NZ245411A - Aromatic substituted amines, amides and ureas - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £45411 Pr.

Co;i.H Clic<f • ..VA;.',?. JI , ■. f ' f. tv., j.v:*'V.U-*. V,u\ .... ^ 6 OCT 1993 '.373 Punl,^ P.O. JCv.r:> «. • ". c. r :: o:,r /7:c:V. r ^(P.;. i f. .V. »' !~1 .vi'c f ,c;' ."If. \*0',is't; i Under the provisions of Rego- ! taiion 23 (1) the i-uhj, SpftOiflcation has been ants-dated /» WW ' -| ..Nfcgw.cuxj&i. 19 3, » JC* ij T,r, r* * * *X * * Patents Form No. 5 This is a divisional out of application number 235985 dated 6 November 1990 CHANGE OF NA!/it OF APPLICANT Cl ( Scit'scb , $2 , r^i2 PV^-k'^/, "ISbo? NEW ZEALAND PATENTS ACT 195 3 COMPLETE SPECIFICATION INTERMEDIATES USEFUL IN THE PREPARATION OF AROMATIC AMINE COMPOUNDS WE, SANOFI, a French Company of 40, Avenue George V, 75008 Paris, FRANCE, hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by page la) The present invention relates to intermediates useful in the preparation of aromatic derivatives substituted by an amino group and by various ester, amine or amide functional groups, and their enantiomers.

The aromatic amine compounds are the subject of New Zealand Patent Specification No. 235985, from which this application has been divided. The description given in NZ 235985 is substantially repeated here, for the sake of completeness.

NZ235985 discloses a method of obtaining the compounds, which can be enantioselective, and the use of the compounds in compositions for therapeutic use and rr.cre particularly in pathological phenomena involving the neurokinin system, such as: pain (D. REC-CLI et al., Life Sciences, 1937, 1CS-117), allergy and ir.f lammation (J. 2. MORLAY et al. , Life Sciences, 1987, 41. 527-544), circulatory insufficiency (J. LOSAY et al., 1S7", Substance P, Von Suler, U.S. and Psr.now ed. , 237-293, Raven Press, New York), gastrointestinal disorders (D. F.EGOLI et al. , Trends Pharmacol. Sci. , 19S5, 431-484) and respiratory disorders (J. MIZRAHI et al., Pharmacology, 1982, 25. 39-50).

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

Neurokinin receptors have been recognized on numerous preparations and are currently classed in three types: NKi, NK2 and NK3. Wherea3 the majority of the preparations studied hitherto have several types of receptors, such as guinea-pig ileum (NKi, NK2 and NK3), some of them are said to possess only one type, 3uch as dog carotid artery (NKi), rabbit pulmonary artery devoid of endothelium (NK2) and rat portal vein (NK3) (D. REGOLI et al., Trends Pharmacol. Sci., 1988, 2, 290-295 and Pharmacology, 1989, 2fi, 1-15).

The recent synthesis of selective agonists has (followed by page 2) mads it possible zo characterize the various receptors more precisely. Thus [Sar3,Met-(02)11]SP, [Nle10 ] NXA4-10 and [MePhe7]NK3 are said to have a selectivity for the NX:., NK2 and NK3 receptors respec- 05 tively (a.v. D. REGOLI, 1988 and 1989, cited above).

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

Thus, according to one of its features, NZ 235985 relates to aromatic amine derivatives of the formula \ r\ ? ? Ar - C - Y S' - (CH2)a - C - CH2 - M - T -Z ...

\ / (I) « ■ « ni in which: - m is 2 or 3; - Ar and Ar' independently are a thienyl group; a phenyl group which is unsubstituted or mono- or di- substituted by a halogen atom, preferably a chlorine or fluorine atom, loy a Ci—C3 alley 1, by a trifluoro-methyl, by an alkoxy in which the alkyl is C1-C3, by a hydroxy1 or by a methylenedioxy; or an imidazolyl group; it also being possible for Ar' to be a benzo- thienyl group which is unsubstituted or substituted by a halogen, preferably by a chlorine or fluorine atom; a naphthyl group which is unsubstituted or substituted by a halogen, preferably by a fluorine atom; a biphenyl group; or an indolyl which is unsubstituted or substituted on the nitrogen by a benzyl group; - X is hydrogen; X' is hydrogen or a hydroxyl group or is joined to X" below to form a carbon-carbon bond, • or X and X' together form an oxo group or a di-alkylaminoalkoxyimino group of the formula =N-0-( CH2)p-Am, in which ? is 2 or 3 and Am is a dialkylamino group, it being possible for each alky! so contain from 1 to 4 carbon atoms; Y is a nitrogen atom or a group C(X"), in which X" is hydrogen or forms a carbon-carbon bond with X'; Q is hydrogen, a C1-C4 alkyl group or an aminoalkyl group of the formula -(CH2)«a-Am', in which q is 2 or 3 and Am' is a piperidino, 4-benzylpiperidino or dialkylamino group, it being possible for each alkyl to contain from 1 to 4 carbon atoms; R is hydrogen, a methyl group or a group (CHz)n-L, in which n is an integer from 2 to 6 and L is hydrogen or an amino group; T is a group selected from W being an oxygen or sulfur atom; and Z is either hydrogen, or M or OM when T is the group -C(=0)-, or H when T is the group -C(=W)-NH-, M being hydrogen; a linear or branched C1-C6 a-lkyl; a phenylalkyl in which the alkyl group contains from 1 to 3 carbon atoms ar.d which is unsubstituted or mcno-or poly-substituted on the aromatic ring by a halogen, a hydroxyl, an alkoxy having 1 to 4 carbon atoms or an alkyl having 1 to 4 carbon atoms; a pyridyl-alkyl in which the alkyl group contains from 1 to 3 carbon atoms; a naphthylalkyl in which the alkyl group contains from 1 to 3 carbon atoms; a pyridyl-thioalkyl in which the alkyl group contains from 1 to 0 W and r- 3 carbon atoms; a styryl; a l-methylimidazol-2-yl-thioalkyl in which the alkyl group contains from 1 to 3 carbon atoms; a l-oxopnenyl-3-indan-2-yl; or an unsubstituted or mono- or poly-substituted aromatic 05 or heteroaromatic group; or to one of their salts with mineral or organic acids.

The salts of the compounds of formula (I) according to NZ 235985 include those with mineral or organic acids which permit a suitable 10 separation or crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, for example a mandelic or camp'nosulfonic acid, as well as those which form phar-maceutically acceptable salts such as the hydro-15 chloride, hydrobromide, sulfate, hydrogensulfate, di-hydrogenphosphate, methanesulfonate , meshyIsulfate, maleare, fumarate, nap'nthaIene-2-sulf onate, glycolate, gluconate, citrate and isethionate.

In particular, in formula (I), Z is a mono-, 20 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 25 phenyl group which can be unsubstituted or may contain one or more substituents.

When Z is a phenyl group, this can preferably be mono- or di-substituted, especially in the 2,4-positions, but also for example in the 2,3-, 4,5-, 3,4-30 or 3,5-positions; it can also be trisubstituted, especially in the 2,4,6-positions, but also for example in the 2,3,4-, 2,3,5-, 2,4,5- or 3,4,5-positions, tetrasubstituted, for example in the 2,3,4,5-positions, or pentasubstituted. The substituents of the phenyl 35 group can be: F; CI; Br; I; CN; OH; NH2; NH-CO-NH2; NOs; CCNH2; C?3; C1-C10 alkyl, preferably C1-C4 alkyl, methyl cr ethyl being preferred, as well as, for example, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or n-per.tyl, hexyl or n-hexyl, heptyl or n-heptyl, octyl or n-octyl, nonyl or n-nonyl or decyl or n-decyl; alkenyl containing 2 so 10 carbcr. atoms, preferably 2-4 carbon atoms, for example vir.yl, ally!, prop-l-enyl, isopropenyl, butenyl or but-1-en-l-, -2-, -3- or -4-yl, but-2-en-l-yl, bus-2-en-2-yl, per.senyl, hexenyl or decenyl; alkynyl containing 2 to 10 carbon atoms, preferably 2-4 carbon atoms, for example ethynyl, prop-l-yn-l-yl, propargyl, butynyl or but-2-yn-l-yl, pentynyl or decynyl; cycloalkyl containing 3 to 8 carbon atoms, preferably 5 or 6 carbon atoms, cyclopentyl or cyclohexyl being preferred, as well as, for example, cyclopropyl, cyclobutyl, 1-, 2-or 3-methylcyclopentyl, 1-, 2-, 3- or 4-methylcyclo-hexyl, cycloheptyl or cyclooctyl; bicycloalkyl con-saining 4 to 11 carbon atoms, preferably 7 carbon atoms, exo- or endo-2-norborny1 being preferred, as well as, for example, 2-iscbornyl or 5-camphyl; hydroxyalkyl containing 1 to 5 carbon atoms, preferably i-2 carbon atoms, hydroxymethyl and 1- or 2-hydroxy-ethyl being preferred, as well as, for example, 1-hydroxy?rop-l-yl, 2-hydroxyprop-l-yl, 3-hydroxyprop-l-ylr l-hydroxyprop-2-y1, 1-hydroxybut-l-y1 -or 1-hydroxypent-l-yl; alkoxy containing 1 to 10 carbon atoms, preferably 1-4 carbon atoms, methoxy cr ethoxy being preferred, as well as, for example, n-propoxy, isopropoxy. n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexyloxy, heptyloxy, octyloxy, nonyl-oxy 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-octylcxyethyl; alkoxyalkoxyalkyi containing up to 10 carbon atoms, preferably from 4 to 7 carbon a"orris, for example alkoxyalkoxymethyl such as 2-methoxyethoxy-methyl, 2-ethoxyethoxymethyl or 2-isopropoxyethoxy-methyl, or alkoxyalkoxyethyl such as 2-(2-methoxy-ethoxy)ethyl cr 2-(2-ethoxyethoxy)ethyl; alkcxyalkoxy containing from 2 to 10 carbon atoms, preferably from 3 zo 8 carbon atoms, for example 2-methoxyethoxy, 2-etnoxyethcxy 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, isopropenyloxy, butenyioxy such as but-l-en-1-, -2-, -3- or -4-yloxy, but-2-en-l-yloxy or but-2-en-2-yloxy, pentenyloxy, "nexenyloxy or decen-yloxy; alkenyloxyalkyl having up to 10 carbon atoms, preferably 3-6 carbon atoms, for example allyloxy-methyl; alkynyloxy containing from 2 to 10 carbon atoms, preferably 2 zo 4 carbon atoms, propargyloxy being preferred, as well a3, for example, ethynyloxy, prop-l-yn-l-yioxy, butynyloxy or but-2-yn-l-yloxy, pentynyloxy or decynylcxy; alkynyloxyalkyl containing from 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms, for example ethynyloxymethyl, propargyloxymethyl or 2-(but-2-yn-l-yloxy)ethyl; cycloalkoxy containing 3 to 8 carbon atoms, preferably 5 or 6 carbon atoms, cyclopentoxy cr cyclchexyloxy being preferred, as well as, for example, cyclopropoxy, cyclobutoxy, 1-, 2- or 3-methylcyclopentoxy, 1-, 2-, 3- or 4-methylcyclohexyl-oxy, cycloheptyloxy or cyclooctyloxy; alkylthio containing from 1 to 10 carbon atoms, preferably 1 to 4 carbon a:oms, methylthio or ethylthio being preferred, as well as, for exajnple, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butyl-thio, pentylthio, hexylthio, octylthio, nonylthio or decylthio; alkylthioalkyl containing from 2 to 10 carbon atoms, preferably 2 to 5 carbon atoms, for example methylthiomethyl, 2-methylthioethyl or 2-n-butylthioethyl; acylamino, namely alkanoylamino containing from 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms, formylamino and acetylamino being preferred, as well as prcpionylamino, butyrylamino, isobutyr-ylamino, valerylamir.c, caproylamir.o or heptanoylamino, or aroylamir.o or benzoylamino; acylaminoalkyl, preferably alkanoylaminoalkyl containing from 2 to 8 carbon atoms, preferably 3 to 6 carbon atoms, such as formyl-amir.oethyl, acetylaminoethyl, propionylamir.oethyl, n-butyrylamincethyl, formylaminopropyl, acetylamino-propyl, propionylaminopropyl, formylamino'outyl or acetylaminobutyl, as well as propionylaminobutyl or butyrylamir.obutyl; acyloxy containing from 1 to 6 carbon atoms, preferably 2 to 4 carbon atoms, acetyl-oxy, propionyloxy or butyryloxy being preferred, as well as, for example, formyloxy, valeryloxy or caproyl-oxy; 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, isobutoxycarbonyl, sec-butoxycarbonyl or tert-butoxycarbonyl; cycloalkoxycarbonyl containing from 4 to 8 carbon atoms, preferably 6 or 7 carbon atoms, cyclopentoxycarbcnyl and eye lohexy loxycarbcr.y 1 being preferred, as well as cyclopropoxycarbonyl, cyclobutoxycarbonyl or cycloheptyloxycarbonyl; alkyl-aminocarbonylamino containing from 2 to 4 carbon atoms, such as methylaminocarbonylamino, ethylaminocarbony1-amino or propylaminocarbonylamino; dialkylaminocar-bonylamino containing from 3 to 7 carbon atoms, preferably 3 to 5 carbon atoms, dimethylaminocarbonylamino being preferred, as well as di-n-propylaminocarbonyl-amino or diisopropylaminocarbonylamino; pyrrolidin-1- yIcarbcnylamino; piperidin-l-ylcarbcnyiamino; cyclo-alkylamir.ocarbony lamino containing from 4 to 8 carbon atoms, preferably 5 or 7 carbon atoms, cyclopentyl-aminocarbonyiamino and cyciohexylaminocarbonylamino being preferred, as well as cyclopropylaxninocarbonyl-amino, ryelobutylamir.ocarbcnylamino or cycioneptyl-aminccarbcnylamino; alkylaminocarbonyiaaiinoalkyl containing from 3 to 9 carbon atoms, preferably 4 to 7 carbon atoms, methylaminocarbonylamincethyl, ethyl-aminocarbonylaminoethyl, ethylaminocarbonylaminopropyl and ethy laaiinocarbonylaminobuty 1 being preferred, as well as, for example, methylaminocarbcnylaminomethyl, n-propy lar-.inccarbonyiamir.obutyl ana n-butylamino-carbonylaminobutyl; dialkylaminocarbonylaniinoalkyl containing from 4 to 11 carbon atoms, for example dime thy laminocarbcnylaminome thy 1, diethylaininocarbonyl-amincethyl, diethylaminocarbonylaminopropyl or diethyl-aminocarbcnylaminobutyl; pyrrolidin-l-ylcarbonylamino-etnyl; piperidin-l-ylcarbonylaininoethyl; cycloalkyl-aminocarbcnyiamir.oalkyl containing from 5 to 12 carbon atoms, preferably 8 to 11 carbon atoms, cyclopentyl-aminocarbonylaminoethyl, cyclopentylaminocarbonylamino-propyl, cyclopentylaminocarbonylaminobutyl, cyclohexyl-aminocarbcnylaminoethy1, cyclohexylaminocarbonylamino-propyl and cyclonexylaminocarbonylaminobuty1 being preferred, as well as, for example, cyclcpropylaminc-carbonylaninomethyl or eyeloheptylaminccarbonylamino-ethyl; alkexycarbonylaminoalkyl containing from 3 to 12 carbon atoms, preferably 4 to 9 carbon atoms, methoxy-carbony la^.inoethy 1, ethoxycarbony laminoethy 1, n- propoxycarbonylaminoetnyl, isopropoxycarbonylamino- ethyl, n-butoxycarbonylaminoethyl, isocutoxycarbonyl-aminoethyl, sec-butoxycarbonylaminoethy1, tert-butoxy-carbonylaminoethyl, ethoxycarbonylaminopropy1, n-butoxycarbonylaminopropyl, ethoxycarbonylaminobutyl and * ; 1 n-buscxycarbonylaminobutyl being preferred, as well as, for example, n-propoxycarbonylaminopropyl, n-propoxy-carbonylaminobutyl or isopropoxycarbonylaminobutyl; cycloalkoxycarbonylaminoalkyl containing from 5 to 12 05 carbon atoms, preferably 8 to 11 carbon atoms, cyclo-pentoxycarbonylaminoethy1, cyclopentoxycarbonylamino-propyl, cyclopentoxycarbonylaminobutyl, cyclohexyloxy-carbonyiaminoes'nyl, cyclonexyloxycarbonylaminopropyl and cyclo'nexyloxycarbonylaminobutyl being preferred, as 10 well as, for example, cyclopropoxycarbonylaminomethyl or cycloheptyloxycarbonylaminoethyl; carbarnoylalkyl containing from 2 to 5 carbon atoms, preferably 2 carbor. atoms, carbamoy line thy 1 being preferred, as well as carbamoylethyl, carbarnoylpropyl or carbamoyIbutyl; 15 alkylar.inocarbonylalkyl containing from 3 to 9 carbon atoms, preferably 3 to o carbon atoms, methylaminocar-bonylethyl, et'nylaminocarbonylmethyl, n-propylaminocar-bonylmethyl, isopropylaminocarbonylmethyl, n-butyl-ami nocarbony line thy 1, isobutylaminocarbonylmethyl, sec-20 butylaminocarbonylmethyl and tert-butylaminocarbonyl-methyl being preferred, as well as, for example, ethylaziinocarbonylethyl, ethylaminocarbonylpropy 1, ethylaminocarbonyIbutyl, n-propylaminocarbonyIbutyl or n-butylaminocarbonyIbutyl; dialkylaminocarbonylalkyl 25 containing from 4 to 11 carbon atoms, preferably 4 to 8 carbon atoms, dimethylaminocarbonylmethyl. -diethyl-aminocarbonylmethyl, di-n-propylaminocarbonylmethy1, as well as, for example, aiethylaminocarbonylethyl, diethylaminocarbonylpropyl, diethylaminocarbonylbutyl; pyrrolidin-30 1-ylcarconylmethyl; piperidin-l-ylcarbonylmethyl; piperidin-l-yl carbonylethyl; cycloalkylaminocarbonylalkyl containing from 5 to 12 carbon atoms, preferably 7 or 8 carbon atoms, cyclopentylaminocarbonylmethyl and cyclohexylaminocar-bonylmethyl being preferred, as well as, for example, i -•!, cyclopropylaminocarbonylmetnyl, cyclobutylaminocar- bonylmet'nyl, cycloneptylaminocarbonylmethyl, cyclo-hexylaminocarbonylethyl, cyclohexylaminocarbonylpropyl or cyclohexylaminocarbonyIbutyl; alkylaminocarbonyl-05 alkoxy containing from 3 to 10 carbon atoms, preferably 3 to 5 carbon atoms, methylaminocarbonylmethoxy being preferred, as well as, for example, methylaminocar-bcnyiethoxy or methylaminocarbonylpropoxy; dialkyl-aminocarbonylalkoxy containing from 4 to 10 carbon 10 atoms, preferably 4 to 7 carbon atoms, such as dime thy lami r.ccarbcr.y Imethoxy, diethylaminccarbcnylethoxy or piperidin-l-ylcarbonylmethoxy; and cycloalkylamino-carbonylalkoxy containing from 5 to 11 carbon atoms, preferably 7 or 8 carbon atoms, such as cyclopentyl-15 aminocarbonylmethoxy or cyclohexylaminocarbonylmethoxy.

