IL115409A - Piperidine derivatives - Google Patents

Description

Piperidine derivatives ELF SANOFI C. 98476 This invention provides novel piperidine derivatives useful as intermediates in the preparation of the pharmacologically active dialkylenepiperidino compounds described and claimed in Israel Patent Specification No. 101763 from which the present application was divided.

The present invention provides compounds of the general formula in which - X is a group -OSCbR', -CH-CH2-Q" or -CH-CN ■ AT" Ax" - P is hydrogen, an N-protecting group (Pro) or a group Z' -T' - provided that when X is -OSO2R1, then P represents an N-protecting group; - Z' is a hydrogen atom or a group M or OM; - M represents hydrogen or a linear or branched C1-C(> alkyl; an -hydroxybenzyl , an -alkylbenzyl or a phenylalkyl in which the alkyl group contains 1 to 3 carbon atoms, unsubstituted, mono- or poly-substituted on the aromatic ring with a halogen, a hydroxyl , an alkoxy of 1 to 4 carbon atoms, an alkyl of 1 to 4 carbon atoms; a pyridylalkyl in which the alkyl group contains 1 to 3 carbon atoms; a naphthylalkyl in which the alkyl group contains 1 to 3 carbon atoms; a pyrxdylthioalkyl in which the alkyl group contains 1 to 3 carbon atoms; a styryl; a l-methyl-2-imidazo- lylthioalkyl in which the alkyl group contains 1 to 3 carbon atoms; a l-oxophenyl-3-indan-2-yl ; an aromatic or heteroaromatic group, said group being unsubstituted or substituted; - T' represents a bond, a -CH2- group or a -C(0)- group; provided that when Z' is hydrogen or OM, ' is other than a bond; - R' represents a C^-C/, alkyl group, a phenyl group or a tolyl group, preferably para-tolyl; - Ar' represents a phenyl, unsubstituted or substituted one or more times with a halogen atom, preferably a chlorine or fluorine atom, with a 0^-03 alkyl, with a trifluoromethyl , with a 0:-03 alkoxy, with a hydroxyl ; a thienyl, pyridyl or naphthyl group, the said groups being unsubstituted or substituted with a halogen, preferably a chlorine or fluorine atom, an indolyl group or a benzothienyl group; - Q" is an amino group or a group: R I -N-T-Z provided that when P is a group Z' -T' - and X is a group -CH-CH2-Q" , Ar' then Q" is an amino group; - R represents hydrogen, a methyl group or a group (CH2-)n-L, where n is an integer from 2 to 6 and L is hydrogen or an amino group; - T represents a group selected from 0 W -"C- and„ -1C1-NH- - W being an oxygen or sulphur atom; and - Z has the same meanings as Z' defined above, provided that when Z is hydrogen or OM, T is other than a group -C(W) -NH-; or their salts.

Formula (XXIV) above comprises the following subclasses of compounds: 1) Compounds of the formula Pro-N y-CH2CH2-OS02R' (II) in which Pro is an N-protecting group and R' is as defined above, and their salts; 2) Arylalkylpiperidines of the formula (CH2)2-CH-CH2-Q" AT' (XXII) in which: - Ar ' is as defined above and either Q' is hydrogen or an N-protecting group and Q' ' is an amino group or a group: R I -N-T-Z where R and T and Z are as defined above, or Q' is a group: Z'-T'- where Z ' , and ' are as defined above and Q '·' is an amino group and' their acid addition salts.

The synthesis intermediates of formula P (XXIII) in which P and Ar' are as defined above, and their salts.

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

The salts of the compounds of formula (XXIV) according to the present invention comprise both those with inorganic or organic acids which permit a suitable crystallisation or separation of the compounds of formula (I), such as picric acid or oxalic acid or an optically active acid, for example a mandelic or camphorsulphonic acid, and those which form pharmaceutically acceptable salts such as the hydrochloride, hydrobromide , sulphate, hydrogen sulphate, dihydrogen phosphate, methanesul- phonate, methyl sulphate, maleate, fumarate, 2- naphthalenesulphonate , glycolate, gluconate, citrate or isethionate .

In particular, in the formula (XXIV), Z and/or Z' represents a mono-, di- or tricyclic aromatic or hetero- aromatic group, capable of bearing one or more sub- stituents, in which a carbon atom of the aromatic carbocycle or aromatic heterocycle is linked directly to the group T or to the group T' .

More especially, the radicals Z and/or Z' can be a phenyl or benzyl group, which can be unsubstituted or optionally contain one or more substituents .

