NO167975B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE AMINOPROPANOLE DERIVATIVES OF 3- (3-HYDROXYPHENYL) -1-PROPANONE COMPOUNDS. - Google Patents

ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE AMINOPROPANOLE DERIVATIVES OF 3- (3-HYDROXYPHENYL) -1-PROPANONE COMPOUNDS. Download PDF

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NO167975B
NO167975B NO882771A NO882771A NO167975B NO 167975 B NO167975 B NO 167975B NO 882771 A NO882771 A NO 882771A NO 882771 A NO882771 A NO 882771A NO 167975 B NO167975 B NO 167975B
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carbon atoms
hydroxy
phenyl
propanone
methoxyphenyl
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NO882771L (en
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Gerd Petrik
Klemens Schubert
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Helopharm Petrik Co Kg
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

Amlnopropanolderlvater av 3-(3-hydroksyfenyl)-l-propanforblndelser av generell formel (I):. og syreaddlsjonssalter derav, hvori. og Rlike eller forskjellige og står for hydrogenatomer, alkyl, cykloalkyl, alkenyl, alklnyl eller. hydroksyalkylgrupper med opp til 6 karbonatomer,. alkoksyalkyl, alkyltloalkyl eller dlalkylamlnoalkyl-grupper med opp til 9 karbonatomer hver, eller. fenylalkyl eller fenoksyalkylgrupper Inneholdende opp. til 6 karbonatomer 1 alkyldelen, fenylgruppen er. eventuelt substituert med en alkyl- eller alkoksygruppe med opp til 3 karbonatomer, eller. Rogdanner sammen med nltrogenatomer som forbinder dem, en 5- til 7-leddet, mettet heterocykllsk ring som eventuelt kan vsre substituert med en eller to fenyl-og/eller hydroksygrupper og 1 ringen Inneholde et oksygenatom eller nltrogenatom, som et ytterligere heteroatom, med et ytterligere nltrogenatom eventuelt substituert med en alkylgruppe med 1 til 3 karbonatomer, eller en fenylgruppe,. Rtår for et hydrogenatom, en alkylgruppe Inneholdende opp til 3 karbonatomer, et fluor-, klor- eller bromatom, en hydroksyl- eller alkoksygruppe med opptil 6 karbonatomer,. R4 står for et hydrogenatom, en alkylgruppe Inneholdende opptil 3 karbonatomer, fluor, klor eller bromatom, en hydroksylgruppe eller en alkoksygruppe med opptil 6 karbonatomer, eller. Rer sammen med fenylgruppen bundet til dette et kondensert aromatisk system Inneholdende opptil 18 karbonatomer, og. n er et helt tall på 1 til 5. Det er videre angitt en fremgangsmåte for fremstilling av forbindelsene.Aminopropanol derivatives of 3- (3-hydroxyphenyl) -1-propane compounds of general formula (I) :. and acid addition salts thereof, wherein. and Rlike or different and represent hydrogen atoms, alkyl, cycloalkyl, alkenyl, alkynyl or. hydroxyalkyl groups having up to 6 carbon atoms ,. alkoxyalkyl, alkyltloalkyl or dlalkylaminoalkyl groups having up to 9 carbon atoms each, or. phenylalkyl or phenoxyalkyl groups Containing op. to 6 carbon atoms in the alkyl moiety, the phenyl group is. optionally substituted with an alkyl or alkoxy group having up to 3 carbon atoms, or. Rye forms together with nitrogen atoms connecting them, a 5- to 7-membered, saturated heterocyclic ring which may be optionally substituted with one or two phenyl and / or hydroxy groups and the ring containing an oxygen atom or nitrogen atom, as an additional heteroatom, additional nitrogen atom optionally substituted with an alkyl group having 1 to 3 carbon atoms, or a phenyl group ,. Rs for a hydrogen atom, an alkyl group containing up to 3 carbon atoms, a fluorine, chlorine or bromine atom, a hydroxyl or alkoxy group having up to 6 carbon atoms. R4 represents a hydrogen atom, an alkyl group containing up to 3 carbon atoms, fluorine, chlorine or bromine atom, a hydroxyl group or an alkoxy group having up to 6 carbon atoms, or. Together with the phenyl group attached thereto a condensed aromatic system containing up to 18 carbon atoms, and. n is an integer from 1 to 5. A process for the preparation of the compounds is further indicated.

Description

Foreliggende oppfinnelse vedrører fremstilling av nye terapeutiske aktive aminopropanonderivater av 3-(3-hydroksy-fenyl)-l-propanonforbindelser av den generelle formel I og fysiologisk akseptable syreaddisjonssalter derav. The present invention relates to the production of new therapeutically active aminopropanone derivatives of 3-(3-hydroxy-phenyl)-1-propanone compounds of the general formula I and physiologically acceptable acid addition salts thereof.

Tysk patent nr. 2.001.431 beskriver 2-(2'-hydroksy-3<*->alkylaminopropoksy)-P-fenyl-propiofenoner av den generelle formelen: German Patent No. 2,001,431 describes 2-(2'-hydroxy-3<*->alkylaminopropoxy)-P-phenyl-propiophenones of the general formula:

og deres syreaddisjonssalter. Selv om disse forbindelsene og deres salter utgjør farmasøytiske forbindelser, viser bare n-propylaminoforbindelsen (propafenon) anti-arytmiaktivitet. and their acid addition salts. Although these compounds and their salts constitute pharmaceutical compounds, only the n-propylamino compound (propafenone) shows anti-arrhythmic activity.

EP-A-0 074 014 beskriver 2-[2'-hydroksy-3'-(1,1-dimetylpro-pylamino)-propoksy]-p<->fenyl-propiofenon (diprafenon) og dens syreaddisjonssalter. Diprafenon er et anti-arytmimiddel. EP-A-0 074 014 describes 2-[2'-hydroxy-3'-(1,1-dimethylpropylamino)-propoxy]-p<->phenyl-propiophenone (dipraphenone) and its acid addition salts. Diprafenone is an anti-arrhythmic drug.

EP-A-0 075 207 beskriver aminopropanolderivater av den generelle formelen: EP-A-0 075 207 describes aminopropanol derivatives of the general formula:

og dens fysiologisk akseptable syreaddisjonssalter. Typiske eksempler på R<1> til R<4> innbefatter hydrogenatomer og alkylgrupper og n har en verdi på 1, 2 eller 3. Disse forbindelsene er farmasøytiske preparater. and its physiologically acceptable acid addition salts. Typical examples of R<1> to R<4> include hydrogen atoms and alkyl groups and n has a value of 1, 2 or 3. These compounds are pharmaceutical preparations.

