NO141608B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE ALKANOLAMINE DERIVATIVES - Google Patents

Abstract

Analogous process for the preparation of therapeutically active alkanolamine derivatives.

Description

This invention relates to analog method to

production of new alkanolamine derivatives which have (3-adrenergic blocking activity. This invention is a modification of the one claimed to be protected in Norwegian patents no. 138,335 and 140,496.

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

where A means an alkylene radical having from 2 to 6 carbon atoms;

X means a carbonyl (-CO-) or sulfonyl (-SO 2 -) radical;

Y means a direct bond or an alkylene or alkyleneoxy

radical with up to 6 carbon atoms or an imino-(-NH-) radical;

and

(a) R means a mono- or bicyclic heterocyclic radical in which at least one ring is a 5- or 6-membered, saturated or unsaturated heteroring containing one, two or three heteroatoms selected from nitrogen, oxygen and sulfur atoms; and wherein ring number two, if present, is a benzene ring; and which heterocyclic radical may optionally contain one or two substituents selected from halogen atoms, alkyl-, alkoxy- and alkanoyl radicals of up to 6 carbon atoms each, aryl radicals of up to 10 carbon atoms, morpholino radicals and, when heterocyclic radical has a suitable degree of unsaturation, it may optionally carry an oxo substituent, or R means a aryl radical with the formula: and R"*" means a heterocyclic radical as defined above for R, or R"*" means an aryl radical of the formula:

2 3 12 13

where R , R , R and R , which may be the same or different, each means a hydrogen or halogen atom, a hydroxy, amino, nitro or cyano radical, an alkyl, alkenyl, alkoxy, alkenyloxy or alkanoyl radical with each up to 6 carbon atoms;

2 3 12 13

or R and R together and/or R and R together form a buta-1,3-dienylene radical so that together with the adjacent benzene ring they form a naphthyl radical;

R 4 means a hydrogen atom or an amide radical with the formula:

where X has the above meaning; Q means a direct bond or an alkylene radical of up to 6 carbon atoms; Q means an alkylene radical of up to 6 carbon atoms; and

R"*"5 means a hydrogen atom or an alkyl radical of up to 6 carbon atoms; and R 14 means an amide radical as defined above

4

for R ; or

(b) R means a heterocyclic radical as defined above, and means an alkyl radical of up to 6 carbon atoms or an aryl radical of the formula:

where R 12 and R 13, which may be the same or different, have the meanings given above,

or an acid addition salt thereof.

It will be seen that the alkanolamine derivative produced according to the invention has an asymmetric carbon atom, namely the carbon atom in the -CHOH- group in the alkanolamine side chain, and it can therefore occur in racemic and optically active forms. It is to be understood that this invention includes the racemic form of alkanolamine derivatives and any optically active form that has (3-adrenergic blocking activity, and it is generally known how a racemic compound can be resolved into optically active forms and how the β-adrenergic blocking activity to these forms can be determined.It will further be understood that the [3-adrenergic blocking activity is usually predominant in the optically active form having the "S" absolute configuration in said -CHOH group.

A suitable meaning for the alkylene radical A is e.g. an ethylene, trimethylene, tetramethylene, hexamethylene, 1-methylethylene, 2-methylethylene or 1,1-dimethylethylene radical.

A is preferably an ethylene, 1-methylethylene or 1,1-dimethylethylene radical.

A suitable meaning for Y when it means an alkylene or alkyleneoxy radical is e.g. a methylene, ethylene, methyleneoxy, ethyleneoxy, trimethyleneoxy, 1-methylethylideneoxy or 1-methylpropylideneoxy radical.

Y is preferably a direct bond or a methylene, methyleneoxy or imino radical.

Suitable substituents in the heterocyclic ring R or R"'' are, for example, chlorine and bromine atoms, methyl, ethyl, methoxy, ethoxy, acetyl, phenyl, p-chlorophenyl or morpholino radicals.''

A particular heterocyclic radical is e.g. a pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, isoindolyl, benzofuranyl -, benzothienyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, quinolyl, chromanyl, chromenyl, thiochromanyl or benzodioxanyl radical, e.g. a 2-pyrrolyl-, 2-furyl-, 2-thienyl-, 3-thienyl-, 2-imidazolyl-, 5-methyl-3-pyrazolyl-, 2-phenyl-5-methyl-3-pyrazolyl-, 2- oxazoly1-, 3-isoxazolyl-, 2- thiazolyl-, 2-p-chlorophenyl-4-thiazolyl-, 4-morpholino-1,2,5-thiadiazol-3-yl-, 4-pyridyl-, 2-methyl- 4-oxo-4H-pyran-3-yl-, 3- methyl-2-pyrazinyl-, 3-phenyl-2-pyrazinyl-, 3-pyridazinyl-, 2-p-chlorophenyl-6-methoxypyrimidin-4-yl- , 2-indolyl-, 3-indolyl-, 4- indolyl-, 2-methylindol-4-yl-, 2,3-dihydro-2-oxo-4-indolyl-, 3- oxo-2-phenylisoindolin-l- yl-, 4-benzo[b]furanyl-, 2,3-dimethyl-4-benzo[b]furanyl-, 2-acetyl-7-benzo[b]furanyl-, 4-benzo[b]-thienyl-, 2-benzimidazolyl-, 5-benzothiazolyl-, 5-(benzo[c]-[1,2,5]-thiadiazolyl)-, 2-quinolyl-, 1,2-dihydro-2-oxo-5-quinolinyl-, 1,4-dihydro-6-methoxy-4-oxo-2-quinolinyl-, 1,2,3,4-tetrahydro-2-oxo-5-quinolinyl-, 4-oxochroman-8-yl-, 4-methyl -2-oxo-2H-chromen-8-yl, thiochroman-8-yl or 1,4-benzodioxan-5-yl radical.

