Compounds and compositions as protein kinase inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds selected from compounds of formulae Ia, lb and Ic, which have protein kinase activity on kinase selected from CDKs, Aurora, Jak2. Rock, CAMKI, FLT3, Tie2, TrkB, FGFR3 and KDR, abnormal activity of which is observed in pathological conditions such as nonmalignant and malignant proliferative diseases. In compounds of formulae , and : n equals 0 or 1, R1 is selected from a group comprising halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted CpC6alkyl and halogen-substituted C1-C6alkoxy, R2 is selected from a group comprising phenyl, 6-member heteroaryl containing 1-2 nitrogen atoms in the heteroaryl ring as heteroatoms, and phenyl(C0-C4)alkyl, where the said phenyl and heteroaryl in R2 are optionally substituted with 1-3 radicals independently selected from a group comprising halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxy, -S(O)0-2R5, -COOR5 and -NR5C(O)R6, where R5 is selected from C1-C6alkyl, and R6 is selected from phenyl, where the said phenyl in R6 is optionally substituted with 1-3 radicals independently selected from a group comprising C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl and halogen-substituted C1-C6alkoxy, X is selected from CR7 and N, where R7 is selected from hydrogen or C1-C6alkyl.

EFFECT: increased effectiveness of using the compounds.

7 cl, 3 dwg, 1 tbl, 3 ex

 

Cross references to related applications

This application claims earlier priority based on provisional application U.S. ser. room 60/681853, registered on may 16, 2005 a Complete description of this application is incorporated into this description by reference in full and with the entire application.

Background of invention

The scope of the invention

The invention proposes 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 misaligned kinase activity, particularly diseases or disorders that involve abnormal activation of the CDK kinases, Aurora, Jak2, Rock, SAMC, FLT3, Tie2, TrkB, FGFR3 and KDR.

Background of invention

Protein kinases represent a large family of proteins that play a Central role in the regulation of a wide range of cellular processes and in the control of cellular functions. The list of such kinases includes, without limitation, receptor tyrosine kinase, such as FLT3, Tie2, TrkB, KDR and receptor fibroblast growth factor FGFR3, and serine/trionychinae, such as CDK, Aurora, Jak2, Rock, SAMK. Abnormal activity of the kinase is observed in many pathological with the tijaniyah, including benign and malignant proliferative diseases, and diseases caused by abnormal activation of the immune and nervous systems.

The new compounds of the present invention inhibit the activity of one or more protein kinases and therefore they can be used for the treatment of diseases associated with protein kinases.

A brief description of the invention

One object of the present invention provides compounds of formula Ia, Ib and IC:

where n is 0, 1 and 2

R1selected from the group including halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl and halogen-substituted C1-C6alkoxy,

R2selected from the group including6-C10aryl(C0-C4)alkyl and C5-C10heteroaryl(C0-C4)alkyl, with the specified aryl or heteroaryl in the composition of R2optionally substituted by 1-3 radicals selected from the group comprising halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxy, -S(O)0-2R5, -R5, -C(O)NR5R6and-NR5C(O)R6and R5choose the C of hydrogen and C 1-C6of alkyl, and R6choose from C6-C10aryl and C5-C10heteroaryl, and specified aryl or heteroaryl in the composition of R6optionally substituted by 1-3 radicals independently selected from the group comprising halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl and halogen-substituted C1-C6alkoxy,

X is chosen from CR7or N, and R7selected from hydrogen and C1-C6of alkyl,

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

The second object of the present invention features a pharmaceutical composition including a compound of formula I or a N-oxide, individual isomers and mixture of isomers, or pharmaceutically acceptable salt, in a mixture with one or more of suitable excipients.

The third object of the present invention features a method of treating disease in an animal, which is that when the inhibition of kinase activity, particularly the activity of CDKs, Aurora, Jac2, Rock, SAMC, FLT3, Tie2, TrkB, FGFR3, and/or KDR, there is a prevention, inhibition or reduction of the intensity of the disease and/or symptoms of diseases, and the way vklyuchayuthie the animal a therapeutically effective amount of the compounds of formula I or a N-oxide, individual isomers and mixtures of isomers, or pharmaceutically acceptable salt.

The fourth object of the present invention features the use of the compounds of formula I to obtain a medicinal product intended for the treatment of the disease in the animal, and kinase activity, especially the activity of CDKs, Aurora, Jac2, Rock, SAMC, FLT3, Tie2, TrkB, FGFR3, and/or KDR, participates in the development of the disease and/or symptoms.

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

Detailed description of the invention

Definition of terms

"Alkyl" as a group, and a structural element of other groups, for example halogen-substituted alkyl and alkoxy is linear or branched. With1-C4alkoxy includes methoxy, ethoxy and other halogen-substituted alkyl includes trifluoromethyl, pentafluoroethyl etc.

"Aryl" means a monocyclic or condensed bicyclic aromatic cycle containing 6-10 carbon atoms in the cycle. For example, aryl means phenyl or naphthyl, preferably phenyl. "Allen" means a divalent radical derived aryl.

"Heteroaryl" has a signature is to be placed, defined above for aryl, and one or more carbon atoms in the cycle are replaced by heteroatoms. For example, With5-C8heteroaryl includes pyridyl, indolyl, indazoles, honokalani, chinoline, benzofuranyl, benzopyranyl, benzothiophene, benzo[1,3]dioxol, imidazolyl, benzimidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl etc.

"Cycloalkyl" means a saturated or partially unsaturated, monocyclic, condensed bicyclic or bridged polycyclic cycle that contains the specified number of atoms in the cycle. For example, With5-C10cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

"Heteroseksualci" means cycloalkyl, as defined in this context, provided that one or more of these carbon atoms in the cycle is replaced by a group selected from the following groups: -O-, -N=, -NR-, -C(O)-, -S-, -S(O)- or-S(O)2-, where R is hydrogen, C1-C4alkyl or azatadine group. For example, With5-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.

"Halogen" preferably means chlorine or FPO is, but it can also mean bromine or iodine.

"The panel of kinases includes the following kinases: Ab1 (human), Ab1 (T315I), JAK2, JAK3, ALK, JNK1α1, ALK4, KDR, Aurora-A, Lck, Blk, MAPK1, Bmx, MAPKAP-K2, BRK, MEK1, CaMKII (rats), Met, CDKl/Cycling, p70S6K, CHK2, PAK2, CK1, PDGFRα, CK2, PDK1, c-kit, Pim-2, c-RAF, RCA (human), 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 (human), SAPK3, CPD, MARGAR-K3, SAPK4, KaMKIV, MARK1, Snk, D2/cyclina, MINK, SRPK1, D3/cyclin, MCC (mouse), TAC, CDK5/p25, R6 (human), TWC, DR6/D3, MLCK, TrkA, D7/cyclin/MAT, MRCKβ, TSSK1, CHK1, MSK1, Yes, CK1d, MST2, ZIPK, c-Kit (D816V), MuSK, DAPK2, NEK2, DDR2, NEK6, DMPK, PAK4, DRAK1, PAR-1Bα, EphAl, PDGFRβ, EphA2, Pim-1, EphA5, PKBβ, EphB2, PKCβI, Ephβ4, PKCδ, FGFR1, PKCη, FGFR2, PKCθ, FGFR4, PKD2, Fgr, PKGlβ, Flt1, PRK2, Hck, PYK2, HIPK2, Ret, IKKα, RIPK2, IRR, ROCK-II (human), JNK2α2, Rse, JNK3, Rsk1 (human), PI3 Kγ, PI3 Kδ and R-β. Compounds of the present invention were analyzed using the specified panel of kinases (wild type and/or mutant form), the results indicate that the compounds inhibit the activity of at least one kinase of the specified bar.

"Mutant forms of BCR-bl" means the replacement of one or several amino acids in the sequence of the kinase wild-type. Mutations in the kinase BCR-ABL often result in damage to important contact sites between the protein and the inhibitor (e.g., inhibitor Gleevec, etc.)inducyruya the transition from the inactive state to the active state is the state, i.e. the transition to a conformation in which BCR-ABL Gleevec and unable to communicate. Analysis of clinical cases suggests that the spectrum of mutations associated with the resistant phenotype, over time, slowly but steadily increases. Apparently, mutations accumulate in four main parts. One group of mutations (G250E, Q252R, Y253F/H, E255K/V) includes amino acids, which form the phosphate-binding loop for ATP (also known as P-loop). The second group of mutations (V289A, F311L, T315I, F317L) found in the binding site with the inhibitor Gleevec and directly interacts with the inhibitor due to hydrogen bonding and Vander Waals forces. The third group of mutations (MT, E355G) is located near the catalytic domain. The fourth group of mutations (H396R/P) is localized in the activation loop, the conformation of which is a molecular switch that regulates the activation/inactivation of kinase activity. Point mutations in BCR-ABL associated with resistance to inhibitor Gleevec found in patients diagnosed with CML and ALL, include 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, these single-letter code indicated in accordance with the sequence specified in the database of GenBank, the number AAW that meet the overall ABL type 1a, Martinelli and others, Haematologica/The Hematology Journal, 90-94, (2005, April). Unless otherwise indicated, All-Abl indicates the wild-type enzyme and its mutant forms.

"Treatment" means a method of reducing or diminishing the intensity of the disease and/or its symptoms.

Detailed description of preferred embodiments of the present invention

The present invention provides compounds, compositions and methods of treatment-related kinases diseases, primarily kinases CDK, Aurora, Jak2, Rock, CAMKII, FLT3, Tie2, TrkB, FGFR3 and KDR.

In one embodiment, the invention provides compounds of formula Ia, Ib and IC,

where n is 0 and 1,

R1means1-C6alkoxy, a R2selected from the group including6-C10aryl(C0-C4)alkyl and C5-C10heteroaryl(C0-C4)alkyl, with the specified aryl or heteroaryl in the composition of R2optionally substituted by 1-3 radicals selected from the group comprising halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl, -S(O)0-2R5, -COOR5and-NR5C(O)R6and R5selected from hydrogen and C1-C6of alkyl, and R6means6-C10aryl, optionally substituted by 1-3 radicals independently selected from halogen-substituted C1-C6the alkyl.

Drugom embodiment of the invention R 1means methoxy, R2selected from phenyl, benzyl and pyridinyl, and specified phenyl, benzyl, or pyridinyl, in the composition of R2optionally substituted by 1-2 radicals independently selected from the group comprising chlorine, bromine, fluorine, methyl, triptoreline, trifluoromethyl, -COO2R5, -S(O)2R5and-NHC(O)R6and R5selected from methyl and ethyl, a R6means phenyl, optionally substituted by trifluoromethyl.

