DD271701A5 - PROCESS FOR PREPARING AMINO-PROPANOL DERIVATIVES OF 3- (2-HYDRO-XYPHENYL) -1-PROPANONE COMPOUNDS AND THEIR SAEUREADDITIONAL SALTS - Google Patents

Abstract

The invention relates to a process for the preparation of aminopropanol derivatives of 3- (2-hydroxyphenyl) -1-propanone compounds of general formula I in which the radicals have the meaning given in the invention. These compounds are antiarrhythmic drugs.

Description

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Title of the invention:

¹¹ Process for the preparation of Aminopropanolderivater of 3- (2-hydroxyphenyl) -1-propanone compounds and their acid addition salts "15

Field of application of the invention;

The application of the present invention is in the field of drugs for the control of cardiac arrhythmias, for the treatment of coronary heart disease and for the prevention of sudden cardiac death.

Characteristic of the known state of the art:

From DE-PS 2 001 431 is a process for the preparation of 2- (2'-hydroxy-3'-alkylaminopropoxy) -ß-phenylpropiophenone of the general formula 30th

and their acid addition salts known. The n-propylamino compounds

27 I 7Of

Binding (propafenone) shows an antiarrhythmic activity. EP-AO 074 014 discloses 2- [2 ¹ -hydroxy-3 '- (1,1-dimethylpropylamino) -propoxy] -β-phenyl-propiophenone (diprafenone) and its acid addition salts. Furthermore, from EP-A 0 075 207 aminopropanol derivatives of the formula

and their salts are known.

4 Typical examples of Ri-R are hydrogen atoms ν'.d alkyl radicals. η has a value of 1, 2 or 3.

Object of the invention:

The aim of the invention is to provide new drugs for the treatment of cardiac arrhythmias, treatment of coronary heart disease and for the prevention of sudden cardiac death available.

Explanation of the essence of the invention

The invention has for its object to provide new drugs for combating cardiac arrhythmias, for the treatment of coronary heart disease and for the prevention of sudden cardiac death available.

The invention relates to a process for the preparation of novel aminopropanol derivatives of 3- (2-hydroxyphenyl) -1-propanone compounds of general formula I.

0-CH ₂ -Ch-CH _n -NR R and their acid addition salts.

Rf /

(I)

1 "2

CH, .- CH _O -CO- '' I 2

< , 2 OH

1 2

In the general formula I, R and R are identical or different and denote hydrogen atoms, alkyl- / cycloalkyl-,! 0 alkenyl, alkynyl or hydroxyalkyl radicals each having up to 6 C atoms, alkoxyalkyl, alkylthioalkyl or dialkylaminoalkyl radicals each having up to to 9 carbon atoms, or Phenylalkyl '' or Pehnoxyalkylreste having up to 6 C atoms in the alkyl moiety, where appropriate, the phenyl radical is substituted by an alkyl or alkoxy radical each having up to 3 carbon atoms, or

1 2

R and R, together with the nitrogen atom connecting them, form a 5- to 7-membered saturated heterocyclic ring which may optionally be substituted by one or two phenyl and / or hydroxyl radicals and may contain an oxygen atom or nitrogen atom as further heteroatom in the ring the additional nitrogen atom may be substituted by an alkyl radical having 1 to 3 C atoms or a phenyl radical. R is a hydrogen atom, an alkyl radical having up to 3 C atoms, a fluorine, chlorine or bromine atom, a hydroxyl group or an alkoxy group

with up to 6 carbon atoms. R is a hydrogen atom, an alkyl radical having up to 3 C atoms, a fluorine, chlorine or bromine atom, a hydroxyl group or an alkoxy group having up to 6 C atoms. η is an integer from 1 to 5.

1 2 Preference is given to compounds in which NR R is a tert-pentylamino, n-propylamino, 1,1-dimethylpropylamino, morpholino, isopropylamino, tert-butylamino, pyrrolidino, piperidino, or cyclohexylaminocarbon is, the rest R a what

Is hydroxyl group,

4 R a water

group is, and

the radical R is a hydrogen atom, a methyl, methoxy or y <

4 R is a hydrogen atom, a methyl, methoxy or hydroxyl

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η is 1, 2 or 3.

