IE83893B1 - Polycyclic amine compounds and their enantiomers, their method of preparation and pharmaceutical compositions in which they are present - Google Patents

Description

Pgycvclic amine compounds and their enantiomers, their method of preparation and pharmaceutical compositions in which thev are present The present invention relates to novel aromatic derivatives substituted by an amino group and by amine or amide groups, and their enantiomers.

The present invention further relates to the method of obtaining the compounds, which can be enantioselective, and to the use of the compounds according to the invention in compositions for use in therapeutics and more particularly in pathological phenomena involving the neurokinin system, such as: Life Sciences, 1987, 4Q, 109- 117), allergy and inflammation (J.E. Morlay et al., Life 1987, Al, 527-544), insufficiency (J. Losay et al., 1977, Substance P, Von U.S. 287-293, gastrointestinal disorders (D. Regoli et al., 1985, Q, 481-484) respiratory disorders (J. Mizrahi et al., Pharmacology, 1982, 25, 39-50).

Ligands endogenous pain (D. Regoli et al., Sciences, circulatory Euler, York), Trends and Pernow ed., Raven Press, New Pharmacol. Sci., and 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) (S.P. Watson, Life Sciences, 1983, , 797-808).

Neurokinin receptors have been recognized on numerous preparations and are currently classed in three types: NK1, NK2 and NK3. Whereas the majority of preparations studied hitherto have several types of receptors, such as guinea-pig ileum (NK1, NK2 and NK3), some of them are thought to possess only one type, such as dog carotid artery (NKl), rabbit pulmonary artery devoid of endothelium (NK2) and rat portal vein (NK3) (D. Regoli et al., Sci., 1988, 2, 290-295, and Pharmacology, 1989, 38, 1-15).

The ‘recent synthesis of selective agonists has Trends Pharmacol. made it possible to characterize the various receptors more precisely. Thus [Sar9,Met-(O2 )11]sp, [N1e10] — NKA4_10 and [MePhe7]-NKB are thought to have a selectivity for the NK1, NK2 and NK3 receptors respectively (cf. D. Regoli, 1988 and 1989, op. cit.).

It has now been found that certain aromatic amine compounds possess valuable pharmacological properties as neurokinin receptor antagonists and are especially useful for the treatment of any substance P—dependent and neurokinin-dependent pathological condition.

Thus, according to one of its aspects, the present invention relates to aromatic amine derivatives of the formula Y (b)N‘(CH2);— \‘/ T\ < CH2 >/”’T‘ ‘ CH2 ’Tz P I Ar‘ ( ) in which: — Y is — either a group Cy—N or Cy— CH2 —N, in which: Cy is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from: a halogen atom, a hydroxyl, a C1-C4 alkoxy, a C1-C4 alkyl, a trifluoromethyl, said substituents being identical or different; a C3-C7 cycloalkyl group; a pyrimidyl group or‘ a pyridyl group; — or a group Ar—‘(CH2fij"C in which Ar is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from: 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; x is zero or one; X is a hydrogen, a hydroxyl, a C1-C4 alkoxy; a C1- C4 acyloxy; a carboxyl; a C1-C4 carbalkoxy; a cyano; a -N(X1)2 group, in which the groups X1 independently are hydrogen, a C1-C4 alkyl, a C1-C4 hydroxyalkyl, a C1-C4 acyl, or else —(X1)2 forms, with the nitrogen atom to which it is bonded, a heterocycle selected from pyrrolidine, piperidine or morpholine; a —S—X2 group, in which X2 is hydrogen or a C1-C4 alkyl group; or else X forms a double bond with the carbon atom to which it is bonded and with the adjacent carbon atom in the heterocycle; m is 2 or 3; Ar‘ is a phenyl which is unsubstituted or monosubstituted or polysubstituted by :3 substituent selected from: a halogen atom, preferably a chlorine or fluorine atom, a trifluoromethyl, a C1-C4 alkoxy, a C1-C4 alkyl, said substituents being identical or different; a thienyl; a benzothienyl; a naphthyl or an indolyl; n is O, 1, 2 or 3; p is 1 or 2, and when p is equal to 2, n is then equal to 1 and Q is two hydrogen atoms; Q is oxygen or two hydrogen atoms; T is a group selected from q is 0, 1, 2 or 3; Z is a mono—, di— or tri-cyclic aromatic or heteroaromatic group which can be unsubstituted or substituted as defined hereinafter ; or else when T is -C=O—, —(CH2)q—Z can also be a benzyl group substituted on the -CH- by a hydroxyl, a C1-C4 alkoxy, a C1—C4 alkyl and unsubstituted or substituted on the aromatic ring by a halogen, more particularly a chlorine or fluorine atom, a tri- fluoromethyl, a C1-C4 alkyl, a hydroxyl, a C1-C4 alkoxy; or one of its possible salts with mineral or organic acids, or, when Y = Ar“(CH2)x c) one of their quaternary ammonium salts or N-oxide derivatives formed with nitrogen (b) of the piperidine.

The limitation relative to p = 2 exists owing to (CH2 )qZ chemical chemical synthesis stresses. For the values CO, accessibility of the products used. when T = the limitation arises from the In the present description the alkyl groups or the alkoxy groups are linear or branched.

The the according to the present invention include those with salts of compounds of formula (I) which permit a suitable the oxalic acid. or an mineral or organic acids separation or compounds of (I), optically crystallization of formula such as picric acid, active acid, for example a mandelic or form the hydrogensulfate, camphosulfonic acid, as well as those which pharmaceutically acceptable salts such as hydrochloride, hydrobromide, sulfate, dihydrogenphosphate, methanesulfonate, methylsulfate, maleate, fumarate, naphthalene—2—sulfonate, glycolate, gluconate, citrate and isethionate. when X I Y = Ar-(CH2 )j—C the compounds of formula (I) can be in the form of a quaternary ammonium salt formed with nitrogen (b) of the piperidine or an N—oxide derivative formed with nitrogen (b), in which case the group x Ar—( CH2 ) N* is represented by the group X /0 Ar'—(CH2);—l¥<:::>N‘*‘ @ or the group in which: - Q‘ is a C1-C5 alkyl group or a benzyl group, and AC) is an anion selected from chloride, bromide, iodide, acetate, methanesulfonate or para- toluenesulfonate.

Roughly, Z in formula (I) is a mono—, di- or tri- cyclic aromatic or heteroaromatic group which can carry one or more substituents and in which a carbon atom of the aromatic carbocycle or of the aromatic heterocycle is directly bonded to the group T.

More particularly, the radical Z can be a phenyl group which can be unsubstituted or may contain one or more substituents. when Z is a phenyl group, this can preferably be monosubstituted or disubstituted, especially in the 2,4 positions, but also for example in the 2,3, 4,5, 3,4 or ,5 it be especially in the 2,4,6 positions, but also for example in the 2,3,4, 2,3,5, substituted, for example in the 2,3,4,5 position; positions; can also trisubstituted, ,4,5 or 3,4,5 positions; tetra- or pentasubstituted. The substituents of the phenyl group can be: F; Cl; Br; I; CN; OH; NH2; NH-CONH2; N02; CONH2; CF3; C1-C10 alkyl, preferably C1-C4 alkyl, 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, heptyl or n-heptyl, octyl or n—octyl, nonyl or n—nonyl as well as decyl or n-decyl; alkenyl containing 2 to 10 carbon atoms, preferably 2-4 carbon atoms, for example vinyl, allyl, prop—l—enyl, isopropenyl, butenyl or buten, , or yl, but—2—en-l—yl, but- 2-enyl, pentenyl, hexenyl or decenyl; alkynyl containing 2 to 10 carbon atoms, preferably 2-4 carbon propargyl , butynyl or but—2-ynyl, pentynyl, decynyl; cycloalkyl atoms, for example ethynyl, prop-l-yn—l—yl, containing 3 to 8 carbon atoms, preferably 5 or 6 carbon atoms, cyclopentyl well - or 3—methylcyclopentyl, or cyclohexyl being preferred, as as, for example, cyclopropyl, -, 2-, 3- cyclooctyl; cyclobutyl, 1-, or 4-methylcyclohexyl, cycloheptyl to 11 or endo—2-norbornyl bicycloalkyl containing 4 carbon atoms, preferably 7 carbon atoms, exo- being preferred, as well as, for example, 2-isobornyl or 5-camphyl; hydroxyalkyl containing 1 to 5 carbon atoms, preferably 1-2 carbon atoms, hydroxymethyl and 1- or 2-hydroxyethyl being preferred, as well as, for 2—hydroxyprop—l—yl, 3- l-hydroxybut—l- to 10 methoxy, example, l-hydroxyprop-l—yl, hydrcxyprop-l—yl, 1-hydroxypropyl, yl, 1-hydroxypent—l-yl; alkoxy containing 1 carbon atoms, preferably 1-4 carbon atoms, ethoxy or isopropoxy being preferred, as well as, for example, n-propoxy, n—butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy; alkoxyalkyl containing 2 to 10 carbon atoms, preferably from 2 to 6 carbon atoms, for example alkoxymethyl or alkoxyethyl, such as methoxymethyl or 1- or 2—methoxyethyl, 1- or 2—n- butoxyethyl or 1- or 2—n—octyloxyethyl; alkoxy- alkoxyalkyl containing up to 10 carbon atoms, preferably from 4 to 7 carbon atoms, for example alkoxyalkoxymethyl, for example 2—methoxyethoxymethyl, 2-ethoxyethoxymethyl or 2-isopropoxyethoxy-methyl, alkoxyalkoxyethyl for example 2-(2—methoxyethoxy)ethyl or 2—(2—ethoxyethoxy)ethyl; alkoxyalkoxy containing from 2 to 10 carbon atoms, preferably from 3 to 6 carbon atoms, for example 2-methoxyethoxy, 2- ethoxyethoxy or 2—n—butoxyethoxy; alkenyloxy containing 2 to 10 carbon atoms, preferably 2 to 4 carbon atoms, allyloxy being preferred, as well as, for example, vinyloxy, propenyloxy, ’ or butenyloxy, isopropenyloxy, butenyloxy such as but-l-en, or yloxy, buten-1—yloxy pentenyloxy, hexenyloxy or decenyloxy; alkenyloxyalkyl containing from 3 to 10 carbon atoms, preferably 3-6 carbon atoms, for example allyloxymethyl; alkynyloxy containing from 2 to 10 carbon atoms, preferably’ 2 to 4 carbon atoms, propargyloxy being preferred, as well as, for example, ethynyloxy, prop—1-yn—1-yloxy, butynyloxy or butyn- l—yloxy, pentynyloxy or decynyloxy; alkynyloxyalkyl containing from 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms, for example ethynyloxymethyl, propargyloxymethyl or 2-(butyn—l-yloxy)ethyl; cyclo- alkoxy containing 3 to 8 carbon atoms, preferably 5 or carbon atoms, cyclopentoxy or cyclohexyloxy being preferred, as well as, for example, cyclopropoxy, cyclobutoxy, 1-, 2- or 3—methylcyclopentoxy, 1-, 2-, - or 4—methylcyclohexyloxy, cycloheptyloxy or cyclooctyloxy; alkylthio containing from 1 to 10 carbon atoms, preferably 1 ‘ma 4 carbon atoms, methylthio or ethylthio being preferred, as well as, for example, n- propylthio, isopropylthio, n-butylthio, isobutylthio, sec—butylthio, tert—butylthio, pentylthio, hexylthio, octylthio, nonylthio or decylthio; alkylthioalkyl containing from 2 to 10 carbon atoms, preferably 2 to 6 methylthiomethyl, 2- 2—n-butylthioethyl; namely alkanoylamino containing from 1 to 7 carbon carbon atoms, for methylthioethyl or example acylamino, atoms, preferably 1 to 4 carbon atoms, formylamino and acetylamino being preferred, as well as propionylamino, butyrylamino, isobutyrylamino, valerylamino, caproyl— amino or heptanoylamino, as well as aroylamino or benzylamino; acylaminoalkyl, preferably alkanoylamino- alkyl containing from 2 to 8 carbon atoms, preferably 3 to 6 acetylaminoethyl, carbon atoms, such as formylaminoethyl, propionylaminoethyl, n-butyrylamino- ethyl, formylaminopropyl, acetylaminopropyl, propionyl- aminopropyl, formylaminobutyl, acetylaminobutyl, as well as propionylaminobutyl, butyrylaminobutyl; acyloxy containing from 1 to 6 carbon atoms, preferably 2 to 4 carbon atoms, acetoxy, propionyloxy or butyryloxy being well caproyloxy; preferred, as as, for example, formyloxy, valeryloxy or alkoxycarbonyl containing from 2 to 5 carbon atoms, preferably 2 or 3 carbon atoms, methoxycarbonyl and ethoxycarbonyl being preferred, as well as, for example, n-propoxycarbonyl, isopropoxycarbonyl, n~butoxycarbonyl, isobutoxy- carbonyl, sec—butoxycarbonyl or tert-butoxycarbonyl; cycloalkoxycarbonyl containing from 4 to 8 carbon atoms, preferably 6 or 7 carbon atoms, cyclopentoxycarbonyl and cyclohexyloxycarbonyl being preferred, as well as cyclopropoxycarbonyl, alkyl- aminocarbonylamino containing from 2 to 4 carbon atoms, cyclobutoxycarbonyl or cycloheptyloxycarbonyl; such as methylaminocarbonylamino, ethylaminocarbonyl- amino, propylaminocarbonylamino; dialkylaminocarbonyl— amino containing from 3 to 7 carbon atoms, preferably 3 to 5 carbon atoms, dimethylaminocarbonylamino being preferred, as well as di-n-propylaminocarbonylamino, diisopropylaminocarbonylamino; (pyrrolidin—l-yl)- carbonylamino; cycloalkylaminocarbonylamino containing fronl 4 to 8 carbon atoms, preferably 6 or 7 carbon atoms, cyclopentylaminocarbonylamino, cyclohexylamino— carbonylamino being preferred, as well as cyclopropylaminocarbonylamino, cyclobutylaminocarbonyl— amino, cycloheptylaminocarbonylamino; alkylamino— carbonylaminoalkyl containing from 3 to 9 carbon atoms, preferably 4 to 7 carbon atoms, methylamino- carbonylaminoethyl, ethylaminocarbonylaminoethyl, ethylminocarbonylaminopropyl, butyl methylaminocarbonylaminomethyl, ethylaminocarbonylamino— being preferred, as well as, for example, n—propylaminocarbonyl— dialkyl— aminocarbonylaminoalkyl containing from 4 to 11 carbon aminobutyl, n-butylaminocarbonylaminobutyl; atoms, for example dimethylaminocarbonylaminomethyl, diethylaminocarbonylaminoethyl, diethylaminocarbonyl- aminopropyl, diethylaminocarbonylaminobutyl, (pyrrolidin—l—yl)carbonylaminoethyl; (piperidin—l— yl)carbonylaminoethyl, cycloalkylaminocarbonylamino— alkyl containing from 5 to 12 carbon atoms, preferably 8 to 11 carbon atoms, ethyl, pentylaminocarbonylaminobutyl, cyclopentylaminocarbonylamino— cyclopentylaminocarbonylaminopropyl, cyclo- cyclohexylamino- carbonylaminoethyl, cyclohexylaminocarbonylaminopropyl and cyclohexylaminocarbonylaminobutyl being preferred, as well as, for example, cyclopropylaminocarbonylamino— methyl, cycloheptylaminocarbonylaminoethyl; alkoxy— carbonylaminoalkyl containing from 3 to 12 carbon atoms, preferably 4 to 9 carbon atoms, methoxy— carbonylaminoethyl, ethoxycarbonylaminoethyl, n- propoxycarbonylaminoethyl, isopropoxycarbonylamino— ethyl, aminoethyl, n—butoxycarbonylaminoethyl, isobutoxycarbonyl- sec-butoxycarbonylaminoethyl, tert-butoxy- carbonylaminoethyl, ethoxycarbonylaminopropyl, n- butoxycarbonylaminopropyl, ethoxycarbonylaminobutyl, n- butoxycarbonylaminobutyl being preferred, as well as, for example, n-propoxycarbonylaminopropyl, n—propoxy— carbonylaminobutyl, isopropoxycarbonylaminobutyl; cycloalkoxycarbonylaminoalkyl containing frmn 5 to 12 carbon atoms, carbon preferably 8 to 11 atoms, cyclopentoxycarbonylaminoethyl, cyclopentoxycarbonyl- aminopropyl, cyclopentoxycarbonylaminobutyl, cyclo- hexyloxycarbonylaminoethyl, cyclohexyloxycarbonylamino- propyl, preferred, cyclohexyloxycarbonylaminobutyl being as well as, for example, cyclopropoxycarbo— nylaminomethyl, cycloheptyloxycarbonylaminoethyl; carbamoylalkyl containing from 2 to 5 carbon atoms, preferably 2 carbon atoms, carbamoylmethyl being preferred, as well as carbamoylethyl, carbamoylpropyl, carbamoylbutyl; alkylaminocarbonylalkyl containing from 3 to 9 carbon atoms, preferably 3 to 6 carbon atoms, methylaminocarbonylethyl, ethylaminocarbonylmethyl, n- propylaminocarbonylmethyl, isopropylaminocarbonyl— methyl, n—butylaminocarbonylmethyl, isobutylamino- carbonylmethyl, sec—butylaminocarbonylmethyl and tert- butylaminocarbonylmethyl being preferred, as well as, for example, ethylaminocarbonylethyl, ethylamino- carbonylpropyl, ethylaminocarbonylbutyl, n—propyl- aminocarbonylbutyl, n—butylaminocarbonylbutyl; dialkyl— 4 to 11 carbon aminocarbonylalkyl containing from carbon atoms, preferably 4 to 8 atoms, dimethylaminocarbonylmethyl, diethylaminocarbonyl— methyl, di-n-propylaminocarbonylmethyl; as well as, for diethyl- diethylaminocarbonylbutyl; example, diethylaminocarbonylethyl, aminocarbonylpropyl, (pyrrolidin—l—yl)carbonylmethyl; (piperidin—l—yl)- carbonylmethyl; (piperidin—l—yl)carbonylethyl; cyclo- alkylaminocarbonylalkyl containing from 5 to 12 carbon atoms, preferably 7 or 8 carbon atoms, cyclopentylaminocarbonylmethyl and cyclohexylamino— carbonylmethyl being preferred, as well as, for example, cyclopropylaminocarbonylmethyl, cyclobutyl- aminocarbonylmethyl, cycloheptylaminocarbonylmethyl, cyclohexylaminocarbonylethyl, cyclohexylaminocarbonyl— propyl, cyclohexylaminocarbonylbutyl; alkylamino- carbonylalkoxy containing from £3 to 10 carbon atoms, preferably 3 to 5 carbon atoms, methylaminocarbonyl— methoxy being preferred, as well as, for example, methylaminocarbonylethoxy, methylaminocarbonylpropoxy; 4 to 10 carbon atoms, preferably 4 to 7 carbon atoms, such as dialkylaminocarbonylalkoxy containing from dimethylaminocarbonylmethoxy, diethylaminocarbonyl- ethoxy, (piperidin—l-yl)carbonylmethoxy; cycloalkyl- aminocarbonylalkoxy containing from 5 to 11 carbon atoms, preferably 7 or 8 carbon atoms, such as cyclopentylaminocarbonylmethoxy, cyclohexylamino- carbonylmethoxy.