A suitable meaning for R"<*>" when it means an alkyl radical, is e.g. a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl or n-octyl radical.

A suitable meaning for R 2 , R 3 , R 12 or R 13 when they mean a halogen atom is e.g. a fluorine, chlorine, bromine or iodine atom.

2 3 12 13

A suitable meaning for R , R , R or R when they mean an alkyl, alkenyl, alkoxy, alkenyloxy or alkanoyl radical is e.g. a methyl, ethyl, n-propyl, allyl, methoxy, isopropoxy, allyloxy, formyl or acetyl radical.

A suitable meaning for Q or Q"<*>" when they mean an alkylene radical is e.g. a methylene, ethylene, trimethylene, ethylidene or 1-methylethylene radical.

A suitable meaning for R"^ when it means an alkyl radical is, for example, a methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-, t-butyl-, n-pentyl- or n- hexyl radical.

14 4

A special meaning for R , or for R when it means an amide acid radical, is e.g. an acetamido, propionamido, methanesulfonamido, carbamoyl, carbarioylmethyl, acetamidomethyl, 3-methylureido, 3-n-butylureido, carbamoylmethoxy or N-methylcarbamoylmethoxy radical. When the substituent R 4 is present, it is preferably in the ortho position on the benzene ring, and the substituent R 14 is preferably in the para position on the benzene ring.

A suitable acid addition salt of an alkanolamine derivative

according to 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, p-naphthoate, adipate or 1,1-methylene-bis-(2-hydroxy-3-naphthoate), or a salt derived from an acidic synthetic resin, for example a sulfonated polystyrene resin.

A preferred alkanolamine derivative prepared according to

to the invention is a compound with the above formula where A means an ethylene, 1-methylethylene or 1,1-dimethylethylene radical, where R means an aryl radical, where R<*> means a monocyclic, 5- or 6-membered, fully unsaturated heterocyclic radical containing a nitrogen, oxygen or sulfur atom as heteroatom,

2 3 4

where R , R and R all mean hydrogen, where X means a carbonyl radical and where Y means a direct bond, or an acid addition salt thereof.

Another preferred alkanolamine derivative prepared according to the invention is a compound with the above formula where A means an ethylene, 1-methylethylene or 1,1-dimethylethylene radical, where R and R 1 both mean aryl radicals, where R 2 means hydrogen or a chlorine -, cyano, nitro or methoxy radical in the 2-position of the aryl nucleus, where R 3 R <4> R <12> and RX 3

14

all means hydrogen, where R means a radical with the formula:

where R means hydrogen or a methyl radical, where Q means a direct bond or a methylene radical, where Q"*" means a methylene radical, where the radical R"^ is in the 4-position of the aryl nucleus, where X means a carbonyl or sulfonyl radical and where Y means a direct bond or a methylene or methyleneoxy radical, or an acid addition salt thereof.

A third preferred alkanolamine derivative prepared according to the invention is a compound with the above formula where A means an ethylene, 1-methylethylene or 1,1-dimethylethylene radical, where R means an aryl radical, where R''" means a heterocyclic

radical, where R 2 means hydrogen or a chlorine or cyano

radical which is in the 2-position of the aryl nucleus, where R"^ and R^

both mean hydrogen, where X means a carbonyl radical and where Y

means a methylene radical, or an acid addition salt thereof.

A fourth preferred alkanolamine derivative produced according to the invention is a compound with the above formula where A means an ethylene, 1-methylethylene or 1,1-dimethylethylene radical, where R means a heterocyclic radical, where R"<*>" means an aryl radical or an alkyl radical of up to 10 carbon atoms,

12

where R means hydrogen or a nitro-, amino-, hydroxy-13 14

or acetyl radical, where R means hydrogen, where R , if present, has the meaning indicated in the second preceding paragraph with respect to the second preferred alkanolamine derivative prepared according to the invention, where X means a carbonyl radical and where Y means a direct bond or an imino-,

methylene or methyleneoxy radical, or an acid addition salt thereof. The heterocyclic radical R is preferably a 4-indolyl-, 4-benzo[b]furanyl, 4-benzo[b]thienyl-, 4-morpholino-1,2,5-thiadiazol-3-yl-, 2-thiazolyl- or 1,4-benzodioxan-5-yl radical.

Specific alkanolamine derivatives produced according to the invention are those which are described later in the examples. Preferred compounds of these, because of their high cardioselective 3-adrenergic blocking activity (discussed later), are: 1-phenoxy-3-3-isonicotinamidoethylamino-2-propanol, 1-phenoxy-3-(3-2-thenamidoethyl )amino-2-propanol, l-phenoxy-3-(3-2-furamidoethyl)amino-2-propanol, l-phenoxy-3-3-(p-acetamidobenzenesulfonamido)ethylamino-2-propanol, l-phenoxy-3 -3~(p-acetamidobenzamido)ethylamino-2-propanol, 1-(2-nitrophenoxy)-3-3-(p-acetamidophenylacetamido)ethylamino-2-propanol, 1-(2-methoxyphenoxy)-3~3~( p-acetamidophenylacetamido)ethylamino-2-propanol, 1-(2-chlorophenoxy)-3-3-(p-acetamidophenylacetamido)ethylamino-2-propanol, 1-(2-cyanophenoxy)-3~3-(p-methanesulfonamidophenylacetamido) ethylamino-2-propanol,

