MXPA99000736A - 1-azoniabicyclo[2.2.1]heptane derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

A compound of formula (I), wherein A is a divalent radical selected from A 1)-O-CO-;A 2)-CH 2-O-CO;A 3)-O-CH 2-CO-;A 4)-O-CH 2-CH 2-;A 5)-N(R 1)-CO-;A 6)-N(R 1)-CO-CO;A 7)-N(R 1)-CH 2-CH 2-;A 8)-O-CH 2-;wherein R 1 is hydrogen or (C 1-C 4)alkyl, and Am is (1). Said compound is useful as a neurokinin receptor antagonist.

Description

DERIVATIVES OF 1-AZONIABICICLO [2.2.1] HEPTANE AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM FIELD OF THE INVENTION The subject of the present invention is new substituted heterocyclic compounds, a process for their preparation and the pharmaceutical compositions contained as an active principle.

BACKGROUND OF THE INVENTION More particularly, the present invention relates to a new class of substituted heterocyclic compounds for therapeutic use, in the pathological phenomena involving the takikinin system, such as, for example, in a non-limiting and exclusive manner: pain (D. Regoli et al. al., Life Sciences, 1987, 40, 109-117), allergy and inflammation (JE Morlay et al., Life Sciences, 1987, 4: 1, 527-544), circulatory failure (J. Losay et al., 1977, Substance P. von Euler, IS and Pernow ed., 287-293, Raven Press, New York), gastrointestinal disorders (Regoli et al., Trends Pharmacol. Sci., 1985, 6, 481-484) , respiratory disorders (J. Mizrahi et al., Pharmacology, 1982, 25, 39-50) REF. : 28923 neurological disorders, neuropsychiatric disorders (C.A. Maggi et al., J. Autonomic, Pharmacol., 1993, 13, 23-93). In recent years numerous search works have been carried out on takikinins and their receptors. Takikinins are distributed both in the central nervous system and in the peripheral nervous system. Takikinin receptors have been recognized and are classified into three types: NKi, NK2, NK3. The substance P (SP) is the endogenous ligand of the NKlf receptors, the neurokinin A (NKA) that of the NK2 receptors and the neurokinin B (NKB), that of the NK3 receptors. The NKX, NK2, NK3 receptors have been shown in different species. A magazine of C.A. Maggi et al., Makes the point in the receptors of the takikinins and their antagonists and exposes the pharmacological studies and the applications in human therapeutics (J. Autonomic Pharmacol., 1993, 13, 23-93). Among the specific NKi receptor antagonists, mention may be made of the following non-peptide compounds: CP-96345 (J. Med Chem., 1992, 35, 2591-2600), RP-68651 (Proc.

Nati Acad. Sci. USA, 1991, 88, 10208-10212), SR 140333 (Curr. J. Pharmacol., 1993, 250, 403-413).

For the NK2 receptor, a selective non-peptide antagonist, SR 48968 has been described in detail (Life Sci., 1992, 50, PL101-PL106). As regards the human NK3 receptor, a selective non-peptide antagonist, (+) - N- [1- [3- [l-benzoyl-3- (3,4-dichlorophenyl) piperid-3-yl hydrochloride] ] propyl] -4-phenylpiperid-4-yl] -N-methylacetamide or SR 142801 has been described (Peptides and their antagonists in tissue injury, Montreal, Canada, 1994, July 31-August 3. Canadian J. Physiol. Pharmacol. , 1994, 72 (Suppl 2), 25, Abst. III, O.9, Life Sci., 1994, 56 (1), 27-32, British Pharmacol Society, Canterburry, 1995, April 6-8; Eur. J. Pharmacol., 1995, 278 (1), 17-25; lst Eur. Congress Pharmacol., Milan, 1995, June 16-19). Patent application EP-A-336230 discloses peptide antagonist derivatives of substance P and neurokinin A useful for the treatment and prevention of asthma. The international patent applications WO 90/05525, WO 90/05729, WO 91/09844, WO 91/18899 and European EP-A-0436334, EP-A-0429466 and EP-A-0430771 describe the antagonists of the substance P European Patent Applications EP-A-0428434, EP-A-0474561, EP-A-512901, EP-A-515240, EP-A-559538, EP-A-591040, EP-A-0625509, EP- A-0630887 and international WO 94/10146, WO 94/29309, WO 94/26735, WO 95/05377, WO 95/12577, WO 95/16682, WO 95/28389, WO 96/06094, WO 96/05193 which they also refer to antagonists of neurokinin receptors. New substituted heterocyclic compounds which are antagonists of neurokinin receptors have now been found.

DESCRIPTION OF THE INVENTION Thus according to one of its aspects, the present invention relates to compounds of the formula: Am- (CH2) IB-C / -C-AH2X-N-T (I) Ar, in which: - A represents a divalent radical selected from: Ai) -0-C0-A2) -CH2-0-C0-A3) -0-CH2-C0-A4) -0-CH2-CH2-As) - N (R?) - CO - A6) - N (R?) - C0 - C0 - A7) - N (R?) - CH2 - CH2 - As) --O - CH2 - in which Ri represents a hydrogen or a (Ci-C4) alkyl; - m is 2 or 3; - Ari represents a phenyl unsubstituted or substituted one or several times by a substituent chosen from: a halogen atom, a hydroxy, a (C 1 -C 4) alkoxy, a (C 1 -C 4) alkyl, a trifluoromethyl, a methylenedioxy, the substituents are identical or different; a thienyl not substituted or substituted by a halogen atom; a benzothienyl unsubstituted or substituted by a halogen atom; a naphthyl unsubstituted or substituted by a halogen atom; an indolyl unsubstituted or N-substituted by a (C 1 -C 4) alkyl or a benzyl; an imidazolyl unsubstituted or substituted by a halogen atom; a pyridyl unsubstituted or substituted by a halogen atom; a diphenyl; - T represents a group selected from: CH2-Z, -CH (C6H5) 2, -C (C6H5) 3; T may also represent the group -C0-B-Z when A represents a divalent radical selected from; -0-CH2-CH2- or -N (R?) - CH2-CH2- or -0-CH2-; - B represents a direct bond or a methylene; Z represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group; - Am represents a group of formula: wherein: - Ar2 represents a pyridyl; a phenyl unsubstituted or substituted one or several times by a substituent chosen from: a halogen atom, a hydroxy, a (Ci- C4) alkoxy, a (C? -C4) alkyl, a trifluoromethyl, a nitro, a methylenedioxy, the substituents are identical or different; a thienyl; a pyrimidyl; an imidazolyl unsubstituted or substituted by a (C? -C) alkyl; n is zero or one; T-X represents an anion as well as its eventual salts with the mineral or organic acids. The compounds of the formula (I) according to the invention comprise both the racemic and the optically pure isomers. More particularly, the radical Z may be a phenyl group, which may be unsubstituted or optionally contain one or more substituents. When Z is a phenyl group, it may be mono substituted or disubstituted mainly in the position 2,4 but also for example in position 2,3 or 4,5 or 3.4 or 3.5; it can also be trisubstituted, mainly in position 2,4,6 but also for example in 2,3,4 or 2,3,5 or 2,4,5 or 3,4,5 tetrasubstituted, for example in 2,3 4,5; or pentasubstituido. The radical Z may also represent a bicyclic aromatic group such as 1- or 2-naphthyl; 1-, 2-, 3-, 4-, 5-, 6-, 7-indenyl; of which one or more bonds may be hydrogenated, the groups which may be unsubstituted or optionally contain one or more substituents such as: the alkyl, phenyl, cyano, hydroxyalkyl, hydroxy, oxo, alkylcarbonylamino, alkoxycarbonyl, thioalkyl, halogen, alkoxy group and trifluoromethyl, in which the alkyls and the alkoxy are from 1 to 4 carbon atoms. The radical Z can also be a pyridyl, thiadiazolyl, indolyl, indazolyl, imidazolyl, benzimidazolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzisothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzodioxinyl, isoxazolyl, benzopyranyl, thiazolyl, thienyl, furyl, pyranyl, chromenyl, isobenzofuranyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, phthalazinyl, quinazolinyl, acridinyl, isothiazolyl, isochromanyl, chromanyl, of which one or more double bonds can be hydrogenated, the groups can be unsubstituted or optionally containing one or more substituents such as: the alkyl, phenyl, cyano, hydroxyalkyl, hydroxy, alkylcarbonylamino, alkoxycarbonyl, thioalkyl group in which the alkyls and the alkoxy are from 1 to 4 carbon atoms. Particularly, the invention relates to the compounds of formula (1) in which; - Z is Z 'and represents: - a phenyl unsubstituted or substituted one or more times by a substituent chosen from: a halogen atom; a trifluoromethyl; a cyano; a hydroxy; a nitro; an amino unsubstituted or substituted once or twice by a (C 1 -C 4) alkyl; a benzylamino; a carboxy; a (C1-C10) alkyl; a (C3-Ca) cycloalkyl unsubstituted or substituted one or more times by a methyl; a (C1-C10) alkoxy; a (C3-C8) cycloalkyloxy unsubstituted or substituted one or more times by a methyl; a mercapto; a (C1-C10) alkylthio; a formyloxy: a (Ci-Cβ) alkylcarbonyloxy; a formylamino; a (Ci- C) alkylcarbonylamino; a benzoylamino; a (Ci- C4) alkoxycarbonyl; a (C3-C7) cycloalkyloxycarbonyl; a carbamoyl unsubstituted or substituted once or twice by a (C 1 -C 4) alkyl; a ureide unsubstituted or substituted once or twice in the 3-position by a (Ci- C4) alkyl or a (C3-C7) cycloalkyl; a phenyl unsubstituted or substituted one or more times by a halogen, a trifluoromethyl, a (C 1 -C 4) alkyl, a hydroxy, a (C 1 -C 4) alkoxy, the substituents are identical or different; a (pyrrolidin-1-yl) carbonylamino; the substituents are identical or different; - a naphthyl unsubstituted or substituted one or several times by a halogen, a trifluoromethyl, a (dC4) alkyl, a hydroxy, a (C1-C4) alkoxy; - a pyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; an imidazolyl; a furilo. In addition to the quaternary ammonium salts, the salts of the compounds of the formula (1) can be formed. These salts also include those with mineral and organic acids which allow a convenient separation or crystallization of the compounds of formula (1), such as picric acid or oxalic acid or an optically active acid, for example a mandelic or camphorsulfonic acid, than those forming pharmaceutically acceptable salts such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, methyl sulfate, maleate, fumarate, 2-naphthalenesulfonate, benzenesulfonate, gluconate, citrate , isethionate, p-toluenesulfonate.

T Anions X are those normally used to salify the quaternary ammonium ions, preferably the chloride, bromide, iodide, acetate, hydrogen sulfate, methanesulfonate, paratoluenesulfonate, benzenesulfonate ions. Preferably, pharmaceutically acceptable anions are used, for example, the chloride, the methanesulfonate or the benzenesulfonate. In the present description the alkyl groups or the alkoxy groups are straight or branched; per halogen atom is meant a chlorine, bromine, fluorine or iodine atom. In the substituents of the group Z = phenyl, (C 1 -C 6) alkyl is understood to mean, for example, a methyl, an ethyl, an n-propyl, an isopropyl, an n-butyl, an isobutyl, a sec-butyl, an tert-butyl, a pentyl or n-pentyl, a hexyl or n-hexyl, a heptyl or an n-heptyl, an octyl or n-octyl, a nonyl or n-nonyl, a decyl or n-decyl; by (C3-C8) cycloalkyl optionally substituted by a methyl is understood for example as a cyclopropyl, a cyclobutyl, a cyclopentyl, a 1-, 2- or 3-methylcyclopentyl, a cyclohexyl, a 1-, 2-, 3-, or 4 -methyl-cyclohexyl, a cycloheptyl, or a cyclooctyl; By (Ci-Cio) alkoxy is meant, for example, a methoxy, an ethoxy, an n-propoxy, an isopropoxy, an n-butoxy, an isobutoxy, a sec-butoxy, a tert-butoxy, a pentyloxy, a hexyloxy, an heptyloxy, a nonyloxy or a decyloxy; by (C3-C8) cycloalkyloxy optionally substituted by a methyl, is meant for example a cyclopropyloxy, a cyclohexyloxy, a 1-, 2-, 3-or 4-methylcyclohexyloxy, a cycloheptyloxy or a cyclooctyloxy; By (Ci-Cio) alkylthio is meant, for example, a methylthio, an ethylthio, an n-propylthio, an isopropylthio, an n-butylthio, an isobutylthio, a sec-butylthio, a tert-butylthio, a pentylthio, a hexylthio, a heptylthio, an octylthio, a r-onylthio or a decylthio; by (Ci-Cβ) alkylcarbonyloxy means, for example, an acetyloxy, a propionyloxy, a butyryloxy, a valeryloxy, a caproyloxy, a heptanoyloxy; by a (Ci-C6) alkylcarbonylamino is meant for example an acetylamino, a propionylamino, a butyrylamino, an isobutyrylamino, a valerylamino, a caproylamino or a heptanoylamino; by (C1-C4) alkoxycarbonyl is meant, for example, a methoxycarbonyl, an ethoxycarbonyl, an n-propoxycarbonyl, an isopropoxycarbonyl, an n-butoxycarbonyl, an isobutoxycarbonyl, a sec-butoxycarbonyl or a tert-butoxycarbonyl; by (C3-C) cycloalkyloxycarbonyl is understood for example as a cyclopropyloxycarbonyl, a cyclobutyloxycarbonyl, a cyclopentyloxycarbonyl, a cyclohexyloxycarbonyl or a cycloheptyloxycarbonyl.

