Organic compounds

FIELD: medicine.

SUBSTANCE: there are described compounds of formula in a free form or in the form of salt where R1 and R2 have values specified in the description of the application which are used for treating inflammatory conditions, first of all inflammatory or obstructive respiratory tract diseases. Besides the application describes the pharmaceutical compositions containing said compounds, and methods for preparing said compounds.

EFFECT: compounds exhibits improved efficiency.

5 cl, 8 ex

 

The present invention relates to organic compounds, to their preparation and use as pharmaceuticals.

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

in free form or in salt form,

where R1selected from the group including1-C8alkyl and C3-C8cycloalkyl, and

R2selected from the group including hydrogen, C2-C8alkylsulphonyl and C3-C8cycloalkylcarbonyl.

The terms used in the description have the following meanings.

"C1-C8alkyl" means alkyl straight or branched chain containing 1-8 carbon atoms. Preferably1-C8alkyl means1-C4alkyl.

"C3-C8cycloalkyl" means cycloaliphatic group containing 3-8 carbon atoms, such as cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutane, cyclopentyl, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl or cycloheptyl, preferably2-C6cycloalkyl.

"C2-C8alkylaryl" means a carbonyl, substituted C2-C8the alkyl mentioned above. A preferred group2-C8alkylsulphonyl is a C2-C4alkylsulphonyl.

"C3-C8cycloalkyl is of IMT" means a carbonyl, substituted cycloaliphatic group containing 3-8 carbon atoms, such as cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutane, cyclopentyl-, cyclohexyl-, methylcyclohexyl, dimethylcyclohexyl or cycloheptyl or cyclooctylmethyl, preferably3-C6cycloalkylcarbonyl.

If not specified, it is understood that the term "includes" or "including"used in the description of the application and in the claims, means on the whole process or stage or group of the whole process or stage, but does not exclude any other whole process or stage or group of the whole process or stage.

The compounds of formula I form acid additive salts, especially pharmaceutically acceptable acid additive salt.

Pharmaceutically acceptable acid additive salts of the compounds of formula I include salts of inorganic acids, such as halogen acids such as hydrofluoric acid, hydrochloric acid, Hydrobromic acid or itestosterone acid, nitric acid, sulfuric acid, phosphoric acid, and organic acids, for example aliphatic monocarboxylic acids such as formic acid, acetic acid, triperoxonane acid, propionic acid and butyric acid, aliphatic what kikicat, such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as maleic acid or succinic acid, aromatic carboxylic acids such as benzoic acid, para-chlorbenzene acid, diphenyloxy acid or triphenylarsine acid, aromatic hydroxy acids such as ortho-oxybenzone acid, para-oxybenzone acid, 1-oxidation-2-carboxylic acid or 3-oxidation-2-carboxylic acid, and sulfonic acids, such as methanesulfonate acid or benzolsulfonat acid. These salts derived from compounds of the formula I by known methods.

Preferred compounds of formula I include compounds where R1selected from the group including1-C8alkyl and C3-C8cycloalkyl, a R2selected from the group including hydrogen and C2-C8alkylsulphonyl.

Preferred primarily compounds of the formula I, in which R1selected from the group including1-C4alkyl and C3-C6cycloalkyl, and R2selected from the group including hydrogen and C2-C4alkylsulphonyl.

More preferred compounds of formula I described in the examples.

Another object of the present invention is a method of obtaining compounds of formula I listed is use, including

(1) (a) obtaining compounds of formula I, where R2means hydrogen, by hydrolysis of the corresponding ester or

(C) obtaining compounds of formula I, where R2selected from the group including2-C8alkylsulphonyl and C3-C8cycloalkylcarbonyl, by acylation of the corresponding compounds of formula I, where R2means hydrogen, and

(2) isolation of the compounds of formula I in free form or in salt form.

The method according to variant (A) is performed using known methods of hydrolysis of esters with formation of the corresponding alcohols. Normally ester hydrolyzing an aqueous solution of an inorganic carbonate such as sodium carbonate, preferably potassium carbonate.

Preferably the reaction is performed in proton solvent, for example methanol, at a temperature of from 0°C. to room temperature.

The method according to variant (C) are performed using known techniques acylation of alcohols to form the corresponding ether. Typically, the alcohol is introduced into the reaction with the anhydride, for example somaclonal anhydride, in the main solvent, for example pyridine, or in a solvent, soderjasim base, at a temperature from 0°C to 35°C.

The third object of the present invention are new intermediate compounds of formula II

in free form or in salt form,

where R1selected from the group including2-C8alkyl and C3-C8cycloalkyl.

These compounds are used as the source of esters in the method according to variant (A).

The compounds of formula II get the reaction of the compounds of formula III

with the compound of the formula IV

where R1selected from the group including2-C8alkyl and C3-C8cycloalkyl, in the presence of paraformaldehyde and base, preferably a secondary amine, such as Diisopropylamine, by known methods of obtaining isoxazolidine cyclopentadiene Nitron. Usually the reaction is performed in proton solvent, for example ethanol. Usually the reaction is carried out at elevated temperature, for example from 60°C to 85°C.

The compound of formula III is a known compound or can be obtained from prednisolone in the manner described in article Yoon and others, Steroids, 60,445-451 (1995).

The compounds of formula IV are commercial products or can be obtained by a method described in the article Tetrahedron Letters, 28, 2993-2994 (1987).

The compounds of formula I in free form can be converted into a salt form and Vice versa in the usual way. Compounds in free form or in salt form can be obtained in the form of hydrates Il is the solvate, solvent used for crystallization.

The compounds of formula I is recovered from the reaction mixture and purified in a known manner.