1-(2-cyanophenoxy)-3-3-(p-acetamidomethylphenoxyacetamido)ethylamino-2-propanol,

1-(2-cyanophenoxy)-3-3-(p-carbamoylmethoxyphenylacetamido)ethylamino-2-propanol,

1-(2-cyanophenoxy)-3-3-(2-thienylacetamido)ethylamino-2-propanol, 1-(2-chlorophenoxy)-3-3-(2-benzimidazol<y>lacetamido)ethylamino-2-propanol,

1-(2-cyanophenoxy)-3-3-(1,4-dihydro-6-methoxy-4-oxoquinolin-2-ylacetamido)ethylamino-2-propanol,

1-(4-indolyloxy)-3-3-isobutyramidoethylamino-2-propanol, 1-(2-thiazolyloxy)-3-3-isobutyramidoethylamino-2-propanol, 1-(4-morpholino-1,2,5-thiadiazole -3-yloxy)-3-3-isobutyramidoethyl-amino-2-propanol,

1-(1,4-benzodioxan-5-yloxy)-3-(1-methyl-2-phenylacetamidoethyl)-amino-2-propanol and

1-(1,4-benzodioxan-5-yloxy)-3-3-(p-3-methylureidophenylacetamido)-ethylamino-2-propanol

and acid addition salts thereof.

According to the invention, the alkanolamine derivatives can be prepared by any chemical process known to be useful in the preparation of chemically analogous compounds.

According to the invention, a method for the production of the alkanolamine derivatives of formula I has been provided. The method is characterized by

(a) a compound of the formula R-OCH-Z 3 where R has

the above meaning and Z 3 means the group

where R^ means hydrogen or a hydrolyzable or hydrogenolysable protecting group, and Z<1> means a replaceable halogen or sulfonyloxy radical, is reacted with an amine of the formula:

where A, R^", X and Y have the meanings given above, and R^ and R^, which may be the same or different, each means hydrogen or a hydrolyzable or hydrogenolyzable protecting group.

The reaction involving an amine with the formula 6 7 1

HNR -A-NR -X-Y-R can be carried out at ambient temperature or it can be accelerated or completed by the application of heat, for example by heating to a temperature of 90-110°C. It can be carried out at atmospheric pressure or at an elevated pressure, for example by heating in a closed vessel, and it can be carried out in an inert diluent or solvent, e.g. methanol, ethanol or n-propanol, or an excess of the amine can be used as diluent or solvent;

(b) a compound of the formula

where R has the meaning given above, is reacted with a compound of the formula

16 7 3

where A, R , R , R , X, Y and Z have the meanings given above. A suitable value for Z is e.g. a halogen atom, such as a chlorine or bromine atom, or a sulfonyloxy radical, e.g.

an alkanesulfonyloxy radical of up to 6 carbon atoms or an arenesulfonyloxy radical of up to 10 carbon atoms, e.g.

a methanesulfonyloxy, benzenesulfonyloxy or toluene-p-sulfonyloxy radical.

The reaction involving a phenolic reactant can be carried out in the presence of an acid-binding agent, e.g. an alkali metal hydroxide such as sodium hydroxy, or an organic base, e.g. piperidine. Alternatively, an alkali metal derivative of the phenolic reactant, e.g. a sodium or potassium derivative is 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 completed by the application of heat, e.g. by heating to the boiling point of the diluent or solvent;

(c) a compound of the formula:

where R, R 6 , R 7 and A have the meanings given above, are reacted with a compound of the formula:

1 4

where R , X and Y have the meanings given above, and Z means a replaceable halogen, sulfonyloxy, alkoxy, aryloxy or hydroxy radical.

A suitable value for Z 4 is e.g. a radical of the formula Z"^ as indicated above, or an alkoxy or aryloxy radical with up to 10 carbon atoms, e.g. a methoxy, ethoxy or phenoxy radical. Alternatively, Z 4 can be a hydroxy radical and in this case the reaction becomes carried out in the presence of a condensing agent, eg a carbodiimide.

If one or both of the groups R 6 and R 7 means a protecting group, one or both protecting groups are removed by hydrolysis or hydrogenolysis.

An alkanolamine derivative in free base form is optionally converted

to an acid addition salt thereof by reaction with an acid.

A suitable meaning for R 1 when it means a protecting group is e.g. a hydrogenolysable radical, e.g. an α-arylalkyl, α-arylalkoxycarbonyl or α-arylalkoxymethyl radical, such as a benzyl, benzyloxycarbonyl or benzyloxymethyl radical, or an acyl radical, e.g. an alkanoyl radical of up to 20 carbon atoms, such as an acetyl, t-butoxycarbonyl or 2,2,2-trichloroethoxycarbonyl radical, or an aroyl radical of up to 10 carbon atoms, e.g. a benzoyl radical, or a Ct-Alkoxyalkyl radical (that is, a ..radical _.spm with the oxidized three-carbon radical formed an acetal radical), e.g. a tetrahydro-pyranyl radical, or a tertiary alkyl radical, e.g. a t-butyl radical.

