DK156568B - ANALOGY PROCEDURE FOR THE PREPARATION OF 3-CONTENT DERIVATIVES - Google Patents

ANALOGY PROCEDURE FOR THE PREPARATION OF 3-CONTENT DERIVATIVES Download PDF

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DK156568B
DK156568B DK313878AA DK313878A DK156568B DK 156568 B DK156568 B DK 156568B DK 313878A A DK313878A A DK 313878AA DK 313878 A DK313878 A DK 313878A DK 156568 B DK156568 B DK 156568B
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compound
indolyl
epichlorohydrin
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amino
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William E Kreighbaum
William T Comer
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Bristol Myers Co
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/10Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
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    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/04Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/06Antiarrhythmics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/08Vasodilators for multiple indications
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/12Antihypertensives

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Description

1 DK 156568 B1 DK 156568 B

Den foreliggende opfindelse angâr en analogifremgangsmâde til fremstilling af 3-indolderivater, og fremgangsmâden er ej endormie lig ved det i krav l's kendetegnende del angivne.The present invention relates to an analogous process for the preparation of 3-indole derivatives, and the process is not endormic to the characterizing part of claim 1.

De oxnhandlede forbindelser har de almene formler I og II eller er syreadditionssalte deraf: CH3 ohThe oxen-treated compounds have the general formulas I and II or are acid addition salts thereof: CH 3

-j-pCH2-C-NHCH2CHCH2-0-Ar-Xn I-j-pCH2-C-NHCH2CHCH2-O-Ar-Xn I

JL JJ CH.JL JJ CH.

HH

ch3 OHch3 OH

--rCH9-C-NHCHoCHCHo-0-Ar-Het II- rCH9-C-NHCHoCHCHo-0-Ar-Het II

CH3 iCH3 i

2 DK 156568 B2 DK 156568 B

I ovenstâende formler har symbolerne Ar, X, n og Het f0lgende betydninger:In the above formulas, the symbols Ar, X, n and Het have the following meanings:

Ar betegner phenyl eller naphthyl, X betegner éventuelle substituenter pâ Ar, som kan være ens eller forskellige grupper udvalgt blandt alkyl, alkenyl, alkynyl, alkoxy, ; alkenoxy, alkanoyl, alkenoyl, alkanoyloxy, alkenoyloxy, alkyl-sulfonyl, alkylsulfinyl, alkylthio, alkanoamido, cycloalkyl med 3-6 ringled og 1-3 eventuellè alkylsubstituenter, cycloalkylalkyl med 3-6 ringled og 1-3 éventuelle alkylsubstituenter, hvori hver af de foregâende grupper har indtil 8 carbonatomer, phenyl, trifluor-methyl, nitro, amino, hydroxyl, halogen, carboxamido, cyano og cyanoalkyl med fra 2 til 4 carbonatomer, i n betegner 0, 1 eller 2, som antallet af X-grupper, og jAr represents phenyl or naphthyl; X represents optional substituents on Ar which may be the same or different groups selected from alkyl, alkenyl, alkynyl, alkoxy; alkenoxy, alkanoyl, alkenoyl, alkanoyloxy, alkenoyloxy, alkylsulfonyl, alkylsulfinyl, alkylthio, alkanoamido, cycloalkyl of 3-6 ring members and 1-3 optional alkyl substituents, cycloalkylalkyl of 3-6 ring members and 1-3 optional alkyl substituents, each of the preceding groups have up to 8 carbon atoms, phenyl, trifluoromethyl, nitro, amino, hydroxyl, halogen, carboxamido, cyano and cyanoalkyl having from 2 to 4 carbon atoms, denote 0, 1 or 2 as the number of X groups, and

Het betegner en over N-atomet bunaet nitrogenholdig heterocyclisk gruppe, hvilken heterocyclisk gruppe bærer fra 0 til 2 ring-substituenter i form af C^g-alkyl, oxo eller carboxamido.Het represents a nitrogen-containing heterocyclic group above the N atom, which heterocyclic group carries from 0 to 2 ring substituents in the form of C 1-6 alkyl, oxo or carboxamido.

Fra US-patentskrift nr. 3.946.009 samt norfek patentskrift nr.From US Patent No. 3,946,009 and Norfek Pat.

110.557 kendes hhv. 2-(3-substituerede amino-2-hydroxypropoxy)-3--substituerede pyraziner og substituerede naphthalenderivater med adrenergisk β-blôkkerende aktivitet. Disse kendte forbindelser adskiller sig fra de ved frëmgangsmâden if0lge den foreliggende opfindelse fremstillede forbindelser og man kan ikke pâ grundlag af disse kendte forbindelser forudsige noget om de if0lge opfin-delsen fremstillede forbindelsers aktivitet.110,557 are known respectively. 2- (3-substituted amino-2-hydroxypropoxy) -3 - substituted pyrazines and substituted naphthalene derivatives with adrenergic β-blocking activity. These known compounds are different from the compounds of the present invention and, on the basis of these known compounds, it is not possible to predict anything about the activity of the compounds of the invention.

De omhandlede forbindelser er enestâende som antihypertensive midler ved at de forener adrenergisk β-blokerende og vasodilatorisk aktivitet. De har ogsâ anvendelighed som antianginale midler, antistress midler, antiarytmiske midler, antithrombogene midler og til behandling af tilstande, hvor det er 0nskeligt at reducere hjertets oxygenbehov, sâsom post-myocardial infarkt. Foretrukne forbindelser har en særligt 0nskelig kombination af de f0rnævnte virkninger og farmakologiske led-sagevirkninger eller mangel derpâ, som g0r dem særligt egnede til spe-cifikke indikationer blandt de anf0rte. Forbindelser med formel I, hvori Ar.betegner phenyl, η = 1 og X sidder i ortho-stillingen, foretrækkes til antihypertensiv brug. Anvendeligheden af forbindelserne med formel I og II kan demonstreres i forskellige dyremodeller, herunder antagonisme af isoproterenol i oralt behandlede ikke-bevidstl0se rotter (adre- 3The present compounds are unique as antihypertensive agents in that they combine adrenergic β-blocking and vasodilatory activity. They also have utility as antianginal agents, antistress agents, antiarrhythmic agents, antithrombogenic agents and in the treatment of conditions where it is desirable to reduce the oxygen demand of the heart, such as post-myocardial infarction. Preferred compounds have a particularly desirable combination of the aforementioned effects and pharmacological linkage effects or deficiencies thereof, which makes them particularly suitable for specific indications among those listed. Compounds of formula I, wherein Ar represents phenyl, η = 1 and X are in the ortho position, are preferred for antihypertensive use. The utility of the compounds of formulas I and II can be demonstrated in various animal models, including antagonism of isoproterenol in orally treated non-conscious rats (

DK 156568 BDK 156568 B

nergisk β-receptor blokerende virkning), spontant hypertensive rotter (antihypertensiv virkning), hunde-bagpote præparationen (vasodilatorisk virkning), ouabain-induceret ventrikulær tachycardia i hunde (anti-arytmisk virkning), i coronar-arterie occluderede hunde (antiarytmisk virkning), in vitro ved mâling af blodpladeaggregering i pladerig plasma fotometrisk efter udsættelse for et thrombogent middel, sâsom adeno-sindiphosphat eller collagen (antithromboÿen virkning), og i forskelli-ge andre dyre- og laboratoriemodeller.nergic β-receptor blocking effect), spontaneously hypertensive rats (antihypertensive effect), canine hindpaw preparation (vasodilatory effect), ouabain-induced ventricular tachycardia in dogs (antiarrhythmic effect), coronary artery occluded (antiarrhythmic) activity, in vitro by measuring platelet aggregation in plate-rich plasma photometrically after exposure to a thrombogenic agent, such as adenosine diphosphate or collagen (antithrombotic effect), and in various other animal and laboratory models.

Til medicinsk brug foretrækkes de farmaceutisk acceptable syre-additionssalte. De farmaceutisk acceptable syreadditionssalte er sâdanne salte, hvori anionen ikke væsentligt bidrager til toxiciteten eller den farmakologiske aktivitet af saltet, og som sâdanne er de farmako-logisk ækvivalente med baserne med ovenstâende strukturformler. I visse tilfælde har saltene fysiske egenskaber, som g0r dem mere 0nske-lige til farmaceutiske præparationsformai, sâsom opl0selighed, mangel pâ hygroskopicitet, kompressibilitet med hensyn til tabletfremstilling og forenelighed med andre bestanddele, med hvilke stofferne kan anvendes til farmaceutiske formâl. Syreadditionssalte, der ikke opfylder de fore-gâende kriterier med hensyn til farmaceutisk accept, f.eks. med hensyn til toxicitet, er undertiden værdifulde som mellemprodukter til isole-ring og rensning af de forskellige forbindelser eller til andre kemiske synteseformâl, sâsom adskillelse af optiske isomere. Fremstillingen af sâdanne salte falder ogsâ indenfor opfindelsens ranimer.For medical use, the pharmaceutically acceptable acid addition salts are preferred. The pharmaceutically acceptable acid addition salts are those salts in which the anion does not significantly contribute to the toxicity or pharmacological activity of the salt and as such are the pharmacologically equivalent to the bases of the above structural formulas. In some cases, the salts have physical properties that make them more desirable for pharmaceutical preparations, such as solubility, lack of hygroscopicity, compressibility with respect to tablet preparation, and compatibility with other ingredients with which the substances can be used for pharmaceutical purposes. Acid addition salts that do not meet the foregoing criteria for pharmaceutical acceptance, e.g. in terms of toxicity, are sometimes valuable as intermediates for isolating and purifying the various compounds or for other chemical synthesis purposes, such as separation of optical isomers. The preparation of such salts also falls within the scope of the invention.

