Bicyclic carboxylic acid, inhibiting the biological activity of leukotriene b4and pharmaceutical composition

 

(57) Abstract:

Bicyclic carboxylic acids of formulas a, b and C, where R2is hydroxyl or lower alkoxyl, are potent antagonists of leukotriene4and therefore suitable for the treatment of inflammatory diseases. 4 c. and 5 C.p. f-crystals, 2 tab.

The object of the invention are bicyclic carboxylic acids of formulas A, B and C:

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where R2in each case, independently of one another denotes a hydroxyl group, a lower CNS group, and Ph denotes phenyl, and compounds of formula C to its geometric isomer, and in the case when R2means a hydroxyl group, pharmaceutically applicable salts of these compounds with a base.

Additionally, R2can mean NR3R4where R3and R4independently of one another denote hydrogen or lower alkyl.

Compounds of formulas A, B and C are potent antagonists of leukotriene B4and therefore suitable for the treatment of inflammatory diseases, e.g. psoriasis, rhinitis, chronic obstructive pulmonary disease, inflammation of the digestive tract, asthma, acute respiratory distress syndrome , is astropathic caused neurosecretory acquired immunodeficiency, gout, ischemia/disorders krovosnabjenia and traumatic injuries, such as damage to the spinal cord.

The object of the present invention are compounds of formulas A, B and C and their pharmaceutically applicable salts as such and used as therapeutically active substances, compounds, medicaments containing these compounds, and the manufacture of such medicaments, as well as the use of compounds of formulas A, B and C and their pharmaceutically applicable salts for the treatment or prevention of disease or to improve health, particularly for the treatment or prevention of inflammatory diseases such as psoriasis, rhinitis, chronic obstructive pulmonary disease, inflammation of the digestive tract, asthma, acute respiratory distress syndrome, mucositis, allergies, arthritis, such as rheumatoid arthritis, dermatitis, such as contact, gastropathy caused neurosecretory acquired immunodeficiency (SPID), gout, ischemia/impaired krovosnabjenia and traumatic injuries, such as damage to the spinal cord.

Another object of the invention is a pharmaceutical conormal A, B and C.

Another object of the invention is an intermediate compound 2-(3-phenylpropanamide)-1,3-cyclohexandione having the formula

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where Ph means phenyl,

and the intermediate compound 3-(2-tzanetaki)-2-(3-phenylpropyl)-2-cyclohexen-1-it formula

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where Ph denotes phenyl.

The present invention relates also to a method of inhibiting the biological activity of leukotriene B4that is the introduction into the organism of a patient who requires such inhibition, an effective amount of compounds of formulas A, B and C.

In this description, the following definitions of common terms, regardless of whether they are used separately or in combination.

Used the term "lower alkyl" means a linear or branched saturated hydrocarbon radical containing 1-7 carbon atoms, preferably 1-4 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, tert. -butyl, neopentyl, pentyl, heptyl, etc., the Term "lower CNS" radical means alkylamino group in which the alkyl mentioned above, for example, methoxy, ethoxy, propoxy, intoxi etc.

Used the term "useplease group" oz the PPU, triftormetilfullerenov or similar; arylsulfonate, for example, p-toluensulfonate or etc.

Islamochristiana hidroxizina group means preferably tetrahydropyranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl etc.

Alkali metal means preferably lithium, sodium, potassium and cesium.

Used the term "hidroxizina group removed by hydrogenation means preferably benzyl, p-methoxybenzyl, triphenylmethyl etc.

A preferred group of compounds represented by formulas A, B and C.

The most preferred compounds according to the invention are:

2-(3-carboxypropanoyl)-6-[6-[[3,4-dihydro-4-oxo-8-(3-phenylpropyl) - 2H-1-benzopyran-7-yl] oxy] hexyl] benzoylpropionate acid (compound of formula (A);

2-(3-carboxypropanoyl)-6-[6-[[5,6,7,8-tetrahydro-5-oxo-1-(3 - phenylpropyl)-2-naphthalenyl] -oxy]hexyl]benzoylpropionate acid (compound of formula (B); and

(E)-2-(3-carboxypropanoyl)-6-[6-[[5,6,7,8-tetrahydro-5-oxo-1-(3 - phenyl-2-propenyl)-2-naphthalenyl]oxy]hexyl]benzoylpropionate acid (compound of formula (C).

Compounds of the present invention of formulas A, B and C can be obtained by the way, koi or hydrogen, the interaction of the compounds of formula

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or

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with the compound of the formula

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where R2'denotes lower alkoxy or hydrogen, and L denotes useplease group

or

b) for compounds of formula A, where R2has the above values, the catalytic hydrogenation of the compounds of formula

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where R2has the above values,

or

to obtain compounds of formula B where R2has the above values, the catalytic hydrogenation of the compounds of formula C, where R2has the above values, or

g) for compounds of formula C, where R2has the above values, the interaction of the compounds of formula

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where R has the above values,

connection

PhL II-4

where Ph means phenyl and L denotes useplease group, or

d) for compounds of formulas A, B and C, where R2denotes a hydroxyl group, saponification of compound A, B or C, where R2means lower alkoxy, and

e) for compounds of formulas A, B and C, where R2means-NR3R4and R3and R4have the above values, the transformation of compounds of formulas A, B or C, where R2
g) if desired, converting compounds of formulas A, B and C in its pharmaceutically applicable Sol.

The reaction conditions for the above-mentioned methods (a) to (e) and to obtain the intermediate compounds shown below in reaction schemes I-VI.

Reaction scheme 1

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where R2'denotes lower alkoxy, R5means kislotoustoytchive hydroxyamino group, L denotes useplease group and M denotes an alkali metal.

In reaction scheme I, 5-hydroxycoumarin, well-known compound of the formula I-1, is converted into the corresponding ester triftoratsetata I-2 by treating the anhydride of triftoratsetata in the presence of an amine as the base. You can use any amine as the base. Preferred pyridine or triethylamine. The transformation is preferably carried out in an environment of solvent is dichloromethane at 0-25oC. the Compound of formula I-2 can be distinguished by conventional methods, for example, by chromatography or recrystallization.

The compound of formula I-2 is subjected to interaction with an acetylene compound of formula I-3, which is known, in the presence of a palladium catalyst and an amine in cacheserver as a catalyst for dichlorobis-(triphenylphosphine)palladium (II) and as a base - of triethylamine in an environment of dimethylformamide at 80-100oC. the Compound of formula I-4 distinguish using conventional chromatographic methods.

The compound of formula I-4 converted into the corresponding hydroxyl-containing ester of cinnamic acid of the formula I-5 by alcoholysis of the lactone ring cycle with the use of a lower alkoxide of an alkali metal in the lower alkanol. This transformation is done by applying a lower alkoxide of lithium, sodium or potassium. Preferably this transformation to be executed in the environment of methanol or ethanol in the presence of sodium methoxide or ethoxide sodium at 60-80oC. the Compound of formula I-5 allocate conventional chromatographic methods or recrystallization.

Alkylation of compounds of formula I-5 is carried out bromodomain ether of the formula I-6, which is a known compound. The process is carried out in the presence of a base, for example, carbonate of an alkali metal, e.g. sodium carbonate or potassium, at a temperature of from about 25 to about 110oC in the environment of the polar aprotic solvent such as acetonitrile, N,N-dimethylformamide, 2-butanone, dimethyl sulfoxide, etc., the resulting compound of formula I-7 allocate by chromatography.

