FR2676225A1 - New intermediates in the synthesis of dialkylenepiperidino compounds - Google Patents

Abstract

The invention relates to a compound of formula: in which - Pro is an N-protecting group - R' represents a C1-C4 alkyl group, a phenyl group or a tolyl, preferably para-tolyl, group or one of its salts.

Description

Novel intermediates for the synthesis of dialkylene piperidino compounds.

 The subject of the present invention is novel aromatic derivatives substituted with an amino group and with various ester, amine or amide functions, as well as their enantiomers.

The present invention also relates to the process for obtaining the compounds, which may be enantioselective and the use of the compounds according to the invention in compositions for therapeutic use and more particularly in pathological phenomena which involve the system of neurokinins such as: Pain (D. REGOLI et al., Life Sciences, 1987, 40, 109-117), allergy and inflammation (JE MORLAY et al., Life Sciences, 1987, 41, 527-544) circulatory insufficiency (J. LOSAY et al., 1977, Substance P, Von Euler, US and Pernow ed., 287-293, Raven
Press, New York), gastrointestinal disorders (D. REGOLI et al., Trends Pharmacol Sci., 1985, 6, 481-484), respiratory disorders (J. MIZRAHI et al., Pharmacology, 1982, 25). , 39-50).

Endogenous ligands to neurokinin receptors have been described, such as substance P (SP), neurokinin A CNKA)
CS.J. BAILEY et al., 1983, Substance P, P. Skrabanck ed., 16-17
Ball Press, Dublin) and Neurokinin B (NKB) (SP WATSON, Life
Science, 1983, 25, 797-808).

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

 A more precise characterization of the different receptors is made possible by the recent synthesis of selective agonists. Thus, Czar9, Net-C02) II SP, CNLe107 NKA410, and [Me Phe7] -NKB would have a respective selectivity for NK1, NK2 and NK3 receptors (see D. REGOLI, 1988 and 1989 cited above).

 It has now been found that certain aromatic amino compounds possess valuable pharmacological properties as neurokinin receptor antagonists and are particularly useful for the treatment of any substance P and neurokinin dependent pathology.

dans laquelle : - Z' représente soit l'hydrogène, soit M ou OM, - N représente l'hydrogène ou un alkyle droit ou ramifié en C1-C6;
un phénylaîkyle dans lequel le groupe alkyle comprend de 1 à
3 atomes de carbone, non substitué, mono ou polysubstitué sur le
cycle aromatique par un halogène, un hydroxy, un alcoxy de 1 à
4 atomes de carbone, un alkyle de 1 à 4 atomes de carbone ; un
pyridylalkyle dans lequel le groupe alkyle comprend de 1 à 3
atomes de carbone ; un naphtylalkyle dans lequel le groupe
alkyle comprend de 1 à 3 atomes de carbone ; un pyridylthio
alkyle dans lequel le groupe alkyle comprend de 1 à 3 atomes de
carbone ; un styryle ; un (méthyl-1) imidazolyl-2 thioalkyle
dans lequel le groupe alkyle comprend de 1 à 3 atomes de
carbone ; un oxo-1 phénylindan-3 yle-2; un groupe aromatique ou
hétéroaromatique non substitué ou substitué ; - m est 0 ou 1 ; - X représente deux atomes d'hydrogène ou un groupe oxo ; - Ar' représente un phényle non substitué ou substitué une ou
plusieurs fois par un atome d'halogène, de préférence
un atome de chlore ou de fluor, par un alkyle en C1-C3, par
un trifluorométhyle, par un alcoxy en C1-C3, par un
hydroxyle ; un groupe thiényle, pyridyle, naphtyle non
substitué ou substitué par un halogène de préférence un
atome de chlore ou de fluor, un indolyle ou un benzo
thiényle ; - R représente l'hydrogène, un groupe méthyle ou un groupe
(CH2)n-L, ou n est un nombre entier de 2 à 6 et L est l'hydro
gène ou un groupe amino, - T représente un groupe choisi parmi

- W étant un atome d'oxygène ou de soufre, et - Z a la même signification que Z' à la condition que Z soit M ou OM Lorsque T représente le groupe

soit M lorsque T représente le groupe

; ou un de leurs sels avec des
acides minéraux ou organiques.Thus according to one of its aspects, the present invention relates to aromatic amine derivatives of formula

in which: Z 'represents either hydrogen, or M or OM, - N represents hydrogen or straight or branched C1-C6 alkyl;
phenylalkyl in which the alkyl group comprises from 1 to
3 carbon atoms, unsubstituted, mono or polysubstituted on the
aromatic ring with a halogen, a hydroxy, an alkoxy of 1 to
4 carbon atoms, alkyl of 1 to 4 carbon atoms; a
pyridylalkyl in which the alkyl group comprises from 1 to 3
carbon atoms; a naphthylalkyl in which the group
alkyl comprises from 1 to 3 carbon atoms; a pyridylthio
alkyl in which the alkyl group comprises from 1 to 3 carbon atoms
carbon; a styryle; a (methyl-1) imidazolyl-2-thioalkyl
wherein the alkyl group comprises from 1 to 3 carbon atoms
carbon; an oxo-1-phenylindan-3-yl-2; an aromatic group or
unsubstituted or substituted heteroaromatic; m is 0 or 1; X represents two hydrogen atoms or an oxo group; Ar 'represents an unsubstituted or substituted phenyl, or
several times by a halogen atom, preferably
a chlorine or fluorine atom, by a C 1 -C 3 alkyl, by
trifluoromethyl with a C 1 -C 3 alkoxy, a
hydroxyl; a thienyl, pyridyl, naphthyl group
substituted or substituted by a halogen preferably
chlorine or fluorine atom, indolyl or benzo
thienyl; R represents hydrogen, a methyl group or a group
(CH2) nL, where n is an integer from 2 to 6 and L is hydro
gene or an amino group, T represents a group selected from

- W being an oxygen or sulfur atom, and - Z has the same meaning as Z 'with the proviso that Z is M or OM When T is the group

let M be when T is the group

; or one of their salts with
mineral or organic acids.

