FR2688218A1 - Quaternary ammonium salts of aromatic amino compounds, their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

The subject of the present invention is quaternary ammonium salts of formula: in which: - J represents either an Ar-CXX'-CX'' group or an Ar-(CH2)xCX1 group in which: . Ar represents an optionally substituted phenyl, a cycloalkyl, a pyridyl or a thienyl; . X represents hydrogen; . X' represents hydrogen or is joined to X'' below in order to form a carbon-carbon bond or else X and X' together form an oxo group; . X'' is hydrogen or, with X', forms a carbon-carbon bond; . x is 0 or 1; . X1 represents a hydroxyl, an alkoxy, an acyloxy, a carboxyl, a carbalkoxy, a cyano or an alkoxyamino group; - Q represents an alkyl group or a benzyl group; - A<-> represents an anion; - m is 2 or 3; - Ar' represents an optionally substituted phenyl, a thienyl, a benzothienyl or a naphthyl; - R represents hydrogen or a C1-C6 alkyl; - T represents chosen from -CO- or -CW-NH-, W being an oxygen or sulphur atom, and - Z represents either hydrogen or M or OM, when T represents the -CO- group, or M, when T represents the -CW-NH- group; M represents in particular an alkyl, a phenylalkyl, a pyridylalkyl, a naphthyl or a naphthylalkyl, a pyridylthioalkyl or a styryl. Application = medicaments, in particular for the treatment of pathological phenomena which involve the neurokinin system.

Description

The present invention relates to novel quaternary ammonium salts of aromatic derivatives substituted with an amino group and with various ester, amine or amide functions, as well as their enantiomers.

The present invention also relates to the process for the preparation of the compounds and the reuse of the compounds according to the invention in compositions for therapeutic use and more particularly in pathological phenomena which involve the neurokinin system such as: pain (D. Regoli et al., Life
Sciences, 1987, po 109-117), allergy and inflammation (JE Morlay et al., Life
Sciences, 1987, q, 527-544), circulatory failure (J. Losay et al., 1977,
Substance P, Von Euler, US and Pernow ed., 287-293, Raven Press, New York), gastrointestinal disorders (D. Regoli et al., Trends Pharmacol. Sci., 1985,, 481484), respiratory disorders ( J. Mizrahi et al., Pharmacology, 1982, 25, 39-50).

Ligands endogenous to neurokinin receptors have been described, such as substance P (SP), neurokinin A (NKA) (S.J. Bailey et al., 1983, Substance P. P.

Skrabanck ed., 16-17 Boole Press, Dublin) and neurokinin B (NKB) (SP Watson,
Life Sciences, 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 so far have several types of receptors, such as the guinea pig ileum (NK1, NK2 and NK3), some of them have only one, such as the artery dog carotid artery (NK1), endothelium-deprived rabbit pulmonary artery (NK2) and rat portal vein (NK3) (D. Regoli et al., Trends Pharmacol. Sci., 1988, X, 1-15 ).

A more precise characterization of the different receptors is made possible by the recent synthesis of selective agonists. Thus, the [Sar9, Met- (O2) 11] SP, the [Nie10] NK4-10, and the [Me Phe7] -NKB would present a respective selectivity for the receptors NK1, NK2 and NK3 (cf D. Regoli, 1988 and 1989 previously cited).

It has now been found that certain quaternary ammonium salts of aromatic amine compounds possess valuable pharmacological properties as antagonists of neurokinin receptors and are in particular useful for the treatment of any substance P and neurokinin dependent pathology.

The NK2 receptor and neurokinin A are, for example, involved in neurogenic inflammations of the respiratory tract (P.J. Barnes, Arch. Int.

Pharmocodyn., 1990, 303 67-82 and G.F. Joos et al., Arch. Int. Pharmacodyn., 1990, 303 132-146).

Patent application EP-A-336230 describes peptide derivatives which are antagonists of substance P and of neurokinin A which are useful for the treatment and prevention of asthma.

International patent applications WO 90/05525, WO 90/05729, WO 91/09844, WO 91/18899 and European patent applications EP-A-436334, EP-A-429466 and EP-A430771 describe antagonists of Substance P.

It has now been found that the quaternary ammonium salts of the compounds claimed in applications EP-A-428434 and EP 91402382 have an increased affinity for the Substance P receptors of human cells of the IM9 line.

Snider et al. (Sciences, 1991 251 435-437) have shown using a non-peptide Substance P antagonist, CP 96,345, that the affinity of such an agonist for Substance P receptors was very strongly dependent on the species. animal.

Thus, according to these authors, the CP 96.345 has a Ki equal to 240 nM for the rat receptor (3H-SP binding on rat cortex membranes) but has a Ki equal to 3 nM for the bovine receptor (3H binding -SP on the beef caudate membrane). Others have shown that CP 96.345 has a Ki equal to 0.4 nM in binding assays of the
Substance P on human lymphoblast cells IM9, U373 MG. (Gitter et al., Eur. J. Pharmacol., 1991, 197 237-238).

The quaternary ammonium salts of aromatic amine compounds according to the invention have shown, quite surprisingly, a significant increase in the affinity of these compounds for the Substance P receptors on human cells (lM9) without, however, decreasing. markedly their affinity for Substance P receptors in the rat cortex.

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

dans lequel Ar représente un phényle non substitué ou substitué une ou plusieurs fois par
un substituant choisi parmi : l'hydrogène, un atome d'halogène, un hydroxyle,
un alcoxy en C1-C3, un alkyle en C1-C3, un trifluorométhyle, lesdits
substituants étant identiques ou différents; un groupe cycloalkyle en C3-C7;
un groupe pyridyle ou un groupe thiényle; X représente l'hydrogène;
X' représente l'hydrogène ou est réuni à X" ci-dessous pour former une liaison
carbone-carbone ou bien X et X' ensemble forment un groupe oxo;
X" est l'hydrogène ou avec X' forme une liaison carbone-carbone; * - soit un groupe