When Z and/or Z' are a phenyl or benzyl group, these groups can preferably be mono- or disubstituted, in particular 2 , 4-disubstituted, but also, for example, 2,3-, 4,5-, 3,4- or 3 , 5-disubstituted; they can also be trisubstituted, in particular 2 , , 6-trisubstituted, but also, for example, i,3,4-, 2,3,5-, 2,4,5- or 3,4,5-trisubstituted; tetra-substituted, for example 2,3,4,5-tetrasubstituted; or pentasubstituted. The substituents of the phenyl or benzyl groups can be: F; , CI; Br; I, CN; OH; NH2; NH-CO-NH2; N02; CONH2; CF3; C^C^ and preferably C1-C4 alkyl, methyl or ethyl being preferred, as well as, for example, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or n-pentyl, hexyl or n-hexyl, heptyl or n-heptyl, octyl or n-octyl, nonyl or n-nonyl as well as decyl or n-decyl; alkenyl containing 2 to 10 and preferably 2-4 carbon atoms, for example vinyl, allyl, 1-propenyl, isopropenyl, butenyl or 1-buten-l-, -2-, -3- or -4-yl, 2-buten-l-yl , 2-buten-2-yl , pentenyl , hexenyl or decenyl; alkynyl containing 2 to 10 and preferably 2-4 carbon atoms, for example ethynyl, 1-propyn-l-yl , propar-gyl, butynyl or 2-butyn-l-yl, pentynyl, decynyl; cyclo-alkyl containing 3 to 8 and preferably 5 or 6 carbon atoms, cyclopentyl or cyclohexyl being preferred, as well as, for example, cyclopropyl, cyclobutyl, 1-, 2- or 3-methylcyclopentyl, 1-, 2-, 3- or 4-methylcyclohexyl , cycloheptyl or cyclooctyl, bicycloalkyl containing 4 to 11 and preferably 7 carbon atoms, exo- or endo-2-norbor-nyl being preferred, as well as, for example, 2-isobornyl or 5-camphyl; hydroxyalkyl containing 1 to 5 and preferably 1-2 carbon atoms, hydroxymethyl and 1- or 2-hydroxy- ethyl being preferred, as well as, for example, 1- hydroxy-1-propyl, 2-hydroxy-1-propyl, 3-hydroxy-1-propyl , l-hydroxy-2-propyl, 1-hydroxy-1-butyl, 1-hydroxy-l- pentyl; alkoxy containing 1 to 10 and preferably 1-4 carbon atoms, methoxy or ethoxy being preferred, as well as, for example, n-propoxy, isopropoxy, n-butoxy, iso- butoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy; alkoxyalkyl containing 2 to 10 and preferably from 2 to 6 carbon atoms, for example alkoxymethyl or alkoxyethyl such as methoxymethyl or 1- or 2-methoxyethyl, 1- or 2-n-butoxy- ethyl, 1- or 2-n-octyloxyethyl ; alkoxyalkoxyalkyl containing from 3 to 10 and preferably from 4 to 7 carbon atoms , for example alkoxyalkoxymethyl , for example 2-methoxyethoxymethyl , 2-ethoxyethoxymethyl or 2-isopro-poxyethoxymethyl , alkoxyalkoxyethyl , for example 2- ( 2-methoxyethoxy) ethyl or 2- ( 2-ethoxyethoxy) ethyl ; alkoxyalkoxy containing from 2 to 10 and preferably from 3 to 6 carbon atoms, for example 2-methoxyethoxy, 2-ethoxyethoxy or 2-n-butoxyethoxy; alkenyloxy containing 2 to 10 and preferably 2 to 4 carbon atoms, allyloxy being preferred, as well as, for example, vinyloxy, propenyloxy, isopropenyloxy, butenyloxy such as 1-buten-l-, -2-, -3- or -4-yloxy, 2-buten-l-yloxy, 2-buten-2-yloxy, pentenyloxy, hexenyloxy or decenyloxy; alkenyloxyalkyl containing from 3 to 10 and preferably 3-6 carbon atoms, for example allyloxymethyl ; alkynyloxy containing from 2 to 10 and preferably from 2 to 4 carbon atoms, propargyloxy being preferred, as well as, for example, ethynyloxy, 1-propyn-l-yloxy, butynyloxy or 2-butyn-l-yloxy, pentynyloxy or decynyloxy; alkynyloxy-alkyl containing from 3 to 10 and preferably 3 to 6 carbon atoms, for example ethynyloxymethyl , propargyloxy-methyl or 2- ( 2-butyn-l-yloxy) ethyl ; cycloalkoxy containing 3 to 8 and preferably 5 or 6 carbon atoms, cyclopentyloxy or cyclohexyloxy being preferred, as well as, for example, cyclopropyloxy, cyclobutyloxy, 1-, 2- or 3-methylcyclopentyloxy, 1-, 2-, 3- or 4-methyl- cyclohexyloxy, cycloheptyloxy or cyclooctyloxy; alkylthio containing from 1 to 10 and preferably 1 to 4 carbon atoms, methylthio or ethylthio being preferred, as well as, for example, n-propylthio , isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, octylthio, nonylthio or decylthio; alkylthioalkyl containing from 2 to 10 and preferably 2 to 6 carbon atoms, for example methylthiomethyl , 2-methylthioethyl or 2-n-butylthioethyl ; acylamino, namely alkanoylamino containing from 1 to 7 and preferably 1 to 4 carbon atoms, formylamino and acetyl- amino being preferred, as well as propionylamino , butyrylamino, isobutyrylamino, valerylamino, capro- ylamino, heptanoylamino, as well as aroylamino or - -benzoylamino ; acylaminoalkyl , preferably alkanoylamino-alkyl containing from 2 to 8 and preferably 3 to 6 carbon atoms, such as formylaminoethyl, acetylaminoethyl , propionylaminoethyl, n-butyrylaminoethyl , formyla-minopropyl, acetylaminopropyl , propionylaminopropyl, formylaminobutyl , acetylaminobutyl, as well as propio-nylaminobutyl , butyrylaminobutyl; acyloxy containing from 1 to 6 and preferably 2 to 4 carbon atoms, acetyloxy, propionyloxy or butyryloxy being preferred, as well as, for example, formyloxy, valeryloxy, caproyloxy; alkoxy-carbonyl containing from 2 to 5 and preferably 2 and 3 carbon atoms, methoxycarbonyl and ethoxycarbonyl being preferred, as well as, for example, n-propoxycarbonyl , isopropoxycarbonyl , n-butoxycarbonyl , isobutoxycarbonyl , sec-butoxycarbonyl or tert-butoxycarbonyl ; cyclo-alkoxycarbonyl containing from 4 to 8 and preferably 6 or 7 carbon atoms, cyclopentyloxycarbonyl , cyclo-hexyloxycarbonyl being preferred, as well as cyclo-propyloxycarbonyl , cyclobutyloxycarbonyl or cyclo-heptyloxycarbonyl; alkylaminocarbonylamino containing from 2 to 4 carbon atoms, such as methylaminocarbonyl-amino, ethylaminocarbonylamino , propylaminocarbonylamino ; dialkylaminocarbonylamino containing from 3 to 7 and preferably 3 to 5 carbon atoms, preferably dime hy1 mino-carbonylamino, as well as di-n-propylaminocarbonylamino, diisopropylaminocarbonylamino ; pyrrolidinocarbonylamino ; piperidinocarbonylamino ; cycloalkylaminocarbonylamino containing from 4 to 8 and preferably 6 or 7 carbon atoms, eyelopentylaminocarbony1amino, cyclohexylaminocar-bonylamino being preferred, as well as cyclopropylamino-carbonylamino, cyclobutylaminocarbonylamino, cyclo-heptylaminocarbonylamino ; alkylaminocarbonylaminoalkyl containing from 3 to 9 and preferably 4 to 7 carbon atoms, methylaminocarbonylaminoethyl , ethylaminocarbonyl-aminoethyl, ethylaminocarbonylaminopropyl, ethyl-aminocarbonylaminobutyl being preferred, as well as, for example, methylaminocarbonylaminomethyl, n-propy1amino-carbonylaminobutyl , n-butylaminocarbonylaminobutyl ; dialkylaminocarbonylaminoalkyl containing from 4 to 11 carbon atoms, for example dimethylaminocarbonylami.no- methyl, diethylamir.ccarbonylaminoethyl , diethylamino- carbonyla inopropyl , diethylaminocarbonylaminobutyl , pyrrolidinocarbonylaminoethyl/ piperidinocarbonylamino- ethyl; cycloal ylaminocarbonylaminoalkyl containing from 5 to 12 and preferably 8 to 11 carbon atoms, cyclopentyl- aminocarbonylaminoethyl , cyclopentylaminocarbonylamino- propyl, cyclopentylaminocarbonylaminobutyl, cyclohexyl- a inocarbonylaminoethyl, cyclohexylaminocarbonylamino- propyl and cyclohexylaminocarbonylaminobutyl being preferred, as well as, for example, cyclopropylamino- carbonylamino.etJny1 , cycloheptylaminocarbonylaminoethyl; alkoxycarbonylaininoalkyl containing from 3 to 12 and preferabl 4 to 9 carbon atoms, methoxycarbonylamino- ethyl, ethoxycarbonyla inoethyl , n-propoxycarbonylamino- ethyl, isopropoxycarbonylaminoethyl , n-butoxycarbonyla- minoethyl, isobutoxycarbonylaminoethyl , sec-butoxycar- bonylaminoethyl, tert-butoxycarbonylaminoethyl , ethoxy- carbonylaminopropyl, nr-butoxycarbonylaminopropyl , ethoxy- carbonylaminobutyl , n-butoxycarbonylaminobutyl being preferred, as well as, for example, n-propoxycarbonyl- aminopropyl, n-propoxycarbonylaminobutyl, isopropoxy- carbonylaminobutyl; eyeloalkoxycarbonylaminoalky1 containing from 5 to 12 and preferably 8 to 11 carbon atoms, cyclopentyloxycarbonylaminoethyl, cyclopentyloxycarbonyl-aminopropyl, cyclopentyloxycarbonylaminobutyl, cyclohexy-loxycarbonylaminoethyl, cyclohexyloxycarbonylaminopropyl, cyclohexyloxycarbonylaminobutyl being preferred, as well as, for example, cyclopropyloxycarbonylaminomethyl , cycloheptyloxycarbonylaminoethyl; carbamoyl lkyl containing from 2 to 5 and preferably 2 carbon acorns, preferably carbamoylmethyl, as well as carbamoylethyl , carbamoylpropyl , carbamoylbutyl ; alkylaminocarbonylalkyl containing, from 3 to 9 and preferably 3 to 6 carbon atoms, methylcLminocarbonylethyl, ethylaminocarbonyl-methyl, n-propylaminocarbonylmethyl , isopropylamino-carbonylmethyl, n-butylaminocarbonylmethyl, isobutyl-aminocarbonylmethyl, sec-butylaminocarbonylmethyl , tert-butylaminocarbonylmethyl being preferred, as well as, for example., ethylaminocarbonylethyl , ethylaminocarbonyl-propyl, ethylaminocarbonylbutyl , n-propylaminocarbonyl-butyl, n-butylaminocarbonylbutyl ; dialkylaminocarbonyl-alkyl containing from 4 to 11 and preferably 4 to 8 carbon atoms, dimethylaminocarbonylmethyl , diethylamino-carbonylmethyl, di-n-propylaminocarbonylmethyl , as well as, for example, diethylaminocarbonylethyl , diethylamino-carbonylpropyl, diethylaminocarbonylbutyl; pyrrolidi-nocarbonylmethyl , piperidinocarbonylmethyl ; piperidino-carbonylethyl ; cycloalkylaminocarbonylalkyl containing from 5 to 12 and preferably 7 or 8 carbon atoms, cyclo-pentylaminocarbonylmethyl and cyclohexylaminocarbonyl-methyl being preferred, as well as, for example, cyclo-propylaminocarbonylmethyl , cyclobutylaminocarbonylmethyl , cycloheptylaminocarbonylmethyl , cyclohexylamino-carbonylethyl, cyclohexylaminocarbonylpropyl , cyclo-hexylaminocarbonylbutyl; alkylaminocarbonylalkoxy containing from 3 to 10 and preferably 3 to 5 carbon atoms, methylaminocarbonylmethoxy being preferred, as well as, for example, methylaminocarbonylethoxy, methylamino-carbonylpropoxy; dialkylaminocarbonylalkoxy containing from 4 to 10 and preferably 4 to 7 carbon atoms, such as dimethylaminocarbonylmethoxy, diethylaminocarbonylethoxy, ( l-piperidyl)carbonylmethoxy; cycloalkylaminocarbonyl-alkoxy containing from 5 to 11 and preferably 7 or 8 carbon atoms, such as cyclopentylaminocarbonylmethoxy, eyelohexylaminocarbonylmethoxy .