The compounds of formula I are used as pharmaceuticals. Therefore, the invention provides compounds of formula I for use as pharmaceuticals. The compounds of formula I have valuable pharmacological properties. For example, they have high anti-inflammatory action, which can be demonstrated by their binding to the glucocorticoid receptor, inhibition of the synthesis of TNF-α and its release into cell lines of human macrophages.

Linking glucorticoid receptor evaluated using the following analysis.

Recombinant human GR expressed in infected with baculovirus insect cells, Sf-9, obtained from Panvera (Madison, WI, USA)and analysis was performed in a buffer solution for analysis containing GR and fluorescent ligand FluormoneTM-GSl (200 nm solution in methanol). The analysis was performed in 384-well tablets sequential addition of solutions of the analyzed compounds in water (2 ml) at serial dilution of the original solutions of DMSO, ligand FluormoneTM-GS1 (2,2 nm solution in buffer solution for analysis, 10 μl) and a solution of GR (8,8 nm in buffer solution is La analysis, 10 ál). The mixture is incubated without access of light at room temperature for 1 h and measured the polarization of the fluorescence on the tablet reader with the wave excitation 485 nm and the wave emission 530 nm. The concentration of the analyzed compounds at half maximum shear polarization took over the IC50. The diagrams of dependence was obtained using the program OriginTMand Ki values were calculated by the equation of Cheng-Prusoff (Cheng-Prussoff). According to this analysis, the compounds described in examples 1, 2, 3 and 4, characterized by the values of Ki of 0.5 to 1.4, 0.4 and 0.2 nm, respectively.

Inhibition of the synthesis of TNF-α and its release into the cells is assessed using the following analysis.

Cell line human macrophages U937 was obtained from American cell culture collection (Rockville, MD) and cultured in medium RPMI 1640, Gibco UK)containing 10% ETS (the company Gibco UK). Cell density was 4×105cells/ml, and cells were differentiated in the presence of myristate/acetate dry formula (PMA, 20 ng/ml) for 4 h PMA was removed by washing and attached to the plate, the cells were incubated for 48 h at 37°C in an incubator with high humidity in the atmosphere of 5% CO2. Differentiated U937 cells were removed using a buffer solution for dissociation of cells (firm Gibco UK) and cell density was brought to 1×106cells/the L. Cell suspension was transferred into a 96-well culture plates (100 μl well), was added 50 μl of medium or solution of the compound in dimethyl sulfoxide at a corresponding concentration. Pre-incubation was carried out for 20 min at 37°C, cells were stimulated by addition of lipopolysaccharide (LPS, firm Sigma, 10 ng/ml), incubated for 24 h at 37°C in an incubator with high humidity in the atmosphere of 5% CO2and collected the supernatant. The concentration of TNFα in supernatants were identified by means of a sandwich ELISA using two monoclonal antibodies recognizing different epitopes of cytokines (Pharmingen company UK). The binding of the second antibody were analyzed by stepwise incubation in the presence of conjugate streptavidin/alkaline phosphatase (firm Sigma UK) and disodium salt of 4-nitrophenylphosphate. The optical density was measured at 405 nm, and the concentration of the cytokine was calculated by a calibration curve obtained by serial dilutions of recombinant TNFα as standard. Graphing and calculation values IC50was performed using the program OriginTM. According to this analysis, the compounds described in examples 1, 2, 3 and 4, characterized by the values of the IC501,16, 4,95, 0,89 and 3.57 nm, respectively.

Thanks to the anti-inflammatory activity of the compounds of formula I are used etc the treatment of inflammatory conditions first of all inflammatory or obstructive diseases of the respiratory tract. The method of treatment according to the invention is symptomatic or preventive.

Inflammatory or obstructive diseases of the respiratory tract according to the present invention include asthma of any type or etiology, including hereditary (non-allergic) asthma and acquired (allergic) asthma, mild asthma, the asthma of moderate severity, severe asthma, asthma, asthma induced exercise, occupational asthma and bacterial asthma. Treatment of asthma involves the treatment of subjects, such as children under the age of 4 or 5 years, who have been symptomatic wheezing or with a diagnosis of children with shortness of breath" and which belong to the category of patients is of paramount medical importance, and which now belong to the asthmatics in the early phase. That asthmatic condition called "syndrome of children with stertorously breathing.

Preventive action in the treatment of asthma evident in reducing the frequency or severity of symptomatic episodes, such as acute asthma attacks or attacks bronchostenosis, to improve the functioning of the lungs or increase hyperresponsiveness of the Airways. In addition, preventive action is their manifests itself as a reduction in the need for other symptomatic treatment, designed to suppress or stop asthma attacks if they are available, for example, the need for anti-inflammatory (e.g., corticosteroid) or bronchodilatation treatment. Prevention in the treatment of asthma, first of all, it is necessary for subjects exposed to "morning attacks". "Morning attacks are known asthmatic syndrome, manifested most asthmatics, which is characterized by asthma attacks, for example, between approximately 4 and 6 am, after a considerable period of time after any previous introduction symptomatic asthma therapeutic agent.

Other inflammatory or obstructive diseases and conditions of the respiratory tract according to the present invention include acute lung injury (ALI), acute respiratory distress syndrome in adults (ARDS), chronic obstructive pulmonary disease, chronic obstruction of the respiratory tract or lungs (COPD, COAD or COLD), including chronic bronchitis or associated shortness of breath, emphysema, as well as exacerbation of hyperresponsiveness of the Airways due to the use of other medicines, first of all, another inhaled medication. The present invention can also be used in the treatment of bronchitis of any t the PA or etiology, including acute, arachnoidal, catarrhal, lobar, or chronic purulent tuberculous bronchitis. In addition, inflammatory or obstructive diseases of the respiratory tract according to the present invention include pneumoconiosis (an inflammatory disease of the lungs that is usually connected with professional activity, accompanied in most cases, acute or chronic obstruction of the respiratory tract, as well as the resulting in repeated inhalation of dusts) of any type or etiology, including, for example, aluminas, antraks, asbestosis, helicos, Philos, sideros, silicosis, tabacos and bissines.

