NZ232543A - 2-amino-7-carboxyalkoxy-tetralin derivatives, intermediate compounds and pharmaceutical compositions thereof - 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

New Zealand Paient Spedficaiion for Paient Number £32543 232543 Priority Daie(s): 'M.s.S.!.

Cotnp'-Ats Specification Filed: Class: <•;!/.''.V.Jiv),\SU\jJI Publication Date: L.^.L.???..

P.O. Journal, No: HO "> h\ Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION ^4feb199o 4 > -f) V / v r- 2-AMINO-7-HYDROXYTETRALIN CARBOXYALKYL ETHERS WE, SANOFI, a French company of 40, Avenue George V, 75008 Paris, FRANCE hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by page la) fii&n 'J - ia- The present invention relates to 2-amino-7-hydroxyte-tralin carboxyalkyi ethers, to a process for the preparation thereof and the intermediates in said process, to the use of said ethers as starting materials in the synthesis 5 of pharmacologically active compounds and to the new 7-substituted phenylethanolaminotetralins endowed with spasmolytic activity thus obtained.

More particularly, in one of its aspects, the present invention concerns 2-amino-7-hydroxytetralin carboxyalkyi 10 ethers of the following formula O-Alk-COCR (I) wherein - Alk represents a straight or branched (C^-C-)alkylene group, and - R represents hydrogen or (C^-C^)alkyl, and their salts.

More particularly, the term Alk may represent R_ R, R, R» R' R'. R' I 2 i 4 | 6 i 2 | 4 | o i 8 (a) a group -CH- , -C—C—C-, -C C—C C-, or -(CH,)_- i ill I I I I 4 3.

RL R3 R5 R? R'3 R*5 R*7 R'g wherein - R^ is ethyl, propyl or butyl, - R2 to R7 are all hydrogen atoms or one of R^ to R7 is a methyl or ethyl group and the others are hydrogen atoms, or two of R2 to R7 are methyl groups and the others are hydrogen atoms• and 30 - R'£ to R'g are all hydrogen atoms or one of R'j to R'g is a methyl group and the others are hydrogen atoms; (followed by page 2) «V 1 ' t * -. • o . • ' ; ' t 2 - ?10 (b) a group -C- wherein R11 _ ^1C and R1 ^ are independently methyl or ethyl or R. , 1 1 propyl and R^ is .nethvl; or" R, . 12 (c) a group -CH—CH- wherein R13 - one of R^2 anc* ^3 is hydrogen and the other is 10 methyl, ethyl or propyl, or one of r12 and is methyl and the other is methyl or ethyl.

The new compounds are useful as starting materials in the preparation of pharmacologically active compounds, in particular 7-substituted phenylethanolaminotetralins with 15 spasmolytic activity.

As used herein the term "tetralin" stands for 1,2 , 3 , 4-tetranydronap'nthalene and the term " 2-tetralone" for the corresponding 2-oxo derivative.

The compounds of above formula (I) and their salts 20 can be prepared by the following general method, which represents a further specific object of the present invention and which comprises : (A) submitting a N-protected 2-amino-7-hydroxytetralin of formula (II) R' NH ^ ^ ^CK (II) wherein - R' is an amino-protscting group which may suitably be 30 removed by catalytic hydrogenation or mild acidic hydrolysis, to a carb(alk)oxyalkylation reaction with a compound of formula (Ilia) Hal-Alk^-COOR (Ilia) ' ' wherein R is as defined above, Hal represents chloro, 3 0 MAR 199?r bromo or iodo, and Alk, represents an alkylene group as 232 5 4 3 defined under (a) above, in the presence of a basic condensation agent, or with a compound of formula (Illb) R10 Cl3C-C-OH (Illb) R11 wherein R1Q and R^ are as defined above under (b) above, in the presence of a strong base, optionally followed by reaction of the obtained product with 10 thionyl chloride in the suitably selected (C^-C^)alka- nol, or with a compound of formula (IIIc) R12 C—C-COOR (IIIc) *13 wherein R, R^< and R^3 are as defined under (c) above, optionally in the presence of catalytic amounts of a quaternary ammonium hydroxide, to obtain a N-protected 2-amino-7-hydroxytetralin 20 carboxyalkyi ether of formula (IV) R'NH^ ^ ^O-Alk-COOR (iv) wherein R', Alk, and R are as defined above, and 25 (B) removing the N-protecting group by catalytic hydrogena-tion or mild acidic hydrolysis and, after optional saponification of the lower carbalkoxy group to carbo-xy, isolating the compound of formula (I), as the free base or as a salt thereof, and optionally converting it 30 into one of its salts.

The term "carb(alk)oxyalkylation" typically identifies a condensation reaction of the phenol hydroxy group with a reactant which is capable of etherifying said hydroxy group with an alkyl group substituted with a 35 carb(alk)oxy group, i.e. a carboxy or carbalkoxy group, 232 5 4 3 wherein the term "carbalkoxy" designates a (C^-C^)alkoxy-carbonyl group.

Preferred N-protecting groups include tert-butoxy-carbonyl (Soc), benzyloxycarbonyl and in general those 5 N-protecting groups which arc conventionally employed in peptide chemistry, or benzyl, benzhydryl, or trityl groups, either unsubstituted or substituted in the benzene ring by a methoxy group.

As starting compounds of formula (Ilia), alkyl 10 bromoalkanoatcs are 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 15 carbonate, typically potassium carbonate.

For the preparation of the compounds of formula (I) wherein Alk is a group -C(R^qR^)-, compounds of formula (IIlb) are reacted with the N-protected 2-amino-7-hydroxy-tetralin (II), according to the general method described in 20 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 when a compound of formula (I) is desired wherein R is different from hydrogen, the obtained acid is treated with 25 thionyl chloride in the suitably selected alkanol.

The reaction between the N-protected 2-amino-7-hydro-xytetralin (II) and the acrylic acid derivatives of formula (IIIc) may be carried out either in the absence or in the presence of an inert, apolar, organic solvent such as 30 benzene, toluene, ethyl ether, methylene chloride, and the like. The reaction may be catalyzed, if desired, by small amounts of a quaternary ammonium hydroxide, e.g. trimethyl-benzylammonium hydroxide. Preferably, to avoid addition of the acrylate to the amino-tetralin bond, when using a 35 reactant of formula (IIIc), the amino group of the reaction 232543 partner (II) is protcctcd with Boc or any other easily removable urethane-type protecting group.

The thus obtained N-protected 2-amino-7-hydroxytetra-lin carboxyalkyi ether of formula (IV) is recovered by 5 standard methods well known to chemists, optionally as a salt thereof, and is then subjected to deprotection.

Removal of the N-protecting group is accomplished by catalytic hydrogenation or mild acidic hydrolysis according to methods well known in the literature. In particular the 10 Boc group is readily cleaved under mild acidic conditions, by the action of trifluoroacctic acid. The other groups listed above are removed by catalytic hydrogenation, preferably using Pd/C as the hydrogenation catalyst. The trityl and methoxy-trityl groups may be removed also by 15 hydrolysis under mild acidic conditions, e.g. with 50% formic acid or with hydrogen chloride in an organic solvent .

To afford the corresponding free carboxylic acids, the compounds of formula (I) may be saponified, either 20 before or after deprotection of the amino group.