The groups Z and Z' are advantageously a phenyl group; a benzyl group; a benzoyl group; a phenylthioalkyl group in which the alkyl is a C!-C3 group; a naphthyl grou .

The phenyl group Z or Z ' is preferably mono- or disubstituted with a halogen or with a C^-C^ alkoxy group, the group 2 , 4-dichlorophenyl being particularly preferred.

The radicals Z or Z ' can also represent a bicyclic aromatic group such as 1- or 2-naphthyl; 1-, 2-, 3-, 4-, 5-, 6-, 7-indenyl; in which one or more bonds may be hydrogenated, it being possible for the said groups to be unsubstituted or optionally to contain one or more substituents such as a halogen, and more particularly a fluorine atom, alkyl, phenyl, cyano, hydroxyalkyl , hydroxyl, oxo, alkylcarbonylamino, alkoxycarbonyl and thioalkyl groups, in which groups the alkyls are C1-C1 groups .

The radicals Z or Z ' can also be a pyridyl, thia-diazolyl, indolyl, indazolyl, imidazolyl, benzimxdazolyl, quinolyl, benzotriazolyl , benzofuranyl , benzothienyl , benzothiazolyl , benzisothiazolyl , isoquinolyl, benzoxa-zolyl, benzisoxazolyl , benzoxazinyl , benzodioxinyl or pyridinyl, isoxazolyl, benzopyranyl , thiazolyl, thienyl, furyl, pyranyl, chromenyl, isobenzofuranyl , pyrrolyl, pyrazolyl, pyrazinyl, pyrxmidinyl, pyridazinyl, indoli-zinyl, phthalazinyl , quinazolinyl , acridinyl, isothi-azolyl, isochromanyl or chromanyl, in which one or more double bonds may be hydrogenated, it being possible for the said groups to be unsubstituted or optionally to contain one or more substituents such as alkyl, phenyl, cyano, hydroxyalkyl, hydroxyl, alkylcarbonylamino, alkoxycarbonyl and thioalkyl' groups , in which groups the alkyls are C1-Ci groups .

The novel compounds of the present invention can be prepared by the following processes: Firstly, the N-protecting and 0-protecting derivative of l-hydroxy-2-(4-piperidinyl) ethane is prepared according to the conventional and usual methods using protecting groups well-known by the person skilled in the art for the N-protecting groups or for the 0-pro- tective groups, according to Scheme 1 which follows, to obtain the protecting amino alcohol which is a novel intermediate being part of the invention.

SCHEME 1 N-protecting agent (II) in which: - Pro denotes an N-protecting group - R' represents a Ci-C^ alkyl group, a phenyl group or a tolyl group, preferably para-tolyl .

