FR2678267A1 - Arylalkylamines, process for their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

The subject of the invention is compounds of formula: in which: - Y represents a group Ar-(CH2)x-CX in which .Ar represents a phenyl, a pyridyl or a thienyl; .x is zero or one; .X represents an NH-CO-alkyl group; - m is 2 or 3; - Ar' represents a phenyl, a thienyl, a benzothienyl, a naphthyl or an indolyl; - R represents hydrogen or a C1-C6 alkyl; - T represents -CO- or -CW-NH-, W being an oxygen or sulphur atom, and - Z either represents hydrogen, or represents M or OM when T represents the -CO- group, or represents M when T represents the -CW-NH- group; M represents an alkyl, a phenylalkyl, a pyridylalkyl, a naphthylalkyl, a pyridylthioalkyl, a styryl, or an optionally substituted mono-, di- or tricyclic heteroaromatic or aromatic group; or one of its salts with inorganic or organic acids. Application: Medicaments, especially in the treatment of pathological phenomena involving neurokinin systems.

Description

Arylalkylamines, process for their preparation and pharmaceutical compositions containing them

 The subject of the present invention is new aromatic derivatives substituted with an amino group and with various ester, amine or amide functions.

 The present invention also relates to the use of the compounds according to the invention in compositions for therapeutic use and more particularly in the pathological phenomena that involve the neurokinin system.

Ligands endogenous to neurokinin receptors have been described, such as substance P (SP), neurokinin A (NKA) (SJ BAILEY et al., 1983, Substance P, P. Skrabanck ed., 16-17).
Boole Press, Dublin) and Neurokinin B (NKB) (SP WATSON, Life
Science, 1983, 25, 797-808).

 Neurokinin receptors have been recognized on many preparations and are currently classified into three types: NK1, NK2 and NK3. While most of the preparations studied to date have several types of receptors, such as the guinea pig ileum (NK1, NK2 and NK3), some of them would have only one such carotid artery dog (NK1), the endothelium-free rabbit pulmonary artery (NK2) and the rat portal vein (NK3) (REGOLI D. et al., Trends Pharmacol Sci., 1988, 9, 290-295 and Pharmacology, 1989, 38, 1-15).

A more precise characterization of the different receptors is made possible by the recent synthesis of selective agonists. Thus, the ESar91 Met-C02) 9 111 SP, the ENle10 NKA4 10 and
EMe Phe 3 -NKB would have a respective selectivity for the NK1, NK2 and NK3 receptors (see D. REGOLI, 1988 and 1989 cited above).

 It has now been found that certain aminated and variously substituted aromatic derivatives possess valuable pharmacological properties as neurokinin A receptor antagonists and are particularly useful for the treatment of any dependent neurokinin A pathology.

The NK2 receptor and neurokinin A are, for example, involved in neurogenic inflammation of the airways (PJ BARNES, Arch Int Pharmacodyn, 1990, 303, 67-82 and
GF JOOS et al., Arch. Int. Pharmacodyn., 1990, 303, 132-146).

 To date, only peptide antagonists of NK2 receptors have been described. A publication by C.A. MAGGI et al., Br. J. Pharmacol., 1990, 100, 588-592, discloses peptides that are selective NK2 receptor antagonists.

 European Patent Application 0 347 802 discloses peptide derivatives antagonists of neurokinin A useful as immunosuppressants, in the treatment of arthritis, asthma, pain of inflammation, gastrointestinal hypermotility , Huntington's disease, psychoses, hynertension, migraines, urticaria etc.

 European Patent Application 0 336 230 also discloses substance P and neurokinin A antagonistic peptide derivatives useful for the treatment and prevention of asthma.

dans laquelle - Y représente - soit un groupe Cy-N dans lequel
Cy représente un phényle non substitué ou substitué une ou
plusieurs fois par l'un des substituants choisis parmi
l'hydrogène, un atome d'halogène, un hydroxyle, un alcoxy en
C1-C4, un alkyle en C1-C4, un trifluorométhyle, lesdits substi
tuants étant identiques ou différents, un groupe cycloalkyle en
C3-C7 ; un groupe pyrimidinyle ou un groupe pyridyle ; - soit un groupe

dans lequel - Ar représente un phényle non substitué ou substitué une ou
plusieurs fois par l'un des substituants choisis parmi
l'hydrogène, un atome d'halogène, un hydroxyle, un alcoxy en C1-C4, un trifluorométhyle, un alkyle en C1 -C4, lesdits substituants étant identiques ou différents ; un groupe pyridyle ; un groupe thiényle ;
x x est zéro ou un ;
X X représente un hydroxyle, un alcoxy en C1-C4; un acyloxy en
C1-C4 ; un carboxy ; un carbalcoxy en C1 -C4 ; un cyano ; un
groupe -N-(X1)2 dans lequel les groupes X1 représentent
indépendamment l'hydrogène, un alkyle en C1-C4 ; un groupe

dans lequel Alk représente un alkyle en C1 -C6 ; un
groupe -S-X2 dans lequel X2 représente l'hydrogène ou un groupe
alkyle en C1-C4 ;
ou bien X forme avec l'atome de carbone auquel il est lié et
avec l'atome de carbone voisin dans l'hétérocycle une double
liaison ; - n est 2 ou 3 ; - Ar' représente un phényle non substitué ou substitué une ou
plusieurs fois par l'un des substituants choisis parmi : l'hydro
gène, un atome d'halogène, de préférence un atome de chlore ou de
fluor, un trifluorométhyle, un alcoxy en C1-C4, un alkyle en
C1-C4, lesdits substituants étant identiques ou différents ; un
thiényle ; un benzothiényle ; un naphtyle ou un indolyle ; - R représente l'hydrogène, un alkyle en C1-C6; - T représente un groupe choisi parmi

Thus, according to one of its aspects, the present invention relates to variously substituted amino aromatic compounds of the formula

in which - Y represents - is a Cy-N group in which
Cy represents unsubstituted or substituted phenyl
several times by one of the substituents chosen from
hydrogen, a halogen atom, a hydroxyl, an alkoxy
C1-C4, a C1-C4 alkyl, a trifluoromethyl, said
the same or different radicals, a cycloalkyl group
C3-C7; a pyrimidinyl group or a pyridyl group; - a group

wherein - Ar represents unsubstituted or substituted phenyl or
several times by one of the substituents chosen from
hydrogen, a halogen atom, a hydroxyl, a C1-C4 alkoxy, a trifluoromethyl, a C1-C4 alkyl, said substituents being identical or different; a pyridyl group; a thienyl group;
xx is zero or one;
XX represents a hydroxyl, a C1-C4 alkoxy; an acyloxy in
C1-C4; a carboxy; C1-C4 carbalkoxy; a cyano; a
group -N- (X1) 2 in which groups X1 represent
independently hydrogen, C1-C4 alkyl; a group

wherein Alk is C1-C6 alkyl; a
-S-X2 group in which X2 represents hydrogen or a group
C1-C4 alkyl;
or else X forms with the carbon atom to which it is linked and
with the neighboring carbon atom in the heterocycle a double
binding; n is 2 or 3; Ar 'represents an unsubstituted or substituted phenyl, or
several times by one of the substituents chosen from: hydro
gene, a halogen atom, preferably a chlorine atom or a
fluorine, trifluoromethyl, C1-C4 alkoxy, alkyl
C1-C4, said substituents being identical or different; a
thienyl; a benzothienyl; naphthyl or indolyl; - R represents hydrogen, a C1-C6 alkyl; T represents a group chosen from

soit M lorsque T représente le groupe

W being an oxygen or sulfur atom, and - Z represents either hydrogen, or M or OM when T represents the group

let M be when T is the group

M represents a C1-C6 alkyl; a phenylalkyl wherein the alkyl is C 1 -C 3, optionally substituted on the aromatic ring by halogen, trifluoromethyl, C 1 -C 4 alkyl, hydroxyl, C 1 -C 4 alkoxy; a pyridylalkyl in which the alkyl is C -C; a naphthylalkyl wherein the alkyl is C1-C8, optionally substituted on the naphthyl ring by halogen, trifluoromethyl, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy; pyridylthioalkyl wherein the alkyl is C1-C3; a styryle; an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group; or a salt thereof with inorganic or organic acids.

 In the present description the alkyl groups or alkoxy groups are straight or branched.

 The salts of the compounds of formula (I) according to the present invention include both those with inorganic or organic acids which allow a suitable separation or crystallization of the compounds of formula CI), such as picric acid or oxalic acid or an optically active acid, for example a mandelic or camphorsulfonic acid, than those which form pharmaceutically acceptable salts such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogenphosphate, methanesulfonate, methylsulfate, maleate, fumarate, spleen, naphthalene-2-sulphonate, glycolate, gluconate, citrate, isethionate.

 In particular, in formula CI), Z represents a mono-, di- or tricyclic aromatic or heteroaromatic group which may carry one or more substituents, one of which carbon of the aromatic carbocycle or the aromatic heterocycle is directly linked to group T.

