DD271108A5 - PROCESS FOR PREPARING AMINO-PROPANOL DERIVATIVES OF 3- (3-HYDROXYPHENYL) -1-PROPANONE COMPOUNDS AND THEIR SAEUREADDITIONAL SALTS - Google Patents

Abstract

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

Description

ι · - ⁴ "

Title of the invention:

Process for the preparation of aminopropanol derivatives of 3- (3-hydroxyphenyl) -1-propanone compounds and their acid addition salts 20

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 oltzlichen cardiac death.

Characteristic of the known state of the art:

From DE-PS 20 01 431 is a process for the preparation of 2- (2'-hydroxy-3'-alkylaminopropoxy) -ß-phenylpropiophenone of the general formula 35th

and their acid addition salts known. The n-propylamino compound (propafenone) exhibits antiarrhythmic activity. From the EP-A 0 074 014 is known the 2- [2'-hydroxy-3 '- (1,1-dimethylpropylamino) -propoxy] -β-phenyl-propiophenone (diprafenone) and its acid addition salts. Furthermore, from EP-A 0 075 207 Aminopropano.lderivate the formula

NR ¹ R ²

R.

4 (n)

and their salts are known.

Typical examples of R-R are hydrogen atoms and 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.

Loan 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.

27 m

· * 5 "·

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

R ³

0-CH ₂ -CH-CH ₂ -NR R OH

and their acid addition salts.

1 2

In the general formula I, R and R are identical or different and denote hydrogen atoms, alkyl, cycloalkyl, alkenyl, alkynyl or hydroxyalkyl radicals having in each case up to 6 C atoms, alkoxyalkyl, alkylthioalkyl or dialkylaminoalkyl radicals having in each case up to 9 C atoms, or phenylalkyl or phenoxyalkyl radicals having up to 6 C atoms in the alkyl moiety, where appropriate the phenyl radical being substituted by an alkyl or alkoxy radical having in each case up to 3 C atoms,

1 2

or 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 hydroxy radicals and can form an oxygen atom or nitrogen atom as a 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 represents a hydrogen atom, an alkyl radical having up to 3 C atoms, a fluorine, chlorine or bromine atom, a hydroxyl or alkoxy group having up to 6 C 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 or R together with the phenyl radical attached thereto is part of an anelllerten aromatic Systems with up to 18 C atoms, η is an integer from 1 to 5.

Preference is given to compounds in which NR R is a tert-pentylamino, n-propylamino, 1,1-dimethylpropylamino, morpholine, isopropylamino, tert-butylamino, pyrrolidino,

3 piperidino or cyclohexylamino group, the radical R is a hydrogen atom, a methyl, methoxy or hydroxyl group

4 is; R sin hydrogen atom, a methyl / methoxy or

Is hydroxyl group, or together with the phenyl radical attached thereto is a 1-naphthyl, 2-naphthyl or 3-phenanthrenyl group and η is 1, 2 or 3. 10

1 Particularly preferred are compounds in which NR R "a

tert.-pentylamino, n-propylamino, isopropylamino, tert-butylamino, piperidino or cyclohexylamino group, the radical R is a hydrogen atom, or a methoxy group, ¹ ^ R ^{4 is} a methyl or methoxy group, or together with the phenyl radical attached thereto is a 2-naphthyl group, and η is 1, 2 or 3.

Most preferred are 1- (3,4,5-trimethoxyphenyl) -3- [3 ¹ - (2-hydroxy-3-tert-pentylaminopropoxy) phenyl] -1-propanone hydrochloride (Example 8).

1- (2,4,6-trimethylphenyl) -3- [3 '- (2-hydroxy-3-tert-butylaminopropoxy) -phenyl] -1-propanone hydrochloride (Example 17).

1- (3,4-Dimethoxyphenyl) -3- [3 '- (2-hydroxy-3-isopropylaminopropoxy) -4-methoxyphenyl] -1-propanone hydrochloride (Example 23).