Syreadditionssaltene fremstilles ved omsætning af en base med ovenstâende almene formel med syren, fortrinsvis ved kontakt i opl0s-ning. De kan ogsâ fremstilles ved metathesis eller behandling med en anionbytterharpiks, hvorved anionen af et sait af forbindelsen erstattes med en anden anion under betingelser, som tillader fraskillelse af de u0nskede stoffer, sâsom ved udfældning fra opl0sning eller ekstraktion i et opl0sningsmiddel eller eluering fra eller tilbageholdelse pâ en anionbytterharpiks. Farmaceutisk acceptable syrer med henblik pâ salt-dannelse omfatter saltsyre, hydrogenbromidsyre, hydrogeniodidsyre, citronsyre, eddikesyre, benzoesyre, phosphorsyre, salpetersyre, slim-syre, isethionsyre, methansulfonsyre, p-toluensulfonsyre, glucosaccharin-syre, palmitinsyre, heptansyre, oxalsyre, cyclamsyre og andre.The acid addition salts are prepared by reacting a base of the above general formula with the acid, preferably by contact in solution. They can also be prepared by metathesis or treatment with an anion exchange resin, whereby the anion of one site of the compound is replaced by another anion under conditions which allow separation of the undesirable substances, such as by precipitation from solution or extraction in a solvent or elution from or retention. on an anion exchange resin. Pharmaceutically acceptable acids for salt formation include hydrochloric, hydrobromic, hydroiodic, citric, acetic, benzoic, phosphoric, nitric, mucic, isethionic, methanesulfonic, p-toluenesulfonic, glucosaccharic, palmitic, heptanoic, others.

De omhandlede forbindelser med de viste almene formler indeholder et asymmetrisk carbonatom i propanolaminsidekæden og forekommer som optisk aktive isomere, samt som racemiske blandinger deraf. Den fore-liggende opfindelse omfatter fremstilling af bâde de optisk aktiveThe compounds of the general formulas shown contain an asymmetric carbon atom in the propanolamine side chain and appear as optically active isomers, as well as racemic mixtures thereof. The present invention comprises the production of both the optically active

4 DK 156568 B4 DK 156568 B

og racemiske former. Nogle af de omhandlede forbindelser indeholder et asymmetrisk carbonatom i X- eller Het-substituenten, og diastereo-isomere par af racemater eksisterer. Disse formers fremstilling er ligeledes omfattet.and racemic forms. Some of the compounds of the present invention contain an asymmetric carbon atom in the X or Het substituent and diastereoisomeric pairs of racemates exist. The manufacture of these forms is also included.

Opspaltning af racemiske blandinger til fremstilling af de optisk aktive isomere af de f0rnævnte forbindelser udf0res f.eks. ved dannelse af et sait med en optisk aktiv syre, hvoraf mange er kendte for fagman-den, sâsom optisk aktive vin-, mandel-, cholin-, 0,0-di-p-toluoylvin-og Ο,Ο-dibenzoylvinsyrer eller andre syrer, som konventionelt anven-des til dette formai. Opfindelsen omfatter sâvel fremstillingen af forbindelserne i form af de forskellige racemiske blandinger som i form af de optisk aktive isomere, hvor dette er muligt.Cleavage of racemic mixtures to prepare the optically active isomers of the aforementioned compounds is carried out e.g. by forming a site with an optically active acid, many of which are known to those skilled in the art, such as optically active wine, almond, choline, 0.0-di-p-toluoyl tartaric acid and Ο, Ο-dibenzoyl tartaric acids or other acids conventionally used for this purpose. The invention includes both the preparation of the compounds in the form of the various racemic mixtures and in the form of the optically active isomers where possible.

Til terapeutiske formai kan man systemisk administrere en effektiv ikke-toxisk mængde af en forbindelse med formel I eller formel II eller et farmaceutisk acceptabelt syreadditionssalt af en af disse til enten et pattedyr, herunder menneske, med en sygdomstilstand, der skyldes over-dreven stimulering af de adrenergiske β-receptorer, eller til et pattedyr, herunder menneske, som kræver vasodilation, eller til et pattedyr, herunder menneske med hypertension. En effektiv mængde skal betyde en dosis, som ud0ver en adrenergisk β-receptor blokerende virkning, en vasodilatorisk virkning eller en antihypertensiv virkning i det angreb-ne dyr uden væsentlige toxiske bivirkninger. Med systemisk administre-ring menes administrering, der omfatter bâde orale og parenterale veje. Eksempler pâ parentéral administrering er intraven0s injektion eller infusion og intraperitoneal, intramuskulær eller subkutan injektion. Rektal administrering ved hjælp af salve eller suppositorium kan anvendes. Doseringen vil variere i afhængighed af administreringsvejen med fra ca. 0,1 ^/ug til ca. 100 mg/kg/legemsvægt af forbindelsen med formel I eller II eller et farmaceutisk acceptabelt syreadditionssalt deraf, som en dosis, der i almindelighed giver den 0nskede terapeutiske virkning. Akutte toxiciteter malt pâ oralt behandlede mus ligger i intervallet fra ca. ALD^g 250 mg/kg til >2000 mg/kg legemsvægt, med ikke-letale tegn pâ lægemiddelvirkning, sâsom centralnervesystem-stimulering eller dépréssion, mydriasis eller lacrimation ved 1/2 til 1/10 af denne dosis.For therapeutic purposes, an effective non-toxic amount of a compound of Formula I or Formula II or a pharmaceutically acceptable acid addition salt of one of these can be administered to either a mammal, including human, with a disease state due to excessive stimulation of the adrenergic β-receptors, or to a mammal, including human requiring vasodilation, or to a mammal, including human with hypertension. An effective amount should mean a dose that exerts an adrenergic β-receptor blocking effect, a vasodilatory effect or an antihypertensive effect in the affected animal without significant toxic side effects. By systemic administration is meant administration comprising both oral and parenteral routes. Examples of parental administration are intravenous injection or infusion and intraperitoneal, intramuscular or subcutaneous injection. Rectal administration by ointment or suppository may be used. The dosage will vary depending on the route of administration with from approx. 0.1 µg to about 100 mg / kg / body weight of the compound of formula I or II or a pharmaceutically acceptable acid addition salt thereof, as a dose which generally provides the desired therapeutic effect. Acute toxicities measured in orally treated mice range from approx. ALD ^ g 250 mg / kg to> 2000 mg / kg body weight, with non-lethal signs of drug action, such as central nervous system stimulation or depression, mydriasis or lacrimation at 1/2 to 1/10 of this dose.

Kombinationen af farmakologiske egenskaber for forbindelsen l-[[2-(3-indolyl)-1,1-dimethylethyl]amino]-3-(2-methylphenoxy)-2-propanol, hydrochlorid (eksempel 10 nedenfor) viser, at den er særligt egnet til antihypertensiv brug. Den har 5 gange sâ stor adrenergisk β-receptorThe combination of pharmacological properties of the compound 1 - [[2- (3-indolyl) -1,1-dimethylethyl] amino] -3- (2-methylphenoxy) -2-propanol hydrochloride (Example 10 below) shows that it is particularly suitable for antihypertensive use. It has 5 times as much adrenergic β-receptor

, DK 156568 B, DK 156568 B

blokerende styrke som propranolol pâvist ved oral administrering til rotter efterfulgt af udsættelse af dyrene for intraven0st administreret isoproterenol. Den sidstnævnte er en velkendt adrenergisk β-receptor stimulant, som bevirker en for0gelse i hjertehastighed og en formind-skelse i hlodtryk. Disse virkninger af isoproterenol antagoniseres af adrenergisk β-receptor blokerende midler, og de ovenfor anf0rte relative styrkeværdier fremkom ved regressionsanalyse af log dosis-reaktions- data for de to forbindelser. Til terapeutisk brug vil dosisst0rrelse og frekvens variere med individet og administrationsvejen, hvorved fra ca. 0,2 mg ved intraven0s administrering indtil ca. 100 mg oralt er passende for mennesket.blocking potency as propranolol demonstrated by oral administration to rats followed by exposure of the animals to intravenously administered isoproterenol. The latter is a well-known adrenergic β-receptor stimulant which causes an increase in heart rate and a decrease in blood pressure. These effects of isoproterenol are antagonized by adrenergic β-receptor blocking agents and the relative strength values stated above were obtained by regression analysis of log dose-response data for the two compounds. For therapeutic use, the dose size and frequency will vary with the individual and the route of administration, 0.2 mg by intravenous administration until approx. 100 mg orally is appropriate for man.

