FR2656607A1 - Phenylethanolaminomethyltetralins - Google Patents

Abstract

The invention relates to new phenylethanolaminomethyltetralins having the following formula (I) in which - E represents hydrogen, a (C1-C4)alkyl group, a (C1-C4)alkoxy group, a phenyl group, a nitro group, a halogen atom or a trifluoromethyl group, - L represents hydrogen, a (C1-C4)alkyl group, a (C1-C4)alkoxy group, a nitro group or a halogen atom, or - E and L, together, represent a -CH=CH-CH=CH or -CH2-CH2-CH2-CH2- group, and - G represents a hydrogen atom, a chloro atom, a hydroxyl group or a group -OG' where G' represents a (C1-C4)alkyl group which is unsubstituted or substituted by a hydroxyl, (C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, carboxyl, or (C3-C7)cycloalkyl group, the carboxyl group being free or esterified by a metabolically labile group; a (C3-C7)cycloalkyl group; or a (C2-C4)alkanoyl group, and to their salts, which have a selective beta-adrenergic activity on the intestines. The invention also relates to a process for the preparation of these compounds and the intermediates of formula (III) useful in this process.n

Description

Phényléthanolaminométhyltétralines
The present invention relates to novel phenyl ethanolaminomethylketetralins having selective intestinal beta-adrenergic activity, a process for the preparation of these compounds, intermediates in this process and pharmaceutical compositions containing said phenylethanolaminomethyltetralines as active ingredients.

dans laquelle X représente l'hydrogène, un halogène, un groupe trifluorométhyle ou un groupe alkyle inférieur et R représente l'hydrogène ou un groupe méthyle non substitué ou substitué par un groupe carboxy ou alcoxycarbonyle, ayant des propriétés pharmacologiques très intéressantes. Entre autres, les composés (A) sont indiqués comme modulateurs de la motricité intestinale et utérine.European Patent 211721 discloses phenylethanolamino-tetralines substituted on the aromatic ring of tetralin, of formula (A) below

wherein X is hydrogen, halogen, trifluoromethyl or lower alkyl and R is hydrogen or methyl unsubstituted or substituted by carboxy or alkoxycarbonyl, having very valuable pharmacological properties. Among others, compounds (A) are indicated as modulators of intestinal and uterine motricity.

 It has now been found that compounds which differ from the known compounds essentially by the presence of a methylene group (-CH 2 -) between the tetralin nucleus and the amino group, have an activity on intestinal motility which is greater than or equal to to that of the corresponding phenylethanolaminotetralins, associated with greater selectivity towards the intestine.

dans laquelle - E représente l'hydrogène, un groupe (C1-C4)alkyle, un groupe
(C1-C4)alcoxy, un groupe phényle, un groupe nitro, un atome
d'halogène, ou un groupe trifluorométhyle, - L représente l'hydrogène, un groupe (C1-C4)alkyle, un groupe
(C1-C4)alcoxy, un groupe nitro ou un atome d'halogène, ou - E et L, ensemble, représentent un groupe -CH=CH-CH=CH- ou
-CH2-CH2-CH2-CH2-, et - G représente un atome d'hydrogène, un atome de chlore, un
groupe hydroxy ou un groupe -OG' où G' représente un groupe
(C1-C4)alkyle non substitué ou substitué par un groupe hydroxy,
(C1-C4)alcoxy, (C1-C4)alcoxycarbonyle, carboxy libre ou esté
rifié par un groupe métaboliquement LabiLe, ou (C3-C7)cyclo
alkyle ; un groupe (C3-C7)cycloalkyle ; ou un groupe (C2-C4)
alcanoyle, et Leurs sels.Thus, the present invention relates, in one of its aspects, phenylethanolaminomethyltetralines having the following formula (I)

in which - E represents hydrogen, a (C1-C4) alkyl group, a group
(C1-C4) alkoxy, a phenyl group, a nitro group, an atom
of halogen, or a trifluoromethyl group, - L represents hydrogen, a (C1-C4) alkyl group, a
(C1-C4) alkoxy, a nitro group or a halogen atom, or - E and L, together, represent a group -CH = CH-CH = CH- or
-CH2-CH2-CH2-CH2-, and -G represents a hydrogen atom, a chlorine atom, a
hydroxy group or a group -OG 'where G' represents a group
(C1-C4) alkyl unsubstituted or substituted with hydroxy group,
(C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, free or fused carboxy
by a metabolically labile group, or (C3-C7) cyclo
alkyl; a (C3-C7) cycloalkyl group; or a group (C2-C4)
alkanoyl, and their salts.

In the present description: the term "(C1-C4) alkyl" designates a monovalent radical of a
saturated hydrocarbon with straight or branched chain, which can
contain 1 to 4 carbon atoms, such as methyl, ethyl,
propyl, isopropyl, n-butyl, sec-butyl or tert-butyl; the term "(C1-C4) alkoxy" denotes an alkoxy chain radical
straight or branched containing from 1 to 4 carbon atoms, such
as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy
or tert-butoxy; the term "(C3-C7) cycloalkyl" refers to a monovalent radical
of a saturated cyclic hydrocarbon containing 3 to 7 carbon atoms
carbon, such as cyclopropyl radicals, cyclobutyl, cyclic
pentyl, cyclopentyl substituted with one or two methyl groups
or by an ethyl group, or cyclohexyl, methyl,
cyclohexyl or cycloheptyl; the term "(C2-C4) alkanoyl" identifies an acyl radical of a
saturated aliphatic carboxylic acid containing 2 to 4 carbon atoms
carbon, namely the acetyl, propionyl and 2-methyl radicals.
propionyl and butyrroyl; the terms "halogen" include the four halogens: fluorine,
chlorine, bromine, iodine, the first three being particularly
preferred; - the terms "tetralin", "tetralinic" and "tetralone" refer to
1,2,3,4-tetrahydronaphthalene.

 The salts of the compounds of formula (I) according to the present invention include both addition salts with pharmaceutically acceptable inorganic or organic acids such as hydrochloride, hydrobromide, sulphate, hydrogen sulfate, dihydrogenphosphate, citrate, maleate, tartrate, fumarate, gluconate, methanesulfonate, 2-naphthalenesulphonate, etc., as salts which allow a suitable separation or crystallization of the compounds of formula CI), such as picrate, oxalate or addition salts with optically active acids, for example camphorsulfonic acids and substituted mandelic or mandelic acids.

 In addition, when the compound of formula (I) has a free carboxy group, its salts also include salts with mineral bases, preferably those with alkali metals such as sodium or potassium, or with organic bases, such as trometamol.

 When the compound of formula (I) has a free carboxy group, the metabolically labile and biologically compatible esters of said acid are also part of the present invention. Metabolically viable esters include acyloxyalkyl esters, for example alkanoyloxymethyl or alkanoyloxyethyl esters such as acetoxymethyl, acetoxyethyl or pivaloyloxymethyl esters.

 In formula (I) above, the two asymmetric carbon atoms are marked with an asterisk. All the compounds of formula (I) can therefore exist in the form of at least four different steric isomers, (R, R), (R, S), (S, S) and (S, R). Optically active stereoisomers, as well as mixtures of the two, three or all four isomers, in any proportion, form part of the present invention. Other centers of asymmetry could be present in the E, L and G radicals. likewise, the stereoisomers derived from the presence of chiral centers and their mixtures are part of the invention.

 Preferred compounds of the present invention include the compounds of formula (I) wherein E and L are as defined above and G is hydrogen, hydroxy or a group -OG 'where G' is a group ( C1-C4) alkyl unsubstituted or substituted with hydroxy, (C1-C4) alkoxy, carboxy, (C1-C4) alkoxycarbonyl or (C3-C7) cycloalkyl, and salts thereof.

 Particularly preferred compounds of the present invention include the compounds of formula (I) wherein E is hydrogen, a (C 1 -C 4) alkyl group, or a halogen atom, L is hydrogen and G is hydrogen, a hydroxy group or a group -OG 'wherein G' represents a (C1-C4) alkyl group unsubstituted or substituted by a carboxyl group or a (C1-C4) alkoxycarbonyl group, and their salts.

dans laquelle E et L sont tels que définis ci-dessus et le radical -W représente un des groupes suivants :

où Hal représente le chlore, Le brome ou L'iode et Y représente un groupe -COOH ou un dérivé fonctionnel de celui-ci ; avec un compose de formule (III)

dans laquelle G a la signification donnée ci-dessus, et, quand -W est autre que

en traitant le produit ainsi obtenu avec un agent réducteur approprié.The compounds of formula (I) may be prepared by treating a compound of formula (II):

wherein E and L are as defined above and the radical -W represents one of the following groups:

where Hal represents chlorine, bromine or iodine and Y represents a -COOH group or a functional derivative thereof; with a compound of formula (III)

in which G has the meaning given above, and, when -W is other than

treating the product thus obtained with a suitable reducing agent.

More particularly, the reaction between the compounds of formula (II) and the 2-aminomethyltetralinic derivative (III) is
It is available according to procedures and under different conditions which are essentially a function of the nature of the starting material of formula (II) used and which depend in particular on the meaning of the group -W.

 These procedures are discussed in detail below and have been designated Methods (a) to (d).

par L'amine (III) est conduite dans un solvant organique tel qu'un alcanol inférieur comme le méthanol, L'méthanol et l'isopropanol, le diméthylsulfoxyde, un éther Linéaire ou cyclique, ou un amide comme le diméthylformamide ou le diméhtylacétamide, en utilisant des quantités au moins équimoléculaires des réactifs, mais de préférence un excès de L'amine (III). La température de la réaction est comprise entre la température ambiante et la température de reflux du solvant choisi. Un agent de condensation basique, tel que
L'hydroxyde de sodium ou L'acétate de sodium, peut etre convenablement utilisé.Method (a)
According to this procedure, the opening of the epoxide of formula (IIa):

by the amine (III) is carried out in an organic solvent such as a lower alkanol such as methanol, methanol and isopropanol, dimethylsulfoxide, a linear or cyclic ether, or an amide such as dimethylformamide or dimethylacetamide, using at least equimolar amounts of the reagents, but preferably an excess of the amine (III). The temperature of the reaction is between room temperature and the reflux temperature of the chosen solvent. A basic condensing agent, such as
Sodium hydroxide or sodium acetate can be suitably used.

avec L'amine (III) et la réduction du produit obtenu, le mode opératoire préféré prévoit que les deux réactions soient conduites simultanément en faisant réagir les composés (IIb) et (III) en présence d'un agent réducteur approprié. Si L'amine de formule (III) et le phénylglyoxal de formule (IIb) ne contiennent pas de groupe sensible à la réduction, la réaction est aisément réalisée par hydrogénation catalytique en présence, par exempLe, de bioxyde de platine ou de nickel Raney et dans un solvant alcoolique, tel que le méthanol ou l'éthanol, à La pression atmosphérique ou sous pression.Selon un autre mode opératoire pour cette réaction, on utilise un hydrure d'un métal aLcaLin, par exemple le borohydrure de sodium, dans un solvant alcoolique tel que l'éthanol, de préférence à basse température.Method (b)
In the reaction which comprises the condensation of phenylglyoxal of formula (IIb)