Due to its anti-inflammatory activity of the compounds of formula I can also be used in the treatment of disorders associated with eosinophils, such as acidosis primarily disorders of the respiratory tract associated with eosinophils (for example, including pathological eosinophilic infiltration of pulmonary tissues)including hypereosinophilia, i.e. the effect on the Airways and/or lungs, as well as, for example, disorders of the respiratory tract associated with eosinophils, resulting from or accompanied syndrome Leffler, eosinophilic pneumonia, parasitic (mostly multicellular, metazoan) infestation (including tropical acidosis), bronchopulmonary aspergillosis, notonyourradar (including syndrome charge-Strauss), eosinophilic granuloma and disorders associated with eosinophils, affecting the respiratory tract because of a reaction to medications.

The compounds of formula I can also be used in the treatment of inflammatory skin diseases, e.g. psoriasis, contact dermatitis, atopic dermatitis, alopecia alopecia, exudative erythema, dermatitis herpetiformis, scleroderma, vitiligo, allergic anghit, urticaria, bullous pemphigoid, lupus erythematosus, a disease acquired bullous apidemos and other inflammatory skin diseases.

The compounds of formula I can also be used to treat other diseases or conditions associated with inflammation, such as for the treatment of diseases and conditions of the eye such as conjunctivitis, siccatives keratoconjunctivitis and seasonal conjunctivitis, diseases of the nasopharynx, including allergic rhinitis, and inflammatory conditions of the gastrointestinal tract, such as inflammation of the bowel, such as ulcerative colitis and Crohn's disease.

The compounds of formula I can also be used as agents for combination therapy in combination with other medicines for the treatment of respiratory diseases, first of all protivovospalitelnye bronchodilators, antihistamines and against the cough medicines primarily in the treatment of obstructive or inflammatory diseases of the respiratory tract specified above, for example, as promoters of therapeutic activity of such drugs or as a means, lowering the required dose or side effects of such medicines. The compound of the formula I can be mixed with other drugs in a fixed pharmaceutical composition or it can be entered separately, prior to or simultaneously with or after other medications. Therefore, the invention includes a combination of the agent according to the invention specified above, with anti-inflammatory, bronchodilatory, antigistaminny or antitussive drug, and the specified agent according to the invention and specified drug contained in one or in different pharmaceutical compositions.

Such anti-inflammatory drugs include antagonists of LTB4, such as BIIL 284, CP-195543, DPC11870, ethanolamide LTB4, LY 293111, LY 255283, CGS025019C, CP-195543, ONO-4057, SB 209247, SC-53228 and others, described in US 5451700; LTD4 antagonists such as montelukast, pranlukast, zafirlukast, accolate, SR2640, Wy-48,252, ICI 198615, MK-571, LY-171883, Ro 24-5913 and L-648051; PDE4 inhibitors, such as cilomilast (Ariflo®, the company GlaxoSmithKline), roflumilast (company Byk Gulden), V-A (firm Napp), BAY19-8004 (Bayer), SCH-351591 (firm Schering-Plogh), Arafellin (company Almirall Prodesfarma), PD189659/PD168787 (company Parke-Davis), AWD-12-281 (firm Asta Medica), CDC-801 (firm Celgene), SelCID(TM) CC-10004 (firm Celgene), VM554/UM565 (company Vernalis), T-440 (firm Tanabe), KW-4490 (firm Kyowa Hakko Kogyo), and others, are described in WO 92/19594, WO 93/19749, WO 93/19750, WO 93/19751, WO 98/18796, WO 99/16766, WO 01/13953, WO 03/104204 WO 03/104205, WO 03/39544, WO 04/000814, WO 04/000839, WO 04/005258, WO 04/018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/018431, WO 04/018449, WO 04/018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/019944, WO 04/019945, WO 04/045607 and WO 04/037805; agonists A2Asuch as described in EP 1052264, EP 1241176, EP A, WO 94/17090, WO 96/02543, WO 96/02553, WO 98/28319, WO 99/24449, WO 99/24450, WO 99/24451, WO 99/38877, WO 99/41267, WO 99/67263, WO 99/67264, WO 99/67265, WO 99/67266, WO 00/23457, WO 00/77018, WO 00/78774, WO 01/23399, WO 01/27130, WO 01/27131, WO 01/60835, WO 01/94368, WO 02/00676, WO 02/22630, WO 02/96462 and WO 03/086408; antagonists And2Bsuch as described in WO 02/42298, and agonists (β)-2-adrenergic receptors, such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol, and above all, formoterol, carmoterol and their pharmaceutically acceptable salts, and compounds (in free form or in salt form or in the form of MES) of the formula I described in WO 0075114, which is included in the description of the application by reference, preferably compounds described in the examples, especially the compounds of formula

and their pharmaceutically acceptable salts, and compounds (in free form or in salt form or in the form of MES) of the formula I described in WO 04/16601, and that the same compound, described in EP 1440966, JP 05025045, WO 93/18007, WO 99/64035, US 2002/0055651, WO 01/42193, WO 01/83462, WO 02/66422, WO 02/70490, WO 02/76933, WO 03/24439, WO 03/42160, WO 03/42164, WO 03/72539, WO 03/91204, WO 03/99764, WO 04/16578, WO 04/22547, WO 04/32921, WO 04/33412, WO 04/37768, WO 04/37773, WO 04/37807, WO 04/39762, WO 04/39766, WO 04/45618 WO 04/46083 and WO 04/80964.

