Aryloxypropanolaminotetralins, a Process for Their Preparation and Pharmaceutical Compositions Containing Them

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 [alpha].sub.D.sup.20. Chromatographies have been carried out on MERCK 70-230 mesh silica gel columns.

(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.degree.-5.degree. 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 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 with hydrogen chloride saturated isopropanol. 2-Benzylamino-7-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride (11.4 g) is thus obtained; m.p. 265.degree.-267.degree. 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.degree.-50.degree. C. After 4 hours, the reaction mixture is filtered and the solvent is evaporated off. The residue is taken up in absolute ethanol and the ethanol is evaporated off. After repeating this last procedure, a white solid is obtained which is taken up in hot isopropanol (70 ml). Upon cooling a precipitate is obtained which is recovered by filtration yielding 2-amino-7-methoxytetralin hydrochloride (7.8 g); m.p. 214.degree.-216.degree. C.

(c) The above product (6.6 g) is suspended into 48% hydrobromic 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 precipitate 2-amino-7-hydroxytetralin hydrobromide as a crystalline product 86.8 g); m.p. 171.degree.-173.degree. C.

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.degree.-192.degree. 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 water (300 ml) and the suspension is basified by the addition of 1N NaOH. The aqueous phase is extracted with ethyl acetate, the organic phase is concentrated to dryness and the residue is taken up in 48% hydrobromic acid (260 ml). The reaction mixture is then heated at reflux for 3 hours and concentrated to dryness under vacuum. The obtained residue is taken up in water (70 ml), the aqueous solution is basified by the addition of concentrated ammonium hydroxide and cooled overnight. The thus obtained R(+)-2-amino-7-hydroxytetralin monohydrate (17 g) is then recovered by filtration; m.p. 143.degree.-144.degree. C., /alpha/ =+85.1.degree. (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).

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). 1N NAOH is then added thereto to afford a basic solution and ethyl acetate is used to extract the free base 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.degree.-191.degree. C.) is obtained which, upon neutralization and demethylation with hydrobromic acid, gives S(-)-2-amino-7-hydroxytetralin monohydrate (17 g); m.p. 143.degree.-144.degree. C., /alpha/ =-86.9.degree. (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).

A solution of 2-amino-7-hydroxytetralin (3 g) 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 1-naphthyloxy-2,3-epoxypropane (3.68 g) in ethanol (80 ml) is refluxed for 5 hours. The reaction mixture is then allowed to cool down to room temperature, the solvent is evaporated off under reduced pressure and the oily residue 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/ethanol 9/1 v/v, up to complete elution of the product. Those fractions which contain the desired product 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-naphthyloxy)pro panamine hydrochloride; m.p. 184.degree.-187.degree. C.

A solution of 2-aminotetralin (3.2 g) obtained from the corresponding hydrochloride by neutralisation with NAOH and extraction with ethyl acetate, and 1-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-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1-naphthyloxy)propanamine hydrochloride; m.p. 209.degree.-212.degree. C.

A solution of 1-aminotetralin (2.65 g) and 1-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 reaction product. Fractions containing the desired product are 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-(1,2,3,4-tetrahydronaphth-1-yl)-2-hydroxy-3-(1-naphthyloxy)propanamine hydrochloride; m.p. 179.degree.-183.degree. C.

A solution of 2-amino-7-hydroxytetralin (4.7 g) and 1-(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 evaporated off, the residue is dissolved in isopropanol and the solution is acidified by the addition of HCl isopropanol. After 30 minutes at 0.degree.-5.degree. 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 N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-allylphenoxy)pr opanamine hydrochloride are obtained; m.p. 232.degree.-235.degree. C.

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

A solution of 1-aminotetralin (2.5 g) and 1-(2-allylphenoxy)-2,3-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 applied to a silica gel column developed 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 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-(1,2,3,4-tetrahydronaphth-1-yl)-2-hydroxy-3-(2-allylphenoxy)propanamine oxalate; m.p. 163.degree.-165.degree. C.

A mixture of 1-[1-(p-toluenesulfonyl)indol-4-yloxy]-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 off under reduced pressure, the residue is dissolved in ethyl acetate 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 the reflux temperature for 4 hours, made slightly acidic by the addition of 1N HCl 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. The obtained residue is taken up in ethanol, filtered and washed on filter with ethanol. The filtrate and the washing ethanol are combined and the solution is basified by the addition of concentrated ammonium hydroxide. The residue which is obtained by evaporating off the solvent is purified by silica gel column chromatography eluting first with ethyl acetate and then with a mixture ethyl acetate/reethanol 9/1 v/v. The product-containing fractions are combined and evaporated to dryness. A mixture of acetic acid and isopropanol is used to take up the product. The precipitate which forms is then recovered by filtration and crystallized from 95% ethanol (60 ml) affording 2.6 g of N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-indol-4-yloxypropa namine acetate; m.p. 167.degree.-170.degree. C.

A mixture of R(+)-2-amino-7-hydroxytetralin monohydrate (6.5 g), obtained as described in PREPARATION II, and 1-[1-(p-toluenesulfonyl)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 with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is taken up in ethanol (150 ml) and in a solution of sodium hydroxide (10 g) in water (60 ml). The reaction mixture is refluxed for 4 hours, made slightly acidic by the addition of 1N HCl and then basified by the addition of concentrated ammonium hydroxide. The reaction mixture is then concentrated under reduced 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. The filtrate and the ethanol washing are combined, and the solution is made basic by the addition of concentrated ammonium hydroxide and concentrated to dryness. The residue is purified by silica gel column chromatography 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-[(R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(RS)-2-hydroxy-3-indol-4-y loxypropanamine as a vitrous solid.

NMR (DMSO-d6): 7.1 (1H, dd , J.perspectiveto.J2=2 Hz, CH alpha), 10.9 (OH+NH).delta.

A solution of 2-amino-6-hydroxytetralin (2.6 g) and 1-naphthyloxy-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 column eluting first with ethyl acetate up to complete elution of the first spot, and then with a mixture ethyl acetate/reethanol 9/1 v/v up to complete elution of the product. The fractions are pooled and concentrated under 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 precipitate is recovered by filtration, washed with ethyl ether and 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 triturated with a small amount of ethyl acetate and filtered yielding 1.9 g of N-(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1-naphthyloxy)pro panamine; m.p. 118.degree.-120.degree. C.