dans lequel: .Ar est tel que défini ci-dessus; x est zéro ou un; X1 représente un hydroxyle, un alcoxy en C1-C4 ; un acyloxy en C1-C4 ; un
carboxy ; un carbalcoxy en C1-C4 ; un cyano ; 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 X1 forme avec l'atome de carbone auquel il est lié et avec l'atome de
carbone voisin dans la pipéridine une double liaison; - Q représente un groupe alkyle en C1-C6 ou un groupe benzyle; - A ef représente un anion choisi par exemple parmi les anions chlorure, bromure,
iodure, acétate, méthanesulfonate, paratoluènesulfonate; - mest2ou3; - Ar' représente un phényle non substitué ou substitué une ou plusieurs fois par un
substituant choisi parmi : l'hydrogène, 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; - R représente l'hydrogène, ou un alkyle en C1-C6; - T représente un groupe choisi parmi:

in which: - I represents * - either a group

in which Ar represents a phenyl which is unsubstituted or substituted one or more times by
a substituent chosen from: hydrogen, a halogen atom, a hydroxyl,
C1-C3 alkoxy, C1-C3 alkyl, trifluoromethyl, said
substituents being the same or different; a C3-C7 cycloalkyl group;
a pyridyl group or a thienyl group; X represents hydrogen;
X 'represents hydrogen or is joined to X "below to form a bond
carbon-carbon or else X and X 'together form an oxo group;
X "is hydrogen or together with X 'forms a carbon-carbon bond; * - either a group

in which: .Ar is as defined above; x is zero or one; X1 represents hydroxyl, C1-C4 alkoxy; C1-C4 acyloxy; a
carboxy; C1-C4 carbalkoxy; a cyano; a group::

in which Alk represents an alkyl
in C1-C6; a group -S-X2 in which X2 represents hydrogen or a group
C1-C4 alkyl;
or X1 forms with the carbon atom to which it is bonded and with the atom of
neighboring carbon in piperidine a double bond; - Q represents a C1-C6 alkyl group or a benzyl group; - A ef represents an anion chosen for example from chloride and bromide anions,
iodide, acetate, methanesulfonate, paratoluenesulfonate; - mest2ou3; - Ar 'represents a phenyl which is unsubstituted or substituted one or more times by a
substituent chosen from: hydrogen, a halogen atom, preferably a
chlorine or fluorine atom, trifluoromethyl, C1-C4 alkoxy, alkyl
in C1-C4, said substituents being identical or different; a thienyl; a benzothienyl; a naphthyl; - R represents hydrogen, or 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 when T represents the group

M represents C1-C6 alkyl; a phenylalkyl in which the alkyl is C1
C3, optionally substituted one or more times on the aromatic ring by a
halogen, trifluoromethyl, C1-C4 alkyl, hydroxyl, alkoxy in
C1-C4; a pyridylalkyl in which the alkyl is C1-C3; a naphthyl or a
naphthylalkyl in which the alkyl is C1-C3, optionally substituted on the
naphthyl ring with a halogen, a trifluoromethyl, a C1-C4 alkyl, a
hydroxyl, C1-C4 alkoxy; a pyridylthioalkyl in which the alkyl is
C1-C3; a styryl; an aromatic or heteroaromatic group mono-, di- or
optionally substituted tricyclic.

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

The tertiary amines, precursors of the quaternary amines (I) according to the invention will be referred to below as compounds of formula (Ia):

The salts of the compounds of formula (Ia) are those formed with mineral or organic acids which allow a suitable separation or crystallization of the compounds of formula (Ia), such as picric acid or oxalic acid or an optically active acid , for example a mandelic or camphosulfonic acid, or hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, methyl sulfate, maleate, fumarate, naphthalene-2 sulfonate, glycolate, gluconate, citrate, isethionate.

