CA1331877C

CA1331877C - Aminopropanol derivatives of 3-(3-hydroxyphenyl)-1- propanone compounds, process for preparing same, and pharmaceutical compositions containing said compounds

Info

Publication number: CA1331877C
Application number: CA000570097A
Authority: CA
Inventors: Gerd Petrik; Klemens Schubert
Original assignee: Helopharm W Petrik and Co KG
Current assignee: Helopharm W Petrik and Co KG
Priority date: 1987-06-23
Filing date: 1988-06-22
Publication date: 1994-09-06
Anticipated expiration: 2011-09-06
Also published as: NO882771L; HRP920925A2; FI92482C; EP0297435A3; PT87793A; DK342288D0; ZA884437B; KR890000401A; IL86813A0; EP0296265A1; GR3003257T3; NO882771D0; AR246246A1; AU606693B2; FI883001A0; SU1634135A3; EP0297435A2; NO167975C; GR890300050T1; PT87793B

Abstract

Abstract:
Described are aminopropanol derivatives of 3-(3-hydroxyphenyl) -1-propane compounds of general formula I

Description

.

Aminopropanol derivatives of 3-(3-hvdroxYDhenyl~ ro~anone compounds. process for preparina same. and pharmaceutical com~ositions containina said com~ounds Backaround of the Invention ~, German Patent No. 2 001 431 discloses 2-(2'-hydroxy-3'-alkylaminopropoxy)-B-phenyl-propiophenones of the general for~3ula .

1l OH N~-R
~

and their acid addltion salts. Although these compounds and their salts constitute pharmaceuticals, only the n-propylamino compound (propafenone) shows antiarrhythmic activity.

European patent publication EP-A-0 074 014 published on March 10 16, 1983 (patented on June 27, 1984) describes 2-t2'-hydroxy-3'-(1,1-dimethylpropylamino)-propoxy]-~-phenyl-propiophenone (diprafenone) and its acid addition salts. Diprafenone is an antiarrhythmic.

European patent publication EP-A-0 075 207 published on 15 Narch 30, 1983 (patented on February 5, 1986) describes aminopropanol derivatives of the general formula .

~:
r.
f~3 ... . . .

Il OH

4(n ~ R3 and its physiologically acceptable acid addition salts. Ty-pical examples for R1-R4 include hydrogen atoms or alkyl groups and n has a value of 1, 2 or 3. These compounds are pharmaceuticals.
.
Summarv of the Invention One object of the invention is to provide novel aminopropa-nol derivatives of 3-(3-hydroxyphenyl)-1-propanone compounds - ~
of the general formula I and physiologically acceptable acid --~10 addition salts which are distinguished by a substantially improved antiarrhythmic activity than that of propafenone and without a corresponding increase in toxicity. It is another object of the invention to provide a process for producing these compounds and acid addition salts. Finally, - -it is an object of the invention to provide pharmaceutical compositions for treating heart rhythm disorders which con-tain those compounds or their physiologically acceptable acid addition salts.

~ Detailed Description of the Invention ; 20 The invention relates to novel aminopropanol derivatives of 3-(3-hydroxyphenyl)-1-propanone compounds of general formula I

CHz-CH2-CO ~ (I) R ~ ~
4' ~ 1 2 O-CH2-fH-CH2-~R R
OH
~ .
.

and their acid addi~ion salts, and to a process for pre-paring same. The invention also relates to pharmaceutical i compositions containing a compound of general formula I or acid addition salts thereof, preferably a physiologically acceptable acid addition salt.

In general formula I, Rl and R2 are the same or different and denote hydrogen atoms, alkyl, cycloalkyl, alkenyl, al-kinyl or hydroxyalkyl groups with up to 6 carbon atoms each, alkoxyalkyl, alkylthioalkyl or dialkylaminoalkyl groups with up to 9 carbon atoms each, or phenylalkyl or phenoxyalkyl groups having up to 6 carbon atoms in the alkyl portion, the phenyl group optionally being substituted by an alkyl or alkoxy group with respectively up to 3 carbon atoms, or Rl and R2 form together with the nitrogen atom which connects them a 5 to 7 membered, saturated heterocyclic ring, which may optionally be substituted by one or two phenyl and/or hydroxy groups and contain in the ring an oxygen or n~trogen atom as a further heteroatom, with the additional nltrogen atom optionally substituted by an alkyl group w~th 1 to 3 carbon atoms, or by a phenyl group. R3 denotes a hydrogen atom, an alkyl group having up to 3 carbon atoms, a fluorine, chlo-rine or bromine atom, a hydroxyl or alkoxy group with up to 6 carbon atoms. R4 denotes a hydrogen atom, an alkyl group having up to 3 carbon atoms, a fluorine, chlorine or bromine atom, a h~droxyl group or an alkoxy group with up to 6 car-bon atoms, or R4 together with the phenyl group bound to it is part of an anellated aromatic system having up to 18 car-bon atoms. n is an integer from 1 to 5.
, .
Preferred are compounds in which NRlR2 is a tert.-pen-tylamino, n-propylamino, l,l-dimethylpropylamino, morpho-lino~ isopropylamino, tert.-butylamino, pyrrolidino, piperi-dino or cyclohexylamino group, the R3 residue is hydrogen, or a methyl, methoxy or hydroxy group, 133~877 R4 is hydrogen, or a methyl, methoxy or hydroxy group, or together with the phenyl group attached thereto is a l-naph-thyl group, 2-naphthyl group or 3-phenanthrenyl group, and n has the value 1, 2 or 3.

