UA72319C2 - Pharmaceutical compositions containing 3-aminoazetidine derivatives, derivatives and a method for obtaining thereof - Google Patents

Abstract

The invention concerns pharmaceutical compositions containing as active ingredient a compound of formula (I) wherein: , ( ) R1 represents a ûNHCOR4 or -N(R5)-Y-R6, radical; is CO or SO2; R4 represents an -alk-SO2R11, -alk-SO2-CH=CH-R11, Het substituted by ûSO2R11 or phenyl substituted by ûSO2-R11 or -alk-SO2-R11 radical; R5 represents a hydrogen atom or an alkyl radical; R6 represents a phenylalkyl radical, Het or Ar; the novel derivatives of formula (I) and their preparation.

Description

The present invention relates to pharmaceutical compositions containing as an active ingredient compounds of the formula: in td i

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

Compounds of the formula I, in which EK" and Kz are phenyl radicals, Ki means the radical -M(H5")-U-Hv, U means the group ZO", But means the methyl radical and Kee means the phenyl radical, described in the UMO patent 99/ 01451.

Other compounds and their pharmaceutically acceptable salts are novel compounds and form part of the invention.

In formula I

В means the radical -МНСОВ»а or -М(А5)-хУ-Нв,

U means CO or 50",

B" and Ez, 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 substituents: halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO- aikK, cyano, -СООН, -СООАик, -СОМААв, -СО-МН-

MA»NAthio, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alkyl-MA?He; or a heteroaromatic radical selected from the rings: benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3- dihydrobenzothienyl, pyrimidinyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 1,2, 3,4- tetrahydroisoquinolyl, thiazolyl and thienyl, which can be unsubstituted or substituted by one or more substituents: halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -СООН, -СбаОайк, -СО-

MH-MAzgAto, -SOMA?Av, -aiKk-MA»hAzo, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl;

You means the radical aik-502-Np, aik-z-SuSnNKkOSnN-Kp, Nei, substituted by the group -502-Kp, or phenyl, substituted by the group -502-Viii or -aikik-5O»2-Bi1;

Az means a hydrogen atom or an alkyl radical;

Ae means a phenylalkyl radical, Nei or Ag;

IN; and Kv, the same or different, mean a hydrogen atom or an alkyl radical, or K" and Kz, 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;

Ne and Kio, the same or different, mean a hydrogen atom or an alkyl radical, -СбОоОайК, cycloalkyl, alkylcycloalkyl, -айк-О-айк or hydroxyalkyl, or Ko and Kіо, together with the nitrogen atom with which they are connected, form a saturated or an unsaturated 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 radicals: alkyl, -COaic, -SOdOaic, -CO-MNaic , -C5-MNaic, oxo, hydroxyalkyl, -aIc-O-aic or -CO-MH»?;

Vii means an alkyl radical, Ag or Ni;

Ag means the phenyl, naphthyl or indenyl radical, which can be replaced by one or more substituents: halogen, alkyl, alkoxy, cyano, -СбО-айк, -СООН, -СООАйк, -СОМА2Виз, -СО-МН-МА14В5, alkylsulfanyl, alkylsulfinyl , alkylsulfonyl, alkyl-MAta"Ni5, -MA14Bi5, alkylthioalkyl, formyl, hydroxy, hydroxyalkyl, Ni, -O-alkyl-MN-cycloalkyl, OSEz, CEz, -"МН-СО-айк, -502МН", -МН- СОСнН», -МН-СоОаакк, Her, or on two adjacent carbon atoms bound by dioxymethylene;

It means an unsaturated or saturated mono- or bicyclic heterocycle having from 3 to 10 members, containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, and which may be substituted by one or more radicals: alkyl, alkoxy, vinyl, halogen, alkoxycarbonyl, oxo, hydroxy, OSE3 or CE3, and nitrogen-containing heterocycles can be in the form of M-oxides.

Vi: and Viz, the same or different, denote a hydrogen atom or an alkyl radical, or Ki» and Kis, 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 alkyl radicals;

Aia and Wis, the same or different, denote a hydrogen atom or an alkyl radical, -COOaC, cycloalkyl, alkylcycloalkyl, -aic-O-aic or hydroxyalkyl, or Ki4 and Ki5, 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, which may contain a second heteroatom selected from oxygen, sulfur, and nitrogen, and be substituted by one or more radicals: alkyl, -"CO-aic, -SOOaic, - "COo-mnaic, -C5-MNaic, oxo, hydroxyalkyl, -aic-O-aicK or -CO-MH"g; ak means an alkyl or alkylene radical.

In the above and subsequent definitions, unless specifically discussed, alkyl or alkylene radicals and molecular parts or alkyl radicals and molecular parts are straight or branched chains 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.

Cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl radicals.

The term halogen is 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, pyrrolidine, triazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, which may be substituted by one or more substituents: alkyl, alkoxy, vinyl, halogen, alkoxycarbonyl, oxo, hydroxy, OSE3 or SEZ.

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

Compounds of formula I are mainly compounds for which:

A:i means the radical -M(A5)-U-Hv,

U means 50",

Ag means either phenyl, unsubstituted or substituted by one or more substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -SOMA;H»e, hydroxyalkyl or -aik-MA?H»e, or a heteroaromatic radical selected from cycles : pyridyl, pyrimidinyl, thiazolyl and thienyl, which may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -

SOMA7B»v, -aik-MA»Nio, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl;

Az means either phenyl, unsubstituted or substituted by one or more substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -SOMA?7H»v, hydroxyalkyl, -alkyl-MA»Vio, or a heteroaromatic radical selected from the rings: pyridyl .

B" means a hydrogen atom or alkyl;

Ae means the radical naphthyl, phenylalkyl, Ni or phenyl, which can be substituted by one or more substituents: halogen, alkyl, alkoxy, cyano, -CO-alkK, -SOOalik, -SOMA2Vis, -alik-MAT4Bi5, -MAchaViv", hydroxy, hydroxyalkyl, Nei, OSEz) SEz, -MH-SOdaic, -502MHg) -MH-SOyaiK, or on two adjacent carbon atoms bound by dioxymethylene;

IN; and Ezv, the same or different, mean a hydrogen atom or an alkyl radical, or K; and K5. 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;

B" and Co, the same or different, mean a hydrogen atom or an alkyl radical, cycloalkyl, alkylcycloalkyl or hydroxyalkyl, or Kz and Co, together with the nitrogen atom to which they are connected, form a saturated or unsaturated mono- or bicyclic heterocycle, which has from 3 to 10 units, which may contain a second heteroatom selected from oxygen, sulfur, and nitrogen, and be substituted by one or more radicals: alkyl, oxo, or -СО-МН?;

Vi: and VIZ, the same or different, stand for a hydrogen atom or an alkyl radical, or Ki? and Keys, together with the nitrogen atom to which they are attached, 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 several alkyl radicals;

Via and Ez5, the same or different, represent a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl or hydroxyalkyl radical, or Ba and Ki5, together with the nitrogen atom to which they are connected, form a saturated or unsaturated mono- or bicyclic heterocycle having from With up to 10 units, which may contain a second heteroatom selected from oxygen, sulfur, and nitrogen, and be substituted by one or more alkyl, oxo, hydroxyalkyl, or -CO- radicals

MN";

It means an unsaturated or saturated mono- or bicyclic heterocycle having from 3 to 10 members, containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, and which may be substituted by one or more radicals: alkyl, alkoxy, vinyl, halogen, alkoxycarbonyl, oxo, hydroxy, and nitrogen-containing heterocycles can be in the form of M-oxides, and, preferably, Nei means a heterocycle selected from the following heterocycles: 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 more substituents: alkyl, alkoxy, vinyl, halogen, oxo, hydroxy, OSE3 or SEZ.

Even more preferred compounds of formula I are selected from the following compounds:

A:i means the radical -M(A5)-U-Hv,

U means 50",

Ag means either phenyl, unsubstituted or substituted by one or more substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy or hydroxyalkyl, or a heteroaromatic radical selected from the rings: pyridyl and pyrimidyl, which may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy , trifluoromethyl or trifluoromethoxy;

Az means either phenyl, unsubstituted or substituted by one or more substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, hydroxyalkyl, or a heteroaromatic radical selected from the rings: pyridyl and pyrimidyl, which may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy , trifluoromethyl, trifluoromethoxy;

B" means a hydrogen atom or alkyl;

Ae means the radical naphthyl, phenylalkyl, Ni or phenyl, which can be replaced by one or more substituents: halogen, alkyl, alkoxy, -MAch14Bi5, hydroxy, hydroxyalkyl, ОСЕ3, КЕ3 or -502МН», or on two adjacent carbon atoms, with dioxymethylene;

Via and Ez5, the same or different, represent a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl or hydroxyalkyl radical, or Ba and Ki5, together with the nitrogen atom to which they are connected, form a saturated or unsaturated mono- or bicyclic heterocycle having from With up to 10 units, which may contain a second heteroatom selected from oxygen, sulfur, and nitrogen, and be substituted by one or more alkyl, oxo, hydroxyalkyl, or -CO- radicals

MN";

It means an unsaturated or saturated mono- or bicyclic heterocycle having from 3 to 10 members, containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, and which may be substituted by one or more radicals: alkyl, alkoxy, vinyl, halogen, alkoxycarbonyl, oxo, hydroxy, and nitrogen-containing heterocycles can be in the form of M-oxides, and, preferably, Nei means a heterocycle selected from the following heterocycles: benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinoline, pyrrole, pyridine, pyrimidine, thiazole, thiadiazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, which can be substituted by one or more substituents: alkyl, alkoxy, vinyl, halogen, oxo, hydroxy, OSE, or CEz.

Compounds of formula I, in which Ki is the radical -MNSON", can be obtained according to the following reaction scheme:

Ve V, t vh

M sn,ZO,s Change 1 Son and "o50,sn,

B: Mn ts ki" y; won Z

M « M y Bennanina z-d

Iv nok, Mn,

In the above formulas, Ka, Nz and Ka have the same values as in formula I.

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 in the range from 15 to 30"C in the presence of a base such as trialkylamine (for example triethylamine, dipropylethylamine) or in pyridine at a temperature in the range from 0 to 30"C.

Stage p is carried out mainly in methanol in an autoclave at a temperature ranging from 50 to 70"С.

Step c is usually carried out in the presence of a condensing agent used in peptide chemistry, such as carbodiimide (e.g. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, M,M'-dicyclohexylcarbodiimide) or M,M'-dimidazolecarbonyl in an inert solvent such as a simple ether (for example, tetrahydrofuran, dioxane), an amide (dimethylformamide) or a chlorine-containing solvent (for example, dichloromethane, 1,2-dichloroethane, chloroform) at a temperature ranging from 0"C to the boiling point of the reaction mixture. You can also use a reactive acid derivative, such as chloride, possibly in the presence of an acid acceptor such as a nitrogen-containing organic base (eg trialkylamine, pyridine, diaza-1,8-bicyclo|5.4.0)undecene-7 or diaza-1,5-bicyclo(|4.3.O| nonene-5), in a solvent as specified above, or in a mixture of these solvents at a temperature ranging from 0"C to the boiling point of the reaction mixture.

Derivatives of CaCOOH are commercial or can be obtained by the methods described by K.S. GAKOSK,

Sotrgenepvzime Ogdapis Tgtapetogtaiyopv5, MSN eayog.

