IE47404B1 - Alkanolamine derivatives - Google Patents

Description

This invention relates to new alkanolamine derivatives which possess β-adrenergic blocking activity. The invention is a modification of that claimed in Patent Specification No. 38602.

In Patent Specification No. 38602 there are claimed alkanol— amine derivatives R2 of the formula 0CH2.CHOH.CH2NH-A-NH-X-Y-R inter alia, the carbonyl radical, wherein Y wherein X may be, may be, inter alia, an iminoalkylene or iminoalkyleneoxy radical each of up to 6 carbon atoms, wherein R2 may be, inter alia, the 10 hydrogen atom or an aryl radical of the formula: 14 , R J and R have various meanings . set out in said specification. There is, however, no specific disclosure in said specification of any particular compound 15 wherein Y stands for an iminoalkylene radical and R1 stands for an aryl radical, or wherein Y stands for an iminoalkyleneoxy radical and R2 stands for the hydrogen atom.

According to the present invention there is provided a new alkanolamine derivative of the formula:2 0CH2.CHOH.CHjNH-A-NH-CO-NH-Y-R wherein either (a) A stands for an alkylene radical of from 2 to 12 carbon atoms; wherein R1 stands for an aryl radical of the formula:- 12 wherein η , R9, R each stands for a hydrogen or halogen atom , a hydroxy, amino, nitro or cyano radical, an alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkoxy, alkenyloxy, alkynyloxy or 10 alkanoyl radical each of up to 6 carbon atoms, or an aryl, aryloxy or aralkoxy radical each of up to 12 carbon atoms; or 12 13 wherein R and ic together, and/or R and R together, form the trimethylene, tetramethylene, 1-oxotetramethylene, propenylene, but-2-enylene or buta-1,3-dienylene radical such that together with the adjacent benzene ring they form respectively the indanyl, ,6,7,8-tetrahydronaphthy1, 5-oxo-5,6,7,8-tetrahydronaphthyl, i) indenyl, 5,8-dihydronaphthyl or naphthyl radical; wherein R stands for the hydrogen atom or for the hydroxy or hydroxymethyl radical or for an aralkoxy radical of up to 12 carbon atoms; η 4 wherein R stands for the hydrogen atom or for the amino radical or for a dialkylamino radical of up to 12 carbon atoms; and wherein Y stands for an alkylene radical of up to 6 carbon atoms; - 3 47404 or (b) R1 stands for the hydrogen atom, Y stands for an alkyleneoxy 2 3 4 radical of from 2 to 6 carbon atoms and A, R , R and R have the meanings stated above; or an acid-addition salt thereof.

It will be observed that the alkanolamine derivative of the invention possesses an asymmetric carbon atom, namely the carbon atom of the -CHOH- group in the alkanolamine sidechain, and it can therefore exist in racemic and optically-active forms. It is to be understood that this invention encompasses the racemic form of the alkanolamine derivative and any opticallyactive form which possesses β-adrenergic blocking activity, it being a matter of common general knowledge how a racemic compound may be resolved into optically-active forms, and how the β-adrenergic blocking activity of these forms may be determined. It is further to be understood that β-adrenergic blocking activity usually predominates in that optically-active form which has the S absolute configuration of the said -CHOH- group.

A suitable value for the alkylene radical A is, for example, the ethylene, trimethylene, tetramethylene, hexamethylene, dodecamethylene, 1-methylethylene, 2-methylethylene or 1,1-dimethylethylene radical. A is preferably the ethylene, 1-methylethylene or 1,1-dimethylethylene radical.

A suitable value for R , R , R or R when it stands for a halogen atom is, for example, the fluorine, chlorine, bromine or iodine atom. 3 12 13 A suitable value for R , R , R or R'*''’ when it stands for an alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkoxy, alkenyloxy, alkynyloxy or alkanoyl radical is, for example, the methyl, ethyl, n-propyl, eyclopropyl, cyclopentyl, - 4 47404 allyl, ethynyl, methoxy, isopropoxy, methylthio, eyclopentyloxy, allyloxy, propargyloxy, formyl or acetyl radical.