Formålet ved oppfinnelsen er å tilveiebringe nye aminopropanolderivater av 3-(2-hydroksyfenyl)-l-propanonforbindelser av den generelle formel I og fysiologisk akseptable syreaddisjonssalter som utmerker seg ved en vesentlig forbedret anti-arytmiaktivitet sammenlignet med den for propafenol og uten en tilsvarende økning i toksisitet. Forbindelsene og deres syreaddisjonssalter kan anvendes ved fremstilling av farmasøytiske preparater egnet for behandling av uregelmes-sigheter i hjerterytme. The purpose of the invention is to provide new aminopropanol derivatives of 3-(2-hydroxyphenyl)-l-propanone compounds of the general formula I and physiologically acceptable acid addition salts which are distinguished by a significantly improved anti-arrhythmic activity compared to that of propaphenol and without a corresponding increase in toxicity. The compounds and their acid addition salts can be used in the preparation of pharmaceutical preparations suitable for the treatment of heart rhythm irregularities.

Oppfinnelsen vedrører fremstilling av nye aminopropanonderivater av 3-(3-hydroksyfenyl)-l-propanonforbindelser av den generelle formel I: The invention relates to the preparation of new aminopropanone derivatives of 3-(3-hydroxyphenyl)-1-propanone compounds of the general formula I:

hvor where

R<*> og R<**> er like eller forskjellige og står for hydrogenatomer, alkyl eller cykloalkylgrupper med opptil 6 karbonatomer, eller R<*> and R<**> are the same or different and represent hydrogen atoms, alkyl or cycloalkyl groups with up to 6 carbon atoms, or

R<*> og R^ danner sammen med nitrogenatomet som forbinder dem, en morfolin- eller piperidinring, R<*> and R^ together with the nitrogen atom connecting them form a morpholine or piperidine ring,

r<3> står for et hydrogenatom eller en alkoksygruppe med opptil 6 karbonatomer, r<3> stands for a hydrogen atom or an alkoxy group with up to 6 carbon atoms,

R<4> står for et hydrogenatom, en alkylgruppe inneholdende opptil 3 karbonatomer eller en alkoksygruppe med opptil 6 karbonatomer, eller R<4> stands for a hydrogen atom, an alkyl group containing up to 3 carbon atoms or an alkoxy group with up to 6 carbon atoms, or

R<4> er sammen med fenylgruppen bundet til denne en naftalen-eller fenantrenring, og R<4> together with the phenyl group is bound to this a naphthalene or phenanthrene ring, and

n er et helt tall på 1 til 5, og syreaddisjonssalter derav. n is an integer from 1 to 5, and acid addition salts thereof.

De mest foretrukne forbindelsene er The most preferred compounds are

l-( 3 ,4 , 5-trimetoksyfenyl )-3-[3'-(2-hydroksy-3-tert. -pentyl-aminopropoksy )-fenyl]-1-propanonhydroklorid, (eksempel 8); 1-(2,4,6-trimetylfenyl)-3-[3'-(2-hydroksy-3-tert.-butylamino-propoksy)-fenyl]-1-propanonhydroklorid, (eksempel 17); l-(3,4-dimetoksyfenyl)-3-[3'-(2-hydroksy-3-isopropylaminopro-poksy)-4'-metoksyfenyl]-1-propanonhydroklorid (eksempel 23); l-( 3,4 ,5-trimetoksyfenyl )-3-[3' - (2-hydroksy-3-cykloheksyl-aminopropoksy)-4 '-metoksyf enyl] -1-propanonhydroklorid, (eksempel 32); l-( 2-naf tyl )-3- [3 ' - (2-hydroksy-3-n-propylaminopropoksy )-4 '-metoksyfenyl]-1-propanonhydroklorid, (eksempel 48). Forbindelsene av den generelle formel I og deres syreaddisjonssalter fremstilles ifølge oppfinnelsen ved omsetning av en fenoleter av generell formel II hvor Rd, R^ og n har den ovenfor angitte betydningen, med et amin av generell formel (III): 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-pentyl-aminopropoxy)-phenyl]-1-propanone hydrochloride, (Example 8); 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-tert-butylamino-propoxy)-phenyl]-1-propanone hydrochloride, (Example 17); 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-isopropylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride (Example 23); 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-cyclohexyl-aminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, (Example 32); 1-(2-naphthyl)-3-[3'-(2-hydroxy-3-n-propylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, (Example 48). The compounds of the general formula I and their acid addition salts are prepared according to the invention by reacting a phenol ether of the general formula II where Rd, R^ and n have the meaning given above, with an amine of general formula (III):

hvori R<1> og R<2> har de ovenfor angitte betydningene og, om ønsket, omvandling av den resulterende forbindelsen med en syre til et syreaddlsjonssalt. wherein R<1> and R<2> are as defined above and, if desired, converting the resulting compound with an acid to an acid addition salt.

Den eventuelle omdanningen av en forbindelse av generell formel I til et syreaddisjonssalt kan f.eks. gjennomføres ved fremgangsmåten beskrevet i europeisk patent nr. 0 074 014. Reaksjonen utføres ved temperaturer varierende fra 10<*> til 120<*>C, dvs. ved romtemperatur eller ved høyere temperaturer, fortrinnsvis ved temperaturer varierende fra 50<*> til 120<*>C, ved atmosfæretrykk eller i en lukket beholder ved forhøyet trykk. The possible conversion of a compound of general formula I into an acid addition salt can e.g. is carried out by the method described in European patent no. 0 074 014. The reaction is carried out at temperatures varying from 10<*> to 120<*>C, i.e. at room temperature or at higher temperatures, preferably at temperatures varying from 50<*> to 120 <*>C, at atmospheric pressure or in a closed container at elevated pressure.

Utgangsforbindelsene av generelle formler II og III kan omsettes uten fortynningsmidler eller oppløsningsmidler. Imidlertid utføres omsetningen fortrinnsvis i nærvær av et inert fortynningsmiddel eller oppløsningsmiddel, så som en lavere alkohol inneholdende 1 til 4 karbonatomer, f.eks. metanol, etanol eller propanol, fortrinnsvis isopropanol eller etanol, en lavere mettet dialkyleter, dialkylglykoleter eller cyklisk eter, så som dietyleter, 1,2-dimetoksyetan, tetrahydrofuran eller dioksan, en benzenhydrokarbon, så som benzen selv eller en alkylbenzen, spesielt toluen eller xylen, eller en alifatisk hydrokarbon, så som heksan, heptan eller oktan, dlmetylsulfoksyd eller i nærvær av vann eller blandinger av de nevnte oppløsningsmidlene. The starting compounds of general formulas 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 containing 1 to 4 carbon atoms, e.g. methanol, ethanol or propanol, preferably isopropanol or ethanol, a lower saturated dialkyl ether, dialkyl glycol ether or cyclic ether, such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, a benzene hydrocarbon, such as benzene itself or an alkylbenzene, especially toluene or xylene , or an aliphatic hydrocarbon, such as hexane, heptane or octane, dlmethylsulfoxide or in the presence of water or mixtures of said solvents.

Når det benyttes i overskudd kan aminet av den generelle formel III også være et egnet fortynningsmiddel eller oppløsningsmiddel. When used in excess, the amine of the general formula III can also be a suitable diluent or solvent.