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

When Z is a phenyl group, the latter may preferably be mono- or disubstituted, in particular in position 2,4, but also, for example, in position 2,3, 4.5, 3.4 or 3.5; it can also be trisubstituted, 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 in 2,3,4,5; or pentasubstituted. The substituents of the phenyl group may be: F; Cl; Br; I; CN;
OH; NH2; NH-CONH2; NO2. CONH2; Cl3; C1-C10 alkyl, preferably C1-C4, methyl or ethyl being preferred, as well as for example n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or n-pentyl, hexyl or n-hexyl, octyl or n-octyl, nonyl or n-nonyl as well as decyl or n-decyl; 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, 2buten -1-yl, 2-buten-2-yl, pentenyl, hexenyl or decenyl; alkynyl containing 2 to 10, preferably 2-4 carbon atoms, for example ethynyl, 1-propyn-1yl, 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 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 -hydroxyprop-1 -yl, 1hydroxyprop-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, tertbutoxy, 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 2methoxyethyl, 1- or 2-n-butoxyethyl, 1- or 2-n -octyloxyethyl alkoxyalkoxyalkyl containing from 3 to 10, preferably from 4 to 7 carbon atoms, for example alkoxyalkoxymethyl, for example 2-methoxyethoxymethyl, 2ethoxyethoxymethyl or 2-isopropoxyethoxymethyl, alkoxyalkoxyethyl for example, for example 2- (2-methoxy) ethyl or 2- (2-methoxy) 2-ethoxyethoxy) ethyl ;; alkoxyalkoxy containing from 2 to 10, preferably from 3 to 6 carbon atoms, for example 2methoxyethoxy, 2-ethoxyethoxy or 2-n-butoxyethoxy; alkenyloxy containing 2 to 10, preferably 2 to 4 carbon atoms, allyloxy being preferred, as well as for example vinyloxy, propenyloxy, isopropenyloxy, butenyloxy such as 1-buten-1-, 2-, -3- or -4-yloxy , 2-buten-1-yloxy, 2-buten-yloxy, pentenyloxy, hexenyloxy or decenyloxy; alkenyloxyalkyl with 2 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 10n, preferably 3 to 6 carbon atoms, for example ethylnyloxymethyl, propargyloxymethyl or 2- (2-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 4methylcyclohexyloxy , cycloheptyloxy or cyclooctyloxy ;; akylthio containing from 1 to 10, preferably 1 to 4 carbon atoms, methylthio or ethylthio being preferred, as well as for example n-propylthio, isopropylthio, n-butylthio, isobutylthio, secbutylthio, 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 atoms of carbon, formylamino and acetylamino being preferred, as well as propionylamino, butyrylamino, isobutyrylamino, valerylamino, caproylamino, heptanoylamino, as well as aroylamino or benzylamino; acylaminoalkyl, preferably alkanoylaminoalkyl containing from 2 to 8, preferably 3 to 6 carbon atoms, such as formylaminoethyl, acetylaminoethyl, propionylaminoethyl, nbutyrylaminoethyl, formylaminopropyl, acetylaminopropyl, propionylaminopropyl, formylaminylaminobution, acaminobutionyl, butaminylaminobution, acaminopropyl, formylaminobutionobution, acaminopropyle 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 ethoxycarbonyl being preferred, as well as for example n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl 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 2 to 4 carbon atoms, such as methylaminocarbonylamino, ethylaminocarbonylamino, propylaminocarbonylamino; dialkylaminocarbonylamino containing from 3 to 7, preferably 3 to 5 carbon atoms, preferably dimethylaminocarbonylamino, as well as di-n-propylaminoearbonylamino, diisopropylaminocarbonylamino, (1pyrrolidino) -carbonylamino ;; cycloaîkylaminocarbonylamino 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 methylaminocarb onylaminomethyl, n-propylaminocarb onylamino-amino, n-propylaminocarbonylamino-amino, n-propylaminocarb onylamino-amino, n-propylaminocarb onylamino-amino; dialkylaminocarbonylaminoalkyl containing from 4 to 11 carbon atoms, for example dimethylamino-carbonylaminomethyl, diethylaminocarbonylaminoethyl, diethylaminocarbonyl-aminopropyl, diethylaminocarbonylaminobutyl, (1 -pyrrolidino) carbonylaminoethyl, (1 piperalkidino), preferably from cyclo-carbonylaminoethyl, (1 piperalkidino), preferably from 8 to 12-carbonylo-amino-carbonyl-containing from 5 to 12 carbon atoms, cyclopentylaminocarbonylaminoethyl, cyclopentylaminocarbonylaminopropyl, cyclopentylaminocarb onyl-aminobutyl, cyclohexylaminocarbonylaminoethyl, cyclohexylaminocarb onylaminopropyl and cyclohexylaminocarbonylaminopropyl being preferred, as well as cycloaminoethylaminoaminoethyl aminopaminopaminoethyl, for example cycloaminopaminoethyl, for example cycloaminoethylaminoaminoethyl, for example, cyclo-aminocarbonylaminopaminoethyl, for example cyclohexylaminocarbonylamino-amino alkoxycarbonylaminoalkyl containing from 3 to 12, preferably 4 to 9 carbon atoms, methoxycarbonylaminoethyl, ethoxycarbonylaminoethyl, n-propoxycarbonyleaminoéthyle, isopropoxycarbonylaminoéthyle, n-butoxycarbonylaminoethyl, isobutoxycarbonylaminoéthyle, sec-butoxycarbonylaminoethyl, t-butoxycarbonylamino ethyl, éthoxycarbonylaminopropyle, n-butoxycarbonylaminopropyl, éthoxycarbonylaminobutyle, n -butoxycarbonylaminobutyl being preferred, as well as for example n-propoxycarbonylaminopropyl, n-propoxycarbonylaminobutyl, isopropoxycarbonylaminobutyl ;; cycloalkoxycarbonylaminoalkyl containing from 5 to 12, preferably 8 to 11 carbon atoms, cyclopentyloxycarbonylaminoéthyle, cyclopentyloxycarbonylaminopropyle, cyclopentyloxycarbonylaminobutyle, cyclohexyloxycarbonylaminoéthyle, cyclohexyloxycarbonylaminopropyle, cyclohexyloxycarbonylaminobutyle being preferred, and for example cyclopropyloxycarb onylaminométhyle, cycloheptyloxycarbonylaminoéthyle carbamoylalkyl containing from 2 to 5, preferably 2 carbon carbon, preferably carbamoylmethyl, as well as carbamoylethyl, carbamoylpropyl, carbamoylbutyl; alkylaminocarbonylalkyl containing from 3 to 9, preferably 3 to 6 carbon atoms, méthylaminocarbonyléthyle, éthylaminocarb onylmethyl, npropylaminocarbonylméthyle, isopropylaminocarbonylméthyle, n-butylaminocarbonylméthyle, isobutylaminocarbonylméthyle, sec-butylaminocarbonylméthyle, tert-butylaminocarbonylméthyle being preferred, and for example éthylaminocarbonyléthyle, éthylaminocarbonylpropyle, éthylaminocarbonylbutyle , n-propylaminocarbonylbutyl, n-butylaminocarbonylbutyl dialkylaminocarbonyl-alkyl containing from 4 to 11, preferably 4 to 8 carbon atoms, dimethylamino-carbonylmethyl, diethylaminocarbonylmethyl, di-npropylaminocarbonylmethyl; as well as, for example, diethylaminocarbonylethyl, diethylaminocarbonylpropyl, diethylaminocarboxybutyl; (1 pyrrolidine) carb onylmethyl, (1-piperidino) carbonylmethyl, (1 - piperidino) carbonylethyl; cycloalkylaminocarbonylalkyl containing from 5 to 12, preferably 7 or 8 carbon atoms, cyclopentylaminocarbonylméthyle and cyclohexylaminocarbonylméthyle being preferred, and for example cyclopropylaminocarbonylméthyle, cyclobutylaminocarb onylmethyl, cycloheptylaminocarbonylméthyle, cyclohexylaminocarbonyléthyle, cyclohexylaminocarbonylpropyle, cyclohexylaminocarbonylbutyle alkylaminocarbonylalkoxy containing from 3 to 10, preferably 3 to 5 carbon atoms, methylaminocarbonylmethoxy being preferred, as well as, for example, methylaminocarbonylethoxy, methylaminocarbonylpropoxy dialkylaminocarbonylalkoxy containing from 4 to 10, preferably 4 to 7 carbon atoms, such as dimethylaminocarbonylmethoxy, diethylaminocarbonylethoxy, (piperidinyl-aminocarbonylethoxy, (piperidinyl-1-carbonylethoxy); cycloalkylaminocarbonylalkoxy containing from 5 to 11, preferably 7 or 8 carbon atoms, such as cyclopentylaminocarbonylmethoxy, cyclohexylaminocarbonylmethoxy.

The Z radical can also represent a bicyclic aromatic group such as 1- or 2-naphthyl; said naphthyl groups possibly being unsubstituted or optionally containing one or more substituents chosen from: halogens, the alkyl, phenyl, cyano, hydroxyalkyl, hydroxy, oxo, alkylcarbonylamino, alkoxycarbonyl or thioalkyl group in which the alkyls are C1-C4.

