DK146977B - METHOD OF ANALOGUE FOR THE PREPARATION OF INDOLIZIN DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS. - Google Patents

METHOD OF ANALOGUE FOR THE PREPARATION OF INDOLIZIN DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS. Download PDF

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DK146977B
DK146977B DK521980AA DK521980A DK146977B DK 146977 B DK146977 B DK 146977B DK 521980A A DK521980A A DK 521980AA DK 521980 A DK521980 A DK 521980A DK 146977 B DK146977 B DK 146977B
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indolizine
benzoyl
oxy
bromo
oxalate
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Gilbert Rosseels
Henri Inion
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Labaz Sanofi Nv
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

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Description

1A69771A6977

Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte indolizinderivater med den almene formel T /R1 ^Nj-C-A-O-tCH^^1 (I) 0 1 5 hvori R betyder en ligekædet eller forgrenet alkylgruppe med 1-8 carbonatomer elle'r en phenylgruppe, som eventuelt er substitueret med en eller to ens eller forskellige substi-tuenter valgt blandt halogen, alkyl med 1-4 carbonatomer og alkoxy med 1-4 carbonatomer, X^ betyder hydrogen, chlor, brom, 10 iod, methyl eller methoxy, A betyder en gruppe med formlen X2 Cl Cl R2 = -<J>- eller R3 = X3 hvori X2 betyder hydrogen, chlor, brom, iod, methyl eller methoxy, og X^ betyder hydrogen, chlor, brom, iod eller methyl, betyder methyl, ethyl, n-propyl eller n-butyl, og n er et 15 helt tal på 2-6, idet dog, når X2 og X3 begge betyder hydrogen eller methyl, x^ er forskellig fra hydrogen, eller farmaceu-. tisk acceptable syreadditionssalte deraf.The present invention relates to an analogous process for the preparation of novel indolizine derivatives of the general formula T / R 11 N-CAO-tCH 14 1 (I) 0 1 5 wherein R represents a straight or branched alkyl group having 1-8 carbon atoms or the like. a phenyl group optionally substituted with one or two identical or different substituents selected from halogen, alkyl of 1-4 carbon atoms and alkoxy of 1-4 carbon atoms, X 1 represents hydrogen, chlorine, bromine, 10 iodine, methyl or methoxy A represents a group of the formula X2 Cl1 Cl R2 = - <J> - or R3 = X3 wherein X2 represents hydrogen, chlorine, bromine, iodine, methyl or methoxy, and X3 represents hydrogen, chlorine, bromine, iodine or methyl, means methyl, ethyl, n-propyl or n-butyl, and n is an integer of 2-6, however, when X 2 and X 3 are both hydrogen or methyl, x 2 is different from hydrogen, or pharmaceutical. tically acceptable acid addition salts thereof.

I den ovenstående almene formel I betyder R fortrinsvis en li-gekædet eller forgrenet alkylgruppe med 1-8 carbonatomer, en 20 phenylgruppe, en mono-fluor-, mono-chlor-, mono-brom-, mono-méthyl- eller mono-methoxy-phenylgruppe, en di-fluor-, di-chlor- eller di-bromphenylgruppe eller en methyl-phenyl-gruppe, som er substitueret i den aromatiske del med et fluor-, chlor- eller bromatom.In the above general formula I, preferably R is a 1-chain or branched alkyl group having 1-8 carbon atoms, a phenyl group, a monofluoro, mono-chloro, mono-bromo, mono-methyl or mono-methoxy -phenyl group, a di-fluoro, dichloro or di-bromophenyl group or a methyl-phenyl group substituted in the aromatic moiety by a fluorine, chlorine or bromine atom.

25 Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i krav l's kendetegnende del anførte.The method according to the invention is characterized by the characterizing part of claim 1.

2 1469772 146977

De omhandlede indolizinderivater har nyttige farmakologiske egenskaber, som gør dem værdifulde ved behandling af visse patologiske tilstande i hjertet, nærmere betegnet ved behandling af angina pectoris og auriculær og ventriculær hjerte-5 arrytmi af forskellige typer.The subject indolizin derivatives have useful pharmacological properties which make them valuable in the treatment of certain pathological conditions in the heart, more specifically in the treatment of angina pectoris and auricular and ventricular cardiac arrhythmias of various types.

Dagsdoser vil fortrinsvis være fra 100 til 300 mg aktivt stof ved oral indgift, idet der fortrinsvis indgives 1 til 3 mg aktivt stof parenteralt til et individ med en legemsvægt på 60 kg.Daily doses will preferably be from 100 to 300 mg of active substance by oral administration, preferably 1 to 3 mg of active substance being administered parenterally to a subject having a body weight of 60 kg.

10 Forbindelser med formlen II kan fremstilles ved at kondensere et alkalimetalsalt, fortrinsvis kalium- eller natriumsaltet af en forbindelse med formlen IV, fordelagtigt i et indifferent medium som f.eks. acetone eller methylethylketon, med en dibromalkan med den almene formel 15 Br-(CH0) -Br (VII) i n hvori n har den i forbindelse med formlen I angivne betydning, til dannelse af den ønskede forbindelse med formlen II.Compounds of formula II can be prepared by condensing an alkali metal salt, preferably the potassium or sodium salt of a compound of formula IV, advantageously in an inert medium such as e.g. acetone or methyl ethyl ketone, with a dibromoalkane of the general formula 15 Br- (CHO) -Br (VII) in n wherein n is as defined in formula I to give the desired compound of formula II.

Forbindelserne med formlen IV, hvori A betyder gruppen R2, er enten beskrevet i GB offentliggørelsesskrift nr.The compounds of formula IV, wherein A is the group R2, are either described in GB Publication no.

20 2.051.812, eller de kan fremstilles i overensstemmelse med de fremgangsmåder, som er anført deri.20,051,812, or they can be prepared according to the methods set forth therein.

De øvrige forbindelser med formlen IV, dvs. de forbindelser, hvor gruppen A betyder gruppen R^, kan fremstilles ved at omsætte den passende 2-substituerede indolizin med 2,3-di-25 chlor-4-acetyloxy-eller 4-tosyloxy-benzoylchlorid. Dette benzo-ylchlorderivat kan igen fremstilles ved acetylering af 1,2-dichlor-anisol ved en Friedel-Crafts-reaktion og oxidation af det dannede acetylderivat med natriumhypochlorit til dannelse af det tilsvarende benzoesyrederivat, som demethyleres 30 med hydrogeniodidsyre i eddikesyre til dannelse af 2,3-di-chlor-4-hydroxy-benzoesyre. Sidstnævnte forbindelse omsættes derefter med acetylchlorid eller tosylchlorid til dannelse 146977 3 af den ønskede 2,3-dichlor-4-acetyloxy-eller 4-tosyloxy-benzoesyre, og det tilsvarende acylchlorid fremstilles derpå på i og for sig kendt måde, f.eks. ved omsætning med thionyl-chlorid.The other compounds of formula IV, i. the compounds where the group A represents the group R 1 can be prepared by reacting the appropriate 2-substituted indolizine with 2,3-dichloro-4-acetyloxy or 4-tosyloxy-benzoyl chloride. This benzoyl chloro derivative may again be prepared by acetylation of 1,2-dichloro-anisole by a Friedel-Crafts reaction and oxidation of the resulting acetyl derivative with sodium hypochlorite to form the corresponding benzoic acid derivative which is demethylated with hydrogen iodide acid in acetic acid to give 2 , 3-di-chloro-4-hydroxy-benzoic acid. The latter compound is then reacted with acetyl chloride or tosyl chloride to give the desired 2,3-dichloro-4-acetyloxy or 4-tosyloxy-benzoic acid, and the corresponding acyl chloride is then prepared in a manner known per se, e.g. by reaction with thionyl chloride.

5 Forbindelserne med formlen VI er omfattet af forbindelserne med formlen I.The compounds of formula VI are comprised of the compounds of formula I.

Indolizinderivater med farmacologiske egenskaber, som gør dem nyttige til behandling af angina pectoris og hjertearryt-mi, er kendt.Indolizine derivatives with pharmacological properties that make them useful in the treatment of angina pectoris and cardiac arrhythmias are known.

10 Fra beskrivelsen til engelsk patent nr. 1.518.443 kendes således 2-ethyl-3-[4-(3-di-n-butylaminopropyl)-oxy-benzoyl]-indolizin, som også kendes under betegnelsen butoprozin.Thus, from the specification to English patent No. 1,518,443, 2-ethyl-3- [4- (3-di-n-butylaminopropyl) -oxy-benzoyl] -indolizine is known, which is also known under the term butoprozin.

I beskrivelsen til ovennævnte engelske patent anføres det, at de kendte indolizinderivater har antianginale egenskaber, 15 da de er i stand til at fremkalde følgende cardiovasculære virkninger: bradycardi , formindskelse af arterietrykket, a-antiadre-nerg virkning, β-antiadrenerg virkning og coronardilatate-rende virkning.In the disclosure of the aforementioned English patent, it is stated that the known indolizine derivatives have antianginal properties as they are capable of inducing the following cardiovascular effects: bradycardia, reduction of arterial pressure, α-anti-adrenergic effect, β-anti-adrenergic effect and coronardilate. running effect.

20 Forøgelsen af blodstrømmen til myocardium fremkaldt af disse forbindelser er faktisk kun ringe, da deres virkning er kortvarig, da den kun udøves i nogle få minutter efter en intravenøs injektion.In fact, the increase in blood flow to myocardium induced by these compounds is only minor, as their effect is short-lived as it is exerted only for a few minutes after an intravenous injection.

Endvidere har de i beskrivelsen til ovennævnte engelske pa-25 tent kun en svag β-adrenerg antagonist-virkning. Denne virkning er kun svag ved den minimale dosis, ved hvilken de øvrige fire ovenfor anførte cardiovasculære virkninger gør sig gældende i væsentlig grad.Furthermore, in the description to the aforementioned English, they have only a weak β-adrenergic antagonist effect. This effect is only weak at the minimal dose at which the other four cardiovascular effects listed above are significant.

Det har overraskende vist sig, at dialkylaminoalkyloxybenzo-30 yl-indolizinderivater substitueret på passende måde med en eller to substituenter valgt blandt methyl, methoxy eller halogen såsom chlor, brom eller iod, er forbindelser, som har et meget mere bredspektret spektrum med hensyn til car- 4 146977 diovasculære virkninger i forhold til de fra beskrivelsen til engelsk patent nr.1,518.443 kendte forbindelser. Endvidere har de omhandlede indolizinderivater en lavere toksicitet end de kendte indolizinderivater.Surprisingly, it has been found that dialkylaminoalkyloxybenzoyl-indolizine derivatives suitably substituted with one or two substituents selected from methyl, methoxy or halogen such as chlorine, bromine or iodine are compounds having a much wider spectrum with respect to carbons. 4,149,777 diovascular effects in relation to the compounds known from the specification of English Patent No. 1,518,443. Furthermore, the indolizine derivatives in question have a lower toxicity than the known indolizine derivatives.

5 De omhandlede indolizinderivater er således stærke coronar-dilatatorer, da de kan forøge blodstrømmen til myocardium i udtalt grad og i et længere tidsrum,end det er muligt med butoprozin. Endvidere bevirker de omhandlede indolizinderivater en formindskelse af hjertefrekvensen og arterietrykket 10 hos dyr.The indolizine derivatives in question are thus strong coronary dilators as they can significantly increase the blood flow to myocardium and for a longer period than is possible with butoprozine. Furthermore, the indolizine derivatives in question cause a decrease in heart rate and arterial pressure 10 in animals.

Desuden har de omhandlede indolizinderivater en lidt stærkere 3-antiadrenerg virkning i forhold til de ovennævnte kendte indolizinderivater. I den minimale dosis til fremkaldelse af bradycardi, formindskelse af arterietrykket, a-antiadre-15 nerg virkning og coronardilataterende virkning i væsentlig grad er den Ø-antiadrenerge virkning fremkaldt af de kendte indolizinderivater faktisk kun svag, hvorimod den tilsvarende virkning er meget kraftigere for de omhandlede indolizinderivater .In addition, the indolizine derivatives in question have a slightly stronger 3-antiadrenergic effect over the above-mentioned known indolizine derivatives. In the minimal dose to induce bradycardia, decrease in arterial pressure, α-antiadrenergic action and coronary dilatating effect to a significant extent, the β-antiadrenergic effect induced by the known indolizine derivatives is in fact only weak, whereas the corresponding effect is much stronger for those the indolizin derivatives.

20 Endvidere bevirker de omhandlede indolizinderivater en formindskelse af oxygenforbruget i myocardium beregnet ved multiplikation af forskellen mellem oxygenindholdet i arterieblodet og veneblodet med coronarblodstrømmen. De omhandlede indolizinderivater fremkalder således en betydelig formind-25 skelse af arterie-vene-differensen, som bevirker en formindskelse af oxygenforbruget til trods for forøgelsen af coronarblodstrømmen.Furthermore, the indolizine derivatives at issue cause a reduction in oxygen consumption in myocardium calculated by multiplying the difference between the oxygen content of the arterial blood and the vein blood by the coronary blood flow. Thus, the indolizine derivatives in question produce a significant reduction in arterial vein difference which causes a decrease in oxygen consumption despite the increase in coronary blood flow.

Til forskel fra butoprozin opnås disse fordelagtige virkninger på oxygenforbruget med de omhandlede forbindelser uden 30 nogen formindskelse af myocardiets kontraktilitet.Unlike butoprozin, these beneficial effects on oxygen consumption with the compounds of this invention are achieved without any reduction in myocardial contractility.

Det har endvidere vist sig, at de omhandlede indolizinderivater har en lavere toksicitet end de fra beskrivelsen til engelsk patent nr.1.518.443 kendte forbindelser. Dyreforsøg til bestemmelse af den akutte toksicitet ved intravenøs og 146977 5 oral indgift viser, at den letale dosis er højere for de omhandlede indolizinderivater, end det er tilfældet med de fra ovennævnte engelske patentbeskrivelse kendte indolizinderivater.Furthermore, it has been found that the indolizine derivatives in question have a lower toxicity than the compounds known from the specification of English Patent No. 1,518,443. Animal studies to determine the acute toxicity of intravenous and oral administration show that the lethal dose is higher for the indolizine derivatives in question than is the case for the indolizine derivatives known from the aforementioned English patent specification.

5 Endvidere kan der opnås større blodkoncentrationer med de omhandlede indolizinderivater end med butoprozin. Det har således vist sig, at der ved oral indgift af samme dosis l-brom-2-methyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-brom-benzoyl]-indolizin og butoprozin til hunde opnås en blod-10 koncentration, som er tre gange så stor for den omhandlede forbindelse som for butoprozin. Ved langtids-behandling af hunde ved peroral indgift fremkalder de omhandlede forbindelser endvidere ikke hjertetoksicitet repræsenteret ved ven-trikulær arrytmi, hvilket ikke er tilfældet med butoprozin.Furthermore, greater blood concentrations can be obtained with the indolizine derivatives in question than with butoprozin. Thus, it has been found that by oral administration of the same dose of 1-bromo-2-methyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl] -indolizine and butoprozine to In dogs, a blood-10 concentration is obtained which is three times as high for the subject compound as for butoprozin. Furthermore, in long-term treatment of dogs by oral administration, the compounds of the present invention do not induce cardiac toxicity represented by venous tricardial arrhythmia, which is not the case with butoprozin.

15 Endelig har de omhandlede indolizinderivater en svagere depressiv virkning på myocardiets kontraktilitet, end det er tilfældet med butoprozin.15 Finally, the indolizine derivatives at issue have a weaker depressive effect on the myocardial contractility than is the case with butoprozin.

Hos mennesker er et anfald af angina pectoris den smertefulde følge af manglende tilførsel af oxygen til myocardium.In humans, a bout of angina pectoris is the painful consequence of the lack of oxygen supply to myocardium.

20 En forbindelse kan således være virksom ved behandlingen af angina pectoris ved enten at forøge oxygentilførslen eller ved at formindske oxygenbehovet. Blandt de forbindelser, som er mest udbredt anvendt til angina pectoris hos mennesker, kan nævnes dipyridamol blandt coronardilatatorerne og amio-25 daron blandt de forbindelser, som formindsker myocardiets oxygenforbrug. Sammenligningsforsøg har imidlertid vist, at de omhandlede indolizinderivater er væsentligt bedre end dipyridamol og amiodaron i forskellige henseender.Thus, a compound may be effective in the treatment of angina pectoris by either increasing the oxygen supply or by decreasing the oxygen demand. Among the compounds most widely used for angina pectoris in humans are dipyridamole among the coronary dilators and amiodarone among the compounds that reduce myocardial oxygen consumption. However, comparative studies have shown that the indolizine derivatives in question are substantially better than dipyridamole and amiodarone in various respects.

Det har især vist sig, at dipyridamol ikke formindsker oxy-30 genforbruget i myocardium, og at amiodaron ikke kan betragtes som en coronardilatator.In particular, it has been found that dipyridamole does not reduce the oxygen consumption in myocardium and that amiodarone cannot be considered a coronary dilator.

De omhandlede indolizinderivater er virksomme ved at påvirke begge disse faktorer, idet de formindsker oxygenforbruget i 6 146977 myocardium som følge af deres virkninger på stofskiftet og forøger coronarblodstrømmen over et længere tidsrum. Endvidere kan de omhandlede indolizinderivater anvendes til forebyggelse eller helbredelse af arrytmitilstande, som ikke kun 5 er fremkaldt af ischæmi i myocardium, men tillige af auricu-lær og ventriculær arrytmi, som skyldes vidt forskellige årsager .The aforementioned indolizine derivatives are effective in affecting both of these factors, reducing oxygen consumption in myocardium as a result of their effects on metabolism and increasing coronary blood flow over a longer period of time. Furthermore, the indolizine derivatives in question can be used to prevent or cure arrhythmia states not only caused by ischemia in myocardium, but also by auriculosis and ventricular arrhythmia, which are due to a wide variety of causes.

