Mono-sodium salt 5-[[(2,3-difluorophenyl)methyl]thio]-7-[[2-hydroxy-1-(hydroxymethyl)-1-methyethyl]amino]-thiazole[4,5-d]pyrimidine-2(3h)-on as modulator of activeness of chemokine receptors, its applications and pharmaceutical composition

FIELD: chemistry; pharmacology.

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

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

10 cl, 2 ex

 

The present invention relates to triazolopyrimidines connection, methods and intermediate compounds used for its production, pharmaceutical compositions containing it and to its use in therapy.

Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules represent a growing superfamily of proteins with a molecular mass of 8-14 kDa characterized by conservative motif of four cysteine residues. Currently, the superfamily of chemokines consists of three groups, demonstrating the characteristic structural motifs, namely a family of Cys-X-Cys (C-X-C), Cys-Cys (C-C) and Cys-X3-Cys (S-X3-With). Family C-X-C and C-C have similar sequence and differ from each other by insertion of one amino acid between NH-proximal pair of cysteine residues. The family of C-X3-Differs from the other two families that contains the insertion of three amino acids between NH-proximal pair of cysteine residues.

Chemokines of the C-X-C include some powerful chemoattractants and activators of neutrophils, such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP2).

Chemokines C-C include powerful chemoattractant monocytes and lymphocytes but not neutrophils. Examples include human macrophage chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted; regulated upon activation, normally expressed and secretory cells called T-cells), eotaxin and macrophage inflammatory proteins 1α and 1β (MIP-1α and MIP-1β).

Chemokine C-X3- (Also known as fractalkine) is a potent chemoattractant and activator of microglia in the Central nervous system (CNS), as well as monocytes, T cells, NK cells and mast cells.

Studies have demonstrated that the actions of chemokines is mediated by subfamilies associated with G-protein receptors, including receptors, denoted as CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for a family of S-C); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for a family of C-X-C) and CX3R1 for a family of C-X3-C. These receptors represent a suitable target for drug development, because the agents that modulate these receptors, can be useful in the treatment of disorders and diseases, such as diseases mentioned above.

In WO-01/25242 revealed a number triazolopyrimidine compounds which are useful as antagonists of the CXCR2. Now unexpectedly found that the compound, l is relevant within the scope of WO-01/25242, but not specifically disclosed there, has an improved pharmacological profile compared with the most similar structure to the compounds of WO-01/25242, that is, Examples 4 and 7.

Therefore, according to the present invention proposed a compound of formula (I) and its pharmaceutically acceptable salt, or their solvate:

The compound of formula (I) are able to exist in tautomeric form. The tautomers and mixtures thereof are also aspect of the present invention.

According to the invention is also a method for obtaining the compound (I), which includes the interaction of the compounds of formula (II):

where R represents a C1-6alkyl, with an acid

and possible after the formation of pharmaceutically acceptable salts.

Preferably R represents ethyl or methyl, more preferably methyl. Preferably the reaction is carried out with the use of dioxane and HCl. Preferred compounds according to the invention receive according to the procedures described in this description as examples.

The compound of formula (II) can be obtained from the corresponding compounds of formula (III):

where R2is a halogen, by treatment with compound ROH in the presence of a base. Preferably, the soybean is inania formula (III) is treated with sodium methylate. Preferably R2represents chloro.

The compounds of formula (III) can be obtained using the following sequence:

Suitable reagents for stages a-f well-known specialists in this field of technology. Preferably stage a-f carried out as described in this description as examples.

Suppose that the compound of formula (II) is novel and forms a further aspect of the invention.

Specialists in the art will note that in the methods of the present invention certain functional groups such as hydroxyl or amino groups in the source reagents or intermediate connection may be in need of protection by protective groups. Thus, obtaining the compounds of formula (I) may include, at an appropriate stage to delete one or more than one protective group. A complete description of setting and removing protection from functional groups described in "Protective Groups in Organic Chemistry", edited by J. W. F. McOmie, Plenum Press (1973) and ' Protective Groups in Organic Synthesis", 2nd edition, by T.W. Greene &P.G.M. Wuts, Wiley-lnterscience (1991).

The above-mentioned compound of formula (I) can be converted into its pharmaceutically acceptable salt, or MES, preferably obtained by joining the Foundation of the salt, such as with the ü sodium, potassium, calcium, aluminum, lithium, magnesium, zinc, benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, ethyldiamine, meglumine, tromethamine or procaine, or received by the accession acid salt such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p-toluensulfonate.

The compound of formula (I) have activity as a pharmaceutical agent, in particular as a modulator of the activity of chemokine receptor (especially CXCR2), and can be used in the treatment (therapeutic or prophylactic) of conditions/diseases in human and animals, a cause of aggravation or occurrence of which is excessive or unregulated production of chemokines. Examples of such conditions/diseases include (condition/illness):

(1) (the respiratory tract) obstructive Airways disease, including chronic obstructive pulmonary disease (COPD); asthma, such as bronchial, allergic, hereditary, acquired bronchial asthma and dust asthma, particularly chronic or neglected asthma (e.g. late asthma and hypersensitivity of the respiratory tract); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including caseous rhinitis, hypertrophic rhinitis, purulent rhinitis, dry rhinitis is rhinitis medication; membranous rhinitis including croupous, fibrinous and pseudobinary rhinitis and scrupulously rhinitis; seasonal rhinitis including nervous rhinitis (hay fever) and vasomotor rhinitis; sarcoidosis, lung farmer's and related diseases, pneumovirus and idiopathic interstitial pneumonia;

(2) (bone and joints) rheumatoid arthritis, seronegative of spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis and the disease Reiter), Behcet's disease, Sjogren syndrome and systemic sclerosis;

(3) (skin) psoriasis, atopic dermatitis, contact dermatitis, and other eczematous dermatitises, seborrhoeic dermatitis, red flat zoster, bladderwort, the bullous disease, bullous bullosa, urticaria, angioneurotic oedema, vasculitis, erythema, cutaneous eosinophilia, uveitis, alopecia alopecia and vernal conjunctivitis;