The Z radical can also be a pyridyl, thiadiazolyl, indolyl, indazolyl, imidazolyl, benzimidazolyl, quinolyl, benzotriazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzisothiazolyl, quinolyl, isoquinolyl, benzoxyazolyl, benzoxazinyl, benzoxazinyl, benzoxazinoxyl, benzoxazinyl, benzoxyl, benzoxyl, benzoxyl, benzoxyl, benzoxyl, benzoxyl, benzoxyl, benzoxy, oxyl, benzoxy, thiazolyl, quinolyl, benzisothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzoxazinyl, benzoxazinyl, isoquinolyl, benzoxazolyl, isoquinolyl, benzoxazolyl, benzoxazolyl, benzoxyoxyl, benzothienyl, benzothiazolyl, benzisothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, thiazolyl, thienyl, furyl, pyranyl, chromenyl, isobenzofuranyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, phthalazinyl, quinazolinyl, acridinyl, isothiazolyl, isochromanyl, chromanyl, double bonds of which one or more carbaryl groups can be said to have one or more carbaryl groups, of which one or more groups can be hydrolyzed, isochromanyl, chromanyl, pyrimidinyl, pyridazinyl, indolizinyl, phthalazinyl, isochromanyl, chromanyl. which may be unsubstituted or optionally contain one or more substituents such as: the alkyl, phenyl, cyano, hydroxyalkyl, hydroxy, alkylcarbonylamino, alkoxycarbonyl or thioalkyl group in which the alkyls are C1-C4.

The group Z is preferably a phenyl group, a naphthyl group substituted with one or more halogen, a benzyl group substituted with one or more C1-C4 alkoxy or a thienyl group; the group T is preferably -C = O and the group
R is preferably hydrogen or a methyl group.

According to another of its aspects, the present invention relates to a process for the preparation of the compounds of formula (I), characterized in that:
a compound of formula (Ia), the amino function of which optionally present on the Z substituent is N-protected by a usual N-protecting group, in the form of its free base, is treated with an excess of alkylating agent of formula:
QA
in which A represents a group capable of forming an anion and is as defined above for (I), preferably a chloride or an iodide and Q is as defined above for (I) and the reaction mixture is heated in a solvent by example chosen from dichloromethane, chloroform, acetone or acetonitrile, at a temperature between room temperature and reflux for one to several hours to obtain, after treatment according to the usual methods and after optional deprotection, a mixture of the conformers axial and equatorial quaternary ammonium salts.

In the case where A (i) represents a non-pharmacologically acceptable anion such as an iodide, or a methanesulfonate anion, this anion can be exchanged for another anion or for a pharmacologically acceptable anion, for example a chloride, by elution of the compound (I ) on an ion exchange resin, for example Amberlite IRA688 or DuoliteA375 (.

The conformers are separated according to the usual methods, for example by chromatography or by recrystallization.

Each of the axial or equatorial conformers of the compounds (I) in the form of racemates or in the form of optically pure R or S enantiomers form part of the invention.

The compounds (ira) are prepared by a process according to which:
- a) a free amine of formula is treated:

dans lequel J est tel que défini précédemment étant entendu que: lorsque J représente le groupe

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

in which J is as defined above, it being understood that: when J represents the group

where X1 is hydroxyl, that hydroxyl is protected; - or with a functional derivative of an acid of formula:
HO - CO - Z (HERE)
in which Z is as defined above, when a compound of formula (Ia) where T is -CO-, - is to be prepared with an iso (thio) cyanate of formula:
W = C = NZ a)
wherein W and Z are as defined above, when a compound of formula (Ia) where T is -C (W) -NH- is to be prepared to form the compound of formula:

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

avec une amine secondaire de formule:

- B) then, when E represents tetrahydropyranyloxy, the tetrahydropyranyl group is removed by the action of an acid,
- C) treating the N-substituted alkanolamine thus obtained of formula:

with methanesulfonyl chloride; - D) the mesylate thus obtained is reacted with the formula:

with a secondary amine of the formula:

in which J is as defined above; and
- E) after optional deprotection of the hydroxyl represented by X1, the product thus obtained is optionally converted into one of its pharmaceutically acceptable salts.

As functional derivative of the acid (III), the acid itself is used, suitably activated for example by cyclohexylcarbodiimide or by benzotriazolyl N-oxytrisdimethylaminophosphonium hexafluorophosphonate (BOP), or else one of the functional derivatives which react with 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 functional derivative, monochloride is used, namely a chloroformate Cl-CO
OM.

When, as starting material, a compound of formula (II) where E represents a group is used:

the process for preparing the compounds (Ia) can be represented and illustrated in detail by Scheme 1 below:
DIAGRAM 1

In formula aIIa) above, the acid chloride is considered as a reactive functional derivative of the acid (III). However, one can use another functional derivative or one can start from the free acid (III) by carrying out a coupling of (II ') with the BOP, then, by adding the acid (III) in the presence of an organic base. such as, for example, triethylamine, in a solvent such as dichloromethane or dimethylformamide, at room temperature; the compounds (I'a) obtained are isolated and purified according to the usual methods, such as for example chromatography or recrystallization.

It is also possible to react aII) with an iso (thio) cyanate W = C = NZ (III ') in an anhydrous inert solvent such as for example benzene, overnight at room temperature then treat the reaction mixture according to the usual methods. to obtain the compounds (l "a).

When as the starting material a compound of formula (11) where E represents a tetrahydropyranyloxy group is used, the process of the present invention can be represented and illustrated from Scheme 2.

The reactions of the compound aI ") with the reagents (IIIa) and aII ') take place as described above for Scheme 1, the acid chloride (IIIa) being able to be replaced by another functional derivative or by the acid. free activated for example by the BOP.

The intermediate a) thus obtained is deprotected by mild acid hydrolysis to lead to the free hydroxyl compound (V) from which the mesylate (VI) is prepared in order to substitute it with a secondary amine of formula (VII) for. finally obtain the compounds (la).

