NO155052B - ANALOGUE PROCEDURE FOR THE PREPARATION OF 1- (2,4-DICHLORPHENOXY) -3- (3,4-DIMETOXY-B-PHENETYLAMINO) -PROPANOL- (2). - Google Patents

Abstract

1. 1-(2,4-Dichlorophenoxy)-3- (3,4-dimethoxy-beta-phenethylamino)-2-propanol of formula I see diagramm : EP0086256,P7,F1 as racemate or in optically active form.

Description

The invention relates to an analogous process for the preparation of 1-(2,4-dichlorophenoxy)-3-(3,4-dimethoxy-3-phenethyl-amino)-propanol-(2) with formula I

The compound selectively blocks the adrenergic β-receptors

by simultaneous stimulation of the ^-receptors, acts as an antihypertensive, antiarrhythmic, cardioprotective and has central effects. It can therefore advantageously be used for the therapy and prophylaxis of angina pectoris, myocardial infarction, hypertension, cardiac arrhythmias, hyperkinetic heart syndrome, hyperthyroidism, migraine, Parkinsonism and the like. 1.phenoxy-3-alkylamino-propanols-(2) are mentioned several times (DE-PS 2259 489, DE-PS 2213 044, DD-AP 45 360, BE-PS 783 086,

NE-PS 6813 616, GB-PS 1148 563, NE-PS 7307 821, DD-AP 93 349,

GB-PS 1078 852, BE-PS 746 107). Also 1-(2,5-dichloro-phenoxy)-3-(3,4-dimethoxy-g-phenethylamino)-propanol-(2) is known (JA-OS 52053 829), it differs in its effect against 2 ,4-dichloro compound according to the invention, however, in that it lacks pronounced stimulating effects on (^-resep-

the tors in the vessels which are of great importance for the therapeutic application.

The purpose of the invention is to provide a 3-adrenolytic active substance of the phenoxypropanolamine type which in itself combines several advantageous pharmacological properties in a hitherto unknown combination.

The invention consists in providing a method for the production of the hitherto unmentioned compound of formula I. Its special pharmacological properties which ad-

differs qualitatively from the properties of the hitherto known Ø receptor blockers. The compound according to the invention can be prepared by: a) Reaction of 1-(2,4-dichloro-phenoxy)-3-chloro-propanol-(2) with 3,4-dimethoxy-g-phenethylamine. To achieve a maximum

complete reaction, the reaction is carried out in the presence of a base, preferably in the presence of an excess of the reaction participant 3,4-dimethoxy-3-phenethylamine. Some examples of suitable bases are alkali hydroxides such as potassium and sodium hydroxide, alkali carbonates such as potassium and sodium carbonates and tertiary amines such as triethylamine and tripropylamine. The turnover of the reaction participants is conveniently carried out in the presence of an organic solvent. Examples of suitable solvents are alkanols such as ethanol and isopropanol, ethers such as dioxane, ketones such as acetone and methyl ethyl ketone, hydrocarbons such as benzene, toluene and xylene and chlorinated hydrocarbons such as chloroform, tetrachloromethane and tetrachloroethane. The reaction time and temperatures can be greatly varied. The reaction is usually carried out within 1 - 48 hours at temperatures from 20 to 200°C. The reaction product is isolated directly as a free base or after treatment with an acid such as acid addition salts. Preferably, the halohydrin is dissolved with twice the equimolar amount of 3,4-dimethoxy-g-phenethylamine in isopropanol, boiled for 16 hours under reflux and the isopropanol is distilled off in a vacuum. The product is extracted with an organic solvent, preferably with those which do not dissolve the 3,4-dimethoxy-3-phenethylamine hydrochloride formed. Examples of suitable solvents are acetone and ethyl acetate. The reaction can also take place in an organic solvent that is immiscible with water, or poorly miscible, such as e.g. chloroform, and the 3,4-dimethoxy-B-phenethylamine hydrochloride formed is removed from the reaction mixture by extraction with water.