Preferred compounds of the present invention are selected from the group including (3-chlorophenyl)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine, (4-forfinal)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine, [4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl](4-trifloromethyl)amine, [4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl](3-triptoreline)Amin, (3,4-differenl)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine, [4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl](4-triptoreline)amine, ethyl ester 4-[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-ylamino]benzoic acid, (3-methoxyphenyl)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine, (3-terbisil)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine, (3,5-acid)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine, (2-methylpyridin-4-yl)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine, (2-chloropyridin-4-yl)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimid the h-2-yl]amine, (2-methoxypyridine-4-yl)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine, (4-methanesulfonyl)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine, pyridine-4-yl[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine, (4-methylpyrimidin-2-yl)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine, (3-bromophenyl)[4-(1-methyl-1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine, (3-chlorophenyl)[4-(1-methyl-1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine, [4-(1-methyl-1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl](3-triptoreline)amine, (3-bromo-4-were)[4-(1-methyl-1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine, 2-{4-[2-(3-brompheniramine)pyrimidine-4-yl]pyrrolo[2,3-b]pyridine-1-yl}ethanol, 2-{4-[2-(3-triptoreline)pyrimidine-4-yl]pyrrolo[2,3-b]pyridine-1-yl}ethanol, 2-{4-[2-(3-chlorpheniramine)pyrimidine-4-yl]pyrrolo[2,3-b]pyridine-1-yl}ethanol, 2-{4-[2-(3-bromo-4-methylphenylimino)pyrimidine-4-yl]pyrrolo[2,3-b]pyridine-1-yl}ethanol, {4-[1-(2-amino-ethyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]pyrimidine-2-yl}(3-bromophenyl)Amin, {4-[1-(2-amino-ethyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]pyrimidine-2-yl}(3-bromophenyl)methylamine, {4-[1-(2-amino-ethyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]pyrimidine-2-yl}(4-triptoreline)amine, N-{4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-ylamino]phenyl}-3-cryptomelane, [4-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-yl](4-triptoreline)amine, (3,5-acid)[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-yl]amine, (3,5-differenl)[4-(1H-p is Rolo[2,3-b]pyridine-3-yl)pyrimidine-2-yl]amine, (3-bromophenyl)[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-yl]amine, (3-methoxyphenyl)[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-yl]amine, (4-chlorophenyl)[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-yl]amine, ethyl ester 4-[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-ylamino]benzoic acid, N-{4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-ylamino]phenyl}-3-cryptomelane, (3-chlorophenyl)[4-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-yl]amine, [4-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-yl](3-triptoreline)amine, (3-bromophenyl)[4-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-yl]amine, N-{4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrimidine-2-ylamino]phenyl}-3-cryptomelane, N-ethyl-4-[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-ylamino]benzosulfimide, N-(2-methoxyethyl)-4-[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-ylamino]benzosulfimide, N-(3-methoxypropyl)-4-[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-ylamino]benzosulfimide, N-(3-methoxypropyl)-4-[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-ylamino]benzosulfimide, (3-bromophenyl)[4-(2-methyl-1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine, (3-chlorophenyl)[4-(2-methyl-1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine, [4-(2-methyl-1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl](3-triptoreline)amine, N-(2-methoxyethyl)-4-[4-(2-methyl-1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-ylamino]benzosulfimide, N-(3-methoxypropyl)-4-[4-(2-IU the Il-1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-ylamino]benzosulfimide, (3-bromophenyl)[4-(1H-pyrazolo[3,4-b]pyridine-4-yl)pyrimidine-2-yl]amine, (3-chlorophenyl)[4-(1H-pyrazolo[3,4-b]pyridine-4-yl)pyrimidine-2-yl]amine, [4-(1H-pyrazolo[3,4-b]pyridine-4-yl)pyrimidine-2-yl](3-triptoreline)amine, (3-chlorophenyl)[4-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrimidine-2-yl]amine, (3-bromophenyl)[4-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrimidine-2-yl]amine and [4-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrimidine-2-yl](3-triptoreline)Amin.

Other preferred compounds of the present invention are listed below in the "Examples" section and in the table.

Pharmacology and industrial applicability

Compounds of the invention modulate the activity of kinases and, as such, are used for the treatment of diseases or disorders in which kinases participate in the development of the pathology and/or symptomatology of the disease. Examples of kinases that are inhibited by the compounds and compositions described in this context, and to suppress using the methods described in this context include, without limitation, CDK, Aurora, Jak2, Rock, CAMKII, FLT3, Tie2, TrkB, FGFR3 and KDR.

Tyrosinekinase of Abelson (i.e. Abl, C-Abl) is involved in regulation of cell cycle, cellular response to genotoxic stress in the transmission of information about the cellular environment through integrity signal. Thus Ab1 protein performs a complex function as a cellular module that interest which demonstrates signals from a variety of intercellular and intracellular sources, what influences the decisions regarding the cell cycle and apoptosis. Tyrosinekinase of Abelson includes subtypes, such as chimeric hybrid protein (oncoprotein) BCR-Abl with misaligned tyrosinekinase activity or v-bl. BCR-Abl plays a crucial role in the pathogenesis in 95% of cases of chronic myelogenous leukemia (CML) and in 10% of cases of acute lymphocytic leukemia. STI-571 (Gleevec) is an inhibitor of the oncogenic tyrosine kinase BCR-Abl, and is used in the treatment of chronic myeloid leukemia (CML). However, some patients at the stage of blast crisis CML observed resistance to STI-571 due to mutations in the kinase BCR-Abl. To date, identified 22 mutations, the most frequent of which are 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 wild type kinase BCR-Abl and mutant forms of the kinase BCR-Abl and therefore suitable for the treatment of SIV-bl-positive cancer and tumor diseases, such as leukaemia (particularly chronic myeloid leukemia and acute lymphocytic leukemia, the development of which is primarily installed apoptotic mechanism of action), as well as have an effect on a subset of leukemic stem cells and can be used for purification of these cells in vitro after their removal and the body (for example, removal of the bone marrow) and replantation cell population purified from cancer cells (for example, the replantation of purified bone marrow cells).

Signaling pathway Ras-Raf-MEK-ERK mediates cellular responses to growth signals. Ras mutated in oncogenic form in ~15% of cases of human cancer. The Raf family belongs to the family of serine/trainingtraining and includes three members of a family of A-Raf, B-Rag and c-Raf (or Raf-1). The study of the Raf as a target of drugs aimed at studying the actions of the Raf as the vast effector for Ras. However, recent evidence suggests that B-Raf performs an important function in the formation of certain tumors without mandatory participation of an activated Ras allele (Nature, 417, 949-954 (01 July 2002). Mutations of B-Raf primarily found in the majority of malignant melanomas.

Existing methods of treatment of melanoma is characterized by lack of efficiency primarily on late-stage disease. Compounds of the present invention also inhibit cellular processes involving protein kinase b-Raf and represent a new therapeutic approach to the treatment of human cancer, especially melanoma.

Compounds of the present invention, in addition, inhibit cellular processes involving protein kinase c-Raf. c-Raf is activated by ras oncogene that is mutated in many types of cancer man. Therefore, inhibition of kinase activity of c-Raf is a promising method of preventing tumor growth mediated ras gene (Campbell S.L., Oncogene, 17, 1395 (1998)).

PDGF (platelet growth factor) is a very common growth factor, which plays an important role in normal growth and in pathological cell proliferation, such as that observed in the oncogenesis and in diseases of the cells of smooth muscles of blood vessels, such as atherosclerosis and thrombosis. Compounds of the invention inhibit the activity of the PDGF receptor (DERIVED) and, therefore, can be used in the treatment of neoplastic diseases, such as glioma, sarcoma, prostate cancer and cancer of the colon, breast and ovary.

Compounds of the present invention can be used not only as suppressing tumor agents, for example in small cell lung cancer, but also as an agent to treat non-malignant proliferative disorders, such as atherosclerosis, thrombosis, psoriasis, scleroderma and fibrosis, as well as for the protection of stem cells, for example, to combat hemotoksicheskie the action of chemotherapeutic agents such as 5-fluorouracil, for the treatment of asthma. Compounds according to the invention first of all you can use for treatment for which olivani, which are sensitive to inhibition of the receptor kinase PDGF.

Compounds of the present invention have a therapeutic effect in the treatment of disorders resulting from transplantation, such as allogeneic transplantation, especially when tissue rejection, such as obliterative bronchiolitis (OB), i.e. chronic rejection of allogenic lung transplants. In contrast to patients not suffering from S, in patients with a diagnosis of S often an increased concentration of PDGF in the bronchoalveolar wash liquid.

Compounds of the present invention are also effective in diseases associated with migration and proliferation of smooth muscle cells of blood vessels (in which PDGF and PDGF-R often play a prominent role), such as restenosis and atherosclerosis. This effect and its subsequent effect on the proliferation and migration of smooth muscle cells of blood vessels in vitro and in vivo can be assessed with the introduction of the compounds of the present invention, as well as in the study of the effect on the thickening of the inner lining of blood vessels after mechanical damage in vivo.

The trk family of receptor Neutrogena (trkA, trkB, trkC) stimulates the survival, growth and differentiation of neural and negarandeh tissues. Protein TrkB is expressed in neuroendocrine cells of the type in thin kick and colon, in α-cells of the pancreas, in monocytes and macrophages of the lymph nodes and spleen and in the granular layers of the epidermis (Shibayama and Koizumi, 1996). The expression of TrkB protein is associated with poor prognosis and progression of tumors Wilms ' tumor and neuroblastoma. Moreover, TkrB is expressed in malignant prostate cells, but not detected in normal cells. Signaling pathway suppression of expression of the trk receptors includes cascade activation MARK involving Shc, activated Ras genes ERK-1 and ERK-2, and path transduction PLC-γ1 (Sugimoto and others, 2001).

Kinase c-Src transmits oncogenic signals from many receptors. For example, overexpression of EGFR or HER2/neu in tumors leads to the constitutive activation of c-src, which is characteristic of malignant cells, but not observed in normal cells. On the other hand, mice with a deficit in the expression of c-src are phenotype "marble disease, indicating the key role of c-src in the functioning of osteoclasts and possible participation in the development of associated disorders.

Kinase of the Tec family, Bmx, preceptory proteincontaining, control the proliferation of epithelial cancer cells of the breast.

It is established that the receptor 3 fibroblast growth factor has a negative regulatory effect on the growth of bone tissue and inhibi the Finance proliferation of chondrocytes. Lethal dysplasia is caused by various mutations in the receptor 3 fibroblast growth factor, and one mutation, TDII FGFR3, has a constitutive tyrosinekinase activity, which activates the transcription factor Stal1 that leads to expression of the inhibitor of the cell cycle, stop the growth and abnormal development of bone tissue (Su and others, Nature, 386, 288-292 (1997)). In addition, FGFR3 often expressed in tumors type of multiple myeloma. Inhibitors of the activity of the FGFR3 can be used for the treatment of inflammatory or autoimmune diseases mediated by T-cells, including, without limitation, rheumatoid arthritis (RA), collagen arthritis II, multiple sclerosis (MS:), systemic lupus erythematosus (SLE), psoriasis, juvenile diabetes, a disease of Shengren, thyroid disease, sarcoidosis, autoimmune uveitis, inflammatory bowel disease (Crohn's disease and ulcerative colitis), coeliac disease and severe pseudoparalysis myasthenia.

The activity of serum and glucocorticoid-regulated kinase (SGK) correlates with the activities of the perturbed ion channels, primarily the activity of sodium and/or potassium channels, and the compounds according to the invention can be used for the treatment of hypertension.

In the works of Lin and others, J.Clin. Invest. 100, 8, 2072-2078 (1997) and .Lin, PNAS, 95, 8829-8834 (1998) found a suppression of growth of opuholei vascularization, and reduction of metastasis in the lungs during adenovirus infection or injection of the extracellular domain of Tie-2 (Tek) in breast tumor and xenograft models of melanoma. The Tie2 inhibitors can be used in cases in which there is abnormal neovascularization (e.g., diabetic retinopathy, chronic inflammation, psoriasis, Kaposi's sarcoma, chronic neovascularization in macular degeneration, rheumatoid arthritis, the infantile hemangioma and cancer).

Lck is involved in the signal transmission T-cells. Mice without the gene Lck low thymocytes. The Lck function as a positive activator of the transmission signal T-cells suggests that inhibitors of Lck can be used to treat autoimmune diseases such as rheumatoid arthritis.

Kinases JNK and other MARK are involved in mediating cellular response to cancer, thrombin-induced platelet aggregation, violations type of immunodeficiency, autoimmune diseases, cell death, allergies, osteoporosis and heart disease. Therapeutic targets associated with activation of the JNK pathway, include chronic myelogenous leukemia (CML), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer and neurodegenerative diseases. In connection with the activation of JNK is associated with Zabo what evanier liver or bouts of hepatic ischemia, compounds according to the invention can also be used for treatment of various disorders of the liver. It is also reported about the involvement of JNK in the development of cardiovascular diseases such as myocardial infarction or congestive heart failure, and found that JNK mediates the hypertrophic response to various forms of cardiac stress. It is established that the JNK cascade is involved in the activation of T cells, including activation of the promoter of IL-2. Thus, the JNK inhibitors may have a therapeutic effect in the correction of the pathological immune response reactions. Established the role of activation of JNK in the development of different types of cancer, which suggests the possibility of effective use of JNK inhibitors in cancer. For example, constitutively activated JNK is associated with oncogenesis mediated HTLV-1 (Oncogene, 13, 135-142 (1996)]. JNK is involved in the development of Kaposi's sarcoma (KS). The proliferative effects of other cytokines involved in the proliferation of KS, such as endothelial growth factor vascular (VEGF), IL-6 and TNFα, may also be mediated by JNK. In addition, regulation of gene c-jun in cells R transformed by BCR-ABL, corresponds to the activity of JNK, suggesting possible applications of JNK inhibitors in the treatment of chronic myelogenous leukemia (CML) (Blood 92, 24502460 (1998)).

