IL45813A - Substituted 2-amino-3-phenyl-1-propanol derivatives their production and pharmaceutical compositions containing the - Google Patents

Abstract

1475913 Phenylpropanolamines BOEHRINGER INGELHEIM GmbH 9 Oct 1974 [11 Oct 1973] 43792/74 Heading C2C Compounds of the general formula (R 1 = H, halogen, CF 3 , OH, C 1-4 alkyl or alkoxy; R 2 = H, C 1-4 alkyl, benzyl) and their salts are prepared by (a) reducing a compound of the formula (R 2 <SP>1</SP> = R 2 , C 1-4 alkanoyl, benzoyl; R 3 =alkoxy, substituted alkoxy) with a complex hydride and, if necessary, deacylating the product, (b) removing the protecting group(s) in a compound of the formula (R 4 = H, protecting group; R 5 = R 1 , OR 7 ; R 6 = R 2 , protecting group; R 7 = protecting group; at least one of M 4,6,7 =protecting group), (c) reducing the corresponding nitropropanol, (d) alkylating or benzylating the primary amine or (e) reducing the corresponding amide, optionally followed by resolution and/or salt formation. The above compounds are sympathicomimetics and increase blood pressure; they may be administered in the form of pharmaceutical preparations containing them in association with a carrier. [GB1475913A]

Description

45813/2 is o'V'-Dan mnpn »T»w3rn ^TJS** Substituted 2-amino~3-phenyl~l-propanol derivatives, their production and pharmaceutical compositions containing them C*H. BOEHRDJGEfi SOHH C:- 43677 The present invention relates to propanol derivatives and their acid addition salts, as well as to processes for the production thereof. The novel compounds possess interesting physiological properties.

According to one feature of the present invention there are provided compounds of the formula: - OH (wherein represents a hydrogen or halogen atom, a hydroxy or trifluoromethyl group or an alkyl or alkoxy group with 1 to i carbon atoms; and 1¾2 represents a hydrogen atom, an alkyl group with 1 to A carbon atoms or a benzyl group) and acid addition salts thereof.

The compounds of formula I as hereinbefore defined contain an asymmetric carbon atom and thus may exist not only in racemic form but also in the form of optically active isomers i.e. the D and the L-isomers. It will be appreciated that all such forms of the compounds of formula I (and acid addition salts thereof) are within the scope of the present invention.

The acid addition salts useful for incorporation in pharmaceutical compositions are physiologically compatible acid addition salts. Other acid addition salts may however be useful in the preparation of compounds of formula I and physiologically compatible acid addition salts thereof.

The compounds of general formula I according to the invention and the physiologically compatible acid addition salts thereof possess interesting physiological properties. In particular compounds according to the invention in general possess sympathicomimetic properties and are potentially useful as cardiac and circulation agents. Moreover the compounds of formula I according to the invention and the physiologically compatible acid addition salts are potentially useful as agents for increasing blood pressure, the effect of these compounds being maintained for a relatively long period of time. Compounds of the present invention which have been tested have been found capable of maintaining their physiological activity for a longer period than commercial preparations at present on the market and possessing a similar physiological activity. In particular the half-life time of activity of 2-amino-3- (3, 5-dihydroxyphenyl )-l-propanol (which is a compound of the present invention) has been found to be about 3 times as long as the half-life time of activity of l-(3-hydroxyphenyl )-2-ethyl-amino-ethano1.

Furthermore compounds according to the invention may serve as intermediates in the preparation of other physiologically active compounds.

Preferred compounds according to the present invention, by virtue of their especially favourable physiological activity include compounds of formula I as hereinbefore defined (wherein represents a hydrogen, fluorine, chlorine or bromine^ atom or a hydroxy, methyl, methoxy or trifluoromethyl group and 1*2 represents a hydrogen atom, or a methyl, ethyl or benzyl group and the acid addition salts thereof.

Particularly preferred compounds of the present invention, by virtue of their particularly favourable physiological activity, include those preferred compounds, in which represents a chlorine atom, or a 5-hydroxy, methyl, methoxy or trifluoromethyl group e.g. 2-amino-3- (3 , 5- -dihydroxyphenyl)-l-propanol and the acid addition salts thereof.

The compounds of formula I (as hereinbefore defined) may, for example, be prepared by one of the following processes (a) to (e) , which processes constitute further features of the present invention a) reducing a compound of the formula: (wherein is as hereinbefore defined, l^' represents the radical or an acyl group with 1 to i carbon atoms or a benzoyl group, and represents an optionally substituted alkoxy group) with a complex hydride and, where a compound of formula I (wherein represents an acyl group) is obtained, deacylating said compound whereby a compound of formula I is obtained. The reduction is preferably effected by the use of a strongly effective hydride e.g. lithium aluminium hydride or SD A. The reduction may also be effected by the use of a weaker reducing complex hydride, e.g. lithium borohy-dride, calcium borohydride or sodium borohydride.

Where, however, a compound of formula II is used as starting material in which R^' represents an acyl group and a weaker reducing complex hydride is employed the amide grouping in the compound of formula II undergoes virtually no reaction. In this case the acyl grouping is removed subsequently by conventional methods e.g. by treatment with hydrochloric acid to form a compound of formula I as hereinbefore defined (in which represents a hydrogen atom). Where, however, a compound of formula II is used in which I^' represents an acyl group and a strongly effective complex hydride is employed the acyl grouping is reduced to the corresponding hydrocarbon group i.e. a compound of formula I is obtained in which represents an alkyl group with l-Λ carbon atoms or a benzyl group, b) reacting a compound of formula:- (III) J [wherein represents a hydrogen atom or a removable phenolic-OH protecting group, R,_ represents the radical R^ as hereinbefore defined or the group -OR-, (in which R7 represents a removable phenolic -OH protecting group) and R^ represents the radical ft^ or a hydrogenolytically removable amino protecting group, with the proviso that at least one of R^ , R^ and R-. represents a removable protecting group] whereby the said compound of formula III is converted into a compound of formula I.

