Octahydropentalene compounds as chemokine receptor antagonists

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula (I) or to its stereoisomers, or to a pharmaceutically acceptable salt, wherein Ra represents H or (C1-C6)alkyl; Rb is specified in an optionally substituted group consisting of -(CH2)n-aryl, -CH(CH3)-aryl, -(CH2)n-arylaryl, -(CH2)n-arylheteroaryl, -(CH2)n-(C3-C8) cycloalkyl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl and -(C3-C8) cycloalkylaryl; or Ra and Rb taken together with a nitrogen atom form 2,3-dihydro-1H-isoindolyl, decahydroisoquinolinyl, optionally substituted piperidinyl or optionally substituted pyrrolidinyl; Y is specified in an an optionally substituted group consisting of 5,6,7,8-tetrahydro[1,6]naphthyridinyl, -NH-(CH2)n-heterocyclyl, wherein NH is attached to carbonyl, and -heterocyclylaryl, wherein heterocyclyl is attached to carbonyl; and n is equal to 0, 1 or 2; wherein each heterocyclyl represents an independent non-aromatic ring system containing 3 to 12 ring atoms, and at least one ring atom specified in a group consisting of nitrogen, oxygen and sulphur; wherein each heteroaryl represents an independent non-aromatic ring system containing 3 to 12 ring atoms and at least one ring atom specified in a group consisting of nitrogen, oxygen and sulphur; and wherein the optional substitutes are independently specified in a group consisting of C1-C6-alkyl, C1-C6-alkoxy, halogen, CN, CF3, OCF3, NH2, NH(CH3), N(CH3)2, hydroxy, cyclohexyl, phenyl, pyrrolidinyl, -C(O)-piperidinyl, -N(H)-C(O)-C1-C6-alkyl and N(H)-S(O)2-C1-C6-alkyl. The invention also describes a pharmaceutical composition having chemokine receptor antagonist activity and a method of treating such diseases, such as rheumatoid arthritis, psoriasis, lupus, etc.

EFFECT: there are prepared and described new chemical compounds that can be used as chemokine receptor antagonists and, as such, may be used in treating certain pathological conditions and diseases, particularly inflammatory pathological conditions and diseases and proliferative disorders and conditions, eg rheumatoid arthritis, osteoarthritis, multiple sclerosis and asthma.

23 cl, 59 ex, 2 tbl

 

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the priority of provisional application U.S. serial No. 60/995148, filed September 25, 2007, the contents of which are included in this description.

The BACKGROUND TO the INVENTION

Chemokines are chemotactic cytokines that are released by a number of cells to attract leukocytes, such as macrophages, T cells, b cells, eosinophils, basophils and neutrophils in place and from places of inflammation, or within specific compartments, for example, lymph nodes (review presents the Schall, Cytokine, 3:165-183 (1991), Schall, et al., Curr. Opin. Immunol., 6:865 - 873 (1994) and Murphy, Rev. Immun., 12:593-633 (1994)). In addition to stimulating chemotaxis other changes can be selectively induced by chemokines in sensitive cells, including changing the shape of cells, transient increase in the concentration of intracellular free calcium ions ([Ca2+]), granular exocytosis, positive regulation of integrins, formation of bioactive lipids (e.g., leukotrienes), and oxidative burst associated with activation of leukocytes. Thus, chemokines are early modulators of the inflammatory response through the release of mediators of inflammation, chemotaxis and transudate in place of infection or inflammation.

Creatures of the em four classes of chemokines, CXC (α), CC (β), C (γ), and CX3C (δ), depending divided on whether the first two cysteines of one amino acid (C-X-C)are adjacent (C-C), have missed cysteine pair (C) or separated by three amino acids (CX3C). the α-chemokines, such as interleukin-8 (IL-8)protein stimulant activity of melanoma growth (MGSA) and factor 1 stromal cells (SDF-1) are hemotoxicity primarily for neutrophils and lymphocytes, whereas β-chemokines, such as RANTES, MIP-1α, MIP-1β, macrophage chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin are chemotactic for macrophages, T cells, eosinophils and basophils (Deng, et al., Nature, 381:661-666 (1996)). Chemokinesis lymphotactin C demonstrates specificity in relation to lymphocytes (Kelner, et al., Science, 266:1395-1399 (1994)), whereas CX3C chemokine, fractalkine shows specificity in respect of lymphocytes and monocytes (Bazan, et al., Nature, 385:640-644 (1997)).

Chemokines are associated with specific cell surface receptors belonging to the family of proteins associated with G-protein with seven transmembrane domains (review presented in Horuk, Trends Pharm. Sci., 15:159-165 (1994)), called "chemokine receptors". When the binding of cognate ligands, chemokine receptors transducer intracellular signal through the associated heterotrimeric G protein, which in result leads to a rapid increase in the concentration of nutriclean calcium. There are at least twelve chemokine receptors person that bind or respond to β-chemokines with the following characteristic profile: CCR1 (or "CKR-1" or "CC-CKR-1") MIP-1α, MIP-1β, MCP-3, RANTES (Ben-Barruch, et al., J. Biol. Chem., 270:22123-22128 (1995); Neote et al., Cell 72:415425 (1993)); CCR2A and CCR2B (or "CKR-2A"/"CKR-2A" or "CC-CKR-2A"/"CC-CKR2A") MCP-1, MCP-2, MCP-3, MCP-4; CCR3 (or "CKR-3" or "CC-CKR-3") eotaxin, RANTES, MCP; (Ponath, et al., J. Exp. Med., 183:2437-2448 (1996)); CCR4 (or "CKR-4" or "CC-CKR-4") TARC, MDC (Imai, et al., J. Biol. Chem., 273:1764-1768 (1998)); CCR5 (or "CKR-5" or "CC-CKR-5") MIP-1α, RANTES, MIP-1β; (Sanson, et al., Biochemistry, 35:3362-3367 (1996)); CCR6 MIP-3α (Greaves, et al., J. Exp. Med., 186:837-844 (1997)); CCR7 MIP-3β and 6Ckine (Campbell, et al., J. Cell. Biol., 141:1053-1059 (1998)); CCR8 I-309, HHV8 vMIP-I, HHV-8 vMIP-II, MCV vMCC-I (Dairaghi et al., J. Biol. Chem., 274:21569-21574 (1999)); CCR9 TECK (Zaballos et al., J. Immunol., 162:5671-5675 (1999)), D6 MIP-1 beta, RANTES, and MCP-3 (Nibbs et al., J. Biol. Chem., 272:32078-32083 (1997)), and antigen blood group Duffy RANTES, MCP-1 (Chaudhun, et al., J. Biol. Chem., 269:7835-7838 (1994)).

It was understood that the chemokine receptors such as CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CX3CR1 and XCR1, are important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.

Chemokinesis receptor CCR2 is expressed primarily in monocytes and activated T-lymphocytes, and its functional activity can be measured by the increase the cytosolic calcium or chemotaxis. CCR2 exists in two isoforms, CCR2A and CCR2B. These two isoforms are variants of alternative splicing of a single gene of the receptor for MCP-1 and differ only carboxykinase tails. Chromosomal localization of the gene CCR2 is located at 3p21. Ligands that have been identified as selective and high-affinity, are CC chemokines, MCP-1, MCP-2, MCP-3 and MCP-4.

The selective expression of CCR2 makes it an ideal target for exposure to interrupt inadequate directed migration of monocytes and T-cells. Clinical indications for such effects occur in inflammatory diseases mediated by T-cells in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, asthma, allergic reactions, chronic obstructive pulmonary disease, atherosclerosis, restenosis, diabetes type I and II, metabolic syndrome, and neuropathic pain. Ectopic expression of MCP-1 and CCR2 in certain tumors indicates that selective antagonists of CCR2 will have importance in immunotherapy of tumors, especially in reducing metastasis.

From the point of view of the clinical importance of CCR2 identification of compounds that modulate the function of CCR2, is attractive in the development of new therapeutic agents. Such compounds presented in this application.

The INVENTION

In the first embodiment, the present invention relates to the compound of formula (I)

Formula (I)

its pharmaceutically acceptable salts, prodrugs of biologically active metabolites or isomers, where

Rarepresents H or optionally substituted C1-C6)alkyl;

Rbselected from the optionally substituted group consisting of -(CH2)n-aryl, -CH(CH3)-aryl, -(CH2)n-arylaryl, -(CH2)n-arylheteroacetic, -(CH2)n-(C3-C8)cycloalkyl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl and -(C3-C8)cycloalkenyl; or

Raand Rbtaken together with the nitrogen atom, form a 2,3-dihydro-1H-isoindolyl, decahydroquinoline, optionally substituted piperidinyl or optionally substituted pyrrolidinyl;

Y is selected from the optionally substituted group consisting of 5,6,7,8-tetrahydro[1,6]nutrigenie, -NH-(CH2)n-heterocyclyl, where NH is attached to the carbonyl and-heterocyclisation where heterocyclyl attached to the carbonyl; and

n is 0, 1 or 2.

In the second embodiment, the present invention relates to a compound corresponding to the above variant implementation, where Y is selected from the optional is tion substituted group, consisting of 5,6,7,8-tetrahydro[1,6]nutrigenie, -NH-(CH2)2-pyrrolidinyl and-piperazineethanol.

In the third embodiment, the invention relates to a compound according to any of the above embodiments, where Rarepresents H or methyl.

In the fourth embodiment, the invention relates to a compound according to any of the above embodiments, where Rbselected from the optionally substituted group consisting of-CH2-phenyl, -CH2-phenylphenyl, -(CH2)2-phenyl, -CH(CH3)-phenyl, -CH2CH2-phenylphenyl, -CH2-phenylpyrazole, phenylpyrazole, indanyl, -(CH2)2indolyl, 1,2,3,4-tetrahydronaphthyl, -(CH2)-pyrazinyl, -(CH2-pyridinyl, -(CH2)2-pyridinyl, -(CH2)2-pyrrolidinyl, -(CH2)2-tanila, tetrahydrothieno-1,1-dioxide, -(CH2)2-piperidinyl, tetrahydropyranyl and-cyclohexylphenol.

In the fifth embodiment, the present invention relates to a compound according to any of the above embodiments, where Rbselected from the optionally substituted group consisting of-CH2-phenyl, -(CH2)2-phenyl, -CH2-phenylpyrazole, indanyl, -(CH2)2indolyl, 1,2,3,-tetrahydronaphthyl, -(CH2)2-pyridinyl and-cyclohexylphenol.

In the sixth embodiment, the invention relates to a compound according to any of the above embodiments, where Y is selected from the optionally substituted group consisting of 5,6,7,8-tetrahydro[1,6]naphthyridine and-piperazineethanol.

In the seventh embodiment, the invention relates to a compound according to any of the above embodiments, where Rbselected from the optionally substituted group consisting of-CH2-phenyl, -(CH2)2-phenyl, 1,2,3,4-tetrahydronaphthyl, -CH2-phenylpyrazole, indanyl, -(CH2)2-pyridinyl and-cyclohexylphenol.

In the eighth embodiment, the invention relates to a compound according to any of the above embodiments, where Rbselected from the optionally substituted group consisting of-CH2-phenyl, 1,2,3,4-tetrahydronaphthyl and-cyclohexylphenol.

In the ninth embodiment, the invention relates to a compound according to any of the above embodiments, where Rboptionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, CN, OH, CF3, OCF3, NH2, NH(CH3) and N(CH3)2

In the tenth embodiment, the invention relates to a compound according to any of the above embodiments, where Y is optionally substituted CF3.

In the eleventh embodiment, the invention relates to a compound according to any of the above embodiments, where Raand Rbtaken together with the nitrogen atom, form a 2,3-dihydro-1H-isoindolyl, 5,6,7,8-tetrahydro[1,6]naphthyridine, optionally substituted piperidinyl or optionally substituted pyrrolidinyl.

In the twelfth embodiment, the present invention relates to a connection in accordance with the eleventh embodiment, where optionally substituted piperidinyl or optionally substituted pyrrolidinyl optionally substituted by substituents selected from the group consisting of optionally substituted cyclohexyl, and optionally substituted phenyl.

In the thirteenth embodiment, the invention relates to a compound according to any of the above embodiments, where Y is optionally substituted 5,6,7,8-tetrahydro[1,6]naphthyridine.

In the fourteenth embodiment, the present invention relates to a connection in accordance with the thirteenth embodiment, where optionally substituted PIP is retinyl substituted by optionally substituted phenyl or optionally substituted pyrrolidinyl.

In the fifteenth embodiment, the present invention relates to a connection in accordance with the fourteenth embodiment, where optionally substituted piperidinyl substituted optionally substituted by pyrrolidinyl.

In the sixteenth embodiment, the present invention relates to a connection in accordance with the fourteenth embodiment, where optionally substituted piperidinyl substituted by optionally substituted phenyl.

In the seventeenth embodiment, the present invention relates to a connection in accordance with the twelfth embodiment, where optionally substituted pyrrolidinyl substituted by an optionally substituted cyclohexyl.

