Derivatives dihydrobenzofuran, pharmaceutical composition and methods of treatment

 

(57) Abstract:

Describes derivatives of dihydrobenzofuran formula 1

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where (a) X is chosen from the group comprising O or S; (b) each Y is independently hydrogen or a straight or branched elkayam having from 1 to 4 carbon atoms; and (C) Z is a branched alkyl having from 3 to about 10 atoms other than hydrogen; (d) W is 0, and (e) R is a straight, branched or cyclic alkyl or aryl, saturated or monounsaturated, with a double bond, having from 1 to about 15 atoms other than hydrogen; pharmaceutical compositions comprising such compounds and methods of treating inflammation or pain, and arthritis using such compounds. 4 C. and 6 C.p. f-crystals, 2 PL.

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The technical field

The invention relates to non-steroidal anti-inflammatory drugs, particularly to substituted dihydrobenzofuran and related compounds.

Art

Discovered that certain compounds dihydrobenzofuran and other structurally related compounds have significant activity, facilitating disease. Such compounds, methods for their preparation and their use is inane, which have effective anti-inflammatory and/or analgesic effect.

Further, this invention relates to new compounds which have a small number of adverse side effects. Also, this invention is methods of treating inflammation and/or pain with use of the compounds of this invention.

Brief description of the invention

The object of the present invention are compounds having the structure:

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where (a) X choose their group comprising O, S, SO or SO2;

(b) each Y is independently hydrogen or straight, branched or cyclic elkayam having from 1 to 4 carbon atoms, or two Y associated with the formation of alkalising ring having from 3 to 7 carbon atoms;

(c) Z is a branched or cyclic alkyl having from 3 to about 10 atoms other than hydrogen;

(d) W is O or S; and

(e) R is a straight, branched or cyclic alkyl or aryl, saturated or mono - or dimensional with a double or triple bond, having from 1 to about 15 atoms other than hydrogen.

Detailed description of the invention.

In this case, if not specified otherwise, the term is rich, unsubstituted or substituted. Preferably the alkyl is a straight chain. Preferably, the branched alkyl has one or two side chains, preferably one side chain. Preferably, the cyclic alkyl is monocyclic, or a combination of straight chain and monocycle, especially a straight chain with a unicycle at the end. Preferably the alkyl is saturated. Unsaturated alkyl has one or more double bond and/or one or more triple bond. Preferably unsaturated alkyl has one or two double bonds or one triple bond, preferably one double bond. Preferably the alkyl is unsubstituted. Preferred substituted alkyl is mono-, di - or tizamidine, more preferably monosubstituted. Preferred alkyl substituents include halogen, hydroxy, oxo, alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, intoxi), aryloxy (for example, phenoxy, chlorophenoxy, tolyloxy, methoxyphenoxy, benzyloxy, allyloxycarbonyl, aryloxyphenoxy), acyloxy (for example, propionyloxy, benzoyloxy, acetoxy), carbamoylated, carboxy, mercapto, alkylthio, atillio, arieti (for example, phenylthio, chlorophenylthio, alkalinity, Alcock bonifer, halophenol), heterocyclyl, heteroaryl, amino (e.g. amino, mono - and di - C1-C3alkanolamine, methylphenylamine, methylbenzylamino), C1-C3alkanolamide, carbonamide, ureido, N'-allylurea, N, N'-dialkylamino, N N N-dialkylamide, guanidino, N'-alkylguanine, N', N",-dialkylamino or alkoxy carbonyl. Preferably alkali also include alkali having heteroatoms selected from the group comprising oxygen, sulfur, nitrogen, and combinations thereof.

In this case, the term "alkenyl" means a saturated alkyl.

In this case, the term "alkoxy" means-O-alkyl.

In this case, the term "terminal carbon atom" means a carbon atom in the alkyl chain, which is associated with only one atom other than hydrogen; the term "non-terminal carbon atom" means a carbon atom in the alkyl chain, associated with two or more atoms other than hydrogen.

In this case, the term "aryl" means a portion having unsubstituted or substituted aromatic ring having from 6 to about 10 carbon atoms. Preferably aryl is phenyl and naphthyl; more preferably aryl is phenyl. Preferably aryl is unsubstituted. Predpochtitelnye aryl substituents include alkyl, alkoxy, hydroxy, thiol, amino, halogen. Preferred alkyl substituents are methyl, ethyl and propyl.

In this case, the term "heterocyclyl" means a portion having a saturated or unsaturated non-aromatic ring containing from 3 to about 8 atoms in the ring including from 2 to about 6 carbon atoms and from 1 to about 4 heteroatoms, selected from O, S and N. Preferably, the heterocycle is saturated. Preferred heterocycles are 5 to 6 atoms in the ring, including 1-2 heteroatoms in the ring, more preferably 1 heteroatom in the ring. Certain preferred heterocycles include piperidinyl, tetrahydrofuranyl, pyrrolidinyl, piperazinil, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, imidazolidinyl, pyrazolidine, oxazolidine, isoxazolidine, oxadiazolidine, isothiazolinones, azepine, oxepin, diazolidinyl. Heterocycles are unsubstituted or substituted, preferably unsubstituted. Preferably the substituted heterocyclic compounds are mono-, di - or tizamidine, more preferably monosubstituted. Preferably the substituents of the heterocycle include alkyl, halogen, hydroxy, alkoxy, thio, amino, amido, ureido, guanidino, thiocarbanilide from 5 to 6 ring atoms, including from 1 to 5 carbon atoms and from 1 to 4 heteroatoms selected from O, S and N. Preferably heteroaryl have 1 or 2 heteroatoms in the ring, more preferably 1 heteroatom in the ring. Certain preferred heteroaryl include pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, isoxazolyl, pyranyl, thienyl, tetrazolyl, thiazolyl, isothiazolin, furyl, oxadiazolyl. Heteroaryl are unsubstituted or substituted, preferably unsubstituted. Preferably substituted heteroaryl are mono-, di - or tizamidine, more preferably monosubstituted. Preferably the substituents of heteroaryl include alkyl, halogen, hydroxy, alkoxy, thio, amino, amido, ureido, guanidino, thiocarbamide, touraid.

In this case, the term "halogen" means fluorine, chlorine, bromine or iodine. Preferably the halogen is fluorine, chlorine and bromine; more preferably is chlorine and bromine, especially chlorine.

This invention includes compounds having the following structure:

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In the above structure, X is O, S, SO or SO2. Preferably X is O or S, more preferably X is O.

In the above structure to about 4 carbon atoms, or Y are linked together form a cyclic alkylene ring, having from 3 to about 7 carbon atoms in the ring. Each Y is preferably hydrogen, stands, ethyl or cyclopropyl; more preferably hydrogen or stands; even more preferably the stands. If Y are linked together form a cyclic ring, the ring preferably is cyclopropyl, cyclobutyl or cyclopentyl, more preferably by cyclopropyl.

In the above structure, Z is chosen from the group comprising branched or cyclic alkyl having from 3 to about 10 atoms other than hydrogen. Z preferably is a branched elkayam having from about 4 to about 8 carbon atoms, more preferably from about 4 to about 6 carbon atoms. Z preferably is a branched elkayam having 2 or more side chains, more preferably 2 side chains. Preferably branched alkenyl Z includes tert-butyl, isopropyl, neopentyl; more preferably tert-butyl. Preferably cyclic alkenyl Z includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; more preferred is cyclopentyl.