 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 preferably mono- or disubstituted, especially in the 2,4-position, but also for example in the 2,3-position; 4.5; 3,4 or 3,5; it can also be substituted tri, in particular in position 2,4,6, but also for example in 2,3,4; 2,3,5 or 2,4,5; 3,4,5; tetrasubstituted, for example 2,3,4,5; or pentasubstituted. The substituents of the phenyl group may be: F; Cl; Br; I; CN; OH ; Nose;
NH-CO-NH2; N02, CONH2; CF3; C1-C10 alkyl, preferably C1-C41 methyl or ethyl being preferred, and for example npropyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or n-pentyl, hexyl or n -hexyl, heptyl or n-heptyl, octyl or n-octyl, nonyl or n-nonyl as well as decyl or necyl; alkenyl containing 2 to 10, preferably 2-4 carbon atoms, for example vinyl, allyl, 1-propenyl, isopropenyl, butenyl or 1-buten-1-, -2-, -3- or -4-yl, 2 1-buten-1-yl, 2-butenyl, pentenyl, hexenyl or decenyl; alkynyl containing 2 to 10, preferably 2-4 carbon atoms, for example ethynyl, 1-propyn-1-yl, propargyl, butynyl or 2-butyn-1-yl, pentynyl, decynyl; cycloalkyl containing 3 to 8, preferably 5 or 6 carbon atoms, cyclopentyl or cyclohexyl being preferred, as well as for example cyclopropyl, cyclobutyl, 1-, 2- or 3-methylcyclopentyl, 1-, 2-, 3- or 4- methylcyclohexyl, cycloheptyl or cyclooctyl; bicycloalkyl containing 4 to 11, preferably 7 carbon atoms, exo or endo 2-norbornyl being preferred, as well as for example 2-isobornyl or 5-camphyl; hydroxyalkyl containing 1 to 5, preferably 1-2 carbon atoms, hydroxymethyl and 1- or 2-hydroxyethyl being preferred, as well as for example 1-hydroxyprop-1-yl, 2-hydroxyprop-1-yl, 3-hydroxypropyl; 1-yl, 1-hydroxyprop-2-yl, 1-hydroxybut-1-yl, 1-hydroxypent-1-yl; alkoxy containing 1 to 10, preferably 1-4 carbon atoms, methoxy or ethoxy being preferred, as well as for example n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy octyloxy, nonyloxy or decyloxy; alkoxyalkyl containing 2 to 10, preferably 2 to 6 carbon atoms, for example alkoxymethyl or alkoxyethyl, such as methoxymethyl or 1- or 2-methoxyethyl, 1 or 2-n-butoxyethyl, 1- or 2-n-octyloxyethyl; alkoxyalkoxyalkyl containing up to 10, preferably from 4 to 7 carbon atoms, for example alkoxyalkoxymethyl, for example 2-methoxyethoxymethyl, 2ethoxyethoxymethyl or 2-isopropoxyethoxymethyl, alkoxyalkoxyethyl for example 2- (2-methoxyethoxy) ethyl or 2- (2-ethoxyethoxy) ) ethyl; alkoxyalkoxy containing from 2 to 10, preferably from 3 to 6 carbon atoms, for example 2-methoxyethoxy, 2-ethoxyethoxy or 2-n-butoxyethoxy; alkenyloxy containing 2 to 10, preferably 2 to 4 carbon atoms, allyloxy being preferred, and for example vinyloxy, propenyloxy, isopropenyloxy, butenyloxy such as 1-butenyl, -2-, -3- or -4-yloxy, 2-buten-1-yloxy, 2-buten-2-yloxy, pentenyloxy, hexenyloxy or decenyloxy; alkenyloxyalkyl with up to 10, preferably 3-6 carbon atoms, for example allyloxymethyl; alkynyloxy containing from 2 to 10, preferably 2 to 4 carbon atoms, propargyloxy being preferred, as well as for example ethynyloxy, 1-propyn-1-yloxy, butynyloxy or 2-butyn-1-yloxy, pentynyloxy or decynyloxy; alkynyloxyalkyl containing from 3 to 10, preferably 3 to 6 carbon atoms, for example ethynyloxymethyl, propyloxymethyl or 2-C2-butyn-1-yloxy) ethyl; cycloalkoxy containing 3 to 8, preferably 5 or 6 carbon atoms, cyclopentyloxy or cyclohexyloxy being preferred, as well as for example cyclopropyloxy, cyclobutyloxy, 1-, 2- or 3-methylcyclopentyloxy, 1-, 2-, 3- or 4- methylcyclohexyloxy, cycloheptyloxy or cyclooctyloxy; alkylthio containing from 1 to 10, preferably 1 to 4 carbon atoms, methylthio or ethylthio being preferred, and for example n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, octylthio, nonylthio or decylthio; alkylthioalkyl containing from 2 to 10, preferably 2 to 6 carbon atoms, for example methylthiomethyl, 2-methylthioethyl or 2-n-butylthioethyl; acylamino, namely alkanoylamino containing from 1 to 7, preferably 1 to 4 carbon atoms, formylamino and acetylamino being preferred, as well as propionylamino, butyrylamino, isobutyrylamino, valerylamino, caproylamino, heptanoylamino, and alkylamino or benzoylamino; acylaminoalkyl, preferably alkanoylaminoalkyl containing from 2 to 8, preferably 3 to 6 carbon atoms, such as formylaminoethyl, acetylaminoethyl, propionylaminoethyl, n-butyrylaminoethyl, formylaminopropyl, acetylaminopropyl, propionylaminopropyl, formylaminobutyl, acetylaminobutyl, as well as propionylaminobutyl, butyrylaminobutyl; acyloxy containing from 1 to 6, preferably 2 to 4 carbon atoms, acetyloxy, propionyloxy or butyryloxy being preferred, as well as, for example, formyloxy, valeryloxy, caproyloxy; alkoxycarbonyl containing from 2 to 5, preferably 2 and 3 carbon atoms, methoxycarbonyl and ethoxy carbonyl being preferred, as well as, for example, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, secbutoxycarbonyl or tert-butoxycarbonyl; cycloalkoxycarbonyl containing from 4 to 8, preferably 6 or 7 carbon atoms, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl being preferred, as well as cyclopropyloxycarbonyl, cyclobutyloxycarbonyl or cycloheptyloxycarbonyl; alkylaminocarbonylamino containing from 2 to 4 carbon atoms, such as methylaminocarbonylamino, ethylaminocarbonylamino, propylaminocarbonylamino; dialkylaminocarbonylamino containing from 3 to 7, preferably 3 to 5 carbon atoms, preferably dimethyl aminocarbonylamino, as well as di-n-propylaminocarbonylamino, diisopropylaminocarbonylamino; (pyrrolidino-1) -carbonylamino; (piperidino-1) carbonylamino; cycloalkylaminocarbonylamino containing from 4 to 8, preferably 6 or 7 carbon atoms, cyclopentylaminocarbonylamino, cyclohexylaminocarbonylamino being preferred, as well as cyclopropylaminocarbonylamino, cyclobutylaminocarbonylamino, cycloheptylaminocarbonylamino; alkylaminocarbonylaminoalkyl containing from 3 to 9, preferably 4 to 7 carbon atoms, methylaminocarbonylaminoethyl, ethylaminocarbonylaminoethyl, ethylaminocarbonylaminopropyl, ethylaminocarbonylaminobutyl being preferred, as well as for example methylaminocarbonylaminomethyl, n-propylaminocarbonylaminobutyl, n-butylaminocarbonylaminobutyl; dialkylaminocarbonylaminoalkyl containing from 4 to 11 carbon atoms, for example dimethylaminocarbonylaminoethyl, diethylaminocarbonylaminoethyl, diethylaminocarbonylaminopropyl, diethylaminocarbonylaminobutyl; 1-pyrrolidino-carbonylaminoethyl; Cpipéridino-l) -carbonylaminoéthyle, cycloalkylaminocarbonylaminoalkyl containing from 5 to 12, preferably 8 to 11 carbon atoms, cyclopentylaminocarbonylaminoéthyle, cyclopentylaminocarbonylaminopropyle, cyclopentylaminocarbonylaminobutyle, cyclohexylaminocarbonylaminoéthyle, cyclohexylaminocarbonylaminopropyle and cyclohexylaminocarbonylaminobutyle being preferred, and for example cyclopropylaminocarbonylaminométhyle, cycloheptylaminocarbonylaminoéthyle; alkoxycarbonylaminoalkyl containing from 3 to 12, preferably 4 to 9 carbon atoms, methoxycarbonylaminoethyl, ethoxycarbonylaminoethyl, n-propoxycarbonylaminoethyl, isopropoxycarbonylaminoethyl, n-butoxycarbonylaminoethyl, isobutoxycarbonylaminoethyl, sec-butoxycarbonylaminoethyl, tert-butoxycarbonylaminoethyl, ethoxycarbonylaminopropyl, n-butoxycarbonylaminopropyl, ethoxycarbonylaminobutyl, n butoxycarbonylaminobutyl being preferred, as well as, for example, n-propoxycarbonylaminopropyl, n-propoxycarbonylaminobutyl and isopropoxycarbonylaminobutyl; cycloalkoxycarbonylaminoalkyl containing from 5 to 12, preferably 8 to 11 carbon atoms, cyclopentyloxycarbonylaminoethyl, cyclopentyloxycarbonylaminopropyl, cyclopentyloxycarbonylaminobutyl, cyclohexyloxycarbonylaminoethyl, cyclohexyloxycarbonylaminopropyl, cyclohexyloxycarbonylaminobutyl being preferred, as well as for example cyclopropyloxycarbonylaminomethyl, cycloheptyloxycarbonylaminoethyl; carbamoylalkyl containing from 2 to 5, preferably 2 carbon atoms, preferably carbamoylmethyl, as well as carbamoylethyl, carbamoylpropyl, carbamoylbutyl; alkylaminocarbonylalkyl containing 3 to 9, preferably 3 to 6 carbon atoms, methylaminocarbonylethyl, ethylaminocarbonylmethyl, n-propylaminocarbonylmethyl, isopropylaminocarbonylmethyl, n-butylaminocarbonylmethyl, sobutylaminocarbonylmethyl, sec-butylaminocarbonylmethyl, tert-butylaminocarbonylmethyl being preferred, as well as, for example, ethylaminocarbonylethyl, ethylaminocarbonylpropyl, ethylaminocarbonylbutyl, n-propylaminocarbonylbutyl, n-butylaminocarbonylbutyl; dialkylaminocarbonylalkyl containing from 4 to 11, preferably 4 to 8 carbon atoms, dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl, di-n-propylaminocarbonylmethyl, (1-pyrrolidinecarbonylmethyl), (1-piperidino) carbonylmethyl being preferred, as for example diethylaminocarbonylethyl, (piperidino-1) carbonylethyl, diethylaminocarbonylpropyl, diethylaminocarbonylbutyl; cycloalkylaminocarbonylalkyl containing from 5 to 12, preferably 7 or 8 carbon atoms, cyclopentylaminocarbonylmethyl and cyclohexylaminocarbonylmethyl being preferred, as well as for example cyclopropylaminocarbonylmethyl, cyclobutylaminocarbonylmethyl, cycloheptylaminocarbonylmethyl, cyclohexylaminocarbonylethyl, cyclohexylaminocarbonylpropyl, cyclohexylaminocarbonylbutyl; alkylaminocarbonylalkoxy containing from 3 to 10, preferably 3 to 5 carbon atoms, methylaminocarbonylmethoxy being preferred, as for example methylaminocarbonylethoxy, methylaminocarbonylpropoxy; dialkylaminocarbonylalkoxy containing from 4 to 10, preferably 4 to 7 carbon atoms, such as dimethylaminocarbonylmethoxy, diethylaminocarbonylethoxy, (piperidinyl-1) carbonylmethoxy; cycloalkylaminocarbonylalkoxy containing from 5 to 11, preferably 7 or 8 carbon atoms, such as cyclopentylaminocarbonylmethoxy, cyclohexylaminocarbonylmethoxy.

 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, said groups may be unsubstituted or optionally contain one or more substituents such as: alkyl group , phenyl, cyano, hydroxyalkyl, hydroxy, oxo, alkylcarbonylamino and alkoxycarbonyl, thioalkyl wherein the alkyls are C1-C4.

 The radical Z may also be pyridyl, thiadiazolyl, indolyl, indazolyl, imidazolyl, benzimidazolyl, quinolyl, benzotriazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzisothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzodioxinyl or pyridinyl, isoxazolyl, benzopyranyl, thiazolyl, thienyl, furyl, pyranyl, chromenyl, isobenzofuranyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, phthalazinyl, quinazolinyl, acridinyl, isothiazolyl, isochromannyl, chromannyl, carbaryl, one or more double bonds of which may be hydrogenated, said groups may be unsubstituted or optionally contain one or more substituents such as: alkyl, phenyl, cyano, hydroxyalkyl, hydroxy, alkylcarbonylamino and alkoxycarbonyl, thioalkyl in which the alkyls are C1-C4.

The Z group is preferably a phenyl group or a thienyl group; the group T is preferably -C = O and the group
R is preferably methyl.

dans laquelle m, Ar' et R sont tels que définis précédemment et E représente un groupe O-protecteur tel que par exemple tétrahydropyrannyl-2-oxy ou un groupe

dans lequel Y est tel que défini précédemment étant entendu que

où X est un hydroxyle, cet hydroxyle est protégé ;; - soit avec un dérivé fonctionnel d'un acide de formule
HO - CO - Z (III) dans laquelle Z est tel que défini précédemment, lorsqu'on doit préparer un composé de formule (I) où T est -CO-, - soit avec un iso(thio)cyanate de formule
W = C = N - Z (III') dans laquelle W et Z sont tels que définis précédemment, lorsqu'on doit préparer un composé de formule (I) où T est -C(W)-NH-, pour former le composé de formule

- b) puis, lorsque E représente le tétrahydropyrannyloxy, on élimine le groupe tétrahydropyrannyle par action d'un acide, - c) on traite l'alcanolamine N-substituée ainsi obtenue de formule : :

avec le chlorure de méthanesulfonyle ; - d) on fait réagir le mésylate ainsi obtenu de formule

avec une amine secondaire de formule

dans laquelle Y est tel que défini précédemment ; et - e) après déprotection éventuelle de l'hydroxyle représenté par X, on transforme éventuellement le produit ainsi obtenu en un de ses sels.According to another of its aspects, the present invention relates to a process for the preparation of the compounds of formula (I) and its salts, characterized in that - a) a free amine of formula:

in which m, Ar 'and R are as defined above and E represents an O-protecting group such as, for example, tetrahydropyranyl-2-oxy or a group

wherein Y is as previously defined being understood that

where X is hydroxyl, that hydroxyl is protected; or with a functional derivative of an acid of formula
HO - CO - Z (III) in which Z is as defined above, when a compound of formula (I) where T is -CO-, or with an iso (thio) cyanate of formula
Where W and Z are as defined above, when a compound of formula (I) where T is -C (W) -NH-, is to be prepared to form the compound Formula

b) then, when E represents tetrahydropyranyloxy, the tetrahydropyranyl group is removed by the action of an acid; and c) the N-substituted alkanolamine thus obtained of formula:

with methanesulfonyl chloride; d) the mesylate thus obtained of formula

with a secondary amine of formula

wherein Y is as previously defined; and e) after possible deprotection of the hydroxyl represented by X, the product thus obtained is optionally converted into one of its salts.