Especially preferred are compounds in which NRlR2 is a tert.-pentylamino, n-propylamino, isopropylamino, tert.-bu-tylamino, piperidino or cyclohexylamino group, the R3 residue is hydrogen, or a methoxy group in the 4-po-sition, R4is a methyl or methoxy group or together with the phenyl group attached thereto is a 2-naphthyl group and and n has the value 1, 2 or 3.

The most preferred compounds are 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-pentyl-aminopropoxy)-phenyl]-l-propanone hydrochloride, (Example 8).
1-(2,4,6-trimethylphenyl)-3-t3'-(2-hydroxy-3-tert.-bu-tylamino-propoxy)-phenyl]-l-propanone hydrochloride, (Example 17).
1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-isopropylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride (Example 23).
1-(3,4,5-trimethoxyphenyl)-3-t3'-(2-hydroxy-3-cyclo- -hexylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochlo-ride, (Example 32).
1-(2-naphthyl)-3-[3'-(2-hydroxy-3-n-propylaminopropoxy)-4'-methoxyphenyl]-l-propanone hydrochloride, (Example 48).

The invention also relates to a process for preparing the compounds of general formula I and their acid addition salts which is characterized by reacting a Phenol ether of general formula II

' ~. . - . . ~. , ~ , -. . - :
... ... . - .. : ; - : ~

r~
r i: . i .- . ' ' ' . - ' , : ` ' ' ~C~2 -CH2 -CO-~
o-CH2-C~-CH2 (II) O

with an amine of general formula III

HNR R (III) Rl, R2, R3, R4 and n have the above meaning.

If appropriate, the resulting compound of general formula I
may be converted with an acid into an acid addition salt.
The reaction may, for instance, follow the method described in European Patent 0 074 014.

The reaction is carried out at temperatures ranging from 10-to 120~C, that is at room temperature or at higher tempera-tures, preferably at temperatures ranging from 50- to 120-C, at atmospheric pressure or in a closed vessel at elevated pressure.

The starting compounds of general formulae II and III can be reacted without diluents or solvents. However, the reaction is preferably carried out in the presence of an inert dil-uent or solvent, such as a lower alcohol having 1 to 4 car-bon atoms, as for instance methanol, ethanol or propanol, preferably isopropanol or ethanol, a lower saturated dial-kylether, dialkylglycol ethers or cyclic ethers, such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or di-oxane, a benzene hydrocarbon, such as benzene itself or an alXyl benzene, in particular toluene or xylene, or an ali- ~-~
phatic hydrocarbon, such as hexane, heptane or octane, di-,~:-; . . . - ' ,. ' . : :

--~`` 1331877 methylsulfoxide or in the presence of water or mixtures of the mentioned solvents.

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

The completeness of the reaction depends on the reaction temperature and is in general achieved within 2 to 15 hours.
The reaction product can be obtained in a conventional man-ner, for instance by filtration or distillation of the dilu-ent from the reaction mixture. The compound obtained is pu-rified in the usual manner, for instance by recrystalli-zation from a solvent, conversion into an acid addition salt or by column chromatography.

The phenyl ether of general formula II can be obtained by alkylating 3-hydroxy-~-phenylpropiophenone having general formula IV

CH2-CH2-CO ~ (IV) OH

with an epihalohydrin. R3, R4 and n have the above meaning.
Examples of epihalohydrins are epichlorohydrin, epibromo-hydrin and epiiodohydrin.

The reaction of the compounds IV for preparing the starting -compounds of general formula II is expediently carried out -at temperatures ranging from 0- to 120C and normal pressure or in a- closed vessel at elevated pressure. Suitable sol-vents or diluents are a lower aliphatic ketone, such as ace-tone, methylethyl ketone or methylisobutylketone, a lower alcohol having 1 to 4 carbon atoms, such as methanol, etha-nol, propanol or butanol, a lower aliphatic or cyclic ether, such as diethylether, tetrahydrofuran or dioxane, a dialkyl-~ 1331877 formamide, such as dimethylformamide or diethylformamide, or dimethylsulfoxide or hexamethylphosphoric acid triamide or an excess amount of the alkylating agent.

The reactions are preferably carried out in the presence of a base as acid-binding agent. Suitable bases are alkali me-tal carbonates, alkali metal bicarbonates, alkali metal hy-droxides, alkali metal hydrides or alkali metal alcoholates, in particular those of sodium and potassium, basic oxides, such as aluminum oxide or calcium oxide, organic tertiary bases, such as pyridine, lower trialkyl amines, such as tri-methyl amine or triethyl amine, or piperidine. The bases can be used in catalytic or stoichiometric amounts or in slightly excess amounts with respect to the alkylating agent used.

3-hydroxy-~-phenylpropiophenone is preferably reacted with epichlorohydrin or epibromohydrin in a polar, aprotic sol-vent, in particular dimethylsulfoxide, at temperatures rang-ing from O-to 50 C, in the presence of at least one mole equivalent base, in particular sodium hydride, based on the alkylating agent.

The starting compound of general formula IV, that is the 3-hydroxy-~-phenylpropiophenone, and its preparation are known.