It is believed that some abnormal proliferative condition associated with expression of the raf and, therefore, sensitive to inhibition of the expression of the raf. Abnormally high levels of expression of a raf protein are also associated with transformation and abnormal cell proliferation. It is envisaged that these abnormal proliferative condition sensitive to inhibition of the expression of the raf. For example, it is assumed that the expression of the protein c-raf plays a role in abnormal cell proliferation, since it is reported that 60% of all cell lines lung carcinoma usually Express high levels of mRNA and protein c-raf. Other examples of abnormal proliferative conditions are hyperproliferative disorders such as cancer, tumors, hyperplasia, pulmonary fibrosis, angiogenesis, psoriasis, atherosclerosis and cell proliferation of smooth muscles of blood vessels, such as stenosis or restenosis after plastic surgery on the blood vessels. Cellular signaling pathway, is part of the raf, also involved in inflammatory disorders characterized by the proliferation of T-cell activation and growth of T cells), such as a tissue graft rejection, endotoxin shock, and glomerular nephritis.

Stress-activated protein kinase (SAPK) are a family of protein kinases that participate on the penultimate stage of the transmission signal, this leads to activation of the transcription factor C-jun and expression of genes regulated by c-jun. First of all, c-jun is involved in the transcription of genes that encode proteins associated with DNA repair, damaged by genotoxic effects. Therefore, agents that inhibit the activity of SAPK in the cell, prevent DNA repair and sensibiliser cell to agents that induce DNA damage or inhibit DNA synthesis and induce apoptosis of cells, or agents that inhibit cell proliferation.

Mitogen-activated protein kinase (MARK) are members of the conservative signal transduction pathways that activate transcription factors, translation factors and other target molecules in response to different extracellular signals. MARK activates the mitogen-activated protein kinases (MKK) by dual phosphorylation on two amino acids in the sequence Thr-X-Tyr. In higher eukaryotes physiological role of signal transmission MARK correlates with cellular processes such as proliferation, oncogenesis, development and differentiation. Accordingly, the ability to adjust signal transmission on the specified routes (primarily involving MCC and MCC) can be used in the development of methods of treatment and prevention of human diseases associated with plumage is of acai signal MARK, such as inflammatory diseases, autoimmune diseases and cancer.

The family of protein kinases ribosomal protein S6 person includes at least 8 members (RSK1, RSK2, RSK3, RSK4, MSK1, MSK2, p70S6K and p70S6 Kb). Proteinkinase ribosomal protein S6 perform important pleiotropy functions, including playing a key role in the regulation of the mRNA during protein biosynthesis (Eur. J. Biochem., 267 (21), 6321-6330 (2000, November); Exp Cell Res., 253 (1), 100-109 (1999, November 25); Mol Cell Endocrinol., 151 (1-2), 65-77 (1999, may 25)). In addition, phosphorylation of ribosomal protein S6 by p70S6 kinase is associated with regulation of cell motility (Immunol. Cell Biol., 78 (4), 447-451 (2000, August)and cell growth (Prog. Nucleic Acid Res. Mol. Biol., 65, 101-127 (2000)), and hence is an important factor in tumour metastasis, immune response and repair tissue, as well as other pathological conditions.

Kinase SAPK (also called jun N-terminal kinase or JNK) are a family of protein kinases that participate on the penultimate stage of the transmission signal, while the activation of the transcription factor c-jun and expression of genes regulated by c-jun. First of all, c-jun is involved in the transcription of genes that encode proteins associated with DNA repair, damaged by genotoxic effects. Agents that inhibit the activity of SAPK in the cell, prevents DNA repair is sensibiliser cell such therapeutic antitumor agents, which have an effect by inducing DNA damage.

CPD plays an important role in the development of autoimmune and/or inflammatory diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, disseminated vasculitis, idiopathic thrombocytopenic purpura (ITP), heavy psevdomatematicheskoe myasthenia gravis, and asthma. Thanks to the participation of CPD in the activation of b-cells, inhibitors of the CPD can be used to suppress pathogenic States, mediated by b-cells, such as the production of autoantibodies, and in the treatment of lymphoma and leukemia cells.

SNK is a checkpoint kinase family of serine/trainingtraining and participates in the control mechanism of DNA damage, such as damage caused by mutagens environmental and endogenous forms of active oxygen. In the result it can be used as a tumor suppressor and target in oncotherapy.

CSK affects metastatic activity of tumor cells, especially colon cancer.

Fes is preceptory proteincontaining, which is involved in several signal transduction pathways involving cytokines and differentiation of myeloid cells. Fes is also a key component in the mechanism of differentiation of granulocytes.

Receptor tyrosinekinase Flt3 involved the development of leukemia and myelodysplastic syndrome. Approximately 25% of the cells of leukemia AML Express a constitutively active form autophosphorylating tyrosine kinase (f)FL3 on the cell surface. Activity f-FLT3 provides growth and survival preferably leukemia cells. Patients with acute leukemia, whose leukemic cells Express a kinase f-FL3, mainly characterized by unfavorable clinical prognosis. Inhibition of kinase f-FLT3 induces apoptosis (programmed cell death) in leukemia cells.

Inhibitors of IKKα and IKKβ (1 and 2) are medicines for the treatment of diseases, including rheumatoid arthritis, graft rejection, inflammatory bowel disease, osteoarthritis, asthma, chronic obstructive pulmonary disease, atherosclerosis, psoriasis, multiple sclerosis, stroke, systemic lupus erythematosus, Alzheimer's disease, cerebral ischemia, traumatic brain injury, Parkinson's disease, amyotrophic lateral sclerosis, subarachnoid hemorrhage and other diseases or disorders associated with excessive production of inflammatory mediators in the brain and Central nervous system.

Met is associated with most types of major human cancers and the expression of this enzyme is often correlates with poor prognosis and metastasis. Inga is itory Met are medicines for the treatment of diseases, including various types of cancer, such as lung cancer, NSCLC (non-small cell lung cancer), cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous and intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, cancer of the colon, breast cancer, gynecologic tumors (e.g., sarcoma of the uterus, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, esophageal cancer, cancer of the small intestine, cancer of the endocrine system (for example, thyroid cancer, parathyroid cancer, or cancer of the adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, childhood solid tumor, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma, carcinoma of the renal pelvis), baby malignant disease, tumors of the Central nervous system (e.g., primary CNS lymphoma, tumors of the spine, brain stem glioma or pituitary adenoma), blood cancer, such as acute myeloid leukemia, chronic myeloid leukemia and so, the plague of Barret's esophagus (a precancerous syndrome), neoplastic skin disease, psoriasis, mushroom fungal infections and benign hypertrophy what I prostate cancer, diseases associated with diabetes, such as diabetic retinopathy, retinal ischemia and retinal neovascularization, hepatic cirrhosis, cardiovascular diseases such as atherosclerosis, immunological disease such as autoimmune disease and renal disease. Preferably the disease means cancer, such as acute myeloid leukemia and colorectal cancer.

Nima-associated kinase 2 (Nek2) is a protein kinase that regulates cell cycle, and the enzyme is localized in the centrosome and has a maximum activity at a stage of mitosis. Functional studies indicate the involvement of Nek2 in the regulation of the centrosome separation and the formation of the spindle. Increased protein content Nek2 (2-5 times) was observed in cell lines derived from some human cancers, such as cervical cancer, ovarian cancer, prostate cancer and especially breast cancer.

Disease or condition mediated p70S6K, include, without limitation, proliferative disorders such as cancer and tuberose sclerosis.

Currently, there are growing data set of reliable and effective treatment with kinase inhibitors cancers, in which the kinase-targeted drugs constitutively activated by mutations in the gene. Publ Kovano a lot of work on mutations identified in the sequences of kinases, which occur as a result of natural selection of tumor. The list of examples of such kinases includes, without limiting the above, the mutant b-raf V599E in more than 60% of cases of malignant melanoma, mutant Flt3-ITD in 30% of AML cases, mutations of c-kit in patients with GIST, PDGFRα in patients with GIST and HES, PDGFRβ in patients with CMML, mutant Pi3K in cancer of the colon and stomach, as well as glioblastoma, and mutant EGFR in 10% of cases of lung cancer (sensitive to iressa) and glioblastomas.

In accordance with the foregoing the present invention also offers a method of preventing or treating any of the diseases or disorders mentioned above, the subject who is in need of such treatment, and this method includes the introduction of a specified subject a therapeutically effective amount (see below in the section introduction Methods and pharmaceutical compositions) of the compounds of formula I or its pharmaceutically acceptable salt. If any of the above apply the required dose can vary depending on the method of administration, the particular condition to be treated, and expected actions.

Methods of administration and pharmaceutical compositions

In General, compounds according to the invention is administered in therapeutically effective quantities of any of the usual and acceptable by known methods, separately or in combination one or more therapeutic agents. Therapeutically effective amount may vary depending on the severity of the disease, the age and relative health of the subject, the activity of the used connections and other factors. In General satisfactory results are achieved with systemic administration of daily doses of from about 0.03 to 2.5 mg/kg of body weight. For the larger mammal, e.g. humans, prescribed daily dose of from approximately 0.5 mg to approximately 100 mg, which you can enter, for example, divided doses up to four times a day or in a form with delayed release. Suitable standard dosage forms for oral administration comprise from about 1 to 50 mg of active ingredient.

Compounds according to the invention can be introduced in the form of pharmaceutical compositions by any acceptable method, first of all enteric way, for example by oral way in the form of tablets or capsules, parenteral way, for example in the form of injection solutions or suspensions, local manner, for example in the form of lotions, gels, ointments or creams, or nazalnam way, or in the form of suppositories. Pharmaceutical compositions comprising the compound of the present invention in free form or in the form of a pharmaceutically acceptable salt in a mixture of at least the one pharmaceutically acceptable carrier or diluent, get in the normal way using conventional methods of mixing, granulating or coating shell. For example, the oral composition may be a tablet or gelatin capsules comprising 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 silicon dioxide, talc, stearic acid, its calcium or magnesium salt and/or polyethyleneglycol, and tablets can also be included) binders, for example magnesium silicate/aluminum, starch, gelatin, tragakant, methylcellulose, Na-carboxymethyl cellulose and/or polyvinylpyrrolidone, and, if necessary g) dezintegriruetsja agents, for example starches, agar, alginic acid or its sodium salt, or effervescent mixtures and/or e) absorbents, colorants, flavors and sweeteners. Injectable compositions can be an aqueous isotonic solutions or suspensions, and suppositories are obtained from fatty emulsions or suspensions. The composition can be sterilized or they may contain adjuvants such as preservatives, stabilizing, wetting or emulsifying agents, contributing to the dissolution agents, salts for regulating osmotic pressure and/or buffer substances. In addition, they can sod who can't make fun of other therapeutically valuable compounds. Suitable formulations for transdermal application include an effective amount of the compounds of the present invention in a mixture with a carrier. The media may include absorbable pharmacologically acceptable solvents to provide suction through the skin of the patient. For example, systems for percutaneous introduction represent a bandage comprising a protective film, a reservoir containing the compound optionally in a mixture with a carrier, optionally a membrane that regulates the delivery of compounds to the skin of the patient with a predetermined and controlled rate for a prolonged period of time, and the device that provides holding the bandage on the skin surface. You can also use matrix percutaneous formulations. Suitable formulations for topical application, for example for application to the skin and eyes, preferably are aqueous solutions, ointments, creams or gels known in this field. Such compositions may contain solubilizing, stabilizing, toning agents, buffering agents and preservatives.