Azetidinols of formula !/ can be prepared using or adapting the methods described

KATEITAKU A.K. with collaboration, U. Negegosusi. Spet., 271 (1994) or OAME R.K., 9. Ogd. Spet., 61, 5453 (1996), and in examples. The work is usually carried out according to the following reaction scheme:

Y A LSh

-7 skh, same yatteko u hop tokettt tsndy i tuf v, HYDROoKenlaAmiV I: V

IN

;

Ve and her

Me sno ik

B in, ! eat more

H

X is the one in whose formulas E2 and Ez have the same values as in formula I, and Na! means a chlorine or bromine atom.

At stage A, they work mainly in an inert solvent such as an aliphatic C1-C4 alcohol (for example, methanol, ethanol), possibly in the presence of alkali metal hydroxide, at the boiling temperature of the reaction medium.

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

At stage C, they work mainly in an inert solvent such as an aliphatic C1-C4 alcohol (for example, ethanol, methanol) in the presence of sodium bicarbonate at a temperature ranging from 207"C to the boiling point of the reaction medium.

At the O stage, they work according to the method described by M. SKIZAE et al., in U. Med. Spet., 885 (1973). A magnesium compound is prepared from the bromine derivative, and then a nitrile in an ether, such as diethyl ether, is introduced into the reaction at a temperature from 0°C to the boiling point of the reaction medium. After hydrolysis with alcohol, the intermediate imine is reduced with sodium borohydride at a temperature from 0°C to boiling point of the reaction medium.

Derivatives of K2-CO-Hz can be purchased on the market or can be obtained using or adapting the methods described by KOMOEMK M.O. with co-author., U. Spet. wasps Regkip Tgap5 1, 2815 (1997);

MOVEMO - MAVVAZ M., Yeig. IN). Honey. Spet., 23 (5) 477 (1988); BKIMMEV with co-author., U. Med. Spet., 14 (6) 546 (1971); NOKM M.K., Teig. Hey., 36 (52) 9453 (1995); MEBISI A. with co-author., Teig. Hek., 24 (28) 2901 (1983);

KIESKE K.0O. with co-author., y. Ogd. Spets., 62 (20) 6921 (1997); KMAVE .. with co-author., Agsp, Rpagt., 306 (9) 648 (1973); SOMZOMKMI MK. with co-author., U. Spet. wasps Regkip Tgapz 1, 1989 (1996); EK-96-2481 and UR-94-261393.

EzVg derivatives are bought on the market or can be obtained using or adapting the methods described in VKAMO5MA G. 5upip. Sott., 20 (11) 1967 with co-author., 3153 (1990); GEMAIKE M. with co-author., Zupii.

Sott., 24 (1) 95 (1994); SOVA N. with co-author., Zupipeviv, 9, 849 (1992) "VAOEKGE R. with co-author., U. Spet. os. Rezhkip Tgapz 2, 489 (1993).

Derivatives of EzSM are bought on the market or can be obtained using or adapting the methods described by VOOUZZOI R. with co-author., 9. Her. Spet., 29 (4) 895 (1992); BODOKIM. with co-author., U. Spet. 5 vol.

Spent Sott., 1523 (1984); MAKVOKO 5. with co-author., y. Her Spet., 17, 1333 (1980); REKSES M. with co-author.,

U. Oga. Spet., 60 (21) 6895 (1995).

Compounds of formula I, in which Ki is the radical -M(H5»)-U-Ne, can be obtained according to the following reaction scheme: , v / te navaik v-A / p cha 7 and yu ak in the formulas of which U, K2, Hz and Kye have the same values as in formula I, and Na! means a halogen atom, preferably an atom of iodine, chlorine or bromine .

Step a is 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 2076.

Stage p is usually carried out in an inert solvent such as tetrahydrofuran in the presence of sodium hydride at a temperature ranging from 0"C to the boiling point of the reaction mixture.

Derivatives of NaI-5O2Nee are purchased on the market or can be obtained by halogenation of the corresponding sulfonic acids, in particular ip 5yi in the presence of chlorosulfonyl isocyanate and alcohol in a halogen-containing solvent (for example, dichloromethane, chloroform).

Nai-SO-Nye derivatives are purchased on the market or can be obtained by the methods described in K.S. GAKOSK,

Sotrgenepvzime Ogdapis Tgtapetogtaiyopv5, MSN eayog.

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

VUS, vve Zh kUsnO yah "t

CAPONIA,

I. is

NM k.-snv-V, vo det i dachni nchatchitt anten chiti tih iti shchi i ich y; in

Like RA

Y g: on

This is Kk, in the formulas of which Ki, H» and Kz have the same values as in formula I, and Ri means phenyl.

Step a is usually carried out in an alcohol such as methanol in the presence of sodium borohydride at a temperature close to 2070.

At stage p, a magnesium 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 0"C 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 in an inert solvent such as dichloromethane, chloroform, carbon tetrachloride or toluene at a temperature from 0"C to the boiling point of the reaction medium .

Step a is carried out using hydrogen in the presence of palladium on carbon in an alcohol such as methanol at a temperature close to 2076.

The stage is carried out in an inert solvent such as acetonitrile in the presence of alkali metal carbonate (for example, potassium carbonate) and potassium iodide at a temperature from 20"C to the boiling point of the reaction medium.

Derivatives of KzVg and B2-СНО are bought on the market or can be obtained by the methods described, for example, by K.S.

IGAVOSK, Sotrgepepvime Ogdapis Tgapeayugtaiyopvy, MES eayog.

Compounds of formula I, in which Ki is the radical -M(H5)-Y-Ne, where Kye means a hydroxy-substituted phenyl radical, can also be obtained by hydrolysis of the corresponding compound of formula I, in which KE: is the radical -M(B5)-

У-ВАв, where Кв means an alkoxy-substituted phenyl radical.

This hydrolysis is usually carried out in an inert solvent such as a chlorine-containing solvent (e.g. dichloromethane, chloroform) using boron tribromide at a temperature close to 2076.

Compounds of the formula I, in which Ki is the radical -M(H5b)-U-No, where Kee means a hydroxyalkyl(1C)-substituted phenyl radical, can also be obtained by the action of diisobutylaluminum hydride on the corresponding compound of the formula I, in which B" is a radical -M(H5)-U-Hv, where Kee means the phenyl radical substituted by oxycarbonyl.

This reaction is usually carried out in an inert solvent such as toluene using diisopropylaluminum hydride at temperatures ranging from -50°C to 2576°C.

Compounds of the formula I, in which Ki is the radical -M(H5")-y-Ne, where Ke is a pyrrolidine-1-yl-substituted phenyl radical, can also be obtained by the action of pyrrolidine on the corresponding compound of the formula I, in which K1 is a radical -

M(Av)-u-Av, where Kv means a fluorine-substituted phenyl radical.

This reaction is preferably carried out in an inert solvent such as dimethyl sulfoxide at a temperature of 9026.

It is obvious to a specialist that when carrying out the methods described above according to the invention, it may be necessary to introduce protective groups for amine, hydroxyl and carboxyl reactive groups in order to avoid side reactions. Such groups are groups that can be removed without disturbing the rest of the molecule. Examples of 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 reactive group include triethylsilyl, tert-butyldimethylsilyl, which can be regenerated with tetrabutylammonium fluoride, or asymmetric acetals (for example, methoxymethyl, tetrahydropyranyl), which are regenerated with hydrochloric acid. As protective groups for carboxyl reactive groups, esters (for example, allyl, benzyl), oxazoles, and 2-alkyl-1,3-oxazolines can be named. Other suitable protecting groups are described by SOKEEME T.UM. with co-author., Rgoiesiipd dgoire ip Ogdapis zZupipeviv, zesopa eyyop, 1991, dhonp UMieu 5 5opv.

Compounds of the formula | can be purified by conventional known methods, such as 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 RISKGE M/N. with co-author., Azutteigis Zupipeviv, my.1,

Asadetis Rge55 (1983) either by the formation of salts or by synthesis from chiral precursors. Diastereoisomers can be obtained using known classical methods (crystallization, chromatography or 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, isothionate, 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 high affinity for cannabinoid receptors and, in particular, for receptors of the SVI type. They are antagonists of the SVI receptor and, therefore, can be used in the treatment and prevention of disorders related to the central nervous system, the immune system, the cardiovascular or endocrine system, the respiratory system, the gastrointestinal system, and disorders of the reproductive system (Noiijzieg, Rpagt. Kem., 38, 1986, 1-20; Vepu and bipna, Rgod. JuOgid. Nez., 36, 71-114 (1991); Sopvgoe and Zapauk, in Magi)papa/Sappabipoid5, Meigobioiodu apa Mepygornuzioiodu, 459; MygrpNu G., apa Vapne A. Edz", SAS Rgezv, 1992).

Thus, these compounds can be used to treat and prevent psychoses, including schizophrenia, anxiety, depression, epilepsy, neurodegeneration, brain and spinal cord disorders, cognitive impairment, head injury, panic attacks, peripheral neuropathies, glaucoma, migraines, Parkinson's disease , Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremors, obsessive-compulsive symptoms, senile dementia, thymus disorders, Tourette's syndrome, tardive dyskinesia of bipolar disorders, cancers, drug-induced motor disorders, dystonias, endotoxic shocks, hemorrhagic shocks, hypotension , insomnia, immunological diseases, multiple sclerosis, vomiting, asthma, appetite disorders (bulimia, anorexia), obesity, memory disorders, when weaning during chronic treatment, and abuse of alcohol or drugs (for example, opioids, barbiturates, cannabis, cocaine, amphetamines, phencyclide, hallucinogens, benzodiazepines ), such as analgesics or enhancers of the analgesic activity of narcotic and non-narcotic drugs. They can also be used to treat or prevent intestinal transit.

Affinity of compounds of formula I! to hemp receptors was determined by the method described by KOZTEV

UE., ZTEMEMZOM 9.I., MMAKO 5.U., OP'AMVKA T.E., Nakhsosk BA in . Rpagtasoi Ex. Tag., 264, 1352-1363 (1993).

In the conducted test, the value of Si5o for compounds of the formula | below or equal to 1000nM.

Their antagonistic activity was demonstrated using the hypothermia model, which is induced by the agonist of cannabis receptors (SR-55940) in the mouse according to the method described by Regpue in K.O. in Magi)chapa, Nagueu 0... edz", 84 Ohooga IVI. Rgevv, 263-277 (1985).

In this test, the OE5O value for compounds of formula I is less than or equal to 5 Ωg/kg.

Compounds of formula I have low toxicity. their AUC is higher than 40 mg/kg when administered subcutaneously in mice.

The following examples illustrate the invention.

Example 1

To a solution of 61.4 mg of 1-(bis(4-chlorophenyl)methyl-azetidin-3-ylamine in 3 cm3 of dichloromethane, 69.3 mm3 of triethylamine and 110 mg of thien-2-yl-sulfonyl chloride are successively added at room temperature in an argon atmosphere. After 68 hours of stirring at room temperature temperature, the reaction mixture is injected into the Vopi EiIshF cartridge

ZS (Ссм3/500mg), sequentially eluting twice with 2cm3 of dichloromethane and then twice with 2cm3 of a 1M solution of ammonia in methanol. Ammonia fractions are combined and evaporated to dryness under reduced pressure (2.7 kPa). The obtained residue is dissolved in 5 cm3 of dichloromethane, washed three times with three cm3 of distilled water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). Obtained in this way bOmg IM-(1-

I(bis(4-chlorophenyl)methyl|azetidin-3-yluhyen-2-yl-sulfonamide in the form of a cream-colored foamy mass

NMR spectrum of "H (30Omgz, SOS", b in m.ch.): 2.77 (t split, 9-7 and 2Hz:2H); 3.40 (t split, 9-7 and 2Hz:2H ); 4.06 (m/n); 4.21 (syn); from 4.85 to 5.25 (m stretched: 1H); 7.06 (t, 9U-4.5HzC1H); from 7.15 up to 7.35 (m:8H); 7.58 (m:2H)I. 1-(Bis(4-chlorophenyl)methyl|azetidin-3-ylamine can be obtained in the following way: up to 27g of 1-Ibis(4- chlorophenyl)methyl|azetidin-3-yl ether of methanesulfonic acid, placed in an autoclave pre-cooled to -60"C, add 400 cm3 of a mixture of methanol and liquid ammonia (50/50 by volume).

