NO128653B - - Google Patents

Description

Analogy method for the production of

therapeutically active alkanolamine derivatives.

This invention relates to a process for the production of new alkanolamine derivatives which possess β-adrenergic blocking activity and which are therefore useful for treatment or preparation

building of heart disorders, e.g. angina pectoris and cardiac

arrhythmia, and for the treatment of hypertension and pheochromocytoma in humans.

According to the invention, a method for the production of new alkanolamine derivatives is provided with the formula:

where R 1 means an isopropyl or t-butyl radical, R 2 means a carbamoyl radical or an alkylcarbamoyl radical where the alkyl radical contains up to 3 carbon atoms, A means a methylene, ethylene or vmylene radical, and R 3 means hydrogen, a halogen atom or alkyl, alkenyl or alkoxy radical each having up to 4 carbon atoms, and the non-toxic, pharmaceutically acceptable acid addition salts thereof.

R 2 can e.g. be a carbamoyl-,. methylcarbamoyl or isopropylcarbamoyl radical.

R 3 can e.g. be a hydrogen, fluorine, chlorine, bromine or iodine atom or a methyl, n-propyl, s-butyl, allyl, methoxy or isopropoxy radical.

Suitable acid addition salts of the alkanolamine derivatives are e.g. salts derived from inorganic acids, e.g. hydrochlorides, hydrobromides, phosphates or sulphates, or salts derived from organic acids, e.g. oxalates, lactates, tartrates, acetates, salicylates, citrates, benzoates, fl-naphthoates, adipates or 1,1-methylene-bis-(2-hydroxy-3-naphthoates), or salts derived from acidic synthetic resins, e.g. . sulfonated polystyrene resins, such as "Zeo-Karb 225".

Particular alkanolamine derivatives are described in the examples. Of these, particularly active compounds are 1-p-carbamoylmethylphenoxy-3-isopropylamino-2-propanol; 1-p-(N-isopropylcarbamoylmethyl)phenoxy-3-isopropylamino-2-propanol; 1-(2-bromo-4-carbamoylmethylphenoxy)-3-isopropylamino-2-propanol; 1-p-carbamoylmethylphenoxy-3-t-butylamino-2-propanol; 1-(2-allyl-4-carbamoylmethylphenoxy)-3-isopropyl-amino-2-propanol; 1-(4-carbamoylmethyl-2-methoxyphenoxy)-3-iso-propylamino-2-propanol; 1-p-(N-methylcarbamoylmethyl phenoxy-3-isopropylamino-2-propanol; 1-(4-carbamoylmethyl-2-iodophenoxy)-3-isopropylamino-2-propanol; 1-(4-carbamoylmethyl-2-methylphenoxy)-3 -isopropylamino-2-propanol; 1-(4-carbamoylmethyl-2-n-propylphenoxy)-3-isopropylamino-2-propano1; 1-(4-carbamoylmethyl-2-s-buty1phenoxy)-3-isopropylamino-2 -propanol; 1-(4-carbamoylmethyl-2-methoxyphenoxy)-3-t-butylamino-2-propanol; 1-(4-N-methylcarbamoylmethyl-2-n-propyl-phenoxy)-3-isopropylamino-2-propanol ; 1-(2-allyl-4-N-methyl-carbamoylmethylphenoxy)-3-isopropylamino-2-propanol; 1-(2-allyl-4-N-methylcarbamoylmethylphenoxy)-3-t-butylamino-2-propanol; 1 -(4-.fi-carbamoylethyl-2-methoxyphenoxy)-3-isopropylamino-2-propanol; l-(4-fl-carbamoylethyl-2-methoxyphenoxy)-3-t-butylamino-2-propanol and l-(4 -(β-carbamoylvinyl-2-methoxyphenoxy)-3-isopropylamino-2-propanol and the acid addition salts thereof.

According to the invention, the new alkanolamine derivatives are produced by a compound with the formula: where R 2 , R 3 and A have the meanings given above, and where X means the group

or the group -CH0H.CHoY, where Y means a halogen atom, is reacted

1 1

with an amine of the formula NH^R , where R has the meaning given above.

A suitable value for Y is e.g. chlorine or bromine. The turnover

can be carried out at room temperature or it can be accelerated or brought to completion by means of heat, e.g. by heating to a temperature of 90-110°C; it can be carried out at atmospheric or at elevated pressure, e.g. by heating in a closed vessel;

and it can be introduced in an inert diluent or solvent, e.g. methanol or ethanol, or an excess of the amine

with the formula NH^R^, where R^" has the meaning given above,

can be used as a thinner or solvent.

The starting material used in the above method can be obtained by reacting the corresponding phenol with an epihalohydrin, e.g. epichlorohydrin. Said starting material can be isolated or it can be produced and used in situ without isolation.

According to another feature of the invention is provided

a method for the production of the new alkanolamine derivatives in that a compound with the formula:

where R 2 , R 3 and A have the meanings given above, or an alkali metal salt. thereof, is reacted with a compound of the formula:

Y .CH 2 .CHOH .CI^NHR 1

where R"<*>" and Y have the meanings given above.