The compound of formula (II) is prepared starting from 2-(4-piperidinyl)ethanol, a commercially available product .

In the present description, the terms "N-protecting group," "N-protecting" and "N-deprotection" or simply "deprotection" are used.

The term "N-protecting group" indicates an amino-protecting group of the type used in peptide or nucleotide chemistry, for example an acyl group, such as formyl, acetyl, propionyl; an alkoxycarbonyl group, such as t . -butoxycarbonyl (BOC); an alkoxyalkylcarbonyl group, such as methoxypropionyl ; a substituted alkoxycarbonyl group, such as trichloroethoxycarbonyl ; a substituted alkylcarbonyl group, such as monochloromethylcarbonyl , monochloroethylcarbonyl, dichloroethylcarbonyl , trichlo-romethylcarbonyl , trichloropropylcarbonyl; an aralkyloxy-carbonyl group, such as benzyloxycarbonyl ; a substituted aralkyloxycarbonyl group, such as 4-nitrobenzyloxycar-bonyl or aroyl such as benzoyl, 2 , 4-dichlorobenzoyl or 4- fluoro-l-naphthyl carbonyl. The term "N-protecting" also includes aralkyl groups such as, for example, a benzyl group, unsubstituted or substituted, for example, with 1 or 2 halogen atoms, preferably chlorine or with 1 or 2 alkoxy groups, preferably methoxy; a diphenylmethyl (or benzhydryl) group, a substituted diphenylmethyl group such as di ( -methoxy) diphenylmethyl (or dimethoxybenz-hydryl), a triphenylmethyl (or trityl) group, a substituted triphenylmethyl group, such as 4-methoxyphenyl-di-phenylmethyl (or methoxytrityl ) or di ( 4-methoxyphenyl ) phenylmethyl (or dimethoxytrityl ) . The term "N-protecting" refers to the product which contains the amine protected with an N-protecting group such as defined above .

The term "N-deprotection" or simply "deprotec-tion" indicates the elimination of the N-protecting group and the formation of the free amine according to the conventional methods well-known by the person skilled in the art, for example by reduction or by acid hydrolysis according to the N-protecting group to be eliminated.

The processes for the preparation of the remaining compounds of the invention are illustrated by Scheme 2.

SCHEME 2 Ar'-CH2-CN+ (II) In this scheme, the compounds of formula VII are indicated as being directly obtained from the compound IV. In reality, when R is a substituent other than hydrogen, the said substituent is introduced on the amine of the compound IV according to the methods described in detail below. The same remark applies to schemes 3 and 4.

The starting compounds of formula (III) are prepared starting from nitriles of formula: Ar' -CH2-CN in which Ar' is as defined above, nitriles which are commercial products or products prepared according to known methods, by reaction with a compound of formula (II); then the N-protected aminonitrile of formula (III) is treated according to one of the synthesis routes (a), (b) or (c), which use the same reactions but in different orders .

Thus, the nitrile (III) is subjected to catalytic hydrogenation in the presence of a catalyst such as, for example, Raney nickel to yield the amine of formula: which is a novel intermediate being part of the invention and which is then functionalised either with a functional derivative of an acid of formula: HO-CO-Z (V) in which Z is as defined above, when a compound of formula (VII) is to be prepared in which T is -CO-, or with an iso ( thio ) cyanate of formula: =C=N-Z (VI) in which W and Z are as defined above, when a compound of formula (VII) is to be prepared in which T is -C(W)-NH-, to yield the derivative of formula: (VII, R = H) which is a novel intermediate being part of the invention.

As the functional derivative of the acid (V) , the acid itself is used, appropriately activated, for example, by cyclohexylcarbodiimide or by N-benzotriazolyl oxytris-dimethylaminophosphonium hexafluorophosphate (BOP) , or else one of the functional derivatives which react with the amines, for example an anhydride, a mixed anhydride, the chloride or an activated ester. When Z is a group OM, the acid concerned is carbonic acid and, as a functional derivative, the monochloride , that is to say a chloro-formate C1-C0-0M, is used.

In a variant, the compound of formula (IV ) can be obtained starting from the compound of formula (X) by hydrogenation in the presence of a catalyst, such as Raney nickel .

According to an alternative synthesis route, the aminonitrile (III) is deprotected according to the usual methods to lead to the free aminonitrile of formula: (X) in which Ar' is as defined above, and onto which is added the halogenated derivative (IX) to lead to the nitrile of formula: in which Z' , ', Ar' are as defined above. This compound (XI) is then hydrogenated in the presence of a catalyst such as Raney nickel to yield the corresponding amino derivative of formula: -CH2-NH2 (XII) which is a novel intermediate being part of the invention „ The preparation of the compounds of formula (VII), where R is other than hydrogen is carried out according to methods known per se .

When it is desired to prepare the compounds of Formula (IV) or (XII) in which R is methyl, the free amine, obtained by hydrogenation of the nitriles (III) or (XI) as described above, is treated with a chloroformate, for example with the chloroformate of formula Cl-CO-OAlk, where Alk is a C^-C^ alkyl, preferably ethyl, to obtain the carbamates of formula: or which are then reduced by known means , such as the action of a reducing agent such as, for example, a metallic hydride, such as sodium aluminium hydride or lithium aluminium hydride, or by a boron hydride, such as borane dimethylsulphide . The reduction is carried out in a solvent, such as ether or toluene, at a temperature between room temperature and 60 °C. The methylamines thus obtained of formula: (XVI) or (XVII) are isolated according to the usual methods.

The methylamine of formula (XVI) above can be deprotected to give piperidine of formula: Starting from the compounds of formulae (XVI), (XVI') and (XVII), the N-substituted compounds are prepared in the same manner as described in schemes 2 to 4 starting, respectively, from the compounds of formulae (IV) f (lvi ) and (XII) .

To prepare the compounds of formula (IV) or (XII) in which R is a group -(CH2)n-L, where n and L are as defined above, the free amine, obtained by hydrogenation of the nitrile (III) or (XI) as described above, is treated with a reactive functional derivative, as defined above, of the acid of formula: L° -(CH-J^-COOH in which L° is hydrogen or a protected amino group, to obtain the amides of formula: -CH2- H-CO-(CH2)n_1 -l.' (XVIII) or The amides (XVIII) or (XIX), by reduction under the same conditions as those described above for the nitriles (III) or (XI), give the desired compound of formula: or Z'-T'^ V (CH2)2-CH-CH2- H-(CH2)n-Le AT' (XXI) The alkylamines of formula (XX) above can be partially deprotected to give the piperidine of formula: Starting from the compounds of formula ( X)/ (XX') and (XXI) above, the N-substituted compounds are prepared in the same manner as described further above in schemes 2 to 4 , starting, respectively, from the compounds (IV) ,. (ιν·) and (XII) . -"■ ' - ■ The N-protecting groups optionally present in the group R when L is an amino group are the conventional N-protecting groups well-known to the person skilled in the art and preferably those which can be eliminated by acid hydrolysis, such as the trityl group, the methoxytrityl group and BOC .