In the above ilicheskom by alkyl or aryl, saturated or mono - or di-unsaturated double bonds, having from 1 to about 15 atoms other than hydrogen. Preferably, R has from 2 to about 9 atoms other than hydrogen; more preferably, R has from 3 to about 7 atoms other than hydrogen. Preferred substituents for R are alkyl, include hydroxy, thiol, amino, halogen, phenyl, carboxy, heterocycle and heteroaryl; more preferred include hydroxy, thiol, halogen, and a heterocycle; even more preferred are hydroxy and chlorine.

Preferably, R being alkyl with straight chain, are alkenyl, including methyl, ethyl, n-propyl and n-butyl. Preferably, R being alkyl with direct chain are unsubstituted or substituted; if substituted, they are preferably monosubstituted hydroxy or halogen, especially chlorine.

Preferably R is a branched alkyl chain, are alcalali, preferably having only alkalinous side chain, more preferably, only one methyl side chain. Preferably R, which elkayam branched chain are unsubstituted or substituted; if substituted, they are preferably apllication-alkyl, are alkanol, preferably cyclopropyl, cyclobutyl or cyclopentyl or C1-C4alkenyl with direct chain with limit cyclopropyl, cyclobutyl or cyclopentyl, preferably by cyclopropyl. Preferably R, which is the cyclic elkayam are unsubstituted.

Preferably R, which is the unsaturated alkyl, have a double bond, preferably between carbon atom associated with carbonylchloride atom and neighbouring terminal carbon atom. Preferably unsaturated R being alkyl are unsubstituted. Preferably unsaturated R being alkyl are straight chain or branched chain with a single side chain, preferably only one methyl side chain.

Preferred cyclic R, which aryl is phenyl or naphthyl, preferably phenyl. Preferably, the cyclic R are aryl are unsubstituted.

Preferred compounds of this invention include those which have the above-mentioned structure, where W is O and X, R, both Y and Z are as defined in the following table. 1.

With the aim of identifying and evaluating pharmaco is IR, well-known experts in this field. Anti-inflammatory effect of these compounds can be adequately demonstrated, using the methodology developed to test the ability of these compounds to anlagenservice local edema, which is characteristic of the inflammatory response. Examples of such well-known tests include Karagandy test for edema in rats, the test for inflammation, stimulated oxazolone on the ear of a mouse, and a test for inflammation caused by arachidonic acid to the ear of a mouse. Analgesic effect can be tested using well-known in this field models, such as phenylbenzophenone-enhanced spiral test in mice and test Randall &Selitto on rats. Other applicable test known in this field, is a test with adjuvant on arthritis in rats, which is used to evaluate anti-inflammatory action, anti-arthritis and protivosudorozhnogo steps in chronic, non-acute model.

These and other appropriate tests of pharmacological action described and/or shown as links in the link 2 (see the end of the description).

Many anti-inflammatory drugs, especially nested-intestinal tract, especially when administered orally; these side effects may include ulcers and erosion. These side effects, which are often asymptomatic, can become so severe that lead to hospitalization and even death. The compounds of this invention typically reduce such gastrointestinal side effects than other NSAIDs. Some compounds of this invention are even protective for the gastrointestinal tract, protecting the stomach and intestinal ulcers and erosions, especially those that are a consequence of the use of ethanol and other NSAID.

Certain NSAID, the systematic introduction lead to undesirable increase in the overall levels of certain liver enzymes. The compounds of this invention typically have small or have no adverse effect on liver enzymes.

The compounds used in this invention can be obtained according to the General scheme 1 reaction.

Scheme 1 R, Y, and Z are such as defined above. Substituted phenols listed as the parent compound in scheme 1 are either known, commercially available or are readily obtained by methods known to experts in Dan. For example, 2,4-dibromo-6-tert-butylphenol is produced by interaction of 2-tert-butylphenol with bromine in MeOH.

Allilirovanie such brominated substituted phenols by allergologicum shown in the stage 2 scheme 1. Allylchloride, such as 4-bromo-2-methyl-2-butene, 5-bromo-3-ethyl-3-penten or cyclopentanemethanol interact with suitable bronirovannymi substituted phenols, using reaction conditions known to any expert in the field of organic chemistry. For example, 4-bromo-2-methyl-2-butene interacts with the substituted phenol in the presence of potassium carbonate and a catalytic Tetra-n-butyl ammonium iodide in acetone with obtaining relevant arilirovaniya connections.

Arilirovaniya connection cyclist getting dihydrobenzofuran via respective intermediate alcohols. After lithium halogen exchange of 2-bromo group with subsequent proton treatment, oxymercuration acetate mercury and sodium borohydride gives the corresponding alcohols. Circuit alcohols to dihydrobenzofuran can be achieved by using various Lewis acids. The use of aluminum chloride in nitromethane shown above. Remove the remaining substituents bromine Mogami, such as palladium on coal or lithium halogen exchange followed by quenching a proton source such as water.

The compounds of this invention are obtained from compounds with condensed ring obtained in one of several ways. The acylation of such compounds with condensed ring of a corresponding carboxylic acid, as shown, can be achieved under the reaction conditions known to a person skilled in this field. For example, this reaction can be carried out as such (without solvent) or in an inert halogenated solvent such as CH2Cl2using an activating agent such as an anhydride triperoxonane acid at a suitable temperature. Alternatively, the same transformation can be achieved using the acid chloride of the acid obtained from a suitable organic carboxylic acid by well-known methods, and as a catalyst, a Lewis acid such as aluminum chloride. Usually suitable organic carboxylic acids, necessary for this reaction, known, commercially available or can be easily obtained by a specialist in this field.

Scheme 2 represents a synthesis of these compounds, where Y = N. As a researcher is propane gives tribromophenoxy ether. Ring closure and removal of the 4-bromo group is achieved at a single stage, using an excess of utility. Phase acylation is carried out as shown in scheme 1.

Scheme 3 shows the synthesis thiochroman with the Z group in position 8. Source substituted thiophenol alkylate 4-bromo-2-methyl-2-butene and received tiefer close to the ring of phosphoric acid and pjatiokisi phosphorus. Substituted thiochroman acelerou by conventional methods, for example, the interaction with the acid chloride of the acid and tin tetrachloride.

The following not limiting the scope of the invention, the examples provide further information relating to the synthesis of compounds of this invention.

Example 1

1-(8-tert-butyl-4,4-dimethyl-2,3-dihydrobenzofuran-6-yl)-1-pentanone

2,4-dibromo-6-tert-butylphenol.

In a 2 liter three-neck flask equipped with an inlet for Ar, reflux condenser, addition funnel and a powerful magnetic stirrer, was placed 2-tert-butylphenol (150.2 g, 1.00 mol) and MeOH (300 ml). Stir the solution is cooled in an ice bath, adding dropwise undiluted Br2(321.6 g, 2.01 mol, 2.01 equiv.) for more than 0.5 hours. (Caution: this reaction is exothermic is 2 hours. The reaction mixture was transferred into a 1 liter chemical beaker with 20 ml of washing, the reaction flask. The red solution hardens quickly in bright orange crystalline mass. The crystalline mass is re-dissolved by heating on the steam bath and then add a solution of Na2S2O5(1.45 g, 5.4 mmol) in 40 ml of H2O, followed by immediate addition of fresh MeOH (60 ml). The resulting suspension is again heated on the steam bath for 10 minutes (the mixture does not dissolve again) and then vigorously stirred until it cooled to room temperature. After 0.5 h, the yellow color disappears almost completely and are precipitated crystals weak orange-white. Their is filtered and dried in a stream of air to obtain the desired compound in the form of plates weak orange-white in color.