Such a bronchodilator include anticholinergic or agents antimuskarinovoe act occurs primarily ipratropium bromide, oxitropium bromide, Tiotropium salt and CHF 4226 (company Chiesi), and glycopyrrolate, and compounds described in EP 424021, US 3714357, US 5171744, WO 01/04118, WO 02/00652, WO 02/51841, WO 02/53564, WO 03/00840, WO 03/33495, WO 03/53966, WO 03/87094, WO 04/018422 and WO 04/05285.

Such anti-inflammatory and bronchodilator includes drugs with dual anti-inflammatory and bronchodilatory activity, primarily agonist (β-2 adrenergic receptors/muscarinic antagonist, such as described in US 2004/0167167, WO 04/74246 and WO 04/74812.

Such joint therapeutic antigistaminny medicines include cetirizine hydrochloride, acetaminophen, fumarate of clemastine, promethazine, loratidine, desloratidine, diphenhydramine hydrochloride and Fexofenadine, activatin, astemizole, azelastine, Bastin, epinastine, mizolastine and defendin, and compounds described in JP 2004107299, WO 03/099807 and WO 04/026841.

Combinations of agents according to the invention and one or more PDE4 inhibitors, agonists A2Aantagonists And2Bagonists of β-2-ADR is nonreceptor and/or LTD4 antagonists can be used, for example, in the treatment of COPD or primarily asthma. Combinations of agents according to the invention and one or more anticholinergic antimuskarinovoe act occurs or agents, PDE4 inhibitors, agonists A2Aantagonists And2Bagonists of β-2-adrenergic receptors and/or LTB4 antagonists can be used, for example, in the treatment of asthma or primarily COPD.

In accordance with the foregoing, the invention features a method of treating an inflammatory condition, especially inflammatory or obstructing diseases of the respiratory tract, which includes an introduction to the subject, first of all the person who needs treatment, an effective amount of the compounds of formula I, described above. Another object of the invention is the use of compounds of formula I, described above, for obtaining a medicinal product intended for the treatment of an inflammatory condition, especially inflammatory or obstructing diseases of the respiratory tract.

The compounds of formula I can be entered in any appropriate manner, for example orally, for example in the form of tablets or capsules, parenteral, for example intravenous, inhalation, for example, in the treatment of inflammatory or obstructive diseases of the respiratory tract, intranasally, for example, for the treatment of allergic rhinitis, topically on the skin, for example, in the treatment of atopic is anyone dermatitis or rectal, for example, in the treatment of inflammatory bowel disease.

Another object of the invention is a pharmaceutical composition comprising as active ingredient a compound of the formula I, optionally in a mixture with a pharmaceutically acceptable diluent or carrier. The composition may contain other therapeutic agent, such as broncholytics or anti-inflammatory drug indicated above. Such compositions obtained using conventional diluents or excipients according to known methods. Oral dosage forms include tablets and capsules. The topical preparations include creams, ointments, gels or system for transdermal delivery, such as patches. Compositions for inhalation include an aerosol or other spray preparations or compounds in the form of dry powders.

Compositions in the form of an aerosol preferably contain, for example, fluorinated hydrocarbons (HFA), such as HFA134a or HFA227 or a mixture thereof, and can contain one or more known co-solvents such as ethanol (up to 20 wt.%), and/or one or more surfactants such as oleic acid or sarbatorile, and/or one or more fillers, such as lactose. The composition is in the form of a dry powder preferably contains, for example, the compound of formula I with a particle diameter of 10 m is m, optionally in a mixture with a diluent or carrier, such as lactose, with particles with the desired distribution by size, and connection for protection against moisture, for example magnesium stearate, usually in amounts of 0.05 to 1.5%. The composition comprising the composition for spraying, preferably contains, for example, the compound of formula I dissolved or suspended in a medium containing water, a co-solvent, such as ethanol or propylene glycol, and a stabilizer such as a surfactant.

The invention includes (a) compound of formula I in the form of inhalation, for example in the form of an aerosol or other dispersed composition or composition for inhalation, for example, in micronized form, (B) drug for inhalation, comprising the compound of formula I in the form of inhalation, (C) a pharmaceutical product comprising a compound of formula I in the form of inhalation in proaste inhalation, (D) an inhalation device containing the compound of formula I in a form suitable for inhalation.

Doses of the compounds of formula I used according to the present invention vary depending on the particular condition to be treated, the desired result and the method of introduction. In General, a suitable daily dose for administration by inhalation is about 0.005 to 10 mg, by oral administration, a daily dose of arr is siteline from 0.05 to 100 mg

The invention is illustrated by the following examples.

Examples 1-5

The compounds of formula I are given in the following table. Methods for their production are described below. This table also indicates the data of mass spectrometry (MN+). Compounds are in free form.

Example No.R1R2MN+
1-CH2-CH2-CH3H430,3
2-CH3H402,1
3-CH2-CH2-CH2-CH3H444,2
4H470,3
5-CO-CH(CH3)2550,1

Example 1

In a mixture of 2-((4R,5S,6S,6bR,9S)-5-hydroxy-4A,6A-d is methyl-2-oxo-8-propyl-2,4A,4b,5,6,6A,8,9,9a,10,10A,10b,11,12-tetradehydro-7-oxa-8-isopentene[2,1-a]phenanthrene-6b-yl)-2-xoetrope ether acetic acid (example 6) (0,082 g, 0,173 mmole) in methanol (2 ml) was added an aqueous solution of potassium carbonate (0,563 g, 4,08 mmole in 2 ml of N2O). The reaction mixture was stirred for 2 h, then was diluted with water and acidified. The product was extracted with dichloromethane, the extract was dried over sodium sulfate and concentrated on a rotary evaporator, to receive the desired product, (4R,5S,6S,6bR,9S)-5-hydroxy-6b-(2-hydroxyacyl)-4A,6A-dimethyl-8-propyl-4A,4b,5,6,6A,6b,8,9,9a,10,10A,10b,11,12-tetradehydro-7-oxa-8-isopentene[2,1-a]phenanthrene-2-it.