With the amine (III) and the reduction of the product obtained, the preferred procedure provides that both reactions are carried out simultaneously by reacting the compounds (IIb) and (III) in the presence of a suitable reducing agent. If the amine of formula (III) and the phenylglyoxal of formula (IIb) do not contain any reduction-sensitive group, the reaction is easily carried out by catalytic hydrogenation in the presence, for example, of platinum dioxide or Raney nickel and in an alcoholic solvent, such as methanol or ethanol, at atmospheric pressure or under pressure. According to another procedure for this reaction, a hydride of an alkali metal, for example sodium borohydride, is used in a alcoholic solvent such as ethanol, preferably at low temperature.

dans un solvant inerte, tel qu'un éther Linéaire ou cyclique, un alcool inférieur comme Le méthanol, L'méthanol ou l'isopropanol, un hydrocarbure aromatique comme Le toluène ou le benzène, un hydrocarbure aliphatique halogéné comme le chloroforme, ou un nitrile comme l'acétonitrile. Cette réaction de substitution nucleophile est conduite avantageusement à la température ambiante ou à froid.Method (c)
According to another procedure, the compounds of formula (I) are obtained by reaction between the amine of formula (III) and an alpha-haloacetophenone of formula (IIc)

in an inert solvent, such as a linear or cyclic ether, a lower alcohol such as methanol, methanol or isopropanol, an aromatic hydrocarbon such as toluene or benzene, a halogenated aliphatic hydrocarbon such as chloroform, or a nitrile like acetonitrile. This nucleophilic substitution reaction is conveniently conducted at room temperature or cold.

The reduction of the product thus obtained can be carried out according to the known techniques, for example by hydrogenation in the presence of a catalyst such as palladium on carbon, Raney nickel, or platinum dioxide, in the presence of an alcoholic solvent, such as than methanol or ethanol, preferably at low temperature; or by the action of lithium aluminum hydride in ethyl ether or tetrahydrofuran or, also, by action of an aluminum alkoxide, such as aluminum isopropoxide, in a solvent such as L isopropanol, preferably under reflux.

dans laquelle E, L et Y sont tels que définis ci-dessus.Method (d)
According to a preferred procedure, which represents another aspect of the present invention, the amine III is reacted with a compound of formula (IId):

wherein E, L and Y are as defined above.

 As a functional derivative of the -COOH group, it is possible to use the chloride, the anhydride, the mixed anhydrides, the active esters or the suitably activated free acid, for example with dicyclohexylcarbodiimide (DCCI) or benzo triazolyl hexafluorophosphate-N -oxytris- (dimethylamino) phosphonium (BOP). The reaction between the compound of formula (IId) above and aminomethyltetralin (III) is carried out in an organic solvent, aprotic, apolar or preferably polar, such as dimethylformamide, dimethylsulfoxide, methylene chloride, benzene toluene, optionally in the presence of a proton acceptor, such as aliphatic tertiary amines, especially triethylamine.

ainsi obtenu peut être directement soumis à une réduction du groupe ami do en groupe méthylèneamino.Mandelamide of formula (IV):

thus obtained can be directly subjected to a reduction of the group ami do in methyleneamino group.

The reduction step is carried out, for example, by the action of a hydride such as lithium aluminum hydride, or diborane, in particular a diborane-generating reagent such as the complex between borane and dimethylsulfide, hereinafter referred to as "borane-methylsutfure". The reaction is carried out in an organic solvent such as tetrahydrofuran and the compound of formula (I) is isolated according to known techniques. In the case of the reduction of a mandelamide of formula (IV) in which G is a group -OG 'where G' represents an alkyl group substituted by an optionally salified carboxy group or a (C1-C4) alkoxycarbonyl group, in use
Reading boranemethylsulfide and operating at low temperature (15-250C), selective reduction of the amido group is preferably obtained.

 In general, when the desired product of formula (I) above contains one or more groups sensitive to reduction, it is suitable to use as starting material (II) a compound of formula (IIa) or to choose reducing agents or specific reaction conditions known in the literature which make it possible to obtain, at least preferably, the selective reduction of the ring between the amino group and the benzene ring, with formation of the desired chain -CH (OH) -CH 2 -NH- without alteration of the other groups.

According to another general procedure for the preparation of the compounds of formula (I) in which G is a group -OG ', the corresponding compound (I) in which G is a hydroxyl group is prepared by the general method described above, and then converted to the desired product by O-alkylation or O-acylation according to conventional procedures which provide for the reaction of the compound of formula (I) wherein G is a hydroxy group with an alkylating agent or acylation of formula G'-D in which
G 'is as defined above and D is an easily removable group. This procedure is even preferable when G is OG 'where G' is (C1-C4) alkyl substituted by carboxy or (C1-C4) alkoxycarbonyl, or alkanoyl.

 O-alkylation, for example, may be conducted using an optionally substituted (C1-C4) alkyl halide, such as chloride, iodide or, preferably, bromide, in the presence of a condensing agent. basic.

 The O-alkylation is carried out in an aprotic polar organic solvent such as acetone, esters such as ethyl acetate, or ethers, preferably cyclic, such as tetrahydrofuran or dioxane. As the basic condensation agent, alkali or alkaline earth carbonates, such as sodium, potassium or calcium carbonates or aliphatic tertiary amines, such as triethylamine, may be used.

 The reaction of O-acylation by the action of (C 2 -C 4) alkanoic acid halides can be carried out in an aqueous or non-aqueous reaction medium, for example in aqueous ketones such as aqueous acetone, in esters such as Ethyl acetate, in halogenated hydrocarbons such as methylene chloride, in amides such as dimethylacetamide, in nitriles such as acetonitrile or in mixtures of two or more such solvents. The temperature is between -50 and +50 ° C., preferably from -20 ° to + 30 ° C., and is preferably carried out in the presence of a proton acceptor fixing the hydrohalic acid which is formed during the reaction. proton acceptors, mention may be made of tertiary amines, for example triethylamine, dimethylaniline or 4-dimethylaminopyridine, and inorganic bases, such as, for example, sodium or potassium carbonate or calcium carbonate, which bind or bind The hydrohalic acid released during the acylation reaction.

 Acylation can be carried out using the carboxylic acids themselves as acylating agents.

 In this case, the reaction is advantageously carried out in the presence of a condensing agent, for example a carbodiimide, such as DCCI, a carbonyl compound, such as carbonyldiimidazole, or an isoxazolium salt such as N-ethyl perchlorate. -S-phenylisoxazolium.

 O-acylation can also be carried out with other derivatives such as, for example, an activated ester, a symmetrical anhydride or a mixed anhydride. The acylation reactions in which the free acids or their abovementioned derivatives are used are advantageously carried out in an anhydrous reaction medium, for example methylene chloride, tetrahydrofuran, dimethylformamide or acetonitrile.

 In particular cases, alternative methods for the introduction of G 'groups can be readily envisaged as these methods are part of conventional chemistry. The compounds (I), wherein G 'is a carboxyl-substituted alkyl group, can be readily prepared, for example, by saponification of the corresponding esters in basic medium.

respectivement, en présence d'une base, suivie d'une réaction avec du chlorure de thionyle dans le (C1-C4)alcanol dont on veut L'ester (J. Am. Chem. Soc., 1948, 70, 1153).Compounds of formula (I) wherein G is a group
Where G 'is 1-methyl-? - (C1-C) alkoxycarbonylethyl or 1-ethyl-1- (C1-C4) alkoxycarbonylethyl may be prepared by reaction of the corresponding compounds (I), where -G is hydroxy with a compound of formula:

respectively, in the presence of a base, followed by reaction with thionyl chloride in the (C1-C4) alkanol of which the ester is desired (J. Am. Chem. Soc., 1948, 70, 1153).

Again, compounds of formula (I), wherein G is OG 'where G' is ethyl substituted with carboxy or CCl-C4) alkoxycarbonyl, may be prepared from the corresponding compounds of formula (I) in which G is a group OG ', where G' is carboxymethyl, according to the reaction of Arndt
Eistert (Ber., 1935, 68, 200) which provides for the conversion of the acid to the corresponding acid chloride followed by the reaction of the latter product with diazomethane and by the hydrolysis of the product thus obtained in the presence of Au20 .

 The O-alkylation or O-acylation reactions can be carried out directly on the compounds of formula CI) having a hydroxy group in the tetralinic aromatic ring, but, to avoid the formation of N-alkylation or N-alkylation products. acylation, the amino group is preferably protected with a temporary N-protecting group R 'before subjecting the compounds (I) to said processes. The N-protecting groups R' desirable are all the conventional groups which are capable of being removed by catalytic hydrogenation or by mild acid hydrolysis, such as benzyloxycarbonyl group, benzyloxycarbonyl group substituted on the aromatic ring, for example by a methoxy or nitro group, the t-alkoxycarbonyl group for example tertbutoxycarbonyl (Boc), or tert-amyloxycarbonyl (Aoc ); the Boc group is particularly preferred.

The N-protecting group R 'is carried out by reacting the compounds of formula (I) wherein G is hydroxyl with the appropriate reagent for the protection of amino groups, as described, for example, by M. Bodanszky and al. Peptide
Synthesis, 2nd edition, John Wiley & Sons, 1976, pages 18 to 49, chapters 3 to 6.

 The Boc and Aoc groups, for example, can be introduced by reaction with di-tert-butyl and, respectively, ditert-amyldicarbonate in basic medium and in an organic solvent such as dioxane, tetrahydrofuran or dimethylformamide.

The benzyloxycarbonyl and substituted benzyloxycarbonyl groups may be introduced according to the general procedure described by
EC Horning, Organic Synthesis, vol. III, Wiley, New York, 1955, page 167.

dans laquelle E, L et R' sont tels que définis ci-dessus, sont soumis à l'O-alkylation ou à l'O-acylation selon les procédés conventionnels décrits ci-dessus et, ensuite, le groupe N-protecteur
R' du composé ainsi obtenu de formule (I") :

où E, L, R' et G' sont tels que définis ci-dessus, est éliminé.The compounds thus obtained of formula (I ')

wherein E, L and R 'are as defined above, are subjected to O-alkylation or O-acylation according to the conventional methods described above and then the N-protecting group.
R 'of the compound thus obtained of formula (I "):

where E, L, R 'and G' are as defined above, is removed.

The removal of the N-protecting groups is carried out by catalytic hydrogenation or by mild acid hydrolysis according to methods well known in the literature. In particular, the groups Boc and
Aoc are removed under acidic conditions by the action of trifluoroacetic acid. The benzyloxycarbonyl and substituted benzyloxycarbonyl groups are removed by catalytic hydrogenation, preferably using palladium on charcoal as a catalyst.

 When a compound of formula (I ") in which -G 'represents a (C1-C4) alkyl-alkoxycarbonyl substituted alkyl group, it can be saponified in basic medium before or after deprotection of the amino group.

