Method of producing angiotensin receptor blocker

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a compound of formula (IIa)

and its salt, involving use of protective groups which can be easily incorporated into the compound, have large mass, are stable in the presence of organometallic reagents and be easily, and with high output, removed from in an acidic medium, as well as to novel intermediate compounds used during steps of this method, having general formula (IVe)

, where R5 and R'5 independently denote C1-C7-alkyl, R6 and R8 denote hydrogen, R7 and R9 together form C2-C5-alkylene.

EFFECT: easy production of angiotensin receptor blocker.

8 cl, 11 ex

 

The present invention relates to a method for producing blocker angiotensin 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 present invention relates to a new method for obtaining compounds of formula (IIA), opened below in the description that includes the following sequence of stages:

i) protection tetrazole group Gallinago the compounds of formula (IVa) of the present invention by the reaction with the compound of the formula (IV) of the present invention;

ii) catalyzed by transition metal reaction cross-combination between the received halide compound of formula (IVC) protected tetrazoles of the present invention and tsinkorganicheskih compound of formula (IVC)

of the present invention; and

iii) removing the protective group.

The literature provides various methods for the preparation of compounds of formula (IIA) of the present invention. For example, the documents of the prior art EP 0550313 and FR 2688503 describe an alternative method that is different from the method according to the present invention a protective group tetrazole rings. Namely, if in accordance with the present invention tetrazol Conn is h while the reaction of a compound of formula (IV) of the present invention, in described in EP 0550313 and FR 2688503 connections protective group tetrazole represents alkyl, for example t-butyl, arylalkyl, for example, triphenylmethyl, alkylsilanes, alkylsilane CH2OR6 or group, where R is selected from the group comprising methyl, phenylmethyl, 1,1-dimethylethyl, 2,2,2-trichlorethyl, benzyloxycarbonyl or 2,2,2-Trichloroisocyanuric. However, none of the examples included in the description and aimed at supporting the corresponding process in the document FR 2688503 not related to the stage of removal of the protective group and the document EP 0550313 describes only the removal of the protective group at tetrazole with trailvoy protecting group (Example 7).

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 ukazannoj tetrazole rings on the basis of relevant cyanoderivatives, which react with N3or 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. The use 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 cyanoprop the one with the 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 be used 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 (II)

or its salt with the compound of formula (IId)

where R3represents an activating group; and

(b) if R1and/or R2the two who are different from hydrogen, the removal of 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.

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 of a mixture, 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°to approximately +200°C, and, if necessary, in a closed vessel, under pressure, in an atmosphere of inert gas and/or under 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.

Soo the relevant terazosina protective group (R 1) 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 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;2-C8alkanoyl, such as acetyl or valeryl; and etherip the sale 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)revenged, trityl, (p-methoxyphenyl)diphenylmethyl; diphenyl(4-pyridyl)methyl, benzoyloxymethyl, 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 groups is b is nil.

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 benzothiazolyl-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 is with the battle 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) reductive amination 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 the reductive amination of hydrogen is or donor is hydrogen, 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, for example, 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 about 100 atmospheres and at room temperature from about -80° to approximately 200°C., 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 salts, 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 and citric acid 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, hydroxyl,

With2-C12alkanoyl, C1-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 OS is Finance 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, for example, three1-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 lithium hydroxide, 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, e.g. an alcohol, such as methanol, ethanol, isopropanol or 2-methoxyethanol, or glyme. If postanal is that the agent uses three-(C 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-butyl methyl ether, 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, e.g. 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 Khujand who are 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°C and 20°C.

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

The present invention also relates to new 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, 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, to the 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 such as calcium sulfate, 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, special is about, 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 of the compounds of formula (IIc') include the corresponding E, and the corresponding Z isomer. Preferred is the E isomer.

The present invention also relates 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-C6-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 of the reaction, if necessary, 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°to approximately +200°C, and, if necessary, in a closed vessel, under pressure, in an atmosphere of inert gas and/or under anhydrous conditions.