Catalogue I-8. This hydrogenation is carried out at normal conditions. More specifically, it is preferable to use a catalyst based on a transition metal on a carrier, for example, 5% or 10% palladium deposited on charcoal. It is also preferable to carry out the hydrogenation at room temperature and at a hydrogen pressure of 1 ATM. The preferred solvent in the hydrogenation are lower alkanols, e.g. methanol or ethanol, or ethers, for example ethyl acetate, or so on, you Can also use mixtures of these solvents.

The removal of the protective group R5in the compound of formula I-8 to obtain the corresponding alcohol of formula I-9 is performed using an acidic catalyst. Preferably this process is the removal of the protective group to hold the lower alkanol, for example, methanol or ethanol. Suitable acid catalysts are organic sulfonic acids or their salts with amines at 20-80oC. is Particularly preferable to perform this transformation using p-toluenesulfonic acid in methanol. The compound of formula I-9 allocate conventional chromatographic methods.

The compound of formula I-9 is transformed into the corresponding derivative of the I-10, using standard methods, the respective reagents, for example, N-bromosuccinimide/triphenylphosphine or N-chlorosuccinimide/triphenylphosphine, in the environment of dichloromethane. Otherwise, the compound of formula I-9 can be converted to the corresponding ether sulfonic acids of the formula I-10 by conventional methods, for example, by treatment of alkyl - or arylsulfonate and organic amine. It is preferable to process the compound of formula I-9 methanesulfonanilide and triethylamine in an environment dichloromethane, simple ether or ethyl acetate at 0-25oC. the esters of methansulfonate in turn can be converted into the corresponding iodides of the formula I-10 by treatment with iodide of an alkali metal in the environment of the polar aprotic solvent. It is preferable to carry out this transformation, using sodium iodide in acetonitrile at 20-80oC. the compounds of formula I-10 allocate conventional methods of extraction.

Reaction scheme II

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where R6means hydroxyamino group is removed by hydrogenation, and R2', L and M have the above values.

In scheme II ortho-hydroxyacetophenone formula II-1, which is a known compound, process known formaleducation formula II-2 at 120-160oC in the environment of aromatic hydrocarbon will restoredefault cyclization by treating the acid with the formation of chromone II-3. Preferred acids for this cyclization are organic sulfonic acids, e.g. p-toluensulfonate. Preferred solvents for this cyclization are the lower alkanols, e.g. methanol and ethanol, at 60-80oC. Groman formula II-3 highlight conventional chromatographic methods or recrystallization.

Chroman formula II-3 condensed with a derivative of benzene of the formula II-4, which is a known compound, in the presence of a base, a palladium catalyst and a Quaternary ammonium salt with the formation of the compounds of formula II-5. Examples of derivatives of benzene are known connection type odensala, phenyltrichlorosilane, etc., it is Preferable that the condensation be carried out using as the base of the acetate of an alkali metal and tetraalkylammonium as a Quaternary ammonium salt. Particularly preferably, the base served as sodium acetate and Quaternary ammonium salt - tetraethylammonium. For carrying out the condensation of the preferred catalyst is palladium (II) acetate. This condensation is preferably carried out at 25-100oC in a polar aprotic process is or recrystallization.

Catalytic hydrogenation of chromone formula II-5, with a concomitant reduction cleavage of the protective group R6results of hydroxychromone formula II-6. The hydrogenation is carried out at normal conditions. The catalyst based on transition metal on the carrier is preferred, for example, 5% or 10% palladium on coal or charcoal. It is preferable that the hydrogenation was conducted at room temperature and the hydrogen pressure is 1 ATM. Preferred solvents for carrying out the hydrogenation are lower alkanols, e.g. methanol or ethanol, or ethers, e.g. ethyl acetate. You can also apply a mixture of these solvents. This hydrogenation can be carried out in two stages, first remove the protective group in the presence of palladium on coal and then restore the double bond using a conventional catalyst is Raney Nickel. The compound of formula II-6 can be distinguished by conventional methods chromatography or recrystallization.

Hydroxychromone formula II-6 is subjected to interaction with the compound of the formula I-10 (scheme I) in the presence of a base, for example, carbonate of alkaline metal such as sodium carbonate or potassium, at a temperature of from approx the, 2-butanone, dimethyl sulfoxide, etc. as a base you can also use the alkali metal hydride, e.g. sodium hydride, in this case, the preferred such inert solvents, such as tetrahydrofuran, simple ether, toluene or N,N-dimethylformamide. In addition, you can use the method according to U.S. patent 4931574. In this case, compounds of formula II-6 and I-10 is subjected to interaction in the presence of a carbonate of an alkali metal, preferably potassium carbonate, and a catalyst transfer phases, preferably Tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1), in an aromatic hydrocarbon solvent, preferably toluene, at 80-110oC. the resulting fluids of formula II-7 can be distinguished by conventional methods, for example, chromatography, and it can be converted into the corresponding decollato formula A2by saponification using an alkali metal hydroxide, e.g. lithium hydroxide, sodium or potassium hydroxide, in a mixture of water and miscible with water solvent, for example methanol, ethanol or tetrahydrofuran, at a temperature of from about 25 to about 60oC. it is Preferable to carry out this saponification at room temperature in aqueous tetrahydrofuran (THF) using lithium hydroxide. The compounds of formula Promotional scheme III

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where L, M and R2'have the above values.

In scheme III known hydroxychromone formula III-1 alkylate compound of formula II-6, as shown in reaction scheme II for the conversion of compounds of formula II-6 in the compound of formula II-7. The compound of formula III-2 allocate conventional chromatography and familyroom with the formation of the compounds of formula III-3, as shown in scheme II for the conversion of compounds of formula II-3 in the compound of formula II-5. The compound of formula III-3 allocate conventional chromatography. Catalytic hydrogenation of the compounds of formula III-3 leads to the formation of the corresponding compounds of formula II-7 secreted by chromatography. This hydrogenation is conducted under the conditions shown in scheme II for the conversion of compounds of formula II-5 in the compound of formula II-6. Saponification of compounds of formula II-7 results in the corresponding decollate formulas AND2as shown in scheme II.

Reaction scheme IV

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where R2', R6and L have the above values.

In reaction scheme IV, 1,3-dimethoxybenzene, well-known compound of the formula IV-1, is converted into a compound of formula IV-3 first processing strong Foundation is open, 3-iodine-1-phenylpropane, 3-[(methylsulphonyl)oxy] -1-phenylpropane, etc., Preferably, the base used in the alkylation was from a number of organolithium compounds, for example, motility, finality, n-utility, etc. and that the alkylation was carried out in an inert simple ether. Particularly preferably, the alkylation, using n-utility in the environment of tetrahydrofuran at a temperature from -20oC to room. The compound of formula IV-3 allocate conventional chromatography.

Acetylation of compounds of formula IV-3 carried out under normal conditions, the reaction Friedel -. Specifically, the processing acetylchloride and aluminofluoride carried out in dichloromethane to obtain the corresponding acetophenone of formula IV-4 secreted by chromatography. Treatment of compounds of formula IV-4 under standard conditions demethylation, for example, using trichromate boron in a solution of dichloromethane at a temperature from -50oC to room, leads to the formation of the corresponding dihydroxyacetophenone formula IV-5 secreted by conventional chromatography or recrystallization.

