CA1152077A

CA1152077A - Indolizine derivatives and process for preparing the same

Info

Publication number: CA1152077A
Application number: CA000365859A
Authority: CA
Inventors: Henri Inion; Gilbert Rosseels
Original assignee: Labaz Sanofi NV
Current assignee: Labaz Sanofi NV
Priority date: 1979-12-06
Filing date: 1980-12-01
Publication date: 1983-08-16
Also published as: AU536320B2; RO84707A; ZW28580A1; AR227093A1; IS1209B6; IL61385A0; IE802520L; AR227036A1; SE441926B; JPS6325591B2; NO157019B; YU42366B; RO85271B; IT1218424B; ZA806831B; YU44483A; IN151241B; DE3046017A1; NO157019C; HU185019B

Abstract

ABSTRACT OF THE DISCLOSURE:
Novel indolizine derivatives represented by the general formula :

and the pharmaceutically acceptable acid addition salts thereof, wherein : R represents an alkyl radical having from 1 to 8 carbon atoms, or a phenyl group non-substituted or bearing one or two substituents, selected from halogen atoms and from lower alkyl and alkoxy groups, X1 represents hydrogen, chlorine, bromine, iodine, methyl or methoxy, A represents a group selected from :

R2= and R3 =

Description

ot~7 This invention rel.ates to heterocyclic compounds and is concerned with novel indolizine derivatives and with a method oE preparing the said novel derivatives.
The indolizine derivatives with which the present invention is concerned are the compoun.ds represented by the general formula :

Xl ~-C-A-O ~C~12) -~ I
O Rl and the pharmaceutically acceptable acid addition salts thereof, for example the oxalate or hydrochloride, wherein :
R represents a branched or straight-chain alkyl radical having from 1 to 8 carbon atoms, or a phenyl group non-substituted or bearing one or two substituents, which may be the same or differentl selected from halogen atoms, for example.
fluorine, chlorine and bromine and from lower alkyl and alkoxy groups for example methyl and methoxy, Xl represents hydrogen, chlorine, bromine iodine, methyl or methoxy, A represents a group selected from :

X Cl Cl ~= ~ / and R3=~
x3 in which X2 represents hydrogen, chlorine, bromine, iodine, methyl or methoxy and X3 represents hydrogen, chlorine, bromine, iodine or methyl, Rl represents a methyl, ethyl, n-propyl or n-butyl radicall ~i~

~5;2(~7~
n represents an i~.tege~ i~ the range of 2 t~ 6 inclusive, with the proviso that ~he~ both X2 and X3 ~epresent hydrogen or methyl, Xl is other than hydrogen.
In the aforesaid general formul.a I, R represents, preferably, a branched- or straight-chain alkyl radical having from 1 to 8 carbon atoms, a phenyl radical, a mono-fluoro-, mono-chloro-, mono-bromo-, mono-methyl-, or mono-methoxy-phenyl radical, a di-fluoro-, di-chlc,ro-, di-bromo-phenyl radical or a methyl-phenyl radical substi.tuted in the aromatic moiety by an atom of fluorine, chlorine or bromine.
The present invention also provides a process for preparing indolizine derivatives corresponding to the general formula (I):
Xl C-A-O-(CH2)n-N \ (I) Rl and pharmaceutically acceptable acid addition salts thereof wherein:
R represents a branched- or straight-chain alkyl radical having from 1 to 8 carbon atorns, or a phenyl group non-substituted or bearing one or two substituents, which may be the same or different selected from halogen atoms and from lower alkyl and alkoxy groups, Xl represents hydrogen, chlorine, bromine, iodine, methyl or methoxy, A represents a group selected from:

R2 ~ Cl Cl - ~ r~
~.~ ~ 2 ~
. ,,~ . ~

;z~

in which X2 represents hydrogen, chlori~e, bromine, .iodine, methyl or methoxy and X3 repre,ents hydrogen,chlorine, bromine, iodine or methyl, Rl represents a methyl, ethyl, n-propyl or n-butyl radical, n represents an integer in the range of 2 to 6 inclusi~e with the proviso that when both X2 and X3 represent hydrogen or methyl, Xl is other than hydrogen, characterized in that (A) to obtain an indolizine derivative corresponding to the general formula (I) as defined above and phar-maceutically acceptable acid addition salts thereof, a substituted bromoalkoxy-benzoyl-indolizine of the general formula: Xl R
-A-O-(CH2)n-Br o wherein Xl, R, A and n have the same meanin~ as defined above, is condensed, with a secondary amine oE the general formula:
/R
H-N \
Rl in which Rl has the same meaning as defined above, to form the required indilizine derivative which, if desired, is reacted with an appropriate organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt thereof, (B) to obtain an indolizine derivative corresponding ........... .~ Oi ~ ~ - 2a -~, "