(4) (gastrointestinal tract) coeliac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, indeterminate colitis, microscopic colitis, inflammatory bowel disease, irritable bowel syndrome, non-inflammatory diarrhea, food allergies, which occur away from the intestine, such as migraine, rhinitis and eczema;

(5) (Central and peripheral nervous system, neurodegenerative diseases, etc is responsible for the dementia disorder, for example, Alzheimer's disease, amyotrophic lateral sclerosis and other motor neuron disease, a disease of Creutzfeldt-Jakob disease and other prion diseases, HIV encephalopathy (complex AIDS-dementia), Huntington's disease, fronto-temporal dementia, dementia with calves Levi and vascular dementia; polyneuropathy, such as Guillain-Barre syndrome, chronic inflammatory demyelinizing polyradiculoneuropathy, multifocal motor neuropathy, plexopathy; demyelination of the CNS, such as multiple sclerosis, acute disseminated/haemorrhagic encephalomyelitis, and subacute sclerosing panencephalitis; neuromuscular disorders such as myasthenia heavy and the syndrome of Lambert-Eaton; spinal disorders such as tropical spastic prepares syndrome and muscle stiffness (stiff-man syndrome); paraneoplastic syndromes, such as cerebral degeneration and encephalomyelitis; CNS injury; migraine; and the blow;

(6) (other tissues and systemic disease) atherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus erythematosus, Hashimoto's thyroiditis, type I diabetes, nephrotic syndrome, eosinophilic fasciitis, Hyper-IgE syndrome, lepromatous leprosy and idiopathic thrombocytopenic purple; postoperative adhesions and sepsis;

(7) the impact of Subar headline hemorrhage, reperfusion injury in the heart, brain, limbs, and other peripheral organs;

(8) (transplant rejection), acute or chronic, after, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic disease graft-versus-host;

(9) cancers, especially non-small cell lung cancer (NSCLC), malignant melanoma, prostate cancer and squamous cancer, and tumor metastases;

(10) diseases in which angiogenesis is associated with elevated chemokine levels of CXCR2 (e.g., NSCLC, diabetic retinopathy);

(11) the cystic fibrosis;

(12) burn wounds and chronic skin ulcers;

(13) diseases of the reproductive system (e.g., disorders of ovulation, menstruation and implantation, premature birth, endometriosis).

Thus, in the present invention proposed a compound of formula (I)or its pharmaceutically acceptable salt, or MES, as defined herein above for use in therapy.

Preferably the connection according to the invention are used to treat diseases in which chemokinesis receptor belongs to the subfamily of chemokine receptor CXC, more preferably chemokine receptor-a target is a receptor CXCR2.

Special conditions that may be subjected to the treatment compound according to the invention, are rheumatoid arthritis, diseases, angiogenesis which is associated with elevated chemokine levels of CXCR2 and HOL. It is preferable to use the compounds according to the invention for the treatment of rheumatoid arthritis and respiratory disease.

As a further aspect of the present invention the compound of formula (I) may find application as an antagonist of the receptor CX3CR1. It is expected that such a connection is particularly useful in the treatment of disorders of the Central and peripheral nervous system and other conditions characterized by activation of microglia and/or infiltration of leukocytes (e.g., shock/ischemia and head trauma). In the following aspect according to the present invention proposed the use of the compounds of formula (I)or its pharmaceutically acceptable salt, or MES, as defined herein before in the manufacture of drugs for use in therapy.

In another aspect according to the present invention proposed the use of the compounds of formula (I)or its pharmaceutically acceptable salt, or MES, as defined herein before in the manufacture of drugs for the treatment of diseases or conditions in humans, in which modulation of the activity of the chemokine receptor has a beneficial effect.

In the context of infusion is its description, in the absence of specific indications to the contrary, the term "therapy" also includes "prevention". The terms "therapeutic" and "therapeutically" should be interpreted accordingly.

Further according to the invention, a method of treating a chemokine-mediated disease, wherein the chemokine binds to the chemokine receptor (in particular, CXCR2), including introduction to the patient a therapeutically effective amount of the compounds of formula (I)or its pharmaceutically acceptable salt, or MES, as defined herein before.

According to the invention is also a method of treatment of inflammatory diseases, in particular rheumatoid arthritis, COPD, respiratory disease or psoriasis, patients suffering from the specified disease or risk of development, which includes an introduction to the patient a therapeutically effective amount of the compounds of formula (I)or its pharmaceutically acceptable salt, or MES, as defined herein before.

For the above-mentioned therapeutic uses the entered dosage will vary depending on the compound, the route of administration, required treatment and identified disorders.

The compound of formula (I) and its pharmaceutically acceptable salt and solvate can be used is designed as such, but in the General case will be introduced in the form of pharmaceutical compositions in which the compound/salt/MES (active ingredient) of formula (I) is in Association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the method of administration of the pharmaceutical composition will preferably contain from 0.05 to 99 wt.% (mass%), more preferably from 0.05 to 80 wt.%, even more preferably from 0.10 to 70 wt.% and even more preferably from 0.10 to 50 wt.% the active ingredient, where the weight percents are calculated on the total weight of the composition.

According to the present invention also proposed a pharmaceutical composition comprising a compound of formula (I)or its pharmaceutically acceptable salt, or MES, as defined herein before in Association with a pharmaceutically acceptable adjuvant, diluent or carrier.

In addition, according to the present invention, a method for preparing the pharmaceutical compositions according to the invention, which involves mixing the compounds of formula (I)or its pharmaceutically acceptable salt, or MES, as defined herein before, with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical composition can be injected locally (for example, light is/or in the respiratory tract, or skin) in the form of solutions, suspensions, heptapteridae aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or subcutaneous injection, or rectally introduction in the form of suppositories or transdermal. The connection according to the invention is preferably administered orally.