Fullstendigheten av reaksjonen avhenger av reaksjonstempera-turen og oppnås generelt i løpet av 2 til 15 timer. Reak-sjonsproduktet kan oppnås på konvensjonell måte, f.eks. ved filtrering eller destillering av fortynningsmidlet fra reaksjonsblandingen. Den oppnådde forbindelsen renses på vanlig måte, f.eks. ved rekrystallisasjon fra et oppløsnings-middel, omvandling til et syreaddisjonssalt eller ved kolonnekromatografi. The completeness of the reaction depends on the reaction temperature and is generally achieved within 2 to 15 hours. The reaction product can be obtained in a conventional manner, e.g. by filtering or distilling the diluent from the reaction mixture. The obtained compound is purified in the usual way, e.g. by recrystallization from a solvent, conversion to an acid addition salt or by column chromatography.

Fenoleteren av generell formel II kan oppnås ved alkylering av 3-hydroksy-e-fenylpropiofenon som har den generelle formelen IV: The phenol ether of general formula II can be obtained by alkylation of 3-hydroxy-e-phenylpropiophenone having the general formula IV:

hvor R**, R^ og n har den ovenfor angitte betydningen med et epihalogenhydrin. Eksempler på epihalogenhydrlner er epiklorhydrin, epibromhydrin og epijodhydrin. where R**, R^ and n have the meaning given above with an epihalohydrin. Examples of epihalohydrins are epichlorohydrin, epibromohydrin and epiiodohydrin.

Reaksjonen av forbindelsene IV for fremstilling av utgangsforbindelsene av generell formel II utføres raskt ved temperaturer varierende fra 0° til 120°C og normaltrykk eller i en lukket beholder ved forhøyet trykk. Egnede oppløsnings-midler eller fortynningsmidler er et lavere alifatisk keton, så som aceton, metyletylketon eller metylisobutylketon, en lavere alkohol inneholdende 1 til 4 karbonatomer, så som metanol, etanol, propanol eller butanol, en lavere alifatisk eller cyklisk eter, så som dietyleter, tetrahydrofuran eller dloksan, et dialkylformamid, så som dimetylformamid eller dietylformamid, eller dimetylsulfoksyd eller heksametylfos-forsyretriamid eller et overskudd av alkyleringsmidlet. The reaction of the compounds IV to produce the starting compounds of general formula II is carried out rapidly at temperatures varying 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, methyl ethyl ketone or methyl isobutyl ketone, a lower alcohol containing 1 to 4 carbon atoms, such as methanol, ethanol, propanol or butanol, a lower aliphatic or cyclic ether, such as diethyl ether, tetrahydrofuran or dloxane, a dialkylformamide, such as dimethylformamide or diethylformamide, or dimethylsulfoxide or hexamethylphosphoric triamide or an excess of the alkylating agent.

Omsetningen utføres fortrinnsvis i nærvær av en base som syrebindende middel. Egnede baser er alkalimetallkarbonater, alkalimetallbikarbonater, alkalimetallhydroksyder, alkall-metallhydrider eller alkalimetallalkoholater, spesielt de av natrium og kalium, basiske oksyder, så som aluminiumoksyd eller kalsiumoksyd, organiske tertiære baser, så som pyridin, lavere trlalkylaminer, så som trimetylamin eller tri-eltylamin, eller piperidin. Basene kan anvendes i katalytiske eller støkiometriske mengder eller i et svakt overskudd med hensyn på alkyleringsmidlet som benyttes. The reaction is preferably carried out in the presence of a base as an acid-binding agent. Suitable bases are alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal hydrides or alkali metal alcoholates, especially those of sodium and potassium, basic oxides, such as aluminum oxide or calcium oxide, organic tertiary bases, such as pyridine, lower trialkylamines, such as trimethylamine or triethylamine, or piperidine. The bases can be used in catalytic or stoichiometric amounts or in a slight excess with respect to the alkylating agent used.

3-hydroksy-p<->fenylpropiofenon omsettes fortrinnsvis med epiklorhydrln eller epibromhydrln i et polart, aprotisk oppløsningsmiddel, spesielt dimetylsulfoksyd, ved temperaturer varierende fra 0 til 50° C, i nærvær av minst en molekvivalent base, spesielt natriumhydrid, basert på alkyleringsmidlet. 3-Hydroxy-p<->phenylpropiophenone is preferably reacted with epichlorohydrin or epibromohydrin in a polar, aprotic solvent, especially dimethylsulfoxide, at temperatures varying from 0 to 50° C, in the presence of at least one molar equivalent of base, especially sodium hydride, based on the alkylating agent.

Utgangsforbindelsen av generell formel IV, dvs. 3-hydroksy-p-fenylpropiofenon, og dens fremstilling er kjent. The starting compound of general formula IV, i.e. 3-hydroxy-p-phenylpropiophenone, and its preparation are known.

Forbindelsen av formel I oppnådd ifølge oppfinnelsen omvandles eventuelt til et syreaddisjonssalt, fortrinnsvis til et salt av en fysiologisk akseptabel syre. Vanlige fysiologisk akseptable uorganiske eller organiske syrer er f.eks. saltsyre, hydrobromsyre, fosforsyre, sveovelsyre, oksalsyre, maleinsyre, fumarsyre, melkesyre, vinsyre, eplesyre, sitronsyre, salisylsyre, adiplnsyre og benzosyre. Andre egnede syrer er f.eks. beskrevet i "Fortschritte der Arzneimittel-forschung", bind 10, side 224-225, Birkhauser Publishers, Basel og Stuttgart, 1966, og Journal of Pharmaceutical Sciences, bind 66, side 1-5 (1977). Saltsyre er foretrukket. The compound of formula I obtained according to the invention is optionally converted to an acid addition salt, preferably to a salt of a physiologically acceptable acid. Common physiologically acceptable inorganic or organic acids are e.g. 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 e.g. described in "Fortschritte der Arzneimittel-forschung", volume 10, pages 224-225, Birkhauser Publishers, Basel and Stuttgart, 1966, and Journal of Pharmaceutical Sciences, volume 66, pages 1-5 (1977). Hydrochloric acid is preferred.

Syreaddisjonssaltene oppnås normalt på konvensjonell måte ved blanding av den frie basen eller dens oppløsning med den tilsvarende syren eller dens oppløsning i et organisk oppløsningsmiddel, f.eks. en lavere alkohol, så som metanol, etanol, n-propanol eller Isopropanol, eller et lavere keton, så som aceton, metyletylketon eller metylisobutylketon, eller en eter så som dietyleter, tetrahydrofuran eller dloksan. The acid addition salts are normally obtained in a conventional manner by mixing the free base or its solution with the corresponding acid or its solution in an organic solvent, e.g. a lower alcohol, such as methanol, ethanol, n-propanol or isopropanol, or a lower ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, or an ether such as diethyl ether, tetrahydrofuran or dloxane.

Blandinger av de nevnte oppløsningsmidlene kan også benyttes for bedre krystallavsetning. Videre kan farmasøytisk akseptable vandige oppløsninger av syreaddisjonssalter av forbindelsen av formel I fremstilles i en vandig syreopp-løsning. Mixtures of the mentioned solvents can also be used for better crystal deposition. Furthermore, pharmaceutically acceptable aqueous solutions of acid addition salts of the compound of formula I can be prepared in an aqueous acid solution.