In the eighteenth embodiment, the invention relates to a method of treating a condition in a patient, introducing a specified patient a therapeutically effective amount of a compound according to paragraph 1 or its physiologically acceptable salts, where the specified condition selected from the group consisting of rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease, sepsis, psoriasis, psoriatic arthritis, inflammatory bowel disease, Crohn's disease, lupus, multiple sclerosis, juvenile chronic arthritis, Lyme arthritis, reactive ar is Rita, septic arthritis, spondyloarthropathy, systemic lupus erythematosus, diseases of the eye, malignancies, solid tumors, fibrosarcoma, osteomas, melanoma, retinoblastoma, a rhabdomyosarcoma, glioblastoma, neuroblastoma, teratocarcinoma, malignant tumors, for example, lung, breast, stomach, bladder, colon, pancreas, ovarian, prostate and rectal cancer and malignant diseases of the blood (leukemia and lymphoma), abetalipoproteinemia, acrocyanosis, acute and chronic parasitic or infectious processes, acute leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infection, acute pancreatitis, acute renal failure, adenocarcinomas, aerial ectopic beats, AIDS dementia, alcoholic hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, deficiency of alpha-1 antitrypsin deficiency, amyotrophic lateral sclerosis, anemia, angina, cellular degeneration of the anterior horn of the spinal cord, anti cd3 therapy, antiphospholipid syndrome, antireceptor hypersensitivity reactions, hypersensitivity reactions, disorders of movements by type of hyperkinesis, exogenous allergic ALV the Olite hypertension, disorders of movements by type of hypokinesis, aortic and peripheral aneurysms, evaluation of the hypothalamic-pituitary-adrenal axis, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia, spenomegaly degenerations, streptococcal myositis, structural lesions of the cerebellum, subacute sclerosing anacephalic, fainting, syphilitic lesions of the cardiovascular system, systemic anaphylaxis, system inflammatory response syndrome, systemic manifestations of juvenile rheumatoid arthritis, T-cell or FAB ALL, telangiectasia, obliterating thromboangiitis, transplants, trauma/hemorrhage, hypersensitivity reactions type III, hypersensitivity type IV, unstable angina, uraemia, urosepsis, rash, heart disease, varicose veins, vasculitis, venous disease, venous thrombosis, ventricular fibrillation, viral and fungal infections, vital encephalitis/aseptic meningitis, hemophagocytic syndrome associated with vital functions, syndrome Wernicke-Korsakov, Wilson's disease, transplant rejection of any organ or tissue, atrial fibrillation (sustained or paroxysmal), atrial flutter, atrioventricular blockade, B-cell lymphoma, rejection to the bone graft, rejection of bone marrow transplant (BMT), transplant rejection small intestine, spinal ataxia, blockade feet beam gissa, Burkitt lymphoma, burns, cardiac arrhythmias, syndrome postischemic disorders of contractile function of the myocardium, heart tumors, cardiomyopathy, inflammatory response to cardiopulmonary bypass, rejection, cartilage transplant, cerebellar cortical degeneration, dysfunction of the cerebellum, chaotic or multifocal atrial tachycardia, disturbances associated with chemotherapy, chronic myeloid leukemia, chronic alcoholism, chronic inflammatory pathologies, chronic lymphocytic leukemia, chronic poisoning by salicylates, colorectal carcinoma, congestive heart failure, conjunctivitis, pulmonary heart, coronary artery disease, disease of Creutzfeldt-Jakob disease, culture negative sepsis, cystic fibrosis, disorders associated with therapy with cytokines, dementia boxers, demyelinating disease, hemolytic of dengue fever, dermatitis, pathological conditions of the skin, diabetic arteriosclerotic disease, diffuse Taurus Levi, dilatational congestive cardiomyopathy, disorders of the basal ganglia, down's syndrome in adulthood, drug induced and means of movement disorders, induced by drugs which block dopamine receptors in CNS sensitivity to the drug, eczema, encephalomyelitis, endocarditis, endocrinopathy, epiglottitis, infection with Epstein-Barr, erythromelalgia, extrapyramidal and cerebellar disorders, family hematopoietins lymphocytic histiocytosis, rejection of the implant embryonic thymus, frda, disorders of the peripheral arteries, fungal sepsis, gas gangrene, gastric ulcers, glomerulonephritis, gram-negative sepsis, gram positive sepsis, granulomas due to intracellular organisms, hairy cell leukemia, a disease Hallervorden-Space, hay fever, rejection, heart transplant, hemachromatosis, hemodialysis, hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, hemorrhage, idiopathic pulmonary fibrosis antibody-mediated cytotoxicity, asthenia, pediatric spinal muscular atrophy, inflammation of the aorta, influenza A, effects of ionizing radiation, iridocyclitis/uveitis/optic neuritis, rheumatoid arthritis, juvenile spinal muscular atrophy, kidney transplant rejection, Legionella, leishmaniasis, lipedema, exclusion of hepatic t is antata, lymphedema, malaria, malignant lymphoma, malignant histiocytosis, malignant melanoma, meningococcemia, metabolic/idiopathic, headaches and migraines, mitochondrial multi-system disorders, monoclonal gammopathy, multiple myeloma, multiple-system degenerations (Mencel Dejerine - Thomas Shi-Drager and Machado-Joseph), myasthenia gravis, intracellular Mycobacterium avium, Mycobacterium tuberculosis, myelodysplasia syndrome, ischemic disorders of the myocardium, carcinoma of the nasopharynx, chronic lung disease of the newborn, nephritis, nephrosis, neurodegenerative diseases, neurogenic muscular dystrophies I neurotically fever, non-Hodgkin's lymphoma, occlusion of the abdominal aorta and its branches, occlusive arterial disorders, okt3 therapy, orchitis/epidemica, orchitis/vasectomy procedures of feedback, organomegaly, osteoporosis, rejection, pancreatic transplant, carcinoma of the pancreas, paraneoplastic syndrome/malignant hypercalcemia, parathyroid transplant rejection cancer, inflammatory diseases of the pelvic organs, chronic rhinitis, diseases of the pericardium, Kaposi's sarcoma, Hodgkin's disease, lymphoma, myeloma, leukemia, malignant ascites, malignant diseases of the hematopoietic system, syndrome Crow-Fukase (POEMS) (pollinaria the AI, organomegaly, endocrinopathy, monoclonal gammopathy, and syndrome of skin changes), diabetic pathologies, such as glaucoma in insulin-dependent diabetes mellitus, diabetic retinopathy or microangiopathy, sickle cell anemia, chronic inflammation, synovitis, glomerulonephritis, transplant rejection, Lyme disease, diseases of Hippel-Lindau, pemphigoid, Paget's disease, fibrosis, sarcoidosis, cirrhosis, Hashimoto, syndrome of increased viscosity of the blood, diseases of Rendu-Weber-Osler, chronic obstructive lung disease, asthma or edema after burns, trauma, radiation, stroke, hypoxia, ischemia, ovarian hyperstimulation syndrome ovarian postperfusion syndrome, postinfuzionnaya syndrome, post-MI kardiogennogo syndrome, pre-eclampsia, menometrorrhagia, endometriosis, pulmonary hypertension, hemangioma younger children, or infection by Herpes simplex, Herpes Zoster, human immunodeficiency virus, parapoxvirus, protozoa or Toxoplasma, progressive supranuclear palsy, primary pulmonary hypertension, radiation therapy, phenomenon and disease, Raynaud's disease, diseases of Resume usual tachycardia with narrow QRS complexes, pochechnokamennoy hypertension, restrictive cardiomyopathy, sarcomas, senile horei, senile dementia type Taurus Levi, shock, skin allotransplant ntata, syndrome, skin changes, swelling of the optic nerve or macular edema, neovascular eye disease, scleritis, radial keratotomy, uveitis, inflammation of the vitreous body, myopia, congenital holes in the optic nerve, chronic retinal detachment, complications after laser treatment, eye disease, Stargardt, disease ILSA, retinopathy, macular degeneration, restenosis, ischemia/reperfusion injury, ischemic stroke, occlusion of vessels, obstruction of the carotid arteries, ulcerative colitis, inflammatory bowel disease, diabetes, diabetes mellitus, insulin-dependent diabetes mellitus, allergic diseases, dermatitis scleroderma, a disease graft vs. host rejection of organ transplant (including, but not limited to, transplant rejection, bone marrow and solid organs), acute or chronic immune disease associated with organ transplantation, sarcoidosis, disseminated intravascular coagulation, Kawasaki disease, nephrotic syndrome, chronic fatigue syndrome, Wegener granulomatosis, purpura's disease-Seleina, microscopic vasculitis of the kidneys, chronic active hepatitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexy is, infectious diseases, parasitic diseases, acquired immunodeficiency syndrome, acute transverse myelitis, Horai Huntington, stroke, primary biliary cirrhosis, hemolytic anemia, malignancies, Addison's disease, idiopathic Addison's disease, sporadic, polyglandular deficiency type I and polyglandular deficiency type II syndrome Schmidt (acute) respiratory distress syndrome of adults, alopecia, alopecia areata, seronegative arthropathy, arthropathy, disease, Reiter, psoriaticescoy arthropathy, arthropathy in ulcerative colitis, enteropathic synovitis, chlamydia, yersiniosis and Salmonella arthropathies, atheromatous disease/arteriosclerosis, atopic Allergy, autoimmune bullous diseases, common water, leaf water, pemphigoid, disease, linear IgA, autoimmune haemolytic anaemia, Coombs positive haemolytic anaemia, acquired pernicious anaemia, juvenile perniciosi anemia, disorders of the peripheral vessels, peritonitis, pernicious anaemia, myalgic encephalitis/chronic fatigue syndrome, chronic candidiasis of skin and mucous membranes, giant cell arteritis diagnostics, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, syndromediabetologia immunodeficiency, diseases associated with acquired immunodeficiency syndrome, hepatitis A, hepatitis B, hepatitis C, arrhythmia associated with blockade bundle branch, HIV infection/HIV neuropathy, common variable immunodeficiency (common variable hypogammaglobulinemia), dilatational cardiomyopathy, female infertility, ovarian function decline, premature ovarian function decline, fibrotic lung disease, prolonged wound healing, cryptogenic fibrosing alveolitis, post-infectious interstitial lung disease, interstitial pneumonitis, Pneumocystis pneumonia, pneumonia, interstitial lung disease associated with disease of connective tissue, lung disease associated with mixed connective tissue disease interstitial lung disease associated with systemic sclerosis, interstitial lung disease associated with rheumatoid arthritis, lung disease associated with systemic lupus erythematosus, lung diseases associated with dermatomyositis/polymyositis, lung diseases that are associated with disease Sjogren's syndrome, lung disease associated with ankylosing spondylitis, vesselinova diffuse lung, lung diseases associated with hemosiderosis, interstitial lung disease induced by drugs, radiation fibrosis, oblitera the ith bronchiolitis, chronic eosinophilic pneumonia, lymphocytic infiltrates of the lung disease, post-infectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, autoimmune hepatitis (classical autoimmune or anti-hepatitis type 1, autoimmune hepatitis (anti-LKM or antibody-based test hepatitis type-2, autoimmune hypoglycemia, insulin resistance In type acanthocardia, hypoparathyroidism, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, osteoarthrosis, primary sclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathic leukopenia, autoimmune neutropenia, NOS renal failure, glomerulonephritis, microscopic vasculitis of the kidneys, Lyme disease, discoid lupus erythematosus, male infertility idiopathic or NOS, autoimmunity to sperm, multiple sclerosis (all subtypes), sympathetic OFTAL, secondary pulmonary hypertension due to connective tissue disease, acute and chronic pain (different forms of pain)syndrome?, pulmonary manifestations of periarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, of still's disease, systemic sclerosis, sin is Roma Sjogren, disease, Takayasu's disease/arteritis, autoimmune thrombocytopenia, toxicity, transplants, idiopathic thrombocytopenia, autoimmune thyroid disease, hyperthyroidism, goitrous autoimmune hypothyroidism (Hashimoto's disease,), atrophic autoimmune hypothyroidism, primary myxedema, patogennogo uveitis, primary vasculitis, vitiligo, acute liver disease, chronic liver diseases, alcoholic cirrhosis, alcohol-induced liver injury, cholestasis, allergic liver disease, drug induced hepatitis, non-alcoholic steatohepatitis, Allergy and asthma, streptococcal infection group, mental diseases (e.g., depression and schizophrenia), diseases mediated Th2 and Th1, and diseases, leading to inappropriate vascularization for example diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, hemangioma children of younger age in people. In addition, such compounds can be used in the treatment of such disorders as ascites, effusions, exudates, including, for example, macular edema, cerebral edema, acute lung damage, respiratory distress syndrome of adults, proliferative disorders such as restenosis, fibrotic diseases, such as cirrhosis of the liver and at rocklers, mesangial cell proliferative disorders, such as diabetic nephropathy, malignant nephrosclerosis, syndromes, thrombotic microangiopathy, and glomerulopathy, myocardial angiogenesis, coronary and cerebral collaterals, ischemic angiogenesis limb ischemia/reperfusion damage, peptide ulcers, diseases associated with Helicobacter, angiogenic disorders induced by viruses, preeclampsia, menometrorrhagia, disease, cat scratching, redness, neovascular glaucoma and retinopathy, such as diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, acute idiopathic polyneuritis, acute or chronic immune disease associated with organ transplantation, acute inflammatory demyelinative polyradiculoneuropathy, acute ischemia of still's disease in adults, allergies, anaphylaxis, syndrome antiphospholipid antibodies, aplastic anemia, atopic eczema, atopic dermatitis, autoimmune dermatitis, autoimmune diabetes, autoimmune disorder associated with Streptococcus infection, autoimmune enteropathy, autoimmune hepatitis, autoimmune hearing loss, autoimmune lymphoproliferative syndrome, autoimmune myocarditis, autoimmune the th neutropenia, autoimmune premature ovarian function decline, autoimmune thrombocytopenia, autoimmune uveitis, diseases behceta, blepharitis, bronchiectasia, medical pemphigoid, catastrophic antiphospholipid syndrome, celiac disease, cervical spondylosis, chronic ischemia, cicatricial pemphigoid, selected clinical syndrome with the risk of developing multiple sclerosis, manifested in childhood mental disorders, dacryocystitis, dermatomyositis, herniated intervertebral disc prolapse intervertebral disc induced by drugs immune hemolytic anemia, endophthalmitis, episcleritis, polymorphic erythema, large, polymorphic erythema, gestational pemphigoid syndrome Guillain-Barr, heart failure, Hughes syndrome, idiopathic Parkinson's disease, idiopathic interstitial pneumonia, IgE-mediated allergies, immune hemolytic anemia, myopathy enabled cells, infectious and inflammatory eye diseases, infectious demyelinating disease, inflammatory heart disease, inflammatory kidney disease, IPF/UIP, inflammation of the iris of the eye, keratitis, dry keratoconjunctivitis, disease, Kussmaul or illness, Kussmaul-Meier, paralysis Landry, histiocytosis Langerhans cells, the mesh is th marble skin, microscopic polyangiitis, Bechterew disease, disorders of motor neurons, pemphigoid mucosa, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, back-and-remitting multiple sclerosis, multiple organ failure, myelodysplastic syndrome, disorders of nerve roots, neuropathy, hepatitis And no, no, osteolysis, ovarian cancer, oligosaccharide JRA, occlusive peripheral artery disease (PAOD), peripheral vascular disease (PVD), peripheral artery disease, phlebitis, polyandria, rheumatic polymyalgia, bloom, policosanol JRA syndrome polyendocrine failure, polymyositis, postperfusion syndrome, primary parkinsonism, prostatitis, psoriatic arthropathy, true red cell aplasia, primary adrenal insufficiency, disease, Reiter, recurrent optionality, rheumatic heart disease, SAPHO (synovitis, acne, pustular rash, hyperstat and esteit), scleroderma, secondary amyloidosis, shock lung, sciatica, secondary adrenal insufficiency, septic arthritis, seronegative arthropathies, connective tissue diseases associated with silicon-containing substances, dermatosis of Sneddon-is lkinson, ankylosing spondylitis, and syndrome of Stevens-Johnson syndrome systemic inflammatory response, temporal arteritis, toxoplasmosis retinitis, toxic epidermal necrolysis, TRAPS (receptor tumor necrosis factor), allergic reactions (type 1, type II diabetes, urticaria, usual interstitial pneumonia, vernal conjunctivitis, spring pigmentosa syndrome Vogt-Koyanagi-Harada (VKH syndrome) and wet macular degeneration.

In the nineteenth embodiment, the present invention relates to a method in accordance with the nineteenth embodiment, where the pathological condition is selected from the group consisting of rheumatoid arthritis, osteoarthritis, asthma and multiple sclerosis.

In the twentieth embodiment, the present invention relates to pharmaceutical compositions containing a compound of the formula (I)

Formula (I)

and pharmaceutically acceptable carrier or excipient, where

Rarepresents H or optionally substituted C1-C6)alkyl;

Rbselected from the optionally substituted group consisting of -(CH2)n-aryl, -CH(CH3)-aryl, -(CH2)n-arylaryl, -(CH2)n-arylheteroacetic, -(CH2)n-(C3-C8)cycloalkyl, -(CH2)n-heteroaryl -(CH 2)n-heterocyclyl and -(C3-C8)cycloalkenyl; or

Raand Rbtaken together with the nitrogen atom, form a 2,3-dihydro-1H-isoindolyl, decahydroquinoline, optionally substituted piperidinyl or optionally substituted pyrrolidinyl;

Y is selected from the optionally substituted group consisting of 5,6,7,8-tetrahydro[1,6]nutrigenie, -NH-(CH2)n-heterocyclyl, where NH is attached to the carbonyl and-heterocyclisation where heterocyclyl attached to the carbonyl; and

n is 0, 1 or 2.

DETAILED description of the INVENTION

In the corresponding aspect of the present invention relates to a method antagonistic effect on CCR2 patient person suffering from a disorder in which the activity of CCR2 has a deleterious effect on health, introducing the patient to the person of the compounds of formula (I)

Formula (I)

thus, to inhibit the activity of CCR2 in a patient person and carry out the treatment.

Many autoimmune diseases and diseases associated with chronic inflammation and acute reactions have been associated with activation of CCR2. These compounds are suitable for the treatment of inflammatory diseases, including rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease (COPD), sepsi is, psoriasis, psoriatic arthritis, inflammatory bowel disease, Crohn's Disease, lupus, multiple sclerosis, juvenile chronic arthritis, Lyme arthritis, reactive arthritis, septic arthritis, spondyloarthropathy and systemic lupus erythematosus, but not limited to them.

Compounds according to the invention are also suitable for the treatment of cardiovascular disorders such as acute myocardial infarction, acute coronary syndrome, chronic heart failure, atherosclerosis, viral myocarditis, rejection serdechno allograft and associated with sepsis dysfunction of the heart. Moreover, the compounds of the present invention is also applicable to the treatment of disorders of the Central nervous system, such as meningococcal meningitis, Alzheimer's disease and Parkinson's disease.

The compound of formula (I) and its pharmaceutically acceptable salts or pharmaceutical compositions containing a therapeutically effective amount applicable for the treatment of disorders selected from the group including CNS disorders, arthritis, rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, and septic arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insul nesavisimy diabetes, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis scleroderma, a disease of the "graft vs. host rejection of organ transplant (including, but not limited to, transplant rejection, bone MoH and solid organs), acute or chronic immune disease associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki disease, graves ' disease, nephrotic syndrome, chronic fatigue syndrome, granulomatous's granulomatosis, purple's disease-Seleina, microscopic vasculitis of the kidneys, chronic active hepatitis, uveitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, infectious diseases, parasitic diseases, acquired immunodeficiency syndrome, acute transverse myelitis, horey Huntington's, Parkinson's disease, Alzheimer's disease, stroke, primary biliary cirrhosis, hemolytic anemia, malignant disease, heart failure, myocardial infarction, Addison's disease, sporadic, polyglandular deficiency type I and polyglandular deficiency type II syndrome Schmidt (acute) respiratory distress syndrome of adults, alopecia, alopecia alopecia, the seronegative arthropathy, arthropathy, disease, Reiter, PS is ariations the arthropathy, the arthropathy in ulcerative colitis, enteropathic synovitis, chlamydia, iersinioz and salmonellosis arthropathy, atheromatous disease/arteriosclerosis, atopic Allergy, autoimmune bullous disease, common bladderwort, the leaf bladderwort, pemphigoid, disease, linear IgA, autoimmune haemolytic anaemia, Coombs positive haemolytic anaemia, acquired pernicious anaemia, juvenile pernicious anaemia, myalgic encephalitis/chronic fatigue syndrome, chronic candidiasis of the skin and mucous membranes, giant cell arteritis diagnostics, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, acquired immunodeficiency syndrome, diseases associated with acquired immunodeficiency syndrome, hepatitis B, hepatitis C, common variable immunodeficiency (common variable gipogammaglobulinemia), dilatation cardiomyopathy, female infertility, loss of ovarian function, premature loss of ovarian function, fibrotic lung disease, prolonged wound healing, cryptogenic fibrosing alveolitis, post-infectious interstitial lung disease, interstitial pneumonitis, interstitial lung disease associated with disease of connective tissue, lung disease, and is associated with mixed disease of connective tissue, intersti the territorial lung disease, associated with systemic sclerosis, interstitial lung disease associated with rheumatoid arthritis, interstitial lung disease associated with systemic lupus erythematosus, interstitial lung disease associated with dermatomyositis/polymyositis, interstitial lung disease associated with disease Sjogren's syndrome, lung disease associated with ankylosing spondylitis, masculine diffuse lung damage, lung disease associated with hemosiderosis, interstitial lung disease induced by drugs, radiation fibrosis, obliterative bronchiolitis, chronic eosinophilic pneumonia, lymphocytic infiltrates of the lung disease, post-infectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type-1 autoimmune hepatitis (classical autoimmune or anti-hepatitis), type-2 autoimmune hepatitis (anti-LKM or antibody-based test hepatitis), autoimmune hypoglycemia, insulin resistance In type acanthocardia, hypoparathyroidism, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, osteoarthrosis, primary sclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathic leukopenia, autoimmune neutropenia, NOS renal week is statusnote, glomerulonephritis, microscopic vasculitis of the kidneys, Lyme disease, discoid lupus erythematosus, male infertility idiopathic or NOS, autoimmune response to spermatozoa, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary due to connective tissue disease syndrome?, pulmonary manifestation of periarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, of still's disease, systemic sclerosis, Sjogren syndrome, Takayasu's disease/arteric, autoimmune thrombocytopenia, idiopathic thrombocytopenia, autoimmune thyroid disease, hyperthyroidism, goitrous autoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxoedema, phacogenic uveitis, primary vasculitis, vitiligo, acute liver disease, chronic liver disease, alcoholic cirrhosis, alcohol-induced liver disease, cholestasis, allergic liver disease, drug-induced hepatitis, non-alcoholic steatohepatitis, Allergy and asthma, streptococcal infection group B (GBS), mental illness (such as depression and schizophrenia), diseases mediated Th2 and Th1, acute and chronic pain (different forms of pain), and malignant neoplasms, for example, lung, breast, stomach, bladder, is Chechnya, pancreas, ovarian, prostate and rectal cancer and hematopoietic diseases (leukemia and lymphoma), and hematopoietic malignant diseases (leukemia and lymphoma), abetalipoproteinemia, acrocyanosis, acute and chronic parasitic or infectious processes, acute leukemia, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute or chronic bacterial infection, acute pancreatitis, acute renal failure, adenocarcinoma, aerial ectopic beats, complex, AIDS-dementia, alcohol-induced hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allograft rejection, alpha deficiency-l-antitrypsin deficiency, amyotrophic lateral sclerosis, anemia, angina, cellular degeneration of the anterior horn of the spinal cord, anti cd3 therapy, antiphospholipid syndrome, antireceptor hypersensitivity reactions, aortic and peripheral vascular, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia, atrial fibrillation (sustained or paroxysmal), atrial flutter, atrioventricular blockade, B cell lymphoma, rejection, bone graft rejection of bone marrow transplant (BMT), the blockade of the leg beam gissa, Burkitt's lymphoma,burns, heart arrhythmia syndrome postischemic disorders of contractile function of the myocardium, tumors of the heart, cardiomyopathy, inflammatory response to cardiopulmonary bypass, the rejection of the cartilage graft, cerebellar cortical degeneration, dysfunction of the cerebellum, chaotic or multifocal atrial tachycardia, disturbances associated with chemotherapy, chronic myelogenous leukemia (CML), chronic alcoholism, chronic inflammatory pathologies, chronic lymphocytic leukemia (CLL), chronic obstructive pulmonary disease (COPD), chronic poisoning by salicylates, colorectal carcinoma, congestive heart failure, conjunctivitis, contact dermatitis, pulmonary heart disease coronary artery disease Creutzfeld-Jakob disease, culture negative sepsis, cystic fibrosis, disorders associated with therapy with cytokines, dementia boxers, demyelinating diseases, hemolytic dengue fever, dermatitis, pathological skin conditions, diabetes, diabetes mellitus, diabetic arteriosclerotic disease, the disease is diffuse Taurus Levi, dilatational congestive cardiomyopathy, disorders of the basal ganglia, down's syndrome in adulthood, induced by drugs of movement disorders induced by drugs which which block dopamine receptors in the Central nervous system, sensitivity to drug, eczema, encephalomyelitis, endocarditis, endocrinopathy, epiglottitis, infection with Epstein-Barr, erythromelalgia, extrapyramidal and cerebellar disorders, family hematopoietically lymphocytic histiocytosis, rejection of the implant embryonic thymus, frda, disorders of the peripheral arteries, fungal sepsis, gas gangrene, gastric ulcer, glomerulonephritis, graft rejection of any organ or tissue, gram negative sepsis, gram positive sepsis, granules due to intracellular organisms, hairy cell leukemia, a disease Hallervorden-Space, thyroiditis Hashimoto, hay fever, rejection of a heart transplant, hemachromatosis, hemodialysis, hemolytic uremic syndrome/thrombolytic thrombocytopenic purple, hemorrhage, hepatitis (A), arrhythmia related to blockade bundle branch, HIV infection/HIV neuropathy, Hodgkin's disease, disorders of movements by type of hyperkinesis, hypersensitivity reactions, exogenous allergic alveolitis, hypertension, disorders of movements by type of hypokinesis, evaluation of the hypothalamic-pituitary-adrenal axis, idiopathic Addison disease, idiopathic pulmonary fibrosis antibody-mediated cytotoxicity, asthenia, baby spinline the muscle atrophy inflammation of the aorta, influenza a, ionizing radiation, iridocyclitis/uveitis/optic neuritis, ischemia-reperfusion injury, ischemic stroke, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma, kidney transplant rejection, Legionella, leishmaniasis, leprosy, lesions of corticospinal system, lipedema, rejection liver transplant, lymphedema, malaria, malignant lymphoma, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, metabolic/idiopathic headache in migraine headache, mitochondrial multi-system violation, mixed disease of connective tissue, the monoclonal gammopathy, multiple myeloma, multi-system degeneration (Mencel Dejerine-Thomas Shi-Drager and Machado-Joseph), myasthenia gravis, intracellular Mycobacterium avium, Mycobacterium tuberculosis, myelodysplasia syndrome, myocardial infarction, ischemic disorders of the myocardium, carcinoma of the nasopharynx, chronic lung disease in newborns, nephritis, nephrosis, neurodegenerative diseases, neurogenic muscular dystrophy I neyroopticheskoe fever, nahodkinskuju lymphoma, occlusion of the abdominal aorta and its branches, occlusive arterial disorders, okt3 therapy, orchitis/epidemic, orchitis/procedure reverse vasectomy, organomegaly the Oia, osteoporosis, pancreatic rejection of the transplant, carcinoma of the pancreas, paraneoplastic syndrome/malignant hypercalcemia, graft rejection parathyroid glands, inflammatory disease of the pelvic organs, chronic rhinitis, diseases of the pericardium, peripheral atherosclerotic disease, disorder peripheral vascular, peritonitis, pernicious anemia, Pneumocystis pneumonia, pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and the syndrome of skin changes), postperfusion syndrome, post-MI cardiotomy syndrome, preeclampsia, progressive supranuclear palsy, primary pulmonary hypertension, radiation terapiya, phenomenon and Raynaud's disease, Raynaud's disease, a disease of Resume usual tachycardia with narrow QRS complexes, pochechnokamennoy hypertension, reperfusion injury, restrictive cardiomyopathy, sarcomas, scleroderma, senile horey, senile dementia type Taurus Levi, seronegative arthropathies, shock, sickle cell anemia, skin allograft rejection syndrome skin changes, graft rejection of the small intestine, solid tumors, specific arrhythmias, spinal ataxia, spenomegaly degeneration, streptococcal myositis, structural lesions of the cerebellum, p is destry sclerosing anacephalic, fainting, syphilitic lesions of the cardiovascular system, systemic anaphylaxis, the system inflammatory response syndrome, systemic manifestations of juvenile rheumatoid arthritis, T-cell or FAB ALL, telangiectasia, obliterating thromboangiitis, thrombocytopenia, toxicity, transplants, trauma/hemorrhage, hypersensitivity reactions type III, hypersensitivity type IV, unstable angina, uremia, urosepsis, hives, heart disease, varicose veins, vasculitis, vein disease, venous thrombosis, ventricular fibrillation, viral and fungal infections, vital encephalitis/aseptic meningitis, hemophagocytosis syndrome associated with vital functions syndrome Wernicke-Korsakov, Wilson's disease, graft rejection of any organ or tissue, and disease, leading to inappropriate vascularization for example diabetic retinopathy, retinopathy of prematurity, the choroidal neovascularization due to age-related macular degeneration, hemangioma children of younger age in people. In addition, such compounds can be used in the treatment for disorders such as edema, ascites, effusions, and exudate, including, for example, macular edema, cerebral edema, acute lung damage, respiratory distress syndrome in adults (ARDS), proliferative disorders, such is as restenosis, fibrotic diseases such as liver cirrhosis and atherosclerosis, mesangial cell proliferative disorders, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic syndromes microangiopathy, glomerulopathy, myocardial angiogenesis, coronary and cerebral collaterals, ischemic angiogenesis limb ischemia/reperfusion damage, peptide ulcers, diseases associated with Helicobacter, angiogenic disorders induced by viruses, syndrome Crow-Fukase (POEMS), pre-eclampsia, menometrorrhagia, disease, cat scratching, redness, neovascular glaucoma and retinopathy, such as diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration disorders of the Central nervous system. In addition, these compounds can be used as active agents against solid tumors, malignant ascites, disease Hippel-Lindau, malignant diseases of the hematopoietic system and hyperproliferative disorders such as thyroid hyperplasia (especially graves ' disease), and cysts (for example, hypervascularization ovarian stroma characteristic of polycystic ovarian syndrome (Stein-Leventhal) and polycystic kidney disease, because such diseases need to be Strait is perezii cells of blood vessels for growth and/or metastasis.

