UA73554C2 - A pharmaceutical composition containing azetidine derivatives, azetidine derivatives and preparation thereof - Google Patents

Abstract

The invention concerns pharmaceutical compositions containing as active principle a compound of formula (I) wherein: R1 represents a -N(R4)R5, -N(R4)-CO-R5, -N(R4)-SO2R6 radical or one of its pharmaceutically acceptable salts, the novel derivatives of formula (I), their pharmaceutically acceptable salts and their preparation.

Description

Description of the invention

The present invention relates to pharmaceutical compositions containing at least one compound of the formula: x and M | )

V or one of its pharmaceutically acceptable salts, to new derivatives of formula I, their pharmaceutically acceptable salts and their preparation.

The compound of the formula I, in which Ko and Kz are phenyl radicals, K. means the radical -M(K.)5O" in, K. means the phenyl radical and Ko means the methyl radical, is described as an intermediate synthesis product in UMO patent 99/01451. Other compounds and pharmaceutically acceptable salts are novel and as such form part of the invention.

In the formula

Ku. means the radical -М(К.)Кв, -М(К4)-СО-К», -МЩ(Ка)-5О2 in,

E" and Kz, the same or different, mean either an aromatic radical selected from phenyl, naphthyl and indenyl, which may be unsubstituted or substituted by one or more substituents selected from halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, - СО-аЙК, циано, -СООН, -СОбакК, -СОМК,;Ра, -СО-МН-МКакКцо, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -aik-MK.Ra; or a heteroaromatic radical selected from the following rings: benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, C 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, o pyrimidyl, quinolyl, 1 . -aik-MCaeKcho, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl; "

KE. means the radical -С(К44)(К42)-Ней, Ней, -С(К44Х(К42)-Аг, Аг, cycloalkyl or norbornyl;

K5 means a hydrogen atom or a hydroxyalkyl radical, -aik-COsaik, -adik-SOMKva, -aikik-MK,Ka, alkoxy, Ag, Nei, -CHnoAg, -CHnoNei or alkyl, possibly substituted by one or more halogens; And c)

Kb means the radical hydroxyalkyl, -alkyl-SODAic, -alkyl-SOMK Ka, -alkyl-MK.Ka, alkoxy, Ag, Nei, -SNoAg, -SNoNei c or alkyl, possibly substituted by one or more halogens;

KE; and Kv, the same or different, mean a hydrogen or alkyl atom, or K, and Ka, together with the nitrogen atom to which they are connected, form a saturated mono- or bicyclic heterocycle having from 3 to 10 members and which may contain a second heteroatom selected from oxygen, sulfur, and nitrogen, and be substituted by one or more alkyls;

Ko and Ko, the same or different, mean a hydrogen atom or an alkyl radical, -COoaiK, cycloalkyl, "alkylcycloalkyl, -aik-O-aikK or hydroxyalkyl, or Ko and Kio, together with the nitrogen atom with which they are connected, form saturated or unsaturated mono- or bicyclic heterocycle having from 3 to 10 members and which may contain a second heteroatom selected from oxygen, sulfur and nitrogen, and be substituted by one or more of the following radicals: alkyl, -COaic, - cSOsbaik, -"CO-MNaik, -C8-MNaik, oxo, hydroxyalkyl, -aik-O-aikK or -CO-MH"; ,» Ki1 means a hydrogen atom or a hydroxyalkyl radical, aik-SOdOaik, ayik-SOMK,Ra, -aik-MK.Ra, alkoxyalkyl, Ag,

Ni, -СНоАг, -СНоНей or alkyl, possibly substituted by one or more halogens;

Ki" means a hydrogen atom or a hydroxyalkyl radical, -alkyl-SOdaic, -alkyl-SOMK.a, -alkyl-MK.Ka, alkoxyalkyl or - alkyl, possibly substituted by one or more halogens; c or K.4 and Ku", together with the carbon atom to which they are connected, form a saturated mono- or bicyclic ring having from C to 10 members and which may contain a second heteroatom selected from oxygen, sulfur and nitrogen, and 1 be substituted by one or more alkyls; sl 50 Ag means phenyl, naphthyl or indenyl, which can be replaced by one or more of the following substituents: halogen, alkyl, alkoxy, -СбО-аиК, cyano, -СООН, -СОБаикК, -СОМКзК.а4, -СО-МН- MK.5Kchv,

I» alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aik-MKu5K.v, -MKu5Kchv, alkylthioalkyl, formyl, SEz, OSE»z, Nei, -O-alkyl-MH-cycloalkyl, -502MH», hydroxy, hydroxyalkyl, -MH-CO -айКк, -МН-СООайЙкК or, on two adjacent carbon atoms, dioxymethylene;

It means an unsaturated or saturated mono- or bicyclic heterocycle having from 3 to 10 members and containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, and which may be substituted by one or more of the following radicals: alkyl, alkoxy , vinyl, halogen, alkoxycarbonyl, oxo, hydroxy, ime) and nitrogen-containing heterocycles can be in the form of M-oxides,

Kz and Ki4 are the same or different, mean a hydrogen or alkyl atom, or K.z and K.44, together with the nitrogen atom to which they are connected, form a saturated mono- or bicyclic heterocycle having from C to 10 unit and which may contain a second heteroatom selected from oxygen, sulfur and nitrogen, and be substituted by one or more alkyls;

Kv and Kv, the same or different, mean a hydrogen or alkyl atom, or K.5 and Kv, together with the nitrogen atom to which they are connected, form a saturated mono- or bicyclic heterocycle having from 3 to 10 members and which 65 may contain a second heteroatom selected from oxygen, sulfur and nitrogen and be substituted by one or more alkyl radicals;

aiK means alkyl or alkylene.

In the above and following definitions, unless specifically discussed, alkyl or alkylene radicals and molecular moieties or alkyl radicals and molecular moieties are straight or branched chain and contain from 1 to b carbon atoms, and cycloalkyl radicals contain from 3 to 10 carbon atoms.

Alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl. Alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, and pentyloxy radicals.

Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl can be named cycloalkyl radicals. 70 The term halogen refers to chlorine, fluorine, bromine and iodine.

Among the heterocyclic radicals denoted by Her, the following heterocycles can be named: benzimidazole, benzoxazole, benzothiazole, benzothiophene, cinnoline, thiophene, quinazoline, quinoxaline, quinoline, pyrazole, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, piperidine , piperazine, triazole, furan, tetrahydroisoquinoline, and tetrahydroquinoline, which may be substituted with one or more of the following substituents: alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OSE"z or CE".

Compounds of formula I! can be in the form of enantiomers or diastereoisomers. These optical isomers and mixtures thereof also form part of the invention.

Preferably, the compounds of formula I are such compounds for which:

Ku. means the radical -M(K.) Kv, -M (K4)-502Kv,

Co is either phenyl, unsubstituted or substituted by one or more of the following substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-αiK, cyano, -"СОМК.Ka, hydroxyalkyl or -айк-MK,Ka, or heteroaromatic a radical selected from the following rings: pyridyl, pyrimidyl, thiazolyl and thienyl, which may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -SOMA Kv, -aik-MCoK.o, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl; high school

Kz means either phenyl, unsubstituted or substituted by one or more of the following substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alK, cyano, -"SOMK.Ka, hydroxyalkyl or -alik-MK,Ka, or ( 8) a heteroaromatic radical selected from the following rings: pyridyl, pyrimidyl, thiazolyl and thienyl, which can be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -СОМА Кв, -айк-МКоК.о, alkylsulfanyl, alkylsulfinyl , alkylsulfonyl or hydroxyalkyl; "g from KE. means the radical -С(К44)(К42)-Ней, Ней, -С(44Х(К42)-Аг, Аг or norbornyl;

K5 means a hydrogen atom or a hydroxyalkyl radical, -aik-SOdaik, -aik-SOMKKa, -aik-MKUKa, alkoxy, -SNeoAg, which) -SnNei! or alkyl; yu

Ke means the radical hydroxyalkyl, -aik-COsaik, -aik-SOMK.Ka, -aikik-MK.Ra, alkoxy, -SNoAg, -SNoNei or alkyl;

KE; and Kv, the same or different, mean a hydrogen or alkyl atom, or K, and Ka, together with a nitrogen atom, with which i)

When THEY are connected, they form a saturated mono- or bicyclic heterocycle having from 3 to 10 members and which may contain a second heteroatom selected from oxygen, sulfur and nitrogen, and be substituted by one or more alkyls;

Ko and Kyo, the same or different, mean a hydrogen atom or an alkyl radical, cycloalkyl, alkylcycloalkyl, -aik-o-aikK or hydroxyalkyl, or Ko and K.o, together with the nitrogen atom to which they are connected, form a saturated or an unsaturated mono- or bicyclic heterocycle having from 3 to 10 members and which may contain a second heteroatom selected from oxygen, sulfur and nitrogen, and be substituted by one or more of the following radicals: , -"CO-MmnNaic, oxo, hydroxyalkyl or -CO-MH";

Ki1 means a hydrogen atom or a hydroxyalkyl radical, -aik-SOOaik, -aik-SOMK.Ra, -aik-MK.,Ra, alkoxyalkyl, with Ag, Nei, -CHnoAg, -CHnoNei or alkyl, possibly substituted by one or more halogens;

K/2 means a hydrogen atom or a hydroxyalkyl radical, aik-COsbaik, ayaik«SOMK»P»a, -aik-MK.Ka, alkoxyalkyl or alkyl, possibly substituted by one or more halogens; -I or K.4 and Ku", together with the carbon atom to which they are connected, form a saturated mono- or bicyclic ring having from 3 to 10 members and which may contain a second heteroatom selected from oxygen, sulfur and nitrogen, and be substituted by one or more alkyls; c Ag means phenyl or naphthyl, which can be replaced by one or more of the following substituents: 5or Halogen, alkyl, alkoxy, -CO-аЙК, cyano, -СОМК.зКи4,- alkylsulfonyl, -айк-МКБКив, -МЕК/5Кив, SE3, OSR», 1 5О»МН», hydroxy, hydroxyalkyl or, for two adjacent carbon atoms, dioxymethylene; "Her" means an unsaturated or saturated mono- or bicyclic heterocycle having from 3 to 10 members and containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, and which may be substituted by one or more of the following radicals: alkyl, alkoxy, halogen, oxo, hydroxy, and nitrogen-containing ov Heterocycles can be in the form of M-oxides and, more specifically, Nei means a heterocycle selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole,

F) pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, furan, tetrahydroisoquinoline and ka tetrahydroquinoline, which can be substituted by one or more of the following substituents: alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OSE" or CEz . in Keys and K.4, the same or different, mean a hydrogen or alkyl atom, or Keys and K.i4, together with the nitrogen atom to which they are connected, form a saturated mono- or bicyclic heterocycle having from C to 10 units and which may contain a second heteroatom selected from oxygen, sulfur and nitrogen and be substituted by one or more alkyls;

Kv and Kv, the same or different, mean a hydrogen or alkyl atom, or K.5 and Kv, together with the nitrogen atom to which they are connected, form a saturated mono- or bicyclic heterocycle having from 3 to 10 members and which may contain a second heteroatom selected from oxygen, sulfur, and nitrogen, and be substituted with one or more alkyls.

More preferred compounds of formula I selected from the following compounds:

Ku. means the radical -M(K./)-502Kv,

Co is either phenyl, unsubstituted or substituted by one or more of the following substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -SOMK,Ka, hydroxyalkyl or -alkyl-MK,Ka, or a heteroaromatic radical selected from the following rings : pyridyl, pyrimidyl, thiazolyl and thienyl, which may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -SOMEK Ka or hydroxyalkyl; 70 Kz means either phenyl, unsubstituted or substituted by one or more of the following substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -SOMK,Ka, hydroxyalkyl or -aik-MK,Ka, or a heteroaromatic radical selected from the following rings: pyridyl, pyrimidyl, thiazolyl and thienyl, which can be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -SOME Ka or hydroxyalkyl;

KE. means the radical -Nei or Ag;

Ke means hydroxyalkyl or alkyl;

KE; and Kv, the same or different, mean a hydrogen or alkyl atom, or K, and Ka, together with the nitrogen atom to which they are connected, form a saturated mono- or bicyclic heterocycle having from 3 to 10 members and which can contain a second heteroatom selected from oxygen, sulfur, and nitrogen, and be substituted by one or more alkyls;

Ag means phenyl or naphthyl, which can be replaced by one or more of the following substituents: halogen, alkyl, alkoxy, -CO-айкК, cyano, -СОМК.зЕ 4, -айк-МКу5Кв, -МК/5Кив, СЕз, ОСЕ3, ЗО2МН», hydroxy or hydroxyalkyl;

It means an unsaturated or saturated mono- or bicyclic heterocycle having from 3 to 10 members and containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, and which may be substituted by one or more of the following radicals: alkyl, alkoxy , halogen, oxo, hydroxy and, more specifically, Her means a heterocycle selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, i) quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, thiazole, thiadiazole, furan . "g zo Keys and K.4, the same or different, mean a hydrogen or alkyl atom, or Keys and K.i4, together with the nitrogen atom with which they are connected, form a saturated mono- or bicyclic heterocycle having from C to 10 units and which o may contain a second heteroatom selected from oxygen, sulfur and nitrogen, and be substituted by one or more yU alkyls;

Kv and Kv, the same or different, mean a hydrogen or alkyl atom, or K.5 and Kv, together with a nitrogen atom, with o

WITH WHICH THEY are connected, form a saturated mono- or bicyclic heterocycle having from 3 to 10 members and which may contain a second heteroatom selected from oxygen, sulfur, and nitrogen, and be substituted by one or more alkyls.

Among the preferred compounds, the following compounds can be named:

M-(1-(bis-(4-chlorophenyl)methyl|azetidin-3-yl)-M-(b-chloropyrid-2-yl)methylsulfonamide, "

M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylI-M-(b-ethylpyrid-2-yl)umethylsulfonamide, with M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl )-M-quinol-b-ylmethylsulfonamide,

M-11-Bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-quinol-5-ylmethylsulfonamide, ; » M-41-I(bis(4-chlorophenyl)methyl|azetidin-3-ylII-M-isoquinol-5-ylmethylsulfonamide,

M-11-1(bis(4-chlorophenyl)methyl-azetidin-3-yl-1-M-pyrid-3-yl-methylsulfonamide,

M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylI-M-(1-oxid-pyrid-3-yl)umethylsulfonamide, -I M-(1kK,25,45)-bicyclo|2.2.1 |hept-2-yl-M-(1-Ibis(4-chlorophenyl)methylI|azetidin-3-ylmethylsulfonamide,

M-(1kK,2kK,45)-bicyclo(|2.2.1|hept-2-yl-M-1-(bis(4-chlorophenyl)methylIazetidin-3-ylliummethylsulfonamide, o M-11-Ibis(4-chlorophenyl )methyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide, with M-11-Ibis(4-chlorophent)methyl|azetidin-3-yl)-M-(thiazol-2-yl)umethylsulfonamide ,

M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylII-M-(3-methoxyphenyl)methylsulfonamide, o M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylII-M-(3 -hydroxyphenyl)methylsulfonamide, M-11-Ibis(4-chlorophenyl)methyl-azetidin-3-yl-M-(3-hydroxymethylphenyl)methylsulfonamide, ethyl ether M-71-(bis(4-chlorophenyl)methyl-azetidin-3 -yl)-M-(methylsulfonyl)-3-aminobenzoic acid,

M-11-I(bis(4-chlorophenyl)methyl|azetidin-3-ylI-M-(1-isobutyl-piperid-4-yl)umethylsulfonamide,

M-benzyl-M-(1-Ibis(4-chlorophenyl)methyl|azetidine-3-ylamine,

M-(1-Bis(4-chlorophenyl)methyl-azetidin-3-yl-M-(3,5-difluorobenzyl)amine,

F) M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylII-M-(3,5-difluorobenzyl)methylsulfonamide, ka M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylII- M-(pyrid-3-ylmethyl)methylsulfonamide,

M-(1-Bis(4-fluorophenyl)methyl-azetidin-3-yl-M-(3,5-difluorophenyl)methylsulfonamide, in (k5)-M-11-(4-chlorophenyl)pyrid-3-ylmethyl|azetidin- 3-yl)-M-(3,5-difluorophenyl)methylsulfonamide, (k)-M-11-(4-chlorophenyl)pyrid-3-ylmethyl|azetidin-3-yl)-M-(3,5-difluorophenyl )methylsulfonamide, (5)-M-11-K4-chlorophenyl)pyrid-3-ylmethyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide, (k5)-M-11-(4- chlorophenyl)pyrid-4-ylmethyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide, (k)-M-11-(4-chlorophenyl)pyrid-4-ylmethyl|azetidin-3-yl )-M-(3,5-difluorophenyl)methylsulfonamide, 65 (5)-M-11-K4-chlorophenyl)pyrid-4-ylmethyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide, (k5)-M-11-(4-chlorophenyl)pyrimidin-5-ylmethyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide,

(k)-M-11-(4-chlorophenyl)pyrimidin-5-ylmethyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide, (5)-M-11-Ibis(4-chlorophenyl )pyrimidin-5-ylmethyl-azetidin-3-yl-M-(3,5-difluorophenyl)methylsulfonamide,

M-11-Bis(4-chlorophenyl)methyl|azetidin-3-yl1-M-(3,5-difluorophenyl)benzylsulfonamide, their optical isomers and their pharmaceutically acceptable salts.

Compounds of formula I in which K 4 is the radical -M(K.)K5, where K represents a hydrogen atom, -M(K/)-СО-K or -M(K4)-5ОоКв, K. means the radical C(K. 4Х(К42)-Аг or -С(К.44ХК42)-Ней, and К/» means a hydrogen atom, can be obtained according to the following reaction scheme: Шебо сича ч (| СН,О,СИ 4 Ин 5О,сн , ra

ME, that n.

Bk KkB-Ssod,, and no HY 1 "Mn, and iv Dt

Nai50,k, te rai yah e| Ngai-sSo-k, her v t r p sch e x m v 5, | | XX o) here are the owls,

In the given formulas Ko", Kz, Ke and K.4 have the same values as in formula I, Ko means the Ag radical or -

Nei, Ag and Nei have the same meanings as in the formula I, and Na! means a halogen atom, preferably chlorine or bromine. yu

Stage a is usually carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorine-containing solvent (for example, dichloromethane, chloroform) at a temperature ranging from 15 to 302C in the presence of a base such as trialkylamine (for example, triethylamine, dipropylethylamine) or in pyridine at a temperature from 0 to 302C. co

Stage 6 is carried out mainly in methanol in an autoclave at a temperature ranging from 50 to 7096.

Step c is usually carried out in an inert solvent such as a chlorine-containing solvent (e.g. dichloromethane) in the presence of sodium triacetoxyborohydride and acetic acid at a temperature close to 2096.

Steps a and c are usually carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorine-containing agent (eg, dichloromethane, chloroform) in the presence of an amine, such as a trialkylamine (eg, triethylamine) at a temperature of 5 to 2096.

Derivatives of K-SOK.41 are industrial products or can be obtained by the methods described in K.S. :z» GAKOSK, Sotrgepepzime Ogdapis Tgapeiogtaiopv, MSN eayog.

Derivatives NaI-502K5 are industrial products or can be obtained by halogenation of the corresponding sulfonic acids, in particular, in the presence of chlorosulfonyl isocyanate and alcohol in a halogen-containing solvent (for example, dichloromethane, chloroform).

Nai-CO-Ke5 derivatives are industrial products or can be obtained by halogenation of the corresponding carboxylic acids, in particular, in the presence of thionyl chloride in a halogen-containing solvent (for example, with dichloromethane, chloroform).

Azetidinols 1 can be obtained using or adapting the methods described by A.K. KATKITAKU. with 1 co.). Selfless. Spet., 271 (1994) or SAME R.K., u. Oh Spet., 61, 5453 (1996), and in examples. work

They are usually carried out according to the following reaction scheme:

F) name) 60 b5

; p ochnu and t HYDROXYLAMIN vu tia, | ! in

Ko ts t o scho, 70 , re) c) Ame n

H

M вх В, in the formulas of which K» and Kz have the same values as in formula I, and Na! denotes a chlorine or bromine atom.

