CH637107A5 - Process for preparing novel 1-aryloxy-2-hydroxy-3-aminopropanes - Google Patents

Abstract

Novel compounds of the formula I are prepared by reacting correspondingly substituted phenols or their alkali metal salts, with compounds of the formula III. The symbols in the formulae I and III have the meaning given in the patent claim. The compounds of the formula I, and their physiologically tolerated acid addition salts, have valuable therapeutic properties, in particular beta -adrenolytic, ô 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.

3rd

637 107

OH [

/

R "

OCH2 - CH - CH2 "N

\

(I),

R '

wherein

R1 and R1 'are identical or different and are hydrogen, an alkyl or alkoxy radical with 1-4 C atoms, the allyl

represent a group, a halogen atom or the nitro group,

R2 is an acrylic acid residue or acrylonitrile residue of the formulas

R "

{

C.

R

I.

C.

C.

II o

- OR

respectively.

R5 R6

- C = C - CN

in which

R5 is hydrogen, a Q-Cs-alkyl radical, an aryl or aryl-lower alkyl radical which is unsubstituted or substituted by lower alkyl or alkoxy,

R6 is hydrogen or an alkyl radical with 1-8 C atoms, R7 is hydrogen, a lower alkyl or an aryl-lower alkyl radical,

R3 and R4 together with the nitrogen atom represent a heterocyclic ring with 5-7 members, optionally substituted with C1-C4-alkyl, in which one carbon atom can be replaced by an oxygen, sulfur atom or a further nitrogen atom, the latter being substituted with an alkyl, alkoxy, oxalkyl, acyl or carbalkoxy radical each having 1-5 C atoms, a pyridyl radical or a phenyl radical, which in turn can be substituted one or more times by the hydroxyl group, halogen or an alkyl or alkoxy radical with 1-4 carbon atoms, or

R3 is hydrogen and

R4 is a phenylalkyl radical of the formula

25th

R

2nd

OH

(II)

R

35 where

R1, R1 'and R2 have the meaning given for the formula I, or one of its alkali metal salts with a compound of the formula III

40

X - CH_ - CH - CH_ - N

/ \

.R ~

(III)

45

OH

R

mean where n is a number from 1 to 3 and

R8 and R9 are the same or different and are hydrogen, an alkoxy radical having 1-3 carbon atoms or the benzyloxy radical or

R8 and R9 together represent the bismethylene dioxy radical, as well as their physiologically compatible acid addition salts.

The above formula includes both the racemic mixtures and the individual optically active isomers.

The process according to the invention for the preparation of compounds of the formula I is characterized in that a phenol of the formula II

wherein

R3 and R4 have the meaning given for formula I and

X represents a halogen atom, the sulfuric acid or a sulfonic acid residue, is reacted in the presence of an acid-binding agent and, if appropriate, the compounds obtained are converted into the physiologically tolerable acid addition salts.

Of the substituents mentioned, the following are preferred: For R4 (if R3 = H): dialkoxyphenylethyl radicals, in particular the 5 ', 4'-dimethoxyphenylethyl radical and the 1-methyl-2-3', 4'-dimethoxyphenylethyl radical.

60 If R3 and R4 together with the nitrogen atom form a heterocyclic ring, preferred ring systems are those with 5 or 6 members, e.g. Pyrrolidine, piperidine and morpholine, which can be substituted once or twice with the lower alkyl radical or with the pyridyl radical. 65 The piperazine ring, which can be substituted on the second nitrogen atom with an alkyl, alkoxy, oxalkyl or acyl group with 1-4 C atoms, with a carbalkoxy group with 1-5 C atoms, with a pyri-

637 107

dyl radical or with an optionally substituted phenyl radical.

For Rs: hydrogen, an unbranched alkyl radical with 1-4 C atoms, in particular the methyl, ethyl and phenyl radical.

For R6: hydrogen, an alkyl radical with 1-4 C atoms.

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

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

The phenol of formula II can also be used in the form of its alkali metal salt, such as sodium or potassium salt. L-Halogen-2-hydroxy-3-alkylaminopropanes are used as reaction components of the formula III. One can also start from sulfuric acid or sulfonic acid esters of 1,2-dihydroxy-3-alkylaminopropanes. The reaction is advantageously carried out in the presence of an acid-binding agent, such as alkali metal hydroxide. In an alkaline medium, the l-halo-2-hydroxy-3-alkylamino-propane used can pass into the corresponding 1,2-epoxypropane, which reacts with the phenol. The reaction can be carried out in the presence or absence of solvents such as e.g. Alcohols, e.g. Methanol, ethanol, isopropanol, aromatic solvents such as benzene, toluene or ether, such as dioxane, tetrahydrofuran or carboxamides, especially dimethylformamide, are generally carried out at normal temperature or at an elevated temperature up to the boiling point of the solvent used. The compounds of formula III used as starting materials are, for example, by reacting an amine of the formula

/ r3

accessible with epichlorohydrin at low temperatures.