A suitable value for R2, r\ R^‘_ or R^ when it stands for an aryl or aryloxy radical is, for example, the phenyl or phenoxy radical.

A suitable value for R2, iP, R *, R·12 or R1^ when it stands for an aralkoxy radical is, for example, the benzyloxy radical.

A suitable value for R when it stands for a dialkylamino radical is, for example the dimethylamino radical.

A suitable value for Y when it. stands for an alkylene, radical is, for example, the methylene or ethylidene (-CH(CHj)-) radical. A suitable value for Y when it stands for an alkyleneoxy radical is, for example, the ethyleneoxy or 1,1-dimethylethyleneoxy (-C(GH^)^CH^O-) radical.

A suitable acid-addition salt of an alkanolamine derivative of the invention is, for example, a salt derived from an inorganic acid, for example a hydrochloride, hydrobromide, phosphate or sulphate, or a salt derived from an organic acid, for example an oxalate, lactate, tartrate, acetate, salicylate, citrate, benzoate, β-naphthoate, adipate or l,l-methylene-bis-(2hydroxy-3-naphthoate), or a salt derived from an acidic synthetic resin, for example a sulphonated polystyrene resin.

A preferred alkanolamine derivative of the invention is a compound of the formula givm above wherein A stands for the ethylene, 1-methy 1 ethy Iene or 1,1-dimethylet.hylene radical, and wherein either R stands for a hydrogen atom, or for a halogen atom or a cyano or methyl radical in the 2- position of the benzene x 4 12 13 14 ring and R , R , R , R and R all stand for hydrogen atoms, - 5 47404 or R1* stands for a hydroxy radical in the 4- position of the 2 5 12 15 14 benzene ring and R , R , R , R and R all stand for hydrogen atoms, or is an aeid-addition salt thereof.

Specific alkanolamine derivatives of the invention are 5 those hereinafter described in the Examples. Of these preferred compounds are 1-(2-fluorophenoxy)-3-6-(3-benzylureidoethylamino)2-propanol and the acid-addition salts thereof.

The alkanolamine derivative of the invention may be manufactured by any chemical process known to be useful for the manufacture of chemically-analogous compounds, particularly those processes disclosed in Specification No. 38602.

One preferred process for the manufacture of an alkanol amine derivative of the invention comprises the reaction of a compound of the formula:15 □ h wherein R , R and R have the meanings stated above, with a compound of the formula r6nh-a-nhconh-y-r 1 wherein A, R^ and Y have the meanings stated above and wherein 20 r6 stands for hydrogen or for a benzyl radical, whereafter if R^ stands for a benzyl radical this is removed by hydrogenolysis.

This process may be carried out in a diluent or solvent for example ethanol, at a temperature of up to the boiling point of the diluent or solvent. - 6 47404 A second preferred process for the manufacture of an alkanolamine derivative of the invention comprises the reaction of a compound of the formula: wherein A, R2, R^, R1* and R^ have the meanings stated above and q wherein R stands for a lisplaeeable radical, for example the phenoxy radical, with an amine of the formula h2n-y-r1 wherein and Y have the meanings stated above, whereafter if r6 stands for a benzyl radical this is removed by hydrogenolysis.

This process may be carried out in a diluent or solvent, for example dioxan or toluene, and it may be carried out at a temperature of up to the boiling point of the diluent or solvent. . 2 3 4 12 A compound wherein one or more of R , R , R , R and R1^ stands for an aryloxy radical, for example the benzyloxy radical, may be converted into the corresponding compound wherein one or more of R , r\ R , R^2 and R·^ st;aacjs for the hydroxy radical by hydrogenolysis.

Opfcically-aetive enantiomorphs of the alkanolamine derivative of the invention may be obtained by the resolution by conventional means of the corresponding racemic alkanolamine derivative of the invention.

The said resolution may be carried out by reacting the racemic alkanolamine derivative with an optically-active acid, followed by fractional crystallisation of the diastereo7 isomeric mixture of salts thus obtained from a diluent or solvent, for example ethanol, whereafter the optically-active alkanolamine derivative is liberated from the salt by treatment with a base.