 As a functional derivative of the acid (III), the acid itself, suitably activated for example by cyclohexylcarbodiimide or benzotriazolyl hexaphosphate N-oxytris (dimethylaminophosphonium BOP), or one of the functional derivatives which react with the amines, for example an anhydride, a mixed anhydride, the acid chloride or an activated ester. When Z is an OM group, the acid concerned is carbonic acid and, as a functional derivative, monochloride is used, namely a Cl-CO-OM chloroformate.

le procédé de la présente invention peut être représenté et illustré en détail par le Schéma 1 ci-après
SCHEMA 1

When starting from a compound of formula (II) where E is a group

the process of the present invention can be shown and illustrated in detail in Scheme 1 hereinafter
SCHEME 1

 In formula (IIIa) above, the acid chloride is considered as reactive functional derivative of the acid (III).

However, another functional derivative can be used or one can start from the free acid (III) by coupling (II ') with BOP (benzotriazolyl hexafluorophosphonate N-oxytrisdimethylamino phosphonium), and then adding the acid ( III) in the presence of an organic base such as triethylamine, in a solvent such as dichloromethane or dimethylformamide, at room temperature, the compounds (I) obtained are isolated and purified according to the usual methods, for example chromatography or recrystallization.

We can also react (ICI) with an iso (thio) cyanate
W = C = NZ (IIII) in an anhydrous inert solvent such as, for example, benzene, overnight at ambient temperature and then treat the reaction mixture according to the usual methods to obtain the compounds (I ").

 When as starting material a compound of formula (II) wherein E is tetrahydropyranyloxy is used, the process of the present invention can be shown and illustrated from Scheme 2.

 The reactions of the compound (II ") with the reagents (IIIa) and (IIII) proceed as described above for Scheme 1, the acid chloride (IIIa) being replaceable by another functional derivative or by the free acid activated for example by the BOP.

 The intermediate (IVE) thus obtained is deprotected by mild acid hydrolysis to yield the free hydroxyl compound (V) from which the mesylate (VI) is prepared to substitute it with a secondary amine of formula (VII) to finally obtain the compounds (I). ) according to the invention.

SCHEME 2

 The products of formula (I) thus obtained are isolated, in free base or salt form, according to conventional techniques.

When the compound of formula (I) is obtained in free base form, the salification is carried out by treatment with the chosen acid in an organic solvent. By treatment of the free base, dissolved for example in an alcohol such as isopropanol, with a solution of the acid selected from the same solvent, the corresponding salt is obtained which is isolated by conventional techniques. hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogenphosphate, methanesulfonate, methylsulfate, oxalate, maleate, fumarate, naphthalene-2-sulfate
At the end of the reaction, the compounds of formula (I) can be isolated in the form of a salt thereof, for example the hydrochloride or the oxalate; in this case, if necessary, the free base can be prepared by neutralizing said salt with a mineral or organic base, such as sodium hydroxide or triethylamine or with an alkali carbonate or bicarbonate, such as sodium carbonate or bicarbonate or potassium.

 The resolution of the racemic mixtures and optionally mixtures of diastereoisomers (I) makes it possible to isolate the enantiomers or diastereoisomers which form part of the invention.

dans laquelle m, E et Arl sont tels que définis ci-dessus, par réduction du nitrile.The starting compounds of formula (II) are prepared from nitriles of formula

wherein m, E and Arl are as defined above, by reduction of the nitrile.

 For the preparation of the compounds of formula (II) in which R is hydrogen, the starting nitriles of formula (VIII) are hydrogenated in an alkanol such as methanol, in the presence of a catalyst such as Raney nickel. , and the primary free amine can be isolated by conventional methods.

qui sont ensuite réduits par des moyens connus, tels que L'action d'un agent réducteur comme par exemple un hydrure métallique, tel que L'hydrure de sodium et d'aluminium, l'hydrure de lithium et d'aluminium ou par un hydrure de bore, tel que le diméthylsulfure de borane. La réduction est réalisée dans un solvant, tel que l'éther, le toluène ou le tétrahydrofuranne, à une température comprise entre la température ambiante et 600C.L'amine ainsi obtenue de formule

est isolée selon les méthodes habituelles.When it is desired to prepare the compounds of formula (II) in which R is methyl, the free amine, obtained by hydrogenation of the nitrile (VIII) as described above, is treated with a chloroformate, for example with chloroformate. formula C1-CO-OR1, where R1 is C1-C6 alkyl, to obtain carbamates of formula

which are then reduced by known means, such as the action of a reducing agent such as a metal hydride, such as sodium hydride and aluminum, lithium aluminum hydride or by a boron hydride, such as borane dimethyl sulfide. The reduction is carried out in a solvent, such as ether, toluene or tetrahydrofuran, at a temperature between room temperature and 600 ° C. The thus obtained amine of formula

is isolated by the usual methods.

dans laquelle m, E, Arl, T et Z sont tels que définis précédemment par un halogénure d'alkyle en présence d'une base forte telle que par exemple un hydrure métallique comme par exemple l'hydrure de sodium, dans un solvant inerte tel que le tétrahydrofuranne chauffé au reflux pour préparer les composés (IV) dans lesquels R est autre que l'hydrogène.It is also possible to treat the compound of formula

in which m, E, Arl, T and Z are as defined above by an alkyl halide in the presence of a strong base such as, for example, a metal hydride such as, for example, sodium hydride, in an inert solvent such as that tetrahydrofuran heated at reflux to prepare compounds (IV) wherein R is other than hydrogen.

The nitriles of formula (VIII) are prepared from nitriles of formula: Ar 1 -CH 2-CN (XI) which, by alkylation with a compound of formula:
E- (CH2) mG (XII) wherein m and E are as defined above and G is a halogen atom, for example bromine or a protected hydroxy group, give the desired compounds (VIII).

(XII, E = THP-O-, G = Br) qui est ensuite additionné, en présence d'hydrure alcalin sur le dérivé acétonitrile (XI) pour préparer l'intermédiaire,

(VIII, E = THP-O-)
La synthèse des nitriles de formule (VIII) où E représente un groupe :

ou Y est tel que défini précédemment, est effectuée selon des méthodes connues par addition sur des dérivés chlorés de formule ::

d'un dérivé nitrile de formule

en présence d'ami dure de sodium dans un solvant tel que le toluène à des températures comprises entre 30 et 800C.The synthesis of nitriles of formula (VIII) in which E is a tetrahydropyranyloxy group is carried out from a tetrahydropyranyloxy derivative (THP-O) obtained by reaction between an alkanol of formula Br- (CH2) -OH with m as defined above and dihydropyran to yield the compound:

(XII, E = THP-O-, G = Br) which is then added, in the presence of alkaline hydride to the acetonitrile derivative (XI) to prepare the intermediate,

(VIII, E = THP-O-)
The synthesis of nitriles of formula (VIII) where E represents a group:

or Y is as defined above, is carried out according to known methods by addition to chlorinated derivatives of formula:

a nitrile derivative of formula

in the presence of sodium hard friend in a solvent such as toluene at temperatures between 30 and 800C.

lui-même préparé à partir de l'amine de formule (VII) dans laquelle, si X = OH, alors le groupe hydroxyle est éventuellement protégé par un groupe O-protecteur selon les méthodes habituelles,

amine sur laquelle on fait réagir, si m = 2, l'oxyde d'éthylène et, si m = 3, un halogéno-3 propanol.The chlorinated derivative (XIII) is prepared by the action of a chlorinating reagent such as thionyl chloride on the hydroxyl derivative of formula

itself prepared from the amine of formula (VII) in which, if X = OH, then the hydroxyl group is optionally protected by an O-protecting group according to the usual methods,

amine on which, if m = 2, ethylene oxide is reacted and, if m = 3, a halogeno-3-propanol.

 The compounds according to the invention have been the subject of biochemical and pharmacological tests.

The antagonistic properties of receptor binding
NK2 have been demonstrated by tests carried out on rat duodenum membranes according to L. BERGSTOM et al., Mol.

Pharmacol., 1987, 32, 764-771.

 Trials have also been performed on the endothelium-free rabbit pulmonary artery, which has NK2 receptors whose activation leads to muscle contraction. The tests on different isolated organs were carried out according to D. REGOLI et al., Trends Pharmacol. Sci., 1988, 9, 290-295 and Pharmacology, 1989, 38, 1-15.

 Bronchospasm tests in guinea pig induced by an NK2 agonist were performed according to H. KONZETT et al., Arch.

Exp. Path. Pharm., 1940, 195, 71-4.

 The compounds according to the invention move C2-125I histidyl-neurokinin A of its receptor with a Ki of the order of 3 to 0.50 nM.

 The same compounds in the rabbit pulmonary artery assays showed a pA2 of 10.4 to 9.

The same compounds, in the tests carried out on the bronchospasm of guinea pigs showed an antagonistic activity of the
10
ENle 3-neurokinin A iv at a dose of 200 μg / kg.

Given the antagonistic properties of neurokinin
The compounds according to the invention are capable of being used in any dependent neurokinin A pathology and more particularly in neurogenic inflammation of the respiratory tract, for example asthma or bronchoconstriction.

 The compounds of the present invention are low in toxicity; in particular, their acute toxicity is compatible with their use as a medicament. For such use, the mammals are administered an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

 The compounds of the present invention are generally administered in dosage units. Said dosage units are preferably formulated in 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 active principle, a compound of formula (I) or a pharmaceutically acceptable salt thereof.

 In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active ingredients can be administered in unit dosage forms, in admixture with conventional pharmaceutical carriers. The appropriate unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral forms of administration, forms of subcutaneous, intramuscular, intravenous, intranasal or intraocular administration, forms of rectal administration, forms of administration by inhalation or by application to the membrane of the mucous membranes such as those of the nose, throat or bronchi , for example with the aid of an aerosol containing the active principle in the form of a spray or a powder dry.

 In order to obtain the desired effect, the dose of active ingredient may vary between 0.25 and 1000 mg per day, preferably between 2 and 250 mg.

 Each unit dose may contain from 0.25 to 250 mg of active ingredient, preferably from 1 to 125 mg, in combination with a pharmaceutical carrier. This unit dose can be administered 1 to 4 times a day.

 When a solid composition in tablet form is prepared, the active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose or other suitable materials or they can be treated in such a way that they have prolonged or delayed activity and continuously release a predetermined amount of active ingredient.

 A preparation in capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

 A syrup preparation or elixir may contain the active ingredient together with a sweetener, preferably a calorie-free sweetener, methylparaben and propylparaben as an antiseptic, as well as a flavoring agent and a suitable colorant.

 Water-dispersible powders or granules may contain the active ingredient in admixture with dispersants or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or scavengers taste.

 For rectal administration, suppositories are used which are prepared with binders melting 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, for example propylene glycol or butylene glycol, are used.

 For administration by inhalation, an aerosol containing, for example, sorbitan trioleate or oleic acid as well as trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethane or any other biologically compatible propellant gas is used.