The compounds of formula (I) according to the invention can be used alone or in combination with another therapeutic agent for the treatment of diseases such specified additional tool is selected by an experienced technician for the designated purpose. For example, the additional agent can be a therapeutic agent known in this area as suitable for treatment of the disease or condition that is treated by the compound of the present invention. Additional means may be a tool that gives a favorable property of therapeutic composition, for example a tool that affects the viscosity of the composition.

Next should be understood that combinations, which are included in the present invention are a combination suitable for the intended purpose. The tools presented below, illustrate these purposes and are not intended to be limiting. Combinations, which are part of the present invention may be a compound of the present invention and at least one additional agent selected from the list below. This combination may also include more than one additional tools, such as two or three additional funds, if this combination is such that the resulting composition may do as much as possible is to take the specified function.

For example, in the treatment or prevention of inflammation, the compounds of the present invention can be used in combination or in combination with anti-inflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, an inhibitor of cyclooxygenase, such as an inhibitor of cyclooxygenase-2, an inhibitor of interleukin, such as an inhibitor of interleukin 1, a NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal anti-inflammatory agent, or a cytokine-suppressive anti-inflammatory agent, for example, a compound such as acetaminophen, aspirin, codeine, fentanyl, ibuprofen, indomethacin, Ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sulindac, tenidap and the like. Similarly, compounds of the present invention can be used to enter analgesic; potentiating agent, such as caffeine, an H2 antagonist, simethicone, aluminum hydroxide or magnesium; decongestants such as phenylephrine, phenylpropanolamine, pseudoephedrine, Oxymetazoline, epinephrine, nafazolina, Xylometazoline, propylhexedrine or left-deoxy-ephedrine; remedy against cough, such as codeine, hydrocodone, caramiphen, carbetapentane or dextromethorphan; a diuretic; and a sedating and is and resedation antihistaminic drug. Similarly, the compounds of the present invention can be used in combination with other drugs used in the treatment/prevention/suppression or amelioration at diseases or pathological States for which the applicable compounds of the present invention. Such other drugs may be administered by and in quantities normally used for that purpose, simultaneously or sequentially with the compound of the present invention. In those cases, when the connection of the present invention is used simultaneously with one or more other drugs, preferred is a pharmaceutical composition containing such other drugs in addition to the compounds of the present invention. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients in addition to the compound of the present invention. Examples of other active ingredients that may be combined with the compound of the present invention, or introduced separately or in the same pharmaceutical compositions, include, but are not limited to: (a) antagonists of VLA-4, (b) steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamet the zones and hydrocortisone; (c) immunosuppressants such as cyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolimus (FK-506, Prograf®), rapamycin (sirolimus, Rapamune®) and other immunosuppressants type FK-506, and mycophenolate, such as mycophenolate mofetil (CellCept®); (d) antihistamines (H1 antagonists of histamine), such as brompheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine at, antazoline, Pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, Fexofenadine, descarboethoxyloratadine and the like; (e) non-steroidal anti-asthma drugs, such as beta 2-agonists (terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, bitolterol and pirbuterol), theophylline, kromolin sodium, atropine, ipratropium bromide, leukotriene antagonists (zafirlukast, montelukast, pranlukast, iralukast, pobilukast, SKB-106,203), inhibitors of leukotriene biosynthesis (zileuton, BAY-1005); (f) non-steroidal anti-inflammatory drugs (NSAIDs)such as propionic acid derivatives (alminoprofen, benoxaprofen, Burlakova acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, Ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid and ticsp is open), derivatives of acetic acid (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, enclosinga acid, fentiazac, furofenac, ibufenac, isoxepac, exping, sulindac, tiopinac, tolmetin, zidometacin, zomepirac)derived fenaminovoj acid (flutamida acid, meclofenamic acid, marennikova acid, niflumova acid and taftalenovaya acid), derivatives biphenylcarbonic acid (diflunisal and flufenisal), oxicam (isoxicam, piroxicam, sudoxicam and tenoxicam), salicylates (acetylsalicylic acid, sulfasalazin) and the pyrazolones (Amazon, baseperiod, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone); (g) inhibitors of cyclooxygenase-2 (COX-2), such as celecoxib (Celebrex®) and rofecoksib (Vioxx®); (h) inhibitors of phosphodiesterase type IV (PDE-IV); (i) gold compounds such as auranofin and aurothioglucose, (j) inhibitors of phosphodiesterase type IV (PDE-IV); (k) other antagonists of the chemokine receptors, especially CCR1, CCR2, CCR3, CCR5, CCR6, CCR8 and CCR10; (l) a means of reducing cholesterol, such as inhibitors of HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, and other statins), airing (cholestyramine and colestipol), nicotinic acid, derivatives fenofibrinova acid (gemfibrozil, clofibrate, fenofibrate and benzafibrate) and probucol; (m) protivodiabeticski the ski means, such as insulin, sulfonylureas, biguanides (Metformin), inhibitors of α-glucosidase (acarbose) and glitazones (troglitazone and pioglitazone); (n) preparations of interferon beta (interferon β-1α; interferon β 1b); (o) etanercept (Enbrel®); (p) or antibody-based test drugs, such as orthoclone (OKT3), daclizumab (Zenapax®), infliximab (Remicade®), basiliximab (Simulect®), and antibody against CD40 ligand (e.g., MRP-1); and (q) other compounds such as 5-aminosalicylic acid and its prodrugs, hydroxychloroquine, D-penicillamine, antimetabolites, such as azathioprine and 6-mercaptopurine, and cytotoxic antitumor chemotherapeutic agents. The mass ratio of the compounds of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Mainly will be used effective dose of each. Thus, for example, in cases where the compound of the present invention together with a NSAID, the mass ratio of the compounds of the present invention to the NSAID will generally be in the range from about 1000:1 to about 1:1000, preferably from about 200:1 to about 1:200. Combinations of compounds of the present invention and other active ingredients also will be in the aforementioned range, but in each the m case, you should use an effective dose of each ingredient.

Immunosuppressants in the scope of the present invention optionally include, but are not limited to, Leflunomide, RAD001, ERL080, FTY720, CTLA-4, or antibody-based test drugs, such as orthoclone (OKT3), daclizumab (Zenapax®), basiliximab (Simulect®), and globulins against thymocytes, such as Thymoglobulin.

In particularly preferred embodiments, the implementation of these methods is aimed at the treatment or prevention of multiple sclerosis using the connection according to the invention either individually or in combination with a second therapeutic agent selected from Betaseron, Avonex, azathioprine (Imurek®, Imuran®), Copaxone, prednisolone and cyclophosphamide. When used in combination practitioner may enter a combination of therapeutic agents or introduction can be consistent.

In some particularly preferred embodiments, the implementation of these methods is aimed at the treatment or prevention of rheumatoid arthritis, where the connection according to the invention is administered either alone or in combination with a second therapeutic agent selected from the group consisting of methotrexate, sulfasalazin, of hydroxychloroquine, cyclosporine A, D-penitsillamin, infliximab (Remicade®), etanercept (Enbrel®), adalimumab (Humira®), auranofin and aurothioglucose.

In one particularly preferred variant of the implementation of these methods is aimed at the treatment or prevention of a pathological condition, associated with organ transplantation, where the compound of the present invention are used alone or in combination with a second therapeutic agent selected from the group consisting of cyclosporine A, FK-506, rapamycin, mycophenolate, prednisolone, azathioprine, cyclophosphamide and antilimfocitarnyi globulin.

Preferred combinations are non-steroidal anti-inflammatory drug(a), also called NSAIDs, which include drugs like ibuprofen. Other preferred combinations are corticosteroids including prednisolone; the well known side effects of steroid use can be reduced or even eliminated by reducing the dose of steroid needed when treating patients in combination with CCR2 antagonists of the present invention. Non-limiting examples of therapeutic agents for the treatment of rheumatoid arthritis with which a compound of the formula (I) according to the present invention can be combined include the following: cytokine suppressive anti-inflammatory drugs (CSAID); antibodies to or antagonists of other cytokines person or growth factors, for example, TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF, and PDGF. Inhibitors of S/T kinase of the present invention can be combined with ant the bodies to molecules on the cell surface, such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligands including CD154 (gp39 or CD40L).

Preferred combinations of therapeutic agents may interfere at different points in the autoimmune and subsequent inflammatory cascade; preferred examples include TNF antagonists like chimeric, humanized antibodies or human antibodies against TNF, D2E7 (HUMIRA®), (US patent # US 6090382), CA2 (REMICADETM), CDP 571, and soluble p55 or p75 TNF receptors, derivatives thereof, (p75TNFR1gG (ENBRELTMor p55TNFR1gG (Lenercept), and also inhibitors of TNFα converting enzyme (TACE); similarly, inhibitors of IL-1 inhibitors (interleukin-1 converting enzyme, IL-1RA etc) can be effective for the same reason. Other preferred combinations include interleukin 11. Yet other preferred combinations are the other key players of the autoimmune response which may act parallel to, dependent or in conjunction with the function of IL-18; particularly preferred are antagonists of IL-12, including IL-12 antibodies or soluble IL-12 receptor, or IL-12 binding proteins. It was shown that IL-12 and IL-18 have overlapping, but different functions, and the combination of antagonists to each of them may be the most effective. Another preferred combination are sustainable anti-CD4 inhibitors. the school some preferred combinations include antagonists of co-stimulating a pathway CD80 (B7.1) or CD86 (B7.2), including antibodies, soluble receptors or antagonistic ligands.

The compound of formula (I) according to the invention can also be combined with tools such as methotrexate, 6-MP, azathioprine, sulfasalazin, mesalazin, olsalazine chlorine/hydroxychloroquine, pencillamine, aurothiomalate (intramuscular and oral), azathioprine, cohesin, corticosteroids (oral, inhaled and local injection), agonists beta-2 adrenergic receptors (salbutamol, terbutaline, salmeterol), xantina (theophylline, aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium and oxitropium, cyclosporine, FK506, rapamycin, mycophenolate mofetil, Leflunomide, NSAIDs, such as ibuprofen corticosteroids, such as prednisolone, phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents, inhibitors of complement, adrenergic tools, tools that disrupt signaling by proinflammatory cytokines such as TNFα or IL-1 (e.g., IRAK, NIK, IKK, p38 or inhibitors of MAP kinase, inhibitors of IL-1β converting enzyme inhibitors transmission signal T-cells, such as inhibitory kinase, inhibitors of metalloproteinases, sulfasalazin, 6-mercaptopurine, inhibitors of angiotensin converting enzyme, soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors and the derivatives p75TNFRIgG (Enbrel TMand p55TNFRIgG (Lenercept)), sIL-1RI, sIL-1RII, sIL-6R), antiinflammatory cytokines (eg, IL-4, IL-10, IL-11, IL-13 and TGFβ), celecoxib, folic acid, hydroxychloroquine sulfate, rofecoksib, etanercept, infliximab, naproxen, valdecoxib, sulfasalazin, methylprednisolone, meloxicam, methylprednisolone acetate, aurothiomalate sodium, aspirin, triamcinolone acetonide, propoksifen napsylat/apap, folate, nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone HCl, hydrocodone bitartrate/acetaminophen, diclofenac sodium/misoprostol, fentanyl, anakinra, tramadol HCl, salsalate, sulindac, cyanocobalamin/FA/pyridoxine, acetaminophen, alendronate sodium, prednisolone, morphine sulfate, lidocaine hydrochloride, indomethacin, glucosamine of self/chondroitin, amitriptyline HCl, sulfadiazine, oxycodone HCl/acetaminophen, olopatadine HCl misoprostol, naproxen sodium, omeprazole, cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18 BP, anti-IL-12, anti-IL15, BIRB-796, SCIO-469, VX-702, AMG-548, VX-740, roflumilast, IC-485, CDC-801 and mesopram. Preferred combinations include methotrexate or Leflunomide and in cases of moderate or severe rheumatoid arthritis cyclosporine and anti-TNF antibodies, as described above.

Non-limiting examples of therapeutic agents for the treatment of inflammatory bowel disease with which a compound of the formula (I) according to the present image is the shadow can be combined include the following: budenoside; epidermal growth factor; corticosteroids; cyclosporin, sulfasalazin; aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide; antioxidants; inhibitors of thromboxane; antagonists of the receptor for IL-1; anti-IL-1β monoclonal antibodies; anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors; compounds pyridinyl-imidazole; antibodies to or antagonists of other cytokines person or growth factors, for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, EMAP-II, GM-CSF, FGF, and PDGF; cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their ligands; methotrexate; cyclosporine; FK506; rapamycin; mycophenolate mofetil; Leflunomide; NSAIDs, for example, ibuprofen; corticosteroids such as prednisolone; phosphodiesterase inhibitors; adenosine agonists; antithrombotic agents; inhibitors of complement; adrenergic tools; tools that interfere with the signaling of proinflammatory cytokines such as TNFα or IL-1 (e.g., inhibitors IRAK, NIK, IKK, or MAP kinase); inhibitors of IL-1β converting enzyme; inhibitors of TNFα converting enzyme; inhibitors of T-cell signal transmission, such as kinase inhibitors; inhibitors of metalloproteinases; sulfasalazin; azathioprine; 6-mercaptopurine; inhibitors angit sin-converting enzyme; soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors, sIL-1RI, sIL-1RII, sIL-6R) and antiinflammatory cytokines (eg, IL-4, IL-10, IL-11, IL-13 and TGFβ). Preferred examples of therapeutic agents for the treatment of Crohn's disease with which a compound of the formula (I) can be combined include the following: TNF antagonists, for example anti-TNF antibodies, D2E7 (U.S. patent No. 6090382; HUMIRA®), CA2 (REMICADETM), CDP 571, design TNFR-Ig, (p75TNFRIgG (ENBRELTMand p55TNFRIgG (LENERCEPTTM)) inhibitors, and inhibitors of PDE4. The compound of formula (I) can be combined with corticosteroids, for example budenoside and dexamethasone; sulfasalazin, 5-aminosalicylic acid; olsalazine; and means, which prevent the synthesis or action of proinflammatory cytokines such as IL-1, for example inhibitors of IL-1β converting enzyme and IL-1ra; inhibitors of T-cell signal transmission, for example, tyrosine kinase inhibitors 6-mercaptopurine; IL-11; mesalamine; prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolone sodium succinate; Diphenoxylate/atropalpus; loperamide hydrochloride; methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water; hydrocodone bitartrate/acetaminophen; tetracycline hydrochloride; fluocinonide; metronidazole; thimerosal/boric acid; cholestyramine/sucrose; ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidine hydrochloride, midazolam hydrochloride; oxycodone HCl/acetaminophen; prometazina hydrochloride; sodium phosphate; sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoksifen napsylat; hydrocortisone; multivitamins; balsalazide disodium; codeinefosfaat/acetaminophen; colesevelam HCl; cyanocobalamin; folic acid; levofloxacin; methylprednisolone; natalizumab and interferon-gamma.

Non-limiting examples of therapeutic agents for multiple sclerosis with which the compounds of formula (I) can be combined include the following: corticosteroids; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine; tizanidine; interferon-β1a (AVONEX®; Biogen Idec); anti-α4 antibody (Tysabri®; Biogen Idec); interferon-B1b (BETASERON®; Chiron/Berlex); interferon α-n3) (Interferon Sciences/Fujimoto), interferon-α (Alfa Wassermann/J&J), interferon β1A-IF (Serono/Inhale Therapeutics), Peginterferon α 2b (Enzon/Schering-Plough), Copolymer 1 (Cop-1; COPAXONE®; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen; intravenous immunoglobulin; claribid; antibodies to or antagonists of other cytokines person or growth factors or their receptors, such as TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15, IL-16, EMAP-II, GM-CSF, FGF, and PDGF. The compound of formula (I) can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD8, CD86, CD90 or their ligands. The compound of formula (I) can also be combined with tools such as methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, Leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adenosine agonists, antitromboticescoe tools, inhibitors of complement, adrenergic tools, tools that interfere with the signaling of proinflammatory cytokines such as TNFα or IL-1 (e.g., inhibitors IRAK, NIK, IKK, p38 or MAP kinase)inhibitors of IL-1β converting enzyme inhibitors, TACE inhibitors, T-cell signal such as kinase inhibitors, inhibitors of metalloproteinases, sulfasalazin, azathioprine, 6-mercaptopurine, inhibitors of angiotensin-converting enzyme, soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors, sIL-1RI, sIL-1RII, sIL-6R) and antiinflammatory cytokines (eg, IL-4, IL-10, IL-13 and TGFβ).