The group Z is advantageously a phenyl group; a naphthyl group.

The phenyl group Z .is preferably monosubstituted or disubstituted by a halogen or an alkoxy, the isopropoxy group being preferred.

The radical Z can also be a bicyclic aromatic group such as naphth—l- or -2—y1; inden, , , — 4-, , be hydrogenated, it being possible for said groups to or -7—yl; in which one or more bonds can be unsubstituted or to contain one or more substituents a halogen, and alkyl, alkylcarbonylamino, selected from: and more particularly a fluorine atom, phenyl, cyano, hydroxyalkyl, hydroxyl, oxo, alkoxycarbonyl and thioalkyl groups, in which the alkyls are C1-C4.

The radical Z can also be a pyridyl, thiadiazolyl, indazolyl, benzimidazolyl, indolyl, imidazolyl, quinolyl, benzotriazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzisothiazolyl, isoquinolyl, benzoxazolyl, benzoxazinyl, benzodioxynyl, isoxazolyl, benzopyranyl, thiazolyl, thienyl, furyl, pyranyl, chromenyl, isobenzofuranyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, phthalazinyl, quinazolinyl, acridinyl, isothiazolyl, isochromanyl or chromanyl group, in which one or more double bonds can be hydrogenated, it being possible for said groups to be unsubstituted or to contain one or alkyl, alkylcarbonylamino, more substituents selected from: phenyl, cyano, hydroxyalkyl, hydroxyl, alkoxy- carbonyl and thioalkyl groups, in which the alkyls are C1-C4.

According to another aspect, the present invention relates to a method of preparing the compounds of formula (I) and their salts, characterised in that: — a) a compound of the formula (CH L‘ Q E‘ ( CH2 2 Y N“H (CH, ){ Ar: (II) is treated in which m, Ar‘, n, p and Q are as defined above and E is a hydroxyl or, if appropriate, an O- protected group such as, for example, tetrahyropyran—2— yloxy or a group Y N”- \__/ in which Y is as defined above, it being understood that: when Y is the group ‘ Ar“(CH2):‘C in which X is a hydroxyl, this hydroxyl can be protected, - either with a functional derivative of an acid of the formula HO—‘fi“‘(CH2):—Z (III) 0 in which q and Z are as defined above, when a compound of formula (I) in which T is —CO— is to be prepared, . or with a halogenated derivative of the formula Ha1- ( CH2 )q,1—z (IV) in which q and Z are as defined above and where Hal is a halogen and preferably a bromine or chlorine atom, when a compound of formula (I) in which T is -CH2— is to be prepared, to give the compound of the formula (CH )n Q E-(CH2):-f _ _ T (CH2)?/N T (CH2)q 2 Ar‘ — b) then, when E is an O—protected group, the O- protecting group is removed by reaction with an acid, — C) the resulting alcohol of the formula (CH2)p/N*T—(CH2)q— z is treated with methanesulfonyl chloride, — d) the resulting mesylate of the formula (CH )n Q CH SO“O‘(CH )—— / 2\\T;; (V11) 3 2 2 “‘ \ N—T— CH —z (CH2)p/ ( 2):; said compounds being novel compounds forming part of the invention, is reacted with a secondary amine of the formula Y NH (VIII) \__/ in which Y is as defined above, and — e) after deprotection of the hydroxyl represented by X, if appropriate, the resulting product, if desired, is converted to one of its salts.

The compounds of formula (II), provided Q is oxygen: — when E = OH or (C1—C6)alkylcarbonyloxy, m = 2 or 3, Ar’ is a phenyl which is substituted by a (C1- C4)alkoxy, n = 3 and p = l; - when E = (C1—C4)alkylcarbonyloxy, m = 2, n = 1 and Ar’ is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a (C1- C4)alkyl, a (Cl—C4)alkoxy or a halogen; provided that when E = OH or a (C1-C4)alkoxy, m = 2, p = 1, Ar’ is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a (C1—C4)alky1, a (Cl—C4)a1koxy or a halogen, n is different from 1, provided that when E = OH, Q = 2H, m = 2, n = 1, p = 2, Ar‘ is different from an unsubstituted phenyl, are novel and form part of the invention.

The compounds excluded from such limitation of the (II) Bochow et al., compounds are described in the publication H.

Chem. 1975, 108, 3475 as well as in applications DE—A—2 345 192 and GB-A-2 056 439.

The compounds of formula (V), provided that when E = OH, Q = 2H, m = 2, n = 1, p = 2, T = —CH2—, q = O and Z = from an unsubstituted phenyl, and OH, Q = 2H, m = 2, n = 1, p = 0 and Z = which is Ber., phenyl, Ar’ is different provided that when E = 1, T = from a —CH2—, q = phenyl, Ar‘ is different phenyl unsubstituted or mono- substituted or polysubstituted by a (C1-C4)a1kyl, a (C1-C4)alkoxy or a halogen, and provided that when E = OH or (C1-C5)alyk1carbonyloxy, Q = 2H, m = 2 or 3, 3, p = 1, T = -CH2—, q = O, , 2 or 3 and Z is an aryl group, Ar’ is different from a phenyl which is substituted by a (C1- C4)alkoxy, are novel and form part of the invention.

The compounds of formula (VI), provided that when Q = 2H, m = 2, n = 1, p = 2, T = — CH2—, q = O and Z = phenyl, Ar‘ is different from an unsubstituted phenyl, and provided that when Q = 2H, m = 2, n = 1, p = 1, T = — O and Z = Ar‘ phenyl which is unsubstituted or monosubstituted or CH2—, q = phenyl, is different from a polysubstituted by a (Cl—C4)a1kyl, a (C1—C4)alkoxy or a halogen, and provided that when Q = 2H, m = T = -CH2-, q = or 3, 3, p = l, O, 1, 2 or 3 and Z is an aryl group, Ar‘ is different from a phenyl which is substituted by a (C1—C4)alkoxy, are novel and form part of the invention.

The compounds excluded from such limitations of the compounds (V) and (VI) are described in the publication Chem. 1975, 108, 3475, in application GB—A-2 056 439 and in application DE—A-2 345 192.

The quaternary ammonium salts which may be formed H. Bochow et al., Ber., with nitrogen (b) of the piperidine when ‘F Y = Ar—(CI-I2)C the free bases of the in which any other amine groups present are prepared by reacting compounds (I), are N—protected by a customary N-protecting group, with an excess of an alkylating agent of the formula A—Q' in which A is a leaving group 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 selected for example from methylene chloride, chloroform, acetone or acetonitrile, at a temperature between room temperature and the reflux point, for one to several hours, to give a mixture of the axial and equatorial diastereoisomers of the quaternary ammonium salts after treatment by the customary methods and after deprotection if appropriate.

A9 is preferably an iodide, which can be exchanged with anion or with a pharmacologically acceptable anion, for example a chloride, by elution of another the compound (I) on an ion exchange resin, for example Amberlite IRA68® or Duolite A375®.

The diastereoisomers the for example by chromatography or are separated by customary methods, recrystallization.

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

The N-oxide derivatives which may be formed with nitrogen (b) of the piperidine when ‘ Y = Ar“(CH2)-x—C are prepared by reaction with 21 peroxide derivative, for example metachloroperbenzoic acid or hydrogen peroxide, by the customary methods.

The functional derivative of the acid (III) used is either the acid itself, suitably activated for example by cyclohexylcarbodiimide or by benzotriazolyl- N—oxytrisdimethylaminophosphonium hexafluorophosphate (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 the starting material used is a compound of formula (II) in which E is a group Y N-" \__/ the method of the present invention can be represented and illustrated in detail by scheme 1 below: SCHEME 1 M /(CH2)n\I4Q Y N—(CH2)m—C N_H @ p’ Ar‘ (II') (Illa) C1-E-(CH2)q—Z CH 0 /—\ /‘ 2)p\fQ Y N—(CH2%n-C N_C%CH *-“ 4; (1; av) Hal-(CH2) 1-Z q+ /__\ /(CH2)pYQ —':’——* Y N-(CH2)m—C (CH Ar fl;T‘= In formula (IIIa) above, the acid chloride is considered as a reactive functional derivative of the acid (III). ent functional derivative or to start from the free (III), (II') with BOP and then to add the acid (III) in the presence of an organic base such as, for example, triethylamine, in It is possible, however, to use a differ- acid the procedure being to couple a solvent such as methylene chloride or dimethylforma- mide, at room temperature. The compounds (I) obtained are isolated and purified by the customary methods such as, for example, chromatography or recrystallization.

