AU606693B2 - Aminopropanol derivatives of 3-(3-hydroxyphenyl)-1-propanone compounds, process for preparing same, and pharmaceutical compositions containing said compounds - Google Patents

Description

PATENT AN D TRADE MARK ATTORNEYS MELBOURNE SYDNEY PERTH ;I i 1

AUSTRALIA

PATENTS AC, 1952 COMPLETE SPECIFICATION F66 93 Form

(ORIGINAL)

FOR OFFICE USE Short Title: Int. Cl: Application Number: Lodged: Complete Specification-Lodged: Accepted: Lapsed: Published: Priority: Related Art: 00 0 L 00 0000 *00* @0 0 0* 00 *0

S

S.

S

06 @0 00 S @0 *r O 5 0 S. S 0S 0 TO BE COMPLETED BY APPLICANT Name of Applicant: Address of Applicant: Actual Inventer: Address for Service: HELOPHARM W. PETRIK GmbH CO. KG WALDSTR. 23-25 D-1000 BERLIN 51

GERMANY

CLEMENT HACK CO., 601 St. Kilda Road, Melbourne, Victoria 3004, Australia.

Complete Specification for the invention entitled: AMINOPROPANOL DERIVATIVES OF 3-(3-HYDROXYPHENYL) -1-PROPANONE COMPOUNDS, PROCESS FOR PREPARING SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAID ,OMPOUNDS The following statement is a full description of this invention including the best method of performing it known to me:-

L

A1 Helopharm W. Petrik GmbH Co. KG Aminopropano]. derivatives of nydroxyphenyl) -1-propanone compounds, process for preparin,,. same, and pharmaceutical compositions containing said compounds I Backg~round of the Invention German Patent No. 2 00). 431 discloses 2-(2'-hydroxv-31-alam inopropoxy) -,G-phenyl -prop iophenones of the general f form a 0 03 H-

S.R

and theLr acid addition salts. Although these compounds and their salts constitute pharmaceuticals, only the n-pro- :pylamino compound (propafenone) shows antiarrhythmic *.:activity.

The EP-A-0 074 014 describes 2-[2'-hydroxy-3'-c1.l-dimethylpropylamino) -propoxy]-p-phenyl-propiophenone (diprafenone) and its acid addition salts. Diprafenone is an antiarrhythmic.

2 The EP-A-0 075 207 describes aminopropanol derivatives of the general formula 0 o NR 1R2

OH

R R 4 3 and its physiologically acceptable acid addition s'lts. 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 *see 9. One object of the invention is to provide novel aminopropanol derivatives of 3-(3-hydroxyphenyl)-l-propanone compounds of the general formula I and physiologically acceptable acid 0* 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, Sit 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 The invention relates to novel aminopropanol derivatives of 3- (3-hvdroxyphenyl)--propanone compounds of general formula I R4 n CH-CH -CO (I) 3 2 2

O-CH

2 -CH-CH-NR R 0OH gii0~'--ii ;l *ii~,yy ~B 3 and their acid addition salts, and to a process for preparing same. The invention also relates to pharmaceutical compositions containing a compound of general formula I or acid addition salts thereof, preferably a physiologically acceptable acid addition salt.

In general formula I, R 1 and R 2 are the same or different 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 alkyl portion, the phenyl group optionally being substituted by an alkyl or alkoxy group with respectively up to 3 carbon atoms, or R 1 and R 2 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/orhydroxy groups and contain in the ring an oxygen or nitrogen atom as a further heteroatom, with the additional nitrogen atom optionally S substituted by an alkyl group with 1 to 3 carbon atoms, or by a phenyl group. R 3 denotes a hydrogen atom, an alkyl group having up to 3 carbon atoms, a fluorine, chlorine or bromine atom, a hydroxyl or alkoxy group with up to 6 carbon 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, or R 4 together with the phenyl group bound to it is part of an anellated aromatic system having up to 18 carbon atoms. n is an integer from 1 to Preferred are compounds in which NR 1

R

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, 4

R

4 is hydrogen, or a methyl, methoxy or hydroxy group, or together with the phenyl group attached thereto is a -naphthyl group, 2-naphthyl group or 3-phenanthrenyl group, and n has the value 1, 2 or 3.