The active ingredient can also be formulated in the form of microcapsules, optionally with one or more supports or additives
The aforesaid compositions may also contain other active products such as, for example, bronchodilators, antitussives or antihistamines.

 The following examples illustrate the invention without limiting it.

 In the examples that follow, the following abbreviations have been used.

F: instantaneous melting point expressed in degrees Celcius.

 NMR spectra were carried out at 200 MHz in deuterated dimethyl sulfoxide.

m: massive, s: singlet, se: expanded singlet, t: triplet,
Mult: multiplet.

EXAMPLE 1
N - [(3,4-Dichlorophenyl) -2- (4-hydroxy-4-phenylpiperidinyl) -4-butyl] -2,4-dichlorobenzamide hydrochloride. SR 47316 A.

a) (3,4-Dichlorophenyl) -3 (2-tetrahydropyranyloxy) -1-cyano-propane.

 16.5 g of 80% sodium hydride in the oil are suspended in 200 ml of dry tetrahydrofuran. A solution of 100 g of 3,4-dichlorophenylacetonitrile in 500 ml of tetrahydrofuran is added dropwise at 20 ° C. over a period of 30 min., And the reaction mixture is stirred at room temperature for 2 hours. The mixture is cooled to -20 ° C. and a solution of 118 g of 1-bromo-2-tetrahydropyranyl ethane in 100 ml of tetrahydrofuran is added, the mixture is allowed to return to room temperature and after 2 hours a solution of 50 g of chloride is added. of ammonium in 3 l of water. Extracted with 1.5 l of ether, washed with saturated sodium chloride solution, decanted, dried over MgSO 4 and concentrated in vacuo.

 The residue is chromatographed on silica gel, eluent: dichloromethane then dichloromethane-ethyl acetate 95-5 (v / v).

The pure product fractions are concentrated under vacuum to provide 118 g of an oil.

b) (3,4-Dichlorophenyl) -2 (2-tetrahydropyranyloxy) -4-butylamine.

118 g of the nitrile obtained above are dissolved in 700 ml of absolute ethanol. 300 ml of concentrated ammonia are added and then, under a nitrogen sweep, nickel is added.
Raney (10% of the amount of starting amine). It is then hydrogenated under a hydrogen atmosphere at room temperature and ordinary pressure.

 16 l of hydrogen are absorbed in 4 h. The catalyst is filtered off on celite, the filtrate is concentrated in vacuo, the residue is taken up in a saturated solution of sodium chloride. After extraction with ether and drying over MgSO 4, 112 g of an oil are obtained.

(c) 3,4-N -dichloro-3,4-phenyl-2-tetrahydropyranyloxy-butyl-2,4-dichlorobenzamide.

 80 g of the amine obtained above are dissolved in 800 ml of dichloromethane. The solution is cooled to 0 ° C., 38.4 ml of triethylamine and then 55 g of 2,4-dichlorobenzoic acid chloride are added. The reaction mixture is then stirred at ambient temperature for 1 h, then washed with water. The organic phase is decanted, dried over MgSO 4 and concentrated under vacuum to give 120 g of an oil.

d) (2,4-Dichlorobenzoylamino) -1- (3,4-dichlorophenyl) butanol-4.

 120 g of the product obtained above are dissolved in 1 l of methanol in the presence of 12 g of para-toluenesulphonic acid. The reaction mixture is stirred for 18 h at room temperature and then concentrated in vacuo. The residue is taken up in dichloromethane and washed with a 10% solution of sodium carbonate. The organic phase is decanted and dried over MgSO 4 to provide 106 g of an oil.

e) N-C (3,4-dichlorophenyl) -2-butyloxy-4-butyl-2,4-dichlorobenzamide.

 106 g of the alcohol obtained above are dissolved in 1 l of dichloromethane and then 44 ml of triethylamine and 24.2 ml of methanesulfonyl chloride are added to the cooled OOC solution. The reaction mixture is stirred at 0 ° C. for 45 minutes, washed 3 times with ice water, decanted, dried over MgSO 4 and concentrated in vacuo.

The residue is recrystallized from isopropyl ether.

m = 95 g f) SR 47316 A.

 A mixture of 1 g of the product obtained above, 0.8 g of 4-hydroxy-4-phenylpiperidine and 1 ml of dimethylformamide is heated at 600C for 2 hours. After cooling, diluted with ether, washed with dilute sodium hydroxide solution and then with water. After drying over MgSO 4, the solvents are evaporated and the residue is chromatographed on 40 g of silica, elution: dichloromethane then dichloromethane / methanol 90/10 (v / v). The concentration of the pure fractions gives 0.9 g of the product of which the hydrochloride is made in dichloromethane by adding hydrochloric ether to pH = 1. The precipitate is separated by filtration and then crystallized in ether.

m = 0.95 g.

NMR: 8.75 (t, 1H); 7.7-7 (m, 11H); 5.4 (s, 1H); 3.6-2.6 (m, 9H); 2.6-1.6 (m, 6H).

EXAMPLE 2
N- (3,4-dichlorophenyl) -2- (4-hydroxy-4-phenylpiperidinyl) -4-butylacetamide hydrochloride. SR 47885 A.

 NC (3,4-dichlorophenyl) -2-mesyloxy-4-butylacetamide is prepared by proceeding as described in Example 1 steps a) b) c) d) and e) replacing in step c) 2,4-dichlorobenzoic acid chloride with acetyl chloride.

 SR 47885 A.

 A mixture of 6.5 g of the previously prepared product, 6.8 g of 4-hydroxy-4-phenylpiperidine and 10 ml of dimethylformamide is heated to 60 ° C.

 After 1 h, the reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is decanted, dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel; eluent: methanol / dichloromethane 10/90 (v / v). The concentration of the pure product fractions gives a residue which is salified with hydrochloric ether and 6 g of hydrochloride are collected.

NMR: 7.95 (t, 1H); 7.7-7.0 (m, 8H); 3.6-2.6 (m, 9H); 2.6-1.3 (m, 9H).

EXAMPLE 3
N-Ethyl NC (3,4-dichlorophenyl) -2- (4-hydroxy-4-phenylpiperidinyl) -4-butylthiophene-2-carboxamide hydrochloride.

SR 47886 A.

a) N-ECdichloro-3,4-phenyl) -2- (4-hydroxy-4-phenylpiperidinyl) -4-butyl ethylamine hydrochloride.

 To a suspension of 0.96 g of lithium aluminum hydride in 10 ml of tetrahydrofuran is added a solution of 5.5 g of the compound SR 47885 A, obtained previously in Example 2, in 20 ml of tetrahydrofuran and then the mixture The reaction is refluxed for 2 hours. It is then cooled and hydrolyzed with 4 ml of 4N sodium hydroxide solution, the alumina is filtered, rinsed with tetrahydrofuran and evaporated. After salification with a solution of hydrochloric ether, the hydrochloride is concretized in an isopropanol / isopropyl ether mixture; 4.7 g are collected.

(b) SR 47886 A
To a solution of 2.45 g of the product obtained previously, in dichloromethane at 0 ° C., 2.75 ml of triethylamine and then 0.8 g of thenoyl chloride-2 are added. After hydrolysis with 0.1N sodium hydroxide solution and extraction with dichloromethane, the product is purified by chromatography on silica H; eluent: methanol / dichloromethane: 2.5 / 97.5 (v / v) The pure product is salified with a solution of hydrochloric ether and finally 1.0 g of hydrochloride is collected.

NMR: 7.75-6.9 (m, 11H); 5.35 (s, 1H); 3.9-2.55 (m, 11H); 2.55-1.5 (m, 6H); 0.95 (t, 3H).

EXAMPLE 4
N- (4-hydroxy-4- (2-pyridinylmethyl) piperidinyl) -4- (3,4-dichlorophenyl) butyl-2,4-dichlorobenzamide dihydrochloride. SR 46702 A.

a) N-C (3,4-dichlorophenyl) -2,4-ethylenedioxy-piperidinyl) -4-butyl 2,4-dichlorobenzamide.

 A mixture of 12.1 g of the mesylate obtained in Example 1 e) and 8.6 g of ethylenedioxy-4,4-piperidine is heated at 100 ° C. for 15 minutes. The mixture is cooled, taken up in dichloromethane and washed with water. The aqueous phase is decanted, dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue is chromatographed on silica gel; eluent: methanol / dichloromethane 2/98 (v / v).

 The concentration of the pure fractions provides 12.15 g of expected product.

(b) 3,4-N- (3,4-dichlorophenyl) -4- (4-piperidone) butyl-2,4-dichlorobenzamide.

 The product obtained is dissolved in 100 ml of acetone and then 100 ml of 6N hydrochloric acid are added. After 2 hours, 1 l of water and 1 l of ether are added and the aqueous phase is recovered. This is then brought to pH = 10 by adding sodium hydroxide and then extracted with 1 l of ether. After drying and evaporation of the organic phase, 9.7 g of pure product are obtained.

(c) SR 46702 A.

 To a solution of 1 g of product obtained previously in 5 ml of tetrahydrofuran at 250 ° C. under nitrogen, a solution of 2.15 M picolyl-lithium in tetrahydrofuran is added until the red coloration persists (see synthesis on page 43, 1974). After hydrolysis and extraction with ether, the residue is chromatographed on silica gel; eluent: methanol / dichloromethane: 15/85 (v / v). After evaporation of the pure fractions and salification of the residue with a solution of hydrochloric ether, 400 mg of a white foam are obtained.

NMR: 8.8-7.15 (m, 11H); 5.3 (bs, 1H); 4-2.55 (m, II H); 2,351.4 (m, 6H).

EXAMPLE 5
N - C (4 - benzyl - 4 - hydroxy - piperidinyl) - (3,4 - dichlorophenyl) -2 - butyl N - naphth-1-yl urea hydrochloride. SR 47117 A.

a) N-C(tétrahydropyrannyl-2 oxy)-4 (dichloro-3,4 phényl)-2 butyl7
N'-napht-1-yl urée.m = 2; R = H;

a) NC (2-tetrahydropyranyloxy) -4- (3,4-dichlorophenyl) butyl)
N'-naphth-1-yl urea.

 To a solution of 7.6 g of naphth-1-yl isocyanate in 50 ml of toluene is added 12 g of (3,4-dichlorophenyl) -2 (2-tetrahydropyranyloxy) -4-butanamine obtained according to the example 1 b) in 50 ml of toluene. After stirring the reaction mixture for 10 minutes, 50 ml of methanol are added and concentrated in vacuo.

b) N-C (3,4-dichlorophenyl) -2-butanol-4N-naphth-1-yl urea.

 To a solution of the product obtained above, 2 g of p-toluenesulphonic acid is added and the mixture is refluxed for 10 minutes. The solution is washed with sodium bicarbonate and concentrated to dryness. After purification of the residue by chromatography on silica gel, eluting with ethyl acetate, 13.1 g of a colorless oil are obtained.

(c) 3,4-N -dichloro-3,4-phenyl-4-mesyloxy-butyl] -N-naphth-1-yl urea.

 To a solution of 13.1 g of the product obtained previously in 100 ml of dichloromethane, 5.37 ml of triethylamine and then 2.77 ml of mesyl chloride are added at 0 ° C. The solution is then washed with 3 times 100 ml of ice water and the organic phase is dried and evaporated. The residue is then recrystallized from isopropanol and then filtered and rinsed with isopropyl ether.

m = 8g F = 1200C d) SR 47117 A
A mixture of 4 g of the product obtained above, 4 g of 4-hydroxy-4-benzylpiperidine and 4 ml of dimethylformamide is heated at 100 ° C. for 20 minutes. The whole is then poured on the water and extracted with dichloromethane. The residue is then purified by chromatography on silica gel, eluting with a methanol / dichloromethane mixture: 4/96 (v / v). After salification with a solution of hydrochloric ether, 1.0 g of pure hydrochloride is collected.

