AU606692B2

AU606692B2 - Aminopropanol derivatives of 3-(2-hydroxyphenyl)-1-propanone compounds, process for preparing same, and pharmaceutical compositions containing said compounds

Info

Publication number: AU606692B2
Application number: AU18241/88A
Authority: AU
Inventors: Gerd Petrick; Klemens Schubert
Original assignee: HELOPHARM PETRIK CO KG; 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: 1991-02-14
Anticipated expiration: 2008-06-22
Also published as: DE3821259A1; DK342188D0; AU1824188A; ZA884436B; FI883002A0; YU119988A; JPH0320382B2; IL86812A; EP0296264A1; HUT51234A; PT87792A; NO882770D0; GR890300035T1; HU204503B; PT87792B; GR3004456T3; SU1628855A3; IL86812A0; DE3868357D1; KR890000400A

Description

PATENT AND0 TRADE MARK ATTORNEYS M E L8 OU RN E S Y DN EY -PE RT H L

AUSTRALIA

PATENTS ACT 1952 C'OMPLETE SPECIFICATION Form

(ORIGINAL)

FOR OFFICE USE F4 0 Short Title: Int. Cl: Application Number: Lodged: Complete Specification-Lodged: Accepted- Lapsed: Publishedi Priority: Related Art:

SOSSOS

S

*SS*

*5 S S *5 0S

S

S.

S

eseese

S

S.

S *5 6S 5 0* f/s

S

*5 S 0* 6O *5 0 S S *5 TO BE COMPLETED BY APPLICANT Name of Applicant: Address of AppliLcant: HELOPHAP.M W. PETRIK GmbH CO. Y(G WALDSTR. 23-25 D-1000 BERLIN 51

GERMANY

Actual. inventor: Address for Service: CLEMENT RACK CO., 601 St. Kilda Road, Melbourne, Victoria 3004, Australia.

Complete Specification for the invention entitled: AMINOPROPANOL DERIVATIVES OF 3- (2-IjYDROXYPHENYL) -1-PROPANONE COMPOUNDS, PROCESS FOPR PREPARING SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAID COMPOUNDS The following statement is a full description of this inveration iacluding the best method of parforming it known to me:- 4t 1A Helopharm W. Petrik GmbH Co. KG 1000 Berlin 51, Federal Republic of GCermany Aminopropanol derivatives of 3-(2-hydroxyphenyl)-l-propanone compounds, process for preparing same, and ph'-maceutical *see*: compositions containing said compounds Background of the Invention German Patent No. 2 001 431 discloses 2-(2'-hydroxy-3'-alkylaminopropoxy)-p-phenyl-propiophenones of the general formula 55 550 HNH-R e* S.

OH

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

The EP-A-0 074 014 describes 2-[2'-hydroxy-3'-(1,1-dimethylpropylamino)-propox, -P-phenyl-propiophenone (cdiprafenone) and its acid addition salts. Diprafenone is anr antiarrhythmic.

The EP-A-0 075 207 describes aminopropanol derivatives of the general formula o 0Yl N NR 1

R

2 2 and its physiologically acceptable acid addition salts.

Typical examples for R 1

-R

4 include hydrogen atoms or alkyl groups and n has a value of 1, 2 or 3. These compounds are pharmaceuticals.

Summary of the Invention One object of the invention is to provide novel aminoprop-nol derivativeF of 3-(2-hydroxyphenyl)-l-propanone compounds of the g .eral formula I and physiologically acceptable acid 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.

S Finally, it is an object of the invention to provide pharmaceutical compositions for treating heart rhythm disorders which contain those compounds or their physiologically acceptable acid addition salts.

Detailed Description of the Invention

*S

The invention relates to novel aminopropanol derivatives of 3- (2-hydroxyphenyl)-l-propanone compounds of general formula I

R

4 fCH2-CH2-CC (n) CH -CCH -NR R 2 2 O-CH2 -CH-CH 2-NR R2

(I)

OH

and their acid addition salts, and to a process for preparing the same. The invention also relates to pharmaceutical compositions containing a compound of the general formula I or an acid addition salt thereof, preferably a physiologically acceptable acid addition salt.

