SE441926B - INDOLICINE DERIVATIVES, PROCEDURES FOR PREPARING THEREOF AND PHARMACEUTICAL COMPOSITION - Google Patents
INDOLICINE DERIVATIVES, PROCEDURES FOR PREPARING THEREOF AND PHARMACEUTICAL COMPOSITIONInfo
- Publication number
- SE441926B SE441926B SE8008444A SE8008444A SE441926B SE 441926 B SE441926 B SE 441926B SE 8008444 A SE8008444 A SE 8008444A SE 8008444 A SE8008444 A SE 8008444A SE 441926 B SE441926 B SE 441926B
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- Prior art keywords
- indolizine
- oxy
- benzoyl
- bromo
- methyl
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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
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- 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
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- 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
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- 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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- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Cardiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
Description
soos444-5 vari R betecknar en grenad eller rak alkylradikal med 1-8 kolatomer, *eller en fenylgrupp, osubstituerad eller med en eller tva sub- stituenter som kan vara samma eller olika och valda från halogen- atomer och lägre alkyl- och alkoxigrupper, X1 är klor, brom, jod, metyl eller metoxi, X2 är väte, klor, brom, jod, metyl eller metoxi, X3 är väte, klor, brom, jod eller metyl och 4 är väte, klor, brom eller jod. wherein R represents a branched or straight chain alkyl radical having 1-8 carbon atoms, * or a phenyl group, unsubstituted or having one or two substituents which may be the same or different and selected from halogen atoms and lower alkyl and alkoxy groups, X1 is chlorine, bromine, iodine, methyl or methoxy, X2 is hydrogen, chlorine, bromine, iodine, methyl or methoxy, X3 is hydrogen, chlorine, bromine, iodine or methyl and 4 is hydrogen, chlorine, bromine or iodine.
Indolizinderivaten enligt uppfinningen har visat sig ha användbara farmakologiska egenskaper, som gör dem värdefulla vid behandling av vissa patologiska hjärtsyndrom, särskilt för behandling av an- gina pectoris och aurikulära och ventrikulära hjärtarytmier av olika ursprung.The indolizine derivatives of the invention have been found to have useful pharmacological properties which make them valuable in the treatment of certain pathological heart syndromes, in particular for the treatment of angina pectoris and auricular and ventricular cardiac arrhythmias of various origins.
Föreliggande uppfinning avser också farmaceutiska och veterinärme- dcinska kompositioner innehållande som aktiv beståndsdel åtminsto- ne ett indolizinderivat med formeln I eller ett farmaceutiskt god- tagbart, surt additionssalt därav samman med någon farmaceutisk bärare eller något utdrygningsmedel.The present invention also relates to pharmaceutical and veterinary compositions containing as active ingredient at least one indolizine derivative of the formula I or a pharmaceutically acceptable, acidic addition salt thereof together with any pharmaceutical carrier or excipient.
Ett annat ändamål med föreliggande uppfinning är att åstadkomma ett _sätt att framställa farmaceutiska eller veterinärmedicinska kompo- sitioner, varvid minst ett indolizinderivat med formeln I eller ett farmaceutiskt godtagbart, surt additionssalt därav är förbundet med en farmaceutisk bärare eller ett utdrygningsmedel.Another object of the present invention is to provide a method of preparing pharmaceutical or veterinary compositions, wherein at least one indolizine derivative of the formula I or a pharmaceutically acceptable acid addition salt thereof is linked to a pharmaceutical carrier or excipient.
Ytterligare ett ändamål med uppfinningen är att åstadkomma en be-_ handlingsmetod för patologiska hjärtsyndrom och särskilt angina pectoris och hjärtarytmier vid behov av dylik behandling. Behand- lingsmetoden består i administrering av en effektiv dos av minst ett indolizinderivat med formeln I eller ett farmaceutiskt godtag- bart, surt additionssalt därav.A further object of the invention is to provide a method of treatment for pathological heart syndromes and in particular angina pectoris and cardiac arrhythmias in need of such treatment. The method of treatment consists in administering an effective dose of at least one indolizine derivative of the formula I or a pharmaceutically acceptable acid addition salt thereof.
Den dagliga dosen är företrädesvis från 100 till 300 mg aktiv be- ståndsdel oralt och företrädesvis 1 - 3 mg aktiv beståndsdel paren- 8008444~5 teralt för en kroppsvikt på 60 kg.The daily dose is preferably from 100 to 300 mg of active ingredient orally and preferably 1 to 3 mg of active ingredient parenterally for a body weight of 60 kg.
Föreningarna med formeln I kan enligt föreliggande uppfinning fram» ställas genom att a) en bromalkoxi-bensoyl-indolizin med den generella formeln X »\ gav H \ N----<|:l-A1-o- (CHZ) n-Br vari R och n har den ovan angivna betydelsen, X5 är väte, klor, brom, jod, metyl eller metoxi, och A1 är en grupp vald från X6 cl cl R _ fl7_í\_ _ /~ššm vari X6 är väte, klor, brom, jod, metyl eller metoxi och X be- 7 tecknar väte, klor, brom, jod eller metyl, kondenseras i ett inert lösningsmedel med en sekundär amin med den generella formeln H~N III vari R1 har samma betydelse som ovan, till att bilda det önskade indOlizinderivatet, eller b) ett alkalimetallsalt av ett indolizinderlvat med den generel- la formeln 8008444-5 a. ,N~-~---?~c-A -OH _ IV ' n ' vari R, A1 och X5 har samma betydelse som ovan, kondenseras i ett aprotiskt lösningsmedel med ett alkylaminoderi- vat med den generella formeln v e / i z-(cHQn-N \ v eller ett syraadditionssalt därav, vari Z betecknar en halogenatom eller en p-toluensulfonyloxigrupp och n och R har samma betydelse som ovan, 1 till det önskade indolizinderivatet, eller c) ett indolizinderivat med den generella formeln ,¿ g/ R I / RT v: l\/N-~ c-Afoflcnyn-N ll X o R1 vari R, A1, n och R1 har den ovan angivna betydelsen, reageras Ä) antingen med N-klorsuccinimid, varvid reaktionen sker i ett lämpligt medium och mellan OOC och rumstemperatur till det oönskade indOlizinderivatet, vari X5 betecknar klor, i form av den fria basen, eller _H) med brom eller jod, varvid reaktionen sker vid rumstemperatur "i något lämpligt lösningsmedel och i närvaro av ett alkalime- tallacetat till det önskade indolizinderivatet, vari X5 be- tecknar brom eller jod, i form av den fria basen, 8008444-5 ln varvid om så önskas den fria basen kan reageras med en organisk eller oorganisk syra till ett farmaceutiskt godtagbart syraaddi- tionssalt.The compounds of formula I can be prepared according to the present invention by: a) a bromoalkoxy-benzoyl-indolizine of the general formula X »\ gave H \ N ---- <|: 1-A1-o- (CHZ) n- Br wherein R and n have the meaning given above, X5 is hydrogen, chlorine, bromine, iodine, methyl or methoxy, and A1 is a group selected from X6 cl cl R _ fl7_ í \ _ _ / ~ ššm wherein X6 is hydrogen, chlorine , bromine, iodine, methyl or methoxy and X represents hydrogen, chlorine, bromine, iodine or methyl, condensed in an inert solvent with a secondary amine of the general formula H ~ N III wherein R1 has the same meaning as above, to to form the desired indolizine derivative, or b) an alkali metal salt of an indolizine derivative of the general formula 8008444-5 a., N ~ - ~ ---? ~ cA -OH _ IV 'n' wherein R, A1 and X5 have the same meaning as above, is condensed in an aprotic solvent with an alkylamino derivative of the general formula ve / i z- (cHQn-N \ v or an acid addition salt thereof, wherein Z represents a halogen atom or a p-toluene ulphonyloxy group and n and R have the same meaning as above, 1 to the desired indolizine derivative, or c) an indolizine derivative of the general formula, ¿g / RI / RT v: l \ / N- ~ c-Afo fl cnyn-N ll X o R1 wherein R, A1, n and R1 have the meaning given above, E) is reacted either with N-chlorosuccinimide, the reaction taking place in a suitable medium and between 0 ° C and room temperature to the undesired indOlizine derivative, wherein X5 represents chlorine, in the form of the free the base, or _H) with bromine or iodine, the reaction taking place at room temperature "in any suitable solvent and in the presence of an alkali metal acetate to the desired indolizine derivative, wherein X5 represents bromine or iodine, in the form of the free base, 8008444 Wherein, if desired, the free base can be reacted with an organic or inorganic acid to a pharmaceutically acceptable acid addition salt.
Föreningarna med formeln II kan fås genom att man. lämpligen i något inert medium såsom exempelvis aceton eller metyletylketon, kondenserar ett alkalimetallsalt, företrädesvis kalium- eller nat- riumsaltet av en förening med formeln IV ovan med en dibromalkan med den generella formeln Br~(CH2)n-Br VII vari n har samma betydelse som i formeln I till den önskade föreningen med formeln II.The compounds of formula II can be obtained by. suitably in some inert medium such as, for example, acetone or methyl ethyl ketone, an alkali metal salt, preferably the potassium or sodium salt of a compound of formula IV above condenses with a dibromalkane of the general formula Br ~ (CH 2) n -Br VII wherein n has the same meaning as in formula I to the desired compound of formula II.
Föreningarna med formeln IV, vari A1 betecknar gruppen R2, är an- tingen föreningar, som beskrives i den svävande brittiska patent- ansökan 80 21924 ingiven den 4 juli 1980, eller föreningar, som kan framfställas enligt de metoder, som beskrivas i denna patent- ansökan.The compounds of formula IV, wherein A1 represents the group R 2, are either compounds described in floating British patent application 80 21924 filed on July 4, 1980, or compounds which can be prepared according to the methods described in this patent. application.
De andra föreningarna med formeln IV, dvs de, i vilka A1 beteck- nar gruppen R3, kan fås genom att reagera den lämpliga 2-substitu- erade indolizinen med 2,3-diklor-4-acetyloxi- eller 4-to yloxi- -bensoyklorid.The other compounds of formula IV, i.e. those in which A1 represents the group R3, can be obtained by reacting the appropriate 2-substituted indolizine with 2,3-dichloro-4-acetyloxy- or 4-tolyloxy- benzoic chloride.
Detta bensoylkloridderivat självt framställes genom acetylering av 1,2-diklor-anisol eller FRIEDEL-CRAFTS reaktion, oxidation av det erhållna acetylderivatet med natriumhypoklorit till motsva- rande bensoesyraderivat, demetylering med jodvätesyra i ättiksy- ra till 2,3-diklor-4-hydroxibensoesyra.This benzoyl chloride derivative itself is prepared by acetylation of 1,2-dichloro-anisole or FRIEDEL-CRAFTS reaction, oxidation of the obtained acetyl derivative with sodium hypochlorite to the corresponding benzoic acid derivative, demethylation with hydroiodic acid in acetic acid-4-hydroxyacrylic acid to 2,3-dichloroic acid .
Denna sistnämnda förening reageras sedan med acetylklorid eller tosylklorid till den önskade 2,3-diklor-4-aeetyloxi- eller 4-to- syloxi-bensoesyran och den motsvarande acylkloriden bildas sedan enligt kända metoder, exempelvis genom reaktion med tionylklorid. 6 8008444-5 Föreningarna med formeln II faller inom ramen för formeln I ovan.This latter compound is then reacted with acetyl chloride or tosyl chloride to give the desired 2,3-dichloro-4-aethyloxy or 4-tosyloxy-benzoic acid and the corresponding acyl chloride is then formed by known methods, for example by reaction with thionyl chloride. The compounds of formula II fall within the scope of formula I above.
Indolizinderivat är tidigare kände, som har farmakologiska effekter, som gör dem användbara för behandling av angina pecto- ris och hjärtarytmier.Indolizine derivatives are previously known, which have pharmacological effects, making them useful for the treatment of angina pectoris and cardiac arrhythmias.
I samband härmed kan nämnas GB-PS 1 518 445, som mera detalje- rat beskriver 2-etyl-5-¿'4-(5-di-n-butylaminopropyl)-oxi-ben- soyl_7-indolizin, som är känd under namnet butoproàin. I den brittiska patentskriften hänföres de antianginala egenskaperna till de däri beskrivna föreningarna, emedan de ger följande kardiovaskulära effekter: - bradykardia, minskning av blodtrycket, a-antiadrenergisk. effekt, 3-antiadrenergisk effekt och koronadilatering.In this connection, mention may be made of GB-PS 1 518 445, which describes in more detail 2-ethyl-5-β- (5-di-n-butylaminopropyl) -oxy-benzoyl-7-indolizine, which is known under namnet butoproàin. In the British patent specification, the antianginal properties are attributed to the compounds described therein, since they give the following cardiovascular effects: bradycardia, reduction of blood pressure, α-antiadrenergic. effect, 3-antiadrenergic effect and coronary dilatation.
Den ökning av blodströmningen till myokardium, som åstadkommas med dessa föreningar, är emellertid endast svag, då deras verkan icke är långvarig utan sker endast ett fåtal minuter efter en intravenös injektion. 7 Vidare har de i den brittiska patentskriften beskrivna förening- arna endast en svag ß-adrenergisk antagonistverkan. Denna ver- ' kan är endast svag vid den minimumdos, vid vilken de andra fyra ovan angivna kardiovaskulära effekterna gör sig gällande i väsentlig utsträckning. ' Det'har nu helt överraskande visat sig, att genom substituering av dialkylaminoalkyloxibensoylindolizinderivat på lämpligt sätt med en eller flera metyl- eller metoxigrupper eller halogenato- _ mer, exempelvis klor, brom eller jod, fås föreningar, som ger ett mycket bredare spektrum av kardiovaskulära egenskaper och med mindre toxicitet än derivaten enligt den brittiska patent- skriften 1 518 445. ' Sålunda har det varit möjligt att visa, att indolizinderivaten enligt uppfinningen kan betraktas som kraftiga koronadilatorer, då de har förmågan att öka blodströmningen till myokardium i markant utsträckning och under längre tid än butoprozin. Före-, ningar enligt uppfinningen visade sig även minska hjärtfrekven- 800844445 7 sen och blodtrycket hos djur.However, the increase in blood flow to the myocardium produced by these compounds is only slight, as their action is not long lasting but occurs only a few minutes after an intravenous injection. Furthermore, the compounds described in the British patent specification have only a weak β-adrenergic antagonist effect. This effect is only weak at the minimum dose at which the other four above-mentioned cardiovascular effects are present to a significant extent. It has now quite surprisingly been found that by substituting dialkylaminoalkyloxybenzoylindolizine derivatives in a suitable manner with one or more methyl or methoxy groups or halogen atoms, for example chlorine, bromine or iodine, compounds are obtained which give a much wider range of cardiovascular properties and with less toxicity than the derivatives of British Patent Specification 1,518,445. Thus, it has been possible to show that the indolizine derivatives of the invention can be considered as potent coronadilators, as they have the ability to significantly increase blood flow to the myocardium and below longer than butoprozine. Compounds of the invention have also been shown to reduce heart rate and blood pressure in animals.
Vidare har indolizinderivaten en mycket kraftigare ß-antiadre-s nergisk effekt än derivaten enligt den brittiska patentskriften.Furthermore, the indolizine derivatives have a much stronger ß-antiadrenergic effect than the derivatives according to the British patent specification.
Vid den minimidos, som erfordras för att ge bradykardia, en minskning av blodtrycket, a-antiadrenergiska och koronadilate- rande effekter i signifikant grad, blir den ß-antiadrenergiska effekten i själva verket endast obetydlig vid derivaten enligt den brittiska patentskriften, medan den blir mycket starkare med indolizínderivaten enligt uppfinningen.At the minimum dose required to give bradycardia, a reduction in blood pressure, α-antiadrenergic and coronadilating effects to a significant degree, the ß-antiadrenergic effect is in fact only insignificant in the derivatives according to the British patent specification, while it becomes very stronger with the indolizine derivatives of the invention.
-Vidare minskar föreningarna enligt uppfinningen myokardiums förbrukning av syre beräknad ur skillnaden i syrehalt mellan arteriellt och venöst blod hos kranskärlens blodströmning.Furthermore, the compounds according to the invention reduce the myocardial's consumption of oxygen calculated from the difference in oxygen content between arterial and venous blood of the coronary blood flow.
Till skillnad mot butoprozin fås vidare dessa fördelaktiga effekter på syreförbrukningen med föreningarna enligt uppfin- ningen utan någon minskning av myokardiums kontraktionsförmàga.In contrast to butoprozine, these beneficial effects on oxygen consumption are obtained with the compounds according to the invention without any reduction in the contractility of the myocardium.
Det har vidare visats, att derivaten enligt uppfinningen är mindre giftiga än föreningarna enligt den brittiska patentskrif- ten 1 518 445. Akuta toxicitetsprov gjorda intravenöst och oralt på djur har visat, att de letala doserna är högre för föreningar enligt uppfinningen än för derivaten enligt den brit- tiska patentskriften.It has further been shown that the derivatives of the invention are less toxic than the compounds of British Patent Specification 1,518,445. Acute toxicity tests performed intravenously and orally on animals have shown that the lethal doses are higher for compounds of the invention than for the derivatives of the invention. British patent.
Vidare kan högre blodnivåer fås med föreningar enligt uppfin- ningen än med butoprozin. Sålunda har det visats, att samma orala dos av 1-brom-2-metyl-5-[-4-(3-di-n-butylaminopropyl)- -oxi-5-brom-bensoyl_7-indolizin och butoprozín till hundar ger en blodnivâ, som är tre gånger högre med föreningen enligt upp- finningen än med butoprozin. Likaledes har föreningarna enligt uppfinningen vid långtidsbehandling med givning genom munnen till hundár icke.visat någon kardisk toxicitet såsom ventri- kulär arytmi, vilket icke är fallet med butoprozin.Furthermore, higher blood levels can be obtained with compounds of the invention than with butoprozine. Thus, it has been shown that the same oral dose of 1-bromo-2-methyl-5 - [- 4- (3-di-n-butylaminopropyl) -oxy-5-bromo-benzoyl-7-indolizine and butoprozine in dogs gives a blood level, which is three times higher with the compound according to the invention than with butoprozine. Similarly, the compounds of the invention in long-term oral administration to dogs have not shown any cardiac toxicity such as ventricular arrhythmia, which is not the case with butoprozine.
Slutligen har indolizinderivaten enligt uppfinningen en mildare undertryckande verkan på myokardiums kontraktionsförmåga än butoprozin. íw sooe444-s 8 För människor är en attack av angina pectoris den smärtsamma d följden av en skillnad mellan myokardiums syretillförsel och_ syrebehov. 7En förening kan sålunda vara aktiv vid behandling. av_angina_pectoris antingen genom att öka syretillförseln eller» genom att minska syrebehovet. Bland de produkter, som allmänt användes i humanmedicinen för behandling av angina pectoris,-g kan nämnas dipyrídamol bland koronadilatorerna och amiodaron bland de föreningar; som minskar myokardiums syreförbrukning.Finally, the indolizine derivatives of the invention have a milder suppressive effect on the contractility of myocardium than butoprozine. íw sooe444-s 8 For humans, an attack of angina pectoris is the painful consequence of a difference between myocardial oxygen supply and oxygen demand. Thus, a compound may be active in treatment. av_angina_pectoris either by increasing the oxygen supply or »by reducing the oxygen demand. Among the products commonly used in human medicine for the treatment of angina pectoris, -g may be mentioned dipyridamole among the coronadilators and amiodarone among those compounds; which reduces myocardial oxygen consumption.
