Derivatives of isothiourea and method of their production, their application and pharmaceutical composition

FIELD: medicine.

SUBSTANCE: invention is related to derivatives of isothiourea of formula I, including their pharmaceutically acceptable salts, which possess properties of antagonist CXCR4. In compounds of formula I , where R1 means remainder of formula (a) , (b) or (c) , R2 means -(CR22R23)1-3-, R3 and R8 each means S, R4 and R5 each independently means C3-C12cycloalkyl, C1-C12alkyl or saturated C8-C12 polycyclic hydrocarbon remainder, such as adamantine, non-substituted phenyl or non-substituted benzyl unnecessarily substituted with group R25, R6 means H or C1-C6alkyl, R7 means CH, R9 means direct connection or -(CR22R23)1-2-, R10-R15 each means H, R16-R23 each independently means H, C1-C6alkyl, or R20 and R21 together with carbon atoms, to which they are connected, create a benzene ring, and R25 has one of values given above for R16-R23.

EFFECT: improved method for production of derivatives of isothiourea.

5 cl, 1 tbl, 24 ex

 

In the present invention proposes derivative estimacion, methods for their preparation, their use and pharmaceutical compositions containing these derivatives.

First of all, the present invention features a compound of formula I,

where R1means the residue of formula (a), (b) or (C)

R2means -(CR22R23)1-3- or-C(O)-,

R3and R8every means independently S, O or NR24,

R4and R5every means independently optionally substituted by a group R25With3-C12cycloalkyl,1-C12alkyl, or saturated With a8-C12polycyclic residue, or optionally substituted groups R26and/or R27aryl, aryl(C1-C4)alkyl or heteroaryl, with up to 4 carbon atoms in the R4and/or R5optionally replaced by S, O or NR24,

R6means H, C1-C6alkyl, C3-C6cycloalkyl or optionally substituted groups R26and/or R27aryl, aryl(C1-C4)alkyl or heteroaryl,

R7mean CR28or N,

R9means a direct bond, -(CR22R23)1-2or NR24,

R10-Rsub> 23and R28each independently mean H, F, Cl, Br, C1-C6alkyl, C2-C6alkoxyalkyl, C1-C6halogenated,3-C6cycloalkyl, optionally substituted by groups R26and/or R27aryl or heteroaryl, CONR29R30, COOR29, CN, NO2or or31or

two of the residues R10-R19together with the carbon atom to which they are attached, form a 3-7-membered nonaromatic cycle, optionally containing up to two heteroatoms, independently selected from N, O and S,

or

R17and R18together with the carbon atoms to which they are attached,

form a 4-7-membered nonaromatic cycle, optionally containing up to two heteroatoms, independently selected from N, O and S, or

R20and R21together with the carbon atoms to which they are attached, form an optionally substituted groups R26and/or R27aryl or heteroaryl,

R24, R29and R30each independently mean H, C1-C6alkyl, C2-C6alkoxyalkyl,

C1-C6halogenated,3-C7cycloalkyl, optionally substituted by groups R26and/or R27aryl, aryl(C1-C4)alkyl or heteroaryl,

R25means 1-4 substituent, each of which independently has one of the values preveden the x above for R 10-R23.

R26means 1-4 substituent, each of which is independently selected from the group including C1-C6alkyl, C1-C6hydroxyalkyl,2-C6alkoxyalkyl, C1-C6halogenated,3-C6cycloalkyl,2-C6alkenyl,3-C6cycloalkenyl,2-C6quinil, aryl, heteroaryl, N-oxidatively, F, Cl, Br, I, HE, OR4, CONH2, CONHR4, CONR4R4, OC(O)R4, OC(O)OR4, OC(O)other4, OC(O)NR4R4, OSO2R4, COOH, COOR4, CF3, CHF2CH2F, CN, NO2, NH2, Other4, NR4R4, NHC(O)R4, NR4C(O)R4, NHC(O)other4, NHC(O)NH2, NR4C(O)other4, NR4C(O)NR4R4, NHC(O)OR4, NR4C(O)OR4, NHSO2R4N(SO2R4)2, NR4SO2R4, SR4, S(O)R4, SO2R4Si(CH3)3and(OS(CH3)2)2,

R27means two neighboring substituent, which form a condensed 4-7-membered nonaromatic cycle, optionally containing up to two heteroatoms, independently selected from N, O and S,

R31means C1-C6alkyl, C3-C7cycloalkyl, optionally substituted by groups R26and/or R27aryl, aryl(C1-C4)alkyl or hetero is the Rila, or CR3.

Any alkyl, alkenyl or quinil is a linear or branched. Halogen means F, Cl, Br or I.

Aryl means phenyl or naphthyl.

Polycyclic residue means, for example, optionally substituted by a group R25of substituted, bicyclo[3,2 .1]]octyl or

where n is 1 or 2.

Heteroaryl means an aromatic ring system, including mono-, bi - or tricyclic system containing up to 4 heteroatoms independently selected from N, O and S. Examples of heteroaryl include, for example, pyridyl, indolyl, benzothiazolyl, thiazolyl, imidazolyl, benzimidazolyl. Examples 3-7-membered non-aromatic cycles containing 1 or 2 heteroatoms include, for example, morpholinyl, piperazinil, piperidyl.

The compounds of formula I exist in the form of vzaimoprevrascheny of tautomers and E/Z isomers, for example

These compounds exist in free form or in salt form, for example, acid additive salts of organic or inorganic acids, such as hydrochloric acid, acetic acid. If the molecule of the compounds of formula I contain one or more asymmetric centers, it should be understood that the scope of the present invention includes various optical isomers and racemates, diastereoisomers and mixtures thereof.

p> Values of the substituents in the compounds of the formula I preferably have the following meanings, which can be used separately or in combination:

1. (a) R10-R23and R28each independently denotes H or C1-C6alkyl,

(b) two of R10-R19together with the carbon atom to which they are attached, form a 3-6-membered nonaromatic cycle, optionally containing up to two heteroatoms, independently selected from N, O and S, or

(c) R17and R18together with the carbon atoms to which they are attached, form a 4-7-membered nonaromatic cycle, optionally containing up to two heteroatoms, independently selected from N, O and S, or

2. R9means a direct bond or-CR22R23-,

3. R24, R29and R30each independently mean H, C1-C6alkyl or C3-C7cycloalkyl.

4. R7mean CR28.

5. R2means-CR22R23-.

6. R4and R5every means independently optionally substituted by a group R25With5-C9cycloalkyl or6-C12alkyl or substituted, and optionally up to 4 carbon atoms in the R4and/or R5replaced by S, O or NR24.

7. R6means N or C1-C6alkyl.

8. R3and R8each independently oz is achet S.

9. Aryl(C1-C4)alkyl means benzyl.

The present invention relates also to a method for obtaining compounds of formula I, including the interaction of the compounds of formula II

with the compound of the formula III

where R1-R6have the meanings defined above, and R32means a leaving group,

and optional conversion of the compounds of formula I obtained in free form, in salt form or Vice versa.

R32preferably means a halogen, more preferably chlorine.

The compounds of formula III are commercial preparations, or get them at the interaction of the compounds of formula IV (a), (b) or (C)

where R8-R21have the meanings given above,

with 1,3-dichloroacetone, and converting the compounds of formula III in free form or in salt form.

The compounds of formula II and IV are commercial preparations, or get them by known methods.

The following examples are given to illustrate the present invention and do not limit its scope.

Example 1

1,3-DICYCLOHEXYL-2-(5,6-dihydroimidazo[2,1-b]thiazole-3-ylmethyl)estimacion

A mixture of N,N'-dicyclohexylcarbodimide (0.21 g, 1.0 mmole), 3-chloromethyl-5,6-Digi is aimedat[2,1-b]thiazole (0,72 g, 3.0 mmole) and acetonitrile (10 ml), 10 boiled under reflux for 4 hours the precipitate was filtered and was led from methanol/ether, there was obtained the dihydrochloride of 1,3-DICYCLOHEXYL-2-(5,6-dihydroimidazo[2,1-b]thiazole-3-ylmethyl)estimacion. MS (ESI): 379 [M+H+].

