IE61811B1 - 2-amino-7-hydroxytetralin carboxyalkyl ethers - Google Patents

Abstract

The invention relates to 2-amino-7-hydroxytetralin carboxyalkyl ethers of formula <IMAGE> in which Alk represents a straight- or branched-chain alkylene group having 3 to 5 carbon atoms and R is hydrogen or a C1-C4 alkyl group, which are useful as starting materials in the synthesis of 7-substituted phenylethanolaminotetralins of formula (XII) <IMAGE> in which X represents hydrogen, halogen or a C1-C4 alkyl or trifluoromethyl group, having spasmolytic activity. The new 7-substituted phenylethanolaminotetralins (XII) as well as the intermediates in the preparation of the compounds (I), the N-protected 2-amino-7-hydroxytetralin carboxyalkyl ethers, are also claimed.

Description

The present invention relates to 2-amino-7hydroxvtetralin carboxyalky1 ethers, to a process and to the intermediates for the preparation thereof, to the use of said ethers as starting products in the preparation of pharmacologically active compounds and to the new ‘/-substituted phenylethanolaminotetralins endowed with spasmolytic activity thus obtained.

More particularly, in one of its features, the object of the present invention is 2-amino-7-hydroxytetralin carboxyalkyl ethers of the formula in which Aik represents a straight or branched alkylene group containing from 3 to 5 carbon atoms, and R represents hydrogen or an alkyl group containing from 1 to 4 carbon atoms, and their salts.

More particularly, the term Aik may represent EL 1 1 Rv, R’, R' R’. 1 1 1 1 (a) a group CH— 1 , -Ο- ι —c—c— I 1 , —c—c—c—c— 1 1 1 1 1 1 R, 1 1 R, R*3 Rs5 R’7 R’g or -(C% )5 — where Κχ is an ethyl, propyl or butyl group; Ry bo are hydrogen atoms or one of the Ry bo Ry radicals is a methyl or ethyl group and the others are hydrogen atoms, or two of the Ro to Ry radicals are methyl groups and the others are hydrogen atoms; e ι; 11 R'2 to RsQ are all hydrogen atoms or one of the R®2 to R'g radicals is a methyl group and the others are hydrogen atoms. (b) a croup -C- where I RlO and Rii are independently a methyl or ethyl group, or Bn is also the propyl group when Ηχο is the methyl group; ^2 (c) a group where one of the R32 and Rig radicals is hydrogen and the other is the methyl, ethyl or propyl group, or one of the Rx2 an<2 Κχ3 radicals is the methyl group and the other is the methyl or ethyl group.

The nex^ compounds are useful as starting products in tha preparation of pharmacologically active compounds, in particular 7 -substituted phenylethanolaminotetralins with spasmolytic activity.

In the present description, the term tetralin stands for the 1,2,3,4-tetrahydronaphthalene and the term 2-tetralone for the corresponding 2-oxo derivative. Tha compounds of formula (I) and their salts can be prepared hy the following method, which represents a further object of the present invention and which is characterized in that: (A) a N-protected 2-amino-7-hydroxytetralin of formula (II) R’— NH CH (II) in which Re is an N-protecting group which may suitably be removed by catalytic hydrogenation or mild acidic hydrolysis, is submitted to a carb(alk)oxyalkylation reaction with a compound of formula (Ilia) Hal-Alk--COOR (Ilia) in which R is as defined above, Hal represents a chlorine, bromine or iodine atom, and Aikrepresents an alkylene group as defined under (a) above, in the presence of a basic condensation agent, or with a compound of formula (Illb) ^10 CI3C—C—OH (Illb) in which R^q and are as defined under (b) above, in the presence of a strong base, optionally followed by reaction of the resulting product with thionyl chloride in a suitably selected Cb-C/^ialkanol, or with a compound of formula (IIIc) HCzzzzC-COOR (IIIc) in which R is as defined above, and Κχ2 snd R13 ere as defined under (c) above, optionally in the presence of a catalytic amount of a quaternary ammonium hydroxide, to obtain an N-protected 2-amino-7-hydroxyteti~alin carboxyalkyl ether of formula (IV) Η'-ΜΗ 0-Alk~€OGR (IV) in which R’, Aik, and R are as defined above, and (B) the N-protecting group is removed by catalytic hydrogenation or mild acidic hydrolysis and, after optional saponification of the lower carbalkoxv group to a carboxy group, the compound of formula (I) is isolated, in the form of a free base or a salt, and it is optionally converted into one of its salts» The term carb(alk)oxyalkylation" typically identifies a condensation reaction of the phenol hydroxy with a reagent which is capable of etherifying said hydroxy with an alkyl group substituted with a carb(alk)oxy group, i.e. carboxy or carbalkoxy, the term ’’carbalkoxy" designating a (Ci -C^-alkoxy )carbonyl group.

Preferred N-protecting groups include tertbutoxycarbonyl (Boc) and bensyloxycarbonyl groups and in general those N-protecting groups which are employed in peptide chemistry, or benzyl, benzhydryl, or trityl groups, either unsubstituted or substituted in the benzene ring by a methoxy group.

As compound of formula (Ilia), an alkyl bromoalkanoate is preferably employed» The reaction between the N~protected 2-amino-7-hydroxytetralin (II) and the compound (Ilia) is carried out in an organic solvent such as acetone, ethyl acetate, or tetrahydrofuran, using a conventional basic condensation agent such as an alkaline carbonate, for example potassium carbonate.

For the preparation of a compound of formula (I) where Aik is a group -Ο(ΗχθΗχχ)-, the compound of formula (Illb) is used as described in J. Am. Chem.

Soc., 1948, 70, 1153-1158. In this case the reaction is preferably carried out in the presence of a strong base, such as sodium or potassium hydroxide, and optionally, the product (I) is obtained in the form of an ester by treating the resulting acid with thionyl chloride in a suitably selected alkanol.

The reaction between the N-protected 2-amino-7hydroxytetralin (II) and the acrylic acid derivative of formula (IIIc) may be carried out either in the absence or in the presence of an inert, apolar, organic solvent such as bensene, toluene, ethyl ether, methylene chloride. The reaction may be catalysed, if desired, by small amounts of a quaternary ammonium hydroxide, e.g. trimethylbensylammonium hydroxide. Preferably, to avoid addition of the acrylate to the amino-tetralin bond, when using a compound of formula (IIIc), the amino group of the reaction partner (II) is protected with the Boc group or any other easily removable urethanetype protecting groups.

The thus obtained N-protected 2-amino-7hydroxytetralin carboxyalkyl ether (IV) is isolated by conventional methods, optionally as a salt thereof, and is then subjected to N-deprotection.

Removal of the N-protecting groups is accomplished by catalytic hydrogenation or mild acidic hydrolysis according to methods well known in the literature. In particular, the Boc group is removed under acidic conditions, by the action of trifluoroacetic acid. The other groups listed above are removed by catalytic hydrogenation, preferably using palladium on charcoal as the catalyst. The trityl and methoxytrityl groups may also be hydrolysed under mild acidic conditions, e.g. with 50% formic acid or with gaseous hydrochloric acid in an organic solvent.

