NO167974B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE AMINOPROPANOLE DERIVATIVES OF 3- (2-HYDROXYPHENYL) -1-PROPANONE COMPOUNDS. - Google Patents

Description

The present invention relates to the production of new, therapeutically active aminopropanol derivatives of 3-(2-hydroxy-phenyl)-1-propanone compounds of the general formula I and physiologically acceptable acid addition salts thereof.

German Patent No. 2,001,431 describes 2-(2'-hydroxy-3'-alkylamlnopropoxy)-p<->phenyl-propiophenones of the general formula:

and their acid addition salts. Although these compounds and their salts constitute pharmaceutical compounds, only the n-propylamino compound (propafenone) shows anti-arrhythmic activity.

EP-A-0 074 014 describes 2-[2'-hydroxy-3'-(1,1-dimethylpropylamino)-propoxy]-p<->phenyl-propiophenone (dipraphenone) and its acid addition salts. Diprafenone is an anti-arrhythmic drug.

EP-A-0 075 207 describes aminopropanol derivatives of the general formula:

and its physiologically acceptable acid addition salts. Typical examples of R<1> to R<4> include hydrogen atoms and alkyl groups and n has a value of 1, 2 or 3. These compounds are pharmaceutical preparations.

The purpose of the invention is to provide new aminopropanol derivatives of 3-(2-hydroxyphenyl)-l-propanone compounds of the general formula I and physiologically acceptable acid addition salts which are distinguished by a significantly improved anti-arrhythmic activity compared to that of propaphenol and without a corresponding increase in toxicity. The compounds and their acid addition salts can be used in the preparation of pharmaceutical preparations suitable for the treatment of heart rhythm irregularities.

The invention relates to the preparation of new aminopropanol derivatives of 3-(2-hydroxyphenyl)-1-propanone compounds of the general formula I:

where

R<1> and R<2> are the same or different and represent hydrogen atoms, alkyl, cycloalkyl or hydroxyalkyl groups of up to 6 carbon atoms or alkoxyalkyl of up to 9 carbon atoms, or

R<1> and R<2> together with the nitrogen atom that connects them form a morpholine, piperidine or piperazine ring which may optionally be substituted with an alkyl group with 1 to 3 carbon atoms,

r<3> stands for a hydrogen atom, an alkoxy group with up to 6 carbon atoms,

R4 stands for a hydrogen atom, an alkyl group containing up to 3 carbon atoms or an alkoxy group with up to 6 carbon atoms, and n is an integer from 1 to 5, and acid addition salts thereof.

The most preferred compounds include 1-(3,4-dimethoxyphenyl)-3-[2'-(2-hydroxy-3-n-propylaminopropoxy)-phenyl]-1-propanone hydrochloride, (Example 1), 1-(3- methoxyphenyl)-3-[2'-(2-hydroxy-3-isopropylamino-propoxy)-phenyl]-1-propanone hydrochloride, (Example 24), 1-phenyl-3-[2'-(2-hydroxy-3- piperidino-propoxy)-phenyl]-1-propanone hydrochloride, (Example 47).

The compounds of the general formula I and their acid addition salts are prepared according to the invention by reacting a phenol ether of the general formula II: where R<3>, R<4> and n have the meanings given above, with an amine of the general formula (III):

where R<1> and R<2> have the meanings given above and, if applicable, conversion of the resulting compound with an acid to an acid addition salt.

The possible conversion of a compound of general formula I into an acid addition salt can e.g. carried out by the method described in European patent no. 0 074 014.

The reaction is carried out at temperatures varying from 10<*> to 120°C, i.e. at room temperature or at higher temperatures, preferably at temperatures varying from 50<*>to 120°C, at atmospheric pressure or in a closed container at elevated pressure.

The starting compounds of general formulas II and III can be reacted without diluents or solvents. However, the reaction is preferably carried out in the presence of a neutral diluent or solvent, such as a lower alcohol containing 1 to 4 carbon atoms, e.g. methanol, ethanol or propanol, preferably isopropanol or ethanol, a lower saturated dialkyl ether, dialkyl glycol ether or cyclic ether, such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, a benzene hydrocarbon, such as benzene itself or an alkylbenzene, especially toluene or xylene , or an aliphatic hydrocarbon, such as hexane, heptane or octane, dimethylsulfoxide or in the presence of water or mixtures of said solvents.