Especially preferred are compounds in which NR 1

R

2 Is a tert.-pentylamino, n-propylamino, isopropylamino, tert.-butylamino, piperidino or cyclohexylamino group, the R35 residue is hydrogen, or a methoxy group in the 4-position, R is a methyl or methoxy group w; together with the phenyl group attached thereto is a 2-naphthyl group and and n has the value 1, 2 or 3.

a The most preferred compounds are aminopropoxy) -phenyl) -l-propanone hydrochloride, (Example 8).

6-trimethylphenyl) (2-hydroxy-3--tert.-butylamino-propoxy)-phenyl)--l-propanone hydrochloride, (Example 17).

l-(3 ,4-dimethoxyphenyl) '-(2-hydroxy-3-isopropylamilopropoxy) -4 '-methoxyphenyl] -1-propanone hydrochloride (Example 23).

l-(3 ,4,5-trimethoxyphenyl) '-(2-hydroxy-3-cyclo- ',:hexylamino-propoxy) -methoxyphenyl] -l-propanon- hydrochlor ide, (Example 32).

1- (2-naphthyl) '-(2-hydroxy-3-n-propylaminopropoxy) methoxyphenyl]-1-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

4 n

CH

2

-CH

2

-CO-

O-CH -CH-CH (II) 2 2 0 4 with an amine of general formula III

HNRR

2

(I)

1 2 3 4 R R 2

R

3 R and n have the above meaning.

teoo

S

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 dil-.

uent or solvent, such as a lower alcohol having 1 to 4 carbon atoms, as for instance methanol, ethanol or propanol, preferably isopropanol or ethanol, a lower saturated dialkylether, dialkylglycol ethers or cyclic ethers, such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran 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, di- L;b~ i 4~ i II methylsulfoxide or in the presence of water or mixtures of the mentioned solvents.

When u:~ed 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 manner, for instance by filtration or distillation of the diluent from the reaction mixture. The compound obtained is purified in the usual manner, for instance by recrystallization fro 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-P-phenylpropiophenone having general formula IV S. S *5 4( 9I S o ow

S

0 S. S 8*

SO

c*4 3 2 3

-CH

2 0

R

OH

(IV)

with an epihalohydrin. R 3

R

4 and n have the above meaning.

Examples of epihalohydrins are epichlorohydrin, epibromohydrin 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 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 dialkyl- 7 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 metal carbonates, alkali ietal 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 foe can be used in catalytic or stoichiometric amounts or in slightly excess amounts with respect to the alkylating agent used.

3-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 3hydroxy-p-phenylpropiophenone, and its preparation are known.

SThe compound of formula I obtained according to the invention is optionally converted into an acid addition salt, I preferably into a salt of a physiologically acceptable acid.

Usual physiologically acceptable inorganic and organic acids 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, Birkhduser L 8 publishers, Basle and Stuttgart, 1966, and Journal of Pharmaceutical Sciences, vol. 66, pp. 1-5 (1977). Hydrochloric acid is preferred.

The acid addition salts are normally obtained in a conventional manner by mixing the free base or its 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 acetone, methylethyl ketone or methyl-isobutyl ketone, or an ether, such as diethyl ether, tetrahydrofuran or dioxane.

S Mixtures of 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.

S

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 oy reaction with inorganic or organic acids, in particular with those which are suitable for the formation of therapeutically useful salts.

0 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 intramu ular application, which apart from the usual carriers aiid uiluents 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.

9 The pharmaceutical compositions of the invention are prepared in a conventional manner with the usual solid or liquid carriers or diluents and the conventional ,harmaceutical 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, filmcoated 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.

S* 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, mannitol, polyvinylpyrrolidone, disintegrating agents, such as corn starch or alginic acid, binde-s, 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, cellulose 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 con- LI? 1- L r(II tain suspension auxiliaries, such as sodium carboxyme cellulose or preservatives, such as p-hydroxybenzoatc 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 mixing the active ingredient with corresponding carriers, such as neutral fats or polyethylene glycol or their derivatives.