The compounds of formula (I) are isolated by conventional methods, preferably as the corresponding addition salts with mineral or organic acids which allow a suitable separation or crystallisation of the compounds (I), such as 25 for instance picric acid, oxalic acid, or with 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, methanesul-30 fonate, methylsulfate, maleate, fumarate, naphthalenesulfa-te, and the like.

The free base may be obtained by neutralization, and converted into another acid addition salt or, when R is hydrogen, into a metal salt thereof, typically an alkaline 35 salt, such as the sodium salt, by conventional procedures. 232543 The N-protected 2-amino-7-hydroxytetralins of formula (II) may be prepared starting from 2-amino-7-hydroxy-tetra-lin of formula (Ila) ^0H (Ila) or directly from 7-methoxy-2-tetralone of formula (V) h2N O . OCH, "Ogr (V) In its turn, 2-amino-7-hydroxytctralin (Ila) may be prepared starting from the corresponding methoxytetralone of formula (V) through reaction with bcnzylamine, reduction with sodium borohydride of the thus obtained benzylimino intermediate, removal of the benzyl group by catalytic hydrogenation and demethylation with 48% hydrobromic acid according to following Scheme 1: SCHEME 1 benrv la-.ir.e h„n. v: W OCH HBr H2 VZ: k2n OCH.

W~' Vila OCH.

The reaction of the compound of formula (V) with 30 benzylajnine is carried out, according to the conventional methods for the preparation of Schiff's bases, in an organic solvent such as toluene, in the presence of p-to-luenesulfonic acid. The thus obtained compound (VI) may then be reduced, without being isolated or purified, with 35 sodium borohydride. Catalytic hydrogenation of said 232543 compound, e.g. with Pd/C, affords 2-amino-7-methoxytetralin of formula (Vila) which is heated in 48 % hydrobromic acid yielding 2-amino-7-hydroxytetralin (Ila) hydrobromide readily converted into the free base by neutralisation.

In the first step of above Scheme 1 leading to the N-protected intermediate, benzylamine may be replaced by tritylaminc or benzhydrylamine; these three compounds may also bear a methoxy group on one of the phenyl rings.

The compounds of formula (II), (Ila), (VII) and 10 (Vila) have a centre of asimmctry at the carbon atom linked to the amino group. Preparation of addition salts from said compounds and a chiral organic acid, preferably optically active mandelic acid, followed by fractional crystallization, may result in compounds which are enriched in one of 15 the enantiomcrs and eventually in the optical resolution of the racematcs leading to the two optically active forms. Optical resolution of these compounds may also be accomplished by specific chromatographic techniques.

Introduction of a N-protecting group R' is achieved 20 by reacting the compound of formula (Ila) with a reactant suitable for protection of the amino groups as described, for instance, by M. Bodanszky et al. in Peptide Synthesis, 2nd Edition, John Wiley & Sons, 1976, p.18-49, Chapters 3 to 6.

As an example the Boc group may be introduced by reaction with di-tert-butyl-dicarbonate under basic conditions. The benzyloxycarbonyl group may be introduced by the general method described by E.C. Horning, in Organic Synthesis, Vol. Ill, Wiley, New York, 1955, p.167. 30 Accordingly, the compounds of formula (I) may be prepared, as an example, by protecting the amino group of 2-amino-7-hydroxytetralin (Ila) with a Boc group, by reaction of the aminotetralin (Ila) with di-tert-butyl-di-carbonate in an organic solvent such as dioxane or dime-35 thylformamide, by treating the thus obtained product with a compound of formula (Ilia) or (Illb) or (IIIc) under the 232 543 above described conditions and by deprotecting the amino group by removal of the Boc group with trifluoroacetic acid according to following Scheme 2: SCHEME 2 BocSK ^ nu Ha .

L > (Ilia) or (Illb) or (xilc) v::: io BocSK\^V^^'0"A:< "COOR -COOR TXX ^ XXX :x i Removal of the protecting group Boc does not affect the carbalkoxy group or the molecule stereoconfiguration. 15 N-protection may also be carried out starting from the 7-methoxy-2-tetralone (V) through formation of a Schiffs base with an amine selected from benzylamine, tritylamir.e, and benzhydrylamine, optionally substituted on one of the phenyl rings with a methoxy group, followed by 20 reduction with sodium borohydride.

Accordingly, as an example, the compounds of formula (I) wherein Alk represents an alkylene group as defined under (a) or (b) may be prepared starting from a 2-benzyl-amino-7-methoxytetralin of formula (VII) (Scheme 1), via 25 demet'nylation with hydrobromic acid, reaction of the corresponding phenol with a compound of formula (IIla) or (Illb) under the above described conditions followed by debenzylation according to following Scheme 3: SCHEME 3 vii HSr <SV fT,T , ,TTThl ^ v ' 2 I (Ilia) or (Illb) \ / 2 I lma) or (in W W » X -Alk -COOR H * 1 232543 - 9 In Schemc 2, the Boc group may be replaced by the benzyloxycarbonyl group or any other N-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 5 replaced by a benzhydryl or trityl group optionally substituted with methoxy on one of the phenyl rings. Deprotection is carried out as described above.

The optically active forms of the compounds of formula (I) may be prepared according to known methods 10 either by the process summarized in Schemc 2 starting from the optically active forms of the compound (Ila), or, by following the process sketched in Scheme 3 and resolving the racemate of the compound (VII), or its benzhydryl or trityl analog optionally substituted with methoxy, or by 15 resolving the racemate of the compound of formula (I), for example by salification with an optically active acid, preferably optically active mandelic acid.

The N-protected 2-amino-7-hydroxytetralin carboxyalkyi ethers of formula (IV) as well as their salts are new 20 compounds and represent the key intermediates in the synthesis of the compounds of formula (I). The present invention includes the individual isomeric forms of the compounds of formula (IV) as well as the mixtures thereof.

The 2-amino-7-hydroxytetralin carboxyalkyi ethers of 25 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 phenylethanolaminotetralins which are endowed with a B-adrenergic receptor agonist activity 30 selective towards the gastro-intestinal tract and are suitable for the preparation of pharmaceutical compositions with spasmolytic activity.

Accordingly, a further specific object of the present invention is the use of the 2-amino-7-hydroxytetralin 35 carboxyalkyi ethers of formula (I) in the preparation of 232543 the corresponding phenylethanolaminotetralins (XII) OH ^H-CH,-NH .O-Alk-COOR of formula (XII) wherein X represents hydrogen, halogen, (C^-C4)alkyl, or trifluoromcthyl, Alk and R arc as defined above, and their pharmaccutically acceptablc salts.

For the preparation of the phcnylethanolaminotetra-lins (XII), the compounds of formula (I) may be reacted with a styrene oxyde of formula (XIII) 0 (XIII) CH CH. wherein 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) OH I CH-COOH X (XIV) wherein X is as defined above, said mandelic acid (XIV) being in racemic or in optically active form, and the amide carbonyl group of the thus obtained intermediate mandelami-de derivatives of formula (XV) OH I CH-CO-NH O-Alk-COOR (XV) wherein X, R, and Alk are as defined above, may be reduced into a methylene group; the obtained compounds (XII) 232543 optionally being converted into the corresponding pharmaceutical^ acceptable salts.

