Compounds and compositions as protein kinase inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine-condensed derivatives of formula , where n is selected from 0, 1, 2, 3 and 4, Z1 is selected from N, C(O) and CR3, where R3 represents hydrogen, Z2 is selected from N and CR4, where R4 is selected from hydrogen and halogen, where the bond between Z1 and Z2 is selected from a single bond and a double bond, R1 is selected from C1-C4alkyl and C1-C4alkoxy, R2 is selected from NR5C(O)R6, C(O)NR5R6 and NR5R6, where R5 represents hydrogen, and R6 is selected from hydrogen, C1-C4alkyl and phenyl, where phenyl as R6 is optionally substituted with 1-2 radicals independently selected from a group comprising halogen(C1-C4)alkyl, heteroaryl(C0-C4)alkyl and heterocycloalkyl(C0-C4)alkyl, where any heteroaryl or heterocycloalkyl substitute R6 can be optionally substituted with a substitute independently selected from C1-C4alkyl and heterocycloalkyl, where the said heteroaryl and heterocyclyl represent a saturated or unsaturated 5-6-member ring containing 1 or 2 N atoms as a heteroatom, and to their pharmaceutically acceptable salts, hydrates, solvates and isomers. The invention also relates to a pharmaceutical composition base on a formula I compound and to use of formula I compound for preparing a medicinal agent which can be used for treating diseases or disorders associated with anomalous or disrupted kinase activity, primarily diseases or disorders related to anomalous activation of kinase Ab1, Bcr-Ab1, BMX, BTK, CHK2, c-RAF, CSK, c-SRC, Fes, FGFR3, Flt3, IKKα, IKKβ, JNK2α2, Lck, Met, MKK4, MKK6, MCST2, NEK2, p70S6K, PDGFRβ, PKA, PKBα, PKD2, Rsk1, SAPK2α, SAPK2β, SAPK3, SGK, Tie2 and TrkB.

EFFECT: novel compounds have useful biological properties.

7 cl, 1 tbl, 2 ex

 

Reference to related (pre) application

This application claims earlier priority based on provisional application U.S. ser. Room 60/662330, registered on March 15, 2005 a Complete description of this proposal are included in the description of the present application by reference in full.

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 impaired kinase activity, particularly diseases or disorders that are associated with abnormal activation of kinases bl, SIV-bl, BMX, CPD, SNK, c-RAF, CSK, c-SRC, Fes, FGFR3, F1t3, IKKα, IKKβ, JNK2α2, Lck, Met, MKK4, MKK6, MCST2, NEK2, p70S6K, PDGFRβ, PKA, PKBα, PKD2, Rsk1, SAPK2α, SAPK2β, SAPK3, SGK, Tie2 and TrkB.

Background of invention

Protein kinases represent a large family of proteins which play a Central role in the regulation of many cellular processes and control cellular functions. A partial list of such kinases includes, without limitation, receptor tyrosine kinase, such as receptor kinase platelet growth factor (PDGF-R), growth factor receptor nerve tissue, trkB, Met and receptor fibroblast growth factor, FGFR3; NERICA the priori tyrosine kinase, such as b1 and hybrid kinase BCR-Ab1, Lck, Csk, Fes, Bmx and c-src, and serine/trionychinae, such as c-RAF, sgk, MAP kinase (e.g., MKK4, MCC etc) and SAPK2α, SAPK2β and SAPK3. Impaired kinase activity is observed in many pathological conditions, including benign and malignant proliferative disorders and diseases associated with 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 can be used for the treatment of kinase associated diseases.

A brief description of the invention

One object of the present invention are the compounds of formula I:

where n is chosen from 0, 1, 2, 3, 4,

Z1selected from N, C(O) and CR3where R3selected from the group comprising hydrogen, halogen, C1-C4alkyl, C1-C4alkoxy, halogen(C1-C4)alkyl, halogen(C1-C4)alkoxy, C6-C12aryl, C5-C8heteroaryl,3-C12cycloalkyl,3-C8heteroseksualci and NR5R6where R5independently selected from the group including hydrogen and C1-C4alkyl, and R6selected from the group including hydrogen, C1-C4alkyl and C6-C12aryl, p is ICEM any aryl, heteroaryl, cycloalkyl or heteroseksualci R3optionally substituted by 1-3 substituents, independently selected from the group comprising hydrogen, halogen, C1-C4alkyl, C1-C4alkoxy, halogen(C1-C4)alkyl and halogen(C1-C4)alkoxy,

Z2selected from the group comprising N and CR4where R4selected from the group comprising hydrogen, halogen, C1-C4alkyl, C1-C4alkoxy, halogen(C1-C4) alkyl, halogen (C1-C4) alkoxy, C6-C12aryl, C5-C8heteroaryl,3-C12cycloalkyl,3-C8heteroseksualci and NR5R5moreover , the relationship between Z1and Z2choose from the simple and the double bond, R5independently selected from the group including hydrogen and C1-C4alkyl and any aryl, heteroaryl, cycloalkyl or heteroseksualci R4optionally substituted by 1-3 substituents, independently selected from the group comprising hydrogen, halogen, C1-C4alkyl, C1-C4alkoxy, halogen(C1-C4)alkyl and halogen(C1-C4)alkoxy,

R1selected from the group including halogen, C1-C4alkyl, C1-C4alkoxy,

R2selected from the group including NR5C(O)NR5R6, NR5C(O)R6, (O)NR 5R6, NR5S(O)0-2R6, S(O)0-2NR5R6and NR5R6and R5independently selected from the group including hydrogen and C1-C4alkyl, a R6selected from the group including hydrogen, C1-C4alkyl, C6-C12aryl, C5-C8heteroaryl,3-C12cycloalkyl and C3-C8heteroseksualci, and any aryl, heteroaryl, cycloalkyl and heteroseksualci R6optionally substituted by 1-3 substituents, independently selected from the group comprising halogen, cyano, nitro, halogen (C1-C4)alkyl, halogen(C1-C4)alkoxy,

With5-C12heteroaryl(C0-C4)alkyl and C3-C12heteroseksualci(C0-C4)alkyl, and any heteroaryl or heterologously substituent R6optionally substituted by the Deputy, is independently selected from the group comprising From1-C4alkyl and C3-C12heteroseksualci,

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

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

The third object of the present invention is a method of treating disease in an animal in which ingibirovanie kinase activity, especially the activity of kinases b1, SIV-b1, BMX, CPD, SNK, c-RAF, CSK, C-SRC, Fes, FGFR3, F1t3, IKKα, IKKβ, JNK2α2, Lck, Met, MKK4, MKK6, MCST2, NEK2, p70S6K, PDGFRβ, PKA, PKBα, PKD2, Rsk1, SAPK2α, SAPK2β, SAPK3, SGK, Tie2 and/or TrkB, prevents, inhibits or softens pathological conditions and/or symptoms of the disease, and this method includes the introduction of the animal a therapeutically effective amount of the compounds of formula I or its N-oxide, individual isomers and mixture of isomers or a pharmaceutically acceptable salt.

The fourth object of the present invention is the use of compounds of formula I to obtain a medicinal product intended for the treatment of a disease in an animal in which kinase activity, especially activity b1, SIV-b1, BMX, CPD, SNK, c-RAF, CSK, c-SRC, Fes, FGFR3, F1t3, IKKα, IKKβ, JNK2α2, Lck, Met, MKK4, MKK6, MCST2, NEK2, p70S6K, PDGFRβ, PKA, PKBα, PKD2, Rsk1, SAPK2α, SAPK2β, SAPK3, SGK, Tie2 and/or TrkB contribute to the development of pathological conditions and/or symptoms.

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

Detailed description of the invention

Determine the value (term)

"Alkyl" as a group or as a structural element of other groups, such as halogenated, halogenoalkane, means a hydrocarbon residue with a straight or branched chain. With1-C4alkoxy includes methoxy, ethoxy etc. Halogenated includes trifluoromethyl, pentafluoroethyl etc.

"Aryl" means a monocyclic or condensed bicyclic aromatic system containing a cycle from six to ten carbon atoms. For example, aryl means phenyl or naphthyl, preferably phenyl. "Allen" means the divalent radical formed aryl group.

"Heteroaryl" has the values specified above for the aryl group, where one or more carbon atoms in the cycle is replaced by a heteroatom. For example, With5-C10heteroaryl includes pyridyl, indolyl, indazoles, honokalani, chinoline, benzofuranyl, benzopyranyl, benzothiophene, benzo[1,3]dioxol, imidazolyl, benzimidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl etc.

"Cycloalkyl" means a saturated or partially unsaturated monocyclic, condensed bicyclic or associated bridge connection polycyclic system containing a loop a specified number of atoms. For example, With3-C10cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, the cycle is hexyl, etc.

"Heteroseksualci" means cycloalkyl specified in the bid, in which one or more carbon atoms in the cycle is replaced by a group selected from-O-,

-N=, -NR-, -C(O)-, -S-, -S(O) - or-S(O)2-, where R is hydrogen, C1-C4alkyl or aminosidine group. For example, when describing the compounds mentioned in the application, With3-C8heteroseksualci 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 fluorine, and bromine, or iodine.