Syreaddisjonssaltene av forbindelsen av formel I kan omvandles til den frie basen ved en fremgangsmåte som i og for seg er kjent, f.eks. med alkallforblndelser eller lonebyttere. Ytterligere salter kan oppnås fra den frie basen ved omsetning med uorganiske eller organiske syrer, spesielt med de som er egnede for dannelsen av terapeutisk anvendbare salter. Disse og andre salter av den nye forbindelsen, så som pikratet, kan også anvendes for rensing av den frie basen hvori den frie basen omvandles til et salt som frasepareres og basen frigjøres igjen fra saltet. The acid addition salts of the compound of formula I can be converted to the free base by a method known per se, e.g. with alkaline compounds or ion exchangers. Additional salts can be obtained from the free base by reaction with inorganic or organic acids, especially with those suitable for the formation of therapeutically useful salts. These and other salts of the new compound, such as the picrate, can also be used for purification of the free base in which the free base is converted into a salt which is separated and the base is released again from the salt.

De farmasøytiske preparatene som inneholder forbindelser med formel I fremstilles på konvensjonell måte med de vanlige faste eller flytende bærerne eller fortynningsmidlene og de konvensjonelle farmasøytiske adjuvansene i en egnet doser-ingsform avhengig av den ønskede tilførselsmåten. De mest fordelaktige preparatene er preparater i doser-ingsenhetsform for oral administrering. Slike farmasøytiske former er f.eks. tabletter, filmbelagte tabletter, drasjéer, kapsler, piller, pulvere, oppløsninger eller suspensjoner eller depotpreparater. The pharmaceutical preparations containing compounds of formula I are prepared in a conventional manner with the usual solid or liquid carriers or diluents and the conventional pharmaceutical adjuvants in a suitable dosage form depending on the desired route of administration. The most advantageous preparations are preparations in dosage unit form for oral administration. Such pharmaceutical forms are e.g. tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions or depot preparations.

Parenterale preparater, så som injeksjonsoppløsninger, er naturligvis også egnede. En annen farmasøytisk form som kan nevnes er f.eks. suppositorier. Parenteral preparations, such as injection solutions, are of course also suitable. Another pharmaceutical form that can be mentioned is e.g. suppositories.

Tilsvarende tabletter kan oppnås f.eks. ved blanding av den aktive bestanddelen med kjente hjelpestoffer, f.eks. med inerte fortynningsmidler, så som dekstrose, sukker, sorbitol, mannitol, polyvinylpyrrolidon, sprengmidler, så som maisstiv-else eller alginsyre, bindemidler, så som stivelse eller gelatin, smøremidler, så som magnesiumstearat eller talkum og/eller midler for å oppnå en depoteffekt, så som karboksy-polymetylen, karboksymetylcellulose, celluloseacetatftalat eller polyvlnylacetat. Tablettene kan omfatte flere lag. Drasjéer kan fremstilles tilsvarende ved å belegge kjerner som er fremstilt analogt tablettene med preparater som vanligvis anvendes i drasjébelegg, så som polyvinylpyrrolldon eller skjellakk, gummi arabikum, talkum, titandioksyd eller sukker. Drasjéskallet kan også bestå av flere lag, hvori hjelpestoffene nevnt ovenfor i forbindelsene med tablettene kan anvendes. Corresponding tablets can be obtained e.g. by mixing the active ingredient with known excipients, e.g. with inert diluents, such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc and/or agents to achieve a depot effect , such as carboxy-polymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets may comprise several layers. Dragees can be produced similarly by coating cores that are prepared analogously to tablets with preparations that are usually used in dragee coatings, such as polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. The dragee shell can also consist of several layers, in which the excipients mentioned above in the compounds with the tablets can be used.

Oppløsninger eller suspensjoner innbefattende den aktive bestanddelen med formel I kan I tillegg inneholde smaks-stoffer, så som sakkarin, cyklamat eller sukker og f.eks. aromatiske stoffer, så som vanilje eller appelsinekstrakt. Solutions or suspensions including the active ingredient of formula I may additionally contain flavoring substances, such as saccharin, cyclamate or sugar and e.g. aromatic substances, such as vanilla or orange extract.

i in

Videre kan de inneholde suspensjonshjelpestoffer, så som natriumkarboksymetylcellulose eller konserveringsmidler, så som p-hydroksybenzoater. Kapsler inneholdende den aktive bestanddelen kan f.eks. fremstilles ved å blande den aktive bestanddelen med en inert bærer, så som laktose eller sorbitol, og innkapsle den i gelatinkapsler. Furthermore, they may contain suspension aids, such as sodium carboxymethyl cellulose or preservatives, such as p-hydroxybenzoates. Capsules containing the active ingredient can e.g. are prepared by mixing the active ingredient with an inert carrier, such as lactose or sorbitol, and encapsulating it in gelatin capsules.

Egnede suppositorier kan f.eks. fremstilles ved å blande den aktive bestanddelen med tilsvarende bærere, så som nøytrale fettyper eller polyetylenglykol eller deres derivater. Suitable suppositories can e.g. are prepared by mixing the active ingredient with corresponding carriers, such as neutral fatty types or polyethylene glycol or their derivatives.

For mennesker er en enkelt dose For humans is a single dose

fra 0,5 til 5 mg/kg for oral tilførsel, from 0.5 to 5 mg/kg for oral administration,

fra 0,05 til 2 mg/kg for intravenøs tilførsel, from 0.05 to 2 mg/kg for intravenous administration,

fra 0,1 til 3 mg/kg for intramuskulær tilførsel, from 0.1 to 3 mg/kg for intramuscular administration,

fra 0,5 til 10 mg/kg for rektal tilførsel. from 0.5 to 10 mg/kg for rectal administration.

Spesielt gjør anti-arytmi- og de p<->sympatolytiske egenskapene for forbindelsene med formel I og deres fysiologiske akseptable syreaddisjonssalter dem spesielt egnede for farmakoterapi av sykdomstilstander ved hjerterytmen, behandling av hjertesykdommer og forebyggelse av plutselig død på grunn av hjertesykdom. Den anti-arytmiske virkningen av forbindelsene med formel I ble etablert både ved elektro-fysiologiske studier på hundehjerte Purkinje-fibre og ved hjelp av en ouabaln-indusert ventrlkulær tachykardl i hunder. In particular, the anti-arrhythmic and the β<->sympatholytic properties of the compounds of formula I and their physiologically acceptable acid addition salts make them particularly suitable for the pharmacotherapy of disease states of the heart rhythm, the treatment of heart diseases and the prevention of sudden death due to heart disease. The anti-arrhythmic action of the compounds of formula I was established both by electrophysiological studies on dog heart Purkinje fibers and by means of a ouabalin-induced ventricular tachycardia in dogs.

I de følgende tabellene (I) og (II) sammenlignes forbindelsene med formel I med propafenon (A). In the following tables (I) and (II), the compounds of formula I are compared with propafenone (A).