When the starting material used is a compound )q'Z ‘i T = -0) ) /N-CH2-(CH2)q-Z 2 q -CH,-> of formula (II) group (THP), the method of the present invention can in which E is a tetrahydropyranyloxy be represented and illustrated by scheme 2. with the reactants (IIIa) and (IV) take place as described above The reactions of the compound (II) for scheme 1, it being possible for the acid chloride (IIIa) to be replaced with a different functional derivative or with the free acid activated for example by BOP.

The intermediate (V) obtained in this way is deprotected by mild acid hydrolysis to give the free (VI). is prepared in order to substitute it with a hydroxylated compound (VII) secondary amine of formula (VIII) in the final step to from which the mesylate give the compounds (I) according to the invention.

SCHEME 2 /(CH2)n\[¢Q / (CH2)p (E = THP) AI’ (II) C1-CO-(CH2)q-Z (Ina) Hal-(CH2)q+1-Z (IV) (CH2) Q / n E-—(CH2)m- c\ Y N-T-(CH ) —Z (V) (CH2)p/ 2 Cl mild hydrolysis (H*) /(CH2)nfi¢Q HO-(CH2)m‘C /N_T_(CH2) _Z (VD (CH2) ‘* P Ar CH3SO2C1 (CH2)n\fQ /N-'1"-(CH2)q-Z (V11) 13 CIO-(CH2)m-C\ (CH2) (VH1) The products of formula (I) obtained in this way are isolated, in the form of the free base or a salt, by the conventional techniques.

When the compound of formula (I) is obtained in the form of the free base, a salt is formed by treatment with the chosen acid in an organic solvent.

Treatment of the free base, dissolved for example in an alcohol such as isopropanol, with. a solution of the chosen acid in the same solvent gives the corresponding salt, which is isolated by the conventional techniques.

The hydrochloride, hydrobromide, sulfate, hydrogen- sulfate, dihydrogenphosphate, methanesulfonate, oxa- late, maleate, fumarate and naphthalenesulfonate, for example, are prepared in this way.

When the reaction is complete, the compounds of formula (I) can be isolated in the form of one of their salts, for example the hydrochloride or oxalate: in this case, if necessary, the free base can be prepared by neutralization of said salt with a mineral or organic base such as sodium hydroxide or triethylamine, or with an alkali metal carbonate or bicarbonate such as sodium or potassium carbonate or bicarbonate.

Starting from the free bases, it is also pos- sible to prepare the quaternary ammonium salts by reac- tion with an alkylating agent, or the N-oxide deriva- tives, on nitrogen (b) of the piperidine, it being understood that any other amine groups present on (I) are N-protected by N-protecting groups which are well known to those skilled in the art.

The starting compounds of formula (II) are pre- pared from commercially available nitriles or prepared by known methods according to the schemes below.

When n is equal to zero, the compound (II) is prepared by the method of D.C. Bishop et al., J. Med.

Chem., 1968, ll, 466-470, according to scheme 3 below: SCHEME 3 Ar‘-CH2-CN + O = C\ Na EtOH E’ EtO-C-CH-CN I Ar. <|cH3>3 ) C—OK, DMF 2) Br-(CHg)m-OQ O \\C/0-cH2cH3 I <:>~O-(CH2)m-C-CN O I O\\ / O-CH2CI-I3 C I ©—O-(CH2)m-lC-CH2- NH2 0 CH3MgI B20 - CH - - Q ( 2)m (l:\/N H (H;E =THP-O-andQ =0) Arl LiA1I-I4 /\ QO'(CH2)m‘ |C\/N_H (II; E = THP-O- and Q = 2H) When n = 1, 2 or 3, the corresponding compounds (II) are prepared according to scheme 4 below: SCHEME 4 O0-(cH2)m-Ha1+ Ar‘-CH2-CN ° 1 Q0-(cH2)m—cH—cN 0 Ar’ Br-(CI-I2)n-CO2Et LDA (CH2)n-CO2Et I O O-(CH2)m—C—CN O I H2, Raney Ni NH3/EIOH Gown) C/(CH2)“\I/O A’ (H; E = mm- and Q = 0) LiA1H4 H <1 O-(CH2) -C O m l'\/N-H A’ (II; E = THP—O- and Q = 2H) Bochow et al., Chem. Ber., SCHEME 5 NC ———~ >=<3~ EtO2C 1) A1"-MgBr G 2) OH HOZC-CH2 I-102C-CH2 Ar‘ v Ar (Ts = tosyl) EtOH HCI EtO2C_CH2 EtO2C-CH2 Ar‘ Ar’ (Tri = trityl) LiA1H4 + deprotection HO-CH2-CH2 N—H Ar. (:1) The OH and NH groups may or may not be protected by conventional O-protecting or N—protecting groups which are well known to those skilled in the art.

The resolution of the racemic mixtures (1) makes it possible to isolate the enantiomers (I*) of formula / \ */(CHZL, Q Y (b)N"(CH2);— \ \__/ T(CH2)/N T (CH2)-q—Z P (I*) Ar‘ in which: _ ll*" means that the carbon atom marked with this symbol has a determined (+) or (—) absolute configuration, — Y, m, Ar’, n, p, Q, T, q and Z are as defined above for the derivatives of formula (I), or one of their salts with mineral or organic acids, or, with nitrogen atom (b), one of their quaternary ammonium salts or N—oxide derivatives.

Said indicated above for the corresponding salts and derivatives salts or N—oxide derivatives are prepared as of the derivatives of formula (I).

The enantiomers of formula (I*) are novel products that form part of the invention.

It is also possible to resolve racemic mixtures of the Ar‘, defined for (I), E is a hydroxyl and Q is hydrogen, in order products of formula (II) in which m, n and p are as to prepare the enantiomers (I*) of the products of formula (I)- The resolution of the racemates is carried out on the intermediates (II) which are capable of giving salts with optically active acids. The enantiomers are then separated by the chiral preparative high—pressure chromatography. conventional methods such as crystallization or The optically pure amino alcohol prepared in this way is a novel compound forming part of the invention and has the formula .26. */< CH2 mfg H0‘(CH2>..—1‘« (II*> \(CH2 )P/N"H Ar’ in which "*" means that the carbon atom marked with this symbol has a determined (+) or (—) configuration.

The optically pure intermediates of formulae (V) and (VIL particular value and represent a further aspect of the in which Q is hydrogen, are novel products of present invention. These products can be brought together under the following formula: G O’(CHQ;*C\ (V*) Ar’ in which: "*"I ml Ar’! nl pl T, q and Z are as defined above and G is hydrogen or a methanesulfonyl group.

The racemic mixtures of the compounds (II) are prepared as indicated in schemes 3, 4 and 5 above.

The (V*) according to the reaction sequence indicated in scheme 2 optically pure compounds are prepared above, starting from the optically pure compounds (II), i.e.

(II*), to give the final products according to the invention in optically pure form, i.e. (I*). when the substituent -(CH2)q-Z is a benzyl group substituted on the -CH— by a hydroxyl, an alkoxy or a C1-C4 alkyl, a mixture of either two or four diastereoisomers is obtained according to whether an optically pure or optically impure a—substituted benzyl derivative is reacted with an optically pure or optically impure amine derivative.

These diastereoisomers form part of the invention.

The compounds according to the invention were subjected to biochemical tests.

The compounds (I) and their salts showed antagonistic in tests properties towards the binding of substance P performed on rat cortical membranes and IM9 lymphoblasts, Biol. Chem., 1983, Paya et al., J. Immunol., 1984, according to M.A. 258, 5158-5164, and D.D. 133, 3260-3265.

The same compounds and their salts showed antagonistic Cascieri et al., J. properties towards the binding of NKA in tests performed on rat duodenal membranes, 1987, 32, 764-771.

The same compounds and their salts showed antagonistic according to L. Bergstom et al., Mol. Pharmacol., properties towards the binding of eledoisin in tests performed on rat membranes, according to A.C. Foster et al., Br. J. Pharmacol., 1988, 24, 602-608.

Eledoisin is a peptide of batrachian origin which is equivalent to neurokinin B.

The compounds according to the invention are antagonistic towards substance P, neurokinin A or neurokinin B.

Thus compound 2 of Example 2 antagonizes the binding of substance P with a Ki of 8.3 nanomolar, compound 7 of Example 7 antagonizes the binding of neurokinin A with a Ki of 1.3 nanomolar and compound 3 of Example 3 antagonizes the binding of eledoisin with a Ki of 200 nanomolar.

The compounds of the present invention are generally Said pharmaceutical administered in dosage units. dosage units are preferably formulated as compositions in which the active principle is mixed with a pharmaceutical excipient.

Thus, according to another aspect, the present invention relates to pharmaceutical compositions containing, as the active principle, a compound of formula (I) or one of its pharmaceutically acceptable salts.

The compounds of formula (1) above and their pharmaceutically acceptable salts 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 can 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.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principles can be administered. to animals and with The appropriate unit humans in unit forms of administration, mixed conventional pharmaceutical carriers. forms of administration include oral forms such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, sublingual and buccal forms of administration, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration. when a solid composition in the form of tablets is prepared, the main 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 appropriate substances or they can be treated so as to have a prolonged or delayed activity and so as to release a puedetermined amount of active principle continuously.

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

A preparation in the form of a syrup or elixir can contain the active principle together with a sweetener, which is preferably calorie—free, methylparaben and propylparaben as antiseptics, a flavoring and an appropriate color.

The water—dispersible granules or powders can contain the active principle mixed with dispersants or wetting agents, or suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors. - 29 _ For rectal administration, suppositories are used. which are prepared. with binders melting at the rectal temperature, for example cacao butter or poly- ethylene glycols. intraocular For parenteral, intranasal or administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions are used which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol.

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

The active principle can also be formulated as microcapsules, with one or more carriers or additives if appropriate. also The above-mentioned compositions can contain other active products such as, for example, bronchodilators, antitussives or antihistamines.

The following Examples illustrate the invention without however implying a limitation.

The melting or decomposition points of the pro- ducts, m.p., were measured on a Koffler heating bench.

The 13C nuclear magnetic resonance spectra were run at MHz in dimethyl sulfoxide.

EXAMPLE 1 —[2—(4—Benzylpiperidin—1-yl)ethyl](3,4-di- chlorophenyl)—1—benzylpiperidinone hydrochloride _ 30 _ A) 3,4-Dichlorotetrahydropyranyloxyethyl-a-benzene- acetonitrile g of a 55-60% dispersion of sodium hydride in oil are suspended in 200 ml of dry tetrahydrofuran.

A solution of 85 g of 3,4-dichlorophenylacetonitrile in 500 ml of tetrahydrofuran is added dropwise at 20°C over 30 minutes and the reaction mixture is then stirred at room temperature for 2 hours. The mixture is cooled to -20”C, a solution of 98 g of 2-bromo- ethoxytetrahydropyran in 100 ml of tetrahydrofuran is added, the mixture is allowed to return to room tem- perature and, after 2 hours, a solution of 50 g of ammonium chloride in 3 liters of water is added. Ex- traction is carried out with 1.5 liters of ether and the extract is washed with a saturated solution of sodium chloride, decanted, dried over MgSO4 and con- centrated under vacuum.

The residue is chromatographed on silica gel using methylene chloride as the eluent. The pure product fractions are concentrated under vacuum to give 83.6 g of an oil.

B) Ethyl 7-tetrahydropyranyloxyethyl-1—cyano—3,4- dichlorobenzylbutanoate g of the nitrile prepared above according to A) are dissolved in 100 ml of tetrahydrofuran, a solu- tion of 0.067 mol of lithium diisopropylamide in 100 ml of tetrahydrofuran is then added dropwise at room tem- perature and the reaction mixture is stirred for one hour at room temperature. 12 g of ethyl bromopro- pionate are then added and the mixture is heated at °C for two hours. It is cooled, poured into a saturated solution of ammonium chloride and extracted with ether, ether phase is separated off by decantation, dried over the extract is washed with water and the Na2SO4 and concentrated under vacuum. The residue is purified by chromatography on silica gel using methy- lene chloride/ethyl acetate 100/1 (v/v) as the eluent.

Concentration of the pure fractions gives 13 g of the expected compound.

C) 5—Tetrahydropyranyloxyethyl(3,4-dich1orophenyl)- piperidinone g of the compound prepared above are dis- solved in 250 ml of ethanol and 40 ml of aqueous ammo- nia and hydrogenated at room temperature and atmos- pheric pressure in the presence of Raney nickel. When the theoretical volume of hydrogen has been absorbed, the mixture is filtered on Célite and the filtrate is concentrated under vacuum. The residue is taken up in water and extracted with ether and the ether phase is then washed with water, dried over MgS04 and concen- trated under vacuum. m = 9 g.

D) 5-Tetrahydropyranyloxyethyl(3,4—dichlorophenyl)— -benzylpiperidinone .05 g of benzyl bromide are added to a solu- tion of 4.5 g of the product prepared above in 60 ml of dimethylformamide, in the presence of 0.3 g of sodium hydride. The reaction mixture is heated at 40-50°C for two hours and concentrated under vacuum. The residue is taken up in water and extracted with ether and the ether phase is washed with water, dried over MgSO4 and concentrated under vacuum. The residue is chromato- graphed on silica gel using methylene chloride/methanol 100/1 (v/v) as the eluent.

The pure product fractions are concentrated under vacuum. m = 2 g.

E) 5—Methanesulfonyloxyethyl(3,4-dichlorophenyl) benzylpiperidinone g of the product prepared above are dissolved in 40 ml of methanol saturated with gaseous hydro- chloric acid and the solution is stirred for two hours at room temperature. The solvents are concentrated under vacuum, the residue is taken up in a 50/50 pen- tane/ether mixture and the precipitate is then filtered off. The precipitate is dissolved in 50 ml of methy- lene chloride, 0.4 g of triethylamine and 0.45 g of mesyl chloride are added and the mixture is stirred for half an hour at room temperature. It is concentrated under vacuum, the residue is taken up in water and extracted with ether and the ether phase is washed with water, decanted, dried over MgSO4 and concentrated under vacuum. m = 1.6 g.