I forhold til de fra engelsk patentbeskrivelse nr.1.518.443 kendte indolizinderivater har de omhandlede indolizinderiva-10 ter således et nyt spektrum af farmakologiske egenskaber, som er værdifulde ved behandling af hjertesygdomme.Thus, relative to the indolizine derivatives known from English Patent Specification No. 1,518,443, the indolizine derivatives in question have a new spectrum of pharmacological properties which are valuable in the treatment of heart disease.

Således kan f.eks. de steder i myocardium, hvor der er en u-tilstrækkelig gennemstrømning, forsynes med blod som følge af den coronardilataterende virkning, som kan inducere udvik-15 ling af en collateral cirkulation. Denne virkning er værdifuld ved behandling af såvel anginale smerter som forstyrrelser i rytmen som følge af ischæmi i myocardium. Den anti-adrenerge virkning er ligeledes værdifuld ved behandling af angina pectoris samt hjertearrytmi i betragtning af den 20 store betydning af hyperaktiviteten af det sympatiske nervesystem ved årsagerne til disse to hjertesygdomme.Thus, e.g. those sites in the myocardium where there is insufficient flow are supplied with blood due to the coronary dilatating effect which can induce the development of a collateral circulation. This effect is valuable in the treatment of both anginal pain and rhythm disturbances due to ischemia in myocardium. The anti-adrenergic effect is also valuable in the treatment of angina pectoris as well as cardiac arrhythmia given the great importance of the hyperactivity of the sympathetic nervous system in the causes of these two heart diseases.

Da den fysiologiske mediator i det sympatiske nervesystem er epinephrin, vil en forbindelse, som hæmmer alle virkninger ved epinephrin, sandsynligvis være mere virksom end en forbindel-25 se, som kun hæmmer en del af disse virkninger.Since the physiological mediator of the sympathetic nervous system is epinephrine, a compound that inhibits all effects of epinephrine is likely to be more effective than a compound that inhibits only some of these effects.

De omhandlede indolizinderivater, der hæmmer såvel a- som (3-virkningerne ved epinephrin, har derfor en fordel i forhold til de fra beskrivelsen til engelsk patent nr.1.518.443 nævnte forbindelser, som praktisk taget kun inhiberer a-virk-30 ningerne ved den minimale dosis, ved hvilken de andre farmakologiske cardiovasculære virkninger optræder.The subject indolizin derivatives, which inhibit both the α- and β-effects of epinephrine, therefore have an advantage over the compounds mentioned in the specification of English Patent No. 1,518,443, which practically only inhibit the α-effects of the minimum dose at which the other pharmacological cardiovascular effects occur.

Blandt de omhandlede indolizinderivater, som har de mest lovende antianginale Virkninger, kan nævnes følgende: 7 148977 1- brom-2-methyl-3-[4-(3-di-n-butylaminopropyl) -oxy-3-brom-5 benzoyl]-indolizin 2- n-butyl-3-[4-(3-di-n-butylaminopropyl) -oxy-3-brom-benzoyl] -indolizin 2-ethyl-3- [4- (3-di -n-butylaminopropyl) -oxy-3-chlor-benzoyl] -indolizin 10 2-n-butyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-chlor-benzoyl] -indolizin 2-isopropyl-3- [ 4- (3-di-n-butylaminopropyl) -oxy-3,5-dichlor-benzoyl]-indolizin l-brom-2-phenyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-chlor-15 benzoylj-indolizin l-chlor-2-ethyl-3-(4- (3-di-n-butylaminopropyl) -oxy-3-chlor-benzoyl]-indolizin l-chlor-2-n-butyl-3-[4-(3-di-n-butylaminopropyl) -oxy-benzo-yl]-indolizin 20 l-brom-2-(4-chlor-phenyl)-3-[4-(3-di-n-butylaminopropyl)-oxy-3-chlor-benzoyl]-indolizin, idet disse forbindelser kan foreligge i form af de frie baser eller farmaceutisk acceptable syreadditionssalte, f.eks. hydrochlorider eller sure oxalater.Among the subject indolizin derivatives having the most promising antianginal effects are the following: 1- bromo-2-methyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-bromo-5-benzoyl ] -indolizine 2- n-butyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl] -indolizine 2-ethyl-3- [4- (3-di-n-butyl) butylaminopropyl) -oxy-3-chloro-benzoyl] -indolizine 2-n-butyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-chloro-benzoyl] -indolizine 2-isopropyl-3 - [4- (3-di-n-butylaminopropyl) -oxy-3,5-dichloro-benzoyl] -indolizine 1-bromo-2-phenyl-3- [4- (3-di-n-butylaminopropyl) -oxy -3-chloro-benzoyl] -indolizine 1-chloro-2-ethyl-3- (4- (3-di-n-butylaminopropyl) -oxy-3-chloro-benzoyl] -indolizine 1-chloro-2-n- butyl 3- [4- (3-di-n-butylaminopropyl) oxy-benzoyl] -indolizine 1-bromo-2- (4-chloro-phenyl) -3- [4- (3-di-benzyl) n-butylaminopropyl) -oxy-3-chloro-benzoyl] -indolizine, these compounds being in the form of the free bases or pharmaceutically acceptable acid addition salts, for example hydrochlorides or acid oxalates.

25 I det følgende anføres resultater af farmakologiske forsøg udført til bestemmelse af de omhandlede indolizinderivaters cardiovasculære egenskaber.25 The following are the results of pharmacological tests performed to determine the cardiovascular properties of the indolizine derivatives.

I. Antianginale egenskaber.I. Antianginal properties.

30 Denne test gennemføres i overensstemmelse med fremgangsmåden beskrevet af R.Charlier og J.Bauthier i Arzneimittel-For-schung "Drug Research" 23, nr. 19, 1305-1311 (1973).This test is performed in accordance with the method described by R.Charlier and J.Bauthier in Arzneimittel-Forschung "Drug Research" 23, No. 19, 1305-1311 (1973).

Der anvendes anæstetiserede hunde, som indgives forsøgsforbindelsen intravenøst. Størrelsen af den maksimale virk-35 ning på blodstrømmen til myocardium udtrykkes i procent af den tilsvarende værdi inden injektionen. Den tid, det tager for den maksimale virkning at aftage til 50%, anvendes som udtryk for virkningens varighed. Denne tid angives i minutter.Anesthetized dogs are used which are administered intravenously to the test compound. The magnitude of the maximum effect on the blood flow to myocardium is expressed as a percentage of the corresponding value prior to injection. The time it takes for the maximum effect to decrease to 50% is used as an expression of the duration of the effect. This time is specified in minutes.

De opnåede resultater anføres i den efterfølgende tabel I.The results obtained are given in the following Table I.

8 1469778 146977

Tabel I.Table I.

sJy r2 \sYy r2 \

]_-C-/ %>-0-(CHJ -N] _- C- /%> - 0- (CHJ -N

^ sW" 2n\n^ sW „2n \ n

KK

: : : : : tji .::::: tji.

: X : X : X : R :R :n: Dosis: Maksi-: opnåel- : . ^ . 2 ; 3 . : : : mg/kg; iral . se af. : 5 : ; ; : : : : . forø- j 50% : ! . . . : : : : gelse ] formind-: . ...(%)! skelse : ! i * : : : : j (min.) _ : 10 i Br ! Br [ H ! n-C^ : 3 i 10 ! 60 \ 90 : : Br : Br · H * CH^ : n-CjH^ : 3 : 10 : 125 : 40 ! ; Br j Br \ H ! n-C^H ! n-C^ j 3 10 J 100 j 20 ; : Br : Br = H = n-C^ : n-C^ : 3 : 10 : 90 · 20 : i Br ! Br j H ! -</ V. ί n-C^ | 3 ! 10 j 100 J 20 \ 15 : : : : Br : : : : : ' : Br : Br : Η : -<^~^> ί n-C^ : 3 : 10 s 150 : 100 * \ Η I Br * H ] \>-Br [ n-CjH^ J 3 ! 10 J 90 J 25 ; : Br : Br : E : CH^ : n-CjHg : 3 : 10 : 77 : k5 : ; Ξ ; Br ; H ; n-C^K ; n-C^ \ 3 \ 2 I 120 i 25 20 : H : Br : H : n-CjH · n-CjB^ : 3 * 5 s 70 : 60 · ; Br .Cl . H . iso-C^ . a-CjHg . 3 . 5 : 133 : 20 j ; d ; η ; h ; n-c^ ; n-c^ ; 3 ; 10 ; 60 30· : : H : Cl : Cl : iso-CJEL : n-C,H : 3 : 10 : 30 : 75 ! ; j 37 .^9..: X: X: X: R: R: n: Dose: Maxi-: attain-:. ^. 2; 3. ::: mg / kg; iral. see off. : 5:; ; ::::. increase 50% :! . . . :::: remedy] diminish-:. ... (%)! schelse:! i *:::: j (min.) _: 10 in Br! Br [H! n-C 2: 3 in 10! 60 \ 90:: Br: Br · H * CH ^: n-CjH ^: 3: 10: 125: 40! ; Br j Br \ H! n-C ^ H! n-C ^ j 3 10 J 100 j 20; : Br: Br = H = n-C ^: n-C ^: 3: 10: 90 · 20: i Br! Br j H! - </ V. ί n-C ^ | 3! 10 j 100 J 20 \ 15:::: Br::::: ': Br: Br: Η: - <^ ~ ^> ί nC ^: 3: 10 s 150: 100 * \ Η I Br * H] \> - Br [n-CjH ^ J 3! 10 J 90 J 25; : Br: Br: E: CH2: n-CjHg: 3: 10: 77: k5 :; Ξ; Br; H; n-C 2 K; n-C ^ \ 3 \ 2 I 120 i 25 20: H: Br: H: n-CjH · n-CjB ^: 3 * 5 s 70: 60 ·; Br .Cl. H. iso-C α-CjHg. 3. 5: 133: 20 j; d; η; h; n-c 2; n-c 2; 3; 10; 60 30 ·:: H: Cl: Cl: iso-CJEL: n-C, H: 3: 10: 30: 75! ; j 37. ^ 9..

; s ; ci ; ci ; -</ ^>-Br ; n-c^ ; 3 ! 10 ; 45 ; 15 j 25 : H : Cl : Cl : iso-C^ : n-C^Hg : 3 : 10 : 30 : 75 = 146977 9; s; ci; ci; - </ ^> - Br; n-c 2; 3! 10; 45; H 25: H: Cl: Cl: iso-C 2: n-C 2 Hg: 3: 10: 30: 75 = 146977 9

Tabel I fort§at: .Table I continued:.

: : Br | : ; ; ; h ; Cl ; h ; ; n-c^ : 3 ; 10 ; 30 i 45 ; ! H · Cl · H i i n-Cfy :3:8: 45 j 25 * : H : Cl ; H ; iso-C^H^ ; n-C^ ; 3 ; 5 ; 80 ; 90 ; 5 | Br j Cl · Η : n-C^Hg : 3 : 10 : 90 : 90 : : Br : Cl ; H ; n-C^ [ n-C^ j 3 [ 10 j 40 | 90 ! i Br : Cl : H : -<^ ^>-Br : n-C^ : 3 : 10 : 50 : 50 : : H ; Cl ; H ; n-C^Hg ; n-C^Hg ; 3 ; 5 ‘ 75 ' 30 ; i H i Cl i H i CH : n-C.Hn : 3 : 6 : 70 : 45 : • _ # 2 5 . 4 9 . . . . .:: Br | :; ; ; h; Cl; h; ; n-c 2: 3; 10; 30 in 45; ! H · Cl · H i i n-Cfy: 3: 8: 45 j 25 *: H: Cl; H; iso-C ^H ^; n-C ^; 3; 5; 80; 90; 5 | Br j Cl · Η: n-C ^ Hg: 3: 10: 90: 90:: Br: Cl; H; n-C ^ [n-C ^ j 3 [10 j 40 | 90! in Br: Cl: H: - <^> - Br: n-C ^: 3: 10: 50: 50:: H; Cl; H; n-C ^Hg; n-C ^Hg; 3; 5 '75' 30; i H i Cl i H i CH: n-C.Hn: 3: 6: 70: 45: • _ # 2 5. 4 9. . . . .

io : Br ; ci ; h ; -<^-ci ; n-c^ ; 3 ; ίο ; 63 ; 45 ; : H : Cl : H : ~^>-Br : n-C^Hg : 3 : 10 : 6θ : 25 : ; Br ; ci ; h ; n-c^H ; n-c^Hg ; 3 ; 2,5 ; 50 ; 60 ; : : : : Br : : : : : : : Cl : Cl : H : : n-Cyi^ : 3 : 8 : 70 : 90 : 5 Cl : Cl ! H : C_H : n-C. H ' 3 ' 1 [ 40 | 15 *.io: Br; ci; h; - <^ - ci; n-c 2; 3; ίο; 63; 45; : H: Cl: H: ~ ^> - Br: n-C ^ Hg: 3: 10: 6θ: 25 :; Br; ci; h; n-c 2 H; n-c Hg; 3; 2.5; 50; 60; :::: Br::::::: Cl: Cl: H:: n-Cyi ^: 3: 8: 70: 90: 5 Cl: Cl! H: C_H: n-C. H '3' 1 [40 | 15 *.

::::25 :49:: : : : 15 : Cl : Cl : H : C^ : n-C^ : 3 : 3,3 : 60 : 25 : ί Cl | Η ; Η | -^>-01 ; n-C^ \ 3 \ 5 ] 50 ] 40 j:::: 25: 49 ::::: 15: Cl: Cl: H: C ^: n-C ^: 3: 3.3: 60: 25: ί Cl | Η; Η | - ^> - 01; n-C ^ \ 3 \ 5] 50] 40 j

’Butoprozin * ‘ 10 ' 120 ' 4 J'Butoprozin *' 10 '120' 4 J

:Amiodaron : : 10 : 36 : 7 :: Amiodarone:: 10: 36: 7:

De i tabel I anførte resultater viser tydeligt, at de omhand-20 lede forbindelser adskiller sig væsentligt fra butoprozin og amiodaron med hensyn til virkningerne på blodstrømmen til myo-cardium.The results set forth in Table I clearly show that the compounds of this invention differ substantially from butoprozin and amiodarone in terms of the effects on myocardium blood flow.

148977 ίο 2) Antiadrenerge virkninger.148977 ίο 2) Antiadrenergic effects.

Ved denne test bestemmes forsøgsforbindelsernes evne til at formindske epinephrin—forøget blodtryk (anti-a-virkning) og epinephrin -accelereret hjerteslag (anti-β-virkning) hos hunde, 5 som forinden er blevet anaestetiserede med pentobarbital og har fået indgivet atropin.This test determines the ability of test compounds to decrease epinephrine-elevated blood pressure (anti-α effect) and epinephrine-accelerated heartbeat (anti-β effect) in dogs previously anaesthetized with pentobarbital and administered atropine.

Ant i-g-virkningAnt i-g effect

For hver enkelt hund foretages først en bestemmelse af den dosis epinephrin, som fremkalder en reproducerbar forøgelse 10 på ca.100 mm Hg i arterietrykket (mellem 5 og 10 Ug/kg).For each dog, a dose of epinephrine which first produces a reproducible increase of about 100 mm Hg in arterial pressure (between 5 and 10 µg / kg) is first determined.

Derpå indgives intravenøst den således bestemte dosis epinephrin efterfulgt af forsøgsforbindelsen. Den procentvise formindskelse af hypertensionen forårsaget af forsøgsforbindelsen sammenlignet med den tidligere bestemte hypertension 15 (ca. 100 mm Hg) bestemmes derpå.Thereafter, the dose of epinephrine thus determined is administered intravenously followed by the test compound. The percentage reduction in hypertension caused by the test compound compared to the previously determined hypertension 15 (about 100 mm Hg) is then determined.

Ånti-β-virkningAanti-β effect

Ved samme forsøg som beskrevet ovenfor fremkalder epinephrin en reproducerbar forøgelse af hjerteslaget på ca. 70 slag pr. minut. Den procentvise formindskelse af den epinephrin-induce-20 rede acceleration af hjerteslaget fremkaldt af forsøgsforbindelsen sammenlignet med det tidligere målte tachvcardia (ca.In the same experiment as described above, epinephrine induces a reproducible increase in heart rate of approx. 70 strokes per minute. The percentage decrease in the epinephrine-induced acceleration of the heartbeat caused by the test compound compared to the previously measured tachycardia (ca.

70 slag) bestemmes derpå. I begge tilfælde udtrykkes resultaterne på følgende måde; + angiver en formindskelse af forøgelsen af trykket eller 25 hjertefrekvensen på mindre end 50% ++ angiver en formindskelse af forøgelsen af trykket eller hjertefrekvensen, som er større end eller lig med 50% +++ angiver en næsten fuldstændig formindskelse af forøgelsen af trykket eller hjertefrekvensen. De opnåede resul- 30 tater er anført i nedenstående tabel XI.70 strokes) is then determined. In both cases, the results are expressed as follows; + indicates a decrease in pressure or heart rate of less than 50% ++ indicates a decrease in pressure or heart rate greater than or equal to 50% +++ indicates a nearly complete decrease in pressure or heart rate. The results obtained are given in Table XI below.

Tabel II.Table II.

X X2 X3 R R·, n Dosis Anti- Anti- ;mgAg) ot- β- virk- virkning ning • Br ; Br ; H j ‘ j n-Cj^ j 3 j 10 !+++!+++ ! : Br : Η : H : : n-C^ : 3 : 6 ;+++;+++ : 146977 11X X2 X3 R R ·, n Dose of Anti-Anti; mgAg) ot-β action • Br; Br; H j 'j n-Cj ^ j 3 j 10! +++! +++! : Br: Η: H:: n-C ^: 3: 6; +++; +++: 146977 11

Tabel II fortsat _ # .....Table II continued _ # .....