Example 2

1,3-DICYCLOHEXYL-2-(3-methyl-2-methylimino-2.3-dihydrothiazolo-4-ylmethyl)estimacion

1,3-DICYCLOHEXYL-2-(3-methyl-2-methylimino-2,3-dihydrothiazolo-4-ylmethyl)sociosocio was obtained from 4-chloromethyl-3-methyl-3H-thiazol-2-ilidenmethyl same way as described in example 1, except that instead of 3-chloromethyl-5,6-dihydroimidazo[2,1-b]thiazole used the specified connection. MS (ESI): 381 [M+H+].

(4-Chloromethyl-3-methyl-3H-thiazol-2-ilidene)methylamine, used as starting material, was obtained by the following method.

A mixture of N,N'-dimethyltitanocene (1.04 g, 10.0 mmole), 1,3-dichloroacetone (1.27 g, 10.0 mmole) and n-butanol (25 ml) was heated at 140°C for 1 h the Solvent was removed and the resulting residue was led from methanol/ether, to receive hydrochloride (4-chloromethyl-3-methyl-3H-thiazol-2-ilidene)methylamine. MS (ESI): 177 [M+H+].

Example 3

1,3-DICYCLOHEXYL-2-(6,6-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-3-ylmethyl)estimacion

1,3-DICYCLOHEXYL-2-(6,6-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-3-ylmethyl)Isotoma the eve was obtained from 3-chloromethyl-6,6-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole in the same way as described in example 1, except that instead of 3-chloromethyl-5,6-dihydroimidazo[2,1-b]thiazole used the specified connection. MS (ESI): 407 [M+H+].

3-Chloromethyl-6,6-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole used as starting material, was obtained by the following method.

A mixture of 4,4-dimethylimidazolidin-2-thione (1.0 g, 7.5 mmole), 1,3-dichloroacetone (1,00 g, 7.5 mmole) and acetonitrile (15 ml) was boiled under reflux for 2 hours Obtained colorless precipitate was filtered, dried, suspended in 1-methoxy-2-(2-methoxyethoxy)ethane and successively heated at 140°C for 2 h, the precipitate was filtered and washed with ether, it was obtained the hydrochloride of 3-chloromethyl-6,6-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole. MS (ESI): 203 [M+H+].

The following examples of compounds of formula V was obtained by a similar method:

ExampleR1R4R6R5M+
4N 427
5N393
6Me393
7MeNMe243
8isopropylNisopropyl299
9N51
10N407
11N435
12NN297
13N373
14N 387
15N365
16N393
17N407
18N393
19N 431
20N431
21N393
22N-hexylN381
23N435
24N 435

The compounds of formula I in free form or in the form of their pharmaceutically acceptable salts are characterized by valuable pharmacological properties, for example, when used as antagonists of CXCR4, as shown when tested in vitro, and therefore, they can be used for treatment. CXCR4 is the receptor of the chemokine associated with G-protein (GPCR) and is expressed in several normal tissues including monocytes. SDF-1 (CXCL12) is specified ligand of the receptor, as well as chemoattractant, which induces chemotaxis of cells expressing CXCR4.

a) Binding to the membrane fraction, including CXCR4

The membrane fraction was obtained from lymphoblasts of T cells SEM, which Express endogenous receptor CXCR4. As the radioactive ligand used SDF-1α, labeled 125-1. The membrane fraction of the radioactive ligand and the compound of formula I incubated and determined the amount of bound radioactive ligand. Obtained data were used to estimate the IC50, i.e. the concentration of compound at which there is 50% inhibition of binding of [I-125]SDF-1α. The value of the IC50for compounds of formula I were less than 50 microns.

b) Functional analysis of CXCR4, the definition of the mobilization of CA2+

The mobilization of CA2+from intracellular source is s, induced SDF-1, was determined using CEM cells loaded with sensitive CA2+fluorochrome (dye) Fluo-4. Cells containing Fluo-4, incubated in the presence of compounds of the formula I, and then induced SDF-1 increase in fluorescence was recorded on a fluorescent plate reader to read the tablets. The inhibitory activity of the compounds was evaluated by the value of the IC50that means the concentration at which there is a decrease in response to SDF-1 by 50%. The value of the IC50for compounds of formula I were less than 50 microns.

C) Functional analysis of CXCR4, chemotaxis

The cell migration (chemotaxis), induced SDF-1, was carried out in the cell with branches from tissue culture Transwell separated by a porous polycarbonate membrane. Target cells (e.g. cells Jurkat T cells, SEM or lymphocytes) were added to the upper compartment and the chemokine SDF-1 in the lower compartment of the cell. In both these departments were added the compounds of formula I at the same concentration. The compounds of formula I inhibited induced SDF-1 chemotaxis, the value of the IC50was less than 50 microns.

Therefore, the compounds of formula I can be used for the prevention and/or treatment of diseases or disorders mediated by the interaction of the chemokine receptors, such as receptor CXCR4, and the ligands, for example, for treatment of complications of transplantation, such as acute or chronic rejection of organ, tissue or cell ALLO - or xenografts or delayed function of transplants, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, thyroiditis Hashimoto, multiple sclerosis, severe myasthenia gravis, diabetes type I and II and related disorders, vasculitis, pernicious anemia, Sjogren syndrome, uveitis, psoriasis, alopecia areata, etc., allergic diseases, e.g. allergic asthma, atopic dermatitis, allergic rhinitis/conjunctivitis, allergic contact dermatitis, inflammatory diseases, not necessarily associated with aberrant reactions, e.g. inflammatory bowel, Crohn's disease or ulcerative colitis, hereditary asthma, inflammatory lung injury, inflammatory liver injury, damage to the renal glomeruli, atherosclerosis, osteoarthrit, contact dermatitis or other eczematous dermatitises, seborrhoeic dermatitis, cutaneous manifestations of immune origin, inflammatory eye diseases, keratoconjunctivitis, myocarditis or hepatitis, ischemia, damage during reperfusion, for example, myocardial infarction, stroke, intestinal ischemia, renal failure or hemorrhagic shock, traumatic shock, etc. in actionee disease, for example, toxic shock (for example, induced superantigens), septic shock, respiratory distress syndrome in adults or viral infection, for example, linking HIV with the cell or its penetration into cells expressing CXCR4, or the development of AIDS. The term "transplantation" means Hello or xenotransplanted, for example, cells, tissues or organs, for example, pancreatic islets, stem cells, bone marrow, corneal tissue, neuronal tissue, heart, lung, tissues, heart-lung, kidney, liver, intestine, pancreas, trachea or esophagus. Chronic rejection is also known as a disease with prosthetic vessels.

Signal transmission involving receptor CXCR4 is associated with the development, invasion or metastasis of tumors, for example, solid tumors. Stromal or epithelial cells, associated with the formation of primary tumors, in most cases, Express SDF-1. Interaction of CXCR4/SDF-1 is included in the processes of consolidation, growth, angiogenesis or localized invasion of the tumor in the primary site, for example, development of blood vessels, or accelerate the penetration of tumor cells into the bloodstream or lomatichesky system, and these processes are induced expressing SDF-1 cells associated with blood vessels, for example, is of Anna stages of metastasis.

In addition, the expression of SDF-1 by bone marrow cells accelerates the accumulation, adhesion or proliferation of tumor cells expressing CXCR4 in bone tissue. The expression of SDF-1 in other parts or tissues similarly induces metastasis or tumors in these areas. Multiple myeloma is an example of a cancer in which the accumulation of cells in the bone marrow plays a major role in the processes of consolidation, education surrounding the tumor tissue and proliferation, which are necessary for the development and tumor progression.