1- (3,4,5-trimethoxyphenyl) -3- [3 · - (Z-hydroxy-S-cyclohexylaminopropoxy) -4'-methoxyphenyl], -] -propanone hydrochloride (Example 32)

 ι_ (2-Naphthyl) -3- [3 '- (2-hydroxy-3-n-propylaminopropoxy) -4'-methoxyphenyl] -1-propanone hydrochloride (Example 48).

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

CH ^ -CH "-CQ - // \

O with an amine of the general formula III

HNR ¹ R ² (III)

implements.

R, R *, R, R and η are as defined above.

Optionally, the resulting compound of general formula I is converted with an acid into an acid addition salt. Tie implementation can be done for example by the method described in EP-PS 0 074 014.

* ® The reaction is carried out at temperatures of 10 to 120 ⁰ C, ie

at room temperature or at higher temperatures, suitably carried out at temperatures of 50 to 120 ° C under atmospheric pressure or in a closed vessel under elevated pressure.

The starting compounds of general formula II and III can be reacted without diluent or solvent. Conveniently, however, the reactions are carried out in the presence of 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 alkylbenzene, in particular toluene or xylene, or an aliphatic

2 7 I ί Ο

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 recovered in a conventional manner, e.g. by filtration or distilling off. of the diluent from the reaction mixture. The compound obtained is purified in a customary manner, for example by recrystallization from a solvent, conversion into an acid addition salt or by column chromatography.

The phenol ether of the general formula II can be obtained by alkylation of a 3-hydroxy-.beta.-phenylpropiophene phenone of the general formula IV

.4

3 4 can be obtained with a Epj ^ Jialogenhydrin. R, R and η are as defined above. Suitable epihalohydrins are epichlorohydrin, epibromohydrin and epiiodohydrin.

The reaction of the .Compounds IV for preparing the starting compounds of general formula II is conveniently carried out at temperatures from 0 to 120 ⁰ C and under atmospheric pressure or in a closed vessel under elevated pressure carried

leads. Suitable solvents or diluents are suitably a lower aliphatic ketone, such as acetone, methyl ethyl ketone or methyl 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, tetrahydrofuran or dioxane, a di-alkylformamide such as dimethylformamide or diethylformamide, or dimethylsulfoxide or hexamethylphosphoric triamide or excess alkylating agent.

Preferably, the reactions are carried out in the presence of a base as the acid-retaining 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 trimethylamine or triethylamine, or piperidine. The bases can be used in relation to the alkylating agent used in catalytic amount or in stoichiometric amount or in slight excess.

Preferably, the S-hydroxy-ß-phenylpropio ^ henone with epichlorohydrin or epibromohydrin in a polar, aprotic solvent, in particular dimethyl sulfoxide, in the presence of at least one molar equivalent of base, in particular sodium hydride, based on the alkylating agent, at temperatures from 0 to 50 ⁰ C. implemented.

The starting compound of general formula IV, i. 3-hydroxy-.beta.-phenylpropiophenone, and its preparation is known.

Optionally, the resulting compound of the formula I prepared according to the invention is converted into an acid addition salt, preferably into a salt of a physiologically acceptable acid, customary physiologically compatible inorganic and

Organic acids are, for example, 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 acids which can be used are described e.g. in Advances in Drug Science, 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 usually in a conventional manner by mixing the free base or its solutions with the corresponding 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 ethyl ketone or methyl isobutyl ketone, or an ether, such as diethyl ether, tetrahydrofuran or dioxane. For better crystal separation, it is also possible to use mixtures of the abovementioned solvents. In addition, 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 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 free base, further salts can be obtained by reaction with inorganic or organic acids, in particular those which are suitable for the formation of therapeutically usable salts. This or auci. other salts of the new compound, e.g. The picrate may also serve to purify the free base by salting the free base, separating it, and releasing the base again from the salt.

27 \ i o

The compound prepared according to the invention can be administered orally, rectally, intravenously or intramuscularly.