Example 2

(4R,5S,6S,6bR,9S)-5-Hydroxy-6b-(2-hydroxyacyl)-4A,6A,8-trimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10A,10b,11,12-tetradehydro-7-oxa-8-isopentene[2,1-a]phenanthrene-2-he received from the connection specified below, according to the method described in example 1.

2-((4R,5S,6S,6bR,9S)-5-Hydroxy-4A,6A,8-trimethyl-2-oxo-2,4A,4b,5,6,6A,8,9,9a,10,10A,10b,11,12-tetradehydro-7-oxa-8-isopentene[2,1-a]phenanthrene-6b-yl)-2-oksietilnye ester of acetic acid described in article Green and others, J. Med. Chem., 25, 1492-1495 (1982).

Example 3

(4R,5S,6S,6bR,9S)-8-Butyl-5-hydroxy-6b-(2-hydroxyacyl)-4A,6A-dimethyl-4A,4b,5,6,6A,6b,8,9,9a,10,10A,10b,11,12-tetradehydro-7-oxa-8-isopentene[2,1-a]phenanthrene-2-he got from the compound described in example 7, according to the method described in example 1.

Example 4

(4R,5S,6S,6bR,9S)-8-Cyclohexyl-5-hydroxy-6b-(2-hydroxyacyl)-4A,6A-dimethyl-4A,4b,5,6,6A,6b,8,9,9a,10,10A,10b,11,12-tetradehydro-7-oxa-8-isopentene[2,1-a]is entren-2-he received from the connection, described in example 8, according to the method described in example 1.

Example 5

A mixture of (4R,5S,6S,6bR,9S)-8-cyclohexyl-5-hydroxy-6b-(2-hydroxyacyl)-4A,6A-dimethyl-4A,4b,5,6,6A,6b,8,9,9a,10,10A,10b,11,12-tetradehydro-7-oxa-8-isopentene[2,1-a]phenanthrene-2-it (0,054 g, 0,115 mmole) and samalanga anhydride is 0.019 g, 0,121 mmole) in pyridine (0.5 ml) was stirred throughout the night. The reaction mixture was heated at 35°C for 2 h, then was added 0.01 g samalanga anhydride and the temperature of the mixture was lowered to room temperature. After 1 h the reaction mixture was diluted hydrochloric acid and the product was extracted with CH2CL2. The organic layer was dried and has given concerts at the rotary evaporator. The crude product was purified by chromatography, it was obtained the desired product, 2-((4R,5S,6S,6bR,9S)-8-cyclohexyl-5-hydroxy-4A,6A-dimethyl-2-oxo-2,4A,4b,5,6,6A,8,9,9a,10,10A,10b,11,12-tetradehydro-7-oxa-8-isopentene[2,1-a]phenanthrene-6b-yl)-2-oksietilnye ether somaclonal acid.

Examples 6-8

The compounds of formula II are provided in the following table. Methods for their production are described below. The table includes the data of mass-spectrometry (MN+). Compounds are in free form.

Example No..R1MN+
6-CH2-CH2-CH3472,2
7-CH2-CH2-CH2-CH3486,2
8512,3

Example 6

A mixture of 2-((10R,11S,13S)-11-Hydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15-decahydro-3H-cyclopent[a]phenanthrene-17-yl)-2-xoetrope ether acetic acid (0,576 g, 1.5 mmole), n-propilgidroksibenzoat (0,166 g, 1.5 mmole), Diisopropylamine (0,166 g, 1.65 mmole) and paraformaldehyde (0,029 g, 0.97 mmole) in ethanol (25 ml) was heated at 85°C for 20 hours, the Reaction mixture was poured into water and the product was extracted with dichloromethane. Extract was dried over sodium sulfate and concentrated on a rotary evaporator, to receive the desired product, 2-((4R,5S,6S,6bR,9S)-5-hydroxy-4A,6A-dimethyl-2-oxo-8-propyl-2,4A,4b,5,6,6A,8,9,9a,10,10A,10b,11,12-tetradehydro-7-oxa-8-isopentene[2,1-a]phenanthrene-6b-yl)-2-oksietilnye ester of acetic acid.

Example 7

2-((4R,5S,6S,6bR,9S)-8-Butyl-5-hydroxy-4A,6A-dimethyl-2-oxo-2,4A,4b,5,6,6A,8,9,9a,10,10A,10b,11,12-tetradehydro-7-oxa-8-isopentene[2,1-a]phenanthrene-6b-yl)-2-oksietilnye ether acetic acid was obtained according to the method described in example 6.

Example 8

2-((4 the R,5S,6S,6bR,9S)-8-Cyclohexyl-5-hydroxy-4A,6A-dimethyl-2-oxo-2,4A,4b,5,6,6A,8,9,9a,10,10A,10b,11,12-tetradehydro-7-oxa-8-isopentene[2,1-a]phenanthrene-6b-yl)-2-oksietilnye ether acetic acid was obtained according to the method described in example 6.

1. The compound of the formula I

in free form or in salt form, where
R1selected from the group including1-C8alkyl and C3-C8cycloalkyl, and
R2selected from the group including hydrogen, C2-C8alkylsulphonyl.

2. The compound according to claim 1, where
R1selected from the group including1-C8alkyl and C3-C8cycloalkyl, and
R2selected from the group including hydrogen, C2-C4alkylsulphonyl.