1 Particularly preferred are compounds; where NR R is a

n-propylamino, isopropylamino, tert.-eutylamino, or ^n- piperidino group, the radical R ° is a hydrogen atom,

4 R is a hydrogen atom, or a methoxy group, and η is 1, 2 or 3.

Most preferred are 1- (3,4-dimethoxyphenyl) -3- [2 '- (2-hydrox.

droxv-3-n-DroDvlamiriODroDoxv) -DhenvIII-1-propanone hydrochloride, (Example 1)

1- (3-Methoxy-phenyl-9-3- [2-hydroxy-S-isopropyl-prop-J5-oxy) -phenyl] -1-propanone hydrochloride, (Example 24)

1-Phenyl-3- [2 ¹ - (2-hydroxy-3-piperidino-propoxy) -phenyl] -1-propanone hydrochloride, (Example 47).

27 1 70t

The process according to the invention for the preparation of the compounds of general formula I and their acid addition salts is characterized in that a phenol ether of general formula II

O-CH ₂ -CH-CH ₂ O

with an amine of general formula III

HNR ¹ R ² (III)

implements.

 ι 2 3 4

R ', R, R and R have the meanings given above. Optionally, the compound of the general formula I * 0 common obtained is converted with an acid into an acid addition salt. The reaction can be carried out, for example, by the process described in EP-PS 0 074 014.

The reaction is carried out at temperatures of 10 to 120'QC, i. at

Room temperature or at elevated temperatures, suitably carried out at temperatures of 50 to 1200C, under atmospheric pressure or in a closed vessel under elevated pressure.

The starting compounds of the formula II and III can be reacted without diluent or solvent. Conveniently, however, the reactions are carried out in the presence

2 7 f 7 O I

j an inert diluent or solvent, for example a lower alcohol having 1 to 4 carbon atoms, such as methanol, ethanol or propanol, preferably isopropanol or ethanol, a lower saturated dialkyl ether, Dialkylglykoläthers or cyclic ether, such as diethyl ether, 1,2-dimethoxyethane , Tetrahydrofuran or dioxane, a benzene hydrocarbon, such as benzene itself or an alkylbenzenes, especially toluene or xylene, or an aliphatic hydrocarbon, such as hexane, heptane or octane, dimethyl sulfoxide or in the presence of water or mixtures of said solvents.

Also, the amine of general formula III used in excess amount is optionally suitable as a diluent or solvent.

The complete reaction depends on the reaction temperature and is generally completed within 2 to 15 hours. The reaction product can be obtained in a conventional manner, for example by filtration or distilling off the diluent from the reaction mixture. A.e. purification of the compound obtained in the usual manner, for example by recrystallization from a solvent, converted into an acid addition salt or by column chromatography.

The phenol ether of the general formula II can by alkylation of a 2-hydroxy-ß-phenylpropiophenons of the general formula IV 30

with an epihalogenhyorin.

.Γ ¹⁰ "

3 4 R, R and η are as defined above.

As Epihalogenhydrine come epichlorohydrin, epibromohydrin and

Epiiodohydrin into consideration

 5

The reaction of the compounds IV for the preparation of the starting compounds of the general formula II is expediently carried out at from 0 to 120 ° C. and under normal pressure or in a closed vessel under elevated pressure. When

* 0 solvent or diluent are suitably a lower aliphatic ketone such as acetone, methyl ethyl ketone or Methy1- _m isobutyl ketone, a lower alcohol having 1 to 4 carbon atoms, such as methanol, ethanol, propanol or butanol, a lower aliphatic or cyclic ether, such as diethyl ether, tetra-

hydrofuran or dioxane, a dialkylformamide such as dimethylformamide or diethylformamide, or dimethylsulfoxide or hexamethylphosphoric triamide or excess alkylating agent.