NMR: 8.7 (s, 1H); 8.2-6.8 (m, 16H); 3.5-2.5 (m, 11H); 2.3-1.3 (m, 6H).

 The compounds described in Tables 1, 2 and 3 below were synthesized according to Examples 1 to 5. These compounds are all hydrochlorides.

TABLE 1

<tb><SEP> n <SEP> SR
<tb> example <SEP> n0 <SEP> Ar <SEP> x <SEP> Spectrum <SEP> of <SEP> NMR
<tb><SEP> n
<tb><SEP> 8.54 <SEP> (t, <SEP> 1 <SEP> H) <SEP>;<SEP> 7.7-7 <SEP> (m, <SEP> 11 <SEP> H) <SEP>;
<tb><SEP> 46418 <SEP> A <SEP><SEP> 1 <SEP> 4.8 <SEP> (s <SEP> Large <SEP> 1 <SEP> H) <SEP>;<SEP> 3.8-2.55 <SEP> (m,
<tb><SEP> 6 <SEP> 9 <SEP> It <SEP> H) <SEP>;<SEP> 2.4-1.25 <SEP> (m, <SEP> 6 <SEP> H).
<Tb>

<SEP> 8.6 <SEP> Ct, <SEP> 1 <SEP> H) <SEP>;<SEP> 7.8-7.2 <SEP> (m,
<tb><SEP> 47322 <SEP> A <SEP> e <SEP> CE <SEP> 1 <SEP> 10 <SEP> H) <SEP>;<SEP> 4.9 <SEP> (s, <SEP> 1 <SEP> H) <SEP>;<SEP> 3.7-2.6
<tb><SEP> 7 <SEP> Cm, <SEP> 11 <SEP> H) <SEP>;<SEP> 2.2-1.4 <SEP> (m, <SEP> 6 <SEP> H).
<Tb>

<SEP> 8.55 <SEP> (t, <SEP> 1 <SEP> H) <SEP>;<SEP> 7.8-7.2 <SEP> (m,
<tb><SEP> 47552 <SEP> A <SEP><SEP> O <SEP> 10 <SEP> H) <SEP>;<SEP> 5.70 <SEP> (s, <SEP> 1 <SEP> H) <SEP>;<SEP> 3.6-2.6
<tb><SEP> 8 <SEP><SEP> (m, <SEP> 9 <SEP> H) <SEP>;<SEP> 2.6-1.6 <SEP> Cm, <SEP> 6 <SEP> H).
<Tb>

<SEP> CF3
<tb><SEP> 8.7 <SEP> (d, <SEP> 2 <SEP> H) <SEP>;<SEP> 8.45 <SEP> (t, <SEP> 1 <SEP> H) <SEP>;
<tb><SEP> 47596 <SEP> A <SEP> N <SEP>><SEP> 1 <SEP> 7.85 <SEP> (d, <SEP> 2 <SEP> H) <SEP>;<SEP> 7.6-7 <SEP> (m, <SEP> 6 <SEP> H) <SEP>;
<tb><SEP> 9 <SEP> 9 <SEP><<SEP> 5.3 <SEP> (s <SEP> wide, <SEP> 1 <SEP> H) <SEP>;<SEP> 4.0-2.3 <SEP> (m,
<tb><SEP>[<SEP> 11 <SEP> H) <SEP>;<SEP> 2.3-0.6 <SEP> (m, <SEP> 6 <SEP> H).
<Tb>

TABLE 2

<SEP> o
<tb><SEP> n <SEP> SR
<tb><SEP> c
<tb><SEP> N <SEP><<SEP> N <SEP> Y <SEP> 8.4-8.8 <SEP> (m, <SEP> 3 <SEP> H) <SEP>;<SEP> 7.2-7.8
<tb> 47415 <SEP> A <SEP> \ N / NMJN <SEP> (m, <SEP> 6 <SEP> H) <SEP>;<SEP> 6.8 <SEP> (t, <SEP> 1 <SEP> H) <SEP>;
<tb><SEP> 10 <SEP> N <SEP> 4.7 <SEP> Cd, <SEP> 2 <SEP> H) <SEP>;<SEP> 2.6-3.8 <SEP> (m,
<tb><SEP> 11 <SEP> H) <SEP>;<SEP> 2.2 <SEP> (Mult., <SEP> 2 <SEP> H).
<Tb>

TABLE 3

<tb><SEP> n <SEP> SR
<tb> example <SEP> n <SEP> R1 <SEP>R'1<SEP><SEP> x <SEP><SEP> Spectrum of <SEP> NMR
<tb><SEP> 7.8-6.8 <SEP> (m, <SEP> 11 <SEP> H) <SEP>;<SEP> 4.75 <SEP> (s,
<tb><SEP> 47735 <SEP> A <SEP> H <SEP> H <SEP> 1 <SEP> 1 <SEP> H) <SEP>;<SEP> 4.0-2.5 <SEP> (m, <SEP> 14 <SE> H) <SEP>;<SEP> 2,3
<tb><SEP> 11 <SEP> 1.3 <SEP> (m, <SEP> 6 <SEP> H).
<Tb>

<SEP> 48056 <SEP> A <SEP> 4-OCH3 <SEP> H <SEP> 0 <SEP> 6.9-7.4 <SEP> (m, <SEP> 5 <SEP> H) <SEP>;<SEP> 3.9-4.9 <SEP> (m,
<tb><SEP> 12 <SEP> 1 <SEP> H) <SEP>;<SEP> 0.6-2.6 <SEP> (m, <SEP> 11 <SEP> H).
<Tb>

EXAMPLE 13
N-methyl NC hydrochloride (3,4-dichlorophenyl) -4- (4-hydroxy-4-phenylpiperidinyl) butyl] benzamide. SR 47921 A.

a) N-C (3,4-dichlorophenyl) -2 (ethyl tetrahydropyranyl-2-oxy) -4-butyl] carbamate.

 80.4 ml of ethyl chloroformate are added dropwise to a solution cooled to -20.degree. C. of 80 g of amine obtained in Example 1b) and 39 ml of triethylamine in 800 ml of dichloromethane. . After 30 min, washed twice with water and then with a buffer solution pH = 2.

 The organic phase is decanted and dried over MgSO 4 and then concentrated under vacuum to obtain 98 g of product in the form of an oil.

(b) N - C (3,4 - dichlorophenyl) (2 - tetrahydropyranyloxy) -4 - butyl] methylamine.

 In a three-necked 2 l nitrogen-swept, 20 g of aluminum hydride are introduced in suspension in 200 ml of tetrahydrofuran. A solution of 98 g of the carbamate obtained previously in 800 ml of tetrahydrofuran is added at 200 ° C.

 Carefully heated to reflux and maintained it for 18 h.

 It is cooled to 0 ° C. and hydrolyzed with 35 ml of water and then with a mixture of 17 ml of concentrated sodium hydroxide solution and 150 ml of water. The minerals are filtered off and concentrated in vacuo to give 80.5 g of product as an oil.

(c) N- (3,4-dichlorophenyl) -hydroxy-4-butyl methylamine hydrochloride.

 To 50 g of protected aminoalcohol obtained previously in solution in 500 ml of ethanol is added 20 ml of concentrated hydrochloric acid. After 2 h 30, concentrated in vacuo, the residue dissolved in 200 ml of acetonitrile then slowly added 350 ml of ether. Stir for 1 hour, filter the crystals, rinsed with ether.

m = 32.8 g
F = 1520C.

d) N-methyl-CN (3,4-dichlorophenyl) -2-butyl methanesulfonyloxy-4-butyl]
tert-butyl carbamate.

 To 32.8 g of the hydrochloride of the product previously dissolved in 300 ml of dioxane and 30 ml of water, 20 ml of triethylamine are added. 27 g of Boc 2 O 3 Cdi-tert-butylcarbonate are then added) and the mixture is stirred at ambient temperature for 15 minutes.

It is heated at 60 ° C. for 30 minutes. After concentration to dryness, it is taken up in ether, washed with water and then with a buffer solution pH = 2, then again with water. It is dried over MgSO4 and concentrated in vacuo to give 40 g of oil.

e) N - [(3,4-dichlorophenyl) -2-methanesulfonyl-4-yl butyl] methylamine.

 To 40 g of alcohol obtained previously in solution in 400 ml of dichloromethane, 17 ml of triethylamine are added. It is cooled to 0 ° C. and 9.3 ml of mesyl chloride are added dropwise. After 15 min, washed 2 times with water, dried over MgSO 4, concentrated to dryness to obtain 49 g of oil.

f) N-methyl-N-C (3,4-dichlorophenyl) -2- (4-hydroxy-4-phenylpiperidinyl) -4-butyl] carbamate tert-butyl hydrochloride.

 A mixture of 20 g of the product obtained above and 18 g of 4-hydroxy-4-phenylpiperidine in 40 ml of dimethylformamide at 70 ° C. is heated for 2 hours for 1 hour 30 minutes. The solution is then poured into 300 ml of ice water, filter the above and rinse with water. The solid is then taken up in ether, dried over MgSO 4 and evaporated. The crude product is purified by chromatography on silica gel eluting with a gradient of methanol in dichloromethane (up to 5%). 22 g of pure product are obtained.

g) N-ECdichloro-3,4-dichlorophenyl) -2- (4-hydroxy-4-phenylpiperidinyl) -4-butyl] methylamine.

 To a solution of 22 g of the previously obtained derivative in 100 ml of methanol is added 100 ml of concentrated hydrochloric acid and 20 ml of water. After 1 h, the reaction mixture is concentrated in vacuo. A foam is obtained which is triturated in ether and then dried m = 20.7 g.

h) SR 47921 A
To a solution of 2 g of the product obtained above and 2 ml of triethylamine in 20 ml of dichloromethane at -780 ° C. under nitrogen, 0.51 ml of benzoyl chloride is added and the mixture is stirred for 10 minutes. After hydrolysis with 0.1N sodium hydroxide solution and extraction with dichloromethane, the product is purified by chromatography, eluting methanol / dichloromethane 10/90 (v / v). 1.37 g of pure product is thus recovered, the hydrochloride is made by adding hydrochloric ether to pH = 1. Finally, 1.40 g of hydrochloride in the form of foam is obtained.

NMR: 7.7-6.6 (m, 13H); 5.35 (s, 1H); 3.8-2.5 (m, 12H); 2.5-1.5 (m, 6H).

EXAMPLE 14
3,4-N-Methyl-3,4-dichlorophenyl) hydrochloride (4-hydroxy-4-phenyl-4-piperidinylbutyl) N'-benzylurea SR 47889 A.

 To a solution of 2 g of the product obtained according to Example 13 g) and 1.2 ml of triethylamine in 20 ml of dichloromethane at 0 ° C. under nitrogen, 0.60 ml of benzyl isocyanate is added and the mixture is allowed to stir. mixing for 1 h. After washing with 0.1N sodium hydroxide solution, the product is purified by chromatography on silica gel; Eluent methanol / dichloromethane 6/94 (v / v) The product is then salified with a solution of hydrochloric ether and 1.8 g of hydrochloride are obtained.

NMR: 7.7-6.9 (m, 13H); 6.75 (t, 1H); 5.4 (bs, 1H); 4.1 (m, 2H); 3.7-2.5 (m, 12H); 2.5-1.4 (m, 6H).

EXAMPLE 15
3,4-N-Methyl-3,4-dichlorophenyl) -4- (4-hydroxy-4-phenylpiperidinyl) -4-butyl] ethyl carbamate hydrochloride.

SR 47887 A.

 To a solution of 2 g of product obtained previously according to Example 13 g) and 2 ml of triethylamine in 20 ml of dichloromethane at -780 ° C. under nitrogen, 0.44 ml of ethyl chloroformate is added. After 5 min, the mixture is hydrolyzed with 0.1N sodium hydroxide solution and extracted with dichloromethane. The product is then purified by chromatography on silica gel; eluent methanol / dichloromethane: 8/92 (v / v). The pure fractions are concentrated in vacuo and the addition of hydrochloric ether gives 1.1 g of hydrochloride in the form of a white foam.

