IL43726A - 1-phenoxy-3-(p-carbamoylphenoxy)ethylamino-2-propanol derivatives and pharmaceutical compositions containing them - Google Patents

Description

43726/2 o' 'aan ηιπρη »">*s?:>m i¾ B-2-ij»oR, 'nR 1-Phenoxy-Xp-cartoamoylphenoxy)ethylaminq^2½ropanol derivatives and pharmaceutical compositions containing them PPIZER CORPORATION Ci 41877 43726/2 P.C. 5*189 The invention relates to propanolamine derivatives having useful therapeutic properties, and is particularly concerned with novel derivatives of l-phenoxy-3-phenoxyethyl-amino-2-propanols in which the phenyl groups of the 1-phenoxy and 3-phenoxyethylamino substituents carry a hydroxy (or protected hydroxy) group and a -car amoyl group, respectively. Such compounds have the property of blocking the ^-adrenergic receptors and are useful in the curative or prophylactic treat-ment of cardiac conditions such as angina pectoris and cardiac arrhythmias, and in the treatment of hypertension.

The compounds of the invention are those having the general formula; where OR represents hydroxy or a readily hydrolyzable or hydrogenlyzable group wherein R is phenyl lower alkyl; R1 represents a lower alkyl or lower alkoxy; and 2 R represents a hydrogen atom or a benzyl group.

In this specification, and the term "lower", used to qualif an alkyl or alkoxy, indicates that such group or compound contains up to 4 carbon atoms. Any such group When R in the Formula (I) represents a protecting group for a hydroxy group, the group OR is defined as a group which Is readil hydrolyzable or hydrogenolyzable, and R is exemplified by the phenyl lover alkyl group.

Acids from which pharmaceutcially-acceptable addition salts of the compounds of the invention can be prepared are those which form non-toxic addition salts containing pharmaceutically-acceptable anions, such as the hydrochloride, hydrobromide , hydroiodide, sulphate or bisulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, saccharate and p-toluene sulphonate salts.

The compounds of the invention may be prepared in a number of ways, including the following: (1) An epoxy compound of the formula: \ where R represents a protecting group for a hydroxy group, is reacted with an amine of the formula: in approximately equimolecular proportions or optionally 2 in the presence of excess amine when R represents a hydrogen atom. Die reaction may be carried out at ambient or elevated temperature in a suitable solvent, e.g. methanol or ethanol, and the crude product is recovered by filtration or evaporation of the solution to dryness. The product may then be purified by crystallization from a suitable solvent to yield the free base, or by dissolution in a suitable solvent, e.g. ethanol or diethyl ether, and precipitation as a suitable salt, e.g. the hydrochloride, fumarate, maleate or oxalate, by addition of the appropriate acid, preferably dissolved in a suitable solvent, e.g. diethyl ether, followed by collection of the precipitated salt by filtration, and recrystallization from a suitable solvent. Alternatively, in some cases when the crude salt has been prepared as a means of obtaining the product in a solid form, this may be rebasified by suspension in a suitable basic medium, e.g. aqueous sodium bicarbonate solution, and the resulting free base collected by filtration and recrystallized to purity.

The epoxy compound used as starting material Is readily prepared from the corresponding phenol of the formula where R represents a protecting group for a hydroxy group, by reaction with epichlorhydrin in aqueous sodium hydroxide solution, and the mono-protected dihydroxybenzene itself is preparable either by selective mono-protection of the corresponding dihydroxybenzene or by mono-protection with production of both isomers, and subsequent separation of the isomers by conventional means. (2) Compounds of the Formula (I) in which R represents a hydrogen atom may be prepared from those in which R represents a protecting group for a hydroxy group by hydrolysis or hydro-genolysis of the group OR as appropriate.

Of the group R exemplified hereinbefore, a phenyl lower alkyl group is removable by catalytic hydrogenation, for example, using palladium on charcoal catalyst with the free base or salt dissolved in a suitable solvent, e.g. aqueous acetic acid solution, the hydrogenation preferably being carried out at ambient temperature and at low pressure, e.g. 60 p.s.i. The product may then be recovered by filtration of the reaction solution to remove the catalyst, evaporation of the filtrate to dryness and purification by the procedure described hereinbefore. This same procedure will remove the benzyl group from compounds of the Formula (I) where additionally R2 represents a benzyl group. (3) An amine of the formula: is reacted with a compound of the formula: respectively, where Z is a halogen atom or other suitable "leaving" group (such a group being defined as one which is readily replaced by a stronger nucleophilic group, an example of such a "leaving group" being a sulphonyloxy group, e.g. benzenesulphonyloxy or p-toluenesulphonyloxy), by heating either optionally in the presence of excess amine in a suitable solvent, e.g. methanol or etl^anol, or in equimolecular proportions in the absence of a solvent, or in the presence of a base, e.g. sodium bicarbonate, and a suitable solvent as before. The crude product may be recovered by filtration or evaporation of the filtrate to dryness, or in some cases by suspending the solid in a suitable medium, e.g. aqueous sodium bicarbonate solution, and collecting the precipitate. Purification may then be effected as in method (1). 2 (4) Those compounds of the Formula (I) in which R represents a hydrogen atom may also be prepared by reacting an amine of the formula: with an aldehyde of the formula: to give the corresponding Schiff's base, which is then hydro-genated in the presence of a catalyst, e.g. platinum, or reduced with sodium borohydride. The product may be recovered by filtration to remove the catalyst and any other residual solid, evaporation of the filtrate to dryness and purifica- tion as in method (l).