The reaction between the compounds of formula (I) and the styrene oxides of formula (XIII) may be carried out 5 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 epoxyde. The reaction, which is generally complete in a few hours, typically 6 to 2 4 hours, may be carried out at room 10 temperature or, preferably, at higher temperatures, typi cally from 50 to 90 C, to speed up the reaction course.

As "functional derivative" of the acid (XIV), the chloride, the anhydride, a mixed anhydride, an active ester, or a free acid suitably activated, for example with 15 dicyclohexylcarbodiimide or benzotriazolyl-N-oxytris(dime-thylamino)phosphonium hexafluorophosphate (BOP) 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 a mandelic 20 acid (XIV) and a compound (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 obtained mandelamide (XV) is then reduced to the 25 desired compound of formula (XII) by means of diborane or a reagent generating diborane such as the complex between boranc and dimethylsulfide, commonly designated as "borane-methylsulfide". The reduction reaction is carried out in the presence of an organic solvent, e.g. tetrahydrofuran. 30 Independently on the method of synthesis, isolation and purification of the desired product (XII) are carried out according to well known conventional techniques.

It will be appreciated that the compounds of formula (XII) contain two centres of asymmetry at the carbon atoms 35 marked with two asterisks in the above formula. In the preparation of these compounds the use of the single 232543 enantiomcrs of both rcactants (I) and (XIII) or (I) and (XIV) will lead to the pure isomers of the compounds (XII). The reaction involved is stcrcoconscrvative and the same absolute configuration of the two chiral carbon atoms of 5 rcactants (I), (XIII), and (XIV), as assigned by the (R,S) convention, is maintained in the end compound of formula (XII). Using one of the rcactants in racemic form will produce a mixture of two diastcreoisomcrs while using both rcactants in racemic form will afford a mixture of four 10 stereoisomers. Fractional crystallization of the diaste-rcoisomers or chromatography of the mixture may produce compounds which arc enrichcd in one of the possible diaste-reoisomers or even a single stereoisomers.

The enantiomcrs of the compounds of formula (XII) 15 wherein X, Alk, and R arc as defined above, and their pharmaceutically acceptable salts, as well as the mixtures of enantiomers or diastcreoisomers in any proportion represent therefore another object of the present invention.

A preferred group of compounds of formula (XII) comprises those compounds wherein X and R arc as defined above and Alk represents a group -C( R^qR^ )~ or a group Alk^ wherein rh' and Al^ are as defined above, either as pure enantiomers or as mixtures of enantiomers or 25 diastereosiomers in any proportion, and the pharmaceutically acceptable acid addition salts thereof.

An even more preferred group of compounds of formula (XII) comprises those compounds wherein X and R are as defined above and Alk represents a group "c^rioRh^~ 30 wherein R1Q and represent methyl, either as the single enantiomers or as a mixture of enantiomers or diastereoiso-mers in any proportion, and the pharmaceutically acceptable acid addition salts thereof.

The compounds of formula (XII) have shown to be more 35 potent, as B-receptor agonists, and/or more selective towards the gastro-intestinal tract than the corresponding 232543 compound bearing an cthoxycarbonylmcthoxy substituent at the 7-position of the tetralin moiety which has been described in EP-211721. They have a good activity on the intestinal motility and arc useful as spasmolytics. Their 5 toxicity 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 of the mammal to be trea-10 ted, 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 (XII) arc generally administered in unit dosage forms containing of form 0.1 to 150 mg, prefe-15 rably from 1 to 50 mg, 1 to 5 times daily.

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

A further specific object of the present invention is therefore a pharmaceutical composition, comprising, as the active ingredient, a compound of formula (XII) or a pharmaceutically acceptable salt thereof, useful for the treatment of gastrointestinal diseases associated with a con-25 traction of the smooth muscle.

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

The pharmaceutical compositions of 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 inven-35 tion without however limiting it. 232543 PREPARATION I 2-amino-7-hydroxytctraIin hydrobromldo. (a) A mixture of 7-methoxy-2-tetralone (8 g) , benzylamine (4.8 g), anhydrous toluene (150 ml) and p-toluencsulfo-5 nic acid (100 mg) is rcfluxed for 3 hours and then evaporated to dryness. The oily residue is taken up in methanol (100 ml) and sodium borohydride (8.5 g) is cautiously added to the obtained solution kept at 0-5 C. The reaction mixture is then stirred overnight 10 at room temperature, water (50 ml) is added thereto and the mixture is stirred again for 30 minutes. The solvent is evaporated off and the residue is taken up in a mixture of water (30 ml) and concentrated ammonium hydroxide (10 ml). The reaction mixture is extracted 15 with ethyl acetate (200 ml), the organic phase is dried over sodium sulfate, filtered and evaporated to dryness. A dark oil is obtained which is purified by flash chromatography cluting with a mixture ethyl acetate/mc-thanol 95/5. The obtained free base is converted into 20 the corresponding hydrochloride by dissolving it in isopropanol (40 ml) and adding hydrochloric acid saturated isopropanol thereto. 2-Benzylamino-7-methoxy-tetralin hydrochloride (11.4 g) is thus obtained. M.p. 265-267°C (dec.). (b) The above product, dissolved in methanol (200 ml) and water (100 ml), is hydrogenated in the presence of 10 % Pd/C (1.2 g), at a temperature of 45-50°C and atmospheric pressure. After 4 hours the catalyst is filtered off, the filtrate is evaporated to dryness and 30 the obtained residue is twice taken up in absolute ethanol and evaporated to dryness. A white solid is obtained which is taken up in hot isopropanol (70 ml). Upon cooling a precipitate is obtained of 2-amino-7-methoxytetralin hydrochloride (7.8 g). M.p. 214-216°C. 35 (c) A suspension of the compound obtained in step (b) (6.6 g) in 48 % hydrobromic acid (80 ml) is refluxed 232543 for 2 hours. The obtained solution is evaporated to dryness and the residue is twice taken up in absolute ethanol and concentratcd to dryness. An oily product is thus obtained which is dissolved in hot isopropanol 5 (20 ml). Ethyl ether (30 ml) is added thereto and a crystalline precipitate of 2-amino-7-hydroxytetralin hydrobromide (6.8 g) is obtained. M.p. 171-173°C.

PREPARATION II R-2-amino-7-hydroxytetralin monohydrate 10 A solution of (+) mandelic acid (43 g) in absolute ethanol (550 ml) is added to a solution of raw 2-amino-7-methoxyte-tralin free base (50 g) in absolute ethanol (550 ml) (said free base being obtained from the corresponding hydrochloride described in Preparation I step (b) by neutralization 15 with 10 % sodium hydroxide followed by extraction with ethyl acetate and evaporation of the organic solvent). The reaction mixture is kept at room temperature overnight, the obtained precipitate is recovered by filtration and crystallized twice from absolute ethanol, recovering the 20 product which crystallizes upon standing overnight at room temperature. The addition salt of ( + ) 2-amino-7-methoxyte-tralin with (+) mandelic acid (34.2 g, 74 %) is thus obtained. M.p. 190-192°C.