The group Z may advantageously be a phenyl group; a benzyl group; a benzoyl group; or a phenyIthioalkyl group in which the alkyl is C1-C3.

The phenyl group 2 is preferably mono- or di-20 substituted by a halogen, the 2,4-dichlorop'nenyl group being particularly preferred.

The radical Z can also be a bicyclic aromatic group such as naphth-1- or -2-yl or inden-1-, -2-, -3-, -4-, -5-, -6- or -7-yl, in which one or mors bonds can 25 be hydrogenated, it being possible for said groups to qio ijp2uds^ 2.t1-!0cl o c o n ^ 3. i. n ens cr ir.crs 3*^^i.3 such as: a halogen, and more particularly a fluorine atom, and alkyl, phenyl, cyano, hydroxyalkyl, hydroxyl, oxo, alkylcarbonylamino, alkoxycarbony1 and thioalkyl 30 groups, in which the alkyls are C1-C4.

The radical Z can also be a pyridyl, thiadia-zolyl, indolyl, indazolyl, imidazolyl, benzimidazolyl, quinolyl, benzotriazolyl, benzofuranyl, benzothienyl, benzothiazoly1, benzisothiazolyl, isoquinolyl, benz-35 oxazolyl, benzisoxazolyl, benzoxazinyl, benzodioxinyl, f A isoxazolyl, benzopyranyl, thiazolyl, thienyl, furyl, pyranyl, chromenyl, isobenzofuranyl, pyrrolyl, pyrazo-lyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, p'nthalazinyl, quinazolinyl, acridinyl, isothiazolyl, 05 isochromanyl or chromanyl group, in which one or more double bonds can be hydrogenated, is being possible for said groups to be unsubstituted or to contain one or more substituents such as: alkyl, phenyl, cyano, hydroxyalkyl, hydroxyl, alkylcarbonyiamino, alkoxycar-10 bonyl and thioalkyl groups, in which the alkyls are Cx-Ca.

According to another of its features, NZ235985 relates to a method of preparing variously substituted aromatic amino compounds for formula (I) and their salts, which comprises in which m, Ar* and Q are as defined above; R° is hydrogen, a methyl group or a group (CH2)n-L°, in which n is as defined above and L° is hydrogen or an amino 25 group protected by an N-protecting group; and E is a hvdroxyl grouo, an O-protacted arouo such as tetrahydropyVan-2-yloxy, or a group a) treating a free amine of the formula Q 3° S-(CH2)n-C-CH-J-NH i Ar' (II) in which Ar, X and Y are as defined above and X® is the group X' as defined above, in which the hydroxyl group is protected by an 0-protecting group, r- i 05 _ 1 n _ - either with a functional derivative of an acid of the formula H0-C0-Z (III) in which Z is as defined above, when it is intended to prepare a compound of formula (I) in which T is -CO-, - or with an iso(thio)cyanate of the formula • • W=C=N-Z (III*) in which W and Z are as defined above, when it is intended to prepare a compound of formula (I) in which T is -C(W)-NH-, in order to form the compound of the formula Q R° E-(CH2)m-C-CH2-N*-T-Z Ar' b) then, when E is tetranydropyranyloxy, eliminating the tetrahydropyranyl group by acid hydrolysis, this hydrolysis being alternatively carried out in steD a), on the starting amine of formula (II), c) treating the resulting N-substituted alka-no1amine of the formula Q R° H0-(CH2)m-C-CH2-N-T-Z (V) Ar' with methanesulfonyl chloride, d) reacting the resulting mesylate of the formula 05 Q 3° i CH3SO2-O- (CH2)m-C-CH2"N'"T-Z (VI ) Ar' with a secondary amine of the formula X X' \ / / \ Ar - C - Y NH (VII) \ / in which Ar, Y, X and X' are as defined above, and e) eliminating any 0-protecting and N-orotecting groups present and, if appropriate, convsr-15 ting the resulting product into one of its salts.

The functional derivative of the acid (III) used is the acid itself, suitably activated for example by cyclohexylcarbodiimide or by benzotriazoly1-N-oxy-trisdimethylaminophosphonium hexafluorophosphate (30?), 20 or one of the functional derivatives which react wish amines, for example an anhydride, a mixed anhydride, the chloride or an activated ester. When Z is a group 0M, the acid in question is carbonic acid and the functional derivative used is the monochloride, namely 25 a chloroformate C1-C0-0M.

Any N-protecting groups present in the group P." of the compound of formula (II) are the conventional N-protecting groups well known to those skilled in the art, and preferably those which can be eliminated by 30 acid hydrolysis, such as the trityl and methoxytrityl groups.

Any 0-protecting groups present in the group X® are also the conventional 0-protecting groups well known to those skilled in the art, and preferably those 35 which can be eliminated by mild acid hydrolysis, such 05 a.s the tetrahydropyran-2-yl, t-butyldimethylsilyl and methcxymethyl groups.

When the starting material used is a compound of formula (II) in which E is a group X X° .

N / / Ar - C - Y the method can be represented and illustrated in detail by-Scheme 1 below: SCHKMS 1 X X°— Q 3° \ '* /\ : l A r - C - Y N - ( C H " ) - - C - C H 9 - N H / > » ■ . A L.

I CL-C-2 (Ilia) I 11 ! 0 XX' I ^ / i > Ar-C-Y + deoroceccion (II') Q R N-(CH2)ra-C-CH2"N-C-2 1 i 11 Ar' 0 (I') i W=C=S-Z (III') X X' Q R H ! ^ / / \ ' I I > Ar-C-Y N'-CCH-yJia-C-C^'N-C-N-Z \ / 1 i " + deprotection V—' Ar W (I") In formula (Ilia) above, the acid chloride is considered to be a reactive functional derivative of the acid (III). The acid chloride is used when it is desired to prepare a compound (I') in which Z is OM. The reaction with the acid chloride is performed in an 35 inert solvent such as methylene chloride or benzene, in the presence of a base such as, for example, triethyl-amine, at room temperature.

In the particular case where Z = OM, the reaction of the compound (II") with the chlcroformate of 05 the formula CI-C-OM II 0 is performed by the usual methods.

When Z is other than OM, it is possible to use another functional derivative or to start from the free acid (III), carrying out a coupling reaction of (II') with HOP (benzotriazolyl-N-oxytrisdimethylaminophos-15 phoniun hexafluorophosphate) and then adding the acid (III) in the presence of an organic base such as, for example, triethylamine, in a solvent such a3 methylene chloride or dimethylformamide, at room temperature, the compounds (I') obtained being isolated and purified by 20 the usual methods such as, for example, chromatography or recrystallization.

It is also possible to react (II') with an iso(thio)cyanate W=C=N-Z (III') in an anhydrous inert solvent such as, for example, benzene, overnight at 25 room temperature, and then to treat the reaction mixture by the usual methods to give the compounds' (I").

When the starting material used is a compound of formula (II) in which E i3 a tetrahydropyranyloxy group, the method can be represented and illustrated by-Scheme 2.

The reactions of the compound (II') with the reactants (Ilia) and (III') take place as described above for Scheme 1, it being possible for the acid chloride (Ilia) to be replaced with another functional 35 derivative or with the free acid activated for example 9 /, * L by 30?.

The resulting intermediate (IV) is deprotected by acid hydrolysis to give the free hydroxylated compound (V). Deprotection by hydrolysis of the tetra-05 hydropyranyloxy group can be carried out direct on the compound (II"). This gives the hydroxylated compound (11''"), which is reacted direct with the reactant (Ilia) cr (III'), as described in Scheme 2 below, to give the compound (V). This is followed by preparation 10 of the mesylate (VI) and then substitution with a secondary amine of formula (VII), which finally gives the compounds (I) according to the invention after de-protection of the amine L° if appropriate.

SCHEME 2 05 1 n Q R \ r i Q i -y HO-(CH2)!n-C-CH2-N,H Uo Ar' Ar ,ii j a:"') Cl-CO-Z (Ilia) or V=C=N-Z (III') V Q R° \ 1 I —0-(Cfi2)ia"C-CH2"N"T"2 (IV) _0 Ar' mild hydrolysis (H+) y HO-CCH2)a-C-CH2-.N-T-Z Ar' (Ilia) or , (III') CH3SO2CI V Q R° 1 I CH3S02-0-(CH2)i«-C-PH2-N-T-Z Ar' (VI) (VII) + deprotection V (I) C\ t f When the product obtained at the end of the reaction of the compound of formula (II) with the compound (III) (as a functional derivative) or (III') has formula (IV) in which S is a group 05 X X° Ar - C - Y N- VJ 1C in which Ar, X, X® and Y are as defined above, the product can either be the final product or have an 0-protected hydroxyl group (in X°) or a protected amino group (L9) or both. In this last case, it is desirable to use the O-protecting and N-protecting groups in the 15 starting material (II) so as to be able to hydrolyze them at the same time.