A suitable optically-active acid is, for example, (+)- or (-)-0, O-di-p-toluoyltartaric acid or (-)-2,3:4,5-di-O-isopropylidene2-keto-L-gulonic acid.

The resolution process may be facilitated by treating the partially resolved alkanolamine derivative in free base form obtained after a single fractional crystallisation of the diaster10 eoisomeric mixture of salts with a solubilising agent, for example a primary amine, for example allylamine, in a relatively nonpolar diluent or solvent, for example petroleum ether.

The alkanolamine derivative of the invention in free base form may be converted into an acid-addition salt thereof by reaction with an acid hy conventional means.

As stated above, the alkanolamine derivative of the invention or an acid-addition salt thereof possesses β-adrenergic blocking activity, and furthermore this activity is cardioselective. This activity may be determined by the reversal of isoprenaline20 induced tachycardia in rats or cats, a standard test for the determination of β-adrenergic blocking activity, and by relative freedom from antagonism of isoprenaline-indueed vasodilation in cats or of the relief produced by isoprenaline of histamine-induced bronchospasm in guinea-pigs. Compounds exhibiting this cardio25 selective action show a greater degree of specificity in blocking the cardiac β-receptors than the β-receptors In peripheral blood vessels and bronchial muscle. Thus, a dose may be selected for such a compound at which the compound blocks the cardiac inotropic and chronotropic actions of a catecholamine such as isoprenaline - 8 47404 but does not block the re' axation of tracheal smooth muscle produced by isoprenaline or the peripheral vasodilator action of isoprenaline. Because of this selective action, one of these compounds may advantageously be used together with a sympathominetic bronchodilator, for example isoprenaline, oreiprenaline, adrenaline or ephedrine, in the treatment of asthma and other obstructive airways diseases, inasmuch as the cardioselective compound will substantially inhibit the unwanted stimulatory effects of the bronchodilator on the heart but will not hinder the desirable therapeutic effect of the bronchodilator, A preferred alkanolamine derivative of the invention is up to ten times more active as a cardioselective β-adrenergic blocking agent than practolol. At doses of an alkanolamine derivative of the invention which produce effective β-adrenergie blockade in rats or cats, no symptoms of toxicity are apparent.

Some of the alkanolamine derivatives of the invention . . 2 3 4 wherein one or more of the substituents R , R and R stands for the hydroxy radical, and in particular those wherein R stands for a hydroxy radical in the 3- or 4-position of the benzene 2 nucleus, R stands for the hydrogen atom or for a hydroxy radical in the 3-position when R^ is in the 4-position of the benzene nucleus and R^ stands for the hydrogen atom possess, in addition to β-adrenergic blocking activity, substantial cardiac stimulant activity. Tie stimulant activity may be demonstrated in either conscious or pentobarbitone-anaesthetised dogs, where the alkanolamine derivative or salt thereof produces an increase in heart rate, and/or an increase in force of contraction of the heart and an increase in the speed of conduction of electrical activity through the tissues of the heart. Unlike isoprenaline, a known cardiac stimulating agent, - 9 47404 a preferred stimulant alkanolamine derivative of the invention or a salt thereof is well absorbed when administered orally and has a substantial duration of action. At doses of an alkanolamine derivative of the invention which produce effective cardiac stimulation in dogs, no symptoms of toxicity are apparent.

The alkanolamine derivative of the invention may be administered to warm-blooded animals, including man, in the form of a pharmaceutical composition comprising as active ingredient at least one alkanolamine derivative of the invention, or an acid-addition salt thereof, in association with a pharmaceuticallyacceptable diluent or carrier therefor, A suitable composition is, for example, a tablet, capsule, aqueous or oily solution or suspension, emulsion, injectable aqueous or oily solution or suspension, dispersible powder, spray or aerosol formulation.