The -OH protecting groups may, for example, be groups removable by hydrolysis, hydrogenation, ether cleavage or deacylation. Hydroxyl protecting groups which may be removed by ether cleavage or deacylation include, for example, alkyl groups such as methyl or benzyl groups or acyl groups. Removal of the -OH protecting groups may be effected in a manner known per se. Thus hydrogenation may, for example, be effected by the use of hydrogen and conventional hydrogenation catalytsts, e.g. platinum, palladium or Raney-nickel and ether cleavage and deacylation may, for example, be effected by the use of hydrobromic acid, hydrochloric acid, boron trifluoride etherate, boron tribromide or aluminium chloride. ' c) reducing a compound of the formula: - OH (wherein R^ is as hereinbefore defined) whereby a compound of formula I is obtained.

The reduction may, for example, be effected catalytically with hydrogen and a conventional hydrogenation catalyst, e.g. platinum, palladium or Raney nickel. d) for the preparation of compounds of formula I as hereinbefore defined (wherein represents an alkyl group with \- carbon atoms or a benzyl group), the alkylation of a compound of the formula: - (wherein R^ is as hereinbefore defined) whereby a compound of formula I (wherein represents an alkyl group with 1 to 4 carbon atoms or a benzyl group) is obtained. e) for the preparation of compounds of formula I as hereinbefore defined (wherein represents an alkyl group with 1-4 carbon atoms or a benzyl group), the reduction of a compound of the formula:- OH (wherein Rn is as hereinbefore defined and RQ represents a hydrogen atom, an alkyl group with 1-3 carbon atoms or a phenyl group) whereby a compound of formula I (wherein represents an alkyl group with 1-4 carbon atoms or a benzyl group) is obtained.

The reduction is preferably effected by the use of a complex hydride e.g. lithium aluminium hydride or S.D.M.A.

The compounds of formula VII are preferably first prepared by acylating a compound of the formula: - OH (wherein is as hereinbefore defined) whereby a compound of formula VII (as hereinbefore defined) is obtained.

If desired, the bases of formula I may be converted according to conventional methods into their acid addition salts e.g. their physiologically compatible acid addition salts, or where the compounds are obtained in the form of salts, these salts may, if desired, be converted into salts with other acids or into the corresponding free bases.

Compounds of general formula I as hereinbefore defined may occur in the form of racemates. Any racemates present may, if desired, be resolved into their optically active isomers by conventional methods e. by means of optically active acids. Thus, for example, the optically active isomers may be prepared either by starting from optically active starting compounds in the processes of the present invention or by resolving the racemates obtained as reaction products into their optical isomers i conventional manner.

The starting materials for the processes of the present invention may be prepared by processes known per se. The a-amino acid esters required for processes (a) and (b) may be obtained, for example, via the corresponding azalactones or by reaction of the correspondingly substituted benzyl halide with acetamido-cyano-acetates or -malonic esters.

The starting materials for process (c) may, for example, be obtained by reacting a correspondingly substituted l-phenyl-2-nitroethane with paraformaldehyde.

According to a still further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient at least one compound of formula I as hereinbefore defined or a physiologically compatible acid addition salt thereof in association with a pharmaceutical carrier or excipient. The compositions may be presented in a form suitable for oral, rectal or parenteral administration. Thus, for example, compositions for oral administration may be solid or liquid and may take the form of granules, tablets, coated tablets, capsules, tinctures, syrups, pills, emulsions, suspensions, powders, or drops, such compositions comprising carriers or excipients conventionally used in the pharmaceutical art. Thus, for example, suitable tabletting excipients include lactose, potato and soluble starches and magnesium stearate.

For parenteral administration, the carrier may be a sterile, parenterally acceptable liquid such as sterile water, or a parenterally acceptable oil e.g. arachis oil, contained in ampoules. Compositions for rectal administration may take the form of suppositories, the carrier comprising a suppository base.

Advantageously, the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Tablets, coated tablets, capsules, suppositories and ampoules are examples of suitable dosage unit forms. Each dosage unit preferably contains 1 to 100 mg and especially 5 to 20 mg, of active ingredient.

The following examples illustrate the preparation of compounds according to the invention, and also pharmaceutical compositions containing such compounds as active ingredients : - Exam le 1 2-Amino-3- (3 , 5-dihydroxyphenyl)- l-propanol-hydrobromide a) 2-Amino-3- (3 , 5-dimethoxypheny1)-1-propano1-hydro- chloride 6.8 g (28 mmol) of 3 , 5-dimethoxyphenylalanine-methyl ester are dissolved in 35 ml of absolute tetrahydrofuran and, at 20 to 30°C, added dropwise to a stirred suspension of 3.2 g (89 mmol) of lithium aluminium hydride in 35 ml of absolute tetrahydrofuran. The mixture is refluxed for 2 hours, cooled and decomposed cautiously with water. Subsequently, the mixture thus obtained is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent distilled off in vacuo. The residue is converted into the hydrochloride with ethereal hydrochloric acid.