When used in excess, the amine of the general formula III can also be a suitable diluent or solvent.

The completeness of the reaction depends on the reaction temperature and is generally achieved within 2 to 15 hours. The reaction product can be obtained in a conventional manner, e.g. by filtering or distilling the diluent from the reaction mixture. The obtained compound is purified in the usual way, e.g. by recrystallization from a solvent, conversion to an acid addition salt or by column chromatography.

The phenol ether of general formula II can be obtained by alkylating 2-hydroxy-e-phenylpropiophenone having the general formula where R<3>, R<4> and n have the above meaning with an epihalohydrin. Examples of epihalohydrins are epichlorohydrin, epibromohydrin and epiiodohydrin.

The reaction of the compounds IV to produce the starting compounds of general formula II is carried out rapidly at temperatures varying from 0<*> to 120<*>C and normal pressure or in a closed container at elevated pressure. Suitable solvents or diluents are a lower aliphatic ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, a lower alcohol containing 1 to 4 carbon atoms, such as methanol, ethanol, propanol or butanol, a lower aliphatic or cyclic ether, such as diethyl ether, tetrahydrofuran or dloxane, a dialkylformamide, such as dimethylformamide or diethylformamide, or dimethylsulfoxide or hexamethylphosphoric triamide or an excess of the alkylating agent.

The reaction is preferably carried out in the presence of a base as an acid-binding agent. Suitable bases are alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal hydrides or alkali metal alcoholates, especially those of sodium and potassium, basic oxides, such as aluminum oxide or calcium oxide, organic tertiary bases, such as pyridine, lower trialkylamines, such as trimethylamine or triethylamine, or piperidine. The bases can be used in catalytic or stoichiometric amounts or in a slight excess with respect to the alkylating agent used.

2-Hydroxy-p-phenylpropiophenone is preferably reacted with epichlorohydrin or epibromohydrin in a polar, aprotic solvent, especially dimethylsulfoxide, at temperatures varying from 0 to 50° C, in the presence of at least one molar equivalent of base, especially sodium hydride, based on the alkylating agent.

The starting compound of the general formula IV, i.e. 2-hydroxy-e-phenylpropiophenone, and its preparation are known. The compound of formula I obtained according to the invention is optionally converted to an acid addition salt, preferably to a salt of a physiologically acceptable acid. Common physiologically acceptable inorganic or organic acids are e.g. hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and benzoic acid. Other suitable acids are e.g. described in "Fortschritte der Arzneimittel-forschung", volume 10, pages 224-225, Birkhauser publishers, Basel and Stuttgart, 1966, and Journal of Pharmaceutical Sciences, volume 66, pages 1-5 (1977). Hydrochloric acid is preferred.

The acid addition salts are normally obtained in a conventional manner by mixing the free base or its solution with the corresponding acid or its solution in an organic solvent, e.g. a lower alcohol, such as methanol, ethanol, n-propanol or isopropanol, or a lower ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, or an ether such as diethyl ether, tetrahydrofuran or dioxane.

Mixtures of the mentioned solvents can also be used for better crystal deposition. Furthermore, pharmaceutically acceptable aqueous solutions of acid addition salts of the compound of formula I can be prepared in an aqueous acid solution.

The acid addition salts of the compound of formula I can be converted to the free base by a method known per se, e.g. with alkali compounds or ion exchangers. Additional salts can be obtained from the free base by reaction with inorganic or organic acids, especially with those suitable for the formation of therapeutically useful salts. These and other salts of the new compound, such as the plcrate, can also be used for purification of the free base in which the free base is converted into a salt which is separated and the base is released again from the salt.