In this regard, the compounds of the present invention can be used for prevention or treatment of proliferative diseases, especially malignant proliferative or neoplastic diseases, for example, tumors of the brain and Central nervous system (e.g., tumors of the meninges, brain, spinal cord, cranial nerves and other parts of Central nervous system, for example, glioblastoma or medullary blastoma), cancer of the head and/or neck, breast cancer, tumors of the circulatory system (e.g. heart, mediastinum or pleura or other intrathoracic organs, tumor vessels, and associated with tumor vascular tissue)tumor excretory system (e.g., kidney, renal pelvis, ureter, bladder and other organo the urinary system), tumors of the gastrointestinal tract (e.g., esophagus, stomach, small intestine, colon, rectum, compounds of the sigmoid colon with the rectum, the rectum, anus and anal canal), tumors of the liver and bile ducts, gall bladder, as well as tumors of other departments of the bile ducts, pancreas, and other organs and digestive organs, head and neck, oral cavity (lips, tongue, gums, floor of the mouth, palate and other departments of the oral cavity, salivary glands and other departments of the salivary glands, tonsils, oropharynx, nasopharynx, pyriform pocket, podporucznik and other departments of the lip, oral cavity and pharynx), tumors of the reproductive system (e.g., vulva, vagina, cervix, uterine body, uterine, ovarian and other departments associated with the organs of the female reproductive system, placenta, penis, prostate, testicles and other departments associated with the organs of the male reproductive system), tumors of the respiratory tract (e.g., nasal cavity and middle ear, sinuses, larynx, trachea, bronchus and lung, for example, small cell lung cancer light or non-small cell lung cancer), tumors of the musculoskeletal system (e.g., bone and articular cartilage of limbs, bone and cartilage), skin tumors (e.g. malignant melanoma of the skin, non-melanoma skin cancer, basal cell carcinoma of skin, flat-cell carcinoma of skin, mesothelioma, Kaposi's sarcoma), and tumors affecting other tissues including peripheral nerves and autonomic nervous system, connective and soft tissue, retroperitoneal and peritoneal space, the eye and adjacent organs, thyroid gland, adrenal gland and other endocrine glands, similar plots, secondary and nonspecific malignant neoplasm of lymph nodes secondary malignant neoplasms of respiratory and digestive systems and secondary malignant tumors in other parts of the body, cancer of the blood and lymphatic system (e.g., Hodgkin's disease, lymphoma non-Hodgkin's lymphoma, Burkitt's lymphoma, lymphoma, AIDS-related malignant immunoproliferative disease, multiple myeloma, and tumor plasma cells, lymphoid leukemia, acute or chronic myeloid leukemia, acute or chronic lymphocytic leukemia, monocytic leukemia, other leukemias of specific cells, leukemia non-specific cells, and other nonspecific malignant lymphoid neoplasms, neoplasms of hematopoietic cells and related tissues, for example, diffuse large-cell lymphoma, lymphoma of T-cell or lymphoma T-CL is current skin). Myeloid cancer includes, for example, acute or chronic myeloid leukemia.

Used in this context, the terms "tumor", "tumor disease", "cancer" or "cancer" means the metastasis in the source organ or tissue and/or in any other Department of the organism, regardless of the locations(a) the location of the tumor and/or metastasis. The compounds of formula I are primarily meant for the treatment of invasive tumors or symptoms associated with the growth of such tumors, to prevent the spread of metastases or to prevent or inhibit the growth of metastases in a subject in need of such treatment, primarily for the treatment or prevention of the spread of metastases in the bone tissue, for example, in the bone marrow. In one embodiment, the compound of formula I is intended for the prevention or treatment of metastasis, invasiveness of tumors or tumor growth mediated expression of the receptors CXCR4 and/or SDF-1.

In another embodiment, the compounds of formula I are intended to suppress or treatment of unregulated angiogenesis, such as angiogenesis, mediated by CXCR4 and/or SDF-1, the subject in need of such treatment.

When using compounds specified destination required dose depends on the method of administration, the specific treatable diseases and the desired effect. In most of the as cases satisfactory results are obtained in the systematic introduction of a daily dose of from about 0.01 to 10 mg/kg of body weight. Daily dose for large mammals, such as humans, is the range from about 0.5 mg to about 1000 mg, and the compound is administered in a standard way, for example, in divided doses up to 4 times per day, or in the form of slow release. Suitable dose for oral administration is from 0.1 to 500 mg, for example, from about 0.5 to 4 mg of the active ingredient.

The compounds of formula I is administered in any suitable way, first of all enteral, e.g. oral, for example, in the form of tablets or capsules, or parenterally way, for example, in the form of solutions or suspensions for injection, local way, for example, in the form of lotions, gels, ointments or creams, or nazalnam way, or in the form of suppositories. Pharmaceutical compositions comprising a compound of formula I in free form or in the form of pharmaceutically acceptable salts in combination with at least one pharmaceutically acceptable carrier or diluent, receive by standard methods, by mixing with a pharmaceutically acceptable carrier or diluent.

The compounds of formula I is administered in free form or in the form of a pharmaceutically acceptable salt, for example, as described above. Such salts receive by standard methods, and they are characterized by an activity of the same order as the connection to free the Orme.

In the present invention serves also:

1.1 a method for preventing or treating disorders or diseases mediated by the interaction of the chemokine receptors, such as receptors CXCR4, with their ligands, for example, with the ligands described above, in a patient in need of such treatment, and this method includes the introduction of a specified patient an effective amount of the compounds of formula I or its pharmaceutically acceptable salt,

1.2 a method for preventing or treating acute or chronic rejection of transplants or inflammatory or autoimmune diseases, such as mentioned above, in a patient in need of such treatment, and this method includes the introduction of a specified patient an effective amount of the compounds of formula I or its pharmaceutically acceptable salt,

1.3 method of prevention or treatment of proliferative diseases, for example, as indicated above, in a patient in need of such treatment, and this method includes the introduction of a specified patient an effective amount of the compounds of formula I or its pharmaceutically acceptable salt,

1.4 method of treatment progression, invasiveness or symptoms associated with the growth of such tumors, prevent the spread of metastases, or prevent or inhibit the growth of metastases, or PR is preventing angiogenesis, associated with tumor development, for example, as indicated above, the subject in need of such treatment, and this method includes the introduction of a specified patient an effective amount of the compounds of formula I or its pharmaceutically acceptable salt,

1.5 method of prevention or treatment of infectious diseases such as viral infections, primarily the prevention or treatment of binding or invasion of the virus into cells expressing chemokinesis receptor, for example, binding or invasion of the HIV virus, such as HIV-1 or HIV-2 in cells expressing the receptor CXCR4, or the development of AIDS.

2. The compound of formula I or its pharmaceutically acceptable salt as a pharmaceutical, e.g. for use in any of the ways described above in PP-1.4.

3. Pharmaceutical composition, e.g. for use in any of the ways described above in PP-1.4, comprising the compound of formula I or its pharmaceutically acceptable salt in combination with a pharmaceutically acceptable diluent or carrier.

4. The compound of formula I or its pharmaceutically acceptable salt to obtain pharmaceutical compositions intended for use in any method, such as method 1.4, above.

The compounds of formula I is administered as a single active ingredient or in combination : the AI for example, adjuvant, with other medicines, for example, immunosuppressive or immunomodulating agents or other anti-inflammatory agents, e.g. for the treatment or prevention of acute or chronic rejection of ALLO - or xenografts or inflammatory or autoimmune diseases, with himioterapevaticheskimi agents or antibacterial agent, for example, an antiviral agent such as an antiretroviral agent or an antibiotic. For example, the compounds of formula I used in combination with an inhibitor of calcineurin, e.g. cyclosporin a or FK 506, a mTOR inhibitor, e.g. rapamycin, 40-O-(2-hydroxyethyl) - rapamycin, CCI779, AWT, AR, AR, AR, AR or TARA 93, ascomycin exhibiting the properties of immunodepressant, for example, ABT-281, ASM981, etc., corticosteroids, cyclophosphamide, azathioprine, methotrexate, Leflunomide, mizoribine, mycophenolic acid, mycophenolate mofetil, 15-desoxypeganine or a homologue, analogue or derivative, having the properties of immunosuppressant, an agonist of sphingosine-1-phosphate receptor, for example, FTY720, monoclonal antibodies to leukocyte receptors, e.g., MHC, CD2, CD3, CD4, CD7, CD8, CD11a/CD18, CD25, CD27, CD28, CD40, CD45, CD58, CD80, CD86, CD137, ICOS, CD150 (SLAM), OX40, 4-1BB or their ligands, for example, CD154, or their antagonists, with other immuno what adulatory, for example, recombinant binding molecules comprising at least a fragment of the extracellular domain of CTLA4 or a mutant, for example, at least the extracellular fragment of CTLA4 or a mutant, sequence-related protein non-CTLA4, for example, CTLA4Ig (the former name of ATSS 68629) or a mutant, for example, LEA29Y, inhibitors of adhesion, for example, antagonists of LFA-1, ICAM-1 or -3, VCAM-4 or VLA-4; or antigenocide antibodies, or antibodies anticipating receptor or antagonists of low molecular weight chemokine receptor, for example, antibodies anti-MCP-1.