 The products (I) are isolated according to conventional methods, preferably in the form of one of their addition salts with inorganic or organic acids which allow a suitable separation or crystallization of the compounds as indicated above, such as L '. picric acid, oxalic acid or an optically active acid, for example a mandelic or substituted mandelic acid, or a camphorsulphonic acid, or with mineral or organic acids which form pharmaceutically acceptable salts, such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, methyl sulphate, maleate, fumarate, naphthalenesulphonate.

 The free base may be released by neutralization and converted to another acid addition salt or, when G is a group OG 'where G' is a carboxyl-substituted alkyl group, to a salt with a metal, especially an alkali metal, such as as sodium salt or calcium.

 The compounds of formula (I) which have the only asymmetric carbon atoms marked with the asterisk can exist in four different isomeric forms. The process of the present invention makes it possible to operate both on racemic mixtures and on optically pure isomers. In particular, the reactions which form the whole of this process do not modify the stereochemistry of the compounds concerned. Thus, starting from a compound of formula (IIb) or (IIc), which does not have a chiral center, or of a compound of formula (IIa) or (IId) in racemic form, and of a compound of formula (III) in racemic form, a mixture of isomers is obtained, in particular the (R, R) isomers, (S, S), (R, S) and (S, R).

 Similarly, using a compound of formula (III) in optically active form, for example having the absolute configuration R, there is obtained a mixture of only two isomers, namely (R, R) and (S, R). In the latter case, using also a starting compound of formula (IIa) or (IId) in optically active form, the pure isomers can be obtained.

 When a mixture of four isomers is obtained, it can be separated into two pairs of enantiomers (R, R) + (S, S) and (R, S) + (S, R), between them diastereoisomeric, by suitable techniques such as fractional crystallization in a suitable solvent, preferably a lower alkanol, such as ethanol, isopropanol or mixtures thereof. Each pair of enantiomers can then be separated in the pure isomers for example by formation of diastereoisomeric salts, or by chromatography on chiral columns, or by other suitable techniques.

 When one of the starting compounds is in optically active form, the mixture of the two diastereoisomers thus obtained is separated in the pure isomers according to the techniques mentioned above.

 The starting compounds of formula (II) are known products, or in any case they can be prepared according to conventional methods described in the chemical literature.

For example, the compounds of formula (IIa) can be obtained by epoxidation of the corresponding styrenic derivatives with oxygen in the presence of a silver catalyst, or by the action of dimethylsulfonium or dimethylsulfoxonium methylide on the corresponding substituted benzaldehyde according to method described by EJ Corey in J. Am. Chem. Soc., 1956, 87, 1353.

 According to a preferred method of preparation, a compound of formula (IIa) can be obtained in optically active form by reducing the substituted mandelic acid having the desired absolute configuration at the alpha-carbon atom in the corresponding glycolic derivative. by esterification of the primary alcoholic group with a functional derivative of a sulfonic acid such as tosyl or mesyl chloride and, next, by cyclization of the compound thus obtained by treatment with a strong base such as an alkaline hydroxide under the conditions of reaction conventionally used for intramolecular nucleophilic substitutions.

 The compounds of formula (IIb) are easily prepared by the action of an oxidizing agent, such as selenium dioxide, on the corresponding acetophenones, in calf or in an organic solvent, such as a cyclic ether, in particular dioxane or tetrahydrofuran.

According to another procedure, said compounds of formula (IIb) are prepared by the action of dimethylsulfoxide on the haloacetophenones of formula (IIc) having the same substitution on the benzene ring according to the method described by N. Kornblum in
J. Am. Chem. Soc., 1957, 79, 6562, or alternatively from the corresponding alpha-haloacetophenones by the reaction described by
F. Venier in CR Acad. Sci., 1968, 266, 1650.

The starting compounds of formula (IIc) are easily obtained by halogenation of the corresponding ketones or, in some cases, by a Friedel-Crafts reaction using the corresponding substituted benzene derivatives and a halide of a haloacetic acid. Finally, functional derivatives of substituted mandelic or mandelic acids of formula (IId) are prepared from the corresponding acids which, in turn, can be obtained by hydrolysis of mandelonitriles having the same substitution on the benzene ring. These latter compounds can be prepared from either substituted or unsubstituted benzaldehyde and
Hydrocyanic acid, either benzaldehyde, substituted or not, sodium cyanide and sodium bisulfite according to methods well known in the chemical literature. The mandelic acids of formula (IId) obtained in racemic form can be easily separated in their optically pure isomers by formation of diastereoisomeric salts with appropriate optically active organic bases according to conventional methods and techniques.

 Compounds of formula (III) in which G represents a chloro atom, a hydroxyl group or an OG 'group, where G' has the same meaning given above, except the compound of formula (III) in which G is a methoxy group at position 7, as well as the optically pure stereoisomers of the compounds of formula (III) in which G represents hydrogen, a chloro atom, a hydroxyl group or a group OG 'where G' has the same meaning given below; above, and their optional salts, are novel products and represent the key intermediates in the preparation of the compounds (I). Said products of formula (III) represent, therefore, another object of the present invention.

 Preferred compounds of formula (III) include those compounds of formula (III) wherein G represents a hydroxy group or an OG 'group where G' represents a carboxyl group (C1 C4) alkyl group or a group (C1- C4) alkoxycarbonyl.

dans laquelle G" représente l'hydrogène, un atome de chloro, un groupe hydroxy ou un groupe méthoxy, selon une méthode générale qui est illustrée dans le schéma I suivant
Schéma I

The compounds of formula (III) can be prepared starting from a 1-tetralone of formula (V)

wherein G "represents hydrogen, a chloro atom, a hydroxy group or a methoxy group, according to a general method which is illustrated in the following Scheme I
Scheme I

<tb><SEP> N- '<SEP> O
<tb> e <SEP> o <SEP> It
<tb> Hc <SEP> CH
<tb> t <SEP><SEP><SEP> cyclization <SEP> G "
<tb><SEP> with <SEP> G "<SEP> forayLationp <SEP>><SEP>G"<SEP> with <SEP> NH
<tb><SEP> (v) <SEP> (vI) <SEP> (vII)
<tb><SEP> opening <SEP> of the <SEP> kernel
<tb><SEP> | <SEP> isoxazolidine
<tb><SEP> oxo <SEP> g <SEP> hydroxyl
<tb><SEP> NC <SEP> | <SEP> oxo <SEP> to <SEP> group
<tb><SEP>><SEP> 1 <SEP> 3) <SEP> dehydration
<tb><SEP> (empty)
<tb><SEP> H2 <SEP><-r<SEP> a <SEP> Production
<tb><SEP> G "<SEP> (vili)
<tb><SEP> = H3 <SEP> (here: <SEP> G <SEP> = <SEP> G "<SEP> -H, <SEP> -Cl, <SEP> -OH, <SEP> OcH
<tb><SEP> 3
<tb><SEP> r <SEP> G "<SEP> = <SEP> -OH
<tb><SEP> h <SEP> l <SEP> G "<SEP> = <SEP> -OH
<tb> protection <SEP> of <SEP> \ <SEP> O-alkylation /
<tb> group <SEP> aiino <SEP> 0-acylation
<tb><SEP> O-alk <SEP> lation <SEP> H <SEP> H
<tb><SEP> O-acyaation <SEP> 2 <SEP>><SEP> OG '
<tb><SEP> deprotection <SEP>: <SEP>: <SEP> G <SEP> = <SEP> -OG '<SEP>;<SEP> -OCH
<tb><SEP> 3
<Tb>
The general method illustrated in Scheme I provides (i) a Claisen reaction for the introduction of a group for
myle in position 2 of 1-tetralone (V), by reaction with
an alkyl formate in the presence of sodium, (ii) the reaction of the compound (VI) thus obtained with hydroxyl-
amine by heating in an acidic medium, (iii) the opening of the isoxazolidine ring of the compound (VII) and the
reduction of the 1-oxo to 1-hydroxy group (for example, according to the
method described in Synthesis, 1981, 449).

(iv) dehydration of the intermediate compound thus obtained, with
a desiccant system such as, for example, Pool3 /
pyridine, obtaining the compound (VIII), and (v) treating the compound (VIII) with a reducing agent
which gives rise to the corresponding compound of formula
III where G = G "and represents hydrogen, a hydroxyl group
or a methoxyl group.

 The reduction of the compound of formula (VIII) can be carried out either in two steps, for example first with sodium borohydride and then with lithium aluminum hydride or isobutylaluminum hydride (DIBAL ) or in a single step, for example directly with lithium aluminum hydride or with DIBAL. In the first case, the 2-cyanotetralin optionally substituted by the G "group can be isolated.

Compounds of formula (III) in which G is an OG group other than methoxy are therefore prepared by O-alkylation or
O-acylation of the compound (III) where G = G "= OH according to the conventional methods described above for O-alkylation or O-acylation of the compounds of formula (I), in which G is hydroxy.

In this case also, the optional O-acylation or O-alkylation of the compounds of formula (III) where G = G "= OH can be carried out with or without prior protection of the amino group. use not only the groups Nprotectors R 'indicated above for the protection of the -NH- group of the compounds (I), but also the benzyl, benzhydryl or trityl groups which are unsubstituted or substituted on the benzene ring or one of the benzene rings by a group methoxy or nitro and 2,2,2-trichloroethyl group or to form phthalimido derivatives.The deprotection of these N-protecting groups is carried out according to conventional techniques, in particular by catalytic hydrogenation with palladium or palladium hydroxide on carbon, in the optionally substituted benzyl, benzhydryl and trityl groups or 2,2,2-trichloroethyl group and by treatment with hydrazine in the case of the phthalimido group. Trityl and methoxytrytyl can also be removed by gentle hydrolysis, for example in 50% formic acid.

The 2-aminomethyl-1,2,3,4-tetrahydronaphthalenes of the formula (III) in which G is a group OG 'where G' is (C1-C4) alkyl substituted by a carboxyl ester esterified with a metabolically labile group may be prepared from the corresponding compounds wherein the carboxyl is free by protecting the amino group with an N-protecting group which can be removed by catalytic hydrogenation, followed by the reaction of the carboxylic acid with the appropriately selected alcohol, which reaction is conducted in an inert solvent, in the presence of an ion exchange resin, preferably using an excess of the esterifying alcohol and protecting the amino group
The compounds of formula (III), in which G is an OH group, may also be prepared starting from a compound of formula (V) wherein G "is a methoxy group in the same position and subjecting the compounds (III) obtained according to the general method of Scheme I to a demethylation reaction with hydrobromic acid.

par réaction avec une quantité au moins équimoléculaire d'un cyanure alcalin, notamment de cyanure de sodium, dans un solvant organique aprotique, de préférence polaire, par exemple le diméthylsulfoxyde ou le diméthylformamide. Cette réaction, qui peut être conduite à une température comprise entre la température ambiante et la température de reflux du mélange réactionnel, porte directement au composé (VIII) qui est ensuite traité comme décrit dans le schéma I.The 2-cyano-3,4-dihydronaphthalene derivatives of formula (VIII) may also be prepared from the corresponding 2-tetralones of formula (IX)

by reaction with at least an equimolar amount of an alkaline cyanide, especially sodium cyanide, in an aprotic organic solvent, preferably polar, for example dimethylsulfoxide or dimethylformamide. This reaction, which can be conducted at a temperature between room temperature and the reflux temperature of the reaction mixture, directly relates to the compound (VIII) which is then treated as described in Scheme I.