NMR: 7.7-7.1 (m, 8H); 5.45 (s, 1H); 4.1-2.6 (m, 14H); 2.6-1.6 (m, 6H); 1.1 (t, 3H).

 The compounds described in Tables 4 and 5 were synthesized according to Examples 13 to 15. These compounds are hydrochlorides.

TABLE 4

<tb><SEP> o
<tb><SEP> n <SEP> SR
<tb><SEP> o
<tb> example <SEP> no <SEP>;<SEP> M <SEP> 5 <SEP> R1 <SEP><SEP> Spectrum of <SEP> NMR
<tb><SEP> I
<tb><SEP> 7.8-7.1 <SEP> (m, <SEP> 8 <SEP> H) <SEP>;<SEP> 3.7-2.65 <SEP> (m,
<tb><SEP> 47914 <SEP> A <SEP> -CH3 <SEP> H <SEP> 12 <SEP> H) <SEP>;<SEP> 2.65-1.6 <SEP> (m, <SEP> 9 <SEP> H).
<Tb>

<SEP> 16
<tb><SEP> 7.7-7.0 <SEP> (m, <SEP> 8 <SEP> H) <SEP>;<SEP> 3.7-2.55 <SEP> (m,
<tb><SEP> 47916 <SEP> A <SEP> -CH2-CH2-CH3 <SEP> H <SEP> 12 <SEP> H) <SEP>;<SEP> 2.55-0.5 <SEP> (m, <SEP> 13 <SEP> H).
<Tb>

<SEP> 17
<tb><SEP> CH <SEP> 7.8-7.1 <SEP> (m, <SEP> 8 <SEP> H) <SEP>;<SEP> 5.5 <SEP> (s,
<tb><SEP> 47915 <SEP> A <SEP> -CH <SEP> H <SEP> Wide, <SEP> 1 <SEP> H) <SEP>;<SEP> 3.9-2.65 <SEP> (m,
<tb><SEP> 18 <SEP> \ <SEP> CH3 <SEP> 13 <SEP> H) <SEP>;<SEP> 2.65-0.5 <SEP> (m, <SEP> 12 <SEP> H).
<Tb>

<SEP> 7.7-6.8 <SEP> (m, <SEP> 13 <SEP> H) <SEP>;<SEP> 5.35 <SEP> (s,
<tb><SEP> 47918 <SEP> A <SEP> -CH <SEP> U <SEP> H <SEP> 1 <SEP> H) <SEP>;<SEP> 3.7-2.5 <SEP> (m, <SEP> 14 <SEP> H) <SEP>;<SEP> 2.5
<tb><SEP> 19 <SEP> 2 <SEP> 1.5 <SEP> (m, <SEP> 6 <SEP> H).
<Tb>

<SEP> 7.8-6.9 <SEP> (m, <SEP> 12 <SEP> H) <SEP>;<SEP> 5.6 <SEP> (s,
<tb><SEP> 47982 <SEP> A <SEP> n <SEP> 4-Cl <SEP> 1 <SEP> H) <SEP>;<SEP> 3.9-2.6 <SEP> (m, <SEP> 12 <SEP> H) <SEP>;
<tb><SEP> 20 <SEP> - <SEP> / <SEP> 2.6-1.6 <SEP> (m, <SEP> 6 <SEP> H).
<Tb>

<SEP> 7.9-7.0 <SEP> (m, <SEP> 10) <SEP>;<SEP> 5.40 <SEP> (m,
<tb><SEP> 47942 <SEP> A <SEP> t <SEP><SEP> 4-CH3 <SEP> 1 <SEP> H) <SEP>;<SEQ> 3,9-2,6 <SEP > (m, <SEP> 12 <SEP> H) <SEP>;
<tb><SEP> 21 <SEP> f <SEP> - <SEP> 2,6-1,6 <SEP> (m, <SEP> 9 <SEP> H).
<Tb>

TABLE 4 (continued)

<tb><SEP> n <SEP> SR
<tb> example <SEP> n0 <SEP> M <SEP> | <SEP> R1 <SEP><SEP> Spectrum of <SEP> NMR
<tb><SEP> n <SEP> R1
<tb><SEP> 7.9-6.5 <SEP> (m, <SEP> li <SEP> H) <SEP>;<SEP> 5.45 <SEP> (s,
<tb><SEP> 47919 <SEP> A <SEP><<SEP> S <SEP> H <SEP> 1 <SEP> H) <SEP>;<SEP> 3.9-2.6 <SEP> (m, <SEP> 12 <SEP> H) <SEP>;<SEP> 2,6
<tb><SEP> 22 <SEP> H <SEP> 1.6 <SEP> (m, <SEP> 6 <SEP> H).
<Tb>

<SEP> 7.8-6.4 <SEP> (m, <SEP> li <SEP> H) <SEP>;<SEP> 5.3 <SEP> (s,
<tb><SEP> 47981 <SEP> A <SEP><SEP> H <SEP> 1 <SEP> H) <SEP>;<SEP> 3.9-2.6 <SEP> (m, <SEP> 12 <SEP> H) <SEP>;<SEP> 2.4
<tb><SEP> 23 <SEP> 1.6 <SEP> (m, <SEP> 6 <SEP> H).
<Tb>

TABLE 5

<tb><SEP> o
<tb><SEP> n <SEP> SR
<tb><SEP> o
<tb> example <SEP> n <SEP> M <SEP><SEP> Spectrum of <SEP> NMR
<tb><SEP> n
<tb><SEP> 7.6-6.9 <SEP> (m, <SEP> 13 <SEP> H) <SEP>;<SEP> 5.35 <SEP> (s <SEP> wide,
<tb><SEP> 47888 <SEP> A <SEP> -CH <SEP><<SEP> 1 <SEP> H) <SEP>;<SEP> 5.1-4.6 <SEP> (m, <SEP> 2 <SEP> H) <SEP>;<SEP> 3.7-2.5
<tb><SEP> 24 <SEP> 2 <SEP> (m, <SEP> 12 <SEP> H) <SEP>;<SEP> 2.5-1.5 <SEP> (m, <SEP> 6 <SEP> H).
<Tb>

EXAMPLE 25
3- (3,4-Dichlorophenyl) -4- (4-hydroxy-4-phenylpiperidinyl) butyl] -N-methylthiophene-2-carboxamide hydrochloride
SR 47732 A.

a) N-E (3,4-dichlorophenyl) -2 (2-tetrahydropyranyloxy) -4-butyl] thiophene-2-carboxamide.

 A mixture of 4.77 g of amine obtained according to Example 1 (b) and 1.7 g of triethylamine in 50 ml of dichloromethane is stirred at ambient temperature. 2.19 g of thenoyl chloride-2 dissolved in 20 ml of dichloromethane are then added dropwise at room temperature, and the reaction mixture is left at ambient temperature overnight. The solvent is concentrated under vacuum, the residue is washed with water, extracted with ether, washed with a 5% solution of sodium bicarbonate and then with a saturated solution of sodium chloride; the organic phase is decanted, dried over Na2O4, filtered and concentrated in vacuo. The residue is chromatographed on silica gel; eluent: methanol / dichloromethane 98/2 (v / v). The pure fractions are collected and concentrated in vacuo. The residue is washed with 5% sodium hydroxide solution, extracted with ether and dried. 4.6 g of colorless oil are obtained.

(b) NC (3,4-dichlorophenyl) -2 (2-tetrahydropyranyloxy) -4-butyl]
N-methyl thiophene-2 carboxamide.

 A mixture of 3.4 g of the amine obtained above and 0.45 g of 55% sodium hydride in tetrahydrofuran zone is stirred at room temperature. The reaction mixture becomes clear orange. 1.23 g of iodomethane in 10 ml of tetrahydrofuran are then added and the mixture is then stirred for 1 hour at room temperature and refluxed for 1 hour. The tetrahydrofuran is concentrated, the residue is taken up in water, extracted with ether, washed a second time with water and with sodium chloride solution and concentrated under vacuum.

m = 3.4 g.

c) N-C (3,4-dichlorophenyl) -2-butanol] N-methyl thiophene-2-carboxamide.

3.5 g of the product obtained above are dissolved in 30 ml of methanol in the presence of 0.35 g of resin (Amberlyts
H-Aldrich, acidic dry sulfonic resin) and the mixture is refluxed for 1 hour 30 minutes.

 The mixture is filtered on celite, the filtrate is concentrated under vacuum, the residue is washed with hexane and then taken up in an ether / hexane mixture. 2.6 g of white crystals are obtained.

M.p. 107-109C.

d) N-C (3,4-dichlorophenyl) -2-methanesulfonyloxy-4-butyl] N-methyl thiophene-2-carboxamine.

 2 g of alcohol obtained above and 0.65 g of triethylamine in 30 ml of dichloromethane are stirred at ambient temperature. A solution of 0.69 g of mesyl chloride in 10 ml of dichloromethane is then added dropwise. At the end of the addition, the mixture is refluxed for 30 minutes. The dichloromethane is evaporated under vacuum, the residue is taken up in water, extracted with ethyl acetate, washed with 5% sodium bicarbonate solution and then with saturated sodium chloride solution, dried over Na 2 SO 4. evaporate the solvent.

m = 1.2 g.

e) SR 47732 A
A mixture of 1 g of the product obtained above, 1 g of 4-hydroxy-4-phenylpiperidine and 2 ml of dimethylformamide is heated at 60 ° C. for 2 hours.

 After cooling, it is diluted with ether, washed with water and then with a dilute solution of sodium hydroxide. It is dried over MgSO4 and then the solvents are evaporated. The residue is chromatographed on silica gel; eluent dichloromethane to dichloromethane supplemented with 2.5% methanol. 0.7 g of product of which the hydrochloride is made; after dissolving in dichloromethane, hydrochloric ether is added until pH = 1, then it is concentrated under vacuum. The hydrochloride is concretized in ether.

m = 0.74 g.

NMR 7.8-6.8 (m, 11H); 5.3 (s, 1H); 3.8-2.5 (m, 12H); 2.5-1.4 (m, 6H).

 The compounds described in Table 6 were prepared according to Example 25. These compounds are all hydrochlorides.

EXAMPLE 26
3,4-N-Methyl-3,4-dichlorophenyl) hydrochloride (4-hydroxy-4-hydroxy-4-hydroxy-4-piperidinyl-butyl) -3-thiophene-carboxamide. SR 47985 A.

a) Preparation of the amine: 4-hydroxy-4-hydroxy-4-phenylpiperidine.

Step 1: 4-benzyloxybromobenzene

 32.6 g of 4-bromophenol, 34.2 g of benzyl bromide and 42 g of potassium carbonate in 150 ml of dimethylformamide are stirred at 400 ° C. for 2 hours.

 The solution is concentrated under vacuum, the residue is taken up in water and then extracted with ether, washed with water, decanted, dried over MgSO 4, and concentrated under vacuum.

 The residue is recrystallized from isopropanol.

m = 30 g
F = 61 C.

Step 2: 1-benzyl-4-benzyloxy-4-phenyl-4-hydroxypiperidine.

 14 g of the product previously prepared are dissolved in 100 ml of tetrahydrofuran and added to 1.2 g of magnesium coated with 20 ml of tetrahydrofuran at 60 ° C. At the end of the addition, the temperature is maintained at 60 ° C. for 2 hours and then cooled to -10 C. A solution of 10 g of 4-benzylpiperidone is then added dropwise and the mixture is allowed to return to room temperature. The mixture is poured into a saturated solution of ammonium chloride, extracted with ether, washed with water, decanted, dried over MgSO 4, and concentrated under vacuum. The residue is chromatographed on silica gel, eluent: dichloromethane methanol 97.5 / 2.5 (v / v). The concentration of the pure fractions provides 9 g of the expected product.

