DD298506A5 - PROCESS FOR PREPARING HALOGEN-SUBSTITUTED 1-PHENOXY-3-ALKYLAMINO-PROPANE-2-OLE - Google Patents

Abstract

The invention relates to a process for the preparation of halogen-substituted 1-phenoxy-3-alkylamino-propan-2-ols, their esters and acid addition salts. These compounds are used for the therapy and prophylaxis of various diseases of the cardiovascular system. The object and the object are to provide a process for the preparation of novel compounds of halogen-substituted 1-phenoxy-3-alkylamino-propan-2-ols, wherein the compounds should have pronounced stimulating and blocking effects on the adrenergic b-receptors. According to the invention, their esters and acid addition salts of the general formula in which X.sup.1, X.sup.2, halogen atoms, by reacting * with 1,1-dimethyl-2-phenyl-ethylamine or 1-dihalogenphenoxy-3-halopropan-2-ol with 1 , 1-dimethyl-2-phenyl-ethylamine or dihalo-phenol with * or dihalo-phenol with *. Formula {manufacture; Connection; 1-phenoxy-3-alkylamino-propan-2-ole; esters; acid-addition salts; * bb receptors; Therapy; Prophylaxis; Cardiovascular system}

Description

/ VOCH ₂ -CH-

f gh

in which χ, X _{2 represent} halogen atoms.

a) by reacting a 1-dihalo-phenoxy-2,3-epoxypropane with 1,1-dimethyl-2-phenylethylamine. The reaction takes place without addition of solvent, but if appropriate also in a solvent and at elevated temperature. The reaction participants are generally reacted in equimolar amounts. However, a moderate excess of each of the reactants can also be used. The reaction is carried out at temperatures of 20-150 ° C and is completed within 15 minutes to 48 hours. Examples of suitable solvents are alkenols such as methanol, ethanol and isopropanol, ethers such as dioxane, esters such as ethyl acetate and butyl acetate, ketones such as acetone and hydrocarbons such as benzene, toluene, xylene, chloroform and carbon tetrachloride.

b) by reacting a 1-Dihalogenphenoxy-3-halopropan-2-ol with 1,1-dimethyl-2-phenyl-ethylamine. It is expedient to use an S-chloropropane-1-ol, although the reaction is also possible with the corresponding bromine derivative. The reaction may optionally be carried out in a solvent. Hieiai the solvents listed in method a can be used. Reaction temperatures and reaction rates also largely correspond to method a. In order to obtain as complete a conversion of the starting materials into the final product, the reaction is carried out in the presence of a base, preferably in the presence of an excess of the reactant 1,1-dimethyl-2-phenyl-ethylamine. Examples of other suitable bases are alkali metal hydroxides such as potassium and sodium hydroxide, alkali metal carbonates such as potassium and sodium carbonate and tertiary amines such as triethylamine.

c) and d) by reacting a dihalogenphenol with 1,2-epoxy-3- (1,1-dimethyl-2-phenyl-ethylamino) -propane or a 1-halo-3- (1,1-dimethyl-2-) phenyl-ethylamino) -propan-2-ol, preferably the 1-chloro or. 1-bromo-3- (1, ¹ -dimethyl-2-phenyl-ethylamino) -propan-2-ol. If desired, the reaction can be carried out in a solvent and at elevated temperature. Reaction temperatures, reaction times and solvents are variable and largely correspond to the conditions selected in process a. Conveniently, the reaction is carried out in the presence of an acid-binding agent, for. As potassium or sodium hydroxide, by. On the other hand, an alkali phenolate can be used as the starting material.

The compounds according to the invention have an asymmetric carbon atom in the side chain and therefore occur as racemate and also as optical antipodes. The optical antipodes can be prepared in a conventional manner by using optically active starting materials or by racemate resolution, expediently with a de. customary auxiliary acids, such as. As optically active tartaric acid, dibenzoyltartaric acid, 3-8romcampher-8-sulfonic acid or mandelic acid. The starting materials required for the preparation of the compounds of the invention are commercially available or can be prepared by conventional methods.