Advantageously, the radical Z represents a phenyl which is unsubstituted or substituted one or more times by a halogen atom, more particularly a chlorine, fluorine or iodine atom, a trifluoromethyl, a (C ± -C4) alkyl , a hydroxy, a (C 1 -C 4) alkoxy; a naphthyl unsubstituted or substituted one or more times by a halogen, a trifluoromethyl, a (C 1 -C 4) alkyl, a hydroxy, a (C 1 -C 4) alkoxy; a pyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; an imidazolyl. A group of preferred compounds according to the present invention are those of the formula: Am < ? J MfG Mf M2-ZA (you) Ar 1 » wherein: - Aa represents a divalent radical selected from: -0-C0; -CH2-O-CO-; -O-CH2-CO-; -N (R?) -C0- or -N (Rj.) -C0-C0-; wherein Ri represents a hydrogen or a (C C) alkyl; - A represents a group of formula: - n is O or 1; T-X represents a pharmaceutically acceptable anion; - Ar2 is as defined above for a compound of formula (1); - Aria represents a phenyl unsubstituted or substituted one or several times by a substituent selected from: a halogen atom, a hydroxy, a (C? -C4) alkoxy, a (C1-C4) alkyl, a trifluoromethyl, the substituents are identical or different; - Za represents a phenyl unsubstituted or substituted one or several times by a substituent selected from: a halogen atom, a trifluoromethyl, a (Ci- C10) alkyl, a (C1-C10) alkoxy, a hydroxy, the substituents are identical or different Among these compounds, those of formula: wherein: Aa is as defined above for a compound of formula (la); - Arria represents a group of formula: T-X represents a pharmaceutically acceptable anion; - Ar'ia represents a 3,4-dichlorophenyl or a 3,4-difluorophenyl; - Z'a represents a 3,5-bis (trifluoromethyl) phenyl, a 3,5-dimethylphenyl or a 2,4-bis (trifluoromethyl) phenyl; they are particularly preferred. Another group of preferred compounds according to the invention are those of the formula: wherein: - Ab represents the divalent radical -0-CH2-CH2-; -N (R?) -CH2-CH2- or -0-CH2-; wherein Ri represents a hydrogen or a (C? -C4) alkyl; Am represents a group of formula: n is 0 or 1; B represents a direct bond or a methylene; T X represents a pharmaceutically acceptable anion; Ar2 is as defined above for a compound of formula (I); ria and Za are such as defined above for a compound of formula (la); Among these compounds, those of the formula: Am CH2-CH3-C-CH2-N-CO-B-Z "a (Fb) wherein: - B represents a direct bond or a methylene; - Ama is as defined above for a compound of formula (I'a); - Ab is as defined above for a compound of formula (Ib); - Ar 'ia is as defined above for a compound of formula (I' a); - Z "a represents a phenyl substituted at the 3-position by a halogen or a (C1-C10) alkoxy group when B represents a methylene or Z" a represents a 3,5-bis (trifluoromethyl) phenyl, a 3, 5- dimethylphenyl or a 2,4-bis (trifluoromethyl) phenyl when B represents a direct bond; they are particularly preferred. According to another of its aspects, the present invention relates to a process for the preparation of the compounds of formula (1) and their salts, characterized in that: 1) a compound of the formula is treated: E-O-ÍCH,) - xC-CAHXj-NH (II) Ar, wherein m, Arx and A are as defined above for a compound of formula (1) and E represents hydrogen or a 0-protecting group. - either with a functional derivative of an acid of formula: H0C0-BZ (III) in which B and Z are as defined above for (1), when a compound of formula (I) must be prepared wherein T is -C0-BZ, - or with a halogenated derivative of the formula: Hal-CH2-Z (IV) wherein Z is as defined above, and Hal represents a halogen, preferably bromine or chlorine, when a compound of formula (1) is to be prepared wherein T is -CH2-Z, - or with a halogenated derivative of formula: Hal-CH (C6H5) 2 (V) when a compound of formula (1) is to be prepared wherein T is a group -CH (C6H5) 2, - or with a halogenated derivative of the formula: Hal-C- (C6H5) 3 (VI) when a compound of formula (1) wherein T is a group -C (C6H5) 3, to obtain a compound of the formula: E-O- (CHj) -C - CAHxj-N-T (VII) 2) the 0-protecting group is optionally removed by the action of an acid or a base, to obtain the alcohol of the formula: 3) alcohol (VIII) is treated with a compound of formula: Y-S02-C1 (IX) wherein Y represents a methyl, phenyl, tolyl, trifluoromethyl group, to obtain a compound of the formula: 4) Compound (X) is reacted with a cyclic tertiary amine of the formula: wherein Ar 2 and n are such as defined for a compound of formula (1); and, 5) the product thus obtained is isolated in the form of a sulphonate and optionally a salt of sulfonic acid or, optionally, the anion and optionally the acid salt thus obtained is exchanged with another anion and optionally another salt of mineral acid or pharmaceutically acceptable organic. When E represents a 0-protecting group, it is chosen from the classical O-protecting groups well known to the person skilled in the art, such as, for example, tetrahydropyran-2-yl, benzoyl or a (Ci-C4) alkylcarbonyl. In stage 1), as the functional derivative of the acid (III), the acid is used by itself, or one of the functional derivatives that react with the amines, for example an anhydride, a mixed anhydride, the acid chloride, or an activated ester, as the para-nitrophenyl ester. When the acid of formula (III) is employed itself, it is operated in the presence of a coupling agent used in peptide chemistry such as 1,3-dicyclohexylcarbodiimide or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate in the presence of a base such as triethylamine or N, N-diisopropylethylamine, in an inert solvent such as dichloromethane or N, N-dimethylformamide at a temperature ranging from 0 ° C to room temperature. When an acid chloride is used, the reaction is carried out in an inert solvent, such as dichloromethane or benzene, in the presence of a base such as triethylamine or N-methylmorpholine and at a temperature between -60 ° C and the room temperature. When a halogenated derivative of formula (IV), (V) or (VI) is used, the reaction is carried out in an inert solvent such as tetrahydrofuran, N, N-dimethylformamide or dimethylsulfoxide in the presence of a base such as potassium tert-butylate, sodium hydride or lithium diisopropylamide at a temperature between 0 ° C and 80 ° C. The compound of formula (VII) thus obtained is optionally deprotected in step 2) in accordance with methods known to the person skilled in the art. For example, when E represents a tetrahydropyran-2-yl group, deprotection is effected by acid hydrolysis using hydrochloric acid in a solvent such as ether, methanol or mixture of these solvents, or using pyridinium p-toluenesulfonate. in a solvent such as methanol or else, using an Amberlyst® resin in a solvent such as methanol. The reaction is carried out at a temperature between room temperature and the reflux temperature of the solvent. When E represents a benzoyl group or a (C 1 -C 4) alkylcarbonyl group, the deprotection is carried out by hydrolysis in an alkaline medium using, for example, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, in an inert solvent such as water, methanol, ethanol, dioxane or a mixture of these solvents, at a temperature between 0 ° C and the reflux temperature of the solvent. In step 3) the reaction of the alcohol of formula (HIV) with a sulfonyl chloride of formula (IX) is carried out in the presence of a base such as triethylamine, pyridine, N, N-diisopropylethylamine or N-methylmorpholine , in an inert solvent such as dichloromethane, benzene or toluene, at a temperature between -20 ° C and the reflux temperature of the solvent. In step 4) when a compound of formula (X) is reacted with a compound of formula (XI), the reaction is carried out in an inert solvent such as N, N-dimethylformamide, acetonitrile, methylene chloride, toluene or propan-2-ol and in the presence or absence of a base. When a base is used, it is chosen from organic bases such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine or between alkali metal carbonates or bicarbonates such as potassium carbonate, sodium carbonate or the sodium bicarbonate. In the absence of base, the reaction is carried out using an excess of the compound of formula (XI) and in the presence of an alkali metal iodide such as potassium iodide or sodium iodide. When in the compound of formula (X), -A- represents the divalent radical -0-CO- or -CH2-0-C0-, the reaction is carried out at a temperature between room temperature and 80 ° C. When in the compound of formula (X) -A- represents the divalent radical -0-CH2-C0-, -0-CH2-CH2-, -N (R?) -COCO-, -N (R?) - CH2 -CH2-, -N (R?) - C0- or -0-CH2-, the reaction is carried out at a temperature between room temperature and 100 ° C. The products of the formula (1) thus obtained are T isolated in the form of sulfonate (YS03) or the sulfonate anion of the quaternary salt thus obtained is optionally exchanged with another pharmaceutically acceptable anion.

T The sulfonate anion YS03 derived from the reaction between the compound of the formula (XI) and the compound of the formula (X) can be exchanged, in situ or after isolation of the compound of the formula (1) in which X ® is TT the ion YS03, by another anion X, according to conventional methods, for example by exchange in solution with a saturated solution of sodium chloride or T with a solution of hydrochloric acid when X represents a chloride anion or by anion exchange by elution of the compound (1) in an ion exchange resin, for example the Amberlite IRA68® or Duolite A375®. The compounds of formula (II) are prepared according to different operating modes. The compounds of formula (II) in which -A- represents the divalent radical -CH2-0-C0- and E represents hydrogen or a 0-protecting group is prepared according to SCHEME 1 below in which my Arx are such as are defined for a compound of formula (1) and Pr designates a 0-protecting group as defined above for E.

SCHEME 1 (xp) pan) al Pr-O-YCHj ^ -CH-CN (XIV) Ar, i "CHj-OH PG.O-ÍCHJ C-CN (XV) Ar, CHj-OH Pr-O-íCHj C-CI ^ -NHj (XVI) Ar, di In step a of SCHEME 1, a compound of formula (XII) is reacted with a compound of formula (XIII) in accordance with the method described in patent applications EP-A-0428434 and EP-A-0474561. The compound (XIV) thus obtained is put into reaction in step bl with an aqueous solution of formaldehyde, in the presence of a base such as 1,8-diazabicyclo [5.4.0] undec-7-ene, in a solvent such such as 1,2-dimethoxyethane, and at a temperature between room temperature and the reflux temperature of the solvent. The nitrile derivative of formula (XV) is reduced in step cl to obtain the primary amine of formula (XVI). This reduction can be effected by means of hydrogen, in the presence of a catalyst such as Raney® nickel, platinum oxide or palladium on carbon, in an inert solvent such as an alcohol, ethanol for example, alone or in mixture with ammonia, or by means of a reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride, borane in THF, in a solvent such as toluene, hexane, petroleum ether, xylene or tetrahydrofuran. The reaction is carried out at a temperature between 0 ° C and 70 ° C. The compound (XVI) is reacted in the di step with a reactive derivative of carbonic acid such as phosgene in solution in toluene, 1,1'-carbonyldiimidazole, in the presence of a base such as triethylamine, N , N-diisopropylethylamine or N-methylmorpholine, in a chlorinated solvent such as dichloromethane, 1,2-dichloroethane or an ether such as tetrahydrofuran, and at a temperature between -70 ° C and room temperature to obtain a compound of the expected formula (II) in which E represents an O-protective group. By hydrolysis, according to the methods described above, the O-protecting group is eliminated (step el) and the compound of formula (II) in which E represents hydrogen is obtained. The compounds of the formula (II) in which -A- represents the divalent radical -0-CH2-C0- and E represents the hydrogen or an O-protecting group, are prepared according to the following SCHEME 2, in which my Arx are as defined for a compound of formula (I). Pri and Pr2 represent the O-protecting group Pr as defined above for E, more particularly Prx represents an O-protective group hydrolysable in acidic medium, Pr2 represents an O-protective group hydrolysable in basic medium.

SCHEME 2 HO- H-CN (xvpi) I d2 OH O Prj-O CHj C-C? J -NH-C-CHj-Hal (?? pi) Ar, g2 h2 In step a2 of SCHEME 2, the synthesis of a cyanohydrin of formula (XVIII) from an aldehyde of formula (XVII) is carried out according to methods well known to the person skilled in the art, such as for example that described in Organic Syntheses; Wiley, New-York, 1932; Collect. vol. 1 p. 336, or by adaptation of this method using the action of sodium metabisulfite and potassium cyanide in aqueous solution. In step b_2, the hydroxy group of the compound of the formula (XVIII) is protected according to methods known to the person skilled in the art. The compound of formula (XIX) thus obtained is treated in step c2 by a strong base such as lithium diisopropylamide, potassium tert-butylate or sodium hydride to provide a carbanion which is reacted with a compound of formula Hal- (CH 2) m-0-Pr 2, in which Hal represents a halogen, preferably bromine or chlorine, to obtain the compound of formula (XX). The reaction is carried out in an inert solvent such as an ether (for example tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane) or an amide (for example N, N-dimethylformamide) or an aromatic hydrocarbon (for example toluene, xylene,) at a temperature between -70 ° C and + 60 ° C. The nitrile derivative of formula (XX) is reduced to step d2 according to the methods described above, to obtain the primary amine of formula (XXI).

In step e2, the compound of formula (XXI) is put into reaction, with a compound of formula Hal-CO-CH2-Hal in which Hal represents a halogen, preferably chlorine or bromine, in the presence of a base such as a tertiary amine (for example triethylamine, N-methylmorpholine, pyridine) to obtain a compound of formula (XXII). The reaction is carried out in an inert solvent such as a chlorinated solvent (for example dichloromethane, dichloroethane, chloroform), an ether (for example tetrahydrofuran, dioxane) or an amide (for example N, N-dimethylformamide) at a temperature comprised between - 70 ° C and room temperature. The O-protective group Prx of the compound of formula (XXII) is eliminated in step f2 by acid hydrolysis according to the methods described above. Alternatively, is it eliminated in stage X? the O-protecting group Pri of the compound of formula (XXI) by acid hydrolysis, then, in step k2, the compound (XXIV) thus obtained is reacted with a compound of formula Hal-CO-CH2-Hal according to the methods described above in step e2. The compound of formula (XXIII) thus obtained is cyclized in the presence of a base to obtain the expected compound of formula (II). When it is desired to obtain a compound of the formula (II) in which E represents a protecting group Pr2, a base such as an alkali metal carbonate (for example potassium carbonate) or an alkali metal hydride (e.g. , sodium hydride) or potassium tert-butylate, in an inert solvent such as an aromatic hydrocarbon (for example, xylene, toluene) or an amide (for example N, N-dimethylformamide) or an ether (for example tetrahydrofuran) ), at a temperature between -30 ° C and the reflux temperature of the solvent (step q2). When it is desired to obtain a compound of the formula (II) in which E represents hydrogen, a base such as an alkali metal hydroxide (for example sodium hydroxide, potassium hydroxide) in concentrated aqueous solution is used in a solvent such as an alkanol (for example propan-2-ol) or an amide (for example N, N-dimethylformamide) or a mixture of these solvents at a temperature between room temperature and the reflux temperature of the solvent ( stage h_2). Optionally, a compound of formula (II) is prepared in step i2 in which E represents a 0-protecting group Pri according to methods known to the person skilled in the art. The compounds of formula (II) in which -A- represents the divalent radical -0-CH2-CH2- and E represents hydrogen or a 0-protecting group, are prepared according to the following SCHEME 3 in which my Ari are as defined for a compound of formula (I) and Pri and Pr2 are as defined in SCHEME 2 above. SCHEME 3 a3 In step a_3 of SCHEME 3, a compound of formula (II) is reduced in which -A- represents the divalent radical -0-CH2-CO- and E represents hydrogen or an O-protecting group, obtained according to SCHEME 2. The reduction is effected by means of a reducing agent such as aluminum and lithium hydride, diisobutylaluminum hydride, sodium borohydride, borane in THF, in an inert solvent such as tetrahydrofuran, ether diethyl, 1,2-dimethoxyethane or toluene at a temperature between room temperature and the reflux temperature of the solvent. The compounds of the formula (I) in which -A- represents the divalent radical -0-C0- and E represents the hydrogen or a 0-protecting group, are prepared according to the following SCHEME 4, in which and Ari are as defined for a compound of formula (I) and Pri and Pr2 are as defined in SCHEME 2 above.