In stage A, they work mainly in an inert solvent such as an aliphatic C 4-C/-alcohol (for example, methanol, ethanol), possibly in the presence of alkali metal hydroxide, at the boiling temperature of the reaction medium.

In stage B, the reduction is usually carried out using lithium aluminum hydride in tetrahydrofuran at the boiling temperature of the reaction medium. with

In stage C, they work mainly in an inert solvent, such as an aliphatic C 4-C.-alcohol (for example, d) ethanol, methanol) in the presence of sodium bicarbonate at a temperature ranging from 202C to the boiling point of the reaction medium.

In stage O, they work according to the method described by SKIZAK M. with co-authors. in U. Med. Spet., 885 (1973). An organomagnesium compound is prepared from a bromine derivative and then a nitrile in an ether, such as diethyl ether, is introduced into the reaction at a temperature from 023 to the boiling point of the reaction medium. After hydrolysis with alcohol, the intermediate KU imine is reduced with sodium borohydride at a temperature from 09 to the boiling temperature of the reaction medium. and

Derivatives K»-СО-Кз are industrial products or can be obtained using or adapting the methods described by KOMOEK M.O. with co-author, U. Spet. wasps Regkip Tgapz 1, 2815 (1997); MOKEMO-MAKKAZ M., Yeishg. 35), Mea. Spet., 23 (5) 477 (1988); ZKIMMEK with co-author, U. Mei4. Spet., 14 (6) 546 (1971); NOKM M.K., Teig. -

IIenf., 36 (52) 9453 (1995); MEOISI A. with co-author, Teig. Gen., 24 (28) 2901 (1983); KIESKE K.O. with co-author,

U. Ogd. Spets., 62 (20) 6921 (1997); KMAVE )3. with co-author, Agsp, Rpagt., 306 (9) 648 (1973); SOMBOMMI K. with co-author, u). Spent 5 people Regkip Tgapz 1, 1989 (1996); EK-96-2481 and UR-94-261393. "

Derivatives of KzVg are industrial products or can be obtained using or adapting the methods described in VKAMO5MA GG. Bupi Sott., 20 (11) 1967 with co-author, 3153 (1990); And EMAIKE M. with co-authors, Zupii. with Sott., 24 (1) 95 (1994); SOVA N. with co-authors, Zupipevziv, 9, 849 (1992); VAOEKIGE R. with co-authors, U. Spet. boss. :z» Reckip Tgapz 2, 489 (1993).

Derivatives of Kz3SM are industrial products or can be obtained using or adapting the methods described by VOOM5BOYUM R. with co-authors, 9). Her Spet., 29 (4) 895 (19923; 5BOD2OKI M. with co-author, ). Spent wasps -1 15 Spet. Sott., 1523 (1984); MAKVYKO 5. with co-author, U. Nei. Spet., 17, 1333 (1980); REXES MU. with co-author, 3).

Oh Spet., 60 (21) 6895 (1995). (95) Compounds of formula I, in which Ku is the radical -M(K.)K", can be obtained according to the following reaction scheme:

In: in p t-A i, s c kuv,mn m i" (d) e she 2 Hers 1 ka in the formulas of which Ko", Kz, K,. and K5 have the same values as in formula I. This reaction is usually carried out in an inert solvent such as a chlorine-containing solvent (e.g., dichloromethane) in the presence

F! sodium triacetoxyborohydride and acetic acid at a temperature close to 2026.

Compounds NM(KA)K5 are industrial products or can be obtained according to classical methods known to specialists or with the application or adaptation of methods described by Ragk K.K., U. Ogud. Spets., 60 (19) 6202 (1995); Kaiig A. u). Honey. Spet., 12 (3) 473 (1969); Zagdez K., 9. Ogd. Spet., 40 (9) 1216 (1975); 7atsdo N.E., 60), Od. Spet., 33 (5) 2167 (1968); May Spet., 10, 128 (1967); U. At. Spent boss, 2244 (1955); Spent Veg., 106, 2890 (1973); Spent Rpagt Vii., 16 (10) 1953 (1968); You are wasps Sleep Rg., 835 (1962).

Azetidinones 2 can be obtained by oxidation of the corresponding azetidinols mainly in dimethylsulfoxide with the help of a pyridine-sulfotrioxide complex at a temperature close to 202С or with the help of dimethylsulfoxide in the presence of oxalyl chloride and triethylamine at a temperature from -70 to -5096. because Compounds of formula I, in which Ki is the radical -МЩ(К)СОК» or -М(К/)5О»о can be obtained according to the following reaction scheme: night (its

Nai-80, A ro MN o nansov, te te ko te t tA

M M because at 70 | -8X GG "KY: And imagine in na va

In the given formulas Ko", Kz, Ku, Kv and Ko have the same values as in formula I, and Na! denotes halogen, mainly chlorine.

Steps a and b are usually carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorine-containing solvent (e.g. dichloromethane, chloroform) in the presence of an amine such as a trialkylamine (e.g. triethylamine) at a temperature of 5 to 2096.

Compounds of formula I, in which K. is the radical -M (Ku) -5O02Kv, in which K / denotes Nei or Ag, can be obtained according to the following reaction scheme:

Kh t ne m pamn-zouya, v

These and S Vod u Pot y. i, s

B to-X, pa-chn-vo vv o " "Mag chE

In the given formulas, Ko", Kz and Ko have the same values as in formula I, Ka denotes the Ag or Nei radical (Nei and Ag have the same values as in formula I), and Me denotes the methanesulfonyloxy radical. at

Stage a is usually carried out in an inert solvent, such as tetrahydrofuran, in the presence of triphenylphosphine and diethylazodicarboxylate at a temperature from 09 to the boiling temperature of the reaction medium. at

Step p is usually carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorine-containing solvent (e.g., dichloromethane, chloroform) at a temperature ranging from 15 to 30°C in the presence of a base such as a trialkylamine (e.g., triethylamine, dipropylethylamine) or in pyridine at a temperature from O to 3020.

Stage c is preferably carried out in an inert solvent, such as dioxane, in the presence of С8СО with a boiling reaction mixture.

Derivatives in which Ka is the M-oxide of a nitrogen-containing heterocycle can be reduced to an unoxidized compound according to the method described by E. ZAMONAMEIGH et al., zupipeviz 1375 (1996). и Derivatives of Ка-МН-502К" can be obtained according to the following reaction scheme: и? na1-80.-V va-mna ---2 V4-MN-5OZVe

In the given formulas, Nai denotes a halogen atom, and Ka denotes a Nai or Ag radical. The reaction is carried out in an inert solvent, such as tetrahydrofuran, dioxane, a chlorine-containing solvent (for example, dichloromethane, chloroform) at a temperature ranging from 15 to 309C in the presence of a base, such as a trialkylamine (for example, o triethylamine, dipropylethylamine) or in pyridine at at a temperature from 0 to 3020. s. Derivatives in which Ka is the M-oxide of a nitrogen-containing heterocycle can be obtained by the method described in KNIE sl 50 K., Neyegosusiev, 41. (2) 323 (1995).

Compounds of formula I can also be obtained according to the following reaction scheme:

Ya» t.-SO-ya, VG i VYSNO xx -7 kisNON-B, p

ГФ) V. with nm .-snV-yak, вх чщ - I 60 ' | yu A "A

M i c

And 1

In the given formulas, K., B" and Kz have the same values as in formula I, and RA denotes phenyl.

Step a is usually carried out in an alcohol such as methanol in the presence of sodium borohydride at a temperature close to 2090.

In stage B, an organomagnesium compound is prepared from a bromine derivative and introduced into the reaction in an inert solvent, such as diethyl ether or tetrahydrofuran, at a temperature ranging from 02C to the boiling point of the reaction medium.

Stage c is carried out using a halogenating agent such as hydrobromic acid, thionyl bromide, thionyl chloride, a mixture of triphenylphosphine and carbon tetrabromide or carbon tetrachloride in acetic acid or 70 in an inert solvent such as dichloromethane, chloroform, carbon tetrachloride or toluene at a temperature from 02C to the boiling point reaction medium.

Stage a is carried out using hydrogen in the presence of palladium on charcoal in an alcohol such as methanol at a temperature close to 2020.

The step is carried out in an inert solvent, such as acetonitrile, in the presence of alkali metal carbonate 75 (for example, potassium carbonate) and potassium iodide at a temperature from 209 to the boiling point of the reaction medium.

Derivatives of K»zVg and derivatives of K--СНО are industrial products or can be obtained by the methods described, for example, by K.S. GG AKOSK, Sotrgepepzime Ogdapis Tgapaiogtayopv, MSN eayog.

Compounds of formula I, in which K. is the radical -M(K/4)-502-Ke, where K. denotes a piperid-4-yl radical, possibly substituted on the nitrogen by an alkyl radical, can also be obtained according to the following reaction scheme: кХ AND

M , se d-yav -- PN "kn, e mn----ya Ge o x v. |nnsol, y Gi 5ogv, -- v vo, 7 / shk sh / da n-( zn y h- K)-jav - x yu

Iii iv) eh o

M 50

I sh - - Mr Mike and"

In the given formulas, K", Kz and Ko have the same values as in formula I, aik denotes an alkyl radical, and Ke denotes a tert-butylcarbonyloxy radical. 20 Stage a is carried out in an inert solvent, such as a chlorine-containing solvent (for example, dichloromethane), in the presence of a hydride, such as sodium triacetoxyborohydride, and acetic acid at a temperature from 09C to the boiling point of the reaction medium. c Step p is usually carried out in an inert solvent such as tetrahydrofuran, dioxane, chlorine-containing solvent (e.g. dichloromethane, chloroform) in the presence of an amine such as trialkylamine (e.g. triethylamine) at a temperature of 5 to 2096. -i Stage c is carried out using hydrochloric acid in dioxane at a temperature from 0 C to the boiling point of the reaction medium. o Stage 4 is carried out using any means known to specialists for alkylating the amine without disturbing the other part of the molecule. Alkyl halides may be used, for example, in the presence of an organic base such as triethylamine, an alkali metal hydroxide (eg, sodium and potassium hydroxide), and possibly in the presence of tetrabutylammonium bromide in an inert solvent such as dimethyl sulfoxide,

HT» dimethylformamide or pyridine, at a temperature from 20 to 5026.

Compounds of formula I, in which K. is the radical -M(K/)-502-Ke, where K. denotes a pyrrolid-1-yl-substituted phenyl radical, can also be obtained by the action of pyrrolidine on the corresponding compound of formula I, in which Ki is the radical 5B o -M(KA)ZO»Kv, where Ku denotes phenyl substituted by a halogen atom.

This reaction is preferably carried out in dimethylsulfoxide at a temperature from 50 to 9596. It is obvious to a specialist that when carrying out the above-described methods according to the invention, it may be necessary to introduce protective groups for amine, hydroxyl and carboxyl functions to avoid side reactions. Such groups are groups that can be removed without disturbing the rest of the molecule. Examples of 60 protective groups for the amine function include tert-butyl or methyl carbamates, which can be regenerated with iodotrimethylsilane, or allyl carbamate, which can be removed with palladium catalysts. Examples of protective groups for the hydroxyl function include triethylsilyl, tert-butyldimethylsilyl, which can be regenerated with tetrabutylammonium fluoride, or asymmetric acetals (for example, methoxymethyl, tetrahydropyranyl), which are regenerated with 65 hydrochloric acid. Protecting groups for carboxyl functions include esters (for example, allyl, benzyl), oxazoles, and 2-alkyl-1,3-oxazolines. Other suitable protecting groups are described by OKEEME T.MU. with co-author, Rgoiesiipud dgoyrz ip Ogdapis Zupipevziv, zesopa eaiiop, 1991, addendum UMieu Kk zopv.

Compounds of formula I can be purified by conventional known methods, for example crystallization, chromatography or extraction.

Enantiomers of compounds of the formula | can be obtained by splitting racemic mixtures, for example, using chromatography on a chiral column according to RISKIE MU.N. with co-author, Azzuteyis BZupipevziv, mo1/.1,

Asadetis Rgezz (1983) either by salt formation or synthesis from chiral precursors. Diastereoisomers can be obtained using known classical methods (crystallization or chromatography from chiral precursors).

Compounds of the formula | can, if necessary, be converted into salt adducts with mineral or organic acids by the action of an acid in an organic solvent, such as an alcohol, a ketone, a simple ether, or a chlorine-containing solvent. These salts also form part of the invention.

Examples of pharmaceutically acceptable salts include the following salts: benzenesulfonate, hydrobromide, hydrochloride, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methanesulfonate, methylene-bis-p-oxynaphthoate, nitrate, oxalate, pamoate, phosphate, salicylate , succinate, sulfate, tartrate, theophylline acetate, and p-toluenesulfonate.

Compounds of the formula | have interesting pharmacological properties. These compounds are characterized by a strong affinity for cannabinoid receptors and, in particular, for receptors of the SVI type. They are receptor antagonists

SVI and, therefore, can be used in the treatment and prevention of disorders affecting the central nervous system, the immune system, the cardiovascular or endocrine system, the respiratory system, the gastrointestinal system and disorders of the reproductive system (Noijivieg, Rpagt. Keu., 38 , 1986, 1-20; Kepu and

Zippa, Rhod. YuOgyd. Kev., 36, 71-114 (1991); Sopvgoe and Zapauk, in Magiina pa/Sappabripoidz, MeiygobBriodu apa

MeihorpuzioIodu, 459; Mygrpu G. apa Vagine A. Edz, SKS Rgezz, 1992). high school

Thus, these compounds can be used to treat and prevent psychoses, including schizophrenia, anxiety states, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, (8) cognitive impairment, traumatic brain injury, panic attacks, peripheral neuropathies, glaucoma, migraines ) shocks, hemorrhagic shocks, hypotension, insomnia, immunological diseases, multiple sclerosis, vomiting, asthma, which) appetite disorders (bulimia, anorexia), obesity, memory disorders, intestinal transit disorders, when chronic treatment is canceled, when treating the syndrome withdrawal or alcohol medication (eg, opioids, barbiturates, cannabis, cocaine, amphetamines , phencyclide, hallucinogens, benzodiazepines), such as analgesics and)

With OR amplifiers of analgesic activity of narcotic and non-narcotic drugs. They can also be used for the treatment or prevention of intestinal transit.

The affinity of compounds of formula I to cannabis receptors was determined by the method described by KOZTEK ..E.,

ZTEMEMZOM .I., MMAKO 5.3)., O'AMVKA T.E., NAZHSOSK 0.A. in 3. Rpagtasoi. Ex. Tneg., 264, 1352-1363 (1993).

In the conducted test, the Sivo value for the compounds of formula I is lower than or equal to 100 Ohm. "

Their antagonistic activity was demonstrated using a model of hypothermia, which is induced with a cannabinoid receptor agonist (SR-55940) in mice, according to the method described by Regimee in K.O. in Magi)isapa, Nagueu 0.3.

And edz, 84 Ohio IKI. Rgezv, 263-277 (1985). and?" In this test, the OE5O value for compounds of formula I is less than or equal to 5 Ω/kg.

Compounds of formula I have low toxicity. Their Si is 5o higher than 4Omg/kg when administered subcutaneously in mice.

The following examples illustrate the invention. - And Example 1

M-11-Bis(4-chlorophenyl)methylIazetidin-3-ylHy-M-(b-chloropyrid-2-yl)umethylsulfonamide can be obtained by the following sequence of operations: to a solution of 1.54 g of 1-Ibis(4-chlorophenyl)methyl |iazetidine-Z-ol and 1.22 g of M-(b-chloropyrid-2-yl)methylsulfonamide in 120 cm? of anhydrous tetrahydrofuran is added under argon 2.4 cm? diethylazodicarboxylate and 1.44 g of triphenylphosphine. After 20 hours of stirring at 20 C, the reaction mixture is evaporated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column with silica gel "z" (granulometry 0.040-0.063 mm, height 30 cm, diameter 4.5 cm), eluting under pressure of 0.5 bar of argon with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting fractions with a volume of bosm3. Fractions 6-9 are combined and evaporated to dryness under reduced pressure (2.7 kPa). 1.75 gm is obtained

M-(1-Bis(4-chlorophenyl)methylI|azetidin-3-yl)-M-(b-chloropyrid-2-yl)umethylsulfonamide in the form of a white foamy mass.

H NMR spectrum (300 MHz, SOCIz, 5 U ppm): 2.85-3.00 (m:2H); 2.91 (cZN); 3.57 (t split, 9-7 and where 2Hz:2H); 4.25 (s/1H); 4.64 (m:/1H); from 7.20 to 7.35 (m:9H); 7.36 (dd, 9U-8 and 1Hz :1H); 7.71 (t, U-8Hz:1H)). 1-IBis(4-chlorophenyl)methyl|azetidin-3-ol can be obtained according to the sequence of operations described by 60 A.V. KATVITKU et al. . U. Neyegosusi. Spet., 271 (1994), based on 35.5 g of hydrochloride

Ibis(4-chlorophenyl)methyliamine and 11.0 cm? epichlorohydrin. 9.0 g of 1-bis(4-chlorophenyl)methyliazetidin-3-ol are isolated.

Ibis(4-chlorophenyl)methyl|amine hydrochloride can be obtained by the method described by SKIZAK M. et al.

U. Med. Spet., 885 (1973).

M-(b-chloropyrid-2-ylmethylsulfonamide) can be obtained by the following sequence of operations: To 65% of a solution of 2-amino-b6-chloropyridine cooled to 592C in 12.5 cm³ of pyridine, 7.8 cm³ of methylsulfonyl chloride is added dropwise for 1 hour. After reaching room temperature and stirring for 20 hours, 140 ml of water was added to the black reaction mixture and 200 ml of dichloromethane was extracted.The organic phase was separated, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa).

The obtained oily residue is chromatographed on a column with silica gel (granulometry 0.063-0.200 mm, height

3 cm, diameter 4 cm), eluting under a pressure of 0.5 bar of argon with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting fractions with a volume of 3 cm?. Fractions 5-10 were combined and evaporated to dryness under reduced pressure (2.7 kPa), obtaining 17 g of M-(6-chloropyrid-2-yl)methylsulfonamide in the form of a yellow oil.

Example 2

M-11-Bis(4-chlorophenyl)methylIazetidin-3-ylIi-M-(b-ethylpyrid-2-yl)umethylsulfonamide can be obtained by repeating the sequence of operations described in example 1, starting from Kk! 0.61g of 1-bis(4-chlorophenyl)methyl|azetidin-3-ol, 0.40g of M-(b-ethylpyrid-2-yl)methylsulfonamide, 5Osm3 of anhydrous tetrahydrofuran, 0.96cm? diethylazodicarboxylate and 0.577 g of triphenylphosphine. The crude product is chromatographed on a column with silica gel (granulometry 0.040-0.06 mm, height 20 cm, diameter 2 cm), eluting under a pressure of 0.5 bar of argon with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting fractions by volume ZOsm?. Fractions 6-9 are combined and evaporated to dryness under reduced pressure (2.7 kPa). 0.3 g of oil is obtained, which is ground in a mixture of 5 ml of diethyl ether and 5 ml of diisopropyl ether. The suspension is filtered, the solid substance is squeezed out and dried under reduced pressure (2.7 kPa), obtaining 0.11 g

M-41-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-(b-ethylpyrid-2-yl)umethylsulfonamide as a white solid.