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

In particular, in the formula (I), Z and / or Z 'represents a mono-, di- or tricyclic aromatic or heteroaromatic group which may carry one or more substituents, of which one carbon atom of the aromatic carbocycle or of aromatic heterocycle is directly linked to the group T or the group - (CX)
More particularly, the radicals Z and / or Z 'may be a phenyl group, which may be unsubstituted or optionally contain one or more substituents.

When Z and / or Z 'are a phenyl group, it may be preferably mono- or disubstituted, especially in the 2,4-position, but also for example in the 2,3, 4,5, 3,4 or 3-position. , 5; it can also be trisubstituted, especially at the 2,4,6-position, but also for example 2,3,4, 2,3,5 or 2,4,5, 3,4,5; tetrasubstituted, for example 2,3,4,5; or pentasubstituted. Substituents of the phenyl group may be: F; Cl; Br; I; CN; OH; NH2; NH-CO-NH2; N02;
CONH2; CF3; C1-C10 alkyl, preferably C1-C4 alkyl, methyl or ethyl being preferred, as well as, for example, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or n-pentyl, hexyl or n-hexyl, heptyl or n-heptyl, octyl or n-octyl, nonyl or n-nonyl as well as decyl or n-decyl alkenyl containing 2 to 10, preferably 2-4 carbon atoms, for example vinyl, allyl , 1-propenyl, isopropenyl, butenyl or 1-buten-1-, -2-, -3- or 4-yl, 2-buten-1-yl, 2-buten-2-yl, pentenyl, hexenyl or decenyl ; alkynyl containing 2 to 10, preferably 2-4 carbon atoms, for example ethynyl, 1-propynyl, propargyl, butynyl or 2-butyn-1-yl, pentynyl, cycloalkyl decynyl containing 3 to 8, preferably 5 or 6 carbon atoms, cyclopentyl or cyclohexyl being preferred, and for example cyclopropyl, cyclobutyl, 1-, 2- or 3-methylcyclopentyl, 1-, 2-, 3- or 4-methylcyclohexyl, cycloheptyl or cyclooctyl bicycloalkyl containing 4 to 11 carbon atoms. preferably 7 carbon atoms, exo or endo 2-norbornyl being preferred, as well as for example isobornyl or 5-camphyl; hydroxyalkyl containing 1 to 5, preferably 1-2 carbon atoms, hydroxymethyl and 1- or 2-hydroxyethyl being preferred, as well as for example 1-hydroxyprop-1-yl, 2-hydroxyprop-1-yl, 3- hydroxyprop-1-yl, 1-hydroxy-prop-2-yl, 1-hydroxybut-1-yl, 1-hydroxypent-1-yl; alkoxy containing 1 to 10, preferably 1-4 carbon atoms, methoxy or ethoxy being preferred, as well as for example n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy; alkoxyalkyl containing 2 to 10, preferably 2 to 6 carbon atoms, for example alkoxymethyl or alkoxyethyl, such as methoxymethyl or 1- or 2-methoxyethyl, 1- or 2-n-butoxyethyl, 1- or 2-n-octyloxyethyl; alkoxyalkoxyalkyl containing up to 10, preferably from 4 to 7 carbon atoms, for example alkoxyalkoxymethyl, for example 2-methoxyethoxymethyl, 2-ethoxyethoxymethyl or 2-isopropoxyethoxymethyl, alkoxyalkoxyethyl, for example 2- (2-methoxyethoxy) ethyl or 2- ( 2-ethoxyethoxy) ethyl; alkoxyalkoxy containing from 2 to 10, preferably from 3 to 6 carbon atoms, for example 2-methoxyethoxy, 2-ethoxyethoxy or 2-n-butoxyethoxy; alkenyloxy containing 2 to 10, preferably 2 to 4 carbon atoms, allyloxy being preferred, and for example vinyloxy, propenyloxy, isopropenyloxy, butenyloxy such as 1-buten-1-, -2-, -3- or -4- yloxy, 2-buten-1-yloxy, 2-buten-2-yloxy, pentenyloxy, hexenyloxy or decenyloxy; alkenyloxyalkyl with up to 10, preferably 3-6 carbon atoms, for example allyloxymethyl; alkynyloxy containing from 2 to 10, preferably 2 to 4 carbon atoms, propargyloxy being preferred, as well as for example ethynyloxy, 1-propyn-1-yloxy, butynyloxy or 2-butyn-1-yloxy, pentynyloxy or decynyloxy; alkynyloxyalkyl containing from 3 to 10, preferably 3 to 6 carbon atoms, for example ethynyloxymethyl, propargyloxymethyl or 2- (2-butyn-1-yloxy) ethyl; cycloalkoxy containing 3 to 8, preferably 5 or 6 carbon atoms, cyclopentyloxy or cyclohexyloxy being preferred, and for example cyclopropyloxy, cyclobutyloxy, 1-, 2- or 3-methylcyclopentyloxy, 1-, 2-, 3- or 4-methylcyclohexyloxy; cycloheptyloxy or cyclooctyloxy; alkylthio containing from 1 to 10, preferably 1 to 4 carbon atoms, methylthio or ethylthio being preferred, and for example n-propylthio, isopropylthio, n-butytthio, isobutylthio, secbutylthio, tert-butylthio, pentylthio, hexylthio, octylthio, nonylthio or decylthio; alkylthioalkyl containing from 2 to 10, preferably 2 to 6 carbon atoms, for example methylthiomethyl, 2-methylthioethyl or 2-n-butylthioethyl; acylamino, namely alkanoylamino containing from 1 to 7, preferably 1 to 4 carbon atoms, formylamino and acetylamino being preferred, as well as propionylamino, butyrylamino, isobutyrylamino, valylamino, caproylamino, heptanoylamino, as well as aroylamino or benzoylamino; acylaminoalkyl, preferably alkanoylaminoalkyl containing from 2 to 8, preferably 3 to 6 carbon atoms, such as formylaminoethyl, acetylaminoethyl, propionylaminoethyl, n-butyrylaminoethyl, formylaminopropyl, acetylaminopropyl, propionylaminopropyl, formylaminobutyl, acetylaminobutyl, as well as propionylaminobutyl, butyrylaminobutyl; acyloxy containing from 1 to 6, preferably 2 to 4 carbon atoms, acetyloxy, propionyloxy or butyryloxy being