: Br ; Br : H ; ; n-C^Hg ; 3 ; 10 ; +++ ; ++ ; ! Br : Br . Br . n-C^ . n-C^ ; 3 ; 10 : +++ : +++ : : H : Br : H : -<^ : n-C^Hg * 3 j 10 j +++ · ++ · 5 ! H j Br ! H *. .' n-C^Hg : 3 : 7,5 ; +++ . : • H : Br : H : n-C^Hg * n-C^Hg · 3 · 5 j +++ · ++ * i Η I Br ! H ! n-C^Hg I n-C^ : 3 : 5 i +++ ++ i : Br : Br · H · CH ; n-C, H ; 3 : i 5 : +++ · ++ : : : : : 5 : * ? : 1 (10 : +++ : +++ : ! H ! Br ! H ! n-C, H ‘ n-C, H · 3 j É 5 . +++ . ++ .: Br; Br: H; ; n-C ^Hg; 3; 10; +++; ++; ! Br: Br. Br. n-C n-C ^; 3; 10: +++: +++:: H: Br: H: - <^: n-C ^ Hg * 3 j 10 j +++ · ++ · 5! H j Br! H *. . ' n-C ^Hg: 3: 7.5; +++. : • H: Br: H: n-C ^ Hg * n-C ^ Hg · 3 · 5 j +++ · ++ * i Η I Br! H! n-C ^ Hg I n-C ^: 3: 5 i +++ ++ i: Br: Br · H · CH; n-C, H; 3: i 5: +++ · ++:::: 5: *? : 1 (10: +++: +++:! H! Br! H! N-C, H 'n-C, H · 3 j E 5. +++. ++.

* [ ] * * . “ . . (10 . +++ . +++ .* [] * *. “. . (10. +++. +++.

10 : H : Br : H : iso-C^H^ : n-C^Hg : 3 · 6 ; ++1· ; * *. ci ! h Ih! n-CjHg ! n-c^Hg ! 3 ! io ! +++ ! -- .10: H: Br: H: iso-C ^ H ^: n-C ^ Hg: 3 · 6; ++ 1 ·; * *. ci! h Ih! n-CjHg! n-c ^ Hg! 3! in Island ! +++! -.

ί Cl : Η · H · n-C^ : n_C4H9 : 3 : 7'^ : +++ * [ ! H ! Cl J H ! n-Cj^Hg ! n-C^Hg ! 3 ! 10 . +++ . .ί Cl: Η · H · n-C ^: n_C4H9: 3: 7 '^: +++ * [! H! Cl J H! n-Cj ^ Hg! n-C ^ Hg! 3! 10. +++. .

: H : Cl : H : C H ·' n-C H : 3 : 10 : ++ : ++ ·* • · · · 2 3 ; 3 i ; ; ; ; ; 15 I H ! Cl ! H ! CgH ! n-C^Hg J 3 . . 6 ; +-H- ; ++ .: H: Cl: H: C H · 'n-C H: 3: 10: ++: ++ · * • · · · 2 3; 3 i; ; ; ; ; 15 I H! Cl! H! CgH! n-C ^ Hg J 3. . 6; + -H-; ++.

i H : Cl : Cl : iso-C^H^ i n-C^Hg ϊ 3 : 10 ! ++ : ++ :i H: Cl: Cl: iso-C ^ H ^ i n-C ^ Hg ϊ 3: 10! ++: ++:

! ί ! ! Br i ! ! i ! I! ί! ! Br i! ! i! IN

; H j Cl ' H ! -<^ J n_CitH9 : 5 : 10 ++ : : H ' : Cl : H : iso-C_H : n-C E : 3 *· 10 : ++ : ++ : : : : : 57 . 5/. . . . .; H j Cl 'H! - <^ J n_CitH9: 5: 10 ++:: H ': Cl: H: iso-C_H: n-C E: 3 * · 10: ++: ++::::: 57. 5 /. . . . .

! Br J Cl * H ; -</ ; n-C^H9 ’ 3 J 10 * ++*+++; 20 : Br i Cl : II : : n-C^ : 3 i 7,8 : ++ : ++ : ! Br i Cl ! H ; -</ ^>-Br j n-C^ j 3 j 10 * ++ ] ++ j : Br : Cl : H : n-C^Hg : n-C^ : 3 : 10 : ++ : + s J Br ί Cl I Η ί \-Cl ] n-C^Hg | 3 ] -10 | ++ | ++ j : Br ! Cl : H : y ~Br : η“°3Η7 : 3 : 10 : ++ : ++ : 25 I Br | Cl j . H j C^ J η"0^Ηα ! 5 ] 10 j +++ ; +++ | 12 146977! Br J Cl * H; - </; n-C3 H9 '3 J 10 * ++ * +++; 20: Br in Cl: II:: n-C ^: 3 in 7.8: ++: ++:! Br in Cl! H; - </ ^> - Br j nC ^ j 3 j 10 * ++] ++ j: Br: Cl: H: nC ^ Hg: nC ^: 3: 10: ++: + s J Br ί Cl I Η ί \ -Cl] nC ^ Hg | 3] -10 | ++ | ++ j: Br! Cl: H: y ~ Br: η “° 3Η7: 3: 10: ++: ++: 25 I Br | Cl j. H j C ^ J η "0 ^ Ηα! 5] 10 j +++; +++ | 12 146977

Tabel II fortsat : Br ; Cl : H ·' ^>-Cl ί n-C^ : 3 : 10 : +++ : ++ : i H ! Cl i H i -</ ^>-Br jn-C^Hg j 3 j 10 j ++ | + j : : : : Br : : : : : : : Br 5 Cl : H : ~^\ y* : n-C3H7 ' ^ * +++ % +++ ’’ 5 i Br i Cl ‘ H ' n-C^ j n-C^ J 3 j 10 ; +++ . +++ ; : : : : Br : : : : : : : Cl : Cl : H : ’<^y> : : 3 : 8 : +++ : ++ : \ ci ; ci i h *; c2h5 ; n-c^ ; 3 ; 0,5 * +++; +; : Cl : Cl : H : C_H : n-C H : 3 : 3,3 : +++ ϊ --+ : 2 5 . 3 / . . . . .Table II continued: Br; Cl: H · '^> - Cl ί n-C ^: 3: 10: +++: ++: i H! Cl i H i - </ ^> - Br jn-C ^ Hg j 3 j 10 j ++ | + j:::: Br::::::: Br 5 Cl: H: ~ ^ \ y *: n-C3H7 '^ * +++% +++' '5 i Br i Cl' H 'nC ^ j nC ^ J 3 j 10; +++. +++; :::: Br::::::: Cl: Cl: H: '<^ y>:: 3: 8: +++: ++: \ ci; ci i h *; c2h5; n-c 2; 3; 0.5 * +++; +; : Cl: Cl: H: C_H: n-C H: 3: 3.3: +++ ϊ - +: 2 5. 3 /. . . . .

; ci ; η ; h ; ^>-ci [ n-c^g i 3 ; i° ! +++; =-*! 10 : Cl : Η : H : -<^ ^>-Cl : n-C^ : 3 : 5 : ++ : + : ; ci ; η ; h ; ; n-c^! 3 | 5 ;+++;+++; : H : Br : H : iso-C-,H_ : n-C ,H„ : 3 : 7,5 : +++ : ++ : . . . . 5 t . 3 ( .; ci; η; h; ^> - ci [n-c ^ g i 3; i °! +++; = - *! 10: Cl: Η: H: - <^ ^> - Cl: n-C ^: 3: 5: ++: +:; ci; η; h; ; n-c ^! 3 | 5; +++; +++; : H: Br: H: iso-C-, H_: n-C, H +: 3: 7.5: +++: ++:. . . . 5 t. 3 (.

* Br ’ 0CH_* H ' CH ' n-CH ' 3 * 7,5 * ++ ’ ++ ' : : j>: : 3 : 3 7 : : : : 1 : Cl : Cl : Cl : C JI_ : n-CH : 3 : 10 : ++ : ++ : . . . . 2 3 3 ( . . . . .* Br '0CH_ * H' CH 'n-CH' 3 * 7.5 * ++ '++':: j>:: 3: 3 7:::: 1: Cl: Cl: Cl: C JI_: n-CH: 3: 10: ++: ++:. . . . 2 3 3.

is ; ci ] ci ; ci; ] η_0^Η9 i 3 ; 10 ; +++; ++; : Cl : Br : H : CgH : n-C^Hg : 3 : 10 : +++ : +++ : ; ci ; Br ; Br * -<^ ; n-c^; 3 ; 10 ; +; +; : Br : Cl : Cl : -,/ : n-C^ : 3 : 10 : ++ : ++ : j o i * · · »j s · · ; Br ; ci j ci; -<^ ; n-c^; 3 j 10 ] ++ J ++ * 20 : Br : CH^ : CH^ : CH^ : n-C^Hg : 3 : 10 *· *** : *+ : 146977 13ice ; ci] ci; Cl; ] η_0 ^ Η9 i 3; 10; +++; ++; : Cl: Br: H: CgH: n-C ^ Hg: 3: 10: +++: +++:; ci; Br; Br * - <^; N-C ^; 3; 10; +; +; : Br: Cl: Cl: -, /: n-C ^: 3: 10: ++: ++: j o i * · · »j s · ·; Br; ci j ci; - <^; N-C ^; 3 j 10] ++ J ++ * 20: Br: CH ^: CH ^: CH ^: n-C ^ Hg: 3: 10 * · ***: * +: 146977 13

Tabel II fortsat ’ fl * Br * Br * ^>-Br * n-C^ \ 3 \ 10 l +++ i +++ \ • Η ϊ Br · Br · ^ · n-C^H^ · 3 · 10 * ++ · ++ : ; och3; ci ; h ; ; n-c^ ; 3 ! 10 ; +++ ; +++ ; 5 : OCRyOCRj : H : -<^ : n-C^ : 3 : 10 s ++ ; ++ : i H :0CH_ : H : C.H 1 n-C, H. : 3 : 10 ! +++ : ++ : • :3: : 2 5 :4-9. · * ; : Br :0CH, : H : C H. : n-C.H : 3 · 5 : ++ : ++ : . . 3. .25 ! Br ;och3 | h ; ch3 ; n-c^ ; 3 ; 7 ; ++ ; ++ ; ; Br ;och3 ; h ; ch3 ; n-c^ ; 3 ; 7,5 ; ++ ; ++ ; 10 : Butoprozin · 5 : +++ ’ + : . Amiodaron ' : 10 \ ++ i ++ iTable II continued 'fl * Br * Br * ^> - Br * nC ^ \ 3 \ 10 l +++ i +++ \ • Η ϊ Br · Br · ^ · nC ^ H ^ · 3 · 10 * ++ · ++:; OCH 3; ci; h; ; n-c 2; 3! 10; +++; +++; 5: OCRyOCRj: H: - <^: n-C ^: 3: 10 s ++; ++: i H: 0CH_: H: C.H 1 n-C, H: 3: 10! +++: ++: •: 3:: 2 5: 4-9. · *; : Br: 0CH,: H: C H.: n-C.H: 3 · 5: ++: ++:. . 3. .25! Br; and 3 | h; ch3; n-c 2; 3; 7; ++; ++; ; Br; and 3; h; ch3; n-c 2; 3; 7.5; ++; ++; 10: Butoprozin · 5: +++ '+:. Amiodarone ': 10 \ ++ i ++ i

Det fremgår af de i tabel II anførte resultater, at de omhandlede forbindelser har en væsentligt bedre virkning end de kendte forbindelser.It is apparent from the results set forth in Table II that the compounds of the present invention have a significantly better effect than the known compounds.

15 II. Anti-arrytmiske virkninger.II. Antiarrhythmic effects.

Disse virkninger bestemmes ved intragastrisk indgivelse af forsøgsforbindelsen til mus under anvendelse af Lawson-testen, jfr. J.Pharmac.Exp.Therap. 1968, 160 (1), side 22-31.These effects are determined by intragastric administration of the test compound to mice using the Lawson test, cf. J.Pharmac.Exp.Therap. 1968, 160 (1), pages 22-31.

Arrytmien fremkaldes ved,at dyrene inhalerer chloroform til to-20 tal asfyksi, hvorefter den ventriculære rytme iagttages.The arrhythmia is elicited by the animals inhaling chloroform to two to twenty numbers of asphyxia, after which the ventricular rhythm is observed.

Der foretages bestemmelse af den dosis af forbindelsen, som beskytter 50% af dyrene mod ventriculær fibrillation, dvs. AD^q-værdien. De opnåede resultater er anført i nedenstående tabel III.The dose of the compound which protects 50% of the animals from ventricular fibrillation, i.e. AD ^ q value. The results obtained are given in Table III below.

Tabel XII.Table XII.

14 146977 X^ X2 X3 R n AD5o -værdi _;_(mg/kg)14 147777 X ^ X2 X3 R n AD 50 value _; _ (mg / kg)

Br Br H CH3 n-C4Hg 3 180 5 H Br H n-C^Hg n-C4Hg 3 170Br Br H CH3 n-C4Hg 3 180 5 H Br H n-C ^ Hg n-C4Hg 3 170

Butoprozin 270 III. Toksicitet.Butoprozin 270 III. Toxicity.

Forsøg til bestemmelse af den akutte toksicitet udføres på 10 rotter og mus. De opnåede resultater er anført i nedenstående tabel IV, hvori anføres resultater af sammenlignings-forsøg foretaget med butoprozin. De omhandlede forbindelser anvendes i form af det sure oxalat bortset fra de med (*) mærkede forbindelser, som anvendes i form af hydrochloridet.Experiments to determine the acute toxicity are performed in 10 rats and mice. The results obtained are given in Table IV below, which gives results of comparative experiments with butoprozin. The compounds of the present invention are used in the form of the acidic oxalate except for the (*) -labelled compounds used in the form of the hydrochloride.

15 Tabel IV.Table IV.

a) Intravenøs indgift til rotter.(a) Intravenous administration to rats.

X1 X2 X3 R R! LD50 (mg/kg) (*) Br Br H CH3 n“C4HQ 3 70 H Br H n-C4Hg n-C4Hg 3 60 20 (*) H Cl H C2H5 n-C4H9 3 65 H Cl Cl iso-C3H7 n-C4Hg 3 >100 (*) Br Cl Η -<^ V. n-C4H9 3 >100 (¾) H Cl H n-C4Hg n-C.H 3 >50 (LDq>50 mg/kg)X1 X2 X3 R R! LD50 (mg / kg) (*) Br Br H CH3 n “C4HQ 3 70 H Br H n-C4Hg n-C4Hg 3 60 20 (*) H Cl H C2H5 n-C4H9 3 65 H Cl Cl iso-C3H7 n- C4Hg 3> 100 (*) Br Cl Η - <^ V. n-C4H9 3> 100 (¾) H Cl H n-C4Hg nC.H 3> 50 (LDq> 50 mg / kg)

Cl Cl H C2H5 n-C4Hg 3 50 25 Cl Η H n-C4Hg n-C4Hg 3 50Cl Cl H C2H5 n-C4Hg 3 50 25 Cl Η H n-C4Hg n-C4Hg 3 50

Br Cl H V-Cl n-C4H 3 >100 (LD0>100 mg/kg)Br Cl H V-Cl n-C 4 H 3> 100 (LDO> 100 mg / kg)

Butoprozin 22 146977 15Butoprozin 22 146977 15

Tabel IV fortsat: b) Intravenøs indgift til mus.Table IV continued: (b) Intravenous administration to mice.

X1 x2 x3 R Rl n LD50 (mg/kg) (*) Br Br H CH3 n_C4H9 3 50 5 Butoprozin 25 » c) Intragastrisk indgift til mus.X1 x2 x3 R Rl n LD50 (mg / kg) (*) Br Br H CH3 n_C4H9 3 50 5 Butoprozin 25 »c) Intragastric administration to mice.

(*) Br Br H CH_ n-C.Hp 3 >5000 * (LDq>5000 mg/kg)(*) Br Br H CH_ n-C.Hp 3> 5000 * (LDq> 5000 mg / kg)

Butoprozin 1600Butoprozin 1600

De i tabel IV anførte resultater illustrerer, at de omhand- 10 lede forbindelser er langt mindre toksiske end butoprozin.The results set forth in Table IV illustrate that the compounds of this invention are far less toxic than butoprozine.

Cardial tolerance og generel toksicitet bestemt ved langtids toksicitetsforsøg.Cardiac tolerance and general toxicity determined by long-term toxicity trials.

1- Brom-2-methyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-brom-benzoyl]-indolizin-hydrochlorid, 2-n-butyl-3-[4-(3-di-n-butyl- 15 aminopropyl)-oxy-3-brom-benzoyl]-indolizin-hydrochlorid og 2- n-butyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-chlor-benzoyl]-indolizin-hydrochlorid fremkalder hverken ventrikulær arrytmi eller dødelighed ved en dosis på 200 mg/kg/dag ved oral indgift til hunde. Butoprozin fremkalder derimod ventrikulær ar- 20 rytmi i en dosis så lav som 50 mg/kg/dag ved oral indgift til hunde, og den letale dosis for denne forbindelse ligger mel- . len 50 og 100 mg/kg/dag.1- Bromo-2-methyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl] -indolizine hydrochloride, 2-n-butyl-3- [4- (3- di-n-butylaminopropyl) oxy-3-bromo-benzoyl] -indolizine hydrochloride and 2- n-butyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-chloro benzoyl] -indolizine hydrochloride does not induce ventricular arrhythmia or mortality at a dose of 200 mg / kg / day when administered orally to dogs. Butoprozin, on the other hand, induces ventricular arrhythmia at a dose as low as 50 mg / kg / day by oral administration to dogs, and the lethal dose for this compound is intermediate. 50 and 100 mg / kg / day.

Til terapeutisk anvendelse af de omhandlede forbindelser indgives disse sædvanligvis i form af et farmaceutisk præparat el-25 ler veterinært præparat, som kan have en enhedsdosisform, som er hensigtmæssig til den pågældende indgiftsmåde.For therapeutic use of the subject compounds, these are usually administered in the form of a pharmaceutical or veterinary preparation which may have a unit dosage form suitable for the particular mode of administration.