Mp 104-1070 ° C.

Step 3: 4-hydroxy-4- (4-hydroxyphenyl) piperidine

 6 g of the product obtained previously in solution in 200 ml of ethanol are hydrogenated at ambient temperature and atmospheric pressure in the presence of 10% palladium on carbon. When the theoretical volume of hydrogen is absorbed, the catalyst is filtered, the filtrate is concentrated under vacuum, the residue is taken up in ether and the crystals are filtered off.

m = 1.1 g
Mp = 232-235C.

(b) SR 47985 A
2.1 g of the product obtained above according to Example 25 d), 1 g of the amine obtained in step 3 of Example 26 a) and 1.1 g of triethylamine are dissolved in 5 ml of dimethylformamide and are heated at 800C for 2 h. The mixture is concentrated under vacuum, the residue is taken up in water and acidified to pH = 3 with a 6N hydrochloric acid solution, extracted with ethyl acetate, decanted, dried over MgSO 4 and concentrated under vacuum.

 The residue is taken up in acetone and concretized in ether.

m = 0.7 g
NMR: 9.3 (s, 1H); 6.6-8 cm, 10 H); 5.2 (s, 1H); 2.6-4 (m, 12H); 1.6-2.4 (m, 6H).

TABLE 6

<tb><SEP> o
<tb><SEP> n <SEP> SR
<tb> 47734 <SEP> A <SEP> IC <SEP><SEP> 7.8-6.8 <SEP> (m, <SEP> 10H) <SEP>;<SEP> 5.5 <SEP> (s, <SEP> I <SEP> H) <SEP>;
<tb><SEP> Z7 <SEP> 4 <SEP> 0-2 <SEP> 6 <SEP> (m, <SEP> 12 <SEP> H) <SEP>;<SEP> 2.6-1.5 <SEP> (m,
<tb><SEP> 6 <SEP>H>,
<tb> 47733 <SEP> A <SEP><<SEP> N- <SEP> 8-7 <SEP> Cm, <SEP> 10 <SEP> H) <SEP>;<SEP> 5.8 <SEP> (s, <SEP> 1 <SEP> H) <SEP>;<SEP> 4
<tb><SEP> 28 <SEP> C <SEP> C <SEP> 2.7 <SEP> (m, <SEP> 12 <SEP> H) <SEP>;<SEP> 2.7-1.7 <SEP> (m, <SEP> 6 <SEP> H).
<Tb>

<SEP> 1 <SEP> 7.85 <SEP> (s, <SEP> I <SEP> H) <SEP>;<SEP> 7.75-7.2 <SEP> (m, <SEP> 7 <SEP> H) <SEP>;
<tb> 47947 <SEP> A <SEP> \ <SEP><<SEP> N- <SEP> 7.05 <SEP> (s, <SEP> 1 <SEP> H) <SEP>;<SEP> 5.8 <SEP> (s, <SEP> 1 <SEP> H) <SEP>;<SEP> 3.8
<tb><SEP> 29 <SEP>!
<tb><SEP> 29 <SEP> CF3 <SEP> 2.6 <SEP> Cm, <SEP> 12 <SEP> H) <SEP>;<SEP> 2.6-1.6 <SEP> Cm, <SEP> 6 <SEP> H).
<Tb>

47736 <SEP> A <SEP> i <SEP> X <SEP> O <SEP> ~ <SEP> 6.8-7.8 <SEP> (m, <SEP> 6 <SEP> H) <SEP>;<SEP> 2,6-4 <SEP> Cm,
<tb><SEP> 30 <SEP> i <SEP> 17 <SEP> H) <SEP>;<SEP> 0.8-2.2 <SEP> (m, <SEP> 12 <SEP> H).
<Tb>

47946 <SEP> A <SEP> \ KMN- <SEP> 8.2 <SEP> (s, <SEP> 2 <SEP> H) <SEP>;<SEP> 6.7-7.8 <SEP> Cm, <SEP> 11 <SEP> H) <SEP>;
<tb><SEP> i <SEP> A <SEP> ~~~~~~~~~~~~~
<tb><SEP> 31 <SEP>'<SEP> 2-4 <SEP> m, <SEP> 18 <SEP> H).
<Tb>

47920 <SEP> A <SEP> \ FN-6.7-7.8 <SEP> Cm, <SEP> 10 <SEP> H) <SEP>;<SEP> 1.8-4 <SEP> Cm,
<tb><SEP> 32 <SEP> ut <SEP> N <SEP> 6 <SEP> 7-7.8 <SEP> (m, <SEP> 10 <SE> H) <SEP>;<SEP> 1.8-4 <SEP> H).
<Tb>

<SEP> OCH
<tb><SEP> 3
<Tb>
TABLE 6 (continued)

<tb><SEP> nO <SEP> SR
<tb> example <SEP> n <SEP>[<SEP> Y <SEP> N- <SEP> \ <SEP><SEP> Spectrum of <SEP> NMR
<tb><SEP> Spectrum <SEP>;<SEP> NMR
<tb><SEP> 47941 <SEP> A <SEP><SEP> (m, <SEP> (m, <SEP> 10 <SEP> H) <SEP>;<SEP> 6.35 <SEP> ( s, <SEP> 1 <SEP> H).
<Tb>

<SEP> CF3
<Tb>
EXAMPLE 34
CN hydrochloride (4-benzyl-4-acetyloxy-piperidinyl) -4- (3,4-dichlorophenyl) butyl] 2,4-dichlorobenzamide. SR 47734 A.

 0.4 g of 4-chlorohydrate (4-benzyl-4-hydroxy-4-piperidinyl) (3,4-dichlorophenyl) -2-butyl] -2,4-dichlorobenzamide (SR 46418 A obtained according to the example) 1), dissolved in 10 ml of dichloromethane in the presence of two equivalents of triethylamine, is added 0.12 g of acetyl chloride.

After stirring for 1 hour at ambient temperature, the mixture is washed with water, the organic phase decanted, dried over MgSO 4 and concentrated in vacuo. The residue is chromatographed on silica gel eluting dichloromethane and then dichloromethane / methanol 95/5 (v / v). The fractions of pure product are concentrated in vacuo and then hydrochloric ether is added until pH = 1 and the ether is concentrated under vacuum.
The hydrochloride is concretized in ether.

m = 0.26 g
NMR: 8.5 (t, 1H); 7.7-6.98 (m, 11H); 3.6-2.6 (m, 11H); 2.4-1.8 (m, 9H).

 The compounds described in Table 7 were prepared according to Examples 1-34.

TABLE 7

<tb><SEP> o
<tb><SEP> n <SEP> SR
<tb><SEP> o
<tb> example <SEP> n <SEP> R1 <SEP><SEP> X <SEP> 0 <SEP> Z <SEP> | <SEP> Spectrum <SEP> of <SEP> NMR
<tb><SEP> 7.8-6.9 <SEP> (m, <SEP> 12 <SEP> H) <SEP>;<SEP> 3.9
<tb><SEP> 47983 <SEP> A <SEP> 4-Cl <SEP> -OC-CH3 <SEP><SEP> 2.7 <SEP> (m, <SEP> 12 <SEP> H) <SEP>;<SEP> 2.7-1.8
<tb><SEP> 35 <SEP> O <SEP> (m, <SEP> 9 <SEP> H).
<Tb>

<SEP> 7.9-6.9 <SEP> (m, <SEP> 11 <SEP> H) <SEP>;<SEP> 4.0
<tb><SEP> 47913 <SEP> A <SEP> H <SEP> -OC-CH3 <SEP><SEP><SEP> 2.6 <SEP> (m, <SEP> 12 <SEP> H) ) <SEP>;<SEP> 2.65-1,
<tb><SEP> 36 <SEP> O <SEP> I <SEP> I <SEP> (m, <SEP> 9 <SEP> H).
<Tb>

<SEP> 47949 <SEP> A <SEP> H <SEP> -CN <SEP> S <SEP> 7-7.9 <SEP> (m, <SEP> 11 <SEP> H) <SEP>;<SEP> 2-4,1
<tb><SEP> 37 <SEP> (m, <SEP> 18 <SEP> H).
<Tb>

<SEP> 47948 <SEP> A <SEP> H <SEP> -C-CH3 <SEP> 7 / rl1 <SEP> 7-7.8 <SEP> (m, <SEP> He <SEP> H) <SEP ><SEP> 1.8-4
<tb><SEP> 38 <SEP> O <SEP> Cm, <SEP> 21 <SEP> H).
<Tb>

<SEP> S <SEP> 7-7.9 <SEP> Cm, <SEP> 11 <SEP> H) <SEP>;<SEP> 2-4,3
<tb><SEP> 47984 <SEP> 479d4 <SEP> A <SEP> --C-OCH2CH3 <SEP> Cm, <SEP> (m, <SEP> 20 <SEP> H) <SEP>;<SEP> 1.15 <SEP> (t,
<tb><SEP> 39 <SEP> O <SEP> 3 <SEP> H).
<Tb>

 The alcohols synthesized according to Example 1 d) above or according to Example 34 c) are key intermediates for the preparation of the compounds (I).

 Table A below describes various alcohols useful for the preparation of the compounds (I).

TABLE A
Synthetic intermediates

<tb><SEP> o
<tb><SEP> n <SEP> SR <SEP> i <SEP> M <SEP> | <SEP> Spectrum <SEP> of <SEP> NMR
<tb> i <SEP> 6.8-7.8 <SEP> (m, <SEP> 8 <SEP> H) <SEP>;<SEP> 4.5 <SEP> (se, <SEP> 1 <SEP> H) <SEP>;
<tb><SEP> 48088 <SEP><<SEP> 2,6-4 <SEP> (m, <SEP> 8 <SEP> H) <SEP>;<SEP> 1.3-2.1 <SEP> (m, <SEP> 2 <SEP> H).
<Tb>

<SEP> CH3 <SEP> 6.8-7.6 <SEP> Cm, <SEP> 6 <SEP> H) <SEP>;<SEP> 3-4.2 <SEP> Cm, <SEP> 5 <SEP> H) <SEP>;
<tb><SEP> 48089 <SEP> CH3 <SEP> 2.4 <SEP> (s, <SEP> 3 <SEP> H) <SEP>;<SEP> 1.4-2.2 <SEP> (m, <SEP> 8 <SEP> H).
<Tb>

<SEP> CH
<tb><SEP> S <SEP> 6.8-7.8 <SEP> (m, <SEP> 6 <SEP> H) <SEP>;<SEP> 4.4 <SEP> (t, <SEP> 1 <SEP> H) <SEP>;
<tb><SEP> 47934 <SEP> Mi <SEP> 2,6-4 <SEP> (m, <SEP> 8 <SEP> H) <SEP>;<SEP> 1.4-1.9 <SEP> (se, <SEP> 2 <SEP> H).
<Tb>

EXAMPLE 40
N-methyl N- [1- (4-phenyl-4-acetylamino-4-piperidinyl) -2- (3,4-dichlorophenyl) butylgenzamide hydrochloride SR 48212 A.

A) Preparation of the amine
4-acetamido-4-phenylpiperidine hydrochloride.

 1. 260 ml of 95% sulfuric acid are added dropwise to 69 g of 1-benzyl-4-hydroxy-4-phenylpiperidine in suspension in 300 ml of acetonitrile while maintaining the temperature between 25 and 30 ° C. The mixture The reaction mixture is then stirred at ambient temperature for 4 hours, then successively poured into ice and neutralized with a 30% sodium hydroxide solution.

 The precipitate is separated by filtration, washed with water and then dried in acetone.

m = 58 g
F = 180.6-1820C
2. 4-acetamido-4-phenylpiperidine hydrochloride.