Dihydroxyacetophenone formula IV-5 is subjected to interaction with the compound of the formula IV-6, II formula IV-6, you can apply, the preferred benzylchloride or benzylbromide. Preferably this alkylation, using as a base potassium carbonate, in an environment of acetone or acetonitrile at 20-80oC. Treatment of compounds of formula IV-7 known formaleducation formula II-2, followed by cyclization in the presence of acid as shown in reaction scheme II for the conversion of compounds of formula II-1 in the compound of formula II-3, leads to the formation of chromone IV-8. This chrome IV-8 usually distinguish conventional chromatography or recrystallization. Catalytic hydrogenation of chromone IV-8 with a concomitant reduction removal arylmethylidene fragments R6results of chromanone formula II-6. This hydrogenation-recovery carried out as shown in reaction scheme II for the conversion of compounds of formula II-5 in chromanone II-6.

Reaction scheme V

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In reaction scheme V 1,3-cyclohexandione, well-known compound of the formula V-1, condense with the known compound is cinnamic aldehyde of formula V-2 in the presence of a catalyst to the secondary amine with the formation of diandian formula V-3 secreted by crystallization. Preferably this aloperidin, in ethanol medium at a temperature of from 0 to 30oC.

Catalytic hydrogenation of diandian formula V-3 carried out using as catalyst palladium on coal, the environment ethyl acetate with formation of the corresponding cyclohexandione formula V-4. Prefer to spend it hydrogenation at room temperature and at a hydrogen pressure of 1 ATM.

The compound of formula V-4 process known connection - 3-hydroxypropionitrile formula V-5 in the presence of an acidic catalyst to obtain enol of the formula of a simple ester of the formula V-6, secreted by conventional chromatography. It is preferable to conduct the reaction using as a catalyst an organic acid, for example, p-toluensulfonate, in an inert hydrocarbon solvent, e.g. benzene or toluene, at 80-120oC.

Scenting Talavera formula V-6 with formation of the corresponding phenol of formula V-7 is achieved by bromirovanii with subsequent dehydrobrominated base. Bromination can be accomplished in any conventional brainwashin with a reagent such as bromine, N-bromosuccinimide, etc., in an inert solvent. Preferably this bromination to hold in solution dig the tion can be done in an inert solvent, using sterically hindered tertiary amine. Preferably spend dehydrobrominated, using as the Foundation of 1,4-diazabicyclo[2.2.2] octane, in toluene solution at 25-110oC. the Phenol of formula V-7 allocate chromatography.

The cyclization of phenol of formula V-7 perform the processing of a strong acid with the formation of hydroxychromone formula II-6, secreted by chromatography or crystallization. This cyclization can be performed using known strong acids such as sulfuric, hydrochloric, phosphoric, etc., it is Preferable to carry out the cyclization, using 85% phosphoric acid in acetic acid solution at 100-150oC.

Reaction scheme VI

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where R2', L and M have the above values.

In scheme VI allyl simple ester of the formula VI-1, a known compound, is subjected to thermolysis to effect the rearrangement of Clausena. Preferably this thermolysis at 180-230oC without solvent or in a solvent with high boiling point, for example, N,N-diethylaniline. The desired isomer of naphtaline formula VI-2 can be distinguished by recrystallization. Naphtaline formula VI-2 alkylate compound of formula I 10 the II-6 in the compound of formula II-7. The compound of formula VI-3 allocate conventional chromatography and familyroom with the formation of the product of formula VI-4, as shown in scheme II in the case of the conversion of the compounds of formula II-3 in the compound of formula II-5. The compound of formula VI-4 distinguish conventional chromatography. Catalytic hydrogenation of compounds of formula VI-4 leads to the production of the compounds of formula VI-5, which emit chromatography. The hydrogenation is conducted under the conditions shown in scheme III, in the case of the conversion of the compounds of formula III-3 in the compound of formula II-7. Saponification of compounds of formula VI-5 leads to the formation of decollate formula B2allocated by recrystallization, and the saponification is carried out, as shown in scheme II for the conversion of compounds of formula II-7 in the compound of the formula A2. Alternative saponification of compounds of formula IV-4 under the same conditions results in a corresponding decollate formula C2allocated by chromatography or recrystallization.

Compounds of formulas A, B and C, where R2means-NR3R4and R3and R4mean hydrogen or lower alkyl, can be obtained from digisat conventional methods known to experts in this field.

The invention also relates to Yu salts with a base. Salts of compounds of formulas A, B and C, which contain a carboxyl group, obtained by interaction with non-toxic, pharmacologically applicable basis. In General, any base which forms a salt with the carboxylic acid and pharmacological properties which have no harmful physiological effects, is within the scope of this invention.

Suitable bases include, for example, hydroxides and carbonates of alkali and alkaline earth metals, etc., for example, calcium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate or etc., ammonia, primary, secondary and tertiary amines, such as monoalkylamines, dialkylamines, trialkylamines, for example, methylamine, diethylamine, triethylamine or etc., nitrogen-containing heterocyclic amines, such as piperidine or so on thus Obtained salt is the functional equivalent of the corresponding compounds of formulas A, B and C, where R2means hydroxyl, and specialist it is obvious that various salts covered by this invention, need only meet the requirement, namely, that the basis used in the preparation of the corresponding salts, should be non-toxic and physiologically p is riena B4(LTB4).

Method.

The reaction of binding of LTB4the receptor.

Study of the binding assays can be performed in the wells on the microtiter plate. Dedicated human neutrophils in Gay salt solution incubated on ice for 45 min, using 0.5 nm3H-LTB4in the presence or in the absence of the tested compounds. Test finish by adding 12 ml of ice-cold 50 mm trisbuffered (pH of 7.4) followed by rapid filtration under vacuum through GF/C filters. The radioactivity determined by scintillation counter. Nonspecific binding is defined as binding, is not manifested at 100-fold excess unlabeled LTB4. Specific binding is defined as the difference between total and nonspecific binding. Nonlinear data analysis carried out using LIGAND (Munson and Rodbard, 1980). TOi(the inhibition constants) determined by the equation of Cheng-Prusoff (Cheng and Prusoff, 1973).

When using representatives of the compounds of formulas A, B or C according to the invention receives the results of the inhibition of binding3H-LTB4shown in the table. 1.

Bronchostenosis in Guinea pigs in vivo.

Spend anesthesia males Eter for drug administration. The pressure in the trachea record using a cannula placed in the trachea and connected to a pressure sensor Gould P231D. After surgical preparation of the animals for some time expect the stabilization of pulmonary function. Then paralyze animals by succinylcholine (1.2 mg/kg, intravenously) and carry out mechanical artificial ventilation (Harvard respirator) with a frequency of 40 breaths/min and tidal otlivnyy displacement of 2.5 cm3. The test compound is administered orally 2 hours before the administration of leukotriene B4. Intravenously injected propranolol (0.1 mg/kg) 5 min before the introduction of leukotriene B4. Then intravenously injected animals intermediate causes narrowing of the bronchial dose of leukotriene B4(200 g/kg).

Average 6 control rats and 6 animals, which introduced the drug, the difference in pressure (cm H2A) artificial respiration, measured the beginning of the experiment and in the peak time. The percentage of ingibirovaniya calculated by the formula:

((Control and Received medicine)/Control)100.

When using representatives of the compounds of formulas A, B and C according to the invention the obtained results are shown in table. 2.