In addition, the invention relates to combination therapies, where the compound of formula (I)or its pharmaceutically acceptable salts, their MES or hydrolyzable in vivo ester, or pharmaceutical composition or drug containing the compound of formula (I), is administered simultaneously or sequentially with therapy and/or agent for the treatment of any of the following diseases: asthma, allergic rhinitis, cancer, HOL, rheumatoid arthritis, psoriasis, inflammatory bowel disease, irritable bowel syndrome, osteoarthritis or osteoporosis.

In particular, for the treatment of inflammatory diseases, rheumatoid arthritis, psoriasis, inflammatory bowel disease, irritable bowel syndrome, COPD, asthma and allergic rhinitis the compounds according to the invention can be combined with such agents as inhibitors of TNF-αsuch as anti - TNF monoclonal antibodies (t is such as Remicade, CDP-870 and D2E7) and TNF receptor immunoglobulin molecules (such as Enbrel), non-selective inhibitors of MOR-1/SOH-2 (such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, Ketoprofen and ibuprofen, fenamate, as, for example, mefenamovaya acid, indomethacin, sulindac, Amazon, pyrazolones, such as phenylbutazone, salicylates such as aspirin), inhibitors MOR-2 (such as meloxicam, celecoxib, rofecoksib, valdecoxib, etoricoxib), methotrexate low dose, lefunomide (lefunomide); ciclesonide; hydroxychloroquine, d-penicillamine, auranofin or parenteral or oral insertion gold. In addition, inflammatory bowel disease and irritable bowel syndrome suitable agents include sulfasalazin and drugs group 5-ASA, steroids, local and systemic effects, immunomodulators and immunosuppressants, antibiotics, probiotics and antiintegrin.

In addition, the present invention is related to a combination of compounds according to the invention with a leukotriene biosynthesis inhibitor, inhibitor of 5-lipoxygenase (5-LO) or an antagonist of a protein that activates 5-lipoxygenase (FLAP), such as zileuton; ABT-761; fenleuton (fenleuton); tepoxalin; Abbott-79175; Abbott-85761; N-(5-substituted)-thiophene-2-alkylsulfonamides; 2,6-di-tert-butylphenol-hydrazones; methoxide hydroporinae, such as Zeneca ZD-2138; the compound SB-210661; pyridinyl-substituted 2-cyanonaphthalene compounds such as L-739010; 2-cyanopyridine compounds such as L-746530; indologie and quinoline compounds such as MK-591, MK-886, and BAY x 1005.

In addition, the present invention is related to a combination of compounds according to the invention with a leukotriene receptor antagonist LTB4, LTC4, LTD4and LTE4selected from the group consisting of phenothiazines-3-ones such as L-651392; amidinami compounds such as CGS-25019c; benzoxazepine, such as ontazolast; benzonorbornadiene, such as BIIL 284/260; and such compounds as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A) and BAY×7195.

In addition, the present invention is related to a combination of compounds according to the invention with a PDE4 inhibitor including an inhibitor of the isoform PDE4D.

In addition, the present invention is related to a combination of compounds according to the invention with antihistamine receptor antagonists H1such as cetirizine, loratadine, desloratadine, Fexofenadine, astemizole, azelastine and chlorpheniramine.

In addition, the present invention is related to a combination of compounds according to the invention with gastroprotective receptor antagonist N2.

In addition, this image is eenie still refers to the combination of compounds according to the invention with vasoconstrictor sympathomimetic agent, which α1and α2-adrenomimetics, such as propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, Oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, Xylometazoline hydrochloride and Ethylmorphine hydrochloride.

In addition, the present invention is related to a combination of compounds according to the invention with anticholinergic agents such as ipratropium bromide; Tiotropium bromide; oxytrope bromide; pirenzepine; and telenzepine.

In addition, the present invention is related to a combination of compounds according to the invention with from β14-adrenoceptor agonists, such as metaproterenol, isoproterenol, izoprenalin, albuterol, salbutamol, formoterol, salmeterol, terbutaline, ortsiprenalin, bitolterol mesilate and pirbuterol; or methylxanthine, including theophylline and aminophylline; cromoglicate sodium; or an antagonist of muscarinic receptors (M1, M2 and M3).

In addition, the present invention is related to a combination of compounds according to the invention with mimetic insulin-like growth factor type I (IGF-1).

In addition, the present invention is related to a combination of compounds according to the invention with the input inhalation by glucocorticoid with reduced systemic side effects, such as prednisone, prednisolone, flunizol is d, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate and mometasone furoate.

In addition, the present invention is related to a combination of compounds according to the invention with an inhibitor of the matrix metalloprotease (MMPs), i.e. stromelysins, collagenases and gelatinase and agriquality; in particular, collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10) and stromelysin-3 (MMP-11 and MMP-12.

In addition, the present invention is related to a combination of compounds according to the invention with other modulators of the functioning of chemokine receptors such as CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for a family of S-C); CXCR1, CXCR3, CXCR4 and CXCR5 (for a family of C-X-C) and CX3R1 for a family of C-X3-S.

In addition, the present invention is related to a combination of compounds according to the invention with antiviral agents such as viracept, AZT, acyclovir, and famciclovir, and antiseptic compounds, such as valant (valant).

In addition, the present invention is related to a combination of compounds according to the invention with cardiovascular agents such as calcium channel blockers, agents, reduces the content of lipids, such as statins, fibrates, beta-blockers, ACE inhibitors (angiotensin converting enzyme), antagonis the s angiotensin receptor-2 and platelet aggregation inhibitors.

In addition, the present invention is related to a combination of compounds according to the invention with CNS agents such as antidepressants (such as sertraline), medicines for Parkinson's disease (such as deprenyl, L-DOPA, requip, mirapex inhibitors IAIA (monoamine-oxidase), such as selgin and rasagiline, inhibitors of COMT (catechol-o-methyltransferase), such as tasmar, a-2 inhibitors, inhibitors of reuptake of dopamine, NMDA antagonists (M-methyl-D-aspartate), agonists nicotine, dopamine agonists and inhibitors neural synthase nitric oxide) and drugs against Alzheimer's disease, such as donepezil, taken inhibitors SOH-2, propentofylline or metrifonate.