Preferred examples of therapeutic agents for multiple sclerosis with which a compound of the formula (I) can be combined include interferon-β, for example, IFNβ1a and IFNβ1b; Copaxone, corticosteroids, caspase inhibitors, for example inhibitors of caspase-1 inhibitors, IL-1, TNF inhibitors, and antibodies to CD40 ligand and CD80.

The compound of formula (I) can also be combined with the means, such as alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride, Fampridine, glatiramer acetate, natalizumab, cannabidiol, a-immunokine NNSO3, ABR-215062, AnergiX.MS, antagonists of chemokine receptors, BBR-2778, calaguala, CPI-1189, LEM (encapsulated in the liposome mitoxantrone), THC.CBD (agonist cannabinoid), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, the antibody against IL-6 receptor, neurovax, pirfenidone allotrope 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF-beta2, diplomatic, antagonists of VLA-4 (for example, TR-14035, VLA4 Ultrahaler, Antegran-ELAN/Biogen), interferon gamma antagonists and agonists of IL-4.

Non-limiting examples of therapeutic agents for the treatment of angina, which compound of formula (I) according to the present invention can be combined include the following: aspirin, nitroglycerin, isosorbide Mononitrate, metoprolol succinate, atenolol, metoprolol tartrate, amlodipine, besylate, diltiazem hydrochloride, the isosorbide dinitrate treatment, clopidogrel bisulfate, nifedipine, atorvastatin calcium, potassium chloride, furosemide, simvastatin, verapamil HCl, digoxin, propranolol hydrochloride, carvedilol, lisinopril, spironolactone, hydrochlorothiazide, enalapril maleate, nadolol, ramipril, enoxaparin sodium, heparin sodium, valsartan, sotalol hydrchloride, fenofibrate, ezetimib, bumetanide, losartan potassium, lisinopril/hydrochlorothiazide, felodipine, captop the silt and bisoprolol fumarate.

Non-limiting examples of therapeutic agents for the treatment of ankylosing spondylitis with which the compounds of formula (I) can be combined include the following: D2E7 (U.S. patent No. 6090382; HUMIRA®), ibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoksib, sulfasalazin, methotrexate, azathioprine, minocycline, prednisone, etanercept, and infliximab.

Non-limiting examples of therapeutic agents for asthma with which the compounds of formula (I) can be combined include the following: albuterol, salmeterol/fluticasone, montelukast sodium, fluticasone propionate, budesonide, prednisone, salmeterol xinafoate, levalbuterol HCl, albuterol sulfate/ipratropium, prednisolone sodium phosphate, triamcinolone acetonide, beclomethasone dipropionate, ipratropium bromide, azithromycin, pirbuterol acetate, prednisolone, anhydrous theophylline, methylprednisolone sodium succinate, clarithromycin, zafirlukast, formoterol fumarate, a vaccine against influenza virus, amoxicillin trihydrate, flunisolide, allergic injection, kromolin sodium, fexofenadin hydrochloride, flunisolide/menthol, amoxicillin/clavulanate, levofloxacin, inhalation accessory, guaifenesin, dexamethasone sodium phosphate, moxifloxacin HCl, doxycycline hyclate, guaifenesin/d-methorphan, p-fue is Rin/code/chlorphenyl, Gatifloxacin, cetirizine hydrochloride, mometazon furoate salmeterol xinafoate, benzonatate, cefalexin, PE/hydrocodone/chlorphenyl, cetirizine HCl/pseudoephedrine, phenylephrine/code/promethazine, codeine/promethazine, cefprozil, dexamethasone, guaifenesin/pseudoephedrine, chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate, epinephrine, methylprednisolone and metaproterenol sulfate.

Non-limiting examples of therapeutic agents for the treatment of COPD, with which the compounds of formula (I) can be combined include the following: LetairsTM(ambrisentan), albuterol sulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone, albuterol, salmeterol xinafoate, fluticasone propionate, prednisone, anhydrous theophylline, methylprednisolone sodium succinate, montelukast sodium, budesonide, formoterol fumarate, triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin, beclomethasone dipropionate, levalbuterol HCl, flunisolide, Ceftriaxone sodium, amoxicillin trihydrate, Gatifloxacin, zafirlukast, amoxicillin/clavulanate, flunisolide/menthol, chlorpheniramine/hydrocodone, metaproterenol sulfate, methylprednisolone, mometazon furoate, p-ephedrine/code/chlorphenyl, pirbuterol acetate, n-pseudoephedrine/loratadine, terbutaline sulfate, Tiotropium bromide, (R,R)-formoterol, TgAAT, cilomilast and roflumilast.

Non-limiting examples of those who appenticeship funds for treatment of HCV, with which the compounds of formula (I) can be combined include the following: interferon-alpha-2a, interferon-alpha-2b, interferon-alpha con1, interferon-alpha-n1, pegylated interferon-alpha-2a, tahilramani interferon-alpha-2b, ribavirin, Peginterferon Alfa-2b + ribavirin, ursodeoxycholic acid, glycyrrhizinic acid, thymalfasin, Maximin, VX-497 and any compounds that are used to treat HCV through exposure to the following targets: HCV polymerase, HCV protease, HCV the helicase and HCV IRES (internal binding site of the ribosome).

Non-limiting examples of therapeutic agents for the treatment of idiopathic pulmonary fibrosis with which the compound of formula (I) can be combined include the following: prednisone, azathioprine, albuterol, colchicine, albuterol sulfate, digoxin, gamma interferon, methylprednisolone sodium succinate, lorazepam, furosemide, lisinopril, nitroglycerin, spironolactone, cyclophosphamide, ipratropium bromide, actinomycin d, alteplase, fluticasone proionta, levofloxacin, metaproterenol sulfate, morphine sulfate, oxycodone HCl, potassium chloride, triamcinolone acetonide, anhydrous tacrolimus, calcium, interferon-alpha, methotrexate, mycophenolate mofetil and interferon-gamma-1β.

Non-limiting examples of therapeutic agents for the treatment of myocardial infarction, with which the connection fo the formula (I) can be combined include the following: aspirin, nitroglycerin, metoprolol tartrate, enoxaparin sodium, heparin sodium, clopidogrel the bisulfate, carvedilol, atenolol, morphine sulfate, metoprolol succinate, warfarin sodium, lisinopril, isosorbide Mononitrate, digoxin, furosemide, simvastatin, ramipril, tenecteplase, enalapril maleate, torsemide, retavase, losartan potassium, inapril HCl/magnesium carbonate, bumetanide, alteplase, enalaprilat, amiodarone hydrochloride, tirofiban HCl m-hydrate, diltiazem hydrochloride, captopril, irbesartan, valsartan, propranolol hydrochloride, fosinopril sodium, lidocaine hydrochloride, eptifibatide, Cefazolin sodium atropine sulfate, aminocaproic acid, spironolactone, interferon, sotalol hydrochloride, potassium chloride, sodium docusinate, dobutamine HCl, alprazolam, pravastatin sodium, atorvastatin calcium, midazolam hydrochloride, meperidine hydrochloride, the isosorbide dinitrate treatment, epinephrine, dopamine hydrochloride, bivalirudin, rosuvastatin, ezetimibe/simvastatin, avasimibe and cariporide.

Non-limiting examples of therapeutic agents for psoriasis with which the compound of formula (I) can be combined include the following: calcipotriene, clobetasol propionate, triamcinolone acetonide, halobetasol propionate, tazarotene, methotrexate, fluocinonide reinforced betamethasone diprop, fluotsinolon acetonide, acitretin tar shampoo, betamethasone valerate, mometazon furoate, ketoconazole, pramoxine/fluotsinolon, hydrocortisone valerate, flurandrenolide, urea, betamethasone, clobetasol propionate/emoll, fluticasone propionate, azithromycin, hydrocortisone, moisturizing composition, folic acid, desonide, pimecrolimus, tar, diflorasone diacetate, etanercept folate, lactic acid, metoksalen, hc/bismuth of subgallate/znox/resor, methylprednisolone acetate, prednisone, sunscreen, halcinonide, salicylic acid, anthralin, clocortolone pivalate extract of coal tar/salicylic acid coal tar/salicylic acid/sulfur, desoximetasone, diazepam, emollient for skin, fluocinonide/emollient for the skin, mineral oil/castor oil/na lact, mineral oil/peanut oil/isopropyl myristate, psoralen, salicylic acid, soap/tribromsalan, thimerosal/boric acid, celecoxib, infliximab, cyclosporine, alefacept, efalizumab, tacrolimus, pimecrolimus, PUVA, UVB and sulfasalazin.

Non-limiting examples of therapeutic agents for the treatment of psoriatic arthritis with which a compound of the formula (I) can be combined include the following: D2E7 (U.S. patent No. 6090382; HUMIRA®), methotrexate, etanercept, rofecoksib, celecoxib, folic acid, sulfasalazine, naproxen, Leflunomide, methylprednisolone acetate, indomethacin, guide oxyglobin sulfate, prednisone, sulindac, reinforced betamethasone dipropionate, infliximab, methotrexate, folate, triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, Ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac sodium/misoprostol, fluocinonide, glucosamine sulfate, aurothiomalate sodium, hydrocodone bitartrate/acetaminophen, ibuprofen, risedronate sodium, sulfadiazine, tioguanin, valdecoxib, alefacept and efalizumab.

Non-limiting examples of therapeutic agents for the treatment of restenosis with which the compound of formula (I) can be combined include the following: sirolimus, paclitaxel, everolimus, tacrolimus, ABT-578 and acetaminophen.

Non-limiting examples of therapeutic agents for the treatment of inflammation of the sciatic nerve, which compound of formula (I) can be combined include the following: hydrocodone bitartrate/acetaminophen, rofecoksib, cyclobenzaprine HCl, methylprednisolone, naproxen, ibuprofen, oxycodone HCl/acetaminophen, celecoxib, valdecoxib, methylprednisolone acetate, prednisone, codeine phosphate/acetaminophen, tramadol HCl/acetaminophen, metaxalone, meloxicam, Methocarbamol, lidocaine hydrochloride, diclofenac sodium, gabapentin, dexamethasone, carisoprodol, Ketorolac tromethamine, indomethacin, acetaminophen, dia is EPAM, nabumetone, oxycodone HCl, tizanidine HCl, diclofenac sodium/misoprostol, propoksifen napsylate/acetaminophen, asa/oxycod/by payday loans credit check ter, ibuprofen/hydrocodone bit, tramadol HCl, etodolac, propoksifen HCl, amitriptyline HCl, carisoprodol/codeine phos/asa, morphine sulfate, multivitamins, naproxen sodium, orphenadrine citrate and temazepam.

Preferred examples of therapeutic agents for the treatment of SLE (lupus), with which the compounds of formula (I) can be combined include the following: NSAIDs, such as diclofenac, naproxen, ibuprofen, piroxicam, indomethacin; COX2 inhibitors, such as celecoxib, rofecoksib, valdecoxib; antimalarials such as hydroxychloroquine; steroids, such as prednisone, prednisolone, budenoside, dexamethasone; cytotoxic tools, such as azathioprine, cyclophosphamide, mycophenolate mofetil, methotrexate; inhibitors of PDE4 or purine synthesis inhibitors, such as Cellcept®. The compound of formula (I) can also be combined with tools such as sulfasalazin, 5-aminosalicylic acid, olsalazine, Imuran® and means, which prevent the synthesis, production or action of proinflammatory cytokines such as IL-1, for example inhibitors of caspase-like inhibitors of IL-1β converting enzyme and IL-1ra. The compound of formula (I) can also be used with inhibitors of T-cell signal transmission, nab, the emer-tyrosine kinase inhibitors; or molecules that direct the molecules of T-cell activation, for example, CTLA-4-IgG or anti-B7 family antibodies, anti-PD-1 family antibodies. The compound of formula (I) can be combined with IL-11 or anticytokine antibodies, for example fontolizumab (anti-IFNg antibody), or antireceptor antibodies, for example, anti-IL-6 receptor antibody and antibodies to surface molecules on B-cells. The compound of formula (I) can also be used with LJP 394 (abetimus), means that Deplete or inactivate B-cells, such as rituximab (anti-CD20 antibody), lymphostat-B (anti-BlyS antibody), TNF antagonists, for example anti-TNF antibodies, D2E7 (U.S. patent No. 6090382; HUMIRA®), CA2 (REMICADETM), CDP 571, designs TNFR-Ig, (p75TNFRIgG (ENBRELTMand p55TNFRIgG (LENERCEPTTM)).

In the present invention, the following definitions apply:

"Therapeutically effective amount" is an amount of the compounds of formula (I), or a combination of two or more such compounds, which inhibits, totally or partially, the progression of the pathological condition or alleviates, at least partially, one or more symptoms of the pathological condition. therapeutically effective amount can be an amount that is effective for prevention. The quantity that is terapeuticas and effective will depend on body size and sex of the patient, the pathological condition being treated, the severity of the condition and the desired result. For a particular patient a therapeutically effective amount can be determined by methods known to experts in this field.

"Physiologically acceptable salts" refers to salts that retain the biological effectiveness and properties of the free bases and which are obtained by reacting with inorganic acids, for example hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid or organic acids such as sulfonic acid, carboxylic acid, organic phosphoric acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, tartaric acid (for example, (+) or (-)-tartaric acid or mixtures thereof), amino acids (such as (+) or (-)amino acids or mixtures thereof), and the like. These salts can be obtained by methods known to experts in this field.

Some compounds of formula (I), which have acidic substituents may exist as salts with pharmaceutically acceptable bases. The present invention reac is no such salts. Examples of such salts include sodium salt, potassium salt, lysine salt and arginine salt. These salts can be obtained by methods known to experts in this field.

Some compounds of formula (I) and their salts may exist in more than one crystal form and the present invention includes each crystal form or a mixture.

Some compounds of formula (I) and their salts may also exist in the form of a solvate, for example hydrates, and the present invention includes each MES and mixtures thereof.

Some compounds of formula (I) can contain one or more chiral centers, and exist in different optically active forms. In those cases where the compounds of formula (I) contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as racemic mixtures. Enantiomers can be separated by methods known to experts in this field, for example through education diastereoisomeric salts which may be separated, for example, by crystallization; via formation diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with ananti the measure-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral substrate, for example, silicon dioxide with a bound chiral ligand or in the presence of a chiral solvent. It will be clear that in cases where the desired enantiomer is converted into another chemical substance under the action of one of the cleaning procedures described above requires an additional step to release the desired enantiomeric form. Alternative specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by transformation of one enantiomer to the other by asymmetric transformation.

In cases where the compound of formula (I) contains more than one chiral center, it may be then reduced to diastereoisomeric forms. Diastereoisomeric compounds can be separated by methods known to experts in this field, such as chromatography or crystallization, and individual enantiomers can be separated as described above. The present invention includes each diastereoisomer compounds of formula (I) and mixtures thereof.

Some compounds of formula (I) may exist in different tautomeric forms, and is in the form of various geometric isomers, and the present invention includes each tautomer and/or geometric isomer of compounds of formula (I) and mixtures thereof.

Some compounds of formula (I) may exist in different stable conformational forms which may be shared. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example due to spatial problems or tension rings can allow separation of different conformers. The present invention includes each conformational isomer of compounds of formula (I) and mixtures thereof.

Some compounds of formula (I) may exist in zwitterionic form, and the present invention includes each zwitterionic form compounds of formula (I) and mixtures thereof.

Used in the context of the present invention, the term "prodrug" refers to a vehicle that turns into the original drug in vivo under physiological action of some chemical processes (for example, the prodrug when casting to physiological pH is converted to the desired drug form). Prodrugs are often appropriate, because in some situations they can be easier to implement than the original drug. They can, for instance, be bioavailable by oral administration whereas the original lcars the public means - no. The prodrug may also have improved solubility in pharmaceutical compositions compared to the original drug. An example, without limitation, a prodrug would be a compound of the present invention, where it is introduced in the form of ester (the"prodrug") to facilitate the passage through the cell membrane where water solubility is not favorable, but it then is metabolically hydrolyzed to the carboxylic acid is already inside the cell where water-solubility is beneficial.

Prodrugs have many useful properties. For example, the prodrug may be more water soluble than the final drug, thereby facilitating intravenous drugs. The prodrug may also have higher oral bioavailability than the final remedy. After the introduction of the prodrug enzymatically or chemically cleaved for delivery of the drug in blood or tissue.

Given as examples of the prodrugs of the cleavage release the corresponding free acid, and such hydrolyzable epioblasma remains of the compounds according to the invention include, but are not limited to, carboxyl substituents (for example, -(CH2)C(O)H or the part that contains to benovoy acid), where is the free hydrogen is replaced by (C1-C4)alkyl, (C2-C12)alkanoyloxy, (C4-C9)1-(alkanoyloxy)ethyl, 1-methyl-1-(alkanoyloxy)ethyl having from 5 to 10 carbon atoms, alkoxycarbonylmethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyl)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyl)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotononitrile, gamma-butyrolactone-4-yl, di-N,N-(C1-C2)alkylamino(C2-C3)alkyl (such as β-dimethylaminoethyl), carbarnoyl-(C1-C2)alkyl, N,N-di(C1-C2-allylcarbamate-(C1-C2)alkyl and piperidino-, pyrrolidino or morpholino(C2-C3)alkyl.

Other cited as an example prodrugs release an alcohol of the formula (I), where the free hydrogen of the hydroxyl substituent (e.g., R1contains hydroxyl)is replaced with (C1-C6)alkanoyloxy, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonylmethyl, N-(C1-C6)alkoxycarbonylmethyl, succinoyl, (C1-C6)alkanoyl, α-am is but(C 1-C4)alkanoyl, arylation and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where these α-aminoaniline part independently represent any natural L-amino acids found in proteins, P(O)(OH)2, -P(O)(O(C1-C6)alkyl)2or glycosyl (radical obtained by removing the hydroxyl polyacetale carbohydrate).

The term "heterocyclic" or "heterocyclyl"used in the context of the present invention, includes a non-aromatic ring system, including, but not limited to, monocyclic, bicyclic and tricyclic rings, which can be completely saturated or which can contain one or more units of unsaturation (for greater accuracy, the degree of unsaturation does not result in an aromatic ring system), and has from 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen or sulfur. To illustrate the purpose, which should not be construed as limiting the scope of the present invention, the following represents examples of heterocyclic rings: azepines, azetidine, morpholine, oxopiperidine, oxopyrrolidin, piperazinil, piperidinyl, pyrrolidinyl, hinokitiol, thiomorpholine, tetrahydropyranyl, tetrahydrofuranyl, 5,6,7,8-tetrahydro[1,6]naphthyridine, decahydro ohioline and 2,3-dihydro-1H-isoindolyl.

The term "heteroaryl"used in the present invention include aromatic ring systems, including, but not limited to, monocyclic, bicyclic and tricyclic rings, which have from 3 to 12 atoms, containing at least one heteroatom, such as nitrogen, oxygen or sulfur. For the purpose of illustration, which should not be considered as limiting scope of the present invention: isoindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzoxazolyl, furanyl, imidazolyl, imidazopyridine, indolyl, indolinyl, indazoles, isoindolines, isoxazol, isothiazolin, oxadiazolyl, oxazolyl, purinol, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, chinoline, hintline, triazolyl, thiazolyl, thiophenyl, tetrahydroindole, tetrazolyl, thiadiazolyl thienyl, thiomorpholine or Trapani.

