5-hydroxybenzothiazole derivatives as β2-adrenoreceptor agonists

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula in free form or in form of a pharmaceutically acceptable salt, where T denotes C1-C10alkyl which is substituted in one position with a -NR1R2 group or C3-C15carboxylic group selected from indan, phenyl, C3-C8cycloalkyl, wherein said C3-C15carboxylic group is optionally substituted in one or two positions with a halogen group, -NR3R4 or C1-C10alkoxy group, or T denotes C3-C15carboxylic group selected from indan, phenyl, C5cycloalkyl which is optionally substituted in one or two positions with a C1-C10alkyl group, C5cycloalkyl or C1-C10alkoxy group which is optionally substituted in one position with phenyl, and R1, R2 independently denote C1-C10alkyl or phenyl, and R3, R4 independently denote C1-C10alkyl. The formula I compound has β2-adrenoreceptor agonist activity.

EFFECT: more effective use as an active ingredient of a pharmaceutical composition.

7 cl, 1 tbl, 3 ex

 

4B the present invention offers organic compounds, methods for their preparation and use as pharmaceuticals.

One object of the invention is a compound of formula I

in free form or in salt form or MES, where

T means hydrogen or C1-C10alkyl, optionally substituted in one, two or three positions by group1-C10alkoxy, -NR1R2A 5 - or 6-membered heterocyclic cycle in a loop containing at least one heteroatom selected from the group comprising atoms of nitrogen, oxygen and sulphur, or With3-C15carbocyclic group, and specified With3-C15carbocyclic group optionally substituted in one, two or three positions by the group halogen, C1-C10alkyl, C3-C10cycloalkyl, halogen(C1-C10)alkyl, -NR3R4A 5 - or 6-membered heterocyclic cycle in a loop containing at least one heteroatom selected from the group comprising atoms of nitrogen, oxygen and sulfur, or a group With1-C10alkoxy, optionally substituted in one, two or three positions With6-C10the aryl,

or T means3-C15carbocyclic group, optionally substituted one, two or three positions group is halogen, C1-C10alkyl, C3-C10cycloalkyl, halogen(C1-C10)alkyl, -NR5R6A 5 - or 6-membered heterocyclic cycle in a loop containing at least one heteroatom selected from the group comprising atoms of nitrogen, oxygen and sulfur, or a group With1-C10alkoxy, optionally substituted in one, two or three positions With1-C4the alkyl or C6-C10the aryl and

R1, R2, R3, R4, R5and R6independently mean hydrogen, C1-C10alkyl, C1-C10alkoxy, C3-C10cycloalkyl or6-C10aryl.

The terms used in the description have the following meanings.

The term "optionally substituted in one, two or three terms used in the description means a group substituted at one, two or three positions by any one of the following radicals or their combination.

The term "halogen", as used in the description means a chemical element, prinadlejaschii to 17 group (formerly group VII) of the Periodic table of elements, such as fluorine, chlorine, bromine or iodine. The preferred halogen is chlorine.

The term "C1-C10alkyl"used in the description means alkyl straight or branched chain, containing from 1 to 10 carbon atoms. If T mean1-C10 alkyl, it is preferably the radical means With1-C8alkyl, especially n-propyl, isopropyl, n-butyl, sec-butyl, -C(CH3)2With2H5, -CH(CH3)3H7or-CH(CH3)CH2C(CH3)3. If T mean5-C10carbocyclic group substituted in one, two or three positions With1-C8the alkyl, C1-C10alkyl preferably means1-C4alkyl, especially ethyl or sec-butyl. If any of R1, R2, R3, R4, R5and R6means1-C10alkyl, preferably the radical means With1-C4alkyl, especially methyl.

The term "C1-C10alkoxy"used in the description means alkoxy, straight or branched chain, containing from 1 to 10 carbon atoms. If T means C1-C10alkyl, substituted in one, two or three positions With3-C15carbocyclic group, which is substituted in one, two or three positions by a group of C1-C10alkoxy, C1-C10alkoxy means preferably1-C4alkoxy, especially methoxy or n-butoxy. If T mean5-C15carbocyclic group substituted in one, two or three positions by a group of C1-C10alkoxy, C1 -C10alkoxy means preferably1-C4alkoxy, especially ethoxy. If any of R1, R2, R3, R4, R5and R6means C1-C10alkoxy, preferably it With1-C4alkoxy.

The term "C3-C10cycloalkyl"used in the description means cycloalkyl containing 3-10 carbon atoms in the cycle, for example monocyclic group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclonona or cyclodecyl, or a bicyclic group, such as bicycloheptene or bicycloalkyl. Preferably3-C10cycloalkyl means3-C6cycloalkyl, primarily cyclopentyl or cyclohexyl.

The term "halogen(C1-C10)alkyl"used in the description means C1-C10alkyl, specified above, substituted by one or more halogen atoms, preferably one, two or three halogen atoms. Preferably halogen(C1-C10)alkyl means a fluorine(C1-C4)alkyl.

The term "C6-C10aryl", as used in the description, means a monovalent carbocyclic aromatic group containing 6 to 10 carbon atoms, for example a monocyclic group such as phenyl, or a bicyclic group such as naphthyl. Preferably6-C 10aryl means6-C8aryl, especially phenyl.

The term "C3-C15carbocyclic group", as used in the description, means a carbocyclic group containing 3 to 15 carbon atoms in the cycle, for example a monocyclic group, an aromatic or non-aromatic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or phenyl, or a bicyclic group such as bicycloalkyl, bicycloalkyl, billeder, indanyl or indenyl.

If T means C1-C10alkyl, substituted in one, two or three positions With5-C15carbocyclic group, With5-C15carbocyclic group preferably means5-C10carbocyclic group, primarily monocyclic group such as phenyl or cyclohexyl. If T mean5-C15carbocyclic group, preferably the radical means With5-C10carbocyclic group, primarily monocyclic non-aromatic group such as cyclopentyl, or a bicyclic group such as indanyl.

The term "5 - or 6-membered heterocyclic loop, in a loop containing at least one heteroatom selected from the group comprising atoms of nitrogen, oxygen and sulphur"as used in the description means, for example, pyrrole, pyrrolidine, piraso is, the imidazole, triazole, tetrazole, furan, thiadiazole, isothiazol, thiophene, oxadiazole, pyridine, oxazole, isoxazol, pyrazin, pyridazine, pyrimidine, piperazine, morpholine, triazine, oxazin or thiazole. Preferred 5 - or 6-membered heterocyclic cycles include unsaturated cycles such as pyridine, furan and thiophene.

The term "MES"used in the description means a complex comprising the compound of the present invention and one or more molecules pharmaceutically acceptable solvent, for example ethanol. The term "hydrate" is used if the solvent is water.

If not specified, it is understood that the term "include" or variations such as "comprises" or "comprising"used in the description and in the claims, means the inclusion of the specified integer or stage, or group of integers or steps, but not the exclusion of any such integer or stage, or group of integers or steps.

Preferred compounds of the present invention include compounds of formula I in free form, in salt form or MES, where T means C1-C10alkyl, optionally substituted in one, two or three positions by the group-NR1R2or5-C15carbocyclic group, and specified With5-C15carbocyclic group is optionally substituted in one, two or three positions by the group halogen, -NR3R4or C1-C10alkoxy, or T means5-C15carbocyclic group, optionally substituted one, two or three positions by a group of C1-C10alkyl, C3-C10cycloalkyl, -NR5R6or group C1-C10alkoxy, optionally substituted in one, two or three positions by group6-C10aryl, and

R1, R2, R3, R4, R5and R6independently mean C1-C10alkyl or C6-C10aryl.

More preferred compounds of the present invention include compounds of formula I, where

T means C1-C8alkyl, optionally substituted at one position by the group-NR1R2or5-C10carbocyclic group, and specified With5-C10carbocyclic group optionally substituted in one or two positions by the group halogen, -NR3R4or1-C4alkoxy,

or T means5-C10carbocyclic group, optionally substituted at one or two positions by group1-C8alkyl, C3-C10cycloalkyl, -NR5R6or1-C4alkoxy, optionally substituted at one position by the group With6-C8aryl, before the package is phenyl, and

R1, R2, R3, R4, R5and R6independently mean C1-C4alkyl or C6-C8aryl, especially phenyl.

The compounds of formula I can form acid additive salts, especially pharmaceutically acceptable acid salt additive. 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, itestosterone acid, nitric acid, sulfuric acid, phosphoric acid and salts of organic acids, for example aliphatic monocarboxylic acids such as formic acid, acetic acid, triperoxonane acid, propionic acid and butyric acid, aliphatic hydroxy acids 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, para-biphenylmethane acid or triphenylarsine acid, aromatic hydroxy acids such as ortho-hydroxybenzoic acid, para-hydroxybenzoic acid, 1-hydroxynaphthalene-2-carboxylic to the slot or 3-hydroxynaphthalene-2-carboxylic acid, cinnamic acids such as 3-(2-naphthalenyl)Papanova acid, para-metaxalona acid or para-medicority acid, and sulfonic acids, such as methanesulfonate acid or benzolsulfonat acid. These salts derived from compounds of the formula I by known methods.

The compounds of formula I may exist in resolutiony and solvated forms. Pharmaceutically acceptable solvate includes hydrates and solvate in which the solvent used for crystallization is replaced by isotopes, for example, D2O, d6-acetone or d6-DMSO.