SCHEME 4 a4 OH Prj-O-iCH ^ -C-C? J-NHj (XXTV) Ar, In step a_4 of SCHEME 4, the 0-protecting group Prx of the compound of formula (XXI), obtained in step d2 of SCHEME 2, is eliminated., by acid hydrolysis according to the methods described above. The compound of formula (XXIV) thus obtained is reacted in step b_4 with a reactive derivative of carbonic acid such as 1,1 '-carbonyldiimidazole, phosgene in toluene, chloroformate of p-nitrophenyl, and in the presence of a base such as triethylamine, N, -diisopropylethylamine, N-methylmorpholine, to obtain a compound of formula (II) expected in which E represents a 0-β-rotective group. The reaction is carried out in an inert solvent such as a chlorinated solvent (for example, 1,2-dichloroethane, dichloromethane) or an ether such as tetrahydrofuran or an amide such as N, N-dimethylformamide or an aromatic solvent such such as toluene at a temperature between -60 ° C and room temperature. By basic hydrolysis, according to the methods described above, the O-protecting group Pr2 is eliminated (step c4) to obtain the compound of formula (II) in which E represents hydrogen. The compounds of formula (II) in which -A- represents the divalent radical -N (R?) -C0-C0- and E represents hydrogen or an O-protecting group, are prepared according to SCHEME 5 below in wherein m, Ari and Ri are as defined for a compound of formula (I) and Pri is as defined above.

SCHEME 5 Ar, to 5 R.-NH-CH-CN (XXV) I Ar, b5 R. Boc-N-CH-CN (XXVI) PrrO. (CH2) m-C-CN (XXVII) Ar, eS NH-R. I HO CHj ^ -C-CHj- Hj (XXX) Ar, le (IT) -A- - -N (R,) - CO-CO- E = H £ (II): -A- - N (R,) - CO-CO- E-Pr, In step a5 of SCHEME 5, the preparation of an a-aminonitrile compound of formula (XXV) is carried out from a aldehyde of formula (XVII) according to the method described in Tetrahedron Letters, 1984, 25 (41), 4583-4586 and using an amine of formula H2N-R ?. The amino group of the compound of formula (XXV) is protected in step b5 by an N-protecting group such as tert-butoxycarbonyl (Boc), benzyloxycarbonyl for example according to methods known to the person skilled in the art. The tert-butoxycarbonyl group is illustrated in SCHEME 5 above. The compound of formula (XXVI) thus obtained is treated in step c5 by a strong base to form a carbanion which is reacted with a compound of formula Hal- (CH 2) m-0-Pr? to obtain a compound of formula (XXVII). The reaction is carried out according to the method described in step c2 of SCHEME 2. The nitrile derivative of formula (XXVII) is reduced in step d_5 according to the methods described above to obtain the primary amine of formula (XXVIII) . The O-protecting group and the N-protecting group of the compound of the formula (XXVIII) are removed in step e5 by acid hydrolysis using hydrochloric acid or trifluoroacetic acid, for example in a solvent such as alcohol (for example methanol) or an ether (for example diethyl ether, dioxane, tetrahydrofuran) or a chlorinated solvent (for example dichloromethane) at a temperature between 0 ° C and the reflux temperature of the reaction mixture. In step f_5, the preparation of the compound of the formula - (II) expected, is carried out by the application or adaptation of the method described by R. Granger, H. Orzalesi and Y. Robbe in Trav. Soc. Pharm. Montpellier, 1965, 25, Phase. 4, 313-317, using the reaction of a compound of formula (XXIX) with diethyl oxalate in an alcohol solvent such as ethanol or an aromatic solvent such as toluene or a mixture of these solvents, at a temperature between the ambient temperature and the reflux temperature of the reaction mixture. Optionally, a compound of formula (II) is prepared in step g_5 in which E represents a 0-protecting group Pri according to methods known to the person skilled in the art. The compounds of the formula (II) in which -A- represents the divalent radical -N (RX) -CH2-CH2- and E represents the hydrogen or an O-protecting group, are prepared according to the following SCHEME 6, wherein m, Ri and Arx are as defined for a compound of formula (I) and Pri designates an O-protecting group as defined above for E. SCHEME 6 ,) - CO-CO- a6 bó In step a6 of SCHEME 6, a compound of formula (II) is reduced in which -A- represents the divalent radical -N (R?) -CO-CO- and E represents a 0-protecting group, obtained in the step 5 of SCHEME 5. The reduction is effected by means of a reducing agent such as aluminum and lithium hydride, in an inert solvent such as an ether (for example tetrahydrofuran, 1,2-dimethoxyethane or diethyl ether) or an aromatic solvent such as toluene at a temperature between room temperature and the reflux temperature of the solvent. Optionally, the 0-protecting group is removed in step b6 by acid hydrolysis according to the methods described above, to obtain the compound of the formula (II) in which E represents hydrogen. The compounds of formula (II) in which -A- represents a divalent radical -N (R?) -C0- and E represents hydrogen or an O-protecting group, are prepared according to SCHEME 7 below in which m, Rx and Arx are as defined for a compound of formula (I) and Pri is as defined in SCHEME 2 above.

SCHEME 7 a7 b7 c7 In step a7, the hydroxyl of the compound of formula (XXIX), obtained in step e5 of SCHEME 5, is protected according to methods known to the person skilled in the art. In step b7, the compound of formula (XXX) thus obtained is reacted with a reactive derivative of carbonic acid such as 1,1 '-carbonyldiimidazole, phosgene in toluene, chloroformate of p-nitrophenyl, in the presence of a base such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, to obtain a compound of formula (II) expected, in which E represents an O-protecting group. The reaction is carried out in an inert solvent such as a chlorinated solvent (for example 1,2-dichloroethane, dichloromethane) or an ether (for example tetrahydrofuran) or an amide (for example N, N-dimethylformamide) or an aromatic solvent (for example toluene) at a temperature between -60 ° C and 60 ° C. Optionally, a compound of formula (II) is prepared in step c7 in which E represents hydrogen according to methods known to the person skilled in the art. The compounds of the formula (II) in which -A- represents the divalent radical -0-CH2- and E represents hydrogen or an O-protecting group, are prepared according to SCHEME 8 below, in which my Arx are as defined for a compound of formula (I) and Pr2 is as defined in SCHEME 2 above.

SCHEME 8 a8 b8 In step a8 of SCHEME 8, a compound of formula (XXIV) is reacted with an aqueous solution of formaldehyde in an inert solvent such as tetrahydrofuran and at a temperature between room temperature and the reflux temperature of the solvent to obtain a compound of formula (II) expected, in which E represents an O-protective group. By basic hydrolysis, according to the methods described above, the O-protecting group Pr2 is eliminated (step b8) to obtain the compound of the formula (II) in which E represents hydrogen. The compounds of formula (XI) are prepared according to known methods such as those described in the following publications: - J. Chem. Soc., 1937, 1523-1526; - J. Chem. Soc., 1938, 400. Compounds of formula (XI) can also be prepared according to SCHEME 9 below in which n and Ar2 are as defined for a compound of formula (I) and Bz represents the benzyl radical.

SCHEME 9 (xxxip) e9 (XI) In step a9 of SCHEME 9, the nitrogen atom of the piperidine of formula (XXXI) is protected by a benzyl group according to methods known to the person skilled in the art. The carboxy group in the 4-position of the piperidine of the formula (XXXII) thus obtained is reduced in step b9 to obtain the compound of the formula (XXXIII) substituted in the 4-position by a hydroxymethyl group. The reduction is effected by means of a reducing agent such as borane in THF or the borane-dimethylsulfide complex, in an inert solvent such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane or dichloromethane at a temperature comprised between the ambient temperature and the reflux temperature of the solvent. The compound of the formula (XXXIII) can also be obtained from the compound of the formula (XXXI) by reduction of the carboxy group (step c9), then the protection of the nitrogen of the piperidine of the formula (XXXIV) obtained (step d9) ) according to the methods mentioned above. In step e_9, the compound (XXXIII) is put into reaction with the methanesulfonyl chloride in the presence of a base such as triethylamine to obtain the compound of the formula (XXXV) cyclized in the form of quaternary ammonium. The reaction is carried out in an inert solvent such as dichloromethane or toluene, at a temperature between -20 ° C and the reflux temperature of the solvent. The compound (XXXV) is deprotected in step f_9 according to methods known to the person skilled in the art. The expected compounds of the formula (XI) are thus obtained. The piperidines of the formula (XXXI) are known or prepared according to known methods such as those described in the international application WO94/26735. In particular, it is possible to prepare a compound of the formula (XXXI) in which n = 1 by acid hydrolysis of a corresponding piperidine substituted in the 4-position by a cyano group, which can be obtained by reaction of a 4-cyanopiperidine. with a halogenide of the formula Ar2-CH2-Hal in the presence of a base such as sodium diisopropylamide. 4-Cyanopiperidine is obtained by reaction of isonipecotamide with phosphorus oxychloride. The enantiomers of the compounds according to the invention, of the formula: Am- (CH2) m-C * - CAHx2-N-T (I *) Ar. in which: - "*" means that the carbon atom thus marked has the absolute (+) or (-) determined configuration; Am, m, Arx, A and T are as defined for the compounds of the formula (I); as well as their eventual salts with mineral or organic acids; they are new compounds that are part of the invention. The resolution of the racemic mixtures of the compounds of the formula (I) makes it possible to isolate the enantiomers of formula (I *). However, it is preferable to carry out the splitting of the racemic mixtures from a compound of the formula (II) or from an intermediate compound useful for the preparation of a compound of the formula (II). Thus, when it is desired to prepare the enantiomers (I *) of the compounds of the formula (I) in which -A-represents the divalent radical -CH2-0-CO-, the splitting of the racemic mixture of a compound is carried out. intermediary of the formula: (xxxvi) in which my and Ari are such as are defined for a compound of the formula (I), obtained by elimination of the O-protector group Pr, according to the methods described above, of a compound of the formula (XVI). When it is desired to prepare the enantiomers (I *) of the compounds of the formula (I) in which -A- represents the divalent radical -0-CO- or -0-CH2-CO or -0-CH2-CH2- or -0-CH2-, the splitting of the racemic mixture of a compound of the formula is carried out: OH Pr2- (MCH ^ -CH2-íffl2 (XXIV) Ar, wherein m and Ari are as defined for a compound of formula (I) and Pr2 is as defined above in SCHEME 2 above. When it is desired to prepare the enantiomers (I *) of the compounds of the formula (I) in which -A- represents the divalent radical -0-CH2-CH2-, it is also possible to carry out the splitting of the racemic mixture of a compound of the formula: wherein m and Ari are as defined for a compound of the formula (I). When it is desired to prepare the enantiomers (I *) of the compounds of the formula (I) in which -A- represents the divalent radical -N (Rx) -C0- or -N (R?) -CO-CO- or -N (R?) - CH2-CH2-, the splitting of the racemic mixture of an intermediate compound of the formula is carried out: wherein m, Arx and Ri are as defined for a compound of the formula (I). When the splitting of the racemates is carried out in the intermediate compounds of formula (XXXVI), (XXIV), (XXIX) or (II) [-A- = -0-CH2-CH2- and E = H] this can be carried out according to known methods by forming a salt with the optically active acids, for example with (+) or (-) tartaric acid. The diastereoisomers are then separated by the classical methods such as crystallization or chromatography then by hydrolysis the optically pure enantiomers are obtained. The compounds of formula (I) above also include those in which one or more hydrogen, carbon or iodine atoms have been replaced by their radioactive isotope, for example, tritium, carbon-14 or iodine-125. . Such labeled compounds are useful in search, metabolism or pharmacokinetic work, in biochemical assays as receptor ligands. The affinity of the compounds for the receptors in the takikinins has been evaluated in vitro by several biochemical assays, using the radioligands. 1) The binding of [125 I] BH-SP (Substance P marked on iodine-125 with the aid of the Bolton-Hunter reagent) in the NKX receptors of human lymphoblastic cells. 2) The [125I] His-NKA bond at the NK2 receptors of the duodenum or rat bladder. 3) The [125I] His [MeFe7] NKB linkage in the NK3 receptors of the cerebral cortex of the rat, of the cerebral cortex of the guinea pig and of the cerebral cortex of the gerbil as well as in the human NK3 cloned receptors expressed by the CHO cells. { Buell et al., FEBS Letters, 1992, 299, 90-95). The tests have been carried out according to X. Emonds-Alt et al. (Eur. J. Pharmacol., 1993, 250, 403-413). The compounds according to the invention generally have an affinity for the receptors of the takikinins mentioned above, with an inhibition constant Ki preferably less than 10"8 M. The compounds of the present invention are mainly the active ingredients of pharmaceutical compositions, whose toxicity is compatible with its use as medicaments The compounds of the present invention are generally administered in dosage units The dosage units are preferably formulated in the pharmaceutical compositions in which the active ingredient is mixed with a pharmaceutical excipient. Thus, according to another of its aspects, the present invention relates to pharmaceutical compositions containing, as an active ingredient, a compound of formula (I) or a pharmaceutically acceptable salt thereof The compounds of formula (I) above and its pharmaceutically acceptable salts can be useful in daily doses of 0.01 to 100 mg per kilo of body weight of the mammal to be treated, preferably at daily doses of 0.1 to 50 mg / kg. In humans, the dose can preferably vary from 0.5 to 4000 mg per day, more particularly from 2.5 to 1000 mg according to the age of the subject to be treated or the type of treatment: prophylactic or curative. In the pharmaceutical compositions of the present invention, for oral, sublingual, inhaled, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active ingredients can be administered in unitary forms of administration, in admixture with conventional pharmaceutical supports , in animals and in human beings. Suitable unit administration forms comprise oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, administration forms subcutaneous, intramuscular, intravenous, intranasal or intraocular and forms of rectal administration. When preparing a solid composition in the form of tablets, the main active ingredient is mixed with a pharmaceutical carrier such as silica, gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The sucrose tablets, various polymers or other suitable materials can be coated or even treated in such a way that they have a prolonged or delayed activity and continuously release a predetermined amount of active ingredient. A preparation of capsules is obtained by mixing the active principle with a diluent such as a glycol or a glycerol ester and incorporating the mixture obtained in the soft or hard capsules. A preparation in the form of syrup or elixir may contain the active ingredient together with a sweetener, preferably a caloric sweetener, of methylparaben and propylparaben as an antiseptic, as well as a flavoring agent and an appropriate colorant. Powders or granules dispersible in water may contain the active ingredient in admixture with dispersing agents or emollient agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or flavor correctors. For a rectal administration, suppositories are used, which are prepared with the binding products that melt at the rectal temperature, for example cocoa butter or polyethylene glycols. For parenteral, intranasal or intraocular administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing dispersing agents and / or pharmacologically compatible wetting agents are used, for example propylene glycol or butylene glycol. For administration by inhalation, an aerosol containing for example sorbitan trioleate or oleic acid as well as trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane or any other biologically compatible propellant gas is used.; it is also possible to use a system that contains the active principle or associated to an excipient, in the form of powder. The active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives. In each dosage unit the active principle of the formula (I) is present in the quantities adapted to the daily doses contemplated. In general, each dosage unit is suitably adjusted according to the dosage and the type of administration envisaged, for example tablets, capsules and the like, sachets, ampoules, syrups and the like, drops so that a dosage unit contains from 0.5 to 1000 mg of active substance, preferably from 2.5 to 250 mg before being administered one to four times per day.