3 In general formula I, R 1 and R 2 are the same or diffe~rnt and denote hydrogen atoms, alkyl, cycloalkyl, alkenyl, alkinyl 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 al vl portion, the phenyl group optionally being substituted by an alkyl or alkoxy group with up to 3 carbon ato.ns each, or R 1 and R 2 form together with the nitrogen atom connecting 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 nitrogen atom as a further heteroatom, with the additional nitrogen atom optionally substituted by an allkyl group with 1 to 3 carbon atoms, or by a phenyl group. R 3 is a hydrogen atom, an alkyl group having up to 3 carbon atoms, a fluorine, chlorine or bromine atom, a hydroxyl group or an alkoxy group with up to 6 carbon 4 atoms. R 4 denotes a hydrogen atom, an alkyl group having up to 3 carbon atoms, a fluorine, chlorine or bromine atom, a hydroxyl group or an alkoxy group with up to 6 carbon atoms.

n is an integer of 1 to Preferred compounds are those in which NR1R 2 is a tert.pentylamino, n-propylamino, 1,l-dimethylpropylamino, morpholino, isopropylamino, tert.-butylamino, pyrrolidino, piperidino or cyclohexylamino group, the R 3 residue is hydrogen, or a methyl, methoxy or hydroxy group,

R

4 is hydrogen, or a methyl, methoxy or hydroxy group and n has the value of 1, 2 or 3.

Especially preferred compounds are those in which NR 1

R

2 is an n-propylamino, isopropylamino, tert.-butylamino or piperidino group, the p 3 residue is hydrogen,

R

4 is hydrogen, or a methoxy group, and n has the value of 1 or 2.

4 The most preferred compounds include 1- (3,4-Dimethoxyphenyl) (2-hydroxy-3-n-propylamin©propoxy)-phenyl]-l-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]lpropanone hydrochloride, (Example 47).

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 4 __n S-CH- C-CH

(II)

0 2 *2 with an amine of general formula III e

HNRR

2

(III)

R1, R 2

R

3

R

4 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 to 120*C, that is at room temperature or at higher temperatures, 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 diluent or solvent, such as a lower alcohol having 1 to 4 carbon atoms, as for instance methanol, etihanol or propanol, preferably isopropanol or ethanol, a lower saturated dialkyl ether, dialkylglycol ethers or cyclic ethers, such as diethyl ether, 1,2-dimethoxyethane, tetrahyd.-ofuran or dioxane, a benzene hydrocarbon, such as benzene itself or an alkyl benzene, in particular toluene or xylene, or an aliphatic hydrocarbon, such as hexane, heptane or octane, dimethylsulfoxide or in the presence of water or mixtures of the mentioned sol-ents.

*t4> When used in excess, the amine of general fomrula III may S also be a suitable diluent or solvent.

S 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 manner, for instance by filtration or distillation of the diluent from the reaction mixture. The compound obtained is pu- S rified in the usual manner, for instance by recryFtallization 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 2-hydroxy-p-phenylpropiophenone having the general formula IV

R

4 n CH -CH -CO-

(IV)

with an epihalohydrin. R 3

R

4 and n have the above meaning.

Examples of epihalohydrin5 are epichlorohydrin, epibromohydrin and epiiodohydrin.

6 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 120'C and normal pressure or in a closed vessel at elevated pressure. Suitable solvents or diluents are a lower aliphatic ketone, such as acetone, methylethyl ketone or methylisobutylketone, a lower alcohol having 1 to 4 carbon atoms, such as methanol, ethanol, propanol or butanol, a lower aliphatic or cyclic ether, such as diethylether, tetrahydrofuran or dioxane, a dialkylformamide, 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 metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, 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 trimethyl amine or triethyl amine, or piperidine. The bases S can be used in catalytic or stoichiometric amounts or in slightly excess amounts with respect to the alkylating agent used.

i 2-hydroxy-p-phenylpropiophenone is preferably reacted with epichlorohydrin or epibromohydrin in a polar, aprotic solvent, in particular dimethylsulfoxide, at temperatures ranging from 0° 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 2hydroxy-p-phenylpropiophenone, and its preparation are known.

The compound of formula I obtained accordiT:g to the invention is optionally converted into an acid addition salt, preferably into a salt of a physiologically acceptable acid.

Usual physiologically acceptable inorganic and organic acido are for instance 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 described for instance in Fortschritte der Arzneimittelforschung, vol. 10, pp. 224-225, Birkhauser f publishers, Basle and Stuttgart, 1966, and Journal of Pharmaceutical Sciences, vol. 66, pp. 1-5 (1977). Hydrochloric acid is preferred.