 To 58 g of the product prepared above, dissolved in 600 ml of methanol, ether saturated with hydrochloric acid is added until the pH = 1 is then hydrogenated at atmospheric pressure and ambient temperature in the presence of 6 g of palladium on 10% coal. When the theoretical volume of hydrogen is absorbed, the catalyst is filtered off, the filtrate is concentrated in vacuo and the residue is recrystallized from ethanol.

m = 45 g
Mp 286.5-2880 ° C.

B) Preparation of compound 40
1) N- [4-methanesulfonyloxy-3,4-dichlorophenyl] -2-buty
N-methyl benzamide. This compound is prepared according to Example 1, step e).

F = 100-1020C,
2) Compound 40
1.4 g of 4-acetamido-4-phenylpiperidine and 1.4 g of the above mesylate are heated at 80 ° C. in 3 ml of DMF for 2 h. Ice is added and extracted with dichloromethane. The organic phase is decanted and successively washed with water and then with saturated NaCl solution and dried over MusO.sub.4. It is concentrated under vacuum and the residue is chromatographed on silica gel, eluent dichloromethane / methanol
The concentration of the fractions of the pure product gives a residue which is taken up in methanol. Addition of ether saturated with hydrochloric acid provides the hydrochloride.

m = 0.8 g.

; 18 H entre 2,10 et 3,90 (m, N-CH3, tous les CH2, CH-C6H5) ; 13 H entre 7,00 et 7,80 (m, H aromatiques) ; 1 H à 8,20

NMR: 3H to 2

; 18H between 2.10 and 3.90 (m, N-CH3, all CH2, CH-C6H5); 13 H between 7.00 and 7.80 (m, aromatic H); 1 to 8.20

EXAMPLE 41
4-Hydrochloride N-4-phenyl-4-acetylamino-piperidinyl) -4- (3,4-dichlorophenyl) butylbenzamide (-) SR 48968 A.

Step 1
(2-Tetrahydropyranyloxyethyl) 3,4-dichlorobenzene acetonitrile

 This compound is prepared according to Example 1 a).

2nd step
(2-Tetrahydropyranyloxyethyl) 3,4-dichlorobenzeneethanamine.

 This compound is prepared according to Example 1 b).

Step 3
Hydroxyethyl- (3,4-dichloro-3-benzeneethanamine.

 81 g of the product obtained above according to step 2 are dissolved in 38 ml of methanol.

 80 ml of a saturated solution of hydrochloric ether are added keeping the temperature between 20 and 25 ° C. Stirred for 30 min at room temperature and then concentrated to dryness. The residue is dissolved in 250 ml of water, washed twice with ether, basified with NaOH solution and extracted with dichloromethane. Afterwards on MgSO 4, concentrated to dryness, taken up in 800 ml of isopropyl ether, the insoluble material is filtered off with Celite, concentrated under vacuum to approximately 300 ml, primer with aminoalcohol crystals, stirred overnight.

 It is filtered, rinsed with isopropyl ether and then with pentane.

30.2 g of the expected product are obtained.

Mp = 90-91 C.

Step 4
3,4-Hydroxyethyl-3,4-dichlorobenzeneethanamine (+)
To a boiling solution of 29 g of D (-) tartaric acid in 800 ml of methanol is added a solution of 44.7 g of product obtained according to the previous step 3 in 300 ml of methanol.

 Allowed to warm to room temperature and stirred for 4 hours. It is filtered, rinsed with methanol and then with ether. 34.1 g of tartrate are obtained.

 It is recrystallized from 1.75 l of methanol to give 26.6 g of tartrate.

-4.2 c = 1, H20
The tartrate is taken up in 120 ml of water. Basified with NaOH solution, extracted twice with dichloromethane, dried over
MgSO4, concentrated to dryness. It is taken up in a little isopropyl ether, added pentane, filter to obtain 15.4 g of product.

M.p. 79-80 ° C.

 [&alpha;] D +9.4 c = 1 MeOH.

Step 5
N- [4-hydroxy-3,4-dichlorophenyl] -2-butyl] ethyl carbamate.

 15 g of product obtained according to the preceding step 4 are dissolved in 200 ml of dichloromethane. 9.9 ml of triethylamine are added.

 It is cooled to 0 ° C. and a solution of 6.3 ml of ethyl chloroformate in 30 ml of dichloromethane is added dropwise at this temperature. After 15 min, washed with water and then with diluted HCl and then with a saturated aqueous solution of NaHCO3.

After drying over MgSO4, concentrate to dryness to obtain 20 g of product in the form of an oil.

Step 6
N-methylhydroxyethylsidichloro-3,4-benzeneethanamine hydrochloride (+).

 To 5.1 g of lithium aluminum hydride suspended in 60 ml of anhydrous THF, a solution of 20 g of the product obtained according to the preceding step 5 in 150 ml of anhydrous THF is added. Refluxed for 1 h. It is hydrolysed with 20 ml of water, the mineral is filtered and concentrated to dryness. The oil obtained is dissolved in 100 ml of acetone. Hydrochloric ether is added until pH = 1, then ether until the haze. The mixture is stirred for 1 hour, the crystals are filtered, rinsed with a little acetone and then ether to obtain 1 g of the product.

 F = 1290C.

[&alpha;] D = +8.4 c = 1, MeOH
Step 7
N- [4-hydroxy-3,4-dichlorophenyl] -2-butyl] -N-methyl-benzamine (-).

 To 8.1 g of the product obtained according to the preceding step 6, suspended in 120 ml of dichloromethane, 8.4 ml of triethylamine are added. It is cooled to 0 ° C. and a solution of 3.4 ml of benzoyl chloride in 35 ml of dichloromethane is added dropwise. After 15 min, the mixture is washed with water and then with dilute HCl and then with aqueous NaHCO 3 solution. It is dried over MgSO4, concentrated to dryness. A solid is obtained which is taken up in ether and filtered.

m = 9.0 g F = 129 C.

[&alpha;] D -19 c = 1, MeOH
Step 8
N-O-4-Methanesulfonyloxy (3,4-dichlorophenyl) butyl]
N-methylbenzamide (-).

 To 10.5 g of the product obtained according to the preceding step 7, dissolved in 120 ml of dichloromethane, 4.8 ml of triethylamine are added. It is cooled to 0 ° C. and 2.7 ml of methanesulfonyl chloride are added dropwise. After 15 min, the mixture is washed twice with water and then with a saturated aqueous solution of NaCl. It is dried over MgSO4 and concentrated to dryness to obtain a foam.

[&alpha;] D = -2.3 c = 1, CHCl3
Step 9
Compound 41
22.7 g of 4-phenyl-4-acetylaminopiperidine hydrochloride are dissolved in 20 ml of water. 10 ml of concentrated sodium hydroxide solution are added. It is extracted twice with dichloromethane and dried over MgSO4. The solution obtained is added to the product obtained in step 8. It is concentrated to dryness, 30 ml of DMF are added and the mixture is heated at 700 ° C. for 1 h 30 min. The solution is poured very slowly over 30 ml of water + ice. The precipitate is filtered, taken several times in water and wrung.

Purification by chromatography on silica elution: pure dichloromethane, then dichloromethane with addition of methanol up to 10%.

 Hydrochloride: the base is dissolved in acetone. Ether saturated with hydrochloric acid to pH = 1 is added. The solution is poured into isopropyl ether, filtered and dried.

; 18 H entre 2,00 et 3,75.m = llg
WD = -29.5 c = 1, MeOH
NMR: 3H to 1.85

; 18 H between 2.00 and 3.75.

(m, N - CH 3, all CH 2, CH - C 6 H 5), 13 H between 6.80 and 7.70 (m, aromatic H); 1 to 8.10

EXAMPLE 42
N-methyl-N1-hydrochloride 4-phenyl-4-acetylamino-4-piperidinyl (3,4-dichlorophenyl) -2-butyl] benzamide (+) SR 48965 A.

The (+) enantiomer is prepared according to the same procedure as for the (-) enantionère described in Example 41 above, replacing, in step 4, the D (-) tartaric acid by the acid
L (+) tartaric.

; 18 H entre 2,00 et 3,75 (m, N-CH3, tous les CH2, CH-C6H5) ; 13 H entre 6,80 et 7,70 (m, H aromatiques) ; 1 H à 8,10

NMR: 3H to 1.85

; 18H between 2.00 and 3.75 (m, N-CH3, all CH2, CH-C6H5); 13 H between 6.80 and 7.70 (m, aromatic H); 1 to 8.10

Claims (9)

 thienyl; a benzothienyl; naphthyl or indolyl; - R represents hydrogen, a C1-C6 alkyl; T represents a group chosen from  C1-C4, said substituents being identical or different; a  fluorine, trifluoromethyl, C1-C4 alkoxy, alkyl  gene, a halogen atom, preferably a chlorine atom or a  several times by one of the substituents chosen from: hydro  C1-C6 alkyl; m is 2 or 3; Ar 'represents an unsubstituted or substituted phenyl, or  in which Alk represents

Ar represents a phenyl which is unsubstituted or substituted one or more times with one of the substituents chosen from hydrogen, a halogen atom, a hydroxyl, a C1-C4 alkoxy, a trifluoromethyl or a C1-C4 alkyl, said substituents being the same or different; a pyridyl group; a thienyl group; x is zero or one; X X represents a group  in which

 in which: - Y represents a group

 1. A compound of formula  substituted for it; or a salt thereof with inorganic or organic acids.  mono-, di- or tri-cyclic aromatic or heteroaromatic  wherein the alkyl is C1-C3; a styryle; a group  C1-C4, hydroxyl, C1-C4 alkoxy; a pyridylthioalkyl  naphthyl with halogen, trifluoromethyl, alkyl  The alkyl is C1-C3, optionally substituted on the ring  which alkyl is C1-C3; a naphthylalkyl in which  C1-C4, hydroxyl, C1-C4 alkoxy; a pyridylalkyl in  aromatic by halogen, trifluoromethyl, alkyl  The alkyl is C1-C3, optionally substituted on the ring  represents a C1-C6 alkyl; a phenylalkyl in which  ; M

 let M be when T is the group

W being an oxygen or sulfur atom, and - Z represents either hydrogen, or M or OM when T represents the group  The compound of claim 1 wherein Ar 'is a 3,4-dichlorophenyl group.  3. The compound of claims 1 and 2 wherein R is methyl.  The compound of claims 1 to 3 wherein T is -C = O.  The compound of claims 1 to 4 wherein T is -C = O and Z is thienyl.  The compound of claims 1 to 5 wherein T is -C = O and Z is phenyl, optionally disubstituted with halogen, such as chlorine.  7. Process for the preparation of compounds according to any one of claims 1 to 6 characterized in that - a) a free amine of formula

 in which m, Ar 'and R are as defined previously in claim 1 and E represents an O-protecting group such as, for example, 2-tetrahydropyranyloxy or a group

 wherein Y is as defined above in claim 1, or with a functional derivative of an acid of formula  HO - CO - Z (III) wherein Z is as defined above in claim 1, when a compound of formula (I) where T is -CO-, or with a iso (thio) cyanate of formula  W = C = N = - Z (III ') wherein W and Z are as defined above in claim 1, when a compound of formula (I) or T is -C (W) -NH- to form the compound of formula

 b) then, when E represents tetrahydropyranyloxy, the tetrahydropyranyl group is removed by the action of an acid; and c) the N-substituted aclanolamine thus obtained of formula:

 with the methanesulfonyl chloride - d) the mesylate thus obtained is reacted with the following formula:

 with a secondary amine of formula

 wherein Y is as defined above in claim 1; and e) the product thus obtained is optionally converted into one of its salts.  8. A pharmaceutical composition containing as active principle a compound of formula (I) according to any one of claims 1 to 7.  9. Pharmaceutical composition according to claim 8, in the form of a dosage unit, wherein the active ingredient is mixed with at least one pharmaceutical excipient.