The preparation of the compounds (VII) is illustrated by schemes 3 and' 4 shown in detail below.

SCHEME 3 (XII) ou (IV) SCHEME 4 (XII) ou (IV) The acid chloride Cl-CO-Z is therefore considered as a reactive functional derivative of the acid (V) . The reaction with the acid choride is performed in an inert solvent, such as dichloromethane or benzene in the presence of a base such as, for example, triethylamine , at room temperature.

In the particular case where Z=OM, the reaction of the compounds (IV) or (XII) with the chloroformate of formula: C1-C-0M II o is performed according to the usual methods.

When Z is other than OM, another functional derivative can be used or the process can start from the free acid (V) by carrying out a coupling of (IV) or (XII) with BOP (N-benzotriazolyloxytrisdimethylaminophosphonium hexafluorophosphate) , then by adding the acid (V) in the presence of an organic base such as, for example, triethylamine , to a solvent such as dichloromethane or dimethylformamide , at room temperature, the compounds (1^ obtained being isolated and purified according to the usual methods, for example chromatography or recrystallisation.

(IV) or (XII) can also be reacted with an iso( thio) cyanate W=C=N-Z (VI) in an anhydrous inert solvent such as, for example, benzene, overnight at room temperature and the reaction mixture can then be treated according to the usual methods to obtain the compounds (I2)« The products of formula (I) thus obtained are isolated, in the form of free base or of salt, according to the conventional techniques .

When the compound of formula (XXIV) is obtained in the form of free base, the salification is performed by treatment with the chosen acid in an organic solvent. By treatment of the free base, dissolved, for example, in an alcohol such as xsopropanol, with a solution of the chosen acid in the same solvent, the corresponding salt is obtained and is isolated according to the conventional techniques. Thus, for example, the hydrochloride, hydrobromide , sulphate, hydrogen sulphate, dihydrogen phosphate, methanesulphonate , oxalate, maleate, fumarate or the 2-naphthalenesulphonate are prepared.

At the end of the reaction, the compounds of formula (XXIV) can be isolated in the form of one of their salts, for example the hydrochloride or the oxalate; in this case, if it is necessary, the free base can be prepared by neutralisation of the said salt with an inorganic or organic base, such as sodium hydroxide or triethylamine or with an alkaline metal carbonate or bicarbonate . - 28 - The examples which follow illustrate the invention without, however, limiting it.

The melting or decomposition points, M.p., were measured on a Koffler heating block. The 13C nuclear magnetic resonance spectra were performed at 50 MHz in dimethyl sulphoxide .

Example 1 N- [4- ( l-benzyl-4-piperidinyl ) -2- ( 3 , 4-dichlorophenyl ) -butyl] -4-fluoronaphtalene carboxamide hydrochloride This compound is prepared by route (a) of scheme 2.

A) Preparation of 4- ( 2-mesyloxy-l-ethynyl ) -I- tert-butoxycarbonylpiperidine . 65 g of l-hydroxy-2- ( 4-piperidinyl) ethane are dissolved in a mixture of 250 ml of dioxane and 60 ml of water. 120 g of di-tert-butyl dicarbonate are added dropwise. The addition keeps the temperature of the reaction mixture at 50-60°C. The addition completed, the reaction mixture is heated to 80 °C and the solvent is then concentrated in vacuo. The residue is taken up in ether and washed successively three times with water and then with a saturated NaCl solution. The ethereal phase is separated after settling has taken place, dried over Na2S04 and concentrated. 110.2 g of a yellowish oil are obtained. 52.5 g of the oil prepared above and 26.6 g of triethylamine are dissolved in 300 ml of dichloromethane . The solution is cooled in ice and then 28.32 g of mesyl chloride dissolved in 5 ml of dichloromethane are added dropwise; The addition completed, the reaction mixture is heated under reflux for two hours.

The solvent is concentrated in vacuo, the residue is taken up in ethyl acetate and then washed successively with water and with a saturated NaCl solution, and the organic phase is separated, dried over Na2S04 and concentrated in vacuo.

The residue is taken up in a mixture of 70 ml of ethyl acetate and 140 ml of hexane. The crystals are separated by filtration, m = 64 g M.p. = 91°C.

B) 1 -( 3 , -Dichlorophenyl )- 3- ( 4-piperidinyl ) -1 - cyanopropane . 1.74 g of 55% sodium hydride suspended in oil are suspended in 150 ml of tetrahydrofuran and cooled to 5°C. 11.16 g of 3 , 4-dichlorophenylacetonitrile and 12.28 g of the amine prepared above according to A) dissolved in 150 ml of tetrahydrofuran are added dropwise. The reaction mixture is stirred overnight at room temperature and then heated under reflux for 30 minutes. The solvent is concentrated in vacuo, the residue is taken up in a pH = 2 buffer solution and the mixture is extracted with ether. The ethereal phase is washed successively with water and with a saturated NaCl solution, dried over Na2S04 and concentrated in vacuo. 20.2 g of 1-(3,4-dich-lorophenyl ) - 3 - ( l-t-butoxycarbonyl-4-piperidinyl ) - 1-cyano-propane are obtained in the form of an oil.

This compound is deprotected by dissolving it in 100 ml of trifluoroacetic acid and by stirring the solution for 30 minutes at room temperature. The acid is concentrated in vacuo, an oil is obtained which is taken up in a 5% sodium hydroxide solution, the mixture is extracted with ether, and the extract is washed successively with water and then with a saturated NaCl solution, dried over Na2S04 and concentrated in vacuo. The oil obtained is dissolved in 300 ml of ethyl acetate and then hydrochloric acid is bubbled through the solution until it is coloured yellow.

The hydrochloride is separated by filtration. m = 12.4 g M.p. = 182°C C) 3-(l-Benzyl-4-piperidinyl)-1-(3,4-dichloro- phenyl)- 1-cyanopropane. 16.75 g of the amine prepared above according to B) and 15.15 g of triethylamine are dissolved in 150 ml of dichloromethane. 8.98 g of benzyl bromide dissolved in 25 ml of dichloromethane are added dropwise and the mixture is then heated under reflux for one hour. The solvent is concentrated in vacuo and the residue is then taken up in a 5% sodium hydroxide solution. The mixture is extracted with ether and then washed successively with water and with a saturated NaCl solution, dried over Na2S04 and concentrated in vacuo.