~lS21~77 to the general formula (I) a.s defined above and pharmaceutically acceptable acid addi-tion salts thereof, an alkali metal salt of a substitu-ted indolizine derivative represented by the general formula: Xl ~/ ~ R
N l-C-A-O~
o in which R, A and Xl have the same meaning as defined above, is condensed with an alkylamino derivative of the general formula:
~ Rl Z (C 2)n Rl or an acid addition salt thereof, in which Z represents a halogen atom or a p-toluenesulphonyl-oxy group and n and Rl have the same meaning as defined above to form the re~uired indolizine derivative which, if desired, is reacted with an appropriate organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt thereof, or (C) to obtain an indoliæi.ne derivative corresponding to the general formula (I) as defined above and pharmaceu-tically acceptable acid addition salts thereof, wherein Xl represents chlorine, bromine or iodine, X2 repre-sents chlorine~ bromine or iodine, methyl or methoxy~
and X3 represents chlorine, bromine, iodine or methyl an indolizine derivative of general formula:

- 2b -~. .,~

` -- 1152(~77 R / ,R

C-A-O-(cH2)n-N \
Rl in which R, A, n and Rl have the same meaning as given above is reàcted:
a) either with N-chlorosuccinimide, between 0C and room-temperature, to form the required indolizine derivative in which Xl repre-sents chlorine, b) or with bromine or iodine, th~ reaction taking place at room-temperautre in the presence of an alkali metal acetate, to form the required indolizine derivative in which Xl represents bromine or iodine the obtained indolizine derivative being reacted, if desired, with an appropriate organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt thereof.
The indolizine derivatives of the invention have been found to posses useful pharmacological properties capable of rendering them of considerable value in the treatment of certain pathological syndromes of the heart, more particularly in the treatment of angina pectoris and auricular and ventricular cardiac arrhythmias of various origins.
The present invention is also concerned with pharma-ceutical and veterinary compositions containing, as active principle, at least one indolizine derivative of formula I
or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutical carrier or excipient therefor.

Another object of the present invention is to provlde a process for preparing pharmaceutical or veterinary compositions whereby at least on,e indolizine derivative of formula I or a pharma~eutically acceptable acid addition salt thereof, is ; ''~
_ 2c -. .~.~ .

1~5;~(~77 associated with a pharmaceutical carrier or excipient therefor.
Yet another object of the present inven-tion is to provide a method of treating pathological syndromes of the heart and particularly angina pectoris and cardiac arrythmias in a subject needing such treatment which method comprises administer-ing to said subject an effective dose of at least one indolizine derivative of formula I or a pharmaceutically acceptable acid ~lSZ~77 addition salt thereo.
Daily dosages will be preferably ~rom 100 to 300 mg of active principle by oral rollte and preferably from 1 to 3 mg of active principle by parenteral route to a subject weighing 60 kgs.
As indicated above, the compounds of formula I may b~e prepared, in accordance with the invention, by condensing, advantageously in an inert solvent such as, for example benzene or toluene, a substituted bromoalkoxy-benzoyl indolizine of the general formula (IIa):

~ _c_A_o-(cll2)n-~r (IIa) wherein Xl, R, A and n have the same meaning as in formula I, with a secondary amine of the general formula (IIIa):

Rl H-N (IIIa) Rl in which Rl has the same meaning as in formula I, to form the required indolizine derivative of formula I which, if desired, is reacted with an appropriate organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt thereof.