The compounds according to the invention and their physiologically acceptable acid addition salts are particularly suitable because of their antiarrhythmic and ß-sympatholytic properties, especially for the pharmacotherapy of cardiac arrhythmias, for the treatment of coronary heart disease and for the prevention of sudden cardiac death. 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 conducted in healthy as well as acutely infarcted dogs. the performed. In the following Table I is presented as an important criterion the safety factor (SF) , 25, the ratio of the antiarrhythmic efficacy (conduction delay C20 Vmax) to negative inotropy (C20 CF) and eggs specifically stronger efficacy at higher frequencies (rate factor from 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.

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 C5 extrinsic islets.

The high antiarrhythmic efficacy is not accompanied by a significant increase in toxicity compared to propafenone. This results from a comparison of the LD ₅₀ values in rats and mice, which are summarized in Table II.

- 14 Table I

Test connection of the example C20 CF (μΜ) C20 Vmax (μΜ) Rate factor of Ymax Prematurity factor Vmax S. F. 7 6.0 2.9 1.21 0.90 2.5 8th 3.0 1.6 5.00 1.08 9.4 9 15.0 9.1 1.26 1.01 2.1 10 5.0 2.6 1.17 0.99 2, c 11 10.0 3.3 1.15 0.95 3.5 14 20.0 11.9 1.47 0.95 2.5 15 7.0 1.0 1.09 0.94 7.6 17 15.0 1.7 1.12 0.99 9.9 22 7.0 3.2 0.97 0.99 2.1 23 6.0 2.2 5.00 1.05 14.0 25 6.0 2.4 1.21 1.01 3.0 27 15.0 3.5 1.25 1.05 5.4 28 6.0 ϊΛ 1.16 1.01 5.0 30 5.0 2.5 1.13 1.01 2.3 31 5.0 1.4 1.15 0.97 4.1 32 , 9.0 1.1 1.25 1.05 10.2 35 10.0 3.0 1.20 0.91 4.0 36 8.0 2.8 1.41 0.99 4.0 37 5.0 2.6 1.22 0.94 2.4 39 4.0 1.2 1.51 0.94 5.0 40 5.0 1.3 1.33 0.94 5.1 44 14.0 1.7 1.03 1.10 8.5 47 17.0 6.1 1.22 1.10 3.4 48 9.0 1.1 1.43 0.90 11.7 49 14.0 12.1 4.00 0.50 4.6

C20 CF: Concentration, which is the contraction of Papi'larmjskels

decreased by 20 % C20 Vmax: Concentration, the Vmax at a cycle length of -1000 msec.

reduced by 20 %

2 7 H O

Rate factor of Vmax:

Prematurity Factor Vmax:

- 15-

(% of control value Vmax for a cycle length of 2000) / (% of control value Vmax for a cycle length of 500) for C20 Vmax {% of control value Vmax for premature extrasystoles) (% of control value Vmax for a normal beat) for Vmax

S.F .:

Safety factor, calculated as rate factor of Vmax * (C20 CF / C20 Vmax)

Table II Mouse (i.v.) LD 50 18 test compound Rat (i.v.) 16 A • 17 18 28 11 18 31 13 36 10

2Q embodiments:

A) Preparation of the starting compounds

example 1

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

100 g (0.35 mol) of 3,4-dimethoxy-β-3'-hydroxyphenyl-propiophenone are refluxed with 300 ml of epichlorohydrin and 24.2 g (0.175 mol) of potassium carbonate for 23 h and stirred. The resulting salt is filtered off and the remaining solution is concentrated to dryness under reduced pressure. The residue is recrystallized from isopropanol. Yield: 109.8 g (91.9%) of the title compound, m.p. 81-84 ° C.

