IE894099L

IE894099L - Aryloxypropanolaminotetralins, a process for their¹preparation and pharmaceutical compositions containing them

Info

Publication number: IE894099L
Application number: IE894099A
Authority: IE
Inventors: Umberto Guzzi; Marco Baroni; Sergio Boveri; Luciano Manara; Alberto Bianchetti
Original assignee: Synthetic Ind Ltd
Priority date: 1988-12-23
Filing date: 1989-12-20
Publication date: 1990-06-23
Also published as: FR2640969B1; FR2640969A1; IE63769B1; PT92671B; DE68906519D1; JPH02275844A; DK645589D0; EP0375560A1; DK645589A; DE68906519T2; PT92671A; ATE89261T1; EP0375560B1; JP2818829B2

Abstract

The present invention relates to aryloxypropanolaminotetralins possessing beta-antagonist activity, of the formula <IMAGE> in which R represents hydrogen, a hydroxyl group or a methoxy group and Ar represents an optionally substituted aromatic or heteroaromatic group, in an optically active or inactive form, as well as their salts with inorganic or organic acids. It also relates to a process for the preparation of these compounds and to the pharmaceutical compositions in which they are present.

Description

P5 . * . i 40 63769 ♦ l-fo'i *7 J % 9 - ARYLOXYPROPANOLAMINOTETRALINS. A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM The present invention relates to beta-antagonists aryloxypropanolaminotetralins and salts thereof, a process for their preparation and pharmaceutical compositions containing said aryloxypropanolaminotetralins or their pharmaceutically acceptable salts, as active ingredients.

It is known that beta-receptors are ubiquitous in the organism and that blockade of said receptors may affect several organs and metabolic systems.

The known beta-antagonists which inhibit the action of catecholamines on the beta-receptors of the cardiovascular tissue, have been put into medical use for the treatment of cardiovascular diseases, mainly as antihypertensive or antiarrhythmic drugs.

Beta-receptors are however present also in the trachea as well as in the bronchi and therefore beta-antagonists may elicit a constriction of the above airways. For this reason, prior research efforts have been directed to the development of cardioselective beta-antagonists devoid of respiratory side-effects.

Beta-adrenergic receptor antagonists have been proposed also for the treatment of diseases other than the cardiac ones, such as thyrotoxicosis, hyperparathyroidism, glaucoma, migraine and anxiety. In these cases not only any action on the trachea, but also on the heart represents an unwanted side-effect.

It is also known that beta-adrenergic receptors are present in the intestin and that both beta-agonists and beta-antagonists affect intestinal motility.

Finally it is also known (EP-B-0211721 and EP-A-0255415) that some phenylethanolaminotetralins have an intestinal, selective, beta-agonist activity which does not affect the heart or the trachea.

It has now been found that by replacing the alkyl or aralkyl substituent of the amino group in the conventional beta-blocker aryloxypropanolamines with a tetralin, either a tetralin-l-yl or a tetralin-2-yl group, compounds are obtained which, while retaining a beta-antagonist activity have a reduced activity on the heart.

It has also been found that, the thus obtained aryloxypropanolaminotetralins have a higher beta-antagonist £37 69 2 activity on the gastro-intestinal tract and a reduced activity or no activity at all on the cardiac tissue and the trachea.

Accordingly, the present invention concerns, according to one of its aspects, aryloxypropanolaminotetralins of formula: wherein R represents hydrogen, a hydroxy group or a methoxy group, and Ar represents an optionally substituted aromatic or heteroaromatic group, and their pharmaceutically acceptable or not acceptable salts with mineral or organic acids.

In particular, in formula (i), Ar is an optionally substituted mono-, di- or tri-cyclic aromatic or heteroaromatic group wherein a carbon atom of the aromatic carbocyle or aromatic heterocycle is directly linked to the oxygen.

More particularly, in formula (i) Ar represents an aromatic or heteroaromatic group of one of the beta-antagonist aryloxypropanolamine molecules. Typically, Ar is the etherifying residue of the 3-positioned hydroxy group of a N-substituted l-amino-2,3-propanediol, the said N-substituted propanediol having a beta-blocking adrenergic activity.

Mono-, di- and tri-cyclic aromatic groups include, among others, such radicals as optionally substituted phenyl, naphthyl, 5,6-, 5,8- and 7,8-dihydronaphthyl, 5,6,7,8-tetrahydronaphthyl, 5,8-ethano-5,6,7,8- tetrahydronaphthyl, ,8-methano-5,6,7,8-tetrahydronaphthyl, 9,10-dihydro-9,10-ethano(or etheno) anthryl and fluorenyl.

Mono-, di- and tri-cyclic heteroaromatic groups include either the phenyl radical fused to a 5 or 6-membered heterocycle containing 1,2 or 3 heteroatoms selected from the oxygen, nitrogen, and sulfur atoms, said heterocycle in its turn being optionally fused to another benzene ring, or the phenyl radical fused to both a furan a a pyran ring, or fused to the pyrrole of a 3 tetrahydropyrido(3,4-c)pyrrole; or 5- or 6-membered heterocyclic radicals containing 1,2,3 or 4 heteroatoms selected from the oxygen, nitrogen and sulfur atoms, optionally fused to a benzene ring, said fused radicals and ring being optionally substituted. 5 More particularly, the radical Ar may represent a phenyl group, which may be unsubstituted or optionally bear one or more substituents. As substituents there may be cited: halogen, cyano, hydroxy, amino, formyl, nitro, carboxyl, carbamoyl, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, binycloalkyl, alkanoyl, 10 alkoxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxyalkoxy, alkenyloxy, alkenyloxyalkyl, alkynyloxy, alkynyloxyalkyl, cycloalkoxv, alkylthio, alkylthioalkyl, morpholino, acylamino, acylaminoalkyl, acyloxy, alkoxycarbonyl, cycloalkoxycarbonyl, aminocarbonylamino, aminocarbonylaminoalkyl, 15 dialkylaminocarbonylalkyl, dialkylaminocarbonylalkoxy, in the last two groups the terminal alkyl groups, together with the nitrogen atom, may also form a cyclic group containing 4 or 5 carbon atoms, cycloalkylaminocarbonylamino, alkylaminocarbonylaminoalkyl, cycloalkylaminocarbonylaminoalkyl, alkoxycarbonylaminoalkyl, 20 cycloalkoxycarbonylaminoalkyl, carbamoylalkyl, alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl or an alkylaminocarbonylalkoxy group.

The radical Ar may also represent a group thiadiazolyl, naphthyl, indenyl, indolyl, indazolyl, imidazolyl, benzimidazolyl, 25 benzotriazolyl, benzofuranyl, benzodioxolyl, benzothienyl, benzothiazolyl, benzisothiazolyl, quinolyl, isoquinolyl, benzodiazinyl, benzothiinyl, benzothiazinyl, benzothiadiazinyl, benzoxathiinyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzodioxinyl or carbazolyl wherein one or more double bonds may be 30 hydrogenated, said groups being optionally unsubstituted or bearing one or more substituents such as: the alkyl, cyano, hydroxyalkyl, hydroxy, oxo, formyl, alkanoyl, alkylcarbonylamino and alkoxycarbonyl group, as well as the morpholino group.

The phenyl group may preferably be mono- or 35 di-substituted, mainly at the 2- and 5-positions, but also at the 2- and 3-, 2- and 4-, 3 and 4-, or 3- and 5- positions; it may also be tri-substituted generally at positions 3-, 4-, and 5-, but also at positions 2-, 3-, and 4-, 2-, 3-, and 5- or 2-, 4-, and 5-; it may also be tetrasubstituted, for instance at positions 2-, 3-, 4-, and 5-; or pentasubstituted. The substituents of the phenyl group may be: F, CI, Br, I, CN, OH, NH., NH-CO-NH ., NO., COOH, CONR , CF , alkyl of from 1 2 2 2 2 3 to 10, preferably 1 to 4, carbon atoms, methyl or ethyl being preferred, well as for instance n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert.- butyl, pentyl or n-pentyl, hexyl or n-hexyl, heptyl or n-heptyl, octyl or n-octyl, nonyl or n-nonyl, as well as decyl or n-decyl; alkenyl of from 2 to 10, preferably 2 to 4, carbon atoms, for instance vinyl, allyl, 1-propenyl, isopropenyl, butenyl i.e. 1-buten-l-, -2-, -3- or -4-yl, 2-buten-l-yl and 2-buten-2-yl, pentenyl, hexenyl or decenyl; alkynyl of from 2 to 10, preferably 2 to 4, carbon atoms, e.g. ethynyl, 1-propyn-l-yl, propargyl, butynyl or 2-butyn-l-yl, pentynyl, decynyl; cycloalkyl of from 3 to 8, preferably 5 or 6, carbon.atoms, more preferably cyclopentyl or cyclohexyl, but also far instance, cyclopropyl, cyclobutyl, 1-, 2- or 3-methylcyclopentyl, 1-, 2-, 3- or 4-methylcyclohexyl, cycloheptyl or cyclooctyl; bicycloalkyl of from 4 to 11, preferably 7, carbon atoms, more preferably exo or endo 2-narbamyl but also for instance 2-isobornyl or 5-camphyl; hydroxyalkyl of from 1 to 5, preferably 1 or 2, carbon atoms, more preferably hydroxymethyl and 1- or 2-hydroxyethyl but also, for instance, 1-hydroxyprop-l-yl, 2-hydroxyprop-l-yl, 3-hydroxyprop-l-yl, l-hydroxyprop-2-yl, 1-hydroxybut-l-yl, 1-hydroxypent-l-yl; alkanoyl of from 1 to 7, preferably 1 to 4, carbon atoms, more preferably formyl, acetyl or propionyl but also, for instance butyryl, isobutyryl, valeroyl, caproyl, heptanoyl; alkoxy of from 1 to 10, preferably 1 to 4, carbon atoms, more preferably methoxy or ethoxy, but also, for Instance, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy; alkoxyalkyl of from 2 to 10, preferably 2 to 6, carbon atoms, such as for instance alkoxymethyl e.g. methoxymethyl, alkoxyethyl e.g. 1- or 2-methoxyethyl, 1- or 2-n-butoxyethyl, 1- or 2-n-octyloxyethyl; alkoxyalkoxyalkyl of up to 10, preferably from 4 to 7, carbon atoms, such as, for instance, alkoxyalkoxymethyl e.g. 2-methoxyethoxymethyl, 2-ethoxyethoxymethyl or 2-isopropoxyethoxymethyl, alkoxyalkoxyethyl e.g. 2-(2-methoxyethoxy)ethyl or 2-(2-ethoxyethoxy)ethyl; t alkoxyalkoxy of from 2 to 10, preferably 3 to 6, carbon atoms, such as for instance 2-methoxyethoxy, 2-ethoxyethoxy or 2-n-butoxyethoxy; alkenyloxy of from 2 to 10, preferably 2 to 4, carbon atoms, more preferably allyloxy but also for instance vinyloxy, propenyloxy, isopropenyloxy, butenyloxy or 1-buten-l-, -2-, -3- or -4-yloxy, 10 2-buten-l-yloxy, 2-buten-2-yloxy, pentenyloxy, hexenyloxy or decenyloxy; alkenyloxyalkyl of up to 10, preferably from 3 to 6, carbon atoms, such as for instance allyloxymethyl; alkynyloxy of from 2 to 10, preferably 2 to 4, carbon atoms, more preferably propargyloxy, but also for instance ethynyloxy, 1-propyn-l-yloxy, 15 butynyloxy or 2-butyn-l-yloxy, pentynyloxy or decynylox^; alkynyloxyalkyl of from 3 to 10, preferably from 3 to 6 carbon atoms, e.g. ethynyloxymethyl, propargyloxymethyl or 2-(2-butyn-l-yloxy)ethyl; cycloalkoxy of from 3 to 8, preferably 5 or 6, carbon atoms, more preferably cyclopentyloxy or cyclohexyloxy , but also for instance cyclopropyloxy, cyclobutyloxy, 1-, 2- or 3-methylcyclopentyloxy, 1-, 2-, 3- or 4-methylcyclohexyloxy, cycloheptyloxy or cyclooctyloxy; alkylthio of from 1 to 10, preferably 1 to 4, carbon atoms, more preferably methylthio or ethylthio, but also for instance n-propylthio, isopropylthio, n- butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, octylthio, nonylthio and decylthio; alkylthioalkyl of from 2 to 10, preferably 2 to 6, carbon, atoms, e.g. methylthiomethyl, 2-methylthioethyl or 2-n-butylthioethyl; acylamino, more particularly alkanoylamino of from 1 to 7, preferably 1 to 4, carbon 30 atoms, more preferably formylamino and acetylamino, but also propionylamino, butyrylamino, isobutyrylamino, valeroylamino, A caproylamino, heptanoylamino, and aroylamino or benzoylamino; acylaminoalkyl, preferably alkanoylaminoalkyl of from 2 to 8, ^ preferably 3 to 6, carbon atoms, such as for instance 35 fonnylaminoethyl, acetylaminoethyl, propionylaminoethyl, n- butyrylaminoethyl, formylaminopropyl, acetylaminopropyl, propionylaminopropyl, formylaminobutyl, acetylaminobutyl, as well as propionylaminobutyl^ and butyrylaminobutyl; acyloxy of 1 to 6, preferably 2 to 4, carbon atoms, more preferably acetyloxy, propionyloxy and butyryloxy, but also formyloxy, valeroyloxy, caproyloxy; alkoxycarbonyl of from 2 to 5, preferably 2 and 3, carbon atoms, more preferably methoxycarbonyl and ethoxycarbonyl,but also far Instance n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl and tert-butoxycarbonyl; cycloalkoxycarbonyl of from 4 to 8, preferably 6 or 7, carbon atoms, more preferably cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, but also cyclopropyloxycarbonyl, cyclobutyloxycarbonyl or cycloheptyloxycarbonyl; alkylaminocarbonylamino of from 2 to 4, carbon atoms, e.g. methylaminocarbonylamino, ethylaminocarbonylamino, propylaminocarbonylamino; dialkylaminocarbonylamino of from 3 to 7, preferably 3 to 5, carbon atoms, more preferably dimethylaminocarbonylamino, but also di-n-propylaminocarbonylamino, diisopropylaminocarbonylamino; (I-pyrroliditio) carbonylamino; (l-piperidino)carbonylamino; cycloalkylaminocarbonylamino of from 4 to 8, preferably 6 or 7, carbon atoms, more preferably cyclopentylaminocarbonylamino and cyclohexylaminocarbonylamino, but also cyclopropylaminocarbonylamino, cyclobutylaminocarbonylamino, cycloheptylaminocarbonylamino; alkylaminocarbonylaminoalkyl of from 3 to 9, preferably 4 to 7, carbon atoms, more preferably methylaminocarbonylaminoethyl, ethylaminocarbonylaminoethyl, ethylaminocarbonylaminopropyl and ethylaminocarbonylaminobutyl, but also for instance methylaminocarbonylaminomethyl, n-propyl-aminocarbonylaminobutyl, n-butylaminocarbonylaminobutyl; dialkyl-aminocarbonylaminoalkyl of from 4 to 11, carbon atoms, e.g. dimethylaminocarbonylaminomethyl, diethylaminocarbonylaminoethyl, diethylaminocarbonylaminopropyl, diethylaminocarbonylaminobutyl; (l-pirrolidino)carbonylaminoethyl; (l-piperidino)carbonyl-aminoethyl; cycloalkylaminocarbonylaminoalkyl of from 5 to 12, preferably 8 to 11, carbon atoms, more preferably cyclopentylaminocarbonylaminoethyl, cyclopentylaminocarbonylaminoprcpyl, cyclopentylaminocarbonylaminobutyl, cyclohexylaminocarbonylaminoethyl, cyclohexylaminocarbonylaminopropyl and cyclohexylaminocarbonylaminobutyl but also, for instance, cyclopropylaminocarbonylaminomethyl, cycloheptylaminocarbonylaminoethyl; alkoxycarbonylaminoalkyl of from 3 to 12, preferably A to 9, carbon atoms, more preferably methoxycarbonylaminoethyl, ethoxycarbonylaminoethyl, n~ propoxycarbonylaminoethyl, isopropoxycarbonylaminoethyl, n-butoxy-carbonylaminoethyl, isobutoxycarbonylaminoethyl, sec-butoxycarbonyl-aminoethyl, tert-butoxycarbonylaminoethyl, ethoxycarbonylamino-propyl, n-butoxycarbonylaminopropyl, ethoxycarbonylaminobutyl and n-butoxycarbonylaminobutyl but also, for instance, n-propoxy-carbonylaminopropyl, n-propoxycarbonylaminobutyl, isopro-poxycarbonylaminobutyl; cycloalkoxycarbonylaminoalkyl of from 5 to 12, preferably 8 to 11, carbon atoms, more preferably cyclopentyloxycarbonylaminoethy1, cyclopentyloxycarbonylaminopropy1, cyclopentyloxycarbonylaminobutyl, cyclohexyloxycarbonylaminoethyl, cyclohexyloxycarbonylaminopropyl, cyclohexyloxycarbonylaminobutyl but also, for instance, cyclopropyloxycarbonylaminomethyl and cvcloheptvloxycarbonylaminoethyl; carbamoylalkyl of from 2 to 5, preferably 2, carbon atoms, preferably carbamoylmethyl, as well as carbamoylethyl, carbamoylpropyl and carbamoylbutyl; alkylaminocarbonylalkyl of from 3 to 9, preferably 3 to 6, carbon atoms, more preferably, methylaminocarbonylethyl, ethylaminocarbonylmethyl, n-propylaminocarbonylmethyl, isopropylaminocarbonylmethyl, n-butylaminocarbonylmethyl, isobutylaminocarbonylmethyl, sec-butylaminocarbonylmethyl and tert- butylaminocarbonylmethyl, but also, for instance e thylaminocarbonyle thyl, ethylaminocarbonylpropyl, ethylaminocarbonylbutyl, n-propylaminocarbonylbutyl, n-but:ylamino- carbonylbutyl; dialkylaminocarbonylalkyl of from 4 to 11, preferably 4 to 8, carbon atoms, more preferably dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl, di-n-propylaminocarbonylmethy.'L, (l-pirrolidino)carbonylmethyl and (1—piperidino)carbonylmethyl, but 8 also, for instance, diethylaminocarbonylethyl, (l-piperidino)carbonylethyl, diethylaminocarbonylpropyl, diethyl-aminocarbonylbutyl; cycloalkylaminocarbonylalkyl of from 5 to 12, preferably 7 or 8, carbon atoms, more preferably, 5 cyclopentylaminocarbonylmethyl and cyclohexylaminocarbonylmethyl, but also, for instance cyclopropylaminocarbonylmethyl, cyclobutylaminocarbonylmethyl, cycloheptylaminocarbonylmethyl, cyclohexylaminocarbonylethyl, cyclohexylaminocarbonylpropyl, cyclohexylaminocarbonylbutyl; alkylaminocarbonylalkoxy of from 3 to 10 preferably 3 to 5, carbon atoms, more preferably, methylaminocarbonylmethoxy but also, for instance methylaminocarbonylethoxy and methylaminocarbonylpropoxy; dialkylaminocarbonylalkoxy of from 4 to 10, preferably 4 to 7, carbon atoms, such as for instance dimethylaminocarbonylmethoxy, 15 diethylaminocarbonylethoxy and (l-piperidino)carbonylmethoxy; cyclo- alkylaminocarbonylalkoxy of from 5 to 11, preferably 7 or 8 carbon atoms, such as for instance cyclopentylaminocarbonylmethoxy and cyclohexylaminocarbonylmethoxy.