The compositions mentioned may also include other active products such as, for example, bronchodilators, antitussives, antihistamines, anti-inflammatories, antiemetics, chemotherapy agents. According to another of its aspects, the present invention relates to the use of products of the formula (I) for the preparation of drugs intended to treat psychological disorders associated with an excess of takikinins and all the pathologies dependent on the neurokinin of the system. respiratory, gastrointestinal, urinary, immune, cardiovascular and central nervous system as well as pain and migraine. For example and in a non-limiting manner: - acute and chronic pains linked, for example, to migraine, to pains of cancer and angina, to chronic inflammatory processes such as osteoarthritis and rheumatoid arthritis, inflammations such as neurogenic inflammations, chronic inflammatory diseases, for example, chronic obstructive respiratory diseases, asthma, allergies, rhinitis, cough, bronchitis, hypersensitivity for example to polens and mites, rheumatoid arthritis, fibrosites , osteoarthritis, psoriasis, ulcerative colitis, Crohn's disease, inflammation of the intestines (irritable bowel), prostatitis, neurological bladder, incontinence, cystitis, urethritis, nephrite, ophthalmic diseases such as conjunctivitis, vitreoretinopathy, cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, eczema, pruritus, burns, especially burns caused by the sun, - diseases of the immune system linked to suppression or stimulation of functions of immune cells for example rheumatoid arthritis, psoriasis, Crohn's disease, diabetes, lupus, rejection reactions after transplantation, - small cell lung cancers, demyelinating diseases such as multiple sclerosis or amyotrophic lateral sclerosis, - neuropsychiatric or neurological diseases of the central nervous system such as anxiety, disorders of vigilance, mood, depression, psychosis, schizophrenia, mania, dementia, epilepsy, Parkinson's disease, Alzheimer's disease, drug dependence, alcoholism , Down syndrome and the San Vito dance of Huntington as well as neurodegenerative diseases, somatic disorders diseases linked to stress, - diseases of the gastrointestinal system such as nausea, vomiting of all origins, irritable bowel, gastric and duodenal ulcers, esophageal ulcers, diarrhea, hypersecretions, - diseases of the cardiovascular system such as hypertension, vascular aspects of migraine, edema, thrombosis, angina pectoris, vascular spasms, circulatory diseases due to vasodilatation, Reynauld's diseases, fibrosis, collagen diseases, frequency and heart rhythm disorders, particularly those that are caused by pain or stress. The present invention also includes a method for treating conditions at the doses indicated above. In the Preparations and Examples the following abbreviations are used: Me, OMe: methyl, methoxy Et, OEt: ethyl, ethoxy EtOH: ethanol MeOH: methanol Ether: diethyl ether Iso: diisopropyl ether DMF: dimethylformamide DMSO: dimethisulfoxide DCM: dichloromethane THF: tetrahydrofuran AcOEt: ethyl acetate Na2C03: sodium carbonate NaHC03: carbonate sodium acid NaCl: sodium chloride Na2S04: sodium sulfate MgSO4: magnesium sulfate NaOH: soda HCl: hydrochloric acid TFA: trifluoroacetic acid hydrochloric acid: solution saturated with hydrochloric acid in ether KCN: potassium cyanide Na2S2? 5: sodium metabisulfite DBU: 1,8-diazabicyclo [5.4.0] undec-7-ene NH4CI: ammonium chloride F: melting point TA: room temperature silica H: silica gel 60H marketed by Merck (DARMSTADT) "NMR: nuclear magnetic resonance d: chemical shift s: singlet sa: singlet broad d: doublet t: triplet cd: cua druplete mt: multiplet m: massive PREPARATIONS Preparation 1.1. 5- (3,4-dichlorophenyl) -5- [2- (tetrahydropyran-2-yloxy) -ethyl] -tetrahydro-2H-1, 3-oxazin-2-one. A) 2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) -butanitrile. A suspension of 17.75 g of sodium hydride (80% in oil) in 750 ml of THF is cooled in an ice bath, a solution of 100 g of 3,4-dichlorophenylacetonitrile in 250 ml of THF is added dropwise. two hours are left under stirring at RT. The reaction mixture is cooled to -20 ° C, a solution of 112.36 g of l-bromo-2- (tetrahydropyran-2-yloxy) ethane in 120 ml of THF is added dropwise and the mixture is left stirring for 2 hours. TA. The reaction mixture is concentrated under vacuum, the residue is taken up in water, extracted with ether, the organic phase is washed twice with a buffer solution pH = 4, with a buffer solution pH = 7, twice with a saturated solution of NaCl, dried over a2S? 4 and the solvent was evaporated under vacuum. The residue is chromatographed on silica eluting with toluene then the toluene / AcOEt mixture (100/3, v / v). 113.5 g of the expected product is obtained which is used as such.

B) 2- (3,4-dichlorophenyl) -2- (hydroxymethyl) -4- (tetrahydropyran-2-yloxy) utan-nitrile. A mixture of 12.56 g of the compound obtained in the preceding step, 9.6 g of a 37% solution of formaldehyde in water, 0.3 g of DBU in 25 ml of 1,2-dimethoxyethane is heated at reflux for 1 hour. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed twice with water, twice by a buffer solution pH = 4, twice with water, twice with a saturated solution of NaCl, Dry over Na2SO4 and evaporate the solvent under vacuum. 17 g of the expected product is obtained which is used as such.

C) 2- (3,4-dichlorophenyl) -2- (hydroxymethyl) -4- (tetrahydropyran-2-yloxy) butylamine. A mixture of 17 g of the compound obtained in the preceding step, 6 g of Raney® nickel in 300 ml of EtOH and 40 ml of a 20% solution of ammonia in the hydrogenate is hydrogenated for 5 hours at 40 ° C and at atmospheric pressure. Water. The catalyst is filtered and the filtrate is concentrated under vacuum. The residue is taken up in DCM, the organic phase is washed with water, a saturated solution of NaCl, dried over MgSO 4 and the solvent evaporated under vacuum. 16.5 g of the expected product are obtained in the form of an oil and this is used as it is.

D) 5- (3,4-dichlorophenyl) -5- [2- (tetrahydropyran-2-yloxy) -ethyl] -tetrahydro-2H-1, 3-oxazin-2-one. Cool to -70 ° C, 24.6 g of a 20% solution of phosgene in the toluene, dilute in 150 ml of DCM, add a dropwise solution of 16.5 g of the compound obtained in the preceding step, 5.7 g. of triethylamine in 100 ml of DCM and left under stirring, allowing the temperature to rise to RT. The reaction mixture is concentrated under vacuum, the residue is taken up in a water / AcOEt mixture, the product is dried, which crystallizes at the interface and a first jet of the expected product is obtained. After decanting the filtrate, the organic phase is washed in water, a buffer solution pH = 4, a saturated solution of NaCl, dried over MgSO and the solvent evaporated under vacuum. The residue is recovered with AcOEt, the crystallized product formed is drained and the second product jet is obtained. A total of 4.5 g of the expected product is obtained.

Preparation 1.2 5- (3,4-Dichlorophenyl) -5- [3- (tetrahydropyran-2-yloxy) -propyl] -tetrahydro-2H-1, 3-oxazin-2-one. A) 2- (3,4-dichlorophenyl) -5- (tetrahydropyran-2-yloxy) pentanenitrile. To a suspension of 12 g of sodium hydride (55% in oil) in 175 ml of THF, a 50.8 g solution is added dropwise to a temperature below 20 ° C. 3-dichlorophenylacetonitrile in 250 ml of THF and leave for 2 hours under stirring at RT. The reaction mixture is cooled to -20 ° C, a solution of 62.5 g of l-bromo-3- (tetrahydropyran-2-yloxy) propane in 60 ml of THF is added dropwise and the mixture is left stirring to raise the temperature to TA. The reaction mixture is poured into a solution of 31 g of ammonium chloride in 1.4 liters of water, extracted with ether, the combined organic phases are washed with a saturated solution of NaCl, dried over MgSO 4 and the solvents. The residue is chromatographed on silica, eluting with toluene, then the toluene / AcOEt mixture (95/5; v / v). 64 g of the expected product is obtained which is used ral which.

B) 2- (3, -dichlorophenyl) -2- (hydroxymethyl) -5- (tetrahydropyran-2-yloxy) pentan-nitrile. A mixture of 15 g of the compound obtained in the preceding step, 11.2 g of a 37% solution of formaldehyde in water, 0.35 g of DBU in 30 ml of 1,2-dimethoxyethane is heated at reflux for 1 hour. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water, twice with a buffer solution pH = 4, twice with water, twice with a saturated solution of NaCl, dried Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica, eluting with toluene then the toluene / AcOEt mixture (80/20, v / v). 15.5 g of the expected product is obtained which is used as such.

C) 2- (3,4-dichlorophenyl) -2- (hydroxymethyl) -5- (tetrahydropyran-2-yloxy) pentylamine. A mixture of 15.5 g of the compound obtained in the preceding step is hydrogenated for 5 hours at 30 ° C and at atmospheric pressure, - 5 g of Raney® nickel in 200 ml of EtOH and 40 ml of a 20% solution of ammonia in Water.

The catalyst is filtered and the filtrate is concentrated under vacuum. The residue is taken up in DCM, the organic phase is washed with water, a saturated solution of NaCl, dried over MgSO 4 and the solvent evaporated under vacuum. 14.9 g of the expected product are obtained in the form of oil and this is used as it is, D) 5- (3,4-dichlorophenyl) -5- [3- (tetrahydropyran-2-yloxy) -propyl] -tetrahydro-2H-1, 3-oxazin-2-one. Cool to -70 ° C, 21.4 g of a 20% solution of phosgene in toluene, dilute in 120 ml of DCM, add a drop of 14.9 g of the compound obtained in the preceding step, 4.98. g of triethylamine in 80 ml of DCM and left under stirring, allowing the temperature to rise to RT. The reaction mixture is concentrated under vacuum, the residue is taken up with water, extracted with ether, the organic phase is washed with water, with a saturated NaCl solution, it is removed over MgSO 4 and the evaporation is low. vacuum the solvent. 12.5 g of the expected product is obtained which is used as such.

Preparation 1.3 6- (3,4-Dichlorophenyl) -6- [2- (tetrahydropyran-2-yloxy) -ethyl] morpholin-3-one. A) 2 (3,4-dichlorophenyl) -2-hydroxyacetonitrile.

A mixture of 70 g of 3,4-dichlorobenzaldehyde, 90 g of Na 2 S 205 in 300 ml of water is left overnight under stirring. The reaction mixture is cooled to 0 ° C, a solution of 52 g of KCN in 100 ml of water is added dropwise and it is left under stirring, allowing the temperature to rise to RT. The reaction mixture is extracted with ether, the organic phase is washed with water, dried over a2S? 4 and the solvent is evaporated under vacuum. 76 g of the expected product is obtained which is used as such.

B) 2- (3,4-dichlorophenyl) -2- (tetrahydropyran-2-yloxy) -acetonitrile. A solution of 76 g of the compound obtained in the preceding step, 0.25 g of p-toluenesulfonic acid monohydrate in 300 ml of DCM is cooled to 0 ° C, a solution of 39 g of 3,4-dihydroxypropionate is added dropwise. 2 H-pyran in 50 ml of DCM and leaving under stirring allowing the temperature to rise to RT. The reaction mixture is washed with a saturated solution of NaHCO 3 with water, the organic phase is dried over Na 2 SO 4 and the solvent is evaporated under vacuum. 33 g of the expected product are obtained after crystallization at 0 ° C in the pentane, F = 61 ° C.

C) 4- (Benzoyloxy) -2- (3,4-dichlorophenyl) -2- (tetrahydropyran-2-yloxy) butan-nitrile.

To -60 C 56 ml of a 2M solution of lithium diisopropylamide in the THF is added, a solution of 32 g of the compound obtained in the preceding step is added dropwise in 50 ml of THF and left stirring for 1 hour. - -60 ° C. Next s-c- add ar -60 ° C, drop by drop, a solution of 25.4 g of 2-bromoethyl benzoate in 50 ml of THF and left under stirring allowing the temperature to rise to RT. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water, a buffer solution pH = 4, dried over Na 2 SO and the solvent evaporated under vacuum. Chromatograph the residue on 3-lice eluting with a toluene / AcOEt mixture (100/5; v / v). 34 g of the expected product are obtained which is used as such.

D) 4- (Benzoyloxy) -2- (3,4-dichlorophenyl) -2- (tetrahydropyran-2-yloxy) or ilamine. A mixture of 34 g of the compound obtained in the preceding step, 10 g of Raney® nickel in 400 ml of EtOH and 40 ml of a concentrated ammonia solution is hydrogenated at RT and at atmospheric pressure. The catalyst is filtered and the filtrate is concentrated under vacuum. The residue is taken up in water, extracted with ether, the organic phase is washed with a saturated solution of NaCl, dried over Na 2 SO 4 and the solvent evaporated under vacuum. The residue is chromatographed on silica H eluting the gradient of the DCM / MeOH mixture from (100/1; v / v) to (100/3; v / v). 16 g of the expected product is obtained which is used as such.

E) N- (2-bromoacetyl) -4- (benzoyloxy) -2- (3,4-dichlorophenyl) -2-hydroxybutylamine. A solution of 16 g of the compound obtained in the preceding step, 4.8 g of triethylamine in 100 ml of DCM is cooled to -60 ° C, a solution of 5.68 g of bromoacetyl chloride in 20 ml of DCM is added dropwise and 30 minutes are left under agitation. The reaction mixture is concentrated under vacuum, the residue is extracted in ether, the organic phase is washed with water, a buffer solution pH = 4, dried over Na 2 SO 4 and the solvent evaporated under vacuum. The product obtained is dissolved in a minimum of MeOH, acidified to pH = 1 by the addition of a saturated solution of HCl gas in ether and the solvents are evaporated under vacuum. The residue is taken up in water, extracted with AcOEt, the organic phase is washed with a saturated solution of NaHCO 3, with water, dried over Na 2 SO 4 and the solvent evaporated under vacuum. 16 g of the expected product is obtained which is used as such.

