyl, benzyl, morpholino where any pyridinyl, imidazolyl, piperazinil or pyrimidinyl in the composition of R1optionally substituted by 1-3 radicals independently selected from the group comprising methyl, methylamino, dimethylaminomethyl, cyclopropylamino, hydroxyethylamino, diethylaminopropylamine, pyrrolidinyl, morpholino, morpholinomethyl, piperazinylmethyl and piperazinil where any morpholino and piperazinil in the composition of R1optionally substituted radical selected from the group comprising methyl, hydroxyethyl and ethyl, a R2, R3and R5each means hydrogen and R4means methyl.

In yet another embodiment, the present of the Britania m is 0 and 1, R10means trifluoromethyl and R11selected from the group including halogen, morpholinomethyl, piperazinil, optionally substituted by methyl group, ethyl or hydroxyethyl; means piperazinylmethyl, optionally substituted with methyl group or ethyl, means imidazolyl, optionally substituted stands, pyrrolidinyloxy and piperidinyl, optionally substituted hydroxy-group.

Preferred compounds of the present invention are selected from the group comprising [2-methyl-5-(3-triphtalocyaninine)phenyl]amide of 2-(3-diethylaminopropylamine)thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-{6-[4-(2-hydroxyethyl)piperazine-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-(2-hydroxyethylamino)thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-{6-[4-(2-hydroxyethyl)piperazine-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide of 2-(3-morpholine-4-ylpropionic)thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide of 2-(3-diethylaminopropylamine)thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-phenylimidazol-5-carboxylic acid {2-methyl-5-[3-(4-Mei-1-yl)-5-Tr is pharmacyventolin]phenyl}amide 2-(2-hydroxyethylamino)thiazole-5-carboxylic acid, {2-methyl-5-[3-(4-Mei-1-yl)-5-triphtalocyaninine]phenyl}amide 2-(3-diethylaminopropylamine)thiazole-5-carboxylic acid {2-methyl-5-[3-(4-Mei-1-yl)-5-triphtalocyaninine]phenyl}amide 2-(3-morpholine-4-ylpropionic)thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-[6-(4-ethylpiperazin-1-yl)-2-methylpyrimidin-4-ylamino]thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide of 2-(6-cyclopropylamino-2-methylpyrimidin-4-ylamino)thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-[6-(2-hydroxyethylamino)-2-methylpyrimidin-4-ylamino]thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-[6-(3-diethylaminopropylamine)-2-methylpyrimidin-4-ylamino]thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide of 2-(2-methyl-6-morpholine-4-Yeremey-4-ylamino)thiazole-5-carboxylic acid {5-[3-(4-hydroxypiperidine-1-yl)-5-triphtalocyaninine]-2-were}amide 2-(2-hydroxyethylamino)thiazole-5-carboxylic acid {5-[3-(4-hydroxypiperidine-1-yl)-5-triphtalocyaninine]-2-were}amide 2-cyclopropylamino-5-carboxylic acid {5-[3-(4-hydroxypiperidine-1-yl)-5-triphtalocyaninine]-2-were}amide 2-(2-morpholine-4-ylethylamine)thiazole-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-METI is phenyl}amide 2-cyclopropylamino-5-carboxylic acid, {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-(2-hydroxyethylamino)thiazole-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-benzylimidazole-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-(2-morpholine-4-ylethylamine)thiazole-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-[6-(2-hydroxyethylamino)-2-methylpyrimidin-4-ylamino]thiazole-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-(6 cyclopropylamino-2-methylpyrimidin-4-ylamino)thiazole-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-(2-methyl-6-morpholine-4-Yeremey-4-ylamino)thiazole-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-[6-(4-ethylpiperazin-1-yl)-2-methylpyrimidin-4-ylamino]thiazole-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-[6-(3-diethylaminopropylamine)-2-methylpyrimidin-4-ylamino]thiazole-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-(2-methyl-6-methylaminopropyl-4-ylamino)thiazole-5-carboxylic acid {2-methyl-5-[3-(4-Mei-1-yl)-5-triphtalocyaninine]phenyl}amide 2-[6-(2-hydro is sidilemine)-2-methylpyrimidin-4-ylamino]thiazole-5-carboxylic acid, {2-methyl-5-[3-(4-Mei-1-yl)-5-triphtalocyaninine]phenyl}amide 2-(6-cyclopropylamino-2-methylpyrimidin-4-ylamino)thiazole-5-carboxylic acid {2-methyl-5-[3-(4-Mei-1-yl)-5-triphtalocyaninine]phenyl}amide 2-(2-methyl-6-morpholine-4-Yeremey-4-ylamino)thiazole-5-carboxylic acid, {2-methyl-5-[3-(4-Mei-1-yl)-5-triphtalocyaninine]phenyl}amide 2-[6-(4-ethylpiperazin-1-yl)-2-methylpyrimidin-4-ylamino]thiazole-5-carboxylic acid {2-methyl-5-[3-(4-Mei-1-yl)-5-triphtalocyaninine]phenyl}amide 2-[6-(3-diethylaminopropylamine)-2-methylpyrimidin-4-ylamino]thiazole-5-carboxylic acid {5-[4-(4-ethylpiperazin-1-ylmethyl)-3-cryptomaterial]-2-were}amide 2-cyclopropylamino-5-carboxylic acid {5-[4-(4-ethylpiperazin-1-ylmethyl)-3-cryptomaterial]-2-were}amide 2-methylaminoethanol-5-carboxylic acid {5-[4-(4-ethylpiperazin-1-ylmethyl)-3-cryptomaterial]-2-were}amide 2-aminothiazol-5-carboxylic acid {5-[4-(4-ethylpiperazin-1-ylmethyl)-3-cryptomaterial]-2-were}amide 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid [2-methyl-5-(4-(morpholine-4-ylmethyl-3-cryptomaterial)phenyl]amide of 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid, [2-methyl-5-(4-piperazine-1-ylmethyl-3-cryptomaterial)phenyl]amide of 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid {2-methyl-[4-(4-methylpiperazin-1-ylmethyl)-3-cryptomaterial]phenyl}amide 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid, {2-methyl-5-[3-(4-Mei-1-yl)-5-cryptomaterial]phenyl}amide 2-cyclopropylamino-5-carboxylic acid {2-methyl-5-[4-(4-methylpiperazin-1-ylmethyl)-3-cryptomaterial]phenyl}amide 2-methylaminoethanol-5-carboxylic acid [2-methyl-5-(4-piperazine-1-ylmethyl-3-cryptomaterial)phenyl]amide 2-cyclopropylamino-5-carboxylic acid, [2-methyl-5-(4-piperazine-1-ylmethyl-3-cryptomaterial)phenyl]amide 2-methylaminoethanol-5-carboxylic acid [2-methyl-5-(4-(morpholine-4-ylmethyl-3-cryptomaterial)phenyl]amide 2-cyclopropylamino-5-carboxylic acid [2-methyl-5-(4-(morpholine-4-ylmethyl-3-cryptomaterial)phenyl]amide 2-methylaminoethanol-5-carboxylic acid, (5-{[1-tert-butyl-5-(4-methylpiperazin-1-ylmethyl)-1H-pyrazole-3-carbonyl]amino}-2-were)amide 2-cyclopropylamino-5-carboxylic acid {2-methyl-5-[3-(4-methylpiperazin-1-yl)-5-triphtalocyaninine]phenyl}amide 2-cyclopropylamino-5-carboxylic acid {2-methyl-5-[3-(4-Mei-1-yl)-5-cryptomaterial]phenyl}amide 2-methylaminoethanol-5-carboxylic acid {2-methyl-5-[4-(4-methylpiperazin-1-ylmethyl)-3-cryptomaterial]phenyl}amide 2-cyclopropylamino-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-cyclopropylamino-5-carboxylic acid {5-[4-(4-this is piperazine-1-ylmethyl)-3-triphtalocyaninine]-2-were}amide 2-cyclopropylamino-5-carboxylic acid, {2-methyl-5-[3-(4-Mei-1-yl)-5-triphtalocyaninine]phenyl}amide 2-cyclopropylamino-5-carboxylic acid (5-{3-[4-(2-hydroxyethyl)piperazine-1-yl]-5-triphtalocyaninine}-2-were)amide 2-cyclopropylamino-5-carboxylic acid {5-[(5-tert-butylthiophene-2-carbonyl)amino]-2-were}amide 2-(2-morpholine-4-ylethylamine)thiazole-5-carboxylic acid {5-[(5-tert-butylthiophene-2-carbonyl)amino]-2-were}amide 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid {5-[(5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl)amino]-2-were}amide 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-{5-[4-(2-hydroxyethyl)piperazine-1-yl]pyridine-2-ylamino}thiazole-5-carboxylic acid (5-{3-[4-(2-hydroxyethyl)piperazine-1-yl]-5-triphtalocyaninine}-2-were)amide 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid [2-methyl-5-(3-cryptomaterial)phenyl]amide of 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid [2-methyl-5-(3-cryptomaterial)phenyl]amide of 2-(pyridine-3-ylamino)thiazole-5-carboxylic acid, [2-methyl-5-(3-cryptomaterial)phenyl]amide 2-cyclopropylamino-5-carboxylic acid [2-methyl-5-(3-cryptomaterial)phenyl]amide of 2-(3-imidazol-1-ylpropyl the Mino)thiazole-5-carboxylic acid, {5-[(5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl)amino]-2-were}amide 2-(2-morpholine-4-ylethylamine)thiazole-5-carboxylic acid [5-(4-chloro-3-triphtalocyaninine)-2-were]amide of 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid {5-[(1-tert-butyl-5-methyl-1H-pyrazole-3-carbonyl)amino]-2-were}amide 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid {2-methyl-5-[3-(pyrrolidin-2-ylethoxy)-5-triphtalocyaninine]phenyl}amide 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid {2-methyl-5-[3-(4-methylpiperazin-1-yl)-5-triphtalocyaninine]phenyl}amide 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid {2-methyl-5-[3-(4-Mei-1-yl)-5-triphtalocyaninine]phenyl}amide 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid [2-methyl-5-(3-cryptomaterial)phenyl]amide of 2-(6-methylpyridin-3-ylamino)thiazole-5-carboxylic acid [2-methyl-5-(3-cryptomaterial)phenyl]amide of 2-(2-morpholine-4-ylethylamine)thiazole-5-carboxylic acid [2-methyl-5-(3-cryptomaterial)phenyl]amide 2-isopropylaminomethyl-5-carboxylic acid [2-methyl-5-(3-cryptomaterial)phenyl]amide 2-[3-(4-methylpiperazin-1-yl)propylamino]thiazole-5-carboxylic acid [2-methyl-5-(4-piperazine-1-ylmethyl-3-triphtalocyaninine)phenyl]amide of 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid {5-[4-(4-ethylpiperazin-1-ylmethyl)-3-triphtalocyaninine]-2-were}amide 2-(pyrid is n-2-ylamino)thiazole-5-carboxylic acid, [2-methyl-5-(4-(morpholine-4-ylmethyl-3-triphtalocyaninine)phenyl]amide 2-cyclopropylamino-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-{6-[4-(2-hydroxyethyl)piperazine-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-[6-(4-methylpiperazin-1-yl)pyrimidine-4-ylamino]thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-{6-[4-(2-hydroxyethyl)piperazine-1-yl]pyrimidine-4-ylamino}thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-[2-methyl-6-(4-methylpiperazin-1-yl)pyrimidine-4-ylamino]thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-{4-[4-(2-hydroxyethyl)piperazine-1-yl]pyridine-2-ylamino}thiazole-5-carboxylic acid.