Forbindelsen if0lge eksempel 10 afviger fra andre adrenergiske β-receptor blokerende lægemidler ved at den er effektiv til sænkning af blodtrykket i den spontant hypertensive rotte. Selv om adrenergiske β-receptor blokerende midler har fundet udstrakt anvendelse i human-medicinen til behandling af hypertension,er deres virkningsmekanisme ukendt, og deres antihypertensive virkning kan i de fieste tilfælde ikke pâvises ved denne dyretest. Med den foreliggende forbindelse i den spontant hypertensive rotte forekommer en blodtryksreduktion pâ 25 mm Hg ved en dosis pâ 100 mg/kg legensvægt oralt med kun en minimal reduktion i hjerteslag. Dette mâ antages at vise anvendelighed til hypertensive indikationer, hvor andre adrenergiske β-receptor blokerende lægemidler er inoperative eller mindre 0nskelige.The compound of Example 10 differs from other adrenergic β-receptor blocking drugs in that it is effective in lowering blood pressure in the spontaneously hypertensive rat. Although adrenergic β-receptor blocking agents have found widespread use in human medicine for the treatment of hypertension, their mechanism of action is unknown and in most cases their antihypertensive effect cannot be demonstrated in this animal test. With the present compound in the spontaneously hypertensive rat, a blood pressure reduction of 25 mm Hg occurs at a dose of 100 mg / kg body weight orally with only a minimal reduction in heart rate. This may be thought to be useful for hypertensive indications where other adrenergic β-receptor blocking drugs are inoperative or less desirable.

Forbindelsen if01ge eksempel 10 bevirker ogsâ en blodtryksreduktion ved intraven0s administrering til anæstetiserede hunde i en dosis pâ 3,33 mg/kg legemsvægt. Den kan yderligere skélnes ved at den ikke sænker hjerteslag eller h0jre ventrikulær kontraktilkraft, sâledes som det er tilfældet med mange hidtil kendte adrenergiske β-receptor blokerende midler. Forbindelsen udviser bâde en positiv inotropisk og en positiv chronotropisk virkning, og disse virkninger kan iagttages, selv nâr dyret f0rst behandles med et adrenergisk β-receptor blokerende middel, sâsom sotalol. Lungearterietrykket forbliver i det væsentlige uændret, mens aortablodstr0m og totalperiferal modstand aftager, ait i den anæstetiserede hund.The compound of Example 10 also causes a blood pressure reduction by intravenous administration to anesthetized dogs at a dose of 3.33 mg / kg body weight. It can be further distinguished by the fact that it does not slow heartbeat or increase ventricular contractile force, as is the case with many known adrenergic β-receptor blocking agents. The compound exhibits both a positive inotropic and a positive chronotropic effect, and these effects can be observed even when the animal is first treated with an adrenergic β-receptor blocking agent, such as sotalol. Pulmonary artery pressure remains essentially unchanged while aortic blood flow and total peripheral resistance decrease, albeit in the anesthetized dog.

Forbindelsen if01ge eksempel 10 besidder vasodilatorisk aktivitet, der i det mindste delvis kan forklare dens enestâende antihypertensive virkning. I anæstetiserede ganglie-blokerede (chlorisondaminchlorid) angïotension-underst0ttede rotter ud0ver direkte virkende vasodilatorer, sâsom diazoxid,en blodtryksreduktion. Forbindelsen if0lge eksempel 10The compound of Example 10 possesses vasodilatory activity that can at least partially explain its unique antihypertensive effect. In anesthetized ganglia-blocked (chloroisone amine chloride) angiotensin-supported rats, in addition to directly acting vasodilators, such as diazoxide, a blood pressure reduction. The compound according to Example 10

6 DK 156568B6 DK 156568B

er styrkemæssigt ækvivalent med deazoxid i denne test. Forbindelsens vasodilatoriske virkning kan ogsâ vises i den pumpe-perfuserede hundebag-pote i doser pâ fra 0,03 til 1,0 mg/min. perfusion. Efter oral admini-strering til rotter forekommer en formindskelse i urinvolumen og en formindskelse i natriumionekskretion, der er typisk for vasodilatoriske forbindelser.is strength equivalent to deazoxide in this test. The vasodilatory effect of the compound can also be demonstrated in the pump-perfused dog-back paw at doses of 0.03 to 1.0 mg / min. perfusion. Following oral administration to rats, a decrease in urine volume and a decrease in sodium ion excretion are typical of vasodilatory compounds.

Den antithrombogene virkning af forbindelsen if0lge eksempel 10 afspejles ved dens evne til at reducere blodpladeaggregering in vitro i pladerig plasma efter udsættelse for ADP eller collagen. Den er sammen-lignelig i in vitro aktivitet med suloctidil eller papaverin.The antithrombogenic effect of the compound of Example 10 is reflected in its ability to reduce platelet aggregation in vitro in plate-rich plasma after exposure to ADP or collagen. It is comparable in in vitro activity to suloctidil or papaverine.

Der ligger en fare i omfattende brug af adrenergiske β-reçeptor-blokerende midler for patienter, som lider af ikke-allergisk bronchospasme pâ grund af disse midlers tendens til at provokere et astmatisk angreb eller til at g0re individet modstandsdygtig overfor behandling med adrenergiske β-receptor stimulerende midler, sâsom isoproterenol, der anvendes til behandling af akutte angreb. Forbindelsen if0lge eksempel 10 mangler bronchospastisk tendens, hvilket er pâvist ved at den ikke reducerer lungeventrikulært tryk og kun fremkalder modérât for0gelse i reaktionen hos sensibiliserede rotter pâ immunologisk indu-ceret broncho-konstriktion ved en dosis pâ 0,5 mg/kg legemsvægt intra-ven0st. I modsætning hertil reducerer propranolol ved en dosis pâ 0,5 mg/kg legemsvægt intraven0st lungeventilært tryk og fremkalder en akut bronchospastisk reaktion hos sensibiliserede rotter pâ immunologisk-induceret bronchokonstriktion.There is a danger in extensive use of adrenergic β-receptor blocking agents for patients suffering from non-allergic bronchospasm because of these agents' tendency to provoke an asthmatic attack or to make the individual resistant to adrenergic β-receptor therapy. stimulants, such as isoproterenol, used to treat acute attacks. The compound of Example 10 lacks bronchospastic tendency, which is shown to not reduce pulmonary ventricular pressure and only induce moderate increase in the response of sensitized rats to immunologically induced broncho-constriction at a dose of 0.5 mg / kg body weight intravenously. . In contrast, at a dose of 0.5 mg / kg body weight, propranolol reduces intravenous pulmonary valve pressure and induces an acute bronchospastic response in sensitized rats to immunologically induced bronchoconstriction.

Til fremstilling af farmaceutiske præparater indeholdende forbin-delserne med formel I eller formel II i form af dosisenheder til oral administrering blandés forbindelsen med en fast, pulverformig bærer, sâsom lactose, saccharose, sorbitol, mannitol, kartoffelstivelse, majsstivelse, amylopectin, cellulosederivater eller gélatine, samt med glittemidler, sâsom magnesiumstearat, calciumstearat, polyethylen-glycolvokser eller lignende og presses til tabletter. Tabletterne kan anvendes uovertrukne eller overtrukne pâ kendt mâde for at forsinke desintegrering og absorption i mavetarmkanalen og derved tilvejebringe en vedvarende virkning over et længere tidsrum. Nâr overtrukne tabletter 0nskes, kan den sâledes fremstillede kerne overtrækkes med en koncentre-ret opl0sning af sukker, hvilken opl0sning kan indeholde f.eks. gummi-arabicum, gélatine, talkum, titaniumdioxid eller lignende. Endvidere kan tabletterne overtrækkes med en lak opl0st i et let flygtigt orga-nisk opl0sningsmiddel eller en blanding af sâdanne opl0sningsmidler og om 0nsket kan farvestof sættes til dette overtræk.For the preparation of pharmaceutical compositions containing the compounds of formula I or formula II in dosage units for oral administration, the compound is admixed with a solid powdered carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine. and with lubricants, such as magnesium stearate, calcium stearate, polyethylene glycol waxes or the like, and pressed into tablets. The tablets may be used uncoated or coated in known manner to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a prolonged period of time. When coated tablets are desired, the core thus prepared can be coated with a concentrated solution of sugar, which solution may contain e.g. gum arabic, gelatin, talc, titanium dioxide or the like. Furthermore, the tablets may be coated with a varnish dissolved in a slightly volatile organic solvent or a mixture of such solvents and, if desired, dye may be added to this coating.

7 DK 156568 B7 DK 156568 B

Til fremstilling af bl0de gelatinekapsler, bestâende af gélatine og f.eks. glycerin og lignende, blandes den aktive bestanddel med en vege-tabilsk olie og indkapsles pâ konventionel mâde. Hârde gelatinekapsler kan indeholde granulater af den aktive bestanddel i kombination med en fast, pulverformig bærer, sâsom lactose, saccharose, sorbitol, mannitol, stivelse (som f.eks. kartoffelstivelse, majsstivelse eller amylopectin), cellulosederivater eller gélatine.For the preparation of soft gelatin capsules, consisting of gelatin and e.g. glycerine and the like, the active ingredient is mixed with a vege-tabilic oil and encapsulated in a conventional manner. Hard gelatin capsules may contain granules of the active ingredient in combination with a solid powdered carrier such as lactose, sucrose, sorbitol, mannitol, starch (such as potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Dosisenheder til rektal administrering kan fremstilles i form af suppositorier indeholdende forbindelsen i blanding med en neutral fedtbase eller i form af en gelatine-rektal kapsel med en blanding af vegetabilsk olie eller paraffinolie.Dosage units for rectal administration can be prepared in the form of suppositories containing the compound in admixture with a neutral fat base or in the form of a gelatin-rectal capsule with a mixture of vegetable oil or paraffin oil.