The term "antiviral agent"used in this context includes, without limitation, anti-retroviral agent, antibodies against the virus, for example, antibodies against HIV, reverse transcriptase inhibitors, such as inhibitors of HIV reverse transcriptase, first of all nucleoside analogues, such as Retrovir® (3'-azido-3'-methoxypyridine, AZT) and 3'-azido-3'-deoxythymidine (AZT) GlaxoSmithKline, HIVID® (2',3'-dideoxycytidine, zalcitabine) company Hoffmann-LaRoche, Videx® or VidexEC® (2',3'-dideoxyinosine, DDI) company Bristol-Myers-Squibb, Epivir® (lamivudine) GlaxoSmithKline, Zerit® (stavudine) company Bristol Myers-Squibb, Viread® (tenofovir DF) firm Gilead, ziagen® (abacavir) GlaxoSmithKline, Emtriva® (emtricitabine, FTC) company Gilead Sciences or non-nucleoside analogues, such as rescriptor® (delaw rain) from Pfizer, Sustiva® (efavirenz) company Bristol Meyer Squibb, viramune® (nevirapine) company Boehringer-Ingelheim, 11-cyclopropyl-5,11-dihydro-4-methyl-(6N)-dipyrido[3,2-b;2',3'-e]-[1,4]diazepin-6-he trinacria salt phosphonoformate, ammonium 21-wolframate-9-antimonate, 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide, an inhibitor of viral or retroviral protease, e.g., a viral inhibitor aspartates, for example, protease inhibitor HIV, such as aganerase® (APV) GlaxoSmithKline, reyataz® (atazanavir) company Bristol-Myers Squibb, lexiva® (fosamprenavir) company GSK, Crixivan® (indinavir) Merck & Co., viracept® (nelfinavir) company Agouron, norvir® (ritonavir) company Abbott, fortovase®, Invirase® (saquinavir) company Hoffmann-LaRoche, as well as other compounds, such as latinovic (5(S)-(tert-butoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)hexanoyl-(L)-poured-N-(2-methoxyethyl)amide), adriamycin, KVX-478 company GlaxoWellcome, VX-478 Vertex firm; 141W94 company Kissei Pharmaceuticals, AG-1343 company Agouron, INSTITUTE of 272 firms Nippon Mining, U-96988 decision Upjohn company, BILA-2011BS (palinavir) company Boehringer-Ingelheim, compounds that prevent the invasion of the virus, such as, for example, polymannose, fusion inhibitors, such as, for example fuzeon® (enfuvirtide, T-20) company Hoffmann-LaRoche, or combinations thereof, such as Epzicom® (abacavir or lamivudine) company GlaxoKlineSmith, Trizivir® (abacavir, lamivudine, and zidovudine) company GlaxoKlineSmith, Truvada® (emtricitabine and tenopir DF) firm Gilead Sciences, Combivir® (lamivudine and sidow the Dean firms GlaxoKlineSmith, kaletra® (lopinavir and ritonavir) company Abbott. The term "antiviral agent" includes an agent, which is used for treatment of opportunistic infections caused immunodepressants the influence of viral infection, such as HIV infection.

The term "HIV"used in this context includes, but is not limited to, HIV-1 and HIV-2.

The compounds of formula I are also used to increase the effectiveness of treatment in combination with other antiproliferative agents. Such antiproliferative agents include, without limitation, aromatase inhibitors, antiestrogens, inhibitors of topoisomerase I, topoisomerase II inhibitors, active agents in respect of microtubules, alkylating agents, inhibitors discontiuation inhibitors farnesyltransferase inhibitors SOH-2, MMP inhibitors, mTOR inhibitors, antineoplastic antimetabolites, platinum compounds, compounds decreasing the protein kinase activity and other antiangiogenic compounds, agonists of gonadorelin, antiandrogens, benhamadi, bisphosphonates, antiproliferative antibody temozolomide (TEMODAL®).

The term "aromatase inhibitors"used in this context, refers to compounds that inhibit the formation of estrogen, i.e. conversion of the substrates Androstenedione and testosterone to estrone and estradiol meet the but. The term includes, without limitation, steroids, primarily exemestane and formestane, and primarily non-steroid compounds, primarily aminoglutethimide, vorozole, fadrozole, anastrozole, primarily letrozole. Ackzemestan enter, for example, in the form of a commercial product, for example, under the trade name AROMASIN™. Formestane is injected, for example, in the form of a commercial product, for example, under the trade name LENTARON™. Fadrozole enter, for example, in the form of a commercial product, for example, under the trade name AFEMA™. Anastrozole is administered, for example, in the form of a commercial product, for example, under the trade name ARIMIDEX™. Letrozole is administered, for example, in the form of a commercial product, for example, under the trade name FEMARA™ or FEMAR™. Aminoglutethimide administered, for example, in the form of a commercial product, for example, under the trade name ORIMETEN™.

The combination of the present invention, including anti-tumor agent, which is an aromatase inhibitor, used primarily for the treatment of hormone receptor-positive breast tumors.

The term "antiestrogens"used in this context, refers to compounds that are active antagonists of the estrogen level estrogen receptors. The term includes, without limitation, tamoxifen, fulvestrant, raloxifene, and raloc Ivana hydrochloride. Tamoxifen is administered, for example, in the form of a commercial product, for example, under the trade name NOLVADEX™. Raloxifene hydrochloride is administered, for example, in the form of a commercial product, for example, under the trade name EVISTA™.

Fulvestrant receive according to the method described in U.S. patent No. 4659516, and enter, for example, in the form of a commercial product, for example, under the trade name FASLODEX™.

The term "inhibitor of topoisomerase I"used in this context includes, but is not limited to, topotecan, irinotecan, 9-nitrocamptothecin and macromolecular conjugate of camptothecin PNU-166148 (compound A1 in the application WO 99/17804). Irinotecan is administered, for example, in the form of a commercial product, for example, under the trade name CAMPTOSAR™.

Topotecan is administered, for example, in the form of a commercial product, for example, under the trade name HYCAMTIN™.

The term "topoisomerase II inhibitor"used in this context includes, without limitation, anthracyclines: doxorubicin (including liposomal composition, e.g., CAELYX™), epirubicin, idarubitsin and nemorubicin, anthraquinones: mitoxantrone and losoxantrone, podophyllotoxin etoposide and teniposide. Etoposide is administered, for example, in the form of a commercial product, for example, under the trade name ETOPOPHOS™. Teniposide is injected, for example, in the form of a commercial product, for example, under tor the new name VM 26-BRISTOL™. Doxorubicin is administered, for example, in the form of a commercial product, for example, under the trade name ADRIBLASTIN™. Epirubicin is administered, for example, in the form of a commercial product, for example, under the trade name FARMORUBICIN™. Idarubitsin enter, for example, in the form of a commercial product, for example, under the trade name ZAVEDOS™. Mitoxantrone is administered, for example, in the form of a commercial product, for example, under the trade name NOVANTRON™.

The term "active agent in respect of microtubules" means the agents, stabilizing and destabilizing microtubules, and includes, without limitation, taxanes: paclitaxel and docetaxel, Vinca alkaloids from Vinca rosea, e.g., vinblastine, especially vinblastine sulfate, vincristine, especially vincristine sulfate, and vinorelbine, discodermolide, and epothilones, such as epothilone and D. Docetaxel administered, for example, in the form of a commercial product, for example, under the trade name TAXOTERE™. Vinblastine sulfate is injected, for example, in the form of a commercial product, for example, under the trade name VINBLASTIN R.P.™. Vincristine sulfate is injected, for example, in the form of a commercial product, for example, under the trade name FARMISTIN™. Discodermolide get the technique described, for example, in U.S. patent No. 5010099.

The term "alkylating agents"used in this contexte, includes, but is not limited to what I listed, cyclophosphamide, ifosfamide and melphalan. Cyclophosphamide is administered, for example, in the form of a commercial product, for example, under the trade name CYCLOSTIN™. Ifosfamide is administered, for example, in the form of a commercial product, for example, under the trade name : HOLOXAN™.

The term "inhibitors discontiuation" means a compound that inhibits discontiuation and which possess antiproliferative activity.

The term "inhibitors farnesyltransferase" means a compound that inhibits farnesyltransferase and which possess antiproliferative activity.