Application in pharmacology

Compounds of the present invention modulate the activity of kinases, and thus, they can be used for treating disorders or diseases in which the kinase involved in the development of the pathology and/or symptoms of the disease. Examples of kinases whose activity is inhibited by the compounds and compositions described in the present description, and in respect of which use the methods in this context include, without limitation, Abl kinase, Bcr-Abl, FGFR3, PDGFRβ, Flt3 and b-Raf.

Tyrosinekinase Abela is a (ie Abl, C-Abl) is involved in regulation of cell cycle, cellular response to genotoxic stress and is involved in the transfer of information about the environmental cell environment through integrity signal. Mostly, it was found that Abl protein performs complex functions as a cellular module that integrates signals from various extracellular and intracellular sources and affects cell cycle and apoptosis. Tyrosinekinase of Abelson includes derivative, such as a hybrid protein (oncoprotein) BCR-Abl with impaired activity of tyrosine kinase or kinase v-Abl. Kinase BCR-Abl plays a major role in the pathogenesis of 95% of cases of chronic myeloid leukemia (CML) and in 10% of cases of acute lymphoid leukemia. Product STI-571 (Gleevec) is an inhibitor of the oncogenic tyrosine kinase BCR-Abl, which is used for the treatment of chronic myeloid leukemia (CML). However, some patients at the stage dedifferentiated leukemia CML is resistant to STI-571 due to mutations in the kinase BCR-Abl. At present we know of 22 mutations, and mutations include G250E, E255V, T315I, F317L and MT.

Compounds of the present invention inhibit abl kinase, primarily kinase v-abl. Compounds of the present invention also inhibit the kinase BCR-Abl wild type and mutant forms, and thus, they can be used for the treatment of Bcr-abl-positive cancer and tumors, such taklakot (primarily chronic myelogenous leukemia and acute lymphoid leukemia, in which appear the specific mechanisms of apoptosis), and also affect a subset of leukemic stem cells, and such compounds can be used for purification of these cells in vitro after their removal (e.g., after removal of the bone marrow) and for re-implantation of the cells after treatment of cancer cells (for example, re-implantation of purified bone marrow cells).

PDGF (platelet-derived growth factor) is a common growth factor, which plays an important role in normal growth, as well as in pathological cell proliferation, such as cancer and disease of the cells of smooth muscles of blood vessels, such as atherosclerosis and thrombosis. Compounds of the present invention inhibit the activity of the PDGF receptor (DERIVED), and thus, they can be used for the treatment of tumors, such as gliomas, sarcomas, tumors of the prostate and tumors of the colon, breast and ovary.

Compounds of the present invention can be used not only as substances that suppress tumors, such as, for example, small cell lung cancer, but also as an agent for the treatment of benign proliferative diseases such as atherosclerosis, thrombosis, psoriasis, scleroderma, fibreboard is, for the protection of stem cells, for example to reduce hemotoxins effects of chemotherapeutic agents such as 5-fluorouracil, for the treatment of asthma. Compounds of the present invention, first of all, can be used for the treatment of diseases responsive to the inhibition of the receptor kinase PDGF.

Compounds of the present invention can be used for treating disorders arising from transplantation, such as, for example, allogenic transplantation, primarily for the rejection of tissue, such as, first of all, obliterative bronchiolitis (S), i.e. chronic rejection of allogenic lung transplants. In contrast to patients not suffering from S in patients with S often an increased concentration of PDGF in the bronchoalveolar wash liquid.

Compounds of the present invention are also effective for the treatment of diseases associated with cell migration of smooth muscles of blood vessels and proliferation (mainly related to PDGF and PDGF-R), such as restenosis and atherosclerosis. This effect and the result of action of the compounds according to the present invention on the proliferation or migration of smooth muscle cells of blood vessels in vitro and in vivo was observed after administration of the compounds of the present invention, as well as the study of the effects of these compounds on salustiana SOS the vascular intima after mechanical injury in vivo.

Some abnormal proliferative condition as it was found to be associated with the expression of a raf protein and, thus, are sensitive to inhibition of expression of a raf protein. Abnormally high level of expression of a raf protein also causes transformation and abnormal cell proliferation. Such abnormal proliferative condition as it was found, are sensitive to inhibition of expression of a raf protein. For example, expression of the protein c-raf affects abnormal cell proliferation, as 60% of all cell lines lung carcinoma observed extremely high levels of mRNA of c-raf and protein. Other examples of abnormal proliferative conditions include hyperproliferative disorders such as cancer, tumors, hyperplasia, pulmonary fibrosis, angiogenesis, psoriasis, atherosclerosis and cell proliferation of smooth muscles in blood vessels, such as stenosis or restenosis after angioplasty. The path of signal transmission in the cell, which includes raf protein is also associated with inflammatory diseases characterized by proliferation of T-cell activation and growth of T cells), such as, for example, rejection of tissue grafts, endotoxic shock and glomerular nephritis.

Kinase Flt3 is part of a family of receptor tyrosinekinase (RTK) type III. Kinase Flt3 (fms kinase-like tyrosinekinase) from the local called kinase FLk-2 (fetal kinase 2 liver). Abnormal expression of the Flt3 gene has been established in adults and children diagnosed with leukemia, such as acute myeloid leukemia (AML), AML, accompanied the three myelodysplasia (AML/TMDS), acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome (MDS). Activating mutations of the Flt3 receptor were detected in approximately 35% of patients suffering from acute myeloid leukemia (AML), and these diseases are characterized by poor prognosis. The most common mutation involves duplication in the frame in kolomanbrunnen domain, and another 5-10% of patients revealed a point mutation (asparagine 835). Both mutations are associated with constitutive activation of the activity of tyrosine kinase Flt3, which leads to proliferation and activation signals in the absence of ligand. It is established that patients who have been diagnosed with a mutant form of the receptor, practically does not respond to treatment. Thus, there is growing evidence that hyperactivemenu (mutant) activity kinase Flt3 is a cause of leukemia and myelodysplastic syndrome person. There is therefore a need for new inhibitors of Flt3 receptor as a promising therapeutic agents for the treatment of patients for whom modern methods of treatment are ineffective, as well as previously applied inefficient FPIC what would be the treatment and/or a method of treatment using stem cells.

Leukemia usually occurs due to acquired or inherited) genetic damage to the DNA of immature hematopoietic cells in the bone marrow, lymph nodes, spleen or other organs of the hematopoietic and immune systems. This disease is observed accelerated growth and maturation blockade cells, resulting in accumulation of cells called "LenOblast"who are unable to perform the functions of normal blood cells, but also to lack of production of normal bone marrow cells, which leads to a deficiency of red blood cells (anemia), platelets and normal lymphocytes. Power cells, as a rule, are formed in the bone marrow and develop into Mature blood cells, including approximately 1% of all bone marrow cells. In the case of leukemia blast cells do not develop properly and accumulate in the bone marrow. In acute myeloid leukemia (AML) these cells are called myeloblastoma, and acute lymphoblastic leukemia (ALL) these cells called lymphoblasts. Another type of leukemia includes mixed leukemia (MLL).

The term "AML involving the three myelodysplasia (AML/TMDS)" means ordinary form of leukemia, which is characterized disseminations picture similar to the picture in acute leukemia, inefficient induction chemotherapy and opportunities for the Yu relapse net myelodysplastic syndrome.

The term "myelodysplastic syndrome (MDS)" means a group of blood disorders that cause dysfunction of the bone marrow, which leads to a deficit in the number of healthy blood cells. Compared with leukemia, in which only one type of blood cells is produced in large quantities, when myelodysplastic syndrome affected some, and sometimes all types of blood cells. Each year in the United States registered for at least 10,000 new cases. One-third of patients diagnosed with MDS develop acute myelogenous leukemia. In this regard, this disease is sometimes called predlagatb. Myelodysplastic syndrome is also sometimes called myelodysplastic demilovato or oligoester leukemia, or smoldering leukemia, in which a large number of blast cells remain in the bone marrow.

Myelodysplastic syndrome, similar to leukemia, occurs when genetic damage to the DNA in a single cell of the bone marrow. In patients with MDS, revealed some violations functions of chromosomes. Such violations referred to as translocation, when part of one chromosome breaks off and attaches to the damaged part of another chromosome. The same offense are typically observed in acute myeloid leukemia. However, MDS differs from leukemia because all the blood cells of the patient are abnormal and ratwani from the same damaged stem cells. In patients suffering from leukemia, the bone marrow contains a mixture of abnormal and healthy blood cells.

AML and advanced myelodysplastic syndromes currently treated with high doses of cytotoxic chemotherapeutic drugs, such as citizenoriented and daunorubicin. This type of treatment leads to hematological remission in approximately 70% of patients. However, more than half of the patients have been in remission and then relapse occurs, despite chemotherapy for extended periods of time. Almost all patients who have not observed remission at the beginning of treatment or have a recurrence of the disease, ultimately dying of leukemia. Bone marrow transplantation effektivno for 50-60% of patients undergoing surgery, but only about one third of all patients suffering from AML or MDS, is able to move the transplant surgery. In this regard there is an urgent need for new and more effective medicines for patients who have not observed remission in the treatment of standard ways, who have been ill and not able to move the transplant surgery. In addition, the inclusion of new effective drugs in the standard therapy will help perfect the AMB induction chemotherapy for all patients.