Flydende præparater, som er egnede til oral administrering, er suspensioner, sirupper og eliksirer indeholdende fra ca. 0,2 til ca.Liquid compositions suitable for oral administration are suspensions, syrups and elixirs containing from ca. 0.2 to approx.

20 vægtprocent af den aktive bestanddel.20% by weight of the active ingredient.

Et passende injektionspræparat omfatter en vandig opl0sning af et vandopl0seligt farmaceutisk acceptabelt syreadditionssalt indstillet pâ en fysiologisk acceptabel pH-værdi.A suitable injection composition comprises an aqueous solution of a water-soluble pharmaceutically acceptable acid addition salt adjusted to a physiologically acceptable pH.

Forbindelserne med formel I og II fremstilles ved anvendelse af i og for sig kendte fremgangsmâder pâ passende udgangsmaterialer. Repræsentative i og for sig kendte fremgangsmâder til fremstilling af aryloxypropanolaminforbindelserne er omhandlet i f0lgende patentskrif-ter: Canadisk patent nr. 834.751 (Troxler) og ü.S.A. patent nr.The compounds of formulas I and II are prepared using methods known per se to suitable starting materials. Representative processes known per se for preparing the aryloxypropanolamine compounds are disclosed in the following patents: Canadian Patent No. 834,751 (Troxler) and ü.S.A. patent no.

3.984.436 (Jaeggi, et al). Mere specielt tilvejebringer den foreliggende opfindelse en fremgangsmâde til fremstilling af forbindelserne med formel I og II i henhold til f01gende reaktionsskema.3,984,436 (Jaeggi, et al). More particularly, the present invention provides a process for preparing the compounds of formulas I and II according to the following reaction scheme.

O (2) CH3O (2) CH3

Ar'-0-CH2CHCH2 3-indolyl-CH2C-NH2 /"''W ch.,Ar'-O-CH 2 CHCH 2 3-indolyl-CH 2 C-NH 2 / '' W ch.,

Ar'-OH formler I og IIAr'-OH formulas I and II

DK 156568 BDK 156568 B

8 I ovenstâende reaktionsskema star symbolet Ar' for grupperne ArXn og ArHet som defineret i formel I og II. Omhandlede fremgangs-m|)de forl0ber i henhold til reaktionerne (1) og (2) , hvori trin (1) involverer omsætning af den passende substituerede phenolforbindelse Ar'-OH med epichlorhydrin i nærvær af en katalytisk mængde af en amin efterfulgt af behandling med vandig alkalimetalhydroxid eller udf0relse af reaktionen i et vandigt alkalimetalhydroxid-reaktions-medium, hvor aminkatalysatoren ikke kræves. Dër fremstilles i trin (1) en Ar'-epoxypropylether, der i trin (2) bringes til at reagere med 2-(3-indolyl)-1,1-dimethylethylamin til dannelse af et produkt med formel I eller II afhængig af arten af den som udgangsmateriale anvendte Ar'OH. Hvert af reaktionstrinnene (1) og (2) finder let sted i sædvanligt laboratorie- eller anlægsapparatur under hensigts-mæssige driftsbetingelser.8 In the above reaction scheme, the symbol Ar 'for the groups ArXn and ArHet denotes as defined in formulas I and II. The present process proceeds according to reactions (1) and (2) wherein step (1) involves reacting the appropriately substituted phenol compound Ar'-OH with epichlorohydrin in the presence of a catalytic amount of an amine followed by treatment. with an aqueous alkali metal hydroxide or carrying out the reaction in an aqueous alkali metal hydroxide reaction medium where the amine catalyst is not required. There, in step (1), an Ar 'epoxypropyl ether is prepared which in step (2) is reacted with 2- (3-indolyl) -1,1-dimethylethylamine to form a product of formula I or II depending on the species of the Ar'OH used as starting material. Each of the reaction steps (1) and (2) readily takes place in conventional laboratory or plant apparatus under appropriate operating conditions.

Opvarmning af epichlorhydrin i væsentligt molært overskud med en phénol Ar'OH indeholdende en eller to drâber piperidin som katalysator pâ et dampbad natten over resulterer i den i trin (1) viste kondensa-tion. En vis mængde af det tilsvarende halogenhydrin-mellemprodukt dannes ogsâ og omdannes uden isolering til den viste oxiran ved behandling af blandingen med vandig alkalimetalhydroxid. Alternativt kan phenolen Ar'OH og epichlorhydrin bringes til at reagere i nærværelse af en tilstrækkelig mængde fortyndet vandig alkalimetalhydroxid til at neutralisere den sure Ar'OH-gruppe ved stuetemperatur under dannelse af /°\ det 0nskede mellemprodukt Ar'OŒ^CHC^. Trin (2) udf0res simpelt ved at opvarme det i trin (1) dannede oxiran-mellemprodukt med 2-(3-indolyl)- 1,1-dimethylethylamin, enten rent eller i nærværelse af et for reaktionen inert organisk opl0sningsmiddel. Ingen katalysator eller konden-sationsmiddel kræves. Egnede opl0sningsmidler. omfatter 95% éthanol, men andre for reaktionen inerte organiske væsker, hvori reaktanterne er opl0selige, kan anvendes. Disse omfatter, men er ikke begrænset til, benzen, tetrahydrofuran, dibutylether, butanol, hexanol, methanol, dimethoxyethan, ethylenglycol, etc. Egnede reaktionstemperaturer er fra ca. 60 til ca. 200°C.Heating epichlorohydrin in substantially molar excess with a phenol Ar'OH containing one or two drops of piperidine as a catalyst in a steam bath overnight results in the condensation shown in step (1). A certain amount of the corresponding halohydrin intermediate is also formed and converted without isolation to the oxirane shown by treating the mixture with aqueous alkali metal hydroxide. Alternatively, the phenol Ar'OH and epichlorohydrin can be reacted in the presence of a sufficient amount of dilute aqueous alkali metal hydroxide to neutralize the acidic Ar'OH group at room temperature to form the desired intermediate Ar'OŒ ^ CHCl3. Step (2) is carried out simply by heating the oxirane intermediate formed in step (1) with 2- (3-indolyl) -1,1-dimethylethylamine, either purely or in the presence of an organic solvent inert for the reaction. No catalyst or condensing agent is required. Suitable solvents. contains 95% ethanol, but other inert organic liquids in which the reactants are soluble may be used. These include, but are not limited to, benzene, tetrahydrofuran, dibutyl ether, butanol, hexanol, methanol, dimethoxyethane, ethylene glycol, etc. Suitable reaction temperatures are from ca. 60 to approx. 200 ° C.

99

DK 156568 BDK 156568 B

I de f01gende eksempler er temperaturerne i °C. Smeltepunkterne er korrigerede værdier i henhold til U.S.P. metoden, hvor angivet ved (corr.)· De kernemagnetiske resonansspektralværdier (NMR) refererer til kemisk skifte (S) udtrykt som dele pr. million (ppm) overfor tetra-methylsilan (TMS) som referencestandard. Det relative areal, som er gengivet for de forskellige skifteværdier svarer til antallet af hydro- genatomer i den specielle funktionstype i molekylet og arten af skifte-værdien med hensyn til multiplicitet er gengivet som bred singlet (bs), singlet (s), multiplet (m), doublet (d), triplet (t) eller kvadruplet (q) med koblingskonstanter (J) anf0rt, hvor det er passende. Opstil-lingen er NMR (opl0sningsmiddel): g(relativt areal, multiplicitet, J-værdi). Anvendte forkortelser er MeOH (methanol), DMSO-dg (deutero-dimethylsulfoxid), i-PrOH (isopropanol), abs.EtOH (absolut éthanol), EtOAc (ethylacetat), EtOH (95% éthanol), i-PrOAc (isopropylacetat), i-P^O (di-isopropylether), d (dekomponering) . André forkortelser har konventionelle etablerede betydninger. De infrar0de spektral-beskrivelser (IR) omfatter kun absorptionsb01getal (cm ^) af værdi til identifikation af funktionelle grupper. KBr anvendtes som fortyn-dingsmiddel til aile IR-spektralbestemmelser. TMS anvendtes som intern reference til NMR-spektralbestemmelse. Elementæranalyserne er gengivet’ som vægtprocenter.In the following examples, the temperatures are in ° C. The melting points are corrected values according to U.S.P. The method where indicated by (corr.) · The nuclear magnetic resonance spectral values (NMR) refer to chemical shift (S) expressed as parts per million (ppm) to tetramethylsilane (TMS) as the reference standard. The relative area reproduced for the different shift values corresponds to the number of hydrogen atoms in the particular function type in the molecule and the nature of the shift value with respect to multiplicity is represented as broad singlet (bs), singlet (s), multiplet ( m), doublet (d), triplet (t) or quadruplet (q) with coupling constants (J) listed where appropriate. The arrangement is NMR (solvent): g (relative area, multiplicity, J value). Abbreviations used are MeOH (methanol), DMSO-dg (deutero-dimethyl sulfoxide), i-PrOH (isopropanol), abs.EthOH (absolute ethanol), EtOAc (ethyl acetate), EtOH (95% ethanol), i-PrOAc (isopropyl acetate) , iP 2 O (di-isopropyl ether), d (decomposition). André abbreviations have conventional established meanings. The infrared spectral descriptions (IR) include only absorbance numbers (cm 2) of value for the identification of functional groups. KBr was used as a diluent for all IR spectral determinations. TMS was used as internal reference for NMR spectral determination. The elemental analyzes are reproduced 'as weight percentages.