The pharmaceutical composition may contain, in addition to the alkanolamine derivative of the invention, one or more drugs selected from sedatives, for example phenobarbitone, meprobamate, chlorpromazine and the benzodiazepine sedative drugs, for example chlordiazepoxide and diazepam; vasodilators, for example glyceryl trinitrate, pentaerythritol tetranitrate and isosorbide dinitrate; diuretics, for example chlorothiazide; hypotensive agents, for example reserpine, bethanidine and guanethidine; cardiac membrane stabilising agents, for example quinidine; agents used in the treatment of Parkinson's disease and other tremors, for example benzhexol; cardiotonic agents, for example digitalis preparations; α-adrenergic blocking agents, for example phentolamine and sympathomimetic bronchodilators, for example isoprenaline, oreiprenaline, adrenaline and ephedrine. 474 04 When used for the treatment of heart diseases, for example angina pectoris and cardiac arrhythmias, or for the treatment of hypertension or anxiety states in man, it is expected that the alkanolamine derivative would be given to man at a total oral dose of between 20 mg. and 600 mg. daily, at doses spaced at 6-8 hourly intervals, or at an intravenous dose of between 1 mg. and 20 mg.

When used for the treatment of acute or chronic heart failure in man, it is expected that a cardiac stimulant alkanolamine derivative would be given to man at a total oral dose of between 10 mg. and 200 mg. daily, at doses spaced at 6-8 hourly intervals, or at an intravenous dose of between 1 mg. and 100 mg.

Preferred oral dosage forms are tablets or capsules containing between 10 and 100 mg., and preferably 10 mg. or 50 mg. of active ingredient. Preferred intravenous dosage forms are sterile aqueous solutions of the alkanolamine derivative or of a non-toxic acid-addition salt thereof, containing between 0.05% and 1% w/v of active ingredient, and more particularly containing 0.1% w/v of active ingredient.

The invention is illustrated but not limited by the following Examples:Example 1 A stirred mixture of l-(2-cyanophenoxy)-2,3-epoxypropane (1-75 g.)., l-(8-aminoethyl)-3-benzylurea (1.93 g·), water (50 ml.) and ethanol (25 ml.) is heated at 90°C. for 16 hours and then evaporated to dryness under reduced pressure. Aqueous 2N-hydrochloric acid (100 ml.) is added, the mixture is washed twice with ethyl acetate (75 ml. each time) and the aqueous solution is then basified to pH 12 with concentrated aqueous sodium hydroxide solution. The mixture is extracted three times with ethyl acetate (100 ml. each time) and the combined extracts are washed with water, dried over magnesium sulphate and evaporated to dryness. The residue is crystallised from acetonitrile and there is thus obtained l-(2-cyanophenoxy)-3-(!-(3-benzylureidoethyl)amino-2-propanol, m.p. 147-149“C.

The process described above is repeated except that the l-(2-cyanophenoxy)-2,3-epoxypropane is replaced by the appropriate l-phenoxy-2,3_epoxypropane. There are thus obtained the compounds shown in the following table: R2 m. p. ( °C.) crystallisation solvent 2-methyl 156-157 ethanol 2-chloro 162 ethanol 2-fluoro 144-146 methyl isobutyl ketone 3-fluoro 152 aqueous isopropanoi 4-fluoro 136-138 methyl isobutyl ketone 2-methoxy 151-152 ethanol The l-(g-aminoethyl)-3~benzylurea used as starting material may be obtained as follows:Benzylamine (55-5 g.) is added during 30 minutes to a stirred suspension if phenyl ohloroformate (78.3 g.) and anhydrous potassium carbonate (151-8 g.) in dioxan (500 ml.) and the mixture is stirred at laboratory temperature for 72 hours and then poured into water. The mixture is extracted with ethyl acetate and the extract is washed with water, dried over magnesium sulphate and evaporated to dryness. The residue is stirred with petroleum ether (b.p. 6O-8O°C.) and the mixture is filtered. There is thus obtained as solid residue phenyl N-benzylcarbamate , which is used without further purification.