The reaction mixture is stirred for 24 hours at 60"C, left in the air to evaporate ammonia, and then evaporated under reduced pressure (2.7 kPa). The residue is absorbed in 500 cm3 of 0.37 N aqueous sodium hydroxide solution and extracted four times with 500 cm3 of diethyl ether. The combined organic phases are successively washed twice with 100 cm3 of distilled water and 100 cm3 of saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The resulting residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol (95/5 by volume)). 14.2 g of 1-Bis(4-chlorophenyl)methyl|azetidin-3-ylamine are obtained in the form of an oil that solidifies with the formation of a cream-colored solid. 1-(Bis(4-chlorophenyl)methyl| azetidin-Z-yl ether of methanesulfonic acid can be obtained in the following way: to a solution of 12 g of 1-I|bis(4-chlorophenyl)methyl|azetidin-Z-ol in 200 cm3 of dichloromethane, 3.5 cm3 of methylsulfonyl chloride is added for 10 minutes under argon, cooled to 5 " and during 3.8 cm3 of pyridine is added for 10 minutes. After stirring for 30 minutes at 52 and then 20 hours at 202C, the reaction mixture is diluted with 100 cm3 of water and 100 cm3 of dichloromethane, after which the mixture is filtered and the phases are separated. 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 subjected to chromatography on a column with silica gel (granulometry: 0.063-0.200 mm, height 40 cm, diameter 3.0 cm), eluting under argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting fractions of with a volume of 100 cm3. Fractions 4-15 are combined and evaporated to dryness under reduced pressure (2.7 kPa), obtaining 6.8 g of 1-bis(4-chlorophenyl)methyl|azetidin-3-yl ether of methanesulfonic acid in the form of a yellow oil. 1-(Bis(4-chlorophenyl)methyl|Iazetidin-3-ol can be obtained according to the sequence of operations described by KATKITAKU A.K. with co-author. U. Neigegosusi. Spet., 271 (1994), starting from 35.5g hydrochloride (bis(4-chlorophenyl)methyliamine and 11.0 cm3 of epichlorohydrin. 9.0 g of 1-bis(4-chlorophenyl)methyl|azetidin-3-ol is isolated.

Hydrochloride (bis(4-chlorophenyl)umethyl|Iamine can be obtained by the method described by SBKIZAK M. with a co-author. U. Mei. Spet., 885 (1973).

Example 2

Repeating the sequence of operations of example 1, but starting with 124 mg of 4-methoxybenzenesulfonyl chloride, 12 mg of M-(11-bis(4-chlorophenyl)methyl|azetidin-3-yl)-4-methoxybenzenesulfonamide is obtained in the form of a cream-colored varnish (NMR spectrum "H ( Zbomgz, SOS", 6 in m.h.): 2.7 (t split, U-7 and 2Hts:2H); 3.35 (t split, U-7 and 2Hts:2H); 3.85 (c:ZN); 3.94 (m:1H); 4.18 (c:1H); 4.83 (d, U-9Hz:1n); 6.94 (d lat., U59Hz:2H); 7.22 (s: 8H); 7.75 (d width, U-9Hz: 2NI.

Example C

Repeating the sequence of operations of example 1, but starting from 140 mg of 4-acetamidophenolsulfonyl chloride, 13 mg of M-I4-(4-(1-(bis(4-chlorophenyl)methyl|azetidin-3-yl)usulfamoyl)phenyl|iacetamide is obtained in the form of cream lacquer color (H NMR spectrum (300 MHz, SOCIz, 6 in m.p.): 2.26 (c:HN); 2.74 (t split, 0-7 and 2HC:2H); 3.39 (t split, U-7 and 2Hts:2H); 4.01 (m/n); 4.22 (s1H); 4.92 (d, u9Hts:1H); 7.32 (m:8H); 7.49 ( c width.1H); 7.68 (width width, U-9Hz:2H); 7.81 (width width, U-9Hz:2NI.

Example 4

Repeating the sequence of operations of example 1, but starting from 114 mg of 4-methylphenylsulfonyl chloride, 19 mg of M-(11-bis(4-chlorophenyl)methyl|azetidin-3-yl)-4-methylphenylsulfonamide is obtained in the form of a colorless varnish (NMR spectrum "H (30Ω , SOSI", 5 in m.ch.): 2.42 (c:ZN); 2.71 (t split, 9-7 and 2HC:2H); 3.36 (t split, 9-7 and 2Hz2H); 3.97 (m:1H); 4.19 (s:1H); 4.81 (d, 9U-9.5Hz:1H); from 7.15 to 7.40 (m:10H); 7.71 (with lat., y-8.5HzC:2H)).

Example 5

Repeating the sequence of operations of example 1, but leaving Kk! 142 mg of 3,4-dimethoxyphenylsulfonyl chloride, 10 mg of M-11-bis(4-chlorophenyl)methyl|azetidin-3-yl)-3,4-dimethoxyphenylsulfonamide is obtained in the form of a cream-colored varnish (NMR spectrum "H (300mg, SOC", 6 in m.ch.): 2.72 (t split., 9U-7.5Hz:2H); 3.37 (t width., U-7.5Hz:2H); from 3.85 to 4.00 (m:1H); 3.91 (s:ZN); 3.93 (s:ZN); 4.19 (s1H); 4.84 (d, U-9Hz:1H); 6.90 (d, 9-8.5Hz:1H); 7.23 (m:8H); 7.29 (d, U-52Hz:1H); 7.43 (dd, U-8.5 and 2Hz:1H)).

Example 6

Repeating the sequence of operations of example 1, but starting from 117 mg of 3-fluorophenylsulfonyl chloride, 13.5 mg of M-(1-(bis(4-chlorophenyl)methyl|azetidin-3-yl-3-fluorophenylsulfonamide) is obtained in the form of a cream-colored varnish (NMR spectrum " H (400mhz, SOSIz, 6 in m.h.): 2.79 (t split, U-7 and 2Hz:2H); 3.43 (t split, 9-7 and 2Hz:2H); 4, 05 (m'1N); 4.24 (s/1N); 4.91 (m:"1N); from 7.20 to 7.40 (m:9N); from 7.50 to 7.65 (m :2H); 7.67 (d width, uU58Hz1H)|.

Example 7

Repeating the sequence of operations of example 1, but starting from 147 mg of 3,4-dichlorophenylsulfonyl chloride, 20 mg of M-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)y-3,4-dichlorophenylsulfonamide is obtained in the form of a cream-colored varnish ( NMR spectrum of "H (ZbOmgc, SOS", b in m.ch.): 2.77 (t split, 9-7 and 2Hz:2H); 3.40 (t split, uU-7 and 2Hz2H); 3.98 (m:1H); 4.21 (c1H); from 4.85 to 5.15 (m:1H); from 7.20 to 7.35 (m:8H); 7.57 (d, 9-8.5HzC:1H); 7.65 (dd, U-8.5 and 2Hz:1H); 7.93 (d, U52Hz1H)).

Example 8

Repeating the sequence of operations of example 1, but starting from 121 mg of 3-cyanophenylsulfonyl chloride, 21 mg of M-(11-bis(4-chlorophenyl)methyl|azetidin-3-yl-3-cyanophenylsulfonamide is obtained in the form of a cream-colored varnish (NMR spectrum "H (Zbomgz , SOS", 5 in m.h.): 2.76 (t split, 9U-7 and 2Hz:2H); 3.39 (t split, 9-7 and 2Hz:2H); 3.99 ( m:1H); 4.21 (s1H); from 4.80 to 5.60 (m very stretched: H); from 7.15 to 7.35 (m:8H); 7.65 (t, U- 8Hz: 1); 7.86 (width, U-8Hz:1H); 8.05 (width, U-58Hz:1H); 8.13 (width 1 NO.

Example 9

Repeating the sequence of operations of example 1, but leaving Kk! 142 mg of 2,5-dimethoxyphenylsulfonyl chloride, 31 mg of M-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2,5-dimethoxyphenylsulfonamide is obtained in the form of a cream-colored varnish (NMR spectrum "H (Zbomgz, SOCIz, 5 in m.h.): 2.73 (t split, 9U-7 and 2Hts:2H); 3.27 (t split, 9U-7 and 2Hts:2H); 3.80 (c:ZN); from 3.85 to 4.00 (m:1H); 3.94 (s:ZH); 4.19 (s:1H); 5.32 (d, U-8Hz:1H); 6.94 (d .

Example 10

Repeating the sequence of operations of example 1, but starting with 147 mg of 3-trifluoromethylphenylsulfonyl chloride, Zm M-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-3-trifluoromethylphenylsulfonamide is obtained in the form of a cream-colored varnish (NMR spectrum "H ( Zb0omtz, SOS", 6 in m.h.): 2.19 (t split, U-7 and 2Hz:2H); 3.41 (t split, U-7 and 2Hz:2H); 4.03 (m:1H); 4.23 (s1H); from 4.80 to 5.10 (m stretched: 1H); from 7.20 to 7.35 (m:8H); 7.68 (t, 9U- 8Hz:1H); 7.87 (d width, U-8Hz:1H); 8.05 (d width, U-8Hz:1H); 8.15 (c width.1H)|.

Example 11

Repeating the sequence of operations of example 1, but starting from 13 mg of naphth-2-ylsulfonyl chloride, 20 mg of M-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl naphth-2-ylsulfonamide is obtained in the form of a cream-colored varnish (NMR spectrum "H (400 MHz, SOS", b in m.ch.): 2.74 (m:2N); 3.35 (m:2N); 4.02 (m.1N); 4.17 (s1N); 4, 96 (m.1H); from 7.10 to 7.30 (m:8H); 7.64 (m:2H); 7.78 (dd, 9-7 and 1.5HC:1H); from 7 .90 to 8.05 (m:ZN); 8.41 (with width 1N)|.

Example 12

Repeating the sequence of operations of example 1, but starting from 13bmg of naphth-1-ylsulfonyl chloride,

receive 52 mg of M-11-(bis(4-chlorophenyl)methyl|azetidin-3-ylunapht-1-ylsulfonamide in the form of a cream-colored varnish (NMR spectrum "H (30Omgz, SOSI"), b in ppm): 2, 63 (t split, 9-7 and 2HC:2N); 3.20 (t split, U-7 and 2HC:2N); 3.90 (m:1N); 4.12 (c:1n); 5.26 (m:1H); 7.16 (m:8H); 7.52 (t, 9U-8Hz:1H); from 7.55 to 7.75 (m:2H); 7.95 (d , 98.5HzC:1H); 8.06 (d, U-28.5Hz:1H); 8.23 (dd, 9-2:7.5 and 1Hz:1H); 8.64 (d, uU- 8.5HA4:1H)|.

Example 13

Repeating the sequence of operations of example 1, but leaving Kk! 128 mg of 3,A-difluorophenylsulfonyl chloride, obtain the mass of M-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-3,4-difluorophenylsulfonamide in the form of a cream-colored varnish (NMR spectrum "H (Zbomgz, SOCI", 6 in m.ch.): 2.76 (t width, U9-7.5HzC:2H); 3.39 (t width, 9U-7.5HzC:2H); 3.98 (m:1H) ; 4.20 (with width 1H); from 4.85 to 5.25 (m stretched: 1H); from 7.15 to 7.35 (m: 9H); from 7.55 to 7.75 (m :2H)|.