When hydrogenstion is used, this may affect the hydro-genol tic cleavage of the group OR, when R represents a phenyl lower alkyl group, e.g. a benzyl group, to afford a compound of the Formula (I) in which R and R2 each represent a hydrogen atom. Conditions are chosen with due regard to the desirability or otherwise of preventing such hydrogenolytic cleavage. (5) Compounds of the Formula (I) in which R represents a protecting group for a hydroxy group may be prepared from those in which R represents a hydrogen atom by various methods* Where R represents a phenyl lower alkyl, a suitable reagent is the halide, e.g. the chloride, of the group R. .

When an acid halide of RH is used, this is suitably reacted in equimolar proportion with the sodio derivative of the phenolic compound of Formula (I) such that when ^ represents a hydrogen atom and/or the secondary hydroxy group is not esterified, the corresponding secondary amino and/or secondary hydroxy groups are not also attacked.

Alternatively, such latter groups are protected by using the aldehyde condensation products of the Formula (II) in the reactions involving either acid halides or anhydrides, and then deprotecting. Λ In the case of compounds of the Formula (I) in which R represents a protecting group for a hydroxy group, the conditions for oxazolidine formation may also be favorable for removing the group R by hydrolysis. Such a possibility must be borne in mind when the condensation reaction is performed, and conditions adjusted accordingly if it is desired not to bring about such hydrolytic cleavage simultaneously.

Oxazolidines of the Formula (II) in which R represents a hydrogen atom may be converted to those wherein R represents a protecting group for a hydroxy group by analogous procedures to those described in method (5)· Compounds of the Formula (I) in which R represents a hydrogen atom may be converted to those in which R represents a lower alkanoyl group under these same conditions, and if it is desired not to bring about this reaction also, conditions should be adjusted accordingly.

The invention is illustrated by the following Examples.

EXAMPLE I (A) To a stirred solution of 4-benzyloxy-2-methylphenol (14. 5 g) in aqueous sodium hydroxide solution ( 2 . 7 g of sodium hydroxide in 100 ml of water) at room temperature was slowly added epichlorhydrin ( 50 ml), and stirring at room" temperature was continued for a further 2 days. The organic layer was then separated from the aqueous layer and the latter extracted with methylene chloride, the combined organic layer and methylene chloride solution then being washed with y, water, dried over anhydrous magnesium sulphate and evaporated in vacuo to give an oil. The latter was dissolved in ethyl acetate and the solution stirred vigorously for several hours in the presence of sodium hydroxide pellets. Finally, the mixture was filtered and the filtrate evaporated in vacuo to afford 16 g of l-(4-benzyloxy-2-methylphenoxy )-2 , 3-epoxypropane as a mobile oil, l D ' 1 . 5778 .

(B) A mixture of l-(4-benzyloxy-2-methylphenoxy)-2 , 3-epoxypropane ( 11 g, the product of (A)), l-benzylamino-2-( 4-carbamoylphenoxy)ethane ( 11 g) and ethanol ( 100 ml) was re-fluxed for 7 days . The ethanol was then removed by evaporation in vacuo and the resulting oil was dissolved0 in the minimum quantity of ethanol. On treatment of this solution with ethereal oxalic acid solution, the oxalate of N- [ 3-(4- benzyloxy-2-methylphenoxy )-2-hydroxypropyl]-N-[ 2-(4-carbamoyl-phenoxy)ethyl]benzylamine was precipitated, and this was collected by filtration and crystallized from methanol to afford two crops of the product in a total yield of 14 g. The purer second crop (9 g) had a melting point of 109-115°C.

EXAMPLE II A solution of the second crop of the product of Example I (9 g) in 50% aqueous acetic acid solution (100 ml) was hydrogenated over 5% palladium on charcoal catalyst at a pressure of 60 p.s.i. and a temperature of 60°C. until hydrogen uptake ceased. After removal of the catalyst by filtration, the solution was evaporated in vacuo to give a gum, which was then dissolved in methanol and converted to the hydrochloride of the product by the addition of excess aqueous hydrochloric acid. The mixture was concentrated by evaporation in vacuo, during which the salt product pre-cipitated, the white product then being collected by filtration and recrystallized from methanol, affording 2.3 g of ethoxy]benzamide hydrochloride monohydrate, m.p. l88-9°C.