To afford the corresponding carboxy group, the compounds of formula (I) may be saponified, eithex’ before or after deprotection of the amino group.

The products (I) are isolated by conventional methods, preferably in the form of an addition salt thereof with mineral or organic acids which allow a suitable separation or crystallization of the compounds, such as picric acid, oxalic acid, or an optically active acid, e.g. a mandelic or camphorsulfonic acid, or with mineral or organic acids that form pharmaceutically acceptable salts such as the hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogenphosphate, methanesulfonate, methylsulfate, maleate, fumarate, naphthalenesulfonate.

The base may be obtained by neutralization, and converted into another acid addition salt or, when R is hydrogen, info a metal salt, typically an alkaline salt, such as the sodium salt, by conventional procedures.

The N-protected 2-amino-7~hydroxytetralin of formula (II) is prepared starting from 2--amino-7" hydroxytetralin of formula (Ila) - IO ("» or directly from 7-methoxy-2~fetralone of formula (V) θγοβΟ"’ (V) without using the 2-amino-7-hydroxytatralin (Ila).

The 2~amino-7~hydroxytetralin (Ila) may be prepared starting from the corresponding methoxy25 tetralone of formula (V) through reaction with benzylamine, reduction with sodium borohydride of the obtained benzylimine, removal of the benzyl group by catalytic hydrogenation and demethylation with 48% hydrobromic acid according to following Scheme 1: SSIEHEJL The benzylamine conventional reaction of the is carried out, product (V) with according to the methods for the preparation of Schiff’s compound isolated Catalytic charcoal, or purified, hydrogenation, bases, in an organic solvent such as toluene, in the presence of p-toluenesulfonlc acid. The thus obtained (VI) may then be reduced, without being with sodium borohydride. e.g. with palladium on affords the 2-amino-7-methoxytetralin (Vila) which is heated in 48% hydrobromic acid yielding the 2amino-7-hydroxytetralin (Ila) as hydrobromide converted into the free base by neutralisation.

In the first step of above Scheme 1, the benzylamine may be replaced by tritylamine or benzhydrylamine; these three products may also be substituted with a methoxy group on a phenyl ring.

The compounds of formula (II), (Ila), (VII) and (Vila) have a centre of asymmetry at the carbon atom linked to the amino group. The preparation of addition salts of these compounds with a chiral organic acid, preferably an optically active mandelic acid, followed by fractional crystallisation, may result in compounds which are enriched in one of the two enantiomers and eventually in the optical resolution of the racemates leading to the two optically active forms. Optical resolution of these compounds may also be accomplished by specific chromatographic techniques.

N-protection by the group R’ is achieved by reacting the compound of formula (Ila) with a reactant suitable for protection of the amino groups as described, for instance, by M. Bodanssky et al. in Peptide Synthesis, 2nd Edition, John Wiley & Sons, 1976, pages 18-49, Chapters 3 to 6.

As an example the 3oc group may be introduced by reaction with di-tert-butyl-dicarbonate under basic conditions. The bensyloxycarbonyl group may be introduced by the general method described by E.C.

Horning, in Organic Synthesis, Vol. Ill, Wiley, New York, 1955, page 167.

Accordingly, the products (I) may be prepared, as an example, by protecting the amino group of 2~ amino-7-hydroxy tetral in (Ila) with a Soc group, by reaction of the aminotetralin (Ila) with di-tert-butyl2Q dicarbonate in an organic solvent such as dioxane or dimethylformamide, by treating the thus obtained product with a compound of formula (Ilia) or (Illb) or (IIIc) under the above described conditions and by deprotecting the amino group by removal of the Soc group with trifluoroacetic acid according to following Scheme 2: SCHEME 2 Ila VIII O-AJJk-COOR CF3COOH -*, IX I Release of the amine (I) by removal of the Nprotecting group Boc does not affect the lower carbalkoxv group or the stereoconfiguration.

N-protection may also be carried out starting from the 7-methoxv-2~tetralone (v) through formation of a Schiff’s base with an amine selected from benzylamine, benzhydrylamine and tritylamine, unsubstituted or substituted on a phenyl ring with a methoxy group, followed by reduction with sodium borohydride.

Accordingly, as an example, the products of formula (I) in which Aik represents an alkylene group as defined under (a) or (b) may be suitably prepared starting from a 2-benzylamino-7-methoxytetralin of formula (VII) (Scheme 1), via demethylation with hydrobromic acid, reaction of the corresponding phenol with a compound of formula (Ilia) or (Illb) under the above described conditions followed by debenzylation according to following Scheme 3: VII HBr 48 St L/-c .OH (IlZa) or (IXIb) -*.

In Scheme 2 above, the Soc group may be replaced by the benzyloxycarbonyl group or any other protecting group as defined above. In Scheme 3 the benzyl group may be substituted on the benzene ring by a methoxy group or it may be replaced on the benzene ring by a benzhydryl or trityl group unsubstituted or substituted with a methoxy group. Deprotection is carried out as described above.

The optically active forms of the products of formula (I) are prepared according to known methods either starting from the optically active compound (Ila), according to Scheme 2 or, according to Scheme 3, after resolving the compound (VII), or its benzhydryl or trityl analog optionally substituted with methoxy, or by resolving the same compound (I), said resolution being carried out, for example by salification with an optically active acid, preferably optically active mandelic acid.

The N-protected 2-amino-7-hydroxytetralin carboxyalkyl ethers (IV) as well as their salts are new products and represent the key intermediates in the preparation of the compounds (I); said products (IV), in the racemic form or in the form of their individual stereoisomers, represent a further feature of the present invention.

The 2-amino-7-hydroxytetralin carboxyalkyl ethers of formula (I) as well as their salts are useful as intermediates in the preparation of pharmacologically active compounds. As an example they may be employed in the preparation of pheny1ethanolaminotetralins which are endowed with a β-adrenergic receptor agonist activity selective towards the gastrointestinal tract and are suitable for the preparation of spasmolytic drugs.

Accordingly, in a further feature, the object of the present invention is the use of the 2-amino-7hydroxytetralin carboxyalkyl ethers of formula (I) in the preparation of the corresponding phenylethanolaminotetralins of formula (XII) in which X represents hydrogen, a halogen, a Ci-C4~ alkyl, or a trifluoromsthyl group, Aik and R are as defined above, and of their pharmaceutically acceptable salts.

For the preparation of the compounds (XII), the compounds (I) may be reacted ·with a styrene oxyde of formula (XIII) (XIII) in which X is as defined above, said styrene oxide being in the racemate or in an optically active form, or they may be reacted with a functional derivative of a mandelic acid of formula (XIV) in which X is as defined above, and then the amide carbonyl group of the thus obtained mandelamide of formula in which X, R, and Aik are as defined above, may be reduced into a methylene group, said mandelic acid (XIV) being in racemic or in optically active form; and the resulting products may be optionally converted into their pharmaceutically acceptable salts.

The reaction between the compounds of formula (I) and the styrene oxides (XIII) may he carried out with or without an inert, preferably polar, organic solvent and optionally in the presence of an equimolar amount of N-trimethylsilylacetamide to control the opening of the epoxide.