Yield: 6.5 g (65% of theory); M.p. 165°C. b) 2-Amino-3- (3 , 5-dihydroxyphen l)-l-propanol-hydrobromide 4.5 g (18.5 mmol) of 2-amino-3-(3 ,5-dimethoxyphenyl)-1-propanol hydrochloride are refluxed together with 45 ml of hydrobromide for one hour. The excess hydrobromic acid is then distilled off in vacuo and the residue is dehydrated azeotropically. The crystalline residue is recrystallized from isopropanol/ether.

Yield: 1.8 g (37% of theory); M.p. 118-120°C.

Example 2 2-Benzylamino-3-(3-hydroxy-4-methylphenyl)-l-propanol-hydrobromide a) 2-Benz lamino-3-(3-methox -4-methylphen l)-l-propanol hydrochloride ,55.5 g (0.16 mol) of N-benzoyl-3- (3-methoxy-4-methylphenyl)-alanine-ethyl ester (m.p. 133°C) are dissolved in 550 ml of absolute tetrahydrofuran and slowly added dropwise to a stirred suspension of 37 g (0.98 mol) of lithium aluminium hydride in 1850 ml of absolute tetrahydrofuran under a nitrogen atmosphere. When the addition has been completed, the mixture is refluxed for 5 hours, allowed to stand overnight and decomposed slowly with water. The inorganic precipitate is filtered off with suction and washed with tetrahydrofuran. The solvent is distilled off in vacuo, the residue is taken up in ether and treated with water. The ether phase is dried over sodium sulfate and distilled off. The residue is recrystallized from petroleum ether. Yield: 45.0 g (97.5% of theory). The base is dissolved in ethyl acetate and on the addition of ethereal hydrochloric acid converted into the hydrochloride.

Yield: 49.5 g (95% of theory); m.p. 191°C. b) 2-Benzylamino-3; -hy^ro^-^-methYlpheny1)-1-gropano1 20 g (62 mmol) of 2-benzylamino-3- (3-methoxy-4-methylphenyl)-l-propanol hydrochloride in 200 ml of 48% hydrobromic acid are refluxed for 1 hour. The mixture is cooled, the precipitated crystals are filtered off with suction and recrystallized from water. Yield: 21.5 g (98.5% of theory), m.p. 199°C.

Example 3 2-Amino-3- (3-hydroxy-4-methyIpheny1)-1-propano1-hydrobromide 21.5 g (61 mmol) of 2-benzylamino-3- (3-hydroxy-4-methylphenyl)-l-propanol hydrobromide (see Example 2) are dissolved in 250 ml of methanol and after the addition of 6 g of palladium/charcoal (5%) debenzylated catalytically at 60°C and 5 atmospheres. When the hydrogenation is J completed, the mixture is filtered off, the methanol is distilled off in vacuo and the residue is dissolved hot in acetonitrile. On cooling, the title compound crystallizes out and is filtered off with suction and dried.

Yield: 13 g (81.5% of theory).

M.p. 115-117°C.

Example 4 2-Amino-3-(3-hydroxy-5-methylphenyl)-l-propanol hydrobromide a) 3-(3-Methoxy-5-meth lphen l)-alanine-ethy_l ester 56 g (0.33 mol) of 3-methoxy-5-methyl-benzylchloride are added dropwise to a solution of 56 g (0.33 mol) of acetamidocyanoethy1 acetate and 7.8 g of sodium in 330 ml of ethanol. The mixture is refluxed for 4 hours, filtered off with suction to remove the precipitated sodium chloride and the alcohol is then distilled off in vacuo. The residue is saponified by boiling with 117 g of potassium hydroxide in 920 ml of water for 20 hours. The resulting product is acidified with concentrated hydrochloric acid and evaporated to dryness.

The amino acid is extracted by treating the amino acid containing mixture twice each time with 1 ltr. of ethanof. The alcohol is distilled off and the hydrochloride of the amino acid obtained as residue is recrystallized from acetonitrile.

Yield: 46 g (57% of theory), m.p. 248°C.

The ethyl acetate is obtained in 65% yield by azeotropic esterification. The hydrochloride melts at 184-185°C. b) 2-Amino-3- (3-methoxy- 5-methylphen 1 ) - 1-propano1_ hydrochloride 33 g of 2-amino-3-(3-methoxy-5-methylphenyl) -alanine ester hydrochloride are suspended in ether and converted into the base on the addition of dilute ammonia. The base is dried over sodium sulfate and the ether is distilled off in vacuo . The resulting product is then dissolved again in 330 ml of absolute ether and added dropwise to the stirred suspension of 13.7 g of lithium aluminium hydride in 700 ml of absolute ether. The resulting product is re-fluxed for 5 hours, decomposed with water, filtered off with suction and evaporated in vacuo . The residue is dissolved in acetonitrile and mixed with the calculated quantity of ethereal hydrochloric acid. The precipitated hydrochloride is filtered off with suction and dried.

Yield: 23 g (83% of theory), m.p. 204 - 205°C. c) 2-Amino-3-(3-hydroxy-5-methylpheny1) - 1-propano1 hydrobromide 23 g (0.1 mol) of 2-amino-3-(3-methoxy-5-methyl-phenyl)-l-propanol hydrochloride are refluxed for one hour after the addition of 230 ml of 48% hydrobromic acid. A part of the hydrobromic acid is distilled off, cooled and filtered off with suction. The product thus obtained is recrystallized from aqueous acetonitrile.

Yield: 20 g (76% of theory), m.p.1 160°C.