16 analogue, the following compounds were prepared:

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

Propanone 1- (3,4,5-trimethoxyphenyl) -3- [3 '- (1,2-epoxy-3-propoxy) -

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

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

1- (3,4-dimethoxyphenyl) -3- [3 '- (1,2-epoxy-3-propoxy) -4'-meth-

oxypheny1] -1-propanone 1- (3,4,5-trimethoxyphenyl) -3- [3 · - (ί, 2-epoxy-3-propoxy) -4'-methoxyphenyl] -1-propanone

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

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

1- (2,4,6-trimethylphenyl) -3- [3 '- (1,2-epoxy-3-propoxy) -4'-methoxy-pheny1] -1-propanone

Example II

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

13.1 g (0.04 mol) of 1- (2-naphthyl) -3- (3'-hydroxy-4-methoxyphenyl) -1-propanone are mixed with 26.3 ml of epichlorohydrin, 90 ml of isopropanol and 1.6 g (0.04 mol) of sodium hydroxide for 5 h under reflux. The resulting salt is filtered off and the remaining solution is concentrated under reduced pressure. The remaining oily residue is used without purification in the next stage. Yield: 16.4 g (" ³¹ M00%).

- 17 Example III

1- (3-phenanthrenyl) -3- [3 '- (1,2-epoxy-3-propoxy) -phenyl] -1-propanone 5

61.6 g (0.18 mol) of 1- (3-phenantrhenyl) -3- (3'-hydroxyphenyl) -1-propanone are mixed with 105.6 ml of epichlorohydrin, 66 ml of methanol and 7.2 g (0.18 Mol) sodium hydroxide for 12 h under reflux. Jas salt formed is filtered off and the remaining solution concentrated under reduced pressure. The residue is used without purification in the next stage. Yield: 65.2 g (? 85.3%).

B) Preparation of the compounds of general formula (I) 15

example 1

1- (3,4-dimethoxyphenyl) -3- [3 · - (2-hydroxy-3-tert-pentylaminopropoxy) -phenyl] -1-propanone hydrochloride

27.4 g (0.08 mol) of 1- (3,4-dimethoxyphenyl) -3- [3 '- (1,2-epoxy-3-propoxy) -phenyl] -1-propanone and 20.9 g ( 0.24 mol) of tert-pentylamine are dissolved in 300 ml of methanol and heated under reflux for 4 h. The solvent and the excess amine are removed under reduced pressure. The oily residue is taken up in methanol and treated with concentrated hydrochloric acid. After heating and cooling, crystals are obtained which are recrystallized from acetone. Yield: 22.8 g (61.2%) of the title compound of mp 117-

119 ° C.

Analog were prepared (Examples 2 to 51):

2. 1- (3,4-Dimethoxyphenyl) -3- [3 · - (2-hydroxy-3-n-propylaminopropoxy) phenyl] -1-propanone hydrochloride, m.p .: 146 147 ° C.

2 7 ί ί Ο

• - 18 -

3. 1- (3,4-Dimethoxyphenyl) -3- [3 '- (2-hydroxy-3-morpholinopropoxy) phenyl] -1-propanone hydrochloride, m.p .: 148-149 ° C

4. 1- (3,4-Dimethoxyphenyl) -3- [3 '- (2-hydroxy-3-isopropylamino-propoxy) -phenyl] -1-propanone hydrochloride,. Mp .: 175-177 ° C.

5. 1- (3,4-Dimethoxyphenyl-3- [3- (2-hydroxy-3-tert-butylamino-propoxy) -phenyl] -1-propanone hydrochloride / m.p .: 179-181 ° C.

6. 1- (3,4-Dimethoxyphenyl) -3- [3 '- (2-hydroxy-3-piperidinopropoxy) -phenyl] -1-propanone hydrochloride, m.p .: 141-142 ° C.

7. 1- (4-Methoxyphenyl) -3- [3 '- (2-hydroxy-3-n-propylaminopropoxy) -1-propanone hydrochloride, m.p .: 128.5-129.5 ⁰ C;

8. 1- (3,4,5-trimethoxyphenyl) -3- [3 · - (2-hydroxy-3-tert-pentylaminopropoxy) -phenyl] -1-propanone hydrochloride,

Mp .: 160-161 ^0C.

