Derivatives of azetidine, methods for their preparation, pharmaceutical composition and a drug based on them

 

The invention relates to new derivatives of azetidine formula

in which R denotes an element of the formula

R1denotes a methyl radical or ethyl, R2denotes a naphthyl radical, hinely, phenyl, possibly substituted by one or more halogen atoms, alkyl radicals, alkoxyl, hydroxyl, etc.,, R3and R4identical or different, represent a phenyl radical, possibly substituted by one or more halogen atoms, alkyl, alkoxyl, formyl, trifluoromethyl, etc.,, R5denotes an alkyl radical or phenyl, substituted by one or more halogen atoms, R6and R7identical or different, denote a hydrogen atom or an alkyl radical, or R6and R7together with the nitrogen atom to which they are connected, form piperidinyl or pieperazinove cycle, substituted alkyl, R’6and R’7identical or different, denote a hydrogen atom or an alkyl radical, or R’6and R’7together with the nitrogen atom to which they are connected, form a pyrolidine or pieperazinove cycle, possibly substituted by one or more alkyl radicals, With the to, hydroxyalkyl, or R6and R7together with the nitrogen atom to which they are connected, form a loop imidazole, piperazinone, thiomorpholine, etc., R8denotes alkyl, R9denotes a hydrogen atom, an alkyl radical or an alkyl, substituted dialkylamino, phenyl, etc.,, R10and R11identical or different, denote a hydrogen atom or alkyl, R12and R13together with the nitrogen atom to which they are connected, form a loop of the research, a R16and R17together with the nitrogen atom to which they are connected, form a loop of piperidine, R’ denotes a hydrogen atom or the radical-CO-ALK, ALK denotes an alkyl or alkylene, and alkyl or alkylene radicals or their parts and CNS radicals or their parts are straight or branched chain, containing from 1 to 6 carbon atoms, and their optical isomers and their salts with mineral or organic acid. Method of producing compounds of the formula I in which R represents a chain of formula A, by dehydration of compounds of formula

in which R1, R2, R3and R4have the meanings specified for formula I, and R" denotes a hydroxy radical, methanesulfonic the social or organic acid. Pharmaceutical composition having an antagonistic effect, containing as active principle at least one compound of formula I in an amount of from 1 to 1000 mg of the Drug, which has antagonistic activity, containing as active substance at least one compound of formula (I). The technical result is new derivatives of azetidine having an antagonistic effect. 26 C. and 2 h.p. f-crystals, 1 table.

The present invention relates to a derivative of azetidine formulas

their optical isomers, their salts, as well as the way they are received and to medicines on the basis of them.

In the formula I

R denotes the chain

R1denotes a methyl radical or ethyl,

R2means either an aromatic radical selected from phenyl, naphthyl and indenyl, which can be unsubstituted or substituted by one or more halogen atoms, radicals: alkyl, alkoxy, -COalk, hydroxy, -COOR5, formyl, trifluoromethyl, trifloromethyl, triptoreline, nitro, -NR6R7, -CO-NH-NR6R7, -N(alk)COOR8, cyano, -CONHR9, -CO-NR16R175, trifluoromethyl, triftormetilfullerenov, triptoreline, nitro, -NR6R7, -CO-NH-NR6R7, cyano, -CONHR9, alkylsulfanyl, hydroxyalkyl or allylthiourea;

R3and R4identical or different, represent either an aromatic radical selected from phenyl, naphthyl and indenyl, which can be unsubstituted or substituted by one or more halogen atoms, radicals: alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, triptoreline, -COalk, cyano, -COOR5, -CONR10R11, -CO-NH-NR6R7alkylsulfanyl, hydroxyalkyl, -alk-NR6R7or alkylthiomethyl; or a heteroaromatic radical selected from the cycles: benzofuran, benzothiazole, benzothiazyl, benzoxazolyl, bromanil, 2,3-dihydrobenzofuran, 2,3-dihydrobenzofuranyl, furyl, isopropanol, ethanolic, pyrrolyl, hinely, 1,2,3,4-tetrahydroxy, by trifluoromethyl, triptoreline, cyano, -COOR5, -CONHR9, -CO-NH-NR6R7, -CO-NR10R11, -alk-NR6R7, alkylsulfanyl, hydroxyalkyl or allylthiourea;

R5denotes an alkyl radical or phenyl, possibly substituted by one or more halogen atoms;

R6and R7identical or different, denote a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylsilanes, -alk-O-alk or hydroxyalkyl, or R6and R7together with the nitrogen atom to which they are attached, form a saturated or unsaturated mono - or bicyclic 3-10-membered heterocycle possibly containing another heteroatom selected from oxygen atoms, sulfur or nitrogen, and possibly substituted by one or more radicals: alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR14R15, oxo, hydroxyalkyl, -alk-O-alk-CO-NH2;

R8denotes alkyl radical;

R9denotes a hydrogen atom or an alkyl radical or an alkyl, substituted dialkylamino, phenyl, cycloalkyl (possibly substituted by a group-COOalk) or a saturated or unsaturated mono - or bicyclic 3-10-membered heterocycle may contain one or more heteroatoms selected from oxygen, sulfur and azole different, represent a hydrogen atom or an alkyl radical, or R10and R11together with the nitrogen atom to which they are attached, form a saturated mono - or bicyclic 3-10-membered heterocycle possibly containing another heteroatom selected from oxygen atoms, sulfur or nitrogen, and possibly substituted alkyl radical;

R12and R13identical or different, denote a hydrogen atom or an alkyl radical or cycloalkyl, or R12and R13together with the nitrogen atom to which they are attached, form a saturated mono - or bicyclic 3-10-membered heterocycle possibly containing another heteroatom selected from oxygen atoms, sulfur or nitrogen, and possibly substituted by alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR14R15or saturated mono - or bicyclic 3-10-membered heterocycle containing one heteroatom selected from oxygen, sulfur and nitrogen;

R14and R15identical or different, denote a hydrogen atom, an alkyl radical or-COOalk;

R16and R17together with the nitrogen atom to which they are attached, form a saturated mono - or bicyclic 3-10-membered heterocycle possibly containing another heteroatom selected from oxygen, sulfur or nitrogen;

R is above or below the definitions, unless stated otherwise, alkyl, alkylene and CNS radicals or parts have normal or branched chain and contain from 1 to 6 carbon atoms.

From alkyl radicals can be called methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl. Of alkoxyalkyl can be called methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy.

The term halogen includes chlorine, fluorine, bromine and iodine.

When R2,and/or R3and/or R4independently represent substituted phenyl, it is mainly mono-, di - and tizanidine.

When R6and R7together with the nitrogen atom to which they are attached, form a saturated or unsaturated mono - or bicyclic 3-10-membered heterocycle, mainly representing the cycle: azetidinol, pyrrolidinyl, piperazinil, piperidyl, morpholinyl, imidazolyl, thiomorpholine or furyl which may be substituted by alkyl radical, hydroxyalkyl, -alk-O-alk, -CONH2, -COalk, -COOalk, oxo, -CSNHalk, -CONHalk or-CO-alk-NR14R15and, in particular, methyl radical, ethyl, propyl, isobutyl, acetyl, N,N-dimethylaminomethylene, methyloxycarbonyl, methylcarbamoyl, 3-N3.

When R10and R11together with the nitrogen atom to which they are attached, form a saturated mono - or bicyclic 3-10-membered heterocycle, the latter is primarily cycle: azetidinol, pyrrolidinyl, piperazinil, piperidyl, morpholinyl or thiomorpholine, which can be substituted by alkyl.

When R12and R13together with the nitrogen atom to which they are attached, form a saturated mono - or bicyclic 3-10-membered heterocycle, the latter is primarily cycle: azetidinol, pyrrolidinyl, piperazinil, piperidyl, morpholinyl or thiomorpholine, which can be substituted by alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR14R15or saturated mono - or bicyclic 3-10-membered heterocycle containing one heteroatom selected from oxygen, sulfur and nitrogen, in particular the radical thiomorpholine.

When R12and R13together with the nitrogen atom to which they are attached, form a saturated mono - or bicyclic 3-10-membered heterocycle, the latter is primarily piperidyl.

When R9denotes alkyl radical, substituted saturated or unsaturated mono - or bicyclic 3-10-cloth, the latter is primarily cycle: pyrrolidinyl, tetrahydrofuryl, morpholinyl or pyrrolyl, which can be substituted by one or more alkyl radicals.

The compounds of formula I may be in the form of enantiomers and diastereoisomers. These optical isomers and mixtures thereof form part of the invention.

The compounds of formula I, where R represents a chain of formula a can be obtained by dehydration of compounds of the formula

in which R1, R2, R3and R4have the same meanings as in formula I, a R’ denotes a hydroxy radical, methansulfonate or atomic charges.

This dehydration is carried out by using any known method to degidratiruth alcohol or one of its derivatives with formation of the corresponding alkene. Mainly use derivatives, in which R’ is methansulfonate or acetyloxy obtained from the corresponding derivatives, in which Ris a hydroxy-group, under the action of methanesulfonanilide or acetylchloride in an inert solvent, such as pyridine, tetrahydrofuran, dioxane, a chlorinated solvent (for example, the m, such as hydroxides of alkali metals (e.g. sodium hydroxide), carbonates of alkali metals (e.g. sodium carbonate or potassium), amines of the type trialkylamines (e.g., triethylamine), 4-dimethylamino-pyridine or diaza-1,8-bicyclo[5.4.0]undec-7-ene at a temperature of from 0C to the boiling temperature of the reaction medium. Methansulfonate or atsetilatsetonatnye can be allocated or used without highlighting.

The compounds of formula I in which R is a chain, where R’ represents a hydrogen atom, can be obtained by the interaction of the derivative of formula II, R1SO2CH2R2in which R1and R2have the meanings specified for formula I, with azetidinol formulas

in which R3and R4have the same meanings as in formula I.

The reaction is usually carried out in an inert solvent such as the simple ether (such as tetrahydrofuran) in the presence of a strong base, such as diisopropylamide lithium, tert-butyl potassium, or n-utility, at a temperature of from -70 -15C.

Derivatives of formula II can be obtained by application or by analogy with the methods described in the examples. In cast the de Hal denotes a halogen atom, mainly chlorine, bromine or iodine, a R1and R2have the same meanings as in formula I.

Reaction (a) is usually carried out in an inert solvent, such as dimethylformamide or aliphatic C1-C4-alcohol, at a temperature of from 20 to 30C.

Reaction (b) is carried out using all known methods to oxidize sulfur-containing derivative without affecting the rest of the molecule, such as the methods described in M. HUDLICKY, Oxidation in organic chemistry, ACS Monograph, 186, 252-263 (1990). In particular, there are organic nagkalat or salt of this nagkalat (nadarbazevi or nadsolevoye acid, in particular natantia acid, 3-chlormadinone acid, 4-nitromidazole acid, peracetic acid, CRYPTOMAGAZINE acid, nagarajuna acid, monongalia acid or mineral acids or their salts (for example, nadwodny or nadkarni acid) in an inert solvent such as a chlorinated solvent (e.g. chloroform, dichlormethane), at temperatures from 0 to 25C. Can also be used hydrogen peroxide or periodate (for example, periodate sodium) in an inert solvent, the ri temperatures from 0 to 20C. you Can also work using tert-butylhydroperoxide in the presence of tetraisopropyl titanium in the environment aliphatic alcohol C1-C4(for example, methanol or ethanol) or water-alcohol mixture at a temperature close to 25With, or using oxoneR(peroxymonosulfate potassium) in the environment aliphatic alcohol C1-C4(for example, methanol or ethanol) in the presence of water, acetic acid or sulfuric acid at a temperature close to 20C.

Reaction (C) is carried out mainly in an inert solvent, such as aliphatic alcohols, C1-C4(for example, methanol or ethanol), at temperatures from 20C to the boiling temperature of the reaction medium.

Derivatives of formula IV can be purchased on the market or obtained from or by analogy with the methods described in the examples. In particular, use halogenoalkane methylated derivative or the corresponding alcohol using a halogenation agent, such as Hydrobromic acid in acetic acid medium at a temperature close to 20S, or N-bro is girod, when the boiling temperature of the reaction medium. Methylated derivatives or the corresponding alcohols are produced on the market or can be obtained by the methods described BRINE G. A. et al., J. Heterocycl. Chem., 26, 677 (1989) and D. NAGARATHNAM, Synthesis, 8, 743 (1992) and in the examples.

Azetidine formula III can be obtained using, or by analogy with the methods described by KATRITZKY A. R. et al., J. Heterocycl. Chem., 271 (1994) or DAVE P. R., J. Org. Chem., 61, 5433 (1996) or in the examples. The reaction is usually carried out in accordance with the following scheme:

where R3and R4in the formula have the same meanings as in formula I, and X denotes a chlorine atom or bromine.

At the stage And the reaction is carried out mainly in an inert solvent, such as aliphatic alcohols, C1-C4(for example, ethanol or methanol), possibly in the presence of alkali metal hydroxide at the boiling temperature of the reaction medium.

On stage In recovery is usually carried out using lithium hydride or aluminum in tetrahydrofuran at the boiling temperature of the reaction medium.

On stage With work primarily in an inert solvent, such as aliphatic C1-C4alcohol (e.g. ethanol, methanol), in the presence of hydrocarbon the Hai D oxidation is usually carried out in DMSO using complex pyridine-sulfurised at a temperature close to 20With, or with dimethyl sulfoxide in the presence of oxalicacid and triethylamine at a temperature of from -70 to -50C.

At stage E, the reaction is carried out according to the method described by M. GRISAR et al. in J. Med. Chem., 885 (1973). Get a magnesium compound of the brominated derivative and then reacting injected nitrile among ordinary ether, for example diethyl ether, at a temperature of from 0C to the boiling temperature of the reaction medium. After hydrolysis, the alcohol intermediate Imin restore in situ with sodium borohydride at a temperature of from 0C to the boiling temperature of the reaction medium.

Derivatives of R3-CO-R4available on the market or can be derived from the use or by analogy with the methods described KINDER N. G. et al., J. Chem. Soc Perkin Trans 1, 2815 (1997); MORENO-MARRAS M., Eur. J. Med. Chem., 23 (5) 477 (1988); SKINNER et al., J. Med. Chem., 14 (6) 546 (1971); HURN N. K., Tet. Lett., 36 (52) 9453 (1995); MEDICI A. et al., Tet. Lett., 24 (28) 2901 (1983); RIECKE R. D. et al., J. Org. Chem., 62 (20) 6921 (1997); KNABE J. et al., Arch. Pharm., 306 (9) 648 (1973); CONSONNI, R. et al., J. Chem. Soc. Perkin Trans 1, 1809 (1996); FR-96-2481 and JP-94-261393.

Derivatives of R3Br available on the market or can be derived from the use or by analogy with the methods RLE R. et al., J. Chem. Soc. Perkin Trans 2, 489 (1993).

Derivatives of R4CN are available on the market or can be derived from the use or by analogy with the methods described by R. BOUYSSOU et al., J. Het. Chem., 29 (4) 895 (1992); SUZUKI N., et al., J. Chem. Soc. Chem. Comm., 1523 (1984); MARBURG, S. et al., J. Het. Chem., 17, 1333 (1980); V. PERCEC et al., J. Org. Chem., 60 (21) 6895 (1995).

The compounds of formula I in which R is a chain, where R’ represents a hydrogen atom, can be obtained by the interaction of the derivative of formula VI, R3CH(Br)R4in which R3and R4have the same meanings as in formula I, with derivative formulas

in which R1and R2have the same meanings as in formula I.

This reaction is usually carried out in the presence of a base such as a carbonate of an alkali metal (e.g. potassium carbonate) in an inert solvent, such as acetonitrile, at the boiling temperature of the reaction medium.

Derivatives of formula VI are available on the market or can be derived from the use or by analogy with the method described by W. E. BACHMANN, J. Am. Chem. Soc., 2135 (1933). Normally carried out by bromination of the corresponding alcohol R3R4using Hydrobromic acid in acetic acid medium at a temperature of from 0 available on the market or can be derived from the use or by analogy with the methods described PLASZ A. S. et al., J. Chem. Soc. Chem. Somme., 527 (1972).

Derivative of formula VII can be obtained by hydrolysis derivatives of the formula

in which R1and R2have the same meanings as in formula I.

This reaction is usually carried out using a chlorine-hydrogen acid in an inert solvent, such as a simple ether (e.g. dioxane) at a temperature close to 20C.

Derivatives of formula VIII is obtained by interaction of vinylchloride with the corresponding compounds of formula I in which R represents a chain of formula (V), where R’ represents hydroxyacyl, and R3and R4are phenyl radicals, in an inert solvent such as a chlorinated solvent (for example, or chloroform), at a temperature of from 0C to the boiling temperature of the reaction mixture.

The compounds of formula I in which R is a chain (C), where R’ represents a radical-CO-alk, can be obtained by the interaction of the halide of the formula Hal-CO-alk, in which Hal denotes a halogen atom and preferably a chlorine atom, a alk denotes alkylene is no a hydrogen atom.

This reaction is usually carried out in an inert solvent, such as tetrahydrofuran, dioxane, a chlorinated solvent (for example dichloromethane or chloroform), at a temperature of from -50 to 20In the presence of n-utillity.

The compounds of formula I in which R2is an aromatic or heteroaromatic radical, substituted by a group-NR6R7where each of R6and R7is a hydrogen atom can also be obtained by reduction of corresponding compounds of the formula I, in which R2means nitrosamines aromatic or heteroaromatic residue.

This reaction is carried out using any method that allows you to restore the nitro-group to the amino group without affecting the rest of the molecule. Mostly use iron in the presence of chloride-hydrogen acid in the medium aliphatic alcohol C1-C4such as ethanol, at the boiling temperature of the reaction mixture.

The compounds of formula I in which R2is an aromatic or heteroaromatic radical, substituted by a group-CONHR9and/or R3and/or R4are aromatic or heteroaromatic radicals, samisen the uly I, in which R2and/or R3and/or R4are aromatic or heteroaromatic radicals, substituted by a group-COOR5in which R5denotes alkyl or phenyl which may be substituted by halogen atoms, respectively Amin H2NR9or HNR10R11where R9, R10and R11have the same meanings as in formula I.

This reaction is usually carried out in an inert solvent such as a chlorinated solvent (for example dichloromethane or chloroform), at a temperature of from 0C to the boiling temperature of the reaction mixture.

The compounds of formula I in which R2is an aromatic radical, substituted by hydroxyl and/or R3and/or R4are aromatic or heteroaromatic radical, substituted by hydroxyl, can be also obtained by hydrolysis of the corresponding compounds of the formula I, in which2is an aromatic radical, substituted alkoxy, and/or R3and/or R4are aromatic or heteroaromatic radicals, substituted alkoxy.

This reaction is carried out using any method of hydrolysis of alkoxygroup in the hydroxy-group without affecting the rest e, such as dichloromethane, at a temperature close to 20C.

The compounds of formula I in which R2is an aromatic radical, substituted by a group-NR6R7where R6denotes alkyl, a R7represents a hydrogen atom, can be obtained by removing protection from the corresponding compounds of the formula I, in which R2represents an aromatic moiety substituted by a group-N(alk)COOR8where R8denotes tert-botilony radical.

This reaction is usually carried out by using chloride-hydrogen acid in the environment of a solvent such as dioxane at a temperature close to 20C.

The compounds of formula I in which R2and/or R3and/or R4means an aromatic or heteroaromatic radical, substituted by a group-COOR5can also be obtained by esterification of compounds of the formula

in which R represents a chain C=C(SO2R1)R’2or C(OR’)CH (SO2R1)R’2, a R1, R’2, R’3and R’4have the same meanings as the substituents R1, R2, R3and R4in formula I, provided that at least one of the Deputy what baxrom, using the derived formula, R5OH, where R5is alkyl or phenyl, possibly substituted by one or more halogen atoms.

In the case when R5is alkyl, the reaction is carried out usually in the presence of a mineral acid (e.g. sulfuric acid) at a temperature of from 20C to the boiling temperature of the reaction medium. When R5is a possibly substituted phenyl, the reaction mainly occurs in the presence of carbodiimides (for example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or N,N’-dicyclohexylcarbodiimide) in an inert solvent type amide (dimethylformamide) or a chlorinated solvent (e.g. methylene chloride, dichloroethane or chloroform) at a temperature of from 0C to the boiling temperature of the reaction mixture.

Derivative of the formula IX in which R represents a chain C=C(SO2R1)R’2or C (OR’) CH (SO2R1)R’2, a R’, R1, R’2, R’3and R’4have the same meanings as the substituents R’, R1, R2, R3and R4in formula I, provided that at least one of the substituents R’2, R’3and R’4is an aromatic or the data above to obtain compounds of the formula I, on the basis of the respective intermediate products, in particular according to the method described in example 29.

The compounds of formula I in which R2and/or R3and/or R4means an aromatic or heteroaromatic radical, substituted by allylthiourea can also be obtained by the interaction of the derivatives of formula IX in which R represents a chain C=C (SO2R1)R’2or C (OR’)CH(SO2R1) R’2, a R’, R1, R’2, R’3and R’4have the same meanings as the substituents R’, R1, R2, R3and R4in formula I, provided that at least one of the substituents R’2, R’3and R’4is an aromatic or heteroaromatic radical, substituted by halogenation, with alkylsilane sodium.

This reaction is usually carried out in inert amide type solvent (e.g. dimethylformamide) at a temperature close to 20C.

Derivative of the formula IX in which R represents a chain C=C(SO2R1)R’2or C(OR’)CH(SO2R1)R’2a R’, R1, R’2, R’3and R’4have the same meanings as the substituents R’, R1, R2, R3and R4in formula I, when the condition is heteroaromatics radical, replaced by halogenation can be obtained by the interaction of trihalogen phosphorus (preferably trichromate phosphorus) with the corresponding compounds of the formula I, in which R2and/or R3and/or R4are aromatic or heteroaromatic radicals, substituted by hydroxyalkyl, in an inert solvent, such as chlorinated solvents such as carbon tetrachloride or chloroform), at a temperature close to 20C.

The compounds of formula I in which R2and/or R3and/or R4means an aromatic radical, substituted by hydroxyalkyl, in which the alkyl contains one carbon atom can also be obtained by reduction of compounds of formula I, in which R2, R3and R4are aromatic radicals, substituted by formyl.

This reaction is usually carried out using sodium borohydride in an aliphatic alcohol With1-C4(for example, methanol or ethanol) at temperatures close to 0C.

The compounds of formula I in which R3and/or R4 is an aromatic radical, substituted by a group-alk-NR6R7in which alk represents alkyl containing one atom ug is it R3and R4is an aromatic radical, substituted by formyl, with amines HNR6R7where R6and R7have the same meanings as in formula I.

This reaction is usually carried out in an inert solvent such as a chlorinated solvent (e.g. dichloromethane) at a temperature close to 20Since, in the presence of triacetoxyborohydride sodium or cyanoborohydride sodium.

The compounds of formula I in which R2is an aromatic or heteroaromatic radical, substituted by a group-CONHR9and/or R3and/or R4are aromatic or heteroaromatic radical, substituted by a group-CO-NR10R1can also be obtained by the interaction of a derivative of formula IX in which R represents a chain C=C(SO2R1)R’2or C(OR’)CH(SO2R1)R’2, a R’, R1, R’2, R’3and R’4have the same meanings as the substituents R’, R1, R2, R3and R4in formula I, provided that at least one of the substituents R’2, R’3and R’4is an aromatic or heteroaromatic radical, substituted by carboxyla, respectively, with an amine H2NR9or is modestino carried out either in the presence used in peptide chemistry condensing agent, such as carbodiimide (for example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or N,N’-dicyclohexylcarbodiimide) or N,N’-diimidazole, in an inert solvent such as ethers (e.g. tetrahydrofuran or dioxane), amides (dimethylformamide) or a chlorinated solvent (e.g. methylene chloride, dichloroethane or chloroform), at a temperature of from 0C to the boiling temperature of the reaction mixture, or after prelink acid on the resin tetraterpenes type the formula

where S denotes aminopenicillin resin, in an inert solvent, such as dimethylformamide, in the presence of 4-dimethylaminopyridine at a temperature close to 20C. the Binding resin is usually carried out in dimethylformamide in the presence of 4-dimethylaminopyridine and 1,3-diisopropylcarbodiimide at a temperature close to 20C.

The compounds of formula I in which R2and/or R3and/or R4are aromatic or heteroaromatic radical, substituted by a group-CO-NH-NR6R7can also be obtained by the interaction of the corresponding compounds formulae, substituted by a group-COOR5where R5denotes an alkyl radical or phenyl, possibly substituted by halogen atoms, with hydrazines H2N-NR6R7where R6and R7have the same meanings as in formula I.

This reaction is usually carried out in an inert solvent, such as dimethylformamide, at a temperature close to 20C.

The compounds of formula I in which R2is an aromatic or heteroaromatic radical, substituted by a group-CO-other9where R9is a hydrogen atom and/or R3,and/or R4are aromatic or heteroaromatic radicals, substituted by a group-CO-NR10R11where R10and R11are hydrogen atoms, can also be obtained by hydrolysis of the corresponding compounds of the formula I, in which2and/or R3and/or R4are aromatic or heteroaromatic radical, substituted by cyano.

This reaction is carried out using any known method, allowing the transition from NITRILES to the corresponding carbamoyl without affecting the rest of the molecule. For this purpose, mainly used chloride-hydrogen acid in the medium of acetic KIS is camping aromatic radical, substituted by a group O-alkNR12R13can also be obtained by the interaction of the derivatives of formula IX in which R represents a chain C=C(SO2R1)R’2or C(OR’)CH(SO2R1)R’2, a R’, R1, R’2, R’3and R’4have the same meanings as the substituents R1, R2, R3and R4in formula I, provided that at least one of the substituents R’2, R’3and R’4is an aromatic radical, substituted by a group-O-alk-Hal, where alk denotes an alkyl radical, a Hal is a halogen atom, preferably chlorine atom or bromine, with amines HNR12R13where R12and R13have the same meanings as in formula I.

This reaction is usually carried out in an inert solvent, such as acetonitrile, in the presence of a carbonate of an alkali metal (e.g. potassium carbonate) at a temperature close to 20C.

Derivative of the formula IX in which R represents a chain C=C(SO2R1)R’2or C(OR’)CH(SO2R1)R’2and R’, R1, R’2, R’3and R’4have the same meanings as the substituents R’, R1, R2, R3and R4in formula I, provided that at least one of the mandated which means an alkyl radical, a Hal denotes a halogen atom, can be obtained by interaction of the corresponding compounds of formula I in which R2is an aromatic radical, substituted by hydroxyl, derivative of formula Hal-alk-Hal, where Hal represents halogen.

This reaction is usually carried out in an inert solvent, ketone type (e.g., methyl) in the presence of bases, such as carbonates of alkali metals (e.g. potassium carbonate), at the boiling temperature of the reaction medium.

The compounds of formula I in which R2and/or R4are aromatic radical, substituted by a group-alk-NR6R7can also be obtained by the interaction of the derivatives of formula IX in which R represents a chain C=C(SO2R1)R’2or C(OR’)CH(SO2R1)R’2and R’, R1, R’3, R’3and R’4have the same meanings as the substituents R’, R1, R2, R3and R4in formula I, provided that at least one of the substituents R3’ and R’4is an aromatic radical, substituted by a group alk-Cl, where alk denotes an alkyl radical, with amines HNR6R7where R6and R7have the same meanings as in formula I.

This reaction obicmeadt nitrogenous base, such as dimethylaminopyridine or diisopropylethylamine, at a temperature of from 5 to 25C.

Derivative of the formula IX in which R represents a chain C=C(SO2R1)R’2or C(OR’)CH(SO2R1)R’2and R’, R1, R’2, R’3and R’4have the same meanings as the substituents R’, R1, R2, R3and R4in formula I, provided that at least one of the substituents R’3and R’4is an aromatic radical, substituted by a group-alk-Cl, can be obtained by the interaction of thionyl chloride with the corresponding compound of formula I, in which at least one of the substituents R3and R4is an aromatic radical, substituted by one or more hydroxyalkyl radicals.

This reaction is usually carried out in an inert solvent such as a chlorinated solvent (e.g. dichloromethane) at a temperature of from 10 to 30C.

The compounds of formula I in which R represents a chain, R’ represents a hydrogen atom, and R3and/or R4are aromatic radicals, substituted by hydroxyalkyl, where alkyl contains one carbon atom, can be obtained came the battle circuit, R’ represents a hydrogen atom, and R3and/or R4are aromatic radical, substituted by one or more radicals-COOR5where R5denotes alkyl radical.

This reaction is usually conducted in the environment of toluene at a temperature of from -30 to 0C.

The compounds of formula I in which R2is a phenyl radical substituted by the group-NR6R7representing a 1-piperazinilnom cycle, substituted in position 4 alkyl radical can also be obtained by the interaction of the corresponding compounds of the formula I, in which R2is a phenyl radical substituted by the group-NR6R7representing a 1-piperazinilnom cycle, with derivatives of the formula alk-CHO, where alk represents a normal or branched alkyl radical with 1-5 carbon atoms.

This reaction is usually carried out in an inert solvent such as a chlorinated solvent (for example dichloromethane or chloroform), in the presence of the N(ASON3)3at a temperature close to 20C.

The compounds of formula I in which R2is a phenyl radical substituted by the group-NR6R7representing a 1-piperidinylidene formula I, in which R2is a phenyl radical substituted by the group-NR6R7representing a 1-piperazinilnom cycle, with a derivative of formula Hal-COOalk, where alk denotes an alkyl radical and Hal represents a halogen atom, preferably chlorine atom.

This reaction is usually carried out in pyridine at a temperature close to 20C.

The compounds of formula I in which R2is a phenyl radical substituted by the group-NR6R7representing a 1-piperazinilnom cycle, substituted in position 4 by a group-CO-NHalk or-CS-NHalk, can be also obtained by the interaction of the corresponding compounds of the formula I, in which R2is a phenyl radical substituted by the group-NR6R7representing a 1-piperazinilnom cycle, with derivatives of the formula Y=C=Nalk, where alk represents a normal or branched alkyl radical with 1-6 carbon atoms, a Y denotes a sulfur atom or oxygen.

This reaction is usually carried out in an inert solvent such as a chlorinated solvent (e.g. dichloromethane) at a temperature close to 20C.

The compounds of formula I in which R2is a phenyl radical, substituted b>R15can also be obtained by the interaction of the corresponding compounds of the formula I, in which R2is a phenyl radical substituted by the group-NR6R7representing a 1-piperazinilnom cycle, with an acid of formula R15R14N-alk-COOH, where alk denotes an alkyl radical, a R15and R14have the same meanings as in formula I, followed by the possible withdrawal of the security from the product, where R14is tert-butoxycarbonyl radical, with the aim of obtaining compounds, where R14is a hydrogen atom.

This reaction is usually carried out in an inert solvent such as a chlorinated solvent (e.g. dichloromethane) at a temperature close to 20C. removing the protection is carried out using formic acid at a temperature close to 20C.

The compounds of formula I in which R2is a phenyl radical substituted by the group-NR6R7representing a 1-piperazinilnom cycle, substituted in position 4 by a group-CO-alk, where alk denotes a methyl radical, may also be obtained by the interaction of the corresponding compounds of the formula I, in which R2is a phenyl radical, substituted g is usually carried out in the presence of pyridine at a temperature close to 20C.

Professionals should be clear that in order to avoid side reactions during the implementation of the above-described methods according to the invention, it may be necessary to introduce protective groups for amino, hydroxyl and carboxyl functions. These groups are such groups that can be removed without causing changes in the rest of the molecule. As examples of protective groups for amino functions can be called tert-butyl and methylcarbamate, which can be regenerated using attributively or allyl using palladium catalysts. As examples of protective groups for hydroxyl functions can be called triethylsilyl and tert-butyldimethylsilyl, which can be regenerated using tetrabutylammonium or asymmetric acetals (for example, methoxymethyl or tetrahydropyranyl -) that regenerate by using chloride-hydrogen acid. As examples of protective groups for the carboxyl function can be called esters (for example, allyl or benzyl), oksazolov and 2-alkyl-1,3-oxazoline. Other suitable protecting groups described in GREENE, T. W. et al., Protecting groups in Organi is in, for example, crystallization, chromatography or extraction.

The enantiomers of compounds of formula I can be obtained by splitting of racemic mixtures, for example by chromatography on a chiral column method PIRCKLE W. H. et al., Asymmetric Synthesis, Vol.1, Academic Press (1983), or by formation of salts or by synthesis from chiral precursors. Diastereoisomer can be obtained using well-known classical methods (crystallization, chromatography or on the basis of chiral precursors).

The compounds of formula I can be converted into additive salts of mineral or organic acids in the environment of an organic solvent, such as alcohols, ketones, ethers or chlorinated solvents. These salts also form part of the invention.

As examples of pharmaceutically acceptable salts can be named the following salts: bansilalpet, hydrobromide, hydrochloride, citrate, aconsultant, fumarate, gluconate, Iodate, isetionate, maleate, methanesulfonate, methylene-bis--xinafoate, nitrate, oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate, theophyllinate and p-toluensulfonate.

The compounds of formula I possess valuable pharmacolo is proram type SW. They are antagonists of the receptor SV and, therefore, can be used in the treatment and prevention of disorders affecting the Central nervous system, immune system, cardiovascular or endocrine system, respiratory system, gastrointestinal tract, and reproductive system (Hollister, Pharm. Rev., 38, 1986, 1-20; Reny and Sinha, Prog. Drug Res., 36, 71-114 (1991); Consroe and Sandyk, Marijuana/Cannabinoids, Neubiology and Neurophysiology, 459; L. Murphy and A. Barthe, Eds, CRC Press, 1992), bacterial, viral and parasitic infections.

Thus, these compounds can be used for the treatment and prevention of psychoses, including schizophrenia, disorders related to anxiety, depression, epilepsy, neurodegeneration, cerebral and spinal disorders, mental disorders, cranial trauma, panic attacks, peripheral neuropathy; glaucoma, migraine, Parkinson's disease, Alzheimer's disease, horii's chorea, Raynaud's syndrome, tremor, disorders associated with an obsessive desire to perform the action, senile dementia, disorders of the thymus, Tourette syndrome, delayed dyskinesia, bipolar disorders, cancers caused by drugs disorders of the locomotor system, dystonia, endotoxemic shock is s, violations of appetite (reduced / increased appetite), obesity, memory disorders; taking from the chest in the case of chronic treatment and in case of abuse of alcohol or drugs (such as opium and its analogues, barbiturates, drugs, cannabis, cocaine, amphetamine, enciclica, hallucinogens, and benzodiazepines); as analgesics and potentialization analgesic activity of narcotic and non-narcotic medications. The compounds of formula I can also be used for treatment or prevention of disorders of the passage through the intestine, as an antibacterial, antiviral and anti-parasitic substances.

The affinity of compounds of the formula I to the receptor hemp was determined by the method described by J. E. KUSTER, STEVENSON J. L., WARD, S. J., D'AMBRA I.e., HAYCOCK, D. A. J. PhaRmacol. Exp. Ther., 264, 1352-1363 (1993).

In this test, CI50compounds of formula I below or equal to 100 nm.

Antagonistic activity was shown using a model of hypothermia caused by the agonist receptor hemp (CP-55940) in mice, according to the method described Pertwee R. G. Marijuana, Harvey D. J. eds, 84 Oxford IRL Press, 263-277 (1985).

In this test, the value of DE50for compounds of formula I below or equal to 50 mg/kg

The compounds of formula I have the SL is the changes of formula I are compounds where:

R represents a chain or a R’ denotes a hydrogen atom or a radical-COalk;

R1denotes a methyl radical or ethyl;

R2means either an aromatic radical selected from phenyl and naphthyl, which are unsubstituted or substituted by one or more halogen atoms or radicals alkyl, alkoxy, hydroxy, -COOR5, trifluoromethyl, trifloromethyl, triptoreline, -NR6R7, -CO-NH-NR6R7, cyano, -CONHR9alkylsulfanyl, hydroxyalkyl, nitro, -CO-NR16R17, -O-alk-NR12R13or alkylthiomethyl or heteroaromatic radical selected from izochinolina, pyridyl, chinoline, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline and tanila, unsubstituted or substituted by halogen atom, alkyl radical, alkoxy, -COOR5, trifluoromethyl, trifloromethyl, triptoreline, -NR6R7, -CO-NH-NR6R7, cyano, -CONHR9alkylsulfanyl, hydroxyalkyl, nitro and alkylthiol;

R3and R4identical or different, represent either an aromatic radical selected from phenyl and naphthyl, unsubstituted or substituted by one or more halogen atoms, the radicals alkyl, alkoxy, trifluoromethyl, triptoreline, -CONRp from thiazolidines and thienyl cycles, unsubstituted or substituted by halogen atom, alkyl, alkoxy, -CO-NR10R11, -alk-NR6R7, hydroxyalkyl or-COOR5;

R5denotes alkyl or phenyl, possibly substituted by one or more halogen atoms;

R6and R7identical or different, denote a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylsilanes, -alk-O-alk or hydroxyalkyl, or R6and R7together with the nitrogen atom to which they are attached, form a saturated or unsaturated mono - or bicyclic 3-10-membered heterocycle may contains another heteroatom selected from oxygen atoms, sulfur or nitrogen, and possibly substituted by one or more radicals alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR14R15, oxo, hydroxyalkyl, -alk-O-alk-CO-NH2;

R9denotes a hydrogen atom, or alkyl, or alkyl substituted dialkylamino, phenyl, cycloalkyl (possibly substituted by a group-COOalk) or a saturated or unsaturated mono - or bicyclic 3-10-membered heterocycle may contain one or more heteroatoms selected from oxygen, sulfur and nitrogen, and possibly substituted by one or more alkyl radicals;

R10and R11, ODM nitrogen, to which they are attached, form a saturated mono - or bicyclic 3-10-membered heterocycle possibly containing another heteroatom selected from oxygen, sulfur or nitrogen, and possibly substituted alkyl radical;

R12and R13identical or different, denote a hydrogen atom or an alkyl radical or cycloalkyl, or R12and R13together with the nitrogen atom to which they are attached, form a saturated mono - or bicyclic 3-10-membered heterocycle possibly containing another heteroatom selected from oxygen, sulfur or nitrogen, and possibly substituted by alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR14R15or saturated mono - or bicyclic 3-10-membered heterocycle containing one heteroatom selected from oxygen, sulfur and nitrogen;

R14and R15identical or different, denote a hydrogen atom, an alkyl radical or-COOalk;

R16and R17together with the nitrogen atom to which they are attached, form a saturated mono - or bicyclic 3-10-membered heterocycle possibly containing another heteroatom selected from oxygen, sulfur or nitrogen;

alk denotes an alkyl radical or alkylene;

their optical isomers, and salts with mineral or organic ccaat chain, or

R’ denotes a hydrogen atom or a radical-COalk,

R1denotes a methyl radical or ethyl,

R2means either an aromatic radical selected from naphthyl, phenyl, phenyl substituted by one or more halogen atoms, the radicals alkyl, alkoxy, hydroxy, -COOR5(where R5denotes an alkyl radical or phenyl, possibly substituted by several halogen atoms), trifluoromethyl, trifloromethyl, triptoreline, -NR6R7(where R6and R7identical or different, denote a hydrogen atom, an alkyl radical or-COOalk, or R6and R7together with the nitrogen atom to which they are attached, form a heterocycle selected from pyrrolidinyl, piperidyl, piperazinil or piperazinil substituted by one or more radicals alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR14R15(where R14and R15identical or different, denote a hydrogen atom or alkyl), -CO-NH-NR6R7(where R6and R7identical or different, denotes a hydrogen atom or alkyl, or R6and R7together with the nitrogen atom to which they are attached, form a heterocycle selected from piperidine, piperazinil or piperazine substituted by one or more of the output may be substituted for dialkylamino, the phenyl, cycloalkyl (possibly substituted by a group-COOalk) or a heterocycle selected from pyrrolidinyl (possibly substituted by alkyl), tetrahydrofuryl, morpholinyl and pyrrolyl), alkylsulfanyl, hydroxyalkyl, nitro, -CO-NR16R17(where R16and R17together with the nitrogen atom to which they are attached, form piperidinyl cycle), -O-alkNR12R13(where R12and R13together with the nitrogen atom to which they are attached, form a loop of morpholino) or alkylthiomethyl or heteroaromatic radical selected from izochinolina, pyridyl, chinoline, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, tanila or teenie substituted by a group-COOR5(where R5denotes an alkyl radical) or NHR9(where R9denotes an alkyl radical),

R3and R4identical or different, represent either an aromatic radical selected from phenyl or phenyl substituted by one or more halogen atoms, the radicals alkyl, alkoxy, trifluoromethyl, triptoreline, hydroxyalkyl, formyl, -COOR5(where R5denotes the radical alkyl), -CONR10R11(where R10and R11identical or different, denotes a hydrogen atom or alkyl), -alk-NR6R7(lk, hydroxyalkyl, or R6and R7together with the nitrogen atom to which they are attached, form a heterocycle selected from piperidine (possibly substituted by alkyl or oxopropoxy), pyrrolidinyl (possibly substituted by alkyl, hydroxyalkyl, -alk-O-alk or-CO-NH2), thiomorpholine, morpholine, pyrrolyl and piperazinil, possibly substituted by oxo groups, alkyl, hydroxyalkyl, -COOR5(where R5is an alkyl radical), or a heteroaromatic radical selected from thiazolyl or tanila, alk denotes an alkyl radical or alkylene, their optical isomers and their salts with mineral or organic acids.

Preferably R2is a substituted phenyl radical which is monosubstituted, in particular at position 3 or disubstituted, in particular in positions 3, 5; 2, 5 or 2, 3.

Preferably R3is a substituted phenyl radical which is monosubstituted, in particular in position 4, or disubstituted, in particular in positions 2, 4.

Preferably R4is a substituted phenyl radical which is monosubstituted, in particular in position 4, or disubstituted, in particular in positions 2, 4.