The term "inhibitor " -2" means a compound that inhibits the enzyme cyclooxygenase type 2 (SOH-2) and which possess antiproliferative activity, such as celecoxib (Celebrex®), rofecoksib (Vioxx®) and lumiracoxib (SOH).

The term "inhibitors of MMP" means a compound that inhibits the matrix metalloproteinase (MMP) and which possess antiproliferative activity.

The term "mTOR inhibitors" means a compound that inhibits the target of rapamycin mammalian (mTOR) and which possess antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and AWT.

The term "antineoplastic antimetabolites" includes, without limitation, 5-fluorouracil, tegafur, capecitabine, cladribine, sitrabi is, fludarabine phosphate, tarorigin, gemcitabine, 6-mercaptopurine, hydroxyurea, methotrexate, edatrexate and salts of the above compounds, as well as ZD 1694 (RALTITREXED™), LY231514 (ALIMTA™), LY264618 (LOMOTREXOL™) and OGT719.

The term "platinum compounds"used in this context includes, but is not limited to, carboplatin, cisplatin and oxaliplatin. Carboplatin is administered, for example, in the form of a commercial product, for example, under the trade name CARBOPLAT™. Oxaliplatin is administered, for example, in the form of a commercial product, for example, under the trade name ELOXATIN™.

The term "compounds that reduce the activity of protein kinases, and other antiangiogenic compounds"used in this context includes, without limitation, compounds that reduce the activity of, for example, vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), c-Src, protein kinase C, platelet-derived growth factor (PDGF), tyrosine kinase Bcr-AbI, c-kit, Flt-3 receptor and insulin-like growth factor (IGF-IR), cyclin-dependent kinases (CDK), and antiangiogenic compounds, characterized by a different mechanism actions in contrast to the reduction of the activity of protein kinases.

Compounds that reduce the activity of VEGF primarily include compounds that inhibit the VEGF receptor, primarily the activity of the receptor tyrosine kinase VEGF, as well as the connection binding to VEGF, and primarily include compounds, proteins and monoclonal antibodies, are described in General terms and in more detail in the applications WO 98/35958 (which describes the compounds of formula (I), WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819, WO 01/55114, WO 01/58899 and European patent EP 0769947; compounds described in articles .Prewett and others, Cancer Research, vol. 59, cc.5209-5218 (1999), F. Yuan and others, Proc. Natl. Acad. Sci. USA, t, cc.14765-14770 (1996), Z.Zhu, and others, Cancer Res., t, cc.3209-3214 (1998), and J.Mordenti and others, Toxicologic Pathology, v.27, No. 1, cc.14-21 (1999); in applications WO 00/37502 and WO 94/10202; angiostatin™, described in the article .S.O''reilly and others, Cell, t, cc.315-328 (1994); and endostatinTMdescribed in article .S.O''reilly and others, Cell, t, cc.277-285 (1997); compounds that inhibit the activity of EGF, include primarily compounds that inhibit the EGF receptor, primarily the activity of the receptor tyrosine kinase EGF, and compounds that bind to the EGF, and primarily compounds described in General terms and in more detail in the application WO 97/02266 (which describes the compounds of formula (IV), in the European patent EP 0564409, in the application WO 99/03854, in European patents EP 0520722, EP 0566226, EP 0787722, EP 0837063, in applications WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and primarily in the application WO 96/33980; compounds that decrease the activity of c-Src include, without limitation, compounds that inhibit the activity proteinkinase c-Src, as described below, and inhibitors of SH2 interaction described in applications WO 97/07131 and WO 9708193;

compounds that inhibit the activity proteinkinase c-Src, include, without limitation, connection class pyrrolopyrimidine primarily pyrrolo[2,3-d]pyrimidines, purines, pyrazolidine, primarily piraso[3,4-d]pyrimidines, pyrazolidine, primarily piraso[3,4-d]pyrimidines and pyridopyrimidines primarily pyrido[2,3-d]pyrimidines. This term means preferably compounds described in applications WO 96/10028, WO 97/28161, WO 97/32879 and WO 97/49706,

compounds that reduce the activity of protein kinase C, primarily include derivatives staurosporine described in European patent EP 0296110 (obtaining pharmaceutical compositions described in the application WO 00/48571), which are inhibitors of protein kinase C,

other compounds that reduce the activity of protein kinases and are used in combination with the compounds of the present invention, include imatinib (Gleevec®/Glivec®), midostaurin, IressaTM(ZD1839), PKI166, vatalanib, ZD6474, GW2016, CHIR-200131, CEP-7055/CEP-5214, CP-547632 and KRN-633,

antiangiogenic compounds, characterized by a different mechanism of action in contrast to the reduction of the activity of protein kinases include, without limitation, for example, thalidomide (THALOMID), celecoxib (Celebrex), SU5416 and ZD6126.

The term "agonist of gonadorelin"used in this context includes, without limitation, abarelix, goserelin and goserelin acetate. Goserelin described in U.S. patent No. 4100274, and it is administered, for example, in the form of a commercial product, for example, under the trade name ZOLADEX™.

Abarelix get the technique described, for example, in U.S. patent No. 5843901.

The term "anti-androgens"used in this context includes, without limitation, bikalutamid (CASODEX™), which is produced according to the method described, for example, in U.S. patent No. 4636505.

The term "benhamadi" means benhamadi and their derivatives, characterized by proliferative properties.

The term "bisphosphonates"used in this context includes, without limitation, trigonomy acid, clodronate acid, tiludronic acid, pamidronovu acid, alendronate acid, ibandronate acid, risedronate acid and zolendronic acid. "Etidronate acid type, for example, in the form of a commercial product, for example, under the trade name DIDRONEL™. "Clodronate acid type, for example, in the form of a commercial product, for example, under the trade name BONEFOS™. "Tiludronate acid type, for example, in the form of a commercial product, for example, under the trade name SKELID™. "Pamidronovu acid type, for example, in the form of a commercial product, for example, under the trade name AREDIA™. "Alendronate acid" BB is changed, for example, in the form of a commercial product, for example, under the trade name FOSAMAX™. "Ibandronate acid type, for example, in the form of a commercial product, for example, under the trade name BONDRANAT™. "Risendronate acid type, for example, in the form of a commercial product, for example, under the trade name ACTONEL™. "Zolendronic acid type, for example, in the form of a commercial product, for example, under the trade name ZOMETA™.

The term "antiproliferative antibodies"used in this context includes, but is not limited to, trastuzumab (Herceptin™), trastuzumab-DMl, erlotinib (Tarceva™), bevacizumab (Avastin™), rituximab (Rituxan®), PR064553 (anti-CD40) and antibodies C.

In the treatment of acute myeloid leukemia (AML) the compounds of formula I are used in combination with standard therapy of leukemia, especially in combination with a therapy used in the treatment of AML. First of all the compounds of formula I is administered in combination with, for example, inhibitors farnesyltransferase and/or other drugs suitable for the treatment of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubitsin, carboplatin and midostaurin.

The structure of the active agents, which is characterized by a code number, common or trade name, described in the current edition of "The Merck Index" or in databases, e.g. the, in Patents International (e.g. IMS World Publications).

The above compounds are used in combination with the compound of the formula I, receive and administered by standard methods described in the papers cited above.

The compounds of formula I is administered in combination with other immunosuppressants/immunomodulators, anti-inflammatory, antiproliferative, antibacterial, antiviral and chemotherapeutic agents, and dose simultaneously introduced immunosuppressants/immunomodulators, anti-inflammatory, antiproliferative, antibacterial, antiviral and chemotherapeutic agents depend on the type jointly injected drugs (e.g., steroid or inhibitor calcineurin), from specific drugs, from curable diseases, etc. In the present invention are also offered the following objects:

5. The method described above comprising co-administration, e.g., simultaneously or sequentially, a therapeutically effective non-toxic amount of the compounds of formula I and at least a second drug, such as immunosuppressant/immunomodulator, anti-inflammatory, antiproliferative, antitumor, antibacterial, antiviral and chemotherapeutic drugs is, for example, as described above.

6. Pharmaceutical composition, for example, the set including a) a first agent which is an antagonist of CXCR4, for example, the compound of formula I, described in this context, in free form or in the form of pharmaceutically acceptable salts, and b) at least one collateral agent, for example, immunosuppressant, immunomodulator, anti-inflammatory, antiproliferative, antibiotic or chemotherapeutic agent. The kit may include instructions for its implementation.