 If desired, the racemic mixtures of the compounds (III) thus obtained are separated into pure isomers by formation of diastereoisomeric salts with optically active organic acids such as camphorsulfonic acids, optionally substituted mandelic acids or other optically active acids. assets.

 When G 'is an alkyl group substituted with a carboxy group, the separation of the racemic mixture into optically pure isomers can be carried out by forming diastereoisomeric salts with optically active organic bases, such as alpha-alkylbenzylamines, menthylamine or other bases used in the conventional technique.

 If aminomethyltetralin (III) contains a second chiral center, the diastereoisomers and the four pure isomers can be isolated as described above. Thus, they can be used for the preparation of all the isomers of the compounds (I).

((X) : Z = OH ou Nu2). According to another suitable procedure for preparing the compounds (III), the corresponding carboxylic acids of the formula (X) in which Z is an OH group are used as starting compounds.

((X): Z = OH or Nu2).

These products are converted into the corresponding amides ((X): Z = NH 2), the amido group of which is then converted into aminomethyl group.

The above acids of formula (X) wherein Z is -OH can be prepared from the corresponding 1-tetralones (V) according to a general method which is illustrated in the following Scheme II
Scheme II

<tb><SEP> O <SEP> o
<tb><SEP> G "<SEP> EtOOC <SEP> It
<tb><SEP> X <SEP> EtOOOO <SEP> tX <SEP> G
<tb><SEP> Na <SEP> G
<tb><SEP> (V) <SEP> CXI)
<tb><SEP> reduction
<tb> ZCO <SEP> Xss <SEP> G "<SEP> Hydrolysis <SEP> EtOOC
<tb><SEP> G "<SEP> E) <SEP>G"
<tb><SEP> hydrolysis
<tb><SEP> ((X): <SEP> Z <SEP> = <SEP> OH) <SEP> (XII)
<tb> and which provides for (i) a Claisen reaction for the introduction of a group
ethoxycarbonyl at the 2-position of 1-tetralone (V), by
reaction with diethylcarbonate in the presence of sodium, (ii) reduction of the 1-oxo group in the compound (XI) by
catalytic, with H2 in the presence of Pd / C, or chemical, with
The triethylsilane / trifluoroacetic acid system
(Tetrahedron, 1967, 23, 2235) or triethylsilanetBF3.Et20
(J. Org Chem., 1985, 50, 3619) or, again, with triethyl
silane / trifluoromethanesulfonic acid (Synthesis, 1986,
779), and (iii) hydrolysis of the ester (XII) in basic medium.

 The conversion of the acids to the corresponding amides of formula (X), in which Z is an NH 2 group, is carried out according to conventional methods which provide the nucleophilic addition of ammonia to the positively polarized carbon of a functional derivative of the 'acid.

 As a functional derivative, it is possible to use the chloride, the anhydride, the mixed anhydrides, the active esters or the free acid suitably activated, for example with DCCI or BOP.

 The reduction step of the amido group is carried out, for example, by the action of a hydride such as lithium aluminum hydride or diborane, especially borane-methylsulfide reagent. The reduction reaction is carried out in an aprotic organic solvent, such as cyclic or alkyl ethers, especially in dioxane or tetrahydrofuran.

 The compounds thus obtained of formula (III), in which G = G "and represents hydrogen, a chloro atom, a hydroxyl group or a methoxy group, may be converted into the other compounds of formula (III) as described above. above.

 Starting from the acid of formula (X) where Z = OH, in optically active form, the compound of formula (III) having the same absolute configuration at the asymmetric carbon atom is obtained.

 The optically active acids of formula (X) can be obtained from the corresponding racemic mixture by forming diastereoisomeric salts with optically active amines such as d-alpha-methylbenzylamine, 1-alpha-methylbenzylamine, d-menthylamine and 1-menthylamine and precipitation of said salts in a suitable solvent.

 The acids and amides of formula (X), in optically active form, are novel products that allow easy preparation of optically pure products (I), and thus represent another specific object of the present invention.

 The compounds of formula (I) and their salts possess valuable pharmacological properties because they have shown themselves to be very active as modulators of intestinal motility.

 In particular, their ability to reduce spontaneous motility of the colon has been observed in standardized pharmacological tests in vitro and has been confirmed in vivo in animals.

In vitro assays, the ability of the phenylethanolaminomethyltetralines of the invention to reduce, according to
the concentration, the contractile response, under particular nor- malized conditions, of proximal colon bands of isolated rats.

Non-fasting, malted rats weighing 250 to 300 g are sacrificed. The proximal portion of the colon, consisting of a 2-3 cm segment, is removed and suspended in a 20 ml organ tank containing a Krebs-Ringer solution having the following mM composition: NaCl 118.4; Kcl 4.7; CaCl2 2.45; MgSO4 1.16;
NaH2PO4 3.7; Glucose 5.6; NaHcO 3 30.9. The solution is aerated by a mixture of oxygen (95%) and CO2 (5%) and its temperature kept constant at 37 c. The segments of the colon, subjected to a traction of about 1 g, contract spontaneously. The compounds under study are added after stabilization of the preparation (2 h).

 The EC50 is determined which represents the concentration of the compound which produces a 50% reduction in the contraction of the affected tissue in the absence of test compounds.

 In this test, the compounds of the present invention showed a very high activity, characterized, for the most active products, by EC50s of the order of 1 to 50 nM.

 The compounds of formula I have also shown surprising specificity for the colon. In vitro tests, carried out according to the same general method, but on the isolated uterus of rats, have shown that a significant effect is obtained on the spontaneous contractility of the uterus at doses much higher than the active doses on the uterus. colon.

 Compared to the compounds described in European Patent 211,721, the compounds of formula I according to the present invention have been found to be more potent and more selective.

For example, the compound of Example 4 (hydrochloride
N - [(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] -2-hydroxy-2- (3-chlorophenyl) ethanamine) is characterized by an EC50 on the colon of 43 nM and a EC50 on the uterus of 2,453 nM which correspond to a selectivity ratio of approximately 57, whereas the compound described in Example 7 of the European Patent 211,721 (N- (7-methoxy-1,2) hydrochloride, 3,4-tetrahydronaphth-2-yl) -2-hydroxy-2- (3-chlorophenyl) ethanamine) is characterized by a colony EC50 of 194 nM and an EC50 on the uterus of 350 nM lower selectivity ratio to 2).

Still, the compound of Example 10, in hydrochloride form, is characterized by an EC50 on the colon of 7 nM and a
EC50 on the uterus of 50 nN selectivity ratio about 7), while the compound described in Example 8 of European patent 211 721, which differs from the first for the group -cH2- between the tetralin nucleus and the group -NH -, is characterized by an EC50 of 110 nM both on the colon and on the uterus ratio of selectivity = 1).

In the in vivo assays, intestinal motility was evaluated in the anesthetized rat according to the technique described in
The compounds of the present invention have shown very good activity at very low doses.

 The phenylethanolaminomethyltetralines of formula (I) and their pharmaceutically acceptable salts have a very low toxicity, compatible with the use of these products as medicaments.

 Thus, the present invention, according to another of its aspects, relates to pharmaceutical compositions useful especially for the treatment of intestinal disorders containing, as active ingredient, one or more compounds of formula (I) above and their pharmaceutically acceptable salts. acceptable.

 In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal or rectal administration, the above active ingredients can be administered in unit dosage forms, in admixture with pharmaceutical carriers. animals, and in humans for the treatment of intestinal motility disorders. 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 administration forms, cutaneous, intramuscular or intravenous and forms of rectal administration.

 In order to obtain the desired therapeutic effect, the dose of active principle may vary between 0.01 and 100 mg per kg of body weight per day.

 Each unit dose may contain from 0.1 to 500 mg of active ingredient in combination with a pharmaceutical carrier. This unit dose can be administered 1 to 4 times a day.

 When preparing a solid composition in tablet form, the main active principle is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose or other 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 the form of syrup or elixir or for administration in the form of drops may contain the active ingredient together with a sweetener, preferably alaloric, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and a suitable dye.

 The water-dispersible powders or granules may contain the active ingredient in admixture with dispersants or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or scavengers. 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 administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol, are used.

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

 The main active ingredient of formula (I) can be administered in free base or pharmaceutically acceptable salt form or in complex form with, for example, a cyclodextrin or in combination or co-administration with other principles. active, for example with tranquillizers.

The following examples illustrate the invention without limiting it. The solvents indicated in parentheses after the melting point are the crystallization solvents. The symbol of the rotation power is indicated by convention / alpha /, but one must
Hear it as Cal 20
Preparation of starting compounds of formula (III) (A) 2-aminomethyl-5-methoxy-1,2,3,4-tetrahydro-hydrochloride
naphthalene (SR 58761 A).

The product 2-cyano-5-methoxy-1,2,3,4-tetrahydro-1 is prepared
naphthol according to the method described in the literature for 2
cyano-6-methoxy-1,2,3,4-tetrahydro-1-naphthol (Synthesis, 1981,
p. 449-451), which is schematized in steps (i) to
(iv) following, and this intermediate is transformed into
2-Aminomethyl-5-methoxy-1,2,3,4-tetrahydro-hydrochloride
naphthalene as described in detail in steps (v) and (vi).

 (i) 2-formyl-5-methoxy-3,4-dihydronaphthalen-1 (2H) -one.

A solution of ethyl formate C2O ml is added,
0.37 moles) in anhydrous benzene (100 ml) to
Sodium ethoxide prepared from sodium
(8.34 g, 0.35 mole) and absolute ethanol, in
anhydrous benzene (100 ml). The reaction mixture is cooled
at approximately 0 ° C and added slowly and
stirring of 5-methoxy-3,4-dihydronaphthalen-1 (2H) -one
(25 g, 0.14 mol) in anhydrous benzene (100 ml). In
treating the reaction mixture according to the method
described in J. Am. Chem. Soc. 1947, 69, 2942, one
collects the product indicated in the title (24.8 g);
mp 68-70C.

(ii) 6-methoxy-4,5-dihydronaphth [2,1-d] isoxazole.

A mixture of product obtained in
Step (i) (23.8 g, 0.11 mol) and hydrochloride
of hydroxylamine (8.2 g, 0.12 mol) in methanol
(300 ml) for ten minutes and then evaporate under
empty. Water is added and extracted with ether
ethyl by obtaining 19 g of product; mp 84-86 C.

(iii) 2-cyano-5-methoxy-3,4-dihydronaphthalen-1 (2H) -one.