F) 6- (3,4-dichlorophenyl) -6- (2-hydroxyethyl) morpholin-3-one. A mixture of 16 g of the compound obtained in the preceding step, 50 ml of propan-2-ol, 15 ml of a solution of NaOH ION and 10 ml of DMF is left stirring for 4 hours. The reaction mixture is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water, dried over Na 2 SO 4 and the solvent evaporated under vacuum. The residue is chromatographed on silica H eluting with the gradient of the DCM / MeOH mixture of (100/3; v / v) to (100/5; v / v). 6.1 g of the expected product are obtained. Proton NMR spectrum at 200 MHz in DMSO ^ d6 d: 2.05 ppm: mt: 2H 3.0 to 4.4 ppm:: 6H 4.5 ppm: t: ÍH 7.3 to 8.3 ppm: m: 4H G) 6- (3,4-dichlorophenyl) -6- [2- (tetrahydropyran-2-yloxy) -ethyl] morpholin-3-one. A solution of 1.7 g of the compound obtained in the preceding step, 0.003 g of p-toluenesulfonic acid monohydrate in 50 ml of DCM is cooled to 0 ° C, 0.588 g of 3,4-dihydro-2H-pyran 10 ml of DCM and leave for 1 hour under stirring at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with a saturated solution of NaHCO 3, with water, dried over Na 2 SO 4 and the solvent is evaporated under vacuum. The resin is subjected to eromarography on silica H eluting with the DCM / MeOH mixture (100/2; v / v). 1.8 g of the expected product is obtained which is used as 1-i-za-tal-qu-l.

Preparation 1.4 6- [2- (Benzoyloxy) ethyl] -6- (3,4-dichlorophenyl) morpholin-3-one. A mixture of 4.8 g of the compound obtained in Step E of Preparation 1.3, 1.4 g of K2C03 erv 100 ml of x-i-lene is heated at 130 ° C overnight. After cooling to RT, the reaction mixture is filtered and the filtrate is concentrated under vacuum. The residue is extracted with ether, the organic phase is washed with a buffer solution pH = 2, with water, dried over MgSO 4 and the solvent evaporated under vacuum. The residue is chromatographed on silica H eluting with the DCM / MeOH mixture (100/1 v / v). 1.4 g of the expected product are obtained. Proton NMR spectrum at 200 MHz in DMSO-d6 d: 2.45 ppm: mt: 2H 3.75 ppm: AB system: 2H 3.9 to 4.5 ppm: m: 4H 7.4 to 7.9 ppm: m: 8H 8.25 ppm: se: 1H This compound can also be obtained by following the three steps of the process described later. A ') 4- (Benzoyloxy) -2- (3) hydrochloride, 4-dichlorophenyl) -2- hydroxybutylamine. This compound is described in step A of Preparation 1.7. B ') N- (2-chloroacetyl) -4- (benzoyloxy) -2- (3,4-dichlorophenyl) -2-hydroxybutylamine. A solution of 20 g of the compound obtained in the preceding step, 10.3 g of triethylamine in 100 ml of DCM is cooled to 0 ° C, 5.8 g of chloroacetyl chloride are added dropwise and the mixture is left stirring for 30 minutes. The reaction mixture is concentrated under vacuum, the residue is extracted into AcOEt, the organic phase is washed with water, a buffer solution pH = 2 is added with water, dried over MgSO 4 and the solvent is evaporated under vacuum. 22 g of the expected product is obtained which is used as such.

C) 6- [2- (benzoyloxy) ethyl] -6- (3,4-dichlorophenyl) morpholin-3-one. A solution of 22 g of the compound obtained in the preceding step in 600 ml of THF is cooled to -10 ° C, 11.42 g of potassium tert-butylate are added and the mixture is left under stirring until completely dissolved. The reaction mixture is concentrated under vacuum, the residue is extracted with AcOEt, the organic fae is washed with a buffer solution pH = 2, with water, dried over MgSC4 and the solvent evaporated under vacuum. 12.8 g of the expected product are obtained after crystallization from ether.

Preparation 1.5 2- (3,4-Dichlorophenyl) -2- (2-hydroxyethyl) morpholine. A suspension of 1.6 g of aluminum and lithium hydroxide in 25 ml of THF is heated at 60 ° C, a solution of 4 g of the compound obtained in step F of Preparation 1.3 in 20 ml is added dropwise. of THF and left for 30 minutes under stirring at reflux. After cooling, 1.5 ml of water, 1.5 ml of 4N NaOH and 4.5 ml of water are added. The mineral salts are filtered over Celite®, the filtrate is decanted and the organic phase is evaporated under vacuum. The residue is taken up in ether, dried over Na 2 SO 4 and the solvent evaporated under vacuum. 3.6 g of the expected product are obtained.

Preparation 1.6 2- (3,4-dichlorophenyl) -2- (3-hydroxypropyl) morpholine.

A) 5- (Benzoyloxy) -2- (3,4-dichlorophenyl) -2- (tetrahydropyran-2-yloxy) pentan-nitrile. 47 ml of a 1.5M solution of lithium diisopropylamide in the THF are cooled to -60 ° C, 3e is added dropwise to a solution of 19.3 g of the compound obtained in step B of Preparation 1.3 in 100 ml of THF and 30 minutes are left under stirring at -60 ° C. Then, at -60 ° C, dropwise, 17 g of 3-bromopropyl benzoate are added and left under stirring, the temperature is allowed to rise to RT. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water, a saturated solution of NaCl, dried over Na 2 SO 4 and the solvent is evaporated under vacuum. 21 g of the expected product are obtained after crystallization in hexane.

B) 5- (Benzoyloxy) -2- (3,4-dichlorophenyl) -2- (tetrahydropyran-2-yloxy) pentylamine. A mixture of 20 g of the compound obtained in the preceding step, 7 g of Raney® nickel in 300 ml of MeOH is hydrogenated at RT and at atmospheric pressure. The catalyst is filtered and the filtrate is concentrated under vacuum. The residue is taken up in water, extracted with ether, the organic phase is washed with water, dried over Na 2 SO 4 and the solvent evaporated under vacuum. 20 g of the expected product is obtained which is used as such.

C) N- (2-Chloroacetyl) -5- (benzoyloxy) -2- (3,4-dichlorophenyl) -2- (tetrahydropyran-2-yloxy) pentylamine. A solution of 9 g of the compound obtained in the preceding step, 2.4 g of triethylamine in 100 ml of DCM is cooled to 0 ° C, a solution of 2.23 g of chloroacetyl chloride in 20 ml of DCM is added dropwise and Leave 30 minutes under agitation. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water, dried over Na 2 SO 4 and the solvent evaporated under vacuum. 9.5 g of the expected product is obtained which is used as such.

D) N- (2-Chloroacetyl) -5- (benzoyloxy) -2- (3, -dichlorophenyl) -2-hydroxypentylamine. To a solution of 9 g of the compound obtained in the preceding step in 50 ml of DCM and 50 ml of MeOH is added until pH = 1, a saturated solution of HCl gas in the ether and left for 30 minutes under stirring at RT. It is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water, a saturated solution of NaHCO3 / - is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica H eluting with the DCM / MeOH mixture (100/3; v / v). 4.7 g of the expected product is obtained which is used as such.

E) 6- (3,4-dichlorophenyl) -6- (3-hydroxypropyl) morpholin-3-one.

Allow 2 hours under stirring at RT, a mixture of 2. 95 g of the compound obtained in the preceding step, 40 ml of propan-2-ol, 3 ml of a solution of NaOH ION. The reaction mixture is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with water, dried over a2SO4 and the solvent evaporated under vacuum. The residue is chromatographed on silica H eluting with the gradient of the DCM / MeOH mixture (100/2; v / v) to (100/5; v / v). 0.5 g of the expected product is obtained, F = 130-132 ° C.

F) 2- (3,4-dichlorophenyl) -2- (3-hydroxypropyl) morpholine. A suspension of 0.82 g of aluminum hydride and lithium in 10 ml of THF is heated at 60 ° C, a solution of 2 g of the compound obtained in the preceding step in 20 ml of THF is added dropwise and left for 30 minutes under agitation at reflux. After cooling, 1 ml of water, 1 ml of 4N NaOH and then 3 ml of water are added. The mineral salts are filtered over Celite®, the filtrate is decanted and the organic phase is evaporated under vacuum. The residue is taken up in ether, dried over Na 2 SO and the solvent evaporated under vacuum. 2 g of the expected product are obtained. NMR spectrum of the proton at 200 MHz in DMS0-d6 d: 0.8 to 2.2 ppm: m: 4H 2.5 to 3. ppm: m: 8H 4.3 ppm: t: ÍH 7.2 to 7.7 ppm: m: 3H Preparation 1.7 5- [2- (Benzoyloxy) ethyl] -5- (3,4-dichlorophenyl) oxazolidin-2-one. A) 4- (Benzoyloxy) -2- (3,4-dichlorophenyl) -2-hydroxybutylamine hydrochloride. To a solution of 12 g of the compound obtained in step D of Preparation 1.3 in 50 ml of MeOH is added at RT until pH = 1, a saturated solution of HCl gas in the ether and left for 1 hour under stirring at RT. The reaction mixture is concentrated under vacuum, the residue is taken up in DCM, the precipitate formed is dried and washed with ether. 3.4 g of the expected product are obtained after recrystallization from propan-2-ol, F = 200-204 ° C.

B) 5- [2- (Benzoyloxy) ethyl] -5- (3,4-dichlorophenyl) oxazolidin-2-one.

To a solution of 3 g of the compound obtained in the preceding step, 0.85 g of triethylamine in 30 ml of 1,2-dichloroethane, 1.4 g of 1,1'-carbonyldiimidazole are added at RT, 30 minutes are left under stirring at RT then it is heated at 50 ° C for 2 hours. The reaction me-z-cla, se-re-ouper-a-el-re-s-lduo- is concentrated in vacuo with water, extracted with DCM, the organic phase is washed with a buffer solution pH = 2. , with water, dry over Na2SO and evaporate the solvent under vacuum. 3 g of the expected product are obtained. Proton NMR spectrum at 200 MHz "in DMS0-d6 d: 2.6 ppm: mt: 2H 3.75 ppm: AB system: 2H 4.35 ppm: mt: 2H 7.4 to 7.8 ppm: m: 8H 7.9 ppm: s: ÍH Preparation 1.8 6- (3,4-Dichlorophenyl) -l-methyl-6- [2- (tetrahydro-drahipran-2-yloxy) ethyl] piperazXn-2, 3-dione. A) 2- (3,4-Dichlorophenyl) -2- (methylamino) -acetonitrile hydrochloride. A mixture of 10 g of 3,4-dichlorobenzaldehyde and 9.5 ml of cyanotrimethylsilane is added in an ice bath, 10 mg of zinc iodide are added and the mixture is left stirring at RT for 30 minutes. Then 20 ml of a 33% solution of methylamine in EtOH are added and heated at 40 ° C for 2 hours. The solvent is concentrated under vacuum, the residue is extracted with ether, the organic phase is dried over MgSO 4 and filtered, a saturated solution of HCl gas is added to the filtrate and the ether until pH = 1, then the acetone is added. up-precipitation of the product The precipitate formed is drained, washed with ether and dried 12.8 g of the expected product are obtained, F = 172 ° C.

B) 2- (tert-butoxycarbonyl-N-methylamino) -2- (3,4-dichloro-phenyl) acetonitrile. To a suspension of 12.8 g of the compound obtained in the previous step in water, a solution of concentrated NaOH is added until pH = 13, extracted with ether, the organic phase is dried over MgSO 4 and the solvent is evaporated under vacuum. The residue is taken up in 20 ml of 1,4-dioxane, 12.5 g of di-tert-butyl dicarbonate are added and the mixture is heated at 60 ° C for 2 hours. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with a buffer solution pH = 2, with a saturated solution of NaCl, with a 10% solution of Na 2 CO 3, dried over MgSO 4 and The solvent is evaporated under vacuum. Chromatograph the residue on silica eluting with heptane, then heptane / AcOEt mixture (96/4; v / v). 12.7 g of the expected product is obtained which is used as such.

C) 2- (tert-butoxycarbonyl-N-methylamino) -2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butanitrile. To a suspension of 1.5 g of sodium hydride (at 60% in oil) in 50 ml of DMF, a solution of 11.1 g of the compound obtained in the preceding step in 60 ml of DMF is added dropwise and maintaining the temperature at 25 ° C and left for 1 hour under stirring at RT. Then a solution of 8.1 g of l-bromo-2- (tetrahydropyran-2-yloxy) ethane in 20 ml of DMF is added and heated at 60 ° C for 4 hours. After cooling to RT, the reaction mixture is poured into an ice / buffer mixture pH = 2, extracted with ether, the organic phase is washed twice with water, dried over MgSO 4 and the solvent evaporated under vacuum. The residue is chromatographed on silica eluting with heptane then with the heptane / AcOEt mixture (75/25; v / v). 13.2 g of the expected product is obtained which is used as such.

D) 2- (tert-butoxycarbonyl-N-methylamino) -2- (3,4-dichloro-phenyl) -4- (tetrahydropyran-2-yloxy) butylamine.

A mixture of 13.2 g of the compound obtained in the preceding step, 4 g of Raney® nickel, in 150 ml of EtOH and 50 ml of a 20% solution of ammonia is hydrogenated at 30 ° C and at atmospheric pressure. After 5 hours, the catalyst is filtered and the filtrate is concentrated under vacuum. The residue is extracted with ether, the organic phase is washed twice with water, dried over MgSO 4 and the solvent evaporated under vacuum. 12.6 g of the expected product is obtained which is used as such.

E) 2- (3,4-Dicls-phenyl) -4-hydrosxy-2- (methylamino) butylamine hydrochloride. A mixture of 4.6 g of the compound obtained in the preceding step, 10 ml of a concentrated HCl solution in 40 ml of MeOH is heated at 70 ° C for 1 hour. The solvent is then concentrated under vacuum, the residue is taken up in the acetone, the precipitate formed is drained off, washed with ether and dried. 2.79 g of the expected product are obtained, F = 240 ° C (dec.).

F) 6- (3,4-dichlorophenyl) -6- (2-hydroxyethyl) -1-methyl-piperazin-2,3-dione. To a suspension of 5.3 g of the compound obtained in the preceding step in water, a solution of concentrated NaOH is added until pH = 13, extracted with ether, the organic phase is dried over MgSO 4 and the solvent is evaporated under vacuum. The product obtained (4 g) is taken up in 50 ml of EtOH, 2.57 g of diethyl oxalate are added and the mixture is left stirring at RT for 1 hour. The reaction mixture is concentrated under vacuum, the residue is taken up in 60 ml of toluene and heated to reflux for 70 hours. It is concentrated under vacuum and 2.8 g of the expected product are obtained after crystallization in the DCM, F = 260 ° C.

G) 6- (3,4-dichlorophenyl) -l-methyl-6- [2- (tetrahydropyran-2-yloxy) ethyl] piperazin-2,3-dione. To a suspension of 2.8 g of the compound obtained in the preceding step in 50 ml of DCM, 0.1 g of p-toluenesulfonic acid monohydrate and then 1.26 ml of 3,4-dihydro-2H-pyran are added and left under stirring overnight. TA. The reaction mixture is washed with a 10% solution of Na 2 CO 3, with water, the organic phase is dried over MgSO 4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica eluting with AcOEt, then with the AcOEt / MeOH mixture (93/7; v / v). 3.1 g of the expected product is obtained which is used as such.