In addition, the present invention is related to a combination of compounds according to the invention with (1) tryptase inhibitors; (2) antagonists of platelet activating factor (PAF); (3) inhibitors of interleukin converting enzyme (ICE); (4) inhibitors of IMPDH (insimenator-dehydrogenase); (5) inhibitors of adhesion molecules, including antagonists of VLA-4; (6) cathepsins; (7) inhibitors MAR-kinases; (8) inhibitors of glucose-6-phosphate-dehydrogenase; (9) antagonists kinin receptor B1and In2; (10) anti-gout, such as colchicine; (11) inhibitors of xanthine oxidase, for example allopurinol; (12) the means for facilitating allocation machevo the acid, for example probenecid, sulfinpirazonom and benzbromarone; (13) means that increase the secretion of growth hormone; (14) transforming growth factor (TGFβ); (15) a platelet growth factor (PDGF); (16) fibroblast growth factor for example basic fibroblast growth factor (bFGF); (17) granulocyte-macrophage colony-stimulating factor (GM-CSF); (18) capsaicinoid cream; (19) receptor antagonists tachykinin NK1and NK3selected from the group consisting of NKP-608C; SB-233412 (talnetant); and D-4418; (20) elastase inhibitors selected from the group consisting of UT-77 and ZD-0892; (21) inhibitors of TNFδ-converting enzyme (TACE); (22) inhibitors induced synthase nitric oxide (iNOS) or (23) molecule homologous receptors of chemoattractants expressed on the surface of Th2 dysbalance cells (CRTH2 antagonists).

Compounds of the present invention can also be used in combination with protivostoyanie agents such as raloxifene, droloxifene, lasofoxifene or fosomax, and immunosuppressive agents such as FK-506, rapamycin, cyclosporine, azathioprine and methotrexate.

Compounds according to the invention can also be used in combination with existing therapeutic agents for the treatment of osteoarthritis. Suitable agents for use in combination include conventional non-steroidal protivo policeline agents (hereinafter NSAID), such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, Ketoprofen and ibuprofen, fenamate, as, for example, mefenamovaya acid, indomethacin, sulindac, Amazon, pyrazolones, such as phenylbutazone, salicylates, such as aspirin, inhibitors SOH-2, as, for example, celecoxib, valdecoxib, rofecoksib, etoricoxib, analgesics and intraarticular therapies, such as corticosteroids and hyaluronic acids such as hyalgan and synvisc, and receptor antagonists RH.

Compounds according to the invention can also be used in combination with existing therapies for cancer treatment. Suitable agents for use in combination include:

(1) antiproliferative/antineoplastic drugs and their combinations, which are used in medical Oncology, such as alkylating agents (for example, cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan and nitrosoanatabine); antimetabolites (for example antifolates such as ftorpirimidinu like 5-fluorouracil and tegafur, raltitrexed, methotrexate, citizenoriented, hydroxyurea, gemcitabine and paclitaxel (TaxoI®)); antitumor antibiotics (for example anthracyclines like adriamycin, bleomycin doxorubicin, the daunomycin, epirubicin, idarubitsina, mitomycin-C, dactinomycin and mithramycin); antimitoticescoe agents (for example Vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine, and taxaide like Taxol and Taxotere); and topoisomerase inhibitors (for example, epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);

(2) cytostatic agents such as antiestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and idoxifene), negative regulators of estrogen receptors (for example fulvestrant), antiandrogens (for example, bikalutamid, flutamide, nilutamide and ciproteron acetate), LHRH antagonists (growth hormone-releasing factor, luteinizing hormone or LHRH agonists (for example, gecelerin, leiprorelina, bullerin), POCs (for example, megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, varsol and exemestane) and inhibitors of 5α-reductase such as finasteride;

(3) agents that inhibit the invasion of cancer cells (for example, inhibitors of metalloproteinases, such marimastat, and inhibitors of the functioning of the receptor plasminogen activator urokinase);

(4) inhibitors of the function of growth factors, for example such inhibitors include antibodies to growth factors, antibodies to receptors of growth factors (e.g., anti-bb2-antibody trastuzumab [Herceptin TM] and anti-rbb2-antibody cetuximab [S]), inhibitors farnesyltransferase, inhibitors tyrosinekinase and inhibitors of serine/trainingin, for example, inhibitors of the family of epidermal growth factors (e.g., inhibitors tyrosinekinase EGFR-family, such as N-(3-chloro-4-forfinal)-7-methoxy-6-(3-morpholinopropan)hinzelin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)hinzelin-4-amine (erlotinib, OSI-774) and 6-acrylamide-N-(3-chloro-4-forfinal)-7-(3-morpholinopropan)hinzelin-4-amine (CI 1033)), for example inhibitors of the family of secreted platelet growth factors and, for example, inhibitors of the family of growth factor hepatocyte;

(5) protivougonnye tools, such as tools, inhibiting the effects of growth factor vascular endothelial (for example, an antibody against growth factor endothelial cells of blood vessels bevacizumab [AvastinTM], compounds such as disclosed in international patent applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354)and compounds acting via other mechanisms (for example, linomide, inhibitors of the function of integrins αvβ3 and angiostatin);

(6) causing vascular damage agents, such as combretastatin A4 and compounds disclosed in international patent applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(7) antisense therapies, for example those which direction the Lena on the target, above, such as ISIS 2503, an anti-ras antisense therapy;

(8) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT approaches (gene therapy based on the activation of anticancer drugs genetic constructs), such as using sitoindosides, timedancing or bacterial enzyme nitroreductase, and approaches to enhance the endurance of patients chemotherapy or radiation therapy, such as gene therapy multidrug resistance; and

(9) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of tumor cells, such as transfection with cytokines, such as interleukin-2, interleukin 4 or granulocyte-macrophage colony-stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using antiidiotypic antibodies.