The latter turnover can conveniently be carried out in the presence of

an acid-binding agent, e.g. sodium hydroxide. Alternatively, an alkali metal salt may . of the phenol reagent, e.g. sodium

or the potassium salt, are used as starting material. The reaction can be carried out in a diluent or solvent, e.g. methanol or ethanol, and it can be accelerated or brought to completion by the application of heat, e.g. by heating to the boiling point of the diluent or solvent.

According to a further feature of the invention is provided

a method for producing the new alkanolamine derivatives where A means one vinylene radical, in that a compound with the formula:

1 3

where R and R have the meanings given above, is reacted in the presence of a base with a compound of the formula:

R<2>.CH2.COOH

where R 2 has the meaning given above.

The reaction with a compound of the formula R 2 -CI 2 .COOH can, for example, be carried out under conditions suitable for the Knoevenagel or Perkin condensation, e.g. in the presence of piperidine as a base, in a diluent or solvent, e.g. pyridine, at elevated temperature, e.g. at a temperature of 90-110°C.

According to a further feature of the invention, a method for the production of the new alkanolamine derivatives is provided in that a compound with the formula: 12 3 7 where R , R , R and A have the meanings given above, and R means an α-arylalkyl radical, or an acid addition salt thereof, is hydrogenolysed.

A suitable meaning for R is e.g. a benzyl radical. Hydrogenolysis can e.g. is carried out by catalytic hydrogenation, e.g. by hydrogenation in the presence of a palladium-on-charcoal catalyst in an inert diluent or solvent, e.g. ethanol or aqueous ethanol. The process can be accelerated or brought to completion by the presence of an acidic catalyst, e.g. hydrochloric acid or oxalic acid.

The starting material used in the latter method can be obtained by a method similar to any of the above methods, except that an amine with the formula

17 1

NHR R is used instead of an amine with the formula NH_R , or

£17

a compound containing the group -NR R is used instead of the corresponding compound containing the group -NHR'''.

According to a further feature of the invention, a method is provided for the production of the new alkanolamine derivatives where R" means an isopropyl radical, in that a compound with the formula:

2 3

where R , R and A have the meanings given above, or an acid addition salt thereof, is reacted under reducing conditions with acetone.

Suitable reducing conditions are those provided by near-

be of hydrogen and a hydrogenation catalyst, e.g. palladium or platinum, in an inert diluent or solvent

agent, e.g. in one or more solvents selected from water, ethanol and an excess of the carbonyl compound used as starting material; or in the presence of an alkali metal borohydride, e.g. sodium borohydride, in an inert diluent or solvent, e.g. in one or more solvents selected from water, ethanol, methanol and an excess of the carbonyl compound used as starting material. It must be understood that when R 3 in the starting material means a halogen atom or an alkyl radical, hydrogen and a hydrogenation catalyst are preferably not used to provide the reducing conditions, to prevent the radical R 3 from being affected by the catalytic hydrogenation.

The amino derivative used as starting material in the last

mentioned method, can be obtained by reacting the corresponding epoxide or halohydrin with ammonia.

The new alkanolamine derivatives can also be prepared by a compound with the formula:

13 11

where R , R and A have the meanings given above, and R means an alkyl radical with up to 5 carbon atoms, is reacted with an amine of the formula R^NI^, where R^ means hydrogen or an alkyl radical with up to 3 carbon atoms.

It should further be understood that a compound where A means a vinylene radical can be reduced, e.g. by catalytic hydrogenation,

e.g. using a platinum oxide catalyst in a diluent or solvent, e.g. ethanol, to the corresponding compound where A means an ethylene radical.

A compound where R 3 means an alkenyl radical may optionally

is reduced to the corresponding compound where R 3 means an alkyl radical.

The alkanolamine derivatives in the free base form can be converted into their acid addition salts by reaction with an acid in the usual way.

As indicated above, the new alkanolamine derivatives and their acid addition salts are valuable for the treatment or prevention of cardiac disorders. Furthermore, some of these compounds have selective β-adrenergic blocking activity. Compounds exhibiting this selective action show a greater degree of specific activity in blocking the cardiac φ receptors than the Æ receptors in peripheral blood vessels and bronchial muscle. One can thus choose such a dose of a compound that the compound blocks the inotropic and chronotropic effects on the heart of a catecholamine (e.g. isoprenaline, i.e. 1-(3,4-dihydroxyphenyl)-2-isopropylaminoethanol), but does not block the relaxation of the tracheal smooth muscle produced by isoprenaline, or the peripheral vasodilator action of isoprenaline. Because of this selective effect, one of these compounds can be suitably used together with a sympathomimetic bronchodilator, e.g. isoprenaline, orciprenaline elis r ephedrine, in the treatment of asthma or other diseases that block the airways as the selective compound will essentially inhibit the unwanted stimulating effect of the bronchodilator on the heart, but will not prevent the desired therapeutic effect of the bronchodilator.