The reactions are preferably carried out in the presence of a base as an acid-binding agent. Suitable bases are alkali metal carbonates, bicarbonates ,. hydroxides, hydrides or alcoholates, in particular of sodium and potassium, basic oxides, such as aluminum oxide or calcium oxide, organic

* ° Tertiary bases, such as pyridine, lower trialkylamines, such as trimethyl or triethylamine, or piperidine, The bases can be used in relation to the alkylating agent used in a catalytic amount or in a stoichiometric amount or in slight excess. This is preferred

2-hydroxy-.beta.-phenylpropiophenone with epichlorohydrin or epibromohydrin '· in a polar, aprotic solvents, especially dimethyl sulfoxide, in the presence of at least one molar equivalent of base, in particular sodium hydride, bezoqen on the alkylating agent, at temperatures of 0 to 50 ⁰ C environmentally

set.

2 7 ί> Οί

The starting compound of general formula IV, i. 2-hydroxy-β-phenylpropiophenone, and its preparation is known.

Optionally, the compound of the general formula I prepared according to the invention is converted into an acid addition salt, preferably into a salt of a physiologically tolerated acid, customary physiologically compatible inorganic and organic acids are, for example, hydrochloric acid, bromine water.

hydrochloric, phosphoric, sulfuric, oxalic, maleic, fumaric, lactic, tartaric, malic, citric, salicylic, adipic and benzoic acids. Other acids which can be used are described z, B. in Advances in Drug Research, Vol. 10, pp. 224-225, Birkhäuser Verlag, Basel and Stuttgart, 1966 and Journal of Pharmaceutical Sciences, Vol. 66, pp. 1-5 (1977). Preference is given to hydrochloric acid.

The acid addition salts are generally known per se in

By mixing the free base or its solutions with the appropriate acid or its solutions in an organic solvent, for example a lower alcohol such as methanol. Ethanol, n-propanol or isopropanol, or a lower ketone such as acetone, methyl ether ketone or methyl

isobutyl ketone, or an ether such as diethyl ether, tetrahydrofuran or dioxane. For better Kristallabscheidunq also mixtures of said solvents can be used. In addition, pharmaceutically acceptable aqueous solutions of acid addition compounds of the compound

of the formula I are prepared in an aqueous acid solution.

The acid addition salts of the compound of the formula I can be prepared in a manner known per se, e.g. with alkalis or ion exchangers are converted into the free base. From the 35th

Free bases can be prepared by reaction with inorganic or organic acids, in particular those which are used to form

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therapeutically useful salts are suitable to win more salts. These or other salts of the new compound, such as. e.g. The picrate can also serve to purify the free base by converting the free base to a salt, separating it, and releasing the base again from the salt.

The compounds according to the invention can be administered orally, rectally, intravenously.

The compounds prepared according to the invention and their physiologically tolerated acid addition salts are especially useful for their antiarrhythmic and β-sympatholytic properties, in particular for the pharmacotherapy of cardiac arrhythmias for the treatment of coronary heart disease and

¹ ^ Prophylaxis of sudden cardiac death suitable. The antiarrhythmic activity of the compounds according to the invention was determined both on the basis of electrophysiological studies on Purkinje fibers from dog hearts and with the aid of ouabain-induced ventricular tachycardias in dogs.

The compounds prepared according to the invention are compared in the following Tables I and II with propafenone (A).

The effect on the contraction force of the heart was examined on guinea pig papillary muscle. Haemodynamic studies have been performed in healthy as well as acutely infarcted dogs. In the following Table I the safety factor (S.F.) is shown as an important criterion

QQ results from the ratio of antiarrhythmic efficacy (lead delay C20 Vmax) to negative inotropy (C20 CF) and the specific stronger efficacy at higher frequencies (rate factor of Vmax). By way of comparison, it should be mentioned that the currently leading antiarrhythmics propafenone and flecainide have an SF of 1.5 and 1.7, respectively.