Stage (i) is carried out, for example, in the presence of 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°C and the boiling temperature of the reaction medium, preferably between 30 to 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 with acid at elevated 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 the share of the ve 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 gr is the PAP 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 of the group 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, which (I) 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 metalloorganic the x 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 assume that 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-C7-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 a1-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 a1-C3-alkyl, such as methyl, 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 R5', independently from each other, represent a1-C7-alkyl, such as methyl or ethyl, or together form the 2-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 temperatures in the region from approximately -10°to approximately room temperature, preferably in the region from about -5°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 CT the courses of alkali metals, morpholine or piperidine 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 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 hydrogen, carboxyl g is the SCP 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 is 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 R1represents 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, for example, 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, the 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, as tetrazoles 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 their derivatives, for example, oxides, such as palladium oxide or platinum, which can be used, if necessary, on the media, for example, coal or calcium carbonate. The hydrogenation preferably can be carried out under a pressure between 1 and about 100 atmospheres and at room temperature from about -80° to approximately 200°C., in particular from room temperature to approximately 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 about CNAME methods of allocation, 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) salt is carried out in a known manner. 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 0°C in vacuum and the remaining water azeotrope was removed with 10 ml of 1-butanol.

1H NMR (CD3OD, 300MHz): δ=8,21 (CH=N, s), to 7.67 (C6H5CH, d), 7,40-7,60 (46H5CH, m), 7,18 (C6H5CH, d), 3,42 (CH, d), 2,31 (CH, 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°C in vacuo 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°C portions) was added sodium borohydride (of 3.78 g; 100 mmol). The reaction mixture was stirred for 30 min at 0-5°C. 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°C in 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 suspendido the Ali in methanol at 50°C 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-tetrazol-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°C in vacuo 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°C portions) was added sodium borohydride (3.13 g; 80 mmol). The reaction mixture was stirred for 30 min at 0-5°C. 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°C in 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 neskolkomi. 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 (according to HPLC):>99.9%uptime.

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°C. 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°C. after 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 steel the second 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, the autoclave was closed and filed 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

is Uspenskiy (S)-3-methyl-2-((2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl)-amino)-butane acid (17.6 g; 50.0 mmol) in 1,2-dimethoxyethane (116 g) was cooled to -5°C. was 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°C in 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°C by addition of 2.0 M Hcl (~98 ml). The organic phase was separated and concentrated at 45°C under vacuum (water azeotrope was removed). Crystallization of the product was launched at 45°C 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°C remained (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) ohlord is whether to -10°C was 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 peremeshivaniem within 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-carbaldehyde (4,13 g, 16.0 mmol) and tri-n-propyl is in (3,20 ml, is 16.8 mmol). The resulting solution was evaporated at 50°C under 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 vacuo and the remaining aqueous mixture was extracted with toluene (60 ml). The organic phase was concentrated at 50°C 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). The clear solution was cooled to 0-5°C and anhydrous conditions on balali N-ethyldiethanolamine (6,1 ml, 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°C and finally 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°C 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°C 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°C To produce 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

The solution of bosilovo what about the 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°C 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°C under vacuum (water azeotrope was removed). Crystallization of the product initiated at 45°C 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°C (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. The colorless organic layer was dried over sodium sulfate, was filtered and was evaporated in vacuo and dried in high vacuum to obtain a colorless Maslama 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 solution of Hcl. 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 mmol) at room temperature. The clear solution was heated to 50°C. and stirred at this temperature for 60 minutes After the end of the PE the work, the reaction mixture was extinguished with methanol (10 ml) at 50°C 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°C 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°C before the addition of 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 0 ml 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 ethanol (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 dichloro the n (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) at 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 vacuum for at the Alenia 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), of 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°C under vacuum (water azeotrope was removed). 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 Ave is 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°C and the pH is brought to 6-7. Methanol drove from the reaction mixture at 50°C in vacuum and the resulting aqueous mixture was extracted with toluene (180 ml). The organic phase was concentrated at 50°C 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 for approximately 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°C, then added water (78 ml) and the resulting biphasic system was brought to pH 2 by addition of 2.0 M hydrochloric the acid (about 10 ml, 20 mmol). The organic phase was separated, was extracted with water (78 ml) and concentrated at 50°C 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°C. 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°C To produce 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°C 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°C under vacuum (water azeotrope was removed). Crystallization of the product initiated at 45°C. and after adding cyclohexane 102 ml) was cooled to -5°C. The solid is collected by filtration and after drying at 50°C was obtained (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)-1 H-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°C. 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) as a yellow liquid.

1H-NMR of N2-isomer (400MHz, 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).