A solution of 2-amino-7-hydroxytetralin (2.45 g) and 1-(2-methylphenoxy)-2,3-epoxypropane (2.5 g) in ethanol (75 ml) is refluxed for 5 hours. Ethanol is evaporated off, the residue is taken up in acetone (20 ml) and the solution is made acidic by the addition of HCl isopropanol. The precipitate which forms is recovered by filtration, washed with ethyl ether and crystallized from 95% ethanol (30 ml), affording 1.7 g of N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-methylphenoxy)p ropanamine hydrochloride m.p. 224.degree.-226.degree. C.

Following the procedure described in Example 2, but replacing 1-naphthyloxy-2,3-epoxypropane with 1-(2-methylphenoxy)-2,3-epoxypropane, 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.degree.-182.degree.-C.

A solution of 1-aminotetralin (2.95 g) and 1-(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 residue is applied to a silica gel column, developed 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.degree.-5.degree. C. The precipitate is recovered by filtration and crystallized from isopropanol (20 ml) yielding 2.5 g of N-(1,2,3,4-tetrahydronaphth-1-yl)-2-hydroxy-3-(2-methylphenoxy)propanamine hydrochloride; m.p. 123.degree.-124.degree. C.

(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 dissolved in ethyl acetate and the 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 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 and filtered and the solid recovered by filtration is dried yielding 3.1 g of N-(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-[1-(p-toluenesulfo nyl)indol-4-yloxy]propanamine hydrochloride; m.p. 228.degree.-231.degree. 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 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. The residue is purified by silica gel column chromatography 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-methoxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(indol-4-yloxy)pro panamine as an amorphous solid.

NMR (DMSO-d6): 3.68 (3H, s, --OCH.sub.3), 7.2 (1H, dd, J1.perspectiveto.J2=2 Hz, CH alpha)

A mixture of 1-aminotetralin (2.94 g) and 1-(2-methoxyphenoxy)-2,3-epoxypropane (3.6 g) and absolute ethanol (100 ml) is refluxed for 5 hours. The solvent is then evaporated off under reduced pressure, the residue is chromatographed on a silica column eluting with ethyl acetate. The 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-(1,2,3,4-tetrahydronaphth-1-yl)-2-hydroxy-3-(2-methoxyphenoxy)propanamin e; m.p. 99.degree.-102.degree. C.

A solution of 2-aminotetralin (2.2 g) and 1-(2-methoxyphenoxy)-2,3-epoxypropane (2.7 g) in ethanol (70 ml) is refluxed for 5 hours and the solvent is then evaporated off under reduced pressure. The 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)propanamin e hydrochloride; m.p. 140.degree.-143.degree. C.

A mixture of 2-amino-6-hydroxytetralin (0.9 g) and 1-(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 purified by silica gel column chromatography 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-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-methoxyphenoxy) propanamine hydrochloride; m.p. 146.degree.-148.degree. C.

A mixture of 2-amino-7-hydroxytetralin (3.15 g) and 1-(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-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-methoxyphenoxy) propanamine hydrochloride; m.p. 173.degree.-176.degree. C.

A mixture of 1-aminotetralin (5.15 g) and 1-(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 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 triturated in a very small amount of ethyl ether, filtered and crystallized from isopropyl ether yielding 2.1 g of N-(1,2,3,4-tetrahydronaphth-1-yl)-2-hydroxy-3-(2-allyloxyphenoxy)propanami ne; m.p. 72.degree.-75.degree. C.

A mixture of 2-aminotetralin (2.2 g) and 1-(2-allyloxy)-phenoxy-2,3-epoxypropane (3.1 g) in absolute ethanol (80 ml) is reflux for 5 hours. The solvent is evadorated off and the residue is purified by a silica gel column chromatography 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-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-allyloxyphenoxy)propanami ne; m.p. 98.degree.-100.degree. C.

A mixture of 2-amino-7-hydroxytetralin (3.4 g) and 1-(2-allyloxy)phenoxy-2,3-epoxypropane (4.12 g) is dissolved in absolute ethanol (50 ml) and the obtained solution is heated to the reflux temperature for 5 hours. Ethanol is then evaporated off 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 HC1/isopropanol. The precipitate which forms is recovered by filtration and crystallized from absolute ethanol affording 3.1 g of N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-allyloxyphenoxy )propanamine hydrochloride; m.p. 183.degree.-185.degree. C.

A mixture of 2-amino-6-hydroxytetralin (2.6 g) and 1-(2-allyloxyphenoxy)-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 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 from isopropanol yielding 2.1 g of N-(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-allyloxyphenoxy )propanamine hydrochloride; m.p. 145.degree.-147.degree. C.

A mixture of 1-aminotetralin (5.15 g) and 1-[1-(p-toluenesulfonyl)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. 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, dried over sodium sulfate, and filtered. Ethyl acetate is then evaporated off and the obtained oily 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 under vacuum yielding 1.5 g of N-(1,2,3,4-tetrahydronaphth-l-yl)-2-hydroxy-3-(4-indolyloxy)propanamine, as a vitreous solid.

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

A mixture of 2-amino-6-hydroxytetralin (3.26 g) and 1-[1-(p-toluenesulfonyl)indol-4-yloxy]-2,3-epoxypropane (6.8 g) in absolute ethanol (80 ml) is refluxed for 5 hours. The solvent is then 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 obtaided solution is washed twice with water, 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 fractions containing pure product are pooled and the solvent is evaporated, the residue is taken up with ethyl ether and filtered yielding 2.4 g of N-(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(4-indolyloxypropa namine); as a vitreous solid.