Now the invention will be further illustrated by reference to the following examples. In these examples, the spectra of nuclear magnetic resonance (NMR) is registrirovali spectrometer Varian Unity Inova 300 or 400 MHz and mass spectrometry (MS) spectra were recorded on a spectrometer Agilent MSD. Where necessary, the reaction was carried out in an inert atmosphere of nitrogen. In General chromatography was performed using Matrex Silica 60®(35-70 micron) or Prolabo Silica gel 60®(35-70 micron)suitable for flash chromatography on silica. Purification by high performance liquid chromatography was performed using a system AutoClean Gilson. Reduction TPL and DMSO used in the examples mean melting point and dimethyl sulfoxide, respectively. Compounds were named using the program on the assignment of names ACD/labs 6.0.

Example 1

5-[[(2,3-differenl)methyl]thio]-7-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]-thiazolo[4,5-d]pyrimidine-2(3H)-he

a) 6-amino-2-[[(2,3-differenl)methyl]thio]-4(3H)-pyrimidinone

4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate (7,1 g) was added in portions to a stirred suspension of 60% sodium hydride (2.4 g) in anhydrous N,N-dimethylformamide (70 ml). After 1 hour, the solution was added 2,3-diferenciada (10 g) in anhydrous N,N-dimethylformamide (10 ml). Was stirred over weekend at room temperature. Was poured into a mixture of ice/water and the precipitate was collected by filtration to obtain 9.6 g of product. Yield 81%.

MS (APCI) (chemical ionization at atmospheric pressure) (+ve) 270 (M+H, 94%).

b) 4-amino-2-[[(2,3-differenl)methyl]thio]-1,6-dihydro-6-oxo-5-pyrimidinones ether ti is cyanic acid

The product from step (a) (28 g) and potassium thiocyanate (40,5 g) in N,N-dimethylformamide (583 ml) were heated together at 65°C. was Added pyridine (14,5 ml) and the solution was cooled to 5°C. was Slowly added bromine (5.0 ml) and the reaction mixture was stirred for 2 hours at 5-10°C. the Reaction mixture was poured into ice water (4200 ml)was stirred for 1 hour and the solid is collected by filtration, washed with water and ether to obtain 24 g of the product. Yield 70%.

MS (APCI) (+ve)327(M+H).

c) 2-amino-5-[[(2,3-differenl)methyl]thio]-thiazolo[4,5-d]pyrimidine-7(6N)-he

A mixture of the product from step (b) (12.1 g), N,N-dimethylformamide (70 ml) and water (20 ml) was heated to 120°C for 24 hours. Colourless solid precipitated from the solution, which was allowed to cool and the solid was collected by filtration receipt of 8.3 g of product. Yield 70%.

MS (APCI) (+ve) 327 (M+H).

d) 7-chloro-5-[[(2,3-differenl)methyl]thio]-thiazolo[4,5-d]pyrimidine-2-amine

The product from step (C) (10.0 g) suspended in chloride phosphoryla (55 ml). Was slowly added N,N-dimethylaniline (5.5 ml) and the reaction mixture was heated at the temperature of reflux distilled for 2 hours. Leave to cool, then poured into ice-intensive stirring; the temperature was not allowed to rise above 45° (added ice). Approximately 20 minutes was set temperature 30°C. obrazovavsheesya solid substance was collected by filtration and washed with water. Was purified column chromatography (EtOAc to 5%Meon in EtOAc) to give the 3,34 g of the product. Yield 31%.

MS (APCI) (+ve) 345 (M+H).

e) 2-[[2-amino-5-[[(2,3-differenl)methyl]thio]thiazolo[4,5-d]pyrimidine-7-yl]amino]-2-methyl-1,3-propandiol

The product from step (d) (1.5 g) suspended in NMP (10 ml)was then added to the base Hunya (1.5 ml) and 2-amino-2-methylpropanol (1,37 g). The reaction mixture was heated to 110°C in an atmosphere of N2within 4 hours. Added additional amount of 2-amino-2-methylpropanol (0,685 g) and heated at 110°C for 5 hours. The mixture was poured into water (400 ml) and the solid collected by filtration. Was purified column chromatography (EtOAc/methanol (95:5)) to obtain the 0,756 g of the product. Yield 42%.

MS (APCI) (+ve) 414 (M+H).

f) 2-[[2-chloro-5-[[(2,3-differenl)methyl]thio]thiazolo[4,5-d]pyrimidine-7-yl]amino]-2-methyl-1,3-propandiol

The product from step (e) (0,485 g) suspended in concentrated HCl (18 ml), which was then cooled to 15°C. was Added a mixture of water (15 ml) and acetonitrile (25 ml)to give solution. Was cooled to 5°and was added dropwise a solution of sodium nitrite (rate £ 0.162 g) in water (1 ml). Was stirred at 5°within a few hours, then left to warm during the night. The solution was cooled to -10°and was neutralized with ammonia, and then concentrated in vacuum. The precipitated yellow was collected by filtration and washed water is. Was dried in vacuum to obtain 0,339 g of the product. Yield 67%.

MS (APCI) (+ve) 433 (M+H).

g) 2-[[5-[[(2,3-differenl)methyl]thio]-2-methoxythiazole[4,5-d]pyrimidine-7-yl]amino]-2-methyl-1,3-propandiol

The product from step (f) (0,339 g) suspended in methanol (32 ml). Was added potassium hydroxide (0,088 g) and the mixture was stirred at 50°C for 20 minutes. Neutralized 2 N. HCl and the solvents were removed in vacuo to obtain a residue of orange color. Added water to remove inorganic substances and solid yellow substance was collected by filtration to obtain 0.3 g of the desired product. Output 90%.

MS (APCI) (+ve) 429 (M+H).

h) 5-[[(2,3-differenl)methyl]thio]-7-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]-thiazolo[4,5-d]pyrimidine-2(3H)-he

The product from step (g) (0.3 g) suspended in a mixture of dioxane (50 ml) and concentrated HCl (1 ml). Was added water (1 ml) and the resulting solution was heated at 60°C for 12 hours. Left to stand for a weekend. The solvents were removed in vacuo and the residue was transferred into the water. The precipitated yellow was collected by filtration and washed with water. Was purified by preparative HPLC (acetonitrile/0.1% ammonium acetate (90:10 to 95:5)) for 25 minutes with obtaining 0,063 g of the desired product. Yield 22%.