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

In particular, the antiarrhythmic and P-sympatholytic properties of the compounds of the invention and their physio- C' logically acceptable acid addiLion salts make them espe- C.C*C cially suitable for pharmacotherapy of heart rhythm disorders, treatment of coronary heart disease, and prophylaxis of sudden death from heart disease. The antiarrhythmic efficacy of the inventie 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 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.

-ne 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 4 11 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 significant increase in toxicity compared to propafenone as seen from a comparison of the LD 50 values in rats and mice which are summarized in table II. I S 9 as 0 4 T e I *e vyu-uxnu, pj.periaino or cyclohexylamino group, the R 3 residue is hydrogen, or a methyl, methoxy or hydroxy group,

R

4 is hydrogen, or a nriethyl; methoxy or hydroxy group or /3 0 U K A 12 Table I Example C20 CF No. (0M) C20 Vmax Rate Factor Prematurity S.F.

(AM) of Vmax Factor Vmax 0O* et o 0 0* 0 Soo 0 *0

S

461 *5 of 6 0 a. S.

o f S

S.

*0 0 so 15.0 10.0 20.0 7.0 15.0 7.0 6.0 15.0 6.0 5.0 5.0 10.0 8.0 5.0 4.0 5.0 14.0 17.0 14.0 5.3 2.9 1.6 9.1 2.6 3.3 11.9 1.0 1.7 3.2 2.2 2.4 3.5 1.4 2.5 1.4 1.1 3.0 2.8 2.6 1.2 1.3 1.7 6.1 1.1 12.1 3.7 1.21 5.00 1.26 1.17 1.15 1.47 1.09 1.12 0.97 5.00 1.21 1.25 1.16 1.13 1.15 1.25 1.20 1.41 1.22 1.51 1.33 1.03 1.22 1.43 4.00 1.08 0.90 1.08 1.01 0.99 0.95 0.95 0.94 0.99 0.99 1.05 1.01 1.05 1.01 1.01 0.97 1.05 0.91 0.99 0.94 0.94 0.94 1.10 1.10 0.90 0.50 0.97 9.4 2.1 2.3 7.6 9.9 2.1 14.0 5.4 2.3 4.1 10.2 2.4 5.1 3.4 11.7 4.6

CF:

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

4 Rate Factor of Vmax: Prematurity Factor Vmax,"

S.F.:

control Vmax at a basic cycle length of 2000 msec)/(% contizol Vmax at a basic cycle length of 500 msec) at C20 Vmax., control Vmax at premature extrasysto'les)/ control Vmax at a normal beat) at Vmax.

Safety factor computed as Rate Factui_ of Vmax CF/C20 Vmax).

Table II

S

4*

S.

S

*5 6 S S *6 *5 6 5

S

S

*5 S S So 4 0 S *6 64 56

SS

*6 0* 6 Test compound

A

Example 2 3 31

LD

50 (mg/kg) rat v.

17 11 13 10 mouse 18 16 18 i8 The invention is illustrated by the examples.

A) Preparation of the starting compounds: Example I 1- dimethoxyphenyl) -3-1 -(1,2-epoxy-,3-propo'xy) -phenyl]- 1-propanone 100 g (0.35 mole) of 3,4-dimethoxy-p6-3'-hydroxvphenylpropiophenone are heated under refluxing for 23 hrs with 300 ml of epichlorohydin and 24.2 g (0.175 mole) of potassium carbonate and stirred. The resulting salt is filtered off, and the remaining solution is evaporated under reduced pressure.

The residue is recrystaillized from isopropanol. Yield: 109.8 g of tho title compound, mp. 81-84*C.