Ar may also represent, for instance, one of the following 20 radicals: 1,2,5-thiadiazol-3-yl, 4-(N-morpholino)-l,2,5- thiadiazol-3-yl; 1- or 2-naphthyl; 1-, 2-, 3-, (preferably) 4-, 5-, 6- or 7-indanyl; l-oxo-4-, -5-, -6-, or (preferably) -7-indanyl; alkyl-l-oxoindanyl, preferably l-oxo-5-methyl-7-indanyl; l-hydroxy-4-, -5-, -6- or (preferably) -7-indanyl; 1-, 2-, 3-, 25 (preferably) 4-, 5-, 6- or 7-indenyl; 1-, 2-, 3-, 4-, (preferably) -, 6-, 7- or 8-tetralyl; oxo-tetralyl, preferably l-oxo-5-tetralyl, as well as 2-, 3- or 4-oxo-5-tetralyl or 1-, 2-, 3- or 4-oxo-6-tetralyl; hydroxytetralyl, (preferably) l-hydroxy-5-tetralyl, but also 2-, 3- or 4-hydroxy-5-tetralyl; (preferably) 4-, 5-, 6- or 30 7-indolyl; alkylindolyl, preferably methylindolyl, such as for ins tance 2-methyl-4-indolyl, 3-methyl-4-indolyl and 6-methyl-4-indolyl, but also, for instance 2-ethyl-4-indolyl and 6-ethyl-4-indolyl; dialkylindolyl, preferably dimethylindolyl, e.g. 2,3-dimethyl-4-indolyl, 2,6-dimethyl-4-indolyl, but also, for ins-35 tance, 2-methyl-3-ethyl-4-indolyl, 2-ethyl-3-methyl-4-indolyl, 9 2,3-diethyl-4-indolyl; cyanoindolyl, e.g. 2-cyano-4-indolyle, 3-cyano-4-indolyl; alkyl-cyano-indolyl, preferably 2-cyano-6-methyl-4-indolyl, but also for instance 3-cyano-6-methyl-4-indolyl; carbamoylindolyl, preferably 2-carbamoyl-4~indolyl, 3-carbamoyl-4-indolyl, but also, for instance * 6-carbamoyl-4-indolyl; alkyl-carbamoyl-indolyl, preferably methyl-carbamoyl-indolyl, e.g. 2-carbamoyl-6-methyl-4-indolyl; hydroxyalkylindolyl, preferably 2-hydroxymethyl-4-indolyl, but also, for instance 2-hydroxymethyl-5-indolyl, 3-hydroxymethyl-4-indolyl, 10 2-(2-hydroxyethyl)-4-indolyl; 2-oxo-indolinyl, preferably 2-oxo-indolin-4-yl, but also 2-oxo-indolin-5-yl; alkyl-2-oxo-indolinyl, preferably methyl-2-oxo-indolin-4-yl, e.g. 3-methyl-2-oxo-indolin-4-yl, but also, for example 3-ethyl-2-oxo-indolin-4-y1, 3-isopropyl-2-oxo-indolin-4-yl dialkyl-2-oxo-indolinyl, e.g. 3,3-dimethyl-2-oxo-indolin-4-yl and 3,3,-diethyl-2-oxo-indolin-4-yl; indazol- (preferably) -4-, -5-, -6-or -7-yl; benzimidazol-4-yl; alkyl-benzimidazol-4-yl, preferably methyl-benzimidazol-4-yl, e.g. 3-methyl-benzimidazol-4-yl, l-methyl-benzimidazol-4-yl, 2-methyl-benzimidazol-4-yl, 20 6-methyl-benzimidazol-4-yl and 7-methyl-benzimidazol-4-yl; benzimidazolin-2-on-4-yl (preferably), benzimidazolin-2-on-5-yl; alkylbenzimidazolin-2-on-4-yl, preferably methyl-benziiaidazolin-2-on-4-yl, e.g. 6-methyl-benzimidazolin-2-on-4-yl, 7-methyl-benzimidazolin-2-on-4-yl; 25 benzotriazol- (preferably) 4- or 5-yl; benzofuran- (preferably) 4-, -, 6- or 7-yl; alkylbenzofuran-4-yl, e.g. 2-methylbenzoi:uran-4-yl, 3-methylbenzofuran-4-yl, and 6-methylbenzofuran-4-yl; alkanoylbenzofuran-4-yl, e.g. 2-acetylbenzofuran-4-yl and 6-acetylbenzofuran-4-yl; bis-alkanoyl-benzofuranyl, e.g. 2,4-diacetylbenzofuran-5-yl, and 2,6-diacetylbenzofuran-4-yl; 1,3-benzodioxolyl, preferably 1,3-benzodioxol-4-yl; alky1-1,3-benzodioxolyl, preferably 2-methyl-l,3-benzodioxol-4-yl, but also, for instance 6-methyl-l,3-benzodioxol-4-yl; dialkyl-1,3-benzodioxolyl, preferably 35 2,2-dimethyl-l,3-benzodioxol-4-yl, but also, for instance 2.2-diethyl-l,3-benzodioxol-4-yl, and 2,6-dimethyl-l,3-benzodioxol- 4-yl; 1,2-benzisoxazol- (preferably) 4-, 5-, 6- ou 7-yl; alky1-1,2-benzisoxazolyl, preferably 3-methyl-l,2-benzisoxazol- 4-yl, but also, as an example 3-ethyl-l,2-benzisoxazol-4-yl, 3-propyl-l,2-benzisoxazol-4-yl, 3-isopropyl-l,2-benzisoxazol-4-yl, and 6-methyl-l,2-benzisoxazol-4-yl; 1,3-benzoxazol- (preferably) 4-, -, 6- or 7-yl; alky1-1,3-benzoxazolyl, preferably 2-methyl- 1.3-benzoxazol-4-yl, but also, for instance 2-ethyl-l,3-benzoxazol- 4-yl, 6-methyl-l,3-benzoxazol-4-yl, and 6—ethyl-1,3-benzoxazol-4-yl; ary1-1,3-benzoxazolyl, preferably 2-phenyl-l,3-benzoxazol-4-yl, and 2-(4-pyridyl)-l,3-benzoxazol-4-yl; benzothien- (preferably) 4-, 5-, 6- or 7-yl; 1,2-benzisothiazol- (preferably) 4-, 5-, 6- or 7-yl; alkyl-1,2-benzisothiazolyl, e.g. 6-methyl-l,2-benzisothiazol-4-yl; 1,3-benzothiazol-4-, -5-, -6- or (preferably) -7-yl; alkyl-1,3-benzothiazol-7-yl, e.g. 2-methyl-l,3-benzothiazol-7-yl, 4-methyl-l,3-benzothiazol-7-yl, and 2-ethyl-l,3-benzothiazol-7-yl; 2-aryl-l,3-benzothiazol-7-yl, e.g. 2-phenyl-l,3-benzothiazol-7-yl^. 2-(4-chlorophenyl)-l,3-benzothiazol-7-yl , and 2-(4-pyridyl)-l,2-benzothiazol-7-yl; 1,2-dihydro-2-oxo-3-, -4-, (preferably) -5-, -6-, -7- or -8-quinolinyl; 1,2,3,4-tetrahydro-(preferably) -5-, -6-, -7- or -8-quinolinyl; 1,2,3,4-tetrahydro-2-oxo (preferably) -5-, -6-, -7- or -8-quinolinyl; 1,2-dihydro-8-hydroxy-2-oxo- (preferably) -5-, -6- or -7-quinolinyl; 1,2-dihydro-8-alkoxy-2-oxo- (preferably) -5-, -6- or -7-quinolinyl, e.g. 1,2-dihydro-8- methoxy-2-oxo-5-quinolinyl; 1,2,3,4-tetrahydro-8-hydroxy-2-oxo- (preferably) -5-, -6-, or -7-quinolinyl; 1,2,3,4-tetrahydro-8-alkoxy-2-oxo- (preferably) -5-, -6- or -7-quinolinyl, e.g. 1,2,3,4-tetrahydro-8-methoxy-2-oxo-5-quinolinyl; 1,2,3,4-te-trahydro-8-alkanoylamino-2-oxo- (preferably) -5-, -6- or -7-quinolinyl, e.g 1,2,3,4-tetrahydro-8-acetylamino-2-oxo-5-quinolinyl; 1,2-dihydro-3-cyano-2-oxo- (preferably) -5-, -6-, -7- or -8-quinolinyl; 1,2-dihydro-3-cyano-2-oxo-7-methyl- -quinolinyl; 1,2-dihydro-l-oxo- (preferably) -4-, -5-, -6-, -7- or -8-isoquinolinyl; 1,2-dihydro-2-alkyl-l-oxo- (preferably) -4-, -5-, 11 -6-, -7- or -8-isoquinolinyl, e.g. 1,2-dihydro-2-methyl-l-oxo-4-isoquinolinyl; 1,2,3,4-tetrahydro-2-alkanoyl-(preferably) -5-, -6-, -7- or -8-isoquinolinyl, preferably 1,2,3,4-tetrahydro-2-formyl-5-isoquinolinyl, as well as for example 5 1,2,3,4-tetrahydro-2-acecyl-5-isoquinolinyl; 1,2-dihydro-2-oxo- 1.3-benzodiazin- (preferably) -5-, -6-, -7- or -8-yl; 2H-3.4-dihydro-5-, -6-, -7- or (preferably) -8-benzopyranyl; 2H-5-, -6-, -7-or (preferably) -8-benzopyranyl; 2H-2-oxo-5-alkyl-7- or (preferably) -8-benzopyranyl, for instance 2H-2-oxo-5-methyl-8-benzopyranyl; 2H-3-cyano-5-, -6-, -7- or (preferably) 8-benzopyranyl; 2H-3,4-dihydro-5-, -6-, -7- or (preferably) -8-benzothiinyl; 3.4-dihydro-lH-2,2-dioxo-2,1-benzothiazin- (preferably) 5-, 6-, 7- or 8-yl; 3,4-dihydro-lH-l-alky1-2,2-dioxo-2,1-benzothiazin- (preferably) -, 6-, 7- or 8-yl, e.g. 3,4-dihydro- lH-l-methyl-2,2-dioxo-2,l-benzothiazin-5-yl; 3,4-dihydro-2H-3-oxo-l,4-benzothiazin-5-, -6-, -7- or (preferably) -8-yl; 5- or 6-alkyl-3,4-dihydro-3-oxo-l,4-benzothiazin-8-yl, e.g. 6-methyl-3,4-dihydro-3-oxo-l,4-benzothiazin-8-yl; 1,1-dioxo-l,2,4-benzothiadiazin-5-, -6-, -7- or -8-yl; 20 1,l-dioxo-3-alkyl-l,2,4-benzothiadiazin-5-, -6-, -7- or -8-yl, e.g. 1,I-dioxo-3-methyl-l,2,4-benzothiadiazin-5-, -6-, -7- or -8-yl; 1,l-dioxo-3-alkanoyl-l,2,4-benzothiadiazin-5-, -6-, -7- or -8-yl, e.g. 1,l-dioxo-3-formyl-l,2,4-benzothiadiazin-5-, -6-, -7- or -8-yl, 1,l-dioxo-3-acetyl-l,2,4-benzothiadiazin-5-, -6-, -7- or -8-yl; 25 1,l-dioxo-3-aroyl-l,2,4-benzothiadiazin-5-, -6-, -7- or -8-yl, e.g. 1,l-dioxo-3-benzoyl-l,2,4-benzothiadiazin-5-, -6-, -7- or -8-yl; 1,l-dioxo-3-(4-pyridyl-carbonyl)-l,2,4- benzothiadiazin-5-» -6-, -7-or -8-yl; 3,4-dihydro-2,2-dioxo-l,2-benzoxathiin- (preferably) -5-, -6-, -7- or (preferably) -8-yl; 1-, 2-, 3- or (preferably) 30 4-carbazolyl. 12 In particular, when in formula (i) above, Ar is an aromatic or heteroaromatic group as defined in the preceding paragraph, said aromatic or heteroaromatic group may be represented by a radical of one of following structures JL to 67.

(Z = a direct bond or a sulfur atom) z'-n r~n (Z = CO or CH2 ; Z' = H, CH3) N H 13 (ZandZ' = ii or halogen or Z s H, Z' = alkyl) 9 (Z = CH CH , CH=CH) (Z = H, halogen , alkylsulfonylar.ino) n = i or 2 (Z = CI, alkyl , alkoxy, phenyl , benzyl , morpholino, pipericino) (Z = H, alkyl ) (Z = H, alkyl , alkoxy, phenyl , benzyl ) (Z' » cycloalkyl , alkyl , aralkyl optionally substituted ar phenyl optionally substituted) * 14 0 II (Z = alkyl ., aralkyl ) 0 Z 10 11 (Z = H, alkyl , aralkyl , alkenyl ) (Z = H, CH3) 12 (Z = CH(OH), CO) (Z a CH , CH OH, CH OCH , COOH, COOAlkyl ) 3 2 2 3 14 r -CO N (Z = hydroxy, alkoxy, amino, methylamino, pyrrolidino, piperidino, morpholino) (Z = amino, alkoxy, alkyiamino, dialkylamino, pyrrolidine, piperidino, morpholino) P (Z = ethyl or propyl , hydroxymethyl ) (Z = H, alkyl ) (Z = K, alkyl ) (Z = hydrogen , alkyl , hydroxyalkyl , halogen , CF , alkanoyl , cyano) 3 (Z = H, OH, alkyl , alkoxy, halogen , CN, NH-CHO. NH-CO-alkyl ., alkenyloxy, alkanoyloxy) 16 (Z = hydrogen , alkyl , alkanoylalkyl , carboxyalky; alkoxycarbonylalkyl ) (Z' = hydrogen , alkyl , phenylalkyl ) 22 (Z = H, halogen ) (Z' = alkyl ) 24 z-r (Z = alkanoyl ■, alcoxycarbonyl , benzoyl ) (Z = alkanoyl ) (Z = alkyl ) Z —| (one of Z and Z' is hydrogen and the other is hydrogen or methyl) 27 17 (2 = hydrogen or methyl ) 28 18 r 19 57 53 (Z = H, alkyl , phenyl ) 59 ■<£> (Z and Z' = H, CH ) w 61 CN "t 62 (Z = H, alkyl , phenylalkyl , phenyl unsubstituted or substituted with halogen , alkyl , alkoxy, alkylthio, CF , OH, carboxy, methylenedioxy) (2 = alkyl , H, phenyl , CM, CT , COOH, COOAlkyl aminocarbonyl carbonyl ) aikyiaminocarbonyl , dialkylanino- 63 (Z = H, alkyl , phenyl , CF ) o (Z = H, NH ) 65 (Z = H, alkyl 65 rr N \ N Z' 67 (Z s H, alkyl , Z' = H, acetyl ) 21 According to a preferred embodiment, the present invention relates to those compounds of formula (i) above, wherein R is as defined above and Ar represents (a) a phenyl group, which may be unsubstituted or bear one or more substituents, optionally fused, at positions 2 and 3, to a 5- or 6-membered carbocycle which - mny contain one or two additonal double bonds, - may bear one or two substituents, - mny be fused to a benzene ring, or - when said carbocycle is a 6-membered ring, may bear a methano or ethano bridge connecting positions 3 and 6; (b) a phenyl ring fused, at positions 3 and 4, to a 5-membered heterocycle containing both a nitrogen atom and a sulfur atom or an -NH- group, or an optionally substituted phenyl group fused at positions 2 and 3 to - a 5- or 6-membered, aromatic or non-aromatic, heterocycle which contains a nitrogen, oxygen or sulfur atom or an -NH- or N-alkanoyl- group, and may contain a double bond or bear a sub- stituent such as a lower alkyl group, in particular methyl, an 20 alkanoyl, typically acetyl, or an oxo group; - a 5-membered heteroaromatic group containing both a nitrogen atom and a sulfur atom or an -NH- group; - a 6-, 7- or 8-membered heterocycle, saturated in the non fused portion, containing two oxygen atoms directly linked to the phenyl group; (c) a phenyl group, optionally substituted at position 4-, fused, at positions 2 and 3, and 5 and 6 to an (a)-furan and a (b)-4-oxopyran ring; (d) a 4-carbazolyl group; (e) an optionally substituted 2-thiazolyl group; (f) an optionally 4-substituted 3-(l,2,5)-thiadiazolyl group; and their salts with mineral ar organic acids.

In meaning (a) above, the phenyl group may be or not be substituted or bears substituents. As suitable additional substituents optionally present on the phenyl ring 35 there may be cited, far example one or mare substituents which are halogen atoms, e.g. fluorine, chlorine, bromine ar iodine atcms, and alkyl, alkoxy ar alkylthio 22 radicals, e.g. methyl, ethyl, isopropyl, t-butyl, methoxy, ethoxy n-butoxy or methylthio, radicals, alkanoyl radicals, e.g. acetyl, phenylalkanoyl or benzoyl, the hydroxy radical and haloalkyl radicals, preferably the trifluoromethyl radical and phenyl, phenoxy, 4-tolyloxy, phenylthio, phenylsulfonyl, anilino, morpholino, benzyl, alpha, alpha-dimethylbenzyl or benzyloxy radicals and the nitro group and alkenyl radicals or the cyano group.

In meaning (a) above, the phenyl may bear only one substituent, said substituent being at position 2. In this case said substituent preferably is an alkyl or alkenyl group, optionally halo substituted, alkynyl, or alkoxy optionally substituted on the alkyl group; alkylthio, alkenyloxy, alkynyloxy, tetrahydrofurfuryloxy or phenoxy, a halogen, a cyano group, a cycloalkyl, cycloalkenyl or 2,5-methanocyclohexyl group or an alkanoyl, phenylalkanoyl or benzoyl group or else a 2-indolyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-quinolinyl, 2-quinoxalinyl, 2-thienyl, 4-thiazolyl or 4-morpholinyl group.

When in meaning (a), Ar is a phenyl group bearing one substituent at the 3-position, said substitutent is preferably a halogen, an optionally halo-substituted alkyl group, in particular trifluoromethyl or an alkenyl, in particular allyl, or cyano.

When in meaning (a), Ar is a phenyl bearing only one substituent at the 4-position, said substituent is preferably an alkyl optionally substituted with one or more halogens, or with an alkoxy, with an alkoxycarbonylamino, with a carbamoyl or with a cycloalkylalkoxy; an alkenyl group optionally substituted with a halogen atom or a cyano group; or an acylamido, haloacylamido or 3-cycloalkylureido group.

When in meaning (a), Ar represents a phenyl bearing two substituents, said substituents may be two halogen atoms, two alkyl groups, one is a halogen atom and the other an alkyl group, or one is a 2-acyl group, e.g. acetyl or benzoyl, and the other is halogen, an acylamido group, e.g. acetylamino, butyrylamino, or benzoylamino, or a 3-mono- or di- substituted ureido group or one is a hydroxy group and the other is an alkyl hydroxymethyl, nitro or carbamoyl group, or one is an alkyl group and the other is an alkylthio group or one may be a 2-acetamido or 4-acetamido group and the other a 3-nitro group. 23 The phenyl group in meaning (a) may also contain 3, 4 or 5 substituents.

Additionally as suitable substituents of the phenyl group (a) there may be mentioned: 2-methyl, 3-methyl, 4-methyl, 4-isopropyl, 2,3-dimethyl, 2,4-dimethyl, 2,5-dimethyl, 3,4-dimethyl, 3,5-dimethyl, 3-methyl-5-ethyl, 2-t-butyl-5-methyl, 2-allyl, 2-chloro, 3-chloro, 4-chloro, 2,3-dichloro, 2,5-dichloro, 3,4-dichloro, 3,5-dichloro, 2.4.5-trichloro, 2-iodo, 3-bromo, 3-fluoro, 4-chloro-3-methyl, 2-chloro-4-methyl, 4-chloro-3,5-dimethyl, 2.4.6-tribromo-3,5-dimethyl, 2-methoxy, 3-methoxy, 2-allyloxy, 2-propargyloxy, 3,5-dimethoxy, 2,3-dimethoxy, 3-t-butyl-4-methoxy, 3-ethoxy, 2-hydroxy, 4-hydroxy, 2-nitro, 3-nitro, 2-acetamido-3-nitro, 4-acetamido-3-nitro, 3-trifluoromethyl, 4-acetyl, 2-phenyl, 2-phenoxy, 3-phenoxy, 3-(4-tolyloxy), 2-benzyl, 2-benzoyl-5-methoxy, 2-phenylthio, 2-cyano, 3-cyano, 4-cyano.

When in meaning (a) , the phenyl group is fused to a 5- or 6-membered carbocycle, the latter preferably farms with said phenyl group a 4-indenyl, 4-indanyl, 1-naphthyl, 5,6-dihydro-l-naphthyl, 5,6,7,8-tetrahydro-l-naphthyl, 5,8-dihydro-l-naphthyl, 6.7-dihydroxy-5,6,7,8-tetrahydro-l-naphthyl, .8-ethano-5,6,7,8-tetrahydro-l-naphthyl, optionally substituted at position 4 with a hydroxy, acylamido or alkylsulfonylamino group, -OXO-5,6,7,8-tetrahydronaphthyl, 8-oxo-5,6,7,8-tetrahydronaphthyl, or 9-oxo-4-fluorenyl radical.