A suitable meaning for R 1 when it means a protecting group is e.g. a hydrogenolysable or tertiary alkyl radical as indicated for R 1 , or a relatively easily hydrolysable acyl radical, e.g. a 2,2,2-trichloroethoxycarbonyl or t-butoxycarbonyl radical. It should be understood that when R^ means an acyl radical, this radical must be able to be removed under conditions which will not destroy the amide acid bond -NR^-X or the amide acid-4 14

bond which may be in the substituent R or R

A suitable meaning for R 7 when it means a protecting group is e.g. a hydrogenolysable or tertiary alkyl group as indicated for R"* or R^. 5 6 7 The hydrogenolysable protecting group R , R or R can be removed, for example by catalytic hydrogenolysis, such as 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 completed in the presence of an acidic catalyst, e.g. hydrochloric acid or oxalic acid.

5 6

The acyl protecting group R or R can be removed by hydrolysis in the presence of a base, e.g. an alkali metal hydroxide,

in a solvent or diluent, e.g. water, methanol, ethanol or a mixture thereof. It should be understood that the hydrolytic conditions used must be sufficiently mild to avoid hydrolysis of the amide acid bond -NR -X or the amide acid bond that may be present in the substituent R 4 or R<14>

The ?-Alkoxyalkyl protecting group R 1 can be removed by hydrolysis in the presence of an acid, e.g. a mineral acid such as aqueous hydrochloric acid, and the hydrolysis can be carried out at a temperature up to 100°C. 5 6 7 The tertiary alkyl-protecting group R , R or R , or the acyl-protecting group R 5 or R 6 when it means a tertiary alkoxycarbonyl radical, e.g. a t-butoxycarbonyl radical, can be removed by treatment with an acid, e.g. hydrochloric acid, under anhydrous conditions, e.g. in an ether solution.

A preferred method for producing the alkanolamine derivatives according to the invention comprises reacting a compound with the formula:

where R has the above meaning (both compounds can be obtained by reacting the corresponding phenolic compound with epichlorohydrin), with an amine of the formula R 6 NH-A-NH-X-Y-R 1 where A, R 1 , X and Y have the above stated meanings and where R 6 means hydrogen or a benzyl radical, after which if R means a benzyl radical, this radical is removed by hydrogenolysis.

Another preferred method according to the invention for the production of the alkanolamine derivatives comprises reacting a compound with the formula R.OCH.CHOH.CH-NH-A-NHR 7 where R and A have the meanings given above and where R 7 means hydrogen or a benzyl radical, with a compound of the formula Z 4 -X-Y-R1

11 4

or OCN-R where R , X, Y and Z have the meanings given above, after which if R<7>means a benzyl radical, this radical is removed by hydrogenolysis.

Alkanolamine derivatives prepared according to the invention

in free base form can be converted into an acid addition salt thereof by reaction with an acid in a conventional manner.

As stated above, the alkanolamine derivative prepared according to the invention or an acid addition salt thereof has 3-adrenergic blocking activity, and furthermore this activity is cardioselective. This activity can be determined by the reversal of isoprenaline-induced tachycardia in rats or cats, which is a standard test for the determination of 3-adrenergic blocking activity, and by relative freedom from the counteraction of isoprenaline-induced vasodilatation in cats or by the relief produced by isoprenaline in histamine-induced bronchospasm in guinea pigs. Compounds exhibiting this cardioselective action have a greater degree of specificity in blocking cardio-3 receptors than the 3-receptors in outer blood vessels and bronchial muscles. A dose of such a compound can thus be chosen whereby the compound blocks the cardio-inotropic and -chronotropic effects of a catecholamine, such as isoprenaline, but does not block the relaxation of the smooth muscles in the trachea produced by isoprenaline or the external vasodilatory effect of isoprenaline. Due to this selective effect, one of these compounds can advantageously be used together with a sympathomimetic bronchodilator, for example isoprenaline, orciprenaline, adrenaline or ephedrine, in the treatment of asthma and other obstructive respiratory diseases, since the cardioselective compound will essentially prevent the unwanted stimulating effects of the bronchodilator on the heart, but will not prevent the desired therapeutic effects of the bronchodilator.

A preferred alkanolamine derivative prepared according to the invention is up to<*> 10 times more active as a cardioselective 3-adrenergic blocking agent than practolol. At the doses of an alkanolamine derivative prepared according to the invention which produce effective 3-adrenergic blockade in rats or cats, no symptoms of toxicity will be seen.

The alkanolamine derivatives produced according to the invention can be administered to warm-blooded animals, including humans, in the form of a pharmaceutical mixture which as active ingredient comprises at least one alkanolamine derivative produced according to the invention, or an acid addition salt thereof, together with a pharmaceutically acceptable diluent or carrier.

The invention is illustrated by the following examples:

Example 1

A mixture of 0.8 g of 3-isonicotinamidoethylamine and 0.75 g of 2,3-epoxy-1-phenoxypropane is heated at 90°C for 18 hours and is then cooled and diluted in 50 ml of ethyl acetate. The solution is added to a solution of 1.26 g of oxalic acid in 50 ml of ethyl acetate. The mixture is filtered and the solid residue is crystallized from isopropanol. 1-phenoxy-3-(3-isonicotine-amidoethyl-araino-2-propanol-oxalate, m.p. 154-156°C) is thus obtained.

The 3-isonicotinamidoethylamine used as starting material can be obtained in the following way: Ethyl isonicotinate hydrochloride (3.75 g) is added portionwise to 5.4 g of ethylenediamine at laboratory temperature. The mixture is allowed to stand for 30 minutes and is then diluted with 50 ml of water, and the mixture is extracted twice with 50 ml of toluene each time. The combined toluene solutions are dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The residue is dissolved in 25 ml of methanol and added to it

ethereal hydrogen chloride solution. The mixture is filtered and the solid residue is extracted with 100 ml of boiling methanol. The mixture is filtered and the combined methanol filtrates are evaporated to dryness under reduced pressure. The residue is crystallized from ethanol and thus 3-isonicotinamidoethylamine dihydrochloride is obtained, m.p. 263-265°C. The free base is re-isolated before use by conventional means.