27 f 7Of

~ 13 -

As an additional criterion, the prematurity index (prematurity factor) was determined, which characterizes the desired activity of the compounds according to the invention in premature extrasystoles. The high antiarrhythmic efficacy is not accompanied by a significant increase in toxicity compared to propafenone. This results from a comparison of the LD _5Q values in rats and mice, which are summarized in Table II.

Table I

No of example C20 CF (μΜ) C20 Vmax (μΜ) Rate factor of Vmax Prematurity factor Vmax S. F. 1 15.0 12.5 5.00 0.50 6.0 2 8.0 3.6 " 1.27 1.15 , 2.8 4 22.0 4.8 1.13 1.01 5.2 5 12.0 4.4 1.39 0.98 3.8 6 20.0 11.3 1.32 0.70 2.3 7 18.0 5.7 1.39 0.98 4.4 8th 13.0 8.3 1.34 0.97 2.1 9 25.0 10.2 1.30 0.97 3.2 12 18.0 5.8 1.14 0.90 3.5 16 9.0 11.9 5.00 0.50 3.8 24 10.0 1.6 1.15 1.01 7.2 26 3.0 1.7 1,1 6 0.93 2.1 27 4.0 1.6 0.99 1.24 2.5 38 7.0 1.7 1.30 0.97 5.4 44 6.0 2.6 1.11 0.99 2.6 46 2.0 2.2 2.50 0.92 2.3 47 2.0 0.3 1.08 0.99 7.2 48 3.0 1.0 1.18 0.91 3.5 A 5.3 3.7 1.08 0.97 1.5

C20 CF: Concentration that reduces contraction of the papillary muscle by 20 %

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C20 Vmax: concentration, the Vmax at a cycle length of 1000 msec.,

reduced by 20 %

Rate factor (% of control value Vmax at a cycle length of 2000) / (% of control value Vmax at a cycle length of 500) at C20 Vmax

Prematurity (% of control value Vmax for premature extra factor Vmax: systole) / (% of control value Vmax for normal -

beat) at Vmax

S.F .: Safety factor, calculated as rate factor of Vmax * (C20 CF / C20 Vmax).

^LD 50 Table II Mouse, i.v. test compound (Mg / kg) 18 16 17 15 A Example 1 Example 38 Rat i.V. EXAMPLES 16 17 15 20

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'-hydroxyphenyl-propiophenone with 600 ml of epichlorohydrin, 300 ml of 2-propanol and 38.5 g (0.97 mol) of sodium hydroxide for 5 hours under Refluxed and stirred. The resulting salt is filtered off and the solution is concentrated to dryness under reduced pressure. The oily residue is used without purification in the next stage. Yield: 334.2 g (100%) of the title compound.

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The following compounds were prepared by analogy with 15:

1- (3,4,5-trimethoxyphenyl) -3- [2'- (1,2-epoxy-3-propoxy) -phenyl] -1-propanone 1- (3,4,5-trimethylphenyl) -3- [2 * - (1,2-epoxy-3-propoxy) phenyl] -

1-propanone 1- (2,4,6-trimethylphenyl) -3- [2 '- (1,2-epoxy-3-propoxy) -phenyl] -1-propanone

1-phenyl-3- [2 '- (1,2-epoxy-3-propoxy) -4'-methoxyphenyl] -1-propanone

1- (3-methoxyphenyl) -3- [2'- (1,2-epoxy-3-propoxy) -phenyl] -1.

Propanone 1- (i-Methoxyphenyl) -3- [2 '- (1,2-epoxy-3-propoxy) -o-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 20

B) Preparation of the compounds of general formula 1

example 1

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

11.3 g (0.033 mol) of 1- (3,4-dimethoxyphenyl) -3- [2 '- (1,1-epoxy-3-propoxy) -phenyl] -1-propanone and 5.9 g (0.099 mol) n-Propylamine are dissolved in 100 ml of methanol and heated under reflux for 3 1/2 h. The solvent ^and the excess amine are removed under reduced pressure. The oily residue is dissolved in 150 ml of isopropanol and treated with concentrated hydrochloric acid. After heating and cooling the solution, crystals are obtained which are filtered off with suction, dried and recrystallized from isopropanol. Yield 8.2 g (56%) of the title compound, mp. 126 ° C.