14 The following compounds were prepared in the same manner: 1-(4-methoxypheny'l) 2-epoxy-3-propoxy) -phenyl]propanone 1-(3,4,5--trimethoxyphenyl)-3-(3 '-(1,2-epoxy-3-propoxy)-phenyl]I-1-propanone 1-(2,4,6-trimethylphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-phenyl] -l-propanone l-phenyl-3-(3 '-(1,2-epoxy-3-propoxy) -4 '-methoxyphenlyl]-'L propanone l-(3,4-dimethoxyplhenyl)-3-[1-(1,2-epoxy-3-propoxy)-4 '-methoxyphenyl]-l-propanone l-(3,4,5-trimethoxyphenyl)-3-[3'-(1,2-epoxy-3-,propoxy)-4'iethoxyphenyl]-l--propanone l-(2-methoxyphenyl) 2-epoxy--3-propoxy) -4 '-methoxyphenyl]-1-propanone 1-(4-methylph' nyl)-3-[3 '-(l,2-epoxy-31-propoxy)-4'-methoxyphenyl] -1-propanone 1-(2,4,6-trimethylphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'methoxyphenyl]J-1-propanone Eample II 1-(2-naphthyl)-3-(3'-(1,2-epoxy-3-propoxy)-4'-methoxyphenyl]I-1'-propanone 13.1 g(0.04 mole) of 1i(2-naphthyl.)-3-(3'-hydroxy-4"-M<,,fluxing with 2C,.3 ml of epichiorohydrin, 9u ml of isopropanol and 1.6 g (0.04 mole) of sodium hydroxide. The resulting salt is filtered off and the remaining solution is evaporated under reduced pressure. The remaining oily residiie is used without purification in the next step. Yield: Example lIT 1-(3-phenanthirenyl) 2-epoxy-3-propoxy) -phenyl]-lpropanone I I 61.6 g (0.18 mole) of 1-(3-phenanthrenyl)-3-(3'-hydroxyphenyl)-1-propanone are heated for 12 hrs under refluxing with 105.6 ml of epichlorohydrin, 66 ml of methanol and 7.2 g (0.3.8 mole) of sodium hydroxide. The resulting salt is filtered off and the remaining solution is evaporated under reduced pressure. The residue is used without purification in the next step. Yield: 65.2 g 85.3 B) Preparation of the inventive compounds: Example 1 1-(3,4-dimethoxyphenyl)-3-[3 '-(2-hydroxy-3-tert.-pentylaminopropoxy)-phenyl]-l-propanone hydrochloride 27.4 g (0.08 mole) of l-(3,4-dimethoxyphenyl)-3-[3'-(1,2epoxy-3-propoxy)-phenyl]-l-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 excess amount of amine are removed under reduced pressure.

The oily residue is taken up in methanol and concentrated S hydrochloric acid is added thereto. After heating and cooling, crystals are obtained which are recrystallized from acetone. Yield: 22.8 g of the title compound, Fp.

117-119*C.

S The following compounds were prepared in the same manner (Examples 2 to 51): 2. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-n-propylaminopropoxy)-phenyl]-l-propanone hydrochloride, mp. 146- 147°C.

3. 1- (3,4-dimethoxyphenyl) '-(2-hydroxy-3-morpholinopropoxy)-phenyl]-l-propanone hydrochloride, mp. 148-149"C.

16 4. 1- 4-dilnethoxyphenyl) C33 '-(2-hydroxy-3-isopropylamiriopropoxy) -phenyl )-l-propanone hydrochloride, m p. 175- 177*C.

S. S 9*

S

5 0

S

.9 0.

S SO I~ S 0O 9) ~S SO #9 5

S.

o *S

SO

RS

1- 4 -d iiethoxypheryl) 3- C3 -hydroxy- 3-tert. -butyl aminopropoxy) -phenyl]--1-propanone hydrochloride, m p. 179- 1810 C.

6. l-(3,4-diinethoxyphen'yl)-3-[3 '-(2,-hydroxy-3-piperidinopropoxy) -phenyl] -l1-prop anone hydrochlor.1de, mp. 14l-142*C.

7. 1- (4 -methoxyphenNyl) 3- [3 (2 hydroxy- 3-n-propyl aminlopropoxy)-phenyl]-l-propanone hydrochloride, mp. 128.5- 12 9.5 *C.

8. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.pentyl1aminopropoxy) -phe ny 1 1-prop anone hydrochloride, mp.