*9 to The acid addition salts are normally obtained in a conventional manner by mixing the free base or its solutions with the corresponding acid or its solutions in an organic solvent, for instance a lower alcohol, such as methanol, ethanol, n-propanol or isopropanol, or a lower ketone, such as q* 9 acetone, methylethyl ketone or methyl-isobutyl ketone, or an ether, such as diethyl ether, tetrahydrofuran or dioxane.

Mixtures o. the mentioned solvents can also be used for better crystal deposition. Moreover, 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 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 inorganic 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 compositions for oral, rectal, intravenous or intramuscular application, 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 tri-atment of heart rhythm disorders.

The pharmaceutical compositions of the invention are prepared in a conventional manner with the usual solid or iiquid carriers or diluents and the conventional pharmaceutical adjuvants in a suitable dosage form in accordance with the desired form of application. The preferred preparations .a are compositions in dosage unit form for oral applications.

a* Such pharmaceutical forms are for instance tablets, film- #98064 coated tablets, dragees, capsules, pills, powders, solutions or suspensions or depot preparations.

t Parenteral preparations, such as injection solutions, are of S course also suitable. Another pharmaceutical form to be Ss, mentioned is, for instance, the suppositories.

Corresponding tablets can be obtained for instance by mixing i h: the active ingredient with known auxiliaries, for instance with inert diluents, such as dextrose, sugar, sorbitol, mannitol, 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 carboxypolymethylene, carboxymethyl cellulose, celulose acetatephthalate 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 polyvinylpyrrolidone or shellac, gum arabic, talcum, titanium dioxide or sugar. The dragee shell may also consist of several layers, wherein the auxiliaries mentioned above in connection with the tablets may be used.

Solutions or suspensions comprising the inventive active ingredient may additionally contain flavoring agents, such as saccharin, cyclamate or sugar and for instance aromatics, such as vanillin or orange extract. Moreover, they may contain suspension auxiliaries, such as sodium carboxymethyl cellulose or preservatives, such as p-hydroxybenzoates. Cap- S sules containing the active ingredient can for instance be prepared by mixing the active ingredient with an inert car- S" rier, such as lactose or sorbitol, and encapsulating it in gelatine capsules.

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

1 In humans, the single dove is from 0.5 5 mg/kg for oral application from 0.05 2 mg/kg for intravenous application from 0.1 3 mg/kg for intramuscular application from 0.5 10 mg/kg for rectal application.

S. In particular, the antiarrhythmic and p-sympatholytic properties of the compounds of the invention and their physiologically acceptable acid addition salts make them especially suitable for the pharmacotherapy of heart rhythm disorders, treatment of coronary heart disease, and prophylaxis of sudden death from heart disease. The antiarrhythmic efficacy of the inventive compounds was established both by electrophysiological studies on c ;'eart Purkinje fibers and with the aid of ouabain-induced ventricular tachycardia in dogs.

In the following tables I and II the compounds of the invention are compared to propafenone The effect on the contractive strength of the heart was tested on guinea pig papillary muscle. Hemodynamic studies were carried out on both healthy and acutely infarcted dogs.

One important criterion in table I which follows is the safety factor which is calculated from the relationship of the antiarrhythmic efficacy, the negative inotropy and the specifically greater efficacy at higher frequencies according to the formula: rate factor of Vmax x (C20 CF/C20 Vmax). By way of comparison it is noted that the currently leading antiarrhythmics propafenone and flecainid have an S.F. of 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 sigifticant increase in toxicity compared to propafenone as G ~oan from a comparison of the LD 50 values in rats and mice which are summarized in table II.

too* io i 11 Table Example S, C20 CF C20 Vmax Rate Factor P olnat22 ity NO. (AM) OLM of Vmax Factor Vmax 4 4***r .4 9.