Many compounds with J3-adrenergic blocking action are known,

and many of these are l-aryloxy-3-amino-2-propanol derivatives,

and it is also known that some of these compounds, especially those where the 1-aryloxy radical carries an acylamino substituent, have selective 13-adrenergic blocking activity. It is a desired, but admittedly not absolutely necessary property of a 13-adrenergic blocking agent to be used clinically, that the agent does not have internal sympathomimetic activity to any significant extent. The compound with which most clinical experience has been obtained, propanolol [1-isopropylamino-3-(naphth-1-yloxy)-2-propanol, which is described in British Patent No. 994,918], is completely devoid of intrinsic sympathomimetic activity.

However, no connection is known to be in possession

of selective 13-adrenergic blocking activity as defined above,

and which are without intrinsic sympathomimetic activity. The selective 13-adrenergic blocking agent with most clinical experience is op-

achieved with, practolol [1-(4-acetamidophenoxy)-3-isopropylamino-2-propanol, which is described in British Patent No. 1,078,852], has significant intrinsic sympathomimetic activity.

We have now found that the compounds produced according to the invention, and in particular the compounds 1-p-carbamoyl-methylphenoxy-3-isopropylamino-2-propanol and 1-(4-13-carbamoylethyl-2-methoxy-phenoxy)-3 -i sopropyl lamino-2-propanol, has selective 13-adrenergic blocking activity as determined by inhibition of isoprenaline-evoked tachycardia in cats, and lack of antagonism to isoprenaline-evoked vasodilatation in cats or to isoprenaline-evoked relaxation of histamine- produced bronchospasm in guinea pigs. However, these compounds are devoid of intrinsic sympathomimetic activity, as shown by their failure to increase heart rate in rats from which natural catecholamines have been removed by pretreatment with syrosingopin. The new alkanolamine derivatives produced according to the invention or acid addition salts thereof can be used in pharmaceutical preparations together with a pharmaceutically acceptable diluent

agent or carrier.

The following examples shall further illustrate the invention:

EXAMPLE 1

A solution of 1 g of 1-p-carbamoylmethylphenoxy-2,3-epoxypropane

and 10 ml of isopropylamine in 25 ml of methanol are heated in a closed tube at 110°C for 12 hours. The mixture is evaporated to dryness, and the residue is distributed between 50 ml of chloroform and 50 ml of aqueous 2N hydrochloric acid. The aqueous, acidic layer is separated, made alkaline with sodium carbonate and extracted twice with 50 ml of chloroform each time. The combined extracts are dried and evaporated to dryness, and the residue is crystallized from ethyl acetate. One thus obtains 1-p-carbamoylmethylphenoxy-3-isopropylaracho-2-propanol, m.p. 146-148°C.

The 1-p-carbamoylmethylphenoxy-2,3-epoxypropane used as starting material can be obtained as follows:

A mixture of 3.2 g of p-hydroxyphenylacetamide, 25 ml of epichlor-

hydrin and 6 drops of piperidine are heated at 95-100°C for 6 hours. The mixture is cooled and filtered, and the solid product is crystallized from methanol. One thus obtains 1-p-carbamoylmethylphenoxy-2,3-epoxypropane, m.p. 158-160°C.

EXAMPLE 2

A solution of 4 g of ethyl p-(3-3-chloro-2-hydroxypropoxy)-phenylacetate

and 15 ml of isopropylamine in 15 ml of methanol are heated in a closed tube at 110°C for 12 hours. The mixture is evaporated to dryness, and resi-

the mixture is partitioned between ethyl acetate and water. The ethyl acetate layer from

separated, dried and evaporated to dryness, and the residue crystallized

is lysed from a mixture of ethyl acetate and petroleum ether (b.p. 60-80°C).

One thus obtains 1-p-(N-isopropylcarbamoylmethyl)phenoxy-3-isopropyl-amino-2-propanol, m.p. 132-134°C.

The ethyl p-(3-chloro-2-hydroxy-propoxy)phenylacetate used as starting material is obtained as follows:

A mixture of 2 g of ethyl p-hydroxyphenyl acetate, 25 ml of epichlorohydrin

and 6 drops of piperidine are heated at 95-100°C for 6 hours and evaporated

then to dryness. The remaining oil consists of ethyl p-(3-chloro-2-hydroxypropoxy)phenylacetate and is used without further purification.

EXAMPLE 3

A solution of 1.2 g of 1-(4-13-carbamoylethyl-2-methoxyphenoxy)-2,3-epoxypropane and 10 ml of isopropylamine in 20 ml of methanol is heated under reflux for 16 hours, cooled and evaporated to dryness under reduced pressure. The residue is crystallized from a mixture of ethyl acetate and petroleum ether (b.p. 60-80°C), and one thus obtains 1-(4-!3-carbamoylethyl-2-methoxyphenoxy)-3-isopropyl-amino-2-propanol, m.p. . 108-109°C.