A mixture of phenyl N-benzylearbamate (90.8 g.) and 1,2-diaminoethane (120 g.) is stirred at laboratory temperature for 16 hours and is then poured into water (500 ml.). The mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. Toluene is added to the residue and removed by evaporation repeatedly until the residue crystallises. The residue is then recrystallised from a mixture of petroleum ether (b.p. 60-80°C.) and toluene. There is thus obtained 1-(βaminoethyl)-3-benzylurea, m.p. 231 °C.

Example 2 A stirred mixture of phenyl N-B-(N-benzyl-N-3-p-benzyloxyphenoxy-2-hydroxypropyl)ethylcarbamate (5-26 g.), ethanolamine (1.2 g.) and toluene (50 ml.) is heated at 95-100°C. for 16 hours and then cooled. Diethyl ether (200 ml.) is added, and sufficient n-butanol is then added to produce a homogenous solution.

The solution is extracted with aqueous N-sodium hydroxide solution - 13 4740 4 (20 ml.) and three times with saturated aqueous sodium chloride solution (20 ml. each time). The organic solution is then dried over magnesium sulphate and evaporated to dryness, and the residue is dissolved in glacial acetic acid (80 ml.). A 30? palladium-on-charcoal catalyst (50 mg.) is added and the mixture is shaken with hydrogen at laboratory temperature and atmospheric pressure until 480 ml. of hydrogen have been absorbed. The mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in ethanol (10 ml.) and a solution of oxalic aeid (0.63 g.) in ethanol (5 ml.) is added. The mixture is filtered and there is thus obtained as solid residue l-£-hydroxyphenoxy-3-8-(3-&-hydroxyethyl ureido)ethylamino-2-propanol hydrogen oxalate, m.p. l45-l47°C, The process described above is repeated except that either 2-amino-2-methylpropanol or benzylamine is used in place of ethanolamine. There are thus obtained respectively 1-g-hydroxy phenoxy-3-β[3-(2-hydroxy-l,1-dimethylethyl)ureido]ethylamino-2propanol, which forms a hydroscopic hydrochloride after crystallisation from water; and l-£-hydroxyphenoxy-3~3-(3~benzylureidoethyl)amino-2-propanol, characterised as its hydrochloride, m.p. 113-130°C. after crystallisation from ethanol.

The phenyl N-0-(N-benzyl-N-3~£-benzyloxyphenoxy-2hydroxypropyllethyl carbamate used as starting material may be obtained as follows :Phenyl chloroformate (17.22 g.) is added during 10 minutes to a stirred mixture of l-g-benzyloxyphenoxy-3-(N-benzylN-g-aminoethyl)amino-2-propanol (40.6 g,), sodium bicarbonate (10.08 g.) and toluene (100 ml.) which is maintained at 0°C. - 14 After a further 5 minutes water is added and the mixture is extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue is stirred with petroleum ether (b.p. 60-80°C.) and then with toluene, and the mixture is filtered. The solid product consists of phenyl Ν-β-(N-benzy1-N-3-£-benzyloxyphenoxy-2-hydroxypropyl)ethyl carbamate, which is used without further purification.

Example 3 A stirred mixture of phenyl N-8-(N-benzyl-N-3-phenoxy2- hydroxypropyl)ethylcarbamate [4.2 g.; prepared by similar means to those described in the last part of Example 2 from 1-phenoxy3- (N-benzyl-N-8-aminoethyl)amino-2-propanoll, benzylamine (1.18 g.) and dioxan (20 ml.) is heated at 95-100 °C. for 18 hours and then cooled. Water is added and the mixture is extracted with ethyl acetate. The extract is dried over magnesium sulphate and evaporated to dryness, and the residue is redissolved in ethyl acetate. A solution of oxalic acid in ethyl acetate is added, and the mixture i.j filtered. The solid product is dissolved in glacial acetic acid and hydrogenated over a 30% palladium-oncharcoal catalyst by a similar method to that described in Example 2, The filtrate after removal of catalyst is evaporated to dryness and the residue is crystallised from a mixture of ethanol and ethyl acetate. There is thus obtained l-phenoxy-3~6(3-benzylureido)ethylamino-2-propanol hydrogen oxalate hemihydrate.. m.p. 94-96 °C. (with decomposition).