From predpochtitelnei-3-[(3-methylsulphonyl)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(3-chlorophenyl)(methylsulphonyl)methylene] azetidine,

1-benzhydryl-3-[(3,5-dichlorphenol)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(2,5-dichlorophenyl)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[[2,3-dichlorophenyl)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(3-forfinal)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(3-bromophenyl)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(3-itfinal)(methylsulphonyl)methylene]azetidine

1-benzhydryl-3-[(methylsulphonyl)(3-trifloromethyl)methylene]azetidine,

1-benzhydryl-3-[(methylsulphonyl)(3-triptoreline) methylene]azetidine,

1-benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl](methylsulphonyl)methylene}azetidine,

1-benzhydryl-3-[(3,5-dibromophenyl)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(3-ethoxycarbonylphenyl)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(3-cyanophenyl)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(3-carbamoylphenoxy)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[{methylsulphonyl)(naphthas-1-yl)(methylsulphonyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(RS)-3-[(3,5-differenl)(methylsulphonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl]azetidin,

(R)-3-[3,5-differenl)(methylsulphonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl]azetidin,

(S)-3-[(3,5-differenl)(methylsulphonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl]azetidin,

1-[bis(4-trifloromethyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-[bis(4-triptoreline)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-{[3,5-bis(trifluoromethyl)phenyl]methylsulfonylmethyl}azetidin,

(RS)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(R)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(S)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(RS)-1-{(4-chlorophenyl)[4-hydroxymethyl)phenyl]methyl}-3-[{3,5-differenl)(methylsulphonyl)methylene]azetidine,

(R)-1-{(4-chlorophenyl)[4-hydroxymethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(S)-1-{(4-chlorophenyl)[4-hydroxymethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(RS)-1-{(4-chlorophenyl)[4-pyrrolidinyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)met edidin,

(S)-1-{(4-chlorophenyl)[4-pyrrolidinyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{{RS)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)-phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(R)-(4-chlorophenyl)[(-(3,3-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(S)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(RS)-(4-chlorophenyl)[4-(thiomorpholine-4-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(R)-(4-chlorophenyl)[(4-(thiomorpholine-4-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(S)-(4-chlorophenyl)[4-(thiomorpholine-4-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(RS)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylamino)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(R)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylamino)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine

1-{(S)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylamino)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine

1-{{(RS)-(4-chlorophenyl){4-[(4-ethoxycarbonylphenyl)methyl]phenyl}methyl}}-3-phenyl}methyl}}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{{(S)-(4-chlorophenyl){4-[(4-ethoxycarbonylphenyl)methyl]phenyl}methyl}}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(RS)(4-chlorophenyl)[4-(N-cyclopropyl-N-propylaminoethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(R) - (4-chlorophenyl)[4-(N-cyclopropyl-N-propylaminoethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(S) - (4-chlorophenyl)[4-(N-cyclopropyl-N-propylaminoethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(RS)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(R)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(S)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{{(RS)(4-chlorophenyl){4-[bis{2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine

1-{{(R)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{{(S)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(RS)-(4-chlorophenyl)[4-(di-n-propylaminoethyl)f the Nile]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(S)-(4-chlorophenyl)[4-(di-n-propylaminoethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(RS)-(4-chlorophenyl)[4-(piperidine-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(R)-(4-chlorophenyl)[4-(piperidine-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(S)-(4-chlorophenyl)[4-(piperidine-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(RS)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(R)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(S)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(RS)(4-chlorophenyl)[4-(morpholine-4-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(R)-(4-chlorophenyl)[4-(morpholine-4-yl-methyl)phenyl]methyl}-3-[{3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(S)-(4-chlorophenyl)[4-(morpholine-4-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(RS)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(R)-(4-chlorine is l)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(RS)-(4-chlorophenyl)[4-(piperazine-2-he-4-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(R)-(4-chlorophenyl)[4-(piperazine-2-he-4-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(S)-(4-chlorophenyl)[4-(piperazine-2-he-4-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(RS)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(R)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(S)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(RS)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(R)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(S)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(RS)-1-{(4-chlorophenyl)[4-(N-ethylcarbazole)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(R)-1-{(4-chlorophenyl)[4-(N-ethylcarbazole)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(S)-1-{(4-chlorophenyl)[4-(N-atalk the l)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(R)-1-[(4-carbamoylphenoxy)(4-chlorophenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(S)-1-[(4-carbamoylphenoxy)(4-chlorophenyl)methyl]-3-[3,5-differenl]methylsulfonylmethyl]azetidin,

1-[bis(4-chlorophenyl)methyl]-3-[(3,5-dichlorophenyl)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(3-methylsulfinylphenyl)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(3-methylsulfonylmethyl)(phenyl)(methylsulphonyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulphonyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[(3-carbamoylphenoxy)(methylsulphonyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulphonyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[{3-hydroxyphenyl)(methylsulphonyl)methylene]azetidine,

1-[bis{4-chlorophenyl)methyl]-3-[(methylsulphonyl)(3-pyrrolidinyloxy)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxymethylene)(methylsulphonyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-{(methylsulphonyl)[3-(N-piperidinylcarbonyl)phenyl]methylene}azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[(methylsulphonyl)(3 trifter-methylsulfinylphenyl)(methylsulphonyl)methylene]azetidine,

1-[bis(4-forfinal)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulphonyl)(phenyl)methylene]azetidine,

(R)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulphonyl)(phenyl)methylene]azetidine,

(S)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulphonyl)(phenyl)methylene]azetidine,

(RS)-1-[(4-chlorophenyl)(Tien-2-yl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(R)-1-[(4-chlorophenyl)(Tien-2-yl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(S}-1-[{4-chlorophenyl)(Tien-2-yl)methyl]-3-[(3,5-diforte-nil)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(ethylsulfonyl)(phenyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-{{3-[N-(4-methylpiperazine)carbarnoyl]phenyl}(methylsulphonyl)methylene}azetidine,

1-[bis(4-chlorophenyl)methyl]-3-{[3-(2,2-dimethylcarbamate)(phenyl](methylsulphonyl)methylene}azetidine,

1-[bis(Tien-2-yl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-[bis(p-tolyl)methyl]-3-[(methylsulphonyl)(phenyl)methylene]azetidine,

1-[(4-chlorophenyl)(4-hydroxymethylene)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[(3-methylaminophenol)(methylsulphonyl)methylene]azetidine,

(RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(R)-1-[(4-chlorophenyl)(mediterrani)(methylsulphonyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[(methylsulphonyl)(2-methoxy-carbonylation-5-yl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-hydroxy-3-[(methylsulphonyl)(2-methoxycarbonylamino-5-yl)methyl]azetidin-(RS),

1-[bis(4-chlorophenyl)methyl]-3-[(2-isobutylparaben-Tien-5-yl)(methylsulphonyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[(3-ethoxycarbonylphenyl) (methylsulphonyl)methyl-(RS)]azetidin-3-ol,

1-[bis(4-chlorophenyl)methyl]-3-[(methylsulphonyl)(pyridine-4-yl)methyl-(RS)]azetidin-3-ol,

1-[bis(4-chlorophenyl)methyl]-3-[(methylsulphonyl)(pyridine-4-yl)methyl-(RS)]azetidin-3-ol,

3({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(3-morpholine-4-ylpropyl)benzamide,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(3-dimethylaminopropyl)benzamide,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(2-pyrrolidin-1-yl-ethyl)benzamide,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(2-dimethylamino-1-methyl-ethyl)benzamide,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(piperidine-1-yl)-benzamid,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(isobutyl)-benzamid,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}meanswhile)-N-{2-dimethylaminoethyl)benzamide,

N’-methylhydrazino-3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)benzoic acid,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(2-morpholine-4-yl-ethyl)benzamide,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamide,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(2,2-dimethylpropyl)benzamide,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-cyclohexylmaleimide,

3-({1-[bis-(4-chlorophenyl}methyl]azetidin-3-ilidene}methanesulfonyl)-N-cyclopropylbenzene,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(2-methylbutyl)benzamide,

3({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(2-phenylpropyl)benzamide,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(tetrahydrofuran-2-ylmethyl)benzamide,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(2,2-diphenylether)benzamid,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(2-ethylbutyl)benzamid,

methyl ester 4-{[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)benzoylamine]methyl}cyclohex piperazin-1-yl}Etalon,

tert-butyl ether(2-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-yl}-2-oxoethyl)carbamino acid,

1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-yl}-2-methylaminoethanol,

tert-butyl ether(2-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-yl}-2-oxoethyl)-N-methylcarbamyl acid,

N-methylamide 4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-carbothioic acid,

N-methylamide 4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-carboxylic acid,

methyl ester 4-[3-((1-[bis-{4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-carboxylic acid,

1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]-4-isobutylpyrazine,

1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]-4-ethylpiperazine,

4-acetyl-1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine,

1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-yl}-2-dimethylaminoethanol,

1-[3-({1-[bis-(4-chlorfenapyr]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-carboxylic acid,

1-[bis(4-ethoxycarbonylphenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

3-acetoxy-1-[bis(4-ethoxycarbonylphenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin,

(RS)-4-[4-((4-chlorophenyl){3-[(3,5-differenl)(methysulfonylmethane]azetidin-1-yl}methyl)benzyl]morpholine,

4-{4-{3-[(1-benzhydrylamine-3-ilidene)methanesulfonamide]phenoxy}butyl)morpholine,

4-(4-{3-[(1-benzhydrylamine-3-ilidene)methanesulfonamide]phenoxy}propyl)morpholine,

their optical isomers and their salts.

Of these compounds, especially preferred are the following compounds:

1-[bis(4-chlorophenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol,

3-acetoxy-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl)methylsulfonylmethyl-(RS)]azetidin,

their optical isomers and their salts with mineral or organic acids.

The invention is illustrated by the following examples without limiting its scope.

Example 1

To a cooled to 5With the solution of 1 g of 1-benzhydryl-3-[(methylsulphonyl)(phenyl)methyl-(RS)]azetidin-3-ol in 10 cm3pyridine add 0.3 cm3the 1 g of 4-dimethylaminopyridine 10 cm3dichloromethane. The solution is stirred for 15 h at room temperature and evaporated to dryness under reduced pressure (2.7 kPa). The obtained residue chromatographic on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 25 cm), elwira dichloromethane under a nitrogen pressure of 0.5 bar and collecting fractions of 80 cm3. Fractions 17 to 20 are combined and then evaporated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from 10 cm3diethyl ether, receiving 0.14 g of 1-benzhydryl-3-[(methylsulphonyl)(phenyl)methylene]azetidine with so pl. 210[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 2,95 (3H, s, S3), of 3.80 (2H, s, NCH2), 4,20 (2H, s, N2), and 4.75 (1H, s, N), 7,20 (2H, t, J=7 Hz, 2 CH arene.), 7,30 (4H, t, J=7 Hz, SN arene.), 7,40-7,60 (N, m, SN arene.)].

1-Benzhydryl-3-[(methylsulphonyl)(phenyl)methyl-(RS)]azetidin-3-ol may be obtained in the following way: to a cooled toTo a solution of 1.4 cm3Diisopropylamine 10 cm3of tetrahydrofuran in an argon atmosphere add 6,25 cm3a 1.6 n solution of n-utility in hexane, cooled to -70With, then add a mixture of 1.7 g benzylation. Then give 2.4 g of 1-benzhydrylamine-3-it is stirred for 20 min and leave the mixture to a spontaneous rise in temperature to room temperature. The reaction mixture is then filtered and evaporated to dryness under reduced pressure (2.7 kPa). The remainder absorb 50 cm3ethyl acetate, 30 cm3water and 20 cm31 N. hydrochloric acid. The precipitate is filtered off, washed with 30 cm3distilled water, squeezed and dried, obtaining 2 g of 1-benzhydryl-3-[(methylsulphonyl)(phenyl)methyl-(RS)]azetidin-3-ol with so pl. 260C.

1-Benzhydryl-3-azetidin-3-one gain, using the sequence of operations described by KATRITZKY A. R. et al. in J. Heterocycl. Chem., 271 (1994).

Example 2

Repeating the sequence of operations of example 1 and on the basis of the 1.9 g of 1-benzhydryl-3-[(3-were)(methylsulphonyl)methyl-(RS)]azetidin-3-ol, of 0.52 cm3methanesulfonanilide and 1.7 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 17 cm), elwira when the nitrogen pressure of 0.5 bar with dichloromethane and then a mixture of dichloromethane ethanol (98,5/a 1.5 by volume), collecting fractions of 100 cm3. Fractions 5 and 6 are combined and then evaporated to dryness under reduced pressure (2.7 KP is the first ether, obtaining 0.9 g of 1-benzhydryl-3-[(3-were)(methylsulphonyl)methylene]azetidine with so pl. 180[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 2,35 (3H, s, Ph3), 2,95 (3H, s, S3), of 3.80 (2H, s, NCH2), 4,20 (2H, S, NCH2), and 4.75 (1H, s, NCH), 7,20 (5H, m, SN arene.), 7,30 (5H, t, J=7 Hz, SN arene.), to 7.50 (4H, d, J=7 Hz, SN arene.)].

1-Benzhydryl-3-[(3-were)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations of example 1 from 2.8 g of methyl(3-methylbenzyl)sulfone and 3.6 g of 1-benzhydrylamine-3-one, obtained after purification on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane and ethanol (98,5/a 1.5 by volume) as eluent 2.6 g of a solid substance. The latter absorb 25 cm3diisopropyl ether and after filtration, extraction and drying gain of 1.9 g of 1-benzhydryl-3-[{3-were)(methylsulphonyl)methyl-(RS)]azetidin-3-ol with so pl. 170C.

Methyl(3-methylbenzyl)sulfon can be obtained as follows: to a solution of 30 cm3water, 30 cm3acetic acid and 15 cm336 N. sulphuric acid are added at room temperature to 10.5 g OksanaRand then 2.6 g marks 100 cm3water and 100 cm3ethyl acetate. The organic phase is washed with saturated aqueous sodium bicarbonate solution, separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa) to give 2.8 g of methyl(3-methylbenzyl)sulfone resin.

Methyl(3-methylbenzyl)sulfide can be obtained as follows: to a solution of 3.7 g of 3-methylbenzylamine 25 cm3of dimethylformamide added under stirring, maintaining the temperature in the range of 30With 1.7 g mertiolate sodium. The mixture is stirred for 2 hours at a temperature of about 20With and absorb 50 cm3ethyl acetate. The organic phase is washed with 3 times 100 cm3water, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa) to give 2.6 g of methyl(3-methylbenzyl)sulfide in the form of butter.

Example 3

To a cooled to 5To a solution of 3.3 g of 1-benzhydryl-3-[(4-were)(methylsulphonyl)methyl-(RS)]azetidin-3-ol in 10 cm3pyridine add 0.3 cm3methanesulfonanilide, stirred for 2 hours at 5With and add 1 g of 4-dimethylaminopyridine 10 cm3dichloromethane at 5C. the Solution is stirred for 15 h at togetherbut on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 25 cm), elwira dichloromethane under a nitrogen pressure of 0.5 bar and collecting fractions of 80 cm3. Fractions 17 to 20 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is recrystallized from acetonitrile, getting 0.14 g of 1-benzhydryl-3-[(4-were)(methylsulphonyl)-methylene]azetidine with so pl. 210[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 2,30 (3H, s, h3), 2,95 (3H, s, S3), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), and 4.75 (1H, s, NCH), 7,20 (4H, m, SN arene.), 7,30 (6N, t, J=7 Hz, SN arene.), was 7.45 (4H, d, J=7 Hz, SN arene.)].

1-Benzhydryl-3-[(4-were)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations of example 1 from 4 g of methyl(4-methylbenzyl)sulfone and 5.1 g of 1-benzhydrylamine-3-one: get 3 g of 1-benzhydryl-3-[(4-were)(methylsulphonyl)methyl-(RS)]azetidin-3-ol with so pl. 226C.

Methyl(4-methylbenzyl)sulfon can be obtained by repeating the sequence of operations of example 2 and from 3.5 g of methyl (4-methylbenzyl)sulfide and 12.3 g OksanaRobtain 3.5 g of methyl(4-methylbenzyl)sulfone in the form of a solid substance.

Methyl(4-methylbenzyl)sulfide can be obtained from the: obtain 4.7 g of methyl(4-methylbenzyl)sulfide in the form of a solid substance.

Example 4

To a solution of 3.3 g of 1-benzhydryl-3-[(2-were)-(methylsulphonyl)methyl-(RS)]azetidin-3-ol in 50 cm3dichloromethane added at room temperature, 0.7 cm3methanesulfonanilide and then 3.8 g of 4-dimethylaminopyridine. The solution is refluxed under stirring for 3 hours and twice extracted with 50 cm3water. The organic phase is separated, dried and evaporated to dryness under reduced pressure (2.7 kPa). The obtained residue chromatographic on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 25 cm), elwira when the nitrogen pressure of 0.5 bar with dichloromethane and then a mixture of dichloromethane ethanol (99/1 by volume) and collecting fractions of 100 cm3. Fractions 6 to 17 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is recrystallized from 50 cm3diethyl ether, obtaining 2.6 g of 1-benzhydryl-3-[(2-were)(methylsulphonyl)methylene]azetidine in the form of an amorphous mass [NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz) of 2.30 (3H, s, Ph3), 2,95 (3H, s, S3), a 3.50 (2H, s, NCH2), 4,20 (2H, s, NCH2), 4,70 (1H, s, NCH), 7,10-to 7.35 (10H, m, SN arene.), was 7.45 (4H, m, SN arene.)].

1-Benzhydryl-3-[(2-were)(methylsulphonyl)methyl-(RS)]azetidin-3-ol MNA and 4.3 g of 1-benzhydrylamine-3-one: obtain 3.4 g of 1-benzhydryl-3-[(2-were)-(methylsulphonyl)methyl-(RS)]azetidin-3-ol with so pl. 218C.

Methyl(2-methylbenzyl)sulfon obtained as follows: repeat the sequence of operations of example 2 with 4.5 g of methyl (2-methylbenzyl) sulfide and 16.2 g OksanaRand obtaining 3.4 g of methyl(2-methylbenzyl)sulfone in the form of a solid substance.

Methyl(2-methylbenzyl)sulfide was prepared as follows: repeat the sequence of operations of example 2 on the basis of 5.6 g of 2-methylbenzylamine and 2.1 g mertiolate sodium, receiving 4.5 g of methyl(2-methylbenzyl)sulfide in the form of a solid substance.

Example 5

Repeating the sequence of operations of example 4, on the basis of 2.1 g of 1-benzhydryl-3-[(2-chlorophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol, 0,55 cm3methanesulfonanilide and 2.3 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 25 cm), elwira dichloromethane under a nitrogen pressure of 0.5 bar and collecting fractions of 100 cm3. Fractions 12 to 18 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from a mixture of 3 cm3dichloromethane and 40 cm3diethyl ether, obtaining 1.1 g of 1-benzhydryl-3-[(2-chlorophenyl)(methylsulphonyl)methylene]azetidine with so pl. 204

1-Benzhydryl-3-[(2-chlorophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations of example 1 from 4 g (2 Chlorobenzyl)methylsulfone and 4.6 g of 1-benzhydrylamine-3-one; the remainder absorb 50 cm3ethyl acetate, then filtered and dried. Obtain 2.4 g of 1-benzhydryl-3-[(2-chlorophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol as a white solid.

(2 Chlorobenzyl)methylsulfone can be obtained by repeating the sequence of operations of example 2 on the basis of 3.4 g (2 Chlorobenzyl)methylsulfone and 12 g OksanaR, resulting in a gain of 4 g (2 Chlorobenzyl)methylsulfone in the form of a crystallizing oil.

(2 Chlorobenzyl)metilsulfate can be obtained by repeating the sequence of operations of example 2 from 4 g of 2-chlorobenzylamino and 1.5 g mertiolate sodium: obtain 3.4 g (2 Chlorobenzyl)methylsulfone in the form of butter.

Example 6

Repeating the sequence of operations of example 4, from 3 g of 1-benzhydryl-3-[(3-chlorophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol, 0,79 cm3methanesulfonanilide and 3.3 g of 4-dimethylene the diameter of 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting fractions of 100 cm3. Fractions 2-5 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from 40 cm3diethyl ether, obtaining 1.7 g of 1-benzhydryl-3-[(3-chlorophenyl)(methylsulphonyl)methylene]-azetidine with so pl. 205[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 2,95 (3H, s, S3), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), 4,70 (1H, s, NCH), 7,20 (2H, t, J=7 Hz, 2CH arene.), 7,30 (4H, t, J=7 Hz, SN arene.), was 7.45 (8H, m, SN arene.)].

1-Benzhydryl-3-[(3-chlorophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations example 1 on the basis of 3.1 g (3 chlorbenzyl)methylsulfone and 3.4 g of 1-benzhydrylamine-3-one: obtain 3.4 g of 1-benzhydryl-3-[(3-chlorophenyl)(methylsulphonyl)-methyl-(RS)]azetidin-3-ol as a white solid.

(3 Chlorbenzyl)methylsulfone can be obtained by repeating the sequence of operations of example 2 on the basis of 3.2 g (3 chlorbenzyl)metilsulfate and 12 g OksanaR: obtain 3.2 g (3 chlorbenzyl)methylsulfone in the form of a white solid.

(3 Chlorbenzyl)methyl sulfide can be obtained by repetition of placentas is ensil)metilsulfate in the form of butter.

Example 7

Repeating the sequence of operations of example 4, on the basis of the 3.3 g of 1-benzhydryl-3-[(4-chlorophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol, of 0.87 cm3methanesulfonanilide and 3.6 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting fractions of 100 cm3. Fractions 8 to 12 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from a mixture of 3 cm3dichloromethane and 30 cm3diethyl ether, obtaining 0.5 g of 1-benzhydryl-3-[(4-chlorophenyl)(methylsulphonyl)methylene]azetidine with so pl. 192[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 2,95 (3H, s, S3), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), 4,70 (1H, s, NCH), 7,20 (2H, t, J=7 Hz, 2CH arene.), 7,30 (4H, t, J=7 Hz, SN arene.), 7,40-of 7.55 (8H, m, SN arene.)].

1-Benzhydryl-3-[(4-chlorophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations of example 1 on the basis of 2.8 g (4-chlorbenzyl)methylsulfone or 3.24 g of 1-benzhydrylamine-3-one: obtain after crystallization from 80 cm3diethyl ether is sorbinil)methylsulfone can be obtained by repeating the sequence of operations of example 2 on the basis of 3.5 g (4-chlorbenzyl)metilsulfate and 12.3 g OksanaR, resulting in a gain of 3.5 g of (4-chlorbenzyl)methylsulfone in the form of a solid substance.

Example 8

Repeating the sequence of operations of example 4, on the basis of 3.1 g of 1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulphonyl)-methyl-(RS)]azetidin-3-ol, 0.75 cm3methanesulfonanilide and 3.1 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting fractions of 100 cm3. Fractions 6-10 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from a mixture of 2 cm3dichloromethane and 30 cm3diethyl ether, obtaining 0.8 g of 1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulphonyl)methylene]azetidine with so pl. 204[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 2,95 (3H, s, S3), 3,85 (2H, s, NCH2), 4,20 (2H, s, NCH2), and 4.75 (1H, s, NCH), 7,20 (2H, t, J=7 Hz, 2CH arene.), 7,30 (4H, t, J=7 Hz, SN arene.), 7,45 (6N, m, SN arene.), of 7.70 (1H, s, CH arene.)].

1-Benzhydryl-3-[(3,5-dichlorophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations of example 1 from 4 g of (3,5-dichloro who yl)-methyl-(RS)]azetidin-3-ol as a white solid.

(3,5-Dichlorobenzyl)methylsulfone can be obtained by repeating the sequence of operations of example 2 on the basis of 5.3g (3,5-dichlorobenzyl)metilsulfate and 17 g OksanaR, resulting in a gain of 5 g of (3,5-dichlorobenzyl)methylsulfone in the form of a white solid.

(3,5-Dichlorobenzyl)metilsulfate can be obtained by repeating the sequence of operations of example 2 starting from 5 g of 3,5-dichlorobenzamide and 2 g mertiolate sodium: get 5.3g (3,5-dichlorobenzyl)metilsulfate in the form of butter.

Example 9

Repeating the sequence of operations of example 4, starting from 5 g of 1-benzhydryl-3-[(3,4-dichlorophenyl)(methylsulphonyl)-methyl-(RS)]azetidin-3-ol, 1.2 cm3methanesulfonanilide and 3.8 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4 cm, height 35 cm) at a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (70/30 by volume) as eluent, collecting fractions with a volume of 35 cm3. Faction 30-55 combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from 50 cm3diethyl ether, obtaining 1.5 g of 1-benzhydryl-3-[(3,4-dichlorophenyl)(methylsulphonyl)methylene]-azetidine with so pl. 170

1-Benzhydryl-3-[(3,4-dichlorophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations of example 1 on the basis of 4.5 g (3,4-dichlorobenzyl)methylsulfone and 4.3 g of 1-benzhydrylamine-3-one: get 5 g of 1-benzhydryl-3-[(3,4-dichlorophenyl)(methylsulphonyl)-methyl-(RS)]azetidin-3-ol as a white solid.

(3,4-Dichlorobenzyl)methylsulfone can be obtained by repeating the sequence of operations of example 2 on the basis of 4.3 g (3,4-dichlorobenzyl)metilsulfate and 13 g OksanaR, resulting in a gain of 4.7 g of (3,4-dichlorobenzyl)-methylsulfone in the form of a white solid.

(3,4-Dichlorobenzyl)metilsulfate can be obtained by repeating the sequence of operations of example 2 with 2.8 g of 3,4-dichlorobenzamide and 1.5 g mertiolate sodium: obtain 4.3 g (3,4-dichlorobenzyl)metilsulfate in the form of butter.

Example 10

Repeating the sequence of operations of example 4, from 1.8 g of 1-benzhydryl-3-[(2,5-dichlorophenyl)(methylsulphonyl)-methyl-(RS)]azetidin-3-ol, 0.4 cm3methanesulfonanilide and 1.8 g of 4-dimethylaminopyridine receive the remainder, which purify the HRO is with dichloromethane as eluent, collecting fractions of 100 cm3. Fractions 8 to 14 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from a mixture of 2 cm3dichloromethane and 30 cm3diethyl ether, obtaining 1.2 g of 1-benzhydryl-3-[(2,5-dichlorophenyl)(methylsulphonyl)methylene]azetidine with so pl. 202[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (250 MHz): 3,00 (3H, s, S3), 3,70 (2H, m, NCH2), 4,25 (2H, m, NCH2), 4,70 (1H, s, NCH), 7,20 (2H, t, J=7 Hz, 2CH arene.), 7,30 (4H, t, J=7 Hz, SN arene.), was 7.45 (4H, d, J=7 Hz, SN arene.), 7,55-of 7.70 (3H, m, S arene.)].

1-Benzhydryl-3-[(2,5-dichlorophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations of example 1 from 1.2 g (2.5-dichlorobenzyl)methylsulfone and 1.2 g of 1-benzhydrylamine-3-one: obtain 1.8 g of 1-benzhydryl-3-[(2,5-dichlorophenyl)(methylsulphonyl) methyl-(RS)]azetidin-3-ol as a white solid.

(2.5-Dichlorobenzyl)methylsulfone can be obtained as follows: to a solution of 2.7 g of 2,5-dichlorobenzaldehyde 30 cm3ethanol is added at room temperature to 1.9 g of methanesulfonate sodium. The mixture is refluxed 5 h, cooled to room temperature, extracted with 50 cm3water and the reed sodium, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa) to give 1.2 g (2.5-dichlorobenzyl)methylsulfone in the form of a white solid.

Example 11

Repeating the sequence of operations of example 4 according to 9.1 g of 1-benzhydryl-3-[(2,4-dichlorophenyl)(methylsulphonyl)-methyl-(RS)]azetidin-3-ol, 2,2 cm3methanesulfonanilide and 7 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 5.5 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting fractions of 40 cm3. Faction 27-39 combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from 20 cm3diethyl ether, obtaining 1.5 g of 1-benzhydryl-3-[(2,4-dichlorophenyl)(methylsulphonyl)methylene ] azetidine with so pl. 165[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (250 MHz): 3,00 (3H, s, S3), the 3.65 (2H, m, NCH2), 4,25 (2H, m, NCH2), and 4.75 (1H, s, NCH), 7,20 (2H, t, J=7 Hz, 2CH arene.), 7,30 (4H, t, J=7 Hz, SN arene.), 7,45 (6N, m, SN arene.), 7,80 (1H, s, CH arene.)].

1-Benzhydryl-3-[(2,4-dichlorophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repetition of a sequence of op is Sheryl-3-[(2,4-dichlorophenyl)-(methylsulphonyl)methyl-(RS)]azetidin-3-ol in the form of a brown amorphous mass.

(2,4-Dichlorobenzyl)methylsulfone can be obtained by repeating the sequence of operations of example 2 from 4 g of (2,4-dichlorobenzyl)metilsulfate and 13 g OksanaR, resulting in a gain of 4.8 g of (2,4-dichlorobenzyl)-methylsulfone in the form of a white solid with so pl. 111C.

(2,4-Dichlorobenzyl)metilsulfate can be obtained by repeating the sequence of operations example 2 with 2.8 g of 2,4-dichlorobenzamide and 1.5 g mertiolate sodium: get 4 g of (2,4-dichlorobenzyl)methyl sulfide in the form of butter.

Example 12

Repeating the sequence of operations of example 4, from 3 g of 1-benzhydryl-3-[(2,3-dichlorophenyl)(methylsulphonyl)-methyl-(RS)]azetidin-3-ol, 1.1 cm3methanesulfonanilide and 3 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane ethanol (98/2 by volume) as eluent, collecting fractions of 100 cm3. Fractions 10-20 combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from 40 cm3diethyl ether, obtaining 1.6 g 1-benzhydryl-3-[(2,3-dichlorophenyl)(methylsulphonyl)METI is): 3,00 (3H, with, S3), of 3.60 (2H, m, NCH2), 4,20 (2H, m, NCH2), 4,70 (1H, s, NCH), 7,20 (2H, t, J=7 Hz, 2CH arene.), 7,30 (4H, t, J=7 Hz, SN arene.), 7,45 (6N, m, SN arene.), of 7.70 (1H, DD, J=8 and 2 Hz, CH arene.)].

1-Benzhydryl-3-[(2,3-dichlorophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations of example 1 on the basis of 3.6 g (2,3-dichlorobenzyl)methylsulfone and 3.6 g of 1-benzhydrylamine-3-one: gain of 5.4 g of 1-benzhydryl-3-[(2,3-dichlorophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol as a white solid.

(2,3-Dichlorobenzyl)methylsulfone can be obtained by repeating the sequence of operations of example 10 based on 3 g of 2,3-dichlorobenzaldehyde and 2.4 g of methanesulfonate sodium, resulting in a gain of 3.6 g of (2,3-dichlorobenzyl)methylsulfone in the form of a white solid.

Example 13

Repeating the sequence of operations of example 4, on the basis of 2.5 g of 1-benzhydryl-3-[(3-forfinal)(methylsulphonyl)methyl-(RS)]azetidin-3-ol, to 0.72 cm3methanesulfonanilide and 2.9 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting fractions of 100 cm3. Fractions of about 2-6 cm3diethyl ether, obtaining 1.5 g of 1-benzhydryl-3-[(3-forfinal)(methylsulphonyl)methylene]-azetidine with so pl. 210[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 2,95 (3H, s, S3), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), 4,70 (1H, s, NCH), 7,10-7,30 (N, m, SN arene.), was 7.45 (5H, m, SN arene.)].

1-Benzhydryl-3-[(3-forfinal)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations of example 1 on the basis of 2.6 g of 3-verbesserungen and 3.3 g of 1-benzhydrylamine-3-one: obtain 2.9 g of 1-benzhydryl-3-[(3-forfinal)(methylsulphonyl)-methyl-(RS)]azetidin-3-ol as a white solid with so pl. 200C.

3-Verbesserungen can be obtained by repeating the sequence of operations of example 2 on the basis of 3.1 g of 3-forbindelsetrafik and 13 g OksanaR, resulting in a gain of 2.7 g of 3-verbesserungen in the form of a white solid.

3-Forbindelsetrafik can be obtained by repeating the sequence of operations of example 2 on the basis of 2.6 g of 3-ftorangidridy and 1.6 g mertiolate sodium: obtain 3.1 g of 3-forbindelsetrafik in the form of butter.

Example 14

Repeating the sequence of operations of example 4, based on the 3.7 g of 4-dimethylaminopyridine, get the remnant that purify by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4.5 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting fractions of 30 cm3. Faction 28-58 combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from 100 cm3diethyl ether, obtaining 2.3 g of 1-benzhydryl-3-[(2-forfinal)(methylsulphonyl)methylene]-azetidine with so pl. 188[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 3,00 (3H, s, S3), the 3.65 (2H, m, NCH2), 4,20 (2H, m, NCH2), and 4.75 (1H, s, NCH), 7,20 (2H, t, J=7 Hz, 2CH arene.), 7,30 (6N, m, SN arene.), 7,50 (6N, m, SN arene.)].

1-Benzhydryl-3-[(2-forfinal)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations of example 1 on the basis of 3.4 g of 2-verbesserungen and 4.2 g of 1-benzhydrylamine-3-one: obtain 4.3 g of 1-benzhydryl-3-[(2-forfinal)(methylsulphonyl)-methyl-(RS)]azetidin-3-ol as a white solid.

2-Verbesserungen can be obtained by repeating the sequence of operations of example 2 from 3 g of 2-forbindelsetrafik and 13 g OksanaR, resulting in a gain of 3.6 g of 2-forbesi the sequence of operations of example 2 on the basis of 2.4 g of 2-ftorangidridy and 1.5 g mertiolate sodium: get 3 g of 2-forbindelsetrafik in the form of butter.

Example 15

Repeating the sequence of operations of example 4 based on 1 g of 1-benzhydryl-3-[(4-forfinal)(methylsulphonyl)methyl-(RS)]azetidin-3-ol, 0.3 cm3methanesulfonanilide and 0.9 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 35 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting fractions of 30 cm3. Fractions 20 to 35 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from 50 cm3diethyl ether, gaining 0.4 g 1-benzhydryl-3-[(4-forfinal)(methylsulphonyl)methylene]-azetidine with so pl. 186[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 2,95 (3H, s, S3), 3,80 (2H, m, NCH2), 4,20 (2H, m, NCH2), and 4.75 (1H, s, NCH), 7,15-to 7.35 (8H, m, SN arene.), 7,45 (6N, m, SN arene.)].

1-Benzhydryl-3-[(4-forfinal)(methylsulphonyl)methyl -(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations of example 1 on the basis of 2.8 g of 4-verbesserungen and 3.6 g of 1-benzhydrylamine-3-one: receive 1 g of 1-benzhydryl-3-[(4-forfinal)(methylsulphonyl)-methyl-(RS)]azetidin-3-ol as a white solid.

4-Tormentil is ethylsulfate and 13 g OksanaR, resulting in a gain of 3 g of 4-verbesserungen in the form of a white solid with so pl. 110C.

4-Forbindelsetrafik can be obtained by repeating the sequence of operations of example 2 on the basis of 2.5 g of 4-ftorangidridy and 1.5 g mertiolate sodium: get 3 g of 4-forbindelsetrafik in the form of butter.

Example 16

Repeating the sequence of operations of example 4, from 3.8 g of 1-benzhydryl-3-[(3,5-differenl)(methylsulphonyl)-methyl-(RS)]azetidin-3-ol, 1 cm3methanesulfonanilide and 4.2 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting fractions of 100 cm3. Fractions 5-10 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from 30 cm3diethyl ether, obtaining 0.8 g of 1-benzhydryl-3-[(3,5-differenl)(methylsulphonyl) methylene]-azetidine with so pl. 172[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (250 MHz): 3,00 (3H, s, S3), 3,85 (2H, m, NCH2), 4,20 (2H, m, NCH2), and 4.75 (1H, s, NCH), 7,10-7,40 (N, m, SN arene.), to 7.50 (4H, d, the iteration sequence of example 1 on the basis of 3.2 g (3,5-diferensial)methylsulfone and 3.7 g of 1-benzhydrylamine-3-one: gain of 3.9 g of 1-benzhydryl-3-[(3,5-differenl)-(methylsulphonyl)methyl-(RS)]azetidin-3-ol as a white solid.

3,5-Diferentialgeichungen can be obtained by repeating the sequence of operations of example 2 according to 4.2 g (3,5-diferensial)metilsulfate and 16 g OksanaR, resulting in a gain of 3.3 g of (3,5-diferensial) methylsulfone in the form of a white solid.

3,5-Differenzierung can be obtained by repeating the sequence of operations of example 2 starting from 5 g of 3,5-diferenciada and 2 g mertiolate sodium: obtain 4.9 g of 3,5-differencematerialised in the form of butter.

Example 17

Repeating the sequence of operations of example 4, on the basis of the 5.2 g of 1-benzhydryl-3-[(2,3-differenl)(methylsulphonyl)-methyl-(RS)]azetidin-3-ol, 2,3 cm3methanesulfonanilide and 7.3 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 6 cm, height 40 cm) at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane with methanol (98/2 by volume) as eluent, collecting fractions of 50 cm3. Faction 65-87 combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from 75 cm3diethyl ether, obtaining 2.5 g of 1-benzhydryl-3-[(2,3-differenl)(methylsulphonyl)methylene]-azetidine with so pl. 208

1-Benzhydryl-3-[(2,3-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations of example 1 from 4 g (2,3-diferensial)methylsulfone and 4.8 g of 1-benzhydrylamine-3-one: obtain 5.5 g of 1-benzhydryl-3-[(2,3-differenl)-(methylsulphonyl)methyl-(RS)]azetidin-3-ol in the form of a solid beige color.

(2,3-Diferensial)methylsulfone can be obtained by repeating the sequence of operations of example 10 from 4.1 g of 2,3-diferenciada and 4.1 g of methanesulfonate sodium, resulting in a gain of 4 g (2,3-diferensial)methylsulfone in the form of a white solid.

Example 18

Repeating the sequence of operations of example 4, on the basis of the 5.2 g of 1-benzhydryl-3-[(2,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol, 2,3 cm3methanesulfonanilide and 7.3 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 6 cm, height 40 cm) at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane with methanol (98/2 by volume) as eluent, collecting fractions of 50 cm3. Faction 73-90 combined and evaporated to dryness under reduced pressure is-3-[(2,5-differenl)(methylsulphonyl)methylene]azetidine with so pl. 176C.

1-Benzhydryl-3-[(2,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations of example 1 from 4 g (2.5-diferensial)methylsulfone and 4.8 g of 1-benzhydrylamine-3-one: obtain 5.9 g of 1-benzhydryl-3-[(2,5-differenl)-(methylsulphonyl)methyl-(RS)]azetidin-3-ol in the form of solid white.

(2.5-Diferensial)methylsulfone can be obtained by repeating the sequence of operations of example 10 from 4.1 g of 2,5-diferenciada and 4.1 g of methanesulfonate sodium, resulting in a gain of 4.8 g (2.5-diferensial)methylsulfone in the form of a white solid with so pl. 95C.

Example 19

Repeating the sequence of operations of example 4, on the basis of 7,7 g 1-benzhydryl-3-[(3-bromophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol, 1,8 cm3methanesulfonanilide and 5.8 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 35 cm) at a nitrogen pressure of 0.5 bar with dichloromethane and then a mixture of dichloromethane with ethanol of 99.5/0.5 to by volume) as eluents, collecting fractions of 100 cm3. Faction 17-28 unite and dry upar is ETANA with 50 cm3diethyl ether, obtaining 3.5 g of 1-benzhydryl-3-[(3-bromophenyl)(methylsulphonyl)methylene]azetidine with so pl. 200[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 2,95 (3H, s, S3), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), and 4.75 (1H, s, NCH), 7,20 (2H, t, J=7 Hz, 2CH arene.), 7,30 (4H, t, J=7 Hz, SN arene.), 7,35-7,55 (6N, m, SN arene.), the 7.65 (2H, m, 2H arene.)].

1-Benzhydryl-3-[(3-bromophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations of example 1 from 8 g of 3-bromobenzimidazole and 7.6 g of 1-benzhydrylamine-3-one: get 8 g of 1-benzhydryl-3-[(3-bromophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol as a white solid.

3-Bromobenzimidazole can be obtained by repeating the sequence of operations of example 2 on the basis of 9 g of 3-bromobenzylcyanide and 27 g OksanaR, resulting in a gain of 8.2 g of 3-bromobenzylamine in the form of a white solid.

3-Bromobenzimidazole can be obtained by repeating the sequence of operations of example 2 on the basis of 10 g of 3-bromobenzylamine and 3.1 g mertiolate sodium: get 9 g 3-bromobenzylcyanide in the form of butter.

Example 20

Repeating the sequence of operations of example 4, IP is Yes and 1.4 g of 4-dimethylaminopyridine, get the remnant that purify by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 35 cm) at a nitrogen pressure of 0.5 bar with dichloromethane and then a mixture of dichloromethane ethanol (99,7/a 0.3 by volume) as eluents, collecting fractions of 100 cm3. Fractions 16 to 24 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from a mixture of 1.5 cm3dichloromethane with 25 cm3diethyl ether, obtaining 0.5 g of 1-benzhydryl-3-[(3-itfinal)(methylsulphonyl)methylene]azetidine with so pl. 198[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 2,95 (3H, s, S3), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), and 4.75 (1H, s, NCH), 7,10-7,30 (7H, m, SN arene.), was 7.45 (5H, m, SN arene.), 7,80 (2H, m, 2CH arene.)].

1-Benzhydryl-3-[(3-itfinal)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations of example 1 on the basis of 3.7 g of 3-identilication and 3 g of 1-benzhydrylamine-3-one: obtain 1.5 g of 1-benzhydryl-3-[(3-itfinal)(methylsulphonyl)methyl-(RS)]azetidin-3-ol as a white solid.

3-Identilication can be obtained by repeating the sequence of operations of example 2 on the basis of 3.6 g of 3-jogbani Agogo substances.

3-Identitiesonly can be obtained by repeating the sequence of operations example 2 starting from 5 g of 3-jodensavanne and 1.3 g mertiolate sodium: get 4 g of 3-yodbenzilguanidina in the form of butter.

Example 21

Repeating the sequence of operations of example 4, on the basis of 2.4 g of 1-benzhydryl-3-[(methylsulphonyl)(3-trifloromethyl)methyl-(RS)]azetidin-3-ol, 0.6 cm3methanesulfonanilide and 1.4 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 35 cm) at a nitrogen pressure of 0.5 bar with dichloromethane and then a mixture of dichloromethane ethanol (99,7/a 0.3 by volume) as eluents, collecting fractions of 100 cm3. Faction 12-25 combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from a mixture of 2 cm3dichloromethane with 30 cm3diethyl ether, gaining 0.7 g of 1-benzhydryl-3-[(methylsulphonyl)(3-trifloromethyl)methylene]azetidine with so pl. 162[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (250 MHz): 3,00 (3H, s, S3), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), and 4.75 (1H, s, NCH), 7,15-7,40 (6N, m, SN arene.), 7,45-of 7.55 (7H, m, SN arene.), of 7.60 (1H, t, J=7 Hz, CH and what uranium sequence example 1 on the basis of 2.4 g of methyl(3-cryptomaterial)sulfone and 2,2 g of 1-benzhydrylamine-3-one: obtain 2.4 g of 1-benzhydryl-3-[(methylsulphonyl)(3-trifloromethyl)methyl-(RS)]azetidin-3-ol as a white solid.

Methyl(3-cryptomaterial)sulfon can be obtained by repeating the sequence of operations example 2 on the basis of 2.6 g of methyl (3-cryptomaterial) sulfide and 7.2 g OksanaR, resulting in a gain of 2.4 g of methyl(3-cryptomaterial)sulfone as a white solid.

Methyl(3-cryptomaterial)sulfide can be obtained by repeating the sequence of operations example 2 from 3 g of 3-cryptomaterial and 1 g mertiolate sodium: gain of 3.3 g of methyl(3-cryptomaterial)sulfide in the form of butter.

Example 22

Repeating the sequence of operations of example 4, on the basis of 4.1 g of 1-benzhydryl-3-[(methylsulphonyl)(3-triptoreline)methyl - (RS)]azetidin-3-ol, 1 cm3methanesulfonanilide and 4.2 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 35 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting fractions of 100 cm3. Fractions 10 to 14 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from a mixture of 2 cm3dichloromethane with 30 cm3diethyl ether, obtaining 1.2 g 1--3-[()(3-�chr/948.gif">in M. D. (300 MHz): 3,00 (3H, s, S3), of 3.80 (2H, s, NCH2), is 4.15 (2H, s, NCH2), 4,70 (1H, s, NCH), 7,20 (2H, t, J=7 Hz, 2CH arene.), 7,30 (4H, t, J=7 Hz, SN arene.), was 7.45 (4H, d, J=7 Hz, SN arene.), 7,60-7,80 (4H, m, SN arene.)].

1-Benzhydryl-3-[(methylsulphonyl)(3-triptoreline)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations example 1 from 3.4 g of methyl(3-trifloromethyl)sulfone and 3.4 g of 1-benzhydrylamine-3-one: gain of 4.2 g of 1-benzhydryl-3-[(methylsulphonyl)(3-triptoreline)methyl-(RS)]azetidin-3-ol as a white solid.

Methyl(3-trifloromethyl)sulfon can be obtained by repeating the sequence of operations example 2 from 3,3 g of methyl (3-trifloromethyl) sulfide and 10 g OksanaR, resulting in a gain of 3.4 g of methyl(3-trifloromethyl)sulfone as a white solid.

Methyl(3-trifloromethyl)sulfide can be obtained by repeating the sequence of operations example 2 based on a 3.9 g of 3-triftormetilfosfinov and 1.4 g mertiolate sodium: gain of 3.3 g of methyl(3-trifloromethyl)sulfide in the form of butter.

Example 23

Repeating the sequence of operations of example 4, from 2.7 g of 1-benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl](methylsulphonyl)methyl-(RS)}aseedaustralia on a column of silica gel (grain size of 0.04-0.06 mm, diameter 6 cm, height 40 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting fractions of 100 cm3. Fractions 7-12 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from 10 cm3diethyl ether, receiving 1 g 1-benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl](methylsulphonyl)methylene}of azetidine with so pl. 192[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 3,00 (3H, s, S3), 3,85 (2H, s, NCH2), is 4.15 (2H, s, NCH2), 4,70 (1H, s, NCH), to 7.15 (2H, t, J=7 Hz, 2CH arene.), 7,30 (4H, t, J=7 Hz, SN arene.), 7,40 (4H, d, J=7 Hz, SN arene.), with 8.05 (2H, s, 2CH arene.), of 8.15 (1H, s, CH arene.)].

1-Benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl](methylsulphonyl)methyl-(RS)}azetidin-3-ol can be obtained by repeating the sequence of operations example 1 on the basis of 3.1 g of methyl[3,5-bis(trifluoromethyl)benzyl]sulfone and 2.4 g of 1-benzhydrylamine-3-one: obtain 2.8 g of 1-benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl](methylsulphonyl)methyl-(RS)}-azetidin-3-ol as a white solid.

Methyl[3,5-bis(trifluoromethyl)benzyl]sulfon can be obtained by repeating the sequence of operations of example 10 based on 3 g of 3,5-bis(trifluoromethyl)benzylchloride and 2 g of methanesulfonate sodium, �//img.russianpatents.com/chr/176.gif">C.

Example 24

Repeating the sequence of operations of example 4, on the basis of 10.7 g of 1-benzhydryl-3-[(3,5-dibromophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol, 2,2 cm3methanesulfonanilide and 7 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 5.5 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting fractions with a volume of 35 cm3. Faction 40-58 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from 50 cm3diethyl ether, obtaining 1.5 g of 1-benzhydryl-3-[(3,5-dibromophenyl)(methylsulphonyl)-methylene]azetidine with so pl. 209[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (250 MHz): 3,00 (3H, s, S3), 3,88 (2H, s, NCH2), 4,22 (2H, s, NCH2), and 4.75 (1H, s, NCH), 7,22 (2H, t, J=7 Hz, 2CH arene.), 7,33 (4H, t, J=7 Hz, SN arene.), of 7.48 (4H, d, J=7 Hz, SN arene.), to 7.68 (2H, s, 2CH arene.), of 7.95 (1H, s, CH arene.)].

1-Benzhydryl-3-[(3,5-dibromophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations example 1 on the basis of 6.2 g of (3,5-dibromobenzyl)methylsulfone and 4.5 g of 1-benzhydrylamine-3-one: obtain 10.7 g of 1-benzhydryl-3-[3,5-dibromo the ü obtained by repeating the sequence of operations example 2 on the basis of 5.8 g (3,5-dibromobenzyl)metilsulfate and 13 g OksanaR, resulting in a gain of 6.2 g (3,5-dibromobenzyl)-methylsulfone in the form of a white solid.

(3,5-dibromobenzyl)metilsulfate can be obtained by repeating the sequence of operations example 2 on the basis of 6.6 g of 3,5-dibromobenzoic and 1.5 g mertiolate sodium: obtain 5.8 g (3,5-dibromobenzyl)metilsulfate in the form of butter.

Example 25

Repeating the sequence of operations of example 4, proceeding from 4.2 g of 1-benzhydryl-3-[(methylsulphonyl)(3-nitrophenyl)-methyl-(RS)]azetidin-3-ol, 1.1 cm3methanesulfonanilide and 2.5 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4 cm, height 35 cm) at a nitrogen pressure of 0.5 bar with a mixture of cyclohexane with ethyl acetate (50/50 by volume) as eluent, collecting fractions with a volume of 400 cm3. Faction 17-33 combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is recrystallized from 15 cm3diethyl ether, obtaining 1.5 g of 1-benzhydryl-3-[ (methylsulphonyl) (3-nitrophenyl) methylene]-azetidine with so pl. 184[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 3,00 (3H, s, S3), 3,85 (2H, s, NCH2), 4,25 (2H, s, NCH2), and 4.75 (1H, s, NCH), arom.), of 8.25 (2H, m, 2CH arene.].