The NMR spectrum of Shi (300 MHz, SOSIz, 5 V mod.) 1.26 (T, 9-7.5 HzC:ZN); 2.76 (sq., 9U-7.5Hz:2H); from 2.85 to 2.95 (m:2H); 2.90 (cZ3H); 3.53 (t split, 9-7 and 2HtsC2H); 4.22 (son); 4.69 (m:1H); 7.07 (d, 9U-7.5HzC:1H); from 7.15 to 7.30 (m:9H); 7, 64 (t, 9-7.5Hz: 1H)). with

M-(b-ethylpyrid-2-ylmethylsulfonamide) can be obtained by the following sequence of operations: To a cooled to 592 solution of 2.50 g of 2-amino-b-chloropyridine in 2.50 cm3 of pyridine, 1.56 cm3 of methylsulfonyl chloride is added dropwise. After 20 hours stirring at 20 C, add 1 cm of water to the reaction mixture, and then filter the mixture. The filtrate is evaporated to dryness at 509С and reduced pressure (2.7kKPa). The residue is chromatographed on a column with silica gel (granulometry 0.040-0.06Zmm, height 30cm, diameter 4cm) , eluting - under a pressure of 0.5 bar of argon, 1.5 l of dichloromethane and then with a mixture of dichloromethane and ethanol (98/2 by volume) and collecting fractions with a volume of bOsm3. Fractions 8-12 are combined and dried under reduced pressure ( 2.7 kPa), obtaining 2.8 g of M-(b-ethylpyrid-2-yl)methylsulfonamide in the form of a yellow oil.

Example From p

M-11-Bis(4-chlorophenyl)methylIazetidin-3-ylHy-N-quinol-b-ylmethylsulfonamide can be obtained in the following way. To a solution of 0.50 g of M-quinol-b-ylmethylsulfonamide in 50 cm? of anhydrous tetrahydrofuran is added under argon to 0.70 g of 1-bis(4-chlorophenyl)methyl|azetidin-3-ol, 0.597 of triphenylphosphine, after which 0.40 cm of diethyl azodicarboxylate is added. After 20 hours of stirring at 202C, the reaction mixture is heated at boiling temperature for 4 hours and 2.98g of triphenylphosphine and 2.0cm of diethylazodicarboxylate are added. After 48 hours of stirring at 202, the mixture is evaporated to dryness under reduced pressure (2.7 kPa). The remainder is taken away by ZOsm? of diethyl ether and the resulting suspension is filtered, and the filtrate is evaporated to dryness. Part of the obtained residue (0.90 g) is chromatographed on a Vopa EiYish column with cation-exchange sulfonic acid resin СХ:з" (granulometry 0.054 mm, height 4 cm, diameter 3 cm), eluting first with methanol and then with 2M ammonia solution for elution of the target product and collecting fractions of 5 cm 3. Fractions 16-19 are combined and evaporated to dryness under reduced pressure (2.7 kPa). 0.33 g of oil are obtained, which are stirred in 1Osm of isopropyl ether. - And the resulting suspension is filtered. After 15 minutes, the refiltered filtrate separates a solid substance, which is dried at 5096 and reduced pressure (2.7 kPa). 8 mg of M-11-bis(4-chlorophenyl)methyl|azetidin-3-yl1-M-quinol-b-ylmethylsulfonamide are obtained as a white solid. o IS spectrum of NMR "H (300 MHz, SOSIZ, 5 in ppm): 2.87 (cIZN); 2.89 (m:2H); 3.55 (t split, 9-7 and 1HzC:2H ); c 20 4.18 (c1H); 4.69 (m:y1H); from 7.15 to 7.30 (m:8H); 7.47 (dd, 9U-8.5 and 4Hz:1H) ; 7.58 (dd, 9-9 and 2.5Htsi1H); 7.73 (d, 9-2.5Hts:1H); 8.10-8.20 (m:2H); 8.97 (dd, 9-4 and 1.5HzC:1H)). i" M-Quinol-b6-ylmethylsulfonamide can be obtained in the following way. To a solution of 1.98 g of b-aminoquinoline cooled to 432 in 1.75 cm? of pyridine, pyridine is added for 1 hour drops of 1.1 cm of methylsulfonyl chloride.

After 20 hours of stirring at 20 C, 5O0cm of dichloromethane is added to the reaction mixture, and then the mixture is filtered. The filtrate is divided into phases. The organic phase is dried over magnesium sulfate, filtered and

HF) is evaporated to dryness under reduced pressure (2.7 kPa), obtaining 1.15 g of M-quinol-b-ylmethylsulfonamide in the form of a yellow-cream colored solid.

Example 4

M-11-Bis(4-chlorophenyl)methylIazetidin-3-ylHy-M-quinol-5-ylmethylsulfonamide can be obtained in the following way. To a solution of 0.50 g of M-quinol-5-ylmethylsulfonamide in 70 cm? of anhydrous tetrahydrofuran is added under argon to 0.70g of 1-(bis(4-chlorophenyl)methyliazetidin-3-ol, 0.597g of triphenylphosphine, after which 0.40cm of diethylazodicarboxylate and 0.45g of 1,2-bisidiphenylphosphine)ethane are added. After 20 hours of stirring at 20 C, the reaction mixture was evaporated to dryness under reduced pressure (2.7 kPa). Is the balance taken by 7Osm? of ethyl acetate and 65% of the resulting solution, washed with 30 ml of saline solution, dried over magnesium sulfate, filtered and evaporated to dryness at 02C and reduced pressure (2.7 kPa). The resulting purple oil is chromatographed on a column with silica gel (granulometry 0.063-0.200 mm, height 35 cm, diameter 3.8 cm), eluting under a pressure of 0.5 bar argon with a mixture of cyclohexane and ethyl acetate (40/60, then 30/70 and 20/80 volume) and collecting fractions with a volume of 50 cm3.

Fractions 6-12 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The residue is taken with 15 cm3 of methanol, the resulting white suspension is filtered, the solid substance is squeezed out and dried at 502C and reduced pressure (2.7 kPa), obtaining 0.35 g of M-1-|bis(4-chlorophenyl)methyl-azetidin-3-yl )-M-quinol-5-ylmethylsulfonamide as a white solid.

H NMR spectrum (300 MHz, SOCIz, 5 ppm): 2.60 (t, 9-7Hz:1H); 2.84 (t, 9-7Hz:1H); 2.99 (s: ZN); 3.36 (t split, 9-7 and 2.5HzC:1H); 3.56 (t split, 9-7 and 2.5HzC:1H); 4.01 (s/1n); 4.85 (m:/1H); from 7.10 to 7.25 70 (m:8H); 7.40 (dd, 9U-7.5 and 1Hz:1H); 7.54 (dd, 9- 8.5 and 4Hz:1H); 7.74 (dd, 9-8 and 7.5Hz:1H); 8.20 (d width 9U-8Hz 1H); 8.54 (d width, 9-9 Hz:1H); 8.99 (dd, 9-4 and 1.5Hz:1H)).

M-quinol-5-ylmethylsulfonamide can be obtained by repeating the sequence of operations described in example C, starting from 2.0g of aminoquinolein, 3.Osm of pyridine and 11cm3 of methylsulfonyl chloride. They get 2.47g

M-quinol-5-ylmethylsulfonamide as a brown-yellow solid.

Example 5

M-11-(Bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-isoquinol-5-ylmethylsulfonamide can be obtained by repeating the sequence of operations described in example 4, starting from Kk! 0.497 g

M-(isoquinol-5-yl)umethylsulfonamide, 7Oosm3 of anhydrous tetrahydrofuran, 0.712g of 1-(bis(4-chlorophenyl)methylazetidin-3-ol, 0.597g of triphenylphosphine, 0.40cm3 of diethylazodicarboxylate and 0.45g of 1,2-bisidiphenylphosphine)ethane. . The obtained crude brown oil is purified by chromatography on a column with silica gel (granulometry 0.063-0.200 mm, height 38 cm, diameter 3 cm), eluting with a mixture of cyclohexane and ethyl acetate (30/70 by volume) and collecting fractions with a volume of 40 cm3. Fractions 8-23 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The remainder is mixed in 15cm? of diethyl ether, the suspension is filtered and the insoluble material is chromatographed on a column with ZSh resin (height 4 cm, diameter 3 cm), washing first with a mixture of methanol and dichloromethane (50/50 by volume) and then eluting with a 2 M solution of ammonia in methanol and i) collecting fractions with a volume of 20 cm?. Fractions 1-6 are combined and the resulting white insoluble solid is filtered off, which is squeezed and then dried at 50 C and reduced pressure (2.7 kPa). 0.169g are obtained

M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylI-M-isoquinol-5-ylmethylsulfonamide as a white solid. "AND

H NMR spectrum (300 MHz, SOSIZ, 5 ppm): 2.64 (t, 9-7Hz:1H); 2.81 (t, 9-7Hz:1H); 2.98 (s: ЗН); 3.36 (t u split., U-/ and 2Hz:1Н); 3.55 (t split., 9U-7 and 2HzС:1Н); 4.02 (s:/1Н); 4, 86 (m:1H); 7.10-7.25 (m:8H); 7.60 (dd, -8 and 1ГцЦСИ1Н); 7.66 (t, 9У-8ГЦС1Н); 7.3 (d width. , 9U-6HzC:1H); 8.06 (width, 9U-8Hz:1H); 8.66 (d, is)

UbHz: 1H); 9.32 (width: 1H)). co

M-(isoquinol-5-yl)umethylsulfonamide can be obtained by repeating the sequence of operations described in example 4, starting from 2.0 g of B-aminoisoquinolein, 3.0 cm3 of pyridine and 1.1 cm3 of methylsulfonyl chloride. in.

2.3 g of M-(isoquinol-5-yl)umethylsulfonamide are obtained as a beige solid.

Example 6

M-11-Bis(4-chlorophenyl)methylIazetidin-3-yl-M-pyrid-3-ylmethylsulfonamide can be obtained in the following way. To a solution of 0.144 g of M-(1-bis(4-chlorophenyl)methylI|azetidin-3-ylI-M-(1-oxidpyrid-3-yl)umethylsulfonamide in

Bcm3 of chloroform, pour 0.042 cm? phosphorus trichloride and heat the mixture at boiling temperature. b) c After stirring for 1 hour, the reaction mixture is left until its temperature returns to room temperature, Bcm3 of 0.1N hydrochloric acid is added, mixed and the phases are separated. The organic phase is diluted with 20cm3 of chloroform, dried over magnesium sulfate, filtered and dried evaporated under reduced pressure 15 (2.7 kPa). The residue is chromatographed on a column with silica gel (granulometry 0.063-0.200 mm, height 9 cm, -1 diameter 1.vsm), eluting under a pressure of 0.1 bar argon with a mixture of dichloromethane and methanol (95/ 5 by volume) and collecting fractions with a volume of 15 cm3. Fractions 2-4 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The residue is stirred in 15 cm? of diethyl ether, the suspension is filtered and the solid material is dried under reduced pressure. sl (2.7 kPa). 35 mg of M-(11-bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-pyrid-3-ylmethylsulfonamide are obtained in the form of a cream-colored solid. (300 MHz, SOSIz, 65 ppm): 2.80-2.95 (m:2H); 2.87 (sZN); 3.51 (t split, 9-7 and "g" 1.5Hz: 2H); 4.18 (c1n); 4.65 (m:1H); 7.15-7.35 (m: 8H); 7.37 (dd width, 9-8 and 5Hz:1H); 7.64 (d reduc.,

UVHC: 1H); 8.52 (d width, U-2Hz:1H); 8.61 (d width, U-5Hz:1H)).

Example 7

M-11-Bis(4-chlorophenyl)methyl-azetidin-3-yl-N-(1-oxypyrid-3-yl)methylsulfonamide can be prepared as follows. To a solution of 0.265g of 1-bis(4-chlorophenyl)methyl|azetidin-3-ol and 0.162g of M-(1-oxidpyrid-3-yl)methylsulfonamide in 25cm3 of anhydrous tetrahydrofuran, add 0.16cm? i.e.) diethylazodicarboxylate and 0.226 g of triphenylphosphine. After 20 hours of stirring at 20 2 and then 24 hours at boiling temperature, the reaction mixture is evaporated to dryness under reduced pressure (2.7 kPa). Residue 60 is chromatographed on a column with silica gel (granulometry 0.063-0.200 mm, height 20 cm, diameter 1.5 cm), eluting under a pressure of 0.5 bar argon with a mixture of dichloromethane and methanol (98/2 by volume) and collecting fractions by volume 4 Osm 3. Fractions 26-64 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The residue is stirred in 10 ml of diethyl ether, the suspension is filtered, the insoluble material is squeezed out and dried under reduced pressure (2.7 kPa). 0.10 g of M-(1-bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-(1-oxypyrid-3-yl)methylsulfonamide is obtained as a white solid.

H NMR spectrum (400 MHz, (СО53)»5O ab, 5 in md.): 2.78 (t, 9-7HzC:2H); 3.06 (c:ZN); 3.37 (t, U -7Hz:2H); 4.45 (c11H); 4.71 (m:/1H); 7.30-7.50 (m:1OH); 8.21 (d width, U-6.5Hz: 1H); 8.27 (with width: 1H)).

M-(1-oxypyrid-3-yl)umethylsulfonamide can be obtained in the following way. To the solution 1.81 g

M-pyrid-Z-yl-methylsulfonamide in 71cm3 of M,M-dimethylformamide and 3cm3 of methanol is added in portions of 7.1g of 50-5595% 3-chloroperbenzoic acid and then 00.5bscm3 of 4095% hydrofluoric acid. After 2 hours of stirring at 202C, the reaction mixture is poured onto 500 g of ice, stirred and then filtered. The filtrate is evaporated to dryness at 609C and reduced pressure (2.7 kPa). Do they take the remaining 50 cm? mixture of dichloromethane with methanol (98/2 by volume) and filtered. The filtrate is chromatographed on a column with silica gel (granulometry 70 0.063-0.200 mm, height 27 cm, diameter 4 cm), eluting under a pressure of 0.5 bar of argon with a mixture of dichloromethane and methanol (98/2 by volume) and collecting fractions with a volume of bOsm3. Fraction 62 is evaporated to dryness under reduced pressure (2.7 kPa).

0.96 g of M-(1-oxide-pyrid-3-yl)methylsulfonamide is obtained in the form of a yellowish solid.

M-pyrid-3-yl-methylsulfonamide can be obtained by repeating the sequence of operations described in example 1, starting from 2 g of C-aminopyridine, 5 cm of C pyridine and 1.8 cm3 of methylsulfonyl chloride. The obtained crude product is stirred in 40 ml of diethyl ether, the suspension is filtered and the solid material is squeezed out and dried under reduced pressure (2.7 kPa), obtaining 2.47 g of M-pyrid-3-yl-methylsulfonamide in the form of a dissolved solid.

Example 8

M-11-Bis(4-chlorophenyl)methylIazetidin-3-yl)-M-cyclohexylmethylsulfonamide can be obtained in the following way. To the solution 1.8 g of M-1-Ibis(4-chlorophenyl)methyl)|azetidin-3-yl). -M-cyclohexylamine, 0.7 cm? of triethylamine and 20 mg of 4-dimethylaminopyridine in 25 cm3 of dichloromethane, add 0.4 cm of methylsulfonyl chloride with stirring. After 48 hours of stirring at 20 C, add 20 cm? of dichloromethane, 20 cm3 of water, mix and separate the phases. with

The organic phase is dried over magnesium sulfate and evaporated at 502C and reduced pressure (2.7 kPa). The brown oily residue is chromatographed on a column with silica gel (granulometry 0.063-0.2 mm, height 20 cm, diameter 2.00 cm), eluting under a pressure of 0.1 bar argon with a mixture of dichloromethane and methanol (96/4 by volume) and collecting the fractions with a volume of 1Osm?. Fractions 2-4 and 5-10 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The residue is volume chromatographed with silica gel (granulometry 0.063-0.2 mm, height 30 cm, diameter 1.5 cm), eluting under a pressure of 0.1 bar of argon with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting fractions by volume 5cm3. IF)

Fractions 7-10 are combined and evaporated to dryness under reduced pressure (2.7kKPa)" 0.10 g of

M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-"M-methylsulfonamide in the form of a cream-colored foamy mass.

H NMR spectrum (300 MHz, SOSIZ, 5 ppm): 0.80-1.p90 (m: "10OH); 2.82 (c:ZN); 3.36 (t width, U-7.5Hz:2H); o with 346 (t, 9U-7.5HZ:2Н); 3.59 (m.1N); 4.08 (m:1H); 4.42 (s/1H); 7.20-7.40 (m:8H)). Cha

M-1-IBis(4-chlorophenyl)methyl|azetidin-3-yl). -M-cyclohexylamine can be obtained in the following way. To a solution of 1.5 g of 1-(bis(4-chlorophenyl)methyl|azetidin-3-one in 25 ml of 1,2-dichloroethane, 0.5 g of cyclohexylamine, 1 g of sodium triacetoxyborohydride, and 0.3 ml of 10096-% acetic acid are added. After stirring for 20 hours at 202 °C, 20 cm3 of dichloromethane and 10 cm3 of water are added to the reaction mixture with stirring, after which the mixture is neutralized to pH 7-8 with a 1 N aqueous solution of sodium hydroxide. The mixture is separated into phases, the organic phase is dried over sulfate magnesium and evaporated to dryness at 509 and reduced pressure (2.7 kPa). 1.8 g of M-1-bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-cyclohexylamine are obtained in the form of a cream-colored paste, which will be used as such in the next stage. 1-IBis(4-chlorophenyl)methyl|iazetidin-3-one can be obtained in accordance with the following sequence - 45 operations: to a solution of 5.0 cm3 of oxalyl chloride in 73 cm? of dichloromethane cooled to -789C, add a solution of 8.1 cm3 of dimethyl sulfoxide in 17.6 cm? dichloromethane. The mixture is kept for 5 hours at -782C and the solution is topped up with 16.0 g. 1-Ibis(4-chlorophenyl)methyl|azetidin-3-ol in 50 cm? dichloromethane. The mixture is kept for 5 hours at -782C, 26.6 cm3 of triethylamine is added dropwise and the mixture is left until its temperature returns to room temperature. After 50 16 hours, the reaction mixture is washed 4 times with 200 cm? of water and then 200 cm? saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The resulting residue is chromatographed on a silica gel column (granulometry 0.04-0.0 mm, diameter 9.2 cm, height 21 cm), eluting under a pressure of 0.5 bar argon with a mixture of ethyl acetate and cyclohexane (40/60 by volume) and collecting fractions with a volume of 200 cm3. Fractions 15-25 are combined and evaporated to dryness under reduced pressure (2.7 kPa), obtaining 8.9 g of 1-ibis(4-chlorophenyl)methyliazetidin-3-one in the form of pale yellow crystals with a melting point of 1112C. (FI Example 9

M-11-(Bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-cyclopropylmethylsulfonamide can be obtained by repeating the sequence of operations described in example 8, starting from 1.6 bg of M-1-Ibis(4-chloro phenyl)methyl|azetidin-3-yl)-M-cyclopropylamine, 25 cm3 of dichloromethane, 0.7 cm3 of triethylamine, 20 mg of 4-dimethylaminopyridine and 0.4 cm? methylsulfonyl chloride and stirring the mixture for 20 hours at 202С.

The crude product is chromatographed on a column with silica gel (granulometry 0.063-0.2 mm, height 30 cm, diameter 2.00 cm), eluting under a pressure of 0.1 bar of argon with a mixture of dichloromethane and methanol (97/3 by volume) and collecting fractions of by 1Osm3. Fractions 6-9 and 10-20 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained residue 65 is chromatographed on a column with silica gel (granulometry 0.063-0.200 mm, height 30 cm, diameter 2.0 cm), eluting under a pressure of 0.1 bar of argon with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting fractions of 10 cm? Fractions 6-11 are combined and evaporated to dryness under reduced pressure (2.7 kPa). 0.14 g is obtained

M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-M-cyclopropylmethylsulfonamide in the form of a cream-colored foamy mass

H NMR spectrum (300 MHz, SOSIZ, 5 ppm): 0.79 (m:2H); 0.95 (m:2H); 2.11 (min); 2.84 (s:ZH ); 3.17 (t width, U-7Hz:2H); 3.50 (m:2H); 4.18 (m/1H); 4.29 (s:1H); 7.20-7, 40 (m:8H)).

M-1-Bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-cyclopropylamine can be obtained as described in example 8, starting from 1.5 g of 1-Bis(4-chlorophenyl)methylIazetidin-3-one , 25cm of 1,2-dichloroethane, 0.37cm3 of cyclopropylamine, g of sodium triacetoxyborohydride and 0.3cm3 of 1009p acetic acid. They receive 1.6 g

M-1-Bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-cyclopropylamine as a brown oil, which will be used as such in the next step.