The compounds of formula I may alternatively be prepared by condensing, advantageously in an aprotic solvent such as, for example, acetone, methyl ethyl ketone or toluene, an alkali metal salt, preferably the potassium or sodium salt or an appropriately substituted indolizine derivative represent-ed by the general formula (II):

. - 3 l~lS~ 7 Xl R (II) ~ -C-A-OH

in which R, A and Xl have the same meaning as in formula I, with an alkylamino derivative of the general formula (III):

Z (C 2)n \ (III) .
Rl or an acid addition salt thereof, in which Z represents a hologen atom such as chlorine or bromine or a p-toluenesulphonyloxy group and n and Rl have the same meaning as in formula I to give the required indolizine derivative which, if desired, is reacted with an appropriate organic or inoganic acid to provide a phar-maceutically acceptable acid addition salt thereof.
In accordance with a further aspect of the invention, the indolizine derivatives of formula I in which Xl represents chlorine, bromine or iodine and A represents the group R3 or a group R2 in which X2 represents chlorine, bromine, iodine, methyl or methoxy and X3 represents chlorine, bromine, iodine or methyl can also be prepared by reacting an indolizine derivative of general form~la (IVa):

l ~ ~ -C-A-0-(C~)n~
O Rl I .

in which R, R1 and n have the same meaning as in formula I and A represents the group R3 or a group R2 in which X2 represents ~ ~ _ 4 ~i5Z(~77 chlorine, bromine, iodine, methyl or methoxy ancl X3 represents chlorine, bromine, iodine or methyl :
a) either with N-chlorosuccinimide, the reaction a~vantageously ~aking place in a suitable medium such as dichlorethane and between 0 C
and room-temperature, to obtain the required compound of formula I in which Xl represents chlorine, b) or with bromine or iodine, the reaction taking place at room-temperature advantageously in a suitable solven-t such as dioxan and in the presence of an alkali metal acetate, for instance sodium acetate, to obtain the required compound of formula I in which Xl represents bromine or iodine, the obtained indolizine derivative being reacted,if desired, wi-~ an appropriate organic or inorganic acid, to provide aphannaceutically acceptable acid addition salt thereof.
The compounds of formula (IIa)can be obtained by condensing, advantageously in an 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 formu-la ~II)hereabove, with a dibromoall<ane of the general formula (VI):

Br-(CH2)n-Br in which n has the same meaning as in formula I to obtain the required compound of formula (IIa).
The compounds of formula(II)in which A represents the group R2 are either compounds described in copending British patent application N 80 21924 filed on the 4th July, 1980 or compounds which can be prepared in accordance with methods described in the aforesaid British patent application.
The other compouncls of formula (II), i.e.those in which A represents the group R3 can be obtained by reacting the appropriate 2-substituted-indolizine with 2,3-dichloro-4-acetyloxy or 4-tosyloxy-benzoyl chloride. This benzoyl chloride .,.;. ~
~ - 5 derivative is itsel preparedl by aeetylating 1,2-dichloro-anisole in aceordance with the eonditions of the FRIEDEI, and CRAF~S reaetion oxydating the acetyl derivative so obtained with sodium hypoehlorite to form the corresponding benzoic aeid derivative, demethylating with hydriodic aeid in aeetic acid to obtain 2,3-dichloro-4-hydroxy-benzoic acid~ This last-cited compound is then reacted with acetyl chloride or tosyl ehloride to form the required 2,3-dichloro-4-acetyloxy or 4-tosyloxy-benzoie aeid and the eorresponding aeyl chloride is subsequently formed in aeeordance with known procedures, for instance by reaetion with thionyl ehloride.
With respeet to the eompounds of formula IVa, these are eompounds falling within the seope of formula I above.
Indolizine derivatives are already known whieh have pharmaeologieal effeets eapable of rendering them useful in the treatment of angina peetoris and eardiac arrhythmias.
In this eonneetion, British patent N l,518,443 can be eited whieh more partieularly deseribes 2-ethyl-3-~4-(3-di-n-butylaminopropyl)-oxy-benzoyl~-indolizine known under the non-proprietary name of butoprozine. In the British patent in question, antianginal propert;ies are attributed to eompounds deseribed therein sinee they produee the following eardiovaseular effeets :
- bradyeardia - deerease in arterial pressure - ~-antiadrenergic effect - ~-antiadrenergic effect - eoronarodilating effeet.
The inerease of the blood-flow to the myocardium provoked by 30 these compound is, in faet, only slight beeause their aetion does not last long : it is e~erted for only a few minutes after an intravenous injeetion.