The 1-(4-.fi-carbamoylethyl-2-methoxy-phenoxy)-2,3-epoxypropane used as starting material can be obtained as follows:

A mixture of 10 g of ethyl J3-(4-hydroxy-3-methoxyphenoxy)-propionate

and 200 ml of aqueous ammonium hydroxide solution (specific gravity 0.880)

kept at room temperature for 16 hours and then evaporated to dryness under reduced pressure. The residue is crystallized from water,

and one thus obtains (4-hydroxy-3-methoxyphenoxy)propionamide,

sm.p. 110-112°C. A mixture of 2 g of this propionamide, 20 ml of epichlorohydrin and 5 drops of piperidine is heated at 95-100°C for 7

hours, cooled and evaporated to dryness under reduced pressure. The residue is crystallized from methanol, and the following 1-(4-13-carbamoylethyl-2-methoxyphenoxy)-2,3-epoxypropane is obtained, m.p. 143-144°c.

EXAMPLE 4

A mixture of 1.18 g of 1-p-formylphenoxy-3-isopropylamino-2-propanol, 1.03 g of malonic acid monoamide, 15 ml of pyridine and 5 drops of piperidine is heated at 95-100°C for 18 hours. The pyridine is removed by evaporation, and the residue is distributed between 30 ml of chloroform and 30 ml of aqueous 2N hydrochloric acid. The aqueous, acidic layer is separated, made alkaline with sodium carbonate and extracted twice with 30 ml of chloroform each time." The combined extracts are dried and evaporated to dryness, and the residue is crystallized from ethyl acetate. One thus obtains l-p-(-carbamoylvinyl)phenoxy-3 -isopropylarho-2-propanol, mp 135-137°C.

EXAMPLE 5

0.05 g of platinum oxide catalyst is added to a solution of

0.2 g of 1-p-(fl-carbamoylvinyl)phenoxy-3-isopropylamino-2-propanol

in 20 ml of ethanol, and the mixture is shaken in an atmosphere of hydrogen until a molecular proportion of hydrogen is absorbed. The mixture is filtered, the filtrate is evaporated to dryness, and the residue is crystallized from ethyl acetate. One thus obtains 1-p-(f-carbamoylethyl)-phenoxy-3-isopropylamino-2"-propanol, m.p. 102-104°C.

EXAMPLE 6

A solution of 1g of 1-(2-bromo-4-carbamoylmethylphenoxy)-3-chloro-2-propanol and 10 ml of isopropylamine in 15 ml of methanol is heated in a closed tube at 110°C for 12 hours. The mixture is evaporated to dryness

hot, and the residue is distributed between 40 ml of chloroform and 40 ml of aqueous 2N hydrochloric acid. The aqueous, acidic layer is separated, made alkaline with sodium carbonate and extracted twice with 30 ral of chloroform each time. The combined extracts are dried and evaporated to dryness,

and the residue is crystallized from a mixture of benzene and petroleum ether (b.p. 60-80°C). One thus obtains 1-(2-bromo-4-carbamoylmethyl-phenoxy)-3-isopropylamino-2-propanol, m.p. 105-107°C.

The 1-(2-bromo-4-carbamoylmethyl-phenoxy)-3-chloro-2-propanol used as starting material can be obtained as follows: A solution of 15 g of (3-bromo-4-hydroxyphenyl)acetic acid in 50 ml of ethanol containing 1.0 ml of sulfuric acid is heated under reflux for 4 hours. The solution is evaporated to half its original volume and poured into 250 ml of water. The suspension is extracted twice with 100 ml of ether each time, and the combined ether extracts are dried and evaporated to dryness. The remaining oil is distilled at 134-138°C/0.5 mmHg, and thus ethyl (3-bromo-4-hydroxyphenyl)acetate is obtained. The distilled product is suspended in 200 ml of aqueous ammonium hydroxide solution (specific gravity 0.880), and the suspension is heated at 110°C for 6 hours. The resulting solution is evaporated to dryness under reduced pressure and the solid residue is crystallized from water and then from ethanol. This gives (3-bromo-4-hydroxyphenyl)acetamide, m.p. 176-178°C. A mixture of 1 g of (3-bromo-4-hydroxyphenyl)acetamide, 10 ml of epichlorohydrin and 3 drops of piperidine is heated at 95-100°C for 6 hours and then evaporated to dryness. The remaining oil consists of 1-(2-bromo-4-carbamoylmethylphenoxy)-3-chloro-2-propanol and is used without further purification.

EXAMPLE 7

A solution of 1.5 g of 1-(2-allyl-4-carbamoylmethylphenoxy)-3-chloro-2-propanol and 10 ml of isopropylamine in 15 ml of methanol is heated in a closed tube at 110°C for 12 hours. The mixture is evaporated to dryness, and the residue is distributed between 50 ml of chloroform and 50 ml of aqueous 2N hydrochloric acid. The aqueous, acidic layer is separated, made alkaline with sodium carbonate and extracted twice with 50 ml of chloroform each time. The combined extracts are dried and evaporated to dryness, and the residue is converted to the hydrogen oxalate thereof in the usual way. The hydrogen oxalate is crystallized from a mixture of methanol and diethyl ether, and one thus obtains 1-(2-allyl-4-carbamoyl-methylphenoxy)-3-isopropylamino-2-propanol hydrogen oxalate, m.p. 101-102°C..