The process described above is repeated except that either α-methylbenzylamine or ethanolamine is used in place of - 15 47404 benzylamine. There are thus obtained respectively l-phenoxy-3&-(3-a-methylbenzylureido)ethylamino-2-propanol, characterised as its hydrogen oxalate hemihydrate, m.p. 93-95°C. after crystallisation from ethyl acetate, and l-phenoxy-3-6-(3-B-hydroxyethyl5 ureido)ethylamino-2-propanol, characterised as its hydrogen oxalate monohydrate, m.p. 74°C. (with decomposition) after crystallisation from ethanol.

Claims (12)

1. What we claim is:1. An alkanolamine derivative of the formula:4 R OCH 2 .CHOH.CHgNH-A-NH-CO-NH-Y-R 1 wherein either (a) A stands for an alkylene radical of from 5 2 to 12 carbon atoms; wherein R 1 stands for an aryl radical of the formula:- P 1 Ρ I Λ wherein R , R , R and R , which may be the same or different, each stands for a hydrogen or halogen atom, a hydroxy, amino, 10 nitr ' or cyano radical, an alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkoxy, alkenyloxy, alkynyloxy or alkanoyl radical each of up to 6 carbon atoms, or an aryl, aryloxy or aralkoxy radical each of up to 12 carbon atoms; or wherein R 2 and R^ together, and/or R 12 and R^ together, form 15 the trimethylene, tetramethylene, 1-oxotetramethylene, propenylene, but-2-enylene or buta-1,3-dienylene radical such that together with the adjacent benzene ring they form respectively the indanyl, 5,6,7,8-tetrahydronaphthyl, 5-oxo-5,6,7,8-tetrahydronaphthyl, „ 4 indenyl, 5,8-dihydronaphthyl or naphthyl radical; wherein R 20 stands for the hydrogen atom or for the hydroxy or hydroxymethyl radical or for an aralkoxy radical of up to 12 carbon atoms; 17 ^4-7 40 4 wherein R stands for the hydrogen atom or for the amino radical or for a dialkylamino radical of up to 12 carbon atoms; and wherein Y stands for an alkylene radical of up to 6 carbon atoms; or (b) R^ stands for the hydrogen atom, Y stands for an alkyleneoxy radical of from 2 to 6 carbon atoms 2 3 4 and A, R , R and R have the meanings stated above; or an acid-addition salt thereof.

2. An alkanolamine derivative as claimed in claim 1 wherein either (a) A stands for the ethylene, trimethylene, tetramethylene, hexamethylene, dodecamethylene, 1-methylethylene, 2-methylethylene or 1,1-dimethylethyIene radical, R 1 stands for an aryl radical of the formula ,12 each stands for a hydrogen, fluorine, chlorine, bromine or iodine atom or for a hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, cyclopropyl, cyclopentyl, allyl, ethynyl, methoxy, isopropoxy, methylthio, cyclopentyloxy, allyloxy, propargyloxy, formyl, acetyl, phenyl, phenoxy or benzyloxy radical, or wherein R £ and R 9 together, and/or R 4- and R together, form the trimethylene, tetramethylene, 1-oxotetramethylene, propenylene, but-2-enylene or buta-1,3-dienylene radical such that together with the adjacent benzene ring they form respectively the indanyl, 5,6,7,8-tetrahydronaphthyl, - 18 4 7 4 0 4 5-oxo-5,6,7,8-tetrahydronaphthyl, indenyl, 5,8-dihydronaphthyl 4 or naphthyl radical; wherein R stands for the hydrogen atom or for the hydroxy, hydroxymethyl or benzyloxy radical; wherein R stands for the hydrogen atom or for the amino or dimethylamino radi:al; and wherein Y stands for the methylene or ethylidene radical; or (h) R 1 stands for the hydrogen atom, Y stands for the ethyl2 3 eneoxy or 1,1-dimethylethyleneoxy radical and A, R , R and 4 . ... R have the meanings stated above, or an acid-addition salt thereof.