The term "mutant forms of BCR-Abl" means the replacement of one or more amino acid residues in the sequence of the kinase wild-type. Currently describes more than 22 mutations, the most common of which are G250E, E255V, T, F317L and MT. Unless otherwise stated, R-AV means wild and mutant forms of the enzyme.

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

Detailed description of preferred embodiments of the invention

A hybrid protein BCR-bl is formed as a result of reciprocal translocation, which hybridize protooncogen bl with SIV genome. Then BCR-bl transforms b cells due to increased mitogenic activity. This increased activity leads which leads to decreased sensitivity to apoptosis, as well as to changes in adhesion and homing precursor cells of CML (chronic myeloid leukemia). The present invention provides compounds, compositions and methods of treating diseases associated with kinase, especially diseases associated with Abl kinase, R-bl, BMX, CPD, SNK, c-RAF, CSK, c-SRC, Fes, FGFR3, F1t3, IKKα, IKKβ, JNK2α2, Lck, Met, MKK4, MKK6, MCST2, NEK2, p70S6K, PDGFRβ, PKA, PKBα, PKD2, Rsk1, SAPK2α, SAPK2β, SAPK3, SGK, Tie2 and TrkB. For example, leukemia and other proliferative diseases associated with SIV-b1, can be treated with kinase inhibition SIV-b1 wild type and its mutant forms.

In one embodiment, the compounds of formula I

n is chosen from 1, 2, 3 and 4

Z1selected from N, O and CH,

Z2selected from N and CR4where R4selected from the group comprising hydrogen and halogen, and the relationship between Z1and Z2choose from a simple link or a double bond,

R1choose from groups With1-C4alkyl and C1-C4alkoxy, and

R2selected from the group including NR5C(O)R6C(O)NR5R6and NR5R6where R5independently selected from the group including hydrogen and C1-C4alkyl, and R6selected from the group including hydrogen, C1-C4alkyl and C6-C12aryl, and any aryl R6optionally substituted by 1-3 radicals independently selected from the group including the processes halogen (C 1-C4) alkyl, C5-C12heteroaryl (C0-C4)alkyl and C3-C12heteroseksualci (C0-C4) alkyl, and any heteroaryl or heterocytolysine the substituents R6optionally substituted by a radical independently selected from the group1-C4alkyl and C3-C12heteroseksualci.

In another embodiment, some preferred compounds are selected from the group comprising N-{3-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]-4-were}-3-cryptomelane, 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-[1-(N-purine-6-yl)-1H-imidazole-2-ylamino]benzamide, 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-[1-(1H-pyrazolo[3,4-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]benzamide, N-{4-methyl-3-[1-(6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}-3-cryptomelane, N-{4-methyl-3-[1-(N-purine-6-yl)-1H-imidazol-2-ylamino]phenyl}-3-cryptomelane and N-{4-methyl-3-[1-(1H-pyrazolo[3,4-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}-3-cryptomelane.

Another variant of the invention are the compounds of formula Ia

in which R1choose from the groups methyl and methoxy,

R2selected from the group including NHC(O)R6C(O)other6and other6where R6selected from the group including hydrogen, marked phenyl, moreover, any phenyl, R6optionally substituted by 1-3 radicals independently selected from the group comprising trifluoromethyl, imidazolyl, piperidinyl, piperazinil and piperazinylmethyl, and any heteroaryl or heterocytolysine the substituents R6optionally substituted by a radical independently selected from the group comprising methyl, ethyl and pyrrolidinyl.

Preferred compounds are selected from the group comprising 4-methyl-N-[4-(2-Mei-1-yl)-3-triptoreline]-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]benzamide, 3-(4-Mei-1-yl)-N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}-5-cryptomelane, 4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[1-(7H-pyrrolo[2,3 - d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}-3 - cryptomelane, 3-(4-ethylpiperazin-1-ylmethyl)-N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}-5-triptoreline, N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}-3-(4-pyrrolidin-1-reparacin-1-yl)-5-cryptomelane, 3-methoxy-N-[4-(2-Mei-1-yl)-3-triptoreline]-5-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]benzamide, 3-(4-Mei-1-yl)-N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}-5-cryptomelane, 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-[1-(7H-pyrrolo[2,3d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]benzamide, N-[4-(4-ethylpiperazin-1-ylmethyl)-3-triptoreline]-3-methoxy-5-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]benzamide, N-[4-(4-ethylpiperazin-1-ylmethyl)-3-triptoreline]-4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]benzamide, 3-(4-ethylpiperazin-1-yl)-N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino] phenyl}-5-trifluoromethyl-benzamide, 3-[1-(5-fluoro-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]-4-methyl-N-(3-triptoreline)benzamide, N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-lH-imidazol-2-ylamino]phenyl}-3-cryptomelane, 4-methyl-N-[4-(2-Mei-1-yl)-3-triptoreline]-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]benzamide, N-{3-[1-(5-chloro-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]-4-were}-3-cryptomelane, N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}benzamide, N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}ndimethylacetamide, 4-methyl-N3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-yl]benzene-1,3-diamine and 3-(4-methylpiperazin-1-yl)-N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}-5-cryptomelane.

Other preferred compounds according to the invention is described in detail in the examples and shown below in table 1.

Pharmacology and industrial applicability

Compounds of the invention modulate the activity of kinases and as t is the same used for the treatment of diseases or disorders, in which kinases participate in the development of the pathology and/or symptoms 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, but not limited to, Abl, SIV-bl (wild type and mutant forms), BMX, CPD, SNK, c-RAF, CSK, c-SRC, Fes, FGFR3, F1t3, IKKα, IKKβ, JNK2α2, Lck, Met, MKK4, MKK6, MCST2, NEK2, p70S6K, PDGFRβ, PKA, PKBβ, PKD2, Rsk1, SAPK2α, SAPK2β, SAPK3, SGK, Tie2 and TrkB.

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 protein b1 performs a complex function as a cellular module that integrates signals from various extracellular and intracellular sources that influence the development of cell cycle and apoptosis. Tyrosinekinase of Abelson includes subtypes, such as chimeric hybrid protein (oncoprotein) BCR-bl with misaligned tyrosinekinase activity or v-Abl. 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 lymphoblastic 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 is which patients at the stage of blast crisis CML observed resistance to STI-571 due to mutations in kinases BCR-Abl. To date, identified 22 mutations, the most common of which are G250E, E255V, T, F317L and MT.

Compounds of the present invention inhibit the kinase b1 primarily kinase v-abl. Compounds of the present invention also inhibit the kinase BCR-Abl wild type 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, which is accompanied primarily 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 from the body (for example, when removing bone marrow) and replantation cell population purified from tumor 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-Raf 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 results suggest 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 (1 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 efficacy, especially at the late stage of the 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 human cancer. 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 smooth muscle cells 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, p is for 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 a means of treatment of non-malignant proliferative disorders, such as atherosclerosis, thrombosis, psoriasis, scleroderma and fibrosis, as well as for the protection of stem cells, for example for protection against genotoksicheskogo action of chemotherapeutic agents such as 5-fluorouracil, and asthma. Compounds according to the invention first of all you can use for the treatment of diseases responsive to the inhibition of the receptor kinase PDGF.

Compounds of the present invention have a beneficial effect in the treatment of disorders resulting from transplantation, such as allogeneic transplantation, especially when tissue rejection, such as, first of all 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 frequent the 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 demonstrated with the introduction of the compounds of the present invention, as well as in the study of their impact on the internal thickening of vascular intima after mechanical damage in vivo.

The family of trk nitrophenolic receptors (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 the small intestine 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 adverse progression of tumors Williams and neuroblastoma. Moreover, TkrB expresiones in malignant prostate cells, but not detected in normal cells. Signaling pathway suppression of trk receptors includes cascade activation MARK involving Shc, activated Ras genes, ERK-1 and ERK-2, and the transmission signal of PLC-γ (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, is not observed in normal cells. On the other hand, mice with a deficit in the expression of c-src are phenotype with marble disease", which indicates 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, controls the proliferation of epithelial tumor 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 suppresses the 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 Stat1, which leads to the expression of the inhibitor of the cell cycle, stop the growth and abnormal development of bone tissue (Su et al., Nature, 386, 288-292 (1997)). In addition, FGFR3 in most cases is expressed in tumors of type 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 excited 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. CHn. Invest. 100, 8, 2072-2078 (1997) and R. Lin, PNAS, 95, 8829-8834 (1998) described the inhibition of tumor growth and vascularization, as well as the reduction of metastasis in the lungs during adenovirus infection or injection of the extracellular domain of Tie-2 (Tek) in a model of 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, pediatric 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 for treatment is an autoimmune disease, such as rheumatoid arthritis.

JNK and other MARC participate in the induction of 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 liver disease, or seizures hepatic ischemia, the 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 the JNK oportuit 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 for cancer treatment. Example is, 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 the possible use of JNK inhibitors in the treatment of chronic myelogenous leukemia (CML) (Blood 92, 2450-2460 (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, gipec the Asia, pulmonary fibrosis, angiogenesis, psoriasis, atherosclerosis, and proliferation of smooth muscle cells 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, 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. 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, facto the s broadcast and other target molecules in response to different extracellular signals. MARK activates the mitogen-activated protein kinases (MKK) by dual phosphorylation 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 the 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 signal transmission 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, MCSK1, MCSK2, 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(l-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 Pat the logical States.