Deprotection is carried out by the known methods; in particular, if a tetrahydropyranyl group is used as the 0-protecting group, hydrolysis can be 20 carried out under mild conditions with dilute p-toluenesulfonic acid. If the molecule of the product (IV) contains both a tetrahydropyranyloxy group and a tritylamino group, hydrolysis of the former can thus be carried out without affecting the N-protecting group, 25 whereas formic acid removes both protecting groups at qarrio A JT>O The resulting products of formula (I) are isolated, in the form of the free base or a salt, by the conventional techniques.

When the compound of formula (I) i3 obtained in the form of the free base, salt formation is effected by treatment with the chosen acid in an organic solvent. Treatment of the free base, for example dissolved in an alcohol such as isopropanol, with a solu-35 tion of the chosen acid in the same solvent gives the corresponding salt, which is isolated by the conventional techniques. The hydrochloride, hydrobromide, sulfate, hydrogensuif ate, dihydrcgenp'nosphate, methane-sulfonate, methylsulfate, oxalate, maleate, fumarate and naphthalene-2-sulfonate, 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 the oxalate; in this case, where 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 ar. alkali metal carbonate or bicarbonate such as sodium or potassium carbonate or bicarbonate.

The enantiomers, which form part of the invention of NZ 235985, can be isolated by resolution of the racemic mixtures (I).

It is also possible to resolve racemic mixtures of the products of formula (II), especially the products of formulae (II') and (II''') or precursors thereof, in order to prepare the enantiomers of the products of formula (I).

The starting compounds of formula (II) are prepared from nitriles of the formula Q E-(CH2):n-C-CN (VIII) , » rt r in which m, E, Q and Ar' are as defined above, by reduction and, if appropriate, alkylation of the amine obtained.

To prepare the compounds of formula (II) in which R° i3 hydrogen, the starting nitriles of formula (VIII) are hydrogenated in an alkanol such as ethanol, in the presence of a catalyst such as, for example, Raney nickel, and the free primary amine can be isolated by the conventional methods.

When it is desired to prepare the compounds of formula (II) in which R° is methyl, the free amine, obtained by hydrogenation of the nitrile (VIII) as described above, is treated with a chloroformate, for example with the chloroformate of the" formula Cl-CO-OAlk, in which Alk is a C1-C4 alkyl, preferably ethyl, to give the carbamates of the formula E-(CH" )-,-C-CH 9-NH-C-OA Ik 1 , " Ar 0 which are then reduced by known means such as reaction with a reducing agent like, for example, a metal hydride such as sodium aluminum hydride or lithium aluminum hydride, or a boron hydride such as borane dimethylsulfide. Reduction is carried out in a solvent such as ether or toluene, at a temperature between room temperature and 60 °C. The resulting methylamine of the formula Q CH3 E-(CHo)m-C-CH2"N-H *" ' , (II, = CHo) Ar is isolated by the usual methods.

To prepare the compounds of formula (II) in which R° is a group -(CH2)n-L°, in which n and L® are as defined above, the free amine, obtained by hydro-genation of the nitrile (VIII) as described above, is treated with a reactive functional derivative of the acid of the formula L°-(CH2)n-i-COOH (IX) to give ar. amide cf she formula Q E-(CH2)m-C-CH2-NH-C0-(CH2)n-i-Lo (X) Ar' in which n, E, Ar', Q and LJ are as defined above.

Cr. reduction under she same conditions as shose described above for the nitrile (VIII), she amide (X) gives she desired compound of the formula Q Z-.;CH2)n-C-CH2-MH-CCH2)n-L0 (II, R° = (Ch*2)n-La) Ar' The nitriles of formula (VIII) are prepared from kr.cvn nitriles (commercially available or prepared by known methods) of the formula Q I Ar'-CH-CN (XI) which, or. aikylation with a compound of the formula S-(CH2)m-J (XII) in which m and E are as defined above and J is a halogen atom, for example a bromine atom, or a hydroxyl group, give the desired compounds (VIII).

The nitriles of formula (VIII) in which E is a tetrahydrcpyranyloxy group are synthesized from a tetrahydropyranyloxy derivative (THP-0-) obtained by reacting an alkanol of the formula Br-(CH2)m-0H, where % - - on - m is as defined above, with dihydropyran to give the ccmDOund 05 3r " (CH-^ " 0 \ (XII, E = TKP-0-, J = 3r) which is then added, in the presence of an alkali metal hydride, to the acetonitrile derivative (XI) in order 10 to prepare the intermediate - 0-(CH2)n - C - CN* (VIII, E = THP-0-, Q = K) 0 Ar' corresponding to the compound of formula (VIII), which is an intermediate precursor of the compound (II') in Scheme 1 above in which Q is hydrogen, which can then be alkylated.

The nitriles of formula (VIII) in which E is a group X X° \_/ in which Ar, X, X" and Y are as defined above, are synthesized by known methods involving the addition of a nitrile derivative of the formula ? H-C-CN (XIV) Ar" to chlorinated derivatives of the formula X x° . w / \ , Ar-C-Y N-CCH-V.-C1 (XII*) 05 in the presence of sodium amide, in a solvent such as toluene, at temperatures of between 30 and 50°C.

The chlorinated derivative (XIII) is' prepared by reacting a chlorinating reagent such as thionyl 10 chloride, for example, with the nydroxylated derivative of the formula X X° _ \ / / V Ar - C - Y N - (CK2)mOH (XV) which is itself prepared from the amine of the formula X X° \ / ^SH w (VII') by reaction with ethylene oxide if m = 2 and a 3-halogenopropanol if m = 3.

The amines (II) are novel products which form the key intermediates for the preparation of the compounds of formula (I) above. Moreover, it has been found, surprisingly, that like the compounds of formula (I), although to a lesser degree, the amines of fnrnula (IT) possess a good 30 antagonistic activity towards neurokinin receptors. The activity of these compounds extends to the derivatives deprotected by the conventional methods referred to above (X® = X' and R° = R).

Thus, according to the present invention relates to 35 compounds of the formula Q E°°-(CH2)ni - C - CH? - NH - R°° (XVI) i Ar' n which: E°° is a tetrahyclropyranyioxy group, a hydroxyl group, or a grouo x :<00 N / / \ Ar - C - Y N- '\_l m is 2 or 3; Ar ar.d Ar' independently are a thienyl group; a phenyl group which is unsubstituted or mono- or di-substituted by a halogen atom, preferably a chlorine or fluorine atom, by a C1-C3 alkyl, by a trifluoro-methyl, by an alkoxy in which the alkyl is C1-C3, by a hydroxyl or by a methylenedioxy; or an imidasolyl group; it being possible for Ar' to be a benzothienyl group wnich is unsubstituted or substituted by a halogen, preferacly by a chlorine or fluorine atom; a naphthyl group which is uns^ostituted or substituted by a halogen, preferably by a fluorine atom; a biphenyl group; or an indolyl which is unsubstituted cr substituted en ^hs m^regsn by a benzyx gxuUp, X is hydrogen; X°0 is hydrogen or a hydroxyl group which is free or protected by an O-protecting group, or is joined to X" below to form a carbon-carbon bond, • or X and X'9 together form an oxo group or a di-alkylaminoalkoxyimino group of the formula =Nf-0-(CH2)p-Am, in which p is 2 or 3 and Am i3 a dialkylamino group, it being possible for each alkyl to contain from 1 to 4 carbon atoms; - Y is a nitrogen atom or a group C(X"), in which X" is hydrogen or forms a carbon-carbon bond with X"; - Q is hydrogen, a Ci-C4 alkyl group or an aminoalkyl group of the formula -(CH2)q-Am', in which a is 2 or 3 and Am" is a piperidino, 4-benzylpiperidino cr dialkylamino group, it being possible for each alkyl to contain from 1 to 4 carbon atoms; and - R"0 i^ 'r.ydraer., a methyl group or a group (CH2! --L0 s, in which n is a number from 2 to 5 ana 0 L*3 is hydrogen cr an amino group which is free or protected by an N-protecting group; cr to one of their salts.

The compounds of formula (XVI) include the compounds of formula (II) which are protected ccm-5 pounds, as well as the corresponding deproteoted compounds .

The compounds of formula XVI, provided that - when m = 2, E°° is a hydroxyl group, R°° is hydrogen and Ar' is an unsubstituted phenyl, then Q is different from H, ethyl or propyl - when m = 2, E°° is a hydroxyl group, R°° is hydrogen and Q is hydrogen, then Ar' is different from a 3,4-dimethoxyphenyl group or a 2-thienyl group - when m = 3, E°° is a hydroxyl, Ar' is an unsubstituted phenyl, Q is ethyl, then R" is not hydrogen are novel products. (followed by page The/ 3re obtained by the process described aoove for the cctention of compounds of formula (II), in which eacn step nay be eventually followed by the elimination of N- and Q-protecting grouos. They may then be transformed into salts with ODticallv active acids, which allows the oreoaration of optically pure compcjncs.

The compounds of formula (XVI) which are particularly oreferrec are those in which E°° is a hydroxyl group and R00 is nydrogen; these compouncs 3nc! their enantiomers are the compounds of formula (II'1 ').

The intermediates of formula (IV) in which E is tetrahydropyranyloxy and the intermediates of formula (V) and of formula (VI) are particularly advantageous novel products and represent a further feature of the present invention. These products, and the corresponding compounds from which the 0- and N-protecting groups have been removed by conventional methods, can be jointly represented by formula (V') below: Q 3°° G-0- (CH'2 )si"C-CH2"N'"T-Z (V') i Ar' in which: - m is 2 or 3; - G is hydrogen, a tetrahydropyranyl group or a methane-sulfonyl group; - Ar' i3 a thienyl group; a phenyl group which is unsubstituted or mono- or cu-suistituted by a halogen afwn preferably 2 chlcrir.c or fluoric- atom, by a triflucromethyl group, by an aikoxy in which the alkyl is C1-C3 or by a hydroxyl; a benzothienyl group which is unsubstituted or substituted by a halogen; a napnthyl group which is unsubstituted or substituted by a halogen, preferably a fluorine atom; a biphenyl group; or an mdolyl grouo which is unsubstituted or substituted on the nitrogen by a benzyl ; - Q is hydrogen or an aminoalkyl group of the formula -(CHa.'q-Am' , in which q is 2 or 3 and Am' is a piperi-dino, 4-benzylpiperidino or dialkylamino group, it being possible for each alkyl to contain from 1 to 4 - R03 i3 hydrogen, a methyl group or a group ,CH2)n-100, in which n is an integer from 2 to 6 and L° ° is hydrogen or an amino group which is free or protected by ar. N-protecting group; - T is a group selected from 0 W and -C-NH-, W being an oxygen or sulfur atom; and - Z is either hydrcgen, or M or OM when T is the group -C(=0)-, or M when T is the group -C(=W)-NH-, M being hydrogen; a linear or branched Ci-Cs alkyl; a phenyl-: alkyl in which the alkyl group contains from 1 to 3 carbon atoms ana which is unsubstituted or mono- or poly-substituted on the aromatic ring by a halogen, a hydroxyl, an alkoxy having 1 to 4 carbon atoms or an alkyl having 1 to 4 carbon atoms; a pyridylalkyl in which the alkyl group contains from 1 to 3 carbon atoms; a naphthylalkyl in which the alkyl group contains from 1 to 3 carbon atoms; a pyridyIthioalkyl in which the alkyl group contains from 1 to 3 carbon atoms; a styryl; a l-methylimidazol-2-yltmoalkyl in which the alkyl group contains from 1 to 3 carbon atoms; a l-oxophenyl-3-indan-2-yl; or an unsubstituted or mono- or poly-substituted aromatic or neteroaro-matic group; and their salts with mineral or organic acids.

The compounds of formula (V'), provided that when m = 3, G is hydrogen, Ar' is an unsubstituted phenyl group, 0 il Q is an ethyl group, T is - C - and Z is a methyl group, then r" is different from hydrogen, are novel compounds.

These compounds are prepared according to Steps a), b) and c) of the method described above for the preparation of the compounds of formula (I), wnich are eventually followed by the elimination of N-protecting groups arter eacn step, exceot that a free amine of the formula 1-5 Q R« I I G-0-(CH2)m-C-CK2-NK Ar" in which n , G , 3 , Ar' are as defined aoove and R° is hydrogen, a methyl grouo, a group (Ch^^-l0 in w'nicn n is an integer from 2 to 6 and L° is hydrogen or an amino group protected by an N-protecting group/is used as the starting material.

As indicated above, the intermediates which are capable of giving salts with optically active acids can be resolved so as to make it possible to prepare the 25 enantiomers of the compounds of formula (I).

It is also pcssibls tc make provision for the stereospecific synthesis of intermediates which do not give a salt permitting separation.

A particularly suitable intermediate for such a 30 stereospecific synthesis is the alcohol of formula (V) above.

Thus, according to another of its features, NZ 235985 relates to the enantiomers and to a method of preparing the enantiomers of the compounds of formula (I) and their salts said enantiomers have formula (I*) below: -4 - 23 :< x' q r \ / / \ i i Ar - C - Y M - CCH->)a - C- - C«2 - .V - T - Z (I*) W i,- m wmcn: Ar, Ar", Z, X, X', Y, Q, R, T and m are as defined above and means that the carbon atom denoted by this symbol has a defined {->■) or (-) absolute confi-suraticn.