Example 14

Repeating the sequence of operations of example 1, but starting from 108 mg of 1-methylimidazole-4-sulfonyl chloride, 22 mg of M-/1-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-1-methyl-1-H-imidazole is obtained -4-yl-sulfonamide in the form of a cream-colored foamy mass (NMR spectrum "H (300 MHz, SOCIz with the addition of a few drops of SOZSOOY ai4, 5 in m.p.): 3.22 (m:2H); 3.67 (m :2H); 3.74 (s:ZH); 4.10 (m:1H); 4.65 (s lat.:1H); 7.27 (m:8H); 7.47 (d lat., 9U-1Hz:1H); 7.53Z (width, U-1Hz1 NO.

Example 15

Repeating the sequence of operations of example 1, but starting from 152 mg of 4-acetamido-3-chlorophenylsulfonyl chloride, 9 mg of M-I4-(M-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)usulfamoyl)-2-chlorophenyl is obtained acetamide in the form of a cream-colored foamy mass (H NMR spectrum (Zbomgtz, SOS), 6 in m.h.): 2.30 (c:3H); 2.73 (m:2H); 3.38 (m :2Н); 3.97 (m:1Н); 4.19 (s/1Н); 7.24 (с:8Н); 7.70 (dd, 9-7 and 1.5Hz:1Н); 7, 78 (with width 1); 7.86 (d, 9-1.5 HzC:1H); 8.61 (d, 9-7 Hz1H)).

Example 16

To a solution of 0.7g of 1-(bis(4-chlorophenyl)methyl|azetidin-3-ylamine in 25cm3 of dichloromethane, 0.79cm3 of triethylamine is added at room temperature in an argon atmosphere. The mixture is cooled to 02С, after which a solution of 1.2g of pyridine is added. Z-ylsulfonyl chloride in 25 cm3 of dichloromethane and stirred for 16 hours at room temperature.

The reaction mixture is diluted with 50 cm3 of dichloromethane and washed twice with 25 cm3 of distilled water. 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 silica gel (eluent: dichloromethane/methanol (97.5/2.5 by volume)! obtaining 0.7 g of M-11-Ibis(4-chlorophenyl)umethyl|azetidine-3-ylpyrid- C3-ylsulfonamide in the form of a cream-colored foamy mass that hardens in the presence of isopropyl alcohol to form a cream-colored powder with a melting point of 164"70.

Pyrid-Z-ylsulfonyl chloride can be obtained by the method described by Vgeap R. in co. Zupipeviv, 10, 833-4 (1983).

Example 17

0.214 g of 4-fluorophenylsulfonyl chloride and 0.28 cm3 of triethylamine are added to a solution of 0.307 g of 1-bis(4-chlorophenyl)methyl|iazetidine-Z-ylamine in 10 cm3 of dichloromethane at room temperature in an argon atmosphere.

After 16 hours of stirring at room temperature, the reaction mixture is washed with 10 cm3 of distilled water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa).

The resulting residue is purified by flash chromatography on silica gel. Eluent: dichloromethane/ethyl acetate gradient (100/0 to 95/5 by volume) | 0.18 g of M-(1-bis(4-chlorophenyl)methyl|azetidin-3-yl-4-fluorophenylsulfonamide is obtained in the form of a white foamy mass (NMR spectrum "H (30Omgz, SOCI»z, b in ppm) : 2.74 (t width, U-7.5HzC:2H); 2.39 (t width, U-7.5Hz:2H); 3.98 (m:1n); 4.20 (sn) ; 4.79 (d, 9-9Hz1H); from 7.10 to 7.35 (mon); 7.86 (m:2H)).

Example 18

Repeating the sequence of operations of example 17, but starting from 0.25 g of quinol-8-ylsulfonyl chloride, 0.36 g of M-/1-(bis(4-chlorophenyl)methyl|azetidin-3-yl)quinol-8-ylsulfonamide is obtained in the form of white powder

NMR spectrum of "H (30 ohms, SOS", b in m.ch.): 2.63 (t split, 9-7 and 2Hz:2H); 3.16 (t split, U-7 and 2Hz:2H ); 3.98 (m:1H); 4.11 (c:1H); 6.77 (d, U-8HC: 1); 7.15 (m:8H); 7.61 (dd, 9- 8 and 4Hz:1H); 7.64 (dd, 9U-8 and 7.5Hz:1H); 8.06 (dd, 9-8 and 1.5Hz:1H); 8.30 (dd, 9-8 and 1.5Hz:1H); 8.40 (dd, 9U-7.5 and 1.5Hz:1H); 9.09 (dd, 9U-4 and 1.5HzC:1H)).

Example 19

Repeating the sequence of operations of example 17, but starting from 0.14 cm3 of phenylsulfonyl chloride, 0.35 g of M-(1-bis(4-chlorophenyl)methyl|iazetidine-3-ylphenylsulfonamide is obtained in the form of a white powder

NMR spectrum of "H (30 ΩHz, SOSI", 5 in m.h.): 2.75 (t width, 9-7.5 Hz:2H); 3.40 (t width, 9-7.5 Hz:2H ); 4.03 (m:1H); 4.22 (s:1H); 4.79 (d, 9U-10Hz1H); 7.31 (s:8H); from 7.45 to 7.65 (m :ZN); 7.87 (d width, U-7.5HZ:2NI.

Example 20

Repeating the sequence of operations of example 17, but starting from 0.21 g of phenylmethylsulfonyl chloride, 0.27 g of M-(1-bis(4-chlorophenyl)methyl|iazetidine-Z-iluphenylmethylsulfonamide is obtained in the form of a white powder (NMR spectrum "H (400mg, SOC" , 6 in m.ch.): 2.76 (t split., 9-7 and 2Hts:2N); 3.41 (t split., 9-7 and 2Hts:2H); 3.85 (m:1H ); 4.20 (s:1H); 4.23 (s:2H); 4.46 (d, 9U-9Hz:1H); from 7.25 to 7.45 (m:13H)).

Example 21

Repeating the sequence of operations of example 17, but starting with 0.42 g of 3,5-difluorophenylsulfonyl chloride in 30 cm3 of dichloromethane, and washing the organic phase twice with 20 cm3 of distilled water. After purification by flash chromatography on silica gel (eluent: dichloromethane/methanol gradient (100/0 to 95/5 by volume)) | obtain

O,1hoM-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-3,5-difluorophenylsulfonamide in the form of a yellow powder

IS NMR spectrum of "H (30 ohms, SOS", b in m.ch.): 2.77 (t split, 9U-7 and 2Hz:2H); 3.41 (t split, U-7 and 2Hz:2H ); 4.01 (m:1H); 4.21 (s1H); 4.90 (d, 9-9Hz:1H); 7.02 (tt, 9U-8.5 and 2.5Hz:1H); from 7.20 to 7.35 (m:8H); 7.38 (m:2H)I.

C3,5-difluorophenylsulfonyl chloride can be obtained by the method described in patent EE 9615887.

Example 22

Repeating the sequence of operations of example 21, but starting from 0.21 g of pyrid-2-ylsulfonyl chloride and 0.17 cm3 of triethylamine, and washing the organic phase twice with 30 cm3 of distilled water, after purification by flash chromatography on silica gel (eluent: a gradient of dichloromethane/methanol (100/0 up to 98/2 by volume) | obtain 0.3 g of M-11-(bis(4-chlorophenyl)methyl|azetidin-3-ylpyrid-2-ylsulfonamide in the form of a white powder | NMR spectrum

IN (Z0omhz, SOS", 6 in m.h.): 2.78 (ton split, 9U-7 and 2Hz:2H); 3.35 (t split, 9-7 and 2Hz:2H); 4.12 (m1H); 420 (c:1H); 5.30 (d, 9U-9Hts1H); from 7.15 to 7.35 (m:8H); 7.47 (ddd, U9-7.5 and 5 and 1Hz1H); 7.90 (ton split, 9U-7.5 and 2Hz1H); 7.98 (width, 9U-7.5Hz: 1H); 8.65 (d width, U-5HZ: 1).

Pyrid-2-ylsulfonyl chloride can be obtained by the method described by Sogeu E.), U. Ogd. Spent (1989) 54(2), 389-93.

Example 23

To a solution of 0.24 g of 1-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-(3,5-difluorobenzene)usulfonamide in bcm3 of dimethyl sulfoxide, 0.104 cm3 of pyrrolidine is added at room temperature and the mixture is heated for 18 hours at 90C. After that, the reaction mixture is diluted with 3330 cm? dichloromethane and washed three times with 30 cm3 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 purified by flash chromatography with dichloromethane as eluent.

Receive 50 mg of /M-11-(bis(4-chlorophent)methyl|azetidin-3-t)-3-fluoro-5-pyrrolidin-1-ylphenylsulfonamide in the form of a white powder (NMR spectrum "H (bbOmgz, SOCIz with the addition of several drops of SOZSOOO a4, 6 in m.h.): 2.04 (m:4H), from 3.20 to 3.35 (m:bH), 3.60 (t, U-8.5Hz:2H); 4.14 (m:1H); 4.57 (s:1H); 6.31 (d width, U-11.5HzC:1H); 6.70 (d width, U-8.5Hz:1H ); 6.72 (with width 1N); from 7.20 to 7.35 (m:8N)).

Example 24

To the 8095th suspension of 20.5 mg of sodium hydride in 10 cm3 of tetrahydrofuran, a solution of 0.26 g of M-(1-(bis(4-chlorophenyl)methyl|azetidin-3-yl-4-fluorophenylsulfonamide) in 5 cm3 of tetrahydrofuran is added at room temperature in an argon atmosphere After stirring for 1 hour at 20"C, bomm?iodomethane is added, the suspension is stirred for another 16 hours, and 30 cm3 of ethyl acetate and 20 cm3 of distilled water are added. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The residue is purified by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate (90/10 by volume)), thus obtaining 19 mg of M-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)u.M- methyl-4-fluorophenylsulfonamide in the form of a white powder

NMR spectrum of "H (30 ohms, SOS", b in m.h.): 2.69 (s:HN); 3.02 (t split, 9-7 and 2HzC:2H); 3.35 (t split ., 927 and 2HC:2H); 3.91 (m:1H); 4.27 (s1H); from 7.15 to 7.35 (m:10H); 7.75 (dd, 9-9 and 5HC :2H)).

Example 25

Repeating the sequence of operations of example 24, but starting from 0.25 g of /M-(1-Ibis(4-chlorophenyl)methyl|azetidin-3-ilquinol-8-ylsulfonamide and 18 mg of 8095 sodium hydride, after purification by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate (80/20 by volume) | obtain 70 mg of M-(1-

Ibis(4-chlorophenyl)methyl|azetidin-3-yl)quinol-Z-ylsulfonamide in the form of a white powder (NMR spectrum "H (30mg, SOCI", b in ppm): from 3.00 to 3.10 (m:2N); 3.05 (s:ZN); 3.35 (m:2N); 4.27 (s/1N); 4.93 (m/1N); from 7.15 to 7.35 (m:8H); 7.50 (dd, U-8.5 and 4HzC:1H); 7.62 (dd, 9-8 and 8.5Hz:1H); 8.03 (dd, U-8, 5 and 1.5Hz:1H); 8.22 (dd, 98.5 and 1.5Hz:1H); 8.48 (dd, 9-8 and 1.5Hz:1H); 8.98 (dd, 9 -4 and 1.5Hz1H)|.