Virkningen på kontraksjonsstyrken av hjerte ble målt på paplllærmuskelen 1 marsvin. Eemodynamiske undersøkelser ble utført både på friske hunder og på hunder med akutt infarkt. Et viktig kriterium i tabell (I) som følger er sikkerhets-faktoren (S.F.), som beregnet fra relasjonen mellom anti-arytmi-virkningen, den negative inotropien og den spesifikt større virkningen ved høyere frekvenser ifølge formelen: ratefaktor for Vmax x (C20CF/C20 Vmax). Ved sammenligning registreres det at de i dag ledende antl-arytmimidlene propafenon og flecanidin har en S.F. på henholdsvis 1,5 og 1,7. The effect on the contraction strength of the heart was measured on the papillary muscle of 1 guinea pig. Haemodynamic examinations were carried out both on healthy dogs and on dogs with acute infarction. An important criterion in table (I) which follows is the safety factor (S.F.), as calculated from the relationship between the anti-arrhythmic effect, the negative inotropy and the specifically greater effect at higher frequencies according to the formula: rate factor for Vmax x (C20CF/ C20 Vmax). By comparison, it is recorded that today's leading antiarrhythmic agents propafenone and flecanidine have an S.F. of 1.5 and 1.7 respectively.

Som et ytterligere kriterium ble prematuritetsfaktoren fastslått. Denne kjennetegner den ønskede virkningen av forbindelsene fremstilt ifølge oppfinnelsen ved premature ekstrasystoler. As a further criterion, the prematurity factor was established. This characterizes the desired effect of the compounds produced according to the invention in premature extrasystoles.

Den høye anti-arytmieffekten er ikke ledsaget av en betydelig økning i toksisitet sammenlignet med propafenon (A) som det fremgår fra en sammenligning av LDsg-verdiene i rotter og mus som er sammenfattet i tabell II. The high anti-arrhythmic effect is not accompanied by a significant increase in toxicity compared to propafenone (A) as can be seen from a comparison of the LDsg values in rats and mice summarized in Table II.

Oppfinnelsen skal illustreres ved hjelp av eksemplene. The invention shall be illustrated by means of the examples.

A) Fremstilling av utgangsforbindelsene: A) Preparation of the starting compounds:

Eksempel I Example I

l-(3 , 4-dimetoksyfenyl)-3-[3'-(l,2-epoksy-3-propoksy)-fenyl]-1-propanon 1-(3,4-dimethoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-phenyl]-1-propanone

100 g (0,35 mol) av 3,4-dimetoksy-P-3'-hydroksyfenylpropio-fenon oppvarmes under tilbakeløp i 23 timer med 300 ml epiklorhydrin og 24,2 g (0,175 mol) av kal iumkarbonat og omrøres. Det resulterende saltet f raf Utreres og den gjenværende oppløsningen Inndampes under redusert trykk. Resten rekrystalliseres fra isopropanol. Utbytte: 109,8 g (91,9#) av forbindelsen i overskriften, smp. 81-84'C. 100 g (0.35 mol) of 3,4-dimethoxy-β-3'-hydroxyphenylpropiophenone is heated under reflux for 23 hours with 300 ml of epichlorohydrin and 24.2 g (0.175 mol) of potassium carbonate and stirred. The resulting salt f raf is evaporated 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, m.p. 81-84'C.

Følgende forbindelser ble fremstilt på samme måte: l-( 4-me tok sy f enyl )-3 - [3 ' - (1,2-epoksy-3-propoksy)-f enyl]-1-propanon The following compounds were prepared in the same manner: 1-(4-Metosyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-phenyl]-1-propanone

i in

1- ( 3 , 4,5-trimetoksyfenyl)-3-[3'-(1,2-epoksy-3-propoksy)-fenyl]-1-propanon 1-(3,4,5-trimethoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-phenyl]-1-propanone

l-(2,4,6-trimetylfenyl)-3-[3 *-(1,2-epoksy-3-propoksy)-fenyl]-1-propanon 1-(2,4,6-trimethylphenyl)-3-[3*-(1,2-epoxy-3-propoxy)-phenyl]-1-propanone

1-f enyl )-3-[3'-(l, 2 -epoksy-3-pr opok sy)-4 '-metoksyf enyl] -1-propanon 1-phenyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'-methoxyphenyl]-1-propanone

l-(3,4-dimetoksyfenyl)-3-[3'-(l,2-epoksy-3-propoksy)-4'-metoksyfenyl]-1-propanon l-(3,4-trimetoksyfenyl)-3-[3'-(1,2-epoksy-3-propoksy)-4 ' - metoksyfenyl]-1-propanon l-(2-me tok syfenyl)-3-[3'-(1,2-epoksy-3-propoksy)-4'-metoksy-fenyl]-1-propanon l-( 4-me tyl f enyl )-3 - [3 ' - (1,2-epoksy-3-propoksy )-4 ' -metoksy-fenyl]-1-propanon l-(2,4,6-trimetylfenyl )-3-[3'-(1,2-epoksy-3-propoksy)-4'-metoksyfenyl]-1-propanon 1-(3,4-dimethoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'-methoxyphenyl]-1-propanone 1-(3,4-trimethoxyphenyl)-3-[ 3'-(1,2-epoxy-3-propoxy)-4'-methoxyphenyl]-1-propanone 1-(2-methoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy )-4'-methoxy-phenyl]-1-propanone 1-(4-methylphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'-methoxy-phenyl]- 1-propanone 1-(2,4,6-trimethylphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'-methoxyphenyl]-1-propanone

Eksempel II Example II

l-( 2-naftyl)-3-[3'-(l,2-epoksy-3-propoksy)-4 *-metoksyfenyl]-1-propanon 1-(2-naphthyl)-3-[3'-(1,2-epoxy-3-propoxy)-4*-methoxyphenyl]-1-propanone

13,1 g (0,04 mol) av l-(2-naftyl)-3-(3'-hydroksy-4'-metoksy-fenyl)-l-propanon oppvarmes i 5 timer under tilbakeløp med 26,3 ml epiklorhydrin, 90 ml isopropanol og 1,6 g (0,04 mol) natriumhydroksyd. Det resulterende saltet filtreres fra, og den gjenværende oppløsningen inndampes under redusert trykk. Den gjenværende oljeformige resten benyttes uten rensing i det neste trinnet. Utbytte: 16,4 g (s: 100#). 13.1 g (0.04 mol) of 1-(2-naphthyl)-3-(3'-hydroxy-4'-methoxy-phenyl)-1-propanone is heated for 5 hours under reflux with 26.3 ml of epichlorohydrin , 90 ml isopropanol and 1.6 g (0.04 mol) sodium hydroxide. The resulting salt is filtered off and the remaining solution is evaporated under reduced pressure. The remaining oily residue is used without purification in the next step. Yield: 16.4 g (s: 100#).