Example 10

M-(1kK,25,45)-Bicyclo|2.2.1|hept-2-yl-M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)umethylsulfonamide can be obtained by repeating the sequence of operations described in example 8, based on Kk! 2.0 g

M-(1kK,25,45)-bicyclo|2.2.1|hept-2-yl-M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)amine, 25 cm3 of dichloromethane, 0.7 cm3 of triethylamine, 20 mg of 4-dimethylaminopyridine and 0.4 cm3 of methylsulfonyl chloride and stirring the mixture for 20 hours. The brown oily residue is chromatographed on a silica gel column (granulometry 0.063-0.2 mm, height 30 cm, diameter 2.0 cm), eluting under a pressure of 0.1 bar argon with a mixture of dichloromethane and methanol (97/3 by volume) and collecting fractions of with a volume of 10 cm3. Fractions 6-18 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column with silica gel (granulometry 0.063-0.2 mm, height 30 cm, diameter 2.00 cm), eluting under a pressure of 0.1 bar argon with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting fractions by volume 1 Osm3. Fractions 8-14 are combined and flattened to dryness under reduced pressure (2.7 kPa). with

They receive 0.70 g

M-(1kK,25,45)-bicyclo|2.2.1|hept-2-yl-M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)methylsulfonamide in the form of a foamy mass of cream color.

NMR spectrum of "H (300 MHz, SOSIZ, 5 ppm): 1.20-1.75 (m:7H); 1.84 (t width, U-12.5HCN); 2.29 ( min); 2.35 (m:1H); 2.82 (s:ZH); 3.35-3.55 (m:ZH); 3.66 (m:1H); 3.90-4.05 (m:2N); 4.51 (s/1N); 7.20-7.45 (m:8N)). "I

M-(1kK,25,45)-Bicyclo(2.2.1|hept-2-yl-M-11-I(bis(4-chlorophenyl)methyl|azetidin-3-yl)iamine can be obtained by repeating the sequence of operations , described in example 8, based on Kk! 1.5g of 1-Ibis(4-chlorophenyl)methyl|azetidin-3-one, 25cm3 of 1,2-dichloroethane, 1.5g of (185,25,45)-bicyclo|2.2. 1 g of heptyl-3-amine, 1 g of sodium triacetoxyborohydride and 0.3 ml of 100965 acetic acid.

2 g of M-(1kK,25,45)-bicyclo(|2.2.1Hept-2-yl-M-(1-Ibis(4-chlorophenyl)methyl|azetidine-3-ylamine) are obtained in the form of 32 brown oil, which will be used as such in the next stage.

Example 11

M-(1kK,2kK,45)-Bicyclo|2.2.1|hept-2-yl-M-(1-Ibis(4-chlorophenyl)methylIazetidine-3Z-ylliummethylsulfonamide can be obtained by repeating the sequence of operations described in example 8, based on 1.8 g "

M-(1K,2kK,45)-bicyclo|2.2.1|hept-2-yl-M-1-Ibis(4-chlorophenyl)methyl|azetidin-3-ilyamine, 25 cm3 of dichloromethane, 3 to 0.7 cm3 of triethylamine, 20 mg of 4-dimethylaminopyridine and 0.4 cm3 of methylsulfonyl chloride and stirring the mixture for 20 hours. The brown oily residue is chromatographed on a column with silica gel (granulometry: z» 0.063-0.2 mm, height 30 cm, diameter 2.0 cm), eluting under a pressure of 0.1 bar of argon with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting fractions with a volume of 10 cm3. Fractions 3-12 are combined and evaporated to dryness at

Reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (granulometry 0.063-0.2 mm, height 30 cm, diameter 2.0 cm), eluting under a pressure of 0.1 bar argon with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting fractions of with a volume of 1Osm3. Fractions 4-10 are combined and evaporated to dryness under reduced pressure (2.7 kPa). 0.1 mg of M-(1K,2K,45)-bicyclo|2.2.1|hept-2-yl-M-1-I(bis(4-chlorophenyl)methyl|azetidine-3-ylmethylsulfonamide in the form of 5 yellow foamy mass. 1st NMR spectrum "H (300 MHz, SOSIi, 5 in ppm): 1.00-1.85 (m:8Н); 2.14 (min); 2.33 (min ); 2.82 (c:ZN);

Thursday" 3Z, 40-3, 60 (m: 4H); 3.71 (dd width, 9-8 and b6HtsC:1H); 4.10 (m:1 H); 4.47 (s/1 N); 7.20-7.40 (m:8H)).

M-(1K,2kK,45)-Bicyclo|2.2.1|hept-2-yl-M-(1-Ibis(4-chlorophenyl)methylI|azetidine-Z-iliamine can be obtained by repeating the sequence of operations described in the example 8, based on Kk! 1.5 g of 1-I(bis(4-chlorophenyl)methyl-azetidin-3-one, 25 cm3 of 1,2-dichloroethane, O,bg (1K,2K,45)-bicyclo (22.11

HF) heptyl-Z-amine, 1.0 g of sodium triacetoxyborohydride and 0.3 cm? of 100965 acetic acid. They receive 1.8 g

M-(1K,2kK,45)-bicyclo|2.2.1|hept-2-yl-M-11-(bis(4-chlorophenyl)methyl|azetidin-3-ilyamine in the form of cream-colored paste, used as such in the next stage.

Example 12 60 IM-((1-Benzhydryl)azetidin-3-yl|-Y-phenylmethylsulfonamide can be obtained in the following way. To a solution of 2g of 1-benzhydryl-3-anilineloazetidine in 40 cm? of dichloromethane, 0.7 cm" of methylsulfonyl chloride is added and then add 1.34 g of triethylamine. After stirring for 4 hours for 1 hour at 20 oC, the reaction mixture is washed twice with water and the organic phase is dried over magnesium sulfate and then evaporated to dryness at 509C and reduced pressure (2./kKPa). The resulting chestnut-colored oil is chromatographed on a column with silica gel bo (granulometry 0.063-0.2mm, height 2bsm, diameter 3,bsm), eluting under a pressure of 0.5 bar of argon with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting fractions with a volume of 5Osm3. 10-15 are combined and evaporated to dryness under reduced pressure (2.7 kPa) The residue is triturated in diethyl ether, the suspension is filtered, the solid material is squeezed out and then dried under reduced pressure (2.7 kPa). 35 mg is obtained

M-(1-benzhydryl)azetidin-3-yl|-M-phenylmethylsulfonamide as a white solid.

IS NMR spectrum "H (300 MHz, (СО4)5580 46 with the addition of a few drops of СОЗСООО 44.5 in ppm): 2.72 (m:2Н); 2.92 (с:ЗН); 3.36 ( m:2H); 4.32 (c:1H); 4.73 (m:1H); 7.10-7.45 (m:15H)). 1-benzhydryl-3-anilinonezetidine can be obtained by repeating the sequence of operations described in example 8, starting from 5g of 1-benzhydrylazetidin-Z-one, 1.92cm of aniline, 74cm3 of 1,2-dichloroethane, 6.3g of sodium triacetoxyborohydride and 12cm of 1009p acetic acid. 8.81g of 1-benzhydryl -3-anilinoazetidine in the form of a chestnut-colored resin, which will be used as such in the next stage.

Example 13

M-11-Bis(4-chlorophenyl)methyl I|azetidin-3-yl Ii-N-(3,5-difluorophenyl)methylsulfonamide can be obtained in 79 the following way. To a solution of 1.23 g of methylsulfonic acid 1-bis(4-chlorophenyl)methyl|azetidin-3-yl ether and

Oh, 6 bg. 1.0 g of cesium carbonate is added to M-(3,5-difluorophenyl)methylsulfonamide in 25 cm3 of dioxane. After 5 hours of stirring at boiling temperature and then 20 hours at 20 C, 50 cm? of diethyl ether and ZOcm?3 salt solution, after which the phases are mixed and separated. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness at 5092C and reduced pressure (2.7 kPa).

The obtained yellow-hot oil is chromatographed on a column with silica gel (granulometry 0.040-0.06 mm, height 25 cm, diameter 2.00 cm), eluting under a pressure of 0.5 bar argon with a mixture of cyclohexane and ethyl acetate (65/35 by volume) and collecting fractions of with a volume of 1Osm3. Fractions 6-10 are combined and flattened to dryness under reduced pressure (2.7 kPa).

The residue is chromatographed on a column with silica gel (granulometry 0.040-0.063 mm, height 15 cm, diameter 1.0 cm), mixing under a pressure of 0.5 bar argon with a mixture of cyclohexane and ethyl acetate (65/35 by volume) and collecting fractions by volume Bsm3. Fraction 7 is evaporated to dryness under reduced pressure (2.7 kPa). Receive 011g o

M-11-Bis(4-chlorophenyl)methyl|azetidin-3-yl-M-(3,5-difluorophenyl)methylsulfonamide in the form of a white powder.

H NMR spectrum (300 MHz, SOSIZ, 5 ppm): 2.82 (siZN); 2.85 (m:2H); 3.52 (t split, 9-7 and 2HzC:2H) ; 4.22 (s/1N); 4.47 (m:1N); 6.75-6.90 (m:ZN); 7.20-7.35 (m:8N)).

Method 2

1.41g of 1-(bis(4-chlorophenyl)methyl)azetidin-3-ol and 0.95g are added to the solution. M-(3,5-difluorophenyl)methylsulfonamide in 100 cm3 of anhydrous tetrahydrofuran is added under argon to 0.78 cm3 of diethylazodicarboxylate and 1.31 g of triphenylphosphine. After 16 hours of stirring at 202C, add Z00cm? ethyl acetate, the reaction mixture is washed twice with 100 cm3 of water, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa). m

The residue is chromatographed on a column with silica gel (granulometry 0.2-0.063 mm, height 50 cm, diameter 4 cm), eluting under a pressure of 0.6 bar of argon with a mixture of cyclohexane and ethyl acetate (75/25 by volume) and collecting fractions with a volume of 125 cm3 . Fractions 6-12 are combined and evaporated to dryness under reduced pressure (2.7 kPa). 1.8 g of a solid are obtained, which dissolve when heated in a mixture of ethyl acetate/isopropyl ether (15/2 by volume), cool and dilute with 100 ml of pentane to initiate crystallization. After filtration and drying, 1.0 g of M-(1-bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide is obtained in the form of white crystals melting at 15490 . "» M-(3,5-Difluorophenyl)methylsulfonamide can be obtained in the following way. To a solution of 33.5 g

To 5-difluoroaniline in 75 cm3 of dichloromethane, slowly add 2.0 cm3 of methylsulfonyl chloride, 3.8 cm3 of triethylamine and 20 mg of 4-dimethylaminopyridine. After 20 hours of stirring at 20 C to the reaction mixture - add 20 cm? of dichloromethane and 20 cm? water, the mixture is stirred and the phases are separated. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column with silica gel (granulometry 0.063-0.200 mm, height 20 cm, diameter 2.00 cm), eluting under a pressure of 0.1 bar of argon with dichloromethane and collecting fractions with a volume of 25 cm?. Fractions 14-20 are combined and evaporated to dryness under reduced pressure (2.7 kPa). 0.66 mg of M-(3,5-difluorophenyl)methylsulfonamide is obtained in the form of a white powder. 1-Bis(4-chlorophenyl)methyl|azetidin-3-yl ester of methylsulfonic acid can be obtained in such a way. . with way. To a solution of 12 g of 1-bis(4-chlorophenyl)methyliazetidin-3-ol in 200 cm" of dichloromethane, add 3.5 cm of methylsulfonyl chloride under argon for 1 hour, cool the mixture to 52C, and add 3.8 cm of pyridine for 10 minutes. After 30 hours of stirring, at 5 2С and then 20 hours at 202С, the reaction mixture is diluted with 100 cm3 of water and 100 cm3 of dichloromethane, filtered and separated into phases. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The obtained oil is chromatographed on a column with silica gel (granulometry 0.063-0.200 mm, height 40 cm, diameter 3.8 cm), eluting under a pressure of 0.5 bar argon with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting fractions of 60 vol. with a volume of 100 cm3. Fractions 4-15 are combined and evaporated to dryness under reduced pressure (2.7 kPa). 6.8 g of methyl sulfonic acid 1-bis(4-chlorophenyl)methyl I|azetidin-3-yl ether is obtained in the form of a yellow oil. 1- Bis(4-chlorophenyl)methyl|Iazetidin-3-sl can be obtained, using following the sequence of operations described by KATKIT2KU A.K. with cooperation, 9U. Selfless. Spet., 271 (1994), based on 35.5 g of hydrochloride

Ibis(4-chlorophenyl)methyliamine and 11.0 cm? epichlorohydrin. b5 Bis(4-chlorophenyl)methylamine hydrochloride can be obtained by the method described by M. OKIZAK et al. in U. May. Spet., 885 (1973).

Example 14

M-01-(Bis(4-chlorophenyl)methyl|azetidin-3-ylI-M-(4,6-dimethylpyrimid-2-yl)methylsulfonamide can be obtained by repeating the sequence of operations described in example 13 (method 2), starting with 0.20g of /MA(4,6-dimethylpyrimid-2-yl)methylsulfonamide and 0.308g of 1-bis(4-chlorophenyl)methyl|azetidin-3-ol. After chromatography on a column with silica gel (granulometry 0.06-0О ,04 mm, height 50 cm, diameter 2 cm), eluting under a pressure of 0.6 bar of argon with dichloromethane and then with a mixture of dichloromethane with 195 methanol and collecting fractions with a volume of 200 cm3, Fractions 4-7 are combined and evaporated to dryness under reduced pressure (2.7 kPa) After crystallization from diisopropyl ether, filtering and drying, 0.20 g of 70...M-1-Ibis(4-chlorophenyl)methyl-azetidin-3-ylI-m-(4,6-dimethylpyrimid-2-yl)umethylsulfonamide is obtained in the form white solid.

H NMR II spectrum (300 MHz, SOSIZ, 5 in ppm): 2.39 (s:bH); 2.89 (t width, U-7.5 HZ:2H); 3.51 (s :ZH); 3.77 (m:2H); 4.27 (s:1H); 4.77 (m:y1H); 6.73 (s/1H); 7.20-7.35 (m: 8H)).

M-(4,6-dimethylpyrimid-2-yl)umethylsulfonamide can be obtained in the following way. To a mixture of 1.23g of 19 2-amino-4,6-dimethylpyrimidine, 0.77cm3 of methylsulfonyl chloride and 5Omg of 4-dimethylaminopyrimidine, dissolved in 5Osm? of dichloromethane, add 1.4 cm? of triethylamine at a temperature of 0°C. The reaction medium is left for 16 hours at room temperature, washed twice with 1700 cm3 of water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). 1.0 g of yellow powder is obtained, which within 1

Are the clocks processed at 1002С 15cm? 1096 sodium hydroxide solution. After cooling, the reaction mixture is extracted twice with 5HOcm? dichloromethane. The aqueous phase is acidified with 5 cm of 10 n. of hydrochloric acid to pH 1 and extract twice with 50 cm3 of dichloromethane. The obtained organic phases are combined, washed with 5 Osm3 of water, dried over magnesium sulfate, filtered and evaporated. 0.20 g of M-(4,6-dimethylpyrimid-2-yl)methylsulfonamide is obtained in the form of a yellow powder. Ha

Example 15

M-11-IBis(4-chlorophenyl)methylIazetidin-3-yl)-M-(1,3,4-thiadiazol-2-yl)umethylsulfonamide can be obtained i) by repeating the sequence of operations described in example 13 (method 2) , based on 010g

IM-(1,3,4-thiadiazol-2-yl)umethylsulfonamide and 0.215 g of 1-bis(4-chlorophenyl)methyl|azetidin-3-ol. After chromatography on a column with silica gel (granulometry 0.06-0.04 mm, height 50 cm, diameter cm), eluting "I under a pressure of 0.8 bar of argon with a mixture of ethyl acetate/cyclohexane 20/80 and then 40/60 by volume and collecting fractions ' from - ! | fractions 26-31 are combined and evaporated to dryness under reduced pressure (2.7 kPa). After crystallization from diisopropyl ether, filtering and drying, 40 mg of IF is obtained)

M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-M-(1,3,4-thiadiazol-2-yl)umethylsulfonamide as a white solid.

H NMR spectrum (300 MHz, SOSIi, 5 in ppm): 3.01 (cZN); 3.09 (t split, uU-7 and 1.5HC2H); 3.70 (t- split ., 3-7 and 1.5HzC:2H); 4.28 (s:1H); 4.76 (m:1H); 7.20-7.35 (m:8H); 9.01 (s: 1H)).

IM-(1,3,4-thiadiazol-2-yl)umethylsulfonamide can be obtained in the following way. To the mixture of 2.02 g of 2-amino-1,3,4-thiadiazole in 10 cm? add 1.5 cm of pyridine? methylsulfonyl chloride. The reaction mixture is left for 2 hours at room temperature, bOsm? water and filter. The collected aqueous phase is acidified with 1 n. hydrochloric acid to pH 2 and extracted twice with 5Osm of ethyl acetate. The organic phase is washed 2 times with 50 cm? of water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa), obtaining 0.1 g of a yellow powder.

Example 16

M-11-(Bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-(thiazol-2-yl)umethylsulfonamide can be obtained -I by repeating the sequence of operations described in example 15, starting from 0.50 g of M -(thiazol-2-yl)umethylsulfonamide and b.5g of 1-I(bis(4-chlorophenyl)methylIazetidin-3-ol. After chromatography on a column with silica gel and (granulometry 0.06-0.04mm, height bOsm, diameter 2 cm), eluting under a pressure of 0.9 bar of argon with a mixture of ethyl acetate/cyclohexane 20/80 and then 40/60 by volume, fractions with a volume of 30 cm3 are collected. Fractions 9-12 are combined and evaporated to dryness under reduced pressure (2, 7 kPa).After crystallization from diisopropyl ether, i.e. filtering and drying, 0.21 g is obtained

HT» M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylI-M-(thiazol-2-yl)umethylsulfonamide in the form of a white solid.

H NMR spectrum (300 MHz, SOSIi, 5 ppm): 2.95-3.10 (m:2H); 3.00 (c3H); 3.59 (m:2H); 4.22 (with width: 1H); 4.69 (m: 1H); 7.20-7.35 (m: 9H); 7.60 (m: 1H)).

M-(thiazol-2-ylmethylsulfonamide can be obtained in the following way. To the mixture 1.0 g of 2-aminothiazole in 10 cm3

GF! add 1.5 cm of pyridine? methylsulfonyl chloride. The reaction mixture is left for 2 hours at room temperature, and bOsm is added to it. of water, filter and collect the solid material (0.35 g). The collected aqueous phase is acidified with 1 N. hydrochloric acid to pH 2 and extracted twice with 40 ml of ethyl acetate. The organic phase is washed 2 times in 50 cm? of water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa), obtaining 0.15 g of a white solid with spectral characteristics close to those of the filtered solid, corresponding to a mixture of M-(thiazol-2-yl)umethylsulfonamide and

M-(thiazol-2-yl)u-di(methylsulfonyl)imide, which is used as such in the next stage.

Example 17 b M-11-Bis(4-chlorophenyl)methyl|azetidin-3-yl]-M-(3-hydroxyphenyl)umethylsulfonamide can be obtained in the following way. 0.5 g to the mixture. M-71-(bis(4-chlorophenyl)methylIazetidin-3-yl)-M-(3-methoxyphenyl)methylsulfonamide in

20 cm3 of dichloromethane is added dropwise at 22 7.63 cm? 1M solution of boron tribromide. The reaction mixture is left for 20 hours at room temperature, poured onto ice and extracted with bOsm? dichloromethane.

The organic phase is washed three times with 80 cm? of water and then twice VOcm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). 0.3g of a white foamy mass is obtained, which is taken up with acetonitrile, filtered and dried, obtaining 0.20g of a white solid.