Among the compounds of the present invention, characterized by the formula (i) above, wherein Ar has meaning (a), an advantageous subclass comprises aryloxypropanol-andnotetralins of formula (iA) wherein R is as defined above, E represents hydrogen, halogen, a group alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, 24 tetrahydrofurfuryloxy, phenoxy, (Cj-CgHycloalkyl, 1-cyclohexenyl, 2-cyclohexenyl, 2,5-methanocyclohexyl, alkylthio, alkanoyl, phenylalkanoyl, cyano, 3-chloroallyl, 2-indolyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-quinolinyl, 2-quinoxalyl, 2-thienyl, 4-thiazolyl 5 or 4-morpholinyl, G is hydrogen, halogen, alkyl, alkenyl,a trifluoro methyl group, a cyano group or an acetamido group, vterein at least one of the E and G substituents is hydrogen, or E and G represent, respectively, an acetamido and a nitro group or E and G taken together represent a group -ch2-ch2-ch2-, -ch2-ch2-ch2-ch2-, -ch=ch-ch2-, -ch2-ch=ch-, -CH=CH-CH2-CH2-, -CH=CH-CH=CH-, -C0-CH2-CH2-CH2-, -CH2-CH2-CH2-C0- or -CH2-CH(0H)-CH(0H)-CH2-, and their salts with mineral or organic acids.

Among the compounds of formula (iA) a particularly preferred subclass comprises those compounds wherein R is as defined above, E 15 represents hydrogen, halogen, an alkyl, alkenyl, alkynyl, alkoxy alkenyloxy or alkynyloxy group, G is hydrogen or E and G taken together represent a group -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH=CH-CH2-, -ch2-ch=ch-, -ch=ch-ch2-ch.2-, -ch=ch-ch=ch-, -co-ch2-ch2-ch2-, -CH -CH -CH„-C0- or -CH -CH(OH)-CH(OH)-CH -, and their salts with 2 2*: 2 2 mineral or organic acids.

An even more preferred subclass comprises those compounds of formula (iA) wherein R is as defined above, E represents a halogen atom, an alkyl, alkenyl, alkoxy, alkenyloxy, or alkynyloxy group and G is hydrogen or E and G taken together represent a group -CH=CH-CH=CH- or 25 -CH^-CH(0H)-CH(0H)-CH2-» and their salts with mineral or organic acids.

The compounds of formula (iA) whereinR is hydrogen or a hydroxy group, E is an allyloxy group and G is hydrogen, their optically active forms (SR), (SS), (RS) and (RR), and their salts are of particular interest.

Also the compound of formula (iA) wherein R is hydrogen, the amino is linked to the 1-position of the tetralin and E and G taken together form a -CHaCH-CH=CH- group, its optically active forms and the corresponding salts are particularly preferred.

Among the compounds of the present invention characterized by the 35 above formula (i) virfrerein Ar has meaning (a) another advantageous sub-class comprises the aryloxypropanolaminotetralins of formula (iB) OH 0 .CH .NH.

CH2 NCH2 ^ (iB) L^V wherein R is as defined above, G' is hydrogen and L represents halogen, an alkyl group, unsubstituted or substituted with an 5 alkoxy, alkoxycarbonylamino, aminocarbonyl or cycloalkylalkoxy group; an unsubstituted or cyano-substituted alkenyl group; ; an alkanoylamino or haloalkanoylamino group; a ureido group N'-mono or di-substituted with alkyl or cycloalkyl groups; an alkoxy group optionally substituted on the alkyl by an alkoxy group; a cyano 10 group; or a hydroxymethyl group etherified with an alkoxyalkyl group; or G' and L represent a nitro and an acetamido group respectively; or G' and L taken together form a group -CH=CH-CH=CH-; as well as their salts with mineral or organic acids.

An even more advantageous subclass comprises the 15 compounds of formula (iB) wherein R is as defined above, G' represents hydrogen and L is a chlorine atom, a cyano group or a 2-methoxyethyl group or G' and L taken together form a group-CH=CH-CH=CH-.

Among the compounds of the present invention, 20 characterized by formula (i) above wherein Ar has meaning (a), another advantageous subclass comprises the aryloxypropanolaminotetralins of formula (iC) OH I ✓CH NH .

, . XXh' "" wherein R is as defined above, E' represents an alkanoyl group and 25 L1 represents halogen, an alkanoylamino group or a ureido group N'-mono or di-substituted with an alkyl group, as well as their salts with mineral or organic acids. 26 Among the compounds of the present invention characterized by formula (i), wherein Ar has meaning (a), a further advantageous subclass comprises the aryloxypropanolaminotetralins of formula (iD) R6 OH I °\ /CH /NH 2 CH2 (ID) R2 R3 wherein R is as defined above and: - either the substituents Rg to Rg may be independently hydrogen, halogen, an alkoxy group or alkylthio group with the proviso that at least two of them are different from hydrogen; or - one of the substituents R^ and Rj. represents a hydroxy group and the other is hydrogen, and R^ represents a group -CONH2 or -CHgOH, R£ and Rg being hydrogen; or - R^ represents an alkanoyloxy group, R2, Rg and Rg are a methyl group and Rg is hydrogen; and their salts with mineral or organic acids.

Among the compounds of the present invention, characterized by formula (i), wherein Ar has meaning (a), another advantageous subclass comprises the aryloxypropanolaminotetralins of formula (iE) Sli 1 < A ^K(iE) R'4 wherein R is as defined above and R'^ is hydrogen, a hydroxy group, an akanoyloxy group or an alkylsulfonylamino group, and their salts with mineral or organic acids.

Among the compounds of the present invention, 25 characterized by Formula (i), wherein Ar has meaning (b), an advantageous subclass comprises the aryloxypropanolaminotetralins of formula (iF) 27 OH ,0 Jh NH (iF) R L" G" wherein R is as defined above, and - either E" is hydrogen and G" and L", taken together, represent a group -N=CH-NH- or -S-CH=N-; or - L" is hydrogen and E" and G", taken together, represent a group -CH=CH-NH-; -CH=C(CH.3)-NH-, -CHCH-0-, -C(CH3)=CH-0-, -CH=C(CH J-0-,-CH=C(COCH )-0-, -CO-O-CH -N=CH-NH-, o o ^ -S-CH2-CH2-CH2-, -0-CH2-CH2-0- or -CH^CH^NCCHOJ-CH^; or - L" is hydrogen, a methyl group or an acetonyloxy group and E" and G", taken cogetner, represent a group -CH ^-CH 2-CO-NH-; or - L" is hydrogen or a methyl group and E" and G", taken togehter, represent a group -0-C0-CH=CH-; and their salts with mineral or organic acids.

Among the compounds of formula (iF), particularly preferred are those compounds wherein R is as defined above, L" is hydrogen and E" and G", taken together represent a group -CH=CH-NH-, and their salts with mineral, or organic acids.

Among the compounds of the present invention, characterized by formula (i), vherein Ar has mealing (c) an advantageous subclass ccrrprises the aryloxypropanolairinotetiBlins of formula (iG) OH 0 (iG) 28 wherein R is as defined above, and their salts with mineral or organic acids.

Among the compounds of the present invention, characterized by formula (i), wherein Ar has meaning (d), an advantageous subclass comprises the aryloxypropanolaminotetralins of formula (iH) oh J, ch \ (ih) wherein R is as defined above, and their salts with mineral or organic acids.

Among the compounds of the preesnt invention, characterized by formula (i), wherein Ar represents grouping (e), an advantageous subclass comprises the aryloxypropanolaminotetralins of formula (il) (il) wherein R is as defined above, as well as their salts with mineral or organic acids.

Among the compounds of the present invention, characterized by formula (i), wherein Ar has meaning (f), an advantageous subclass comprises the aryloxypropanolaminotetralins of formula (iJ) n- /s\ n n J L V-/ T ch \ x V. ch N:h (iJ) 29 wherein R is as defined above and X represents an oxygen atom or a methylene group, as well as their salts with mineral or organic acids.

Among the compounds of formula (i), in particular there are comprised those wherein Ar represents the following preferred groups I to LXXVI /~\ H s If T I n >-ch 0^ K— a- 3 T ii i" ch _ch=ch ch -ch=ck-c1 -2——2 ^ 2 iv vi XIII xiv xv xvi xvii xviii sch co-ch ch 2 xix xx xxi ch ch -ch=ch_ 2 2 cn xxii xxiii xxiv cf CI ch. 3n ch ch xxv xxvi xxvii ch o-ch ch 3 2 2 ch ooc-nh-ch ch 3 2 2 xxviii xxix xxx ch„conh• 3 h_n—co-ch 2 2 f>—ch och_ch_ 2 2 2 xxxiv xxxv xxxvi 32 jHr ho conh_ ch conh W ch ch ch conh—kn. / ^nnnt. coch 3 2 2 coch 3 J xlvi xlvii xlviii coch ch ch_ 2 2 3 (c h ) n-co-n 2 5 2 coch. ch. ch. ch. il li ch. 3- ch.co1 3 ch. ch. ch. ch-o-ch ch —o-ch | 2 2 2 ch.

Ofii h-co-n\ lii liii liv lv lvi lvii 33 ho ho lxii lxiii nhso ch3 lxiv u6 lxv lxvi ch co lxvi i lxviii lxix lxx lxxi lxxii och2coch ch. lxxiii lxxiv lxxv lxxvi 34 The compounds of above formula (i) can be either in an optically inactive form or in any optically active form selected from those of the enantiomers, the diastereoisomers and their mixtures. All these compounds and their salts can be used within the scope of the present in-5 vention.

In the present description, the terms "alkyl", "alkenyl" and "alkynyl" unless otherwise expressly specified designate monovalent hydrocarbon radicals containing up Co A carbon atoms, which may be saturated or contain a double or triple bond such as methyl, ethyl, propyl, isopropyl, allyl, ethynyl and propargyl. 10 The terms "alkoxy", "alkenyloxy" or "alkynyloxy" identify a hydroxy group substituted with an alkyl, alkenyl or alkynyl group as defined above.

The terms "alkanoyl" and "alkanoyloxy" identify, respectively, an alkylcarbonyl group and an hydroxy group substituted with an 15 alkylcarbonyl group, wherein "alkyl" is as defined above.

The terms "tetralin" and "tetralone" refer to 1,2,3,4-tetrahydronaphthalene.

The term "aryloxypropanolaminotetralin" identifies a compound of formula (i) whose correct chemical name 2o N-(tetrahydronaphthyl)-3-aryloxy-2-hydroxypropanamine.

To avoid any uncertainty, in naming the compounds of formula (i), the position of attachment of the amino group to the tetralin moiety is considered to be either position 1- or 2-, and therefore the substituent R is considered to be attached to any of positions 5-, 6-, 7- or 8-.

The terms "beta-antagonist" and "beta-blocker" have the following meaning:"antagonist of the beta-adrenergic receptors".

The mineral or organic acids which form the acid addition salts according to the present invention Include both those acids which give pharmaceutical^ acceptable salts such as the hydrochloride, the 30 hydrobromide, the sulfate, the hydrogensulfate, the dihydrogenphosphate, the methanesulfonate, the methylsulfate, the maleate, the fumarate, the naphthalenesulfonate, and those acids which do not produce pharmaceutically acceptable salts but allow a suitable separation or crystallization of the compounds of formula (i), such as picric acid, oxalic acid or an optically active acid, e.g. a mandelic ar canpharsulphordr acid.

Another object of the present invention is a process for the preparation of the aryloxypropanolaminotetralins of formula (i) and their salts, characterized in that it comprises reacting a 1-aryloxypropane of formula (ii) wherein Ar' has the same meaning as Ar above, but may contain N-prutecting groups fixed on M^orW-feroups, A is a hydroxy group and B is a halogen selected from chlnnne, tannine and iodine, ar A and B taken together farm an epoxy group, with an aminotetralin of formula wherein R is as defined above, optionally in the presence of a tertiary amine; optionally deprotecting the obtained compound by removing the N-protecting group; when in the starting compound of formula (ii) Ar' represents a 2-acetamido-3-nitrophenyl or a A-acetamido-3-nitrophenyl group, optionally deacetylating the obtained product by heating it in hydrochloric acid and optionally hydrogenating the obtained product in 97% formic acid in the presence of 10% Pd/C; and optionally converting the obtained product in one of its salts with mineral or organic acids.

As used herein the term "N-protecting group" designates an easily removable amino protecting group, such as a formyl group, an alkylcarbonyl group, e.g. acetyl or propionyl, an arylcarbonyl group such as benzoyl, an alkylsulfonyl group such as methanesulfonyl or an arylsulfonyl group such as benzenesulfonyl or p—toluenesulfonyl; preferred N-protecting groups are the arylsulfonyl groups and in particular benzenesulfonyl and p-toluenesulfonyl.

The reaction between the 1-aryloxypropane (ii) and the aminotetralin (iii) is carried out by refluxing a solution of the two reactants in a suitable solvent such as a polar aprotic solvent e.g. a b (ii) dimethylsulfoxide or dimethylacetamide, or a lower alcohol, such as ethanol, n-propanol or isopropanol, optionally in the presence of a tertiary amine e.g. triethylamine or 1-methylpiperidine.

The optional removal of the N-protecting group of the thus obtained product is carried out according to conventional methods, as an example by refluxing a solution of the product in a suitably selected solvent such as a lower alcohol e.g. ethanol, n-propanol or isopropanol, in the presence of an alkali metal hydroxide such as sodium hydroxide.

When in the starting compound of above formula (ii) Ar' represents a 2-acetamido-3-nitrophenyl or A-acetamido-3-nitrophenyl group, the thus obtained product may be deacetylated by heating it in a hydrochloric acid solution, preferably in 4N HC1, to afford a compound of formula (i) wherein Ar represents a 2-amino-3-nitrophenyl or 4-amino-3-nitrophenyl group. Furthermore the nitro group of these products may be catalytically hydrogenated (10% Pd/C) in 97% formic acid to afford reduction of the nitro group and simultaneous cyclysation to obtain a compound of formula (i) wherein Ar is 4- or 5-benzimidazolylr The thus obtained compound of formula (i) is isolated, as the free base or a salt thereof, by conventional techniques.

When the compound of formula (i) is obtained as the free base, salification is carried out by treatment with the selected acid in an organic solvent. Treatment of the free base dissolved for instance in an alcohol such as isopropanol, with a solution of the suitably selected acid in the same solvent, affords the corresponding addition salt which is isolated according to conventional techniques. Far example, the hydrochloride, the hydrobromide, the sulfate, the hydrogensulfate, the dihydrogenphosphate, the methanesulfonate, the methylsulfate, the oxalate, the maleate, the fumarate, the naphthalene-2-sulfbnate are prepared in this way.

At the end of the reaction between the compound of formula (ii) and the aminotetralin of formula (iii), compound (i) may be isolated as one of its salts, e.g. as the hydrochloride or the oxalate; in this case, if necessary, the free base may be prepared by 37 neutralization of said salt with a mineral or organic base such as sodium hydroxide or triethylamine or with an alkaline carbonate or bicarbonate such as sodium or potassium carbonate or bicarbonate.

The reactions involved in the above overall process do not alter the stereochemistry of the involved compounds. It is therefore possible to apply the process of the present invention to the preparation of racemates as well as of optically pure isomers.

Accordingly, by reacting a 1-aryloxypropane (ii) racemate with an 10 aminotetralin (iii) racemate, a mixture of stereoisomers RR, SS, RS and SR, is obtained. Analogously, b«j reacting an optically active l-aryloxy-2,3-epoxypropane with an aminotetralin racemate, a couple of diastereoisamers of an aryloxypropanolaminotetralin of formula (i) is obtained, either (RR+RS) or (SS+SR), which can be separated into the single pure enantiomers (RR) 15 and (RS) or (SS) and (SR). Preferably, when an optically active l-aryloxy-2,3-epoxypropane is used, an aminotetralin of formula (iii) in optically active form is employed to afford an optically pure isomer.

The starting compands of above formula (ii) are generally described in the literature 20 or they may be obtained by methods well known in the art.

Typically, the general methods for preparing the compounds of formula (ii) are described in US Patent 3,501,769.

Accordingly, 1-aryloxypropanes of formula (ii) , wherein A is hydroxy and B is halogen, are prepared starting from the corresponding 25 phenols Ar'OH and an epihalogenohydrin, preferably epichlorohydrin, in the presence of a tertiary amine.

Also the 1-aryloxypropanes of formula (ii) wherein A and B, taken together represent an epoxy group, are prepared starting from the corresponding phenols Ar'OH, in the form of their alkaline salts (i.e. carrying out the reaction in the presence of an alkali hydroxide, e.g. sodium hydroxide, to provide a basic reaction medium) and epichlorohydrin.

The compounds of formula (ii) , wherein A and B, taken together represent an epoxy group, in optically active form are prepared by known methods. More particularly they are prepared by reacting the corresponding phenol with the optically active epichlorohydrin, either (R) or (S) (J. Org. Chem. 1978, 43, 4876-4878), in the same operating conditions as above. The epoxides having configuration (S) may alsn be prepared by the method described in DE 2,453,324.

As an example, the compounds of formula (ii) wherein Ar' is one of groups 1_ tC 6_7, are described in the documents listed hereinbelow: 1_: US 3,912,733; 2: DE 2 240 599; 3: DE 2 353 996; 4: DE 2 418 776; 5: BE 813.751; 6: BE 753.917; 7: BE 733.390;8: FR 1 588 855, DE 2 021 958; 9: US 3,920,691 ; 10: NL 73/05478; 11_: BE 794.669; 12.: FR 1 466 164; 13: BE 724.929; 14: BE 754.860; _15; BE 764.659, BE 739.545; 16: CH 526 542, CH 526 544; 17_: CH 527 188; .18: BE 793.073; 19_: BE 765.313; 20: NL 72/14438; 21: DE 2 362 877; 22: BE 852.556; 23: JP 73-01070; 2£: BE 783.440; 25: DE 2 620 179; 26: FR 2 042 378, DE 2 021 958; 27_, 28, 29, 30, 47, 48, 49, 50, 51_, 52, 53, 54, 55, 56, 57: J. Med. Chem., 1972 , 15, 260-266 ; 31_: US 3,894,058; 32: DE 2 404 858; 33: BE 815.745; 34: FR 2 077 694; 35: JP 49-048649; 36: JP 49-094666; 37.: NL 70/07503; 38: BE 753.840; 39: BE 773.205; 40: BE 739.545; 41: NL 69/011816; 42: BE 739.195; 43: DE 1 955 229; 44: JP 72-00055; 45: JP 49-051258; ^6: NL 86/05887; 58: BE 863.622; 59: DE 2 711 382, BE 846.010; 60: BE 866.278; 6J_: BE 866 .596; 62: DE 2 720 613; 63: US 3,940,407; 64: DE 2 608 448; 65: BE 845.049; 66: JP 52-053868; 67: BE 853.949.

More particularly, the compounds of formula (ii) wherein Ar' is one of the above preferred grottps I to LXXVII are described in the following documents: I: FR 2 009 110; II: FR 2 199 463; III: FR 2 023 556 or US 3,501,769; IV, V, XXIII, XXXII: FR 1 479 614; VI: FR 1 510 271; VII: US 3,501,769; VIII: FR 2 051 536; IX: FR 1 463 034; X: FR 1 583 559; XI, XII, XXII, XXVII: US 3,501,769; XIII, XIV, XXVIII: FR 1 583 559, NL 67/17837; XIV: GB 1 294 159; XV: FR 1 575 615; XVI, XVII, XVIII: DE 2 636 725; XIX: FR 2 267 095 or FR 2 361 106; XX: FR 1 552 786; XXI: FR 2 144 601; XXII: FR 1 555 463 or US 3,501,769; XXV, XXVI: US 3,501,769; XXIX, XXX: FR 2 081 523; XXXI: FR 2 044 806; XXXIII: FR 2 353 520; XXXIV: FR 1 458 635; XXXV: FR 2 034 561; XXXVI: FR 2 330 383; XXXVII: US 3,501,769; XXXVIII: FR 2 113 982; XXXIX: FR 2 261 001 or US 3,501,769; XL: FR 2 130 284 or US 3,501,769; XLI: FR 39 2 070 102; XLII: US 3 501 769; XLIII: BE 691.159 or US 3,309,406; XLIV: FR 2 073 434 or FR 2 215 419 or US 3,501,769; XLV: US 3,857,873; XLVI: US 3 883 560; XLVII, XLVIII: GB 1 247 384; IL: FR 2 276 032; L: FR 2 255 058; LI: US 3,501,769; LII: FR 1 567 149; LIII: BE 859.425, LIV: DE 2 620 179; LV: GB 994 918; LVI: FR 1 601 338; LVII: BE 641.417; LVIII: FR 2 035 816; LIX: FR 8298 M, BE 641.417; LX: FR 2 018 626 or BE 755.071; LXI: EP 67 106; LXII: FR 2 100 811, DE 2 258 995; LXIII: FR 2 059 580; LXIV: FR 2 157 897; LXV, LXVI: FR 1 466 164; LXVII: J. Med. Chem., 1979, 22, 210-214, wherein the precursor l-(2-acetamido-3-nitrophenoxy)-2,3-epoxypropane of formula (ii) wherein Ar is 2-acetamido-3-nitrophenyl, is described; LXVIII: FR 2 137 901; LXIX: FR 2 231 387; LXX: FR 2 092 004; LXXI: J. Med. Chem., 1972, 15, 260-266; LXXII: FR 2 179 715; LXXIII: FR 2 344 538; LXXIV: FR 2 042 378; LXXV: FR 2 196 165; LXXVI: FR 2 225 153.