1-Benzhydryl-3-[(methylsulphonyl)(3-nitrophenyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations example 1 based on a 3.9 g of methyl(3-nitrobenzyl)sulfone and 4.2 g of 1-benzhydrylamine-3-one: gain of 4.2 g of 1-benzhydryl-3-[(methylsulphonyl)(3-nitrophenyl)methyl-(RS)]azetidin-3-ol as an amorphous mass.

Methyl(3-nitrobenzyl)methylsulfone can be obtained by repeating the sequence of operations example 2 according to 18.1 g of methyl (3-nitrobenzyl) sulfide and 68 g OksanaR, resulting in a gain of 13.9 g of methyl(3-nitrobenzyl)sulfone in the form of an amorphous mass.

Methyl(3-nitrobenzyl)sulfide can be obtained by repeating the sequence of operations example 2 according to 17.2 g of 3-nitrobenzylamine and 7.7 g mertiolate sodium: gain of 18.2 g of methyl(3-nitrobenzyl)sulfide in the form of butter.

Example 26

A mixture of 0.34 g of 1-benzhydryl-3-[(methylsulphonyl)(3-nitrophenyl) methylene]azetidine, 16 cm31 N. chloride-hydrogen acid in 8 cm3ethanol and 16 cm3of tetrahydrofuran is heated to boiling under reflux, added 0.17 g of iron powder and continue boiling for 3 hours the Mixture is then cooled to room temperature and filtered nearstore sodium chloride. The aqueous phase is shaken out three times 40 cm3dichloromethane. Extracts combine, dried over sodium sulfate and evaporated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with a mixture of cyclohexane with ethyl acetate (50/50 by volume) as eluent, collecting fractions of 20 cm3. Faction 13-31 combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is recrystallized from 15 cm3diethyl ether, receiving 0.17 g of 3-[(3-AMINOPHENYL) (methylsulphonyl) methylene]-1-benzhydryl-azetidin with so pl. 197[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (250 MHz): 2,95 (3H, s, S3), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), and 4.75 (1H, s, NCH), a 5.25 (2H, s, NH2), 6,55 (3H, m, SN arene.), 7,05 (1H, t, J=7 Hz, CH arene.), then 7.20 (2H, t, J=7 Hz, 2CH arene.), 7,30 (4H, t, J=7 Hz, SN arene.), was 7.45 (4H, d, J=7 Hz, SN arene.)].

Example 27

Repeating the sequence of operations of example 4, on the basis of 1.2 g of 1-benzhydryl-3-[(3-ethoxycarbonylphenyl)(methylsulphonyl)methyl-(RS) ] azetidin-3-ol, 0.3 cm3methanesulfonanilide and 1.3 g of 4-dimethylaminopyridine receive the residue, which is distilled chromatographytandem and then a mixture of dichloromethane with ethyl acetate (99,5/a 0.5 by volume) as eluents, collecting fractions of 100 cm3. Fraction 18 evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid substance periostat of 5 cm3diethyl ether, receiving of 0.13 g of 1-benzhydryl-3-[(3-ethoxycarbonylphenyl)-(methylsulphonyl)methylene]azetidine in the form of a solid amorphous material [NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz) 2,95 (3H, s, S3), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), and 4.75 (1H, s, NCH), 7,20 (2H, t, J=7 Hz, 2CH arene.), 7,30 (4H, t, J=7 Hz, SN arene.), was 7.45 (4H, d, J=7 Hz, SN arene.), of 7.60 (1H, t, J=7 Hz, CH arene.), of 7.70 (1H, d, J=7 Hz, CH arene.), of 8.00 (2H, m, 2CH arene.)].

1-Benzhydryl-3-[(3-ethoxycarbonylphenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations example 1 from 3 g (3-methoxycarbonylbenzyl)methylsulfone and 3.6 g of 1-benzhydrylamine-3-one. After purification by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with dichloromethane and then a mixture of dichloromethane ethanol (99/1 by volume) as eluents obtain 1.2 g of 1-benzhydryl-3-[3-ethoxycarbonylphenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol as an amorphous mass.

(3-Methoxycarbonylbenzyl)methylsulfone can be obtained sup>, resulting in a gain of 3.4 g of (3-methoxycarbonylbenzyl)methylsulfone in the form of a white solid.

(3-Methoxycarbonylbenzyl)metilsulfate can be obtained by repeating the sequence of operations example 2 starting from 5 g of 3-methoxycarbonylmethylene and 1.7 g mertiolate sodium: obtain 4.3 g (3-methoxycarbonyl-benzyl)metilsulfate in the form of butter.

Example 28

Repeating the sequence of operations of example 4, on the basis of 6.2 g of 1-benzhydryl-3-[(3-cyanophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol, 1,6 cm3methanesulfonanilide and 6.8 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with dichloromethane and then a mixture of dichloromethane with ethyl acetate (99,5/a 0.5 by volume) as eluents, collecting fractions of 250 cm3. Fractions 10-15 combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from a mixture of 5 cm3dichloromethane and 70 cm3diethyl ether, gaining 2.9 g of 1-benzhydryl-3-[(3-cyanophenyl)(methylsulphonyl)methylene]azetidine with so pl. 152[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 M is, t, J=7 Hz, SN arene.), was 7.45 (4H, d, J=7 Hz, SN arene.), the 7.65 (1H, t, J=7 Hz, CH arene.), of 7.75 (1H, d, J=7 Hz, CH arene.), of 7.90 (2H, m, 2CH arene.)].

1-Benzhydryl-3-[(3-cyanophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations example 1 on the basis of 3,9 g (3-cyanobenzyl)methylsulfone and 4.7 g of 1-benzhydrylamine-3-one: obtain 6.2 g of 1-benzhydryl-3-[3-cyanophenyl)-(methylsulphonyl)methyl-(RS)]azetidin-3-ol as a white solid.

(3-Cyanobenzyl)methylsulfone can be obtained by repeating the sequence of operations example 2 on the basis of 6.7 g (3-cyanobenzyl)metilsulfate and 27.6 g OksanaR, resulting in a gain of 3.9 g of (3-cyanobenzyl)methylsulfone in the form of a white solid.

(3-Cyanobenzyl)metilsulfate can be obtained by repeating the sequence of operations example 2 from 8 g of 3-cyanobenzaldehyde and 3.1 g mertiolate sodium: obtain 6.8 g (3-cyanobenzyl)metilsulfate in the form of butter.

Example 29

A mixture of 3 g of the hydrochloride of 1-benzhydryl-3-[(3-carboxyla-nil)(methylsulphonyl)methylene]azetidine, 1.3 g of pentafluorophenol and 1.4 g of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 30 cm3of dimethylformamide is stirred for 15 h at room temperature, absorb 100 ml of water and 100 ml NAND magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 35 cm) at a nitrogen pressure of 0.5 bar with dichloromethane and then a mixture of dichloromethane with methanol (99,4/0,6 by volume) as eluents, collecting fractions of 100 cm3. Fractions 13 to 16 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from a mixture of 10 cm3diethyl ether, receiving 0.6 g 1-benzhydryl-3-[(methylsulphonyl)(3-pentafluoroethanesulfonyl)methylene]azetidine with so pl. 182[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (400 MHz) of 3.00 (3H, s, S3), a-3.84 (2H, s, NCH2), 4,25 (2H, s, NCH2), and 4.75 (1H, s, NCH2), 7,20 (2H, t, J=7 Hz, 2CH arene.), 7,30 (4H, t, J=7 Hz, SN arene.), was 7.45 (4H, d, J=7 Hz, SN arene.), of 7.70 (1H, t, J=7 Hz, CH arene.), to 8.20 (2H, m, 2CH arene.)].

Hydrochloride of 1-benzhydryl-3-[(3-carboxyphenyl)(methylsulphonyl)methylene]azetidine can be obtained in the following way: a mixture of 10 g of 1-benzhydryl-3-[(3-cyanophenyl)-(methylsulphonyl)methylene]azetidine 40 cm3acetic acid and 40 cm3concentrated hydrochloric acid (d=l,18) heated for 7 days at 45C, cooled in an ice bath and filtered formed osado the slots (50/50 by volume), then 3 times 20 cm3water and, finally, 20 cm3of ethanol. The obtained white solid is dried at 45C and reduced pressure (2.7 kPa), and then obtain 2.5 g of the hydrochloride of 1-benzhydryl-3-[(3-carboxyphenyl) (methylsulphonyl) methylene] azetidine in the form of a white solid.

Example 30

A solution of 0.65 g of 1-benzhydryl-3-[(3-methylsulphonyl)(3-pentafluoroethanesulfonyl)methylene]azetidine 25 cm36,2 n ammonia in ethanol is stirred for 4 hours at room temperature. The mixture is then evaporated to dryness under reduced pressure (2.7 kPa), receiving and remnant that purify by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane ethanol (99/1 by volume) and then with a mixture of dichloromethane ethanol (98/2 by volume) as eluents, collecting fractions of 60 cm3. Fractions 18-30 evaporated to dryness under reduced pressure (2.7 kPa) to give 0.2 g of 1-benzhydryl-3-[(3-carbamoylphenoxy)(methylsulphonyl)methylene]azetidine with so pl. 140[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 3,00 (3H, s, S3), of 3.80 (2H, s, NCH2), 4,25 (2H, s, N2), and 4.75 (1H, s, NCR), 7,25 (2H, t, J=7 Hz, 2CH arene.), 2
CONH2)].

Example 31

Repeating the sequence of operations of example 4, on the basis of 4.6 g of 1-benzhydryl-3-[(3-methoxyphenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol, 1.2 cm3methanesulfonanilide and 3.8 g of 4-dimethylaminopyridine, obtained after recrystallization from 150 cm3acetonitrile 2.6 g of 1-benzhydryl-3-[(3-methoxyphenyl)(methylsulphonyl)methylene]azetidine with so pl. 179[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (250 MHz): 2,95 (3H, s, S3in ), 3.75 (3H, s, och3), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), and 4.75 (1H, s, NCH), to 7.00 (3H, m, SN arene.), 7,20-7,12 (11N, m, 10H family and 1 CH arene.)].

1-Benzhydryl-3-[(3-methoxyphenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations example 1 from 3.4 g (3-methoxybenzyl)methylsulfone and 4 g of 1-benzhydrylamine-3-one: obtain 4.6 g of 1-benzhydryl-3-[(3-methoxyphenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol as a white solid.

(3-Methoxybenzyl)methylsulfone can be obtained by repeating the sequence of operations example 2 on the basis of 3.4 g (3-methoxybenzyl) metilsulfate and 7.2 g OksanaR, resulting in a gain of 4 g (3-methoxybenzyl)methylsulfone in the form of a white solid with so pl. 71 the ti operations example 2 on the basis of 3.1 g of 3-methoxybenzylamine and 1.5 g mertiolate sodium: obtain 3.4 g (3-methoxybenzyl)metilsulfate in the form of butter.

Example 32

To a solution of 3 g of 1-benzhydryl-3-[(4-methoxyphenyl)-(methylsulphonyl)methylene]azetidine 100 cm3dichloromethane added under stirring to 10 cm31 M solution tribromide boron in dichloromethane, stirred for further 16 h at room temperature and absorb the reaction mixture 100 cm3ice water. The organic phase is washed three times with 50 cm3water, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa). The remainder periostat of 150 cm3diisopropyl ether and dissolved in 50 cm3dichloromethane. The organic phase is washed three times 30 cm3saturated aqueous sodium bicarbonate solution, separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa). The remainder periostat of 80 cm3diethyl ether, receiving 0.36 g of 1-benzhydryl-3-[(3-hydroxyphenyl)(methylsulphonyl)methylene]azetidine with so pl. 248[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 2,95 (3H, s, S3), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), and 4.75 (1H, s, NCR), 6,85 (3H, m, SN arene.), of 7.25 (3H, m, SN arene.), to 7.35 (4H, t, J=7 Hz, SN arene.), to 7.50 (4H, d, J=7 Hz, SN arene.), to 9.50 (1H, s, OH)].

Example 33

Repeating the sequence of operations note is tribromide boron and 100 cm3dichloromethane, get the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 24 cm) at a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (50/50 by volume) as eluent, collecting fractions of 25 cm3. Faction 21-37 combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from 30 cm3diethyl ether, receiving 0.6 g 1-benzhydryl-3-[(4-hydroxyphenyl)(methylsulphonyl)methylene]azetidine with so pl. 211[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 2,90 (3H, s, S3), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), and 4.75 (1H, s, NCH), to 6.80 (2H, d, J=7 Hz, 2CH arene.), 7,10-to 7.35 (8H, m, SN arene.), of 7.48 (4H, d, J=7 Hz, SN arene.), 9,80 (1H, s, OH)].

1-Benzhydryl-3-[(4-methoxyphenyl)(methylsulphonyl)methylene]azetidine can be obtained by repeating the sequence of operations of example 4 from 3.5 g of 1-benzhydryl-3-[(4-methoxyphenyl)(methylsulphonyl)methyl-(RS)]-azetidin-3-ol, 0.9 cm3methanesulfonanilide and 2.9 g of 4-dimethylaminopyridine, purifying the obtained residue by recrystallization from 100 cm3acetonitrile and receiving 1 g 1-benzhydryl-3-[(4-methoxyphenyl)(methylsulphonyl)methylene]azetidine with so pl. but the repetition of a sequence of operations example 1 on the basis of 3.5 g (4-methoxybenzyl)methylsulfone and 4 g of 1-benzhydrylamine-3-one: obtain 3.6 g of 1-benzhydryl-3-[4-methoxyphenyl)-(methylsulphonyl)methyl-(RS)]azetidin-3-ol as a white solid.

(4-Methoxybenzyl)methylsulfone can be obtained by repeating the sequence of operations example 2 on the basis of 3.4 g (4-methoxybenzyl)metilsulfate and 13 g OksanaR, resulting in a gain of 3.5 g of (4-methoxybenzyl)methylsulfone in the form of a white solid with so pl. 113C.

(4-Methoxybenzyl)metilsulfate can be obtained by repeating the sequence of operations example 2 on the basis of 3.1 g of 4-methoxybenzylamine and 1.5 g mertiolate sodium: obtain 3.4 g (4-methoxybenzyl)metilsulfate in the form of butter.

Example 34

Repeating the sequence of operations of example 32, from 1.4 g of 1-benzhydryl-3-[(2-methoxyphenyl)(methylsulphonyl)methylene]azetidine, 10 cm31 M solution tribromide boron and 100 cm3dichloromethane, get the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting fractions of 40 cm3. Faction 15-34 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from 30 cm3diethyl ether, gaining 0.7 g of 1-benzhydryl-3-[(2-hydroxyphenyl)(methylsulphonyl)methylene]azetidine with so pl. 196

1-Benzhydryl-3-[(2-methoxyphenyl)(methylsulphonyl)methylene]azetidine can be obtained by repeating the sequence of operations of example 4 according to 4.2 g of 1-benzhydryl-3-[(2-methoxyphenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol, 1.1 cm3methanesulfonanilide and 3.5 g of 4-dimethylaminopyridine, purifying the obtained residue by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane with ethyl acetate (50/50 by volume) as eluent, collecting fractions of 40 cm3. Faction 23-54 combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from 40 cm3diethyl ether, receiving of 1.9 g of 1-benzhydryl-3-[(2-methoxyphenyl)(methylsulphonyl) methylene]azetidine with so pl. 204C.

1-Benzhydryl-3-[(2-methoxyphenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations example 1 from 4 g (2-methoxybenzyl)methylsulfone and 4.5 g of 1-benzhydrylamine-3-one: obtain 4.3 g of 1-benzhydryl-3-[2-methoxyphenyl obtained by repeating the sequence of operations of example 10 on the basis of 3.1 g of 2-methoxybenzylamine and 4.1 g of methanesulfonate sodium, resulting in a gain of 4 g (2-methoxybenzyl)methylsulfone in the form of a white solid.

Example 35

Repeating the sequence of operations of example 4 and from 2.1 g of 1-benzhydryl-3-[(methylsulphonyl)(naphthas-2-yl)methyl-(RS)]azetidin-3-ol, 0.5 cm3methanesulfonanilide and 2.2 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4 cm, height 30 cm), elwira dichloromethane under a nitrogen pressure of 0.5 bar and collecting fractions of 100 cm3. Fractions 6-10 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from 20 cm3diethyl ether, receiving 0.6 g 1-benzhydryl-3-[(methylsulphonyl)(naphthas-2-yl)methylene]azetidine with so pl. 178[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 3,00 (3H, s, S3), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), and 4.75 (1H, s, NCH), 7,20 (4H, m, SN arene.), 7,30 (4H, t, J=7 Hz, SN arene.), was 7.45 (4H, d, J=7 Hz, SN arene.), 7,52 (3H, m, SN arene.), of 7.90 (4H, m, SN arene.)].

1-Benzhydryl-3-[(methylsulphonyl)(naphthas-2-yl)methyl-(RS)]-azetidin-3-ol can be obtained by repeating the sequence of operations example 1 on the basis of 3.5 g of methyl(naphthas-2-ylmethyl)sulfone and 3.8 g of 1-benzhydryl the CSOs substances so pl. 196C.

Methyl(naphthas-2-ylmethyl)sulfon can be obtained by repeating the sequence of operations example 2 proceeding from 4.2 g of methyl (naphthas-2-ylmethyl) sulfide and 13.7 g OksanaR, resulting in a gain of 3.6 g of methyl(naphthas-2-ylmethyl)sulfone in the form of a cream solid color.

Methyl(naphthas-2-ylmethyl)sulfide can be obtained by repeating the sequence of operations example 2 starting from 5 g of 2-bromoethylamine and 1.8 g mertiolate sodium: gain of 4.2 g of methyl(naphthas-2-ylmethyl)sulfide in the form of butter.

Example 36

Repeating the sequence of operations of example 4 and from 4.3 g of 1-benzhydryl-3-[(methylsulphonyl)(naphthas-1-yl)methyl-(RS)]azetidin-3-ol, 1.1 cm3methanesulfonanilide and 4.6 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4 cm, height 30 cm), elwira dichloromethane under a nitrogen pressure of 0.5 bar and collecting fractions of 100 cm3. Fractions 6-14 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from 30 cm3diethyl ether, obtaining 2.5 g of 1-benzhydryl-3-[(methylsulphonyl)(naphthas-1-yl)methylene]azetidine with so pl. 196[Range of I is), 4,35 (2H, m, NCH2), and 4.75 (1H, s, NCH), 7,10-7,70 (14N, m, SN arene.), of 8.00 (3H, m, SN arene.)].

1-Benzhydryl-3-[(methylsulphonyl)(naphthas-1-yl)methyl-(RS)]-azetidin-3-ol can be obtained by repeating the sequence of operations example 1 from 4.1 g of methyl(naphthas-1-ylmethyl)sulfone and 4,4 g of 1-benzhydrylamine-3-one: obtain 4.3 g of 1-benzhydryl-3-[(methylsulphonyl)(naphthas-1-yl)methyl-(RS)]azetidin-3-ol in the form of a solid substance.

Methyl(naphthas-1-ylmethyl)sulfon can be obtained by repeating the sequence of operations example 2 with 4.3 g of methyl(naphthas-1-ylmethyl) sulfide and 13.9 g OksanaR, resulting in a gain of 4.1 g of methyl(naphthas-1-ylmethyl)sulfone as a white solid.

Methyl(naphthas-1-ylmethyl)sulfide can be obtained by repeating the sequence of operations example 2 from 4 g of 1-chloromethylketone and 1.8 g mertiolate sodium: obtain 4.5 g of methyl(naphthas-1-ylmethyl)sulfide in the form of butter.

Example 37

Repeating the sequence of operations of example 4, on the basis of 0.6 g 1-benzhydryl-3-[(methylsulphonyl)(3-pyrrolidinyl)methyl-(RS)]azetidin-3-ol, 0.15 cm3methanesulfonanilide and 0.6 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 2 cm, height of shares by volume of 20 cm3. Fractions 8 to 13 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from 8 cm3diethyl ether, receiving 0.36 g of 1-benzhydryl-3-[(methylsulphonyl)(3-pyrrolidinyl)methylene]-azetidine with so pl. 153[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (250 MHz): 1,95 (4H, m, 2CH2), 2,95 (3H, s, S3), 3,20 (4H, m, 2NCH2), of 3.80 (2H, s, NCH2), 4,20 (2H, s, N2), and 4.75 (1H, s, NCH), 6,60 (3H, m, SN arene.), then 7.20 (3H, m, SN arene.), 7,30 (4H, t, J=7 Hz, SN arene.), of 7.48 (4H, d, J=7 Hz, SN arene.)].

1-Benzhydryl-3-[(methylsulphonyl)(3-pyrrolidinyl)-methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations example 1 on the basis of 0,77 g 3-pyrrolidineethanol and from 0.76 g of 1-benzhydrylamine-3-one: obtain 0.6 g of 1-benzhydryl-3-[ (methylsulphonyl) (3-pyrrolidinyl)methyl-(RS)]azetidin-3-ol in the form of a solid substance.

Methyl(3-pyrrolidinones)sulfon can be obtained by repeating the sequence of operations example 2 on the basis of 1 g of methyl(3-pyrrolidinones)sulfide and 3,3 g OksanaR, resulting in a gain of 0.8 g of methyl(3-pyrrolidinones) sulfone in the form of a solid substance.

Methyl(3-pyrrolidinones)sulfide can be obtained after orida 1,1’-bis(diphenylphosphino)ferienanlage, 0,63 g of 1,1’-bis (diphenylphosphino)ferrocene and 60 cm3of tetrahydrofuran is refluxed for 3 hours in a stream of nitrogen, after which the reaction mixture is cooled to room temperature and filtered on a porous filter. The precipitate is washed with 20 cm3of tetrahydrofuran and 10 cm3dichloromethane. The filtrate is evaporated to dryness under reduced pressure (2.7 kPa) and absorb the remainder of the 30 cm3ethyl acetate and 30 cm33 N. hydrochloric acid. The aqueous phase is separated, neutralized (pH 7-8) by the addition of 35 cm33 n sodium hydroxide solution and absorb 50 cm3ethyl acetate. The organic phase is extracted, add 4 g of silica and evaporated mixture to dryness under reduced pressure (2.5 kPa). The resulting powder was washed on a porous glass with 20 g of silicon oxide with a mixture of cyclohexane with ethyl acetate (90/10 by volume). The filtrate is evaporated to dryness under reduced pressure (2.7 kPa) to give 1.2 g of methyl(3-pyrrolidinones)sulfide in the form of butter.

Chloride 1,1’-bis(diphenylphosphino)ferienanlage receive according to Hayashi T. et al. J. Am. Chem. Soc., 106, 158 (1984).

Example 38

Method 1

The solution to 2.94 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol in 250 cm3dichloromethane at 223distilled water and once with 150 cm3saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The obtained residue chromatographic on a column of silica gel (grain size of 0.04-0.06 mm, diameter 5.5 cm, height 15 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (1/9 by volume) as eluent and collecting fractions of 70 cm3. Faction 15-36 combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 1.86 g of a white amorphous mass, which crystallized from diisopropyl ether, obtaining a solid substance with so pl. 190C. Recrystallization of the latter from 145 cm3ethanol gives a 1.08 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine with so pl. 206[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 3,00 (3H, s, S3), a 3.87 (2H, s, NCH2), 4,20 (2H, s, NCH2), and 4.75 (1H, s, NCH), to 7.15 (2H, d, J=7 Hz, 2CH arene.), 7,30 (5H, m, SN arene.), was 7.45 (4H, d, J=7 Hz, SN arene.)].

Method 2

To a solution of 2.2 g of 3-acetoxy-1-[by temperature add to 0.80 g of powdered sodium hydroxide, leave the mixture at room temperature for 16 h and add 50 cm3water and 100 cm3ethyl acetate. The mixture was separated and again washed organic phase is 100 cm3water, then dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa) to give a white amorphous mass which is crystallized from diisopropyl ether, receiving of 0.85 g of solid substance with so pl. 190C. Recrystallization of the latter from 20 cm3the ethanol 0,70 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene] azetidine with so pl. 205C.

Example 39

To a solution of 6.8 g of bis(4-chlorophenyl)bromomethane 300 cm3acetonitrile add to 6.75 g of the hydrochloride of 3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol and then of 2.97 g of potassium carbonate. The reaction mixture is refluxed for 2 hours, cooled to room temperature, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The obtained residue chromatographic on a column of silica gel (grain size of 0.04-0.06 mm, diameter 8.5 cm, height 22 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (25/75 by volume) as eluent, collecting fractions of 250 enyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol [NMR Spectrum1H (300 MHz, DMSO-d6,in M. D.): 2,00 (s: 3H), 2,94 (s: 3H) at 3.25 (m: 2H), 3,48 (d, J=9 Hz: 1H), 3,80 (d, J=9 Hz: 1H), 4,54 (s: 1H), 5,34 (s: 1H), 7,15 (d, J=8.5 Hz: 2H), 7,20-7,40 (m: 8H), 7,50 (t OSiR., J=9 Hz: 1H)].

Bis (4-chlorophenyl) bromatan can be obtained according to the method described by W. E. BACHMANN, J. Am. Chem. Soc., 2135 (1933).

Hydrochloride 3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol may be obtained in the following way: to a solution of 37 g of 3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-1-ol 160 cm3dioxane add 160 cm36,2 n solution of hydrogen chloride in dioxane and leave the mixture for 16 h at room temperature, then evaporated to dryness under reduced pressure (2.7 kPa). The obtained residue absorb 320 cm3ethanol is boiled for 1 hour and cooled in an ice bath. The formed solid is filtered off, washed with diethyl ether and dried at 40C and reduced pressure (2.7 kPa), receiving 29,85 g of white crystals with so pl. above 260C.

3-[(3,5-Differenl)(methylsulphonyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-ol may be obtained in the following way: to a solution of 60,18 g 1-benzhydryl-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol in 1 cm3dichloromethane and the reaction mixture is stored for 20 h at room temperature, then evaporated to dryness under reduced pressure (2.7 kPa). The obtained residue chromatographic on a column of silica gel (grain size of 0.04-0.06 mm, diameter 11 cm, height 32 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (3/7 by volume) as eluent, collecting fractions with a volume of 1000 cm3. Fractions 8-18 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 37 g of 3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-ol as white crystals with so pl. 195C.

Example 40

To a solution of 4.77 g (3,5-diferensial)methylsulfone 70 cm3of tetrahydrofuran is added in an argon atmosphere at -7014 cm3a 1.6 n solution of utility in hexane, leave for 1 h at -70C, add a solution of 6.8 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one in 30 cm3of tetrahydrofuran and, after 1 h, a solution of 2.34 cm3acetylchloride 20 cm3tetrahydrofuran (THF), and raise the temperature of the reaction mixture to room within 1 hour. Then add 50 cm3water and 200 cm3ethyl acetate and divide the mixture into phases. Oraut over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa) to give 14.4 g of 3-acetoxy-[bis(4-chlorophenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl)methylsulfonylmethyl-(RS)]azetidine in the form of a yellow oil [NMR Spectrum1H (400 MHz, Dl3,in M. D.): 2,79 (s: 3H), 3.04 from (AB, J=9 Hz: 2H), with 3.27 (d, J=9 Hz: 1H), 3.45 points (s: 1H), 3,81 (d, J=9 Hz: 1H), 4,32 (s: 1H), 4,49 (s: 1H), 6,68 (TT, J=9 and 2.5 Hz: 1H), 7,20-7,35 (m: 10H)].

1-[Bis(4-chlorophenyl)methyl]azetidin-3-one can be obtained using the following sequence of operations: to a cooled to -78To a solution of 5.0 cm3oxalicacid 73 cm3dichloromethane add a solution of 8.1 cm3dimethyl sulfoxide 17.6 cm3dichloromethane, leave for 0.5 hour at -78With and poured a solution of 16.0 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ol in 50 cm3dichloromethane. The mixture is kept for 5 h at -78With that added dropwise to 26.6 cm3of triethylamine and provide spontaneous rise of the temperature of the mixture to room. Then the reaction mixture was washed 4 times with 200 cm3water and then 200 cm3saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated to dryness under pangender 9.2 cm, height 21 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (40/60 by volume) as eluent, collecting fractions of 200 cm3. Fractions 15 to 25 are combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving of 8.9 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ol in the form of pale yellow crystals with so pl. 111C.

1-[Bis(4-chlorophenyl)methyl]azetidin-3-ol may be obtained using the procedure described in A. R. KATRITZKY et al., J. Heterocycl. Chem., 271 (1994), on the basis of 35.5 hydrochloride [bis(4-chlorophenyl)methyl]amine and 11.0 cm3epichlorohydrin: allocate 9.0 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ol.

Hydrochloride [bis(4-chlorophenyl)methyl]amine can be obtained according to the method described by M. GRISAR et al. in J. Med. Chenn., 885 (1973).

Example 41

Repeating the sequence of operations of example 38 (method 1), according to 0.72 g of 1-[bis(4-methoxyphenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol, after chromatography was carried out on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4.0 cm, height 16.5 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (2/8 by volume) as eluent, collecting fractions of 40 cm3and obtain 0.10 g of a white amorphous mass. After triethylsulfonium)methylene]azetidine in the form of a solid substance with so pl. 180[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (250 MHz): 3,00 (3H, s, S3), 3,70 (6N, C, 2 co3), of 3.80 (2H, s, NCH2), is 4.15 (2H, s, NCH2), 4,58 (1H, s, NCH), 6,85 (4H, d, J=7 Hz, SN arene.), to 7.15 (2H, d, J=8 Hz, 2CH arene.), 7,30 (5H, m, SN arene.)].

1-[bis(4-methoxyphenyl)methyl]-3-[(3,5-differenl)-(methylsulphonyl)methyl-(RS)]azetidin-3-ol may be obtained using the sequence of operations of example 39 from 1.2 g of bis(4-methoxyphenyl)brometane and 1.2 g of the hydrochloride of 3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol. After chromatography was carried out on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4.8 cm, height 18 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (25/75 by volume) as eluent collected fraction volume of 50 cm3, fractions 9-18 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 0.55 g of 1-[bis(4-methoxyphenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol.

Bis(4-methoxyphenyl)bromatan can be obtained using the procedure described BACHMANN, W. E., J. Am. Chem. Soc., 2135 (1933).

Example 42

Repeating the sequence of operations of example 38 (method 1), according to 0.47 g of 1-[bis(4-were)methyl]-3-[(3,5-difthe is of 0.04-0.06 mm, diameter 3.2 cm, height 18.5 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (1/9 by volume) as eluent, collecting fractions with a volume of 35 cm3and get to 0.30 g of a white solid. After crystallization from diisopropyl ether obtain 0.20 g of 1-[bis(4-were)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine in the form of white needles with so pl. 200C.

1-[bis(4-were)methyl]-3-[(3,5-differenl)-(methylsulphonyl)methyl-(RS)]azetidin-3-ol may be obtained using the sequence of operations of example 39 from 0.7 g of bis (4-were) brometane and 0.8 g of the hydrochloride of 3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol, after chromatography was carried out on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4.0 cm, height 19 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (2/8 by volume) as eluent, collecting fractions of 40 cm3, fractions 35-40 combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving of 0.47 g of 1-[bis(4-were)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol.

Bis(4-were)bromatan can be obtained using the procedure described BACHMANN, W. E., J. Am. Chem. So)(methylsulphonyl)-methyl-(RS)]-1-[(4-methoxyphenyl)(phenyl)methyl-(RS)]azetidin-3-ol, a mixture of two diastereoisomers, after chromatography was carried out on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4.0 cm, height 21 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (2/8 by volume) as eluent, collecting fractions of 40 cm3and obtain 0.10 g of a white solid. After crystallization from diisopropyl ether to receive 50 mg of (RS)-3-[(3, 5-differenl)(methylsulphonyl)methylene]-1-(4-methoxyphenyl)(phenyl)-methyl]azetidine in the form of a white solid [NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 2,23 (6N, C, 2 h3), to 3.00 (3H, s, SCH3), of 3.80 (2H, s, NCH2), of 4.12 (2H, s, NCH2), 4,58 (1H, s, NCH), was 7.08 (4H, d, J=7 Hz, SN arene.), to 7.15 (2H, d, J=8 Hz, 2CH arene.), of 7.25 (5H, m, SN arene.)].

A mixture of diastereoisomers 3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]-1-[(4-methoxyphenyl)(phenyl)methyl-(RS)]azetidin-3-ol may be obtained using the sequence of operations of example 39 from 2,52 g of (RS)-bromo(4-methoxyphenyl)(phenyl)methane and 2.85 g of the hydrochloride of 3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol, after chromatography was carried out on a column of silica gel (grain size of 0.04-0.06 mm, diameter 5.6 cm, height 19 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (25/75 by the ri reduced pressure (2.7 kPa), getting to 1.16 g of a mixture of diastereoisomers 3-[(3,5-differenl)(methylsulphonyl)-methyl-(RS)]-1-[(4-methoxyphenyl)(phenyl)methyl-(RS)]azetidin-3-ol.

(RS)-Bromo(4-methoxyphenyl)(phenyl)methane can be obtained using the procedure described ANN W. E., J. Am. Chem. Soc., 2135 (1933).

Example 44

Repeating the sequence of operations of example 38 (method 1), according to 0.47 g of 1-[bis(4-trifloromethyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol, after chromatography was carried out on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4.2 cm, height 14 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (2/8 by volume) as eluent, collecting fractions of 25 cm3and obtain 0.28 g of 1-[bis(4-trifloromethyl) methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine in the form of a solid [NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 3,05 (3H, s, S3), of 3.95 (2H, s, NCH2), 4,25 (2H, s, NCH2), the 4.90 (1H, s, NCH), 7,20 (2H, d, J=8 Hz, 2CH arene.), to 7.32 (5H, m, SN arene.), of 7.60 (4H, d, J=7 Hz, SN arene.)].

1-[bis(4-trifloromethyl)methyl]-3-[(3,5-differenl) (methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations of example 39 according to 1.59 g of bis(4-t is after the chromatography was carried out on a column of silica gel (grain size of 0.04-0.06 mm, the diameter of 4.8 cm, height 17 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (25/75 by volume) as eluent collected fraction volume of 50 cm3, fractions 15-23 are combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving of 0.49 g of 1-[bis(4-trifloromethyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol.

Bis(4-trifloromethyl)bromatan can be obtained according to the method described by W. E. BACHMANN, J. Am. Chem. Soc., 2135 (1933), 1.39 g of bis(4-trifloromethyl)methanol, 3 cm333% Hydrobromic acid in acetic acid and 0.6 cm3acetylproline. Get to 1.59 g of bis(4-trifloromethyl)brometane in the form of a reddish-brown oil.

Bis(4-trifloromethyl)methanol receive according to the method of PAVIA, M. R., J. Med. Chem., 4238 (1992).

Example 45

Repeating the sequence of operations of example 38 (method 1), starting from 0.25 g of 1-[bis(4-triptoreline)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol, after chromatography was carried out on a column of silica gel (grain size of 0.04-0.06 mm, diameter 2.4 cm, height 14 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (2/8 by volume) as eluent, collecting fractions of 20 cm3and obtain 0.12 g of 1-[bis(4-trifluoromethyl who DMSO-d6, T=300 K,in M. D. (300 MHz): 3,05 (3H, s, S3), of 3.95 (2H, s, NCH2), 4,25 (2H, s, NCH2), the 4.90 (1H, s, NCH), 7,20 (2H, d, J=8 Hz, 2CH arene.), to 7.32 (5H, m, SN arene,), 7,60 (4H, d, J=7 Hz, SN arene.)].

1-[bis(4-triptoreline)methyl]-3-[(3,5-differenl)-(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations of example 39 from 1,46 g of bis(4-triptoreline)brometane and 1.2 g of the hydrochloride of 3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol. After chromatography was carried out on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4.8 cm, height 17 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (30/70 by volume) as eluent, collecting fractions of 50 cm3, fractions 9 to 14 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 0.25 g of 1-[bis(4-triptoreline)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol.

Bis(4-triptoreline)bromatan can be obtained according to the method described by W. E. BACHMANN, J. Am. Chem. Soc., 2135 (1933), 2.5 g of bis(4-triptoreline)methanol, 6 cm333% Hydrobromic acid in acetic acid and 1.2 cm3acetylproline. Obtain 2.9 g of bis(4-triptoreline)-brometea in the form of reddish-brown m, the sequence of operations of example 38 (method 2), according to 3.16 g of 3-acetoxy-1-[bis(4-chlorophenyl)methyl]-3-{[(3,5-bis(trifluoromethyl)phenyl](methylsulphonyl)methyl-(RS)}-azetidine and 0.96 g of powdered sodium hydroxide, after keeping the mixture for 16 h at room temperature receives a yellow amorphous mass, which chromatographical on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4.8 cm, height 14 cm) when the pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (15/85 by volume) as eluent, collecting fractions of 40 cm3. Get 1,49 g of 1-[bis(4-chlorophenyl)methyl]-3-{[(3,5-bis-(trifluoromethyl) phenyl] (methylsulphonyl) methylene} of azetidine in the form of a white amorphous mass [NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 3,05 (3H, s, S3), 3,90 (2H, s, NCH2), 4,30 (2H, s, NCH2), 4,80 (1H, s, NCH), 7,40 (2H, d, J=7 Hz, 2CH arene.), to 7.50 (2H, d, J=7 Hz, 2CH arene.), 8,10 (2H, s, 2CH arene.), to 8.20 (1H, s, CH arene.)].

3-Acetoxy-1-[bis(4-chlorophenyl)methyl]-3-{[(3,5-bis-(trifluoromethyl)phenyl](methylsulphonyl)methyl-(RS)}azetidin can be obtained by repeating the sequence of operations of example 40 from 2.0 g [3,5-bis(trifluoromethyl)-benzyl]methylsulfone, 4.1 cm3a 1.6 n solution of utility in hexane, 2.0 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 0.77 cm3acetylchloride 20 cm3betwedn the R 5.6 cm, height 16 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (1/9 by volume) as eluent collected fraction volume of 100 cm3and receive of 3.56 g of 3-acetoxy-1-[bis(4-chlorophenyl)methyl]-3-{[(3,5-bis(trifluoromethyl)phenyl](methylsulphonyl)methyl-(RS)}of azetidine in the form of a white amorphous mass.

[3,5-Bis(trifluoromethyl)benzyl]methylsulfone obtained by repeating the sequence of operations of example 10 of 1.8 g of 3,5-bis(trifluoromethyl)benzylchloride and 1.22 g of methanesulfonate sodium. Received 1.86 g [3,5-bis(trifluoromethyl)benzyl]-methylsulfone in the form of a white solid.

Example 47

Repeating the sequence of operations of example 38 (method 1) on the basis of 0.27 g of a mixture of two diastereoisomers 1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl-(RS)]-3-[(3,5-differenl)-(methylsulphonyl)methyl-(RS)]azetidin-3-ol, after chromatography was carried out on a column of silica gel (grain size of 0.04-0.06 mm, diameter 2.4 cm, height 7.5 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (15/85 by volume) as eluent collecting fractions of 20 cm3and obtain 0.10 g of (RS)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)-methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine in the form of a white solid [NMR Spectrum in DMSO-d6, T=300 K,in M. b>2), 4,35 (1H, DD, J=3 and 16 Hz, NCH2), 5,12 (1H, s, NCH), 7,18 (2H, d, J=8 Hz, 2CH arene.), to 7.32 (1H, t, J=8 Hz, CH arene.), 7,38 (2H, d, J=7 Hz, CH arene.), was 7.45 (2H, d, J=7 Hz, CH arene.), of 7.48 (1H, DD, J=2 and 7 Hz, CH arene.), 7,58 (1H, d, J=2 Hz, CH arene.), 7,80 (1H, d, J=7 Hz, CH arene.)].

A mixture of diastereoisomers 1-[(4-chlorophenyl) (2,4-dichlorophenyl)-methyl(RS)]-3-[(3,5-differenl)(methylsulphonyl)methyl - (RS)]azetidin-3-ol may be obtained using the sequence of operations of example 39 from 0.56 g (RS)-bromo(4-chlorophenyl)(2,4-dichlorophenyl)methane and 0.50 g of the hydrochloride of 3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol. After chromatography was carried out on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4.0 cm, height 13 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (20/80 by volume) as eluent collected fraction volume 40 cm3, fractions 9 to 14 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 0.27 g of a mixture of diastereoisomers 1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl-(RS)]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol.

(RS)-Bromo(4-chlorophenyl)(2,4-dichlorophenyl)methane can be obtained according to the method described by W. E. BACHMANN, J. Am. Chem. Soc., 2135 (1933), of 4.05 g of (RS)-(4-chlorophenyl)(2,4-dichlorophenyl)methanol, 10 cm333% Hydrobromic acid in accusativo oil.

(RS)-(4-chlorophenyl)(2,4-dichlorophenyl)methanol receive according to the method of PAVIA, M. R. et al., J. Med. Chem., 4238 (1992).

Example 48

To a solution of 18.9 g of 1-{(4-chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl]methyl-(RS)}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine 80 cm3tetrahydrofuran (THF) add 75,6 cm35 N. hydrochloric acid. The reaction mixture is left for 3 hours at room temperature, absorb dichloromethane and distilled water, then add 30% sodium hydroxide to pH 14 and separated phases. The organic phase is twice washed with 100 cm3water and then 100 cm3saturated aqueous solution of sodium chloride, then dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa) to give 16 g of (RS)-1-[(4-chlorophenyl)(4-formylphenyl)methyl]-3-[(3,5-differenl](methylsulphonyl) methylene]azetidine in the form of a white amorphous mass [NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): a 3.06 (3H, s, S3), of 3.95 (2H, m, NCH2), 4.26 deaths (2H, m, NCH2), 4,91 (1H, s, NCH2), 7,20 (2H, d, J=8 Hz, 2CH arene.), of 7.36 (1H, t, J=8 Hz, 1 CH arene.), 7,40 and 7,52 (4H, 2D, J=7.5 Hz, SN arene.), 7,70 and 7,88 (4H, 2D, J=7.5 Hz, SN arene.), becomes 9.97 (1H, s, CH aldagen.)].

1-{(4-chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl]methyl-(RS)}-3-[(3,5-differenl)(methylsulphonyl)methylene]aestheticaly-2-yl)phenyl]methyl-(RS)}-3-[(3,5-differenl)(methylsulphonyl) methyl-(RS)]azetidine 400 cm3of tetrahydrofuran in an argon atmosphere at 0With added dropwise 13.0 cm31,8-diazabicyclo[5,4,0]undec-7-ene and after conventional treatment and chromatography was carried out on a column of silica gel (grain size of 0.04-0.06 mm, diameter 10.2 cm, height 23 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (2/8 by volume) as eluent and collecting fractions of 250 cm3obtain 16.6 g of 1-{(4-chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl] methyl-(RS)}-3-[(3,5-differenl)(methylsulphonyl)methylene] azetidine in the form of a white solid.

A mixture of two diastereoisomers 3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl]methyl-(RS)}-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin can be obtained using the sequence of operations of example 40 from 11.6 g (3,5-diferensial)-methylsulfone, 35,1 cm3a 1.6 n solution of n-utility in hexane, 19.3 g of 1-{(4-chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl]methyl-(RS)}azetidin-3-one and 8.8 cm3acetylchloride 500 cm3tetrahydrofuran (THF). Get of 37.8 g of a mixture of two diastereoisomers 3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl] methyl - (RS)}-3-[(3,5-differenl)(methylsulphonyl)-methyl-(RS)]azetidine in the form of a white amorphous mass.

1-{(4-Chlorophenyl)[4-(1,3-dioxolane-2-LAN-2-yl)phenyl]methyl-(RS)}azetidin-3-ol in 200 cm3the add dimethyl sulfoxide at room temperature 46 cm3of triethylamine and then added dropwise a solution of 34 g of a complex of pyridine-sulfurdioxide 100 cm3dimethyl sulfoxide. Leave the reaction mixture at 0.25 hour at room temperature, poured on ice, extracted with ethyl acetate, washed with 3 times 400 cm3water and then 400 cm3saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The obtained residue chromatographic on a column of silica gel (grain size of 0.04-0.06 mm, diameter of 9.2 cm, height 21 cm) at a nitrogen pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (20/80 by volume) and collecting fractions of 250 cm3. Fractions 9 to 18 are combined and evaporated to dryness under reduced pressure (2.7 kPa). Get to 20.4 g of 1-{(4-chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl]methyl-(RS)}-azetidin-3-one as a yellow oil.

1-{(4-Chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl]methyl-(RS)}azetidin-3-ol may be obtained using the procedure described in A. R. KATRITZKY et al. in J. Heterocycl. Chem., 271 (1994), 35,0 g of {(4-chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl]methyl-(RS)}amine, 8,3 g epibromohydrin, 5,1 g of sodium bicarbonate and 400 cm3of ethanol. dioxolane-2-yl)-phenyl]methyl-(RS)}amine can be obtained by the method, described M. GRISAR et al. in J. Med. Chem., 885 (1973), and 67.2 g of 4-(1,3-dioxolane-2-yl)benzonitrile, 88,2 g of 1-bromo-4-chlorobenzene, 11 g of magnesium and 600 cm3diethyl ether. Get 42,3 g of {(4-chlorophenyl)[4-(1,3-dioxolane-2-yl)-phenyl]methyl-(RS)}amine as a yellow oil.

Example 49

To a solution of 0.50 g of (RS)-1-{(4-chlorophenyl)(4-formylphenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine 15 cm3methanol at 0To add 0,020 g of sodium borohydride. The reaction mixture is left for 1 h at 0With add 40 cm3water and extracted the product 100 cm3dichloromethane. The organic phase is washed twice with 40 cm3water and then 40 cm3saturated aqueous solution of sodium chloride, then dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3.2 cm, height 14 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate and cyclohexane (30/70 by volume) and collecting fractions of 20 cm3. Fractions 20-25 combined and evaporated to dryness under reduced pressure (2.7 kPa). Get to 0.29 g of (RS)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]ASN3), 3,90 (2H, s, NCH2), 4,20 (2H, s, NCH2), was 4.42 (2H, d, J=5 Hz, och3), and 4.75 (1H, s, NCH), 5,10 (1H, t, J=5 Hz, HE), 7,10-7,50 (11N, m, 11 CH arene.)].