Example 5 2-Amino-3- (3-hydroxy-4-methoxyphenyl) -1-propanol hydrochloride 6 g (18.6 mmol) of 2-benzylamino-3-(3-hydroxy-4-methoxyphenyl)-1-propanol hydrochloride are dissolved in 60 ml of methanol. After the addition of palladium/charcoal (5%) the mixture is debenzylated catalytically. Afte uptake of the calculated quantity of hydrogen, the catalyst is filtered off, the solvent is distilled off in vacuo and the residue recrystallized from acetonitrile. Yield: g (92% of theory), m.p. 181-182°C.

Example 6 2-Amino-3-(3-hydroxyphenyl)-l-propanol-hydrobromide a) 2-Amino-3-(3-methoxyphenyl)-1-propanol hydrochloride 29 g (0.139 mol) of 3- (3-methoxyphenyl) -alaninemethyl ester are dissolved in 170 ml of absolute tetrahydrofuran and added dropwise to a stirred suspension of 10.6 g (0.278 mol) of lithium aluminium hydride in 170 ml of absolute tetrahydrofuran. After 2-hours' boiling, the reaction mixture is further processed as described in the preceding Examples. The hydrochloride of 2-amino- 3- (3-methoxyphenyl)-1-propanol is obtained in a yield of 26.5% of theory with a melting point of 145°C. b) 2-Amino-3-(3-hydroxyphenyl)-1-propanol hydrobromide 8 g of 2-amino-3-(3-methoxyphenyl)-l-propanol hydrochloride are refluxed in 80 ml of 48% hydrobromic acid for 1 hour. Subsequently, the reaction mixture is evaporated to dryness in vacuo, the water is removed by distillation after the addition of xylene and the residue is recrystallized from glacial acetic acid.

Yield: 6 g (66% of theory), m.p. 150-152°C.

Example 7 2-Amino-3- (3 , 5-dihydroxyphenyl)-l-propanol-hydrobromide a) l-(3 , 5-Dimethoxyj?hen l)-2-nitroethane 27 g (0.129 mol) of 3 ,5-dimethoxy-^-nitro-styrol are dissolved in 540 ml of benzene. Nitrogen is passed through the solution in the presence of 1.3 g of tris-(triphenylphosphine)-rhodium-I-chloride as catalyst. Then, at 60°C and 5 atmospheres pressure the calculated quantity of hydrogen is introduced. When the hydrogenation is completed, the benzene is distilled off and the residue triturated with ether. This processing causes the catalyst to precipitate. The catalyst is filtered off with suction, the ether is distilled off and the product remaining is recrystallized from methanol.

Yield: 21.3 g (78.5% of theory), m.p. 51-53°C. b) 3-(3 , -Dimethox phen l)-2-nitro-l-proganol 10 g (47.4 mmol) of 1- (3 , 5-dimethoxyphenyl) -2-nitro-ethane are dissolved in 100 ml of ethanol. 1 ml of cone, sodium hydroxide solution is then added to the solution. 5 g (50 mmol) of a 30% formalin solution is then added dropwise slowly, the temperature being kept below 20°C.

The reaction mixture is allowed to stand for 70 hours at room temperature; it should be observed that the solution maintains an alkaline reaction during this time. The solution is acidified with 2 N acetic acid and the solvent is distilled off in vacuo. The resultant product is distributed between ethyl acetate/water, the organic phase is dried over sodium sulfate and the solvent is distilled off in vacuo. The residue is triturated with warm toluene, whereby crystallization takes place.

Yield: 8.9 g (78% of theory), m.p. 81-83°C. c) 2-Amino-3-(3 ,5-dimethoxyphen l)-l-propanol hydrochloride 8.5 g of 3- (3 ,5-dimethoxyphenyl)-2-nitro-l-propanol are dissolved in 100 ml of methanol and after addition of platinum dioxide it is hydrogenated under normal conditions. After uptake of the calculated quantity of hydrogen, the catalyst is filtered off and the solution evaporated to dryness in vacuo. The residue is dissolved in acetonitrile; on the addition of the calculated quantity of ethereal hydrochloric acid the hydrochloride of melting point 165°C is obtained.

Yield: 5.3 g (71% of theory).

In order to produce 2-amino-3- (3 , 5-dihydroxyphenyl) - 1-propanol-hydrobromide , the resultant product is further processed as described in Example 1.

Exam le 8 2-Amino-3- ( 3-hydroxy- 5- trifluoromethyl-phenyl)- 1-propanol- hydrobromide a) 3-Methoxy-5-trifluoromethy1-benzaldehyde 125 g of 3-methoxy-5-trifluoromethyl-aniline are diazotized and reacted according to the method of BEECH (J. Chem.Soc. 1954, 1297) to give 3-methoxy- 5-trifluoro- 20 methyl-benzaldehyde. (B.p.Q χ: 58 - 60°C, n^ = 1.4833). b) N-Benzoy1-3-methoxy- 5-trifluoro-methyIpheny1-alanine- methylester 3-methoxy-5-trifluoromethylbenzaldehyde is reacted with hippuric acid to give the azalactone (m.p. 149 - 150°C).