MS (APCI) (+ve) 415 (M+H).

1H NMR: δ (DMSO) 1.25 (3H, s), 3.54-3.66 (4H, m), 4.39 (2H, s), 4.65-4.69 (2H, t), 6.34 (1H, s), 7.12-7.20 (1H, m), 7.29-7.41 (2H, m), 12.43 (1H, s).

TPL 230-23° C.

Example 2

5-[[(2,3-differenl)methyl]thio]-7-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]-thiazolo[4,5-d]pyrimidine-2(3H) -, monosodium salt

The product from step (h) of Example 1 (0.87 g) suspended in water (80 ml)was added 1.0 M sodium hydroxide (3.0 ml), then methanol (15 ml) and the mixture was heated on the steam bath. When dissolution was nearly completed, the mixture was filtered while hot and the filtrate cooled during the night by getting after filtration of fluffy white precipitate. It was dried in a vacuum oven overnight at 50° (0,60 g).

MS (APCI) (+ve) 415 (M+H).

1H NMR: δ (DMSO) 1.23 (3H, s), 3.47-3.58 (4H, m), 4.37 (2H, s), 4.94 (2H, t), 5.29 (1H, s), 7.14 (1H, m), 7.31 (1H, m), 7.35 (1H, m).

TPL 238°C (decomp.).

Pharmacological data

Analysis of the binding of the ligand

[125I]IL-8 (human, recombinant) was purchased from Amersham (U.K.) with specific activity 2000 CI/mmol. All other reagents were of chemically pure. High levels hrCXCR2 expressed in SOME cells 293 (kidney cells of a human embryo 293, ESAS No. 85120602) (Lee et al. (1992) J. Biol. Chem. 267 pp.16283-16291). cDNA hrCXCR2 amplified and cloned from mRNA of human neutrophils. DNA cloned into PCRScript (Stratagene) and the clones identified using DNA. The coding sequence was subcloned into the eukaryotic expression vector RcCMV (Invitrogen). Plasmid DNA was obtained using Quiagen Megapre 2500, and transferrable in cells of SOME 293 using the reagent lipofectamine (Gibco BRL). Cells of vysokodispersnogo clone was collected in phosphate buffered saline containing 0.2% (wt./about.) ethylenediaminetetraacetic acid (EDTA), and centrifuged (200 g, 5 min). Cellular precipitate after centrifugation resuspendable in chilled on ice buffer for homogenization [10 mm HEPES (pH 7.4), 1 mm dithiothreitol, 1 mm EDTA, and a set of protease inhibitors (1 mm phenylmethylsulfonyl, 2 μg/ml soybean trypsin inhibitor, 3 mm benzamidine, 0.5 μg/ml leupeptin and 100 μg/ml bacitracin)] and the cells were left to swell for 10 minutes. The cell preparation was destroyed using a hand-held glass mortar/plastikowy homogenizer PTFE, and collected the cell membrane by centrifugation (45 min, 100000g, 4°). The membrane preparation was stored at -70°buffer for homogenization, supplemented salt solution Tyrode (Tyrode) (137 mm NaCl, 2.7 mm KCl, 0.4 mm NaH2PO4), 0.1% (wt./about.) gelatin and 10% (vol./about.) glycerol. All analyses were performed in 96-well filtration tablets MultiScreen 0.45 µm (Millipore, U.K.). Each analysis used ˜50 PM [125I]IL-8 and membranes (equivalent to ˜200000 cells) in the buffer for analysis [salt solution Tired, supplemented with 10 mm HEPES (pH 7.4), 1.8 mm CaCl2, 1 mm MgCl2, 0.125 mg/ml bacitracin and 0.1% (wt./about.) what elatina]. In addition, the compound of formula (I), corresponding to the Examples, pre-dissolved in DMSO and were added to achieve final concentration of DMSO is 1% (vol./vol.). The analysis was initiated by addition of membranes and after 1.5 hours at room temperature, the membranes were collected by filtration using a vacuum manifold Millipore MultiScreen, and twice washed with buffer for analysis (without bacitracin). The back of the tablet was removed from the tablet device MultiScreen, the filters were dried at room temperature, removed and counted on γ-counter Cobra.

For the compounds of formula (I) the value of the IC50is less than (<) 10 ám.

Analysis of the mobilization of intracellular calcium

Human neutrophils were prepared from EDTA treated peripheral blood as described previously (Baly et al. (1997) Methods in Enzimology 287, pp.70-72), in the buffer for storage [salt solution Tyrode (137 mm NaCl, 2.7 mm KCl, 0.4 mm NaH2RHO4with 5,7 mm glucose and 10 mm HEPES (pH 7.4)].

Chemokine GROα (human, recombinant) was purchased from R&D Systems (Abingdon, U.K.) All other reagents were of chemically pure. Changes in the content of intracellular free calcium was measured fluorimetrically by making neutrophils are sensitive to the calcium dye fluo-3 as described previously (Merritt et al. (1990) Biochem. J. 269, pp.513-519). The cells were placed for 1 hour at 37°in the buffer for the application of (b the fer for storage with 0.1% (wt./about.) gelatin), containing 5 μm, an ester of fluo-3 AM, washed with buffer for drawing and then resuspendable in saline solution Tired, supplemented 5,7 mm glucose, 0.1% (wt./about.) bovine serum albumin (BSA), 1.8 mm CaCl2and 1 mm MgCl2. Cells were pietravalle in 96-well microplate with black wall and clear bottom (Costar, Boston, U.S.A.) and centrifuged (200g, 5 min, room temperature).

The compound of formula (I), corresponding to the Examples, pre-dissolved in DMSO and were added to achieve final concentration of DMSO is 1% (vol./vol.). Assays were initiated by addition of concentrations of GROαequal to A50and registered short-term increase in the fluorescence of fluo-3 (λEx=490 nm and λEm=520 nm) were recorded using a FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices, Sunnyvale, U.S.A.).

The compound of formula (I) were tested and found that it is an antagonist of CXCR2 in human neutrophils.