Example 50

To a solution of 0.10 g of pyrrolidine 20 cm3dichloroethane add 0.75 g of (RS)-1-{(4-chlorophenyl)(4-formylphenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine and then 0,68 g triacetoxyborohydride sodium. The mixture is left for 20 hours at room temperature, add 2 cm31 n sodium hydroxide solution, extracted with product 100 cm3dichloromethane. The organic phase is twice washed with 50 cm3water and then 50 cm3saturated aqueous solution of sodium chloride, then dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The obtained residue chromatographic on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4.1 cm, height 13 cm) at a pressure of argon 0.5 bar with ethyl acetate as eluent and collecting fractions of 20 cm3. Fractions 10-18 are combined and evaporated to dryness under reduced pressure (2.7 kPa). Obtain 0.39 g of (RS)-1-{(4-chlorophenyl)[4-(pyrrolidinyl)phenyl] methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine in the form of a white amorphous mass [NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 1sub>2), and 4.75 (1H, s, NCR), 7,15-7,40 (N, m, SN arene.), of 7.48 (2H, d, J=7 Hz, 2CH arene.)].

Example 51

Repeating the sequence of operations of example 50, from 0,93 cm32 M solution of dimethylamine in methanol, 30 cm31,2-dichloroethane, 0.75 g of (RS)-1-[(4-chlorophenyl}(4-formylphenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]-azetidine and then 0.9 g of triacetoxyborohydride sodium, after chromatography was carried out on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4 cm, height 17.5 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (30/70 by volume) as eluent and collecting fractions of 40 cm3receive and 0.46 g of (RS)-1-[(4-chlorophenyl)(4-dimethylaminomethyl)-methyl]-3-[(3,5-differenl){methylsulphonyl)methylene]azetidine in the form of a white solid [NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 2,12 (6N, s, N(CH3)2), to 3.02 (3H, s, S3), of 3.32 (2H, s, NCH2Ph), 3,90 (2H, s, NCH2), 4,20 (2H, s, NCH2), and 4.75 (1H, s, NCH), 7,18 (2H, d, J=8 Hz, 2CH arene.), 7,22 (2H, d, J=8 Hz, 2CH arene.), to 7.35 (1H, t, J=8 Hz, CH arene.), 7,39 (4H, m, SN arene.), of 7.48 (4H, d, J=7 Hz, SN arene.)].

Example 52

Mix a solution of 0.5 g of (RS)-1-[(4-carboxyphenyl)(4-chlorophenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)-methylene] azetidine 10 cm3dichloromethane at 0in M. D. (300 MHz): 2,85 (3H, user., N3), 2,95 (3H, user., NCH2), to 3.00 (3H, s, S3), 3,90 (2H, s, NCH2), 4,20 (2H, s, NCH2), 4,80 (1H, s, NCH), to 7.15 (2H, d, J=8 Hz, 2CH arene.), 7,30 (1H, t, J=8 Hz, CH arene.) to 7.35 (4H, m, SN arene.), to 7.50 (4H, d, J=7 Hz, SN arene.)].

(RS)-1-[(4-carboxyphenyl)(4-chlorophenyl)methyl]-3-[(3,5-differenl)(Meinel)methyl}-3-[(3,5-differenl){methylsulphonyl)methylene]azetidine 10 cm3acetone was added when 0With 1.0 cm3the Jones reagent. After 5 h the reaction mixture was poured into distilled water and extracted the product 50 cm3ethyl acetate. The organic phase is twice washed with 50 cm3water and then 50 cm3saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The obtained solid is crystallized from a mixture of ethyl acetate with cyclohexane, filtered and dried, obtaining of 0.50 g of (RS)-1-[(4-carboxyphenyl)(4-chlorophenyl)methyl]-3-[(3,5-differenl) (methylsulphonyl)methylene]azetidine in the form of a white solid.

Example 53

Repeat the sequence of operations of example 52, based on 1 g of (RS)-1-{(4-carboxyphenyl)(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, of 0.38 g of the hydrochloride 1,3-dimethylaminopropyl-3-ethylcarbodiimide, 22 mg hydroxybenzotriazole, 30 cm3dichloromethane and 0,83 cm32 M solution of ethylamine in THF, chromatographia on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4.1 cm, height 15 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (45/55 by volume) as eluent and collecting fractions of 30 cm3in M. D. (300 MHz) with 1.07 (3H, t, J=6 Hz, CH3), to 3.00 (3H, s, S3), to 3.35 (2H, m, NCH2), 3,90 (2H, s, NCH2), 4,20 (2H, s, NCH2), 4,80 (1H, s, NCH), to 7.15 (2H, d, J=8 Hz, 2CH arene.), 7,30 (1H, t, J=8 Hz, CH arene.), to 7.35 (2H, d, J=7 Hz, 2CH arene.), of 7.48 (4H, m, SN arene.), 7,74 (2H, d, J=7 Hz, 2CH arene.), of 8.37 (1H, m, CONH)].

Example 54

Repeat the sequence of operations of example 52, based on 1 g of (RS)-1-{(4-carboxyphenyl)(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine of 0.38 g of the hydrochloride 1,3-dimethylaminopropyl-3-ethylcarbodiimide, 22 mg hydroxybenzotriazole, 40 cm3dichloromethane and 0.24 cm37 M solution of ammonia in methanol, chromatographia on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4.1 cm, height 15 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (60/40 by volume) as eluent and collecting fractions with a volume of 35 cm3. Faction 38-48 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 0.29 grams of solid, which after processing diisopropyl ether and drying gives 0,22 g (RS)-l-[(4-carbamoylphenoxy)(4-chlorophenyl)methyl-(RS)]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine in the form of a white solid [NMR Spectrum in DMSO-d6, T=300 K,in M. D. J=8 Hz, CH arene.), 7,38 (2H, d, J=7 Hz, 2CH arene.), to 7.50 (5H, m, SN arene. and1/2CONH2), 7,80 (2H, d, J=7 Hz, 2CH arene.), of 7.90 (1H, s,1/2CONHa)].

Example 55

Repeat the sequence of operations of example 4, from 1.7 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-dichlorophenyl)-(methylsulphonyl)methyl-(RS)]azetidin-3-ol, 0,35 cm3methanesulfonanilide and 1.5 g of 4-dimethylaminopyridine. The obtained residue chromatographic on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 35 cm) at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane with ethanol of 99.5/0.5 to by volume) as eluent, collecting fractions of 100 cm3. Fractions 7-10 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The solid residue is crystallized from 15 cm3diethyl ether, receiving 0.2 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-dichlorophenyl) (methylsulphonyl)methylene]azetidine with so pl. 200[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 3,00 (3H, s, S3), of 3.80 (2H, s, N2), 4,20 (2H, s, NCH2), and 4.75 (1H, s, NCH), 7,35 (4H, t, J=7 Hz, SN arene.), 7,45 (6N, m, SN arene.), to 7.67 (1H, s, CH arene.)].

1-[Bis(4-chlorophenyl)methyl]-3-[(3,5-dichlorophenyl)(methylsulphonyl)-methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations p is seiden-3-ol. The resulting residue is purified by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 40 cm) at a nitrogen pressure of 0.5 bar with dichloromethane and then with a mixture of dichloromethane ethanol (99/1 by volume) as eluents, collecting fractions of 100 cm3. Fractions 15 to 19 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 1.7 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-dichlorophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol as an amorphous mass.

Bis(4-chlorophenyl)bromatan can be obtained according to the method described by W. E. BACHMANN, J. Am. Chem. Soc., 2135 (1933).

Hydrochloride 3-[(3,5-dichlorophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations of example 39 from 5.6 g of 3-[(3,5-dichlorophenyl) (methylsulphonyl)methyl - (RS)]-1-(vinyloxycarbonyl)-azetidin-3-ol and 56 cm36,2 n solution of hydrogen chloride in dioxane. Received of 5.1 g of the hydrochloride of 3-[(3,5-dichlorophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol as an amorphous mass.

3-[(3,5-Dichlorophenyl)(methylsulphonyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-ol can be obtained by repeating the sequence of operations of example 39 on the basis of the 7.4 g of 1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol and 1.6 cm3VI is likehell (grain size of 0.04-0.06 mm, diameter 3 cm, height 40 cm) at a nitrogen pressure of 0.5 bar with a mixture of ethyl acetate with cyclohexane (30/70 by volume) as eluent, collecting fractions of 100 cm3. Fractions 4 to 10 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 5.6 g of 3-[(3,5-dichlorophenyl)-(methylsulphonyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-ol as an amorphous mass.

Example 56

Repeat the sequence of operations of example 4, based on 0.5 g of 1-benzhydryl-3-[(3-dimethylaminophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol, 0.1 cm3methanesulfonanilide and 0.5 g of 4-dimethylaminopyridine. The obtained residue chromatographic on a column of silica gel (grain size of 0.04-0.06 mm, diameter 2 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane ethanol (98/2 by volume) as eluent, collecting fractions of 20 cm3. Fractions 8 to 13 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from 8 cm3diethyl ether, receiving 0.3 g 1-benzhydryl-3-[(3-dimethylaminophenyl)(methylsulphonyl)methylene]azetidine with so pl. 176[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (250 MHz): 2,90 (6N, S, N(CH3)2), 2,95 (3H, s, S3), of 3.80 (2H, s, N2

1-Benzhydryl-3-[(3-dimethylaminophenyl)(methylsulphonyl)-methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations example 1 on the basis of 0.4 g (3-dimethylaminobenzoyl)methylsulfone, 0.4 g of 1-benzhydrylamine-3-one and 1,2 cm3a 1.6 M solution of n-utility in hexane: receive 0.5 g 1-benzhydryl-3-[(3-dimethylaminophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol in the form of a solid substance with so pl. 185C.

(3-Dimethylaminobenzoyl)methylsulfone can be obtained by repeating the sequence of operations example 2 on the basis of 1.4 g (3-dimethylaminophenyl) methyl sulfide and 5.1 g OksanaR: obtain 1.1 g (3-dimethylaminobenzoyl)methylsulfone in the form of a white solid with so pl. 195C.

(3-Dimethylaminobenzoyl)metilsulfate can be obtained by repeating the sequence of operations of example 37, on the basis of 4 g (3-jobensis)metilsulfate, 1.4 g of dimethylamine dissolved in 5 cm3of tetrahydrofuran, 2.9 g of tert-butyl sodium, 0.56 g of chloride bis(diphenylphosphino)ferienanlage and 1.3 g of 1,1' -bis(diphenylphosphino)ferrocene 35 cm3tetrahydrofuran (THF). Obtain 0.9 g (3-dimethylaminobenzoyl)metilsulfate in the form of butter.

Example 57

Repeat the sequence of operations is/sup> methanesulfonanilide and 1.4 g of 4-dimethylaminopyridine. The obtained residue chromatographic on a column of silica gel (grain size of 0.04-0.06 mm, diameter 2 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane ethanol (98/2 by volume) as eluent, collecting fractions of 20 cm3. Fractions 11 to 13 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from 15 cm3diethyl ether, receiving 0.6 g 1-benzhydryl-3-[(3-methylsulfinylphenyl)(methylsulphonyl)methylene]azetidine with so pl. 146[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 2,45 (3H, s, hS3), 2,95 (3H, s, S3), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), and 4.75 (1H, s, NCH), 7,10-7,50 (14N, m, SN arene.)].

1-Benzhydryl-3-[(3-methylsulfinylphenyl)(methylsulphonyl)-methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations example 1 on the basis of 1.1 g of methyl(3-methylsulfonylbenzoyl)sulfone and 1.2 g of 1-benzhydrylamine-3-one: obtain 1.3 g of 1-benzhydryl-3-[(3-methylsulfinylphenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol in the form of a solid substance.

Methyl(3-methylsulfonylbenzoyl)sulfon can be obtained in the following way: a mixture of 5 g (3-jobensis)matilal the temperature, close to 100With, within 1 hour, add 2.5 g mertiolate sodium and continue heating at 100C for 18 h then the reaction mixture is cooled to room temperature, absorb 700 cm3ethyl acetate and 500 cm3water. The organic phase is separated, washed 10 times 500 cm3water and 500 cm3saturated aqueous solution of sodium chloride, filtered on a Frit and evaporated to dryness under reduced pressure (2.7 kPa). The resulting residue is purified by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with a mixture of cyclohexane with ethyl acetate (70/30, then 60/40, then 50/50 by volume) as eluent, collecting fractions of 30 cm3. Fractions 26 to 30 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 1.2 g of methyl(3-methylsulfonylbenzoyl)sulfone in the form of butter.

Example 58

To a cooled to 5To a solution of 1.1 g of 1-benzhydryl-3-{[3-(tert-butyldimethylsilyloxy)phenyl](methylsulphonyl)-methylene}of azetidine 10 cm3tetrahydrofuran (THF) add 4 cm31 M solution of tetrabutylammonium fluoride in tetrahydrofuran. The mixture is stirred for 3 hours at water. The organic phase is separated, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa). The resulting residue is purified by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 2 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane ethanol (95/5) as eluent, collecting fractions of 60 cm3. Fractions 4-6 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 0.5 g of 1-benzhydryl-3-[(3-hydroxymethylene](methylsulphonyl)methylene]-azetidine in the form of a white solid with so pl. 152[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 2,95 (3H, s, S3), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), 4,50 (2H, d, J=5 Hz, OCH2), and 4.75 (1H, s, NCH), a 5.25 (1H, t, J=5 Hz, HE), 7,20 (2H, t, J=7 Hz, 2CH arene.), 7,30 (8H, m, SN arene.) was 7.45 (4H, d, J=7 Hz, SN arene.)].

1-Benzhydryl-3-{[3-(tert-butyldimethylsilyloxy)phenyl](methylsulphonyl)methylene}azetidine can be obtained by repeating the sequence of operations of example 4 on the basis of 1.6 g of 1-benzhydryl-3-{[3-(tert-butyldimethylsilyloxy)-phenyl](methylsulphonyl)methyl - (RS)}azetidin-3-ol, 0.3 cm3methanesulfonanilide and 1.4 g of 4-dimethylaminopyridine. The resulting residue is purified by chromato as eluent, collecting fractions of 60 cm3. Fractions 15 to 30 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 1.1 g of 1-benzhydryl-3-{[3-(tert-butyldimethylsilyloxy)phenyl](methylsulphonyl)methylene}of azetidine in the form of a white solid with so pl. 148C.

1-Benzhydryl-3-{[3-(tert-butyldimethylsilyloxy)phenyl](methylsulphonyl)methyl-(RS)}azetidin-3-ol can be obtained by repeating the sequence of operations example 1 from 2 g of [3-(tert-butyldimethylsilyloxy)benzyl]methylsulfone and 1.5 g of 1-benzhydrylamine-3-one: get a 1-benzhydryl-3-{[3-(tert-butyldimethylsilyloxy)phenyl](methylsulphonyl)methyl-(RS)}azetidin-3-ol as a white solid with so pl. 175C.

[3-(Tert-butyldimethylsilyloxy)benzyl]methylsulfone can be obtained in the following way: a mixture of 13.4 g of (3-hydroxymethylene)methylsulfone, 11 g of imidazole and 12 g of tert-butyldimethylsilyloxy stirred for 18 h at a temperature close to 20C. the Solution is then evaporated to dryness under reduced pressure (2.7 kPa) and the obtained residue is purified by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 5 cm, height 50 cm) at a nitrogen pressure of 0.5 is pariwat under reduced pressure (2.7 kPa), getting to 5.7 g of [3-(tert-butyldimethylsilyloxy)benzyl]methyl-sulfon in the form of a white solid with so pl. 80C.

(3-Hydroxymethylene)methylsulfone can be obtained in the following way: a mixture of 26 g of 3-(methylsulfonylmethyl)-benzoic acid and 4.6 g of lithium aluminum hydride in 600 cm3of tetrahydrofuran is stirred for 18 hours at a temperature close to 20C, cooled to 0With and consistently add 15 cm3ethyl acetate, 5 cm3water, 5 cm315% aqueous sodium hydroxide solution and 30 cm3water. The mixture is filtered through celite and absorb the filtrate 600 cm3ethyl acetate. The organic phase is washed with 500 cm3water and then 200 cm3saturated aqueous solution of sodium chloride, after which it is separated, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa) to give 10.4 g (3-hydroxymethylene)methylsulfone resin.

3-(Methylsulfonylmethyl)benzoic acid can be obtained by repeating the sequence of operations of example 10, on the basis of 23.3 g of 3-chloromethylbenzene acid and 23.3 g of methanesulfonate sodium: get 26 grams of 3-(methylsulfonylmethyl)benzoic Calidris-3-[(3-bromomethylphenyl-(methylsulphonyl)methylene]azetidine 8 cm3of dimethylformamide added, keeping the temperature below 30With, of 0.13 g mertiolate sodium, stirred the mixture at a temperature close to 20With, and absorb 30 cm3ethyl acetate and 50 cm3water. The organic phase is separated and washed with 3 times 50 cm3water, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa). The resulting residue is purified by chromatographytandem on a column of silica gel (grain size of 0.04-0.06 mm, diameter 2 cm, height 28 cm) at a nitrogen pressure of 0.5 bar with a mixture of cyclohexane with ethyl acetate (90/10 by volume) as eluent, collecting fractions of 50 cm3. Fractions 8 to 14 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 0.3 g of 1-benzhydryl-3-{[3-(methylsulfanyl)phenyl](methylsulphonyl)methylene}of azetidine in the form of a white solid with so pl. 150[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 1,95 (3H, s, S3), 2,95 (3H, s, S3in ), 3.75 (2H, s, SCH2), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), and 4.75 (1H, s, NCH), 7,20 (2H, t, J=7 Hz, CH arene.), 7,30 (8H, d, J=7 Hz, SN arene.), was 7.45 (4H, d, J=7 Hz, SN arene.)].

1-Benzhydryl-3-[(3-bromomethylphenyl)(methylsulphonyl)methylene]azetidine can be p the and 10 cm3dichloromethane at a temperature close to 20To add to 0.23 cm3trichromate phosphorus and then one drop of pyridine. Continue stirring at the same temperature for 18 h and absorb the reaction mixture is 20 cm3water and 10 cm3saturated aqueous solution of sodium chloride. The organic phase is separated, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa) to give 1 g of 1-benzhydryl-3-[(3-bromomethylphenyl)(methylsulphonyl)methylene]azetidine in the form of an amorphous mass that is used for the subsequent syntheses without further purification.

Example 60

Repeating the sequence of operations of example 4, on the basis of 6.6 g of 1-benzhydryl-3-[(methylsulphonyl)(China-8-yl)methyl-(RS)]azetidin-3-ol, 1,7 cm3methanesulfonanilide and 5.2 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 6.5 cm, height 35 cm) at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane with methanol (95/5 by volume) as eluent, collecting fractions of 100 cm3. Fractions 7-15 combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from 1002[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (250 MHz): 3.15 in (3H, s, S3), 3,55 (2H, user., NCH2), 4,30 (2H, s, NCH2), 4,70 (1H, s, NCH), 7,18 (2H, t, J=7 Hz, 2CH arene.), of 7.25 (4H, t, J=7 Hz, SN arene.), the 7.43 (4H, d, J=7 Hz, SN arene.), a 7.62 (2H, m, 2CH chinoline.), of 7.75 (1H, DD, J=2 and 7 Hz, CH chinoline.), with 8.05 (1H, DD, J=2 and 7 Hz, CH chinoline.), 8,43 (1H, DD, J=2 and 8 Hz, CH chinoline.), of 9.00 (1H, DD, J=2 and 5 Hz, CH chinoline.)].

1-Benzhydryl-3-[(methylsulphonyl)(China-8-yl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations example 1 on the basis of 5.5 g of methyl(China-8-ylmethyl)sulfone, 5.9 g of 1-benzhydrylamine-3-one and 18.8 cm3a 1.6 M solution of n-utility in hexane: obtain 6.6 g of 1-benzhydryl-3-[(methylsulphonyl)(China-8-yl)methyl-(RS)]azetidin-3-ol in the form of a solid beige color.

Methyl(China-8-ylmethyl)sulfon can be obtained by repeating the sequence of operations of example 10 of 4.5 g of 8-chloromethylpyridine and 4.4 g of methanesulfonate sodium: obtain 5.7 g of methyl(China-8-ylmethyl)sulfone in the form of a solid beige color.

8-Chlormethine can be obtained as follows: to a solution of 7.1 g of 8-methylinosine 250 cm3carbon tetrachloride was added when the temperature close to 20With 6.7 g of N-chlorosuccinimide cooled to 20C, and then filtered on a porous filter. The filtrate, evaporated to dryness under reduced pressure (2.7 kPa). The resulting residue is purified by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 5.5 cm, height 32 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting fractions of 40 cm3. Fractions 21-40 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 4.5 g of 8-chloromethylpyridine in the form of oils used for further syntheses without further purification.

Example 61

Repeating the sequence of operations of example 4, on the basis of 6.2 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol, 1,4 cm3methanesulfonanilide and 6.1 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4 cm, height 60 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting fractions of 100 cm3. Fractions 4-7 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from 25 cm3diethyl ether, gaining 0.7 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulphonyl)methylene]azetidine with so pl. 178

1-[Bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations of example 1 from 5.5 g (3-cyanophenyl)methylsulfone and 6.1 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 13.8 cm3a 1.6 M solution of n-utility in hexane: obtain 6.3 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol as an amorphous mass.

Example 62

A mixture of 4.5 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl) (methylsulphonyl)methylene]azetidine 50 cm3acetic acid and 50 cm3concentrated hydrochloric acid (d=l,18) is heated for 20 h at 50C, cooled to room temperature and evaporated to dryness under reduced pressure (2.7 kPa). The oil obtained absorb 100 cm3ethanol, and the solution was evaporated to dryness under reduced pressure (2.7 kPa). The remainder periostat of 60 cm3diethyl ether. The obtained solid is purified by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 2.5 cm, height 40 cm) at a nitrogen pressure of 0.5 bar with sup>3. Faction 35-46 combined and evaporated to dryness under reduced pressure (2.7 kPa). The solid is crystallized from 15 cm3ethyl acetate, receiving 0.2 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-carbamoylphenoxy)(methylsulphonyl)methylene]azetidine in the form of a solid substance with so pl. 192[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 2,95 (3H, s, SCH3), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), 4,80 (1H, s, NCH), 7,35 (4H, d, J=7 Hz, SN arene.), was 7.45 (5H, d, J=7 Hz, SN arene. and1/2CONH2), to 7.50 (2H, m, 2CH arene.), the 7.85 (2H, m, 2CH arene.)].

Example 63

Repeating the sequence of operations example 1 on the basis of 0.8 g of 1-benzhydryl-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)phenyl](methylsulphonyl)methyl-(RS)}azetidin-3-ol, 0.2 cm3methanesulfonanilide and 0.7 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 2 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane ethanol (98/2 by volume) as eluent, collecting fractions of 20 cm3. Fractions 4 to 8 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is recrystallized from 10 cm3ethyl acetate, receiving 0.5 g 1-benched the VA so pl. 161[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 1,30 (N, with, (CH3)3), 2,95 (3H, s, SCH3) and 3.15 (3H, s, N3in ), 3.75 (2H, c, SCH2), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), and 4.75 (1H, s, NCH), 7,15-7,50 (14N, m, SN arene.)].

1-Benzhydryl 3-{[3-(N-tert-butyloxycarbonyl-N-methyl - amino)phenyl](methylsulphonyl)methyl-(RS)}azetidin-3-ol can be obtained by repeating the sequence of operations of example 1 from 1.6 g of [3-(N-tert-butyloxycarbonyl-N-methylamino)benzyl]methylsulfone, 1.3 g of 1-benzhydrylamine-3-one and 3.8 cm3a 1.6 M solution of n-utility in hexane: obtain 0.8 g of 1-benzhydryl 3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)-phenyl](methylsulphonyl)methyl-(RS)}azetidin-3-ol as a white solid.

[3-(Tert-butyloxycarbonyl-N-methylamino)benzyl]methylsulfone can be obtained as follows: to a cooled to 0To a solution of methyl(3-methylaminomethyl)sulfone in 30 cm3dioxane is added 2.5 g of di-tert-BUTYLCARBAMATE 40 cm3dioxane. Continue stirring at room temperature for 18 h and absorb the reaction mixture is 75 cm3dichloromethane. The organic phase after washing with 75 cm3water and then 75 cm3busy in the offer under reduced pressure (2.7 kPa). The resulting residue is purified by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 2 cm, height 35 cm) at a nitrogen pressure of 0.5 bar with a mixture of cyclohexane with ethyl acetate (50/50 by volume) as eluent, collecting fractions of 20 cm3. Fractions 5-10 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 1.8 g of [3-(N-tert-butyloxycarbonyl-N-methylamino)benzyl]methylsulfone in the form of a colorless oil.

Methyl (3-methylaminomethyl)sulfon can be obtained in the following way: a mixture of 9.7 cm3formic acid (d=1.22 respectively) and 19,6 cm3acetic anhydride (d=1,08) is heated for 3 hours at 50With, and then lowered to room temperature, add 40 cm3of tetrahydrofuran, cooled the mixture to -20With and add then 14.8 g (3-aminobenzyl)methylsulfone and 200 cm3tetrahydrofuran (THF). Stir the mixture for 2 hours at -20And then 48 h at room temperature, then filtered on a Frit. The precipitate washed three times with 50 cm3diisopropyl ether and dried. The filtrate is evaporated to half volume (2.7 kPa), the precipitate is filtered off on a Frit, washed three times its 30 cm3Laidout to 0With add 100 cm32 M solution of dimethyl sulfide borane in tetrahydrofuran, refluxed for 3 h, cooled to 5With and added within 20 min 60 cm3of methanol. Stirred for 1 hour at room temperature, then the solution will verbatimout stream of hydrogen chloride for 5 minutes then the reaction medium is refluxed for 1 hour, cooled to room temperature and absorb 300 cm3water. The solution is alkalinized 3 N. NaOH and then with an aqueous solution of sodium bicarbonate. The organic phase is twice extracted with 250 cm3ethyl acetate, washed with 300 cm3an aqueous solution of saturated sodium bicarbonate and 2 more times on 300 cm3. The mixture is evaporated to dryness under reduced pressure (2.7 kPa), the resulting oil absorb 100 cm34 N. hydrochloric acid, then 100 cm3ethyl acetate. The aqueous phase is alkalinized 120 cm33 N. NaOH, then with an aqueous solution of sodium bicarbonate. The organic phase is twice extracted with 75 cm3ethyl acetate, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa) to give 9 g of methyl(3-methylaminomethyl)sulfone in the form of pink is m refrigerator 15 minutes a mixture of 23.7 g of methyl(3-nitrobenzyl)sulfone, 65 cm3hydrochloric acid (d=1,18) and 150 cm3of methanol. Within 10 min type of 18.5 g of iron, the mixture is refluxed for 4 h and left it on 18 hours at room temperature. Then the reaction mixture was alkalinized with an aqueous solution of ammonia and then with an aqueous solution of sodium bicarbonate. The organic phase is shaken out three times with 250 cm3ethyl acetate, dried over magnesium sulfate, filtered on a Frit and evaporated to dryness under reduced pressure (2.7 kPa) to give 14.9 g (3-aminobenzyl)methylsulfone in a solid beige color used for the subsequent syntheses without further purification.

Example 64

A mixture of 0.3 g of 1-benzhydryl 3-{[3-N-tert-Butylochka-carbonyl-N-methylamino)phenyl](methylsulphonyl)methylene}of azetidine, 4 cm34,7 n solution of hydrogen chloride in dioxane and 4 cm3dioxane is stirred 18 h at room temperature and evaporated to dryness under reduced pressure (2.7 kPa). The remainder absorb 100 cm3water and 20 cm3diethyl ether. The aqueous phase is alkalinized 30 cm3an aqueous solution of sodium bicarbonate. The organic phase is twice extracted with 40 cm3water, washed twice 30 cm3water, separated, dried over without of 20 cm3diethyl ether, receiving 0.16 g of 1-benzhydryl 3-[(3-methylaminophenol)(methylsulphonyl)methylene]azetidine in the form of a solid substance with so pl. 161[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (250 MHz): to 2.65 (3H, d, J=5 Hz, N3), 2,95 (3H, s, SCH3), of 3.80 (2H, s, N2), 4,20 (2H, s, NCH2), and 4.75 (1H, s, NCH), 5,80 (1H, q, J=5 Hz, NH), 6,60 (3H, m, SN arene.), to 7.15 (1H, t, J=7 Hz, CH arene.), 7,22 (2H, t, J=7 Hz, CH arene.), 7,30 (4H, t, J=7 Hz, SN arene.), of 7.48 (4H, d, J=7 Hz, SN arene.)].

Example 65

Repeating the sequence of operations of example 4, on the basis of 11.3 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulphonyl}methyl-(RS)]azetidin-3-ol, 2,6 cm3methanesulfonanilide and 10.9 g of 4-dimethylaminopyridine, after recrystallization from 20 cm3diethyl ether to obtain 5 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulphonyl)methylene]azetidine with so pl. 181[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 2,95 (3H, s, SCH3), of 3.77 (3H, s, och3), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), 4,80 (1H, s, NCH), to 6.95 (3H, m, SN arene.), to 7.35 (5H, m, SN arene.), was 7.45 (4H, d, J=7 Hz, SN arene.)].

1-[Bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulphonyl) methyl-(RS)]azetidin-3-ol can be obtained by repeating the follower is3a 1.6 M solution of n-utility in hexane: obtain 11.4 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol as a white solid with so pl. 130C.

Example 66

Repeating the sequence of operations of example 32, from 4.8 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulphonyl)methylene]azetidine and 32 cm31 M solution trichromate boron in dichloromethane, get the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane ethanol (98/2 by volume) as eluent, collecting fractions of 20 cm3. Fractions 16 and 17 are combined and evaporated to dryness under reduced pressure (2.7 kPa). After recrystallization from 5 cm3diethyl ether obtain 0.1 g of 1-[bis(chlorophenyl)methyl]-3-[(3-hydroxyphenyl) (methylsulphonyl)methylene]azetidine in the form of a solid substance with so pl. 114[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (250 MHz): 2,92 (3H, s, SCH3), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), 4,80 (1H, s, NCH2), to 6.80 (3H, m, SN arene.), then 7.20 (1H, t, J=7 Hz, CH arene.), 7,37 (4H, t, J=7 Hz, SN arene.), 7,47 (4H, d, J=7 Hz, SN arene.)].

Example 67

P is originalfor)methyl-(RS)]azetidin-3-ol, 0.1 cm3methanesulfonanilide and 0.5 g of 4-dimethylaminopyridine. The obtained residue chromatographic on a column of silica gel (grain size of 0.04-0.06 mm, diameter 2 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane ethanol (98,5/a 1.5 by volume) as eluent, collecting fractions of 10 cm3. Fraction 4 evaporated to dryness under reduced pressure (2.7 kPa). After recrystallization from 5 cm3diethyl ether, to obtain 0.5 g of 1-[bis(4-chlorophenyl)methyl]-3-[(methylsulphonyl)(3-pyrrolidinyloxy)methylene]azetidine in the form of a solid substance with so pl. 133[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (400 MHz): 2,00 (4H, m, 2CH2), 2,95 (3H, s, SCH3), 3,20 (4H, m, 2NCH2), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), 4,80 (1H, s, NCH), of 6.50 (1H, s, CH arene.), 6,60 (1H, d, J=7 Hz, CH arene.), of 6.65 (1H, d, J=7 Hz, CH arene.), then 7.20 (1H, t, J=7 Hz., CH arene.), 7,40 (4H, d, J=7 Hz, SN arene.), to 7.50 (4H, d, J=7 Hz, SN arene.)].

1-[Bis(4-chlorophenyl)methyl]-3-[(methylsulphonyl)(3 pyrrolidin-milfoil)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations example 1 on the basis of 0.5 g of methyl(3-pyrrolidinyl)sulfone, 0.6 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 1.4 cm3a 1.6 M solution of n-utility in hexane: obtain 0.6 g of 1-[bis(4-Chlo color.

Example 68

Repeat the sequence of operations of example 58, from a 5.1 g of 1-[bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxy) phenyl](methylsulphonyl)methylene}of azetidine and 17 cm31 M solution of tetrabutylammonium chloride in tetrahydrofuran, get the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 2 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane ethanol (97/3 by volume) as eluent, collecting fractions of 100 cm3. Fractions 10 to 14 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained yellow solid absorb 2 cm 4 dichloromethane and 10 cm3ethyl acetate, and then filtered on a Frit and washed with 2 cm3ethyl acetate, obtaining 1.6 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxymethylene)(methylsulphonyl)methylene]azetidine in the form of a white solid with so pl. 214[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (400 MHz): 2,95 (3H, s, SCH3), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), 4,50 (2H, J=5 Hz, och3), 4,80 (1H, s, NCH), a 5.25 (1H, t, J=5 Hz, HE), 7,30 (1H, d, J=7 Hz, CH arene.), 7,35-7,45 (7H, m, SN arene.), to 7.50 (4H, d, J=7 Hz, SN arene.)].

1-[Bis(4-chlorophenyl)methyl]-3-{[3(tert-butylimide is piracy of example 4, on the basis of 10.8 g of 1-[bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxy)phenyl](methylsulphonyl)methyl-(RS)}azetidin-3-ol, 2 cm3methanesulfonanilide and 8.5 g of 4-dimethylaminopyridine. The resulting residue is purified by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4 cm, height 40 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting fractions of 100 cm3. Faction 12-29 combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 5.2 g of 1-[bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxy)phenyl](methylsulphonyl)methylene}of azetidine resin.

1-[Bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxy)phenyl](methylsulphonyl)methyl-(RS)}azetidin-3-ol can be obtained by repeating the sequence of operations of example 1 of 5.8 g of [3-(tert-butyldimethylsilyloxy)benzyl]methylsulfone and 5.6 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one: obtain 10.8 g of 1-[bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxy)phenyl](methylsulphonyl)methyl-(RS)}azetidin-3-ol in the form of resin.

Example 69

A mixture of 0.45 g of 1-[bis(4-chlorophenyl)methyl]-3-{(methylsulphonyl)[3-(pentafluorobenzoyl)phenyl]methylene}of azetidine, 0,07 cm31-aminopiperidine 4 cm3dimethylether is GDI washed with 50 cm3water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa) to give 0.2 g of 1-[bis(4-chlorophenyl)methyl]-3-{(methylsulphonyl)[3-(N-piperidinylcarbonyl)phenyl]methylene}of azetidine with so pl. 175[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (400 MHz): 1,40 (2H, m, CH2), to 1.60 (4H, m, 2CH3), 2,85 (4H, m, 2NCH2), to 3.00 (3H, s, SCH3), of 3.80 (2H, S, NCH2), 4,20 (2H, s, NCH2), 4,80 (1H, s, N), 7,45-OF 7.60 (10H, m, SN arene.), of 7.75 (2H, m, 2CH arene.), to 9.45 (1H, s, NH)].

1-[Bis(4-chlorophenyl)methyl]-3-{(methylsulphonyl)[3-(pentafluorobenzoyl)phenyl]methylene}azetidin can be obtained by repeating the sequence of operations of example 29 from 2.6 g of the hydrochloride of 1-[bis(4-chlorophenyl)methyl]-3-[(3-carboxyla-nil)(methylsulphonyl)methylene]azetidine, 0.9 g of pentafluorophenol, 0.9 g of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 25 cm3of dimethylformamide. The resulting residue is purified by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 2 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane ethanol (99/1 by volume) as eluent, collecting fractions of 30 cm3. Fractions 7-12 are combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving 0,9 the Oh mass.

1-[Bis(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)(methylsulphonyl)methylene]azetidine can be obtained as follows: to a cooled to 5With a mixture of 0.5 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxymethylene)(methylsulphonyl)-methylene]azetidine 9 cm3acetone add 2 cm3the Jones reagent. Stirred at the same temperature for another 2 hours and add 50 cm3a mixture of ice water and 50 cm3ethyl acetate. The organic phase is separated, washed with 50 cm3saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The resulting residue is purified by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane with ethanol as eluent, collecting fractions of 60 cm3. Fractions 12 to 14 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized from 10 cm3diethyl ether, receiving 32 mg of 1-[bis(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)-(methylsulphonyl)methylene]azetidine in the form of a solid substance with so pl. 205[NMR Spectrum in DMSO-d6, T=300 K,1H, d, J=7 Hz, CH arene.), 7,42 (4H, d, J=7 Hz, SN arene.), 7,49 (1H, t, J=7 Hz, CH arene.), EUR 7.57 (1H, d, J=7 Hz, CH arene.), of 7.90 (2H, s, CH arene. and NH+)].

Example 70

Repeating the sequence of operations of example 4, on the basis of 0.8 g of 1-[bis(4-chlorophenyl)methyl]-3-[(methylsulphonyl)(3-triftormetilfullerenov)methyl-(RS)]azetidin-3-ol, 0,24 cm3methanesulfonanilide and 0.7 g of 4-dimethylaminopyridine receive the remainder, which is cleaned by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 2 cm, height 18 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting fractions of 50 cm3. Fractions 12-17 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is again purified by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 2 cm, height 20 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting fractions of 30 cm3. Fractions 15 to 28 are combined and evaporated to dryness under reduced pressure (2.7 kPa). Obtain 0.25 g of 1-[bis(4-chlorophenyl)methyl]-3-[(methylsulphonyl)(3-triftormetilfullerenov)methylene]azetidine with so pl. 70[NMR Spectrum in DMSO-d6 + CD3CO2D, T=300 K,in M. D. (300 MHz): 3,00 (3H, s, SCH3), 3,80 (N,75 (2H, m, 2CH arene.)].

1-[Bis(4-chlorophenyl)methyl]-3-[(methylsulphonyl)(3-three-formatterconverter)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations example 1 from 2 g of methyl(3-triftormetilfullerenov)sulfone, 2.3 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 5,5 cm3a 1.6 M solution of n-utility in hexane: obtain 0.9 g of 1-[bis(4-chlorophenyl)methyl]-3-[(methylsulphonyl)(3-triftormetilfullerenov)methyl-(RS)]azetidin-3-ol as a white solid.

Methyl(3-triftormetilfullerenov)sulfone can be obtained by repeating the sequence of operations of example 10 from 5 g of 3-triftormetilfullerenov and 3.2 g of methanesulfonate sodium: gain of 5.2 g of methyl(3-triftormetilfullerenov)sulfone as a white solid with so pl. 125C.

Example 71

Repeating the sequence of operations of example 38 (method 1), according to 0.72 g of 1-[bis(4-forfinal)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol, 0,18 cm3methanesulfonanilide and 0.66 g of 4-dimethylaminopyridine, after chromatography was carried out on a column of silica gel (grain size of 0.04-0.06 mm, diameter 2.5 cm, height 15 cm) at a pressure of 1 bar argon with a mixture of ethyl acetate with cyclohexane (15/85 Porvenir)(methylsulphonyl)methylene]azetidine in the form of a white amorphous mass [NMR Spectrum in DMSO-d6, T=300 K,in M. D. (250 MHz): 3,05 (3H, s, SCH3), 3,90 (2H, s, NCH2), 4,20 (2H, s, NCH2), 4,80 (1H, s, NCH), 7,15 (6N, m, SN arene.), to 7.35 (1H, t, J=8 Hz, CH arene.), to 7.50 (4H, DD, J=6 and 8 Hz, SN arene.)].

1-[Bis(4-forfinal)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol may be obtained using the sequence of operations of example 39 from 2.25 g of bis(4-forfinal)brometane, 1.1 g of potassium carbonate and 2.5 g of the hydrochloride of 3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol. After chromatography was carried out on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4.4 cm, height 25 cm) at a pressure of argon 0,9 bar with a mixture of ethyl acetate with cyclohexane (2/8 by volume) as eluent collected fractions of 60 cm3that faction 23-39 combined and evaporated to dryness under reduced pressure (2.7 kPa), getting to 0.72 g of 1-[bis(4-forfinal)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol as a white solid.

Bis(4-forfinal)bromatan can be obtained using the procedure described BACHMANN, W. E., J. Am. Chem. Soc., 2135 (1933), 4 g of 4,4’-diferensial, 2,70 cm3acetylamino and 14 cm333% solution of Hydrobromic acid in acetic acid.

Example 72

The surface is(methylsulphonyl)methyl-(RS)]azetidin-3-ol, 0,29 cm3methanesulfonanilide and 1.1 g of 4-dimethylamino-pyridine, after chromatography was carried out on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 23 cm) at a pressure of 1 bar argon with a mixture of ethyl acetate with cyclohexane (15/85 by volume) as eluent collected fractions of 60 cm3and get 0,117 g of 1-[bis(2-forfinal)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine in the form of a white amorphous mass [NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 3,05 (3H, s, SCH3), of 3.95 (2H, s, NCH2), 4,25 (2H, s, NCH2), to 5.35 (1H, s, NCH), 7,20 (6N, m, SN arene.), to 7.35 (3H, m, SN arene.), at 7.55 (2H, m, 2CH arene.)].

1-[Bis(2-forfinal)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol may be obtained using the sequence of operations of example 39, from 2 g of bis(2-forfinal)brometane, 1.0 g of potassium carbonate and 2,22 g of the hydrochloride of 3-[(3,5-differenl)-(methylsulphonyl)methyl-(RS)]azetidin-3-ol. After chromatography was carried out on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 17 cm) at a pressure of 1 bar argon with a mixture of ethyl acetate with cyclohexane (2/8 by volume) as eluent collected fractions of 60 cm3, fractions 6-10 are combined and evaporated to dryness under reduced daleyjonathan solid.

Bis(2-forfinal)bromatan can be obtained using the procedure described NN W. E., J. Am. Chem. Soc., 2135 (1933), of 1.80 g of 4,4’-diferensial, 1,22 cm3acetylamino and 6.5 cm333% solution of Hydrobromic acid in acetic acid.

4,4’-Diferensial can be obtained as follows: to a cooled to -70With under argon to a solution of 8.8 g of 2-bromptonville 100 cm3the tetrahydrofuran is poured dropwise 32 cm3a 1.6 M solution of n-utility in hexane. After stirring for 10 min at -70With slowly added 2.1 cm3ethylformate, then stirred the mixture for 30 min at -70With the raise the temperature to 0C and add 50 cm3the ethyl acetate and 100 cm3saturated aqueous solution of ammonium chloride. After stirring the organic phase is separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa) and a temperature of 55With getting 3,63 g of 2,2’-diferensial in the form of a yellow oil.

Example 73

Repeating the sequence of operations of example 38 (method 1), according to 1.15 g of 1-[bis(3-forfinal)methyl]-3-[iloperidone, after chromatography was carried out on a column of silica gel (grain size of 0.06-0,200 mm, diameter 2.8 cm, height 15 cm) at a pressure of 1 bar argon with a mixture of ethyl acetate with cyclohexane (15/85 by volume) as eluent, collecting fractions of 60 cm3and obtain 0.55 g of 1-[bis(4-forfinal)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine in the form of a white solid with so pl. 178[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (250 MHz): 3,05 (3H, s, SCH3), of 3.95 (2H, s, NCH2), 4,25 (2H, s, N2), 4,80 (1H, s, NCH), 7,10 (2H, m, 2CH arene.), then 7.20 (2H, m, 2CH arene.), 7,30-to 7.50 (7H, m, SN arene.)].

1-[Bis(3-forfinal)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol may be obtained using the sequence of operations example 1 from 1.2 g (3.5 differentil)methylsulfone and 1.5 g of 1-[bis(3-forfinal)methyl]azetidin-3-one. After purification by chromatography on a column of silica gel (grain size of 0.06-0,200 mm, diameter 3.2 cm, height 30 cm) at a pressure of 1 bar argon with a mixture of ethyl acetate with cyclohexane (2/8 by volume) as eluent, collecting fractions of 60 cm3and gain of 1.95 g of 1-[bis(3-forfinal)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol as a white solid with so pl. is coherence operations, described by KATRITZKY A. R. et al. in J. Heterocycl. Chem., 271 (1994), 4.9 g of [bis (3-forfinal)methyl]amine and 1,78 cm3of epichlorohydrin.

[Bis(3-forfinal)methyl]amine can be obtained as follows: to a suspension of 1.27 g of lithium aluminum hydride in 80 cm3the tetrahydrofuran is poured for 30 min in argon atmosphere a solution of 5.17 g of the oxime of 3,3’-deformazione 30 cm3tetrahydrofuran (THF). After boiling under reflux for 5 h under stirring successively added 1.3 cm3water, 1.3 cm34 n sodium hydroxide solution, 2.6 cm3water and then 50 cm3ethyl acetate. After drying on magnesium sulfate and evaporation to dryness under reduced pressure (2.7 kPa) to obtain 4.9 g of [bis(3-forfinal)methyl]amine as a yellow oil.

The oxime of 3,3’-deformazione can be obtained using the following sequence of operations: to a solution of 5.0 g of 3,3’-deformazione 10 cm3ethanol is poured dropwise a solution of 1.6 g of hydroxylaminopurine 8 cm3water, then add small portions of 1.2 g of pellets of sodium hydroxide. After boiling for 10 min, the reaction mixture is cooled to 20And then acidified with 7.5 cm34 N. hydrochloric acid. The resulting oil and dried at 35C and reduced pressure (2.7 kPa), receiving of 5.17 g of the oxime of 3,3’-deformazione in the form of a white solid.