preferred, as well as, for example, formyloxy, valeryloxy, caproyloxy; alkoxycarbonyl containing from 2 to 5, preferably 2 and 3 carbon atoms, methoxycarbonyl and ethoxycarbonyl being preferred, as well as, for example, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, secbutoxycarbonyl or tert-butoxycarbonyl; cycloalkoxycarbonyl containing from 4 to 8, preferably 6 or 7 carbon atoms, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl being preferred, as well as cyclopropyloxycarbonyl, cyclobutyloxycarbonyl or cycloheptyloxycarbonyl; alkylaminocarbonylamino containing from 2 to 4 carbon atoms, such as methylaminocarbonylamino, ethylaminocarbonylamino, propylaminocarbonylamino; dialkylaminocarbonylamino containing from 3 to 7, preferably 3 to 5 carbon atoms, preferably dimethylaminocarbonylamino, as well as di-n-propylaminocarbonylamino, diisopropylaminocarbonylamino; (1-pyrrolidino) carbonylamino; (1-piperidino) carbonylamino; cycloalkylaminocarbonylamino containing from 4 to 8, preferably 6 or 7 carbon atoms, cyclopentylaminocarbonylamino, cyclohexylaminocarbonylamino being preferred, as well as cyclopropylaminocarbonylamino, cyclobutylaminocarbonylamino, cycloheptylaminocarbonylamino; alkylaminocarbonylaminoalkyl containing 3 to 9, preferably 4 to 7 carbon atoms, methylaminocarbonylaminoethyl, ethylaminocarbonylaminoethyl, ethylaminocarbonylaminopropyl, ethylaminocarbonylaminobutyl being preferred, as well as, for example, methylaminocarbonylaminomethyl, n-propylaminocarbonylaminobutyl, n-butylaminocarbonylaminobutyl; dialkylaminocarbonylaminoalkyl containing from 4 to 11 carbon atoms, for example dimethylaminocarbonylaminomethyl, diethylaminocarbonylaminoethyl, diethylaminocarbonylaminopropyl, diethylaminocarbonylaminobutyl, (1-pyrrolidino) carbonylaminoethyl, (1-piperidin) carbonylaminoethyl, cycloalkylaminocarbonylaminoalkyl containing from 5 to 12, preferably 8 to 11 atoms carbon, cyclopentylaminocarbonylaminoethyl, cyclopentylaminocarbonylaminopropyl, cyclopentylaminocarbonylaminobutyl, cyclohexylaminocarbonylaminoethyl, cyclohexylaminocarbonylaminopropyl and cyclohexylaminocarbonylaminobutyl being preferred, as well as, for example, cyclopropylaminocarbonylaminomethyl, cycloheptylaminocarbonylaminoethyl; alkoxycarbonylaminoalkyl containing from 3 to 12, preferably 4 to 9 carbon atoms, methoxycarbonylaminoethyl, ethoxycarbonylaminoethyl, n-propoxycarbonylaminoethyl, isopropoxycarbonylaminoethyl, n-butoxycarbonylaminoethyl, isobutoxycarbonylaminoethyl, sec-butoxycarbonylaminoethyl, tert-butoxycarbonylaminoethyl, ethoxycarbonylaminopropyl, n-butoxycarbonylaminopropyl, ethoxycarbonylaminobutyl, n- butoxycarbonylaminobutyl being preferred, as well as for example n-propoxycarbonylaminopropyl, n-propoxycarbonylaminobutyl, isopropoxycarbonylaminobutyl; cycloalkoxycarbonylaminoalkyl containing from 5 to 12, preferably 8 to 11 carbon atoms, cyclopentyloxycarbonylaminoethyl, cyclopentyloxycarbonylaminopropyl, cyclopentyloxycarbonylaminobutyl, cyclohexyloxycarbonylaminoethyl, cyclohexyloxycarbonylaminopropyl, cyclohexyloxycarbonylamino nobuty being preferred, as well as for example cyclopropyloxycarbonylaminomethyl, cycloheptyloxycarbonylaminoethyl; carbamoylalkyl containing from 2 to 5, preferably 2 carbon atoms, preferably carbamoylmethyl, as well as carbamoylethyl, carbamoylpropyl, carbamoylbutyl; alkylaminocarbonylalkyl containing from 3 to 9, preferably 3 to 6 carbon atoms, methylaminocarbonylethyl, ethylaminocarbonylmethyl, n-propylaminocarbonylmethyl, isopropylaminocarbonylmethyl, n-butylaminocarbonylmethyl, isobutylaminocarbonylmethyl, sec-butylaminocarbonylmethyl, tert-butylaminocarbonylmethyl being preferred, and for example ethylaminocarbonylethyl, ethylaminocarbonylpropyl, ethylaminocarbonylbutyl, n-propylaminocarbonylbutyl, n-butyl aminocarbonylbutyl; dialkylaminocarbonylalkyl containing from 4 to 11, preferably 4 to 8 carbon atoms, dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl, di-n-propylaminocarbonylmethyl, as well as, for example, diethylaminocarbonylethyl, diethylaminocarbonylpropyl, diethylaminocarbonylbutyl; (1-pyrrolidino) carbonylmethyl, (1-piperidino) carbonylmethyl; (1-piperidino) carbonylethyl; cycloalkylaminocarbonylalkyl containing from 5 to 12, preferably 7 or 8 carbon atoms, cyclopentylaminocarbonylmethyl and cyclohexylaminocarbonylmethyl being preferred, as well as for example cyclopropylaminocarbonylmethyl, cyclobutylaminocarbonylmethyl, cycloheptylaminocarbonylmethyl, cyclohexylaminocarbonylethyl, cyclohexylaminocarbonylpropyl, cyclohexylaminocarbonylbutyl; alkylaminocarbonylalkoxy containing from 3 to 10, preferably 3 to 5 carbon atoms, methylaminocarbonylmethoxy being preferred, as for example methylaminocarbonylethoxy, methylaminocarbonylpropoxy; dialkylaminocarbonylalkoxy containing from 4 to 10, preferably 4 to 7 carbon atoms, such as dimethylaminocarbonylmethoxy, diethylaminocarbonylethoxy, (piperidinyl-1) carbonylmethoxy; cycloalkylaminocarbonylalkoxy containing from 5 to 11, preferably 7 or 8 carbon atoms, such as cyclopentylaminocarbonylmethoxy, cyclohexylaminocarbonylmethoxy.