Jämförande försök har emellertid visat, att föreningarna enligt- uppfinningen är mycket överlägsna dipyridamol och amiodaron ur flera synpunkter; lßärskílt har det visats, att dipyridamol içke minskar myokardiums syreförbrukning och att amiodaron icke- ' kan betraktas som en koronadílator§ Derivaten enligt föreliggande uppfinning verkar genom båda_dessa faktorer;: Sålunda-minskar"de myokardiums syreförbrukningigenomi sina metaboliska effekter och ökar även kranskärlens blodsträm- ning pà ett långvarigt sätt. Vidare kan de förebygga eller bota *ej endast arytmier framkallade av ischemi hos myokardium utan även aurikulära oçh.ventrikulära arytmier av vitt skilda orsaker, Det-framgår sålunda, att halogeneringen, metoxyleringen eller metyleringen av indolizinderiaten enligt den brittiska patent- skriften 1 518f445~ger föreningar med ett nytt spektrum av far- makológiska egenskaper värdefulla vid behandling av hjärtdefek-' ter. ' T.ex,; - de ställen av myokardium, som är otillräckligt försörjda, kand ges näring med hjälp av koronadilatationseffekten, som kan 'bidraga till att framkalla en_ytterligare kollateralcirkula- _tídn: -Dennafieffekt är värdefnll för behandlingen av såväl anginal smärta som rytmstårningar beroende på ischemi i myo- kardium. I i “i ät 1' I ïw i i i i" i -- »Den antiadrenergiska effekten är också värdefull för behand- n1ing'av'både angina pectoris och hjärtarytmi med hänsyn till den viktiga roll hyperaktiviteten i det sympatetiska systemet 8008444-5 9 spelar för orsakerna till dessa tvâ hjärtàkommor.However, comparative experiments have shown that the compounds of the invention are very superior to dipyridamole and amiodarone from several points of view; In particular, it has been shown that dipyridamole does not reduce myocardial oxygen consumption and that amiodarone cannot be considered a coronadilator. The derivatives of the present invention act through both of these factors; thus reducing the myocardial oxygen consumption through their metabolic effects and also increasing blood flow. Furthermore, they can prevent or cure * not only arrhythmias induced by ischemia of myocardium but also auricular and ventricular arrhythmias for a wide variety of reasons. It is thus apparent that the halogenation, methoxylation or methylation of the brinolytic patent according to the The document 1 518f445 provides compounds with a new range of pharmacological properties valuable in the treatment of heart defects. For example, those sites of myocardium which are insufficiently supplied can be nourished by the coronadilation effect, which can 'contribute to the development of a further collateral circle- _tídn: -This fi effect is valuable for the treatment of both anginal pain and arrhythmias due to ischemia in the myocardium. The antiadrenergic effect is also valuable for the treatment of both angina pectoris and cardiac arrhythmia, given the important role that hyperactivity in the sympathetic system 8008444-5 9 plays for the causes of these two heart conditions.
Då den fysiologiska förmedlaren för det sympatetíska systemet är epinefrin, är förmodligen en förening, som inhiberar alla epi- nefrins verkningar, mera aktiv än en förening som endast inhibe- rar en del av dessa effekter. Av detta skäl är föreningarna enligt föreliggande uppfinning, som inhiberar både a- och ß- effekterna av epinefrin, ett framsteg framför derivaten enligt den brittiska patentskriften 1 518 445, som praktiskt taget en- dast inhiberar u-effekterna vid den minimidos, vid vilken de övriga, farmakologiska, kardiovaskulära effekterna inträder.Since the physiological mediator of the sympathetic system is epinephrine, a compound which inhibits all the effects of epinephrine is probably more active than a compound which inhibits only some of these effects. For this reason, the compounds of the present invention, which inhibit both the α- and β-effects of epinephrine, are an advance over the derivatives of British Patent Specification 1,518,445, which practically only inhibit the u-effects at the minimum dose at which they other, pharmacological, cardiovascular effects occur.
Bland de föreningar enligt uppfinningen, som visat de bästa anti- anginala verkningarna, kan nämnas följande: 1-brom-2_metyl-5-[_4-(5-di-n-butylaminopropyl)-oxi-5-brom- -bensoyl_7-indolizin 2-n-butyl-5-¿"4-(5-di-n-butylaminopropyl)-oXi-5-brom-bensoyl7- -indolizín 2-etyl-5-¿"4-(5-di-n-butylaminopropyl)-oxí-5~klor-bensoyl7- -indolizin 2-n-butyl-5-¿"4-(5-di-n-butylaminopropyl)-oxi-5-k1or-bensoyl7- -indolizin 2-isopropyl-5-¿"4-(5-di-n-butylamínopropyl)-oxi-5,5~diklor- 4bensoyl7-indolizin 4~brom~2-fenyl-5-¿'4-(5-di~n-butylaminopropyl)-oxi-5-klor- -bensoyl7-indolizin 1-klor_2_etyl-5-[-4-(5-di-n-butylaminopropyl)-oxi~5-klor- -bensoyl7-indolizin 1»klor-2-n-butyl-5-¿"4-(5-di-n-butylaminopropyl)-oxi-bensoyl7- -indolizin 4-brom-2_(4-klor-fenyl)-5-¿"4~(5-di~n-butylaminopropyl)-oxi-5- -klor-bensoyl7-indolizin.Among the compounds of the invention which have shown the best anti-anginal effects may be mentioned the following: 1-bromo-2-methyl-5 - [- 4- (5-di-n-butylaminopropyl) -oxy-5-bromo-benzoyl-7-indolizine 2-n-butyl-5-β "4- (5-di-n-butylaminopropyl) -oxy-5-bromo-benzoyl-7-indolizine 2-ethyl-5-β" 4- (5-di-n-butylaminopropyl ) -oxy-5-chloro-benzoyl-7-indolizine 2-n-butyl-5- [4- (5-di-n-butylaminopropyl) -oxy-5-chloro-benzoyl] -indolizine 2-isopropyl-5- 4- (5-di-n-butylaminopropyl) -oxy-5,5-dichloro-4-benzoyl-7-indolizine 4-bromo-2-phenyl-5-[4- (5-di-n-butylaminopropyl) -oxy -5-chloro-benzoyl-7-indolizine 1-chloro-2-ethyl-5 - [- 4- (5-di-n-butylaminopropyl) -oxy-5-chloro-benzoyl-7-indolizine 1 »chloro-2-n-butyl-5 4- (5-di-n-butylaminopropyl) -oxy-benzoyl-7-indolizine 4-bromo-2- (4-chloro-phenyl) -5- -4- (5-di-n-butylaminopropyl) - oxy-5-chloro-benzoyl-7-indolizine.
Dessa föreningar kan vara i form av den fria basen eller av ett farmaceutiskt godtagbart, surt additionssalt, såsom exempelvis hydrokloriden eller det sura oxalatet. 8-008444-5 Resultaten av farmakologiska prov gjorda för att bestämma de kardiovaskulära egenskaperna hos föreningarna enligt uppfinningen angíves nedan. d BI. Antianginala egenskaper Ü iïëä<ïàåšë°fllsïfëlíïlíåfêšlíilä Hiêffiïëlëfl; Detta prov gjordes enligt den teknik, som beskrivas av R,Char- lier & J, Bauthier i Arzneimittel - Forschun "Drug Research" d , Dr 19, 1505-1541 (1975).These compounds may be in the form of the free base or of a pharmaceutically acceptable acid addition salt, such as, for example, the hydrochloride or the acid oxalate. 8-008444-5 The results of pharmacological tests performed to determine the cardiovascular properties of the compounds of the invention are set forth below. d BI. Antianginal properties Ü iïëä <ïàåšë ° fl lsïfëlíïlíåfêšlíilä Hiêf fi ïëlëfl; This test was performed according to the technique described by R, Charles & J, Bauthier in Arzneimittel - Forschun "Drug Research" d, Dr 19, 1505-1541 (1975).
Provet gjordes pà sövda hundar, som fick substansen intravenöst under observation. Intensiteten för den maximala effekten pâ_ blodströmningen till myokardium uttrycktes i procent av mot- B svarande värde före injektion. Den tid, som erfordrades för' den maximala effekten att minska med 50 %, representerade effek- tens varaktighet. Denna tid mättes i minuter. Följande resul- tat registrerades: - X1 X2 i / / -B i a /R1 I C._ / \ _0_(0H2)n_11 _ \ _" __* /. \R1 0 X1 X2 X5 R B10 r Dos, Max. ök- mia för mg/ ning, % minsk- kg ning till 59 %, min.The test was performed on anesthetized dogs, which received the substance intravenously during observation. The intensity of the maximal effect on blood flow to the myocardium was expressed as a percentage of the corresponding value before injection. The time required for the maximum effect to decrease by 50% represented the duration of the effect. This time was measured in minutes. The following results were recorded: - X1 X2 i / / -B ia / R1 I C._ / \ _0_ (0H2) n_11 _ \ _ "__ * /. \ R1 0 X1 X2 X5 R B10 r Dose, Max. - billion for mg / ning,% reduction- kg to 59%, min.
Br Br B 02115 nrqflg 5 10 60 i 90 Br Br H 0115' r-cqsg 5 10 125 40, Br Br H rrctpng recšfl? 5 10 100 20 Br Br H' mean? nv-cšn? 5 10 90 20 Br Br H _® frrcšn? 5 10 100 20 8008444-5' 11 X X X. R R n ïios 'Max. Tid för 1 2 j I] Ung/ä ining, % fninsk- kg ' ning till á I 50 9á,m1'_n. 1 Br i I 1 H1 Br H _© n-C4H9 10 i 150 100 H H1 H ~//_\\~H1 ~ 1004H9 5 10 90 25 \-/ _ 1 i : H1 H1 H 0H3 1004H9 5 M0 77 45 H H15 H 1005H7 10c4H9 5 2 = 120 25 Br H 11_04H9 1004119 5 5 70 60 B1- 01 H 1s<005H7 10041195 5 '155 20 01 H H 1004H9 10041195 10 60 50 H 01 01 1S1005H7 1004119 5 10 50 75 H 01 01 _@_H1 1004119 5- 10 45 15 H Cl Cl íso-Cšíí? n-C4H9 5 10 50 75 Br H 01 H _Ö 1004H9 5 10 50 45 Br H 01 H -Ö 1005117 5 s 45 25 H 01 H 111005117 1005117 5 5 ao 90 H1 01 H _® 1004119 5 10 90 90 H1 01 H 1004119 1005117 5 10 40 90 H1- 01 H -/ \-H1~ 10051175 10 50 '50 H 01 H 1004119 1004119 5 5 75 50 I sooa444~5 12 X4' X2 X R R1 Dos, Max. ök- Tid för H H mg/ ning; % minsk- kg ning till 50 %,min.Br Br B 02115 nrq fl g 5 10 60 i 90 Br Br H 0115 'r-cqsg 5 10 125 40, Br Br H rrctpng recš fl? 5 10 100 20 Br Br H 'mean? nv-cšn? 5 10 90 20 Br Br H _® frrcšn? 5 10 100 20 8008444-5 '11 X X X. R R n ïios' Max. Time for 1 2 j I] Ung / ä ining,% fninsk- kg 'ning to á I 50 9á, m1'_n. 1 Br i I 1 H1 Br H _ © n-C4H9 10 i 150 100 H H1 H ~ // _ \\ ~ H1 ~ 1004H9 5 10 90 25 \ - / _ 1 i: H1 H1 H 0H3 1004H9 5 M0 77 45 H H15 H 1005H7 10c4H9 5 2 = 120 25 Br H 11_04H9 1004119 5 5 70 60 B1- 01 H 1s <005H7 10041195 5 '155 20 01 HH 1004H9 10041195 10 60 50 H 01 01 1S1005H7 1004119 5 10 50 75 H 01 01 _ @ _H1 1004119 5- 10 45 15 H Cl Cl íso-Cšíí? n-C4H9 5 10 50 75 Br H 01 H _Ö 1004H9 5 10 50 45 Br H 01 H -Ö 1005117 5 s 45 25 H 01 H 111005117 1005117 5 5 ao 90 H1 01 H _® 1004119 5 10 90 90 H1 01 H 1004119 1005117 5 10 40 90 H1- 01 H - / \ -H1 ~ 10051175 10 50 '50 H 01 H 1004119 1004119 5 5 75 50 I sooa444 ~ 5 12 X4 'X2 XR R1 Dos, Max. increase- Time for H H mg / ning; % reduction kg to 50%, min.
H Cl H 02115 H_C4H9 6 70 45 Br cl H _ / \_c1 n_c5H7 flo e; 45 H G1 H nQ-Br 11414119 10 ao 25 Br Cl H¶ n-C5H7 n¿C4H9 2,5 50 60 Br c1 c1 H -/ \\ rncšn? a 70 90 Cl Cl H C2H5 n-C4H9 > 7 40 15 G1 01 H 02115 n-CEH? 5,5 60 _25 01 H H _®¿c1_ n-CEH? 5 50 40 Butoprozin 10 120 4 Amiodaron 40 56 7 Dessa resultat visar klart, att föreningarna enligt uppfinningen är bättre än butoprozin och amiodaron med hänsyn till effekterna på blodströmningen till myokardíum. 2) Antiadrenergiska effekter. Ändamålet med detta prov var att bestämma de ifrågavarande före- ningarnas förmåga att reducera epinefrin-ökat blodtryck, anti- -u~effekt,och epínefrin-accelererad hjärthastighet, anti-ß-effekt, Anti-a-effekt I på hundar, som sövts med pentobarbital och fått atropin. 80Ü8444~5 45 För varje hund bestämdes först den dos epínefrin, som gav en re- producerbar ökning av det arteriella trycket med omkring 100 mm Hg, mellan 5 och 10 /ug/kg.H Cl H 02115 H_C4H9 6 70 45 Br cl H _ / \ _c1 n_c5H7 fl o e; 45 H G1 H nQ-Br 11414119 10 ao 25 Br Cl H¶ n-C5H7 n¿C4H9 2,5 50 60 Br c1 c1 H - / \\ rncšn? a 70 90 Cl Cl H C2H5 n-C4H9> 7 40 15 G1 01 H 02115 n-CEH? 5.5 60 _25 01 H H _®¿c1_ n-CEH? 5 50 40 Butoprozine 10 120 4 Amiodarone 40 56 7 These results clearly show that the compounds of the invention are better than butoprozine and amiodarone in view of the effects on blood flow to the myocardium. 2) Antiadrenergic effects. The purpose of this test was to determine the ability of the compounds of the compounds to reduce epinephrine-increased blood pressure, anti-u-effect, and epinephrine-accelerated heart rate, anti-ß-effect, Anti-a-effect I in anesthetized dogs with pentobarbital and given atropine. For each dog, the dose of epinephrine was first determined, which gave a reproducible increase in arterial pressure by about 100 mm Hg, between 5 and 10 / ug / kg.
Därefter gavs den så bestämda epinefrindosen àtföljt av en intra- venös dos av den förening, som studerades, Den procentuella sänkningen av hypertensionen genom föreningen jämfört med den tidigare erhållna hypertensíonen, omkring 400 mm Hg, registrera- des.Thereafter, the thus determined epinephrine dose was given followed by an intravenous dose of the compound studied. The percentage reduction in hypertension by the compound compared with the previously obtained hypertension, about 400 mm Hg, was recorded.
Anti-g-effekt Under samma prov som beskrivits ovan àstadkom epinefrinet en re- producerbar ökning av hjärthastígheten med omkring 70 slag/min.Anti-g effect During the same test as described above, the epinephrine achieved a reproducible increase in heart rate by about 70 beats / min.
Den procentuella minskningen av den epinefrininducerade ökningen av hjärthastigheten med den undersökta föreningen jämfört med den tidigare uppmätta, ökade hjärtverksamheten, omkring 70 slag, registrerades sedan, I båda fallen uttrycktes resultaten på följande sätt: 0 + för en < 50-procentig minskning av ökningen i tryck eller hjärtfrekvens, ++ för en 2,50-procentig minskning av ökningen i tryck eller hjärtfrekvens, +++ för en subtotal minskning av ökningen i tryck eller hjärt- frekvens.The percentage decrease in the epinephrine-induced increase in heart rate with the test compound compared to the previously measured, increased heart rate, about 70 beats, was then recorded. In both cases, the results were expressed as follows: 0 + for a <50% decrease in pressure or heart rate, ++ for a 2.50% decrease in pressure or heart rate, +++ for a subtotal decrease in increase in pressure or heart rate.
Följande resultat erhölls: fX1f Xzf X5: R = R1 f nf Dos, 3 Anti- fAnti- ° ° ' f f I I mg/kg: -a-effekt I-ß-effekt fBTf Brf H f' C2H5 f 11474519 f šf 40 f +++ z +++ fBrf H f H fC2H5 3 n-C4H9 f Öf 6 f +++ f +++ a . n I U n - o '_14 soos444-5 n. 2 .- .r ¿1 2 .- .f + + nu »I I Z 1J HO) nænw nu I .- _ 2 .- .. .. .. .u .. .. .. .. .n .e .. a. .. .. .. .. .n .u HHHHfi +++++ .. .. .. u. u. .o .o 32/53. .. ~. .. .n .. .. .u .. 9 7 9 H Hu. HBK... m. n 4 4 n n n n nwz .nw nu/ nu/ H1... H...The following results were obtained: fX1f Xzf X5: R = R1 f nf Dose, 3 Anti-fAnti- ° ° 'ff II mg / kg: -a-effect I-ß-effect fBTf Brf H f' C2H5 f 11474519 f šf 40 f +++ z +++ fBrf H f H fC2H5 3 n-C4H9 f Öf 6 f +++ f +++ a. n IU n - o '_14 Soos444-5 n. 2 .- .r ¿1 2 .- .f + + nu »IIZ 1J HO) nænw nu I .- _ 2 .- .. .. .. .u. .. .. .. .n .e .. a. .. .. .. .. .n .u HHHH fi +++++ .. .. .. uu .o .o 32/53. .. ~. .. .n .. .. .u .. 9 7 9 H Hu. HBK ... m. N 4 4 n n n n nwz .nw nu / nu / H1 ... H ...
H244H3 CnnC .. .. .. .o .o .n .n nn» WH» ”un nu ..o .. .n .. .s .n .a rrrr BBBB "uu "uu "nu _ .o .o .. .u .n .n .a HH ¿| .T .. .. ..H244H3 CnnC .. .. .. .o .o .n .n nn »WH» ”un nu ..o .. .n .. .s .n .a rrrr BBBB" uu "uu" nu _ .o. o .. .u .n .n .a HH ¿| .T .. .. ..
C/ nv 1. l\r\.\ n-CuI-íg nH%ul h. 4 n "HM ' i-~F í-4-4- Cl .. .. .- Fuf. “mv I n| na. . .. .. .. 1-4- 4--F 102 o. o. .n o. .. + + w + fnu _). "uu "ua ~|+ nu .|¿ nu _.. 4“4- 1 C . u wnn W. ".“ 4--F ++' Anu nu I.- II ~fiJ nam/ n.w"~. nu .., .- o. .o Cl .o .n .. .- .f ¿. .v .T .r ~fi4 OI nä "n%u1 fi¶n7 nu .. .. _ . Il II 1. nu .. .- »Å “nu .. .. o.C / nv 1. l \ r \. \ N-CuI-íg nH% ul h. 4 n "HM 'i- ~ F í-4-4- Cl .. .. .- Fuf.“ Mv I n | na.. .. .. .. 1-4- 4 - F 102 oo .n o. .. + + w + fnu _). "uu" ua ~ | + nu. | ¿nu _ .. 4 “ 4- 1 C. U wnn W. ".“ 4 - F ++ 'Anu nu I.- II ~ fi J nam / nw "~. Nu .., .- o. .O Cl .o .n .. .- .f ¿. .v .T .r ~ fi4 OI nä "n% u1 fi¶ n7 nu .. .. _. Il II 1. nu .. .- »Å“ nu .. .. o.
H n-Cšñ? .o .. .. .. ¿. .f .. .- nu .I .. .- 2/ .. .. nnw/| nwïl n .. .. m _ _ .. .. .. .. .|* nu .. .. w. _ .. .. o. o. oo .o ..H n-Cšñ? .o .. .. .. ¿. .f .. .- nu .I .. .- 2 / .. .. nnw / | nwïl n .. .. m _ _ .. .. .. ... | * nu .. .. w. _ .. .. o. o. oo .o ..
L. ¿| .. o.L. ¿| .. o.
.Y + .. ...Y + .. ..
Anu All ~nJ .o .u AH4 unu n4wu| nu -Cl .o aa .. .- 1; nu .. .- w.Anu All ~ nJ .o .u AH4 unu n4wu | nu -Cl .o aa .. .- 1; nu .. .- w.