Compounds according to the invention can be introduced in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combination). For example, a synergistic effect is achieved by using a combination with other immunomodulatory and the anti-inflammatory substances, for example, when using combination with cyclosporine, rapamycin or ascomycin, or immunodepressants analogs, e.g. cyclosporin A (CsA), cyclosporin G, FK-506, rapamycin, or similar compounds, corticosteroids, cyclophosphamide, azathioprine, methotrexate, brequinar, Leflunomide, mizoribine, mycophenolate acid, mycophenolate mofetil, 15-desoxypeganine, immunodepressants antibodies, especially monoclonal antelami to the receptors of leukocytes, e.g., MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD45, CD58 or their ligands, or other immunomoduliruushimi compounds such as CTLA41g. If the compounds according to the invention is administered in conjunction with other therapeutically active agents, doses in conjunction input connections vary depending on the type of the jointly-used drug, from a particular drug, the condition to be treated, etc.

In addition, the invention relates to pharmaceutical combinations, for example, the set including a) a first agent which is a compound according to the invention specified above, in free form or in the form of pharmaceutically acceptable salts, and b) at least one collateral agent. The kit includes instructions for administration of medicines.

The terms "co-administration" Il the combined introduction" or similar terms, used in the description means the introduction of selected therapeutic agents to a single patient, as well as the course of treatment, according to which the agents are not necessarily administered simultaneously and in the same way.

The term "pharmaceutical combination", as used in the description of the application, means a product that is formed by mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound of formula I and collateral agent, are administered to a patient simultaneously in the form of a single material or dose. The term "non-fixed combination" means that the active ingredients, e.g. a compound of formula I and collateral agent, is administered to the patient separately, simultaneously, together or sequentially, without time limits, and this introduction provides achieve therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to the combined treatment, for example for the introduction of three or more active ingredients.

Methods for producing compounds according to the invention

The present invention also includes methods for producing compounds according to the invention. When using these methods, there is necessary the cost to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxypropyl, if these groups must be present in the final product, to avoid their unwanted participation in the reactions. Standard protective groups introduced by conventional methods as described, for example, in the book T.W.Greene and P.G.M.Wuts "Protective Groups in Organic Chemistry", John Wiley and Sons (1991).

The compounds of formula I are given as shown in scheme I

where n, R1and R2have the meanings given in the section "Brief description of the invention". The compound of formula Ia obtained when the interaction of the compounds of formula 2 with the compound of the formula 3 in the presence of a suitable solvent (for example, sec-butanol and the like). The reaction is carried out at a temperature from about 20°to about 80°C for approximately 24 h to complete the reaction.

The compounds of formula I get is the same as shown in scheme II

where n, R1and R2have the meanings given in the section "Brief description of the invention". The compound of formula Ib obtained when the interaction of the compounds of formula 5 with a compound of formula 6 in the presence of a suitable solvent (for example, sec-butanol and the like) and a suitable catalyst (e.g., monohydrate para-toluensulfonate acid and the like). The reaction is carried out at temperature is approximately 60°C to about 130°C for approximately 24 h to complete the reaction.

In another embodiment, the compound of formula Ib obtained when the interaction of the compounds of formula 5 with a compound of formula 6 in the presence of a suitable solvent (e.g. dioxane and the like), a suitable catalyst (e.g. palladium acetate and the like) and a suitable ligand (for example, XantPhos, and so on). The reaction is carried out at a temperature of from about 60°to about 130°C for approximately 24 h to complete the reaction.

The compounds of formula I get is the same as shown in scheme III

where n, R1and R2have the meanings given in the section "Brief description of the invention". The compound of the formula I get in the interaction of the compounds of formula 4 with the compound of the formula 3 in the presence of a suitable solvent (for example, sec-butanol and the like). The reaction is carried out at a temperature from about 20°to about 80°C for approximately 24 h to complete the reaction.

Detailed description of the synthesis of the compounds of formula I are given below in the "Examples"section.

Additional methods for producing compounds according to the invention

The connection according to the 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 others the d variant pharmaceutically acceptable basic additive salt get in the interaction of compounds in the form of the free acid with a pharmaceutically acceptable inorganic or organic base.

In another embodiment of the compounds according to the invention in the form of salts derived from salts of the source or intermediate materials.

Compounds according to the invention in the form of free acid or free base is obtained from the primary additive salt or acid salt additive, respectively. For example, the connection according to the invention in the form of an acid additive salt can be converted into the corresponding free base by treatment with suitable base (for example, a solution of ammonium hydroxide, sodium hydroxide and the like). The connection according to the invention in the form of a basic additive salts can be converted into the corresponding free acid in the processing of suitable acid (e.g. hydrochloric acid, and the like).

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

Prodrugs of the compounds according to the invention receive well-known methods (see Saulnier and other Bioorganic and Medicinal Chemistry Letters, v.4, s (1994)). For example, appropriate prodrugs receive when interacting n is modified compounds according to the invention with suitable carbamimidoyl agent (for example, 1,1-aryloxyalkanoic, para-nitrophenylarsonic or the like).

Protected derivatives of compounds according to the invention receive by known methods. More detail methods for the introduction and removal of the protective groups described in the book T.W.Greene "Protective Groups in Organic Chemistry", 3rd ed., John Wiley and Sons, Inc. (1999).

Compounds according to the invention is manufactured in the form of a solvate (e.g. hydrate). Hydrates of the compounds of the present invention is obtained by recrystallization from an aqueous/organic solvent mixture, using organic solvents, such as dioxane, tetrahydrofuran or methanol.

Compounds according to the invention obtained as individual stereoisomers in the interaction of racemic mixtures of compounds with optically active separating agent with the formation of pairs diastereoisomeric compounds for the separation of diastereomers and obtaining optically pure enantiomers. Since the separation of enantiomers using covalent diastereomeric derivatives of the compounds according to the invention, preferred are dissociable complexes (e.g., crystalline diastereomeric salt). Diastereomers have different physical properties (e.g. melting point, boiling point, solubility, reactivity, etc. and they are easy to share using these times is ice. The diastereomers separated by chromatography or, preferably, by the way, based on their different solubility, thus obtain optically pure enantiomers, along with a separating agent, by any method, in which no racemization occurs. A more detailed description of the allocation of stereoisomers of their racemic mixtures is given in the book of Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley and Sons, Inc. (1981).

Thus, the compounds of formula I get way, which is that

(a) conducting the reaction as described in scheme I, II or III and

(b) the compound according to the invention is not necessarily transform in pharmaceutically acceptable salt,

(c) the salt of the compounds according to the invention is not necessarily transform in mesolevel form

(d) non-oxidized form of the compounds according to the invention is not necessarily transformed into a pharmaceutically acceptable N-oxide,

(e) the N-oxide compounds according to the invention is not necessarily transform in non-oxidized form,

(f) from a mixture of isomers optional allocate individual isomer of the compounds according to the invention,

(g) unmodified compound according to the invention is not necessarily transform in a pharmaceutically acceptable prodrug, and

(h) the prodrug is not necessarily transform in unmodified compound according to the invention.

If the original materials are not op is Sano detail compounds known or get them by known methods or as described below in the "Examples"section.

It should be understood that the above transformations are given only to illustrate the methods of preparing compounds of the present invention, and that it is possible to use other known methods.

Examples

The examples illustrate the formation of compounds of formula I of the present invention, without limiting its scope.

Example 1

4-[2-(Substituted phenylamino)pyrimidine-4-yl]-1H-pyrrolo[2,3-b]pyridine

Obtaining 1H-pyrrolo[2,3-b]pyridine 7-oxide (2)

To a solution of 7-azaindole (10 g, and 84.6 mmole) in ethyl acetate (80 ml) was added msrv (18,96 g, 103,21 mmole) at 0°C for 30 minutes the reaction mixture was heated to CT and was stirred for 3 h, then was cooled to 0°C and was stirred for 1 h, the Residue was separated by filtration, washed with ethyl acetate and dried, to receive N-oxide in the form of a salt msrwa.

The suspension obtained above salt in water (80 ml) was cooled to 15°C and added To2CO3(30%) to pH 10. The reaction mixture was stirred at RT for 1 h, cooled to 0°C and maintained for 1 h, the Residue was separated by filtration, washed with cold water (10 ml) and was dried, it was obtained N-oxide (7 g).

Getting 4-bromo-1H-Pierre is lo[2,3-b]pyridine (3)

A suspension of 1H-pyrrolo[2,3-b]pyridine 7-oxide (6 g, 44,8 mmole) and bromide of Tetramethylammonium (of 5.17 g, 34 mmole) in DMF (60 ml) was cooled to 0°C., was stirred for 15 min and added methanesulfonyl anhydride (7.8 g, 44,8 mmole) at the same temperature. The suspension was heated to CT and was stirred for 4 h, then the reaction mixture was poured into water (100 ml) and the resulting solution was neutralized with NaOH (50%). The solution was cooled to a temperature of from 0 to 10°C, then the obtained solid substance was separated by filtration and dried, it was obtained 4-bromo-7-azaindole. MS m/z: 198,1 (M+1).

1H NMR (600 MHz, DMSO-d6): δ 10,81 (.s, 1H), at 8.36 (d, J 3.2 Hz, 1H), 7,63 (d, J 3.2 Hz, 1H), 7,52 (d, J a 4.1 Hz, 1H), 6,79 (d, J 3.6 Hz, 1H).

Getting 4-acetyl-1H-pyrrolo[2,3-b]pyridine (5)

4-Bromo-7-azaindole (1 g, 5 mmol) was dissolved in THF (15 ml) and cooled to -78°C, then at the same temperature for 10 min was slowly added n-BuLi (the 5.25 ml, 2 M solution, 2.1 EQ.). The mixture was stirred for 45 min, and then at the same temperature was slowly added N-methoxy-N-methylacetamide (1.1 ml, 10.5 mmole). The resulting reaction mixture was heated to CT and was stirred for 3 hours the Reaction was stopped by adding a saturated solution of NH4Cl (2 ml) at -78°C. the Reaction mixture was treated with ethyl acetate, the organic layer was washed salt solution is m and dried over Na 2SO4. The solvent was removed in vacuo, the crude compound was purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate). MS m/z: owed 161.1 (M+1).

1H NMR (600 MHz, DMSO-d6): δ 11,02 (.s, 1H), to 8.41 (d, J 3.2 Hz, 1H), 7,53 (d, J 3.2 Hz, 1H), 7,54 (d, J 4.4 Hz, 1H), 6,09 (d, J 3.5 Hz, 1H), 2,47 (s, 3H).

Getting enaminone (7)

A mixture of 4-acetyl-7-azaindole (1 g, 6.2 mmole) and Bredereck's reagent (2,56 ml, 12.4 mmole) was heated in a microwave reactor at 110°C for 1 h, the Excess reagent was removed under vacuum, thus received enamine, which was used in the next stage without additional purification.

Getting 4-[2-(substituted phenylamino)pyrimidine-4-yl]-1H-pyrrolo[2,3-b]pyridine (9)

A mixture of enaminone (35 mg, 0.16 mmole), nitrate 3-brompheniramine (48,57 mg, 0,178 mmole), LiOH (11,5 mg, 48 mmol) in sec-butanol (1 ml) was heated at 130°C for 24 h the Solvent was removed in vacuum and the crude solid was purified reversed-phase LC-MS, this has been specified in the header connection. MS m/z: 366,2 (M+1).

1H NMR (600 MHz, DMSO-d6): δ 11,92 (.s, 1H), 9,83 (s, 1H), 8,65 (d, J 4.8 Hz, 1H), 8.38 (d, J 4.8 Hz, 1H), 8,12 (t, J 2 Hz, 1H), to 7.77 (m, 1H), 7,69 (m, 1H), 7,65 (d, J 4.8 Hz, 1H), to 7.59 (t, J 2 Hz, 1H), 7,50 (d, J 5.2 Hz, 1H), 7,33 (t, J and 8.4 Hz, 1H), 7,06-7,07 (m, 1H).