 The groups Z and Z 'are advantageously a phenyl group; a benzyl group; a benzoyl group; a phenylthioalkyl group in which the alkyl is C1-C3; a naphthyl group.

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

The radicals Z or Z 'may also represent a bicyclic aromatic group such as 1- or 2-naphthyl; 1-, 2-, 3-, 4-, 5-, 6-, 7-indenyl; one or more bonds may be hydrogenated, said groups may be unsubstituted or optionally contain one or more substituents such as: a halogen and more particularly a fluorine atom, the alkyl group, phenyl, cyano, hydroxyalkyl, hydroxy, oxo, alkylcarbonyl amino and alkoxycarbonyl, thioalkyl wherein the alkyls are C -C
The Z or Z 'radicals may also be pyridyl, thiadiazolyl, indolyl, indazolyl, imidazolyl, benzimidazolyl, which are necyl, benzotriazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzisothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzodioxinyl or pyridinyl groups, isoxazolyl, benzopyranyl, thiazolyl, thienyl, furyl, pyranyl, chromenyl, isobenzofuranyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, phthalazinyl, quinazolinyl, acridinyl, isothiazolyl, isochromannyl, chromannyl, one or more double Liai sounds may be hydrogenated said groups may be unsubstituted or optionally contain one or more substituents such as: alkyl, phenyl, cyano, hydroxyalkyl, hydroxy, alkylcarbonylamino and alkoxycarbonyl, thioalkyl wherein the alkyls are C1-C4.

 According to another of its aspects, the present invention relates to a process for the preparation of different substituted aromatic amine compounds of formula (I) and their salts.

 Firstly, the N-protected and O-protected derivative of 1-hydroxy-4- (4-piperidinyl) ethane is prepared according to the conventional and usual methods using the protective groups which are well known to the man of the for the N-protecting groups or for the O-protecting groups, according to the following scheme 1, to obtain the protected amino alcohol which is a new intermediate forming part of the invention.

SCHEME 1

dans lequel : - Pro désigne un groupe N-protecteur - R' représente un groupe alkyle en C -C , un groupe phényle ou un
groupe tolyle, de préférence para-tolyle.<tb><SEP> Agent <SEP> of
<tb><SEP> N-protcti <SEP> on
<tb> HN (CH2) 2-OH <SEP> Pro-N <SEP> (CH2) 2-OH
<Tb>

in which: - Pro denotes an N-protecting group - R 'represents a C 1 -C 6 alkyl group, a phenyl group or a
tolyl group, preferably para-tolyl.

 The compound of formula (II) is prepared from 4-piperidinylethanol, a commercially available product.

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

 The term "N-protecting group" denotes 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, trichloromethylcarbonyl, trichloropropylcarbonyl; an aralkyloxycarbonyl group such as benzyloxycarbonyl; a substituted aralkyloxycarbonyl group, such as 4-nitrobenzyloxycarbonyl or aroyl such as benzoyl, 2,4-dichlorobenzoyl or 4-fluoro-1-naphthylcarbonyl.The term "N-protecting" also includes aralkyl groups such as, for example, a benzyl group, substituted 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 (4-methoxy) diphenylmethyl (or dimethoxybenzhydryl), a triphenylmethyl (or trityl) group, a substituted triphenylmethyl group, such as 4-methoxyphenyl-diphenylmethyl (or methoxytrityl) or di (4-methoxyphenyl) phenylmethyl (or dimethoxytrityl). The term "N-protected" refers to the product which contains the amine protected by an N-protecting group as defined above.