The 1-(2-allyl-4-carbamoylmethyl-phenoxy)-3-chloro-2-propanol used as starting material can be obtained as follows: A mixture of 6 g of 4-hydroxyphenylacetamide, 200 ml of acetone, 4.4 g of allyl bromide, 2 .8 g of solid potassium carbonate and a trace of potassium iodide are stirred and heated under reflux for 16 hours. 200 ml of water is then added, and the acetone is removed by evaporation under reduced pressure. The suspension is extracted twice with

200 ml of chloroform each time, and the combined chloroform extracts are dried and evaporated to dryness. The solid residue is crystallized from methanol, and 4-allyloxyphenylacetamide is thus obtained, m.p. 178-179°C. A solution of 4 g of 4-allyloxyphenylacetamide in 50 ml of diphenyl ether is heated under reflux for 10 minutes. The mixture is cooled, 200 ml of chloroform is added, and the mixture is extracted twice with 100 ml of aqueous 2N sodium hydroxide solution each time. The combined extracts are acidified and the resulting suspension is extracted twice with 100 ml of chloroform each time. The combined chloroform extracts are dried and evaporated

to dryness, and the residue crystallized from hot water. One thus obtains 3-allyl-4-hydroxyphenylacetamide, m.p. 80-82°C. A mixture of 1.5 g of 3-allyl-4-hydroxyphenylacetamide, 15 ml of epichlorohydrin and 4 drops of piperidine is heated at 95-100°C for 6 hours and then evaporated to dryness. The remaining oil consists of 1-(2-allyl-4-carbamoylmethylphenoxy)-3-chloro-2-propanol and is used without further purification.

EXAMPLE 8

A solution of 1 g of 3-chloro-1-p-(N-methylcarbamoylmethyl)-phenoxy-2-propanol and 20 ml of isopropylamine in 15 ml of methanol is heated in

a closed tube at 110°C for 12 hours. The mixture is evaporated to dryness, and the residue is distributed between 40 ml of chloroform and 50 ml

aqueous 2N hydrochloric acid. The aqueous, acidic layer is separated, made alkaline with sodium carbonate and extracted twice with 30 ml of chloroform each time. The combined extracts are dried and evaporated to dryness, and the residue is crystallized from a mixture of ethyl acetate and petroleum ether (b.p. 60-80°C). One thus obtains 3-isopropyl-amino-1-p-(N-methylcarbamoylmethyl)phenoxy-2-propanol, m.p. 87-89°C.

The starting material used 3-chloro-1-p-(N-methylcarbamoyl-

methyl) phenoxy-2-propanol can be read as follows:

A mixture of 2 g of ethyl (p-hydroxyphenyl) acetate and 40 ml of a

40% aqueous solution of monomethylamine is stirred for 24 hours and then evaporated to dryness. The remaining brown oil solidifies on standing and is crystallized from ethyl acetate. One thus obtains p-hydroxyphenyl-N-methylacetamide, m.p. 119-321°C. A mixture of 1 g of p-hydroxyphenyl-N-methylacetamide, 10 ml of epichlorohydrin and 3

drops of piperidine are heated at 95-100°C for 6 hours and then evaporated to dryness. The remaining oil consists of 3-chloro-1-p-(N-methylcarbamoylmethyl)phenoxy-2-propanol and is used without further purification.

EXAMPLE 9

The procedure described in example 1 is repeated, except that t-butylamine is used instead of isopropylamine. One thus obtains 1-p-carbamoylmethylphenoxy-3-t-butylamino-2-propanol, m.p. 119.120°C.

EXAMPLE 10

The procedure described in example 3 is repeated, except that t-butylamine is used instead of isopropylamine and that the product is isolated in the usual way as the hydrogen oxalate. One thus obtains 1-(4-Æ-carbamoylethyl-2-methoxyphenoxy)-3-t-butylamino-2-propanol hydrogenoxalate, m.p. 148-149°C. (Crystallized from a mixture of methanol and ether).

EXAMPLE 11

0.25 g of a 5% palladium-on-charcoal catalyst is added

a solution of 1 g of 1-p-carbamoylmethylphenoxy-3-N-benzyl-N-isopropylaminopropan-2-ol in 30 ml of ethanol, and the mixture is shaken in an atmosphere of hydrogen until a molecular equivalent of hydrogen is absorbed. The mixture is filtered, and the filtrate is evaporated to dryness. One thus obtains l-p-carbamoylmethylphenoxy-3-isopropyl-aminopropan-2-ol which is identical to the material described in example !•

The 1-p-carbamoylmethylphenoxy-3-N-benzyl-N-isopropylaminopropan-2-ol used as starting material can be obtained as follows:

A mixture of 1 g of l-p-carbamoylmethylphenoxy-2,3-epoxypropane,

25 ml of methanol and 0.75 g of N-benzylisopropylamine are heated in a closed tube at 110°C for 12 hours and then evaporated to dryness. The residue is distributed between 50 ml of aqueous IN hydrochloric acid and 50 ml of chloroform, and the hydrochloric acid solution is separated, made basic with solid sodium carbonate and extracted twice with 50 ml of chloroform each time. The combined chloroform extracts are dried and evaporated to dryness, and thus 1-p-carbamoylmethylphenoxy-3-N-benzyl-N-isopropylaminopropan-2-ol is obtained as a residue.