2,4-dibromo-6-tert-butyl-1-(2-butylene-3-methyl)benzene.

To a solution of 2,4-dibromo-6-tert-butylphenol (10.00 g, 32.5 mmol) in ethanol (50 ml) add K2CO3(6.73 g, 48.7 mmol, 1.5 equiv.) a catalytic amount of h-Bu4NI and 4-bromo-2-methyl-2-butene (5.80 ml, 39.0 mmol, 1.2 EQ.). The resulting suspension is stirred at room temperature for 48 hours, filtered and concentrated. The remainder of the PTS is I (12.40 g, 100%) as oil.

4-bromo-2-tert-butyl-1-(2-butenyloxy-3-methyl)benzene

To a cooled (-78oC) a solution of 2,4-dibromo-6-tert-butyl-1-(3-methyl-2-butenyloxy) benzene (12.47 g, 33.15 mmol) in THF/hexane (100 ml/25 ml) added dropwise n-BuLi (13.3 ml, 2.5 M/hexane, 33.15 mmol, 1.0 EQ.). The obtained pale-yellow solution is stirred at a temperature of -78oC for 15 minutes and the reaction quenched by slow addition of water, diluted with hexane and washed with water followed by washing with brine. The aqueous layers are extracted with hexane, the combined organic layers are dried (MgSO4), filtered and concentrated. The residue is purified using flash column-chromatography with silica (hexane) to obtain the target compound (9.35 g, 95%) as oil.

4-bromo-2-tert-butyl-1-(3-hydroxy-3-methylbutoxy)benzene.

To the yellow suspension Hg(OAc)2(6.36 g, 19.94 mmol, 1.0 EQ.) in THF/water (25 ml/30 ml) added dropwise 4-bromo-2-tert-butyl-1-(2-butenyloxy-3-methyl) benzene (5.93 g, 19.94 mmol) in THF (5 ml) and stirred at room temperature for 4 hours. To the resulting pale yellow solution was added NaOH (15 ml, 3M), followed by addition of NaBH4(0.75 g, 19.94 mmol, 1.0 equiv. ) in NaOH (5 ml, 3M). The resulting suspension PE the DOI, saturated aqueous NH4Cl and brine. The aqueous layers are extracted with hexane; the combined organic layers are dried (MgSO4), filtered and concentrated. The residue is purified using flash column-chromatography with silica (hexane/EtOAc; 10/1--->3/1) to obtain the target compound (4.21 g, 67%) as oil.

6-bromo-8-tert-butyl-4,4-dimethyl-2,3-dihydrobenzofuran

To a cold (0oC) suspension AlCl3(1.67 g, 12.51 mmol, 1 EQ.) in nitromethane (20 ml) add a solution of 4-bromo-2-tert-butyl-1-(3-hydroxy-3-methylbutoxy)benzene (3.94 g, 12.51 mmol) in nitromethane (5 ml). The obtained red solution is stirred at a temperature of 0oC. After 1 hour the reaction is stopped by the slow addition of water, diluted with hexane and washed with water and brine. The aqueous layers are extracted with hexane; the combined organic layers are dried (MgSO4), filtered and concentrated. The residue is purified using flash column-chromatography with silica (hexane) to obtain the target compound (2.87 g, 77%) as a solid, which is recrystallized using hexane to obtain white crystals.

8-tert-butyl-4,4-dimethyl-2,3-dihydrobenzofuran

To a cold (-78oC) a solution of 6-bromo-8-ml, 2.5 M/hexane, 9.26 mmol, 1.2 EQ.). The obtained pale - yellow solution is stirred for 30 minutes at a temperature of -78oC and the reaction stopped by the slow addition of water, diluted with hexane and washed with 1N HCl, water and brine. The aqueous layers are extracted with hexane; the combined organic layers are dried (MgSO4), filtered and concentrated. The residue is purified using flash column-chromatography with silica (hexane) to obtain the target compound (1.60 g, 95%) as a solid, which is recrystallized using hexane, to obtain white crystals.

1-(8-tert-butyl-4,4-dimethyl-2,3-dihydrobenzofuran-6-yl)-1-pentanone.

To undiluted 8-tert-butyl-4,4-dimethyl-2,3-dihydrobenzofuran (0.40 g, 1.83 mmol) is added pentane acid (0.20 g, 1.93 mmol, 1.05 equiv.) and triperoxonane anhydride (0.28 ml, 2.02 mmol, 1.1 EQ). The obtained red solution was stirred at room temperature for 2 hours, diluted with hexane and washed with water (2x) and brine. The aqueous layers are extracted with hexane; the combined organic layers are dried (MgSO4), filtered and concentrated. The residue is purified using flash column-chromatography with silica (hexane, hexane/EtOA is A.

Using essentially the last stage of the methodology of example 1 (and making the appropriate substitution of the corresponding carboxylic acid) are obtained the following compounds in examples 2 and 5.

Example 2

1-(8-tert-butyl-4,4-dimethyl-2,3-dihydrobenzofuran-6-yl)-4 - cyclopropyl-1-butanone: yield 83%, oil.

Example 3

1-(8-tert-butyl-4,4-dimethyl-2,3-dihydrobenzofuran-6-yl)-3 - hydroxy-3-methyl-1-butanone.

1-(8-tert-butyl-4,4-dimethyl-2,3-dihydrobenzofuran-6-yl) - 1-Etalon.

To a suspension of AlCl3(0.32 g, 2.39 mmol, 1.2 EQ.) in CH2Cl2(6 ml) add acetylchloride (0.15 ml, 2.19 mmol, 1.1 EQ.). The resulting suspension is stirred at room temperature for 5 minutes and cooled to -78oC. is added dropwise a solution of 8-tert-butyl-2,3-dihydro-4,4-dimethylbenzofuran (0.44 g, 1.99 mmol) in CH2Ck2(2 ml). After complete addition, the reaction mixture was stirred at -78oC for 2 hours and then the reaction stopped by slow addition of water at -78oC. the resulting suspension allowed to warm to room temperature, diluted with hexane and washed with water (2x) and brine. The aqueous layers are extracted with hexane; the combined organic layers are dried (MgSO4), filtered and con the Ac; 20/1) to give the solid, which is recrystallized using hexane, to obtain the target compound (0.40 g, 76%) as a white solid.

1-(8-tert-butyl-4,4-dimethyl-2,3-dihydrobenzofuran-6-yl)- 3-hydroxy-3-methyl-1-butanone.