Examples 2A and 2b

Pyridine-2-yl-[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine (2A) and (3-bromo-4-were)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine (2b)

Getting 4-[2-chloropyrimidine-4-yl]-1H-pyrrolo[2,3-b]pyridine (11)

To a solution of 4-bromo-7-azaindole (500 mg, 2.5 mmole) in THF at -78°C was added n-BuLi (2.6 ml, 2 M solution in hexane, 2.1 EQ.). The mixture was stirred for 45 min at the same temperature, and then was added dropwise 2-chloropyrimidine (314,9 mg of 2.75 mmole) in THF. The resulting reaction mixture was stirred for 2 h, then was added water (1 ml) and stirring continued for a further 20 minutes In the mixture at -78°C was added DDQ (618,7 mg of 2.75 mmole) in THF, the reaction mixture was heated to 0°C and was stirred for 1 h the Reaction was stopped by adding NaOH solution (1 ad), the reaction mixture was treated with ethyl acetate. The organic layer was washed with saturated solution of NaHCO3, saline and water, the combined organic layer was dried over MgSO4and evaporated, to receive the crude 4-pyrimidine-substituted azaindole. The compound was purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate). MCm/z: 231,0 (M+1).

1H NMR (600 MHz, DMSO-d6): δ 12,05 (.s, 1H), 8,91 (d, J 5.2 Hz, 1H), to 8.41 (d, J 4.8 Hz, 1H), 8,25 (d, J 5.2 Hz, 1H), 7,76 (d, J 5.2 Hz, 1H), 7,72 (.s, 1H), 7,09 (.s, 1H).

Receive (3-bromo-4-were)[4-(1H-pyrrolo[2.3-b1-4-yl)pyrimidine-2-yl]amine (13)

In the vial Smith (2-5 ml) were placed compound 11 (26.5 mg, 0,115 mmole), 3-bromo-4-methylaniline (42,54 mg of 0.23 mmole) and monohydrate para-toluensulfonate acid (4.4 mg, is 0.023 mmole), second-VION (0.5 ml). The vessel was purged with argon, sealed and heated at 100°C for 1.5 h in a Smith synthesizer. The resulting solution was purified reversed-phase LC-MS, this has been specified in the header connection. MS m/z: 380,04 (M+1).

Getting pyridine-2-yl[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine (15)

To a solution of 4-[2-chloropyrimidine-4-yl]-1H-pyrrolo[2,3-b]pyridine (26.5 mg, 0.12 mmole) in dioxane (1 ml) was added Pd(OAc)2(2.6 mg, 0,0115 mm), XantPhose (9,98 mg of 0.017 mmole), s3(112,40 mg, 0,345 mmole) and 2-aminopyridine (16,17 mg, 0,172 mmole). The vessel was purged with argon, sealed and heated at 150°C for 10 min in a microwave reactor. The mixture was filtered and evaporated in vacuum. The resulting solution was purified reversed-phase LC-MS, this has been specified in the header connection. MS m/z: 289,10 (M+1).

1H NMR (600 MHz, DMSO-d6): δ of $ 11.97 (.s, 1H), 11,55 (.s, 1H), 8,79 (d, J 4.8 Hz, 1H), of 8.37-8,35 (m, 2H), 8,12 (d, J 4.8 Hz, 1H), 7,84-7,83 (m, 2H), of 7.70 (d, J 4.8 Hz, 1H), 7,65 (d, J 4.8 Hz, 1H), 7,25-7,20 (m, 2H).

Example 3

(3-Chlorophenyl)[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-yl]amine

4-Methoxy-1H-pyrrolo[2,3-b]pyridine (16)

4-Methoxy-1H-pyrrolo[2,3-b]pyridine was obtained from 7-azaindole according to the method described in the article Cottan H.B., Girfis N.S., Robins R.., Journal of Heterocyclic Chemistry, 26(2), 317-325 (1989).

3-Acetyl-1H-pyrrolo[2,3-b]pyridine (17)

7-Azaindole (1 g, 8.4 mmole) was dissolved in dichloromethane and the resulting solution at RT was added to the suspension ll3(5.6 g, 42 mmole) in dichloromethane, and then at the same temperature was stirred for 1 h, was slowly added acetylchloride (1.8 ml, 25.2 mmole) and stirred for 2 hours After completion of the reaction (according to IHVR) the reaction mixture was cooled to 0°C and the reaction was stopped by the careful addition of methanol (3 ml). The reaction mixture was concentrated and the residue was washed with hexane. The residue was neutralized with aqueous NaOH (30%) and was extracted with dichloromethane. The filtrate was washed with saline, dried over MgSO4and evaporated, to receive the crude product, which was recrystallized from hexane/dichloromethane, to receive the purified product.

Getting enaminone (19)

A mixture of 3-acetyl-7-azaindole (1 g, 6.2 mmole) and Bredereck's reagent (2.5 EQ.) was heated in a microwave reactor at 110°C for 1 h, the Excess reagent was removed under vacuum, thus received enamine, which was used in the next stage without additional purification.

Received the e (3-chlorophenyl)[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-yl]amine (21)

A mixture of enaminone (35 mg, 0.16 mmole), nitrate 3-chlorophenylalanine (41,29 mg, 0,178 equiv.) LiOH (11,5 mg, 48 mmol) in sec-butanol (1 ml) was heated at 130°C for 24 h the Solvent was removed and the residue was washed with water and hexane, and it was obtained the desired compound, which was purified reversed-phase LC-MS, this has been specified in the header connection. MS m/z: 322,14 (M+1).

1H NMR (600 MHz, DMSO-d6): δ 12,41 (s, 1H), 9,71 (s, 1H), 8,90 (d, J 7,6 Hz, 1H), 8,53 (d, J 2.8 Hz, 1H), scored 8.38 (d, J 5.6 Hz, 1H), with 8.33 (dd, J of 4.4, 1.6 Hz, 1H), 7,85-7,83 (m, 2H), 7,39 (d, J 2.4 Hz, 2H), 7,38 (s, 1H), 7,24 (dd, J 7,6, 4,4 Hz, 1H).

The compounds of formula I, shown in the table was obtained according to the methods described in the above examples, using appropriate starting materials.

No. of connectionsStructurePhys. data1H NMR 400 MHz (DMSO-d6and/or MS (m/z)
1δ 11,88 (.s, 1H), to 9.91 (s, 1H), to 8.62 (d, J 4.8 Hz, 1H), 8,32 (d, J 4.8 Hz, 1H), of 8.06 (t, J 2 Hz, 1H), 7,66 (m, 1H), 7,65 (m, 1H), to 7.61 (d, J 4.8 Hz, 1H), to 7.59 (t, J 2 Hz, 1H), 7,49 (d, J 5.2 Hz, 1H), 7,26 (t, J and 8.4 Hz, 1H), 7,06-7,07 (.s, 1H). MS: m/z 322,1 (M+1)
2 δ 11.87 per (.s, 1H), 9,71 (s, 1H), 8,55 (d, J 5.2 Hz, 1H), 8,31 (d, J 4.8 Hz, 1H), 7,78 to 7.75 (m, 2H), to 7.61 (d, J 5.2 Hz, 1H), 7,58 (t,J 3.2 Hz, 1H), 7,42 (d, 15.2 Hz, 1H), 7,12-6,98 (m, 3H). MS: m/z 306,11 (M+1)
3δ 11,88 (.s, 1H),9,90 (s, 1H), at 8.60 (d, J 4.8 Hz, 1H), 8,32 (d, J 4.8 Hz, 1H), 7,89 (d, J 2.4 Hz, 1H), 7,87 (d, J 2.1 Hz, 1H),7.62mm (d, J 5.2 Hz, 1H), to 7.59 (t, J 3.2 Hz, 1H), 7,26-7,24 (m, 2H),? 7.04 baby mortality-7,03 (m, 2H). MS: m/z 372,09 (M+1)
4δ 11,85 (.s, 1H), 10,01 (s, 1H), 8.59 (d, J 4.8 Hz, 1H), 8.30 to-8,29 (m, 1H), 8,27 (d, J 4.8 Hz, 1H), 7,94 (d, J 7,6 Hz, 1H), to 7.59 (d, J 4,8, 1H), 7,53-7,52 (m, 1H), 7,47 (d, J 4.8 Hz, 1H), 7,42 (t, J 7,6 Hz, 1H), 7,18 (d, J a 7.6 Hz, 1H), 6,99 (m, 1H). MS: m/z 356,12 (M+1)
5MS: m/z 324,2 (M+1)
6MS: m/z 356,15 (M+1)
7MS: m/z 360,13 (M+1)
8MC: m/z 318,12 (M+1)
9MS: m/z 320,2 (M+1)
10MC: m/z 348,1 (M+1)
11δ 12,04 (.s, 1H), is 11.39 (s, 1H), 8,91 (d, J 5.2 Hz, 1H), charged 8.52 (d, J 6.8 Hz, 1H), 8,44 (d, J 4,8 Hz, 1H), 8,27 is 8.22 (m, 1H), 8,09-8,08 (m, 1H), of 7.90 (d, J 5.2 Hz, 1H), 7,75-7,72 (m, 2H), 7,14 (m, 1H), 2,62 (s, 3H). MC: m/z 303,13 (M+1)
12MC: m/z 323,07 (M+1)
13MS: m/z 319,13 (M+1)
14MS: m/z 366,21 (M+1)
15MS: m/z 289,11 (M+1)
16MS: m/z 304,31 (M+1)
17MS: m/z 380,04 (M+1)
18MS: m/z 336,21 (M+1)
19 MC: m/z 370,15 (M+1)
20MS: m/z 394,04 (M+1)
21MS: m/z 410,15 (M+1)
22MS: m/z 400,13 (M+1)
23MC: m/z 366,20 (M+1)
24MS: m/z 424,10 (M+1)
25MS: m/z 409,18 (M+1)
26MS: m/z 423,21 (M+1)
27MS: m/z 399,25 (M+1)
28MC: m/z 489,14 (M+1)
29δ to 12.52 (s, 1H), 10,08(s, 1H), 9,17 (dd, J of 4.8, 1.6 Hz, 1H), 8,72 (s, 1H), 8,65 (d, J 5.2 Hz, 1H), 8,54 (dd, J of 4.8, 1.6 Hz, 1H), compared to 8.26(d, J 8,4 Hz, 2H), to 7.64 (d, J 8,4 Hz, 2H), 7,63 (d, J 5.6 Hz, 1H), 7,24 (dd, J 7,6, and 4.4 Hz, 1H). MC: m/z 356,32 (M+1)
30δ 12,34 (s, 1H), 9,43 (s, 1H), 9,01 (d, J 7,6 Hz, 1H), and 8.50 (s, 1H), 8,42 (d, J 5.2 Hz, 1H), at 8.36 (d, J 4.6 Hz, 1H), 7,37 (d, J 5,6, 1H), 7,24 (dd, J of 8.0, 4.8 Hz, 1H), 7,16 (s, 2H), to 6.19 (t, J 2.0 Hz, 1H). MS: m/z 348,37 (M+1)
31MS: m/z 324,09 (M+1)
32MS: m/z 366,02 (M+1)
33MC: m/z 318,14 (M+1)
34MS: m/z 322,01 (M+1)
35MS: m/z 360,14 (M+1).
36MS: m/z 489,33 (M+1)
37MS: m/z 352,21 (M+1)
38 MC: m/z 386,32 (M+1)
39MS: m/z 396,09 (M+1)
40MS: m/z 489,21 (M+1)
41MC: m/z 395,01 (M+1)
42MS: m/z 425,12 (M+1)
43MS: m/z 439,13 (M+1)
44MC: m/z 439,15 (M+1)
45MS: m/z 439,15 (M+1)
46MS: m/z 336,21 (M+1)
47MS: m/z 370,12 (M+1)
48 MS: m/z 439,14 (M+1)
49MS: m/z 453,16 (M+1)
50MS: m/z 367,01 (M+1)
51MS: m/z 323,05 (M+1)
52MS: m/z 357,12 (M+1)
53MC: m/z 322,14(M+1)
54MS: m/z 366,21 (M+1)
55MS: m/z 356,12 (M+1)

Methods of analysis

Compounds of the present invention analyzed for their ability to inhibit kinase CDK, Aurora, Jak2, Rock, CAMKII, FLT3, Tie2, TrkB, FGFR3 and KDR.

