Tetrahydropyranyl-cyclopentyl-tetrahydropyridopyridine modulators of chemokine receptor activity

FIELD: organic chemistry, medicine, veterinary science, pharmacy.

SUBSTANCE: invention relates to derivatives of tetrahydropyranyl-cyclopentyl-tetrahydropyridopyridine of the formula (1): , wherein R3 means oxygen atom or absent; R8 is chosen from: (a) hydrogen atom; (b) (C1-C3)-alkyl that can be unsubstituted or substituted with 1-6 fluorine atoms; (c) -O-(C1-C3)-alkyl; (d) fluorine atom, and (e) hydroxy-group, and their pharmaceutically acceptable salts and separate diastereomers. These compounds are modulators of activity of chemokine receptors. Also, invention relates to a pharmaceutical composition based on compounds of the formula (1), method for modulation of activity of chemokine receptors in humans and animals and a method for preparing a medicinal agent. Invention provides preparing novel modulators of chemokine receptors activity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 13 ex

 

Chemokines are a family of small (70 to 120 amino acids), anti-inflammatory cytokines with potent chemotactic activity. Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract a variety of cells, such as monocytes, macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation (described in Schall,Cytokine, 3, 165-183 (991) and Murphy,Rev. Immun., 12, 593-633 (1994)). These molecules were originally identified four saved cysteine and are divided into two subfamilies based on the location of the first cysteine pairs. In the family of CXC-chemokines, which includes IL-8, GROα, NAP-2 and IP-10, these two cysteines separated by one amino acid, while in the family of CC-chemokines, which includes RANYES, MCP-1, MCP-2, MCP-3, MIP-1α, MIP-1β and eotaxin, these two balance are nearby.

Chemokines are secreted by a wide range of cells and to bind with specific receptors coupled with G-protein (GPCR) (described in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)), present in leukocytes and other cells. Such chemokine receptors form a subfamily of GPCR, which currently consists of fifteen characterized members and a number of individual members. Unlike receptors for heterogeneous chemoattractants, such as Sa, fMLP, PAF, and LTB4, receptors of emakina more selectively expressed on a subset of leukocytes. Thus, the formation of specific chemokines provides a mechanism for the replenishment of specific subsets of leukocytes.

When linking with their cognate ligands, chemokine receptors convert intracellular signal through the associated three-dimensional G protein, which leads to a rapid increase in the concentration of intracellular calcium. There are at least seven chemokine receptors person that bind or respond to β-chemokines following characteristic pattern: CCR-1 (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); Beote, et al.,Cell, 72, 415-425 (1993)); CCR-2A and CCR-2B (or "CKR-2A"/"CKR-2A" or "CC-CKR-2A"/"CC-CKR-2A") [MCP-1, MCP-2, MCP-3, MCP-4]; CCR-3 (or "CKR-3" or "CC-CKR-3") [Eotaxin, Eotaxin 2, RANTES, MCP-2, MCP-3] (Rollins, et al.,Blood, 90, 908-928 (1997)); CCR-4 (or "CKR-4" or "CC-CKR-4") [MIP-1α, RANTES, MCP-1] (Rollins, et al.,Blood, 90, 908-928 (1997)); CCR-5 (or "CKR-5" or "CC-CKR-5") [MIP-1α, RANTES, MIP-1β] (Sanson, et al.,Biochemistry, 35, 3362-3367 (1996)); and antigen blood group Duffy [RANTES, MCP-1] (Chaudhun, et al.,J. Biol. Chem., 269, 7835-7838 (1994)). β-chemokines include eotaxin, MIP ("inflammatory macrophage protein"), MCP ("chemoattractant protein of monocyte) and RANTES ("regulated upon activation, expressed and secreted normal T"), among other cytokines.

The chemokine receptors, such as CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, CXCR-4, are considered important mediate the Rami of inflammatory and immunoregulatory diseases and disorders, including asthma, rhinitis and allergic diseases as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. It is believed that people who are homozygous for deletions 32-the main couple in the gene CCR-5, less susceptible to rheumatoid arthritis (Gomez, et al.,Arthritis & Rheumatism, 42, 989-992 (1999)). Overview of the role of eosinophils in allergic inflammation presents Kita, H., et al., inJ. Exp. Med.183, 2421-2426 (1996). An overview of the role of chemokines in allergic inflammation presents Lugster, A.D.,New England J. Med., 338(7), 426-445 (1998). A subset of chemokines is a powerful chemoattractant for monocytes and macrophages. The most characterized of these is MCP-1 (chemoattractant protein of monocyte-1), the primary receptor is CCR2. MCP-1 is produced in many cell types in response to inflammatory stimulation in different species, including rodents and humans, and stimulates chemotaxis in monocytes and a subset of lymphocytes. In particular, the production of MCP-1 correlated with the infiltration of monocytes and macrophages to the site of inflammation. Deletion of either MCP-1 or CCR2 homogeneous recombination in mice results in a significant weakening of the replenishment of monocytes in response to injection of thioglycolate and Listeria monocytogenes infection (Lu et al.,J. Exp. Med., 187, 601-608 (1998); Kurihara et al.,J. Exp. Med., 186, 1757-1762 (1997); Boring et al.,J. Clin. Invest., 100, 2552-2561 (1997); Kuziel et al.,Prc. Natl. Acad. Sci., 12053-12058 (1997)). Moreover, these animals show a reduced infiltration of monocytes in granulomatous damage caused by injection schistosomal or mycobacterial antigens (Boring et al.,J. Clin. Invest., 100, 2552-2561 (1997); Warmington et al.,Am. J. Path., 154, 1407-1416 (1999)). These data confirm that induced MCP-1 activation of CCR2 plays a major role in addition to monocytes in areas of inflammation, and that antagonism of this activity will provide significant suppression of immune response to therapeutic use in inflammatory and autoimmune diseases. Therefore, agents that modulate chemokine receptors, such as receptor CCR-2 will be useful in these disorders and diseases. In addition, replenishment of monocytes in the inflamed lesions of blood vessels is the main component of the pathogenesis and education of atherogenic plaques. MCP-1 is produced and secreted by endothelial cells and the cells of the intimal smooth muscle after injury of the vessel wall when hypercholesterinemia States. Monocytes resulting in the injury site, infiltrate in the vessel wall and differentiate into foam cells in response to the selection MCP-1. Some groups have demonstrated that the amount of damage to the aorta, the content of macrophages and necrosis weakened in MCP-1 -/- or CCR2-/- mice, the reverse is crossed with the APO-E -/-, LDL-R -/- or Apo B transgenic mice receiving food with a high fat level (Boring et al.,Nature, 394, 894-897 (1998); Gosling et al.,J. Clin Invest., 103, 773-778 (1999)). Thus, CCR2 antagonists can inhibit the formation of atherosclerotic lesions and pathological development by reducing the replenishment of monocytes and differentiation in the wall of the artery.

This invention provides compounds that are modulators of the activity of the receptor of the chemokine, and are useful for prevention or treatment of certain inflammatory and immunoregulatory disorders and diseases, allergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. This invention is also pharmaceutical compositions containing such compounds, and the use of these compounds and compositions for the prevention and treatment of such diseases with the involvement of chemokine receptors.

This invention relates to compounds of formula I

where R3is oxygen or absent;

R8choose from:

(a) hydrogen,

(b) (C1-3of alkyl, which is unsubstituted or substituted by 1-6 fluorine atoms,

(s) -O-C1-3of alkyl,

(d) fluorine and

(e) hydroxy;

and their pharmaceutically acceptable salts and individual diastereomers.

In one embodiment of this invention R3no. In one embodiment of this invention R3is hydrogen.

In this invention, preferably, when R8choose from:

(a) hydrogen,

(b) trifloromethyl,

(c) methyl,

(d) methoxy,

(e) ethoxy,

(f) ethyl,

(g) fluorine and

(h) hydroxy.

Examples of compounds in accordance with this invention include those compounds which are represented in the examples and their pharmaceutically acceptable salts and individual diastereomers.

Compounds in accordance with this invention have at least two asymmetric centre in positions 1 and 3 cyclopentene rings. Additional asymmetric centers may be present depending on the nature of the various substituents in the molecule. Each such asymmetric center will independently give two optical isomers, and assumes that all possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included in the scope of this invention. Independent synthesis of diastereomers and enantiomers or their chromatographic separation can be carried out by methods known in the art, appropriate modification met the wild described below. Their absolute stereochemistry can be determined by x-ray crystallography of crystalline products or crystalline intermediates which receive, if necessary, with a reagent containing an asymmetric center is known absolute configuration.

As it is clear to experts in a given field of technology1-3the alkyl group includes, having 1, 2 or 3 carbon atoms in linear or branched arrangement, such that C1-3alkyl includes methyl, ethyl, n-propyl and isopropyl.

The phrase "pharmaceutically acceptable" refers to compounds, materials, compositions and/or dosage forms which are, from a medical point of view, suitable for use in contact with the tissues of humans and animals without excessive toxicity, damage, allergic reactions or other problems or complications, and have a reasonable ratio of benefit/risk. In this description, the term "pharmaceutically acceptable salts" refers to derivatives, in which the original connection modify a transformation in its acidic or basic salt. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmacist is Cesky acceptable salts include conventional non-toxic salts or the Quaternary ammonium salts of the parent compound, formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric, Hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, Panova, maleic, hydroxymaleimide, phenylacetic, glutamic, benzoic, salicylic, Sultanalieva, 2-acetoxybenzoic, fumaric, toluensulfonate, methanesulfonate, ethicality, oxalic acid, setinova and the like.

Pharmaceutically acceptable salts in accordance with this invention can be obtained from starting compounds which contain a basic or acidic group, conventional chemical methods. Typically, such salts can be obtained by the interaction of the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of both; preferably in a non-aqueous environment, such as a simple ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Suitable salts are described, for example, in Remington''s Pharmaceutical Sciences, 17thed., Mack Publishing Compay, Easton, PA, 1985, pp. 1418.

Certain compounds in accordance with this invention include compounds that are selected from the group comprising: the connection specified in the headers of examples; and their pharmaceutically acceptable salts and individual diastereomers.

Compounds in accordance with this invention are useful in the method of modulating the activity of the receptor of the chemokine to the patient and, if necessary, such modulation, where the method includes introducing an effective amount of the compounds. This invention is intended for use the following compounds as modulators of the activity of the receptor of the chemokine. In particular, these compounds are useful as modulators of the chemokine receptors, especially CCR-2.

The use of compounds in accordance with this invention as modulators of the activity of the receptor of the chemokine can be demonstrated by a method known in the art, such as studies of the binding of a chemokine, described Van dance floor : riper, et al., inJ. Exp. Med., 177, 851-865 (1993), which can be easily adapted to measure the binding CCR-2.

The affinity of the receptor in the study on the binding of CCR-2 is determined by measuring the inhibition of125I-MCP-1 to the endogenous receptor CCR-2 in various cells, including monocytes, cells TNR-1, or after heterologous expression of the cloned Retz is ptor in eukaryotic cells. Cells suspended in binding buffer (50 mm HEPES, pH of 7.2, 5 mm MgCl2, 1 mm CaCl2and 0.50% BSA) and added to the test compound or DMSO and125I-MCP-1 at room temperature for 1 hour to bind. The cells are then collected on filters GBF, washed with 25 mm HEPES buffer containing 500 mm NaCl, and counting cells associated with125I-MCP-1.