The compound of formula I obtained according to the inven-tion is optionally converted into an acid addition salt, preferably into a salt of a physiologically acceptable acid.
Usual physiologically acceptable inorganic and organic acids are for instance hydrochloric acid, hydrobromic acid, phos-phoric acid, sulfuric acid, oxalic acid, maleic acid, fuma-ric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and benzoic acid. Other suitable acids are described for instance in Fortschritte der Arzneimittelforschung, vol. 10, pp. 224-225, Birkhauser . ., .: ~... . - :

. , . -.. ~. . . .~ .:. . -:
, ~ . ... . ...................... .. . ... .

, . . :- - . - - . .. ... : . , - .. , : . , .:' . . . : :: ':.: :::' ' .. ,-.-: . ':: : ' . -~ . :

publishers, Basle and stuttgart, 1966, and Journal of Pharmaceutical sciences, vol. 66, pp. 1-5 (1977). Hydro-chloric acid is preferred.

The acid addition salts are normally obtained in a conven-tional manner by mixing the free base or its solutions with the corresponding acid or its solutions in an organic sol-vent, for instance a lower alcohol, such as methanol, etha-nol, n-propanol or isopropanol, or a lower ketone. such as acetone, methylethyl 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 bet-ter crystal deposition. Moreover, pharmaceutically accept-able aqueous solutions of acid addition salts of the com- `
pound of formula I can be prepared in an aqueous acid solu-tion.

The acid addition salts of the compound of formula I can be converted into the free base in a manner known per se, as for instance with alkalis or ion exchangers. Further salts can be obtained from the free base by reaction with inorga-nic or organic acids, in particular with those which are . .
suitable for the formation of therapeutically useful salts.
These and other salts of the new compound, such as the picrate, can also lend themselves to the purification of the free base wherein the free base is converted into a salt, which is separated and the base is again liberated from the salt.

The present invention also relates to pharmaceutical compo- ;-~
sitions for oral, rectal, intravenous or intramuscular ap-plication, which apart from the usual carriers and diluents contain the compound of formula I or its acid addition salt as active ingredient. Furthermore it relates to the use of the new compounds and their physiologically acceptable salts in the treatment of heart rhythm disorders.

~, .... . ........ .......... ...... .. . .. . .

-` 1331877 The pharmaceutical compositions of the invention are pre-pared in a conventional manner with the usual solid or liquid carriers or diluents and the conventional pharmaceu-tical adjuvants in a suitable dosage form in accordance with the desired form of application. The preferred preparations are compositions in dosage unit form for oral applications.
Such pharmaceutical forms are for instance 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 to be mentioned is, for instance, the suppositories.

Corresponding tablets can be obtained for instance by mixing the active ingredient with known auxiliaries, or instance with inert diluents, such as dextrose, sugar, sorbitol, man-nitol, polyvinylpyrrolidone, disintegrating agents, such as corn starch or alginic acid, binders, such as starch or gelatine, lubricants, such as magnesium stearate or talcum and/or agents for achieving a depot effect, such as carboxy-polymethylene, carboxymethyl cellulose, cellulose ace-tatephthalate or polyvinylacetate. The tablets may comprise several layers.

Dragees can be prepared correspondingly by coating cores which have been manufactured analogously to the tablets with compositions commonly used in dragee coatings, such as poly-vinylpyrrolidone or shellac, gum arabic, talcum, titanium dioxide or sugar. The dragee shell may also consist of sev-eral layers, wherein the auxiliaries mentianed above in connection with the tablets may be used.

Solutions or suspensions comprising the inventive active in-gredient may additionally contain flavoring agents, such as saccharin, cyclamate or sugar and for instance aromatics, such as vanillin or orange extract. Moreover, they may con-! . . . ` `
.j:-`' :' ' ` '' ' ~' ' ` ~ '`' ' : , ' ' : ~ ':

, ~, . ~ , ,. ~ .
:" ,': -: ' . . ' ` - ~ ~ . : - .. ' :

~' ' .

~ 1331877 tain suspension auxiliaries, such as sodium carboxymethyl cellulose or preservati~es, such as p-hydroxybenzoates.
Capsules containing the active ingredient can for instance be prepared by mixing the active ingredient with an inert carrier, such as lactose or sorbitol, and encapsulating it in gelatine capsules.

Suitable suppositories can, for example, be prepared by mi-xing the active ingredient with corresponding carriers, such as neutral fats or polyethylene glycol or their derivatives.

In humans, the single dose is from 0.5 - 5 mg/kg for oral application from 0.05 - 2 mg/kg for intravenous application from O.l - 3 mg/kg for intramuscular application from 0.5 - 10 mg/kg for rectal application.

In particular, the antiarrhythmic and ~-sympatholytic pro-perties of the compounds of the invention and their physio-logically acceptable acid addition salts make them espe-cially suitable for phar~acotherapy of heart rhythm disor-ders, treatment of coronary heart disease, and prophylaxis of sudden death from heart disease. The antiarrhythmic ef-ficacy of the inventive compounds was established both by electrophysiological studies on dog heart Purkinje fibers and with the aid of ouabain-induced ventricular tachycardia in dogs.
.;
In the following tables I and II the compounds of the inven-tion are compared to propafenone (A).
, The effect on the contractive strength of the heart was tested on guinea pig papillary muscle. Hemodynamic studies werè carried out on both healthy and acutely infarcted dogs.
One important criterion in table I which follows is the safety factor (S.F.), which i8 calculated from the relationship of the antiarrhythmic efficacy, , .
` . ~ ~. ~ - ' : ' :
: . , , . :
~... . . ..