In practice, the use of the invention the dose of a compound of formulas A, B, C or e C or its salts and method of its introduction, as well as the degree and nature of disease and age of the mammal undergoing treatment, and so on, Oral doses of the compounds of formulas A, B or C or its salts range from 2 mg to 2 g per day, preferably from about 2 mg to 1 g per day in one dose or multiple doses.

The following examples illustrate the invention.

The compound of formula A, B or C, or salt, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula A, B or C or its salt is introduced by methods well known in the art. Thus, the compounds of formulas A, B or C or their salts can be entered either by themselves or with other pharmaceutical agents, such as antihistamines, inhibitors of selection of the mediator, methylxanthines, beta-agonists or anti-asthma hormones, such as prednisone and prednisolone, orally, parenterally, rectally or by inhalation, for example, in aerosol form, finely divided powder or spray solution. For oral administration they can be applied in the form of tablets, capsules, for example, in a mixture with talc, starch, milk sugar or other inert ingredients, i.e., the pharmaceutically primenyaemie with sugar or other sweeteners, fragrances, dyes, thickeners and other conventional pharmaceutical excipients. For parenteral application can be applied in the form of solutions or suspensions, e.g. in the form of an aqueous solution or suspension, or solution in peanut oil, using fillers and carriers commonly used in this kind of introduction. When used in the form of aerosols can be dissolved in a suitable pharmaceutically acceptable solvent, for example, ethyl alcohol or mixture of solvents, and mixed with a pharmaceutically acceptable propellant. Such aerosol compositions are packaged in a container under pressure, fitted with an aerosol valve for selection of the composition under pressure. Preferably, the aerosol valve was dosing, i.e., such that during operation produces a given effective dose aerosol composition. For local application connections are assigned in the form of ointment, cream, lotion, powder, gel or similar Suitable carriers for topical application are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, glycols,C denotes the geometric isomers. Geometric isomers can be divided into the corresponding E - and Z-isomers, using known methods, as described below in the examples.

In the following examples, "conventional selection includes three specific extraction solvent. The organic extracts are combined, washed with water and saturated saline; dried over anhydrous magnesium sulfate, filtered and concentrate under pressure from a water aspirator. The residue is dried to constant weight under high vacuum at 45oC. All reactions, except for the hydrogenation is carried out in an inert atmosphere of nitrogen or argon.

Example 1.

Obtain 7-(phenylmethoxy)-8-(2-propenyl)-4H-1-benzopyran-4-it.

A mixture of 5.0 g (17,73 mmole) 1-[2-hydroxy-4-(phenylmethoxy)-3-(2 - propenyl)phenyl] ethanone, 2.3 g (19,48 mmole) of dimethylformamidine and 5.0 ml of xylene is stirred and heated on an oil bath at 120-130oC during the distillation of methanol for 2.5 h using a Vigreux column (3 inches = 7.62 cm). Then the bath temperature was raised to 150-160oC and the reaction mixture stirred at this temperature for another 30 minutes the Mixture is cooled and concentrated at 60oC/high vacuum. To a viscous red-brown oily residue add 3.7 g (19,48 IMO the refrigerator 24 hours, then cooled and diluted with water. The usual selection of simple ether leads to the obtaining of a technical product, which is recrystallized from a mixture of hexane-ethyl acetate. Get 3.5 g (67,6%) 7(phenylmethoxy)-8-(2-propenyl)-4H-1-benzopyran-4-it is in the form of a yellow solid with a melting point 90-92oC.

Elemental analysis. Calculated for C19H16O3IN %: C 78,06; H 5,52. Found, %: C 77,97; H 5,56.

Example 2.

Obtaining (E)-7-(phenylmethoxy)-8-(Z-phenyl-2-propenyl)-4H-1 - benzopyran-4-it.

The mixture 8,76 g (30 mm) 7-(phenylmethoxy)-8-(2-propenyl)-4H-1 - benzopyran-4-it (the previous example), 6.7 g (32,84 mmole) of odensala, 5,11 g (30,84 mmole) of tetraethylammonium, to 8.94 g (91,22 mmole) of anhydrous sodium acetate and 64 ml of dry n, N-dimethylformamide was stirred at room temperature and cleaned in an argon atmosphere. The palladium (II) acetate (0,38 g, 1.7 mmole) is added with stirring at room temperature for 24 hours the Mixture is a dark color diluted with water and produce simple ether in the usual manner (the ether extracts are additionally washed with 12% aqueous solution of sodium bisulfite). Recrystallization of the technical product from acetonitrile yields a 6,13 g (55,5%) of the final product is mperature melting point 131-133oC.

Elemental analysis. Calculated for C25H20O3IN %: C 81,50; H 5,47. Found, %: C 81,34; H 5,10.

Example 3.

Obtain 2,3-dihydro-7-hydroxy-8-(3-phenylpropyl)-4H-1 - benzopyran-4-it.

A mixture of 6.1 g (of 16.6 mmole) of (E)-7-(phenylmethoxy)-8-(3-phenyl-2-propenyl)-4H-1-benzopyran-4-it is from the previous example, 1 g of 10% palladium on coal, 100 ml of methanol and 300 ml of ethyl acetate was stirred at room temperature in hydrogen atmosphere until used approximately one third of theoretical volume of hydrogen gas. The catalyst is filtered off under vacuum and concentrate the filtrate in vacuo. The residue is dissolved in 150 ml of methanol and add 0.5 g of Raney Nickel. Continue hydrogenation with careful monitoring by thin layer chromatography. When the restoration is almost complete, the catalyst is filtered off under vacuum, and the filtrate was concentrated in vacuo. The solid residue (4,75 g) connect with 6.4 g, obtained in another experiment (23.9 mmole), and chromatographic on silica gel. Elution with a mixture of hexane-ethyl acetate leads to the production of 10.73 g (93.9 per cent) of the final product as a colourless solid, melting point 110-112oC.

Example 4.

Example 5.

Obtaining 1-[2,4-dimethoxy-3-(3-phenylpropyl)phenyl]ethanone.

The solution 15,28 g (59,6 mmole) of 1,3-dimethoxy-2-(3-phenylpropyl)-benzene from the previous example and 4.68 g (59,6 mmole) acetylchloride in 306 ml of dichloromethane was stirred at-5-0oC and add to 7.95 g (59,6 mmole) of aluminum chloride. The resulting mixture was stirred at-5 - 0oC for 2 h and then left to warm to room temperature before pouring into the ice. The treatment is simple is the mixture of 7:3 hexane-simple ether leads to obtain 10.0 g (56,3%) of final product as a pale yellow oil.

Example 6.

Obtaining 1-[2,4-dihydroxy-3-(3-phenylpropyl)phenyl]ethanone.

A solution of 10.0 g (of 33.5 mmole) of 1-[2,4-dimethoxy-3-(3-phenylpropyl) phenyl] ethanone from the previous example in 250 ml of dichloromethane was stirred at -50oC, while for 15 min add 67 ml (67 mmole) of 1M trichromate boron in dichloromethane. The reaction mixture is stirred at -50oC for 1 h and at room temperature for 3 days before it was poured on ice. Processing a mixture of 9:1 dichloromethane and methanol in the usual manner yields a product that chromatographic on silica gel. Elution with a mixture of hexane-simple ether results in 6,69 g (74%) of the final compound as a solid substance. Recrystallization of a sample from a mixture of simple ether-hexane yields a colorless solid with a melting point 120-122oC.

Elemental analysis. Calculated for C17H18ABOUT3IN %: C 75,53; H OF 6.71. Found, %: C 75,31; H 6.73 X.