Example 2

The procedure described in example 1 is repeated, except that 1.4 g of 3-2-thenamidoethylamine is used instead of 0.8 g of 3-isonicotinamidoethylamine. Thus 1-phenoxy-3-(3-2-thenamidoethyl)amino-2-propanol oxalate is obtained,

sm.p. 169-171°C after crystallization from ethanol.

The 3-2-thenamidoethylamine used as starting material can be prepared from ethyl 2-thenoate and ethylenediamine by a similar method to that described in the second part of example 1, and it is characterized as the oxalate salt, m.p. 175-177°C after crystallization from ethanol.

Example 3

The procedure described in example 1 is repeated, except that 1.54 g of 3-2-furamidoethylamine is used instead of 0.8 g of 3-isonicotinamidoethylamine. Thus, 1-phenoxy-3-(3-2-furamidoethyl)amino-2-propanol oxalate is obtained, m.p. 154-156°C after crystallization from ethanol.

The 3~2-furamidoethylamine used as starting material can be prepared from ethyl 2-furoate and ethylenediamine by a similar method to that described in the second part of example 1, and it is characterized as the hydrochloride, m.p. 155-159°C after crystallization from ethanol.

Example 4

A solution of 2.3 g of p-acetamidobenzenesulfonyl chloride in 20 ml of chloroform is added portionwise over the course of 10 minutes to a solution of 3.0 g of 1-3-(N-benzylamino)-ethylamino-3-phenoxy-2-propanol and 1 g of triethylamine in 75 ml of chloroform. The mixture is shaken successively with 60 ml of an aqueous 10% w/v sodium bicarbonate solution, 50 ml of saturated saline and 50 ral of water, and the chloroform phase is then dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The residue is dissolved in a mixture of 50 ml ethanol and 1 ml acetic acid and the solution is shaken in a hydrogen atmosphere at laboratory temperature and atmospheric pressure in the presence of 0.3 g of a 30% palladium-on-charcoal catalyst up to 220 ml hydrogen has been absorbed. The mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is diluted with 20 ml of water and the mixture is neutralized with aqueous 10% w/v sodium bicarbonate solution and extracted three times with 20 ml of ethyl acetate each time. The combined ethyl acetate extracts are dried over anhydrous magnesium sulfate and ethereal hydrogen chloride is added. The mixture is filtered and the solid residue is crystallized from 60 ml of a 9:1 v/v mixture of ethanol and water. Thus 3-3-(p-acetamidobenzenesulfonamido)-ethylamino-1-phenoxy-2-propanol hydrochloride is obtained, m.p. 231-233°C.

Example 5

A mixture of 2.2 g of 3-(p-acetamidobenzamido)-ethylamine, 40 ml of n-propanol and 1.5 g of 1,2-epoxy-3-phenoxypropane is heated under reflux for 18 hours, is cooled and filtered and the solid residue is crystallized from ethanol. Thus 3-B-(p-acetamido-benzamido)ethylamino-1-phenoxy-2-propanol is obtained, m.p. 157-159°C.

Example 6

The procedure described in Example 1 is repeated, except that a suitable 2,3-epoxy-1-phenoxypropane derivative and a suitable heterocyclic 3-amidoethylamine are used as starting materials. Thus, the compounds described in the following table are obtained:

Example 7

A mixture of 3/1 g of 3-chloro-1-(2-iodophenoxy)-2-propanol, 1.9 g of 3-2-furamidoethylamine, 1.68 g of sodium bicarbonate, 5 ml of water and 40 ml of n-propanol is heated under reflux for 18 hours, is cooled, diluted with 50 ml of water and is extracted successively with 75 ml and 25 ml of ethyl acetate. The combined ethyl acetate extracts are dried and added to a solution of 1.26 g of oxalic acid in 25 ml of ethyl acetate. The mixture is filtered and the solid residue is crystallized from aqueous ethanol. Thus 3-(0-2-furamidoethyl)amino-1-(2-iodophenoxide)-2-propanol oxalate is obtained, m.p. 203-204°C.

Example 8

The procedure described in Example 5 is repeated, except that a suitable 1-aryloxy-2,3-epoxypropane and a suitable 3-amidoethylamine are used as starting materials. Thus, the compounds described in the following table are obtained:

The 3-(4-carbamoylmethyl-phenoxyacetamido)-ethylamine used as starting material can be obtained in the following way: A mixture of 2.37 g of ethyl-4-carbamoylmethyl-phenoxyacetate and 5 ml of ethylenediamine is heated for 18 hours at 90°C and is then stirred with 50 ml of water. The mixture is filtered and the filtrate becomes evaporated to dryness under reduced pressure. The residue is crystallized from isopropanol and 3-(4-carbamoyl-methylphenoxyacetamido)ethylamine, m.p. 148-150°C.

In a similar way, using 23.7 g of ethyl 4-acetamidophenoxyacetate and 60 ml of ethylenediamine as starting materials, 3-(4-acetamidophenoxyacetamido)ethylamine is obtained,

sm.p. 210-212°C.