.: -.,, -` 11 1331877 the negative inotropy and the specifically greater efficacy at higher frequencies according to the formula rate factor of Vmax x (C20CF/C20 Vmax). By way of comparison it is noted that the currently leading antiarrhythmics propafenone and flecainid have an S.F. of 1.5 and 1.7 respectively.

As a supplementary criterion the prematurity factor was established. This characterizes the desired efficacy of the inventive compounds in premature extrasystoles.

The high antiarrhythmic effect is not accompanied by a significant increase in toxicity compared to propafenone (A) as seen from a comparison of the LD50 values in rats and mice which are summarized in table II.

.. .. .. ..
:, . ..
~ .
.. . . . . .
. ; - ~

., - , ~ :

.

~ 1331877 Table I

Example C20 CF C20 Vmax Rate Factor Prematurity S.F.
No. (~M) (~M) of Vmax Factor Vmax ____________________________________________________________ 7 6.0 2.9 1.21 0.902.5 8 3.0 1.6 5.00 1.089.4 9 15.0 9.1 1.26 1.012.1 5.0 2.6 1.17 0.992.3 11 10.0 3.3 1.15 0.953.5 14 20.0 11.9 1.47 0.952.5 7.0 1.0 1.09 0.947.6 17 15.0 1.7 1.12 0.999.9 22 7.0 3.2 0.97 0.992.1 23 6.0 2.2 5.00 1.0514.0 6.0 2.4 1.21 1.013.0 27 15.0 3.5 1.25 1.055.4 28 6.0 1.4 1.16 1.015.0 5.0 2.5 1.13 1.012.3 31 5.0 1.4 1.15 0.974.1 32 9.0 1.1 1.25 1.0510.2 10.0 3.0 1.20 0.914.0 36 8.0 2.8 1.41 0.994.0 37 5.0 2.6 1.22 0.942.4 39 4.0 1.2 1.51 0.945.0 5.0 1.3 1.33 0.945.1 44 14.0 1.7 1.03 1.108.5 47 17.0 6.1 1.22 1.103.4 48 9.0 1.1 1.43 0.9011.7 49 14.0 12.1 4.00 0.504.6 A 5.3 3.7 1.08 0.971.5 _________ C20 CF: Concentration that reduces contractions of the papillary muscle by 20%.
C20 Vmax: Concentration that reduces Vmax by 20% at a basic cycle length of 1000 msec.

. - ... ~ . . : .: . :
,' : - . . , ~, -: - - . . ~ . , : -. . i - ~ . , ~ .. -.. ,, ~ .. .
, .... : :::; - :. . -Rate Factor (% control Vmax at a basic cycle length of of Vmax: 2000 msec)/(% control Vmax at a basic cycle length of 500 msec) at C20 Vmax.
Prematurity (% control Vmax at premature extrasystoles)/
Factor Vmax: (% control Vmax at a normal beat) at Vmax.
S.F.: Safety factor computed as Rate Factor of Vmax (C20 CF/C20 Vmax).

Table II
LD50(mg/kg) Test compound rat(i.v.) mouse (i.v.) Example 28 11 16 , The invention is illustrated by the examples.

A) Preparation of the starting compounds:

ExamDle I

1-(3,4-dimethoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-phenyl]-l-propanone :
100 g (0.3S mole) of 3,4-dimethoxy-~-3'-hydroxyphenylpro-piophenone are heated under refluxing for 23 hrs with 300 ml of epichlorohydin and 24.2 g (0.175 mole) of potassium car-bonate and stirred. The resulting salt is filtered off, and the remaining solution is evaporated under reduced pressure.
The residue is recrystallized from isopropanol. Yield:
109.8 g (91.9%) of the title compound, Fp. 81-84'C.

,,., ~, ~ ,.: - . ~ .
~ - . .
.~ . ...
' . ': .

The following compounds were prepared in the same manner:

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)-phe-nyl]-l-propanone 1-(2,4,6-trimethylphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-phe-nyl]-l-propanone l-phenyl-3-[3'-(1,2-epoxy-3-propoxy)-4'-methoxyphenyl]-1-propanone 1-(3,4-dimethoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'-me-thoxyphenyl]-l-propanone 1-(3,4,5-trimethoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'-methoxyphenyl]-l-propanone 1-(2-methoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'-methoxy-phenyl]-l-propanone 1-(4-methylphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'-methoxy-phenyl]-l-propanone 1-(2,4,6-trimethylphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'-methoxyphenyl]-l-propanone Exam~le II
1-(2-naphthyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'-methoxy-phenyl]-l-propanone 13.1 g (0.04 mole) of 1-(2-naphthyl)-3-(3'-hydroxy-4'-me-thoxyphenyl)-l-propanone are heated for 5 hrs under re-fluxing with 26.3 ml of epichlorohydrin, 90 ml of isopropa-nol and 1.6 g (0.04 mole) of sodium hydroxide. The resul-ting salt is filtered off and the remaining solution is evaporated under reduced pressure. The remaining oily resi-due is-used without purification in the next step. Yield:
16.4 g (~ 100 %).

Example III
1-(3-phenanthrenyl)-3-~3'-(1,2-epoxy-3-propoxy)-phenyl]-1-propanone :~ . . - . :. - .
. . ~

~, ~ ,. -:

-` 1331877 61.6 g (0.18 mole) of 1-(3-phenanthrenyl)-3-(3'-hydroxy-phenyl)-l-propanone are heated for 12 hrs under refluxing with 105.6 ml of epichlorohydrin, 66 ml of methanol and 7.2 g (0.18 mole) of sodium hydroxide. The resulting salt is filtered off and the remaining solution is evaporated un-der reduced pressure. The residue is used without purifica-tion in the next step. Yield: 6S.2 g (= 85.3 %).