10 DK 156568 BDK 156568 B

Fremstillinq af udgangsforbindelser Eksempel 1 4-(methylsulfonyl)-m-tolyloxymethyloxiranPreparation of Starting Compounds Example 1 4- (methylsulfonyl) -m-tolyloxymethyloxirane

Til en blanding af 3-methyl-4-methylsulfonylphenol, 8,1 g (0,0435 mol og 20,0 g (0,216 mol) epichlorhydrin sættes 2 drâber piperidin som kondensationskatalysator, og blandingen opvarmes ved 105-108° i 18 timer. Overskydende epichlorhydrin fjernes dernæst ved destination under anvendelse af toluen som opsamler. En opl0sning af 2,1 g natrium-hydroxid i 50 ml vand og 70 ml dimethoxyethan tilsættes dernæst, og blandingen omr0res i 2 timer med lejlighedsvis opvarmning pâ dampbad til omdannelse af eventuel phenoxychlorhydridforbindelse til oxiranen. Opl0sningsmidlet fjernes dernæst ved destination i vakuum, og remanen-sen opl0ses i en 1:1 (vol/vol) blanding af ether og benzen. Opl0sningen t0rres over vandfri natriumcarbonat og unders0ges ved tyndtlagskromato-grafi for renhed af den 0nskede oxiran under anvendelse af en 9:1 blanding af chloroform og methanol til udvikling (R^ = 0,8). Opl0snings-midlet fjernes dernæst ved destination til opnâelse af 10,7 g af en remanens, som udg0r :den 0nskede oxiran. Mâling af det infrar0de absorp-tionsspektrum anvendes til at bekræfte det væsentlige fravær af hy'droxyl-holdige forureninger. Dette materiale er egnet til yderligere omsætning i eksempel 3 uden yderligere rensning.To a mixture of 3-methyl-4-methylsulfonylphenol, 8.1 g (0.0435 mol and 20.0 g (0.216 mol) of epichlorohydrin is added 2 drops of piperidine as a condensation catalyst and the mixture is heated at 105-108 ° for 18 hours. Excess epichlorohydrin is then removed by distillation using toluene as a collector A solution of 2.1 g of sodium hydroxide in 50 ml of water and 70 ml of dimethoxyethane is then added and the mixture is stirred for 2 hours with occasional heating on a steam bath to convert any phenoxychloride compound. The solvent is then removed by distillation in vacuo and the residue is dissolved in a 1: 1 (v / v) mixture of ether and benzene. The solution is dried over anhydrous sodium carbonate and assayed by thin layer chromatography for purity of the desired oxirane under using a 9: 1 mixture of chloroform and methanol for development (R 2 = 0.8), the solvent is then removed at distillation to give 10.7 g of a residue which is: the 0 spoon an oxirane. Measurement of the infrared absorption spectrum is used to confirm the essential absence of hydroxyl-containing contaminants. This material is suitable for further reaction in Example 3 without further purification.

Eksempel 2 2-chlorphenoxymethyloxiranExample 2 2-Chlorophenoxymethyloxirane

En opl0sning af 12,9 g 2-chlorphenol (0,1 mol) i 125 ml vand inde-holdende 6,5 g (0,162 mol) natriumhydroxid og 18,5 g (0,2 mol) epichlorhydrin omr0res sammen ved 25° i 20 timer. Blandingen ekstraheres dernæst to gange med 70 ml portioner methylenchlorid. Ekstrakten t0rres over vandfri natriumcarbonat, og opl0sningsmidlet fjernes ved destination i vakuum. Remanensen udg0r den 0nskede oxiran og er egnet til yderligere omdannelse som beskrevet i eksempel 4.A solution of 12.9 g of 2-chlorophenol (0.1 mole) in 125 ml of water containing 6.5 g (0.162 mole) of sodium hydroxide and 18.5 g (0.2 mole) of epichlorohydrin is stirred together at 25 ° C. 20 hours. The mixture is then extracted twice with 70 ml portions of methylene chloride. The extract is dried over anhydrous sodium carbonate and the solvent is removed by distillation in vacuo. The residue is the desired oxirane and is suitable for further conversion as described in Example 4.

1111

DK 156568 BDK 156568 B

Fremstilling af slutprodukter Eksempel 3 1- [ [2- (3-indolyl) -1,1-dimethylethyl] amino] -3- [4- (methyls.ulfonyl) -m-tolyloxy]-2-propanolPreparation of End Products Example 3 1- [[2- (3-Indolyl) -1,1-dimethylethyl] amino] -3- [4- (methylsulfonyl) -m-tolyloxy] -2-propanol

Oxiranen fra eksempel 1, 10,7 g, opl0ses i 150 ml toluen, 8,2 g (0,044 mol) 2-(3-indolyl)-1,1-dimethylethylamin tilsættes, og blandinge tilbagesvales i 18 timer. Toluenet fjernes ved destination i vakuum, og en portion af remanensen omdannes til acetatsaltet, smeltepunkt 142-147°C. Strukturen bekræftes ved unders0gelse af de infrar0de absorptions- og kernemagnetiske resonansspektra. Resten af pr0ven omdanne til hydrochloridsaltet ved behandling med en acetonitrilopl0sning deraf med 8 N ethanolisk HCl. Efter omkrystallisation fra CH^CN/MeOH opnâs 12,5 g af produktet, smeltepunkt 174,0-177,0° (corr.)The oxirane of Example 1, 10.7 g, is dissolved in 150 ml of toluene, 8.2 g (0.044 mole) of 2- (3-indolyl) -1,1-dimethylethylamine is added, and mixtures are refluxed for 18 hours. The toluene is removed by distillation in vacuo and a portion of the residue is converted to the acetate salt, mp 142-147 ° C. The structure is confirmed by examining the infrared absorption and nuclear magnetic resonance spectra. The remainder of the sample is converted to the hydrochloride salt by treatment with an acetonitrile solution thereof with 8N ethanolic HCl. After recrystallization from CH 2 CN / MeOH, 12.5 g of product is obtained, mp 174.0-177.0 ° (corr.)

Analyse fundet: C, 59,40; H, 6,90; N, 5,87.Found: C, 59.40; H, 6.90; N, 5.87.

NMR (DMSO-dg): 1,29 (6, s); 2,52 (3, s); 3,12 (3, s); 3,16 (4, m); 4,18 (3, m); 5,95 (1, bs); 7,10 (8, m); 9,00 (2, bs) og 11,12 (1, bs).NMR (DMSO-d 6): 1.29 (6, s); 2.52 (3, s); 3.12 (3, s); 3.16 (4, m); 4.18 (3, m); 5.95 (1, bs); 7.10 (8, m); 9.00 (2, bs) and 11.12 (1, bs).

IR: 740, 765, 1120, 1290, 1450, 1590 og 3270.IR: 740, 765, 1120, 1290, 1450, 1590 and 3270.

Eksempel 4 1-(2-chlorphenoxy)-3-[[2-(3-indolyl)-1,1-dimethylethyl]amino]-2-propano En portion af oxiranen fremstillet i eksempel 2, 7 g (0,033 mol), tilbagesvales i opl0sning med 6,3 g (0,033 mol) 2-(3-indolyl)-1,1-dimethylethylamin i 70 ml éthanol. Efter 24 timer fjernes opl0snings-midlet ved destination i vakuum, og den viskose flydende remanens opl0ses i 200 ml ether, g0res sur med 8 N ethanolisk HCl, og opl0snings· midlet fjernes igen ved destination. Udkrystallisation forârsages ved tilsætning af acetonitril og gnidning med en glasstang. Omkrystallisation fra acetonitril og di-isopropylether til opnâelse af 4,8 g produkt, smeltepunkt 150,5-153,5°C (corr.).Example 4 1- (2-Chlorophenoxy) -3 - [[2- (3-indolyl) -1,1-dimethylethyl] amino] -2-propano A portion of the oxirane prepared in Example 2, 7 g (0.033 mol), is refluxed in solution with 6.3 g (0.033 mol) of 2- (3-indolyl) -1,1-dimethylethylamine in 70 ml of ethanol. After 24 hours, the solvent is removed by distillation in vacuo and the viscous liquid residue is dissolved in 200 ml of ether, acidified with 8 N ethanolic HCl and the solvent is again removed at destination. Crystallization is caused by the addition of acetonitrile and rubbing with a glass rod. Recrystallization from acetonitrile and di-isopropyl ether to give 4.8 g of product, mp 150.5-153.5 ° C (corr.).