In a chemotactic study chemotaxis carried out with application of RVMS depleted T-cells from whole venous blood or leukophoresis blood, and purified by centrifugation Ficoll-Hipac with subsequent resetting treated with neuraminidase erythrocytes of sheep. After isolation, the cells are washed with HBSS containing 0.1 mg/ml BSA and suspended in 1×107cells/ml Cells have been labelled in the dark fluorescent with 2 μm Calcien-AM (molecular sample) for 30 minutes at a temperature of 37°C. Labeled cells are washed twice and suspended in 5×106cells/ml in RPMI 1640 with L-glutamine without phenol red)containing 0.1 mg/ml BSA. MCP-1 (Petrotech) at 10 ng/ml diluted in the same medium only or medium was added to the bottom of the hole (27 μl). In the upper part of the filter add monocytes (150,000 cells) (30 μl) and then a 15 minute pre-incubation with DMSO or with various concentrations of test compounds. Equal concentrations of test compound or DMSO to ablaut on the bottom of the hole to prevent dilution by diffusion. After 60 min incubation at 37 ° °C, 5% CO2the filter is removed and the upper part is washed with HBSS containing 0.1 mg/ml BSA to remove cells that are not passed to the filter. Spontaneous migration (chemokines) determine in the absence of chemoattractant.

In particular, compounds of the following examples have activity when binding to the CCR-2 receptor in the research mentioned above, usually with IC50below approximately 1 μm. These results show the activity inherent connections in their use as modulators of the activity of the receptor of the chemokine.

The receptor of the chemokine mammals represent a target for intervention or stimulation functions eosinophil and/or lymphocytes in mammals such as man. Compounds that inhibit or stimulate the function of the receptor of the chemokine, especially useful for modulating the function of eosinophil and/or lymphocyte for therapeutic purposes. Therefore, compounds that inhibit or stimulate the function of the receptor of the chemokine may be useful for treatment, prevention, amelioration, control or reduce the risk of a wide range of inflammatory and immunoregulatory disorders and diseases, allergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmun the x pathologies, such as rheumatoid arthritis and atherosclerosis. For example, the connection is instantaneous, which inhibits one or more functions of the receptor of the chemokine mammal (e.g., a receptor of the chemokine human)may be administered to inhibit (e.g., reduce or prevent) inflammation. In the inhibited one or more inflammatory processes, such as the emigration of leukocytes chemotaxis, exocytosis (e.g., of enzymes, histamine) or selection of a mediator of inflammation.

In addition to primates, such as person, the method in accordance with this invention can be used to treat a variety of other mammals. For example, it is possible to treat mammals, including but not limited to them, cows, sheep, goats, horses, dogs, cats, Guinea pigs, rats or other cow, sheep, horse, dog, cat, rat or murine species. However, the method can also be applied to other species, such as birds (e.g. chickens).

Diseases and conditions associated with inflammation and infection, can be treated using compounds in accordance with this invention. In a preferred embodiment, the disease or condition is one in which the action of lymphocytes is inhibited or stimulated for modulating the inflammatory response.

Disease and condition of man and other species which can be treated with inhibitors of receptor function of chemokine include, but are not limited to: inflammatory or allergic diseases and conditions, including respiratory allergic diseases such as asthma, particularly bronchial asthma, allergic rhinitis, hypersensitivity lung, hypersensitive defined signes of pneumonit, eosinophilic pneumonias (e.g., syndrome Leffler, chronic eosinophilic pneumonia), delayed-type hypersensitivity, intermediate lung disease (PBL) (e.g., idiopathic pulmonary fibrosis, or PBL, is associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, rheumatoid Sjorgen, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity reaction, allergies to medicines (e.g., to penicillin, cephalosporins), allergies to insect bites; autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, bulbospinal palsy, children's initial diabetes; glomerulonephritis, autoimmune thyroiditis, a disease Beckett; graft rejection (e.g., in transplantation), including allograft rejection or graft versus host disease; inflammatory bowel disease, such as disease is Ron and ulcerative colitis; spondyloarthropathy; scleroderma; psoriasis (including psoriasis, mediaready T-cells) and inflammatory skin diseases such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., nekrotizirovannye, and skin hypersensitive vasculitis); eosinophilic myositis, eosinophilic fasciitis; cancer of the skin or organs with infiltration of leukocytes. Other disease or condition which can be treated inhibiting undesirable inflammatory responses include, but are not limited to, reperfusion injury, atherosclerosis, certain hematological malignancy caused by toxic cytokine response (e.g., septic shock, endotoxic shock), polymyositis, dermatomyositis.

Diseases or conditions of humans or other species which can be treated with modulators of the action of the receptor of the chemokine include, but are not limited to: immunosuppression, such as in patients with the syndrome of immunodeficiency, such as AIDS or other viral infection, in patients receiving radiation therapy, chemotherapy, therapy for autoimmune disease or drug therapy (e.g., corticosteroid therapy), which causes immunosuppression; immunosuppression due to congenital deficiency of receptor function or other causes; and in actionee disease, such as parasitic diseases, including, but not limited to helminth infections, such as nematodes (round worms), (Trichuriasis, Enterobiasis, Ascariasis, Hookworm, Strongylodiasis, Trichinosis, Filariasis), trematodes (flatworms) (Schistosomiasis, Clonorchiasis), cestodes (tape worms) (Echinococcosis, Taeniasis saginata, Cysticercosis), visceral worms, migraines from visceral larvae (e.g., Toxocara), eosinophilic gastroenteritis (e.g., Anisaki sp., Phocanema sp.) and migraines from cutaneous larvae (Ancylostona brazilience, Ancylostoma caninum). In addition, the treatment of the above inflammatory, allergic and autoimmune diseases could be promoters of receptor function of the chemokine, if they deliver a sufficient number of connections for terminating the expression of the receptor in cells through inducing internalization of the receptor of the chemokine, or delivery connection in a way that gives the wrong direction of cell migration.

Compounds in accordance with this invention are useful for the treatment, prevention, amelioration, control or reduce the risk of a wide range of inflammatory and immunoregulatory disorders and diseases, allergic conditions, atopic conditions, as well as autoimmune pathologies. In a specific embodiment, this invention relates to the use of compounds in accordance with this invention for treatment pros who ACTICE, improve, control or reduce the risk of autoimmune diseases such as rheumatoid arthritis or psoriatic arthritis.

In another embodiment, the invention can be used to assess the alleged specific agonists or antagonists of chemokine receptors, including CCR-2. Therefore, the present invention relates to the use of such compounds for obtaining and carrying out screening studies of compounds that modulate the activity of chemokine receptors. For example, the compounds in accordance with this invention is useful for selecting mutants of the receptor, which are excellent tools for screening more powerful connections. Moreover, the compounds in accordance with this invention are useful for establishing or determining the binding sites of other compounds with the receptor of the chemokine, e.g., through competitive inhibition. Compounds in accordance with this invention are also useful for assessing the alleged specific modulators of chemokine receptors, including CCR-2. As recognized in the art, comprehensive assessment of specific agonists and antagonists of the above receptors chemokine hindered by the lack of availability of non-peptide (metabolically stable compounds with high affinity binding to such receptors. the thus, the compounds in accordance with this invention are commercial products that can be sold for these purposes.

This invention also relates to a method for producing a drug to modulate the activity of the receptor of the chemokine in humans and animals comprising combining the compound in accordance with this invention with a pharmaceutical carrier or diluent.

This invention also relates to the use of these compounds for the treatment, prevention, amelioration, control or reduce the risk of infection by a retrovirus, in particular, herpes virus or human immunodeficiency virus (HIV)infection, or treating or delaying the onset of subsequent pathological conditions such as AIDS. AIDS treatment or prevention or treatment of infection by HIV is defined as including, but not limited to, treating a wide range of States of HIV infection: AIDS, SSK (AIDS-related complex), symptomatic and asymptomatic, and acute or potential exposure to HIV. For example, the compounds in accordance with this invention are useful for the treatment of HIV infection after the alleged contact with HIV, such as blood transfusion, organ transplantation, exchange of body fluids, bites, accidental needle sticks or contact with the blood of a patient during surgical operations.

In predpochtite the flax embodiment of this invention the compound in accordance with this invention can be used in the method of inhibiting the binding of a chemokine to the receptor of the chemokine, such as CCR-2 target cells, which includes the interaction of target cells with the amount of compound that is effective for inhibiting the binding of a chemokine to the receptor of the chemokine.

The object of treatment in the above way is a mammal, preferably human, male or female, for which it is desirable modulation of activity of a receptor of the chemokine. "Modulation" in this context implies antagonism, agonism, partial antagonism, inverse agonism and/or partial agonism. In a preferred embodiment of the present invention the modulation refers to the antagonism in relation to the activity of the receptor of the chemokine. The term "therapeutically effective amount" means such amount of the compounds in accordance with this invention, which causes the biological or medical response of a tissue, system, animal or human, which is expected by the researcher, veterinarian, medical doctor or other Clinician.

The term "composition", as used herein, refers to a product containing certain ingredients in certain amounts, as well as to any product that is obtained, directly or indirectly, from combination of certain ingredients in certain quantities. By "pharmaceutically acceptable" refers to media, rabbanites is or excipient, which must be compatible with other ingredients of the formulation, and not to cause harm to the patient. The terms "introduction" and/or "input" connection understand the supply connection in accordance with this invention a patient in need of treatment. In this case, the term "treatment" means the treatment and prevention or prophylactic treatment of the above conditions.

Combination therapy for modulating the activity of the receptor of the chemokine for the treatment, prevention, amelioration, control or reduce the risk of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis, and pathology, above, illustrates the combination of compounds in accordance with this invention and other compounds that are known for such purposes.

For example, in the treatment, prevention, improvement, control or reduce the risk of inflammation, the compound of this invention can be used 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 the interleukin is -1, the 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-vast anti-inflammatory agent, for example, a compound such as acetaminophen, aspirin, codeine, embrel, fentanyl, ibuprofen, indomethacin, Ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgetic, Sufentanil, canlendar, tenidap and the like. Also, the compounds in accordance with this invention can be administered with anesthetic; the potential means, such as caffeine, an H2 antagonist, simethicone, aluminum hydroxide or magnesium; protivozastojnye means, such as phenylephrine, phenylpropanolamine, pseudophedrine, Oxymetazoline, ephinephrine, nafazolina, Xylometazoline, propylhexedrine or left-deoxy-ephedrine; remedy against cough, such as codeine, hydrocodone, caramiphen, carbetapentane or dextramethorphan; a diuretic; and a sedating or non-sedating antihistamine.

Connections, in accordance with this invention can be used in combination with other drugs used for the treatment/prevention/suppression or reduction of the intensity of the symptoms of diseases or conditions for which useful compounds in accordance with this invention. These other medicines can in titsa manner and amount, usually applied, simultaneously or sequentially with the compound in accordance with this invention. If the connection is in accordance with this invention is administered with one or more drugs, it is preferable to use a pharmaceutical composition containing such other drugs in addition to the connection in accordance with this invention. Consequently, pharmaceutical compositions in accordance with this invention are compositions that also contain one or more other active ingredients, in addition to the connection in accordance with this invention.