By means of boiling in methanol in the presence of catalytic quantities of potassium carbonate the a-benzamido-3- methoxy-5-trifluoromethyl-methyl-cinnamate is obtained (m.p. 143 °C) , which is hydrogenated catalytically to give the N-benzoy1-3-methoxy- 5-1rifluoromethyIpheny1-alanine- methyl ester (m.p. 133°C). c) 2-Benzylamino-3- (3-methoxy- 5-1rifluoromethylpheny1) -1-propanol hydrochloride 17 g of the ester mentioned under (b) are reduced to the amino alcohol according to the method described in Example 2(a). The melting point of the hydrochloride amounts to 161°C. d) 2-Benzylamino-3-(3-hydroxy-5-trifluoromethylphen 1)-1-propanol hydrobromide 15 g of 2-benzylamino-3-(3-methoxy-5-trifluoro-methylphenyl)-l-propanol hydrochloride are demethylated by boiling with 48% hydrobromic acid for one hour. Then, the reaction mixture is cooled, the precipitated crystals are filtered off with suction and dried.

Yield 11 g; m.p. 206 - 207°C. e) 2-Amino-3- (3-hydroxy- 5-trifluoromethylpheny1) - 1-propanol hydrobromide Debenzylation is effected catalytically in methanol. After uptake of the calculated quantity of hydrogen, the catalyst is filtered off, the solvent is distilled off in vacuo and the residue recrystallized in acetonitrile.

The 2-amino-3- (3-hydroxy-5-trifluoromethylpheny1)- 1-propanol hydrobromide melts at 155-156°C.

Example 9 2-Amino-3- (2-chloro-5-hydroxypheny1) -1-propanol hydrobromide The azalactone is obtained in the manner described in Example 8 starting from 2-chloro-5-methoxy-benzaldehyde by condensation with hippuric acid (m.p. 167°C), from which the corresponding hydroxymethyl-cinnamate (m.p. 121-123°C) is obtained following which reduction with lithium aluminium hydride yields the hydrochloride of 2-benzylamino-3-(2-chloro-5-methoxyphenyl)- 1-propanol (m.p. 167 - 168°C). After catalytic debenzylation (m.p. 153 - 155°C) and demethylation with 48% hydrobromic acid, the hydrobromide of 2-amino-3-(2-chloro-5-hydroxy-phenyl)- 1-propanol of m.p. 174-175°C is obtained.

Example 10 ^2-Ethylamino-3- (3 , 5-dihydroxypheny1)-1-propano1 hydrobromide a) -Acet l-3 ,5-dimethoxyDhenyl-alanine-meth^lester 3 ,5-dimethoxy-benzaldehyde is condensed with aceturic acid, yielding 45% of a product having a m.p. 142- 143 °C. By refluxing in methanol in the presence of potassium carbonate and subsequent hydrogenation the N-acetyl-3 ,5-dimethoxyphenyl-alanine-methyl ester (m.p. 110 - 111°C) is obtained. b) 2-Ethylamino-3-(3 ,5-dimethoxYphen^)-l-propanol hydrobromide 42 g of N-acetyl-3 ,5-dimethoxyphenylalaninemethyl ester are reduced in absolute tetrahydrofuran with lithium aluminium hydride to yield the 2-ethylamino- 3-(3 ,5-dimethoxyphenyl)-l-propanol (m.p. 82 - 83°C). The hydrobromide melts at 175°C. c) 2-Ethylamino-3- ( 325-dihydroxypheny1) - 1- ropano1 hydrobromide 10 g of 2-ethylamino-3-(3 ,5-dimethoxyphenyl)-l- propanol hydrobromide are demethylated by boiling with 48% hydrobromic acid. After distilling off the excess hydrobromic acid, the remaining residue is recrystallized from acetonitrile . The 2-ethyl- amino-3-(3 ,5-dihydroxyphenyl)-l-propanol hydrobromide melts at 167 - 168 °c.

Example 11 2-Methylamino-3-(3 t5-dihydroxyphenyl-l-propanol hydro bromide The hydrobromide of 2-methylamino-3- (3 ,5-dimethoxyphenyl)-l-propanol , m.p. - 142 °C, is obtained by a process similar to that of Example 10 starting from N-formyl-3 ,5-dimethoxyphenyl-alanine-methyl ester by reduction with lithium aluminium hydride. The demethylation with 4870 hydrobromic acid yields 2-methylamino-3-(2 ,5-dihydroxyphenyl)-l-propanol hydrobromide , m.p. 183 - 186°C.

Example 12 2-Amino-3- ( 3-hydroxy- 2-methylphenyl)-l-propanol hydrobromide a) N-Benzoy^ l-3-methoxy-2-methy^phenYlalanine-methYlester 3-methoxy-2-methyl-aniline is reacted according to BEECH (see Example 8) to yield 3-methoxy-2-methyl-benzaldehyde. Reaction of this latter compound with hippuric acid yields the corresponding azalactone (m.p. 166°C) , which is then reacted by boiling with methanol/ potassium carbonate followed by catalytic hydrogenation to yield the N-benzoyl-3-methoxy-2-methylphenyl-alanine methyl ester (m.p. 143-144 °C). b) 2-Ami o-3-(3-h droxY;2-methylphen l)-l- roganol N-benzoyl-3-methoxy-2-methylphenyl-alanine-methyl ester reacts with lithium aluminium hydride to yield 2-benzy1amino-3-(3-methoxy-2-methylpheny1)-1- ropano1. The hydrochloride melts at 17 °C. By means of boiling with 48% hydrobromic acid, the 2-benzylamino-3-(3-hydroxy-2-methylphen l)-l-propanol-hydrobromide (m.p. 153°C) is obtained. This latter compound is debenzylated catalytically to yield the 2-amino-3- (3-hydroxy-2-methylphenyl)-l-propanol hydrobromide. (m.p. 166°C).

Example 13 2-Amino-3- (3-hydroxy-6-methylphenyl)-l-propanol hydro-bromide a) N-Benzoy_1-3-methoxy-6-methylpheny1-alanine-methy1-ester 2,5-cresotic acid is methylated with dimethylsulfate to yield 5-methoxy-o-toluylic acid (m.p. 152-154°C).