.Hu .. .. o. 4>í-4- 1-1'4' nu nl .. ...Hu .. .. o. 4> í-4- 1-1'4 'nu nl .. ..
~«J 9 n-Cqlí .. .. -/ nnw/Q nu "uu .. .- m. nu .. .. w. nn”. .. .- ïBr fa =Br :Br :Cl fcl :Cl fcl :Cl- fc1 :H ïBr :Cl fcl :Cl fel :Br ïBr :Br íCl n o: nu a; n u» oo n n n eu Cl Cl Cl Cl Cl Cl : Br z ocfl Cl fcl u nu n en n Br Br Cl ju :CH w II II O! II I! n n no n u nu u u nu n n av oo u :CH DI u n D! I I! O! II II I! I OI II I! Il Il I I I \N “J å: _ '1 . n - i JT' Ii \O n n-CH n-C3H7 - .. .. .- O 211 . n u n u n-Cqflg n: .. ..l. N Û “' å: |- . n-Czlí? s Å: |-' n-cuflg f I n-CBH? i I n-C H ' : ll-Å::3ɶ17 3 III w- .z Eš n: å: Cl: cl: \ / n-Cgflg H i 02115 n-chngï Br -© 1143117: “å “ßfvš cl; -® j n-chug: \N u ro n u u n n n o: '10 0.5 jlñ ïvø -vä u en nu u n n u n: oo n n u u oo oo n u n ou u: n av u u vu u o: n n av u n .o n u av nu 'åÛ08444'-5 +++ : : ++ z +++ : : +++ _ . : +++ : +++ ' 2 +++ z +++ ' 2 ++ : +++ ' +~+-F g +~i- = ++ g : +++ : 2 +++ g + : : ++ ¿ ++ g : +++ .~ «J 9 n-Cqlí .. .. - / nnw / Q nu" uu .. .- m. Nu .. .. w. Nn ”. .. .- ïBr fa = Br: Br: Cl fcl: Cl fcl: Cl- fc1: H ïBr: Cl fcl: Cl fel: Br ïBr: Br íCl no: nu a; nu »oo nnn eu Cl Cl Cl Cl Cl Cl: Br z oc fl Cl fcl u nu n en n Br Br Cl ju: CH w II II O! II I! nn no nu nu uu nu nn av oo u: CH DI un D! II! O! II II I! I OI II I! Il Il III \ N “J å: _ '1. N - i JT' Ii \ O n n-CH n-C3H7 - .. .. .- O 211. Nunu n-Cq fl g n: .. ..l. N Û “'å: | -. N -Czlí? S Å: | - 'n-cu fl g f I n-CBH? I I nC H': ll-Å :: 3ɶ17 3 III w- .z Eš n: å: Cl: cl: \ / n -Cg fl g H i 02115 n-chngï Br - © 1143117: “å“ ßfvš cl; -® j n-chug: \ N u ro nuunnno: '10 0.5 jlñ ïvø -vä u en nu unnun: oo nnuu oo oo nun ou u: n av uu vu uo: nn av un .onu av nu 'åÛ08444'-5 +++:: ++ z +++:: +++ _.: +++: +++' 2 ++ + z +++ '2 ++: +++' + ~ + -F g + ~ i- = ++ g: +++: 2 +++ g +:: ++ ¿++ g: ++ +.
. ++I +++ : +++ ++ ß : + . . 1-1--P I ' 4-4- +++ 'P+ ++ ++ ++- 4~í-1- ++ ++ ++ gu no nu »- n o: n u n nu u n n co n o: co co n au av u n co u u u n u soos444-5 u u n n n u n a. n u u o- CH CH CH CH Br l-»IbJbJb-ï CH CH CH CH CH3 CH3 CH Br :OCH :ocH =ocn šocn Br Br Cl |.~J w UJ :OCH Qcn =cH la! U) LGUJ CH k» Br 1 Br Br Br CH3 CH3 CH 1 Br I Br :cl I Br Br E 5 W I I S W I I E W W u n u u n .- u u n- u no u u u n n n u u u o- m I N G I u n n. u u n n v n u n n u n n n u n u n n u u. iso-CSH7 n-C4H9 16 u n n u u n u. n n u nu u n u u ¿ n-C H .. n 1 n-C H : n-C H n-C3H7 n-C4H9 n-C3H7 n-C3H7 n-C439 n-C4H9 n-C4H9 n-C3H7 4 9 1 n-C4H9 n-CÅHQ n-CAH9 n-C4H9 4 9 n-C4H9 n-C4H9 4 9 1 n-C H 4 9 n-C3H7 n-C4H9 n-C3H7 n-C4H9 2 nrC H u n n» u n u n u; u n u 3 7 n~C4H9 n-C4H9 n-C3H7 n-C4H9 n-CÅH9 u n n 0 -ßLnb-IUJLQ UJUJUIWWWWWUJWUIWLDLAILQ u u n n n» n u u n n u u u n . n u u u u u u n u u u 8.76 6.3 I +++ I +++ _ +++ 2 ++ 2 Z+++Z u n n u n - ++2 +++ ++ ++ ++ ++ I +++ +++ ++ +4- 3 +++ n n u +++ ++ +++ I +++ 2 ++ I 2 +++ I ++ I 2 +++ I I+++I ++ :+++-l I +++ I +++ I ++ 2 +++ 2 ++2 ++f ++ : ++f ++ : : ++ _ +++ : +++ 3 ++ : ++ ++ I +++ ++ 2 +++ ' +++ : + f ++ I ++ 2 +++ I +++ I ++ f ++ : ++f +++ : ++ 1 -< l = : 17 - . . _ i Br I sr = u ï -Q-ocua = n-cáug = 3 = 10 Ä ++ Ä + 2 “ Ef I f ß f m2 +¥ -¥ : H : Br : Br f _ /í_ø*\ -ocna i n-cang š 3 E 10 Ä + 2 + Q : : = Br 2 : : ; 2 2 i Br i BI' H å - i n-C4H9 å 3 i 10 i +++ E 4.4. i X1 Cl Cl // -R R1 N _ _ _ _ _ / , \ E 0 (CH2)nN\ 0 R 1 2 X1 2 R : R1 : n : Dose f Anti u 3 Anti 8 f , , =_ , , (ms/kat . effekt j effekt j i Br 3 CZHS i n-C4H9 3 3 i 3 å +++ ; +++ 2 i H 3 n-C¿H9 3 n-CAH9 : 3 f 10 E ++ _ï ++ ; .i Br f n-CÅHQ i n-C4H9 f 3 3 10 3 ++ : + 2 i H - n-C¿H9 3 g 10 g + + Butoprozin 5 +++ + ++ ++ Amiodaron Dessa resultat visar åter, att föreningarna enligt uppfin- ningen är bättre än de tidigare.. ++ I +++: +++ ++ ß: +. . 1-1 - PI '4-4- +++' P + ++ ++ ++ - 4 ~ í-1- ++ ++ ++ gu no nu »- no: nun nu unn co no: co co n au av un co uuunu Soos444-5 uunnnun a. nuu o- CH CH CH CH Br l- »IbJbJb-ï CH CH CH CH CH3 CH3 CH Br: OCH: ocH = ocn šocn Br Br Cl |. ~ J w UJ : AND Qcn = cH la! U) LGUJ CH k »Br 1 Br Br Br CH3 CH3 CH 1 Br I Br: cl I Br Br E 5 WIISWIIEWW unuun .- uu n- u no uuunnnuuu o- m INGI un n. Uunnvnunnunnnununnu u. Iso-CSH7 n- C4H9 16 unnuun u. Nnu nu unuu ¿nC H .. n 1 nC H: nC H n-C3H7 n-C4H9 n-C3H7 n-C3H7 n-C439 n-C4H9 n-C4H9 n-C3H7 4 9 1 n-C4H9 n-CÅHQ n-CAH9 n-C4H9 4 9 n-C4H9 n-C4H9 4 9 1 nC H 4 9 n-C3H7 n-C4H9 n-C3H7 n-C4H9 2 nrC H unn »ununu; u n u 3 7 n ~ C4H9 n-C4H9 n-C3H7 n-C4H9 n-CÅH9 u n n 0 -ßLnb-IUJLQ UJUJUIWWWWWUJWUIWLDLAILQ u u n n n »n u u n n u u u n. nuuuuuunuuu 8.76 6.3 I +++ I +++ _ +++ 2 ++ 2 Z +++ Z unnun - ++ 2 +++ ++ ++ ++ ++ I +++ +++ ++ + 4- 3 +++ nnu +++ ++ +++ I +++ 2 ++ I 2 +++ I ++ I 2 +++ I I +++ I ++: +++ - l I +++ I +++ I ++ 2 +++ 2 ++ 2 ++ f ++: ++ f ++:: ++ _ +++: +++ 3 ++: ++ ++ I +++ ++ 2 +++ '+++: + f ++ I ++ 2 +++ I +++ I ++ f ++: ++ f +++: ++ 1 - <l = : 17 -. . _ i Br I sr = u ï -Q-ocua = n-cáug = 3 = 10 Ä ++ Ä + 2 “Ef I f ß f m2 + ¥ - ¥: H: Br: Br f _ / í_ø * \ - ocna i n-cang š 3 E 10 Ä + 2 + Q:: = Br 2::; 2 2 i Br i BI 'H å - i n-C4H9 å 3 i 10 i +++ E 4.4. i X1 Cl Cl // -R R1 N _ _ _ _ _ /, \ E 0 (CH2) nN \ 0 R 1 2 X1 2 R: R1: n: Dose f Anti u 3 Anti 8 f,, = _, , (ms / cat. effect j effect ji Br 3 CZHS i n-C4H9 3 3 i 3 å +++; +++ 2 i H 3 nC¿H9 3 n-CAH9: 3 f 10 E ++ _ï ++ ; .i Br f n-CÅHQ i n-C4H9 f 3 3 10 3 ++: + 2 i H - nC¿H9 3 g 10 g + + Butoprozine 5 +++ + ++ ++ Amiodarone These results again show, that the associations according to the invention are better than the previous ones.
II. Anti-arytmiska egenskaper Dessa egens ifrâgavaran test, J. Pharmac. Exp. Therap. 1968, kaper visades efter intragastrisk administrering av de förening till möss med användning av Lawson's 160 (1) Bídy. 22-31. 8-8G8444-r5 t '18 _ Arytmin âstadkoms genom att låta djuren inandas Kloroform till total asfyxí och därvid observera den ventrikulära rytmen. Den dos av föreninoen, som skyddade 50 t av djuren mot ventríku- lärt flimmer. dvs. ADSO, noterades. Följande resultat er- hölls. ßr nr H C113 n-c4ag 3 180 g H Bro š H š n-C4H9 n-CÅH-g 3 I; 170 Bra cuä oss C113 n-chug 3 < 100 ' 1 _ C113 m3 czus šn-c4u9 3 100 Butoprozin _ 270 III. Toxicitet èkBtJ=9Xi<=it§t Prover:på akut toxicitet gjordes på råttor/möss. Följande re- sultat registrerades i jämförelse med butaprozin. Föreningarna enligt uppfinningen användes i form av sura oxalat förutom de med (x) markerade, som provades i hydrokloridform. a) Intravenös givning till råttor X1 X2 X3 R Ri n fLDSO (mg/kg)f : H : Br : H f : nrC4H9 : n-C489 : : 60 : f (x) u f c1 f n šczns šn-cang 2 š es j H Cl Cl V íso-C3H7 n-Cbflg V3 > 100 Ä (a) n: Ä c1 Ä H Ä -® Ä n-cáng Ä Ä > 1oo Ä = (a) H i c1 i n i 11-0439- i 311-04119 i 3 i > 50' } i f j j a j a j j :uno > somg/kç) f cl i G1 i H :czfls ~ :“'°4H9 3 5° l” 19 3 Cl É H f H 3 n-C4H9 3 n-C4H9 3 : Br : cl : H : -<<::::>>-c1 : n-cang Butøprozin b) Intravenös givning till möss: É (1) Br 3 Br H I CH3 3 n-säng . 3 H CH3 H E n~C¿H9 f n-CSH7 i 3 CH3 3 Br f H i n-C4H9 3 n-CSH7 3 Butoprozin c) Intragastrisk givning till Inöss E (2) Br É Br H = CH3 f n-c4H9 3 Butoprozín 8008444-5 5O > 100 _ =(LDo> 1oomg/kg) 22 50 - u : > 5000 f(Ln0>5ooomg/kg) 1600 8008444-5 Dessa resultat visar, att föreningarna enligt uppfinningen är mycket mindre giftiga än butoprozin.II. Anti-arrhythmic properties These properties are the test in question, J. Pharmac. Exp. Therap. 1968, caper was shown after intragastric administration of the compound to mice using Lawson's 160 (1) Bídy. 22-31. 8-8G8444-r5 t '18 _ Arrhythmia is achieved by allowing the animals to inhale Chloroform to total asphyxia, thereby observing the ventricular rhythm. The dose of the compound, which protected 50 t of the animals against ventricular fibrillation. i.e. ADSO, noted. The following results were obtained. ßr nr H C113 n-c4ag 3 180 g H Bro š H š n-C4H9 n-CÅH-g 3 I; 170 Bra cuä oss C113 n-chug 3 <100 '1 _ C113 m3 czus šn-c4u9 3 100 Butoprozin _ 270 III. Toxicity èkBtJ = 9Xi <= it§t Tests: in acute toxicity were performed in rats / mice. The following results were recorded in comparison with butaprozine. The compounds of the invention were used in the form of acid oxalates in addition to those marked with (x), which were tested in hydrochloride form. a) Intravenous administration to rats X1 X2 X3 R Ri n fLDSO (mg / kg) f: H: Br: H f: nrC4H9: n-C489:: 60: f (x) uf c1 fn šczns šn-cang 2 š es j H Cl Cl V íso-C3H7 n-Cb fl g V3> 100 Ä (a) n: Ä c1 Ä H Ä -® Ä n-cáng Ä Ä> 1oo Ä = (a) H i c1 ini 11-0439- i 311 -04119 i 3 i> 50 '} ifjjajajj: uno> somg / kç) f cl i G1 i H: cz fl s ~: “' ° 4H9 3 5 ° l” 19 3 Cl É H f H 3 n-C4H9 3 n- C4H9 3: Br: cl: H: - << :::: >> - c1: n-cang Butøprozin b) Intravenous administration to mice: É (1) Br 3 Br HI CH3 3 n-bed. 3 H CH3 HE n ~ C¿H9 f n-CSH7 i 3 CH3 3 Br f H i n-C4H9 3 n-CSH7 3 Butoprozine c) Intragastric administration to Inöss E (2) Br É Br H = CH3 f n-c4H9 Butoprozine 8008444-5 5O> 100 _ = (LDo> 1oomg / kg) 22 50 - u:> 5000 f (Ln0> 5ooomg / kg) 1600 8008444-5 These results show that the compounds of the invention are much less toxic than butoprozine .
Hjärttolerans och generell toxicitet vid långvariga toxicitets- BEg¥='"_-=-=====:==:===:===================:=:=:=:=::==::::':=:==== 1-brom-2-metyl-3-¿'4-(5-di-n-butylaminopropyl)-oxi-5-brom- -bensoyl7-indolizin-hydroklorid, 2-n-butyl-5-¿_4-(5-di-n-butyl- aminopropyl)-cxí-5-brom-bensoyl7-indo1izin-hydroklorid och 2-n- -butyl-5-[_4-(5-di-n-butylaminopropyl)-oxi-Z-klor-bensoyl7-indo- lízin-hydroklorid åstadkom varken ventrikulär arytmi eller morta- litet vid en dosering av 200 mg/kg/dag vid oral administrering till hundar.Cardiac tolerance and general toxicity in case of prolonged toxicity- BEg ¥ = '"_- = - =====: ==: ===: ==================: =: =: =: = :: == :::: ': =: ==== 1-bromo-2-methyl-3-β'- (5-di-n-butylaminopropyl) -oxy-5 -bromo- -benzoyl-7-indolizine hydrochloride, 2-n-butyl-5-β- (5-di-n-butyl-aminopropyl) -xi-5-bromo-benzoyl-7-indolizine hydrochloride and 2-n- butyl 5 - [- 4- (5-di-n-butylaminopropyl) -oxy-Z-chloro-benzoyl] -indolizine hydrochloride did not cause ventricular arrhythmia or mortality at a dose of 200 mg / kg / day orally administration to dogs.
Däremot visade sig butoprozin åstadkomma ventrikulär arytmi med så låg dos som 50 mg/kg/dag vid oral givning till hundar, och den dödliga dosen av denna förening var mellan 50 och 100 mg/kg/dag; Det skall noteras, att för terapeutisk användning administreras föreningarna enligt uppfinningen normalt i form av en farmaceu- tisk eller veterinärmedicinsk komposition, som kan vara i form av en enhetsdos lämplig för det önskade administrationssättet.In contrast, butoprozine was found to cause ventricular arrhythmias as low as 50 mg / kg / day when administered orally to dogs, and the lethal dose of this compound was between 50 and 100 mg / kg / day; It should be noted that for therapeutic use, the compounds of the invention are normally administered in the form of a pharmaceutical or veterinary composition, which may be in the form of a unit dose suitable for the desired mode of administration.
Sålunda kan defarmaceutiska eller veterinärmedicinska komposi- tionen vara i form av en enhetsdos lämplig för oral administre- ring, exempelvis en överdragen eller oglaserad tablett, en hård eller mjuk gelatinkapsel, ett förpackat pulver eller en diskret mängd av en suspension eller en sirap. Kompositionen kan alter- nativt ha formen av ett suppositorium för rektal administrering eller av en lösning eller suspension för parenteral administre- ring.Thus, the defamatory or veterinary composition may be in unit dosage form suitable for oral administration, for example, a coated or unglazed tablet, a hard or soft gelatin capsule, a packaged powder or a discrete amount of a suspension or syrup. The composition may alternatively be in the form of a suppository for rectal administration or of a solution or suspension for parenteral administration.
I enhetsdosform kan kompositionen innehålla exempelvis frân 45 till 50 vikt-% av den aktiva beståndsdelen per enhetsdos för oral administrering, från 5 till 15 vikt-% av den aktiva be- ståndsdelen per enhetsdos för rektal administrering och från 5 till 5 vikt-% av den aktiva bestàndsdelen per enhetsdos för parenteral administrering.In unit dosage form, the composition may contain, for example, from 45 to 50% by weight of the active ingredient per unit dose for oral administration, from 5 to 15% by weight of the active ingredient per unit dose for rectal administration and from 5 to 5% by weight of the active ingredient per unit dose for parenteral administration.
Oberoende av kompositionens form framställes den farmaceutiska 8Û08444~5 21 eller veterinärmedicinska kompositíonen enligt uppfinningen nor- malt genom att blanda minst en av föreningarna med formeln I eller något farmaceutiskt godtagbart surt addítionssalt därav med någon lämplig, farmaceutisk bärare eller utdrygníngsmedel, exempelvis ett eller flera av följande ämnen: mjölksocker, stärkelse, talk, magnesiumstearat, polyvinylpyrrolidon, algin- syra, kolloidal kiseldioxíd, destillerat vatten, bensylalkohol eller smakämnen.Regardless of the form of the composition, the pharmaceutical or veterinary composition of the invention is normally prepared by mixing at least one of the compounds of formula I or some pharmaceutically acceptable acid addition salt thereof with any suitable pharmaceutical carrier or excipient, for example one or more excipients. the following substances: milk sugar, starch, talc, magnesium stearate, polyvinylpyrrolidone, alginic acid, colloidal silica, distilled water, benzyl alcohol or flavoring substances.