P7'7 Furthermore, the compounds described in the aforesaid British patend only possess a weak ~-adrenergic antagonist action. This action is only slight at the minimum dose at which the other four cardiovascular effects cited above manifest themselves to a significat degree~
It has now been found quite surprisingly that by substituring in an appropriate manner with one or more methyl or methoxy groups or halogen atoms for example chlorine, bromine or iodine, dialkylaminoalkyloxybenzoyl indolizine derivatives, compounds are obtained which present a much broader spectrum of cardiovascular properties then the derivatives of British patent N 1,518,443 while showing less toxicity.
Thus, it has been possible to demonstrate that the indolizine derivatives of the invention can be regarded as powerful coronarodilators since they are capable of increasing the blood-flow to the myocardium to a marked degree and for a longer period oE time than butoprozine. Compounds of the invention were also found to reduce cardiac frequency and arterial pressure in the animal.
Furthermore, the indolizine derivatives present a ~-antiadrenergic effect which iS much more powerful than that of the derivatives of the aforesaid British patent. At the minimum dose required to produce bradycardia, a reduction in arterial pressure, ~-antiadrenergic and coronarodilatory effects to a significat degree, the ~-antiadrenergic effect is, in fact, only slight in the case of the derivatives of the British patent in question whereas it is much stronger with the indolizine derivatives of the invention.
Moreover, the compounds of the invention reduce the consumption of oxygen by the myocardium calculated by multiplying the difference between the artirial and venous blood in oxygen by the coronary blood-flow. Thus the compounds of the invention ~lS2(~77 cause a consi~erable reduction in the arterio-venous difference which induces a decrease in t:he consumption of oxygen in spite of the increase of the coronary bloo-Elow.
Furthermore, unlike butoprozine, these beneficial effects on the consumption of oxygen are obtained with the compounds of the invention without any decrease in the con-tractility of the myocardium.
It has been further demonstrated that the derivatives of the invention are less toxic than the compounds of British 10 patent N 1,518,443. Acute toxicity tests carried out by intra-venous and oral routes in the animal have shown that the lethal doses are higher in the case of compounds of the invention than in the case of derivatives of the British patent in question.
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 l-bromo-2-methyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-bromo-benzoyl~-indolizine and of butoprozine administered to the dog induces a blood level which is three times higher with the compound of the invention than with butoprozine. Likewise, the compounds of the invention, when administered in long-term treatment per os in the dog have shown no cardiac toxicity as represented by ventricular arrhythmia which is not the case with butoprozine.
Finally, the indolizine derivatives of the invention exert a milder depressant action on the contractility of the myocardium than does butoprozine.
In man, an attack of angina pectoris is the painful consequence of a deficiency between the supply and the requirement in oxygen of the myocardium.
A compound can thus be active in the treatment of angina pectoris either by increasing the supply of oxygen or by -1~5iZ~7~7 devreasing the need for oxygen. Amongst the products commonly used in humans for treating angina pectoris, can be cited dipyridamole amongst the coronarodilators and amiodarone amongst the compounds which decrease the consumption of oxygen by the myocardium.
Comparative tests have~ however, 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 decrease the consumption of oxygen by the myocardium and that amiodarone cannot be regarded as a coronarodilator.
The derivatives of the present invention exert their effect through both of these factors~ Thus, they decrease the consumption of oxygen by the myocardium through their metabolic effects and also increase the coronaty blood-flow in a long-lasting manner. Moreover, they are capable of preventing or curing nct only arrhythmias induced by ischemia of the myocardium but also the auticular and ventricular arrhythmias of widely varying origins.
Thus, it appears that the halogenating, methoxylating or methylating o indolizine derivatives of British patent N
1,518,443 gives rise to compounds possessing a novel spectrum of pharmacological properties valuable in the treatment of cardiac deficiencies.
For instance :
- thesites of the myocardium which are insufficiently irrigated can be nourished by means of the coronarodilating effect which can induce the development of an additional collateral circu-lation . This effect is valuable for the treatment of both anginal pain and the disturbances of rhythm consequent upon ischemia of the myocardium.
- the antiadrenergic effect is also valuable for the treatment of _ 9 _ ~l~ZC~7~'7 both angina pectoris and cardiac arrhythmia in view of the important role played by hyperacti,vity of the sympathetic system in the etiology of these two cardiac diseases.
Since the physiological mediator of the sympathetic system is epinephrine, a compound which inhibits all the effects of epinephrine will probably be moxe active than a compound which only inhibits a part of these effects.
For this reason, the compounds of the present invention which inhibit both ~and ~effects,of epinephrine present an advantage over the derivatives of the British patent N 1,518,443 which practically only inhibit the ~effects at the minimum dose at which the other pharmacological cardiovascular effects occur.
Amongst the compounds of the invention which have shown the most outstanding anti-anginal potentialities, the following may be cited :
1-Bromo-2-methyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-bromo-benzoyl~-indolizine