Examples of pharmaceutical compositions

Injection solution

The connection according to the invention5 mg
Glucose250 mg
Water for injectionas it takes up to 5 ml

The connection according to the invention and glucose are dissolved in water for injection and the resulting process is ampoliros.

Gelatin capsule

The connection according to the invention100 mg
Talc24 mg
Silica gel1 mg
Total weight per capsule125 mg

These substances are mixed and the obtained mixture is filled gelatin capsule.

Tablet

The connection according to the invention400 mg
Silica gel10 mg
Stearic acid20 mg
Corn starch45 mg
Total weight per tablet475 mg

Mix the compound according to the invention, silica gel and corn starch (part specified number). The mixture granularit using starch paste obtained granules optivault stearic acid and pressed into a pill.

1. Monosodium salt of 5-[[(2,3-differenl)methyl]thio]-7-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]-thiazolo[4,5-d]pyrimidine-2(3H)-it.

2. The compound according to claim 1 to obtain drugs in the form for oral administration to treat conditions or diseases of the respiratory tract.

3. The compound according to claim 1 for Lekarstvo the th means in the form for oral administration for the treatment of asthma, allergic rhinitis, COPD (chronic obstructive pulmonary disease), inflammatory bowel disease, osteoarthritis, rheumatoid arthritis.

4. The compound according to claim 1 to obtain drugs in the form for oral administration for the treatment of cancer.

5. The use of compounds according to claim 1 in the manufacture of a medicinal product having the property of a modulator of the activity of chemokine receptors, in the form for oral administration.

6. A method of obtaining a compound according to claim 1, which includes the interaction of the compounds of formula (II):

where R represents a C1-6alkyl, with an acid, followed by obtaining a pharmaceutically acceptable monosodium salt.

7. Pharmaceutical composition having the property of a modulator of the activity of chemokine receptors containing the compound according to claim 1 in Association with a pharmaceutically acceptable adjuvant, diluent or carrier.

8. The pharmaceutical composition according to claim 7 for the treatment of asthma, allergic rhinitis, COPD, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis.

9. The pharmaceutical composition according to claim 7 for the treatment of cancer.

10. The method of preparation of the pharmaceutical composition according to any one of claims 7 to 9, which comprises mixing the compound according to claim 1 with a pharmaceutically acceptable hell is Vantomme, diluent or carrier.



 

Same patents:

FIELD: chemistry; pharmacology.

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

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

33 cl, 17 dwg, 11 tbl, 391 ex

FIELD: chemistry.

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

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

15 cl, 67 ex

FIELD: chemistry.

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

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

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

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

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

19 cl, 5 tbl, 165 ex

FIELD: chemistry.

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

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

6 cl, 4 tbl, 106 ex

FIELD: chemistry.

SUBSTANCE: invention was targeted at obtaining crystals of acetonitrile solvate of 6-fluor-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (compound B), which is an intermediate compound in obtaining crystals of 6-fluor-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid of III type (compound A). Compound B crystals are mostly precipitated by regulation of super-saturation during crystallisation involving acetonitrile as a solvent. Then compound A crystals of III type are obtained crystal desolvation.

EFFECT: increased efficiency of compounds.

6 cl, 4 dwg, 4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention refers to cyclic sulphonamide derivatives of general formula I where bonds indicated with wavy lines represent mutually cis- in relation to cyclohexane ring; R3 represents H or hydrocarbon group having up to 10 carbon atoms; Ar1 and Ar2 independently represent phenyl which carries 0-3 substitutes independently selected from halogen, CF3, CHF2; or its pharmaceutically acceptable salt. Besides, invention refers to technology of compounds of general formula I and to pharmaceutical composition based on compounds of general formula I and applied as gamma-secretase inhibitor.

EFFECT: new derivatives of cyclic sulphonamide, activating gamma-secretase inhibition and suitable for treatment and prevention of Alzheimer's disease.

9 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the general formula (I): wherein R1 is chosen from group consisting of hydrogen atom (H), -(CH2)3-, -(CH2)4-, -CH2-S-CH2-, -S-CH2-CH2-; R2 is chosen from group consisting of nitrogen (N), sulfur (S) atom; n = 0 or 1; Z is chosen from group consisting of (C2-C10)-alkyl; R3 is chosen from group consisting of H; m = 0-2; R4 is chosen from group consisting of oxygen atom (O), -CH2-; R5 is chosen from group consisting of the following groups:

wherein R6 is chosen from group consisting of H, alkyl-(C1-C5)-alkoxyl; W is chosen from group consisting of -NH wherein each "alkyl" can be linear or branched and can be also cyclic or linear, or branched and comprises such cyclic residues, and each "aryl" comprises monocyclic aromatic group comprising 5-12 carbon atoms bound with one or some heteroatoms chosen from N, O or S atoms, and to their salts and solvates. Also, invention relates to a pharmaceutical composition, to a method for their synthesis and using compounds by claims 1-6. Invention provides synthesis of novel active compounds and pharmaceutical compositions based on thereof that possess affinity to serotonin receptors of subtype 5-HT1A.

EFFECT: valuable medicinal properties of compounds, improved method of synthesis.

10 cl, 4 tbl, 26 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention proposes use of 2-amino-7-bromo-4-acetylazo[5,4-b]indol depicted by formula: against hyperbaric and hematic hypoxia and protection of liver against carbon tetrachloride poisoning. Use of this compound reduces concentration of AlAT by a factor of 2.6 and that of AcAT by a factor of 1.67.

EFFECT: increased therapeutic activity.

3 tbl

FIELD: medicine.

SUBSTANCE: declared is nonspecific immunotherapy agent containing embryonic antitumor modulator (EATM) as active agent and pharmaceutically acceptable carrier. EATM is made of embryonic substances by cryodestruction, extraction and sedimentation in spirits of increasing concentration and contains hyaluronic acid complex, tumour-associated antigens of normal embryogenesis. Agent can be produced in the form of solution, liniment, cream, tooth paste.

EFFECT: it is possible to use as highly effective agent for nonspecific immunotherapy.