NMR (DMSO-d6): 7.15 (1H, dd, J1.perspectiveto.J2=2 Hz), CH alpha), 10.9 (OH+NH).delta.. IR(KBr): 3408, 2923, 1501, 1240, 742 cm-1

A mixture of 2-aminotetralin (5 g) and 1-[1-(p-toluenesulfonyl)-indol-4-yloxy]-2,3-epoxypropane (11.7 g) in absolute ethanol (150 ml) is refluxed for 6 hours. The solvent is evaporated, the obtained residue is dissolved under stirring in hot isopropanol (100 ml) and the solution is made acidic by the addition of hydrochloric acid in isopropanol. 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 off and the residue is dissolved 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 fractions containing pure product are pooled. The solvent is evaporated and the residue is dissolved in ethyl ether (20 ml) and crystallized therefrom yielding 3.5 g of N-(1,2,3,4-tetrahydronaphth- 2-yl)-2-hydroxy-3-(4-indolyloxy)propanamine; m.p. 65.degree.-68.degree. C.

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-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-allylphenoxy)pr opanamine hydrochloride; m.p. 212.degree.-215.degree. C.

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-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-methylphenoxy)p ropanamine hydrochloride; m.p. 232.degree.-234.degree. C.

2-Aminotetralin (1.4 g) is added to a solution of 1-(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 dissolved in isopropanol, the obtained solution is heated and hydrogen chloride saturated isopropanol is stirred in. The precipitate is recovered by filtration affording N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1-phenothiazinyloxy)propana mine hydrochloride ((i): R=H, Ar=radical 2 wherein Z is >S, and the chain is attached to position 2 of the tetralin moiety).

Following the procedure of Example 27, but starting from 6-(2,3-epoxypropoxy)-1-oxo-1,2,3,4-tetrahydro-beta-carboline (2.46 g), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1-oxo-1,2,3,4-tetrahydro-be ta-carbolin-6-yloxy)propanamine hydrochloride is obtained ((i): R=H, Ar=radical 3 wherein Z is >C.dbd.O and Z' is H, and the chain is attached to position 2 of the tetralin moiety).

Operating as described in Example 27, but starting from a solution of 1-(2,3-epoxypropoxy)-9,10-dihydro-9,10-ethanoanthracene (2.78 g) in ethanol (30 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(9,10-dihydro-9,10-ethanoant hr-1-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 moiety).

Following the general procedure of Example 27, but starting from 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)propanamin e hydrochloride is obtained ((i): R=H, Ar=radical 8 wherein Z is hydrogen, and the chain is attached to position 2 of the tetralin moiety).

A mixture of 2-aminotetralin (22.7 g), 3-chloro-2-hydroxy-1-(4-methylcoumarin-7-yloxy)propane (26.9 g), in absolute ethanol (35 ml) is charged in a sealed vessel and heated to 100.degree. C. for 4 hours. The reaction mixture is then cooled and concentrated under reduced pressure. The residue is taken up in 1N hydrochloric acid (200 ml) and the aqueous solution is washed with chloroform 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 precipitate N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(4-methylcoumarin-7-yloxy)pr opanamine hydrochloride, ((i): 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.

A mixture of 5-hydroxy-3-methyl-1-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.degree. C. for 90 minutes and then concentrated under reduced pressure. The obtained residue is treated 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 gel column. The obtained 5-(2,3-epoxypropoxy)-3-methyl-1-phenylpyrazole (2.5 g) 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-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(3-methyl-1-phenylpyrazol-5- yloxy)propanamine dihydrochloride ((i): R=H, Ar=radical 9 wherein Z is methyl and Z' is phenyl, and the chain is attached to position 2 of the tetralin moiety) is obtained.

A mixture of 3-hydroxy-2-methyl-4-oxopyrane (12.6 g), sodium 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 extracts are combined, washed with water, dried and evaporated to dryness yielding 8.3 g of 3-(2,3-epoxypropoxy)-2-methyl-4-oxopyrane. A mixture of said product and 2-aminotetralin (7.3 g) in absolute ethanol (100 ml) is charged into a sealed vessel, heated to 80.degree. 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 then added thereto. The precipitate which forms is recovered by filtration and crystallized from ethanol affording N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-methyl-4-oxopyran-3-yloxy )propanamine hydrogenfumarate ((i): R=H, Ar=radical 10 wherein Z is methyl, and the chain is attached to position 2 of the tetralin moiety).

By operating according to Example 27, but starting from 5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril (2 g) and 2-aminotetralin (1.35 g) in ethanol (40 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(3,4-dihydrocarbostyryl-5-ox y)propanamine hydrochloride ((i): R=H, Ar=radical 11 wherein Z is H and the chain bridges position 4 of the radical Ar to position 2 of the tetralin moiety) is obtained.

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 500.degree. C., epichlorohydrin (7 g) is added thereto and the reaction mixture is then stirred at 50.degree. 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)propan amine hydrochloride ((i): R=H, Ar=radical 13 wherein Z is >C.dbd.O, and the chain is attached to position 2 of the tetralin moiety).

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)p ropanamine hydrochloride is obtained ((i): R=H, Ar=radical 14 wherein Z is methyl, and the chain is attached to position 2 of the tetralin moiety).

Following the procedure described in Example 27, but starting from ethyl 4-(2,3-epoxypropoxy)indole-2-carboxylate (25.1 g), obtained 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-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-ethoxycarbonylindol-4-ylo xy)propanamine hydrochloride is obtained ((i): R=H, Ar=radical 15 wherein Z is ethoxy, and the chain is attached to position 2 of the tetralin moiety) which is crystallized from a mixture ethanol/isopropanol 2/1.

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-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-ethoxycarbonylmethylindol -4-yloxy)propanamine hydrochloride is obtained ((i): R=H, Ar=radical 16 wherein Z is ethoxy, and the chain is attached to position 2 of the tetralin moiety) which is crystallized from a mixture ethanol/isopropanol 2/1.

Following the procedure described in Example 27, but starting from 2-ethyl-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 (90 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-ethylindol-4-yloxy)propan amine hydrochloride is obtained ((i): R=H, Ar=radical 17 wherein Z is ethyl, and the chain is attached to position 2 of the tetralin moiety).

Following the procedure described in Example 27, but starting from 4-(2,3-epoxypropoxy)-2-oxoindoline (20.5 g) and 2-aminotetralin (14.81 g) in ethanol (150 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-oxo-2,3-dihydroindol-4-yl oxy)propanamine hydrochloride is obtained, ((i): R=H, Ar=radical 18 wherein Z is H, and the chain is attached to position 2 of the tetralin moiety).