I

*4 A *4

A

15.0 22.0 12.0 20.0 18 0 13.0 25.0 18.0 9.0 10.0 4.0 6.0 2.0 5.7 12.51 3,0 4* 3 4 1.7 .8 11.0 1.6 1.7 1.0 2.) 2.2 0 1.0 3.7 5.00 1.27 1.13 1.39 1.32 1.39 1.34 1.30 1.14 5.00 1.15 1.16 0.90 1.30 1.11 2.50 1.08 1.18 1.08 0.50 1.15 1.01 0.98 70 0.98 0.97 0.0? 0.90 0.50 1.01 0.52 1.24 0.97 0.99 0.92 0.99 a. 9 0.07 6. Q 2.8 3.8 2 .2 4.4 2.1 3 7.2 5.4 2.

em e C20 CF: 020 Vmax: Rate Factor of Vmax Prematurity Factor Vmax:

S.F.:

Concentration that reduces contractions of "the papillary muscle by Concentration that reduces Vmax by 20% at a basic cycle lenath of 1000 msec.

control Vmax at a basic cycle length of 2000 msec)/(% control Vmax at a basic cycle length of 500 msec) at C20 Vmax.

control Vmax at premature extrasystoles), control Vnax at a normal beat) at Vmax.

Safety factor computed as "ate Factor of Vmax x CF/C20 Vnax).

v -I

CLAIM

Aminopropanol derivatives of 3- (2-hydroxyphenyl) -1-propanone Compounds of general torrnula I.

12 Table 11i

LD

50 (mg/kg) ft

U

.ftftft a

II...

ft. ft ft ft If, ft.

ft ft

I.

ft Oft ftft ft ft.

ft ft ft.

ft ft S.

a,.

0* 4 0 ft...

aft ft ft ft 4ft ft. ft ft ft.

*4 Test qompound. Rat (i.v Mouse -~iv Example 1 17 16 11 38 1.9 17 The invention is illustrated by the examples.

A) Preparation of the starting compounds: Example T 1- 4-Dimethox.yphenyl) 21 1,2-epoxy-3-propoxy) -phenyl] 1-propanone 275.4 g (0.96 mole) of 3, 4-dimethoxy-P 2 1-hydroxyplienyl -propiophc~ione are heated under refluxing for 5 hirs with 500 ml of ep,Lchlorohydrin, 300 ml of 2-propanol and 38.5 q (0.97 mole, of sodium hydrox-ide and stirred. The resu2.tinq salt is filtered off, and the solution is evaporated under reduced pressure. The oily resicdue is usod without purification in the next step, Yield: 334.2 q (100 of the title compound.

Thy' following compounds were prepared in the same manner: 1- 5-trimethoxyphenyl) 2-epoxy--3-propoxy) -pheryl] -l-propano-ne l-(3 ,4,5-trirmethylphenyi) (l,2-epoxy--3-propoxy) -'heanyl] -1-propanone 1- 6-trimethylphenyl) 2-epoxy-3--propoxy) -phe-' nyl I-2,-propartone I-phenyl-K3-[2'-(2,2-epoxy-3-propoxy) -methoxyphenyl3-Lpropanone 1- (3-methoxyphenyl) -3-Fr2'- 2-epoxy-3-ptopoxy) -phenyl] -1propanone 13 l-(4-methoxyphenyl) -3-[21'-(1,2-epoxy-3-propoxy) -phenyl]-lpropanone I-(2-methoxyphenyl)-3-[2'- (1,2-epoxy-3-propoxy)-phenyl]-lpropanone !-(4-methylphenyl)-3-[21-(1,2-epoxy-3-pr dropanone l-phenyl-3-[2-(1, 2-epoxy-3-propoxy) -phenyl propanone B) Preparation of the inventive compounds: Example 1 I- (3,4-diinethoxyphenyl) [2 (2-hydroxy--3-n-propylaminopropoxy) -phenyl]-l-propanone hy.rochloride 11.3 g (0.033 mole) of 1-(3,4-d.methoxypheny)-3-[2-(1,2epoxy-3-propoxy) -phenyl]-l-propanone and 5.9 g ('0.099 mole) of n-propvlamine are dissolved in 100 ml of methanol and heated for 3 1/2 hrs under refluxing. The solvent and the amount of amine are removed under reduced pressure.

Thr oily residue is dissolved in 150 ml of isopropanol, and concentrated hydrochloric acid is added thereto. After heating and cooling the solution, crystals are obtained ft.. which are drawn off, dried and recrystallized from isopropanol. Yield: 8.2 g of the title compound, mp. 126*C.

The following compounds were prepared in the same manner (Examples 2 to 49): 2. 1-(3,4-dimethoxypheyl) -3 (2 -hydroxv-3-tert -pentylaimiinopropoxy) -phenylj-1-propanone hydrochloride, mp. 151j 152 0

C.