The FGFR3 kinase is part of a family of structurally related receptor tyrosinekinase encoded by 4 different genes. Specific point mutations in different domains of FGFR3 gene result in constitutive activation of the receptor and are associated with autosomally dominant bone disease, multiple myeloma, and with most types of cancer of the bladder and cervix (see Cappellen et al., Nature, V.23). Activating mutations in FGFR3 gene of the mouse and the effect on activated FGFR3 leads to the formation in the cartilage growth plate, which is the cause of dwarfism in mice. Similarly, targeted disruption of the gene FGFR3 leads to the overgrowth of the long bones and spine in mice. In addition, from 20% to 25% of multiple myeloma cells contain chromosomal translocation t(4;14)(p16.3;q32.3) with point breaks R centromere FGFR3 size 50-100 kDa. In rare cases in the area of multiple myeloma were identified activating mutations of FGFR3, previously observed in diseases of the skeletal system, which is always accompanied by a specified chromosomal translocation. Recently been identified somatic missense mutations of FGFR3 (R248C, S249C, G372C and CE) in many cancer cells of the bladder and in some cancer cells of the cervix, which are essentially identical activating em is finalnum mutations, causing lethal dysplasia, lethal dwarfism in the neonatal period. Compounds of the present invention exhibit higher efficacy in the treatment of multiple myeloma compared with modern methods of treatment, as well as in the treatment of bladder cancer without the use of cystectomy changing the quality of life, and in the treatment of cervical cancer patients who want to preserve fertility.

Thus, the present invention relates to a method for prevention or treatment of a subject suffering from any of the above disorders or diseases and in need of such treatment, and specified the method according to the present invention includes the introduction of a specified subject a therapeutically effective amount (see below the Chapter on "Methods of administration of medicines and pharmaceutical compositions") the compounds of formula I or its pharmaceutically acceptable salt. In any above using the required dosage varies depending on the method of administration of the medicinal product, the particular condition to be treated, and the desired result of the treatment.

Methods of administration of medicines and pharmaceutical compositions

As a rule, the compounds of the present invention is administered in a therapeutically effective amount by any standard is acceptable ways, known in the art, alone or in combination with one or more therapeutic agents. A therapeutically effective amount varies over a wide range depending on the severity of the disease, the age and condition of the subject, the efficiency of the used connections and other factors. As a rule, satisfactory treatment results are achieved with a systematic introduction connections in a daily dose of from about 0.03 mg/kg to 2.5 mg/kg of body weight. The specified daily dose for a large mammal, such as man, is from about 0.5 mg to about 100 mg, for example, in the form of shared so up to four times per day, or in the form of a delayed release of the drug. Suitable standard dosage forms for oral administration comprise from about 1 mg to 50 mg of active ingredient.

Compounds of the present invention is administered in the form of pharmaceutical compositions by any standard method, first of all enteric way of introduction, for example by oral way, for example, in the form of tablets or capsules, or parenterally by way of introduction, for example, in the form of injection solutions or suspensions, local way of introduction, for example, in the form of lotions, gels, ointments or creams, or in a form designed the La insertion through the nose, or in the form of a suppository. Pharmaceutical compositions comprising compounds of the present invention in free form or in the form of pharmaceutically acceptable salts in a mixture with at least one pharmaceutically acceptable carrier or diluent, receive a standard method, such as mixing, granulating or coating. For example, compositions intended for oral administration include tablets or gelatin capsules containing the active ingredient in a mixture with (a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, (b) an oil, such as, for example, silica, talc, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol, and to obtain tablets also mixed with b) binding agents such as, for example, a silicate of magnesium, starch paste, gelatin, tragakant, methylcellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone, if necessary g) dezinfeciruyuhimi agents such as, for example, starches, agar, alginic acid or its sodium salt, or effervescent mixtures and/or e) absorbents, colorants, flavors and sweeteners. Injectable compositions include aqueous isotonic solutions or suspensions, and suppositories are obtained from EMU is si or suspensions of fats.

The composition is sterilized and/or compositions include adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, dissolution accelerators, salts for regulating osmotic pressure and/or buffer substances. In addition, the compositions also include other therapeutically acceptable substances. Suitable medicines for percutaneous introduction, include an effective amount of the compounds of the present invention in a mixture with a carrier. The carrier includes absorbable pharmacologically acceptable solvents, designed to enhance the permeability of drugs through the skin of the subject. For example, the means for dermal use in the form of a bandage comprising a substrate, a reservoir containing the compound optionally in a mixture with the media, optional wall regulating the delivery rate of the compound in the skin of a subject at a certain pre-level for an extended period of time, and means for securing the device to the skin. Use the compositions for administration of drugs in the matrix. Suitable compositions for local administration, such as, for example, the introduction to the skin and eyes, preferably include aqueous solutions, ointments, creams or gels known in the art. Such compositions are also on the look soljubilizatory, stabilizers, agents that increase the concentration, buffering agents and preservatives.

Compounds of the present invention is administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combination). For example, you can observe a synergistic effect in combination with other immunomodulatory or anti-inflammatory substances, for example, when used in combination with cyclosporine, rapamycin or ascomycin, or immunodepressants analogues, such as, for example, cyclosporin a (CsA), cyclosporin G, FK-506, rapamycin, or similar compounds, corticosteroids, cyclophosphamide, azathioprine, methotrexate, brequinar, Leflunomide, mizoribine, mycofenolate acid, mycophenolate mofetil, 15-doxicillin, immunodepressant antibodies, especially monoclonal antibodies against leukocyte receptors, such as, e.g., MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD45, CD58 or their ligands, or other immunomodulatory compounds, such as CTLA41g. With the introduction of the compounds of the present invention in combination with other methods of treatment the dose of administered jointly compounds vary depending on the nature of the conjunction of the input connections on the specificity of the medicinal product, the condition of the patient to be treated, etc.

Present from reenie also relates to pharmaceutical combinations, such as, for example, the set including a) a first agent which is a compound of the present invention, is described in this context, in free form or in the form of pharmaceutically acceptable salts, and b) at least one additional agent. The set includes instructions for its use.

The terms "co-administration"or "introduction in the form of a mixture," or similar terms used in this description, means the introduction of selected therapeutic agents to a single patient and include treatments in which agents do not necessarily impose the same way or not necessarily at the same time.

The term "pharmaceutical combination"as used in this description, means the product that is obtained after mixing 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, such as, for example, the compound of formula I and an additional agent is administered to a patient simultaneously in the form of a single standard dose. The term "non-fixed combination" means that the active ingredients, such as, for example, the compound of formula I and an additional agent is administered to the patient in the form of various dosage forms, at the same time, together or sequentially without is definitely the time of introduction, this route of administration provides therapeutically effective levels of the two compounds in the body of the patient. This method of introduction also includes combination therapy, such as, for example, the introduction of three or more active ingredients.

Methods for obtaining compounds of the present invention

The present invention also relates to methods of preparing compounds of the present invention. When carrying out the above reactions, there is a need to protect reactive functional groups, such as, for example, hydroxy, amino, imino, thio or carboxylate, to obtain the final product, including these groups in order to exclude unwanted participation of such groups in reactions in obtaining the final product. Standard protective group used using standard methods, for example, see the book T.T.W.Greene and P.G.M.Wuts, "Protective Groups in Organic Chemistry", John Wiley and Sons (1991).

The compounds of formula I get the following scheme I:

Scheme I

where n, R1, R2, R3, R4, R5and R6defined in the description of the invention. The compound of the formula I get in the interaction of the compounds of formula 2 with the compound of the formula 3 in the presence of a suitable solvent (such as, for example, 1,3-dimethyl-2-imidazolidone or the like). The reaction is avodat at a temperature of from approximately 50°to approximately 120°C for 12 h to complete the reaction.

Detailed examples of the synthesis of the compounds of formula I are presented in the Examples section below.

Other 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, compounds of the present invention in the form of salts is obtained using salts as starting materials or intermediates.

Compounds of the present invention in the form of the free acid or base is obtained from the corresponding primary additive 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 free base by treatment with suitable base (such as, 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 is Oli converted into the corresponding free acid in the processing of suitable acid (such as, for example, 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 (such as, for example, sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, trichloride phosphorus, tribromide phosphorus or the like) in a suitable inert organic solvent (such as, for example, acetonitrile, ethanol, aqueous dioxane, or the like) at a temperature from 0°C to 80°C.

Prodrugs of the compounds of the present invention is produced by methods known in the art (see Saulnier and others, Bioorganic and Medicinal Chemistry Letters, v.4, s (1994)). For example, appropriate prodrugs receive when interacting with unmodified compounds of the present invention with suitable carbamimidoyl agent (such as, for example, 1,1-aryloxyalkanoic, para-nitrophenylarsonic or the like).

Protected derivatives of compounds of the present invention is produced by methods known in the art. Detailed description of techniques for the introduction of protective groups and their removal are presented in the book .W.Greene, "Protecting Groups in Organic Chemistry", 3rded., John Wiley and Sons, Inc., (1999).

Compounds of the present invention is produced by methods of the present invention in the form of a solvate (such as, for example, hydrates). G shall include the compounds of the present invention is obtained by recrystallization from a mixture of water/organic solvent with the use of organic solvents, such as dioxin, tetrahydrofuran or methanol.

Compounds of the present invention obtained as their individual stereoisomers by interaction of racemic mixtures of compounds with optically active separating agent with the formation of a pair of diastereomers that share, and then receive the optically pure enantiomers. When the separation of enantiomers using covalent derivatives of diastereoisomers of the compounds of the present invention, preferably dissociable complexes (such as, for example, a crystalline salt of diastereomers). The diastereomers are characterized by different physical properties (such as melting point, boiling point, solubility, reactivity and the like), and, thus, their share in light of these various properties. The diastereomers separated by chromatography or preferably separated using differences in solubility. Then get optically pure enantiomer and a separating agent any of the standard methods, which do not cause racemization. A more detailed description of methods suitable for separation of stereoisomers of compounds from their racemic mixture, represented in the book by Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., (1981).