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), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(thiochroman-8-yloxy)propana mine 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 moiety).

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

Following the procedure described in Example 27, but starting from 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-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-acetylbenzofuran-7-yloxy) propanamine hydrochloride is obtained ((i): 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 moiety).

By operating as described in Example 43, but starting from 2-acetyl-4-(2,3-epoxypropoxy)benzofuran, N-(1,2,3,4-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.dbd.C(COCH.sub.3)--O--, R is H, and the chain is attached to position 2 of the tetralin moiety).

Following the procedure of Example 27, but starting from 4-(4,5,6,7-tetrahydrobenzofuran-2-yl)-1-(2,3-epoxypropoxy)benzene (27 g), obtained according to the teaching of U.S. Pat. No. 3,894,058, and 2-aminotetralin (14.85 g) in ethanol (150 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-[[4-(4,5,6,7-tetrahydrobenzo furan-2-yl)]phenoxy]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 moiety).

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-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2,1,3-benzothiadiazol-4-ylo xy)propanamine hydrochloride is obtained ((i): R=H, Ar=radical 32, and the chain is attached to position 2 of the tetralin moiety).

Following the procedure described in Example 27, but starting from 7-(2,3-epoxypropoxy)phtalide (20.6 g), obtained from 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" taken together, form a group --CO--O--CH.sub.2 --, R=H, and the chain is attached to position 2 of the tetralin moiety).

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) in absolute ethanol (150 ml), the hydrochloride of khellin quinol 3-(1,2,3,4-tetrahydronaphth-2-ylamino)-2-hydroxypropyl ether is obtained ((i): R=H, Ar=radical 34, and the chain is attached to position 2 of the tetralin moiety).

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-3-(1-oxoindan-4-yloxy)propanam ine hydrochloride is obtained ((i): R=H, Ar=radical 35, and the chain is attached to position 2 of the tetralin moiety).

Following the procedure of Example 27, but starting from 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)-propa namine hydrochloride is obtained ((i): R=H, Ar=radical 36, and the chain is attached to position 2 of the tetralin moiety).

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-1-yloxy)propan amine hydrochloride is obtained ((i): R=H, Ar=radical 37, and the chain is attached to position 2 of the tetralin moiety).

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 extracted with methylene chloride. The organic phase is dried and evaporated to dryness. 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-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-methoxymethylindol-4-ylox y)propanamine hydrochloride is obtained ((i): R=H, Ar=radical 38, and the chain is attached to position 2 of the tetralin moiety).

Following the procedure of Example 27, but starting from 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-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2,2,5,7,8-pentamethylchroma n-6-yloxy)propanamine hydrochloride is obtained ((i): R=H, Ar=radical 41, and the chain is attached to position 2 of the tetralin moiety).

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

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-yloxypropanamine hydrochloride is obtained ((i): R=H, Ar=radical 43, and the chain is attached to position 2 of the tetralin moiety).

Following the procedure of Example 27, but starting from 8-(2,3-epoxypropoxy)-2H-chromene (20.4 g) and 2-aminotetralin (14.85 g) in absolute ethanol (120 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2H-chromen-8-yloxy)-propana mine hydrochloride is obtained ((i): R=H, Ar=radical 44, and the chain is attached to position 2 of the tetralin moiety).

A mixture of 1,4-dihydroxyindane (1.4 g), epichlorohydrin (1 g) and sodium hydroxide (0.4 g) is 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 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-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1-hydroxyindan-4-yloxy)prop anamine hydrochloride is thus obtained ((i): R=H, Ar=radical 45, and the chain is attached to position 2 of the tetralin moiety).

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), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-indan-4-yloxypropanamine hydrochloride is obtained ((iA): E and G, taken together, represent a group --CH.sub.2 --CH.sub.2 --CH.sub.2 --, R=H, and the chain is attached to position 2 of the tetralin moiety).

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

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

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 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-aminotetralin (4.35 g) in ethanol (20 ml) is then added thereto. The reaction mixture is then processed as described in Example 27 affording N-(1,2,3,4-tetrahydronaphth-2-yl)- 2-hydroxy-3-(2-oxobenzimidazolin-4-yloxy)propanamine hydrochloride ((i): R=H, Ar=radical 61, Z=Z'=H, and the chain is attached to position 2 of the tetralin moiety).

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-aminotetralin (14.8 g) in ethanol (100 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-cyanothien-3-yloxy)p ropanamine 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 moiety).

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-ethoxycarbonyl-1,2,3-t hiadiazol-5-yl)phenoxy]propanamine hydrochloride is obtained ((i): R=H, Ar=radical 63, wherein Z is a 4-COOC.sub.2 H.sub.5 group, and the chain is attached to position 2 of the tetralin moiety).

Following the procedure of Example 27, but starting from 2-[3-(2,3-epoxypropoxy)phenyl]-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-tetrahydronaphth-2-yl)-2-hydroxy-3-[3-(4-trifluoromethylimidazo l-2-yl)phenoxy]propanamine hydrochloride is obtained ((i): 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 moiety).

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 evaporated off under reduced pressure and epichlorohydrin (10.2 g) is added to the resulting solution kept at 25.degree. C. The reaction mixture is stirred at 25.degree. C. for 4 hours then poured into ice/water (500 mi) and extracted with chloroform (100 ml+75 ml+50 ml+25 ml). The organic extracts are pooled, washed with water (50 ml), dried and evaporated to afford 3-(2,3-epoxypropoxy)pyridine as an oily residue. Part of said oily product (3 g) is dissolved in ethanol (20 ml) and a solution of 2-aminotetralin (3 g) in ethanol (20 ml) is added thereto. Following then the procedure of Example 27, N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-pyrid-3-yloxypropanamine hydrochloride is obtained ((i): R=H, Ar=radical 65, wherein Z is H, and the chain is attached to position 2 of the tetralin moiety).

Following the procedure of Example 27, but starting from 1-acetyl-5-(2,3-epoxypropoxy)-1,2,3,4-tetrahydroquinoline (2.77 g) and 2-aminotetralin (1.49 g) in ethanol (30 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1-acetyl-1,2,3,4-tetrahydro quinolin-5-yloxy)propanamine hydrochloride is obtained ((i): R=H, Ar=radical 66, wherein Z is methyl, and the chain is attached to position 2 of the tetralin moiety).