1N-I Is R 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-butylmethylamine ether (40 ml) was heated to 45°C. 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°C was added a solution of 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-(tetrahydropyran-2-yl)-1H-tetrazole (N1-isomer) in a ratio of about 93:7 (in accordance with1H-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), 3,8-3,86 (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°C was 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°C. was added 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-(tetrahydropyran-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(trifinio the fin)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' -diethoxylate-biphenyl-2-yl)-2-(tetrahydropyran-2-yl)-2H-tetrazole (0,408 g; 1.00 mmol) was added to 94% this is Nol (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°C. to obtain 2'-(N-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

or its salts, including
(i) reaction of compounds of formula

or its salts, where Hal represents halogen, in the presence of acid with the compound of the formula

where R6, R7and R8independently from each other selected from hydrogen and C1-C6-alkyl, and R9represents a C1-C6-alkyl, or R7and R9together form2-C5-alkylen, or R6and R8together form3-C6-alkylen,
(ii) reaction of the compounds of the formula

in the presence of a catalyst of a transition metal compound of the formula
< / br> where X represents a halogen, a R5and R'5independently from each other, represent a1-C7-alkyl, or together form With the2-C4-alkylen; and
(iii) removing sequentially or at the same stage protective group from the resulting compound of the formula

by treatment with an acid,
(iv) the allocation of the compounds of formula (IIA') or its salt.

2. The method according to claim 1, where the stage (i) is carried out in the presence of from 0.0001 to 0.1 equivalents of acid Branstad.

3. The method according to claim 1, where the stage (ii) is carried out using a platinum or palladium catalyst.

4. The method according to claim 2, where the stage (ii) is carried out using a platinum or palladium catalyst.

5. The method according to any one of claims 1 to 4, where the compound of formula (IVd) receive (i) the interaction of the compounds of formula

where X represents a halogen, with magnesium in the conditions of the Grignard reaction, obtaining the compounds of formula

(ii) processing the obtained compound of formula (IVd) by Zn(X)2where X represents a halogen.

6. The method according to claim 5, where the reaction of the compound of formula (IVd') with magnesium in the conditions of the Grignard reaction is carried out in the presence of 1,2-dibromethane.

7. The compound of the formula

where R5and R'5independent the one from the other, represent1-C7-alkyl,
R6and R8represent hydrogen,
R7and R9together form2-C5-alkylen.

8. The connection according to claim 7 having the formula



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel derivatives of 1H-imidazole of formula I, in which R1 represents hydrogen, halogen atom, C1-3-alkyl group, and said C1-3-alkyl groupcan include 1-3 fluorine atoms or R1 represents cyclopropyl, piano, or methylsulfanyl group, R2 represents phenyl group, which can be substituted with 1 substituent Y, selected from methoxy, chlorine, fluorine, trifluoromethyl and cyano, or R2 represents pyridyl group, on condition that R2 is not 6-methyl-2-pyridyl group, or R2 represents fully saturated 6-7-member monocyclic, condensed bicyclic ring system or benzothiazolyl, benzodioxane or thiazole group, and said groups can be substituted by 1 fluorine atom, or R2 represents group of general formula CH2-R5, in which R5 represents phenyl group or fully saturated 7-member condensed bicyclic carbocyclic ring system, or R5 represents piperidine or tetrahydrofuran ring system, which can be substituted by methyl, or R2 represents methylsulfonylamino(C3)alkyl group, R3 represents hydrogen, halogen atom, C1-6-alkylsulfonyl, cyanogroup, or R3 represents C1-8-alkyl group, and said C1-8-alkyl group can be substituted by 1-3 fluorine atoms, or R3 represents phenyl group, which is substituted by substituent Y, where Y has value, specified above, or R3 represents furanyl group, R4 represents one of subgroups (i) or (ii), where R6 represents C4-8-branched or linear alkyl group or naphtyl group, R7 represents hydrogen atom, linear C1-6-alkyl group, R8 represents C2-6-alkyl group, substituted by 1-3 fluorine atoms, or R8 represents C3-8-cycloalkyl group, piperidine group, C3-8-cycloalkyl- C1-2-alkyl group, tetrahydrofuranyl- C1-2-alkyl group, C5-10-bicycloalkyl group, C5-10-bicycloalkyl-C1-2-alkyl group, C6-10-tricycloalkyl group, C6-10-tricycloalkyl-C1-2-alkyl group, and said groups can be substituted by 1-3 substituents, selected from methyl or hydroxyl, or R8 represents phenyl group, substituted by 1-2 substituents Y, specified above, or R8 represents naphtyl, 1,2,3,4-tetrahydronaphtyl or indanyl group, and said groups can be substituted by 1 substituent Y, or R8 represents phenyl- C1-3-alkyl group, diphenyl- C1-3-alkyl group, and said groups can be substituted ob their phenyl ring by 1 substituent Y, where Y has value specified above, or R8 represents benzyl group, substituted by 2 substituents Y, or R8 represents quinilinyl, pyridinyl, benzimidazole or naphtylmethyl group which can be substituted by substituent Y, where Y has value, specified above, or R8 represents asabicyclo[3,3,0]octanyl group, on condition that R8 is neither 6-methoxybenzothiazole-2-yl group, nor [3-chlor-5-(trifluoromethyl)pyrid-2-yl]methyl group, or R7 and R8 together with nitrogen atom, to which they are bound, form saturated, non-aromatic, monocyclic or bicyclic heterocyclic group, including only one nitrogen atom, having 7-10 ring atoms, which can be subslituted by 3 C1-3-alkyl groups, or R7 and R8 together with nitrogen atom, to which they are bound, form saturated, monocyclic heterocyclic group, optionally including another N atom, having 6 ring atoms, and said heterocyclic group is substituted by C1-3-alkyl groups, on condition that R7 and R8 together with nitrogen atom, to which they are bound, do not form trimethylsubstituted asabicyclo[3,3,0]octanyl group, as well as their stereoisomers and pharmacologically acceptable salts of said formula (I) compounds and their stereoisomers Invention also relates to intermediate compounds of formula XIV, pharmaceutical composition based on formula I compound, method of obtaining such pharmaceutical composition and application of formula T compound.