The use of the term "substituted heterocyclic" (or heterocyclyl) or substituted heteroaryl" means heterocyclic group substituted by one or more substituents, which may be done by the person skilled in the art, and results in a molecule, which is an antagonist of CCR2. For purpose of illustration, which should not be construed as limited to the surrounding scope of the present invention, preferred substituents of the heterocycle according to the present invention each independently selected from the optionally substituted group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, alkyl, alkylsulphonyl, alkyl ester, alkyl-O-C(O)-, alkylchlorosilanes, alkylcyclohexane, alkynylaryl of quinil amino, amino, aminoalkyl, aminocarbonyl, carbonitrile, carbonyloxy, carboxamido, CF3CN, -C(O)OH, -C(O)H, -C(O)-C(CH3)3, -OH, -C(O)O-alkyl, -C(O)O-cycloalkyl, -C(O)O-heterocyclyl, -C(O)-alkyl, -C(O)-cycloalkyl, -C(O)heterocyclyl, cycloalkyl, dialkylaminoalkyl, dialkylaminomethylcalix, dialkylaminoalkyl, halogen, heterocyclyl, geteroseksualnoe group, heterocyclic, hydroxy, hydroxyalkyl, nitro, OCF3, oxo, phenyl, -SO2CH3, -SO2CR3,tetrazolyl, tamilarasi, triftormetilfullerenov, triftormetilfullerenov, geterotsiklicheskikh, heterocyclyl-S(O)pcycloalkyl-S(O)p, alkyl-S-, heterocyclyl-S, geterotsiklicheskie, cycloalkenyl, heterocycly, cycloalkyl, -Z105-C(O)N(R)2, -Z105-N(R)-C(O)-Z200, -Z105-N(R)-S(O)2-Z200, -Z105-N(R)-C(O)-N(R)-Z200, -N(R)-C(O)R, -N(R)-C(O)OR, OR-C(O)heterocyclyl-OR, Rcand-CH2ORc;

where R3presented yet a C 1-C4alkyl, C3-C6cycloalkyl or phenyl;

where p is 0, 1 or 2;

where Rcfor each case independently represents hydrogen, optionally substituted alkyl, optionally substituted aryl, -(C1-C6)-NRdRe, -E,-(CH2)t-NRdRe, -E,-(CH2)t-O-alkyl, -E-(CH2)t-S-alkyl or-E-(CH2)t-OH;

where t is an integer from about 1 to about 6;

Z105for each case independently represents a covalent bond, alkyl, alkenyl or quinil; and

Z200for each case independently selected from the optionally substituted group selected from the group consisting of alkyl, alkenyl, quinil, phenyl, alkylphenyl, alkenylphenol or alkenylphenol;

E represents a direct bond, O, S, S(O), S(O)2or NRfwhere Rfrepresents H or alkyl, and Rdand Reindependently represent H, alkyl, alkanoyl or SO2-alkyl; or Rd, Reand the nitrogen atom to which they are attached, together form a five - or six-membered heterocyclic ring.

Used in the context of the present invention, the group "heteroseksualci"represents a heterocyclic group, which is associated with the connection aliphatic group having from one to the roughly eight carbon atoms. For example, heterocytolysine group is morpholinomethyl group.

Used in the context of the present invention "alkyl" means C1-C8and includes hydrocarbons with straight or branched chain, which are completely saturated. The preferred alkilani are methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl and its isomers. Used in the context of the present invention "of alkenyl" and "quinil" means C2-C8and includes hydrocarbons with straight or branched chain, containing one or more units of unsaturation, one or more double bonds to alkenyl and one or more triple links for quinil.

Used in the context of the present invention, the aromatic group or aryl group include aromatic carbocyclic ring system (e.g., phenyl and cyclopentadienyl) and the condensed polycyclic aromatic ring systems (e.g. naphthyl, biphenylyl and 1,2,3,4-tetrahydronaphthyl).

Used in the context of the present invention cycloalkyl means C3-C12monocyclic or polycyclic (e.g. bicyclic, tricyclic, etc.) hydrocarbons which are completely replaced or have one or more unsaturated bonds, but not ar represents thematic group. Preferred examples cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.

Used in the context of the present invention, many functional groups or substituents are named either as "substituted"or "optionally substituted". In those cases, when the functional group is defined by one of these terms, unless otherwise indicated, this means that any part of a functional group, which is known to the person skilled in the art as available for substitution may be substituted, which comprises one or more substituents, where, if more than one substituent, then each Deputy chosen independently. Such substitutions are well known in the art and/or presents a real description. For the purpose of illustration, which should not be construed as limiting the scope of the present invention, some examples of groups that are substituents are: alkeneamine group, alkoxygroup (which itself may be substituted, for example, -O-C1-C6-alkyl-OR, -O-C1-C6-alkyl-N(R)2and OCF3), alkoxyalkane, alkoxycarbonyl, alkoxycarbonylmethyl, alkyl groups (which can also be substituted, for example, -C1-C6-alkyl-OR, -C1-C6-alkyl-N(R)sub> 2and-CF3), alkylamino, alkylsulphonyl, alkyl ester alkynylaryl, alkylsulfonyl, amino, aminoethoxy, CF3, SON, COOH, CN, cycloalkyl, dialkylamino, dialkylaminoalkyl, dialkylaminoalkyl, dialkylaminomethylcalix, dialkylaminoalkyl, esters (-C(O)-OR, where R represents groups such as alkyl, heteroseksualci (which may be substituted), heterocyclyl etc. which may be substituted), halogen or halogroup (F, Cl, Br, I), hydroxy, morpholinoethoxy, morpholinoethyl, nitro, oxo, OCF3, optionally substituted phenyl, S(O)2CH3, S(O)2CF3and sulfonyl, N-alkylamino or N,N-dialkylamino (in which the alkyl groups can also be substituted).

One or more compounds of the present invention can introduce a person to a patient as such or in pharmaceutical compositions where they can be mixed with a biologically suitable carriers or excipients at doses to treat or relieve symptoms of a disease or pathological condition, as described in the present invention. Mixtures of these compounds can also enter the patient in the form of a simple mixture or in the form of an appropriately crafted pharmaceutical compositions. A therapeutically effective dose refers to the amount of compound or compounds, sufficient for implementation is the result of prevention or attenuation of a disease or pathological condition, described in the present description. The method and the introduction of the compounds of the present invention can be found in the links, well-known specialist in this field, such as "Remington''s Pharmaceutical Sciences" Mack Publishing Co., Easton, PA, latest edition.

Suitable routes of administration may, for example, include oral administration, eye drops, rectal, through the mucous membranes, local or putting in the introduction; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.

Alternatively, you can enter the connection is local rather than systemic manner, for example by injection of the compound directly into the site swelling, often in the composition of the prolonged action or slow release.

In addition, you can enter the drug in the system for targeted drug delivery, for example, in a liposome coated with an antibody specific against endothelial cells.

The pharmaceutical compositions of the present invention can be obtained in a known manner, for example by means of conventional mixing, dissolving, granulation, making pills, otmuchivanie, emulsification, encapsulation, capture or process the AMI lyophilization.

Pharmaceutical compositions for use in accordance with the present invention, therefore, can be obtained in the usual way using one or more physiologically acceptable carriers contain excipients and additives, which facilitate processing of the active compounds into preparations which can be used pharmaceutically. A suitable composition depends on the selected route of administration.

For injection means according to the invention can be obtained in aqueous solutions, preferably in physiologically compatible buffers such as Hanks solution, ringer's solution or saline. For insertion through the mucous membranes in the composition used wetting agents suitable for barrier through which the composition. Such wetting agents are mostly known in this field.

For oral administration the compounds can be obtained simply by combining the active compounds with pharmaceutically acceptable carriers well known in the prior art. Such carriers enable you to obtain the compounds according to the invention in the form of tablets, pills, coated tablets, capsules, liquids, gels, syrups, thick slurries, suspensions and the like for oral administration by the patient undergoing treatment. Pharmaceutical preparations for oral use is to be placed can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture, and processing the mixture of granules, followed by adding suitable additional substances, if desired, to obtain core tablets or pills. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; preparations of cellulose, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hypromellose, carboxymethylcellulose sodium and/or polyvinylpyrrolidone (PVP). If desired, can be added dezintegranty, such as poperechnyy polyvinylpyrrolidone, agar or alginic acid or their salts, such as sodium alginate.

The dragee cores provide suitable coatings. For this purpose, can be used in concentrated solutions of sugars, which may not necessarily contain the Arabian gum, talc, polyvinylpyrrolidone, carbopol gel, polietilenglikol and/or titanium dioxide, solutions, varnish, and appropriate ograniczenie solvents or solvent mixtures. Dyes or pigments can be added to the coating to the tablets or dragee to identify or describe different combinations of doses of active compounds.

Pharmaceuticals, which can the be used orally include hard capsules made of gelatin, and also soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Hard capsules can contain the active ingredients in a mixture with fillers, such as lactose, binders, such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, can be added stabilizers. All compositions for oral administration should be in dosages suitable for such administration.

For hominids application of the composition can take the form of tablets or candies, obtained in the usual way.

For administration by inhalation, the compounds for use in accordance with the present invention are usually delivered in the form of a pharmaceutical form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. DICHLORODIFLUOROMETHANE, trichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the unit dosage can be determined by providing what lepanam for delivering a measured quantity. Capsules and cartridges of, for example, gelatin for use in an inhaler or injector for air can be obtained containing a powder mix of the compound and a suitable powder base such as lactose or starch.

The compound can be obtained for parenteral administration by injection, for example bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, for example in ampoules or containers with multiple doses, with added preservative. The compositions may take such forms as suspensions or emulsions in oily or aqueous carriers, and may contain tools for creating songs such as suspendida, stabilizing and/or dispersing the funds.

Pharmaceutical compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds can be obtained in the form of appropriate oily injection suspensions. Suitable lyophilic solvents or carriers include fatty oils such as sesame oil, or synthetic esters of fatty acids, such as etiloleat or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of WM is enzie, such as carboxymethylcellulose sodium, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or tools that enhance the solubility of compounds to obtain a highly concentrated solutions.

Alternative active ingredient may be in powder form for dilution with a suitable filler, such as sterile pyrogen-free water, before use.

The connection can also be obtained in the form of rectal compositions such as suppositories or retention enemas, e.g. containing conventional bases for suppositories, such as cocoa butter or other glycerides.

In addition to the compositions described previously, the compounds can also be obtained in the form of depot preparations. Such compositions prolonged action can be administered by implantation (for example subcutaneously or intramuscularly, or by intramuscular injection). Thus, for example, the compound can be obtained with suitable polymeric or hydrophobic materials (for example, in the form of an emulsion in a suitable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

An example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system containing benzyl JV is RT, nonpolar surfactant, miscible with water, the organic polymer and aqueous phase. The cosolvent system may be a system of co-solvents VPD. VPD is a solution of 3% wt./about. benzyl alcohol, 8% wt./about. nonpolar surfactant Polysorbate 80 and 65% wt./about. polyethylene glycol 300, brought to the mark with absolute ethanol. The cosolvent system VPD (VPD:5W) consists of VPD, diluted 1:1 with 5% dextrose in water solution. This system of co-solvents a good solvent for hydrophobic compounds, and she gives a low toxicity upon systemic administration. Of course, the proportions of the system of co-solvents can vary substantially without disrupting its solubility and toxicity characteristics. Moreover, the component elements of the cosolvent can be changed: for example, can be used other nonpolar surfactants instead of Polysorbate 80; the fraction size of polyethylene glycol may be changed; other biocompetitive polymers may replace polyethylene glycol, e.g pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.

Alternatively, it may be used in other delivery systems for hydrophobic pharmaceutical compounds. Liposomes and emulsions are well-known is the reamers fillers or carriers delivery system for hydrophobic drugs. Can also be used in certain organic solvents, such as dimethylsulfoxide, although usually at a cost of increased toxicity. Additionally, the compounds may be delivered using a slow-release, such as semipermeable matrices of solid hydrophobic polymers containing therapeutic agent. Different materials for slow release have been established and are well known to specialists in this field. Capsule delayed release may, depending on their chemical nature, release the compounds for a few weeks up to 100 days. Depending on the chemical nature and the biological stability of therapeutic reagent can be used for additional stabilization strategy proteins.

Pharmaceutical compositions may also contain suitable solid or gel-like carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

Many of the compounds of the present invention can be provided as salts with pharmaceutically acceptable counterions. Pharmaceutically compatible salts may be is formed with many acids, including, but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than the corresponding form of the free bases.

Pharmaceutical compositions suitable for use in the present invention include compositions where the active ingredients are contained in an effective amount to achieve the intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the patient undergoing treatment. Determination of the effective amounts is within the competence of specialists in this field.

For any compound used in the method according to the present invention, therapeutically effective dose can be determined initially on the basis of cell research. For example, the dose may be obtained at the cellular or animal models to achieve a range of circulating concentrations that includes the IC50defined in cell research (i.e. the concentration of test compound, which provides half the maximum inhibition of a given activity CCR2). In some cases it is expedient to determine the IC50in p outstay 3-5% serum albumin, because this definition approximates the effects of binding of plasma proteins to the compound. Such information can be used for more accurate determination of the dose used in humans. Further, the most preferred compounds for systemic injections effectively inhibit CCR2 signaling in intact cells at levels that are safely achieved in plasma.

A therapeutically effective dose refers to that amount of a compound that leads to relief of symptoms in the patient. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, to determine the maximum tolerated dose (MTD) and ED50(effective dose for 50% of maximum response). The ratio of doses between toxic and therapeutic effects is a therapeutic index and can be expressed as the ratio between MTD and ED50. Compounds which exhibit high therapeutic indices are preferred. The data obtained in the analysis of cell cultures and animal studies can be used to generate interval of doses for use in humans. Doses of such compounds preferably are in the range circulate the concentrations, which include ED50with little toxicity or no toxicity. The dosage may vary within this interval depending on the dosage form and route of administration. The exact composition, route of administration and dosage can be chosen personal physician from the point of view of the patient. (See, e.g., Fingl et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p1). In the treatment of crises, emergencies introduction of bolus or infusion approach MTD may be required to obtain a rapid response.

The number of doses and interval may be adjusted individually to provide plasma levels of the active substance, which is sufficient to maintain CCR2 modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be determined according to the in vitro; for example, the concentration necessary to achieve 50-90% inhibition of CCR2, using the assays described in the present invention. The dose needed to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC analysis, or biological research can be used to determine plasma concentrations.

The spacing of the doses can also be defined with the value of the MEC. Connections should be entered using the schema level which supports the plasma above the MEC for 10-90% of the time preferably between 30-90% and most preferably between 50-90% to achieve the desired relief of symptoms. In cases of local injection or selective capture the effective local concentration of the drug may not be comparable to the concentration in plasma.

The amount of the composition will, of course, depend on the patient being treated, the body weight of the patient, the severity of the disease, the route of administration and the opinion of the treating physician.

The compositions can, if desired, be presented in a pack or dispenser, which may contain one or more unit dosage forms containing the active ingredient. The package may, for example, contain a metal foil or polymer film, such as a blister pack. The pack or dispenser may be provided with instructions for use. The compositions containing the compound of the present invention, obtained in a compatible pharmaceutical carrier may also be obtained, placed in an appropriate container and labeled for treatment of the specified condition.

In some formulations it may be useful to use the compounds of the present invention in the form of particles of very small size, for example, obtained by grinding in a fluidized bed.

The use of compounds of the present invention in the production is the tion of pharmaceutical compositions is illustrated by the following description. In the present description, the term "active compound" means any compound according to the invention, but particularly any compound which is the final product of one of the previous examples.

a) Capsules

Upon receipt of the capsules 10 parts by weight of active compound and 240 parts by weight of lactose can be disaggregated and mixed. This mixture can be filled hard gelatin capsules, each capsule contains a single dose or part of a unit dose of active compounds.

b) Tablets

Tablets can be obtained, for example, from the following ingredients.

Part by weight
Active connection10
Lactose190
Corn starch22
Polyvinylpyrrolidone10
Magnesium stearate3

The active compound, lactose and a certain amount of starch, can be disaggregated, stir, and the resulting mixture can be granulated with a solution of polyvinylpyrrolidone in ethanol. Dry the th granules may be mixed with the magnesium stearate and the remaining starch. The mixture is then pressed into a tablet machine to obtain tablets, each containing a single dose or part of a unit dose of active compounds.

c) Tablets with enteric coating

Tablets can be obtained by the method described above in paragraph (b). The tablets may be coated enteric coated in the usual way, using a solution of 20% azettftalat cellulose and 3% diethylphthalate in ethanol:dichloromethane (1:1).

d) Suppositories

Upon receipt of suppositories, for example, 100 parts by weight of the active substance can be included in 1300 parts by weight triglyceride bases for suppositories, and the mixture is formed into suppositories, each containing a therapeutically effective amount of the active ingredient.

In the compositions of the present invention, the active compound can, if desired, be associated with other compatible pharmaceutically active ingredients. For example, the compounds of the present invention can be introduced in combination with another therapeutic agent, which is known to cure the disease or pathological condition described in the present invention. For example, one or more additional pharmaceutical drugs, which inhibit or prevent the production of VEGF or angiopoietin, weaken intracellular Rea is in the VEGF or angiopoietin, block intracellular signal transmission, inhibit hyperproliferate vessels, reduce inflammation or inhibit or prevent the formation of edema or neovascularization. Compounds of the present invention can be entered before, after or simultaneously with an additional pharmaceutical agent, regardless of the applied course introduction. Additional therapeutic agents include, but are not limited to, anti-inflammatory steroids, NSAID, ras inhibitors, anti-TNF tools, anti-IL1 tools, antihistamines, PAF-antagonists, inhibitors of COX-1, COX-2 inhibitors, inhibitors of NO synthase, inhibitors of Akt/PTB, inhibitors of IGF-1R, PKC inhibitors, inhibitors of PI3 kinase, calcineurin inhibitors and immunosuppressants. Compounds of the present invention and additional pharmaceutical agents are either cumulatively or synergistically. Thus, the introduction of such a combination of substances that inhibit angiogenesis, vascular hyperproliferate and/or inhibit the formation of edema, can provide greater relief of damaging action of hyperproliferative disorders, angiogenesis, vascular hyperprolinemia or swelling than the introduction of any of the substances individually. In the treatment of malignant diseases in combination with antiproliferative or cytotoxic tuberculosis treatment is iticheskie means or radiation included in the scope of the present invention.

The present invention also includes the use of compounds of formula (I) as a drug.

An additional aspect of the present invention relates to the use of compounds of formula (I) or its salts in the production of drugs for the treatment of vascular hyperprolinemia, angiogenesis-dependent disorders, proliferative diseases and/or disorders of the immune system in mammals, particularly in humans.

The present invention also relates to a method of treatment of vascular hyperprolinemia, inadequate neovascularization, proliferative diseases and/or disorders of the immune system, which provides for the introduction of therapeutically effective amounts of compounds of formula (I) to a mammal, in particular a person in need.

All references, including journal articles, patents and published patent applications is hereby incorporated into this description by reference in full.

Enzymatic studies

Assays for screening compounds of formula (I)

The efficiency of in vitro compounds with antagonistic effect on CCR2, the present invention is described in the prior art, can be determined using methods described in detail below.

The CHO cells expressing either human CCR2b is for CCR2 mouse received the following way. CCR2b cDNA person (cloned from human blood) and mouse CCR2 (cloned from the brain of a mouse or PEC) was cloned into plasmid pcDNA3.1 (Invitrogen). The resulting plasmids separately was transfusional in CHO cells expressing Ga16 person (Molecular Devices). The sequence of the open reading frames transfitsirovannykh CCR2 in the resulting cell lines were identical to those of human CCR2b (NM_000648) and mouse CCR2 (NM_00915.1), respectively.

Inhibition of binding of MCP-1 with hCCR2 or mCCR2

Assays radioligand binding was performed on CHO cells expressing either human CCR2B and Gα16conjugated protein or mouse CCR2 and Gα16conjugated protein. All compounds were dissolved in DMSO and the study was performed at the final concentration of DMSO 1% (vol./vol.). [125I]-labeled MCP-1 human and mouse were purchased from PerkinElmer. Unlabeled MCP-1 human and mouse were purchased from Peprotech. Studies on cells expressing human CCR2B, conducted with MCP-1 person, and studies on cells expressing CCR2 mice, conducted with MCP-1 mouse.