The reaction, which is generally complete in a few hours, typically 6 to 24 hours, may be carried out at room temperature or, preferably, at higher temperatures, typically from 50 to 90‘G, to speed up the reaction course.

As functional derivative of the mandelic acid (XIV), the chloride, the anhydride, a mixed anhydride, an active ester, or a free acid suitably activated, for example with dicyclohexylcarbodiimide or benrotriarolyl -N-oxytrisC dimethylamino)phosphonium hexafluorophosphate (BO?) may conveniently be employed. A mandelic acid activated with a condensing agent such as BOP is preferably employed.

The reaction between the functional derivative of the mandelic acid (XXV) and a compound of formula (I) is generally carried out in an inert organic solvent such as methylene chloride, optionally in the presence of a proton acceptor such as triethylamine.

The thus obtained mandelamide (XV) is then submitted to the reduction of the amido group into a methylene-amino group yielding the desired product of formula (XII) by means of diborane or a reagent generating diborane such as the complex between borane and dimethylsulfide, commonly designated as boranemethylsulfide. The reaction is carried out in an organic solvent, e.g. tetrahydrofuran.

Independently of the method of synthesis, isolation and purification of the desired compound of formula (XII) are carried out according to well known conventional techniques.

The compounds of formula (XII) contain two centres of asymmetry at the carbon atoms marked with two asterisks in the above formula. In the preparation of these compounds the use of one of the enantiomers (I) and of one of the enantiomers (XIII) or (XIV) will lead to the pure stereoisomers of the compounds (XII). The reaction involved is stereopreservative and the same absolute configuration of the two chiral carbon atoms of substrates (I), (XIII), and (XIV), as assigned by the (R,S) Convention, is maintained in the end product (XII).

Using one of the starting products in racemic form will produce a mixture of two diastereoisomers while using both reagents in racemic form will afford a mixture of four stereoisomers. Fractional crystallisation of the diastereoisomers or chromatography of the mixture may produce compounds which are enriched in one of the possible diastereoisomers or even pure stereoisomers.

The enantiomers of the compounds of formula (XII) in which X, Aik, and R have the meaning defined above, and their pharmaceutically acceptable salts, as well as the mixture of enantiomers or diastereoisomers in any proportion represent therefore another object of the present invention.

A preferred group of compounds of formula (XII) comprises those compounds of formula (XII) in which X and R are as defined above and Aik represents a group C(RxqRii)- or a group Aik1, where Ηχο, ^11 an<^ Aik1 are as defined above, either as pure enantiomers or as mixtures of enantiomers or diastereoisomers in any proportion, and the pharmaceutically acceptable acid addition salts thereof.

An even more preferred group of compounds of formula (XII) comprises those compounds of formula (XII) in which X and R are as defined above and Aik represents a group '^(ΚχθΗχχ)-, where Ηχο, and Ηχχ represent a methyl, either as pure enantiomers or as mixtures of enantiomers or diastereoisomers in any proportion, and the pharmaceutically acceptable acid addition salts thereof.

The compounds of formula (XII) have shown to be more potent, as β-adrenergic receptor agonists, and/or more selective towards the gastro-intestinal tract than the corresponding compound substituted at the 7position of the tetralin moiety by an ethoxycarbonylmethoxy group which has been described in European patent EP-211721.

The compounds of formula (XII) according to the present invention have a good activity on the intestinal motility and are useful as spasmolytics. The toxicity of the compounds (XII) and of their pharmaceutically acceptable salts is very low and compatible with their use as active ingredients in pharmaceutical compositions.

According to the present invention the compounds of formula (XII) may be administered in a daily dosage of from 0.01 to 10 mg/kg of body weight, depending on the route of administration, the type of treatment, whether curative or prophylactic, the age of the subject to be treated, and the severity of the disease.

The compounds of formula (XXX) are generally administered in unit dosage forms containing of from 0.1 to 150 mg, preferably from 1 to 50 mg, 1 to 5 times daily.

Said unit doses are preferably formulated in pharmaceutical compositions in which the active principle of formula (XII) is combined with a pharmaceutical carrier.

A further specific object of the present invention is therefore a pharmaceutical composition, comprising, as the active principle, a compound of formula (XII) or a pharmaceutically acceptable salt thereof, useful for the treatment of gastrointestinal disorders associated with a contraction of the smooth muscle.

The pharmaceutical compositions according to the present invention may be formulated for the oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, or rectal administration route.

The compositions according to the present invention can be prepared by conventional methods and using conventional ingredients or excipients as known in the field of industrial pharmacy.

The following examples further illustrate the invention without however limiting· it.

PREPARATION I 2-amino°7-hvdrQxytetralin hvdrohromide (a) A mixture of 8 g of 7-methoxy-2-tetralone, 4.,8 g of benzylamine, 150 ml of anhydrous toluene and 100 mg of p-toluenesulfonic acid is refluxed for 3 hours. The oily residue is evaporated to dryness, taken up in 100 ml of methanol and 8.5 g of sodium borohvdride are carefully added at 0-5 C to the obtained solution. The mixture is stirred overnight at room temperature, 50 ml of water are then added thereto and the mixture is stirred again for 30 minutes. The solvent is evaporated and the residue is taken up in 30 ml of water and 10 ml of a concentrated solution of ammonium hydroxide. The reaction mixture is extracted with 200 ml of ethyl acetate, the organic phase is dried over sodium sulfate, filtered and evaporated to dryness. A dark oil is obtained which is purified by flash chromatography using a 95/5 ethyl acetate/methanol mixture as the eluent. The obtained base is converted into its hydrochloride by dissolving It in 40 ml of isopropanol and by adding isopropanol saturated with gaseous hydrochloric acid thereto. 11.4 g of 2-foenzylamino-7~methoxytetralin hydrochloride are obtained; m.p. 265-267C (dec.). (b) The above product, dissolved in 200 ml of methanol and 100 ml of water, is hydrogenated in the presence of 1.2 g of 10% palladium on charcoal, at a temperature of 45-50*C and at atmospheric pressure. After 4 hours, the reaction mixture is filtered, the filtrate is evaporated to dryness and the obtained residue is taken up twice in absolute ethanol and evaporated to dryness. A white solid is obtained which is taken up in 70 ml of hot isopropanol. Upon cooling, the obtained suspension precipitates and gives 7.8 g of 2-amino-7-methoxytetralin hydrochloride; m.p. 214-216"C . (c) 6.6 g of the above product are suspended in 80 ml of 48% hydrobromic acid and the mixture is refluxed for 2 hours. The obtained solution is evaporated to dryness and the residue is taken up twice in 5 absolute ethanol and concentrated to dryness every time. An oily product is thus obtained which is dissolved in 20 ml of hot isopropanol. 30 ml of ethyl ether are added to the solution and 6.8 g of crystalline 2-amino-7-hydroxytetralin hvdrobromide are obtained; m.p. 171-173C.