3. The compound according to claim 1, which means
(4R,5S,6S,6bR,9S)-5-hydroxy-6b-(2-hydroxyacyl)-4A,6A-dimethyl-8-propyl-4A,4b,5,6,6A,6b,8,9,9a,10,10A,10b,11,12-tetradehydro-7-oxa-8-isopentene[2,1-a]phenanthrene-2-it,
(4R,5S,6S,6bR,9S)-5-hydroxy-6b-(2-hydroxyacyl)-4A,6A,8-trimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10A,10b,11,12-tetradehydro-7-oxa-8-isopentene[2,1-a]phenanthrene-2-it,
(4R,5S,6S,6bR,9S)-8-butyl-5-hydroxy-6b-(2-hydroxyacyl)-4A,6A-dimethyl-4A,4b,5,6,6A,6b,8,9,9a,10,10A,10b,11,12-tetradehydro-7-oxa-8-isopentene[2,1-a]phenanthrene-2-it,
(4R,5S,6S,6bR,9S)-8-cyclohexyl-5-hydroxy-6b-(2-hydroxyacyl)-4A,6A-dimethyl-4A,4b,5,6,6A,6b,8,9,9a,10,10A,10b,11,12-tetradehydro-7-oxa-8-isopentene[2,1-a]phenanthrene-2-it,
2-((4R,5S,6S,6bR,9S)-8-cyclohexyl-5-hydroxy-4A,6A-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10A,10b,11,12-tetradehydro-7-oxa-8-isopentene[2,1-a]phenanthrene-6b-yl)-2-oksietilnye ether somaclonal key is lots
2-((4R,5S,6S,6bR,9S)-5-hydroxy-4A,6A-dimethyl-2-oxo-8-propyl-2,4A,4b,5,6,6A,8,9,9a,10,10A,10b,11,12-tetradehydro-7-oxa-8-isopentene[2,1-a]phenanthrene-6b-yl)-2-oksietilnye ether acetic acid,
2-((4R,5S,6S,6bR,9S)-8-butyl-5-hydroxy-4A,6A-dimethyl-2-oxo-2,4A,4b,5,6,6A,8,9,9a,10,10A,10b,11,12-tetradehydro-7-oxa-8-isopentene[2,1-a]phenanthrene-6b-yl)-2-oksietilnye ether acetic acid, or
2-((4R,5S,6S,6bR,9S)-8-cyclohexyl-5-hydroxy-4A,6A-dimethyl-2-oxo-2,4A,4b,5,6,6A,8,9,9a,10,10A,10b,11,12-tetradehydro-7-oxa-8-isopentene[2,1-a]phenanthrene-6b-yl)-2-oksietilnye ether acetic acid.

4. Pharmaceutical composition having anti-inflammatory activity comprising as an active ingredient the compound according to any one of claims 1 to 3, optionally in a mixture with a pharmaceutically acceptable diluent or carrier.

5. Method of producing compounds of the formula I according to claim 1, comprising (1) (a) obtaining compounds of formula I, where R2means hydrogen, by hydrolysis of the corresponding ester or
(C) obtaining compounds of formula I, where R2means2-C8alkylsulphonyl, by acylation of the corresponding compounds of formula I, where R2means hydrogen, and
(2) isolation of the compounds of formula I in free form or in salt form.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: described is a 15β-substituted oestradio derivative having selective oestrogenic activity. The preferred compound is 7α-ethyl-15β-methyl-19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17β-diol.

EFFECT: obtaining compounds which can be used in treating or preventing diseases or physiological conditions related to oestrogen receptors.

11 cl, 4 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention relates to new 3.15-substituted estrone derivatives that are inhibitors of 17β-hydroxysteroid-dehydrogenase type 1 (17β-HSD1), to their salts, pharmaceutical compositions, containing specified compounds and to methods of such compound producing. Besides the invention refers to application in medicine of specified new 3,15-substituted estrone derivatives firstly to their application for treatment or prevention of steroid-dependent diseases or disorder such as steroid-dependent diseases or disorders treatment of which requires inhibition of 17β-hydroxysteroid dehydrogenase type 1 and/or reducing of endogenous 17β-estradiol concentration. The invention also relates to general application of selective inhibitors of 17β-hydroxysteroid-dehydrogenase type 1 that do not bind with estrogen receptor or display antipathic affinity to estrogen receptor.

EFFECT: possibility of application for treatment and prevention of benign gynaecologic diseases.

49 cl, 836 ex, 42 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to synthesis of [18F]fluororganic compounds ensured by reaction of [18F]fluoride and relevant halogenide or sulphonate with alcoholic vehicle of formula 1 where R1, R2 and R3 represent hydrogen atom or C1-C18 alkyl.

EFFECT: possibility for mild process with low reaction time and high yield.

21 cl, 2 tbl, 27 ex

FIELD: technological processes.