16 14697716 146977

Fremgangsmåden ifølge opfindelsen illustreres nærmere i de følgende eksempler.The process of the invention is further illustrated in the following examples.

Eksempel 1.Example 1.

l-Brom-2-ethyl-3-[4-(3-di-n-propylaminopropyl) -oxy-3-brom-5 benzoyl]-indolizin og dets sure oxalat.1-Bromo-2-ethyl-3- [4- (3-di-n-propylaminopropyl) -oxy-3-bromo-benzoyl] -indolizine and its acidic oxalate.

a)_l-Brom-2-ethyl-3-[4-(3-brompropyl)-οχγ-^θηζογίΐ-ΐηάοΐΐζίη.a) _l-Bromo-2-ethyl-3- [4- (3-bromopropyl) -οχγ- ^ θηζογίΐ-ΐηάοΐΐζίη.

En blanding af 7,7 g (0,018 mol) l-brom-3-(3-brom-4-hydroxy-benzoyl)-indolizin, 5 g (0,036 mol) vandfrit kaliumcarbonat og 50 ml methylethylketon omrøres i en kolbe i 30 minutter.A mixture of 7.7 g (0.018 mol) of 1-bromo-3- (3-bromo-4-hydroxy-benzoyl) -indolizine, 5 g (0.036 mol) of anhydrous potassium carbonate and 50 ml of methyl ethyl ketone is stirred in a flask for 30 minutes. .

10 Til reaktionsblandingen sættes 14,4 g (0,072 mol) 1,3-dibrom-propan, hvorefter blandingen tilbagesvales i 20 timer. Efter afkøling frafiltreres mineralsaltene, som vaskes med acetone. Opløsningsmidlerne samt overskud af 1,3-dibrom-propan fordampes. På denne måde fås 13,2 g af et produkt, som renses ved 15 eluering på siliciumdioxid under anvendelse af benzen som elueringsmiddel. Der fås en første fraktion af et ukendt stof og derpå en fraktion på 8 g af den ønskede forbindelse.To the reaction mixture is added 14.4 g (0.072 mole) of 1,3-dibromo-propane and then the mixture is refluxed for 20 hours. After cooling, the mineral salts which are washed with acetone are filtered off. The solvents and excess 1,3-dibromo-propane are evaporated. In this way, 13.2 g of a product is obtained which is purified by elution on silica using benzene as the eluent. A first fraction of an unknown substance is obtained and then a fraction of 8 g of the desired compound.

På denne måde fremstilles l-brom-2-ethyl-3-[4-(3-brompropyl)-oxy-benzoyl]-indolizin i et udbytte på 83,6%.In this way, 1-bromo-2-ethyl-3- [4- (3-bromopropyl) -oxy-benzoyl] -indolizine is prepared in 83.6% yield.

20 smp. 105-106°C.20 m.p. 105-106 ° C.

^l_ill£22}z2-ethyl-3-_[4-_(3-di-n-propylaminopro2Yl)_-oxy-3-br0in-L_ill £ ^ z 2} 22-ethyl-3 -_ [4 -_ (3-di-n-propylaminopro2Yl) _- oxy-3-br0in-

En blanding af 2,2 g (0,004 møl) l-brom-2-ethyl-3-[4-(3-brom-propyl)-oxy-benzoyl]-indolizin, 1,2 g (0,012 mol) di-n-propyl-25 amin og 25 ml toluen tilbagesvales i en kolbe i 20 timer. Efter afkøling vaskes reaktionsblandingen med to gange 10 ml vand, og opløsningsmidlet fordampes i vakuum. På denne måde fås 2,5 g remanens, som renses ved kromatografering på siliciumdioxid under anvendelse af ethylacetat som elueringsmiddel.A mixture of 2.2 g (0.004 moles) of 1-bromo-2-ethyl-3- [4- (3-bromo-propyl) -oxy-benzoyl] -indolizine, 1.2 g (0.012 mol) of di-n -propyl-25 amine and 25 ml of toluene are refluxed in a flask for 20 hours. After cooling, the reaction mixture is washed with twice 10 ml of water and the solvent is evaporated in vacuo. This gives 2.5 g of residue which is purified by chromatography on silica using ethyl acetate as eluant.

30 På denne måde fås 2,4 g l-brom-2-ethyl-3-[4-(3-di-n-propylaminopropyl) -oxy-3-brom-benzoyl] -indolizin i form af den frie base.In this way, 2.4 g of 1-bromo-2-ethyl-3- [4- (3-di-n-propylaminopropyl) -oxy-3-bromo-benzoyl] -indolizine is obtained as the free base.

146977 17 c)__l-Brgm-2-ethYl233X4-|3-dl-n-gro2^1amino£rogYl)i-oxY-3-brom- kgnzoylX-indolizin^urt^oxalat^C) __-1-Brgm-2-ethyl233X4- [3-dl-n-gro2β1amino] rogyl] i-oxY-3-bromo-quinzoylX-indolizine ^ herb ^ oxalate ^

Den ovenfor under b) fremstillede base opløses i 30 ml ethyl-ether, hvorpå der tilsættes 0,55 g oxalsyre i 70 ml ethylether, 5 hvorved der fås 2,4 g af det ønskede salt i rå form. Ved omkrystallisation af denne mængde fra 75 ml isopropanol fås 2,0 g rent l-brom-2-ethyl-3-[4-(3-di-n-propylaminopropyl)-oxy- 3-brom-benzoyl]-indolizin surt oxalat.The base prepared under b) is dissolved in 30 ml of ethyl ether, then 0.55 g of oxalic acid is added in 70 ml of ethyl ether, to give 2.4 g of the desired salt in crude form. Recrystallization of this amount from 75 ml of isopropanol gives 2.0 g of pure 1-bromo-2-ethyl-3- [4- (3-di-n-propylaminopropyl) oxy-3-bromo-benzoyl] -indolizine acid oxalate .

Udbytte: 75%.Yield: 75%.

10 Smp. 139-140°CM.p. 139-140 ° C

Eksempel 2.Example 2.

l-Brom-2-methyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-brom-benzoyl]-indolizin og salte deraf.1-Bromo-2-methyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl] -indolizine and its salts.

Til en 1 liter-kolbe sættes en blanding af 180 ml vand, 180 ml 15 toluen, 73 g (0,178 mol) l-brom-2-methyl-3-(3-brom-4-hydroxy-benzoyl)-indolizin, 42,7 g (0,21 mol) l-di-n-butylamino-3-chlor-propan og 34,5 g kaliumcarbonat under omrøring. Reaktionsblandingen opvarmes under tilbagesvaling i 20 timer.To a 1 liter flask is added a mixture of 180 ml of water, 180 ml of toluene, 73 g (0.178 mol) of 1-bromo-2-methyl-3- (3-bromo-4-hydroxy-benzoyl) -indolizine, 42 g. , 7 g (0.21 mol) of 1-di-n-butylamino-3-chloropropane and 34.5 g of potassium carbonate with stirring. The reaction mixture is heated at reflux for 20 hours.

Efter afkøling til stuetemperatur dekanteres den vandige fase, 20 og toluenlaget vaskes med 3 gange 200 ml vand. Toluenopløsningen overføres til en kolbe, og toluenet afdestilleres under atmosfæretryk til tørhed, hvorefter den fremkomne remanens afkøles.After cooling to room temperature, the aqueous phase is decanted, and the toluene layer is washed with 3 times 200 ml of water. The toluene solution is transferred to a flask and the toluene is distilled off under atmospheric pressure to dryness, after which the residue obtained is cooled.

På denne måde fremstilles rå l-brom-2-methyl-3-[4-(3-di-n-25 butylaminopropyl)-oxy-3-brom-benzoyl]-indolizin i form af den frie base.In this way, crude 1-bromo-2-methyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl] -indolizine is prepared as the free base.

Der fremstilles nedenstående salte af denne forbindelse: ål_5Yi§£22]2i2£*£§iiThe following salts are prepared from this compound: eel_5Yi§ £ 22] 2i2 £ * £ §ii

Til den ovenfor fremstillede frie base sættes en opløsning af 30 8 g saltsyre i 61 ml ethylacetat. Det dannede bundfald isole- 18 146977 res ved sugefiltrering (104 g) , vaskes med ethylacetat og omkrystalliseres fra 500 ml isopropanol. På denne måde fås 93 g 1- brom-2-methyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-brom-benzoyl]-indolizin-hydrochlorid.To the free base prepared above is added a solution of 8 g of hydrochloric acid in 61 ml of ethyl acetate. The precipitate formed is isolated by suction filtration (104 g), washed with ethyl acetate and recrystallized from 500 ml of isopropanol. In this way, 93 g of 1-bromo-2-methyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl] -indolizine hydrochloride are obtained.

5 Udbytte: 84,7%, smp.: 172°C.Yield: 84.7%, mp: 172 ° C.

b) Det sure oxalat^b) The acidic oxalate ^

Til en etheropløsning af den fremstillede base sættes en ækvi-molær opløsning af oxalsyre i ethylether. Det fremstillede salt omkrystalliseres fra isoprppanol.To an ether solution of the prepared base is added an equimolar solution of oxalic acid in ethyl ether. The salt obtained is recrystallized from isoprppanol.

10 på denne måde fås l-brom-2-methyl-3-[4-(3-di-n-butylaminopropyl) -oxy-3-brom-benzoyl]-indolizin surt oxalat med smp.In this way, 1-bromo-2-methyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl] -indolizine acid oxalate is obtained, m.p.

89-90°C.89-90 ° C.

Eksempel 3.Example 3

2- Methyl-3-[4- (3-di-n-butylaminopropyl) -oxy-3,5-dibr'om-15 benzoyl]-indolizin surt oxalat.2- Methyl 3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dibromo-benzoyl] -indolizine acid oxalate.

Til en 250 ml-kolbe sættes en blanding af 4 g (0,01 mol) 2-methyl-3-(3,5-dibrom-4-hydroxy-benzoyl)-indolizin og 150 ml acetone. Når indolizinen er opløst, tilsættes 4 g vandfrit kaliumcarbonat og 2,2 g di-n-butylaminopropylchlorid.To a 250 ml flask is added a mixture of 4 g (0.01 mole) of 2-methyl-3- (3,5-dibromo-4-hydroxy-benzoyl) -indolizine and 150 ml of acetone. When the indolizine is dissolved, 4 g of anhydrous potassium carbonate and 2.2 g of di-n-butylaminopropyl chloride are added.

20 Reaktionsblandingen tilbagesvales under omrøring i 16 timer.The reaction mixture is refluxed with stirring for 16 hours.

Efter afkøling til stuetemperatur frafiltreres mineralsaltene, som vaskes med acetone på filteret. Acetonen afdestilleres under formindsket tryk under anvendelse af en rotationsfordamper, og den olieagtige remanens opløses i ca. 100 ml 25 ethylacetat. Blandingen filtreres på et filter, og der sættes 1,5 g vandfri oxalsyre til filtratet. Reaktionsblandingen henstilles, og det udkrystallisecedeoxalat frafiltreres, vaskes på filteret med ethylacetat og tørres under vakuum.After cooling to room temperature, the mineral salts which are washed with acetone are filtered off on the filter. The acetone is distilled off under reduced pressure using a rotary evaporator and the oily residue is dissolved in approx. 100 ml of ethyl acetate. The mixture is filtered on a filter and 1.5 g of anhydrous oxalic acid is added to the filtrate. The reaction mixture is quenched and the crystallized cedeoxalate is filtered off, washed on the filter with ethyl acetate and dried under vacuum.

På denne måde fremstilles 6,2 g 2-methyl-3-[4-(3-di-n-butyl-30 aminopropyl)-oxy-3,5-dibrom-benzoyl]-indolizin surt oxalat. Udbytte: 92,7%.In this way, 6.2 g of 2-methyl-3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dibromo-benzoyl] -indolizine acid oxalate is prepared. Yield: 92.7%.

Smp.: 96°C.Mp: 96 ° C.

Eksempel 4.Example 4

19 146977 l-Brom-2-ethyl-3-[4-(3-di-n-propylaminopropyl)-oxy-3,5-di-chlor-benzoyl]-indolizin surt oxalat.1-Bromo-2-ethyl-3- [4- (3-di-n-propylaminopropyl) oxy-3,5-dichloro-benzoyl] -indolizine acid oxalate.

Til en 250 ml-kolbe sættes 2,8 g (0,005 mol) 2-ethyl-3-[4-5 (3-di-n-propylaminopropyl)-oxy-3,5-dichlor-benzoyl]-indolizin surt oxalat og 80 ml dioxan. Reaktionsblandingen omrøres, og når indolizinen er opløst, tilsættes 0,8 g vandfrit natriumacetat. Derpå tilsættes dråbevis og under kraftig omrøring gennem en tildrypningstragt en opløsning af 0,8 g brom i 20 ml 10 dioxan. Temperaturen holdes på ca. 20°C under tilsætningen af bromet.To a 250 ml flask is added 2.8 g (0.005 mol) of 2-ethyl-3- [4-5 (3-di-n-propylaminopropyl) oxy-3,5-dichlorobenzoyl] indolizine acid oxalate and 80 ml of dioxane. The reaction mixture is stirred and when the indolizine is dissolved, 0.8 g of anhydrous sodium acetate is added. Then a solution of 0.8 g of bromine in 20 ml of 10 dioxane is added dropwise and with vigorous stirring through a drip funnel. The temperature is kept at approx. 20 ° C during the addition of the bromine.

Efter omrøring af blandingen i to timer ved stuetemperatur afdestilleres dioxanet under vakuum på en rotationsfordamper.After stirring the mixture for two hours at room temperature, the dioxane is distilled off under vacuum on a rotary evaporator.

Den faste remanens opløses i vand, gøres basisk med en na-15 triumhydroxidopløsning og ekstraheres med chloroform. Chloro-formopløsningen vaskes 3 gange med vand, og chloroformen af-destilleres under formindsket tryk. Den fremkomne olieagtige remanens optages i tør ethylether, og efter filtrering dannes det sure oxalat.The solid residue is dissolved in water, made basic with a sodium hydroxide solution and extracted with chloroform. The chloroform solution is washed 3 times with water and the chloroform is distilled off under reduced pressure. The resulting oily residue is taken up in dry ethyl ether and, after filtration, the acid oxalate is formed.

20 På denne måde fås 1,8 g l-brom-2-ethyl-3- [4-(3-di-n-propylaminopropyl) -oxy-3,5-dichlor-benzoyl]-indolizin surt oxalat efter omkrystallisation fra ethylacetat.In this way, 1.8 g of 1-bromo-2-ethyl-3- [4- (3-di-n-propylaminopropyl) oxy-3,5-dichloro-benzoyl] -indolizine acid oxalate is obtained after recrystallization from ethyl acetate .

Udbytte: 55,8%.Yield: 55.8%.

Smp.: 135°C.Mp: 135 ° C.

25 Under anvendelse af egnede udgangsforbindelser og de i ovenstående eksempler beskrevne fremgangsmåder fremstilles nedenstående forbindelser.Using suitable starting compounds and the methods described in the above examples, the following compounds are prepared.