B) Preparation of the inventive compounds:

Exam~le 1 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-pentyl-aminopropoxy)-phenyl]-l-propanone hydrochloride 27.4 g (0.08 mole) of 1-(3,4-dimethoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-phenyl]-1-propanone and 20.9 g (0.24 mole) of tert.-pentylamine are dissolved in 300 ml of methanol and heated for 4 hrs under refluxing. The solvent and the ex-cess amount of amine are removed under reduced pressure.
The oily residue is taken up in methanol and concentrated hydrochloric acid is added thereto. After heating and cool-ing, crystals are obtained which are recrystallized from acetone. Yield: 22.8 g (61.2~) of the title compound, Fp.
117-ll9-C.

The following compounds were prepared in the same manner tExamPles 2 to 51):

2. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-n-pro-pylaminopropoxy)-phenyl]-l-propanone hydrochloride, Fp. 146-147-C.

3. 1-(3,4-dimethoxyphenyl)-3-t3'-(2-hydroxy-3-morpholino-propoxy)-phenyl]-1-propanone hydrochloride, Fp. 148-149-C.

- -- - - . . : ~ : . ' ` - :

fi : ~ ~ ` . " .~

4. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-isopro-pylaminopropoxy)-phenyl]-l-propanone hydrochloride, Fp. 175-177-C.

5. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-butyl-aminopropoxy)-phenyl]-l-propanone hydrochloride, Fp. 179-181C.

6. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-piperidino-propoxy)-phenyl]-l-propanone hydrochloride, Fp. 141-142-C.

7. 1-(4-methoxyphenyl)-3-t3'-(2-hydroxy-3-n-propylamino-propoxy)-phenyl]-l-propanone hydrochloride, Fp. 128.5-129.5-C.

8. 1-(3,4,5-trimethoxyphenyl)-3-t3'-(2-hydroxy-3-tert.-pentylaminopropoxy)-phenyl]-1-propanone hydrochloride, Fp.
160-161-C.

9. 1-(3,4,5-trimethoxyphenyl)-3-t3'-(2-hydroxy-3-isopro-pylaminopropoxy)-phenyl]-1-propanone hydrochloride, Fp.
119.5-120.5-C.

10. 1-(3,4,5-trimethoxyphenyl)-3-t3'-(2-hydroxy-3-tert.-butylaminopropoxy)-phenyl]-1-propanone hydrochloride, Fp.
158-159-C.

11. 1-(2,4,6-trimethylphenyl)-3-[3'(2-hydroxy-3-tert.-pen-tylaminopropoxy)-phenyl]-l-propanone hydrochloride, Fp. 103-105-C.

12. 1-(2,4,6-trimethylphenyl)-3-t3'-(2-hydroxy-3-piperi-dinopropoxy)-phenyl]-l-propanone hydrochloride, Fp. 158-159.5'C.

.~.`` `

D ~ e~ ~ ~ 5 `-" 1331877 13. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-morpho-linopropoxy)-phenyl]-l-propanone hydrochloride, Fp. 170-171-C.

14. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-t~rt.-bu-tylaminopropoxy)-phenyl]-l-propanone hydrochloride, Fp. 129-131-C.

15. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-isopro-pylaminopropoxy)-phenyl]-l-propanone semi-oxalate, Fp. 146-148-C.

16. 1-(2,4,6-trimethylphenyl)-3-t3'-(2-hydroxy-3-n-pro-pylaminopropoxy)-phenyl]-1-propanone hydrochloride, Fp. 84-85-C.

17. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-tert.-bu-tylaminopropoxy)-phenyl]-1-propanone hydrochloride, Fp.
123.5-125.5-C.

18. 1-phenyl-3-t3'-(2-hydroxy-3-tert.-pentylaminopropoxy)-4'-methoxyphenyl]-1-propanone semi-oxalate, Fp. 162-164-C.

19. 1-phenyl-3-t3'-(2-hydroxy-3-isopropylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, Fp. 157-158-C.

20. 1-phenyl-3-[3'-(2-hydroxy-3-tert.-butylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, Fp. 158-159-C.

21. 1-phenyl-3-[3'-(2-hydroxy-3-piperidinopropoxy)-4'-me-thoxyphenyl]-l-propanone hydrochloride, Fp. 115-117-C.

22. 1-(3,4-dimethoxypheny].)-3-[3'-(2-hydroxy-3-n-pro-pylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydro-chloride, Fp. 115-116.5-C.

23. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-iso-propylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-chloride, Fp. 128-131-C.

24. 1-(3,4-dimethoxyphenyl)-3-t3'-(2-hydroxy-3-morpholino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, Fp.
158-161C.

25. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-bu-tylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-chloride, Fp. 168-170-C.

26. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-cyclo-hexylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-chloride, Fp. 117.5-120.5-C.

27. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-pen-tylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-chloride, Fp. 147-148-C.

28. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-pentylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-chloride, Fp. 126-129 C.

29. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-n-pro-pylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-chloride, Fp. 103.5-106-C.

30. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-isopro-pylàminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-chloride, Fp. 115-116C.

31.` l-(3,4,5-trimethoxyphenyl)-3-~3'-(2-hydroxy-3-tert.-bu-tylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-chloride, Fp. 150.5-152C.