The compounds of the invention can be converted in the usual way in their physiologically acceptable acid addition salts and esters. Examples of suitable acids for the preparation of the acid addition salts are hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, oxalic acid, lactic acid, tartaric acid and maleic acid. For the preparation of the ester can be z. As azyl halides such as acetyl chloride and butyryl chloride or Azylanhydride as Azetanhydrid use. Surprisingly, the compounds according to the invention showed superior pharmacological properties in animal experiments compared with the known P-receptor blockers oxprenolol, practolol, propranolol and talinolol. So z. For example, the compounds of the present invention stimulate and block to varying degrees the adrenergic β-receptors of the rabbit intestine. For the extent of the stimulatory effect, the pD ₂ values, ie the negative decadic logarithms of the concentrations which produce a half-maximal effect, and the blocking effect, the pA ₂ values were determined on the isolated rabbit jejunum, ie the negative decadic logarithms of the concentrations of the Test substances that cause the concentration of a stimulating substance to be pre-duplicated in order to achieve the original receptor stimulation. The determined pD ₂ and pA ₂ values are listed in the following table.

connection X2 Effect on the ß-receptors blockade 3-CI stimulation pA ₂ ± s Xi 4-CI pD ₂ ± s 7.83 ± 0.26 2-CI 5-CI 6.10 ± 0.49 - 2-CI 6-Cl 6.30 ± 0.34 7,39 + 0,10 2-CI 4-CI - - 2-CI 5-CI 6.26 ± 0.17 7.22 ± 0.06 3 cl 4-CI - 7.77 ± 0.49 3-CI 4-Br 6.49 ± 0.37 8.71 ± 0.33 2-Br 6.04 ± 0.24 7.86 ± 0.33 2-Br - 7.88 ± 0.35 oxprenolol 3.68 + 0.09 6.24 ± 0.17 practolol 3.19 ± 0.10 7.75 ± 0.62 propranolol - 6.89 ± 1.09 talinolol -

β = standard deviation.

The 2,4- and 2,6-dichloro derivative showed only stimulating effects on the β-receptors of the rabbit jejunum, whereas the 2,5 · and 3,4-dichloro derivative as well as the 2,4-dibroniderivate acted as pure β-receptor blockers. The 2,3- and 3,5-dichloro derivative as well as the 2-bromo-4-chloro derivative both combine pharmacological effects, advantageously in one molecule, i. According to the strength of sympathetic tone in the organism, these substances act as simulators or blockers.

The effects of the substituted in 2,3-, 2,4-, 2,5- and 3,4-substituted 1-dichlorophenoxy-3- (1,1-dimethyl-2-phenyl-ethylamino) -propan-2-ols on heart rate and blood pressure (bloodless / measurement) were studied on anesthetized Wistar rats. The animals were orally administered 12.5 mg, 25 mg and 50 mg test substance in an ethyl cellulose suspension per kg body weight. Initially, the substances caused an increase in heart rate, which lasted for about 20 minutes and followed by a heart rate reduction of 10-20 beats / min. The frequency-increasing effect was particularly pronounced in the 2,4-di-chloro derivative and averaged 40 beats / min. In contrast, the 3,4-dichloro derivative dominated the frequency-lowering effects, which amounted to a maximum of 45 beats / min. The effect on the blood pressure in the acute test corresponded to that of the known β-receptor blocker, z. As oxprenolol, propranolol, practolol and talinolol and was relatively low. The 2,4- and 2,5-dichloro derivatives indicated an increase of systolic blood pressure by 20-30mm Hg and of diastolic by 10-15mm Hg, while 12,5mg / kg of the 2,3-dichloro derivative had a weaker hypotensive effect.

By stimulating or blocking the adrenergic β-receptors, the compounds according to the invention have a cardiotonic or antihypertensive, antianginal, antiarrhythmic and cardioprotective action. They can therefore be used advantageously for the therapy and prophylaxis of cardiac insufficiency, hypertension, angina pectoris, cardiac arrhythmias, hyperkinetic heart syndrome and myocardial infarction. The compounds according to the invention can be brought into the usual pharmaceutical application forms such as tablets, dragees, capsules, solutions or depots. Daboi can use the usual pharmaceutical excipients and manufacturing methods. The therapeutic single doses of the compounds according to the invention are between 5-300 mg when given orally and between 1 and 50 mg when given intravenously.