To a cold (-78oC) solution of 1-(8-tert-butyl-4,4-dimethyl-2,3-dihydrobenzofuran-6-yl)-1-ethanone (0.35 g, 1.36 mmol) in CH2Cl2(3.0 ml) was added dropwise TMSOTf (0.32 ml, 1.63 mmol, 1.2 EQ.) and (ISO-Pr)2NEt (0.28 ml, 1.63 mmol, 1.2 EQ.). Received the red mixture is stirred at a temperature of -78oC for 30 minutes and then she is allowed to warm to room temperature over 1 hour. The obtained pale-red solution is re-cooled to -78oC and added dropwise acetone (0.12 ml, 1.63 mmol, 1.2 EQ.) and TiCl4(0.15 ml, 1.36 mmol, 1.0 EQ.). The resulting deep red solution allowed to warm to room temperature over 3.5 h and 0.5 N HCl and the mixture is stirred for 30 minutes. The reaction mixture was diluted with hexane and washed with water and brine. The aqueous layers are extracted with hexane; the combined organic layers are dried (MgSO4), filtered and concentrated. The residue is purified using column flash chromatograph solids, which is recrystallized using pentane so pl. 92-98oC.

Example 4

1-(8-tert-butyl-2,3-dihydrobenzofuran-6-yl)-3-hydroxy-3 - methyl-1-butanone.

1,5-dibromo-2-(3-bromopropionic)-3-tert-butylbenzoyl.

To pale brown solution of 2,4-dibromo-6-tert-butylphenol (5.00 g, 16.24 mmol) in acetone (70 ml) is added 1,3-dibromopropane (3.30 ml, 32.47 mmol, 2 EQ. and K2CO3(6.70 g, 48.72 mmol, 3 EQ.) and refluxed. After 14 hours the mixture is filtered, concentrated and the residue purified using flash column-chromatography with silica (hexane) with a white oil, which is subjected to distillation on a Kugelrohr to obtain the target compound (6.13 g, 88%) as a pale yellow oil.

8-tert-butyl-2,3-dihydrobenzofuran.

To a cold (-95oC, MeOH/Et2O fluid. N2) to a solution of 1,5-dibromo-2-(3-bromopropionic)-3-tert-butylbenzene (5.00 g, 11.66 mmol) in THF/hexane (100 ml/20 ml) added dropwise utility (11.60 ml, 29.14 mmol, 2.5 EQ.) and allowed to mix at -95oC for 30 min and heated to -80oC. After 4 hours the reaction mixture was poured into saturated NH4Cl, extracted with EtOAc and washed with water (2x) and brine. The aqueous layers are extracted with the using flash column-chromatography with silica (hexane) with a white oil, which is subjected to distillation on a Kugelrohr to obtain the target compound (1.92 g, 87%) of a white oil.

1-(8-tert-butyl-2,3-dihydrobenzofuran-6-yl)-1-Etalon.

To a suspension of AlCl3(0.54 g, 4.05 mmol, 1.1 EQ.) in CH2Cl2(20 ml) add acetylchloride (0.28 ml, 4.05 mmol, 1. 1 EQ.). The resulting suspension is stirred at a temperature of -78oC for 30 minutes and added dropwise a solution of 8-tert-butyl-2,3-dihydrobenzofuran (0.70 g, 3.68 mmol) in CH2Cl2(5 ml), using an additional funnel. After complete addition, the reaction mixture (pale yellow precipitate) allowed to warm to room temperature over 4 h, the resulting suspension is cooled to 0oC and the reaction stopped by the slow addition of water, washed with water and brine. The aqueous layers extracted with CH2Cl2; United

the organic layers are dried (MgSO4) filtered and concentrated. The obtained white solid is recrystallized using hexane, to obtain the target compound (0.67 g, 79%) as white crystals.

1-(8-tert-butyl-2,3-dihydrobenzofuran-6-yl)-3-hydroxy-3-methyl - 1-butanone.

To a cold (-78oC) solution of 8-tert-butyl-2,3 - dihydrobenzofuran-6-yl)-1-Etalon ml, 2.31 mmol, 1.2 EQ.). The obtained pale yellow mixture is stirred at a temperature of -78oC for 15 minutes and then she is allowed to warm to room temperature over 1 hour. The obtained colorless solution was re-cooled to -78oC and added dropwise acetone (0.17 ml, 2.31 mmol, 1.2 EQ.) and TiCl4(0.21 ml, 1.93 mmol. 1.0 EQ.). The resulting deep red solution allowed to warm to room temperature over 2 h and add 1 N HCl and the mixture is stirred for 30 minutes. The reaction mixture was diluted with CH2Cl2and washed with water and brine. The aqueous layers extracted with CH2Cl2; the combined organic layers are dried (MgSO4), filtered and concentrated. The residue is purified using flash column-chromatography with silica (hexane, hexane/EtOAc; 10/1, 8/1, 4/1) to give crude oil, which is subjected to distillation to obtain the target compound (0.40 g, 72%) as a colourless oil.

Example 5

1-(8-tert-butyl-2,3-dihydrobenzofuran-6-yl)-3 - methyl-2-butane-1-he (or 1-(8-tert-butelman-6-yl)-3-methyl-2-butene-1-he).

< / BR>
To clean 8-tert-butylamino (1,00 g of 5.26 mmol) is added 3,3-dimethylacrylic acid (0.55 g, 5,52 mmol, of 1.05 equiv.) and triflora is for 4 h, diluted with EtOAc and washed with saturated NaHCO3, water and brine. The aqueous layers extracted with EtOAc, the combined organic layers are dried (MgSO4), filtered and concentrated. The residue is purified flash chromatography on silica (hexane, hexane/EtOAc; 10/1) to give crude oil, which is distilled, obtaining the title compound (0,845 g, 60%) as a colourless oil.

Molecular weight: 272,386

So Kip.: 138-141oC (0.5 mm RT.CT.)

1H NMR (CDCl3, 500 MHz): of 7.75 (d, J = 2.4 Hz, 1H), 7,54 (d, J = 1.5 Hz, 1H), 6,69 (t, J = 1.2 Hz, 1H), 4.26 deaths (t, J = 5.3 Hz, 2H, OCH2), 2,85 (t, J = 6.6 Hz, 2H, ArCH2), of 2.16 (d, J = 1.2 Hz, 3H, CH3), 2,02 (m, 2H), 2,00 (d, J = 1.2 Hz, 6N, 2XCH3), to 1.38 (s, N, (CH3C).

13C (CDCl3, 125 MHz): 191,0 (CO), 157,8 (C), 137,7 (C) 130,5 (C), 128,9 (CH), 125,1 (CH), 121,9 (C), 121,4 (CH), 66,2 (OCH2), 34,8 (C) AND 29.5 (CH3), WHILE 27.8 (CH2), 25.4MM (CH3), 21,9 (CH3), TO 20.9 (CH2)

IR (KBr, cm-1): 2953 (m), 2913 (m), 2872 (m), 1656 (m), 1570 (w), 1440 (m), 1230 (m), 734 (w)

Rf: 0,30 (10/1; hexane/EtOAc)

Example 6

1-(8-tert-butyl-2,3-dihydrobenzofuran-6-yl)-3-chloro-3-methyl-1-butanone or 1-(8-tert-butelman-6-yl)-3-chloro-3-methyl-1-butanone).

< / BR>
Through a solution of 1-(8-tert-butelman-6-yl)-3-methyl-2-butene-1-she (and 0.62 g of 2.26 mmol) in Et2O (10 ml) for 15 min, bubbled gazoobraznym. Received whitish oil purified flash chromatography on silica (hexane, hexane/EtOAc; 10/1) to give crude oil, which is distilled, obtaining the title compound (0,425 g, 61%) as a pale yellow oil.