Compounds are serially diluted in DMSO before dilution buffer for research (25 mm HEPES, pH of 7.4, 5 mm MgCl2, 1 mm CaCl2and 0.5% BSA) with cryopreserved CHO cells expressing either human CCR2B and Gα16conjugated protein or mouse CR2 and Gα 16conjugated protein (50×103/well) and [125I]-MCP-1 (50 PM for CCR2 person, 100 PM for CCR2 mouse). The reaction mixture was incubated at room temperature for 90 minutes before being transferred to a filter plate GF/C (PerkinElmer), pre-treated with 0.3% polyethylenimine for 2 hours at 4°C. the Filter plate was washed six times in ice-cold wash buffer (25 mm HEPES, pH of 7.4, 5 mm MgCl2, 1 mm CaCl2, 500 mm NaCl, and dried before adding 50 ál/well of Microscint in each well. Plates were counted on a scintillation counter Packard Topcount, which defines the background binding of 100 nm MCP-1, and control the total binding is determined by adding DMSO instead of test compound. The value of radioactivity (imp./min) was used to calculate percent inhibition at a given concentration of the compound and the data were approximatively to the sigmoid curve in semi-logarithmic coordinates for determining the values of the IC50.

Inhibition of MCP-1-induced release of calcium in the cells expressing hCCR2 or mCCR2

Research excessive release of calcium were performed on CHO cells expressing either human CCR2B and Gα16conjugated protein or mouse CCR2 and Gα16conjugated protein. All compounds were dissolved in DMSO and research conducted at the final concentration of DMSO 1% (vol./vol.). MCP-1 h the rights and mouse were purchased from Peprotech and used in the final study concentration of 10 nm. Studies on cells expressing human CCR2B, conducted with MCP-1 person, and studies on cells expressing CCR2 mice, conducted with MCP-1 mouse.

Briefly, cells were cultured over night in the microtiter plate at 40000 per well. The next day the resulting adhesive cells were incubated in the buffer for the study (20 mm HEPES pH of 7.4, with 0.1% bovine serum albumin and 2.5 mm Probenocid in buffered Hanks solution)containing 5 μg/ml μm dye Fluo-4 (Molecular Probes)at room temperature for 60 minutes Buffer for studies containing dye were removed and replaced with a buffer for research without dye. Research excessive release of calcium was carried out on the device FLIPR Tetra (Molecular Devices) by adding the compounds to the cells after addition of MCP-1 and measured the changes in fluorescence as a function of time. The maximum and minimum values of fluorescence was determined using 100 nm MCP-1 and the addition of a buffer, respectively. The fluorescence values were used to calculate percent inhibition at a given concentration of the compound and the data were approximatively to the sigmoid curve in semi-logarithmic coordinates for determining the values of the IC50.

Compounds according to the invention can be obtained by using the scheme of the synthesis is shown in scheme A. the Original substances are the Xia commercially available or can be obtained by means described in the present invention, or by methods that are well known to experts in the field of organic chemistry. The cases used in this diagram are defined in the description or in the claims. Common procedures are noted in parentheses.

Scheme A

The method of obtaining 2-aminoacetophenone-3a-carboxamide compounds of the present invention is illustrated in scheme A. In scheme A, step i, respectively, substituted 4,5,6,6a-tetrahydroindole-2(1H)-he 1 gidrogenit, usually in the presence of hydrogen and a metal catalyst (such as Pd/C) in an organic solvent (such as EtOH). Hydrolysis of esters, typically conducted in an organic solvent, such as THF, treated with aqueous sodium hydroxide, after which Amida connecting with a suitable amine (stage ii), gives an intermediate compound 3. The reaction of the compound amide ketone with an appropriately substituted amine usually proceeds in an organic solvent (such as DMA) in the presence of a base (such as Et3N) and the activating agent (such as HOBT) and binding reagent (such as PS-carbodiimide) at ambient temperature. The reaction of reductive amination (stage iii or iv) is usually carried out in an organic solvent (such as 1,2-dichloroethane) at on the th temperature triacetoxyborohydride sodium and acetic acid. Ester 4 functionalitywith using a chemical reaction, similar to that described above in stage (ii), to obtain the product 5. Product 5 can then be isolated and purified using standard techniques such as crystallization, column flash chromatography or liquid chromatography with reversed phase).

REDUCTION

DCEDihloretan
DCMDichloromethane
DMAN,N-Dimethylacetamide
DMSOThe sulfoxide
Et3NThe triethylamine
Et2ODiethyl ether
HOBT1-Hydroxybenzotriazole
HPLCHigh performance liquid chromatography
MeCNAcetonitrile
MeOHMethanol
MgSO4Magnesium sulfate
i-D2-Propanol
n-D1-Propanol
PS-carbodiimideN-Cyclohexylcarbodiimide-N'-propelaccelerator
RPReversed phase
RtRetention time
THFTetrahydrofuran

DETAILED description of the SYNTHESIS

Analytical data are included either in the General illustrations of methods, either in the tables of examples. Unless otherwise noted, all data1H or13C-NMR spectrum obtained on the instrument Varian Mercury Plus 400 MHz; chemical shifts are given in parts per million (ppm). Analytical data of high-performance liquid chromatography (HPLC) or described in detail in the experiments, or link in the table of conditions HPLC with a lowercase letter to denote the way in table A.

Table A
The list of ways HPLC
MethodConditions of HPLC
If not stated otherwise, the mobile phase A consisted of 10 mm ammonium acetate, ACC is mportant phase B consisted of acetonitrile qualification for HPLC".
a5-95% B over 3.7 min with a hold at 95% B for 1 min (flow rate 1.3 ml/min). Column of 4.6×50 mm Waters Atlantis dC18 (particles of 5 microns). Methods of detection are diode matrix (DAD) and evaporative light scattering detection (ELSD), as well as positive/negative electrospray ionization.
b5-60% B for 1.5 min then 60-95% B to 2.5 min with a hold at 95% B for 1,2 min (flow rate 1.3 ml/min). Column of 4.6×30 mm Vydac Genesis C8 (particles 4 microns). Methods of detection are diode matrix (DAD) and evaporative light scattering detection (ELSD), as well as positive/negative electrospray ionization.
c5-95% B over 3.7 min with a hold at 95% B for 1 min (flow rate 1.3 ml/min). Column of 4.6×50 mm Waters Atlantis dC18 (particles of 5 microns). Methods of detection are diode matrix (DAD) and evaporative light scattering detection (ELSD), and positive/negative chemical ionization at atmospheric pressure (APCI).
d10-70% gradient for 19 min isopropanol in heptane with 0.2% diethylamine on column Daicel AD-H (a 4.6×250 mm) at 35°C and a flow rate of 1.0 ml/min UV wavelength observation is possible = 265 nm).

GENERAL METHODS AND EXAMPLES

General scheme of synthesis, which were used to obtain most of the compounds described in the present application is described below in schemes 1-2.

Scheme 1. Common path synthesis for obtaining octahydrophenanthrene-3a-carboxamido (General method A, B)

Scheme 2. Common path synthesis for the preparation of 2-aminoacetophenone (General method C)

A list of common techniques:

General method A: Hydrolysis of ester to carboxylic acid.

General method B: Getting through amide peptide compounds.

General method C: Getting amine by reductive amination.

Intermediate connections:

Methyl 5-oxo-1,2,3,3a,4,5-hexahydrophthalic-3a-carboxylatereceived by the method described in J. Org. Chem. 1981, 46, 2816-2818.

3-Trifluoromethyl-5,6,7,8-tetrahydro-[1,6]naphthiridinereceived by the method described in WO 2005/044264.

Methyl 2-oxooctanoate-3a-carboxylate:Methyl5-oxo-1,2,3,3a,4,5-hexahydrophthalic-3a-carboxylate (2.5 g, 12.8 mmol) in ethanol (25 ml) was purged with nitrogen for approximately 10 minutes under stirring. Added palladium on the where (0,043 g, 20 mol.%) and the reaction vessel was purged with nitrogen for about 10 minutes. The flow of nitrogen was stopped and the vessel was rinsed with a stream of hydrogen. The reaction mixture was stirred overnight in a hydrogen atmosphere. The vessel was rinsed with a stream of nitrogen for about 20 minutes. The reaction mixture was passed through a layer of Celite® and the filtrate was concentrated in vacuum. The residue was purified using flash column-chromatography (elwira 25% ethyl acetate/heptane) to give ethyl 2-oxooctanoate-3a-carboxylate (2,04 g, 10.4 mmol, 81%).

Alphanumeric codes common methods are the way of the synthesis of the final product. Calculated example of defining such a way below using the synthesis of the drug No. 3, as non-limiting explanation. Preparation No. 3 ([2-(2,4-dimethylbenzylamine)hexahydrophthalic-3a-yl]-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthiridine-6-yl)methanon) was obtained from 2-(2,4-dimethylbenzylamine)octahydrophenanthrene-3a-carboxylic acid and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine using General method B, as shown in the following synthesis scheme.

The acid was obtained using the path (C, A). This translates in the following sequence, where the original substance of the acid used in the General method B, is a product of the following techniques With and in the order specified.

General method A: Hydrolysis of ester to carboxylic acids

In a mixture of ester (1 equivalent) in an organic solvent (preferably THF) is added an aqueous solution of an inorganic hydroxide (1-30 equivalents, preferably about 10 equivalents) (preferably sodium hydroxide). The reaction mixture is stirred at about 20-50°C (preferably at approximately 25°C) for about 1-24 h (preferably about 18 h). The solvent is removed under reduced pressure and the residue is divided between an organic solvent (preferably DCM) and water, then separated and dried over a desiccant (preferably magnesium sulfate) and concentrated. The crude product can be purified by chromatography or crystallization or used without additional purification.

Illustration of the General methodology A

The preparation step 1:

2-(4-Phenylpiperazin-1-yl)hexahydrophthalic-3a-carboxylic acid

To a solution of ethyl 2-(4-phenylpiperazin-1-yl)octahydrophenanthrene-3a-carboxylate (1.85 g, 5,42 mmol) in THF (35 ml) was added a solution of sodium hydroxide (2.16 g, a 54.2 mmol) in water (35 ml). The reaction mixture was stirred at ambient temperature for about 18 hours RA is the solvent was removed under reduced pressure and the crude product was extracted into DCM (3×20 ml). The combined organic phases were washed with water (3×50 ml) and dried over MgSO4. Concentration in vacuo gave 2-(4-phenylpiperazin-1-yl)hexahydrophthalic-3a-carboxylic acid (1.70 g), which was used in the next stage without additional purification.

General method B: obtain the amide by peptide compounds

A mixture of acid (1 equivalent), appropriately substituted amine (1-5 equivalents, preferably 1 equivalent), the binding reagent (1-10 equivalents, preferably 1.5 equivalents, preferably PS-carbodiimide), the activating reagent (1-3 equivalents, preferably 1 equivalent, preferably HOBT) and base (1-10 equivalents, preferably 1 equivalent, preferably Et3N) in an organic solvent (preferably DMA) was stirred at about 20-50°C (preferably at approximately 25°C) for about 1-72 h (preferably about 48 hours). The resin is removed by filtration and the solvent is removed under reduced pressure. The crude product can be purified by chromatography or crystallization.

The illustration of a General method B

The preparation step 2:

{2-[(2,4-Dimethylbenzyl)amino]hexahydrophthalic-3a-yl}-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthiridine-6-yl)methanon

A mixture of 2-((2,4-dimethylbenzyl)(methylamino)octahydrophenanthrene-3a-carboxylic acid (0.075 g, 0.25 mmol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine (0,050 g, 0.25 mmol), N-((3-(4-methylbenzylamino)propylimino)methylene)cyclohexanamine (linked resin of 1.42 mmol/g, 0,262 g, 0,373 mmol), 1H-benzo[d][1,2,3]triazole-1-ol (0,034 g, 0.25 mmol) and triethylamine (0.025 g, 0.25 mmol) in DMA (3.1 ml) was stirred at ambient temperature for about 48 hours the Resin was removed by filtration and the solvent was removed under reduced pressure. The crude substance was purified using RP-HPLC to obtain {2-[(2,4-dimethylbenzyl)methylamino]hexahydrophthalic-3a-yl}-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthiridine-6-yl)methanone (0,026 g). RP-HPLC (table A, method b) Rtof 1.78 min; m/z: (M+H)+472.

General method C: Getting amine by reductive amination

To a solution of ketone (1 equivalent) in an organic solvent (preferably DCE) to add Amin (1-5 equivalents, preferably 1 equivalent) and the mixture was stirred at about 20-50°C (preferably at approximately 25°C) for about 1-72 h (preferably about 2 h), then add the reducing agent (1-10 equivalents, preferably about 1.5 equivalents, preferably triacetoxyborohydride sodium) with acid additive or without it (about 1-5 equivalents, preferably about 1.5 equivalents, preferably acetic acid is the acid). The mixture is then stirred at about 20-50°C (preferably at approximately 25°C) for about 1-72 h (preferably about 18 h). The reaction is quenched by addition of an aqueous base, preferably aqueous sodium bicarbonate, and then share with an organic solvent (preferably DCM). The solvent is removed under reduced pressure. The crude product can be purified by chromatography or crystallization.

The illustration of a General method C

Preparation No. 3:

[2-(4-Phenylpiperazin-1-yl)hexahydrophthalic-3a-yl]-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthiridine-6-yl)methanon

To a solution of 3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-she (0,175 g, 0,497 mmol) in DCE (4.3 ml) was added 4-phenylpiperidine (0,080 g, 0.50 mmol). The reaction mixture was stirred at ambient temperature for about 2 h, then was added triacetoxyborohydride sodium (0,158 g, 0,745 mmol) and acetic acid (0,043 ml to 0.74 mmol). Then the reaction mixture was stirred at ambient temperature for about 18 hours the reaction mixture was added saturated aqueous sodium bicarbonate and the product was extracted into DCM (3×10 ml). The solvent was removed under reduced pressure and the crude substance was purified using RP-HPLC with what rucenim [2-(4-phenylpiperazin-1-yl)hexahydrophthalic-3a-yl]-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthiridine-6-yl)methanone in the form of a mixture of four diastereomers (0.075 g). RP-HPLC (table A, method c) Rtis 2.05 min; m/z: (M+H)+498. In addition, the diastereomers were separated using two-stage method chiral HPLC (stage 1: the Division of diastereoisomers: isocratic using 85% heptane, 7.5% methanol, 7.5% ethanol with 0.2% diethylamine in column (Daicel OD-H (20×250 mm) at 35°C and a flow rate of 12 ml/min (monitored at UV wave length = 265 nm). Stage 2: Separation of enantiomers: 10-70% gradient for 19 min isopropanol in heptane with 0.2% diethylamine on column Daicel AD-H (20×250 mm) at 35°C and a flow rate of 16 ml/min (monitored at UV wave length = 265 nm) to obtain the four enantiomers absolute configuration of each connection has not been determined. Isomer 1: RP-HPLC (table A, method d) Rt12,66 minutes Isomer 2: RP-HPLC (table A, method d) Rt13,57 minutes Isomer 3: RP-HPLC (table A, method d) Rt8,46 minutes Isomer 4: RP-HPLC (table A, method d) Rt11,76 minutes

Table 1
Examples synthesized using General method In
AminCoreProductno prima-RAHPLC Rt(method)m/z, or1H-NMR (d6 -DMSO, 400 MHz)
3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine2-(methyl(tetrahydro-2H-Piran-4-yl)amino)octahydrophenanthrene-3a-carboxylic acid, (C, A)1,1of 1.57 min (b)(M+H)+452
1-(4-(trifluoromethyl)phenyl) piperazine2-(methyl(tetrahydro-2H-Piran-4-yl)amino)octahydrophenanthrene-3a-carboxylic acid, (C, A)1,2of 1.88 min (b)(M+H)+480
2-(pyrrolidin-1-yl)ethanamine2-(methyl(tetrahydro-2H-Piran-4-yl)amino)octahydrophenanthrene-3a-carboxylic acid, (C, A)1,30,82 min (b)(M+H)+364
3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine2-(methyl(2-(piperidine-1-yl)ethyl)amino)octahydro pentalen-3a-carboxylic acid, (C, A)1,4145 min (b) (M+H)+479
3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine2-[(2,4-dimethylbenzyl)methylamino] hexahydrophthalic-3a-carboxylic acid, (C, A)1,5to 2.06 min (c)(M+H)+486

Table 2
Examples synthesized using General method C
AminCoreProductno prima-RAHPLC Rt(method)m/z, or1H-NMR (d6-DMSO, 400 MHz)
(2,4-dimethylbenzyl)methylamine3a-[4-(3-triptoreline)piperazine-1-carbonyl]hexahydrophthalic-2-he (A, B)2,12,32 min (a)(M+H)+514

4-phenylpiperidine3a-[4-(3-Tr is formationl)piperazine-1-carbonyl]hexahydrophthalic-2-he (A, B)2,2to 2.29 min (a)(M+H)+526
4-phenylcyclohexylamine3a-[4-(3-triptoreline)piperazine-1-carbonyl]hexahydrophthalic-2-he (A, B)2,3at 2.45 min (a)(M+H)+540
(tetrahydropyran-4-yl)methylamine3a-[4-(3-triptoreline)piperazine-1-carbonyl]hexahydrophthalic-2-he (A, B)2,41,89 min (a)(M+H)+480

2,3-dihydro-1H-isoindole3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,5of 1.78 min (a)(M+H)+456
4-forbindelsen3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyldiimidazole-2(1H)-he (A, B)2,6is 1.81 min (a)(M+H)+462
2-forbindelsen3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,71,77 min (a)(M+H)+462
4-aminomethylbenzoic3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,8a 1.75 min (a)(M+H)+469

indan-1-ylamine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,9to 1.83 min (a)(M+H)+470
3,4-dimethylbenzylamine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-after the DIN-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,10of 1.93 min (a)(M+H)+472
2,5-dimethylbenzylamine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,11of 1.93 min (a)(M+H)+472

2-methoxybenzylamine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,12to 1.83 min (a)(M+H)+474
3-methoxybenzylamine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,131,79 min (a)(M+H)+474
4-methoxybenzylamine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-aftereden-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,14of 1.85 min (a)(M+H)+474

3-chlorobenzylamino3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,15of 1.93 min (a)(M+H)+478
4-chlorobenzylamino3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,161,9 min (a)(M+H)+478
1,2,3,4-tetrahydronaphthalen-1-ylamine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,17a 1.96 min (a)(M+H)+484

(3-aminomethylphenol)dimetil the Ying 3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,18of 1.88 min (a)(M+H)+487
N-(4-aminomethylphenol)ndimethylacetamide3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,19to 1.61 min (a)(M+H)+501
3-pyrazole-1-eventelement3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,201,79 min (a)(M+H)+510

3-triftormetilfosfinov3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)of 2.212,22 min (a)(MH) +512
2-triftormetilfosfinov3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,221,95 min (a)(M+H)+512
2,4-dichloraniline3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,231,99 min (a)(M+H)+512

3,4-dichloraniline3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,242,07 min (a)(M+H)+512
biphenyl-4-ylmethylamino3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,25(M+H)+520
2-cryptomaterial3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)of 2.262,08 min (a)(M+H)+528

3-cryptomaterial3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,27to 2.06 min (a)(M+H)+528
N-(4-aminomethylphenol)methane sulfonamide3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,281,77 min (a)(M+H)+537
indan-2-ylamine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B) to 2.29to 1.86 min (a)(M+H)+470

2-o-trilateration3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,301,94 min (a)(M+H)+472
2-p-trilateration3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,311,94 min (a)(M+H)+472
2-m-trilateration3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,321,94 min (a)(M+H)+472

4-(2-amino-ethyl)
phenol
3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-carbonyl)hexahydrophthalic-2(1H)-he (And, In)2,331,69 min (a)(M+H)+474
2-(2,5-dimethyle-
nil)ethylamine
3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (a, b)2,342, 02 min (a)(M+H)+486
2-(2,4-dimethyle-
nil)ethylamine
3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (a, b)2,35to 2.06 min (a)(M+H)+486

2-(4-triptoreline)ethyl amine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,362,07 min (a)(M+H)+526
2-(3-triptoreline)ethyl amine 3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,372,03 min (a)(M+H)+526
2-(3,4-dichlorophenyl)ethylamine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,382,05 min (a)(M+H)+526

2-biphenyl-2-ylethylamine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,392,17 min (a)(M+H)+534
2-biphenyl-4-ylethylamine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,402,13 min (a)(M+H)+534
(R)-1-phenylethylamine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,41of 1.87 min (a)(M+H)+458

