Method of valsartan obtainment

FIELD: chemistry.

SUBSTANCE: compound of general formula IIa or its salt, where R1 is hydrogen or protection group of tetrazol, undergoes reaction with compound of formula or its salt, where R2 is hydrogen or carboxy protection group, under conditions of reduction amination, with further acylation of obtained compound of formula or its salt by compound of formula , where R3 is the group to be separated; and with removal of protection groups if required.

EFFECT: new compounds with useful biological properties.

12 cl, 11 ex

 

The present invention relates to a method for producing blocker angiotensinogen receptor (ARB; also called antagonist of the angiotensin II receptor or a receptor antagonist AT1) and its salts, to new intermediate compounds and phases of the method. ARB may, for example, be used for the treatment of hypertension and related diseases and conditions.

The ARB class includes compounds with different structural features, particularly preferable ones are compounds. For example, there can be mentioned compounds selected from the group consisting of valsartan (EP 443983), losartan (EP 253310), candesartan (EP 459136), eprosartan (EP 403159), irbesartan (EP 454511), olmesartan (EP 503785) and tasosartan (EP 539086), or, in each case, their pharmaceutically acceptable salts.

All these ARB include the following common structural element:

Education tetrazole ring is a critical stage in obtaining these compounds. Methods of obtaining ARB with such structural features include the education of the specified tetrazole rings on the basis of relevant cyanoderivatives that react with HN3or a suitable salt of an alkali metal such as sodium azide, or with an organic tin azide, such as azide inputs of TBT or silylation. When is the change of azides to get tetrazole ring system requires a complex system to ensure the safety of reactions in large-scale production. Accordingly, the aim is to develop an alternative method that would preclude the use of azides in the final stages of obtaining the appropriate ARB.

The aim of the present invention is the synthesis of compounds of formula (I), which (1) does not include the stage of the method using azide, (2) leads to good outputs, (3) reduces environmental pollution, for example, excluding organic compounds of tin, (4) is efficient through the use of a smaller number of reaction stages to obtain the compounds of formula (I), (5) provides enantiomerically pure final products and high ability to crystallization. In addition, since terazosina ring system formed in the early stages of the reaction, (6) the risk of contamination of the final product (and the last intermediate compounds) trace quantities of components tin is smaller. Usually, tetrazole ring is formed by reaction of the corresponding cyanoderivatives with an organic compound of tin such as azide presence of TBT. For environmental reasons, heavy metal, tin and especially organic tin compounds administered with caution. In addition, (7) another objective of this invention is to provide a method which can be carried out on an industrial scale and can use isolates for the appropriate way to obtain and to eliminate, for example, racemization, and, thus, to separate any of enantiomers.

Unexpectedly it was found that the method in accordance with the present invention meets the above objectives.

The present invention relates to a method for obtaining compounds of formula (I)

or its salts, including:

(a) reaction of compounds of formula (IIa)

or its salts, where R1represents hydrogen or a protective group tetrazole, with the compound of the formula

or its salt, where R2represents hydrogen or carboxyamide group, under conditions of reductive amination; and

(b) acylation of the obtained compound of the formula (IIc)

or its salt with the compound of formula (IId)

where R3represents an activating group; and

(b) if R1and/or R2are other than hydrogen, removing the protective group (s) in the resulting compound of formula (IIe)

or its salt; and

(g) isolation of the compounds of formula (I) or its salt; and, optionally, converting the obtained free acid of the formula (I), its salt, or the conversion of the salts of the compounds of formulas is (I) in the free acid of the formula (I), or the conversion of the salts of the compounds of formula (I) into a different salt.

The above and further reactions in the embodiments provide, for example, in the absence of or usually in the presence of a suitable solvent or diluent or a mixture thereof, the reaction is optionally carried out under cooling, at room temperature or while heating, for example at a temperature in the region of approximately from -80°C to the boiling temperature of the reaction medium, preferably from approximately -10°With approximately +200°and, if necessary, in a closed vessel, under pressure, in an atmosphere of inert gas and/or in anhydrous conditions.

Compounds of formula (IIa), (IIb), (IIc) and (IIe), in which one or both R1and R2represent hydrogen, can form salts with bases, and since unprotected tetrazole ring, and unprotected carboxypropyl have acid properties, whereas the compounds of formulas (IIb) and (IIe) can also form salts with acids.

Corresponding terazosina protective group (R1) is selected from the groups known from the prior art. Especially R1is selected from the group consisting of tert-C4-C7-alkyl, such as tert-butyl; C1-C2-alkyl, which is mono-, di or triamese by phenyl, such as benzyl or benzhydryl or trityl, where the phenyl ring is the tsya unsubstituted or substituted by one or more, for example, two or three residues, such as residues selected from the group consisting of tert-C1-C7-alkyl, hydroxy, C1-C7-alkoxy, C2-C8-alkanoyloxy, halogen, nitro, cyano and trifloromethyl (CF3); picoline; butoxide; has been studied; allyl; cynnamoyl; fluorenyl; Silla, such as three-From1-C4-alkylsilane, such as trimethylsilyl, triethylsilyl or tert-butyldimethylsilyl, or di-C1-C4-alkylresorcinol, for example dimethylphenylsilane; C1-C7-alkylsulfonyl; arylsulfonyl, such as phenylsulfonyl, where the phenyl ring is unsubstituted or substituted by one or more, for example two or three, residues, such as residues selected from the group consisting of C1-C7-alkyl, hydroxy, C1-C7-alkoxy, C2-C8-alkanoyloxy, halogen, nitro, cyano and CF3; C2-C8alkanoyl, such as acetyl or valeryl; and esterified carboxy, such as1-C7-alkoxycarbonyl, for example methoxy-, ethoxy - or tert-Butylochka-carbonyl; and allyloxycarbonyl. Examples of preferred protective groups are tert-butyl, benzyl, p-methoxybenzyl, 2-phenyl-2-propyl, diphenylmethyl, di(p-methoxyphenyl)methyl, trityl, (p-methoxyphenyl)diphenylmethyl; diphenyl(4-pyridyl)methyl, b is silkymail, methoxymethyl, ethoxymethyl, methylthiomethyl, 2-tetrahydropyranyl, allyl, trimethylsilyl and triethylsilyl.

Corresponding carboxyamide group (R2) is selected from the groups known from the prior art. Especially R2is selected from the group consisting of C1-C7-alkyl, such as methyl, ethyl or tert-C4-C7-alkyl, especially tert-butyl; C1-C2-alkyl, which is mono-, di - or tizamidine by phenyl, such as benzyl or benzhydryl, where the phenyl ring is unsubstituted or substituted by one or more, for example two or three, residues, such as residues selected from the group consisting of C1-C7-alkyl, hydroxy, C1-C7-alkoxy, C2-C8-alkanoyloxy, halogen, nitro, cyano and CF3; picoline; butoxide; allyl; cinnamyl; tetrahydrofuranyl; tetrahydropyranyl; methoxyethoxymethyl and benzyloxyethyl. Preferred examples of the protective group is benzyl.

Activating the group R3represents, for example, an activating group, which is used in the chemistry of peptides, such as halogen, such as chlorine, fluorine or bromine; C1-C7-alkylthio, such as methylthio, ethylthio or tert-butylthio; pyridylthio, such as 2-pyridylthio; imidazoles, such as 1-imidazolyl; benzothiazolinone, such as estazolam-2-hydroxy-; benzotriazoles, such as benzotriazolyl-1-hydroxy-; C2-C8-alkanoyloxy, such as butanoyloxy or pivaloyloxy; or 2,5-dioxopyrimidine.

Used here and hereinafter : General terms have the following meanings, unless otherwise indicated:

With1-C7-Alkyl represents, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or the appropriate pentyl, hexyl or heptyl. With1-C4-alkyl, especially methyl, ethyl or tert-butyl, are preferred.

With1-C7-Alkoxy is, for example, methoxy, ethoxy, n-propyloxy, isopropoxy, n-Butylochka, isobutoxy, sec-Butylochka, tert-Butylochka or the corresponding pentyloxy, hexyloxy or heptyloxy. C1-C4-alkoxy is preferred. Especially preferred is methoxy, ethoxy and tert-butoxy.

With2-C8-Alkanoyl in C2-C8-alkanoyloxy represents acetyl, propionyl, butyryl, isobutyryl or pivaloyl. With2-C5-Alkanoyl is preferred. Especially preferred is acetyl or pivaloyl.

A represents a halogen, in particular chlorine, fluorine or bromine, and in a broad sense includes iodine. Chlorine is preferred.

Stage (a):

In reaction stage (a) recovery Amini, the Finance is carried out in the presence of a reducing agent. Suitable regenerating agent is a borohydride, which can also be in the form of a complex, or hydrogen or a hydrogen donor, in the presence of a hydrogenation catalyst. In addition, the regenerating agent is suitable selenide or silane.