The compounds of formula I include at least one asymmetrically carbon atom and can therefore exist in individual optically active isomers or as mixtures thereof, e.g. as racemic or diastereomeric mixtures. The present invention includes the individual optically active R and S isomers and their mixtures, e.g. racemic or diastereomeric mixture. These isomers are separated by the known methods, for example by fractional crystallization or by chromatography on a column.

The most preferred connections according to the invention are compounds described below in the Examples section below.

In the present invention it is also proposed a method of obtaining soedineniya I in free form, in the form of a salt or MES. This method includes:

(1) (a) interactions of the compounds of formula II

where Raand Rbmeans a protective group, a Rcmeans1-C4alkyl or C6-C10aryl, with a compound of formula III

where T has the values listed above, or

(C) the interaction of compounds IIA

where Raand Rbmeans a protective group, with a compound of formula III where T has the values listed above,

(2) removal of protective groups, and

(3) the allocation of the compounds of formula I in free form or in salt form or MES.

The method according to option a is conducted according to known methods of interaction of esters of sulfonic acids with amines or in the same way as described in the examples. Rcpreferably means1-C4alkyl, but above all methyl. Usually the reaction is carried out in an organic solvent such as toluene. Usually the reaction temperature is from 0°C to 200°C, preferably from 70°C to 100°C., especially from 80°C to 90°C. the Reaction is usually carried out under heating or under microwave irradiation.

The method according to option b is conducted according to known methods of interaction of epoxides with amines or in the same way as described in the examples. Usually the reaction is carried out in an organic solvent such as toluene. Usually the reaction temperature is from 0°C to 200°C, preferably from 70°C to 100°C., especially from 80°C to 90°C. the Reaction is usually carried out under heating or under microwave irradiation.

Protective group, Raand Rbchoose in accordance with the structure of the functional group, for example, as described in the monograph Protective Groups in Organic Synthesis, T.W.Greene and P.G.M.Wuts, John Wiley & Sons Inc, Third Edition (1999), which also describes procedures suitable for replacement of the protective groups for the hydrogen atom. Rapreferably means1-C4alkyl, especially isopropyl. Rbpreferably means1-C4alkyl, especially tert-butyl.

The protective group can be entered or removed by the usual methods. For example, the hydroxy-group protecting benzyl group, which is then removed by catalytic hydrogenation in the presence of palladium on coal by conventional methods, for example according to the methods described in the examples.

The compounds of formula I in free form can be converted into the salt form and Vice versa in the usual way. Compounds in free form or in salt form can be obtained in the form of a hydrate or of a solvate containing solvent used for crystallization. The compounds of formula I can be isolated from the reaction mixture and purify the usual way. Isomers, such as enantiomers, you will receive the usual way, for example by fractional crystallization or asymmetric synthesis of respectively asimmetricheskii substituted, for example, optically active starting materials.

The compounds of formula II are new and you can get them in the interaction of the compounds of formula IV

where Raand Rbare protective groups, with sulphonylchloride, such as methanesulfonamido by known methods selective mono-sulfonylamine described in article Zhou and others, J. Organic Letters, 4 (1), 43-46 (2002), or similarly, as described below in the Examples section below. In the interaction of sulphonylchloride with (R)-1-(5-tert-butoxy-2-isopropoxybenzonitrile-7-yl)ethane-1,2-diola get the R-enantiomer, the interaction of sulphonylchloride with (S)-1-(5-tert-butoxy-2-isopropoxybenzonitrile-7-yl)ethane-1,2-diola get S-enantiomer. Usually the reaction is carried out in an organic solvent such as pyridine. The temperature of the reaction mixture is usually from -20°C to 30°C, preferably about 0°C.

The compounds of formula IIA are new and can be obtained by using known methods of obtaining oxiranyl-substituted heterocyclic compounds, for example as described in international application WO 04/016601. For example, the compounds of formula IIA can be obtained by heating compounds of formula II, for example, accountnow temperatures up to 150°C, preferably at a temperature of from 50 to 100°C., in the presence of a base in a solvent such as toluene, tetrahydrofuran or dichloroethane. The compounds of formula IIA can also be obtained as intermediates in carrying out the above reaction of compounds of the formula II with compounds of formula III to form compounds of formula I.

The compounds of formula III are known compounds or can be obtained by known methods or analogously to, as described below in the Examples section below.

The compounds of formula IV can be obtained by the interaction of the compounds of formula V

where Raand Rbare protective groups, with gidrauxiliruetsa agent such as osmium tetroxide in the presence or in the absence of a catalyst, for example, (DHQD)2PHAL (1,4-bis(dihydropyridines)phthalazine) and deoxidant, for example, K3Fe(CN)6or in the presence of pre-added hydroxyperoxy reagents, such as AD-mix-α or AD-mix-β, using well-known techniques of asymmetric hydroxylation of alkenes or similar, as described below in the Examples section below. Usually the reaction is carried out in an organic solvent, for example tert-butanol/water, in the presence of osmium tetroxide, preferably in the presence of a catalyst, such as (DHQD)2PHAL, and K3Fe(CN)6as a researcher who, as deoxidant. The temperature of the reaction mixture is usually from -10°C to 10°C, preferably about 0°C.

The compounds of formula V can be obtained by rafinirovannom the compounds of formula VI

where Raand Rbare protective groups, by known methods of transformation of aldehydes to alkenes, for example by Wittig reaction, or the same, as described below in the Examples section below. Usually the reaction is carried out in an organic solvent, for example THF or DHM. The temperature of the reaction mixture is usually from 10°C to 40°C., preferably the reaction is carried out at room temperature.

The compounds of formula VI can be obtained by the reaction of compounds of formula VII

where Raand Rbare protective groups, and X is halogen, preferably fluorine, with a strong base such as tert-butyllithium. Intermediate anion is neutralized by adding an electrophilic compounds, such as dimethylformamide, and the reaction is carried out according to the method described in the article Stanetty, etc., J. Org. Chem., 61, 5130-5133 (1996), or similarly, as described below in the Examples section below. Usually the reaction is carried out in an organic solvent, for example THF. The temperature of the reaction mixture typically ranges from -90°C to 20°C, preferably from about -78°C to about -10°C.

Conn is of formula VII can be obtained by the reaction of compounds of formula VIII

where Rbmeans a protective group, and X is halogen, with a compound of formula IX

where Rameans a protective group, by known methods, for example, by the reaction isothioscyanates with alcohols to form THIOCARBAMATE, or similar, as described below in the Examples section below. R1preferably means1-C4alkyl, especially isopropyl. Usually the reaction is preferably carried out in the presence of a base, such as triethylamine. The temperature of the reaction mixture is usually from 0°C to 120°C, preferably about 60°C.

The compounds of formula VIII can be obtained by the known methods of transformation of anilines in isothiocyanates, for example, by the reaction of compounds of formula X

where Rbmeans a protective group, and X is halogen, with thiophosgene (thiocarbanilide) using well-known methods of transformation of amines in isothiocyanates or similar, as described below in the Examples section below. Usually the reaction is carried out in an organic solvent such as chloroform, preferably in the presence of a base, for example sodium carbonate. The temperature of the reaction mixture is usually from -20°C to 20°C, preferably about 0°C.

The compounds of formula IX are known is s or you can get them known methods or analogously to as described below in the Examples section below.

The compounds of formula I in free form, in salt form or MES, are used as medicines. Accordingly, the invention features a compound of formula I in free form, in salt form or MES, as a medicinal product. The compounds of formula I in free form, in salt form or MES, denoted in this context as "agents according to the invention have a high agonistic effect on β2-adrenergic receptors. β2-Agonistic activity, onset of action and duration of action of the agents according to the invention is evaluated by using strips of tracheal tissue of Guinea pigs in vitro according to the method described in the article R.A.Coleman and ..Nials, J. Pharmacol. Methods, 21, 71 (1989). The binding efficiency and selectivity for β2-adrenergic receptors compared with β1-adrenergic receptors define a classic analysis of binding to the filters according to the method described in Current Protocols in Pharmacology, S.J.Enna (editor-in-chief) et al, John Wiley & Son, Inc. (1998), or determining the level of camp in cells expressing β2- or β1-adrenergic receptors according to the method described in the article .January and others, Brit. J. Pharmacol., 123, 701 (1998).

The agents according to the invention usually have a fast action and have long-lasting stimulatory effect on β2-adrenal captor. The compounds described below in the examples are characterized by values of Ki2) from 0.1 to 1000 nm and a duration from 1 hour up to 12 o'clock Many of the compounds exhibit selectivity for β2-adrenergic receptors, 1.5 to 500 times the selectivity for β1-adrenergic receptors. The compounds described in examples 2, 4, 9, 14 and 17, characterized by the efficiency of binding to β2defined classical analysis of binding to the filters, for example, these compounds values of Kiare 0,061, 0,027, 0,016, 0,056 and of 0.002 μm, respectively.

The compounds described in examples 1 and 18, are characterized by time T(50%) (min) >672 at a concentration of 100 nm and 595 at a concentration of 10 nm, respectively, according to analysis using strips tracheal tissue of Guinea pigs, where T(50%) mean duration of inhibition of contraction by reducing 50% of the maximum value.

Thanks β2-agonistic activity of the agents according to the invention can be used in the treatment of any condition which prevented or facilitated by activating β2-adrenergic receptors. Through continued selective β2-agonistic action of the agents according to the invention can be used for relaxation of bronchial smooth muscles and to reduce the intensity of halogen with exceptiona is bronchostenosis, which is assessed on the models such as plethysmographically model in vivo, as described in articles Chong and others, J. Pharmacol. Toxicol. Methods, 39, 163 (1998), Hammelmann, and others, Am. J. Respir. Crit. Care Med., 156, 766 (1997), and similar models.