5 cl

FIELD: medicine.

SUBSTANCE: declared is application of embryonic antitumour modulator (EATM) as agent of antimetastatic action. EATM is made of embryonic substances by cryodestruction, extraction and precipitation in alcohols of increasing concentration and contains proteoglycan complex of hyaluronic acid, tumour-associated antigens of normal embryogenesis.

EFFECT: provides antimetastatic action.

1 ex

FIELD: medicine.

SUBSTANCE: oral introduction of monoacetyldiacylglycerin derivatives detains development of hamster's induced cancer by activation of lymphocytes, monocytes and dendritic cells, as well as apoptosis induction of cancer cells owing to intensified cytotoxicity of immune cells in relation to cancer cells. Besides, induction of septic shock at mice is accompanied with shown 100% survival rate even in 120 hours, reached by immunity control and suppressing apoptosis effect. Monoacetyldiacylglycerin derivatives according to this invention can be effectively applied as agent for sepsis and cancer treatment and as healthy food preventing cancer or autoimmune diseases.

EFFECT: discovers application of monoacetyldiacylglycerin derivatives extracted from antler as agent suppressing cell abnormality resulted from autoresponse.

11 cl, 16 dwg, 11 ex, 6 tbl

FIELD: medicine.

SUBSTANCE: for treatment of atopic dermatitis, use the autologous T-lymphocytes, activated with the help of anti CD3 antibodies and interleukin-2. The activated T-lymphocytes are administered subcutaneously once a week within 4 weeks and further once a month within one year. Simultaneously perform basic therapy by antihistamine preparations and topical glucocorticosteroids.

EFFECT: depression of clinical implications of disease at the expense of influence on the changed immune response through an induction of the antiergotypical response.

2 ex

FIELD: medicine; pediatrics.

SUBSTANCE: administer arbidol in a dose of 50 mg 2 times a week in a combination with active selenium in a dose of 25 mkg on selenium once a day. Duration of prevention - 3-4 weeks.

EFFECT: reduction of frequency and general duration of respiratory infections at the expense of simultaneous correction of disturbances of the immune and metabolic status.

2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new histamine receptor blockers in the form of 2,3,4,5-tetrahydro-1H-pyrido-[3,4-b]indoles of the general formula 1 , where: R1 is an aminogroup substitute selected out of optionally substituted C1-C5alkyl; R2i is one or several same or different substitutes selected out of hydrogen, halogen, C1-C3 alkyl, CF3; Ar is phenyl or 5-6-member heterocycle containing 1-2 nitrogen or sulphur atoms in the cycle, unsubstituted or substituted by halogen, C1-C5alkyl, C1-C5alkoxy, substituted aminogroup or trifluormethyl; W is CH2 group optionally substituted CH2CH2 group or optionally substituted CH=CH group.

EFFECT: enhanced antiallergic and autoimmune effect.

4 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: agent possessing wound-healthing, antiinflammatory, antibacterial, immunomodulating, anaesthetising and antitumoral activity on a basis of terpenoids, contains a capsule extract of plants of Pinaceae bloodline exposed to short-term stressful influence, enriched with monoterpenes, obtained from a capsule extract. The pharmaceutical composition possessing wound-healthing, antiinflammatory, antibacterial, immunomodulating, anaesthetising and antitumoral activity, contains the above described agent in effective quantity and the target additive. Application of the above described agent for preparation of a medicinal preparation for treatment of pyoinflammatory diseases.

EFFECT: increased wound-healthing; antiinflammatory; antibacterial; immunomodulating; anaesthetising and antitumoral activities.

8 cl, 1 dwg, 6 tbl, 8 ex

FIELD: medicine; pharmacology.

SUBSTANCE: application of water-soluble polysaccharides made of coltsfoot leaves as agent of immunomodulating activity stimulating Th1-dependent immune response. Water-soluble polysaccharides made of coltsfoot leaves possess immunomodulating activity, effectively stimulate Th1-dependent immune response.

EFFECT: higher immunomodulating activity.

2 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns the pharmaceutical, food and cosmetic industry. Perform extraction of the raw material crushed with water with obtaining of a water extract and pulp. The pulp, obtained after extraction of raw materials by the water, is extracted in two steps with ethyl alcohol. At the first step of extraction the constrictor is extracted within 4-6 hours using the following proportion: ethyl alcohol 1:(5-7) with concentration of alcohol of 30% either 50%, or 70%, at temperature of 60-75°C, obtaining an ethanolic extract of the first step of extraction and pulp; then, this pulp is repeatedly extracted within 4-6 hours with ethyl alcohol using the following proportion: ethyl alcohol 1:(3-5) with concentration of alcohol of 30% either 50%, or 70%, at temperature of 60-75°C, obtaining an ethanolic extract of the second step of extraction and pulp. After that the ethanolic extract of the first step of extraction is aggregated with the ethanolic extract of the second step of extraction.

EFFECT: increase in active substances content in an extract.

1 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to of serotonin receptor 5-NT6 antagonists, simultaneously regulating calcium ions homeostasis in cells, representing substituted 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole of general formula I, its pharmaceutically acceptable salt and/or hydrate. In general formula I where: R1 is amides substitute selected from optionally substituted C1-C5 alkyl; R2i represents one or number of identical or various substitutes selected from hydrogen, halogen, C1-C3 alkyl, CF3, OCF3; Ar represents halogen unsubstituted or substituted C1-C6 alkyl, C1-C6 alkoxy, phenyl substituted with amides or trifluoromethyl or optionally substituted aromatic hexamerous heterocycle containing 1-2 nitrogen atoms per one cycle, W represents ethyl group-CH2CH2 - vinyl group or ethynyl group. Invention also concerns new compounds selected from group of compounds of formula 1, methods of production thereof, pharmaceutical compositions and methods of their use.

EFFECT: production of composition that simultaneously regulates calcium ions homeostasis in cells.

34 cl, 7 dwg, 4 tbl, 9 ex

FIELD: chemistry.

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

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

15 cl, 67 ex

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