FGFR3 (enzymatic analysis)

Analysis of kinase activity of purified FGFR3 (firm Upstate) was performed in a final volume of 10 μl containing 0.25 μg/ml of enzyme in a buffer solution to determine kinase (30 mm Tris-HCl, pH 7.5, 15 mm MgCl2, 4.5 mm MnCl2, 15 µm Na3VO4and 50 μg/ml BSA), substrates (5 μg/ml Biotin-poly-EY (Glu, Tight) (company CIS-US, Inc.) and 3 μm ATP. The analysis was performed using the two solutions: the first solution (5 μl)containing the FGFR3 enzyme in a buffer solution to determine kinase, was added to 384-well tablets ProxiPlate® (firm Perkin-Elmer), to each well was added 50 nl of a solution of the compounds in DMSO, and then 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 ál of the mixture to discovery HTRF containing 30 mm Tris-HCl, pH 7.5, 0.5 M KF, 50 mm ETDA, 0.2 mg/ml BSA, 15 μg/ml streptavidin-L665 (firm CIS-US, Inc.) and 150 ng/ml conjugate cryptate and antiphosphotyrosine antibodies (firm CIS-US, Inc.). The mixture is incubated at room temperature for 1 h for the formation of a complex of streptavidin/Biotin, fluorescent signals with a time resolution was registered on fluorimetry Analyst GT (company Molecular Devices Corp.). The value of the IC50was calculated by the method of linear regression on the percentage inhibition of each compound at 12 concentrations (dilution 1:3 initial solution from 50 μm to 0.28 nm). According to this analysis, the compounds according to the invention have values IC50in the range from 10 nm to 2 μm.

FGFR3 (analysis in the culture of cells is to)

Compounds according to the invention were analyzed for the ability to inhibit the proliferation of transformed cells Ba/F3-TEL-FGFR3, which is dependent on the activity of cellular kinases FGFR3. Cells Ba/F3-TEL-FGFR3 were cultured in suspension in RPMI medium 1640 containing 10% fetal calf serum to a concentration of 800,000 cells/ml the Cells were inoculated into 384-well tablets with a density of 5000 cells/well in 50 μl of culture medium. Compounds according to the invention was dissolved and diluted in dimethylsulfoxide (DMSO). Received 12 solutions in DMSO at serial dilution of 1:3 is usually from 10 mm to 0.05 microns. In wells with cells were added in 50 nl of diluted solutions of the compounds and incubated for 48 h in the incubator for cell cultures. Then in the wells with the cells was added to the reagent AlamarBlue® (firm TREK Diagnostic Systems) to a final concentration of 10%, which is used to register a reducing environment posed by proliferating cells. The mixture is incubated at 37°C in incubator for cell cultures for a further 4 h and determined the intensity of the fluorescence is restored AlamarBlue® (excitation at 530 nm, emission at 580 nm) on fluorimetry Analyst GT (company Molecular Devices Corp.). The value of the IC50was calculated by the method of linear regression on the percentage inhibition of each compound at 12 concentrations.

FLT3 (analysis in cell culture)/p>

The action of the compounds according to the invention on cellular activity (activity in the cells) FLT3 was estimated using the methods described above to determine the cellular activity of FGFR3, and the place cells Ba/F3-TEL-FGFR3 used cells Ba/F3-FLT3-ITD.

Radiopharmacy analysis in the substrate binding on the filter using a set of "Upstate KinaseProfiler™"

Compounds according to the invention were analyzed for their ability to inhibit the activity of individual members of the kinase panel. Compounds were analyzed by double repeat with the final concentration of 10 μm by the following General method. The composition of buffer solution to determine kinases and substrates vary in the analysis of various kinases included in the set of "Upstate KinaseProfiler™". Buffer solution to determine kinase (2,5 μl, 10×, containing, if necessary, MnCl2), active kinase (0.001 to 0.01%, and 2.5 μl), a specific peptide or poly(Glu4-Tight) (5-500 μm or 0.01 mg/ml) in buffer solution to determine the kinase and buffer solution to determine kinase (50 ám, 5 ml) was mixed in an Eppendorf tube in an ice bath. 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 (20 μl) were applied to the square of the s pieces of paper P81 (phosphocellulose, 2 cm×2 cm, in the case of a positively charged peptide substrate) or Whatman No. 1 (in the case of peptide substrate poly(Glu4-Tight). Squares washed four times (each time for 5 min) of 0.75% phosphoric acid, once with acetone (within 5 min), was transferred to a scintillation vial was added 5 ml of scintillation fluid and measured the incorporation of phosphorus32P (u/min) in the peptide substrate on the scintillation counter Beckman. For each reaction 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, as shown in the in vitro tests described in the proposal. For example, the compounds of formula I preferably are characterized by the values of the IC50in the range from 1×10-10up to 1×10-5M, preferably less than 500 nm, 400 nm, 300 nm and 200 nm for at least one kinase, the above panel of kinases. The compounds of formula I in free form or in the form of pharmaceutically acceptable salts exhibit valuable pharmacological properties, for example, as described in this context in the analysis of in vitro, at a concentration of 10 μm, preferably inhibit more than 50%, preferably more than about 70% of the activity of CDK kinases, Aurora, Jak2, Rock, SAMC, FLT3, Tie2, TrkB, FGFR3 and KDR.

It should be understood that the described is, in this context, examples and embodiments of the invention provided for illustrative purposes only and that various modifications or changes obvious to a person skilled in the art, is included in the scope and essence of the present invention and the points of the attached claims. All publications, patents and published applications cited in this context included in this description as a reference.

1. A compound selected from compounds of the formulae Ia, Ib and Ic:

where n is 0 or 1,
R1selected from the group including halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl and halogen-substituted C1-C6alkoxy,
R2selected from the group comprising phenyl, 6-membered heteroaryl containing 1-2 nitrogen atom in the heteroaryl ring, as heteroatoms, and phenyl(C0-C4)alkyl, and specified phenyl and heteroaryl in the composition of R2optionally substituted by 1-3 radicals independently selected from the group comprising halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxy,
-S(O)0-2R5, -COOR5and-NR5C(O)R6and R5selected from C1-C6the alkyl, a R6selected from phenyl, with the specified phenyl in the composition of R6optionally substituted by 1-3 radicals and, independently selected from the group comprising C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl and halogen-substituted C1-C6alkoxy,
X is chosen from CR7and N, and R7selected from hydrogen and C1-C6of alkyl, as well as its pharmaceutically acceptable salt, hydrate, solvate and isomers.

2. The compound according to claim 1, where
n is 0 and 1,
R1means C1-C6alkoxy,
R2selected from the group comprising phenyl(C0-C4)alkyl and 6-membered heteroaryl containing 1-2 nitrogen atom in the heteroaryl ring, as heteroatoms, with the specified phenyl or heteroaryl in the composition of R2optionally substituted by 1-3 radicals independently selected from the group comprising halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl, -S(O)0-2R5, -COOR5and-NR5C(O)R6and R5selected from C1-C6of alkyl, and R6means phenyl, optionally substituted by 1-3 radicals independently selected from halogen-substituted C1-C6the alkyl.

3. The compound according to claim 2, where
R1means methoxy, R2selected from phenyl, benzyl and pyridinyl, and specified phenyl, benzyl, or pyridinyl, in the composition of R2optionally substituted by 1-2 radicals, illegal is isimo selected from the group includes chlorine, bromine, fluorine, methyl, triptoreline, trifluoromethyl, -COOR5, -S(O)2R5and-NHC(O)R6and R5selected from methyl and ethyl, and R6means phenyl, optionally substituted by trifluoromethyl.

4. A compound selected from the group including
(3-chlorophenyl)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine,
(4-forfinal)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine,
[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl](4-trifloromethyl)amine,
[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl](3-triptoreline)amine,
(3,4-differenl)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine,
[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl](4-triptoreline)amine,
ethyl ester of 4-[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-ylamino]benzoic acid
(3-methoxyphenyl)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine,
(3-terbisil)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine,
(3,5-acid)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine,
(2-methylpyridin-4-yl)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine,
(2-chloropyridin-4-yl)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine,
(2-methoxypyridine-4-yl)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine,
(4-methanesulfonyl)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine,
pyridine-4-yl[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine,
(4-IU is Yeremey-2-yl)[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine,
(3-bromophenyl)[4-(1-methyl-1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine,
(3-chlorophenyl)[4-(1-methyl-1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine,
[4-(1-methyl-1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl](3-triptoreline)amine,
(3-bromo-4-were)[4-(1-methyl-1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine,
2-{4-[2-(3-brompheniramine)pyrimidine-4-yl]pyrrolo[2,3-b]pyridine-1-yl}ethanol,
2-{4-[2-(3-triptoreline)pyrimidine-4-yl]pyrrolo[2,3-b]pyridine-1-yl}ethanol,
2-{4-[2-(3-chlorpheniramine)pyrimidine-4-yl]pyrrolo[2,3-b]pyridine-1-yl}ethanol,
2-{4-[2-(3-bromo-4-methylphenylimino)pyrimidine-4-yl]pyrrolo[2,3-b]pyridine-1-yl}ethanol,
{4-[1-(2-amino-ethyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]pyrimidine-2-yl}(3-bromophenyl)amine,
{4-[1-(2-amino-ethyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]pyrimidine-2-yl}(3-bromophenyl)methylamine,
{4-[1-(2-amino-ethyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]pyrimidine-2-yl}(4-triptoreline)amine,
N-{4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-ylamino]phenyl}-3-cryptomelane,
[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-yl](4-triptoreline)amine,
(3,5-acid)[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-yl]amine,
(3,5-differenl)[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-yl]amine,
(3-bromophenyl)[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-yl]amine,
(3-methoxyphenyl)[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-yl]amine,
(4-chlorophenyl)[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-yl]am is h, ethyl ester of 4-[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-ylamino]benzoic acid
N-{4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-ylamino]phenyl}-3-cryptomelane,
(3-chlorophenyl)[4-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-yl]amine,
[4-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-yl](3-triptoreline)amine,
(3-bromophenyl)[4-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-yl]amine,
N-{4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrimidine-2-ylamino]phenyl}-3-cryptomelane,
N-ethyl-4-[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-ylamino]benzosulfimide,
N-(2-methoxyethyl)-4-[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-ylamino]benzosulfimide,
N-(3-methoxypropyl)-4-[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-ylamino]benzosulfimide,
N-(3-methoxypropyl)-4-[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-ylamino]benzosulfimide,
(3-bromophenyl)[4-(2-methyl-1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine,
(3-chlorophenyl)[4-(2-methyl-1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl]amine,
[4-(2-methyl-1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-yl](3-triptoreline)amine,
N-(2-methoxyethyl)-4-[4-(2-methyl-1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-ylamino]benzosulfimide,
N-(3-methoxypropyl)-4-[4-(2-methyl-1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidine-2-ylamino]benzosulfimide,
(3-bromophenyl)[4-(1H-pyrazolo[3,4-b]pyridine-4-yl)pyrimidine-2-yl]amine,
(3-chlorphen the l)[4-(1H-pyrazolo[3,4-b]pyridine-4-yl)pyrimidine-2-yl]amine,
[4-(1H-pyrazolo[3,4-b]pyridine-4-yl)pyrimidine-2-yl](3-triptoreline)amine,
(3-chlorophenyl)[4-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrimidine-2-yl]amine,
(3-bromophenyl)[4-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrimidine-2-yl]amine and
[4-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrimidine-2-yl](3-triptoreline)Amin.

5. Pharmaceutical composition having the properties of an inhibitor of the activity of kinases selected from the group including CDKs, Aurora, Jak2, Rock, CAMKII, FLT3, Tie2, TrkB, FGFR3 and KDR, comprising a therapeutically effective amount of a compound according to claim 1 in combination with pharmaceutically acceptable excipients.

6. Method of inhibiting kinase activity, where the kinase is selected from the CDKs, Aurora, Jak2, Rock, SAMC, FLT3, Tie2, TrkB, FGFR3 and KDR, including the introduction of a therapeutically effective amount of a compound according to claim 1.