H NMR spectrum (300 MHz, SOSIi, 5 in ppm): 2.81 (cIZN); 2.86 (t lat., U-7.5Hz:2H); 3.50 (t lat., 9U-7.5HC:2H); 4.20 (c:1H); 4.53 (m:1H); 5.36 (m:1H); 6.70-6.85 (m:ZH); 7 ,15-7,35 (m:9Н)).70 Example 18

M-11-Bis(4-chlorophenyl)methylIazetidin-3-ylI-M-(3-methoxyphenyl)umethylsulfonamide can be obtained by repeating the sequence of operations described in example 15, starting from Kk! 1.58 g

M-(3-methoxyphenyl)methylsulfonamide and 2.0 g of 1-bis(4-chlorophenyl)methyl|azetidin-3-ol. After chromatography on a column with silica gel (granulometry 0.06-0.04 mm, height 24 cm, diameter 7.8 cm), eluting under a pressure of 0.7 bar of argon with a mixture of ethyl acetate/cyclohexane 50/50 and then 40/60 by volume, fractions with a volume of 100 cm3 are collected. Fractions 7-10 are combined and evaporated to dryness under reduced pressure (2.7kPa) (2.05g). After crystallization from diisopropyl ether, filtering and drying, /-0.21g is obtained

M-(1-Bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-(3-methoxyphenyl)methylsulfonamide.

M-(3-Methoxyphenyl)methylsulfonamide can be obtained in the following way. To a mixture of 5.0 g of Z-methoxyaniline in 150 cm3 of pyridine, add 3.14 cm? methylsulfonyl chloride. Leave the reaction medium for 20 hours at room temperature, add 200 cm? of water and 400 cm3 of ethyl acetate and separate into phases.

The organic phase is washed with 400 cm? of water and 400 cm? saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). After chromatography on a He column with silica gel (granulometry 0.06-0.04 mm, height 23 cm, diameter 7.8 cm), eluting under a pressure of 0.7 bar with argon with a mixture of ethyl acetate/cyclohexane 25/75 by volume, fractions of with a capacity of 10 Osm3. Fractions 24-36 are combined and evaporated to dryness under reduced pressure (2.7 kPa), obtaining 6.21 g

M-(3-methoxyphenyl)methylsulfonamide in the form of a yellow-brown oil.

Example 19 "

M-11-(Bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-(3-hydroxymethylphenyl)methylsulfonamide can be obtained in the following way. To a mixture of 0.Bg of ethyl ether of m-71-(bis(4-chlorophenyl)methylIazetidin-3-yl)-M-(methylsulfonyl)-3-aminobenzoic acid in 20 cm? toluene is added dropwise at -502С 1.46 bsm? of a 2096% toluene solution of diisopropylaluminum hydride. The reaction medium is left for 1.5 hours at 02С and 1.5 hours at 202С, cooled to 02С and slowly added 20 cm3 of water. After filtering the sediment and extracting it with ethyl acetate, the organic phase is washed 2 times with 80 cm? of water and then 8 VOcm?3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa).

0.46 g of oil is obtained, which is chromatographed on a column with silica gel (granulometry 0.06-0О0.4 mm, height « 20 1bsm, diameter 4.0 cm), eluting under a pressure of 0.7 bar of argon with a mixture of ethyl acetate/cyclohexane (60/40 volume) and 7 s collecting fractions with a volume of 20 cm3. Fractions 72-76 are combined and evaporated to dryness under reduced pressure (2.7 kPa). y Receive 0.20 g of M-1-|Ibis(4-chlorophenyl)methylIazetidin-3-yl)-M-(3-hydroxymethylphenyl)umethylsulfonamide In the form of a white solid.

H NMR spectrum (300 MHz, SOCI3, 5 ppm): 1.80 (min); 2.83 (cIZN); 2.87 (m:2H); 3.52 (m:2H); - | Example 20 c Ethyl ether of M-(1-bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-(methylsulfonyl)-3-aminobenzoic acid can be obtained by repeating the sequence of operations described in example 15, based on 1.58 g of M-(methylsulfonyl)-3-aminobenzoic acid ethyl 1 ether and 2.0 g of 1-bis(4-chlorophenyl)methyl|azetidin-3-ol. After chromatography on a silica gel column (granulometry 0.06-0, 04 mm, height 24 cm, diameter 7.8 cm), eluting under a pressure of 0.7 bar of argon with a mixture of ethyl acetate/cyclohexane 50/50 and then 40/60 by volume, collect fractions with a volume of 100 cm3. Fractions 7-10 are combined and evaporated to dryness under reduced pressure (2.7 kPa), obtaining 2.0 g of yellow oil.

M-(methylsulfonyl)-3-aminobenzoic acid ethyl ester can be obtained in the following way. To mixture 52 5.0 g of ethyl-Z-amino benzoate in 150 cm? pyridine is added at 32C 2.35 cm? methylsulfonyl chloride. They leave

HF) reaction medium for 20 hours at room temperature, add 200 cm3 of water and 400 cm3 of ethyl acetate to it

He is divided into phases. The organic phase is washed with 400 cm of water and 400 cm? saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). After chromatography on a column with silica gel (granulometry 0.06-0.04 mm, height 25 cm, diameter 7.8 cm), eluting under a pressure of 0.7 bar of argon with a mixture of ethyl acetate/cyclohexane 25/75 by volume, collect fractions of with a volume of 100 cm3.,

Fractions 27-36 are combined and evaporated to dryness under reduced pressure (2.7 kPa), obtaining 5.24 g of ethyl ether

M-(methylsulfonyl)-3-aminobenzoic acid in the form of yellow-brown oil.

Example 21 65 M-11-(Bis(4-chlorophenyl)methylIazetidin-3-yl)-M-(1-isobutylpiperid-4-yl)methylsulfonamide can be obtained in the following way. To the solution 0.47 g

M-411-Ibis(4-chlorophenyl)methylIazetidin-3-yl)-M-(1-piperid-4-yl)umethylsulfonamide in 20 cm3 of dichloromethane add 0.11 cm3 of isobutyric aldehyde, 0.057 cmM of 10095% acetic acid and 320 mg of triacetoxyborohydride sodium After 20 hours of stirring at 20 C, 50 cm? of a saturated aqueous solution of sodium bicarbonate and separate the phases. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on a column with silica gel (granulometry 0.063-0.200 mm, height 20 cm, diameter 2 cm), eluting under a pressure of 0.5 bar of argon with a mixture of cyclohexane and ethyl acetate (40/60 by volume) and collecting fractions with a volume of 30 ml. Fractions 3-15 are combined and evaporated to dryness under reduced pressure (2.7 kPa). 0.22 g of 790...M-1-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-M-(1-isobutylpiperid-4-yl)methylsulfonamide is obtained in the form of a white foamy mass.

NMR spectrum of 1H (300 MHz, SOSIz, 5 in m.d3): 0.87 (d, 9U-7Hz:bn); 1.60-1.90 (m:5H); 1.93 (t width, 911.5Hz:2H); 2.03 (d, 9U-7.5HZ:2H); 2.84 (c:3H); 2.89 (d width, U-11.5HzC:2H); 3.38 (t width, U-7HzC:2H); 3.47 (t width, U-7Hz:2H); 3.62 (m:1H); 4.08 (m:1H); 4.43 (s/1H); 7.20-7.40 (m:8H)). 12 11-Bis(4-chlorophenyl)methylylazetidin-3-yl)-M-(1-piperid-4-ylmethylsulfonamide) can be obtained in the following way. To a solution of 19g

M-71-I(bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-(1-tert-butoxycarbonyl-piperid-4-yl)methylsulfonamide in 199cm3 of dioxane is slowly added with 5Osm? 6 n. solution of hydrochloric acid in dioxane. After 20 hours of stirring at 202C, the reaction mixture is evaporated at 502C and reduced pressure (2.7 kPa). The remainder is taken with 200 cm of ethyl acetate and 200 cm? water The aqueous phase is alkalized with 4 n. with an aqueous solution of sodium hydroxide and then extract 200 cm? ethyl acetate. This organic phase is dried over magnesium sulfate, filtered and evaporated to dryness at 5096 and reduced pressure (2.7 kPa). They receive 15.5 g

M-11-Bis(4-chlorophenyl)methyl|azetidin-3-yl]-M-(piperid-4-yl)umethylsulfonamide in the form of a foamy mass with a cream color.

M-11-Bis(4-chlorophenyl)methylIazetidin-3-ylI-N-(1-tert-butoxycarbonyl-piperid-4-yl)umethylsulfonamide can be obtained in the following way. To a solution of 14.7 g of 4-11-Ibis(4-chlorophenyl)methylIazetidin-3-ylamino)-(1-tert-butylcarbonyl)upiperidine in 250 cm3 of dichloromethane, 4.60 cm3 of methylsulfonyl chloride, then 4.0 cm3 of triethylamine and 100 mg of Zh 4- dimethylaminopyridine. After 20 hours of stirring at 20 C, 200 cm? of a saturated aqueous solution of sodium bicarbonate, after which the mixture is stirred for 30 minutes and separated into phases. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure M (2.7 kPa). 4.vOsm3 of methylsulfonyl chloride, then 4.v0sm3 of triethylamine and 100mg of 4-dimethylaminopyridine are again slowly added to the obtained foamy mass, taken with 250cm3 of dichloromethane. After 20 hours of stirring at 202, 200 cm? of a saturated aqueous solution of sodium bicarbonate, after which the mixture is stirred for 30 minutes and separated into phases. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on a column with silica gel (granulometry 0.063-0.200 mm, height 35 cm, diameter 5 cm), eluting under "0 PRESSURE 0.5 bar argon with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting fractions with a volume of 73 s 250 cm3. Fractions 4-18 are combined and evaporated to dryness under reduced pressure (2.7 kPa). They receive 19 g

M-11-Bis(4-chlorophenyl)methyl|azetidin-3-yl1-M-(1-tert-butylcarbonylpiperid-4-yl)umethylsulfonamide in the form of a foamy cream-colored mass, which will be used as such in the next stage . 4-1-Bis(4-chlorophenyl)methyl-azetidin-3-ylamino)-(1-tert-butoxycarbonyl)piperidine can be prepared as follows. To a solution of 9.22 g of 1-bis(4-chlorophenyl)methyl|azetidin-3-ylamine in 300 cm3 of dichloromethane, add -I 6.58 g. 1-tert-butoxycarbonylpiperidin-4-one. 9.54 g of sodium triacetoxyborohydride is added in two portions to the mixture cooled to 59 and then 1.72 cm? 10095 acetic acid. After 20 hours of stirring at 20 C, slowly add 500 cm? saturated aqueous solution of sodium bicarbonate, after which the mixture is well mixed and separated into phases. The organic phase is dried for 20 minutes over magnesium sulfate, filtered and evaporated to dryness at 5092C and reduced pressure (2.7 kPa). 15 g of 4-(1-bis(4-chlorophenyl)methyl-azetidin-3-ylamino)- are obtained. (1-tert-butoxycarbonyl)piperidine in the form of a foamed mass

T" is cream-colored, which will be used as such in the next stage.

Example 22

M-Benzyl-M-11-(Bis(4-chlorophenyl)methyl|azetidin-3-yl)amine: To a solution of Zbomg 29 1-(bis(4-chlorophenyl)methyl|azetidin-33-ylamine in 15 ml of dichloromethane is added at room temperature in

HF) in an argon atmosphere of 0.134 cm3 of benzaldehyde. The mixture is cooled to 02C, after which 382 mg is successively added

GI sodium triacetoxyborohydride and then 7bmm? acetic acid. After 16 hours of stirring at room temperature, the mixture is poured into 5b0cm? of a saturated aqueous solution of sodium bicarbonate, after which 25 cm? dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The resulting residue is purified by flash chromatography on a column with silica gel (eluent: dichloromethane/methanol (95/5 by volume). 0.29g are obtained

M-benzyl-M-(11-IBis(4-chlorophenyl)methylI|azetidin-3-ilyamine in the form of a colorless oil.

NMR spectrum "H" (300 MHz, SOSIa; 85 u mch): 2.71 (ton width, U-7Hz:2H); 3.42 (m:2H); 3.49 (m/n); 3, 70 65 (c2H); 4.25 (c:1H); 7.20-7.40 (m:13H)). 1-Bis(4-chlorophenyl)methyl|Iazetidin-3-ylamine can be obtained in the following way , Up to -27

1-(bis(4-chlorophenyl)methyl|azetidin-3-yl ester of methylsulfonic acid, placed in an autoclave pre-cooled to -602С, add 400 cm of a mixture of methanol and liquid ammonia (50/50 by volume).

The reaction medium is then stirred for 24 hours at 60 C, then left in the air to evaporate ammonia and, finally, evaporated to dryness under reduced pressure (2.7 kPa). The remainder is taken 500 cm from 0.37 n. of an aqueous solution of sodium hydroxide and extract four times 500 cm? diethyl ether. The combined organic phases are successively washed twice with 100 cm3 of water and 100 cm? saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The obtained residue is purified by flash chromatography on a column with silica gel (eluent: dichloromethane/methanol (95/5 by 70. volume)). 14.2 g of 1-|Ibis(4-chlorophenyl)methyl|azetidin-3-ylamine are obtained in the form of an oil that solidifies with the formation of a cream-colored solid.

Example 23

M-Benzyl-M-11-(Bis(4-chlorophenyl)methyl|azetidin-3-ylylmethylsulfonamide

To a solution of 120 mg of M-benzyl-M-/1-Ibis(4-chlorophenyl)methyl|azetidine-Z-illiamine in 5 cm? 104 mm3 of triethylamine is added to dichloromethane at room temperature in an argon atmosphere. The mixture is cooled to 09C and then 46.4 mm? of methylsulfonyl chloride and stirred for 16 hours at room temperature, after which it was diluted with 20 cm? of dichloromethane and washed twice with 15 cm? distilled water. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa) with the formation of varnish, which is crystallized by trituration in methanol.

42 mg of M-benzyl-M-11-Bis(4-chlorophenyl)methyl I|azetidin-3-yllium methylsulfonamide are obtained in the form of a cream-colored powder melting at 171960.

Example 24

M-01-(Bis(4-chlorophenyl)methyl)azetidin-3-yl)-M-(3,5-difluorobenzyl)amine can be obtained as in example 22, except using 188 mg of 3,5-difluorobenzaldehyde and Zb9 mg 1-Ibis(4-chlorophenyl)methyl|azetidin-3-ylamine and 382 mg of sodium triacetoxyborohydride without purification by flash chromatography. They receive O.48 g o

M-(1-Bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-(3,5-difluorobenzyl)amine as a colorless oil.

NMR spectrum of H (300 MHz, SOSI5, 5 ppm): 2.73 (m:2H); 3.40-3.55 (m:ZN); 3.70 (s-2H); 4 "

Example 25

M-11-Bis(4-chlorophenyl)methyl-azetidin-3-yl-M-(3,5-difluorobenzyl)methylsulfonamide

To a solution of 4ZZmg o //M-1-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-M-(3,5-difluorobenzyl)amine in 30 cm? dichloromethane is added at room temperature in an argon atmosphere of 347 mm? triethylamine. The mixture is cooled to 0°C and then a solution of 46.4 mm? of methylsulfonyl chloride in 5 cm of dichloromethane and stirred for 1 hour

Zo at room temperature, after which the reaction mixture is diluted with 20 ml of dichloromethane and washed twice with 15 ml of distilled water. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The residue is injected as an ethanolic solution into the Vopa Esh CX cartridge (10Gg), successively eluting with methanol and a 1M solution of ammonia in methanol. Ammonia fractions are combined and evaporated to dryness « 40. under reduced pressure (2.7 kPa), thus obtaining 0.44 g of

M-(1-Bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-(3,5-difluorobenzyl)methylsulfonamide in the form of a cream-colored foamy mass. 5 in mch): 2.81 (sIZN); 3.02 (t width, U-7.5Hz:2H); 3.38 (t width, 9-7.5Hz:2H); 4.23 ( c:1H); 4.40 (m:1H); 4.54 (c:2H); 6.75 (tt, U-9 and 2HzC:1H); 6.95 (m:2H); 7.25 (m:8H)).

Example 26 - I M-11-Bis(4-chlorophenyl)methylI|azetidin-3-yl)-M-(3,5-difluorobenzyl)acetamide Add to a solution 2 g of M-/1-Ibis(4-chlorophenyl)methylIazetidin- 3-yl)-M-(3,5-difluorobenzyl)amine in 75 cm? dichloromethane is added at room temperature in an argon atmosphere of 1.6 cm? triethylamine. The mixture is cooled to 09C and then a solution of 0.6 ppm of acetyl chloride is added dropwise and stirred for 16 hours at room temperature, 4! 20, after which the reaction mixture is diluted with 50 ml of dichloromethane and washed twice with 20 ml? distilled water.

Their organic phase is dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The resulting residue is purified by flash chromatography on a column with silica gel (eluent: dichloromethane/methanol (98/2 by volume). 1.2 g are obtained

M-(1-Bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-(3,5-difluorobenzyl)acetamide in the form of a colorless oil.

H NMR spectrum (300 MHz, SOCI5, 5 in m.h.), a mixture of rotamers is observed: 2.06 and 2.14 (2c:ZH in the sum);

HF) 2.97 (m:2Н); 3.43 (m2N); 420 and 4.25 (2s1H in total); 4.54 and 4.75-4.80 (m/n in total); 4.68 and 4.78 (2s

Ge width: 2H in total); 6.70 (m:ZN); 7.24 (with width: 8H)).

Example 27 in M-11-(Bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-(pyrid-4-ylmethyl)methylsulfonamide

To a solution of 398 mg of M-1-bis(4-chlorophenyl)methyl-azetidin-3-yl-M-(pyrid-4-ylmethyl)amine in ml? dichloromethane is added at room temperature in an argon atmosphere to 34 bmm3 of triethylamine. The reaction mixture is cooled to 02C, 155 mm? of methylsulfonyl chloride, stir for an hour at room temperature, dilute with ZBcm? of dichloromethane and washed twice with 20 cm? distilled water. The organic phase is dried over 65% magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The resulting residue is purified by flash chromatography on a silica gel column (eluent: dichloromethane/methanol (97/3 by volume)). They receive

288 mg of M-11-Bis(4-chlorophenyl)methylI|azetidin-3-yl)-M-(pyrid-4-ylmethyl)methylsulfonamide in the form of a cream-colored foamy mass.

H NMR spectrum (300 MHz, SOSIi, 5 u mch): 2.83 (cIZN); 3.02 (t width, U-7.5HzC2H); 3.40 (t width, 4ET,ZHTC2H); 423 (s1H); 4.43 (m:1H); 4.57 (s2H); 7.20-7.35 (m:8H); 7.32 (d width, 9U-5.5HzC:2H) ; 8.60 (width, height, height-5.5Hz: 2H)).

Example 28

M-11-IBis(4-chlorophenyl)methyl|azetidin-3-yl)-M-(pyrid-4-ylmethyl)amine can be obtained in the following way. To a solution of ZbOmg 1-Ibis(4-chlorophenyl)methyliazetidine-Z-ylamine in 15 cm? dichloromethane is added at room temperature of 70 in an argon atmosphere to 0.12 bcm3 of 4-pyridoxal. The reaction mixture is cooled to 09C and then 382 mg of sodium triacetoxyborohydride and then 70 mm? acetic acid. After 72 hours of stirring at room temperature, the mixture is poured into 100 ml of saturated aqueous solutions of sodium bicarbonate, after which it is extracted twice with 100 ml of dichloromethane. The combined organic phases are washed with 5 BOcm? of distilled water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The remainder is administered as a solution in 5cm? of methanol into the Vopa Esh CH cartridge (10g), sequentially eluting with 5Osm? methanol and bbsm? 1M solution of ammonia in methanol. Ammonia fractions are combined and evaporated to dryness under reduced pressure (2.7 kPa), thereby obtaining O.48 g

M-11-Bis(4-chlorophenyl)methyl|azetidin-3-ylI-M-(pyrid-4-ylmethyl)amine in the form of a colorless oil.