According to the Rosenmund method, 5-methoxy-o-tolualde-hyde (b.p.^ ^ 75°C) is obtained via the acid chloride (b.p.Q 3 81-83°C). As described in Example 12, the azalactone (m.p. 170-171°C) as well as the N-benzoyl-3-methoxy-6-methylphenyl-alanine-methyl ester (m.p. 98°C) are produced. b) 2-Amino-3-(3-h dro y-6-methYlphen l)-l-pro anol hYdrobromide The 2-benzylamino-3-(3-methoxy-6-methylphenyl)-l-propanol hydrochloride obtained by reduction with lithium aluminium hydride is first demethylated (m.p. 166-167°C) and then catalytically debenzylated to yield 2-amino-3-(3-hydroxy-6-methylphenyl)-l-propanol hydrobromide (m.p. 143°C).

Example 14 2-Amino-3- (3 ,5-dihydroxyphenyl)-!- ropanol hydrochloride a) 2-Benzamido-3- (3 , 5-dimethox phen l)- 1-propanol To 34.3 g of N-benzoyl-3-(3 , 5-dimethoxyphenyl)-alanine methylester in 350 ml of tetrahydrofuran are added 4.2 g of sodium borohydride, while stirring at room temperature. The mixture is first stirred for 30 minutes and it is then refluxed for 5 hours. After cooling, the solvent is distilled off in vacuo, the residue is suspended in water and acidified with acetic acid. The precipitating crystals are filtered off with suction, washed with water and dried. By recrystallization from toluene 2-benzamide-3-(3 , 5-dimethoxyphenyl)-1-propanol of m.p. 117-118°C is obtained. b) 2-Amino-3-(3 ,5-dih drox ghenYl)-l-propanol hydrochloride 21 g of 2-benzamido-3-(3 , 5-dimethoxypheny1)-1-propanol are refluxed in 200 ml of 6 N hydrochloric acid for 8 hours. After cooling,. the mixture is extracted three times with chloroform and evaporated to dryness in vacuo. The residue is recrystallized from glacial acetic acid. The hydrochloride of the 2-amino-3-(3 ,5-dihydroxyphenyl)-l-propanol melts at 167°C.

Example 15 2-Benzylamino-3-(3-hydroxy-4-methoxypheny1)-l-propanol hydrochloride 13 g of N-benzoyl-3-(3-hydroxy-4-methoxyphenyl)-alaninemethyl ester (m.p. 11 -116°C) are dissolved in 130 ml of absolute tetrahydrofuran and added dropwise to a stirred suspension of 9 g lithium aluminium hydride in 450 ml of absolute tetrahydrofuran. The mixture is refluxed for 6 hours, allowed to stand overnight and decomposed with water. The precipitate is filtered off with suction, extracted twice with dimethylformamide at 60°C and the two organic solutions are evaporated to dryness. The residue is dissolved in 2 N hydrochloric acid, extracted with ethyl acetate and made alkaline again by the addition of potash. After drying over sodium sulfate, the solvent is distilled off in vacuo. The residue is dissolved in acetonitrile, mixed with the calculated quantity of ethereal hydrochloric acid and filtered off with suction.

Yield: 6 g (47% of theory), m.p. 128°C.

Example 16 2-Amino-3- ( 3 , 5-dihydroxypheny1)- 1-propanol hydrochloride a) Ν-Βεηζο 1-3 , 5-dih droxY-phenylalanine-methy^lester 31 g (0.067 mol) of 2-phenyl-4-(3 , S-bisbenzyloxy-benzylidene^S-oxazolone are suspended in ten times the quantity of methanol and, after the addition of 1 g of anhydrous potash, refluxed for 10 minutes. The solution obtained is filtered warm into a hydrogenation vessel and hydrogenated after the addition of Raney-nickel until the uptake of hydrogen is completed. The catalyst is filtered off with suction and the methanol is distilled off in vacuo. The residue is dissolved in a little methanol and brought to crystallization by the addition of water. The precipitate is filtered off with suction and dried. Yield: 18 g (85% of theory), m.p. 168°C. b) 2-Benzamido-3-(3 , 5-dihvdrox hen l) - 1-pr^anol 12.7 g (0.144 mol) of calcium chloride are dissolved at room temperature in 360 ml of ethanol. 18 g of (0.057 mol) of N-benzoyl-3 , 5-dihydroxypheny1-alanine-methyl ester are then added and the mixture is cooled to -10°C. At this temperature 11 g (0.288 mol) of sodium borohydride are cautiously added. When the addition is completed, the reaction mixture is stirred for 1 hour at -10°C, 1 hour at -5°C and two hours more at 0°C. The alcohol is distilled off in vacuo (temperature of bath 40 to 50°C). The residue is mixed with water and, while cooling, acidified with 2 N hydrochloric acid. The product thus obtained is extracted 4 to 5 times with hot ethyl acetate, dried over sodium sulfate and the solvent is distilled off in vacuo. The residue is dissolved in a little methanol and by adding water slowly precipitated in crystalline form. The precipitate is filtered off with suction and recrystallized several times from ethyl acetate.

Yield: 12.5 g (76% of theory), m.p. 132-134°C. c) 2-Amino-3- (3 , 5-dihYdroxyphenYl)- l-propanol_ hydrochloride 39 g (0.136 mol) of 2-benzamido-3-(3 , 5-dihydroxyphenyl)-1-propanol in 390 ml of 2 N hydrochloric acid are refluxed for 18 hours. The reaction mixture is cooled, the benzoic acid is extracted with chloroform and the remainder is distilled to dryness in vacuo.