Examples of other active ingredients that may be combined with the compound in accordance with this invention, and be administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) antagonists of VLA-4, such as described in US 5510332, WO 95/15973, WO 96/01644, WO 96/06108, WO 96/20216, WO 96/22966, WO 96/31206, WO 96/40781, WO 97/03094, WO 97/02289, WO 98/42656, WO 98/53814, WO 98/53817, WO 98/53818, WO 98/54207 and WO 98/58902, (b) steroids such as beclomethasone, methylprednisolone, beta metaSAN, prednisolone, dexamethasone, and hydrocortisone; (C) immunosuppressants such as cyclosporine, tacrolimus, rapamycin and other immunosuppressants type FK-506; (d) antihistamines (H1 antagonists of histamine), such as bromine is tiramin, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine at, antazoline, Pheniramine, pyrilamine, astemizole, terfenadine, loratadine, desloratadine, cetirizine, Fexofenadine, descarboethoxyloratadine and the like; (e) non-steroidal anti-asthma drugs, such as β2-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, cuprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, Ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, Turoverov acid and tioxaprofen), derivatives of acetic acid (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclova acid, fentiazac, furofenac ibufenac, isoxepac, exping, sulindac, tiopinac, tolmetin, zidometacin, zomepirac)derived fenaminovoj acid (flutina the new 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, sulfasalazine) and the pyrazolones (Amazon, baseperiod, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone); (g) inhibitors of cyclooxygenase-2 (SOH-2); (h) inhibitors of phosphodiesterase type IV (PDE-IV); (i) other antagonists of the chemokine receptors, especially CCR-1, CCR-2, CCR-3, CXCR-3 and CCR-5; (j) agents, lowering cholesterol, such as inhibitors of HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, rosuvastatin, and other statins), sequestrate (cholestyramine and colestipol), inhibitors of cholesterol absorption (ezetimibe), derivatives of nicotine and fenofibrate acid (gemfibrozil, clofibrate, fenofibrate and benzafibrate) and probucol; (k) anti-diabetic agents such as insulin, sulfonylureas, biguanides (Metformin), inhibitors α-glucosidase (acarbose and glitazone (troglitazone and pioglitazone); (l) preparations of interferon beta (interferon beta-1αinterferon-beta-1β); (m) other compounds such as 5-aminosalicylic acid and its prodrugs, antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxic chemotherapy is Genty for the treatment of cancer.

The mass ratio of the compounds in accordance with this invention, the second active ingredient may vary and depends on the effective dose of each ingredient. In General, applies effective dose of each ingredient. Thus, for example, if the connection is in accordance with this invention together with a NSAID, the mass ratio of the compounds in accordance with this invention to the NSAID generally ranges from about 1000:1 to about 1:1000, preferably from about 200:1 to 1:200. The combination of compounds in accordance with this invention and other active ingredients also typically is in the aforementioned range, but in each case shall apply effective dose of each ingredient. In such combinations the connection in accordance with this invention and the other active ingredient can be administered separately or in combination. In addition, the introduction of one element may be performed before, during or after administration of the other agent (agent).

Compounds in accordance with this invention can be administered orally, parenteral routes (e.g., intramuscular, intraperitoneal, intravenous, intracerebroventricular ways, intracisternally by injection or infusion, subcutaneous injection, or implant), inhalation, intranasal, rectal, vaginally is, sublingual or local routes of administration and may be formulated, alone or together, in suitable standard dosage forms, containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and fillers that are appropriate for each route of doing. In addition to the treatment of warm-blooded animals, such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds in accordance with this invention are effective for the treatment of humans.

Pharmaceutical compositions for administration of the compounds in accordance with this invention can be comfortable in standard dosage forms and can be obtained by any method well known in the pharmaceutical field. All methods include the stage of combining the active ingredient with the carrier which consists of one or more additional ingredients. In General, the pharmaceutical compositions have a uniform and thorough connection of the active ingredient with liquid carriers or finely ground solid carrier, or both, and then, if necessary, shaping the product into the desired dosage form. In the pharmaceutical composition the active compound is contained in a quantity sufficient to produce a desired effect in the existing process or condition of diseases. In this context, the term "com who osize" refers to the product containing certain ingredients in certain amounts, as well as to any product that is obtained, directly or indirectly, from combination of certain ingredients in certain amounts.

Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use can be obtained by any method known in the field of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, dyes and preservatives, to obtain pharmaceutically excellent and tasty songs. Tablets contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients which are suitable for receiving tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and loosening agents, for example corn starch or alginic acid; binding agents, for example, krahm the scrap, gelatin or acacia, and lubricating agents, e.g. magnesium stearate, stearic acid or talc. Tablets may not have a shell or can be covered with well-known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a prolonged action over a longer period. For example, as inhibiting substances can be used such as glycerylmonostearate or glycerylmonostearate. They can also be covered using the techniques described in the U.S. patents 4256108, 4166452 and 4265874, to obtain the osmotic therapeutic tablets for controlled release.

Compositions for oral administration may be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules in which the active ingredients are mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active materials in a mixture with excipients suitable to obtain aqueous suspensions. Such excipients include suspendresume agents, such as sodium carboxymethyl cellulose, methylcellulose, hydroxypropylmethylcellulose the memory, sodium alginate, polyvinylpyrrolidone, tragacanth resin and the Arabian gum; dispersing or wetting agents are natural phosphatides, for example lecithin, or condensation products of accelerated and fatty acids, for example, polyoxyethylenated, or condensation products of ethylene oxide and long-chain aliphatic alcohols, for example, heptadecafluorooctane, or condensation products of ethylene oxide and partial esters obtained from fatty acids and hexitol, such as polyoxyethylenesorbitan, or condensation products of ethylene oxide and partial esters derived from fatty acids and anhydrides hexitol, for example, polyethylenterephthalat. Aqueous suspensions can also contain one or more preservatives, for example ethyl or n-propyl, n-hydroxybenzoate, one or more colouring agents, one or more flavoring agent, one or more sweetener, such as sucrose or saccharin. Oil suspensions can be obtained by suspendirovanie active ingredient in a vegetable oil, such as peanut oil, olive oil, hemp oil or coconut oil, or in mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. For getting oral composition is th can be added sweeteners, such as described above, and flavoring agents. These compositions may be preserved by the addition of antioxidants, such as ascorbic acid. Dispersible powders and granules suitable for obtaining aqueous suspension by the addition of water, contain the active ingredient mixed with dispersing or wetting agent, suspenders agent and one or more preservatives. Suitable dispersing or moisturizing agents and suspendresume agents are those described above. There may be additional fillers, such as sweeteners, flavoring agents and dyes. Pharmaceutical compositions in accordance with this invention can also be in the form of emulsions of oil in water. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or mineral oil, for example liquid paraffin or a mixture. Suitable emulsifying agents may be natural resins, for example, Arabian gum or tragakant, natural phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and anhydrides hexitol, for example, monooleate sorbitan, and condensation products of these partial esters and ethylene oxide, for example polyoxyethylene sorbitan monooleate. EMU is sii may also contain sweeteners and flavoring agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such compositions may also contain painkillers, preservatives and flavoring agents and dyes.

The pharmaceutical compositions can be in the form of a sterile aqueous or oily suspensions for injection. These suspensions can be obtained in accordance with methods known in this field, using suitable dispersing or wetting agents and suspendida agents listed above. Sterile dosage forms for injection can also be sterile solutions or suspensions for injection in a non-toxic parenterally acceptable diluent or solvent, for example, in a solution of 1,3-butanediol. Among the acceptable vehicles and solvents that may apply, can be mentioned water, ringer's solution and isotonic sodium chloride solution. In addition, as a solvent or suspendida environment may apply sterile, fatty oil. For this purpose, can be used any soft fatty oils, including synthetic mono - or diglycerides. In addition, to obtain forms for injection can be applied fatty acids such as oleic acid. Compounds in accordance with this invention can also be administered in the form of suppositories for rectal administration of medicinal means. T is the cue compositions can be obtained by mixing the drug with a suitable not irritating excipient, which is solid at ordinary temperatures but liquid at rectal temperature and therefore melt in the rectum to release the drug. Such materials are coconut oil and glycols. For local applications use creams, ointments, jellies, solutions or suspensions, etc. containing compounds in accordance with this invention. (For the purposes of this invention, compositions for topical application include rinse mouth and gargle for the throat).

Pharmaceutical compositions and method in accordance with this invention may also include other therapeutically active compounds as noted above, which are usually applied for the treatment of these pathological conditions. In the treatment, prevention, improvement, control and reduce the risk of conditions which require modulation of the receptor of the chemokine, a suitable dosage is typically from about 0.01 to 500 mg per kilogram of body weight of the patient per day and may be administered one or more doses. Preferably, the level of dosage is from about 0.1 to 250 mg/kg / day, more preferably from about 0.5 to about 100 mg/kg / day. A suitable dose is from about 0.01 to 250 mg/kg / day, from about 0.05 to 100 mg/kg / day, from about 0.1 to 50 mg/kg / day. In this interval, the dose may be 0,05-05, 0.5 to 5 or 5-50 mg/kg / day. For oral administration the compositions preferably have the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, preferably 2.0 to 500, more preferably 3.0 to 200, especially 1, 5, 10, 15, 20, 25, 30, 50, 75, 100, 125, 150, 175, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 milligrams of the active ingredient to bring the dose depending on the subject to the treatment of the patient. Connections can be entered in the mode from 1 to 4 times a day, preferably once or twice a day.

It should be clear that a certain level of dosage and frequency of dosage for any particular patient may vary and depends on many factors, including the activity of a used compound, the metabolic stability and length of action of this compound, the age, body weight, General health, sex, diet, mode and time of administration, rate of release, combination drugs, the severity of a particular condition and accept the patient therapy.

Several methods for obtaining compounds in accordance with this invention is illustrated in the following examples. Compounds in accordance with this invention can be obtained by modification of the techniques described in the examples. Educt get known methods or as shown in Arah. The following examples are given to illustrate and not limit the disclosed invention. The following are examples of methods for obtaining compounds used in the examples presented here, or which may be substituents of the compounds shown in the examples, which may not be commercially available.

Concentration of solutions are usually carried out on a rotary evaporator under reduced pressure. Flash chromatography is performed on silica gel (230-400 mesh mesh). GHSD - liquid chromatography medium pressure, is carried out in a stationary phase of silica gel, unless otherwise noted. The NMR spectrum of the gain in solution CDCl3if not stated otherwise. Constant interaction (J) are given in Hertz (Hz). Abbreviations: diethyl ether (ether), triethylamine (tea), N,N-diisopropylethylamine (DIEA), saturated aqueous (us.), room temperature (CT), hours (h), minutes (min).

In some cases the order of carrying out the following reactions can be modified to facilitate the reaction or to avoid unwanted reaction products. Examples are presented for illustration only and do not limit the disclosed invention.

The following are examples of methods of producing compounds used in the examples presented here, or which may be substituents of the compounds shown in the examples, which is may not be commercially available.

The intermediate connection 1

The intermediate connection 1 receive according to the method described inJ. Am. Chem. Soc.,1991,113, 2079-2089.

Intermediate compound 2

To a solution of tetrahydro-4H-Piran-4-it (5.0 g, 50 mmol) and hexamethylphosphoramide (8,70 ml) in tetrahydrofuran (150 ml) is added slowly a solution of diisopropylamide lithium (31,25 ml, 3M solution) in 125 ml of tetrahydrofuran at a temperature of -78°C. the Reaction mixture was stirred for 5 min and then add ethyliodide (16.0 ml, 200 mmol). The mixture is gradually heated to a temperature of 0°C for more than 2 hours, the Reaction mixture was quenched with saturated solution of NH4Cl and then extracted with simple ether (4×100 ml). The ether layer is washed with saturated salt solution, dried (anhydrous magnesium sulfate), concentrated and purified flash chromatography on a column elwira a mixture of hexane/ethyl acetate (4:1) to give the intermediate compound 2 (1.20 g, 20%).