Följande exempel illustrerar uppfinningen: Exempel 1 4-brom-2_etyl-5-¿"4-(5-di-n-propylaminopropyl)-oxi~5-brom- -bensgyl7-indolizin och dess sura oxalat. a) 4-brom-2-etyl-5-['4-(5-brompropyl)~oxi-bensoyl7-indolizin En blandning av 7,7 g, 0,018 mol, 1~brom-5-(5-brom-4-hydroxi- -bensoyl)-indolizin, 5 S, 0,056 mol, vattenfritt kaliumkarbonat och 50 ml metyletylketon omrördes i en kolv i 50 min, Till detta reaktíonsmedium tillsattes sedan 14,4 g, 0,072 mol, 1,5-dibrom- -propan och blandningen àterflödeskokades i 20 timmar, Efter avkylning avfiltrerades mineralsalterna och tvättades med aceton.The following examples illustrate the invention: Example 1 4-bromo-2-ethyl-5- [4- (5-di-n-propylaminopropyl) -oxy-5-bromo-benzyl] -indolizine and its acid oxalate. A) 4-bromo- 2-Ethyl-5 - [4- (5-bromopropyl) -oxy-benzoyl] -indolizine A mixture of 7.7 g, 0.018 mol, 1-bromo-5- (5-bromo-4-hydroxy-benzoyl) indolizine, 5 S, 0.056 mol, anhydrous potassium carbonate and 50 ml of methyl ethyl ketone were stirred in a flask for 50 minutes. To this reaction medium was then added 14.4 g, 0.072 mol, of 1,5-dibromo-propane and the mixture was refluxed for 20 hours. After cooling, the mineral salts were filtered off and washed with acetone.
Lösningsmedlen avdrevs tillsammans med överskottet av 1,3-dibrom- propan. Pâ detta sätt erhölls 15,2 g av en produkt, som renades genom elueringskromatografi på kiselsyragel med bensen som elue~ ringsmedel. En första fraktion av en okänd produkt erhölls och sedan en andra fraktion pà 8 g av den önskade produkten. På så sätt erhölls 1-brom_2_etyl-5-[-4-(5-brompropyl)-oxi-bensoyl7- -indolizin med ett utbyte på 83,6 %. Smältpunkt: 405-10600. b) 1-brom-2-etyl-5-¿'4-(5-di-n-propylaminopropyl)-oxi-5-brom- -bensoyl7-indolízin En blandning av 2,2 g, 0,004 mol,1-brom-2-etyl-5-¿'4-(5-brompro- pyl)-oxi-bensoyl7-indolizin, 1,2 g, 0,012 mol, di-n-propylamin och 25 ml toluen àterflödeskokades i en kolv i 20 timmar, Efter kylning tvättades reaktionsmediet två gånger med 10 ml vatten och lösningsmedlet avdrevs i vakuum. På så sätt erhölls 2,5 g av en återstod, som renades genom elueringskromatografi på kiseldioxid med etylacetat som elueringsmedel. Med denna metod erhölls 8008444-5 22 2,4 g 1-brom~2-etyl-3-¿'4-(5-di-n-propylaminopropyl)-oxi-5-brom- -bensoyl7~indolizin i form av fri bas. 1 c) 1-brom-2-etyl-5-[-4-(5-di-n-propylaminopropyl)-oxi-5-brom- -bensoylï-indolizinväteoxalat Den tidigare erhållna basen löstes i 50 ml etyleter och reagera- des sedan med 0,55 5 oxalsyra i 70 ml etyleter till att ge 2,4 g av det önskade saltet i rå form. Från denna mängd erhölls 2,0 g ren 1-brom-2-etyl-5-¿'4-(3-di-n-propylaminopropyl)-oxi-5-brom- -bensoyl7-indolizinväteoxalat genom omkristallisation ur 75 ml isopropanol. Utbytet var 75 % och smältpunkten 159-14000.The solvents were evaporated together with the excess 1,3-dibromopropane. In this way, 15.2 g of a product were obtained, which was purified by elution chromatography on silica gel with benzene as eluent. A first fraction of an unknown product was obtained and then a second fraction of 8 g of the desired product. There was thus obtained 1-bromo-2-ethyl-5 - [- 4- (5-bromopropyl) -oxy-benzoyl] -indolizine in a yield of 83.6%. Melting point: 405-10600. b) 1-Bromo-2-ethyl-5-β- (5-di-n-propylaminopropyl) -oxy-5-bromo-benzoyl-7-indolizine A mixture of 2.2 g, 0.004 mol, 1-bromo -2-ethyl-5- [4- (5-bromopropyl) -oxy-benzoyl] -indolizine, 1.2 g, 0.012 mol, di-n-propylamine and 25 ml of toluene were refluxed in a flask for 20 hours, After cooling, the reaction medium was washed twice with 10 ml of water and the solvent was evaporated in vacuo. There was thus obtained 2.5 g of a residue, which was purified by elution chromatography on silica using ethyl acetate as eluent. By this method, 800 g of 1-bromo-2-ethyl-3- [4- (5-di-n-propylaminopropyl) -oxy-5-bromo-benzoyl] -indolizine were obtained in the form of free base. 1 c) 1-Bromo-2-ethyl-5 - [- 4- (5-di-n-propylaminopropyl) -oxy-5-bromo-benzoyl] -indolizine hydrogen oxalate The previously obtained base was dissolved in 50 ml of ethyl ether and reacted then with 0.55 oxalic acid in 70 ml of ethyl ether to give 2.4 g of the desired salt in crude form. From this amount, 2.0 g of pure 1-bromo-2-ethyl-5- [4- (3-di-n-propylaminopropyl) -oxy-5-bromo-benzoyl] -indolizine hydrogen oxalate was obtained by recrystallization from 75 ml of isopropanol. The yield was 75% and the melting point 159-14000.
Exemgel 2 1-brom-2-metyl-5-¿"4-(5-di-n-butylaminopropyl)-oxi-š-brom- -bensoyl7-indolizin och salter därav I en 1 1 kolv satsades under omröring en blandning av 180 ml vat- ten, 180 ml toluen, 73 g, 0,178 mol, 1-brom-2-metyl-5-(5~brom-4- -hydroxi-bensoyl)~indolizin, 42,7 g, 0,21 mol, 1-di-n-butylamino- -5-klorpropan och 54,5 g kaliumkarbonat. Reaktionsmediet upphet- tades under återflöde i 20 timmar. Efter kylning till rumstempe- ratur dekanterades vattenfasen och toluenskiktet tvättades tre gånger, varje gång med 200 ml vatten. Toluenlösningen överfördes till en kolv och toluen avdestillerades till torrhet vid atmosfäre- tryck och den så erhållna återstoden kyldes. På detta sätt er- hölls rå 1_brom~2-metyl-3-¿"4-(5-di-n-butylaminopropyl)-oXi-5- -brom-bensoyl7-indolizin i form av fri bas. Följande salter av denna förening framställdes: a) hydroklorid Till den tidigare erhållna fria basen tillsattes en lösning av 8 g saltsyra i 61 ml etylacetat. Den så bildade fëllningen, dvs. 104 g, vakuumfiltrerades, tvättades med etylacetat och omkristal- liserades ur 500 ml isopropanol§ På detta sätt erhölls 93 g 1- -brom-2-metyl-5-¿"4-(5-di~n-butylaminopropyl)-oxí-5~brom-bensoyl7- -ina011zinnyar0k1@r1a. Utbyte: 84,7 %, sms: 172%, b) väteoxalat 8008444-5 23 Till en eterlösning av den tidigare erhållna basen tillsattes en ekvimolekylär lösning av oxalsyra i etyleter. Det så erhållna saltet omkristalliserades ur isopropanol. Pà detta sätt erhölls 1-brom-2-metyl~5-¿_4-(5-di-n~butylaminopropyl)-oxi-5-brom- -bensoyy-inaolizinväteoxaiat med smp. a9_9o°c.Example 2 2-Bromo-2-methyl-5-β "4- (5-di-n-butylaminopropyl) -oxy-β-bromo-benzoyl-7-indolizine and salts thereof In a 1 L flask, a mixture of 180 ml water, 180 ml toluene, 73 g, 0.178 mol, 1-bromo-2-methyl-5- (5-bromo-4-hydroxy-benzoyl) -indolizine, 42.7 g, 0.21 mol 1-di-n-butylamino--5-chloropropane and 54.5 g of potassium carbonate The reaction medium was heated under reflux for 20 hours After cooling to room temperature the aqueous phase was decanted and the toluene layer was washed three times, each time with 200 ml of water The toluene solution was transferred to a flask and the toluene was distilled off to dryness at atmospheric pressure and the residue thus obtained was cooled. This gave crude 1-bromo-2-methyl-3-β "4- (5-di-n-butylaminopropyl) -oXi-5--bromo-benzoyl-7-indolizine in the form of free base. The following salts of this compound were prepared: a) Hydrochloride To the previously obtained free base was added a solution of 8 g of hydrochloric acid in 61 ml of ethyl acetate. The filling thus formed, ie. 104 g, vacuum filtered, washed with ethyl acetate and recrystallized from 500 ml of isopropanol. In this way, 93 g of 1-bromo-2-methyl-5-yl-4- (5-di-n-butylaminopropyl) -oxy 5 ~ bromo-benzoyl7- -ina011zinnyarOk1 @ r1a Yield: 84.7%, sms: 172%, b) hydrogen oxalate 8008444-5 23 To an ether solution of the previously obtained base was added an equimolecular solution of oxalic acid in ethyl ether. The salt was recrystallized from isopropanol to give 1-bromo-2-methyl-5-β- (5-di-n-butylaminopropyl) -oxy-5-bromo-benzoyl-inoolizine hydrogen oxyate, mp 90 DEG-90 DEG.
Exemnel 5 _ . 2-metyl-5-[24-(5-di-n-butylaminopropyl)-oxi-5,5-dibrom-bensoyl7- -indolizinväteoxalat I en 250 ml kolv satsades en blandning av 4 g, 0,01 mol, 2-metyl- -5-(5,5-dibrom~4-hydroxi-bensoyl)-indolizin och 150 ml aceton.Example 5 _. 2-Methyl 5- [24- (5-di-n-butylaminopropyl) -oxy-5,5-dibromo-benzoyl] -indolizine hydrogen oxalate In a 250 ml flask was charged a mixture of 4 g, 0.01 mol, 2- methyl -5- (5,5-dibromo-4-hydroxy-benzoyl) -indolizine and 150 ml of acetone.
Sedan indolizinen lösts, tillsattes 4 g vattenfritt kaliumkarbo- nat och 2,2 g di-n-butylaminopropylklorid_ Reaktionsblandningen återflödeskokades i 16 timmar under omröring. Efter kylning till rumstemperatur avfiltrerades mineralsalterna och tvättades med aceton på filtret. Acetonen avdestillerades vid undertryck med användning av en roterande indunstare och den oljiga återstoden löstes i omkring 100 ml etylacetat, Mediet filtrerades på ett filter och 1,5 g vattenfri oxalsyra tillsattes till filtratet.After the indolizine was dissolved, 4 g of anhydrous potassium carbonate and 2.2 g of di-n-butylaminopropyl chloride were added. The reaction mixture was refluxed for 16 hours with stirring. After cooling to room temperature, the mineral salts were filtered off and washed with acetone on the filter. The acetone was distilled off under reduced pressure using a rotary evaporator and the oily residue was dissolved in about 100 ml of ethyl acetate, the medium was filtered on a filter and 1.5 g of anhydrous oxalic acid was added to the filtrate.
Reaktionsmediet fick stå och oxalatet, som utkrístalliserade, av- filtrerades, tvättades på filtret med etylacetat och torkades i vakuum. På detta sätt erhölls 6,2 g 2-metyl-5-[-4-(5-di-n-butyl- aminopropyl)-oxi-5,5~dibrom-bensoyl7-indolizinväteoxalat. Utbyte 92,7 %, smp. 9600.The reaction medium was allowed to stand and the oxalate which crystallized out was filtered off, washed on the filter with ethyl acetate and dried in vacuo. There was thus obtained 6.2 g of 2-methyl-5 - [- 4- (5-di-n-butylaminopropyl) -oxy-5,5-dibromo-benzoyl] -indolizine hydrogen oxalate. Yield 92.7%, m.p. 9600.
Exemgel 4 1-brom~2-etyl-5-/_4-(5-di-n-propylaminopropyl)-oxi-5,5-diklor- -bensoyl7-indolizinväteoxalat.Example 4 1-Bromo-2-ethyl-5- [4- (5-di-n-propylaminopropyl) -oxy-5,5-dichloro-benzoyl] -indolizine hydrogen oxalate.
Till en 250 ml kolv tillsattes 2,8 g, 0,005 mol, 2_etyl-5-¿"4~ -(5-di-napropylaminopropyl)-oxi-5,5-diklor-bensoyl7-indolizin- väteoxalat och 80 ml dioxan. Reaktionsblandningen omrördes och sedan indolizinen hade lösts tillsattes 0,8 g vattenfritt nat- riumacetat. Genom en dropptratt tillsattes droppvis och under livlig omröring en lösning av 0,8 g brom i 20 ml dioxan. Tem- peraturen hölls vid omkring 20°C under bromtillsättningen.To a 250 ml flask was added 2.8 g, 0.005 mol, of 2-ethyl-5-"- 4- (5-di-napropylaminopropyl) -oxy-5,5-dichloro-benzoyl-7-indolizine hydrogen oxalate and 80 ml of dioxane. was stirred and after the indolizine had dissolved, 0.8 g of anhydrous sodium acetate was added, a solution of 0.8 g of bromine in 20 ml of dioxane was added dropwise and with vigorous stirring, the temperature being maintained at about 20 ° C during the addition of bromine.
Sedan mediet omrörts i 2 timmar vid rumstemperatur, avdestillera- des dioxanen i vakuum med en roterande indunstare. Den fasta återstoden löstes i vatten, gjordes alkalísk med en natrium- 800844-4-5 24 .hydroxidlösning och extraherades med kloroform. Kloroformlösnin- qen tvättades tre gånger med vatten och kloroformen avdunstades vid undertryck. Den så erhållna oljiga återstoden togs upp i torr etyleter och efter filtrering på ett filter bildades det sura oxalatet. I På detta sätt erhölls 1,8 g 1-brom-2~etyl-3-[Ä~(3-di-n-propYlami~ nopropyl)-oxi-3,5-diklor-bensoyl7-indolizinväteoxalat efter om- kristallisering ur etylacetat. Utbyte 55,8%, smp. 135oC.After the medium was stirred for 2 hours at room temperature, the dioxane was distilled off in vacuo with a rotary evaporator. The solid residue was dissolved in water, made alkaline with a sodium hydroxide solution and extracted with chloroform. The chloroform solution was washed three times with water and the chloroform was evaporated under reduced pressure. The oily residue thus obtained was taken up in dry ethyl ether and, after filtration on a filter, the acid oxalate was formed. In this way, 1.8 g of 1-bromo-2-ethyl-3- [α- (3-di-n-propylamino-propyl) -oxy-3,5-dichloro-benzoyl] -indolizine hydrogen oxalate were obtained after recrystallization from ethyl acetate. Yield 55.8%, m.p. 135oC.
Med användning av lämpliga utgångsmaterial framställdes följande föreningar med användning av de i föregående exempel beskrivna, olika processerna.Using suitable starting materials, the following compounds were prepared using the various processes described in the preceding examples.
Exempel 5 1-klor-2-etyl-3-[Ä-(3-di-n-propylamingpropyl)-oxi-3,5 gi-k10r_bens_ soylj-indolizinväteoxalat 13111 en lösning av 57,05 g, 0,12 moi, Letyi-s-ß-(ædi-n-propyi- aminopropyl)«oxi-3,5-diklor-bensoyl7-indolizin i 1100 ml diklor- etan, tillsattes 26,8 g (0,2 mol), N~klorsuccinimid i delportioner under 2 timmar. Härunder hölls temperaturen mellan 0 och 10°C.Example 5 1-Chloro-2-ethyl-3- [N- (3-di-n-propylaminopropyl) -oxy-3,5 g-chlorobenzoyl] -indolizine hydrogen oxalate 13111 a solution of 57.05 g, 0.12 mol, Lethyl-s-β- (edi-n-propylaminopropyl) oxy-3,5-dichloro-benzoyl-7-indolizine in 1100 ml of dichloroethane, 26.8 g (0.2 mol) of N-chlorosuccinimide were added in portions for 2 hours. Below this the temperature was kept between 0 and 10 ° C.
Dikloretanlösningen omrördes i 1 timme och tvättades med 500 ml vatten. Lösningsmedlet avdestillerades i vakuum och den sålunda erhållna, oljiga återstoden togs upp i torr etyleter.The dichloroethane solution was stirred for 1 hour and washed with 500 ml of water. The solvent was distilled off in vacuo and the oily residue thus obtained was taken up in dry ethyl ether.
Efter detta tillsattes en eterlösning av torr oxalsyra och saltet omkristalliserades ur etylacetat. På så sätt erhölls 18,3 g 1-klor- -2-etyl-3-ÅÄ-(3-di~n-propylaminopropyl)-oxi-3,5-diklor-bensoylff -indolizinväteoxalat.After this, an ethereal solution of dry oxalic acid was added and the salt was recrystallized from ethyl acetate. There was thus obtained 18.3 g of 1-chloro-2-ethyl-3-α- (3-di-n-propylaminopropyl) -oxy-3,5-dichloro-benzoyl-indolizine hydrogen oxalate.
Utbyte: 30%, smp. 141oC.Yield: 30%, m.p. 141oC.
Exempel 6 1-brom-2-(4-brom-fenyl)-3-ÄÃ-(3-di-n-butylaminopropyl)-oxi-ben- soyly-indolizinväteoxalat Till en lösning av 23,5 q (0,05 mol) 1-brom-2~(4-brom~fenyl)-3- :fiöw 8008444-5 QUALITY -(4-hydroxi-bensoyl)-indolizin i 250 ml dimetylformamid tillsat- tes 7,6 g, (0,055 mol) vattenfritt kaliumkarbonat. Under omröring upphettades mediet under 1 timme vid 70-8000, och efter kylning tillsattes 18,8 g (0,055 mol) 1-tosyloxi-3-di-n-butylamino-propan.Example 6 1-Bromo-2- (4-bromo-phenyl) -3-α- (3-di-n-butylaminopropyl) -oxy-benzoyl-indolizine hydrogen oxalate To a solution of 23.5 q (0.05 mol ) 1-bromo-2- (4-bromo-phenyl) -3-: 8008444-5 QUALITY - (4-hydroxy-benzoyl) -indolizine in 250 ml of dimethylformamide was added 7.6 g, (0.055 mol) anhydrous potassium carbonate. With stirring, the medium was heated for 1 hour at 70-8000, and after cooling, 18.8 g (0.055 mol) of 1-tosyloxy-3-di-n-butylaminopropane were added.
Omröringen fortsattes i 15 timmar vid rumstemperatur och bland- ningen upphettades vidare vid 70-80OC i 1 timme. Det sura oxalatet av den så erhållna basen framställdes sedan med användning av oxal- syra.Stirring was continued for 15 hours at room temperature and the mixture was further heated at 70-80 ° C for 1 hour. The acid oxalate of the base thus obtained was then prepared using oxalic acid.
På så sätt uppsamlades 26,3 g 1-brom-2-(4-brom-fenyl)-3-[Ä-(3~di- -n-butylaminopropyl)-oxibensoyl]-indolizinväteoxalat efter omkris- tallisering ur isopropanol. Utbyte 72%, smp. 92-94°C.Thus, 26.3 g of 1-bromo-2- (4-bromo-phenyl) -3- [N- (3-di--n-butylaminopropyl) -oxybenzoyl] -indolizine hydrogen oxalate were collected after recrystallization from isopropanol. Yield 72%, m.p. 92-94 ° C.