The starting aminotetralins of formula (iii) are described in literature or they can be easily synthetized by reacting the appropriate 1- or 2-tetralones of formula (iv) wherein R° represents hydrogen or a methoxy group, with benzylanine, reducing the thus obtained benzylimine with sodium borohydride, removing the benzyl group by catalytic hydrogenation and. optionally demethylating with 48% HBr.

The two optically active forms of the aminotetralins (iii) can be prepared by resolution of the racemates according to known procedures, e.g. salification with an optically active acid, preferably a mandelic acid.

The compounds of formula (i) are beta antagonists which are capable of inhibiting the intestinal beta-receptors and are characterized by a reduced activity on the cardiac and respiratory (iv) 40 receptors (guinea pig right atrium and guinea pig trachea, respectively).

The antagonistic activity of beta-adrenergic receptors on isolated rat colon has been assessed by the method 5 described in EP-A-0255415. Said antagonistic activity has been proved both toward the classical beta-agonists, such as isoprenaline, and toward the selective ones, such as the compound coded SR 58375 A described in EP-A-0211721.

The activity on the cardiac and respiratory receptors 10 has been evaluated by the conventional in vitro tests using isolated guinea pig atrial and tracheal preparations (Pharmacol. Res. Comm., 1988, 20, 147-151). In these tests the compounds of formula (i) proved to be poorly active.

More particularly, it has been shown that the compounds of for-15 mula (i) are much more active than the known beta-antagonists on isolated rat colon and much less active than the known compounds on atrium and trachea .. In view of these surprising properties of the compounds of above formula (i), their use as beta-antagonists in non-cardiovascular and non-respiratory fields can be envisaged.

Furthermore, the compounds of formula (i) are poorly toxic; in particular their acute toxicity is compatible with their use as drugs, mainly as gastro-intestinal, psychotropic, antiglaucomatous and antimigraine drugs, or in general for the treatment of those disorders where beta-antagonists have been considered, such as thyrotoxicosis, or hyperparathyroidism, in mammals.

For such a use, an effective amount of a compound of formula (i) or of a pharmaceutically acceptable salt thereof is administered to a mammal in need of such a treatement.

The compounds of formula (i) hereinabove as well as their pharmaceutically acceptable salts can be utilized in a daily dose of from 0.01 to 100 mg per kg of body weight of the mammal to be treated, preferably in a daily dose of from 0.1 to 50 mg/kg. In human beings, the daily dose may preferably vary from 0.5 mg to 5000 mg, 41 more particularly from 2.5 to 2500 mg according to the age of the treated subject, to the type of treatment, prophylactic or curative, and to the severity of the disease. The compounds of formula (i) are generally administered in unit dosage forms of 5 from 0.1 to 500 mg, preferably of from 0.5 to 250 mg active ingredient, 1 to 5 times daily.

Said unit doses are preferably formulated in pharmaceutical compositions in which the active principle is in admixture with a pharmaceutical carrier.

Thus, according to another of its aspects, the present invention provides pharmaceutical compositions which comprise a compound of formula (i) hereinabove or one of its pharmaceutically acceptable salts as the active principle.

In the pharmaceutical compositions of the present invention, 15 for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, transdermal or rectal administration, the active ingredients of formula (i) above may be administered in unit administration forms, mixed with conventional pharmaceutical carriers, to animals and to human beings, for the treatment of the 20 above disorders. Appropriate unit administration forms include forms for oral administration, such as tablets, capsules, powders, granules and oral solutions or supensions, forms for sublingual and buccal administration, forms for subcutaneous, intramuscular or intravenous administration, forms for topical administration and 25 forms for rectal administration.

When a solid composition is prepared in the form of tablets, the main active ingredient is mixed with a pharmaceutical excipient such as gelatine, starch, lactose, magnesium stearate, talc, arabic gum and the like. Tablets may be coated with sucrose or other 30 suitable materials or they may be treated so that their activity is extended or delayed and that they continually release a predetermined amount of active ingredient. 42 A preparation in capsules is obtained by mixing the active ingredient with a diluent and pouring the mixture thus obtained into soft or hard capsules.

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

Water-dispersible powders or granules may contain the active ingredient mixed with dispersing agents or wetting agents, or suspending agents such as polyvinylpyrrolidone as well as, with sweeteners or flavour correctors.

For topical administration the active principle can be admixed with an excipient suitable for the preparation of creams or ointments or it is dissolved in a vehicle suitable for intraocular administration, for example as a collyrium.

For rectal administration, suppositories which are preoared with binders melting at rectal temperature, for example, cocoa butter or polyethyleneglycols^ are employed.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions are used, which contain pharmacologically compatible dispersing and/or wetting agents, for example propyleneglycol or butyleneglycol, are used.

The active principle may also be formulated in the form of microcapsules, possibly with one or more carriers or additives.

The compounds of formula (i), typically those isotopically labelled, may also be employed as laboratory tools in biochemical assays.

The compounds of formula (i) bind selectively to a beta-adrenergic receptor which is present in the mammalian Intestinal tract and which is distinct from the generally recognized beta-1 and beta-2 receptors. These compounds can therefore be employed in a conventional binding assay, using the rat colon wherein said receptor is particularly abundant and determining the amount of compound (i) displaced by the compound to be assayed 43 in order to evaluate the affinity of said compound to the binding sites of this particular receptor.

Combining this biochemical assay with other conventional binding assays in which the binding to beta-1 and beta-2 receptors is evaluated, it is possible to screen out those assayed organic compounds which can specifically bind to said receptor and which therefore may exert a specific action on the intestinal tract without producing any cardiac or respiratory side-effect.

A further specific object of the present invention is therefore a reagent suitable for use in biochemical assays to dif&entiate the beta-adrenergic receptors, which comprises at least one of the compounds of formula (i), suitably labelled.

The following examples further illustrate the invention without however limiting it. The symbol of the rotatory power, which is indicated as /alpha/ should read as /alphaj^ . Chromatographies have been carried out on MERCK 70-230 mesh silica gel columns.

PREPARATION I 2-amino-7-hydroxytetralin hydrobromide (a) A mixture of 7-methoxy-2-tetralone (8 g), benzylamine (4.8 g), anhydrous toluene (150 ml) and p-toluenesulfonic acid (100 mg) is heated to the reflux temperature for 3 hours. The solvent is then evaporated off and the oily residue is taken up in methanol (100 ml). Sodium borohydride (8.5 g) is cautiously added to the thus obtained solution maintained at 0-5°C. The reaction mixture is stirred overnight at room temperature, water (50 ml) is then added thereto and stirring is prolonged for additional 30 minutes. The solvent is evaporated off and the residue is taken up'in water (30 ml) and concentrated ammonium hydroxide (10 ml). The aqueous solution is extracted with ethyl acetate (200 ml), the organic phase is dried over sodium sulfate , filtered and concentrated to dryness, yielding a dark oil which is purified by flash chromatography eluting with ethyl acetate/methanol 95/5, The thus obtained base is then converted into the corresponding hydrochloride by dissolving it into isopropanol (40 ml.) and adding thereto hydrogen chloride saturated Isopropanol. 44 2-Benzylamino-7-methoxy-l,2,3,4-tetrahydronaphthalene hydrochloride (11.4 g) is thus obtained; m.p. 265-267°C (dec.). (b) The above product is dissolved in a mixture methanol (200 ml)/ water (100 ml) and hydrogenated in the presence of 10% Pd/C (1.2 g) at atmospheric pressure and 45-50°C. After 4 hours, the reaction mixture is filtered and the solvent is evaporated off. The residue is taken up twice in absolute ethanol and the ethanol is evaporated off to obtain a white solid which is taken up in hot isopropanol (70 ml). Upon cooling the suspension obtained precipitates to give 2-amino-7-methoxytetralin hydrochloride (7.8 g); m.p. 214-216°C. (c) The above product (6.6 g) is suspended into 48% hydrooromic acid (80 ml) and the reaction mixture is refluxed for 2 hours. The obtained solution is concentrated to dryness, the residue is taken up in absolute ethanol and the solvent is evaporated off twice. The obtained oil is dissolved in hot isopropanol (20 ml) and ethyl ether (30 ml) is then added thereto to give 2-amino-7-hydroxytetralin hydrobromide as a crystalline product 86.8 g); m.p. 171-173°C.

PREPARATION II R(+)-2-amino-7-hydroxytetralin monohydrate.

A solution of (+) mandelic acid (43 g) in absolute ethanol (550 ml) is added to a solution of raw 2-amino-7-methoxytetralin (50 g), free base, obtained from the corresponding hydrochloride (PREPARATION I (b)) by neutralisation with 10% sodium hydroxide and extraction with ethyl acetate followed by evaporation of the solvent, in absolute ethanol (550 ml). The precipitate which is obtained upon standing overnight at room temperature, is recovered by filtration and crystallized twice from absolute ethanol, each time recovering the product crystallized upon standing at room temperature overnight. The pure salt of (+)-2-amino-7-methoxytetralin with (+) mandelic acid (34.2 g, 74%) is thus obtained; m.p. 190-192°C. (The mother liquors of the first crystallization are separately recovered and used in the following PREPARATION III). The obtained salt (34 g) is suspended in 45 water (300 ml) and the suspension Is baslfled by the addition of IN NaOH. The base is extracted with ethyl acetate, the organic phase is concentrated to dryness and the residue 1s taken up In 48% hydrobromic acid (260 ml). The reaction mixture is then heated at re-5 flux for 3 hours and concentrated to dryness under vacuum. The obtained residue is taken up in water (70 ml), the aqueous solution is baslfled by the addition of concentrated ammonium hydroxide, cooled overnight and filtered off to give R(+)-2-amino-7-hydroxvt.etralin. monohydrate (17 g) 143.1440c, /alpha/ » + 85.1° (methanol, c ■ 0.5 %).

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

PREPARATION III 15 S(-)-2-amino-7-hydroxytetralin monohydrate The mother liquors of the first crystallization described in PREPARATION II are concentrated to dryness and the obtained residue is suspended in water (300 ml). IN NaOH is then added thereto to afford a basic solution and ethyl acetate is used to extract the free base 20 therefrom. By following the procedure described in PREPARATION II but starting from the thus obtained base and (-) mandelic acid, the (-)-2-amino-7-methoxytetralin salt with (-) mandelic acid (m.p. 189-191°C) is obtained which, upon neutralization and demethylation with hydrobromic acid, gives S(-)-2-amino-7-hydroxytetralin 25 monohydrate (17 g); m.p. 143-144°C, /alpha/ • - 86.9° (methanol, c ■ 0.5 %).

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

EXAMPLE 1.

A solution of 2-amino-7-hydroxytetralin (3g) obtained from the corresponding hydrobromide described in PREPARATION I by neutralization with ammonium hydroxide and extraction with ethyl acetate/ethanol 9/1 v/v, and l-naphthyloxy-2,3-epoxypropane (3.68 g) 35 in ethanol (80 ml) is refluxed for 5 hours. The reaction mixture is 46 then allowed to cool down to room temperature, the solvent is evaporated off under reduced pressure and the oily residue thus obtained is purified by silica gel column chromatography eluting first with ethyl acetate, up to complete elution of the first spot, and then with ethyl acetate/methanol 9/1 v/v, up to ccrrplete elution of the fractions of .the product. The fractions thus obtained are pooled and concentrated under reduced pressure. The residue is dissolved in hot isopropanol (25 ml), the solution is acidified by the addition of hydrochloric acid in isopropanol and the crystalline precipitate is recovered by filtration yielding 3.6 g of N-(7-hydroxy- 1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1-naph thyloxy)propanamine hydrochloride; m.p. 184-187°C.

EXAMPLE 2.

A solution of 2-aminotetralin (3.2 g) obtained from the corresponding hydrochloride by neutralisation with NaOH and extraction with ethyl acetate, and l-naphthyloxy-2,3-epoxypropane (4.34 g) in absolute ethanol (90 ml) is refluxed for 6 hours. The organic solvent is then evaporated off, the obtained residue is dissolved in isopropanol (50 ml) and the solution is acidified by the addition of HCl/isopropanol. The precipitate is recovered by filtration and crystallized from 95% ethanol (150 ml) yielding 3 g of N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(l-naphthyloxy)propanamine hydrochloride; m.p. 209-212°C. EXAMPLE 3.

A solution of 1-aminotetralin (2.65 g) and l-naphthyloxy-2,3-epoxypropane (3.6 g) in absolute ethanol (80 ml) Is refluxed for 6 hours, the reaction solvent is then evaporated off under reduced pressure and the obtained oil is purified by silica gel column chromatography eluting with ethyl acetate up to complete elution of the fractions of the product, which are then pooled and evaporated under reduced pressure. The obtained product is dissolved in isopropanol (40 ml) and the solution is acidified by the addition of hydrochloric acid in isopropanol. The thus obtained precipitate is recovered by filtration and crystallized from 95% ethanol (70 ml) yielding 2.5 g of N-(l,2,3,4-tetrahydronaphth-l-yl)-2-hydroxy-3-(l-naphthyloxy)propanamine hydrochloride; m.p. 179-183°C. 47 EXAMPLE 4.

A solution of 2-amino-7-hydroxytetralin (4.7 g) and l-(2-allyl)-phenoxy-2,3-epoxypropane (5.48 g) in absolute ethanol (120 ml) is heated to the reflux temperature for 5 hours. The solvent is then 5 evaporated off, the residue is taken ud in isoDropanol and the solu tion is acidified by the addition of HC1/isopropanol. After 30 minutes at 0-5°C, the obtained precipitate is recovered by filtration, washed with isopropyl ether and dried in the oven. Upon crystallization from absolute ethanol (250 ml), 3.1 g of 10 N-(7-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-allyl- phenoxy)propanamine hydrochloride are obtained; m.p. 232-235°C.

EXAMPLE 5.

Operating as described in Example 2 but replacing 1-naphthyloxy-2,3-epoxypropane with l-(2-allyl)phenoxy-2,3-epoxypropane, a product 15 is obtained which, upon crystallization from absolute ethanol affords N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-allylphenoxy)-propanamine hydrochloride; m.p. 175-177°C; yield 57%.

EXAMPLE 6.

A solution of 1-aminotetralin (2.5 g) and l-(2-allylphenoxy)-2,3-20 epoxypropane (3.23 g) in ethanol (70 ml) is refluxed for 5 hours and then evaporated under reduced pressure yielding an oily residue which is chromatographed on a silica gel column eluting with ethyl acetate up to complete elution of the product containing fractions. Said fractions are pooled and evaporated under reduced pressure to afford an oil 25 which is then dissolved in ethyl ether (50 ml). Upon the addition of a solution of oxalic acid (1.1 g) in acetone (10 ml), a precipitate forms which is recovered by filtration and crystallized from 95% ethanol yielding 3.0 g of N-(l,2,3,4-tetrahydronaphth-l-yl)-2-hydroxy-3-(2-allylphenoxy)propanamine oxalate; m.p. 163-165°C. 30 EXAMPLE 7.

A mixture of l-[l-(p-toluenesulfonyl)indol-4-yloxy7-2,3-epoxypropane (20 g), prepared as described in EP-A-228356, and 2-amino-7-hydroxytetralin (10.5 g) in isopropanol (300 ml) is heated to the reflux temperature for 4 hours. The solvent is then evaporated 35 off under reduced pressure, the residue is dissolved in ethyl acetate 48 and the organic solution is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is taken up first in ethanol (200 ml) and then in a solution of sodium hydroxide (15 g) in water (90 ml). The reaction mixture is heated to 5 the reflux temperature for 4 hours, made slightly acidic by the addi tion of IN HC1 and then basified by the addition of concentrated ammonium hydroxide. The reaction mixture is concentrated under reduced pressure, the residue is taken up in absolute ethanol and concentrated to dryness and this last procedure is repeated twice. The 10 obtained reside is taken up in ethanol, sodium chloride is filtered and washed on filter with ethanol to recover all the product. The solution is basified by the addition of concentrated ammonium hydroxide. The residue which is obtained by evaporating off the solvent is chromatographed on a silica gel column eluting 15 first with ethyl acetate and then with a mixture ethyl acetate/methanol 9/1 v/v. The product-containing fractions are combined and evaporated to dryness. A mixture of acetic acid and isopropanol is then added to the product. The precipitate which forms is then recovered by filtration and crystallized from 95% 20 ethanol (60 ml) affording 2.6 g of N-(7-hydroxy-l,2,3,4- tetrahydronaphth-2-yl)-2-hydroxy-3-indol-4-yloxypropanamine acetate; m.p. 167-170°C.

EXAMPLE 8.

A mixture of R(+)-2-amino-7-hydroxytetralin monohydrate (6.5 g), 25 obtained as described in PREPARATION II, and l-/l-(p-toluene- sulfonyl)indol-4-yloxy/-2,3-epoxypropane (12.45 g) in isopropanol (200 ml) is heated to the reflux temperature for 4 hours, the solvent is then evaporated off under reduced pressure and the obtained residue is dissolved in ethyl acetate. The organic solution is washed 30 with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is taken up in ethanol (150 ml) and in a solu-- tlon of sodium hydroxide (10 g) in water (60 ml). The reaction mixture is refluxed for 4 hours, made slightly acidic by the addition of IN HC1 and then basified by the addition of concentrated ammonium 35 hydroxide. The reaction mixture is then concentrated under reduced 49 pressure, the obtained residue Is taken up In absolute ethanol and concentrated to dryness, this last procedure being repeated twice. The residue is finally taken up in ethanol. Sodium chloride is filtered off and washed with ethanol to recover all the product. The solution is made basic by the addition of concentrated ammonium hydroxide and concentrated to dryness. The residue is chromatographed on a silica pel column eluting with a mixture methylene chloride/ethanol 9/1 v/v. The product-containing fractions are pooled and evaporated to dryness yielding 1 g of N-Z"(R)-7-hydroxy-l, 2,3,4-tetrahydronaphth-2-yl7-(RS) -2-hydroxy- 3-indol-4-yloxypropanamine as a vitrous solid.

NMR (DMS0-d6): 7.1 (IH, dd , JL-J2=2Hz, CH alpha), 10.9 (0H+NH)S EXAMPLE 9.

A solution of 2-amino-6-hydroxytetralin (2.6 g) and 1-naphthyloxy-15 2,3-epoxypropane (3.2 g) in ethanol (80 ml) is refluxed for 5 hours, and then allowed to cool to room temperature. The solvent is evaporated off under reduced pressure and the thus obtained oil is chromatographed on a silica gel colum (NE3CK 70-230 mesh) eluting first with ethyl acetate up to complete elution of the first spot, and then with a 20 mixture ethyl acetate/methanol 9/1 v/v up to complete elution of thefractions of the pro&ict. The fractions thus obtained are pooled aid concentrated inder reduced pressure. The residue is dissolved in isopropanol (20 ml) and a solution of fumaric acid (0.95 g) in isopropanol (10 ml) is then added thereto. The mixture is filtered, washed with ethyl et.her and the residue is dissolved in water. A concentrated sodium hydroxide solution is then added thereto up to a basic pH and the solution is extracted with ethyl acetate. The organic extract is dried over sodium sulfate and concentrated to dryness. The residue is: taken up in a small amount of ethyl acetate and filtered yielding 1.9 g of 30 N-(6-hydroxy-l»2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3- (1-naphthyloxy)propanamine; m.p. 118-120°C.