Example 26

Repeating the sequence of operations of example 24, but starting from 0.21 g of M-(1-bis(4-chlorophenyl)methyl|azetidin-3-iluphenylsulfonamide, 17 mg of 8095 sodium hydride and introducing iodomethane twice with an interval of 3 hours. Obtained in this way 8b0mg of M-(1-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-M- methylphenylsulfonamide in the form of a white varnish (NMR spectrum "H (ZbOmgc, SOCI3, 6 in ppm): 2.70 (c:ZN); 3.03 (t width, U9-7.5Hz:2H); 3.37 (t width, U9-7.5Hz:2H); 3.94 (m:1H); 4 .28 (s.IN); from 7.20 to 7.35 (m:8H); from 7.45 to 7.65 (m:ZH); 7.74 (d width, U-8Hz:2H) AND.

Example 27

Repeating the sequence of operations of example 26, but starting from 00.17 gM-(1-Ibis(4-chlorophenyl)methyl|azetidin-3-iluphenylmethylsulfonamide, 14 mg of 8095 sodium hydride and then stirring the mixture at 207"C for 48 hours, after purification by flash chromatography on silica gel (eluent: dichloromethane/ethyl acetate (95/5 by volume), 120 mg of M-11-|bis(4-chlorophenyl)methyl|azetidin-3-yl)-M-methyl(phenylmethane)sulfonamide are obtained in in the form of a white foamy mass |NMR spectrum of "H (Zb0O0mgz, SOS", b in m.p.): 2.81 (C:ZN); 2.88 (t split., 9U-7 and 2Hz:2H); 3 ,16 (ton split, U-7 and 2Hz:2Н); from 4.10 to 4.25 (m:4Н); from 7.20 to 7.40 (m.1ЗН)).

Example 28

To a solution of 0.412 g of benzene-1,3-disulfodichloride and 0.165 cm3 of triethylamine in 20 cm3 of acetonitrile, a solution of 0.0307 g of 1-I|bis(4-chlorophenyl)methyl|azetidine-Z-ylamine in 10 cm3 of acetonitrile is added dropwise at room temperature. After 3 hours of stirring at room temperature, 0.28 cm3 of 2095% ammonia solution is added and the mixture is left at room temperature. After 18 hours, the mixture is filtered and evaporated to dryness under reduced pressure (2.7 kPa). After chromatography on a column with silica gel (granulometry: 0.06-0.200 mm, height 35 cm, diameter 2 cm), eluting under argon pressure of 0.9 bar with dichloromethane, then with a mixture of dichloromethane 10% methanol and then with a mixture of dichloromethane 20695 methanol and collecting the fractions by volume

Zosm?3, fractions 23-34 are combined, evaporated to dryness under reduced pressure (2.7 kPa), obtaining 90 mg of M-(1-|bis(4-chlorophenyl)methyl|azetidin-3-yl-3-sulfamoylphenylsulfonamide in the form of a white solid substances (Spectr

NMR "H (30 ohms, SOSI", 6 in m.h.): 2.78 (t width, 9-7Hz:2H); 3.35 (t width, U-7Hz:2H); 4.01 (mn); 4.24 (sn); 5.27 (m:2H); 5.61 (m:1H); from 7.15 to 7.35 (m:8H); 7.67 (t, U -8Hz:1H); 8.04 (width, U-8Hz:1H); 8.12 (width,

U-8Hz:H); 8.49 (with a width of 1N)).

Example 29

To a solution of 80.1 mg of benzenesulfonylacetic acid and 27 mg of hydroxybenzotriazole in 0.5 cm3 of dimethylformamide, 0.031 cm3 of isopropyl carbodiimide, a solution of ZOmg 1-I(bis(4-chlorophenyl)methyl|azetidin-3-ylamine in 0 .5cm3 of anhydrous dichloromethane and 3cm3 of anhydrous dichloromethane. The reaction mixture is left for 17 hours at a temperature close to 237С and is loaded into a 5RE cartridge with a volume of 3cm3, containing the phase 5СХ pre-conditioned with methanol. After washing twice with 5cm3 of methanol and then 4cm3 0 , tons of ammonia methanol, the target product is eluted with 4 cm3 of 1 N ammonia methanol. The fraction containing the target product is evaporated in a stream of air at a temperature close to 45"C and then dried under reduced pressure (1 mbar) at a temperature close to 40"C. 2-benzenesulfonyl-M-(11-(bis(4-chlorophenyl)methyl|azetidin-3-ilyacetamide) is obtained in this way in the form of a white solid substance (NMR spectrum "H (500mg, SOC", b in ppm): 2.96 (m:2N ); 3.51 (m:2H); 4.00 (c:2H); 4.34 (m:1H); 4.48 (m:1H); 7.10 (m:1H); from 7.20 to 7.45 (m:8H); 7.57 (t, u8GHz:2H); 7.70 (t, U-8Hz:1H); 7.90 (d, U-8Hz:2H)).

Example 30

To a solution of 85.7 mg of toluenesulfonylacetic acid and 27 mg of hydroxybenzotriazole in 0.5 cm3 of dimethylformamide, 0.031 cm3 of isopropylcarbodiimide, a solution of ZOmg 1-I(bis(4-chlorophenyl)methyl|azetidin-Z-ylamine) is added in an inert atmosphere of argon at a temperature close to 23"С in 0.5cm3 of anhydrous dichloromethane and 3cm3 of anhydrous dichloromethane. The reaction mixture is left for 17 hours at a temperature close to 23"С, loaded into a 5RE cartridge with a volume of 3cm3, containing the phase 5СХ pre-conditioned with methanol. After washing twice with 5cm? of methanol and then 4 cm3 of 0.1 N ammonia methanol, the target product is eluted with 4 cm3 of 1 N ammonia methanol. The fraction containing the target product is evaporated in a stream of air at a temperature close to 45 "С and then dried under reduced pressure (1 mbar) at a temperature close to 40 "C. M-(1-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(toluene-4-sulfonyl)acetamide is obtained in the form of a yellow varnish (NMR spectrum "H (500mg, SOCI3, b in m.ch.): 2.85 (t, U«:7Hz:2Н); 3.07 (С:3ЗН) ; 3.48 (t, U9-7Hz:2H); 4.24 (c:1H); 4.49 (m'1H); 7.19 (d width, U-6Gu:1H); from 7.20 to 7.40 (m:8H); 8.40 (CH).

Example 31

Repeating the sequence of operations of example 30, starting from a solution of 85.7 mg of 3-chloro-4-methylsulfonylthiophene-2-carboxylic acid, 27 mg of hydroxybenzotriazole in 0.5 cm? of dimethylformamide, 0.031 cm3 of diisopropyl carbodiimide, a solution of ZbOmg 1-I(bis(4-chlorophenyl)methyl|iazetidine-Z-ylamine in 0.5 cm3 of anhydrous dichloromethane and 3 cm3 of anhydrous dichloromethane, obtain (3-chloro-4-methylsulfonylthiophene-2-carboxy) -/1-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)amide in the form of a yellow varnish (NMR spectrum "H (500mg, SOS with, in ppm): 2.44 (c:3H); 2.96 (m:2H); 3.52 (m:2H); 3.98 (s2H); 4.35 (m:1H); 4.49 (m:/1H); from 7.00 to 7 .30 (m stretched: 2H); from 7.20 to 7.45 (m:.10H); 7.76 (d, U-8HC: 2NI.

Example 32

Repeating the sequence of operations of example 30, leaving Kk! 96.1 mg of 3-(2-phenylethylenesulfonyl)upropionic acid, 27 mg of hydroxybenzotriazole, dissolved in 0.5 cm3 of dimethylformamide, 0.031 cm3 of diisopropylcarbodiimide, a solution of Zbmg 1-Ibis(4-chlorophenyl)methyl|azetidin-3-ylamine in 0.5 cm3 of anhydrous of dichloromethane and 3 cm3 of anhydrous dichloromethane, M-(1-bis(4-chlorophenyl)methyliazetidin-3-yl-3-(2-phenylethylenesulfonyl)propionamide is obtained in the form of a white foamy mass (Spectrum

NMR "H (500 MHz, SOSI", 6 ppm): 2.64 (t, 9-7Hz: 2H); 2.88 (m: 2H); 3.33 (t, 927Hz: 2H); 3.49 (m:2H); 4.29 (m1H); 4.48 (m/1H); from 5.90 to 6.15 (m stretched: 1H); 6.41 (d, 9-12HzC1H) 7.17 (d, U-12Hcy1H), from 7.20 to 7.35 (m:8H), 7.41 (m:ZH), 7.64 (m:2H).

Example 33

Repeating the sequence of operations of example 31, starting from 58.5 mg of 4-methylsulfonylbenzoic acid and 26.4 mg of hydroxybenzotriazole, dissolved in 0.5 cm3 of dimethylformamide, 0.0302 cm3 of diisopropylcarbodiimide, a solution of ZOmg of 1-Ibis(4-chlorophenyl)methyl|iazetidine-Z-ylamine in 0.5 cm? of anhydrous dichloromethane and Ccm3 of anhydrous dichloromethane, M-11-I(bis(4-chlorophenyl)methyl|azetidin-3-yl)-4-methylsulfonylbenzamide is obtained in the form of white crystals (NMR spectrum "H (300mg, SOCI3, b in m. h.): 3.03 (m:2H); 3.09 (s:ZN); 3.61 (t width, 9-7.5HZ:2H); 4.35 (s:1H); 4, 73 (m:1H); 6.55 (d width, 9U-7.5Hz:1H); from 7.20 to 7.35 (m:8H); 7.96 (d, U-8Hz:2H) ; 8.03 (d, U-8Hz:2NO.

Example 34

Repeating the sequence of operations of example 31, starting from 58.5 mg of 4-phenylsulfonylbenzoic acid and 26 4 mg of hydroxybenzotriazole, dissolved in 0.5 cm? of dimethylformamide, 0.0302 cm3 of diisopropylcarbodiimide, a solution of ZOmg of 1-Ibis(4-chlorophenyl)methyl|iazetidine-Z-ylamine in 0.5 cm? of anhydrous dichloromethane and Ccm3 of anhydrous dichloromethane, M-(1-Ibis(4-chlorophenyl)methyl|azetidin-3-yl-methanesulfonylbenzamide is obtained in the form of a varnish (NMR spectrum "H (300mg, SOC", b in ppm): 2.71 (t, 927.5 Hz:2H); 2.86 (m:2H); from 3.40 to 3.55 (m:4H); 4.26 (s:1H); 4.45 (m '1H); 6.22 (d width, 9-7.5HzC:1H); from 7.20 to 7.35 (m:8H); 7.59 (t width, U9-7.5Hz:2H ); 7.69 (tt, 9U-7.5 and 1.5Hz: 1H); 7.93 (width, U-7.5Hz: 2H).

Example 35

Repeating the sequence of operations of example 31, starting from 60.2 mg of 5-methylsulfonylthiophene-2-carboxylic acid and 26.4 mg of hydroxybenzotriazole, dissolved in 0.5 cm3 of dimethylformamide, 0.0302 cm3 of diisopropylcarbodiimide, a solution of Zbmg 1-Ibis(4-chlorophenyl)methyl|azetidine -Z-ylamine in 0.5 cm3 of anhydrous dichloromethane and 3 cm3 of anhydrous dichloromethane, obtaining (5-methylsulfonylthiophene-2-carboxy)-/1-I(bis(4-chlorophenyl)methyliazetidine-3-ylamide in the form of white crystals (NMR spectrum Н (З0Омгц, СОСИ», 6 in m.h.): 3.03 (m:2Н), 3.21 (с:З3Н), 3.57 (dd, 9-8 and 7.5HzС:2Н); 4.34 (s:/1H), 4.67 (m:1H), 6.40 (d width, 9-7.5 HzC:1H), from 7.20 to 7.35 (m:8H); 7.48 (d, U-4Hz1H); 7.67 (d, U54Hz1H)).