EXAMPLE 12

3.8 g of 1-chloro-3-isopropylaminopropan-2-ol hydrochloride are added to a solution of 3 g of 4-hydroxyphenylacetamide and 1.6 g of sodium hydroxide in 40 ml of water, and the resulting solution is heated at 90-95°C for 18 hours. The mixture is made basic to pH 10 and extracted three times with 50 ml of chloroform each time. The combined chloroform extracts are dried and evaporated to dryness, and the residue is ethylated three times with 50 ml of cyclohexane each time. The residue is dissolved in 10 ml of ethyl acetate, and the ethyl acetate solution is diluted with 15 ml of petroleum ether (b.p. 60-80°C), which is added in portions over the course of several hours. The mixture is kept at 0°C for 17 hours and then filtered, and the semi-solid residue is crystallized from ethyl acetate. One thus obtains l-p-carbamoylmethylphenoxy-3-isopropylaminopropan-2-ol which is identical to the material described in example 1.

EXAMPLE 13

0.5 g of a 5% palladium-on-charcoal catalyst is added

a solution of 1.2 g of 1-p-carbamoylmethylphenoxy-3-aminopropan-2-ol in 50 ml of acetone, and the mixture is shaken in an atmosphere of hydrogen until a molecular equivalent of hydrogen is absorbed. The mixture is filtered, the solid residue is extracted twice with 100 ml of boiling ethyl acetate each time, and the combined organic solution is evaporated to dryness. As a residue, 1-p-carbamoylmethylphenoxy-3-isopropylamino-2-ol is thus obtained, which is identical to the material described in example 1.

The 1-p-carbamoylmethylphenoxy-3-aminopropan-2-ol used as starting material can be prepared as follows: Ammonia gas is bubbled for one hour to give a solution of 1 g of 1-p-carbamoylmethylphenoxy-2,3-epoxyprop. in 50 ml of methanol. The solution is kept at room temperature for 3 days and then evaporated to dryness. As a residue, 1-p-carbamoyl-1-methylphenoxy-3-aminopropan-2-ol is thus obtained, a crystalline, solid substance which is used without further purification.

EXAMPLE 14

A solution of 0.4 g of 1-(2-allyl-4-N-methylcarbamoylmethylphenoxy)-3-isopropylamino-2-propanol in 50 ml of ethanol is shaken with 0.2 g of a 5% palladium-on-charcoal catalyst in a atmosphere of hydrogen at atmospheric pressure and room temperature until hydrogen absorption ceases. The mixture is filtered, the filtrate is evaporated to dryness, and the residue is crystallized from ethyl acetate. One thus obtains 1-(-4-N-methylcarbamoylmethyl-2-n-propylphenoxy)-3-isopropylamino-2-propanol, m.p. 125-127°C.

EXAMPLE 15

The procedure described in Example 6 is repeated using the appropriate 1-p-carbamoylmethylphenoxy-3-chloro-2-propanol derivative and isopropylamine or t-butylamine as starting materials and the compounds described in the following table are thus obtained:

The 1-p-carbamoylmethylphenoxy-3-chloro-2-propanol derivatives used as starting materials can be obtained by reacting the corresponding phenols with epichlorohydrin by a method similar to that described in the last part of example 6. Many of the phenols themselves are new compounds, and these can be obtained by usual chemical methods using known starting materials,

as follows:

(3-Metosky-4-hydroxyphenyl)acetamide, m.p. 113-115°C and (3-iodo-4-hydroxyphenyl)acetamide, m.p. 179-181°C are kept from the corresponding acetic acid derivatives by a method similar to that described in example 6 for the production of (3-bromo-4-hydroxyphenyl)acetamide.

(3-methyl-4-hydroxyphenyl)acetamide, m.p. 138-140°C; (3-s-butyl-4-hydroxyphenyl)acetamide, m.p. 110-116°C; is likewise obtained from the corresponding acetic acid derivatives, in that the methyl ester is used rather than the ethyl ester in the case of the 3-s-butyl derivative. The compound (3-methyl-4-hydroxyphenyl)acetic acid, m.p. 98-lOl°C, is prepared itself by heating 3-methyl-4-hydroxyacetophenone with sulfur and morpholine (the Willgerodt reaction) and hydrolysis of the product with aqueous sodium hydroxide solution. The compound (3-s-butyl-4-hydroxyphenyl)acetic acid (an oil) is similarly obtained from 3-s-butyl-4-hydroxyacetophenone, m.p. 128-130°c, which itself is obtained by reacting 2-s-butylphenol with acetic anhydride and then reacting the 2-s-butylphenylacetate thus obtained with aluminum chloride in nitrobenzene solution.