Förening SME-_32 1-brom-2-etyl~5-¿_4-(5-di-n-butylaminopropyl)_ -oxi-bensoyl7-indolízínväteoxalat 1Q7_108 (isopropanol) 1-brom-2-(4-brom-fenyl)-5-¿'4-(5-di-n- -butylaminopropyl)-oxi-bensoyl7-índolizinè 92-94 väteoxalat (ïS°P1'°Pafl°1) 1~k1or_2-metyl-5-¿"4-(5~di-n~butylaminopropy1)- -oxi-bensoyl7-índolizínväteoxalat 92-95 (isopropanol) 1-k1or-2-etyl-5-¿_4-(5-di-n-propylamínopropyl)- -oxi-bensoyl7-índolizinväteoxalat 162 _ (isopropanol) 1-klor_2_n-propyl-5-¿'4-(5-di-n-butylamíno- propyl)-oxi-bensoyl7-indolízinväteoxalat _ 111-112 (isøpropanol) 1-klor-2-n-butyl-5{"4-(5-di-n-butylaminopro- pyl)_0xí-bensoyl7-índolizinväteoxalat _ 106-108 (isopropanøl) q_k1Or_2_feny1_5-¿'4_(5-di-n-propylaminopro- pyl)-oxi-bensoyl7-indolizinväteoxalat (islšlggšâol) “-klor~2-(4-klor-fenyl)-5-¿'4_(5_di-n_buty1_ amín0PP0DY1)-0Xí-ÖQHSOYÄ7-indolizinväteoxalat 15g_159 (metanol) 7~kl0P-2-ffiHïl~5~Å_4-(5-di-n-butylaminopropyl)- -oxi-bensoyl7-índolizinvâteoxalat q5O_q61 (metanol) 3008444-5 26 1-klor-2-n-butyl-5-¿_4-(6~di-n-butylaminohexyl)- -oxi-bensoyl7-indolizínväteoxalat , 80-82 _ " (bensen) 2-metyl-5-¿"4-(5-di-n-butylaminopropyl)-oxi-5- -brom-bensoy17-indolizinväteoxalat _ 141-145 _ (10:1 etylacetat/ isopropanol 2-etyl~5-¿"4-(5-di-n-propylaminopropyl)- -oxifšflbrom-bensoyl7-indolízínväteoxalat 165 (ísopropanol) 2-etyl-5~¿"4-(5-di-n-butylaminopropyl)-oïi- -5-brom-bensoylf-indolizínväteoxalat ' 98-99 _ (ísopropanol) 2-n-propyl-5-¿_4-(5-di-n-propylaminopropyl)- ' -oxí-5-brom-bensoyl7-indolizínväteoxalat 145 _ (isopropanol 2-n-propyl-5-¿"4-(5-di-n-butylaminopropyl)oxi- _5-bromfbensoyl7-indolizinväteoxalat 115-115 1 « (isopropanol) 2-isopropyl-5-¿"4-(5-dí~n-butylaminopropyl)-oxi- -5-brom-bensoy;7-indolizinväteoxalat 105-107 (bensen)" 2-n-butyl-5~¿'4-(5-di-n-propylaminopropyl)- -oxi-5-brom-bensoy;7-indolízinväteoxalat 136-157 ' isopropanol) 2-n-butyl-3-¿'4-(5-di-n-butylamínopropyl)-oxif A -5-brom-bensøy}7-indolizinväteoxalat 86-87 W ~ (isopropanol) 2-feny1-5-¿"4-(5-di-n-propylaminopropyl)-oxi- -5-brom-bensoy;7-indolízinväteoxalat 148-149 ' (ísopropanol) 2-fenyl-5-¿_4-(5-di-n-butylamínopropyl)-oxi- -brom -bensoyl7-índolizinväteoxalat 129-150 (isopropanol) 2-(4-fluor-fenyl)-5-¿'4~(5-dí-n-butylamino- propyl)-oxi-5-brom-bensoyl7-índolizínväte- oxalat 110 (içopropanol) I 2-(4-klor-fenyl)-3-¿_4-(5-dí-n-propylamino- propyl)-oxi-5-brom-bensoyl7-índolízinväte- 1 oxalat - _ 165-164 (metanol) 2-(4-klor-fenyl)-5-[-4-(5-di-n-butylaminopro- pyl)-oxi-5_brom-bensoy}7-indolizinväteoxalat I 159-140 1 (isopropanol) 27 2-(5_brom-fenyl)-5-[-4-(5-di-n-propylaminoprø- pyl)-øxí-5-brom-bensoyl7-indo1izinväteoxalat 2_(4-brom-fenyl)-5-¿°4-(5-di-n-butylaminopro- pyl)-oxi-5~brom~bensoyl7-índolizínväteoxalat 2-(4-metoxi-fenyl)-5-¿"4-(5-dí-n-butylamínopro- pyl)~oXi-5-brom-bensoy;7-indolizinväteoxalat 2-isopropy1-5-¿"4-(5-di-n-butylaminopentyl)-oxi- -5-brom-bensoy}7-índolíZínväteoxalat 2-isopropy1-5-¿_4-(5-di-n-propylaminopropyl)-oxi- _š-brom-bensoyl7-indolizinväteoxalat 2_metyl-5-¿_4-(5-di-n-butylamínopropyl)-oxi- -5-klor-bensoyl7-índolízinväteoxalat 2-etyl~5-¿_4-(5-di-n-propylaminopropyl)-oxi- -5-klor-bensoy}7-indolizinväteoxalat 2-etyl-5-¿"4-(5-di-n~buty1aminopropyl)-oxi-5- -klor-bensoy}7-indolizinväteoxalat 2-isopropyl-5-['4-(5_di-n-butylaminopropyl)-oxí- -5-klor-bensoy}7-índolizinväteoxalat 2-isopropyl-5-¿"4-(5-di-n-propylaminopropyl)- ~oxi-5-klor-bensoy17-índolizinväteoxalat 2-n-butyl-š-¿_4-(5-di-n-butylaminopropyl)-oxi- -5-klor-bensoy17-índolizinväteoxalat 2-n-butyl-5-/-4-(5-di-n-propylaminoprøpyl)-oxi- -5-klor-bensoy}7-indolizinväteoxalat 2-fenyl-5-¿"4-(5-di-n-butylaminopropyl)oxí-5- -klor-bensoy}7indolízinväteoxalat ' 2-fenyl-5-¿'4-(5-di-n-propylamínopropyl)-oxi- -5-klor-bensoy;7-indolízinväteoxalat 8Û08444~5 142-145 (isopropanol) 147_14s;5 (metanol) 169 (isopropanol) 80-82 (bensen) 179 (isopropanol) 141-145 (isøpropanol) 161-162 (metanol) 116-117 (isopropanol) 115-117 (ísopropanol) 168-169 (metanol) g4_85 och 407-109 (isopropanol) 150-151 (isopropanol 121-122 (isopropanol) 157-159 (metanol) _snne444-5 28 2¿(4-metyl-fenyl)-5-¿ï-(š-di~n-propylaminopro- pyl)-oxi-5~klor-bensoy17-índolizínyäteoxalat 2-(4-brom-fenyl)-5-¿_4-(5-di-n-propylamínopro- pyl)~oxí-5-klor-bensoy;7-índolizinväteoxalat 2~(4-brom-fenyl-5-¿"4-(5-di-n-butylamifiopro- pyl)~oXi-5-klor-bensQy;7-indolizínväteoxalat 2f(3-brom-fenyl)-5-¿"4-(5-di-n-butylamínopro- pyl)-oxi-5-klor-bensoyšï-índolizínväteoxalat 2-(5-brom~fenyl-5-¿'4-(5-di-n-propy1aminopro- pyl)-oxi-5-klor-bensoy;7~indolizinväteoxalat 2_(4-klor-fenyllš-¿_4_(5-di-n-butylaminopro- pyl)-oxi-5-klor-bensoy}7-indolizinväteoxalat 2-(4-klo:-fenyl)-5-1' ~(5-di-n-propylamino- propyl)-oxi-5-klor-bensoyl7-indolizinväte- oxalat 1-brom-2-metyl-5-¿"4-(5-di-n-butylaminopro- pyl)~oxi-5-brom-bensoyl7èíndolízinväteoxalat 1fbrom-2-metyl-5-¿"4-(5-di-n-propylaminopro- pyl)-oxi-5-brom~bensoy;7-indolizinväteoxalat 1-brom-2-etyl-5-¿"4-(2-dímetylamínoetyl)- -Qxi-5-brom-bensoy;7-indolízinväteoxalat 1-brom-2-etyl-3-¿'4-(5-dímetylaminopropyl)- -oxi-5-brom-bensoyl7-indolízinväteoxalat¶ 1-brom-2-etyl-5-¿'4-(2-dietylaminoetyl)- -oxi-3-brom-bensoyl7-indolizinväteoxalat 1-brom-2-etyl-3-¿'443-dietylaminopropyl- -oxi-5-brom-bensoyl7-indolizinväteoxalat 1-brom-2-etyl-5-[-4-(2-di-h-propylaminoetyl)_ -oxi-5-brom-bensoylï-indolizinväteoxalat 1-brom-2-efiyl-5-[-4-(5-di-n-pfopylaminopro- 154-155 (isopropanol) 754-155 (metanol) 154-155 (isopropanol) 92-95 (isopropanol) 14s_45o (isopropanol) 116-718 (isopropanol) 159-160 , (metanol) 89-90 (isopropanol) 164-165 (isopropanol/ metanol) 464-165 (dikloretan) 450-151 (dikloretan) 1es_169 (dikloretan) 1ao_1a1,5 (isopropanol) 165~¶64 (ísopropanol) 29 pyl)-oxí-5-brom-bensoyl7-indolizinväteoxalat 4-brom~2_etyl-5-¿“4-(2-di-n-butylamínoetyl)- oxi-5-brom-bensoyl7~índolízinväteoxalat 1-brom~2_etyl~5-[-4-(5-di-n-butylaminopro- pyl)-oxi-5-brom-bensoy;7-indolizinväteoxalat 1-brom-2~n-propyl-5-¿'4-(5-di-n-buty1aminopro- pyl)-oxi~5-brom-bensoy;7-indolízinväteoxalat 1-brom_2-n-propyl-5-¿"4-(5-di-n-propylamínopro- pyl)-oxi-5-brom-bensoy;7-indolízinväteoxalat 1-brom-2-n-butyl-5-¿"4-(š-dí-n-propylaminøprø- pyl)-oxi-5-brom-bensoyl)-indolizinväteoxalat 1-brom-2-n-butyl-š~¿'4-(5-di-n-butylaminopro- pyl)-oxi-5-brom-bensoy;7-indolízinväteoxalat 4-brom-2-fenyl-5-1-4-(5-di-n-propylamínopro~ pyl)-oxi-5-brom-bensoyl7-indolízínväteoxalat 7-brom-2-fenyl-5-¿'4-(5-dí-n-butylaminopro- pyl)-oxi-5~brom-bensoyl7-índolizínväteoxalat 1-brom-2-(4-metoxi-fenyl)-5-¿"4-(5-di-n-butyl- amínopropyl)-oxi-5-brom-bensoy;7-indolizin_ väteoxalat 1-brom-2_(4-metyl-fenyl)-§-¿'4-(5-di-n-buty1- aminopropyl)-oxi-3-brom-bensoy;7-indolízín- väteoxalat 1¿brom-2_(4~fluor-fenyl)-5-¿_4-(5-dí-n-butyl- aminopropyl)-oxi-5-brom~bensoy}7~indolizin- väteoxalat 1-brom-2_(5_brom-fenyl)-3-¿'4-(5-di-n-butyl~ amínopropyl)-oxi-5-brom-bensoy}7-indo1ízin- väteoxalat 8008444-5 159-140 (ísopropanol) 164-165 (isopropanol) 4o1_4o1,5 (isopropanol) .(bensen) ¶152_156 (isopropanol) 151-152 (2:1 isopropanol/ metanol) 101-105 (ísopropanol) 169-170 (414 metanol/iso- propanol) 467-169 (isopropanol) 178-179 (metanol) 169_17o,5 (4:1 ísopropanol/ metanol) ¶ 170-171 (metanol) 172-175 (metanol) $ÛÛ3444'5 1-brom-2-n-buty1-5-¿"4-(4-di-n-butylaminø- butyl)-oxí-3~brom-bensoyl7-indolizinväteoxalat 1_k1QrQ2-ety1-5-¿"4-(5-di-n-butylamínopropyl)- -oxi-5-klor-bensoy}7-índolizinväteoxalat 1-klor-2-ety1-3-¿_4-(5-di-n~propylaminopro- pyl)-oxi-5-klor-bensoy;7~índolizínväteoxalat 1-k10r_2_(5_br0m-fenylâ-5;¿'4-(5_di_n_buty1_ aminopropyl)-oxi-5-klor-bensoy;7-indo1ízin- Väteoxalat A 1-klor-2-(5-brom-fenyl)-5-¿"4-(5~di-n~propy1- aminopropyl)-oxí-5-klor-bensoy}7-indolízín- väteoxalat 1fklor-2»ety1_5-¿"4-(5-di-n-propylaminopro- pyl)-oxi-5,5-diklor-bensoy}7-índolizinväte- oxalat 1-klor-2-etyl-3-¿'4-(5-di-n-buty1aminopro- pyl)-oxi-5,5-dik10r_bens0y;7-inaolizinväte_ oxalat ¶ ¶ 1-klor-2-fenyl-5-¿“4-(5-di-n-propylamínopro- pyl)-oxi-5,5-diklor-bensoy;7-indolizínväte- oxalat 1-klor~2-feny1;5-1" -(5-di-n-butylaminópro- pyl)-oxi-3,5-diklor-bensoyl7-índolizínväte- oxalat - 1-brom-2-metyl-5-[fä-(3-di-n-propylaminopro- pyl)4oxi-5-klor-bensoyl7-indolizinväteoxalat 1-brom-2-metyl-5-¿'4-(5-di-n-butylaminopro- pyl)-oxí-5-klor-bensoy;7-indolizinväteoxalat 1-brom-2-etyl-5-['4-(5-di-n-propylaminopro- pyl)-oxí-5-klor-bensoy;7-indo1izinväteoxalat 1~brom-2-ety1-5-¿"4-(5-di-n-butylaminopro- pyl)-oxi-5-klor-bensoy;7-indolízinväteoxalat 118-¶2O (isopropanol) 115-117 (isopropanol) 157-758 (isopropanol) 471-472 ' (metanol) 194-195 (metanol) 741 (etylacetat) 129 (etylacetat) 1§6 (isopropanol) 156 (isopro anol/ heptan 11o_112 (isopropanol) 408-410 (isopropanol) (isopropanol) 105-105 8ÛÛ8444~5 31 (isopropanol) 1-brom-2-n-propyl-5-¿E-(5-di-n-butylamínopro- pyl)-oxí-5-k1or-bensoyl7-índolizinväteoxalat 95-96 " (isopropanol) 1-brom-2-isopropYl-5-¿"4-(5-di-n-butylamino~ propyl)-oxi-5-klor-bensoy}7-indolizínväte- oxalat 116 (ísopropanol) 1-brom-2-n-butyl-5-/"4-(5-dí-n,progylamino- propyl)-oxí-5-klorfšensoyl7~indo1izinväte- oxalat 1 159-160 (metanol) 1-brom-2-n-butyl-5-/"4-(5-di-n-butylamíno- propyl)-oxi-5-klor-bensoy}7-índolízinväte- oxalat 101-105 isopropanol) 1-brom-2_fenyl-5-/"4-(5-di-n-buty1aminopro~ pyl)-oxi-5-klor-bensoy}7-indolizinväteoxalat 167,5_169 (metanol) 1_brom-2-feny1-5-¿"4-(5-di-n-propylamínopro- pyl)-oXi»E-klor~bensoyl7-indolizinväteoxalat 169-170 " (metanol) 1-brom-2-(4-klor-fenyl)-š-¿_4~(š-di-n-butyl- amínopropyl)-oxi-5-klor-bensoy}7-indolizín- väteoxalat . 160-161 (ísopropanol) 4-brom~2_(4-klor-fenyl)-5-¿_4-(5~dí-n-propyl- aminopropyl)-oxi-5-klor-bensoyl)-indolizin- vätebxalat 184-185 (metanol) 1-brom~2_(4-brom-fenyl)-3-¿“4-(5-di-n-propyl- aminopropyl)-oxi-3-klør-bensoyl)-indo1izínväte- oxalat 176«177 (metanol) 1-brom-2_(4-brom-fenyl)-5-¿_4-(5-dí-n-butyl- aminopropyl)-oxí-5-klor-bensoy}7-indolízinväte_ oxalat 1168-169 (isopropanol) 1-brom-2-(5-brom-fenyl)-5-¿_4-(5-di-n-propyl- amínopropyl)-oxi-5-klor-bensoyl7-índolizin- väteoxalat 1 200-201 (metanol) 1-brom-2-(5-brom-fenyl)~5-¿'4-(5~di-n-buty1- 8Û08444*5 32 amínopropyl)-oxí-5~klor-bensoyl7-indolizinväte= oxalat ¶ 170,5-172 ' (metanol) 1-klor-2-etyl-5~¿_4-(5-di-n-buty1amínopro- pyl)-oxi-5-brom-bensoyl7-indolizinväteoxalat 104-105 (isoprppanol) 4=klor-2-etyl-5-¿"4-(5-di-n-propylamínopro~ pyl)-oxi-5,5-dibrom-bensoy;7-indolizinväte- oxalat . 157 ~ (isopropanol) 1-klor-2-etyl-5-[-4-(5-di-n-butylamínopro- pyl)-oxi-5,5-dibrom-bensoyäï-indolizinväte_ øxalat ¶ ¶ fluoí (ísopropanol) 1-klår-2-fenyl-5-¿f4-(5-di~n-propylamínopro- pyl)oxi-5,5-díbrom-bensoyšï-indolizinväteoxalat ¶ 172 (isopropanol) 4-klor-2-fenyl-5-[-4-(5-dí-n-butylamínopro- pyl)-oxi-5,5-dibrom-bensoy;7-indolizinväte_ øxalat ' 146 * (isopropanol) 2-metyl-5>¿'4-(5-di-n-propylaminopropyl)-oxi- -5,5-dibrom-bensoyl7-indolizinseskvi- oxalat 156 _ (etylacetat) 2_etyl-5-[-4-(5-dimetylaminopropyl)~øxi- -5,5-dibrom-bensoy}7-indolizinväteoxalat ' 148 ¶ _ (etylacetat) 2-etyl-5-¿'4-(2-dietylaminøetyl)-oxi-5,5-di- ¶ - brom-bensoyl7-índolizinväteoxalat ' 171 (etanol) 2;ety1_5-¿"4_(5-aiecy1amin0pr0py1)_0xi_5,5-¶ -dibrom~bensoy}7-indolizinhydrokloríd 191 (50:5O etylacetat/ aceton 2-etyl-5-¿_4-(5-di-n-prppylaminopropyl)-_ -oxi-5,5-dibrom-bensoy}7-indolízinhydro-_ klorid I - 166 (etylacetat) 2-etyl-5-¿"4-(5-di-n-butylaminopropyl)- -oxi-5,5-díbrom-bensoyl7-índolizinhydroklorid 157 (etylacetat) 2-n-propyl-51-4-(5~dí-n-propylamínopropyl)-oxi- ,5-dibrom-bensoyl7-índolizinhydroklorid 145 (etylacetat) _ :_.....,. -,,__,.,_. 