Analyse fundet: C, 61,54; H, 6,41; N, 6,94.Found: C, 61.54; H, 6.41; N, 6.94.

i2 DK 156568 Bi2 DK 156568 B

NMR (DMSO-dg): 1,28 (6, s); 3,22 (4, m) ; 4,25 (3, m)} 5,96 (1, bs); 7,23 (9, m); 8,84 (2, bs) og 11,12 (1, bs).NMR (DMSO-d 6): 1.28 (6, s); 3.22 (4, m); 4.25 (3, m)} 5.96 (1, bs); 7.23 (9, m); 8.84 (2, bs) and 11.12 (1, bs).

IR: 745, 1250, 1455, 1480, 1590 og 2780.IR: 745, 1250, 1455, 1480, 1590 and 2780.

Ved anvendelse af de f0romtalte fremgangsmâder fremstilles de i den efterf01gende tabel anf0rte produkter.Using the aforementioned methods, the products listed in the following table are prepared.

urd· DK 156568 Burd · DK 156568 B

o co ·>σ>οο «·> o "itf ["· O Γ~· Ο ^ 00o co ·> σ> οο «·> o" itf ["· O Γ ~ · Ο ^ 00

OrltN 30 H CN H H CNOrltN 30 H CN H H CN

O H HO H H

00 ^ ·*. i—l k k i—l * k ο ο ο ο ιη o * t co *ki o -r'cri tncNLO O 3D OCNlT) Γ'' i—I i—I Γ·* t—1 i—| 1> i—1 i—1 r- r- K. m» ». < « O O "O o » o o o on® invûco ο n co sf00 ^ · *. i — l k k i — l * k ο ο ο ιη o * t co * ki o -r'cri tncNLO O 3D OCNlT) Γ '' i — I i — I Γ · * t — 1 i— | 1> i — 1 i — 1 r— r— K. m »». <«O O" O o "o o o on® invûco ο n co sf

Pi uiH'i «3< <n in LOCNmoo H H rl l> H H Γ'ΗΗΟΟ Ό ^ —- g ω co —s—..-^cQ'-'Cfltncn ^tflw 1 03 g g t) ^ -p Λ m » g Sa εΛΛΛ m g ε·ΰ^εΛΛ 0 %.k.fc>k*kl.sk.tk>h» k.*.k.i*|SJk»»**.Pi uiH'i «3 <<n in LOCNmoo HH rl l> HH Γ'ΗΗΟΟ Ό ^ —- g ω co —s —..- ^ cQ '-' Cfltncn ^ tflw 1 03 ggt) ^ -p Λ m» g Sa εΛΛΛ mg ε · ΰ ^ εΛΛ 0% .k.fc> k * kl.sk.tk> h »k. *. ki * | SJk» »**.

03 W^Olrl ïi HMH lûCl'inHCJlHHH ΜΟ'^ΠΗίΧίΟΓιΗΗ Q ^ o oo ^ oo h »03 ο o ooooonroocNfMo oor^n ·>οωο03 W ^ Olrl ïi HMH lûCl'inHCJlHHH ΜΟ '^ ΠΗίΧίΟΓιΗΗ Q ^ o oo ^ oo h »03 ο o ooooonroocNfMo about ^ n ·> οωο

g CNCNCNO^fOOiO (v3C'lHH03Ht'-HO OOCsJrHOLOO^OOrOg CNCNCNO ^ fOOiO (v3C'1HH03Ht'-HO OOCsJrHOLOO ^ OOrO

2 k, k» K k, k «, k. Vk,k.k.k.Sk.k.k, k K It kl k K k izî HrO^VD > 00 H HCMCO^inr^OOCTtH H fO ^ Γ'-ΟΟσϊ i—I i—!2 k, k »K k, k«, k. Vk, kkkSk.kk, k K It kl k K k izî HrO ^ VD> 00 H HCMCO ^ inr ^ OOCTtH H fO ^ Γ'-ΟΟσϊ i — I i -!

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17 DK 156568 B17 DK 156568 B

Eksempel 15 - Tabletter F01gende ingredienser blandes i det angivne vægtforhold i hen-hold til konventionelle farmaceutiske fremgangsm&der til fremstilling af en tabletbasis.Example 15 - Tablets Following ingredients are mixed in the weight ratio according to conventional pharmaceutical methods for preparing a tablet base.

Ingrediens MængdeQuantity of Ingredients

Lactose 79Lactose 79

Majsstivelse 10Corn starch 10

Talkum 6Talc 6

Tragant 4Tragant 4

Magnesiumstearat 1Magnesium stearate 1

Denne tabletbasis blandes; med tilstrækkelig· 1-[[2-(3-indolyl)-1/ 1-dimethylethyl] amino] -3- (2-methylphenoxy) -2-propanol,hydrochlorid (eksempel 10) til at fremstille tabletter, der indeholder 10, 20, 40, 80, 160 og 320 mg af den aktive bestanddel, og presses i en kon-ventionel tabletpresse.This tablet base is mixed; with sufficient 1 - [[2- (3-indolyl) -1 / 1-dimethylethyl] amino] -3- (2-methylphenoxy) -2-propanol hydrochloride (Example 10) to prepare tablets containing 10, 20, 40, 80, 160 and 320 mg of the active ingredient, and pressed into a conventional tablet press.

Eksempel 16 - T0rre fyldte kapsler F0lgende ingredienser blandes pâ konventionel mâde i det angivne vægtforhold.Example 16 - Dry filled capsules The following ingredients are mixed in a conventional manner in the specified weight ratio.

Ingrediens MængdeQuantity of Ingredients

Lactose, U.S.P. 50Lactose, U.S.P. 50

Stivelse 5Starch 5

Magnesiumstearat 2Magnesium stearate 2

Tilstrækkelig 1-[[2-(3-indolyl)-1,1-dimethylethyl]amino]-3-(2-methylphenoxy)-2-propanol,hydrochlorid (eksempel 10) sættes til blandingen til fremstilling af kapsler indeholdende 10, 20, 40, 80, 160 og 320 mg af den aktive bestanddel, soin fyldes i hârde gelatine-kapsler af passende st0rrelse.Sufficient 1 - [[2- (3-indolyl) -1,1-dimethylethyl] amino] -3- (2-methylphenoxy) -2-propanol hydrochloride (Example 10) is added to the mixture to make capsules containing 10, 20 , 40, 80, 160 and 320 mg of the active ingredient are loaded into hard gelatin capsules of appropriate size.

Eksempel 17 - Qpl0sningExample 17 - Solution

En opl0sning af l-[[2-(3-indolyl)-l,l-dimethylethyl]amino]-3-(2-methylphenoxy)-2-propanol,hydrochlorid (eksempel 10) fremstilles af de f0lgende ingredienser.A solution of 1 - [[2- (3-indolyl) -1,1-dimethylethyl] amino] -3- (2-methylphenoxy) -2-propanol hydrochloride (Example 10) is prepared from the following ingredients.

18 DK 156568 B18 DK 156568 B

Ingrediens MængdeQuantity of Ingredients

Aktiv bestanddel 20 gActive ingredient 20 g

Saccharose, U.S.P. 400 gSucrose, U.S.P. 400 g

Sorbitol, ü.S.P. 100 gSorbitol, U.S.P. 100 g

Bentonit 20 gBentonite 20 g

Smagsstoffer, q.s.Flavors, q.s.

Vand, q.s. indtil 1 literWater, q.s. up to 1 liter

Hver milliliter opl0sning indeholder ca. 20 mg af den aktive bestanddel.Each milliliter of solution contains approx. 20 mg of the active ingredient.

Ved at anvende fremgangsmâderne i eksemplerne 1 eller 2 pâ en passende phénol eller ved andre konventionelle fremgangsmâder fremstil-les de f0lgende oxiraner som dernæst omdannes til produkterne med formel I eller II ved omsætning med 2-(3-indolyl)-1,1-dimethylethyl-amin i henhold til eksemplerne 3 og 4.By applying the methods of Examples 1 or 2 to a suitable phenol or by other conventional methods, the following oxiranes are prepared which are then converted to the products of Formula I or II by reaction with 2- (3-indolyl) -1,1-dimethylethyl -amine according to Examples 3 and 4.

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Eksempel 18Example 18

Eksempel 20 Λ Λ °oExample 20 Λ Λ ° o

Eksempel 21Example 21

19 DK 156568 B19 DK 156568 B

Fysiske egenskaber bestemmes soin f0lger:Physical properties are determined as follows:

Eksempel 19 1- [[2-(3-indolyl)-1,1-dimethylethyl] amino]-3-[2-(2-propenyl)phenoxy]- 2- propanol,hydrochlorid, smp. 163,0-168,6° (corr.), omkrystalliseret fra MeOH/i-P^O.Example 19 1- [[2- (3-indolyl) -1,1-dimethylethyl] amino] -3- [2- (2-propenyl) phenoxy] -2-propanol, hydrochloride, m.p. 163.0-168.6 ° (corr.), Recrystallized from MeOH / i-P 2 O.

Analyse fundet: C, 69,22; H, 7,56; N, 6,70.Found: C, 69.22; H, 7.56; N, 6.70.

NMR (DMSO-dg): 1,30 (6,s); 3,32 (6,m); 4,20 (3,m); 5,03 (2,m); 6,00 (2,m); 7,25 (9,m); 8,90 (l,bs); 9,60 (l,bs) og 11,40 (l,bs).NMR (DMSO-d 6): 1.30 (6, s); 3.32 (6, m); 4.20 (3, m); 5.03 (2, m); 6.00 (2, m); 7.25 (9, m); 8.90 (1, bs); 9.60 (l, bs) and 11.40 (l, bs).