A suitable borohydride or borhydride complex is, for example, alkali metal borohydride such as sodium borohydride or lithium borohydride; borohydride alkaline-earth metal such as calcium borohydride; cyanoborohydride alkali metal, such as cyanoborohydride sodium or cyanoborohydride lithium tri-(C1-C7-alkoxy)-borohydride of an alkali metal, such as trimethoxyborohydride sodium; Tetra-C1-C7-alkylamino-(cyano)borohydride, such as tetrabutylammonium or tetrabutylammonium.

A suitable catalyst for reductive amination with hydrogen or a hydrogen donor is, for example, Nickel, such as Raney Nickel, noble metals or derivatives thereof, for example oxides, such as palladium, platinum or platinum oxide, which can be used, if necessary, on the media, such as coal or calcium carbonate, for example platinum on coal. Hydrogenation with hydrogen or a hydrogen donor may preferably be carried out under a pressure between 1 and approx the tion to 100 atmospheres and at a room temperature of approximately from -80° approximately 200°With, in particular between room temperature and about 100°C.

The preferred hydrogen donor is, for example, the system comprising 2-propanol and, if necessary, the base, or, most preferably, formic acid or its salt, for example, alkaline metal, or three-From1-C7-alkyl-ammonium salt, for example sodium or potassium hydroxide, optionally in the presence of a tertiary amine such as triethylamine. Other hydrogen donors include other alcohols, such as ethanol, 2-ethoxyethanol, benzyl alcohol, benzhydrol, pentane-2-ol, 1,2-ethanediol, 2,3-butanediol or cyclohexanediol, hydrazine, cyclohexene, cyclohexadiene, indan, tetralin, indolin, tetrahydroquinolin, hydroquinone, gipofosfita acid or a suitable salt such as sodium salt, tetrahydroborate sodium, carbohydrates, ascorbic acid, citric or silanes. The hydrogen donor may also be used as a solvent, especially 2-propanol or formic acid.

Suitable selenide is, for example, selenophene, which is unsubstituted or substituted. Suitable substituents include, for example, one, two or three substituent selected, for example, from halogen, trifloromethyl, triptoreline,1-C7-alkyl, C1-C7-alkoxy, nitro, cyano, GI is Roxie, With2-C12alkanoyl,1-C12-alkanoyloxy and carboxy. Preferred are those silanes which are completely soluble in the reaction medium and which can produce organically soluble by-products. Especially preferred are tri-C1-C7-alkylsilane, especially triethylsilane and triisopropylsilane. Preferred are commercially available selenides.

A suitable silane is, for example, silane, which is trisemester Deputy selected from the group consisting of C1-C12-alkyl, especially With1-C7-alkyl, and C2-C30-acyl, especially C1-C8-acyl. Preferred are commercially available silanes.

Reductive amination is preferably carried out in an acid, neutral or preferably basic conditions. Suitable base includes, for example, the hydroxide or carbonate of an alkali metal such as sodium hydroxide, potassium hydroxide or potassium carbonate. In addition, can be used amine base, such as tri-C1-C7-alkylamine, such as triethylamine, tri-n-Propylamine, tributylamine or ethyldiethanolamine, piperidine derivatives, such as N-methylpiperidine, or research, such as N-methylmorpholine. Preferred bases include hydroxy is lithium sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate. Especially preferred is sodium hydroxide, sodium carbonate or tri-n-Propylamine.

Reductive amination is carried out in a suitable inert solvent or mixture of solvents, including water. Inert solvents typically do not react with the corresponding source reagents of the formulae (IIa) and (IIb). If the reducing agent is used, the alkali metal borohydride such as sodium borohydride or lithium borohydride; borohydride alkaline-earth metal such as calcium borohydride; cyanoborohydride alkali metal, such as cyanoborohydride sodium or cyanoborohydride lithium, for example, preferred is a polar solvent, for example an alcohol, such as methanol, ethanol, isopropanol or 2-methoxyethanol, or glyme. If the reducing agent is used three (1-C7-alkoxy)-borohydride of an alkali metal, such as trimethoxyborohydride sodium; Tetra-C1-C7-alkylamino-(cyano)borohydride, such as tetrabutylammonium-borohydride or tetrabutylammonium-cyanoborohydride, for example hydrocarbons, such as toluene, esters such as ethyl acetate or isopropylacetate, ethers, such as tetrahydrofuran or tert-butylmethylamine EF the R, are preferred. If the retrieval system uses hydrogen or a hydrogen donor, each in the presence of a hydrogenation catalyst, a polar solvent is preferred. Reductive amination can also be, for example, in a mixture of organic solvent in water, mono - and two-phase state. In the two-phase system can be added to the catalyst transfer phases, such as tetrabutylammonium halide, for example bromide, or halide designed, for example chloride.

If R1and R2both represent a protective group, and if the compound of formula (IIb) is a freelance basis, the presence of a base is not required. However, if R1represents hydrogen and R2represents a protective group, can be added to not less than the molar equivalent of the base. To eliminate the racemization reaction is preferably carried out less than one equimolar amount of base. If R1and R2each represents hydrogen, racemization does not occur, even if the reaction is carried out is equal to or more than one equivalent of base under mild conditions, preferably at temperatures between -10°and 20°C.

The present invention also relates to compounds of the formula (IIa), which could is t be used as intermediates for obtaining the compounds of formula (I).

The present invention also relates to compounds of the formula (IIb), which can be used as intermediates for obtaining the compounds of formula (I).

The reaction of the compound of formula (IIa) with the compound of the formula (IIb) immediately leads to the production of imine (Schiff base) of the formula (IIc'):

which can, under certain reaction conditions, can be allocated or which may be subject to recovery without highlighting.

Reductive amination is a two-step reaction involving the formation of the imine with the elimination of water molecules with the subsequent stage of recovery. Banding is a reversible reaction that can be performed to obtain the imine with constant removal of water, for example, azeotropic removal. In addition, the removal or inactivation of free water can be used sink water, which can act in a physical way, such as absorption or adsorption, or chemical reaction. Suitable water receiver includes, but is not limited to, anhydrides of organic acids, silicates, such as molecular sieves, other zeolites, finely ground silica, finely ground aluminum, anhydrides of inorganic acids, such as anhydride phosphorus (P2O5), inorganic sulfates, so is e as calcium sulfate, the sodium sulfate and magnesium sulfate and other inorganic salts such as calcium chloride.

If stage (a) is performed with the receipt and allocation of the compounds of formula (IIc'), the compound of formula (IIa) is subjected to reaction with the compound of the formula (IIb), possibly in the presence of a base, if R1and/or R2represent hydrogen. The compounds of formula (IIc') can then be converted into the corresponding compounds of formula (IIc) the restoration of the compounds of formula (IIc') corresponding regenerating agent specified above.

Intermediate Imin formula (IIc'), for example, can be isolated by removing the solvent, e.g. by distillation, especially with azeotropic removal of water.

In a preferred embodiment, reductive amination carried out without isolating the compounds of formula (IIc').

Reductive amination is most preferably carried out without removal of free water, especially if R1and R2represent hydrogen, with a base, such as sodium hydroxide, in a solvent such as methanol, and regenerating reagent such as sodium borohydride.

Thanks imine structural element, the compounds of formula (IIc') include the corresponding E, and the corresponding Z-isomer. Preferred is the E-isomer.

The present invention also regarding the Xia to compounds of the formula (IIc'), in which R1represents hydrogen or a protective group tetrazole and in which R2represents hydrogen or carboxyamide group. Such compounds can be used as intermediates for obtaining the compounds of formula (I). Preferred are the compounds of formula (IIc'), in which at least one of R1and R2represents hydrogen or both R1and R2represent hydrogen.

Compounds of formulas (IIa) and (IIb) are known and can be obtained by known methods.

Another embodiment of the present invention is a method of obtaining the compounds of formula

or its salts, including

(i) reaction of compounds of formula

or its salts, where Hal represents halogen, with a compound of the formula

where R6, R7and R8independently from each other represent hydrogen or C1-C5-alkyl, such as methyl or ethyl, and R9represents a C1-C6-alkyl, or R7and R9together form2-C5-alkylene, such as ethylene, propylene, butylene, or R6and R8together form3-C6-alkylen, in the presence of acid; and

ii) reaction of the compounds of the formula

with the compound of the formula

where X is a halogen, such as iodine, bromine or chlorine, and R5and R'5independently from each other represents a C1-C7-alkyl, such as methyl or ethyl, or together form With the2-C4-alkylene, such as ethylene, propylene, butylene or 1,2-dimethylethylene or 2,2-dimethylpropylene, in the presence of a transition metal catalyst; and

(iii) removing the next, or at the same stage protective group from the resulting compound of the formula

by treatment with an acid, preferably in the presence of water,

(iv) obtaining the compounds of formula (IIa') or its salt.