The term "co-administration" or "co-administration" or the like, used in this context, means the administration of the selected therapeutic agents to a single patient, and this term includes treatments that do not require agents to enter the same way or at the same time.

The term "pharmaceutical combination"used in this context, means the product obtained by mixing or mixing more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means the administration to the patient of the active ingredients, for example, the compounds of formula I and the concomitant agent, such as an antiviral agent, at the same time as total dose or drug Fort is s. The term "non-fixed combination" means the administration to the patient of the active ingredients, for example, the compounds of formula I and the concomitant agent, for example, an antiviral agent, in the form of divided doses at the same time, together or sequentially in an unlimited period of time, and this introduction provides for the delivery of therapeutically effective amounts of two compounds in the body of the patient. The latter term also applies to combination therapy, for example, to the introduction of three or more active ingredients.

1. The compound of the formula I

where R1means the residue of formula (a), (b) or (C)
,
R2means -(CR22R23)1-3-,
R3and R8every means S,
R4and R5every means independently optionally substituted by a group R25With3-C12cycloalkyl,1-C12alkyl or saturated C8-C12polycyclic hydrocarbon residue, such as adamantane, unsubstituted phenyl or unsubstituted benzyl,
R6means N or C1-C6alkyl,
R7means CH,
R9means a direct bond or -(CR22R23)1-2-,
R10-R15every means N
R16-R23each is independently mean H, C1-C6alkyl, or
R20and R21together with the carbon atoms to which they are attached, form a benzene ring, and
R25has one of the meanings given above for R16-R23,
or pharmaceutically acceptable salts of such compounds.

2. The compound according to claim 1, which is chosen from the group comprising 1,3-DICYCLOHEXYL-2-(5,6-dihydroimidazo[2,1-b]thiazole-3-ylmethyl)estimacion, 1-cyclohexyl-3-cyclopentyl-2-(5,6-dihydroimidazo[2,1-b]thiazole-3-ylmethyl)estimacion, 1-cycloheptyl-3-cyclohexyl-2-(5,6-dihydroimidazo[2,1-b]thiazole-3-ylmethyl)estimacion, 1,3-DICYCLOHEXYL-2-(5,6-dihydroimidazo[2,1-b]thiazole-3-ylmethyl)estimacion, 1-cyclohexyl-3-cyclooctyl-2-(5,6-dihydroimidazo[2,1-b]thiazole-3-ylmethyl)estimacion, 1,3-DICYCLOHEXYL-2-(6,6-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-3-ylmethyl)estimacion, 1,3-DICYCLOHEXYL-2-(5,6-dihydroimidazo[2,1-b]thiazole-3-ylmethyl)sociosocio and 1,3-DICYCLOHEXYL-2-(6,6-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-3-ylmethyl)sociosocio.

3. Pharmaceutical composition having the properties of CXCR4 antagonist comprising a therapeutically effective amount of a compound according to claim 1 in free form or in the form of a pharmaceutically acceptable salt in combination with a pharmaceutically acceptable diluent or carrier.

4. The use of compounds according to claim 1 in free form or in formathematical acceptable salt for a medicinal product, intended for the prevention or treatment of diseases mediated by interactions between chemokine receptors such as CXCR4.

5. The method of obtaining the compounds of formula I, including the interaction of the compounds of formula II

with the compound of the formula III

where R1-R6have the meanings defined above in claim 1, a R32means a leaving group,
and neobyazatelno the transformation of compounds of formula I obtained in free form, in salt form or Vice versa.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on HsEg5. In formula (I) A is C=O or CH2; B is optionally substituted C1-6alkyl, D is O or N, where O is substituted with one R8, and where N is substituted with one or more R8, R1 and R2 together with the carbon atoms with which they are bonded form optionally substituted isothiazole or isoxazole, condensed with a pyrimidine ring, optionally substituted with a substitute which is C1-6 alkyl. Values of the rest of the radicals are given in the formula of invention.

EFFECT: invention relates to use of disclosed compounds in making medicinal agents with inhibitory effect on HsEg5, to a method of obtaining inhibitory effect on HsEg5, to a pharmaceutical composition which contains the disclosed compound as an active ingredient.

22 cl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-acyl-2-aminothiazoles of formula (I) and their pharmaceutically acceptable salts as antagonist of adenosine receptor A2B and to a pharmaceutical composition based on the said compounds. In formula (I) X is -CH2-, -CH2CH2-, -(CH2)3- and O(CH2)-; R is a 5- or 6-member saturated or unsaturated carbocyclic or heterocyclic ring system, which can optionally contain one or more heteroatoms, chosen from N, O and S, where the said ring system is optionally substituted with one or more substitutes, chosen from a group consisting of halogen, hydroxy, lower alkyl, nitrile group, sulfonamide, aminosulfonyl, lower alkoxycarbonyl, lower alkylsufonyl, benzyl, benzoyl, phenylsulfonyl, and the said benzyl, benzoyl or phenylsulfonyl are optionally substituted with a halogen, trihalogeno-lower alkyl group; R1 is chosen from a group consisting of hydrogen, halogen or lower alkoxy group.

EFFECT: obtaining compounds which can be used for treating and preventing diseases caused by adenosine receptors A2B, such as diabetes, diabetic retinopathy, asthma and diarrhea.

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel derivatives of 2,6-dihydro-7H- pyrazolo[3,4-d]pyradazin-7-one, 1,4-dihydropyrazolo[3,4-b]thiazin-5(6H)-one; N-acylated 4-imidazo[1,2-a]pyridin-2-yl- and 4-imidazo[1,2-a]pyrimidin-2-yl- anilines; amides of [(4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]pyperidin-4-carboxylic acid; amides of 2-(4-carbamoylpyperidin-1-yl)isonicotinic acid; amides of N-sulfonyl-1,2,3,4-tetrahydrochinolin-6-carboxylic acid; as well as to N-acylated 3-azolyl derivatives of 2-amino-4,5,6,7-tetrahydtithieno[2,3-c]pyridine possessing properties of Hh-signal cascade inhibitors.

EFFECT: compounds can be applied for use in pharmaceutical compositions and medications for treating diseases induced by abberant activity of Hedgehog (Hh) signal system, in particular, oncological diseases, for instance, for pancreatic carcinoma treatment.

23 cl, 13 dwg, 11 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new annelated azaheterocyclic amides, including a pyrimidine fragment, with the general formula 1, method of obtaining them and their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of P13K kinase, in compounds with the general formula 1: , where: X represents an oxygen atom, sulphur atom or not necessarily substituted at the nitrogen NH group, where the substitute is selected from lower alkyls and possibly a substituted aryl; Y represents an atom of nitrogen or substituted at the carbon atom CH group, where the substitute is selected from lower alkyls; Z represents an oxygen atom; R1 represents a hydrogen atom or not necessarily substituted C1-C6alkyl, or Z represents a nitrogen atom, which is together with a carbon atom, with which it is joined, form through Z and R1 annelated imidazole cycle; R2 and R3 independently from each other represent hydrogen, not necessarily substituted with C1-C6alkyl, C3-C6cycloalkyl, not necessarily substituted with phenyl, not necessarily substituted with 6-member aza-heteroaryl, under the condition, when Y represents a nitrogen atom, or R2 and R3 independently from each other represent not necessarily substituted C1-C6alkyl, not necessarily substituted with phenyl, not necessarily substituted with 5-7-member heterocycle with 1-2 heteroatoms, selected from nitrogen and oxygen, and possibly annelated with a phenyl ring, under the condition, when Y does not necessarily represent a substituted carbon atom at the CH group, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents a substituted aminoC1-C6alkyl and not necessarily substituted 5-6-member aza-heterocycloalkyl, under the condition, when Y represents a group which is substituted at the CH atom, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents phenyl which is not necessarily substituted, pyridyl which is not necessarily substituted, pyrimidinyl which is not necessarily substituted, under the conditions, when R1 represents a substituted aminoC1-C6alkyl, substituted C2-C3hydroxyalkyl and aza-heterocycloalkyl not necessarily substituted, Y represents a group with CH substituted, and X represents an oxygen atom, sulphur, and the substitute of the above indicated substituted alkyl, phenyl, heterocycle, pyridyl, pyrimidyl are selected from groups of hydroxyl-, cyano-groups, hydrogen, lower alkyls, possibly mono- or di-substituted lower alkyl sulfamoyl, carbamoyl, C1-C6alkoxycarbonyl, amino, mono- or di-lower alkyl-amine, N-(lower alkyl), N-(phenylC1-C6alkyl)amine, phenyl, possibly substituted with a halogen atom, C1-C6alkyl, haloid-C1-C6alkyl; phenylC1-C6alkyl, saturated or non-saturated 5-6-member heterocycle containing 1-2-heteroatoms, selected from nitrogen, oxygen and sulphur, and possible condensation with a benzene ring R4 represents hydrogen or a lower alkyl.