Example 29

M-11-(Bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-(pyrid-3-ylmethyl)methylsulfonamide

Repeating the sequence of operations of example 27, but leaving Kk! Zvomg

M-41-I(bis(4-chlorophenyl)methyl|azetidin-3-ylI-M-(pyrid-3-ylmethyl)amine, receive 319 mg

M-11-Ibis(4-chlorophenyl)methyl)azetidin-3-yl)-M-(pyrid-3-ylmethyl)methylsulfonamide In the form of a foamy mass of urine

Cream color. at

H NMR spectrum (300 MHz, SOSIZ, 85 ppm): 2.80 (cZN); 3.02 (t split, U-7 and 1.5 HC:2H); 3.38 (t split, 9-7 and 1.5Hz:2H); 4.22 (s:/1H); 4.35 (m:1H); 4.56 (s-2H); 7.23 (with width: 8H); 7.31 (dd, 9-8 and 5Hz:1H); 7.80 (d width, U-8Hz:1H); 8.57 (dd, 9-5 and 1.5Hz:1H); 8.63 (width, 9U-1.5Hz:1H)).

Example 30 "

M-11-(Bis(4-chlorophenyl)methyl-azetidin-3-yl-yl-M-(pyrid-3-ylmethyl)amine can be obtained as in example 28, but starting from 0.124 cm of Z-pyridoxal, 0.3 bg 1 -|bis(4-chlorophenyl)methylIazetidin-3-ylamine and 0.38 g of sodium triacetoxyborohydride. 044 g of

M-11-Bis(4-chlorophenyl)methylazetidin-3-ylyl-N-(pyrid-3-ylmethyl)amine in the form of a colorless oil. co

Example 31 3o M-21-(Bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-(1,1-dioxo-1H-1-5,6-benzo|4|isothiazol-3-yl) amen in

182 mg of 1,2-benzisothiazol-3-amine-1,1-dioxide and 32 mg of cesium carbonate are added to 300 mg of methylsulfonic acid 1-(bis(4-chlorophenyl)methyl Iiazetidin-3-yl ester in 1Osm of dimethylformamide. After that, the reaction medium is stirred 9 hours at 10092 and evaporated to dryness under reduced pressure (2.7 kPa). " 20 The residue is washed four times with 5 cm? of boiling distilled water, broken up by stirring in bcm 3 of distilled water at room temperature, then filtered and purified by flash chromatography on a c column with silica gel (eluent: dichloromethane/methanol (98/2 by volume) 5 mg; t M-71-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-(1,1-dioxo- 1H-1-5,6-benzo|d|isothiazol-3-yl)amine in the form of a pasty product.

H NMR spectrum (300 MHz, SOSI5, 5 in mch): 3.17 (m:2H); 3.61 (t width, 9U-7.5Hz:2H); 4.37 (syn); 4, 75 -I (m:1H); 6.30-6.40 (m:1H); 7.20-7.35 (m:8H); 7.62 (d width, 9U-7.5HzC:1H ); 7.69 (t width, 9U-7.5HzC:1H); 7.76 (t width, U-7.5Hz:1H); 7.93 (d width, U-7.5Hz: 1H)). o 1,2-benzisothiazol-3-amine-1,1-dioxide can be obtained by the method described by Ziovz5z R. with co-authors, with Spec. Veg. (1975), 108 (12), 3855 - 63.

Example 32 and M-11-Bis(4-chlorophenyl)methylIazetidin-3-ylI-M-(3,5-difluorophenyl)-M'-tert-butyloxycarbonylsulfamide can be obtained in the following way. To a solution of 0.095 cm3 of tert-butyl alcohol in 2 cm? of anhydrous dichloromethane, add 0.048 cm3 of chlorosulfonyl isocyanate, stir for 2 minutes and successively add 0.21 g

M-(1-Bis(4-chlorophenyl)methylIazetidin-3-yl)-M-(3,5-difluorophenyl)amine in 1.25 cm? of anhydrous dichloromethane and 25 then 0.084 cm? triethylamine. After stirring for 1 hour at a temperature close to 202C, add (F) with rapid stirring 2cm? saturated sodium bicarbonate solution. The reaction mixture is divided into phases,

He is dried over magnesium sulfate, filtered and evaporated to dryness at 509 and reduced pressure (2.7 kPa).

The resulting residue is chromatographed in a Magiap cartridge (bsm) containing Zg thin silica gel 6o (0.040-0.063 mm), introducing and eluting with a mixture of petroleum ether/ethyl acetate using an Oshgatai pump and collecting fractions with a volume of 2 cm?. Fractions 6-17 are combined and evaporated to dryness under reduced pressure (2.7kPa) and 402C for 2 hours. Bimg is obtained in this way

M-(1-Bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-(3,5-difluorophenyl)-M'-tert-butyloxycarbonylsulfamide In the form of a white foamy mass. 65 NMR spectrum "H (400 MHz, SOSIi, 5 in mch): 1.47 (s9H); 2.77 (t width, 9U-8HzC:2H); 3.52 (m:2H); 4.19 (s/1H); 5.06 (m:1H); 6.75 - 6.90 (m:ZN); 7.15 - 7.35 (m:8H)).

Example 33 (k5)-M-71-(4-chlorophenyl)pyridin-3-ylmethyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide can be obtained in the following way. To a mixture of 0.2 g of 3-Ibromo-(4-chlorophenyl)methyl|Ipyridine and 0.22 g of hydrochloride

M-azetidin-Z-yl-M-(3,5-difluorophenyl)methylsulfonamide in 10cm3 of acetonitrile add 0.2g of potassium carbonate and 2Zmg of potassium iodide, after which the mixture is boiled for 3 hours. After adding 0.2 g of potassium carbonate, the mixture is boiled for another 15 hours. After cooling to 2123, insoluble material is removed by filtration and the filtrate is evaporated to dryness at 409C and a pressure of 2.7 kPa. 17Omg of a colorless varnish is obtained, which is purified by chromatography in a silica gel cartridge (51/-020-005, RiazpRask, dopez SpPgothaiodgarpu Iitieda, Mem Koad, 70. Nepdoed, Mid Siatogdap, CE82 WASH, Great Britain), eluting with a mixture of cyclohexane/ethyl acetate 1/1 (bsm 3/min, fractions of 5 cm"). Fractions from B/-5/57 (cyclohexane/ethyl acetate, plate with silica gel, Megsk 1.05719, Megtsk

Koda, 64271 Juagptwiadi, Germany) are combined and evaporated to dryness at a pressure of 2.7 kPa and 402C, which gives 100 mg of (k5)-M-11-(4-chlorophenyl)pyridin-3-ylmethyl|azetidin-3-yl)-M -(3,5-difluorophenyl)methylsulfonamide melting at 11026 ); 3.38 (m:2H); 4.50 (syn); 4.70 (min); 7.11 (m:2H); 7.20-7.40 (m:2H); 7.34 (d, 9U-8HzC:2H); 7.41 (d, U-8Hz:2H); 7.72 (d width, U-8HzC:1H); 8.40 (dd, 9-5 and 1, 5Hz:1H); 8.58(d, 9U-1.5Hz:1H).

Both isomers of (k5)-M-71-(4-chlorophenyl)pyridin-3-ylmethylIazetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide can be separated on a stationary chiral phase SNIKASEIGI 00.

The first isomer:

H NMR spectrum (300 MHz, SOSIi, 5 in mch): 2.82 (cZN); 2.87 (m:2H); 3.53 (m:2H); 4.29 (syn); 447 (m :i1H); 6.80 (m:3H); 7.19 (dd, 9U-8 and 5HtsCi2H); 7.20-7.35 (m:4H); 7.62 (d lat., 9U-8HtsC :1H); 8.45 (d width, with chkOGc1H); 8.59 (with width.1H)). o

The second isomer:

H NMR spectrum (300 MHz, SOSIi, 5 u mch): 2.82 (cIZN); 2.87 (m:2H); 3.54 (m:2H); 4.29 (sn); 4.48 (min); 6.80 (m:ZN); 7.19 (dd, 9-8 and B5HC1H); 7.25-7.35 (m:4H); 7.62 (dt, 9-8 and 2Hz :1H); 8.46 (dd, 9-5 and 2Hz1H); 8.59 (d width, U-2Hz:1H)). "I

M-azetidin-3-yl-M-(3,5-difluorophenyl)methylsulfonamide hydrochloride can be obtained in the following way. A solution of 1 g is hydrogenated for 4 hours in a 5Obsm C hydrogenator

M-(1-benzhydrylazetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide in a mixture of 2.5 cm? of hydrochloric acid and 0.41 cm3 of acetic acid in the presence of 0.161 g of palladium hydroxide under a pressure of 30 bar of hydrogen. The catalyst is removed by filtration through a layer of celite, after which the filtrate is evaporated to dryness at 40 2С and a pressure of 2.7 kPa, obtaining bZOmg of M-azetidin-3-yl-M-(3,5-difluorophenyl)methylsulfonamide, melting at 21626. -

M-(1-benzhydrylazetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide can be obtained by repeating the sequence of operations described in example 13 (method 2) in the following way. To a solution of 2 g of 1-benzhydrylazetidin-3-ol in 100 cm3 of tetrahydrofuran, 0.86 mg of 20 M-(3,5-difluorophenyl)methylsulfonamide, 3.28 g of triphenylphosphine, and then 2 ml of diethyl azodicarboxylate are successively added, and the temperature rises from 22 to 292 C in s. as well as the formation of a precipitate after the addition is complete. diethylazodicarboxylate. The mixture is left for 20 hours at 222C, the precipitate is removed by filtration and the filtrate is evaporated to dryness at 402C and a pressure of 2.7 kPa. The remaining 20 minutes are rubbed with 5 cm? of methanol at 212C, obtaining 1.07 g. M-(1-benzhydryl-azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide as a white amorphous solid. -| 1-benzhydrylazetidin-3-ol can be obtained according to the sequence of operations described by KATKITKU syu A.K. with collaboration, -). Ne(egosusi. Spet., 271 (1994). 3-I(Bromo-(4-chlorophenyl)methyl|pyridine is obtained in the following way. To 1.5 g of (4-chlorophenyl)pyrid-3-ylmethanol, add 3.5 cm of a 48965% solution of hydrobromic acid in acetic acid and 1 cm of acetyl bromide. The amber-colored mixture obtained in this way in step 20 is boiled for 4 hours, then cooled to 20 C and evaporated to dryness at 402 C at a pressure of 2.7 kPa, obtaining 1.53 g of 3-Ibromo-(4-chlorophenyl)methyl|pyridine (K-75/90, 254 nm,

T» plates with silica gel, type 1.05719, Megsk Kda, 64271 Juagtviadi, Germany). (4-Chlorophenyl)pyrid-3-ylmethanol is obtained in the following way. Add 20 cm? 1M solution of 4-chlorophenylmagnesium bromide in diethyl ether. After cooling to 202С 25, the reaction is continued for 15 hours with stirring. After that, add 20 cm of saturated solution

F) ammonium chloride and then 20 cm? ethyl acetate. The mixture is separated into phases and the organic phases are extracted with additional 20 cm3 of ethyl acetate. The organic extracts are combined and dried over magnesium sulfate, after which they are evaporated to dryness at 402C and a pressure of 2.7 kPa. The obtained residue is chromatographed on silica gel (Artichoke, 20-45 um, 60 50 g of silica gel, a column with a diameter of bcm), eluting with a mixture from 80/20 to 50/50 under an argon pressure of 0.4 bar.

Fractions containing the compound from KT-13/53 (plates with silica gel, MegsK 1.05719, Megsk Kda, 64271 Yuagtviavdiyi,

Germany) combine (Ryu and evaporate to dryness at 409Сb pressure 2.7 kPa, obtaining 2.53 gH of (4-chlorophenyl)pyrid-3-ylmethanol.

Example 34 bB M-11-Bis(4-fluorophenyl)methyl-azetidin-3-yl-M-(3,5-difluorophenyl)methylsulfonamide was obtained in the following manner. To a mixture of 0.2 g of 4,4-difluorobenzhydryl chloride and 0.26 g of hydrochloride

0.36g of potassium carbonate and 27mg of potassium iodide are added to M-azetidin-3-yl-M-(3,5-difluorophenyl)methylsulfonamide in 1O0cmU of acetonitrile, after which the mixture is boiled for 3 hours. After cooling to 21 C, insoluble material is removed by filtration and the mixture is evaporated to dryness at 402 C and a pressure of 2.7 kPa. The residue is triturated with 300 cm3 of ethyl acetate and the solid material is removed by filtration. The filtrate is evaporated to dryness at 402C and a pressure of 2.7kPa, obtaining 9Omg of a pale yellow solid substance, which is purified by chromatography in a Vopajevici ZSH cartridge containing 2g of grafted silicon oxides (1225-6019, Magiap Azzosia(ev, Ips, 24201 Rgatriop Amepiye, Nagrog Sue,

CA9ZO710, OA), eluting with 2M methanolic ammonia solution. Fractions from CT 16/82 (cyclohexane/(ethyl acetate 7/3, silica gel plate, type 1.05719, Megsk Koda, 64271 RBagtviadi, Germany) were combined and evaporated at 2.77 kPa and 409 to give 243 mg

M-411-Ibis(4-fluorophenyl)methyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide, melting at 9820.

H NMR spectrum (300 MHz, (c03)2uO av, 5 in mch): 2.74 (t width, U-7HzC:2H); 3.00 (c:ZN); 3.37 (t width. ,

U-7HzC:2H); 4.43 (c:/1H); 4.69 (m:1H); 7.05-7.20 (m:bH); 7.28 (tt, 9-9 and 2.5Hz:2H); 7.40 (m:4H)).

Example 35 (K5)-M-11-IBis(4-chlorophenyl)pyrid-4-ylmethyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide can be obtained in the following way. To the mixture, approximately 10 mg of (4-pyridyl)-(4-chlorophenyl)chloromethane, 14 mg

M-azetidin-3-yl-M-(3,5-difluorophent)methylsulfonamide, 17 mg of potassium iodide and 200 mg of potassium carbonate in 5 cm? of acetonitrile is stirred for about 18 hours at a temperature close to 2020. After that, the reaction mixture is boiled for 3 hours, 17 mg of potassium iodide is added and boiling is continued for another 2 hours. After cooling to a temperature close to 202, the reaction mixture is filtered on porous glass. The solid material is rinsed with acetonitrile and then 2 times with Zcm? ethyl acetate. The combined filtrate is evaporated to dryness under reduced pressure.

23mg of a pale yellow paste is obtained, which is purified by means of preparative chromatography in a thin layer of silica gel (4 preparative plates Mgesk Kieseide! 60254; 20x20cm, thickness 00.5mm)|, eluting with a mixture of "su methanol/dichloromethane (5/95 by volume ).After elution of the zone corresponding to the target product, filtration on porous glass and evaporation of the solvents under reduced pressure and a temperature close to 409, 12 mg of o(k5)-M-11-Ibis(4-chlorophenyl)pyrid-4-ylmethyl-azetidin-3 are obtained -ylI-M-(3,5-difluorophenyl)methylsulfonamide.

NMR spectrum of H (300 MHz, SOSI5, 5 in m.h.): 2.82 (cIZN); 2.96 (m:2H); 3.50-3.80 (m:2H); 4.33 (min); 4.54 (m:1H); 6.82 (m:ZH); 7.20-7.45 (m:bn); 8.53 (d width, U-5.5Hz:2H )). "

Both isomers of (k5)-M-11-(bis(4-chlorophenyl)pyrid-4-ylmethylylazetidin-3-ylI-M-(3,5-difluorophenyl)methylsulfonamide can be separated into immobile chiral phases SNIKASEI 00. IF)

The first isomer: p

NMR spectrum "H (300 MHz, SOSIZ, 5 in m.h.): 2.83 (cIZN); 2.87 (t width, 9-7.5 Hz: 2H); 3.51 (m:1H) ; 3.60 (m:/1H); 4.24 (s:1H); 4.50 (m:1H); 6.82 (m:ZH); 7.20-7.35 (m:bn) 8.50 (d width, U-5.5Hz:2H)).

The second isomer:

NMR spectrum of "H (300 MHz, SOSIi, 5 in mch): 2.83 (cIZ3H); 2.88 (t, 9-7.5 Hz: 2H); 3.51 (m:1H); 3.61 ( m/n); 4.25 (c11N); 4.51 (m:/1N); 6.81 (m:ZN); 7.20-7.35 (m:bn); 8.50 (d width ., 9U-5.5Hz:2H))|. "du(4-pyridyl)-(4-chlorophenyl)uchloromethane can be obtained in the following way. 100mg of (4-pyridyl)-4-chlorophenyl)umethanol is added to the suspension 0.0598 cm3 of thionyl chloride is added to 2 cm3 of toluene cooled to a temperature close to 02 C. The reaction medium is left for 2 hours at a temperature close to 02 C and then for 1 hour at a temperature close to 202 C and evaporated under reduced pressure. Approximately 10mg of (4-pyridyl)-(4-chlorophenyl)chloromethane is obtained as a white solid. (4-Pyridyl)-4-chlorophenyl)umethanol can be obtained in the following way. To a solution of /-2g - 4-(4-chlorobenzoyl)pyridine in 1b60cm? of ethanol is added at a temperature close to 202 348 mg of sodium tetrahydroboride. After 2 hours of stirring at a temperature close to 202, add 39Omg of sodium tetrahydroboride. sl After 1.5 hours (at the same temperature), the reaction medium is diluted with 200 ml of dichloromethane and 200 ml of water. The pH of the aqueous phase is brought to 5 by adding approximately 133 cm C 1 n. hydrochloric acid. After 1 20 phase separation, the aqueous phase is extracted with 100 cm? dichloromethane. The organic phases are combined, dried over

They" with magnesium sulfate, filtered and evaporated under reduced pressure. 2 g of (4-pyridyl)-4-chlorophenyl)methanol is obtained in the form of a white powder.

Example 36

24.4 mg of a 7595% dispersion of hydride (F, sodium in mineral oil) is added to a solution of 300 mg of M-11-bis(4-chlorophenyl)methyl-azetidin-3-yl-3,5-difluorobenzyl)amine in 25 cm3 of tetrahydrofuran at room temperature in an argon atmosphere. The mixture is stirred for 1 hour at room temperature and 5 ohm?

GI of methyl chloroformate and continue stirring for 18 hours under the same conditions. 0.3 cm3 of distilled water is added to the reaction mixture and tetrahydrofuran is distilled off on a rotary evaporator. The resulting residue is extracted with dichloromethane, the organic phase is dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The resulting residue is purified by flash chromatography on a silica gel column

(eluent: dichloromethane/methanol (97.5/2.5 by volume). 328 mg of 11-bis(4-chlorophenyl)methyl-yl-azetidin-3-yl)-(3,5-difluorobenzyl)carbamic acid methyl ester are obtained in types of colorless oil.

NMR spectrum of H (300 MHz, SOSIi, 5 u mch): 2.97 (m:2H); 3.39 (m:2H); 3.71 (cIZN); 4.24 (with lat.H); 65 4.45 (m:1H); 4.57 (c:2H); 6.65-6.80 (m:ZH); 7.15-7.30 (m:8H)).

Example 37

(k5)-M-11-(4-chlorophenyl)pyrimidin-5-ylmethyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide can be obtained by repeating the sequence of operations described in example 33, starting from 0.16 (K5)-5-I(bromo-(4-chlorophenyl)methyl|pyrimidine, 0.131 g of hydrochloride

M-azetidin-Z-yl-M-(3,5-difluorophenyl)methylsulfonamide in Bcm3 of acetonitrile, ZOZmg of potassium carbonate and 95mg of potassium iodide. 26 mg of (k5)-M-11-(4-chlorophenyl)pyrimid-5-ylmethyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide are obtained in the form of a yellow foamy mass.

H NMR spectrum (400 MHz, SOSIi, 5 u mch): 2.83 (cIZN); 2.91 (m:2H); 3.57 (m:2H); 4.31 (sn); 4.50 70. (m:1Hn); 6.75-6.90 (m:ZH); 7.29 (s:4H); 8.71 (s:2H); 9.08 (s:1H)|.

Medicinal products according to the invention consist of a compound of formula I or an isomer or a salt of this compound in its pure state or in the form of a composition in which this compound is associated with any other pharmaceutical compatible product that may be inert or physiologically active. Medicinal products according to the invention can be used orally, parenterally, rectally or topically.