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

The process for preparing the compounds (I) is illustrated by the following scheme 2:
SCHEME 2

<tb><SEP>Ar'-CH<SEP> 2-CN <SEP> + <SEP> (II)
<tb><SEP> 1
<tb><SEP> Pro-N <SEP> 3 <SEP> (CH2) 2-CH-CN <SEP> (III)
<tb><SEP> ss <SEP> protection <SEP> + <SEP> Y
<tb><SEP> II
<tb> HN: = <SEP>) (<SEP> CH), - CH-CN <SEP> (CH2) 2-CH-CH2-NH2
<tb><SEP> Ar '<SEP>Ar'
<tb><SEP> (X) <SEP><<SEP> \ <SEP> (IV)
<tb><SEP> I <SEP> rotection
<tb><SEP>Z'-ÇC-Hal<SEP> (CH2) 2 <SEP> CH <SEP> CH2 <SEP> 2
<tb><SEP> xm <SEP> (it) <SEP> HN <SEP> Ar '
<tb><SEP> \ <SEP> / <SEP> (IV ')
<tb> At (C <SEP> (CH3) 2 <SEP> FH-CN <SEP> Pro <SEP> V = 3) r "<SEP> z] z. <SEP> R,
## STR2 ##
<tb><SEP> Ar '
<tb><SEP> Ar '
<tb><SEP> (XI) <SEP> (VII)
<tb><SEP>Z'-C-Hal
<tb><SEP> O
<tb><SEP> H2 <SEP> 1) <SEP> deprotection <SEP> (Z = Z ')
<tb><SEP> Ni <SEP> Raney <SEP> 2) <SEP> t <SEP> xFCsElaL
<tb><SEP>
<tb><SEP> lane <SEP> (a) <SEP> lane <SEP> (b) <SEP> lane <SEP> (c)
<tb><SEP> I
<tb><SEP> llXCss <SEP>) iN'À (CH2) <SEP> j
<tb><SEP> Ar '<SEP><<SEP> I) <SEP> / <SEP> (Z = Z')
<tb><SEP> (I)
<Tb>
The starting compounds of formula (III) are prepared from nitriles of formula:
Ar '-CH2-CN in which Ar' is as defined above, nitriles which are commercial products or prepared according to known methods, by reaction with a compound of formula (II); then aminonitrile
N-protected formula (III) is treated according to one of the synthetic routes (a), (b) or (c), which use the same reactions but in different orders.

qui est un intermédiaire nouveau faisant partie de L'invention et qui est ensuite fonctionnalisée soit avec un dérivé fonctionnel d'un acide de formule :
HO-CO-Z (V)
dans laquelle Z est tel que défini précédemment, lorsqu'on doit
préparer un composé de formule (I) dans lequel T est -CO-, soit avec un iso(thio)cyanate de formule ::
W=C=N-Z (VI)
dans laquelle W et Z sont tels que définis précédemment lorsqu'on
doit préparer un composé de formule (I) dans lequel T est
-C(W)-NH-, pour fournir le dérivé de formule

qui est un intermédiaire nouveau faisant partie de L'invention et qui est alors déprotégé pour conduire à l'amine libre de formule :

dans laquelle Ar', T et Z sont tels que définis précédemment, puis cette amine est additionnée sur un dérivé halogéné de formule :

Thus according to route (b), the nitrile (III) is catalytically hydrogenated in the presence of a catalyst such as, for example, Raney nickel to provide the amine of formula:

which is a novel intermediate forming part of the invention and which is then functionalized with either a functional derivative of an acid of formula:
HO-CO-Z (V)
wherein Z is as defined above, when
to prepare a compound of formula (I) in which T is -CO-, or with an iso (thio) cyanate of formula:
W = C = NZ (VI)
wherein W and Z are as previously defined when
must prepare a compound of formula (I) in which T is
-C (W) -NH-, to provide the derivative of formula

which is a new intermediate forming part of the invention and which is then deprotected to yield the free amine of formula:

in which Ar ', T and Z are as defined above, then this amine is added to a halogenated derivative of formula:

in which Z ', X and m are as defined above and where
Hal represents a halogen, more particularly an atom of
chlorine or bromine, to yield the compounds (I) according to
the invention.

dans laquelle Ar' est tel-que défini précédemment, et sur lequel on additionne le dérivé halogéné (IX) pour conduire au nitrile de formule :

dans laquelle Z', m, X, Ar' sont tels que définis précédemment.According to the synthetic route (a) the aminonitrile (III) is deprotected according to the usual methods to yield the free aminonitrile of formula:

in which Ar 'is as defined above, and on which the halogenated derivative (IX) is added to give the nitrile of formula:

wherein Z ', m, X, Ar' are as previously defined.

This compound (XI) is then hydrogenated in the presence of a catalyst such as Raney nickel to provide the corresponding amino derivative of formula:

which is a new intermediary forming part of the invention and
which is then functionalized to provide the compound (I) according to
the invention in the same way as previously for
the preparation of compounds (I) from intermediates (VII)
that is to say by reacting: with a functional derivative of an acid of formula:
HO-CO-Z (V)
wherein Z is as defined above, when
to prepare a compound of formula (I) in which T is -CO-, or with an iso (thio) cyanate of formula:
W = C = NZ (VI)
wherein W and Z are as previously defined when
must prepare a compound of formula (I) in which T is
-C (W) -NH-, to provide the derivative (I).