SUBSTANCE: invention is related to automation of technological processes and may be used in automation of process of production of loose form of powdery choline chloride from its aqueous solution. In method that provides for use of crushed and fractionated dry sugar beet pulp as active adsorbent, its mixing with previously heated aqueous solution of choline chloride, and then drying in vibration dryer by superheated steam of atmospheric pressure, separation of spent superheated steam flow into the main one, sent to vibration dryer with creation of recirculation circuit, and additional one sent for reheating of choline chloride prior to its supply for mixing, the novelty is the fact that superheating of atmospheric pressure steam is done with heating steam, at that heating steam is produced by means of steam generator with electric heating elements, feed pump and safety valve, heating steam condensate produced in this process after superheating and condensate produced during heating of aqueous solution of choline chloride is taken to condensate collector, and then in mode of closed circuit is supplied in steam generator, at that flow rate of crushed and fractionated dry pulp is measured, as well as aqueous solution of choline chloride coming for mixing, flow rate and temperature of superheated steam upstream vibration dryer, choline chloride temperature before and after its heating, pressure of choline chloride after heating, temperature and humidity of mixture of crushed and fractionated dry pulp and aqueous solution of choline chloride prior to supply for drying, amplitude and frequency of oscillations in gas-distributing grid of vibration dryer, flow rate and humidity of powdery choline chloride after drying, level of condensate in steam generator and pressure of heating steam, at that flow arte of dry sugar beet pulp after fractionation is used to set flow rate of heated choline chloride coming for mixing, and flow rate and humidity of prepared mixture of crushed and fractionated dry pulp and aqueous solution of choline chloride prior to supply for drying, flow rate and humidity of powdery choline chloride after drying are used to determine amount of evaporated moisture in vibration dryer, which is used to establish flow rate of superheated steam in the main circuit of recirculation, and its temperature is established by current value of temperature of mixture of crushed and fractionated dry pulp and aqueous solution of choline chloride by setting of specified capacity of steam generator affecting power of electric heating elements, at that in case condensate level in steam generator falls below specified value, condensate is supplied from condensate collector, and when pressure of steam in steam generator reaches upper limit value, steam pressure is released through safety valve, if flow rate of mixture of crushed and fractionated dry pulp and aqueous solution of choline chloride deviates prior to supply for drying to the side of increase from specified value, at first frequency is increased, and then amplitude of oscillations in gas-distributing grid of vibration dryer, if flow rate of mixture of crushed and fractionated dry pulp and aqueous solution of choline chloride deviates to the side of reduction from specified value, at first frequency is reduced, and then amplitude of oscillations in gas-distributing grid of vibration dryer, current values of temperature and flow rate of choline chloride prior to heating are used to set flow rate of spent superheated steam in additional recirculation circuit, at that temperature of choline chloride after heating is used to set specified pressure of choline chloride at the inlet to mixer.

EFFECT: provides for increased quality of finished product, accuracy and reliability of control, increased yield of finished product, reduced specific heat and power inputs and prime cost of finished product.

1 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns novel compounds of formula I: , where M is macrolide subunit of substructure II: , L is chain of substructure III: -X1-(CH2)m-Q-(CH2)n-X2-, D is steroid or non-steroid subunit derived from steroid or non-steroid NSAID medicines (nonsteroid anti-inflammatory drug) with anti-inflammatory effect; pharmaceutically acceptable salts and solvates of claimed compounds; methods and intermediary compounds for obtainment of claimed compounds.

EFFECT: improved therapeutic effect, application in inflammatory disease and state treatment for humans and animals.

37 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel fusidic acid derivatives of general formula [I], where X represents halogen, trifluoromethyl, C1-C7alkyl, substituted with phenyl, C2-C9alkenyl, optionally substituted with C1-C7alkyl, halogen or phenyl, phenyl, optionally substituted with one or two similar or different substituents, selected from group consisting of halogen, C1-C7alkyl, C2-C9alkenyl, phenyl, C1-C6alkoxy, nitro, C1-C6alkyltio, trifluoromethyl and cyano; or X represents naphtyl; Y and Z both represent hydrogen or together with bond C-17/C-20 form double bond between C-17 and C-20 or together represent methylene and form cyclopropane ring in combination with C-17 and C-20; A represents O, S or S(O); B represents C1-6alkyl, C2-6alkenyl, C1-6acyl, phenyl or benzoyl, where C1-6alkyl is optionally substituted with one or more halogens, hydroxy, C2-6alkenyl, phenyl, C1-4heteroaryl or C1-6alkoxy; Q1 represents -(CHOH)-, or -(CHW)-, where W represents halogen or azido; Q2 represents -(CHOH)-; to their pharmaceutically acceptable salts and easily hydrolysed esters and to pharmaceutical compositions, including said derivatives, as well as to their application in therapy.

EFFECT: application in therapy.

31 cl, 127 ex, 5 tbl

FIELD: veterinary.

SUBSTANCE: claimed is method, which allows to separate from pregnant horse urine by hard-phase extraction mixture of conjugated estrogens, depleted of phenol urine components and non-conjugated lipophilic compounds from group including non-conjugated flavonoids, non-conjugated isoflavonoides, non-conjugated norisoprenoids, non-conjugated steroids, first of all, androstane and preganane steroids, and comparable with them non-conjugates compounds.

EFFECT: improved method of obtaining extract, containing natural mixture of conjugated horse estrogens.

16 cl, 3 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns improved methods of obtaining eplerenone pharmaceutical compound: (9α,11α-epoxy-17β-hydroxypregn-4-en-3-one-7α,21-dicarbonic acid, γ-lactone, methyl ether) involving new intermediary products. Methods are implemented by Δ4,6-3-ketosteroid or its ketal transformation into respective Δ4-3-ketosteroid-7α-carbonic acid through a number of stages including oxidation, methylation, epoxydation stages.

EFFECT: reduced process stage number, high yield of product.

11 cl, 38 ex, 15 dwg

FIELD: chemistry.

SUBSTANCE: polyaminosteroid branched derivatives of general formula I are described, where R1 is saturated or unsaturated C2-C10alkyl (conjugated or branched) or methyl, R2 is COOH or branched polyamine fragments, R3 is H, OR19, where R19 is H or C1-6acyl, R4 is H, R5 is H, CH3, R6 is H, CH3, R7=R8=R9=H, R10 is H, CH3, R11 is OH,-OSO3, - O-acyl, -(Z)n-(NR-Z)p-N(R)2, Z is linear hydrocarbon diradical, n=0, 1, p=1, R-H, C1-6alkyl, C1-6aminoalkyl, possibly substituted by C1-6alkyl, R12=R13=R15=H, R16 is H, OH, R17 is H, R18 is H, CH3, possible double bond. Compounds possess bactericidal activity and can be used for prevention of bacterial infections.

EFFECT: production of polyaminosteroid derivatives, possessing bactericidal activity which can be used for prevention of bacterial infections.

27 cl, 31 ex, 1 tbl, 2 dwg

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention refers to pharmacology and medicine and concerns ethonogestrel new esters of formula 1 , 2 , 3 , applied for male and female contraception. Compositions are characterised by improved disposition profile.