3. 1-(3,4-dimethoxyphenyl)-3-[2-(2-hydroxy-3-morpholinopropoxy)-phenyl]-l-propanone hydrochloride, mp. 150-151*C.

1 L .L 14 4. 1,,--(3,4-dimethoxypheriyl) -3-212- (2-hydroxy-3-isopropylaIminopropoxy) -plenyl] -1-propanone hydrochloride, tap. 135- 1360 C.

1-(3,4-dimethoxyphenyl)-3-[2'-(2-hydroxy-3-tert.-butylaininopropoxy) -phenj l]J- -propanone i.,drochloride, fup. 164- 1650 C.

6. 1-(3 ,4-dimethoxyphenyl)-3-(2 '-(2--hydroxy--3-piperidinopropoxy) -phenyl] -1-propanone hydrochloride, mnp. l24-125*C.

7. l-(3,4-dimethoxyphenyl)-3-[2'-(2-hydr-oxy-3-(2"1-hydroxypropyl amino) -propoxy) -phenyl] -1-propanone hydrochloride, fnp.

*a 109-2,ll 0

C.

8. l-(3,4-dimethoxyphenyl)-3-(2'-(2-hydroxy-3--(21"-hyzxyethy 1amino) -propoxy) -phenyl) -1-propanone hydrochloride, mp. 146-l47.5*2..

9. 1-(3 ,4-dimethoxyph-nnyl)-3-(2 '-(2-hydroxy-3- (l"-hydroxy-

P

0.a.S'but- 2 -ylamnino) -propoxy) -phenyl 1-propanone oxalate, rnp.

195-197*C.

-A "See 10. imethoxyphernyl)-3-(2'-(2-hydroxy-3-tert.pentylaminopropoxy) -phenyl] -l-propanone hydrochloride, inp. 179-180*C.

*11. 1-(3,4,5-trimethoxyphenyl)-3-f2'-(2-hydroxy-3-n-propylaminopropoxy) -phenyl]-1-propanone hydrochlo,.ide, i1p. 140-- 142*C.

12. 1-(3,4,5-trimethoxyphenyl)-3-(2'-(2-hydroxy-3-isopr-opylaim"Lnopropoxy) -phenyl] -1-propanone hydrochloride, rnp.

161-62*C.

0 0- r NR R

GH

13. 4, 5-trimethoxyphenyl) -3-L2'-(2-hydroxy-3-tert.-butyli:.nopropoxy) -phe.nyl] -1-propanone hydrochloride, rnp.

178.5-179. 14. 1-(3,4,5-trimethoxyphenyl)-3-[2'-(2-hydroxy-3-piperidinopropoxy)-phenyl--propanole hydrochloride, mp. 148.5- 1500 C.

1-(3,4,5-trimnethoxypheny1)-3-t2'-(2-hydroxy-3-morpholinopropoxy) -phenylj-1-propanone hydrochloride, mp. 166.5- 167. 5 0

C.

16. 1-(3,4,5-trimethoxypheny)-3-[I2'-(2-hydroxy-3-cycl0- -phenyl)-1-propanone hydrocrhloride, mp.

0158. 5-159.5' C.

0 17. 1-(3,4,5-trimethlylpheny)-3-f2'-(2-hydroxy-3-piperidinopropoxy)-phenyl]-l-propanone hydrochloride, mp. 133- 13 4 *Q.

1-(2,4,6-triiethypheny)3-2-(2-hydr0xy-3-flpropylam!inopropoxy) -pheny )1 1-prop anone oxalate, rap. 184-185*C.

*a 19. 1-(2,4,6-trimethypheny)-3-I2-(2.-hydroxy-3-tert.-butyla!Ainopropoxy) -pheriyl]-1-propanone oxalate, mp. 148-150*C.

1-(2,4,6-trimethylphenyl)-3-[2'-(2-hydroxy-3-tert.-peltylaininopropoxy) -pheniyl)]-1-propanone hydrochloride, mp. 118-120*C.

21. 1-246tiehlhnl--2-2hdoy3io propylaminopropoxy) -phenyl] -1-propanone hydrochloride, mp.

111-1,120 C.

22. 1-(2,4,6-trimethylphenyl)-3-I2'-(2-hydroxy-3-morpholinopropoxy) -phenyl)-l-propanone hydrochloride, mrp. 132-133'C.

16 23. I-pheriyl-3- (2-hydroxy-3-tert. -pentylaninopropoxy) 41-rnethoxyphenyl]---propanone oxalate, nip. ll8-120*C.