Example 7.

Obtaining 1-[2-hydroxy-4-(phenylmethoxy)-3-(3-phenylpropyl)phenyl]ethanone.

The mixture 6,69 g (24.7 mmole) of 1-[2,4-dihydroxy-3-(3-phenylpropyl) phenyl]ethanone from the previous example, 5.35 g (31,3 mmole) of benzylbromide, 14.9 g (to 0.108 mo is the IR under stirring for 8 hours After cooling, the suspension is filtered under vacuum and the solid residue is well washed with acetone. The filtrate and wash water are combined and concentrated under reduced pressure with the formation of a yellow oil, which chromatographic on silica gel. Get to 5.57 g (62.6 percent) of the desired monoether in the form of a pale yellow solid. Recrystallization of a sample from a mixture of hexane-ethyl acetate allows to obtain the target compound as colorless needles with a melting point 115-116oC.

Elemental analysis. Calculated for C24H24ABOUT3IN %: C 79,97; H OF 6.71. Found, %: C 79,97; H 6,80.

Example 8.

Obtain 7-(phenylmethoxy)-8-(3-phenylpropyl)-4H-1-benzopyran-4-it.

Using the procedure of example 1, 1-[2-hydroxy-4-(phenylmethoxy)-3- (3-phenylpropyl)phenyl] Etalon from the previous example make the final connection, receive a colourless solid with a melting point 106-107,5oC (recrystallization from a mixture of hexane-ethyl acetate) to yield of 56.7%.

Elemental analysis. Calculated for C25H22ABOUT3IN %: C 81,05; H 5,99. Found, %: C 81,20; H 5,99.

Example 9.

Obtain 2,3-dihydro-7-hydroxy-8-(3-phenylpropyl)-4H-1-benzopyran-4-it.

The wire is d 10% palladium on coal at room temperature and a pressure of 1 ATM in a mixture 1:1 methanosarcinaceae. Technical product purified by chromatography on silica gel, using as eluent a mixture of simple ether-dichloromethane. Get the target compound as a colourless solid with a melting point 110-112oC (recrystallization from a mixture of hexane-simple ether), the output is 44.9%.

Elemental analysis. Calculated for C18H18ABOUT3IN %: C 76,57; H TO 6.43. Found, %: C 76,42; H To 6.43.

Example 10.

Getting 2-oxo-2H-1-benzopyran-5-silt ether triftormetilfullerenov acid.

A mixture of 1.62 g (10 mmol) 5-hydroxycoumarin and 10 ml of dry pyridine in 25 ml of dichloromethane is stirred while cooling in an ice bath, while added dropwise 4.5 g (16 mmol) of anhydride triftormetilfullerenov acid. The mixture is stirred in the cold for 30 min and then allowed to warm to room temperature and stirred for further 30 min before poured into 3N hydrochloric acid. The treatment is simple with ether in the usual manner yields a yellow solid. After rapid chromatography on silica gel using as eluent a mixture of 2:1 hexane-ethyl acetate to obtain 2.6 g (88,4%) 2-oxo-2H-1-benzopyran-5-silt ether triftormetilfullerenov acid is but for C10H5F3O5S, %: C 40,83; H 1,71. Found, %: C 40,65; H 1,59.

Example 11.

Getting rat-5-[6-[(tetrahydro-2H-Piran-2-yl)oxy]-1-hexenyl]- 2H-1-benzopyran-2-it.

A mixture of 1.47 g (5 mmol) of 2-oxo-2H-1-benzopyran-5-silt ether triftormetilfullerenov acid from the previous example, 1.0 g (5.5 mmole) rat-6-[(tetrahydro-2H-Piran-2-yl)oxy] -1-hexyne, 75 mg of copper iodide, 0.3 g (0,428 mmole) of dichloro-bis(triphenylphosphine)palladium (II), 7.5 ml of triethylamine and 35 ml of dry N,N-dimethylformamide is stirred and heated at 100oC for 24 h, the Reaction mixture is cooled, poured into water and treated with simple ether in the usual manner. Dark brown oily residue quickly chromatographic on silica gel. Elution with a mixture of 2:1 hexane-ethyl acetate leads to the production of 1.09 g (67%) rat-5-[6-[(tetrahydro-2H-Piran-2-yl)oxy]- 1-hexenyl]-2H-1-benzopyran-2-it is in the form of an orange oil.

Example 12.

Obtaining methyl ester rat-(E)-3-[2-hydroxy-6-[6-[(tetrahydro - 2H-Piran-2-yl)oxy]-1-hexenyl]phenyl]-2-propanolol acid.

A solution of 1.09 g (3.3 mmole) rat-5-[6-[(tetrahydro-2H-Piran-2-yl)oxy]- 1-hexenyl] -2H-1-benzopyran-2-it is from the previous example and 1.8 ml (7,9 mmole) of 25% methanolic solution of methoxide n and reduced pressure. The residue is treated 1H hydrochloric acid and treated with ethyl acetate in the usual manner (organic extracts additionally washed with saturated aqueous sodium bicarbonate). The residue is purified by rapid chromatography on silica gel, using as eluent a mixture of 2:1 hexane-simple ether. Obtain 0.7 g (59%) of methyl ester rat-(E)-3-[2-hydroxy-6-[(tetrahydro-2H-Piran-2-yl)oxy] -1-hexenyl]- phenyl]-2-propanolol acid as a yellow oil. Processing of the sample thus obtained, hexane yields a colorless solid with a melting point 66-67,5oC.

Elemental analysis. Calculated for C21H26O5IN %: C 70,37; H 7,31. Found, %: C 70,24; H 7,33.

Example 13.

Obtaining the ethyl ester rat(E)-4-[2-(3-methoxy-3-oxo-1-propenyl)- 3-[6-[(tetrahydro-2H-Piran-2-yl)oxy]-1-hexenyl]-phenoxy]butane acid.

The mixture 7,16 g (20 mmol) of methyl ether rat-(E)-3-[2-hydroxy - 6-[6-(tetrahydro-2H-Piran-2-yl)oxy] -1-hexenyl] phenyl] -2-propanolol acid from the previous example, 4,37 g (22.4 mmole) ethyl-4-bromobutyrate, 8,32 g (60,29 mmole) of anhydrous granular potassium carbonate and 50 ml of dry dimethyl sulfoxide was stirred at room temperature in techage ether rat(E)-4-[2-(3-methoxy-3-oxo-1-propenyl)-3-[6-[(tetrahydro-2H - Piran-2-yl)oxy]-1-hexenyl]-phenoxy]butane acid as a yellow oil, containing approximately 10% ethyl-4-bromobutyrate (NMR data). This substance is used without further purification.

Example 14.

Obtaining methyl ester rat-2-(4-ethoxy-4-oxobutanoic)- 6-[6-[(tetrahydro-2H-Piran-2-yl)oxy]hexyl]benzoylpropionic acid.

9,73 g (20 mmol) sample of technical ethyl ester rat-4-[2-(3-methoxy-3-oxo-1-propenyl)-3-[6-[(tetrahydro-2H-Piran-2 - yl)oxy]-1-hexenyl]-phenoxy]butane acid from the previous example hydronaut in 275 ml of ethyl acetate over 0.75 g of 10%aqueous palladium on coal at room temperature and a pressure of 1 ATM for 24 h Methyl ether rat-2-(4-ethoxy-4-oxobutanoic)-6-[6-[(tetrahydro-2H-Piran-2 - yl)oxy] hexyl] benzoylpropionic acid in the form of oils extracted by filtering catalyzate and concentration of the filtrate with a quantitative yield (9,74 g).