Following the procedure of Example 27, but starting from 1-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), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1-acetylindazol-4-yl)propan amine hydrochloride ((i): R=H, Ar=radical 67, wherein Z is H, Z' is acetyl, and the chain is attached to position 2 of the tetralin moiety).

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= Z'=H, and the chain is attached to position 2 of the tetralin moiety).

Following the procedure of Example 27, but starting from 6-(2,3-epoxypropoxy)-1-hydroxyxanthen-9-one (2.84 g), prepared as described in U.S. Pat. No. 3,912,733, and 2-aminotetralin (1.49 g) in absolute ethanol (40 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1-hydroxy-9-oxoxanth-6-ylox y)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 moiety).

Following the procedure of Example 32, and reacting epichlorohydrin with 4-hydroxy-2-methylbenzofuran, 4-hydroxybenzofuran, 5-hydroxybenzofuran, 5-hydroxy-2-methylbenzofuran, 6-hydroxy-3-methylbenzofuran or 7-hydroxybenzofuran, in the presence 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)p ropanamine hydrochloride (Ex. 70);

N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-benzofuran-4-yloxypropanamine hydrochloride (Ex. 71);

N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-benzofuran-5-yloxypropanamine hydrochloride (Ex. 72);

N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-methylbenzofuran-5-yloxy)p ropanamine hydrochloride (Ex. 73);

N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(3-methylbenzofuran-6-yloxy)p ropanamine hydrochloride (Ex. 74); and

N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-benzofuran-7-yloxypropanamine hydrochloride (Ex. 75),

(i.e. compounds (i): R=H, Ar=radical 27, wherein one of Z and Z' is H and the other is methyl, and the chain is attached to position 2 of the tetralin moiety).

Analogously, starting from, respectively, 4-hydroxybenzothiophene or 5-hydroxybenzothiophene, the following compounds are obtained:

N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-benzothien-4-yloxypropanamine hydrochloride (Ex. 76); and

N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-benzothien-5-yloxypropanamine hydrochloride (Ex. 77),

((i): R=H, Ar=radical 28, wherein Z is H, and the chain bridges position 4 or 5 of the Ar group to position 2 of the tetralin moiety).

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-(1,2,3,4-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 moiety).

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

Analogously, but starting from 6-hydroxy-3,4-dihydro-2H-1,5-benzodioxepine or 7-hydroxy-2,3,4,5-tetrahydro-1,6-benzodioxocine, the following compounds are obtained respectively:

N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(3,4-dihydro-2H-1,5-benzodiox epin-6-yloxy)propanamine hydrochloride (Ex. 80); and

N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2,3,4,5-tetrahydro-1,6-benzo dioxocin-7-yloxy)propanamine hydrochloride (Ex. 81), ((i): R=H, Ar=radical 48, wherein n is 3 or 4 respectively, and the chain is attached to position 2 of the tetralin moiety).

Following the procedure of Example 33, but starting from epichlorohydrin and 8-hydroxyquinoline or 5-hydroxyquinoline 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-yloxypropanamine hydrochloride (Ex. 82) ((i): R=H, Ar=radical 50, 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-yloxypropanamine hydrochloride (Ex. 82) ((i): R=H, Ar=radical 49, and the chain is attached to position 2 of the tetralin moiety).

Operating as described in Example 27, but starting from 8-acetylmethoxy-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril, 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-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(8-acetylmethoxy-3,4-dihydro carbostyril-5-yloxy)propanamine hydrochloride is obtained ((iF): R=H, L"=acetonyloxy, E" and G", taken together, represent a group --CH.sub.2 --CH.sub.2 --CO--NH--, and the chain is attached to position 2 of the tetralin moiety).

Following the procedure of Example 27, but starting from 2-propargyloxy-l-(2,3-epoxypropoxy)benzene (2.04 g) and 2-aminotetralin in absolute ethanol (30 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-propargyloxyphenyl)propan amine hydrochloride is obtained, m.p. 129.degree.-130.degree. 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:

N-(1,2,3,4-tetrahydronaphth-1-yl)-2-hydroxy-3-(2-propargyloxyphenyl)propana mine hydrochloride, m.p. 114.degree.-116.degree. C. (Ex. 86);

N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-propargyloxyphen yl)propanamine hydrochloride, m.p. 158.degree.-160.degree. C. (Ex. 87); and

N-(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-propargyloxyphen yl)propanamine hydrochloride, m.p. 179.degree.-182.degree. C. (Ex. 88).

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 ((iA): R=H, E=acetamido, G=nitro, and the chain is attached to position 2 of the tetralin moiety) (Ex. 89). A mixture of N-(1,2,3,4-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. The air contained in the reaction vessel is replaced by nitrogen and 10% Pd/C (0.25 g) is rapidly introduced therein. Hydrogenation is carried out at room temperature and 2.5 bar until the theoretical amount of hydrogen has been consumed. The reaction mixture is then heated, at atmospheric pressure, for 2 hours by means of a boiling water-bath. The catalyst is filtered off, the filtrate is evaporated to dryness and the obtained residue is taken up in hydrogen chloride saturated-isopropanol.

N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-benzimidazol-4-yloxypropanami ne dihydrochloride is thus obtained ((iF): R=L"=H, E" G", taken together, form a group --N.dbd.CH--NH--, and the chain is attached to position 2 of the tetralin moiety) (Ex. 90).

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 hours. Excess epichlorohydrin is then removed by distillation and the residue is dissolved in ethyl acetate (50 ml). The organic solution is washed with 2N NaOH (20 ml) and concentrated to dryness yielding 1-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 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-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy -3-oxoxanth-4-yloxypropanamine hydrochloride ((i): R=H, Ar=radical 29, wherein Z is >C.dbd.0, and the chain is attached to position 2 of the tetralin moiety)(Ex. 91). Analogously, but starting from 4-hydroxyxanthene, N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-xanth-4-y loxypropanamine hydrochloride is obtained ((i): R=H, Ar=radical 29, wherein Z is a methylene group, and the chain is attached to position 2 of the tetralin moiety) (Ex. 92).