EFFECT: production of composition with improved disposition profile.

3 cl, 2 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new steroid compounds of formula (I): or its physiologically acceptable solvate.

EFFECT: compound has glucocorticoid agonistic activity and can be used in treating inflammatory and allergenic diseases.

27 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention claims compound of formula (I) , where X is O or S; R1 is C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkylmethyl, any of which can be optionally substituted by one or more methal groups or halogen atoms, or R1 is 4-(diethylamino)sulfonylphenyl, 2,6-difluorophenyl, 4-methoxyphenyl, 4-cyanomethyl, 3-difluoromethylthiopnehyl, 5-chloro-4-methoxy-thiophene-3-yl, 2-isopropyl-1,3-thiazol-4-yl, quinoline-2-yl, 5-trifluoromethyl-furan-2-yl, 5-methylsulfonyl-thiophene-2-yl, 5-methylthio-thiophene-2-yl, or 5-ethylisoxazene-2-yl; R2 is hydrogen, methyl which can be either in α- or β-configuration; R3 and R4 are the same or different, each is independently hydrogen, halogen, and is simple or double link; or its pharmaceutically acceptable salt or solvate.

EFFECT: obtaining compound with glycocorticosteroid effect.

20 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention concerns (a) new compounds of the formula I: , where M is a macrolipid subunit (macrolipid group) obtained from a macrolipid inclined to accumulation in inflamed cells, S is a steroid subunit (steroid group) obtained from a steroid medicine with anti-inflammatory effect, and L is a linker molecule connecting M and S; (b) their pharmacologically acceptable salts, prodrugs and solvates; (c) methods and mediators for their obtaining; and (d) methods of their application in treatment of human and animal inflammation diseases and conditions. The claimed compounds are inhibiting many cytokines and immune mediators participating in immune reactions that cause inflammation, allergy or alloimmunity, including IL (interleukin)-1, 2, 4, 5, 6, 10, 12, GMCSF (Granulocyte Macrophage Colony Stimulating Factor), ICAM (Intercellular Adhesion Molecule) and TNF (tumour necrosis factor) - α without limitation. At that, antiinflammation steroids have immediate anti-inflammatory effect due to the link to glycocorticosteroid receptor.

EFFECT: application in treatment of human and animal inflammation diseases and conditions.

30 cl, 40 ex, 4 dwg

FIELD: medicine.

SUBSTANCE: remedy has glucocorticosteroids, heparin, antimycotic and antibiotic providing synergetic action. It is usable in any form like pastes, ointments, crèmes, gels, sprays or solutions.

EFFECT: enhanced effectiveness of treatment; avoided complications related to glucocorticosteroids application.

2 cl, 1 tbl

The invention relates to medicine, namely to surgery, and can be used in cardiosurgical patients for the treatment and prevention of heart failure

The invention relates to pharmaceutical industry and relates to a composition for the treatment of respiratory distress syndrome

The invention relates to the field of medicine and is suitable for the treatment of rheumatism, rheumatic inflammatory diseases, diseases of Edison, acute insufficiency of the adrenal cortex, bronchial asthma, acute and chronic allergic diseases, hepatitis, hepatic coma, hypoglycemic conditions, diseases of the kidneys, the blood, skin and eye diseases, systemic diseases of connective tissue

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns drugs and covers a combination applicable for treating a respiratory disease representing asthma, acute or chronic bronchitis, emphysema, chronic obstructive pulmonary disease, bronchial hyperactivity or rhinitis, containing effective amount of (a) corticosteroid and effective amount of (b) M3 muscarine receptors antagonist which represents 3(R)-(2-hydroxy-2,2-dithiene-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane in the form of salt containing anion X which is pharmaceutically acceptable anion of mono-or polyvalent acid. There is also disclosed application of 3(R)-(2-hydroxy-2,2-dithiene-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane and corticosteroid for preparing a drug for treating a respiratory disease and the method of treating said respiratory disease.

EFFECT: combinations under the invention provide improved therapeutic effect in treating the respiratory diseases.

21 cl, 1 dwg, 1 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention refers to 3-oxo-28-(N-methylpiperazine)-carbonyl-lup-20(29)-ene of formula (I) which can be used in medicine as a corrective agent for paraneoplastic damages and toxic effects of cytostatic polychemotherapy. .

EFFECT: compound I shows an apparent anticancer activity, reduces severity of pathological changes in tissues caused by paraneoplastic syndromes; in cytostatic polychemotherapy, it exhibits an apparent antioxidant and cytoprotective effect in normal cells of viscera and thereby does not stimulate proliferation and dissemination of a tumour.

8 ex, 8 tbl

FIELD: medicine.

SUBSTANCE: invention covers drugs and concerns a combination intended for treating respiratory disease, containing (a) effective amount of corticosteroid, and (b) effective amount of antagonist of muscarine receptors M3 representing (3R)-1-phenethyl-3-(9N-xantene-9-xarbonyloxy)-1-azoniumbicyclo[2.2.2]octane in the form of salt with an anion X which represents a pharmaceutically acceptable anion of mono- or polyvalent acid. There is also disclosed application of (3R)-1-phenethyl-3-(9N-xantene-9-carbonyloxy)-1-azoniumbicyclo[2.2.2]octane and corticosteroid for making a drug for respiratory disease and the method of treating respiratory disease.

EFFECT: improved therapeutic effect in treating respiratory diseases.

20 cl, 1 dwg, 1 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to steroids with (11β)-[4-(aza-aryl)phenyl] substitutes which modulate progesterone receptors, or pharmaceutically acceptable salts and/or hydrated form, and/or prodrug thereof.

EFFECT: compounds exhibit combined activity profile of PR agonist and PR antagonist which makes them suitable for contraception and treating gynaecological disorders.

30 cl, 28 ex, 1 tbl

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