This method comprises treating a compound of the formula H H Q J C"-M-C-(C;-!2)m-l"^"c^2"-VJHS0 (XVII*) V—L CH3 0 Ar' in a solvent such as, for example, dioxane, in an acid medium, for example in the presence of hydrocnlonc 20 acid, to give the amino acid of the formula Q H 0 - C - ( C H 2) a - 1 - i " " C H 2 - N H R 0 (XVIII*) 0 Ar' which is esterified in an alkanol AlkOH, in which Alk is an alkyl having 1 to 4 carbon atoms, in an acid medium, and then treating the corresponding ester of the formula Q AlkO-C-(CH2)m-i-i*-CH2-MHP° „ - ■■■ - - MR (XIX*) 0 Ar' in which Alk, Q, Ar', R® and m are as defined above, 05 - either with a functional derivative of an acici of the formula HG-CO-Z (III) - or with an iso(thio)cyanate of the formula W=C=N-Z (III*) Z and W being as defined above, under operating conditions identical to those used for the preparation of the derivatives (IV) above, to give the ester of the formula Q R i i O AlkO-C-(CH? )m-1 -C"-CHtN-T-Z t VY* ^ ,| - - , v j 0 Ar' which is then reduced to the corresponding alcohol of 20 the formula Q R° H0-(CH2)m-C*-CH2-N-T-Z (V*) Ar' These alcohols (V*) correspond to the compounds of formula (V) above in which m, Q, T, Ar' and Z are as defined above, G is hydrogen and H°0 is R° , the latter being as defined above, said compounds being in 30 optically pure form. These compounds are novel and form part of the invention.

The alcohol (V-) is converted into the methane-sulfonate derivative of the formula Q R i i CH3S02-0-(CH2)m-C*-CH2-N-T-Z Ar' (VI-) under operating conditions identical to those used for the preparation of the derivatives (VI) above.

The derivatives (VI") correspond to the compounds of formula (V*) above in which in, Q, T, Ar' and 2 are as defined above, G is methanesulfonyl and R°" is R° , the latter being as defined above, said compounds being in optically pure form. These compounds are novel and form part of the invention.

Substitution of the mesylate (VI*) with an amine of the formula Ar X X' .

■ C/- Y ST N'H (VII) \ under the conditions described for the preparation of (I) above makes it possible to prepare the derivatives (I*), after deprotection if appropriate, these derivatives being eventually transformed into one of their salts, using known methods.

The compounds of formula (av'II*) are known or can easily be prepared by the method described by G. HELMCHEN et al., Angew. Chem. Int. Ed. Engl., 1S79, 1, 18, 65, according to the following scheme: 9 L r u SCHEM? a 05 Q H-C-CN' Ar1 Hal--C-O-C-(CH3)3 jJ 0 \y Q (C:-:3)3-C-0-C-(CK-7)ni-i-C-CNT " 1 , 0 i Ar' »2 V I (CH3)3-C-0-C-(CH2)m-l-C-CH2NH2 11 1 . 0 Ar' TFA r«i /. t— I H0-C-(CH2)m-l-C-CH2NH3eC?3C02S 05 S Ar* SOCoO V Q H0-C-(CHo)m-i-C-N-H3CC 11 0 Ar' BOP H \\^-ck-sh2 W tK3 . ' / V CXVII*. R° = 3CC) The resulting products of formula (Im) are isolated, in the form of the free base or a salt, by the 25 conventional techniques.

When the compound of formula (I*) is' obtained in the form of the free base, salt formation is effected by treatment with the chosen acid in an organic solvent. Treatment of the free base, for example dis-30 solved in an alcohol such as isopropanol, with a solution of the chosen acid in the 3anie solvent gives the corresponding salt, which is isolated by the conventional techniques. The hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogenphosphate, methane-35 sulfonate, methylsulfate, oxalate, maleate, fumarate 2 '■ ^ is. 1 and naphthalene-2-sulfonate, 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 05 their salts, for example the hydrochloride or the oxalate; in this case, where necessary, the free base can be prepared by neutralization of said salt with a mineral or organic base.

The compounds of the invention and of NZ235985 were 10 subjected to biochemical and pharmacological test3.

The compounds (I) and (I*) and the compounds (XVI) in which Y y® O ♦» f~ % \ / / ^\ is E° = Ar - C - Y .V- x°° = X', R°° = 3 \J and their salts showed antagonistic properties towards the binding of substance P in test3 performed on rat 20 cortical membranes and IM9 lymphoblast membranes, according to M.A. CASCIERI et al., J. Biol. Chem., 1983, 258. 5158-5164 and D.D. PAYA et al., J. Immunol., 1984, 122, 3260-3265.

The same compounds and their salt3 showed an-25 tagonistic properties towards the binding of NKA in on d\ioclon2L2. msinbrcir.ss ? "to L. 3ERGST0M et al., Mol. Pharmacol., 1987, 22, 764-771.

The same compounds and their salts showed antagonistic properties towards specific NKi, NKs and NKa 30 receptor agonists in tests performed on different isolated organs, according to D. REGOLI et al., Trends Pharmacol. Sci., 1988, S, 290-295.

The same compounds and their salt3 showed overall antagonistic properties towards NKi, NK2 and NK3 in 35 tests performed on different isolated organs, according 1 ! so D. REGOLI st al., Trends Pharmacol. Sci., 1983, £, 2S0-295 and Pharmacology, 1389, ££, 1-15.

The same compounds ana their salt3 showed antagonistic properties towards the hypermotility induced 05 in rats by substance P in pharmacological tests performed according to Elliot et al., Brain Res., 198S, 361. 68-75.

The antagonistic properties towards the salivation induced in rats by substance P or a specific MXi "10 agonist ([3ar3Met(02)11]SP) were demonstrated by means of pharmacological tests performed according to TAXEDA Y. and XRAUSE J.E. , Proc. Natl. Acad. Sci. USA, 1989, 35, 392-396.

The analgesic properties were demonstrated by 15 means of pharmacological tests performed on arthritic rat3 according to V. XAYSER et al., Proceedings of the Vth World Congress on Pain, DUMMER R. , GE3HART G.F. and BOND M.R. ed., Elsevier Biomedical Division, 1988, 72-79.

The compounds have a low toxicity; in particular, their acute toxicity is compatible with their use as drugs. For such a use, an effective amount of a compound of formula (I), (I*) or (XVI) or of one of their pharmaceutically acceptable salts is administered to mammals.

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

Thu3, according to another of its features, the present invention relates to pharmaceutical compositions containing, as the active principle, a compound of formula (XVI) or one of their pharmaceutically acceptable salts.

C 4 D 4 The compounds of formula (I), (I*) or (XVI) above ana their pharmaceutically acceptable salts can be used at daily doses of 0.01 to 100 mg per kilo of body weight of the mammal to be treated, preferably at daily doses of 0.1 to 50 mg/kg. In humans, the dose can preferably vary from 0.5 to 4000 mg per day, more particularly from 2.5 to 1000 mg, depending cn the age of the subject to be treated cr the type of treatment: prophylactic or curative.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, percutaneous, local or rectal administration, the active principles can be administered in unit forms of administration, mixed with conventional pharmaceutical carriers, to animals and to humans. The appropriate unit ferns 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 is prepared in the form of tablets, the main active principle is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabio 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 predetermined 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. - 36 - O / FT / / \ " s /) '• , "" w* A preparation in the form of a syrup or elixir can contain the active principle together with a sweetener, which is preferably calorie-free, methyl-paraben and propylparaben as antiseptics, a taste 05 corrector and an appropriate colorant.

The water-dispersible granules or powders can contain the active principle mixed with di3persants or wetting agents, or suspending agents such ■ as polyvinylpyrrolidone, as well as with sweeteners or taste 10 correctors.

For rectal administration, suppositories are used which are prepared with binders melting at the rectal temperature, for example cacao butter or polyethylene glycols.

For parenteral, intranasal or intraocular ad ministration, aqueous solutions, isotonic saline solutions or sterile injectable solutions are used which contain pharmacologically compatible dispersants and/or wetting agent3, for example propylene glycol or buty-20 lene glycol.

The active principle can also be formulated as microcapsules, with one or more carriers or additives if appropriate.

The following Examples illustrate the invention 25 without however implying a limitation. The Examples also illustrate the invention of NZ235985. 9 /, R /, 1 "V . "T f 05 EXAMPLE 1 N- [4- (4-3enzylpiperidin-l-yl) -2- (3, 4-dic'nloro-phenyl)butyl]-2,4-dichlorobenzamide hydrochloride. SR 45672 A X' r (I) : Ar - C' - Y' \M - = /' CH2 V "N- ; a = 2 ; Q = H ; \ / /~\ /r\ : - y >]- = // Ar' = -/ V CI ; 3 = H ; T - Z = - C V V CI 3 ^ // ci c: A) l-Amino-4-(4-benzylpiperidin-l-yl)-2-(3,4-dichloro-phenyl)butane dihydrochloride 14.5 g of 4-(4-benzylpiperidin-l-yl)-2-( 3,4-dichlorophenyl)butyronitrile hydrochloride are dissolved in 400 ml of 95° ethanol. A solution of 20 ml 20 of concentrated ammonia in 40 ml of water and Raney nickel (10% by weight of the amount of amine) are added to the mixture, which is then placed under a hydrogen atmosphere, with vigorous stirring, for 4 hours, after which 1.S7 1 of hydrogen have been consumed. After 25 filtration of the cataly3t, the filtrate is concentrated under vacuum and the residue is taken up in ethyl acetate, washed with water, dried and concentrated under vacuum. The residue is taken up in a solution of hydrogen chloride in methanol, filtered off 30 and recrystallized from a 3/7 acetone/ether mixture, m = 10.2 g M.p. = 210°C.

B) SR 45672 A 2.3 g of the product obtained above and 1 g of 35 2,4-dichlorobenzoyl chloride are dissolved in 100 ml of methylene chloride in the presence of 0.03 g of tri-ethylamine. The reaction mixture is stirred for 4 hours at room temperature and then concentrated under vacuum and the residue is taken up in water, extracted 05 with ether, dried over MgSO* ana concentrated under vacuum. The residue is chromatographed on silica gel using a 97/3 methylene cnloride/methanol mixture as the eluent. Concentration of the pure fractions • gives a residue, which is taken up in a solution of hydrogen 10 chloride in ether. m = 1 g M.p. = 86-879C.

EXAMPLE 2 N—[5— C4-BenzyIpiperidin-l-yl)-2-(3,4-dichloro- pneny 1) penty 1 ] -2, 4-dichlorobenzamide hydroch .'.oride. SR 45083 A (I) : Ar -V- CH2 ■>/ ^N- ; m = 3 ; Q = H ; W W \J Ar' = ^ // CI ;R = H;T-Z = - C1 CI CI If the procedure of Example 1 is followed, except that 5-(4-benzylpiperidin-l-yl)-2-(3,4-dichloro-30 phenyl)pentylnitrile i3 used as the starting material, SR 45083 A is obtained, which is recrystallized from a methylene c'nloride/pentane mixture.

M.p. = 98-100"C. f*> *• / d:.

S.A* It 05 EXAMPLE 3 M—[4—(4-3enzyl?i?eridin-i-yl)-2-(3,4-difluoro-phenyl)butyl]-2,4-dimethylbenzamide hydrochloride hemi-hydrate. SR 4631S A X X' x / /~\ /~T\ Cj : Ar - C - Y M - = ^ y- C'do 1 " = 2 ; Q = H ' = \ /■?; 3=H; 1 -2 = -1 ca3 CH3 1.2 g of BOP are added to a solution of 1 g of l-amino-3-(4-benzylpiperidin-l-yl)-2-(3,4-difluoro-phenyl)butane, 0.34 g of 2,4-dimethylbenzoic acid and 1 g of triethylamine in 50 ml of methylene chloride. The reaction mixture is stirred for one hour at room 20 temperature and concentrated under vacuum. The residue is taken up in water, extracted with ether, washed with water and then with a solution of sodium bicarbonate, dried over MgSCU and then concentrated under vacuum. The residue is taken up in methylene chloride for pre-25 paration of the hydrochloride, which is filtered off and washed with ether. m = 0 . 4 g M.p. = 99-103"C.

The compounds described in Tables 1 and 2 were 30 prepared according to Example 1, 2 or 3.