24. 1- (3 -inethoxyphenyl) -3 1- (2 -hydroxy- 3 -isopropyl aminopropoxy) -phenyl]--propanone hydrochloride, nip. 109.5*C.

1- (3-inethoxyphenyl) (2-hydroxy-3-tert. -pentylaminopropoxy) -phenyl) -1-propanone hydrochloride, nip.

113. 5* C.

26.* 1- (3 -mnethoxyphenyl) 3- [2 (2 -hydrox 3 ropyl aminopropoxy) -phenyl] -1-proparione hydrochloride, nip. 105.50 C.

27. 1-(3-znethoxyphenyl)-3-212-(2-hydroxy-3-tert.-butylaininopropoxy) -phenyl]-1-propanone hydrochloride, nip. 110- 111*C.

1- (3 -iethoxyphenyl) (2-hyLroxy-3 -morphol mno-, propoxy) -phenyl] -1--propanone hydrochloride, nip. 124. 29. 1- (4-methoxyphenyl) (2-hydroxy-3-tert. pentylaiinopror-oxy) -phenyl 1-1-propanone hydrochloride, mp.

114.5-115. 5 *C, 1- (4 -methoxyphenyl) (2-hydroxy-3-piperidinopropoxy) -phenyl] -1-propanone hydrochloride, mp. 1510 C.

31. 1- (4 -methoxyphenyl) [2 -hydroxy-) -n-propylamincpropoxy)-phenyl]-1-propanone hydrochloride, nip. 115.5-116.5*C.

32. 1-(4-methoxyphenyl)-3-(2'-(2-hydroxy-3-tert.-butylaninopropoxy) -phenyllJ-1-propanone hydrochloride, nip. 142-143 0

C.

33. 1- (2-methoxyphenyl) -hydroxcy-3 -isopropylaminopropoxy) -phenyJ. I-1-propanone hydrochloride, nip. 147-148 0

C.

17 34. 1- (2-methoxyphenyl) [21- (2-hydroxy-3-tert. -pentylaminopropoxy) -phienyl] -1-propanone hydrochloride, rnp. 146- 149 00.

l-(2-imethoxyphenyl) 3-1 -(2-hydroxy-3-iperidinopropoxy) phenyl)-l-propanone hydrochloride, mp. l07.5-l09.5*C.

36. 1-(2-methoxyphenyl)-3-[2'-(2-hydroxy-3-(4"1-ethyl-1"1piperaziny2,) -propoxy) -phenyl] -l-propanone hydrochloride, itp. 172-1751C.

37. 1- (2-methoxyphenyl) (2-hydroxy-3-n-propy'Lainopropoxy),-phenyl]-l-propanone hydrochloride, mp. l25-l28*C.

00:6 38. l-(2-xnethoxyphenyl)-3-(2'-(2-hydroxy-3-tert.-butylairinopropoxy)-phenyl]-l-propanone hydrochloride, rnp. 145- 147*C.

39. 1- (2-methoxyphenyl) (2-hydroxy-3-morpholinopropoxy)-phenyl]-l-pro,-7one hydrochloride, nip. 94-96*C.

4,0to0 40. 1- (4-xnethylphenyl) (2-hydroxy-3-isopropylaniinopro- PCx.Vy) -phenyl]-l-propanone hydrochloride, nip. 126.5-128.5*C.

41. 1- (4-inethyiphenyl) (2-hydroxy-3-cyclohexylaminopropoxy) -phenyl]-l-propanone hydrochloride, nip. 154-156*C.

42. l-(4-methylphienyl)-3-[2'-(2-hydroxy-3-tert.-pentylaminopropoxy) -phenyl]-l-propanone hydrochloride, nip.

43. 1-(4--methylphenyl) -3-C 2 -(2-hydroxy-3-n-propylaminopropox~y) -phenyl]-l-propanone hydrochloride, nip. 109-111'C.j 44. 1- (4-methylphenyl) (2-hydroxy-3-tert. -butylaminopropoxy)-phenyl]-l-propanone hydrochloride, nip. 132.5-133.5*C.{ 18 l-phenyl-3-[2 I- (2-hydroxy-3-isopropylarninopropoxy) -phenyl]-l-propanone hydrochloride, mp. 85-90*C.