Intermediate compound 3

Stage And

To a mixture of 5,6-dihydro-4-methoxy-2H-Piran (10.0 g, of 87.5 mmol) in methanol (200 ml) at a temperature of 0°C added dropwise a solution of 3-chloroperoxybenzoic acid (30,2 g, 175 mmol) in methanol (50 ml) via an additional funnel. Receive the config solution is stirred for 5 h, allowing it to warm to room temperature. The methanol is removed under reduced pressure to obtain white solid. The substance is dissolved in 500 ml of dichloromethane and cooled to a temperature of 0°C. To the vigorously stirred mixture portions add an excess of solid calcium hydroxide (50-60 g). After stirring for a further 30 minutes the mixture is filtered through a layer of celite and the filtrate is evaporated under reduced pressure to obtain are 11.62 g (82%) of the desired product as a clear oil.

1H NMR (500 MHz, CDCl3) δ 3,88-of 3.80 (m, 2H), of 3.73-3,68 (m, 2H), 3,54-of 3.48 (m, 1H), or 3.28 (s, 3H), of 3.27 (s, 3H), 2.00 in of 1.93 (m, 1H), 1,82-to 1.77 (m, 1H).

Stage

To a cooled (0° (C) to a solution of product from step A, intermediate compound 3 (9,40 g, 58,0 mmol) in tetrahydrofuran (200 ml) in an atmosphere of nitrogen was slowly added NaH (2,32 g, 58,0 mmol) and the resulting suspension stirred for 1 h at a temperature of 0°C. Then the suspension through a syringe add itmean (7,22 ml, 116 mmol) and the resulting mixture is stirred overnight, allowing to warm to room temperature. The reaction is quenched with a saturated solution of ammonium chloride (200 ml) and the organic layer is then removed using a separating funnel. The aqueous layer was extracted with simple ether (3×150 ml) and all organic layers are combined, dried over anhydrous sulfate is m sodium filtered and evaporated in vacuum. Cleaning is performed flash chromatography on a column using gradient elution with a mixture of 10-60% simple ether/hexane to obtain 8,46 g (83%) of the desired product as a clear oil.

1H NMR (500 MHz, CDCl3) δ 3,98 (DD, J=2,5, and 12.4 Hz, 1H), of 3.77 (DDD, J=3,5, 7,1, to 10.8 Hz, 1H), only 3.57 (DD, J=1,4, and 12.4 Hz, 1H), 3,50 (DD, J=2,5, 11.7 Hz, 1H), 3.46 in (s, 3H), of 3.25 (s, 3H), up 3.22 (s, 3H), 3,22-3,20 (m, 1H), 1,96 (DDD, J=4,7, 11,8, 16.5 Hz, 1H), 1,75 (ush. DD,J=1,7, of 14.2 Hz, 1H).

Stage

A solution of product from step B, intermediate compound 3 (3.0 g, 17,04 mmol) in a mixture of tetrahydrofuran/water (60 ml/10 ml) is treated with concentrated hydrochloric acid (6 ml) and the resulting solution was stirred at room temperature for 1 h the Mixture was concentrated in vacuo to remove tetrahydrofuran and then the aqueous layer was extracted with simple ether (6×50 ml). The organic layers are combined, dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain an intermediate compound 24 (1.75 g, 79%) as a clear oil.

1H NMR (500 MHz, CDCl3) δ to 4.23 (DDD, J=1,2, 11,4, and 12.4 Hz, 1H), 4,15-4.09 to (m, 1H), 3,82 (DD, J=5,95, and 8.7 Hz, 1H), 3,74 (DDD, J=5,5, 8,5, to 13.6 Hz, 1H), of 3.56 (DD, J=8,8, 11.3 Hz, 1H), 3,50 (s, 3H), 2,61 (app DD, J=5.0 and a 8.9 Hz, 2H).

Intermediate compound 4

This intermediate connection recip who have similar technique to obtain the intermediate compound 3, except that itmean replace iodatum. Cleaning IHSD (gradient elution 0-40% ethyl acetate/hexane) gives 693 mg (66%) of the final compound as a clear oil.

The intermediate compound 5

To a mixture of 5,6-dihydro-4-methoxy-2H-Piran (0.5 g, 4 mmol) in a mixture of acetonitrile/water (15 ml, 1:1) at room temperature add bis(tetrafluoroborate) 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane (1.5 g, 4.4 mmol, SELECTFLUOR™) in one portion and the resulting reaction mixture was stirred at room temperature until completion of the reaction. Then add solid NaCl and the reaction mixture is extracted with simple ether (4×50 ml). The ether layer is dried (anhydrous magnesium sulfate) and concentrate to obtain 0.34 g (65%) indicated in the title compound, which does not require further purification.

1H NMR (500 MHz, CDCl3) δ of 4.95 (m, 1H), 4,4-is 4.21 (m, 2H), 3.72 points-of 3.65 (m, 2H), 2,75 (m, 2H).

The intermediate compound 6

Stage And

A mixture of tetrahydro-4H-Piran-4-she (10.0 g, 100 mmol) and pyrrolidine (11 g, 150 mmol) was stirred at room temperature for 1 h, the Excess pyrrolidine removed in vacuum and the residue is dried overnight in high vacuum. Enamin receive in the form of a yellow liquid (14,7 g), which is used in the next stage without further purification.

Stage

Enamin obtained at stage A, the intermediate compound 6 (1.54 g, 10 mmol) and 4-N,N-dimethylpyridin (1.22 g) is treated with N,N-dimethylformamide (25 ml). The mixture is cooled to a temperature of 0°C and add solid triftorbyenzola 5-(trifluoromethyl)dibenzothiophene (4.0 g, 10 mmol). The resulting mixture is stirred at a temperature of 0°C for 1 h, then quenched with 30 ml of concentrated aqueous HCl. The resulting mixture was stirred for 2 h and then extracted with simple ether (4×70 ml). The combined ether layers washed with water (50 ml) and saturated salt solution (50 ml), dried over Na2SO4, filtered and evaporated. The residue is purified on silica gel (eluent: 10% ether/hexane) to obtain the two components. The more polar component (200 mg) is the desired product.1H-NMR showed that the product may be in the form of polumetla.

1H NMR (500 MHz, CDCl3) δ 4,43-to 3.38 (m, 5H), 3,24, 3,18 (SS, 3H) 2,52 (m, 1H), equal to 1.82 (m, 1H).

The less polar product (100 mg) confirmed as alpha-alpha'-dateformatlength-4H-Piran-4-one.

1H NMR (500 MHz, CDCl3) δ 4,59 (DD, 2H), 3,24, of 3.80 (t, J=11.3 Hz, 2H), 3,42 (m, 2H).

Intermediate compound 7

Stage And

To a solution of 5-trifluoromethyl-2-pyridinol (51G, 310 mmol) and sodium acetate (26,2 g, 319 mmol) in glacial acetic acid (200 ml) is added bromine (16,7 ml, 325 mmol) and the resulting mixture is heated to a temperature of 80°C for 2.5 h, the Reaction mixture was cooled to room temperature and then evaporated under reduced pressure. The residue is neutralized with saturated NaHCO3solution and extracted with ethyl acetate (3×200 ml). The organic layers are combined, dried over MgSO4, filtered and evaporated in vacuum to obtain 74,45 g (98%) of the crude product.

1H NMR (400 MHz, CDCl3) δ of 8.04 (d, J=2.6 Hz, 1H), 7,89 (m, 1H).

Stage

In the atmosphere of nitrogen substituted pyridine described in stage A, the intermediate compound 7 (48,8 g, 202 mmol) added in small portions to a suspension of NaH (8,9 g, 220 mmol) in anhydrous tetrahydrofuran (500 ml). When you are finished adding the intermediate reaction mixture is cooled to a temperature of -78°C and treated with tert-butyllithium (260 ml, 444 mmol), is added dropwise via syringe. After stirring for 5 minutes, slowly add N,N-dimethylformamide (50 ml, 707 mmol) to maintain the solution temperature below -50°C. the resulting mixture was then stirred for 10 h, allowing to warm to room temperature. The mixture was quenched with 2n. HCl and then diluted with ethyl acetate (1000 ml). The body of the static layer is separated, washed with saturated salt solution, dried over MgSO4and evaporated in vacuum. The desired product precipitated from ethyl acetate and hexane and filtered to obtain a light brown solid (28,55 g, 74%).

1H NMR (500 MHz, CD3OD) δ 10,13 (s, 1H), 8,21 (s, 2H).

Stage

A mixture of the intermediate from step B, intermediate compound 7 (18 g, 95 mmol), sodium formate (7,1 g, 110 mmol), hydroxylamine hydrochloride (7,3 g, 110 mmol) and formic acid (150 ml) was stirred at room temperature for 2 h and then heated to the boiling temperature under reflux overnight. The reaction mixture is cooled and allowed to stand at room temperature for 7 days. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The combined organic layers washed with water (2×), saturated NaHCO3and saturated salt solution, dried over Na2SO4, filtered and concentrated in vacuo to give the desired product as a brown powder (17,84 g, 90%).

1H NMR (400 MHz, CD3OD) δ of 8.37 (d, J=2.7 Hz, 1H), 8,19 (kV, J=0.7 Hz, 0.3 Hz, 1H).

Stage D

To a mixture of phosphorus oxychloride (13.4 ml, 144 mmol) and quinoline (8,7 ml, 73 mmol) is added the product from step C, intermediate compound 8 (4.6 g, 131 mmol) and the resulting mixture heated to the boiling temperature under reflux for 3 hours, the Reaction mixture is cooled to a temperature of 100°C before the slow addition of water (70 ml). The mixture is then cooled to room temperature and carefully neutralized with saturated NaHCO3solution. The aqueous layer was extracted with ethyl acetate (3×) and the organic layers combined, dried over MgSO4, filtered and evaporated in vacuum. The crude product is purified flash chromatography to obtain (23,5 g, 87%) of the desired compound.

1H NMR (500 MHz, CDCl3) δ 8,88 (d, J=2.0 Hz, 1H), compared to 8.26 (d, J=2.5 Hz, 1H).

Stage E

To a suspension of NaH (7,8 g, 200 mmol) in tetrahydrofuran (100 ml) in an atmosphere of nitrogen was added dropwise a solution of tert-butylmalonate (20 ml, 120 mmol) in anhydrous tetrahydrofuran (100 ml) via syringe. The reaction mixture was stirred for 0.5 h, then slowly add a solution of the intermediate compound obtained in stage D, the intermediate compound 8 (20,1 g, which is 97.6 mmol) in tetrahydrofuran (200 ml)via syringe. The reaction mixture was stirred at room temperature overnight, then quenched with saturated solution of NH4Cl. The organic layer is separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers washed with water (3×), drying the above Na 2SO4, filtered and evaporated in vacuum. Flash chromatography gives 31,76 g (95%) of pure desired product.

1H NMR (500 MHz, CDCl3) δ 9,03 (d, J=1.5 Hz, 1H), 8,25 (d, J=2.0 Hz, 1H), 5.25 in (s, 1H), 3,86 (s, 3H), of 1.52 (s, 9H).

Stage F

A suspension of Raney Ni (1 g) and the product from step E, the intermediate compound 7 (18.2 g, to 52.9 mmol) in ethanol (130 ml) was placed on a Parr apparatus and hydronaut at 40 f/d2H2throughout the night. The suspension is filtered through celite and the filtrate is evaporated in vacuum to obtain 16,35 g (98%) of the crude product.

1H NMR (500 MHz, CDCl3) δ 8,83 (s, 1H), 7,89 (s, 1H), 7,82 (s, 1H), a 4.83 (d, J=16 Hz, 1H), 4.72 in (s, 1H), 4,49 (d, J=16 Hz, 1H), 1,45 (s, 9H).