The final product is isolated from the reaction mixture as hydrochloride by treatment with isopropanolic or ethereal hydrochloric acid or by introducing anhydrous hydrogen chloride.

b) Reaction of 1-(2,4-dichlorophenoxy)-2,3-epoxypropane with 3,4-dimethoxy-g-phenethylamine. The reaction takes place if necessary

in a solvent and at an elevated temperature. The reaction is usually carried out within 15 minutes to 48 hours at a temperature of 15 to 150°C. Examples of suitable solvents are alkanols such as methanol, ethanol and isopropanol, ethers such as dioxane, ketones such as acetone and methyl ethyl ketone, hydrocarbons such as benzene, toluene and xylene and chlorinated hydrocarbons such as chloroform, tetrachloromethane and tetrachloroethane. The reaction participants are usually converted in equimolar amounts, although they can also be used in moderate excess. c) Hydrolysis of 3-(3,4-dimethoxy-g-phenethyl)-5-(2,4-dichloro-phenoxymethyl)-oxazolidone-(2).

Hydrolysis of the oxazolidone is conveniently carried out with

an alkali lye such as aqueous solutions of sodium or potassium hydroxide. Optionally, an organic solvent can also be added during this reaction. Suitable solvents are e.g. alkanols such as ethanol and methanol. d-e) Reaction of 2,4-dichlorophenol with 1,2-epoxy-3-(3,4-dimethoxy-g-phenethylamino)-propane or a 1-halo-3-(3,4-dimethoxy-g-phenethylamino)-propanol -(2), preferably 1-chloro-respectively 1-bromo-3-(3,4-dimethoxy-g-phenethylamino-propanol-(2).

The reaction can conveniently be carried out in the presence of an acid-binding agent, e.g. potassium or sodium hydroxide. On the other hand, an alkali phenolate can be used as starting material. The reaction can optionally take place in a solvent at an elevated temperature, e.g. the boiling temperature of the solvent. Examples of suitable solvents are alkanols such as methanol and isopropanol, hydrocarbons such as benzene, toluene and xylene and hydrocarbons such as benzene, toluene and xylene and chlorinated hydro-

carbons such as chloroform, tetrachloromethane and tetrachloroethane.

f) Reaction of 1-(2,4-dichlorophenoxy)-3-aminopropanol-(2)-with 3,4-dimethoxy-B-phenethyl chloride. The reaction is carried out

suitably in the presence of an acid-binding agent, e.g. sodium hydroxide or sodium bicarbonate. The reaction can optionally take place at an elevated temperature in a solvent, e.g. an alkanol such as ethanol, n-propanol and isopropanol.

g) Reaction of 2,4-dichlorophenol with 1-(3,4-dimethoxy-3-phenethyl)-azetidinol-(3). Appropriately implements

the reaction is carried out under the exclusion of water and oxygen and in the presence of a basic or acidic catalyst such as sodium or potassium hydroxide, triethylamine and trifluoroacetic acid. The reaction can optionally take place at an elevated temperature, preferably at 120 - 250°C and in a solvent. Suitable solvents are e.g. alkanols such as benzyl alcohol and chlorinated hydrocarbons such as chlorobenzene. h) The protecting group is cleaved in 1-(2,4-dichlorophenoxy)-3-{3,4-dimethoxy-3-phenethylamino)-propane-tetrahydropyranyl-ether-oxalate. The cleavage takes place suitably by heating with aqueous or alkanol alkali lye or preferably with acetals with an acid, such as e.g. hydrochloric acid.

They for the implementation of procedures options

a to h necessary starting materials are partly already known, partly they can be prepared according to usual methods.

The compound according to the invention can be transferred in the usual way

in its physiologically tolerable acid addition salts and esters. Examples of suitable acids for the production of the acid addition salts are hydrochloric acid, hydrobromic acid, solic acid, phosphoric acid, acetic acid, oxalic acid, methanesulfonic acid, lactic acid, tartaric acid, malic acid and maleic acid. The transfer of the compound according to the invention in its esters can e.g. take place by reaction with acyl halides or acyl anhydrides such as acetyl chloride, acetic anhydride and butyryl chloride.