Thus, the agents according to the invention can be used in the treatment of obstructive or inflammatory diseases of the respiratory tract. Thanks to the continuous action of the agents according to the invention can be used to treat such diseases once. In addition, the agents according to the invention usually have bad side effects are usually specific for β2-agonists, such as tachycardia, tremor and restless state, and, therefore, such agents suitable for use in emergency care, and preventive therapy of obstructive or inflammatory diseases of the respiratory tract.

The treatment of the present invention is symptomatic or preventive. Inflammatory or obstructive diseases of the respiratory tract, in respect of which can be applied in the present invention include asthma of any type and of any cause, including congenital (non-allergic) asthma and acquired (allergic) 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 dia is Outlook "children with asthma", 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 bronchostenosis, to improve the functioning of the lungs or increase hyperresponsiveness of the Airways. In addition, the preventive effect is manifested 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., with use of corticosteroid or bronchodilator treatment. Prevention in the treatment of asthma primarily required for entities subject to the "morning attacks". "Morning attacks are known asthmatic syndrome, characteristic of the majority of asthma, which is characterized by asthma attacks, for example, between approximately 4 and 6 am, i.e. through a significant period of time after any previous introduction symptomatic asthma therapeutic agent.

Other inflammatory or and safety Deposit box is aktivnye diseases and conditions of the respiratory tract, in respect of which can be applied in the present invention include acute respiratory distress syndrome in adults (ARDS), chronic obstructive lung disease and respiratory (COPD or COAD), including chronic bronchitis, or associated with it shortness of breath, emphysema, and increased 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 type or etiology, including, for example, acute, arachnoidal, catarrhal, lobar, or chronic purulent tuberculous bronchitis. Other inflammatory or obstructive diseases of the respiratory tract, in respect of which can be applied in 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, asbestos, helicos, Philos, sideros, silicosis, tabacos and bissines.

Thanks β2-agonistic activity of the agents according to the invention can be used in the treatment comprising the Oia, requiring relaxation of smooth muscles of the uterus or the vascular system. Thus, they can be used to prevent or relieve pain in preterm births. These agents can also be used in the treatment of chronic and acute urticaria, psoriasis, allergic conjunctivitis, actinica, hay fever and mastocytosis.

The agents according to the invention can also be used as a combined therapeutic agents for use in combination with other drugs such as anti-inflammatory, bronchodilatory, antihistamine or cough medicines, primarily for the treatment of obstructive or inflammatory diseases of the respiratory tract, such as the diseases mentioned above, for example, as the agents potentiate therapeutic activity of these drugs, or as a means for reducing the required dose or possible side effects of these drugs. The agent according to the invention is mixed with other drugs in a fixed pharmaceutical composition or administered separately before the introduction of other drugs, along with him or after him. Thus, the invention includes a combination of the agent on the image the structure, described above, with anti-inflammatory, bronchodilatory, antihistamine or cough medicine, and the specified agent according to the invention and indicated the drug can be in the same or in different pharmaceutical compositions.

Suitable anti-inflammatory agents include steroids, especially corticosteroids, such as budesonide, dipropionate of beclamethasone, fluticasone propionate, ciclesonide or mometasone furoate, or steroids described in WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679 (primarily compounds described in the examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101), WO 03/35668, WO 03/48181, WO 03/62259, WO 03/64445, WO 03/72592, WO 04/39827 and WO 04/66920, non-steroidal agonists of the glucocorticoid receptor such as described in DE 10261874, WO 00/00531, WO 02/10143, WO 03/82280, WO 03/82787, WO 03/86294, WO 03/104195, WO 03/101932, WO 04/05229, WO 04/18429, WO 04/19935 and WO 04/26248, LTB4 antagonists, such as BIIL 284, CP-195543, DPC11870, LTB4 of ethanolamide, LY 293111, LY 255283, CGS025019C, CP-195543, ONO-4057, SB 209247, SC-53228, and agents described in US 5451700, LTD4 antagonists, including montelukast, pranlukast, zafirlukast, accolate, SR2640, Wy-48252, ICI 198615, MK-571, LY-171883, Ro 24-5913 and L-648051, PDE4 inhibitors, such as cilomilast (Ariflo® GlaxoSmithKline), roflumilast (company Byk Gulden),V-11294A (firm Napp), BAY19-8004 (Bayer), SCH-351591 (firm Schering-Plough), arofylline (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 agents 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, and antagonists And2Bsuch as described in WO 02/42298.

Suitable bronchodilators include anticholinergic or agents antimuskarinovoe act occurs primarily ipratropium bromide, bromide oxytrope, salts of Tiotropium and CHF 4226 (company Chiesi), and glycopyrrolate, but also the agents 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.

Suitable bronchodilators with double action include agonist β2-adrenergic receptors/antagonists at the muscarinic receptor, such as described in US 2004/0167167, WO 04/74246 and WO 04/74812.

Suitable antihistamines include cetirizine hydrochloride, acetaminophen, fumarate of clemastine, promethazine, loratidine, desloratidine, diphenhydramine hydrochloride and Fexofenadine, activatin, astemizole, Azay Astin, Bastin, epinastine, mizolastine and defendin, and agents described in JP 2004107299, WO 03/099807 and WO 04/026841.

The agents according to the invention can also be used as a combined therapeutic agents for use in combination with other agonists of β-adrenergic receptors as drugs for emergency treatment. Suitable agonists β2-adrenoreceptor include albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, carmoterol, procaterol and above all, formoterol and pharmaceutically acceptable salts, and compounds (in free form, in salt form or MES) of the formula I described in WO 0075114 included in the description of the application as a reference, preferably compounds described in the examples, especially the compound of the formula

its pharmaceutically acceptable salts, and compounds (in free form, in salt form or MES) of the formula I described in WO 04/16601, and compounds 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, WO 04/80964, EP1460064, WO 04/087142, WO 04/089892, EP 01477167, US 2004/0242622, US 2004/0229904, WO 04/108675, WO 04/108676, WO 05/033121, WO 05/040103 and WO 05/044787.

Other combinations of agents according to the invention with protelos the extreme drugs are a combination with antagonists of chemokine receptors, for example, CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, primarily antagonists of CCR-5, such as antagonists SC-351125, SCH-55700 and SCH-D (firm Schering-Plough), antagonists, offered by the company Takeda, such as chloride, N-[[4-[[[6,7-dihydro-2-(4-were)-5H-benzocycloheptene-8-yl]carbonyl]amino]phenyl]methyl]tetrahydro-N,N-dimethyl-2H-Piran-4-amine (TAK-770), and antagonists of CCR-5, described in US 6166037 (primarily PHP and 19), WO 00/66558 (primarily in section 8), WO 00/66559 (primarily in item 9), WO 04/018425 and WO 04/026873.

Combinations of agents according to the invention and steroids, PDE4 inhibitors, agonists A2A, agonists A2Bor LTD4 antagonists can be used, for example, in the treatment of COPD or primarily asthma. Combinations of agents according to the invention and anticholinergic antimuskarinovoe act occurs or agents, PDE4 inhibitors, agonistsA2A, agonists A2Bthe agonists of the dopamine receptor or antagonists of LTB4 can be used, for example, in the treatment of asthma or primarily COPD.

In accordance with the foregoing the present invention also offers a method for the treatment of obstructive or inflammatory airway disease, which includes an introduction to the subject, first of all the person who needs treatment, the compounds of formula I or its pharmaceutically acceptable salt or MES specified above. Another object of the invention is with the unity of formula I or its pharmaceutically acceptable salt or MES, described above, for use in preparation of medicines intended for the treatment of obstructive or inflammatory Airways disease.

The agents according to the invention can be entered in any conventional manner, for example orally, for example in the form of tablets or capsules, parenterally, for example intravenously, topically on the skin, for example, in the treatment of psoriasis, intranasally, for example, in the treatment of hay fever, or preferably by inhalation, primarily in the treatment of obstructive or inflammatory diseases of the respiratory tract.

Another object of the invention is also a pharmaceutical composition comprising a compound of formula I in free form or in the form of its pharmaceutically acceptable salt or MES, optionally in a mixture with a pharmaceutically acceptable diluent or carrier. Such compositions obtained using conventional diluents or excipients known in pharmacology methods. Thus, forms for oral administration include tablets and capsules. Forms for local injection include creams, ointments, gels or system transdermal delivery, such as patches. Compositions for inhalation include an aerosol or other spray compositions or powder formulations.

If the composition comprises an aerosol composition, such whom azizia preferably contains ftoruglevodorodnye propellant (HFA), such as HFA134a or HFA227 or a mixture thereof, and may contain one or more co-solvents known in the art, such as ethanol (up to 20 wt.%) and/or one or more surfactants such as oleic acid or trioleate sorbitol, and/or one or more fillers, such as lactose. If the composition includes a powder composition, the composition preferably contains, for example, the compound of formula I in the form of particles with a diameter up to 10 microns, optionally in a mixture with a diluent or carrier, such as lactose, of the desired particle size and connectivity that protects the product from damage due to moisture, such as magnesium stearate, for example, from 0.01 to 1.5%. If the composition comprises spraying the composition, the composition 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, which may mean surfactants.

The invention also includes (a) compound of formula I as defined above, in free form or in the form of its pharmaceutically acceptable salt or MES in the form of inhalation, (B) drug for inhalation, comprising such a compound in the form of inhalation in a mixture with a pharmaceutically acceptable carrier in inhalation form, (C) a pharmaceutical product comprising such a compound in inhalation form together with nebulizer and (D) inhaler, containing such a compound in inhalation form.