The oil obtained is dissolved in 150 ml of ethanol, hydrochloric acid is bubbled through and the hydrochloride is filtered. m = 15 g M.p. = 233°C D) -(l-Benzyl-4-piperidinyl)-2-(3,4-dichloro- phenyl ) - 1 -aminobutane . 13.3 g of the product prepared above dissolved in a mixture of 150 ml of ethanol, 20. ml of concentrated ammonia and in the presence of 2 g of Raney nickel are hydrogenated at atmospheric pressure and room temperature. The hydrogenation completed, the reaction mixture is filtered on Celite and the filtrate is concentrated in vacuo after having twice added 100 ml of absolute ethanol . 13.5 g of a colourless oil are obtained.

E) Compound 1 1.95 g of amine prepared above according to D) , 0.95 g of 4-fluoronaphthoic acid and 1.01 g of triethylamine are dissolved in 40 ml of dichloromethane. 2.21 g of BOP (N-benzotriazolyloxytrisdimethylaminophos-phonium hexafluorophosphate) are added and the reaction mixture is left at r.oom temperature for 24 hours. The solvent is concentrated in vacuo, the residue is taken up in ether and the mixture is washed successively with a 5% sodium hydroxide solution and then with a saturated NaCl solution. The ethereal phase is dried over Na3S04 and concentrated in vacuo. The residue is chromatographed on silica gel, eluent: dichloromethane/methanol 93:7 (v/v) .

Concentration of the pure fractions yields a residue, starting from which the hydrochloride is prepared in ethyl acetate. m = 1.31 g M.p. = 174-176°C.

Example 2 N- [4- [ 1- ( fluorobenzyl ) -4-piperidinyl] -2- (3,4- dichlorophenyl ) -butyl] -2, 4-dichlorobenzamide hydrochloride.

- - This comDound is prepared by route (b) of scheme 2.

A) 1-(3,4-Dichlorophenyl) -3-( 1-tert-butoxycarbonyl- 4-piperidinyl ) - 1 -cyanopropane.

This compound is prepared according to Example 1 step B but is not deprotected.

B ) 2- ( 3 , 4-Dichlorophenyl ) - 4 - ( 1-tert-butoxycarbonyl- 4-piperidinyl ) - 1-aminobutane . 17.4 g of the cyano derivative prepared above are dissolved in 300 ml of ethanol at 95 °C, 20 ml of water and 70 ml of concentrated ammonia in the presence of 2 g of Raney Nickel. The mixture is then hydrogenated at room temperature and atmospheric pressure. The hydrogenation completed, the reaction mixture is filtered on Celite and the filtrate is concentrated in vacuo. The residue is taken up in acetone and the precipitate formed is separated by filtration and then dissolved in ether, and washed with a 10% sodium hydroxide solution and then with a saturated NaCl solution. The ethereal phase is dried over MgS04 and concentrated in vacuo. m = 16.2 g C) . N- [ 2- ( 3 , -Dichlorophenyl) - - ( 1-tert-butoxy- carbonyl-4-piperidinyl ) - butyl ] -2 , 4-dichloro- benzamide. 16.2 g of the amide prepared above and 8.16 g of triethylamine are dissolved in 200 ml of dichloromethane. A solution of 9.31 g of 2 , 4-dichlorobenzoyl chloride is then added dropwise, the reaction mixture is left for three hours at room temperature and then heated to 60 °C for 4 hours, and the solvent is removed in vacuo. The residue is taken up in water and extracted with ethyl acetate. The organic phase is washed successively with a - - 10% sodium hydroxide solution, twice with water and then with a saturated NaCl solution, dried over Na2S04 and concentrated in vacuo. The residue is chromatographed on silica gel, eluent: dichloromethane/methanol 98:2 (v/v) . Concentration of the pure fractions yields a residue which is used as such for the deprotection.

D) N-[ 2- ( 3 , 4-Dichlorophenyl ) -4- ( 4-piperidinyl ) - butyl ] -2 , -dichlorobenzamide .

The residue obtained above is taken up in a sodium hydroxide solution and then extracted with dichlo-romethane. The organic phase is washed with a saturated NaCl solution and then dried over Na2S04 and concentrated in vacuo. The residue is crystallised in ethyl acetate. m = 11.6 g M.p. = 118°C E) Compound 2 1 g of the compound prepared above and 0.81 g of K2C03 are heated to 60 °C in 15 ml of dimethylformamide . 0.37 g of 4-fluorobenzyl bromide is then added and heating is continued at 60°C with stirring for one hour. The solvent is removed in vacuo, the residue is taken up in water and the mixture is then extracted with ethyl acetate. The organic phase is washed successively with a 10% sodium hydroxide solution, with water and then with a saturated NaCl solution, dried over MgS04 and concentrated in vacuo .

The residue is chromatographed on silica gel, eluent: dichloromethane/methanol 98:2 (v/v).

Concentration of the pure fractions yields a residue which is taken up in ethyl acetate and from which the hydrochloride is prepared by bubbling through hydrochloric acid. m = 0.6 g M.p. = 110°C.

The compounds described in Tables 1, 2, 3 and 4 which follow are prepared according to the preceding Examples 1 or 2. -34- Table 1 -35- Table 1 (continued) -36- Table 2 Examplen* Z M.p. ; °C Salt Route 12 146 2HC1,0,8H20 a 13 179 HCl a -37- Table 3 Exampleπ* Ζ' Γ M. p. °C Salt Route 14 125 HC1 a -CH2- 15 0 115 HCI a II -38- TABLE 4 Example 18 -Methyl- N- [ - ( l-benzyl-4 -piperidinyl ) -2 - ( 3 , 4- dichlorophenyl ) -butyl] 3-isopropoxyphenylacetamide hydrochloride A) Ethyl-N- [ - ( l-benzyl-4-piperidinyl ) -2- ( 3 , 4- dichlorophenyl ) -butyl] -carbamate. 2.13 g of the amine prepared according to Example 1, D) are dissolved in 10 ml of dichloromethane and treated at -15 °C, under a nitrogen atmosphere, with 0.6. ml of ethyl chloroformate and 1 ml of triethylamine . The reaction mixture is brought back to room temperature, washed successively with 5% NaOH, H20 and saturated NaCl, and dried over MgSO«. 2.25 g of colourless oil are obtained.

B ) N-methyl-4- ( l-Benzyl-4-piperidinyl ) -2- ( 3 , 4- dichlorophenyl ) -butylamine hydrochloride.

The carbamate obtained above is dissolved in 20 ml of THF. The mixture is added to 0.50 g of LiAlH4 suspended in 20 ml of THF. The mixture is allowed to react for 3 hours under reflux, 2.5 ml of H20 are then - -added at 0°C, the mixture is filtered and the filtrate is evaporated. The oil is redissolved in dichloromethane and the hydrochloride is precipitated by adding a solution of HC1/4N ether. m = 2.45 g M.p. = 185°C.