The compound (3-n-propyl-4-hydroxyphenyl)acetamide, m.p. 115-116°C is obtained by hydrogenation of (3-allyl-4-hydroxyphenyl)-acetamide (Example 7) in ethanol solution with hydrogen in the presence of a 5% palladium-on-charcoal catalyst.

The compound (3-allyl-4-hydroxyphenyl)-N-methylacetamide, m.p. 78-80°C is obtained from 4-hydroxyphenyl-N-methylacetamide (example 8) by a method similar to that described in example 7 for the production of (3-allyl-4-hydroxyphenyl)acetamide. The intermediate 4-allyloxyphenyl-N-methylacetamide, m.p. 64-66°C has the specified melting point.

EXAMPLE 16.

A suspension of 1 g of 1-p-ethoxykaibo, lmethiphenoxy-3-isopropyl-amino-2-propanol in 75 ml of aqueous ammonia solution (specific gravity 0.88) is stirred at room temperature for 18 hours, and the resulting solution is then evaporated to dryness. One thus obtains 1-p-carbamoylmethylphenoxy-3-isopropylamino-2-propanol which is identical to the material described in example 1.

The 1-p-ethoxycarbonylmethylphenoxy-3-isopropylamino-2-propanol used as starting material can be obtained as follows: Hydrogen chloride gas is bubbled for 6 hours through a boiling solution of 4.5 g of 1-p-cyanomethylphenoxy-3-isopropylamino-2-propanol in 150 ml absolute ethanol, and the solution is kept at room temperature for an additional 16 hours and then evaporated to dryness. The residue is dissolved in 10 ml of water, and the solution is made basic with solid sodium carbonate and extracted twice with 100 ml of chloroform each time. The combined chloroform extracts are dried and evaporated to dryness. The residue is dissolved in a minimal amount of ethyl acetate, 100 ml of petroleum ether (b.p. 60-80°C) is added, and the mixture is allowed to stand for 30 minutes. The liquid on top is decanted off and evaporated to dryness, and the residue is crystallized from petroleum ether (b.p. 60-80°C).

One thus obtains 1-p-' ethoxycarbonylmethylphenoxy-3-isopropylamino-2-propanol, m.p. 51-52°C.

EXAMPLE 17

The procedure described in example 6 is repeated during use

of the appropriate 1-phenoxy-3-chloro-2-propanol derivative and isopropylamine as starting materials, and one thus obtains the compounds described in the following table:

The 1-phenoxy-3-chloro-2-propanol derivatives used as starting materials can be obtained by reacting the corresponding phenols with epichlorohydrin by a method similar to that described in the last part of example 6. Many of the phenols themselves are new compounds, and these can be obtained by usual chemical means using known starting materials, as follows: The compounds 13-(3-bromo-4-hydroxyphenyl)propionamide, m.p. 130-132°c is obtained from the corresponding propionic acid derivative and by a method similar to that described in example 6 for the production of (3-bromo-4-hydroxyphenyl)acetamide.

Preparation 13-(3-allyl-4-hydroxy)propionamide, which is an oil, is obtained from 1-(4-hydroxyphenyl)propionamide by a procedure similar to that described in example 7 for the preparation of (3-allyl-4-hydroxyphenyl) acetamide. The intermediate I3-(4-allyloxyphenyl)propionamide (m.p. 120-121°C) has the indicated melting point.

The compounds 3-methoxy-4-hydroxycinnamamide, m.p. 147-149°C

and N isopropyl-3-methoxy-4-hydroxycinnamamide, m.p. 177-179°C is obtained by reacting the corresponding carboxylic acids with acetyl chloride and then with thionyl chloride, reacting the thus formed 4-acetoxyphenyl acyl chloride derivatives with isopropylamine or gaseous ammonia as appropriate, and rapid hydrolysis of the thus formed 4-acetoxyphenyl acylamide derivatives with aqueous sodium hydroxide solution.

EXAMPLE 18

A solution of 1.5 g of 1-(4-carbamoylmethyl-2-fluorophenoxy)-3-chloro-2-propanol and 5 ml of isopropylamine in 10 ml of methanol is heated in a closed tube at 110°C for 12 hours. The mixture is evaporated to dryness, and the residue is distributed between 40 ml of chloroform and 50 ml of aqueous 2N hydrochloric acid. The aqueous, acidic layer is separated, made alkaline with sodium carbonate and extracted twice with 30 ml of chloroform each time. The combined extracts are dried and evaporated to dryness, and the residue is crystallized from a mixture of benzene and petroleum ether (b.p. 60-80°C). One thus obtains 1-(4-carbamoyl-methyl-2-fluorophenoxy)-3-isopropylamino-2-propanol, m.p. 97-100°C.

The procedure described above is repeated, except that t-butylamine is used instead of isopropylamine. One thus obtains 1-(4-carbamoylmethyl-2-fluorophenoxy)-3-t-butylamino-2-propanol, m.p. 92-95°C.