Example 15.

Obtain methyl ester of 2-(6-hydroxyhexyl)-6-(4-methoxy-4 - oxobutanoic)benzoylpropionic acid.

The solution 9,74 g (20 mmol) of methyl ether rat-2-(4-ethoxy-4-oxobutanoic)-6-[6-[(tetrahydro-2H-Piran-2 - yl)oxy]hexyl]benzoylpropionic acid from the previous example, to 0.53 g of the monohydrate of p-toluenesulfonic acid in 270 ml of methanol is stirred and heated under reverse ether. The ether solution washed with saturated sodium bicarbonate solution and treated in the usual way of obtaining oil. This substance chromatographic on 200 g of silica gel, using as eluent a mixture of hexane-ethyl acetate. Get 7,03 g (92,5%) methyl ester of 2-(6-hydroxyhexyl)-6-(4-methoxy-4-oxobutanoic)benzoylpropionic acid as a colourless oil.

Example 16.

Obtain methyl ester of 2-(4-methoxy-4-oxobutanoic)-6-[6- [(methylsulphonyl)oxy] hexyl]benzoylpropionic acid.

The solution 7,03 g (18.5 mmole) of the methyl ester of 2-(6-hydroxyhexyl)-6-(4-methoxy-4-oxobutanoic)benzoylpropionic acid from the previous example and 22.5 ml of triethylamine in to 67.5 ml of ethyl acetate is stirred under cooling in an ice bath, while dropwise within 10 min add to 6.75 ml (87,25 mmole) of methanesulfonamide. The obtained thick suspension was stirred at 0-5oC for 10 min and then aged for 21 h at 0-5oC. the Mixture is treated with 100 ml of water and 100 ml of simple ether under cooling. The treatment is simple with ether in the usual manner (organic extracts additionally washed 1H aqueous solution of hydrochloric acid and saturated aqueous sodium bicarbonate) preproposal acid in the form of a pale yellow oil, which is used without further purification.

Example 17.

Obtain methyl ester of 2-(6-iohexol)-6-(4-methoxy-4 - oxobutanoic)benzoylpropionic acid.

The mixture 10,81 g (approximately 23,37 mmole) of technical methyl ester of 2-(4-methoxy-4-oxobutanoic)-6-[6-[(methylsulphonyl)oxy] hexyl]benzoylpropionic acid from the previous example, 7.01 g (46,7 mmole) of anhydrous sodium iodide and 44 ml of dry acetonitrile was stirred at room temperature for 17 h and then heated under reflux for 3.5 hours, After cooling the mixture is diluted with 200 ml of simple ether and filtered under vacuum. The solid is washed thoroughly simple ether. Combine the filtrate and the washing water and washed with 12% aqueous solution of sodium bisulfite, then treated in the usual manner. Get 11,14 g (97,3%) methyl ester of 2-(6-iohexol)-6-(4-methoxy-4-oxobutanoic)benzoylpropionic acid as a yellow oil.

Example 18.

Obtaining methyl ester 2-[6-[(3,4-dihydro-4-oxo-8-(3-phenylpropyl)- 2H-1-benzopyran-7-yl)oxy]hexyl]-6-(4-methoxy-4-oxobutanoic)benzoylpropionic acid.

The mixture 12,25 g (25 mmole) of the methyl ester of 2-(6-iohexol)-6-(4 - methoxy-4-oxobutanoic)bensultap the example 9), of 8.3 g (60 mmol) of anhydrous potassium carbonate and 60 ml of dry acetonitrile is stirred and heated under reflux for 22 hours, After cooling the mixture is diluted with simple ether and filtered under vacuum. Solid well washed with simple ether. Combine the filtrate and the washing water and concentrate under vacuum to obtain 16.5 g of a yellow oil. This substance chromatographic on silica gel, using as eluent a mixture of hexane-ethyl acetate. Get of 13.75 g (85,4%) of pure dimethyl ether, mentioned in the title, in the form of butter.

Example 19.

Getting 2-(3-carboxypropanoyl)-6-[6-[[3,4-dihydro-4-oxo-8-(3 - phenylpropyl)-2H-1-benzopyran-7-yl]oxy]hexyl]benzoylpropionic acid.

Fluids from the previous example (of 13.75 g; 21,35 mmol) omelet with stirring in 500 ml of tetrahydrofuran containing 60 ml of 3N aqueous lithium hydroxide at room temperature for 24 hours, the Tetrahydrofuran is removed under vacuum, the residue is dissolved in water and acidified with 3N aqueous solution of hydrochloric acid. The mixture is treated with ethyl acetate in the usual manner to obtain white solids. This substance is purified by rapid chromatography on silica gel, using as eluent a mixture of three leads to obtain 10.4 g (79%) decollate, specified in the title, in the form of a colourless solid with a melting point 104-106oC.

Elemental analysis. Calculated for C37H44O8IN %: C 72,06; H 7,19. Found, %: C 71,74; H 7,27.

Example 20.

Obtaining 3,4-dihydro-6-hydroxy-5-(2-propenyl)-1(2H)naftalina.

The solution 12,51 g (61,93 mmole) of 3,4-dihydro-6-(2-propenyloxy)- (2H)naftalina in 125 ml of N, N-diethylaniline stirred and heated on an oil bath with a temperature 225-230oC for 20,5 hours the resulting solution was dark amber color is cooled and poured into 300 ml of cold 3N HCl. The mixture is treated with simple ether in the usual manner with the formation of 12,29 g of yellow solid which is a mixture of 5 - and 7-allyl-isomers oxidational. This substance is recrystallized from ethyl acetate to obtain pure 5-allyl isomer with the release of 60% in several stages. The sample for analysis is a yellow solid with a melting point 145-148oC.

Elemental analysis. Calculated for C13H14ABOUT2IN %: C 77,20; H 6,98. Found, % : C 76,97; H 7,00.

Example 21.

Obtain methyl ester of 2-(4-methoxy-4-oxobutanoic)-6-[6-[[5,6,7,8- tetrahydro-5-oxo-1-(2-propenyl)-2-naphthalenyl] is talinay (from example 20), 8.5 g (of 17.35 mmole) of the methyl ester of 2-(6-iohexol)-6-(4-methoxy-4-oxobutanoic)benzoylpropionic acid (example 17), 5.8 g (42,0 mmole) of anhydrous potassium carbonate and 40 ml of anhydrous acetonitrile is stirred and heated under reflux for 24 hours the mixture is cooled, diluted with simple ether and filtered under vacuum. The solid is washed thoroughly with simple ether, then the combined filtrate and wash water and concentrated in vacuo. The residue is subjected to chromatographic purification on silica gel, using as eluent a mixture of hexane-ethyl acetate. End fluids get with quantitative yield (9,73 g) as a pale yellow oil.

Example 22.

Obtaining methyl ester (E)-2-(4-methoxy-4-oxobutanoic)-6- [6-[[5,6,7,8-tetrahydro-5-oxo-1-(3-phenyl-2-propenyl)-2-naphthalenyl] oxy] hexyl]benzoylpropionic acid.