Doses used in the implementation of the invention vary depending on, for example, on the particular condition to be treated, the desired result, and the method of introduction. In the General case, a suitable daily dose for administration by inhalation is from 1 to 5000 mcg.

The invention is illustrated by the following examples.

Examples

More preferred compounds of formula I are the compounds of formula XI

where T has the values listed in the table, and the method of obtaining described below. All connections are in the form of salt or in free form. Unless otherwise stated, the spectra of 1H-NMR was shot at 400 MHz in CDCI3. Mass spectra were obtained under conditions of ionization electrospray in combination with LC (eluent: gradient 5 acetonitrile/water + 1% formic acid, 5% to 95%).

No.TMS [MN]+
1359,26
2337,21
3 374,27
4431,15
5331,04
6339,09
7398,96
8343,03
9359,05

No.TMS [MN]+
10402,15
11375,05
12399,09
13 399,13
14363.08
15295,04
16401,09
17401,05
18402,15

The intermediate compounds

List of abbreviations: DHM means dichloromethane, DMF means dimethylformamide, DMSO means dimethylsulfoxide, THF means tetrahydrofuran.

1-Bromo-3-tert-butoxy-5-torbenson

tert-Butanol (28,2 g) was dissolved in dimethylacetamide (200 ml) and for 15 min was added NaH (15.6 g, 60% dispersion in oil). The reaction mixture was stirred at room temperature for 2 h, and then for 30 min was added dropwise 3.5 deferrement (50 g). The reaction mixture was stirred at room temperature until completion of the reaction according to GHUR. The reaction was stopped by adding water (10 ml), the mixture was washed the ode (1×), the organic phase was dried over MgSO4was filtered and the solvent was removed in vacuum, to receive specified in the header of the connection.

1H-NMR (CDCl3, 400 MHz): δ 7,00 (ddd, 1H), 6,95 (dd, 1H), of 6.68 (ddd, 1H), 1,4 (s, N).

3-tert-Butoxy-5-forfinally

1-Bromo-3-tert-butoxy-5-torbenson (56,1 g), benzophenone (50,9 g), NaOMe (50.5 g) and 2,2'-bis-diphenylphosphanyl[1,1']binaphthalene (17.5 g) was dissolved in toluene (500 ml). The reaction mixture was purged with argon, was added Pd2(dba)3(5,4 g) and was heated at 80°C for 40 hours the Reaction was stopped by adding water, the organic phase was separated, dried over MgSO4was filtered and the solvent was removed in vacuum. The intermediate compound was obtained after purification Express chromatography on a column of silica gel (eluent: dichloromethane).

The obtained product was dissolved in Meon (1 l)was added NaOAc (46,1 g), hydroxylamine hydrochloride (29,1 g) and the reaction mixture was stirred at room temperature for 2.5 hours the Reaction was stopped by adding 0.1 M NaOH, the mixture was extracted with DHM (2×), the extract was dried overMgSO4was filtered and the solvent was removed in vacuum, to receive specified in the header of the connection.

1H-NMR (CDCl3, 400 MHz): δ of 6.20 (m, 3H), 3,75 (user. s, 2H), 1,4 (s, N).

1-tert-Butoxy-3-fluoro-5-isothiocyanatobenzene

To a solution of 3-tert-butoxy-5-ftorhinolona (42.9 g) in CHC 3(350 ml) at 0°C. separately or simultaneously added dropwise thiophosgene (33,6 g) in CHCl3(250 ml) and K2CO3(64,7 g) in N2O (450 ml) and the reaction mixture was heated to room temperature over night. The organic phase was separated, washed with water (3×), brine (1×), dried over MgSO4was filtered and the solvent was removed in vacuum. Specified in the title compound was obtained after purification Express chromatography on a column of silica gel (eluent: dichloromethane/isohexane, 1:3).

1H-NMR (CDCl3, 400 MHz): δ 6,70 (m, 3H), of 1.40 (s, N).

O-Isopropyl ester (3-tert-butoxy-5-forfinal)thiocarbamide acid

1-tert-Butoxy-3-fluoro-5-isothiocyanatobenzene (24,0 g) and triethylamine (10,9 g) was dissolved in isopropanol (150 ml). The reaction mixture is boiled under reflux for 18 h and the solvent was removed in vacuum. The crude product was dissolved in hexane/diethyl ether (19:1), diethyl ether was removed in vacuum and the solution was cooled to 0°C for 3 hours the Solution was filtered, to receive specified in the header of the connection.

1H-NMR (CDCl3, 400 MHz): δ 8,10 (user. s, 1H), 6,65 (user. s, 2H), 6,45 (ddd, 1H), ceiling of 5.60 (Sept, 1H), 1,35 (d, 6N), of 1.30 (s, N).

5-tert-Butoxy-2-isopropoxybenzonitrile-7-carbaldehyde

O-Isopropyl ester (3-tert-butoxy-5-forfinal)thiocarbamide acid (2.2 g) was dissolved in dry tet is hydrofuran (20 ml), the reaction mixture was cooled to -78°C and for 20 min was added tert-utility (15.2 ml, 1.5 M solution). Then the reaction mixture was heated to -10°C for 75 minutes, again cooled to -78°C, was added N,N-dimethylformamide (1.5 g)was slowly heated to room temperature, and then stirred at -10°C for 1 h the Reaction was stopped by adding 2 M hydrochloric acid (5 ml), the organic phase was distributed between ethyl acetate/water and the solvent was removed in vacuum. Specified in the title compound was obtained after purification Express chromatography on a column of silica gel (eluent: ethyl acetate/isohexane, 1:9). MS (ES+): m/e 294 (MN+), LCT50865.

5-tert-Butoxy-2-isopropoxy-7-vinylbenzoate

Ph3PMe.Br (5.0 g) was dissolved in dry tetrahydrofuran (100 ml) in an argon atmosphere. Then at room temperature for 10 min was added N-utility (8,8 ml, 1.6 M solution) and the reaction mixture was stirred for another 30 min. the reaction mixture was added dropwise a solution of 5-tert-butoxy-2-isopropoxybenzonitrile-7-carbaldehyde (1.25 g) in dichloromethane (40 ml) and the mixture was stirred at room temperature for 4.5 hours, the Solvent was removed in vacuo, the residue was dissolved in ethyl acetate, washed with water (3×), brine (1×), dried over MgSO4was filtered and the solvent was removed in vacuum. Specified in the header of the link is received after purification Express chromatography on a column of silica gel (eluent: ethyl acetate/isohexane, 1:9). MC (ES+): m/e 292 (MH+), LCT55980.

(R)-1-(5-tert-Butoxy-2-isopropoxybenzonitrile-7-yl)ethane-1,2-diol

K3Fe(CN)6(1.2 g), K2CO3(0.5 g), (DHQD)2PHAL (19 mg) was dissolved in tert-butanol/water (15 ml, 1:1) in an argon atmosphere and was stirred for 15 minutes, the Reaction mixture was cooled to 0°C, was added OsO4(3.1 mg), and then 5-tert-butoxy-2-isopropoxy-7-vinylbenzoate (0.35 g). The reaction mixture was stirred at room temperature overnight. The reaction was stopped by adding meta-bisulfate sodium (1 g) and stirred for 1.5 hours the mixture was added ethyl acetate, the organic layer was separated, washed with water (2×), brine (1×), dried over MgSO4was filtered and the solvent was removed in vacuum. Specified in the title compound was obtained after purification Express chromatography on a column of silica gel (eluent: ethyl acetate/isohexane, 2:5). MS (ES+): m/e 326 (MN+), LCT56091.

(R)-2-(5-tert-Butoxy-2-isopropoxybenzonitrile-7-yl)-2-hydroxyethyloxy ether methanesulfonate acid

To a solution of (R)-1-(5-tert-butoxy-2-isopropoxybenzonitrile-7-yl)ethane-1,2-diol (100 mg) in pyridine (2 ml) at 0°C was added methanesulfonamide (35 mg) and the reaction mixture was stirred at 0°C for 3.5 hours, the Solvent was removed in vacuo, the residue was distributed between 2 M hydrochloric acid and ether. The organic phase is washed with water(1×) and brine (1×), dried over MgSO4was filtered and the solvent was removed in vacuum, to receive specified in the header of the connection.

1H-NMR (CDCl3, 400 MHz): δ 7,20 (d, 1H), 6,80 (d, 1H), and 5.30 (Sept., 1H), 5,10 (t, 1H), 4,30 (d, 2H), 3.00 and (s, 3H), 1,40 (d, 6N), of 1.30 (s, N).

(S)-1-(5-tert-Butoxy-2-isopropoxybenzonitrile-7-yl)ethane-1,2-diol

K3Fe(CN)6(3.4 g), K2CO3(1.4 g), (DHQ)2PHAL (53 mg) in tert-butanol/water (40 ml, 1:1) under argon atmosphere was stirred for 20 minutes, the Reaction mixture was cooled to 0°C, was added OsO4(8.6 mg), and then 5-tert-butoxy-2-isopropoxy-7-vinylbenzoate (1.0 g). The reaction mixture was stirred at room temperature overnight, the reaction was stopped by adding meta-bisulfate sodium (1.2 g) and the mixture was stirred for 1.5 hours the mixture was added ethyl acetate, the organic phase was separated, washed with water (2×) and solavie solution (1×), dried over MgSO4was filtered and the solvent was removed in vacuum. Specified in the title compound was obtained after purification Express chromatography on a column of silica gel (eluent: ethyl acetate/isohexane, 1:3). MS (ES+): m/e 326,12, LCT60289.