160-161*C.

9. l-(3,4,5-trimethoxyphenyl)-3-L'"-(2-hydroxy-3-isoPropylaminopropoxy) -phenyl.]-l-propanone hydrochloride, mp.

119.5-120.5 0

C.

l-(3,4,5-trimethoxyphenyl)--3-[13-(2-hydroxy-3-tert.butylarninopropoxy) -phenyl -1-propanone hyce.rochloride, m p.

158-159*C.

11, l-(2,4,6-triniethylphen-yl)--3-t3' (2-hydroxy-3-tert. -pentylaminopropoxy) -phenyl] -l-propanone hydrochloride, In p. 103- 105*C.

12. 1-(2,4,6-trimo-thylphenyl)-3-[3 '-(2-hydroxy-3-piperidinopropoxy) -pher,yl]-l-propanone hydrochloride, In p. 158- 159.5*C.

I

group, 17 13. 1-(2,4,6-trixnethylphenyl)-3-(3'-(2-hydroxy-3-norpholinopropoxy) -phenyl] -l-propanoie hydrochloride, mp. 170- 17l 0

C.

14. 1-(2,4,6-trimethylphenyVl)-3-313-(2-hydroxy-3-tert.--utylaminopropoxy) -phenyl]-l-propanone hydrochloride, mp. 129l3l 0

C.

6-trimethyiphenyl) '-(2-hydroxy-3-isopropylaminopropoxy)-phenyl]-l-propanone semi-oxalate, mnp. 146- :148*C.

16. l-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3--n-propylaiinopropoxy)-phenyl]-l-propanone hydrochloride, mp. 84- 17. l-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-tert.-butylaminopropoxy) -phenyl] -1-propanone hydrochloride, mp.

123 .5-125. 18. l-phenyl-3-[3 '-(2-hydroxy-3-tert. -pentylaminopropoxy) 4'-methoxyphenyl]-l-propanone semi-oxalate, mp. 162-164*C.

19.: 1-lphnyl33(2hydroxy3isopropylaninopropoxy) metoxyhenl]--prpaonehydochorie, p.157-158*C.

l-phenyl-3-1-(2-hydroxy-3-tert. -butylaminopropoxy) 4 '-Iethoxyphenyl]-l-propanone hydro~chloride, mp. 158-159 Sc.

21. l-phenyl-3-(3 '-(2-hydroxy-3-piperidinopropoxy)-4'-methoxyphenyl]-l-propanone hydrochloride, mp. 115-117'C.

22. 1-(3,4-dimethoxyphenyl)-3-rJ'-(2-h.,droxy-3-n-propylamino-propoxy) -4 '-methoxyphenyl]I-1-propanone hydrochloride, mp. 115-116.5-C.

18 23. l-(3,4-dimetLhoxypheflyl)--3[3'-(2-hydroxy- 3 -isopropylaininopropoxY) -4 -iethoxypheflyl -1-propanone hiydrochloride, nip. 128-131*C.

24. 1- (3,4-dimethoxyphelYl) '-(2-hydroxy-3-norpholilopropoxy) -4 '-rethoxyphenyl]-l-propaloe hydrochloride, mp.

158-161' C.

1-(3,4-~dimethoxyphnyl)-3-3-(2-hydroxy--tertbu tylaminopropoxy) -4 '-iethoxyphenyl 3-1-propanone hydrochloride, nip. 168-l70*C.

26. 1-(3,4--dimethoxypheflyl)-3-[3'-(2-hydroxy-3-cyclohexyl am inopropoxy) -4 1-nethoxyphelyl i--proPanonle hydrochloride, nip. 117.5-l20.5 C.

27. 1- 4-dimethoxyphenyl)-3- C31- (2-hydroxy-3 -trt.-penltylaminopropoxy) -4 '-methoxyphenyl] -1-propanonc, hydrochloride, nip. 147-148-C.

28. 5-triinethoxyphenyl) '-(2-hydroxy-3-tert.- 0 Ila pentylaminopropoxy) -4 -inethoxyphenyl] -1-propanone hydrochloride, nip. 126-129*C.