Example 36

Repeating the sequence of operations of example 31, starting from 71.9 mg of 5-methylsulfonyl-3-methyl-4-vinylthiophene-2-carboxylic acid, a solution of 26.4 mg of hydroxybenzotriazole in 0.5 cm3 of dimethylformamide, 0.0302 cm3 of diisopropylcarbodiimide, a solution of ZOmg 1-Ibis( 4-chlorophenyl)methyl|azetidin-Z-ylamine in 0.5 cm3 of anhydrous dichloromethane and 3 cm3 of anhydrous dichloromethane, obtaining (5-methylsulfonyl-3-methyl-4-vinylthiophene-2-carboxy)-/1-Ibis(4-chlorophenyl) methyl|azetidin-3-ilamide in the form of a white powder (NMR spectrum "H (30Omgz, SOC", 6 in mol): 2.47 (c:3H); 2.97 (m:2H); 3, 14 (c:ZN), 3.57 (dd, 928 and 7.5HC:2H), 4.32 (CH), 4.65 (m.1H);

5.69 (dd, 9-18 and 1HtsCyN); 5.77 (dd, 9-12 and 1HzC:1H); 6.30 (d lat., 9U-7.5HzC:1H); 6.96 (dd, 9-18 and 12/1H); from 7.20 to 7.35 (m:8H)|.

Example 37

Repeating the sequence of operations of example 31, starting from 62.6 mg of Z-methylsulfonylmethylbenzoic acid, a solution of 26.4 mg of hydroxybenzotriazole in 0.Bcm3 of dimethylformamide, 0.0302 cm3 of diisopropylcarbodiimide, a solution of 30 mg of 1-Ibis(4-chlorophenyl)methyl|azetidin-Z-ylamine in 0.5 cm3 of anhydrous dichloromethane and 3 cm3 of anhydrous dichloromethane give (5-methylsulfonyl-3-methyl-4-vinylthiophene-2-carboxy)-(1-bis(4-chlorophenyl)methyl|azetidin-3-yl)amide in the form of white needles (NMR spectrum "H (30Omg, (C03)250 ab with SOS additive", 6 in m.h.): 2.84 (s:ZN); 3.02 (t width, U9-7HC:2H) ; 3.48 (t, 9-7 HC:2H); 4.38 (s:ZN); 4.53 (m.1H); 7.21 (d, 9U-8HCC4H); 7.34 (d, 9U-8Hz:4H); 7.40 (t, 9U-7.5Hz1H); 7.53 (d width, 9U-7.5HzC:1H); 7.84 (d width, 9-7.5Hz :1H); 7.89 (with width 1H); 8.54 (d, 9U-7HzC1H)).

Example 38 (85)-M-1-(4-Chlorophenyl)pyrid-3-ylmethyl|azetidin-3-ylII-3,5-difluorobenzenesulfonamide can be obtained in the following way: to a mixture of 0.3 g of hydrobromide (A5)-3 -I(bromo(4-chlorophenyl)methylpyridine and 0.28 g of M-azetidin-3-yl-3,5-difluorobenzenesulfonamide hydrochloride in 20 cm of acetonitrile add 0.46 g of potassium carbonate and 41 mg of potassium iodide, after which the mixture is boiled for 4 hours. After cooling to a temperature close to 207"C, insoluble materials are removed by filtration and the mixture is evaporated to dryness under reduced pressure. The resulting residue is absorbed in 100 cm3 of ethyl acetate. The organic phase is washed twice with 50 cm3 of water, dried over magnesium sulfate in the presence of charcoal, filtered on celite and evaporated to dryness under reduced pressure. 230 mg of a yellow-hot solid is obtained, which is dissolved in a mixture of cyclohexane/ethyl acetate (50/50 by volume) and purified by pressure chromatography on a cartridge with 10 g of silica gel with the same eluent mixture at a flow rate of bcm3/min. Fractions 22-56 are combined and dry evaporate under reduced pressure, obtaining 100 mg of (85)-M-11-(4-chlorophenyl)pyridin-3-ylmethyl|azetidin-3-yl)-3,5-difluorobenzenesulfonamide in the form of a pale yellow foamy mass melting at 707С NMR spectrum "H (30 ohms, SOSI", b in m.h.): 2.81 (m:2H); 3.42 (m:2H); 4.03 (m:1H); 4.29 (c: 1H); 5.43 (d, U-9Hz:1H); 7.01 (tt, U-9 and 2.5 Hz: 1H); 7.22 (dd, 9-8 and 5Hz:1H); 7.28 (m:4H); 7.36 (m:2H); 7.62 (d width, U-8Hz:1H); 8.48 (dd, 9-5 and 1Htsin); 8.59 (d, U-1Hcy1H)I. (85)-3-IBromo(4-chlorophenylmethylpyridine) is obtained in the following way: to 1.5 g of (4-chlorophenyl)pyrid-3-ylmethanol, 3.5 cm? of a 4895 solution of hydrobromic acid in acetic acid and 1 cm3 of acetyl bromide are added. this way, the amber-colored mixture is boiled for 4 hours, after which it is cooled to 20"C, evaporated to dryness at 40"C and a pressure of 2.7kPa, which gives 1.53g of (AB5)-3-I(bromo(4-chlorophenyl )methylpyridine (K-75/90, 254 nm, plates with silica gel, reference 1.05719, Megsk KdaA, 64271

Wagtweiiii, Germany).

Hydrochloride of M-azetidin-3-yl-3,5-difluorobenzenesulfonylamide can be obtained in the following way: hydrogenate a solution of 7.5 g of M-(1-benzhydrylazetidin-3-yl)-3 in a hydrogenator with a volume of 2000 cm3 for about 20 hours ,5-difluorobenzenesulfonylamide in a mixture of 10 cm3 of concentrated (3695 mass) hydrochloric acid, 1.7 cm3 of acetic acid and 500 cm3 of methanol in the presence of 4.21 g of palladium hydroxide on charcoal (2095 mass of the catalyst) under a pressure of 1.7 bar of hydrogen. The catalyst is removed by filtration through a layer of celite, after which the filtrate is evaporated to dryness under reduced pressure. The resulting residue is triturated for approximately 16 hours with 100 cm³ of isopropyl ether at a temperature close to 20°C. The suspension is filtered and the solid residue is triturated again with 100 cm³ of diethyl ether at a temperature close to 20°C. After that, the filtered paste is dried under reduced pressure at a temperature close to 40"C, obtaining 5.52 g of M-azetidin-3-yl-3,5-difluorobenzenesulfonylamide hydrochloride, in the form of a white powder.

M-(1-benzhydrylazetidin-3-yl)-3,5-difluorobenzenesulfonylamide can be obtained in the following way: to a suspension of 5g of 1-benzhydrylazetidin-3-ylamine in 80cm3 of dichloromethane at a temperature close to 20, 5.1g of 3.5 -difluorobenzenesulfonyl chloride and then 4.2 cm3 of triethylamine. After 20 hours of stirring at a temperature close to 207C, 50 cm3 of water is added, the organic phase is separated, washed twice with 50 cm3 of water, dried over magnesium sulfate and evaporated under reduced pressure. In this way, 8.99 g of yellow oil, which gradually crystallizes, is obtained. 4.5 g of this product is purified by pressure chromatography on 500 g of Artichoke silica gel (particle diameter 0.020-0.045 mm), eluting with a mixture of methanol/dichloromethane (1/99 by volume). Fractions containing the target product were combined and evaporated to dryness under reduced pressure, yielding 3.58 g of M-(1-benzhydrylazetidin-3-yl)-3,5-difluorobenzenesulfonylamide. in the form of a beige powder. The remaining amount of yellow oil obtained above is purified under the same conditions, obtaining 3.92 g of M-(i-benzhydrylazetidin-3-yl)-3,5-difluorobenzenesulfonylamide as a beige powder. 1-Benzhydrylazetidin-3-ylamine can be prepared as described in 4. Apirioi., 39(9), 1243-1256, 1986.

C3,5-difluorobenzenesulfonyl chloride can be obtained as described in EC patent 2757509.

Example 39 (85)-M-1-(4-Chlorophenyl)pyrimid-3-ylmethyl-Iazetidin-3-yl)-3,5-difluorobenzenesulfonamide can be obtained by repeating the sequence of operations to obtain /(A5)-M-11-( 4-chlorophenyl)pyrid-3-ylmethyl|azetidin-3-ylyl-3,5-difluorobenzenesulfonamide: based on 0.64 g of hydrobromide (K5)-5-Ibromo(4-chlorophenyl)methylpyrimidine, 0.5 g of M-azetidine hydrochloride 3-yl-3,5-difluorobenzenesulfonamide in 20 cm3 of acetonitrile, 1.213 g of potassium carbonate and 379 mg of potassium iodide, thereby obtaining 71 mg of (K5)-M-11-(4-chlorophenyl)pyrimidin-5-ylmethyl|azetidin-3-yl -3,5-difluorobenzenesulfonamide in the form of a yellow foamy mass

NMR spectrum of "H (Zbomgtz, SOS", 6 in m.h.): 2.83 (m:2H); 3.46 (m:2H); 4.03 (m:1H); 4.30 (s :1H); 5.00 (d, U-9Hz 1); 7.04 (tt, 9-9 and 2.5HzC1H); from 7.20 to 7.35 (m:4H); 7.37 (m :2H); 8.69 (s:2H);9.09(s:1H). (85)-5-IBromo(4-chlorophenyl)methylpyrimidine can be obtained by repeating the sequence of operations for obtaining (K5)-3- And (bromo-(4-chlorophenyl)methyl|pyridine, starting from (4-chlorophenyl)pyridin-5-ylmethanol. (4-chlorophenyl)pyridin-5-ylmethanol can be obtained as in the preparation of (4-chlorophenyl)pyridin-3 - ylmethanol, based on pyrimidine-5-carboxaldehyde and 4-chlorophenylmagnesium bromide.

Medicinal products according to the invention are a compound of formula I! or an isomer or salt of this compound in its pure state, or in the form of a composition in which this compound is associated with any other pharmaceutically acceptable 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 may also contain other substances other than diluents, such as one or more lubricating agents such as magnesium stearate or talc, a dye, a coating (dragée) 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.

Sterile compositions for parenteral use can be mainly aqueous or non-aqueous solutions, suspensions or emulsions. Water, propylene glycol, polyethylene glycol, vegetable oils (especially olive oil), acceptable for injection organic esters such as ethyl oleate, or other suitable organic solvents can be used as a solvent or carrier. These compositions may also contain auxiliaries, including wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be carried out in many ways, for example, by aseptic filtration, the 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.

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, the compounds of the invention may, in particular, be used for the treatment and/or prevention of psychoses, including schizophrenia, anxiety, depression, epilepsy, neurodegeneration, brain and spinal cord disorders, cognitive impairment, cranial trauma, panic attacks, peripheral neuropathies . and abuse of alcohol or drugs (such as opioids, barbiturates, cannabis, cocaine nom, amphetamines, phencyclide, hallucinogens, benzodiazepines), such as analgesics or enhancers of the analgesic activity of narcotic and non-narcotic drugs.

Doses depend on the desired effect, the duration of treatment and the method of administration used.

Usually they range from 5 to 1000 mg per day for oral use in an adult, while single doses vary from 1 to 250 mg of the active substance.