-16 were prepared analogously (Examples 2 to 49).

2. 1- (3,4-Dimethoxyphenyl) -3- [2 · - (2-hydroxy-3-tert-pentylamino-propoxy) -phenyl] -1-propanone hydrochloride, m.p .: 151-152 ° C ,

3. 1- (3,4-dimethoxyphenyl) -3- [2 '- (2-hydroxy-3-morpholinopropoxy) -phenyl] -1-propanone hydrochloride,

Mp: 150-151 ⁰ C. 10

4. 1- (3,4-Dimethoxyphenyl) -3- [2 ¹ - (2-hydroxy-3-isoptophenylaminopropoxy) phenyl] -1-propanone hydrochloride, m.p .: 135-13 ° C.

5. 1- (3,4-Dimethoxyphenyl) -3- [2 '- (2-hydroxy-3-tert-butylamino-propoxy) -phenyl] -1-propanone hydrochloride, m.p .: 164-165 ° C ,

6. 1- (3,4-Dimethoxyphenyl) -3- (2 '- (2-hydroxy-3-piperidino- * Qpropoxy) -phenyl] -1-propanone hydrochloride, m.p. 12 <- 125 ^O C.

7. 1- (3,4-Dimethoxyphenyl) -3- [2 '- (2-hydroxy-3- (2''-hydroxypropylamino) -propoxy) -phenyl] -1-propanone hydrochloride, m.p .: 109- 111 ⁰ C.

8. 1- (3,4-dimethoxyphenyl) -3- [2 • - (2-hydroxy-3 - ('2 "-hydroxyethylamino) -propoxy) -phenyl] -1-propanone hydrochloride,

Mp .: 146 to 147.5 ⁰ C.

9. 1- (3,4-dimethoxyphenyl) -3- [2 '- (2-hydroxy-3- (1 "-hydroxybut-2-ylamino) -propoxy) -phenyl-1-propanone oxalate, m.p. : 195-197 ° C.

10. 1- (3,4,5-Trimethoxyphenyl) -3- [2 · - (2-hydroxy-3-tert-pentylamino-propoxy) -phenyl] -1-propanone hydrochloride, m.p .: 179-180 ⁰ C.

11. 1- (3,4,5-Trimethoxyphenyl) -3- [2 '- (2-hydroxy-3-n-propylamino-propoxy) -phenyl] -1-propanone hydrochloride, m.p .: 140-142 ° C.

12. 1- (3,4,5-trimethoxyphenyl) -3- [2 '- (2-hydroxy-3-isopropylaminopropoxy) -phenyl] -i-propanone hydrochloride / Fp .: 161-162 ⁰ C.

13. 1 - (3, 4, 5-Trimethoxyphenyl) -3- [2 '- (2-hydroxy-3-tert-butylamino-propoxy) -phenyl] -1-propanone hydrochloride, m.p .: 178.5 -179.5 ⁰ C.

14. 1- (3,4,5-Trimethoxyphenyl) -3- [2 '- (2-hydroxy-3-piperidinopropoxy) -phenyl] -1-propanone hydrochloride, m.p .: 148.5-150 ° C.

15. 1- (3,4,5-trimethoxyphenyl) -3- [2 · - (2-hydroxy-3-morpholinopropoxy) -phenyl] -1-propanone hydrochloride,

Mp: 166.5-167.5 ° C

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16. 1- (3, 4,5-trimethoxyphenyl) -3- [2 ¹ - (2-hydroxy-2-cyclohexyl-amino-propoxy) -phenyl] -1-propanone hydrochloride, m.p .: 158.5-159 , 5 ° C.

17. 1- (3,4,5-trimethylphenyl) -3- [2 '- (2-hydroxy-3-piperidinopropoxy) -phenyl] -1-propanone hydrochloride, m.p .: 133-134 ° C.