Stage G

To a mixture of the product from step F, the intermediate compound 7 (16 g, 51 mmol) in dichloromethane (60 ml) add TFOC (30 ml) and the resulting mixture was stirred at room temperature for 0.5 hours, the Solution is evaporated under reduced pressure and the residue is dissolved in dichloromethane. The mixture was neutralized by slow addition of saturated solution of sodium bicarbonate and the organic layer removed. The aqueous layer was extracted with dichloromethane (4×) and the combined organic layers dried over Na2SO4, filtered and evaporated in vacuum to obtain 10,42 g (95%) of the desired product.

1H NMR (500 MHz, CDCl 3) δ 8,81 (s, 1H), 7,78 (s, 1H), 7,30 (s, 1H), 4,63 (s, 2H), 3,90 (s, 2H).

Stage N

To a solution of the product from step G of intermediate compound 7 (18.0 g, and 83.3 mmol) in tetrahydrofuran (50 ml) is added 1.0 M of borane in tetrahydrofuran (417 ml, 420 mmol) and the resulting solution was stirred at room temperature overnight. The solution is evaporated under reduced pressure and the residue is treated with a solution of 1% HCl/methanol. The resulting mixture is heated to a temperature of 50°C overnight to decompose the complex of borane. Treatment with acidic methanol was repeated twice to ensure the removal of the complex of borane. The solution of this crude product (83,3 mmol, presumably 100% conversion) and diisopropylethylamine (43 ml, 250 mmol) in dichloromethane is treated with di-tert-BUTYLCARBAMATE (35.4 g, 167 mmol) and the resulting mixture was stirred at room temperature overnight. The solution was washed with saturated aqueous sodium bicarbonate, water and saturated salt solution. The aqueous layers are combined and washed again with dichloromethane (2×). Then the combined organic layers dried over Na2SO4, filtered and evaporated to dryness. The crude product is purified flash chromatography and GHSD obtaining (11,89 g, 47%) as a yellow solid.

1H NMR (500 MHz, CDCl3

Stage I

The product described at stage N, the intermediate compound 8 (11,89 g) is treated with a solution of 4n. HCl in dioxane. The solution was stirred at room temperature for 2 h and then evaporated in vacuum to obtain intermediate compound 8 (10,85 g, 99%) as a yellow powder. LC-MS for C9H10F3N2designed 202,07, found [M+H]+203,0.

Intermediate compound 8

Method And

Stage And

A mixture of (1S)-(+)-2-azabicyclo[2.2.1]hept-5-ene-3-one (10.3 g, 94,4 mmol) in ethyl acetate (200 ml) and 10% Pd/C (0.5 g) hydronaut at room temperature. After 24 hours the reaction mixture is filtered and evaporated, leaving less than 10.4 g (100%) of product, which was placed in a 250 ml methanol and HCl (12 M, 6 ml). The resulting mixture was stirred at room temperature until until the reaction is completed (72 h). Evaporation of methanol, followed by drying under high vacuum gives specified in the title compound in the form of not-quite-white solid (16.0 g, 96%).

1H NMR (500 MHz, D2O): δ 3,70 (s, 3H), 3,01 (m, 1H), of 2.38 (m, 1H), 2,16-of 1.73 (m, 6H).

Stage

To a suspension of the intermediate article is Hai And (10.2 g, of 56.8 mmol) in dry dichloromethane (200 ml) add benzophenone (10.2 g, with 56.8 mmol) at room temperature and the resulting mixture was stirred for 24 h, the Reaction mixture was filtered and the filtrate is evaporated to obtain a yellow oil, which was triturated with simple ether (100 ml), filtered and evaporated. This operation is repeated twice to ensure that the product does not contain impurities of ammonium chloride. The oil obtained is carefully dried in vacuum to obtain specified in the connection header (18,03 g, >100%) and it does not require further purification.

1H NMR (500 MHz, CDCl3): δ 7,5-to 7.18 (m, 10H), of 3.75 (m, 1H), and 3.7 (s, 3H), 2,78 (m, 1H), 2.26 and-1,71 (m, 6H).

Stage

To a solution of Diisopropylamine lithium (obtained from Diisopropylamine (7.7 g, 76 mmol) and n-utility (30,4 ml, 2.5 M in hexane, 76 mmol) in tetrahydrofuran (120 ml) at a temperature of -78°C add a simple broadcast from the stage In (18.0 g, with 56.8 mmol). The resulting red solution is stirred for 20 min, then quenched with 2-iodopropane (14,9 mg, 88 mmol). The reaction mixture is gradually heated for 3 hours to a temperature of 0°C and this temperature is maintained for another 3 hours. The reaction is quenched with water and extracted with ethyl acetate. The organic layer is washed with water, saturated salt solution, dried (anhydrous magnesium sulfate) and concentrate is getting oil. To a solution of the crude Schiff bases (20,0 g) in tetrahydrofuran (100 ml) is added HCl (5.0 ml, 12 M). The resulting reaction mixture was stirred at room temperature for 3 hours After removal of all volatiles cleaners containing hydrochloride salt is placed in dichloromethane (250 ml), add a saturated solution of sodium bicarbonate (250 ml) and di-tert-BUTYLCARBAMATE (26,0 g, 1.4 EQ.). The resulting mixture is separated and washed with water, saturated salt solution, dried (anhydrous magnesium sulfate) and concentrate to obtain oil. Purification with flash chromatography on a column (eluent:hexane/ethyl acetate 19:1) to give the desired product (4,91 g, 30%).

1H NMR (500 MHz, CDCl3): 4,79 (ush., 1H), 4,01 (m, 1H), 3,71 (s, 3H), 2,18 is 1.60 (m, 6H), of 1.44 (s, 9H), of 0.87 (d, J=6.9 Hz, 3H), 0,86 (d, J=6.9 Hz, 3H).

Stage D

To a solution of ester from step C (4,91 g, and 17.2 mmol) in methanol (100 ml) was added LiOH solution (3.6 g, 85 mmol) in water (20 ml) and tetrahydrofuran (10 ml). The resulting mixture is heated to a temperature of 80°C to complete the reaction (18 h). The methanol is removed in vacuo and the crude product is placed in a mixture of water/ethyl acetate (200 ml, 1:4), and cooled to a temperature of 0°C. the Acidity of the mixture was adjusted to pH 6. The ethyl acetate layer was separated, washed with water, saturated salt solution, dried (anhydrous magnesium sulfate) and concentrate to obtain oil. Clean flash chromatog what afia in column (eluent:hexane/ethyl acetate 1:1 + 2% AcOH) to give the intermediate compound 8 (3,9 g, 84%).

1H NMR (500 MHz, CDCl3): 11,36 (ush., 1H), of 6.49 (ush., 1H), a 4.83 (m, 1H), 3,71 (s, 3H), 2,30-of 1.55 (m, 6H), of 1.46 (s, 9H), were 0.94 (d, J=6.9 Hz, 3H), 0,933 (d, J=6.9 Hz, 3H).

Method In

Stage And

Commercially available (1R,4S)-4-aminocyclopent-2-ene-1-carboxylic acid is converted into the hydrochloride methyl ester classical method.

Stage

To a suspension of amine from step A (of 6.31 g, 35.5 mmol) in acetone (40 ml), water (20 ml) was added in several portions of solid NaHCO3(6.6 g, 78 mmol). After 5 min add a solution of di-tert-BUTYLCARBAMATE (8.5 g, 39 mmol) in acetone (60 ml) and the reaction mixture was stirred at room temperature. After 3 h, the acetone removed in vacuo and the residue is divided between a simple ether (500 ml) and saturated aqueous NaHCO3(120 ml). The ether layer is optionally washed with aqueous solution of NaHCO3(1×100 ml), saturated salt solution (1×100 ml), dried over anhydrous Na2SO4, concentrated and purified flash chromatography (15% ethyl acetate/hexane) to give the product (7,25 g, 85%).

Stage

To a solution of bis(trimethylsilyl)amide lithium (10.4 g, to 62.1 mmol) in tetrahydrofuran (100 ml) add a solution of the intermediate from step B (of 6.71 g, 27.8 mmol) in tetrahydrofuran (10 ml) for 10 min at tempera is ur -78° C. the resulting solution was stirred at a temperature of -78°C for 30 min, then add one portion of isopropylated (3,3 ml, 33 mmol). The reaction mixture is heated to a temperature of -25°C and this temperature is maintained for the night. Then the reaction quenched with saturated aqueous NH4Cl (250 ml). The organic layer is separated and the aqueous layer was further extracted with diethyl ether (3×100 ml). The combined organic layers are then washed with saturated salt solution (1×100 ml), dried over anhydrous Na2SO4, filtered, concentrated and purified flash chromatography (5-10% ethyl acetate/hexane) to give the product (5,66 g, 72%) as a clear oil (CIS/TRANS=4,3/1).

1H NMR (500 MHz, CDCl3) CIS-isomer: δ 5,79 (s, 2H), and 4.75 (m, 1H), and 3.72 (s, 3H), 2,28-of 2.20 (m, 2H), 2,0 (DD, J=15, 4 Hz, 1H), 1,45 (s, 9H), of 0.85 (d, J=6.6 Hz, 3H), 0,81 (d, J=7 Hz, 3H).

Stage D

To a solution of product from step C (1.6 g, 5.7 mmol) in tetrahydrofuran (50 ml), methanol (50 ml) and water (10 ml) is added LiOH monohydrate (400 mg) and the reaction mixture is heated to boiling point under reflux until until TLC indicates complete reaction. Organic solvents are removed in vacuo and the aqueous layer was washed with simple ether (1×) and then slowly acidified with concentrated HCl to achieve a pH of 4. The resulting suspension ex is reginout CH 2Cl2(3×). The combined organic layers dried over anhydrous MgSO4filter and concentrate to obtain the product as a mixture of two CIS/TRANS-isomers (1.5 g) as a foamy yellow solid substance. This solid is dissolved in ethyl acetate (2 ml) when heated and diluted with hexane (50 ml) to obtain a transparent solution. The solution is cooled to room temperature for 1 h and then aged at a temperature of -25°C in the refrigerator over night. The TRANS-isomer crystallizes together with a certain quantity of the desired CIS-isomer (500 mg total). The mother liquor is collected and concentrated to obtain specified in the title compound (1 g, 66%, only CIS-isomer).

1H NMR (500 MHz, CDCl3) CIS-isomer: δ 5,80 (m, 2H), 4,80 (m, 11-1), 2,40-of 2.20 (m, 2H), 2,15-2,0 (m, 1H), 1,5 (m, 9H), 1,0-0,8 (m, 3H).

Stage E

To a solution of product from step D (1 g) in ethanol (30 ml) is added 10% Pd/C (100 mg) and the mixture was stirred in a Parr apparatus at a pressure of 50 f H2throughout the night. The mixture is filtered through celite and concentrated in vacuo to obtain specified in the title compound (1 g, 99%).

1H NMR (500 MHz, CDCl3): 11,36 (ush., 1H), of 6.49 (ush., 1H), a 4.83 (m, 1H), 3,71 (s, 3H), 2,30-of 1.55 (m, 6H), of 1.46 (s, 9H), were 0.94 (d, J=6.9 Hz, 3H), 0,933 (d, J=6.9 Hz, 3H).