EFFECT: obtaining new annelated aza-heterocyclic amides, including a pyrimidine fragment, with the general formula with the possibility of their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of PI3K kinase.

16 cl, 5 tbl, 5 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention relates to mono-sodium salt 5-[[(2,3-difluorophenyl)methyl]thio]-7-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]thiazole[4,5-d]pyrimidine-2(3H)-on as a modulator of the activeness of chemokine receptors, method of obtaining it and pharmaceutical composition on its basis, and also its application in production of medicinal agents.

EFFECT: obtaining compounds, which can find application in treatment of diseases mediated by chemokine receptors, such as asthma, allergic rhinitis, COPD (chronic obstructive pulmonary disease), inflammatory bowel disease, osteoarthritis, and rheumatoid arthritis.

10 cl, 2 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention relates to new condensed dicyclic nitrogen-containing heterocycles with the general formula (I), their pharmaceutically accepted salts and stereoisomers, possessing DGAT inhibiting action. In the compound of formula (I): , X is selected from a group, which consists of C(R1) and N; Y is selected from a group, which consists of C(R1), C(R2)(R2), N and N(R2); Z is selected from a group, which consists of O; W1 is selected from cyclo(C3-C6)alkyl, aryl and 5- or 6-member heteroaryl, containing 1-2 heteroatoms, selected from a group, which comprises of nitrogen and sulphur, W2 selected from cyclo(C3-C8)alkyl, (C5-C6)heterocycloalkyl, containing 1 or 2 heteroatoms, selected from groups, consisting of nitrogen or oxygen, benzol and 5-or 6-member heteroaryl, containing 1-2 nitrogen atoms as heteroatoms, L1 is the link; L2 is selected from a group consisting of links, 0, (C1-C4)alkylene and (C1-C4)oxyalkylene; m denotes 0 or 1; its not a must that when m denotes 1 and L2 denotes a link, the substitute for W2 can be integrated with the substitute for W1 forming a 5-or 6-member ring, condensed with c W1 forming a spiro-system or condensed with W2, where specified ring could be saturated or unsaturated and has 0 or 1 atom O, as a member of the ring R1 is H; R2 is H; R3 and R4 are independently selected from groups consisting of H and (C1-C8) alkyl; optionally, R3 and R4 can together form 3-, 4-, 5- or 6-member spirorings, R5 and R6 are independently H; optionally, when Y includes the group R1 or R2, R5 or R6 can be joined with R1 and R2 forming a 5- or 6-member condensate ring, containing a nitrogen atom, to which R5 or R6 are joined, and optionally containing an oxo-group; R7 is selected from a group, composed of H, (C1-C8) alkyl, halogen(C1-C4)alkyl, 0Ra and NRaRb ; Ra selected from groups composed of H and (C1-C8)alkyl; and Rb selected from groups consisting of H and (C1-C8)alkyl; a dotted line indicates a possible bond. The invention also relates to pharmaceutical compositions and applications of the compounds.

EFFECT: obtaining compounds which can be used for getting medicinal agents to treat or prevent diseases or a mediated action state of DGAT, such as obesity, diabetes, syndrome X, resistance of insulin, hyperglycemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, disease of non-alcoholic fatty infiltration of the liver, atherosclerosis, arteriosclerosis, coronary artery disease and myocardial infarction.

33 cl, 17 dwg, 11 tbl, 391 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 can be similar or different and represent, each independently, hydrogen, halogen, hydroxyl, unsubstituted (C1-C6)alkyl, (C1-C6)alkoxy, or neighbouring groups R2 and R3 together with carbon atoms to which they are bound, can form benzol ring; R13 and R14 can be similar or different and represent each independently, hydrogen, unsubstituted (C1-C6)alkyl, optionally, R13 and R14 together with nitrogen atom can form 5-, 6-member heterocyclic ring, where heterocycle also can be substituted (C1-C6)alkyl, and it can have "additional heteroatoms", selected from O, N; "n" is an integer in interval from 1 to 4, and carbon chain, to which it relates is linear.

EFFECT: compound possess the characteristic of activity modulators 5-HT and can be applied for treatment of such diseases as anxiety, depression, convulsive syndromes, migraine.

15 cl, 67 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new derivatives of 2-pyridinecarboxamide and their pharmaceutical salts, which have glucokinase activating properties. In formula (I): D represents O or S; R2 and R3 each represents a hydrogen atom; formula (II) represents triazole group, imidazole group, thiazole group and pyridine group, which can have in the ring, 1 or 2 substitutes; formula (III) represents a thiazole group, thiadiazole group, isoxazolyl group, pyrazine group, pyridothiazolyl group or pyridyl group, ring B can have 1 or 2 substitutes. The invention also relates to pharmaceutical compositions based on the invented compounds.

EFFECT: new derivatives can be used for treating such diseases as sugar diabetes.

19 cl, 5 tbl, 165 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula II as neuropeptide FF receptor antagonist, their pharmaceutically acceptable acid-additive salts, medication based on them, as well as their application. Compounds can be applied for treatment and prevention of diseases mediated by activity of neuropeptide FF receptor, such as pain, hyperalgesia, enuresis, for elimination of syndromes arising in case of alcohol, psychotropic and nicotine addiction, for regulation of insulin release, digestion, memory functions, blood pressure or electrolytic and energy exchange. In general formula II , A together with thiazole ring forms 4,5,6,7-tetrahydrobenzothiazole, 5,6,7,8-tetrahydro-4H-cycloheptathiazole, 5,6-dihydro-4H-cyclopentathiazole fragments; R1 represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tret-butyl, 1,1-dimethylpropyl or phenyl; R2-R6 each represents hydrogen or methyl.

EFFECT: obtaining solutions, which ca be used for treatment and prevention of diseases, mediated by activity of neuropeptide FF receptor.

6 cl, 4 tbl, 106 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention can be used for treating or preventing diseases and conditions, mediated by peroxisome proliferator activated gamma receptor (PPARγ). In formula (I) W represents a COOH group or -COOC-C1-C4alkyl; Y represents NH; Z represents S or O; X represents O; R1-R6 each independently represents a hydrogen atom or substitute, chosen from a group consisting of: C1-C4-alkyl, thienyl or phenyl, where phenyl is optionally substituted with one or more substitutes, independently chosen from a group consisting of C1-C4-alkyl, C1-C4-alkoxy, a halogen atom; -NO2 and -CN; A represents C1-C4-alkyl, -N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl, aryl, chosen from a group consisting of phenyl, naphthyl, or heteroaryl, chosen from a group consisting of oxazolyl, isoxazolyl, thienyl, pyridyl, thiazolyl, thiadiazolyl, benzo[b]thienyl, imidazolyl, indolyl and carbazolyl, where aryl and heteroaryl are substituted or not substituted with one or more substitutes, independently chosen from a group consisting of C1-C4-alkyl, C1-C4-alkoxy, phenyl and a halogen atom; and n is an integer from 0 to 4. The invention also relates to a pharmaceutical composition, containing the invented compound as an active component, use of the compounds to make a medicinal agent, and method of treatment.

EFFECT: obtaining new biologically active compounds.

22 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of formula (I) and its pharmaceutically acceptable salts and esters. Compounds of the present invention are characterised with properties of DGAT-1 inhibitor. In general formula (I) , Q represents O, S or NR5; A represents a linker chosen from where p is equal to 1 or 2, and , where m is equal to 0, and n is equal to 1, 2, 3 or 4, or m is equal to 1, while n is equal to 1, 2 or 3, where specified linker is optionally substituted with one or two groups R8; R1 and R2 are independently chosen from hydrogen, haloid; R3 is chosen from hydrogen, (C1-C6)alkyl optionally substituted with hydroxyl and phenyl optionally substituted with haloid; R4 is chosen from hydrogen, nitro and (C1-C6)alkyl; or R3 and R4 together with carbon atoms whereto attached, can form benzene ring optionally substituted with 1-2 substitutes. The invention also concerns compounds of formula (Ia) and (Ib) with structural formulas presented in the patent claim, and also to a pharmaceutical composition, a medical product, to application of compounds for making a medical product and compound process.