Reaction stage (i)to(iv)described above in embodiments, is carried out, for example, in the absence of or usually in the presence of a suitable solvent or diluent or a mixture thereof, the reaction is optionally carried out under cooling, at room temperature or while heating, for example at a temperature in the region of approximately from -80°C to the boiling temperature of the reaction medium, preferably from approximately -10°With approximately +200°and, if necessary, in a closed vessel, under pressure in the atmosphere of inert gas and/or under anhydrous conditions.

Stage (i) is carried out, for example, in Pris the accordance from 0.0001 to 0.1 equivalents, preferably from 0.001 to 0.04 equivalents of acid Bronsted, such as sulfuric acid, hydrochloric acid, phosphoric acid, methanesulfonate acid, econsultancy acid, para-toluensulfonate acid, camphor-10-sulfonic acid, triperoxonane acid, trichloroacetic acid, O,O'-dibenzoyltartaric acid and the like.

The reaction is carried out in a solvent which is stable enough to anhydrous acidic conditions, for example in ethyl acetate, izopropilazette in an aromatic solvent such as toluene or xylene, or in an ether solvent, such as tert-butyl methyl ether, tetrahydrofuran, butyl ether, or 1,2-dimethoxyethane, or a nitrile, such as acetonitrile. The preferred solvent is toluene. The temperature of the reaction support between 15°and the boiling temperature of the reaction medium, preferably between 30 and 60°C.

Stage (ii) is carried out, for example, using a conventional transition metal catalyst, for example, corresponding to the commonly used platinum or palladium catalyst, such as dichlorobis(triphenylphosphine)palladium(II).

Stage (iii) is carried out, for example, by dissolving the compounds of formula (IVe) in water or in a mixture of water and a suitable organic solvent and subsequent treatment of the acid with appreciation the TES temperature. Crystallization of the product is accompanied by distillation of all or part of the organic solvent, adding water, cooling the mixture, or combine these methods. Suitable organic solvents are ethers, such as tetrahydrofuran, 1,4-dioxane, butyl ether, NITRILES, such as acetonitrile, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, isopropylacetate, toluene, xylene, acetic acid or formic acid. Preferred solvents are methanol and ethanol. Suitable acids are acid Bronsted, such as sulfuric acid, hydrochloric acid, phosphoric acid, methanesulfonate acid, econsultancy acid, para-toluensulfonate acid, benzoic acid, acetic acid, formic acid. Preferred acids are sulfuric acid and hydrochloric acid. The acid is used in amounts of from 0.05 to 6.0 equivalents relative to the source reagent, preferably from 0.1 to 1.5 equivalents.

Stage (iv) the selection carried out by conventional methods of separation, such as crystallization of the compounds of formula (IIa') from the reaction mixture, if desired or necessary after the treatment, especially extraction, or chromatography of the reaction mixture.

The compounds of formula (IVd) are obtained by the reaction of compounds of formula

where X represents a halogen, for example bromine, magnesium in the conditions of the Grignard reaction, especially in anhydrous conditions, preferably in the presence of an activator, such as 1,2-dibromethane, obtaining the compounds of formula

which is then treated with Zn(X)2X represents halogen, especially chlorine.

As stated in the beginning of the description, most of receptor antagonists angiotensin II includes, as the structural features tetrazole ring. In the sequence of receipt of such compounds for tetrazole rings necessary protective group.

For example, is used triphenylethylene group to protect tetrazole ring against ORGANOMETALLIC reagents. Triphenylethylene group later cleaved in acidic conditions. The disadvantage triphenylmethyl group is its molecular weight. 2-Phenyl-2-propylnitrosamine protective group is used when interacting with the metal until the next reaction. The removal of this protective group requires the use of corrosive and toxic reagents, such as Efrat of boron TRIFLUORIDE, or the stage of removing protection, catalyzed by the transition metal, which is undesirable.

Protection tetrazole rings in respect of ORGANOMETALLIC reagents with 2-methyl-2-through GRU the dust is another option. To remove this group required a hard acidic conditions that are not suitable for sensitive functional groups end connections.

Alternatively, use 2-cyanoethylene protective group tetrazole. The low stability of this protective group relative to the majority of ORGANOMETALLIC reagents and the formation of toxic by-products during the removal of protection are its disadvantages.

Tetrazole rings can also be protected (phenylmethyl)oxymethylene group. However, one of the two received isomers is unstable in respect of ORGANOMETALLIC reagents, not only at high temperatures.

The aim of the present invention is a method of synthesis of compounds of formula (IIa') or its salt with protective groups that (1) does not have the above shortcomings, (2) are easily entered with a good yield, (3) have a low molecular weight, (4) are stable in the presence of ORGANOMETALLIC reagents, such as zingarelle and maggiorenni connection (5) is easily removed with a high yield in acidic conditions suitable sensitive functional groups such as formyl group.

It has been unexpectedly discovered that the above method meets the above objectives. For example, a specialist in the art could not before ologit, the compounds of formula (IVc) can be used to bind with the compound of the formula (IVd) as appropriate protective groups tetrazole ring compounds of the formula (IVd), which is not considered to be stable in such reactions ORGANOMETALLIC binding. The specialist in this area would suggest that the appropriate protective group tetrazole formula (IVd) was tsapralis. In addition, the specialist in this area would suggest that the appropriate protective group tetrazolo formula (IVe) was tsapralis would easily under mild conditions specified above.

Accordingly, another embodiment of the present invention are new compounds of the formulas (IVa), (IVb), (IVc), (IVd), (IVd'), (IVd) and (IVe), especially the compounds of formula (IVe).

The preferred implementation of this variant of the present invention relates to the compound of the formula

where R5and R'5independently from each other, represent a1-C7-alkyl, such as methyl or ethyl, or together form With the2-C4-alkylene, such as ethylene, propylene, butylene or 1,2-dimethylethylene or 2,2-dimethylpropylene, or where R6, R7and R8independently from each other represent hydrogen or C1-C7-alkyl, such as methyl or ethyl, and R9represents a C1-the 7-alkyl, or R7and R9together form2-C5-alkylene, such as ethylene, propylene, butylene, or R6and R8together form3-C6-alkylen.

Preferred compounds of formula (IVe) are compounds where R5and R'5independently from each other, represent a1-C4-alkyl, such as methyl or ethyl, or together form With the2-C4-alkylene, such as ethylene, propylene, butylene or 1,2-dimethylethylene or 2,2-dimethylpropylene, or where R6, R7and R8independently from each other represents hydrogen or C1-C4-alkyl, such as methyl or ethyl, and R9represents a C1-C4-alkyl, or R7and R9together form2-C5-alkylene, such as ethylene, propylene, butylene.

Even more preferred compounds of formula (IVe) are compounds where R5and R'5independently from each other, represent a C1-C3-alkyl, such as methyl, ethyl or propyl, or where R6, R7and R8represents hydrogen, and R9represents a C1-C4-alkyl.

The most preferred compounds of the formula (IVe) are compounds where R5and R'5independently from each other, represent a C1-C3-alkyl, such as IU the sludge, ethyl or propyl, and R6and R8represent hydrogen, and R7and R9together form2-C3-alkylene, such as ethylene or propylene.

Especially preferred are the compounds of formula (IVe), which are specifically described in the examples.

In another embodiment of the invention the reaction stage (a) can be combined with the formation of the compounds of formula (IIa) in the usual oxidation of the corresponding hydroxymethylene derivative of the formula

the normal recovery of the corresponding carboxylic acid derivative of the formula

where R4represents, for example, hydroxy, C1-C7-alkoxy or halogen, such as chlorine; or by hydrolysis of the acetal of the formula

where R5and R'5independently from each other, represent a1-C7-alkyl, such as methyl or ethyl, or together form With the2-C4-alkylene, such as ethylene, propylene or butylene or 1,2-dimethylethylene.

The present invention also relates to the reaction stage (a), particularly to the recovery stage by reductive amination. If the reaction is carried out, for example, borohydride and under basic conditions in a polar solvent, optionally in the presence of water, preferably in the lower (especially anhydrous) alkanol, such as methanol, ethanol, isopropanol or glyme, the obtained compound of the formula (IIc) or (IIc'), respectively, may be obtained essentially in enantiomerically pure form. It is assumed that the basic conditions, usually at least partial racemization. In contrast, unexpectedly, for example, can be obtained enantiomeric excess (EE) of the compounds of formula (IIc) or (IIc') respectively ≥95%, preferably ≥98% and most preferably ≥99%.

Stage (a) is preferably carried out under mild conditions, especially at a temperature in the region of from about -10°With approximately room temperature, preferably in the region from about -5°C to +5°C.

Stage (b):

In reaction stage (b) carry out the acylation, for example, in the absence or in the presence of a suitable base.