In the formula below, the group Z indicated in formula I is a phenyl group which is unsubstituted or mono-, di- or tri-substituted by A, A' and A". 2 4 5 4 1 1 TABLE 1 Product SR (Example ns) Ar' A' A" : °C. Recrvst, solvent. Salt 47807 A (4) 46679 A (5) 46101 A (6) 46099 A (7) CI CI CI '/ V CI 2-F 2-F '2-F 4-F 4-F 116 isopropyl ether HCl 100 - 102 penrane/ether HCl. O'.S H?0 81 - 84 CH2Cl2/«ther HCl. 0.5 H2O 78 - 80 CH2CI2/ether HCl. 0.5 H2O ? 4 5 4 1 1 05 13 45965 A (5) 46022 A (9) 47704 A (10) 46454 A (11) 47462 A (12) 47301 A (13) // k CI CI // CI //\ I i! V\i I CI ( CI CI // {'i \\ / V 2-F 2-Cl 3-Cl 4-Cl 2-Cl 4-F 4-Cl 83 - 86 isopropyl ether HCl. 0.5 H20 186 ether HCl 153-160 AcOEt HCl 112 - 114 CH2Cl2/ether HCl. 0.5 H2O 95 ether HCl. 0.5 H2O 103 ether HCl. 0.5 H?0 / -/A ^ U 1 46100 A (14) 46233 A (15) 45910 A (16) 46152 A (17) 46011 A (18) 45672 B (19a) // V I J) v CI v ci 1 Cl CI // Cl Cl 2-Cl 2-Cl 2-Cl 2-Cl 2-Cl '2-Cl 4-Cl 4-Cl 4-Cl 4-Cl 4-Cl 4-Cl 95 - 97 CH2Cl2/ether HCl. 0.5 H?0 96 - 101 isopropyl ethe: HCl. 0.5 H?0 33 - 35 CH2Cl2/ether HCl 94 pentane/ether HCl. 0.5 H">0 107 - 110 ether HCl S3 - 90 pentane methanesulfonate hydrate 24 5 4 05 ZD 45672 C C 19b) 45672 D (19 c) (19c) 45672 F (19e) 45672 H (19f) A Cl Cl f" r Cl Cl V il A Cl Cl Cl Cl A W / * i ci 2-Cl 2-Cl 2-Cl 2-Cl 2-Cl -Cl 4-Cl 4-Cl 4-Cl 4-Cl H 70 - 72 pentane glycolate 144 - 146 pentane gluconate 103 - 105 pentane citrate hemihydrate 86 - 90 pentane isethionate hemihydrate 136-138-methanol free base o A R h l. J *t 46153 A (20) 46133 A (21) 4636^ A (22) 47153 A (23) 47225 a (24) 46493 A v. j Cl 1 Cl \/ v !. il V och3 OC H 3 .A \\ a •A / \ v CF3 Vs, CH3 \ A A V/ vA \ I II \\A\ 2-Cl 4-Cl H 104-106 pentane/ether HCl 2-Cl 4-Cl H 117 - 121 ether' HCl 2-Cl 4-Cl H 92 CH2Cl:/ether HCl. 0.5 Hz0 2-Cl 4-Cl H 96-93 pentane/ether HCl 2-Cl 4-Cl H 92 pentane/ether HCl 2-Cl 4-Cl H 112-114 CH2Cl2/ether HCl. 0.5 H2O 2 4 £ h 45261 A (26) 453 70 A (27) 46362 A (23) 47743 A (29) 46344 A (30) 46360 A Ml > v. m //\ A / 6 y N CH2 CoH5 A I II ll W 2-Cl 2-Cl •Cl 2-Cl 2-Cl 2-Cl 4-Cl 4-Cl 4-Cl 4-Cl 4-Cl 4-Cl 90-94 isopropanol mechanesulfonace 112-114 pencane HCl." 0.5 H2O 102 pencane HCl 115-113 AcOEc HCl 126-123 echer HCl. 0.5 H2O 133-144 CH2Cl2/eCher HCl ? 4 *i 4 1 46206 A A 1 1 1 3-Cl -Cl H (32) V 05 Cl 45235 A Cl 1 Cl vA/ 1 1 1 1 O -Cl H (33) V 46501 A A 2-Cl 6-C1 H (34) 1 II Vex I Cl 46499 A a 1 11 2-Cl 4-1 H (35) y\i Cl 45871 A (36) Aa w 2-Cl 4-0H H 46315 A (37) n 1—» 2-Cl 4-CH3 H 108 CH2Cl2/ether 108 90 ' ' CH2Cl2/ether HCl 123-130 CH2Cl2/ether HCl. 0.5 H?0 112-114 CH2Cl2/ether HCl. 0.5 H2O 142-144 CH2Cl2/ether HCl . 0.5 H->0 92 hexane HCl 47145 A (38) 46221 A (39) 46315 A (40) 45911 A (41) 46561 A (42) 45912 A (43) 2-Cl 4-NO? H 160-164 AcOEt HCl 4-OH H H 134 ether HCl 2-OH 4-QH H 136-141 CH2Cl2/ether HCl. 0.5 H2O 3-CF3 H H 86-39 ether HCl. 0.5 H2O 2-OCH3 4-OCH3 H 104 CH2Cl2/ether HCl 3-OCH3 4-OCH3 86-89 ether HCl. 0.5 H2O - 4R 3 Li r *- * o 0 0 a c^o o _ u n »O O O .n so) *615 — a r ' 7 a v •*' j 46525 A (48) 46833 A (49) /A cl cl //\ v\ a y ci .' \ \ i :i A i i cl cl ^ A v cl i Cl 3 -NO? 2-n'o? 2-.v;c-> z -so-> i.ru, - -'«3 2"^ A i-n'oi - NO? 4-ch3 0-CH3 119 AcOEt HCl 112-120 isopropyl echer HCl 194-193 ether HCl 115-120 ether HCl 128-130 ch2cl2/ether HCl - 175 ether HCl 46209 A (50) 46560 A (51) 46317 (52) 46672 A (53) 46391 A (54) f \A i ci 0 ci l a V A Ybi cl V- i ci cl v H H 195 ether HCl A i! 0 H H 132' CH2CI2/ether HCl t f » i I: 4-C' 6 H H 95-100 CH2CI2/ether HCl. 0.5 H2O /. • r if - T w . 1 / 1 i i A y H H 134 ether HCl 4-CH? ! ~ s CH3 i » / '» N N y H H 207 sthyl acetate 2HC1 24 5 4 : 4-CH: : I : S A : ■ < i H H : 153 : echyl . ii 1 . ; \f ; • kltU 1 24 54 1 o -l TA3LE 2 // V CHo \ / n - (ch2)n " ?h - ch2 - h i N - C - Z ii Q i' i a Ci cl : r'roauct : m : Z : M.p., °C. Secryst. : : (Example -=) : solvent. Salt : : i::o: A , O : H : ether : : ; : HCl : : 47122 .A . 2 : -CH3 : 77 : : ether : : (57) : HCl : : 170 : : 45599 .A : 2 : -CH2CH3 : ether : : (53) : HCl : : 170 : : /. 7 2 13 A . o . ^n\\ _ / r-'f . > . w»» «. : ether : : (59) : HCl : : 150 : : <47531 A . *3 . -j : -C;{-(CK3)2 : isopropyl ether : : (60) : HCl : 47314 A (61) 45946 A (62) 47144 A (63) 45305 A (64) 47242 A (65) 47939 A (66) 45947 A r a7 ^ 47721 A (63) •C-(CH3)3 ■ch2-(ch2)2"ch2ch3 // v b / c ■\ r ? 160 ether HCl 1S3 ether HCl 32-34 ether HCl 160 ether HC1. 0.5 HoO 122 ether 104 isopropyl ether HCl 166 ether ouri 170 AcOEt HCl ? /s U 11 v.. , « J J 05 z3 .7720 .A (59) i79C9 .A (70) C504 3 A (71) >6695 A (721 46212 A (73) 46341 A (74) a </ V s 0 <! i V/ ch3 0 I! 4 f CK3 A V\ 135 HCl 104 echer HCl 92 isopropyl ethe: HCl 100 (decomposition) ether un 213 ether HCl 224 acetone HCl 46669 A (75) "00 / J (75) 45330 A (77) 4d341 a ( - 5 \ v / 0 / 45792 A (79) 45369 A (30) 46215 A (31) AA i i vV ./V/' \ i i !! ^ / -ckw^^ '/-Cl /; -CHW OH •ch0-ch2v/ \s -CH =ch-v^ -ch2 210 acetone HCl 153 echyl ace: 114-116 echer HCl i-*0 ether kci 110 ethe: HCl 90-92 ch2cl2/ethe HCl 145 ethe: HCl - oo - 9 A * 46213 A (32) *o<j - - a (33) 46339 A (34) »6294 A (35) o793 A (36) -CHo \ /£\ r «i ' \ -CH"-S !i w -ch?-s-v'y ^ i ^ n V' 125 echer HCl • ■ u ^ c 2HC1 123 ethyl acetate 2 HCl 163 echer 2HC1 130 echer HCl o • r, /, i / •• ••• , 5 "1" i example •:? NT' - [ 4-( 4-Bcr.^vlr iperi din-1-y1 )-2- ( 3, 4-dichloro-phenyi)butyl 3-N-naphzh-l-ylurea hydrochloride.

SR 45924 A X X' y ci) : Ar -V- r' \ v - = // w / w r. o v — / \ N- ; m = 2 ; Q = H ; 2.52 g of I-am:no-4-(4-benzylpiperidin-1-yl)-2- (3,4-dichlcrophenyibutane are dissolved in 30 ml of anhydrous benzene, 1.09 g of naphth-i-yl isocyanate are then added and the reaction mixture is stirred over-nigh:. at rcom temperature. The excess isocyanate is 20 decomposed by addir.g 10 ml of methanol and heating the mixture at the boil for 30 minutes.

The mixture is concentrated under vacuum and the residue is taken u? in an ethyl acetate/water mixture, washed with a 10% solution of sodium hydroxide 25 and then water, decanted, dried over MgS04 and concentrated under vacuum. The residue is taken up in acetone, a solution of hydrogen chloride in ether is then adced and tne hydrochloride is filtered off and solidified in ether. in = 3.3 g M.p. = 174°C.

The compounds described in Table 3 were prepared according to Example 37.

O E OJ 2 4 5 4 1 ta3le 'a\ '/ \\-r-t x _ / h n'-cch2)m-c-c!{2-n'h-c-sfh- Ar' Of • - - c« o . i o vl C » w'A ,n , t Z T" ? * M.p., °C. Recryst.

{Example n') sclver.c. Salt L ^ ^592- 3 \ /' \ / % i ; /AvA : t < 0 153 echer (37b) y« CL Vv .•nethar.esulfonate hemihydrate 4552- C (37c) 2 A L ll V Cl 1 Cl ,AA ^ • •< » 1 i !> L .\v 7 V V 0 135 ether g lycolate i A A 124 45924 D 2 // \ 0 ethyl acetate (37d) V'ci ! I I VV gluconate Cl ! 1 ✓v A 1/0 * ■» w 45924 £ 2 A 0 hexane (37e) ! n Y c.i Cl 1 i 1! vv crifluoroacecate 24 54 11 05 Id 45924 ? (37:) 45923 A (88) 4530S A (S9) ^oo/i a (90) 45671 A ran \ / i i! y, ci M i i ii vV vci ci i ci '\ ' //V I li Cl CH-> unv i cl 133 ether isethionate 132 ethe: uri 120 etr.er HCl. 0.5 H2O 1uj-1u/ ether/isopropanol HCl . H2O 96-93 hexane 24 54 11 46670 A (92) 45903 A (53) 46937 A (94) 46986 A (95) // i V cl cl // cl cl ti V« i ci '/ ./ s. ii V f cl cl r V CH-> A i ii y CCCH3 A i / cl V ci 178 echer HCl 135 ether HCl 225 ether hydrochloride 215 ether hydrochloride 0 /, n A 1 / u j -f i EXAMPLE 35 Ser.zyi N- [4- ( 4-benzylpiperidin-l-yl)-2-(3 , 4-dichlorophenyl)butyl]carbamate hydrochloride.

SR 46940 A 05 _ Ar' = •*/' CI ;R = H;T-Z = -C-0 -CK2 0 ci 2.26 g of l-amino-4-(4-benzylpiperidin-l-yl)-2- (3,4-dichlcrophenyl) butane hydrochloride and 0.39 g of benzyl chloroformate are dissolved in 30 ml of methylene chloride. The mixture is cooled to 0°C and a solution ox 1.52 s of triethylamiiie in 10 nil of nictliy— 20 lene chloride is then added. The reaction mixture is left for 1 hour at room temperature and then concentrated under vacuum. The residue is taken up in water, extracted with ethyl acetate, washed with a 10% solution of sodium hydroxide and then a saturated solution 25 of sodium chloride, dried over MgSCU and concentrated under vacuum. The residue is chromatographed on silica gel using a 96/4 methylene chloride/methanol mixture as the eluent. After concentration of the pure fractions under vacuum, the residue is taken up in ether, a 30 solution of hydrogen chloride in ether is added and the hydrochloride is filtered off. m = 1.7 g M.p. = 130°C.