F) Compound 1 .68 g of the product prepared above and 0.63 g of 4-benzylpiperidine are dissolved in 2 ml of di- methylformamide and the mixture is heated at 80°C for two hours. The solution is cooled, poured into water and extracted with ethyl acetate and the organic phase is decanted, dried over MgSO4 and concentrated under The residue is purified by chromatography on /3 vacuum . silica gel using methylene chloride/methanol (v/v) as the eluent.

The pure product fractions are concentrated under vacuum and this is followed by preparation of the which is solidified in a 50/50 ether/ pentane mixture. hydrochloride, m = 0.25 g.

M.p. = 115°C. -33 ..

EXAMPLE 2 3-[2-(4-Benzylpiperidinyl)ethyl](3,4- dichlorophenyl)—1-phenylacetylpiperidine hydrochloride .. -_- CH2~CN_;m=2;n=2 ;p=1; Cl (D: Y N \__/ A) 3-Tetrahydropyranyloxyethyl(3,4-dichlorophenyl)- piperidine .5 g of 5-tetrahydropyranyloxyethyl(3,4- dichlorophenyl)piperidinone prepared according to Example 1 C) are dissolved in 50 ml of tetrahydrofuran and the solution is added to a suspension of 0.9 g of lithium aluminum hydride, heated to 60°C. The reaction mixture is heated for one hour at 60°C and then cooled. 1 ml of water, 1 ml of 4 N sodium hydroxide and 3 ml of water are added. The inorganic material is filtered off and the filtrate is concentrated under vacuum. The residue is taken up in ether, dried over MgSO4 and concentrated under vacuum to give 3.5 g of the expected product.

B) 3—Tetrahydropyranyloxyethyl-3—(3,4-dichlorophenyl)- -phenylacetylpiperidine .75 g of phenylacetyl chloride is added to a solution of 1.7 g of the product prepared above and 0.9 g of triethylamine in 50 ml of methylene chloride.

The reaction mixture is stirred for one hour at room temperature and concentrated under vacuum. The residue is taken up in ethyl acetate and then washed with water -34 _ and the organic phase is dried over MgSO4 and concen- trated under vacuum. The residue is purified by chro- matography on silica gel using methylene chloride/ methanol 100/0.5 (v/v) as the eluent.

Concentration of the pure fractions gives 1 g of the expected product.

C) 3-Methanesulfonyloxyethyl(3,4-dichlorophenyl)—1— phenylacetylpiperidine .8 g of the product obtained above is dis- solved in 40 ml of methanol saturated with hydrochloric acid and the mixture is stirred for half an hour at room temperature. It is concentrated under vacuum and the residue is taken up in 40 ml of methylene chloride. 0.4 g of triethylamine and 0.23 g of mesyl chloride are added and the reaction mixture is stirred for one hour at room temperature and then concentrated under vacuum.

The residue is taken up in ethyl acetate and washed with water and the organic phase is separated off by decantation, dried over MgSO4 and concentrated under vacuum. m = 0.71 g.

D) Compound 2 .7 g of the product prepared above and 0.52 g of 4—benzylpiperidine dissolved ix: 2 nu. of dimethyl— formamide are heated at 80°C for three hours. The cooled, into water and reaction mixture is poured extracted with ether, the ether phase is washed with water, dried over MgSO4 and concentrated under vacuum and the hydrochloride is then recrystallized from a methylene chloride/ether mixture. m = 0.12 g.

M.p. = 210-212°C.

Compounds 3 to 6 described in Table I below are prepared by following the procedure of Example 1.

TABLE I C1 C1 Example n° Y\ /N— n 'T’(CH2)q’Z C “ CH @ 250 N_ 2 ' 2 HC1. 0.51120 4 QZIZCN‘ 1 CH @ 168 ' 2 \ C = O HC1 1 H 142 N‘ ‘C 2 HC1 HO 6 2 136 HO O-CH3 _36 ..

Compounds 7 to 15 described in Table II below are prepared by following the procedure of Example 2.

TABLE II % /(CH2)nE Y N—(CH2)2—C N-T-(CH ) -z \/ \ / Zq \ C1 C1 0 Example n° Y\ /N_ n 'T'(CH2)q'Z 7 I c@ N" H HC1 HO 0 _@ 112 'ff'C"2 HC1 C@ 160 H HC1 0 H0 2 _@ 142 N— —c H HC1 O\ 0 ? ‘ 0 CH3 F 11 2 _ _ 114 ©C”2C”" Tl CH2 HC1 TABLE II (continued) / \ 0 0 Y N- _T_(CH ) _Z M.p., C Example n \ / 2 Q Salt I C = O 168 @@ H” F - -CH 13 @>c»»<:~— E *5? oczns HCI 169 O OiPr \(|: = O 110 H3CO 0C1-13 iPr = isopropyl _ 38 _ Compounds 16 to 19 described in Table III below are obtained by following the procedure of Examples 1 and 2 above, replacing the nitri le with a—naphthylacetonitri 1e .

TABLE III N-(CH2)2-CM \__./ K/N—T-(cH_,_)q-z , 4-dichlorophenyl aceto- M “C 0 Y N: _ _ _ . .; Example 11 \ / Q T (CH2)q Z 331%) O 104 H 115 ‘fi@ O 13 H 105 ©CH2C"' 'fi@°CH3 H0 O OCI-I3 HO 19 H _C OCH3 110 N‘ H HC1 O EXAMPLE 20 —[2-(4-Benzy1piperidin—1—yl)ethyl](3,4- dichlorophenyl)—1—(3-isopropoxyphenyl)acetylazepine hydrochloride C1; -T-(CI-I2)q—Z = -CH2 C1 O-iPr A) Ethyl 5-tetrahydropyranyloxyethylcyano-3,4- dichlorobenzylpentanoate 4.6 g of 60% NaH are added in small portions to 36 g of zeneacetonitrile ,4-dichloro-a-tetrahydropyranyloxyethylben— (prepared according to step A of Example 1) dissolved iJ1 100 nu. of dimethylformamide.

The reaction mixture is stirred for 3 hours at room temperature and cooled to 0°C and 22.4 g of ethyl 4- bromobutyrate in 40 ml of dimethylformamide are then added. room temperature, poured into water and extracted with The reaction mixture is stirred for 3 hours at ether and the extract is washed with a saturated solu- tion of Nacl, dried over Na2sO4 and concentrated under vacuum. The residue obtained is purified by chromato- graphy on silica gel using toluene as the eluent. m = 24 g.

B) 6-Tetrahydropyranyloxyethyl(3,4-dichloropheny1)- azepinone A solution of 8 g of the product obtained above in 120 ml of ethanol is hydrogenated. at atmospheric - 40 _ pressure and room temperature in the presence of Raney nickel. when the theoretical volume of hydrogen has the catalyst is filtered off and the filtrate is concentrated under vacuum. been consumed, The oil obtained is then taken up in 20 ml of xylene and the reaction mixture is refluxed for 48 hours. It is evaporated and the residue obtained is purified by chromatography on silica gel using methy- lene chloride/methanol 100/1 (v/V) as the eluent.

This gives 4 g of an oil.

C) 3—Tetrahydropyranyloxyethyl—3-(3,4-dichlorophenyl)- azepine .7 g of the expected product are obtained in the form of an oil from 2 g of the product obtained above and 0.49 g of lithium aluminum hydride by fol- lowing the procedure of Example 2, step A.

D) 3-Tetrahydropyranyloxyethyl-3—(3,4—dichlorophenyl)— —(3-isopropoxyphenyl)acetylazepine .7 g of the expected product are obtained from 1.7 g of the product obtained above by following the procedure of Example 2, step B.

E) 3-Methanesulfonyloxyethyl(3,4—dichlorophenyl)—l- (3~isopropoxyphenyl)acetylazepine .5 g of the expected product are obtained from 1.7 g of the product obtained above and 0.34 g of mesyl chloride by following the procedure of Example 2, step C.

F) Compound 20 .5 g of the product obtained above and 1.4 g of 4-benzylpiperidine dissolved in :3 ml of dimethyl— formamide are heated at 80°C for 2 hours. The reaction mixture is cooled, poured into water and extracted with ether and the organic phase is washed with water, dried over Na2SO4 and concentrated under vacuum. .41 ..

The residue obtained in this way is purified by chromatography on silica gel using CH2Cl2/CHBOH 100/2 (v/v) as the eluent. The pure fractions are concentra- ted and the hydrochloride is prepared in isopropyl ether, filtered off, washed with ether and dried under vacuum to give 1.3 g of the expected product.

M.p. = 164°C.

EXAMPLE 21 —[2-(4—Benzylpiperidinyl)ethyl](3,4-di- chlorophenyl)-1—(3-methoxyphenyl)acetylazetidine hydrochloride ; Y (D , , N— : Q = AI’ = ; = ' 0 The above compound was prepared according to scheme 3 of the description.

A) 3-Tetrahydropyranyloxyethyl(3,4—dichloropheny1)- -(3-methoxyphenyl)acetylazetidine .5 g of BOP are added to a solution of 1 g of 3—tetrahydropyranyloxyethy1—3-(3,4-dichlorophenyl)- azetidine in 50 ml of methylene chloride, in the pre- sence of 1 g of triethylamine and 0.5 g of 3—methoxy- phenylacetic acid. The reaction mixture is stirred for 1 hour at room temperature and evaporated to dryness and the residue is taken up in ethyl acetate and washed with water, dilute sodium hydroxide solution, a buffer of pH 2 and finally a saturated aqueous solution of <::;:>F-CEI2—{<::::N¥-; n1: 2 ;n = 0 ;p =1 ; C1 OCH3 Nacl. evaporated to dryness.

The organic phase is dried over MgSO4 and The residue is purified by chromatography on silica gel using CH2Cl2/CHSOH 100/ 0.75 (v/v) as the eluent.

This gives 0.50 g of an oil.

B) 3-Methanesulfonyloxyethyl-3—(3,4-dichlorophenyl) (3-methoxyphenyl)acetylazetidine Ether saturated with hydrochloric acid is added to a solution of 0.50 g of the product prepared above in 50 ml of methanol until the pH is 1. The solution is stirred at room temperature for 1 hour and evapora- ted to dryness, the residue is taken up in water and extracted with AcOEt and the extract is washed with water, dried over MgSO4 and evaporated to dryness.

The oil obtained is taken up in 30 ml of methylene chloride, and 0.20 g of triethylamine and 0.12 g of mesyl chloride are added. The reaction mixture is stirred at room temperature for 1 hour and evaporated to dryness and the residue is taken up in ethyl acetate, washed with water, dried over MgSO4 and evaporated to dryness.

This gives 0.50 g of an oil.

C) Compound 21 A solution of 0.50 g of the product described above in 2 ml of dimethylformamide, with 0.40 g of 4- is heated at 80°C for 3 hours. The reaction mixture is benzylpiperidine, cooled, poured into water and extracted with ethyl acetate and the extract is washed with water, dried over MgSO4 and evaporated to dryness.

The residue obtained in this way is purified by chromatography on silica gel using CH2Cl2/CHBOH 100/2.5 (v/v) as the eluent.

The pure fractions are concentrated under vacuum and the hydrochloride is prepared by the addi- tion of ether saturated with hydrochloric acid. The residue is taken up in methylene chloride and the hydrochloride is precipitated in ether, filtered off, washed with ether and dried under vacuum.

This gives 0.22 g of the expected product.

M.p. = 102°C.

EXAMPLE 22 —[2-(4—Benzylpiperidinyl)ethyl]-4—(3- methylphenyl)(3-chlorophenyl)acetylpiperidine hydrochloride (1): Y N-= CH2 N—;m=2;n=1;p=2' Q = 2H; Ar’ = @K ;-T-(CH2)q-Z = — |C|—CH2 0 CH3 C1 The above compound is prepared according to scheme 5 of the description.

A) 4-Methanesulfonyloxyethyl—4—(3-methylphenyl)—N— tritylpiperidine 3.8 ml of methanesulfonyl chloride are added dropwise to 21 g of 4—(2-hydroxyethyl)(3—methyl— phenyl)-N—tritylpiperidine (prepared according to scheme 5) dissolved in 200 ml of methylene chloride, cooled to 0°C. an hour at room temperature, washed twice with water, The reaction mixture is left for half dried over MgSO4 and concentrated under vacuum.

This gives 23.5 g of a foam.

B) 4-[2-(4-Benzylpiperidin-l—yl)ethyl](3—methyl- phenyl)-N-tritylpiperidine A solution of 18.5 g of the mesylate described above and 13.5 g of 4-benzylpiperidine in 40 ml of dimethylformamide is heated for 4 hours at 60°C. The reaction mixture is poured into 500 ml of iced water and the precipitate is filtered off and rinsed with water. The precipitate is taken up in ether, washed with dilute NaOH and then water, dried over MgSO4 and concentrated to dryness.

The residue obtained is purified by chromato- graphy on silica gel using CHZCI2/CH30H 100/3 (v/v) as the eluent.

This gives 18 g of a foam.

C) 4—[2-(4-Benzylpiperidin-1—yl)ethyl]-4—(3—methyl— phenyl)piperidine dihydrochloride A solution of 18 g of the above product in 150 ml of 50% formic acid is heated at 60°C for 30 minutes.

It is cooled, the triphenylcarbinol is filtered off and rinsed with water and the filtrate is concentrated to dryness. The residue is taken up in water, washed with ether, rendered alkaline with a solution of NaOH and extracted with methylene chloride and the extract is dried over MgSO4 and concentrated to dryness.

The base is dissolved in methylene chloride, ether saturated with hydrochloric acid is added and the The hydrochloride prepared in this way is stirred in ether, filtered off mixture is concentrated to dryness. and dried. m = 12.7 g.

M.p. = 160°C.

D) Compound 22 .4 g of BOP are added to a solution of 2 g of ml chloride, with 0.77 g of 3—chlorophenylacetic acid and the product prepared above in of methylene .2 g of triethylamine. The reaction mixture is stirred for 30 minutes at room temperature and concen- trated to dryness and the residue is taken up in ethyl acetate, washed with water, then a dilute solution of NaOH and then a saturated aqueous solution of Nacl, dried over MgSO4 and concentrated under vacuum. The residue is purified by chromatography on silica gel using CH2Cl2/CH3OH 100/10 (v/v) hydrochloride is prepared by the addition of ether as the eluent . The saturated with hydrochloric acid and the mixture is concentrated to dryness. The residue is taken up in isopropyl ether, filtered off and dried under vacuum.