` ~ -- ` :

1`' , - 1331~77 ~ . 19 32. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroXy-3-CyClo-hexylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-chloride, Fp. 136.5-138.5-C.

33. 1-(2-methoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-pen-tylaminopropoxy)-4'-methoxyphenyl]-1-propanone acetate, Fp.
119-120-C.

34. 1-(2-methoxyphenyl)-3-t3'-(2-hydroxy-3-n-propylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, Fp.
141.5-143-C.

35. 1-(2-methoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-bu-tylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-chloride, Fp. 166.5-167-C.

36. 1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-tert.-pentyl-aminopropoxy)-4'- methoxyphenyl]-1-propanone hydrochloride, Fp. 107.5-109.5-C.

37. 1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-n-propylaminopro-poxy)-4'-methoxyphenyl]-1-propanone hydrochloride, Fp. 108-llOC.

38. 1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-morpholinopro-poxy)-4'-methoxyphenyl]-1-propanone hydrochloride, Fp. 117-119 . S C .

39. 1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-tert.-butylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, Fp.
117-ll9 C.

40. 1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-piperidinopro-po~y)-4'-methoxyphenyl]-1-propanone hydrochloride, Fp.
138.5-140'C. -~
- ~ ~
,; : .

C
;- ~: -.

~ 1331877 41. 1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-cyclohexylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, Fp.
134-136-C.

42. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-tert.-pen-tylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-chloride, Fp. 117-118-C.

43. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-piperi-dinopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, Fp. 119-120-C.

44. 1-(2,4,6-trimethylphenyl)-3-t3'-(2-hydroxy-3-n-propyl-aminopropoxy)-4'-methoxyphenyl]-1-propanone oxalate, Fp.
121-122-C.

45. 1-(2,4,6-trimethylphenyl)-3-~3'-(2-hydroxy-3-isopropyl-aminopropoxy)-4'-methoxyphenyl~-1-propanone hydrochloride, Fp. llO-lll-C.

46. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-morpho-linopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, Fp. 154-lSS-C.

47. 1-(2-naphthyl)-3-t3'-(2-hydroxy-3-tert.-pentylaminopro-poxy)-4'-methoxyphenyl]-1-propanone hydrochloride, Fp. 130-132-C.

48. 1-(2-naphthyl)-3-t3'-(2-hydroxy-3-n-propylaminopro-poxy)-4'-methoxyphenyl]-1-propanone hydrochloride, Fp. 142-143-C.

49. 1-(2-naphthyl)-3-[3'-(2-hydroxy-3-isopropylaminopro-poxy~-4'-methoxyphenyl]-1-propanone hydrochloride, Fp. 133-135-C.

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--` 133187~

50. 1-(3-phenanthrenyl) -3-[3'-(2-hydroxy-3-isopropylamino-propoxy)-phenyl]-1-propanone hydrochloride, Fp. 140-142'C.

51. 1-(3-phenanthrenyl) -3-[3'-(2-hydroxy-3-n-propylamino-propoxy)-phenyl]-1-propanone hydrochloride, Fp. 149-152-C.

2 x a m p l e 5 2 Manufacturing Process for Tablets a) Ingredients Compound of Example 1 75.00 g Microcrystalline cellulose (powder, 50 ~m) 15.75 g Poly-(1-vinyl-2-pyrrolidone) 5.00 g Hydroxypropylmethyl cellulose 2910 3.75 g Magnesium stearate 0.50 g lO0.00 g b) Mixing and Granulating The compound of Example l is optionally screened. All ma-terials except for magnesium stearate are then mixed in a mixer where they are moistened with a suitable amount of granulation liquid (for instance water or isopropanol-di-chloromethane l:l). The moist mixture is passed through a suitable sieve, dried in a drying cabinet and screened again. The dried granulate is mixed with the magnesium stearate in the mixer.
c) Pressing of Tablets The mixture prepared according to (a) is pressed in a tablet press into tablets weighing from 40 to 400 mg. The pressing force and the tablet diameter are so selected ~ ~
that the disintegration time in the testing device ~ -according to the Eur. Pharm. is less than 15 minutes and the tablets are sufficiently stable mechanically.

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. -, - . . : . : : :' ' - `

133187~
E x a m ~ l e 5 3 Manufacturing Process for Film-coated Tablets A. Ingredients a) Tablet (see manufacturing process for tablets, Example 52).

b) Film coating The total amount applied is 5-20% of the tablet weight and consists of:
~ydroxypropylmethyl cellulose 2910 77 %
Macrogol~R) 6000 (plasticizer) 23 %

B. Preparation of the Tablets (see manufacturing process for tablets, Example S2).

C. Preparation of the Film-coated Tablets The ingredients of the film coating are dissolved in a suit-able solvent (for instance water or ethanol/water 70:30).
The tablets are sprayed in a film coating apparatus with the solution containing the film former and plasticizer and are dried in a hot air stream. The film-coated tablets are fur-ther dried in a drying cabinet.