EXAMPLE 10.

A solution of 2-amino-7-hydroxytetralin (2.45 g) and l-(2-methylphenoxy)-2,3-epoxypropane (2.5 g) in ethanol (75 ml) is 35 -refluxed for 5 hours. Ethanol is evaporated off, the residue is taken 50 up in acetone (20 ml) and the solution is made acidic by the addition of HCL/isopropanol. The mixture is filtered off, washed with ethyl ether and the product thus obtained is recxystaUized from 95% ethanol (30 ml), affording 1.7 g of N-(7-hydroxy-l,2,3,4-tetrahydro- naphth-2-yl)-2-hydroxy-3-(2-methylphenoxy)propanamine hydrochloride ; m.p. 224-226°C.

EXAMPLE 11.

Following the procedure described in Example 2, but replacing 1-naphthyloxy-2,3-epoxypropane with l-(2-methylphenoxy)-2,3-epoxy-propane, and crystallizing the obtained product from absolute ethanol, N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-methylphenoxy)-propanamine hydrochloride is afforded; m.p. 180-182°C.

EXAMPLE 12.

A solution of 1-aminotetralin (2.95 g) and l-(2-methylphenoxy)-2,3-epoxypropane (3.3 g) in ethanol (80 ml) is heated to the reflux temperature for 5 hours. Ethanol is then evaporated off and the reside is chromatographed on a silica gel colurrn eluting with a mixture ethyl acetate/cyclohexane 7/3 v/v. The combined fractions are evaporated to dryness and the residue is taken up in Isopropanol (40 ml). The solution is made acidic by the addition of HCl/isopropanol, then isopropyl ether (40 ml) is added thereto and the reaction mixture is allowed to stand for 2 hours at 0-5°C. The precipitate is recovered by filtration and crystallized from isopropanol (20 ml) yielding 2.5 g of N-(1,2,3,4-tetrahydronaphth-l-yl)- 2-hydroxy-3-(2-methylphenoxy)propanamine hydrochloride; m.p. 123-1248C.

EXAMPLE 13. (a) A solution of 1-/1-(p-toluenesulfonyl)indol-4-yloxy/-2,3- epoxypropane (3.9 g) and 2-amino-7-methoxytetralin (2.2 g) in isopropanol (40 ml) is refluxed for 3 hours. The reaction mixture is then evaporated to dryness, the residue is taken up in ethyl acetate and the thus obtained solution is washed with water, dried over sodium sulfate and evaporated to dryness. The residue is taken up in ethyl acetate/isopropanol and the obtained solution 51 is made acidic by the addition of HCl/isopropanol. The precipitate which forms is recovered by filtration, and suspended in hot ethanol. The suspension is then cooled, filtered and dried yielding 3.1 g of N-(7-tnethoxy-l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3« £l-(p-toluenesulfonyl)indol-4-yloxy/propanamine hydrochloride; m.p. 228-231°C. (b) A mixture containing the above product (12.5 g), and sodium hydroxide (5.4 g) In water (34 ml) and 95% ethanol (76 ml) is 10 refluxed for 4 hours and then cooled to room temperature. Ethyl acetate (400 ml) is then added thereto and the organic phase is separated, washed with water, dried over sodium sulfate and evaporated to dryness. jhe residue is chromatographed on 3 silica gel column eluting with a mixture ethyl acetate/methanol 95/5 v/v. The fractions containing the pure product are pooled and evaporated to dryness yielding 6 g of N- ( 7-me thoxy-1,2,3,4-1 e t rahydronaph th-2-y1)-2-hydroxy-3-(indol-4-yloxy)propanamine as an amorphous solid.

NMR (DMS0-d6): 3.68 (3H, s,*OCH ), 7.2 (IH, dd, Jl«J2=2Hz, CH 3 alpha) EXAMPLE 14.

A mixture of 1-aminotetralin (2.94 g) and l-(2-methoxyphenoxy)-2,3-epoxypropane (3.6 g) in absolute ethanol (100 ml) is refluxed for 5 hours. The solvent is then evaporated off under reduced pres-25 sure, the residue is chromatographed on a silica column eluting with ethyl acetate. The thus obtained fractions are combined and evaporated to dryness and the residue is taken up in a mixture hexane/isopropyl ether 1/1 v/v and filtered. The solid on filter is crystallized from ethyl acetate yielding 2 g of N-(l,2,3,4-tetrahydro-30 naphth-l-yl)-2-hydroxy-3-(2-methoxyphenoxy)propanamine; m.p. 99-102°C.

EXAMPLE 15.

A solution of 2-aminotetralin (2.2 g) and l-(2-methoxyphenoxy)-2,3-epoxypropane (2.7 g) in ethanol (70 ml) is refluxed for 5 hours 35 and the solvent is then evaporated off under reduced pressure. The 52 residue is taken up in isopropanol and the hot stirred solution is acidified by the addition of HCl/isopropanol. The precipitate is recovered by filtration yielding 2.1 g of N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-methoxyphenoxy)propanamine hydrochloride; m.p. 140-143°C.

EXAMPLE 16.

A mixture of 2-amino-6-hydroxytetralin (0.9 g) and l-(2-methoxy)-phenoxy-2,3-epoxypropane (1 g) in absolute ethanol (30 ml) is refluxed for 5 hours. The solvent is then evaporated under reduced pressure and the residue is chromatographed on a silica gel column eluting first with ethyl acetate and then with a mixture ethyl acetate/methanol 9/1 v/v. The fractions containing the product are pooled and evaporated to dryness, the obtained residue is dissolved in acetone and the hot solution is acidified by stirring in HCl/isopropanol. The precipitate is recovered by filtration yielding 0.25 g of N-(6-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-methoxyphenoxy)propanamine hydrochloride; m.p. 146-148°C.

EXAMPLE 17.

A mixture of 2-amino-7-hydroxytetralin (3.15 g) and l-(2-methoxy)-phenoxy-2,3-epoxypropane (3.45 g) in absolute ethanol (100 ml) is refluxed for 5 hours. The solvent is then evaporated under reduced pressure and the residue is chromatographed on a silica gel column eluting first with ethyl acetate and then with a mixture ethyl acetate/methanol 85/15 v/v. The combined fractions are evaporated to dryness, the oily residue is dissolved in absolute ethanol and acidified by the addition of HCl/isopropanol. The precipitate is then recovered by filtration yielding 2 g of N-(7-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)- 2-hydroxy-3-(2-methoxyphenoxy)propanamine hydrochloride; m.p. 173-176°C.

EXAMPLE 18.

A mixture of 1-aminotetralin (5.15 g) and l-(2-allyloxy)-phenoxy-2,3-epoxypropane (7.22 g) in absolute ethanol (80 ml) is refluxed for 5 hours, the solvent is evaporated off under reduced 53 pressure and the residue is chromatographed on a silica gel column eluting with a mixture ethyl acetate/cyclohexane 7/3 v/v. The pooled fractions are evaporated to dryness under reduced pressure,, the residue is taken up in a very small amount of ethyl ether, filtered and crystallized from isopropyl ether yielding 2.1 g of N-(1,2,3,4-tetrahydronaph th-l-yl)-2-hydroxy-3-(2-allyloxyphenoxy)propanamine; m.p. 72-75°C.

EXAMPLE 19.

A mixture of 2-aminotetralin (2.2 g) and l-(2-allyloxy)-phenoxy-2,3-epoxypropane (3.1 g) in absolute ethanol (80 ml) is refluxed for 5 hours. The solvent is evaporated off and the residue is chromatographed on a silica gel column eluting first with ethyl acetate and then with a mixture ethyl acetate/methanol 9/1 v/v. The product-containing fractions are pooled and evaporated to dryness and the obtained residue is taken up in ethyl ether and filtered yielding 2.6 g of N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-allyloxy-phenoxy)propanamine; m.p. 98-100°C.

EXAMPLE 20.

A mixture of 2-amino-7-hydroxytetralin (3.4 g) in absolute ethanol (80 ml) and l-(2-allyloxy)phenoxy-2,3-epoxypropane (4.12) in absolute ethanol (50 ml) is heated to the reflux temperature for 5 hours. Ethanol is then evaporated off to dryness and the obtained residue is chromatographed on a silica gel column eluting first with ethyl acetate and then with a mixture ethyl acetate/methanol 9/1 v/v. The fractions which contain the desired product are pooled and evaporated to dryness, the thus obtained oily residue is dissolved in isopropanol and the solution is made acidic by the addition of HCl/isopropanol. The precipitate which forms is recovered by filtration and crystallized from absolute ethanol affording 3.1 g of N-(7-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-allyloxyphenoxy)propanamine hydrochloride; m.p. 183-185°C.

EXAMPLE 21. 54 A mixture of 2-amino-6-hydroxytetralin (2.6 g) and l-(2-allyl-oxyphenoxy)-2,3-epoxypropane (3.3 g) in absolute ethanol (80 ml) is refluxed for 5 hours, the solvent is then evaporated off under reduced pressure and the residue is chromatographed on a silica gel 5 column eluting first with ethyl acetate and then with a mixture ethyl acetate/methanol 9/1 v/v. The combined fractions are evaporated to dryness, the obtained residue is dissolved in Isopropanol, and the solution is acidified by the addition of HCl/isopropanol. The precipitate which forms is recovered by filtration and crystallized 10 from isopropanol yielding 2.1 g of N-(6-hydroxy-l,2,3,4-tetrahydronaphth- 2-yl)-2-hydroxy-3-(2-allyloxyphenoxy)propanamine hydrochloride; m.p. 145-147°C.

EXAMPLE 22.

A mixture of 1-aminotetralin (5.15 g) and l-/l-(p-toluene- sulfonyl)indol-4-yloxy/-2,3-epoxypropane (12 g) in absolute ethanol (150 ml) is refluxed for 6 hours. The solvent is then evaporated off and the oily residue is dissolved in absolute ethanol (100 ml). A solution of sodium hydroxide (7.5 g) in water (30 ml) is added thereto. 20 The obtained reaction mixture is refluxed for 6 hours and then evaporated under reduced pressure. The residue which is obtained is then dissolved in ethyl acetate (150 ml), the organic solution is thoroughly washed with water and dried over sodium sulfate.

Ethyl acetate is then evaporated off and the obtained oily 25 residue is chromatographed on a silica gel column eluting with a mixture ethyl acetate/cyclohexane 7/3 v/v. The combined fractions are evaporated to dryness, the oily residue is taken up in a very small amount of ethyl ether which is then removed using a vane punp yielding 1J5 g of N-(1,2,3,4-tetrahydronaphth-l-yl)-2-hydroxy-3-30 (4-indolyloxy)propanamine, as a vitreous solid.

IR(KBr): 3404, 2926, 1361, 1244, 1092, 740 cm-1 EXAMPLE 23.

A mixture of 2-amino-6-hydroxytetralin (3.26 g) and l-/l-(p-toluenesulfonyl)indol-4-yloxy7-2,3-epoxypropane (6.8 g) in 35 absolute ethanol (80 ml) is refluxed for 5 hours. The solvent is then 55 evaporated off and the residue is suspended in absolute ethanol (185 ml). A solution of sodium hydroxide (4.8 g) in water (55 ml) is then added thereto and the reaction mixture is refluxed for 6 hours. The solvent is evaporated off under reduced pressure, the residue is dissolved in ethyl acetate (200 ml) and the obtained solution is v^ashed twice with water, the organic phase is dried over sodium sulfate and evaporated under reduced pressure. The obtained residue is chromatographed on a silica gel column eluting first with ethyl acetate and then with a mixture ethyl acetate/methanol 85/15 v/v. The combined fractions are concentrated to dryness, the residue is taken up with ethyl ether and filtered yielding 2.4 g of N-(6-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(4-indolyloxy )propanamine as a vitreous solid.

NMR (DMS0-d6): 7.15 (*H, dd, Jl~J2=2Hz),CH alpha), 10.9 (OH+NH)& IR(KBr): 3408, 2923, 1501, 1240, 742 cm-1 EXAMPLE 24.

A mixture of 2-aminotetralin (5 g) and l-£l-(p-toluenesulfonyl)-indol-4-yloxy7-2,3-epoxypropane (11.7 g) in absolute ethanol (150 ml) is refluxed for 6 hours. The solvent is evaporated to dryness, the} obtained residue is taken up in hot isopropanol (100 ml) and the solution is made acidic by the addition of hydrochloric acid in isopropanol under stirring. The precipitate which forms is recovered by filtration, dissolved in a mixture of ethanol (250 ml) and aqueous sodium hydroxide (7.6 g in 85 ml of water). The reaction mixture is refluxed for 6 hours, the solvent is evaporated to dryness and the residue is taken up in ethyl acetate (200 ml). The obtained solution is washed twice with water, dried over sodium sulfate and concentrated by evaporating off the solvent. The residue is chromatographed on a silica gel column eluting with ethyl acetate. The cantoned fractions are concentrated to dryness and the residue is dissolved in ethyl ether (20 ml) and crystallized therefrom yielding 3.5 g of N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(4-indolyloxy)propanamine; m.p. 65-68°C. 56 EXAMPLE 25.

A mixture of 2-amino-6-hydroxytetralin (2.6 g) and 1-(2-allylphenoxy)- 2,3-epoxypropane (3.05 g) in absolute ethanol (80 ml) is refluxed for 5 hours. The solvent is removed by evaporation under reduced pressure and the residue is dissolved in a mixture isopropanol/ethyl ether 1/1 v/v. The solution is made acidic by the addition of HCl/isopropanol and the precipitate is recovered by filtration yielding 2.8 g of N-(6-hydroxy-l,2,3,4-tetrahydronaphth- 2-yl)-2-hydroxy-3-(2-allylphenoxy)propanamine hydrochloride; m.p. 212-215°C.

EXAMPLE 26.

A mixture of 2-amino-6-hydroxytetralin (0.9 g) and 1-(2-methylphenoxy)-2,3-epoxypropane (0.91 g) in absolute ethanol (30 ml) is refluxed for 5 hours. The solvent is evaporated off, the residue is dissolved in isopropanol (120 ml) and the obtained solution is made acidic by the addition of HCl/isopropanol. The precipitate which forms is recovered by filtration and crystallized from 95% ethanol giving 0.55 g of N-(6-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-methylphenoxy)propanamine hydrochloride; m.p. 232-234°C.

EXAMPLE 27. 2-Aminotetralin (1.4 g) is added to a solution of l-(2,3-epoxypropoxy)phenothiazine (2.71 g) in absolute ethanol (30 ml) and the obtained reaction mixture is refluxed for 8 hours. The solvent is then evaporated off under reduced pressure, the residue is taken up in Isopropanol, the obtained solution is heated and hydrogen chloride saturated isopropanol is added thereto inder starring. The precipitate is recovered by filtration affording N-( 1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3- (1-phenothiazinyloxy)propanamine hydrochloride ((1) : R= H, Ar ■ radical 2 wherein Z is S, and the chain is attached to position 2 of the tetralin.)' EXAMPLE 28.

Following the procedure of Example 27, but starting from 6-(2,3-epoxypropoxy)-l-oxo-l,2,3,4-tetrahydro-beta-carboline (2.46 57 g), N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(l-oxo-l,2,3,4-tetrahydro-beta-carbolin-6-yloxy)propanami.ne hydrochloride is obtained ((i): R = H, Ar = radical 2 wherein Z is CD and Z' is H, and the chain is attached to position 2 of the 5 tetralin) .

EXAMPLE 29.

Operating as described in Example 27, but starting from a solution of l-(2,3-epoxypropoxy)-9,10-dihydro-9,10-ethanoanthracene (2.78 g) in ethanol (30 ml), N-(l,2,3,4-tetrahydronaphth-lO 2-yl)-2-hydroxy-3-(9,10-dihydro-9,10-ethanoanthr-l-yloxy)propanamine hydrochloride is obtained ((i): R ■ H, Ar - radical 5 wherein Z is ethylene, and the chain is attached to position 2 of the tetralin).

EXAMPLE 30.

Following the general procedure of Example 27, but starting from 15 5-(2,3-epoxypropoxy)coumarin (2.18 g) in ethanol (30 ml), N—(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3- (coumarin-5-yloxy)propanamine hydrochloride is obtained ((1): R = H, Ar = radical 8 wherein Z is hydrogen, and the chain is attached to position 2 of the tetralin).

EXAMPLE 31.

A mixture of 2-aminotetralin (22.7 g), 3-chloro-2-hydroxy-l-(4-methylcoumarin-7-yloxy)propane (26.9 g), in absolute ethanol (35 ml) is charged in a sealed vessel and heated to 100°C for 4 hours. The reaction mixture is then cooled and 25 concentrated under reduced pressure. The residue is taken up in IN hydrochloric acid (200 ml), extracted with chloroform; the aqueous phase is separated off and neutralized with sodium carbonate. Water is then evaporated off and the residue is taken up with isobutylmethylketone and filtered. Hydrogen chloride is then bubbled into the filtrate to completely 30 precipitate N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy- 3-(4-methylcoumarin-7-yloxy)propanamine hydrochloride, ((1): R - H, Ar ■ radical 8 wherein Z is methyl, and the chain is attached to position 2 of the tetralin moiety) which is then crystallized from Isopropanol. 58 EXAMPLE 32.

A mixture of 5-hydroxy-3-methyl-l-phenylpyrazole (or 3-methyl-1-phenyl-1,2-pyrazolin-5-one) (5.22 g) , epichlorohydrin (16.6 g) and piperidine (2 drops) is heated to 110°C for 90 minutes 5 and then concentrated under reduced pressure. The obtained residue is taken up with 33% sodium hydroxide (45 ml) under stirring for 30 minutes, and then extracted with chloroform. The organic phase is washed with water, dried and concentrated under reduced pressure to afford a residue which is dissolved in chloroform and passed through a silica 10 gel coiunn. The solvent is then evaporated off to obtain 5-(2,3-epoxypropoxy)-3- nethyl-l-phenylpyrazole (2.5 g) which is dissolved in absolute ethanol (30 ml) and 2-aminotetralin (1.61 g) is then added thereto. Following the general method described in Example 27, N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(3-methy1-1-phenylpyrazol-5-yloxy)propanamine 15 dihydrochloride ((i): R = H, Ar = radical 9 wherein Z is methyl and Zf is phenyl, and the chain Is attached to position 2 of the tetralin ) is obtained.

EXAMPLE 33.

A mixture of 3-hydroxy-2-methyl-4-oxopyrane (12.6 g), sodium 20 hydroxide (4 g), epichlorohydrin (9.25 g) and water (50 ml) is stirred at room temperature, under nitrogen atmosphere, for 3 hours; then it is extracted four times with chloroform (120 ml) and the organic phase is washed with water, dried and evaporated to dryness yielding 8.3 g of 25 3-(2,3-epoxypropoxy)-2-methyl-4-oxopyrane. A mixture of said product and 2-amlnotetralin (7.3 g) in absolute ethanol (100 ml) is charged into a sealed vessel, heated to 80°C for 5 hours, then cooled and evaporated under reduced pressure. The obtained residue is dissolved into ethyl acetate and a solution of fumaric acid in ethyl acetate Is 30 then added thereto. The precipitate which forms is recovered by fil tration and crystallized from ethanol affording N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-methyl-4-oxopyran-3-yloxy)propanamine hydrogenfumarate ((i): R ■ H, Ar = radical _1£ wherein Z is methyl, and the chain is attached to position 2 35 of the tetralin). 59 EXAMPLE 34.

By operating according to Example 27, but starting from 5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril (2 g) and 2-am:Lnotetralin (1.35 g) in ethanol (40 ml), N—(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(3,4-dihydrocarbostyryL 5-oxy)propanamine hydrochloride ((i) : R " H, Ar ■ radical 1_1 wherein Z is H and the chain bridges position 4 of the radical Ar to position 2 of the tetralin) is obtained.

EXAMPLE 35.

A mixture of 4-hydroxy-9-oxofluorene (10 g) and sodium hydroxide (1.9 g) in water (100 ml) is refluxed under nitrogen atmosphere for 1 hour. The reaction mixture is then allowed to cool to 50°C, epichlorohydrin (7 g) is added thereto and the reaction mixture is then stirred at 50°C for 16 hours. Acetone (40 ml) is added thereto and the obtained mixture is extracted three times with ethyl acetate. The organic extracts are combined, washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue (13.5 g) is taken up in ethanol (150 ml) and 2-aminotetralin (8 g) is then added thereto. The reaction mixture is refluxed for 8 hours and then worked-up as described In Example 27, giving N- (1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(9-oxofluoren-4-yloxy)propanamine hydrochloride ((i): R = H, Ar ■ radical wherein Z Is ^OO, and the chain is attached to position 2 of the tetralin ).