Suitable bases are, for example, hydroxides or carbonates of alkali metals, morpholino or piperidino amines, unsubstituted or substituted pyridine, anilines, naphthalenamine amines, tri-C1-C7-bonds alkylamines, basic heterocycles, or hydroxides, Tetra-C1-C7alkylamine. Examples are sodium hydroxide, potassium carbonate, triethylamine, Tripropylamine, tributylamine is or ethyldiethanolamine, N-methyl-morpholine or N-methylpiperidin, dimethylaniline or dimethylaminonaphthalene, lutein, kallidin or hydroxide designed. The preferred base is three-From1-C4-alkylamine, such as ethyldiethanolamine, or pyridine.

The acylation is carried out in a suitable inert solvent or solvent mixture. Specialist in the art can select a suitable solvent or solvent system. For example, an aromatic hydrocarbon, such as toluene, esters such as ethyl acetate, or a mixture of ethyl acetate and water, halogenated hydrocarbons such as methylene chloride, nitrile, such as acetonitrile or propionitrile, simple ether, such as tetrahydrofuran or dioxane, 1,2-dimethoxyethane, amide, such as dimethylformamide, or a hydrocarbon, such as toluene, can be used as a solvent.

In the process of acylation of the compounds of formula (IIc), if R2represents a hydrogen, a carboxyl group can be allerban obtaining a mixed anhydride. This intermediate product is highly subjected to racemization, mainly in the basic environment. Racemization however, can be addressed first by adding the compounds of formula (IId), especially halide to the compound of formula (IIc) in a suitable inert solvent (for example,dimethoxyethane, tetrahydrofuran or acetonitrile), followed by slow addition of substochiometric number base, especially pyridine, relative to the compounds of formula (IId). A small amount of water the reaction mixture, preferably two equivalent, can further reduce racemization.

The reaction can also be simultaneous or alternate adding the compounds of formula (IId) and bases, such as pyridine, all the while maintaining the acidity of the reaction mixture.

The invention also relates to the compound of formula (IIc), where R1represents hydrogen or tetrazolo protective group and R2represents hydrogen or carboxyamide group, excluding a compound of the formula (IIc), where R1represents ethyl and R2represents trityl; which can be used, for example, as intermediate compounds for obtaining the compounds of formula (I).

The invention also relates to reaction stage (b). The compound obtained of the formula (IIe) can be obtained essentially in enantiomerically pure form. For example, can be obtained enantiomeric excess (EE) of the compounds of formula (IIc) or (IIc') respectively ≥95%, preferably ≥98% and most preferably ≥99%.

If R2represents a protective group, and R1is the battle hydrogen or a protective group, for example, add two equivalent relative to the compound of formula (IId), for example the corresponding halide, and a base, such as ethyldiethanolamine or tri-n-Propylamine to the corresponding compound of formula (IIe), dissolved in a suitable solvent, for example toluene. Suddenly, racemization does not occur.

Usually in the corresponding compounds of the formula (IIc), where R2represents hydrogen or a protective group, you can expect at least partial racemization, mainly in the presence of a base or acid and at elevated temperatures. However, racemization does not occur in the conditions described in accordance with the invention.

Usually in the corresponding compounds of the formula (IIc), where R2represents hydrogen, expected racemization. However, in the presence of a base, racemization does not occur.

If R1represents hydrogen and R2represents a protective group, tetrazole ring can also be allerban. When, however, the reaction mixture is neutralized, for example, water or alcohol, such as methanol, can be obtained from the corresponding compound where R1represents hydrogen.

The compounds of formula (IId) are known or can be obtained by known methods.

Stage (in):

Removal of protective groups, ka is tetrazole, and carboxyamide group, can be carried out by methods known from the prior art.

For example, the benzyl ester can be converted into the corresponding acid especially by hydrogenation in the presence of a suitable hydrogenation catalyst. Suitable catalyst includes, for example, Nickel, such as Raney Nickel, noble metals or derivatives thereof, for example oxides, such as palladium oxide or platinum, which can be used, if necessary, on the media, such as coal or calcium carbonate. The hydrogenation preferably can be carried out under a pressure between 1 and about 100 atmospheres and at a room temperature of approximately from -80° approximately up to 200°With, in particular from room temperature to about 100°C.

Remove trailvoy or tert-butilkoi groups, respectively, can be achieved by treatment of the corresponding protected compounds acid, especially in mild conditions.

Stage (d)

Stage (d) allocation of compounds of formula (I) is carried out in accordance with conventional methods of extraction, such as crystallization of the compounds of formula (I) from the reaction mixture, if desired or necessary, after treatment, especially extraction, or chromatography of the reaction mixture.

The transformation of the acid of formula (I) in salt implement swetnam way. For example, a salt with the base compounds of formula (I) is obtained by treatment of the acid form of the base. Salt with reason, on the other hand, to be converted to the acid (loose coupling) in the usual way, and salt with a base can be converted, for example, by treatment with a suitable acid agent.

The present invention also relates to new compounds, as described in the examples section.

The following examples illustrate the invention described above; however, they are in no way intended to limit its scope.

Examples

Example 1

a) Obtaining 3-methyl-2{[1-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl]-meth-(E/Z)-ilidene]-amino)-butane acid

Aqueous 30% sodium hydroxide solution (4,2 ml; to 31.5 mmol) was added to a stirred suspension of L-valine (2,43 g; 20,8 mmol) and 2'-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde (5 g; and 19.6 mmol) in water (20 ml) at room temperature until reaching a pH of 11. The resulting solution was stirred at room temperature for 15 minutes. The clear solution was evaporated at 60°in vacuum and the remaining water azeotrope was removed with 10 ml of 1-butanol.

1H NMR (CD3OD, 300 MHz): δ=8,21 (CH=N, s), to 7.67 (C6H5CH, d), 7,40-7,60 (46H5CH, m), 7,18 (C6H5CH, d), 3,42 (SN, d), 2,31 (SN, m), and 0.98 (CH3, d)0,82 (CH3d).

B1 Obtaining (S)-3-methyl-2-((2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl)-amino)-butane acid

Water of 2.0 M sodium hydroxide solution (approximately 100 ml; 200 mmol) was added to a stirred suspension of L-valine (11,8 g; 100 mmol) and 2'-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde (25,1 g; 100 mmol) in water (100 ml) at room temperature until pH 11. Net, the solution was evaporated at 60°in vacuum and the remaining water azeotrope was removed with 1-butanol. The remainder (Imin in the form of a solid foam) was dissolved in absolute ethanol (300 ml) and to the solution at 0-5°With portions was added sodium borohydride (of 3.78 g; 100 mmol). The reaction mixture was stirred for 30 min at 0-5°and after the reaction (HPLC) was suppressed by addition of water (100 ml) and hydrochloric acid 2.0 M (80 ml, 160 mmol). Organic solvent (ethanol) was removed from the clear solution (pH 7) at 50°With vacuum. The remaining aqueous concentrate was brought to pH 2 by slow addition of 2.0 M hydrochloric acid (approximately 70 ml, 140 mmol) at 40°C. during the addition has precipitated the desired product. It was collected by filtration, washed with water and dried in vacuum. The crude product is suspended in methanol at 50°and turbid mixture was cooled to room temperature. (S)-3-Methyl-2-((2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl)-amino)-butane acid was collected by filtration and then dried in vacuum.

B2) Alternatively, (S)-3-methyl-2-((2'-(1H-tetraza the-5-yl)-biphenyl-4-yl-methyl)-amino)-butane acid can be obtained, for example, as follows:

Water 10 M sodium hydroxide solution (approximately 41 ml, 410 mmol) was added to a stirred suspension of L-valine (24.8 g; 210 mmol) and 2'-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde (50 g; 200 mmol) in water (200 ml) at room temperature until pH 11. The obtained clear solution was evaporated at 60°in vacuum and the remaining water azeotrope was removed with 1-butanol. The remainder (Imin in the form of a solid foam) was dissolved in methanol (600 ml) and to the solution at 0-5°With portions was added sodium borohydride (3.13 g; 80 mmol). The reaction mixture was stirred for 30 min at 0-5°and after the reaction (HPLC) was suppressed by addition of water (300 ml) and hydrochloric acid 2.0 M (160 ml, 320 mmol). Organic solvent (methanol) was removed from the clear solution (pH 7) at 50°With vacuum. The remaining aqueous concentrate was brought to pH 2 by slow addition of 2.0 M hydrochloric acid (approximately 90 ml) at 40°C. during the addition has precipitated the desired product. It was collected by filtration, washed with water and dried in vacuum. The crude product is suspended in methanol at 50°C and stirred for a few minutes. Then turbid mixture was cooled to room temperature. (S)-3-Methyl-2-((2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl)-amino)-butane acid was collected by filtration and then dried in vacuum.