(The mother liquors of the first crystallization are 25 separately recovered and employed in Preparation III below.) The obtained salt (34 g) is suspended in water (300 ml) and the reaction mixture is made basic by the addition of IN sodium hydroxide. The (+) 2-amino-7-methoxytetralin free 30 base is extracted therefrom with ethyl acetate, the organic solvent is evaporated off and the residue is taken up in 48 % hydrobromic acid (260 ml). The reaction mixture is heated to the reflux temperature for 3 hours and then concentrated to dryness under vacuum. The residue is taken 35 up in water (70 ml), the aqueous solution is basified by the addition of concentrated ammonium hydroxide, and cooled 2525 4 overnight; the precipitate is recovered by filtration yielding R-2-ainino-7-hydroxytetralin monohydrate (17 g) .

M.p. 143-144°C; [cl]^ = + 85.1° (c = 0.5 % in methanol). The corresponding hydrochloride has a rotatory power which 5 correponds to that reported in the literature (Molecular Pharmacology, 1982, 22, 281-289).

PREPARATION III S-2-amino-7-hydroxytetralin monohydrate The mother liquors of the first crystallization of the 10 product of Preparation II, which contain the salt of (-) 2-amino-7-methoxytetralin with (+) mandelic acid, are evaporated to dryness, the residue is suspended in water (300 ml) and the reaction mixture is made basic by the addition of IN sodium hydroxide. The free base is extracted 15 with ethyl acetate and the organic solution is then processed as described in Preparation II but using (-) mandelic acid instead of (+) mandelic acid, the yielding the addition salt of (-) 2-amino-7-methoxytetralin with (-) mandelic acid (m.p. 189-191°C) which is neutralized and demethy-20 lated with HBr, affording S-2-aMno-7-hydroxytetralin monohydrate (17 g) . M.p. 143-144°C; [a.]= - 86.9° (c =? 0.5 °i in methanol).

The corresponding hydrochloride has a rotatory power which corresponds to that reported in the literature (Molecular 25 Pharmacology, 1982, 22, 281-289).

PREPARATION IV 2-benzylamino-7-hydroxytetralin A mixture of 2-benzylamino-7-methoxytetralin hydrochloride (2.5 g) described in Preparation I step (a), and 33 % 30 hydrobromic acid in acetic acid (215 ml) in the presence of 48 % hydrobromic acid (36 ml) is refluxed, under stirring, for 2 hours. The reaction mixture is then concentrated to dryness under reduced pressure and the residue is taken up in absolute ethanol (100 ml) and concentrated to dryness. 35 The step of taking up in absolute ethanol and concentrating to dryness is repeated two other times and the thus 232 5 4 3 obtained product is finally triturated with acetone (150 ml) and filtered yielding 2-benzylamino-7-hydroxy-tetralin hydrobromide (25.3 g). M.p. 198-200°C.

This product is then dissolved in hot water (1300 ml), the 5 solution is cooled and concentrated ammonium hydroxide is then added thereto. The free base is extracted with ethyl acetate, the organic solution is dried and the solvent is evaporated off yielding a solid which is crystallized from toluene (250 ml). 2-Benzylamino-7-hydroxytetralin free base 10 (14 g) is thus obtained . M.p. 161-163°C.

PREPARATION V S-2-benzylamino-7-methoxytetralin hydrochloride A solution of (-) mandelic acid (24.5 g) in absolute ethanol (150 ml) is added to a solution of 2-benzylamino-15 7-methoxytetralin free base (44 g), described in Preparation I, step (a), in absolute ethanol (140 ml). The precipitate which forms upon standing at room temperature overnight is recovered by filtration, washed and crystallized twice from absolute ethanol (250 ml) yielding the addition salt of (-) 2-benzylamino-7-methoxytetralin with ?o (-) mandelic acid (33 g). M.p. 155-157°C. fa^365 = "316° (c = 1 % in methanol).

(The mother liquors from the first crystallization are recovered separately and employed in Preparation VII 25 below.) The obtained salt (30 g) is dissolved in water (400 ml) and the aqueous solution is basified by the addition of 32 % ammonium hydroxide. The free base is extracted with ethyl acetate, the organic extract is washed with water, dried 30 over sodium sulfate and concentrated to dryness affording an oily product (20 g) which is dissolved in isopropanol. Upon the addition of hydrogen chloride saturated isopropanol, a precipitate forms which is recovered by filtration, dried (22 g) and crystallized twice from a mixture metha-35 nol/water 1/1 yielding the compound of the title, 232543 S-2-bcnzylamino-7-methoxytetralin hydrochloride. M.p. 287-290°C. [a]^°5 = -231° (c = 1 % in methanol).

Absolute configuration of this compound (S) has been assigned by removing the N-benzyl group and comparing the 5 rotatory power of the thus obtained product with that known in the literature.

PREPARATION VI S-2-benzylamino-7-hydroxytetraIin hydrobromide A solution of S-2-benzylamino-7-methoxytetralin hydrochlo-10 ride (15 g) in a mixture of 33 % hydrobromic acid in acetic acid (100 ml) and 48 % hydrobromic acid (100 ml) is reflu-xed under stirring for 3 hours. The obtained solution is evaporated to dryness under reduced pressure and the residue is taken up in absolute ethanol and the ethanol 15 solution is evaporated to dryness. The step of taking up the residue in absolute etahnol and concentrating to dryness the ethanol solution is repeated three times. The oily residue thus obtained is dissolved in hot acetone and crystallized therefrom. The precipitate is recovered by 20 filtration, washed with acetone and ethyl ether and dried yielding S-2-bcnzylamino-7-hydroxytetralin hydrobromide (17 g). M.p. 198-202°C. [^365 = "201.7° (c = 1 % in methanol).

PREPARATION VII 25 R-2-benzylamino-7-methoxytetralin hydrochloride The mother liquors from the first crystallization of the addition salt of (-) 2-benzylamino-7-methoxytetralin with (-) mandelic acid (Preparation V) are concentrated to dryness and the obtained residue is dissolved in water 30 (400 ml). The aqueous solution is basified by the addition of 32 % ammonium hydroxide and the free base is extracted therefrom with ethyl acetate. The organic extract is washed with water, dried over sodium sulfate and concentrated to dryness- The residue is dissolved in ethanol and a solution 35 of ( + ) mandelic acid (12.5 g) in absolute ethanol (75 ml) is added thereto. The precipitate which forms upon standing 232543 at room temperature overnight is recovered by filtration, washed and crystallized three times from absolute ethanol yielding the addition salt of (+) 2-bcnzylamino-7-methoxy- tetralin with ( + ) mandelic acid (24 g). M.p. 152-154°C. ^a^365 = (c = 1 % in methanol).

The obtained salt (20 g) is dissolved in water (300 ml) and the aqueous solution is basified by the addition of 32 % ammonium hydroxide. The free base is extracted with ethyl acetate, the organic extract is washed with water, dried 10 over sodium sulfate and concentrated to dryness. The residue is dissolved in isopropanol and hydrogen chloride saturated isopropanol is then added thereto to precipitate raw R-2-benzylamino-7-methoxytetralin hydrochloride which is recovered by filtration, dried and crystallized twice from a mixture methanol/water 1/1. M.p. 278-282°C. ? o ^a^365 = +229.9° (c = 1 % in methanol).