Example 74

Repeating the sequence of operations of example 1 and according to 1.30 g of 1-[(4-chlorophenyl)(thiazol-2-yl)methyl-(RS)]-3-[(methylsulphonyl)(phenyl)methyl-(RS)]azetidin-3-ol, 0,35 cm3methanesulfonanilide and 1.22 g of 4-dimethylaminopyridine, after chromatography was carried out on a column of silica gel (grain size of 0.06-0,200 mm, diameter 2.4 cm, height 25 cm) at a nitrogen pressure of 1 bar with a mixture of ethyl acetate with cyclohexane (1/1 by volume) and collecting fractions of 30 cm3obtain 0.7 g of (RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulphonyl)(phenyl)methylene]azetidine in the form of a pinkish solid [NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 2,95 (3H, s, SCH3), of 3.95 (2H, m, NCH2), 4,35 (2H, m, NCH2in ), 5.25 (1H, s, NCH), 7,45 (N, m, SN arene.), the 7.65 (1H, d, J=2 Hz, CH of thiazole), of 7.70 (1H, d, J=2 Hz, CH of thiazole)].

A mixture of diastereoisomers 1-[(4-chlorophenyl)(thiazol-2-yl)methyl - (RS)]-3-[(methylsulphonyl)(phenyl)methyl - (RS)]azetidin-3-ol may be obtained using the sequence of operations of example 39 from 4,47 g of (RS)-bromo(4-chlorophenyl)(thiazol-2-yl)methane and or 4.31 g of the hydrochloride of 3-[(methylsulphonyl)(phenyl)methyl-(RS)]azetidin-3-ol after chromatography bar with a mixture of ethyl acetate with cyclohexane (25/75 by volume) to fraction 35 and then with pure ethyl acetate as eluents to collecting fractions of 60 cm3that faction 38-40 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 1.3 g of a mixture of diastereoisomers 1-[(4-chlorophenyl)(thiazol-2-yl)methyl-(RS)]-3-[(methylsulphonyl)(phenyl)methyl-(RS)]azetidin-3-ol in the form of a whitish solid.

(RS)-Bromo(4-chlorophenyl)(thiazol-2-yl)methane can be obtained using the procedure described NN W. E., J. Am. Chem. Sc., 2135 (1933) of 3.5 g of (RS)-(4-chlorophenyl)(2-thiazolyl)methanol, 3,81 g acetylamino and 12.0 cm333% solution of Hydrobromic acid in acetic acid.

(RS)-(4-Chlorophenyl)(2-thiazolyl)methanol can be obtained in accordance with the sequence of operations described EVAN G. BOSWELL et al., J. Heterocyclic Chem., 32, 1801 (1955), based on 4,22 g of 4-chlorobenzaldehyde and to 4.92 g of 2-bromothiazole.

Example 75

Repeating the sequence of operations of example 1, on the basis of 0.52 g of a mixture of diastereoisomers 1-[(4-chlorophenyl)(Tien-2-yl)methyl-(RS)]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol, of 0.14 cm3methanesulfonanilide and 0.49 g of 4-dimethylaminopyridine, after chromatography was carried out on a column of silica gel (grain size of 0.06-0,200 mm, diameter 2.4 cm, height 20 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (20/80 by volume) as eluent and collecting tile]azetidine in the form of a white solid with so pl. 176[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 2,98 (3H, s, SCH3), 3,90 (2H, m, NCH2), 4,20 (2H, s, NCH2), to 5.03 (1H, s, NCH), 6,85 (1H, DD, J=3 and 5 Hz, CH thiophene), was 7.08 (3H, m, 2CH arene. and 1 CH thiophene), 7,22 (1H, t, J=8 Hz, CH arene), 7,32 (3H, m, 2CH arene. and 1 CH thiophene), 7,40 (2H, d, J=7 Hz, 2CH arene.)].

A mixture of diastereoisomers 1-[(4-chlorophenyl)(Tien-2-yl)methyl - (RS)]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol may be obtained using the sequence of operations example 1 on the basis of 1,60 cm3a 1.6 M solution of n-utility in hexane, 0,83 g (3,5-diferensial)methylsulfone and 1.06 g of 1-[(4-chlorophenyl)(Tien-2-yl)methyl-(RS)]azetidin-3-one, after purification on a column of silica gel (grain size of 0.06-0,200 mm, diameter 2.8 cm, height 30 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (25/75 by volume) as eluent and collecting fractions of 40 cm3obtain 0.55 g of a mixture of diastereoisomers 1-[(4-chlorophenyl)(Tien-2-yl)methyl-(RS)]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol in the form of a whitish solid.

1-[(4-Chlorophenyl)(Tien-2-yl)methyl-(RS)]azetidin-3-one can be obtained as follows: to a cooled to -70With the solution of 1.83 cm3octaoxide, stirred for 30 min at -60With, poured over 20 min a solution of 5.2 g of 1-[(4-chlorophenyl)(Tien-2-yl)methyl-(RS)]azetidin-3-ol in 80 cm3dichloromethane, stirred mixture of 3 hours at a temperature of from -60 to -70With and add 9,12 cm3of triethylamine. Then leave the mixture to a spontaneous rise to room temperature and diluted with water. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The remainder chromatographic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 4 cm, height 36 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (1/9 by volume) as eluent, collecting fractions of 60 cm3. Gain of 3.3 g of 1-[(4-chlorophenyl)(Tien-2-yl)methyl-(RS)]azetidin-3-one as a yellow oil that crystallized at room temperature.

1-[(4-Chlorophenyl)(Tien-2-yl)methyl-(RS)]azetidin-3-ol may be obtained in the following way: to a solution of 11.0 g of 1-[(4-chlorophenyl)(Tien-2-yl)methyl-(RS)]amine in 80 cm3ethanol add 4.12 g of sodium bicarbonate, heating the mixture to 65And add a 4.03 g of epichlorohydrin. After stirring for 20 h at 65With the mixture of the cooling gap is the PMC with silica gel (grain size of 0.06-0,200 mm, the diameter of 3.6 cm, height 32 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (25/75 by volume) as eluent, collecting fractions of 60 cm3. Obtain 6.3 g of 1-[(4-chlorophenyl)(Tien-2-yl)methyl-(RS)]azetidin-3-ol as a pale yellow oil.

1-[(4-Chlorophenyl)(Tien-2-yl)methyl-(RS)]amine can be obtained as follows: to a cooled to 10From a suspension of 4-chlorpheniramine (prepared from 19,15 g of 4-bromchlorenone and 2.43 g of magnesium) in 120 cm3anhydrous diethyl ether is slowly poured a solution of 10.92 g of 2-thiophenecarbonitrile 80 cm3diethyl ether. After boiling under reflux for 1 hour the mixture is cooled to 10C, slowly add 40 cm3methanol and filtered the mixture through a super-Sol. Then for 15 min add in an argon atmosphere small portions of 4.54 g of sodium borohydride and stirred the reaction mixture for 20 h at 20C. the resulting mixture was diluted with ethyl acetate and washed with water. The organic phase is dried over magnesium sulfate and evaporated to dryness at 50C and reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (grain size of 0.06 as eluent, collecting fractions of 100 cm3. One stripped off to dryness of fractions 6-12 give 13 g of the imine as a yellow oil. The latter absorb 100 cm3methanol is added to the resulting solution of 2.4 g of sodium borohydride and stirred for 1 h at 5C. the resulting mixture was diluted with ethyl acetate and washed with water. The organic phase is dried over magnesium sulfate and evaporated to dryness at 50C and reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 3.2 cm, height 40 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (4/6 by volume) as eluent, collecting fractions of 60 cm3. Gain of 11.0 g of 1-[(4-chlorophenyl)(Tien-2-yl)methyl-(RS)]amine as a yellow oil.

Example 76

Repeating the sequence of operations of example 75, from 1.66 g of a mixture of two chiral diastereoisomers 1-[(4-chlorophenyl)(Tien-2-yl)methyl-(R*)]-3-[(3,5-differenl)-(methylsulphonyl)methyl-(R*)]azetidin-3-ol and 1-[(4-chlorophenyl)-(Tien-2-yl)methyl-(R*)]-3-[(3,5-differenl)(methylsulphonyl)-methyl-(S*)]azetidin-3-ol, 50 cm3dichloromethane, 0,45 cm3methanesulfonanilide and 1.64 g of 4-dimethylaminopyridine, obtain 0.6 g (+)-1-[(4-)(-2-)]-3-[(3,5-232d/chr/945.gif">]20D=+3,2(C=0.5% in dichloromethane).

A mixture of two chiral diastereoisomers 1-[(4-chlorophenyl)(Tien-2-yl)methyl-(R*)]-3-[(3,5-differenl)(methylsulphonyl)methyl-(R*)]azetidin-3-ol and 1-[(4-chlorophenyl)(Tien-2-yl)methyl(R*)]-3-[(3,5-differenl)(methylsulphonyl)methyl-(S*)]azetidin-3-ol may be obtained as described in example 75 from 1.06 g(+)-1-[(4-chlorophenyl)(Tien-2-yl)methyl]azetidin-3-it, of 0.82 g (3,5-diferensial)-methylsulfone, 2.5 cm3a 1.6 n solution of n-utility in hexane and 25 cm3tetrahydrofuran (THF). After purification by chromatography obtain 1.7 g of a mixture of two chiral diastereoisomers 1-[(4-chlorophenyl)(Tien-2-yl)methyl-(R*)]-3-[(3,5-differenl)(methylsulphonyl)methyl-(R*)]azetidin-3-ol and 1-[(4-chlorophenyl)(Tien-2-yl)methyl(R*)]-3-[(3,5-differenl)(methylsulphonyl)methyl-(S*)]azetidin-3-ol as a white solid.

(+)-1-[(4-Chlorophenyl)(Tien-2-yl)methyl]azetidin-3-one may be obtained as described in example 75 from 12.4 g(+)-1-[(4-chlorophenyl)(Tien-2-yl)methyl]azetidin-3-ol, 220 cm3dichloromethane, 7.1 cm3dimethyl sulfoxide, 4,4 cm3oxalicacid and 21.5 cm3of triethylamine. Get 9.2 grams(+)-1-[(4-chlorophenyl)(Tien-2-yl)methyl]azetidin-3-one as a pale yellow oil that crystallized at 20

(+)-1-[(4-Chlorophenyl)(Tien-2-yl)methyl]amine can be obtained as follows: to a solution of 109 g of [(4-chlorophenyl)(Tien-2-yl)methyl-(RS)]amine in 500 cm3methanol added 73 g of D-(-)-tartaric acid and evaporated to dryness mixture under reduced pressure (2.7 kPa). The obtained amorphous mass absorb 2,05 l of an ethanol water mixture (90/10 by volume). After stirring for 20 h at 20To the resulting suspension of crystals was filtered, washed with crystals minimal amount of solvent mixture and dried. Repeated recrystallization produced in the same conditions using 1.5 l of the same solvent mixture. Get to 44.9 g of crystals of tartrate salt of amine, []20D=+10,3(C=0.5% in dimethylformamide). This compound is recrystallized from 600 cm3an ethanol water mixture (80/20 by volume), filtering and washing twice crystals 30 cm3the same mixture of solvents with subsequent press, after which the compound is recrystallized in the same condition is l]amine as white crystals, []20D=+10,8(C=0.5% in dimethylformamide).

The obtained Sol absorb 400 cm31 N. aqueous sodium hydroxide solution and 100 cm3ethyl acetate. The organic phase is separated, washed with 100 cm3water, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa) to give 16.1 g(+)-1-[(4-chlorophenyl)(Tien-2-yl)methyl]amine in the form of crystallized at 20With oil []20D=+32,7(C=0.5% in dichloromethane).

Example 77

Repeating the sequence of operations of example 75, from 1.30 grams of a mixture of two chiral diastereoisomers 1-[(4-chlorophenyl)(Tien-2-yl)methyl-(S*)]-3-[(3,5-differenl)-(methylsulphonyl)methyl-(R*)]azetidin-3-ol and 1-[(4-chlorophenyl)-(Tien-2-yl)methyl-(S*)]-3-[(3,5-differenl)(methylsulphonyl)-methyl-(S*)]azetidin-3-ol, 40 cm3dichloromethane, 0,35 cm3methanesulfonanilide and 1.28 g of 4-dimethylaminopyridine receive 0.97 g(-)-1-[(4-chlorophenyl)(Tien-2-yl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene)]azetidine in the form of white crystals with so pl. 135C []20D=-3,4(C=0.5% in dichloromethane).

A mixture of d is lidin-3-ol and 1-[(4-chlorophenyl)(Tien-2-yl)methyl-(S*)]-3-[(3,5-differenl)(methylsulphonyl)methyl-(S*)]azetidin-3-ol may be obtained as described in example 75 from 1.06 g(-)-1-[(4-chlorophenyl)(Tien-2-yl)methyl]azetidin-3-one, 0,82 g (3,5-diferensial)-methylsulfone, 2.5 cm3a 1.6 n solution of n-utility in hexane and 25 cm3tetrahydrofuran (THF). After purification by chromatography obtain 1.3 g of a mixture of two chiral diastereoisomers 1-[(4-chlorophenyl)(Tien-2-yl)methyl-(S*)]-3-[(3,5-differenl)(methylsulphonyl)methyl-(R*)]azetidin-3-ol and 1-[(4-chlorophenyl)(Tien-2-yl)methyl-(S*)]-3-[(3,5-differenl)(methylsulphonyl)methyl-(S*)]azetidin-3-ol as a white solid.

(-)-1-[(4-Chlorophenyl)(Tien-2-yl)methyl]azetidin-3-one may be obtained as described in example 75 from 11.4 g(-)-1-[(4-chlorophenyl)(Tien-2-yl)methyl]azetidin-3-ol, 220 cm3dichloromethane, 4.0 cm3dimethyl sulfoxide, 4.0 cm3oxalicacid and 19.5 cm3of triethylamine. Get 8,3 g(-)-1-[(4-chlorophenyl)(Tien-2-yl)methyl]azetidin-3-one as a pale yellow oil that crystallized at 20C.

(-)-1-[(4-Chlorophenyl)(Tien-2-yl)methyl]azetidin-3-ol may be obtained as described in example 75 from 15,4 (-)-1-[(4-chlorophenyl)(Tien-2-yl)methyl]amine, 120 cm3ethanol, 5.8 cm3of epichlorohydrin and 5.8 g of sodium bicarbonate. After purification by chromatography receive 10.7 g(-)-1-[(4-chlorophenyl)(Tien-2-yl)methyl]azetidin-3-ol in the form of butter cream color.

(-)-1-[(4-Chlorophenyl)(Tien-2-yl)methyl]amine can be obtained sliney acid. The resulting mixture was crystallized for 2 h at room temperature. The crystals are filtered and washed twice with 10 cm3methanol, after which produce recrystallization from 500 cm3an ethanol water mixture (80/20 by volume). The crystals are filtered and washed twice 30 cm3the same mixture of solvents, and then dried in vacuum at 45C. the Last recrystallization produced from 350 cm3a mixture of ethanol-water (78/22 by volume), by stirring for 29 h at 20C. the resulting crystals are squeezed and dried under reduced pressure (2.7 kPa). Get 26 grams of L-(+)-tartrate, (- )- [(4-chlorophenyl)(Tien-2-yl)methyl]amine as white crystals, []20D=-10,7(C=0.5% in dimethylformamide).

The obtained Sol absorb 400 cm31 N. aqueous sodium hydroxide solution and 100 cm3ethyl acetate. The organic phase is separated, washed with 100 cm3water, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa), getting to 15.4 g(-)-1-[(4-chlorophenyl)(Tien-2-yl)methyl]amine in the form of crystallized at 20With oil []20D=-31,73methanesulfonanilide and 3.8 g of 4-dimethylaminopyridine, after recrystallization from 40 cm3acetonitrile gain of 1.9 g of 1-benzhydryl-3-[(ethylsulfonyl)-(phenyl)methylene]azetidine in the form of crystals with so pl. 210[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): to 1.15 (3H, t, J=6 Hz, CH3), of 2.92 (2H, kb, J=6 Hz, CH2), 3,83 (2H, s, NCH2), 4,20 (2H, s, NCH2), and 4.75 (1H, s, NCH), 7,15-7,50 (15 NM, m, 3 phenyl)].

1-Benzhydryl-3-[(ethylsulfonyl)(phenyl)methyl-(RS)]-azetidin-3-ol can be obtained by repeating the sequence of operations example 1 on the basis of 2.4 g of ventilationthe, 2.2 cm3Diisopropylamine and 10 cm3a 1.6 n solution of n-utility in hexane, 65 cm3tetrahydrofuran (THF) and 3.1 g of 1-benzhydrylamine-3-one. After recrystallization from 30 cm3Acrylonitrile obtain 3.6 g of 1-benzhydryl-3-[(ethylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol as white crystals with so pl. 222C.

Ventilationthe can be obtained by repeating the sequence of operations of example 2 of 6.3 g of benzylacrylamide, 50 cm3acetic acid, 50 cm3water, 25 cm336 N. sulfuric acid and 24.8 g OksanaR. After recrystallization from 20 cm3diethyl ether is lipid can be obtained as follows: to a solution of 5 g of benzylmercaptan 50 cm3of dimethylformamide is added in an argon atmosphere with small portions of 1.2 g of sodium hydride and then maintaining the temperature 45With, poured 3,36 cm3ethyliodide. The mixture is stirred for 2 hours and absorb 200 cm3diethyl ether. The organic phase is washed with 200 cm3water, then three times 100 cm3water, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa) to give 6.3 g of benzylacrylamide in the form of a pale yellow liquid.

Example 79

To a solution of 0.45 g of 1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluorobenzoyl)phenyl]methylene}of azetidine 5 cm3of dimethylformamide add 0.083 g of 1-amino-4-methylpiperazine, stirred for 20 h at room temperature and add 40 cm3ethyl acetate. The organic phase is washed 4 times 20 cm3water, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa). The residue is triturated in 10 cm3diethyl ether, filtered and dried, obtaining 0.2 g of 1-[bis(4-chlorophenyl)methyl]-3-{(methylsulphonyl)[(N-4-methylpiperidino)phenyl]methylene}of azetidine in the form of a yellow solid with so pl. 162[NMR Spectrum in DMSO-d6, T=300 K,in m(2N, s, NCH2), 4,80 (1H, s, NCH), 7,40 (4H, d, J=7 Hz, SN arene.), to 7.50 (4H, d, J=7 Hz, SN arene.), at 7.55 (2H, m, 2CH arene.), 7,80 (2H, m, 2CH arene.), to 9.50 (1H, s, CONH)].

1-[Bis(4-chlorophenyl)methyl]-3-{(methylsulphonyl)[3-(pentafluorobenzoyl)phenyl]methylene}azetidin can be obtained as follows: to a solution of 2.9 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)(methylsulphonyl)methylene]-azetidine 25 cm3of dimethylformamide add to 0.94 g of hydrochloride (3-dimethylaminopropyl-N’-ethylcarbodiimide and 0,89 g pentafluorophenol, stirred for 20 h at room temperature and absorb 50 cm3ethyl acetate. The organic phase is washed with 100 cm3water, 200 cm3saturated aqueous sodium bicarbonate and then twice with 50 cm3distilled water, then dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (grain size of 0.04-0.06 mm, diameter 2 cm), elwira mixture with dichloromethane-ethanol (99/1 by volume), getting to 0.92 g of 1-[bis(4-chlorophenyl)methyl]-3-{(methylsulphonyl)[3-(pentafluorobenzoyl)phenyl]methylene}azetidine in the form of a white amorphous mass.

1-[Bis(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)(methylsulphonyl)methylene]azetidine can be obtained in the following way/sup>acetic acid is added at a temperature of 50To a solution of 36% hydrochloric acid, heat the mixture for 48 h and evaporated to dryness under reduced pressure (2.7 kPa). The remainder absorb 30 cm3ethanol and again evaporated to dryness. The residue is triturated in 35 cm3diethyl ether, obtaining 3.8 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)(methylsulphonyl)methylene]azetidine in a solid beige color.

1-[Bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulphonyl)methylene]azetidine can be obtained by repeating the sequence of operations of example 4 from 11 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol, 150 cm3dichloromethane, 2.54 cm3methanesulfonanilide and 10.7 g of 4-dimethylaminopyridine at room temperature for 3 hours, the Obtained residue is purified by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4.5 cm), elwira mixture with dichloromethane-ethanol (99,6/a 0.4 by volume). Mpariwa fractions under reduced pressure (2.7 kPa), to obtain 3.8 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulphonyl)-methylene]azetidine in the form of a white amorphous mass.

1-[Bis(4-chloro phenyl)methyl]-3-[(3-cyanophenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol is solution of n-utility in hexane in 30 cm3tetrahydrofuran for 10 minutes added under argon a solution of 5 g (3-cyanobenzyl)methylsulfone 500 cm3tetrahydrofuran (THF). The mixture is stirred for 1 h 30 min and poured within 10 min a solution of 7.8 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one in 80 cm3of tetrahydrofuran, stirred for further 1 h 30 min, poured 60 cm3saturated aqueous solution of ammonium chloride and leave the mixture to the spontaneous establishment at room temperature. After that, the mixture absorb 300 cm3ethyl acetate, the organic phase is washed with 200 cm3saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa). Obtain 11 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)-(methylsulphonyl)methyl-(RS)]azetidin-3-ol as an amorphous mass.

(3-Cyanobenzyl)methylsulfone can be obtained as follows: to a solution of 20.2 g of 3-chloromethylbenzene 200 cm3ethanol added to 17.4 g of 85% of methanesulfonate sodium, boil under reflux for 20 h under stirring and absorb 500 cm3ethyl acetate and 500 cm3water. The insoluble portion removed by filtration and the organic phase of the filtrate is dried over magnesium sulfate and dry mariafeliciaoliva and dried, getting 21 grams (3-cyanobenzyl)methylsulfone in the form of white crystals with so pl. 165C.

3-Chloromethylbenzene can be obtained in the following way: 32 g 3-chloromethylbenzene 200 cm3the phosphorus oxychloride is heated 3 hours at 95With, enter 1 l of ice, stirred for 1 h and extracted with a mixture of 500 cm3dichloromethane. The organic phase is washed with 200 cm3water, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa) to give 20.2 g of 3-chloromethylbenzene in the form of a white solid.

3-Chloromethylbenzene can be obtained as follows: to a solution of 50 g of 3-chlorodibenzofuran 500 cm3diethyl ether is poured 150 cm3ammonia solution (d=0,90), cooled, stirred for 1 h, filtered and twice washed with 200 cm3diethyl ether, receiving 32 g 3-chloromethylbenzene in the form of white crystals.

Example 80

Repeating the sequence of operations of example 79, from 0.5 g of 1-[bis(4-chlorophenyl)methyl]-3-{(methylsulphonyl)[3-(pentafluorobenzoyl)phenyl]methylene}of azetidine, 0,06 cm31,1-dimethylhydrazine and 5 cm3of dimethylformamide, receive 0.125 g of 1-[bis(4-chlorophenyl)methyl]-3-{[3-(2,2-dimethylcarbamate)phenyl](IU DMSO-d6, T=300 K,in M. D. (300 MHz): 2,60 (6N, s, N(CH3)2), 2,95 (3H, s, SCH3), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), 4,80 (1H, s, NCH), 7,35 (4H, d, J=7 Hz, SN arene.), was 7.45 (4H, d, J=7 Hz, SN arene.), to 7.50 (2H, m, 2CH arene.), 7,80 (2H, m, 2CH arene.), to 9.50 (1H, s, CONH)].

Example 81

Repeating the sequence of operations example 1 on the basis of 2.2 g of 1-[bis(Tien-2-yl)methyl]-3-[(3,5-differenl)-(methylsulphonyl)methyl-(RS)]azetidin-3-ol, 0,64 cm3methanesulfonanilide, 2.3 g of 4-dimethylaminopyridine and 75 cm3dichloromethane, after purification by chromatography and crystallization from isopropyl ether to obtain 1.3 g of 1-[bis(Tien-2-yl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine in the form of white crystals with so pl. 165[NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 3,00 (3H, s, SCH3), to 3.92 (2H, s, NCH2), 4,28 (2H, s, NCH2), of 5.40 (1H, s, NCH), to 6.95 (2H, DD, J=5 and 2 Hz, 2CH thio.), to 7.15 (2H, d, J=2 Hz, 2CH thio.), then 7.20 (2H, m, 2CH arene.), to 7.35 (1H, t, J=8 Hz, CH arene.), to 7.50 (2H, d, J=5 Hz, 2CH thio.)].

1-[Bis(Tien-2-yl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations example 1 on the basis of 1.5 g of 1-[bis(Tien-2-yl)methyl]azetidin-3-one, 4 cm3a 1.6 n solution of n-utility in hexane, 1.3 g (3,5-Dien-2-yl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol as white crystals with so pl. 145C.

1.5 g of 1-[Bis(Tien-2-yl)methyl]azetidin-3-one may be obtained as described in example 75 on the basis of 4 g of 1-[bis(Tien-2-yl)methyl]azetidin-3-ol, 2,6 cm3dimethyl sulfoxide, 7.7 cm3of triethylamine, 7.7 cm3oxalicacid and 100 cm3dichloromethane. The resulting residue is purified by chromatography on a column of silica gel (grain size of 0.04-0.06 mm, diameter 3 cm, height 30 cm) with a mixture of cyclohexane with ethyl acetate (1/1 by volume) as eluent. The obtained fractions evaporated to dryness under reduced pressure (2.7 kPa) to give 3.2 g of 1-[bis(Tien-2-yl)methyl]azetidin-3-it is in the form of cream-coloured crystals with so pl. 70C.

1-[Bis(Tien-2-yl)methyl]azetidin-3-ol may be obtained as described in example 75, from 6 g of 1-[bis(Tien-2-yl)methyl]amine, 2.5 cm3epibromohydrin, 2.6 g of sodium bicarbonate and 50 cm3ethanol, to obtain 4 g of 1-[bis(Tien-2-yl)methyl]azetidin-3-ol in the form of beige crystals with so pl. 115C.

1-[Bis(Tien-2-yl)methyl]amine can be obtained as follows: to a cooled to 10With suspension Tien-2-imagebased (prepared from 1.20 g of magnesium and 3.22 cm32-bromothiophene 75 cm3diethyl ether) at 10With and poured dropwise 20 cm3of methanol. The suspension is filtered, the precipitate washed with methanol and add to the filtrate (reddish-brown solution) in an atmosphere of argon portions a solution of 2.45 g of sodium borohydride. The mixture is stirred for 16 h at room temperature, diluted with ethyl acetate and slowly add water. Extracted organic phase is washed with water, dried over magnesium sulfate and evaporated to dryness at 55C and reduced pressure (2.7 kPa). Obtained a reddish-brown oil chromatographic on a column of silica gel (grain size of 0.02-0,063 mm, diameter 8 cm, height 25 cm), with a mixture of cyclohexane with ethyl acetate (90/10 and then 85/15 by volume). Fractions 21 to 30 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 11 g of 1-[bis (Tien-2-yl)methyl]amine in the form of crystals.

Example 82

Repeating the sequence of operations of the example 1 according to 0.47 g of 4-dimethylaminopyridine, 0,13 g methanesulfonanilide, 25 cm3dichloromethane and of 0.48 g of 1-(bis-p-trimethyl)-3-[(methylsulphonyl)(phenyl)methyl-(RS)]azetidin-3-ol, after purification by chromatographytandem, cristalle is in the form of a white solid [NMR Spectrum in DMSO-d6, T=300 K,in M. D. (250 MHz): 2,23 (6N, C, 2 h3), 2,98 (3H, s, SCH3), 3,76 (2H, s, NCH2), 4,20 (2H, s, NCH2), to 5.55 (1H, s, NCH), 7,10 (4H, d, J=7 Hz, SN arene.), to 7.32 (4H, d, J=7 Hz, SN arene.), the 7.43 (5H, s, phenyl)].

1-(Bis-p-trimethyl)-3-[(methylsulphonyl)(phenyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations of example 39 from 0,59 g bromine(bis-p-tolyl)methane, 20 cm3acetonitrile, 0.3 g of potassium carbonate and 0.6 g of the hydrochloride of 3-[(methylsulphonyl)(phenyl)methyl-(RS)]azetidin-3-ol. The obtained residue chromatographic on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4 cm, height 16 cm), elwira with a mixture of cyclohexane with ethyl acetate (7/3 by volume). Fractions evaporated to dryness under reduced pressure (2.7 kPa), receiving of 0.48 g of 1-(bis-p-trimethyl)-3-[(methylsulphonyl)(phenyl)methyl-(RS)]azetidin-3-ol as a white solid.

Bromine(bis-p-tolyl)methane can be obtained in accordance with the sequence of operations described ANN W. E., J. Am. Chem. Soc., 2135 (1933).

Hydrochloride 3-[(methylsulphonyl)(phenyl)methyl - (RS)]azetidin-3-ol can be obtained by repeating the sequence of operations of example 39 from 7 g of 3-[(methylsulphonyl)(phenyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-ol, 35 cm3dioxane and 35 cm3

3-[(Methylsulphonyl)(phenyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-ol can be obtained by repeating the sequence of operations of example 38 (method 1) on the basis of 10 g of 1-benzhydryl-3-[(methylsulphonyl)(phenyl)methyl-(RS)]-azetidin-3-ol, 600 cm3dichloromethane and 2.52 cm3vinylnorbornene. The resulting residue is purified by chromatography on a column of silica gel (grain size of 0.06-0,200 mm, diameter 5.2 cm, height 36 cm), elwira with a mixture of cyclohexane with ethyl acetate (7/3 by volume). Fractions evaporated to dryness under reduced pressure (2.7 kPa) to give 7 g of 3-[(methylsulphonyl)(phenyl)methyl-(RS)]-1-(vinyloxycarbonyl)-azetidin-3-ol as a white solid.

Example 83

To a solution of 0.77 g(-)-1-[(4-chlorophenyl)(4-formylphenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine 20 cm3methanol is poured at 0In an argon atmosphere a solution of 30 mg of sodium borohydride in 2 cm3methanol is stirred for 4 hours at 0With, add water and extracted with dichloromethane. The organic phase is washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa).

Received a white amorphous mass of purified on a column of 40 by volume). After crystallization from 1.5 cm3absolute ethanol 0.1 g(+)-1-[(4-chlorophenyl)(4-hydroxymethylene)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine in the form of white crystals with so pl. 190C []20D=+4.2V(C=0.5% in methanol) [NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 3,05 (3H, s, SCH3), of 3.95 (2H, s, NCH2), 4,22 (2H, s, NCH2), 4,48 (2H, d, J=6 Hz, CH2About), and 4.75 (1H, s, NCH), of 5.15 (1H, t, J=6 Hz, HE), 7,20 (2H, m, 2CH arene.), 7,28 (2H, d, J=7 Hz, 2CH arene.), yield of 7.40 (5H, m, SN arene.), to 7.50 (2H, d, J=7 Hz, 2CH arene.)].

(-)-1-[(4-Chlorophenyl)(4-formylphenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine can be obtained as follows: to a solution of 0.83 g(+)-1-{(4-chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine 5 cm3the tetrahydrofuran is poured 3,32 cm35 N. hydrochloric acid, stirred for 20 h, add dichloromethane and water and then 30% aqueous solution of sodium hydroxide to achieve a pH of 14. The organic phase is extracted with dichloromethane, the organic phase is washed successively with water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and henyl)(methylsulphonyl)methylene]azetidine in the form of a white amorphous mass.

(+)-1-{(4-Chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine can be obtained as follows: to a solution 2,42 g of a mixture of two diastereoisomers 3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl]methyl(R*)}-3-[(3,5-differenl)(methylsulphonyl)methyl-(R*)]azetidine and 3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl]methyl-(R*)}-3-[(3,5-differenl)(methylsulphonyl)methyl-(S*)]azetidine 25 cm3the tetrahydrofuran is poured dropwise at 0With under argon 0,93 g of 1,8-diazabicyclo[5.4.0]undec-7-ene. After stirring for 1 h 30 min at 0To the reaction mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The crude product is purified on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4.8 cm, height 17.5 cm), elwira with a mixture of cyclohexane with ethyl acetate (80/20 by volume), receiving 1,21 g(+)-1-{(4-chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine in the form of a yellow amorphous mass.

A mixture of two diastereoisomers 3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl]IU which-methyl-(R*)}-3-[(3,5-differenl(methylsulphonyl)methyl-(S*)]azetidine can be obtained as follows: to a cooled to -70With the solution of 1.08 g (3,5-diferensial)methylsulfone poured dropwise with 3.27 cm3n-utility, stirred for 1 h at -70C and then poured dropwise a solution of 1.80 g(+)-1-{(4-chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl]methyl}azetidin-3-one in 10 cm3tetrahydrofuran (THF). After stirring for 3 h at -70C and 1 h at -20With poured a solution of 0.74 cm3acetylchloride 10 cm3anhydrous diethyl ether at -20C and stirred for 2 cov at -20C. the Reaction medium was poured into water and extracted with a mixture of ethyl acetate. The organic phase is washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa), getting to 2.42 g of a mixture of two 3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl]methyl-(R*)}-3-[(3,5-differenl (methylsulphonyl)methyl-(R*)]azetidine and 3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl]methyl-(R*)}-3-[(3,5-differenl)(methylsulphonyl)methyl-(S*)]azetidine in the form of a yellow oil.

(+)-1-{(4-Chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl]-methyl}azetidin-3-one can be obtained as follows: to a solution of 1.38 g(+)-1-{(4-chlorophenyl)[4-(1,3-dhona of 2.24 cm3of triethylamine and then dropwise of a solution of 1.65 g of a complex of pyridine-sulfurdioxide 20 cm3anhydrous dimethyl sulfoxide. After stirring for 1 h 15 min at room temperature, the reaction mixture is poured on ice and extracted with ethyl acetate. The organic phase is washed with water and then saturated aqueous sodium chloride, then dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The obtained oily residue (1,31 g) are combined with the same raw connection from another experience (1,21 g) and jointly purified on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4.8 cm, height 18 cm), elwira with a mixture of cyclohexane with ethyl acetate (80/20 by volume). Get 1,87 g(+)-1-{(4-chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl]methyl}azetidin-3-one as a yellow oil, []20D(365 nm)=+5,9(C=0.5%, methanol).

(+)-1-{(4-Chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl]methyl}-azetidin-3-ol can be obtained by repeating the sequence of operations of example 75, based on 4,43 g (+)-{(4-chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl]methyl}amine, 40 cm3absolute ethanol, 1.25 cm3epibromohydrin and 1.28 g of sodium bicarbonate: obtain 1.66 g(+)-1-{(4-chloralum-2-yl)phenyl]methyl}amine can be obtained as follows: to a suspension 18,16 g chiral hydrochloride (R*)-1-[(4-chlorophenyl)(4-formylphenyl)methyl]amine in the 1000 cm3toluene is poured 3,95 cm3of ethylene glycol and type of 0.82 g of the monohydrate of p-toluenesulfonic acid. After stirring for 20 h at boiling temperature under reflux, the reaction mixture is cooled, washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The obtained residue is purified on a column of silica gel (grain size of 0.04-0.06 mm, diameter 8.4 cm, height 21.5 cm), elwira with a mixture of cyclohexane with ethyl acetate (30/70 by volume), collecting fractions of 250 cm3. Fractions 23-30 evaporated to dryness under reduced pressure (2.7 kPa) to give 1.39 g of chiral (+)-{(4-chlorophenyl)[4-(1,3-dioxolane-2-yl)phenyl]methyl}amine as a yellow oil.

Chiral hydrochloride, (R*)-[(4-chlorophenyl)(4-formylphenyl)methyl]amine can be obtained as follows: to a solution 51,4 g diastereoisomer N-{(4-chlorophenyl)[4-(diethoxylate)phenyl]methyl-(R*)}-(R)-2-phenylglycinol 660 cm3anhydrous dichloromethane is poured 330 cm3methanol, cooling the mixture in an ice bath, add 60,96 g leads to compounds, which lead, stirred for 5 min and poured in 1 l of a solution of phosphate buffer, p dichloromethane. The organic phase is evaporated to dryness under reduced pressure (2.7 kPa). The remainder absorb 1 liter of diethyl ether and add 1 l of 3 N. hydrochloric acid. The mixture is stirred for 15 min at room temperature, separating the aqueous phase, washed her with ethyl acetate and then evaporated to dryness under reduced pressure (2.7 kPa), receiving 18,16 g chiral hydrochloride (R*)-[(4-chlorophenyl)(4-formylphenyl)methyl]amine as a white solid.

N-{(4-Chlorophenyl)[4-(diethoxylate)phenyl]methyl-(R*)}-(R)-2-phenylglycinol can be obtained as follows: to a cooled to -70With the solution 87,7 g of 4-bromchlorenone poured dropwise in an argon atmosphere 286 cm3a 1.6 n solution of n-utility in hexane and stirred for 15 min at -70C. the thus Obtained solution is added dropwise to a cooled to 0With a solution of 30 g of (R)-N-[4-(diethoxylate)benzylidene]-2-phenylglycinol 300 cm3diethyl ether. The mixture is stirred for 2 hours at 0C and poured into water. The organic phase is washed with water, then saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). Received the and 45 cm), elwira with a mixture of cyclohexane with ethyl acetate (85/15, then 80/20 and 75/25 by volume), collecting fractions with a volume of 1 liter Fractions 11-17 evaporated to dryness under reduced pressure (2.7 kPa), receiving 39,85 g one diastereoisomer N-{(4-chlorophenyl)[4-(diethoxylate)-phenyl]methyl-(R*)}-(R)-2-phenylglycinol in the form of a red-orange oil.

(R)-N-[4-(Diethoxylate)benzylidene]-2-phenylglycinol may be as follows: to a white suspension of 24.7 g (R)-(-)-2-phenylglycinol 500 cm3toluene is poured 35,9 cm34-(diethoxylate)benzaldehyde. The turbid yellow solution is refluxed with stirring for 6 h 30 min, and then stirred for 20 h at room temperature. After evaporation of the reaction medium to dryness under reduced pressure (2.7 kPa) get 61,6 g (R)-N-[4-(diethoxylate)benzylidene]-2-phenylglycinol in the form of a yellow oil.

Example 84

Repeating the sequence of operations example 1 from a mixture of 5.6 g of 1-[bis(4-chlorophenyl)methyl]-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)phenyl](methylsulphonyl)methyl-(RS)}azetidin-3-ol, 100 cm3dichloromethane, 1,59 g methanesulfonanilide and 4.5 g of 4-dimethylaminopyridine. The reaction mixture is stirred 3 hours at room temperature and purify the product on a column of silaceata and cyclohexane (30/70 by volume), collecting fractions of 100 cm3. Fractions 12 to 18 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 3.2 g of 1-[bis(4-chlorophenyl)methyl]-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)phenyl](methylsulphonyl)methylene}of azetidine in the form of a white amorphous mass [NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 1,30 (N, s, OC(CH3)3), to 2.65 (3H, s, J=6 Hz, N3), 2,85 (3H, s, SCH3), a 3.50 (2H, s, NCH2), 3,90 (2H, s, NCH2), of 4.45 (1H, s, NCH), 6,85-7,05 (8H, m, SN arene.), 7,10 (4H, d, J=7 Hz, SN arene.)].

1-[Bis(4-chlorophenyl)methyl]-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)phenyl](methylsulphonyl)methyl-(RS)}azetidin-3-ol can be obtained by repeating the sequence of operations example 1 from 3.8 g of [3-(N-tert-butyloxycarbonyl-N-methylamino)benzyl]methylsulfone, 50 cm3tetrahydrofuran (THF, 9.5 cm3a 1.6 n solution of n-utility in hexane, 3,82 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one. The crude product is purified on a column of silica gel (grain size of 0.04-0.06 mm, diameter 4 cm, weight of 250 g silica gel), elwira when the nitrogen pressure of 0.5 bar with dichloromethane and then a mixture of dichloromethane ethanol (99/1 by volume), collecting fractions with a volume of 500 cm3. Fractions 10 to 16 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 5.6 g of 1-[the form of an amorphous mass.

Example 85

A mixture of 2.7 g of 1-[bis(4-chlorophenyl)methyl]-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)phenyl](methylsulphonyl)methylene}of azetidine 30 cm3dioxane and 30 cm34,7 n solution of hydrogen chloride in dioxane is stirred for 20 hours, then evaporated to dryness under reduced pressure (2.7 kPa), absorb 50 cm3water and 50 cm3ethyl acetate, stirred and carefully neutralized with saturated aqueous sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulfate, treated with activated charcoal, and evaporated under reduced pressure (2.7 kPa) to approximately 25 cm3, and then filtered and evaporated to dryness under reduced pressure, obtaining 1.3 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-methylaminophenol)(methylsulphonyl)methylene]azetidine in the form of white crystals with so pl. 228[NMR Spectrum in DMSO-d6, T=300 K, 5 in M. D. (300 MHz): to 2.65 (3H, s, J=6 Hz, NCH3), 2,95 (3H, s, SCH3), of 3.80 (2H, s, NCH2), 4,20 (2H, s, NCH2), 4,80 (1H, s, NCH), to 5.85 (1H, kb, J=6 Hz, NH), 6,55 (3H, m, SN arene.), to 7.15 (1H, t, J=7 Hz, CH arene.), 7,40 (4H, d, J=7 Hz, SN arene.), to 7.50 (4H, m, SN arene.)].

Example 86

Repeating the sequence of operations example 1 on the basis of 0.40 g of the mixture of the two stereoisomers of 1-[(4-chlorophenyl)(thiazol-2-yl)IU is nephridia, after chromatography was carried out on a column of silica gel (grain size of 0.06-0,200 mm, diameter 1.2 cm, height 20 cm) at a nitrogen pressure of 1 bar with a mixture of ethyl acetate with cyclohexane (40/60 by volume) as eluent and collecting fractions of 20 cm3gain of 0.13 g of (RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine in the form of a pinkish solid [NMR Spectrum in DMSO-d6, T=300 K,in M. D. (300 MHz): 3,05 (3H, s, SCH3), of 4.05 (2H, s, NCH2), 4,35 (2H, m, NCH2in ), 5.25 (1H, s, N), 7,20 (2H, d, J=8 Hz, 2CH arene.), to 7.35 (1H, t, J=8 Hz, CH arene.), was 7.45 (2H, d, J=7 Hz, 2CH arene.), to 7.50 (2H, d, J=7 Hz, 2CH arene.), of 7.70 (1H, d, J=7 Hz, CH of thiazole), of 7.75 (1H, d, J=2 Hz, CH of thiazole)].

A mixture of two stereoisomers of 1-[(4-chlorophenyl)(thiazol-2-yl)methyl-(RS)]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol can be obtained by repeating the sequence of operations of example 72 on the basis of 1.01 g (RS) bromo(4-chlorophenyl)thiazol-2-Ileana and 0.55 g of hydrochloride (RS)-3-[(3,5-differenl)(methylsulphonyl)methyl]-azetidin-3-ol. After chromatography was carried out on a column of silica gel (grain size of 0.06-0,200 mm, the diameter of 4.4 cm, height 38 cm) at a pressure of argon 0.5 bar with a mixture of ethyl acetate with cyclohexane (30/70 by volume, then 40/60 for fractions 16) and collecting fractions of 60 cm< two diastereoisomers 1-[(4-chlorophenyl)(thiazol-2-yl)methyl-(RS)]-3-[{3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol in the form of bloatage solid.

Example 87

To a solution of 0.32 g of 1-{(R*)[4-(chloromethyl)phenyl](4-chlorophenyl)-methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, isomer forms, and 5 mg of sodium iodide in 10 cm3dichloromethane are added 50 mm3pyrrolidine, stirred for 20 h at 20To add a mixture of 50 mm3pyrrolidine, stirred for 8 h, again add 50 mm3pyrrolidine and stirred for further 20 h at 20C. the Reaction mixture is then washed with water, dried the organic phase over magnesium sulfate and evaporated it to dryness under reduced pressure (2.7 kPa). The obtained residue is purified on a column of silica gel (grain size of 0.06-0,200 mm, diameter 1.2 cm, height 30 cm) at a pressure of argon 0.1 bar, elwira dichloromethane and then a mixture of dichloromethane with methanol (97,5/a 2.5 by volume), collecting fractions of 3 cm3. Faction 12-40 combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 0.18 g of 1-{(R*)-(4-chlorophenyl)[4-(pyrrolidinyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, isomer form And in the form of a white amorphous mass, []20D(365 nm) = -22,5+/- 0,7 (C=0,5%, dichloromethane) [NMR Spectrum1H (300 MHz, CDCl3,

1-{(R*)-[(4-chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, isomer forms And can be obtained as follows: to a solution of 28.0 g of a mixture of two stereoisomers (forms) 1-{(R*)-[(4-chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(R)-(3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol and 1-{(R*)-[(4-chloromethyl)-phenyl]-(4-chlorophenyl)methyl}-3-[(S)-(3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol, 32 g of 4-dimethylaminopyridine 500 cm3dichloromethane type of 12.4 cm3methanesulfonanilide. After stirring for 1 hour at 0With and then for 1 hour at 20With the reaction mixture is washed with 500 cm3water, the organic phase is dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 6 cm, height 30 cm), at a pressure of argon 0.2 bar, elwira dichloromethanol and collecting fractions of 250 cm3. Faction 9-25 combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 6.3 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine isomer form And in the form of a white amorphous mass.

Smutil]azetidin-3-ol and 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(S)-(3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol may be obtained in the following way: to a solution of 0.20 g of a mixture of 2 diastereoisomers (a forms) 1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]-methyl}-3-[(R)-(3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol and 1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl}phenyl]methyl}-3-[(S)-(3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol in 10 cm3dichloromethane add 60 mm3thionyl chloride, stirred for 20 h at 20To add 5 cm3saturated aqueous solution of sodium bicarbonate and stirred for 15 minutes the mixture is divided into phases, the organic phase is washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (grain size of 0.04-0.06 mm, diameter 1.0 cm, height 20 cm) at a pressure of argon 0.2 bar, elwira with a mixture of cyclohexane with ethyl acetate (75/25 by volume), collecting fractions of 20 cm3. Fractions 4-7 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 0.17 g of a mixture of two diastereoisomers (a forms) 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(R)-(3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol and 1-{(R*}-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(S)-(3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol as a white amorphous mass.