As a functional derivative of the acid (V), the acid itself is suitably activated, for example by cyclohexylcarbodiimide or benzotriazolyl hexafluorophosphate.
N-oxytris-dimethylaminophosphonium (BOP), or 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 OM, the acid of interest is carbonic acid and, as a functional derivative, monochloride is used, namely a CI-CO-ON chloroformate.

 According to the synthetic route (c), the nitrile III is subjected to hydrogenation as in route (b), then the compound (IV) obtained is deprotected to form the corresponding compound (IV ') which is then reacted. with the halogenated derivative Z'-C (O) -Hal to form the compound of formula (I) in which Z = Z '.

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

The N-protecting groups optionally present in the group R when L is an amino group are the groups
Conventional n-protectants well known to those skilled in the art and preferably those which are removable by acid hydrolysis, such as the tri-tyl and methoxytrityl group.

 The preparation of compounds (VII) or (I) is illustrated by Schemes 3 and 4 detailed below.

SCHEME 3

SCHEMA 4

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

est effectuée selon les méthodes habituelles.In the particular case of Z = OM, the reaction of the compounds (IV) or (XII) with the chloroformate of formula:

is carried out according to the usual methods.

 When Z is other than OM, another functional derivative may be used or one may start from the free acid (V) by coupling (IV) or (XII) with BOP (benzotriazolyl hexafluorophosphate N-oxytris-dimethylaminophosphonium), and then adding the acid (V) in the presence of an organic base such as triethylamine, in a solvent such as dichloromethane or dimethylformamide, at room temperature, the compounds (I1) obtained being isolated and purified according to the usual methods such as chromatography or recrystallization.

 It is also possible to react (IV) or (XII) with an iso (thio) cyanate W = C = NZ (VI) in an anhydrous inert solvent such as, for example, benzene, overnight at ambient temperature and then treat the reaction mixture. according to the usual methods for obtaining the compounds (12).

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

 When the compound of formula (I) is obtained in free base form, the salification is carried out by treatment with the chosen acid in an organic solvent. By treatment of the free base, dissolved for example in an alcohol such as isopropanol, with a solution of the acid selected in the same solvent, the corresponding salt is obtained which is isolated according to conventional techniques. For example, hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogenphosphate, methanesulphonate, oxalate, maleate, fumarose and naphthalene-2-sulphonate are prepared.

 At the end of the reaction, the compounds of formula (I) can be isolated in the form of a salt thereof, for example the hydrochloride or the oxalate; in this case, if it is necessary, the free base can be prepared by neutralizing said salt with a mineral or organic base, such as socium hydroxide or triethylamine or with an alkaline carbonate or bicarbonate, such as carbonate or sodium bicarbonate or potassium.

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

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

sont isolées selon les méthodes habituelles.When it is desired to prepare the compounds of formula (IV) or (XII) in which R is different from hydrogen, for example methyl, the free amine obtained by hydrogenation of the nitriles (III) or (XI) is treated as described above, with a chloroformate, for example with the chloroformate of formula Cl-CO-OAlk, where Alk is a C1-C3 alkyl, preferably ethyl, to obtain the carbamates of formula

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

are isolated by the usual methods.

The methylamine of formula XVI above may be deprotected to give the piperidine of formula:

 From the compounds of formulas (XVI), (XVI ') and (XVII), the N-substituted compounds are prepared in the same manner as described in Schemes 2 to 4 from, respectively, compounds of formulas IV ( (b) and (c)) and XII (lane (a)).

To prepare the compounds of formula (IV) or (XII) in which R is a - (CH 2) n L group, where n and L are as defined above, the free amine obtained by hydrogenation of the nitrile is treated ( III) or (XI) as described above, with a reactive functional derivative of the acid of formula:
L- (CH2) n-1-COOH wherein L is hydrogen or an amino group, to obtain the amides of formula:

Amides (XVIII) or (XIX), by reduction under the same conditions as those described above for nitriles (III) or (XI), give the desired compound of formula

The methylamine of formula (XX) above can be deprotected to give the formula piperidine ::

 From the compounds of formulas (XX), (XX ') and (XXI) above, the N-substituted compounds are prepared in the same manner as described above in Schemes 2 to 4, respectively, from compounds IV (lanes (a) and (b)) and XII (lane (a)).

 The invention also relates to the intermediates used in the process described above for obtaining compounds of the invention (see diagram 2).

dans laquelle : - Ar' est tel que défini précédemment ; et - soit Q est l'hydrogène ou un groupe N-protecteur et Q' est un groupe amino ou un groupe :

où R et T et Z sont tels que définis précédemment, - soit Q est un groupe :

où Z', m et X sont tels que définis précédemment et
Q' est un groupe amino et les sels d'addition d'acides desdites aralkylpipéridines lorsqu'elles sont basiques.These intermediates are the arylalkylpiperidines of formula:

in which: Ar 'is as defined previously; and either Q is hydrogen or an N-protecting group and Q 'is an amino group or a group:

where R and T and Z are as previously defined, - or Q is a group:

where Z ', m and X are as previously defined and
Q 'is an amino group and the acid addition salts of said aralkylpiperidines when basic.

dans laquelle G est l'hydrogène, un groupe protecteur (Pro) ou un groupe de formule

dans lequel Z', X et m sont tels que définis précédemment, Ar' a la signification donnée pour les composés de formule I, sont également des composés nouveaux qui font partie du cadre de l'invention.Synthesis intermediates of formula:

wherein G is hydrogen, a protecting group (Pro) or a group of formula

in which Z ', X and m are as defined above, Ar' has the meaning given for the compounds of formula I, are also new compounds that are part of the scope of the invention.