PREPARATION VIII R-2-benzvlamino-7-hydroxytetralin hydrobromide A solution of R-2-bcnzylamino-7-methoxytetralin hydrochlo-20 ride (15 g) in a mixture of 33 % hydrobromic acid in acetic acid (100 ml) and 48 % hydrobromic acid (100 ml) is reflu-xed under stirring for 3 hours. The obtained solution is evaporated to dryness under reduced pressure and the residue is taken up in absolute ethanol and the ethanol solu-25 tion is evaporated to dryness. The step of taking up the residue in absolute ethanol and concentrating to dryness the ethanol solution is repeated three times. The obtained residue is dissolved in hot acetone and crystallized therefrom. The precipitate is recovered by filtration, washed 30 with acetone and ethyl ether and dried yielding R-2-benzyl-amino-7-hydroxytetralin hydrobromide (15.5 g). M.p. 198-202°C. [a]3°5 = +198-4° (c = 1 % in methanol). 232 5 4 3 Example 1 2-benzylamino-7-(ethoxycarbonylpentan-5-yIoxy)tetralin hydrochloride A mixture of 2-benzylamino-7-hydroxytetralin free base (8 g), described in Preparation IV, and 55 % sodium hydride (1.7 g) in toluene (250 ml) is maintained under a nitrogen stream and heated to 70°C for 30 minutes. The reaction mixture is allowed to cool to room temperature and a mixture of 6-bromohexanoic acid ethyl ester (10.5 g) and tctrabutylammonium bromide (0.5 g) in toluene (200 ml) is slowly dripped in. After refluxing for 8 hours, the reaction mixture is cooled to room temperature and water (100 ml) is added thereto. The organic phase is separated, washed with 3N sodium hydroxide, dried and concentrated to dryness. The obtained residue is dissolved in isopropanol and hydrogen chloride saturated isopropanol is then added thereto to precipitate the compound of the title (8.9 g) M.p. 140-142°C.

Example 2 2-amino-7-(ethoxycarbonylpentan-5-yloxy)tetralin hydrochloride A solution of 2-benzylamino-7-(ethoxycarbonylpentan-5-yloxy)tetralin hydrochloride (8.9 g), prepared as described in Example 1, in 95 % ethanol (150 ml) is hydrogenated at atmospheric pressure and 60°C in the presence of 10 % Pd/C (1 g) as the hydrogenation catalyst. After 3 hours the catalyst is filtered off, the filtrate is concentrated to dryness and the residue is twice taken up in absolute ethanol (100 ml) and concentrated to dryness. The obtained product is then triturated with acetone (100 ml), filtered and crystallized from isopropanol (50 ml) affording 5.5 g of the compound indicated in the title. M.p. 114-117°C. Example 3 2-benzylamino-7-(ethoxycarbonylpropan-3-yloxy)tetralin hydrochloride ***** 232543 A mixture of 2-benzylamino-7-hydroxytetralin free base (15 g), described in Preparation IV, and 95 % sodium hydride (2.8 g) in toluene (400 ml), maintained under a nitrogen stream, is heated to 70°C for 30 minutes. The 5 reaction mixture is allowed to cool to room temperature and a mixture of 4-bromobutanoic acid ethyl ester (9.2 ml) and tetrabutylammonium bromide (0.5 g) in toluene (200 ml) is slowly dripped in. After heating at 90°C for 8 hours, the reaction mixture is cooled to room temperature and extrac-10 ted twice with ethyl ether (100 ml). The organic phase is washed with a mixture of 0.IN sodium hydroxide and water and concentrated to dryness. The residue is dissolved in isopropanol (100 ml), activated charcoal is added to the obtained solution and the suspension is filtered. The 15 filtrate is acidified by the addition of hydrogen chloride saturated isopropanol to precipitate the compound of the title (14 g) M.p. '75-177° C.

Example 4 2-amino-7-(ethoxycarbonylpropan-3-yloxy)tetralin hydrochlo-20 ride A solution of 2-benzylamino-7-(ethoxycarbonylpropan-3-yloxy)tetralin hydrochloride (14 g), prepared as described in Example 3, in a mixture of 95 % ethanol (250 ml) and water (10 ml) is hydrogenated at atmospheric pressure and 25 60°C in the presence of 10 % Pd/C (2 g) as the hydrogenation catalyst. After 5 hours the catalyst is filtered off, the filtrate is concentrated to dryness and the residue is taken up in absolute ethanol (100 ml) and concentrated to dryness a few times. The obtained product is then tritura-30 ted with acetone, filtered and crystallized from isopropanol affording 8.8 g of the compound of the title. M.p. 134-136°C.

Example 5 2-benzylamino-7-(ethoxycarbonylbutan-4-yloxy)tetralin 35 hydrochloride 232543 A solution of 2-bcnzyla.Tuno-7-hydroxytctralin free base (10 g), prepared as described in Preparation IV, and 80 % sodium hydride (1.6 g) in dimothylsulfoxide (140 ml) is stirred at room temperature, under a nitrogen stream, for 5 30 minutes. A catalytic amount of potassium iodide and 5-bromovaleric acid ethyl ester (10.45 g) are added to the reaction mixture and stirring at room temperature is continued for 17 hours. Ice/water (400 ml) is then added thereto and the reaction mixture is extracted with ethyl 10 acetate. The organic phase is washed with 2N NaOH and then with water, dried over sodium sulfate and concentrated to dryness under vacuum. The residue is dissolved in isopropanol and the compound of the title is precipitated from the obtained solution by the addition of hydrogen chloride 15 saturated isopropanol and crystallized from isopropanol (100 ml). Yield : 10.7 g. M.p. 154-156°C.

Example 6 2-amino-7-(ethoxycarbonylbutan-4-yloxv)tetralin hydrochlo-ri dc A solution of 2-bcnzylamino-7-(ethoxycarbonylbutan-4-yloxy)tetralin hydrochloride (10.7 g), prepared as described in Example 5, in 95 % ethanol (250 ml) and water (25 ml) is hydrogenatcd at 60°C and atmospheric pressure using 10 % Pd/C (1.2 g) as the hydrogenation catalyst. 25 After 6 hours the catalyst is filtered off, the filtrate is concentrated and the residue is taken up in absolute ethanol and concentrated to dryness a few times. The obtained product is then triturated with ethyl ether and filtered. The residue is crystallized from isopropanol 30 yielding 8 g of the compound indicated in the title. M.p. 131-133 °C.