46. l-phenyl-3-j2 (2-hydroxy-3-cyclohexyl am inopropoxy) phenyl]-l-propanone hydrochloride, mp. 1,37-140*C.

47. 1-phenyl-3-[2'- (2-hydroxy-3-piperidinopropoxy) -phenyl]- 1-propanone hydrochloride, mp. 132-133*C.

48. l-phenyl-3-[2 '-(2-hydroxy--3-tert.-butylaminopropoxy) phenyl]-l-propanone hydrochloride, inp. 108-109*C.

49. l-phenyl-3-[2'- (2-hydroxy-3-(3"1-methoxypropylamino) propoxy) -phenyl]-l-propanone hydrochloride, mp. 114-1l6*C. S 400 OS S 0 0 *5e4 4. 0

S.

*0 *0 0 0 55 4 a 0 0*

S.

00 0

OS

40

S

4500 00 4 00 0* 55 0

OS

.4 E x am ole 5 0 Manufacturing Process f'or Tablets a) Ingredients Compound of Example 1 Microcrystalline cellulose (powder, 50 Am) Poly- (l-vinyl-2-pyrrolidone) Hydroxypropylmethyl cellulose 2910 Magnesium stearate 75.00 g 15.75 g 5.00 g 3.75 g 0.50 cr 100Q.00 g b) Mixing and Granulating The compound of Example I is optionally screened. All materials except for magnesium stearate are then mixed in a mixer where they are mo].stened with a suitable amount of granulation liquid (for instance water or isopropanoldichloromethane 1l,) The moist mixture is passed through a suitable sieve, dried in a drying cabinet and screened

Y

era 4 19 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.

Exampl e 5 1 Manufacturing Process for Film-coated Tablets A. Ingredients a) Tablet (see manufacturing process for tablets, Example 52).

e Ga a b) Film coating The total amount applied is 5-20% of the tablet weight and consists of: Hydroxypropylmethyl cellulose 2910 77 Macrogol(R) 6000 (plasticizer) 23 B. Preparation of the Tablets (see manufacturing process for tablets, Example 52).

C. Preparation of the Film-coated Tablets I The ingredients of the film coating are dissolved in a suitable 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 ft :ther dried in a drying cabinet.

E X, a m D 1 e 5 2 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 p

S

5455 54 4 41* 4

S

0 4 5 ,1.

5 4 0 4' S *0 O up S .4 54 5

S

4p 5* a. S S S '0 44 consists of: Saccharose Tal1cum Calcium sulfate hemihydrate Starch syrup Gum arabic Macrogo-,(R) 6000 Titanium (IV) oxide Finely dispersed silica Sodium dodecylsulfate 51.4 24.0 10.3 3.9% 2.9% 1.6 0.8 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 suspension a) Dragee soluti-nf Saccharose Starch syrup Gum araibic Distil1sd water 47.6% 3.8% 29.5% 100.0% L- which is separatea ana -ne oaude -s aya -i salt.

21 Precoating Composition Talcum 70.0 Calcium sulfate hemihydrate 26.7 Finely dispersed silica 3.3 100.0 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 9 100.0 9 99 Coating of Dragee Cores

S

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 9 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.

W1J.t-,JL I.JL Y~l.1-4 V .AS. IAk l lVAl-- compositions commonly used in dragee coatings, such as polyvinylpyrrolidone or shellac, gum arabic, talcum, titanium I L I _I 'I -"II 'r' i- .e Example Manufacturing Process for Capsules A. Dosage of the active ingredient of 75 mg and more 1. Ingredients Compound of Example 2 Microcrystalline cellulose (powder, 50 pm) Poly-(l-vinyl-2-pyrrolidine) Hydroxypropylmethyl cellulose 2910 75.00 g 16.25 g 5.00 g 3.75 c 100.00 g 0 0.

o f 0 a 0 S C *5

S

2. Mixing and granulating according to Example 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 30-75 mg 1. Ingredients Compound of Example 4 Microcrystalline cellulose (powder, 50 gm) Poly-(l-vinyl-2-pyrrolidone) Hydroxypropylmethyl cellulose 2910 30.00 75.00 g 61.25 16.25 g 5.00 g 3.75 c 100.00 g The sum of the amounts of active ingredient and microcrystalline cellulose should always be 91.25 g. The amount of active ingredient is a thousand times the amount of the single dose.

i

I

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

F Y a m n1 e 5 4 Manufacturing Process for Ampoules 1. Ingredients Compound of Example 8 Water for injection purposes ad: 1.5 g 100.0 ml 0 *Oee 0e** 0 0*

B

0 *0 9 B B *0

B

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

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

4. Sterilization The ampoules are vapor-sterilized for 20 minutes at 120'c, Exam n 1 e 5 Manufacturing Process for Suppositories a. Ingredients Compound of Example 22 30 200 mg Hard fat (melting point 35-36.5"C) ad: 2000 mg i-pra3li~- sll I~ I ~P~YYI~ 24 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 37-38°C 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.