Intermediate compound 9

Stage And

Intermediate compound 8 (4.6 g, 16 mmol) and intermediate compound 11 (4.0 g, 14 mmol) is first dried by azeotropic distillation with toluene (3×50 ml) and placed in a high vacuum for 30 minutes In nitrogen atmosphere successively added 4-dimethylaminopyridine (1.08 g, 8.60 mmol), anhydrous dichloromethane (40 ml) and diisopropylethylamine (7.0 ml, 40 mmol). After the conversion of intermediate compound 8 in the solution add hexaphosphate bromo-Tris-pyrrolidinone (6,80 g of 14.3 mmol), and immediately add another diisopropylethylamine (7.0 ml, 40 mmol). The reaction mixture was stirred at room temperature overnight and then quenched with saturated NaHCO3. The aqueous layer was again washed with dichloromethane (3×50 ml) and the organic layers combined, dried over Na2SO4, filtered and evaporated in vacuum. The crude product is purified flash chromatography on a column (stepwise gradient of 0-60% ethyl acetate/hexane) to give the product (4,80 g, 74%) as a yellow foam.

1H NMR (500 MHz, CDCl3) δ 8,72 (s, 1H), of 7.70 (s, 1H), 4,88 (USD, J=17,0 Hz, 1H), 4,78 (d, J=17.6 Hz, 1H), 4.04 the-a-3.84 (m, 2H), 3,52 (USS, 1H), 3,12 (OST, J=5.6 Hz, 1H), 2,32-to 2.06 (m, 3H), 1,98 is 1.70 (m, 4H), 1,64-and 1.54 (m, 1H), 1,44 (s, 9H), 0,92-of 0.82 (m, 6H). LC-MS for C23H32F3N3About the calculated 4555,24, found [M+H]+456,2.

Stage

The product from step B, intermediate compound 19 (1.2 g, 2.6 mmol) is dissolved with 4h. HCl in dioxane (50 ml) and the resulting solution was stirred at room temperature for 1 h, the Reaction mixture is evaporated in vacuum to obtain the product (904 mg, 97%) as a white powder. LC-MS for C18H24F3N3About the calculated 355,20, found [M+H]+356,2.

Intermediate compound 10

Stage And

To a solution of the product described in stage A, the intermediate 19 (2.0 g, 4.4 mmol) in dichloromethane (80 ml) is added 3-chloroperoxybenzoic acid (2,11 g, 8,83 mmol) and the resulting solution is stirred over night at room temperature. The mixture is cooled to a temperature of 0°C and, with vigorous stirring, added in several portions of solid calcium hydroxide (about 6 g). The suspension is stirred for a further 30 min, then filtered through celite to remove all solids. The filtrate is evaporated in vacuo and the residue purified IHSD (gradient elution 40-100% ethyl acetate/hexane) to obtain 1,32 g (64%) of the desired compound.

1H NMR (500 MHz, CDCl3) δ 8,46 (s, 1H), 7,28 (s, 1H), 4,88 (USD, J=and 17.2 Hz, 1H), 4,78 (d, J=17.7 and Hz, 1H), 4,05-a-3.84 (m, 2H), 3,12 (USS, 1H), 2,34-to 2.06 (m, 3H), 1,88 is 1.70 (m, 4H), 1,62-and 1.54 (m, 1H), USD 1.43 (s, 9H), 0,90-of 0.85 (m, 6H). LC-MS for C23H32F3N About5designed 471,20, found [M+H]+472,2.

Stage

The product from step B, intermediate compound 20 (1,32 g, 2.82 mmol) was dissolved in 4n. HCl in dioxane (50 ml) and the resulting solution was stirred at room temperature for 1 h, the Reaction mixture is evaporated in vacuum to obtain the product (1.10 g, 98%) as a white powder. LC-MS for C18H24F3N3About2designed 371,20, found [M+H]+372,2.

Example 1

A solution of intermediate compound 9 (980 mg, of 2.08 mmol), tetrahydro-4H-Piran-4-it (320 mg, of 3.13 mmol), diisopropylethylamine (1,10 ml, 6,24 mmol) and crushed molecular sieves (4E, 500 mg) in dichloromethane (50 ml) is treated with triacetoxyborohydride sodium (2.20 g, 10.4 mmol) and stirred at room temperature overnight. The reaction is quenched with saturated sodium bicarbonate solution (50 ml) and diluted with 25 ml dichloromethane. The organic layer is separated and the aqueous layer washed with dichloromethane (2×25 ml). The organic layers are combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product is purified HPLC with reversed phase with obtaining compounds of Example 1 (915 mg, 86,0%). LC-MS for C23H31F3N3About2designed 439,24, found [M+H]+440,2.

the example 2

A solution of intermediate compound 9 (304 mg, 0,712 mmol), intermediate 1 (160 mg, of 1.42 mmol), diisopropylethylamine (370 μl, 2.14 mmol) and crushed molecular sieves (4, 150 mg) in dichloromethane (25 ml) is treated with triacetoxyborohydride sodium (755 mg, of 3.56 mmol) and stirred at room temperature overnight. The reaction is quenched with saturated sodium bicarbonate solution (25 ml) and diluted with 25 ml dichloromethane. The organic layer is separated and the aqueous layer washed with dichloromethane (2×20 ml). The organic layers are combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue is purified preparative TLC (eluent: 0.5% of NH4OH/5% methanol/94.5% of CH2Cl2with getting 239 mg (74%) of final product as a mixture of diastereoisomers. CIS and TRANS racemates relatively Pyrenophora ring is shared by HPLC on a column with a Preparative ChiralCel OD (eluent: 5% ethanol/95% hexane). CIS racemate further separated in a column with a Preparative ChiralCel AD (eluent: 5% ethanol/95% hexane). LC-MS for C24H35F3N3About2designed 453,26, found [M+H]+454,30.

Example 3

The product is obtained according to the method of example 2, except that intermediate compound 1 replace intermediate compound 2. Purification preparative TLC (alue the t: 0.5% of NH 4OH/5% methanol/94.5% of CH2Cl2) give 203 mg (92%) as a mixture of four diastereomers. Separate the isomers obtained by HPLC purification on a column with a Preparative ChiralCel OD, elwira 5% ethanol/95% hexane at a flow rate of 9 ml/min LC-MS for C25H36F3N3About2designed 467,28, found [M+H]+468,3 for all 4 isomers.

Example 4

The product is obtained according to the method of example 2, except that intermediate compound 1 replace the intermediate compound 5. Cleaning give 312 mg (88%) of product as a mixture of four diastereomers. LC-MS for C30H36ClF3N3About4designed 593,23, found [M+H]+594,3.

Example 5

To a solution of the product described in example 4 (286 mg, 0,482 mmol) in methanol is added 0.5 M solution of sodium methoxide in methanol (1.2 ml, of 0.58 mmol) and the resulting mixture was stirred at room temperature for 2 hours After completion of the reaction the mixture is evaporated in vacuum and purified preparative TLC (eluent: 1,0% NH4OH/10% methanol/89% CH2Cl2) to obtain the compound of example 21 (201 mg, of 91.6%) as a mixture of four diastereomers. LC-MS for C23H33F3N3About3designed 455,24, found [M+H]+456,25.

Example 6

The solution PR is an interstitial compound 9 (500 mg, at 1.17 mmol), intermediate 3 (458 mg, 3,51 mmol), diisopropylethylamine (407 μl, 2.34 mmol) and crushed molecular sieves (4E, 250 mg) in dichloromethane (25 ml) is treated with triacetoxyborohydride sodium (1.24 g, of 5.85 mmol) and stirred at room temperature overnight. The reaction is quenched with saturated sodium bicarbonate solution (25 ml) and diluted with 25 ml dichloromethane. The organic layer is separated and the aqueous layer washed with dichloromethane (2×20 ml). The organic layers are combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue is purified preparative TLC (eluent: 1,0% NH4OH/10% methanol/89% CH2Cl2) to obtain 210 mg (86%) of the final product in the form of a mixture of four diastereomers. Separate the isomers receive HPLC on a column with a Preparative ChiralCel OD, elwira 20% ethanol and 80% hexane at a flow rate of 9 ml/min LC-MS for C24H34F3N3About3designed 469,21, found [M+H]+470,2 for all 4 isomers.

3rd isomer from the column ChiralCel OD:1H NMR (500 MHz, CDCl3) δ 8,72 (s, 1H), 7,69 (s, 1H), 4,87 (USD, J=and 17.2 Hz, 1H), and 4.75 (d, J=17,4 Hz, 1H), 4,12 (DD, J=3,1, and 12.4 Hz, 1H), 3,99-3,86 (m, 3H), 3,47-3,39 (m, 1H), 3,41 (s, overlapping, 3H), 3,35-3,30 (m, 2H), 3,20-is 3.08 (m, 3H), 2,87 is 2.80 (m, 1H), 2,62-of 2.54 (m, 1H), 2,16-2,02 (m, 2H), 1,95 (USS, 1H), 1,88-of 1.81 (m, 1H), 1,78-of 1.57 (m, 6H), 1.41 to to 1.32 (m, 1H), of 0.96 (d, J=6,7 Hz, 3H), from 0.84 (d, J=6.6 Hz, 3H).

4th isomer from the column ChiralCel OD:1H NMR (500 MHz, CDCl 3) δ 8,72 (s, 1H), 7,69 (s, 1H), 4,87 (USD, J=17.6 Hz, 1H), and 4.75 (d, J=17.5 Hz, 1H), 4,10 (DD, J=3.1 and 12.3 Hz, 1H), 3,99-3,88 (m, 3H), 3.46 in-3,39 (m, 1H), 3,41 (s, overlapping, 3H), 3,35-3,30 (m, 2H), 3,17-to 3.09 (m, 3H), 2,86 is 2.80 (m, 1H), 2,64 is 2.55 (m, 1H), 2,16 is 2.10 (m, 1H), 2.05 is (USS, 1H), 1,95-to 1.82 (m, 2H), 1,76-of 1.55 (m, 6H), 1,33-1,24 (m, 1H), 0,95 (d, J=6,7 Hz, 3H), or 0.83 (d, J=6.6 Hz, 3H).

Example 7

The product is obtained according to the method of example 2, except that intermediate compound 1 replace intermediate compound 4. Separate the isomers obtained by HPLC purification on a column with a Preparative ChiralCel OD, elwira 15% ethanol and 85% hexane at a flow rate of 9 ml/min LC-MS for C25H36F3N3About3designed 483,23, found [M+H]+484,2 for all 4 isomers.

JHMS: 2,7 min, 484,3 NMR (CO3OD): ppm 8,82 (s, 1H), 8,23 (s, 1H), 4,94 (s, 2H), 4,86 (H2O), 4,24-4,4 (m, 1H), 3,9-4,4 (m, 3H), and 3.8 (m, 1H), 3,7 (s, 1H), 3,6 (m, 2H), 3.46 in (m, 2H), 3,4 (m, 1H), 3,3 (Meon), 3,2 (m, 3H), 2,4 (m, 1H), 2,2-2,4 (m, 4H), 2,90 (m, 1H), 1,2 (m, 4H), and 0.9 (C, 6N)

Example 8

The product is obtained according to the method of example 2, except that intermediate compound 1 replace the intermediate compound 5. LC-MS for C24H31F3N3O2designed 457,23, found [M+H]+458,2 for all 4 isomers.

Example 9

The product is obtained according to the method of example 2 except that the intermediate compounds is of 1 replace an intermediate compound 6. Separate the isomers obtained by HPLC purification on a column with a Preparative ChiralCel OD, elwira 5% ethanol and 95% hexane at a flow rate of 9 ml/min LC-MS for C24H31F6N3O2designed 507,23, found [M+H]+508,2 for all 4 isomers.