In = 2.1 g.

M.p. = 106°C. -46 ..

The compounds described in Table IV below are prepared by following the procedure indicated above in Example 22.

TABLE IV 0 / \ J\ Y N-CH2-CH2 N (CH2)q,Z _ HCI CH3 Y N- Example n° \._/ '(CH2)q'Z M-P-; 23 CH _ “H3 105 OCH3 24 CH2‘<:N— OCH3 146 OCH3 “O 1 EXAMPLE 26 —[3-(4-Benzylpiperidin—1—yl)propyl](3,4- dichlorophenyl)—1-(3-methoxyphenyl)acetylpiperidine hydrochloride G): Y Q _—_; AI" : ; = ‘ c1 0 OCH3 Cl A) 3,4—Dichlorotetrahydropyranyloxypropyl-a-benzene- acetonitrile g of the expected product are obtained in an identical manner to step A of Example 1, starting from 37.2 g of 3,4-dichlorophenylacetonitrile and 44.6 g of 3—bromopropoxytetrahydropyran.

B) Ethyl 1-tetrahydropyranyloxypropylcyano-3,4- dichlorobenzylbutanoate g of the expected product are obtained from g of the product obtained above and 19.2 g of ethyl bromopropionate by following an identical procedure to step B of Example 1.

C) 5-Tetrahydropyranyloxypropyl(3,4—dichlorophenyl)- piperidone A solution of 23 g of the product obtained above in 650 ml of ethanol is hydrogenated at atmos- pheric pressure and room temperature in the presence of Raney nickel. When the theoretical volume of hydrogen the catalyst is filtered off, the filtrate is evaporated to dryness and the residue is has been consumed, taken up in ether, washed with water and a buffer of pH 2, dried over Na2SO4 and evaporated to dryness.

This gives 18 g of the expected product.

D) 3—Tetrahydropyranyloxypropyl—3-(3,4-dichlorophenyl)— piperidine A solution of 14 g of the product obtained above in 50 ml of tetrahydrofuran is added dropwise to a suspension of 2.75 g of lithium aluminum hydride, heated to 60°C.

The temperature is kept at 60°C for 1 hour.

The reaction mixture is cooled and hydrolyzed by the addition of 3 ml of water, 3 ml of a 4 N solution of NaOH and 9 ml of water. The inorganic material is separated off and the organic phase is evaporated under vacuum.

This gives 12.4 g of the expected product.

E) 3—Tetrahydropyranyloxypropyl-3—(3,4-dichlorophenyl)- 1—(3—methoxypheny1)acetylpiperidine .9 g of BOP are added to a solution of 3 g of the product prepared above, 2.4 g of triethylamine and 1.3 g of 3-methoxyphenylacetic acid in 50 ml of methy- lene chloride. The reaction mixture is stirred for 1 hour at room temperature and evaporated to dryness and the residue is taken up in AcOEt, washed with water, dried over Na2S04 and evaporated to dryness.

The residue obtained in this way is purified by chromatography on silica gel using CH2Cl2/CHBOH 100/2 (v/v) as the eluent.

Concentration of the pure fractions gives 3 g of the expected product.

F) 3-Methanesulfonyloxypropyl(3,4-dichlorophenyl) (3-methoxyphenyl)acetylpiperidine The expected compound is obtained from 3 g of the product prepared above and 0.68 g of mesyl chloride by following the procedure described in step C of - 49 _ Example 2. 2 g of the expected product are obtained after purification by chromatography on using CH2Cl2/CH3OH 100/1.5 (V/v) concentration of the pure product fractions.

G) Compound 26 A solution of 2 g of the product obtained above silica gel as the eluent and and 1.6 g of 4-benzylpiperidine in 3 ml of dimethyl— formamide is heated for 1 hour at 70°C. The reaction mixture is cooled, poured into water and extracted with ether and the extract is washed with water, dried over Na2SO4, filtered and concentrated under vacuum.

The residue obtained in this way is purified by chromatography on silica gel using CH2Cl2/CHJOH 100/3 (V/V) trated under vacuum, the residue is taken up in acetone as the eluent. The pure fractions are concen- and the hydrochloride is prepared by the addition of The hydro- chloride is filtered off, washed with pentane and dried ether saturated with hydrochloric acid. under vacuum over P205.

This gives 1.1 g of the expected product.

M.p. = 108°C.

EXAMPLE 27 -[3—(4-Phenyl-4—acetamidopiperidin—l—yl)- propyl](3,4-dichlorophenyl)—l-benzoylpiperidine hydrochloride a);Y N-= N—;m=3;n=2;p=1;Q=2H; PIN \ ‘f‘° CH3 c1; -T—(CH2)q-Z = - () Cl A) 3—Tetrahydropyranyloxypropyl(3,4-dichlorophenyl)— 1-benzoylpiperidine .13 g of benzoyl chloride are added to 3 g of 3-tetrahydropyranyloxypropyl—3-(3,4-dichlorophenyl)- piperidine prepared according to Example 26, step D, in the presence of a solution of 1.62 g of triethylamine in 50 ml of methylene chloride. The reaction mixture is stirred for 30 minutes at room temperature and eva- porated to dryness and the residue is taken up in ether, washed with water, dried over Na2SO4 and eva- porated to dryness. The residue obtained in this way is purified by chromatography on silica gel using CH2Cl2/CHBOH 100/1 (v/v) as the eluent.

This gives 3 g of an oil.

B) 3-Methanesulfonyloxypropyl(3,4-dichlorophenyl) benzoylpiperidine Ether saturated with hydrochloric acid is added to a solution of 3 g of the product prepared above in 50 ml of methanol until the pH is 1. mixture is stirred for 30 minutes at room temperature The reaction and evaporated to dryness. The residue is taken up in 50 ml of methylene chloride and 1.07 g of triethyl- amine, and 0.72 g of mesyl chloride is then added. The mixture is stirred at room temperature for 1 hour and evaporated to dryness and the residue is taken up in ethyl acetate, washed with water, dried over Na2SO4, filtered and concentrated under vacuum. The residue is purified by chromatography on silica gel using CH2Cl2/ AcOEt 100/3 (v/v) as the eluent.

This gives 1.6 g of the expected product. _ 51 _ C) Compound 27 A solution of 1.5 g of the product prepared above and 1.5 g of 4-phenylacetamidopiperidine in 5 ml of dimethylformamide is heated at 80°C for 4 hours.

The reaction mixture is cooled, poured into water and extracted with methylene chloride and the extract is filtered and The residue is purified by washed with water, dried over Na2SO4, concentrated under vacuum. chromatography on silica gel using CH2Cl2/CH3OH 100/5 (v/v) as the eluent. The pure product fractions are concentrated and taken up in methylene chloride, the hydrochloride is prepared by the addition of ether saturated with hydrochloric acid, the mixture is eva- porated to dryness and the residue is taken up in ethanol and precipitated in ether. The precipitate is filtered off, vacuum . washed with pentane and dried under m = 0.60 g.

M.p. = 184°C.

EXAMPLE 28 -[3-(4-Hydroxyphenylpiperidin-1—yl)propyl]- —(3,4—dich1orophenyl)—1-(3—methoxybenzy1)piperidone hydrochloride (I):Y N-= N——;m=3;n=2;p=1;Q=O; \_/ Oil C1 ; -T-(CH2)q-Z = - CH2 C1 OCH3 A) 5—Tetrahydropyranyloxypropyl—5-(3,4—dichlorophenyl)- 1-(3—methoxybenzyl)piperidone .66 g of 60% NaH is added to a solution of 6.4 g of 5—tetrahydropyranyloxypropyl(3,4-dichloro- phenyl)piperidone, described in step C of Example 26, The reaction mixture is 2.5 g of 3-methoxybenzyl chloride are then added dropwise and in 60 ml of dimethylformamide. stirred for 30 minutes at room temperature. the reaction mixture is heated for 1 hour at 80°C. The dimethylformamide is evaporated off under vacuum, the residue is extracted with methylene chloride and the extract is washed with water, dried over Na2s04 and evaporated to dryness.

The residue obtained in this way is purified by chromatography on silica gel using CH2Cl2/AcOEt 100/5 (v/V) as the eluent. The pure product fractions are concentrated to give 6 g of an oil.

B) 5—(3—Hydroxypropyl)-5—(3,4-dichlorophenyl)—1-(3- methoxybenzyl)piperidone A solution of 6 g of the product prepared above in 50 ml of methanol saturated with hydrochloric acid is stirred at room temperature for one hour.

The reaction mixture is evaporated to dryness to give 4.3 g of an oil.

C) 5-Methanesulfonyloxypropyl(3,4-dichlorophenyl) (3-methoxybenzyl)piperidone .14 g of mesyl chloride are added to 4.3 g of the product prepared above, in the presence of a solu- tion of‘ 2 g of triethylamine in 50 ml of methylene chloride. The reaction mixture is stirred for 1 hour at room temperature and evaporated to dryness and the residue is taken up in AcOEt, washed with water and a saturated aqueous solution of Nacl, dried over Na2SO4 and evaporated to dryness.

The residue obtained in this way is purified by _ 53 - chromatography on silica gel using CH2Cl2/CHBOH 100/2 (V/V) concentrated to give 4 g of an oil. as the eluent. The pure product fractions are D) Compound 28 A solution of 4 g of the product prepared above and 3.1 g of 4—hydroxyphenylpiperidine in 5 ml of It is cooled, poured into water and extracted with AcOEt and dimethylformamide is heated at 80°C for 2 hours. the extract is washed with water, dried over Na2S04 and evaporated to dryness. The oil obtained is taken up in ether and the hydrochloride is prepared by the addition of ether saturated with hydrochloric acid. is filtered off, vacuum .

The product washed with ether and dried under m 4 g.

M.p. = 110-117“c.

EXAMPLE 2 9 -[3-(4-Hydroxyphenylpiperidin—1-yl)propyl]- 3-(3,4-dichlorophenyl)(3—methoXybenzyl)piperidine dihydrochloride ’ ‘ .

(I):Y N-= N—;m=3;n=2;p=1;Q=H, \__/ OII ’.

II C1;—T-(CH2)q-Z = -CH2 g of 5-[3-(4-hydroxyphenylpiperidin—1-yl)- propyl]-5—(3,4—dichlorophenyl)-l—(3-methoxybenzyl)pipe- ridone are added to a suspension of 0.60 g of lithium aluminum hydride in 50 ml of tetrahydrofuran. The _ 54 - reaction mixture is heated for 1 hour at 60°C, cooled and hydrolyzed with 5 ml material is filtered off and the filtrate is evaporated of water, the inorganic to dryness.

The residue obtained in this way is purified by chromatography on silica gel using CHZCI2/CHBOH 100/5 (V/V) concentrated and the as the eluent, the pure product fractions are hydrochloride is prepared in methylene chloride by the addition of ether saturated with hydrochloric acid.

The hydrochloride is filtered off, washed with ether and dried under vacuum over P205. m = 1.5 g.

M.p. = 160-175°C.

EXAMPLE 30 3—[2-(4-Hydroxy—4-phenylpiperidinyl)ethyl]- 3-(3,4-dichlorophenyl)benzylpyrrolidine dihydro- chloride ___ OF} H): Y N7-= N=—; n1= 2;r1= 1; p:=1 ;Q2= 2H; C1 The expected product is obtained by following the procedure of Example 29, starting from the product described in Example 5.

M.p. = 170°C. _ 55 _ EXAMPLE 31 3—[2-(4-Benzylpiperidin-1—yl)ethy1](naphth- 1-yl)benzylpiperidine dihydrochloride (I):Y N-= CH2~C:N-;m=2;n=2;p=1; \_/ Q: H; M: ;-T—(CH2)q-Z=-CH2 The above compound is obtained by following the procedure of Example 29, starting from the product des- cribed in Example 17.

M.p. = 140°C.

EXAMPLE 32 3-[2—(4-Benzylpiperidin—l—yl)ethyl]—3—(3,4-di- chlorophenyl)(3—isopropoxyphenyl)acetylpiperidine Q = 2H; Ar‘: ;-T—(CH2)q-Z = -fi-CH2 Cl 0 Cl (—) hydrochloride (1): Y N \__/ O—H% I - PREPARATION OF THE OPTICALLY PURE AMINO ALCOHOL A) 3-(2-Hydroxyethyl)—3—(3,4-dichlorophenyl)piperidine A solution of hydrochloric acid in ether is added to a solution of 55 g of 3-tetrahydropyranyloxy— ethyl-3—(3,4-dichlorophenyl)piperidine in 200 ml of methanol until the pH is 1. The mixture is stirred for half an hour at room temperature and concentrated to dryness, the residue is taken up in water, rendered basic with a solution of sodium hydroxide and extracted with methylene chloride and the extract is washed with a saturated solution of NaC1, dried over Na2SO4 and evaporated to dryness to give an oil.

This is taken up in 200 ml of a 50/50 (v/v) isopropyl ether/ether mixture. The medium is stirred and the product is filtered off, washed with ether and dried under vacuum over P205. m = 45 g.

M.p. = 122°C.

B) 3-(2—Hydroxyethyl)(3,4-dichlorophenyl)piperidine (+) A solution of 23.54 g of L(+)—tartaric acid in 750 ml of 100° ethanol is added to a refluxing solution of 43 g of the product obtained above in 250 ml of 100° ethanol. The reaction mixture is refluxed for half an hour and allowed to return to room temperature and the crystals obtained are filtered off, washed with 100° ethanol and dried under vacuum at 50°C over P205. m = 31 g.