EFFECT: obtained are novel derivatives of IH-imidazole, which are modulators of cannabinoid CB2-receptors.

8 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of novel 4-(1H-indol-3-yl)-but-3-en-2-one derivatives of general formula 3: , : which can be used in synthesis of novel preparations for pharmaceutical and agricultural purposes. The method involves mixing 2-alkyl-5-(2-amino-4-alkylphenyl)-furans 1 with aromatic and heteroaromatic aldehydes 2 in acetic acid in equimola ratio at temperature 35°C for 40 minutes in the presence of 0.01 ml hydrochloric acid.

EFFECT: improved method.

2 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula where: R1 denotes -OR1', -SR1", 6-member heterocycloalkyl with one O atom and possibly one N atom, phenyl or 5-member heteroaryl with two N atoms, 6-member heteraryl with one N atom; R1'/R1" denote C1-6-alkyl, C1-6-alkyl substituted with a halogen, -(CH2)x-C3-6cycloalkyl or -(CH2)x-phenyl; R2 denotes S(O)2-C1-6-alkyl, -S(O)2NH-C1-6-alkyl, CN; denotes the group: , and where one extra N atom of the nucleus of an aromatic or partially aromatic bicyclic amine may be present in form of its oxide ; R3 - R10 denotes H, halogen, C1-6-alkyl, C3-6cycloalkyl, 4-6-member heterocycloalkyl with one N or O atom, 6-member heterocycloalkyl with two O atoms or two N atoms, 6-8-member heterocycloalkyl containing on N atom or one O or S atom, 5-member heteroaryl with two or three N atoms, 5-member heteroaryl with one S atom, in which one carbon atom may be also substituted with N or O, 6-member heteroaryl with one or two N atoms, C1-6-alkoxy, CN, NO2, NH2, phenyl, -C(O)-5-member cyclic amide, S-C1-6-alkyl, -S(O)2-C1-6-alkyl, C1-6-alkyl substituted with halogen;C1-6-alkoxy substituted with halogen, C1-6-alkyl substituted with OH, -O-(CH2)y-C1-6-alkoxy, -O(CH2)yC(O)N(C1-6-alkyl)2, -C(O)-C1-6-alkyl, -O-(CH2)x-phenyl, -O-(CH2)x-C3-6cycloalkyl, -O-(CH2)x-6-member heterocycloalkyl with one O atom, -C(O)O-C1-6-alkyl, -C(O)-NH-C1-6-alkyl, -C(O)-N(C1-6-alkyl)2, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; R' and R'" in group (e) together with -(CH2)2- with which it is bonded can form a 6-member ring; R, R', R" and R"' independently denote H, C1-6-alkyl; and where all groups - phenyl, cycloalkyl, cyclic amine, heterocycloalkyl or 5- or 6-member heteroaryl, as defined for R1, R1', R1" and R3 - R10, can be unsubstituted or substituted with one or more substitutes selected from OH, =O, halogen, C1-6-alkyl, phenyl, C1-6-alkyl substituted with halogen, or C1-6-alkoxy; n, m o, p, q, r, s and t = 1 , 2; x =0, 1 or 2; y = 1 , 2; and their pharmaceutically acceptable acid addition salts.