7. The use of compounds according to claim 1 for obtaining a medicinal product intended for the treatment of diseases in which the kinase activity of CDKs, Aurora, Jak2, Rock, SAMC, FLT3, Tie2, TrkB, FGFR3, and KDR is associated with the development of the disease and/or symptoms of the disease.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydropyridoindole derivatives of general formula , where R1, R2, R3 and R4 independently represent hydrogen; C1-C5alkyl, which can be optionally substituted and represents trifluoromethyl if C1-C5alkyl is substituted; C1-C3alkoxy or halogen, and R5 is C1-C6alkylcarbonyl, C1-C5alkylcarbamoyl, C1-C5alkoxycarbonyl, C2-C5alkenylcarbonyl, C3-C6cycloalkylcarbonyl, C3-C6cycloalkyl(C1-C3)alkylcarbonyl, C3-C6cycloalkylcarbamoyl, C3-C6cycloalkylthiocarbamoyl, phenylcarbonyl or phenyl(C1-C3)alkylcarbonyl, where the phenyl residue in these two groups contains one, two, three or four substitutes, independently selected from a group comprising C1-C4alkyl, C1-C3alkoxy, halogen, trifluoromethyl and trifluoromethoxy, monosubstituted with a C3-C6cycloalkyl group, or monosubstituted with a phenyl group which in turn is substituted with a C1-C3alkyl group; phenyl(C1-C3)alkoxycarbonyl, phenylcarbamoyl or phenylthiocarbamoyl (where these two groups are optionally independently monosubstituted with a C1-C5alkyl group or halogen atoms); phenyl(C1-C3)alkylcarbamoyl, phenyl(C1-C3)alkylthiocarbamoyl, biphenylcarbamoyl, naphthylcarbonyl, naphthyl(C1-C3)alkylcarbonyl or naphthylcarbamoyl (where the naphthyl residues in these three groups are optionally monosubstituted with substitutes independently selected from a group comprising C1-C3alkyl, C1-C3alkoxy and halogen); fluorenylcarbonyl, optionally substituted with an oxo group, fluorenyl(C1-C3)alkoxycarbonyl; or 5-9-member heteroarylcarbonyl groups containing one or two heteroatoms, independently selected from a group comprising oxygen, nitrogen and sulphur, where the said groups can be substituted with one or two groups independently selected from C1-C3alkyl and halogen, provided that if R1, R2, R3, R4 are hydrogen, R5 is not ethoxycarbonyl or tert-butoxycarbonyl, or salt thereof. The invention also relates to a pharmaceutical composition based on the compound of formula I and to use of the compound in preparing a medicinal agent.

EFFECT: obtaining novel tetrahydropyridoindole derivatives which have CRTH2 receptor antagonistic activity.

14 cl, 14 tbl, 171 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel therapeutically suitable derivatives of pyridazin-3(2H)-one of formula and pharmaceutical compositions containing the said derivatives. These compounds are used for treating, preventing or inhibiting corresponding pathological conditions, diseases or disorders, mainly asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, atopic dermatitis, psoriasis or irritable colon syndrome.

EFFECT: obtaining compounds which are active and selective phosphodiesterase 4 (PDE4) inhibitors.

11 cl, 1 tbl, 182 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), their N-oxide forms, pharmaceutically acceptable additive salts and stereochemically isomeric forms as 11-HSD1 inhibitors, to their use, a pharmaceutical composition based on the said compounds and method of obtaining the said compounds. In general formula (I) , X is C or N; Y is C or N; L is methyl or a single bond; Z1 is a single bond, C1-2alkyl or a radical of formula -CH=; Z2 is a single bond, C1-2alkyl; R1 is hydrogen, halogen, hydroxy; R2 is hydrogen, halogen or C1-4alkyloxy; A is phenyl or a monocyclic heterocycle selected from a group consisting of thiophenyl or pyrridinyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by 11-HSD1.

9 cl, 7 dwg, 2 tbl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolopyrimidine and pyrrolopyridine of general formula (I), substituted with a cyclic amino group (II), or their pharmaceutically acceptable salts having CRF antagonist properties. In general formula the cyclic amino group has formula , in which the cyclic amino group is a 6-member saturated cyclic amine, the said cyclic amine is substituted with a group of formula -(CH2)mX; in which X is -CO2H, -CONH2,-P(=O)(OH)2 or -S(=O)2OH; Y is N or CH; m is an integer selected from 1, 2 and 3; R4 is hydrogen; R5 is hydrogen; R6 is C1-5alkyl; R7 and R8 are identical or different and independently represent hydrogen, C1-5alkyl, Ar is phenyl which is unsubstituted or substituted with one or more substitutes which are identical or different and are selected from a group consisting of halogen, C1-5alkyl, C1-5alkoxy, C1-5alkylthio, trifluoromethyl and trifluoromethoxy.

EFFECT: compounds can be used for therapeutic or preventive treatment of diseases where CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension etc.

12 cl, 6 dwg, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention provides novel pyrrolo[2,3-c]pyridine derivatives of formula (I), where radicals R1, R2, R3, R4 and R5 are as indicated in paragraph 1 of the formula of invention, or their pharmaceutically acceptable salts, as well as methods of producing the said compounds and a pharmaceutical composition having proton pump inhibiting effect.

EFFECT: novel compounds which exhibit excellent proton pump inhibiting effect and can have reversible proton pump inhibiting effect are obtained and described.

6 cl, 927 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: new compounds have formula (I) , where values of radicals R1 - R10 are as given in paragraph 1 of the formula of invention; n equals 2 or 3, --- denotes absence of substitution or a single bond; and denotes a single bond or a double bond, or to salts thereof. The invention also relates to a method of producing compounds of formula (Ic), to a NK2 receptor antagonist, to a pharmaceutical agent, to a method of antagonising the NK2 receptor, to a method of preventing or treating functional gastrointestinal diseases, as well as to use of compounds given in paragraph 1.

EFFECT: obtaining new biologically active compounds with antagonistic effect on the NK2 receptor.

31 cl, 331 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the trihydrate of 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of formula (I) .

EFFECT: novel compound is obtained, which is thermodynamically stable and has antibacterial activity.

1 cl, 3 tbl, 2 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: described are novel compounds with general formula , their stereoisomers and pharmaceutically acceptable salts or solvates, where the dashed line can represent a double bond (together with the present single bond); R represents phenyl or benzodioxolyl, each of which can be substituted; R1, R3 and R4 independently represent hydrogen or C1-C6alkyl; R5 represents C1-C6alkyl; R7 represents hydrogen; R12 represents R3 or -C(O)R2, where R2 represents C1-C4 alkyl; D and G represent -CH2 - or -CH- when they are bonded to each other by a double bond; m equals 1; a pharmaceutical composition containing said compounds, and use of the novel compounds in treating conditions mediated by corticotropin-releasing factor (CRF).

EFFECT: increased effectiveness of compounds.

11 cl, 13 ex, 11 tbl

FIELD: medicine.

SUBSTANCE: invention relates to compounds of general formula (I) and their pharmaceutically acceptable salts and pharmaceutically acceptable asters, possessing activity with respect to LXRα and/or LXRβ receptors. Compounds can be applied for treatment and prevention of diseases mediated by LXRα and/or LXRβ receptors, namely: increased level of lipids and cholesterol level, atherosclerotic diseases, diabetes, metabolic syndrome, dyslipidermia, sepsis, inflammatory diseases, pancreatitis, liver cholestasis/fibrosis, and diseases which include inflammatory component, such as Alzheimer's disease and reduced/improvable cognitive function. In general formula n represents integer number from 0 to 3; R1 is independently selected from group consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, -OR11, pyperidinyl and -N(R11)(R11), where R11 is independently selected from lower alkyl and H, X1, X2, X3 and X4 are independently selected from nitrogen and carbon, on condition that, not more than two of X1, X2, X3 and X4 can simultaneously represent nitrogen, and in case when two of X1, X2, X3 and X4 represent nitrogen, n represents 0,1 or 2; k represents integer number 0 or 1; R2 represents H; R3 represents H, lower alkyl or halogen; R4 represents aryl, heteroaryl, lower alkylaryl or lower alkylheteroaryl, each of which is optionally substituted with substituents in amount from one to five, which are independently selected from group consisting of halogen, lower alkyl, -OR41, lower alkinyl and NR42R43, where R41 represents lower alkyl, R42 and R43 independently on each other represent hydrogen or lower alkyl, or NR42R43 represents pyrrolidinyl, or R4 represents lower alkyl; R5 is selected from group, heteroaryl, consisting of and , said aryl and heteroaryl being optionally substituted in one or more positions with one or more substituents, independently selected from group consisting of H, halogen, lower alkyl and (CH2)VR53, where R51 is selected from group consisting of H, lower alkyl, lower alkenyl and lower alkylaryl, said lower alkylaryl is optionally substituted in one or more positions with one or more lower alkyl, -CN, halogen, group -COOR54 and group -CH2OR54, where R54 represents lower alkyl or H; R52 represents lower alkyl or -H; R53 represents H, lower alkyl, C3-C6-cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, CF3, -CONH2 or -CH2OR55, where R55 is independently selected from group consisting of lower alkyl, -H, -C(O)aryl or -C(O)-lower alkyl, and R56 is selected from group consisting of H, lower alkyl, -C(O)CF3, -C(O)aryl, -C(O)-lower alkyl and lower alkylaryl, and where said aryl and lower alkylaryl are optionally substituted in one or more positions with one or more lower alkyl, halogen, group COOR57 and group -CH2OR57, where R57 represents lower alkyl or -H, or R55 and R56 together with atom to which they are bound, form ring system; or R53 represents aryl, which can be optionally substituted with benzyloxy, carboxy, lower alkoxycarbonyl, hydroxy-(lower alkyl), halogen, carbamoyl, (lower alkyl)carbamoyl, di-(lower alkyl)carbamoyl, m represents integer number from 0 to 2; v represents integer number from 0 to 4; where term "lower alkyl" separately or in combination with other groups refers to branched or linear monovalent alkyl radical, containing from one to six carbon atoms, where term "aryl" separately or in combination with other groups refers to phenyl or naphthyl, and where term "hetyeroaryl" refers to aromatic 5- or 6-member ring, which can include 1-3 heteroatoms selected from nitrogen, oxygen and/or sulphur, and which can be condensed with phenyl group.

EFFECT: increase of compound application efficiency.

38 cl, 5 dwg, 137 ex

FIELD: medicine.

SUBSTANCE: there are described new compounds of general formula

where Xa represents 2 to 4 condensed cycloalkyl, aryl, heterocyclic rings containing 1 to 2 heteroatoms, chosen of N and O, and heteroaryl rings containing 1 to 4 heteroatoms, chosen of N, O or S where said rings can be additionally substituted. (Radical values R1-R4, R1, Y and n are specified in the patent claim), specific representatives of said compounds and a pharmaceutical composition containing them.

EFFECT: new compounds are effective in stimulation of endogenous development or release of growth hormone and can be used in treating obesity, osteoporosis and for increasing muscle bulk and muscle strength.