The product is then recrystallized from 540 ml of 100° ethanol and the crystals are filtered off, washed with ether and dried under vacuum over P205. m = 25 g. [a]D2° = +8.5 (c = 1, H20). _ 57 _ The tartrate is then taken up in water, neutra- lized with a solution of NaOH and extracted with methy- lene chloride and the extract is washed with water, The oil is taken up in an ether/isopropyl ether mixture and the dried over Na2SO4 and evaporated to dryness. crystals are filtered off, washed with ether and dried under vacuum at 50°C. m = 13.5 g.

M.p. = 138°C. [a]D2° = +3.2” (c = 1, CHBOH).

C) 3-(2-Hydroxyethyl)(3,4—dichlorophenyl)piperidine (-) The (-) enantiomer is obtained by following the above procedure, starting from D(—)-tartaric acid.

M.p. = 139°C. [a]D2° = -8.4“ (c = 1, CHSOH).

II - PREPARATION OF COMPOUND 32 A) 3—(2—Hydroxyethyl)(3,4-dichlorophenyl)-1—tert- butylcarbamoylpiperidine .4 g of di-tert-butyl dicarbonate are added to a solution of 13 g of 3-(2—hydroxyethyl)(3,4-di- chlorophenyl)piperidine (+) in 100 ml of dioxane. The It is evaporated to dryness and the residue is taken up in mixture is then stirred for 1 hour at 40°C. ether and washed with water, then a buffer solution of pH 2 and finally water. The ether phase is dried over Na2SO4, filtered and evaporated to dryness. The resi- due is purified by chromatography on silica gel using CH2Cl2/CHBOH 100/2 (v/V) as the eluent. 16.7 g of the expected product are thus obtained in the form of an oil after concentration of the pure fractions.

B) 3—Methanesulfonyloxyethy1(3,4-dichlorophenyl) tert-butylcarbamoylpiperidine .5 g of mesyl chloride are added dropwise to a solution of 16.5 g of the product prepared above in 100 ml of methylene chloride, in the presence of 4.9 g of triethylamine. The mixture is stirred for half an hour at room temperature and evaporated to dryness and the residue is taken up in ether, washed with water, dried over Na2SO4 and concentrated under vacuum to give 19 g of an oil.

C) 3—[2-(4-Benzylpiperidin—1-yl)ethyl](3,4-dichloro— phenyl)—1—tert-butylcarbamoylpiperidine A solution of 18 9; of the above product and 14 g of 4-benzylpiperidine in 40 ml of dimethylforma— mide is heated at 80°C for 3 hours. The dimethylforma— mide is then evaporated off, the residue is taken up in water and extracted with ether and the extract is washed with water, dried over Na2SO4 and concentrated under vacuum. The residue is purified by chromato- graphy on silica gel using CH2Cl2/CHJOH 100/3 (v/v) as the eluent. The pure fractions are concentrated under vacuum. m = 15 g.

D) 3-[2-(4-Benzylpiperidin-1—yl)ethy1](3,4-dichloro- phenyl)piperidine (-) dihydrochloride g of the above product dissolved in 75 ml of methanol, 60 ml of concentrated hydrochloric acid and ml of water are stirred at room temperature for 1 hour. The mixture is evaporated to dryness, the resi- due is taken up in 100 ml of methylene chloride and the product is precipitated in ether. The precipitate is filtered off, washed with ether and dried under vacuum. -59..

E) Compound 32 .6 g of BOP are added to a solution of 11 g of the above product, 6.09 g of triethylamine and 4.65 g of 3—isopropoxyphenylacetic acid in 100 ml of methylene chloride. The mixture is stirred at room temperature for 1 hour and evaporated to dryness and the residue is taken up in ethyl acetate, washed with water, dried over Na2SO4, filtered and concentrated under vacuum. graphy on silica gel using CH2Cl2/CHBOH 100/5 (V/v) as the eluent. vacuum, the hydrochloride is prepared in CH2Cl2 by the The residue is purified. by chromato- The pure fractions are concentrated under addition of ether saturated with hydrochloric acid, the mixture is evaporated to dryness, the residue is crys- tallized from isopropyl ether and the crystals are filtered off, washed with ether and dried under vacuum. m = 11.4 g.

M.p. = 1o5"c. [a]D2° = -2.9 (c = 1, CH3OH).

EXAMPLE 33 3—[2—(4-Benzylpiperidin—1-yl)ethyl]-3—(3,4-di- chlorophenyl)-l—(3-isopropoxyethyl)acetylpiperidine (+) Q =2H; Ar‘ = ;-T-q-z = -ficaz C1 0 Cl hydrochloride (1)1 Y’ N ;rx= 2;;)= 1; \__4/ -60..

The above compound 33, (+) enantiomer, is obtained by following the procedure of Example 32, using the (-) enantiomer of 3—(2—hydroxyethyl)—3—(3,4- dichlorophenyl)piperidine as the starting material.

M.p. = 105°C. [a]D2° = +3.0 (C = 1, CHBOH).

EXAMPLE 34 -[2-(4-Hydroxy—4—pheny1piperidin—1-yl)ethy1]- 3-(3,4-dichlorophenyl)benzoylpiperidine (-) hydro- chloride /‘T O“ ’ 7 7 " I 0 Cl A) 3—[2-(4-Hydroxyphenylpiperidinyl)ethyl]—3— (3,4-dichlorophenyl)—1—tert—butylcarbamoylpiperidine A solution of 0.9 g of 3-methanesulfonyloxy- ethyl—3-(3,4-dichlorophenyl)tert—butylcarbamoylpipe— ridine, prepared according to Example 32, step B), and 0.88 g of 4-hydroxy-4—phenylpiperidine in 3 ml of dimethylformamide is heated at 80°C for 2 hours. It is evaporated to dryness, the residue is taken up in water and extracted with AcOEt and the extract is washed with a saturated aqueous solution of Nacl, dried over MgSO4 and evaporated to dryness. The residue is purified by chromatography on silica gel using CH2Cl2/CHBOH 100/2 (v/v) as the eluent. The pure fractions are concentra- ted to give 0.8 g of an oil. _ 51 _ B) 3-[2-(4-Hydroxyphenylpiperidinyl)ethyl]—3- (3,4—dichlorophenyl)piperidine .8 g of the above product dissolved in 5 ml of methanol, 4 ml of concentrated hydrochloric acid and 1 ml of water is stirred for 1 hour at room temperature.

The mixture is then evaporated to dryness and the residue is used as such for the next step. m = 0.77 g.

C) Compound 34 .26 g of benzoyl chloride is added to a solu- tion of 0.77 g of the above product and 0.3 g of tri- ethylamine in 30 ml of methylene chloride. The reac- tion mixture is stirred for 1 hour at room temperature and evaporated to dryness and the residue is taken up in ethyl acetate, washed with water, dried over Na2SO4 and evaporated to dryness. The residue is purified by chromatography on silica gel using CH2Cl2/CH3OH 100/3 (V/V) trated and taken up in CH2Cl2 and the hydrochloride is as the eluent. The pure fractions are concen- prepared by the addition of ether saturated with hydro- chloric acid. The mixture is evaporated to dryness, the residue is crystallized from ether and the crystals are filtered off, washed with ether and dried under vacuum. m = 0.2 g.

M.p. = 176°C. [a]D2° = -32.0“ (c = 1, cH3oH). - 52 _ EXAMPLE 35 3-[2—(4-Hydroxy-4—phenylpiperidin-1—yl)ethyl]- 3—(3,4-dichlorophenyl)-l—benzoylpiperidine (+) hydro- chloride Ofi 2 2 2H a): Y N- = N—-;n1= ;n = ;p =1 ;Q = ; \_/ ; = ‘C ll c1 0 C1 The above (+) enantiomer is obtained by fol- lowing the procedure of Example 34, starting from 3-(2- hydroxyethyl)—3-(3,4—dichloropheny1)piperidine (-).

M.p. = 176°C. [a]D2° = +32.5° (c = 1, CHBOH).

EXAMPLE 36 N(a)-Methyl-3—[2—(4—benzylpiperidinium)- ethyl](3,4-dichlorophenyl)—1-(3-isopropoxyphenyl)- acetylpiperidine iodide Q.

N4 e<<:>>cH2 »»< A <3 A C) <3 I m=2;n=kp=1;Q=2H; X (I) :Ar—(CH2)x ;-T-(CH2)q—Z = -fi—CH2 C1 0 Cl A solution of 1 g of the product described in Example 14 in 10 ml of methyl iodide is stirred at room temperature for 24 hours. It is then concentrated under vacuum. The residue is chromatographed on silica gel using CH2Cl2/CHBOH 100/3 (V/V) as the eluent. The first product eluted corresponds to that in which the methyl located on nitrogen (b) of the 4-benzylpiperi- dine is in the axial position. m = 0.35 g.

C NMR spectrum: \ /C“3 /$\ .369 ppm EXAMPLE 37 N(e)-Methyl-3—[2—(4-benzyl-1—piperidinium)- ethyl]—3—(3,4-dich1orophenyl)—1-(3—isopropoxypheny1)- acetylpiperidine iodide /Q' /C”3 C) A C) CD I(D m=2;n=2;p=1HQ=2H; (1) :Ar-(CH2)x _ 64 _ ;-T- CH -Z= - - H O .

C1 O-1Pr C1 The product in which the methyl on nitrogen (b) of the 4-benzylpiperidine is in the equatorial position is obtained by following the procedure of Example 36 described above, collecting the second fraction eluted. m = 0.15 g. 13C NM spectrum: \\ //c“3 /E\ : 50 . 614 ppm _ 55 _ The quaternary ammonium salts described in Table V below are prepared by following the procedure of Examples 36 and 37 above.

TABLE V Q 0 / CD A G O 2 C1 C1 Example n“ Q’ (conforrnation) A 9 Z M.p.; °C IH C 2 Br‘ -O-iPr 124 £;E] (m CH2 Br‘ ~O-iPr 144 (w 40 -C2Hs (a) 1 - -O-iPr 116 41 -C2Hs <6) 1- 19: 122 42 -CH3 (a) 1~ -0C2H5 120 43 -CH3 (6) I ' -0C2H5 126 EXAMPLE 44 N(a)—Methyl—3—[2-(4-benzylpiperidinium)- ethyl]—3-(3,4—dichlorophenyl)(3—isopropoxyphenyl)— acetylpiperidine (-) chloride X Q’ CH3 (1) :Ar-(CH2)xA<: L = CH2 N/— ; 93 AG (9 C16 m=2;n=2;p=l;Q=2H; A,» ;-T-(CH2)q-Z = -|c'—cH2 C1 O O-iPr Cl A) Preparation of the iodide derivative A solution of 10 g of the product described in Example 32 in 50 ml of methyl iodide is stirred at room temperature for 2 hours. It is evaporated to dryness and the residue is chromatographed on silica gel using CHZC12/cH3oH 100/3 (v/V) mational isomer which is eluted first corresponds to as the eluent. The confor- that in which the methyl is in the axial position on nitrogen (b) of the 4-benzylpiperidine.

B) Preparation of the chloride derivative The iodide ion is then exchanged with the chloride ion by eluting the product on an Amberlite IRA68® ion exchange resin.

This gives 5.6 g of the quaternary ammonium chloride. 103°C. [a]D2° = -12.8” (c = 1, CHBOH).

‘ 'U II EXAMPLE 45 N(a)-Methyl[2-(4-benzylpiperidinium)— ethyl]-3—(3,4-dichlorophenyl)-l—(3—isopropoxypheny1)— acetylpiperidine (+) chloride / (I) : Ar-(CH2)x N— CH2 — ; (3 A C) <3 CH3 m=2;n=2;p=1;Q=2H; ; -T-(CH2)q-Z = —fi-CH2 C1 O 0-in CI .9 g of the expected quaternary ammonium salt are obtained by following an identical procedure to Example 44, starting from the product described in Example 33.

M.p. = 104°C. [a]D2° = +13.o° (c = 1, CH3OH).

EXAMPLE 46 N(e)—Methyl-3—[2-(4-benzylpiperidinium)- ethyl]—3-(3,4-dichlorophenyl)—l—(3—isopropoxyphenyl)- acetylpiperidine (-) iodide x CH3 QI N: N4 ; <3 (3 C) ICD (1) : Ar-(CH2)x m=2;n=2;p=1;Q=2H; _ 68 _ C1 C1 ;-T-(CH2)q-Z = -hi-CH2 The enantiomer in which the methyl on nitrogen (13) of the 4-benzylpiperidine is in the equatorial position is obtained by following the procedure of Example 44 A), collecting the second fraction eluted.

This gives 2.6 g of the quaternary ammonium salt.

°C. [a]D2° = -0.1 M.p. = EXAMPLE 47 (c = 1, CH3OH).

N(e)-Methyl[2-(4-benzylpiperidinium)— ethyl](3,4-dichlorophenyl)(3-isopropoxyphenyl)- acetylpiperidine (+) iodide X Q’ (1) ; Ar—(cH2)x3<3 L E9 CH /' 3 N-— . (3 C) 1 m=2;n=2gud;Q=2H; C1 C1 ; = 'fi'CH2 The expected product is obtained by following the procedure of Example 46, described in Example 33. starting from the product M.p. = 110°C. [a]D2° = +0.1 (C = 1, CH3OH).

EXAMPLE 48 3-[2—(4-Benzyl—1-piperidinium)ethyl]—3-(3,4- dichlorophenyl)(3—isopropoxyphenyl)acety1piperidine N-oxide X (I) : Ar-(CH2)x / / m=2;n=2m=1; ;-T-(CI-I2)q-Z = -E-CH2 Cl 0 Cl g of the free base of the compound of Example 14 are dissolved in 20 ml of tetrahydrofuran. 1.1 g of metachloroperbenzoic acid are added and the reaction mixture is stirred for 2 hours at room temperature. It is concentrated under vacuum to a volume of 5 ml and the residue is diluted in 10 ml of methylene chloride.

The solution is washed twice with a saturated solution of NaHCO3, decanted, dried over MgSO4 and concentrated under vacuum. The residue is chromatographed on silica gel using CH2Cl2/CHBOH 100/5 (v/V) as the eluent. The pure product fractions are concentrated under vacuum and the residue is crystallized from isopropyl ether. m = 1.47 g.

M.p. = 135°C.