EFFECT: new compounds possess useful biological activity.

19 cl, 2 tbl, 7 dwg, 215 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts and esters wherein R1 means phenyl, naphthyl, 5-6-membered heterocyclyl comprising oxygen (O), nitrogen (N) or sulfur atom (S) as heteroatoms and wherein phenyl, naphthyl and heterocyclyl are optionally substituted with 1-3 substitutes chosen from halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy, nitro; di-(C1-C6)-alkylamino or (C1-C6)-alkoxy groups; R2 means hydrogen atom; R3 means (C1-C6)-alkyl or trifluoromethyl; A1 means C-R3 or nitrogen atom; A2 means piperidine or pyrrolidine wherein nitrogen atom in piperidine or pyrrolidine ring is added to A3 wherein A3 means -S(O)2- or -C(O)-; n = 0, 1 or 2. Also, invention relates to a pharmaceutical composition based on compounds proposed by the invention. Proposed compounds possess properties of NPY receptors antagonists and can be used in treatment arthritis, diabetes mellitus, nutrition disorders, obesity and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 1 tbl, 1 dwg, 26 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel cyclic compounds of the formula (I) and (II) or tier pharmaceutically acceptable salts wherein radical values given in formula (I) and (II) are indicated in the invention description. Also, invention relates to a pharmaceutical composition containing at least one compound of the formula (I), and to using these compounds for preparing a drug. Invention provides synthesis of novel compounds and preparing a compositions containing hereof that possess inhibitory activity with respect to protein-tyrosine kinase.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

24 cl, 3 tbl, 582 ex

FIELD: organic chemistry, biochemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to novel diaminothiazoles of the formula (I) , their pharmaceutically acceptable salts and esters, and to a pharmaceutical composition based on thereof. Proposed compounds inhibit activity of cyclin-dependent kinase 4 (Cdk4), shows selectivity with respect to Cdk2 and Cdk1 and can be used in treatment against cancer, in particular, against solid tumors. In the general formula (I) R2 and R3 represent hydrogen atom; R4 is chosen from group comprising lower alkyl, (C3-C6)-cycloalkyl, O-lower alkyl, halogen atom, -NO2, S-lower alkyl, -CF3 and -CN; R5 is chosen from group comprising hydrogen atom, O-lower alkyl, lower alkyl, halogen atom and -OH, or, alternatively, R4 and R in common with two carbon atoms and a bond binding them belonging to benzene cycle (C) to which R4 and R5 are bound can form a cycle consisting of 5-6 atoms comprising one or two heteroatoms chosen from oxygen atom and optionally substituted with (C1-C4)-alkyl; R6 and R are chosen independently from group comprising hydrogen atom, lower alkyl and -COOR12, or, alternatively, group -NR6R7 can mean cycle consisting of 5-6 atoms optionally comprising heteroatom chosen from nitrogen or oxygen atoms; R8 and R9 are chosen independently from group comprising hydrogen atom and lower alkyl; R10 is chosen from group comprising hydrogen atom, lower alkyl, lower alkyl substituted with hydroxyl, and -COOR12; R11 is chosen from group comprising hydrogen atom, lower alkyl and -COOR12 wherein R12 means lower alkyl; m can mean 1 or 2; n can mean 0, 1 or 2 under condition that if m means 2 and R4 means fluorine atom then R5 is not hydrogen atom, and under condition if m means 1 and R4 means lower alkyl then R5 is not hydroxyl.

EFFECT: valuable biochemical and medicinal properties of compounds and pharmaceutical compositions.

20 cl, 6 sch, 3 tbl, 153 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to new derivatives of 2-arylimino-2,3-dihydrothiazoles of the general formula (I): wherein radical values R1, R2, R3 and R4 are given in the claim invention. New compounds are useful in treatment of pathological states or diseases wherein one or some somatostatin receptors are implicated, for example, acromegaly, hypophysis adenomas or gastroenteropancreatic endocrine tumors with carcinoid syndrome and gastroenteric bleedings.

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

14 cl, 2825 ex

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

The invention relates to new and nitrate salts of heterocyclic compounds of formulas (a) and (b), where R is hydrogen, alkoxyl, R1- alkyl, alkoxyl, R2is hydrogen, alkyl, R3- alkyl, alkoxyl, X denotes N-R11or oxygen, R11means the free valence, Y represents N-R16, sulfur or alkyl, R16means hydrogen; other values radicals presented in the description of the invention

The invention relates to branched amino-thiazole, methods for their preparation and the pharmaceutical compositions

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of common formula IC1: , where A represents cyano; B represents hydrogen; R1, R2, R3 and R4 independently represent hydrogen; alkyl; halogen or nitro; R5 and R6 independently represent hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; heteroaryl; heteroarylalkyl; alkenyl; carboxyalkyl; cyanoalkyl; diphenylalkyl; aryl, arylalkoxyaryl, arylalkyl, arylalkylaryl, arylcarbonylaryl or aryloxyaryl, or R5 and R6, together with atom of nitrogen, to which they are connected, create heterocyclic ring system; or to salts of such compound; at the same time "heteroaryl" used separately or in combination, is related to mono-, bi- or tricyclic aromatic ring system, which contains up to 14 atoms included in ring, in which at least one ring contains at least one heteroatom, independently chosen from nitrogen, oxygen or sulfur, besides specified heteroaryl group may be unsubstituted or substituted with one to three substituents, independently selected from alkyl and alkoxy; "diphenylalkyl" is related to alkyl group, where each of two atoms of hydrogen is substituted with unsubstituted phenyl group; "aryl" is related to carbocyclic group, selected from group, which consists of phenyl, biphenyl, 1,2,3,4-tetrahydronaphthyl, naphthyl, antryl, phenantryl, fluorenyl, indanyl, 2,3-dihydrobenzo[1,4]dioxynyl and benzo[1,3]dioxolyl group, besides specified aryl group may be unnecessarily substituted with functional groups in number from one to three, which are separately and independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, cyano, halogen, halogenlkoxy, halogenalkyl and nitro groups, where in certain specific cases, if aryl group represents condensed system from several rings, in which not all the rings are aromatic, one of carbon atoms of which is not included into aromatic ring may be in oxidised condition, and according fragment of ring -CH2- will be substituted by fragment-C(O); "arylalkoxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkoxygroup, where aryl group is unsubstituted; "arylalkyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkyl group, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "aryloxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via oxygen bridge, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "arylcarbonyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via carbonyl group, where aryl group is unsubstituted; "heterocyclic ring system", used separately or in combination, is related to monocyclic, bicyclic or polycyclic ring system, which contains up to 15 atoms included into ring, at least one of which represents heteroatom, independently selected from nitrogen, oxygen or sulfur, besides specified ring system may be saturated, partially unsaturated, unsaturated or aromatic, where specified heterocyclic fragment may be unnecessarily substituted with one or more substituents, every of which separately and independently is selected from group made of halogen and halogenalkyl, excluding the following compounds: {3-[(E)-2-cyano-2-(4-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-m-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(3-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-phenylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-benzylcarbamoyl-2-cyanovinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-o-tolylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-t-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(4-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-ethylphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2~cyano-2-(4- ethoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-isopropylcarbamoylvinyl)indole-1-yl]acetic acid; {3-[(E)-2-cyano-2-(3-etoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-[[2-(1H-indole-3-yl)ethyl]amino]-3-oxo-1-propenyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-chlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-(4-methyl-piperidine-1-yl)-3-oxopropenyl]indole-1-yl}acetic acid; {3-[(E)-2-(3-chloro-4-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(3-phenylpropylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2,3-dichlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-(5-chloro-2-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxybenzylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; and {3-[(E)-2-cyano-3-oxo-3-(4-phenyl-piperazine-1-yl)propenyl]indole-1-yl}acetic acid. Invention is also related to pharmaceutical composition, and also to application of compounds of clause 1.

EFFECT: production of biologically active compounds, which have activity of antagonist coupled with G-protein of chemoattractant receptor of molecules homologue released by Th2-cells.

11 cl, 156 ex, 8 tbl

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