29. 1-(3,4,5-trinethoxyphenyl)-3-I31-(2-hydroxy-3-fl-Propylaminopropoxy)-4-methoxyphenyll-l-propaloe hydrochloride, nip. 103.5-106*C.

1-(3,4,5-trimethoxypi-ienyl)-3-[313-(2-hydroxy-3-isopropylaminopropoxy) -methoxyphenyl] -l-propanone hydrochloride, nip. 115-116*C.

31. 1-(3,4,5-trimethoxyphenyl)-3-II3'-(2-hydroxy-3-tert.-butylaininopropoxy)- methoxyphenyl)-l-propanofle hydrochloride, nip. 150.5-152'0.

priatic hydrocarbon, such as hexane, heptane or octane, di- 19 32. l-(3,4,5-trimnethoxyphenyl)-3-[1 -(2-hydroxy--3-cyclohexylaminopropoxy) -4 '-methoxyphenyl] -1-propanone hydrochloride, mp. 136.5-138.5*C.

33. l-(2-methoxyphel)-3-[3 '-(2-hydroxy-3-tert.-pentylaminopropoxy) -4 -xethoxyphenyl]-l-propanone acetate, mp.

1l9-l20* C.

34. 2-(2-methoxyphenyl) -(2-hydroxy-3-fl-propylaminopropoxy) 4' -methoxyphenyl] -1-prop anone hydrochloride, rnp.

141.5-l43*C.

tylaininopropoxy) -methoxyphenyl,]-1-propanone hydro- ***chloride, mP. 166.5-167*C.

36. l-(4-inethylphenyl) -3-[13 (2-hydroxy-3-tert.-peltylaminopropoxy)-4 '-'rethylphenyl]-l-propanofle hydrochloride, **smp. 107.5-109.5*C.

37. l-(4-methylphenyl) -(2-hydroxy-3-n-propylaminopro- *~poxy)-4'-iethoxyphenyl)-1-propanone hydrochloride, mp. 108- 110G.

38. l-(4-rnethylphenyl) -(2-hydroxy-3-morpholinopropoxy)-4'-methoxyphenyl]-l-propanone hydrochloride, mp. 117- 119.5'C.

39. l-(4-methylphenyl) hydroxy-3-tert.-butylaminopropoxy) -4'1 -methoxyphenyl -l-prolanone hydrochloride, m p.

117-119*C.

l-(4-methylphenyli -3-13 '-(2-hydroxy-3-piperidinopropoxy) -4'1 -methoxypheriyl 4 ,!-l-propanone hydrochloride, m p.

138.5-140*C.

41. 1-(4-methylphenyl)-3-313-(2-hydroxy-3-cyclohexylamilopropoxy) -m iethoxyphenyl -1-propanone hydrochloride, m p.

134-1360 C.

42. 6-trimethylphenyl) -3-[3'-(2-hydroxy-3-tert. -penlty lamninopropoxy) 4' 1 .rethoxypheny 1]-1 -ropa none hydrochloride, mp. 117-ll8*C.

43. (2,4,6-trimethyl.henyl)-3-[31-(2-hydroxy-3-piperidinopropoxy) -4 1 -methoxyphenyl] -1-propanone hydrochloride, mp. 1J19-120'C.

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

9*9990 121-122*C.

1-(2,4 ,6-trimethylphenyl) '-(2-hydroxy-3-isopropylaminopropoxy) -4'1 -inethoxyphenyl] -1--propanone hydrochloride, np. l10-111*C.

46. 6-triinethylphenyl) '-(2-hydroxy-3-morpholinopropoxy) -4 '-methoxyphenyl] -1-propanone hydrochloride, mp. 154-155'C.

47. 1-(2-naphthyl)-3-[3'-(2-hydroxy-3-tert.-pentylahinopro- POXy)-4'-methoxyphenyl]-l-propanone hydrochloride, mp. 130- 132*C.

48. l-(2-naphthyl) '-(2-hydroxy-3-n-propylaminopropoxy) -4 '-iethoxyphenyli-l-propanone hydrochloride, nip. 142- 143 0

C.