The mixture 9,73 g (17,23 mmole) of the methyl ester of 2-(4-methoxy-4 - oxobutanoic)-6-[6-[[5,6,7,8-tetrahydro-5-oxo-1-(2-propenyl)-2 - naphthalenyl]oxy]hexyl] benzoylpropionic acid from example 21, of 3.84 g (18,86 mmole) of yogashala, of 2.93 g (17,72 mmole) of tetraethylammonium, 5,13 g (52,25 mmole) of anhydrous sodium acetate and 37 ml of dry N,N-dimethylformamide was stirred at room temperature and is based temperature for 22 hours The dark brown mixture is treated with simple ether and water and filtered through celite. The filtrate is treated with simple ether in the usual manner (ether extract is additionally washed with 12% aqueous solution of sodium bisulfite with getting 11,54 g technical product. This substance is subjected to chromatographic purification on 350 g of silica gel, using as eluent a mixture of hexane-ethyl acetate. Get 8,63 g (78%) of olefin, mentioned in the title, in the form of a pale yellow oil.

Example 23.

Obtain methyl ester of 2-(4-methoxy-4-oxobutanoic)-6-[6-[[5,6,7,8- tetrahydro-5-oxo-1-(3-phenylpropyl)-2-naphthalenyl] oxy] hexyl] benzoylpropionic acid.

Methyl ester (E)-2-(4-methoxy-4-oxobutanoic)-6-[6-[[5,6,7,8-tetrahydro - 5-oxo-1-(3-phenyl-2-propenyl)-2-naphthalenyl] oxy]hexyl]benzoylpropionic acid (0.54 g; 0,84 mmole) of the previous example hydronaut in 25 ml of ethyl acetate over 0.1 g of 10%aqueous palladium on coal at room temperature and a pressure of 1 ATM for 2 hours the Catalyst is filtered off and the filtrate is concentrated to obtain 0.52 g (96%) diapir specified in the title, in the form of a pale yellow oil.

Example 24.

Getting 2-(C-carboxypropanoyl)-6-[6-[[5,6,7,8-tetrahydro-5-oxo - 1-(3-phenylpro is 6-[[5,6,7,8-tetrahydro - 5-oxo-1-(3-phenylpropyl)-2-naphthalenyl] oxy] hexyl]benzoylpropionic acid from the previous example (0.52 g; 0.8 mmole) amyraut under stirring in 22 ml of tetrahydrofuran containing 2,6 ml of 3N aqueous solution of lithium hydroxide at room temperature for 24 h the Mixture was concentrated in vacuo. The residue is dissolved in water and acidified with 3N aqueous solution of hydrochloric acid. The treatment is simple with ether in the usual manner yields a viscous oily residue, which is subjected to a rapid chromatographic purification on silica gel, using as eluent a mixture of 90:10:5 toluene-ethyl acetate-acetic acid. Recrystallization of the United pure fractions from a mixture of hexane-ethyl acetate results in decollate indicated in the title, with the release of 73% (0.36 g) as a colourless solid with a melting point 89-91oC.

Elemental analysis. Calculated for C38H46O7IN %: C 74,24; H 7,54. Found, %: C 74,15; H 7,75.

Example 25.

Obtain methyl ester of 2-(4-methoxy-4-oxobutanoic)-6-[6-[(4-oxo - 8-(2-propenyl)-4H-1-benzopyran-7-yl)oxy]hexyl]benzoylpropionic acid.

To a suspension of 202 mg (of 5.05 mmole) of 60% dispersion of sodium hydride in mineral oil (previously washed with pentane) in 3 ml of anhydrous N,N-dimethylformamide add a solution of 0.77 g (3,81 mmole) 7-heroey room temperature for 15 min, then for 1 min add a solution of 2.1 g (4,29 mmole) of the methyl ester of 2-(6-iohexol)-6-(4-methoxy-4-oxobutanoic)benzoylpropionic acid (example 17) in 15 ml of anhydrous N,N-dimethylformamide. The resulting mixture was stirred at room temperature for 3 h, then treated with ice water and treated with ethyl acetate in the usual manner. The oily product chromatographic on silica gel, using as eluent a mixture of hexane-ethyl acetate. Obtain 1.7 g (79,1%) of the compound indicated in the title, in the form of a yellow oil.

Example 26.

Obtain methyl ester of 2-(4-methoxy-4-oxobutanoic)-6-[6-[(4-oxo-8- (3-phenyl-2-propenyl)-4H-1-benzopyran-7-yl)oxy] hexyl]benzoylpropionic acid.

Using the procedure of example 22, methyl ester 2-(4-methoxy-4-oxobutanoic)- 6-[6-[(4-oxo-8-(2-propenyl)-4H-1-benzopyran-7-yl)oxy]hexyl]benzoylpropionic acid from the previous example make the connection specified in the title, get blignault oil with a yield of 73%.

Example 27.

Obtaining methyl ester 2-[6-[(3,4-dihydro-4-oxo-8-(3-phenylpropyl)- 2H-1-benzopyran-7-yl)oxy]hexyl]-6-(4-methoxy-4-oxobutanoic)benzoylpropionic acid.

Using the method of example 23, metalowy acid is subjected to catalytic hydrogenation to obtain the compound, mentioned in the title, in the form of butter.

Example 28.

Getting 2-(3-phenylpropanamide)-1,3-cyclohexandione.

A solution of 11.2 g (0.1 mole) of 1,3-cyclohexanedione in 110 ml of ethanol was stirred at room temperature by adding 1 ml of piperidine and added dropwise over 2 min 13 ml (0,103 mole) transcoding aldehyde. The resulting mixture was stirred at room temperature for 2 h and then in an ice bath for 1 h Obtained yellow suspension is filtered under vacuum, and the solid is dried under high vacuum, receiving a 13.9 g (61,5%) Dion, mentioned in the title. Recrystallization of a sample of this substance from ethyl acetate yields a yellow solid with a melting point of 115.5-118oC.

Elemental analysis. Calculated for C15H14ABOUT2IN %: C 79,62; H 6,24. Found, %: C 79,46; H 6,34.

Example 29.

Getting 2-(3-phenylpropyl)-1,3-cyclohexandione.

A mixture of 6.8 g (30 mmol) of 2-(3-phenylpropanamide)-1,3-cyclohexandione from the previous example, 0.7 g of 10% palladium on coal and 150 ml of ethyl acetate was stirred at room temperature in hydrogen atmosphere until there is no further absorption of gas. The catalyst otfit is, the white solid that is used without further purification.

Example 30.

Obtaining 3-(2-tzanetaki)-2-(3-phenylpropyl)-2-cyclohexen-1-it.

A mixture of 6.7 g (29 mmol) of 2-(3-phenylpropyl)-1,3-cyclohexandione from the previous example, 9,9 ml (0,145 mole) 3-hydroxypropionitrile, 0.3 g of the monohydrate of p-toluenesulfonic acid and 110 ml of toluene is stirred and heated under reflux using to remove the water trap Dean-stark for 3 hours the Mixture is cooled, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. Processing completed in the usual manner, gaining 9.3 g of a yellow oil. This substance chromatographic on silica gel. Elution with a mixture of hexane-ethyl acetate leads to obtain 5.9 g (71.6 per cent) of the compound indicated in the title, in the form of a yellow oil.

Example 31.

Obtaining 3-(2-tzanetaki)-2-(3-phenylpropyl)phenol.