Thus, the compounds of formula I to obtain the FPIC of the BOM, who is that

(a) carry out the reaction shown 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 a free form

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

(d) optional transform N-oxide compounds of the present invention in its non-oxidized form,

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

(g) optional turn unmodified compound of the present invention in a pharmaceutically acceptable prodrug, and

(C) optional conversion of dosage forms of the compounds of the present invention in its unmodified form.

Obtaining starting materials is not described, as known connections get by known methods or obtaining them are described below in the Examples section below.

The above transformation is provided only to illustrate methods of preparing compounds of the present invention, other known methods can also be used to obtain compounds truly is obreteniyu.

Examples

The following examples are given for illustration only obtain the compounds of the present invention of the formula I and do not limit the scope and essence of the invention.

Example 1

[2-Methyl-5-(3-triphtalocyaninine)phenyl]amide of 2-(3-diethylaminopropylamine)thiazole-5-carboxylic acid

3-Cryptomathematical (4,90 g, was 31.0 mmole) was added to stirred solution of 4-methyl-3-nitroaniline (1,00 g, 6,57 mmole) and triethylamine (1,10 ml, 7,89 mmole) at 0°C and the resulting mixture was stirred at room temperature for 1 h the Reaction mixture was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO4and concentrated under reduced pressure, it was obtained the crude product, which was dissolved in the Meon and the solution was added 10% Pd/C. the Reaction mixture was stirred in hydrogen atmosphere at room temperature for 12 hours, the Reaction mixture was then filtered through celite, and the filtrate was concentrated under reduced pressure, was obtained N-(3-amino-4-were)-3-cryptomelane in a solid dark gray color.

Hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (355 mg, of 0.93 mmole) was added to stirred solution of N-(4-methyl-3-nitrophenyl)-3-cryptomelane is (250 mg, of 0.85 mmole), 2-bromothiazole-5-carboxylic acid (177 mg, of 0.85 mmole) and diisopropylethylamine (of 0.59 ml, 3.4 mmole) in DMF, the mixture was stirred at room temperature for 12 hours, the Reaction mixture was diluted EtO and washed with 10% aqueous sodium thiosulfate solution. The organic layer was dried over MgSO4and concentrated under reduced pressure. The crude product was purified preparative GHUR, it was received [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-bromothiazole-5-carboxylic acid in the form of a solid light brown color.

[2-Methyl-5-(3-triphtalocyaninine)phenyl]amide 2-bromothiazole-5-carboxylic acid (25 mg, 52 μmol) was dissolved 3-(diethylamino)Propylamine and the mixture was stirred at 80°C for 4 h, the Crude product was diluted in DMSO (1 ml) and was purified preparative GHUR, it was received [2-methyl-5-(3-triphtalocyaninine)phenyl]amide of 2-(3-diethylaminopropylamine)thiazole-5-carboxylic acid in the form of triptoreline. MS: m/z 534,4 (M+1).

1H-NMR (400 MHz, DMSO-d6): δ 9,67 (s, 1H), 9,43 (user., 1H), 8,35 (t, 1H), 8,29 (s, 1H), compared to 8.26 (d, 1H), of 7.96 (d, 1H), 7,94 (s, 1H), 7,80 (d, 1H), 7,58 (d, 1H), 7,25 (d, 1H), 3,35 (q, 2H), 2,89 (m, 6H), are 2.19 (s, 3H), of 1.93 (m, 2H), 1,20 (t, 6H).

Example 2

[2-Methyl-5-(3-triphtalocyaninine)phenyl]amide 2-{6-[4-(2-hydroxyethyl)piperazine-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxylic acid

4,6-Dichloro-2-methylpyrimidin (of 5.05 g, was 31.0 mmole) in DMF was added to a suspension of methyl ester 2-aminothiazol-5-carboxylic acid (4,90 g, was 31.0 mmole) and NaH (60% dispersion in mineral oil, 1,36 g, 34.1 mmole) in DMF at 0°C and the resulting mixture was stirred at room temperature for 2 hours the Reaction mixture was diluted with EtOAc and washed with 10% aqueous sodium thiosulfate solution. The organic layer was dried over MgSO4and concentrated under reduced pressure. The crude product was led from the Meon, received methyl ester of 2-(6-chloro-2-methylpyrimidin-4-ylamino)thiazole-5-carboxylic acid in the form of a solid white color.

4 N. NaOH (15 ml) was added a mixed solution of methyl ester of 2-(6-chloro-2-methylpyrimidin-4-ylamino)thiazole-5-carboxylic acid (of 3.97 g of 14.0 mmole) in Meon and the resulting mixture was stirred at 60°C for 12 h, the Reaction mixture was neutralized 1 N. Hcl, the precipitate was separated by filtration and washed Meon, received 2-(6-chloro-2-methylpyrimidin-4-ylamino)thiazole-5-carboxylic acid in the form of a solid white color.

Hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (355 mg, of 0.93 mmole) was added to a solution of 2-(6-chloro-2-methylpyrimidin-4-ylamino)thiazole-5-carboxylic acid (230 mg, of 0.85 mmole), N-(3-amino-4-were)-3-cryptomelane (250 mg, of 0.85 mmole) and diisopropyl the ethylamine (0,59 ml, 3.4 mmole) in DMF and the resulting mixture was stirred at room temperature for 12 hours the Reaction mixture was diluted with EtOAc and washed with 10% aqueous sodium thiosulfate solution. The organic layer was dried over MgSO4and concentrated under reduced pressure. The crude product was purified preparative GHUR, it was received [2-Methyl-5-(3-triphtalocyaninine)phenyl]amide of 2-(6-chloro-2-methylpyrimidin-4-ylamino)thiazole-5-carboxylic acid in the form of a solid white color.

Excess 2-piperazine-1-retinol (100 mg) in 1,3-dimethyl-2-imidazolidinone (0.2 ml) was added to the stirred solution of [2-methyl-5-(3-triphtalocyaninine)phenyl]amide of 2-(6-chloro-2-methylpyrimidin-4-ylamino)thiazole-5-carboxylic acid (25 mg, 46 mcmole) in 1,3-dimethyl-2-imidazolidinone (0.2 ml) and the resulting mixture was stirred at 60°C for 4 h, the Crude product was diluted in DMSO (1 ml) and was purified preparative GHUR, it was received [2-Methyl-5-(3-triphtalocyaninine)phenyl]amide 2-{6-[4-(2-hydroxyethyl)piperazine-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxylic acid in the form of triptoreline. MS: m/z to 641.5 (M+1).

1H-NMR (400 MHz, MeOH-d4): δ compared to 8.26 (s, 1H), to 8.20 (d, 1H), 8,15 (s, 1H), of 7.90 (d, 1H), 7,83 (s, 1H), 7,74 (t, 1H), 7,55 (d, 1H), 7,31 (d, 1H), 6,20 (user., 1H), 3,93 (dd, 2H), 3,50 (user., 8H), the 3.35 (dd, 2H), 2,53 (s, 3H), 2,31 (s, 3H).

Example 3

{5-[3-(4-Ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-2-hydroxyethylamino)thiazole-5-carboxylic acid

Hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (710 mg, 1.9 mmole) was added to stirred solution of 4-methyl-3-nitroaniline (259 mg, 1.7 mmole), 3-(4-ethylpiperazin-1-yl)-5-triftorperasin acid (514 mg, 1.7 mmole) and diisopropylethylamine (1,19 ml, 6.8 mmole) in DMF and the resulting mixture was stirred at room temperature for 12 hours the Reaction mixture was diluted with EtOAc and washed with 10% aqueous sodium thiosulfate solution. The organic layer was dried over MgSO4and concentrated under reduced pressure, it was obtained the crude product, which was dissolved in the Meon and the solution was added 10% Pd/C. the Reaction mixture was stirred in hydrogen atmosphere at room temperature for 12 hours, the Reaction mixture was then filtered through celite, and the filtrate was concentrated under reduced pressure, was obtained N-(3-amino-4-were)-3-(4-ethylpiperazin-1-yl)-5-cryptomelane.

Hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (355 mg, of 0.93 mmole) was added to stirred solution of N-(3-amino-4-were)-3-(4-ethylpiperazin-1-yl)-5-cryptomelane (345 mg, of 0.85 mmole), 2-bromothiazole-5-carboxylic acid (177 mg, of 0.85 mmole) and diisopropylethylamine (of 0.59 ml, 3.4 mmole) in DMF and the resulting mixture was stirred at room temperature for 12 hours, the Reaction mixture is abbasli EtOAc and washed with 10% aqueous sodium thiosulfate solution. The organic layer was dried over MgSO4and concentrated under reduced pressure. The crude product was purified preparative GHUR, while {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-bromothiazole-5-carboxylic acid in the form of a solid light brown color.

{5-[3-(4-Ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-bromothiazole-5-carboxylic acid (25 mg, 42 μmol) was dissolved in ethanolamine and the resulting mixture was stirred at 80°C for 4 h, the Crude product was diluted in DMSO (1 ml) and was purified preparative GHUR it was received {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-(2 hydroxyethylamino)thiazole-5-carboxylic acid in the form of triptoreline. MS: m/z 577,5 (M+1).

1H-NMR (400 MHz, MeOH-d4): δ 7,87 (s, 1H), to 7.77 (s, 1H), of 7.75 (s, 1H), 7,71 (s, 1H), 7,51 (d, 1H), 7,46 (s, 1H), 7,24 (d, 1H), 4,50 (user., 2H), and 3.72 (m, 2H), 3,68 (user., 2H), 3.45 points (m, 2H), 3,22 (user., 6N), of 2.23 (s, 3H), of 1.38 (t, 3H).

The compounds of formula I are presented in table 1, was obtained in the same way as described in the examples described above, using appropriate starting materials.

Methods of analysis

Compounds of the present invention were evaluated for their ability to selectively inhibit cell proliferation of Ba/F3 expressing BCR-Abl (Ba/F3-p210), compared with the original BaF3 cells. Compounds that selectively inhibit the proliferation of transformed cells BCR-Abl, were evaluated for their antiproliferative activity against cells Ba/F3 expressing Bcr-abl wild-type or mutant forms identified in patients resistant to Gleevec (mutations G250E, E255V, T315I, F317L and M351T).