IR: 752, 1120, 1245, 1455, 1490, 1590, 1600, 2790, 2980 og 3350. Eksempel 20 1-[[2-(3-indolyl)-1,1-dimethylethyl]amino]-3-[2-(2-methyl-l-propyl)-phenoxy]-2-propanol,hydrochlorid, smp. 163-166,0° (corr.), omkrystalliseret fra MeOH/CH^CN.IR: 752, 1120, 1245, 1455, 1490, 1590, 1600, 2790, 2980 and 3350. Example 20 1 - [[2- (3-indolyl) -1,1-dimethylethyl] amino] -3- [2- (2-methyl-1-propyl) -phenoxy] -2-propanol, hydrochloride, m.p. 163-166.0 ° (corr.), Recrystallized from MeOH / CH 2 CN.

Analyse fundet: C, 69,34; H, 8,19; N, 6,49.Found: C, 69.34; H, 8.19; N, 6.49.

NMR (DMSO-dg): 0,81 (3,t, 7,0 Hz); 1,17 (3,d, 7,0 Hz); 1,32 (6,s); 1,39 (2,m); 3,28 (5,m); 4,22 (3,m); 6,04 (l,bs); 7,22 (9,m); 9,00 (l,bs); 9,60 (l,bs); 11,20 (l,bs).NMR (DMSO-d 6): 0.81 (3, t, 7.0 Hz); 1.17 (3, d, 7.0 Hz); 1.32 (6, s); 1.39 (2, m); 3.28 (5, m); 4.22 (3, m); 6.04 (1, bs); 7.22 (9, m); 9.00 (1, bs); 9.60 (1, bs); 11.20 (1, bs).

IR: 750, 1100, 1240, 1450, 1490, 1582, 1600, 2780, 2960 og 3320.IR: 750, 1100, 1240, 1450, 1490, 1582, 1600, 2780, 2960 and 3320.

Eksempel 21 3- (2-ethylphenoxy)-1-[[2-(3-indolyl)-1,1-dimethylethyl]amino]-2-propanol,hydrochlorid, smp. 170,0-171,5° (corr.) omkrystalliseret fra EtOH.Example 21 3- (2-Ethylphenoxy) -1 - [[2- (3-indolyl) -1,1-dimethylethyl] amino] -2-propanol, hydrochloride, m.p. 170.0-171.5 ° (corr.) Recrystallized from EtOH.

Analyse fundet: C, 68,36; H, 7,95; N, 6,85.Found: C, 68.36; H, 7.95; N, 6.85.

NMR (DMSO-dg): 1,21 (3,5, 7,0 Hz); 1,33 (6,s); 2,64 (2,m); 3,24 (4,m); 4,21 (3,m); 6,00 (l,bs); 7,25 (9,m); 9,00 (l,bs) og 9,55 (l,bs).NMR (DMSO-d 6): 1.21 (3.5, 7.0 Hz); 1.33 (6, s); 2.64 (2, m); 3.24 (4, m); 4.21 (3, m); 6.00 (1, bs); 7.25 (9, m); 9.00 (1, bs) and 9.55 (1, bs).

IR: 750, 1130, 1240, 1460, 1495, 1590, 1605, 2800, 2970 og 3350.IR: 750, 1130, 1240, 1460, 1495, 1590, 1605, 2800, 2970 and 3350.

20 DK 156568 BDK 156568 B

Den biologiske aktivitet af forbindelser fremstillet if0lge den foreliggende opfindelse angives nedenfor i tabellen. Forbin-delserne fra eksempel 22-32 er hhv.The biological activity of compounds of the present invention is given below in the table. The compounds of Examples 22-32 are respectively.

Eks. nr.Ex. no.

22 2-[2-hydroxy-3-[[2-(3-indolyl)-lf1-dimethylethyl]-amino]--propoxy]-benzonitril, hydrochlorid, smp. 185-187°C, 23 1-(2,3-dimethylphenoxy)-3-[[2-(3-indolyl)-1,1-dimethyl-ethyl]-amino)-2-propanol, hydrochlorid, smp. 173,5-175,5°C (korr.) 24 1-(4-chlor-2-methylphenoky)-3-[[2-(3-indolyl)-1,1-dimethylethyl ]-amino]-2-propanol,oxalat (2:1), hemihydrat, smp, 168-172°C (dek., korr.), 25 1-(2,4-dimethylphenoxy)-3-[[2-(3-indolyl)-1,1-dimethylethyl] -amino] -2-propanol, hydrochlorid, smp. 161,5-164,5°C (korr.) 26 l-[[2-(3-indolyl)-1,l-dimethylethyl]-amino]-3-[2-methyl--4r(methylsulfonyl)-phenoxy]-2-propanol,oxalat (2:1), hydrat, smp. 209,5-211°C (dek., korr.) 27 1-t[2-(3-indolyl)-l,l-dimethylethyl]-amino]-3-[2-(l-methylpropyl)-phenoxy]-2-propanol, hydrobhlorid, smp. 163-166°C (korr.) 28 1-(2-cyclohexylphenafcy)-3-[[2-(lH-indol-3-yl)-1,1-dimethylethyl] -amino]-2-propanol, hydrochlorid, smp.2- 2- [2-hydroxy-3 - [[2- (3-indolyl) -1H-dimethylethyl] amino] propoxy] -benzonitrile, hydrochloride, m.p. 185-187 ° C, 23 1- (2,3-Dimethylphenoxy) -3 - [[2- (3-indolyl) -1,1-dimethyl-ethyl] -amino) -2-propanol, hydrochloride, m.p. 173.5-175.5 ° C (corr.) 24 1- (4-Chloro-2-methylphenoxy) -3 - [[2- (3-indolyl) -1,1-dimethylethyl] amino] -2- propanol, oxalate (2: 1), hemihydrate, mp, 168-172 ° C (dec., corr.), 1- (2,4-dimethylphenoxy) -3 - [[2- (3-indolyl) -1 , 1-dimethylethyl] amino] -2-propanol, hydrochloride, m.p. 161.5-164.5 ° C (corr.) 26 1- [[2- (3-indolyl) -1,1-dimethylethyl] amino] -3- [2-methyl-4r (methylsulfonyl) phenoxy ] -2-propanol, oxalate (2: 1), hydrate, m.p. 209.5-211 ° C (dec., Corr.) 27 1-t [2- (3-indolyl) -1,1-dimethylethyl] amino] -3- [2- (1-methylpropyl) phenoxy] -2-propanol, hydrochloride, m.p. 163-166 ° C (corr.) 28 1- (2-Cyclohexylphenaphcy) -3 - [[2- (1H-indol-3-yl) -1,1-dimethylethyl] amino] -2-propanol, hydrochloride, mp.

189,5-191,5°C (korr.) 29 1-(2-fluorphenoxy)-3-[[2-(3-indolyl)-1,1-dimetbylethyl]-amino]-2-propanol, oxalat, smp. 203-205°C (dek., korr.)189.5-191.5 ° C (corr.) 29 1- (2-fluorophenoxy) -3 - [[2- (3-indolyl) -1,1-dimethbylethyl] amino] -2-propanol, oxalate, mp. 203-205 ° C (dec., Corr.)

DK 156568 BDK 156568 B

21 30 1- [ [2- (3-indolyl) -1, l-dimethyleühyl] -amino] -3- [2- (tri-fluormethyl) -phenoxy]-2-propanol, oxalat, hemihydrat, £mp. 202,5°C (dek.) 31 1- [ [2- (3-indolyl) -1,1-dimet^ÿlèthyl] -amino] - S-Uni trophenoxy)-2-propanol, smp. 127-128°C (korr.) 32 1-(2-aminophenoxy)-3-[[2-(3-indolyl)-1,1-dimethylethyl]-amino]-2-propanol, dihydrochlorid, smp. 253,5-255,5°C (dek. korr.).·21 1- [[2- (3-indolyl) -1,1-dimethylethyl] amino] -3- [2- (trifluoromethyl) phenoxy] -2-propanol, oxalate, hemihydrate, m.p. 202.5 ° C (dec.) 31 1- [[2- (3-indolyl) -1,1-dimethyl] ethyl] amino] -S-Uni trophenoxy) -2-propanol, m.p. 127-128 ° C (corr.) 32 1- (2-Aminophenoxy) -3 - [[2- (3-indolyl) -1,1-dimethylethyl] amino] -2-propanol, dihydrochloride, m.p. 253.5-255.5 ° C (dec. Corr.) ·

Aktiviteten af de ovenfor anf0rte forbindelser unders0gtes som angivet i det fdlgende.The activity of the above compounds was investigated as given below.

Den /?-adregernisk blokkerende aktivitet af de omhandlede forbindelser blev under sammenligning med propranolol bestemt i bedpvede rotter som evnen til at hindre isoproterenol-forârsaget forpgelse af hjertefrekvensen 2 og 4 timer efter oral dosering. Den dosis af propranolol, som var npdvendig for at frembringe samme /l-blokkerende aktivitet som en testforbindelse bestemtes og forholdet mellem propranolol og testforbindelsen udtrykte testforbindel-sens relative aktivitet.The β-adrenergic blocking activity of the compounds of the present invention was compared with propranolol in bed-ridden rats as the ability to prevent isoproterenol-induced attenuation of heart rate 2 and 4 hours after oral dosing. The dose of propranolol needed to produce the same β-blocking activity as a test compound was determined and the ratio of propranolol to the test compound expressed the relative activity of the test compound.