The enantiomeric excess (on the data HPLC): > 99,9%.

B3) Alternative, (S)-3-methyl-2-((2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl)-amino)-butane acid can be obtained, for example, as follows:

Sodium hydroxide (1,71 g; 41,89 mmol) was added in portions to a stirred suspension of L-valine (2,48 g; 21 mmol) in 15 ml of methanol. The mixture was stirred at room temperature for 30 minutes. Then added 2'-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde (5 g; 20 mmol). The mixture became a transparent solution in a few minutes. The mixture then was cooled to -5°and to the solution of the portions was added sodium borohydride (0,315 g; 8 mmol). The temperature during the addition was maintained between 0-5°C. the resulting mixture was stirred for 2 hours at 0°With the completion of the reaction was observed according to HPLC, then extinguished the addition of water (10 ml) and hydrochloric acid 37% (5.3g) to a pH of 2-2 .5. Further processing and crystallization were carried out in accordance with example 1 B2).

The enantiomeric excess (according to HPLC): >99.9%uptime.

B4) Alternative, (S)-3-methyl-2-((2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl)-amino)-butane acid can be obtained, for example, as follows:

In a steel autoclave of 50 ml under argon was loaded 3-methyl-2{[1-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl]-meth-(E/Z)-ilidene]-amino}-butane acid (1.5 g, 3.2 mmol) and 5% Pt/C (7.5 mg, 5 wt%). Then added 15 ml of methanol and the autoclave was closed and the awali argon and hydrogen. The pressure was maintained equal to 5 bar and the reaction mixture was stirred at room temperature. After completion of the reaction was monitored via HPLC data. Then, the autoclave was filed argon and the catalyst was filtered. Further processing and crystallization was carried out similarly to example 1 B2).

B5) Alternative, (S)-3-methyl-2-((2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl)-amino)-butane acid can be obtained, for example, as follows:

2'-(1H-Tetrazol-5-yl)-biphenyl-4-carbaldehyde (0,79 g; 3.2 mmol) and L-valine (0.4 g; 3.4 mmol) suspended in 15 ml of methanol. Then added sodium hydroxide (0.27 g; 6,72 mmol) and the reaction mixture was stirred at room temperature until a clear solution. Was added 5% Pt/C (15.8 mg; 2% wt.). The autoclave was closed and filed argon and hydrogen. The pressure was maintained equal to 5 bar and the reaction was stirred at 60°C. after completion of the reaction was monitored via HPLC data. Then, the autoclave was filed argon and the catalyst was filtered. Further processing and crystallization was carried out similarly to example 1 B2).

The enantiomeric excess (according to HPLC): >99.9%uptime.

C) Obtaining (S)-3-methyl-2-{pentanoyl-5-yl)-[2'-(tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-butane acid

A suspension of (S)-3-methyl-2-((2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl)-amino)-butane acid (17.6 g; 50.0 mmol), 2-dimethoxyethane (116 g) was cooled to -5° With and added valerolactone (9,9 ml, 80 mmol), then slowly added pyridine (6.0 ml; 75 mmol), diluted with 1,2-dimethoxyethane (60 ml). [1] After the reaction, the reaction mixture was extinguished with methanol (18 ml). At the end was added water (50 ml) at room temperature and after stirring for 1 h the pH of the mixture was brought to 7.5 by addition of an aqueous 10% solution of sodium carbonate (˜116 ml, 120 mmol) at 0°C. the Organic solvent was removed at 50°With vacuum. The remaining water to the concentrate was added ethyl acetate (125 ml) and the pH of the biphasic system was brought to 2 at 0-5°With the addition of 2.0 M HCl (˜98 ml). The organic phase was separated and concentrated at 45°With vacuum (water azeotrope was removed). Crystallization of the product was started at 45°and after addition of cyclohexane (102 ml) was finished by cooling to -5°C. the Solid residue was collected by filtration and after drying at 50°remained With (S)-3-methyl-2-{pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-butane acid as a white powder.

Melting point: 108-110°C.

The enantiomeric excess (according to HPLC): >99.5%pure.

[1] Alternative pyridine and valerolactone can be added in the following way: a Suspension of (S)-3-methyl-2-((2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl)-amino)-butane acid (25,5 g; to 72.6 mmol) in 1,2-dimethoxyethane (126 g) was cooled to -10� With and added valerolactone (8,75 g; to 72.6 mmol) for 15 min, followed by slow addition of a mixture of (7,16 g), pyridine (5.6 g) and water (1.5 g) within 61 minutes After stirring for 30 min was added valerolactone (5.3g; to 43.5 mmol) for 8 min, then was slowly added for 30 min the mixture of (4.3 g) in pyridine (3.4 g) and water (0.9 g). After each addition of pyridine pH was controlled sampling (hydrolysis in water). the pH of the samples should always be below 2.5. The reaction was stirred for 25 min, then was added water (25.6 g) for 30 minutes and the Mixture was stirred for 30 min, then was heated to 23°C for 30 min and stirred for another 2 hours. Regulation of pH, removal of organic solvent by distillation, further processing and crystallization was carried out as described in example 1B) above.

Example 2

This example is illustrated by the following reaction scheme:

a) Obtaining benzyl ester (S)-3-methyl-2-{[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amino}-butane acid

Toilet L-valine benzyl ester (6,38 g, a 16.8 mmol) in toluene (40 ml) were extracted with sodium carbonate solution (2,36 g of 22.0 mmol) in water (40 ml). The organic phase containing L-validentry ether in the form of a free base, separated and at room temperature was added 2'-(1H-tetrazol-5-yl)-biphenyl-4-to baldegg (4,13 g, 16.0 mmol) and tri-n-Propylamine (3,20 ml of 16.8 mmol). The resulting solution was evaporated at 50°With vacuum (water azeotrope was removed). The remaining oil containing intermediate Imin, was dissolved in absolute ethanol (40 ml) and the portions was added sodium borohydride (0.68 g, 17.6 mmol) for 10 minutes (min) at 0-5°C. the resulting solution was stirred for 30 min at 0-5°C. After the reaction, the reaction mixture was extinguished with water (10 ml) and brought to pH 6-7 by the addition of hydrochloric acid 2 M (16 ml, 32 mmol) at room temperature. Ethanol drove from the reaction mixture at 50° in vacuum and the remaining aqueous mixture was extracted with toluene (60 ml). The organic phase was concentrated at 50°in vacuum to approximately 50% of the original volume by distillation (water and ethanol azeotrope was removed). The resulting concentrate (35 ml)containing benzyl ether (S)-3-methyl-2-{[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amino}-butane acid used as the starting reagent for the next stage of acylation.

b) Obtaining benzyl ester (S)-3-methyl-{2-pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amino}-butane acid

A solution of benzyl ether (S)-3-methyl-2-{[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amino}-butane acid (approximately 7.0 g, 16.0 mmol) in toluene (35 ml) from the previous step was diluted with toluene (35 ml). Transparent the initial solution was cooled to 0-5° In anhydrous conditions was added and N-ethyldiethanolamine (6,1 ml of 35.2 mol) and valerolactone (4,1 ml, 33.6 mmol) at this temperature. The reaction mixture was heated to 50°C for 30 min and stirred at 50°C for approximately 1 h after the reaction was suppressed by the addition of methanol (10 ml) at 50°C. a Clear solution was stirred for approximately 30 min at 50°and in the end was cooled to room temperature. Was added water (30 ml) and the pH of the obtained two-phase system was brought to 2 by addition of 2.0 M hydrochloric acid (approximately 11 ml, 22 mmol). Organicheskoi phase was separated, was extracted with water (30 ml) and concentrated at 50°in vacuum to approximately 50% of the original volume by distillation (water and methanol azeotrope was removed). In the resulting concentrate in toluene (40 ml) was added a seed crystal at 40°for the onset of crystallization and stirred at this temperature for approximately 1 hour (h). The suspension was slowly cooled to 0°C for 6-10 hours, the Solid was separated by filtration, washed with cold toluene (30 ml) and dried in vacuum at 50°obtaining benzyl ester (S)-3-methyl-{2-pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amino}-butane acid.

Melting point: 115-116°C.

The enantiomeric excess (according to HPLC): >99.8 per cent.

C) Obtaining (S)-3-meta the-2-{pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amino)-butane acid

A solution of benzyl ether (S)-3-methyl-{2-pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amino}-butane acid (10.6 g; 20.0 mmol) in ethyl acetate (43 ml) was first made with 4 bar/50°in the presence of a catalyst of 5% wet palladium on coal (1.12 g, containing 50% water). After completion of the reaction (the cessation of hydrogen absorption), the catalyst was removed by filtration and the filtrate was concentrated at 45°With vacuum (water azeotrope was removed). Crystallization of the product initiated at 45°and after addition of cyclohexane (102 ml) was completed by cooling to -5°C. the Solid is collected by filtration and after drying at 50°With (S)-3-methyl-2-{pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amino}-butane acid was obtained as a white powder.