In general, the physician should determine the appropriate dosage depending on the age, weight, and other factors relevant to the treatment of the individual undergoing such treatment.

The compositions of the invention are illustrated by the following examples:

EXAMPLE

Using conventional methods, prepare gelatin capsules with a dose of 50 mg of the active product, which have the following composition:

The compound of the formula | 50 mg

Cellulose 18 mg

Lactose 55 mg

Colloidal silica 1 mg

Sodium carboxymethyl starch 10 mg

Talc 10 mg

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 the formula | 50 mg

Lactose 104 mg

Cellulose 4Omg

Polyvidone 10 mg

Sodium carboxymethyl starch g22mMg

Talc 10 mg

Magnesium stearate 2 mg

Colloidal silica 2 mg

A mixture of hydroxymethyl cellulose, 245 mg in glycerin and titanium oxide final (72/3.5/24.5) in a sufficient amount of a tablet with a shell

EXAMPLE S

A solution for injections is prepared, which contains 1 mg of the active product, which has the following composition:

The compound of the formula | 10 mg

Benzoic acid 80 mg

Benzyl alcohol O,Oobml

Sodium benzoate 80mg 9595th ethanol O4ml

Sodium hydroxide 24mMg

Propylene glycol 1, b6 ml

Sufficient water up to 4 mL

Claims (14)