Kinase SAPK (also called "N-terminal jun 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. Kinase C-jun is involved primarily 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, prevent DNA repair and sensibiliser cell such therapeutic anticancer agents that have an effect due to the induction of 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 (TR), heavy psevdomatematicheskoe myasthenia gravis, and asthma. Thanks to the participation of CPD in the activation of b-cells inhibitor CPD can be used to suppress pathogenic States, mediated by b-cells, such as the production of autoantibodies, and in the treatment of lymphoma b cells and leukemia.

SNK is a checkpoint kinase family of serine/trainingtraining and participates in the control mechanism of DNA damage such as rot is idania, 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 F1t3 participates in the development of leukemia and myelodysplastic syndrome. Approximately 25% of the cells of leukemia AML Express a constitutively active form autophosphorylating tyrosine kinase (f)FLT3 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-FLT3, mainly characterized by unfavorable clinical prognosis. Inhibition of kinase f-FLT3 induces apoptosis (programmed cell death) in leukemia cells.

Inhibitors Iα and IKKβ (1 and 2) are medicines for the treatment of diseases, including rheumatoid arthritis, graft rejection, inflammatory bowel disease, osteoa the threat, 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 expression of this enzyme is often correlates with poor prognosis and metastasis. The Met inhibitors are drugs to treat diseases including various cancers, 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, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., thyroid cancer, parathyroid cancer or cancer over the otechnical), sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, childhood solid tumor, lymphocytic informy, bladder cancer, 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 the like, the plague of Barret's esophagus (a precancerous syndrome), neoplastic skin disease, psoriasis, mushroom fungal infections and benign prostatic hypertrophy, 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 colorchannel 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. Functioning of the social studies testify to the participation 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.

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 lies in the fact that the specified subject is administered a therapeutically effective amount (see below in the section introduction Methods and pharmaceutical compositions) of the compounds of formula 1 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 with one or more therapeutic agents. A therapeutically effective amount of can is subject to change depending on the severity of the disease, 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, single 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 in any acceptable manner, primarily by oral means, for example, in the form of tablets or capsules, parenteral way, for example, in the form of injection solutions or suspensions, local way, 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 pharmaceutically acceptable salts in a mixture with at least one pharmaceutically acceptable carrier or diluent, get in the normal way using conventional is erodov mixing, granulating or coating. 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 paste, 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 compositions can be sterilized and/or may contain adjuvants such as preserving, stabilizing, wetting or emulsifying agents, contributing to the dissolution agents, salts for regulating osmotic pressure and/or buffer substances. In addition, they can contain other therapeutically valuable compounds. Prigodin the e 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 base, a reservoir containing the compound optionally in a mixture with a carrier, optionally a membrane that regulates the delivery of compounds to the skin surface at a given speed for a long time, and the layer for holding the device on the skin surface. You can also use matrix percutaneous formulations. Suitable formulations for topical application, for example 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 agent (pharmaceutical combination). For example, a synergistic effect is achieved by using a combination with other immunomodulatory or anti-inflammatory substances, for example when used in combination with cyclosporine, rapamycin or ascomycin, or immunodepressants analogues, such as cyclo what porins And (s), 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 antibodies to receptors of leukocytes, such as MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD45, CD58 or their ligands, or other immunomodulatory 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 second agent. The kit includes instructions for administration of medicines.

The terms "co-administration" or "combined introduction" or similar terms used in the description means the introduction of selected therapeutic agents to a single patient, and chickens the treatment, according to which the agents are not necessarily entered at the same time 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 product or dose. The term "non-fixed combination" means that the active ingredients, e.g. a compound of formula I and collateral agent, are 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 solutions, 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. In the above reactions it is necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxypropyl, if they have risedronate in the final product. The introduction of protective groups allows to exclude the participation of such functional groups in the ongoing reactions. Appropriate protective groups are used in accordance with accepted practice, for example, see T.W.

Greene and P. G.M. Wuts, "Protective Groups in Organic Chemistry", John Wiley and Sons(1991).

The compounds of formula I receive, as shown in figure 1:

Scheme 1

Scheme 1 n, Z1, Z2, R1and R2have the meanings specified in section a Brief description of the invention. The compound of the formula I get in the interaction of the compounds of formula 2 with the compound of the formula 3 in the presence of a suitable acid (for example, S3N, TsOH and the like) and an appropriate solvent (for example, DMSO, dioxane and the like). The reaction is carried out at a temperature of from about 100°to about 150°C for approximately 24 h to complete the reaction.

The compounds of formula I in which R2means-NR5C(O)R6receive as shown in figure 2:

Scheme 2

Figure 2 n, Z1, Z2, R1, R5and R6have the meanings specified in section a 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 5 in the presence of a suitable condensing reagents (e.g., HATU, and the like), which is adequate solvent (for example, DMF, THF or the like) and the appropriate base (such as DIEA, tea, etc.). The reaction is carried out at a temperature of from approximately 0°to approximately 50°C for approximately 20 h to complete the reaction. The compounds of formula I in which R2means-C(O)NR5R6get a similar reaction from the corresponding starting materials.

The compounds of formula I in which R2means-NR5S(O)2R6receive, as shown in figure 3:

Scheme 3

In scheme 3 n, Z1, Z2, R1, R5and R6have the meanings specified in section a 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 6 in the presence of an appropriate solvent (such as DMF, THF or the like) and a suitable base (such as DIEA, tea, etc.). The reaction is carried out at a temperature of from approximately 0°to approximately 50°C for approximately 20 h to complete the reaction.

The compounds of formula I in which R2means-NR5C(O)NR5R6receive as shown in figure 4:

Scheme 4

Scheme 4 n, Z1, Z2, R1, R5and R6have the meanings specified in section a Brief description of the invention. The compound of formula I floor the look at the interaction of the compounds of formula 4 with the compound of the formula 7 in the presence of an appropriate solvent (for example, DMF, THF or the like) and a suitable base (such as DIEA, tea, etc.). The reaction is carried out at a temperature of from approximately 0°to approximately 50°C for approximately 20 h to complete the reaction.

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

Additional methods for producing compounds according to the invention

The connection according to the invention can be obtained in the form of a pharmaceutically acceptable acid additive salts by the reaction of the free base compounds with pharmaceutically acceptable inorganic or organic acid. In another embodiment, a pharmaceutically acceptable basic additive salt of the compounds according to the invention can be obtained by reaction of the free acid of the compound with a pharmaceutically acceptable inorganic or organic base.

In another embodiment, the salts of the compounds according to the invention can be obtained by using salts of the starting materials or intermediate compounds.

Free acid or free base of the compounds according to the invention are obtained from the corresponding 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 appropriate base (for example, a solution g is droxide ammonium, 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 the appropriate acid (e.g. hydrochloric acid, and the like).

Compounds according to the invention in unoxidized form can be 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 phosphorus or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at a temperature from 0°C to 80°C.

The prodrug compounds according to the invention receive known methods (for example, see Saulnier and others, Bioorganic and Medicinal Chemistry Letters, 4, 1985 (1994)). For example, appropriate prodrugs can be obtained by the interaction of unmodified compounds according to the invention with suitable carbamimidoyl agent (for example, 1,1-aryloxyalkanoic, para-nitrophenylarsonic or the like).

Compounds according to the invention containing a protective group, can be obtained by the known methods. Detailed description of methods of introducing protective groups and their removal can be found in the monograph by T.W. Greene, "Protecting Groups in Organic Chemistry", 3rd ed., John Wiley and Sons, Inc. (1999).

Compounds according to the invention can be obtained, including the number of the e method according to the invention, in the form of a solvate (e.g. hydrate). Hydrates of the compounds of the present invention is obtained by recrystallization from a mixture of water/organic solvent, such as dioxane, tetrahydrofuran or methanol.

Compounds according to the invention can be obtained in the form of an individual stereoisomer in the interaction of racemic mixtures of compounds with optically active separating agent with the formation of pairs diastereoisomeric compounds, separating the diastereomers and the allocation of optically pure enantiomers. Although the separation of enantiomers carried out 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 because of this they can be separated by simple means. The diastereomers separated by chromatography or preferably by the method based on the difference in solubility. Then optically pure enantiomer is isolated using a separating agent in any way, excluding racemization. A more detailed description of the methods used for the separation of stereoisomers of the compounds present in the form of RA is imicheskih mixtures, can be found in the monograph by Jean Jacques, Andre Cottet, Samue! H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc. (1981). In the end, the compounds of formula I can be obtained by the method, which is that:

(a) carry out the reaction, as shown in schemes 1, 2, 3 and 4, and

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

(in) does not necessarily make the salt of the compounds according to the invention in mesolevel (free) form,

(g) optional turn oxidized form of the compounds according to the invention in a pharmaceutically acceptable N-oxide,

d) optional transform N-oxide compounds according to the invention in its unoxidized form,

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

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

(C) does not necessarily make the prodrug compounds in unmodified form.

Obtaining starting materials is not described in detail, since the compounds are known or can be obtained by the known methods or as described below in the Examples section below.

For the person skilled in the art it is obvious that the above syntheses and modifications are provided to illustrate methods for obtaining compounds of the present invention and their can be obtained using other known methods.