EFFECT: compounds have glycine transporter 1 inhibiting activity, which enables their use in a pharmaceutical composition.

20 cl, 2 tbl, 12 dwg, 382 ex

FIELD: medicine.

SUBSTANCE: invention refers to a polymer derivative of cytidine antimetabolite of formula (1) which can be used as an antineoplastic drug: (1), where R is hydrogen or alkyl; A is hydrogen, acyl or alkoxycarbonyl; m is within 3 to 200; n is within 5 to 2000; X is a residue of cytidine antimetabolite, hydroxyl or a hydrophobic substitute, and X means a residue of cytidine antimetabolite in amount 3-100 % m, hydroxyl in amount 0-95 % m and the hydrophobic substitute in amount 0-80 % m.

EFFECT: preparation of new antineoplastic compounds.

8 cl, 5 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 4(5)-(2-hetaryl) and 4(5)-(2-hetaryl)-2-(2'-hetaryl)-imidazoles of general formula R=2-furyl, 2-thienyl; R'H; and R=2-furyl, 2-thienyl; R'=2-furyl is obtained using 2-bromoacetylfuran (thiophene) of general formula 2-thienyl and aldehydes in the presence of copper acetate, synthesis of a 2-bromoacetylfuran (thiophene) precursor is carried out by reacting 2-acetylfuran (thiophene) with copper (II) bromide.

EFFECT: increased safety of the process.

2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds, specifically to 4-substituted-3-(1-alkyl-2-chloro-1H-indol-3-yl)furan-2,5-diones of general formula I , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R3=phenyl, naphthyl, 2-phenyl-1-ethenyl, thienyl, furyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, synthesis method thereof and use as compounds capable of photochemical generation of stable fluorophores of formula II, which can be used, for instance in information storage systems, particularly as photosensitive components of material for three-dimensional recording and storage of information. The invention also relates to novel 4,5-substituted-6-alkyl-1H-furo[3,4-c]carbazole-1,3(6H)diones of general formula II , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R4=H, R5=phenyl, R4, R5=benzo, naphtho, thieno, furo, pyrrolo, benzothieno, benzofuro, indolo, method for synthesis of said compounds and use as fluorophores.

EFFECT: obtaining novel compounds and possibility of using said compounds as fluorophores.

14 cl, 2 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new chroman derivatives of formula I: , or to their pharmaceutically acceptable salts where m has a value of 0; p has a value of 2; q has a value of 2; Ar represents phenyl optionally substituted with halogen atom; R2 represents ; X represents -NR9-; n has a value of 2 or 3; each R3, R4, R5 and R6 independently represents hydrogen or C1-12alkyl; each R7 and R8 independently represents either hydrogen, or C1-12-alkyl, or R7 and R8 together with nitrogen whereto attached, can form 4-6-members ring, or one of R7 and R8 and one of R5 and R6 together with atoms whereto attached can form 4-6-members ring; and R9 represents hydrogen or C1-12-alkyl, or when R7 represents hydrogen or methyl, R9 together with R8 and atoms whereto attached can form 6-members ring.

EFFECT: preparation of chroman new derivatives and the pharmaceutical composition containing compounds of formula (I).

22 cl, 1 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of existing and novel N-sulfamoyl- N'-arylpiperazines and their physiologically compatible acid-addition salts of formula I , where Ar denotes a monocyclic or bicyclic C6-C10aryl in which ring carbon atoms are optionally substituted with 1-3 nitrogen or oxygen atoms, and/or where the C6-C10aryl ring system optionally contains 3-5 double bonds, and/or where the C6-C10aryl ring system is optionally substituted with 1 or 2 substitutes which can be identical or different and which can be selected from a group containing halogen, trifluoromethyl, cyano group, nitro group, C1-C4alkyl, C1-C4alkoxy group, C1-C4alkylsulfonyl; and two oxygen atoms which are bonded to two neighbouring carbon atoms of the C6-C10aryl ring system and are bonded by a C1-C2alkylene bridge; or where the C6-C10aryl ring system is substituted with phenyl which can optionally be substituted in the phenyl ring by one substitute which can be selected from a group containing halogen; for preventing or treating obesity and related diseases.