PREPARATION II R-2-amino-7-hydroxytetralin monohydrate A solution of 43 g of (-t-)-mandelic acid in 550 ml of absolute ethanol is added to a solution of 50 g of raw base 2-amino-7-methoxvtetralin in 550 ml of absolute ethanol, said raw base being obtained from the T 5 corresponding hydrochloride (PREPARATION I (b)) by neutralization with 10% sodium hydroxide followed by extraction with ethyl acetate and evaporation of the solvent. After standing overnight at room temperature, the obtained precipitate is filtered and crystallized twice from absolute ethanol, recovering every time the product which crystallizes upon standing overnight at 2° room temperature. 34.2 g (74%) of pure salt of the ( + )mandelic acid with the (+)-2-amino-7-methoxytefralin are thus obtained; m.p. 190-192’C. The mother liquors of this first crystallization are separated and employed in PREPARATION III below. 34 g of the resulting salt are suspended in 300 ml of water and the reaction mixture is made basic by the addition of IN sodium hydroxide. The base is extracted with ethyl acetate, the organic phase is evaporated to dryness and the residue is taken up in 260 ml of 48% hydrobromic acid. The reaction mixture is refluxed for 3 hours and then evaporated to dryness under vacuum, The residue is taken up in 70 ml of water, the aqueous solution is made basic by the addition of concentrated ammonium hydroxide, cooled overnight and filtered. 17 g of R-2amino-7-hydroxytetralin monohvdrate are obtained; m.p. 143-144’C, [a]D20 = 4-85.1*' (c = 0.5% in methanol).

The hydrochloride of this product has a rotary power which corresponds to that reported in the literature (Molecular Pharmacology, 1982, 22, 281-289).

PREPARATION III S-2-amino-7-hvdroxvtetralin monohydraxe The mother liquors of the first crystallization of the product of PREPARATION II, which contain the salt of ( + )-mandelic acid with the (-)-2-amino-7-methoxytetralin are evaporated to dryness, the resulting residue is suspended in 300 ml of water and the solution is made basic by the addition of IN sodium hydroxide. The base is extracted with ethyl acetate. Following the operating procedure described in PREPARATION II and using the thus obtained base and the (-)-mandelic acid as the starting products, the salt of (-)-mandelic acid with the (-)-2-amino-7-methoxytetralin is obtained (m.p. 189-191C) which, by neutralisation and demethylation with HBr gives 17 g of S-2-amixio-7-hydroxytetralin monohydrate; m.p. 143144‘C, [α]Ώ2θ = -85.9* (c = 0.5% in methanol).

The hydrochloride of this product has a rotary power which corresponds to that reported in the literature (Molecular Pharmacology, 1982, 22, 281-289).

PREPARATION IV 2-bensvlamlno_-7°hydroxvtetral-in g of 2~bensylamino-7-methoxytetralin hydrochloride, PREPARATION I (a), in 215 ml of a 33% solution of hydrobromic acid in acetic acid and in the presence of 35 ml of 48% hydrobromic acid are refluxed, under stirring, for 2 hours. After concentration under reduced pressure, the residue is taken up 3 times in 100 ml of absolute ethanol and is dried every time. The thus obtained product is triturated in 150 ml of acetone and filtered thus yielding 25.3 g of 2· benzylamino-7-hydroxytetralin hydrobromide; m.p. 198200 C. The salt is dissolved in 1300 ml of hot water and after cooling, concentrated ammonium hydroxide is added thereto. The base is extracted with ethyl acetate, the organic phase is dried and a solid is obtained which is crystallized from 250 ml of toluene. 14 mg of 2-benzylamino-7-hydroxytetralin base are thus obtained; m.p. 161-163'C.

PREPARATION V S-2-benzvlamino-7-methoxytetralin hydrochloride Ά solution of 24.5 g of (-)-mandelic acid in 150 ml of absolute ethanol is added to a solution of 44 g of 2benzylamino-7-methoxytetralin base, PREPARATION I (a), in 140 ml of absolute ethanol. After standing overnight at room temperature, the obtained solution is filtered, washed and crystallized twice from 250 ml of absolute ethanol yielding 33 g of pure salt of (-)- mandelic acid with (-)-2-benzvlamino-7-methoxytetralin; m.p. 155-157C; [^1365^0= -316*' (c = 1% in methanol).

The mother liquors from this first crystallization are separated and employed in Preparation VII below. g of the resulting salt are dissolved in 400 ml of water and. the solution is made basic by the addition of 32% ammonium hydroxide. The base is extracted with ethyl acetate, the organic phase is washed with water and dried over sodium sulfate. The solvent is evaporated and 20 g of an oil which is dissolved in isopropanol are obtained. A solution of isopropanol saturated with gaseous hydrochloric acid is added thereto and a product which is dried after filtration is obtained» 22 g of a product which is crystallized twice from a 1/1 methanol/water mixture are obtained thus yielding the S-2~bensylamino-7-methoxytetralin hydrochloride; m.p. 287-290"C; [ο,Ιββ^Ο- -231 (c = 1% in methanol).

Absolute configuration of this compound (S) was assigned by removing the N-benzyl group and comparing the rotary power of the resulting product with that known in the literature.

PREPARATION VI S_2-benzylamino-7-hydroxvtetralin hydrobromide A solution of 15 g of S-2-benzylamino-7-methoxyfetra.lin hydrochloride in 100 ml of 48% hydrobromic acid and 100 ml of 33% hydrobromic acid In acetic acid is refluxed under stirring for 3 hours. The resulting solution is evaoorated to drvness under reduced pressure. The product is taken up three times in absolute ethanol and the solution is evaporated to dryness every time. The oily residue is dissolved in hot acetone and crystallized therefrom. After filtration, the filtrate is washed with acetone, with ethyl ether and is then dried. 17 g of the S-220 benzylamino-7-hydroxytetralin hydrobromide are obtained; m.p. 198-202’C; [α]3652θ= -201.7 (c = 1% in methanol).

PREPARATION VII The mother liquors of the first crystallization of the salt of (-)-2~bensylamino~7~methoxytetralin with (-)mandelic acid (Preparation V) are evaporated to dryness and the resulting residue is suspended in 400 ml of water. The solution is made basic with 32% ammonium hydroxide and the base is extracted with ethyl acetate. The organic solution is washed with water, dried over sodium sulfate and evaporated to dryness. The resulting residue is dissolved in ethanol and a solution of 12.5 g of (+)—mandelic acid in 75 ml of absolute ethanol is added thereto. The precipitate which forms upon standing at room temperature overnight is filtered, washed and crystallised three times from absolute ethanol and 24 g of the addition salt of ( + )2-benzylamino-7-methoxytetralin with (+)~mandelic acid are obtained; m.p. 152-154‘C; [s *309" (c = 1% in methanol). Π g of the resulting salt are dissolved in 300 ml of water and the aqueous solution is made basic by the addition of 32% ammonium hydroxide. The base is extracted with ethyl acetate, the organic phase is washed with water, dried over sodium sulfate and evaporated to dryness. The obtained residue is dissolved in isopropanol and isopropanol saturated with gaseous hydrochloric acid is added thereto, thus recovering the R-2~benzylamino-7-methoxytetralin hydrochloride by filtration. The resulting product is dried and crsyballized twice from a 1/1 methanol/water mixture; m.p. 278-282C; [β]365^θ= *229.9’ (c = 1% In methanol).