1. A pharmaceutical composition containing as an active ingredient a compound of the formula: KE, in ish Kk, Y 0 in which Ai means the radical -MHCOV" or -M(H5)-X-Hv, U means CO or 50", Vg and Ez , the same or different, mean or an aromatic radical selected from phenyl, naphthyl and indenyl, which may be unsubstituted or substituted by one or more substituents: halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -СбО-айК, cyano, -СООН, -СбООайкК, -СОМА;НАв, -СО-МН-МРАзВО, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -aik-MA;Ag; or a heteroaromatic radical selected from the rings: benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, pyrimidinyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 1,2, 3,4-tetrahydroisoquinolyl, thiazolyl and thienyl, which can be unsubstituted or substituted by halogen, alkyl, alkyl, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -СООН, -СООАЙК, -СО-МН-МА»АЙО, -СОМНА7Нв, -АЙК -MA»Vio, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfonylalkyl, alkylsulfonylalkyl or hydroxyalkyl; Ba means the radical ayl-502-Bi1, ayl-502-CH-CH-Bi, Nei substituted by a group -502-Ni, or phenyl substituted by a group -502-Ni1 or -aik-5O05-Ni1; A5 means a hydrogen atom or an alkyl radical; Ae means a phenylalkyl radical, Nei or Ag; IN; and B", the same or different, mean a hydrogen atom or an alkyl radical, or EK"; and Kv, together with the nitrogen atom to which they are attached, 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 several alkyls; B" and Ko, the same or different, mean a hydrogen atom or an alkyl radical, -co-alkyl, cycloalkyl, alkylcycloalkyl, -aik-O-alkyl or hydroxyalkyl, or Ke and Kio, together with the nitrogen atom to which they are connected, form saturated or unsaturated 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 radicals: alkyl, -COaik, -bOpak, - bOo- MNaic, -C5-MnNaic, oxo, hydroxyalkyl, -aic-O-aic or -CO-MH»5; Vii means an alkyl radical, Ag or Ni; Ag means a phenyl, naphthyl or indenyl radical, which can be replaced by one or more substituents: halogen, alkyl, alkoxy, cyano, -СбО-айк, -СООН, -СбО0байк, -СОМАх2Виз, -СО-МН-МАза4Вив, alkylsulfanyl, alkylsulfinyl , alkylsulfonyl, aik-MAchaVii5, -MAch14Bi alkylthioalkyl, formyl, hydroxy, hydroxyalkyl, Nei, -O-aik-MH- cycloalkyl, ОСЕ3, СЕ3, -МН-СО-айк, -502МНг, -МН-СОСН»3, - MH-cOOaik, Nei, or two adjacent carbon atoms connected by dioxymethylene; It means an unsaturated or saturated mono- or bicyclic heterocycle having from 3 to 10 members containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, and which may be substituted by one or more radicals: alkyl, alkoxy, vinyl, halogen, alkoxycarbonyl, oxo, hydroxy, OSE3 or CE3, and nitrogen-containing heterocycles can be in the form of M-oxides; Are Wi" and Kis the same or different, do they mean a hydrogen atom or an alkyl radical, or Ki?" and Keys, together with the nitrogen atom to which they are attached, 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 several alkyl radicals; Via and E5, the same or different, mean a hydrogen atom or an alkyl radical, -SOdaik, cycloalkyl, alkylcycloalkyl, -aik- O-aikK or hydroxyalkyl, or Kia and Ki5, 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, which may contain a second heteroatom selected from oxygen, sulfur, and nitrogen, and be substituted by one or more radicals: alkyl, -COaik, -bOpak, - bOo-MNaik , -C5-MnAlkyl, oxo, hydroxyalkyl, -alk-O-alk or -CO-MH»5; ak means an alkyl or alkylene radical, and alkyl or alkylene radicals and parts of molecules or alkyl radicals and parts of molecules are in a straight or branched chain and contain from 1 to 6 carbon atoms, and cycloalkyl radicals contain from 3 to 10 carbon atoms, an optical isomer of such compound or one of its pharmaceutically acceptable salts. 2. Pharmaceutical composition according to claim 1, in which in the compound of formula I: It is selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, cinnoline, thiophene, quinazoline, quinoxaline, quinoline, pyrazole, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, piperidine, piperazine, pyrrolidine, triazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, which may be substituted by one or more substituents: alkyl, alkoxy, vinyl, halogen, alkoxycarbonyl, oxo, hydroxy, OSE, or CEz. 3. Pharmaceutical composition, according to claim 1, containing as an active principle at least one compound of formula I, in which: Ai means the radical -M(H5)-X-Hv, U means 50", Ag means either phenyl, unsubstituted or substituted by one or by several substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -SOMARv, hydroxyalkyl or -alkyl-MA7Rv, or a heteroaromatic radical selected from the rings: pyridyl, pyrimidinyl, thiazolyl and thienyl, which may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -SOMA;Hve, /--aik-MA»Vo, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl; Az means either phenyl, unsubstituted or substituted by one or more substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -SOMAUNase, hydroxyalkyl, -alkyl-MA7;Av, or a heteroaromatic radical selected from the rings: pyridyl, pyrimidinyl, thiazolyl and thienyl, which may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -SOMA; Nae, /-aik-MA»B0, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl; B5 means a hydrogen or alkyl atom; Ae means the radical naphthyl, phenylalkyl, Ni, or phenyl, which may be substituted by one or more substituents: halogen, alkyl, alkoxy, cyano, -SbO-alkyl, -SOOalkyl, -SOMA12Viz -alkyl-MAchaViv, -MAzaViv, hydroxy, hydroxyalkyl, Nei, ОСЕз, СЕз, -МН-СО-аик, -502МНг2, -МН-СООак, or two carbon atoms connected by dioxymethylene; IN; and Kz, the same or different, mean a hydrogen atom or an alkyl radical, or KE"; and Kv, together with the nitrogen atom to which they are attached, 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 several alkyls; Ne and Kio, the same or different, represent a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl or hydroxyalkyl radical, or C and Kio, together with the nitrogen atom to which they are attached, form a saturated or unsaturated mono- or bicyclic heterocycle having from 3 to 10 units, which may contain a second heteroatom selected from oxygen, sulfur and nitrogen, and be substituted by one or more radicals: alkyl, oxo or -СО-МН?; Vi" and Kis, the same or different, mean a hydrogen atom or an alkyl radical, or Ki" and Kis, 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 alkyl radicals; Aa and Wiz, the same or different, mean a hydrogen atom or an alkyl radical, cycloalkyl, alkylcycloalkyl or hydroxyalkyl, or Ka and K:i5, together with the nitrogen atom to which they are connected, form a saturated or unsaturated mono- or bicyclic heterocycle, which has from 3 to 10 units, which may contain a second heteroatom selected from oxygen, sulfur, and nitrogen, and be substituted by one or more alkyl, oxo, hydroxyalkyl, or -CO-MH»g radicals; It means an unsaturated or saturated mono- or bicyclic heterocycle having from 3 to 10 members, containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, and which may be substituted by one or more radicals: alkyl, alkoxy, vinyl, halogen, alkoxycarbonyl, oxo, hydroxy, and nitrogen-containing heterocycles can be in the form of M-oxides, and, preferably, Nei means a heterocycle selected from the following heterocycles: benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, furan, tetrahydroisoquinoline, and tetrahydroquinoline, which may be substituted with one or more substituents: alkyl, alkoxy, vinyl, halogen, oxo, hydroxy, OC3 or CE, an optical isomer of such a compound or one of its pharmaceutically acceptable salts. 4. Pharmaceutical composition, according to claim 1, containing as an active principle at least one compound of formula I, in which: Ai means the radical -M(H5)-X-Hv, U means 50", Ag means either phenyl, unsubstituted or substituted by one or by several substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy or hydroxyalkyl, or a heteroaromatic radical selected from the rings: pyridyl and pyrimidyl, which may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl or trifluoromethoxy; Az means either phenyl, unsubstituted or substituted by one or more substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, hydroxyalkyl, or a heteroaromatic radical selected from the rings: pyridyl and pyrimidyl, which may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy , trifluoromethyl, trifluoromethoxy; B5 means a hydrogen or alkyl atom; Ae means the radical naphthyl, phenylalkyl, Nei or phenyl, which can be replaced by one or more substituents: halogen, alkyl, alkoxy, -MA14Bi5, hydroxy, hydroxyalkyl, OSE3, CE3 or -502MH»g, or by two carbon atoms, bound by dioxymethylene; Aa and Wiz, the same or different, mean a hydrogen atom or an alkyl radical, cycloalkyl, alkylcycloalkyl or hydroxyalkyl, or Ka and K:i5, together with the nitrogen atom to which they are connected, form a saturated or unsaturated mono- or bicyclic heterocycle, which has from 3 to 10 units, which may contain a second heteroatom selected from oxygen, sulfur and nitrogen, and be substituted by one or more alkyl, oxo, hydroxyalkyl or -FO-MH»g radicals; It means an unsaturated or saturated mono- or bicyclic heterocycle having from 3 to 10 members, containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, and which may be substituted by one or more radicals: alkyl, alkoxy, vinyl, halogen, alkoxycarbonyl, oxo, hydroxy, and nitrogen-containing heterocycles can be in the form of M-oxides, and, preferably, Nei means a heterocycle selected from the following heterocycles: benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinoline, pyrrole, pyridine, pyrimidine, thiazole, thiadiazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, which may be substituted by one or more substituents: alkyl, alkoxy, vinyl, halogen, oxo, hydroxy, OSE3 or CE3, an optical isomer of such a compound or one of its pharmaceutically acceptable salts. 5. Z-aminoazetidine derivatives of formula I: Кк, в иш Кк, Й "FO in which В means the radical -МНСОВ" or -М(А5)-ху-Нв, У means СО or 50», Вг and Ез, 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: halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -СбО-айК, cyano, -СООН, -СбООайкК, -SOMA;НАв, - СО-МН-МРАзВо, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfonylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -aik-MA;Ag; or a heteroaromatic radical selected from the rings: benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, pyrimidinyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 1,2, 3,4-tetrahydroisoquinolyl, thiazolyl, and thienyl, which may be unsubstituted or substituted by one or more substituents: halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -SOOalic, -CO-MH-MA»Ato, -"SOMAVv, -aik-MA"Vio, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfonylalkyl, alkylsulfonylalkyl or hydroxyalkyl; Ba means the radical ayl-502-Bi1, ayl-502-CH-CH-Bi, Nei, substituted by a group -502-Ni, or phenyl substituted by a group -502-Ni or -aik-5O2-Ni; A5 means a hydrogen atom or an alkyl radical; Ae means a phenylalkyl radical, Nei or Ag; IN; and Kz, the same or different, mean a hydrogen atom or an alkyl radical, or KE"; and Kv, together with the nitrogen atom to which they are attached, 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 several alkyls; Az and Vo, the same or different, denote a hydrogen atom or an alkyl radical, -coalkyl, cycloalkyl, alkylcycloalkyl, -alkyl-O-alkyl, or hydroxyalkyl, or Ke and Kio, together with the nitrogen atom to which they are attached, form a saturated or an unsaturated 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 radicals: alkyl, -COaic, -SOOaic, -"CO- MNaic, -C5-MNaic, oxo, hydroxyalkyl, - aic-O-aicK or -CO-MH»g; Vii means an alkyl radical, Ag or Ni; Ag means a phenyl, naphthyl or indenyl radical, which can be replaced by one or more substituents: halogen, alkyl, alkoxy, cyano, -BO-alic, -COOH, -SOOalicK, -SOMAch2Vis, -CO-MH-MAiaVi5 alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkyl-MAchzaVii5, -MAch14V alkylthioalkyl, formyl, hydroxy, hydroxyalkyl, Nei, -O-alkyl-MH- cycloalkyl, OSEz, CEz, -MH-CO-alkyl, -502МНг, -МН-СОСН»з, -МН -СООаикК, Ней, or two carbon atoms connected to each other through dioxymethylene; It means an unsaturated or saturated mono- or bicyclic heterocycle having from 3 to 10 members, containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, and which may be substituted by one or more radicals: alkyl, alkoxy, vinyl, halogen, alkoxycarbonyl, oxo, hydroxy, OSE3 or CE3, and nitrogen-containing heterocycles can be in the form of M-oxides; Vi" and Kis, the same or different, mean a hydrogen atom or an alkyl radical, or RK" and Ris, 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 alkyl radicals; Via and Kis are the same or different, mean a hydrogen atom or an alkyl radical, -COOaic, cycloalkyl, alkylcycloalkyl, -aic- O-aicK or hydroxyalkyl, or Kia and Ki5, 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, which may contain a second heteroatom selected from oxygen, sulfur, and nitrogen, and be substituted by one or more radicals: alkyl, -COaic, -bOpack, - co-MNaic, -C5-MnNaic, oxo, hydroxyalkyl, -aic-O-aic or -CO-MH»5; ak means an alkyl or alkylene radical, and alkyl or alkylene radicals and parts of molecules or alkyl radicals and parts of molecules are in a straight or branched chain and contain from 1 to 6 carbon atoms, and cycloalkyl radicals contain from 3 to 10 carbon atoms, their optical isomers and their pharmaceutically acceptable salts, except for the compound in which Co" and Kz are phenyl radicals, Ki is the radical -M(H5)-U-Hv, M is 50", H5 is a methyl radical and Kv is a phenyl radical. 6. Compounds of formula I according to claim 5, in which Ni is selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, cinnoline, thiophene, quinazoline, quinoxaline, quinoline, pyrazole, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, piperidine, piperazine, pyrrolidine, thiazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, which may be substituted by one or more substituents: alkyl, alkoxy, vinyl, halogen, alkoxycarbonyl, oxo, hydroxy, OSE3 or CE3, P" and Kz denote phenyl radicals, Ki means the radical -M(H5)-U- Av, U means 50", H5 means the methyl radical and Kye means the phenyl radical. 7. Compounds of the formula | according to claim 5, in which Ai means the radical -M(H5)-X-Hv, U means 50", Ag means either phenyl, unsubstituted or substituted by one or more substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, - SOMARv, hydroxyalkyl or -alkyl-MA7Pv, or a heteroaromatic radical selected from the rings: pyridyl, pyrimidinyl, thiazolyl and thienyl, which can be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -SOMA; Nae, /- -aik-MAHVO, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl; Az means either phenyl, unsubstituted or substituted by one or more substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -SOMAURaz, hydroxyalkyl, -alkyl-MA7;Av, or a heteroaromatic radical selected from the rings: pyridyl, pyrimidinyl, thiazolyl and thienyl, which may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -SOMA;Nae, /--aik-MA»Vo, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl; B5 means a hydrogen or alkyl atom; Ae means the radical naphthyl, phenylalkyl, Ni, or phenyl, which may be substituted by one or more substituents: halogen, alkyl, alkoxy, cyano, -СбО-айкК, -СО0айк, -СОМАх2Віз, -айк-МАХзаВі5, -MA14Ві5, hydroxy, hydroxyalkyl . IN; and Kz, the same or different, mean a hydrogen atom or an alkyl radical, or KE"; and Kv, together with the nitrogen atom to which they are attached, 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 several alkyls; No and Kyo, the same or different, represent a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl or hydroxyalkyl radical, or Kz and Kyo, together with the nitrogen atom to which they are attached, form a saturated or unsaturated mono- or bicyclic heterocycle having from 3 to 10 units, which may contain a second heteroatom selected from oxygen, sulfur and nitrogen, and be substituted by one or more radicals: alkyl, oxo or -СО-МН?; Vi" and Kis, the same or different, mean a hydrogen atom or an alkyl radical, or Ki" and Kis, 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 alkyl radicals; Aa and Wiz, the same or different, mean a hydrogen atom or an alkyl radical, cycloalkyl, alkylcycloalkyl or hydroxyalkyl, or Ka and K:i5, together with the nitrogen atom to which they are connected, form a saturated or unsaturated mono- or bicyclic heterocycle, which has from 3 to 10 units, which may contain a second heteroatom selected from oxygen, sulfur, and nitrogen, and be substituted by one or more alkyl, oxo, hydroxyalkyl, or -CO-MH»g radicals; It means an unsaturated or saturated mono- or bicyclic heterocycle having from 3 to 10 members, containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, and which may be substituted by one or more radicals: alkyl, alkoxy, vinyl, halogen, alkoxycarbonyl, oxo, hydroxy, and nitrogen-containing heterocycles can be in the form of M-oxides, and, preferably, Nei means a heterocycle selected from the following heterocycles: 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 more substituents: alkyl, alkoxy, vinyl, halogen, oxo, hydroxy, OSE3 or CE, their optical isomers and their pharmaceutically acceptable salts, except for the compound in which Co" and Kz are phenyl radicals, Ki is the radical -M(H5)-U-Hv, M is 50", H5 is a methyl radical and Kv is a phenyl radical. 8. Compounds of the formula | according to claim 5, in which Ai means the radical -M(H5)-X-Hv, U means 50", Ag means either phenyl, unsubstituted or substituted by one or more substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy or hydroxyalkyl, or a heteroaromatic radical selected from the rings: pyridyl and pyrimidyl, which may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl or trifluoromethoxy; Az means either phenyl, unsubstituted or substituted by one or more substituents: halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, hydroxyalkyl, or a heteroaromatic radical selected from the rings: pyridyl and pyrimidyl, which may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy , trifluoromethyl, trifluoromethoxy; B5 means a hydrogen or alkyl atom; Ae means a naphthyl, phenylalkyl, Ni, or phenyl radical, which may be substituted by one or more substituents: halogen, alkyl, alkoxy, -MAch14Bi5, hydroxy, hydroxyalkyl, OSE3, CE3 or -502МНх2, or two carbon atoms bonded between itself through dioxymethylene; Aa and Kis, the same or different, mean a hydrogen atom or an alkyl radical, cycloalkyl, alkylcycloalkyl or hydroxyalkyl, or Ka and K:i5, together with the nitrogen atom to which they are connected, form a saturated or unsaturated mono- or bicyclic heterocycle, which has from 3 to 10 units, which may contain a second heteroatom selected from oxygen, sulfur, and nitrogen, and be substituted by one or more alkyl, oxo, hydroxyalkyl, or -CO-MH»g radicals; It means an unsaturated or saturated mono- or bicyclic heterocycle having from 3 to 10 members, containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, and which may be substituted by one or more radicals: alkyl, alkoxy, vinyl, halogen, alkoxycarbonyl, oxo, hydroxy, and nitrogen-containing heterocycles can be in the form of M-oxides, and, preferably, Nei means a heterocycle selected from the following heterocycles: benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinoline, pyrrole, pyridine, pyrimidine, thiazole, thiadiazole, furan, tetrahydroisoquinoline and tetrahydroquinoline which may be substituted with one or more substituents: alkyl, alkoxy, vinyl, halogen, oxo, hydroxy, OSE3 or CE3, their optical isomers and their pharmaceutically acceptable salts, except for the compound in which Ko» and Kz are phenyl radicals, Ki is the radical -M(H5)-U-Hv, M is 50», H5 is a methyl radical and Ki is a phenyl radical. 9. The method of obtaining compounds of formula I! according to claim 5, in which Ki is the radical -MNSONB", which differs in that the acid KASOOH, in which Ka. has the same values as in claim 5, is introduced into the interaction with the derivative of the formula: c, in ish MN, in which Ko and Kz have the same values as in claim 5, isolate the product and, if necessary, convert it into a pharmaceutically acceptable salt. 10. The method of obtaining compounds of the formula I according to claim 5, in which Ki is the radical -M(E5)-y-He, which differs in that the derivative of the formula: c, c is MH, in which E" and Ez have the same values , as in claim 5, is introduced into the interaction with the Na1I-XU-Nee derivative, in which U and Kye have the same values as in claim 5, and NaiYi means a halogen atom, and then, if necessary, with the Nai-aiYIK derivative, where Na! means a halogen atom, and ak means an alkyl radical (1-6 C in a straight or branched chain), obtaining compounds in which K5 is alkyl, isolate the product and, if necessary, convert it into a pharmaceutically acceptable salt. 11. The method of obtaining compounds of the formula | according to claim 5, which differs in that the derivative K2-SNVI-Nz, in which EK" and Kz have the same values as in claim 5, is introduced into interaction with the compound of the formula: 7 K, in which Ki has the same values, as in claim 5, isolate the product and, if necessary, convert it into a pharmaceutically acceptable salt. 12. The method of obtaining compounds of the formula !/ according to claim 5, in which Ki is the radical -M(H5)-U-No, where Ke means a hydroxy-substituted phenyl radical, which differs in that they carry out hydrolysis of the corresponding compound of formula I, in which Ki is with the radical -M(H5")-y-Ne, where Kye means an alkoxy-substituted phenyl radical, the product is isolated and, if necessary, it is converted into a pharmaceutically acceptable salt. 13. The method of obtaining compounds of the formula !/ according to claim 5, in which Ki is the radical -M(H5)-Y-No, where Ke means a hydroxyalkyl(1C)-substituted phenyl radical, which differs in that diisobutylaluminum hydride is introduced into the interaction with with the corresponding compound of the formula !, in which Ki is the radical -M(H5)-U-Hv6, where Ke means an oxycarbonyl-substituted phenyl radical, isolate the product and, if necessary, convert it into a pharmaceutically acceptable salt. 14. The method of obtaining compounds of the formula I according to claim 5, in which Ki is the radical -М(Н5)-у-Нв, where Ke means a pyrrolidine-1-substituted phenyl radical, which differs in that pyrrolidine is introduced into the interaction with the corresponding compound of the formula And, in which Ki is the radical -M(H5»)-U-Nvye, where Kye means a fluorine-substituted phenyl radical, isolate the product and, if necessary, convert it into a pharmaceutically acceptable salt.