De omhandlede forbindelsers antihypertensive aktivitet bestemtes i spon-tant hypertensive rotter. Hos testdyrene mal tes blodtrykket fpr og 22 timer efter oral dosering med 100 mg/kg af omhandlede forbindelser. Værdierne i tabellen {A mmHgj agi ver bl odtryiksændringen (positiv eller negativ), idet ogsâ den procentvise ændring af hjertefrekvensen {% Δ H.R.) er angivet.The antihypertensive activity of the compounds of this invention was determined in spontaneously hypertensive rats. In the test animals, the blood pressure is measured fpr and 22 hours after oral dosing with 100 mg / kg of the subject compounds. The values in the table {A mmHgj indicate the change in pressure (positive or negative), also indicating the percentage change in heart rate (% Δ H.R.).

Den vasodilatoriske virkning bestemtes under anvendelse af angiotensin-behandlede, ganglieblokkerede rotter. Værdierne i tabellen (% Δ blodtryk) angiver blodtryksforandringen i de bedpvede rotter 30 minutter efter intra-ven0s administrering med 3 mg/kg af de omhandlede forbindelser.The vasodilatory effect was determined using angiotensin-treated, ganglia-blocked rats. The values in the table (% Δ blood pressure) indicate the change in blood pressure in the bed rats 30 minutes after intravenous administration with 3 mg / kg of the compounds.

Endelig mâltes den akute letale dosis (ALD5Q) under anvendelse af oralt behandlede mus.Finally, the acute lethal dose (ALD5Q) was measured using orally treated mice.

22 DK 156568 B22 DK 156568 B

TabelTable

Adrenergisk β-receptor-blokkerende og vasodilatorisk virkning 8-adrenergisk Antihypertensiv Vasodila-Eksempel blokkerende Δ mm · % Δ torisk A 1) nr._virkning_Hg_H.R._%Δ blodtryk_50 lb) 7 -5 -29 - >2000 2b) 7 0 -14 - 125-250 38 -3 -23 - >2000 47 0 -22 - >2000 57 0 -20 67 0 -21 - 250-500 7 - -12 0 - 500 8 10 -25 -12 -221 2 125-250 9 10 7 -13 -10 11 12 ca.10 -24 -25 +19 125 13 5-10 -22 -14 -27 500 14 2-5 -5 -8 -30 500-100 15 5-10 -12 -11 -29 250-500 22 5 -44 -14 -25 125-250 23 >10 -37 -13 +8 >2000 24 1 -14 -25 +11 >2000 25 10 -30 -22 +13 2000 26 2 -23 -19 -8 >2000 : n 27 5-10 . -24 -20 +22 500 28 6 -13 -23 +18 >1200 29 >10 -19 -5 -33 500-1000 30 10 -37 -3 -34 125 31 2-5 -22 -5 -38 125 32 1-3 -40 -19 -11 500-1000Adrenergic β-receptor blocking and vasodilatory effect -14 - 125-250 38 -3 -23 -> 2000 47 0 -22 -> 2000 57 0 -20 67 0 -21 - 250-500 7 - -12 0 - 500 8 10 -25 -12 -221 2 125 -250 9 10 7 -13 -10 11 12 ca.10 -24 -25 +19 125 13 5-10 -22 -14 -27 500 14 2-5 -5 -8 -30 500-100 15 5-10 - 12 -11 -29 250-500 22 5 -44 -14 -25 125-250 23> 10 -37 -13 +8> 2000 24 1 -14 -25 +11> 2000 25 10 -30 -22 +13 2000 26 2 -23 -19 -8> 2000: n 27 5-10. -24 -20 +22 500 28 6 -13 -23 +18> 1200 29> 10 -19 -5 -33 500-1000 30 10 -37 -3 -34 125 31 2-5 -22 -5 -38 125 32 1-3 -40 -19 -11 500-1000

Omtreïitlig værdi for or ait behandlede mus 2Approximate value for orally treated mice 2

Dosis 10 mg/kg intraven0sDose 10 mg / kg intravenous

Claims (3)

23 DK 156568 B23 DK 156568 B 1. Analogifremgangsmâde til fremstilling af 3-indolderivater med den almene formel I eller II ch3 OH -rpCH2-C-NHCH2CHCH2-0“Ar-Xn I <sJl JJ <=3 \/xr J H CH3 oh -rCH~-C-NHCHoCHCH„-0-Ar-Het I 2 , 2 2 k Ji U CH-, II H og syreadditionssalte deraf, hvori Ar betegner phenyl eller naphthyl, X betegner éventuelle substituenter pâ Ar, som kan være ens eller forskellige grupper udvalgt blandt alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkanoyl, alkenoyl, alkanoyloxy, alkenoyloxy, alkyl-sulfonyl, alkylsulfinyl, alkylthio, alkanoamido, cycloalkyl med 3-6 ringled og 1-3 eventuellè alkylsubstituenter, cycloalkylalkyl med 3-6 ringled og 1-3 éventuelle alkylsubstituenter, hvori hver af de foregâende grupper har indtil 8 carbonatomer, phenyl, trifluor-methyl, nitro, amino, hydroxyl, halogen, carboxamido, cyano og cyanoalkyl med fra 2 til 4 carbonatomer, n betegner 0, 1 eller 2, som antallet af X-grupper, og Het betegner en over N-atomet bundet nitrogënholdig heterocyclisk gruppe med 5 ringled, hvilken heterocyclisk gruppe bærer fra 0 til 2 ringsubstituenter i form af C^g-alkyl, oxo eller carboxamido, kendetegnet ved, at man omsætter en substitueret phenol-forbindelse med den almene formel Ar'-OH DK 156568 B hvori Ar1 betegner ArX^ eller ArHet, der har den foran anf0rte betyd-ning, med epichlorhydrin til dannelse af en epoxypropylether med den almene formel: Λ Ar'-0-CH2CHCH2 hvori Ar1 har den foran anf0rte betydning, hvorefter man, eventuelt i et for reaktionen inert opl0sningsmiddel, omsætter epoxypropylethe-ren med 2-(3-indolyl)-l,l-dimethylethylamin til dannelse af en forbin-delse med formel I eller II, hvorefter en fremstillet forbindelse om 0nsket omdannes til et syreadditionssalt deraf. 2f Fremgangsmâde if0lge krav 1, kendetegnet ved, at man foretager omsætningen mellem phenolforbindelsen og epichlorhydrin i nærværelse af en katalytisk mængde af en amin efter fulgt af behandling med vandig alkalimetalhydroxid.1. Analogous Process for Preparation of 3-Indole Derivatives of General Formula I or II CH3 OH -rpCH2-C-NHCH2CHCH2-0 “Ar-Xn I <s -O-Ar-Het I 2, 2 2 k Ji U CH-, II H and acid addition salts thereof, wherein Ar represents phenyl or naphthyl, X represents optional substituents on Ar which may be the same or different groups selected from alkyl, alkenyl , alkynyl, alkoxy, alkenoxy, alkanoyl, alkenoyl, alkanoyloxy, alkenoyloxy, alkylsulfonyl, alkylsulfinyl, alkylthio, alkanoamido, cycloalkyl of 3-6 ring linking and 1-3 optional alkyl substituents, cycloalkylalkyl of 3-6 ring linking and 1-3 optional alkyl substituents wherein each of the foregoing groups has up to 8 carbon atoms, phenyl, trifluoromethyl, nitro, amino, hydroxyl, halogen, carboxamido, cyano and cyanoalkyl having from 2 to 4 carbon atoms, n represents 0, 1 or 2 as the number of X and Het represents a nitrogen-containing heterocyclic group containing 5 ringl ed, which heterocyclic group carries from 0 to 2 ring substituents in the form of C 1-6 alkyl, oxo or carboxamido, characterized by reacting a substituted phenol compound of the general formula Ar or ArHet having the aforementioned meaning with epichlorohydrin to form an epoxy propyl ether of the general formula: Λ Ar'-O-CH 2 CHCH 2 wherein Ar , the epoxypropyl ether is reacted with 2- (3-indolyl) -1,1-dimethylethylamine to form a compound of formula I or II and then a desired compound is converted to an acid addition salt thereof. A process according to claim 1, characterized in that the reaction is carried out between the phenolic compound and epichlorohydrin in the presence of a catalytic amount of an amine followed by treatment with aqueous alkali metal hydroxide. 3. Fremgangsmâde if01ge krav 1, kendetegnet ved, at man foretager omsætningen mellem phenolforbindelsen og epichlorhydrin i et vandigt alkalimetalhydroxiamedium. K0benhavn, den 19. juni 1989A process according to claim 1, characterized in that the reaction is carried out between the phenolic compound and epichlorohydrin in an aqueous alkali metal hydroxy medium. Copenhagen, June 19, 1989
DK313878A 1977-07-13 1978-07-12 ANALOGY PROCEDURE FOR THE PREPARATION OF 3-CONTENT DERIVATIVES DK156568C (en)

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