Examples

The present invention is illustrated by the following examples, not ohranyayuschie its volume:

Example 1

4-Methyl-N-[4-(2-Mei-1-yl)-3-triptoreline]-3-[1-(7H-pyrrolo[2.3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]benzamide

To a solution of 6-chlordiazepoxide (2.0 g, 13 mmol, 1.0 EQ.) in dichloromethane (65 ml) was added triethylamine (1,98 ml, 14.3 mmole, 1.1 EQ.) and 4-dimethylaminopyridine (as a catalyst). In the reaction mixture was added in portions taillored (2.55 g, a 13.4 mmole, 1.03 EQ.) and was stirred for 30 minutes, the Reaction mixture was distributed between dichloromethane and water. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with water, dried over Na2SO4was filtered and concentrated, to receive 4-chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine, which was used in the next stage without additional purification.

To a solution of 2-chloro-1H-imidazole (252 mg, 2,47 mmole) in DMSO (10 ml) at RT was added NaH (60% dispersion in mineral oil, 94 mg of 2.35 mmole) was stirred for 30 min and was added 4-chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (691 mg, 2.25 mmole). The flask was sealed and heated at 80°C for 1 h, the Reaction mixture was cooled to CT, neutralized by adding a saturated solution of chloride and mania and was twice extracted with ethyl acetate. The combined organic layers were washed with saline, dried over Na2SO4, filtered and concentrated. The product was purified by chromatography on a column of silica gel (eluent: gradient ethyl acetate/hexane, 5% to 50%), was obtained 4-(2-chloroimidazo-1-yl)-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine. MS: m/z 374,00 (M+1).

1H-NMR (400 MHz, CDCl3): δ 8,99 (s, 1H), 8,15 (d, 2H, J 8.0 Hz), 7,88 (d, 1H, J 8,4 Hz), of 7.36-7,38 (m, 3H), 7,16 (d, 1H, J 2.0 Hz), 6,70 (d, 1H, J 8.0 Hz), 2,43 (s, 3H).

A mixture of 4-(2-chloroimidazo-1-yl)-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (393 mg, 1.05 mmole), TBAF (1 M solution in THF, was 1.58 ml, was 1.58 mmole) in THF (16 ml) was stirred at 60°C over night. The reaction mixture was cooled to CT and concentrated. The product was purified AFGH/MS, was obtained 4-(2-chloroimidazo-1-yl)-7H-pyrrolo[2,3-C1]pyrimidine. MS: m/z 219,9 (M+1).

1H-NMR (400 MHz, DMSO-d6): δ 12,67 (s, 1H), 8,83 (s, 1H), 7,81 (d, 1H, J 1.6 Hz), 7,78 (t, 1H, J 1.9 Hz), 7,20 (d, 1H, J 1.6 Hz), 6,59 (dd, 1H, J is 2.8, and 1.6 Hz).

A solution of 4-(2-chloroimidazo-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (to 21.6 mg, 0,098 mmole), 3-amino-4-methyl-N-[4-(2-Mei-1-yl)-3-triptoreline]benzamide (37 mg, 0,098 mmole) and S3N (12,76 μl, 0,197 mmole) in 1,3-dimethyl-2-imidazolidinone (0.5 ml) was stirred and heated at 80°C for 36 h, the Reaction mixture was cooled to CT and cleansed OF LC/MS, this has been specified in the header connection. MS: m/z 558,2 (M+1).

1H-NMR (400 MHz,DMSO-d 6): δ of 12.73 (s, 1H), of 11.45 (s, 1H), 10,88 (s, 1 H), 8,98 (s, 1 H), 8,83 (s,l H), 8,54 (d, 1H, J 1.9 Hz), at 8.36 (dd, 1H, J 1,6, 8,8 Hz), 7,95 (d, 1H, J 1.9 Hz), 7,92 (s, 1H), 7,86 (d, 1H, J is 8.8 Hz), 7,81 (d, 1H, J 2.4 Hz), 7,79 (t, 1H, J 2.8 Hz), the 7.65 (d, 1H, J 7.8 Hz), of 7.48 (d, 1H, J 8.0 Hz), 7,12-to 7.09 (m, 2H), 2,50 (s, 3H), 2.40 a (s, 3H).

Example 2

3-(4-Mei-1-yl)-N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-Y1)-1H-imidazol-2-ylamino]phenyl}-5-cryptomelane

In the solution diethylacetal of aminoacetaldehyde (13,16 g, 99 mmol) in ether (35 ml) at RT was added a suspension of CNBr (10,47 g, 99 mmol) in hexane (35 ml). The reaction mixture was stirred at RT over night. A solid substance was separated by filtration and washed with ether. The combined filtrates were concentrated and purified by chromatography on a column of silica gel (eluent: gradient dichloromethane to Meon (4%)/dichloromethane), was obtained N-(2,2-diatexite)carbodiimide. Rf: 2,70, (eluent: 4% Meon/dichloromethane, manifestation: 10% solution phosphomolybdenum acid in ethanol).

1H-NMR (400 MHz, CDCl3): δ 4,58 (t, J 5.2 Hz, 1H), of 3.77 at 3.69 (m, 2H), 3,65 (user. s, 1H), 3,60-to 3.52 (m, 2H), and 3.16 (t, J 5.6 Hz, 1H), 1,23 (t, 6H, J 6.8 Hz).

To a solution of 4-methyl-3-nitroaniline (15,86 g, 104 mmole), pyridine (17,0 ml, 208 mmol) in CH2CL2(150 ml) at 0°C was added dropwise a benzoyl chloride (13,30 ml, 114 mmol) and stirred at RT for 2 h the Mixture was concentrated, the residue was washed with a saturated solution of sodium carbonate in the water and ethyl ether, it was obtained the desired compound, which was used in the next stage without additional purification. MS: m/z 257,3 (M+1).

1H-NMR (600 MHz, acetone-d6): δ 9,85 (s, 1H), 8,61 (s, 1H), 8,05 -8,02 (m, 3H), 7,60 (t, 1H, J 7.2 Hz), 7,53 (t, 2H, J 7.2 Hz), 7,46 (d, 1H, J 7.8 Hz), of 2.54 (s, 3H).

The above compound was dissolved in ethanol (250 ml) and was first made in the presence of palladium (10 wt.% on wet activated carbon, Degussa type, 5 g) in a Parr apparatus at a pressure of H220-30 pounds/square inch, for 16 hours, the Reaction mixture was filtered through celite and washed with ethanol. The combined filtrate and wash fractions were concentrated, was obtained N-(3-amino-4-were)benzamide, which was used in the next stage without additional purification. MS: m/z 227,3 (M+1).

1H-NMR (600 MHz, acetone-d6): δ 9,40 (s, 0,4H), 9,23 (s, 0,6H), of 7.96 (t, 2H, J 7.8 Hz), 7,55-7,52 (m, 1H), 7,49 (d, 1H, J 7.2 Hz), 7,47 (d, 1H, J 7.2 Hz), 7,37 (d, 0,4H. J 8,4 Hz), 7,31 (s, 0,6H), 7,17 (s, 0,4H), 7,11 (d, 0,4H, J 8,4 Hz), 7,95 (d, 0,6H, J 8,4 Hz), to $ 7.91 (d, 0,6H, J 8,4 Hz), of 4.44 (user. s, 1,2H), 2,90 (user. s, 0,8H), 2,11 (s, N), to 1.98 (s, 1,2H).

A mixture of N-(2,2-diatexite)carbodiimide (10,38 g, 65.6 mmole), 3-amino-4-were]benzamide (7,42 g, 32,8 mmole), methanesulfonic acid (3,20 ml, 49,3 mmole) in ethanol (200 ml) was boiled under reflux for 19 hours Then the mixture was concentrated, the residue was dissolved in 6 BC model HC1 (30 ml)was stirred overnight at 0°C, neutralized by addition of 25% solution NaO to pH 6, and then podslushivaet the addition of a saturated solution of sodium carbonate to a pH of 11. The mixture was stirred for 30 min and was extracted with 10% solution of ethanol in CH2CL2. The combined organic layers were dried over Na2SO4was filtered , concentrated and dried in vacuum. The residue is triturated in CH2Cl2(50 ml), the solid was separated by filtration, washed with CH2C12and dried, it was obtained N-[3-(1H-imidazol-2-ylamino)-4-were]benzamid in a solid white color. MS: m/z 293,4 (M+l).

1H-NMR (600 MHz, DMSO-d6): δ 10,79 (s, 1H), 10,11 (s, 1H), 8,00 (d, 1H, J 2.4 Hz), 7,94 (d, 2H, J 7.2 Hz), 7,60 (s, 1H), 7,56 (t, 1H, J 7.2 Hz), 7,49 (t, 2H, J 7.2 Hz), 7,25 (dd, 1H, J of 2.4, and 8.4 Hz),? 7.04 baby mortality (d, 1H, J 7.8 Hz), 6,80 (.s, 1H), 6,65 (user. s, 1H), measuring 2.20 (s, 3H).