Example 9

A mixture of 2.0 g of 3-isobutyramidoethylamine, 3.0 g of 2,3-epoxy-1-(4-indolyloxy)propane and 50 ml of isopropanol is heated at 90°C for 18 hours and then evaporated to dryness under reduced Print. The residue is dissolved in 30 ml of acetonitrile, the mixture is filtered and the filtrate is added to a solution of 2.52 g of oxalic acid in 25 ml of acetonitrile. The mixture is cooled and filtered, and the filtrate is evaporated to dryness under reduced pressure and the residue triturated twice with 25 ml of ethanol each time. The mixture is filtered and thus obtained as a solid residue 1-(4-indolyloxy)-3-3-isobutyramidoethylamino-2-propanol-hydrogen-oxalate, m.p. 168-171°C.

The procedure described above is repeated, except that an appropriate 1-substituted-2,3-epoxypropane and an appropriate 3-amidoethylamine are used as starting materials. Thus, the compounds described in the following table are obtained:

Example 10

A mixture of 2.08 g of 2,3-epoxy-1-(benzodioxan-5-yloxy)-propane, 1.92 g of 1-methyl-2-phenylacetamidoethylamine and 50 ml of isopropanol is heated under reflux for 4 hours and then evaporated to dryness under reduced pressure. The residue is dissolved in 50 ml of ethyl acetate and the solution is extracted twice with 50 ml of water each time. The ethyl acetate solution is dried and evaporated to dryness under reduced pressure and the residue is crystallized from toluene. Thus 1-(benzodioxan-5-yloxy)-3-(1-methyl-2-phenylacetamidoethyl)amino-2-propanol is obtained,

sm.p. 93-94°C

Example 11

A mixture of 2.08 g of 2,3-epoxy-1-(benzodioxan-5-yloxy)-propane, 1.44 g of Y-isobutyramidopropylamine and 50 ml of isopropanol is heated under reflux for 4 hours and then evaporated to dryness under reduced pressure. The residue is dissolved in 50 ml of ethyl acetate and the solution is extracted twice with 50 ml of water each time. The ethyl acetate phase is separated, dried and added to a solution of 1.26 g of oxalic acid in 30 ml of acetone. The mixture is filtered and the solid residue is crystallized from acetonitrile. Thus 1-(benzodioxan-5-yloxy)-3-Y-isobutyramido-propylamino-2-propanol hydrogen oxalate is obtained, m.p. 122-125°C.

Example 12

A mixture of 2.43 g of 3-(2,3-epoxypropoxy)-4-morpholino-1,2,5-thiadiazole, 1.3 g of 3-isobutyramidoethylamine and 50 ml of isopropanol is heated at 90°C for 18 hours and is then evaporated to dryness under reduced pressure. The residue is stirred with 100 ml of aqueous 2N hydrochloric acid and the mixture is extracted three times with 50 ml of ethyl acetate each time. The aqueous acid phase is separated, basified with linoleic sodium hydroxide solution and extracted three times with 75 ml of ethyl acetate each time.

The combined ethyl acetate extracts are dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure,

and the residue is dissolved in 25 ml of acetone. The solution is added to a solution of 2.5 g of oxalic acid in 25 ml of acetone, the mixture is filtered and the solid is washed with acetone and crystallized from ethanol. Thus, 3-3-isobutyramidoethylamino-1-(4-morpholino-1,2,5-thiadiazol-3-yloxy)-2-propanol-hydrogen-

oxalate, m.p. 194-196°C (with cleavage).

Example 13

A mixture of 3.1 g of 1-chloro-3-3-isobutyramidoethylamino-2-propanol hydrogen oxalate, 1.5 g of 4-hydroxybenzo[b]thiophene, 1.4 g of sodium hydroxide, 5 ml of water and 50 ml of isopropanol is heated under reflux for 18 hours and then evaporated to dryness under reduced pressure. The residue is stirred with 100 ml of water and the mixture is extracted twice with 50 ml of chloroform each time. The combined chloroform extracts are dried and evaporated

dryness under reduced pressure and the residue is crystallized from ethyl acetate. Thus 1-(benzo[b]thien-4-yloxy)-3-isobutyr-amido-ethylamino-2-propanol is obtained, m.p. 121-123°C.

Example 14

A mixture of 2.81 g of ethyl 2-p-chlorophenylthiazol-4-yl-acetate and 2.52 g of 3-3-aminoethylamino-1-(2-cyanophenoxy)-2-propanol is heated at 90°C for 18 hours and is then dissolved in 25 ml of acetonitrile. The solution is cooled and filtered and the solid residue is crystallized from ethanol. Thus 1-(2-cyanophenoxy)-3-3-

(2-p-chlorophenylthiazol-4-ylacetamido)ethylamino-2-propanol,

sm.p. 113-114°C.

The procedure described above is repeated, except that a suitable ethyl ester is used as starting material, and in one case the corresponding 2-chlorophenoxy derivative is used. Thus, the compounds described in the following table are obtained:

Example 15

A mixture of 0.84 g of 3-B-aminoethylamino-1-(2-cyanophenoxy)-2-propanol and 0.88 g of ethyl 4-acetamido-methylphenoxyacetate is heated at 90°C for 2 hours, and then dissolved in 25 ml hot

acetonitrile. The mixture is filtered, the solids are discarded and the filtrate is cooled and then filtered again. The solid residue is crystallized from acetonitrile, and thus 3-3-(4-acetamido-methylphenoxyacetamido)ethylamino-1-(2-cyanophenoxy)-2-propanol is obtained, m.p. 98-100°C.