PREPARATION VIII R-2-benzylamino-7-hydroxvtetr_aIin_hydro_brQialdg!_ g of R-2-benzylamino-7-methoxytetralin hydrochloride are dissolved in a mixture of 100 ml of a solution of 33% hydrobromic acid in acetic acid and 100 ml of 48% hydrobromic acid and the resulting solution is refluxed under stirring for 3 hours. After concentration under reduced pressure, the residue is taken up three times in absolute ethanol and dried every time. The residue is dissolved in hot acetone and crystallized therefrom.

The product is recovered by filtration, washed with acetone and ethyl ether and dried thus yielding 15„5 g of the R-2-bensylamino-7"hydroxytetralin hydrobromide; m.p. 198-202’C; Ε°ϋ3ό5^θ= +198.4" (c = 1% in methanol). 2-bensy2sm±no-7- (ethoxy carhonylpentan-5-ylaxy) tetralin hydrochloride g of 2-bensylamino~7-hydroxytefraIIn base, PREPARATION IV, and 1.7 g of 55% sodium hydride in 250 ml of toluene are heated at 70 "C under a nitrogen stream for 30 minutes. The reaction mixture is allowed to cool at room temperature and a mixture of 10.5 g of Ίθ 6-bromohexanoic acid ethyl ester and 0.5 g of tetrabutylammonium bromide in 200 ml of toluene is added dropwise. After refluxing for 8 hours, the reaction mixture is cooled and 100 ml of water are added thereto. The organic phase is separated, washed with a solution of 3N sodium hydroxide, dried and concentrated. The resulting product is dissolved in isopropanol and a solution of isopropanol saturated with gaseous hydrochloric acid is added thereto thus yielding 8.9 g of 2-benzylamino-7-(ethoxycarbonylpentan-5-yloxy)tetralin hydrochloride; m.p. 140-142"C; (8.9 g). 2o 2-amino-7- (ethoxycarbonylpentan-5-yloxy) tetralin hydrochloride A solution of 8.9 g of 2-benzylamino~7-(ethoxycarbonylpentan-5-yloxv)tetralin hydrochloride, EXAMPLE 1, in 150 ml of 95% ethanol is hydrogenated at atmospheric pressure and at the temperature of 60 C using 1 g of 10% palladium on charcoal as th® catalyst.

After 3 hours, the solution is filtered, the filtrate is concentrated to dryness and the residue is taken up twice in 100 ml of absolute ethanol and dried every time. The obtained product is triturated in 100 ml of acetone, filtered and crystallised from 50 ml of isopropanol. 5.5 g of 2-amino-?-(ethoxycarbonylpentan5-yloxy)tetralin hydrochloride are obtained; m.p. 114117-C. 2-henzylamino-7-(ethoxycarbonylpropan-3-yloxy)tetralin hydrochloride g of 2-benzylamino-7-hydroxytetralin base, PREPARATION IV, and 2.8 g of 95% sodium hydride in 400 ml of toluene are heated at 70 C under a nitrogen stream for 30 minutes. 9.2 ml of 4-bromobutanoic acid ethyl ester in 200 ml of toluene and 0.5 g of tetrabutvlammonium bromide are added dropwise at room temperature and then the reaction mixture is heated for 8 hours at 90"C, cooled and extracted twice with 100 ml of ethyl ether. The organic phase is washed with a mixture of 0.1N sodium hydroxide and water and is then dried. The resulting product is dissolved in 100 ml of isopropanol, and after the addition of charcoal, it is filtered. The solution is made acid with isopropanol saturated with gaseous hydrochloric acid. 14 g of 2benzylamino-7 -(ethoxycarbonylpropan-3-vloxy)tetralin hydrochloride are obtained; m.p. 175-177’C; (14 g). EXAMPLES 2-amino-7-(ethoxycarbonylpropan-3 -y1oxy)tetralin hydrochloride A solution of 14 g of 2-benzylaraino-7-(ethoxycarbonylpropan-3-yloxy)tetralin hydrochloride, EXAMPLE 3, in 250 ml of 95% ethanol and 10 ml of water, is hydrogenated at atmospheric pressure and at the temperature of 60 ’C using 2 g of 10% palladium on charcoal as the catalyst. After 5 hours, the solution is filtered, the filtrate is evaporated to dryness and the residue is taken up several times in absolute ethanol and dried every time. The obtained product is triturated in acetone, filtered and crystallized from isopropanol. 8.8 g of 2-amino-7-(ethoxycarbonylpropan-3"yloxy)tetralin hydrochloride are obtained; m.p. 134-136‘C,. 2-henzyleaiino-7- (ethoxycarbonylbutan-4-yloxy) tetr&lin hydrochJ. ozlde A solution of 10 g of 2-benzylamino=7--hydroxytetralin base, PREPARATION IV, and 1.6 g of 80% sodium hydride in 140 ml of dimethylsulfoxide is stirred at room temperature, under a nitrogen stream, for 30 minutes. 10.45 g of 5-bromovaleric acid ethyl aster and a catalytic amount of potassium iodide are added to the resulting reaction mixture and stirring at room temperature is continued for 17 hours. 400 ml of a water/Ice mixture are then added thereto and the resulting mixture is extracted with ethyl acetate. The organic phase is washed with a solution of 2N sodium hydroxide and then with water, dried over sodium sulfate, filtered and concentrated under vacuum. The residue is dissolved in isopropanol and isopropanol saturated with gaseous hydrochloric acid is added thereto. Crystallisation from 100 ml of isopropanol gives 10.7 g of 2-benzylamino-7"(ethoxycarbonylbutan"4" yloxy)-tetralin hydrochloride; m.p. 154-156*C.

EXAMPLE 6 2-amino-7-(ethoxycarbonylbutan-4-yloxy)tetralin hydrochloride A solution of 10.7 g of 2-benzylamino-7~(ethoxycarbonyltoutan-4-yloxy)tetralin hydrochloride, EXAMPLE 5, in 250 ml of 95% ethanol and 25 ml of water, is hydrogenated at atmospheric pressure and at the temperature of 50 C using 1.2 g of 10% palladium on charcoal as the catalyst. After 6 hours, the solution is filtered, the filtrate is concentrated to dryness and the residue is taken up several times in absolute ethanol and dried every time. The obtained product is triturated in ethyl ether and filtered. Crystallization from isopropanol gives 8 g of 2-amino-7-(ethoxycarbonylbutan-4-yloxy)tetralin hydrochloride; m.p. 131133*C. example . ? 2-benzylejsino-7- (2~carboxyp?opan-2-yIoxy) tetralin and 2-benzylsai±no-7- (2~ethoxycarbonylpropan-2-yloxy) tetralin oxalate A solution of 19 g of 2-benzylamino-7-hydroxvtetralin base, PREPARATION IV, and 26.6 g of 1,1,l-trichloro-2methyl-2-propanol in 500 ml of acetone is stirred at room temperature for 15 minutes. The reaction mixture 1θ is then cooled to 15'C, 10.9 g of potassium hydroxide are added thereto and stirring is continued at room temperature for 2 hours. Two additional portions of potassium hydroxide (10.9 g 10.9 g) are then added thereto and the reaction mixture is stirred at room temperature overnight and then concentrated under reduced pressure. 250 ml of a water/ice mixture are then added and the solution is washed with ethyl ether. Charcoal is added thereto, the solution Is filtered and made acid with hydrochloric acid up to pH 5-6. 14 g of 2-benzylamino-7-(2-carboxypropan-2-yloxy)tetralin are recovered by filtration. The resulting product and 3.6 ml of thionyl chloride in 100 ml of absolute ethanol are refluxed for 4 hours. After concentration under reduced pressure, a water/ice mixture is added to the solution which is made basic by the addition of ammonia. The solution is extracted with ethyl acetate, dried, filtered and evaporated to dryness. The resulting base is dissolved in acetone and oxalic acid is added thereto. Crystallization of the precipitate from 180 ml ox 95% ethanol gives 11.3 g of 2-benzylamino-7-(2-ethoxycarbonylpropan-2-vloxy) tetralin oxalate; m.p. 174-176"C.