(S)-1-phenylethylamine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,42of 1.85 min (a)(M+H)+458
pyridine-2-ylmethanone3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,43of 1.62 min (c)(M+H)+445
2-(pyridin-2-yl)ethanamine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,441,67 min (c) (M+H)+459

2-(pyridin-3-yl)ethanamine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,45of 1.57 min (c)(M+H)+459
(5-methylpyrazine-2-yl)methanamine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,46of 1.57 min (c)(M+H)+460
2-(thiophene-2-yl)ethanamine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,471,79 min (c)(M+H)+464

1,1-dioxymethamphetamine-3-ylamine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B) 2,481,60 min (c)(M+H)+472
Decahydroquinoline3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,491,91 min (c)(M+H)+476
2-cyclohexylpiperidine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,502,02 min (c)(M+H)+490

4-(pyrrolidin-1-yl)piperidine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)of 2.51of 1.34 min (c)(M+H)+491
2-(1H-indol-3-yl)ethanamine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-ka is bonyl)hexahydrophthalic-2(1H)-he (A, B)2,52of 1.88 min (c)(M+H)+497
2-(1-methyl-1H-indol-3-yl)ethanamine3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,532,00 min (c)(M+H)+511
piperidine-1-yl(piperidine-2-yl)methanon3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-6-carbonyl)hexahydrophthalic-2(1H)-he (A, B)2,541,76 min (c)(M+H)+533

1. The compound of formula (I)

or a stereoisomer, or pharmaceutically acceptable salt of the compounds, or a stereoisomer, where
Rarepresents H or (C1-C6)2alkyl;
Rbselected from the optionally substituted group consisting of -(CH2)n-aryl, -CH(CH3)-aryl, -(CH2)n-arylaryl, -(CH2)n-arylheteroacetic, -(CH2)n-(C3-C8)cyclol the La, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl and -(C3-C8)cycloalkenyl; or
Raand Rbtaken together with the nitrogen atom, form a 2,3-dihydro-1H-isoindolyl, decahydroquinoline, optionally substituted piperidinyl or optionally substituted pyrrolidinyl;
Y is selected from the optionally substituted group consisting of 5,6,7,8-tetrahydro[1,6]naphthyridine, -NH-(CH2)n-heterocyclyl, where NH is attached to the carbonyl, and-heterocyclisation where heterocyclyl attached to the carbonyl; and n is 0, 1 or 2;
where each heterocyclyl represents independently non-aromatic ring system containing from 3 to 12 ring atoms and at least one ring atom is selected from the group consisting of nitrogen, oxygen and sulfur;
where each heteroaryl represents independently an aromatic ring system containing from 3 to 12 ring atoms and at least one ring atom is selected from the group consisting of nitrogen, oxygen and sulfur; and
where the optional substituents are independently selected from the group consisting of C1-C6-alkyl, C1-C6-alkoxy, halogen, CN, CF3, OCF3, NH2, NH(CH3), N(CH3)2, hydroxy, cyclohexyl, phenyl, pyrrolidinyl, -C(O)-piperidinyl, -N(H)-C(O)-C1-C6-alkyl and N(H)-S(O)2-C 1-C6-alkyl.

2. The compound or stereoisomer according to claim 1 or its pharmaceutically acceptable salt, where Y is selected from the optionally substituted group consisting of 5,6,7,8-tetrahydro[1,6]naphthyridine, -NH-(CH3)2-pyrrolidinyl and piperazinyl.

3. The compound or stereoisomer according to claim 2 or its pharmaceutically acceptable salt, where Rarepresents H or methyl.

4. The compound or stereoisomer according to claim 3 or its pharmaceutically acceptable salt, where Rbselected from the optionally substituted group consisting of-CH2-phenyl, -CH2-phenylphenyl, -(CH2)2-phenyl, -CH(CH3)-phenyl, -CH2CH2-phenylphenyl, -CH2-phenylpyrazole, phenylpyrazole, indanyl, -(CH2)2indolyl, 1,2,3,4-tetrahydronaphthyl, -(CH2)-pyrazinyl, -(CH3-pyridinyl, -(CH2)2-pyridinyl, -(CH2)2-pyrrolidinyl, -(CH2)2-tanila, tetrahydrothieno-1,1-dioxide, -(CH2)2-piperidinyl, tetrahydropyranyl and-cyclohexylphenol.

5. The compound or stereoisomer according to claim 4 or pharmaceutically acceptable salt, where Rbselected from the optionally substituted group consisting of-CH2-phenyl, -(CH2)2-phenyl, -CH2-phenylpyrazole, indanyl, -(CH2)2indolyl, 1,2,3,4-tetrahydronaphthyl, -(CH2)2-pyridi the sludge and cyclohexylphenol.

6. The compound or stereoisomer according to claim 5 or its pharmaceutically acceptable salt, where Y is selected from the optionally substituted group consisting of 5,6,7,8-tetrahydro[1,6]naphthyridine and-piperazineethanol.

7. The compound or stereoisomer according to claim 6 or its pharmaceutically acceptable salt, where Rbselected from the optionally substituted group consisting of-CH2-phenyl, -(CH2)2-phenyl, 1,2,3,4-tetrahydronaphthyl, -CH2-phenylpyrazole, indanyl, (CH2)2-pyridinyl and-cyclohexylphenol.

8. The compound or stereoisomer according to claim 7 or its pharmaceutically acceptable salt, where Rbselected from the optionally substituted group consisting of-CH2-phenyl, 1,2,3,4-tetrahydronaphthyl and-cyclohexylphenol.

9. The compound or stereoisomer of claim 8 or its pharmaceutically acceptable salt, where Rboptionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, CN, IT, CF3, OCF3, NH3, NH2(CH3) and N(CH3)2.

10. The compound or stereoisomer according to claim 9 or its pharmaceutically acceptable salt, where Y is optionally substituted CF3.

11. The compound or stereoisomer according to claim 2 or its pharmaceutically acceptable salt, where Raand Rbtaken together with the nitrogen atom, form a 2,3-dihydro-1H-isoindolyl, optional what about the substituted piperidinyl or optionally substituted pyrrolidinyl.

12. The compound or stereoisomer according to claim 11 or its pharmaceutically acceptable salt, where optionally substituted piperidinyl or optionally substituted pyrrolidinyl optionally substituted by substituents selected from the group consisting of optionally substituted cyclohexyl, and optionally substituted phenyl.

13. The compound or stereoisomer according to item 12 or its pharmaceutically acceptable salt, where Y is an optionally substituted 5,6,7,8-tetrahydro[1,6]naphthyridine.

14. The compound or stereoisomer according to item 13 or its pharmaceutically acceptable salt, where optionally substituted piperidinyl substituted by optionally substituted phenyl or optionally substituted pyrrolidinyl.

15. The compound or stereoisomer by 14 or its pharmaceutically acceptable salt, where optionally substituted piperidinyl substituted optionally substituted by pyrrolidinyl.

16. The compound or stereoisomer by 14 or its pharmaceutically acceptable salt, where optionally substituted piperidinyl substituted by optionally substituted phenyl.

17. The compound or stereoisomer by 14 or its pharmaceutically acceptable salt, where optionally substituted pyrrolidinyl substituted by an optionally substituted cyclohexyl.

18. A method of treating a pathological condition of the patient, providing for the introduction of the criminal code is related to the patient a therapeutically effective amount of a compound or stereoisomer according to claim 1, or its pharmaceutically acceptable salts, in which the specified pathological condition selected from the group consisting of rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease, sepsis, psoriasis, psoriatic arthritis, inflammatory bowel disease, Crohn's disease, lupus, multiple sclerosis, juvenile chronic arthritis, Lyme arthritis, reactive arthritis, septic arthritis, spondyloarthropathy and systemic lupus erythematosus.

19. The method according to p, in which a pathological condition selected from the group consisting of rheumatoid arthritis, osteoarthritis, asthma and multiple sclerosis.

20. Pharmaceutical composition having antagonistic activity against chemokine receptors containing a therapeutically effective amount of a compound or stereoisomer of formula (I)

or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient, where
Rarepresents H or (C1-C6)2alkyl;
Rbselected from the optionally substituted group consisting of -(CH2)n-aryl, -CH(CH3)-aryl, -(CH2)n-arylaryl, -(CH2)n-arylheteroacetic, -(CH2)n-(C3-C8)cycloalkyl, -(CH2)n-heteroaryl, -(CH 2)n-heterocyclyl and -(C3-C8)cycloalkenyl; or
Raand Rbtaken together with the nitrogen atom, form a 2,3-dihydro-1H-isoindolyl, decahydroquinoline, optionally substituted piperidinyl or optionally substituted pyrrolidinyl;
Y is selected from the optionally substituted group consisting of 5,6,7,8-tetrahydro[1,6]naphthyridine, -NH-(CH2)n-heterocyclyl, where NH is attached to the carbonyl, and-heterocyclisation where heterocyclyl attached to the carbonyl; and
n is 0, 1 or 2;
where each heterocyclyl represents independently non-aromatic ring system containing from 3 to 12 ring atoms and at least one ring atom is selected from the group consisting of nitrogen, oxygen and sulfur;
where each heteroaryl represents independently an aromatic ring system containing from 3 to 12 ring atoms and at least one ring atom is selected from the group consisting of nitrogen, oxygen and sulfur; and
where the optional substituents are independently selected from the group consisting of C1-C6-alkyl, C1-C6-alkoxy, halogen, CN, CF3, OCF3, NH2, NH(CH3), N(CH3)2, hydroxy, cyclohexyl, phenyl, pyrrolidinyl, -C(O)-piperidinyl, -N(H)-C(O)-C1-C6-alkyl and N(H)-S(O)2-C1-C6-alkyl.

21. Soy is inania or stereoisomer according to claim 1 or its pharmaceutically acceptable salt, selected from the group consisting of:






22. Pharmaceutical composition having antagonistic activity against chemokine receptors containing a therapeutically effective amount of a compound or stereoisomer according to item 21 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient.

23. A method of treating a pathological condition of a patient, introducing a specified patient a therapeutically effective amount of a compound or stereoisomer according to item 21, or its pharmaceutically acceptable salts, in which the specified pathological condition selected from the group consisting of rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease, sepsis, psoriasis, psoriatic arthritis, inflammatory bowel disease, Crohn's disease, lupus, multiple sclerosis, juvenile chronic arthritis, Lyme arthritis, reactive arthritis, septic arthritis, spondyloarthropathy and systemic lupus erythematosus.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline modification of para-methoxyanilide of 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid of formula: (I) , which is obtained by crystallisation from ethyl acetate, where values of interplanar distance (d) and relative reflection intensities (Irel) are given in claim 1.

EFFECT: novel crystalline modification exhibits a high diuretic effect.

2 dwg, 9 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where: A is CA1; E is CE1; W is (CH2)n; Y is (CH2)P; n and p are independently equal to 0 or 1; R1 is a phenyl which is substituted with a phenyl {which is optionally substituted with a halogen, hydroxy, CH(O), CO2H, C1-4alkyl, C1-4alkyl-(N(C1-4alkyl)2), C1-4alkyl(NH2), C1-4alkyl(NH(C1-4alkyl)), C1-4hydroxyalkyl, CF3, C1-4alkylthio, C1-4alkyl(heterocyclyl) or C1-4alkylNHC(O)O(C1-4alkyl)} or a heterocyclyl; and the heterocyclyl is optionally substituted with C1-6alkyl; R2 is NHC(O)R3; and R3 is C1-4alkyl {substituted with NR7R8 or a heterocyclyl}, C3-7cycloalkyl (optionally substituted with a NR43R44 group) or a heteroaryl; where R7, R8, R43 and R44 are as defined in claim 1; wherein the heteroaryl is optionally substituted with a halogen, C1-4alkyl, CF3, C1-4alkoxy, OCF3, heterocyclyl or an amino(C1-4alkyl) group; R7 and R8 are independently C1-6alkyl; A1, E1 and G1 are independently hydrogen or halogen; unless otherwise stated, the heterocyclyl is optionally substituted with C1-6alkyl; R25 is C1-6alkyl; R50 is hydrogen or C1-6alkyl (optionally substituted with a NR51R52 group); R30, R36, R40, R42 or R44 is independently hydrogen, C1-6alkyl(optionally substituted with hydroxy, C1-6alkoxy, C1-6alkylthio, C3-7cycloalkyl (which is optionally substituted with hydroxy) or NR45R46), C3-7cycloalkyl (optionally substituted with a hydroxy(C1-6alkyl) group) or a heterocyclyl (optionally substituted with C1-6alkyl); R29, R35, R39, R41, R43, R45, R46 and R51 are independently hydrogen or C1-6alkyl; where the heterocyclyl is a non-aromatic 5- or 6-member ring containing one or two heteroatoms selected from a group comprising nitrogen and oxygen; and where the aryl is phenyl or naphthyl; and where the heteroaryl is an aromatic 5- or 6-member ring, optionally condensed with another ring (which can be carbocyclic and aromatic or non-aromatic), having one or two heteroatoms selected from a group comprising nitrogen, or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a PDE4-mediated disease state.

10 cl, 81 dwg, 15 tbl, 375 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel tetrahydroisoquinolin-1-one derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is: lower alkylene-OH, lower alkylene-N(R0)(R6), lower alkylene-CO2R0, C5-6cycloalkyl, C6-10cycloalkenyl, aryl, heterocyclic group, -(lower alkylen, substituted OR0)-aryl or lower alkylene-heterocyclic group, where the lower alkylene in R1 can be substituted with 1-2 groups G1; cycloalkyl, cycloalkenyl and heterocyclic group in R1 can be substituted with 1-2 groups G2; aryl can be substituted with 1-2 groups G3; R0: identical or different from each other, each denotes H or a lower alkyl; R6: R0, or -S(O)2-lower alkyl, R2 is: lower alkyl, lower alkylene-OR0, lower alkylene-aryl, lower alkylene-O-lower alkylene-aryl, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-aryl, -C(O)N(R0)-lower alkylene-aryl, aryl or heterocyclic group, where the aryl in R2 can be substituted with 1-3 groups G4; R3 is: H or lower alkyl, or R2 and R3 can be combined to form C5-alkylene; R4 is: -N(R7)(R8), -N(R10)-OR7, -N(R0)-N(R0)(R7), -N(R0)-S(O)2-aryl or -N(R0)-S(O)2-R7, R7 is: lower alkyl, halogen-lower alkyl, lower alkylene-CN, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-C(O)N(R0)2, lower alkylene-C(O)N(R0)N(R0)2, lower alkylene-C(=NOH)NH2, heteroaryl, lower alkylene-X-aryl or lower alkylene-X-heterocyclic group, where the lower alkylene in R7 can be substituted with 1-2 groups G1; aryl, heteroaryl and heterocyclic group in R7 can be substituted with 1-2 groups G6; X is: a single bond, -O-, -C(O)-, -N(R0)-, -S(O)p- or *-C(O)N(R0)-, where * in X has a value ranging from a bond to a lower alkylene, m is: an integer from 0 to 1, p is: is 2, R8 is: H, or R7 and R6 can be combined to form a lower alkylene-N(R9)-lower alkylene group, R9 is: aryl, R10 is: H, R5 is: lower alkyl, halogen, nitro, -OR0, -N(R0)2, or -O-lower alkylene-aryl, where the group G1 is: -OR0, N(R0)(R6) and aryl; group G2 is: lower alkyl, lower alkylene-OR0, -OR0, -N(R0)2, -N(R0)-lower alkylene-OR0, -N(R0)C(O)OR0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)N(R0)2, -N(R0)C(=NR0)-lower alkyl, -N(R0)S(O)2-lower alkyl, -N(lower alkylene-CO2R0)-S(O)2-lower alkyl, -N(R0)S(O)2-aryl, -N(R0)S(O)2N(R0)2, -S(O)2-lower alkyl, -CO2R0, -CO2-lower alkylene-Si(lower alkyl)3, -C(O)N(R0)2, -C(O)N(R0)-lower alkylene-OR0, -C(O)N(R0)-lower alkylene-N(R0)2, -C(O)N(R0)-lower alkylene-CO2R0, -C(O)N(R0)-O-lower alkylene-heterocyclic group, -C(O)R0, -C(O)-lower alkylene-OR0, C(O)-heterocyclic group and oxo; under the condition that "aryl" in group G2 can be substituted with one lower alkyl; group G3 is: -OR0; group G4 is: halogen, CN, nitro, lower alkyl, -OR0, -N(R0)2) -CO2R0; group G5 is: halogen, -OR0, -N(R0)2 and aryl; group G6 is: halogen, lower alkyl which can be substituted with -OR0, halogen-lower alkyl which is substituted with -OR0, -OR0, -CN, -N(R0)2, -CO2R0, -C(O)N(R0)2, lower alkylene-OC(O)R0, lower alkylene-OC(O)-aryl, lower alkylene-CO2R0, halogen-lower alkylene-CO2R0, lower alkylene-C(O)]N(R0)2, halogen-lower alkylene-C(O)N(R0)2, -O-lower alkylene-CO2R0, -O-lower alkylene-CO2-lower alkylene-aryl, -C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, -S(O)2-lower alkyl, -S(O)2N(R0)2, heterocyclic group, -C(-NH)=NO-C(O)O-C1-10-alkyl, -C(=NOH)NH2, C(O)N=C(N(R0)2)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)OR0, -C(aryl)3 and oxo; under the condition that the "heterocyclic group" in group G6 is substituted with 1 group selected from a group consisting of -OR0, oxo and thioxo (=S); where the "cycloalkenyl" relates to C5-10 cycloalkenyl, including a cyclic group which is condensed with a benzene ring at the site of the double bond; the "aryl" relates to an aromatic monocyclic C6-hydrocarbon group; the "heterocyclic group" denotes a cyclic group consisting of i) a monocyclic 5-6-member heterocycle having 1-4 heteroatoms selected from O, S and N, or ii) a bicyclic 8-9-member heterocycle having 1-3 heteroatoms selected from O, S and N, obtained via condensation of the monocyclic heterocycle and one ring selected from a group consisting of a monocyclic heterocycle, a benzene ring, wherein the N ring atom can be oxidised to form an oxide; the "heteroaryl" denotes pyridyl or benzimidazolyl; provided that existing compounds given in claim 1 of the invention are excluded. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treatment using the compound of formula (I).

EFFECT: obtaining novel tetrahydroisoquinolin-1-one derivatives which are useful as a BB2 receptor antagonist.

11 cl, 302 tbl, 59 ex

FIELD: chemistry.

SUBSTANCE: invention relates to complexes of lanthanides and organic ligands which are luminescent in the visible spectrum and are used in electroluminescent devices, means of protecting security paper and documents from falsification etc. Disclosed are novel luminescent coordination compounds of lanthanides of formula: where Ln is Eu3+, Tb3+, Dy3+, Sm3+, Gd3+.

EFFECT: said compounds have high luminescence intensity and considerable thermal tolerance of up to 400°C, which enables use thereof in modern production of light-emitting diodes.

4 dwg, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel imidazopyridin-2-one derivatives of general formula or pharmacologically acceptable salts thereof, where (R1)n-A is a 1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group or 3-chloro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, B is a 3-6-member saturated or partially saturated monocyclic hydrocarbon group and can contain 1 or 2 oxygen atoms, a nitrogen atom and/or sulphonyl groups as ring components, B can have as substitutes identical or different R2 in amount of m, R2 is a substitute represented at a carbon atom or a nitrogen atom forming B, R2 is a substitute selected from a group consisting of a hydroxy group, a halogen atom, a cyano group, an oxo group, a C1-4alkyl group (where the C1-4 alkyl group can be substituted with 1 C1-4 alkoxy group) and a C1-4 alkoxy group, when R2 is a substitute represented at a carbon atom forming B, and R2 is a substitute selected from a group consisting of a C1-4 alkyl group and a C1-4 alkylcarbonyl group, when R2 is a substitute represented at a nitrogen atom forming B, m is any integer from 0 to 2, Q is a bond or a C1-4 alkylene group, R3 and R4 are identical or different and each denotes a hydrogen atom or a halogen atom, and R5 and R6 are identical or different and each denotes a hydrogen atom, a halogen atom or a C1-4 alkyl group. The invention also relates to specific compounds of formula (I), pharmacologically acceptable salts of compounds of formula (I), a pharmaceutical composition based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel imidazopyridin-2-one derivatives, having mTOR inhibiting action, are obtained.