Preparation 1.9 2- (3,4-Dichlorophenyl) -l-methyl-2- [2- (tetrahydropyran-2-yloxy) ethyl] piperazine.

To a suspension of 1.2 g of aluminum hydride and lithium in 20 ml of THF, a solution of 2 g of the compound obtained in Preparation 1.8 in 20 ml of THF is added dropwise and heated to reflux for 1 hour. After cooling, add 5 ml of water, filter the mineral salts, concentrate the filtrate under vacuum, recover the residue with ether, dry the organic phase over MgSO and evaporate the solvent under vacuum. 1.9 g of the expected product are obtained in the form of oil.

Preparation 1.10 6- [2- (Benzoyloxy) ethyl] -6- (3,4-difluorophenyl) morpholin-3-one. A) 2- (3,4-difluorophenyl) -2-hydroxyacetonitrile. A solution of 80.2 g of Na 2 S 2 → 5 in 250 ml of water is heated at 50 ° C, 50 g of 3,4-difluorobenzaldehyde are added, and stirring is continued for 1 hour at 50 ° C and overnight at RT. The reaction mixture is cooled to 0CC, a solution of 77.7 g of KCN in 100 ml of water is added dropwise and it is left under stirring allowing the temperature to rise to RT, then the stirring is continued for 1 hour at RT. The reaction mixture was extracted with ether, 3e washed the organic phase with water, dried over MgSO 4 and the solvent evaporated under vacuum. 48 g of the expected product is obtained which is used as such.

B) 2- (3,4-difluorophenyl) -2- (tetrahydropyran-2-yloxy) acetonitrile. A solution of 48 g of the compound obtained in the preceding step, 0.2 g of p-toluenesulfonic acid monohydrate in 500 ml of DCM is cooled to 0 ° C, a solution of 28.6 g of 3,4-dihydro-2H is added dropwise. -piran in 50 ml of DCM and leaving under stirring allowing the temperature to rise to RT, then stirring continues overnight at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with a 10% solution of Na 2 CO 3, with water, the organic phase is dried over Na 2 SO 4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica eluted by the toluene / AcOEt mixture (100/15; v / v). 43 g of the expected product is obtained which is used as such.

C) 4- (Benzoyloxy) -2- (3,4-difluorophenyl) -2- (tetrahydropyran-2-yloxy) butan-nitrile. A mixture of 1.5M of lithium diisopropylamide in THF is added dropwise to -60 ° C, a solution of 43 g of the compound obtained in the preceding step in 250 ml of THF is added dropwise and left stirring for 30 minutes. at -60 ° C. A solution of 45.8 g of 2-brsmsethyl benzoate in 100 ml of THF is then added dropwise at -60 ° C and left under stirring, allowing the temperature to rise to RT. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water, a buffer solution pH = 4, dried over Na 2 SO 4 and the solvent evaporated under vacuum. The residue is chromatographed on silica eluting with the toluene / AcOEt mixture (100/5; v / v). 47 g of the expected product is obtained which is used as such.

D) 4- (Benzoyloxy) -2- (3,4-difluorophenyl) -2- (tetrahydropyran-2-yloxy) butylamine. A mixture of 47 g of the compound obtained in the preceding step, 10 g of Raney® nickel in 400 ml of EtOH is hydrogenated at RT and at atmospheric pressure. The catalyst is filtered and the filtrate is concentrated under vacuum. The residue is taken up in water, extracted with ether, the organic phase is washed with water, dried over Na2S? and the solvent is evaporated under vacuum. 45 g of the expected product is obtained which is used as such.

E) 4- (Benzoyloxy) -2- (3,4-difluorophenyl) -2-hydroxybutylamine hydrochloride.

To a solution of 45 g of the compound obtained in the preceding step in 250 ml of MeOH, a saturated solution of gas HCl in ether is added at RT until pH = 1 and left for 30 minutes under stirring at RT. The reaction mixture is concentrated under vacuum, the residue is taken up in ether, the precipitate formed is dried and washed with ether. 15 g of the expected product are obtained after recrystallization from propan-2-ol, F = 202-204 ° C.

F) N- (2-chloroacetyl) -4- (benzoyloxy) -2- (3,4-difluorophenyl) -2-hydroxybutylamine. A solution of 12.2 g of the compound obtained in the preceding step, 7.88 g of triethylamine in 100 ml of DCM is cooled to 0 ° C, a solution of 3.85 g of chloroacetyl chloride in 100 ml of DCM is added dropwise and Leave 30 minutes under agitation. The reaction mixture is concentrated under vacuum, the residue is extracted by the ether / AcOEt mixture (50/50; v / v), the organic phase is washed with water, a buffer solution pH = 4, with water, dried Na2SO4 and the solvent is evaporated under vacuum. 13.5 g of the expected product is obtained which is used as such.

G) 6- [2- (benzoyloxy) ethyl] -6- (3, 4-difluorophenyl) morpholin-3-one.

A mixture of 13.5 g of the compound obtained in the preceding step, 20.7 g of K2C03 in 100 ml of toluene is heated at reflux overnight. The reaction mixture is concentrated under vacuum, the residue is taken up in ether and filtered. The filtrate is washed with water, a buffer solution pH = 2, with water, dried over MgSO 4 and the solvent evaporated under vacuum. The residue is chromatographed on silica H eluting with the DCM / MeOH mixture (100/1; v / v). 4.9 g of the expected product are obtained. Proton NMR spectrum at 200 MHz in DMS0-d6 d: 2.35 ppm: mt: 2H 3.65 ppm: AB system: 2H 3.8 to 4.35 ppm: m: 4H 7.1 to 7.8 ppm: m: 8H 8.2 ppm: se: ÍH Preparation 1.11 2- (3,4-difluorophenyl) -2- (2-hydroxyethyl) morpholine. To a solution of 2.8 g of the compound obtained in Preparation 1.10 in 20 ml of THF, a suspension of 1.8 g of aluminum and lithium hydride and 20 rolls of THF is added dropwise to TA, then it is heated to reflux. 5 hours. After cooling, 2 ml of water, 2 ml of 4N NaOH and then 6 ml of water are added. The mineral salts are filtered and the filtrate is concentrated under vacuum. The residue is dissolved in the DCM, acidified to pH = 1 by the addition of a saturated solution of HCl gas in ether, water is extracted, the aqueous phase is washed with ether, the aqueous phase is made alkaline until pH = 8 by the adding a concentrated NaOH solution, extracting the DCM, washing the organic phase with water, drying over MgSO4 and evaporating the solvent under vacuum. 0.77 g of the expected product are obtained.

Preparation 1.12 5- [2- (Benzoyloxy) ethyl] -5- (3,4-difluorophenyl) -oxazolidin-2-one. To a solution of 2.1 g of the compound obtained in step E of Preparation 1.10, 0.63 g of triethylamine in 50 ml of 1,2-dichloroethane, 1 g of 1,1'-carbonyldiimidazole is added at RT, then 1 hour under stirring at RT then heated at 50 ° C for 2 hours. The reaction mixture is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with water, with a buffer solution pH = 2, with water, dried over MgS? and the solvent is evaporated under vacuum. 1.5 g of the expected product are obtained.

Preparation 1.13 5- (3,4-Dichlorophenyl) -l-methyl-5- [2- (tetrahydropyran-2-yloxy) ethyl] -imidazolidin-2-one. A) 2- (3, 4-diclorsphenyl) -2- (methylamino) -4- (tetrahydropyran-2-yloxy) utylamine. A mixture of 3.4 g of the compound obtained in step E of Preparation 1.8, 0.05 g of p-toluenesulfonic acid monohydrate, 2.1 ml of 3,4-dihydro-2H-pyran in 30 ml is heated at 60 ° C for 45 minutes. of DMF. The reaction mixture is poured onto the ice, made alkaline by the addition of concentrated NaOH, extracted with ether, the organic phase is washed with water, dried over MgSO 4 and the solvent evaporated under vacuum. 4.3 g of the expected product is obtained which is used as such.

B) 5- (3,4-dichlorophenyl) -l-methyl-5- [2- (tetrahydropyran-2-yloxy) ethyl] imidazolidin-2-one. To a solution of 3.2 g of the compound obtained in the preceding step in 100 ml of 1,2-dichloroethane is added 1.6 g of 1,1'-carbonyldiimidazole and left for 30 minutes under stirring at RT. It is then heated at 60 ° C for 2 hours and the reaction mixture is concentrated under vacuum. The residue is extracted with AcOEt, the organic phase is washed with a buffer solution pH = 2, with a saturated solution of NaCl, with a 10% solution of Na 2 CO 3, dried over MgSO 4 and the solvent evaporated under vacuum. The residue is chromatographed on silica H eluting with DCM then DCM / MeOH (98/2; v / v). 2.4 g of the expected product are obtained in the form of oil.

Preparation 1.14 6- [3- (Benzoyloxy) propyl] -6- (3,4-dichlorophenyl) morpholin-3-sna. A mixture of 7.5 g of the compound obtained in step D of Preparation 1.6, 9.3 g of K2C03, 3.75 g of sodium iodide in 100 ml of methyl ethyl ketone is heated overnight to reflux. After cooling, the reaction mixture is concentrated under vacuum, the residue is taken up in ether, the mineral salts are filtered, the filtrate is washed with a buffer solution pH = 2, with water, the organic phase is dried over MgSO 4 and evaporates the solvent under vacuum. The residue is chromatographed on silica H eluting with DCM then the gradient of the DCM / MeOH mixture of (99/1; v / v) to (98/2; v / v). 1.3 g of the expected product are obtained. Proton NMR spectrum at 200 MHz in DMS0-d6 d: 1.1 to 2.3 ppm: m: 4H 3.65 ppm: AB system: 2H 3.8 to 4.4 ppm: m: 4H 7.2 to 8.05 ppm: m: 8H 8.2 ppm: s: ÍH Preparation 1.15 6- [2- (Benzoyloxy) ethyl] -6- (3,4-difluorophenyl) morpholin-3-one, (-) isomer. A) 4- (Benzoyloxy) -2- (3,4-difluorophenyl) -2-hydroxybutylamine, (+) isomer. A solution of 41 g of L - (+) - tartaric acid in 1200 ml of MeOH is heated to reflux, then a solution of 81.4 g of the compound obtained in step E of Preparation 1.10 is added at once. Free base form in 200 ml of MeOH and leave for 48 hours in crystallization allowing the temperature to return to RT. The crystals formed are drained and washed with ether. 42.5 g of tartaric acid salt are obtained. do20 = + 36.2 ° (c = 1; DMF) The salt thus obtained is recrystallized from 1450 ml of 70 EtOH, and after the ether has been drained off and washed with the crystals formed, 35 g of tartaric acid salt are obtained. aD20 = + 38.9 ° (c = 1 DMF) The salt thus obtained is recovered in 2000 ml of AcOEt, 40 ml of a 10% Na2C03 solution are added, then, after stirring and decanting, the organic phase is washed with water, dry over MgSO4 and evaporate the solvent under vacuum. 23.5 g of the expected product are obtained after crystallization in the iso / pentane ether mixture, F = 100.5-100.6 ° C. aD2Q = + 42.5 ° (c = 1; MeOH) B) N- (2-Chloroacetyl) -4- (benzoyloxy) -2- (3,4-difluoro-phenyl) -2-hydroxybutylamine, (+) isomer. A solution of 23.5 g of the compound obtained in the preceding step, 8.1 g of triethylamine in 300 ml of DCM is cooled to 0 ° C, a solution of 8.3 g of chloroacetyl chloride in 50 ml of DCM is added dropwise and 30 minutes under stirring at 0 ° C. The reaction mixture is concentrated under vacuum, the residue is extracted by the AcOEt / ether mixture (50/50, v / v), the organic phase is washed with a buffer solution pH = 2, dried over MgSO 4 and evaporated under vacuum the solvent. 24.8 g of the expected product are obtained after crystallization in the iso / pentane ether mixture. OD20 = + 26.1 ° (c = 1; MeOH) C) 6- [2- (benzoyloxy) ethyl] -6- (3, 4-difluorophenyl) morpholin-3-one, (-) isomer. A solution of 23.6 g of the compound obtained in the preceding step in 750 ml of THF is cooled to 0 ° C, and 13.7 g of potassium tert-butylate are added and the mixture is left stirring for 15 minutes. The reaction mixture is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with a buffer solution pH = 2, with water, dried over MgSO 4 and the solvent evaporated under vacuum. The residue is chromatographed on silica H eluting with the DCM / MeOH mixture (100/1; v / v) to (100 / 1.5; v / v). Obtained 14.5 g of the expected product after crystallization in the pentane. aD20 = -7.1 ° (c = 1; MeOH) Preparation 1.16 6- [2- (Benzoyloxy) ethyl] -6- (3,4-difluorophenyl) morpholin-3-one, (+) isomer. A) 4- (Benzoyloxy.) -2- (3, -difluorophenyl) -2-hydroxybutyl-amine, (-) isomer. The drying or washing juices or extracts obtained by crystallization are then concentrated under vacuum. recrystallization of the tartaric acid salt prepared in step A of Preparation 1.15 The residue is treated with a 10% Na 2 CO 3 solution, extracted with AcOEt, the organic phase is dried over MgSO 4, the solvent is evaporated under vacuum and 49 g of aminoalcohol are obtained in the form of a mixture of isomers. The aminoalcohol is dissolved in 120 ml of MeOH and this solution is added in one portion to a refluxing solution of 24.1 g of D- (-) acid. ) -thartaric in 730 ml of MeOH, leave for 48 hours in crystallization allowing the temperature to return to RT.The crystals formed are dried and washed with ether to obtain 40.7 g of the salt of tartaric acid.The salt is recrystallized thus obtained in 1445 ml of EtOH 70, and it is obtained, after drying and washing. With the crystals formed, 35 g of tartaric acid salt are added. The salt thus obtained is recovered in 2000 ml of AcOEt, a 10% Na 2 CO 3 solution is added, then, after stirring and decanting, the organic phase is washed with water, dried over MgSO 4 and the solvent evaporated under vacuum . 27 g of the expected product are obtained, F = 102 ° C. aD20 = -40.5 ° (c = 1; MeOH) B) N- (2-Chloroacetyl) -4- (benzoyloxy) -2- (3,4-difluorophenyl) -2-hydroxybutylamine, (-) isomer. A solution of 27 g of the compound obtained in the preceding step, 13 ml of triethylamine in 500 ml of DCM is cooled to -30 ° C, 5.8 g of chloroacetyl chloride are added dropwise and the mixture is left stirring for 15 minutes. The reaction mixture is then washed with water, a 1N HCl solution, a 10% Na 2 CO 3 solution, the organic phase is dried over MgSO 4 and the solvent is evaporated under vacuum. This gives 28.6 g of the expected product after crystallization in the iso / pentane ether mixture, F = 63 ° C. aD20 = -31.5 ° (c = 1; MeOH) C) 6- [2- (benzoyloxy) ethyl] -6- (3, 4-difluorophenyl) morpholin-3-one, (+) isomer. A solution of 28.5 g of the compound obtained in the preceding step in 250 ml of THF is cooled to -30 ° C, 18.5 g of potassium tert-butylate is added in one portion and left for 45 minutes under stirring. The reaction mixture is poured into 1000 ml of a buffer solution pH = 2, extracted in ether, the organic phase is dried over MgSO 4 and the solvent evaporated under vacuum. 20.5 g of the expected product are obtained after crystallization in the ether / iso ether mixture, F = 92 ° C. aD20 = +8. 2 ° (c = 1; MeOH) Preparation 1.17 2- [2- (Benzoyloxy) ethyl] -2- (3,4-difluorophenyl) morpholine, (-) isomer. To 100 ml of a 1M borane solution in the THF, a solution of 12 g of the compound obtained in Preparation 1.15 ((-) isomer) in 75 ml of THF is added dropwise at RT and left for 30 minutes under stirring. to TA. The reaction mixture is then refluxed for 3 hours, 40 ml of a 1M solution of borane in the THF are added and the reflux is continued for 30 minutes. 80 ml of boiling MeOH are added and the reflux is continued for 30 minutes. The reaction mixture is cooled in an ice bath, 30 ml of a saturated solution of HCl gas are added to the ether and left overnight under stirring at RT. The reaction mixture is concentrated under vacuum, the residue is taken up in a 10% Na 2 CO 3 solution, extracted with ether, the organic phase is washed with water, a saturated solution of NaCl, dried over MgSO 4 and evaporated under reduced pressure. vacuum the solvent. 11.2 g of the expected product are obtained in the form of oil.