O 9 I K h 1 05 £ a - 61 - EXAMPLE 97 Ethyl >J-[ 4- (4-benzylpiperidin-1-y1) -2-(3,4-dichlorophsnyl)butyl]carbamate hydrochloride \ /x' /t~\ /"a (I) : Ar - C - Y N - = (' \y- CH? V N- ; si = 2 ; Q = H ; w v/ Ar' = cl ;r = h ;T-z = -C-0 -C0H5 0 c: 9.S g of l-amino-4-( 4-benzylpiperidin-l-yl )-2-15 (3,4-dichlorophenyl)butane dihydrochioride and 6.7 g cf triethylamine are dissolved in 200 ml of methylene chloride. 2.25 g of ethyl chloroformate are added dropwise to this solution at room temperature and the reaction mixture is left to stand for one hour at room 20 temperature, with stirring. The reaction mixture is concentrated under vacuum and the residue is taken up in ethyl acetate/water and washed successively with a 5% solution of sodium hydroxide, water and a saturated solution of sodium chloride. The organic phase is 25 dried over Na2SC)4 and concentrated under vacuum to give a residue, which is chromatograpned on silica gel using a 94/6 methylene chloride/methanol mixture as the eluent. Concentration of the pure fractions gives a residue, which i3 taken up in ethyl acetate. A solu-30 tion of hydrogen chloride in ether is added to the ethyl acetate solution and the hydrochloride is filtered off. m = 6. 5 g M.p. = 108-110°C. 05 24 5 4 1 1 EXAMPLE 98 N-Methyl-N-[4-{4-benzylpiperidin-l-yl)—2—(3,4— dichlcrcphenyI)butyl]-2,4-dichlorobenzamide hydrochloride. SR 46650 A X' \ / /~\ (I) : Ar - C'- Y' \v; - = -V Vy- CH? V 'N- ; a = 2 ; Q = H ; \ / \-/ \_/ 3.) 4-(4-3enzylpiperidin-l-yl)-2-(3,4-dichiorophenyl)-l-N-methylaminobutane hydrochloride 6.5 g of the product obtained in Example 97 and 1.6 g of lithium aluminum hydride are dissolved in i5u ml of tetra'nydrofuran ana refluxea for 5 hours. 20 The reaction mixture is hydrolyzed by the addition of a 2 N solution of sodium hydroxide and then filtered on Celite. The filtrate is concentrated under vacuum, the residue is taken up in ethyl acetate and the hydrochloride is obtained by the addition of a solution of 25 hydrogen chloride in ether. m = 4 . 3 g M.p. = 234-236°C. b; 5R 46650 A SR 46650 A is obtained by reacting 2,4-ai-30 chlorobenzoyl chloride with the product obtained above, following the procedure described in Example 1. M.o. = 140-i42°C. 05 * 10 - DO - 2 4 5 4 11 EXAMPLE 99 N- ; i-Arninohexy 1 )-N- [ 4- ( 4-ber.zylpiperidin- 1-yl )-2- (3,4-dicnlorophenyl )butyl]-2,4-dichiorober.2amide di-hydrochloride hernihydraLe. SR 45510 A X^ X' Cl) : Ar -Y- 'i \ - = VV XV CH2 V XN'- ; a = 2 ; Q = H ; \ / ^ CH: -/ V ; a = 2 ; V/ \y Ar' = - //' Cl ; 3 = - CH: " (CH.2)i " CH2 " NH; ; \—/ cl ,/ cl / / cl a) 4-(4-3enzylpi?eridin-l-yl)-2-(3,4-dichiorophenyl)-l-N-tritylaminopentylamidobutane 3 g of l-amino-4-(4-ber.zylpiperidin-l-yl)-2-(3 ,4-dichloropher.yl)butane hydrochloride are suspended in 60 ml of methylene chloride in the presence of 25 3.2 ml of triethylamine. After the diamine has dissolved, 2.5 g of tritylaminocaproic acid and then 3.2 g of BOP are added. The reaction mixture is stirred at room temperature for 30 minutes, washed with water, a dilute solution of sodium hydroxide and then water, decanted, 30 dried over MgS04, filtered and concentrated under vacuum. The residue is chrcmatographed on silica gel using a 95/5 methylene chloride/methanol mixture as the eluent. Concentration of the pure fractions gives 3.6 g of the expected product. 2 4 5 4 1 b) 4- ( 4-3enzylpiperidin-l-yl )-2- ( 3, 4-dichloropher.yl )-l-N-(i-tritylaminohexyl jaminobutane 3.5 g o£ the product obtained above are dissolved in 40 ml of tetrahydrofuran and added dropwise 05 to a suspension of 600 mg of lithium aluminum hydride in 20 mi of tetrahydrofuran. The reaction mixture is refluxed for IS hours and then cooled, hydrolyzed, filtered ar.d concentrated under vacuum. The residue is chrcmatcgraphed cr. silica gel using an 30/2C methylene 10 chloride/methanol mixture as the eluent. Concentration of the pure fractions gives 1.9 g of the expected product . c) N-[4-(4-Benzyipi?eridin-i-yl)-2-(3,4-dichloro-p'nenyl )-N-( I-*sritylaminohexyl )aminobutyl]-2 , 4- dichlorobensamide l.S g of the product obtained above are dissolved in 30 mi of methylene chloride. The solution is cooled to -200 C and 0.57 g of 2,4-dichlorobensoyl chloride in 10 ail of methylene chloride is then added. 20 The mixture is left to return ^o rocm temperature, washed twice with water, decanted, dried over MgSCU and concentrated under vacuum. The residue is chromato-graphed on silica gel using a 95/5 methylene chloride/ methanol mixture as the eluent. Concentration of the 25 pure fractions gives 1.5 g of the expected amide. d) SR 46510 A 1.5 g of the tritylated derivative obtained above; are dissolved in 15 mi of a 50% solution of formic acid in water and stirred at 60°C for one hour. 30 The cooled mixture is filtered and the filtrate is concentrated under vacuum. The residue is taken up in water, washed with ether, rendered alkaline with sodium hydroxide, extracted with methylene chloride, decanted, dried over MgS04 and concentrated under vacuum. The 35 residue obtained is taken up in 5 ml of methylene 2 4 5 4 1 1 - dc - chloride, and a solution of hydrogen chloride in ether is added until the ?H is 1. m = 1 g M.p. = 100'C (decomposition). 05 C\ / f t -? - CO - 7A3LE / t. ch3 // vV CH- -V S- (Cib),n - CH - CH-> - N - C - 2 \ I " 11 N—/ A 0 aW 5r Examole i3 Elemental analysis C H X Calculated Z Found o or M.p. °C and Salt ► 7327 A (ICO) .7352 A (101) 47239 A (102} >■7329 A (103) 3-Cl 3-Cl 3-Cl 4-Cl 4-Cl 4-Cl / / V II ii s / V / 60.70 5.37 5.03 60.73 6.75 4.93 HCl. 38 HCl 59.94 6.10 4.99 59.84 6.10 4.35 HCl. 0*5 HoO 59.94 6.10 4.99 59.83 6.30 4.77 HCl. 0.5 H2O 24 5 4 1 1 47241 A (104) (los: 47240 A (106) 3-Cl 3-Cl ■cl 4-Cl 4-Cl 4-Cl A/ v cl // V cl 60.57 6.31 4.87 60.3S 6.47 4.74 HCl. 0.5 H^O 64.92 6.54 5.04 64.59 6.77 4.38 HCl . 0.5 H2O 53.36 5.63 4.39 53.46 5.65 4.63 HCl. 0.5 H?0 / 4 ^ L 1 1 L, "t —ill EXAMPLE 107 N-[4-( 4-BenzyIpiperidin-l-yl) —2— ( 3, 4-dichloro-phenyl)-2-isobutylbutyl]-2,4-dichlorobenzamice hydrochloride. SR 46753 A a) 4-(4-Senzyipiperidin-l-yl)-2-(3,4-dichiorophenyl)-2-20 isobutylbutyror.itrile 6 g of 4-(4-benzylpiperidin-i-yl)-2-(3,4-di-chlorophenyD'cutyronitrile are dissolved in 70 ml of anhydrous ether in the presence of 0.S2 g of sodium amide. The reaction mixture i3 refluxed for 2 hours 25 and then left to return to room temperature and 2.12 g of l-bromo-2-methylpropane are added. The reaction mixture is refluxed for 24 hours and concentrated under vacuum. The residue is taken up in water, extracted with ethyl acetate, decanted, dried over MgSO-i, fil-30 tered and concentrated under vacuum.

The expected product is obtained after purification by chromatography on silica gel using a 90/10 hexane/ethyl acetate mixture as the eluent. - s3 - 24 5 4 1 b ; i-Air.ir.3-4- ( 4-benzylpiperidin-l-yl ) -2- ( 3 , 4-dichioro-pnenyl )-2-i3obutylbutane 2.5 g of the product obtained above are dissolved in a mixture of 30 ml of ammonia and 20 ml of 05 water. A catalytic amount of Haney nickel is added and hydroger.ation is carried out at atmospheric pressure and at rccm temperature. The catalyst is filtered off and the filtrats is cor.cer.:ra:ec under vacuum. The residue is taken up in methanol and the hydrochloride 10 is obtained by the addition of a solution of hydrogen chloride in ether. c) SR 46753 A SR 45753 A is obtained by reacting the product obtained above with 2,4-dichlorobenzoyl chloride, as 15 described in Example 1.

M.p. = 126°C.

The compounds described in Table 5 were synthesized according to Example 107.

In the formula celcw, the group Ar" indicated 20 in Formula I is a 3,4-dichlorophenyl group and the group Z is a 2,4-dichloropher.yl group.

TA3LE 5 /V* q h t i / "i "3 // v-cl // cl \ cl cl Product SR rr (example M.p., "C. Recryst. solvent. Sale n (ICS) -(CH2)3-N / ch3 s CH3 1-5-15 7 methylene chloride/ethe: 2 HCl -0,0- (109"; •cch9)?-.n,/ vch? \ i 124 pencar.e/echer 2HC1. H?0 •*0300 Cue) -cch2)3"n / \ 135-144 methylene chloride/ether 2HC1. H2O 24 54 11 EXAMPLE ill N- [ -4- (4-rentcy l?i?er idir.-l-y 1) -2- ( 3 , 4-dichloro-pnenyljbutylj-2,4-dichlorobenzamide hydrochloride. SR 46153 A cd x :<• \ / / Ar - C'- Y* n - = \y c ^n- \=/ 0 Y/ = 0 2 ; 0. = H ; ^c: ci' a) 3-[3,4-Dichlorcphenyi)-l-(tetrahydropyran-2-yloxy)-3-nitrilcpropane g of sodium hydride as a 55-50% dispersion in oil are suspended in 200 ml of dry tetrahydrofuran. A solution of 35 g of 3,4-dichlcrophenylacetonitrile in 20 500 ml of tetrahydrofuran is added dropwise at 20°C, in 30 minutes, and the reaction mixture is then stirred at room temperature for 2 hours. The mixture is cooled to -200C, a solution of S3 g of l-bromo-2-tetrahydropyranyl-oxyethane in 100 ml of tetrahydrofuran is added, the 25 mixture is left to return to room temperature and, after 2 hours, a solution of 50 g of ammonium 'chloride in 3 liters of water is added. The mixture is extracted with 1.5 liters of ether, washed with a saturated solution of sodium chloride, decanted, dried over MgS04 30 and concentrated under vacuum.

The residue is chrcmatographed on silica gel using methylene chloride as the eluent. The pure product fractions are concentrated under vacuum to give 83.5 g of an oil. o t n / 4 / 5 ^ 1 b - l-Arr.ir.o-2- ( 3 , 4-dicnlorophenyl) -4- ( tetrahydropyran-2-yicxy) butane 33.6 g of the r.itrile obtained above are dissolved in ICC .Til of absolute ethar.cl. 350 ml cf con-05 cer.trated ammonia are added and P.ar.ey nickel (10% of the amount cf starting amine) is then added while sweeping with nitrogen. Hydrcgenaticr. is then carried out under a hydrogen atmosphere at room temperature and orainary pressure. 11. S liters of hydrogen are absorbed in 3 hours. The cacalyst is filtered off on Celite, the filtrate is concentrated under vacuum and the residue is taken up in a saturated solution of sodium chloride. 32.5 g of an oil are obtained after extraction with 15 ether and drying over MgSC^. o) l-( 2,4-Dichlcrocenzoylamino)-2-(3,4-dichlorophenyl)-4-(cetrahydropyran-2-yloxy)butane g 3f the amine obtained above are dissolved i.'. GOG ii:l <~>Z me thy -cae c.'i.'.nce. The scxut^on is 20 cooled to 0°C and 38.4 ml of triethylami.ne and then 55 g cf 2,4-dichiorobenzoyl chloride are added. The reaction mixture is subsequently stirred at room temperature for one hour and then washed with water. The organic phase is decanted, dried over MgS04 and con-25 centrated under vacuum to give 120 g of an oil. d) l-(2,4-Dichlorobenzoylamino)-2-(3,4-dichlorophenyl)-butan-4-ol 120 g of the product obtained above are dissolved in 1 liter of methanol in the presence of 12 g 30 of paratciuer.esulfonic acid. The reaction mixture is stirred for 18 hours at room temperature and then concentrated under vacuum. The residue is taken up in methylene chloride anc washed with a 10% solution of sodium carbonate. The organic phase is decanted and 35 dried ever MgSCU to give 106 g of an oil. o / n ' * «i / l~.' . f £»} $ J e ) I-.;:, 4-Bichicrobenzoy lamino)-2-(3, 4-dichlorophenyl )-4 —me sy 1 oxy bu t cr.e 106 g of the alcohol obtained above are dissolved in 1 1 of methylene chloride, the solution is 05 cooled to 09C and 44 mi of triethylamine and 24.2 ml of mesyi chloride are then added. The reaction mixture is stirred at 0°C for 45 minutes, washed 3 times with iced water, decanted, dried over MgSCU and concentrated l*nci0r* vclciiwiiii« The residue is recrystallized from isopropyl e ther. m = 35 g. s \ ^ z? « ^ • r: o * — j »-»- v -t - 3 g of the mesylate obtained above and 3.1 g of 15 4-benzcylpiperidine are dissolved in 7 ml of methylene chloride and the reaction mixture is refluxed for - 24 hours. The mixture is diluted in methylene chloride and washed with water, then with a dilute solution of sccium hydroxide and then again with water. The 20 organic phase is decanted, dried over MgSCU and concentrated under vacuum. The residue is chrcmatograpr.ed on silica gel using a 70/30 methylene chloride/methanol mixture as the eluent.

The pure product fractions are concentrated 25 under vacuum, the residue is diluted in methylene chloride and the hydrochloride i3 obtained' by the addition of a solution of hydrogen chloride in ether. m - 92C mg.