In a similar manner, using 1.2 g of 3-((5-aminoethylamino)-1-(2-cyanophenoxy)-2-propanol and 1.29 g of ethyl 4-methanesulfonamidophenyl acetate as starting materials, 1-( 2-cyanophenoxy)-3-3-(4-methanesulfonamido-phenylacetamido)-ethylamino-2-propanol, isolated as its oxalate, mp 180-182°C after crystallization from isopropanol.

In a similar manner, using 2.36 g of 3-(3-aminoethylamino)-1-(cyanophenoxy)-2-propanol and 2.37 g of ethyl 4-carbamoylmethoxyphenyl acetate as starting materials, 3-3-(4 -carbamoylmethoxyphenylacetamido)ethylamino-1-(2-cyanophenoxy)-2-propanol, isolated as its hydrogen oxalate, m.p. 123-125°C after crystallization from ethyl acetate.

The 4-acetamidomethylphenoxyacetate used as starting material in the first part of this example can be obtained in the following way: A mixture of 2.5 g of 4-acetamidomethylphenol, 15 ml of acetone, 2.1 g of potassium carbonate and 1.8 ml of ethyl bromoacetate is heated under reflux in 18 hours and is then filtered, and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in 30 ml of ethyl acetate and the solution is washed

twice with 25 ml of water each time, is dried and evaporated to dryness under reduced pressure. The residue is crystallized from toluene and thus ethyl 4-acetamidomethylphenoxyacetate is obtained, m.p. 85-86°C.

Example 16

A mixture of 2.68 g of 3-3-aminoethylamino-1-(benzodioxan-5-yloxy)-2-propanol and 2.25 g of ethyl p-nitrophenoxyacetate is heated at 90°C for 18 hours and then dissolved in 50 ml of ethyl acetate. The solution is washed twice with 50 ml of water each time and is then dried and added to a solution of 1.26 g of oxalic acid in 50 ml of ethyl acetate. The mixture is filtered and the solid residue is heated under reflux with 50 ml of acetonitrile. The solution is cooled and filtered and the solid residue is crystallized from ethanol. Thus 1-(benzodioxan-5-yloxy)-3-3-(p-nitrophenoxyacetamido)ethylamino-2-propanol hydrogen oxalate is obtained, m.p. 162-164°C.

The procedure described above is repeated, except that the ethyl-p-nitrophenoxyacetate is replaced by either ethyl-p-acetylphenoxyacetate or ethyl-p-(3-methylureidophenyl)acetate and that the product in one case is isolated as the hydrochloride while the product in the other case is isolated as the free base.

1-(benzodioxan-5-yloxy)-3-fS-(p-acetylphenoxyacetamido)ethylamino-2-propanol hydrochloride hydrate, m.p. 129-131°C after crystallization from ethanol, and 1-(benzo-dioxan-5-yloxy)-3-3-(p-3-methylureidophenylacetamido)ethylamino-2-propanol, m.p. 115-117°C after crystallization from acetonitrile.

The 3-(3-aminoethylamino)-1-(benzodioxan-5-yloxy)-2-propanol used as starting material can be obtained in the following way: A mixture of 20.8 g of 1-(benzodioxan-5-yloxy)-2, 3-Epoxypropane and 120 g of ethylenediamine are heated at 90°C for 18 hours and then evaporated to dryness under reduced pressure. The residue is stirred with 100 ml of water and the mixture is extracted four times with 100 ml of chloroform each time. The combined chloroform extracts are dried and evaporated to dryness under reduced pressure and thus 3-3-aminoethylamino-1-(benzodioxan-5-yl-oxy)-2-propanol is obtained as a residue.

Example 17

A mixture of 0.86 g of quinoline-2-carboxylic acid, 50 ml of ethyl acetate, 1.1 g of 2,4,5-trichlorophenol and 1.25 g of N,N-dicyclohexylcarbodiimide is stirred at laboratory temperature for 2 hours and is then filtered, and the filtrate is added to a solution of 1.17 g of 3-3-aminoethylamino-1-(2-cyanophenoxy)propanol in 30 ml of acetonitrile. The mixture is stirred at laboratory temperature for 18 hours and

is then extracted twice with 50 ml of aqueous 10% volume/volume acetic acid solution each time. The combined extracts are made basic with aqueous linseed sodium hydroxide solution and the mixture is extracted twice with 30 ml of ethyl acetate each time. The combined extracts are dried and evaporated to dryness under reduced pressure, the residue is dissolved in 20 ml of acetonitrile and the solution is added to a solution of 0.63 g of oxalic acid in 20 ml of acetonitrile. The mixture is filtered, and the solid residue is crystallized from water. Thus 1-(2-cyanophenoxy)-3-3"(quinoline-2-carboxamido)ethylamino-2-propanol hydrogen oxalate is obtained, m.p. 179-181°C.

Example 18

1.6 g of 1-(benzodioxan-5-yloxy)-3-3-(p-nitrophenoxyacetamido)ethylamino-2-propanol hydrogen oxalate (Example 16) is converted to its free base form by conventional methods, and the base is dissolved in 50 ml of ethanol. 200 mg of one is added

30% palladium-on-charcoal catalyst and the mixture is shaken

with hydrogen at laboratory temperature and atmospheric pressure until 2 30 mg of hydrogen has been absorbed. The mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in 30 ml of acetonitrile and an excess of saturated ethereal hydrogen chloride solution is added. The mixture is filtered and the solid residue is crystallized from 20 ml of ethanol. Thus 3-3-(p-aminophenoxyacetamido)ethylamino-1-(benzodioxan-5-yloxy)-2-propanol dihydrochloride is obtained, m.p. 200-202°C.