The residue is triturated with acetonitrile until crystallization is achieved and the crystals are then filtered off with suction. The hydrochloride of the 2-amino-3-(3 , 5-dihydroxyphenyl) - 1-propanol is recry-stallized from 150 ml of glacial acetic acid in the presence of 5 drops of 40% sodium bisulfite solution and activated charcoal.

Yield: 25 g (84% of theory), m.p. 166-167°C.

Example 17 2-Benzylamino-3- ( 3 , 5-dihydroxyphenyl)-1-propanol hydrobromide 15.7 g (0.05 mol) of N-benzoyl-3-(3 , 5-dihydroxyphenyl) - -alanine-methyl ester (m.p. 168°C) are dissolved in 200 ml of absolute tetrahydrofuran and slowly added dropwise to a stirred suspension of 15.2 g (0.4 mol) of lithium aluminium hydride in 600 ml of absolute tetrahydrofuran. The reaction mixture is refluxed for 3 hours and allowed to stand overnight. The excess lithium aluminium hydride is decomposed, filtered off with suction and the residue extracted with warm dimethylformamide. The organic phase is evaporated in vacuo. The residue is dissolved in dilute hydrobromic acid, filtered over activated charcoal and then evaporated to dryness in vacuo. The hydrobromide of 2-benzylamino-3-(3 , 5-dihydroxyphenyl)-l-propanol (m.p. 117-119°C) thus obtained is recrystallized from acetonitrile.

Example 18 2-Amino-3-(3-hydroxy-6-methylphenyl)-l-propanol hydrochloride 10 g of 3-(3-hydroxy-3-methyl)-2-nitro-l-propanol , prepared in a manner similar to Example 7, are dissolved in 200 ml of methanol and after the addition of platinum oxide hydrogenated under normal conditions at room temperature. After uptake of the calculated quantity of hydrogen, the catalyst is filtered off and evaporated to dryness in vacuo. The residue is dissolved in dilute hydrobromic acid and the solution is evaporated to dryness in vacuo. The residue thus obtained is first triturated with acetonitrile and then recrystallized from glacial acetic acid. The 2-amino- (3-hydroxy-6-methylphenyl)-l-propanol hydrobromide melts at 1 1-143°C.

Example 19 2-Eth lamino-3-( 3 , 5-dihydroxypheny1) - 1-propano1 hydrobromide 13.2 g (0.05 mol) of 2-amino-3-(3 ,5-dihydroxyphenyl) 1-propanol hydrochloride are dissolved in 100 ml of methanol and refluxed for 1 hour after the addition of 2.2 g (0.05 mol) of acetaldehyde. Subsequently the reaction mixture is cooled and after the addition of 10 g of palladium charcoal (5%) hydrogenated at 5 atmospheres pressure until the uptake of hydrogen is completed. The catalyst is filtered off with suction and evaporated to dryness in vacuo. The residue is taken up in dilute hydrobromic acid, filtered over activated charcoal and the filtrate evaporated to dryness in vacuo. By recrystallization from acetonitrile 2-ethylamino-3-(3 ,5-dihydroxyphen 1)-1-propano1-hydro-bromide is obtained.

Melting point: 167 - 168°C.

Pharmaceutical Composition Examples Example A Tablets Composition: Active ingredient according to the invention 5 parts by weight stearic acid 6 " " glucose 589 " The components are processed in the conventional way to form tablets each weighing 0.600 g. If desired, the active ingredient content may be decreased or increased and the quantity of glucose used increased or decreased accordingly.

Example B Suppositories Composition: 2-Amino-3- (3 , -dihydroxypheny1) - 1-propanol hydrobromide 20 parts by weight lactose, pulverized 5 parts by weight cocoa butter 1635 parts by weight The components are processed in the conventional way to form suppositories each weighing 1.7 g.

Example C Capsules Composition: Active ingredient according to the invention 10 parts by weight lactose 90 " corn starch 400 " " " The capsules are formulated by carefully mixing 1000 mg of the finely pulverized components and filled into hard gelatin capsules.

Claims (41)

1. Compounds of the formula: OH (wherein R^ represents a hydrogen or halogen atom, a hydroxy or trifluoromethyl group or an alkyl or alkoxy group with 1 to carbon atoms; and R2 represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms or a benzyl group) and acid addition salts thereof.

2. Compounds as claimed in claim 1 wherein R^ represents a hydrogen, fluorine, chlorine or bromine atom or a hydroxy, methyl, methoxy or trifluoromethyl group; and R2 represents a hydrogen atom or a methyl, ethyl or benzyl group.

3. Compounds as claimed in claim 2 wherein R^ represents a chlorine atom or a 5-hydroxy, methyl, methoxy or trifluoromethyl group.

4. 2-Amino-3-(3,5-dihydroxyphenyl)-l-propanol and acid 45813/2 addition salts thereof.

5. Compounds as claimed in any of the preceding claims in the form of optically active isomers.

6. Compounds as claimed in any of claims 1-4 in the form of racemates.

7. Compounds as claimed in any of the preceding claims in .the form of their physiologically compatible acid addition salts.