In addition, compounds were evaluated for their ability to inhibit Abl kinase, Bcr-Abl, FGFR3, PDGFRβ, Flt3 and b-Raf.

Inhibition of cell proliferation is dependent on BCR-Abl (Express method)

As the cell line used a mouse line Ba/F3 cells of Pro-transformed cDNA BCR-Abl (Ba/F3-p210). These cells were cultured in medium RPMI/10% ETS (RPMI/ETS)containing 50 μg/ml penicillin, 50 μg/ml streptomycin, and 200 mm L-gluten is. Balocny method were cultured normal cells Ba/F3 adding recombinant IL3 mouse.

Inhibition of cell proliferation is dependent on BCR-Abl

Cells Ba/F3-p210 was added to the wells of the 96-hole tablet TC at a density of 15,000 cells per well. To each well was added 50 μl of 2-fold serial dilutions of the compounds (Cmaxis 10 μm as a positive control was used STI571). After incubation of the cells for 48 h at 37°C and 5% CO2to each well was added to 15 μl of MTT reagent (Promega) and the cells incubated for a further 5 hours the Optical density was measured spectrophotometrically at 570 nm and the value of the IC50, i.e. the concentration of compound required for 50% inhibition was calculated by the response curve dose-response.

Effect on cell cycle distribution

Cells Ba/F3 and Ba/F3-p210 was added to the wells of a 6-hole tablet TC at a density of 2.5×106of cells per well in 5 ml of medium was added to the studied compound at a concentration of 1 or 10 μm (as a control was used STI571). Cells were incubated for 24 h or 48 h at 37°C and 5% CO2. 2 ml of Cell suspension was washed FSB, were fixed in 70% EtOH for 1 h and treated with a mixture FSB/EDTA/Mcasa And within 30 minutes was Added iodide of propecia (Cf is 10 ág/m is) and the intensity of fluorescence was determined by flow cytometry in a FACScalibur system (BD Biosciences). It is established that the compounds of the present invention exhibit apoptotic effect on cells Ba/F3/p210, but does not induce apoptosis of the original cells Ba/F3.

The effect on autophosphorylation BCR-Abl in cells

The level of autophosphorylation BCR-AbI was determined quantitatively by ELISA for binding using specific antibodies against C-abl antibodies against phosphotyrosine. Cells Ba/F3-p210 was added to the wells of the 96-hole tablet TC at a density of 2×105cells in 50 μl of medium in the well. To each well was added 50 μl of 2-fold serial dilutions of the compounds (Cmaxis 10 μm as a positive control was used STI571). After incubation of the cells for 90 min at 37°C and 5% CO2cells were treated with 150 μl chilled on ice buffer for lysis (50 mm Tris-HCl, pH 7.4, 150 mm NaCl, 5 mm EDTA, 1 mm EGTA, and 1% NP-40)containing protease inhibitors and phosphatase for 1 h In the wells of 96-hole tablet optiplate with pre-printed with specific antibodies anti-abl, treated with blocking buffer, was added 50 μl of cell lysate. The plates were incubated for 4 h at 4°C. After washing with buffer TBS/tween-20, the wells were added to 50 ál conjugate of Titel against phosphotyrosine and alkaline phosphatase and the plate is incubated in ECENA night at 4°C. After washing with buffer TBS/tween-20, the wells were added to 90 μl of the fluorescent substrate and the luminescence was measured in the system Acquest (Molecular Devices). The compounds according to the invention, which inhibit proliferation of cells expressing BCR-Abl, inhibit autophosphorylation cellular BCR-Abl depending on the dose.

Action on the proliferation of cells expressing mutant forms of Bcr-abl

Compounds of the present invention were evaluated for their antiproliferative activity against cells Ba/F3 expressing BCR-Abl wild-type or mutant forms of BCR-Abl (mutations G250E, E255V, T315I, F317L and MT), who show resistance or decreased sensitivity to STI571. Antiproliferative effect of these compounds on cells expressing mutant BCR-Abl, and is not transformed cells was determined as described above. The value of the IC50for connections, it does not show toxicity against normal cells, was calculated using the response curve dose-response.

FGFR3 (Enzymatic analysis method)

Kinase activity of purified FGFR3 (Upstate) was determined in the final volume of the reaction mixture of 10 μl containing 0.25 μg/ml of enzyme in a buffer solution for the determination of kinase activity (30 mm Tris-HCl, pH 7.5, 15 mm MgCl2, 4.5 mm MnCl2, 15 μm Na3VO4and 0 μg/ml BSA) and substrates (5 μg/ml Biotin-poly-EY(CIu, Tight) (CIS-US, Inc.) and 3 μm ATP). Prepared two solutions: to each well of 384-hole tablet ProxiPlate (Perkin-Elmer) was added to 5 μl of the first solution containing the FGFR3 enzyme in solution to determine the kinase, and added in 50 nl of compounds dissolved in DMSO, followed by 5 μl of the second solution containing the substrate (poly-EY) and ATP in a buffer solution to determine the kinase. The reaction mixture was incubated at room temperature for 1 h, the reaction was stopped by adding 10 μl of the mixture for the detection of HTRF containing 30 mm Tris-HCl, pH 7.5, 0.5 M KF, 50 mm ETDA, 0.2 mg/ml BSA, 15 μg/ml of streptavidin-L665 (CIS-US, Inc.) and 150 ng/ml conjugate antibodies against phosphotyrosine and cryptate (CIS-US, Inc.). After incubation at room temperature for 1 h, sufficient for interaction of streptavidin with Biotin, registered resolved in time fluorescent signals in the system Analyst GT (Molecular Devices Corp.). The value of the IC50was calculated by the method of linear regression analysis of the inhibition percentage for each connection, with 12 concentrations (dilution 1:3 from 50 μm to 0.28 nm). According to this analysis, the compounds according to the invention are characterized by the value of the IC50in the range from 10 nm to 2 μm.

FGFR3 (Analysis using cell)

Compounds according to the invention were evaluated for their ability to inhibit the proliferation of transformed glue is OK Ba/F3-TEL-FGFR3, which depends on the activity of FGFR3 kinase in cells. Cells Ba/F3-TEL-FGFR3 were cultured at a density of 800,000 cells/ml in suspension in RPMI medium containing 10% ETS. Cells were added in 50 μl culture medium in wells of 384-well plate at a density of 5000 cells per well. Compounds according to the invention was dissolved and diluted in DMSO. Got a serial dilution of 1:3 in DMSO at 12 concentrations from 10 mm to 0.05 microns. In wells with cells were added in 50 nl of diluted compounds and the mixture incubated for 48 h in an incubator to culture cells. To register a reducing environment produced during cell proliferation, the cells were added to the AlamarBlue reagent (Trek Diagnostic Systems) at a final concentration of 10%. After incubation for another 4 h at 37°C in incubator for culture of cells fluorescent signals were recorded during recovery of the AlamarBlue reagent (wavelength excitation 530 nm, emission 580 nm) in the system Analyst GT (Molecular Devices Corp.). The value of the IC50was calculated by the method of linear regression analysis of the inhibition percentage for each connection, with 12 concentrations.

FGFR3 and PDGFRβ (Analysis using cell)

The action of the compounds according to the invention on the cellular activity of FLT3 and PDGFRβ were evaluated by similar methods as described for the cellular activity of FGFR3, but using instead of Ba/F3-TEL-FGFR3 kinase Ba/F3-FLT3-ITD and Ba/F3-el-PDGFRβ, respectively.

b-Raf (Enzymatic analysis method)

Compounds according to the invention were evaluated for their ability to inhibit the kinase activity of b-Raf. The analysis was performed in 384-well the tablet MaxiSorp (Nunc) with black wall and clear bottom. To each well was added to 15 μl of IκBα substrate diluted in DPBS buffer solution (1:750). Tablet incubated at 4° C overnight and washed three times with buffer TBST (25 mm Tris, pH 8.0, 150 mm NaCl and 0.05% tween-20) using a device for washing tablet EMBLA. The plates were blocked with Superblock solution (15 μl in the hole) for 3 h at room temperature, washed 3 times with TBST buffer solution and dried gently. To each well was added 10 μl of buffer solution for analysis containing 20 μm ATP, and then 100 or 500 nl nl connection. B-Raf was diluted in a buffer solution for analysis (1 ál 25 ál) and to each well was added 10 μl of a dilute solution of b-Raf (0,4 µg / well). The plates were incubated at room temperature for 2.5 hours Kinase reaction was stopped when washing tablets 6 times with TBST solution. Antibodies Phosph-IicBa (Ser32/36) was diluted in Superblock solution (1:10000) and to each well was added to 15 μl. The plates were incubated at 4°C overnight and washed 6 times with TBST solution. Conjugate AR-goat antimachine IgG was diluted in Superblock solution (1:1500) and to each well was added to 15 μl. P is anxiety incubated at room temperature for 1 h and washed 6 times with TBST solution. To each well was added to 15 μl of the fluorescent substrate Attophos AP (Promega) and the plates were incubated at room temperature for 15 minutes Tablets read in the system Acquest or Analyst GT using the program for measuring the intensity of fluorescence (wavelength of 455 nm excitation, emission 580 nm).

B-Raf (Analysis using cell)

Compounds according to the invention were evaluated for their ability to inhibit the phosphorylation of MEK in cells A. Cell line A3 75 (ATS) were obtained from the tissue of a patient with melanoma and includes the V599E mutation in a gene called B-Raf. The levels of phosphorylated MEK increase due to mutations of B-Raf. Cells A in phase from subconfluent to confluentes incubated in the presence of the compounds for 2 h at 37°C in medium containing no serum. Then the cells were washed once with cold FSB and literally in the buffer solution for lysis, containing 1% Triton X100. After centrifugation supernatant was applied to a polyacrylamide gel and perform electrophoresis SDS page-ordinator, and then zone were transferred to nitrocellulose membrane. Membranes were subjected to Western-blotting in the presence of antibodies anti-phospho-MEK (ser217/221, Cell Signaling). The amount of phosphorylated MEK was determined by density zones phosphor-MEK on nitrocellulose membrane.