Eksempel III Example III

l-(3-fenantrenyl)-3-[3 *-(1,2-epoksy-3-propoksy)-fenyl]-1-propanon 1-(3-phenanthrenyl)-3-[3*-(1,2-epoxy-3-propoxy)-phenyl]-1-propanone

61,6 g (0,18 mol) l-(3-fenantrenyl)-3-(3'-hydroksyfenyl)-l-propanon oppvarmes i 12 timer under tilbakeløp med 105,6 ml epiklorhydrin, 66 ml metanol og 7,2 g (0,18 mol) natriumhydroksyd. Det resulterende saltet filtreres fra, og den 61.6 g (0.18 mol) of l-(3-phenanthrenyl)-3-(3'-hydroxyphenyl)-l-propanone is heated for 12 hours under reflux with 105.6 ml of epichlorohydrin, 66 ml of methanol and 7.2 g (0.18 mol) of sodium hydroxide. The resulting salt is filtered off, and the

gjenværende oppløsningen inndampes under redusert trykk. Resten benyttes uten rensing i det neste trinnet. Utbytte: 65,2 g (= 85,3#). the remaining solution is evaporated under reduced pressure. The remainder is used without purification in the next step. Yield: 65.2 g (= 85.3#).

B) Fremstilling av forbindelsene med formel I: B) Preparation of the compounds of formula I:

Eksempel 1 Example 1

1-(3,4-dimetoksyfenyl)-3-[3'-(2-hydroksy-3-tert.-pentylamino-propoksy)-fenyl]-1-propanonhydroklorid 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert-pentylamino-propoxy)-phenyl]-1-propanone hydrochloride

27,4 g (0,08 mol) l-(3,4-dimetoksyfenyl)-3-[3'-(1,2-epoksy-3-propoksy)-fenyl]-1-propanon og 20,9 g (0,24 mol) tert. pentylamin oppløses i 300 ml metanol og oppvarmes i 4 timer under tilbakeløp. Oppløsningsmidlet og overskuddet av amin fjernes under redusert trykk. Den oljeformige resten tas opp 1 metanol og konsentrert saltsyre tilsettes. Etter oppvarming og avkjøling oppnås krystaller som rekrystalliseres fra aceton. Utbytte: 22,8 g (61,25») av forbindelsen i overskriften, smp. 117-119-C. 27.4 g (0.08 mol) of 1-(3,4-dimethoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-phenyl]-1-propanone and 20.9 g ( 0.24 mol) tert. pentylamine is dissolved in 300 ml of methanol and heated for 4 hours under reflux. The solvent and excess amine are removed under reduced pressure. The oily residue is taken up in 1 methanol and concentrated hydrochloric acid is added. After heating and cooling, crystals are obtained which are recrystallized from acetone. Yield: 22.8 g (61.25") of the title compound, m.p. 117-119-C.

