CH637109A5 - Process for preparing novel 1-aryloxy-2-hydroxy-3-aminopropanes - Google Patents

Abstract

Novel compounds of the formula I are prepared by hydrolysing compounds of the formula II. The symbols in the formulae I and II have the meaning given in the patent claim. The compounds of formula I, and their physiologically tolerated acid addition salts, have valuable therapeutic properties, in particular beta -adrenolytic, beta 1-adrenolytic and/or hypotensive and/or antiarrhythmic properties. <IMAGE>

Description

The present invention relates to a process for the preparation of new basic substituted phenol ethers of the formula I.

0 N - R

wherein R1, R1 ', R2 and R4 have the meaning given for formula I, and Z represents a carbonyl group or a 60 methylene group optionally substituted with a phenyl group or one or two lower alkyl radicals, hydrolyzed, and the compounds obtained optionally in the physiologically tolerable acid addition salts transferred.

Of the substituents mentioned, the following are preferred:

For R4: dialkoxyphenylethyl radicals, in particular the 5 ', 4'-65 dimethoxyphenylethyl and the l-methyl-2-3', 4'-dimethoxyphenylethyl radical.

For Rs: hydrogen, an unbranched alkyl radical having 1 to 4 carbon atoms, in particular the methyl, ethyl and phenyl radical.

3rd

637 109

For R6: hydrogen, an alkyl radical with 1 to 4 carbon atoms.

For R7: an alkyl radical with 1 to 4 carbon atoms, in particular the methyl, ethyl and tert-butyl radical and the benzyl radical.

For R1 and R1 ': hydrogen, alkyl and alkoxy radicals with 1 to 3 carbon atoms, fluorine, chlorine and the nitro group.

Such oxazolidones of the formula II can be obtained, for example, if corresponding l-amino-2-hydroxy-3- (phenoxy) propane is reacted with a reactive derivative of carbonic acid, such as diethyl carbonate, chlorinated carbonic acid methyl ester or phosgene, or if one is optionally reacted in 3 Position correspondingly substituted 5-hydroxymethyloxazolidone (2) in the form of a hydrohalic acid, sulfuric acid or sulfonic acid ester with a corresponding alkali phenolate. Suitable oxazolidines can be e.g. produce by reacting corresponding 1-amino-2-hydroxy-3-phenoxypropanes of the formula with aldehydes or ketones. Oxazolidones or oxazolidines which are not substituted on the nitrogen atom can be alkylated with compounds of the formula X — R4. The hydrolysis of these oxazolide or oxazolidine derivatives can be carried out in an acidic or alkaline medium, for example by means of dilute hydrochloric acid, dilute sulfuric acid, dilute sodium hydroxide solution or dilute potassium hydroxide solution. It is advantageous to heat to accelerate the hydrolysis. The hydrolysis can also be carried out in the presence of water-soluble solvents, e.g. lower alcohols.

The process products can be obtained as a free base or in the form of their salts and, if necessary, can be purified by the customary workup methods, for example by recrystallization or, if appropriate, conversion to the free base and subsequent treatment with a suitable acid. The process products can, if appropriate, be converted into the salts of physiologically compatible organic or inorganic acids.

Examples of organic acids are:

Vinegar, malonic, propionic, milk, amber, wine, maleic, fumaric, lemon, apple, benzoic, salicylic, oxyethanesulfonic, acetic, ethylenediaminetetraacetic, embonic and acidic Synthetic resins containing groups.

Examples of suitable inorganic acids are: hydrogen halide, such as hydrogen chloride or hydrogen bromide, sulfuric, phosphoric and amidosulfonic acid.

The optically active isomers of the racemic, basic substituted phenol ethers of the formula I can be obtained if the latter are broken down into their components using optically active acids.

Examples of acids which can be used for the production of optically active salts are: (+) - and (-) - tartaric acid, (+) - and (-) - dibenzoyltartaric acid, (+) - and (- ) -Ditoluyl-tartaric acid, (+) - and (-) - mandelic acid, (+) - and (-) - camphoric acid, (+) - camphor-ß-sulfonic acid, (-t -) - a-bromo- camphor-a-sulfonic acid and N- (p-nitrobenzoyl) - (+) -glutamic acid. The optically active salts can be prepared in water, water-containing or water-free organic solvents. The use of alcohols or esters of organic carboxylic acids has proven to be advantageous.

To prepare optically active compounds, the racemate of the base can be reacted in a solvent, preferably in molar proportions, with an optically active acid and the optically active salt of the compounds of the formula I can be isolated. In certain cases, it is also possible to use only half an equivalent of the optically active acid in order to remove the one optically active antipode from the racemate, just as one can also use excess amounts of optically active acid.

Depending on the type of optically active acid, the desired antipode can be obtained either directly or from the mother liquor of the first crystal lisate. The optically active base can then be released from the salt in a conventional manner and this optically active base can be converted into a salt of one of the physiologically compatible organic or inorganic acids mentioned.

The compounds of formula I or their physiologically compatible acid addition salts have shown valuable therapeutic, in particular ß-adrenolytic, ß, -adreno-lytic, and / or hypotensive and / or antiarrhythmic properties in animal experiments on dogs and can therefore be used, for example, for the treatment or prophylaxis of Diseases of the coronary arteries, for the treatment of cardiac arrhythmias and for the treatment of high blood pressure in human medicine.