A mixture of N-[3-(1H-imidazol-2-ylamino)-4-were]benzamide (627 mg, and 2.14 mmole), 4-chloro-7-(toluene-4-sulfonyl)-7H-pyrrol[2,3-d]pyrimidine (600 mg, of 1.95 mmole), DIEA (of 1.02 ml, 5,86 mmole) in 1,3-dimethyl-2-imidazolidinone (2.0 ml) was heated at 120°C for 8 h, the Reaction mixture was cooled to CT and added water. A solid substance was separated by filtration, washed with water, dried and used in the next stage without additional purification. The solid was dissolved in THF (30 ml) was added TBAF (1M in THF, 3.0 ml, 3.0 mmole) and the reaction mixture was heated at 60°C for 16 hours, the Reaction mixture was cooled to CT, removed T the f and added water. A solid substance was separated by filtration, washed with methanol and dried, it was obtained N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}ansamed, which was used in the next stage without additional purification. MS: m/z 410,1 (M+1).

1H-NMR (400 MHz, DMSO-d6): δ 12,63 (s, 1H), 11,23 (s, 1H), of 10.25 (s, 1H), 8,82 (d, 1H, J 2.0 Hz), 8,80 (s, 1H), to 7.99 (d, 2H, J 7.2 Hz), 7,86 (d, 1H, J 2.8 Hz), 7,74 (t, 1H, J 3.2 Hz), 7,60 -7,56 (m, 1H), 7,52 (t, 2H, J and 7.6 Hz), was 7.36 (dd, 1H, J of 8.0, 1.9 Hz), 7,18 (d, 1H, J 1.8 Hz), 7,06 (m, 1H), 6,99 (d, 1H, J 2.4 Hz), 2.40 a (s, 3H).

A mixture of N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino] phenyl}benzamide (470 mg) and 6 N. Hcl (20 ml) was heated at 80°C during the night. The reaction mixture was cooled to CT, a solid substance was separated by filtration, the filtrate was concentrated and podslushivaet the addition of sodium carbonate solution. A solid substance was separated by filtration, washed with water and dried, it was obtained 4-methyl-N-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-yl]benzene-1,3-diamine, which was used in the next stage without additional purification. MS: m/z 306,1 (M+1).

To a solution of 4-methyl-N3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-yl]benzene-1,3-diamine (15,0 mg 0,049 mmole), 3-(4-Mei-1-yl)-5-triftorperasin acid (16.0 mg, 0,059 mmole), DIEA (35 μl, of 0.20 mmole) in DMF (2 ml) was added HATU (21 mg, by 0.055 mmole). The reaction mixture was stirred at RT for 1 h, and R is storytell was removed in vacuum. The residue was dissolved in DMSO (1 ml). The resulting solution was purified OF GHWR, it was obtained 3-(4-Mei-1-yl)-N-{4-methyl-3-[1-(7H-pyrrolo[2,3-(1]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}-5-cryptomelane. MS: m/z 558,2 (M+1).

1H-NMR (600 MHz, DMSO-d6): δ of 12.73 (s, 1H), made 11.32 (s, 1H), 10,67 (s, 1H), 9,60 (s, 1H), 8,82 (s, 1H), 8,64-8,56 (m, 2H), 8,46 (s, 1H), 8,43 (s, 1H), 8,17 (s, 1H), to 7.93 (d, 1H, J 2.8 Hz), 7,79 (t, 1H, J 3.2 Hz), 7,52 (d, 1H, J 8.0 Hz), 7,30 (d, 1H, J 8.0 Hz), 7,11 (s, 1H), 7,07 (m, 1H), 2,39 (s, 3H), of 2.36 (s, 3H).

Methods of analysis

Compounds of the present invention were analyzed for their ability to selectively inhibit the proliferation of 32D cells expressing BCR-Abl (32D-p210), in comparison with the original 32D cells. For compounds which selectively inhibit the proliferation of these cells transformed by BCR-bl, defined antiproliferative activity against cells BA/F3 expressing wild type or mutant forms of SIV-bl. In addition, the compounds were analyzed for their ability to inhibit FGFR3 kinase, b-RAF, bl, BMX, CPD, SNK, c-RAF, CSK, c-SRC, Fes, F1t3, IKKα, IKKβ, JNK2α2, Lck, Met, MKK4, MKK6, MCST2, NEK2, p70S6K, PDGFRα, PKA, PKBβ, PKD2, Rsk1, SAPK2α, SAPK2β, SAPK3, SGK, Tie2 and TrkB.

Inhibition of BCR-Abl-dependent cell proliferation (quick test)

For the analysis used the cell line mouse that was a hematopoietic precursor cells lines 32D, transformed cDNA BCR-Abl (32D-p210). These cells were cultured in medium RPMI/10% fetal calf serum (RPMI/FCS)containing penicillin (50 µg/ml), streptomycin (50 μg/ml) and L-glutamine (200 mm). Nontransgenic 32D cells were cultured in similar conditions adding medium containing 15% WEHI as a source of IL3.

Cell suspension 32D or 32D-p210 were sown in 384-well microplates of Greiner (black) with a density of 5000 cells per well in 50 μl medium. To each well was added 50 nl of a solution of the analyzed compounds (1 mm initial solution in DMSO) (including STI571 as a positive control). Cells were incubated at 37°C for 72 h in an atmosphere of 5% CO2in each well was added 10 μl of a 60% solution of Alamar Blue reagent (firm Tek diagnostics) and cells were incubated for another 24 hours, the fluorescence Intensity (excitation at 530 nm, emission at 580 nm) was measured using the system AcquestTM(company Molecular Devices).

Inhibition of BCR-Abl-dependent cell proliferation

Cells 32D-p210 were sown in 96-well TC tablets with a density of 15,000 cells per well. To each well was added 50 μl of a solution of the analyzed compounds with two serial dilution (Gusto is 40 μm) (including STI571 as pological the aqueous control). Cells were incubated at 37°C for 48 h in an atmosphere of 5% CO2in each well were added to 15 μl of MTT solution (firm Promega) and the cells incubated for a further 5 hours the Optical density at 570 nm was measured by spectrophotometry and on schedule according to the dose/response was determined value IC50i.e. the concentration providing 50% inhibition.

The effect on the cell cycle

Cells 32D and 32D-p210 were sown in 6-hole CU tablets with a density of 2.5×10 cells per well in 5 ml of medium was added to the analyzed compound at a concentration of 1 or 10 μm (including STI571 as a control). The cells are then incubated at 37°C for 24 h or 48 h in an atmosphere of 5% CO2. Cell suspension (2 ml) was washed FSB, were fixed in 70% EtOH for 1 h and was treated with PBS/EDTA/Mcasa And within 30 minutes Then added iodide of propecia (Cf 10 μg/ml) and measured the intensity of fluorescence flow cytometry using a FACScalibur system (company BD Biosciences). The analyzed compounds of the present invention showed apoptotic effect on cells 32D-p210, but did not cause apoptosis in the original 32D cells.

Effect on autophosphorylation of cellular protein BCR-bl

Autophosphorylation of BCR-bl was determined by ELISA with the capture antigen in the presence of immobilized antibodies specific to the C-ab1 and antibody to phosphotyrosine. Glue the key 32D-p210 were sown in 96-well TC tablets with a density of 2×10 5of cells per well in 50 μl medium. To each well was added 50 μl of a solution of the analyzed compounds with two serial dilution (Cmaxis 10 μm) (including STI571 as a positive control). Cells were incubated at 37°C for 90 min in an atmosphere of 5% CO2. Then cells were treated for 1 h in an ice bath 150 μl of buffer solution for lysis (50 mm Tris-HCl, pH 7.4, 150 mm NaCl, 5 mm EDTA, 1 mm EGTA, and 1% NP-40)containing protease inhibitors and phosphatase. 50 μl of Cell lysate was added to 96-well plates (optiplates), pre-coated with specific antibodies anti-b1 and treated with the blocking solution. The plates were incubated at 4°C for 4 h, washed with buffer TBS/tween-20, was added 50 μl of a solution of alkaline phosphatase conjugate with antibodies to phosphotyrosine and the plate is incubated at 4°C over night. The tablet was washed with buffer TBS/tween-20 was added to 90 μl of a luminescent substrate and was measured by luminescence using system AcquestTM(company Molecular Devices). The analyzed compounds according to the invention, which inhibit proliferation of cells expressing BCR-Abl, inhibit autophosphorylation of cellular BCR-Abl dose-dependent manner.

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

For compounds according to the invention ODA is delali antiproliferative activity against cells Ba/F3, expressing BCR-bl wild-type or mutant forms (G250E, E255V, T, F317L, MT), which have resistance or decreased sensitivity to STI571. Antiproliferative effect of these compounds on cells expressing mutant BCR-Abl, and nontransgenic cells were analyzed at concentrations of 10, 3,3, 1,1 and 0.37 μm, as described above (in the environment, not containing IL3). The value of the IC50for connections that do not have toxicity against normal cells, was determined according to the schedule according to the dose/response, as described above.