Preparation 1.18 2- [2- (Benzoyloxy) ethyl] -2- (3,4-difluorophenyl) morphoiin, (+) isomer. The mixture is heated at 60 ° C for 2 hours 19. 9 g of the compound obtained in Preparation 1.16 (isomer (+)) and 300 ml of a 1M solution of boraa THF 60 ml of boiling MeOH is added and the reflux is continued for 30 minutes. The reaction mixture is cooled to 10 ° C, 50 ml of a gas HCl solution in ether are added and the mixture is left at RT overnight. The reaction mixture is concentrated under vacuum, the residue is taken up in 300 ml of a 10% Na 2 CO 3 solution, 300 ml of ether are added and the mixture is left stirring for 30 minutes. After decanting, the organic phase is dried over MgSO 4 and the solvent evaporated under vacuum. 20 g of the expected product are obtained in the form of oil.

Preparation 1.19 2- [2- (Benzoyloxy) ethyl] -2- (3,4-dichlorophenyl) morpholine.

To 76 ml of a 1M solution of bsraps in the THF, a solution of 6 g of the compound obtained in Preparation 1.4 in 30 ml of THF is added to TA and dripped, then it is heated to reflux for 4 hours. 30 ml of MeOH are added dropwise and the reflux is continued for 30 minutes. The reaction mixture is cooled to 0 ° C, 30 ml of a saturated solution of HCl gas in ether are added and left overnight under stirring at RT. The reaction mixture is concentrated under vacuum, the residue is taken up in a 10% Na 2 CO 3 solution, extracted with ether, the organic phase is washed with a 10% Na 2 CO 3 solution, with water, dried over MgSO 4 and evaporates the solvent under vacuum. 5 g of the expected product are obtained.

Preparation 1.20 5- [2- (Benzoyloxy) ethyl] -5- (3,4-difluorophenyl) oxazolidin-2-one, (-) isomer. 30 minutes under stirring at RT a mixture of 4 g of the compound obtained in step A of Preparation 1.16 (isomer (-)), 2.2 g of 1,1 '-carbonyldiimidazole and 40 ml of DCM, then heated to reflux for 1 hour. After cooling to RT, the reaction mixture is washed twice with a solution of IN HCl, the organic phase is dried over MgSO 4 and the solvent is evaporated under vacuum. 4.18 g of the expected product are obtained after crystallization from iso ether, F = 147 ° C. aD20 = -62.2 ° (c = 1; DMF) Preparation 1.21 2- [2- (Benzoyloxy) ethyl] -2- (3, -difluorophenyl) morpholine.

To 700 ml of a 1M solution of borane in THF, 48 g of the compound obtained in Preparation 1.10 are added at RT and portions are then heated at 60 ° C for 2 hours. 150 ml of MeOH are added dropwise and the heating is continued for 30 minutes. The reaction mixture is cooled to 10 ° C, 120 ml of hydrochloric ether are added and the mixture is left overnight at RT. The reaction mixture is concentrated under vacuum, the residue is taken up in 600 ml of a saturated solution of Na 2 CO 3 and 500 ml of ether and left for 1 hour under stirring at RT. After decanting, the organic phase is washed with water, dried over MgSO 4 and the solvent evaporated under vacuum. The residue is recovered in 400 ml of propan-2-ol, 15 g of fumaric acid are added, 30 minutes are left under stirring and the formed precipitate is drained. The precipitate is recovered in 400 ml of a 10% Na2CO3 solution, extracted with ether, the organic phase is dried over MgSO4 and the solvent is evaporated under vacuum. 22 g of the expected product are obtained in the form of oil. Preparation 1.22 5- [2- (Benzoyloxy) ethyl] -5- (3, 4-dicloyl) oxazolidin. To a solution of 9 g of the compound obtained in step A of Preparation 1.7 (in the form of a free base) in 100 ml of THF, 4 g of a 37% solution of formaldehyde in water are added and then heated to reflux for 30 minutes and one night is left under agitation at TA. It is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water, Na 2 SO 4 and the solvent is evaporated under vacuum. 9 g of the expected product are obtained. Proton NMR spectrum at 200 MHz in DMSO-d6: d r 2.4 ppm: mt: 2H; 3.2 ppm: mt: 2H; 3.8 to 5.0 ppm:: 4H; 7.0 to 8.0 ppm: m: 8H.

Preparation 1.23 5- [2- (Benzoyloxy) ethyl] -5- (3,4-difluorophenyl) oxazolidin-2-one, (+) isomer. This compound is prepared in accordance with the procedure described in Preparation 1.20 from the compound obtained in Step A of Preparation 1.15 ((+) isomer). aD20 = + 61 ° (c = 1; DMF).

Preparation 2.1 4-Phenyl-1-azabicyl methanesulfonate [2.2. l] heptane.

A) l-Benzyl-4-carboxy-4-phenylpiperidine. To a suspension of 100 g of p-toluenesulfonate of 4-carboxy-4-phenylpiperidine in 600 ml of water, add 106 ml of a solution to 30% NaQH, then dissolve the solution obtained at 5 ° C, add dripping a solution of 47.6 g of benzyl bromide in 100 ml of acetone and leaving it for 1 hour under stirring, allowing the temperature to rise to RT. The acetone is evaporated under vacuum, the pH of the remaining aqueous phase is induced to 9.5 by the addition of a concentrated solution of HCl, then it is adjusted to pH = 8.5 by the addition of a 2N HCl solution. The precipitate formed is drained off and washed with water then with acetone. 70 g of the expected product are obtained, F = 286 ° C.

B) l-benzyl-4- (hydroxymethyl) -4-phenylpiperidine. A suspension of 70 g of the compound obtained in the preceding step in 150 ml of THF is cooled to 5 ° C, 237 ml of a 1M solution of borane in the THF are added rapidly and then refluxed for 1 hour. Subsequently, 474 ml of a 1M solution of borane in THF is added and refluxing is continued for 3 hours. 100 ml of MeOH are added, hot and for 30 minutes, then, by heating and in 30 minutes, 150 ml of a concentrated HCl solution. After cooling to RT, the reaction mixture is diluted with water, made alkaline by addition of a 30% solution of NaOH, extracted by an ether / THF mixture, the organic phase is washed with water, dried over Na2SO4, and the solvents are evaporated under vacuum. 16 g of the expected product are obtained after two crystallizations in the cycloshexane, F = 127 ° C. This compound can also be obtained by following the two steps of the process described later.

A ') 4- (Hydroxymethyl) -4-phenylpiperidine hydrochloride.

A mixture of 10.25 g of 4-carboxy-4-phenylpiperidine p-toluenesulfonate and 150 ml of a 1M solution of borane in THF is refluxed for 1 hour. 30 ml of MeOH are added, hot and in 20 minutes, then, after cooling to RT, a saturated solution of HCl gas in ether is added until pH = 1 and left overnight under stirring at RT. The solvents are concentrated under vacuum, the residue is recovered by hot acetone and left in crystallization. The crystals formed are drained and washed with acetone then with ether. 11.1 g of the expected product are obtained, F = 263 ° C.

B ') l-benzyl-4- (hydroxymethyl) -4-phenylpiperidine. A solution of 20.5 g of the compound obtained in the preceding step in 100 ml of water and 200 ml of acetone is heated at 40 ° C, 27 ml of a 30% solution of NaOH are added, then, dropwise, a solution of 17 g of benzyl bromide in 50 ml of acetone and leave for 1 hour under stirring. The acetone is evaporated, diluted with water, the precipitate formed is drained off, washed with water and dried. The precipitate is recovered in 800 ml of hot cyclohexane, an insoluble one is filtered off and left in crystallization at RT. 19.3 g of the expected product are obtained.

C) 4-Phenyl-1-benzyl-1-azoniabicyclo [2.2.1] heptane methanesulfonate. A mixture of 14.05 g of the compound obtained in step B and 5.55 g of triethylamine in 200 ml of DCM is cooled to 5 ° C, a solution of 6.01 g of methanesulfonyl chloride in 15 ml of DCM is added dropwise and 15 minutes under stirring at RT. It is concentrated under vacuum at 30 ° C, the residue is extracted with 500 ml of AcOEt, the organic phase is washed with water, dried over Na 2 SO 4 and the solvent evaporated under vacuum. 19.1 g of an oil are obtained which is dissolved in 180 ml of n-butanol and heated to reflux for 2 hours. Concentrate under vacuum, recover the residue with 150 ml of hot acetone and leave under stirring at RT. The crystallized product obtained is drained off and washed with ether. 16.85 g of the expected product are obtained, F = 193 ° C.

D) 4-Phenyl-1-azabicyclomethanesulfonate [2.2. l] heptane. A mixture of 15 g of the compound obtained in the preceding step and 1.5 g of 10% palladium on carbon in 150 ml of EtOH 95 is hydrogenated for 4 hours at 40 ° C and at atmospheric pressure. The catalyst is filtered on Celite. ®, washed with EtOH, and the filtrate is concentrated under vacuum. The residue is recovered with AcOEt while hot and left to crystallize. 10.1 g of the expected product are obtained after drying or draining, F = 130 ° C.

EXAMPLE 1 Chloride of 5- (3,4-difluorophenyl) -5- [2- [4-phenyl-1-azoniabicyclo [2.2.1] hept-1-yl] ethyl] -3- [3, 5-bis ( trifluoromethyl) benzyl] oxazolidin-2-one, monohydrate, isomer (+).

A) 5- [2- (Benzoyloxy) ethyl] -5- (3,4-difluorophenyl) -3- [3,5- bis (trifluoromethyl) benzyl] oxazolidin-2-one, (+) isomer • To one solution 3.5 g of the compound obtained in Preparation 1.23 ((+) isomer) in a 50 ml mixture of THF and 10 ml of DMF, 1.2 g of potassium tert-butylate are added to TA and left at stirring for 30 minutes at RT. Then 2.7 g of 3,5-bis (trifluoromethyl) benzyl chloride is added and heated at 60 ° C for 6 hours. The reaction mixture is poured onto 200 ml of buffer pH = 2, extracted with ether, the organic phase is washed with water, dried over MgSO 4 and the solvent evaporated under vacuum. The residue is chromatographed on silica H eluting with DCM. 3.6 g of the expected product are obtained.

B) 5- (3,4-difluorophenyl) -5- (2-hydroxyethyl) -3- [3,5- bis (trifluoromethyl) benzyl] oxazolidin-2-one, isomer (+) • A mixture of 3.6 g of the compound obtained in the preceding step, 0.32 g of lithium hydroxide monohydrate in 50 ml of MeOH and 5 ml of water is left under stirring at RT for 2 hours at RT. The reaction mixture is concentrated under vacuum, the residue is taken up with water, extracted with ether, the organic phase is washed twice with water, dried over MgSO 4 and the solvent evaporated under vacuum. The residue is chromatographed on silica H eluting with DCM then DCM / MeOH (98/2; v / v). 2.6 g of the expected product are obtained.

C) 5- (3, 4-difluorophenyl) -5- [2-methanesulfonyloxyethyl] -3- [3,5-bis (trifluoromethyl) benzyl] oxazolidin-2-one, (+) isomer. A solution of 2.6 g of the compound obtained in the preceding step in 50 ml of DCM is cooled to 0 ° C, 1.14 ml of triethylamine and then 0.62 ml of methanesulfonyl chloride are added and the mixture is left stirring for 10 minutes. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed twice with water, dried over MgSO and the solvent evaporated under vacuum. 3 g of the expected product is obtained which is used as such.