EXAMPLE 49 3-[2—(4—Benzylpiperidinyl)ethyl]-3—(3,4- dichlorophenyl)piperidine dihydrochloride Synthesis intermediate of formula (II).

CH2/j\N ‘(CH2)2 N-H C1 C1 A) 4—(4—Benzylpiperidinyl)-2—(3,4-dichlorophenyl)— butyronitrile .5 g of sodium amide are added in small portions to a solution of 94 g of 3,4-dich1oropheny1- acetonitrile in 500 ml of anhydrous ether. The mixture is subsequently stirred for 1 hour at room temperature It is cooled to 0°C and a solution of 129 g of 2—(4-benzylpiperidinyl)- and then for 3 hours under reflux. —chloroethane in 300 ml of ether is added dropwise.

The reaction mixture is allowed to return to room tem- perature and then refluxed for 3 hours. It is cooled and poured into 600 ml of water and the organic phase is decanted, washed with water and extracted twice with 500 ml of a 15% solution of HCl. stirred and the product precipitates in the form of the The aqueous phase is hydrochloride. This is filtered off, washed with water and dried under vacuum. The residue is recrystallized from 600 ml of isopropanol to give 95 g of crystals.

The product is taken up in water and the solu- tion is neutralized with a solution of NaOH. The mix- _ ture is extracted with ether and the extract is washed with water, dried over Na2SO4 and evaporated to dryness to give 87 g of an oil.

B) Ethyl 7-[2-(4—benzylpiperidin-l-yl)ethyl]—7-cyano- 3,4—dichlorobenzylbutanoate A solution of 87 g of the product described above, 28 g of ethyl acrylate and 2.5 ml of triton B in It is dried over Na2S04 and evaporated to dryness to give 109.5 g ml of dioxane is heated for 24 hours at 80°C. cooled, taken up in ether, washed. with. water, of an oil.

C) 5-[2-(4-Benzylpiperidin—1-yl)ethyl]—5-(3,4-dichloro- phenyl)piperidone A solution of 100 g of the product prepared above in 1.5 liters of ethanol is hydrogenated at 60°C and at atmospheric pressure in the presence of Raney Ni. When the volume of hydrogen has been consumed, the catalyst is filtered off, the filtrate is evaporated to dryness and the residue is taken up in methylene chlo- ride, washed with water and dried over Na2SO4. The hydrochloride is then formed and recrystallized from 220 ml of isopropanol. The crystals are filtered off and dried under vacuum. The product is taken up in water, neutralized with a solution of NaOH and extrac- ted with ether and the extract is dried over Na2SO4 to give 44 g of an oil.

D) Compound 49 A solution of 44 g of the above product in 200 ml of tetrahydrofuran is added dropwise to a suspension of 9.4 g of lithium aluminum hydride in 250 ml of heated to 60°C. tinued for 3 hours. ml of water, 10 ml of 4 N NaOH and 30 ml of water are added in succession. filtered off, tetrahydrofuran, Refluxing is con- The mixture is cooled in ice, and The inorganic material is the filtrate is evaporated to dryness, _ 72 _ the residue is taken up in methylene chloride and the hydrochloride is prepared. The mixture is evaporated to dryness, the residue is triturated in pentane and the product is filtered off and dried under vacuum. m=35g.

M.p. = 170°C.

EXAMPLE 50 -[2-(4-Benzylpiperidinyl)ethyl]—3-(3,4- dichlorophenyl)(2-phenylmethoxy)acetylpiperidine hydrochloride Diastereoisomer of lower polarity.

(D; Y N—= CH2 N——nn=2 ;n=2; p=1; C1 0 OCH3 Cl .5 g of the diamine prepared in Example 49, 1.06 g of triethylamine, 0.55 g of (i)-a-methoxyphenyl- acetic acid and 1.6 g of BOP in 25 ml of methylene chloride are stirred for 2 hours. The mixture is evaporated to dryness and the residue is taken up in ethyl acetate, washed with water, dried over Na2SO4 and evaporated to dryness. The residue is purified by chromatography on silica gel using CH2C12/CHBOH 100/0.5 (v/v) as the eluent. The product which is eluted first The fractions are concentra- the hydro- is the expected product. ted under vacuum and taken up in CH2Cl2, chloride is prepared, the mixture is evaporated to dry- ness, the residue is triturated in pentane and the product is filtered off and dried under vacuum. m = 0.50 g.

M.p. = 134°C.

EXAMPLE 51 -[2—(4—Benzylpiperidin—1—yl)ethy1]—3—(3,4- dichlorophenyl)(2—pheny1methoxy)acetylpiperidine hydrochloride Diastereoisomer of higher polarity.

Q=2H;AI'= ; -T—(CH2)q-Z = -fl}-$H The diastereoisomer of higher polarity is obtained by following the procedure of Example 50, using a 100/2 (V/v) CH2Cl2/CHBOH mixture as the eluent.

The hydrochloride is prepared in methylene chloride, the mixture is evaporated to dryness and the residue is taken up in pentane. m = 0.50 g.

M.p. = 118°C.

The pairs of diastereoisomers 52/53, 54/55 and 56/57 described in Table VI below are prepared by fol- lowing the procedure of Examples 50 and 51.

The reactant a—hydroxyisopropoxyphenylacetic acid used to prepare the compounds of Examples 56 and -74.. is a novel product and can be prepared as indicated below. a—Hydroxyisopropoxyphenylacetic acid Step 1 g of KZCOB and then 60 ml of 2-iodopropane are added to a solution of 50 g of 3—hydroxybenzalde- hyde in 250 ml of DMF.

The reaction mixture is heated at 50°C for 18 hours. The mixture obtained is poured into 2.5 1 of water and extracted with ether, the extract is washed with a dilute solution of NaOH and then water and dried over MgS04 and the solvent is evaporated off to give 53.5 g of a liquid residue.

S e 2 g of the product obtained according to step 1 above are added to a solution of 38 g of sodium bisulfite in 120 ml of water. The mixture is stirred for 20 hours and a solution of 44.2 g of potassium cyanide in 90 ml of water is then added at 20°C.

After 2 hours the mixture is extracted with ether, the extract is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum.

The residue is chromatographed on silica gel using heptane/ethyl acetate 100/30 (v/V) as the eluent. 57 g of product are recovered in the form of an oil.

Step 3 g of the product obtained according to step 2 above are added to 50 ml of water and 50 ml of con- centrated Hcl. The mixture is heated at 110°C for 1 hour. After cooling, it is extracted with ether and the extract is washed with water. The acid is extrac- ted with a dilute solution of NaOH. is acidified and extracted with ether, the extract is The aqueous phase dried over MgSO4 and the solvents are evaporated off.

The acid is crystallized from a 1/2 (v/v) toluene/ pentane mixture. m = 27.5 g.

TABLE VI Z1 Z .I{C1 C1 C1 Example n" 21 2 Physical property M.p.; C —CH3 H diastereoisomer of 112 lower polarity -CH3 H diastereoisomer of 120 higher polarity —C2H5 H diastereoisomer of 124 lower polarity -C2H5 H diastereoisomer of 124 higher polarity -OH -O—iPr diastereoisomer of 120 lower polarity —OH —O—iPr diastereoisomer of 125 higher polarity -76..

EXAMPLE 58 —[2-(4—Benzylpiperidinyl)ethyl]—3—(3,4- dichlorophenyl)[2—(3-chlorophenyl)hydroxy]acety1- piperidine (+) hydrochloride ;-T-(CH2)q-Z = —C-(IJH A1”: C1 C1 A solution of 0.67 g of 3-[2-(4—benzylpipe- ridin-l-yl)ethyl](3,4-dichlorophenyl)piperidine (—) dihydrochloride described in Example 32, step D, 0.17 g of triethylamine, 0.32 g of S(+)-a-hydroxychloro- phenylacetic acid and 0.82 g of BOP in 10 ml of methy- lene chloride is stirred for 2 hours. It is evaporated to dryness and the residue is taken up in ethyl ace- tate, centrated under vacuum. washed with water, dried over Na2SO4 and con- The residue is purified by chromatography on silica gel using CH2Cl2/CHBOH 100/1.5 (v/v) as the eluent. The pure fractions are concen- trated under vacuum and taken up in methylene chloride, the hydrochloride is prepared, the mixture is evapora- ted to dryness and the residue is taken up in pentane.

The product is filtered off, washed with ether and dried under vacuum. m = 0.40 g.

M.p. = 122”c. [a]D2° = +68.4° (c = 1, CH3OH).

EXAMPLE 59 -[2-(4-Benzylpiperidin-l—y1)ethyl]—3-(3,4- dichlorophenyl)—l—[2—(3—chlorophenyl)—2-hydroxy]acety1- piperidine (-) hydrochloride (1); Y N—= 2 N——,m=2,n=2,p=1, H \__/ Q = 2H-,AII = ;-T-(CH2)q-Z= -C-CH OH c1 0 C1 The expected product is obtained by following the procedure of Example 58, starting from 3-[2-(4- benzylpiperidinyl)ethyl](3,4-dich1orophenyl)pipe- ridine (+) prepared according to Example 32, step D, from 3-(2-hydroxyethyl)(3,4-dichlorophenyl)piperi- dine (-) described in step C of the preparation of the optically pure amino alcohol, and with R(-)—a-hydroxy- 3-chlorophenylacetic acid. m = 0.50 g.

M.p. = 122°C. [a]D2° = —74° (c = 1, CH3OH).

EXAMPLE 60 -[2-(4-Benzylpiperidin—l-yl)ethyl]—3—(3,4- dichlorophenyl)[2-(3-chlorophenyl)hydroxy]acetyl- piperidine (-) hydrochloride -78..

Q : A1’. : ; = -lC‘_$H H C1 0 C1 C1 A solution of 0.67 g of 3-[2—(4-benzylpipe— ridin-1—yl)ethyl]—3—(3,4-dichlorophenyl)piperidine (-), 0.32 g of R(-)-a-hydroxychlorophenylacetic 0.17 g of triethylamine and 0.82 g of BOP in 50 ml of methylene chloride is stirred at room temperature for 2 acid, hours. The expected product is obtained by subse- quently following the procedure of Example 58. m = 0.40 g.

M.p. = 128°C. [a]D2° = -34“ (c = 1, CH3OH).

EXAMPLE 61 —[2-(4-Benzylpiperidinyl)ethyl]—3-(3,4- dichlorophenyl)[2—(3-chlorophenyl)-2—hydroxy]acetyl- piperidine (+) hydrochloride Q = AI-' = = 'C'CH OPI Cl 0 C1 The expected product is obtained by following the procedure of Example 58, starting from S(+)-a- hydroxychlorophenylacetic acid and 3-[2-(4-benzyl- piperidinyl)ethyl]—3-(3,4-dichlorophenyl)piperidine (+) prepared according to Example 32, step D, from 3-(2-hydroxyethyl)(3,4-dichlorophenyl)piperidine (—) described in step C of the preparation of the optically pure amino alcohol. m = 0.4 g.

M.p. = 127°C. [a]D2o = +35“ (c = 1, CHBOH).

Claims (2)