(S)-2-(5-tert-Butoxy-2-isopropoxybenzonitrile-7-yl)-2-hydroxyethyloxy ether methanesulfonate acid

To a solution of (S)-1-(5-tert-butoxy-2-isopropoxybenzonitrile-7-yl)ethane-1,2-diol (289 mg) in pyridine (2 ml) at 0°C was added methanesulfonamide (mg) and the reaction mixture was stirred at 0°C for 3 hours The solvent was removed in vacuo, the residue was distributed between 2 M hydrochloric acid and ether. The organic phase is washed with water (2×) and brine (1×), dried over MgSO4was filtered and the solvent was removed in vacuum, to receive specified in the header of the connection.

1H-NMR (CDCl3, 400 MHz): δ 7,20 (d, 1H), 6,80 (d, 1H), and 5.30 (Sept., 1H), 5,10 (t, 1H), 4,30 (d, 2H), 3.00 and (s, 3H), 1,40 (d, 6N), of 1.30 (s, N).

2-(4-Butoxyphenyl)-1,1-dimethylethylamine

Indicated compound was obtained according to the method described in international application WO 01/83462. MS (ES+): m/e 222,20 (MN+), 20% LCT59933.

[4-(2-Amino-2-methylpropyl " phenyl]dimethylamine

The specified connection was obtained according to the method described in international application WO 01/83462, MS (ES+): m/e 193 (MN+), 2% LCT59932.

(S)-5-Isobutylidene-2-ylamine

(a) (8)-5-Bromantan-2-ylamine

The specified connection was obtained according to the methods described in international application WO 96/23760.

(b) Benzyl ester (8)-(5-isobutylidene-2-yl)carbamino acid

A suspension of (S)-5-bromantan-2-ylamine (1.0 g) in dichloromethane (10 ml) was cooled to 0°C, was added dropwise benzylchloride (0,74 ml) and the reaction mixture was stirred for 0.5 hours, the Solution was filtered, got benzyl ester (S)-(5-bromantan-2-yl)carbamino acid. In a dry flask argon atmosphere was placed PdCl2(dppf)2(59 mg) was added isobutyramide (50 ml, 0.5 M solution wtgf). Benzyl ester (5-bromantan-2-yl)carbamino acid (2.50 g) was dissolved in dry THF (2 ml), the resulting solution was added to the specified reaction mixture and stirred at 50°C for 18 h Then the reaction was stopped by adding 2 M hydrochloric acid and the mixture was distributed between ethylcatechol and water. The organic layer was dried over MgSO4was filtered and the solvent was removed in vacuum. Specified in the title compound was obtained after purification Express chromatography on a column of silica gel (eluent: ethyl acetate/isohexane, 1:4).

1H-NMR (CDCl3, 400 MHz): δ 7,35 (m, 5H), 7,10 (d, 1H), 7,00 (s, 1H), 6.90 to (d, 1H), 5,1 (s, 2H), 4,55 (m, 1H), 3,30 (t, 2H), 2,75 (dt, 2H), 2,45 (d, 2H), 1,80 (m, 1H), 0,90 (d, 6N).

(c) (S)-5-Isobutylidene-2-ylamine

Benzyl ether of (S)-(5-isobutylidene-2-yl)carbamino acid was dissolved in methanol (100 ml)was added 10% Pd/C (200 mg) and the flask was filled with hydrogen (0.35 bar). The reaction mixture was stirred for 18 h, the catalyst was separated by filtration and the solvent was removed in vacuum, to receive specified in the header of the connection.

1H-NMR (CDCl3, 400 MHz): δ 7,10 (d, 1H), 7,00 (s, 1H), 6.90 to (d, 1H), 3,85 (m, 1H), 3.15 in (dd, 2H), 2,65 (dt, 2H), 2,45 (d, 2H), 1,80 (user. m, 3H), of 0.90 (d, 6N).

5,6-Dietlinde-2-ylamine

The specified connection was obtained according to the method described in international application WO 03/76387.

(R, R)-Bicyclopentyl-2-ylamine

The specified connection was received from the bi is clopotel-2 on methodology, described in article S.Hartmann and others, Eur. J. Med. Chem., 35, 377-392 (2000). MS (ES+): m/e 154,23 (MH+), LCT59419.

Example 1

(R)-7-[2-(1,1-Dimethyl-2-phenylethylamine)-1-hydroxyethyl]-5-hydroxy-3H-benzothiazol-2-he

a) (R)-1-(5-tert-Butoxy-2-isopropoxybenzonitrile-7-yl)-2-(1,1-dimethyl-2 - phenylethylamine)ethanol

(R)-2-(5-tert-Butoxy-2-isopropoxybenzonitrile-7-yl)-2-hydroxyethyloxy ether methanesulfonate acid (122 mg) and phentermine (165 mg) was dissolved in toluene (2 ml) and the reaction mixture was heated at 90°C for 20 hours the Solvent was removed in vacuum, (R)-1-(5-tert-Butoxy-2-isopropoxybenzonitrile-7-yl)-2-(1,1-dimethyl-2-phenylethylamine)ethanol was obtained after purification by chromatography on column with reversed phase using the system for rapid chromatography Jones Flashmaster Personal™ (column: ISOLUTE FLASH C18, eluent: gradient AcCN/water, from 0% to 60%). MS (ES+): m/e 457,32 (MN+), LCT56716.

b) (R)-7-[2-(1,1-Dimethyl-2-phenylethylamine)-1-hydroxyethyl]-5-hydroxy-3H-benzothiazol-2-he

(R)-1-(5-tert-Butoxy-2-isopropoxybenzonitrile-7-yl)-2-(1,1-dimethyl-2-phenylethylamine)ethanol (40 mg) was stirred in formic acid (2 ml) for 72 h Formic acid was removed in vacuo specified in the title compound was obtained after purification by chromatography on a column of reversed phase using the system for rapid chromatography Jones Flashmaster Personal™ (column: ISOLUTE FLASH C18, eluent: gradient AcCN/water, from 0% to 50%). The s (ES+): m/e 359,26 (MN +), LCT57144.

Examples 2-17

The compounds described in examples 2-17 were obtained by methods similar to those described in example 1.

Example 18

(S)-7-{2-[2-(4-Dimethylaminophenyl)-1,1-dimethylethylamine]-1-hydroxyethyl}-5-hydroxy-3H-benzothiazol-2-he

a) (S)-1-(5-tert-Butoxy-2-isopropoxybenzonitrile-7-yl)-2-[2-(4-dimethylaminophenyl)-1,1-dimethylethylamine]ethanol

[4-(2-Amino-2-methylpropyl " phenyl]dimethylamine (210 mg), and

(S)-2-(5-tert-butoxy-2-isopropoxybenzonitrile-7-yl)-2-hydroxyethyloxy ether methanesulfonate Islami (120 mg) was dissolved in toluene (2 ml) and the reaction mixture was heated at 80°C for 20 hours the Solvent was removed in vacuum, it was received (S)-1-(5-tert-butoxy-2-isopropoxybenzonitrile-7-yl)-2-[2-(4-dimethylaminophenyl)-1,1-dimethylethylamine]ethanol. MS (ES+): m/e 500.

b) (S)-7-{2-[2-(4-Dimethylaminophenyl)-1,1-dimethylethylamine]-1-hydroxyethyl}-5-hdroxy-3H-benzothiazol-2-he

(S)-1-(5-tert-Butoxy-2-isopropoxybenzonitrile-7-yl)-2-[2-(4-dimethylaminophenyl)-1,1-dimethylethylamine]ethanol (40 mg) was stirred in formic acid (2 ml) for 72 h Formic acid was removed in vacuo specified in the title compound was obtained after purification by chromatography on a column of reversed phase using the system for rapid chromatography Jones Flashmaster Personal™ (column: ISOLUTE FLASH C18, eluent: gradient AcCN/water, from 0% up to 50%). MS (ES+): m/e 402,15.

1. The compound of the formula I

in free form or in the form of pharmaceutically acceptable salts, where T means C1-C10alkyl, substituted in one position with the group-NR1R2or3-C15carbocyclic group selected from indena, phenyl, C3-C8cycloalkyl, and specified With3-C15carbocyclic group optionally substituted in one or two positions by the group halogen, -NR3R4or group C1-C10alkoxy,
or T means3-C15carbocyclic group selected from indena, phenyl, C5cycloalkyl, optionally substituted at one or two positions by a group of C1-C10alkyl, C5cycloalkyl or group C1-C10alkoxy, optionally substituted at one position by a phenyl, and
R1, R2independently mean C1-C10alkyl or phenyl, and
R3, R4independently mean C1-C10alkyl.

2. The compound according to claim 1, where
T mean1-C8alkyl, substituted in one position with the group-NR1R2or5-C10carbocyclic group selected from indena, phenyl, and specified With5-C10carbocyclic group optionally substituted in one or two positions by the group halogen, -NR3R4or1-C4alkoxy,
or T means 5-C10carbocyclic group selected from indena, phenyl, optionally substituted at one or two positions by group1-C8alkyl, C5cycloalkyl or1-C4alkoxy, optionally substituted at one position by a phenyl, and
R1, R2independently mean C1-C10alkyl or phenyl, and
R3, R4independently mean C1-C10alkyl.