Melting point: 108-110°C.

The enantiomeric excess (according to HPLC): >99.5%pure.

Example 3

a) Obtaining tert-butyl ether (S)-3-methyl-2-((2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl)-amino)-butane acid

To a suspension of the hydrochloride tert-butyl ester L-valine (419,4 mg; 2 mmol) in 5 ml of isopropylacetate was added sodium carbonate (265 mg; 2.5 mmol) in 5 ml of water. After the dissolution of the two phases were separated immediately. The aqueous layer was washed once with 4 ml of isopropylacetate. The combined organic layers washed with 5 ml of water. Colorless the organic layer was dried over sodium sulfate, was filtered, evaporated in vacuo and dried in high vacuum to obtain a colorless oil. The oil was dissolved in 4 ml of methanol. After adding 2'-(1H-tetrazol-2-yl)-biphenyl-4-carbaldehyde (515 mg; 2 mmol) and triethylamine (0,278 ml; 2 mmol), the yellow solution was stirred for 5 minutes before evaporation in vacuo to obtain a yellow oil. After dissolving in 4 ml of ethanol solution was cooled to 0°C. was Added sodium borohydride (78 mg; 2 mmol) in 4 portions with stirring until the disappearance of the imine (HPLC). Yellowish solution was acidified to pH 11 to pH 6 with 3.2 ml of 1.0 M HCl solution. Evaporation of ethanol resulted in the receipt of a mixture of yellow oil in water. This mixture was extracted with isopropylacetate. The combined organic layers were dried over sodium sulfate, was filtered and was evaporated in vacuo and dried in high vacuum to obtain tert-butyl ether (S)-3-methyl-2-((2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl)-amino)-butane acid in the form of oil.

b) Obtain tert-butyl ether (S)-3-methyl-{2-pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amino}-butane acid

Tert-butyl ether (S)-3-methyl-2-((2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl)-amino)-butane acid (8.5 g; ˜16.0 mmol) was dissolved in toluene (63 ml) and N-ethyldiethanolamine (6,1 ml; of 35.2 mmol) was added valerolactone (4,1 ml; 33,6 m is ol) at room temperature. The clear solution was heated to 50°C and stirred at this temperature for 60 minutes After the end of the reaction, the reaction mixture was extinguished with methanol (10 ml) at 50°and at the end was added water at room temperature. the pH of a two-phase system was brought to 2 by addition of 2.0 M HCl (˜5 ml). The organic phase was separated and concentrated at 50°in vacuum, the remaining water azeotrope was removed). Upon cooling to room temperature the product crystallized from toluene. Tert-butyl ether (S)-3-methyl-{2-pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amino}-butane acid was obtained as a white powder after filtration and drying in vacuum.

Melting point: 153,4°C.

The enantiomeric excess (according to HPLC): >99.8 per cent.

Example 4

a) Obtaining (S)-2-((2'-(2"-tert-butyl-tetrazol-5"-yl)-biphenyl-4-ylmethyl)-amino)-3-methyl-butane acid

A solution of sodium carbonate (1 mol/l; 1.0 ml, 1.0 mmol) was added to L-valine (117,15 mg; 1.0 mmol). After dissolving the reaction was evaporated. To the white solid substance was added 2'-(1H-tert-butyl-tetrazol-2-yl)-biphenyl-4-carbaldehyde (306,4 mg, 1 mmol) and 4 ml of methanol. After dissolution, the reaction mixture was evaporated and the yellowish oil was dried under high vacuum. Imin was dissolved in 4 ml of ethanol and cooled to 0°before whom the making sodium borohydride (38 mg; 1.0 mmol) in 2 portions with stirring until the disappearance of the imine. Yellowish solution was acidified with 1.8 ml of 1N HCl solution to pH 6-7. Evaporation in vacuum resulted in obtaining a white solid. Added 10 ml of isopropylacetate and 10 ml of water. The white precipitate was filtered, washed with water and dried to obtain 2-((2'-(2"-tert-butyl-tetrazol-5"-yl)-biphenyl-4-yl-methyl)-amino)-3-methyl-butane acid.

Melting point: 189,7°C.

Example 5

a) Obtaining benzyl ester (S)-2-{[2'-(2-benzyl-2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-3-methyl-butane acid

Toilet benzyl ester L-valine (0.97 mmol, 368 mg) suspended in isopropylacetate (4 ml). To this suspension was added a solution of sodium carbonate (1,21 mmol, 128 mg) in water (2 ml) at room temperature. The resulting mixture was stirred for 2 minutes, transferred into a separate funnel and the phases were separated. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the free base as a colourless oil. 2'-(1H-Benzyl-tetrazol-2-yl)-biphenyl-4-carbaldehyde (0.88 mmol, 300 mg) was dissolved in 1,2-dimethoxyethane (4 ml) at room temperature and the resulting solution was added to the residue, the free base. After 8 hours the solvent was removed in vacuum and the residue was dissolved in et is zero (4 ml). To the reaction mixture was added sodium borohydride (1.1 mmol, of 41.6 mg). The obtained opaque solution was stirred at room temperature for more than 2 hours and then concentrated in vacuo to remove ethanol. Was added water (20 ml) and dichloromethane (20 ml) and the pH of the aqueous phase was brought to 1 by addition of 1N HCl. The phases were separated and the aqueous phase was extracted again with dichloromethane (10 ml). The combined organic phases were washed with water (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to obtain specified in the title compounds as colorless oils.

Example 6

a) Obtaining tert-butyl ether (S)-2-{[2'-(2-tert-butyl-2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-3-methyl-butane acid

Hydrochloride tert-butyl ester L-valine (1,32 mmol, 278 mg) suspended in isopropylacetate (5 ml). To this suspension was added a solution of sodium carbonate (1,65 mmol, 175 mg) in water (5 ml) at room temperature. The resulting mixture was stirred for 2 minutes, transferred into a separate funnel and the phases were separated. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the free base as a colourless oil.

2'-(1H-Tert-butyl-tetrazol-2-yl)-biphenyl-4-carbaldehyde (1.2 mmol, 367,2 mg) was dissolved in ethanol (5 ml) and room temperature and the resulting solution was added to the residue, the free base. After 90 minutes the reaction mixture was added sodium borohydride (1.5 mmol, of 56.7 mg). The obtained opaque solution was stirred at room temperature for 2 hours and then concentrated in vacuo to remove ethanol. Was added water (20 ml) and dichloromethane (20 ml) and the pH of the aqueous phase was brought to 1 by addition of 1N HCl. The phases were separated and the aqueous phase was extracted again with dichloromethane (10 ml). The combined organic phases were washed with water (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to obtain specified in the title compounds as colorless oils.

1H NMR (CD3OD, 400 MHz): δ=7,86 (1H, d, J=8 Hz), 7,41-to 7.68 (3H, m), 7,44 (2H, d, J=8 Hz), 7,24 (2H, d, J=8 Hz), 4,17 (1H, d, J=13 Hz), 4,08 (1H, d, J=13 Hz), of 3.56 (1H, d, J=2 Hz), and 2.27 (1H, m), 1,12 (3H, d, J=7 Hz) and 1.06 (3H, d, J=7 Hz).

Example 7

a) Obtaining benzyl ester (S)-3-methyl-2-{[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amino}-butane acid

Toilet benzyl ester L-valine (20,1 g, 53 mmol) in toluene (90 ml) were extracted with sodium carbonate solution (7,3 g, 69 mmol) in water (125 ml). The organic phase (containing the free base of the benzyl ester of L-valine) was separated and added 2'-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde (12.5 g, 50 mmol) and N-ethyldiethanolamine (9.0 ml, 52 mmol) at room temperature. The resulting solution was evaporated at 50°With vacuum (water is removed azeotrope). The remaining oil (containing intermediate Imin) was dissolved in methanol (160 ml) and the portions was added sodium borohydride (0.84 g, 22 mmol) for 10 min at 0-5°C. the resulting solution was stirred for 30 min at 0-5°C. After the conversion, the reaction mixture was suppressed by the addition of 1.0 M hydrochloric acid (approximately 42 ml, 42 mmol) at 0-5°and the pH is brought to 6-7. Methanol drove from the reaction mixture at 50°in vacuum and the resulting aqueous mixture was extracted with toluene (180 ml). The organic phase was concentrated at 50°in vacuum to approximately 50% of the original volume by distillation (water and methanol azeotrope was removed). The resulting concentrate (approximately 80 g)containing benzyl ether (S)-3-methyl-2-{[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amino}-butane acid was used as the feedstock for the next stage of acylation.

b) Obtaining benzyl ester (S)-3-methyl-{2-pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amino}-butane acid

A solution of benzyl ether (S)-acid in toluene (approximately 80 g, 48-50 mmol) from the previous step was diluted with toluene (85 ml). In anhydrous conditions was slowly added N-ethyldiethanolamine (24,0 ml, 140 mol) and valerolactone (17.3 ml, 140 mmol) at a temperature within vessel 20°C. the Reaction mixture was stirred approximately during the 30 min and after the transformation was suppressed by the addition of methanol (31 ml) at 20° C. a Clear solution was stirred for 30 min at 20°With, then added water (78 ml) and the resulting biphasic system was brought to pH 2 by addition of 2.0 M hydrochloric acid (about 10 ml, 20 mmol). The organic phase was separated, was extracted with water (78 ml) and concentrated at 50°in vacuum to approximately 50% of the original volume by distillation (water and methanol azeotrope was removed). In the resulting concentrate in toluene (˜94 g) was added a seed crystal at 40°to initiate crystallization and stirred at this temperature for about 1 h, the Suspension was slowly cooled to 0°C for 6-10 hours, the Solid was separated by filtration, washed with cold toluene (60 ml) and dried in vacuum at 50°obtaining benzyl ester (S)-3-methyl-{2-pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amino}-butane acid.