EFFECT: design of a method of obtaining the said compounds and a pharmaceutical composition based on the said compounds.

25 cl, 9 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of the formula (I) R is radical selected out of i) , ii) , iii) , iv) , where R7 is halogen, cyano, C1-4alkyl, C1-4alkoxy; p is integer within 0 to 3; R1 is hydrogen, C2-4alkenyl or C1-4alkyl; R2 is hydrogen or C1-4alkyl; R3 and R4 are independently hydrogen or C1-4alkyl; R5 is: phenyl substituted with 1-3 groups selected independently out of trifluoromethyl, C1-4alkyl, cyano or halogen; naphthyl substituted with 1-3 groups selected independently out of trifluoromethyl, C1-4alkyl, cyano or halogen; benzofurane substituted with 1-3 groups selected independently out of C1-4alkyl or halogen; R6 is hydrogen or (CH2)qR8; R8 is hydrogen; m is zero or 1; n is 1; q is an integer within 1 to 4; r is 1 or 2; provided that if R5 is phenyl substituted with 1-3 groups selected independently out of trifluoromethyl, C1-4alkyl, cyano or halogen, then R is not radical i) ; and pharmaceutically acceptable salts or solvates thereof. The invention also refers to method (A) of compound obtainment, to compound application, to pharmaceutical composition, as well as to mammal treatment method.

EFFECT: obtainment of novel bioactive compounds with tachykinin receptor antagonist activity.

16 cl, 116 ex

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula I where A represents an optionally substituted aryl or heteroaryl, B - a benzene or thiophene cycle, C - a benzene or aliphatic hydrocarbon cycle, while values of other radicals are disclosed in the description. The compound according to the present invention, and the based pharmaceutical compositions exhibit a strong antagonistic effect in relation to GnRH receptor that makes them applicable for treatment of GnRH-related diseases, particularly prostate cancer, benign prostatic hyperplasia, breast cancer, endometriosis and/or uterine fibroid tumour.

EFFECT: improved clinical effectiveness.

11 cl, 70 tbl, 765 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel anthranilic acid derivatives having inhibitory effect on production of matrix metalloprotease 13 of formula 1 , where R1 is a hydrogen atom or carboxy protective group selected from C1-3alkyl; R2 is phenyl, C3-6cycloalkyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-3 heteroatoms selected from N, O, S, which can be condensed with phenyl, which can be optionally substituted with C1-6alkyl, C1-6alkoxy, acetyl, acetoxy, halogen, halogenC1-6alkyl, nitro group, hydroxyl group, CN, amino group, phenyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-4 heteroatoms selected from N, O, S, which can be disubstituted with C1-6alkyl; R3 is phenyl, C3-6cycloalkyl, C5cycloalkenyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-3 heteroatoms selected from N, O, S, which can be condensed with phenyl (except benzoxazole), which can be optionally substituted with C1-6alkyl, C1-6alkoxy, phenyl, acetyl, halogen, halogenC1-6alkyl, halogenC1-6alkoxy, nitro group, hydroxyl group, hydroxyC1-6alkyl, CN, acetylamino, ketone, phenoxy, benzoyl, benzyl, amino group, which can be disubstituted with C1-6alkyl, carboxy group, C1-6alkylsufonyl group or pyrrolyl; X1 is a carbonyl group or sulfonyl group; X2 is a C1-3alkylene, C2-3alkenylene or C2-3alkynylene group which can be optionally substituted with C1-3alkyl, or a bond; provided that when X1 is a sulfonyl group and X4 is a bond, X2 is a C1-3alkylene, C2-3alkenylene or C2-3alkynylene group which can be optionally substituted with C1-3alkyl; X3 is an oxygen atom or a bond; and X4 is a group with general formula -X5-X6- or -X6-X5-, where the bond on the left side of each formula is bonded to R3; and X5 is an oxygen atom, a sulphur atom, an imino group which can be optionally protected or a bond; X6 is a C1-4alkylene, C2-3alkenylene or C2-3alkynylene group or a bond, as well as to their pharmaceutically acceptable salts. The invention also relates to a matrix metalloprotease 13 production inhibitor and a therapeutic agent for making a medicinal agent for treating rheumatoid arthritis.