Example 7 2-BenzyIamino-7-(2-carboxy-propan-2-yloxy)tetralin and 2-Benzylamino-7-(2-ethoxycarbonyl-propan-2-yloxy)tetralin oxalate 232543 A solution of 2-benzylamino-7-hydroxytetralin free base (19 g) prepared as described in Preparation IV and 1,1,1-trichloro-2-methyl-2-propanol (26.6 g) in acetone (500 ml) is stirred at room temperature for 15 minutes. The reaction mixture is then cooled to 15°C, potassium hydroxide (10.9— g) is added thereto and the reaction mixture is stirred at room temperature for 2 hours. Two additional portions of potassium hydroxide (10.9 g + 10.9 g) arc then added thereto and the obtained reaction mixture is stirred at room temperature overnight, and then concentrated to dryness under reduced pressure. Ice/water (250 ml) is the added and the solution is washed with ethyl ether, decolorized with activated charcoal and acidified by the addition of HCl up to pH 5-6. The precipitated 2-benzylamino-7-(2-carboxy-propan-2-yloxy)tetralin is recovered by filtration (14 g) and added to a solution of thionyl chloride (3.6 ml) in absolute ethanol (100 ml). The mixture is heated to the reflux temperature for 4 hours and then concentrated to dryness. A mixture of ice/water is added thereto and the solution is made basic by the addition of ammonium hydroxide. The solution is extracted with ethyl acetate, the organic extract is dried and concentrated to dryness. The obtained free base is dissolved in acetone and oxalic acid is added thereto. The precipitate is recovered by filtration and crystallized from 95 % ethanol (180 ml), yielding 11.3 g of 2-benzylamino-7-(2-ethoxycarbonyl-propan-2-yloxy)tetralin oxalate. M.p. 174-176°C.

A small sample of the above obtained 2-benzylamino-7-(2-carboxy-propan-2-yloxy)tetralin has been washed with water, treated with acetone and dried. M.p.240-242°C.

Hydrogenation of said acid by the procedure described in Example 2 affords the corresponding deprotected 2-amino-7-(2-carboxypropan-2-yloxy)tetralin.

Example 8 2-amino-7-(2-ethoxycarbonylpropan-2-yloxy)tetralin oxalate 232543 A solution of 2-benzylamino-7-(2-ethoxycarbonyl-propan-2-yloxy)tetralin free base (9.1 g), prepared as described in Example 7, in 95 % ethanol (100 ml) and hydrochloric acid (4 ml) is hydrogenated at 60°C and atmospheric pressure using 10 % Pd/C (1 g) as the hydrogenation catalyst. After 4 hours the catalyst is filtered off, the filtrate is concentrated and the residue is taken up in absolute ethanol and concentrated to dryness a few times. The obtained product is then dissolved in diluted ammonium hydroxide and extracted with ethyl ether. The organic phase is dried and concentrated to dryness and the residue is purified by flash chromatography eluting with a mixture methylene chloride/ethanol 8/2. The fractions containing the desired product are pooled together and concentrated to dryness. The residue is dissolved in acetone and oxalic acid is added to precipitate the compound of the title which is then crystallized from acetone (10 ml) yielding 0.66 g. M.p. 140-142°C.

Example 9 S-2-Benzvlamino-7-(2-ethoxycarbonylpropan-2-yloxy)tetralin hydrochloride > i _ ■ .

The compound of the title has been prepared by following substantially the same procedure as in Example 7 but starting from S-2-benzylamino-7-hydroxytetralir. free base (prepared from the corresponding hydrobromide described in preparation VII by dissolving the hydrobromide in water, basifying the aqueous solution by the addition of concentrated ammonium hydroxide, extracting the free base with ethyl acetate and evaporating off the organic solvent). At the end of this procedure, the free base so obtained is dissolved in isopropanol and isopropanol saturated with hydrochloric acid is added to precipitate the hydrochloride which is separated by filtration and crystallized from isopropanol . - 156.2° (c = 0.5% in methanol). M.p. 152-154°C. 232543 Example 10 R-2-Benzylamino-7- (2-ethoxycarbonvlpropan-2-yloxy)tetralin hydrochloride The compound of the title has been prepared by following substantially the same procedure as in Example 7 but 5 starting from R-2-benzylamino-7-hydroxytetralin free base (prepared from the corresponding hydrobromide described in Preparation VIII by dissolving the hydrobromide in water, basifying the aqueous solution by the addition of concentrated ammonium hydroxide, extracting the free base with 10 ethyl acetate and evaporating off the organic solvent). At the end of this procedure, the free base so obtained is dissolved in isopropanol and isopropanol saturated with hydrochloric acid is added to precipitate the hydrochloride which is separated by filtration and crystallized from 15 isopropanol.

ZX/ijgs = + 158.4° (c = 0.5% in methanol); M.p. 1 48- 1 50°C. 26 - Example 11 S-2-amlrto-7- f 2-ethoxycarbonylpropan-2-yloxy) tetralin oxalate The compound of the title has been prepared by following 5 substantially the same procedure as in Example 8 but starting from the compound obtained in Example 9.

C ct- 3 355 = ~ 140.4° (c = 1% in methanol); M.p. 132-1 34 3C. Example 12 R-2-amino-7-(2-ethoxycarbonylnrooan-2-vloxv)tetralin 10 oxalate The compound of the title has been prepared by following substantially the same procedure as in Example 8 but starting from the compound obtained in Example 10. [a]^55 = + 140.9° (c = 1% in methanol) ; M.p. 131-134°C. 1 5 Example 13 N-f*l-(ethoxvcarbonylbutan-4-yloxv)-1,2,3,4-tetrahvdronaoht-h-2-yl_7-2-hvdroxy-2-(3-chloroohenvl)ethanamine hydrochloride A solution of 2-amino-7-(ethoxycarbonylbutan-4-yloxy)tetra-20 lin free base (5 g) (obtained by dissolving the corresponding hydrochloride, prepared as described in Example 6, in water, making the aqueous solution basic by the addition of concentrated ammonium hydroxide, extracting the free base with ethyl acetate and evaporating off the solvent) and 25 3-chlorostyrene oxide (4.6 g) in anhydrous djjnethylsulfoxi-de (15 ml) is heated to 80°c under stirring and under a nitrogen stream, for 11 hours. After standing at room temperature overnight the reaction mixture is poured into a mixture ice/water and extracted with ethyl acetate. The 30 organic phase is washed with water, dried over sodium wAR 1992 v- 232543 sulfate and concentrated to dryness. The obtained residue is dissolved in ethyl ether and hydrogen chloride saturated isopropanol is added thereto. The precipitate is recovered by filtration, dried and crystallized twice from isopropa-5 nol (40 ml) affording 3.9 g of the compound of the title. M.p. 127-130°C.

Example 14 N-/f7-(ethoxycarbonylpcntan-5-yloxy)-1,2,3,4-tetrahydronaph-th-2-yl7~2-hydroxy-2-(3-chlorophenyl)ethanaminc hydrochlo-10 ride A solution of 2-amino-7-(ethoxycarbonylpentan-5-yloxy)-tetralin free base (4.2 g), obtained from the corresponding hydrochloride, prepared as described in Example 2, by neutralization and trimethylsilylacetamide (2.4 g) in 15 anhydrous dimethylsulfoxide (10 ml) is stirred at 25°C for 20 minutes. 3-Chlorostyrcne oxide (3.6 g) is then added thereto and the reaction mixture is heated to 80°C for 9 hours and then poured into water (100 ml) containing concentrated hydrochloric acid (3 ml). Ethyl acetate 20 (50 ml) is added and the obtained mixture is stirred for 1 hour. The aqueous phase is separated and washed with ethyl acetate (2 x 50 ml); the organic washings are combined with the separated organic phase, washed with water, diluted ammonium hydroxide, and water. The washed organic phase is 25 then dried and concentrated to dryness. The residue is purified by flash chromatography eluting with ethyl acetate. The product obtained by evaporating off the solvent in the recovered fractions is dissolved in isopropyl ether (100 ml) and hydrogen chloride saturated isopropanol is 30 then added thereto. The oily product which separates solidifies upon standing and is therefore recovered by filtration (3.9 g). Crystallization from isopropanol (20 ml) affords 2 g of the compound of the title. M.p. 109-112°C. 232543 Example 15 N-/7- (cthoxvcarboriylpropan-3-yloxY) -1,2,3, 4-tetrahydronaph-th-2-y17-2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride A mixture of 2-amino-7-(ethoxycarbonylpropan-3-yloxy)tetralin free base (5.3 g), obtained by neutralization of the corresponding hydrochloride, prepared as described in Example 4, and N-trimethylsilylacetamide (2.75 g) in anhydrous dimethylsulfoxide (10 ml) is charged into a 10 reaction vessel under anhydrous conditions and kept at 25°C for 20 minutes under a nitrogen stream. 3-Chlorostyrene oxide (3 g) is 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 15 water and extracted with ethyl acetate.The organic phase is thoroughly washed with water, dried and concentrated to dryness. The obtained residue is dissolved in isopropanol and hydrogen chloride saturated isopropanol is then added thereto. The precipitate is recovered by filtration and 20 crystallized from isopropanol (80 ml) yielding 4.4 g of the . compound of the title. M.p. 156-158°C.