Molecular weight: 308,847

1H NMR (CDCl3, 500 MHz) to 7.77 (d, J = 2.0 Hz, 1H), 7,56 (d, J = 2.0 Hz, 1H), 4,28 (t, J = 5.0 Hz, 2H, OCH2), of 3.46 (s, 2H, OCCH2), of 2.86( t, J = 6.5 Hz, 2H, ArCH2), 2,02 (m, 2H), 1,81 (s, 6N, HSR3), to 1.38 (s, N, (CH3C)

13C NMR (CDCl3, 125 MHz): 195,7 (CO), 158,6 (C) 138,0 (C), to 129.2 (CH), 128,9 (C), 125,2 (CH), 122,1 (C) 68,5 (C), 66,3 (OCH2), 51,7 (OCCH2), 34,9 (C) 32,5 (CH3) AND 29.5 (CH3), 25.4MM (CH2, 21,9 (CH2)

IR (KBr, cm-1): 2953 (m), 2912 (m), 2872 (w), 1656 (s), 1615 (m), 1580 (m), 1440 (m), 1231 (s), 1147 (s), 1014 (m)

Rf: 0,42 (10/1; hexane/EtOAc)

Example 7

8-tert-butyl-4,4-dimethyl-6-(1-oxobutyl)thiochroman

2-tert-butylphenyl 1-(3'-methylbut-2'-enyl)sulfide:

2 g (69 mmol) of 80% dispersion of sodium hydride in mineral oil is washed twice with hexane in a nitrogen atmosphere. To this add 20 ml of anhydrous tetrahydrofuran. The mixture is cooled to 0oC. Separately, 10 g (60 mmol) of 2-tert-butylthiophenol dissolved in 60 ml of tetrahydrofuran. This solution is added slowly to a mixture of sodium hydride. Mixture is allowed to mix for 40 min the and. The mixture is stirred for 30 minutes at 0oC and for 15 minutes at room temperature. The reaction mixture is diluted with 500 ml ether and washed with 1 M NaOH. The organic layers dried over sodium sulfate and concentrated under reduced pressure to obtain 13.5 g (96% yield) of 2-tert-butylphenyl 1-(3'-methylbut-2'-enyl) sulfide in the form of a reddish-brown liquid, which is used without further purification.

8-tert-butyl-4,4-dimethylthiochroman: 11 g (47 mmol) of 2-tert-butylphenyl-1-(3'-methylbut-2'-enyl) sulfide and 8.25 g (71.6 mmol) of 85% H3PO4in 110 ml of benzene was stirred at the boil under reflux for 16 hours. Then, after 8 hours boiling under reflux the mixture was added 3 servings P2O5on 5.5 g (116 mmol) each. Next, the reaction mixture is stirred at the boil under reflux for another 16 hours. The mixture is allowed to cool to room temperature. The solution is decanted from the red residue in 10% sodium chloride solution in a separating funnel. The residue is washed with ether and 10% sodium chloride and both of these washings added to the separating funnel. The product is extracted into benzene/ether layer washed again with brine. The organic layers dried over sodium sulfate and concentrate the l-4,4-dimethyl-6-1-oxobutyl)-thiochroman:

To 500 mg (2.1 mmol) of 8-tert-butyl-4,4-dimethylthiochroman and 0.29 ml (2.34 mmol) pentanoyl chloride in 10 ml of benzene at 0oC add 0.27 ml (2.34 mmol) of tin tetrachloride. The reaction mixture is stirred for 1 hour at 0oC and then diluted with ether and washed with water and 10% sodium chloride. The product was then purified using flash column-chromatography, elwira hexane: ethyl acetate in a ratio of 7:3, to obtain 250 mg (37% yield) of the target compound.

Example 8

8-tert-butyl-4,4-dimethyl-6-(1-oxo-1-(3 - tetrahydrofuryl) methyldibromo

To 600 mg (2.56 mmol) of 8-tert-butyl-4.4-dimethylthiochroman and 0.38 g (2.84 mmol) chloride()tetrahydro-3-frankenboob acid (which is produced by the interaction of 1.5 g (12.9 mmol) () tetrahydro-3-frankenboob acid with 1.38 ml (15.5 mmol) of oxalyl chloride in 40 ml of benzene at 50oC for 1 hour, followed by concentration of volatile compounds under reduced pressure) in 10 ml of benzene at 0oC added 0.32 ml (2.73 mmol) of tin tetrachloride. The reaction mixture is stirred for 1 hour at 0oC and then diluted with ether and washed with water and sodium chloride. The product was then purified using flash column-chromatography, diluting with hexane:ethyl acetate in the ratio 7:
8-tert-butyl-4,4-dimethyl-6-(1-oxo-1-(3-tetrahydrofuryl)) thiochroman.

To 590 mg (2,52 mmol) of 8-tert-butyl-4,4-dimethylthiochroman and 370 mg (2,75 mmol) of acid chloride of 3-tetrahydrofuranate acid in 10 ml of benzene at 0oC type of 0.32 ml (2,75 mmol) of tin tetrachloride. The reaction mixture is stirred for one hour at 0oC. Thin layer chromatography shows the presence of mainly one more polar product with a small amount of other impurities. To the reaction mixture, water is added and the mixture is stirred. The product is extracted with ether. Flash chromatography gives 0,2088 g of product, representing a viscous oil. Recrystallization from methanol gives 0,70 mg of product.

Elemental analysis, %: Calculated C 72,46; H 8,21

Found C 71,95 H 8,42

The compositions of this invention comprise a safe and effective amount of the compounds of this invention and a pharmaceutically acceptable carrier. In this case, "safe and effective amount" means an amount of compound sufficient for a significant increase in positive changes in the condition being treated, and low enough to avoid any serious side effects (at a reasonable sootnositel to vary depending on the specific treat the condition, age and physical condition, treat the patient, the severity of the condition, the duration of treatment, the nature of the accompanying therapy, specific pharmaceutically acceptable carrier and the like factors within the knowledge and expertise of the treating physician.

The compositions of this invention preferably include from about 0.1% to about 99.9 wt. % concentration, more preferably from about 20% to about 80%, and most preferably, from about 40% to about 70%. In addition to compounds, compositions of this invention contain a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" means one or more compatible solid or liquid diluents or substances in a gelatin capsule, which is suitable for administration to a human or lower animal. The term "compatible" in this case means that the components of the composition is able to be mixed with the compound of this invention and with each other so that there are no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use. Pharmaceutically acceptable carriers must, of course, to have a fairly high degree cassim animals.

Some examples of substances which can serve as pharmaceutically acceptable carriers or their components are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate; powdered tragant; malt; gelatin; talc; solid lubricants, such as stearic acid, magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cotton seed, hemp oil, olive oil, corn oil, and cocoa butter; polyols, such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers, such as Tweensmoisturizing agents such as sodium lauryl sulfate; coloring agents; fragrances; fillers; tabletiruemye agents; antioxidants, preservatives; buspirona water; isotonic saline; and phosphate buffer solutions.

The choice of pharmaceutically acceptable carrier used together with the compound of the present invention is mainly determined by way of introduction connections.

If this connection whitesky acceptable carrier is sterile saline solution, compatible with blood suspendium agent, the pH of which is adjusted to about 7.4. Such compositions for parenteral administration preferably contain from about 1% to about 50% of the compound of the present invention, more preferably from about 5% to about 25%, also preferably from about 10 mg to about 600 mg of the compound of this invention per dose.