21 cl, 161 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazo[4,5-b]pyrazine derivatives of general formula or to its pharmaceutically acceptable salt wherein: R1 represents either aryl unsubstituted or substituted by one of the groups: halogen, hydoxyl, C1-6alkyl, C1-6alkoxyl, NH2, NHC1-6alkyl, N(C1-6alkyl)2, NHC1-6alkylC1-6alkoxy, C1-6alkylhydroxy, -C(O)NH2, -C(O)OC1-6alkyl, -C(O)NH C1-6alkyl, cyano, carboxy, heteroaryl and heterocycloalkyl; or heteroaryl unsubstituted or substituted by one of the groups: C1-6alkoxy, hydroxy, -C1-6alkyl, NH2 and NHC1-6alkyl; heterocycloalkyl unsubstituted or substituted by one group =O; and R2 represents H; unsubstituted C3-4alkyl; C1-4alkyl substituted by C5-6cycloalkyl unsubstituted or substituted by one group specified in amino, hydroxyl, C1-6alkoxy, or heterocycloalkyl unsubstituted or substituted by 1-2 groups specified in =O, C1-6alkyl; or C5-6cycloalkyl substituted by one group specified in hydroxyl, C1-6alkoxyl, C1-6alkylC1-6alkoxy, C1-6alkylhydroxy, CONH2; or substituted ir unsubstituted heterocycloalkyl; wherein aryl represents an aromatic structure consisting of 6-10 carbon atoms containing one ring or two condensed rings; wherein heteroaryl represents a 5-10-member aryl ring system containing 1-2 heteroatoms specified in nitrogen, oxygen and sulphur; wherein heterocycloalkyl represents a 5-9-member nonaromatic cycloalkyl wherein 1-2 heteroatoms specified in nitrogen and oxygen; provided the compound does not represent 1,3-dihydro-5-phenyl-2H-imidazo[4,5-b]pyrazin-2-one. Also, the invention refers to the specific imidazo[4,5-b]pyrazine derivatives, to a based pharmaceutical composition, to a method of treating or preventing cancer, inflammatory conditions, immunological diseases, metabolic conditions, and to a method of kinase inhibition in a cell expressing said kinase.

EFFECT: there are produced new imidazo[4,5-b]pyrazine derivatives showing effective biological properties.

17 cl, 2 tbl, 210 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and

possessing the protein kinase inhibitor property, their pharmaceutically acceptable salts, solvates and hydrates, as well as to the use thereof and a based pharmaceutical composition. In general formula (1) X1 represents N, CRt1; X2 represents N, CRt2, X3 represents N, CRt3, X4 represents N, CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H, halogen, -COOH, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, -CH3OH; Rt2 represents -H, halogen, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, CH2OH, -NH2; Rt3 represents -H, -S(O)rR4, halogen, -CN, -COOH, -CONH2, -COOCH3, -COOCH2CH3; the cycle A represents phenyl or a 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R'; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb; Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5, -NR4SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -O-, -S-, -NR3-; L1 represents NR3C(O) or C(O)NR3; R3, R4 and R5 are independently specified and represent H, C1-C6-alkyl, and also the group NR4 R5 may represent a 5- or 6-member saturated or aromatic cycle; in each case R6 is independently specified and represents C1-C6-alkyl optionally substituted by C1-C6- alkyl or 5-6 merous heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; In general formula (II) Z represents CH; X, represents CRt1; X2 represents CRt2, X3 represents CRt3 X4 represents CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H; Rt2 represents -H, -F; Rt3 represents -H, -F; the cycle A represents phenyl or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R3; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb, Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -NR3-; L represents NR3C(O) or C(O)NR3; R4 and R5 are independently specified and represent H, C1-C6-alkyl, also the group NR4R3 may represent a 6-member saturated cycle; in each case R6 is independently specified and represents, C1-C6-alkyl optionally substituted by C1-C6-alkyl or 5-6 member heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; m is equal to 1; p is equal to 1.2.

EFFECT: preparing the compounds possessing the protein kinase inhibitor property.

16 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylpyrrolidinyl methylpyrrolidine amides of formula , where R, R1, R2 and R3 are identical or different and independently denote H, (C1-C4)alkyl, CF3; R4 denotes phenyl, cyclohexyl, pyridinyl, furanyl, isoxazolyl, quinolinyl, naphthyridinyl, indolyl, benzoimidazolyl, benzofuranyl, chromanyl, 4-oxo-4H-chromenyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxolyl and 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e]][1,4]diazepinyl; where said R4 is optionally substituted one to more times with a substitute selected from halogen, hydroxy, (C1-C4) alkyl, (C1-C4) alkoxy, CF3, hydroxymethyl, 2-hydroxyethylamino, methoxyethylamide, benzyloxymethyl, piperidinyl, N-acetylpiperidinyl, pyrrolyl, imidazolyl, 5-oxo-4,5-dihydropyrazolyl; or pharmaceutically acceptable salt thereof or enantiomer or diastereomer thereof.

EFFECT: compounds have modulating activity on histamine H3 receptor, which enables use thereof to prepare a pharmaceutical composition.

10 cl, 3 dwg, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylbipyrrolidine carboxamides of formula , where values of R, R1, R2, R3 and R4 are given in claim 1.

EFFECT: compounds have activity which binds to the H3 ligand, which allows use thereof in pharmaceutical compositions for treating sleep disorder.

10 cl, 1 tbl, 4 dwg, 153 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to (aza)indole derivatives of formula

wherein the values T, X1-X3, R1, Q, Y, J are presented in clause 1 of the patent claim.

EFFECT: compounds possess xanthine oxidase inhibitory action that enables using it in a pharmaceutical composition for treating a disease specified in a group consisting of hyperuricemia, gouty tophus, gouty arthritis, renal diseases associated with hyperuricemia and nephrolithiasis.

19 cl, 62 tbl, 332 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound selected from a group consisting of: 4-[(2-{[(2S)-2-fluoropropyl](pyridin-2-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl]benzoic acid, 4-[(2-{[(2R)-2-fluoropropyl](pyridin-2-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl]benzoic acid, 4-{[(6-{[(2R)-2-fluoropropyl](pyridin-2-ylsulfonyl)amino}-2,3-dihydro-1H-inden-5-yl)oxy)methyl} benzoic acid, 4-[(5-chlor-2-{[(2S)-2-fluoropropyl](pyridin-2-ylsulfonyl)amino}-4-methylphenoxy)methyl]benzoic acid, 4-[(5-chlor-2-{[(2R)-2-fluoropropyl](pyridin-2-ylsulfonyl)amino}-4-methylphenoxy)methyl]benzoic acid, 4-[(2-{[(2R)-3-fluor-2- methylpropyl](pyridin-2-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl]benzoic acid, 4-[(2-{[(2S)-3-fluor-2- methylpropyl](pyridin-2-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl]benzoic acid, 4-{[(6-{[(2R)-2-fluorobutyl](pyridin-2-ylsulfonyl)amino}-2,3-dihydro-1H-inden-5-yl)oxy)methyl} benzoic acid, 4-{[(6-{[(2S)-2-fluorobutyl](pyridin-2-ylsulfonyl)amino}-2,3-dihydro-1H-inden-5-yl)oxy)methyl}benzoic acid, 4-[(5-chlor-2-{[(2R)-2-fluoropropyl] (pyridin-3-ylsulfonyl)amino}-4-methylphenoxy)methyl]benzoic acid, 4-[(5-chlor- 2-{[(2S)-2-fluoropropyl](pyridin-3-ylsulfonyl)amino}-4-methylphenoxy)methyl] benzoic acid, 4-[(2-{[(2S)-2-fluoropropyl](pyridin-3-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl]benzoic acid, 4-[(2-{[(2R)-2-fluoropropyl](pyridin-3-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl] benzoic acid, 4-{[(6-{[(2S)-2-fluoropropyl](pyridin-3-ylsulfonyl)amino}-2,3-dihydro-1H-inden-5-yl)oxy)methyl} benzoic acid and 4-{[(6-{[(2R)-2-fluoropropyl](pyridin-3-ylsulfonyl)amino}-2,3-dihydro-1H-inden-5-yl)oxy)methyl}benzoic acid, or a pharmaceutically acceptable salt thereof. These compounds have an EP1 receptor antagonist effect and may be used for treating the dysfunction pollakiuria.

EFFECT: preparing the sulfonamide compounds with a strong EP1 receptor antagonist effect.

23 cl, 24 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrimidine derivatives and their pharmaceutically acceptable salts possessing the properties of a HIV replication inhibitor. In formula (I'): , R1 means a hydrogen atom; R7 means a hydrogen atom; C1-6alkyl; R8 means a hydrogen atom; C1-6alkyl; R4 means cyano; R9 means -CH=CH-CN; R5 means C3-7cycloalkyl; C1-6alkyloxy; aryl; Het; C1-6alkyl substituted by a radical specified in hydroxy, C1-6alkyloxy, cyano, amino, mono- and di-C1-6alkylamino, C1-6alkylcarbonylamino, aryl, Het, dioxoalanine optionally substituted by one or two C1-6alkyl radicals, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl optionally substituted by C1-6alkyl or C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, aryl C1-6alkyloxycarbonyl and C3-7cycloalkyl; or R5 means C1-6alkyl substituted by two C1-6alkyloxy radicals; R6 means a hydrogen atom or C1-6alkyl; X means -NR1- or -O; the values of Het are presented in the patent claim. The invention also refers to a pharmaceutical composition containing said compounds.

EFFECT: preparing the pharmaceutically acceptable salts possessing the properties of a HIV replication inhibitor.

9 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (1) and pharmaceutically acceptable salts thereof, which exhibit inhibitory activity on phospholipase A2 enzyme and therefore have prostaglandin and/or leucotriene production suppressing action. In formula X is a halogen atom, cyano group, C1-C3 alkyl group, which can be substituted with halogen atoms, C1-C3 alkoxy group or hydroxy group, C2-C4 alkenyl group, C1-C3 alkoxy group or hydroxy group; Y is a hydrogen atom or C1-C3 alkyl group; Z is C1-C3 alkyl group; G is selected from formulae and , where in formulae (G2) and (G5) R4 is a hydrogen atom or C1-C6 alkyl group which can be substituted with halogen atoms; D is -NR10C(O)-, -C(O)NR10-, -S(O)2NR10- or -N(R11)-; R10 is a hydrogen atom; R11 is a hydrogen atom or C1-C3 alkyl group; A is a single bond, C1-C6 alkylene, which can be substituted with a phenyl group, or C2-C4 alkenylene; Q is a phenyl group or a 5-6-member aromatic heterocyclic group containing 1-3 heteroatoms selected from N, O, S, optionally substituted with a benzene ring; R5, R6 and R7 all or independently denote a hydrogen atom, a halogen atom, C1-C6 alkyl group which can be substituted with halogen atoms, C1-C6 alkoxy group which can be substituted with halogen atoms, phenyloxy group, phenyl group or a 5-6-member aromatic heterocyclic group containing 1-3 heteroatoms selected from N, O, where said phenyl group and 5-6-member aromatic heterocyclic group can be substituted with a C1-C3 alkyl group which can be substituted with halogen atoms or a C1-C3 alkoxy group. The invention also relates to specific compounds, a medicinal agent, a pharmaceutical composition, a phospholipase A2 enzyme activity inhibitor and a treatment method.

EFFECT: improved method.

21 cl, 56 tbl, 561 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylpyrrolidinyl methylpyrrolidine amides of formula , where R, R1, R2 and R3 are identical or different and independently denote H, (C1-C4)alkyl, CF3; R4 denotes phenyl, cyclohexyl, pyridinyl, furanyl, isoxazolyl, quinolinyl, naphthyridinyl, indolyl, benzoimidazolyl, benzofuranyl, chromanyl, 4-oxo-4H-chromenyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxolyl and 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e]][1,4]diazepinyl; where said R4 is optionally substituted one to more times with a substitute selected from halogen, hydroxy, (C1-C4) alkyl, (C1-C4) alkoxy, CF3, hydroxymethyl, 2-hydroxyethylamino, methoxyethylamide, benzyloxymethyl, piperidinyl, N-acetylpiperidinyl, pyrrolyl, imidazolyl, 5-oxo-4,5-dihydropyrazolyl; or pharmaceutically acceptable salt thereof or enantiomer or diastereomer thereof.

EFFECT: compounds have modulating activity on histamine H3 receptor, which enables use thereof to prepare a pharmaceutical composition.

10 cl, 3 dwg, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylbipyrrolidine carboxamides of formula , where R denotes (C1-C4)-alkyl; R1 and R2 are identical or different and independently denote H, (C1-C4)-alkyl, CF3; R3 denotes H; R4 denotes cyclopropyl, cyclopentyl, cyclohexyl, bicyclo[2,2,1]heptyl, cyclopentylmethyl, tetrahydropyranyl, furanyl, oxazolyl, isoxazolyl and pyrazolyl; where R4 is optionally substituted one or more times by a substitute selected from methyl, ethyl, pyridinyl, 2-oxo-2H-pyridin-1-yl; or a pharmaceutically acceptable salt thereof, an enantiomer or a diastereomer thereof.

EFFECT: compounds have activity which binds to the H3 ligand, which allows use thereof to prepare a pharmaceutical composition for treating central nervous system diseases.

10 cl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylbipyrrolidine carboxamides of formula , where values of R, R1, R2, R3 and R4 are given in claim 1.

EFFECT: compounds have activity which binds to the H3 ligand, which allows use thereof in pharmaceutical compositions for treating sleep disorder.

10 cl, 1 tbl, 4 dwg, 153 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or pharmaceutically acceptable salts thereof, where W is where each R4 independently denotes H or CN; R2 denotes a cycloalkyl which can be independently substituted with two of the following substitutes: C(1-3)alkyl; Z denotes H; J denotes CH or N; X denotes or ; where R1 denotes -ORa, -CN, -NA1A2, -SO2CH3, -COORa, -CO2CH3, -CH2-NA1A2, -CONA1A2, -CH2ORa, -NHCH2CH2ORa, -OC(1-4)alkylNA1A2, OCH2CO2Ra and tetrazolyl; Rz and Ry independently denotes H or -C(1-4)alkyl, where both Rz may have syn or anti stereochemistry; alternatively both Rz in syn interaction may be taken together to form -(CH2)n-, where n equals 2; R3 denotes C(1-3)alkyl-CF3 or -COCH3; A1 denotes H or -C(1-4)alkyl; A2 denotes H or -C(1-4)alkyl; alternatively, A1 and A may be taken together with a nitrogen atom with which they are bonded to form a heterocyclic ring selected from: , where Ra denotes H or C(1-4)alkyl; Rbb denotes H, -C(1-4)alkyl, and -CH2CO2H, where cycloalkyl relates to a partially unsaturated ring with 6 carbon atoms. The invention also relates to specific compounds of formula I, a pharmaceutical composition based on the compound of formula I and methods of treating inflammation and autoimmune diseases.

EFFECT: novel compounds of formula I which are useful as c-fms inhibitors are obtained.

10 cl, 2 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, where Q is phenyl or pyridinyl; A is pyrazolyl or triazolyl, where each A is independently additionally unsubstituted or substituted with 1 or 2 substitutes represented by Ra, or A is formula (a); Va is C(R4), Vb is N or C(R5) and Vc is N; or Va is N, Vb is C(R5) and Vc is N or C(R6); R4 is hydrogen, R5 is hydrogen, C1-6alkyl, -ORb, -SRb, aryl, selected from phenyl, heteroaryl, selected from thienyl, or cycloalkyl, selected from cyclopropyl; R6 is hydrogen or aryl, selected from phenyl; R7 is hydrogen or C1-6alkyl; R3 is hydrogen, C1-3alkyl, -OH, -S(O)2R1, or heteroaryl, selected from tetrazolyl, where the heteroaryl is bonded to a nitrogen atom through a ring carbon atom; Rb, Rx, Ry, Rza, Rzb, Rw, Re, Rk, Rm, Rn, Rq and R1, in each case, are independently hydrogen, C1-3alkyl or C1-3haloalkyl; and Rf, in each case, is independently hydrogen, C1-3alkyl or -OH (the rest of the substitutes assume values given in the claim). The invention also relates to a pharmaceutical composition, having inhibiting action on DGAT-1, which contains a compound of formula (I), and a treatment method.

EFFECT: compounds of formula (I) as DGAT-1 inhibitors are provided.

16 cl, 9 dwg, 1 tbl, 127 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a benzazepin compound of general formula (1) possessing the property of vasopressin antagonist, and to a based pharmaceutical composition. In general formula (1) R1 means a group (1-1) or (1-3) to (1-7): (1-1) represents a group -CO-(CH2)n-COR2 wherein n means an integer 1 to 4, R2 means (2-1) hydroxyl group; (2-2) lower alkoxy group if necessary substituted by hydroxyl group, lower alkanoyl group, lower alkanoyloxy group, lower alkoxycarbonyloxy group, cycloalkyloxycarbonyloxy group or 5-methyl-2-oxo-1,3-dioxol-4-yl; or (2-3) amino group if necessary substituted by hydroxyl lower alkyl; (1-3) represents a group -CO-(CH2)p-O-CO-NR5R6 wherein p means an integer 1 to 4, R5 means lower alkyl group, and R6 means a group of lower alkoxycarbonyl lower alkyl; (1-4) represents a group -CO-(CH2)q-X-R7 wherein q means an integer 1 to 4, X means an oxygen atom, a sulphur atom or a sulphonyl group, and R7 means a group of carboxy lower alkyl or a group of lower alkoxycarbonyl lower alkyl; (1-5) represents a group -CO-R8, (wherein R8 means (8-1) alkyl group if necessary substituted by a halogen atom, lower alkanoyloxy group or phenyl group (substituted by dihydroxyphosphoryloxy group wherein hydroxyl groups may be substituted by benzyl groups, and lower alkyl group), a (8-2) lower alkoxy group substituted by a halogen atom, lower alkanoyloxy group or dihydroxyphosphoryloxy group, (8-3) pyridyl group or (8-4) lower alkoxyphenyl group; (1-6) represents a lower alkyl group substituted by a group consisting of a lower alkylthio group, a dihydroxyphosphoryloxy group and a lower alkanoyloxy group; and (1-7) represents a peptide residue if necessary substituted by one or more protective groups.

EFFECT: compound of formula (1) is able to maintain the blood tolvaptan level for a long period of time that enables providing the desired pharmaceutical effects.

FIELD: chemistry.

SUBSTANCE: compound, represented by formula

,

or its pharmaceutically acceptable salt, where Y1 represents nitrogen atom or group, represented by CRA, Y2 represents nitrogen atom or group, represented by CRB, Y3 represents nitrogen atom or group, represented by CRC, RA, RB and RC, which can be similar or different, each represents hydrogen atom, etc. (except in the case, when Y1 is CRA, Y2 is CRB and Y3 is CRC), X represents oxygen atom, etc., R1 represents C1-C6alkyl group, etc., R3 represents optionally substituted phenyl group, etc., R4 represents hydrogen atom, etc., and R5 represents optionally substituted phenyl group, etc.), possesses inhibiting action with respect to S1P binding with its receptor Edg-1(SlP1).

EFFECT: obtaining composition, which can be used as therapeutic medication in case of autoimmune diseases, rheumatoid arthritis, asthma, atopic dermatitis, rejection after organ transplantation, cancer, retinopathy, psoriasis, osteoarthritis or age-related macula lutea degeneration, etc.

13 cl, 9 ex, 1 tbl, 4 dwg

FIELD: chemistry.

SUBSTANCE: present invention relates to novel compounds of formula , where X is -O-; values of Ar, R1-R5, R11 are given in the formula of invention. The said compounds have inhibitory effect on HIV reverse transcriptase. The invention also relates to a pharmaceutical composition containing the invented compounds or their pharmaceutically acceptable salts.

EFFECT: obtaining new compounds and a pharmaceutical composition containing said compounds.

8 cl, 61 ex, 2 tbl

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