49. 1-(2-naphthyl)-3-[3'-(2-hydroxy-3-isopropylaminopropoxy) -4 '-methoxyphenyl]-l-propanone hydrochloride, nip. 133- 1350 C.

Ifi l-(3-phenanthrenyl)-3-[ 3 droxy-3-isopropylaminopropoxy)-phenyl]l--propanone hydr.ochloride, mp. 140-142'C.

51. 1-(3-phenanthrenyl)-3-[3 -(2-hydroxy-3-n-propylaminopropoxy)-phenyl]-l-propanone hydrochloride, mp. 149-152"C.

Examp e 52 @0 4* 0 9000 *0I 0S S *r 0 00 0

S.

0 0* 0 0 00 0

SO

0* 0 *0 Manufacturing Process for Tablets a) Ingredients Compound of Example 1 Microcrystalline cellulose (powder, 50 pm) Poly-(l-vinyl-2-pyrrolidone) Hydroxypropylmethyl cellulose 2910 Magnesium stearate 75.00 g 15.75 g 5.00 g 3.75 g 0.50 q 100.00 g b) Mixing and Granulating The compound of Example 1 is optionally screened. All materials 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-dichloromethane 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 is pressed in a tablet press into tablets weighing from 40 to 400 mg. The pressing L'frce 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'.

'i c ~L the new compounds and their physiologically acceptable salts in the treatment of heart rhythm disorders.

i j-, i x"Y~ Examp e 53 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

S

0*O S* S *r

S

consists of: Hydroxypropylmethyl cellulose 2910 Macrogol(R) 6000 (plasticizer) 77 23 B. Preparation of the Tablets (see manufacturing process for tablets, Example 52).

S.

C. Preparation of the Film-coated Tablets 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 further dried in a drying cabinet.

S

Examp e 54 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: L I i_ i i i -i L 23 Saccharose 51.4% Talcum 24.0% Calcium sulfate h(;mihydrate 10.3% Starch syrup Gum arabic 3.9% Macrogol(R) 6000 2.9% Titanium (IV) ojxide 1.6 Finely dispersed silica 0.8 Sodiumi dodecylsulfate 0.1% 100.0% B. Preparation of the Dragee Cores (see manufacturing process for tablets) Preparation of the Dragee! P~ Composition of the dragee solution used, Precoating composition and dragee coating suspension a) Dragee solution Saccharose 47.6 Starch syrup 19.1 Gum arabic 3.8 Distilled water 29.5 100.0% a: c) Precoating Composition Talcum 70.0 Calcium sulf ate hemihydrate 26.7 Finely dispersed si~lica 3',3 100.0 24 d) 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 .26.4 100.0% 4X Coating of Dragee Cores The dragee cores are first moistened in a rotating vessel with dragee solution and then powdered with sufficient *precoatinq composit 'on f~or them to roll freely again, After the cores,4 are dried, this process is repeated. The cores are as then dried in a drying cabinet. The cores are then layerwise coated with the drag-ee coattng suspension until the desired final weight is achieved, The cores must be dried af~ter application of each. layer.

a E xam nl1e 5 Manufacturing Proces!s for Capsules A. Dosage of the active jivgredient of 75 mg and more 1. Ingredients compound of Example 2 75.00 g Microcrystalliiie cellulose (powder, 50 Amn) 16.25 g Poly- (1-vinyl-2--pyrrolidone) 5.00 g H-ydroxyp ropy Ime thy 1 cellulose 2910 3.75 c 100.00 g L 'If 2. Mixing and granulating acording to Exampl* 52b) 3. FLll~q the Granulate into Capsules The granulate is filled by means of a capsulating machine into hard gelatine capsules of size 3, 2, 1 or O, the amount filled into each capsule depending on the desired dosage of the active ingredient.

60 *6e 6 9* 0 S 6 6 6 @6 3 6 *0 6 86 0 6 B. Dosage of the active ingredient 30-75 mg 1. Ingredients Compound of Example 3 30.00 Microcrystalline cellulose (powder, 50 pm) 61.25 Poly-(l-vinyl-2-pyrrolidone) 5.