Example 10

A solution of intermediate compound 10 (641 mg, 1,60 mmol), tetrahydro-4H-Piran-4-it (220 mg, 2,24 mmol), molecular sieves (4E, 320 mg) in dichloromethane (20 ml) is treated with triacetoxyborohydride sodium (1.70 g, 8,00 mmol) and stirred at room temperature for no more than 5 hours the Reaction is quenched with saturated sodium bicarbonate solution (50 ml) and diluted with 30 ml dichloromethane. The organic layer is separated and the aqueous layer washed with dichloromethane (2×30 ml). The organic layers are combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product is purified preparative TLC (eluent: 0,75% NH4OH/7.5% methanol/91,75% CH2Cl2with getting 626 mg (86%) of the final product.

1H NMR (500 MHz, CDCl3) δ 8,45, (s, 3H), 7,25 (s, 1H), 4,88 (USD, J=17,4 Hz, 1H), 4,77 (d, J=17.6 Hz, 1H), 4,00-of 3.85 (m, 4H), 3,41 (app t, J=11.7 Hz, 2H), 3,22,(p, J=6,8 Hz, 1H), 3,13-of 3.07 (m, 2H), 2,82-to 2.74 (m, 1H), 2,54-2,47 (m, 1H), and 2.14 (DD, J=6,8, to 12.8 Hz, 1H), 2,07 is 2.00 (m, 1H), 1,94 is 1.86 (m, 2H), 1,84-to 1.77 (m, 3H), 1,65-of 1.57 (m, 2H), 1,46-of 1.26 (m, 3H), of 0.93 (d, J=6.8 Hz, 3H), or 0.83 (d, J=6.8 Hz, 3H). LC-MS for C23H32F3N3About3the expect is but 455,24, found [M+H]+456,20.

Example 11

The product is obtained according to the method of example 10 except that tetrahydro-4H-Piran-4-one substituted intermediate compound 1. Separate the isomers obtained by HPLC purification on a column with a Preparative ChiralCel OD, elwira 7% ethanol and 93% hexane at a flow rate of 9 ml/min LC-MS for C24H34F3N3About3designed 469,24, found [M+H]+470,20 for all 4 isomers.

Example 12

The product is obtained according to the method of example 10 except that tetrahydro-4H-Piran-4-one substituted intermediate compound 2. Separate the isomers obtained by HPLC purification on a column with a Preparative ChiralCel OD, elwira 5% ethanol and 95% hexane at a flow rate of 9 ml/min LC-MS for C25H36F3N3About3designed 483,24, found [M+H]+484,20 for all 4 isomers.

Example 13

The product is obtained according to the method of example 10 except that tetrahydro-4H-Piran-4-one substituted intermediate compound 3. Separate the isomers obtained by HPLC purification on a column with a Preparative ChiralCel OD, elwira 21% ethanol and 79% hexane at a flow rate of 9 ml/min LC-MS for C24H34F3N3About4designed 485,25, found [M+H]+486,30 for all 4 isomers.

Although this is the connection described and illustrated specific options specialist in the art will understand that various adaptations, changes, modifications, substitutions, deletions, or additions may be made without exceeding the limits and scope of this invention. For example, can be used effective dose, other than certain dosages indicated above, due to changes in reaction treat a mammal according to any one of the indications of the connection mentioned above. Also observed pharmacological response may vary according to and depending on the particular active compound, or present pharmaceutical carriers, as well as the type of dosage form and route of administration, and such expected variations or differences in the results are discussed in the objects and the practice of the present invention. Therefore understood that the invention defined by the following claims, and the items specified by the claims be interpreted as broadly as is reasonable.

1. Tetrahydroprotoberberine formula I

where

R3is oxygen or absent;

R8choose from

(a) hydrogen,

(b) C1-3of alkyl, which is unsubstituted or substituted by 1-6 fluorine atoms,

(c) -O-C1-3of alkyl,

(d) fluorine and

(e) hydroxy;

and their pharmaceutically acceptable salts and individual diastereomers.

2. The compound according to claim 1, in which R3is missing.

3. The compound according to claim 1, in which R3is oxygen.

4. The compound according to claim 1, in which R8choose from

(a) hydrogen,

(b) trifloromethyl,

(c) methyl,

(d) methoxy,

(e) ethoxy,

(f) ethyl,

(g) fluorine and

(h) hydroxy.

5. Tetrahydroprotoberberine selected from the group including

and their pharmaceutically acceptable salts and individual diastereomers.

6. Pharmaceutical composition having modulating activity against chemokine receptors, which comprises an inert carrier and a compound according to claim 1.

7. The method of modulating the activity of the receptor of the chemokine in mammals, which includes the introduction of an effective amount of a compound according to claim 1.

8. The method of obtaining drugs for modulating the activity of the receptor of the chemokine in humans and animals comprising combining the compound according to claim 1 with a pharmaceutically acceptable carrier or diluent.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinoquinoline of the formula (II): or their tautomers, or their pharmaceutically acceptable salts wherein ring A represents ortho-condensed phenyl and monosubstituted with R4 wherein R4 means halogen atom; R1 represents -(CH2)nL wherein n means a whole number from 1 to 6; L is chosen from unsubstituted phenyl or its benzo-derivative, or L is chosen from phenyl or its benzo-derivative and substituted with one or two groups chosen from -CN, -CF3, (C1-C4)-alkyl, or L is chosen from -OH, -OCOR', -SOmR' wherein m means 0, 1 or 2, -NR'R'' under condition that -NR'R'' differs from -NH2, -NR'COR'', or L is chosen from heterocycle or heteroaryl wherein in each abovementioned case any group from R' or R'' is chosen from hydrogen atom, (C1-C4)-alkyl, (C3-C6)-cycloalkyl, phenyl, phenyl-(C1-C4)-alkyl and wherein any group from R' or R'' is unsubstituted or substituted 1, 2 or 3 times with phenyl, -OH, O-(C1-C4)-alkyl at carbon atoms wherein in any abovementioned case heterocycle is chosen from five- or six-membered heterocyclic ring comprising 1, 2 or 3 heteroatoms chosen from oxygen (O), nitrogen (N) or sulfur (S) atoms or its condensed benzo-derivative, indicated heterocycle wherein carbon atom is disubstituted to form (C5-C7)-spiro-group and indicated heterocycle wherein carbon atom © is substituted for oxygen atom (O) to form carbonyl group and wherein in any case heteroaryl is chosen from unsubstituted thiophene, furan, imidazole, triazole, tetrazole. Compounds of the formula (II) are antagonists of glycine-receptors and can be used in preparing pharmaceutical agents designated for treatment or prophylaxis of ischemic disease.

EFFECT: valuable medicinal properties of compounds.

5 cl, 8 tbl, 148 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to the substituted pyrazoles, pharmaceutical compositions comprising these compounds and methods for their using in treatment of autoimmune diseases wherein cathepsin S is their mediating agent. Described substituted pyrazoles represent compounds of the formula (I): wherein a dotted line is placed near the group -C-R6 or absent, or it represents a bond; Y represents nitrogen atom or -CR20; Z represents nitrogen atom or -CR21; T represents nitrogen atom or -CR2; S represents nitrogen atom or -CR3 under condition that from 0 to 3 among S, T, Y and Z represent nitrogen atom, and additionally under condition that one among S, T, Y and Z can represent the group =N+-O- if other three are not nitrogen atom; R20 is chosen from hydrogen, halogen atom, hydroxy-, cyano-group, 4-7-membered heterocycle comprising nitrogen and oxygen atom; R21 represents hydrogen atom; R2 is chosen from hydrogen, halogen atom and hydroxy-group; R3 is chosen from hydrogen, halogen atom, (C1-C5)-alkoxy-group, (C1-C5)-alkyl, cyano-group, -RgRhN, 4-7-membered heterocyclyl comprising nitrogen and oxygen atom and -R17OC=O; R5 and R6 represent hydrogen atom; R7 and R8 can be combined in common and form optionally substituted 5-7-membered carbocylic or heterocyclic ring comprising nitrogen atom and wherein the indicated ring can be unsaturated or aromatic and this ring is substituted optionally with -Rt(C=O)- or -RtSO2; Rt represents (C1-C6)-alkyl; Rg, Rh and R17 represent (C1-C5)-alkyl; G represents (C3-C6)-alkanediyl; Ar represents monocyclic aryl ring optionally substituted from 1 to 3 substitutes chosen independently from halogen atom, (C1-C5)-alkyl and (C1-C5)-halogenalkyl; R32 represents hydrogen atom, (C1-C5)-alkyl, cyano-group, C1-C5)-hydroxyalkyl, -(C=O)NRvRx, -CHO or (C1-C6)-alkoxycarbonyl wherein each from Rv and Rx is chosen independently from hydrogen atom (H), (C1-C5)-alkyl, (C1-C5)-hydroxyalkyl, (C1-C5)-heterocyclyl comprising nitrogen and oxygen atom, (C1-C5)-heterocyclyl comprising nitrogen and oxygen atom-(C1-C5)-alkylene, (C1-C5)-aminoalkylene; Q represents -NR33, sulfur (S) or oxygen (O) atom; R33 represents hydrogen atom, (C1-C5)-alkyl, (C2-C5)-heterocyclyl comprising oxygen atom-(C1-C5)-alkylene, -R35OC=O and -R35OC=O; R35 represents (C1-C5)-alkyl, or their pharmaceutically acceptable salts, amides and esters, or their stereoisomeric forms.

EFFECT: improved for inhibition, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

25 cl, 3 tbl, 135 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to bicyclic heterocyclic substituted phenyloxazolidinones that represent compounds of the formula (I): wherein R is taken from the group consisting of -OH, O-heteroaryl, -N3, -OSO2R'', -NR'''R'''', or the formula: wherein: (ii) R'' represents direct or branched alkyl comprising up to 5 carbon atoms; (iii) R''' and R'''' are taken independently from the group consisting of hydrogen atom (H), -CO2-R1, -CO-R1, -CS-R1 and -SO2-R4 wherein R1 is taken among the group consisting of cycloalkyl comprising from 3 to 6 carbon atoms and direct or branched alkyl comprising up to 6 carbon atoms; R4 is taken from direct or branched alkyl comprising up to 4 carbon atoms; and R4a represents -CN or -NO2; R4b represents -SR4c, amino-group, -NHR4c or -NR4cR4d wherein R4c and R4d are taken independently from hydrogen atom (H) or alkyl; X represents from 0 to 4 members taken independently from the group consisting of halogen atom; and Y represents radical of the formula (II): or (III): wherein R5, R6, R7 and R8 represent independently hydrogen atom (H), or R and R6 and/or R7 and R8 form in common oxo-group; R9 and R10 represent independently hydrogen atom (H); A, B, C and D are taken from carbon atom (C) and nitrogen atom (N) to form phenyl ring or 5-6-membered heteroaromatic ring wherein the indicated heteroaromatic ring comprises from 1 to 4 members taken from the group consisting of nitrogen atom (N); Z is taken from alkyl, heteroaryl comprising nitrogen atom (N); and m represents 0 or 1. These compounds are useful as antibacterial agents and can be used for treatment of patient with the state caused the bacterial infection or with the bacterial infection caused by S. aureus and E. faecium.

EFFECT: valuable medicinal properties of compounds.