A mixture of two diastereoisomers (a forms) 1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol and 1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl)methyl}-3-[(S)-(3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol may be obtained in the following obra-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(R)-(3,5-differenl)(methylsulphonyl)methyl]azetidine and 3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl}phenyl]-methyl}-3-[(S)-(3,5-differenl)(methylsulphonyl)methyl]azetidine in 10 cm3anhydrous toluene is added in an argon atmosphere 1.6 cm3solution 1.5 M hydride diisobutylaluminum in toluene, stirred for 15 min at -30With, again add 1.0 cm3the same solution of the hydride and leave the mixture to a spontaneous rise in temperature to 0C. After stirring for 30 min to the mixture add 3 cm3water and 6 cm31 n sodium hydroxide, then extracted with 25 cm3dichloromethane. The organic phase is washed with 5 cm3water, 5 cm3saturated salt solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 1.2 cm, height 30 cm) at a pressure of argon 0.1 bar with a mixture of cyclohexane with ethyl acetate (50/50 by volume), collecting fractions of 30 cm3. Fractions 4 to 12 are combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving at 0.42 g of a mixture of two diastereoisomers (a forms) 1-{(R*)-{4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(R)-{3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol and 1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl)methyl}-3-[(S)-(3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol in the form of a white lacquer.

3tetrahydrofuran (THF) 3 cm3a 1.6 n solution of n-utility in hexane, 1.45 g of 1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-one, isomer forms And, and 0.43 cm3acetylchloride. Obtain 1.28 g of a mixture of 2 diastereoisomers (forms A) 3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(R)-(3,5-differenl)(methylsulphonyl)methyl]azetidine and 3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(S)-(3,5-differenl)(methylsulphonyl)methyl]azetidine in the form of an amorphous mass of beige.

1-{(R*)-(4-Chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-azetidin-3-one, isomer forms And may be obtained as described in example 40 from 0,55 cm3oxalicacid, 25 cm3dichloromethane, 0,90 cm3dimethyl sulfoxide, about 1.75 g of 1-{(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-ol and 2.70 cm3of triethylamine, receiving 1.45 g of 1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-one, isomer forms And, as a yellow amorphous mass.

1-{(R*)-(4-Chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-azetidin-3-ol, a isomer form, And can be obtained by repeating the sequence of operations described by KATRITZKY A. R. et al. in J. Heterocycl. Chern., 271 (1994), 2.0 g of methyl (+)-4-[(R*)-amino-(4-harfe g of 1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-ol, isomer form And in the form of a pasty solid.

Methyl (+)-4-[(R*)-amino-(4-chlorophenyl)methyl]benzoate may be obtained in the following way: to a solution of 9.2 g of methyl 4-[(RS)-amino-(4-chlorophenyl)methyl]benzoate in 10 cm3methanol type of 2.51 g of D-(-)-tartaric acid and evaporated to dryness the solution under reduced pressure (2.7 kPa). The amorphous mass of cream-colored diluted with 50 cm3ethanol containing 5% water, and the resulting solution is left to crystallize for 20 h at 20C. the Crystals are filtered, washed with ethanol with 5% water, squeezed and dried under reduced pressure (2.7 kPa) to give 3.4 g of white crystals, called “crystal A” (which is saved for later retrieval of the second enantiomer of methyl (-)-4-[(R*)-amino-(4-chlorophenyl)methyl]benzoate). Royal solutions evaporated to dryness, obtaining a white amorphous mass (8.1 g) which is dissolved in 100 cm3ethyl acetate. To the resulting solution was added 50 cm31 n sodium hydroxide, stirred and separated into phases. The organic phase is washed with 50 cm3water, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa). The obtained yellow solid was dissolved in 100 cm33ethanol and 4% water left to crystallize for 29 h at 20C. the Crystals are filtered, washed with ethanol, 4% water, squeezed and dried under reduced pressure (2.7 kPa) to give 3.4 g of crystals of L-(+)-tartrate methyl (+)-4-[(R*)-amino-(4-chlorophenyl)methyl]benzoate, which is recrystallized from 60 cm3ethanol with 5% water. After pressing and drying receive 2,78 g of white crystals, which dissolve in 50 cm3ethyl acetate. To the resulting solution add 100 cm31 N. sodium hydroxide and separated phases. The organic phase is washed with 50 cm3water, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa) to give 2.1 g of methyl 4-[(R*)-amino-(4-chlorophenyl)methyl]benzoate as a white solid.

Methyl 4-[(RS)-amino-(4-chlorophenyl)methyl]benzoate may be obtained in the following way: to a suspension of 16.3 g of methyl 4-[(RS)-phthalimido-(4-chlorophenyl)methyl]benzoate in 200 cm3methanol add 3.9 cm3hydrazine hydrate is added, the reaction mixture is stirred 5 hours at the boil under reflux, followed by 20 h at 20C, filtered and evaporated to dryness of the filtrate polizeistaat within 15 minutes The resulting suspension is filtered and the filtrate is separated in a separating funnel into phases. The organic phase is washed with 50 cm3water, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa), receiving of 8.4 g of methyl 4-[(RS)-amino-(4-chlorophenyl)methyl]benzoate as a pale yellow oil.

Methyl 4-[(RS)-phthalimido-(4-chlorophenyl)methyl]benzoate may be obtained in the following way: to a solution of 11.6 g of methyl 4-[(RS)-bromo-(4-chlorophenyl)methyl]benzoate in 70 cm3of dimethylformamide type of 12.6 g of phthalimide potassium, the reaction mixture is stirred at the boiling point under reflux and cooled to 20With, and then add 300 cm3ethyl acetate and 300 cm3water. After mixing, the mixture is divided into phases, the organic phase is extravert double-100 cm3ethyl acetate, the combined organic phases washed twice their 400 cm3water, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa). Obtain 16.3 g of methyl 4-[(RS)-phthalimido-(4-chlorophenyl)methyl]benzoate as a yellow pasty substances.

Methyl 4-[(RS)-bromo-(4-chlorophenyl)methyl]benzoate may be obtained in the following way: to a solution of 17.4 g of methyl 4-[(RS)-(4-chlorophenyl)(hydromica, stirred the reaction mixture for 30 min at 20With, then refluxed for 2 h, stirred for further 2 hours at 20With and evaporated to dryness under reduced pressure (2.7 kPa). The mixture absorb dichloromethane and chromatographic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 7 cm, height 30 cm) at a pressure of argon 0.5 bar with dichloromethane as eluent, collecting fractions with a volume of 500 cm3. Fractions 3-6 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 11.6 g of methyl 4-[(RS)-bromo-(4-chlorophenyl)methyl]benzoate in the form of oil, used without purification for the next stage.

Methyl 4 [(RS)-(4-chlorophenyl)(hydroxy)methyl]benzoate may be obtained in the following way: to a suspension of methyl 4-(4-chlorobenzoyl)benzoate in 200 cm3methanol at 20With added slowly in small portions (heating medium 50(C) to 1.21 g of sodium borohydride. After stirring for 20 h at 20With the reaction mixture is evaporated to smaller volume and add 150 cm3dichloromethane and stirring 100 cm30,5 N. hydrochloric acid. After separation of the phases the organic f the S)-(4-chlorophenyl)(hydroxy)methyl]benzoate in the form of a slowly crystallizing at 20Colourless oil, used without purification for the next stage.

Methyl 4-(4-chlorobenzoyl)benzoate acid can be obtained in the following way: to a cooled to -22To a solution of 19.3 g of the acid chloride nanometrology ester of terephthalic acid in 200 cm3of tetrahydrofuran is added in an argon atmosphere 27,4 cm3tri-n-butylphosphine, stirred for 20 min at -22With and poured, while maintaining this temperature, a solution of 4-chlorpheniramine (prepared from 19,15 g bromo-4-chlorobenzene, 2,43 g of magnesium and one crystal of iodine in boiling under reflux diethyl ether). After stirring for 30 min at -22Slowly add 150 cm31 N. hydrochloric acid, leave the mixture to a spontaneous rise in temperature to 20With and diluted with 200 cm3diethyl ether. The obtained white suspension was filtered, the solid residue is washed with 2 times 50 cm3water, then twice with 50 cm3diethyl ether, after receiving the cake, and drying under reduced pressure (2.7 kPa) 16.2 g of methyl 4-(4-chlorobenzoyl)benzoate as a white solid with so pl. 170C.

Example 88

Carried the yl}-3-[(3,5-differenl) (methylsulphonyl)-methylene]azetidine, isomer forms And 1.0 cm3dichloromethane and 0.025 g of 3,3-dimethylpyridine. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 8 mm, height 8 cm), elwira 80 cm3dichloromethane and then a mixture of dichloromethane with methanol (95/5 by volume), collecting formed by eluting with a mixture of fractions with a volume of 2.5 cm3. Fractions 3-8 combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving 0,040 g of 1-{(R*)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, isomer form And in the form of a white amorphous mass [NMR Spectrum1H (300 MHz, CDCl3,in M. D.): 0,94 (: 6N), 1,21 (m: 2H), 1,50-of 1.65 (m: 2H), 1,99 (user.: 2H), and 2.27 (m: 4H), 2,81 (s: 3H), 3,36 (s: 2H), 3,85 (m: 2H), 4,33 (m: 2H), 4,49 (s: 1H), at 6.84 (TT, J=8.5 and 2.5 Hz: 1H), 6,98 (m: 2H), 7,20-7,40 (m: 8H)].

Example 89

Perform the sequence of operations as described in example 87, on the basis of 0.05 g of 1-{(R*)-[(4-chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)-methylene]azetidine, isomer forms And 1.0 cm3dichloromethane and 0.025 g thiomorpholine. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 8 mm, height 8 cm), elwira 80 cm3dichloromethane and then a mixture of dichloromethane with the complementary and evaporated to dryness under reduced pressure (2.7 kPa), getting 0,038 g of 1-{(R*)-(4-chlorophenyl)[4-(thiomorpholine-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)-(methylsulphonyl)methylene]azetidine, isomer form And in the form of a white amorphous mass [NMR Spectrum1H (300 MHz, l3,in M. D.): 2,60-2,75 (m: 8H), 2,80 (s: 3H), 3,44 (s: 2H), 3,84 (m: 2H), 4,33 (m: 2H), 4,50 (s: 1H), 6,83 (TT, J=8.5 and 2.5 Hz: 1H), 6,97 (m: 2H), 7,20-7,40 (m: 8H)].

Example 90

Perform the sequence of operations as described in example 87, on the basis of 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)-methylene]azetidine, isomer forms And 1.0 cm3dichloromethane and 0.025 g of N-cyclohexyl-N-ethylamine. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 8 mm, height 8 cm), elwira 80 cm3dichloromethane and then a mixture of dichloromethane with methanol (95/5 by volume), collecting formed by eluting with a mixture of fractions with a volume of 2.5 cm3. Fractions 5-8 are combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving of 0.022 g of 1-{(R*}-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylamino)phenyl]-methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, isomer form And in the form of a white amorphous mass [NMR Spectrum1H (300 MHz, Dl3with the addition of a few drops CD3COOD d4

Example 91

Perform the sequence of operations as described in example 87, on the basis of 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, isomer forms And 1.0 cm3dichloromethane and to 0.032 g of 4-(etoxycarbonyl)piperazine. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 8 mm, height 8 cm), elwira 80 cm3dichloromethane and then a mixture of dichloromethane with methanol (95/5 by volume), collecting formed by eluting with a mixture of fractions with a volume of 2.5 cm3. Fractions 2-8 combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving 0,021 g of 1-{(R*)-(4-chlorophenyl){4-[(4-ethoxycarbonylphenyl)methyl]phenyl}methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, isomer form And in the form of a white amorphous mass [NMR Spectrum1H (400 MHz, CDCl3,in M. D.): a 1.25 (t, J=7 Hz: 3H), 2,36 (m: 4H), 2,80 (s: 3H), 3,44 (s: 2H), 3.46 in (m: 4H), 3,85 (m: 2H), 4,13 (kV, J=7 Hz: 2H), 4,34 (m: 2H), 4,50 (s: 1H), 6,83 (TT, J=9 and 2.5 Hz: 2H), 6,98 (m: 2H), 7,20-7,40 (m: 8H)].

Example 92

Perform the sequence of operations as described in example 87, on the basis of 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-x and is 0.023 g of N-cyclopropyl-N-Propylamine. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 8 mm, height 8 cm), elwira 80 cm3dichloromethane and then a mixture of dichloromethane with methanol (95/5 by volume), collecting formed by eluting with a mixture of fractions with a volume of 2.5 cm3. Fractions 3 to 9 are combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving 0,026 g of 1-{(R*)-(4-chlorophenyl)[4-N-cyclopropyl-N-propylaminoethyl)phenyl]-methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, isomer form And in the form of a white amorphous mass [NMR Spectrum1H (400 MHz, Dl3with the addition of a few drops CD3COOD d4in M. D.): 0,34 (m: 2H), 0,70 (m: 2H), of 0.91 (t, J=7 Hz: 3H), 1,08 (m: 1H), 1,76 (m: 2H), 2,82 (s: 3H), of 2.92 (d, J=7 Hz: 2H), 3,00 (m: 2H), 3,90 (m: 2H), 4,25 (s: 2H), 4,37 (m: 2H), 4,59 (s: 1H), 6,83 (TT, J=9 and 2.5 Hz: 1H), 7,00 (m: 2H), 7,20 was 7.45 (m: 8H)].

Example 93

Perform the sequence of operations as described in example 87, but stirring the reaction mixture for 6 days at 20With and on the basis of 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)-(methylsulphonyl)methylene]azetidine, isomer forms And 1.0 cm3dichloromethane, 5 mg of sodium iodide and 0,020 g Diisopropylamine. The crude product chromatografic on a column of silica gel (size evil (95/5 by volume), collecting formed by eluting with a mixture of fractions with a volume of 2.5 cm3. Fractions 2-8 combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving 0,028 g of 1-{(R*)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, isomer form And in the form of a white amorphous mass [NMR Spectrum1H (300 MHz, l3,in M. D.): 1,00 (m: N), 2,80 (s: 3H), 2,90-3,10 (m: 2H), to 3.58 (m: 2H), 3,84 (m: 2H), 4,33 (m: 2H), 4,48 (s: 1H), 6,82 (TT, J=8.5 and 2.5 Hz: 1H), 6,97 (m: 2H), 7,20-7,40 (m: 8H)].

Example 94

Perform the sequence of operations as described in example 87, on the basis of 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, isomer forms And 1.0 cm3dichloromethane and 0.027 g of bis(2-methoxyethyl)amine. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 8 mm, height 8 cm), elwira 80 cm3dichloromethane and then a mixture of dichloromethane with methanol (95/5 by volume), collecting formed by eluting with a mixture of fractions with a volume of 2.5 cm3. Fractions 3 to 10 are combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving of 0.014 g of 1-{{(R*)-(4-chlorophenyl){4-[bis(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-differenl)(methylsulphonyl)methylene]azeti is in M. D.): 2,70 (t OSiR., J=5.5 Hz: 4H), 2,81 (s: 3H), 3,29 (: 6N), of 3.46 (t OSiR., J=5.5 Hz: 4H), 3,65 (user.: 2H), 3,85 (m: 2H), 4,33 (m: 2H), 4,49 (s: 1H), at 6.84 (TT, J=9 and 2.5 Hz: 1H), 6,98 (m: 2H), 7,20-7,40 (m: 8H)].

Example 95

Perform the sequence of operations as described in example 87, on the basis of 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, isomer forms And 1.0 cm3dichloromethane and 0,020 g of di-n-Propylamine. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 8 mm, height 8 cm), elwira 80 cm3dichloromethane and then a mixture of dichloromethane with methanol (95/5 by volume), collecting formed by eluting with a mixture of fractions with a volume of 2.5 cm3. Fractions 3-8 combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 0.025 g of 1-{(R*)-(4-chlorophenyl)[4-(di-n-propylaminoethyl)phenyl]methyl}-3-[(3,5-differenl)-(methylsulphonyl)methylene]azetidine, isomer form And in the form of a white amorphous mass [NMR Spectrum1H (400 MHz, CDCl3,in M. D.): 0,85 (t, J=7.5 Hz: 6N), 1,45 (m: 4H), of 2.34 (t, J=7.5 Hz: 4H), 2,80 (s: 3H), 3,48 (s: 2H), 3,84 (m: 2H), 4,33 (m: 2H), 4,50 (s: 1H), 6,83 (TT, J=9 and 2.5 Hz: 1H), 6,98 (m: 2H), 7,20-7,40 (m: 8H)].

Example 96

Perform the sequence of operations as described in example 87, on the basis of 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-) and 0.017 g of piperidine. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 8 mm, height 8 cm), elwira 80 cm3dichloromethane and then a mixture of dichloromethane with methanol (95/5 by volume), collecting formed by eluting with a mixture of fractions with a volume of 2.5 cm3. Fractions 5-10 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 0.035 g of 1-{(R*)-(4-chlorophenyl)[4-(piperidine-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)-(methylsulphonyl)methylene]azetidine, isomer form And in the form of a white amorphous mass [NMR Spectrum1H (300 MHz, CDCl3,in M. D.): 1,35-of 1.65 (m: 6N), 2,35 (m: 4H), 2,80 (s: 3H), 3,41 (user.: 2H), 3,84 (m: 2H), 4,33 (m: 2H), 4,50 (s: 1H), at 6.84 (TT, J=8.5 and 2.5 Hz: 1H), 6,98 (m: 2H), 7,20-7,40 (m: 8H)].

Example 97

Perform the sequence of operations as described in example 87, on the basis of 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, isomer forms And 1.0 cm3dichloromethane and 0,020 g of N-methylpiperazine. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 8 mm, height 8 cm), elwira 80 cm3dichloromethane and then a mixture of dichloromethane with methanol (95,5 by volume), collecting formed by eluting with a mixture of fractions with a volume of 2.5 cm3. Macarisin-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, isomer form And in the form of a white amorphous mass [NMR Spectrum1H (300 MHz, CDCl3,in M. D.): 2,28 (s: 3H), 2,30-2,60 (m: 8H), 2,80 (s: 3H), 3.45 points (s: 2H), 3,84 (m: 2H), 4,33 (m: 2H), 4,50 (s: 1H), at 6.84 (TT, J=8.5 and 2.5 Hz: 1H), 6,98 (m: 2H), 7,20-7,40 (m: 8H)].

Example 98

Perform the sequence of operations as described in example 87, on the basis of 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, isomer forms And 1.0 cm3dichloromethane and 0,018 g of the research. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 8 mm, height 8 cm), elwira 80 cm3dichloromethane and then a mixture of dichloromethane with methanol (95/5 by volume), collecting formed by eluting with a mixture of fractions with a volume of 2.5 cm3. Fractions 3-8 combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving of 0.022 g of 1-{(R*)-(4-chlorophenyl)[4-(morpholine-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)-(methylsulphonyl)methylene]azetidine, isomer form And in the form of a white amorphous mass [NMR Spectrum1H (300 MHz, CDCl3,in M. D.): to 2.41 (t, J=5 Hz: 4H), 2,80 (s: 3H), 3.43 points (s: 2H), 3,69 (t, J=5 Hz: 4H), 3,85 (m: 2H), 4,33 (m: 2H), 4,50 (s: 1H), at 6.84 (TT, J=8.5 and 2.5 Hz: 1H), 6,98 (m: 2H), 7,20-7,40 (m: 8H)].

Example 99

Carry out a sequence of Opera is Lionel)methylene]azetidine, isomer forms And 1.0 cm3dichloromethane and 0,020 g D-prolinol. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 8 mm, height 8 cm), elwira 80 cm3dichloromethane and then a mixture of dichloromethane with methanol (95/5 by volume), collecting formed by eluting with a mixture of fractions with a volume of 2.5 cm3. Fractions 3-8 combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 0.025 g of 1-{(R*)-(4-chlorophenyl)[4-((2R)-hydroxyethylpyrrolidine-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, isomer form And in the form of a white amorphous mass [NMR Spectrum1H (300 MHz, (CD3)2SO with the addition of a few drops CD3COOD d4in M. D.): 1,60-of 2.15 (m: 4H), 2,90 was 3.05 (m: 1H), 2,98 (s: 3H), 3,13 (m: 1H), 3,38 (m: 1H), 3,50-3,60 (m: 1H), of 3.56 (d, J=5 Hz: 2H), 3,90 (m: 2H), Android 4.04 (d, J=13.5 Hz: 2H), 4,21 (m: 2H), and 4.40 (d, J=13.5 Hz: 2H), 4,78 (s: 1H), 7,14 (m: 2H), 7,27 (TT, J=9 and 2.5 Hz: 1H), 7,30-of 7.55 (m: 8H)].

Example 100

Perform the sequence of operations as described in example 87, on the basis of 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, isomer forms And 1.0 cm3dichloromethane and 0.015 g diethylamine. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, mu), collecting formed by eluting with a mixture of fractions with a volume of 2.5 cm3. Fractions 4 to 9 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 0.025 g of 1-{(R*)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, isomer form And in the form of a white amorphous mass [NMR Spectrum1H (400 MHz, Dl3,in M. D.): of 1.03 (t, J=7 Hz: 6N), 2,50 (kV, J=7 Hz: 4H), 2,81 (s: 3H), 3,50 (s: 2H), 3,85 (m: 2H), 4,34 (m: 2H), 4,49 (s: 1H), at 6.84 (TT, J=9 and 2.5 Hz: 1H), 6,99 (m: 2H), 7,20-7,40 (m: 8H)].

Example 101

Perform the sequence of operations as described in example 87, on the basis of 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)-methylene]azetidine, isomer forms And 1.0 cm3dichloromethane and was 0.026 g of N-(hydroxyethyl)piperazine. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 8 mm, height 8 cm), elwira 80 cm3dichloromethane and then a mixture of dichloromethane with methanol (95/5 by volume), collecting formed by eluting with a mixture of fractions with a volume of 2.5 cm3. Fractions 3 to 10 are combined and evaporated to dryness under reduced pressure (2.7 kPa), getting to 0.032 g 1-{(R*)-(4-){4-[4-()-1--]}}}-3-[(3,5-)()2D/chr/948.gif">in M. D.): 2,40-2,60 (m: 8H), of 2.54 (t, J=5.5 Hz: 2H), 2,80 (s: 3H), 3,44 (s: 2H), 3,60 (t, J=5.5 Hz: 2H), 3,84 (m: 2H), 4,33 (m: 2H), 4,50 (s: 1H), at 6.84 (TT, J=9 and 2.5 Hz: 1H), 6,98 (m: 2H), 7,20-7,40 (m: 8H)].

Example 102

Perform the sequence of operations as described in example 87, on the basis of 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)-methylene]azetidine, isomer forms And 1.0 cm3dichloromethane and is 0.023 g of 2(RS),6(RS)-dimethylpyridine. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 8 mm, height 8 cm), elwira 80 cm3dichloromethane and then a mixture of dichloromethane with methanol (95/5 by volume), collecting formed by eluting with a mixture of fractions with a volume of 2.5 cm3. Fractions 2 to 9 are combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving 0,024 g of a mixture of isomers of 1-{(R*)-(4-chlorophenyl)[4-(2(RS),6(RS)-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, isomer form And in the form of a white amorphous mass [NMR Spectrum1H (400 MHz, CDCl3with the addition of a few drops CD3COOD d4, at a temperature of 353 K,in M. D.): 1,20-1,45 (m: 2H), 1,60 (d, J=7 Hz: 6N), 1,80-2,10 (m: 4H), 2,80 (s: 3H), 3,17 (m: 2H), 3,90 (m: 2H), 4,34 (t OSiR., J=16 Hz: 1H), and 4.40 (m: 2H), 4,43 (t user. J=16 Hz: 1H), 4,62 (s: 1H), 6,82 (TT, J=9 and 2.5 Hz: 1H), 6,98 (is from 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)-methylene]azetidine, isomer forms And 1.0 cm3dichloromethane and 0.024 g of piperazine-2-it. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 8 mm, height 8 cm), elwira 80 cm3dichloromethane and then a mixture of dichloromethane with methanol (95/5 by volume), collecting formed by eluting with a mixture of fractions with a volume of 2.5 cm3. Fractions 3-8 combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving of 0.022 g of 1-{(R*)-(4-chlorophenyl)[4-(piperazine-2-he-4-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)-(methylsulphonyl)methylene]azetidine, isomer form And in the form of a white amorphous mass [NMR Spectrum1H (400 MHz, CDCl3,in M. D.): 2,62 (t, J=5.5 Hz: 2H), 2,80 (s: 3H), 3,11 (s: 2H), 3,34 (m: 2H), 3,51 (s: 2H.), of 3.85 (m: 2H), 4,34 (m: 2H), 4,51 (s: 1H), USD 5.76 (m: 2H), 6,84 (t OSiR., JHF=9 Hz: 1H), 6,98 (m: 2H), 7,20-7,40 (m: 8H)].

Example 104

Perform the sequence of operations as described in example 87, on the basis of 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)-methylene]azetidine, isomer forms And 1.0 cm3dichloromethane and 0,020 g L-prolinol. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 8 mm, height 8 cm), elwira 80 cm3dichloromethane and then a mixture of dichloromethane with methanol (95/5 evaporated under reduced pressure (2.7 kPa), getting 0,028 g of 1-{(R*)-(4-chlorophenyl){4-[(2S)-(hydroxymethyl)pyrrolidin-1-yl-methyl]phenyl}methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, isomer form And in the form of a white amorphous mass [NMR Spectrum1H (300 MHz, CDCl3,in M. D.): 1,50-2,00 (m: 4H), 2,24 (m: 1H), 2,71 (m: 1H), 2,80 (s: 3H), 2,93 (m: 1H), 3,28 (d, J=13.5 Hz: 1H), 3,45 (m: 1H), the 3.65 (d, J=11,4 Hz: 1H), 3,84 (m: 2H), 3,91 (d, J=13.5 Hz: 1H), 4,33 (m: 2H), 4,50 (s: 1H), 6,83 (TT, J=8.5 and 2.5 Hz: 1H), 6,98 (m: 2H), 7,20-7,40 (m: 8H)].

Example 105

Perform the sequence of operations as described in example 87, on the basis of 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[{3,5-differenl)(methylsulphonyl)-methylene]azetidine, isomer forms And 1.0 cm3dichloromethane and is 0.023 g of (2S)-(methoxymethyl)pyrrolidine. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 8 mm, height 8 cm), elwira 80 cm3dichloromethane and then a mixture of dichloromethane with methanol (95/5 by volume), collecting formed by eluting with a mixture of fractions with a volume of 2.5 cm3. Fractions 2 to 6 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 0.037 g of 1-{(R*}-(4-chlorophenyl){4-[(2S)-(methoxymethyl)pyrrolidin-1-yl-methyl]phenyl}methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, isomer form And in the form of a white amorphous massin), 2,89 (m: 1H), of 3.25 to 3.45 (m: 4H), and 3.31 (s: 3H), 3,84 (m: 2H), Android 4.04 (d, J=13.5 Hz: 1H), 4,33 (m: 2H), 4,50 (s: 1H), at 6.84 (TT, J=8.5 and 2.5 Hz: 1H), 6,98 (m: 2H), 7,20-7,40 (m: 8H)].

Example 106

Perform the sequence of operations as described in example 87, on the basis of 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)-methylene]azetidine, isomer forms And 1.0 cm3dichloromethane and 0,020 g 2(RS),5(RS)-dimethylpyrimidine. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 8 mm, height 8 cm), elwira 80 cm3dichloromethane and then a mixture of dichloromethane with methanol (95/5 by volume), collecting formed by eluting with a mixture of fractions with a volume of 2.5 cm3. Fractions 3-6 are combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving 0,024 g of a mixture of isomers of 1-{(R*)-(4-chlorophenyl)[4-(2(RS),5(RS)-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)-methylene]azetidine, isomer form And in the form of a white amorphous mass [NMR Spectrum1H (400 MHz, Dl3with a few drops CD3COOD d4in M. D.): 1,68 (d, J=7 Hz: 6N), 2,00-of 2.15 (m: 4H), 2,82 (s: 3H), 3,22 (m: 2H), 3,92 (m: 2H), 4,30 (s: 2H), 4,33 (m: 1H), 4,45 (d, J==16.5 and 3 Hz: 1H), 4,63 (s: 1H), at 6.84 (TT, J=8.5 and 2.5 Hz: 1H), 7,00 (m: 2H), 7,20-of 7.55 (m: 8H)].

Example 107

Exercise sequence is tilsley)-methylene]azetidine, isomer forms And 1.0 cm3dichloromethane and is 0.023 g L-prolinamide. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 8 mm, height 8 cm), elwira 80 cm3dichloromethane and then a mixture of dichloromethane with methanol (95/5 by volume), collecting formed by eluting with a mixture of fractions with a volume of 2.5 cm3. Fractions 2-5 are combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving 0,028 g of 1-{(R*)-(4-chlorophenyl)[4-((2S)-carbamoylation-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl}methylene]azetidine, isomer form And in the form of a white amorphous mass [NMR Spectrum1H (400 MHz, CDCl3,in M. D.): 1,65-of 1.85 (m: 2H), 1,92 (m: 1H), of 2.15 to 2.35 (m: 2H), 2,80 (s: 3H), 3,00 (m: 1H), and 3.16 (DD, J=10 and 5.5 Hz, 1H), 3,41 (d, J=13.5 Hz: 1H), 3,86 (m: 2H), 3,89 (d, J=13.5 Hz: 1H), 4,33 (m: 2H), 4,51 (: 1H), 5,23 (m: 1H), at 6.84 (TT, J=9 and 2.5 Hz: 1H), 6,98 (m: 2H), 7,17 (m: 1H), 7,20-7,40 (m: 8H)].

Example 108

Perform the sequence of operations as described in example 87, on the basis of 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)-methylene]azetidine, isomer forms And 1.0 cm3dichloromethane and 0,021 g of diethanolamine. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 8 mm, height 8 cm), elwira 80 cm33
. Fractions 2 to 9 are combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving 0.004 g of 1-{(R*)-(4-chlorophenyl)[4-(dihydroxycinnamate)phenyl)methyl}-3-[(3,5-differenl)-(methylsulphonyl)methylene]azetidine, isomer form And in the form of a white amorphous mass [NMR Spectrum1H (300 MHz, CDCl3,in M. D.): 2,69 (t, J=5.5 Hz: 4H), 2,80 (s: 3H), 3,61 (t, J=5.5 Hz: 4H), 3,65 (s: 2H), 3,84 (m: 2H), 4,33 (m: 2H), 4,50 (s: 1H), 6,83 (TT, J=9 and 2.5 Hz: 1H), 6,98 (m: 2H), 7,20-7,40 (m: 8H)].

Example 109

To a solution of 0.24 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, isomer forms And, in 5 cm3dichloromethane add to 0.055 g of imidazole, refluxed for 3 hours and added to a mixture of 5 mg of sodium iodide. After 20 hours boiling under reflux with stirring and cooling to 20With the reaction mixture chromatographic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 1.0 cm, height 20 cm), elwira 120 cm3dichloromethane without fractionation and then a mixture of dichloromethane with methanol (98/2 by volume, then 96/4), collecting fractions with a volume of 4.0 cm3. Fractions 12 to 14 are combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving 0,039 g of 1-{(R*)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)>/p>Example 110

Perform the sequence of operations as described in example 87, on the basis of 0.50 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)-methylene]azetidine, a isomer form, 5 mg of sodium iodide, 15 cm3dichloromethane and 0,190 g pyrrolidine. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 1.5 cm, height 20 cm) at a pressure of argon 0.1 bar, elwira dichloromethane and then a mixture of dichloromethane with methanol (95/5 by volume), collecting fractions of 25 cm3. Fractions 20-40 combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 0.28 g of 1-{(R*)-(4-chlorophenyl)[4-(pyrrolidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, isomer form And in the form of a white amorphous mass, []20(365 nm)=+26,8+/- 0,8 (C=0,5%; dichloromethane) [NMR Spectrum1H (300 MHz, CDCl3,in M. D.): 1,78 (m: 4H), 2,50 (m: 4H), 2,80 (s: 3H), 3,57 (s: 2H), 3,84 (m: 2H), 4,34 (m: 2H), 4,50 (s: 1H), at 6.84 (TT, J=9 and 2.5 Hz: 1H), 6,98 (m, 2H), 7,20-7,40 (m: 8H)].

1-{(R*)-[4-(Chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, a isomer form, may be obtained as described in example 87 on the basis of 7.3 g of a mixture of 2 GeoStereo is 3-ol and 1-{(R*)-[4-(chloromethyl)-phenyl]-(4-chlorophenyl)methyl}-3-[(S)-(3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol, of 8.2 g of 4-dimethylaminopyridine, 150 cm3dichloromethane and 3.2 cm3methanesulfonanilide. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 3 cm, height 30 cm) at a pressure of argon 0.2 bar, elwira dichloromethane and collecting fractions of 100 cm3. Fractions 15 to 30 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 2.50 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, a isomer form, in the form of a white amorphous mass.

A mixture of 2 diastereoisomers 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl]methyl}-3-[(R)-(3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol and 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl]methyl}-3-[(S)-(3,5-differenl)(methylsulphonyl)-methyl]azetidin-3-ol may be obtained as described in example 87 from the 11.0 g of a mixture of 2 diastereoisomers 1-{(R*)-(4-chlorophenyl)[4-hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol and 1-{(R*)-(4-chlorophenyl)[4-hydroxymethyl)phenyl]methyl}-3-[(S)-(3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol, 250 cm3dichloromethane and 3.1 cm3thionyl chloride. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 3 cm, height 30 cm) at a pressure of argon and 9-25 combined and evaporated to dryness under reduced pressure (2.7 kPa), getting to 7.3 g of a mixture of 2 diastereoisomers (a forms) 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(R)-(3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol and 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(S)-(3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol as a white amorphous mass.

A mixture of 2 diastereoisomers (a forms) 1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol and 1-{(R*)(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(S)-(3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol may be obtained as described in example 87, on the basis of 18.0 g of a mixture of 2 diastereoisomers (forms) 3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(R)-(3,5-differenl)-(methylsulphonyl)methyl]azetidin-3-ol and 3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(S) - (3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol, 150 cm3anhydrous toluene and 100 cm320%-aqueous solution of diisobutylaluminium in toluene. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 3 cm, height 30 cm) at a pressure of argon 0.1 bar, elwira with a mixture of cyclohexane with ethyl acetate (50/50 by volume), collecting fractions of 50 cm3. Fractions 15 to 30 are combined and evaporated to dryness at]methyl}-3-[(R)-(3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol and 1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(S)-(3,5-differenl)(methylsulphonyl)methyl]azetidin-3-ol as a white amorphous mass.

A mixture of 2 diastereoisomers (forms) 3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(R)-(3,5-differenl)(methylsulphonyl)methyl]azetidine and 3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(S)-(3,5-differenl)(methylsulphonyl)methyl]azetidine can be obtained as described in example 40 on the basis of 11.2 g (3,5-diferensial)methylsulfone, 350 cm3tetrahydrofuran (THF), 34 cm3a 1.6 n solution of n-utility in hexane, 11.2 g of 1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-one, isomer forms, and 5.5 cm3acetylchloride. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 4 cm, height 40 cm), elwira with a mixture of cyclohexane with ethyl acetate (70/30 by volume), collecting fractions of 100 cm3. Fractions 10 to 30 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 21 g is not sufficiently pure amorphous mass of cream color, which chromatographic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 4 cm, height 40 cm), elwira dichloromethane, collecting fractions of 100 cm3. Faction 11-30 combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving of 20.0 g of a mixture of 2 diastereoisomers (a forms) 3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)-phenyl]methyl}-3-[(S)-(3,5-differenl)(methylsulphonyl)methyl]-azetidine in the form of a white amorphous mass.

1-{(R*)-(4-Chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-azetidin-3-one, isomer form, may be obtained as described in example 40 on the basis of 8.7 cm3oxalicacid, 350 cm3dichloromethane, 14.2 cm3dimethyl sulfoxide, 29.0 g of 1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-ol, a isomer form, and 43 cm3of triethylamine. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 4 cm, height 40 cm), elwira dichloromethane and collecting fractions of 250 cm3. Fractions 7 to 25 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 1.55 g of 1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-one, isomer form, in the form of an orange oil.

1-{(R*)-(4-Chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-azetidin-3-ol, a isomer form, may be obtained by repeating the sequence of operations described by KATRITZKY A. R. et al. in J. Heterocycl. Chem., 271 (1994), of 25.5 g of methyl(-)-4-[1-(R*)-amino-1-(4-chlorophenyl)methyl]benzoate, 250 cm3ethanol, 7.9 g of sodium bicarbonate and 7.7 cm3epibromohydrin. Obtain 2.9 g of 1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-ol, a isomer form, in the form of a yellow oil.

Methyl (-)-4-[(R*)-amino-(4-chlorophenyl)methyl]benzoate may be obtained held the 8 cm3boiling under reflux of ethanol with 5% water. The resulting crystals are filtered, drained and dried under reduced pressure (2.7 kPa) to give 2.2 g of D-(-)-tartrate methyl (-)-4-[(R*)-amino-(4-chlorophenyl)methyl]benzoate in the form of white crystals, which are then dissolved in 50 cm3ethyl acetate. To the resulting solution was added 50 cm31 n sodium hydroxide solution. The solution is stirred and divided into phases. The organic phase is washed with 50 cm3water, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa) to give 1.9 g of methyl (-)-4-[(R*)-amino-(4-chlorophenyl)methyl]benzoate as a white solid, []20(365 nm)=-58,1+/- 1 (C=0,5%).

Example 111

Repeat the sequence of operations of example 110, stirring the reaction mixture for 48 h at 20With and on the basis of 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)-methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, a isomer form, 10 cm3dichloromethane and 0,030 cm3N-methylpiperazine. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 small, diameter 8 mm, height 5 cm), elwira 50 cm3dichloromethane and then a mixture of dichlor combined and evaporated to dryness under reduced pressure (2.7 kPa), getting 0.025 g of 1-{(R*)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, a isomer form, in the form of a white amorphous mass [NMR Spectrum1H (300 MHz, CDCl3,in M. D.): 2,28 (s: 3H), 2,44 (m: 8H), 2,80 (s: 3H), 3.45 points (s: 2H), 3,85 (m: 2H), 4,34 (m: 2H), 4,50 (s: 1H), at 6.84 (TT, J=9 and 2.5 Hz: 1H), 6,99 (m: 2H), 7,20-7,40 (m: 8H)].

Example 112

Repeat the sequence of operations of example 110, stirring the reaction mixture for 48 h at 20With and on the basis of 0.05 g of 1-{(R*)-[(4-chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]-azetidine, a isomer form, 10 cm3dichloromethane and 0,030 cm3L-prolinol. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 8 mm, height 5 cm), elwira 50 cm3dichloromethane, then with a mixture of dichloromethane with methanol (95/5 by volume), collecting formed by eluting with a mixture of fractions of 3 cm3. Fractions 2-8 combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 0.025 g of 1-{(R*)-(4-chlorophenyl){4-[(2S)-(hydroxymethyl)pyrrolidin-1-yl-methyl]phenyl}methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, a isomer form, in the form of an amorphous mass of cream-colored [NMR Spectrum1H (300 is (m: 1H), the 3.65 (d, J=10.5 and 3.5 Hz: 1H), 3,85 (m: 2H), 3,92 ( d, J=13.5 Hz: 1H), 4,34 (m: 2H), 4,50 (s: 1H), at 6.84 (TT, J=8.5 and 2.5 Hz: 1H), 6,98 (m: 2H), 7,15-7,40 (m: 8H)].

Example 113

Repeat the sequence of operations of example 110, stirring the reaction mixture for 48 h at 20With and on the basis of 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]-azetidine, a isomer form, 10 cm3dichloromethane and 0,030 cm3D-prolinol. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 8 mm, height 5 cm), elwira 50 cm3dichloromethane, then with a mixture of dichloromethane with methanol (95/5 by volume), collecting formed by eluting with a mixture of fractions of 3 cm3. Fractions 2 to 9 are combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving 0,029 g of 1-{(R*)-(4-chlorophenyl){4-[(2R)-(hydroxymethyl)pyrrolidin-1-yl-methyl]phenyl}methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, a isomer form, in the form of an amorphous mass of cream-colored [NMR Spectrum1H (300 MHz, CDCl3,in M. D.): 1,50-2,00 (m: 4H), 2,24 (m: 1H), 2,71 (m: 1H), 2,81 (s: 3H), 2,93 (m: 1H), 3,28 (d, J=13.5 Hz: 1H), 3,44 (t rassal., J=10.5 and 2.5 Hz: 1H), 3,66 (DD, J=10.5 and 3.5 Hz: 1H), 3,85 (m: 2H), 3,92 (d, J=13.5 Hz: 1H), 4,33 (m: 2H), 4,50 (s: 1H), at 6.84 (TT, J=9 and 2.5 Hz: 1H), 6,98 (m: 2H), 7,15-7.40 Uchenie 48 h at 20With and on the basis of 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]-azetidine, a isomer form, 10 cm3dichloromethane and 0,030 cm3of the research. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 8 mm, height 5 cm), elwira 50 cm3dichloromethane, then with a mixture of dichloromethane with methanol (95/5 by volume), collecting formed by eluting with a mixture of fractions of 3 cm3. Fractions 2 to 9 are combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving 0,047 g of 1-{(R*)-(4-chlorophenyl)[4-(morpholine-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, a isomer form, in the form of a white amorphous mass [NMR Spectrum1H (300 MHz, CDCl3,in M. D.): 2,40 (m: 4H), 2,81 (s: 3H), 3.43 points (s: 2H), 3,69 (m: 4H), 3,84 (m: 2H), 4,34 (m: 2H), 4,50 (s: 1H), at 6.84 (TT, J=8.5 and 2.5 Hz: 1H), 6,99 (m: 2H), 7,20-7,40 (m: 8H)].

Example 115

Repeat the sequence of operations of example 110, stirring the reaction mixture for 48 h at 20With and on the basis of 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]-azetidine, a isomer form, 10 cm3dichloromethane and 0,030 cm3thiomorpholine. The crude product chromatographic Am a mixture of dichloromethane with methanol (95/5 by volume), collecting formed by eluting with a mixture of fractions of 3 cm3. Fractions 2 to 9 are combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving 0,047 g of 1-{(R*)-(4-chlorophenyl)[4-(thiomorpholine-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, a isomer form, in the form of a white amorphous mass [NMR Spectrum1H (300 MHz, CDCl3,in M. D.): 2,60-2,75 (m: 8H), 2,81 (s: 3H), 3,44 (s: 2H), 3,85 (m: 2H), 4,34 (m: 2H), 4,50 (s: 1H), at 6.84 (TT, J=8.5 and 2.5 Hz : 1H), 6,98 (m: 2H), 7,15-7,40 (m: 8H)].

Example 116

Repeat the sequence of operations of example 110, stirring the reaction mixture for 48 h at 20With and on the basis of 0,200 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]-azetidine, a isomer form, 5.0 cm3dichloromethane and 0,120 cm3piperazine-2-it. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 1 cm, height 10 cm), elwira 50 cm3dichloromethane, then with a mixture of dichloromethane with methanol (95/5 by volume), collecting formed by eluting with a mixture of fractions of 5 cm3. Faction 3-13 combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving 0,090 g of 1-{(R*)-(4-chlorophenyl)[4-(piperazine-2-on-1-yl-methyl)phenyl]methyl}-3-[(3,5-di the Ute sequence of operations of example 110, based on 0,200 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]-azetidine, a isomer form, 5.0 cm3dichloromethane and 0,120 cm33.3 dimethylpiperidine. The crude product chromatografic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 1 cm, height 10 cm), elwira 50 cm3dichloromethane, then with a mixture of dichloromethane with methanol (95/5 by volume), collecting formed by eluting with a mixture of fractions of 5 cm3. Fractions 4 to 11 are combined and evaporated to dryness under reduced pressure (2.7 kPa), receiving 0,120 g of 1-{(R*)-(4-chlorophenyl)[4-(3,3-dimethylpiperidino)phenyl]methyl}-3-[(3,5-differenl)-(methylsulphonyl)methylene]azetidine, a isomer form, in the form of a white powder.

Example 118

Repeat the sequence of operations of example 110, stirring the reaction mixture for 72 h at 20With and on the basis of 0,200 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, a isomer form, 5.0 cm3dichloromethane and 0,080 cm3imidazole. The reaction mixture is directly chromatographic on a column of silica gel (grain size of 0.06-0,200 mm, diameter 1.0 cm, height 10 cm), elwira 100 cm3dichloromethane without fractionation and then the mixture is m3. Fractions 5 to 12 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 0.035 g of 1-{(R*)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)-(methylsulphonyl)methylene]azetidine, a isomer form, in the form of a white powder, []20D=-6,7(C=0,5%, dichloromethane).

Example 119

To a cooled to -70With suspension 6,12 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one and of 5.15 g of methyl 5-(methylsulphonyl)thiophene-2-carboxylate in 200 cm3of tetrahydrofuran is added in an argon atmosphere 2,47 g of potassium tert-butylate, stirred the mixture for 1 h 30 min at a temperature close to -70With, then add a solution of 1.7 cm3methanesulfonanilide 8 cm3diethyl ether. After stirring for 1 hour at a temperature close to -70With that, the mixture is left to the spontaneous establishment at room temperature, add 80 cm3distilled water, evaporated on a rotary evaporator up to one-third the original volume and extracted with 500 cm3dichloromethane. The organic phase is washed three times with 80 cm3distilled water, dried over magnesium sulfate and evaporated to dryness PR,04 mm diameter 7.5 cm, height 35 cm) at a nitrogen pressure of 0.2 bar, elwira with a mixture of cyclohexane with ethyl acetate (70/30 by volume), collecting fractions of 40 cm3. Fractions 19 to 29 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 1.6 g of 1-[bis(4-chlorophenyl)methyl]-3-[(methylsulphonyl)(2-methoxycarbonylamino-5-yl)methylene]azetidine in the form of an amorphous mass of cream-colored [NMR Spectrum1H (400 MHz, CDCl3,in M. D.): 2.91 in (s: 3H), 3,88 (s: 3H), 4,08 (m: 2H), 4,37 (m: 2H), 4.53-in (s: 1H), 7,25 was 7.45 (m: N), 7,71 (d, J=3.5 Hz: 1H)].