Hydroxypropylmethyl cellulose 291.0 3.

100 75.00 g 16.25 g 00 g 75 q 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.

2. Mixing and granulating according to Example 52b) 3. Filling the Granulate into Capsules 1C0 mg each of granulate are filled into hard gelatine capsules of size 3 or 2 with the aid of a capsulating machine.

Ex a m p e 5 6 06 6 'I 0 If *6 6 6 6 0 Manufacturing Process fot Ampoules 1. Ingredients Compol'nd of Example 6 Water for injection purposes ad: 1.5 g 100.0 ml

J

ii 26 2. Preparation of the Solution of the water necessary for the batch selected is placed into 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 in depending on the dosage desired. The glass ampoules are then sealed by fusion.

The ampoules are vapor-sterilized for 20 mnutes at 12.'C.

E x a m p 1 e 5 7 Manufacturing Process for Suppositories a. Ingredients Compound of Example 50 30 200 mg Hard fat (melting point 35-36.5°C) ad: 2000 mg e t c i 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 40C. The active ingredient is pressed through an 0.8 mm sieve and mixed into

S.

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 sippository is 2,)00 mg. The suppository form is sealed after solidification of the melt.

Claims (9)

1. Aminopropanol derivatives of 3-(3-hydroxyphenyl)-l-pro- panone compounds of general formula I R 4 I n CH 2 -CH 2 -CO- 1 (I) .OCH 2-H-CH2-NR R2 *OH and their acid addition salts, wherein R 1 and R 2 are the same or different and denote hydrogen atoms, alkyl, cyclo- alkyl, alkenyl, alkinyl or hydroxyalkyl groups with up to 6 carb-n atoms each, alkoxyalkyl, alkylthioalkyl or dial- kylaminoaivyl groups with up to 9 carbon atoms each, or phe- nylalkyl or phenoxyalkyl groups having up to 6 carbon atoms S 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 R and R 2 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 oxgyen 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, R 3 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, 4 R 4 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 R 4 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 28

2. Compounds according to Claim 1, characterized in that NR 1 R 2 is a tert.-pentylamino, n-propylamino, 1,1-dimethyl- propylamino, morpholino, isopropylamino, tert. -butylamino, pyrrolidino, piperidino or cyclohexylamino group, the R 3 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 NR 1 R 2 is a tert.-pentylamino, n-propylamino, isopropylamino, tert.-butylamino, piperidino or cyclohexylamino group, the R 3 residue is hydrogen, or a methoxy group, in the 4-po- sition, '4i is a methyl or inethoxy group or R 4 together with the phenyl group attached thereto is a 2- naphthyl group and e:n has the value 1, 2 or 3. l-(3,4,5-trimethoxyphenyl)-3-[3 '-(2-hydroxy-3-ter~t.-pen- tylaminopropoxy) phenyl] -1-propanone hydrochloride. .4 5. l-(2,4,6-trimethylphenyl)-3-[3'-(2-ydroxy-3-tert.-bu- tylaminopropoxy) phenyl] -1-propanone hydrochloride.

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

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

8. 2 -naphthyl)-3-f3'-(2-hydroxy-3-n-propylaminopropoxy) 4 '-methoxyphenyl]-l-propanone hydrochloride. 29

9. Process for preparing the compounds according to Claims 1 to 8 and their acid addition salts, characterized by re- acting a phenol ether of general formula II 4 R R CH 2-CH -CO-/ R O_2 2- 2 (II) I ^O-CH -CH-CH 2 2 0 wherein R 3 R 4 and n have the meaning indicated in Claim 1, with an amine of general formula III HNRR 2 (III) wherein R 1 and R2 have the meaning indicated in Claim 1, and S if appropriate, converting the resulting compound with an acid into an acid addition salt.

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

11. A method of treating heart rhythm disorders which com- S O prises administering to a patient requiring said treatment a S" compound according to Claims 1 to 8 in an amount sufficient to produce an antiarrhythmic activity. 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.