The compound according to the invention surprisingly shows in animal experiments compared to the known g-receptor blockers propanolol ("Obsidan"), talinolol ("Cordanum"), practolol and Cl 775 superior pharmacological properties. For example, the compound with formula I on pea for g-receptor blocker hitherto unknown combination combines two anti-anginal principles of action: by blocking the cardiac B-^-receptors, the heart's

oxygen consumption,

- by stimulation of the adrenergic 32-receptors, the vessels dilate, as the peripheral vascular resistance is lowered and thus relieves the heart.

On rat myocardial infarction model (oral application of 3, 6

and 12 mg/kg of compound I over 2 8 days before ligation of the right coronary artery assessment criteria: CPK, GOT, ECG change, relative infarct weight) compound I after prophylactic administration showed an approximately twice stronger cardioprotective effect than propranolol. The strength of the B^-receptor blockade by compound I is species-dependent (isoproterenolantagonismus, propranolol = 100):

On the γ-receptors of cats and dogs (heart rate and contractility of the whole animal), compound I was only half as effective as propranolol. While propranolol cancels the blood-pressure-lowering effect of isoprotenerol in cats and dogs by blocking the 32~resPtors in the vessels, administration of compound I results in a strengthening of the isoprotenerol effect due to the 32~a<3renergic stimulation. Due to the 32-adrenergic action of the compound according to the invention, the conditional vasodilatation leads to an unusually strong antihypertensive effect for the known 3-receptor blockers, which is approximately ten times stronger than with propranolol (spontaneously hypertensive rat). Of great therapeutic importance is also the stimulation of the adrenergic 32 receptors of the bronchial musculature, which can be demonstrated both on isolated tracheal muscle and also in whole animal experiments. Thus, the administration of 0.1 mg/kg of the compound according to the invention to an anesthetized dog leads to an isoproterenol-like increase in the respiratory volume, while propranolol decreases this by its bronchoconstrictor effect. In awake guinea pigs, 0.76 mg/kg causes a doubling of the tolerance time to the asthma-triggering histamine (isoproterenol: ED5Q = 0.04 mg/kg), while 9.1 mg/kg propranolol decreases this as an expression of the bronchoconstrictor effect around half. For this reason, the use of non-selective g-receptor blockers in patients with obstructive respiratory diseases is contraindicated. But also the use of so-called cardioselective g-receptor blockers, e.g. of practolol, talinolol and C1775 is dangerous in such patients as clinical experience shows, as the corresponding dosages and disposition of the patient belong to dyspnoea and can trigger an asthma attack. As the compound according to the invention has B2-adrenergic effects, it can advantageously be used without the risk of an increase in respiratory resistance or the triggering of an asthma attack. In addition, the compound according to the invention shows distinct and therapeutically significant antiarrhythmic effects that surpass those of propanolol, talinolol, practolol and the known antiarithmetic tachmalin (ED5Q, increase of the electrical flicker threshold in guinea pigs: Compound according to the invention = 0.22 mg/kg, propanolol = 1 .4 mg/kg, Talinolol = 0.31 mg/kg, Tachmalin = 0.71 mg/kg). Also the "central effect" of the compound according to the invention is therapeutically significant, thus this compound shows approximately the same anti-Parkinson effect as trihexylphenidyl ("Parkofan") on nicotine tremor in guinea pigs. The toxicity of the compound according to the invention is less than that of propanolol and talinolol (i.p. application to mice LE>5q: compound according to the invention = 141 mg/kg, propanolol = 107 mg/kg, talinolol = 96 mg/kg).

The compound according to the invention has the same indication range

however, like the already known g receptor blockers, the hitherto novel combination of g-^-receptor blockade and simultaneous g2-stimulation has stronger anti-anginal cardioprotective and antihypertensive effects and can also be used in patients with obstructive respiratory diseases. It can therefore advantageously be used for the treatment of angina pectoris, myocardial infarction, hypertension and for the therapy of central nervous diseases such as, for example Parkinsonism, migraine, drug addiction and psychosis.

The single therapeutic dose of the compound according to the invention lies between 21 mg for intravenous application and between 10 and 100 mg for oral administration.