Analysis : Found: C, 55-6; H, 6.6; N, 6.7% Required for C19H2i,N205 "HCl-HgO: C, 55-0; H,.6.6; N, 6.8% The compounds of the invention exist in D- and L-optically-active isomeric forms, and the invention includes these forms as well as the racemic mixtures. The general methods starting from an epoxide or a propan-2-ol derivative may be used to prepare optically-active isomers by using the appropriate enantiomers as starting materials. Alternatively, the racemic product of any of the above methods may be resolved by well-known techniques, e.g. by fractional crystal- lization of an acid addition salt formed with an optically-active acid.

The activity of compounds of the invention as β-aarenergic blocking agents is shown by their effectiveness in one or more of the following tests : (a) measuring and comparing inhibition of catecholamine induced changes in Isolated guinea-pig atria and trachea; (b) measuring and comparing suppression of tachycardia and relaxation <¼f the trachea induced by isoprenaline in the anaesthetized guinea-pig; and (c) measuring suppression of the tachycardia induced by isoprenaline in the conscious dog.

In test (a) the isolated guinea pig atria and trachea, in controlled physiological liquid environments, are stimulated electrically and the effects of adding increasing amounts of adrenaline to the liquid environment, on the rate and force of contraction of the atria, and of isoprenaline on the degree of relaxation of the trachea, are measured.

The test compound is then added to the liquid environment at various concentrations and the effects of adding adrenaline and isoprenaline, respectively, are measured again. The concentrations of test compound which give 50¾ inhibition of the effects of adrenaline and isoprenaline are then calculated and taken as a measure of its activity in respect of myocardial and peripheral j -receptors , respectively.

In test (b), blood pressure, heart rate, and pressure within a segment of the trachea of a guinea-pig anaesthetized with sufficient pentobarbitone sodium to prevent spontaneous respiration, are measured while artificial respiration is maintained directly into the lung at a constant rate.

Isoprenaline at a standard dose of 0.5 mlcrogranune is injected intravenously to induce tachycardia, cause relaxation of the trachea and lower blood pressure. The ability of the test com pound to suppress the tachycardia and/or antagonize the relaxation of the trachea and/or the fall in blood pressure caused by the isoprenaline is then measured by injecting the test compound prior to isoprenaline.

In test (c), conscious dogs are dosed with the test compound intravenously (0.125 to 0.25 mg/kg) or orally (0.5 to Ί mg/kg), and the effect of an isoprenaline challenge on heart rate is measured. Heart rates are recorded before dosing and for 30 minutes after, and the dogs are then given a subcutaneous challenge of isoprenaline. The degree of iso-prenaline-induced tachycardia is recorded a .15. minute intervals .

For administration to man in the treatment of cardiac conditions such as angina pectoris and cardiac arrhythmias, it is expected that oral dosages of the most active compounds of the invention will be in the range from 0.3 to 6.5 mg/kg/day, and in the treatment of hypertension in the range from 2 to 15 mg/kg/day, given in 3 or divided doses per day. Dosage levels for intravenous administration may be expected to be about one-tenth of the above in a single dose per day. Thus for a typical adult patient (70 kg), individual tablets or capsules might contain from 5 to 350 mg of active compound, and intravenous dosages from 2.5 to 100 mg, in a suitable pharmaceutically-acceptable vehicle or carrier.

The compounds of the invention can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They may be injected parenterally , for example, intramuscularly or subcutaneously . For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other solutes, for example, enough salts or glucose to make the solution isotonic.

Claims (5)

43726/3 P.C. 5489 C L A I M S

1. Compounds having the general formula: were OR represents hydroxy or a readily hydrolyzable or hydrogenlyzable group wherein R is phenyl lower alkyl; R represents a lower alkyl or lower alkoxy; and y. R^ represents a hydrogen atom or a benzyl group; and the pharmaceutically-acceptable acid addition salts thereof.

2. 4- [2- (3-{4-hydroxy-2-methylphenoxy}-2-hydroxyprop-ylamino)ethoxy]benzamide and its pharmaceutically-acceptable acid addition salts.

3. N- [3- (4-benzyloxy-2-methylphenoxy) -2-hydroxypropyl] -N- [2- (4-carbamoylphenoxy) ethyl] benzylamine and its pharmaceutically-acceptable acid addition salts .

4. A pharmaceutical composition comprising a compound as claimed in any preceding claim and a pharmaceutical carrier or diluent.

5. A compound as claimed in claim 1, the preparation of which is described in any one of the Examples . HEtnk th1A» >