Anfuhrungsbeispiele example 1

A mixture of 11 g of 1- (2,4-dichloro-phenoxy) -2.o-epoxypropane and 7.5 g of 1,1-dimethyl-2-phenyl-ethylamine is heated at 100 ° C for 5 hours. The resulting colorless oil is dissolved in ether and introduced dry hydrogen chloride. A precipitate forms which is filtered off with suction, washed with ether and recrystallised from dilute ethanol. The hydrochloride of 1- (2,4-dichloro-phenoxy) -3- (1,1-dimethyl-2-phenyl-ethylamino) -propan-2-ol is obtained as colorless crystals of mp. 14O-142 ° C. y. 12.4g! 61% d. Th.).

Example 2

7.9 g of 1- (2-bromo-4-chlorophenoxy) -2,3-epoxypropane and 4.5 g of 1,1-dimethyl-2-phenylethylamine are dissolved in 30 ml of isopropanol and heated under reflux for 20 hours. The isopropanol is distilled i. Vak. The residue is taken up in ether, the ethereal solution is dried over sodium sulphate and dry hydrogen chloride is introduced. The precipitate formed is sucked off and recrystallized from ethanol / ethyl acetate. The hydrochloride of 1- (2-bromo-4-chloro-phenoxy) -3 (1,1-dimethyl-2-phenyl-ethylamino) -propan-2-ol is obtained as a colorless, finely crystalline powder of mp. 147-150 ⁰ C. Ausb. 4.2 g (31%

Example.-)

7.0 g of 1- (2,4-dibromo-phenoxy) -2,3-θpoxypropanund3,7g1,1-dimethyl-2-phθnyl · θthylamin are heated to 100 ⁰ C for 20 hours. The reaction mixture is taken up in ether and introduced dry hydrogen chloride. The hydrochloride of 1- (2,4-dibromophenoxy) -3- (1,1-dimethyl-2-phenylethylamino) -2-ol precipitates as a white precipitate, is filtered off with suction and recrystallized from ethanol / ethyl acetate. Colorless, finely crystalline powder of mp. 93-95 ° C. Y. 4.4g (32% of theory).

Example 4

10.9 g of 1- (2,6-dichlorophenoxy) -2,3-epoxypropane and 7.5 g of 1,1-dimethyl-2-phenylethylamine are dissolved in 30 ml of ethyl acetate and heated under reflux for 16 hours. The reaction mixture is evaporated, the residue taken up in ether and the solution washed with water. Subsequently, the ethereal solution is dried over sodium sulfate, filtered off and evaporated. This gives the 1- (2,6-dichloro-phenoxy) -3- (1,1-dimethyl-2-phenyl-ethylamino) -propan-2-ol as a colorless oil, which solidifies after prolonged standing to give colorless crystals, the be recrystallized in ethanol. M.p. 118-12O ⁰ C. Ext. 8.4 g (46% of theory).

Example 5

A mixture of 2,6p 1- (2,3-dichlorophenoxy) -3-chloropropan-2-ol, 3.0 g of 1,1-dimethyl-2-phonyl-ethylamine and 20 ml of ethanol is refluxed for 15 hours heated. Subsequently, the solvent i.Vak. distilled off and the residue, as described below / Example 2, worked up. This gives the hydrochloride of 1- (2,3-dichloro-phenoxy) -3- (1,1-dimethyl-2-phenylethyla; nino) propan-2-ol as colorless crystals of melting point 177-179 ⁰ C.. y. 3.2 g (78% of theory).

Example β

5.1 g of 1- (2,5-dichlorophenoxy) -3-chloropropan-2-ol and 6.0 g of 1,1-dimethyl-2-phenyl-ethylamine are dissolved in 50 ml of ethyl acetate and refluxed for 15 hours heated. The ethyl acetate is i.Vak. distilled off and the residue, as described in Example 2, worked up. The hydrochloride of 1- (2,5-dichloro-phenoxy) -3- (1,1-dimethyl-2-phenyl-ethylamino) -propan-2-ol is obtained as a colorless, finely crystalline powder of mp. 95-97 ⁰ C. Ausb. 4.2 g (52% of theory).

Example 7

8.2 g of 3,4-dichlorophenol and 2.0 g of sodium hydroxide are dissolved in 150 ml of ethanol, 12.7 g of 1,2-Rpcxy-3- (1,1-dimethyl-2-phenylethyl-amino) -propane was added, the reaction mixture 8 Heated for hours and then the ethanol i.Vak. distilled off. The residue is taken up in chloroform, extracted with water and the organic phase dried over sodium sulfate. The solution is added to the double-charged amount of ether, introduced dry hydrogen chloride and the precipitate formed is filtered off with suction. After recrystallization from ethanol / ethyl acetate, the hydrochloride of 1- (3,4-dichlorophenoxy) -3- (1,1-dimethyl-2-phenylethylamino) -propan-2-ol was obtained as colorless crystals of mp 18 & -187 ⁰ C. Yield 7.4 g (37% of theory).