The compound according to the invention can be brought in the usual galenic application forms such as tablets, capsules, dragees, powders, solutions, emulsions and depot forms, as the usual pharmaceutical excipients and the usual production methods are used for their preparation. The compound according to the invention can advantageously be used in combination with other pharmacodynamically active substances. Examples of

substances suitable for combination are anti-anginal drugs such as propanetriol trinitrate, pentaerythritol tetranitrate and dipyridamole, cardiac glycosides such as digitoxin and digoxin, antihypertensives such as clonidine and dihydralazine, diuretics such as purosemid and hydrochlorothiazide and centrally acting drugs such as diazepam and lepinal.

The invention will be explained in more detail with the help of some examples.

Example 1

5.1 g of 1-(2,4-dichloro-phenoxy)-3-chloro-propanol-(2) and 7.2 g of 3,4-dimethoxy-g-phenethylamine are dissolved in 15 ml of ethyl acetate and heated for 20 hours under reflux . The precipitated 3,4-dimethoxy-g-phenethylamine hydrochloride is sucked off the reaction mixture, extracted with water and the organic phase is dried over sodium sulphate. The residue formed after evaporation is dissolved in excess isopropanolic hydrochloric acid. The reaction mixture is evaporated, the residue is washed with ether, recrystallized from ethyl acetate/ethanol. The hydrochloride of 1-(2,4-dichlorophenoxy)-3-(3,4-dimethoxy-g-phenethylamino)-propanol-(2) is obtained as colorless crystals of melting point 151 to 152°C. Yield 6.5 g (74% of the theoretical).

Example 2

Dissolve 21.9 g of 1-(2,4-dichloro-phenoxy)-2,3-epoxy-propane in 50 ml of isopropanol, mix with 18.1 g of 3,4-dimethoxy-g-phenethyl-

amine in 50 ml of isopropanol and heated for 10 hours under reflux. The isopropanol is distilled off in a vacuum, the residue is taken up in ether and the ethereal solution is washed with water. The ethereal solution is dried over sodium sulphate, distilled off and evaporated to give 1-(2,4-dichloro-phenoxy)-3-(3,4-dimethoxy-3-phenethylamino)-propanol-(2) as a colourless, crystalline residue which recrystallized from ethyl acetate/ethanol. Colorless, fine crystalline powder, melting point 120 to 121°C, yield 38 g (95% of theory).

Example 3

5 g of 3-(3,4-dimethoxy-3-phenethyl)-5-(2,4-dichloro-phenoxy-methyl)-oxazolidone-(2) can be dissolved in 20 ml of methanol and heated with 20 ml of 50% caustic soda in 3 hours under reflux. The methanol is distilled off and acidified with hydrochloric acid. Then extract with ether and the aqueous phase, alkalize with caustic soda. The precipitated 1-(2,4-dichlorophenoxy)-3-(3,4-dimethoxy-B-phenethylamino)-propanol-(2) is filtered off with suction and recrystallized from ethyl acetate/ethanol. Colorless, fine crystalline powder of melting point 120 to 121°C. Yield 2.8 g (60% of the theoretical).

Example 4

16.3 g of 2,4-dichlorophenol and 4.0 g of sodium hydroxide are dissolved in 300 ml of ethanol, 28.5 g of 1,2-epoxy-3-(3,4-dimethoxy-B-phenethyl-amino)-propane are added, the reaction mixture is heated for 4 hours under reflux. The mixture is then evaporated to dryness in vacuo, the residue is taken up in 80 ml of chloroform, extracted with water and the organic phase is dried over sodium sulphate. After filtration, double the amount of ether is added to the solution and dry hydrogen chloride is introduced. The formed precipitate is filtered off, washed with ether and recrystallized from dilute ethanol. The hydrochloride of 1-(2,4-dichloro-penoxy-3-(3,4-dimethoxy-g-phenethylamino)-propanol-(2) is obtained as a colorless, fine crystalline powder with a melting point of 151 to 152°C.

Yield 9.7g (22% of the theoretical).