2-n-Butyl-3-C4-(3-di-n-butylaminopropyl)-oxy-3-bromo-benzoyl~-indolizine 2-Ethyl-3-~4-,(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl~-indolizine 2-n-Butyl-3-f4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoy~J-indolizine 2-Isopropyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3,5-dichloro-benzoyll-indol,izine l-Bromo-2-phenyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-chloro-bensoyl~- indolizine l-Chloro-2-ethyl-3- ~4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl'l-indolizine l-Chloro-2-n-butyl-3-~4-(3-di-n-butylaminopropyl)-oxy-benzoyl]-indolizine 1-Bromo-2-(4-chloro-phenyl3-3-~4-(3-di-n-butylaminopropyl)-oxy-

3-chloro-benzoyl]-indolizine these compounds being in the form of the free base or of a llS~ 77 pharmaceutically acceptable acid addition salt such as, for example, the hydrochloride or acid oxalate.
The results of pharmacological tests carried out in order to determine the cardiovascular properties of the compounds of the invention are given hereunder.
I, Antianginal proPerties 1) Effect on blood-flow to the myocardium.

This test was carried out in accordance with the technique described by R. CHARLIER & J.BAUTEIIER in Arzneimittel - Forschung "Drug Research" 23, n 19, 1305-1311 (1973).
It was undertaken on anaesthetized dogs which received the substance under study by intravenous route. The intensity of the maximum effect on blood-fLow to the myocardium was expressed in percentage of the corresponding value before injection. The time required for the maximum effect to decrease by 50% repre-sented the duration of the effect. This time was measured in minutes.

il5~2~77 The following results were registered :

RX2 _o / R

i C~ (CH2) n N~
3 . Rl Xl x2 X3 R R1n Dose Max. Time (mg/ lnCrea requi-. kg) se~(%) decdrea-~ _ se Br Br H C2H5 n-C4Hg 310 60 90 Br Br H CH3 n-C4Hg 310125 40 Br Br EI n-C4Hg n~C3H7 3 lo 100 20 Br Br H 3 7 n~C3H7 3 10 90 20 Br Br H ~ n~C3H7 3 10 100 20 ,Br Br Br H ~ n-C4Hg 3 10 150 100 H Br H ~ ~ -Br N-C4~Ig 310 90 25 Br Br H CH3 n-C4Hg 310 77 45 H Br H 3 7 n-C4Hg 32 120 25 H Br H n-C4Hg n-C4Hg 3 5 70 60 Br Cl H iso-C H n-C4Hg 3 5 133 20 Cl H H n-C4Hg n-C4~Ig 3 10 60 30 H Cl C1 iso-C3H n-C4Hg 3 10 30 75 H Cl Cl - ~ > -Br n-C4Hg 3 10 45 15 H C1 ¦ Cl iso-C3H7 n-C4H9 3 10 30 75 . - 12 -~15Z~

H C 1 H n-C 4H 9~ ~ 1 0 3 0 ; 4 S

H -.. Cl H ~~ n~C3H7 38 45 25 El Cl H i so-C H7 n- C3117 35 8 0 9 0 Br Cl H ~ n-C4Hg 310 90 90 Br Cl H n-C4Hg n~C3H7 310 40 90 Br Cl H ~ ~ -Br n~C3H7 310 50 50 H Cl H n-C4Hg n-C4Hg 35 75 30 H Cl H C2H5 n-C4EIg 36 70 45 Br Cl H -~-Cl n~C3H7 310 63 45 H Cl H ~ ~ -Br n-C4Hg 310 60 2 5 Br Cl H n-C l-I n-C~EIg 32 . 5 50 60 Cl Cl H ~~ n-C3I~7 38 70 90 Cl Cl H C2H5 n-C4Hg 31 40 15 Cl Cl H C2H5 n~C3H7 33, 3 60 25 Cl , ~ _~_ Cl n-C3117 35 50 40 Butoprozine 10 120 4 Amiodarone 10 36 7 30 These results clearly show that the compounds of the invention are more valuable than butoprozine and amiodarone as regards the effects on blood-flow to the mycardium.