We treat the product obtained in the previous step
(19 g, 0.094 mole), about OOC, with methoxide
sodium prepared from sodium (4.7 g, 0.188 mole)
and anhydrous methanol (250 ml) for one hour. We
evaporate under vacuum, add water and extract by
ethyl acetate. The indicated product is obtained
in the title (16.7 g); mp 120-122 C.

(iv) 2-cyano-5-methoxy-1,2,3,4-tetrahydro-1-naphthol.

The product obtained in step (iii) is reduced (16.2 g,
0.080 moles) with sodium borohydride (3.1 g,
0.082 moles) in absolute methanol (500 ml). We eva
pore under vacuum, add a mixture of water and ice,
dify with concentrated HCl and extract with
ethyl acetate. After evaporation of the solvent, we obtain
2-cyano-5-methoxy-1,2,3,4-tetrahydro-1-naphthol
(16.2 g); mp 96-98 C.

(v) 2-cyano-5-methoxy-3,4-dihydronaphthalene.

We heat at 1200C external, for 3 hours, a
mixture of the product obtained in step (iv) (16.2 g,
0.079 moles) and POCl3 (30 ml, 0.32 moles) in
pyridine (200 ml). The mixture is cooled and
difies by adding chlorhy acid drop by drop
2N. The solution is treated with acetate
of ethyl, the organic phase is separated and washed
with a saturated solution of sodium bicarbonate and
some water. Dry sodium sulfate), filter and
evaporates to dryness by obtaining the product indicated in
title (9.8 g); mp 47-490C (isopropyl ether).

(vi) 2-Aminomethyl-5-methoxy-1,2,3,4-tetrahydrochloride
hydronaphtalène.

A solution of the product of
step (v) (9.2 g, 0.05 mol) in tetrahydro
anhydrous furan (150 ml) in a mixture of hydride
lithium and aluminum (3.8 g, 0.1 mole) and tetrahydro
anhydrous furan (50 ml) under a nitrogen atmosphere. We
reflux the reaction mixture during
4 hours, cooled down and added very slowly
water (40 ml). It is extracted with acetate
of ethyl (2 x 300 ml), the organic phase is dried and
we evaporate it. The residue is purified by flash chromato
graphie using a methanol mixture: ammonia 97: 3
as an eluent. The hydrochloride is prepared by treatment
of the free base thus obtained with isopropanol
saturated with hydrochloric acid. We obtain 9 g of
SR 58761 A; mp 231-2320C (ethanol).

(B) 2-Aminomethyl-6-methoxy-1,2,3,4-tetrahydro hydrochloride
naphthalene (SR 58677 A).

The product is obtained according to the operating method described in
preparation (A) above, but from 6-methoxy-3,4
dihydronaphthalen-1-one in place of 5-methoxy-3,4-dihydro
naphthalen-1-one; mp 222-224 ° C (ethanol).

(C) 2-Aminomethyl-8-methoxy-1,2,3,4-tetrahydro-hydrochloride
naphthalene (SR 58847 A).

Cyanide is dripped for 10 minutes.
trimethylsilyl (6.9 g, 9.3 ml, 0.07 mol) in a mixture of
8-methoxy-3,4-dihydronaphthalen-2 (1H) -one (10.9 g, 0.06 mol)
prepared as described by literature (J. Chem Soc., 1958, 409), anhydrous acetonitrile C 60 ml), and a catalytic amount of zinc iodide under a nitrogen atmosphere. We heat to
the external temperature of 80 C for 3 hours. We cool
The reaction mixture is slowly added with 1N hydrochloric acid (ml) and stirred at room temperature for 2 hours. The mixture is concentrated in vacuo, taken up
the residue thus obtained with ethyl acetate, the solution is washed with water, dried over Na 2 SO 4 and, after filtration, evaporated to dryness. The product obtained is triturated with
The petroleum ether was filtered and dissolved in pyridine (100 ml). POCl3 (C2O ml) was added dropwise over 10 minutes and the reaction mixture was heated to external 120 C for 3 hours. The mixture is poured onto ice, the mixture is acidified with concentrated hydrochloric acid and extracted with ethyl ether. The organic phase is washed with water, dried and evaporated. By crystallization of the residue in isopropyl ether, we obtain
2-cyano-8-methoxy-3,4-dihydronaphthalene (7.2 g); p 6668 C.

The product thus obtained is hydrogenated at room temperature and pressure in 95% ethanol (100 ml) using 5% palladium on carbon catalyst.

When the theoretical amount of hydrogen has been consumed, the reaction mixture is filtered, the filtrate is concentrated under reduced pressure, the residue is triturated with petroleum ether and collected by filtration, obtaining 2-cyano-8. -methoxy-1,2,3,4-tetrahydronaphthalene (7 g); m.p. 6668 C.

This product is dissolved in anhydrous tetrahydrofuran
C.sub.3O ml), the solution thus obtained is added to a suspension of lithium aluminum hydride (1.5 g, 0.04 mol) in anhydrous tetrahydrofuran (20 ml) and refluxed for 4 hours. Cool to room temperature and treat the mixture with water and then with ethyl acetate. Separate the organic phase, treat it with
diluted hydrochloric acid, the acidic waters are separated and
makes them basic by ammonia. It is extracted by
ethyl acetate, the organic phase is washed with water and dried
and evaporates to dryness. The residue is taken up with isopropanol
and SR 58847 A (2.49 g) was precipitated by treatment with
Isopropanol saturated with hydrochloric acid. Pf 210-2120C
(Isopropanol).

(D) 2-Aminomethyl-8-hydroxy-1,2,3,4-tetrahydrohydrobromide
naphthalene (SR 58848 A).

The mixture is heated under reflux for 4 hours.
preparation (C) above (3 g, 0.013 mole) and a solution
48% aqueous hydrobromic acid (50 ml). We concentrate
under vacuum, and the residue is taken up with absolute ethanol
(3 x 50 ml) by evaporating the solvent each time. We triturate
residue with acetone, filter and wash with
Acetone and then with ethyl ether. We obtain
thus SR 58848 A (2.8 g). mp 233-235 ° C (isopropanol).

(E) 2-Aminomethyl-5-hydroxy-1,2,3,4-tetrahydro-hydrobromide
naphthalene (SR 58762 A).

Following the procedure of the previous preparation, but in
using as starting material the compound of the preparation
(B), the compound indicated above is obtained. Pf 212-2140c
(Ethanol).

(F) 2 (S) -aminomethyl-7-methoxy-1,2,3,4-tetrahydro-hydrochloride
naphthalene (SR 58832 A).

(i) 7-Methoxy-1,2,3,4-tetrahydronaphthalen-2 (S) -carboxy
liquee (SR 58776).

(R) - (+) - alpha-methylbenzylamine (25.8 ml,
0.2 mole) to a solution of the racemic mixture of the acid 7
methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (41 g,
0.2 mole) in acetone (800 ml) and after about 2 hours
at room temperature the salt (45.2 g) is filtered off. It is recrystallized from acetone twelve times to obtain a product characterized by a / alpha / constant of -20.5 (chloroform, c = 1.4%). The resulting salt is taken up in water (30 ml), the solution is acidified with concentrated hydrochloric acid, and the acid solution is extracted with ethyl ether. The organic phase is dried, evaporated to dryness and the acid thus obtained was recrystallized from benzene (20 ml) to obtain SR 58776 (0.9 g); mp 133-135 ° C .alpha. = - 45.1 (chloroform, c = 1.4%).

For the assignment of its absolute configuration, the product thus obtained is transformed into the corresponding 2-amino-7-methoxy-1,2,3,4-tetrahydronaphthalene according to the Curtius reaction.

The 2-amino-7-methoxy-1,2,3,4-tetrahydronaphthalene thus obtained has a / alpha / corresponding to the isomer 2 (S) - which is described in European Patent Application 303545. As the order The priority of the asymmetric carbon groups of 2-amino-7-methoxy-4,2,3,4-tetrahydronaphthalene is identical to that of 7-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid. and that the Curtius reaction is stereoconservative, the absolute configuration (S) can be correctly assigned to the 7-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid obtained as described above.

(ii) 7-methoxy-1,2,3,4-tetrahydro-2 (S) -naphthalene carboxamide
(SR 58830).

To a solution of the acid obtained in step (i) (10.8 g, 0.052 mol) in acetone (200 ml), cooled to -100 ° C., a solution of triethylamine (10.2 ml) is added. 0.072 mol) in acetone (50 ml) for 15 minutes and a solution of ethyl chloroformate (7.9 ml, 0.080 mol) in acetone (80 ml). After 1.5 hours at -100 ° C., a concentrated solution of ammonia (16.6 ml, 0.133 mol) is added dropwise and the reaction mixture is left at -100 ° C. for 1 hour and at room temperature for 3 hours.

The acetone is evaporated, the residue is taken up in ethyl acetate (500 ml) and the solution is washed successively with
water, a solution of sodium bicarbonate, acid
6N hydrochloric acid, and water, then dried and evaporated.

The residue is triturated in isopropyl ether, filtered
and the amide indicated above (9.5 g) is obtained; pf 159
161 C (ethyl acetate). / alpha / = - 52.2 (chloroform,
c = 1.4%). Enantiomeric excess: 96.5%.

(iii) 2 (S) -aminomethyl-7-methoxy-1,2,3,4 hydrochloride
tetrahydronaphthalene (SR 58832 A).

Under a nitrogen atmosphere, a solution of
compound of step (ii) (9.5 g, 0.046 mol) in tetra
anhydrous hydrofuran (167 ml) and added dropwise
10M borane-methylsulfide solution (14.2 ml, 0.142 mol)
in anhydrous tetrahydrofuran (60 ml). We heat the
refluxing for 4 hours, it is cooled to 0-5 ° C.,
methanol (95 ml) is slowly added, the solution is heated
under reflux for 1 hour and evaporated to dryness. We
take up the residue with a solution of 1N sodium hydroxide,
extracted in ethyl acetate, the organic phase is washed
water, dry and evaporate. Purify the
residue by flash chromatography eluting with a mixture
methanol / ammonia 98 / 2.Dissolved product thus obtained
in isopropanol (30 ml) and isopropanol
saturated with hydrochloric acid By filtration, the
SR 58832 A (5.3 g); mp 228-2300C; / alpha / = 80.40
(methanol, c = 1.4%).

2 R) -aminomethyl-7-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride (SR 58831 A).

(i) 7 - methoxy - 1,2,3,4 - tetrahydro - 2 (R) - naphthalene -
carboxylic acid (SR 58775).

The mother waters of the 1st and 2nd recrystalli are combined
described in the preparation (F, i), and evaporated.

The residue is added hydrochloric acid, the
solution with ethyl ether and the organic phase is evaporated
Dry, obtaining 7-methoxy-1,2,3,4-tetrahydro-2-naphthalenecarboxylic acid (26 g, 0.126 mol). This acid is dissolved in acetone (250 ml) and (S) - (-) - alpha-methylbenzylamine (16.3 ml, 0.126 mol) is added to the solution thus obtained. After 2 hours at room temperature, the precipitated salt (33.5 g) is filtered and collected. This salt is recrystallized from acetone ten times and then taken up with water (30 ml), the solution is made acid by adding concentrated hydrochloric acid and the acid solution is extracted with ether. The organic phase is dried, filtered, evaporated to dryness and 7-methoxy-1,2,3,4-tetrahydro-2- (R) -naphthalenecarboxylic acid (1 g) is obtained. .