Forbindelser Smp.°CCompounds Mp ° C

l-Brom-2-ethyl-3[4-(3-di-n-butylaminopropyl)- 107-108 30 oxy-benzoyl]-indolizin surt oxalat (isopropanol) l-Brom-2-(4-brom-phenyl)-3-[4-(3-di-n-butyl- 92-94 aminopropyl)-oxy-benzoyl]-indolizin surt oxalat(isopropanol) 20 146977 l-Chlor-2-methy1-3-[4-(3-di-n-butylaminopropyl)- 92-93 oxy-benzoyl]-indolizin surt oxalat (isopropanol) l-Chlor-2-ethyl-3-[4-(3-di-n-propylamino- 162 propyl)-oxy-benzoyl]-indolizin surt oxalat (isopropanol) 5 l-Chlor-2-n-propyl-3-[4-(3-di-n-butylainino- 111-112 propyl)-oxy-benzoyl]-indolizin surt oxalat (isopropanol) l-Chlor-2-n-butyl-3-[4-(3-di-n-butylamino- 106-108 propyl)-oxy-benzoyl]-indolizin surt oxalat (isopropanol) l-Chlor-2-phenyl-3-{4-( 3-di-n-propylamino- 161-162 10 propyl)-oxy-benzoyl]-indolizin surt oxalat (isopropanol) l-Chlor-2-(4-chlor-phenyl)-3-[4-(3-di-n- 158-159 butylaminopropyl)-oxy-benzoyl]-indolizin surt (methanol) oxalat 1-Chlor-2-pheny1-3-[4-(3-di-n-butylamino- 160-161 15 propyl)-oxy-benzoyl]-indolizin surt oxalat (methanol) 1- Chlor-2-n-butyl-3-[4-(6-di-n-butylamino- 80-82 hexyl)-oxy-benzoyl]-indolizin surt oxalat (benzen) 2- Methyl-3-[4-(3-di-n-butylaminopropyl)- 141-143 oxy-3-brom-benzoyl]-indolizin surt oxalat (10/1 ethylacetat/ 20 isopropanol) 2-Ethyl-3-[4-(3-di-n-propylaminopropyl)- 163 oxy-3-brom-benzoyl]-indolizin surt oxalat (isopropanol) 2- Ethyl~3-[4-(3-di-n-butylaminopropyl)-oxy- 98-99 3- brom-benzoyl]-indolizin surt oxalat (isopropanol) 25 2-n-Propyl-3-[4-(3-di-n-propylaminopropyl)- 145 oxy-3-brom-benzoyl]-indolizin surt oxalat (isopropanol) 2-n-Propyl-3-[4-(3-di-n-butylaminopropyl) - 113-115 oxy-3-brom-benzoyl]-indolizin surt oxalat (isopropanol) 2-Isopropyl-3-[4-(3-di-n-butylaminopropyl)- 105-107 30 oxy-3-brom-benzoyl]-indolizin surt oxalat (benzen) 2-n-Butyl-3-[4-(3-di-n-propylaminopropyl)- 136-137 oxy-3-brom-benzoyl]-indolizin surt oxalat (isopropanol) 2-n-Butyl-3-[4-(3-di-n-butylaminopropyl)- 86-87 oxy-3-brom-benzoyl]-indolizin surt oxalat (isopropanol) 35 2-Phenyl-3-[4-(3-di-n-propylaminopropyl)- 148-149 oxy-3-brom-benzoyl]-indolizin surt oxalat (isopropanol) 2-Phenyl-3-[4-(3-di-n-butylaminopropyl)- 129-130 oxy-3-brom-benzoyl]-indolizin surt oxalat (isopropanol) 21 U6977 2-(4-Fluor-phenyl)-3-[4-(3-di-n-butylamino- . 110 propyl)-oxy-3-brom-benzoyl]-indolizin (isopropanol) surt oxalat 2-(4-Chlor-phenyl) -3- [4-(3-di-n-propylamino- 163-164 5 propyl)-oxy-3-brom-benzoyl]-indolizin (methanol) surt oxalat 2-(4-Chlor-pheny1)-3-[4-(3-di-n-butylamino- 139-140 propyl)-oxy-3-brom-benzoyl]-indolizin (isopropanol) surt oxalat 10 2-(3-Brom-phenyl)-3-[4-(3-di-n-propylaminopro- 142-143 pyl)-oxy-3-brom-benzoyl]-indolizin surt oxalat (isopropanol) 2-(4-Brom-phenyl)-3-[4-(3-di-n-butylaminopro- 147-148,5 pyl)-oxy-3-brom-benzoyl]-indolizin surt oxalat (methanol) 2-(Methoxy-phenyl)-3-(4-(3-di-n-butylaminopro- 169 15 pyl)-oxy-3-brom-benzoyl]-indolizin surt oxalat (isopropanol) 2- Isopropyl-3-[4-(5-di-n-butylaminopentyl)-oxy- 80-82 3- brom-benzoyl]-indolizin surt oxalat (benzen) 2- Isopropyl-3-[4-(3-di-n-propylaminopropyl)- 179 oxy-3-brom-benzoyl]-indolizin surt oxalat (isopropanol) 20 2-Methyl-3-[4-(3-di-n-butylaminopropyl)-oxy- 141-143 3- chlor-benzoyl]-indolizin surt oxalat (isopropanol) 2- Ethyl-3-[4-(3-di-n-propylaminopropyl)-oxy- 161-162 3- chlor-benzoyl]-indolizin surt oxalat (methanol) 2-Ethyl-3- [4- (3-di-n-butylaminopr-opyl) -oxy- 116-117 25 3-chlor-benzoyl]-indolizin surt oxalat (isopropanol) 2-Isopropyl-3-[4-(3-di-n-butylaminopropyl)- 115-117 oxy-3-chlor-benzoyl]-indolizin surt oxalat (isopropanol) 2- Isopropyl-3-[4-(3-di-n-propylaminopropyl)- 168-169 oxy-3-chlor-benzoyl]-indolizin surt oxalat (methanol) 30 2-n-Butyl-3-[4-(3-di-n-butylaminopropyl)-oxy- 84-85 og 107-109 3- chlor-benzoyl]-indolizin surt oxalat (isopropanol) 2-n-Butyl-3-[4-(3-di-n-propylaminopropyl)- 130-131 oxy-3-chlor-benzoyl]-indolizin surt oxalat (isopropanol) 2-Phenyl-3-[4-(3-di-n-butylaminopropyl)-oxy- 121-122 35 3-chlor-benzoyl]-indolizin surt oxalat (isopropanol) 2-Phenyl-3-[4-(3-di-n-propylaminopropyl)- 157-159 oxy-3-chlor-benzoyl]-indolizin surt oxalat (methanol) 146977 22 2- (4-Methyl-phenyl) -3- [4- (3-di-n-propylamino- 134-135 propyl)-oxy-3-chlor-benzoyl]-indolizin (isopropanol) surt oxalat 2-(4-Brom-phenyl)-3-[4-(3-di-n-propylamino- 154-155 5 propyl)-oxy-3-chlor-benzoyl]-indolizin (methanol) surt oxalat 2-(4-Brom-phenyl)-3-[4-(3-di-n-butylaminopro- 134-135 pyl)-oxy-3-chlor-benzoyl]-indolizin surt oxalat(isopropanol) 2-(3-Brom-phenyl)-3-[4-(3-di-n-butylaminopro- 92-93 10 pyl)-oxy-3-chlor-benzoyl]-indolizin surt oxalat (isopropanol) 2-(3-Brom-phenyl)-3-[4-(3-di-n-propylamino- 148-150 propyl)-oxy-3-chlor-benzoyl]-indolizin (isopropanol) surt oxalat 2-(4-Chlor-phenyl)-3-[4-(3-di-n-butylamino- 116-118 15 propyl)-oxy-3-chlor-benzoyl]-indolizin (isopropanol) surt oxalat 2- (4-Chlor-phenyl)-3-[4-(3-di-n-propylamino- 159-160 propyl)-oxy-3-chlor-benzoyl]-indolizin (methanol) surt oxalat 20 l-Brom-2-methyl-3-[4-(3-di-n-butylaminopropyl)- 89-90 oxy-3-brom-benzoyl]-indolizin surt oxalat (isopropanol) l-Brom-2-methyl-3-[4-(3-di-n-propylaminopro- 164-165 pyl)-oxy-3-brom-benzoyl]-indolizin surt oxalat (isopropanol/ methanol) 25 l-Brom-2-ethyl-3-[4-(2-dimethylaminoethyl)-oxy- 164-165 3- brom-benzoyl]-indolizin surt oxalat (dichlorethan) l-Brom-2-ethyl-3-[4-(3-dimethylaminopropyl)- 150-151 oxy-3-brom-benzoyl]-indolizin surt oxalat (dichlorethan) l-Brom-2-ethyl-3-[4-(2-diethylaminoethyl)- 168-169 30 oxy-3-brom-benzoyl]-indolizin surt oxalat (dichlorethan) l-Brom-2-ethyl-3-[4-(3-diethylaminopropyl)- 140-141,5 oxy-3-brom-benzoyl]-indolizin surt oxalat (isopropanol) l-Brom-2-ethyl-3-[4-(2-di-n-propylaminoethyl)- 16 3-164 oxy-3-brom-benzoyl]-indolizin surt oxalat (isopropanol) 35 l-Brom-2-ethyl-3-[4-(3-di-n-propylaminopropyl)- 139-140 oxy-3-brom-benzoyl]-indolizin surt oxalat (isopropanol) l-Brom-2-ethyl-3-[4-(2-di-n-butylaminoethyl)- 164-165 oxy-3-brom-benzoyl]-indolizin surt oxalat (isopropanol) 146977 23 l-Brom-2-ethyl-3-[4-(3-di-n-butylaminopropyl)- 101-101,5 oxy-3-brom-benzoyl]-indolizin surt oxalat (isopropanol) l-Brom-2-n-propyl-3-[4-(3-di-n-butylaminopro- 92 pyl)-oxy-3-brom-benzoyl]-indolizin surt oxalat (benzen) 5 l-Brom-2-n-propyl-3-[4-(3-di-n-propylamino- 132-136 propyl)-oxy-3-brom-benzoyl]-indolizin (isopropanol) surt oxalat l-Brom-2-n-butyl-3-[4-(3-di-n-propylaminopro- 151-152 pyl)-oxy-3-brom-benzoyl]-indolizin surt oxalat (2/1 isopropan-10 ol/methanol) l-Brom-2-n-butyl-3-[4-(3-di-n-butylaminopro- 101-103 pyD-oxy-3-brom-benzoyl]-indolizin surt oxalat (isopropanol) l-Brom-2-phenyl-3-[4-(3-di-n-propylaminopro- 169-170 pyl)-oxy-3-brom-benzoyl]-indolizin surt oxalat (1/1 methanol/ 15 isopropanol) l-Brom-2-phenyl-3-[4-(3-di-n-butylaminopro- 167-169 pyl)-oxy-3-brom-benzoyl]-indolizin surt oxalat (isopropanol) l-Brom-2-(4-methoxy-phenyl)-3-[4-(3-di-n-butyl- 178-179 aminopropyl)-oxy-3-brom-benzoyl]-indolizin (methanol) 20 surt oxalat l-Brom-2-(4-methyl-phenyl)-3-[4-(3-di-n-butyl- 169-170,5 aminopropyl)-oxy-3-brom-benzoyl]-indolizin (1/1 isopropan- surt oxalat ol/methanol) l-Brom-2-(4-fluor-phenyl)-3-[4-(3-di-n-butyl- 170-171 25 aminopropyl)-oxy-3-brom-benzoyl]-indolizin (methanol) surt oxalat l-Brom-2-(3-brom-phenyl)-3-[4-(3-di-n-butyl- 172-173 aminopropyl)-oxy-3-brom-benzoyl]-indolizin (methanol) surt oxalat 30 l-Brom-2-n-butyl-3-[4-(4-di-n-butylaminobutyl)- 118-120 oxy-3-brom-benzoyl]-indolizin surt oxalat (isopropanol) l-Chlor-2-ethyl-3-[4- (3-di-n-butylaminopro- 115-117 pyl)-oxy-3-chlor-benzoyl]-indolizin surt oxalat(isopropanol) l-Chlor-2-ethyl-3-[4-(3-di-n-propylaminopro- 137-138 35 pyl)-oxy-3-chlor-benzoyl]-indolizin surt oxalat(isopropanol) l-Chlor-2-(3-brom-phenyl)-3-[4-(3-di-n-butyl- 171-172 aminopropyl)-oxy-3-chlor-benzoyl]-indolizin (methanol) surt oxalat 146977 24 l-Chlor-2-(3-brom-phenyl)-3-[4-(3-di-n-propyl- 194-195 åminopropyl)-oxy-3-chlor-benzoyl]-indolizin (methanol) surt oxalat l-Chlor-2-ethyl-3-[4-(3-di-n-propylaminopro- 141 5 pyl)-oxy-3,5-dichlor-benzoyl]-indolizin (ethylacetat) surt oxalat l-Chlor-2-ethyl-3-[4-(3-di-n-butylaminopropyl)- 129 oxy-3,5-dichlor-benzoyl]-indolizin surt oxalat (ethylacetat) l-Chlor-2-phenyl-3-[4-(3-di-n-propylaminopro- 156 10 pyl)-oxy-3,5-dichlor-benzoyl]-indolizin (isopropanol) surt oxalat l-Chlor-2-phenyl-3-[4-(3-di-n-butylaminopro- 136 pyl)-oxy-3,5-dichlor-benzoyl]-indolizin (isopropanol/hep- surt oxalat tan) 15 l-Brom-2-methyl-3-[4-(3-di-n-propylamino- 110-112 propyl)-oxy-3-chlor-benzoyl]-indolizin (isopropanol) surt oxalat l-Brom-2-methy1-3-[4-(3-di-n-butylaminopro- 108-110 pyl)-oxy-3-chlor-benzoyl]-indolizin (isopropanol) 20 surt oxalat l-Brom-2-ethyl-3-[4-(3-di-n-propylaminopro- 136,5-138 pyl)-oxy-3-chlor-benzoyl]-indolizin surt oxa- (isopropanol) lat l-Brom-2-ethyl-3-[4-(3-di-n-butylaminopropyl)- 103-105 25 oxy-3-chlor-benzoylJ-indolizin surt oxalat (isopropanol) l-Brom-2-n-propyl-3-[4-(3-di-n-butylaminopro- 95-96 pyl)-oxy-3-chlor-benzoyl]-indolizin surt oxalat (isopropanol) l-Brom-2-isopropyl-3-[4-(3-di-n-butylaminopro- 116 pyl)-oxy-3-chlor-benzoyl]-indolizin surt (isopropanol) 30 oxalat l-Brom-2-n-butyl-3-[4-(3-di-n-propylaminopro- 159-160 pyl)-oxy-3-chlor-benzoyl]-indolizin surt oxalat (methanol) l-Brom-2-n-butyl-3-[4-(3-di-n-butylaminopro- 101-103 pyl)-oxy-3-chlor-benzoyl]-indolizin surt oxalat (isopropanol) 35 l-Brom-2-phenyl-3-[4-(3-di-n-butylaminopropyl)- 167,5-169 oxy-3-chlor-benzoyl]-indolizin surt oxalat (methanol) l-Brom-2-phenyl-3[4-(3-di-n-propylaminopropyl)- 169-170 oxy-3-chlor-benzoyl]-indolizin surt oxalat (methanol) 146977 25 l-Brom-2- (4-chlor-phenyl) -3- [4- (3-di-n-.butyl- 160-161 aminopropyl)-oxy-3-chlor-benzoyl]-indolizin (isopropanol) surt oxalat l-Brom-2-(4-chlor-phenyl)-3-[4-(3-di-n-propyl- 184-185 5 aminopropyl)-oxy-3-chlor-benzoyl]-indolizin (methanol) surt oxalat l-Brom-2-(4-brom-phenyl)-3-[4-(3-di-n-propyl- 176-177 aminopropyl)-oxy-3-chlor-benzoyl]-indolizin (methanol) surt oxalat 10 l-Brom-2-(4-brom-phenyl)-3-[4-(3-di-n-butyl- 168-169 aminopropyl)-oxy-3-chlor-benzoyl]-indolizin (isopropanol) surt oxalat l-Brom-2-(3-brom-phenyl)-3-[4-(3-di-n-propyl- 200-201 aminopropyl)-oxy-3-chlor-benzoyl]-indolizin (methanol) 15 surt oxalat l-Brom-2-(3-brom-phenyl)-3-[4-(3-di-n-butyl- 170,5-172 aminopropyl)-oxy-3-chlor-benzoyl]-indolizin (methanol) surt oxalat l-Chlor-2-ethyl-3-[4-(3-di-n-butylaminopro- 104-105 20 pyl)-oxy-3-brom-benzoyl]-indolizin surt oxalat (isopropanol) l-Chlor-2-ethyl-3-[4-(3-di-n-propylaminopro- 157 pyl)-oxy-3,5-dibrom-benzoyl]-indolizin surt (isopropanol) oxalat l-Chlor-2-ethyl-3-[4-(3-di-n-butylaminopro- 140 25 pyl)-oxy-3,5-dibrom-benzoyl]-indolizin surt (isopropanol) oxalat 1- Chlor-2-phenyl-3-[4-(3-di-n-propylaminopro- 172 pyl)-oxy-3,5-dibrom-benzoyl]-indolizin surt (isopropanol) oxalat 30 l-chlor-2-phenyl-3-[4-(3-di-n-butylaminopro- 146 pyl)-oxy-3,5-dibrom-benzoyl]-indolizin surt (isopropanol) oxalat 2- Methyl-3-[4-(3-di-n-propylaminopropyl)-oxy- 136 3,5-dibrom-benzoyl]-indolizin-sesqui-oxalat (ethylacetat) 35 2-Ethyl-3-[4-(3-dimethylaminopropyl)-oxy-3,5- 148 dibrom-benzoyl]-indolizin surt oxalat (ethylacetat) 2-Ethyl-3-[4-(2-diethylaminoethyl)-oxy-3,5- 171 dibrom-benzoyl]-indolizin surt oxalat (ethanol) 26 US977 2-Ethyl-3-[4-(3-diethylaminopropyl)-oxy-3,5- 191 dibrom-benzoyl]-indolizin-hydrochlorid (50/50 ethylacetat/ acetone) 2-Ethyl-3-[4-(3-di-n-propylaminopropyl)-oxy- 166 5 3,5-dibrom-benzoyl]-indolizin-hydrochlorid (ethylacetat) 2-Ethy1-3-[4-(3-di-n-butylaminopropyl)-oxy- 157 3.5- dibrom-benzoyl]-indolizin-hydrochlorid (ethylacetat) 2-n-Propyl-3-[4- (3-di-n-propylaxninopropyl) -oxy- 145 3.5- dibrom-benzoyl]-indolizin-hydrochlorid (ethylacetat) 10 2-n-Propyl-3-[4-(3-di-n-butylaminopropyl)- 107 oxy-3,5-dibrom-benzoyl]-indolizin surt oxalat (ethylacetat) 2-Isopropyl-3-[4-(3-di-n-propylaminopropyl)- 126 oxy-3,5-dibrom-benzoyl]-indolizin surt oxalat (ethylacetat/ ethano1) 15 2-Isopropyl-3-[4-(3-di-n-butylaminopropyl)-oxy- 86 3.5- dibrom-benzoyl]-indolizin surt oxalat (ethylacetat/ ethylether) 2-n-Butyl-3-[4-(3-di-n-propylaminopropyl) - 146 oxy-3,5-dibrom-benzoyl]-indolizin surt oxalat (ethylacetat) 20 2-n-Butyl-3-[4-(3-di-n-butylaminopropyl)- 110 oxy-3,5-dibrom-benzoyl]-indolizin surt oxalat (ethylacetat) 2-Phenyl-3-[4-(3-di-n-propylaminopropyl)-oxy- 142 3.5- dibrom-benzoyl]-indolizin surt oxalat (ethylacetat/ ethano1) 25 2-Pheny1-3-[4-(3-di-n-butylaminopropyl)- 86 oxy-3,5-dibrom-benzoyl]-indolizin surt oxalat (ethylacetat) 2-(4-Fluor-phenyl)-3-[4-(3-di-n-propylamino- 166 propyl)-oxy-3,5-dibrom-benzoyl]-indolizin surt (ethylacetat/ oxalat ethanol) 30 2-(4-Fluor-phenyl)-3-[4-(3-di-n-butylamino- 152 propyl)-oxy-3,5-dibrom-benzoyl]-indolizin (isopropanol) surt oxalat 2-(4-Chlor-phenyl)—3—[4—(3-di-n-propylamino- 190 propyl)-oxy-3,5-dibrom-benzoyl]-indolizin (ethylacetat) 35 surt oxalat 2-(4-Chlor-pheny1)-3-[4-(3-di-n-butylaminopro- 88 pyl)-oxy-3,5-dibrom-benzoyl]-indolizin surt (ethylacetat) oxalat 146977 27 2-(3,4-Dichlor-phenyl)-3-[4-(3-di-n-propyl- 114 aminopropyl) -oxy-3,5-dibrom-benzoyl] -indolizin- (ethylacetat/ sesquioxalat isopropanol) 2-(3,4-Dichlor-phenyl)-3-[4-(3-di-n-butylamino- 95 5 propyl) -oxy-3,5-dibrom-benzoyl] -indolizin surt (ethylacetat/ oxalat isopropanol) 2-(3-Brom-phenyl)-3-[4-(3-di-n-propylamino- 136 propyl) -oxy-3,5-dibrom-benzoy]] -indolizin surt (ethanol) oxalat 10 2- (3-Brom-phenyl)-3-[4-(3-di-n-butylaminopro- 122 pyl)oxy-3,5-dibrom-benzoyl]-indolizin surt (ethylacetat) fumarat 2-(4-Methyl-phenyl)-3-[4-(3-di-n-propylamino- 126 propyl)-oxy-3,5-dibrom-benzoy1]-indolizin (ethylacetat/ 15 surt oxalat isopropanol) 2-(4-Methyl-phenyl)-3-[4-(3-di-n-butylamino- 90 propyl)-oxy-3,'5-dibrom-benzoyl ]-indolizin surt (ethylacetat) oxalat 2-(4-Methoxy-phenyl)-3-[4-(3-di-n-propylamino- 167 20 propyl)-oxy-3,5-dibrom-benzoyl]-indolizin surt (acetone) oxalat1-Bromo-2-ethyl-3 [4- (3-di-n-butylaminopropyl) - 107-108 oxy-benzoyl] -indolizine acid oxalate (isopropanol) 1-Bromo-2- (4-bromo-phenyl) -3- [4- (3-di-n-butyl-92-94 aminopropyl) -oxy-benzoyl] -indolizine acid oxalate (isopropanol) 1-Chloro-2-methyl-3- [4- (3- di-n-butylaminopropyl) -92-93 oxy-benzoyl] -indolizine acid oxalate (isopropanol) 1-Chloro-2-ethyl-3- [4- (3-di-n-propylamino-162-propyl) -oxy-benzoyl ] -indolizine acid oxalate (isopropanol) 5-Chloro-2-n-propyl-3- [4- (3-di-n-butylamino-111-112 propyl) -oxy-benzoyl] -indolizine acid oxalate (isopropanol) 1-Chloro-2-n-butyl-3- [4- (3-di-n-butylamino-106-108-propyl) -oxy-benzoyl] -indolizine acid oxalate (isopropanol) 1-Chloro-2-phenyl-3 - {4- (3-di-n-propylamino-161-162-propyl) -oxy-benzoyl] -indolizine acid oxalate (isopropanol) 1-Chloro-2- (4-chloro-phenyl) -3- [4- (3-di-n-158-159 butylaminopropyl) -oxy-benzoyl] -indolizine acid (methanol) oxalate 1-Chloro-2-phenyl-3- [4- (3-di-n-butylamino) 160-161 propyl) -oxy-benzoyl] -indolizine acid oxalate (methanol) 1- Chloro-2-n- butyl 3- [4- (6-di-n-butylamino-80-82 hexyl) -oxy-benzoyl] -indolizine acid oxalate (benzene) 2- Methyl-3- [4- (3-di-n-butylaminopropyl) ) - 141-143 oxy-3-bromo-benzoyl] -indolizine acid oxalate (10/1 ethyl acetate / isopropanol) 2-Ethyl-3- [4- (3-di-n-propylaminopropyl) - 163 oxy-3- bromo-benzoyl] -indolizine acid oxalate (isopropanol) 2- Ethyl ~ 3- [4- (3-di-n-butylaminopropyl) oxy-98-99 3- bromo-benzoyl] -indolizine acid oxalate (isopropanol) 2 -n-Propyl-3- [4- (3-di-n-propylaminopropyl) - 145 oxy-3-bromo-benzoyl] -indolizine acid oxalate (isopropanol) 2-n-Propyl-3- [4- (3- di-n-butylaminopropyl) - 113-115 oxy-3-bromo-benzoyl] -indolizine acid oxalate (isopropanol) 2-Isopropyl-3- [4- (3-di-n-butylaminopropyl) - 3-bromo-benzoyl] -indolizine acid oxalate (benzene) 2-n-Butyl-3- [4- (3-di-n-propylaminopropyl) - 136-137 oxy-3-bromo-benzoyl] -indolizine acid oxalate ( isopropanol) 2-n-Butyl-3- [4- (3-di-n-butylaminopropyl) - 86-87 oxy-3-bromo-benzoyl] -indolizine acid oxalate (isopropanol) 2-Phenyl-3- [4 - (3-di-n-propylaminopropyl) - 148 -149 oxy-3-bromo-benzoyl] -indolizine acid oxalate (isopropanol) 2-Phenyl-3- [4- (3-di-n-butylaminopropyl) - 129-130 oxy-3-bromo-benzoyl] -indolizine acid oxalate (isopropanol) 2- (4-Fluoro-phenyl) -3- [4- (3-di-n-butylamino). 