The pharmaceutical preparations containing compounds of formula I are prepared in a conventional manner with the usual solid or liquid carriers or diluents and the conventional pharmaceutical adjuvants in a suitable dosage form depending on the desired route of administration. The most advantageous preparations are preparations in dosage unit form for oral administration. Such pharmaceutical forms are e.g. tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions or depot preparations.

Parenteral preparations, such as injection solutions, are of course also suitable. Another pharmaceutical form that can be mentioned is e.g. suppositories.

Corresponding tablets can be obtained e.g. by mixing the active ingredient with known excipients, e.g. with inert diluents, such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc and/or agents to achieve a depot effect , such as carboxy-polymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets may comprise several layers.

Dragees can be prepared similarly by coating cores which are prepared analogously to the tablets with preparations that are usually used in dragee coatings, such as polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. The dragee shell can also consist of several layers, in which the excipients mentioned above in the compounds with the tablets can be used.

Solutions or suspensions including the active ingredient of formula I may additionally contain flavoring substances, such as saccharin, cyclamate or sugar and e.g. aromatic substances, such as vanilla or orange extract. Furthermore, they may contain suspension aids, such as sodium carboxymethyl cellulose or preservatives, such as p-hydroxybenzoates. Capsules containing the active ingredient can e.g. is prepared by mixing the active ingredient with an inert carrier, such as lactose or sorbitol, and encapsulating it in gelatin capsules.

Suitable suppositories can e.g. are prepared by mixing the active ingredient with corresponding carriers, such as neutral fatty types or polyethylene glycol or their derivatives.

For humans is a single dose

from 0.5 to 5 mg/kg for oral administration,

from 0.05 to 2 mg/kg for intravenous administration,

from 0.1 to 3 mg/kg for intramuscular administration,

from 0.5 to 10 mg/kg for rectal administration.

In particular, the anti-arrhythmic and the β<->sympatholytic properties of the compounds of formula I and their physiologically acceptable acid addition salts make them particularly suitable for the pharmacotherapy of disease states of the heart rhythm, the treatment of heart disease and the prevention of sudden death due to heart disease. The anti-arrhythmic effect of the compounds prepared according to the invention was established both by electro-physiological studies on dog heart Purkinje fibers and by means of an ouabain-induced ventricular tachycardia in dogs.

In the following tables (I) and (II), the compounds of formula I are compared with propafenone (A).

The effect on the contraction strength of the heart was measured on the papillary muscle in guinea pigs. Haemodynamic examinations were carried out both on healthy dogs and on dogs with acute infarction. An important criterion in table (I) which follows is the safety factor (S.F.), as calculated from the relationship between the anti-arrhythmic effect, the negative inotropy and the specifically greater effect at higher frequencies according to the formula: rate factor for Vmax x (C20CF/ C20 Vmax). By comparison, it is recorded that today's leading antiarrhythmic agents propafenone and flecanidine have an S.F. of 1.5 and 1.7 respectively.

As a further criterion, the prematurity factor was established. This characterizes the desired effect of the compounds produced according to the invention in premature extrasystoles.

The high anti-arrhythmic effect is not accompanied by a significant increase in toxicity compared to propafenone (A) as can be seen from a comparison of the LDsg values in rats and mice summarized in Table II. The invention shall be illustrated by means of the following examples.

A) Preparation of the starting compounds:

Example I 1-(3,4-dimethoxyphenyl)-3-[2'-(1,2-epoxy-3-propoxy)-phenyl]-1-propanone 275.4 g (0.96 mol) of 3,4 -dimethoxy-β-2'-hydroxyphenylpropiophenone is heated under reflux for 5 hours with 600 ml of epichlorohydrin, 300 ml of 2-propanol and 38.5 g (0.97 mol) of sodium hydroxide and stirred. The resulting salt is filtered off and the remaining solution is evaporated under reduced pressure. The oily residue is used without purification in the next step. Yield: 334.2 g (100S6) of the title compound. The following compounds were prepared in the same manner: 1 -(3,4,5-trimethoxyphenyl)-3-[2'-(1,2-epoxy-3-propoxy)-phenyl]-1-propanone 1-(3, 4,5-trimethoxyphenyl)--3-[2'-(1,2-epoxy-3-propoxy)-phenyl]-1-propanone 1 -(2,4,6-trimethoxyphenyl)-3-[2'- (1,2-epoxy-3-propoxy)-phenyl]-1-propanone 1-phenyl-3-[2'-(1,2-epoxy-3-propoxy)-4'-methoxy phenyl]-1- propanone l-(3-methoxyphenyl)-3-[2'-(1,2-epoxy-3-propoxy)-phenyl]-l-propanone l-(4-methoxyphenyl)-3-[2'-(1 ,2-epoxy-3-propoxy)-phenyl]-1-propanone 1-(2-methoxyphenyl )-3-[2 *-(1,2-epoxy-3-propoxy )-phenyl]-1-propanone 1- ( 4-methylphenyl)-3-[2'-(1,2-epoxy-3-propoxy)-phenyl]-1-propanone 1-phenyl-3-[2'-(1,2-epoxy-3-propoxy )-phenyl]-1-propanone B) Preparation of the compounds of formula I: Example 1

1-(3,4-dimethoxyphenyl)-3-[2'-(2-hydroxy-3-n-propylaminopropoxy)-phenyl]-1-propanone hydrochloride i d

11.3 g (0.033 mol) of 1-(3,4-dimethoxyphenyl)-3-[2<*->(1,2-epoxy-3-propoxy)-phenyl]-1-propanone and 5.9 g (0.099 mol) of n-propylamine was dissolved in 100 ml of methanol and heated for 3.5 hours under reflux. The solvent and excess amine are removed under reduced pressure. The oily residue is dissolved in 150 ml of isopropanol, and the concentrated hydrochloric acid is added. After heating and cooling the solution, crystals are obtained which are removed, dried and recrystallized from isopropanol. Yield: 8.2 g ($56) of the title compound, m.p. 126°C.