Mp 133-1350C (benzene); / alpha / = +45.2 (chloroform, c = 1.4%).

According to the method described in Preparation (F, i), the above acid is converted into 2-amino-7-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride. A product is obtained characterized by a / alpha / = +66.6 (methanol, c = 0.5%) which corresponds to / alpha / of 2 (R) -amino-7-methoxy-1,2,3 4-Tetrahydronaphthalene (Molecular Pharmacology, 1982, 22, 281). The absolute configuration of the SR 58775 is thus confirmed.

(ii) 7-methoxy-1,2,3,4-tetrahydro-2 (R) -naphthalenecarboxamide
(SR 58829).

Using the procedure described in Preparation (F, ii), but starting from 7-methoxy-1,2,3,4-tetrahydro-2 (R) -naphthalenecarboxylic acid (10.8 g, 0.052). mole) gives 7methoxy-1,2,3,4-tetrahydro-2 (R) -naphthalenecarboxamide (9.5 g).

Mp 157-1590C (ethyl acetate); / alpha / = +52.70 (chloroform, c = 1.4%). Enantiomeric excess: 94%.

(iii) 2 (R) -aminoethyl-7-methoxy-1,2,3,4-tetrahydrochloride
Hydronaphthalene (SR 58831 A).

By following the procedure described in Preparation (F, iii), but starting from 7-methoxy-1,2,3,4-tetrahydro-2 (R) naphthalenecarboxamide (9 g, 0.044 mol), the
SR 58831 A (5.5 g); mp 229-2310C (isopropanol); / alpha / = +83.6 (methanol, c = 1.4%).

(H) 2 (R) -aminomethyl-7-hydroxy-1,2,3,4-tetrahydronaphthalene
(SR 58833).

A solution of the product is refluxed for 5 hours.
of the preparation (G) (5 g, 0.022 mol) in Acid
48% aqueous hydrobromic solution (100 ml) and then evaporated to
dry. The residue is taken up in concentrated ammonia
C.sub.3O ml), the solution is extracted with ethyl acetate
(4 x 200 ml), the combined organic extracts are dried,
filter and evaporate to dryness. By recrystallization of the residue
in C 80 ml isopropanol) SR 58833 (2.4 g) is obtained.

 Mp 192-1940C; / alpha / = +116.780 methanol, c = 1%).

(I) 2 (S) -aminomethyl-7-hydroxy-1,2,3,4-tetrahydronaphthalene
(SR 587834).

According to the procedures of the preparation (H), but
using as starting material the compound of the preparation
(F) (5 g, 0.022 mol) gives SR 58834 (2.9 g);
mp 191-1930C; / alpha / = -106.50 (methanol, c = 1%).

(J) 2-Aminomethyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene
(SR 58700).

By following the procedures of the preparation (H), but
using as starting material the compound of the preparation
(B), SR 58700 is obtained. M.p. 181-183 C (isopropanol).

(K) hydrochloride ethyl ester of EC2-aminomethyl acid
1,2,3,4-tetrahydro-7-naphthyl) oxy] acetic acid (SR 58745 A).

(i) 7-hydroxy-2- (N-tert-butoxycarbonyl) -1,2,3,4-aminomethyl
tetrahydronaphthalene (SR 58744).

2-Aminomethyl-7-methoxy-1,2,3,4-tetrahydro-
naphthalene according to the method described in Preparation (A),
but from 7-methoxy-3,4-dihydronaphthalen-1-one, and
it is treated with aqueous hydrobromic acid according to
method described in Preparation (H). We prepare a sus
this 2-aminomethyl-7-hydroxy-1,2,3,4-tetrahydro-
naphthalene (6 g, 0.034 mol) thus obtained in dimethylformamide (80 ml) and triethylamine (4.7 ml, 0.034 mol).

This suspension is stirred at room temperature for 10 minutes and 90% di-tert-butyl dicarbonate (8.2 g, 0.034 mol) is added thereto. The reaction mixture is stirred at room temperature for 3 hours, poured into water (about 400 ml) and the aqueous solution thus obtained is extracted with ethyl acetate. The organic solution is washed with water, dried over sodium sulfate, filtered and evaporated. An oil is obtained which is purified by flash chromatography using a mixture of ethyl acetate: cyclohexane 2: 8.

By vacuum treatment of the oily product thus obtained, SR 58744 is obtained in the form of a vitreous powder.

-1
IR (KBr): 3364 (b): OH, CON-H; 1690: OC = ONH cm 1 (ii) ethyl ester of C (2- (N-tert-butoxycarbonyl)
Aminomethyl-1,2,3,4-tetrahydro-7-naphthyl) oxy] acetic acid.

The mixture is stirred at room temperature for 30 minutes.
mixture of product obtained above (3.4 g, 0.009 mol),
of potassium carbonate powder (4 g, 0.09 mol) and
acetone (100 ml) and then the
ethyl bromoacetate (4.56 g, 3 ml, 0.027 mol). We
heat the reaction mixture to reflux for
5 hours, filtered and concentrated in vacuo. We
dissolve the residue in ethyl ether, wash the
solution obtained with water, it is dried over sodium sulfate
sodium, filtered and evaporated to dryness under pressure
scaled down. Triturate the product with iso ether
propyl and filtered. The ester is thus obtained
C (2- (N-tert-butoxycarbonyl) amino acid ethyl)
1,2,3,4-tetrahydro-7-naphthyl) oxy] acetic acid (mp

 94-970C).

(iii) EC2-amino-methyl-1,2,3,4-tetrahydro-7-naphthyl) oxyacetic acid ethyl ester hydrochloride
(SR 58745 A).

A mixture of the product obtained is cooled to about OOC
in step (ii) (2.1 g, 0.0058 mole) and methanol
absolute (15 ml) and an ethanolic solution is added
7.2 N gaseous HCl (5 ml). When the addition is
finished, the mixture is heated to about 50 ° C. for
30 minutes, concentrated under vacuum, triturated
residue with acetone and filtered. We obtain
thus SR 58745 A (1.2 g); pf 136-138 C (iso
propanol).

(L) hydrochloride of the ethyl ester of C (2-aminomethyl)
1,2,3,4-tetrahydro-7-naphthyl) oxy] butanoic acid (SR 58806 A).

A mixture is stirred at ambient temperature for 30 minutes.
of the compound obtained in the preparation (K, i) (SR 58744) (3.8 g,
0.013 mol) of powdered potassium carbonate (4 g) and
acetone (100 ml) and then add 4-bromobutanoate
of ethyl (11.5 g, 0.06 mol). The reaction mixture is heated
at reflux for 10 hours, it is filtered and evaporated to dryness
and the residue is taken up with absolute methanol (15 ml) and
with a 6N solution of gaseous HCl in absolute ethanol
(25 ml). This mixture is heated to 90 C external for
4 hours, then concentrated under vacuum. Triturate the residue
in acetone and filtered by obtaining the product
in the title (2.7 g); mp 146-148C.

(M) 2-Aminomethyl-7-hydroxy-1,2,3,4-tetrahydronaphthalene
(SR 58672).

According to the procedure of the preparation (H), but from
of 2-aminomethyl-7-methoxy-1,2,3,4-tetrahydro-
naphthalene (prepared as described in the patent application
213080), there is obtained 2-aminomethyl-7-hydroxy-1,2,3,4-tetra
hydronaphtalène; mp 187-189 ° C (isopropanol).

(N) 2-Aminomethyl-7-hydroxy-1,2,3,4-tetrahydro-hydrochloride
naphthalene (SR 58756 A).

According to the procedure of preparation (C), but from
3,4-dihydronaphthalen-2 (1H) -one, the compound is obtained
indicated in the title; mp 228-2300C (ethanol).

Example 1
N - [(2 (R) -7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] - (2R) -2-hydroxy-2- (3-chlorophenyl) ethanamine hydrochloride (SR 58836 A).

(i) N - [(2 (R) -7-hydroxy-1,2,3,4-tetrahydronaphthyl) methyl] - (R) -3
chloromandelamide CSR 58835).

A suspension is stirred for 5 hours at ambient temperature.
product obtained in the preparation (H) above
(SR 58833) (2.2 g, 0.013 mol) of (R) -3-chloro acid
mandelic acid (2.3 g, 0.013 mol), hexafluorophosphate
benzotriazolyl-N-oxytris- (dimethylamino) phosphonium
(BOP - 5.2 g, 0.013 mol) in methylene chloride
anhydrous (100 ml) and triethylamine (1.8 ml, 1.3 g,
0.013 moles). C5O ml brine is added and the mixture is shaken.
mix for 30 minutes. The organic phase is separated and
washed successively with 2N hydrochloric acid
(2 x 30 ml), water, saturated aqueous solution of bicarbonate
Sodium Bonate, and Water, then dry it and evaporate it
Dry. The product obtained by flash chromatography is purified.
using a mixture of ethyl acetate: cyclohexane 1: 1
as an eluent. The oily product thus obtained is dried under
reduced pressure at 40 C for 2 days and we get the amide
SR 58835 (3.1 g) as a vitreous powder;
/ alpha / = +31.6 (methanol, c = 1%).

(ii) N - [(2 (R) -7-hydroxy-1,2,3,4-tetrahydronaphth-2-hydrochloride
yl) methyl] - (2R) -2-hydroxy-2- (3-chlorophenyl) ethanamine
(SR 58836 A).

A solution of the product obtained in
Step (i) above (2.7 g, 0.008 mole) in tetrahydro
anhydrous furan C5O ml) under a nitrogen atmosphere and
add dropwise borane-methylsulfide solution
10 M (2.4 ml, 0.024 mol) in anhydrous tetrahydrofuran
C2O ml). The reaction mixture thus obtained is heated
reflux for 4 hours, cooled and added
methanol (20 ml) dropwise. The mixture is heated
reflux for 30 minutes, evaporate to dryness and purify
the product thus obtained in the form of free base by flash
chromatography using methanol as eluent. We
dissolves the SR 58836 base thus obtained in acetone
(40 ml) and the solution is made acid with isopropanol
saturated with hydrochloric acid. SR 58836 A (1 g) is obtained
which is dried under reduced pressure at 40 C for 2 days.

 Mp = 145-1480C; / alpha / = +340 methanol, c = 1%).

Example 2
N - [(2 (S) -7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] - (2R) -2-hydroxy-2- (3-chlorophenyl) ethanamine (SR 58838).

(i) N - [(2 (S) -7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] - (R)
3-chloromandelamide (SR 58837).

Following the procedures of Example iCi), but in
both of a mixture of the product of Preparation (I) (SR 58834)
t3.0 g, 0.017 mole) of (R) -3-chloromandelic acid (3.2 g,
0.017 mole), BOP (6.8 g, 0.017 mole) and triethylamine
(2.4 ml, 0.017 mole) in anhydrous methylene chloride
(120 ml), the amide SR 58837 (4 g) is obtained in the form of
vitreous powder. / alpha / = 80.60 methanol, c = 1%).