110 propyl) -oxy-3-bromo-benzoyl] -indolizine (isopropanol) acid oxalate 2- (4-Chloro-phenyl) -3- [4- (3-di-n-propylamino-163-164-propyl) - oxy-3-bromo-benzoyl] -indolizine (methanol) acid oxalate 2- (4-Chloro-phenyl) -3- [4- (3-di-n-butylamino-139-140-propyl) -oxy-3-bromo -benzoyl] -indolizine (isopropanol) acid oxalate 2- (3-Bromo-phenyl) -3- [4- (3-di-n-propylaminopropyl-142-143-pyl) -oxy-3-bromo-benzoyl] - indolizine acid oxalate (isopropanol) 2- (4-Bromo-phenyl) -3- [4- (3-di-n-butylaminopropyl-147-148.5-pyl) -oxy-3-bromo-benzoyl] -indolizine acid oxalate (methanol) 2- (Methoxy-phenyl) -3- (4- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl] -indolizine acid oxalate (isopropanol) 2- Isopropyl-3 - [4- (5-di-n-butylaminopentyl) oxy-80-82 3-bromo-benzoyl] -indolizine acid oxalate (benzene) 2- Isopropyl-3- [4- (3-di-n-propylaminopropyl) - 179 oxy-3-bromo-benzoyl] -indolizine acid oxalate (isopropanol) 2-Methyl-3- [4- (3-di-n-butylaminopropyl) -oxy-141-143-3-chloro-benzoyl] -indolizine acid oxalate (isopropanol) 2- Ethyl 3- [4- (3-di-n-propylamide) nopropyl) oxy-161-162 3-chloro-benzoyl] -indolizine acid oxalate (methanol) 2-Ethyl-3- [4- (3-di-n-butylaminopropyl) -oxy-116-117 chloro-benzoyl] -indolizine acid oxalate (isopropanol) 2-Isopropyl-3- [4- (3-di-n-butylaminopropyl) - 115-117 oxy-3-chloro-benzoyl] -indolizine acid oxalate (isopropanol) 2- Isopropyl-3- [4- (3-di-n-propylaminopropyl) - 168-169 oxy-3-chloro-benzoyl] -indolizine acid oxalate (methanol) 2-n-Butyl-3- [4- (3- di-n-butylaminopropyl) oxy-84-85 and 107-109 3-chloro-benzoyl] -indolizine acid oxalate (isopropanol) 2-n-Butyl-3- [4- (3-di-n-propylaminopropyl) - 130-131 oxy-3-chloro-benzoyl] -indolizine acid oxalate (isopropanol) 2-Phenyl-3- [4- (3-di-n-butylaminopropyl) -oxy-121-122-3-chloro-benzoyl] - indolizine acid oxalate (isopropanol) 2-Phenyl-3- [4- (3-di-n-propylaminopropyl) - 157-159 oxy-3-chloro-benzoyl] -indolizine acid oxalate (methanol) 2- (4- Methyl-phenyl) -3- [4- (3-di-n-propylamino-134-135-propyl) -oxy-3-chloro-benzoyl] -indolizine (isopropanol) acid oxalate 2- (4-Bromo-phenyl) - 3- [4- (3-di-n-propylamino-154-155-propyl) -oxy-3-chloro-benzoyl] -indolizine (methanol) acid oxalate 2- (4-Bromo-phenyl) -3- [4- (3-di -n-butylaminopro-134-135-pyl) -oxy-3-chloro-benzoyl] -indolizine acid oxalate (isopropanol) 2- (3-Bromo-phenyl) -3- [4- (3-di-n-butylaminopropyl) 92-93 (pyl) -oxy-3-chloro-benzoyl] -indolizine acid oxalate (isopropanol) 2- (3-Bromo-phenyl) -3- [4- (3-di-n-propylamino-148-150 propyl) ) -oxy-3-chloro-benzoyl] -indolizine (isopropanol) acid oxalate 2- (4-Chloro-phenyl) -3- [4- (3-di-n-butylamino-116-118-propyl) -oxy- 3-Chloro-benzoyl] -indolizine (isopropanol) acid oxalate 2- (4-Chloro-phenyl) -3- [4- (3-di-n-propylamino-159-160-propyl) -oxy-3-chloro-benzoyl ] -indolizine (methanol) acid oxalate 1-Bromo-2-methyl-3- [4- (3-di-n-butylaminopropyl) - 89-90 oxy-3-bromo-benzoyl] -indolizine acid oxalate (isopropanol) 1-Bromo-2-methyl-3- [4- (3-di-n-propylaminopropyl-164-165-pyl) -oxy-3-bromo-benzoyl] -indolizine acid oxalate (isopropanol / methanol) 2-Ethyl-3- [4- (2-dimethylaminoethyl) oxy-164-165 3-bromo-benzoyl] -indolizine acid oxalate (dichloroethane) 1-Bromo-2-ethyl-3- [4- (3-dimethylaminopropyl) 150-151 oxy-3-bromo-benzoyl] -indolizine acid oxalate (dichloroethane) 1-Bromo-2-ethyl 3- [4- (2-diethylaminoethyl) - 168-169 oxy-3-bromo-benzoyl] -indolizine acid oxalate (dichloroethane) 1-Bromo-2-ethyl-3- [4- (3-diethylaminopropyl) - 140 -141,5 oxy-3-bromo-benzoyl] -indolizine acid oxalate (isopropanol) 1-Bromo-2-ethyl-3- [4- (2-di-n-propylaminoethyl) - 16 3-164 oxy-3- bromo-benzoyl] -indolizine acid oxalate (isopropanol) 1-Bromo-2-ethyl-3- [4- (3-di-n-propylaminopropyl) - 139-140 oxy-3-bromo-benzoyl] -indolizine acid oxalate (isopropanol) 1-Bromo-2-ethyl-3- [4- (2-di-n-butylaminoethyl) - 164-165 oxy-3-bromo-benzoyl] -indolizine acid oxalate (isopropanol) 2-Ethyl-3- [4- (3-di-n-butylaminopropyl) - 101-101,5 oxy-3-bromo-benzoyl] -indolizine acid oxalate (isopropanol) 1-Bromo-2-n-propyl-3 - [4- (3-di-n-butylaminopropyl) oxy-3-bromo-benzoyl] -indolizine acid oxalate (benzene) 5-Bromo-2-n-propyl-3- [4- (3) -di-n-propylamino-132-136 propyl) -oxy-3-bromo-bone zoyl] -indolizine (isopropanol) acid oxalate 1-Bromo-2-n-butyl-3- [4- (3-di-n-propylaminopropyl-151-152-pyl) -oxy-3-bromo-benzoyl] -indolizine acid oxalate (2/1 isopropanol / methanol) 1-Bromo-2-n-butyl-3- [4- (3-di-n-butylaminopro-101-103 pyD-oxy-3-bromo-benzoyl] - indolizine acid oxalate (isopropanol) 1-Bromo-2-phenyl-3- [4- (3-di-n-propylaminoprop-169-170-pyl) -oxy-3-bromo-benzoyl] -indolizine acid oxalate (1/1 methanol / isopropanol) 1-Bromo-2-phenyl-3- [4- (3-di-n-butylaminopropyl-167-169-pyl) -oxy-3-bromo-benzoyl] -indolizine acid oxalate (isopropanol) 1- Bromo-2- (4-methoxy-phenyl) -3- [4- (3-di-n-butyl-178-179-aminopropyl) -oxy-3-bromo-benzoyl] -indolizine (methanol) acid oxalate 1- Bromo-2- (4-methyl-phenyl) -3- [4- (3-di-n-butyl-169-170,5-aminopropyl) -oxy-3-bromo-benzoyl] -indolizine (1/1 isopropane) acid oxalate ol / methanol) 1-Bromo-2- (4-fluoro-phenyl) -3- [4- (3-di-n-butyl-170-171-aminopropyl) -oxy-3-bromo-benzoyl] - indolizine (methanol) acid oxalate 1-Bromo-2- (3-bromo-phenyl) -3- [4- (3-di-n-butyl-172-173 aminopropyl) -oxy-3-bromo-bone zoyl] -indolizine (methanol) acid oxalate 1-Bromo-2-n-butyl-3- [4- (4-di-n-butylaminobutyl) - 118-120 oxy-3-bromo-benzoyl] -indolizine acid oxalate (isopropanol) 1-Chloro-2-ethyl-3- [4- (3-di-n-butylaminopropyl-115-117-pyl) -oxy-3-chloro-benzoyl] -indolizine acid oxalate (isopropanol) 2-Ethyl-3- [4- (3-di-n-propylaminopropyl-137-138-pyl) -oxy-3-chloro-benzoyl] -indolizine acid oxalate (isopropanol) 1-Chloro-2- (3-bromo -phenyl) -3- [4- (3-di-n-butyl-171-172 aminopropyl) oxy-3-chloro-benzoyl] -indolizine (methanol) acid oxalate 1-Chloro-2- (3- bromo-phenyl) -3- [4- (3-di-n-propyl-194-195-aminopropyl) -oxy-3-chloro-benzoyl] -indolizine (methanol) acid oxalate 1-Chloro-2-ethyl-3- [4- (3-di-n-propylaminopropyl) oxy-3,5-dichloro-benzoyl] -indolizine (ethyl acetate) acid oxalate 1-Chloro-2-ethyl-3- [4- (3- di-n-butylaminopropyl) - 129 oxy-3,5-dichloro-benzoyl] -indolizine acid oxalate (ethyl acetate) 1-Chloro-2-phenyl-3- [4- (3-di-n-propylaminopropyl) ) -oxy-3,5-dichloro-benzoyl] -indolizine (isopropanol) acid oxalate 1-Chloro-2-phe Nyl 3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dichloro-benzoyl] -indolizine (isopropanol / hepatic acid oxalate) 1-Bromo-2-methyl 3- [4- (3-di-n-propylamino-110-112 propyl) -oxy-3-chloro-benzoyl] -indolizine (isopropanol) acid oxalate 1-Bromo-2-methyl-3- [4- (3) -di-n-butylaminopro-108-110-pyl) -oxy-3-chloro-benzoyl] -indolizine (isopropanol) acid oxalate 1-Bromo-2-ethyl-3- [4- (3-di-n-propylaminopro) 136.5-138 pyl) -oxy-3-chloro-benzoyl] -indolizine acid oxa (isopropanol) lat 1-Bromo-2-ethyl-3- [4- (3-di-n-butylaminopropyl) - 103 -105 oxy-3-chloro-benzoyl] -indolizine acid oxalate (isopropanol) 1-Bromo-2-n-propyl-3- [4- (3-di-n-butylaminopropyl-95-96-pyl) -oxy-3 -chloro-benzoyl] -indolizine acid oxalate (isopropanol) 1-Bromo-2-isopropyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-chloro-benzoyl] -indolizine acid ( isopropanol) oxalate 1-Bromo-2-n-butyl-3- [4- (3-di-n-propylaminopro-159-160-pyl) -oxy-3-chloro-benzoyl] -indolizine acid oxalate (methanol) 1 -Bromo-2-n-butyl-3- [4- (3-di-n-butylaminopropyl-101-103-pyl) -oxy-3-chloro-benzoyl] -indolizine acid oxalate (isopropanol) 1-Bromo-2-phenyl-3- [4- (3-di-n-butylaminopropyl) - 167.5-169 oxy-3-chloro-benzoyl] -indolizine acid oxalate (methanol) ) 1-Bromo-2-phenyl-3 [4- (3-di-n-propylaminopropyl) - 169-170 oxy-3-chloro-benzoyl] -indolizine acid oxalate (methanol) 1-Bromo-2- ( 4-chloro-phenyl) -3- [4- (3-di-n-butyl-160-161-aminopropyl) -oxy-3-chloro-benzoyl] -indolizine (isopropanol) acid oxalate 1-Bromo-2- ( 4-chloro-phenyl) -3- [4- (3-di-n-propyl-184-185-aminopropyl) -oxy-3-chloro-benzoyl] -indolizine (methanol) acid oxalate 1-Bromo-2- ( 4-bromo-phenyl) -3- [4- (3-di-n-propyl-176-177-aminopropyl) -oxy-3-chloro-benzoyl] -indolizine (methanol) acid oxalate 1-Bromo-2- ( 4-bromo-phenyl) -3- [4- (3-di-n-butyl-168-169-aminopropyl) -oxy-3-chloro-benzoyl] -indolizine (isopropanol) acid oxalate 1-Bromo-2- (3 -bromo-phenyl) -3- [4- (3-di-n-propyl-200-201 aminopropyl) -oxy-3-chloro-benzoyl] -indolizine (methanol) acid oxalate 1-Bromo-2- (3 -bromo-phenyl) -3- [4- (3-di-n-butyl-170.5-172-aminopropyl) -oxy-3-chloro-benzoyl] -indolizine (meth anol) acid oxalate 1-Chloro-2-ethyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-bromo-benzoyl] -indolizine acid oxalate (isopropanol) 1- Chloro-2-ethyl-3- [4- (3-di-n-propylaminopropyl) -oxy-3,5-dibromo-benzoyl] -indolizine acid (isopropanol) oxalate 1-Chloro-2-ethyl-3 - [4- (3-di-n-butylaminopropyl) oxy-3,5-dibromo-benzoyl] -indolizine acid (isopropanol) oxalate 1- Chloro-2-phenyl-3- [4- (3) -di-n-propylaminopropyl-172-pyl) -oxy-3,5-dibromo-benzoyl] -indolizine acid (isopropanol) oxalate 1-chloro-2-phenyl-3- [4- (3-di-n-butylaminopro 146-pyl) -oxy-3,5-dibromo-benzoyl] -indolizine acid (isopropanol) oxalate 2- Methyl-3- [4- (3-di-n-propylaminopropyl) -oxy-136 3,5-dibromo benzoyl] indolizine sesqui oxalate (ethyl acetate) 2-Ethyl-3- [4- (3-dimethylaminopropyl) oxy-3,5- 148 dibromo-benzoyl] indolizine acid oxalate (ethyl acetate) 2-Ethyl-3 - [4- (2-diethylaminoethyl) oxy-3,5-171 dibromo-benzoyl] -indolizine acid oxalate (ethanol) 2-Ethyl-3- [4- (3-diethylaminopropyl) -oxy-3,5 - 191 dibromo-benzoyl] -indolizine hydrochlo (50/50 ethyl acetate / acetone) 2-Ethyl-3- [4- (3-di-n-propylaminopropyl) oxy-3,5-dibromo-benzoyl] -indolizine hydrochloride (ethyl acetate) 2-Ethyl -3- [4- (3-di-n-butylaminopropyl) oxy-157 3,5-dibromo-benzoyl] -indolizine hydrochloride (ethyl acetate) 2-n-Propyl-3- [4- (3-di-n- propyllaxininopropyl) oxy-145 3,5-dibromo-benzoyl] -indolizine hydrochloride (ethyl acetate) 2-n-Propyl-3- [4- (3-di-n-butylaminopropyl) -107 oxy-3,5-dibromo benzoyl] -indolizine acid oxalate (ethyl acetate) 2-Isopropyl-3- [4- (3-di-n-propylaminopropyl) - 126 oxy-3,5-dibromo-benzoyl] -indolizine acid oxalate (ethyl acetate / ethanol) 2 -Isopropyl-3- [4- (3-di-n-butylaminopropyl) oxy-86 3,5-dibromo-benzoyl] -indolizine acid oxalate (ethyl acetate / ethyl ether) 2-n-Butyl-3- [4- (3- di-n-propylaminopropyl) - 146 oxy-3,5-dibromo-benzoyl] -indolizine acid oxalate (ethyl acetate) 2-n-Butyl-3- [4- (3-di-n-butylaminopropyl) - 110 3,5-dibromo-benzoyl] -indolizine acid oxalate (ethyl acetate) 2-Phenyl-3- [4- (3-di-n-propylaminopropyl) -oxy-142 3,5-dibromo-benzoyl] -i 2-Phenyl-3- [4- (3-di-n-butylaminopropyl) - 86 oxy-3,5-dibromo-benzoyl] -indolizine acid oxalate (ethyl acetate) 2- (4) -Fluoro-phenyl) -3- [4- (3-di-n-propylamino-166-propyl) -oxy-3,5-dibromo-benzoyl] -indolizine acid (ethyl acetate / oxalate ethanol) 2- (4-Fluoro -phenyl) -3- [4- (3-di-n-butylamino-propyl) -oxy-3,5-dibromo-benzoyl] -indolizine (isopropanol) acid oxalate 2- (4-Chloro-phenyl) -3 - [4- (3-di-n-propylamino-190-propyl) -oxy-3,5-dibromo-benzoyl] -indolizine (ethyl acetate) acid oxalate 2- (4-Chloro-phenyl) -3- [4- (3-di-n-butylaminopropyl) -oxy-3,5-dibromo-benzoyl] -indolizine acid (ethyl acetate) oxalate 2- (3,4-Dichloro-phenyl) -3- [4- ( 3-di-n-propyl-114-aminopropyl) -oxy-3,5-dibromo-benzoyl] -indolizine (ethyl acetate / sesquioxalate isopropanol) 2- (3,4-Dichloro-phenyl) -3- [4- (3 -di-n-butylamino-propyl) -oxy-3,5-dibromo-benzoyl] -indolizine acid (ethyl acetate / oxalate isopropanol) 2- (3-Bromo-phenyl) -3- [4- (3-di -n-propylamino-136-propyl) -oxy-3,5-dibromo-benzoyl] -ind olizine acid (ethanol) oxalate 2- (3-Bromo-phenyl) -3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dibromo-benzoyl] -indolizine acid (ethyl acetate) fumarate 2- (4-Methyl-phenyl) -3- [4- (3-di-n-propylamino-126-propyl) -oxy-3,5-dibromo-benzoyl] -indolizine (ethyl acetate / acid oxalate isopropanol) 2 - (4-Methyl-phenyl) -3- [4- (3-di-n-butylamino-propyl) -oxy-3,5-5-dibromo-benzoyl] -indolizine acid (ethyl acetate) oxalate 2- (4- Methoxy-phenyl) -3- [4- (3-di-n-propylamino-167-propyl) -oxy-3,5-dibromo-benzoyl] -indolizine acid (acetone) oxalate