33 2-n-propyl-5-¿_4-(5-di-n-butylamínopropyl)-oxi- -3,5-díbrom-bensoyl7-indolizinväteoxalat 2-isopropyl-5-/'4-(5-di-n-propylaminopropyl)-oxi- -5,5-díbrom-bensoy}7-indolizínväteoxalat 2-isopropyl-5-¿Ä-(3-di-n-butylaminopropyl)-oxi- -5,5-díbrom-bensoy}7-indolizínväteoxalat 2-n~buty1-5-¿"4-(5-di-n+propylaminopropy1)Äoxi- -5,5-dibrom-bensoygï-indolizinväteoxalat 2_n-butyl-5-¿"4-(5-di-n-butylaminopropyl)-oxi- ~5,5-dibrom-bensoy;7-indolizinväteoxalat 2-fenylåš-¿'4-(5~di-n-propylaminopropyl)-oxi- -5,5-dibrom-bensoyl7-indolízinväteoxalat 2-fenyl-5-¿_4-(5-di-n-butylamínopropyl)~oXi- -5,5-díbrom-bensoyl7-indolízínväteoxalat 2_(4-fluor-fényl)-5-¿"4-(5-di-n-propy1amino- propyl)-oxi-5,5-dibrom-bensøyl7-indolizinväte- oxalat 2-(4-fluor-fenyl)-5-¿'4-(5-di-n-butylamino- propyl)-oxi-5,5-dibrom-bensoyl7-indolizinväte- oxalat 2-(4-k1or-fenyl)-5-¿_4-(5-di-n-propylamino- propyl)-oxi-5,5-dibrom-bensoy}7-índolízinväte- cxalat 2_(4-klor-fenyl)-5-¿"4-(5-di-n-buty1aminopro- pyl)-oxi-5,5-dibrom-bensoy}7-índolizinväte- oxalat 2-(5,4-diklor-fenyl)-5-¿'4_(5-di-n-propylamino- I propyl)~oxí-5,5~díbrom#bensoy§7-indolizínSeSkvi- oxalat 8008444-5 107 (etylacetat) 126 (etylacetat/ etanol) 86 (etylacetat/ etyleter) 146 (etylacetat) 410 (etylacetat) 142 (etylacetat/ etanol 86 (etylacetat) 166 (ety1acetat/ etanol) 152 (ísopropanol) 190 (etylacetat) 88 (etylacetat) 114 (ety1acetat/ ísopropanol) ¶8008444~5 34 2_(5,4-diklor-fenyl)-5-¿"4-(3-di-n-butylaminopro- pyl)-oxi-5,5-dibrom-bensoy}7-índolizínväteoxalat 2-(5fbrom-fenyl)-5-¿'4-(5-di-n-propylaminopro- py1)_0xi-5,5_aibr0m_bens0y;7_1fia0lizinväteoxalat 2-(5-brom-fenyl)-5-¿"4-(5-di-n-butylamínopro- pyl)-oxi-5,5-dibrom-bensoy}7-indolizínväte- fumarat I ¶2_(4-metyl-fenyl)-5-[74-(5-di-n-propylaminopro- pyl)-oxi-5,5-dibrom-bensoy}7-indolizinväte- oxalat 2-(4-metyl-fenyl)-5-¿_4-(5-di-n-butylaminopro- pyl)-oxí-5,5~dibrom-bensoyl7-indolizinväte- dxalat 2_(4-metoxi-fenyl)-5-¿'4-(5-di-n-própy1aminopro- pyl)-oxi-5,5-dibrom-bensQyl7_¿ndolizinväte- oxalat ' 2-(4-metoxi-fenyl)-5-¿'4-(5-di-n-butylamino- propyl)-oxí-5,5-dibrom-bensoyl7-indolizinväte- oxalat 2-metyl~5-¿'4- (5~di-n-propylaminopropyl)- -oxi-5,5-äiklor-bensoyl7-indolízinväteoxalat 2-mety1-5-¿'4-(5-di-n-butylamínopropyl)-oxi~ -3;5-diklor-bens0y¿7-indolizinväteoxalat 2-etyl-5-¿_4-(5-di-n-propylaminopropyl)-oxi- -5,5_diklor-bensoy;7-indolizínväteoxalat 2-etyl-5-¿_4-(3-di-n-butylamínopropyl)-oxi- -5,5-diklor-bensoy}7-indolizinväteoxalat 2-n-propyl-5-¿"4-(5-di-n-propylamínopropyIL -Qxi-5,5-díklor-bensoyl7-indolizínväteoxalat 95 Ü (etylacetat/ isopropanol) 436 (etanol) 122 (etylacetat) 126 (etylacetat/ isopropanol) 90 (etylecetat) 167 (aceton) pastalík vid ca 7000 (etanol/etyl- eter 145 (etylacetat/ etanol) 95 (etylacetat/etyl- eter 100 pastalik (etylacetat) 95 (etylacetat) 142 (ísopropanol) 8ÛÛ8444~5 2-n-propyl-5-¿"4_(5-di-n~buty1aminopropy1)~oxi- -5,5-díklor-bensoyl7-índolizínväteoxalat 114 ' (isqpropanol) 2-ísopropyl-š-¿'4-(5-di-n-propylamínopropyl)- -oxí-5,5-dík1or-bensoyl7-indolízinväteoxalat 86 " (etylacetat) 2-ísopropyl-5-¿"4-(5-di-n-butylamínopropyl)- -oxi-5,5-díklor~bensoyl7-indolízinväteoxalat 90 _" ' (etylacetat) 2-fenyl-5-¿“4-(5-di-n-propylamínopropyl)-oxi- -5,5-diklor-bensoyl7-indolízinväteoxalat ' 146 ' 1 (etanol) 2-fenyl-5-¿"4-(5-di-n-butylaminopropyl)- ~oxí-5,5~diklor-bensoy;7~indolizinväte- pastalik vid oïalat Ca 9000 (etylacetat) 2-(4-brom-fenyl)-5-¿"4-(5-di-n-propy1amino- propyl)-oxí-5,5-díklor-bensoyl7~indo1ízin- väteoxalat 174 (etylacetat) 2-(4-brom-fenyl)-5-¿'4-(5-di-n-butylamíno- propyl)-oxi-5,5-diklor-bensoy;7-indolízín- väteoxalat * 155 - (etylacetat) 1-brom-2-metyl-5-¿“4-(5-di-n-buty1amino~ propyl)-oxi-5,5~díbrom-bensoy;7-indolízin- väteoxalat 141-145 (isopropanol) 1-brom_2_n-propyl-5-¿'4_(5_ai_n_pr0py1amino- propyl)-oxí-5,5-dibrom-bensoyl7-indo1izin- väteoxalat 153-159 (isopropanol) 1-brom-2-etyl-5-[-4-(5-di-n-butylaminopro- pyl)-oxí-5,5_díbrom-bensoy17-índolízinväte- oxalat 131_152,5 (isopropanol) 1-brom¿2-fenyl-5~¿_4-(5-di-n-Quty1aminopro- pyl)-oxi-5,5-díbrom-bensoy}7-índolizinväte- oxalat 160-161 (ísopropanol) 1-brom-2_(4-metyl-fenyl)-5-¿_4-(3-di-n-buty1~ amínopropyl)-oxi-5,5-dibrom-bensoy}7-indo- lizinväteoxalat 105-106 (isopropanol) 8008444-5 36 4-brom~2-(4-brom-fenyl)-5-[-4-(5-di-n-butylamino- propyl)~oxi-5,5-díbrom-bensoyl7-indolizinväte- oxalat 1-brofi-2_(5,4-díklor-fenyl)~5-¿'4-(5-di-n- -butylaminopropyl)-oxi-5,5-dibrom-bensoyl7- -indolizinväteoxalat > '1-brom-2-(5-klor-4~metyl-fenyl)-5-/"4-(5-di- -n-butylaminopropyl)-oxí-5,§-dibrd;-bensoyl7- -indolizínväteoxalàt 4-brom-Euétyl-5-¿"4-Qš-di-n-butylaminopro- pyl)-oxí«5,5-diklor-benspyl7-indolizinväte- oxalát _ 4-brom-2_fenyl-š-¿'4-(5-di-n-propylamíno- propyl)-oxí-5,5-diklor-bensoy}7-indolízin- väteoxalat 1-brom-2-fenyl-5-¿'4-(5-di-n-butylamíno- propyl)-oxi-5,5-diklor-bensoy;7+indo1izín- väteokalat - 2-n-butyl-5-¿'4-(3-di-n-butylaminopropyl)- -oxi-5-brom-bensoy;7-índolizinhydroklorid 2-n-propy1-5-[_4-(5~dietyl-aminopropyl)-oxi- -5,5-dibrom-bensoy;7-indolizinhydroklorid 2-etyl-5-[-4-(5-di-n-butylafiinopropyl)-oxi- -5~klQr-bensoyl7-indolizinhydrokloríd 2-n-buty1_5_¿"4_(5_ai_n_buty1amin0pr0py1)- -oxi-5-klor-bensoy}7-indolízinhydroklorid 1-brom-2-fenyl-5-¿'4-(5-di-n«butylaminopro- pyl)-oxi-3-klor-bensoy}7-indolízinhydroklorid 1~klor-2-(4-klor-fenyl)-5-¿"4-(5-di-n-propyl- amínopropyl)-oXi~bensoyl7-indolizinväteoxalat 1fmetuxi-2-feny1~5-¿"4¿(5Qdi-n-propylamínopro- _ 143-149 (isopropanol) 196-19? ísopropanol) 1es;1e9 (isopropanol) 734 (isopropanol) 145 (etylacetat) 106 ” (etylacetat) 115_115,5 (etylacetat) 154 (8o=2o etylacetat/ aceton 152-153 (etylacetat/ isopropanol) 104 (etylacetat) ¶ flse-157 16a_169 (metanol) pyl)-oxi-bensoy}7-indolizinväteoxalat 1-metoxi-2_fenyl-5-/_4_(5-di-n-butylamino- propyl)-oxi-bensoy}7-indolízinväteoxalat I1-mètoxi-2_fenyl-5-/~4-(5-di-n-propylamino- propyl)-oxi-5-klor-bensoy}7-índolizínväte_ oxalat 1~metoxi-2-fenyl-5-/-4-(5-di-n-butylamíno- propyl)-oxi-5-klor-bensoy;7-indolizínväte- oxalat 4-metoxi-2_fenyl-5~¿_4-(5-di-n-propylamino- propyl)-oxí-5-brom-bensoy}7-indolizínväte- oxalat 1-metoxi-2-fenyl-5-¿"4-(5-di-n-butylamino- propyl)-oxi-5~brom-bensoy}7-indolízinväte- oxalat 4-metoxi~2-feny1-5-/"4-(5-di-n~propylamíno- propyl)-oxi-3-metoxi-bensoyl7-indolizin- väteoxalat 4-metoxi_2-fenyl-š~¿_4-(5-dí-n-butylamíno- propyl)-oXi-5-metoXi-bensoyl7-indo1izin- väteoxalat 1-metoxi-2-(4-fluor-fenyl)-5-¿"4-(5-di-n- -propylaminoprcpyl)-oxi-5-metoxí-bensoy}7- 37 -indolízinväteoxalat 2-metyl-5-¿'4-(5-di-n-butylaminopropyl)-oxi- -5-metoxí-bensoy;7~indolizinväteoxalat 2-metyl-5-¿'4-(5-di-n-propylaminopropyl)- -oxí-5-metoxi-bensoyl7-indolizinväte- oxalat 2-etyl-5~/"4-(5-di-n-butylamínopropyl)-oxí- -5-metoxi-bensoy}7-indolizinväteoxalat 2_etyl-5-¿"4-(5-di-n-propylaminopropyl)-oxí- 8008444-5 117 (etylacetat) SO (etylacetat) 172 (etylacetat) 120 '(etylacetat) 460 (etylacetat) 78 (etylacetat) 148 (etylacetat) 78 (etylacetat) 79 (etylacetat) 459 (ísopropanol) 171 (metanol) 88 (etylacetat) 8008444-5- 38 -E-metoxí~bensoy}7-índoliiinväteoxalat 121-122 (etylacetat) 2«n-butyl-3-[Ä-(3-di-n-propy}aminopropyl)oxí- -3-metyl-bensoy;7-índolizínväteoxalat 147' 1.2~dímety1-3-LÃ-(3-dí-n-Bntylamínopropyl)- Qxí-5-metyl-bensoy}7-índolizinväteoxalat 2_ety1_5-/"4-(5-di-n-butylamínopropyl)- (ísopropanol) oxí-3-brom-bensoy;7-índolizínväteoxàlat 105 > ' ' (etylacetat) 1-brom-2-metyl-5-¿"4-(5-di-p-butylamino_ propyl)-oxí-5-metoxí-bens0yl7_índ01izin_ väteoxalat g7_9O (bensen) 1-brom-2_metyl-5-1-4-(E-di-n-propy1amin°_ propyl)-oxi-5-metoxi-bensoy}7-índolízin- väteoxalat 1§9_141 _ » isopropanol) 1-brom_2_ety1-5~¿_4-(5-di-n-butylamíno- prqpyl)-oxi-5-metoxí-bensoyl7-indolizin- väteoxalat 111 (bensen) 1-brom-2-etyl-5-¿"4_(5_di-n-propylamino- propyl)-oxí-5-metoxi-bensoy;7-índo1ízín- väteoxalat f 149 (isopropanol) 2_(4-fluor-fenyl)-5-¿_4-(5-dí-n-butyl- aminopropyl)-oxí-5-metoxi-bensoy;7-indo- lízinväteoxalat * 85 (etylacetat) 2_mety1_5;/'4_(5-di-n-butylaminopropyl)- 1U9 (isopropanol) 0xi_§_mety1-bensoylï-indolizínväteoxalat 155 ¶ ' (etylacetat) 1-metyl-2-n-propyl~3-LÃ-(3Pdi-n-butylaminopropyl)- -oxi-3-brom-bensoyäf-indolizinväteøxalat 127 (etylacetat) 2_iSOpr0py1_5_¿"4_(5-dí-n-buty1amínopro- _ 911 1 pyl)_0xi-3-metyl-bensoy;7-indolizinväte- (1S°pr°Pan°1) oxalat DDR F uumw 39 2_n-butyl-5-¿"H-(5-di-n-butylamínopropyl)- -oxí-5-metyl-bensoy}7-indolizinväteoxalat 1-mety1-2-n-butyl-3-¿Ü-(3-di-n-butylaminoprø- pyl)-oxi-3-brom-bensoyl7-índolízínväteoxalat 1-íodo-2~ety1-3-[Ä-(3-di-n-buty1amínopropyl)- - -oxí-3,5-dímetyl-bensoy;?-índolízínväteoxalat 2-feny1-3-¿Ã-(3-di-n-butylaminopropyl)oxí-3- -metyl-bensoyL7-índolízínväteoxalat 2-fenyl-3-[Ä-(3-di-n-pfopylamínopropyl)-oxi- -3-metyl-bensoygj-índolízinväteoxalat 1-mety1-2-feny1-3-LÃ-(3-di-n-butylamínoprppyl)- -oxí-3-brom-bensoy¥7-índolízínväteoxalat 1-metyl-2-fenyl-3-[Ä-(3-dí-n-propy1amínopro- pyl)-oxi-3-hrøm-bensoyL7-índolízínväteoxalat l-metyl-2-feny1-3-[Ä-(3-dí-n-propy1aminopro- pyl)-oxí-bensoy;]-índolízinväteoxalat 1-metyl-2-fenyl-3-[Ä-(3-di-n-butylaminopropyl)- -oxí-bensoy§7-índolízínväteoxalat l-mety1-2-n-butyl-3-[Ã-(3-dí-n-propy1amino- propyl)-oxi-3-brom-bensoyä]-íhdo1ízínväte- oxalat 1-metyl-2-n-buty1-3-¿Ä-(3-di-n-buty1amínopro- pyl)-oxí-3-klor-bensoy§7-índolizinväteoxalat 1-mety1-2-n-buty1-3-LÄ-(3-dí-n-butylamínopro- pyl)-oxi-bensoyg]-índolízínväteoxalat 80084 44-5 39 Císopropanol) 99 (etylacetat) 115 íetylacetat) 137 (etylacetat) 149 (ísopropanol) 143 (etylacetat) 160 (etylacetat) 130 (etylacetat) 96 (etylacetat) 143 (aceton) 98 (aceton) 130 (aceton) .8008444~5 40 1-metyfl-2-n-butyl-3-[Ä-(3-dí-n-propylamínopro- pyl)-oxí-bensoyL7-índolízínvâteoxalat 1-metyl-2-n-butyl-3-¿É,3-diklor-4-(3-di-n- propylamínopropyl)-oxi-bensoy§7-indolízin 1-metyl-2-n-butyl-3-[2,3-dík1or-4-(3-dí-n-bu- tylamínopropyl)-oxí-bensoyäy-índolizín 2-ecyl-3-¿§.3-díklor-4-(3-dí-h-propylamíno- propyl)-oxí-bensoyiy-indolízín 2-etyl-3-Åšï3-dik1or-4-(3-dí-n-buty1ámíno- propyl)-cxí-bensoy[Y~índolizín 2-fenyl-3~¿š,3-diklor-4-(3-di-n-propylamíno- propyl)-oxi;bensoy§7-índolízin 2-fenyl-3-Li,3-díklor-4-(3-di-n-buty1amíno- propyl)-bxí-bensoyiï-indolizin 2-(4-f1uor~feny1)-3-1_ë, s-diklor-q-(a-di-n- -propylamínopropyl)-oxi-bensoy;7-índolízín 2-(4-fluor-fenyl)-3-ÅÉ,3-dík1or-4-(3-dí-n- -butylaminoprøpyl)-oxí-bensoyL7-índolízín 1_brom-2-ecy1-a-[z, a-aiklor-aqa-ai-n-butyl- amínopropyl)-oxí-bensoyflï-índolízínväteoxalat 1-brom-2-fenyl-3-12,3-diklor-4-(3-di-n-propyl- amínopropyl)-oxí-bensoyI]-índolizínväteoxalat 1-klor-2-fènyl-3-Lä,3-dík1or-4-(3-di-n-propyl- aminopropyl)-oxí-bensoyL]-indolízín 2-n-butyl-3-[Ä-(3-di-n-butylaminopropyl)oxí-3- -jod-bensoyiy-índolízín 133 (aceton) 150 (aceton) '90 (aceton) 117 (heptan) 95 (heptan) 997 (heptan) 87 (heptan) 119 (heptan) 95-96 (heptan) 164 (ísopropanol) 171 f (ísopropanol) 136 (heptan) 90-92 (etylacetat) 8GO8444~5 41l Exempel 5 Enligt känd farmaceutisk teknik framställdes mjuka gelatinkapslar Innehêllande följande beståndsdelar: ï~sLändsdel må ;-n-butyl-5-¿Û-(5-di-n-butylaminopropyl)-oxi-5~brom/eller- -5-klor-bensoyl7-índolizinhydroklorid i 100 Snärkelse 99,5 Kolloidal kiseldioxid 2oo,ø ïšempel 6 Enligt känd farmaceutisk teknik framställdes injicerbara lösningar innehållande följande beståndsdelar: ß Beståndsdel mg ?-n-butyl-5-[Ü-3-di-n-butylaminopropyl)- _3Xi-}_br0m/ eller -5-klor-bensoyl7-indolizin- nydroxioria 150 Eolysorbat BO 150 šensylalkohol 7 75 Vatten till 5 ml Exem el Enligt känd farmaceutísk teknik framställdes suppositoríer in~ nehàllande följande beståndsdelar: Beståndsdel EB 2-n-butyl-5;¿'4=(5-di-n-butylaminopropyl)-oxi- -š-brom/eller -B-klor-bensoyU-indolizin- hydrokioria ' 100 Blandníng av mono- och di-Elycerïåef av mättade syror (C42 till C48) _jf22 4500 e Pär? QUALÉY _,2lâ_Compound SME-32-1-bromo-2-ethyl-5- [4- (5-di-n-butylaminopropyl) -oxy-benzoyl] -indolizine hydrogen oxalate 1Q7_108 (isopropanol) 1-bromo-2- (4-bromo-phenyl) -5- [4- (5-di-n- -butylaminopropyl) -oxy-benzoyl] -indolizine 92-94 hydrogen oxalate (SS ° P1 '° Pa fl ° 1) 1-chloro_2-methyl-5-β "4- ( 5-Di-n-butylaminopropyl) -oxy-benzoyl-7-indolizine hydrogen oxalate 92-95 (isopropanol) 1-chloro-2-ethyl-5- [4- (5-di-n-propylaminopropyl) -oxy-benzoyl] -indolizine hydrogen oxalate 162 (Isopropanol) 1-chloro-2-n-propyl-5-β- (5-di-n-butylaminopropyl) -oxy-benzoyl-7-indolizine hydrogen oxalate 111-112 (isopropanol) 1-chloro-2-n-butyl 4- {"4- (5-di-n-butylaminopropyl) -oxy-benzoyl-7-indolizine hydrogen oxalate-106-108 (isopropanol) q-chloro-2-phenyl-5-β- (5-di-n-propylaminopropyl) -oxy-benzoyl7 indolizine hydrogen oxalate (isoslgisazole) -chloro-2- (4-chloro-phenyl) -5-β'4_ (5-di-n-butyl_amine0PP0DY1) -OX1-QQHSOY - (5-di-n-butylaminopropyl) -oxy-benzoyl-7-indolizinate oxalate q5O_q61 (methanol) 3008444-5 26 1-chloro-2-n-butyl-5-β-4- (6-d in-butylaminohexyl) -oxy-benzoyl-7-indolizine hydrogen oxalate, 80-82 "(benzene) 2-methyl-5- [4- (5-di-n-butylaminopropyl) -oxy-5-bromo-benzoyl] -indolizine hydrogen oxalate 141-145 (10: 1 ethyl acetate / isopropanol 2-ethyl-5- [4- (5-di-n-propylaminopropyl) -oxy] bromo-benzoyl] -indolizine hydrogen oxalate 165 (isopropanol) 2-ethyl-5-yl 4- (5-di-n-butylaminopropyl) -oyl-5-bromo-benzoyl-indolizine hydrogen oxalate 98-99 (isopropanol) 2-n-propyl-5-β- (5-di-n-propylaminopropyl) - '-oxy-5-bromo-benzoyl-7-indolizine hydrogen oxalate 145 - (isopropanol 2-n-propyl-5-"- 4- (5-di-n-butylaminopropyl) oxy-5-bromobenzoyl7-indolizine hydrogen oxalate 115-115 1« ( isopropanol) 2-isopropyl-5-"- 4- (5-din-n-butylaminopropyl) -oxy-5-bromo-benzoyl; 7-indolizine hydrogen oxalate 105-107 (benzene)" 2-n-butyl-5-β 4- (5-di-n-propylaminopropyl) -oxy-5-bromo-benzoyl; 7-indolizine hydrogen oxalate 136-157 'isopropanol) 2-n-butyl-3- [4- (5-di-n- butylaminopropyl) -oxy-5-bromo-benzoyl} 7-indolizine hydrogen oxalate 86-87 W - (isopropanol) 