A sample of the above obtained 2-bensylamino-7-(2carboxypropan-2-yloxy)tetralin is washed with water, triturated in acetone and dried; m.p. 240-242*C, Hydrogenation of said compound according to the procedure of Example 2 affords the corresponding deprotected product, the 2-amino-7-(2-carboxypropan-2yloxy)tetralin. 2-amino-7- (2-ethoxycarbonylpropan-2-yloxy) tetralin oxalate A solution of 9.1 g of 2-bensylaminO"7~(2-ethoxy~ carbonyIpropan-2-yloxy)tetralin base, EXAMPLE 7, in 100 ml of 95% ethanol and 4 ml of hydrochloric acid, is hydrogenated at atmospheric pressure and at the temperature of 60 C using 1 g of 10% palladium on charcoal as the catalyst. After 4 hours, the solution is filtered, concentrated under reduced pressure and the residue is taken up several times in absolute ethanol and dried every time. The residue is dissolved in dilute ammonia. After extraction with ethyl ether, the organic phase is separated, made anhydrous, filtered and evaporated to dryness. The residue is purified by flash chromatography using an 8/2 methylene chloride/ethanol mixture. The resulting product is dissolved in acetone containing some oxalic acid. After crystallisation from 10 ml of acetone, 0.66 g of 2amino-7 - (2 -ethoxvcarbony Ipropan- 2 -yloxy) tet r al in oxalate is obtained; m.p. 140-142C. zwiple s.

S-2-benzylamino-7- (2-ethoxycarbonylpropan-2-yloxy) tetralin hydrochloride The compound of the title was prepared by following substantially the same procedure as in Example 7 but starting from S-2~bensylamino-7-hydroxytetralin base (prepared from the corresponding hydrobromide described in Preparation VII, by dissolving this product in water, by adding a concentrated solution of ammonium hydroxide to make the solution basic, by extracting the free base with ethyl acetate and by evaporating the solvent). At the end of this procedure, the resulting free base is dissolved in isopropanol and isopropanol saturated with gaseous hydrochloric acid is added to precipitate the hydrochloride which is separated by filtration and crystallized from isopropanol. [<χ]3552θ= -156.2"' (c = 0.5% in methanol); m.p. 152154’C.

EXAMPLE IQ R-2-benzylamino-7~ f 2-eihoxyca.rbonylpropan-2-yloxy) 1 0 tetralin hydrochloride The compound of the title was prepared by following substantially the same procedure as in Example 7 but starting from R-2-bensylamino-7-hydroxytetralin base (prepared from the corresponding hydrobromids described in Preparation VIII, by dissolving this product In water, by adding a concentrated solution of ammonium hydroxide to make the solution basic, by extracting the free base with ethyl acetate and by evaporating the solvent). At the end of this procedure, the resulting free base is dissolved in isopropanol and isopropanol saturated with gaseous hydrochloric acid is added to precipitate the hydrochloride which is separated by filtration and crystallized from isopropanol. [α]3552θ= +158.4'’ (c = 0.5% in methanol); m.p. 148150C.

S-2-a^ino-7~(2-ethoxycarbonylpropan-2-yloxy)tetralin oxalate The compound of the title was prepared by following the procedure of Example 8 but starting from the compound obtained in Example 9. [h]35520= -140.4 (c = 1% in methanol); m.p. 132~134"C.

H-2-amino-7- (2-ethoxycarbonylpropan-2-yloxy) tetralin oxalate The compound of the title was prepared by following the procedure of Example 8 but starting from the compound obtained in Example 10. [σ]35520= 4-140.9" (c = 1% in methanol); m.p. 131-134"C„ ffl- [7- (ethoxycarbonylbutan-4-yloxy) -1,2,3, 4-tetrahydronaphth-2-yl]-2-hydroxy-2-(3-chlorophenyl) ethanamine hydrochloride h solution of 5 g of 2-amino-7-(ethoxycarbonylbutan-4Ί0 yloxy)tetralin base (obtained by dissolving its hydrochloride described in Example 6, in water, by adding a concentrated solution of ammonium hydroxide up to basic pH, by extracting the free base with ethyl acetate and by evaporating the organic solvent), in 15 ml of anhydrous dimethylsulfoxide and 4.6 g of 3chlorostyrene oxide is heated at 80C under stirring, 15 under a nitrogen stream, for 11 hours. After standing at room temperature overnight, the reaction mixture is poured into a water/ice mixture, extracted with ethyl acetate, washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The resulting residue is dissolved in ethyl ether and the solution Is made acid with isoorooanol saturated with hydrochloric acid, filtered, dried and crystallised twice from 40 ml of isopropanol thus yielding 3.9 g of N-[7-(ethoxycar~ bonylbutan-4-yloxy)-1,2,3,4-tetrahydronaphth-2~yl]-2hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride; m.p. 127-130"C.