C H N : Calculated % 55.33 4.84 4.49 C29H23CI4N2O2.HCI.O.5H2O : Found % 55.69 4.97 4.71 The compounds of the Examples listed in Table 6 (I, Ar' = 3,4-dichlorophenyl; Z = 2,4-dichlorophenyl) were prepared according to Example 111. 9 /, n a v ~y ! The compcur.ds of the Examples listed in Table 7 (I. Ar' = 3.4-dirhloropher.yl) and Table 8 (I, Ar' = 3,4-dichlorophenyl or 3-trifluoromethylphenyl) were prepared according to Example 1, 2 or 3. 05 _ 75 - •»** t v.* P 1% 4 1 ^ TA3LZ 6 X X' _ H \ / / \ i // \ Ar - C - Y K-CH-j-CH^-CH-CHi-N-CV ^ \—/ ' A ' cl cl \ 0 >=• cl / v-Cl Produce SR n3 (Example n3) X X' ar -V- : n'- \ / Elemental analysis : H 'J Calcul2t2G "j Found % Sale ► / 4 ■» 0 A (112) 46415 A (113) *6160 A (114) CH-> .\ HC /\ I n \ • \ H i \ /> n OK CH /A/ I 4 \/\ // v I » V 55.55 5.15 4.47 55 .71 5.25 4 .30 HCl 53.16 4.38 53.36 5.00 HCl 55.65 3 . 3j./2 3.33 HCl. 0.5 H2O £». o / 4.49 4. A 7 4.35 / o - " /, f 1 1 -3 46503 a (115) 46509 a (116) too 19 a (1175 46690 A (113) 47147 (119) 47678 A (120) A /1 \ ./\ /wo ' ^ s-r 3 v ,/V^A !' ii i i A/ !1 \ gch-'ch-i-.v / \ CHs f ~ V V\ \\/ '|X / w o /'' n-ch2v n 1 i T ' v — ! L ? '\ 54.27 4.55 54.50 4.61 HCl. 0.5 H2O 4 .13 32 .32 HCl 51.34 5.27 51.72 5.53 HCl. 0.5 H?0 32.00 52 .Co 2 HCl 53.52 53. 51 4.90 5 .02 £ .53 A.72 HCl. 0.5 HgO ao to ~ ^ J m/ • \J \J 43.21 5.23 2HC1. H?0 4.37 4.22 4.10 3.97 7.32 7.09 O .30 6.42 .72 5.46 3.63 8.28 - 77 46261 A (121) 46445 A (122) 46153 A (123) 4515 7 A (124) 46511 A (125) 46238 A (126) 47343 A (127) . -rv-v V 'u ii 11 / ^ x, I1 '-/ 0 V N- \ / \ / s \u / 2v/ ii . r'V V \ /V\a II ! ! i ./ / V"£v V C?3 ,5. / \ V \ r CH n CH-\ "1 5 4 11 52.53 4.91 4.55 52.91 5.01 4.47 HCl. 0.5 H2O 32.23 4.33 4.51 51.39 4.53 4.33 HCl. 0.5 H2O 55.47 4.97 4.46 55.57 4.97 4.43 HCl. 0.5 H2O 54.05 4.34 4.34 54.10 4.91 4.23 HCl. 0.5 H2O 53.37 4.52 4.19 53.69 4.75 4.05 HCl 56.30 5.35 4.39 55.91 5.29 4C56 HCl .0.5- H2O 49.73 4.74 6.00 50.13 4.72 5.34 2HC1 . H2O <r> f "41 1 05 TABLE 7 /Vc ^ ^ CHo -ST N'- CH2CH2 - CH - NH - T - Z V\i i ci Elemental analysis h n Calculacad * Found % Salt j/./i r - •"*."* r ~ r\ .' « « v. j , j j 2HC1. 0.5 H?0 57.71 5.47 9.28 57.80 5.41 9.21 2HC1. 0.5 H?0 52.63 5.84 8.77 52.19 6.07 8.32 3HC1. H2O S3 a3 ExaniDie rr 4692- A C12SJ 46925 A (129) 46913 A (130) T - 7. \*\j CM - CO V/ ln nh- co ^y/ \/ 1 05 - 46922 A (131) 45915 a (132) 1-6313 A (133) n'hi - CO i \A NH-> - CO -v/ - CO - N'H cl J \ \ // \_/ 50.61 5.31 51.01 5,45 2HC1. 0.5 H?0 53.90 5.83 53.62 6.01 3HCl. H<?0 3.43 8.21 50.61 5.31 50.30 5.43 3HC1. 0.5 H2O 3.43 3.15 8 .54 3.42 945411 \A3LE 3 "( CH-J) m-CH-CHTN'H-C-Z Ar' 05 Product SR n° : m (Example r.3) -6721 A (I3-) 46327 A (135) <*0c5yu a (136) 47099 A (137) Ar' w cl cl iix) /V v/V (- V i... 0ch3 0ch3 \ / ch3 a/ H5C6 N' \ A A v r jj r/\av 0 0 A\ I ! A 'A Cl N Cl M.p., X. Rec: solvent. Salt etr.er 2hci 107-110 CH2CI2/isopropyl ether HCl 113-123 ch2ci2/ec2o HCl 120-130 ch2cl2/et20 HCl 24 5 4 1 1 05 - zo 47157 A (133) 47221 A (139) 47234 A (140) 47437 A (141) 47306 A (142) 47036 A (143) '/ Vcf3 / V„ i cl ch3 i 0 H5C0 s n—m-c6h5 n m ch3 h5c6 \ n ii 11 i n -V ci A A/ v-A n 1 \/V Ii 112 ?entane/£c20 HCl 170-174 CH2Cl2/isopropyl ether HCl ch2ci2/ec2o HCl 93-100 echer HCl 124 isopropyl ether/O^C^ HCl 159-161 AcOEt: HCl 0 fi R A i S i /v\ ii v\ // 153-155 ch2cl2/echer HCl 200 AcOEc HCl 130 isopropyl ether HCl 05 ?. 4 5 4 1 1 EXAMPLE 147 N- [4-(4-Benzylpiperidin-l-yl)-2-(3,4-dichlorophenyl) butyl] -2, 4-dichlorobenzamide ( + ) hydrochloride. SR 47050 A X X' (I*) : Ar -V- JH - = CH2 ->/ ; a = 2 ; Q = H ; The optical rotations cf the compounds below were measured at 25''C.

A) M - (1-Phenylethyl) -0- (tert-butoxycarbonylaminc-methy1)-3,4-dichlorobenzenepropionamide 1 A solution of 39.5 ml of diisopropylaaiine in 200 ml of anhydrous THF is introduced into a 2-liter three-necked flask swept with nitrogen. The solution is cooled to -SO°C and the following are added in order at this temperature: - 176 ml of a 1.6 M solution of butyllithium in hexane, - 50 g of 3,4-dichlorobenzeneacetonitrile in 300 ml of THF, and then - 39.4 ml of tert-outyl bromoacetate in 100 ml of THF.

The mixture is left to return to a temperature 30 of 0°C in 2 hours 30 minutes. It is poured into 3 1 of a saturated aqueous solution of ammonium chloride. The mixture is extracted twice with ether and dried over magnesium sulfate and the solvents are evaporated off. The oil obtained is chromatographed on 1 kg of silica H 35 using a 95/5 cyclohexane/ethyl acetate mixture as the - a4 - 24 54 11 eluent. This gives 44.3 g of tert-butyl .3-cyano-3, 4-dichlorcbenzenepropionate.

M.p. = 67 *C. step 2 A mixture of 40 g of the product obtained above (Step 1;, 700 ml cf absolute sthar.oi, 200 ml of concentrated ammonia (20%) and 2 spatulas of Rar.ey nickel is stirred under a hydrogen atmosphere for 5 hours. After filtration of the catalyst and evaporation of the solvents, 38.3 g of tert-butyl 3-aminomethyl-3,4-di-chlorober.zenepropionate are obtained in the form of an » i on. ~ t e d 3 A solution of 23.5 g of the product obtained above (Step 2) in 150 ml of methylene chloride is cooled to -10°C. 250 ml of trifiuoroacetic acid are added and the mixture is then left to return to a temperature of 20"C in 1 h 30 min.

After removal of the solvents, 27 g of p-amino-methy1-3,4-dicnlcrobenzenepropicnic acid trifluoro-acetate are obtained in the form of an oil.

Stgp 4 150 ml of dioxane, then 30 ml of triethylamine and then a solution of 23 g of ditert-butyl dicarbonate in 50 mi of dioxane are added to a solution of 27 g of the product obtained above (Step 3) in 150 ml of water. The mixture is heated at 100°C for 1 hour. The dioxane is removed under vacuum and the solution obtained is washed with isopropyl ether. The aqueous phase is poured into 1.5 1 of a phosphate buffer solution of pK 2. After extraction with ether and drying over magnesium sulfate, the solvents are evaporated off. The oil obtained is crystallized from isopropyl ether to give 20.3 g of 0-(tert-butoxycarbonylaminomethyl)-3,4-dichlorobenzenepropionic acid.

A K L 1 1 The following are added in order to a solution of 10 g of the product obtained above (Step 4) in 150 mi of methylene chloride: 05 - 3 mi cf triethylamine, - 3.5 g of S(-)-a-methylbenzylamine, ana - 14 g of 50? (benzotriazoiyl-N-oxytrisdimethylamino-phosphcniuir. hexafluorophosphate).

.After stirring at room temperature for 1 hour, -10 the mixture is washed with water, then with a phosphate buffer solution of pH 2 and then with a saturated aqueous solution of sodium bicarbonate. It is dried over magnesium sulfate ana the solvents are removed under vacuum to give 12 g of N- (1-phenylethyl )-{3- (tert-15 butcxycarbonylaminome thyi)-3,4-dichlorobenzenepropion-amide. 3) Methyl c2ter of ;3-(2,4-dichlorobenzoylaminomethyl)- 3,4-dichlorobenzeneprcpionic acid (+) . . « Separation cf the diastereoisomers of N- (1- phenylsthy1)-0-(tert-butoxycarbonylaminomethyl)-3,4-dicnlcrobenzenepropionamiae The crude product is a mixture of two dia-stereoisomers. They can be separated by thin layer 25 chromatography. They are separated preparatively by means of chromatography on 400 g of silica H using an 30/20 toluene/ethyl acetate mixture as the eluent. The less polar isomer emerges first ana 5.5 g thereof are collected.

M.p. = 146-147°C [o]d = -43.5° (c = 1 in chloroform).

Step 2 A solution of 5 g of the product obtained above in 10 ml of dioxane and 50 ml of 6 N hydrochloric acid 35 is refluxed overnight. After cooling, the solution is 2 454 11 washed with ether and the acuecus phase is then progressively neutralized with solid sodium bicarbonate until the pH is 7. This gives a precipitate, which is filtered off and washed with water, isopropanol and then ether. After drying, 1.38 g of 0-aminomethyl-3,4-dichlorcber.zenepropionic acid ars obtained.

M.p. = 202-204°C.

St go 3 1.10 ml of thionyl chloride are added to a suspension of 1.85 g of the product obtained above (Step 2) in 20 ml of methanol, cooled to -20°C and under nitrogen, and the mixture is then left to return to a temperature of 20°C. 2 hours later, 200 ml of ether are added ana the product which has crystallized is filtered off and washed with ether. After drying, 2.15 g of methyl 0-aminomethyl-3,4-dichlorobenzenepro-pionate (-) are obtained.

M.p. = 184-136°C [a]d - -4.3r (c = i in methanol,1. 4 A solution of 2,4-dichlorobenzoyl chloride (1.54 g) in 5 ml of methylene chloride is added to a solution of 2.0 g of the product obtained above (Step 3) and 1.5 g of triethylamine in 20 ml of methylene chloride, cooled to 0°C. 5 min later, the solution is concentrated to dryness, water i3 added and extraction is carried out with ethyl acetate. The residue obtained is then crystallized from isopropyl ether to give 2.72 g of methyl 0-(2,4-dichlorobenzoylamino-ethyl)benzenepropionate (+).

M.p. = 105-107 °C [a]D = +26.6° (c = 1 in chloroform).

C) Methyl ester of £3-( 2 , 4-dichlorcbenzoylaminomethyl)-3,4-dichl3robenzsr.epr3picr.ic acid (-) s-.^p 1 Following the procedure described in Example 1 3), Step 1, the more polar isomer is collected using an 30/2C and then 50/40 toluene/ethyl acetate mixture as the elusr.t. Concentration of the fractions gives 5.4 g of N-( 1-phenylethyl)-.6-(tert-butoxycarbonylamino methyl ) -3, 4-dichlorobenzeneprcpicr.amide .

M.p. = 151-152"C LG.jr> = -13.4° (c = 1 in chloroform).

SZ5P 2 y-Aminomethyl-3,4-dichlorobenzenepropionic acid is prepared following the procedure described in Example 1 3), Step 2.

M.p. = 202-204'C.

Stop 3 Methyl J3-aminomethyl-3,4-dichlorobenzenepro-pionate (-) is prepared following the procedure described in Example 1 3), Step 3.

M.p. = 184-185°C [gjd = +3.9" (c = 1 in methanol).

St^p 4 Methyl 0-(2,4-dichlorobenzoylaminomethy1)-3,4-dichlorobenzenepropionate (-) is prepared following the procedure described in Example 1 3), Step 4.

M.p. = 108-109°C [cJd = -27.7® (c = 1 in chloroform).

D) Reduction cf the methyl esters of {3- (2,4-dichlorobenzoy laninomethy1)-3,4-dichlorobenzenepropionic acid (+) or (-) First of all, a 0.5 M solution of calcium boro-hydride in THF is prepared by stirring a suspension of sodium borohydride (0.1 mol) and calcium chloride (0.05 mol) in 100 ml of THF for 3 hours. 13 ml of this 2 4 5 4 1 solution are then added to a solution of 2.5 g of the methyl ester of .3- (2 .--dichlcrobenzoylarnincmethyl )-3, 4-dichlorobenzenepropionic acid (->■) or (-) in 20 ml of THF. The mixture is stirred overnight. The next day, 05 the solution is cooled to 0°C and subsequently hydro-lysed with water ana then dilute hydrochloric acid. After extraction with ether, the practically pure alcohol (-) cr •;-) is collected in the form of an oil. Z) Preparation of the mesylate (methanesulfonate) deri-10 vatives of V-(2, 4-dichlorobenzoylaminoinethyi)-3 ,4-dichlorobenzenepropanol (+) or (-) 1.3 g of the alcohol obtained above are dissolved in 30 mi of methylene chloride, the solution is cooled to 0°C and 0.5 ml of triethylamine and 0.3 ml of 15 mesyl chloride are then added. The reacticr. mixture is stirred at O'T for 45 minutes, washed 3 times with iced water, decanted, dried ever MgSO-* and concentrated under vacuum.

The residue is chromatograp'ned on silica gel 20 using a 60/40 ethyl acetate/pentane mixture as the eluent. The pure fractions are concentrated under vacuum.

Thus, starting from the ester (+), a residue is obtained which is recrystallized from isopropyl ether 25 to give 1.1 g of tf-(2,4-dichlorobenzoylaminomethyl )-3,4-dichlorobenzenepropanol ( + ) methanesulfonate.

M.p. = 74-77°C [a]D = +21.2" (c = 1 in chloroform).