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 kinase buffer solution (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 kinase buffer solution was added to 384-well tablets ProxiPlate®) (firm Perkm-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 kinase buffer solution. The reaction mixture was incubated at room temperature for 1 h, the reaction was stopped EXT is a pressure of 10 µl of the mixture HTRF for manifesting 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 with a concentration of 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 cell culture)

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 Cells were sown in 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 at a concentration of usually from 10 mm to 0.05 μm. 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 the wells were added to the reagent AlamarBIue®) (company TREK Diagnostic SysteMCS) 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 AlamarBIue®) (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 and PDGFRβ (analysis in cell culture)

The action of the compounds according to the invention on cellular activity (activity in the cells) FLT3 and PDGFRβ were evaluated 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 and Ba/F3-Tel-PDGFRβ, respectively.

b-Raf (enzymatic analysis)

Compounds according to the invention were analyzed for the ability to inhibit the activity of b-Raf. The analysis was performed in 384-well tablets MaxiSorp, NUNC) with black wall and clear bottom. The substrate IBα was diluted in DPBS (1:750) and to each well was added to 15 μl. Tablets inquire the Ali at 4°C overnight and washed three times TBST (25 mm Tris, pH 8.0, 150 mm NaCl and 0.05% tween-20) using a device for washing tablets EMBLA. The plates were blocked reagent Superblock (15 μl/well) for 3 h at room temperature, three times washed with TBST and the plate was dried gently. Then to each well was added a buffer solution for analysis containing 20 μm ATP (10 μl) and 100 nl and 500 nl of a solution of the compound. B-Raf was diluted in a buffer solution for analysis (1 ál 25 ál) and to each well was added 10 μl of a dilute solution of b-Raf (0,4 µg/well). The plates were incubated at room temperature for 2.5 hours Kinase reaction was stopped at six-washing of the plate with TBST solution. Antibodies FOSFA-Iα (Ser 32/36) was diluted in reagent Superblock (1:10000) and to each well was added to 15 μl. The plates were incubated at 4°C overnight and washed six times with TBST solution. Conjugate AR and IgG (antonysamy, goat) was diluted in reagent Superblock (1:1500) and to each well was added to 15 μl. The plates were incubated at room temperature for 1 h and the six-washing with TBST solution. To each well was added to 15 μl of the fluorescent substrate Attophos AP (firm Promega) and the plates were incubated at room temperature for 15 minutes, the Tablets were analyzed on a tablet reader Acquest or Analyst G using the program for the analysis of fluorescence intensity (excitation at 455 nm, zlecenie at 580 nm).

b-Raf (analysis in cell culture)

Compounds according to the invention were analyzed using A375 cells by the ability to inhibit the phosphorylation of MEK. Cell lines A ATS) were obtained from a patient with melanoma of the person and contained the V599E mutation in a gene called B-Raf. The level of phosphorylated MEK increased due to mutations of B-Raf. Subconfluent and confluent cells A375 cells were then incubated in the presence of compounds for 2 h at 37°C in serum-free medium. Cells once washed cold FSB and literally in the buffer solution for lysis, containing 1% Triton X100. After centrifugation supernatant were analyzed by electrophoresis in DDS-page and transferred to nitrocellulose membranes. Then the membrane was analyzed by the method of Western blotting using antibodies anti-phospho-MEK (ser. No. 217/221, company Cell Signaling). The amount of phosphorylated MEK was detected intensity zones phospho-MEK on nitrocellulose membranes.

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

Compounds according to the invention were analyzed for their ability to inhibit the activity of individual members of the kinase panel, including, without limitation, kinase Abl, BMX, CPD, SNK, c-RAF, CSK, c-SRC, Fes, FGFR3, F1t3, IKKα, IKKβ, JNK2α2, Lck, Met, MKK4, MKK6, MCST2, NEK2, p70S6K, PDGFRβ, PKA, PKBα, PKD2, Rsk1, SAPK2α, SAPK2 is, SAPK3, SGK, Tie2 and/or TrkB. Compounds were analyzed by double repeat with the final concentration of 10 μm by the following General method. The composition of kinase buffer solution and the substrates vary in the analysis of various kinases included in the set of "Upstate KinaseProfiIerTM". Kinase buffer solution (2,5 ál, 10x, containing, if necessary, MnCl2), active kinase (0.001 to 0.01%, and 2.5 μl), a specific peptide or poly(Glu-4-Tyr) (5-500 μm or 0.01 mg/ml) in kinase buffer solution, and kinase buffer solution (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 [γ32- P]-ATP (3000 CI/mmol)and the reaction mixture is incubated at about 30°C for approximately 10 minutes, the Reaction mixture (20 μl) was applied on square 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-Tyr). 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 (repl. in min) in the peptide substrate on the counter Beckman. For each reaction was calculated percentage inhib the simulation.

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, 250 nm, 100 nm and 50 nm against BCR-b1 wild-type and mutant forms G250E, E255V, T, F317L and MT. The compounds of formula I, preferably at a concentration of 10 μm, preferably inhibit more than 50%, preferably more than about 70% of the activity of kinases Ab1, BMX, CPD, SNK, c-RAF, CSK, c-SRC, Fes, FGFR3, Flt3, IKKα, IKKβ, JNK2α2, Lck, Met, MKK4, MKK6, MCST2, NEK2, p70S6K, PDGFRβ, PKA, PKBα, PKD2, Rsk1, SAPK2α, SAPK2β, SAPK3, SGK, Tie2 and/or TrkB.

For example, 3-(4-Mei-1-yl)-N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}-5-cryptomelane (example 2):

a) is characterized by the values of the IC50<0.5 nm, 56 nm, 43 nm, 63 nm, <0.5 nm and <0.5 nm against kinase wild-type and mutant forms G250E, E255V, T, F317L and MT SIV-b1 respectively,

b) is characterized by the values of the IC502 nm and 32 nm against b-RAF (according to enzymatic analysis and analysis on cell culture,respectively)

c) is characterized by the value of the IC504 nm against PDGFRp (analysis in cell culture), and

d) at a concentration of 10 μm and will gebirol following kinase, as indicated in the brackets (in %, for example, 100% means complete inhibition of 0% indicates no inhibition): b1 (99%), SIV-b1 (99%), BMX (99%), TCE (99%), c-RAF (98%), CSK (97%), c-SRC (100%), Fes (71%), FGFR3 (89%), Lck (99%), MCC (99%), p70S6K (86%), PDGFRβ (83%), Rsk1 (88%), SAPK2α (97%), Tie2 (99%)and TrkB(100%).

For example, N-[4-(4-ethylpiperazin-l-ylmethyl)-3-triptoreline]-3-methoxy-5-[l-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]benzamide (compound 9 in table 1) is characterized by the values of the IC504 nm and 40 nm against FGFR3 (according to enzymatic analysis and analysis on cell culture, respectively).

Is understood that the examples and embodiments of the invention are provided for illustration, and various modifications or changes will be proposed by the person skilled in the art within the entity and the amount of the specified application and the attached claims. All publications, patents and applications cited in the description, included in the description by reference in full.

1. The compound of the formula I

where n is chosen from 0, 1, 2, 3 and 4
Z1selected from N, S(O) and CR3where R3represents hydrogen,
Z2selected from N and CR4where R4selected from hydrogen and halogen,
moreover, the relationship between Z1and Z2choose from simple and double bonds,
R1choose from C1-With4the alkyl and C1-Csub> 4alkoxy,
R2choose from NR5C(O)R6C(O)NR5R6and NR5R6and R5represents hydrogen, a R6selected from hydrogen, C1-C4the alkyl and phenyl, where phenyl as R6optionally substituted by 1-2 radicals independently selected from the group comprising halogen(C1-C4)alkyl, heteroaryl(C0-C4)alkyl and heteroseksualci(C0-C4)alkyl, and any heteroaryl or heterologously substituent R6may be optionally substituted by the Deputy, is independently selected from C1-C4the alkyl and geterotsiklicheskie where these heteroaryl and heterocyclyl represent a saturated or unsaturated 5-6 membered cycle containing 1 or 2 N atom as the heteroatom,
and its pharmaceutically acceptable salt, hydrate, solvate and isomers.

2. The compound according to claim 1, in which
n is chosen from 1 and 2
Z1selected from N, S(O) and CH,
Z2selected from N and CR4where R4selected from hydrogen and halogen, and
where the relationship between Z1and Z2choose from a simple link and dual link,
R1choose from C1-C4the alkyl and C1-C4alkoxy, and
R2choose from NR5C(O)R6C(O)NR5R6and NR5R6where R5represents hydrogen, a R selected from hydrogen, C1-C4the alkyl and phenyl, where phenyl as R6optionally substituted by 1-2 radicals independently selected from the group comprising halogen(C1-C4)alkyl, heteroaryl(C0-C4)alkyl and heteroseksualci(C0-C4)alkyl, where any heteroaryl or heterologously substituent R6may be optionally substituted by the Deputy, is independently selected from C1-C4the alkyl and geterotsiklicheskie.

3. Compounds according to claim 1, selected from the group including
N-{3-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]-4-were}-3-cryptomelane,
4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-[1-(N-purine-6-yl)-1H-imidazol-2-ylamino]benzamide,
4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-[1-(1H-pyrazolo[3,4-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]benzamide,
N-{4-methyl-3-[1-(6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}-3-cryptomelane,
N-{4-methyl-3-[1-(N-purine-6-yl)-1H-imidazol-2-ylamino]phenyl}-3-cryptomelane,
and N-{4-methyl-3-[1-(1H-pyrazolo[3,4-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}-3-cryptomelane.