9. 1- (3,4,5-trimethoxyphenyl) -3- [3 ¹ - (2-hydroxy-3-isopropylamino-propoxy) -phenyl] -1-propanone hydrochloride,

Mp .: 119.5 to 120.5 ⁰ C

 25

10. 1- (3,4,5-Trimethoxyphenyl) -3- [3 '- (2-hydroxy-3-tert-butylaminopropoxy) phenyl] -1-propanone hydrochloride, m.p .: 158-159 ° C ,

11. 1- (2,4,6-trimethylphenyl) -3- [3 '- (2-hydroxy-2-tert-pentyl-aminopropoxy) -phenyl] -1-propanone hydrochloride, mp 103-105 ⁰ C.

12. 1- (2,4,6-trimethylphenyl) -3- [3 '- (2-hydroxy-3-piperidinopropoxy) -phenyl] -1-propanone hydrochloride, m.p .: 158-159.5 ° C.

13. 1- (2,4,6-trimethylphenyl) -3- [3 '- (2-hydroxy-3-morpholinopropoxy) -phenyl] -i-propanone hydrochloride, m.p .: 170-171 ° C.

14. 1- (2,4,6-trimethylphenyl) -3- [3 '- (2-hydroxy-3-tert-butyl-aminopropoxy) -phenyl] -1-propanone hydrochloride, m.p .: 129-131 ° C.

15. 1- (2,4,6-Trimethylphenyl) -3- [3 '- (2-hydroxy-3-isopropylaminopropoxy) phenyl] -1-propanone semioxalate, m.p .: 146-148 ° C.

16. 1- (2,4,6-trimethylphenyl) -3- [3 '- (2-hydroxy-3-n-propylaminopropoxy) -phenyl] -1-propanone hydrochloride, m.p .: 84-85 ° C.

17. 1 - (2,4 ', 6-Trimethylphenyl) -3- [3' - (2-hydroxy-3-tert-butylaminopropoxy) phenyl] -1-propanone hydrochloride, m.p .: 123.5% 125.5 ° C.

j

18. 1-Phenyl-3- [3 '- (2-hydroxy-3-tert-pentylaminopropoxy) -4'-methoxyphenyl] -1-propanone semi-oxalate, m.p .: 162-164 ° C.

19. 1-Phenyl-3- [3 '- (2-hydroxy-3-isopropylaminopropoxy) -4'-methoxyphenyl] -1-propanone hydrochloride, m.p. 157-158 ° C.

20. 1-Phenyl-3- [3 '- (2-hydroxy-3-tert-butylaminopropoxy) -4'-methoxyphenyl] -1-propanone hydrochloride, m.p .: 158-159 ° C.

21. 1-Phenyl-3- [3 '- (2-hydroxy-3-piperidinopropoxy) -4'-methoxyphenyl] -1-propanone hydrochloride, m.p .: 115-117 ° C,

22. 1- (3,4-Dimethoxyphenyl) -3- [3 '- (2-hydroxy-3-n-propylaminopropoxy) -4'-methoxyphenyl] -1-propanone hydrochloride, m.p. 115-116.5 ° C.

-20 -.

23. 1- (3,4-Dimethoxyphenyl) -3- [3 '- (2-hydroxy-3-isopropylaminopropoxy) -4 -methoxyphenyl] -1-propanone hydrochloride, m.p .: 128-131 ° C.

24. 1- (3,4-Dimethoxyphenyl) -3- [3 '- (2-hydroxy-3-morpholinopropoxy) -4'-methoxyphenyl] -1-propanone hydrochloride, m.p .: 158-161 ° C.

25. 1- (3,4-dimethoxyphenyl) -3- [3 '- (2-hydroxy-3-tert.-butylaminopropoxy) -4'-methoxyphenyl] -1-propanone hydrochloride, m.p .: 168-170 ⁰ C.