EFFECT: possibility of making a medicinal agent for treating rheumatoid arthritis.

8 cl, 7 tbl, 633 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of obtaining compounds of formula ,

involving reaction of a mixture of a compound of formula IVa and a compound of formula IVb

with a compound of formula

or pharmaceutically acceptable salt thereof in the presence of KOH, NaOH and LiOH as bases, and dialkylphosphite reducing agent, a tetraalkyl ammonium chloride phase transition catalyst; and possibly washing the formula II compound with a solvent and then possibly conversion of the formula II compound to a pharmaceutically acceptable salt. The invention also relates to the method of obtaining formula compounds.

EFFECT: design of a new method of obtaining a compound used as an intermediate product in irbesartan synthesis.

3 ex

FIELD: medicine.

SUBSTANCE: there is described new compound - choline salt 2-(3,4-dimethylphenyl)-4-{[2-hydroxy-3'-(1H-tetrazole-5-yl)biphenyl-3-yl]hydrazono}-5-methyl-2,4-dihydropyrazole-3-one, a pharmaceutical composition containing it, and method for making said composition.

EFFECT: new compound is an improved thrombopoietin mimetic and can be used as a TRO-receptor agonist.

3 cl, 4 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

FIELD: medicine.

SUBSTANCE: new derivatives of diphenyl urea having general formula I or their pharmaceutically comprehensible salts, where Ro - hydrogen are described; Rm - hydrogen or trifluoromethyl; Rp - hydrogen, halogeno, trifluoromethyl, trifluoromethoxy, C1-6alkyl or C1-6alkoxy; provided that Ro, Rm and Rp simultaneously cannot mean hydrogen; R2, R3, R4 and R5 independently mean hydrogen, halogeno or trifluoromethyl, provided that the bond does not represent N-(3-trifluoromethyl-phenyl)-N'-[3-(1N-tetrazole-5-il)-4'-trifluoromethyl-biphenyl-4-il]-urea, a pharmaceutical composition, their containing, and their application as blockers of chloride channels.

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

12 cl, 3 ex, 1 tbl

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

FIELD: chemistry.

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.

EFFECT: using compounds as biologically active agent and creating pharmaceutical compositions based on said compounds.

124 cl, 52 ex, 17 tbl, 2 dwg

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I): wherein R1 means quinolinyl possibly substituted with (C1-C5)-alkoxy-group, isoquinolinyl, quinoxalinyl, pyridinyl, pyrazinyl, benzyl possibly substituted with halogen atom, naphthalinyl, thiophenyl, furanyl, cinnolyl, phenylvinyl, quinolylvinyl or 4-oxo-4H-chromenyl possibly substituted with halogen atom, (C1-C5)-alkyl or (C1-C5)-alkoxy-group; R2, R5, R8 and R11 mean hydrogen atom; R3 and R4 mean halogen atom, (C1-C5)-alkoxy-group; R6 and R7 mean hydrogen atom (H) or (C1-C5)-alkyl or form in common radical -CH2-CH2-; R9 and R10 mean (C1-C5)-alkoxy-group; m and n mean a whole number from 0 to 4 independently; X means -CH2- or sulfur atom (S). Also, invention describes their pharmaceutically acceptable salts, a method for their preparing and pharmaceutical composition based on thereof. Proposed compounds are inhibitors of P-glycoprotein, enhance bioavailability of anti-cancer drug and can be used in medicine.

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

7 cl, 3 tbl, 33 ex

FIELD: organic chemistry.

SUBSTANCE: invention describes novel substituted benzoylcyclohexenones of the general formula (I): wherein values Q, Y, Z, R1-R5 and their possible tautomeric forms and their possible salts given in the invention claim. Invention proposes substituted benzoylcyclohexenones of the general formula (I) that possess the herbicide activity.

EFFECT: valuable property of compounds.

2 cl, 10 tbl, 6 ex

FIELD: inorganic synthesis and explosives.

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%.

EFFECT: increased preparation safety due to less sensitive starting material and reduced sensitivity of product to friction.

3 cl, 2 tbl, 10 ex

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