Følgende forbindelser ble fremstilt på samme måte (eksempler 2 til 51): 2. l-(3,4-dimetoksyfenyl)-3-[3'-(2-hydroksy-3-n-propyl-aminopropoksy)-fenyl]-1-propanonhydroklorid, smp. 146-147'C. 3. l-(3 , 4-dimetoksyfenyl )-3-[3 ' -(2-hydroksy-3-morfolino-propoksy)-fenyl]-1-propanonhydroklorid, smp. 148-149'C. 4. l-(3,4-dimetoksyfenyl )-3-[3'-(2-hydroksy-3-isopropyl-aminopropoksy)-fenyl]-1-propanonhydroklorid, smp. 175-177<*>C. 5. 1-(3,4-dimetoksyfenyl)-3-[3'-(2-hydroksy-3-tert. - butylaminopropoksy )-fenyl]-1-propanonhydroklorid, smp. 179-181°C. 6. l-( 3 , 4-dimetoksyfenyl )-3-[3 '-(2-hydroksy-3-piperidino-propoksy)-fenyl]-1-propanonhydroklorid, smp. 141-142<*>C. 7. 1-( 4-metoksyf enyl )-3 - [3 ' - (2-hydroksy-3-n-propylamino-propoksy)-fenyl]-1-propanonhydroklorid, smp. 128,5-129 ,5°C. 8. l-(3,4,5-trimetoksyfenyl)-3-[3'-(2-hydroksy-3-tert.-pentylaminopropoksy)-fenyl]-1-propanonhydroklorid, smp. 160-161<*>C. 9. l-(3,4,5-trimetoksyfenyl)-3-[3'-(2-hydroksy-3-isopropyl-aminopropoksy)-fenyl]-1-propanonhydroklorid, smp. 119,5-120,5<*>C. 10. l-(3,4,5-trimetoksyfenyl)-3-[3'-(2-hydroksy-3-tert.-butylaminopropoksy)-fenyl]-l-propanonhydroklorid, smp. 158-159<*>C. 11. l-(2 ,4 ,6-trimetylfenyl ) -3-[3 * - (2-hydroksy-3-tert. - pentylaminopropoksy)-fenyl]-1-propanonhydroklorid, smp. 103-105<*>C. 12. l-( 2 , 4 , 6-tr imetylfenyl)-3-[3'-(2-hydroksy-3-piperidino-propoksy)-fenyl]-1-propanonhydroklorid, smp. 158-159,5°C. 13. l-( 2 ,4 , 6-trimetylfenyl )-3-[3*-(2-hydroksy-3-morfolino-propoksy)-fenyl]-1-propanonhydroklorid, smp. 170-171'C. 14. l-(2 ,4 ,6-trimetylfenyl )-3-[3 * - ( 2-hydroksy-3-tert. - butylaminopropoksy)-fenyl]-1-propanonhydroklorid, smp. 129-131'C. 15 . l-( 2 , 4 ,6-trimetylfenyl )-3-[3 '-(2-hydroksy-3-isopropyl-aminopropoksy)-fenyl]-1-propanonsemi-oksalat, smp. 146-148<*>C. 16. l-(2,4 ,6-trimetylfenyl )-3-[3 '-(2-hydroksy-3-n-propyl-aminopropoksy)-fenyl]-1-propanonhydroklorid, smp. 84-85<*>C. 17. l-(2 ,4 ,6-trimetylfenyl )-3-[3 ' - (2-hydroksy-3-tert. - butylaminopropoksy)-fenyl]-1-propanonhydroklorid, smp. 123,5-125,5<*>C. 18. 1-f enyl -3-[3'-(2-hydroksy-3-tert.-pentylaminopropoksy)-4'-metoksyfenyl]-1-propanonsemi-oksalat, smp. 162-164*C. 19. l-fenyl-3-[3'-(2-hydroksy-3-Isopropylamlnopropoksy)-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 157-158<*>C. 20. l-f enyl-3-[3'-( 2-hydroksy-3-tert.-butylaminopropoksy )-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 158-159<*>C. 21. l-fenyl-3-[3'-(2-hydroksy-3-piperIdinopropoksy)-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 115-117°C. 22. l-(3,4-dimetoksyfenyl)-3-[3'-(2-hydroksy-3-n-propyl-aminopropoksy)-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 115-116,5<*>C. 23. l-( 3 , 4-dimetoksyfenyl )-3 - [3 ' - ( 2-hydroksy-3-isopropyl-aminopropoksy)-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 128-131<*>C. 24. l-(3, 4-dimetoksyfenyl )-3-[3 * - ( 2-hydroksy-3-morfolino-propoksy)-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 158-161<*>C. 25. 1-(3,4-dimetoksyfenyl)-3-[3'-(2-hydroksy-3-tert .-butylaminopropoksy)-4 ' -metoksyfenyl] -1-propanonhydroklorid, smp. 168-170<*>C. 26. l-( 3,4-dimetoksyfenyl)-3-[3'-(2-hydroksy-3-cykloheksyl-aminopropoksy )-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 117,5-120,5<e>C. 27. l-(3,4-dimetoksyfenyl )-3-[3'-(2-hydroksy-3-tert. - pentylaminopropoksy)-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 147-148'C. 28. 1-(3,4,5-trimetoksyfenyl)-3-[3'-(2-hydroksy-3-tert.-pentylaminopropoksy)-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 126-129°C. 29. 1 -(3,4,5-trimetoksyfenyl)-3-[3 *-(2-hydroksy-3-n-propy laminopropoksy)-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 103,5-106'C. 30. l-(3,4,5-trimetoksyfenyl)-3-[3'-(2-hydroksy-3-isopropyl-aminopropoksy)-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 115-116'C. 31. l-(3,4,5-trimetoksyfenyl)-3-[3'-(2-hydroksy-3-tert. - bu ty laminopropoksy) -4 ' -metoksyf enyl] -1-propanonhydroklorid, smp. 150,5-152°C. 32. l-(3,4,5-trimetoksyfenyl)-3-[3'-(2-hydroksy-3-cyklo-heksylaminopropoksy)-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 136,5-138,5°C. 33. l-(2-metoksyfenyl)-3-[3'-(2-hydroksy-3-tert.-pentyl-aminopropoksy ) -4 '-metoksyfenyl]-1-propanonhydroklorid, smp. 119-120'C. 34. l-( 2-metoksyf enyl ) -3- [ 3 ' - ( 2-hydroksy-3-n-propylamino-propoksy)-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 141,5-143<*>C. 35. l-(2-metoksyfenyl)-3-[3'-(2-hydroksy-3-tert.-butylamino-propoksy )-4 ' -metoksyf enyl] -1-propanonhydroklorid , smp. 166,5-167'C. 36. l-(4-metylfenyl)-3-[3'-(2-hydroksy-3-tert.-pentylamino-propoksy)-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 107,5-109,5'C. 37 . 1 - ( 4-metyl f enyl )-3-[3 * -(2-hydroksy-3-n-propylamino-propoksy )-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 108-110'C. 38. l-(4-metylfenyl)-3-[3 *-(2-hydroksy-3-morfolinopropoksy)-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 117-119,5°C. 39. l-( 4-metylf enyl )-3-[3 '-( 2-hydroksy-3-tert. -butylamino-propoksy )-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 117-119'C. 40. l-(4-metylfenyl)-3-[3'-(2-hydroksy-3-piperidino-propoksy)-metoksyfenyl]-1-propanonhydroklorid, smp. 138,5-140°C. 41. l-( 4-metylf enyl )-3-[3 ' - (2-hydroksy-3-cykloheksylamino-propoksy)-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 134-136°C. 42. l-(2 ,4 ,6-trimetylfenyl ) -3-[3 ' - ( 2-hydroksy-3-tert. - pentylaminopropoksy )-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 117-118°C. 43. l-( 2 ,4 , 6-trimetylfenyl)-3-[3'-(2-hydroksy-3-piperidino-propoksy)-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 119-120'C. 44. l-( 2 , 4 , 6-trimetylfenyl )-3-[3 '-( 2-hydroksy-3-n-propyl-aminopropoksy)-4 *-metoksyfenyl]-1-propanonoksalat, smp. 121-122<*>C. 45 . l-( 2 , 4 , 6-trimetylf enyl )-3-[3 '-(2-hydroksy-3-isopropyl-aminopropoksy)-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 110-111'C. 46. l-(2 ,4 ,6-trimetylfenyl )-3-[3'-(2-hydroksy-3-morfolino-propoksy)-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 154-155°C. 47. l-(2-naftyl )-3-[3 ' - (2-hydroksy-3-tert.-pentylaminopro-poksy)-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 130-132°C. 48. l-(2-naftyl)-3-[3'-(2-hydroksy-3-n-propylaminopropoksy)-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 142-143"C. 49. l-(2-naftyl)-3-[3 ' -(2-hydroksy-3-isopropylaminopro-poksy)-4'-metoksyfenyl]-1-propanonhydroklorid, smp. 133-135'C. 50. l-( 3-fenantrenyl )-3-[3 * -( 2-hydroksy-3-isopropylamino-propoksy)-fenyl]-l-propanonhydroklorid, smp. 140-142'C. 51. l-(3-fenantrenyl)-3-[3'-(2-hydroksy-3-n-propylamino-propoksy)-fenyl]-1-propanonhydroklorid, smp. 149-152°C. The following compounds were prepared in the same manner (Examples 2 to 51): 2. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-n-propyl-aminopropoxy)-phenyl]-1 -propanone hydrochloride, m.p. 146-147'C. 3. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-morpholino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 148-149'C. 4. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-isopropyl-aminopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 175-177<*>C. 5. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-butylaminopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 179-181°C. 6. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-piperidino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 141-142<*>C. 7. 1-(4-Methoxyphenyl)-3-[3'-(2-hydroxy-3-n-propylamino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 128.5-129.5°C. 8. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert-pentylaminopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 160-161<*>C. 9. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-isopropyl-aminopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 119.5-120.5<*>C. 10. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert-butylaminopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 158-159<*>C. 11. 1-(2,4,6-trimethylphenyl)-3-[3*-(2-hydroxy-3-tert.-pentylaminopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 103-105<*>C. 12. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-piperidino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 158-159.5°C. 13. 1-(2,4,6-trimethylphenyl)-3-[3*-(2-hydroxy-3-morpholino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 170-171'C. 14. 1-(2,4,6-trimethylphenyl)-3-[3*-(2-hydroxy-3-tert.-butylaminopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 129-131'C. 15 . 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-isopropyl-aminopropoxy)-phenyl]-1-propanone semi-oxalate, m.p. 146-148<*>C. 16. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-n-propyl-aminopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 84-85<*>C. 17. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-tert.-butylaminopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 123.5-125.5<*>C. 18. 1-phenyl-3-[3'-(2-hydroxy-3-tert-pentylaminopropoxy)-4'-methoxyphenyl]-1-propanone semi-oxalate, m.p. 162-164*C. 19. 1-phenyl-3-[3'-(2-hydroxy-3-Isopropylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 157-158<*>C. 20. 1-phenyl-3-[3'-(2-hydroxy-3-tert-butylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 158-159<*>C. 21. 1-phenyl-3-[3'-(2-hydroxy-3-piperIdinopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 115-117°C. 22. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-n-propyl-aminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 115-116.5<*>C. 23. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-isopropyl-aminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 128-131<*>C. 24. 1-(3,4-dimethoxyphenyl)-3-[3*-(2-hydroxy-3-morpholino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 158-161<*>C. 25. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-butylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 168-170<*>C. 26. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-cyclohexyl-aminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 117.5-120.5<e>C. 27. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-pentylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 147-148'C. 28. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-pentylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 126-129°C. 29. 1-(3,4,5-trimethoxyphenyl)-3-[3*-(2-hydroxy-3-n-propylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 103.5-106°C. 30. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-isopropylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 115-116'C. 31. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-butylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 150.5-152°C. 32. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-cyclohexylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 136.5-138.5°C. 33. 1-(2-Methoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-pentyl-aminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 119-120'C. 34. 1-(2-Methoxyphenyl)-3-[3'-(2-hydroxy-3-n-propylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 141.5-143<*>C. 35. 1-(2-Methoxyphenyl)-3-[3'-(2-hydroxy-3-tert-butylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 166.5-167'C. 36. 1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-tert-pentylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 107.5-109.5'C. 37 . 1 - ( 4-methyl phenyl )-3-[3 * -(2-hydroxy-3-n-propylamino-propoxy )-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 108-110'C. 38. 1-(4-methylphenyl)-3-[3*-(2-hydroxy-3-morpholinopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 117-119.5°C. 39. 1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-tert.-butylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 117-119'C. 40. 1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-piperidino-propoxy)-methoxyphenyl]-1-propanone hydrochloride, m.p. 138.5-140°C. 41. 1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-cyclohexylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 134-136°C. 42. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-tert.-pentylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 117-118°C. 43. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-piperidino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 119-120'C. 44. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-n-propyl-aminopropoxy)-4*-methoxyphenyl]-1-propanone oxalate, m.p. 121-122<*>C. 45 . 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-isopropyl-aminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 110-111'C. 46. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-morpholino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 154-155°C. 47. 1-(2-naphthyl)-3-[3'-(2-hydroxy-3-tert-pentylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 130-132°C. 48. 1-(2-naphthyl)-3-[3'-(2-hydroxy-3-n-propylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 142-143"C. 49. 1-(2-Naphthyl)-3-[3'-(2-hydroxy-3-isopropylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 133-135" C. 50. 1-(3-phenanthrenyl)-3-[3*-(2-hydroxy-3-isopropylamino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 140-142'C. 51. 1-( 3-phenanthrenyl)-3-[3'-(2-hydroxy-3-n-propylamino-propoxy)-phenyl]-1-propanone hydrochloride, mp 149-152°C.