The following can be used as such amines:

1. Primary amines, such as. B .:

Phenylethylamine, 3-phenylpropylamine, 1-phenylethylamine, l-methyl-2-phenylethylamine, l-methyl-2- (4-meth-oxy) phenylethylamine, 1-methyl-2- (3rd , 4-dimethoxy) phenylethylamine, 3,4-dimethoxyphenylethylamine, 3-methoxy-4-ethoxyphenylethylamine, 3-methoxy-4-hydroxyphenylethylamine, 3-methoxy-4-benzyloxyphenylethylamine, 3- Benzyloxy-4-methoxyphenylethylamine, 3,4-methylenedioxyphenylethylamine, 2,5-dimethoxyphenylethylamine, 2,4-dimethoxyphenylethylamine, 2,3-dimethoxyphenylethylamine, 3,4,5-trimethoxyphenylethylamine, 2-methoxyphenylethylamine, 3-methoxyphenylethylamine, 4-methoxyphenylethylamine, 3,4-dimethoxyphenylmethylamine, 2-hydroxy-2-phenylethylamine, l-methyl-2-hydroxy-2-phenylethylamine, 3, 4-dimethylphenylethylamine, 4-chlorophenylethylamine, 3,4-di-chlorophenylethylamine, 4-hydroxyphenylethylamine. The use of homoveratrylamine has proven to be particularly advantageous.

2. 5- to membered cyclic secondary amines such as: N-phenylpiperazine, N-2'-methylphenylpiperazine, N-3'-methylphenylpiperazine, N-4'-methylphenylpiperazine, N-2'-methoxyphenylpiperazine, N-3 ' -Methoxyphenylpiperazine, N-4'-methoxyphenylpiperazine, N-2'-chlorophenylpiperazine, N-3'-chlorophenylpiperazine, N-4'-chlorophenylpiperazine, N-2'-pyridylpiperazine, N-3'-pyridylpiperazine, N-4'- Pyridylpiperazine, N-2'-hydroxyphenylpiperazine, N-3'-hydroxyphe-

nylpiperazin, N-4'-Hydroxyphenylpiperazin, N-Oxyäthylpi-perazin, N-Methylpiperazin, N-Äthylpiperazin, N-Carbme-thoxypiperazin, N-Carbäthoxypiperazin, N-Carb- (2-hydro-xy-2-methyl) -propoxypiperazin , 2-methylpiperazine, 2,6-dimethylpiperazine, 2,6-dimethylpiperidine, 3-ß-pyridylpiperidine, piperidine, morpholine, and pyrrolidine.

In the process according to the invention, it can sometimes be advantageous to combine the preparation of the starting compounds directly with the further reaction, i.e. not to isolate the raw materials separately.

The process products can be obtained as the 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 which may be mentioned are: acetic acid, malonic acid, propionic acid, lactic acid, succinic acid, tartaric acid, maleic acid, fumaric acid, citric acid, malic acid, benzoic acid, salicylic acid, oxyethanesulfonic acid, acetic acid, ethylenediaminetetraacetic acid, embonic acid and synthetic groups containing acidic acid.

Examples of suitable inorganic acids are:

Hydrohalic acids such as hydrochloric acid or hydrobromic acid, sulfuric acid, phosphoric acid 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 (-) - Ditoluyltartaric acid, (+) - and (-) - mandelic acid, (+) - and (-) - camphoric acid, (+) - camphor-ß-sulphonic acid, (+) - a-bromocampher-a-sulphonic acid and N- (p-Ni-trobenzoyl) - (+) - ghitamic 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 crystals. 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 tolerable acid addition salts have shown valuable therapeutic, in particular ß-adrenolytic, ßI-adrenolytic 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, to Be4

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

637 107

treatment of cardiac arrhythmias and for the treatment of high blood pressure in human medicine.

The following should be emphasized in particular:

The compounds of formula I, in which R4, when R3 = H, means a phenylalkyl radical, are shown in particular by a therapeutically favorable split between the β1 and β2 receptor blocking action, the β2 receptors not being blocked. E.g. shows <D, L> -3- <4- (3-2 *, 6 * -Di-methylpiperidino-2-hydroxypropoxy) -phenyl> -croton-acrylonitrile hydrochloride a much stronger ßj-sympathetic-thicolytic (in the absence of ß2 -sympathicolytic) effect than the already known l - [(3,4-dimethoxyphen-ethyl) -amino-3-aryloxy-2-propanols, such as the l - [(3,4-dimethoxyphenothyl) amino-3- (m-tolyloxy) -2-propanolhydrochloride (M.L. Hoefle et al., J. Med. Chem. 18 [1975]

148).

The process products can be administered orally in the form of the free bases or their physiologically tolerable salts

Forms of tablets or dragées, optionally mixed with standard pharmaceutical carriers and / or stabilizers or parenterally in the form of solutions in ampoules. Suitable carriers for tablets are, for example, milk sugar, starch, tragacanth and / or magnesium stearate.