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

 The compounds (I) and their salts have shown anagonistic properties of substance P binding in tests carried out on membranes of rat cortex and IM9 lymphoblastic cells, according to A.A. CASCIERI et al., J. Biol. Chem., 1983, 258, 5158-5164 and D. D. PAYA et al., J. Immunol., 1984, 133, 3260-3265.

 The compounds according to the invention are substance P antagonists.

 Thus, for example, compounds 3, 7 and 11 antagonize the binding of substance P with Ki of 23,15 and 30 nanomolar, respectively.

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

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

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

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

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

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

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

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

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

 For parenteral, intranasal or intraocular administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing dispersing avents and / or pharmacologically compatible wetting agents, for example propylene glycol or butylene glycol, are used.

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

 The active ingredient may also be formulated in the form of microcapsules, optionally with one or more supports or additives.

 The aforesaid compositions may also contain other active products such as, for example, bronchodilators, antitussives or antihistamines.

 The following examples illustrate the invention without limiting it.

Example 1
CN hydrochloride (1-benzyl-4-piperidinyl) -1- (3,4-dichloro-phenyl) (4-fluoro-1-naphthoyl) -43-butaneamine (compound 1)

This compound is prepared by the route (a) of Scheme 2.

A) Preparation of (2-mesyloxy-ethynyl) -4-tert-butoxycarbonyl-1
piperidine.

 65 g of 1-hydroxy-4- (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 maintains the temperature of the reaction mixture at 50-60 C. The addition is complete, the reaction mixture is heated to 800C and then the solvent is concentrated in vacuo. The residue is taken up in ether and washed successively three times with water and then with a saturated solution of NaCl. The ether phase is separated by decantation, dried over Na 2 SO 4 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. When the addition was complete, the reaction mixture was refluxed for 2 hours.

 The solvent is concentrated under vacuum, the residue is taken up in ethyl acetate and then washed successively with water, with a saturated solution of NaCl, the organic phase is separated off which is dried over Na 2 SO 4 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
F = 91 C.

B) 3,4-Dichlorophenyl) -4-piperidinylhydrochloride
cyano-3 propane.

 1.74 g of 55% sodium hydride suspended in the oil are suspended in 150 ml of tetrahydrofuran and cooled to 5 C. Then 11.16 g of 3,4-dichlorophenylacetonitrile are added dropwise. and 12.28 g of the amine prepared above according to A) dissolved in 150 ml of tetrahydrofuran.

The reaction mixture is stirred overnight at room temperature and then refluxed for 30 minutes. The solvent is concentrated under vacuum, the residue is taken up in a buffer solution pH = 2 and extracted with ether. The ether phase is washed successively with water, with saturated NaCl solution, dried over NaSO 4 and concentrated under vacuum. There is obtained 20.2 g of 3- (3,4-dichlorophenyl) -3- (1-tert-butoxycarbonyl-4-piperidinyl) -3-cyanopropane in the form of an oil.

 This compound is deprotected by placing it in solution in 100 ml of trifluoroacetic acid and stirring for 30 minutes at room temperature. The acid is concentrated under vacuum, an oil is obtained which is taken up in a 5% sodium hydroxide solution, extracted with ether, washed successively with water and then with saturated NaCl solution, dried over Na2SO4 and concentrated in vacuo. The oil obtained is dissolved in 300 ml of ethyl acetate and then hydrochloric acid is bubbled to yellow coloration.

 The hydrochloride is separated by filtration.

m = 12.4 g F = 1820C
C) (1-Benzylpiperidinyl-4) -l hydrochloride (3,4-dichlorohydrochloride)
phenyl) -3-cyano-3 propane.

 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 in solution in 25 ml of dichloromethane are then added dropwise and the mixture is refluxed for one hour. The solvent is concentrated in vacuo and the residue is taken up in 5% sodium hydroxide solution. Extracted with ether and then washed successively with water and with a saturated solution of NaCl, dried over Na 2 SO 4 and concentrated in vacuo.

 The oil obtained is dissolved in 150 ml of ethanol, hydrochloric acid is bubbled and the hydrochloride is filtered off.

m = 15 g
Mp = 233 ° C
D) (1-Benzyl-4-piperidinyl) -1 (3,4-dichlorophenyl) -4-amino-4
butane.

 13.3 g of the product previously prepared in solution 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 at room temperature. After the hydrogenation has ended, the reaction mixture is filtered through Celite and the filtrate is concentrated under vacuum after adding 2 times 100 ml of absolute ethanol.

 13.5 g of a colorless oil are obtained.

E) Compound 1
1.95 g of amine prepared previously according to D), 0.95 g of 4-fluoro-naphthoic acid and 1.01 g of triethylamine are dissolved in 40 ml of dichloromethane. 2.21 g of BOP (benzotriazolyl N-oxytris-dimethylaminophosphonium hexafluorophosphate) are added and the reaction mixture is left at room temperature for 24 hours. The solvent is concentrated under vacuum, the residue is taken up in ether and washed successively with 5% sodium hydroxide solution and then with saturated NaCl solution. The ether phase is dried over Na 2 SO 4 and concentrated in vacuo. The residue is chromatographed on silica gel, eluent dichloromethane-methanol 93/7 (v / v).

 The concentration of the pure fractions provides a residue from which the hydrochloride is prepared in ethyl acetate.

Ni = 1.31 g
Mp 174-176 ° C.