Faction 34-48 are combined and then evaporated to dryness under reduced pressure (2.7 kPa) to give 2.6 g of 1-[bis(4-chlorophenyl)methyl]-3-hydroxy-3-[(methylsulphonyl)(2-methoxy-carbonylation-5-yl)methylene]azetidine-(RS) in the form of a cream-colored powder [NMR Spectrum1H (400 MHz, (CD3)2SO d6,in M. D.): 2,87 (s: 3H), 2,89 (l, 0=8 Hz: 1H), 2,96 (d, J=8 Hz: 1H), 3,21 (d, J=8 Hz: 1H), 3,76 (d, J=8 Hz: 1H), 3,81 (s: 3H), 4,55 (s: 1H), 4,86 (s: 1H), 6,86 (C: 1H), 7,35-7,45 (m: N), 7,73 (d, J=4 Hz: 1H)].

Methyl 5-(methylsulphonyl)thiophene-2-carboxylate can be obtained in the following way: to a solution of 16 g of methyl 5-bromomethylbiphenyl 150 cm3the add tetrahydrofuran at room temperature 6,94 g methanesulfonate sodium. The suspension is boiled with reverse holocom under stirring for further 3 hours. The mixture is evaporated to dryness under reduced pressure (2.7 kPa), to the obtained residue, add 150 cm3distilled water, then twice extracted with 300 cm3ethyl acetate. The organic phase is successively washed with 100 cm3distilled water and 2 times 50 cm3saturated aqueous solution of sodium chloride, then dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa), thus obtaining 14 g of methyl 5-(methylsulphonyl)thiophene-2-carboxylate in the form of a yellow solid with so square up to 133[NMR Spectrum1H (400 MHz, (CO3)2SO d6 at a temperature of 373 K,in M. D.): 3,05 (s: 3H), 4,22 (m: 2H), and 4.40 (m: 2H), 4,98 (user.: 1H), 7,30 (d, J=3.5 Hz: 1H), 7,39 (d, J=8 Hz: 4H), 7,50 (d, J=8 Hz: 4H), 7,66 (d, J=3.5 Hz: 1H)].

Methyl 5-bromomethylbiphenyl can be obtained by the method Curtin, M. L., S. K. Davidsen, H. R., Heyman, Garland R. B., Sheppard, G. S., J. Med. Chem., 1998, 41 (1), 74-95.

Example 120

To a solution of 163,5 mg of the hydrochloride of 1-[bis(4-chlorophenyl)methyl]-3-[(methylsulphonyl)(2-hydroxycarbonyl-5-yl)methylene]azetidine 3 cm3dichloromethane added at room temperature 47 μl of N,N’-diisopropylcarbodiimide, 3,66 mg 4-dimethylaminopyridine and 60 μl of isobutylamine, stir the mixture for 18 h the mixture with dichloromethane-ethyl acetate (90/10 by volume). Receive 60 mg of 1-[bis(4-chlorophenyl)methyl]-3-[(2-isobutyleneisoprene-5-yl)(methylsulphonyl)methylene]-azetidine in the form of colorless nail Polish [NMR Spectrum1H (400 MHz, CDCl3,in M. D.): 0,97 (d, J=7 Hz: 6N), a 1.88 (m: 1H), 2,90 (s: 3H) at 3.25 (t, J=7 Hz: 2H), 4,08 (m: 2H), 4,36 (m: 2H), to 4.52 (s: 1H), 4,56 (t OSiR., J=7 Hz: 1H), 7,20-7,40 (m: 10H)].

Hydrochloride of 1-[bis(4-chlorophenyl)methyl]-3-[(methylsulphonyl)(2-hydroxycarbonyl-5-yl)methylene]azetidine can be obtained as follows: to a solution of 1-[bis(4-chlorophenyl)methyl]-3-[(methylsulphonyl)(2-methoxycarbonylamino-5-yl)methylene]azetidine 250 cm3acetic acid is added at room temperature to 250 cm3concentrated hydrochloric acid. The mixture is stirred at a temperature of 50C for 38 h and evaporated to dryness under reduced pressure (2.7 kPa). To the residue 3 times add 250 cm3toluene and evaporated to dryness under reduced pressure (2.7 kPa). After trituration of the residue in 400 cm3diethyl ether obtain 14.2 g of the hydrochloride of 1-[bis(4-chlorophenyl)methyl]-3-[(methylsulphonyl)(2-hydroxycarbonyl-5-yl)methylene]azetidine in the form of a powder beige.

Example 121

To a cooled to -70With the solution of 0.92 g of 1-[bis(4-chlorophenyl)methyl]azetidine of 0.37 g of potassium tert-butylate and stirred for 2 hours at -70C. then add 10 cm30.1 G. of hydrochloric acid and leave the mixture to the spontaneous establishment at room temperature. After adding 50 cm3ethyl acetate, the reaction mixture is divided into phases, the organic phase is dried over magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (grain size of 0.20-0.06 mm, diameter 3 cm, height 50 cm) at a nitrogen pressure of 0.8 bar, elwira with a mixture of cyclohexane with ethyl acetate (70/30 by volume), collecting fractions with a volume of 120 cm3. Fractions 11-18 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 10 cm3diisopropyl ether and 30 cm3pentane, receiving of 0.30 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-ethoxycarbonylphenyl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol as a white solid [NMR Spectrum1H (400 MHz, CDCl3,in M. D.): 2,73 (s: 3H), 3,05 (AB, J=9 Hz: 2H), with 3.27 (d, J=9 Hz: 1H), 3,63 (s: 1H), 3,79 (d, J=9 Hz: 1H), 3,95 (s: 3H), 4,32 (s: 1H), 4,59 (s: 1H), 7,15-7,35 (m: 8H), 7,51 (t, J=8 Hz: 1H), 7,94 (t OSiR., J-8 Hz: 1H), 8,10 (t OSiR., J=8 Hz: 1H), 8,32 (user.,: 1H)].

Example 122

Repeating the sequence of operations example 1 on the basis of 0.66 g of methyl (pyridin-4-yl)sulfone and 1.18 g of 1-[biesta 50 cm) at a nitrogen pressure of 0.5 bar with a mixture of cyclohexane with ethyl acetate (70/30 by volume) as eluent and collecting fractions with a volume of 120 cm3obtain 0.20 g of a white solid. The latter absorb 20 cm3diisopropyl ether. After filtration, the cake and drying obtain 0.16 g of 1-[bis(4-chlorophenyl)methyl]-3-[(methysulfonyl)(pyridine-4-yl)methyl-(RS)]azetidin-3-ol [NMR Spectrum1H (400 MHz, CDCl3,in M. D.): was 2.76 (s: 3H), 3,03 (AB, J=9 Hz: 2H), with 3.27 (d, J=9 Hz: 1H), 3,53 (s: 1H), 3,83 (d, J=9 Hz: 1H), 4,32 (s: 1H), 4,51 (s: 1H), 7,20-7,30 (m: 8H), 7,63 (d, J=6 Hz: 2H), 8,68 (d, J=6 Hz: 2N)].

Methyl(pyridin-4-yl)sulfon can be obtained in accordance with JP 43002711.

Example 123

Repeating the sequence of operations of the example 1 according to 0.47 g of methyl (pyridin-3-yl)sulfone and of 0.83 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one, after purification on a column of silica gel (grain size of 0.20-0.06 mm, diameter 3 cm, height 50 cm) at a nitrogen pressure of 0.5 bar with a mixture of cyclohexane with ethyl acetate (70/30 by volume) as eluent and collecting fractions with a volume of 120 cm3obtain 0.50 g of a white solid. The latter absorb 30 cm3diisopropyl ether. After filtration, the cake and drying obtain 0.40 g of 1-[bis(4-chlorophenyl)methyl]-3-[(methylsulphonyl)(pyridin-3-yl)methyl-(RS)]azetidin-3-ol [NMR Spectrum1H (300 MHz, CDCl3,in M. D.): 2,77 (s: 3H), 3,03 (AB, 0=9 Hz: 2H), 3,28 (d, J=9 Hz: 1H), 3,66 (s: 1H), 3,83 (l, J,/p>Methyl(pyridine-3-ylmethyl)sulfon can be obtained in accordance with JP 43002711.

Example 124

To a suspension of 150 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)benzoic acid, activated on tetraterpenoids (TFF) resin (165 μm) in 3 cm3dichloromethane after pre-mixing for 90 minutes at a temperature close to 20With add at the same temperature 0,00388 cm3N-(3-aminopropyl)of the research. The suspension is stirred for 22 hours at a temperature close to 20With, and filtered on a porous filter. The solid residue washed twice with 1.5 cm3dichloromethane. The filtrates are combined and evaporated to dryness under reduced pressure (2.7 kPa) and temperatures approaching 40With, thus receiving 60 mg of 3-({1-bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(3-morpholine-4-yl-propyl)benzamide as a pale yellow amorphous mass.

3-({1-Bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(3-morpholine-4-yl-propyl)benzamide can also be obtained in the following way: to a solution of 300 mg of 3-({1-bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)benzoic acid in 10 cm3anhydrous (over chloride is, close to 20With, dimethylformamide 0,083 cm3N-(3-aminopropyl)of the research, 110 mg of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 5 mg of 4-dimethylaminopyridine. The resulting solution is stirred for about 22 hours at a temperature close to 20With, and then evaporated to dryness under reduced pressure (2.7 kPa) and temperatures approaching 40C. the Solid residue absorb 25 cm3dichloromethane, washed twice 20 cm3saturated aqueous sodium bicarbonate solution. After phase separation the organic phase is dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa) and temperatures approaching 40C. Receive 400 mg of yellow oil which is purified by chromatography under a nitrogen pressure of 0.8 bar 60 cm3silica gel (0,040-0,063 mm) in a column with a diameter of 2.2 cm, elwira a mixture of methanol/dichloromethane (2/98 by volume). The fractions containing only the desired product are pooled and evaporated to dryness under reduced pressure (2.7 kPa) and 40C for 2 hours Get 130 mg 3-({1-[(4-)]-3-})-N-(3--4--)948.gif">in M. D.): 1,68 (m: 2H), 2,25-2,40 (m: 6N), 2,97 (: CH3), 3,20-to 3.35 (m: 2H), only 3.57 (t, J=4.5 Hz: 4H), 3,81 (m: 2H), 4,22 (m: 2H), 4,79 (s: 1H), was 7.36 (d, J=8.5 Hz: 4H), 7,46 (d, J=8.5 Hz: 4H), 7,50-7,60 (m: 2H), 7,83 (user.: 1H), 7,86 (t OSiR., J=8 Hz: 1H), 8,53 (t, J=5.5 Hz: 1H}].

Example 125

Working under the conditions described in example 124, from 150 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}-methanesulfonamide)benzoic acid, activated on TF-resin (165 μm), and 0,033 cm3N,N’-dimethyl-1,3-propandiamine obtain 52 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(3-dimethylaminopropyl)benzamide as a white powder [NMR Spectrum1H (400 MHz, (CD3)2SO d6,in M. D.): 1,65 (m: 2H), 2,18 (: 6N), of 2.20 to 2.35 (m: 2H), 2,98 (s: 3H), of 3.25 to 3.45 (m: 2H), 3,82 (m: 2H), 4,23 (m: 2H), 4,80 (s: 1H), was 7.36 (d, J=8.5 Hz: 4H), 7,46 (d, J=8.5 Hz: 4H), 7,50-7,60 (m: 2H), 7,83 (user.: 1H), 7,86 (t OSiR., J-8 Hz: 1H), to 8.57 (t, J=5.5 Hz: 1H)].

Example 126

Working under the conditions described in example 124, from 150 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}-methanesulfonamide)benzoic acid, activated on TF-resin (165 μm), and 0,033 cm31-(aminoethyl)pyrrolidine obtain 39 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(2-pyrrolidin-1-yl-ethyl)-benzamide as a pale yellow powder [NMR Spectrum 1,80-2,00 (m: 4H), 2,97 (s: 3H), 3,20 (m: 6N), of 3.57 (t, J=6.5 Hz: 2H), 3,80 (m: 2H), 4,23 (m: 2H), 4,77 (s: 1H), 7,35 (d, J=8.5 Hz: 4H), 7,45 (d, J=8.5 Hz: 4H), 7,50-the 7.65 (m: 2H), 7,87 (user.: 1H), of 7.90 (d of usher., J=7.5 Hz: 1H)].

Example 127

Working under the conditions described in example 124, from 150 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}-methanesulfonamide)benzoic acid, activated on TF-resin (165 μm), and 0,033 cm31-(dimethipin)-2-Propylamine obtain 49 mg of 3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ilidene}methanesulfonyl)-N-(2-dimethylamino-1-methylethyl)benzamide as a white powder [NMR Spectrum1H (400 MHz, (CD3)2SO d6,in M. D.): 1,13 (d, J=6.5 Hz: 3H), 2,10-of 2.25 (m: 1H), 2,15 (: 6N), of 2.38 (DD, J=13 and 8 Hz: 1H), 2,98 (s: 3H), 3,80 (m: 2H), 4,14 (m: 1H), 4,23 (m: 2H), 4,79 (s: 1H), was 7.36 (d, J=8 Hz: 4H), 7,45-7,60 (m: 2H), 7,46 (d, J=8 Hz: 4H), 7,83 (user.: 1H), 7,87 (t OSiR., J=8 Hz: 1H), 8,16 (t OSiR., J=8 Hz: 1H)].

Example 128

Working under the conditions described in example 124, from 150 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}-methanesulfonamide)benzoic acid, activated on TF-resin (165 μm), and was 0.026 cm3piperidine obtain 56 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-piperidine-1-yl-benzamide as a white powder [NMR Spectrum1H (400 MHz, (CD3)2SO d6,p>Working under the conditions described in example 124, from 150 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}-methanesulfonamide)benzoic acid, activated on TF-resin (165 μm), and 0,0265 cm3isobutylamine obtain 46 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-isobutylbenzene in the form of a white powder [NMR Spectrum1H (400 MHz, (CD3)2SO d6,in M. D.): 0,89 (d, J=7 Hz: 6N), of 1.85 (m: 1H), 2,98 (s: 3H), to 3.09 (t, J-6.5 Hz: 2H), 3,82 (m: 2H), 4,23 (m: 2H), 4,79 (s: 1H), was 7.36 (d, J=8.5 Hz: 4H), 7,46 (d, J=8.5 Hz: 4H), 7,50-7,60 (m: 2H), 7,84 (user.: 1H), 7,88 (t OSiR., J=8 Hz: 1H), 8,51 (t, J=6 Hz: 1H)].

Example 130

Working under the conditions described in example 124, from 150 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}-methanesulfonamide)benzoic acid, activated on TF-resin (165 μm), and 0,0316 cm3N-(3-aminopropyl)imidazole obtain 54 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(3-imidazol-1-yl-propyl)benzamide as a yellow amorphous mass [NMR Spectrum1H (400 MHz, (CD3)2SO d6,in M. D.): 1,97 (m: 2H), 2,98 (s: 3H) at 3.25 (m: 2H), 3,81 (m: 2H), was 4.02 (t, J-7 Hz: 2H), 4,23 (m: 2H), 4,79 (s: 1H), 6,85-6,95 (m: 2H), was 7.36 (d, J=8.5 Hz: 4H), 7,46 (d, J=8.5 Hz: 4H), 7,50-7,60 (m: 2H), 7,84 (user.: 1H), 7,88 (t OSiR., J=8 Hz: 1H), 8,56 (t, J=5.5 Hz: 1H)].

PR is n}-methanesulfonamide)benzoic acid, activated on TF-resin (165 μm), and 0,030 cm3N,N-(dimethyl)Ethylenediamine obtain 53 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(2-dimethylaminoethyl)benzamide in the form of an amorphous mass ochre [NMR Spectrum1H (400 MHz, (CD3)2SO d6,in M. D.): 2,18 (2C: 6N), 2,35 at 2.45 (m: 2H), 2,98 (s: 3H), 3,25-3,50 (m: 2H), 3,81 (m: 2H), 4,23 (m: 2H), 4,79 (s: 1H), was 7.36 (d, J=8 Hz: 4H), 7,46 (d, J=8 Hz: 4H), 7,45-7,60 (m: 2H), 7,83 (user.: 1H), 7,86 (t OSiR., J=8 Hz: 1H), 8,43 (t, J=6.5 Hz: 1H)].

Example 132

Working under the conditions described in example 124, from 150 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}-methanesulfonamide)benzoic acid, activated on TF-resin (165 μm), and 0,0141 cm3methylhydrazine, obtain 42 mg of N’-methylhydrazino 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)benzoic acid as a pale yellow amorphous mass [NMR Spectrum1H (400 MHz, (CD3)2SO d6,in M. D.): 2,96 (s: 3H), 3,18 (user.: 3H), 3,83 (m: 2H), 4,22 (m: 2H), 4,80 (user.: 2H), 7,35-the 7.65 (m: N)].

Example 133

Working under the conditions described in example 124, from 150 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}-methanesulfonamide)benzoic acid, activated on TF-resin (165 μm), and 0,0345 cm3N-(2-amino-ethyl)benzamide in the form of an amorphous mass ochre [NMR Spectrum1H (400 MHz, (CD3)2SO d6,in M. D.): 2,30-of 2.45 (m: 4H), 2,46 (t, J=7.5 Hz: 2H), 2,98 (s: 3H), 3,38 (m: 2H), 3,50-the 3.65 (m: 4H), 3,82 (m: 2H), 4,24 (m: 2H), 4,79 (s: 1H), was 7.36 (d, J=8.5 Hz: 4H), 7,46 (d, J=8.5 Hz: 4H), 7,50-7,60 (m: 2H), 7,83 (user.: 1H), a 7.85 (DD, J=8 and 2 Hz: 1H), 8,45 (t, J=6.5 Hz: 1H)].

Example 134

Working under the conditions described in example 124, from 150 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}-methanesulfonamide)benzoic acid, activated on TF-resin (165 μm), and 0,0396 cm32-(aminomethyl)-N-ethylpyrrolidin obtain 58 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamide in the form of an amorphous mass ochre.

3-({1-[Bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamide can also be obtained in the conditions described in example 126, from 700 mg of 3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ilidene}methanesulfonamide)benzoic acid, activated on TF-resin (770 µm) 0,324 cm3of triethylamine and 0.25 cm32-(aminomethyl)-N-ethylpyrrolidin and getting 370 mg of a solid product, which is purified by chromatography under a nitrogen pressure of 0.7 bar at 100 cm3silica gel (0,040-0,063 mm) in a column of diameter 2.5 cm, elwira a mixture of methanol, diplom pressure (2.7 kPa) and 40C for 2 h Receive 160 mg of 3-({1-[Bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(1-ethylpyrrolidin-2-ylmethyl) benzamide as a pale yellow powder [NMR Spectrum1H (400 MHz, (CD3)2SO d6,in M. D.): the 1.04 (t, J=7 Hz: 3H), 1,50-1,70 (m, 3H), 1,78 (m: 1H), and 2.14 (m: 1H), 2,28 (m: 1H), 2,59 (m: 1H), 2,83 (m: 1H), 2,98 (s: 3H), 3.00 and is 3.15 (m: 2H), 3,30 is-3.45 (m: 1H), 3,82 (m: 2H), 4,23 (m: 2H), 4,79 (s: 1H), was 7.36 (d, 0=8.5 Hz: 4H), 7,46 (d, J=8.5 Hz: 4H), 7,50-7,60 (m: 2H), 7,86 (user.: 1H), 7,85 (t OSiR., J=8 Hz: 1H), to 8.41 (t, J=6 Hz: 1H)].

Example 135

Working under the conditions described in example 124, on the basis of 110 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}-methanesulfonamide)benzoic acid, activated on TF-resin (121 μm), and is 0.023 cm3neopentylene obtain 44 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-cyclohexylmaleimide in the form of a pale yellow powder [NMR Spectrum1H (400 MHz, (CD3)2SO d6,in M. D.): 0,90 (: N), 2,98 (s: 3H), 3,11 (d, J=6.5 Hz: 2H), 3,82 (m: 2H), 4,23 (m: 2H), 4,79 (s: 1H), was 7.36 (d, J=8 Hz: 4H), 7,46 (d, J=8 Hz: 4H), 7,45-7,60 (m: 2H), 7,83 (t usher.: 1H), 7,86 (t OSiR., J=8 Hz: 1H), of 8.37 (t, J=6.5 Hz: 1H)].

Example 136

Working under the conditions described in example 124, on the basis of 110 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}- methanesulfonamide)benzoic acid is 4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-cyclohexylmaleimide in the form of a pale yellow powder, has the following characteristics: [NMR Spectrum1H (400 MHz, (CD3)2SO d6,in M. D.): 0,92 (m: 2H), 1,17 (m: 4H), of 1.45 and 1.80 (m 5H), 2,97 (s: 3H), 3,10 (d, J=6 Hz: 2H), 3,80 (m: 2H), 4,23 (m: 2H), 4,79 (s: 1H), was 7.36 (d, J=8 Hz: 4H), 7,46 (d, J=8 Hz: 4H), 7,45-7,60 (m: 2H), 7,83 (user.: 1H), 7,86 (t OSiR., J=8 Hz: 1H), of 8.47 (t, J=6 Hz: 1H)].

Example 137

Working under the conditions described in example 124, on the basis of 110 mg of 3-[{1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}-methanesulfonamide)benzoic acid, activated on TF-resin (121 µm) was 0.026 cm3of triethylamine and 21 mg of the hydrochloride of aminomethylpropanol, obtain 68 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-cyclopropanecarboxamide in the form of a yellow amorphous mass [NMR Spectrum1H (400 MHz, (CD3)2SO d6,in M. D.): 0,24 (m: 2H), 0,44 (m: 2H), 1,03 (m: 1H), 2,98 (s: 3H) and 3.15 (t, J=6 Hz: 2H), 3,82 (m: 2H), 4,23 (m: 2H), 4,79 (s: 1H), was 7.36 (d, J=8.5 Hz: 4H), 7,46 (d, J=8.5 Hz: 4H), 7,50-7,60 (m: 2H), 7,86 (user.: 1H), 7,89 (t OSiR., J=8 Hz: 1H), 8,64 (t, J=6 Hz: 1H)].

Example 138

Working under the conditions described in example 124, on the basis of 110 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}-methanesulfonamide)benzoic acid, activated on TF-resin (121 μm), and is 0.023 cm32-methylbutylamine obtain 49 mg of 3-({1-[bis(4-chlorophenyl)methyl]azeti src="https://img.russianpatents.com/chr/948.gif">in M. D.): to 0.80-0.95 (m: 6N), 1,05-1,20 (m: 1H), 1,41 (m: 1H), 1,64 (m: 1H), 2,98 (s: 3H), 3,06 (m: 1H), 3,19 (m: 1H), 3,81 (m: 2H), 4,23 (m: 2H), 4,79 (s: 1H), was 7.36 (d, J=8 Hz: 4H), 7,46 (d, J=8 Hz: 4H), 7,35-7,60 (m: 2H), 7,84 (user.: 1H), 7,87 (t OSiR., J=8 Hz: 1H), 8,49 (t, J=5.5 Hz: 1H)].

Example 139

Working under the conditions described in example 124, on the basis of 110 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}-methanesulfonamide)benzoic acid, activated on TF-resin (121 μm), and 0,028 cm32-methylphenylamine obtain 42 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(2-phenylpropyl)benzamide as a yellow pasty substances [NMR Spectrum1H (400 MHz, (CD3)2SO d6,in M. D.): 1,24 (d, J=7 Hz: 3H), 2,97 (s: 3H), of 3.07 (m: 1H), 3,20-3,50 (m: 2H), 3,80 (m: 2H), 4.2V.3 (m: 2H), 4,80 (s: 1H), 7,10-7,40 (m): 5H), 7,38 (d, J=8 Hz: 4H), 7,47 (d, J=8 Hz: 4H), 7,50-7,60 (m: 2H), to 7.77 (user.: 1H), 7,79 (t OSiR., J=8 Hz: 1H), 8,55 (t, J=6 Hz: 1H)].

Example 140

Working under the conditions described in example 124, on the basis of 110 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}-methanesulfonamide)benzoic acid, activated on TF-resin (121 μm), and at 0.020 cm3tetrahydrofurfurylamine obtain 42 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(tetrahydrofuran-2-yl-methyl)-benzamide as a yellow testoobraznoj the 2,98 (s: 3H), 3,20-3,40 (m: 2H), 3,63 (m: 1H), of 3.77 (m: 1H), 3,82 (m: 2H), 3,98 (m: 1H), 4,23 (m: 2H), 4,79 (s: 1H), was 7.36 (d, J=8 Hz: 4H), 7,46 (d, J=8 Hz: 4H), 7,50-7,60 (m: 2H), 7,84 (user.: 1H), 7,88 (t OSiR., J=8 Hz: 1H), at 8.60 (t, J=6 Hz: 1H)].

Example 141

Working under the conditions described in example 124, on the basis of 110 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}-methanesulfonamide)benzoic acid, activated on TF-resin (121 μm), and 39 mg of 2,2-diphenylethylamine obtain 39 mg of 3-((1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}-methanesulfonyl)-N-(2,2-diphenylether)benzamide as a yellow pasty substances [NMR Spectrum1H (400 MHz, (CD3)2SO d6,in M. D.): 2,95 (s: 3H), of 3.77 (m: 2H), 3,90 (DD, J=8 and 6.5 Hz: 2H), 4,22 (m: 2H), 4,42 (t, J=8 Hz: 1H), 4,79 (s: 1H), 7,10-7,40 (m: 10H), 7,38 (d, J=8.5 Hz: 4H), 7,45-7,60 (m: 2H), of 7.48 (d, J=8.5 Hz: 4H), of 7.70 (m: 2H), 8,56 (t, J=6.5 Hz: 1H)].

Example 142

Working under the conditions described in example 124, on the basis of 110 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}-methanesulfonamide)benzoic acid, activated on TF-resin (121 μm), and 19 mg of 2-ethylbutylamine obtain 47 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(2-ethylbutyl)benzamide as a pale yellow powder [NMR Spectrum1H (400 MHz, (CD3)2SO d6,in M. D.): 0,86 (t, J=7 Hz: 6N), 1,20-1,40 (m: 4H), 1,50 (, ,86 (e OSiR., J=8 Hz: 1H), 8,42 (t, J=6 Hz: 1H)].

Example 143

Working under the conditions described in example 124, on the basis of 110 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}-methanesulfonamide)benzoic acid, activated on TF-resin (121 µm) was 0.026 cm3of triethylamine and 39 mg of methyl ester hydrochloride 4-aminoheterocycles-carboxylic acid get 47 mg methyl ester 4-{[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)benzoylamine]methyl}cyclohexanecarboxylic acid in the form of a pale yellow pasty substances [NMR Spectrum1H (400 MHz, (CD3)2SO d6,in M. D.): 0,90-1,05 (m: 2H), 1,20-1,40 (m: 2H), 1,52 (m: 1H), 1.70 to 2,00 (m: 4H), and 2.27 (m: 1H), 2,98 (s: 3H), of 3.12 (t, J=6.5 Hz: 2H), 3,60 (s: 3H), 3,80 (m: 2H), 4,23 (m: 2H), 4,79 (s: 1H), was 7.36 (d, J=8 Hz: 4H), 7,46 (d, J=8 Hz: 4H), 7,45-7,60 (m: 2H), 7,83 (user.: 1H), 7,87 (t OSiR., J=8 Hz: 1H), and 8.50 (t, J=6 Hz: 1H)].

3-({1-[Bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)benzoic acid, activated on TF-resin can be obtained in the following conditions: pre-mixed for 10 min at a temperature close to 20With the suspension of 1.07 g of resin THF (free phenolic function, 1.1 mmol/g, i.e., 1,17 mm) 15 cm3anhydrous dimethylformamide was added when, after stirring for 10 minutes at a temperature close to 20To add 14 mg of 4-dimethylaminopyridine, stirred for another 10 min at the same temperature and add 0,185 cm31,3-diisopropylcarbodiimide. After stirring for 23 hours at a temperature close to 20C, the suspension was filtered, the resin washed with 45 cm3of dimethylformamide, 45 cm3of tetrahydrofuran and 45 cm3dichloromethane, and then dried in vacuum to constant weight, thus obtaining 1.5 g activated on TFF-pitch 3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ilidene}methanesulfonamide)benzoic acid as a pale yellow resin.

Tetraterpenoids resin, characterized by the following structure:

can be obtained as follows: to a suspension of 2 g sales aminomethylpropanol resin (0,39 mmol/g; 0.78 mmol) in 15 cm3of dimethylformamide after 5 min stirring at a temperature close to 20With consistently add 492 mg diisopropylcarbodiimide, 819,3 mg of 2,3,5,6-titrator-4-hydroxybenzoic acid and 50 mg of 4-dimethylaminopyridine. After stirring for 20 h at a temperature close to 20With, the suspension is filtered and washed with whom. The obtained resin was dried under reduced pressure and a temperature close to 40With, after approximately 20 h, stirred at a temperature close to 20With, in the form of a suspension in a mixture of piperidine-dimethylformamide (10/90 by volume). The suspension is then filtered and washed the resin 3 times with 20 cm3of dimethylformamide, 3 times 20 cm3of tetrahydrofuran and 3 times 20 cm3dichloromethane. The resulting resin was dried under reduced pressure and a temperature close to 40With, then it is used in this state.

Example 144

A solution of 76 mg of tert-butyl methyl ether(2-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-yl}-2-oxoethyl)carbamino acid 2.5 cm3formic acid is stirred for 1 h at a temperature close to 45C. the Reaction mixture is evaporated to dryness under reduced pressure (5 kPa) and temperatures approaching 30C. the Residue absorb 10 cm3ethyl acetate and alkalinized with 10 cm3saturated aqueous sodium bicarbonate solution. After phase separation the organic phase is washed with 10 cm3water, dried over magnesium sulfate, filtered what I 51 mg of 2-amino-1-{4-[3-({1-bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-yl}ethanone in the form of a beige lacquer colors [NMR Spectrum1H (300 MHz, Dl3,in M. D.): 1,95-of 2.25 (m of user.: 2H), 2,77 (s: 3H), 3,10-3,30 (m: 4H), 3,50-3,60 (m: 2H), 3,56 (user.: 2H), 3.75 to 3,90 (m: 4H), 4,34 (m: 2H), 4,50 (s: 1H), 6,84 (t OSiR., J=8 Hz: 1H), 6,91 (DD, J=8 and 2 Hz: 1H), 7,01 (m: 1H), 7,20-7,40 (m: N)].

Example 145

To 108,5 mg 1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine successively added at a temperature close to 20With, of 1.02 g of 1-{3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) media (5 mm), 44 mg of N-BOC-glycine and 10 cm3dichloromethane. After stirring for 20 h at a temperature close to 20C, the reaction mixture is filtered on a Frit. The resin is washed three times 5 cm3dichloromethane. The combined filtrates washed with 20 cm3water, dried over magnesium sulfate, filtered on a Frit and evaporated to dryness under reduced pressure (1 kPa) and temperatures approaching 40With getting 143 mg of tert-butyl methyl ether(2-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-yl}-2-oxoethyl)carbamino acid in the form of a cream-colored lacquer [NMR Spectrum1H (400 MHz, (CD3)2SO d6,in M. D.): 1,40 (: N),N), of 6.99 (DD, J=8 and 2.5 Hz: 1H), 7,27 (t, J=8 Hz: 1H), was 7.36 (d, J=8 Hz: 4H), 7,46 (t, J=8 Hz: 4H)].

Reagent EDCI media is corrupt and can also be obtained by the method of M. Desai, L. Stramiello, Tetrahedron Letters, 34, 48, 7685-7688.

Example 146

A solution of 81 mg of tert-butyl methyl ether(2-{4-[3-({1-bis(4-chlorophenyl)methyl]-azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-yl}-2-oxoethyl)-N-methylcarbamyl acid 2.5 cm3formic acid is stirred for 1 h at a temperature close to 45C. the Reaction mixture is evaporated to dryness under reduced pressure (5 kPa) and temperatures approaching 30C. the Residue absorb 10 cm3ethyl acetate and alkalinized with 10 cm3saturated aqueous sodium bicarbonate solution. After phase separation the organic phase is washed with 10 cm3water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (1 kPa) and temperatures approaching 40With, receiving 58 mg 1-{4-[3-({1-bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-yl}-2-methylaminoethanol in the form of a beige lacquer colors [NMR Spectrum1H (300 MHz, Dl3,in M. D.): 1,95-2,15 (m of user.: 2N), of 2.51 (user.: 3H), 2,77 (s: 3H), 3,10-3,30 (m: 4H), 3,49 (user.: 2H), 3,5

To 108,5 mg 1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine successively added at a temperature close to 20With, of 1.02 g of reagent EDCI media (5 mm) of 47.3 mg N-SIDE-sarcosine and then 10 cm3dichloromethane. After stirring for 20 h at a temperature close to 20C, the reaction mixture is filtered on a Frit. The resin is washed three times 5 cm3dichloromethane. The combined filtrates washed with 20 cm3water, dried over magnesium sulfate, filtered on a Frit and evaporated to dryness under reduced pressure (1 kPa) and temperatures approaching 40With getting 143 mg of tert-butyl methyl ether(2-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-yl}-2-oxoethyl)-N-methylcarbamyl acid in the form of a cream-colored lacquer [NMR Spectrum1H (400 MHz, (CD3)2SO d6,in M. D.) (at room temperature is observed mixture of rotamers): 1,31-1,41 (2C: N in total), 2,78-2,81 (2C: 3H in total), 2,93 (2 s: 3H), 3,10-3,25 (m: 4H), 3.45 points-of 3.65 (m: 4H), 3,80 (m: 2H), 4,06-4.09 to (2C: 2H in total), 4,19 (M: 2H), 4,78 (s: 1H), 6,83 (t OSiR., J=8 Hz: 1H), 6,93 (user.: 1H), 7,00 (DD, J=8 and 2.5 Hz.: 1H), 7,27 (t, J=8 Hz: 1H), was 7.36 (d, J=8 Hz: 4H), 7,46 (t, J=8 Hz:ina successively added at a temperature close to 20With 2 cm3dichloromethane and 11 mg methylisothiocyanate. After stirring for 6 h at a temperature close to 20With, to the reaction mixture of 0.05 cm3water. After stirring for 15 min at the same temperature, the reaction mixture was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (1 kPa) and temperatures approaching 40With, receiving 61 mg N-methylamide 4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-thiocarbonic acid in the form of a beige lacquer colors [NMR Spectrum1H (400 MHz, Dl3,in M. D.): 2,77 (s: 3H), 3,20 (d, J=5 Hz: 3H), 3,32 (t, J=5.5 Hz: 4H), 3,81 (m: 2H), 4.00 points (t, J=5.5 Hz: 4H), 4,33 (m: 2H), 4,49 (s: 1H), 5,63 (kV OSiR., J=5 Hz: 1H), 6,80 (d, J=8 Hz: 1H), 6,85 (DD, J=8 and 2.5 Hz: 1H), 6,94 (user.: 1H), 7,20-7,30 (m): 5H), 7,32 (d, J=8 Hz: 4H)].

Example 149

To 54,25 mg 1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine successively added at a temperature close to 20With 2 cm3dichloromethane and 11.5 mg of methyl isocyanate. After stirring for 4 h at a temperature close to 20With, to the reaction mixture add the Ute over magnesium sulfate, filtered on a paper filter and evaporated to dryness under reduced pressure (1 kPa) and temperatures approaching 40With getting 66 mg N-methylamide 4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-carboxylic acid in the form of a beige lacquer colors [NMR Spectrum1H (400 MHz, CDCl3,in M. D.): 2,75 (s: 3H), 2,85 (d, J=5 Hz: 3H), 3,19 (t OSiR., J=5.5 Hz: 4H), 3,52 (t OSiR., J=5.5 Hz: 4H), 3,80 (m: 2H), 4,33 (m: 2H), 4,45 (kV OSiR., J=5 Hz: 1H), 4,49 (s: 1H), for 6.81 (d, J=8 Hz: 1H), 6.89 in (DD, J=8 and 2.5 Hz: 1H), 6,98 (user.: 1H), 7,20-7,30 (m): 5H), 7,32 (d, J=8 Hz: 4H)].

Example 150

To 54,25 mg 1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine successively added at a temperature close to 20With 2 cm3pyridine and 10.4 mg methylcarbamate. After stirring for 6 h at a temperature close to 20C, the reaction mixture is evaporated to dryness under reduced pressure (5 kPa) and temperatures approaching 30C. the Obtained residue absorb 5 cm3ethyl acetate and 5 cm3water. After phase separation the organic phase is washed with 2 cm3water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced on henyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-carboxylic acid in the form of a beige lacquer colors [NMR Spectrum1H (400 MHz, Dl3,in M. D.): 2,75 (s: 3H), 3.15 in (t OSiR., J=5.5 Hz: 4H), 3,62 (m: 4H), 3,74 (s: 3H), 3,80 (m: 2H), 4,32 (m: 2H), 4,49 (s: 1H), for 6.81 (d, J=8 Hz: 1H), 6.90 to (DD, J=8 and 2.5 Hz: 1H), 6,99 (user.: 1H), 7,20-7,40 (m: N)].

Example 151

To a solution of 54,25 mg 1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine in 2 cm3dichloroethane successively added at a temperature close to 20With 3.2 mg of acetoxyvalerenic of sodium and 22 mg samalanga aldehyde. After stirring for 4 h at a temperature close to 20With, to the reaction mixture add 3 cm3dichloromethane and 2 cm3saturated aqueous sodium bicarbonate solution. After phase separation the organic phase is dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (1 kPa) and temperatures approaching 40With, receiving 63 mg 1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]-4-isobutylpyrazine in the form of a beige lacquer colors [NMR Spectrum1H (400 MHz, Dl3,in M. D.): 0,92 (d, J=7 Hz: 6N), 1,82 (m: 1H), and 2.14 (d, J=8 Hz: 2H), 2,54 (t, J=5.5 Hz: 4H), 2,75 (s: 3H), 3,18 (t, J=5.5 Hz: 4H), 3,81 (m: 2H), 4,32 (m: 2H), 4,49 (s: 1H), 6,78 (d, J=8 Hz: 1H), 6,89 (DD, J=8 and 2.5 Hz: the Dean-3-ilidene)methanesulfonamide)phenyl]piperazine in 2 cm3dichloroethane successively added at a temperature close to 20With 3.2 mg of acetoxyvalerenic sodium and 13 mg of acetaldehyde. After stirring for 21 hours at a temperature close to 20With, to the reaction mixture add 2 cm3saturated aqueous sodium bicarbonate solution. After separation of the phases the organic phase extravert 2 cm3dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (1 kPa) and a temperature close to 20With, receiving 60 mg of solid residue, which absorb 2 cm3methanol and 0.5 cm3dichloromethane. The resulting solution was placed on a block of silicon oxide (500 mg SCX phase). Block washed with 5 cm3methanol and then target product elute 5 cm32 N. methanolic ammonia solution and then an additional 5 cm3of methanol. The filtrate is evaporated to dryness under reduced pressure (1 kPa) and temperatures approaching 30With getting 42 mg 1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]-4-ethylpiperazine in the form of colorless nail Polish beige [NMR Spectrum1H (300 M is usher., J=5 Hz: 4H), 3,82 (m: 2H), 4,33 (m: 2H), 4,49 (s: 1H), 6,79 (t OSiR., J=8 Hz: 1H), 6,91 (DD, J=8 and 2 Hz: 1H), 6,98 (m: 1H), 7,20-7,40 (m: N)].

Example 153

To 54 mg 1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine successively added at a temperature close to 20With 2 cm3pyridine and 11.5 mg of acetic anhydride. After stirring for 23 hours at a temperature close to 20C, the reaction mixture is evaporated to dryness under reduced pressure (1 kPa) and temperatures approaching 30C. the Obtained residue absorb 5 cm3ethyl acetate and 2 cm3water. After phase separation the organic phase is washed with 2 cm3water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (1 kPa) and temperatures approaching 40With, receiving 52 mg of 4-acetyl-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine in the form of an amorphous mass beige [NMR Spectrum1H (300 MHz, Dl3,in M. D.): 2,16 (s: 3H), 2,77 (s: 3H), 3,10-3,25 (m: 4H), 3,63 (t OSiR., J=5.5 Hz: 2H), 3,78 (t OSiR., J=5.5 Hz: 2H), 3,82 (m: 2H), 4,34 (m: 2H), 4,50 (s: 1H), 6,84 (t OSiR., J=8 Hz: 1H), 6,92 (DD, J=8 and 2 Hz: 1H), 7,02 (m: 1H), 7,20-7,40 (m: N)].

Example 154

add at a temperature close to 20With, 511 mg of EDCI media (2.5 mm), and 11.5 mg of N,N-dimethylglycine and 5 cm3dichloromethane. After stirring for 24 cow at a temperature close to 20To add 35 mg N,N-dimethylglycine. After stirring for 96 hours at a temperature close to 20C, the reaction mixture is filtered on a Frit, three times washing the resin 2.5 cm3dichloromethane. The combined filtrates are washed with 10 cm3water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (5 kPa) at a temperature close to 20With, receiving 53 mg 1-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-yl}-2-dimethylaminoethanol in the form of an amorphous mass beige [NMR Spectrum1H (400 MHz, (CD3)2SO d6,in M. D.): 2,20 (: 6N), 2,94 (s: 3H), 3,12 (s: 2H), and 3.16 (m: 4H), to 3.58 (m: 2H), 3,68 (m: 2H), 3,80 (m: 2H), 4,19 (m: 2H), 4,78 (s: 1H), for 6.81 (d of usher., J=8 Hz: 1H), 6,93 (user.: 1H), 6,99 (DD, J=8 and 2.5 Hz: 1H), 7,26 (t, J=8 Hz: 1H), was 7.36 (d, J=8 Hz: 4H), 7,46 (d, J=8 Hz: 4H)].

Example 155

A solution of 320 mg of tert-butyl methyl ether 4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]-piperazine-1-carboxylic acid 5 cm3C. the Reaction mixture is evaporated to dryness under reduced pressure (5 kPa) and temperatures approaching 30C. the Residue absorb 20 cm3ethyl acetate and alkalinized with 10 cm3saturated aqueous sodium bicarbonate solution. After phase separation the organic phase is washed three times with 10 cm3water, filtered and evaporated to dryness under reduced pressure (1 kPa) and temperatures approaching 40C. the resulting residue is purified by applying in the form of a solution in a minimum amount of dichloromethane to put on a plate of silica gel [gel thickness of 0.5 mm, 5 plates 2020 cm, eluent: dichloromethane, methanol (80/20 by volume)]. Detected using UV radiation zone, the corresponding adsorbed to the desired product, scraped, and collected by the silica gel was washed on a porous glass with a mixture of dichloromethane-methanol (75/25 by volume). The filtrates are combined and evaporated to dryness under reduced pressure (1 kPa) and temperatures approaching 30With, receiving 180 mg 1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]-piperazine in the form of a white powder [NMR Spectrum1H (300 MHz, Dl3,

Tert-butyl ether 4-[3-({1-[bis(4-chlorophenyl)-methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-carboxylic acid can be obtained by repeating the sequence of operations of example 4 according to 1.32 g of tert-butyl methyl ether 4-[3-({1-[bis(4-chlorophenyl)methyl]-3-hydroxyazetidine-3-yl}methanesulfonamide)phenyl]piperazine-1-carboxylic acid, 0,232 cm3methanesulfonanilide and 0,733 g of 4-dimethylaminopyridine, purifying the obtained residue by chromatography on a column of silica gel (grain size of 0.06-0,200 mm, diameter 2 cm, height 35 cm) at atmospheric pressure with a mixture of dichloromethane-methanol (99,5/a 0.5 by volume) as eluent and collecting fractions with a volume of 15 cm3. The fractions containing the desired product are pooled and evaporated to dryness under reduced pressure (5 kPa) and temperatures approaching 30With getting 0,86 g tert-butyl ester 4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-carboxylic acid as a white amorphous mass [NMR Spectrum1H (400 MHz, Dl3,in M. D.): 1,50 (: N), 2,77 (s: 3H), 3,14 (t, J=5 Hz: 4H), of 3.57 (t, J=5 Hz: 4H), 3,81 (m: 2H), 4,34 (m: 2H), 4,49 (s: 1H), for 6.81 (d, J=8 Hz: 1H), 6.90 to (DD, J=8 and 2.5 Hz: 1H), 6,99 (user.: 1H), 7,20-7,30 (m): 5H), 7,32 (d, J=8 Hz: 4H)].

3a 1.6 M solution of n-utility in hexane; gain of 1.37 g of tert-butyl methyl ether 4-[3-({1-[bis(4-chlorophenyl)methyl]-3-hydroxyazetidine-3-yl}methanesulfonamide)phenyl]piperazine-1-carboxylic acid in the form of a powder beige.

Tert-butyl ester 4-(3-methanesulfonyl)phenyl)piperazine-1-carboxylic acid can be obtained by repeating the sequence of operations of example 10 from 1.55 g of tert-butyl ester 4-(3-chloromethylene)piperazine-1-carboxylic acid and 0,766 g methanesulfonate sodium: obtain 0.9 g of tert-butyl ester 4-(3-methanesulfonyl)phenyl)piperazine-1-carboxylic acid in the form of a powder beige.

Tert-butyl ester 4-(3-chloromethylene)piperazine-1-carboxylic acid can be obtained by reaction of 16.4 g of tert-butyl ester 4-(3-hydroxymethylene)piperazine-1-carboxylic acid in 150 cm3dichloromethane at a temperature close to 20C 29 cm3diisopropylethylamine and 8.7 cm3methanesulfonanilide, in which, after purification through column chromatography (silica gel 0,063-0,200 mm, diameter 6 cm, height 45 cm, fraction volume of 100 cm3) with dichloromethane as eluent, to obtain 15 g of tert-rubble ester 4-(3-hydroxymethylene)piperazine-1-carboxylic acid can be obtained by reaction of 15.8 g of a mixture of tert-butyl esters of 4-(3-ethoxycarbonylphenyl)-piperazine-1-carboxylic acid and 4-(3-n-butyloxycarbonyl)-piperazine-1-carboxylic acid in a solution of 500 cm3anhydrous THF at a temperature close to -10With 102 cm320%-aqueous solution of hydride diisobutylaluminum in toluene. Obtain 12.8 g of tert-butyl ester 4-(3-hydroxymethylene)piperazine-1-carboxylic acid in the form of oil beige.