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

A therapeutically desirable long-lasting significant reduction in blood pressure with little or no ß-receptor blockade is shown by the compounds of For-i5 mei I, in which R3 together with R4 and the N atom represent a heterocycle, such as the unsubstituted or substituted on the second N atom Represent piperazino, piperidino or morpholine residue.

A solution of 2.3 g of sodium in 25 ml of ethanol is added to 14.5 g of m-cumaronitrile in 25 ml of ethanol with stirring.

After the addition of 25.5 g of 1 -2 * methoxyphenyl-4- (2-hydroxy-3-chloropropyl) piperazine, the reaction mixture is heated to 65 ° with further stirring. After stirring for 3 hours, the ethanol is distilled off in vacuo and the distillation residue is taken up in methylene chloride and washed with dilute sodium hydroxide solution and water. After drying over sodium sulfate, the extract is evaporated to dryness, dissolved in the just sufficient amount of ethanol and adjusted to a pH of 2 to 2.5 with hydrochloric acid. Then 51 is added to water and extracted several times with toluene.

Then the clear aqueous phase with conc. Soda solution made alkaline and finally extracted exhaustively with toluene / ethyl acetate. The combined organic extracts are evaporated to dryness in vacuo and the crude free base is dissolved in 50 ml of ethanol

example

<D, L> -3- <3- (3-N-2 * -methoxyphenyl-piperazino-2-hydroxy-propoxy) -phenyl> -acrylonitrile-dihydrochloride and adjusted to pH 4 by dropwise addition of concentrated hydrochloric acid and then evaporated to dryness in vacuo. By repeated evaporation i.V. The distillation residue is dried with toluene and then recrystallized from a little ethanol and ether and then again from ethanol. It was dissolved in 12.5 g of 30 <D, L> -3- <3- (3-N-2 * -methoxyphenyl-piperazino-2-hydroxy-propoxy) -phenyl> -acrylonitrile dihydrochloride of Schm. 210 ° C (dec.) Transferred.

The 1-2 * methoxy-phenyl-4- (2-hydroxy-3-chloropropyl) piperazine used as the starting material can be obtained as follows.

A solution of 9.2 g of epichlorohydrin and 19.2 g of 2 * methoxyphenylpiperazine in 60 ml of diisopropyl ether are stirred at 35-40 ° for 30 hours. Then the solvent i.V. evaporated and the resulting crystals recrystallized from isopropanol / hexane. 23.4 g of l-2 * methoxyphenyl-4- (2-hydroxy-3-chloropropyl) piperazine with a melting point of 104-105 ° are obtained.

Claims (2)

637 107 2nd PATENT CLAIM Process for the preparation of new compounds of formula I. OCH. OH I. / R " CH - CH2 - N \ (I), R ' in which represent a group, a halogen atom or the nitro group, R1 and R1 'are the same or different and are hydrogen, R2 is an acrylic acid residue or acrylonitrile residue which is an alkyl or alkoxy residue with 1-4 C atoms, the allyl formulas R- - C = C - C - OR ' II o R5 R6 or - C = C - CN in which R5 is hydrogen, a C 1 -C 5 -alkyl radical, an aryl or aryl-lower alkyl radical which is unsubstituted or substituted by lower alkyl or alkoxy, R6 is hydrogen or an alkyl radical with 1-8 C atoms, R7 is hydrogen, a lower alkyl or an aryl-lower alkyl radical, R3 and R4 together with the nitrogen atom represent a heterocyclic ring with 5-7 members, optionally substituted with Cj-C4-alkyl, in which one carbon atom can be replaced by an oxygen, sulfur atom or another nitrogen atom, the latter being substituted with an alkyl, alkoxy, oxalkyl, acyl or carbalkoxy radical each having 1-5 C atoms, a pyridyl radical or a phenyl radical, which in turn can be substituted one or more times by the hydroxyl group, halogen or an alkyl or alkoxy radical with 1-4 carbon atoms, or R3 is hydrogen and R4 is a phenylalkyl radical of the formula (CH2> n mean where n is a number from 1 to 3 and R8 and R9 are the same or different and are hydrogen, an alkoxy radical having 1-3 carbon atoms or the benzyloxy radical or R8 and R9 together represent the bismethylene dioxy radical, and of their physiologically tolerable acid addition salts, characterized in that a phenol of the formula II R V 35 (II) 3 R 40 wherein R1, R1 'and R2 have the meaning given for the formula I, or one of its alkali metal salts with a compound of the formula III 45 R ~ X - CH_ - CH - CH., - N 50 OH / \. (HI) 3 R wherein R3 and R4 have the meaning given for the formula I, 55 and X represent a halogen atom, the sulfuric acid or a sulphonic acid residue, reacted in the presence of an acid-binding agent and, if appropriate, the compounds obtained are converted into the physiologically tolerable acid addition salts. 60 65