(ii) N - [(2 (S) -7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] - (2R)
2-hydroxy-2- (3-chlorophenyl) ethanamine (SR 58838).

Following the procedures of Example 1 (ii), but
starting from the amide above (3.6 g, 0.010 mol),
the desired product in the form of free base which is purified
by flash chromatography using a methanol mixture:
60:40 ethyl acetate as eluent and then by crystal
in methanol. 1.9 g of SR 58838 are obtained;
mp 159-1610C. / alpha / = 77.20 (methanol, c = 0.5%).

Example 3
N - [(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] -2-hydroxy-2- (3-chlorophenyl) ethanamine hydrochloride (SR 58849 A).

(i) N - [(8-hydroxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] -3-chloro
mandelamide.

A mixture is stirred for 5 hours at room temperature
of the product obtained in Preparation (D) (SR 58848 A)
(2.2 g, 0.0085 mol) of 3-chloromandelic acid (1.6 g,
0.0085 moles), BOP (3.4 g, 0.0085 moles) and triethylamine
(2.4 ml, 1.72 g, 0.017 mole) in methylene chloride
(50 ml). This mixture is diluted with ethyl acetate
and afterwards it is washed successively with water,
diluted hydrochloric acid, a saturated aqueous solution of
sodium bicarbonate and water, then it is dried and eva
dry pore. The amide above (1.6 g) having a
IR absorption spectrum that corresponds to the structure
assigned.

 IR (KBr): 3342 (d): O-H, CON-H; 1641: HNC = 0 cm.

(ii) N-EC8-hydroxy-1,2,3,4-tetrahydronaphth-2-yl hydrochloride)
methyl] -2-hydroxy-2- (3-chlorophenyl) ethanamine (SR 58849 A).

A solution of the product obtained in
step (i) above (1.6 g, 0.0046 mol) in tetra
hydrofuran (30 ml) under a nitrogen atmosphere and added
Slowly a mixture of a 10 M solution of borane-methyl
sulphide (1.4 ml, 0.0014 mol) and anhydrous tetrahydrofuran
(10 ml). The resulting solution is heated to reflux
4 hours, then add very slowly methanol
(10 ml). Concentrate in vacuo, dissolve the residue in
ethyl ether, the resulting solution is made acidic
with isopropanol saturated with hydrochloric acid and
obtained, by filtration, 0.9 g of SR 58849 A; mp 175 1780C.

Examples 4 to 9
Following the procedures of Examples 1 to 3 above, but starting from 3-chloromandelic acid and the corresponding 1,2,3,4-tetrahydronaphthalene derivative, the following compounds of formula I are obtained via the intermediates of compounds of formula IV indicated in parentheses and characterized by the indicated infrared absorption maxima.

Example 4
N - [(7-Methoxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] -2-hydroxy-2- (3-chlorophenyl) ethanamine hydrochloride (SR 58658 A). Mp 170-1730C
(isopropanol) (N - [(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] 3-chloromandelamide).

IR (liquid without solvent): 3390 (sh), 3324: OH, CON-H; 1655:
-1
NHC = O cm
Example 5
N - [(6-Methoxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] -2-hydroxy-2- (3-chlorophenyl) ethanamine hydrochloride (SR 58686 A). Mp 205-208 ° C
(absolute ethanol) (N - [(6-methoxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] 3-chloromandelamide).

IR (KBr): 3520 (sh), 3300 (sh), 3247: OH, CON-H; 1627, 1650:
-1
NHC = O cm
Example 6
N - [(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] -2-hydroxy-2- (3-chlorophenyl) ethanamine hydrochloride (SR 58701 A). Mp 174-1760C (isopropanol) (N - [(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] 3-chloromandelamide).

IR (KBr): 3349 (b): O-H, CON-H; 1659: NHC = 0 cm-1.

Example 7
N - [(5-hydroxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] -2-hydroxy-2- (3-chlorophenyl) ethanamine hydrochloride (SR 58763 A). Mp 177-180 ° C (acetone) (N - [(5-hydroxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] -3-chloromandelamide).

IR (KBr): 3365 (b): O-H, CON-H; 1659: NHC = 0 cm-1.

Example 8
N - [(8-Methoxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] -2-hydroxy-2- (3-chlorophenyl) ethanamine hydrochloride (SR 58885 A). Mp 186-1880C (isopropanol) (N - [(8-methoxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] 3-chloromandelamide) (SR 58884).

IR (KBr): 3319 (d): O-H, CON-H; 1658: NHC = 0 cm-1.

Example 9
N - [(5-methoxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] -2-hydroxy-2- (3-chlorophenyl) ethanamine hydrochloride (N - [(5-methoxy-1,2) , 3,4tétrahydronapht-2-yl) methyl] -3-chloromandelamide).

Example 10
N - [(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] -2-hydroxy-2- (3-chlorophenyl) etanamine oxalate (SR 58673 A).

 This compound is prepared according to the procedure of Example 1 (i) and (ii), but treating the compound obtained, in free base form, with a solution of oxalic acid in acetone.

Mp 218-220 C (acetone).

Example 11
EC2-EN-E2-C3-chlorophenyl) -2-hydroxy] ethyl] aminomethyl-1,2,3,4-tetrahydronaphth-7-yl] oxy] acetic acid ethyl ester hydrochloride (SR) 58746 A).

 A mixture of the product of the preparation (K) in free base form (2.8 g, 0.010 mol) of 3-chlorostyrene oxide (2.6 g) is heated at 80 ° C. for 8 hours under stirring. 0.015 moles) and anhydrous dimethylsulfoxide (15 ml). The reaction mixture is poured into water, the solution is extracted with ethyl acetate, the organic phase is washed with water, dried over sodium sulfate, filtered and filtered. evaporate to dryness. The residue is dissolved in hot isopropanol (40 ml) and isopropanol saturated with hydrochloric acid. By filtration, SR 58746 A (1.4 g) was collected by filtration. Mp 157-161 C.

Example 12
4 - [[2- [2- (3-Chlorophenyl) -2-hydroxy] ethyl] aminomethyl-1,2,3,4-tetrahydronaphth-7-yl] oxyethyl ester hydrochloride ] butanoic (SR 58807 A).

 By operating according to the procedures of Example 11, but using the product obtained in the prepration (L), the compound indicated in the title is obtained; m.p. 138-1450C (isopropanol).

Example 13
N - [(7-Methoxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] -2-hydroy-2- (3,4-dichlorophenyl) ethanamine hydrochloride (SR 58871 A).

(i) N - [(7-Methoxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] -3,4-di
chloromandelamide (SR 58870).

According to the procedures of Example 1 (i), but in
Both 3,4-dichloromandelic acid (3.1 g, 0.014 mol) and
2-Aminomethyl-7-methoxytetralin (2.67 g, 0.014 mol)
N - [(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl) -
methyl7-3,4-dichloromandelamide (SR 58870) (4.5 g) in the form
of oily product characterized by the maxima of absorption
Infrared: 3380 (b): OH, CON-H; and 1641
-1
NHC = O cm
(ii) N - [(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl) hydrochloride
methyl] -2-hydroxy-2- (3,4-dichlorophenyl) ethanamine
(SR 58871 A).

A solution of the product obtained in
Step (i) above (4.5 g, 0.0114 mol) in tetra
hydrofuran (75 ml) under a nitrogen atmosphere and added
slowly a mixture of a 10 M solution of borane-methyl
sulfide (3.5 ml, 0.035 mole) and tetrahydrofuran (10 ml).

The solution thus obtained is heated under reflux for
4 hours, then methanol (25 ml) is added very slowly.

Concentrated under reduced pressure, the residue is dissolved in
isopropanol and the SR 58871 A is precipitated by addition
hydrochloric acid in isopropanol. We crystallize the
product thus obtained in ethanol and 1.87 g of
SR 58871 A; pf 194-198 C.

Example 14
EE2-EEN-C2-phenyl) -2-hydroxy] ethyl] aminomethyl-1,2,3,4-tetrahydronaphth-7-yl] oxy] acetic acid ethyl ester hydrochloride (SR 58877 A).

 Following the procedure of Example 11, but replacing the 3-chlorostyrene oxide with styrene oxide gave SR 58877 A; m.p. 163-1700C (isopropanol).

Example 15
N - [(7-Methoxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] -2-hydroxy-2-phenylethanamine hydrochloride (SR 58875 A).

 A mixture of styrene oxide (1 g, 0.0083 mol), 2-aminomethyl-7-methoxy-1,2,3,4-tetrahydronaphthalene (1.5 g, 0.0078) is heated for 10 hours at 800 ° C. mole) in dimethylsulfoxide (20 ml). The reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated to dryness. An oily residue is obtained and subjected to flash chromatography, eluting with a 95: 5 methylene chloride / methanol mixture. The combined fractions are evaporated, the residue thus obtained is dissolved in ethyl ether and isopropanol saturated with hydrochloric acid is added thereto.

The precipitate is filtered and SR 58875 A (0.5 g) is obtained; m.p.

187-192 C.

Example 16
N - [(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] -2-hydroxy-2-phenylethanamine hydrochloride (SR 58876 A).

 Following the procedure of Example 15, but replacing 2-aminomethyl-7-methoxy-1,2,3,5-tetrahydronaphthalene with the compound of Preparation (M), a product which was washed at a small temperature was obtained. amount of acetone gives the SR 58876 APf 155-158 C.

Example 17
N - [(1,2,3,4-Tetrahydronaphth-2-yl) methyl] -2-hydroxy-2- (3-chlorophenyl) ethanamine hydrochloride (SR 58808 A).

A mixture of 2-aminomethyltetralin base (1.4 g, 0.0087 mol), obtained by neutralization of its hydrochloride (preparation (N)) with sodium hydroxide, is heated at 800 ° C. for 8 hours with stirring. extraction with ethyl acetate, and 3-chlorostyrene oxide (2 g, 0.013 mol) in dimethylsulfoxide (15 ml). The reaction mixture is poured into water (about 100 ml), extracted with ethyl ether. The organic phase is washed with water, dried and evaporated to dryness. The residue is taken up in petroleum ether and filtered. The product thus obtained (1.5 g) was dissolved in acetone (50 ml) with gentle heating and isopropanol saturated with hydrochloric acid. The precipitate is filtered and the
SR 58808 A (1.5 g); mp 232-235 C.

Example 18
[[2- [N- [2- (3-chlorophenyl) -2-hydroxy] ethyl] aminomethyl] -2,3,4-tetrahydronaphth-7-yl] oxy] acetic acid.

 A mixture of the product of Example 11 in free base form (SR 58746) (2.5 g, 0.006 mol) of potassium hydroxide (0.45 g, 0.0081) is heated at 50 ° C. for 2 hours. mole), 95% methanol (40 ml) and water (30 ml). The ethanol was evaporated, water (20 ml) was added and extracted with ethyl ether (2 x 50 ml). The organic phase is treated with charcoal, filtered and acidified with 1N HCl to pH 6.5. The precipitate is filtered and the product indicated in the title is obtained.