Claims (6)

1. Analogifremgangsmåte for fremstilling av terapeutisk aktive aminopropanolderivater av 3-(3-hydroksyfenyl)-l-propanonfor-bindelser med generell formel (I) hvor R<1> og R<2> er like eller forskjellige og står for hydrogenatomer, alkyl eller cykloalkylgrupper med opptil 6 karbonatomer, eller r! og R<2> danner sammen med nitrogenatomet som forbinder dem, en morfolin- eller piperidinring, R<3> står for et hydrogenatom eller en alkoksygruppe med opptil 6 karbonatomer, R<4> står for et hydrogenatom, en alkylgruppe inneholdende opptil 3 karbonatomer eller en alkoksygruppe med opptil 6 karbonatomer, eller R<4> er sammen med fenylgruppen bundet til denne en naftalen-eller fenantrenring, og n er et helt tall på 1 til 5, og syreaddisjonssalter derav, karakterisert ved at den innbefatter omsetning av en fenoleter med generell formel (II): hvor R<3>, R<4> og n har den ovenfor angitte betydningen, med et amin av generell formel (III): hvori R<1> og R<2> har de ovenfor angitte betydningene og, om ønsket, omvandling av den resulterende forbindelsen med en syre til et syreaddisjonssalt.1. Analogous process for the preparation of therapeutically active aminopropanol derivatives of 3-(3-hydroxyphenyl)-1-propanone compounds of general formula (I) where R<1> and R<2> are the same or different and stand for hydrogen atoms, alkyl or cycloalkyl groups with up to 6 carbon atoms, or r! and R<2> together with the nitrogen atom connecting them form a morpholine or piperidine ring, R<3> stands for a hydrogen atom or an alkoxy group with up to 6 carbon atoms, R<4> stands for a hydrogen atom, an alkyl group containing up to 3 carbon atoms or an alkoxy group with up to 6 carbon atoms, or R<4> together with the phenyl group is bound to this a naphthalene or phenanthrene ring, and n is an integer from 1 to 5, and acid addition salts thereof, characterized in that it includes reaction of a phenol ether with general formula (II): where R<3>, R<4> and n have the meaning given above, with et amine of general formula (III): wherein R<1> and R<2> have the above meanings and, if desired, converting the resulting compound with an acid to an acid addition salt. 2. Fremgangsmåte ifølge krav 1 for fremstilling av l-(3,4,5-trlmetoksyf enyl )-3-[3 ' -(2-hydroksy-3-tert.-pentylaminoprop-oksy)fenyl]-1-propanonhydroklorid, karakterisert ved at tilsvarende utgangsmaterialer anvendes.2. Process according to claim 1 for the production of 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-pentylaminopropoxy)phenyl]-1-propanone hydrochloride, characterized in that corresponding starting materials are used. 3. Fremgangsmåte ifølge krav 1 for fremstilling av l-(2,4,6-trimetylfenyl)-3-[3'-(2-hydroksy-3-tert.-butylaminopropoksy)-fenyl]-1-propanonhydroklorid, karakterisert ved at tilsvarende utgangsmaterialer anvendes.3. Process according to claim 1 for the production of 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-tert-butylaminopropoxy)-phenyl]-1-propanone hydrochloride, characterized in that corresponding starting materials are used. 4. Fremgangsmåte ifølge krav 1 for fremstilling av l-(3,4-dIme tok sy fenyl)-3-[3'-(2-hydroksy-3-isopropylaminopropoksy)-4'-metoksyfenyl]-1-propanonhydroklorid, karakterisert ved at tilsvarende utgangsmaterialer anvendes.4. Process according to claim 1 for the production of 1-(3,4-diMetoxyphenyl)-3-[3'-(2-hydroxy-3-isopropylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, characterized in that corresponding starting materials are used. 5. Fremgangsmåte ifølge krav 1 for fremstilling av l-(3,4,5-tr imetoksyf enyl )-3- [3 ' - ( 2-hydroksy-3-cykloheksylaminoprop-oksy)-4'-metoksyfenyl]-1-propanonhydroklorid, karakterisert ved at tilsvarende utgangsmaterialer anvendes.5. Process according to claim 1 for the production of 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-cyclohexylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, characterized in that corresponding starting materials are used. 6. Fremgangsmåte ifølge krav 1 for fremstilling av l-(2-naftyl)-3-[3' - (2-hydroksy-3-n-propylaminopropoksy )-4'-metoksyfenyl]-1-propanonhydroklorid, karakterisert ved at tilsvarende utgangsmaterialer anvendes.6. Process according to claim 1 for the production of 1-(2-naphthyl)-3-[3'-(2-hydroxy-3-n-propylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, characterized in that corresponding starting materials are used.
NO882771A 1987-06-23 1988-06-22 ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE AMINOPROPANOLE DERIVATIVES OF 3- (3-HYDROXYPHENYL) -1-PROPANONE COMPOUNDS. NO167975C (en)

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