EXAMPLE 36.

Following the procedure described in Example 27, but starting from 2,3-dimethyl-4-(2,3-epoxypropoxy)indole (10 g) and 2-aminotetralin (6.9 g) in ethanol (100 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy- 3-(2,3-dimethylindol-4-yloxy)propanamine hydrochloride is obtained ((i): R = H, Ar ■ radical 1^ wherein Z is methyl, and the chain is attached to position 2 of the tetralin ).

EXAMPLE 37.

Following the procedure described in Example 27, but starting from ethyl 4-(2,3-epoxypropoxy)indole-2-carboxylate (25.1 g), obtained 60 from ethyl 4-hydroxyindole-2-carboxylate and epichlorohydrin according to the method of Belgian Patent 739,545, and 2-aminotetralin (14.8 g) in ethanol (120 ml), N-(l,2,3,4-tetrahydro-naphth-2-yl)-2-hydroxy-3-(2-ethoxycarbonylindol-4-yloxy)propanamine hydrochloride is obtained ((i): R = H, Ar = radical L5 wherein Z is ethoxy, and the chain is attached to position 2 of the tetralin ) which is crystallized from a mixture ethanol/isopropanol 2/1.

EXAMPLE 38.

Following the procedure described in Example 27, but starting from ethyl 4-(2,3-epoxypropoxy)indole-2-acetate (27.5 g), obtained from ethyl 4-hydroxyindole-2-acetate and epichlorohydrin according to the method of Swiss Patent 526,542, and 2-aminotetralin (14.8 g) in ethanol (120 ml), N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-ethoxycarbonylmethylindol-4-yloxy)propanamine hydrochloride is obtained ((i): R = H, Ar = radical lj> wherein Z is ethoxy, and the chain is attached to position 2 of the tetraliii) which is crystallized from a mixture ethanol/isopropanol 2/1.

EXAMPLE 39.

Following the procedure described in Example 27, but starting from 2-ethy1-4-(2,3-epoxypropoxy)indole (10 g), obtained from 2-ethyl-4-hydroxyindole and epichlorohydrin according to the method described in Swiss Patent 527,188, and 2-aminotetralin (7.95 g) in ethanol (90ml), N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-ethyllndol-4-yloxy)propanamine hydrochloride is obtained ((i): R = H, Ar = radical 1_7 wherein Z is ethyl, and the chain is attached to position 2 of the tetralin ) .

EXAMPLE 40.

Following the procedure described In Example 27, but starting from 4-(2,3-epoxypropoxy)-2-oxoindoline (20.5 g) and 2-amlnotetralin (14.81 g) in ethanol (150 ml), N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-oxo-2,3-dihydroindol-4-yloxy)propanamine hydrochloride is obtained, ((i): R ■ H, Ar - radical lj5 wherein Z is H, and the chain is attached to position 2 of the tetraliii) .

EXAMPLE 41. 61 Following the general method described in Example 27, but starting from 8-(2,3-epoxypropoxy)thiochromane (22.2 g), obtained from 8-hydroxythiochromane and epichlorohydrin according to the teaching of Belgian Patent 765,313, and 2-aminotetralin (14.82 g), 5 N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(thiochroman-8-yloxy)propanamine' hydrochloride is obtained ((i): R = H, Ar = radical 19_ wherein Z is H and the chain bridges position 8 of the Ar radical and position 2 of the tetralin ) .

EXAMPLE 42.

Following the procedure described in Example 27, but starting from 7-(2,3-epoxypropoxy)-3-methylindene (19 g), obtained from 3-methy1-7-indenol and epichlorohydrin according to the teaching of JP 73-01070, and 2-aminotetralin (14.83 g), N-(l,2,3,4-tetrahydro-naphth-2-yl)-2-hydroxy-3-(3-methylinden-7-yloxy)propanamine hydrochloride is obtained ((1): R = H, Ar = radical 23 wherein Z is H et Z' is methyl, and the chain is attached to position 2 of the tetralin ) .

EXAMPLE 43.

Following the procedure described in Example 27, but starting from 20 2-acetyl-7-(2,3-epoxypropoxy)benzofuran (23.2 g), obtained from 2-acetyl-7- hydroxybenzofuran and epichlorohydrin according to the teaching of Belgian Patent 783,440, and 2-aminotetralin (14.81 g) in ethanol (120 ml), N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-acetylbenzofuran-7-yloxy)propanamine hydrochloride is obtained 25 ((1): R = H, Ar = radical 24 wherein Z is acetyl and the chain bridges position 4 of the Ar group to position 2 of the tetralin) .

EXAMPLE 44.

By operating as described In Example 43, but starting from 2-acety1-4-(2,3-epoxypropoxy)benzofuran, 30 N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-acetylbenzofuran- 4-yloxy)propanamine hydrochloride is obtained ((IF), L" ■ H, E" and G", together, form a group -CH=C(C0CH3)-0-, R is H, and the chain Is attached to position 2 of the tetralin) .

EXAMPLE 45. 62 Following the procedure of Example 27, but starting from A-(4,5,6,7-tetrahydrobenzofuran-2-yl)-l-(2,3-epoxypropoxy)benzene (27 g), obtained according to the teaching of US Patent 3,894,058, and 2-aminotetralin (14.85 g) in ethanol (150 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-32^4-(4,5,6,7- tetrahydrobenzofuran-2-yl)_/phenox2£/propanamine hydrochloride is obtained ((i): R = H, Ar = radical 31_ wherein Z is H, and the chain is attached to position 2 of the tetralin).

EXAMPLE 46.

Following the procedure of Example 27, but starting from 4-(2,3-epoxypropoxy)-2,1,3-benzothiadiazole (20.8 g), prepared according to the teaching of DE-2,404,858, and 2-aminotetralin (14.82 g) in absolute ethanol (125 ml), N-(l,2,3,4-tetrahydro-naphth-2-yl)-2-hydroxy-3-(2,1,3-benzothiadiazol-4-yloxy)propanamine 15 hydrochloride is obtained ((i): R = H, Ar = radical 32_, and the chain is attached to position 2 of the tetralin).

EXAMPLE 47.

Following the procedure described in Example 27, but starting from 7-(2,3-epoxypropoxy)phtalide (20.6 g), obtained from 20 7-hydroxyphtalide and epichlorohydrin according to the teaching of Belgian Patent 815,745, and 2-aminotetralin (14.81 g) in absolute ethanol (125 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-phtalid-7-yloxypropanamine hydrochloride is obtained ((iF): L" = H, E" and G" 25 taken together, form a group -CO-O-CHp-, R = H, and the chain is attached to position 2 of the tetralin).

EXAMPLE 48.

By operating as described in Example 27, but starting from khellin quinol 2,3-epoxypropyl ether (28.8 g) and 2-aminotetralin (14.83 g) 30 In absolute ethanol (150 ml), the hydrochloride of khellin quinol 3-(l,2,3,4-tetrahydronaphth-2-ylamino)-2-hydroxypropyl ether is obtained ((1): R ■ H, Ar - radical 14, and the chain is attached to position 2 of the tetralin) .

EXAMPLE 49.

Following the procedure of Example 27, but starting from 4-(2,3-epoxypropoxy)-1-oxoindane (18.8 g, see JP 49-048649) and 2-aminotetralin (14.81 g) in absolute ethanol (120 ml), N-(1,2,3,4-tetrahydronaphth-2—yl)-2-hydroxy- 63 3-(l-oxoindan-4-yloxy)propanamine hydrochloride is obtained ((i): R = H, Ar = radical 35, and the chain i.s attached to position 2 of the tetralin). EXAMPLE 50.

Following the procedure of Example 27, but starting from 5 4-(2,3-epoxypropoxy)-2-oxoindoline (20.3 g, see JP 49-094666) and 2-aminotetralin (14.81 g) in ethanol (100 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-oxoindolin-4-yloxy)-propanamine hydrochloride is obtained ((i): R = H, Ar « radical 36, and the chain is attached to position 2 of the tetralin). 10 EXAMPLE 51.

Following the procedure of Example 35, but starting from 1-hydroxy-9-oxofluorene, N-(1,2,3,4-tetrahydronaphth-2-yl)- 2-hydroxy-3-(9-oxofluoren-l-yloxy)propanamine hydrochloride is obtained ((i): R = H, Ar = radical 37 > and the chain is attached to position 2 of the tetralin ).

EXAMPLE 52.

A mixture of 4-hydroxy-2-methoxymethylindole (8.3 g), epichlorohydrin (8.9 g) and sodium hydroxide (1.92 g) in water (35 ml) and dioxane (35 ml) is stirred at room temperature for 24 hours, and then it is 20 extracted with methylene chloride. The organic phase is dried and the solvent evaporated off. The obtained residue (10.2 g) is taken up in absolute ethanol (80 ml) and 2-aminotetralin (6.49 g) is added thereto. By operating then as described in Example 27, N-(l,2,3,4-tetrahydronaphth-2-yl)-30 2-hydroxy-3-(2-methoxymethylindol-4-yloxy)propanamine hydrochloride is obtained ((i): R « H, Ar ° radical 38, and the chain is attached to position 2 of the tetralin ) .

EXAMPLE 53.

Following the procedure of Example 27, but starting from 35 2,2,5,7,8 -pentamethyl-6-(2,3-epoxypropoxy)chromane (27.4 g), prepared by the method described in NL-A-6911816, and 2-aminotetralin (14.85 g), N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2,2,5,7,8-pentamethylchroman-6-yloxy)propanamine hydrochloride is obtained ((i): R ■ H, Ar = radical 4_1, and the chain is attached to 40 position 2 of the tetralin).

EXAMPLE 54. 64 Following the procedure of Example 27, but starting from 5-(2,3-epoxypropoxy)-l-oxotetralin (20.2 g), prepared as described in BE 739,195, and 2-aminotetralin (14.81 g) in absolute ethanol (130 ml), N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-5 (1-oxo-l,2,3,4-tetrahydronaphth-5-yloxy)propanamine hydrochloride is obtained ((iA), R = H, E and G, taken together form a group -CH2-CH2-CH2-CO-, and the chain is attached to position 2 of the tetralin).

EXAMPLE 55.

Following the procedure of Example 27, but starting from 7-(2,3-epoxypropoxy)indene (18.8 g) , obtained from 7-hydroxyindene and epichlorohydrin by the method described in DE 1,955,229, and 2-aminotetralin (14.85 g) in absolute ethanol (120 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-inden-7-yloxy-15 propanamine hydrochloride is obtained ((i): R = H, Ar = radical 43, and the chain is attached to position 2 of the tetralin ) .

EXAMPLE 56.

Following the procedure of Example 27, but starting from 8-(2,3-epoxypropoxy)-2H-chromene (20.4 g) and 2-aminotetralin (14.85 20 g) in absolute ethanol (120 ml), N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2H-chromen-8-yloxy)-propanamine hydrochloride is obtained ((i): R ■ H, Ar = radical 44, and the chain is attached to position 2 of the tetralin ) .

EXAMPLE 57.

A mixture of 1,4-dihydroxyindane (1.4 g), epichlorohydrin (1 g) and sodium hydroxide (0.4 g) in water (15 ml) is stirred at room temperature for 24 hours and then it is extracted with ethyl ether. The organic phase is dried and evaporated to dryness and the obtained residue (1.2 g) Is taken up In absolute ethanol (20 ml). A solution 30 of 2-aminotetralin (0.87 g) in ethanol (10 ml) is added thereto and the reaction mixture Is then processed as decribed in Example 27. N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy- 3-(l-hydroxyindan-4-yloxy)propanamine hydrochloride is thus obtained ((1): R » H, Ar ■ radical 45, and the chain is attached to position 2 of the tetralin ) • i 65 EXAMPLE 58.

Following the procedure of Example 27, but starting from 4-(2,3-epoxypropoxy)indane (19 g) and 2-aminotetralin (14.81 g) in absolute ethanol (150 ml), 5 N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-indan-4-yloxypropanamine hydrochloride is obtained ((iA): E and Gt taken together, represent a group -CH2-CH2-CH2-, R = H, and the chain is attached to position 2 of the tetralin ).

EXAMPLE 59.

Following the general procedure of Example 27, but starting from 4-(2,3-epoxypropoxy)-1,2-benzisothiazole (20.7 g) prepared as described in 8E 863,622, and 2-aminotetralln (14.82 g) in absolute ethanol (150 ml), N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(l,2-benzisothiazol- 4-yloxy)propanamine hydrochloride is 15 obtained ((i): R = H, Ar = radical 58_, and the chain is attached to position 2 of the tetralin).

EXAMPLE 60.

Following the procedure of Example 27, but starting from 4-(2,3-epoxypropoxy)-3-methy1-1,2-benzisoxazole (20.5 g) 20 (DE-2,711,382) and 2-aminotetralin (14.82 g) in absolute ethanol (150 ml), N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(3-methyl-l,2-benzisoxazol-4-yloxy)propanamine hydrochloride is obtained ( (1), R = H, Ar = radical 59, and the chain is attached to position 2 of the tetralin).

EXAMPLE 61.

A solution of sodium hydroxide (1.175 g) in water (16 m) is added to a solution of 4-hydroxy-2-benzimidazolinone (4 g) in methanol (24 ml) and epichlorohydrin (4.16 g) is then added to the obtained mixture. After stirring at room temperature for 17 hours, the solvent is 30 evaporated off and the residue is extracted with ethyl acetate. The organic extract is washed with water, dried over magnesium sulfate and concentrated to dryness. The residue is taken up in ethanol (30 ml) and a solution of 2-aminotetralln (4.35 g) in ethanol (20 ml) is then added thereto. The reaction mixture is then processed as 35 described in Example 27 affording N-(l,2,3,4-tetrahydronaphth-2-yl)- 66 2-hydroxy-3-(2-oxobenzimidazolin-4-yloxy)propanamine hydrochloride C(i): R = H, Ar = radical 6JL_, Z = Z' = H, and the chain is attached to position 2 of the tetralin).

EXAMPLE 62.

Following the procedure of Example 27, but starting from 3-(2,3-epoxypropoxy)-2-cyanothiophene (18.1 g), prepared by the method described in DE-2,720,613 and 2-amlnotetralln (14.8 g) in ethanol (100 ml), N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy- 3-(2-cyanothien-3-yloxy)propanamine hydrochloride is obtained ((i): R ■ H, Ar = radical 62: wherein Z is H, the cyano group is at position 2 of the Ar radical and the chain bridges position 5 of the Ar group to position 2 of the tetralin ) .

EXAMPLE 63.

Following the procedure of Example 27, but starting from 4-(4-ethoxycarbonyl-1,2,3-thiadiazol-5-yl)-1-(2,3-epoxypropoxy)benzene (2.94 g) and 2-aminotetralin (1.49 g) in absolute ethanol (20 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy- 3-/4-(4-ethoxycarbony1-1,2,3-thiadiazol-5-yl)phenoxy7propanamine hydrochloride is obtained ((1): R = H, Ar ■ radical 63, wherein Z is a 4-C00C2H5 group, and the chain is attached to position 2 of the tetralin ).

EXAMPLE 64.

Following the procedure of Example 27, but starting from 2-/3-(2,3-epoxypropoxy)phenyl7-4-trifluoromethylimidazole (2.81 g), prepared as described in DE-2,608,448 and 2-aminotetralin (1.5 g) in absolute ethanol (20 ml), N-(1,2,3,4-tetraLydronaphth-2-yl)-2-hydroxy-3-Z3-(4-trifluoromethylimidazol-2-yl)phenoxY/propanamine hydrochloride Is obtained ((1): R = H, Ar - radical 64, wherein Z is trifluoromethyl, the positions of attachment of the Imidazole to the benzene ring are 2 and 4 respectively and the chain is attached to position 2 of the tetralin).

EXAMPLE 65.

A solution of sodium (2.3 g) in methanol (40 ml) is added to a solution of 3-pyridinol (9.5 g) in dimethylsulfoxide (100 ml). Methanol is then distilled off under reduced pressure and epichlorohydrin 67 (10.2 g) is added to the resulting solution kept at 25°C. The reaction mixture is stirred at 25°C for 4 hours then poured into ice/water (500 ml) and extracted with chloroform (100 ml + 75 ml + 50 ml + 25 ml). The organic extracts are pooled, washed with water (50 5 ml), dried and the solvent is evaporated to afford 3-(2,3-epoxypropoxy)pyridine as an oily residue. The oil thus obtained (3 g) is dissolved in ethanol (20 ml) and a solution of 2-amlnotetralln (3 g) in ethanol (20 ml) is added thereto. Following then the procedure of Example 27, N-(1,2,3,4-tetrahydronaphth-2-yl)-10 2-hydroxy-3-pyrid-3-yloxypropanamine hydrochloride is obtained ((1): R ■ H, Ar ■ radical 65^, wherein Z is H, and the chain is attached to position 2 of the tetralin)-EXAMPLE 66.

Following the procedure of Example 27, but starting from 15 l-acetyl-5-(2,3-epoxypropoxy)-1,2,3,4-tetrahydroquinoline (2.77 g) and 2-aminotetralin (1.49 g) in ethanol (30 ml), N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(l-acetyl-l,2,3,4-tetrahydroquinolin-5-yloxy)propanamine hydrochloride is obtained ((i): R = H, Ar = radical 6£, wherein Z is methyl, and the chain is 20 attached to position 2 of the tetralin) .

EXAMPLE 67.

Following the procedure of Example 27, but starting from l-acetyl-4-(2,3-epoxypropoxy)indazole (2.33 g) prepared as described in BE 853,949, and 2-aminotetralin (1.49 g) in ethanol (30 ml), 25 N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1-acetylindazol- 4-yl)propanamine hydrochloride is obtained ((i) : R = H, Ar = radical 67, wherein Z is H, Z' is acetyl, and the chain is attached to position 2 of the tetralin ) .

EXAMPLE 68.

Following the procedure of Example 27, but starting from 4-(2,3-epoxypropoxy)indazole (1.91 g), prepared as described in BE 853,949, and 2-aminotetralin (1.49 g) in absolute ethanol (30 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-indazol-4-ylpropanamine hydrochloride is obtained ((i): R = H, Ar ■ radical 67^ wherein Z ■ 35 Z1 = H, and the chain is attached to position 2 of the tetralin). 68 EXAMPLE 69.

Following the procedure of Example 27, but starting from 6-(2,3-epoxypropoxy)-l-hydroxyxanthen-9-one (2.84 g), prepared as described in US 3,912,733, and 2-aminotetralin (1.49 g) in absolute 5 ethanol (40 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1-hydroxy-9-oxoxanth-6-yloxy)propanamine hydrochloride is obtained ((i): R = H, Ar = radical 1., wherein Z is H, and the chain is attached to position 2 of the tetralin ) .

EXAMPLES 70 TO 77.

Following the procedure of Example 32, and reacting epichlorohydrin with 4-hydroxy-2-methylbenzofuran, 4-hydroxybenzofuran, -hydroxybenzofuran, 5-hydroxy-2-methylbenzofuran, 6-hydroxy-3-methylbenzofuran or 7-hydroxybenzofuran, in the presence 15 of piperidine, dissolving the thus obtained raw epoxide in absolute ethanol and adding thereto an ethanol solution of 2-aminotetralin, the following compounds are obtained respectively - N—(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-methylbenzofuran- 4-yloxy)propanamine hydrochloride (Ex. 70); -N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-benzofuran-4-yloxy- propanamine hydrochloride (Ex. 71); - N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-benzofuran-5-yloxy-propanamine hydrochloride (Ex. 72); - N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-methylbenzofuran-25 5-yloxy)propanamine hydrochloride (Ex. 73); - N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(3-methylbenzofuran-6-yloxy)propanamine hydrochloride (Ex. 74); and - N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-benzofuran-7-yloxy-propanamine hydrochloride (Ex. 75), (i.e. compounds (i): R «= H, Ar E radical 2T_, wherein one of Z and Z' is H and the other is methyl, and the chain is attached to position 2 of the tetralin ).