Upstate KinaseProfiler (Radiodermatitis analysis of binding filter)

Connection p the invention were evaluated for their ability to inhibit individual kinase from a special panel of kinases. Compounds were analyzed in two repetitions at a final concentration of 10 μm by the following General method. Note that the composition of the buffer solution for the analysis of kinases and substrates vary depending on various kinases included in the panel Upstate KinaseProfiler. In an Eppendorf tube on ice, mixed buffer solution for the analysis of kinase (2,5 ál, 10x, containing, if necessary, MnCl2), active kinase (0,001-0,01 Ed., 2.5 μl), a specific peptide or poly(Glu4-Tight) (5-500 μm or 0.01 mg/ml) in buffer solution for the analysis of kinase and buffer solution for the analysis of kinase (50 ám, 5 ml). Then was added a mixture of Mg/ATP (10 μl, 67,5 (or 33,75) mm MgCl2, 450 (or 225) μm ATP and 1 µci/µl [γ-32P]-ATP (3000 CI/mmol) and the reaction mixture is incubated at about 30°C for approximately 10 minutes, the Reaction mixture was applied (20 µl) into squares of material of size 2 × 2 cm of the following type: D81 (phosphocellulose for positively charged peptide substrates) or Whatman No. 1 (peptide substrate poly(Glu4-Tyr). The squares were washed 4 times for 5 min with 0.75% phosphoric acid and once with acetone for 5 minutes Boxes carried in the acquired scintillation vial was added 5 ml of acquired scintillation mixture and determined the inclusion of32P (pulse/min) in the peptide substrate on the acquired scintillation counter Beckman. For each reaction is Oh mixture was calculated percent inhibition.

The compounds of formula I in free form or in the form of pharmaceutically acceptable salts exhibit valuable pharmacological properties, for example, according to in vitro assays, as described in this context. For example, the value of the IC50for compounds of formula I preferably is in the range from 1×10-10up to 1×10-5M, preferably less than 150 nm in relation to at least one of the following kinases: Abl, SIV-bl, FGFR3, PDGFRβ, b-Raf and Flt-3. For example,

(1) the value of the IC50for [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-[6-(4-ethylpiperazin-1-yl)-2-methylpyrimidin-4-ylamino]thiazole-5-carboxylic acid (example 8) is 5 nm to 2.29 ám, 12 nm, 1,27 µm 5 nm and 5 nm in relation kinase wild-type, G250E, E255V, T315I, F317L and MT SIV-bl respectively,

(2) the value of the IC50for {2-methyl-5-[3-(4-Mei-1-yl)-5-diftormetilirovaniya]phenyl}amide 2-[6-(4-ethylpiperazin-1-yl)-2-methylpyrimidin-4-ylamino]thiazole-5-carboxylic acid (example 29) is 8 nm and 570 nm against kinase wild-type and T351I Bcr-bl respectively,

(3) the value of the IC50for {2-methyl-5-[3-(4-Mei-1-yl)-5-diftormetilirovaniya]phenyl}amide 2-(2-methyl-6-morpholine-4-Yeremey-4-ylamino)thiazole-a-carboxylic acid (example 28) is 5 nm against PDGFRβ and

(4) the value of the IC50for {2-methyl-5-[3-(4-Mei-1-yl)-5-diftormetilirovaniya]phenyl}amide 2-[6-(hydroxyethylamino)-2-methylpyrimidin-4-ylamino]thiazole-5-carboxylic acid (compound 5) is 41 nmav against Flt-3.

The percentage of inhibition of one of the following kinases: Abl, Bcr-Abl, FGFR3, PDGFRβ, b-Raf and Flt-3 compounds of formula I at a concentration of 10 μm is preferably more than 50%, preferably more than about 70%.

It should be understood that the present description, the examples and embodiments of the invention are given only to illustrate the invention and that experts in the field of technology it is evident that various modifications and changes that are included in the scope and essence of the invention as defined in the claims. All publications, patents and applications for patents cited in this context, are included in this description as a reference.

1. The compound of formula Ia

where m is selected from 0 and 1,
R1selected from the group comprising hydrogen, methyl, isopropyl, imidazolidinyl, piperazinyl, pyridinyl, diethylaminopropyl, hydroxyethyl, pyrimidinyl, morpholinopropan, phenyl, cyclopropyl, morpholinoethyl, benzyl, morpholino where any pyridinyl, imidazolyl, piperazinil or pyrimidinyl in the composition of R1optionally substituted by 1-3 radicals independently selected from the group comprising methyl, methylamino, dimethylaminomethyl, cyclopropylamino, hydroxyethylamino, diethylaminopropylamine, pyrrolidinyl, morpholino, morpholine is methyl, piperazinylmethyl and piperazinil, and any morpholino and piperazinil in the composition of R1optionally additionally substituted by a radical selected from the group comprising methyl, hydroxyethyl and ethyl,
R2, R3and R5each means hydrogen,
R4means methyl,
L is chosen from the group comprising-NR5C(O)- and-C(O)NR5-,
R10means trifluoromethyl, and
R11selected from the group including halogen, morpholinomethyl, piperazinil, optionally substituted by methyl group, ethyl or hydroxyethyl; piperazinylmethyl, optionally substituted with methyl group or ethyl, imidazolyl, optionally substituted stands, pyrrolidinyloxy and piperidinyl, optionally substituted hydroxy-group.