18. 1- (2,4,6-trimethylphenyl) -3- [2 - (2-hydroxy-3-n-propylaminopropoxy) -phenyl] -1-propanone oxalate, m.p .: 1S4-185 ^O C.

19. 1- (2,4,6-trimethylphenyl) -3- [2 '- (2-hydroxy-3-tert-butyl-amino-propoxy) -phenyl] -1-propanone oxalate, m.p .: 148 -150 ° C.

? 7 1 70 f

20. 1 - (2,4, 6-Trimethylpheny 1) -3- [2 '- (2-hydroxy-3-tert -pentylarainopropoxy.) -Phenyl] -1-propanone hydrochloride, m.p .: 118-120 ⁰ C.

21.! - (2,4,6-Trimethylphenyl) -3- [2 '- (2-hydroxy-3-J.sopropylaminopropoxy) phenyl] -1-propanone hydrochloride, m.p. 111-112 ° C.

22. 1- (2,4,6-trimethylphenyl) -3- [2 '- (2-hydroxy-3-morpholinopropoxy) -phenyl] -i-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 ⁰ C.

24. 1- (3-methoxyphenyl) -3- [2 '- (2-hydroxy-3 ~ isopropylaminopropoxy) -phenyl] -1-propanone hydrochloride, m.p .: 109.5 ⁰ C.

25. 1- (3-Methoxyphenyl) -3- [2 · - (2-hydroxy-3-tert-pentylaminopropoxy) phenyl] -1-propanone hydrochloride, m.p .: 113.5 ° C.

26 1- {3-methoxyphenyl) -3- [2 '- (2-hydroxy-3-n-propylaminopropoxy) -phenyl] -1-propanone hydrochloride, m.p .: 105.5 ⁰ C.

27. 1- (3-methoxyphenyl) -3- [2 * - (2-hydroxy-3-tert.-butylaminopropoxy) phenyl] -1-propanone hydrochloride, m.p .: 110-111 ⁰ 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-pentylaminopropoxy) phenyl] -i-propanone hydrochloride / m.p .: 114.5-115.5 ° C.

• ₅ 30. 1- (4-Methoxyphenyl) -3- [2 '- (2-hydroxy-3-piperidino-propoxy) -phenyl] -i-propanone hydrochloride, mp: 151C.

31. 1- (4-Methoxyphenyl) -3- [2 '- (2-hydroxy-3-n-propylaminopropoxy) -phony1] -1-propanone hydrochloride, m.p .: 115.5-116.5 ° C.

32. 1- (4-Methoxyphenyl) -3- [2 '- (2-hydroxy-3-tert-butylaminopropoxy) phenyl] -1-propanone hydrochloride, m.p .: 142-143 ° C.

33. 1- (2-methoxyphenyl) -3- [2 ¹ - (2-hydroxy-3-isopropylamino)

propoxy) -phenyl] -1-propanone hydrochloride, m.p .: 147-148 ° C.

34. 1- (2-Methoxyphenyl) -3- (2 ¹ - (2-hydroxy-3-tert-pentylaminopropoxy) -phenyl] -1-propanone hydrochloride, m.p .: 146-149 ° C.

35. 1- (2-methoxyphenyl) -3- [2 ¹ - (2-hydroxy-3-piperidinopropoxy) phenyl] -1-propanone hydrochloride, m.p .: 107.5 to 109.5 ⁰ 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-tert-butylaminopropoxy) -phenyl] -1-propanone hydrochloride, m.p .: 125-128 ° C.

38. 1- (2-Methoxyphenyl) -3- [2 '- (2-hydroxy-3-tert-butyl, n-butylaminopropoxy) phenyl] -i-propanone hydrochloride, m.p .: 145-147 ° C.

39. 1- (2-Methoxyphenyl) -3- [2 '- (2-hydroxy-3-morpholino-propoxy) phenyl] -1-propanone hydrochloride, m.p .: 94-96 ° C

40. 1- (4-Methylphenyl) -3- [2 '- (2-hydroxy-3-isopropylaminopropoxy) phenyl] -1-propanone hydrochloride, m.p .: 126.5-128.5 ° C.