M-[7- (ethoxycarbonylpentan-5-yloxy)-1,2,3,4-tetrahydronaphth-2-yl]-2-hydroxy-2- (3-chlorophenyl )ethanamine hydrochloride A solution of 4.2 g of 2-amino-7-(ethoxycarbonylpentan5-yloxy)tetralin base, obtained by neutralizing its hydrochloride described in Example 2, and 2.4 g of trimethylsilylacetamide in 10 ml of anhydrous dimethyl sulf oxide is stirred at 25 '°C for 20 minutes. 3.6 g of 3-chlorostyrene oxide are then added thereto and the reaction mixture is heated to 80"C for 9 hours and then poured into 100 ml of water containing 3 ml of concentrated hydrochloric acid. 50 ml of ethyl acetate are added thereto and the mixture is stirred for 1 hour. The two phases are separated: the aqueous phase is washed with ethyl acetate (2 x 50 ml) and the washing liquids are added to the organic phase. This organic solution, is washed with water, with a dilute solution of ammonium hydroxide and again with water, dried and evaporated to dryness. The residue is purified by flash chromatography using ethyl acetate. The residue obtained by evaporation to dryness of the combined fractions is dissolved in 100 ml of isopropyl ether and isopropanol saturated with gaseous hydrochloric acid is added thereto. The oily product which separates, solidifies upon recovered by filtration (3.9 g). crystallised from 20 ml of isopropanol thus yielding 2 g of the compound of the title; m.p. 109-112’C. EXAMPLE 15 standing and This product is is W- [7-( ethoxycarbonyl propan-3-yloxy )-1,2,3,4-tetrahyc.ronaphth-2-yl]-2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride Ά mixture of 5.3 g of 2-amino-7-(ethoxycarbonylpropan3-vloxy)tetralin base, obtained by neutralising its hydrochloride described in Example 4, and 2.75 g of Ntrixnethylsilylacetamide in 10 ml of anhydrous dimethylsulfoxide is kept at 25 C for 20 minutes under a nitrogen stream. 3 g of 3-chlorostyrene oxide are then added thereto and the reaction mixture is heated to 60'C for 7 hours. After standing at room temperature overnight, the reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is thoroughly washed with water, dried and evaporated to dryness. The residue is dissolved in isopropanol and isopropanol saturated with gaseous hydrochloric acid is added thereto. The precipitate is recovered by filtration and crystallized from 80 ml of isopropanol yielding 4.4 g of the compound of the title; m.p. 156158C.

EXAMPLE 16 N-[7-(2-ethoxycarbonylpropan-2-yloxy)-1,2,3,4-tetrahy1 θ dronaphth-2-yl]-2-hydroxy-2-(3-chlorophenyl) ethanamine hydrochloride A mixture of 3.2 g of 2-amino-7-(2-ethoxycarbony1propan-2-yloxy)tetralin base, obtained by neutralising its oxalate described in Example 8, and 2.5 g of Ntrimethylsilylacetamide in 10 ml of anhydrous dimethvlsulfoxide is stirred at room temperature, under a nitrogen stream and anhydrous conditions, for 20 minutes and 2.8 g of 3-chlorostyrene oxide are then added thereto. The reaction mixture is heated to 80'C for 8 hours, and after standing at room temperature overnight, a further 1.0 g of 3-chlorostyrene oxide is added thereto, it is heated to 80C for 5 hours and 2θ then poured into 150 ml of a water/ice mixture. A few milliliters of concentrated hydrochloric acid and 100 ml of ethyl acetate are added thereto and the obtained mixture is stirred at room temperature for 1 hour. The two phases are separated, the aqueous phase is washed twice with 50 ml of ethyl acetate and these two washing portions of ethyl acetate are added to the separated organic phase. The organic phase is washed with water, with a dilute solution of ammonium hydroxide end again with water, dried and evaporated to dryness thus yielding 6.6 g of oily product. This product is purified by flash chromatography using ethyl acetate and the resulting purified product is converted into its hydrochloride by dissolving it in isopropyl ether and making the solution acid by the addition of isopropanol saturated with gaseous hydrochloric acid, upon standing a precipitate forms which is recovered by filtration and cristallized twice from isopropanol. 1 g of the compound, of the title is obtained; m.p. 142144’C.

EXAMPLE 17 N-[(23)-7-(2-ethoxycarhonylpropan-2-yloxy)-1,2,3,4-tetrahydronaphth-2-yl]- (2R)-2-hydroxy-2-(3-chlorophenyl )ethanamine hydrochloride The compound of the title was prepared by following the procedure of Example 16 but starting from (R)-3chlorostvrene oxide and S-2-amino-7-(2-ethoxycarbonylpropan-2-yloxy)tetralin base obtained by neutralizing the corresponding oxalate described in Example 11. [κ]365^θ= -270 (c = 1% in methanol); m.p. 205-208"'C.

M-[(2R)-7-(2-ethoxycarhonylpropan-2-yloxy)-1,2,3,4-tetrahydronaphth-2-yl]~(2R)-2-hydroxy-2-(3-chlorophenyl) ethanamine hydrochloride The compound of the title was prepared by following the procedure of Example 16 but starting from (R)-3chlorostyrene oxide and R-2-amino-7-(2-ethoxycarbonylpropan-2-yloxy)tetralin base obtained by neutralizing the corresponding oxalate described in Example 12. [ο.]3552θ= +125.7’ (c = 1% in methanol); m.p. 109-112C, The compounds of Examples 13 and 16 were evaluated in the isolated rat colon test, carried out according to the method described in patent application EP-A-255415.

The activity of said products expressed as IC50, showed to be higher than that of N-[7-( ethoxycarbonvImethoxv)-1,2,3,4-tetrahydronaphth-2-v1]-225 hydroxy-2-(3-chlorophenyl)ethanamine oxalate described in Example 11 of EP 211721.

Claims (21)

CLAIMS:

1. A 2-amino-7-hydroxytetralin carboxyalkyl ether of formula in which Aik represents a straight or branched alkylene group containing from 3 to 5 carbon atoms, and R represents hydrogen or an alkyl group containing from 1 to 4 carbon atoms, or one of its salts.

2. Compound according to claim 1, in which Aik represents I 2 R, «5 1 1 K’ 2 r ! , I R s , R’ I I (a) a group CH— , I 1 —c— I -c—c— I 1 , -Ο- ι -c— I I 1 1 1 Kb 1 I R, R' 3 R’ 5 R'S R’ g or -(0¾ ) 5 where Kl is an ethyl, propyl or butyl group; ϊ?2 to Ry are ell hydrogen atoms or one of the Ry ΐο Ry radicals is a methyl or ethyl group and the others are hydrogen atoms, or two of the R2 to Ry radicals are methyl groups and the others are hydrogen atoms; R*2 to R’g are all hydrogen atoms or one of the H : y to R’g radicals is a methyl group and the others are hydrogen atoms; l· 10 (b) a arouo -c- where I RjO an<3 · R 11 are independently a methyl or ethyl group; or Ηχχ is also the propyl group when Ηχο is the methyl group; R I 12 (c) a group CH—CH

3. where one of the Ηχ2 and Ηχβ radicals is hydrogen atom and the other is a methyl, ethyl propyl group, or one of the Rx2 and R13 radicals the methyl group and the other is the methyl ethyl group. Compound according to claim 2, in which represents a group: a or is or Aik where Rx-Ry, Rxq, R ll/ and are as defined in claim 2,

4. Compound according to claim 3 which is selected from the group consisting of 2-amino-?- (ethoxycarbonylpropan-3-yloxy) -tetralin, 2-amino-7- (ethoxycarbonylbutan-4-yloxy) -tetralin, 2-amino-7- (ethoxycarbonylpentan- 5-yloxv) -tetralin, 2-amino-7~ (2-ethoxycarbonylpropan-2-yloxy) -tetralin and salts thereof.