Example 16 N-Z7-(2-cthoxycarbonyl-propan-2-yloxy)-1,2,3,4-tetrahydron-aphth-2-yl7-2-hydroxv-2-(3-chlorophenyl)ethanamine hydro-25 chloride A mixture of 2-amino-7-(2-ethoxycarbonyl-propan-2-yloxy)-tetralin free base (3.2 g), obtained by neutralization of the corresponding oxalate prepared as described in Example 8 and N-trimethylsilylacetamide (2.5 g) in anhydrous 30 dimethylsulfoxide (10 ml) is stirred at room temperature, under a nitrogen stream and anhydrous conditions for 20 minutes. 3-Chlorostyrene oxide (2.8 g) is then added thereto and the reaction mixture is heated to 80"C for 8 hours, allowed to stand at room temperature overnight, 35 treated with an additional amount of 3-chlorostyrene oxide (1.0 g), heated to 80°C for further 5 hours and then poured 232543 into ice/water (150 ml). Concentrated hydrochloric acid (a few mis) and ethyl acetate (100 ml) arc added thereto and the obtained mixture is stirred at room temperature for 1 hour. The two phases are separated, the aqueous one is 5 washed with ethyl acetate (2 x 50 ml) and the organic washings are combined with the separated organic phase, washed sequentially with water, diluted ammonium hydroxide, and water, dried and concentrated to dryness yielding an oily product (6.6 g) which is purified by flash chromato-10 graphy eluting with ethyl acetate. The thus purified product is converted into the corresponding hydrochloride by dissolving it in isopropyl ether and making the obtained solution acidic by the addition of hydrogen chloride saturated isopropanol. Upon standing a precipitate forms 15 which is recovered by filtration and crystallized twice from isopropyl alcohol affording 1 g of the compound of the title. M.p. 142-144°C.

Example 17 N-Z~( 2S) -7- ( 2-ethoxycarbonyl-propan-2-yloxy)-1,2,3, 4-tetra-20 hydronaphth-2-y17-(2R)-2-hvdroxv-2-(3-chlorophenyl)ethan-amine hydrochloride The compound of the title has been prepared by following substantially the same procedure as in Example 16 but starting from (R)-3-chlorostyrene oxide and S-2-amino-7- (2-ethoxycarbonylpropan-2-yloxy)tetralin free base obtained by neutralization of the corresponding oxalate prepared in Example 11. ^365 = ~ 270° (c = 1% in methanol) ; M.p. = 206-208°C Example 18 N-/~( 2R) -7-( 2-ethoxycarbonyl-propan-2-yloxy) -1,2,3 ,4-tetra-hydronaphth-2-yl7~(2R)-2-hydroxy-2-(3-chlorophenyl)ethan-amine hydrochloride The compound of the title has been prepared by following substantially the same procedure as in Example 16 but 35 starting from (R)-3-chlorostyrene oxide and R-2-amino-7-(2-ethoxycarbonylpropan-2-yloxy)tetralin free base obtained

Claims (6)

232543 by neutralization of the corresponding oxalate prepared in Example 12. r„i20 - ^ J365 ~ + 125.7 (c = 1 in methanol) A. p. 109-112°C The compounds of Examples 13 and 16 have been evaluated in the isolated rat colon test, carried out according to the method described in EP-A-255415. The activity of said compounds expressed as shown to be higher than that of N-£?-(ethoxycarbonylmethoxy)-l,2,3,4-tetrahydro-naphth-2-yl7-2-hydroxy-2-(3-chlorophenyl)ethanamine oxalate described in Example 11 of EP-A-211721. ^,-aaiS r -■ t ; . j , ) - 31 - WHAT tfvVE CLAIM IS:- 10 15 20 25 30

1. A 2-ajnino-7-hydroxy:;etralin carboxyalkyi ether of formula (I) -C-Alk-COOR or wherein Alk represents a straight or branched alkylene chain, and R represents hydrogen or alky 1, or a salt thereof. A compound according to claim 1 wherein Alk represents «VC5>- 'W" a) a group -CH- k ?2 RA 1 4 R. 1 0 R' 7 1

2 R' A 1 4 R 1 C — | -C — 1 .r- - r 1 -C 1 -c— 1 -c R3 R5 R7 R,3 R' 5 I R r< a i 8 C-, or R' -(CH2)5- wherein R^ is ethyl, propyl or butyl, R2 to R~ are all hydrogen atoms or one of R£ to is a methyl or ethyl group and the others hydrogen atoms, or two of to R^ are methyl groups and the others are hydrogen atoms, and R? are 2 to R'g are all hydrogen atoms or one of R' R'g is a methyl group and the others are hydrogen atoms; R, b) a group 1 RI1 wherein. R 110 -C- 10 and R.j .J are independently methyl or ethyl or pr 12 R^ is alsq^ propyl and is methyl; or c) a group -CH—CH— R, wherein l13 3o»ari99. 23254 3 - 32. - one of R12 and R13 is hydrogen and the other is methyl, ethyl or propyl, or one of R12 and R13 is methyl and the other is methyl or ethyl.