26. 1 - (3,4-Dimethoxyphenyl) -3- [3 '- (2-hydroxy-3-cyclohexylaminopropoxy) -4'-methoxyphenyl] -1-propanone hydrochloride, m.p .: 117.5-120.5 ⁰ C.

, 27. 1- (3,4-Dimethoxyphenyl) -3- [3 ¹ - (2-hydroxy-3-tert-pentylaminopropoxy) -4-methoxyphenyl] -1-propanone hydrochloride, m.p .: 147-148 ° C

 20

28. 1- (3,4,5-Trimethoxyphenyl) -3- [3 '- (2-hydroxy-3-tert-pentylaminopropoxy) -4'-methoxyphenyl] -1-propanone hydrochloride, m.p. 129 ° C.

29. 1- (3,4,5-Trimethoxyphenyl) -3- [3 '- (2-hydroxy-3-n-propylaminopropoxy) -4'-methoxyphenyl] -1-propanone hydrochloride, m.p .: 103.5 -106 ⁰ C.

30. 1- (3,4,5-Trimethoxyphenyl) -3- [3 '- (2-hydroxy-3-isopropylaminopropoxy) -4'-methoxyphenyl] -1-propanone hydrochloride, m.p .: 115-116 ° C ,

31. 1- (3,4,5-Trimethoxyphenyl) -3- [3 '- (2-hydroxy-3-tert-butylaminopropoxy) -4'-methoxyphenyl] -1-propanone hydrochloride, m.p .: 150.5-152 ⁰ C.

27 η O

- 21 -

32. 1 - (3 ·, 4, 5-Trimethoxyphenyl) -3- [3 '- (2-hydroxy-3-cyclohexylamihopropoxy) -4'-methoxyphenyl] -1-propanone hydrochloride, m.p .: 136.5- 138.5 ⁰ C.

33. 1- (2-Methoxyphenyl) -3- [3 '- (2-hydroxy-3-tert-pentylaminopropoxy) -4'-methoxyphenyl] -1-propanone acetate, m.p .: 119-120 ⁰ C.

34. 1- (2-methoxyphenyl) -3- [3 '- (2-hydroxy-3-n-propylaminopropoxy) -4'-methoxyphenyl] -1-propanone hydrochloride,

Mp: 141.5-143 ⁰ C.

35. 1- (2-methoxyphenyl) -3- [3 '- (2-hydroxy-3-tert.butyland.nopropoxy) -4'-methoxyphenyl] -1-propanone hydrochloride,

Mp: 166.5-167 ° C.

36. 1- (4-Methylphenyl) -3- [3 '- (2-hydroxy-3-tert-pentylaminopropoxy) -4m-thoxyphenyl] -1-propanone hydrochloride, m.p .: 107.5-109 , 5 ⁰ C.

37. 1- {4-methylphenyl) -3- [3 '- (2-hydroxy-3-n-propylaminopropanol)

oxy) -4'-methoxyphenyl] -1-propanone hydrochloride, m.p .; 108-110 ⁰ C.

38. 1- (4-methylphenyl) - · 3- [3 '- (2-hydroxy-3-morpholinopropoxy) · 4'-methoxyphenyl] -1-propanone hydrochloride, m.p .: 117 to 119.5 ⁰ C.

39. 1- (4-methylphenyl) -3- [3 '- (2-hydroxy-3-tert-butylaminogo-propoxy) -4'-methoxyphenyl] -1-propanone hydrochloride,

Mp .: 117-119 ° C.

40. 1. (4-methylphenyl) -3- [3 '- (2-hydroxy-3-piperidinopropoxy) -4'-methoxyphenyl] -1-propanone hydrochloride,

Mp: 138.5-140 ⁰ C.

41. 1- (4-Methylphenyl) -3- [3 '- (2-hydroxy-3-cyclohexylaminopropoxy) -4'-methoxyphenyl] -1-propanone hydrochloride, m.p .: 134-136 ° C.