E x a m ~ 1 e 5 4 Manufacturing Process for Dragees A. Ingredients a) Dragee core .
(see manufacturing process for tablets) b) Dragee shell the total amount applied is 25-100% of the core weight and consists of:

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Saccharose 51.4 %
Talcum 24.0 %
Calcium sulfate hemihydrate 10.3 %
Starch syrup 5.0 %
Gum arabic 3.9 %
Macroqol(R) 6000 2.9 %
Titanium (IV) oxide 1.6 %
Finely dispersed silica 0.8 %
Sodium dodecylsulfate 0.1 %
100. 0 %

B. Preparation of the Dragee Cores (see manufacturing process for tablets) C. Preparation of the Dragees Composition of the dragee solution used, Precoating composition and dragee~coatin~ suspension a) Dragee solution Saccharose 47.6 %
Starch syrup 19.1 %
Gum arabic 3.8 %
Distilled water 29.5 %
100.0 %

-b) Precoating Composition Talcum 70,0%
Calcium sulfate hemihydrate 26.7%
Finely dispersed silica 3.3%
100.0%

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23a c) Coating suspension for Dragees Saccharose 47.8%
Talcum 9.6%
Calcium sulfate hemihydrate 4.8%
Gum arabic 3.6~
Starch syrup 3.2%
Macrogol (R) 6000 2.9%
Titanium (IV) oxide 1.6%
Sodium dodecylsulfate 0.1%
Distilled water 26.4%
100 . O %

Coating of Dragee Cores The dragee cores are first moistened in a rotating vessel with dragee solution and then powdered with sufficient precoating composition for them to roll freely again.
After the cores are dried, this process is repeated. The cores are then dried in a drying cabinet. The cores are then layerwise coated with the dragee coating suspension until the desired final weight is achieved. The cores must be dried after application of each layer.
E x a m ~ 1 e 5 5 Manufacturing Process for Capsules A. Dosage of the active ingredient of 75 mg and more 1. Ingredients Compound of Example 2 75.00 g Microcrystalline cellulose (powder, S0 ~m) 16.25 g Poly-(l-vinyl-2-pyrrolidone.)5.00 g Hyd~oxypropylmethyl cellulose 2910 3.75 q lOo.oo g , :` :

-:
~' :
:`

.

Saccharose 51.4 %
Talcum 24.0 %
Calcium sulfate hemihydrate 10.3 %
Starch syrup 5.0 %
Gum arabic 3.9 %
Macrogol(R) 6000 2.9 %
Titanium (IV) oxide 1.6 %
Finely dispersed silica0.8 %
Sodium dodecylsulfate0.1 %
100. 0 %

B. Preparation of the Dragee Cores (see manufacturing process for tablets) C. Preparation of the Dragees Composition of the dragee solution used, Precoating composition and dragee suspension a) Dragee solution Saccharose 47.6 %
Starch syrup 19.1 %
Gum arabic 3.8 %
Distilled water 29.5 %
100. 0 %

E x a m p 1 e 5 5 Manufacturing Process for Capsules A. Dosage of the active ingredient of 75 mg and more ~:

1. Ingredients Compound of Example 275.00 g ;:
Microcrystalline cellulose (powder, 50 ~m) 16.25 g ~ :
Poly-(l-vinyl-2-pyrrolidone)5.00 g Hydroxypropylmethyl cellulose 2910 3.75 g 100.00 g : : :

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. - .. . . . .

- - . . , ,:

2. Mixing and granulating acording to Example 52b) 3. Filling the Granulate into Capsules The granulate is filled by means of a capsulating machine into hard gelatine capsules of size 3, 2, 1 or 0, the amount filled into each capsule depending on the desired dosage of the active ingredient.

B. Dosage of the active ingredient 30-7S mg 1. Ingredients Compound of Example 3 30.00 - 75.00 g Microcrystalline cellulose (powder, S0 ~m) 61.2S - 16.2S g Poly-(l-vinyl-2-pyrrolidone) S.00 g Hydroxypropylmethyl cellulose 2910 3.7S q 100.00 g The sum of the amounts of active ingredient and micro-crystalline cellulose should always be 91.2S g. The amount of active ingredient is a thousand times the amount of the single dose.

2. Mixing and granulating according to Example S2b) 3. Filling the Granulate into Capsules 100 mg each of granulate are filled into hard gelatine cap-sules of size 3 or 2 with the aid of a capsulating machine.

E x a m D 1 e S 6 Manufacturing Process for ~mpoules 1. Ingredients Compound of Example 6 1.5 g Water for injection purposes ad: 100.0 ml .... . ..
",~ , .

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.~ . .

-~ 13318~

2. Preparation of the Solution 90% of the water necessary for the batch selected is placed into the reaction vessel. The active ingredient is dis-solved in said water under heat. The final volume is achieved by adding the necessary amount to the solution af-ter cooling.

3. Filling the Solution into Ampoules The finished solution is filled into glass ampoules, the amount filled in depending on the dosage desired. The glass ampoules are then sealed by fusion.

4. Sterilization The ampoules are vapor-sterilized for 20 minutes at 120C.

E x a m ~ 1 e 5 7 Manufacturing Process for Suppositories a. Ingredients Compound of Example 50 30 - 200 mg Hard fat (melting point 35-36.5C) ad: 2000 mg :: :
b. Preparation of the Melt containing the Active Substance The amount of hard fat necessary for a specific number of suppositories is melted in a water bath at 40-C. The active ingredient is pressed through an 0.8 mm sieve and mixed into the melt to give a suspension.
::
c. Preparation of the Suppositories The melt is allowed to cool down to 37-38C and filled under steady stirring into suppository forms in such amounts that --the weight of one suppository is 2000 mg. The suppository form is sealed after solidification of the melt.