4. The compound according to claim 1 of formula Ia

where R1selected from methyl and methoxy,
R2selected from NHC(O)R6With(O)other6and other6where R 6selected from hydrogen, methyl and phenyl, where phenyl as R6optionally substituted by 1-2 radicals independently selected from the group comprising trifluoromethyl, imidazolyl, piperidinyl, piperazinil and piperazinylmethyl, and any heteroaryl or heterocytolysine the substituents R6optionally substituted by the Deputy, is independently selected from methyl, ethyl and pyrrolidinyl.

5. The compound according to claim 4, selected from the group including
4-methyl-N-[4-(2-Mei-1-yl)-3-triptoreline]-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]benzamide,
3-(4-Mei-1-yl)-N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}-5-cryptomelane,
4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}-3-cryptomelane,
3-(4-ethylpiperazin-1-ylmethyl)-N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}-5-cryptomelane,
N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}-3-(4-pyrrolidin-1-reparacin-1-yl)-5-cryptomelane,
3-methoxy-N-[4-(2-Mei-1-yl)-3-triptoreline]-5-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]benzamide,
3-(4-Mei-1-yl)-N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}-5-cryptomelane,
4-methyl-N-[3-(4-methyl shall midazol-1-yl)-5-triptoreline]-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]benzamide,
N-[4-(4-ethylpiperazin-1-ylmethyl)-3-triptoreline]-3-methoxy-5-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]benzamide,
N-[4-(4-ethylpiperazin-1-ylmethyl)-3-triptoreline]-4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]benzamide,
3-(4-ethylpiperazin-1-yl)-N - {4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}-5-cryptomelane,
3-[1-(5-fluoro-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]-4-methyl-N-(3-triptoreline)benzamid,
N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}-3-cryptomelane,
4-methyl-N-[4-(2-Mei-1-yl)-3-triptoreline]-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]benzamide,
N-{3-[1-(5-chloro-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]-4-were}-3-cryptomelane,
N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}benzamide,
N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}acetamide", she
4-methyl-N3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-yl]benzene-1,3-diamine, and
3-(4-methylpiperazin-1-yl)-N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-imidazol-2-ylamino]phenyl}-5-cryptomelane.

6. Pharmaceutical composition having inhibitory activity against protein kinases, particularly Abl, Bcr-Abl, BMX, CPD, SNK, c-RAF, CSK, c-SRC, Fes, FGFR3, Flt3, IKKα, IKKβ, JNK2α2, Lck, Met, MKK4, MKK6, MCST2, NEK2, p70S6K, PDGFRβ PKA, PKBα, PKD2, Rsk1, SAPK2α, SAPK2β, SAPK3, SGK, Tie2 and TrkB kinases, comprising a therapeutically effective amount of a compound according to claim 1 in combination with pharmaceutically acceptable excipients.

7. The use of compounds according to claim 1 for obtaining a medicinal product intended for the treatment of a disease in an animal in which the activity of kinases Abl, Bcr-Abl, BMX, CPD, SNK, c-RAF, CSK, C-SRC, Fes, FGFR3, Flt3, IKKα, IKKβ, JNK2α2, Lck, Met, MKK4, MKK6, MCST2, NEK2, p70S6K, PDGFRβ, PKA, PKBα, PKD2, Rsk1, SAPK2α, SAPK2β, SAPK3, SGK, Tie2 and TrkB promotes the development of diseases and/or symptoms of the disease.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula : in which R1 represents a hydrogen atom or alkyl optionally substituted with (1) aralkyloxy group, (2) aroyl, (3) isoquinolinyl or (4) aryl, optionally substituted with an alkoxy group; the solid line and the dashed line between A1 and A2 represent a double bond (A1=A2) or a single bond (A1-A2); A1 is a group of formula C(R4), and A2 is a nitrogen atom when the solid line and the dashed line between A1 and A2 represents a double bond (A1=A2); A1 is a group of formula C=O, and A2 is a group of formula N(R5) when the solid line or the dashed line between A1 and A2 represent a single bond (A1-A2); R2 represents alkyl optionally substituted with a cyano group, aryl optionally substituted with an alkoxy group, aralkyl optionally substituted with a halogen atom, a cyano group, an alkoxy group, an alkyl or carbamoyl or alkynyl; R3 represents a hydrogen atom, a halogen atom, cyano, formyl, carboxyl, alkyl optionally substituted with (1) amino group optionally substituted with alkyl, or (2) alkoxy group, aryl optionally substituted with an alkoxy group, tetrazolyl, alkylcarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, where heteroaryl is a 4-6-member monocyclic radical containing 1-2 heteroatoms selected from a nitrogen atom or oxygen atom, alkoxycarbonyl, carbamoyl optionally substituted with alkyl, cycloalkyl or cycloalkylalkyl, hydroxyl, alkoxy group or a group of formula: -Rd-C(O)O-Re, where Rd represents a single bond, and Re represents a group of formula: -CH(R4a)OC(O)R4b, where R4a represents alkyl or R4b represents cycloalkyloxy or aryloxy; R represents a hydrogen atom, hydroxyl, cyano, alkyl, carbamoyl, carboxyl, aryloxy optionally substituted with an alkoxy group or carbamoyl, alkylsulfonyl, alkylcarbonyl or alkoxycarbonyl; R5 represents a hydrogen atom or alkyl; -Y represents a group of formula (A) given below: in which m1 equals 2, and R6 is absent, or to pharmaceutically acceptable salts of the said compounds. The invention also relates to compounds of formula (VI), to pharmaceutical compositions, to a dipeptidyl peptidase IV inhibitor, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds with dipeptidyl peptidase IV inhibition properties.

20 cl, 76 ex, 1 tbl

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: 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: described are novel derivatives of pyrazolo[1,5-a]pyrimidine with general formula 1 (values of radicals are given in the formula of invention), a pharmaceutical composition containing said derivatives and use of the novel compounds for preparing a medicinal agent for treating one or more diseases associated with cyclin-dependant kinalse CDK2.

EFFECT: novel compounds have useful biological properties.

36 cl, 87 tbl, 607 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of benzene sulphonamide of formula (I), tautomeric and stereoisomeric forms and physiologically acceptable salts thereof: where X is O, S; R1 is H, halogen; R2 is H, halogen; halogen; R3 is NO2, CN; R4 is: ,

where R71 is H; R72 is H; Z1 is -[CH2]P-, where p = 2.

EFFECT: compounds have antagonistic activity towards CCR3, which enables for their use in making medicinal agents.

13 cl, 1 tbl, 3 ex

FIELD: pharmacology.

SUBSTANCE: present invention relates to antagonists of serotonin 5-HT5 receptors with general formula 1 and their pharmaceutically acceptable salts and/or hydrates, particularly to substituted 3-sulphonyl-[1,2,3]triazolo[1,5-a]quinazolines and 3-sulphonyl-thieno[2,3-e][1,2,3]triazolo [1,5-a]pyrimidines, as active compounds for pharmaceutical compositions and medicinal agents, and methods of producing said compounds. In general formula 1 , Ar is a phenyl which is unsubstituted or substituted with halogen or at least one lower alkyl; R1 is a hydrogen atom or optionally substituted amine group, or optionally substituted 5-6 member azaheterocyclyl, bonded by a nitrogen atom to a carbon atom of a triazolopyrimidine ring with 1-2 heteroatoms selected from nitrogen, oxygen or sulphur, and optionally annulated with a benzene ring; where the substitutes are selected from hydrogen, optionally substituted C1-C5alkyl, optionally substituted C3-C8cycloalkyl, alkoxy group, acyl, saturated or unsaturated optionally annulated 5-7 member heterocyclyl, where heteroatoms are selected from nitrogen, oxygen or sulphur, optionally substituted phenyl; R2 and R3 together with carbon atoms to which they are bonded form an optionally substituted benzene or thiophene ring, where substitutes are selected from C1-C5alkyl or halogen atom.

EFFECT: invention also relates to pharmaceutical compositions and medicinal agents, a method of treating or preventing development of CNS diseases mediated by action of serotonin 5-HT5 receptors, for example Alzheimer's disease.

20 cl, 6 dwg, 4 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrazolpyrimidine derivatives of formula (I) where p is 0 or 1; R1 and R2 can independently represent H, halogen, lower alkyl, lower alkoxy, possibly substituted with one or more halogens or CF3; R3 is lower alkyl, hydroxy-lower alkyl or NRaRb; Ra and Rb are independently selected from a group consisting of H; cycloalkyl containing 3-6 carbon atoms; phenyl; lower alkyl possibly substituted with one or more hydroxy, fluorine, C3-6cycloalkyl, phenyl, pyridyl or NRcRd, where Rc and Rd are independently selected from H or lower alkyl; or where Ra and Rb together with the nitrogen atoms to which they are bonded can form a 5- or 6-member hetero-ring, possibly additionally containing 1 or 2 heteroatoms selected from O or N, and possibly substituted with lower alkyl or hydroxy-lower alkyl; R4 is H, Cl, lower alkoxy, cycloalkyl, containing 3-6 carbon atoms, or straight lower alkyl which is possibly substituted with one or more F; R5 is H; halogen or lower alkyl; as well as to their pharmaceutically acceptable salts.