4 4* q' 9 9 9 9 .9 9 9 9 9 9 9**9 99 9 4 9 9.

9 9* @9 d

Claims

1. Aminopropanol derivatives of 3-(2-hydroxyphenyl)-l-pro- panone compounds of general formula I 4 -Cli-COj N12 O-CH 2-CH-CH -NR R OH and their acid addition salts, wherein R 1 and R 2 are thc. same or different and denote hydrogen atoms, alkyl, cyclo- alkyl, alkenyl, alkinyl or hydroxyalkyl groups with up to 6 carbon atoms c ch, alkoxyalkyl, alkylthioalkyl or di- alkylaminoalkyl groups with up to 9 carbon atoms each, or phenylalkyl or phenoxyalkyl groups having up to 6 carbons Satoms in the alkyl portion, and the phenyl radical is op- tionally substituted by an alkyl or alkoxy group with up to 3 carbon atoms each, or R 1 and R 2 form together with the nitrogen atom connecting them a 5 to 7 Iembered, 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 nitrogen atom as a further heteroatom, with the additional nitrogen atom op- tionally substituted by an alkyl group with 1 to 3 carbon atnms, or by a phenyl group, R 3 denotes a hydrogen atom, an alkyl group having up t- 3 carbon atoms, a fluorine, chlorine or bromine atom, a hy- droxy group or an alkoxy group with up to 6 carbon atoms, R 4 denotes a hydrogen atom, an alkyl group having up to 3 carbon ato .s a fluorine, chlorine or bromine atom, a hy- droxy group or an alkoxy group with up to 6 carbon atoms, and n is an integer from 1 to 26

2. Compounds according to Claim 1, characterized in that NR R 2 is a tert.-pentylamino, n-propylamino, 1,1-dimethyl- propylamino, morpholino, isopropylamino, tert. -butylamino, pyrrolidino, piperidino or ckyclohexylamino group, the R 3 residue is hydrogen, or a methyl, methoxy or hydroxy group, R4 is hydrogen, or a mnethyl, methoxy or hydroxy group, and in that n has the value of 1, 2 or 3.

3. Compounds according to Claim 1, characterized in that NR 1 R 2 is an n-propylamino, isopropylamino, tert.-butylamino or piperidino group, the R 3 residue is hydrogen, Ris hydrogen or a methoxy group and n has the value of 1. or 2. amino-propoxy) -phenylj--l-propanone hydrochloride. 1- (3-methoxyphonyl) -(2-hydroxy-3-isopropylamfino- propoxy) -phenyl]J-1-propanone hydrochloride.

6. l-phenyl-3-[1 (2-hydroxy-3-piperidilopropoxy) -phenyl]- ?-propanone hydrochloride.

7. Process for preparing the compounds according to Claims 1 to 6 and their acid addition salts, characterized by re-'-c- S ting a phenol ether of general formula II R 0 wherein R 3 R4 and n have the meaning indicated in Claim 1, with an amine of general formula I I r HNR 1 R 2 (III) wherein R 1 and R 2 have the meaning indicated in Claim 1, and if appropriate, converting the resulting compound with an acid into an acid addition salt.

8. A pharmaceutical composition suitable for the treatment of heaxc rhythm disorders which comprises a compound accor- ding to Claims 1 to 6 in an amount sufficient to produce an antiarrhythmic activity and in combination with a pharmaceu- tical carrier. S

9. A method of treating heart rhythm disorders which com- prises administering to a patient requiring said treatment a compound according to Claims 1 to 6 in an amount sufficient to produce an antiarrythmic activity. *t DATED THIS 22ND DAY OF JUNE 1988 HELOPHARM W. PETRIK GmbH CO. KG By its Patent Attorneys: CLEMENT HACK CO. Fellows Institute of Patent Attorneys of Australia.