2-(4-Methoxy-phenyl)-3-[4-(3-di-n-butylamino- pastaagtigt ved propyl)-oxy-3,5-dibrom-benzoyl]-indolizin ca. 70°C2- (4-Methoxy-phenyl) -3- [4- (3-di-n-butylamino-paste-like by propyl) -oxy-3,5-dibromo-benzoyl] -indolizine approx. 70 ° C

surt oxalat (ethanol/ethyl- 25 ether) 2-Methyl-3-[4-(3-di-n-propylaminopropyl)-oxy- 145 3.5- dichlor-benzoyl]-indolizin surt oxalat (ethylacetat/ ethanoi) 2-Methyl-3-[4-(3-di-n-butylaminopropyl)-oxy- 95 30 3,5-dichlor-benzoyl]-indolizin surt oxalat (ethylacetat/ ethylether) 2-Ethyl-3-[4-(3-di-n-propylaminopropyl)- pastaagtigt vedacid oxalate (ethanol / ethyl ether) 2-Methyl-3- [4- (3-di-n-propylaminopropyl) oxy-145 3,5-dichlorobenzoyl] indolizine acid oxalate (ethyl acetate / ethano) 2-Methyl -3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dichloro-benzoyl] -indolizine acid oxalate (ethyl acetate / ethyl ether) 2-Ethyl-3- [4- (3-di -n-propylaminopropyl) - paste-like

oxy-3,5-dichlor-benzoyl]-indolizin surt oxalat 100°Coxy-3,5-dichloro-benzoyl] -indolizine acid oxalate 100 ° C

(ethylacetat) 35 2-Ethyl-3-[4-(3-di-n-butylaminopropyl)-oxy- 95 3.5- dichlor-benzoyl]-indolizin surt oxalat (ethylacetat) 2-n-Propyl-3-[4-(3-di-n-propylaminopropyl)- 142 oxy-3,5-dichlor-benzoyl]-indolizin surt oxalat (isopropanol) 146977 28 2-n-Propyl-3-[4-(3-di-n-butylaminopropy1) - 114 oxy-3,5-dichlor-benzoyl]-indolizin surt oxalat (isopropanol) 2-Isopropyl-3-[4-(3-di-n-propylaminopropyl)- 86 oxy-3,5-dichlor-benzoyl]-indolizin surt oxalat (ethylacetat) 5 2-Isopropyl-3-[4-(3-di-n-butylaminopropyl)- 90 oxy-3,5-dichlor-benzoyl]-indolizin surt oxalat (ethylacetat) 2-Phenyl-3-[4-(3-di-n-propylaminopropyl)-oxy- 146 3,5-dichlor-benzoyl]-indolizin surt oxalat (ethanol) 2-Phenyl-3-[4-(3-di-n-butylaminopropyl)- pastaagtigt ved(ethyl acetate) 2-Ethyl-3- [4- (3-di-n-butylaminopropyl) oxy-95 3,5-dichloro-benzoyl] -indolizine acid oxalate (ethyl acetate) 2-n-Propyl-3- [4- (3-di-n-propylaminopropyl) - 142 oxy-3,5-dichloro-benzoyl] -indolizine acid oxalate (isopropanol) 2-n-Propyl-3- [4- (3-di-n-butylaminopropyl) - 114 oxy-3,5-dichloro-benzoyl] -indolizine acid oxalate (isopropanol) 2-Isopropyl-3- [4- (3-di-n-propylaminopropyl) - 86-oxy-3,5-dichloro-benzoyl] - indolizine acid oxalate (ethyl acetate) 2-Isopropyl-3- [4- (3-di-n-butylaminopropyl) - 90 oxy-3,5-dichloro-benzoyl] -indolizine acid oxalate (ethyl acetate) 2-Phenyl-3- [4- (3-di-n-propylaminopropyl) oxy-146 3,5-dichloro-benzoyl] -indolizine acid oxalate (ethanol) 2-Phenyl-3- [4- (3-di-n-butylaminopropyl) - pasty

10 oxy-3,5-dichlor-benzoyl]-indolizin ca. 90°C10 oxy-3,5-dichloro-benzoyl] -indolizine approx. 90 ° C