EFFECT: invention also relates to pharmaceutical compositions based on these compounds and their use in preparing medicine for treating or preventing acute and/or chronic neurological disorders in which activation of mGluR2 is involved.

19 cl, 179 ex

FIELD: pharmacology.

SUBSTANCE: invention refers to new 2-alkylamino-3-arylsulphonylcycloalkano[e]pyrazolo[1,5-a]pyrimidines of general formula 1 and 2-alkylamino-3-arylsulphonylcycloalkano[d]pyrazolo[1,5-a]pyrimidines of general formula 2 with properties of serotonin 5-NT6 receptor antagonists, to pharmaceutical compositions containing specified compounds as a principle, medical products and method of treatment and the prevention of CNS diseases. In general formulae 1 and 2, R1 represents hydrogen atom or C1-C3 alkyl; R2 represent C1-C3 alkyl; R3 represent hydrogen atom, one or two optionally substituted identical halogen atoms, C1-C3 alkyl or hydroxyl optionally substituted with C1-C3alkyl; n represents an integer 1, 2 or 3. The invention also relates to the method for making the compounds of general formula 1 or 2 by interaction of 3-amino-4-arylsulphonyl-2H-pyrazoles of general formula 3 with relevant β-dicarbonyl compounds of general formula 4 or their derivatives of general formula 5. 3, 4, 5, where: R1, R2, R3 and n have said values.

EFFECT: new 2-alkylamino-3-arylsulphonyl-cycloalkano[e or c1]pyrazolo[1,5]pyrimidines - serotonin 5-NT6 receptor antagonists, methods of making and applying thereof.

12 cl, 1 dwg, 4 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: invention is related to 4-((2)-4'-hydroxybutene-2'-yl)-2-R-6-phenyl-1,2,4-triazolo[5,1-c][1,2,4]triazine-7-ons of common formula (1) ,

where R=H, CH3,SCH3 have antiviral action against herpesvirus of simple type 1 (HSV-1).

EFFECT: new derivatives have useful biological properties.

1 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of benzoindazole of formula I , where radicals A1, A2, A3, R1, R2, R3, R4 and n have values mentioned in formula of invention, and their pharmaceutically acceptable salts, and also to application of these compounds for production of medicinal agent intended for modulation of α2-subsort of GABA receptor, and pharmaceutical composition that contains it.

EFFECT: application of compounds for preparation of medicinal agent intended for treatment of depression, disorder in the form of anxiety, psychic disorder, disturbed ability to learning and cognition, sleep disturbance, disorder in the form of cramps or fits or pain.

16 cl, 5 tbl, 40 ex

FIELD: medicine.

SUBSTANCE: extraction of young immature fruits with diametre not more than 3 mm is carried out. Fresh raw material is preliminarily grinded, covered with 60% alcohol with ratio 1:2 and extraction with addition of propylene glycol in amount 1% at temperature 50° during 5 hours is carried out, extract is poured out. Second stage of extraction is performed at room temperature during 15 hours with ratio raw material extractant 1:2. Raw material is squeezed, extracts are poured together, recovered material is filtered.

EFFECT: increasing yield of active substances.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a group of novel chemical compounds pharmacologically acceptable salts thereof having formula , where A represents COOH; B represents H; n equals 0; V represents -CH2-, a single bond; W represents a 5-7-member heteroaromatic group with one heteroatom selected from N, O, S which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A, when V represents a -CH2-group, where if V represents a single bond, W represents a bicyclic condensed a ring -member heterocyclic group with one heteroatom selected from O, S, which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A; X represents a 5-7-member heteroaromatic group with one O atom and one or two N atoms, which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A; Y represents C6-C10 aryl which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A, a 5-7-member heteroatomatic group with one S atom which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A; Z represents C1-C8 alkyl, C3-C7 cycloalkyl which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A; C6-C10 aryl which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A; C6-C10 aryloxy which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A, or C1-C12 aralkyl which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A; group of substitutes A represents halogen, C1-C6 alkyl, halogen C1-C6 alkyl, C1-C6 alkoxy.

EFFECT: compounds exhibit inhibitory activity towards HvGR which enables their use to prepare a pharmaceutical composition used in therapy for autoimmune diseases.

33 cl, 6 tbl, 30 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I: where A,Y,R and R2 assume values given in the description. The invention also relates to methods of producing compounds of formula I and their intermediate compounds, pharmaceutical compositions and methods of using the compounds and their pharmaceutical compositions for inhibiting caspase.

EFFECT: novel compounds have useful biological properties.

44 cl, 5 tbl, 66 ex

FIELD: veterinary science.

SUBSTANCE: therapeutic preparation for young growth of agricultural animals represents an alcohol infusion from ground plant mix of herbs and blossoms of purple coneflower, foalfoot, herb of Syrian rue and roots of common licorice, taken in equal amounts. For prevention of gastrointestinal diseases of calves on the background of passive immunisation against rota-coronaviruses by subcutaneous injection of blood serum of animal-survivors, containing specific antibodies against rota-coronaviruses in titres of not lower than 1:128 and 1:64 accordingly, therapeutic preparation is taken inside in dose of 20 ml for 10 days with interval of 48-72 hours as representing an alcoholic infusion of mixture of equal amounts of herbs and blossoms of purple coneflower, foalfoot, herb of Syrian rue and roots of common licorice in the form of 7-8% aqueous solution, with preventive purpose - in dose of 1.0- 1.5 ml/kg of animal live mass with interval of 24 hours for 7-10 days.

EFFECT: improved efficiency of prevention.

2 cl, 3 tbl, 3 ex

FIELD: veterinary science.

SUBSTANCE: preparation for immune correction of animal organisms represents polycarboxyethylene - . Introduction of polycarboxyethylene into animal body causes systematic therapeutic effect, which is based on normalisation of processes in immune system, stimulates number of circulating neutrophils in peripheral blood, activates migration, phagocytal and functional activity of phagocytes, proliferation of B- and T-lymphocytes s a result of increased number of T-helpers and T-effectors, without influence at number of T-suppressors, is not accompanied with side effect.

EFFECT: improved medical and preventive effect.

7 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: immunocorrecting preparation contains levamisole, vitamins, microelements and bentonite clay in the following ratio, g/kg: levamisole -75-80; vitamin A - 0.35-0.40; vitamin C - 0.2-0.3; zinc - 9.0-10.0; copper - 0.5-0.6; iron - 1.5-2.0; selenium - 0.03-0.04; bentonite clay - the remaining part. Application of claimed preparation by adding to animal and poultry forage produces expressed stimulating impact on immunocompetent systems of organism, which, in its turn, contribute to enhancement of protective functions of organism and increase of animal productivity and safety.

EFFECT: preparation can be used for stimulation of antibody-formation during vaccine prophylaxis of farm animals and poultry.

3 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: there is offered a monoclonal antibody specific to human interleukine-4 (hIL-4) containing two domains with the related CDR1-3 region. There are described versions thereof that contain specified CDR, polynucleotide coding said antibody. There are described an expression vector and a host-cell for preparing the antibody to human interleukine-4 (hIL-4). There are opened: application of the antibody for preparing a pharmaceutical agent for treating the diseases mediated by interleukine-4 and/or IgE. There is discovered the pharmaceutical composition for treating the diseases mediated by interleukine-4 and/or IgE is opened.

EFFECT: application of the invention ensured the high-affinity neutralised monoclonal antibodies to human interleukine-4.

14 cl, 1 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds that are lipoxin A4 analogues of general formula (I) and (II) where R1, R2, R3, R4 and R5 have values specified above. The inventions also refers to specific compounds of formula 1 and 11, to pharmaceutical compositions based thereon and to methods of treating inflammatory and autoimmune diseases in a human, and also treating inflammation of pulmonary or respiratory tracts in a human.

EFFECT: higher clinical effectiveness.

40 cl, 14 ex

FIELD: medicine.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and concerns preparation of a solid dosage form for treating respiratory allergosis and arresting nasopharynx edema. There is offered a tableted medical product containing mixed active substance and excipient. As an active substance, it contains a corticosteroid preparation, and according to the invention, additionally contains an active substance presented with adrenaline or noradrenaline. The inside of a tablet contains the corticosteroid preparation, while the exterior contains adrenaline. As a corticosteroid preparation it contains dexamethasone, prednisolone or celestone. Also there is offered a tableted medical product that contains mixed active substance and excipient. As an active substance, it contains a corticosteroid preparation, and additionally contains active substances presented with adrenaline or noradrenaline, and also aminophylline and mesatone. The tablet is multilayered, its inside contains mesatone, the layer containing aminophylline adjoins the inside, then the layer containing the corticosteroid preparation is executed, and the exterior contains adrenaline or noradrenaline.

EFFECT: there is offered a tableted medical product.

4 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound N-(1-{(3R)-3-(3,5-difluorophenyl)-3-[1-(methylsulfonyl) piperidin-4-yl]propyl}piperidin-4-yl)-N-ethyl-2-[4- (methylsufonyl)phenyl]acetamide or its pharmaceutically acceptable salts. The invention also relates to a method for synthesis of the compound in paragraph 1, as well as to a pharmaceutical composition.

EFFECT: obtaining a novel biologically active compound with activity towards CCR5 (chemokine receptor 5).

6 cl, 6 ex, 2 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

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