DIAGRAM 2

<tb><SEP> H <SEP> R <SEP> H <SEP> R
<tb><SEP> I <SEP> I <SEP> I <SEP> I
<tb> XoiCH2) m4-CH2H <SEP> HO <SEP> Ho {CH2) m4-CH2 <SEP> NH
<tb><SEP> Ar '<SEP> Ar
<tb><SEP> Cl-CO-Z <SEP> (IIIa) <SEP> or
<tb><SEP> W = C = NZ <SEP> (III ')
<tb><SEP> H <SEP> R
<tb><SEP> I <SEP> I
<tb><SEP> 0 <SEP>) - (CH) m-CH, -NTz <SEP> (IV ')
<tb><SEP> O <SEP> Ar '
<tb><SEP> mild <SEP> hydrolysis <SEP> (H +)
<tb><SEP> H <SEP> R <SEP> (IIIa) <SEP> or
<tb><SEP> I <SEP> I
<tb><SEP> H <SEP> O <SEP> - (CH2), - C-CH <SEP> (IIIw)
<tb><SEP> Ar '
<tb><SEP> CH3SO2Cl
<tb><SEP> H <SEP> R
<tb><SEP> (VIT ')
<tb><SEP> CH3SO2O <SEP> (CH2), - CH2-NTZ
<tb><SEP> Ar '<SEP> (VI)
<tb><SEP> (VII) <SEP> + <SEP> (VII)
<tb><SEP> fl <SEP> r
<tb><SEP> (la) <SEP> AQ <SEP> (l)
<tb>
The products of formula (Ia) thus obtained are isolated, in the form of free base or of salt, according to conventional techniques.

When the compound of formula (Ia) is obtained in the form of the free base, it can be purified or crystallized by salification by treatment with an acid in an organic solvent. Thus, by treating the free base, dissolved for example in an alcohol such as isopropanol, with a solution of the acid chosen in the same solvent, the corresponding salt is obtained which is isolated according to conventional techniques. Thus, for example, the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogenphosphate, methanesulfonate, methylsulfate, oxalate, maleate, fumarate, 2-naphthalenesulfonate are prepared.

At the end of the reaction, the compounds of formula (Ia) can be isolated in the form of one of their salts, for example the hydrochloride or the oxalate. The free base can be prepared by neutralization of said salt with an inorganic base or organic, such as sodium hydroxide or triethylamine or with an alkali carbonate or bicarbonate, such as sodium or potassium carbonate or bicarbonate.

The resolution of the racemic mixtures (Ia) allows the isolation of the enantiomers.

It is also possible to carry out the resolution of racemic mixtures of the products of formula (II), in particular of the products of formula (II ") and (E" ') or of their precursors, in order to prepare the enantiomers of the products of formula (Ia).

The starting compounds of formula (II) are prepared from nitriles of formula:

in which m, E and Ar 'are as defined above, by reduction of the nitrile.

For the preparation of compounds of formula aD where R is hydrogen, the starting nitriles of formula (VIII) are subjected to hydrogenation in an alkanol such as ethanol, in the presence of a catalyst such as Raney nickel , and the primary free amine can be isolated according to conventional methods.

When it is desired to prepare the compounds of formula (II) where R is the methyl group, the free amine, obtained by hydrogenation of the nitrile (VIII) as described above, is treated with a chloroformate, for example with chloroformate. formula Cl-CO-ORl, where R1 is C1-C6 alkyl, to obtain the carbamates of formula:

est isolée selon les méthodes habituelles.which are then reduced by known means, such as the action of a reducing agent such as for example a metal hydride, such as sodium aluminum hydride, 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 amine thus obtained of formula :

is isolated according to the usual methods.

It is also possible to treat the compound of formula:

in which m, E, Ar ', 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 tetrahydrofuran heated to reflux to prepare the compounds (where R is other than hydrogen.

Nitriles of formula (Vm) are prepared from nitriles of formula:
Ar'-CH2-CN W)
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 a bromine atom or a protected hydroxy group, give the desired compounds (VIII).

The synthesis of the nitriles of formula (where E is a tetrahydropyranyloxy group is carried out from a tetrahydropyranyloxy derivative (THP-O) obtained by reaction between an alkanol of formula Br- (CH2) m-OH with m as defined above and dihydropyran to lead to the compound:

which is then added, in the presence of alkali hydride, to the acetonitrile derivative (ksi) to prepare the intermediate of formula:

The synthesis of the nitriles of formula (VIII) where E represents a group:

d'un dérivé nitrile de formule::

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

of a nitrile derivative of formula:

in the presence of sodium amide in a solvent such as toluene at temperatures between 30 and 80ex.

The chlorinated derivative (XIII) is prepared by the action of a chlorinating reagent such as thionyl chloride on the hydroxylated derivative of formula:

itself prepared from the amine of formula (vit) in which, if X1 = OH, the hydroxyl group is optionally protected by an O-protecting group according to the usual methods,

amine with which one reacts, if m = 2, ethylene oxide and, if m = 3, a halogeno-3 propanol.

An alternative to the preparation of the compounds (I) according to the invention consists in reacting a tertiary amine of formula:

in which J and Q are as defined above for (I) with the methanesulfonate compound (VI) to directly obtain the quaternary ammonium (I) for which A 0 is represented by the methanesulfonate anion without passing through the intermediate (the ). This reaction is carried out according to the usual methods well known to those skilled in the art. The methanesulfonate anion thus obtained is then optionally exchanged with another anion chosen from A (3 as defined above, for example with the chloride anion using an ion exchange resin as indicated above.

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

Thus, the compounds according to the invention antagonize the binding of Substance P to its receptor with a Ki of between 0.7 and 800 nM in tests carried out on the rat cortex and with a Ki of between 0.2 and 30 nM in assays performed on the IM9 lymphoblastic cell line.

The compounds of the present invention are not very toxic; in particular, their acute toxicity is compatible with their use as a medicament. For such use, mammals are administered an effective amount of a compound of formula (1).

The compounds of the present invention are generally administered in a dosage unit. Said dosage units are preferably formulated in pharmaceutical compositions in which the active principle 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 ([).

The compounds of formula (I) above can be used at daily doses of 0.01 to 100 mg per kilogram of body weight of the mammal to be treated, preferably at daily doses of 0.1 to 50 mg / kg. In humans, the dose may preferably vary from 0.5 to 4000 mg per day, more particularly from 2.5 to 1000 mg depending on the age of the subject to be treated or the type of treatment: prophylactic or curative.