3. The compound according to claim 1 or 2, which means the compound of formula XI

where T has the values listed in the table

T

T

T

4. The connection according to one of claims 1 to 3, intended for use as a drug with agonistic action on β2-adrenoreceptor.

5. Pharmaceutical composition having agonistic effect on β2-adrenergic receptors, comprising as an active ingredient the compound according to any one of the preceding paragraphs or its pharmaceutically acceptable salt, in a mixture with a pharmaceutically acceptable carrier.

6. The use of compounds according to any one of claims 1 to 3 to obtain medicines with agonistic action on β2-adrenergic receptors.

7. The method of obtaining the compounds of formula I according to claim 1 in free form or in the form of its salts, including:
(1) the interaction of the compounds of formula II

where Raand Rbmean protective group3-C4alkoxy, a Rcmeans1-C4alkyl, with a compound of formula III

where t has the meanings indicated in claim 1,
(2) removal of protective groups, and
(3) the allocation of the compounds of formula I in free form or in the form of its salts.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula (1) , where substitutes are as defined in paragraph 1 of the invention. The compounds have fungicide properties. The method of obtaining formula (1) compounds is described, in which n equals 0. Described also is a fungicide composition based on formula (1) compounds and a phytopathogenic fungus control method which uses compounds in paragraph 1 or a composition based on the said compounds.

EFFECT: obtaining novel compounds which can be used as fungicides.

24 cl, 312 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention is related to compounds of formula (II) as inhibitor of leukotriene A4-hydrolase (LTA4H) and their enantiomers, racemic compounds and pharmaceutically acceptable salts, and also to treatment methods, method inhibition and pharmaceutical composition on their basis. In general formula (II) , X is selected from group that consists of O and S; Y is selected from group that consists of CH2 and O; R4 represents H; R6 represents H or F; and R2' is determined as R2, and R3' is determined as R3, as follows: R2 and R3, each, is independently selected from group that consists of A) H, C1-7alkyl, C3-7cycloalkyl, where each of substitutes of A) is independently substituted with 0 or 1 RQ, and each of mentioned RQ is substitute at carbon, which is distanced from nitrogen at least by one carbon atom; alternatively, R2 and R3, taken together with nitrogen, to which they are connected, create heterocyclic ring, which contains at least one heteroatom, which is specified nitrogen of connection, and specified heterocyclic ring is selected from group that consists of i) (4-7)-member heterocyclic ring HetRb, where specified (4-7)-member heterocyclic ring HetRb has single heteroatom, which is specified nitrogen of connection, and 0, 1 or 2 are substituted by substitutes at the same or different substituted atoms, at that specified substitutes are selected from group that consists of -RY, -C(O)RY, -C0-4alkylCO2RY, -C0-4alkylC(O)NRYRZ, -C0-4alkylNRYC(O)Rz, -C0-4alkylNRYC(O)CH2ORY, -C0-4alkylNRYCO2RY, -C0-4alkylNRYC(O)NRYRz, -C0-4alkylNRyC(S)NRyRz, -NRyC(O)CO2Ry, -C0-4alkylNRwSO2RY, tetrazol-5-yl, -C0-4alkylN(RY)(SO2)NRYRY, -C0-4alkylN(RY)(SO2)NRYCO2RY, ii) (5-7)-member heterocyclic ring HetRc, where specified (5-7)-member heterocyclic ring has single additional heteroatom distanced from specified nitrogen of connection at least by one carbon atom, thereat the specified additional heteroatom is selected from group that consists of O, S(=O)0-2 and >NRM, and where mentioned (5-7)-member heterocyclic ring HetRc has 0 or 1 carbonyl group; iv) one of 2,8-diazaspyro[4.5]decan-1-on-8-yl, 4-{[(2-tret- butoxycarbonylaminocyclobutancarbonyl)amino]methyl}-piperidine-1-yl, 4-{[(2-aminocyclobutancarbonyl)amino]methyl}piperidine-1-yl, tret-butyl ether of 3,9-diazaspyro [5.5]undecan-3-carbonic acid-9-yl; where RK is selected from group that consists of H, -C1-4alkyl, each not necessarily substituted by 1 substitute RN; RM is selected from group that consists of -SO2RY, -C(O)RY, -C(O)C1-4alkylORY, each not necessarily substituted by 1 substitute RN; RN is selected from group that consists of OH, NH2, CF3; RQ is selected from group that consists of -C0-4alkylRAr', -C0-4alkylCO2RY, -C0-4alkylNRYRz, -C0-4alkylNRYCORY, -C0-4alkylNRyCONRyRz; Rw is selected from group that consists of RY and -C3-7cycloalkyl; RY is selected from group that consists of H, -C1-4alkyl, -C0-4alkylRAr and -C0-4alkylRAr', each not necessarily substituted by 1 substitute RN; Rz is selected from group that consists of RY, -C1-2alkylCO2RY; RAr represents fragment connected via carbon atom, and specified fragment is selected from phenyl, pyridyl; RAr' represents (5-6)-member cyclic ring, having 1 or 2 heteroatoms selected from group that consists of O, N and >NRY, having 0 unsaturated connections, having 0 or 1 carbonyl group, where each atom, when allows for valency, in every of mentioned cyclic rings is independently substituted by 0 or 1 RK; provided that (a) specified R2' and R3', moreover, satisfy the following requirements: (e1): specified R2' and R3', both, are not H, when Y represents O and X represents S; (e3): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperazine group, when X represents O and Y is one of O and CH2; (e4): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperidine group, which is mono-substituted by 6-member cyclic group, when X represents O and Y is one of O and CH2; and (e5): specified R2' and R3', taken together with nitrogen, with which they are connected, create neither substituted piperidine group or substituted piperazine group, where specified substituted piperidine group or specified substituted piperazine group is substituted in position 4 by substitute XG, at that specified XG has structure , where n=0, 1, and when ne=1, then XL represents C1-6alkyl, OSG represents O or S, and XR1 and XR2, taken together with nitrogen, with which they are connected, create one of piperidine group, piperazine group, morpholine group, thiomorpholine group and pyrrolidine group, or each of XR1 and XR2, taken independently, represent one of H, C1-6alkyl, aryl, aralkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, heteroalkyl, heteroaryl-C1-6alkyl, heterocycloalkyl and heterocycloalkyl-C1-6alkyl; where aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be not necessarily substituted by one or several substitutes, independently selected from halogen, hydroxy, C1-6alkyl, C1-6alkoxy, halogenated C1-6alkyl, halogenated C1-6alkoxy, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, heteroaryl or heterocycloalkyl; and (b) further provided that when X represents S and Y represents O, then one of R2' and R3' is not XCG, while the other represents C1-6alkyl, where XCG represents group , where HC16 represents one of H, C1-6alkyl, halogenC1-6alkyl, allyl and C1-6alcoxymethyl, and GO represents group connected to carbon atom, which has substitute =0, creating amido group with nitrogen, with which all mentioned GO group is connected.

EFFECT: compounds may find application for treatment and prevention of diseases mediated by LTA4H, for instance, asthma, chronic obstructive lung disease, atherosclerosis, rheumatoid arthritis, disseminated sclerosis, inflammatory disease of bowels and psoriasis.

39 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula (I), in which Ar represents group of formula (A), (B1), (B2) or (C), or (D1), or (D2); R1, R2, R3, R4, R5, n, A1, A2, A3, A4, A5, Ka, Kb, L, M, V, W, X, Y, Z havevalues, determined in i.1 of invention formula, fungicide composition and method of combatting phytopathogenic fungi or their elimination, using compounds of formula (I).

EFFECT: high fungicide activity.

22 cl, 142 tbl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. The compounds claimed by the invention have inhibition effect on VR1 receptor activation and can be applied in pain prevention or treatment. In the general formula (I) , or , L is a low alkylene, E cycle is benzene or 5-membered heteroaromatic ring containing sulfur atom as a heteroatom, D cycle is a monocyclic or bicyclic hydrocarbon cycle optionally condensed with C5-7 cycloalkyl, 6-membered monocyclic heteroaromatic cycle containing nitrogen atom as heteroatom or 9-11-membered bicyclic heteroaromatic cycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O, G cycle is a 5-7-membered monocyclic saturated or partially saturated heterocycle or 10-membered bicyclic heterocycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O. The invention also concerns pharmaceutical composition based on the said compounds, and application thereof in obtaining pain prevention or treatment medication, and a method of pain prevention or treatment.

EFFECT: obtaining prevention or treatment medium against pain.