Analogously, starting from, respectively, 4-hydroxybenzothiophene or -hydroxybenzothiophene, the following compounds are obtained: 69 - N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-benzothien-4-yloxy-propanamine hydrochloride (Ex. 76); and - N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-benzothien-5-yloxy-propanamine hydrochloride (Ex. 77), ((i): R = H, Ar » radical 28, wherein Z is H, and the chain is attached to position 2 of the tetralin).

EXAMPLE 78.

Following the procedure of Example 33, but starting from 7-hydroxy-3-methylthiophene and epichlorohydrin in the presence of sodium hydroxide and contacting a solution of the obtained raw epoxide in absolute ethanol with a solution of 2-aminotetralin in absolute ethanol, N-(l,2,3,4-tetrahydronaphth-2-yl)- 2-hydroxy-3-(3-methylbenzothien-7-yloxy)propanamine hydrochloride is obtained ((i): R ■ H, Ar = radical 28, wherein Z is methyl and the chain bridges position 7 of the Ar radical and position 2 of the tetralin ) .

EXAMPLES 79 TO 81.

Following the procedure of Example 32, but starting from 5-hydroxy-1,4-benzodioxane and epichlorohydrin in the presence of piperidine and reacting an alcohol solution of the obtained epoxide with an alcohol solution of 2-aminotetralin, N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1,4-benzod:Loxan-5-yloxy)propanamine hydrochloride (Ex. 79) is obtained ((:LF): E" and G", taken together, represent a group -O-CH^-CH^-O-, L" and R are hydrogen and the chain is attached to position 2 of the tetralin).

Analogously, but starting from 6-hydroxy-3,4-dihydro-2H-l,5-benzodioxepine or 7-hydroxy-2,3,4,5-tetrahydro-l,6-benzodioxocine, the following compounds are obtained respectively: - N-(1,2,3,4-te trahydronaphth-2-yl)-2-hydroxy-3~(3,4-dihydro-2H-l,5-benzodioxepin-6-yloxy)propanamine hydrochloride (Ex. 80); and - N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2,3,4,5-tetra° hydro-1,6-benzodioxocin-7-yloxy)propanamine hydrochloride (Ex. 81), 70 ((i): R = H, Ar ■ radical 4i3, wherein n is 3 or 4 respectively, and the chain is attached to position 2 of the tetralin ).

EXAMPLES 82 AND 83.

Following the procedure of Example 33, but starting from epichlorohydrin and 8-hydroxyquinoline or 5-hydroxyquinoline respectively in the presence of sodium hydroxide and then treating an alcohol solution of the thus obtained epoxide with an alcohol solution of 2-aminotetralin, the following compounds are obtained respectively: - N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-quinolin-8-yloxy-propanamine hydrochloride (Ex. 82) ((i): R = H, Ar = radical 5(), and the chain is attached to position 2 of the tetralin moiety), and - N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-quinolin-5-yloxy-propanamine hydrochloride (Ex. 82) ((i): R ■ H, Ar = radical 49, and the chain is attached to position 2 of the tetralin ) .

EXAMPLE 84.

Operating as described in Example 27, but starting from 8-acetylmethoxy-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril (2.91g ^prepared by reacting 5,8-dihydroxy-3,4-dihydrocarbostyril with bromoacetone in the presence of potassium carbonate and in a mixture water/acetone 4/1, at the reflux temperature for 5 hours, and 2-aminotetralin (1.48 g) in absolute ethanol (30 ml), N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(8-acetylmethoxy-3,4-dihydrocarbostyril-5-yloxy)propanamine hydrochloride is obtained ((iF): R = H, L" = acetonyloxy, E" and G", taken together, represent a group -CI^-CHp-CO-NH-, and the chain is attached to position 2 of the tetralin).

EXAMPLES 85 A 88.

Following the procedure of Example 27, but starting from 2-propargyloxy-l-(2,3-epoxypropoxy)benzene (2.04 g) and 2-aminotetralln in absolute ethanol (30 ml), N-(l,2,3,4-tetra-hydronaphth-2-yl)-2-hydroxy-3-(2-propargyloxyphenyl)propanamine hydrochloride is obtained, m.p. 129-130°C (Ex. 85).

Analogously, starting from 2-propargyloxy-l-(2,3-epoxypropoxy)-benzene (2.04 g) and 1-aminotetralin (1.48 g), or 2-amino-7-hydroxytetralin (1.64 g), or 2-amino-6-hydroxytetralin (1.64 g), the following compounds are obtained, respectively: 71 - N-(1,2,3,4-tetrahydronaphth-l-yl)-2-hydroxy-3-(2-propargyl-oxyphenyl)propanamine hydrochloride, m.p. 114-116°C (Ex. 86); - N-(7-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-propargyloxyphenyl)propanamine hydrochloride, m.p. 158-160°C (Ex. 87); and - N-(6-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-propargyloxyphenyl)propanamine hydrochloride, m.p. 179-182°C (Ex. 88).

EXAMPLES 89 AND 90.

Following the procedure of Example 27, but starting from 1-(2-acetamido-3-nitrophenoxy)-2,3-epoxypropane (5 g) and 2-aminotetralin (2.96 g) in absolute ethanol (80 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy- 3-(2-acetamido-3-nitrophenoxy)propanamine hydrochloride is obtained 15 ((iA): R = H, E = acetamido, G = nitro, and the chain is attached to position 2 of the tetralin). (Ex. 89).

A mixture of N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-acetamido-3-nitrophenoxy)propanamine hydrochloride (4 g) and 97% formic acid (19 ml) is charged in a hydrogenation vessel and freezed. 20 The air contained in the reaction vessel is replaced by nitrogen and % Pd/C (0.25 g) is rapidly introduced therein. Hydrogenation is carried out at room temperature and 2.5 bar until the hydrogen has been completely absorbed. The reaction mixture is then heated, at atmospheric pressure, for 2 hours by means of a boiling 25 water-bath. The catalyst is filtered off, the filtrate is evaporated to dryness and the obtained residue is taken up in hydrogen chloride saturated-lsopropanol.

N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-benzimidazol-4-yloxy-propanamine dlhydrochloride is thus obtained ((iF): R • L" ■ H, E" 30 and G", taken together, form a group -N-CH-NH-, and the chain is attached to position 2 of the tetralin). (Ex. 90).

EXAMPLES 91 AND 92.

A mixture of 4-hydroxy-9-oxoxanthene (1.1 g), epichlorohydrin (4 g) and piperidine (0.01 g) is heated on a boiling water-bath for 5 35 hours. Excess epichlorohydrin is then removed by distillation and the 72 residue is dissolved in ethyl acetate (50 ml). The organic solution is washed with 2N NaOH (20 ml) and concentrated to dryness yielding l-chloro-2-hydroxy-3-(9-oxoxanth-4-yloxy)propane (0.6 g) as a raw product. A solution of this product in absolute ethanol (20 ml) is 5 then added to a solution of 2-aminotetralin (0.3 g) in ethanol (10 ml) and the mixture is refluxed for 4 hours and then evaporated to dryness. The obtained residue is taken up in hydrogen chloride saturated-isopropanol affording the desired N-(l,2,3,4-tetra-hydronaphth-2-yl)-2-hydroxy-3-<9-°x°xanth-4-yloxy) propanamine hydrochloride 10 ((i): R = H, Ar «■ radical 29_, wherein Z is ,C=0, and the chain is attached to position 2 of the tetralin). (Ex. 91).

Analogously, but starting from 4-hydroxyxanthene, N-(l,2,3,4-tetra-hydronaphth-2-yl)-2-hydroxy-3- (xanth-4-yloxy)propanamirie hydrochloride is obtained ((i) : R = H, Ar - radical 29_, wherein Z is a methylene 15 group, and the chain is attached to position 2 of the tetralin).

(Ex.92) EXAMPLES 93 TO 96.

Following the procedure of Example 91, but starting respectively from 4-hydroxy-l-methylcarbostyril, 4-hydroxy-l-ethylcarbostyril, 20 4-hydroxy-l-allylcarbostyril, or 4-hydroxy-l-phenylcarbostyril and reacting the raw chlorohydrin thus obtained with 2-aminotetralin, the following compounds are prepared respectively: - N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(l-methyl-2-oxo-1,2-dihydroquinolin-4-yloxy)propanamine hydrochloride (Ex. 93); -N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(l-ethyl-2-oxo- 1,2-dihydroquinolin-4-yloxy)propanamine hydrochloride (Ex. 94); - N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(l-allyl-2-oxo- 1,2-dihydroquinolin-4-yloxy)propanamine hydrochloride (Ex. 95); and - N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroJcy-3-(l-phenyl-2-oxo-30 1,2-dihydroquinolin-4-yloxy)propanamine hydrochloride (Ex. 96); ((i): R ■ H, Ar - radical 30, wherein Z is methyl, ethyl, allyl and phenyl respectively; and the chain is attached to position 2 of the tetralin ).

EXAMPLE 97. 73 Following the procedure of Example 27, but starting from l-(l-phenyltetrazol-5-yloxy)-2,3-epoxypropane (A.37 g) prepared as described in BE 866,278 and 2-aminotetralin (1.48 g) in absolute ethanol (60ml), N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-5 3-(l-phenyltetrazol-5-yloxy)propanamine hydrochloride is obtained ((i): R = H, Ar = radical 60, wherein Z = Z' = H and the chain is attached to position 2 of the tetralin).

EXAMPLE 98.

A mixture of l-(2-naphthyloxy)-2,3-epoxypropane (1.95 g), 2-aminotetralin (2.65 g) and ethanol (35 ml) is heated to the reflux temperature for 5 hours. The solvent is then evaporated off and the thus obtained solid residue is crystallized from ethyl acetate (5 ml), recovered by filtration, washed with ethyl acetate and then with ethyl ether, and dessicated yielding 1.8 g of 15 N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-naphthyloxy)propanamine, as the free base; m.p. 109-115°C.

EXAMPLE 99.

Following the general procedure of Example 98, but starting from l-(2-naphthyloxy)-2,3-epoxypropane (4.5 g) and 1-aminotetralin (2.95 20 g)» N-(l,2,3,4-tetrahydronaphth-l-yl)-2-hydroxy-3- (2-naphthyloxy)propanamine free base is obtained as an oily product which is dissolved in an isopropyl ether/isopropanol 1/1 mixture (40 ml) and acidified with HC1/Isopropanol. The corresponding hydrochloride is thus obtained which is crystallized from isopropanol 25 (20 ml). Yield: 2.2 g; m.p. 135-137°C.

EXAMPLE 100.

Following the general procedure of Example 98, but starting from (R)-l-(l-naphthyloxy)-2,3-epoxypropane (3.8 g; /alpha/ ■ -31.08° (c ■ 1.5 z in methanol)), prepared from 1-naphthol by the method described 30 in Heterocycles, 1983, 20, 1975-1978, and S(+)-l-aminotetralin (2.8 g) obtained from S(-)-1-aminotetralin hydrochloride (II Farmaco Ed.

Sci., 1971, 26, 475-486) by neutralization with 15Z sodium hydroxide and extraction with ethyl ether, in the presence of S(-)-1-aminotetralin hydrochloride (5 mg), 3 5 N-£"( S ) -1,2,3,4-tetrahydronaphth-l-yl)7 - (R) -2-hydroxy-3- (1-naphthyloxy) propanamine 74 is obtained as a yellow oil. Upon the addition of a small amount of isopropyl ether, the desired product crystallizes out and is recrystallized from isopropanol (50 ml) yielding 3.6 g of product; m.p. 107-109°C, /alpha/ = + 6.6° (c= 1% in methanol).

EXAMPLE 101.

Following the general procedure of Examples 98 and 100, but starting from (S)-l-(l-naphthyloxy)-2,3-epoxypropane (4.5 g, /alpha/ - + 30.4° (c = 1.5 % in methanol), see Example 100) and R(-)-l-aminotetralin (3.3 g) obtained from the hydrochloride (II Farmaco Ed. Sci., 1971, 26, 475-486), N-£(R)-1,2,3,4-tetra- hydronaphth-l-yl)J-(S)-2-hydroxy-3-(l-naphthyloxy)propanamine is obtained; m.p. 107-109°C, /alpha/ = - 6.5° (c =» 1%, methanol).

EXAMPLE 102.

Starting from (R)-l-(l-naphthyloxy)-2,3-epoxypropane (4.5 g) and R(-)-l-aminotetralin (3.3 g), and following the general procedure of Example 99, but crystallizing the product from ethanol (50 ml) instead of isopropanol, N-/(R)-1,2,3,4-tetrahydronaphth-1-y1)7-(R)-2-hydroxy-3-(l-naphthyloxy)propanamine hydrochloride (4.4 g) is obtained; m.p. 176-178°C, /alpha/ = + 21.9° (c - 1% in methanol).

EXAMPLE 103.

Starting from (S)-l-(l-naphthyloxy)-2,3-epoxypropane (3.3 g),and S(+)-l-aminotetralin (2.5 g) in the presence of S(-)-1-aminotetralin hydrochloride (5 mg), and following the procedure of Example 102, N-/"(S)-l,2,3,4-tetrahydronaphth-1-yl)7-(S)-2-hydroxy-3-(1-naphthyloxy)propanamine hydrochloride (3.4 g) is obtained after crystallisation from ethanol (40 ml) m.p. 177-179°C, /alpha/ = - 20.5"(c = 3% in methanol).

EXAMPLES 104 - 107.

The following compounds are obtained either as the free bases or the hydrochlorides, by operating as described in Examples 98 or 99: - N-(l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(5,6,7,8-tetrahydro-naphth-l-yloxy)propanamine; m.p. 90-93°C (crystallised from ethyl acetate) (Ex. 104); 75 - N- (7-hydroxy-l,2,3,4-tetrahydronaphth-2-y1)-2-hydroxy-3-naphth-2-yloxypropanamine hydrochloride; m.p. 184-187°C (from ethanol) (Ex. 105); - N-(7-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(5,6,7,8-tetrahydronaphth-l-yloxy)propanamine hydrochloride; m.p. 172-175°C (from isopropanol) (Ex. 106); - N-(1,2,3,4-tetrahydronaphth-l-yl)-2-hydroxy-3-(5,6,7,8-tetrahydro-naphth-l-yloxy)propanamine hydrochloride; m.p. 172-176°C (from isopropanol) (Ex. 107).

EXAMPLES 108 - 112.

In the same way, the following compounds (iA; are ODtalned: - N-(l,2,3,4-tetrahydronaphth-l-yl)-2-hydroxy-3-(2-cyanophenoxy)-propanamine hydrochloride; m.p. 161-163°C (from isopropanol) (Ex. 108); - N—(1,2,3,4-tetrahydronaphth-l-yl)-2-hydroxy-3-(3-cyanophenoxy)-propanamine hydrochloride; m.p. 185-187°C (from 95% ethanol) (Ex. 109); - N-(1,2,3,4-tetrahydronaphth-l-yl)-2-hydroxy-3-(3-trifluoro-methylphenoxy)propanamine hydrochloride; m.p. 135-137°C (from isopropanol) (Ex. 110); - N—(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(3-trifluoro-methylphenoxy)propanamine; m.p. 84-89°C (from isopropyl ether) (Ex. ill); - N-(7-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(3-trifluoromethylphenoxy)propanamine hydrochloride; m.p. 215-217°C (from isopropanol) (Ex. 112).

EXAMPLES 113 - 119.

The following compounds of formula (iB) are prepared in the same way - N-(l,2,3,4-tetrahydronaphth-l-yl)-2-hydroxy-3-(4-cyanophenoxy)-propanamine hydrochloride; m.p. 156-160°C (from acetone) (Ex. 113); - N-( 7-hydroxy-l ,2,3,4-tetrahydronaphth-2-yl) -2-hydroxy-3--/.4-(2-methoxyethyl)phenoxx7propanamine hydrochloride; m.p. 153-156°C (from isopropanol) (Ex. 114); 76 - N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-/4-(2-methoxyethyl)-phenoxyjpropanamine; m.p. 95-97°C (from isopropyl ether) (Ex. 115); - N-(l,2,3,4-tetrahydronaphth-l-yl)-2-hydroxy-3-Z4-(2-methoxy-ethyl)phenoxy/propanamine hydrochloride; m.p. 136-139°C (from isopropanol) (Ex. 116); - N- (7-hydroxy-1,2,3,4-tetrahydronaphth-2-y1)-2-hydroxy-3-(4-chlorophenoxy)propanamine hydrochloride; m.p. 168-170°C (from isopropanol) (Ex. 117); - N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(4-chlorophenoxy)-propanamine; m.p. 117-119°C (from ethyl acetate) (Ex. 118); - N-(l,2,3,4-tetrahydronaphth-l-yl)-2-hydroxy-3-(4-chlorophenoxy)-propanamine hydrochloride; m.p. 131-135°C (from isopropanol) (Ex. 119).

EXAMPLES 120 - 122.

Following the general procedure of Example 1, but starting respectively from 1-aminotetralin, 2-aminotetralin or 2-amino-7-hydroxytetralin and 3-(2,3-epoxy-l-propoxy)-4-morpholino-l,2,5-thiadiazole, prepared as described in J. Org. Chem., 1979, 44, p. 1826, the following compounds are obtained respectively: - N-(l,2,3,4-tetrahydronapht-l-yl)-2-hydroxy-3-(4-morpholino- 1,2,5-thiadiazol-4-yloxy)propanamine hydrochloride; m.p. 156-159°C (from isopropanol) (Ex. 120); - N-(1,2,3,4-tetrahydronapht-2-yl)-2-hydroxy-3-(4-morpholino- 1,2,5-thiadiazol-4-yloxy)propanamine hydrochloride; p.f. 171-174°C (from isopropanol) (Ex. 121); - N-(7-hydroxy-l,2,3,4-tetrahydronapht-2-yl)-2-hydroxy- 3-(4-morpholino-l, 2,5-thiadiazol-4-yloxy) propanamine; m. 187-191°C (from isopropanol) (Ex. 122).

EXAMPLE 123. (a) Epichlorohydrin (46.9 ml) is added to a solution of 3-chloro phenol (51.42 g) in a solution of sodium hydroxide (17.2 g) in water (70 ml) and the obtained reaction mixture is stirred at room temperature overnight and then extracted with ethyl ether. The organic phase is washed with IN NaOH, and with water, dried over sodium 77 sulfate, and concentrated to dryness under reduced pressure yielding l-(3-chlorophenoxy)-2,3,-epoxypropane (46 g); b.p. 105-110°C/0.5 mmHg. (b) A mixture of the above product (2.77 g) and 1-aminotetralin (2.2 g) in absolute ethanol (75 ml) is refluxed for 5 hours, concentrated to dryness and the residue is dxrarHtographed on a silica gel column elLting with ethyl acetate/cyclohexane 9/1 v/v. The combined fractions are concentrated to dryness, the obtained residue is dissolved in isopropanol (25 ml) and the solution is acidified by the addition of HCl/isopropanol. The precipitate is recovered by filtration yielding 1.6 g of N-(l,2,3,4-tetra-hydronaphth-l-yl)-2-hydroxy-3-(3-chlorophenoxy)propanamine hydrochloride; m.p. 157-158°C.

EXAMPLE 124.

A solution of 2-amino-7-hydroxytetralin (2.0 g) and l-(3-chlorophenoxy)-2,3-epoxypropane (2.25 g) in absolute ethanol (50 ml) is heated to the reflux temperature for 5 hours. Ethanol is then evaporated off under reduced pressure and the obtained residue is chromatographed on a silica gel column eluting first with ethyl acetate and then with a mixture ethyl acetate/methanol 9/1 v/v up to complete elution of the product-containing fractions. The thus obtained fractions are pooled and evaporated to dryness. The residue is dissolved in isopropanol (20 ml) and the solution is acidified by the addition of HCl/isopropanol. A precipitate forms which is recovered by filtration and washed with ethyl ether yielding 2.2 g of N-(7-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(3-chlorophenoxy)propanamine hydrochloride; m.p. 193-195°C.

EXAMPLE 125.

A solution of 2-aminotetralin (1.1 g) and l-(3-chlorophenoxy)-2,3-epoxypropane (1.38 g) in absolute ethanol (50 78 ml) is heated to the reflux temperature for 5 hours. Ethanol is evaporated off under reduced pressure and the residue is taken up in ethyl acetate (15 ml) and crystallized therefrom. The obtained product is then dissolved in isopropanol (20 ml) and the solution is 5 made acidic by the addition of HCl/isopropanol. The precipitate which forms is recovered by filtration, and crystallized from 95% ethanol (50 ml) yielding 1.0 g of N-( 1,2,3 ,4-tetrahydronap'nth-2-yl) -2-hydroxy-3-(3-chlorophenoxy)propanamine hydrochloride; m.p. 172-174°C.