1- (4-Methylphenyl) -3- [2'-U-hydroxy-S-cyclohexylaminopropoxy) phenyl] -1-propanone hydrochloride, m.p .: 154-156 ° C.

42. 1- (4-methylphenyl) -3- [2 '- (2-hydroxy-3-tert-pentylamino-propoxy) -phenyl] -1-propanone hydrochloride,

Mp .: 120.5 to 121.5 ⁰ C

 20

43. 1- (4-methylphenyl) -3- [2 ¹ - (2-hydroxy-3-n-propylaminopropoxy) -phenyl] -1-propanone hydrochloride, m.p .: 109-111 ⁰ C.

44. 1- (4-Methylphenyl) -3- [2 '- (2-hydroxy-3-tert-butylaminopropoxy) phenyl] -1-propanone hydrochloride, m.p .: 132.5-133.5 ° C ,

45. 1-Phenyl-3- [2 '- (2-hydroxy-3-isopropylamino-propoxy) -phenyl] -1-propanone hydrochloride, m.p. 85t.90 ° C.

46. 1-Phenyl-3- [2 '- (2-hydroxy-3-cyclohexylamino-propoxy) -phenyl] -1-propanone hydrochloride, m.p .: 137-140 ⁰ C.

27 170t

- 21 -

47. 1-Pheny1-3- [2 '- (2-hydroxy-3-piperidino-propoxy) -phenyl] -1-propanone hydrochloride, m.p .: 132-133 ° C.

48. i-phenyl-3- [2 ¹ - (2-hydroxy-3-tert-butylamino-propoxy) -phenyl] -1-propanone hydrochloride, m.p .: 103-109 ⁰ C.

49. 1-Phenyl-3- [2 ¹ - (2-hydroxy-3- (3 "-methoxypropylamino) -

propoxy) -phenyl] -i-gropanone hydrochloride, m.p .: 114-116 ° C.

Claims (1)

35 -vf - 2 claims 1. A process for the preparation of Arainopropanolderivaten of 3- (2-hydroxyphenyl) -1-propanone compounds of the general formula I. (I) 0-CH ₀ -CH-CH ₀ -NR R
2.2 OH 1 2 in which R and R are identical or different and are hydrogen atoms, alkyl, cycloalkyl, alkenyl, alkynyl or hydroxyalkyl radicals having in each case up to 6 C atoms, alkoxyalkyl, alkylthioalkyl or dialkylaminoalkyl radicals each having up to 9 C atoms or phenylalkyl or phenoxyalkyl radicals having up to 6 C atoms in the alkyl moiety and, where appropriate, the phenyl radical being substituted by an alkyl or alkoxy radical having in each case up to 3 C atoms, oto 1 2 ^ ^w interpret or R and R together, with which they connect Nitrogen atom form a 5- to 7-membered saturated heterocyclic ring, which may optionally be substituted by one or two phenyl and / or hydroxy and may contain an oxygen atom or nitrogen atom as a further heteroatom in the ring, wherein the additional nitrogen atom by, an alkyl radical with 1 may be substituted by 3 C atoms or a phenyl radical, R is a hydrogen atom, an alkyl radical having up to 3 C atoms, a fluorine, chlorine or bromine atom, a hydroxyl radical OQ ° group, an alkoxy group having up to 6 C atoms, R is a .Wasserstoffatom, alkyl having up to 3 carbon atoms, a fluorine, chlorine or bromine atom, a hydroxy group, or an alkoxy group having up to · 6 carbon ^{atoms: and;} '-n is an integer having a value of 1 to 5, and their acid addition salts, characterized in that a phenol ether of the general formula II 3 in which R, R and η have the abovementioned meaning, with an amine of the general formula III HNR ¹ R ² (III) 1 in which R and R have the meaning given in claim 1, and if appropriate converting the compound obtained with an acid into an acid addition salt. 15 20 25 30 35