2) Atladrenerqlc ef~ects The purpose of this test was to determine the capacity oE the compounds under study to reduce epinephrine-increased blood-pressure (anti-~effect) and epinephrine-accelerated heart rate (anti ~ effect) in the do~ previously anaesthetized with pentobarbital and atropinized.
- Ant~ ==e=_=ct For each dog, the dose of epinephrine was first determined which provoked a reproductible increase by about 100 mm. Hg in the arterial pressure (between 5 and 10 ~g/kg).
After that/ the dose of epinephrine so determined was administered followed by a dose by intravenous route of the compound to be studied~ The percentage of reduction of the hypertension provoked by the compound under study in comparison with the hypertension previously obtained (about 100 mm.Hg) was then registered.

- Aati~~==8=f==Ct During the same test as that described above, the epinephrine provoked a reprocluctible increase in the heart-rate of about 70 beats/min. The percentage of reduction of theepinephrine-induced accelerat:ion of heart-rate produced by the compound under study in comparison with the tachycardia previ-ously measured (about 70 beats) was then registered.
In both cases, the results were expressed as follows:
+ for a <50%-reduction of the increase in pressure or cardiac frequency ++ for a ~50~-reduction of t:he increase in pressure or cardiac frequency +++ for a subtotal reduction of the increase in pressure or cardiac frequency 1~52(~77 The foLlowing results were registered:

Xl x2 X3 R Rl Dose Anef~ ~nef~
Kg) ~ect fect , _. .... _ ~ - .
Br Br H C2H5 n~C4H9 3 lO +++ +++
. Br H H C2H,5_ n-c4H9 36 +++ +++

Br E3 r H _ </.=,9-F n-C 4Hg 3 l 0 +++ ++

Br Br Br 3 7 n-C3H7 3 lO +++ +++

H Br H _ ~ ~ n-c4H9 3 10 +++ ++

H Br EI C2H5 n-C4Hg 3 7.5 +++ ++
H Br H n-c4H9 n-c4H9 35 +++ ++
H Br H n-C4Hg n~C3H7 35 +++ ++
Br Br H CH3 n-c4H9 3~105 +++ +++

H Br H n-C4Hg n-C4Hg 3( 5 +++ ++
~10 +++ +++
H Br H i So-C H n-C4Hg 36 +++ ++
Cl E~ H n-C4Hg n~C4H9 3 lO +++ ++
Cl H H n~C3H7 n~C4H9 3 7.5 +++ +++
H Cl H n-C4Hg n~C4H9 3 10 +++ ++
H Cl H C2H5 n~C3H7 3 lO++ ++
H Cl H C2H5 n-C4Hg 3 6+++ ++
H Cl Cl iso C3~E7 n-c4H9 3 10 ++ ++

H Cl H ~ ~ n-c4H9 3 lO ++ ++

H Cl H iso-C3E~7 n-C3H7 3 lO ++ ++

Br Cl H ~~ n-C4Hg 3 lO ++ +++
Br Cl H c2 5 n-C3H7 3 7 . 8 ++ ++

Br Cl H -~-Br n-C3H7 3 lO ++ ++

-- :15 --2(~77 Br Cl H n~C4H9 n~C3H7 3 10 ++ +

Br Cl H - ~ Cl n~C4H9 3 10 ++ ++

Br Cl II ~ ~_Br n~C3H7 3 10 ++ ++

. Br Cl H C2H5 n~C4H9 3 10 +++ +++

Br Cl H~ ~_Cl n~C3H7 3 10 +~+ ++

H Cl H~ Br n-C4Hg 3 10 ++ +
~B:r Br Cl H ~ ~ n~C3H7 3 10 +++ +++

3r Cl ~ ~ 3H~n-C4~19~ ~ 10 ~ +++ +++

Cl Cl h ~n~C3H7 3 8 -~++ ++

Cl Cl H C2H5n-C4Hg 3 0.5 +++ +
Cl Cl H C2H5_n~C3H7 3 3.3. +++ +++

Cl H H - ~ ~ Cl n~C4E19 3 10 +++ ++

Cl 11 M - ~ ~-Cl n-C3117 3 5 +-~ +

Cl H H ~ n-C4119 3 5 ~ +++

H Br H iso-C3H7 n-C3117 3 7.5 +++ +-~
Br OCH3 11 CH3 n~C3H7 3 7.5 ++ ++
Cl Cl Cl C~H5 n~C3H7 3 10 ++ ++

Cl Cl Cl ~ n-C4Hg 3 10 +++ ++

Cl Br H C2H5 n-C4Hg 3 10 +-~+ -~++

Cl Br Br ~ ~ ~ n~C3H7 3 10 + +
.