42. 1- (2,4,6-trimethylphenyl) -3- [3 '- (2-hydroxy-3-tert-pentylaminopropoxy) -4'-methoxyphenyl] -i-propanone hydrochloride. Mp .: 117-118 ° C.

43. 1 - (2,4,6-trimethylphenyl) -3- [3 '- (2-hydroxy-3-piperidinopropoxy) -4'-methoxyphenyl] -1-propanone hydrochloride, m.p .: 119-120 ⁰ C. ,

44. 1- (2,4,6-trimethylphenyl) -3- [3 '- (2-hydroxy-3-n-propylaminopropoxy) -4'-methoxyphenyl] -1-propanone oxalate.

Mp .: 121-122 ⁰ C.

45. 1- _(2,4; 6-trimethylphenyl) -3- [3 '- (2-hydroxy-3-isopropylaminopropoxy) -4'-methoxyphenyl] -1-propanone hydrochloride, m.p .: 110-111 ⁰ C. ,

46. 1- (2,4 _/ 6-Trimethylphenyl) -3- [3 '- (2-hydroxy-3-morpholinopropoxy) -4'-methoxyphenyl] -1-propanone hydrochloride, m.p .: 154-155 ° C ,

47. 1- (2-Naphthyl) -3- [3 '- (2-hydroxy-3-tert-pentY. "" Aminopropoxy) 4'-methoxyphenyl] -1-propanone hydrochloride, m.p .: 130-132 ⁰ C,

^N 48. 1- (2-Naphthyl) -3- [3 '- (2-hydroxy-3-n-propylaminopropoxy) 4'-methoxyphenyl] -1-propanone hydrochloride, m.p .: 142-143 ° C.

49. 1- (2-Naphthyl) -3- [3 '- (2-hydroxy-3-isopropylaminopropoxy) -4'-methoxyphenyl] -1-propanone hydrochloride, mp 133-135 ° C.

50. 1- (3-phenanthrenyl) -3- [3 ¹ - (2-hydroxy-3-isopropylaminopropoxy) -phenyl] -1-propanone hydrochloride, m.p .: 140-142 ⁰ C.. "·

1 51. 1- (3-phenanthrenyl) -3- [3 '- (2-hydroxy-3-n-propylamino)

propoxy) -phenyl-1-propanone hydrochloride, m.p .: 149-152 ° C.

Claims (1)

4-2
claims 1. A process for the preparation of Aminopropanolderivaten of 3- (3-hydroxyphenyl) -1-propanone compounds of the general formula I. CH ₀ -CH ₂ -CO , 0-CH ₂ - ^; "OH 0-CH ₂ -CH-CH ₂ -NR ¹ R ² 1 2 and their acid addition salts in which R and R are the same or different and are hydrogen atoms, alkyl, cyclo alkyl ¹ ^, alkenyl, alkynyl or hydroxyalkyl residues with up to 6 C-atoms, alkoxyalkyl, alkylthioalkyl or dialkylaminoalkyl each having up to ode 9 carbon atoms, phenylalkyl or Phenoxyalkylreste 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, 25 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 R ^{3 is} a hydrogen atom, an alkyl radical having up to 3 C atoms, a fluorine, chlorine or bromine atom, a hydroxyl group, an alkoxy group having up to 6 C atoms, R is a hydrogen atom, an alkyl radical having up to 3 C atoms, a fluorine, chlorine or bromine atom, a hydroxyl group, 4 is an alkoxy group having up to 6 C atoms, or where R together with the phenyl radical attached thereto forms part of a { 25 30 fused aromatic system having up to 18 carbon atoms, and η 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 ^ • ^ O-CH - CH-CH- ° 3 4
in which R, R and η have the abovementioned meaning, with an amine of the general formula III HNR ¹ R ² (III) 15 1 2 in which R and R have the abovementioned meaning, and if appropriate converting the compound obtained with an acid 3 into an acid addition salt. 20 35