2. The compound according to claim 1, selected from the following compounds:
[2-methyl-5-(3-triphtalocyaninine)phenyl]amide of 2-(3-diethylaminopropylamine)-thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-{6-[4-(2-hydroxyethyl)piperazine-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-(2-hydroxyethylamino)thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-{6-[4-(2-hydroxyethyl)piperazine-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxylic acid [2-methyl-5-(3-cryptomelane is amino)phenyl]amide of 2-(3-morpholine-4-ylpropionic)thiazole-5-carboxylic acid, [2-methyl-5-(3-triphtalocyaninine)phenyl]amide of 2-(3-diethylaminopropylamine)thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-phenylimidazol-5-carboxylic acid {2-methyl-5-[3-(4-Mei-1-yl)-5-triphtalocyaninine]phenyl}amide 2-(2-hydroxyethylamino)thiazole-5-carboxylic acid {2-methyl-5-[3-(4-Mei-1-yl)-5-triphtalocyaninine]phenyl}amide 2-(3-diethylaminopropylamine)thiazole-5-carboxylic acid {2-methyl-5-[3-(4-Mei-1-yl)-5-triphtalocyaninine]phenyl}amide 2-(3-morpholine-4-ylpropionic)thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-[6-(4-ethylpiperazin-1-yl)-2-methylpyrimidin-4-ylamino]thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide of 2-(6-cyclopropylamino-2-methylpyrimidin-4-ylamino)thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-[6-(2-hydroxyethylamino)-2-methylpyrimidin-4-ylamino]thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-[6-(3-diethylaminopropylamine)-2-methylpyrimidin-4-ylamino]thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide of 2-(2-methyl-6-morpholine-4-Yeremey-4-ylamino)-thiazole-5-carboxylic acid {5-[3-(4-hydroxypiperidine-1-yl)-5-triphtalocyaninine]-2-were}amide 2-(2-hydroxyethylamino)thiazole-5-carboxylic KIS is the notes, {5-[3-(4-hydroxypiperidine-1-yl)-5-triphtalocyaninine]-2-were}amide 2-cyclopropylamino-5-carboxylic acid {5-[3-(4-hydroxypiperidine-1-yl)-5-triphtalocyaninine]-2-were}amide 2-(2-morpholine-4-ylethylamine)thiazole-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-cyclopropylamino-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-(2-hydroxyethylamino)thiazole-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-benzylimidazole-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-(2-morpholine-4-ylethylamine)thiazole-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-[6-(2-hydroxyethylamino)-2-methylpyrimidin-4-ylamino]-thiazole-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-(6-cyclopropylamino-2-methylpyrimidin-4-ylamino)thiazole-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-(2-methyl-6-morpholine-4-Yeremey-4-ylamino)thiazole-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-[6-(4-ethylpiperazin-1-yl)-2-methylpyrimidin-4-ylamino]thiazole-5-carboxylic acid {5-[3-(4-e is reparacin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-[6-(3-diethylaminopropylamine)-2-methylpyrimidin-4-ylamino]thiazole-5-carboxylic acid, {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-(2-methyl-6-methylaminopropyl-4-ylamino)thiazole-5-carboxylic acid {2-methyl-5-[3-(4-Mei-1-yl)-5-triphtalocyaninine]phenyl}amide 2-[6-(2-hydroxyethylamino)-2-methylpyrimidin-4-ylamino]thiazole-5-carboxylic acid, {2-methyl-5-[3-(4-Mei-1-yl)-5-triphtalocyaninine]-phenyl}amide 2-(6-cyclopropylamino-2-methylpyrimidin-4-ylamino)thiazole-5-carboxylic acid {2-methyl-5-[3-(4-Mei-1-yl)-5-triphtalocyaninine]phenyl}amide 2-(2-methyl-6-morpholine-4-Yeremey-4-ylamino)thiazole-5-carboxylic acid, {2-methyl-5-[3-(4-Mei-1-yl)-5-triphtalocyaninine]phenyl}amide 2-[6-(4-ethylpiperazin-1-yl)-2-methylpyrimidin-4-ylamino]thiazole-5-carboxylic acid {2-methyl-5-[3-(4-Mei-1-yl)-5-triphtalocyaninine]phenyl}amide 2-[6-(3-diethylaminopropylamine)-2-methylpyrimidin-4-ylamino]thiazole-5-carboxylic acid {5-[4-(4-ethylpiperazin-1-ylmethyl)-3-cryptomaterial]-2-were}amide 2-cyclopropylamino-5-carboxylic acid {5-[4-(4-ethylpiperazin-1-ylmethyl)-3-cryptomaterial]-2-were}-amide 2-methylaminoethanol-5-carboxylic acid {5-[4-(4-ethylpiperazin-1-ylmethyl)-3-cryptomaterial]-2-were} amide 2-aminothiazol-5-carboxylic acid {5-[4-(4-ethylpiperazin-1-ylmethyl)-3-cryptomaterial]-2-were}amide 2-(who iridin-2-ylamino)thiazole-5-carboxylic acid, [2-methyl-5-(4-(morpholine-4-ylmethyl-3-cryptomaterial)phenyl]amide of 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid [2-methyl-5-(4-piperazine-1-ylmethyl-3-cryptomaterial)phenyl]amide of 2-(pyridine-2-ylamino)-thiazole-5-carboxylic acid {2-methyl-5-[4-(4-methylpiperazin-1-ylmethyl)-3-cryptomaterial]phenyl}amide 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid {2-methyl-5-[3-(4-Mei-1-yl)-5-cryptomaterial]phenyl}amide 2-cyclopropylamino-5-carboxylic acid {2-methyl-5-[4-(4-methylpiperazin-1-ylmethyl)-3-cryptomaterial]phenyl}amide 2-methylaminoethanol-5-carboxylic acid [2-methyl-5-(4-piperazine-1-ylmethyl-3-cryptomaterial)phenyl]amide 2-cyclopropylamino-5-carboxylic acid [2-methyl-5-(4-piperazine-1-ylmethyl-3-cryptomaterial)phenyl]amide 2-methylaminoethanol-5-carboxylic acid [2-methyl-5-(4-(morpholine-4-ylmethyl-3-cryptomaterial)phenyl]amide 2-cyclopropylamino-5-carboxylic acid [2-methyl-5-(4-morpholine-4-ylmethyl-3-cryptomaterial)phenyl]amide 2-methylaminoethanol-5-carboxylic acid (5-{[1-tert-butyl-5-(4-methylpiperazin-1-ylmethyl)-1H-pyrazole-3-carbonyl]amino}-2-were)amide 2-cyclopropylamino-5-carboxylic acid {2-methyl-5-[3-(4-methylpiperazin-1-yl)-5-triphtalocyaninine]phenyl}amide 2-cyclopropylmethanol-5-carboxylic acid {-methyl-5-[3-(4-Mei-1-yl)-5-cryptomaterial]phenyl}amide 2-methylaminoethanol-5-carboxylic acid, {2-methyl-5-[4-(4-methylpiperazin-1-ylmethyl)-3-cryptomaterial]phenyl}amide 2-cyclopropylamino-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-cyclopropylamino-5-carboxylic acid {5-[4-(4-ethylpiperazin-1-ylmethyl)-3-triphtalocyaninine]-2-were}amide 2-cyclopropylmethanol-5-carboxylic acid {2-methyl-5-[3-(4-Mei-1-yl)-5-triphtalocyaninine]phenyl}amide 2-cyclopropylamino-5-carboxylic acid (5-{3-[4-(2-hydroxyethyl)piperazine-1-yl]-5-triphtalocyaninine}-2-were)amide 2-cyclopropylamino-5-carboxylic acid {5-[(5-tert-butylthiophene-2-carbonyl)amino]-2-were}amide 2-(2-morpholine-4-ylethylamine)thiazole-5-carboxylic acid {5-[(5-tert-butylthiophene-2-carbonyl)amino]-2-were}amide 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid {5-[(5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl)amino]-2-were}amide 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid [2-methyl-5-(3-trifloromethyl-amino)phenyl]amide 2-{5-[4-(2-hydroxyethyl)piperazine-1-yl]pyridine-2-ylamino}thiazole-5-carboxylic acid (5-{3-[4-(2-hydroxyethyl)piperazine-1-yl]-5-triphtalocyaninine}-2-were)amide 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid {5-[3-(4-ethylpiperazin-1-yl)-5-triphtalocyaninine]-2-were}amide 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid, 2-methyl-5-(3-cryptomaterial)phenyl]amide of 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid, [2-methyl-5-(3-cryptomaterial)phenyl]amide of 2-(pyridine-3-ylamino)thiazole-5-carboxylic acid [2-methyl-5-(3-cryptomaterial)phenyl]amide 2-cyclopropylamino-5-carboxylic acid [2-methyl-5-(3-cryptomaterial)phenyl]amide of 2-(3-imidazol-1-ylpropionic)thiazole-5-carboxylic acid {5-[(5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl)amino]-2-were}amide 2-(2-morpholine-4-ylethylamine)thiazole-5-carboxylic acid [5-(4-chloro-3-triphtalocyaninine)-2-were]amide of 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid {5-[(1-tert-butyl-5-methyl-1H-pyrazole-3-carbonyl)amino]-2-were}amide 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid {2-methyl-5-[3-(pyrrolidin-2-ylethoxy)-5-triphtalocyaninine]phenyl}amide 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid {2-methyl-5-[3-(4-methylpiperazin-1-yl)-5-triphtalocyaninine]phenyl)amide 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid, {2-methyl-5-[3-(4-Mei-1-yl)-5-triphtalocyaninine]phenyl}amide 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid [2-methyl-5-(3-cryptomaterial)phenyl]amide of 2-(6-methylpyridin-3-ylamino)thiazole-5-carboxylic acid [2-methyl-5-(3-cryptomaterial)phenyl]amide of 2-(2-morpholine-4 ylethylamine)thiazole-5-carboxylic acid [2-methyl-5-(3-cryptomaterial)phenyl]amide 2-isopropylaminomethyl-5-carboxylic acid [2-methyl-5-(3-Tr is pharmacyphentermine)phenyl]amide 2-[3-(4-methylpiperazin-1-yl)propylamino]thiazole-5-carboxylic acid, [2-methyl-5-(4-piperazine-1-ylmethyl-3-triphtalocyaninine)phenyl] amide of 2-(pyridine-2-ylamino)-thiazole-5-carboxylic acid {5-[4-(4-ethylpiperazin-1-ylmethyl)-3-triphtalocyaninine]-2-were}amide 2-(pyridine-2-ylamino)thiazole-5-carboxylic acid [2-methyl-5-(4-(morpholine-4-ylmethyl-3-triphtalocyaninine)phenyl]amide 2-cyclopropylamino-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-{6-[4-(2-hydroxyethyl)piperazine-1-yl]-2-methylpyrimidin-4-ylamino }thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-[6-(4-methylpiperazin-1-yl)pyrimidine-4-ylamino]thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-{6-[4-(2-hydroxyethyl)piperazine-1-yl]pyrimidine-4-ylamino}thiazole-5-carboxylic acid [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-[2-methyl-6-(4-methylpiperazin-1-yl)pyrimidine-4-ylamino]thiazole-5-carboxylic acid and [2-methyl-5-(3-triphtalocyaninine)phenyl]amide 2-{4-[4-(2-hydroxyethyl)piperazine-1-yl]pyridine-2-ylamino}thiazole-5-carboxylic acid.

3. Pharmaceutical composition having the properties of an inhibitor of a protein kinase comprising a therapeutically effective amount of a compound according to claim 1 in combination with pharmaceutically acceptable excipients.

4. The use of compounds according to claim 1 for obtaining a medicinal product having the properties in which hibitor protein kinase.



 

Same patents:

FIELD: medicine.

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

EFFECT: higher efficiency.

12 cl, 2 tbl, 50 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: present invention refers to the aminopyridin compound of general formula (I) or its salt wherein X1, X2, X3, Z, Y1, Y2 are carbon or nitrogen atom, R, R1, R5, R6 are hydrogen atom, alkyl group, further see formula of the invention, and R7 is hydrogen or halogen atom, nitro or cyano group, -CpH2(p-1)(Ra1)(Ra2)-O-Ra3, -C(=O)-Rd1, 5-or 6-membered saturated heterocycle group, aromatic heterocycle group, -N(Rh1)(Rh2), further see formula of the invention. The invention refers also to the pharmaceutic composition thereof intended for treatment or prevention of allergic diseases, autoimmune diseases caused by malignant tumour, to the Syk inhibitor containing the compound of formula I and to the therapeutic and/or preventive agent.

EFFECT: compounds which not only possess high Syk inhibition activity but are selective Syk inhibitors are obtained and described.

24 cl, 24 ex, 2 tbl

Cynnamide compound // 2361872

FIELD: chemistry.

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

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry; medicine.

SUBSTANCE: compounds of claimed invention possess properties of positive allosteric modulator mGluR5. In general formula I , W represents 6-member heterocycloalkyl ring with 1-2 heteroatoms, selected from N, O; R1 and R2 independently represent hydrogen, C1-C6-alkyl; P and Q each independently is selected from: , R3, R4, R5, R6 and R7 independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-member heteroaryl with 1-2 atoms N as heteroatoms; 6-member heterocycle with 2 heteroatoms representing N, O; phenyl, optionally substituted with halogen; naphtyl; -OR8; where optionally two substituents together with located between them atoms form 9-10-member bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S; R8 represents hydrogen, C1-C6-alkyl; D, E, F, G and H independently represent -C(R3)=, -O-, -N=, -N(R3)- or -S-; A represents ethinyl, -C(=O)NR8- or group of formula . B represents -C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6-alkenyl-. Invention also relates to pharmaceutical composition based on invention compounds.

EFFECT: novel compounds possess useful biological proprties.

20 cl, 3 dwg, 75 ex

FIELD: chemistry.

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

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

39 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of formula I: , their optical isomers or optical isomer mix, and pharmaceutically acceptable salts, where: R1 is independently selected out of group including: aryl, heteroaryl, arylcarboxyamido, heteroarylcarboxyamido, aryloxy, arylalcoxy or arylamino, and where indicated groups of aryl, aryalkyl or heteroaryl can be substituted by 0-3 substitutes R1a, where R1a is independently selected out of group including: halogen, alkyl, alkenyl, alcoxy, alcoxyalkyl, hydroxyalkyl, mono-, di- or trihalogenoalkyl, mono-, di- or trihalogenoalcoxy, mono- or disubstituted aminoalkyl, aminocarbonyl, mono- or disubstituted aminocarbonyl, cyclic aminocarbonyl, alkylsulfonyl, etherified carboxylic acid residue, arylcarbonylamino, carbamate, R1b-aryl or R1b-heteroaryl where R1b is H, halogen, OH, amino, mono- or disubstituted amino, mono-, di- or trihalogenoalkyl, alkcoxy, mono-, di- or trihalogenoalcoxy, hydroxyalkyl; R2 is independently selected out of group including: H, OH, cyano, halogen or aryl; optionally R1 and R2 can be linked to form spirocyclyl; R3, R4, R5 and R6 are H; optionally R1 and R3 can be cyclised to form carbocycle; optionally R3 and R4 or R5 and R6 are cyclised to form bicyclic bridge system including ethylene bridge; optionally R3 and R6 are cyclised to form bicyclic bridge system including methylene or ethylene group; R7 and R8 are independently selected out of group including hydrogen, OH, C1-C8alkyl, arylalcoxy, heteroarylalcoxy; optionally R7 and R9 can be cyclised to form spirocarbocycle or spiroheterocycle; and m=0-5; where "aryl" term denotes aromatic carbocyclic groups such as phenyl, biphenyl, indenyl, naphthyl, and aromatic groups condensed with heterocycles; where "heterocycle" term denotes aromatic and non-aromatic rings including 3 to 10 atoms in the ring, 1-4 of which are heteroatom selected out of oxygen, sulfur or nitrogen; where "alkyl" term, when used separately or as suffix, denotes branched or non-branched alkyl group including 1 to 8 carbon atoms in chain; where "alkenyl" term denotes non-saturated branched or non-branched alkyl group including 2 to 12 carbon atoms in chain.