To a stirred solution of 6.7 g (23.7 mmole) 3-(2-tzanetaki)-2-(3-phenylpropyl)-2-cyclohexen-1-it (the previous example) in 75 ml of dichloromethane, cooled to 0-5oC add 6.8 g (of 23.8 mmole) of 1,3-dibromo-5,5-dimethylhydantoin. After stirring for 30 min in the cold, add 50 ml of saturated water restate substance is dissolved in 125 ml of toluene and added to 7.1 g (63.4 mmole) of 1,4-diazabicyclo[2.2.2] octane. The mixture is stirred and heated under reflux for 30 min, then cooled and treated with 2n. the hydrochloric acid. Treatment of ethyl acetate in the usual manner leads to an orange oil, which chromatographic on silica gel. Elution with a mixture of hexane-ethyl acetate leads to obtain 3.5 g (52.6 per cent) of phenol, mentioned in the title, in the form of a yellow oil.

Example 32.

Obtain 2,3-dihydro-7-hydroxy-8-(3-phenylpropyl)-4H-1-benzopyran-4-it.

A mixture of 3.5 g (12.5 mmole) of 3-(2-tzanetaki)-2-(3-phenylpropyl)phenol (previous example), 16 ml of 85% phosphoric acid and 7.7 ml of acetic acid is stirred and heated at 125oC for 23 hours After cooling, the mixture is diluted with water and treated with ethyl acetate in the usual manner to obtain 4 g of red oil. This substance chromatographic on silica gel. Elution with a mixture of hexane-ethyl acetate allows to obtain 2.3 g (65.2 percent) of the connection specified by name, in the form of a yellow solid.

Example 33.

Obtaining (E)-2-(3-carboxypropanoyl)-6-[6-[[5,6,7,8-tetrahydro-5-oxo-1- (3-phenyl-2-propenyl)-2-naphthalenyl]oxy]hexyl]benzoylpropionic acid.

Methyl ester (E)-2-(4-methoxy-4-oxobutanoic)-6-[6-[[5,6,7,8-tetraols the method of example 19, getting decollate indicated in the title, with the release of 82% in the form of a colourless solid with a melting point of 102-104oC, recrystallized from a mixture of hexane-ethyl acetate.

Elemental analysis. Calculated for C38H44O7IN %: C 74,49; H 7,24. Found, %: C 74,28; H 7,14.

Examples 34-39 listed at the end of the description.

1. Bicyclic carboxylic acids of formulas a, b and C

< / BR>
< / BR>
< / BR>
where R2in each case, independently of one another denote a hydroxyl group or a lower CNS group, Ph denotes phenyl, and compounds of formula With its geometric isomer, and in the case when R2means a hydroxyl group, a pharmaceutically applicable salt of this compound with the base.

2. Connection on p. 1 of formula A.

3. Connection on p. 2, which is 2-(3-carboxypropanoyl)-6-[6-[[3,4-dihydro-4-oxo-8-(3-phenylpropyl)-2H-1-benzopyran-7-yl] oxy] hexyl]benzoylpropionate acid.

4. Connection on p. 1 formula Century.

5. Connection on p. 4, which is 2-(3-carboxypropanoyl)-6-[6-[[5,6,7,8-tetrahydro-5-oxo-1-(3-phenylpropyl)-2-naphthalenyl] oxy] hexyl]benzoylpropionate acid.

6. Connection on p. 1 FeO-5-oxo-1-(3-phenyl-2-propenyl)-2-naphthalenyl] oxy]hexyl]benzoylpropionate acid.

8. The compound according to any one of paragraphs.1-7, inhibiting the biological activity of leukotriene4.

9. The pharmaceutical composition inhibiting the biological activity of leukotriene4containing the compound according to any one of paragraphs.1-7 as an effective dose and a therapeutically inert carrier.

 

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< / BR>
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The invention relates to the field of acids, in particular to a method for producing derivatives of propanolol acid of General formula

and their stereoisomers, where A is hydrogen, halogen, C1-C4-alkyl, C1-C4-alkoxy, hydroxy, phenoxy or1-C4-alkylsulphonyl; It represents oxygen or sulfur; X IS O, S(O)n, NH, NR1: CH2, CHR2, CO, CH2CH2CH = CH, OCH2, (CH2)mO, CHR1O, OCH2O, S(O)nCH2, S(O)CH2O, NR1CH2, COO, OOC, SO2O COCH2O, COCHR1O, CONH, NHCO, NHSO2COS, SCO, N = N, CH2OCO, CH2SCO, CH2NHCO, CH2ON = CH2, OCH2CH2O, NR1N = CH, CH2OCON, CH = CHCH2O, (R2)2P+CH2Q-, N(COR1), N = CH, CH(OH), CO2CH2, SCH2O, NR1CO, S(O)2NH or CONR1; R1- C1-C4-alkyl; R2is phenyl; n is 0,1 or 2; m - 1,2,3,4, or 5; Q is a halide anion; Z is phenyl (possibly monosubstituted WITH1-C6-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, phenoxy,

by phenyl, amino, hydroxy, 1-(C1-C4-alkoxycarbonyl is, or mono - or disubstituted by halogen, nitro, C1-C4-alkyl or cyano; naphthyl, chinoline, pyridinyl (possibly monosubstituted WITH1-C4-alkyl, C1-C4-alkoxycarbonyl, amino, halogen, nitro, C1-C4-alkylcarboxylic, di-(C1-C4-alkylsulfonyl)amino, or CH(O)NH, or mono - or disubstituted WITH1-C4-haloalkyl or cyano, or a disubstituted amino group and one from cyano, halogen or1-C4-alkoxygroup or disubstituted by nitro-group and one of cyano, halogen, di-(C1-C4-alkyl)amino or1-C4-alkoxygroup or substituted by cyano and two WITH1-C4-alkyl groups); pyrimidinyl (possibly: monosubstituted WITH1-C4-alkyl, C1-C4-haloalkyl,1-C4-alkylthio, cyano, nitro, phenyl, HO2C1-C4-alkoxycarbonyl or1-C4-alkylsulfonyl, or mono - or disubstituted WITH1-C4-alkoxy, or mono-, di - or tizamidine halogen, or disubstituted by halogen and one from C1-4alkyl or C1-4alkylthio, or disubstituted WITH1-4alkyl and C1-4haloalkyl), pyrazinyl (possibly mannose is hydrated WITH1-C4-alkoxy, phenyl or aminocarbonyl, or mono - or disubstituted by halogen, or disubstituted by halogen and C1-C4-alkyl), benzothiazolyl, thienyl (possibly monosubstituted by pyrazolyl), which itself Disaese1-C4the alkyl and C1-C4-haloalkyl (or pyridinyl), which itself may monogamist nitro (or disubstituted by halogen), 1,2,4-triazolyl, honokalani (monosubstituted by halogen), 1,3,5-triazinyl (disubstituted by halogen, or disubstituted by halogen and C1-C4-alkoxy), thiazolyl (possibly monosubstituted nitro or mono-or disubstituted WITH1-C4-alkyl), benzoxazolyl, pyridinyl-N-oxide, thieno[2,3-d] pyrimidinyl, pyrrolyl (possibly monosubstituted WITH1-C4-alkyl), isoxazolyl (monosubstituted WITH1-C4-alkyl), 1,3,4,-thiadiazole, pyrazolyl (substituted with halogen and two WITH1-C4-alkyl groups) or 1,2,4-triazinyl (monosubstituted with phenyl); provided that, when Z represents unsubstituted phenyl, and X and both represent oxygen, then A is not hydrogen; which possess fungicidal activity
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