Under the pharmaceutical conditions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, topical or rectal administration, the active principles can be administered in unit administration forms, in admixture with conventional pharmaceutical carriers. , animals and humans. Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and buccal administration forms, subcutaneous administration forms , intramuscular, intravenous, intranasal or intraocular and rectal administration forms.

When preparing a solid composition in the form of tablets, the active principle is mixed with a pharmaceutical vehicle 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 else they can be treated so that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle.

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

A preparation in the form of a syrup or an elixir may contain the active principle together with a sweetener, preferably calorie-free, methylparaben and propylparaben as antiseptic, as well as a flavoring agent and an appropriate coloring.

The water-dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or color correctors. taste.

For rectal administration, suppositories are used which are prepared with binders melting at 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 are used which contain pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol.

For administration by inhalation, an aerosol containing, for example, sorbitan trioleate or oleic acid as well as trichloromethane, dichlorofluoromethane, dichlorotetrafluoromethane or any other biologically compatible propellant is used.

The active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.

The aforementioned compositions can also contain other active products such as, for example, bronchodilators, cough suppressants or antihistamines.

The following examples illustrate the invention without, however, limiting it.

The intermediate compounds of formula (Ia) are prepared according to the process described in the present description and according to patent application EP-A-428434.

The optically pure compounds (la) are also obtained according to the process described in application EP-A-428434.

The proton nuclear magnetic resonance spectra were performed at 200
MHz. Chemical shifts are expressed in ppm.

The melting points, F, were measured on the Koffler heating bench.

(a) or (e) mean the axial or equatorial position of the substituent Q.

EXAMPLE 1
4-Benzyl-N (a) -methyl-N- [1- [3- (3,4-dichlorophenyl) -4- (4-fluoro-1-naphthoylamino)] butyl] piperidinium iodide.

Q = axial CH3; m = 2;

2 g of N [4- (benzyl- 1-piperidinyl) -2- (3,4-dichlorophenyl) butyl] -4-fluoro- 1 - naphthyl-amide prepared as indicated above according to EP-A-428434 are placed dissolved in 20 ml of methyl iodide. The solution is stirred at room temperature for 24 hours then concentrated in vacuo. The residue is chromatographed on silica gel, eluent: dichloromethane / methanol 97/3 (v / v), then dichloromethane / methanol 95/5 (v / v).

The first product eluted corresponds to that in which the methyl in position 1 on the nitrogen of the piperidine is in the axial position. The corresponding fraction is concentrated under vacuum.

m = 1.3g F = 120-122 C.

NMR: 1H
7H between 1.3 and 2.4 (2CH2 and CH piperidine, -CH2ss); 14H between 2.45 and 3.9 (2CH2N piperidine, CH2 Ar, N + CH3, N + CH2, CH Ar ', NH-CH2); 14H between 7 and 8.2 (all aromatic Hs); 1H to 8.5 (NH); DMSO at 2.49.

EXAMPLE 2
4-Benzyl-N (e) -methyl-N- [1- [3- (3,4-dichlorophenyl) -4- (4-fluoro-1 -naphthoylamino)] butyl] piperidinium iodide.

; Q = equatorial CH3; m = 2;

By proceeding as described above in Example 1 and collecting the fraction eluted in the second place, the compound corresponding to that of which the methyl in position 1 on the nitrogen of the piperidine is in the equatorial position is obtained.

m = 0.3 g
F = 120-122 C.

NMR: 1H
7 H between 1.3 and 2.4 (2CH2 and CH piperidine, CH2; 14 H between 2.45 and 4 (2CH2N piperidine, CH2 Ar, N + CH3, N + CH2, CH Ar ', CH2 NH); 14 H between 7 and 8.3 (all aromatic Hs); 1 H at 8.6 (NH); DMSO at 2.49.

EXAMPLE 3
4-Benzyl-N (a) -methyl-N- [1- [3- (3,4-dichlorophenyl) -4- (3-ethoxyphenyl-1-acetamido)] butyl] piperidinium iodide.

; Q = axial CH3; m = 2;

By proceeding according to Example 1 and using N [4- (4-benzyl-1-piperidinyl 1) -2- (3,4-dichlorophenyl) butyl] -3-ethoxy-1-phenylacetamide as starting product, it is possible to prepare the above compound.

F = 90 C.

EXAMPLE 4
4-Benzyl-N (e) -methyl-N- [1- [3- (3,4-dichlorophenyl) -4- (3-ethoxyphenyl-1-acetamido)] butyl] piperidinium iodide.

; Q = equatorial CH3; m = 2;

Proceeding according to Example 2 and using N [4- (4-benzyl-1-piperidinyl- 1) -2- (3,4-dichlorophenyl) butyl] -3-ethoxy-1-phenylacetamide as starting material the above compound is prepared F = 105.C.

EXAMPLE 5
4-Benzyl-N (a) -methyl-N- [1- [3- (3,4-dichlorophenyl) -4- (3-ethoxy-1-benzoylamino)] butyl] piperidinium chloride.

; Q = axial CH3; m = 2;

1 g of the iodide obtained according to Example 3 is dissolved in 5 ml of 95r ethanol. 40 ml of Duolite A 375 8 resin are conditioned in the form of chloride and the solution prepared above is eluted on this column by then rinsing with 95 * methanol. The eluate is concentrated in vacuo and the residue is taken up in ether. It is filtered to obtain 0.69 g of the expected chloride.

M = 105 C.

EXAMPLE 6
4-Phenyl-N (a) -methyl-N [1- [3- (3, 4-dichlorophenyl) -4- (2-thienoylamino] butyl] piperidinium (-) iodide.

; QQ = axial CH3; m = 2

Step 1
a (2-Tetrahydropyranyloxethyl) -3,4-dichlorobenzeneacetonitrile.

16.5 g of 80% sodium hydride in 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 30 minutes, then the reaction mixture is stirred at room temperature for 2 hours. The mixture is cooled to -200C and a solution of 118 g of 1-bromo-2tetrahydropyranyloxyethane 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. ammonium in 3 l of water. Extracted with 1.5 l of ether, washed with saturated sodium chloride solution, decanted, dried over MgSO4 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 in vacuo to provide 118 g of an oil.

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

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 nitrogen purging, Raney nickel (10% of the starting quantity of nitrile) is added. It is then hydrogenated under a hydrogen atmosphere at room temperature and ordinary pressure.