24 cl, 470 ex, 41 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: invention is related to the compounds of general formula (I) and their pharmaceutically acceptable salts with properties β2-adrenoreceptor agonists, to the method of their production and based on them pharmaceutical composition. The compounds can be used for treatment of conditions when the symptomatic severity can be reduced by β2- adrenoreceptor activation, e.g., obstructive or inflammatory respiratory diseases. In the general formula (I) , X means -R1-Ar-R2 or -Ra-Y; Ar means phenylen, optionally substituted by group of the row: halogen, hydroxy, C1-C10alkyl, C1-C10alcoxy, phenyl, C1-C10 alcoxy, substituted by phenyl group or phenyl, substituted by C1-C10 alcoxy group; R1 and R2 are bound to the adjacent carbon atoms within Ar group, and either R1 means C1-C10alkylen, and R2 means hydrogen, C1-C10alkyl or halogen, Ra means the bond or C1-C10 alkylen optionally substituted by group of the row: hydroxy, C1-C10 alcoxy, C6-C10aryl or C7-C14aralkyl; Y means C1-C10alkyl, or C2-C10alkynil, optionally substituted by hydroxyl group, C3-C10cycloalkyl, optionally condensed with one or more benzene rings and optionally substituted by group of the row: C1-C10alkyl, C1-C10alcoxy, C3-C10cycloalkyl, C7-C14aralkyl, C7-C14aralkyloxy or C6-C10aryl, where groups C7-C14aralkyl, C7-C14aralkyloxy or C6-C10 aryl are optionally substituted by group of the row: halogen, C1-C10alkyl, C1-C10alcoxy; C6-C10aryl, optionally substituted by group of the row: halogen, hydroxy, C1-C10alkyl, C1-C10alcoxy, C1-C10halogenalkyl, phenoxy, C1-C10alkylthio, C6-C10aryl, 5-6-term saturated heterocyclic ring, containing one nitrogen atom in cycle; phenoxy, optionally substituted by C1-C10alcoxy group; 5-6-term heterocyclic ring, containing one or two nitrogen or oxygen atoms in cycle, and the described heterocyclic ring is optionally substituted by group of the row: C1-C10alkyl, C6-C10aryl, C7-C14aralkyl, C1-C10alcoxycarbonil or 5-7-term heterocyclil (C1-C10)alkyl, containing one nitrogen atom in cycle; -NRdRe, where Rd means hydrogen or C1-C10alkyl, and Re means C1-C10alkyl, or Re means C6-C10aryl, or Re means 5-6-term heterocyclic ring, containing one nitrogen or sulfur atom in cycle, and the ring is optionally substituted by halogen-substituted phenyl group or Re means C6-C10arylsypfonil, optionally substituted by groups C1-C10alkylamino or di(C1-C10alkyl)amino; -SRf, where Rf means C6-C10aryl or C7-C14aralkyl, optionally substituted by group of row: halogen or C1-C10halogenalkyl; or -CONHRg, where Rg means C6-C10aryl, provided, if Ra means the bond, then Y doesn't mean C1-C5alkyl.

EFFECT: compound can prevent or reduce symptom's intensity.

15 cl, 4 tbl, 157 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for synthesis of 2-cyano-6-methoxybenthiazole that is a key intermediate compound used in synthesis of luminescent biological systems, in particular, lupiferin. Method involves cyaniding reaction of 2-chloro-6-methoxybenzthiazole wherein acetonecyanohydrine is used as a cyaniding agent that is treated with alkaline metal alcoholate alcoholic solution, benzene is added and azeotropic mixture alcohol-benzene is distilled off followed by addition of dimethylsulfoxide and 2-chloro-6-methoxybenzthiazole. Method allows avoiding contact of workers with highly toxic cyanides and to obtain 2-cyano-6-methoxybenzthiazole with higher yield 50-50.8% as compared with the prototype (40%).

EFFECT: improved method of synthesis.

3 ex

The invention relates to amide derivative of the formula I

< / BR>
in which R3stands WITH1-C6alkyl or halogen; Q1denotes heteroaryl, which is optionally substituted by 1, 2, 3 or 4 substituents selected from the group comprising hydroxy, halogen, trifluoromethyl, cyano, amino, C1-C6alkyl, C2-C6alkenyl,2-C6quinil,1-C6alkoxy, etc., R2denotes hydroxy, halogen, C1-C6alkyl, C2-C6alkenyl,2-C6quinil,1-C6alkoxy, p = 0, 1, or 2; q = 0, 1, 2, 3 or 4; and Q2denotes aryl, aryl-C1-C6alkoxy, aryloxy, arylamino, N-C1-C6alkylamino, aryl-C1-C6alkylamino, cycloalkyl, heteroaryl, heteroallyl, heteroaryl-C1-C6alkylamino or heterocyclyl and so on, or its pharmaceutically acceptable salt or cleaved in vivo ester

The invention relates to a new derived benzothiazolone formulas I and II, where X denotes naphthyl and its pharmaceutically acceptable salts

The invention relates to new derivatives of benzothiazolone General formula I where X is-SO2NH - or-NНSО2-; p, q and r independently of one another represent 2 or 3; Y represents thienyl, optionally substituted C1-6by alkyl or halogen, or phenylthio or phenyl, optionally substituted C1-6by alkyl or halogen; each R independently represents H or C1-6alkyl; its optical isomers and pharmaceutically acceptable salts

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to otorhinolaryngology and can be used for treating sinusitis. That is ensured by the integrated treatment that includes ceftriaxone, 1 g of dry substance dissolved in 5 ml of 1% novocaine. Ceftriaxone solution is introduced in a single dosage of 0.5 ml on each side into a skin fold of wing of nose from the vestibule with an insulin needle of external diametre 0.25-0.35 mm.

EFFECT: invention provides higher clinical effectiveness and reduced treatment length due to a certain mode of the lymphotropic introduction of ceftriaxone that allows creating its depot in the immediate proximity from an involved organ with prolonged release into the paranasal sinuses in the therapeutic concentration.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is offered application of 5-biphenyl-4-yl-5-[4-(4-nitrophenyl)-piperazine-1-yl]pyrimidine-2,4,6-trione for preparation of a drug for treatment or prevention of inflammatory bronchial diseases.

EFFECT: higher clinical effectiveness in asthma, decrease in eosinophilia caused by allergen action.

2 cl, 5 tbl, 3 dwg, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is offered application of 5-biphenyl-4-yl-5-[4-(4-nitrophenyl)-piperazine-1-yl]pyrimidine-2,4,6-trione for preparation of a drug for treatment or prevention of inflammatory bronchial diseases.

EFFECT: higher clinical effectiveness in asthma, decrease in eosinophilia caused by allergen action.

2 cl, 5 tbl, 3 dwg, 6 ex

FIELD: medicine.

SUBSTANCE: rehabilitation of children with remitted chronic rhinosinusitis is ensured by the administration of Sinupret as a cytoprotector. The preparation is introduced by 25 drops 3 times a day, daily for 24-30 days. Rehabilitation is conditioned by ensured competence of nasal mucosa cells due to newly ascertained reparative ability of Sinupret, with local destructive processes of pavement and columnar epithelium cells and neutrophils be decreased.

EFFECT: higher rehabilitation effectiveness.

5 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel purine derivatives of general formula I in free form or in form of a pharmaceutically acceptable salt which have A2A agonist properties. In formula I , R1 denotes a N-bonded 5-6-member heterocyclic group containing 1-4 nitrogen atoms in the ring, which can be optionally substituted with oxo, phenyl or C1-8-alkyl, optionally substituted with hydroxy; R2 is hydrogen or C1-C8-alkyl, optionally substituted with hydroxy or 1-2 phenyls possibly substituted with hydroxy or C1-C8-alkoxy; R3 is C2-C8-alkynyl or C1-C8-alkoxycarbonyl, or R3 is amino substituted with C3-C8-cycloalkyl, optionally substituted with amino, hydroxy, benzyloxy or NH-C(=O)-NH-R6, or R3 is amino substituted with R4, -R4-benzyl or C5-C10-mono- or bicarbocyclic group, optionally substituted with hydroxy or C1-C8-alkoxycarbonyl, or R3 is aminocarbonyl optionally substituted with R5, or R3 is C1-C8-alkylamino optionally substituted with hydroxy, R5, NH-C(=O)-C1-C8-alkyl, -MH-SO2-C1-C8-alkyl, -NH-C(=O)-NH-R6 or phenyl, optionally substituted with phenyloxy, or R3 is a N-bonded 5-member heterocyclic group containing 1 nitrogen atom in the ring which may optionally be substituted with amino, C1-C8-alkylamino, di(C1-C8-alkyl)amino and other groups.

EFFECT: compounds can be useful in treating conditions mediated by activation of the adenosine A2A receptor, especially inflammatory or obstructive respiratory tract diseases.

9 cl, 5 tbl, 161 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel crystalline modifications of [6-methoxy-5-(2-methoxyphenoxy)-2-pyridin-4-ylpyrimidin-4-yl]amide-5-methylpyridine-2-sulfonic acid, which produces an endothelial antagonistic effect and is suitable for treating diseases associated with abnormal vascular tone and endothelial dysfunction, such as heart failure, pulmonary hypertension etc. The crystalline modification which is denoted modification B is characterised by a powder X-ray diffractogram with characteristic peaks expressed through the d-parametre value (interplanar distance) (Å) obtained on a conventional X-ray powder diffractometre using Cuka radiation: 10.7 (m), 9.4 (m), 8.6 (vs), 8.3 (m), 7.6 (m), 6.7 (m), 6.4 (m), 6.0 (m), 5.69 (m), 5.30 (m), 5.17 (m), 4.95 (vs), 4.76 (m), 4.56 (m), 4.43 (s), 4.13 (vs), 3.80 (s), 3.45 (s), 3.41 (s), 3.37 (s) and 3.03 (m). The invention also relates to crystalline pseudopolymorphous modifications of [6-methoxy-5-(2-methoxyphenoxy)-2-pyridin-4-ylpyrimidin-4-yl]amide-5-methylpyridine-2-sulfonic acid selected from: a) pseudopolymorphous modification, solvate with ethanol, denoted modification D; b) pseudopolymorphous modification, polysolvate with acetone, denoted modification E; c) pseudopolymorphous modification, solvate with tetrahyrofuran, denoted modification F; d) pseudopolymorphous modification, solvate with methanol, denoted modification G; e) pseudopolymorphous modification, solvate with isopropanol, denoted modification H; f) pseudopolymorphous modification, solvate with dichloromethane, denoted modification I; and g) pseudopolymorphous modification, solvate with 2-butanol, denoted modification J. The invention also relates to a method of obtaining crystalline modification B, a pharmaceutical composition and use.