Melting point: 115-116°C.

The enantiomeric excess (according to HPLC):>99.8 per cent.

C) Obtaining (S)-3-methyl-2-{pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amino}-butane acid

A solution of benzyl ether (S)-3-methyl-{2-pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amino}-butane acid (10.6 g; 20.0 mmol) in ethyl acetate (43 ml) was first made with 4 bar/50°in the presence of a catalyst of 5% wet palladium on coal (1.12 g, containing 50% water). After reacts and (cessation of hydrogen absorption), the catalyst was removed by filtration and the filtrate was concentrated at 45° C in vacuum (water azeotrope was removed). Crystallization of the product initiated at 45°and after addition of cyclohexane (102 ml) was cooled to -5°C. the Solid is collected by filtration and after drying at 50°received (S)-3-methyl-2-{pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amino}-butane acid as a white powder.

Melting point: 108-110°C.

The enantiomeric excess (according to HPLC): >99.5%pure.

Example 8

5-(2-Chlorophenyl)-2-(tetrahydropyran-2-yl)-2H-tetrazole and 5-(2-chlorophenyl)-1-(tetrahydropyran-2-yl)-1H-tetrazol

Methansulfonate acid (0,141 g; 1.44 mmol) was added to a suspension of 5-(2-chlorophenyl)-1H-tetrazole (88,46 g; 480,0 mmol) in toluene (660 ml). The resulting mixture was heated to 50°and the solution was added 3,4-dihydro-2H-Piran (42,88 ml, 494 mmol) in toluene (60 ml) for 90 minutes. The mixture was further stirred at 50°C for 90 minutes. The resulting solution was washed twice 0,5N aqueous sodium hydroxide solution (96 ml each) and twice with water (96 ml each). The obtained turbid organic phase was concentrated in vacuum using a blade mixer to obtain a mixture of 5-(2-chlorophenyl)-2-(tetrahydropyran-2-yl)-2H-tetrazole (N2-isomer) and 5-(2-chlorophenyl)-1-(tetrahydropyran-2-yl)-1H-tetrazole (N1-isomer) in a ratio of about 95:5 (in accordance with1H-NMR) in view of the yellow liquid.

1H-NMR of N2-isomer (400 MHz, CDCl3): 1,72-of 1.84 (m, 3 H), 2,16 was 2.25 (m, 2 H), 2,46 is 2.55 (m, 1 H), 3,80-3,86 (m, 1 H), was 4.02-4,07 (m, 1 H), 6,12-6,14 (m, 1 H), of 7.36-7,44 (m, 2 H), 7,52-7,56 (m, 1 H), of 7.96-7,98 (m, 1 H).

1H-NMR N1-isomer (400 MHz, CDCl3): 5,44-vs. 5.47 (m, 1H). A characteristic signal, which is not present in the signals N2-isomer.

Example 9

5-(2-Bromophenyl)-2-(tetrahydropyran-2-yl)-2H-tetrazole and 5-(2-bromophenyl)-1-(tetrahydropyran-2-yl)-1H-tetrazol

A suspension of 5-(2-bromophenyl)-1H-tetrazole (4,50 g; 20.0 mmol) in tert-butylmethylether ether (40 ml) was heated to 45°and added methanesulfonyl acid (0,058 g; a 0.60 mmol). To the mixture was added a solution of 3,4-dihydro-2H-Piran (1.90 ml; 21 mmol) in tert-butylmethylether ether (21 ml) for 1 hour at 45°C. the Mixture then was stirred for 6 hours at 45°C. the resulting solution was cooled to approximately 0°and the solution was added sodium bicarbonate (2.4 g) in water (30 ml). The aqueous phase was separated and was extracted with tert-butylmethylamine ether (10 ml). The combined organic phases are washed twice 1N solution of KOH (10 ml each) and once with a solution of 10 wt%. sodium chloride in water (10 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuum to obtain a mixture of 5-(2-bromophenyl)-2-(tetrahydropyran-2-yl)-2H-tetrazole (N2-isomer) and 5-(2-bromophenyl)-1-(tetrahydro the Iran-2-yl)-1H-tetrazole (N1-isomer) in a ratio of about 93:7 (in accordance with 1H-NMR) as an orange oil.

1H-NMR of N2-isomer (400 MHz, CDCl3): 1,72-of 1.85 (m, 3 H), 2,18-of 2.26 (m, 2 H), 2,45-of 2.54 (m, 1 H), 3,80-3,86 (m, 1 H), 4,01-4,07 (m, 1 H), 6,12-x 6.15 (m, 1 H), 7,31-7,35 (m, 1 H), 7,41 was 7.45 (m, 1 H), 7,73 to 7.75 (m, 1 H), 7,87-of 7.90 (m, 1 H).

Example 10

5-(4′-Diethoxylate-biphenyl-2-yl)-2-(tetrahydropyran-2-yl)-2H-tetrazol

To a suspension of magnesium turnings (5,11 g) in anhydrous tetrahydrofuran (40 ml) was added 1,2-dibromoethane (0,106 ml; 1.2 mmol). The suspension was cooled to 12°and added 6 ml of a solution of 1-bromo-4-(diethoxylate)benzene (53,6 g; 200 mmol) in anhydrous tetrahydrofuran (120 ml). After start of the reaction was added to the remaining solution of 1-bromo-4-(diethoxylate)benzene within 90 minutes. The resulting mixture was then stirred at 20-25°C for 2.5 hours. The mixture was diluted with anhydrous tetrahydrofuran (THF) to a total volume of 250 ml of getting solution of the corresponding bromide ariline concentration of approximately 0,78 M In anhydrous conditions 15.0 ml of the specified 0,78 M solution of bromide ariline (11.7 mmol) was cooled to approximately 0°and added a 0.5 M solution of zinc chloride in tetrahydrofuran (and 23.4 ml, 11.7 mmol) for 15 minutes. The resulting suspension was stirred at room temperature for 30 minutes to complete the formation of the corresponding arizonavov reagent. In another flask a solution of a mixture of 5-(2-bromophenyl)-2-(tetrahydro the Iran-2-yl)-2H-tetrazole and 5-(2-bromophenyl)-1-(tetrahydropyran-2-yl)-1H-tetrazole (2,78 g; 9.0 mmol) in tetrahydrofuran (9 ml) was added to dichlorobis(triphenylphosphine)palladium(II) (0,253 g; 0.36 mmol) in anhydrous conditions. With careful stirring, the yellow-orange suspension was added at room temperature to the suspension arizonavov reagent for 40 minutes. The mixture was further stirred at room temperature for 17 hours. Then was added a solution of sodium bicarbonate (1.2 g) in water (15 ml) and ethyl acetate (20 ml). The aqueous phase was separated and was extracted with ethyl acetate (60 ml). The combined organic phases are washed twice with a solution of sodium bicarbonate (1.2 g) in water (15 ml each) and twice with water (15 ml each) and was evaporated in vacuum. The yellow-orange oil was dissolved in a small amount of tert-butyl methyl ether, was filtered through the filter was evaporated in vacuo and was purified column chromatography on silica gel, elwira mixture 1:4 ethyl acetate and hexane to obtain the main isomer (N2-isomer) 5-(4'-diethoxylate-biphenyl-2-yl)-2-(tetrahydropyran-2-yl)-2H-tetrazole in the form of a colorless oil.

1H-NMR of N2-isomer (400 MHz, CDCl3): 1,24 (t, J=7.2 Hz, 6 H), 1,61-of 1.66 (m, 3 H), 1,88-2,03 (m, 2 H), 2,11-to 2.18 (m, 1 H), 3,50-3,71 (m, 6 H)5,49 (s, 1 H), 5,97 of 5.99 (m, 1 H), 7.18 in-7,20 (m, 2 H), 7,38-7,40 (m, 2 H), 7,43-7,56 (m, 3 N), of 7.90-a 7.92 (m, 1 H).