Thus, starting from the ester (-), ^-(2,4-30 dichlorobenzoylaminomethyl)-3,4-dichlorobenzenepropanol (-) methanesulfonate is obtained following the above procedure.

M.p. = 72-7S°C [ci]d = -22.5° (c = 1 in chloroform). ? /, r /• -f ?) Preparation of N-C4-(4-benzylpiperidin-l-yl)-2-(3,4-dichlorcphenyl)butyl: -2 . 4-dirhlorober.camide ( + ) hydrochloride. SR 47050 A 0.5 g of the mesylate (t-) obtained above and 05 0.54 i of 4-benzylpiperidine are dissolved in 1 ml of dimethyIformamide and the reaction mixture is heated at S0°C for 30 minutes. Water is added and extraction is carried out with ethyl acetate. The organic phase is concentrated under vacuum and the residue is chromato-10 graphed or. silica gel using a 97/3 methylene chloride/ methanol mixture as the eluent.

The pure product fractions are concentrated under vacuum, the residue is diluted in methylene chloride ana the hydrochloride is obtained by the 15 addition of a solution of hydrogen chloride in ether, m = 0.5 g [c]d = f14.0° (c = 1 in chloroform).

EXAMPLE 143 N'- [ 4- (4-3enzylpiper idin-l-yl) -2- (3,4-dichloro phenyl )butyl]-2,4-dichlorobenzamide (-) hydrochloride. SR 47051 A v... /v ch2 y~\.; (I") : Ar - C - /^~ ' m = ~ ; Q = H ; Ar' = V- Cl ; R = H cl £R 47051 A is obtained following the same procedure as above (according to Example 147 F) ) , except that the mesylate isomer (-) is used as the starting c / r™ 4 materia:. [a]D = -14.5° (c = 1 in chloroform).

EXAMPLE 149 05 The compound below is prepared following the procedure described in Example 147 above: - M — C 4 — (4-benzylpiperidin-l-yl)-2- (3, 4-difluorophenyl)-butyl]-2, 4-dichlorobenzamide (-) hydrochloride. SR 47243 A x x' /, (I") : Ar -NC/- Y' N - = // CH" N- ; m = 2 ; Q = H V_/ W " V./ [cOd = -8.5" (c = 1 in chloroform).

EXAMPLE 150 The compound below is prepared following the procedure described in Example 147 above: 25 - N-[4-(4-benzylpiperidin-l-yl)-2-(3,4-difluorophenyl)-butyl]-2.4-dichlorobenzamide f+) hydrochloride.

SR 47238 A X X' (I*) : Ar - Z - Y N- ; m = 2 ; Q = H ; -SI- 4 54 1 1 ~-Io = t".3° (c = 1 in chloroform). example 151 .N'- £ 4- ( 4-BenzyIpiper idin-I-y 1)-2-( 3, 4-dichioro-p'nenyl )butyl ]-4-f luorcr.aphthalene-l-carboxamide ( + ) and (-) hydrochloride .. «. » A A (:*) • -nc/- y n - = /' ch") m- ; m = 2 ; Q - h \ / \ _/ Ar = -v sr:go 1 l-Amino-2- ( 3,4-dichlorophenyl)-4-hydroxybutane 150 ml of a saturated solution of hydrogen chloride in ether are added to a solution of 149 g of 4-(tetrahyaropyran-2-yloxy)-2-(3,4-dichlorophenyl)-l-aminobutane in 700 ml of methanol. The mixture is stirred for hour at room temperature and concentrated under vacuum and the residue is taken up in 500 ml of water and washed with ether. The aqueous phase- i3 rendered alkaline with a solution of sodium hydroxide ana extracted twice with methylene chloride. The organic phases are dried over MgSO-*, filtered and concentrated under vacuum. The residue i3 taken up in 400 ml of isopropyl ether and the mixture is stirred for one hour at room temperature. The precipitate is filtered off and washed with ether. m = 98.2 g M.p. = 90-91°C. ^ k £ 1 1 c $ 'J *T k I step 2 (r)-Ep.an'iomer of l-amino-2-( 3, 4-dichlorophenyl )-4-hydroxybutane A solution of S3 g of the racsma-e, previously prepared according to Step 1, in 300 ml cf methanol is added to a refluxing solution of 59.55 g of D(-)-tartaric acid in 2 liters of methanol. The mixture is left to return to rocm temperature and the crystals are filtered off, washed with methanol and dried under vacuum at 50°C over P2O5. m = 64.5 g [a]o = -5.2° (c = 1 in water).

The product is then recrystallized from 2.96 I of methanol and the crystals are filtered off, washed with methanol and dried under vacuum at 50°C over ?20s. m = 45 . 3 g = -4.5° (c = 1 in water) M.p. = 2019 C.

The D(-)-tartrate is taken up in 250 ml of water, rendered alkaline with a concentrated solution of sodium hydroxide, extracted with 3 times 200 ml of methylene chloride, washed with a saturated solution of sodium chloride, decanted, dried over MgSO-4, filtered and concentrated under vacuum. The residue is taken up in isopropyl ether, the mixture is stirred for one hour at room temperature and the crystals are filtered off and washed with isopropyl ether. m - 24.7 g [a]o = +9.0° (c = 1 in methanol) M.p. = 79-30°C.

(-)-Enantiomer of l-amino-2-(3,4-dichlorophenyl ) -4-hydroxybutane The (-)-enantiomer i3 obtained following the above procedure and using L(+)-tartaric acid. [ci]d = -9.2° (c = 1 in methanol) 24 54 11 M.p. = 79-80°C.

Step 3 N-[2- (3,4-Dichloropheny1)-4-mesyloxybutyl]-4-fluorona?hthalene-l-carboxamide ((-)-enantiomer) A solution of 4.45 g of 4-fluoronaphthoyl chloride in 50 ml of methylene chloride is added drop-wise at -S0°C to a solution cf 5 g of the product obtained above i. (i-)-enantiomer) in 100 ml of methylene chloride in the presence of 2.5 g of triethylamine. The mixture is stirred for 15 minutes at -50®C and left to return to a temperature of -30°C. 2.5 g of triethylamine ana 2.7 g of mesyl chloride are then added and the mixture is left to return to room temperature. It is washed with water and the organic phase is dried over MgSC'4 and concentrated under vacuum. The residue is chromatographed on silica gel using a 99.5/0.5 methylene chloride/methanol mixture as the eluent.

The pure fractions are concentrated under vacuum. m = 3.4 g [a]D = -22.8® (c = 1 in methanol).

N-[2-(3,4-Dichloropheny1)-4-mesyloxybutyl]-4-f luoror.apnthaiene-1-carboxamide ((+)-enantiomer) The (+)-enantiomer is obtained following the procedure described above in Step 3, except that the (-)-enantiomer of Step 2 is used. [a]s = +22.7° (c = 1 in methanol).

St.ep 4 N— C 4— C4-Benzylpiperidin-l-yl)—2—(3,4-dichlorophenyl )butyl]-4-fluoronaphthalene-l-carboxamide hydrochloride. (-)-Enantiomer. SR 48225 A 7 g of the (-)-enantiomer obtained in Step 3 and 5.02 g of 4-benzylpiperidine are dissolved in 15 ml of dimethylformamide and the reaction mixture is heated at 70 °C for two hours. The mixture is poured into 4 5 4 i 1 water and extracted with ethyl acetate and the organic phases are washed with a saturated solution of sodium chloride, dried over MgSCU and concentrated under vacuum. The residue i3 c'nrcmatographed on silica gel 05 using a S7/'3 methylene chloride/methanol mixture as the eluent.

The pure product fractions are concentrated under vacuum, the residue is diluted in methylene chloride and the hydrochloride is obtained by the 10 addition of a solution of hydrogen chloride in ether. m = 6.2 g [i]d = -35.5' (c = 1 in methanol).

It)-Enantiomer. SR 43225 A The (+)-enantiomer is obtained following the 15 same procedure as for the (-)-enantiomer prepared above, except that the (f)-enantiomer obtained in Step 3 is used. m = 7 g [c]d = +36.03 (c = 1 in methanol).

EXAMPLE 151 : N-methyl-N £3-(4-benzylpiperidin-l-yl)-2-(3,4-dichlorophenyl)butyl7 phenylacetamide hydrochloride. SR 48172A.

The 4-(4-benzylpiperidin-l-yl)-2-(3,4-dichlorophenyl)-1-methyl amino outane hydrochloride obtained in step a) of example 98 is 25 treated with phenylacetic chl orids acccrH'inn q whs p**cc*ss example 1, to obtain the compound SR 48172A.

Claims (8)

WHAT WE CLAIM IS:-

1. A compound of the formula - r . c-- - v-v _ J 0 0 .* a - (XVI) .ar in which: - E" is a tetrahydropyranyloxy group, a hydroxyl group, or a group X X00 Ar -Xc'- Y N- w - X°0 is hydrogen or a hydroxyl group which is free or protected by an O-protecting group, or is joined to X" below to form a carbon-carbon bond, ■ or X and X°0 together form an oxo group or a di-alkylaminoalkoxyimino group of the formula =N-0-(CH2)p-Am, in which p is 2 or 3 and Am is a dialkylamino group, it being possible for each alkyl to contain from 1 to 4 carbon atoms; - Y is a nitrogen atom or a group C(X"), in which X" i3 hydrogen or forms a carbon-carbon bond with X° ®; - R°° is hydrogen, a methyl group or a group (CH2)n-L°°, in which n is a number from 2 to 6 and L°0 is hydrogen or an amino group which is free or protected by an N-protecting group; - m is 2 or 3; - Ar and Ar' independently are a thienyl group; a phenyl group which is unsubstituted or mono- or disubstituted by a halogen atom, by a C^-C^ alkyl, by a tnfluoromethyl, by an alkoxy in - 96 - which zne 3i<'l is C1-C-, oy a nydroxyi or by a methylenedioxy; or an imidazolyl grouo; it also being possible for Ar1 to be a oenzctmenyl group which is unsubstituted or substituted by a halogen ; a nsshtnyl group which is unsubstituted or substituted h\/ a hsil nn~n* a ni nnony ]_ gr«o>j• nr oD ifJCClyl WfliCrJ "" 3 unsubstitutec or substituted cn the nitrogen by a benzyl arcup; X is hydrogen; anc} Q is hydrogen, a C1-C4 alkyl group or an aminoalkyl group of the formula -(CH2)q.-Ain', in which q is 2 or 3 and Am' is a piperidino, 4-benzylpiperidino or dialkylamino group, it being possible for each alkyl co contain from 1 to 4 carbon atomsj provided that - when m = 2, E°° is a hydroxyl group, R" is hydrogen and Ar' is an unsubstituted phenyl, then Q is different from H, ethyl or propyl - when m = 2, E°° is a hydroxyl group, R°° is hydrogen and Q is hydrogen, then Ar' is different from a 3,4-dimethoxyphenyl group or a 2-thienyl group - when m=3, E°° is a hydroxyl group, Ar' is an unsubstituted phenyl, Q is ethyl, then R°° is not hydrogen ; or one of its salts. 1 f - 97 -

2. A compound according to claim 1, of formula (XVI), in which m, Q and Ar' are as defined in claim 1, E°° is a hydroxy group and R° ° is hydrogen, a methyl group or a group (CH~) -L°, in which n is as defined in claim 1 and L° is 1 2' n hydrogen or an amino group protected by an N-protecting group the said compound being an optically pure form.

3. A compound of the formula Q R°° g-0 - (ch2)m - c - ch2 - N " t " z (V') in which: - G is hydrogen, a tetrahydropyranyl group or a methanesulfonyl group; - R°° is hydrogen, a methyl group or a group (CHj^-L00, in which n is a number from 2 to 6 and L°° is hydrogen or an amino group which is free or protected by an N-protecting group; - m, Ar' and Q are as defined in claim 1; - T is a group selected from o w -(!!- arid -(H-NH-, - ^ ' ' W being an oxygen or sulfur atom; and - Z is either hydrogen, or M or OM when T is the group -C(=0)—, or M when T is the group -C(=W)-NH-, M being hydrogen; a linear or branched C^-Cg alkyl; a phenyl-alkyl in which the alkyl group contains from 1 to 3 carbon atoms and which is unsubstituted or mono- or poly-substituted on - 98 - 21 5 4 1 f the aromatic ring by a halogen, a hydroxyl, an alkoxy having 1 to 4 carbon atoms or an alkyl having 1 to 4 carbon atoms; a pyridylalkyl in which the alkyl group contains from 1 to 3 carbon atoms; a naphthylalkyl in which the alkyl group contains from 1 to 3 carbon atoms; a pyridylthioalkyl in which the alkyl group contains from 1 to 3 carbon atoms; a styryl; a l-methylimidazol-2-ylthioalkyl in which the alkyl group contains from 1 to 3 carbon atoms; a l-oxophenyl-3-indan-2-yl; or an unsubstituted or mono- or poly-substituted aromatic or hetero-aromatic group; provided that when m=3, G is hydrogen, Ar' is an unsubstituted phenyl group, Q is an ethyl group, 0 ii T is - C - and Z is a methyl group, then R00 is different from hydrogen; or one of its salts.

4. A compound according to claim 3, of formula (V'), in which m, Q and Ar' are as defined in claim 1, T and Z are as defined in claim 3, G is hydrogen and R°0 is as defined in claim 2, said compound being in optically pure form.

5. A compound according to claim 3, of formula (V'), in which m, Q and Ar' are as defined in claim 1, T and Z are as defined in claim 3, G is a methanesulfonyl group and Rco is as defined in claim 2, said compound being in optically pure form.

6- A compound according to claim 1, in which Eoc is a v hydroxyl group and Reo is hydrogen. 2p /, ■'>0 - 99 -

7. A compound according to any one of claims 1-6/ substantially as herein described. )

8. A pharmaceutical composition containing as active principle a compound of any one of the preceding claims, together with one or more pharmaceutically acceptable adjuvants. SANOFI ^jfMOy^L, By^/Tneir Attorneys BALDWIN, SON & CAREY