EFFECT: compounds applicable as chemokine receptor activity modulators.

15 cl, 1 tbl, 372 ex

FIELD: chemistry.

SUBSTANCE: there are disclosed 1-(2-aminobenzol)piperazine derivatives of formula (I) and pharmaceutically acceptable acid-additive salts with radical values specified in patent claim. The compounds are characterised with inhibiting effect on glycine I carrier. There is also disclosed medical product based on the compounds of formula (I).

EFFECT: compound can be used for treatment of the diseases associated with glycine uptake inhibition.

12 cl, 5 tbl, 396 ex

FIELD: chemistry.

SUBSTANCE: described is novel compound of formula (I)

or its pharmaceutically acceptable salt, values of radicals are given in invention formula Compound has ability to inhibit receptor mGluR5, which intends it for prevention and/or treatment of receptor mGluR5- associated disturbances. Also described is pharmaceutical composition, method of inhibiting activation of receptors mGluR5, using compound of formula (I). Described is method of obtaining compound of formula 1a or 1b structure.

EFFECT: increasing output of suitable product.

18 cl, 825 ex

FIELD: chemistry.

SUBSTANCE: invention refers to benzothiazol derivatives of general formula (I) and to their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands and to based medicinal agent. In general formula (I) , R1 represents 1,4-dioxepanyl or tetrahydropyran-4-yl; R2 represents -N(R)-(CH2)n-5- or 6-merous nonaromatic heterocycle containing 1-2 nitrogen heteroatoms optionally substituted with one-two substitutes chosen from group, consisting of C1-C6alkyl or -NR2, or represents -(CH2)n-5- or 6-merous nonaromatic heterocycle containing 1-2 heteroatoms chosen of N, S or O, optionally substituted with group -(CH2)n-OH, C1-C6alkyl, C1-C6alkoxy, or represents -(CH2)n-5-or 6-merous aromatic heterocycle containing 1-2 nitrogen heteroatoms optionally substituted with the following group: C1-C6alkyl, C1-C6alkoxy, halogen, halogen-(C1-C6alkyl), -CH2N(R)(CH2)2OCH3, -N(R)(CH2)2OCH3, - CH2-morpholinyl or -CH2-pyrrolidinyl or represents (CH2)n-C3-C6cycloalkyl optionally substituted with group hydroxy, or represents -N(R)-C3-C6cycloalkyl optionally substituted with group hydroxy or C1-C6alkyl, or represents phenyl optionally substituted with group C1-C6alkoxy, halogen, halogen-(C1-C6alkyl), C1-C6alkyl, -CH2-pyrrolidine-1-yl, CH2N(R)(CH2)2OCH3 or -CH2-N(R)C(O)-(C1-C6alkyl), or represents 1,4-dioxa-8-azaspiro[4,5]decane, or 2-oxa-5-azabicyclo[2,2,1]heptane, or 1-oxa-8-azaspiro[4,5]decane, or -N(R)-7-oxabicyclo[2,2,1]hept-2-yl, or 2-azabicyclo[2,2,2]octane; R represents hydrogen or C1-C6alkyl; n stands for 0 or 1.

EFFECT: compounds can be applied for treatment and prevention of diseases mediated by adenosine A2A and A1 receptors, eg Alzheimer's disease, some depressions, toxicomania, Parkinson's disease.

8 cl, 3 dwg, 61 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: compounds of formula (I) as inhibitors of phosphotyrosine phosphotase 1B and their pharmaceutically acceptable salts, their application, based pharmaceutical composition and method of production. In general formula (I) , R1 indicates phenyl, naphthyl, thionaphthyl, pyridyl. Phenyl, naphthyl, thionaphthyl and pyridyl can be single- or multiple-substituted with F, Cl, Br, (CH2)0-2OH, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkinyl, CF3, OCF3, N(R9)(R10), piperidinone, piperazine, piperazinone, N-(C1-C6-alkylene)-piperazine, N-(C1-C6-alkylene)-piperazinone, morpholine, thiomorpholine, NO2, CN, O-(C1-C6)-alkyl, S(O)0-2-(C1-C6)-alkyl, SO2-N(R9)(R10), CO-(C1-C6)-alkyl, -COOH, (C1-C6)-alkylene-COOH, COO(C1-C6)-alkyl, (C1-C6)-alkyleny-COO(C1-C6)-alkyl, (C3-C10)-cycloalkyl, phenyl. These piperidinone, piperazine, piperazinone, N-(C1-C6-alkylene)-piperazine, N-(C1-C6-alkylene)-piperazinone, morpholine, thiomorpholine, and phenyl rings can be single- or multiple-substituted with F, Cl, Br, (CH2)0-2OH, COOH, CN, NO2, O-(C1-C6)-alkyl, -NH-O-(C1-C6)-alkyl, -(CO)-NH-O-(C1-C6)-alkylene-N(R9)(R10), -(CO)-(C1-C6)-alkyl, -(C1-C6)-alkyl, CF3, OCF3, N(R9)(R10); R2 indicates H, (C1-C6)-alkyl, COOH, (C1-C6)-alkylene-COOH, COO(C1-C6)-alkyl, (C1-C6)-alkylene-COO(C1-C6)-alkyl; R3 indicates H, (C1-C6)-alkyl, (C1-C6)-alkylenphenyl, -C(O)-phenyl, (C1-C6)-alkylenheterocycle, where heterocycle represents 5-6-merous heterocyclic ring containing 1-2 heteroatoms, chosen of nitrogen and oxygen, CO-(C1-C6)alkyl; R4, R5 indicate H; R6 indicates H, R9 indicates H, (C1-C4)-alkyl; R10 indicates H, (C1-C4)-alkyl.

EFFECT: applications for treating diseases mediated with phosphotyrosine phosphotase 1B activity, such as diabetes type II, lipidosis and carbohydrate metabolic imbalance, insulin resistivity, reduced sugar content in blood.

9 cl, 2 tbl, 1 ex

FIELD: chemistry.

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

EFFECT: compound has inhibitory activity towards cysteinprotease.

10 cl, 16 tbl, 8 dwg, 224 ex

FIELD: chemistry.

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

EFFECT: obtaining compounds which possess agonistic or antagonistic activity.

7 cl, 5 ex

Cynnamide compound // 2361872

FIELD: chemistry.

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

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

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

EFFECT: new compounds have useful biological properties.

18 cl, 195 ex

FIELD: chemistry, medicine.

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

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

8 cl, 1 tbl, 7 ex

FIELD: chemistry.

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

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

39 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

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

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

21 cl, 228 ex

FIELD: chemistry.

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

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

29 cl, 746 ex, 6 tbl

FIELD: pharmacology.

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

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

41 cl, 14 dwg, 1 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: compounds of formula (I) as inhibitors of phosphotyrosine phosphotase 1B and their pharmaceutically acceptable salts, their application, based pharmaceutical composition and method of production. In general formula (I) , R1 indicates phenyl, naphthyl, thionaphthyl, pyridyl. Phenyl, naphthyl, thionaphthyl and pyridyl can be single- or multiple-substituted with F, Cl, Br, (CH2)0-2OH, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkinyl, CF3, OCF3, N(R9)(R10), piperidinone, piperazine, piperazinone, N-(C1-C6-alkylene)-piperazine, N-(C1-C6-alkylene)-piperazinone, morpholine, thiomorpholine, NO2, CN, O-(C1-C6)-alkyl, S(O)0-2-(C1-C6)-alkyl, SO2-N(R9)(R10), CO-(C1-C6)-alkyl, -COOH, (C1-C6)-alkylene-COOH, COO(C1-C6)-alkyl, (C1-C6)-alkyleny-COO(C1-C6)-alkyl, (C3-C10)-cycloalkyl, phenyl. These piperidinone, piperazine, piperazinone, N-(C1-C6-alkylene)-piperazine, N-(C1-C6-alkylene)-piperazinone, morpholine, thiomorpholine, and phenyl rings can be single- or multiple-substituted with F, Cl, Br, (CH2)0-2OH, COOH, CN, NO2, O-(C1-C6)-alkyl, -NH-O-(C1-C6)-alkyl, -(CO)-NH-O-(C1-C6)-alkylene-N(R9)(R10), -(CO)-(C1-C6)-alkyl, -(C1-C6)-alkyl, CF3, OCF3, N(R9)(R10); R2 indicates H, (C1-C6)-alkyl, COOH, (C1-C6)-alkylene-COOH, COO(C1-C6)-alkyl, (C1-C6)-alkylene-COO(C1-C6)-alkyl; R3 indicates H, (C1-C6)-alkyl, (C1-C6)-alkylenphenyl, -C(O)-phenyl, (C1-C6)-alkylenheterocycle, where heterocycle represents 5-6-merous heterocyclic ring containing 1-2 heteroatoms, chosen of nitrogen and oxygen, CO-(C1-C6)alkyl; R4, R5 indicate H; R6 indicates H, R9 indicates H, (C1-C4)-alkyl; R10 indicates H, (C1-C4)-alkyl.

EFFECT: applications for treating diseases mediated with phosphotyrosine phosphotase 1B activity, such as diabetes type II, lipidosis and carbohydrate metabolic imbalance, insulin resistivity, reduced sugar content in blood.

9 cl, 2 tbl, 1 ex

FIELD: chemistry.

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

EFFECT: new compounds have useful biological properties.

18 cl, 195 ex

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