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Claims

1. Aminopropanol derivatives of 3-(3-hydroxyphenyl)-1-pro-panone compounds of general formula I

(I) and their acid addition salts, wherein R1 and R2 are the same or different and denote hydrogen atoms, alkyl, cyclo-alkyl, alkenyl, alkinyl or hydroxyalkyl groups with up to 6 carbon atoms each, alkoxyalkyl, alkylthioalkyl or dial-kylaminoalkyl groups with up to 9 carbon atoms each, or phe-nylalkyl or phenoxyalkyl groups having up to 6 carbon atoms in the alkyl portion, the phenyl group optionally being sub-stituted by an alkyl or alkoxy group with respectively up to 3 carbon atoms, or R1 and R2 form together with the nitrogen atom which connects them a 5 to 7 membered, saturated heterocyclic ring, which may optionally be substituted by one or two phe-nyl and/or hydroxy groups and contain in the ring an oxygen or nitrogen atom as a further heteroatom, with the additional nitrogen atom optionally substituted by an alkyl group with 1 to 3 carbon atoms, or a phenyl group, R3 denotes a hydrogen atom, an alkyl group having up to 3 carbon atoms, a fluorine, chlorine or bromine atom, a hy-droxyl or alkoxy group with up to 6 carbon atoms, R4 denotes a hydrogen atom, an alkyl group having up to 3 carbon atoms, a fluorine, chlorine or bromine atom, a hy-droxyl group or an alkoxy group with up to 6 carbon atoms, or R4 together with the phenyl group bound to it is part of an anellated aromatic system having up to 18 carbon atoms, and n is an integer from 1 to 5.

2. Compounds according to Claim 1, characterized in that NR1R2 is a tert.-pentylamino, n-propylamino, 1,1-dimethyl-propylamino, morpholino, isopropylamino, tert.-butylamino, pyrrolidino, piperidino or cyclohexylamino group, the R3 residue is hydrogen, or a methyl, methoxy or hydroxy group, R4 is hydrogen, or a methyl, methoxy or hydroxy group or together with the phenyl group attached thereto is a 1-naph-thyl group, 2-naphthyl group or 3-phenanthrenyl group and n has the value 1, 2 or 3.

3. Compounds according to Claim 1, characterized in that NR1R2 is a tert.-pentylamino, n-propylamino, isopropylamino, tert.-butylamino, piperidino or cyclohexylamino group, the R3 residue is hydrogen, or a methoxy group, in the 4-po-sition, R4 is a methyl or methoxy group or R4 together with the phenyl group attached thereto is a 2-naphthyl group and n has the value 1, 2 or 3.

4. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-pen-tylaminopropoxy)phenyl]-1-propanone hydrochloride.

5. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-tert.-bu-tylaminopropoxy)phenyl]-1-propanone hydrochloride.

6. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-isopro-pylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-chloride.

7. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-cyclo-hexylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-chloride.

8. 1-(2-naphthyl)-3-[3'-(2-hydroxy-3-n-propylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride.

9. Process for preparing a compound according to Claim 1, Claim 2, Claim 3, Claim 4, Claim 5, Claim 6, Claim 7 or Claim 8 and acid addition salts thereof, characterized by reacting a phenol ether of general formula II

(II) wherein R3, R4 and n have the meaning indicated in Claim 1, with an amine of general formula III
HNR1R2 (III) wherein R1 and R2 have the meaning indicated in Claim 1, and if appropriate, converting the resulting compound with an acid into an acid addition salt.

10. A pharmaceutical composition suitable for the treatment of heart rhythm disorders which comprises a compound according to Claim 1, Claim 2, Claim 3, Claim 4, Claim 5, Claim 6, Claim 7 or Claim 8 in an amount sufficient to produce an antiarrhythmic activity and in combination with a pharmaceutical carrier.

11. The use of aminopropanol derivatives of 3-(3-hydroxyphenyl)-1-propanone compounds of general formula I
(I) and their acid addition salts, wherein R1 and R2 are the same or different and denote hydrogen atoms, alkyl, cyclo-alkyl, alkenyl, alkinyl or hydroxyalkyl groups with up to 6 carbon atoms each, alkoxyalkyl, alkylthioalkyl or dial-kylaminoalkyl groups with up to 9 carbon atoms each, or phe-nylalkyl or phenoxyalkyl groups having up to 6 carbon atoms in the alkyl portion, the phenyl group optionally being sub-stituted by an alkyl or alkoxy group with respectively up to 3 carbon atoms, or R1 and R2 form together with the nitrogen atom which connects them a 5 to 7 membered, saturated heterocyclic ring, which may optionally be substituted by one or two phe-nyl and/or hydroxy groups and contain in the ring an oxygen or nitrogen atom as a further heteroatom, with the additional nitrogen atom optionally substituted by an alkyl group with 1 to 3 carbon atoms, or a phenyl group, R3 denotes a hydrogen atom, an alkyl group having up to 3 carbon atoms, a fluorine, chlorine or bromine atom, a hy-droxyl or alkoxy group with up to 6 carbon atoms, R4 denotes a hydrogen atom, an alkyl group having up to 3 carbon atoms, a fluorine, chlorine or bromine atom, a hy-droxyl group or an alkoxy group with up to 6 carbon atoms, or R4 together with the phenyl group bound to it is part of an anellated aromatic system having up to 18 carbon atoms, and n is an integer from 1 to 5; for treating heart rhythm disorders, comprising administering to a patient requiring said treatment said derivative or salt in an amount sufficient to produce an antiarrhythmic activity.