C) Compound 18 1 g of the diamine prepared above is dissolved in 15 ml of CH2C12. 1 ml of triethylamine, 400 ml of 3-iso-propoxyphenylacetic acid and 1.06 g of BOP (N-benzothia-zolyloxytrisdimethylaminophosphonium hexafluorophosphate ) are added successively and the mixture is left at room temperature for 30 minutes. The solvent is evaporated in vacuo, the residue is taken up in ethyl acetate, and the mixture is washed successively with 5% NaOH and a solution of water saturated with NaCl, dried over MgSO„ and evaporated. The residue is chromatographed on silica gel, eluent: CH2C1-/CH30H 98:2 (v/v) . Concentration of the pure fractions yields a residue, starting from which the hydrochloride is prepared in dichloromethane. m = 0.60 g M.p. = 106°C.

Proceeding according to Example 18 above, the compounds 19 to 22 described in Table 5 below are prepared.

TABLE 5 Example 23 N-Methyl-N- [4- [ 1- ( 4-methoxybenzyl ) -4-piperidinyl ] - 2-(3, 4-dichlorophenyl) -butyl] -3-chlorophenylacetamide hydrochloride.

This compound is prepared according to route b of scheme 2.

A) - ( 3 , 4 -Dichloropheny 1 ) -3 ■ ( l-trityl-4-piperi- ainyl ) - 1-cyanopropane . 25 g of l - ( 3 , 4-dichlorophenyl ) -3 - ( 4-piper-idinyl ) -1 -cyanopropane hydrochloride (Example IB) are dissolved in 400 ml of CH2C12. 22 g of trityl chloride and 21 ml of trxethylamxne are added dropwise to the solution. The reaction mixture is left for 2 hours without stirring, and washed successively with H-O, an aqueous solution buffered to pH = 2, and a solution saturated with NaCl. It is dried over MgS04 and evaporated. The residue is chromatographed on silica gel, eluent: heptane/ ethyl acetate 9:1 (v/v) . 39 g of oil are obtained.

B) 2-(3,4-Dichlorophenyl)-4-( l-trityl-4- piperidinyl ) - 1 -butaneamine .

The oil prepared above is dissolved in 500 ml of glycol monomethyl ether; 50 ml of ammonia are added and a hydrogenation under atmospheric pressure and at room temperature is carried out in the presence of Raney Ni. The mixture is carried then evaporated in vacuo and 39 g of oil are obtained.

C ) N-methyl-2- ( 3 , 4-Dichlorophenyl ) -4- ( l-trityl-4- piperidinyl ) -butylamine .

The oil prepared above is dissolved in 250 ml of dichloromethane at -15 °C under nitrogen and treated with 8 g of ethyl chloroformate and 10 ml of trxethylamxne. After washing with 5% NaOH, H-0 and a saturated NaCl solution, the organic phase is dried and evaporated. The oil obtained is taken up in 200 ml of THF and poured dropwise onto 5.2 g.of LiAlH4 suspended in 200 ml of THF. After refluxing for 3 hours, the reaction mixture is cooled and 27 ml of H20 are added. The mixture is filtered, the filtrate is evaporated and the residue is chromatographed on silica gel, eluent: CH2Cl2/MeOH 100:2 (v/v) . 24 g of oil are obtained.

D ) N-methyl-N- [4- [ l-trityl-4-piperidinyl] -2- ( 3 , 4- dichlorophenyl ) -butyl] -3-chlorophenylacetamide. -43- 11.53 g of the above amine, 3.8 g of 3-chloro-phenylacetic acid, 3 ml of triethylamine and 9.73 g of BOP are dissolved successively in 200 ml of CH2C12. After reacting for 30 minutes, the mixture is washed with a 5% NaOH solution and H20, dried over MgS04 and evaporated. The residue is chromatographed on silica gel, eluent: pentane/ethyl acetate 80:20 (v/v) . The fractions are concentrated to obtain 8 g of a foam.

E) Compound 23 8.0 g of the amine obtained above are dissolved in 50 ml of formic acid; 50 ml of H20 are added dropwise. The mixture is allowed to react for 30 minutes at 60 °C, filtered and evaporated, and the residue is taken up in 100 ml of H20, the mixture is rendered basic with a 30% NaOH solution to pH 10 and extracted twice with 150 ml portions of ethyl ether, dried over MgS04 and evaporated. 6 g of oil are obtained, of which 2.2 g are taken to dissolve them in 15 ml of DMF. 5 g of K2C03 and 0.75 g of paramethoxybenzyl chloride are added. The mixture is allowed to react at 65 °C for 2 hours and the reaction mixture is then poured into 250 ml of H20. The mixture is extracted twice with 200 ml portions of ether, and the organic phase is washed with H20, dried over MgS04, filtered and evaporated. The residue is purified by chromatography on silica gel, eluent: CH2C12/CH30H 98:2 (v/v) . Concentration of the pure fractions yields a residue starting from which the hydrochloride is prepared in dichloromethane. m = 2 g M.p. « 100°C.

Proceeding according to Example 23, the compounds described in Table 6 below are prepared.

- - TABLE 6 Example 26 N-Methyl-N- [4- ( l-hydroxybenzyl-4-piperidinyl ) -2- ( 3 , 4-dichlorophenyl ) -butyl] -3-isopropoxyphenylacetamide hydrochloride .

A) Methyi-4- (methoxymethyl ether) benzoate.

The reaction is carried out according to: Synthesis 1976, 244. 15.3 g of methylparaben (methyl- -hydroxy benzoate) are dissolved in 500 ml of dichloromethane . 50 ml of dimethoxymethane and a spatula tip full of paratoluenesulphonic acid are added. The mixture is left under reflux over a Soxhlet provided with 3 Angstrom molecular sieve. After reacting for 24 hours, the product is filtered, washed successively with a solution of NaHC03, with water and with a saturated NaCl solution and then the organic phase is evaporated. 17 g of yellow liquid are obtained.

B) 4- (Methoxymethyl ether)benzyl alcohol. 17 g of the product prepared above diluted in 100 ml of THF are added to 5 g of LiAlH4 suspended in 75 ml of THF. The mixture is evaporated and the residue is chromatographed on silica gel, eluent: heptane/ethyl acetate 8:2 (v/v) . 15 g of colourless oil are obtained.

C) 4- (Methoxymethyl) benzyl ether chloride. 10 g of the oil above are dissolved in 20 ml of acetonitrile and then 15 g of triphenylphosphine and 8 g of N-chlorosuccinimide are added at 0°C. After 1 hour, the mixture is evaporated, the residue is taken up in ether, the' mixture is filtered and the filtrate is evaporated. The residue is chromatographed on silica gel, eluent: heptane/ethyl acetate 9:1 (v/v). 4.3 g of expected product are obtained.