2-phenyl-5- [4- (5-di-n-propylaminopropyl) -oxy--5-bromo- b 7-indolizine hydrogen oxalate 148-149 '(isopropanol) 2-phenyl-5- [4- (5-di-n-butylaminopropyl) -oxy-bromo-benzoyl] -indolizine hydrogen oxalate 129-150 (isopropanol) 2- (4- fluoro-phenyl) -5- [4- (5-di-n-butylaminopropyl) -oxy-5-bromo-benzoyl] -indolizine hydrogen oxalate 110 (isopropanol) I 2- (4-chloro-phenyl) -3 -4- (5-di-n-propylamino-propyl) -oxy-5-bromo-benzoyl-7-indolizine hydrogen oxalate - 165-164 (methanol) 2- (4-chloro-phenyl) -5 - [- 4- (5-di-n-butylaminopropyl) -oxy-5-bromo-benzoyl} 7-indolizine hydrogen oxalate I 159-140 1 (isopropanol) 27 2- (5-bromo-phenyl) -5 - [- 4- (5-di -n-propylaminopropyl) -oxy-5-bromo-benzoyl-7-indolizine hydrogen oxalate 2- (4-bromo-phenyl) -5-β- (5-di-n-butylaminopropyl) -oxy-5-bromo- benzoyl 7-indolizine hydrogen oxalate 2- (4-methoxy-phenyl) -5- [4- (5-di-n-butylaminopropyl) -Oxy-5-bromo-benzoyl; 7-indolizine hydrogen oxalate 2-isopropyl-5-yl] 4- (5-di-n-butylaminopentyl) -oxy-5-bromo-benzoyl} 7-indolizine hydrogen oxalate 2-isopropyl-5- [4- (5-di-n-propylaminopropyl) -oxy-β-bromo-benzoyl] -indolizine hydrogen oxalate 2-methyl-5- [4- (5-di-n-butylaminopropyl) -oxy- -5-chloro-benzoyl-7-indolizine hydrogen oxalate 2-ethyl-5- [4- (5-di-n-propylaminopropyl) -oxy] -5-chloro-benzoyl} 7-indolizine hydrogen oxalate 2-ethyl-5-"- 4- ( 5-di-n-butylaminopropyl) -oxy-5-chloro-benzoyl} 7-indolizine hydrogen oxalate 2-isopropyl-5 - [4- (5-di-n-butylaminopropyl) -oxy--5-chloro-benzoyl} 7- Indolizine hydrogen oxalate 2-isopropyl-5-β "4- (5-di-n-propylaminopropyl) -oxy-5-chloro-benzoyl] -indolizine hydrogen oxalate 2-n-butyl-β-β- (5-di-n-butylaminopropyl ) -oxy-5-chloro-benzoyl-17-indolizine hydrogen oxalate 2-n-butyl-5 - [[4- (5-di-n-propylaminopropyl) -oxy] -5-chloro-benzoyl} 7-indolizine hydrogen oxalate 2-phenyl- 5-β "4- (5-di-n-butylaminopropyl) oxy-5-chloro-benzoyl} 7-indolizine hydrogen oxalate 2-phenyl-5-β- (5-di-n-propylaminopropyl) -oxy- -chloro-benzoyl; 7-indolizine hydrogen oxalate 8Û08444 ~ 5 142-145 (isopropanol) 147_14s; 5 (methanol) 169 (isopropanol) 80-82 (benzene) 179 (isopropanol) 141-145 (isopropanol) 161-162 (methanol) 116 -117 (isopropanol) 115-117 (isopropanol) 168-169 (methanol) g4_85 and 407-109 (isopropanol) 150-151 (isopropanol 121-122 (isopropanol) 157-159 (with (4-Methyl-phenyl) -5-N- (β-di-n-propylaminopropyl) -oxy-5-chloro-benzoyl] -indolizinyl oxalate 2- (4-bromo-phenyl) ) -5- [4- (5-di-n-propylaminopropyl) -oxy-5-chloro-benzoyl; 7-indolizine hydrogen oxalate 2- (4-bromo-phenyl-5-β- 4- (5-di- n-Butylamino-propyl) -Oxy-5-chloro-benzyl; 7-indolizine hydrogen oxalate 2f (3-bromo-phenyl) -5-β "4- (5-di-n-butylaminopropyl) -oxy-5-chloro -benzoyl-indolizine hydrogen oxalate 2- (5-bromo-phenyl-5-β- (5-di-n-propylaminopropyl) -oxy-5-chloro-benzoyl; 7-indolizine hydrogen oxalate 2- (4-chloro-phenyl) -is- 4 - (5-di-n-butylaminopropyl) -oxy-5-chloro-benzoyl} 7-indolizine hydrogen oxalate 2- (4-chloro-phenyl) -5-1 '- (5-di-n-propylamino- propyl) -oxy-5-chloro-benzoyl-7-indolizine hydrogen oxalate 1-bromo-2-methyl-5- (4- (5-di-n-butylaminopropyl) -oxy-5-bromo-benzoyl-7-indolizine hydrogen oxalate 1-bromo-2 -methyl-5-"- 4- (5-di-n-propylaminopropyl) -oxy-5-bromo-benzoyl; 7-indolizine hydrogen oxalate 1-bromo-2-ethyl-5-" - 4- (2-dimethylaminoethyl) ) -Qoxy-5-bromo-benzoyl; 7-indolizine hydrogen oxalate 1-bromo-2-ethyl-3- [4- (5-dimethylaminopropyl) -oxy-5-bromo-benzoyl] -indolizine hydrogen Oxalate 1-bromo-2-ethyl-5-β- (2-diethylaminoethyl) -oxy-3-bromo-benzoyl-7-indolizine hydrogen oxalate 1-bromo-2-ethyl-3-β'443-diethylaminopropyl-oxy -5-bromo-benzoyl-7-indolizine hydrogen oxalate 1-bromo-2-ethyl-5 - [- 4- (2-di-h-propylaminoethyl) -oxy-5-bromo-benzoyl] -indolizine hydrogen oxalate 1-bromo-2-ethyl 5 - [- 4- (5-di-n-p -popylaminopro- 154-155 (isopropanol) 754-155 (methanol) 154-155 (isopropanol) 92-95 (isopropanol) 14s_45o (isopropanol) 116-718 (isopropanol) 159 -160, (methanol) 89-90 (isopropanol) 164-165 (isopropanol / methanol) 464-165 (dichloroethane) 450-151 (dichloroethane) 1es_169 (dichloroethane) 1ao_1a1,5 (isopropanol) 165 ~ ¶64 (isopropanol) 29 pyl) -oxy-5-bromo-benzoyl-7-indolizine hydrogen oxalate 4-bromo-2-ethyl-5- [4- (2-di-n-butylaminoethyl) -oxy-5-bromo-benzoyl] -indolizine hydrogen oxalate 1-bromo-2-ethyl-5 - [- 4- (5-di-n-butylaminopropyl) -oxy-5-bromo-benzoyl; 7-indolizine hydrogen oxalate 1-bromo-2-n-propyl-5-β- (5-di-n -butylaminopropyl) -oxy-5-bromo-benzoyl; 7-indolizine hydrogen oxalate 1-bromo-2-n-propyl-5- [4- (5-di-n-propylaminopropyl) -oxy-5-bromo-benzoyl 7-indole Hydrogen hydrogen oxalate 1-bromo-2-n-butyl-5-β "4- (β-di-n-propylamino-propyl) -oxy-5-bromo-benzoyl) -indolizine hydrogen oxalate 1-bromo-2-n-butyl-β 4- (5-di-n-butylaminopropyl) -oxy-5-bromo-benzoyl; 7-indolizine hydrogen oxalate 4-bromo-2-phenyl-5-1-4- (5-di-n-propylaminopropyl) -pyl) -oxy-5-bromo-benzoyl-7-indolizine hydrogen oxalate 7-bromo-2-phenyl-5-β- (5-di-n-butylaminopropyl) -oxy-5-bromo-benzoyl-7-indolizine hydrogen oxalate 1- bromo-2- (4-methoxy-phenyl) -5- [4- (5-di-n-butylaminopropyl) -oxy-5-bromo-benzoyl; 7-indolizine hydrogen oxalate 1-bromo-2- (4- methyl-phenyl) -β- [4- (5-di-n-butyl-aminopropyl) -oxy-3-bromo-benzoyl; 7-indolizine hydrogen oxalate] -bromo-2- (4-fluoro-phenyl) -5 -4- (5-Di-n-butyl-aminopropyl) -oxy-5-bromo-benzoyl} 7-indolizine hydrogen oxalate 1-bromo-2- (5-bromo-phenyl) -3-β- 4- (5-di -n-butyl-aminopropyl) -oxy-5-bromo-benzoyl} 7-indolizine hydrogen oxalate 8008444-5 159-140 (isopropanol) 164-165 (isopropanol) 4o1_4o1,5 (isopropanol). (benzene) ¶152_156 (isopropanol ) 151-152 (2: 1 isopropanol / methanol) 101-105 (isopropanol) 169-170 (414 methanol / isopropanol) 467-169 (isopropanol panol) 178-179 (methanol) 169_17o, 5 (4: 1 isopropanol / methanol) ¶ 170-171 (methanol) 172-175 (methanol) $ 1Û3444'5 1-bromo-2-n-butyl] -5-¿" 4- (4-Di-n-butylamino-butyl) -oxy-3-bromo-benzoyl-7-indolizine hydrogen oxalate 1- [1-C] -2-ethyl-5- [4- (5-di-n-butylaminopropyl) -oxy-5-chloro- Benzoyl} 7-indolizine hydrogen oxalate 1-chloro-2-ethyl-3- [4- (5-di-n-propylaminopropyl) -oxy-5-chloro-benzoyl; 7-indolizine hydrogen oxalate 1-chloro-2- (5-bromo-phenyl] -5 4- (5-Di-butyl-aminopropyl) -oxy-5-chloro-benzoyl; 7-indolizine-Hydrogen oxalate A 1-Chloro-2- (5-bromo-phenyl) -5-β- 4- (5-di-n propyl-aminopropyl) -oxy-5-chloro-benzoyl} 7-indolizine hydrogen oxalate 1-chloro-2-ethyl-5-yl-4- (5-di-n-propylaminopropyl) -oxy-5,5-dichloro-benzoyl 7-Indolizine hydrogen oxalate 1-chloro-2-ethyl-3- [4- (5-di-n-butylaminopropyl) -oxy-5,5-dichlorobenzoyl; 7-inaolizine hydrogen oxalate 1-chloro- 2-Phenyl-5-"- 4- (5-di-n-propylaminopropyl) -oxy-5,5-dichloro-benzoyl; 7-indolizine hydrogen oxalate 1-chloro-2-phenyl; 5-1" - (5-di-n-butylaminopropyl) -oxy-3,5-dichloro-benzoyl-7-indolizine hydrogen oxalate-1-bromo-2-methyl-5- [b] (3-di-n-propyl laminopropyl) 4-oxy-5-chloro-benzoyl-7-indolizine hydrogen oxalate 1-bromo-2-methyl-5- [4- (5-di-n-butylaminopropyl) -oxy-5-chloro-benzoyl; 7-indolizine hydrogen oxalate 1-Bromo-2-ethyl-5 - ['4- (5-di-n-propylaminopropyl) -oxy-5-chloro-benzoyl; 7-indolizine hydrogen oxalate 1-bromo-2-ethyl-5-β - (5-di-n-butylaminopropyl) -oxy-5-chloro-benzoyl; 7-indolizine hydrogen oxalate 118-2 2 O (isopropanol) 115-117 (isopropanol) 157-758 (isopropanol) 471-472 '(methanol) 194-195 (methanol) 741 (ethyl acetate) 129 (ethyl acetate) 1§6 (isopropanol) 156 (isoproanol / heptane 11o_112 (isopropanol) 408-410 (isopropanol) (isopropanol) 105-105 8ÛÛ8444 ~ 5 31 (isopropanol) 1 -bromo-2-n-propyl-5-N- (5-di-n-butylaminopropyl) -oxy-5-chloro-benzoyl-7-indolizine hydrogen oxalate 95-96 "(isopropanol) 1-bromo-2-isopropyl- 5- [4- (5-Di-n-butylamino-propyl) -oxy-5-chloro-benzoyl} -7-indolizine hydrogen oxalate 116 (isopropanol) 1-bromo-2-n-butyl-5-yl - (5-Di-n, progylaminopropyl) -oxy-5-chlorophenzoyl-7-indolizine hydrogen oxalate 1 159-160 (methanol) 1-bromo-2-n-butyl-5 - [- 4- (5-di- n-butylaminopropyl) -oxy-5-chloro-be Nosyl} 7-indolizine hydrogen oxalate 101-105 isopropanol) 1-bromo-2-phenyl-5 - [4- (5-di-n-butylaminopropyl) -oxy-5-chloro-benzoyl} 7-indolizine hydrogen oxalate 167.5_169 (methanol) 1-bromo-2-phenyl-5- [4- (5-di-n-propylaminopropyl) -oxy] -E-chloro-benzoyl] -indolizine hydrogen oxalate 169-170 "(methanol) 1-bromo-2- ( 4-Chloro-phenyl) -s-β- (β-di-n-butyl-aminopropyl) -oxy-5-chloro-benzoyl} 7-indolizine hydrogen oxalate. 160-161 (Isopropanol) 4-bromo-2- (4-chloro-phenyl) -5- [4- (5-di-n-propyl-aminopropyl) -oxy-5-chloro-benzoyl) -indolizine hydrogen oxalate 184- 185 (Methanol) 1-Bromo-2- (4-bromo-phenyl) -3- [4- (5-di-n-propylaminopropyl) -oxy-3-chloro-benzoyl) -indolizine hydrogen oxalate 176 «177 (methanol) 1-bromo-2- (4-bromo-phenyl) -5-β- (5-di-n-butyl-aminopropyl) -oxy-5-chloro-benzoyl} 7-indoline-hydrogen oxalate 1168-169 (isopropanol ) 1-Bromo-2- (5-bromo-phenyl) -5- [4- (5-di-n-propyl-aminopropyl) -oxy-5-chloro-benzoyl] -indolizine hydrogen oxalate 1 200-201 (methanol) 1-bromo-2- (5-bromo-phenyl) -5- [4- (5-di-n-butyl-8Û08444 * 5 32 aminopropyl) -oxy-5-chloro-benzoyl] -indolizine hydrogen = oxalate ¶170, 5-172 '(methanol) 1-chloro-2-ethyl-5 - [4- (5-di-n-butylaminopropyl) -oxy-5-bromo-benzoyl] -indolizine hydrogen oxalate 104-105 (isopropylanol) 4 = chlorine -2-ethyl-5- [4- (5-di-n-propylaminopropyl) -oxy-5,5-dibromo-benzoyl; 7-indolizine hydrogen oxalate. 157- (isopropanol) 1-chloro-2- Ethyl 5 - [- 4- (5-di-n-butylaminopropyl) -oxy-5,5-dibromo-benzoyl] -indolizine hydrogen oxalate ¶ 6 (isopropanol) 1-chloro-2-phenyl- 5-β- (5-Dien-propylaminopropyl) oxy-5,5-dibromo-benzoyl-indolizine hydrogen oxalate 172 (isopropanol) 4-chloro-2-phenyl-5 - [- 4- (5-di -n-butylaminopropyl) -oxy-5,5-dibromo-benzoyl; 7-indolizine hydrogen oxalate '146 * (isopropanol) 2-methyl-5' - 4- (5-di-n-propylaminopropyl) -oxy- -5,5-Dibromo-benzoyl-7-indolizine sesquioxalate 156 _ (ethyl acetate) 2-ethyl-5 - [- 4- (5-dimethylaminopropyl) -oxy--5,5-dibromo-benzoyl} 7-indolizine hydrogen oxalate '148 ¶ _ ( ethyl acetate) 2-ethyl-5- [4- (2-diethylaminoethyl) oxy-5,5-di-bromo-benzoyl] -indolizine hydrogen oxalate '171 (ethanol) 2; ethyl5- [4- (5-alkylaminopropyl) 7-Indolizine hydrochloride 191 (50: 5O ethyl acetate / acetone 2-ethyl-5-β- (5-di-n-propylaminopropyl) -oxy-5,5-dibromobenzo benzoyl} 7-indolizine hydrochloride I - 166 (ethyl acetate) 2-ethyl-5-[4- (5-di-n-butylaminopropyl) -oxy-5,5-dibromo-benzoyl] -indolizine hydrochloride 157 (ethyl acetate) 2-n-propyl-51-4- (5-di-n-propylaminopropyl) -oxy-, 5-dibromo-benzoyl-7-indolizine hydrochloride 145 (ethyl acetate). - ,, __,., _. 33 2-n-propyl-5- [4- (5-di-n-butylaminopropyl) -oxy] -3,5-dibromo-benzoyl-7-indolizine hydrogen oxalate 2-isopropyl-5- [4- (5-di-n -propylaminopropyl) -oxy--5,5-dibromo-benzoyl} 7-indolizine hydrogen oxalate 2-isopropyl-5-N- (3-di-n-butylaminopropyl) -oxy--5,5-dibromo-benzoyl} 7- indolizine hydrogen oxalate 2-n-butyl-5-β "4- (5-di-n + propylaminopropyl) oxy-5,5-dibromo-benzoyl-indolizine hydrogen oxalate 2-n-butyl-5-β" 4- (5-di-n -butylaminopropyl) -oxy-5,5-dibromo-benzoyl; 7-indolizine hydrogen oxalate 2-phenylase-4- (5-di-n-propylaminopropyl) -oxy--5,5-dibromo-benzoyl-7-indolizine hydrogen oxalate 2- Phenyl 5-β- 4- (5-di-n-butylaminopropyl) -Oxy-5,5-dibromo-benzoyl-7-indolizine hydrogen oxalate 2- (4-fluoro-phenyl) -5-β- 4- (5-di-n -propylamino-propyl) -oxy-5,5-dibromo-benzoyl-7-indolizine hydrogen oxalate 2- (4-fluoro-phenyl) -5-β- (5-di-n-butylaminopropyl) -oxy-5 5-Dibromo-benzoyl-7-indolizine hydrogen oxalate 2- (4-chloro-phenyl) -5-β- (5-di-n-propylaminopropyl) -oxy-5,5-dibromo-benzoyl} 7-indolizine hydrogen Oxalate 2- (4-chloro-phenyl) -5- [4- (5-di-n-butylaminopropyl) -oxy-5,5-dibromo-benzoyl} 7-indolysis Hydrogen oxalate 2- (5,4-dichloro-phenyl) -5- [4- (5-di-n-propylamino-propyl) -oxy-5,5-dibromo-benzoyl] -7-indolizine Sequi oxalate 8008444- 107 (ethyl acetate) 126 (ethyl acetate / ethanol) 86 (ethyl acetate / ethyl ether) 146 (ethyl acetate) 410 (ethyl acetate) 142 (ethyl acetate / ethanol 86 (ethyl acetate) 166 (ethyl acetate / ethanol) 152 (isopropanol) 1902 (isopropanol ethyl acetate) 114 (ethyl acetate / isopropanol) δ8008444 ~ 5 34 2- (5,4-dichloro-phenyl) -5-β- (3-di-n-butylaminopropyl) -oxy-5,5-dibromo- Benzoyl} 7-indolizine hydrogen oxalate 2- (5-bromo-phenyl) -5-β- (5-di-n-propylaminopropyl) -oxy-5,5-abromobenzoyl; 7-fi-olizine hydrogen oxalate 2- (5-bromo-phenyl) -5- 4- (5-di-n-butylaminopropyl) -oxy-5,5-dibromo-benzoyl} 7-indolizine hydrogen fumarate -n-propylaminopropyl) -oxy-5,5-dibromo-benzoyl} 7-indolizine hydrogen oxalate 