Tablets, pills, powders (gelatin capsules, starch wafers) or granules can be used as solid compositions for oral administration. The active starter according to the invention is mixed in these compositions in a stream of argon with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica. These compositions, in addition to diluents, may also contain other substances, for example, one or more lubricating agents, such as magnesium stearate or talc, a dye, a shell (dragé) or a varnish.

Pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerin, vegetable oils or paraffin oil can be used as liquid compositions for oral administration. These compositions may also contain substances other than diluents, such as wetting, sweetening, thickening, flavoring or stabilizing products. Ge

Sterile compositions for parenteral use can be mainly aqueous or non-aqueous solutions, suspensions or emulsions. The solvent or carrier may be water, propylene glycol, polyethylene glycol, vegetable oils, particularly olive oil, injectable organic esters such as ethyl oleate, or other suitable organic solvents. These compositions may also contain auxiliary means, in particular, wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization "I can be carried out in many ways, for example, by aseptic filtration, introduction of sterilizing agents into the composition, irradiation or heating. They can also be obtained in the form of solid sterile compositions that can be dissolved immediately before use in sterile water or any other sterile environment suitable for injections. with

Compositions for rectal use are suppositories or rectal capsules that, in addition to the active product, contain fillers such as cocoa butter, semi-synthetic glycerides or polyethylene glycols. -

Compositions for local use can, for example, be creams, lotions, eye lotions, mouthwashes, nose drops or aerosols.

In the field of human therapy, compounds according to the invention can be, in particular, used for the treatment and "prevention of psychoses, including schizophrenia, anxiety states, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, impaired cognitive functions, traumatic brain injury, panic attacks, peripheral neuropathy, glaucoma, migraine, Parkinson's disease, Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremors, obsessive-compulsive syndrome, senile dementia, disorders of the thymus, Tourette's syndrome, tardive dyskinesia, bipolar disorders, cancer, disorders of the motor apparatus under the influence medicine, dystonia, endotoxemic shocks, hemorrhagic shocks, hypotension, insomnia, immunological diseases, multiple sclerosis, vomiting, asthma, appetite disorders (bulimia, anorexia), obesity, memory disorders, intestinal transit disorders, when chronic treatment is canceled , in the treatment of this syndrome, the withdrawal of alcohol or drugs (for example, opioids, barbiturates rations, cannabis, cocaine, amphetamines, phencyclide, hallucinogens, benzodiazepines), such as analgesics or enhancers of the analgesic activity of narcotic and 1 non-narcotic drugs. сл 50 Doses depend on the desired effect, on the duration of treatment and on the method of administration used.

Usually they range from 5 to 1000 mg per day when administered orally to an adult, while single doses vary from 1 to 2500 mg of the active substance.

In general, the doctor should determine the appropriate dosage depending on the age, weight and other factors related to the treatment of the treated individual.

Compositions according to the invention are illustrated by the following examples: o Example A

Using conventional methods, prepare gelatin capsules with a dose of 50 mg of the active product, having the following composition: v Compound of formula I Bomg

Cellulose 18 mg

Lactose BBmg

Colloidal silica 1 mg

Sodium carboxymethyl starch 100mg 65 Talc 1mg

Magnesium stearate 1 mg

Example B

Using conventional methods, tablets with a dose of 50 mg of the active product are prepared, having the following composition:

The compound of formula I Bomg

Lactose 104 mg

Cellulose dOmMg

Polyvidone 1Omg

Sodium carboxymethyl starch 22 mg

Talc 1Omg

Magnesium stearate 2 mg

Colloidal silica 2mMg 19 Mixture of hydroxymethylcellulose, glycerin and titanium oxide (72/3.5/24.5) in a sufficient amount to 245mg in the final tablet with a shell.

Example C

Prepare a solution for injections containing 1 mg of the active product, which has the following composition:

Compound of formula I 1Omg

Benzoic acid 8Omg

Benzyl alcohol O, Obml

Sodium benzoate 8Omg 9595th ethanol O4ml p

Sodium hydroxide 24mg He)

Propylene glycol 1, bml

Water in sufficient quantity up to A4ml "I

Claims (1)