16 i of hydrogen are absorbed in 4 hours. The catalyst is separated by filtration over Celite, the filtrate is concentrated in vacuo, the residue is taken up in saturated sodium chloride solution. After extraction with ether and drying over MgSO4, 112 g of an oil are obtained.

Step 3 ss-Hydroxethyl-3,4-dichlorobenzeneethanamine.

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

80 ml of a saturated solution of hydrochloric ether are added while maintaining the temperature between 20 and 250C. Stirred for 30 minutes at room temperature, then concentrated to dryness. The residue is dissolved in 250 ml of water, washed twice with ether, basified with NaOH solution, extracted with dichloromethane. After drying over MgSO4, the mixture is concentrated to dryness, taken up in 800 ml of isopropyl ether, an insoluble material is separated by filtration on Celite, concentrated in vacuo to approximately 300 ml, primed with amino alcohol crystals, stirred overnight.

Filtered, rinsed with isopropyl ether and then with pentane. 30.2 g of the expected product are obtained.

M = 90-91iC.

Step 4
, B-Hydroxyethyl-3,4-dichlorobenzeneethanamine (+).

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

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

Recrystallized from 1.75 l of methanol to obtain 26.6 g of tartrate.

20
= -4.2 (c = 1, H2O).

The tartrate is taken up in 120 ml of water. Basified with a NaOH solution, extracted twice with dichloromethane, dried over MgSO4, concentrated to dryness. The residue is taken up in a little isopropyl ether, pentane is added and filtered to obtain 15.4 g of product.

M = 79-80C.

20
= +9.4 (c = 1, CH3OH).

Step 5
Ethyl N- [4-hydroxy 2- (3,4-dichlorophenyl) butyl] carbamate.

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

Cooled to 00C and added dropwise at this temperature a solution of 6.3 ml of ethyl chloroformate in 30 ml of dichloromethane. After 15 minutes, it is washed with water and then with dilute HCl, then with a saturated aqueous solution of
NaHCO3. After drying over MgSO4, it is concentrated to dryness to obtain 20 g of product in the form of an oil.

Step 6
N-methyl -, - hydroxyethyl-3,4-dichlorobenzeneethanamine hydrochloride (+).

To 5.1 g of lithium / aluminum hydride suspended in 60 ml of anhydrous TIF, a solution of 20 g of product obtained according to step 5 in 150 ml of anhydrous THF is added. The mixture is heated at reflux for 1 hour. Hydrolysis is carried out with 20 ml of water, the mineral is filtered off and concentrated to dryness. The oil obtained is dissolved in 100 ml of acetone. Ether saturated with hydrochloric acid is added until pH = 1, then ether until cloudy. Stirred for 1 hour, the crystals are filtered, rinsed with a little acetone and then ether to obtain 11 g of the expected product.

Mp = 129C.

[&alpha;] D20 = +8.4 (c = 1, CH30H).

D
Step 7
N- [4-Hydroxy-2-53,4-dichlorophenyl) butyl] -N-methyl -2-thiophene carboxamide (-).

8.4 ml of triethylamine are added to 8.1 g of the product obtained according to the preceding step 6, suspended in 120 ml of dichloromethane. Cooled to 00C and a solution of 2.97 g of 2thiophenecarboxylic acid chloride in 35 ml of dichloromethane is added dropwise. After 15 minutes, it is washed with water, then with dilute HCl, then an aqueous solution of NaHCO3. Dried over MgSO4, concentrated to dryness. A solid is obtained which is taken up in ether and filtered.

m = 9, Og
Mp 107-108sC.

20
[a] D = -47.2 (c = 1, CH3OH).

Step 8
N- [4-Methanesulfonyloxy-2- (3, 4-dichlorophenyl) butyl] N-methyl 2thiophenecarboxamide (-).

To 10.71 g of product obtained according to the preceding step 7, dissolved in 120 ml of dichloromethane, 4.8 ml of triethylamine is added. Cooled to 0 ° C. and 2.7 ml of methanesulfonyl chloride are added dropwise. After 15 minutes, the mixture is washed twice with water and then with a saturated aqueous NaCl solution. It is dried over MgSO4 and concentrated to dryness to obtain a foam.

Step 9
N [4- (Hydroxy-4-phenyl-1-piperidinyl) -2- (3,4-dichlorophenyl) butyl] -N-methyl-2-thiophenecarboxamide (-).

12.12 g of the product obtained according to the preceding step 8 and 11.8 g of 4-hydroxy-4phenylpiperidine are dissolved in 30 ml of dimethylformamide and heated at 700C for one and a half hours. The solution is poured into 30 ml of ice water, a precipitate is filtered off and dried. The precipitate obtained is purified by chromatography on silica gel, eluent: dichloromethane-methanol, 90-10 (v / v). The pure product fractions are concentrated under vacuum and then the residue is crystallized from ether.

Mp = 120-121iC.

The hydrochloride is prepared in acetone by adding ether saturated with hydrochloric acid until pH = 1. The precipitate is filtered off and dried.

20
[a] D = -51.0 (c = 1, CH3OH).

Step 10 - Compound of Example 6.

By proceeding as previously according to Example 1, by alkylation with methyl iodide, piperidinium iodide is prepared from the base described above in step 9.

The compound whose methyl is in the axial position on the nitrogen of the piperidine is eluted first.

Mp = 150iC.

[&alpha;] D20 = -44.9 (c = 1, CH30H).

EXAMPLE 7
4-Phenyl-N (e) -methyl-N [1 - [3- (3,4-dichlorophenyl) -4- (2-thienoylamino] butyl] piperidinium (-) iodide.

; Q = equatorial CH3; m = 2;

By proceeding according to Example 6 and collecting the compound eluted second in step 10, the quaternary salt is obtained, the methyl of which in position 1 on the nitrogen of the piperidine is in the equatorial position.

Mp = 130C.

20
[a] D = -5.1 (c = 1, CH3OH).

By proceeding according to Examples 1 to 7 above, compounds 8 to 13 described in Table 1 below are prepared.