Example 19
Tablets based on the compound of Example 6 having the following composition are prepared:
compound of Example 6 (SR 58701 A) 20 mg
microcrystalline cellulose 30 mg
corn starch 30 mg
lactose 100 mg
magnesium stearate 5 mg by grinding the active ingredient to a particle size of 0.4 mm, passing it through a 0.4 mm mesh sieve, mixing the milled material with the others components and compressing to form tablets. In the same way, tablets containing 40 mg of active ingredient are prepared.

Example 20
By operating as described in Example 19, but using the compound of Example 7, tablets having the following composition are prepared:
compound of Example 7 (SR 58763 A) 50.0 mg
corn starch dried 100.0 mg
lactose 95.0 mg
talc 4.5 mg
magnesium stearate 0.5 mg
Example 21
10 000 capsules with an active substance content of 50 mg are prepared from the following constituents: 500 g of N-EC7-methoxy-1,2,3,4-tetrahydronaphth-2-yl) methyl-2-hydroxyhydrochloride -2- (3-chlorophenyl) ethanamine (SR 58658 A), 495 g of microcrystalline cellulose, 5 g of amorphous silica gel. The above constituents are well mixed and introduced into 4 hard gelatin capsules.

Example 22
A sterile aqueous solution suitable for parenteral use in hydrochloride-based ampoules is prepared.
N - [(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl) methyl] -2-hydroxy-2- (3chlorophenyl) ethanamine (SR 58701 A) having the following composition:
SR 58701 to 30 mg
sodium chloride 5 mg
distilled water qs 2 ml

Claims (16)

 1. A phenylethanolaminomethyltetraline of the following formula (I)

 in which - E represents hydrogen, a (C C) alkyl group, a group  (C1-C4) alkoxy, a phenyl group, a nitro group, an atom  of halogen, or a trifluoromethyl group, - L represents hydrogen, a (C1-C4) alkyl group, a  (C1-C4) alkoxy, a nitro group or a halogen atom, or - E and L, together, represent a group -CH = CH-CH = CH- or  -CH2-CH2-CH2-CH2-, and -G represents a hydrogen atom, a chloro atom, a  hydroxy group or a group OG 'where G' represents a group  (C1-C4) alkyl unsubstituted or substituted with hydroxy group,  (C1-C4) alkoxy, CC1-C4) alkoxycarbonyl, carboxy free or is  with a metabolically labile group, or (C3-C7) cyclo  alkyl; a (C3-C7) cycloalkyl group; or a group (C 2 -C 4) -  alkanoyl, or a salt thereof.  2. A phenylethanolaminomethyltetralin according to claim 1, wherein G represents hydrogen, a hydroxyl group or a group OG ', where G' represents a substituted or unsubstituted CC1-C4) alkyl group.  3. A phenylethanolaminomethyltetralin according to claim 2, wherein G represents hydrogen, a hydroxyl group or a group OG ', where G' represents a CC1-C4) alkyl group which is unsubstituted or substituted with a carbo (C 1 -C 4) group. alkoxy or carboxy.  4. A phenylethanolaminomethyltetralin according to any of claims 1 to 3 as a pure stereoisomer or a mixture of two enantiomers.  5. Process for the preparation of a compound of formula (I) below

 in which - E represents hydrogen, a (C -C) alkyl group, a group  14  (C1-C4) alkoxy, a phenyl group, a nitro group, an atom  of halogen, or a trifluoromethyl group, - L represents hydrogen, a C -C -C) alkyl group,  14  CC1-C4) alkoxy, a nitro group or a halogen atom, or - E and L, together, represent a group -CH = CH-CH = CH- or  -CH2-CH2-CH2-CH2-, and -G represents a hydrogen atom, a chloro atom, a  hydroxy group or a group OG 'where G' represents a group  CC1-C4) alkyl unsubstituted or substituted with a hydroxy group,  (C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, free or fused carboxy  with a metabolically labile group, or (C3-C7) cyclo-  alkyl; a (C3-C7) cycloalkyl group; or a Cc 2 -c4 group) -  alkanoyl, or a salt thereof, characterized in that a compound of formula (II) is reacted

  in which - E and L have the same meaning given above and the radical  -W represents one of the following groups (a) to (d)

 compound of formula  1-ethyl-1- (C1-C4) alkoxycarbonylethyl by treatment with a  Which G 'is 1-methyl-1- (C1-C4) alkoxycarbonylethyl or  correspondents, where G is a group of formula OG 'in  is hydroxy can convert this compound into compounds  substituted by carboxy, by basic hydrolysis, (iii) when a compound of formula (I) in which G is obtained  in the corresponding compound, where OG 'is an alkyl group  (C1-C4) alkoxycarbonyl group, this compound can be converted  is a group OG 'where G' is an alkyl group substituted with a  from the amino group, (ii) when a compound of formula (I)  easily removable group, after or not tempo protection  in which G 'is as defined above and D is a  with an alkylating agent or acylation of formula G'-D  corresponding compounds where G is a group OG ', by reaction  is a hydroxy group, this compound can be converted into  the reaction product is treated with a suitable reducing agent and optionally the compound of formula (I) thus obtained is converted into one of its salts by methods which are themselves known; this process being subsequently characterized in that (i) when a compound of formula (I) in which G is obtained

 in which G has the same meaning given above, and, when -W is other than

 a -COOH group or a functional derivative thereof, with a compound of formula (III)  where Hal represents chlorine, bromine or iodine and Y represents  or in pairs of enantiomers according to conventional methods.  mixture of isomers, they can be separated into the pure isomers  and optionally esterifying, and (v) when a compound of formula (I) is obtained in the form of a  by the hydrolysis of the product thus obtained in the presence of Ag20  followed by reaction of the latter with diazomethane and  carbonyl by conversion of the acid into the acid chloride  ethyl substituted with a carboxy or (C1-C4) alkoxy group  this compound in the corresponding compound where G is a group  is a group OG 'where G' is carboxymethyl, it is possible to convert  with thionyl chloride in a (C 1 -C 4) alkanol, (iv) when a compound of formula (I) in which G is obtained  respectively, in the presence of a base, followed by a reaction  6. A compound of formula (IV) below

  in which - E represents hydrogen, a (C1-C4) alkyl group, a group  (C1-C4) alkoxy, a phenyl group, a nitro group, an atom  of halogen, or a trifluoromethyl group, - L represents hydrogen, a CCl-C4) alkyl group, a  (C1-C4) alkoxy, a nitro group or a halogen atom, or - E and L, together, represent a group -CH = CH-CH = CH- or  -CH2-CH2-CH2-CH2-, and -G represents a hydrogen atom, a chloro atom, a  hydroxy group or a group OG 'where G' represents a group  CC1-C4) alkyl unsubstituted or substituted with a hydroxy group,  CC1-C4) alkoxy, CC1-C4) alkoxycarbonyl, carboxy free or is  rified by a metabolically lable group, or (C3-C7) cyclo  alkyl; a (C3-C7) cycloalkyl group; or a group (C2-C4)  alkanoyl, or a salt thereof.  7. A compound according to claim 6, characterized in that G is a hydrogen atom, a hydroxy group or a group OG ', where G' is an unsubstituted (C1-C4) alkyl group or (C (C3-C7) ) cycloalkyl.  8. Process for the preparation of a compound of formula (IV) below

 in which - E represents hydrogen, a CC1-C4) alkyl group, a group  (C1-C4) alkoxy, a phenyl group, a nitro group, an atom  of halogen, or a trifluoromethyl group, - L represents hydrogen, a (C1-C4) alkyl group, a group  (C1-C4) alkoxy, a nitro group or a halogen atom, or - E and L, together, represent a group -CH = CH-CH = CH- or  -CH2-CH2-CH2-CH2-, and -G represents a hydrogen atom, a chloro atom, a  hydroxy group or a group OG 'where G' represents a group  CC1-C4) alkyl unsubstituted or substituted with a hydroxy group,  (C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, free or fused carboxy  with a metabolically labile group, or (C3-C7) cyclo  alkyl; a (C3-C7) cycloalkyl group; or a (C2-C4) -alkyl group, or a salt thereof, characterized in that a compound of formula

 in which E and L have the same meaning given above and W represents a group

 where Y represents a -COOH group or a functional derivative thereof, with a compound of formula (III)

 in which G has the same meaning given above.  9. A compound of formula (III)

  wherein G is chloro, hydroxy or OG 'where G' is (C1-C4) alkyl unsubstituted or substituted by hydroxy, (C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, carboxy, free or esterified by a metabolite group Labile, or (C3-C7) cycloalkyl, a (C3-C7) cycloalkyl, or a CC2-C4) alkanoyl group, but G is other than -OCH3 group in position 7, or one of its salts.  10. A compound according to claim 9, characterized in that G is a hydroxy group or a group OG 'where G' is CC1-C4) alkyl substituted by a carboxy group of CC1-C4 alkoxycarbonyl.  11. A compound of formula (III)

 wherein G is hydrogen, chloro, hydroxy or OG 'where G' is CC1-C4) alkyl unsubstituted or substituted by hydroxy, CC1-C4) alkoxy, (C1- C4) alkoxycarbonyl, carboxy, free or esterified by a metabolically labile group, or (C3-C7) cycloalkyl, a (C3-C7) -cycloalkyl, or a CC2-C4) alkanoyl group, in pure isomeric stereo form, or a of its salts.  12. Process for the preparation of a compound of formula (III)

 wherein G is hydrogen, chloro, hydroxy or OG 'where G' is (C1-C4) alkyl unsubstituted or substituted by hydroxy, (C1-C4) alkoxy, ( C1-C4) alkoxycarbonyl, carboxy, free or esterified with a metabolically labile group, or (C (C3-C7) cycloalkyl, a (C3-C7) -cycloalkyl group, or a (C2-C4) alkanoyl group, but other than an -OCH 3 group at position 7, or a salt thereof, characterized in that a compound of formula chosen between

 wherein G "is hydrogen, chloro, hydroxy or methoxy and Z is -NH2, obtaining a compound of formula (III) wherein G = G", and subjecting the compound of formula (III) in which G "is hydroxyl to conventional alkylation or acylation procedures with or without prior protection of the amino group, which process is further characterized in that when a compound of formula ( III) wherein G = G "is a methoxy group, can be converted to the corresponding compound wherein G = G" is a hydroxyl group by demethylation with hydrobromic acid.  13. A compound of formula

 wherein Z is -OH or -NH 2 and G "is hydrogen, chloro, hydroxy or methoxy, in optically active form, or a salt thereof.  A pharmaceutical composition containing, as the main active ingredient, one or more compounds according to any one of claims 1 to 4.  15. Pharmaceutical composition according to claim 14 in the form of a dosage unit, containing from 0.1 to 500 mg of active principle.  16. Pharmaceutical composition according to claim 14 or 15 for the treatment of disorders of intestinal motility.