Example 2
NC (4-fluoro-benzyl) -1-piperidinyl-4-chlorohydrochloride (3,4-dichlorophenyl) -3,4-dichlorobenzamide (compound 2)

This compound is prepared by the route (b) of Scheme 2.

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

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

B) (3,4-Dichlorophenyl) -3 (tert-butoxycarbonyl-1-piperidinyl-4) -1
4-amino butane.

 17.4 g of the cyano derivative prepared above are dissolved in 300 ml of 950 ethanol, 20 ml of water and 70 ml of concentrated ammonia in the presence of 2 g of Raney nickel. It is then hydrogenated at room temperature and atmospheric pressure.

After the hydrogenation has ended, the reaction mixture is filtered on
Celite and concentrate the filtrate under vacuum. The residue is taken up in acetone and the precipitate formed is separated by filtration and then dissolved in ether, washed with a 10% sodium hydroxide solution and then with a saturated solution of Nazi. The ether phase is dried over MgSO4 and concentrated under vacuum.

m = 16.2 g
C) NE (3,4-Dichlorophenyl) -3 (tert-butoxycarbonyl-1-piperidinyl-4)
1-butyl-47-dichloro-2,4-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 at 600 ° C. for 4 hours and the solvent is removed under vacuum. The residue is taken up in water and extracted with ethyl acetate. The organic phase is washed successively with a solution of 10% sodium hydroxide, twice with water and then with a saturated solution of
NaCl, dried with Na2SO4 and concentrated in vacuo. The residue is chromatographed on silica gel, eluent: dichloromethanemethanol 98/2 (v / v). The concentration of pure fractions provides a residue that is used as such for deprotection.

D) NC-3,4-dichlorophenyl-) - 3 (4-piperidinyl) -1-butyl-4] -dichloro
2,4 benzamide.

 The residue obtained above is taken up in a solution of sodium hydroxide and then extracted with dichloromethane. The organic phase is washed with a saturated NaCl solution and then dried over Na 2 SO 4 and concentrated in vacuo. The residue is crystallized in ethyl acetate.

m = 11.6 g F = 1180C
E) Compound 2
1 g of the compound prepared above and 0.81 g of K2CO3 are heated at 600C in 15 ml of dimethylformamide. 0.37 g of 4-fluoro-benzoyl bromide is then added and heating is continued at 600 ° C. with stirring for one hour. The solvent is removed in vacuo, the residue is taken up in water and then extracted with ethyl acetate. The organic phase is washed successively with 10% sodium hydroxide solution, with water and then with saturated NaCl solution, dried over MgSO 4 and concentrated in vacuo.

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

 The concentration of the pure fractions gives a residue which is taken up in ethyl acetate and the hydrochloride is prepared by bubbling hydrochloric acid.

 m = 0.6 g F = 1100C.

 The molecules described in the following Tables 1, 2 and 3 are prepared according to Examples 1 or 2 above.

Table 1

<tb> o
<tb> n <SEP> example <SEP> Ar <SEP> m <SEP> F <SEP>;<SEP> OC <SEP>, <SEP> Salt <SEP> Way
<tb><SEP> 3 <SEP> t <SEP> 1 <SEP> 116 <SEP> HCl <SEP> a
<tb><SEP> 3 <SEP> 1 <SEP> 116 <SEP> HCL <SEP> a
<tb><SEP> CL
<tb><SEP> 4 <SEP> U <SEP> 1 <SEP> 130 <SEP> HCI <SEP> b
<tb><SEP> CL <SEP> Cl
<tb><SEP> 5 <SEP><<SEP> 1 <SEP> 114 <SEP> HCL <SEP> b
<tb><SEP> 6 <SEP> 2 <SEP> 1 <SEP> 114 <SEP> HCL <SEP> b
<tb><SEP> OCH3
<Tb>
Table 1 (continued)

<tb> 7 <SEP> tE <SEP> 1 <SEP> 124 <SEP> HCL, H20 <SEP> b
<tb><SEP> OH
<tb> 8 <SEP> 4 <SEP> N <SEP> 1 <SEP> 128 <SEP> HCL <SEP> b
<tb> 9 <SEP><<SEP> AT <SEP> 1 <SEP> 146 <SEP> 2HCI, 0, SHzO <SEP> b
<tb> 10 <SEP> t <SEP> 0 <SEP> 87 <SEP> 0.5ho <SEP> b
<tb> CN
<tb> it <SEP> O <SEP> 82 <SEP> base <SEP> b
<tb><SEP> N02
<Tb>
Table 2

<tb> o
<tb> n <SEP> example <SEP> Z <SEP> F <SEP>;<SEP> C <SEP>, <SEP> Salt <SEP> Way
<tb><SEP><SEP> C4H9
<tb><SEP> 12 <SEP> CH2-N <SEP> 146 <SEP> 2HC1,0,8H20 <SEP> a
<tb><SEP> C4H9
<tb><SEP> CH3
<tb><SEP> 13 <SEP> 5 <SEP> 9 <SEP> CH3 <SEP> p <SEP> 179 <SEP> HCl <SEP> a
<Tb>
Table 3

<tb> 14 <SEP> 105 <SEP> to <SEP> F <SEP> C <SEP>, <SEP> HCI <SEP> Path <SEP> b
<tb> 15 <SEP> to. <SEP> 134 <SEP> HCl <SEP> b
<Tb>

Claims (1)

 CLAIM i. Compound of formula:

 in which - Pro is an N-protecting group - R 'is a C 1 -C 4 alkyl group, a phenyl group or a  tolyl group, preferably para-tolyl,  or one of its salts.