The compound 1-(4-carbamoylmethyl-2-fluorophenoxy)-3-chloro-2-propanol

which is used as starting material, can be produced as follows:

A mixture of 3.0 g of 3-fluoro-4-hydroxyphenylacetic acid, 30 ml

methanol and 0.5 ml of concentrated sulfuric acid are heated under reflux for 4 hours. The mixture is evaporated to dryness, and the residue is distributed between 50 ml of diethyl ether and 10 ml of water. The ether layer is dried and evaporated to dryness. 50 ml of aqueous ammonium hydroxide solution (specific gravity 0.880) is added to the remaining oil, and the mixture is kept at room temperature for 16 hours. The solution is then evaporated to dryness under reduced pressure and the residue crystallized from water. One thus obtains 3-fluoro-4-hydroxyphenylacetamide, m.p. 151-153°C.

A mixture of 1.0 g of 3-fluoro-4-hydroxyphenylacetamide, 10 ml of epichlorohydrin and 2 drops of piperidine is heated at 95-100°C for 6 hours and then evaporated to dryness. The remaining white solid consists of 1-(4-carbamoylmethyl-2-fluorophenoxy)-3-chloro-2-propanol and is used without further purification.

EXAMPLE 19

The procedure described in example 18 is repeated, except that 1-(4-carbamoylmethyl-2-chlorophenoxy)-3-chloro-2-propanol and isopropylamine or t-butylamine are used as starting materials. One thus obtains respectively 1-(4-carbamoylmethyl-2-chlorophenoxy)-3-isopropyl-amino-2-propanol, m.p. 101-102°C, and 1-(4-carbamoylmethyl-2-chloro-phenoxy)-3-t-butylamino-2-propanol, m.p. 100-101°C.

The compound 1-(4-carbamoylmethyl-2-chlorophenoxy)-3-chloro-2-propanol

which is used as starting material, can be prepared from 3-chloro-4-hydroxyphenylacetic acid by a method similar to that described in example 18 for the preparation of 1-(4-carbamoylmethyl-2-fluorophenoxy)-3-chloro-2-propanol from 3 -fluoro-4-hydroxyphenyl-acetic acid. The intermediate 3-chloro-4-hydroxyphenylacetamide has m.p. 163-164°C.

Claims (2)

1. Analogous method for the preparation of therapeutically active alkanolamine derivatives with the formula: 1 2 where R means an isopropyl or t-butyl radical, R means a carbamoyl radical or an alkylcarbamoyl radical where the alkyl radical contains up to 3 carbon atoms, A means a methylene, ethylene or vinylene radical, and R 3 means hydrogen, a halogen atom or an alkyl, alkenyl or alkoxy radical with up to 4 carbon atoms each, and the non-toxic, pharmaceutically acceptable acid addition salts thereof, characterized in that a) a compound with the formula: 2 3 where R , R and A have the meanings given above, and • where X means the group or the group -CHOH.CH„Y, where Y means a halogen atom, if-11 is substituted with an amine of the formula NH2R , where R has the above for stated meaning; or b) a compound of the formula: where R 2 , R 3 and A have the meanings given above, or an alkali metal salt thereof, is reacted with a compound of the formula: Y. CH 2 . CHOH. CI^NHR1 where R"*" and Y have the meanings given above; or c) a compound of the formula: 13 where R and R have the meanings given above, is reacted in the presence of a base with a compound of the formula: R<2>.CH2.COOH where R 2 has the above meaning, whereby A in the reaction product becomes a vinylene radical; or d) a compound with the formula: 12 3 . where R , R , R and A have the meanings given above, and R 1 means an α-arylalkyl radical, or an acid addition salt thereof, is hydrogenolysed; or e) a compound with the formula: 2 3 where R , R and A have the above-mentioned meanings, or an acid addition salt thereof, is reacted under reducing conditions with acetone, whereby R^" in the reaction product becomes an isopropyl radical; or f) a compound with the formula: 13 . 11 where R , R and A has the meanings given above, and R means an alkyl radical with up to 5 carbon atoms, is reacted with an amine of the formula R^NHj, where R^"0 means hydrogen or an alkyl radical with up to 3 carbon atoms; whereupon optionally a compound where A means a vinylene radical is reduced to the corresponding compound where A means an ethylene radical; and or whereupon optionally a compound where R 3 means an alkenyl radical is reduced to the corresponding compound where R < 3 > means an alkyl radical; and or whereupon the alkanolamine derivative in free base form is converted into a non-toxic, pharmaceutically acceptable acid addition salt thereof by reaction with an acid. 2. Process as stated in alternatives a, b, d, e and f in claim 1 for the production of l-(p-carbamoyl-methyl-phenoxy)-3-isopropylamino-2-propanol, characterized in that starting materials are used where R " means an isopropyl radical, R 2 in alternatives a, b, d and e means a carbamoyl radical, R 10 in alternative f means hydrogen, A means a methylene-3 radical, and R means hydrogen.