Example 5

Dissolve 16.3 g of 2,4-dichlorophenol and 8.0 g of sodium hydroxide in 100 ml of ethanol and 20 ml of water and add 32.9 g of 1-chloro-3-(3,4-dimethoxy-g-phenethylamino)-propanol- (2). The mixture is heated for 4 hours under reflux and evaporated to dryness in vacuo. For the preparation of 1-(2,4-dichloro-penoxy)-3-(3,4-dimethoxy-g-phenethylamino)-propanol-(2) the residue was further processed as described under example 2. Yield 11.2 g

(28% of the theoretical).

Example 6

A mixture of 27.3 g of 1-(2,4-dichloro-phenoxy)-3-amino-propanol-(2), 16.8 g of sodium bicarbonate, 20.1 g of 3,4-dimethoxy-g-phenethyl chloride and 30 0 ml of n-propanol is heated for 18 hours under reflux, then evaporated to dryness in a vacuum and the residue is worked up as indicated under example 2. Yield 24.3 g

(56% of the theoretical).

Example 7

A mixture of 13.4 g of 2,4-dichlorophenol, 23.7 g of 1-(3,4-dimethoxy-6-phenethyl)-azetidinol-(3), 0.5 g of potassium hydroxy in 50 ml of benzyl alcohol is stirred under stirring in a stream of nitrogen for 15 hours at 140°C. After cooling, 150 ml of ethyl acetate are added, shaken 3 times with each time 100 ml of 2 N hydrochloric acid and the aqueous phase is washed with ethyl acetate. After drying the organic phase over sodium sulphate, it is sucked off and dry hydrogen chloride is introduced.

The precipitated hydrochloride of 1-(2,4-dichloro-phenoxy)-3-(3,4-dimethoxy-g-phenethylamino)-propanol-(2) is filtered off with suction and recrystallized from ethyl acetate/ethanol. Colorless, fine crystalline powder of melting point 151 to 152°C. Yield 12.4 g (36% of the theoretical).

Example 83 g of 1-(2,4-dichloro-phenoxy)-3-(3,4-dimethoxy-B-phenethyl)amino-propane-tetrahydropyranyl ether oxalate are dissolved in 25 ml of 2 N hydrochloric acid and heated for 15 minutes under reflux. The reaction mixture is extracted with ether and the aqueous phase is made alkaline with caustic soda. The separated oil is taken up in ether, the ethereal solution is washed with water, dried over sodium sulphate, filtered off and evaporated to about half. After introduction of dry hydrogen chloride, a precipitate forms which is sucked off, washed with ether and recrystallized from water. Hydrochloride of 1-(2,4-dichloro-phenoxy)-3-(3,4-dimethoxy-3-phenethylamino)-propanol-(2) is obtained as colorless, fine crystalline powder with a melting point of 151 to 152°C.

Yield 1.7 g (62% of theoretical).

Claims (1)

Analogous method for the production of the new cardiac circulatory agent 1-(2,4-dichlorophenoxy)-3- (< 3,4-dimethoxy-B-phenethylamino)-propanol-(2), characterized in that .a) 1-(2 ,4-dichlorophenoxy)-3-chloropropanol-(2) is reacted with 3,4-dimethoxy-B-phenylamine or that b) 1-(2,4-dichlorophenoxy)-2,3-epoxypropane is reacted with 3,4-dimethoxy -B-phenylamine, or that c) 3-(3,4-dimethoxy-B-phenethyl)-5-(2,4-dichloro-phenoxymethyl)-oxazolidone-(2) is hydrolysed, or that d) 2,4- dichlorophenol is reacted with 1,2-epoxy-3-(3,4-dimethoxy-B-phenethylamino)-propane, or e) 2,4-dichlorophenol is reacted with 1-halo-3-(3,4-dimethoxy-B-phenethylamino) )-propanol-(2), or that f) 1-(2,4-dichlorophenoxy)-3-aminopropanol-(2) is reacted with 3,4-dimethoxy-B-phenethyl chloride, or that g) 2,4-dichlorophenol is reacted with 1-(3,4-dimethoxy-e-phenethyl)-azetidinol-(3), or that h) the protecting group is cleaved in 1-(2,4-dichlorophenoxy)-3-(3,4-dimethoxy-B- phenethylamino)-propane-tetrahydro-pyranyl ether-oxalate.