The following should be emphasized in particular: A therapeutically favorable split between βr and β2-receptor blocking action, the β2-receptors not being blocked, is shown in particular by the compounds of the formula I in which R4 is a phenylalkyl radical. E.g. shows [D, L] -3- [4- (3-2 *, 6 * -Dimethyl-piperidino-2-hydroxypropoxy) phenyl] crotonitrile hydrochloride a much stronger ßj-sympathicolytic (in the absence of ß2-sympathicolytic) effect than the already known l - [(3,4-Dimethoxyphenäthyl) amino-3-aryloxy-2-propanols such as the 1 - [(3,4-dimethoxyphenothyl) amino-3- (m-tolyloxy) -2-propanol hydrochloride [M.L. Hoefle et al., "J. Med. Chem. ", 18 (1975), 148].

The process products can be administered in the form of the free bases or their salts orally in the form of tablets or dragees, optionally mixed with pharmaceutically customary carriers and / or stabilizers or parenterally in the form of solutions in ampoules. Milk sugar, starch, tragacanth and / or magnesium stearate, for example, are suitable as carrier substances for tablets.

For injection purposes, a dosage of 2-20 mg is generally suitable, while the oral dosage is generally between 6 and 150 mg: a single tablet or a tablet can usually contain about 5 to 50 mg of active ingredient.

The compounds of formula I, in which R3 together with R4 and the N atom show a heterocycle, such as the unsubstituted or on the second N atom, show a therapeutically desirable long-lasting significant reduction in blood pressure with little or no ß-receptor blockade represent substituted piperazino, piperidino or morpholino.

example

0.32 g of Na are dissolved in 6 ml of anhydrous glycol monoethyl ether in a nitrogen atmosphere. Then 3.5 g of 5- (pl * -methyl-2 * -cyanovinylphenoxymethyl) -2-oxazolidone and 3.4 g of I-bromo-2-3 *, 4 * -dimethoxyphenylethane are stirred in and then with exclusion of moisture and under nitrogen 1 Heated to boiling for zi h. Then it is slightly acidified with a little glacial acetic acid and the reaction mixture is freed from solvent in vacuo. The distillation residue is taken up in 25 ml of methanol and, after the addition of 0.60 g of sodium hydroxide in 2 ml of water, refluxed for 30 minutes. It is then dissolved in 50 ml of ethanol and adjusted to pH 4 by dropwise addition of concentrated hydrochloric acid and then evaporated to dryness in vacuo. The distillation residue is dried by repeated evaporation in vacuo with toluene and then recrystallized from a little ethanol and ether and then again from ethanol.

2.1 g of [D, L] -3- [4- (3 *, 4 * -dimethoxyphenylethylamino-2-hydroxypropoxy) phenyl] crotonic acid nitrile hydrochloride, mp. 148-149 'C.

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Claims (3)

637 109 2nd PATENT CLAIM Process for the preparation of new compounds of formula I. OH I OCH_ - CH - CH. - N OCH "- OH I CH / IT - CH "- N (I) \ P. wherein R1 and R1 'are the same or different and represent hydrogen, an alkyl or alkoxy radical having 1 to 4 carbon atoms, the allyl group, a halogen atom or the nitro group, R2 is an acrylic acid residue or acrylonitrile residue of the formulas wherein R1 and R1' are the same or are different and represent hydrogen, an alkyl or alkoxy radical having 1 to 4 carbon atoms, the allyl group, a halogen atom or the nitro group, R2 is an acrylic acid residue or acrylonitrile residue of the formulas R5 R6 -C = C R5 R6 OR7 or C - CN R5 R6 I I -c = c - c II O R5 R6 I I OR7 or -C = C - CN O in which R5 is hydrogen, a C 1 -C 4 -alkyl radical, an unsubstituted or substituted with lower alkyl or alkoxy aryl or aryl-lower alkyl radical, R6 hydrogen or an alkyl radical with 1 to 8 C atoms, R7 hydrogen, a lower alkyl or represent an aryl-lower alkyl radical, R3 is hydrogen and R4 is a phenylalkyl radical of the formula (CVn in which n is a number from 1 to 3 and R8 and R9 are identical or different and are hydrogen, an alkoxy radical having 1 to 3 carbon atoms or the benzyloxy radical, or R8 and R9 together represent the bismethylene dioxy radical, as well as their physiologically tolerable acid addition salts, characterized in that a compound of formula II in which Rs is hydrogen, a C to Cs alkyl radical, an unsubstituted or substituted with lower alkyl or alkoxy aryl or aryl lower alkyl radical, R6 hydrogen or an alkyl radical with 1 to 8 C atoms, R7 hydrogen, a lower alkyl or represent an aryl-lower alkyl radical, R3 is hydrogen and R4 is a phenylalkyl radical of the formula > 8 30th - (CH2> n, in which n is a number from 1 to 3, and R8 and R9 are identical or different and are hydrogen, an alkoxy radical having 1 to 3 carbon atoms or the benzyloxy radical, or Rs and R9 together are the bismethylene dioxy radical represent 40 and their physiologically tolerable acid addition salts. The above formula includes both the racemic mixtures and the individual optically active isomers. The process according to the invention for producing Verbin-45 fertilizers of the formula I is characterized in that a compound of the formula II 1 ' 1 ^ CH, CH CH. 0 N - R wherein R1, R1 ', R2 and R4 have the meaning given for the formula I, and Z represents a carbonyl group or a methylene group which is optionally substituted by a phenyl group or one or two lower alkyl radicals, hydrolyzed, and the compounds obtained are converted, if appropriate, into the physiologically tolerated acid addition salts . CH, CH CH, (Ii) 1]