Example 19

A mixture of 1.7 g of 3-3-(p-benzyloxyphenoxyacetamido)-ethylamino-1-(benzodioxan-5-yloxy)-2-propanol oxalate

(m.p. 187-189°C, prepared by a similar method as

that described in Example 9), 0.2 g of a 30% palladium-on-charcoal catalyst and 40 ml of acetic acid are shaken with hydrogen at laboratory temperature and atmospheric pressure until 125 ml of hydrogen has been absorbed. 40 ml of water is then added and the mixture is filtered. The filtrate is evaporated to dryness under reduced pressure, the residue is dissolved in 30 ml of acetonitrile and the solution obtained is added to a solution of 0.42 g of oxalic acid in 30 ml of acetonitrile. The mixture is filtered and the solid is crystallized from ethanol. Thus 1-(benzodioxan-5-yloxy)-3-3-(p-hydroxyphenoxyacetamido)-ethylamino-2-propanol hydrogen oxalate is obtained, m.p. 188-190°C.

The procedure described above is repeated, except that 1-(2-benzyloxyphenoxy)-3-(3-2-furamidoethyl)amino-2-propanol (m.p. 84-85°C, prepared by a similar procedure to the which is described in example 6) is used as starting material. Thus 1-(2-hydroxyphenoxy)-3-(3-2-furamido-ethyl)amino-2-propanol-hydrogen-oxalate is obtained, m.p. 176-178°C after crystallization from water.

Example 20

A solution of phenyl isocyanate (0.6 g) in acetonitrile

(10 ml) is added over the course of 5 minutes to a stirred solution of 1-(benzodioxan-5-yloxy)-3-3-aminoethylamino-2-propanol (1.34 g)

in acetonitrile (50 ml) which is kept at -30°C, and the mixture is then warmed to room temperature and filtered. The solid residue is crystallized from ethanol and thus 1-(benzodioxan-5-yloxy)-3-3-(3-phenylureido)ethylamino-2-propanol is obtained, m.p. 154-155°C.

Claims (1)

Analogy method according to patent 140,496 for the production of additional alkanolamine derivatives with 6-adrenergic blocking action and with the general formula where A means an alkylene radical having from 2 to 6 carbon atoms; X means a carbonyl (-CO-) or sulfonyl (-SO 2 - ) radical; Y means a direct bond or an alkylene or alkyleneoxy radical of up to 6 carbon atoms or an imino-(-NH-) radical; and (a) R means a mono- or bicyclic heterocyclic radical in which at least one ring is a 5- or 6-membered, saturated or unsaturated heteroring containing one, two or three heteroatoms selected from nitrogen, oxygen and sulfur atoms; and wherein ring number two, if present, is a benzene ring; and which heterocyclic radical may optionally contain one or two substituents selected from halogen atoms, alkyl, alkoxy and alkanoyl radicals of up to 6 carbon atoms each, aryl radicals of up to 10 carbon atoms, morpholino radicals and, when the heterocyclic radical has a suitable degree of unsaturation, it may optionally carry an oxo substituent, or R means an aryl radical with the formula: and R^" means a heterocyclic radical as defined above for R, or R"<*>" means an aryl radical of the formula: 2 3 12 13 where R , R , R and R , which may be the same or different, each means a hydrogen or halogen atom, a hydroxy, amino, nitro or cyano radical, an alkyl, alkenyl, alkoxy, alkenyloxy or alkanoyl radical each having up to 6 carbon atoms; 2 3 "213 or R and R together and/or Rx and R together form a buta-1,3-dienylene radical so that together with the adjacent benzene ring they form a naphthyl radical; R 4 means a hydrogen atom or an amide radical with the formula: where X has the above meaning; Q means a direct bond or an alkylene radical of up to 6 carbon atoms; Q1 means an alkylene radical of up to 6 carbon atoms; and 15 R means a hydrogen atom or an alkyl radical of up to 6 14 carbon atoms; and R means an amide radical as defined above 4 for R ; or (b) R means a heterocyclic radical as defined above, and R^ means an alkyl radical of up to 6 carbon atoms or an aryl radical of the formula: 12 13 where R and R , which may be the same or different, have the meanings given above; or an acid addition salt thereof, characterized in that (a) a compound with the formula R-OCH_Z" where R has 3 the meaning given above and Z means the group where R<5> means hydrogen or a hydrolyzable or hydrogenolysable protecting group, and Z1 means a replaceable halogen or sulfonyloxy radical, is reacted with an amine of the formula: where A, R<1>, X and Y have the meanings given above, and R^ and R<7>, which may be the same or different, each means hydrogen or a hydrolyzable or hydrogenolyzable protecting group; or (b) a compound of the formula where R has the meaning stated above, is reacted with a compound of the formula 16 7 3 where A, R , R , R , X, Y and Z have the meanings given above; or (c) a compound of the formula: where R, R 6 , R 7 and A have the meanings given above, are reacted with a compound of the formula: where R 1 , X and Y have the meanings given above, and Z 4 denotes a replaceable halogen, sulfonyloxy, alkoxy, aryloxy or hydroxy radical; 6 7 after which, if one or both of the groups R and R means a protecting group, the one or the two protecting groups are removed by hydrolysis or hydrogenolysis; and after which an alkanolamine derivative in free base form is optionally converted into an acid addition salt thereof by reaction with an acid.