EXAMPLE 126.

A solution of 1-aminotetralin (2.95 g) and £"2-(2-propynyloxy)phenoxy_7- 2,3-epoxypropane (4.09 g) prepared by the method described in NL-A-6516433, in ethanol (100 ml) is heated to the reflux temperature for 5 hours. The solvent is then evaporated to dryness and the obtained residue is chromatographed on a si lira gel 15 column eluting with ethyl acetate. Those fractions which contain the desired product are pooled and evaporated to dryness. The obtained residue is dissolved in isopropanol (25 ml) and a solution of HCl/isopropanol is added thereto. The precipitate which forms is recovered by filtration and crystallized from isopropanol (12 ml) yielding 2.25 g of N-(l,2,3,4-tetrahydronaphth-l-yl)-2-hydroxy-3- £2-(2-propynyloxy)phenoxx7propanamine hydrochloride; m.p. 114-116°C. EXAMPLE 127.

Following the general procedure of Example 1, but starting from 25 2-amino-7-hydroxytetralin (2.55 g) and £*2-(2-propynyloxy)- phenoxy7-2,3-epoxypropane (3.18 g), a product is obtained which is washed with isopropanol first and then with ethyl ether yielding 2.6 g of N-(7-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-Z*2-(2-propynyloxy)phenoxy7propanamine hydrochloride; m.p. 158-160°C. 79 EXAMPLE 128.

Following the general procedure of Example 126, but starting from 2-aminotetralin instead of 1-aminotetralin, a precipitate :Ls obtained which is washed with isopropanol first and then with ethyl ether yielding the desired N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-/2-(2-propynyloxy)phenoxyJpropanamine hydrochloride; m.p. 129-130°C.

EXAMPLE 129.

Following the general procedure of Example 1, but starting from 2-amino-6-hydroxytetralin (0.6 g) and /2-(2-propynyloxy)- phenoxy7*2,3-epoxypropane (0.75 g) , 0.2 g of N-(6-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-/2- (2-propynyloxy)phenox^£7propanamine hydrochloride is obtained; m.p. 179-182°C.

EXAMPLE 130.

A solution of l-(2-chlorophenoxy)-2,3-epoxypropane (2.65 g) prepared by the method described in British Patent 767,991, and 2-aminotetralin (2.1 g) in ethanol (70 ml) is heated to the reflux temperature for 5 hours. Ethanol is then evaporated to dryness and the thus obtained residue is chromatographed on a silica gel column eluting with ethyl acetate. The residue which is obtained upon evaporation to dryness of the combined fractions is crystallized from ethyl acetate (10 ml) yielding 1.5 g of N-(l,2,3,4-tetrahydro- naphth-2-yl)-2-hydroxy-3-(2-chlorophenoxy)propanamine; m.p. 98-101°C. EXAMPLE 131.

A mixture of 1-aminotetralin (2.95 g) and l-(2-chlorophenoxy)-2,3-epoxypropane (3.69 g) in absolute ethanol (100 ml) is refluxed for 5 hours and then evaporated to dryness. The thus obtained residue is chromatographed on a silica gel column eluting with ethyl acetate/cyclohexane 7/3 v/v. The combined fractions are evaporated to dryness, the obtained residue is taken up in isopropanol (10 ml) and filtered. The solid on filter is crystallized from isopropanol (10 ml) and washed with hexane yielding 3.0 g of N-(1,2,3,4-tetrahydronaphth-l-yl)-2-hydroxy-3-(2-chlorophenoxy)propanamine; m.p. 78-81°C. 80 EXAMPLE 132.

A mixture of 2-amino-7-hydroxytetralin (1.9 g) and 1-(2-chlorophenoxy)-2,3-epoxypropane (2.15 g) in absolute ethanol (60 ml) is refluxed for 5 hours and then ethanol is evaporated off under reduced pressure. The thus obtained residue is chromatographed on a silica gel column eluting first with ethyl acetate up to the complete elution of the first spot and then with a mixture ethyl acetate/methanol 9/1 v/v. The obtained fractions are pooled and concentrated to dryness. The residue is dissolved in Isopropanol (20 10 ®1) and the obtained solution is acidified by the addition of HCl/isopropanol. The precipitate is recovered by filtration yielding 2.25 g of N-(7-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)- 2-hydroxy-3-(2-chlorophenoxy)propanamine hydrochloride; m.p. 201-203°C.

EXAMPLE 133.

A mixture of 2-aminotetralin (2.5 g) and l-(A-acetamidophenoxy)-2,3-epoxypropane (3.52 g) in dimethylsulfoxide (40 ml) is heated at 80°C for 5 hours. The reaction mixture is allowed to cool to room temperature and water (180 ml) is then added thereto. The precipitate 20 which forms is recovered by filtration and crystallized from absolute ethanol (120 ml) yielding 2.15 g of N-(1,2,3,4-tetrahydronaphth-2-y1)-2-hydroxy-3-(4-acetamidophenoxy)-propanamine; m.p. 133-136°C.

EXAMPLE 134.

A mixture of 1-aminotetralin (5.92 g) and l-(4-acetamidophenoxy)-2,3-epoxypropane (8.30 g) in absolute ethanol (200 ml) is heated to the reflux temperature for 5 hours and then it is evaporated to dryness. The thus obtained residue is washed with isopropanol and then with ethyl ether, yielding 11.3 g of a product 30 with a m.p. of 325-130°C. Said product is dissolved in acidic water, the pH of the solution is brought to 10-11 by the addition of NaOH and the precipitate which forms is recovered by filtration, dissolved in a small amount of methanol, and chrcmstographed on a silica gel column eluting with a mixture ethyl acetate/methanol 9/1 v/v. The 35 combined fractions are concentrated to dryness and washed with hexane 81 yielding 2 g of N-(l,2,3,4-tetrahydronaphth- 1-yl)-2-hydroxy-3-(4-acetamidophenoxy)propanamine; m.p. 80-84°C. EXAMPLE 135.

A mixture of 1-aminotetralin (0.8 g) and l-^ftrans-6,7-dihydroxy-5,6,7,8-tetrahydronaphth-l-yl)oxy_7-2,3-epoxypropane (1.3 g), prepared by the method described in J. Med. Chem., 1978, 2l_, No. 9, 913-922, in absolute ethanol (20 ml) is refluxed for 5 hours and the solvent is then evaporated off. The residue is chromatographed oh a silica gel column eluting first with ethyl acetate and then with a mixture ethyl acetate/methanol 7/3 v/v. The combined fractions are evaporated to dryness yielding 1.0 g of N—(1,2,3,4-tetrahydronaphth-l-yl)-2-hydroxy-3-(trans-6,7-dihydroxy-5,6,7,8-tetrahydronaphth-l-yloxy)propanamine as a vitreous solid. IR (KBr): 3362, 2930, 1454, 1253, 1065 cm-1 EXAMPLE 136. (a) A solution of R(+)-2,3-epoxy-l-^ropanol (5 g), 2-allylphenol (7.54 g) and triphenylphosphine (14.7 g) in anhydrous tetrahydrofuran (80 ml) is cooled to 0-5°C and diethyl azodlcarboxylate (11.7 g) is slowly dripped in. The reaction mixture is then allowed to stand at room temperature for 3 hours, the solvent is evaporated off and the thus obtained residue is taken up in ethyl ether and washed with 10% NaOH and then with water. The organic solution is dried over sodium sulfate and then concentrated under reduced pressure. The thus formed oily residue is chromatographed on a silica gel column eluting with a mixture hexane/ethyl acetate 7/3 v/v.

S(+)-l-(2-allylphenoxy)-2,3-epoxypropane (9.0 g) is thus obtained which is purified by distillation; b.p. 100-105°C/0.3 mmHg, /alpha/ « + 14.3° (c ■ 1 % in methanol). (b) A mixture of the above product (2.2 g) and S(-)-2-aminotetralin (1.7 g) in absolute ethanol (30 ml) Is refluxed for 5 hours. Ethanol Is then evaporated off and the obtained residue is chromatographed on a silica gel column eluting with ethyl acetate. The combined fractions are evaporated to dryness and the oily residue, taken up in a mixture ethyl acetate (10 ml)/hexane 82 (10 ml), crystallizes therefrom.

N-/"(S) -1,2,3,4-tetrahydronaphth-2-yl7-(S) -2-hydroxy-3-(2-allylphenoxy)propanamine (1.1 g) is then recovered by filtration ; m.p. 70-72°C (from isopropyl ether). /alpha/ = -51.0° (c = 0.5 X in methanol).

EXAMPLE 137.

Following the general procedure of Example 136, but starting from R(+)-2-aminotetralin (2.2 g) and S(+)-l-(2-allylphenoxy)-2,3-epoxypropane (2.85 g) , N-/"(R)-1,2,3,4-tetrahydro-naphth-2-yiy-(S)-2-hydroxy-3-(2-allylphenoxy)propanamine (2.3 g) is obtained; m.p. 65-68°C; /alpha/ = + 32.0° (c « 0.5 1 in methanol).

EXAMPLE 138. (a) By operating as described in Example 136 (a), but using S(-)-2,3-epoxy-l-propanol instead of R(+)-2,3-epoxy-l-propanol, R(-)-l-(2-allylphenoxy)-2,3,-epoxypropane is obtained which is characterized by /alpha/ ■ -11,8°C (c = 1 Z in methanol). (b) A mixture of the above product (2.2 g) and S(-)-2~aminotetralin (1.7 g) in absolute ethanol (30 ml) is refluxed for 5 hours.

Ethanol is then evaporated off and the obtained residue is chromatographed on a silica gel column eluting with ethyl acetate. Those fractions which contain the desired product are pooled together and concentrated to dryness. The residue Is taken up in ethyl ether and filtered yielding 1.8 g of N-/(S)-1,2,3,4-tetrahydronaphth-2-y]J-(R)-2-hydroxy-3-(2-allylphenoxy) propanamine; m.p. 70-72°C (from ethyl acetate); /alpha/ ■ -31.3° (c = 0.5 % in methanol).

EXAMPLE 139.

Starting from R(+)-2-aminotetralin (2.2 g) and R(-)-l-(2-allylphenoxy)-2,3-epoxypropane (2.85 g), and following the same procedure as In Example 138, 3.0 g of N-f(R)-1,2,3,4-tetrahydronaphth- 2-ylJ-(R)-2-hydroxy-3-(2-allylphenoxy)propanamine are obtained; m.p. 71-73°C (from isopropyl ether); /alpha/ - + 53,6° (c - 0,5 Z in methanol).

EXAMPLES 140 - 143. 83 Following the general procedure of Examples 136-139, but using S(-)-2-amino-7-hydroxytetralin instead of S(-)-2-aminotetralin and R(+)-2-amino-7-hydroxytetralin instead of R(+)-2-aminotetralin, the compounds listed hereinbelow are obtained: 5 - N-AS)-7-hydroxy-l,2,3,4-tetrahydronaphth-2-ylj7-(S)-2-hydroxy-3- (2-allylphenoxy)propanamine; m.p. 173-174°C (isopropyl ether); /alpha/ = -79.6° (c = 0.5 % in methanol) (Ex. 140); - N-/(R)-7-hydroxy-l,2,3,4-tetrahydronaphth-2-yl^-(S)-2-hydroxy-3-(2-allylphenoxy)propanamine; m.p. 167-169°C (isopropyl ether); /alpha/ ® +31.4° (c ■ 0.5 Z in methanol) (Ex. 141); - N-Z~(S)-7-hydroxy-l,2,3,4-tetrahydronaphth-2-yl^-(R)-2-hydroxy-3-(2-allylphenoxy)propanamine; m.p. 168-170°C (isopropyl ether); /alpha/ = -36.3° (c = 0.5 Z in methanol) (Ex. 142); - N-£"(R)-7-hydroxy-l ,2,3,4-tetrahydronaphth-2-yiy-(R)-2-hydroxy-3-15 (2-allylphenoxy)propanamine; m.p. 173-175°C (isopropyl ether); /alpha/ = +75.6° (c = 0.5 % in methanol) (Ex. 143).

EXAMPLES 144 - 147.

By operating substantially as described in Examples 136-139, but using S(-)-1-aminotetralin instead of S(-)-2-aminotetralin and 20 R(+)-1-aminotetralin instead of R(+)-2-aminotetralin, the following compounds are obtained, either as the free base or as the hydrochlorides: - N-Z(S)-1,2,3,4-tetrahydronaphth-l-yl$-(S)-2-hydroxy-3-(2-allyl-phenoxy)propanamine hydrochloride; m.p. 127-129°C (isopropanol); /alpha/ - -23.4° (c = 0.5 Z in methanol) (Ex. 144); - N-i?(R) -1,2,3,4-tetrahydronaphth-1 -yl^- (S) -2-hydroxy-3- (2-allyl-phenoxy)propanamine; m.p. 71-73°C (isopropyl ether); /alpha/ ■ -13.1° (c « 0.5 Z in methanol) (Ex. 145); - N-ZT(S)-1,2,3,4-tetrahydronaphth- 1-y 1 J-(R)-2-hydroxy-3-(2-ally 1- phenoxy)propanamine; m.p. 72-74°C (isopropyl ether); /alpha/ ■ +12.6° (c s 0.5 Z in methanol) (Ex. 146); - N-/"?R)-1,2,3,4-tetrahydronaphth-l-yl^-(R)-2-hydrexy-3-(2-ally 1-phenoxy)propanamine hydrochloride; m.p. 126-128°C (isopropanol); /alpha/ ■ +21.7° (c ■ 0.5 Z in methanol) (Ex. 147). 84

Claims

claims

1. A compound of formula (i) OH A R (i) wherein R is hydrogen, a hydroxy group or methoxy group, and Ar represents an optionally substituted aromatic or heteroaromatic group, or one of its mineral or organic acid salts whether pharmaceutically acceptable or not.

2. A compound according to claim 1, of formula (i), wherein the mineral or organic acids are pharmaceutically acceptable.

3. A compound according to claim 2, of formula (i) , wherein Ar represents an optionally substituted mono-, di- or tri-cyclic aromatic or heteroaromatic group, of which a carbon atom of the aromatic carbocycle or of the aromatic heterocycle is directly linked to the oxygen of the aryloxypropanolaminotetralin.

4. A compound according to claim 3, of formula (i) wherien Ar is the etherifying residue in the 3-position of an N-substituted l-amino-2,3- propandiol, having a beta-blocking adrenergic activity.

5. A compound according to claim 3 of formula (iA) or (iB)

6.OH 0

7.CH

8.■NH 85

9.OH 0

10.NH

11.UB)

12.R

13.L

14.G' wherein R is such as defined in claim 1, E represents hydrogen, a halogen, an alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, tetrahydrofurfuryloxy, phenoxy, cycloalkyl group of from 3 to 6 carbon atoms, 1-cyclohexenyl, 2-cyclohexenyl, 2,5-methano-cyclohexyl, alkylthio, alkanoyl, phenylalkanoyl, cyano, 3-chloroallyl, 2-indolyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-quinolinyl, 2-quinoxalinyl, 2-thienyl, 4-thiazolyl, 4-morpholinyl; G is hydrogen, a halogen, an alkyl, an alkenyl, a trifluoromethyl group, a cyano group or an acetamido group, with at least one of the substituents E and G being hydrogen; or E and G represent, respectively, an acetamido group and a nitro group, or E and G taken together form a group -CHg-CHg-CHg-, -ch2-ch2-ch2-ch2-, -ch=ch-ch2-, -ch2-ch=ch-,

15.-CH=CH-CH2-CH2-, -CH=CH-CH=CH-, -C0-CH2-CH2-CH2-, -CH2-CH2-CH2-C0- or -CHg-CH(OH)-CH(OH)-CH2-; G* is hydrogen; L is halogen, an alkyl group non-substituted or substituted with an alkoxy, alkoxycarbonylamino, aminocarbonyl or cycloalkylalkoxy group, an alkenyl group, non-substituted or substituted by a cyano group; an alkanoylamino or haloalkanoylamino group; a ureido N'-mono or di-substituted with alkyl or cycloalkyl groups; an alkoxy group optionally substituted on the alkyl by an alkoxy group; a cyano group; or a hydroxymethy1 group etherified with an;86;alkoxyalkyl group; or G' and L represent, respectively, a nitro group and an acetamido group, or G1 and L, taken together for a group -CH=CH-CH=CH-; as well as its pharmaceutically acceptable mineral or organic acid salts.;6. A compound according to claim 5, of formula (iA) or (iB), wherein E is hydrogen, halogen, an alkyl,;alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy and G is hydrogen, or E and G, taken together, form a group -CH2-CH2-CH2-; -CH2-CH2-CH2-CH2-; -CH=CH-CH2-;;-ch2-ch=ch-, -ch=ch-ch2-ch2-, -ch=ch-ch=ch-, -c0-ch2-ch2-ch2-; -ch2-ch2-ch2-c0- or;-CH2~CH (OH)-CH(OH)-CHg-; G' represents hydrogen, L represents an atom of chloride, a cyano group or a 2-methoxyethyl group or G1 and L, taken together form a grouD -CH=CH-CH=CH-.;7. A compound according to claim 6, of formula (iA), wherein E is halogen, an alkyl, alkenyl, alkoxy,;alkenyloxy or alkynyloxy group, or E and G, taken together, form a group -CH=CH-CH=CH- or -CH2-CH(0H)-CH(0H)-CH2-.;8. A compound according to claim 7 which is N(l,2,3,-4-tetrahydronaphth-l-yl)-2-hydroxy-3-(l-naphtyloxy)-propanamine in optically active or inactive form, or one of its pharmaceutically acceptable mineral or organic acid salts .;9. A compound according to claim 7 which is N-£"(R)-1,2,3 , 4-tetrahy dronaphth-l-yl)^ -(S)-2-hydroxy-3-(1-naphthyloxy)propanamine or one of its pharmaceutically acceptable mineral or organic acid salts.;10. A compound according to claim 7 which is N-(7-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-^3-(2-allylphenoxy)7propanamine in optically active or inactive form or one of its pharmaceutically acceptable mineral or organic acid salts.;87;11. A compound according to claim 10 which is;N-(7-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-£3~ (2-allylphenoxy)_7propanamine hydrochloride, in optically active or inactive form.;12. A Compound according to claim 2, of formula (iF);wherein R is as defined in claim 1, LB is hydrogen and E" and G" , taken together form a -CH=CH-NH- group, as well as its pharmaceutically acceptable mineral or organic acid salts.;13. A process for preparing a compound according to claim 1, characterized in that it comprises treating a 1-aryloxypropane of formula (ii);wherein Ar1 has the same meaning as that given in claim 1 to Ar, although it may contain N-protecting groups fixed on NH,, or NH groups, A is a hydroxy group and B is a halogen selected from chlorine, bromine or iodine, or A and B, taken together form an epoxy group, with an aminotetralin of formula (iii);L";A B I I;Ar'-O-CH-CH-CH;(ii);(iii);88;wherein R is as defined in claim 1, optionally in the presence of a tertiary amine; optionally deprotecting the obtained product by removing the N-protecting group or groups; when the starting compound of formula (ii);5 in which Ar1 is a 2-acetamido-3-nitrophenyl or;4-acetamido-3-nitropheny1 group, optionally deacetylating the obtained product by heating it in hydrochloric acid and optionally hydrogenating the obtained product in 97% formic acid in the presence of;10 10% Pd/C; and optionally converting the obtained product in one of its salts.;14. A pharmaceutical composition containing as the active ingredient, a compound of formula (i) according to any one of claims 2 to 12.;15 15. A pha rmaceutical* composition according to claim 14, in dosage unit form, wherein the active ingredient is mixed with a pharmaceutically acceptable carrier.

16. A pharmaceutical composition according to one of claims 14 and 15, containing from 0.1 to 500 mg of 20 active ingredient per dosage unit.

17. a reagent for differentiating between the beta-adrenergic receptors in biochemical assays, characterized in that it comprises a suitably labelled compound according to claim 1. 25

18. A compound according to claim 1, substantially as herein described in the Examples.

19. A process according to claim 13, for preparing a compound according to claim 1, substantially as herein described in the Examples. 30

20. A reagent for differentiating between the beta- adrenergic receptors in biochemical assays, according to claim 17, substantially as herein described. MACLACHLAN & DONALDSON, Applicants' Agents, 47, Merrion Square, DUBLIN 2.