CLAIMS A compound of the formula (CH )n Q y (b)N‘(CH2)_—T/ ZY Ar’ (I) in which: - Y is - either a group Cy—N or Cy- CH2—N, in which: Cy is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from: a halogen atom, a hydroxyl, a C1-C4 alkoxy, a C1-C4 alkyl, a trifluoromethyl, said substituents being identical or different; a C3-C7 cycloalkyl group; a pyrimidyl group or 23 pyridyl gI‘OUp,' - or a group X I Ar"(CH2);-C in which Ar is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from: 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; x is zero or one; X is a hydrogen, a hydroxyl, a C1-C4 alkoxy; a C1- C4 acyloxy; a carboxyl; a C1-C4 oarbalkoxy; a cyano; a in which the groups X1 a C1-C4 alkyl, or else -(X1)2 forms, -N(X1)2 group, independently are hydrogen, a C1-C4 hydroxyalkyl, a C1-C4 acyl, with the nitrogen atom to which it is bonded, a heterocycle selected from pyrrolidine, piperidine or morpholine; a —S—X2 group, in which X2 is hydrogen or a C1-C4 alkyl group; or else X forms a double bond with the carbon atom to which it is bonded and with the adjacent carbon atom in the heterocycle; m is 2 or 3; Ar‘ is a phenyl which is unsubstituted or monosubstituted or polysubstituted by 21 substituent selected from: a halogen atom, a trifluoromethyl, a C1-C4 alkoxy, a C1-C4 alkyl, said substituents being identical or different; a thienyl; a benzothienyl; a naphthyl or an indolyl; n is O, 1, 2 or 3; p is 1 or 2, and when p is equal to 2, n is then equal to 1 and Q is two hydrogen atoms; Q is oxygen or two hydrogen atoms; T is a group selected from ——c—— and H 0 q is O, 1, 2 or 3; Z is a phenyl which is unsubstituted or monosub- stituted or polysubstituted by a substituent selected from halogen, CN, OH, NH2, NH—CO-NH2, N02, CONH2, CF3, C1—C1O alkyl, alkenyl containing 2 to 10 carbon atoms, alkynyl containing 2 to 10 carbon atoms, cycloalkyl containing 3 to 8 carbon atoms, bicycloalkyl containing 4 to 11 carbon atoms, hydroxyalkyl containing 1 ‘U3 5 carbon atoms, alkoxy containing 1 to 10 carbon atoms, alkoxyalkyl containing 2 to 10 carbon atoms, alkoxyalkoxyalkyl containing 3 ‘U: 10 carbon atoms, alkoxyalkoxy con- taining 2 to 10 carbon atoms, alkenyloxy containing 2 to 10 carbon atoms, alkenyloxyalkyl containing 3 to 35 _82_ 10 carbon atoms, alkynyloxy containing 2 to 10 carbon atoms, alkynyloxyalkyl containing 3 to 10 carbon atoms, cycloalkoxy containing 3 ‘U3 8 carbon atoms, alkylthio containing 1 to 10 carbon atoms, alkyl— thioalkyl containing 2 to 10 carbon atoms, acylamino containing 1 to 7 carbon atoms, acylaminoalkyl con- taining 2 to 8 carbon atoms, acyloxy containing 1 to 6 carbon atoms, alkoxycarbonyl containing 2 to 5 carbon atoms, cycloalkoxycarbonyl containing 4 to 8 carbon atoms, alkylaminocarbonylamino containing 2 to 4 carbon atoms, dialkylaminocarbonylamino containing 3 to 7 carbon atoms, (pyrrolidin—l—yl)carbonylamino, cycloalkylaminocarbonylamino containing 4 to 8 carbon atoms, alkylaminocarbonylaminoalkyl containing 3 to 9 carbon atoms, dialkylaminocarbonylaminoalkyl con- taining 4 to 11 carbon atoms, (PYrrolidin—l- yl)carbonylaminoethyl, (piperidin—l—yl)carbonylamino— ethyl, alkoxycarbonylaminoalkyl containing 3 to 12 carbon atoms, cycloalkoxycarbonylaminoalkyl con- taining 5 to 12 carbon atoms, carbamoylalkyl containing 2 to 5 carbon atoms, alkylaminocarbonyl— alkyl containing 3 to 9 carbon atoms, dialkylamino— carbonylalkyl carbon containing 4 to 11 atoms, (pyrrolidinyl)carbonylmethyl, (piperidin—1—y1)— carbonylmethyl, (piperidin—l—yl)—carbonyethyl, cyclo- alkylaminocarbonylalkyl containing 5 to 12 carbon atoms, alkylaminocarbonylalkoxy containing 3 to 10 carbon atoms, dialkylaminocarbonylalkoxy containing 4 to 10 carbon atoms, (piperidin—1—yl)carbonylmethoxy, cycloalkylaminocarbonylalkoxy containing 5 to 11 carbon atoms, cycloalkylaminocarbonylaminoalkyl containing 5 to 12 carbon atoms; a naphthyl or indenyl group in. which one or‘ more bonds can be hydrogenated, it being possible for said groups to be unsubstituted or monosubstituted or polysubstituted by a halogen, an alkyl, phenyl, cyano, hydroxyalkyl, hydroxyl, oxo, alkylcarbonyl- amino, alkoxycarbonyl, thioalkyl group, in which the alkyls are C1-C4 alkyls; a pyridyl group; a thiadiazolyl, indolyl, indazolyl, imidazolyl, benzimidazolyl, quinolyl, benzotriazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benziso- thiazolyl, isoquinolyl, benzoxazolyl, benzoxazinyl, benzodioxinyl, isoxazolyl, pyranyl, pyrazolyl, benzopyranyl, thiazolyl, thienyl, furyl, chromenyl, isobenzofuranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, phthalazinyl, quinazolinyl, acridinyl, isothiazolyl, isochromanyl, chromanyl, in which one or more double bonds can be hydrogenated, it being possible for said groups to be unsubstituted or" monosubstituted or polysubstituted by an alkyl, phenyl, cyano, hydroxyalkyl, hydroxyl, alkylcarbonyl- in which the -C=O-, —(CH2)q-Z can also be a benzyl group substituted on amino, alkoxycarbonyl, thioalkyl group, alkyls are C1-C4 alkyls; or else when T is the —CH— by a hydroxyl, a C1-C4 alkoxy, a Cl-C4 alkyl and unsubstituted or substituted on the aromatic ring by a halogen, a trifluoromethyl, a C1-C4 alkyl, a hydroxyl, a C1-C4 alkoxy; or, if appropriate, one of its salts with mineral or organic acids, or, when X | Y = Ar"(CH2r;-C its quaternary ammonium salts formed with the derivative formed with this same nitrogen atom. one of nitrogen (b) of piperidine, or an N—oxide 2. An optically pure compound according to claim 1, of the formula */(CHZL, Q Y (b)N’(CH);— \ , 2 T\(CH2)p/N—T-(cH2)q—z Ar’ (I*) in which: - "*" means that the carbon atom marked with this symbol has a determined (+) or (—) absolute configuration, — Y, m, Ar’, n, p, Q, T, q and Z are as defined in claim 1, or one of its salts with mineral or organic acids, or, with nitrogen atom (b), one of its quaternary ammonium salts or an N—oxide derivative. 3. A compound according to claim 1 or claim 2, in which Z is a phenyl group which is unsubstituted or monosubstituted or disubstituted by a halogen or an alkoxy; a naphthyl group. 4. A compound according to one of claims 1 to 3 , of formula (I) or (I*) / \ _ /(cH2X§T§5Q Y (b)N (CH2): \ _ _ Z \_/ (CH2)/N T (CH2):- P Ar’ (I) /—\ */(cH2>n\]¢Q Y (b)N‘(CH f—' \ , 2 ... T\(CH )/N—T“(CH2)q—Z 2 " Ar’ in which: Y is a group 1‘ Ar-‘(CH2r;’C in which Ar, x and X are as defined in claim 1; — m, Ar‘, n, p, Q, T, q and Z are as defined in claim 1; in the form of a quaternary ammonium salt or an N—oxide derivative, 5 characterised in that the group X is then represented by the group 9 X 0 / Ar—(CHZ) N— GD 10 or the group X /Q Ar*"(CH2)x g£‘" AG in which: Q’ is a C1-C5 alkyl group or a benzyl group, and 15 - N9 is an anion selected from chloride, bromide, iodide, acetate, methanesulfonate or paratoluene— sulfonate. 5. A method of preparing the compounds of formula (I) according to claim 1, characterised in that: 20 — a) a compound of the formula E—(CH) /“’“2’n\%Q 2" \ /N—H (CH2)? Ar: (II) is treated in which m, Ar’, n, p and Q are as 25 defined in claim 1 and E is a hydroxyl or, if appropriate, an O—protected group or a group 20 Y N-- \_/ in which Y is as defined in claim 1, it being understood that: when Y is the group ‘f Ar“(CH2fi:‘C in which X is a hydroxyl, this hydroxyl can be protected, either with a functional derivative of an acid of the formula HO"lCl2—(CH2):-Z (III) 0 in which q and Z are as defined in claim 1, when a compound of formula (I) in which T is -CO— is to be prepared, or with a halogenated derivative of the formula I-Ial*"(CH2) —z (IV) CV1 in which q and Z are as defined above and where Hal is a halogen when a compound of formula (I) in which T is —CH2— is to be prepared, to give the compound of the formula (CH )n Q E‘(CH2)_—T: 2 Y (V) (CH2 )p/N*’T-(CH2 )q— z Ar’ - b) then, when E is an O—protected group, the O- protecting group is removed by reaction with an acid, — c) the resulting alcohol of the formula 5 HO (CH) /“”’2’n\%" ‘ “ (VI) 2 In \ __ __ __ f (CH2):/N T (CH2)q Z Ar’ is treated with methanesulfonyl chloride, — d) the resulting mesylate of the formula 10 “' ‘ “ VII CH SO 0 (CH ) /(CH2fi>T;;Q ( ) 3 2 2 m \ _ __ _: T (CH2):/N T (CH2)q Z Ar‘ is reacted with a secondary amine of the formula Y NH (VIII) 15 in which Y is as defined above, and — e) after deprotection of the hydroxyl represented by X, if appropriate, the resulting product, if 20 desired, is converted to one of its salts with mineral or organic acids, or to one of its quaternary ammonium salts formed with nitrogen (b) of the piperidine, or to an N—oxide derivative formed with this same nitrogen atom. 25 6. A compound of the formula _8g_ (CH ) Q / 2 n E“( CH2 )m—T\ V N“H (ca, ),,/ Ar’ (II) in which m, Ar‘, n, p and Q are as defined in claim 1 and E is a hydroxyl or, if appropriate, an O—protected group or a group Y N‘— \__/ in which Y is as defined in claim 1, provided Q is oxygen: — when E = OH or (Cl—C6)alkylcarbonyloxy, m = 2 or 3, Ar‘ is a phenyl which is substituted by a (C1- C4)alkoxy, n = 3 and p = 1; 1 and unsubstituted or (C1- — when E = (Cl—C4)alkylcarbonyloxy, m = 2, n = Ar’ is a phenyl which is monosubstituted or polysubstituted by a C4)alkyl, a (C1—C4)alkoxy or a halogen; provided that when E = p = 1, Ar‘ monosubstituted or polysubstituted by a (C1—C4)alkyl, OH or a (C1—C4)alkoxy, m = 2, is a phenyl which is unsubstituted or a (Cl—C4)alkoxy or a halogen, n is different from 1, OH, Q = is different from an unsubstituted phenyl. provided that when E = 2, Ar‘ 2H, m = 2, n = 1, p = or one of its salts with mineral or organic acids. 7. A compound of the formula / E‘(CI-12):‘ _ _ __ (v) T\(CH2)p/N T (CH2)q z Ar‘ _89... in which E is a hydroxyl, an O-protected group and m, Ar’, n, p, Q, T and Z are as defined in claim 1 provided that when E = OH, Q = 2H, m = 2, n = 1, p = 2, T = -CH2-, q = O and Z = phenyl, Ar’ is different 5 from an unsubstituted phenyl, and provided that when E = OH, Q = 2H, m = 2, n = 1 1 . P = , T = -CH2—, q = O and Z = phenyl, Ar’ is different from a phenyl which is unsubstituted or monosubstituted or polysubstituted by a (C1—C4)alky1, 10 a (C1—C4)alkoxy or a halogen, and provided that when E = OH or (C1—C6)alyklcarbonyloxy, Q = 2H, m = 2 or 3, n = 3, p = 1, T = —CH2—, q = O, 1, 2 or 3 and Z is an aryl group, Ar‘ is different from a phenyl which is substituted by a (C1- 15 C4)alkoxy, or one of its salts with mineral or organic acids. 8. A compound according to claim 7, of the formula / ( CH2 ),,\fQ Ho-(CH );- (VI) 2 T\(CH2)p/N-T-(cH2)q——z Ar‘ 20 in which m, Ar’, Q, n, p, T, q and Z are as defined in claim 1, provided that when Q = 2H, m = 2, n = 1, p = 2, T = -CH2—, q = O and Z = phenyl, Ar’ is different from an 25 unsubstituted phenyl, and provided that when Q = 2H, m = 2, n = 1, p = 1 T = -CH2—, q = O and Z = phenyl, Ar’ is different from a I phenyl which is unsubstituted or monosubstituted or polysubstituted by a (C1-C4)alkyl, a (C1-C4)alkoxy or 30 a halogen, and provided that when Q = 2H, m = 2 or 3, n = 3, p = 1, T = -CH2-, q = O, 1, 2 or 3 and Z is an aryl group, _90_ Ar’ is different from a phenyl which is substituted by a (Cl-C4)alkoxy, or one of its salts with mineral or organic acids. 9. A compound of the formula 5 "“ ‘ "“ VII CH so 0 (CH ) /(CH2fi>T;;Q ( ) 3 2 2 In \ _ _ __ T (CH2):/N T (CH2)q Z Ar‘ in which m, Ar‘, n, p, Q, T, q and Z are as defined in claim 1, or one of its salts with mineral or 10 organic acids. 10. A compound of the formula 0 ( ) */(CH2)n Q H _ CH2 —— (I-1*) “' \ N—H T,/ Ar’ 15 in which m, Ar’, n and p are as defined in claim 1 and Q represents 2 hydrogen atoms, said compound being in optically pure form, provided that when m = 2 or 3, n = 3 and p = 1, Ar‘ is different from a phenyl substituted by a C1-C4 alkoxy. 20 11. A compound of the formula */(CH2X§T;§Q G-o- ( CH, >,,—T (v*) \(CH2):,N“T‘"(CH2);-Z Ar’ in which G is hydrogen or a methanesulfonyl group, 25 m, Ar‘, n, p, q, T and Z being as defined in claim

1 and Q represents 2 hydrogen atoms, said compound being in optically pure form, provided that when G is hydrogen, m = 2 or 3, n = 3, p = 1 and Z is an 3 aryl group, Ar’ is different from a phenyl substituted by a C1-C4 alkoxy. A pharmaceutical composition containing, as the active principle, a compound according to any one of claims 1 to 4, or one of its pharmaceutically acceptable salts. A pharmaceutical composition according to claim 12, in the form of a dosage unit, in which the active principle is mixed with at least one pharmaceutical excipient. A composition according to claim 12 containing from

2.5 to 1000 mg of active principle. Compounds according to any one of claims 1 to 4, in which A’ and/or Z is/are a phenyl group which is monosubstituted or polysubstituted by a chlorine or fluorine atom. characterised in (III), A method according to claim 5, that in the compound of formula E is a tetrahydropyran-2—yloxy group. A compound according to claim 6 or 7, in which E is a tetrahydropyran—2-yloxy group. A compound of formula (II) according to claim 6, selected from: — 5-Tetrahydropyranyloxypropyl—5-(3,4—dichloro— phenyl)—piperidinone, — 3-Tetrahydropyranyloxypropyl-3—(3,4—dichloro— phenyl)—piperidine, and — 3—(2—Hydroxyethyl)—3-(3,4-dichlorophenyl)— piperidine. An of selected from: optically pure compound formula (II*) according to claim 10, — 3—(2—Hydroxyethyl)—3-(3,4-dichlorophenyl)— piperidine (+), and - 3-(2-Hydroxyethyl)(3,4-dichlorophenyl)— piperidine (—). A compound of the formula (I) according to claim 1, or an optically pure compound of the formula (I*) according to claim 2, or a compound of the formula (11) according to claim 6, or a compound of the formula (V) according to claim 7, or a compound of the formula (VII) according to claim 9, or a compound of the formula (II*) according to claim 10, or a compound of the formula (V*) according to claim 11, or an optically pure compound of formula (II*) according to claim 19, substantially as herein described in the Examples. A method according to claim 5 of preparing a compound of formula (I) as defined in claim 1, substantially as herein described. A pharmaceutical composition according to claim 12, substantially as herein described. MACLACHLAN & DONALDSON, Applicants’ Agents, 47 Merrion Square, DUBLIN 2.