Following the procedure of Example 91, but starting from 4-hydroxy-1-methylcarbostyril, 4-hydroxy-1-ethylcarbostyril, 4-hydroxy-1-allylcarbostyril, or 4-hydroxy-1-phenylcarbostyril and reacting the raw chlorohydrin thus obtained with 2-aminotetralin, the following compounds are prepared respectively:

N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1-methyl-2-oxo-1,2-dihydroqu inolin-4-yloxy)propanamine hydrochloride (Ex. 93);

N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1-ethyl-2-oxo-1,2-dihydroqui nolin-4-yloxy)propanamine hydrochloride (Ex. 94);

N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1-allyl-2-oxo-1,2-dihydroqui nolin-4-yloxy)propanamine hydrochloride (Ex. 95); and

N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1-phenyl-2-oxo-1,2-dihydroqu inolin-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 moiety).

Following the procedure of Example 27, but starting from 1-(1-phenyltetrazol-5-yloxy)-2,3-epoxypropane (4.37 g) prepared as described in BE 866,278 and 2-aminotetralin (1.48 g) in absolute ethanol (60 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1-phenyltetrazol-5-yloxy)pr opanamine hydrochloride is obtained ((i): R=H, Ar=radical 60, wherein Z=Z'=H and the chain is attached to position 2 of the tetralin moiety).

A mixture of 1-(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 dried yielding 1.8 g of N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-naphthyloxy)propanamine, as the free base; m.p. 102.degree.-115.degree. C.

Following the general procedure of Example 98, but starting from 1-(2-naphthyloxy)-2,3-epoxypropane (4.5 g) and 1-aminotetralin (2.95 g), N-(1,2,3,4-tetrahydronaphth-1-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 (20 ml). Yield: 2.2 g; m.p. 135.degree.-137.degree. C.

Following the general procedure of Example 98, but starting from (R)-1-(1-naphthyloxy)-2,3-epoxypropane (3.8 g; /alpha/=-31.08.degree. (c=1.5 % in methanol)), prepared from 1-naphthol by the method described in Heterocycles, 1983, 20, 1975-1978, and S(+)-1-aminotetralin (2.8 g) obtained from S(-)-1-aminotetralin hydrochloride (Il Farmaco Ed. Sci., 1971, 26, 475-486) by neutralization with 15% sodium hydroxide and extraction with ethyl ether, in the presence of S(-)-1-aminotetralin hydrochloride (5 mg), N-[(S)-1,2,3,4-tetrahydronaphth-1-yl]-(R)-2-hydroxy-3-(1-naphthyloxy)propa namine 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; m.p. 107.degree.-109.degree. C., /alpha/=+6.6.degree. (c=1% in methanol).

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

Starting from (R)-1-(1-naphthyloxy)-2,3-epoxypropane (4.5 g) and R(-)-1-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-yl)]-(R)-2-hydroxy-3-(1-naphthyloxy)prop anamine hydrochloride (4.4 g) is obtained; m.p. 176.degree.-178.degree. C., /alpha/=+21.9.degree. (c=1% in methanol).

Starting from (S)-1-(1-naphthyloxy)-2,3-epoxypropane (3.3 g), S(+)-1-aminotetralin (2.5 g) and a small amount of S(-)-1-aminotetralin hydrochloride (5 mg), and following the procedure of Example 102, N-[(S)-1,2,3,4-tetrahydronaphth-1-yl)]-(S)-2-hydroxy-3-(1-naphthyloxy)prop anamine hydrochloride (3.4 g) is obtained; m.p. 177.degree.-179.degree. C., /alpha/ =-20.5.degree. (c=1% in methanol).

The following compounds are obtained either as the free bases or the hydrochlorides, by operating as described in Examples 98 or 99:

N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(5,6,7,8-tetrahydronaphth-1-y loxy)propanamine; m.p. 90.degree.-93.degree. C. (from ethyl acetate) (Ex. 104);

N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-naphth-2-yloxypropa namine hydrochloride; m.p. 184.degree.-187.degree. C. (from ethanol) (Ex. 105);

N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(5,6,7,8-tetrahydro naphth-1-yloxy)propanamine hydrochloride; m.p. 172.degree.-175.degree. C. (from isopropanol) (Ex. 106);

N-(1,2,3,4-tetrahydronaphth-1-yl)-2-hydroxy-3-(5,6,7,8-tetrahydronaphth-1-y loxy)propanamine hydrochloride; m.p. 172.degree.-176.degree. C. (from isopropanol) (Ex. 107).

By operating as described in Examples 98 or 99 the following compounds (iA) are obtained:

N-(1,2,3,4-tetrahydronaphth-1-yl)-2-hydroxy-3-(2-cyanophenoxy)-propanamine hydrochloride; m.p. 161.degree.-163.degree. C. (from isopropanol) (Ex. 108);

N-(1,2,3,4-tetrahydronaphth-1-yl)-2-hydroxy-3-(3-cyanophenoxy)-propanamine hydrochloride; m.p. 185.degree.-187.degree. C. (from 95% ethanol) (Ex. 109);

N-(1,2,3,4-tetrahydronaphth-1-yl)-2-hydroxy-3-(3-trifluoromethylphenoxy)pro panamine hydrochloride; m.p. 135.degree.-137.degree. C. (from isopropanol) (Ex. 110);

N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(3-trifluoromethylphenoxy)pro panamine; m.p. 84.degree.-89.degree. C. (from isopropyl ether) (Ex. 111);

N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(3-trifluoromethylp henoxy)propanamine hydrochloride; m.p. 215.degree.-217.degree. C. (from isopropanol) (Ex. 112).