5. A process for the preparation of a 2-amino-7hydroxytetralin carboxyalkyl ether of formula (1) in which Aik and R are as defined in claim 1, or a salt thereof, characterised in that (A) a N-protected 2~amino-7-hydroxytetralin of formula (ID R'-ϊ (XI) in which R' is an amino-protecting group which may suitably be removed by catalytic hydrogenation or mild acidic hydrolysis, is submitted to a carb(alk)oxyalkylation reaction, with a compound of formula (Ilia) Hal-AlkX-COOR (Ilia) in which R is a defined above, Hal represents a chlorine, bromine or iodine atom, and Aik 1 represents a group -(ch 2 ) 5 ?2 ?4 ?6 ?’2 T*4 Γδ Γ Γ8 C—C—C-, -C-C C-C-, or 111 I 1,1 I R 3 K 5 R 7 R' 3 R’ s R' 7 R’ where Rj is an ethyl, propyl or butyl group; R2 K 7 ar ® all hydrogen atoms or one of the R? to Ry radicals Is a methyl or ethyl group and the others are hydrogen atoms, or two of the Ry to Ry radicals are methyl groups and the others are hydrogen atoms; R # 2 ΐο κ *9 are hydrogen atoms or one of the R’y to R’g radicals is a methyl group and the others axe hydrogen atoms; in the presence of a basic condensation agent; or with a compound of formula (Illb) T*° CLC—C—CH (Illb) I Rl! in which ΗχΟ an< ^ Ηχχ are independently a methyl or ethyl group; or Ηχχ is also the propyl group when Ηχο is the methyl group, in the presence of a strong base, optionally followed by reaction of the resulting compound with thionyl chloride in a suitably selected Cx-C^-alkanol, or with a compound of formula (IIIc) HC=C-COOH (IIIc) I R. in which R is as defined above, and one of the Rx2 and Ηχ3 radicals is hydrogen and the other is the methyl, ethyl or propyl group, or one of the Ηχ2 and Rxg radicals is the methyl group and the other is the methyl or ethyl group, optionally in the presence of catalytic amounts of a quaternary ammonium hydroxide; to obtain an N-protected 2-&mino~7-hydroxytetralin of formula (IV) R’-NH O-AXk-OCQR o (IV) in which R', Aik, and R are as defined above, and (3) the N-protecting group is removed by catalytic hydrogenation or mild acidic hydrolysis and, after optional saponification of the lower carbalkoxy group to a carboxy group, the compound of formula 5 (I) is isolated, in the form of a free base or a salt, and it is optionally converted into one of its salts.

6. Process according to claim 5, characterized in that the N-protecting group R' is selected from the groups consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and the benzyl, benzhydryl, and trityl 1θ groups, unsubstituted or substituted on a phenyl ring by a methoxy group.

7. N-protected 2-amino-7-hydroxytetralin carboxyalkyl ether of formula (IV) in which R, Aik and R' are as defined in claim 5, or one of its salts.

8. , Compound according to claim 7 where R' is as defined in claim 6.

9. Compound according to claim 8 selected from the group consisting of 2-benzylamino~7~ (ethoxycarbonylpropan-3-yloxy) tetralin, 2-benzylamino~7-( ethoxycarbonylbutan-4-yloxy )tetralin, 2-bensylamino-7-( ethoxycarbonylpentan-5-yIoxy)~ tetralin, 2-bensylamino-7- (2-ethoxycarhonylpropan~2-yloxy) tetralin and salts thereof.

10. A phenylethanolaminotetralin of formula (ΧΪΪ) in which X represents hydrogen, a halogen, a Cy-C^-alkyl, or a trifluoromethyl group, R represents hydrogen or a C^-C^-alkyl, and Aik is as defined in any one of claims 1 to 3 and the pharmaceutically acceptable salts thereof,

11. A process for preparing a phenylethanolaminotetralin of claim 10, characterized in that a compound of formula (I) in which Aik represents a straight or branched alkylene group containing from 3 to 5 carbon atoms, and R represents hydrogen or an alkyl group containing from 1 to 4 carbon atoms, is reacted with a styrene epoxide of formula (XIII) in which X is as defined in claim 10, or with a functional derivative of a mandelic acid of formula (XIV) ΧΟΗ CK-CCQH (XIV) in which X is as defined above, and then the amide carbonyl group of the thus obtained intermediate mandelamide of formula in which X, R, and Aik are as defined above, is reduced into a methylene group, and the resulting product of formula (XII) is optionally converted into one of the pharmaceutically acceptable salts thereof.

12. Compound according to claim 10 in which Aik represents a group -CH R. R- R I 2 I -C—C I I R 3 r ΚΙ 2 j 4 1 6 | 8 C-.q-c-C-, -(C1L ) c -, or I I I I 25 R' 3 R' s R’ ? R’g 110 -ΟΙ R 11 where Ri is an ethyl, propyl or butyl group; R2 to Hy are all hydrogen atoms or one of the r?2 Ry radicals is a methyl or ethyl group and the others are hydrogen atoms, or two of the R2 R 7 radicals are methyl groups and the others are hydrogen atoms; R' 2 to R 5 g are all hydrogen atoms or one of the R' j to R’g radicals is a methyl group and the others are hydrogen atoms; Rxq and Ηχχ are independently a methyl or ethyl group; or Ηχχ is also the propyl group when Ηχθ is the methyl group;

13. Compound according to claim 12 in which Aik represents R 1 10 a group -cI R ι 1 where Κχθ and Κχχ are as defined in claim 12.

14. Compound according to claim 10, which is N-[7~ (ethoxvcarbonyIbutan-4-yloxy)-1,2,3,4-tetrahydronaphth-2-yl] -2~hycroxy-2-( 3-chlorophenyl) ethanamine and the pharmaceutically acceptable salts thereof.

15. Compound according to claim 10, which is N-[7(ethoxycarbonylpropan-3-yloxy )-1,2,3,4-tetrahydronaphth-2-yl] -2-hydroxy-2-( 3-chlorophenyl) ethanamine and the pharmaceutically acceptable salts thereof.

16. Compound according to claim 10, which is N-[7(ethoxycarbonylpentan-5~yloxy )-1,2,3,4-tetrahydronaphth-2-yl] -2-hydroxy-2~( 3-chlorophenyl) ethanamine and the pharmaceutically acceptable salts thereof.

17. - Compound according to claim 10, which is N-[7-(2ethoxycarbonylpropan-2-yloxy)-1,2,3,4-tetrahydronaphth-2-yl] -2-hydroxy~2-(3-chlorophenyl )ethanamine and the pharmaceutically acceptable salts thereof.

18. Pharmaceutical composition for the treatment of gastrointestinal diseases, characterized in that it contains a compound of claim 10 as the active ingredient.

19. A 2-amino-7-hydroxytetralin carboxyalkyl ether of ‘ formula (I) as claimed in claim 1, an N-protected 2-amino-7“hydroxytetralin carboxyalkyl ether of formula > (IV) as claimed in claim 7, or a phenylethanolamino5 tetralin derivative of formula (XII) as claimed in claim 10, substantially as described in the Examples.

20. A process for the preparation of a 2-amino-7hydroxytetralin carboxyalkyl ether of formula (I) as claimed in claim 5, or a process for preparing a 10 phenylethanolaminotetralin of formula (XXII) as claimed in claim 11, substantially as described in the Examples.

21. A 2-amino-7-hydroxytetralin carboxyalkyl ether of formula (I) or a pheylethanolaminotetralin of formula (XII) whenever prepared by a process as claimed in claim 15 20.