The following compounds were prepared in the same manner (Examples 2 to 49): 2. 1-(3,4-dimethoxyphenyl)-3-[2'-(2-hydroxy-3-tert.-pentylaminopropoxy)-phenyl]-1- propanone hydrochloride, m.p. 151-152°C. 3. 1-(3,4-dimethoxyphenyl)-3-[2'-(2-hydroxy-3-morpholino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 150-151'C. 4. 1-(3,4-dimethoxyphenyl)-3-[2'-(2-hydroxy-3-isopropyl-aminopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 135-136°C. 5. 1-(3,4-dimethoxyphenyl)-3-[2'-(2-hydroxy-3-tert-butylaminopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 164-165°C. 6. 1-(3,4-dimethoxyphenyl)-3-[2'-(2-hydroxy-3-piperidino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 124-125°C. 7. 1-(3,4-dimethoxyphenyl)-3-[2'-(2-hydroxy-3-(2"-hydroxy-propylamino)-propoxy)-phenyl]-1-propanone hydrochloride, mp 109-111° C. 8. 1-(3,4-dimethoxyphenyl)-3-[2»-(2-hydroxy-3-(2"-hydroxy-ethylamino)-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 146-147.5°C. 9. 1-(3,4-dimethoxyphenyl)-3-[2'-(2-hydroxy-3-(1"-hydroxy-but-2-ylamino)-propoxy)-phenyl]-1-propanone oxalate, m.p. 195-197° C. 10. 1-(3,4,5-trimethoxyphenyl)-3-[2'-(2-hydroxy-3-tert-pentylaminopropoxy)-phenyl]-1-propanone hydrochloride, mp 179- 180° C. 11. 1 -(3,4,5-trimethoxyphenyl)-3-[2'-(2-hydroxy-3-n-propylaminopropoxy)-phenyl]-1-propanone hydrochloride, mp 140-142°C 12. 1-(3»4,5-trimethoxyphenyl)-3-[2'-(2-hydroxy-3-isopropyl-aminopropoxy)-phenyl]-1-propanone hydrochloride, mp 161-162°C. 13. 1-(3,4,5-triMethoxyphenyl)-3-[2'-(2-hydroxy-3-tert-butylaminopropoxy)-phenyl]-1-propanone hydrochloride, mp 178.5-179.5°C. 14. 1-(3,4,5-trimethoxyphenyl)-3-[2'-(2-hydroxy-3-piperidinopropoxy)-phenyl]-1-propanone hydrochloride, mp 148.5-150°C. 15. 1-(3,4,5-trimethoxyphenyl)-3-[2'-(2-hydroxy-3-morpho-linopropoxy)-phenyl]-1-propanone hydrochloride, mp 166.5-167.5°C 16. 1-(3,4,5-trimethoxyphenyl)-3-[2'-(2-hydroxy-3-cyclohex-ylaminopropoxy)-phenyl]-1-propanone hydrochloride, mp 158.5-159.5° C. 17. 1-( 3 , 4, 5-trimethylphenyl)-3-[2'-(2-hydroxy-3-piperidino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 133-134°C. 18. 1-(2,4,6-trimethylphenyl)-3-[2'-(2-hydroxy-3-n-propyl-aminopropoxy)-phenyl]-1-propanone oxalate, m.p. 184-185'C. 19. 1-(2,4,6-trimethylphenyl)-3-[2'-(2-hydroxy-3-tert.-butylaminopropoxy)-phenyl]-1-propanone oxalate, m.p. 148-150<*>C. 20. 1-(2,4,6-trimethylphenyl)-3-[2'-(2-hydroxy-3-tert.-pentylaminopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 118-120'C. 21. 1-(2,4,6-trimethylphenyl)-3-[2'-(2-hydroxy-3-isopropyl-aminopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 111-112°C. 22. 1-(2,4,6-trimethylphenyl)-3-[2*-(2-hydroxy-3-morpholino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 132-133°C. 23. 1-phenyl-3-[2'-(2-hydroxy-3-tert.-pentylaminopropoxy)-4'-methoxyphenyl]-1-propanone oxalate, m.p. 118-120°C. 24 . 1-(3-methoxyphenyl)-3-[2'-(2-hydroxy-3-isopropylamino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 109.5°C. 25. 1-(3-Methoxyphenyl)-3-[2'-(2-hydroxy-3-tert.-pentyl-aminopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 113.5°C. 26. 1-(3-Methoxyphenyl)-3-[2'-(2-hydroxy-3-n-propylamino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 105.5°C. 27. 1-(3-Methoxyphenyl)-3-[2'-(2-hydroxy-3-tert-butylamino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 110-111°C. 28. 1-(3-Methoxyphenyl)-3-[2'-(2-hydroxy-3-morpholinopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 124.5"C. 29. 1-(4-Methoxyphenyl)-3-[2'-(2-hydroxy-3-tert.-pentyl-aminopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 114.5 -115.5° C. 30. 1-(4-Methoxyphenyl)-3-[2*-(2-hydroxy-3-piperidinopropoxy)-phenyl]-1-propanone hydrochloride, mp 151<*>C 31. 1-(4-methoxyphenyl)-3-[2'-(2-hydroxy-3-n-propylamino-propoxy)-phenyl]-1-propanone hydrochloride, mp 115.5-116.5°C 32. 1-(4-Methoxyphenyl)-3-[2*-(2-hydroxy-3-tert-butylamino-propoxy)-phenyl]-1-propanone hydrochloride, mp 142-143°C. 33. l -(2-methoxyphenyl)-3-[2'-(2-hydroxy-3-isopropylamino-propoxy)-phenyl]-1-propanone hydrochloride, mp 147-148° C. 34. 1-(2-methoxyphenyl) -3-[2'-(2-hydroxy-3-tert.-pentyl-aminopropoxy)-phenyl]-1-propanone hydrochloride, mp 146-149'C. 35. 1-(2-methoxyphenyl)-3- [2 * - ( 2-Hydroxy-3-piperidinopropoxy)-phenyl]-1-propanone hydrochloride, mp 107.5-109.5<*>C. 36. 1-(2-Methoxyphenyl)-3-[ 2'-(2-hydroxy-3-(4"-methyl-1"-piperazinyl)-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 172-175°C. 37. 1-(2-methoxyphenyl )-3-[2'-(2-hydroxy-3-n-propylamino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 125-128"C. 38. 1-(2-Methoxyphenyl)-3-[2'-(2-hydroxy-3-tert-butylamino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 145-147° C. 39. 1-(2-Methoxyphenyl)-3-[2'-(2-hydroxy-3-morpholinopropoxy)-phenyl]-1-propanone hydrochloride, mp 94-96<*>C. 40. l -(4-methoxyphenyl)-3-[2'-(2-hydroxy-3-isopropylamino-propoxy)-phenyl]-1-propanone hydrochloride, mp 126.5-128.5<*>C. 41. l -(4-Methoxyphenyl)-3-[2'-(2-hydroxy-3-cyclothiexylamino-propoxy)-phenyl]-1-propanone hydrochloride, mp 154-156<*>C. 42. 1-(4-Methoxyphenyl )-3-[2'-(2-hydroxy-3-tert.-pentyl-aminopropoxy )-phenyl]-1-propanone hydrochloride , mp 120.5-121.5<*>C. 43. l-( 4-Methoxyphenyl)-3-[2*-(2-hydroxy-3-propylaminopropoxy)-phenyl]-1-propanone hydrochloride, mp 109-111° C. 44. 1-(4-Methoxyphenyl)-3 -[2*-(2-hydroxy-3-tert-butylamino-propoxy)-phenyl]-1-propanone hydrochloride, mp 132.5-133.5° C. 45. 1-phenyl-3-[2' -(2-hydroxy-3-isopropylaminopropoxy)-phenyl]-1-propanone hydrochloride, mp 85-90° C. 46. 1-phenyl-3-[2'-(2-hydroxy-3-cyclohexylaminop ropoxy)-phenyl]-1-propanone hydrochloride, m.p. 137-140°C. 47. 1-phenyl-3-[2'-(2-hydroxy-3-piperidinopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 132-133°C. 48. 1-phenyl-3-[2'-(2-hydroxy-3-tert-butylaminopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 108-109°C. 49. 1-Phenyl-3-[2'-(2-hydroxy-3-(3"-methoxypropylamino)-propoxy)-phenyl]-1-propanone hydrochloride, mp 114-116°C.