D) 5- (3,4-difluorophenyl) -5- [2- [4-phenyl-1-azoniabicyclo [2.2.1] hept-1-yl] ethyl] -3- [3, 5-bis ( trifluoromethyl) benzyl] oxazolidin-2-one, monohydrate, (+) isomer. A mixture of 2.4 g of the compound obtained in the preceding step, 1.6 g of 4-phenyl-1-azabicyclo [2.2.1] heptane methanesulfonate and 1.7 g of K 2 CO 3 in 2 ml of DMF is heated at 80 ° C for 5 hours. . After cooling to RT, the reaction mixture is poured into water, extracted with DCM, the organic phase is washed with a 10% solution of HCl, a saturated solution of NaCl, dried over Na2SO4 and evaporated under vacuum the solvent The residue is subjected to chromatography on silica H eluting with the DCM / MeOH mixture (100/5; v / v). 1.46 g of the expected product are obtained. aD20 = + 25.8 ° (c = 1; MeOH). Proton NMR spectrum at 200 MHz in DMSO-d6: d: 2.0 at 2.4 ppm: m: 4H 2.5 ppm: t: 2H 3.1 at 4.0 ppm: m: 10H 4.6 ppm: AB system: 2H 7.0 at 8.1 ppm: m : 11H EXAMPLE 2 Chloride of 6- (3,4-dichlorophenyl) -6- [2- [4-phenyl-1-azonia bicyclo [2.2.1] hept-1-yl] ethyl] -4- [3, 5-bis] (trifluoromethyl) -benzyl] morpholin-3-one. A) 6- [2- (Benzoyloxy) ethyl] -6- (3,4-dichlorophenyl) -4- [3,5- bis (trifluoromethyl) benzyl] morpholin-3-one. A mixture of 2.1 g of the compound obtained in Preparation 1.4 is left under stirring at RT., 0.616 g of potassium tert-butylate in 50 ml of THF, 1.44 g of 3,5-bis (trifluoromethyl) encyl chloride is added and heated at reflux for 1 hour. The reaction mixture is concentrated under vacuum, the residue is taken up in a buffer solution pH = 4, extracted with ether, the organic phase is washed with water, dried over Na 2 SO 4 and the solvent evaporated under vacuum. Chromatograph the residue on silica H eluting with the DCM / MeOH mixture (100 / 0.5; v / v). 1.8 g of the expected product are obtained. Proton NMR spectrum at 200 MHz in DMS0-d6: d: 2.4 ppm: mt: 2H 4.05 ppm: AB system: 2H 4.15 at 4.6 ppm: m: 4H 4.75 ppm: AB system: 2H 7.3 to 8.2 ppm: m: 11H B) 6- (3,4-dichlorophenyl) -6- (2-hydroxyethyl) -4- [3,5-bis (trifluoromethyl) benzyl] morpholin-3-one. A mixture of 1.8 g of the compound obtained in the preceding step, 4 ml of a concentrated NaOH solution in 30 ml of MeOH is left stirring at 0 ° C at 0 ° C then stirring is continued for 1 hour at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water, dried over Na 2 SO 4 and the solvent evaporated under vacuum. 1.1 g of the expected product are obtained.

Proton NMR spectrum at 200 MHz in DMS0-d6: d: 2.0 ppm: t: 2H 2.9 to 3.45 ppm: mt: 2H 3.9 ppm: AB system: 2H 4.2 ppm: AB system: 2H 4.45 ppm: t: ÍH 4.7 ppm: AB system: 2H 7.1 to 8.2 ppm: m: 6H C) 6- (3,4-dichlorophenyl) -6- [2- (methanesulfonyloxy) ethyl] -4- [3,5-bis (trifluoromethyl) encyl] morpholin-3-one. To a solution of 1.1 g of the compound obtained in the preceding step, 0.22 g of triethylamine in 30 ml of DCM, 0.25 g of methanesulfonyl chloride are added at RT and left stirring for 1 hour. The reaction mixture is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water, dried over Na 2 SO 4 and the solvent evaporated under vacuum. 1.2 g of the expected product is obtained which is used as such.

D) 6- (3,4-dichlorophenyl) -6- [2- [4-phenyl-1-azoniabicyclo [2.2. l] hept-l-yl] ethyl] -4- [3,5-bis (trifluoromethyl) benzyl] morpholin-3-one. A mixture of 1.5 g of the compound obtained in the preceding step, 0.67 g of 4-phenyl-1-azabicyclomethanesulfonate [2.2.] Is heated at 80-100 ° C for 3 hours. 1) heptane and 1 g of K2CO3 in 2 ml of DMF. After cooling to RT, the reaction mixture is poured into water, extracted with DCM, the organic phase is washed with a 10% solution of HCl, with a saturated solution of NaCl, with water, dried over Na 2 SO 4 and evaporates the solvent under vacuum. The residue is chromatographed on silica H eluting with the DCM / MeOH mixture (100/5; v / v) to (100 / 7.5; v / v). The product obtained is dissolved in hot DCM, poured onto the pentane and the formed precipitate is drained. 0.4 g of the expected product are obtained. Proton NMR spectrum at 200 MHz in DMSO-d6: d: 2.0 to 2.7 ppm: m: 6H 3.0 to 4.05 ppm: m: 10H 4.2 to 5.0 ppm: m: 4H 7.2 to 8.2 ppm: m: 11H.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property

Claims (10)

1. A compound of the formula: Am- (CH2) I1I-CX-CAH2X-N-T (I) Ar, characterized in that: - A represents a divalent radical selected from: - Ai) -0-C0-A2) -CH 2 -O-CO--A3) -O-CH 2 -CO-A4) -0-CH 2 -CH 2 - - A5) -N (R?) - CO- - A7) -N- (R?) - CH2-CH2- in which Ri represents a hydrogen or a (Ci-C4) alkyl; - m is 2 or 3; - Ari represents a phenyl unsubstituted or substituted one or several times by a substituent selected from: a halogen atom, a hydroxy, a (C 1 -C 4) alkoxy, a (Ci-C 4) alkyl, a trifluoromethyl, a methylenedioxy, the substituents are identical or different; a thienyl unsubstituted or substituted by a halogen atom; a benzothienyl unsubstituted or substituted by a halogen atom; a naphthyl unsubstituted or substituted by a halogen atom; an indolyl unsubstituted or N-substituted by a (C 1 -C 4) alkyl or a benzyl; an imidazolyl unsubstituted or substituted by a halogen atom; a pyridyl unsubstituted or substituted by a halogen atom; a diphenyl; - T represents a group selected from: CH2-Z, -CH (C6Hs) 2, -C (C6H5) 3; T may also represent the group -CO-B-Z when A represents a divalent radical selected from; -0-CH2-CH2- or -N (R?) - CH2-CH2- or -0-CH2-; - B represents a direct bond or a methylene; Z represents: a phenyl unsubstituted or substituted one or more times by a substituent chosen from: a halogen atom; a trifluoromethyl; a cyano; a hydroxy; a nitro; an amino unsubstituted or substituted once or twice by a (C 1 -C 4) alkyl; a benzylamino; a carboxy; a (C1-C10) alkyl; a (C3-C8) cycloalkyl unsubstituted or substituted one or more times by a methyl; a (Cx-C10) alkoxy; a (C3-C8) cycloalkyloxy unsubstituted or substituted one or more times by a methyl; a mercapto; a (C1-C10) alkylthio; a formyloxy; a (Ci- C6) alkylcarbonyloxy; a formylamino; a (Ci-?) alkylcarbonylaraine; a benzoylamino; a (Ci- C4) alkoxycarbonyl; a (C3-C7) cycloalkyloxycarbonyl; a carbamoyl unsubstituted or substituted once or twice by a (C 1 -C 4) alkyl; a ureido unsubstituted or substituted once or twice in the 3-position by a (C1-C4) alkyl or a (C3-C) cycloalkyl; a phenyl unsubstituted or substituted one or several times by a halogen, a trifluoromethyl, a (C? -C4) alkyl, a hydroxy, a (C? -C4) alkoxy, the substituents are identical or different; a (pyrrolidin-1-yl) carbonylaraine; the substituents are identical or different; - a 1- or 2-naphthyl; 1-, 2-, 3-, 4-, 5-, 6-, 7-indenyl, of which one or more bonds can be hydrogenated, the groups which can be unsubstituted or optionally contain one or more substituents such as: the alkyl, phenyl, cyano, hydroxyalkyl, hydroxy, oxo, alkylcarbonylamino, alkoxycarbonyl, thioalkyl, halogen, alkoxy and trifluoromethyl group, in which the alkyls and the alkoxy are C? -C4; a pyridyl, thiadiazolyl, indolyl, indazolyl, imidazolyl, benzimidazolyl, benzotriazolyl, benzotriazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzisothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzodioxinyl, isoxazolyl, benzopyranyl, thiazolyl, thienyl, furyl, pyranyl, chloromenyl group , isobenzofuranyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, phthalazinyl, quinazolinyl, acridinyl, isothiazolyl, isochromanyl, chromanyl, whose one or more double bonds can be hydrogenated, the groups which can not be replaced or optionally contain one or more substituents such as: the alkyl, phenyl, cyano, hydroxyalkyl, hydroxy, alkylcarbonylamino, alkoxycarbonyl, thioalkyl group in which the alkyls and alkoxy are from 1 to 4 carbon atoms; - Am represents a group of formula: wherein: - Ar2 represents a pyridyl; a phenyl unsubstituted or substituted one or more times by a substituent chosen from: a halogen atom, a hydroxy, a (Ci-C4) alkoxy, a (C? -C4) alkyl, a trifluoromethyl, a nitro, a methylenedioxy, the substituents are identical or different; a thienyl; a pyrimidyl; an imidazolyl unsubstituted or substituted by a (C-1-C4) alkyl; n is zero or one; - represents a pharmaceutically acceptable anion and its optional salts with mineral or organic acids.

2. An optically pure compound according to claim 1 of the formula: Am- (CH2) m-C x * -CXH2-N-T (I *) Ar, characterized in that: "*" means that the carbon atom thus marked has the absolute (+) or (-) determined configuration: Am, m, Arx, A and T are as defined for the compounds of the formula (I) in claim 1, as well as its salts with mineral or organic acids.

3. A compound according to any of claims 1 or 2, of the formula (I) or (I *) characterized in that: - Z is Z 'and represents: - a phenyl unsubstituted or substituted one or more times by a chosen substituent between: a halogen atom; a trifluoromethyl; a cyano; a hydroxy; a nitro; an amino unsubstituted or substituted once or twice by a (C? -C4) alkyl; a benzylamino; a carboxy; a (C1-C10) alkyl; a (C3-C8) cycloalkyl unsubstituted or substituted one or more times by a methyl; a (Ci-C? o) alkoxy; a (C3-C8) cycloalkyloxy unsubstituted or substituted one or more times by a methyl; a mercapto; a (Ci-Cio) alkylthio; a formyloxy; a (Ci-Cβ) alkylcarbonyloxy; a formylamino; a (Ci-Cd) alkylcarbonylamino; a benzoylamino; a (Ci-C) alkoxycarbonyl; a (C3-C) cycloalkyloxycarbonyl; a carbamoyl unsubstituted or substituted once or twice by a (C? -C4) alkyl; a ureide unsubstituted or substituted once or twice in the 3-position by a (C? -C4) alkyl or a (C3-C7) cycloalkyl; a phenyl unsubstituted or substituted one or more times by a halogen, a trifluoromethyl, a (C? -C4) alkyl, a hydroxy, a (C1-C4) alkoxy, the substituents are identical or different; a (pyrrolidin-1-yl) -carbonylamino; the substituents are identical or different; - a naphthyl unsubstituted or substituted one or more times by a halogen, a trifluoromethyl, a (Ci-C4) alkyl, a hydroxy, a (C1-C4) alkoxy; - a pyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; an imidazolyl; a furilo; Am, m, Arx, A and T are as defined for a compound of the formula (I) in claim 1; and its salts with mineral or organic acids.

4. A compound according to one of claims 1 or 2 of the formula: Am-CHj-CHj-C-CHj-N-CHj-Za (the) characterized in that: - Aa represents a divalent radical selected from: -0-CO-; -CH2-0-CO-; -0-CH2-CO-; -N (R?) - CO- or -N (R?) - CO-CO-; wherein Ri represents a hydrogen or a (Ci- C4) alkyl; - Am represents a group of the formula: A ^ - - n is 0 or 1; T-X represents a pharmaceutically acceptable anion; - Ar2 is as defined for a compound of the formula (I) in claim 1; - Aria represents a phenyl unsubstituted or substituted one or several times by a substituent selected from: a halogen atom, a hydroxy, a (C? -C4) alkoxy, a (C? ~ C4) alkyl, a trifluoromethyl, the substituents they are identical or different; Za represents a phenyl unsubstituted or substituted one or several times by a substituent selected from: a halogen atom, a trifluoromethyl, a (Ci-Cio) alkyl, a (Ci- C? O) alkoxy, a hydroxy, the substituents are identical or different.

5. A compound according to one of claims 1 or 2 of the formula: Am-? 2- < H2- -CH2-? -CO-B - Za (Ib) characterized in that: - Ab represents the divalent radical -0-CH2-CH2-; -N (R?) - CH2-CH2- or -O-CH2-; in which Ri represents a hydrogen or a (C? ~ C4) alkyl; - Am represents a group of the formula: - n is 0 or 1; B represents a direct bond or a methylene; T-X represents a pharmaceutically acceptable anion; - Ar2 is as defined for a compound of the formula (I) in claim 1; - Aria represents a phenyl unsubstituted or substituted one or several times by a substituent chosen from: a halogen atom, a hydroxy, a (C? -C4) alkoxy, a (Ci-C4) alkyl, a trifluoromethyl, the substituents are identical or different; - Za represents a phenyl unsubstituted or substituted one or several times by a substituent selected from: a halogen atom, a trifluoromethyl, a (Ci-Cio) alkyl, a (Ci-C? O) alkoxy, a hydroxy, the substituents They are identical or different.

6. A process for the preparation of the compounds of the formula (I) according to claim 1 and its salts, characterized in that: 1) a compound of the formula: Ar is treated, wherein m, Ari and A are as defined for a compound of formula (I) in claim 1 and E represents hydrogen or an O-protecting group, - either with a functional derivative of an acid of formula : HOCO-B-Z (III) wherein B and Z are as defined above for (I) in claim 1, when a compound of formula (I) wherein T is -CO-B-Z, - or with a halogenated derivative of the formula: Hal-CH2-Z (IV) wherein Z is as defined in claim 1, and Hal represents a halogen, when a compound of formula (I) wherein T is -CH 2 -Z, or with a halogenated derivative of the formula: Hal-CH (C6H5) 2 (V) when a compound of formula (I) is to be prepared wherein T is a group -CH (C6Hs) 2, - or with a halogenated derivative of the formula: Hal-C- (C6H5) 3 (VI) when a compound of formula (I) is to be prepared wherein T is a group -C (C6H5) 3, to obtain a compound of formula: E-O-íCHj) - xC-CXHj-N-T (VII) wherein E, m, Arx, A and T are as defined above: 2) The O-protecting group is optionally removed by the action of an acid or a base, to obtain the alcohol of the formula: HO-ICH-C-C? ^ N-T (vm) Ar, in which m, Arx, A and T are as defined above; 3) alcohol (VIII) is treated with a compound of formula: Y-S02-C1 (IX) wherein Y represents a methyl, phenyl, tolyl, trifluoromethyl group, to obtain a compound of the formula: in which Y, m, ri, A and Y are as defined above; 4) Compound (X) is reacted with a cyclic tertiary amine of the formula: wherein Ar2 and n are such as defined for (I) in claim 1; and, 5) the product thus obtained is isolated in the form of a sulphonate and optionally a salt of sulfonic acid or, optionally, the anion and optionally the acid salt thus obtained is exchanged with another anion and optionally another salt of mineral acid or pharmaceutically acceptable organic.

7. A pharmaceutical composition containing as active ingredient, a compound according to any of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition according to claim 7, in the form of a dosage unit, in which the active ingredient is mixed with at least one pharmaceutical excipient.

9. A pharmaceutical composition according to claim 8, characterized in that it contains 0.5 to 1000 mg of active ingredient.

10. A pharmaceutical composition according to claim 9, characterized in that it contains 2.5 to 250 mg of active ingredient.