Suitable pharmaceutically acceptable carriers for topical application include those that are suitable for use in lotions, creams, gels and the like. Compositions for topical application preferably contain from about 1% to about 50% softening substance, more preferably from about 5% to about 25% softening agents such compositions for topical application preferably comprise from about 0.1% to about 50% of the compound of the present invention, more preferably from about 0.5% to about 10%, also preferably from about 5 mg to about 1000 mg per dose.

The preferred method of introducing the compounds of this invention is oral administration. Therefore, the preferred unit dosage form are tablets, capsules and the like, containing a safe and effective amount of a compound, which, the most preferably from about 25 mg to about 600 mg

The main part of the compounds of this invention are hydrophobic. If it is desired to obtain a composition based on water or the composition is soluble or miscible with the aqueous medium, the composition may be included solubilizers agent. Non-limiting examples of such solubilizing agents include polyethylene glycol, propylene glycol, ethanol and polyoxyethylene (35) castor oil.

Particularly preferred carriers for oral compositions for compositions of this invention are disclosed in U. S. Patent Nos. 5189066 of Kelm&Bruns, published February 23, 1993, entitled "Pharmaceutical Compositions of Tebufelone and 5281420 of Keim&Dobrozsi, published January 25, 1994, entitled "Solid Dispersion Compositions of Tebufeione", which is included here as a reference.

Another aspect of the present invention are methods of treatment or prevention of diseases characterized by inflammation, the introduction of safe and effective amount of the compounds of this invention to a human or lower animal in need of such treatment. The term "disease characterized by inflammation" in this case means a painful condition that involves inflammation and Moguchy arthritis, juvenile arthritis, Reiter syndrome, infectious arthritis and ankylosis spondylitis, systemic lupus erythematous, and gout), and the presence of inflammation, associated or not with a certain disease. The disease, characterized by inflammation, then you can include inflammation in the oral cavity (e.g., inflammation associated with gingivitis or periodontal disease); inflammation in the gastrointestinal tract (e.g., inflammation associated with ulcers and irritation of the bowel); inflammation associated with skin diseases (e.g. psoriasis, acne and other skin inflammation); inflammation associated with respiratory tract (e.g., asthma, bronchitis and allergies); and inflammation of the Central nervous system (for example, Alzheimer's disease).

Another aspect of the present invention are methods of treatment or prevention of pain, including the introduction of safe and effective amount of the compounds of this invention to a human or lower animal in need of such treatment. Pain that can be treated or prevented by the introduction of the compounds of the present invention may include peripheral pain, menstrual pain, toothache and pain in the lower back.

Another aspect of davidina safe and effective amount of the compounds of this invention to a human or lower animal in need of such treatment. If not limited to a particular mechanism, suppose that the compounds of this invention inhibit the synthesis of leukotrienes, reducing, thus, the accumulation of neutrophils at the site of inflammation.

Another aspect of the present invention are methods of treatment or prevention of gastric or duodenal ulcers or erosions involving the introduction of a safe and effective amount of the compounds of this invention to a human or lower animal in need of such treatment. In particular, such an ulcer or erosion caused by ethanol or non-steroidal anti-inflammatory drugs (NSAID) can be cured or prevented their formation by the introduction of preferred compounds of this invention.

Appropriate tests to determine gastrointestinal safety or protective for gastrointestinal properties of the compounds of this invention are known.

How to determine significant gastrointestinal safety disclosed and/or marked as links in the link 3 (see end of description).

In the disclosed here are methods stomachs of animals usually check two hours after administration of the compound. Ways to determine podpisany).

Methods for determining acute gastroprotective disclosed and/or marked as references in the reference 5 (see the end of the description).

In the here described method females Lewis rats (130 - 175 g) orally administered the compound of the present invention (40 mg/kg n/d) or filler for two hours and immediately before the introduction of dangerous gastric dose of indomethacin. Rats were killed after 4 hours asphyxiation CO2. Damage gastritis housing (millimeters hemorrhagic lesions) was measured with a digital reflection.

The preferred method of administration of the compounds of this invention is oral administration, but takes into account other ways of introducing, for example, the introduction to the skin and mucous membranes (for example, skin, rectal, and the like) and parenteral (e.g. subcutaneous injection, intramuscular injection, intra-articular injection, intravenous injection and the like). Also included is an introduction to the eyes and inhalation. These specific routes of administration include, but are not limited to, oral, transcutaneous, introduction to the mucosa, sublingual, intranasal, intravenous, intraperitoneal, subcutaneous and local introduction.

Predpochtiteljno from about 0.5 mg/kg to about 12 mg/kg The preferred dose for injection is from about 0.1 mg/kg to about 10 mg/kg of the compounds of this invention. Preferred doses for local administration are from about 1 mg/cm2to about 200 mg/cm2the compounds of this invention applied to the skin surface. Preferred doses for oral administration comprise from about 0.5 mg/kg to about 50 mg/kg, more preferably from about 1 mg/kg to about 20 mg/kg, even more preferably from about 2 mg/kg to about 10 mg/kg of the compounds of this invention. Such dose is preferably administered from one to six times per day, more preferably from two to about four times a day. Such a daily dose is preferably administered at least one week, also preferably at least 1 month, preferably at least 2 months, preferably at least 6 months, 1 year, 2 years or more.

The following examples illustrate, but not limit, the invention.

An example of A

Pharmaceutical composition in tablet form, obtained by the usual methods, such as mixing and direct pressing, made up as follows:

The ingredient Quantity (mg who I am 30

Magnesium stearate - 3

When administered orally twice daily, the above composition substantially reduces inflammation in a patient suffering from rheumatoid arthritis. A significant benefit is also achieved by the introduction of this composition twice a day to a patient suffering from osteoarthritis.

Example B

Pharmaceutical composition in the form of capsules obtained by the usual methods, is composed as follows:

The ingredient Quantity (mg / capsule)

Connection 2 - 200

Lactose - up to full volume capsules

The above capsule with the introduction of once a day significantly reduces the symptoms of patients suffering from rheumatoid arthritis or osteoarthritis.

Example C

Pharmaceutical composition in liquid form, obtained by the usual methods, is composed as follows:

Ingredient - Number

Connection 3 to 200 mg

EtOH - 4 ml

Methylcellulose - 0.4 mg

Distilled water is 76 ml

Tween 80 - 1.6 ml

50 ml of the above composition, administered orally once daily, significantly reduced the symptoms in a patient suffering from rheumatoid arthritis or osteoarthritis.

Example D

Pharmaceutical composito

Microcrystalline (micronized) Connection 4 - 200 mg

Avicel (microcrystalline cellulose), 50 mg

Tween 80 - 1.6 ml

Methylcellulose - 0.4 mg

Deionized water 80 ml

50 ml of the above composition, administered orally twice daily, significantly reduce the symptoms in a patient suffering from rheumatoid arthritis or osteoarthritis.