Example 8

8.2 g of 3,5-dichlorophonol and 4.0 g of sodium hydroxide are dissolved in 60 ml of ethanol and 10 ml of water, 14.9 g of 1-chloro-3- (1,1-dimethyl-2-phenylethylamino) -propan-2-one ol-hydrochloride was added and the mixture heated under reflux for 6 hours. Subsequently, c * is reaction mixture i.Vak. evaporated to dryness and the residue, as described in Example 7, further processed. The hydrochloride of 1- (3,5-dichloro-phenoxy) -3- (1,1-dimethyl-2-phenyl-ethylamine) -propan-2-ol is obtained as a colorless, finely crystalline powder of mp. 159-160 ⁰ C. Ausb. 6.8 g (34% of theory).

Claims (1)

-1- 298 506 1. A process for the preparation of halogen-substituted 1-phenoxy-3-alkylamino-propan-2-ols, their esters and acid addition salts, characterized in that 1-dihalogenophenoxy-3- (1,1-dimethyl-2-phenyl-ethylamino) -propane -2-ols, their esters and acid addition salts of the general formula (JH CH - GH ₂ - IiH - in which Xi, X _{2 represent} halogen atoms by reacting 1-dihalogenophenoxy-2,3-epoxypropane with 1,1-dimethyl-2-phenyl-ethylamine or 1-dihalogenophenoxy-3-halogenopropan-2-ol with 1,1-dimethyl 2-phenyl-ethylamine or dihalo-phenol with 1-halo-3- (1,1-dimethyl-2-phenylethylamino) -propane or dihalo-phenol with 1-halo-3- (1,1-dimethyl-2-phenyl-ethylamino) -propan-2-ol are prepared and the resulting compounds are then converted by reaction with suitable auxiliary acids in their diastereomeric salts and the latter zufönnt. 2. The method according to claim 1, characterized in that optically active starting materials are used. Field of application of the invention The invention relates to a process for the preparation of halogen-substituted 1-phenoxy-3-alkylaminc-propan-2-ols, their esters and acid addition salts. These compounds stimulate and block the adrenergic β-receptors to varying degrees and thereby have cardiotonic, antihypertensive, antianginal, antiarrhythmic, cardioprotective and central effects. They can therefore be used advantageously for the therapy and prophylaxis of various diseases of the cardiovascular system, preferably of cardiac insufficiency, hypertension, angina, myocardial infarction, cardiac arrhythmias and hyperkinetic heart syndrome. Field of application of the invention is the pharmaceutical industry. Characteristic of the (known technical solutions Halo-substituted 1-phenoxy-3-alkylamino-propan-2-ols have already been prepared. Thus, in JA 52053829, DT 2259489, DL153682 and DL 204248, halogen-containing 1-phenoxy-3- (3,4-dimethoxy-β-phenethylamino) -propan-2-ols are described. In GB 1269776 the preparation of optically active 1-phenoxy-3-alkylamino-propan-2-ols from a substituted phenol and an optically active epoxide or halohydrin is listed. The patents BE 783086, DT 2503222, NL 7017367 and NL 7500209 describe the preparation of p-phenoxy-3-alkylamino-propan-2-ols via the azetidinol derivatives. Object of the invention The aim of the invention is to develop a process for the preparation of novel compounds of halogen-substituted i-phenoxy-3-alkylaminopropan-2-oO, which are used by the pharmaceutical industry as potential cardiovascular drugs. Explanation of the essence of the invention The invention has for its object to provide a process for the preparation of novel compounds of halogen-substituted 1-phenoxy-3-alkylamino-propan-2-olezu. These compounds should be characterized by pronounced stimulating and blocking effects on the adrenergic β-receptors and have such pharmacological properties over the known β-receptor blockers that are used to improve the current drug therapy of cardiovascular diseases. This object is achieved in that acidic and optically active 1-Dihalogenphenoxy-i - (1,1-dimethyl-2-phenyl-ethylamino) -propan-2-ols, their esters and acid addition salts of the general formula