3. A compound according to claim 2 wherein Alk represents R0 R, Rc l 2 i 4 | 6 R' , 1 2 R' A 1

4 R' I 6 1 8 -C | -c 1 -c- 1 -C-, -CCH2)5-, or R' 3 R' 5 1 R' 7 R 9 a group -CH- , -C—C—C-, i ill R1 R3 R

5 R7 R10 -C-i Rll_ wherein to ^ R*2 are as defined in claim 2. . A compound according to claim 3 which is selected from the group consisting of 2-amino-7-(1-ethoxycarbonyl-propan-3-yloxy) tetralin, 2-amino-7-( 1-ethoxycarbonylbu-tan-4-yloxy ) tetralin, 2-amino-7- (1-ethoxycarbonylpentan-5-yloxy) tetralin, 2-amino-7-(2-ethoxycarbonylpropan-2-yloxy)tetralin, and salts thereof. , A process for the preparation of a 2-amino-7-hydroxytetralin carboxyalkyi ether of formula (I) - O-Alk-COOR (I) wherein Alk and R are as defined in claim 1, or a salt thereof, which comprises (A) submitting a N-protected 2-amino-7-hydroxytetralin of formula (II) R'NH A ^OH (II) wherein R' is an amino-protecting group which may suitably be removed by catalytic hydrogenation or mild acidic hydrolysis, to a reaction with a compound of formula (Ilia) Hal-Alk1~COOR ;■ • ... (Ilia) 23 JUFi 1392 wherein R is as defined above, Hal represents chloro, bromo or iodo, and Alk^ represents a group -<pH- wherein R1 may represent ethyl, propyl or butyl, R2 to R-j are all hydrogen atoms or one of R., to is a methyl or ethyl group and the others are hydrogen atoms, or two of R2 to are methyl groups and the others are hydrogen atoms/ and R'2 are all hydrogen atoms or one of R2 to Rg is a methyl group and the others are hydrogen atoms in the oresence of a basic condensation acent, or - a compound of formula (Illb) wherein R10 represents methyl or ethyl, and R^ is methyl, ethyl or, when R^q is methyl, propyl; in the presence of a strong base, optionally followed by reaction of the obtained product with thionyl chloride in the suitably selected (C1-C4)alkanol, or a compound of formula (IIIc) *12 C=C-CCOR (IIIc) wherein 232543 34 one of R^2 and R^3 hydrogen and the other .is methyl, ethyl or propyl, or one of R12 and R., 3 is methyl and the other is methyl or ethyl, optionally in the presence of catalytic amounts of a quaternary ammonium hydroxide, to get a N-protected 2-amino-7-hydroxytetralin of formula (IV) wherein R', Alk, and R are as defined above, and (3) removing the N-protecting group by catalytic hydrogenation or mild acidic hydrolysis and, after optional saponification of the (C^-C^)alkoxycarbonvl group to carboxy, isolating the compound of formula (I), as the free base or a salt thereof, and optionally converting it into one of its salts. The process of claim 5 wherein the N-protecting group is selected from the group consisting of tert-butoxy-carbonyl, benzyloxycarbonyl, and optionally methoxy-substituted benzyl, benzhydryl, and trityl. A N-protected 2-amino-7-hydroxytetralin carboxyalkyi ether of formula (IV) wherein R', Alk, and R are as defined in claim 5, or a salt thereof. A compound according to claim 7 wherein R' is as defined in claim

6. A compound according to claim 8 which is selected from the group consisting of 2-benzylamino-7-(l-ethoxycarbon-ylpropan-3-yloxy) tetralin, 2-benzy lamino-7- (1-ethoxycar-bonylbutan-4-yloxy) tetralin, 2-benzylamino-7-( 1-ethoxy-carbonylpentan-5-yloxy)tetralin, 2-benzylamino-7-(2- (IV) R'N*^ O-Alk-CCOR (iv) ! n.z. pat " "] l 23 JUi'I 1S92 ! - 35 - ethoxycarbonyIpropan-2-yloxy)tetralin, and salts thereof. A phenylethanolaminotetralin derivative of formula (XII) OH ch-ch2-nh O-Alk-COOR O or (XII) X wherein X represents hydrogen, halogen, (C^-C^)alkyl, trifluoromethyl, R represents hydrogen or a (C.-C.)alky! group, J. 4 and Alk is as defined in any one of claims 1 to 3 and the pharmaceutically acceptable salts thereof. A process for preparing a phenylethanolaminotetralin of claim 10 which comprises reacting a compound of formula (i) 0-Alk-COOR (I) wherein Alk represents a straight or branched (C^-C-)-alkylene chain, and R represents hydrogen or (C^-C^)-alkyl with - a styrene oxide of formula (XIII) ^O. ch ch- (XIII) wherein X is as defined above, or with - a functional derivative of a mandelic acid of formula (XIV) 232543 - 36 ~ 10 15 20 25 30 35 12 13 X oh I ,CH-COOH (xiv) wherein X is as defined above, and reducing the amide carbonyl group of the thus obtained intermediate mandelamide derivative of formula (XV) oh <!:h-co-nh O-Alk-COOR [XV) wherein X, R, and Alk are as defined above, into a methylene group, and optionally converting the obtained compound into a corresponding pharmaceutically acceptable salt. A compound as in claim 10 wherein Alk represents a group ?10 -c- l R11 . wherein -ch-I R, R0 R. Rc I2 |4 ,6 c-r<r r5 r7 R' R» I 2 | 4 R I R' -C- t R' I 6 -C— I R' D ' i 8 -c-, -(ch2)5-, R'g r, may represent ethyl, propyl or butyl, to are all hydrogen atoms or one of R2 to R^ is a methyl or ethyl group and the others are hydrogen atoms, or two of R2 to R7 are methyl groups and the others are hydrogen atoms, R'2 to R'g are all hydrogen atoms or one of R'2 to R'g is a methyl group and the others are hydrogen atoms , R^q represents methyl or ethyl, and R^1 is methyl, ethyl or, when R1Q is methyl, propyl. A compound as in claim 12 wherein Alk represents a group \! z. PA-I - ■ * 23 JUf; 1S92 232543 — 32 — T7~ 110- -c=~ I: Rii wherein R^q and are as defined' in claim" 12". 5 1*4 . A compound according to claim 10 which is N-/7-(1-ethoxv-carbor.ylbutan-4-ylojcy) -1, 2,3", 4-tetrahydronaphth-2-yl7-2-'nydroxy-2-(3-chlorophenyl)ethanamine and the pharmaceutically acceptable salts thereof. 15". A" compound" as in claim 10 which is N-£7- (1-ethoxycarbon- 10 ylpropan-3-yloxy)-1,2,3,4-tetrahydronaphth-2-yl7~2- hydroxy-2-(3-chlorophenyl)ethanamine and the pharmaceutically acceptable salts thereof.

16. A compound as in claim 10 which is H-/J-(1-ethoxycarbon-ylpentan-5-yloxv)-1,2,3,4-tetrahydronaphth-2-vl/-2- 15 hydroxy-2-(3-chlorophenyl)ethanamine and the pharmaceu tically acceptable salts thereof.

17. A compound as in claim 10 which is N-/7-(2-ethcxycar-bonylpropan-2-yloxy) -1, 2', 3,4-tetrahydronaphth-2-yl7-2-hydro:<y-2-( 3-chlorophenyl)ethanamine and the pharmaceu- 20 tically acceptable salts thereof.

13. A pharmaceutical composition containing a compound of claim 10 as the active ingredient for the treatment of gastrointestinal diseases.

19. A carboxylakyl ether as claimed in claim 1 or claim 7, substantially as herein described.

20. A carboxylakyl ether as claimed in claim 1 or claim 7, substantially as described in any Example thereof.

21. A process as claimed in claim 5 or claim 11/ substantially as herein described.

22. A process as claimed in claim 5 or claim 11, substantially as described in any one of the Preparation Examples.

23. A derivative as claimed in Claim 10, substantially as herein described.

24. A pharmaceutical composition as claimed ir. claim 13, substantially as herein described. ... SANOPI PA'i ; , 23 JUW 1992 3v Their Attorneys BALDWIN SON & CAREY %