TABLE 1

<tb> Example <SEP> J <SEP> Q * <SEP> R <SEP> Z <SEP>F;'C
<tb> number <SEP> \
<tb><SEP> 8 <SEP> C6H5-CH2-CH <SEP> CH3 <SEP> (a) <SEP> CH3 <SEP>411'9<SEP> 127
<tb><SEP> FM
<tb><SEP> 2
<tb><SEP> 9 <SEP> c6H5H2 <SEP> CH3 <SEP> (a) <SEP> CH3 <SEP> i29
<tb><SEP> O-CH
<tb><SEP> M
<tb><SEP> CH3
<tb><SEP> CH2
<tb><SEP> / <SEP> ,, CCHH32 ~ <SEP> 136
<tb><SEP> 10 <SEP> C6H5-CH2-CH <SEP> CH3 <SEP> (e) <SEP> CH3 <SEP> O-CH <SEP> 155
<tb><SEP> OH
<tb><SEP> M
<tb><SEP> CH3
<tb><SEP> y <SEP> CH2 <SEP> O <SEP> CH3
<tb><SEP> C6H5-CH2-CH <SEP> CH3 <SEP> (a) <SEP> CH3 <SEP> ÀÇ <SEP> 100
<tb><SEP> OCH3
<tb>

<tb><SEP> y
<tb> Example <SEP> J <SEP> Q <SEP>'<SEP> I, <SEP> Z <SEP>F;; 0C
<tb> number <SEP> \
<tb><SEP> y <SEP> CH2 <SEP> OCH3
<tb><SEP> 12 <SEP> C6H5H2fflH <SEP> CH3 <SEP> CH <SEP> CH3 <SEP> (e) <SEP> CH3 <SEP> ÀÇ <SEP> 115
<tb><SEP> OCH3
<tb><SEP> OH
<tb><SEP> C6H5 <SEP> 157
<tb><SEP> 13 <SEP> y <SEP> CH3 (a) <SEP> cH3 <SEP> 157
<tb> * Configuration of the Q substituent: a = axial; e = equatorial.

Claims (8)

1 Quaternary ammonium salts of formula:

in which Alk represents an alkyl

carboxy; C1-C4 carbalkoxy; a cyano; a group: . x is zero or one; . X1 represents hydroxyl, C1-C4 alkoxy; C1-C4 acyloxy; a in which: .Ar is as defined above;

carbon-carbon or else X and X 'together form an oxo group; X "is hydrogen or together with X 'forms a carbon-carbon bond; * - either a group a pyridyl group or a thienyl group; X represents hydrogen; . X 'represents Hydrogen or is joined to X "below to form a bond substituents being the same or different, a C3-C7 cycloalkyl group; C1-C3 alkoxy, C1-C3 alkyl, trifluoromethyl, said a substituent chosen from: hydrogen, a halogen atom, a hydroxyl, Ar represents a phenyl which is unsubstituted or substituted one or more times by in which

in which: - J represents * - either a group

let M when T represents the group

W being an oxygen or sulfur atom, and - Z represents either hydrogen, or M or OM when T represents the group optionally substituted tricyclic. C1-C3; a styryl; an aromatic or heteroaromatic group mono-, di- or benzothienyl; a naphthyl; - R represents hydrogen, or a C1-C6 alkyl; - T represents a group chosen from: in C1-C4, said substituents being identical or different; a thienyl; a chlorine or fluorine atom, trifluoromethyl, C1-C4 alkoxy, alkyl substituent chosen from: hydrogen, a halogen atom, preferably a methanesulfonate, paratoluenesulfonate; - mest2Ou3; - Ar 'represents a phenyl which is unsubstituted or substituted one or more times by a neighboring carbon in piperidine a double bond; - Q represents a C1-C6 allyl group or a benzyl group; - A - represents an anion chosen from chloride, bromide, iodide, acetate, or X1 forms with the carbon atom to which it is bonded and with the atom of C1-C4 alkyl; in C1-C6; a group -S-X2 in which X2 represents hydrogen or a group hydroxyl, C1-C4 alkoxy; a pyridylthioalkyl in which the alkyl is naphthyl ring with a halogen, a trifluoromethyl, a C1-C4 alkyl, a naphthylalkyl in which the alkyl is C1-C3, optionally substituted on the C1-C4; a pyridylalkyl in which the alkyl is C1-C3; a naphthyl or a halogen, trifluoromethyl, C1-C4 alkyl, hydroxyl, alkoxy in C3, optionally substituted one or more times on the aromatic ring by a M represents C1-C6 alkyl; a phenylalkyl in which Valkyle is C1 2 A compound according to claim 1 of formula (I) in which Z represents naphthyl, benzyl, phenyl optionally substituted by a selected substituent from chlorine or fluorine, alkyl or alkoxy in C1-C4. 3 A compound according to claim 2 of formula (I) in which R represents hydrogen or methyl, Ar 'represents a phenyl disubstituted with chlorine, m, Q, J, A - having the same meanings as in claim 1. 4 Process for the preparation of the compounds of formula (I) characterized in that one reacts with the amino derivative of formula:

quaternaries (I) which are separated by recrystallization or chromatography. a mixture of axial and equatorial conformers of ammonium salts after treatment according to the usual methods and after possible deprotection room temperature and reflux for one to several hours to obtain chloroform, acetone or acetonitrile at a temperature between reaction mixture in a solvent chosen from dichioromethane, in which A and Q are as defined above for (I) and the A-Q by an N-protecting group, an alkylating agent of formula: (I) it being understood that if Z contains an amino substituent, the latter is protected in which J, m, Ar ', R, T and Z have the same meaning as in the formula 5 Process for the preparation of compounds of formula (I) in which Q, m, A Ar ', R, T and Z are as defined in claim 1 and in which J represents a group:

characterized in that the mesylate of formula is reacted:

wherein m, Ar ', R, T and Z are as defined in claim 1, with a secondary amine of the formula:

compounds (I). reaction with an alkyl halide according to claim 4 to obtain the transforms the product (la) thus obtained into its quaternary ammonium salt by in which Ar ', x and X1 are as defined in claim 1, then 6 Process for preparing the compounds of formula (I) characterized in that lion reacts on the derivative of formula:

in which m, Ar ', R, T and Z are as defined in claim 1 a tertiary amine of the formula:

in which J and Q are as defined in claim 1 to obtain compound (I) in which A - represents methanesulfonyl, this anion possibly then be optionally exchanged with a chloride anion by elution on a ion exchange resin. 7 Pharmaceutical composition, characterized in that it contains at least one compound according to one of claims 1 to 3 associated with at least one excipient. 8 Pharmaceutical composition according to claim 7 in unit form dosage.