surt oxalat (ethylacetat) 2-(4-Brom-phenyl)-3-[4-(3-di-n-propylamino- 174 propyl)-oxy-3,5-dichlor-benzoyl]-indolizin (ethylacetat) surt oxalat 15 2-(4-Brom-phenyl)-3-[4-(3-di-n-butylamino- 133 propyl)-oxy-3,5-dichlor-benzoyl]-indolizin (ethylacetat) surt oxalat l-Brom-2-methyl-3-[4-(3-di-n-butylaminopro- 141-143 pyl)-oxy-3,5-dibrom-benzoyl]-indolizin surt (isopropanol) 20 oxalat l-Brom-2-n-propyl-3- [4-(3-di-n-propylamino- 138-139 propyl)-oxy-3,5-dibrom-benzoyl]-indolizin (isopropanol) surt oxalat l-Brom-2-ethyl-3-[4-(3-di-n-butylaminopropyl)- 131-132,5 25 oxy-3,5-dibrom-benzoyl]-indolizin surt oxalat (isopropanol) l-Brom-2-phenyl-3-[4-(3-di-n-butylaminopro- 160-161 pyl)-oxy-3,5-dibrom-benzoyl]-indolizin surt (isopropanol) oxalat 1-Brom-2-(4-methyl-phenyl)-3-[4-(3-di-n-buty1- 105-106 30 aminopropyl)-oxy-3,5-dibrom-benzoyl]-indolizin (isopropanol) surt oxalat l-Brom-2-(4-brom-pheny1)-3-[4-(3-di-n-butyl- 148-149 aminopropyl)-oxy-3,5-dibrom-benzoyl]-indolizin (isopropanol) surt oxalat 35 l-Brom-2-(3,4-dichlor-phenyl)-3-[4-(3-di-n- 196-197 butylaminopropyl)-oxy-3,5-dibrom-benzoyl]- (isopropanol) indolizin surt oxalat 146977 29 l-Brom-2-(3-chlor-4-methyl-phenyl)-3-[4-(3- 168-169 di-n-butylaminopropyl)-oxy-3,5-dibrom-benzo- (isopropanol) yl]-indolizin surt oxalat 1-Brom—-2-ethyl-3-[4-(3-di-n-butylaminopro- 134 5 pyl)-oxy-3,5-dichlor-benzoyl]-indolizin surt (isopropanol) oxalat 1- Brom-2-phenyl-3-[4-(3-di-n-propylaminopro- 145 pyl)-oxy-3,5-dichlor-benzoyl]-indolizin surt (ethylacetat) oxalat 10 l-Brom-2-phenyl-3-[4-(3-di-n-butylaminopro- 106 pyl)-oxy-3,5-dichlor-benzoyl]-indolizin surt (ethylacetat) oxalat 2- n-Butyl-3-[4-(3-di-n-butylaminopropyl)-oxy- 113-113,5 3- brom-benzoyl]-indolizin-hydrochlorid (ethylacetat) 15 2-n-Propyl-3-[4-(3-diethyl-aminopropyl)-oxy- 154 3,5-dibrom-benzoyl]-indolizin-hydrochlorid (80/20 ethylacetat/ - acetone) 2- Ethyl-3-[4-(3-di-n-butylaminopropyl)-oxy- 132-133 3- chlor-benzoyl]-indolizin-hydrochlorid (ethylacetat/iso- 20 propanol) 2- n-Butyl-3-[4-(3-di-n-butylaminopropyl)-oxy 104 3- chlor-benzoyl]-indolizin-hydrochlorid (ethylacetat) l-Brom-2-phenyl-3-[4-(3-di-n-butylaminopropyl)- 156-157 oxy-3-chlor-benzoyl]-indolizin-hydrochlorid 25 l-chlor-2-(4-chlor-phenyl)-3-[4-(3-di-n-pro- 168-169 pylaminopropyl)-oxy-benzoyl]-indolizin surt (methanol) oxalat l-Methoxy-2-phenyl-3-[4-(3-di-n-propylamino- 117 propyl)-oxy-benzoyl]-indolizin surt oxalat (ethylacetat) 30 l-Methoxy-2-phenyl-3-[4-(3-di-n-propylamino- 80 propyl)-oxy-benzoyl]-indolizin surt oxalat (ethylacetat) l-Methoxy-2-phenyl-3-[4-(3-di-n-propylamino- 172 propyl)-oxy-3-chlor-benzoyl]-indolizin surt (ethylacetat) oxalat 35 l-Methoxy-2-phenyl-3-[4-(3-di-n-butylamino- 120 propyl)-oxy-3-chlor-benzoyl]-indolizin surt (ethylacetat) oxalat 146977 30 l-Methoxy-2-phenyl-3-[4-(3-di-n-propylamino- 160 propyl)-oxy-3-brom-benzoyl]-indolizin surt (ethylacetat) oxalat l-Methoxy-2-phenyl-3-[4-(3-di-n-butylamino- 78 5 propyl)-oxy-3-brom-benzoyl]-indolizin surt (ethylacetat) oxalat l-Methoxy-2-phenyl-3-[4-(3-di-n-propylamino- 148 propyl)-oxy-3-methoxy-benzoyl]-indolizin surt (ethylacetat) oxalat 10 l-Methoxy-2-phenyl-3-[4-(3-di-n-butylamino- 78 propyl)-oxy-3-methoxy-benzoyl]-indolizin surt (ethylacetat) oxalat 1- Methoxy-2-(4-fluor-phenyl)-3-[4-(3-di-n-propyl- 79 aminopropyl) -oxy-3-methoxy-benzoyl] -indolizin surt oxalat (ethylacetat) 15 2-Methyl—3-[4-(3-di-n-butylaminopropyl)-oxy- 159 3-methoxy-benzoyl]-indolizin surt oxalat (isopropanol) 2- Methyl-3-[4-(3-di-n-propylaminopropyl)-oxy- 171 3- methoxy-benzoyl]-indolizin surt oxalat (methanol) 2-Ethyl-3-[4-(3-di-n-butylaminopropyl)-oxy- 88 20 3-methoxy-benzoyl]-indolizin surt oxalat (ethylacetat) 2- Ethyl-3-[4-(3-di-n-propylaminopropyl)-oxy- 121-122 3- methoxy-benzoyl]-indolizin surt oxalat (ethylacetat) l-Brom-2-methyl-3-[4-(3-di-n-butylaminopro- 87-90 pyl)-oxy-3-methoxy-benzoyl]-indolizin surt (benzen) 25 oxalat l-Brom-2-methyl-3-[4-(3-di-n-propylaminopro- 139-141 pyl)-oxy-3-methoxy-benzoyl]-indolizin surt (isopropanol) oxalat l-Brom-2-ethyl-3— [ 4- (3-di-n-butylaminopro- 111 30 pyl)-oxy-3-methoxy-benzoyl]-indolizin surt (benzen) oxalat 1- Brom-2-ethyl-3-[4-(3-di-n-propylaminopro- 149 pyl)-oxy-3-methoxy-benzoyl]-indolizin surt (isopropanol) oxalat 35 2-(4-Fluor-phenyl)-3-[4-(3-di-n-butylamino- 85 propyl)-oxy-3-methoxy-benzoyl]-indolizin surt (ethylacetat) oxalat 2- Methyl-3-[4-(3-di-n-butylaminopropyl)-oxy- 149 3- methyl-benzoyl]-indolizin surt oxalat (isopropanol) 146977 31 2- Ethyl-3-[4-(3-di-n-butylaminopropyl)-oxy- 133 3- methyl-benzoyl]-indolizin surt oxalat (ethylacetat) 1- Methyl-2-n-propyl-3-[4-(3-di-n-butylamino- 127 propyl)-oxy-3-brom-benzoyl]-indolizin surt (ethylacetat) 5 oxalat 2- Isopropyl-3-[4-(3-di-n-butylaminopropyl)- 91 oxy-3-methyl-benzoyl]-indolizin surt oxalat (isopropanol) 2- n-Butyl-3-[4-(3-di-n-butylaminopropyl)-oxy- 89 3- methyl-benzoyl]-indolizin surt oxalat (isopropanol) 10 l-Methyl-2-n-butyl-3-[4-(3-di-n-butylamino- 99 propyl)-oxy-3-brom-benzoyl]-indolizin surt (ethylacetat) oxalat l-Methyl-2-ethyl-3-[4-(3-di-n-butylaminopro- 117 pyl)-oxy-3-brom-benzoyl]-indolizin surt oxalat (ethylacetat) 15 l-Brom-2-methyl-3-[4-(3-di-n-butylaminopropyl)- 120-122 oxy-3,5-dimethyl-benzoyl]-indolizin surt oxa- (isopropanol) lat 1- Iod-2-ethyl-3-[4-(3-di-n-butylaminopropyl)- 115 oxy-3,5-dimethyl-benzoyl]-indolizin surt oxalat(ethylacetat) 20 2-Ethyl-3-(2,3-dichlor-4-(3-di-n-propylamino- 117 propyl)-oxy-benzoyl]-indolizin (heptan) 2- Ethyl-3-[2,3-dichlor-4-(3-di-n-butylamino- 95 propyl)-oxy-benzoyl]-indolizin (heptan) 2-Phenyl-3-[2,3-dichlor-4-(3-di-n-propyl- 99 25 aminopropyl)-oxy-benzoyl]-indolizin (heptan) 2-Phenyl-3-[2,3-dichlor-4-(3-di-n-butyl- 87 aminopropyl)-oxy-benzoyl]-indolizin (heptan) 2-(4-Fluor-phenyl)-3-[2,3-dichlor-4-(3-di-n- 119 propylaminopropyl)-oxy-benzoyl]-indolizin (heptan) 30 2-(4-Fluor-phenyl)-3-[2,3-dichlor-4-(3-di-n- 95-96 butylaminopropyl)-oxy-benzoyl]-indolizin (heptan) l-Brom-2-ethyl-3-[2,3-dichlor-4-(3-di-n- 164 butylaminopropyl)-oxy-benzoyl]-indolizin surt (isopropanol) oxalat 35 l-Brom-2-phenyl-3-[2,3-dichlor-4-(3-di-n-pro- 171 pylaminopropyl)-oxy-benzoyl]-indolizin surt oxalat (isopropanol) 1- Chlor-2-phenyl-3-[2,3-dichlor-4-(3-di-n- 136 propylaminopropyl)-oxy-benzoyl]-indolizin (heptan) 2- n-Butyl-3-[4-(3-di-n-butylaminopropyl)- 90-92 40 oxy-3-iod-benzoyl]-indolizin surt oxalat (ethylacetat)acid oxalate (ethyl acetate) 2- (4-Bromo-phenyl) -3- [4- (3-di-n-propylamino-174-propyl) -oxy-3,5-dichloro-benzoyl] -indolizine (ethyl acetate) acid oxalate 2- (4-Bromo-phenyl) -3- [4- (3-di-n-butylamino-133-propyl) -oxy-3,5-dichloro-benzoyl] -indolizine (ethyl acetate) acid oxalate 1-Bromine 2-methyl-3- [4- (3-di-n-butylaminopropyl-141-143-pyl) -oxy-3,5-dibromo-benzoyl] -indolizine acid (isopropanol) oxalate 1-Bromo-2-n- propyl 3- [4- (3-di-n-propylamino-138-139 propyl) -oxy-3,5-dibromo-benzoyl] -indolizine (isopropanol) acid oxalate 1-Bromo-2-ethyl-3- [ 4- (3-di-n-butylaminopropyl) - 131-132,5 oxy-3,5-dibromo-benzoyl] -indolizine acid oxalate (isopropanol) 1-Bromo-2-phenyl-3- [4- (3 -di-n-butylaminopro-160-161-pyl) -oxy-3,5-dibromo-benzoyl] -indolizine acid (isopropanol) oxalate 1-Bromo-2- (4-methyl-phenyl) -3- [4- ( 3-di-n-butyl-105-106-aminopropyl) -oxy-3,5-dibromo-benzoyl] -indolizine (isopropanol) acid oxalate 1-Bromo-2- (4-bromo-phenyl) -3- [4 - (3-di-n-butyl-148-149 aminopropyl) oxy-3,5-dibromo-benzoyl] -indolizine (isopropanol) acid oxalate 1-Bromo-2- (3,4-dichloro-phenyl) -3- [4- (3-di-n-196-197 butylaminopropyl) oxy-3,5-dibromo-benzoyl] - (isopropanol) indolizine acid oxalate 1-Bromo-2- (3-chloro-4-methyl-phenyl) -3- [4- (3- 168-169 di-n-butylaminopropyl) oxy-3,5-dibromo-benzo- ( isopropanol) yl] -indolizine acid oxalate 1-Bromo-2-ethyl-3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dichloro-benzoyl] -indolizine acid ( isopropanol) oxalate 1- Bromo-2-phenyl-3- [4- (3-di-n-propylaminopropyl) oxy-3,5-dichloro-benzoyl] -indolizine acid (ethyl acetate) oxalate 10-Bromo 2-phenyl-3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dichloro-benzoyl] -indolizine acid (ethyl acetate) oxalate 2- n-Butyl-3- [4 - (3-di-n-butylaminopropyl) oxy-113-113.5 3-bromo-benzoyl] -indolizine hydrochloride (ethyl acetate) 2-n-Propyl-3- [4- (3-diethyl-aminopropyl) -oxy-154 3,5-dibromo-benzoyl] -indolizine hydrochloride (80/20 ethyl acetate / acetone) 2- Ethyl-3- [4- (3-di-n-butylaminopropyl) oxy-132-133 3 - chloro-benzoyl] -indolizine hydrochloride (ethyl acetate / isopropanol) 2- n-butyl 3- [4- (3-di-n-butylaminopropyl) -oxy-104-3-chloro-benzoyl] -indolizine hydrochloride (ethyl acetate) 1-Bromo-2-phenyl-3- [4- (3-di-n- butylaminopropyl) 156-157 oxy-3-chloro-benzoyl] -indolizine hydrochloride 1-chloro-2- (4-chloro-phenyl) -3- [4- (3-di-n-pro-168-169 pylaminopropyl) -oxy-benzoyl] -indolizine acid (methanol) oxalate 1-Methoxy-2-phenyl-3- [4- (3-di-n-propylamino-117-propyl) -oxy-benzoyl] -indolizine acid oxalate (ethyl acetate ) 1-Methoxy-2-phenyl-3- [4- (3-di-n-propylamino-propyl) -oxy-benzoyl] -indolizine acid oxalate (ethyl acetate) 1-Methoxy-2-phenyl-3- [ 4- (3-di-n-propylamino-172-propyl) -oxy-3-chloro-benzoyl] -indolizine acid (ethyl acetate) oxalate 1-Methoxy-2-phenyl-3- [4- (3-di-n -butylamino-120-propyl) -oxy-3-chloro-benzoyl] -indolizine acid (ethyl acetate) oxalate 1-Methoxy-2-phenyl-3- [4- (3-di-n-propylamino-160-propyl) - oxy-3-bromo-benzoyl] -indolizine acid (ethyl acetate) oxalate 1-Methoxy-2-phenyl-3- [4- (3-di-n-butylamino-propyl) -oxy-3-bromo-benzoyl] -indolizine acid (ethyl acetate) oxalate l-Methox γ-2-phenyl-3- [4- (3-di-n-propylamino-148-propyl) -oxy-3-methoxy-benzoyl] -indolizine acid (ethyl acetate) oxalate 1-Methoxy-2-phenyl-3- [4- (3-di-n-butylamino-propyl) -oxy-3-methoxy-benzoyl] -indolizine acid (ethyl acetate) oxalate 1- Methoxy-2- (4-fluoro-phenyl) -3- [4- (3-di-n-propyl-79-aminopropyl) -oxy-3-methoxy-benzoyl] -indolizine acid oxalate (ethyl acetate) 2-Methyl-3- [4- (3-di-n-butylaminopropyl) -oxylate 159 3-Methoxy-benzoyl] -indolizine acid oxalate (isopropanol) 2- Methyl 3- [4- (3-di-n-propylaminopropyl) -oxy-171 3-methoxy-benzoyl] -indolizine acid oxalate (methanol) 2 -Ethyl-3- [4- (3-di-n-butylaminopropyl) oxy-88 3-methoxy-benzoyl] -indolizine acid oxalate (ethyl acetate) 2- Ethyl-3- [4- (3-di-n -propylaminopropyl) oxy-121-122 3-methoxy-benzoyl] -indolizine acid oxalate (ethyl acetate) 1-Bromo-2-methyl-3- [4- (3-di-n-butylaminopropyl-87-90-pyl) - oxy-3-methoxy-benzoyl] -indolizine acid (benzene) oxalate 1-Bromo-2-methyl-3- [4- (3-di-n-propylaminopropyl-139-141-pyl) -oxy-3-methoxy] benzoyl] -indolizine acid (isopropanol) oxalate 1-Bromo-2-ethyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-methoxy-benzoyl] -indolizine acid (benzene) oxalate 1- Bromo-2-ethyl -3- [4- (3-di-n-propylaminopropyl) oxy-3-methoxy-benzoyl] -indolizine acid (isopropanol) oxalate 2- (4-Fluoro-phenyl) -3- [4- (3-di-n-butylamino-propyl) -oxy-3-methoxy-benzoyl] -indolizine acid (ethyl acetate) oxalate 2- Methyl-3- [4- (3-di-n-butylaminopropyl) oxy-149 3-Methyl-benzoyl] -indolizine acid oxalate (isopropanol) 2- Ethyl 3- [4- (3-di-n-butylaminopropyl) oxy-133-methyl-benzoyl] -indolizine acid oxalate (ethyl acetate) 1- Methyl 2-n-propyl-3- [4- (3-di-n-butylamino-127-propyl) -oxy-3-bromo-benzoyl] -indolizine acid (ethyl acetate) oxalate 2- Isopropyl-3- [4- (3-di-n-butylaminopropyl) - 91 oxy-3-methyl-benzoyl] -indolizine acid oxalate (isopropanol) 2- n-Butyl-3- [4- (3-di-n-butylaminopropyl) - oxy-89 3-methyl-benzoyl] -indolizine acid oxalate (isopropanol) 1-Methyl-2-n-butyl-3- [4- (3-di-n-butylamino-99-propyl) -oxy-3-bromo -benzoyl] -indolizine acid (ethyl acetate t) Oxalate 1-Methyl-2-ethyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-bromo-benzoyl] -indolizine acid oxalate (ethyl acetate) 1-Bromo-2 -methyl-3- [4- (3-di-n-butylaminopropyl) - 120-122 oxy-3,5-dimethyl-benzoyl] -indolizine acid oxa (isopropanol) lat 1- iodo-2-ethyl-3- [4- (3-di-n-butylaminopropyl) - 115 oxy-3,5-dimethyl-benzoyl] -indolizine acid oxalate (ethyl acetate) 2-Ethyl-3- (2,3-dichloro-4- (3- di-n-propylamino-117-propyl) -oxy-benzoyl] -indolizine (heptane) 2- Ethyl-3- [2,3-dichloro-4- (3-di-n-butylamino-propyl) -oxy-benzoyl ] -indolizine (heptane) 2-Phenyl-3- [2,3-dichloro-4- (3-di-n-propyl-99-aminopropyl) -oxy-benzoyl] -indolizine (heptane) 2-Phenyl-3- [2,3-Dichloro-4- (3-di-n-butyl-87-aminopropyl) -oxy-benzoyl] -indolizine (heptane) 2- (4-Fluoro-phenyl) -3- [2,3-dichloro 4- (3-di-n-119-propylaminopropyl) -oxy-benzoyl] -indolizine (heptane) 2- (4-Fluoro-phenyl) -3- [2,3-dichloro-4- (3-di-n 95-96 butylaminopropyl) -oxy-benzoyl] -indolizine (heptane) 1-Bromo-2-ethyl-3- [2,3-dichloro-4- (3-di-n-164-butylaminopropyl) -oxy-benzoyl] -in ndolizine acid (isopropanol) oxalate 1-Bromo-2-phenyl-3- [2,3-dichloro-4- (3-di-n-propylaminopropyl) oxy-benzoyl] -indolizine acid oxalate (isopropanol) 1- Chloro-2-phenyl-3- [2,3-dichloro-4- (3-di-n-136-propylaminopropyl) -oxy-benzoyl] -indolizine (heptane) 2- n-Butyl-3- [4- (3-di-n-butylaminopropyl) - 90-92 oxy-3-iodo-benzoyl] -indolizine acid oxalate (ethyl acetate)

Claims (3)

1. Analogifremgangsmåde til fremstilling af indolizin-20 derivater med den almene formel X1 I i Ri V i 2 n x 0 hvori R betyder en ligekædet eller forgrenet alkylgruppe med 1-8 carbonatomer eller en phenylgruppe, som eventuelt er substitueret med en eller to ens eller forskellige substi- 146977 tuenter valgt blandt halogen, alkyl med 1-4 carbonatomer og alkoxy med 1-4 carbonatomer, X-^ betyder hydrogen, chlor, brom, lod, methyl eller methoxy, A betyder en gruppe med formlen X2 Cl ClAn analogous process for the preparation of indolizine derivatives of the general formula X1 I in R 1 V in 2 nx 0 wherein R represents a straight or branched alkyl group having 1-8 carbon atoms or a phenyl group optionally substituted by one or two identical or various substituents selected from halogen, alkyl of 1-4 carbon atoms and alkoxy of 1-4 carbon atoms, X1 represents hydrogen, chlorine, bromine, solute, methyl or methoxy, A represents a group of the formula X2 Cl1 5 R2 = eller E3 “ -O- X3 hvori betyder hydrogen, chlor, brom, iod, methyl eller methoxy, og X3 betyder hydrogen, chlor, brom, iod eller methyl, R^ betyder methyl, ethyl, n-propyl eller n-butyl, n er et helt tal på 2-6, idet dog,når både X2 og X^ betyder hydro-10 gen eller methyl, X-^ er forskellig fra hydrogen, eller farmaceutisk acceptable syreadditionssalte deraf, kendetegnet ved, at 1. en brom-alkoxy-benzoyl-indolizin med den almene formel X1 vv N-1 -C-A-0-(CHo) -Br (H) II 2 n o 15 hvori X^ R, A og n har de ovenfor angivne betydninger, kondenseres i et indifferent opløsningsmiddel med en sekundær amin med den almene formel /Rl H-N (III) Xri hvori R^ har den ovenfor angivne betydning, eller 20 2) et alkalimetalsalt af et indolizinderivat med den almene formel 146977 X1 VN_l -C-A-OH (IV) II 0 hvori R, A og X^ har de ovenfor angivne betydninger, kondenseres i et aprotisk opløsningsmiddel med et alkylaminoderivat med den almene formel ΛR 2 = or E 3 - -O-X 3 wherein hydrogen, chlorine, bromine, iodine, methyl or methoxy, and X 3 means hydrogen, chlorine, bromine, iodine or methyl, R 2 means methyl, ethyl, n-propyl or n butyl, n is an integer of 2-6, however, when both X 2 and X 2 represent hydrogen or methyl, X 1 is different from hydrogen, or pharmaceutically acceptable acid addition salts thereof, characterized in that 1. a bromo-alkoxy-benzoyl-indolizine of the general formula X1 vv N-1 -CA-O- (CHo) -Br (H) II 2 no 15 wherein X 1 R, A and n have the above meanings are condensed in a an inert solvent of a secondary amine of the general formula / R1 HN (III) X1 wherein R4 has the meaning given above, or 2) an alkali metal salt of an indolizine derivative of the general formula 146977 X1 VN_1 -CA-OH (IV) II 0 wherein R, A and X1 have the above meanings are condensed in an aprotic solvent with an alkylamino derivative of the general formula Λ 5 Z-(CH2)n"NC (V) *1 eller et syreadditionssalt deraf, hvori Z betyder et halogenatom eller en p-toluensulfonyloxygruppe, og n og R^ har de ovenfor angivne betydninger, eller 3. til fremstilling af et indolizinderivat med den almene for-10 mel I, hvori R, R^, n og A har de under formel (I) anførte betydninger, betyder chlor eller brom, og X2 og Xg har de under formel (I) anførte betydninger med undtagelse af hydrogen, et indolizinderivat med den almene formel ,.ν N_ -C-A-0- (CH0) -N iVI) V- II 2 n ne, O 15 hvori R, A, n og R^ har de ovenfor angivne betydninger, omsættes med a) N-chlorsuccinimid i et egnet medium ved en temperatur mellem 0°C og stuetemperatur til dannelse af det ønskede indolizinderivat, hvori X^ betyder chlor, i fri baseform, 20 eller med b) brom ved stuetemperatur i et egnet opløsningsmiddel og i nærværelse af et alkalimetalacetat til dannelse af det ønskede indolizinderivat, hvori X^ betyder brom,i fri baseform, 25 hvorpå den under 1), 2) eller 3) dannede forbindelse, om øn-Z- (CH2) n "NC (V) * 1 or an acid addition salt thereof, wherein Z represents a halogen atom or a p-toluenesulfonyloxy group and n and R4 have the meanings given above, or 3. to prepare an indolizine derivative having the general formula I, wherein R, R 2, n and A have the meanings given in formula (I), means chlorine or bromine, and X 2 and X g have the meanings given in formula (I) with the exception of hydrogen, an indolizine derivative of the general formula, wherein N is -CA-O- (CHO) -N iVI) V-II 2 n ne, O 15 wherein R, A, n and R 2 have the meanings given above are reacted with a) N-chlorosuccinimide in a suitable medium at a temperature between 0 ° C and room temperature to form the desired indolizine derivative, wherein X 1 represents chlorine, in free base form, or with b) bromine at room temperature in a suitable solvent and in the presence of a alkali metal acetate to form the desired indolizine derivative, wherein X ^ represents bromine, in free base form, whereupon it forms under 1), 2) or 3) orbitation, if desired
DK521980A 1979-12-06 1980-12-05 METHOD OF ANALOGUE FOR THE PREPARATION OF INDOLIZIN DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS. DK146977C (en)

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