Example E

Solid pharmaceutical composition for oral administration obtained by the usual methods, is composed as follows:

The ingredient Amount (wt.%)

Connection 5 - 20

Pluronic F108 - 40

Tween 80 - 40

Example F

Solid pharmaceutical composition for oral administration obtained by the usual methods, is composed as follows:

The ingredient Amount (wt.%)

Connection 6 - 50

Triglycerides and their derivatives - 45

Creamphor EL - 5

Despite the fact that have been described in certain variations of the present invention, the person skilled in the art it is obvious that can be done various changes and modifications of the disclosed here compositions, without departing from the scope of this invention. The claims cover all such modifications within this invention.


%I=[(C-T)/C] 100,

where C is the average difference between the volume of the paws (after processing before processing) in the control group (medium), and T is the average difference in animals treated with the test compound. Statistical analysis comparison of the relationship of volume (after/before) processed Gras). Variation of percent inhibition of swelling of feet during the inspection or test compounds were statistically significant, such that these values CPE can statistically different or not different from the control.

2. The test caused by familienaam compression of the stomach (PAC)

Male mice CD-I (18-22 g; Harlan Laboratiries) were deprived of food for 4 h oral and injected them with vehicle (10 ml/kg) tebufelone (positive control, 70 mg/kg) or test compound at 10, 40 and 70 mg/kg (N = 6 per group). The dosing solutions were prepared as described in CPE. After 1 h were injected intraperitoneally with 10 ml/kg 0,02% solution of finishinga (Sigma) and counted compression of the stomach for the next 10 minutes the Results were expressed as percentage inhibition of writhing, using the formula above, in the method of the CPE. Maximum inhibition was about 90%. Statistical analysis to compare responses in the treated groups was performed using either least-squares method or the direct method ANOVA, and determine the values of the ED50using regression analysis.

3. The test excipient for the treatment of arthritis

After measuring the volume of the paws on the baseline with the use of mercury plethysmometer samz the roit, MI) in mineral oil at the dose volume 0.5 ml/kg On day 14, the volume of the paws again measured and the animals were randomly divided into test groups (N = 6). From the 14th to the 28th day, the animals were injected orally with vehicle (5 ml/kg per day) tebufelone (1, 3 or 10 mg/kg per day, positive control) or the test compound (3, 10 or 30 mg/kg per day). The dosing solutions were prepared as described in CPE. On the 28th day measured the amount of feet and weight of animals, and the animals were subjected to euthanasia. For a graphical representation of the data were expressed as percent inhibition of increase in paw from 14 th to 28-th day, using the formula:

%I-[(C-T)/(C-H)] 100,

where C is the average difference between the volume of the paws (28-day 14-day) in the control group (medium), T is the average difference in animals treated with the test compound, and H is the average difference in healthy (reinjection auxiliary substance) animals. For statistical analysis compared the volume of the right and left paws in groups on the 28th day, using the ANOVA technique. Determine the values of the ED50using linear regression volumes paws as a function of log (dose).

4. Protection from acute gastritis.

Rats, weighing 180-200 g, were injected once petrogale their euthanasia, using aspicio CO2. In a separate experiment was performed in response to doses of naproxen in 20, 50 and 100 mg/kg, and it was found that UD50is 31 mg/kg Dosing solutions were prepared as described in CPE. The stomachs were removed, cut along the greater curve, washed to clean in physiological saline and was laid out on the maps. Was measured and the length and area of hemorrhagic lesions, using the analysis software Image Pro Plus (Media Cybernetics, Silver Spring, MD) and both parameters were compared statistically treated groups using non-parametric method (Wilcoxon rank-sum test).

Representatives of the claimed compounds showed the following: % of inhibition (% 1), the CPE index and % PAC in the above-described CPE and test PAC (PL. 2)

The CPE index was determined as the ratio of volume reduction paws for tested compounds relative to tebufelone. Value > 1 means that the connection is more active than tebufelone, the value of < 1 means that the compound is less active than tebufelone.

1. Derivatives dihydrobenzofuran formula I

< / BR>
where (a) X is chosen from the group comprising O or S;

(b) each Y is independently hydrogen or a straight or branched elkayam having from 1 to 4 atoms ug is is O;

(e) R is a straight or branched or cyclic alkyl, saturated or monounsaturated, with a double bond, having from 1 to 15 atoms other than hydrogen.

2. Connection on p. 1, in which each Y is independently selected from the group comprising hydrogen, methyl or ethyl, and Z is chosen from the group comprising unsubstituted C4- C6extensive alkenyl with 2 branches, preferably both Y are hydrogen or stands; Z is tert-bootrom and W is oxygen.

3. Connection under item 1 or 2, in which R is C4- C7the alkyl straight chain or with one branch, saturated or unsaturated with one double bond between nekozumi carbon atoms, or C4- C6cycloalkenyl, unsubstituted or monosubstituted by a Deputy selected from the group comprising hydroxy, and heterocycle, and R is from 1 to 7 atoms other than hydrogen.

4. The compound according to any one of the preceding paragraphs, in which R is chosen from the group comprising methyl, ethyl, n-propyl, n-butyl, ISO-propyl, cyclopropyl, cyclopentyl, 3-cyclopropylmethyl, 2-hydroxy-2-methylpropyl, 2-methyl-1-propenyl, 3-tetrahydrofuryl, preferably R is selected from the group including Metamucil-2-propenyl and 2-methyl-1-propenyl.

5. The compound according to any one of the preceding paragraphs, in which both Y are hydrogen and R is chosen from the group comprising 2-hydroxy-2-methylpropyl and 2-methyl-1-propenyl.

6. The compound according to any one of the preceding paragraphs, in which both Y are stands and R are selected from the group comprising n-butyl, 3-cyclopropylmethyl and 2-hydroxy-2-methylpropyl.

7. The compound according to any one of the preceding paragraphs, in which X is sulfur and R is chosen from the group comprising butyl and 3-tetrahydrofuryl, it is preferable if both Y are stands, R is 3-tetrahydrofuryl or bootrom.

8. Pharmaceutical composition having anti-inflammatory activity, including active active ingredient and a pharmaceutically acceptable carrier, characterized in that as activitiesthese substances it contains the connection PP.1 - 7 in an effective amount.

9. A method of treating inflammation or pain comprising the administration to a human or lower animal in need of such treatment, a safe and effective amount of a compound according to any one of the preceding paragraphs 1 - 7.

10. A method of treating arthritis comprising the daily oral administration to a person in need so the

 

Same patents:

The invention relates to new derivatives of amino(thio)ethers of the formula I

< / BR>
where X represents oxygen, sulfur, sulfinil, sulfonyl or, if R0and R1together are not alkalinous chain with 1 to 3 atoms, CH2:

Z represents -(CH2)n1-(CHA)n2-(CH2)n3and

n1 = 0, 1, 2 or 3,

n2 = 0 or 1,

n3 = 0, 1, 3 or 3, provided that

n1 + n2 + n3 < 4;

R0represents hydrogen or A;

R1represents hydrogen, A, OA, phenoxy, Ph, OH, F, Cl, Br, CN, CF3, COOH, COOA, acyloxy with 1-4 carbon atoms, carboxamido, -CHNH2, -CH2NHA, -CH2NA2,

-CH2NHAc, -CH2NHSO2CH3,

or

R0and R1together represent alkylenes chain with 1 to 3 carbon atoms or alkenylamine chain with 2 to 3 carbon atoms;

R2represents hydrogen, A, Ac, or-CH2-R4;

R3represents-CH2-R4or-CHA-R4;