8. Compounds as claimed in claim 1, other than as claimed in claim 4 , as herein specifically disclosed.

9. _ A process for the preparation of compounds of formula I as defined in claim 1 which comprises reducing a compound of the formula: 45813/2 (wherein R^ is as defined in claim 1, ' represents the radical R2 or an acyl group with 1 to 4 carbon atoms or a benzoyl group, and represents an optionally subsituted alkoxy group) with a complex hydride and, where a compound of formula I (wherein R2 represents an acyl group) is obtained, deacylating said compound whereby a compound of formula I is obtained.

10. A process as claimed in claim 9 wherein the deacy-lation is effected by treatment with hydrochloric acid.

11. A process as claimed in claim 9 wherein the complex hydride comprises lithium aluminium hydride.

12. A process as claimed in claim 9 wherein the complex hydride comprises S.D.M.A.

13. A process as claimed in claim 7 or claim 8 wherein the complex hydride comprises lithium borohydride, sodium borohydride or calcium borohydride.

14. A process for the preparation of compounds of formula I as defined in claim 1 which comprises reacting a compound of the formula:- 45813/2 [wherein represents a hydrogen atom or a removable phenolic -OH protecting group, represents the radical R^ (as defined in claim 1) or the group -OR^ (in which R^ represents a removable phenolic -OH protecting group) and R^ represents the radical R2 or a hydrogenolytically removable amino protecting group, with the proviso that at least one of R^*^ and R^ represents a removable protecting group] whereby the said compound, of formula III is converted into a compound of formula I.

15. A process as claimed in claim 14, where a compound of formula III is used (in which R^ and/or R^, where present, represents a removable phenolic -OH protecting group) and the said protecting group(s) is removed by hydrolysis, hydrogenation, ether cleavage or deacylation.

16. A process as claimed in claim 15 wherein a compound 45813/2 of formula III is used in which R^and/or R-. , where present, represents an alkyl or acyl group, said compound being subjected to ether cleavage or deacylation.

17. A process as claimed in claim 16 wherein a compound of formula III is used in which R^and/or R^ represents a methyl or benzyl group, said compound being subjected to ether cleavage.

18. A process as claimed in claim 15 wherein the hydrolysis is effected by the use of an aqueous acid or base.

19. A process as claimed in claim 15 wherein the hy-drogenation is effected in the presence of platinum, palladium or Raney nickel as hydrogenation catalyst.

20. A process as claimed in claim 15 wherein the ether cleavage or deacylation is effected by the use of hydrobromic acid, hydrochloric acid, boron trifluoride etherate, boron tribromide or aluminium chloride. •V

21. · A process for the preparation of compounds of formula I as defined in claim 1 which comprises reducing a compound of the formula: - OH (wherein is as defined in claim 1) whereby a compound of formula I is obtained.

22. A process as claimed in claim 21 wherein the reduction is effected by catalytic hydrogenation.

23. A process as claimed in claim 22 wherein the catalytic hydrogenation is effected in the presence of platinum, palladium or Raney nickel as hydrogenation catalyst.

24. A process for the preparation of compounds of formula I as defined in claim 1 (wherein R2 represents 3ci alkyl group with 1- carbon atoms or a benzyl group) which comprises alkylating a compound of the formula: - (wherein is as defined in claim 1) whereby a compound of formula I (wherein represents an alkyl group with 1 to 4 carbon atoms or a benzyl group) is obtained.

25. A process for the preparation of compounds of formula I as defined in claim 1 (wherein ^ represents an alkyl group with 1-4 carbon atoms or a benzyl group) which comprises reducing a compound of the formula: - (wherein R^^ is as defined in claim 1 and Rg represents a hydrogen atom, an alkyl group with 1-3 carbon atoms or a phenyl group) whereby a compound of formula I (wherein represents an alkyl group with 1-4 carbon atoms or a benzyl group) is obtained.

26. A process as claimed in claim 25 wherein the reduction is effected by the use of a complex hydride.

27. A process as claimed in claim 25 wherein the complex hydride comprises lithium aluminium hydride or S.D.M.A.

28. A process as claimed in any of claims 25 to 27 wherein the compound of formula VII is first prepared by acylating a compound of the formula: - (wherein is as defined in claim 1) whereby a compound, of formula VII as defined in claim 25 is obtained.

29. A process as claimed in any of claims 9 to 28 wherein the compound of formula I obtained is subsequently converted into an acid addition salt thereof.

30. A process as claimed in any of claims 9 to 28 45813/2 wherein a racemate as claimed in claim 1 is obtained and is subsequently separated into its optically active isomers.

31. A process as claimed in any of claims 9 to 30 substantially as herein described.

32. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any of Examples 1 to 19.

33. Compounds as claimed in claim 1 when prepared by a process as claimed in any of claims 9 to 32.

34. Pharmaceutical compositions comprising as active ingredient at least one compound of formula I as claimed in any of claims 1 to 6, 8 or 33 or a physiologically compatible acid addition salt thereof in association with a pharmaceutical carrier or excipient.

35. Compositions as claimed in claim 34 in a form suitable for oral, parenteral or rectal administration.

36. Compositions as claimed in claim 34 or claim 35 in the form of granules, tablets, coated tablets, capsules, pills, syrups, tinctures, emulsions, suspensions, 45813/2 powders, drops, suppositories or injection solutions.

37. Compositions as claimed in any of claims 34 to 36 in the form of dosage units.

38. Compositions as claimed in claim 36 wherein each dosage unit contains from 1 to 100 mg of the said active ingredient.

39. Compositions as claimed in claim 38 wherein each dosage unit contains from 5 to 20 mg of the said active ingredient .

40. Compositions as claimed in claim 34 substantially as herein described.

41. Pharmaceutical compositions substantially as here in described in any of Examples A to C. HE:dn