A mixture of tert-butyl esters of 4-(3-ethoxycarbonylphenyl)piperazine-1-carboxylic acid and 4-(3-n-Butylochka-carbonitril)piperazine-1-carboxylic acid can be obtained according to the method described in patent WO 9726250.

Example 156

Repeating the sequence of operations of example 38 (method 2) on the basis of 0.3 g of 3-acetoxy-1-[bis(4-ethoxycarbonylphenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]-azetidin and 105 mg hydroxide monohydrate lithium 10 cm3acetonitrile, at a temperature close to 70To receive 0.24 g of 1-[bis(4-ethoxycarbonylphenyl)methyl]-3-[(3,5-differenl)-(methylsulphonyl)methylene]azetidine as an orange amorphous mass [NMR Spectrum1H (300 MHz, Dl3,in M. D.): 2,81 (s: 3H), 3,85-3,95 (m: 2H), 3,89 (: 6N), 4,37 (m: 2H), 4,67 (s: 1H), at 6.84 (TT, J=9 and 2.5 Hz: 1H), 6,99 (m: 2H), 7,50 (d, J=8: 4N), of 7.97 (d, J=8 Hz: 4H)].

Example 157

Repeating the sequence of operations of example 40, from of 4.45 g (3,5-diferensial)methylsulfone, 6,36 g of 1-[the lithium in hexane. Obtain 10.8 g of 3-acetoxy-1-[bis(4-ethoxycarbonylphenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)of azetidine in the form of a pale yellow amorphous mass [NMR Spectrum1H (400 MHz, (CD3)2SO d6,in M. D.): 2,03 (s: 3H), 2,96 (s: 3H), 3.25 to 3.40 in (m: 2H), 3,52 (t OSiR., J=8 Hz: 1H), 3.75 to 3,90 (m: 1H), 3,82 (s: 3H), 3,83 (s: 3H), 4.72 in (s: 1H), are 5.36 (s: 1H), 7,27 (d, J=8 Hz: 2H), 7,35-7,45 (m: 2H), 7,43 (d, J=8 Hz: 2H), 7,54 (TT, J=9.5 and 2.5 Hz: 1H), 7,81 (d, J=8 Hz: 2H), 7,88 (d, J=8 Hz: 2H)].

1-[Bis(4-ethoxycarbonylphenyl)methyl)azetidin-3-one may be obtained in the same way as 1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-one (example 110), 1-[bis(4-ethoxycarbonylphenyl)methyl]-azetidin-3-ol.

1-[Bis (4-ethoxycarbonylphenyl)methyl]azetidin-3-ol may be obtained in the same way as 1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-ol (example 110), bis(4-ethoxycarbonylphenyl)methylamine.

Bis(4-ethoxycarbonylphenyl)methylamine can be obtained in the same way as methyl ester 4-[(RS)-amino-(4-chlorophenyl)methylbenzoic acid (example 87), of 4,4’-dimethoxybenzophenone.

Example 158

Repeating the sequence of operations of example 110, on the basis of 40 mg of (RS)-1-{[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl) methyl)matilal what){3-[(3,5-differenl)methysulfonylmethane]azetidin-1-yl}methyl)benzyl]the research in the form of a white amorphous mass [NMR Spectrum1H (400 MHz, Dl3,in M. D.): 2,41 (m: 4H), 2,80 (s: 3H), 3,42 (s: 2H), 3,69 (t, J=4.5 Hz: 4H), 3,84 (m: 2H), 4,33 (m: 2H), 4,50 (s: 1H), 6,83 (TT, J=9 and 2.5 Hz: 1H), 6,98 (m: 2H), 7,20-7,40 (m: 8H)].

(RS)-1-{[4-(Chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-differenl)(methylsulphonyl) methyl)methylsulfonylmethyl]azetidin can be obtained by repeating the sequence of operations of example 87 on the basis of 415 mg (RS)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine, 5 cm3dichloromethane, 0,19 cm3methanesulfonanilide and 0.53 cm3diisopropylethylamine: receive UAH 421,2 mg of (RS)-1-{[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-differenl)-(methylsulphonyl) methyl)methylsulfonylmethyl]azetidine in the form of an amorphous mass of cream color.

Example 159

To a solution of 33 mg of 1-benzhydryl-3-{[3-(4-bromobutyrate)phenyl]methysulfonylmethane}of azetidine 2 cm3anhydrous acetonitrile at a temperature close to 20With, successively added in an inert atmosphere of argon 25 mg of potassium carbonate and 0,016 cm3of the research. After stirring for 17 h at a temperature close to 20C, the reaction mixture is diluted with 10 cm3ethyl acetate and 4 cm3water. Separated the blockhead magnesium, filtered on a Frit and evaporated to dryness under reduced pressure (1 kPa) and temperatures approaching 40C. the resulting residue is purified by applying in the form of a solution in a minimum amount of dichloromethane to put on a plate of silica gel [gel thickness of 0.5 mm, 2 plates 2020 cm, eluent: dichloromethane/methanol (92,5/a 7.5 by volume)]. Detected using UV radiation zone, the corresponding adsorbed to the desired product, scraped and collected by the silica gel was washed on a porous glass with a mixture of dichloromethane-methanol (80/20 by volume). The filtrates are combined and evaporated to dryness under reduced pressure (1 kPa )and temperatures approaching 40With getting to 25.2 mg 4-(4-{3-[(1-benzhydrylamine-3-ilidene)methysulfonylmethane)phenoxy}butyl)research in the form of a pale yellow amorphous mass [NMR Spectrum1H (400 MHz, Dl3,in M. D.): of 1.66 (m: 2H), 1,81 (m: 2H), 2.40 a (t, J=7.5 Hz: 2H), 2,46 (m: 4H), 2,77 (s: 3H), and 3.72 (t, J=5 Hz: 4H), 3,84 (m: 2H), 3.96 points (t, J=6.5 Hz: 2H), 4,36 (m: 2H), 4.53-in (s: 1H), 6.87 in (DD, J=8 and 2 Hz: 1H), 6,93 (d, J=8 Hz: 1H), of 6.96 (d, J=2 Hz: 1H), 7,10-7,35 (m 7H), 7,42 (d, J=8 Hz: 4H)].

1-Benzhydryl-3-{[3-(4-bromobutyrate)phenyl]methysulfonylmethane}azetidin can be obtained as follows: to a solution of 5 is the temperature, close to 20With, successively added in an inert atmosphere of argon 0,586 cm31,4-dibromobutane and 255 mg of potassium carbonate. Then the reaction mixture was refluxed for 7 h in an inert atmosphere of argon, leave for 4 days at a temperature close to 20With, and filtered on a porous filter through celite. The solid residue is rinsed with ethyl acetate and then the filtrate is evaporated to dryness under reduced pressure (10 kPa) and temperatures approaching 40C. the Obtained brown oil is purified by chromatography at atmospheric pressure on 40 g of silica gel (0,063-0,200 mm) placed in a column of diameter 3 cm, elwira a mixture of methanol-dichloromethane (0.5 in/99,5 by volume). Fractions (10 cm3containing only the desired product are pooled and evaporated to dryness under reduced pressure (to 0.27 kPa) and 40C for 2 hours Get 408,4 mg 1-benzhydryl-3-{[3-(4-bromobutyrate)phenyl]methysulfonylmethane}of azetidine in the form of a brown amorphous mass.

Example 160

To a solution of 1-benzhydryl-3-{[3-(4-bromopropylate)phenyl]-methysulfonylmethane}of azetidine 3.5 cm3anhydrous acetonitrile at a temperature close to 20With consistently Uchenie 20 hours at a temperature of, close to 20C, the reaction mixture is diluted with 40 cm3ethyl acetate and 10 cm3water. The separated organic phase is washed with 10 cm3water and then with 2 times 10 cm3saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered on a Frit and evaporated to dryness under reduced pressure (9 kPa) and temperatures approaching 40C. the Obtained yellow clear lacquer coating in the form of a solution in a minimum amount of dichloromethane to put on a plate of silica gel [gel thickness of 0.5 mm, 2 plates 2020 cm, eluent: dichloromethane/methanol (97,5/a 2.5 by volume)]. Detected using UV radiation zone, the corresponding adsorbed to the desired product, scraped and collected by the silica gel was washed on a porous glass with a mixture of dichloromethane-methanol (85/15 by volume). The filtrates are combined and evaporated to dryness under reduced pressure (1 kPa) and temperatures approaching 40With getting 33 mg 4-(4-{3-[(1-benzhydryl-azetidin-3-ilidene)methysulfonylmethane)phenoxy}propyl)the research in the form of a white amorphous mass [NMR Spectrum1H (300 MHz, (CD3)2SO d6,in M. D.): 1,87 (m: 2H), 2,37 (m: 4H), 2,42 (t, J=Hz: 4H), of 7.48 (d, J=7.5 Hz: 4H)].

1-Benzhydryl-3-{[3-(4-bromopropylate)phenyl]methysulfonylmethane}azetidin can be obtained as follows: to a solution of 500 mg of 1-benzhydryl-3-[(3-hydroxyphenyl)(methylsulphonyl)methylene]azetidine 10 cm3methyl ethyl ketone at a temperature close to 20With, successively added in an inert atmosphere of argon 0.5 cm31,4-dibromopropane and 255 mg of potassium carbonate. Then the reaction mixture was refluxed for 7 h in an inert atmosphere of argon, leave for 4 days at a temperature close to 20With, and filtered on a porous filter through celite. The solid residue is rinsed with ethyl acetate and then the filtrate is evaporated to dryness under reduced pressure (10 kPa) and temperatures approaching 40C. the Obtained brown oil is purified by chromatography at atmospheric pressure on 40 g of silica gel (0,063-0,200 mm) placed in a column of diameter 3 cm, elwira a mixture of methanol-dichloromethane (0.5 in/99,5 by volume). Fractions (10 cm3containing only the desired product are pooled and evaporated to dryness under reduced pressure (to 0.27 kPa) and 40C for 2 hours Get 511,1 mg 1-benzhydryl-3-{[3(4-bromopropylate)phenyl]methanesulfonic the th compounds of formula I or their isomers, or salts of these compounds as such or in the form of compositions in which these compounds combined with any other pharmaceutically compatible product, which can be inert or physiologically active. Drugs can be administered orally, parenterally, rectally or topically.

As solid compositions for oral administration can be used in tablets, pills, powders (gelatin or starch capsules or granules. The active ingredient according to the invention in the above compositions are mixed in a stream of argon with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica. These compositions may also contain substances which are not diluents, for example one or more lubricating means, such as magnesium stearate or talc, a colorant, forming a shell (pills) or lustering.

As liquid compositions for oral administration can be used in solutions, suspensions, syrups and pharmaceutically acceptable elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. Song data can mitigatory or stabilizers.

Sterile compositions for parenteral administration can be predominantly aqueous and non-aqueous solutions, suspensions or emulsions. As solvent or filler can be used water, propylene glycol, polyethylene glycol, vegetable oils (particularly olive oil) suitable for injectable organic esters (for example, etiloleat) or other suitable organic solvents. These compositions can also contain adjuvants, in particular moisturizing, isotonic, emulsifying, dispersing and stabilizing agents. Sterilization can be done in several ways, such as aseptic filtration, by the introduction into the composition of sterilizing agents, by irradiation or by heating. The composition can also be prepared in the form of sterile solid compositions which can be dissolved just before the introduction of sterile water or other sterile injectable medium.

Compositions for rectal injection are candles or rectal capsules containing in addition to the active product neutral substances, such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

mi, to these nose drops or sprays.

In human therapy the compositions according to the invention is particularly valuable in the treatment and/or prevention of psychoses, including schizophrenia, anxiety, depression, epilepsy, neurodegeneration, cerebral and spinal disorders, cranial trauma, panic attacks, peripheral neuropathy, glaucoma, migraine, Parkinson's disease, Huntington's chorea, Raynaud's syndrome, tremor, obsessive desire to perform the action, senile dementia, disorders of the thymus, Tourette syndrome, retarded dyskinesia, bipolar disorders, cancers, disorders of the locomotor system, cancers caused by drugs, dystonia, endotoxemia shocks, hemorrhagic shocks, hypotension, insomnia, immunological diseases, multiple sclerosis, vomiting, asthma, disorders of appetite (bulimia, anorexia), obesity, memory impairment, disorders of the passage through the intestines; when taking from the chest in the case of chronic treatment or abuse of alcohol or drugs (such as opioids, barbiturates, drugs, cannabis, cocaine, amphetamine, enciclica, hallucinogens, benzodiazepines), as analgesics or amplifiers analiticheskoi drug activity or the threat depends on the desired result, the duration of treatment and route of administration. They usually range from 5 to 1000 mg per day in case of ingestion in adults with single doses of 1 to 250 mg of active substance.

In General, the doctor will determine the appropriate dose depending on the age, weight and other related to patient factors.

Compositions of the invention illustrate the examples below.

Example a

The usual way to prepare gelatin capsules containing 50 mg of active ingredient and having the following composition mg:

The compound of formula I 50

Cellulose 18

Lactose 55

Colloidal silica 1

Sodium carboximetilkrahmal 10

Talc 10

Magnesium stearate 1

Example B

The usual way to prepare tablets containing 50 mg of active ingredient and having the following composition mg:

The compound of formula I 50

Lactose 104

Cellulose 40

Polyvinylpyrrolidone 10

Sodium carboximetilkrahmal 22

Talc 10

Magnesium stearate 2

Colloidal silica 2

A mixture of hydroxymethylcellulose,

glycerin, titanium oxide

(72/3,5/24,5) adequate

up to bring

weight tablets to 245

Example C

Prepare a solution for injection containing 10 mg active the initial alcohol 0.06 ml

Sodium benzoate 80

95% ethanol, 0.4 ml

Sodium hydroxide 24

Propylene glycol 1.6 ml

Water in sufficient quantity to 4 ml

Claims

1. Derivatives of azetidine formulas

in which R denotes a link formulas

R1denotes a methyl radical or ethyl;

R2denotes a naphthyl radical, hinely, phenyl, possibly substituted by one or more halogen atoms, alkyl radicals, alkoxyl, hydroxyl, -COOR5, trifluoromethyl, trifloromethyl, triptoreline, nitro, -NR’6R’7, -CO-NH-NR6R7, -N(ALK)COOR8, cyano, -CONHR9, -CO-NR16R17alkylsulfanyl, hydroxyalkyl, -O-ALK-NR12R13or alkylthiomethyl or thienyl substituted by a group-COOR5or-CO-N or pyridyl;

R3and R4identical or different, represent a phenyl radical, possibly substituted by one or more halogen atoms, alkyl, alkoxyl, formyl, trifluoromethyl, cryptomaterial, group-Cooalk, -CONR10R11, hydroxyalkyl or a group-ALK-NR6R7, thiazolium or Tienam;

Rsub>7identical or different, denote a hydrogen atom or an alkyl radical, or R6and R7together with the nitrogen atom to which they are connected, form piperidinyl or pieperazinove cycle, substituted alkyl;

R’6and R’7identical or different, denote a hydrogen atom or an alkyl radical, or R’6and R’7together with the nitrogen atom to which they are connected, form a pyrolidine or pieperazinove cycle, possibly substituted by one or more radicals alkyl, -Coalk-Cooalk-N, -CS-N, -CO-ALK-NH2, -CO-ALK-NH-Cooalk or-CO-ALK-N(ALK)2,

R6and R7identical or different, denote an alkyl radical, cycloalkyl, -ALK-O-ALK, hydroxyalkyl or R6and R7together with the nitrogen atom to which they are connected, form a loop imidazole, piperazinone, thiomorpholine, research, piperidine, possibly substituted by alkyl, piperazine, possibly substituted by a group-Cooalk, alkyl, hydroxyalkyl, or pyrrolidine, possibly substituted by alkyl, hydroxyalkyl, ALK-O-ALK or-CO-NH2;

R8denotes alkyl;

R9denotes a hydrogen atom, an alkyl radical or an alkyl, substituted dialkylamino, phenyl, cycloalkyl (possibly samisen the p>R10and R11identical or different, denote a hydrogen atom or alkyl;

R12and R13together with the nitrogen atom to which they are connected, form a loop of the research, a R16and R17together with the nitrogen atom to which they are connected, form a loop of piperidine;

R’ denotes a hydrogen atom or the radical-CO-Ala;

ALK denotes an alkyl or alkylen,

moreover alkyl or alkylene radicals or their parts and CNS radicals or their parts are straight or branched chain, containing from 1 to 6 carbon atoms,

and their optical isomers or their salts with mineral or organic acid.

2. Connection on p. 1, selected from the following compounds:

1-benzhydryl-3-[(methylsulphonyl)(phenyl)methylene]azetidine,

1-benzhydryl-3-[(3-were)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(3-chlorophenyl)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(2,5-dichlorophenyl)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(2,3-dichlorophenyl)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(3-forfinal)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(3,5-differenl)(methylsulphonyl)met the methylsulphonyl)methylene]azetidine

1-benzhydryl-3-[(methylsulphonyl)(3-trifloromethyl)methylene]azetidine,

1-benzhydryl-3-[(methylsulphonyl)(3-triptoreline)methylene]azetidine,

1-benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl](methylsulphonyl)methylene}azetidine,

1-benzhydryl-3-[(3,5-dibromophenyl)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(3-ethoxycarbonylphenyl)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(3-cyanophenyl)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(3-carbamoylphenoxy)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(methylsulphonyl)(naphthas-1-yl)(methylsulphonyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-[bis(4-methoxyphenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-[bis(4-were)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(RS)-3-[(3,5-differenl)(methylsulphonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl]azetidin,

(R)-3-[(3,5-differenl)(methylsulphonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl]azetidin,

(S)-3-[(3,5-differenl)(methylsulphonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl]azetidin,

1-[bis(4-trifloromethyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-[bis(4-trift iformity)phenyl]methylsulfonylmethyl}azetidin,

(RS)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(R)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(S)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(RS)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(R)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(S)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(RS)-1-{(4-chlorophenyl)[4-(pyrrolidinyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(R)-1-{(4-chlorophenyl)[4-(pyrrolidinyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(3)-1-{(4-chlorophenyl)[4-(pyrrolidinyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(RS)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(R)-(4-chlorophenyl)[(4-(3,3-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(S)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(R)-(4-chlorophenyl)[4-(thiomorpholine-4-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(S)-(4-chlorophenyl)[4-(thiomorpholine-4-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(RS)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylamino)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(R)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylamino)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine

1-{(S)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylamino)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine

1-{{(RS)-(4-chlorophenyl){4-[(4-ethoxycarbonylphenyl)methyl]phenyl}methyl}}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{{(R)-(4-chlorophenyl){4-[(4-ethoxycarbonylphenyl)methyl]phenyl}methyl}}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{{(S)-(4-chlorophenyl){4-[(4-ethoxycarbonylphenyl)methyl]phenyl}methyl}}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(RS)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propylaminoethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(R)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propylaminoethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(3)-(4-chlorophenyl)[4-(N-cicmil)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-differenl)-(methylsulphonyl)methylene]azetidine,

1-{(R)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-differenl)-(methylsulphonyl)methylene]azetidine,

1-{(S)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}3-[(3,5-differenl)-(methylsulphonyl)methylene]azetidine,

1-{{(RS)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{{(R)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{{(S)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(RS)-(4-chlorophenyl)[4-(di-n-propylaminoethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(R)-(4-chlorophenyl)[4-(di-n-propylaminoethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(S)-(4-chlorophenyl)[4-(di-n-propylaminoethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(RS)-(4-chlorophenyl)[4-(piperidine-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(R)-(4-chlorophenyl)[4-(piperidine-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(S)-(4-chlorophenyl)[4-(piperidine-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)IU the l)methylene]azetidine,

1-{(R)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(S)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(RS)-(4-chlorophenyl)[4-(morpholine-4-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(R)-(4-chlorophenyl)[4-(morpholine-4-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(S)-(4-chlorophenyl)[4-(morpholine-4-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(RS)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(R)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(S)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(RS)-(4-chlorophenyl)[4-(piperazine-2-he-4-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(R)-(4-chlorophenyl)[4-(piperazine-2-he-4-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(S)-(4-chlorophenyl)[4-(piperazine-2-he-4-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(RS)-(4-chloro who l)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-{(S)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(RS)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(R)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(S)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(RS)-1-{(4-chlorophenyl)[4-(N-ethylcarbazole)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(R)-1-{(4-chlorophenyl)[4-(N-ethylcarbazole)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(S)-1-{(4-chlorophenyl)[4-(N-ethylcarbazole)phenyl]methyl}-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(RS)-1-[(4-carbamoylphenoxy)(4-chlorophenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(R)-1-[(4-carbamoylphenoxy)(4-chlorophenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(S)-1-[(4-carbamoylphenoxy)(4-chlorophenyl)methyl]-3-[3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[(3,5-dichlorophenyl)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(3-methylsulfinylphenyl)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-3-[(3-metals the Nile)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[(3-carbamoylphenoxy)(methylsulphonyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulphonyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxyphenyl)(methylsulphonyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[(methylsulphonyl)(3-pyrrolidinyloxy)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxymethylene)(methylsulphonyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-{(methylsulphonyl)[3-(N-piperidinylcarbonyl)phenyl]methylene}azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[(methylsulphonyl)(3-triftormetilfullerenov)(methylsulphonyl)methylene]azetidine,

1-[bis(4-forfinal)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-[bis(2-forfinal)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-[bis(3-forfinal)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulphonyl)(phenyl)methylene]azetidine,

(R)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulphonyl)(phenyl)methylene]azetidine,

(S)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulphonyl)(phenyl)methylene]azetidine,

(RS)-1-[(4-chlorophenyl)(Tien-2-yl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(R)-1-[(4-chlorphentermine)(methylsulphonyl)methylene]azetidine,

1-benzhydryl-6-[(ethylsulfonyl)(phenyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-{{3-[N-(4-methylpiperazine)carbarnoyl]phenyl}(methylsulphonyl)methylene}azetidine,

1-[bis(4-chlorophenyl)methyl]-3-{[3-(2,2-dimethylcarbamate)(phenyl)](methylsulphonyl)methylene}azetidine,

1-[bis(Tien-2-yl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-[bis(p-tolyl)methyl]-3-[(methylsulphonyl)(phenyl)methylene]azetidine,

1-[(4-chlorophenyl)(4-hydroxymethylene)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[(3-methylaminophenol)(methylsulphonyl)methylene]azetidine,

(RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(R)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

(S)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[(methylsulphonyl)(2-methoxycarbonylamino-5-yl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-hydroxy-3-[(methylsulphonyl)(2-methoxycarbonylamino-5-yl)methyl]azetidin-(RS),

1-[bis(4-chlorophenyl)methyl]-3-[(2-isobutyleneisoprene-5-yl)(methylsulphonyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[(3-ethoxycarbonylphenyl)(methyl who-ol,

1-[bis(4-chlorophenyl)methyl]-3-[(methylsulphonyl)(pyridin-3-yl)methyl-(RS)]azetidin-3-ol,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(3-morpholine-4-yl-propyl)benzamide,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(3-dimethylaminopropyl)benzamide,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(2-pyrrolidin-1-yl-ethyl)benzamide,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(2-dimethylamino-1-methyl-ethyl)benzamide,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(piperidine-1-yl)-benzamid,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-isobutyl-benzamide,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(3-imidazol-1-yl-propyl)benzamide,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(2-dimethylaminoethyl)benzamide,

N’-methylhydrazino 3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)-benzoic acid,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(2-morpholine-4-yl-ethyl)benzamide,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamide,

3-({1-enyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-cyclohexylmaleimide,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-cyclopropylbenzene,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(2-methylbutyl)benzamide,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(2-phenylpropyl)benzamide,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(tetrahydrofuran-2-ylmethyl)benzamide,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(2,2-diphenylether)benzamid,

3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-N-(2-ethylbutyl)benzamid,

methyl ester 4-{[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)benzoylamine]methyl}cyclohexanecarboxylic acid,

2-amino-1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-yl}Etalon,

tert-butyl ether(2-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-yl}-2-oxoethyl)carbamino acid,

1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-yl}-2-methylaminoethanol,

tert-butyl ether(2-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-yl}-2-oxymethyl)-phenyl]piperazine-1-carbothioic acid,

N-methylamide 4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-phenyl]piperazine-1-carboxylic acid,

methyl ester 4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonyl)-phenyl]piperazine-1-carboxylic acid,

1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]-4-isobutylpyrazine,

1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]-4-ethylpiperazine,

4-acetyl-1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]-piperazine,

1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]-piperazine-1-yl}-2-dimethylaminoethanol,

1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]-piperazine,

tert-butyl ether 4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ilidene}methanesulfonamide)phenyl]piperazine-1-carboxylic acid,

1-[bis(4-ethoxycarbonylphenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

3-acetoxy-1-[bis(4-ethoxycarbonylphenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)-methyl-(RS)]azetidin,

(RS)-4-[4-((4-chlorophenyl){3-[(3,5-differenl)(methysulfonylmethane)]azetidin-1-yl}-methyl)benzyl]morpholine,

4-(4-{3-[(1-benzhydrylamine-3-ilidene)metopropol)morpholine,

their optical isomers and their salts with mineral and organic acid.

3. Connection on p. 1, selected from the following compounds:

1-[bis(4-chlorophenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methylene]azetidine,

1-[bis(4-chlorophenyl)methyl]-3-[(3,5-differenl)(methylsulphonyl)methyl-(RS)]azetidin-3-ol,

3-acetoxy-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-differenl)-(methylsulphonyl) methyl)methylsulfonylmethyl-(RS)]azetidin,

their optical isomers and their salts with mineral or organic acids.

4. The method of obtaining compounds of formula I under item 1, in which R represents a chain of formula A, wherein the compound of formula Ia

in which R1, R2, R3and R4have the meanings specified for formula I;

R" denotes a hydroxy radical, methansulfonate or atomic charges,

subjected to dehydration with subsequent isolation of the target compound, which is optionally converted into the salt with a mineral or organic acid.

5. The method of obtaining compounds of formula I under item 1, in which R represents a chain of formula V, in which R’ is a hydrogen atom, wherein the derivative of formula II

R1SO2CH2R2the one of the formula III

in which R3and R4have the values listed in paragraph 1,

with subsequent isolation of the target compound, which is optionally converted into the salt with a mineral or organic acid.

6. The method of obtaining compounds of formula I under item 1, in which R represents a chain of formula V, in which R’ is a hydrogen atom, characterized in that the derived formulas

R3CH(Br)R4,

where R3and R4have the values listed in paragraph 1,

subjected to interaction with a derivative of formula VII

in which R1and R2have the values listed in paragraph 1,

with subsequent isolation of the target compound, which is optionally converted into the salt with a mineral or organic acid.

7. The method of obtaining compounds of formula I under item 1, in which R represents a chain of formula V, in which R’ is a radical-CO-alk, wherein the halide Hal-CO-alk, where Hal denotes a halogen atom, a alk represents a normal or branched C1-C6is an alkyl radical, is subjected to the interaction with the corresponding compound of formula I in which R represents a chain In which R’ is an atom or an organic acid.

8. The method of obtaining compounds of formula I under item 1, in which R2represents phenyl substituted by a group - NR6R7where each of R6and R7is a hydrogen atom, characterized in that it restores the corresponding compound of formula I, in which R2is phenyl, substituted nitro group, followed by separation of the target compound, which is optionally converted into the salt with a mineral or organic acid.

9. The method of obtaining compounds of formula I under item 1, in which R2represents phenyl substituted by a group-CONHR9and/or R3and/or R4represent phenyl, substituted by a group CONR10R11, characterized in that the compound of the formula I, in which R2and/or R3and/or R4represents phenyl substituted by a group-R5where R5denotes alkyl or phenyl, possibly substituted by halogen atoms, is subjected to the interaction, respectively, with an amine H2NR9or HNR10R11where R9, R10and R11have the values listed in paragraph 1, followed by separation of the target compound, which is optionally converted into the salt with a mineral or organic is built by hydroxyl, characterized in that it is subjected to hydrolysis of the corresponding compound of formula I, in which R2represents phenyl, substituted alkoxygroup, followed by separation of the target compound, which is optionally converted into the salt with a mineral or organic acid.

11. The method of obtaining compounds of formula I under item 1, in which2represents phenyl substituted by a group-N, characterized in that the compound of the formula I, in which R2represents phenyl substituted by a group-N(alk)COOR8where R8denotes tert-botilony radical, is subjected to the removal of protection, followed by separation of the target compound, which is optionally converted into the salt with a mineral or organic acid.

12. The method of obtaining compounds of formula I under item 1, in which2and/or R3and/or R4represent phenyl, substituted by a group-COOR5or Cooalk, characterized in that atrificial derivative of the formula IX

in which R represents a chain C=C (SO2R1)R’2or C(OR’)CH(SO2R1)R’2, a R1, R’2, R’3and R’4have the meanings indicated for the radicals R1, R4 is phenyl, substituted by carboxyla, using the derived formula, R5OH, where R5denotes alkyl or phenyl, possibly substituted by one or more halogen atoms,

with subsequent isolation of the target compound, which is optionally converted into the salt with a mineral or organic acid.

13. The method of obtaining compounds of formula I under item 1, in which2denotes phenyl, substituted alkylthio-alkyl group, wherein the derivative of formula IX

in which R represents a chain C=C(SO2R1)R’2or C(OR’)CH(SO2R1)R’2and R’, R1, R’3and R’4have the meanings indicated for the radicals R’, R1, R3and R4in paragraph 1, and the radical R’2is phenyl, substituted by halogenation,

subjected to interaction with alkylthiols sodium, where the alkyl part is a normal or branched chain with 1-6 carbon atoms, followed by separation of the target compound, which is optionally converted into the salt with a mineral or organic acid.

14. The method of obtaining compounds of formula I under item 1, in which2and/or R3and/or R4are : restore the connection of the formula I, in which at least one of the radicals R2, R3and R4represents an aromatic radical, substituted by formyl, followed by separation of the target compound, which is optionally converted into the salt with a mineral or organic acid.

15. The method of obtaining compounds of formula I under item 1, in which3and/or R4represent an aromatic moiety substituted by a group-alk-NR6R7in which alk represents alkyl containing one carbon atom, characterized in that the compound of the formula I, in which at least one of the radicals R3and R4represents an aromatic radical, substituted by formyl, is subjected to the interaction with the amine HNR"6R7where R6and R7have the meanings specified for formula I, with subsequent isolation of the target compound, which is optionally converted into the salt with a mineral or organic acid.

16. The method of obtaining compounds of formula I under item 1, in which2represents phenyl substituted by a group-CONHR9and/or R3and/or R4denote phenyl, substituted by a group-CO-NR10R11, characterized in that a derivative of formula IX

, R’2, R’3and R’4have the meanings mentioned for the substituents R’, R1, R2, R3and R4under item 1, provided that at least one of the substituents R’2, R’3, R’4denotes phenyl, substituted carboxyla,

subjected to interaction with the corresponding amine H2NR9or HNR10R11in which R9, R10and R11have the same meanings indicated for formula I, with subsequent isolation of the target product, and optionally convert the compound obtained in the salt with a mineral or organic acid.

17. The method of obtaining compounds of formula I under item 1, in which2means phenyl, substituted by a group-CO-NH-NR6R7, characterized in that the compound of the formula I, in which R2represents phenyl substituted by a group-COOR5where R5represents an alkyl radical or phenyl, possibly substituted by halogen atoms, are subjected to interaction with hydrazine H2N-NR6R7where R6and R7have the meanings specified for formula I, with subsequent isolation of the target compound, which is optionally converted into the salt with a mineral or organic acid.

18. The other9where R9denotes a hydrogen atom and/or R3and/or R4represent phenyl, substituted by a group-CO-NR10R11where R10and R11denote hydrogen atoms, wherein the hydrolyzing a corresponding compound of formula I, in which2and/or R3and/or R4represent phenyl, substituted by a cyano group, followed by separation of the target compound, which is optionally converted into the salt with a mineral or organic acid.

19. The method of obtaining compounds of formula I under item 1, in which2represents phenyl substituted by a group-O-alk-NR12R13, characterized in that a derivative of formula IX

in which R represents a chain C=C(SO2R1)R’2or C(OR’)CH(SO2R1)R’2and R’, R1, R’3and R’4have the meanings indicated for the radicals R’, R1, R3and R4in paragraph 1, and the radical R’2denotes phenyl, substituted by a group-O-alk-Hal, where alk denotes an alkyl radical with normal or branched chain, containing from 1 to 6 carbon atoms, a Hal denotes a halogen atom,

subjected to interaction with the amine HNR12R13where R12and R in salt with a mineral or organic acid.

20. The method of obtaining compounds of formula I under item 1, in which3and/or R4represent phenyl, substituted by a group-alk-NR6R7, characterized in that a derivative of formula IX

in which R represents a chain C=C(SO2R1)R’2or C(OR’)CH(SO2R1)R’2, a R’, R1, R’2, R’3and R’4have the meanings indicated for the radicals R’, R1, R2, R3and R4in paragraph 1, provided that at least one of the radicals R’3and R’4is phenyl, substituted by a group-alk-Cl, where alk denotes an alkyl radical with normal or branched chain, containing from 1 to 6 carbon atoms, is subjected to the interaction with the amine HNR"6R7where R6and R7have the values listed in paragraph 1, followed by separation of the target compound, which is optionally converted into the salt with a mineral or organic acid.

21. The method of obtaining compounds of formula I under item 1, in which R represents a chain of formula, R’ represents a hydrogen atom, and R3and/or R4represent phenyl, substituted hydroxyalkyl, in which the alkyl residue contains one carbon atom, characterized in that a R3and/or R4denote an aromatic radical, substituted by one or more radicals-Cooalk, is subjected to the interaction with the hydride diisobutylaluminum, followed by separation of the target compound, which is optionally converted into the salt with a mineral or organic acid.

22. The method of obtaining compounds of formula I under item 1, in which2represents a phenyl radical substituted by the group-NR’6R’7representing a 1-piperazinilnom cycle, substituted in position 4 alkyl radical, characterized in that the compound of the formula I, in which R2represents a phenyl radical substituted by the group-NR’6R’7representing a 1-piperazinilnom cycle, is subjected to the interaction with the derived alk-CHO, where alk denotes an alkyl radical with normal or branched chain, containing from 1 to 5 carbon atoms, with subsequent isolation of the target compound, which is optionally converted into the salt with a mineral or organic acid.

23. The method of obtaining compounds of formula I under item 1, in which2represents a phenyl radical substituted by the group-NR’6R’7representing a 1-piperazin the crystals I, in which R2represents a phenyl radical substituted by the group-NR’6R’7representing a 1-piperazinilnom cycle, is subjected to the interaction with a derivative of formula Hal-COO-alk, where alk denotes an alkyl radical with normal or branched chain, containing from 1 to 6 carbon atoms, a Hal denotes a halogen atom, followed by separation of the target compound, which is optionally converted into the salt with a mineral or organic acid.

24. The method of obtaining compounds of formula I under item 1, in which2represents a phenyl radical substituted by the group-NR6R7representing a 1-piperazinilnom cycle, substituted in position 4 by the radical-CO-NH-alk or-CS-NH-alk, wherein the corresponding compound of formula I, in which R2represents a phenyl radical substituted by the group-NR6R7representing a 1-piperazinilnom cycle, is subjected to the interaction with the derived formula Y=C=N-alk in which alk denotes an alkyl radical with normal or branched chain, containing from 1 to 6 carbon atoms, a Y denotes a sulfur atom or oxygen, with subsequent isolation of the target compound, which is optionally converted into the 2
represents a phenyl radical substituted by the group-NR’6R’7representing a 1-piperazinilnom cycle, substituted in position 4 by the radical-CO-alk-NHCOOalk, characterized in that the compound of the formula I, in which R2represents a phenyl radical substituted by the group-NR’6R’7representing a 1-piperazinilnom cycle, is subjected to the interaction with the acid of the formula alk-OOC-HN-alk-COOH, in which alk denotes an alkyl radical with normal or branched chain, containing from 1 to 6 carbon atoms, with the subsequent removal of the protection of the product, selection of target compound, which is optionally converted into the salt with a mineral or organic acid.

26. The method of obtaining compounds of formula I under item 1, in which2represents a phenyl radical substituted by the group-NR’6R’7representing a 1-piperazinilnom cycle, substituted in position 4 by the radical-CO-alk, where alk denotes a methyl radical, characterized in that the compound of the formula I, in which R2represents a phenyl radical substituted by the group-NR’6R’7representing a 1-piperazinilnom cycle, subjected to vzaimodeistvie with a mineral or organic acid.

27. Pharmaceutical composition having an antagonistic effect, containing as active principle at least one compound of formula I under item 1 or 2 in an amount of from 1 to 1000 mg.

28. The drug, which has antagonistic activity, containing as active substance at least one compound of formula I according to one of p. 1 or 2.

 

Same patents:

The invention relates to new derivatives epothilone formula I, where the bond indicated by a wavy line indicates that the bond “a” is either CIS-or TRANS-form; (I) R2absent or represents oxygen; “a” denotes a single or double bond; “b” is absent or represents a simple bond; and “C” is absent or represents a simple bond, provided that when R2denotes oxygen, then “b” and “C” both represent a simple bond and a represents a simple bond; if R2no, the “b” and “C” both are absent and “a” represents a double bond; and if “a” represents a double bond, R2“b” and “C” are absent; R3denotes a radical selected from the group comprising hydrogen; (ness.)alkyl, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl; -CH2F; -CH2-OH; R4and R5independently of one another denote hydrogen; R1denotes a radical of the structure (a-d); (II) if R3means (ness.)alkyl, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl; -CH2F; CH2-HE; and other symbols except for the R1have the values listed above in their characters except for the R1have the above values, R1can also represent a fragment of formula (j); or a salt of the compounds of formula I, if there is a salt-forming group

The invention relates to 1-(3-heteroaromatic or prop-2-enyl)-4-benzylpiperidine formula (1), where X Is O, NR1, S, or CH2; Y is CH; Z is CH; Y and Z together may denote C= S; R1, R2and R3is hydrogen, R4- fluorine

The invention relates to novel polycyclic to dihydrothiazolo General formula (I), where Y is a simple bond; X is CH2; R1 is H, F, Cl, NO2, CN, COOH, (C1-C6)-alkyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, and alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine; (CH2)n-phenyl, SO2-(C1-C6)-alkyl, and n = 0 and the phenyl residue up to twice may be substituted by F, Cl, CF3, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; O-(CH2)n-phenyl, and n = 0 and phenyl cycle can be one - to twofold substituted by Cl, (C1-C6)-alkyl; 1 - or 2-naphthyl, 2 - or 3-thienyl; R1' is hydrogen; R2 is H, (C1-C6)-alkyl, R3 is hydrogen; R4 - (C1-C8)-alkyl, (C3-C7-cycloalkyl, (CH2)n-aryl, and n = 0-1, and aryl can be phenyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2 - or 3-furyl, indol-3-yl, indol-5-yl, and aryl or heteroaryl residue up to twice may be substituted by F, Cl, HE, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, 2-, 3-, 4-pyridium, pyrrol-1-yl, with peregrinae ring may be substituted CF3; and their physio is

The invention relates to new indole derivative of the formula I

< / BR>
in which R1is hydrogen, (NISS

The invention relates to a group of new compounds - heterocyclic derivatives of glycyl-beta-alanine General formula I

< / BR>
or pharmaceutically acceptable salt of this compound, where

< / BR>
is a 5-8-membered monocyclic heterocyclic, optionally unsaturated ring containing from 1 to 4 heteroatoms selected from the group comprising N and S, and1selected from the group comprising SN, SN2, N, NH, O and S, provided that

< / BR>
is not pyrrolidinium when V represents NH;

A represents a group of the formula

< / BR>
where Y1selected from the group comprising N-R2and R2means hydrogen; R2means hydrogen, R7when not with R2and R8mean hydrogen, alkyl, substituted alkoxy group, or R2together with R7form a 4 to 12-membered ring containing 2 nitrogen atom a heterocycle, optionally substituted by one or more substituents selected from the group comprising hydroxy, C1-C10< / BR>
where R2together with R7form a 5-8-membered ring containing two nitrogen atom a heterocycle, R5means hydrogen, R8means alkyl, optionally substituted by alkoxygroup; or A signifies a group

< / BR>
where R2together with R7form a 5-8-membered ring containing 2 nitrogen atom a heterocycle, optionally substituted hydroxy-group; R8- alkyl, substituted alkoxygroup; V means-N(R6)-; R6is hydrogen; Y and Z denote hydrogen, t = 0, n and R = 1, 2; R means X-R3where X is-O-; R3is hydrogen, alkyl; R1selected from the group including aryl, alkyl, optionally substituted one or more times by halogen, alkyl, HE; monocyclic heterocycle; haloalkyl; R11means hydrogen, or a pharmaceutically acceptable salt of the compounds; pharmaceutical compositions having properties antagonistV3-integrin, as well as to a method of treating diseases mediatedV3-integrin in a mammal

The invention relates to new chemical compounds derived from anthra[2,1-d]isothiazol-3,6,11-trione General formula I, where a is the lowest alkylene, R1and R2(independent) - lower alkyl, or R1and R2together with the nitrogen atom form a six-membered saturated, a heterocycle, which may optionally contain a heteroatom such as oxygen atom, and their pharmaceutically acceptable salts

The invention relates to new epothilone formula 1, where R=CH3N

The invention relates to a derivative benzofurazan or benzo-2,1,3-thiadiazole of the formula I, in which R1represents oxygen or sulfur, R2and R3independently selected from the group consisting of-CR=, M is =CR4- where R4independently represents R, R8is hydrogen, R5selected from the group consisting of-CR=CR1-, -CR=CX-, -(СRR1)n-, R7selected from the group consisting of -(CRR1)n-, -C(O)-, -CRX-, -CXX1-, R6selected from the group consisting of -(CRR1)m-, -C(O)-, -CRX -, -CXX1-, -S - and-O-

The invention relates to a series peptidergic heterocyclic compounds, intermediates used in their receiving and containing pharmaceutical compositions

The invention relates to inhibitors tyrosinekinase type bis-indolylmaleimide compounds of the formula I

< / BR>
where Z denotes a group of General formula II

< / BR>
where A, B, X, Z, R1-R10have the meanings indicated in the claims, as well as the way they are received and drug based on these compounds

The invention relates to derivatives of cyclic amines and their use as pharmaceuticals, particularly to a compound represented by the General formula (I), its pharmaceutically acceptable acid additive salts or its pharmaceutically acceptable C1-C6alcaldicios salt, R1-phenyl, C3-8-cycloalkyl, aromatic heterocycle with 1-3 heteroatoms selected from O, S, N, or combinations thereof, and these groups may be condensed with benzene ring or an aromatic heterocyclic group with heteroatoms, selected from O, S or N, or combinations thereof, and may also have different substituents

The invention relates to new salts of pyridinium General formula (I) or their pharmaceutically acceptable salts, where R1is-R4- R5or-N(R7)N(R7R9, R4choose from the group of-N(R7R6O-, N(R7R6N(R7), -OR6O-,

-OR SIG6N(R7)-, where R6- alkyl, R5choose from the group of alkyl, aryl, including heteroaryl, -COR7, -SO2R7and-COR10where R7Is H, alkyl or aryl, including heteroaryl, R2Is F, Cl, Br, J, alkyl, aryl, including heteroaryl, formyl, acyl, C(O)NR7R10or C(O)or SIG7, m = 0, 1, or 2, R3selected from the group comprising R7OR7N(R7)(R10) and CH(R7)C(O)R8, R8is R7OR7and NR7R10, R9is hydrogen, alkyl, aryl, including heteroaryl, -C(O)R10, -SO2R10, -C(S)OTHER10, -C(NH)NH(R10), -C(O)OTHER10, R10- H, alkyl, or aryl, including heteroaryl, and in each case, it is not necessarily different from R7X represents an ion halogen provided that 1) when two alkyl groups are the same carbon or nitrogen, they are not necessarily linked together with the formation of a cyclic structure, and (2) nitrogen heteroaryl ring R1

The invention relates to trilateralization formula (I) in which R1 means a hydrogen atom, halogen atom or lower alkyl radical, R2, R3 and R4 independently denote a hydrogen atom or a lower alkyl radical, Az means a nitrogen-containing aromatic N-methylseleninic the five-membered heterocycle containing one to three nitrogen atoms, with analgesic activity

The invention relates to derivatives of 1-(N-phenyliminomethyl)piperazine of the formula I, where R is H, alkyl -, cycloalkyl-substituted cycloalkyl-WITH or monocyclic heteroaryl-CO; R1Is h or lower alkyl; R2- halogen, alkoxy, phenoxy, NO2, CN, acyl, NH2, NH(acyl), alkyl-SO2NH, alkoxycarbonyl, NH2WITH, (alkyl)NHCO (alkyl)2NCO, (acyl)NHCO, CF3or polyporaceae; benzyl or mono - or bicyclic aryl, or heteroaryl, all of which are optionally substituted

The invention relates to new substituted derivatives of piperidine derivatives, to processes for their preparation, to pharmaceutical compositions and to their use in medical therapy, particularly in treatment of psychotic disorders

The invention relates to a piperidine derivative of General formula I

< / BR>
and their pharmaceutically acceptable salts, where R1is hydrogen, C1-C6-alkyl, C2-C6alkenyl, C3-C8-cycloalkyl, C6-C10aryl that may be substituted for CH3, halogen, OR5where R5- C1-C6-alkyl, C1-C2-alkyl-heteroaryl containing as heteroatoms of S, N or O; And a is phenyl, substituted carbonyl or amino group; - C6-C10-aryl or C5-C10-heteroaryl containing as heteroatoms of S, N or O

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group
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