17 cl, 339 ex, 10 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydropyridoindole derivatives of general formula , where R1, R2, R3 and R4 independently represent hydrogen; C1-C5alkyl, which can be optionally substituted and represents trifluoromethyl if C1-C5alkyl is substituted; C1-C3alkoxy or halogen, and R5 is C1-C6alkylcarbonyl, C1-C5alkylcarbamoyl, C1-C5alkoxycarbonyl, C2-C5alkenylcarbonyl, C3-C6cycloalkylcarbonyl, C3-C6cycloalkyl(C1-C3)alkylcarbonyl, C3-C6cycloalkylcarbamoyl, C3-C6cycloalkylthiocarbamoyl, phenylcarbonyl or phenyl(C1-C3)alkylcarbonyl, where the phenyl residue in these two groups contains one, two, three or four substitutes, independently selected from a group comprising C1-C4alkyl, C1-C3alkoxy, halogen, trifluoromethyl and trifluoromethoxy, monosubstituted with a C3-C6cycloalkyl group, or monosubstituted with a phenyl group which in turn is substituted with a C1-C3alkyl group; phenyl(C1-C3)alkoxycarbonyl, phenylcarbamoyl or phenylthiocarbamoyl (where these two groups are optionally independently monosubstituted with a C1-C5alkyl group or halogen atoms); phenyl(C1-C3)alkylcarbamoyl, phenyl(C1-C3)alkylthiocarbamoyl, biphenylcarbamoyl, naphthylcarbonyl, naphthyl(C1-C3)alkylcarbonyl or naphthylcarbamoyl (where the naphthyl residues in these three groups are optionally monosubstituted with substitutes independently selected from a group comprising C1-C3alkyl, C1-C3alkoxy and halogen); fluorenylcarbonyl, optionally substituted with an oxo group, fluorenyl(C1-C3)alkoxycarbonyl; or 5-9-member heteroarylcarbonyl groups containing one or two heteroatoms, independently selected from a group comprising oxygen, nitrogen and sulphur, where the said groups can be substituted with one or two groups independently selected from C1-C3alkyl and halogen, provided that if R1, R2, R3, R4 are hydrogen, R5 is not ethoxycarbonyl or tert-butoxycarbonyl, or salt thereof. The invention also relates to a pharmaceutical composition based on the compound of formula I and to use of the compound in preparing a medicinal agent.

EFFECT: obtaining novel tetrahydropyridoindole derivatives which have CRTH2 receptor antagonistic activity.

14 cl, 14 tbl, 171 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a free base (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)- ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine in crystalline form, having a powder X-ray diffraction pattern with peaks at diffraction angles (2θ) 15.7±0.1, 17.3±0.1 and 19.7±0.1. The invention also relates to a pharmaceutical composition, to methods of treating cancer in mammals, as well as to a method of treating abnormal cell growth in mammals in need of such treatment.

EFFECT: obtaining an novel biologically active compound having the said inhibitory activity.

12 cl, 1 ex, 3 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to an agent, which is in form of fluorinated 1,4-naphthoquinone derivatives of general formula (I) which have cytotoxic effect on human cancer cells in a culture. In general formula (I) 1) R1=NHC(CH3)3, R2, R3=F; 2) R1=NHCH2CH2SCH3, R2, R3=F; 3) R1=N(CH2CH2)2, R2, R3=F; 4) R1=N(CH2CH2)2, R2, R3=F; 5) R1=NHCH2CH2CH2CH3, R2, R3=F; 6) R1=NHC6H5R2, R3=F; 7) R1=H(CH3)CH2CH2OH, R2, R3=F; 8) R1, R3=NHCH2CH2CH2CH3, R2=F; 9) R1=N(CH2CH2OH)2, R2, R3=F; 10) R1=NHC6H5, R2=CH3, R3=F; 11) R1=OCH3, R2, R3=F; 12) R1=NH(CH2)2SS(CH2)2NH(2-pentafluoro-1,4-naphthoqunonyl), R2, R3=F; 13) R1=NHC2H5, R2, R3=F; 14) R1=N+C5H5, R2=O; R3=F; 15) R1=NHCH2CH2OH, R2,R3=F; 16)R1, R2=OCH3, R3=F.

EFFECT: proposed compounds can be used in medicine as a base for designing drug formulations of preparations used in malignant growth therapy.

2 dwg, 4 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: testosterone is introduced intramuscularly and applied on the stomach and breast skin to ensure the steady high blood concentration. 6-8 hours prior to a session of gamma-ray teletherapy, a composite is introduced through rectum. The composite contains sodium alginate, dimethyl sulphoxide solution and testosterone. 6-8 hours later, the composite is removed from rectum. It is followed with gamma-ray teletherapy with "РОД" 5 Gy and local microwave hyperthermia.

EFFECT: method allows enhancing radio modifying treatment effect, inhibiting growth and metastasis of the tumour to the extent of regression, reducing number of by-effects and contraindications.

2 cl, 2 tbl, 1 ex

Oncotherapy // 2387456

FIELD: medicine.

SUBSTANCE: therapy involves introduction of sonicated human DNA combined with nonhistone protein to the patient with the length of human DNA fragments making 200-6000 pairs of bases, and the ratio of sonicated human DNA/nonhistone protein being 1/0.8. The complex is administered in a dose to ensure the blood concentration of sonicated human DNA 25 ng/ml - 1000 ng/ml.

EFFECT: application of the invention implies oncotherapy ensured by substitution of replacement oncolocus by a DNA fragment with nonmutant allele to form a nucleotide stable complex.

2 cl, 4 tbl, 11 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula Ia: and its pharmaceutically acceptable salt, where: p equals 0 or 1; n assumes values from 1 to 3, q equals 1; R5 is selected from hydrogen, -XNR7R8, pyrimidine-C0-4alkyl, pyridine-C0-4alkyl, phenyl, C3-10cycloalkyl-C0-4alkyl and C3-6heterocycloalkyl-C0-4alkyl, where C3-6heterocycloalkyl is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is hydrogen or C1-4alkyl; R7 and R8 represent C1-4alkyl; R6 denotes hydrogen; or R5 and R6 together with a nitrogen atom to which they are both bonded form morpholine or piperidine; where any piperdine-C0-4alkyl, piperidine-C0-4alkyl or C3-10cycloalkyl-C0-4alkyl of substitute R5 or a combination of radicals R5 and R6 can be optionally substituted with 1-2 radicals which are independently selected from -XNR7R8 and -XOR7, the said phenyl of substitute R5 is substituted with a -XR9 group, the said C3-6heterocycloalkyl-C0-4alkyl of substitute R5 is optionally substituted with a -XOR7 group, where X is a single bond or C1-4alkylene; R7 and R8 are independently selected from hydrogen and C1-4alkyl; R9 is selected from C3-10heterocycloalkyl which is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is as given above; R10 denotes hydrogen; R15 is selected from halogen, C1-6alkyl and C1-6alkoxy; and R16 is selected from halogen, methoxy, nitro, -NR12C(O)R13, -C(O)NR12R12, -NR12R12, -C(O)OR12 and -C(O)NR12R13; each R12 is selected from hydrogen and C1-6alkyl; R13 is selected from phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl, where any phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl of substitute R13 can be optionally substituted with 1-2 radicals which are independently selected from halogen, C1-6alkyl, halogen-substituted C1-6alkyl, imidazole-C0-4alkyl, C3-10cycloalkyl, C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl; where the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl each represent a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R assumes values given above; and the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl can each be optionally substituted with 1 radical independently selected from C1-6alkyl, hydroxyl-substituted C1-6alkyl and NR7R8, where R7 and R8 assume values given above. The invention also relates to pharmaceutical compositions containing the said compounds.

EFFECT: obtaining novel compounds and compositions based on the said compounds which can be used in medicine for treating and preventing diseases or disorders associated with abnormal or uncontrolled kinase activity, particularly diseases or disorders associated with abnormal activity of kinase c-Src, FGFR3, KDR and/or Lck.

12 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and biotechnology and concerns an anticancer drug based on nanoparticles bearing recombinant human tumour necrosis factor alpha. Substance of the invention includes the anticancer drug representing nanoparticles each of which contains a nucleus consisting of polynucleotide complex representing double-helical RNA (dhRNA) - an interferonogenesis inducer, and coated with a layer of spermidine conjugate with polyglucin held by ionic interaction between negative polynucleotide complex and positive spermidine, while recombinant human tumour necrosis factor alpha is covalently bound with activated polyglucin. As double-helical RNA, the anticancer drug contains double-helical RNA of Saccharomyces cerevisiae yeast. Nanoparticles are ball shaped and sized about 50-70 nm; 60-80 molecules of recombinant human TNF-α of cytolytic activity 106 ME/mg of protein and higher, 60-80 molecules of polyglucin and 1000-1300 molecules of spermidine are necessary for one molecule of double-helical RNA of Saccharomyces cerevisiae yeast.

EFFECT: reduced dose of TNF-α and lower toxicity.

5 cl, 5 ex, 4 dwg

FIELD: medicine.

SUBSTANCE: invention refers to preparation of a plant drug for treating stomach cancer. The drug for treating stomach cancer contains cod-liver oil, badger fat, plant seed blood chosen from the group: pomegranate, hot pepper, fennel and activated coal in the following ratio, wt %: cod-liver oil 28; badger fat 28; seed blood 42; activated coal the rest.

EFFECT: treatment with the declared drug involves activating body defences, resistance ensured by improved functioning of an individual's organs and systems, and targeting the lesion focus.

2 ex

Cancer therapy // 2386442

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely oncology and can be used in mesothelioma treatment. The method consists in monthly subcutaneous introduction to the patient of powdered fibrin solution recovered from the donor's blood clot in a dose 100-600 mg of dry powder per one introduction session.

EFFECT: application of the invention allows for effective cancer therapy by fibrin preparation only without administration of cytostatic agents, radioactive drugs and radioisotopes that ensures reduced complications.

3 dwg, 1 ex

Biomarker // 2385944

FIELD: medicine.

SUBSTANCE: invention describes a biomarker intended for determining sensitivity of proliferative diseases, such as cancer, to mTORs inhibitor combined with a cytotoxic agent, first of all with a cytotoxic agent (CA) that damages or disturb DNA integrity. According to the invention, the biomarker designated as p21 represents cip/kip-family of cyclinkinase inhibitors. Sensitivity or response of the proliferative disease in an individual on treatment with mTOR inhibitor combined with CA is determined by the level of p21 expression after CA treatment and a combination therapy with using CA and mTOR inhibitor. Favorable treatment and sensitivity of disease to the combination therapy is predicted by the absence of expression induction reduced. Besides according to the invention, the biomarker can be used in the method to overcome the CA resistance in the patient treated with CA. That is ensured by evaluating p21 level in a sample, the increasing regulation of p21 expression following CA introduction to the patient, mTOR inhibitor is administered in combination with CA, while lowered expression regulation observed following the combination therapy ensures to continue treatment with mTOR inhibitor with simultaneous or consecutive CA introduction.

EFFECT: application of the invention allows for more accurate prediction of sensitivity of a proliferative diseases in an individual to the combination therapeutic treatment.

4 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 1-thio-D-glucitol compounds of formula I or to pharmaceutically acceptable salts thereof or hydrates of the compound or salts: , [where R1, R2, R3 and R4 are identical or different, and each is a hydrogen atom, C1-C6-alkyl group), A is -(CH2)n-, -CONH(CH2)n-, -O- or -(CH2)nCH=CH- (where n is an integer from 0 to 3, Ar1 is an arylene group, heteroarylene group, which is an unsaturated 5-9-member mono- or bicyclic group, containing 1-2 heteroatoms, selected from S and N, Ar2 is an aryl group or heteroaryl group which is an unsaturated 5-9-member mono- or bicyclic group containing 1-2 heteroatoms selected from O, S and N, and R5, R6, R7, R8, R9 and R10 are identical or different, and each is (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) C1-8-alkyl group, optionally substituted with hydroxyl group(s), (v) -(CH2)m-Q {where m is an integer from 0 to 4, and Q is -CO2H, -ORc1, -CO2Ra3, -SRe1, -NHRa6 or -NRa7Ra7 (where each of Ra3, Ra6 and Ra7 is a C1-6-alkyl group, Rc1 is a C1-6-alkyl group, and Rc1 is a C1-6-alkyl group)}, (vi) -O-(CH2)m'-Q' {where m' is an integer from 1 to 4, and Q' is a hydroxyl group,-CO2H, -CO2Ra8, -CONRa10Ra10, -NRa12Ra12 (where each of Ra8, Ra10 and Ra12 is a C1-6-alkyl group)}, (vii) -ORf {where Rf is C3-7-cycloalkyl group or tetrahydropyranyl group)}, (viii) morpholine group, (ix) phenyl group, (x) pyridyl group]. The invention also relates to 1-thio-D-glucitol compounds of formulae IA, II, III, IV, to a pharmaceutical agent, to methods of obtaining 1-thio-D-glucitol compounds, as well as to compounds of formulae XIII, XIV.

EFFECT: obtaining novel biologically active compounds which are inhibitors of sodium-dependent co-transporter-2-glucose.

25 cl, 140 ex, 3 tbl

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