The following compounds of formula (iB) are obtained by operating as described in Examples 98 or 99:

N-(1,2,3,4-tetrahydronaphth-1-yl)-2-hydroxy-3-(4-cyanophenoxy)propanamine hydrochloride; m.p. 156.degree.-160.degree. C. (from acetone) (Ex. 113);

N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-[4-(2-methoxyethyl) phenoxy]propanamine hydrochloride; m.p. 153.degree.-156.degree. C. (from isopropanol) (Ex. 114);

N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-[4-(2-methoxyethyl)phenoxy]pr opanamine; m.p. 95.degree.-97.degree. C. (from isopropyl ether) (Ex. 115);

N-(1,2,3,4-tetrahydronaphth-1-yl)-2-hydroxy-3-[4-(2-methoxyethyl)phenoxy]pr opanamine hydrochloride; m.p. 136.degree.-139.degree. C. (from isopropanol) (Ex. 116);

N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(4-chlorophenoxy)pr opanamine hydrochloride; m.p. 168.degree.-170.degree. C. (from isopropanol) (Ex. 117);

N-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(4-chlorophenoxy)-propanamine; m.p. 117.degree.-119.degree. C. (from ethyl acetate) (Ex. 118);

N-(1,2,3,4-tetrahydronaphth-1-yl)-2-hydroxy-3-(4-chlorophenoxy)propanamine hydrochloride; m.p. 131.degree.-135.degree. C. (from isopropanol) (Ex. 119).

Following the general procedure of Example 1, but starting from 1-aminotetralin, 2-aminotetralin or 2-amino-7-hydroxytetralin and 3-(2,3-epoxy-1-propoxy)-4-morpholino-1,2,5-thiadiazole, prepared as described in J. Org. Chem. 1979, 44, p. 1826, the following compounds are obtained respectively:

N-(1,2,3,4-tetrahydronapht-1-yl)-2-hydroxy-3-(4-morpholino-1,2,5-thiadiazo1 -4-yloxy)propanamine hydrochloride; m.p. 156.degree.-159.degree. C. (from isopropanol) (Ex. 120);

N-(1,2,3,4-tetrahydronapht-2-yl)-2-hydroxy-3-(4-morpholino-1,2,5-thiadiazo1 -4-yloxy)propanamine hydrochloride; p.f. 171.degree.-174.degree. C. (from isopropanol) (Ex. 121);

N-(7-hydroxy-1,2,3,4-tetrahydronapht-2-yl)-2-hydroxy-3-(4-morpholino-1,2,5- thiadiazo1-4-yloxy)propanamine (as the free base avoiding the addition of HC1/isopropanol); p.f. 187.degree.-191.degree. C. (from isopropanol) (Ex. 122.).

(a) Epichlorohydrin (46.9 ml) is added to a solution of 3-chloro phenol (51.42 g) and 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 1N NaOH, and with water, dried over sodium sulfate, and concentrated to dryness under reduced pressure yielding 1-(3-chlorophenoxy)-2,3,-epoxypropane (46 g); b.p. 105.degree.-110.degree. 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 applied to a silica gel column developed 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 HC1/isopropanol. The precipitate is recovered by filtration yielding 1.6 g of N-(1,2,3,4-tetrahydronaphth-1-yl)-2-hydroxy-3-(3-chlorophenoxy)propanamine hydrochloride; m.p. 157.degree.-158.degree. C.

A solution of 2-amino-7-hydroxytetralin (2.0 g) and 1-(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 HC1/isopropanol. A precipitate forms which is recovered by filtration and washed with ethyl ether yielding 2.2 g of N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(3-chlorophenoxy)p ropanamine hydrochloride; m.p. 193.degree.-195.degree. C.

A solution of 2-aminotetralin (1.1 g) and 1-(3-chlorophenoxy)-2,3-epoxypropane (1.38 g) in absolute ethanol (50 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 made acidic by the addition of HC1/isopropanol. The precipitate which forms is recovered by filtration, and crystallized from 95% ethanol yielding 1.0 g of N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(3-chlorophenoxy)propanamine hydrochloride; m.p. 172.degree.-174.degree. C.

A solution of 1-aminotetralin (2.95 g) and [2-(2-propynyloxy)phenoxy]-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 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 and evaporated to dryness. The obtained residue is dissolved in isopropanol (25 ml) and the solution is made acidic by the addition of HC1/isopropanol. The precipitate which forms is recovered by filtration and crystallized from isopropanol (12 ml) yielding 2.25 g of N-(1,2,3,4-tetrahydronaphth-1-yl)-2-hydroxy-3-[2-(2-propynyloxy)phenoxy]pr opanamine hydrochloride; m.p. 114.degree.-116.degree. C.

Following the general procedure of Example 1, but starting from 2-amino-7-hydroxytetralin (2.55 g) and [2-(2-propynyloxy)phenoxy]-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-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-[2-(2-propynyloxy) phenoxy]propanamine hydrochloride; m.p. 158.degree.-160.degree. C.

Following the general procedure of Example 126, but starting from 2-aminotetralin instead of 1-aminotetralin, a precipitate is 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)phenoxy]pr opanamine hydrochloride; m.p. 129.degree.-130.degree. C.

Following the general procedure of Example 1, but starting from 2-amino-6-hydroxytetralin (0.6 g) and [2-(2-propynyloxy)-phenoxy]-2,3-epoxypropane (0.75 g), 0.2 g of N-(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-[2-(2-propynyloxy) phenoxy]propanamine hydrochloride is obtained; m.p. 179-.degree.182.degree. C.

A solution of 1-(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 off 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-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-chlorophenoxy)propanamine ; m.p. 98.degree.-101.degree. C.

A mixture of 1-aminotetralin (2.95 g) and 1-(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 purified by silica gel column chromatography 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-1-yl)-2-hydroxy-3-(2-chlorophenoxy)propanamine ; m.p. 78.degree.-81.degree. C.

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 ml) and the obtained solution is acidified by the addition of HC1/isopropanol. The precipitate is recovered by filtration yielding 2.25 g of N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-chlorophenoxy)p ropanamine hydrochloride; m.p. 201.degree.-203.degree. C.

A mixture of 2-aminotetralin (2.5 g) and 1-(4-acetamidophenoxy)-2,3-epoxypropane (3.52 g) in dimethylsulfoxide (40 ml) is heated at 80.degree. C. for 5 hours. The reaction mixture is allowed to cool toat room temperature and water (180 ml) is then added thereto. The precipitate 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-yl)-2-hydroxy-3-(4-acetamidophenoxy)-propana mine; m.p. 133.degree.-136.degree. C.