Mass spectrum (ES+): m/z=409 [M+H]+.

Example 11

2'-(2H-Tetrazol-5-yl)biphenyl-4-carbaldehyde

To 5-(4'-IER is oxymethyl-biphenyl-2-yl)-2-(tetrahydropyran-2-yl)-2H-tetrazole (0,408 g; 1.00 mmol) was added 94% ethanol (2.5 ml) and 2N aqueous solution of hydrochloric acid (0.5 ml; 1.0 mmol). The resulting solution was heated at 45°C for 3 hours. After adding water (approximately 2 ml) and the mixture was cooled to room temperature and then was stirred at 0-5°C for 30 minutes. The resulting suspension was filtered and the solid residues were washed with water, dried in vacuum at 40°obtaining 2'-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde in the form of white crystalline powder.

Melting point: 187,5-190,0°C.

The mass spectrum of high resolution (ES+): found: m/z=251,0928 [M+H]+; calculated: m/z= 251,0927.

1. The method of obtaining the compounds of formula (I)

or its salts, including:

(a) reaction of compounds of formula (IIa)

or its salts, where R1represents hydrogen or a protective group tetrazole, with the compound of the formula

or its salt, where R2represents hydrogen or carboxyamide group, under conditions of reductive amination; and

(b) acylation of the obtained compound of the formula (IIc)

or its salt with the compound of formula (IId)

where R3represents an activating group; and

(b) if R1and/or R2are other than hydrogen, removing the protective group(s) in the resulting compound of formula (IIe)

or its salt; and

(g) isolation of the compounds of formula (I) or its salt; and, optionally, converting the obtained free acid of the formula (I), its salt, or the conversion of the salts of the compounds of formula (I) in the free acid of the formula (I), or the conversion of the salts of the compounds of formula (I) into a different salt.

2. The method according to claim 1, where in the compounds of formulas (IIa), (IIb), (IIc) and (IIe) R1represents hydrogen and R2represents a hydrogen, and where in the compounds of formula (IId) R3represents a halogen.

3. The method according to claim 1 or 2, where the reductive amination is carried out in the presence of a reducing agent such as borohydride, which can also be in the form of the complex, either hydrogen or a hydrogen donor in the presence of a hydrogenation catalyst.

4. The method according to claim 1 or 2, in which the reaction of reductive amination at the stage (a) is carried out in two stages:

first condense the compound of formula (IIa) with the compound of the formula (IIb) and after removal of water get Imin formula

then, the obtained compound of the formula (IIc') restore in the presence of a reducing agent to obtain compounds of formula (IIc)

5. The method according to claim 1 or 2, where stage (b) is carried out first by adding the compounds of formula (IId) to the compound of formula (IIc), and then slowly adding substochiometric amount of base relative to the compound of formula (IId).

6. The method of obtaining the compounds of formula

where R1represents hydrogen or a protective group tetrazole and R2represents hydrogen or carboxyamide group, comprising the reaction of compounds of formula (IIa)

or its salts, where R1represents hydrogen or a protective group tetrazole, with the compound of the formula

or its salt, where R2represents hydrogen or carboxyamide group, under conditions of reductive amination.

7. The method according to claim 6, in which the reaction of reductive amination is carried out in two stages:

first condense the compound of formula (IIa) with the compound of the formula (IIb) and after removal of water get Imin formula

then the resulting compound of formula (IIc') restore in the presence of a reducing agent to obtain compounds of formula (IIc)

8. The compound of the formula

where R1represents hydrogen, tert-C4-C7-alkyl or C1-C2-alkyl, monosubstituted by phenyl, and

R2represents hydrogen, C1-C7-alkyl or C1-C2-alkyl, monosubstituted by phenyl.

9. The compound of formula (IIc) of claim 8, selected from the group consisting of (S)-3-methyl-2-((2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl)-amino)-butane acid,

benzyl ether (S)-3-methyl-2-{[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amino}-butane acid,

tert-butyl ether (S)-3-methyl-2-((2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl)-amino)-butane acid,

(S)-2-((2-(2"-tert-butyl-tetrazol-5"-yl)-biphenyl-4-ylmethyl)-amino)-3-methyl-butane acid,

benzyl ether (S)-2-{[2'-(2-benzyl-2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-3-methyl-butane acid and

tert-butyl ether (S)-2-{[2'-(2-tert-butyl-2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-3-methyl-butane acid.

10. The compound of the formula

where R1represents hydrogen, tert-C4-C7-alkyl or C1-C2-alkyl, monosubstituted by phenyl, and

R2represents hydrogen, C1-C7-Ala is l or C 1-C2-alkyl, monosubstituted by phenyl.

11. The compound of formula (IIc') of claim 10, which represents a 3-methyl-2{[1-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl]-meth-(E/Z)-ilidene]-amino)-butane acid.

12. The method of obtaining the compounds of formula

where R1represents hydrogen or a protective group tetrazole selected from the group comprising tert-C4-C7-alkyl, C1-C2-alkyl, mono - or disubstituted by phenyl, where the phenyl ring is unsubstituted or substituted by one or more residues selected from the group consisting of tert-C1-C7-alkyl, hydroxy, C1-C7-alkoxy, C2-C8-alkanoyloxy, halogen, nitro, cyano and trifloromethyl (CF3); picoline; piperonyl; Cumyl; allyl; cynnamoyl; fluorenyl; silyl; C1-C7-alkylsulfonyl; arylsulfonyl, where the phenyl ring, when the aryl represented by phenyl that is unsubstituted or substituted by one or more residues selected from the group consisting of C1-C7-alkyl, hydroxy, C1-C7-alkoxy, C2-C8-alkanoyloxy, halogen, nitro, cyano and CF3;2-C8-alkanoyl and esterified carboxy, a R2represents hydrogen or carboxyamide group,

including the acylation with the organisations of the formula (IIc)

or its salt with the compound of formula (IId)

where R3represents an activating group.



 

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SUBSTANCE: novel compounds of formulas , , , , , , (designation of all groups are given in invention formula) are used for treatment of different metabolic diseases, such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver, cachexia, obesity, atherosclerosis and arteriosclerosis.

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22 cl, 23 sch, 4 tbl, 501 ex

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SUBSTANCE: invention relates to methods for preparing explosives, in particular to a method of preparing (5-nitroterazolato)pentaammino cobalt(III) perchlorate, which can be used in production of initiators of elevated safety in handling. Synthesis is accomplished via interaction of aquapentaammino cobalt(III) perchlorate with 50nitroterazole sodium salt tetrahydrate in 1.0-4,0% chloric acid aqueous solution at 89-96°C and molar ration of reactants between 1:1.2 and 1:1.5, respectively, followed by double recrystallization of product from o.1-0.3% chloric acid solution under simplified conditions. In order to reduce sensitivity of product to mechanic effects and to enable transportation thereof to long distances, product is moistened to 30-40% moisture with water/ethanol mixture. Yield of (5-nitroterazolato)pentaammino cobalt(III) perchlorate is increased by 12%.

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EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

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FIELD: organic chemistry, chemical technology, pharmacy.

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

7 cl, 3 tbl, 33 ex

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124 cl, 52 ex, 17 tbl, 2 dwg

FIELD: chemistry.

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12 cl, 11 ex

FIELD: medicine.

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EFFECT: rising of efficiency of a composition and its application in medicine.

12 cl, 3 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable acid-additive salts. The compounds under the present invention are active to bind cannabinoid (CB) receptor. In general formula (I) , X stands for -S-, -S(=O)-, -S(=O)2-, -S(=O)2N(H)-, -P(=O)(OCH3)-, -P(=O)(OH)-, -N(H)-, -N(CH3)-, -N(H)C(=O)N(H)-, -C(=O)-, -C(=O)O-, -N(H)C(=O)-, -C(H)(OH)-, -C(H)=N-, -C(H)=C(H)-, -CH2N(H)-or -C(=NH)-; R1 stands for phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indolyl, quinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, benzimidazolyl, 2-oxo-1,3-dihydrobenzimidazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl or indanyl which can be optionally substituted; R2 stands for hydrogen, -OR4 or -N(R5)R6; R3 stands for hydrogen; cyano; oxadiazolyl, piperazinyl or tetrazolyl optionally substituted with methyl; -C(=O)R7, -OR8 or N(R9)R10. Besides, the invention concerns method of producing compound of formula I and to pharmaceutical composition active to bind cannabinoid (CB) receptor, containing compound of formula I as an active component.

EFFECT: higher efficiency of compounds.

5 cl, 14 ex

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