EFFECT: wider field of use of the compounds.

8 cl, 9 dwg, 9 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel crystalline modifications of [6-methoxy-5-(2-methoxyphenoxy)-2-pyridin-4-ylpyrimidin-4-yl]amide-5-methylpyridine-2-sulfonic acid, which produces an endothelial antagonistic effect and is suitable for treating diseases associated with abnormal vascular tone and endothelial dysfunction, such as heart failure, pulmonary hypertension etc. The crystalline modification which is denoted modification B is characterised by a powder X-ray diffractogram with characteristic peaks expressed through the d-parametre value (interplanar distance) (Å) obtained on a conventional X-ray powder diffractometre using Cuka radiation: 10.7 (m), 9.4 (m), 8.6 (vs), 8.3 (m), 7.6 (m), 6.7 (m), 6.4 (m), 6.0 (m), 5.69 (m), 5.30 (m), 5.17 (m), 4.95 (vs), 4.76 (m), 4.56 (m), 4.43 (s), 4.13 (vs), 3.80 (s), 3.45 (s), 3.41 (s), 3.37 (s) and 3.03 (m). The invention also relates to crystalline pseudopolymorphous modifications of [6-methoxy-5-(2-methoxyphenoxy)-2-pyridin-4-ylpyrimidin-4-yl]amide-5-methylpyridine-2-sulfonic acid selected from: a) pseudopolymorphous modification, solvate with ethanol, denoted modification D; b) pseudopolymorphous modification, polysolvate with acetone, denoted modification E; c) pseudopolymorphous modification, solvate with tetrahyrofuran, denoted modification F; d) pseudopolymorphous modification, solvate with methanol, denoted modification G; e) pseudopolymorphous modification, solvate with isopropanol, denoted modification H; f) pseudopolymorphous modification, solvate with dichloromethane, denoted modification I; and g) pseudopolymorphous modification, solvate with 2-butanol, denoted modification J. The invention also relates to a method of obtaining crystalline modification B, a pharmaceutical composition and use.

EFFECT: wider field of use of the compounds.

8 cl, 9 dwg, 9 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I

in form of a salt, where R1 and R2 each independently denotes phenyl, where one or both R1 and R2 are substituted in one, two or three positions by the following groups: halogen, C1-C8alkyl or C1-C8alkoxy, and R3 is hydroxy, or R1 and R2 each denotes an unsubstituted phenyl, and R is hydrogen, C1-C8alkyl, C1-C8alkoxy or C1-C8alkylthio, or R1 is C3-C8cycloalkyl and R2 is phenyl or a 5-member heterocycle containing at least one heteroatom in the ring selected from a group which includes oxygen and sulphur, and R3 is hydroxy, or -CR1R2R3 denotes 9-hydroxy- 9H-fluoren-9-yl or 9-hydroxy-9H-xanthen-9-yl, and R4 is C1-C8alkyl substituted in one, two or three positions by a -CO-N(R5)R6 group, where R5 is hydrogen and R6 is a 5-member heterocycle containing at least one heteroatom in the ring selected from a group which includes nitrogen and oxygen, optionally substituted with phenyl, or R1 and R2 each denotes an unsubstituted phenyl, and R3 is hydroxy and R4 is C1-C8alkyl substituted in one, two or three positions by a -CO-N(R5)R6 group, where R5 is hydrogen and R6 is 5-methyl-3-isoxazolyl or R1 and R2 each denote unsubstituted phenyl, and R3 is hydroxy and R4 is 1-ethyl substituted in one, two or three positions by a -CO-N(R5)R6 group, where R5 is hydrogen, R6 is a 5-member heterocycle containing at least one heteroatom in the ring selected from a group which includes nitrogen and oxygen, provided that the formula I compound is not (R)-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-(pyrazin-2-ylcarbamoylmethy)-1-azoniumbicyclo[2.2.2]octane, (R)-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-azoniumbicyclo [2.2.2]octane bromide or (R)-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-(pyrimidin-4-ylcarbamoylmethyl)-1-azoniumbicyclo [2.2.2]octane bromide. The invention also relates to a pharmaceutical composition, to use of compounds in any of claims 1-8, as well as to methods for synthesis of formula I compounds.

EFFECT: obtaining new biologically active compounds which have M3 muscarinic receptor mediated activity.

14 cl, 254 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I , where: R1, R2, R3 and R4 independently from each other mean hydrogen, F, CI, Br, I; R5 designates hydrogen, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, or cycloalkyl with 3, 4, 5 or 6 C atoms; R6 designates hydrogen; R7 and R8 independently from each other mean hydrogen, W means CrH2r or CsH2S-2; and one or more CH2-groups in C2H2r and CsH2s-2 can be substituted with NR17, oxygen or S; R17 means hydrogen, alkyl with 1, 2, 3 or 4 C atoms; r means 1, 2, 3, 4, 5 or 6; s means 2, 3 or 4; X designates-with C(O)- or -S(O)2-; Z means -C(O)- or a bond; and also to their pharmaceutically acceptable salts and trifluoroacetates. The invention also concerns application of the compounds of formula I, and also to a pharmaceutical composition.

EFFECT: preparation of new biologically active compounds exhibiting NHE3 inhibiting activity.

16 cl, 64 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I , where: R1, R2, R3 and R4 independently from each other mean hydrogen, F, CI, Br, I; R5 designates hydrogen, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, or cycloalkyl with 3, 4, 5 or 6 C atoms; R6 designates hydrogen; R7 and R8 independently from each other mean hydrogen, W means CrH2r or CsH2S-2; and one or more CH2-groups in C2H2r and CsH2s-2 can be substituted with NR17, oxygen or S; R17 means hydrogen, alkyl with 1, 2, 3 or 4 C atoms; r means 1, 2, 3, 4, 5 or 6; s means 2, 3 or 4; X designates-with C(O)- or -S(O)2-; Z means -C(O)- or a bond; and also to their pharmaceutically acceptable salts and trifluoroacetates. The invention also concerns application of the compounds of formula I, and also to a pharmaceutical composition.

EFFECT: preparation of new biologically active compounds exhibiting NHE3 inhibiting activity.

16 cl, 64 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds, which possess qualities to estrogen modulators, of general formula (1) or its pharmaceutically acceptable salt, where R1 represents hydrogen atom or (C1-C6)alkyl, -SO2NR7R8, phenyl (C1-C3)alkyl or (C1-C3)alkyl, substituted with 5-8-member heterocyclic radical, containing nitrogen atom; R2 and R3 each independently represents hydrogen atom or hydroxyl, halogen atom or (C1-C6)alkoxy; X represents O, S, SO, SO2 or NR4; R4 represents hydrogen atom or (C1-C6)alkyl, phenyl, phenyl(C1-C3)alkyl, (C1-C3)alkyl, substituted with 5-8-member saturated heterocyclic radical, containing one nitrogen atom, or group -COR7, -CO2R7 or -SO2NR7R8, where phenyl is not substituted or is substituted with at least one substituent, selected from group which includes hydroxyl, halogen atom or phenyl(C1-C3)alkoxy; Y represents direct bond, -(CR10R11)n- or -R10C=CR11-; R7 and R8 each independently represents hydrogen atom or (C1-C6)alkyl group; R10 and R11 each independently represent hydrogen atom or cyano, or group CONR7R8; n equals 1 or 2; A represents (C3-C12)cycloalkyl or phenyl, where phenyl is not substituted or is substituted with at least one substituent, selected from group which includes hydroxyl, halogen atom, (C1-C3)alkyl, (C1-C3)alkoxy; when X represents NR4, Y and R2 together with containing them indazole cycle can also form 1H-pyrano[4,3,2-cd)indazole; on condition that: 1) when X represents O, S or NR4, R1 represents hydrogen atom or (C1-C6)alkyl, and Y stands for direct bond, then A is not optionally substituted phenyl; 2) when X represents O, R1O represents 6-OH or 6-OCH3, Y represents direct bond and A represents cyclopeptyl, then (R2, R3) or (R3, R2) are different from (H, CI) in position 4, 5; 3) when X stands for O, R1O represents 6-OH, R2 and R3 represent H, and Y represents CH=CH, then A is not phenyl or methoxyphenyl; 4) when X represents SO2, A represents phenyl and R1O represents 5-or 6-OCH3, then (R2, R3) or (R3, R2) are different from (H, OCH3) in position 6- or 5-, compound not being one of the following: 3-phenyl-5-(phenylmethoxy)-1H-indazole; n-hydroxy-3-phenylmethyl-7-(n-propyl)-benz[4,5]isoxazole; 3-(4-chlorphenylmethyl)-6-hydroxy-7-(n-propyl)-benz[4,5]isoxazole; 6-hydroxy-3-(2-phenylethyl)-7(n-propyl)-benz[4,5]isoxazole; 3-cyclopropyl-6-hydroxy-3-phenylmethyl-7-(n-propyl)-benz[4,5|isoxazole; 3-cyclohexylmethyl-6-hydroxy-3-phenylmethyl-7-propyl-benz[4,5]isoxazole. Invention also relates to pharmaceutical composition, application and method of prevention and treatment of disease, where modulation of estrogen receptors is required.

EFFECT: obtaining novel compounds, which possess qualities of estrogen receptors modulators.

18 cl, 7 dwg, 8 tbl, 97 ex

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