The formula of the invention is about yuyu 1. Pharmaceutical composition containing as an active ingredient at least one compound of the formula: со Е ХК - VE. tsu with F " VE - s in which :z" Ku. means the radical -М(К.)Кв, -М(К4)-СО-К», -МЩ(Ка)-5О2 in, E» and Kz, the same or different, mean either an aromatic radical selected from phenyl, naphthyl and indenyl, Which can be unsubstituted or substituted by one or more of the following substituents: halogen, alkyl, - alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO-аЙК, cyano, -СООН, -СОбайКК, -СОМК, Пв, -СО -МН-МКоКио, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfinylalkyl, o alkylsulfonylalkyl, hydroxyalkyl or -aik-MK;Ka; or a heteroaromatic radical selected from the following c rings: benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidyl, quinolyl, 1 1 . , -alkyl-MCoKio, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl; KE. means the radical -С(К44)(К42)-Ней, Ней, -С(К44Х(К42)-Аг, Аг, cycloalkyl or norbornyl; K5 means a hydrogen atom or a hydroxyalkyl radical, -айк-СОсайк, -адик-СОМКВа, - ayik-MK,Ka, alkoxy, Ag, Nei, (F; -CHnoAg, -CHnoNei or alkyl, possibly substituted by one or more halogens; GI Kv means a hydroxyalkyl radical, -aik-SOdaik, -adik-SOMK.Ka, -aiik -MKKa, alkoxy, Ag, Nei, -CHNoAg, -CHNoNei or alkyl, possibly substituted by one or more halogens; in KE; and Kv, the same or different, mean a hydrogen atom or an alkyl, or K, and Ka, together with an atom of the nitrogen to which they are attached form a saturated mono- or bicyclic heterocycle having from 3 to 10 members and may contain a second heteroatom selected from oxygen, sulfur and nitrogen and be substituted by one or more alkyls; Co and Co, the same or different means a hydrogen atom or an alkyl radical, -COoAlK, cycloalkyl, alkylcycloalkyl, -Aik-O-AlKK or hydroxyalkyl, or Co and Kio, together with the nitrogen atom to which they are connected, where they form a saturated or not a saturated mono- or bicyclic heterocycle having from 3 to 10 members and may contain a second heteroatom selected from oxygen, sulfur and nitrogen, and be substituted by one or more of the following radicals: alkyl, -COaic, -"SOSaic, -"CO -MmnNaic, -C5-MNaic, oxo, hydroxyalkyl, -aic-O-aicK or -CO-MH»; Ki1 means a hydrogen atom or a hydroxyalkyl radical, -aik-SOOaik, -aik-SOMK.Ra, -aik-MK.,Ra, alkoxyalkyl, Ag, Nei, -SNoAg, -SNoNei or alkyl, possibly substituted by one or more halogens; Ki" means a hydrogen atom or a radical of hydroxyalkyl, alkyl-SOcaic, alkyl-SOMAK.Ka, -akik-MK.Ra, alkoxyalkyl or alkyl, possibly substituted by one or more halogens; or K.4 and Ku", together with the carbon atom to which they are connected, form a saturated mono- or bicyclic ring having from C to 10 members and may contain a second heteroatom selected from oxygen, sulfur and nitrogen, and be substituted by one or more alkyls; 70 Ah means phenyl, naphthyl or indenyl, which can be replaced by one or more of the following substituents: halogen, alkyl, alkoxy, -СбО-аиК, cyano, -СООН, -СОбаикК, -СОМКзК.а4, -СО-МН-МК .5Kchv, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aik-MKu5K.v, -MKu5Kchv, alkylthioalkyl, formyl, CEz, OSE»z, Nei, -O-alkyl-MH-cycloalkyl, -502MH», hydroxy, hydroxyalkyl, -MH- СО-айКк, -МН-СООайЙкК or, on two adjacent carbon atoms, dioxymethylene; It means an unsaturated or saturated mono- or bicyclic heterocycle having from 3 to 10 members and containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, and which may be substituted by one or more of the following radicals: alkyl, alkoxy, halogen . , form a saturated mono- or bicyclic heterocycle having from 3 to 10 members and may contain a second heteroatom selected from oxygen, sulfur and nitrogen, and be substituted by one or more alkyls; Kv and Kv, the same or different, mean a hydrogen or alkyl atom, or K.5 and Kv, together with the nitrogen atom to which they are connected, form a saturated mono- or bicyclic heterocycle having from 3 to 10 members and may contain a second heteroatom selected from oxygen, sulfur, and nitrogen, and be substituted by one or more alkyl radicals; aiK means alkyl or alkylene, (8) and alkyl or alkylene radicals and parts of molecules or alkyl radicals and parts of molecules have a straight or branched chain and contain from 1 to 6 carbon atoms, and cycloalkyl radicals contain from 3 to 10 carbon atoms; optical isomers of this compound and its pharmaceutically acceptable salts with mineral or organic acids. 2. Pharmaceutical composition according to claim 1, for which in formula I it is selected from benzimidazole, benzoxazole, o benzothiazole, benzothiophene, cinnoline, thiophene, quinazoline, quinoxaline, quinoline, pyrazole, pyrrole, pyridine, u imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, piperidine, piperazine, triazole, furan, tetrahydroisoquinoline, and tetrahydroquinoline, which may be substituted with one or more of the following me) substituents: alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OSE, or CE. uh- Z. The pharmaceutical composition according to claim 1, for which the formula is combined Ku. means the radical -M(K.)Kv, -M(K4)-5O2Kv, Ko means either phenyl, unsubstituted or substituted by one or more of the following substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-aiK, cyano , -"SOMK.Ka, hydroxyalkyl or -aik-MK,Ka, or "heteroaromatic radical selected from pyridyl, pyrimidyl, thiazolyl and thienyl which may not be substituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, . -SOMA Kv, -aik-MKoK.o, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl; and? Kz means either phenyl, unsubstituted or substituted by one or more of the following substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-aikK, cyano, -SOMK.Ka, hydroxyalkyl or -aik-MAK,Ka, or a heteroaromatic radical , selected from pyridyl, pyrimidyl, thiazolyl and thienyl, which may be non-I substituted or substituted with halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -SOMA Kv, -aik-MCoK.o, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl ; about KE. means the radical -С(К44)(К42)-Ней, Ней, -С(44Х(К42)-Аг, Аг or norbornyl; с К5 means a hydrogen atom or a hydroxyalkyl radical, -айк-СОсайк, -адик-СОМК,Ка, -alkyl-MK.Ka, alkoxy, -CNeoAg, -SnNei! or alkyl; 1Ke means a hydroxyalkyl radical, -aik-COsaik, -aik-SOMK.Ka, -aiik-MK.Ra, alkoxy, -CHnoAg, -SNoNei or alkyl; и» KE; and Kv, the same or different, mean a hydrogen atom or an alkyl, or K, and Ka, together with the nitrogen atom with which they are connected, form a saturated mono- or bicyclic heterocycle having from With up to 10 members and may contain a second heteroatom selected from oxygen, sulfur and nitrogen and be substituted by one or more alkyls; Co and Co, the same or different, denote a hydrogen atom or an alkyl radical, -COaiK, cycloalkyl, alkylcycloalkyl, -aik- O-alkyl or hydroxyalkyl, or Co and Kio, together with the nitrogen atom to which they are connected, Ф) form a saturated or unsaturated mono- or bicyclic heterocycle having from 3 to 10 members and may contain a second heteroatom, selected from oxygen, sulfur and az that is, and be substituted by one or more of the following radicals: alkyl, -COaic, -SOaic, -"CO-Mnaic, oxo, hydroxyalkyl or -CO-MH"; in Ki1 means a hydrogen atom or a hydroxyalkyl radical, aik-SOdOaik, ayik-SOMK,Ra, -aik-MK.Ra, alkoxyalkyl, Ag, Nei, -SNoAg, -SNoNei or alkyl, possibly substituted by one or several halogens; Ki" means a hydrogen atom or a radical of hydroxyalkyl, alkyl-SOcaic, alkyl-SOMAK.Ka, -akik-MK.Ra, alkoxyalkyl or alkyl, possibly substituted by one or more halogens; or K.4 and Ku", together with the carbon atom to which they are connected, form a saturated mono- or bicyclic b5 ring having from 3 to 10 members, which may contain a second heteroatom selected from oxygen, sulfur and nitrogen, and be substituted by one or more alkyls; Ag means phenyl or naphthyl, which can be replaced by one or more of the following substituents: halogen, alkyl, alkoxy, -CO-аЙК, cyano, -СОМК.зКиа4, alkylsulfonyl, -айк-МКи5Кив, -МКи5Кив, СЕз, ОСЕ». 5О»МН», hydroxy, hydroxyalkyl or, for two adjacent carbon atoms, dioxymethylene; It means a heterocycle selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, which may be substituted by one or by several of the following substituents: alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OSE"z or CE". Keys and K.4, the same or different, represent a hydrogen or alkyl atom, or Keys and K.i4, together with the nitrogen atom to which they are connected, form a saturated mono- or bicyclic heterocycle having from C to 10 members and may contain a second heteroatom selected from oxygen, sulfur, and nitrogen, and be substituted by one or more alkyls; Kv and Kv, the same or different, mean a hydrogen or alkyl atom, or K.5 and Kv, together with the nitrogen atom to which they are connected, form a saturated mono- or bicyclic heterocycle having from 3 to 10 members and which may contain a second heteroatom selected from oxygen, sulfur and nitrogen and be substituted by one or more alkyls; optical isomers of this compound and its pharmaceutically acceptable salts with mineral or organic acids. 4. Pharmaceutical composition according to claim 1, for which the formula is combined Ku. means the radical -M(K./)-502Kv, Ko means either phenyl, unsubstituted or substituted by one or more of the following substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -SOMK,Ka, hydroxyalkyl or -aik- MK,Ka, or a heteroaromatic radical selected from pyridyl, pyrimidyl, thiazolyl, and thienyl, which may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -SOMEK Ka, or hydroxyalkyl; Kz is either phenyl, unsubstituted or substituted by one or more of the following substituents: halogen, C 1 -alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -SOMK,Ka, hydroxyalkyl or -alkyl-MK,Ka, or a heteroaromatic radical selected from pyridyl . KE. means the radical -Nei or Ag; "g" means "hydroxyalkyl" or "alkyl"; KE; and Ka, the same or different, mean a hydrogen or alkyl atom, or K; and Kv, together with the nitrogen atom to which they are connected, form a saturated mono- or bicyclic heterocycle having from 3 to 10 members, which may contain a second heteroatom selected from oxygen, sulfur, and nitrogen, and be substituted by one or more alkyls; Ag means phenyl or naphthyl, which can be replaced by one or more of the following substituents: me) Zv Halogen, alkyl, alkoxy, -CO-аіК, cyano, -"СОМЕК за, "акме в, "МАх5Кв, СЕз, ОСЕ", -5О02МН», hydroxy or n-hydroxyalkyl; It means a heterocycle selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, thiazole, thiadiazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, which may be substituted with one or more of the following "substituents: alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, ОСЕ" with or ШЕ"; with c Keys and K.4, the same or different, mean a hydrogen or alkyl atom, or Keys and K.i4, together with the nitrogen atom to which they are connected, form a saturated mono- or bicyclic heterocycle having from C up to 10 links, which can;" contain a second heteroatom selected from oxygen, sulfur, and nitrogen, and be substituted by one or more alkyls; K5 and Kv are the same or different, mean a hydrogen or alkyl atom, or K.5 and Kv, together with the nitrogen atom to which they are connected, form a saturated mono- or bicyclic heterocycle having from 3 to 10 members, which -I may contain a second heteroatom selected from oxygen, sulfur, and nitrogen, and be substituted by one or more alkyls; optical isomers of this compound and its pharmaceutically acceptable salts with mineral or organic acids. o 5. The composition according to claim 1, for which the compound of formula I is selected from the following compounds: c M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylI-M-(b-chloropyrid-2-yl)umethylsulfonamide, M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylI-M-(b-ethylpyrid-2-yl)umethylsulfonamide, o M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylI- M-quinol-b6-ylmethanesulfonamide, M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-M-quinol-5-ylmethylsulfonamide, M-11-Ibis(4-chlorophenyl)methyl|azetidine -3-ylI-M-isoquinol-5-ylmethylsulfonamide, M-11-I(bis(4-chlorophenyl)methylIazetidin-3-ylIi-M-pyrid-3-yl-methylsulfonamide, M-11-Ibis(4-chlorophenyl )methyl|azetidin-3-ylI-M-(1-oxypyrid-3-yl)methylsulfonamide, M-(1kK,25,45)-bicyclo|2.2.1|hept-2-yl-M-(1-Ibis (4-chlorophenyl)methylI|azetidin-3-ylmethylsulfonamide, F) M-(1kK,2kK,45)-bicyclo(|2.2.1|hept-2-yl-M-1-(bis(4-chlorophenyl)methylIazetidine -3-iliumethylsulfonamide, ka M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylIi-M-(3,5-difluorophenyl)methylsulfonamide, M-11-Ibis(4-chlorophenyl)methyl|azetidine-3 -ylI-M-(thiazol-2-yl)umethylsul fonamide, in M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylII-M-(3-methoxyphenyl)methylsulfonamide, M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylII-M- (3-hydroxyphenyl)methylsulfonamide, M-11-Bis(4-chlorophenyl)methyl|azetidin-3-ylI-M-(3-hydroxymethylphenyl)methylsulfonamide, ethyl ether M-71-(bis(4-chlorophenyl)methyl-azetidin-3 -ylI)-M-(methylsulfonyl)-3-aminobenzoic acid, M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylI-M-(1-isobutylpiperid-4-yl)methylsulfonamide, 65 M-benzyl -M-(1-Ibis(4-chlorophenyl)methyl|azetidine-3-ylamine, M-(1-Ibis(4-chlorophenyl)methylylazetidin-3-yl)-M-(3,5-difluorobenzyl)amine, M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylII-M-(3,5-difluorobenzyl)methylsulfonamide, M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylII-M-( pyrid-3-ylmethyl)methylsulfonamide, M-(1-Bis(4-fluorophenyl)methyl-Iazetidin-3-ylI-M-(3,5-difluorophenyl)methylsulfonamide, (k5)-M-11-(4-chlorophenyl)pyride -3-ylmethyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide, (k)-M-11-(4-chlorophenyl)pyrid-3-ylmethyl|azetidin-3-yl)-M -(3,5-difluorophenyl)methylsulfonamide, (5)-M-11-K4-chlorophenyl)-pyrid-3-ylmethyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide, (k5) -M-11-(4-chlorophenyl)pyrid-4-ylmethyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide, (k)-M-11-(4-chlorophenyl)pyrid-4 -ylmethyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide, 70 (5)-M-11-K4-chlorophenyl)pyrid-4-ylmethyl|azetidin-3-yl)-M-( 3,5-difluorophenyl)methylsulfonamide, (k5)-M-11-(4-chlorophenyl)pyrimidin-5-ylmethyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide, (k)-M -11-(4-chlorophenyl)pyrimidin-5-ylmethyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide, (5)-M-11-K4-chloro phenyl)pyrimidin-5-ylmethylIazetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide, M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylI-M-(3,5-difluorophenyl )benzylsulfonamide. 6. The combination of the formula: Ez vy z (Z V EC. In which Ku. means the radical -М(К.)Кв, -М(К4)-СО-К», -МЩ(Ка)-5О2 in, c E» and Kz, the same or different, mean either an aromatic radical selected from phenyl, naphthyl and indenyl, d) which may be unsubstituted or substituted by one or more of the following substituents: halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -СО-аЙК, cyano, -СООН, -СОбайКК, -СОМК,Рв . or a heteroaromatic radical selected from benzofuryl, - benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidyl, quinolyl, 1,2, 3,4-tetrahydroisoquinolyl, thiazolyl, and thienyl, which may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -СООН, -СООАик, -СО-МН-МКеКцио, se -СОМКОКа, - aik-MCoKio, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, 30 alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl; uh- KE. means the radical -С(К44)(К42)-Ней, Ней, -С(К44Х(К42)-Аг, Аг, cycloalkyl or norbornyl; K5 means a hydrogen atom or a hydroxyalkyl radical, -айк-СОгдайк, -айк-СОМК.К »a, -aiik-MKRa, lkoxy, Ag, Nei, -CHNoAg, -CHnoNei or alkyl, possibly substituted by one or more halogens; « Kv means a hydroxyalkyl radical, -aiik-SOdaik, -adik-SOMK.Ka, -aiik- MKKa, alkoxy, Ag, Nei, -CHNoAg, -CHNoNei or alkyl, possibly substituted by one or more halogens; Z c KE; and Kv, the same or different, mean a hydrogen atom or an alkyl, or K, and Ka, together with an atom nitrogen, with which they are connected, form a saturated mono- or bicyclic heterocycle having from 3 to 10 members and may contain a second heteroatom selected from oxygen, sulfur and nitrogen, and be substituted by one or more alkyls; Co and Ko, the same or different, mean a hydrogen atom or an alkyl radical, -СОоайК, cycloalkyl, alkylcycloalkyl, -айк-О-айКК or hydroxyalkyl, or Ke and Kyo, together with the nitrogen atom with which they are connected, ш- form saturated or an unsaturated mono- or bicyclic heterocycle having from 3 to 10 members and may contain a second heteroatom selected from oxygen, sulfur and nitrogen, and be substituted by one or more of the following radicals: alkyl, -COaic, -"SOSaic, -" CO-MmnNaic, -C5-MNaic, oxo, hydroxyalkyl, -aic-O-alic or -CO-MH"; 1 Ki1 means a hydrogen atom or a hydroxyalkyl radical, -aik-SOOaik, -aik-SOMK.Ra, -aik-MK.,Ra, alkoxyalkyl, c 20 Ak, Nai, -SNoAg, -SNoNai or alkyl, possibly substituted by one or more halogens; Ki" means a hydrogen atom or a hydroxyalkyl radical, -alkyl-SOdaic, -alkyl-SOMK.a, -alkyl-MK.Ka, alkoxyalkyl or 1" alkyl, possibly substituted by one or more halogens; or K.4 and Ku", together with the carbon atom to which they are connected, form a saturated mono- or bicyclic ring having from C to 10 members and may contain a second heteroatom selected from oxygen, sulfur and nitrogen, and be 99 substituted by one or more alkyls; HF) Ag means the phenyl, naphthyl or indenyl radical, which can be replaced by one or more of the following substituents: halogen, alkyl, alkoxy, -СбО-аиК, cyano, -СООН, -СОбаикК, -СОМКзК.а4, -СО-МН -MK.5Kchv, o alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -aik-MK5Kchv, -MK.5Kv, alkylthioalkyl, formyl, CEz, OSE", Nei, -O-alkyl-MH-cycloalkyl, -502MH", hydroxy, hydroxyalkyl, -МН-СО-айКк, -МН-СООайЙкК or, for two adjacent 60 carbon atoms, dioxymethylene; It means an unsaturated or saturated mono- or bicyclic heterocycle having from 3 to 10 members and containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, and which may be substituted by one or more of the following radicals: alkyl, alkoxy, halogen , alkoxycarbonyl, oxo, hydroxy, and nitrogen-containing heterocycles can be in the form of M-oxides; b5 Kis and K.4, the same or different, mean a hydrogen or alkyl atom, or Kis and K.i4, together with the nitrogen atom to which they are connected, form a saturated mono- or bicyclic heterocycle having from C to 10 units and may contain a second heteroatom selected from oxygen, sulfur and nitrogen, and be substituted by one or more alkyls; Kv and Kv, the same or different, mean a hydrogen or alkyl atom, or K.5 and Kv, together with the nitrogen atom to which they are connected, form a saturated mono- or bicyclic heterocycle having from 3 to 10 members and may contain a second heteroatom selected from oxygen, sulfur and nitrogen and be substituted by one or more alkyl radicals; aiK means alkyl or alkylene, and alkyl or alkylene radicals and parts of molecules or alkyl radicals and parts of molecules /0 have a straight or branched chain and contain from 1 to 6 carbon atoms, and cycloalkyl radicals contain from 3 to 10 carbon atoms; optical isomers of these compounds and their pharmaceutically acceptable salts with mineral or organic acids, except for the compound in which K » and Kz mean phenyl, Ki means the radical -М(К/)5О»оКв, where Ku; stands for phenyl and Co stands for methyl. 7. The compound of formula I according to claim 6, in which it is selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, cinnoline, thiophene, quinazoline, quinoxaline, quinoline, pyrazole, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, piperidine, piperazine, triazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, which may be substituted by one or more of the following substituents: alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OSE" or CEz. 8. The compound of formula I according to claim 6, in which Ku. means the radical -M(K.)Kv, -M(K4)-5O2Kv, Ko means either phenyl, unsubstituted or substituted by one or more of the following substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-aiK, cyano , -"СОМК.Ка, hydroxyalkyl or -айк-МК,Ка, or сх heteroaromatic radical selected from pyridyl, pyrimidyl, thiazolyl and thienyl, which may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, i) -SOMA Ka, -aik-MKoK.o alkylsulfonyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl; Kz means either phenyl, unsubstituted or substituted by one or more of the following substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alK, cyano, -"SOMK.Ka, hydroxyalkyl or -alik-MK,Ka, or " g zo is a heteroaromatic radical selected from pyridyl, pyrimidyl, thiazolyl, and thienyl, which may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, o-COMe Ka, aik-MCoK.o, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl; yu KE. means the radical -С(К44)(К42)-Ней, Ней, -С(44Х(К42)-Аг, Аг or norbornyl; K5 means a hydrogen atom or a hydroxyalkyl radical, -айк-СОсайк, -адик-СОМК,Ка, - aiik-MK.Ka, lkoxy, -SNeoAg, and) -SnNei! or alkyl; cha Ke means the radical hydroxyalkyl, -aik-COsaik, -aik-SOMK.Ka, -aikik-MK.Ra, alkoxy, -SNoAg, -SNoNei or alkyl; KE; and Kv, the same or different, mean a hydrogen or alkyl atom, or K, and Ka, together with the nitrogen atom to which they are connected, form a saturated mono- or bicyclic heterocycle having from C to 10 members and may contain a second heteroatom selected from oxygen, sulfur, and nitrogen, and to be substituted by one or more alkyls; " Ko and Ko, the same or different, mean a hydrogen atom or an alkyl radical, cycloalkyl, alkylcycloalkyl, nta) c-aik-o-aikK or hydroxyalkyl, or Ko and K.o, together with the nitrogen atom with which they are connected , form a saturated or unsaturated mono- or bicyclic heterocycle having from 3 to 10 members and may contain a second ;" a heteroatom selected from oxygen, sulfur, and nitrogen, and be substituted by one or more of the following radicals: alkyl, -COaic, -SOSaic, -"CO-MnNoxy, oxo, hydroxyalkyl, or -CO-MH"; Ki1 means a hydrogen atom or a hydroxyalkyl radical, aik-SOdOaik, ayik-SOMK,Ra, -aik-MK.Ra, alkoxyalkyl, Ag, -I Nei, -SNoAg, -SNoNei or alkyl, possibly substituted by one or more halogens; Ki" means a hydrogen atom or a radical of hydroxyalkyl, -alkyl-SOdaik, -ayaik-SOMK.a, -akik-MK.Ka, alkoxyalkyl or o-alkyl, possibly substituted by one or several halogens; c or K.4 and Ku", together with the carbon atom to which they are connected, form a saturated mono- or bicyclic 5p ring having from 3 to 10 members and may contain a second heteroatom selected from oxygen, sulfur and nitrogen, and be 1 substituted by one or more alkyls; "Ar" means phenyl or naphthyl, which can be replaced by one or more of the following substituents: halogen, alkyl, alkoxy, -CO-alkyl, cyano, -SOMK.zK.,, alkyl sulfonyl, -alkyl-MK.5Kchiv, - MKu5Kiv, СЕз, ОСЕ», -502МН», hydroxy, hydroxyalkyl or, for two adjacent carbon atoms, dioxymethylene; 5B Her means a heterocycle selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, F) thiadiazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, which may be substituted by one or more of the following substituents: alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, ОСЕ" or СЕ"; Keys and K.4, the same or different, mean a hydrogen or alkyl atom, or Keys and K.i4, together with the nitrogen atom to which they are connected, form a saturated mono- or bicyclic heterocycle having from C to 10 units and may contain a second heteroatom selected from oxygen, sulfur and nitrogen, and be substituted by one or more alkyls, Kv and Kv, the same or different, mean a hydrogen atom or an alkyl, or K.5 and Kv, together with a nitrogen atom , with which they are connected, form a saturated mono- or bicyclic heterocycle having from 3 to 10 members and may contain a second heteroatom selected from oxygen, sulfur and nitrogen, and be substituted by one or more alkyls; 65 optical isomers of these compounds and their pharmaceutically acceptable salts with mineral or organic acids, except for the compound in which Ko and Kz are phenyl radicals, K.; is the radical -M(K/)5O»oKeo, where Ki means phenyl and Ko means methyl. 9. Compounds of formula I according to claim 6, in which Ku. means the radical -M(K./)-502Kv, Ko means either phenyl, unsubstituted or substituted by one or more of the following substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -SOMK,Ka, hydroxyalkyl or -aik- MK,Ka, or a heteroaromatic radical selected from pyridyl, pyrimidyl, thiazolyl, and thienyl, which may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -SOMEK Ka, or hydroxyalkyl; 70 Kz means either phenyl, unsubstituted or substituted by one or more of the following substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -SOMK,Ka, hydroxyalkyl or -aik-MK,Ka, or a heteroaromatic radical selected from pyridyl . KE. means -Nei or Ag; Ke means hydroxyalkyl or alkyl; KE; and Kv, the same or different, mean a hydrogen or alkyl atom, or K, and Ka, together with the nitrogen atom to which they are connected, form a saturated mono- or bicyclic heterocycle having from C to 10 members and may contain a second heteroatom selected from oxygen, sulfur, and nitrogen, and to be substituted by one or more alkyls; Ag means phenyl or naphthyl, which can be replaced by one or more of the following substituents: halogen, alkyl, alkoxy, -СО-айкК, cyano, -СОМК.зЕ 4, -аййк-МКу5Кв, -МК.5Кв, СЕз, ОСЕ»z, -"50О2МН", hydroxy or hydroxyalkyl; It means a heterocycle selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, thiazole, thiadiazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, which may be substituted by one or by several of the following substituents: alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, ОСЕ"z or СЕ"; (8) K.z and K.4, the same or different, mean a hydrogen or alkyl atom, or K.z and K.4, together with the nitrogen atom to which they are connected, form a saturated mono- or bicyclic heterocycle having from C up to 10 units and may contain a second heteroatom selected from oxygen, sulfur and nitrogen, and be substituted by one or more alkyls; "E zo Kv and Kv, the same or different, mean a hydrogen or alkyl atom, or K.5 and Kv, together with the nitrogen atom with which they are connected, form a saturated mono- or bicyclic heterocycle having from C to 10 units and may o contain a second heteroatom selected from oxygen, sulfur and nitrogen, and be substituted by one or several alkyls; optical isomers of these compounds and their pharmaceutically acceptable salts with mineral or organic acids, with the exception of the compound in which Ko and Kz are phenyl radicals, K.; is the radical -M(K/)5O»oKeo, where Ki stands for oZ phenyl and Ke stands for methyl. uh- 10. The compound of formula I according to claim 6, selected from the following compounds: M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylI-M-(b-chloropyrid-2-yl)umethylsulfonamide, M-11-Ibis (4-chlorophenyl)methyl|azetidin-3-ylI-M-(b-ethylpyrid-2-yl)umethylsulfonamide, M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-M-quinol-b -ylmethylsulfonamide, M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-M-quinol-5-ylmethylsulfonamide, with M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl -M-isoquinol-5-ylmethylsulfonamide, . M-11-I(bis(4-chlorophenyl)methylIazetidin-3-ylIi-M-pyrid-3-yl-methylsulfonamide, i?» M-11-Ibis(4-chlorophenyl)methylI|azetidin-3-ylI-M -(1-oxypyrid-3-yl)methylsulfonamide, M-(1kK,25,45)-bicyclo|2.2.1|hept-2-yl-M-(1-Ibis(4-chlorophenyl)methylI|azetidine-3 -ylmethylsulfonamide, M-(1kK,2kK,45)-bicyclo(|2.2.1|hept-2-yl-M-1-(bis(4-chlorophenyl)methylylIazetidine-3-ylylmethylsulfonamide, -I M-11-Ibis (4-chlorophenyl)methyl|azetidin-3-ylII-M-(3,5-difluorophenyl)methylsulfonamide, M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylII-M-(thiazol-2-yl) )umethylsulfonamide, o M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylIi-M-(3-methoxyphenyl)methylsulfonamide, c M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylI- M-(3-hydroxyphenyl)methylsulfonamide, M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylI-M-(3-hydroxymethylphenyl)methylsulfonamide, o ethyl ether M-71-(bis(4-chlorophenyl) Methyl-azetidin-3-yl)-M-(methylsulfonyl)-3-aminobenzoic acid, M-11-bis(4-chlorophenyl)methyl-azetidin-3-yl-M-(1-isobutylpiperid-4-yl)methylsulfonamide , M-benzyl-M-(1-Ibis(4-chloro rphenyl)methyl|azetidine-3-ilyamine, M-(1-Ibis(4-chlorophenyl)methylyIazetidin-3-ylI-M-(3,5-difluorobenzyl)amine, M-11-Ibis(4-chlorophenyl)methyl| azetidin-3-ylII-M-(3,5-difluorobenzyl)methylsulfonamide, M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylII-M-(pyrid-3-ylmethyl)methylsulfonamide, F) M- (1-Ibis(4-fluorophenyl)methyl-azetidin-3-yl-M-(3,5-difluorophenyl)methylsulfonamide, ka (k5)-M-11-(4-chlorophenyl)pyrid-3-ylmethyl|azetidin-3- yl)-M-(3,5-difluorophenyl)methylsulfonamide, (k)-M-11-(4-chlorophenyl)pyrid-3-ylmethyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide , in (5)-11-K(4-chlorophenyl)|pyrid-3-ylmethylazetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide, (k5)-M-11-(4-chlorophenyl) pyrid-4-ylmethyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide, (k)-M-11-(4-chlorophenyl)pyrid-4-ylmethyl|azetidin-3-yl)- M-(3,5-difluorophenyl)methylsulfonamide, (5)-M-11-K4-chlorophenyl)pyrid-4-ylmethyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide, (k5) -M-11-(4-chlorophenyl)pyrimidin-5-ylmethyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide, 65 (k)-M-11-(4-chlorophenyl)pyrimidin-5-ylmethyl|azetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide, (5)-M-11-K4-chlorophenyl)pyrimidine -5-ylmethylIazetidin-3-yl)-M-(3,5-difluorophenyl)methylsulfonamide, M-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl1-M-(3,5-difluorophenyl)benzylsulfonamide, optical isomers of these compounds and their pharmaceutically acceptable salts with mineral or organic acids. 11... Mch-11-Ibis(4-chlorophenyl)methylI|azetidin-3-ylI)-M-(3,5-difluorophenyl)methylsulfonamide, its optical isomers and pharmaceutically acceptable salts with mineral or organic acids. 12. The method of obtaining compounds of formula I! according to point b, in which K is the radical -M(K.)K", in which K represents a hydrogen atom, K represents the radical -SK.4K42-Ag or -SK.4K.2-Nei, and K. /" means a hydrogen atom, which differs in that the derivative KO-SOK.4, in which K.4 have the same values as in claim 6, is introduced into the interaction with the derivative of the formula: in. AH MN. Kb means Ag or Nei radical, K»o, Kz, K.4, Ag and Nei have the same meanings as in item b, isolate the product and, if necessary, convert it into a pharmaceutically acceptable salt. 13. The method of obtaining compounds of formula I according to item b, in which K 4 is the radical -M(K/)-СО-К5, in which K means the radical -С(К.44ХК42)-Ней or -С(К44) (K42)-Ag and Ku" means a hydrogen atom, which differs in that the derivative NaI-SOK" is introduced into interaction with the derivative of the formula: EZ M KE sa ? she o M i n Na! means a halogen atom, KO means Ag or Nei, K", Kz, Kv, K.4, Ag and Nei have the same meanings as in claim 6, isolate the product and, if necessary, convert it into a pharmaceutically acceptable salt. WITH 14. The method of obtaining compounds of formula I according to item b, in which K 4 is the radical -M(K/)-502-Ke, in which K; means (u -F(К14ХК42)-Аг or -С(К414Х(Кч42)-Ней and КК" means a hydrogen atom, which differs in that the derivative NaI-5О2К»e is introduced into the interaction with the derivative of the formula: о И со АХ - with Otsdrug МОС « her no s Ko, Kz, K/4, K5 have the same values as in item b, NaI means a halogen atom, and KO means Ag and Nei, isolate the product and, if necessary, convert it into a pharmaceutically acceptable salt. :z" 15. The method of obtaining compounds of the formula | according to claim 6, in which K.4 is the radical -M(K.)K", which differs in that the derivative K5(K.)MH is introduced into the interaction with derivative of the formula: Kk - F (65) V M ; s ini x s s T» KE», Kz, Ku, Kv have the same values as in claim 6, isolate the product and, if necessary, convert it into a pharmaceutically acceptable salt. 16. The method of obtaining compounds of the formula I according to claim 6, in which K.4 is the radical -М(К/)5О»2Рв, which differs in that the 5voО/shО derivative NaI-5О2К»e is introduced into the interaction with the derivative of the formula: О Во t And because Kz t! KE. because R", Kz, K.; and Ke have the same meanings as in paragraph b, and Na! means a halogen atom, isolate the product and, if necessary, convert it into a pharmaceutically acceptable salt. 17. The method of obtaining compounds of the formula I according to claim 6, in which K.4 is the radical -M(K.)SOK", which differs in that the derivative NaI-SOK" is introduced into the interaction with the derivative of the formula: X EK M o (g KE. /5 R", Kz, K.; and K5 have the same values as in item b, and Na! means a halogen atom, isolate the product and, if necessary, convert it into a pharmaceutically acceptable salt. 18. The method of obtaining compounds of formula I! according to point b, in which K is the radical -M(K/)-5025-Ke, in which K; means the radical Nei or Ag, which differs in that the derivative Ka-mMnH-5O»2-Ke is introduced into the interaction with the derivative of the formula: khee shi v on o or vu t Ed M mu ni i OM so ka means Ag or Nei, Ko, Kz and Ke have the same meanings as in item b, and M5 means the ych-methylsulfonyloxy radical, isolate the product and, if necessary, convert it into a pharmaceutically acceptable salt. 19. The method of obtaining compounds of the formula | according to claim 6, which differs in that the derivative Ko-SNVI-K»z is introduced into the interaction with the derivative of the formula: " du НЯ - с , . "» KE Ku, Ko and Kz have the same values as in claim 6, isolate the product and, if necessary, convert it into a pharmaceutically acceptable salt. - 20. The method of obtaining compounds of the formula I according to item b, in which K 4 is by the radical -M(K/)-5025-Ke, in which K stands for piperid-4-yl, substituted on nitrogen by an alkyl radical, which differs in that it alkylates the corresponding compound of formula I, in which K is the radical -M( K/)-502-Ke, in which K. stands for piperid-4-yl, isolate product 1 and, if necessary, convert it into a pharmaceutically acceptable salt. K 4 is the radical -M(K/)-5025-Ke, in which K; means phenyl substituted with pyrrolid-1-yl, which differs in that pyrrolidine is introduced into the interaction with the corresponding compound of formula I, in which K 4 is the radical -M(K/)-502-Ke, in which KK. means phenyl substituted by a halogen atom, isolate the product and, if necessary, convert it into a pharmaceutically acceptable salt. 22 Official Bulletin "Industrial Property" . Book 1 "Inventions, useful models, topographies of integrated Ge! microcircuits", 2005, M 8, 15.08.2005. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. name) 60 b5