A mixture of 1-aminotetralin (5.92 g) and 1-(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 with m.p. 125.degree.-130.degree. 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 purified by silica gel column chromatography eluting with ethyl acetate/methanol 9/1 v/v. The combined fractions are concentrated to dryness and washed with hexane yielding 2 g of N-(1,2,3,4-tetrahydronaphth1-yl)-2-hydroxy-3-(4-acetamidophenoxy)propanami ne; m.p. 80-.degree.84.degree. C.

A mixture of 1-aminotetralin (0.8 g) and 1-[(trans-6,7-dihydroxy-5,6,7,8-tetrahydronaphth-1-yl)oxy]-2,3-epoxypropan e (1.3 g), prepared by the method described in J. Med. Chem., 1978, 21, 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 on 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-1-yl)-2-hydroxy-3-(trans-6,7-dihydroxy-5,6,7,8 -tetrahydronaphth-1-yloxy)propanamine as a vitreous solid.

IR (KBr): 3362, 2930, 1454, 1253, 1065 cm-1.

(a) A solution of R(+)-2,3-epoxy-1-propanol (5 g), 2-allylphenol (7.54 g) and triphenylphosphine (14.7 g) in anhydrous tetrahydrofuran (80 ml) is cooled to 0.degree.-5.degree. C. and diethyl azodicarboxylate (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(+)-1-(2-allylphenoxy)-2,3-epoxypropane (9.0 g) is thus obtained which is purified by distillation; b.p. 100.degree.-105.degree. C./0.3 mmHg, /alpha/=+14.3.degree. (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 purified by silica gel column chromatography 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 (10 ml), crystallizes therefrom.

N-[(S)-1,2,3,4-tetrahydronaphth-2-yl]-(S)-2-hydroxy-3-(2-allylphenoxy)propa namine (1.1 g) is then recovered by filtration and crystallized from isopropyl ether; m.p. 70.degree.-72.degree. C.; /alpha/=-51.0.degree. (c=0.5% in methanol).

Following the general procedure of Example 136, but starting from R(+)-2-aminotetralin (2.2 g) and S(+)-1-(2-allylphenoxy)-2,3-epoxypropane (2.85 g), N-[-(R)-1,2,3,4-tetrahydronaphth-2-yl]-(S)-2-hydroxy-3-(2-allylphenoxy)pro panamine (2.3 g) is obtained; m.p.. 65.degree.-68.degree. C.; /alpha/=+32.0.degree. (c=0.5% in methanol).

(a) By operating as described in Example 136 (a), but using S(-)-2,3-epoxy-1-propanol instead of R(+)-2,3-epoxy-1-propanol, R(-)-1-(2-allylphenoxy)-2,3,-epoxypropane is obtained which is characterized by /alpha/=-11,8.degree. C. (c=1% in methanol).

(b) A mixture of the above product (2.2 g) and S(-)-aminotetralin (1.7 g) in absolute ethanol (30 ml) is refluxed for 5 hours. Ethanol is then evaporated off and the obtained residue is purified by silica gel column chromatography 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-y1-]-(R)-2-hydroxy-3-(2-allylphenoxy)-pr opanamine; m.p. 70.degree.-72.degree. C. (from ethyl acetate); /alpha/=-31.3.degree. (c=0.5 % in methanol).

Starting from R(+)-2-aminotetralin (2.2 g) and R(-)-1-(2-allylphenoxy)-2,3-epoxypropane (2.85 g), and following the same procedure as in Example 138, 3.0 g of N-[(R)-1,2,3,4-tetrahydronaphth-2-yl]-(R)-2-hydroxy-3-(2-allylphenoxy)prop anamine are obtained; m.p. 71-73.degree. C. (from isopropyl ether); /alpha/=+53,6.degree. (c=0,5% in methanol).

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:

N-,[(S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)]-(S)-2-hydroxy-3-(2-allylp henoxy)propanamine; m.p. 173.degree.-174.degree. C. (isopropyl ether); /alpha/=-79.6.degree. (c=0.5% in methanol) (Ex. 140);

N-[(R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)]-(S)-2-hydroxy-3-(2-allylph enoxy)propanamine; m.p. 167-.degree.169.degree. C. (isopropyl ether); /alpha/=+31.4.degree. (c=0.5% in methanol) (Ex. 141);

N-[(S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)]-(R)-2-hydroxy-3-(2-allylph enoxy)propanamine; m.p. 168-.degree.170.degree. C. (isopropyl ether); /alpha/=-36.3.degree. (c=0.5% in methanol) (Ex. 142);

N-[-(R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-2-hydroxy-3-(2-allylph enoxy)propanamine; m.p. 173-.degree.175.degree. C. (isopropyl ether); alpha/=+75.6.degree. (c=0.5% in methanol) (Ex. 143).

By operating substantially as described in Examples 136-139, but using S(-)-1-aminotetralin instead of S(-)-2-aminotetralin and R(+)-1-aminotetralin instead of R(+)-2-aminotetralin, the following compounds are obtained, either as the free base or as the hydrochlorides:

-N-[(S)-1,2,3,4-tetrahydronaphth-1-yl)]-(S)-2-hydroxy-3-(2-allylphenoxy)pro panamine hydrochloride; m.p. 127.degree.-129.degree. C. (isopropanol); /alpha/=-23.4.degree. (c 0.5 % in methanol) (Ex. 144);

N-[(R)-1,2,3,4-tetrahydronaphth-1-yl]-(S)-2-hydroxy-3-(2-allylphenoxy)propa namine; m.p. 71.degree.-73.degree. C. (isopropyl ether); /alpha/=-13.1.degree. (c=0.5 % in methanol) (Ex. 145);

N-[(S)-1,2,3,4-tetrahydronaphth-1-yl)](R)-2-hydroxy-3-(2-allylphenoxy)propa namine; m.p. 72.degree.-74.degree. C. (isopropyl ether); /alpha/=+12.6.degree. (c=0.5 % in methanol) (Ex. 146);

N-[(R)-1,2,3,4-tetrahydronaphth-1-yl)]-(R)-2-hydroxy-3-(2-allylphenoxy)prop anamine hydrochloride; m.p. 126.degree.-128.degree. C. (isopropanol); alpha/=+21.7.degree. (c=0.5 % in methanol) (Ex. 147).