R4is a Ph, 2-, 3 - or 4-pyridyl (unsubstituted or monosubstituted R5) or thiophene (unsubstituted, mono - or disubstituted by A, OA, OH, F, Cl, Br, CN and/or CF3or the other what it is, di-, tri-, Tetra-, or pentamidine F, CF3partially or fully fluorinated A, A and/or OA;

R6, R7, R8and R9each independently represents H, A, OA, phenoxy, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NHA, NA2, Ac, Ph, cycloalkyl c 3-7 carbon atoms, -CH2NH2, -CH2NHA, -CH2NA2, -CH2N HAC or-CH2NHSO2CH3or two coming together constitute the remainder alkylenes chain with 3-4 carbon atoms, and/or R1and R6together predstavljaet a chain with 3 or 4 carbon atoms;

A represents alkyl with 1-6 carbon atoms;

Ac is alkanoyl with 1-10 carbon atoms or aroyl with 7 to 11 carbon atoms;

Ph represents phenyl (unsubstituted or substituted R5, 2-, 3 - or 4-pyridium or phenoxyl group);

and physiologically acceptable salts, their derivatives

The invention relates to vasoconstrictor /(benzodioxan, benzofuran and benzopyran)-alkylamino/-alkyl-substituted guanidine formula I, their pharmaceutically acceptable salts, or their stereochemical isomers, where X = O, CH2or a direct bond; R1= H, C1-C4alkyl, R2= H, C1-C6alkyl, C3-C6alkenyl, C3-C6quinil, R3= H, C1-C4alkyl; or R2and R1taken together, may form a bivalent radical of the formula/CH2/m-, where m = 4 or 5; or R1and R2taken together may form a bivalent radical of formula-CH=CH -, or the formula/CH2/n-, where n = 2, 3 or 4; or R3may indicate a relationship when R1and R2taken together form a bivalent radical of formula-CH=CH-CH= -, -CH= CH-N= or-CH=N-CH=; where one or two hydrogen atom substituted by a halogen atom, a C1-C6alkoxygroup, C1-C6the alkyl, CN, NH, mono - or di(C1-C6alkyl) amino group, aminocarbonyl, C1-C6alkylaminocarbonyl, R4-H or C1-C6-alkyl; Alk1denotes a divalent C1-C3-ascandilwy radical, A denotes dwuhvalentny a radical of the formula /, lk2represents C2-C15-alcander or C5-C7-cycloalkenyl, and each "R" represents 0, 1, 2, R7and R8each independently is H, a halogen atom, a C1-C6by alkyl, hydroxyl, C1-C6allyloxycarbonyl, C1-C6alkoxygroup, cyano, amino, C1-C6the alkyl, carboxyla, nitro or amino group, aminocarbonyl, C1-C6alkylcarboxylic or mono - or di-(C1-C6)alkylamino, provided that excluded /2-/ (2,3-dihydro-1,4-benzodioxin-2-yl)-methyl/-amino/-ethyl-guanidine

The invention relates to new derivatives of pianolasociety, pharmaceutical compositions containing these derivatives, their use for the treatment of hypertension or asthma in mammals, including humans, and method for producing the above compounds and compositions

The invention relates to a method for producing new derivatives benzocycloheptene acids

The invention relates to medicine and refers to the extract from plants of the family Labiatae, cultured in in vitro conditions, in the form of a cosmetic or pharmaceutical composition comprising as active ingredient an effective amount of the above-mentioned extract, which is intended for the treatment of cutaneous or systemic inflammatory diseases, with more favorable result

The invention relates to new triaromatic compounds of General formula I, characterized in p

The invention relates to medicine, namely to rheumatology, and can be used for treatment of juvenile rheumatoid arthritis predominantly articular form

The invention relates to new derivatives of chromone General formula 1, in which ring a is unsubstituted or one-deputizing halogen, and where the ring is unsubstituted or substituted by one to four substituents selected from the group consisting of lower alkyl, hydroxyl, lower alkoxyl, lower alkylthio or halogen, and their salts, also describes a method of production thereof and pharmaceutical composition based on compounds of the formula I, which has antagonistic activity against neirokinina 1

The invention relates to certain CIS - and TRANS-benzopyrane having substituted benzamide in position C-4, and to their use for the treatment and/or prevention (prophylaxis) of certain CNS disorders

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new compounds of coumarone class, namely, to 6-nitro-2-iminocoumarin 3-carboxylic acid 4-toluidide silver salt of the formula (1): that elicits an antibacterial effect and can be used in medicine. Invention provides preparing a new compound eliciting an antibacterial effect with respect to S. aureus, E. coli, and C. albicans with mononuclear cells values 0.25; 0.5 and 7.8 mcg/ml, respectively, and with acute toxicity value LD50 for these compounds 2 460 ± 230 mg/kg.

EFFECT: valuable properties of compound.

1 cl, 1 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new derivatives of carbamic acid esters of the general formula (I):

and their pharmaceutically acceptable salts eliciting activity with respect to metabotropic glutamate receptors mGlu of group I that can be used for treatment of acute and/or chronic neurological disorders. In the general formula (I) R1 means hydrogen atom or (C1-C7)-alkyl; R2 and R2' mean independently of one another hydrogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom or trifluoromethyl; X means oxygen (O), sulfur (S) atom or two hydrogen atoms not forming a bridge; A1/A2 mean independently of one another phenyl or 6-membered heterocycle comprising 1 or 2 nitrogen atom; B represents group of the formula:

wherein R3 means (C1-C7)-alkyl and others; Y means -O-, -S- or a bond; Z means -O- or -S-; or B means 5-membered heterocyclic group of formulae: (a) , (b) , (c) or (d) . Also, invention relates to methods for preparing compounds and to a medicinal agent based on thereof.

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

22 cl, 1 tbl, 2 sch, 78 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to new flavone, xanthone and coumarone derivatives of formula I

[R and R1 each are independently lower C1-C6-alkyl or together with nitrogen atom attached thereto form 4-8-membered heterocycle, optionally containing one or more heteroatoms, selected from group comprising N or O, wherein said heterocycle is optionally substituted with benzyl; Z has formula (A) , wherein R3 and R4 each are independently hydrogen, optionally substituted aromatic group containing in cyclic structure from 5 to 10 carbon atoms, wherein substituents are the same or different and represent lower C1-C4-alkyl, OR10 (OR10 is hydrogen, saturated or unsaturated lower C1-C6-alkyl or formula ) or linear or branched C1-C6-hydrocarbon; or R2 and R3 together with carbon atom attached thereto form 5-6-membered carbocycle; and R4 represents hydrogen or attaching site of group –OCH2-C≡CCH2NRR1; or formula (B) , wherein R5 is hydrogen, linear or branched lower C1-C6-hydrocarbon, with the proviso, that when Z represents R and R1 both are not methyl or R and R1 together with nitrogen atom attached thereto cannot form groups , or ]. Also disclosed are drug component with proliferative activity for prophylaxis or treatment of neoplasm and pharmaceutical composition with proliferative activity based on the same. Derivatives of present invention have antyproliferative properties and are useful as modulators of drug resistance in cancer chemotherapy; as well as in pharmaceuticals for prophylaxis or treatment of neoplasm, climacteric disorders or osteoporosis.

EFFECT: new compounds with value bioactive effect.

31 cl, 2 tbl, 32 ex

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