D ) N-methyl-N- [4- ( l-trityl-4-piperidinyl ) -2- ( 3 , 4- dichlorophenyl ) -butyl] -3 - isopropoxyphenylacetamide . 3 g of the amine prepared according to Example 23 step C, 1.05 g of 3-isopropoxyphenylacetic acid, 0.70 g of triethylamine and 2.4 g of BOP are dissolved in 50 ml of CH2C12. After reacting for 30 minutes, the mixture is washed with a 5% NaOH solution, with water and then with a saturated NaCl solution. It is dried over MgS04 and evaporated. 3.8 g of oil are obtained.

E ) N-methyl-N- [4- [1- (methoxymethyl) benzylether-4- piperidinyl] -2- (3 , 4-dichlorophenyl) -butyl ] -3-iso- propoxyphenylacetamide .

The oil obtained above is dissolved in 35 ml of formic acid; 25 ml of H20 are added to the solution and it is allowed to react for 30 minutes at 60 °C. The mixture is filtered, the filtrate is evaporated and the oil obtained is redissolved in 50 ml of H20. The solution is rendered basic to pH 10, extracted with ether and dried over MgS04. 2.8 g of oil are obtained after evaporation, which are dissolved in 20 ml of D F. 5 g of K2C03 and 1.2 g of 4- (methoxymethyl) benzyl ether chloride (prepared in C) are added. After reacting for 2 hours at 65 °C, the mixture is poured into 200 ml of H20 and extracted with ether, and the extract is washed with H20, dried over MgS04 and evaporated. 3.5 g of oil are obtained.

F) Compound 26 The oil obtained above is diluted in 25 ml of THF, 25 ml of 2-propanol and 15 ml of HCl/ether solution (4N). After stirring for 2 hours, the mixture is evaporated and chromatographed on silica gel, eluent: CH2C12/CH30H 98:2 (v/v) . m = 2.5 g M.p. = 125°C.

EXAMPLE 27 N-benzyl-l-methyl-4- (3- (3 , 4-dichlorophenyl) -4- [ ' -methyl- (3-isopropoxy) acetamido] -butyl) - piperidinium iodide. -47- 1-5 g of the compound prepared according to Example 18 are dissolved in 50 ml of CH2C12. The mixture is stirred with 10 ml of a 10% NaOH solution, and the organic phase is dried over MgS04 and evaporated. The oil obtained is dissolved in 50 ml of methyl iodide, left for one hour at room temperature and then evaporated. The residue is chromatographed on silica gel H, eluent: CH2Cl2/CH3OH 97:3 (v/v) . The fractions of pure product are concentrated. m = 1.3 g M.p. = 108°C.

The methyl group in position 1 on the piperidine is of axial configuration. 13C NMR spectrum: CH3 axial : δ = 44.18 ppm equatorial EXAMPLE 28 N-benzyl-l-methyl-4- (3- (3 , 4-dichlorophenyl) -4- [ ' -methyl- (3-isopropoxy) acetamido] -butyl) - piperidinium iodide .

- - The above chromatography column is eluted with a CH2C12/CH30H 95:5 (v/v) mixture to obtain 0.20 g of a fraction corresponding to the product in which the methyl in position 1 of the piperidine is of equatorial configuration .

M.p. = 105°C 13C NMR spectrum: N-CH3 equatorial: δ = 51.20 ppm axial: δ = 59.85 ppm Passages of the description which are not within the scope of the claims do not form part of the invention.

Claims (4)

1. - 49 - CLAIMS :

2. 1. Compounds of the general formula in which - X is a group OS02R', -CH-CH2 -Q" or -CH-CN ; i I AT' AT' - P is hydrogen, an N-protecting group (Pro) or a group Ζ' -Ί" - provided that when X is -OSO2R1, then P represents an N-protecting group; - Z' is a hydrogen atom or a group M or OM; - M represents hydrogen or a linear or branched alkyl; an a-hydroxybenzyl , an g-alkylbenzyl or a phenylalkyl in which the alkyl group contains 1 to 3 carbon atoms, unsubstituted, mono- or poly-substituted on the aromatic ring with a halogen, a hydroxyl , an alkoxy of 1 to 4 carbon atoms, an alkyl of 1 to 4 carbon atoms; a pyridylalkyl in which the alkyl group contains 1 to 3 carbon atoms; a naphthylalkyl in which the alkyl group contains 1 to 3 carbon atoms ; a pyridylthioalkyl in which the alkyl group contains 1 to 3 carbon atoms; a styryl; a l-methyl-2-imidazo- lylthioalkyl in which the alkyl group contains 1 to 3 carbon atoms; a l-oxophenyl-3-indan-2-yl ; an aromatic or heteroaromatic group, said group being unsubstituted or substituted; - ' represents a bond, a -CH2- group or a -C(0)- group; provided that when Z' is hydrogen or OM, T' is other than a bond; - R' represents a C!-C alkyl group, a phenyl group or a tolyl group, preferably para-tolyl; - Ar' represents a phenyl, unsubstituted or substituted - 50 - one or more times with a halogen atom, preferably a chlorine or fluorine atom, with a Cr-C3 alkyl, with a trifluoromethyl , with a C!-C3 alkoxy, with a hydroxyl ; a thienyl, pyridyl or naphthyl group, the said groups being unsubstituted or substituted with a halogen, preferably a chlorine or fluorine atom, an indolyl group or a benzothienyl group; - Q" is an amino group or a group: R -N-T-Z provided that when P is a group Ζ' -Ί" - and X is a group -CH-CH2-Q" , Ar" then Q" is an amino group; R represents hydrogen, a methyl group or a group (CH2-)n-L, where n is an integer from 2 to 6 and hydrogen or an amino group; T represents a group selected from being an oxygen or sulphur atom; and Z has the same meanings as Z' defined above, provided that when Z is hydrogen or OM, T is other than a group -C(W)-NH-; their salts. - 51 - Compounds according to Claim 1 of formula in which Pro is an N-protecting group and R' is as defined in Claim 1, and their salts.

3. Compounds according to Claim 1 of formula: (XXII) in which Ar' is as defined in Claim 1, either Q' is hydrogen or an N-protecting group and Q " is an amino group or a group: R -N-T-Z ' where R and T and Z are as defined in Claim 1, or Q' is a group: 2 ' -T ' ~< where Z' and T* are as defined in Claim 1 and Q" is an amino group, and their acid addition salts. - 52 -

4. Compounds according to Claim 1 of formula: (XXIII) in which P and Ar' are as defined in Claim 1, and their salts. For the Applicants, 98V76Div. I/ND/prg