2- (4-methyl-phenyl) -5-β- (5-di-n-butylaminopropyl) - Oxy-5,5-dibromo-benzoyl-7-indolizine hydroxyxalate 2- (4-methoxy-phenyl) -5- [4- (5-di-n-propylaminopropyl) -oxy-5,5-dibromo-benzyl] -β Indolizine hydrogen oxalate '2- (4-methoxy-f enyl) -5- [4- (5-di-n-butylaminopropyl) -oxy-5,5-dibromo-benzoyl] -indolizine hydrogen oxalate 2-methyl-5- [4- (5-di-n -propylaminopropyl) -oxy-5,5-chloro-benzoyl-7-indolizine hydrogen oxalate 2-methyl-5- [4- (5-di-n-butylaminopropyl) -oxy] -3,5-dichloro-benzoyl] -indolizine hydrogen oxalate 2-Ethyl-5- [4- (5-di-n-propylaminopropyl) -oxy--5,5-dichloro-benzoyl; 7-indolizine hydrogen oxalate 2-ethyl-5- [4- (3-di-n-butylaminopropyl) - oxy-5,5-dichloro-benzoyl} 7-indolizine hydrogen oxalate 2-n-propyl-5-β "4- (5-di-n-propylaminopropyl-xxy-5,5-dichloro-benzoyl] -indolizine hydrogen oxalate 95 Ü / isopropanol) 436 (ethanol) 122 (ethyl acetate) 126 (ethyl acetate / isopropanol) 90 (ethyl acetate) 167 (acetone) pastal at about 7000 (ethanol / ethyl ether 145 (ethyl acetate / ethanol) 95 (ethyl acetate / ethyl ether 100 pastal (ethyl acetate) 95 (ethyl acetate) 142 (isopropanol) 8-N-propyl-5-β "-4- (5-di-n-butylaminopropyl) -oxy--5,5-dichloro-benzoyl] -indolizine hydrogen oxalate 114 '( ispropanol) 2-Isopropyl-β-β- 4- (5-di-n-propylaminopropyl) -oxy-5,5-dichloro-benzoyl-7-indolizine hydrogen oxalate 86 "(ethyl acetate) 2-Isopropyl-5-" - 4- (5-di-n-butylaminopropyl) -oxy-5,5-dichloro-benzoyl-7-indolizine hydrogen oxalate 90-"(ethyl acetate) 2-phenyl-5- 4- (5-di-n-propylaminopropyl) -oxy-5,5-dichloro-benzoyl-7-indolizine hydrogen oxalate '146' 1 (ethanol) 2-phenyl-5-β "4- (5-di-n- butylaminopropyl) -oxy-5,5-dichloro-benzoyl; 7-indolizine hydrogen pastal at olate Ca 9000 (ethyl acetate) 2- (4-bromo-phenyl) -5-β- 4- (5-di-n-propylamino propyl) -oxy-5,5-dichloro-benzoyl-5-indolizine hydrogen oxalate 174 (ethyl acetate) 2- (4-bromo-phenyl) -5-β- (5-di-n-butylaminopropyl) -oxy -5,5-dichloro-benzoyl; 7-indolizine hydrogen oxalate * 155 - (ethyl acetate) 1-bromo-2-methyl-5- [4- (5-di-n-butylamino-propyl) -oxy-5, 5-Dibromo-benzoyl; 7-indolizine hydrogen oxalate 141-145 (isopropanol) 1-bromo-2-n-propyl-5-β-4 (5-al-propylamino-propyl) -oxy-5,5-dibromo-benzoyl-7-indolizine-3-oxalate (isopropanol) 1-bromo-2-ethyl-5 - [- 4- (5-di-n-butylaminopropyl) -oxy-5,5-dibromo-benzoyl] -indolizine hydrogen oxalate 131-215.5 (isopropanol) 1-bromo 2-Phenyl-5-β- (5-di-n-Qutyylaminopropyl) -oxy- 5,5-Dibromo-benzoyl} 7-indolizine hydrogen oxalate 160-161 (Isopropanol) 1-Bromo-2- (4-methyl-phenyl) -5-β- (3-di-n-butyl-aminopropyl) -oxy -5,5-dibromo-benzoyl} 7-indolizine hydrogen oxalate 105-106 (isopropanol) 8008444-5 36 4-bromo-2- (4-bromo-phenyl) -5 - [- 4- (5-di-n -butylamino-propyl) -oxy-5,5-dibromo-benzoyl-7-indolizine hydrogen oxalate 1-bromo-2- (5,4-dichloro-phenyl) -5- [4- (5-di-n--butylaminopropyl) -oxy-5,5-dibromo-benzoyl-7-indolizine hydrogen oxalate> 1-bromo-2- (5-chloro-4-methyl-phenyl) -5- [4- (5-di--n-butylaminopropyl) - Oxy-5,4-dibrid-benzoyl-7-indolizine hydrogen oxalate 4-bromo-ethyl-5-(4-C6-di-n-butylaminopropyl) -oxy-5,5-dichloro-benzyl-7-indolizine hydrogen oxalate 4-Bromo-2-phenyl-β-β- (5-di-n-propylaminopropyl) -oxy-5,5-dichloro-benzoyl} 7-indolizine hydrogen oxalate 1-bromo-2-phenyl-5-β 4- (5-di-n-butylaminopropyl) -oxy-5,5-dichloro-benzoyl; 7 + indolizine hydrogen ocalate - 2-n-butyl-5-β- (3-di-n- butylaminopropyl) -oxy-5-bromo-benzoyl; 7-indolizine hydrochloride 2-n-propyl-5- [4- (5-diethyl-aminopropyl) -oxy] -5,5-dibromo-benzoyl; 7-indolizine hydrochloride 2- ethyl-5 - [- 4- (5-di-n-butyl] inopropyl) -oxy-5-chloro-benzoyl-7-indolizine hydrochloride 2-n-butyl-5-β "-4- (5-a-butylamino] propyl) -oxy-5-chloro-benzoyl} 7-indolizine hydrochloride -bromo-2-phenyl-5- [4- (5-di-n-butylaminopropyl) -oxy-3-chloro-benzoyl} 7-indolizine hydrochloride 1-chloro-2- (4-chloro-phenyl) - 5- [4- (5-Di-n-propylaminopropyl) -oxy] benzoyl] -indolizine hydrogen oxalate 1-methoxy-2-phenyl-5-yl-4β (5-di-n-propylaminopropyl) 143-149 (isopropanol) 196 -19? isopropanol) 1es; 1e9 (isopropanol) 734 (isopropanol) 145 (ethyl acetate) 106 ”(ethyl acetate) 115_115.5 (ethyl acetate) 154 (8o = 2o ethyl acetate / acetone 152-153 (ethyl acetate / isopropanol) 104 (ethyl acetate) 157 16a_169 (methanol) pyl) -oxy-benzoyl} 7-indolizine hydrogen oxalate 1-methoxy-2-phenyl-5 - [4- (5-di-n-butylaminopropyl) -oxy-benzoyl} 7-indolizine-hydrogen oxalate I1-methoxy-2_phenyl- 5- [4- (5-di-n-propylamino-propyl) -oxy-5-chloro-benzoyl} 7-indolizine hydrogen oxalate 1-methoxy-2-phenyl-5 - [- 4- (5-di-n -butylamino-propyl) -oxy-5-chloro-benzoyl; 7-indolizine hydrogen oxalate 4-methoxy-2-phenyl-5 - [4- (5-di-n-propylamino-propyl) -oxy-5-bromo-benzoyl} 7-Indolizine hydrogen oxalate 1-methoxy-2-phenyl-5- [4- (5-di-n-butylaminopropyl) -oxy-5-bromo-benzoyl} 7-indolizine hydrogen oxalate 4-methoxy-2- Phenyl-5 - [4- (5-di-n-propylamino-propyl) -oxy-3-methoxy-benzoyl] -indolizine hydrogen oxalate 4-methoxy-2-phenyl-β-4- (5-di-n-butylamino propyl) -oxy-5-methoxy-benzoyl-7-indolizine hydrogen oxalate 1-methoxy-2- (4-fluoro-phenyl) -5- [4- (5-di-n--propylaminopropyl) -oxy-5- methoxy-benzoyl} 7- 37 -in dolizine hydrogen oxalate 2-methyl-5-β- (5-di-n-butylaminopropyl) -oxy-5-methoxy-benzoyl; 7-indolizine hydrogen oxalate 2-methyl-5-β- (5-di-n- propylaminopropyl) -oxy-5-methoxy-benzoyl-7-indolizine hydrogen oxalate 2-ethyl-5- [4- (5-di-n-butylaminopropyl) -oxy--5-methoxy-benzoyl} 7-indolizine hydrogen oxalate 2-ethyl-5 4- (5-di-n-propylaminopropyl) -oxy-8008444-5 117 (ethyl acetate) SO (ethyl acetate) 172 (ethyl acetate) 120 '(ethyl acetate) 460 (ethyl acetate) 78 (ethyl acetate) 148 (ethyl acetate) 78 (ethyl acetate) 79 (ethyl acetate) 459 (isopropanol) 171 (methanol) 88 (ethyl acetate) 8008444-5- 38 -E-methoxybenzoyl} 7-indolium hydrogen oxalate 121-122 (ethyl acetate) 2 «n-butyl-3- [Ä - (3-Di-n-propyl} aminopropyl) oxy-3-methyl-benzoyl; 7-indolizine hydrogen oxalate 147 '1.2-Dimethyl-3-L- (3-di-n-Methylaminopropyl) - Qxy-5-methyl- benzoyl} 7-indolizine hydrogen oxalate 2-ethyl-5 - ["4- (5-di-n-butylaminopropyl) - (isopropanol) oxy-3-bromo-benzoyl; 7-indolizine hydrogen oxalate 105 -" (ethyl acetate) 1-bromo-2-methyl- 5- [4- (5-Di-p-butylamino-propyl) -oxy-5-methoxy-benzyl] -indolizine hydrogen oxalate g7_9O (benzene) 1- bromo-2-methyl-5-1-4- (E-di-n-propylamine-_-propyl) -oxy-5-methoxy-benzoyl} 7-indolizine hydrogen oxalate 1§9_141 (isopropanol) 1-bromo-2-ethyl-5-yl 4- (5-Di-n-butylamino-propyl) -oxy-5-methoxy-benzoyl-7-indolizine hydrogen oxalate 111 (benzene) 1-bromo-2-ethyl-5-β- (5-di-n-propylaminopropyl) ) -oxy-5-methoxy-benzoyl; 7-indolizine hydrogen oxalate (149 (isopropanol) 2- (4-fluoro-phenyl) -5- [4- (5-di-n-butyl-aminopropyl) -oxy-5- methoxy-benzoyl; 7-indolizine hydrogen oxalate * 85 (ethyl acetate) 2-methyl_5; 4 '(5-di-n-butylaminopropyl) -1U9 (isopropanol) oxy_§_methyl-benzoyl] -indolizine hydrogen oxalate 155 ¶' - 1-ethyl-1-ethyl 2-n-propyl-3-L1- (3β-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl-indolizine hydrogen oxalate 127 (ethyl acetate) 2-isOpropyl-5-β "-4- (5-di-n-butylaminopropyl) -911 Oxy-3-methyl-benzoyl; 7-indolizine hydrogen (1S ° pr ° Pan ° 1) oxalate DDR Fumum 39 2-n-butyl-5-β "H- (5-di-n-butylaminopropyl) -oxy-5 -methyl-benzoyl} 7-indolizine hydrogen oxalate 1-methyl-2-n-butyl-3-β- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl-7-indolizine hydrogen oxalate 1-iodo-2- ety1-3- [Ä- ( 3-di-n-butylaminopropyl)---oxy-3,5-dimethyl-benzoyl; -indolizine hydrogen oxalate 2-phenyl-3-β- (3-di-n-butylaminopropyl) oxy-3-methyl-benzoyl] -indolizine hydrogen oxalate 2-phenyl-3- [α- (3-di-n-popylaminopropyl) -oxy--3-methyl-benzoyl] -indolizine hydrogen oxalate 1-methyl-2-phenyl-3-L- (3-di-n- butylaminopropyl) -oxy-3-bromo-benzoyl-7-indolizine hydrogen oxalate 1-methyl-2-phenyl-3- [N- (3-di-n-propylaminopropyl) -oxy-3-chloro-benzoyl] -7-indolizine hydrogen oxalate -Methyl-2-phenyl-3- [N- (3-di-n-propylaminopropyl) -oxy-benzoyl;] -indolizine hydrogen oxalate 1-methyl-2-phenyl-3- [N- (3-di-n) -butylaminopropyl) -oxy-benzoyl-7-indolizine hydrogen oxalate 1-methyl-2-n-butyl-3- [α- (3-di-n-propylamino-propyl) -oxy-3-bromo-benzoyl] -hydrolizine hydrogen- Oxalate 1-methyl-2-n-butyl-3-N- (3-di-n-butylaminopropyl) -oxy-3-chloro-benzoyl-7-indolizine hydrogen oxalate 1-methyl-2-n-butyl-3 -LÄ- (3-di-n-butylaminopropyl) -oxy-benzoyl] -indolizine hydrogen oxalate 80084 44-5 39 Cisopropanol) 99 (ethyl acetate) 115 ethyl acetate) 137 (ethyl acetate) 149 (isopropanol) 143 (ethyl ethyl acetate) ) 130 (ethyl acetate) 96 (ethyl acetate) 143 (acetone) 98 (acetone) 130 (acetone) .8008444 ~ 5 40 1-Methyl-2-n-butyl-3- [N- (3-di-n-propylaminopropyl) -oxy-benzoyl] -indolizine vate oxalate 1-methyl-2-n-butyl-3-β, 3-dichloro-4- (3-di-n-propylaminopropyl) -oxy-benzoyl-7-indolizine 1-methyl-2-n-butyl- 3- [2,3-Dichloro-4- (3-di-n-butylaminopropyl) -oxy-benzoyl] -indolizine 2-ecyl-3-β-3,3-dichloro-4- (3-di-h- propylamino-propyl) -oxy-benzoyl-indolizine 2-ethyl-3-α-β-dichloro-4- (3-di-n-butylaminopropyl) -coxy-benzo [γ-indolizine 2-phenyl-3-β, 3-Dichloro-4- (3-di-n-propylaminopropyl) -oxy; benzoyl] -7-indolizine 2-phenyl-3-Li, 3-dichloro-4- (3-di-n-butylaminopropyl) -bxy-benzoyl-indolizine 2- (4-fluoro-phenyl) -3-1-e, s-dichloro-q- (α-di-n--propylaminopropyl) -oxy-benzoyl; 7-indolizine 2- (4-fluoro -phenyl) -3-ÅE, 3-dichloro-4- (3-di-n--butylaminopropyl) -oxy-benzoyl-7-indolizine 1-bromo-2-ethyl-α- [z, α-chloro-aqa-ai-n -butyl-aminopropyl) -oxy-benzoyl-indolizine hydrogen oxalate 1-bromo-2-phenyl-3-12,3-dichloro-4- (3-di-n-propyl-aminopropyl) -oxy-benzoyl] -indolizine hydrogen oxalate 1-chloro -2-phenyl-3-Lä, 3- Dichloro-4- (3-di-n-propyl-aminopropyl) -oxy-benzoyl] -indolizine 2-n-butyl-3- [N- (3-di-n-butylaminopropyl) -oxy-3-iodo-benzoyl] -indolizine 133 (acetone) 150 (acetone) '90 (acetone) 117 (heptane) 95 (heptane) 997 (heptane) 87 (heptane) 119 (heptane) 95-96 (heptane) 164 (isopropanol) 171 f (isopropanol) 136 (heptane) 90-92 (ethyl acetate) 8GO8444 ~ 5 41l Example 5 According to the known pharmaceutical art, soft gelatin capsules were prepared containing the following ingredients: ï ~ sLend part may; -n-butyl-5-β- (5-di-n-butylaminopropyl ) -oxy-5-bromo / or--5-chloro-benzoyl-7-indolizine hydrochloride in 100 Starch 99.5 Colloidal silica 20, Example 6 Injectable preparations were prepared according to the known pharmaceutical technique containing the following ingredients: ß Ingredient mg? -n-butyl -5- [Ü-3-di-n-butylaminopropyl) - - 3Xi -} - bromine / or -5-chloro-benzoyl-7-indolizin-hydroxyurea 150 Eolysorbate BO 150 stencil alcohol 7 75 Water to 5 ml Examples According to known pharmaceutical techniques, suppositories were prepared containing the following ingredients : Ingredient EB 2-n-butyl-5: 4 = (5-di-n-butylaminopropyl) -oxy-β-bromo / or -B-chloro-benzoyl-indolizine-hydrochloride '100 Mixture of mono- and di-Elycerïæef of saturated acids (C42 to C48) _jf22 4500 e Pär? QUALÉY _, 2lâ_
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GB7942146 | 1979-12-06 |
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SE441926B true SE441926B (en) | 1985-11-18 |
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JP (1) | JPS56103181A (en) |
AR (4) | AR227036A1 (en) |
AT (1) | AT376438B (en) |
AU (1) | AU536320B2 (en) |
BE (1) | BE886511A (en) |
BG (2) | BG35598A3 (en) |
BR (1) | BR8007691A (en) |
CA (1) | CA1152077A (en) |
CH (1) | CH651041A5 (en) |
CS (3) | CS222692B2 (en) |
DD (1) | DD155069A5 (en) |
DE (1) | DE3046017C2 (en) |
DK (1) | DK146977C (en) |
ES (4) | ES8205798A1 (en) |
FI (1) | FI67846C (en) |
GR (1) | GR70224B (en) |
HK (1) | HK65884A (en) |
HU (1) | HU185019B (en) |
IE (1) | IE50519B1 (en) |
IL (1) | IL61385A (en) |
IN (1) | IN151241B (en) |
IS (1) | IS1209B6 (en) |
IT (1) | IT1218424B (en) |
KE (1) | KE3438A (en) |
LU (1) | LU82983A1 (en) |
MA (1) | MA19007A1 (en) |
NL (1) | NL184683C (en) |
NO (1) | NO157019C (en) |
NZ (1) | NZ195754A (en) |
OA (1) | OA06711A (en) |
PH (1) | PH17028A (en) |
PL (3) | PL127865B1 (en) |
PT (1) | PT72151B (en) |
RO (3) | RO85271B (en) |
SE (1) | SE441926B (en) |
SG (1) | SG33384G (en) |
SU (3) | SU1058505A3 (en) |
YU (3) | YU42366B (en) |
ZA (1) | ZA806831B (en) |
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GB1518443A (en) | 1976-02-19 | 1978-07-19 | Labaz | Indolizine derivatives and process for preparing the same |
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1981
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1984
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