Claims (4)

1. Analogous process for the preparation of therapeutically active aminopropanol derivatives of 3-(2-hydroxyphenyl)-1-propanone compounds with the general formula (I): where R<1>and R<2>are the same or different and represent hydrogen atoms, alkyl, cycloalkyl or hydroxyalkyl groups of up to 6 carbon atoms or alkoxyalkyl of up to 9 carbon atoms, or R<*>and R<2> together form with the nitrogen atom connecting them a morpholine, piperidine or piperazine ring which may optionally be substituted with an alkyl group with 1 to 3 carbon atoms, R<3> stands for a hydrogen atom, an alkoxy group with up to 6 carbon atoms, R4 stands for a hydrogen atom, an alkyl group containing up to 3 carbon atoms or an alkoxy group with up to 6 carbon atoms, and n is an integer from 1 to 5, and acid addition salts thereof, characterized in that it includes reaction of a phenol ether of general formula (II): where R 3 , R 4 and n have the meanings given above, with an amine of general formula (III): where R<*> and R<2> have the meanings given above and, if applicable, conversion of the resulting compound with an acid to an acid addition salt. 2. Process according to claim 1 for the production of 1-(3,4-dimethoxyphenyl)-3-[2'-(2-hydroxy-3-n-propylaminopropoxy)-phenyl]-1-propanone hydrochloride, characterized in that corresponding starting materials are used. 3. Process according to claim 1 for the production of 1-(3-methoxyphenyl)-3-[2'-(2-hydroxy-3-isopropylaminopropoxy)-phenyl]-1-propanone hydrochloride, characterized in that corresponding starting materials are used. 4. Process according to claim 1 for the production of 1-phenyl-3-[2*-(2-hydroxy-3-piperidinopropoxy)-phenyl]-1-propanone hydrochloride, characterized in that corresponding starting materials are used.