45 cl, 1 tbl, 50 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to derivatives of carboline of the general formula (I): wherein R3 means hydrogen atom (H), hydroxyl (OH), -O-(C1-C6)-alkyl; R4 means -N(R17)2 wherein R17 means hydrogen atom (H), (C1-C6)-alkyl, -C(O)-phenyl, -C(O)-(C1-C10)-alkyl, -S(O)y-R14 wherein y = 0, 1 or 2; R14 means (C1-C6)-alkyl, phenyl substituted with halogen atom; or R means amino-group (-NH2), -NH-C(O)-R15 wherein R15 means pyrrolidine, pyrazolidine, furan, pyridine, pyrazine, imidazoline, isoxazolidine, 2-isoxaline, thiophene possibly substituted with -CF3 or (C1-C6)-alkyl; (C3-C7)-cycloalkyl, -N(R13)2 wherein R12 means hydrogen atom (H) or phenyl under condition that -N(R13)2 doesn't mean -NH2; phenyl possibly substituted with (C1-C6)-alkyl, -CF3 if two substituted at phenyl form dioxalane ring; R5 means hydrogen atom (H), or R and R5 in common with nitrogen atom (N) form a heterocycle. Also, invention describes a method for their preparing. Compounds of the formula (I) are suitable for preparing medicinal agents used in prophylaxis and treatment of diseases wherein the enhanced activity of 1 κB is involves.

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

6 cl, 2 tbl, 83 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydropyridine of the formula (I): wherein (a) means unsubstituted phenyl group or phenyl group substituted with 1, 2 or 3 substitutes chosen independently among (C1-C4)-alkoxy-group, or (b) means unsubstituted indolyl group; R1 and R2 are similar or different and mean hydrogen atom, (C1-C4)-alkyl or phenyl group; X means alkylene group with a direct chain comprising 5, 6, 7 carbon atoms, and to their pharmaceutically acceptable salts also. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to HDAC based on these compounds. Invention provides new compounds and pharmaceutical composition based on thereof for aims the stimulation of anti-proliferative effect in warm-blooded animals, such as humans.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 1 tbl, 9 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for preparing substituted imidazopyridine of the general formula (1): wherein R1 means (C1-C6)-alkoxy-group or -NH2. Method involves interaction of compound of the formula (2): with 3-halogen-2-butanone in cyclohexanone medium at temperature 80-100°C. Using cyclohexanone as a solvent allows reducing the process period and to enhance the yield of the end product.

EFFECT: improved preparing method.

9 cl, 19 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to a method for preparing a pharmaceutically active compound 3-{2-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidine-1-yl]ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one (risperidone) of the formula (I): that possesses the neuroleptic properties. Method involves the condensation reaction of (2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-yl)acetaldehyde of the formula (II): with (6-fluoro-3-piperidinyl)-1,2-benzisoxazole of the formula (IV): to yield intermediate enamine representing 3-{2-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidine-1-yl]vinyl}-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-4-one of the formula (III): and the following reduction of this enamine in the presence of hydride. Also, invention claims intermediate compounds of the formula (II) and formula (III) and describes a method for preparing compound of the formula (II) comprising oxidation of 3-(2-hydroxyethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one of the formula (X): Method is characterized by high reproducibility in large-scale manufacturing and represents the unique combination of the synthesis simplicity, decreased cost, safety and protection of the environment.

EFFECT: improved preparing method.

9 cl, 3 ex

FIELD: organic chemistry of heterocyclic compounds, pharmacy.

SUBSTANCE: invention relates to new bicyclic heteroaromatic compounds of the general formula (I): wherein R1 represents phenyl optionally substituted with NHR5 or OR5; R2 represents (C1-C4)-alkyl or phenyl; R5 represents phenylcarbonyl, (C4-C6)-heterocycloalkylcarbonyl, (C2-C8)-alkenylsulfonyl and others; Y represents nitrogen atom (N); Z represents -NH2 or -OH. A represents sulfur atom (S) or a bond; B represents -N(H) or oxygen atom (O); X1-X2 represent C=C, -NH-C(O), C=N and others; Proposed compounds show agonistic activity with respect to LH receptor and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 34 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

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

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of pyridopyrimidines of the formula (I): or (II): wherein Z means nitrogen atom (N) or -CH; W means -NR2; X1 means oxygen atom (O), -NR4 (wherein R4 means hydrogen atom or alkyl), sulfur atom (S) or -CR5R6 (wherein R5 and R6 mean hydrogen atom); X2 means oxygen atom (O); Ar1 means unsubstituted or substituted phenyl; R2 means hydrogen atom, alkyl or acyl; R1 means hydrogen atom, alkyl, halide alkyl and others; R3 means alkyl; cycloalkyl and others; R8 and R9 mean hydrogen atom, alkylsulfonyl and others, and to their pharmaceutically acceptable salts, and to intermediate compounds that are used for preparing compounds of the formula (I) and (II). Indicated compounds show inhibitory activity with respect to activity of p38 kinase and can be used in preparing a medicine agent for treatment of p38-mediated disturbances.

EFFECT: improved preparing methods, valuable medicinal properties of compounds and composition.

38 cl, 3 tbl, 116 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 2-phenylaminoimidazoline phenylketone that can be used as IP antagonists. Invention describes 2-phenylaminoimidazoline phenylketone of the general formula (I): wherein R1 mean optionally substituted aryl wherein R1 is optionally substituted with 1, 2 or 3 substitutes chosen independently from series including alkoxy-group, aryl aryloxy-, aralkyloxy-group, halogen atom, ethylenedioxy-group or optionally substituted heterocyclyl that means a monovalent saturated carbocyclic radical comprising from 3 to 7 atoms in cycle and comprising one or two heteroatoms chosen independently from nitrogen and oxygen atoms, and can be optionally substituted with one or more substitutes chosen independently from alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkyl sulfonyl, furanyloxy-group; R2 means hydrogen atom; A means -C(O)-(CH2)n- or -C(O)-CH2-O-; index n means a whole number from 2 to 6, or its pharmaceutically acceptable salt or solvate. Invention provides preparing novel compounds showing useful biological properties.

EFFECT: valuable properties of compounds.

16 cl, 1 tbl, 23 ex

FIELD: pharmaceutical industry, in particular cyprofloxacine solution.

SUBSTANCE: claimed solution contains cyprofloxacine hydrochloride, sodium salt of ethylenediamine-N,N,N1,N1-tetraacetic acid, α-hydroxypropionic acid, sodium chloride, water for injections.

EFFECT: drug of increased biological availability without side effects.

3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of amide of the general formula (I)

wherein X means -CH; Y means -CH or nitrogen atom (N); m = 1 or 2; R1 means (C1-C6)-alkyl, (C1-C)-alkoxy-group, N,N-di-[(C1-C6)-alkyl]-amino-group, heterocyclyl-(C1-C6)-alkyl wherein heterocyclyl represents piperazinyl or homopiperazinyl; n = 3; R2 means halogen atom, (C1-C6)-alkyl; R3 means hydrogen atom; Q means phenyl optionally substituted with cyano-group, or pyridyl optionally substituted with morpholino-group, or their pharmaceutically acceptable salts, to methods for synthesis of indicated compounds, pharmaceutical compositions containing thereof and their using in treatment of diseases or states mediated by cytokines.

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

10 cl, 2 tbl, 7 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing modified glycosaminoglycans possessing analgesic properties. Method involves interaction of glycosaminoglycans with 1-phenyl-2,3-dimethyl-4-aminopyrazolone-5-(4-aminoantipyrine) in aqueous medium at pH = 4.7-4.8 in the presence water-soluble 1-ethyl-3-[3-(dimethlamino)propyl]carbodiimide as a condensing agent at room temperature followed by purification from low-molecular reagents. Method involves a single step that simplifies technology in preparing modified glycosaminoglycans.

EFFECT: improved preparing method.

3 ex

FIELD: biotechnology.

SUBSTANCE: invention relates to inhibitor of matrix metalloproteinases representing extract from fungus Canoderma atrum obtained by using of water and/or lower alcohols as extractant. Also disclosed are pharmaceutical agent for inhibition of tumor metastasis containing of 0.03-10 wt.% of abovementioned extract and foodstuff containing claimed extract.

EFFECT: improved inhibitor of matrix proteinases.

3 cl, 18 ex, 4 tbl

FIELD: pharmacy.

SUBSTANCE: invention proposes a medicinal agent for oral administration possessing an anti-inflammatory effect. Medicinal agent is made as a solid dosed formulation for oral administration that comprises meloxicam as an active substance, stearic acid or stearate as a slipping substance, maltodextrin as a binding agent, croscarmellose sodium salt as a disintegrating agent and dextrin as a filling agent taken in the definite ratio of components. Invention provides enhancing the biological availability of agent and improving its consumption properties. Invention can be used in the development of a medicinal agent made as a solid dosed formulation for oral administration possessing an anti-inflammatory effect.

EFFECT: improved and valuable pharmaceutical properties of agent.

10 cl, 11 tbl, 32 ex

FIELD: pharmaceutical industry, in particular anesthetic and vasodilating ointment.

SUBSTANCE: claimed ointment is prepared on the base of fine dispersed formulation contains apitoxin extract melittin, camphor, lavender, rosemary and eucalyptus oils and revitalin in specific component ratio. Ointment of present invention is useful in treatment of reumathysm, muscle and joint diseases, myodynia, radiculitis, ischias, neurodynia, polyneuritis, etc.

EFFECT: ointment with reduced apiotoxin toxicity, decreased side effects and improved therapeutic effect.

2 tbl

FIELD: pharmaceutical industry, in particular production of ointment having antiinflammation and antimicrobial activity.

SUBSTANCE: method for ointment production includes extraction of ground dogwood stones with chloroform during certain time followed by solvent removing and isolation of lipophilic fraction. Then dried solvent cake from dogwood stones is extracted with boiled purified water, solvent is removed and hydrophilic fraction is isolated. Further emulsifier, petrolatum and lipophilic fraction taken in specific ratio are fused at certain temperature; mixture is cooled and blended with water purified and heated up to certain temperature; obtained mixture is blended with solution comprising purified hydrophilic fraction, glycerol and water taken in specific ratio.

EFFECT: ointment of increased antiinflammation and antimicrobial activity.

2 tbl, 6 ex

FIELD: pharmaceutical industry, in particular production of ointment having antiinflammation and antimicrobial activity.

SUBSTANCE: method for ointment production includes grinding of plant raw materials namely solid coconut husk up to certain particle size; extraction with chloroform during certain time followed by solvent removing and isolation of lipophilic fraction. Further emulsifier, lipophilic fraction and coconut oil are fused under specific conditions; mixture is cooled to certain temperature and blended with celandine juice heated up to certain temperature.

EFFECT: ointment of increased antiinflammation and antimicrobial activity.

3 tbl, 15 ex

FIELD: organic chemistry, medicine, rheumatology.

SUBSTANCE: invention proposes a medicinal agent comprising derivative of aminostilbazol as an active component of the formula : or its salt wherein G represents phenyl optionally substituted with (C1-C6)-alkoxy-group; R represents (1) hydrogen atom, (2) (C1-C6)-hydroxyalkyl, or (3) the group -CORo wherein Ro represents (C1-C6)-alkyl, (C1-C6)-alkoxy-, phenoxy-group. The preferable compound is (E)-4-{2-[2-{N-acetyl-N-[(4-methoxyphenyl)sulfonyl]amino}phenyl]ethenyl}pyridine 1-oxide. The proposed agent is designated for treatment of chronic articular rheumatism.

EFFECT: realization of invention, valuable medicinal properties of agent.

7 cl, 2 tbl, 7 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of diphenylazethidinone of the formula (I): wherein R1 means hydrogen atom; R2 means -(CH2)0-1-NH-C(O)-(C3-C12)-alkylene-C(O)NH-L; R3 and R6 mean hydrogen atom; R4 and R5 mean atoms F, Cl, Br, J; L means compound of the formula: wherein Rx, Ry and Rz mean hydrogen atom (H), and to their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit cholesterol-declining activity and can be used in medicine.

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

4 cl, 9 ex

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