3. An alkanolamine derivative as claimed in claim 2 wherein A stands for the ethylene, 1-methylethylene or 1,1dimethylethylene radical, or an acid-addition salt thereof.

4. An alkanolamine derivative as claimed in claim 1 wherein A stands f>r the ethylene, 1-methylethylene or 1, 1-dimet-lylethylene radical, R stands for a hydrogen atom, or for a halogen atom or a cyano or methyl radical in 3 4 12 13 the 2- position of the benzene ring and R , R , R , R and ih ... R all stand for hydrogen atoms, or an acid-addition salt thereof.

5. An alkanolamine derivative as claimed in claim 1 wherein A has the meaning stated in claim 4, R 2 * stands for a hydroxy radical in the 4- position of the benzene ring and R 2 , R 3 , R 12 , R 13 and R llf all stand for the hydrogen atoms, or an acid-addition salt thereof.

6. The compound l-(2-fluorophenoxy)-3-P-(3-bensy]ureidoethylamino)-2-propanol or an acid-addition salt thereof.

7. An acid-addition salt as claimed in any of claims 1 - 19 47404 to 6 which is a hydrochloride, hydrobromide, phosphate, sulphate, oxalate, lactate, tartrate, acetate, salicylate, citrate, benzoate, (5-naphthoate, adipate or 1,1-methylenebis-(2-hydroxy-3-naphthoate), or a salt derived from a sulphonated polystyrene resin.

8. A process for the manufacture of an alkanolamine derivative or acid-addition salt thereof, claimed in any of claims 1 to 7, which comprises either (a) the reaction of a compound of the formula:ίο 2 3 4 wherein R , R and R have the meanings stated in any of claims 1 to 5, with a compound of the formula R 6 NH-A-NHCONH-Y-R 1 wherein A, R 1 and Y have the meanings stated in any of claims 1 to 5 and wherein R^ stands for hydrogen or for a benzyl radical, whereafter if R^ stands for a benzyl radical this is removed by hydrogenolysis; or (b) the reaction of a compound of the formula: 0CH 2 .CHOH.CH 2 NR 6 -A-NH-CO-R 9 wherein A, R , 9 and wherein R 3 h R , R and stands for R^ have the meanings stated above a displaceable radical, with an 20 47404 amine of the formula HjN-Y-R 1 wherein R 1 and Y have the meanings stated above, whereafter if stands for a benzyl radical this is removed by hydrog. 2 enolysis; whereafter a compound wherein one or more of R , 3 t 12 15 R , R , R and R y stands for an aryloxy radical may be converted into the corresponding compound wherein one or more of R 2 , r\ r\ R 12 and R 1 ^ stands for the hydroxy radical by hydrogenolysis; whereafter a racemic alkanolamine derivative may be resolved into its optically-active enantiomorphs by conventional means; and whereafter an alkanolamine derivative in free base form may be converted into an acid-addition salt thereof by reaction with an acid by conventional means.

9. A pharmaceutical composition which comprises as active ingredient at least one alkanolamine derivative or an acid-addition salt thereof, claimed in any of claims 1 to 7, in association with a pharmaceutically-acceptable diluent or carrier therefor.

10. A composition as claimed in claim 9 which is in the form Of a tablet, capsule,aqueous or oily solution or suspension, emulsion, injectable aqueous or oily solution or suspension, dispersible powder, spray or aerosol formulation.

11. A composition as claimed in claim 9 or 10 which additionally contains one or more drugs selected from sedatives, vasodilators, diuretics, hypotensive agents, cardiac membrane stabilising agents, agents use 1 in the treatment of Parkinson's disease and other tremors, cardiotonic agents, a-adrenergic 4-74 Ο 4 blocking agents and sympathomimetic bronchodilators.

12. An alkanolamine derivative or acid-addition salt thereof, claimed in any of claims 1 to 7, as hereinbefore particularly described in any one of Examples 1 to 3.