- ]-6 -~5~(~77 Br Cl Cl ~ n~C3H7 3 10 ++ ++

Br Cl Cl ~ ' n-c4H9 3 10 ++ ++

Br CH3 CH3 CH3 n-C4Hg 3 10 +++ ++

H Br Br - ~ -Br n~C3H7 3 10 +++ +++

H Br Br _ ~ n-C4Hg 3 10 ++ ++

OCH3 Cl H _ ~ ,n-C3ll7 3 l0 +++ +++

OCH3 OCH3 H _ ~n~C3H7 310 ++ ++

H OCH3 H C2II5 n-C4Hg 310 +++ ++
Br OCH3 H C2H5 n-C4ll9 3 5 ++ ++
Br OCH3 H CH3 n~C4H9 3 7 ++ ++
Br OCH3 H 3 n-C3B7 37 5 Butoprozine 5 +++ +
Amiodatone 10 ++ ++

These results again show that the compounds of the invention are more valuable than those of the prior art.
II. Anti-arrhythmic properties.
These properties were demonstrated after administration of the compound under study by intragastric route to mice using the LAWSON test (J. Pharmac. Exp. Therap. 1968, 160 (l) p. 22-31).
The arrhythmia was provoked by making the animals inhale chloroform to total asphyxia and by later observing the ventricular rhythm.
The dose of compound protecting 50% of the animals against ventricular fibrillation i.e. the AD50 was then recorded.
The following results were reg:istered :

l~Ci~77 Xl X2 X3 R Rl n AD50 (my/kg) , ._ . . _ . .

Br Br H CH3 n-C4Hg 3 180 Br H n~C4H9 4 9 3 170 Butoprozine 270 III Toxicity Acute toxicity _____________ Acute toxicity tests were carried out on rats and mice.
The following results were registered in comparison with butoprozine.
The compounds of the invention were used in oxalate acid form except those marked (x) which were tested in hydrochloride form.
a) B=y=i~tr==ven==o===_o======to==r===

Xl X2 X3 R Rl n(mg/kg (x) Br Br H CH3 n~C4M9 3 70 H Br H 4 9 n-C4Hg 3 60 (x) H Cl H C2H5 n~C4E~9 3 65 H Cl Cl iso-C H n-C4Hg 3>100 (x) Br Cl H~ ~ ~ n-C4Hg 3>lO0 (x) H Cl EE n~C4H9 n-C4H9 3 > 50 , (LD ~50 mg/kg Cl Cl HC2H5 n~C4H9 3 50 Cl H E~4 9 ~-C4H9 3 50 Br Cl H- ~ ~-Cl n-C4Hg 3>lO0 (Ld~ lO0 mg/kg Botoprozine 22 b) By _nt=a=venous=ro=t=e==t=o=m=_ce=

(x) Br¦ Br ¦ El ¦ CH3 ¦ n~C4ll9 ¦ 31 50 Butoprozine 25 c) By=i=n=t==g=s=__=c=_o===t==t=o=l=ni=c=

(x) Br ¦Br ¦ H ~ CH3 ~ n~C4Hg ~ 3 ~>5000 Butoprozine 1600 These results show that the compounds of the invention are far less toxic than butoprozine.

- C===dl==c==to=l=_=a=c=e====d=a==n==a_=t=o=xl=cl=ty=l=n=_o==n~-=t=e==m=t=oxi=city ====t=

l-Bromo-2-methyl-3-~4-(3-di-n--butylaminopropyl)-oxy-3-bromo-benzoyl~-indolizine hydrochloride, 2-n-butyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-bromo--benzoyl~-indolizine hydrochloride and 2-n-butyl-3-~4-(3-di-n-but:ylaminopropyl)-oxy-3-chloro-benzoyl~-indolizine hydrochloride provoked neither venticular arrhythmia nor mortality at the dose of 200 mg/kg/day by oral route in the dog.

As against this, butoprozine was found to provok ventricular arrhythmia.with a close as low as 50 mg/kg/day by oral route in the dog, the lethal close of this compound being between 50 and 100 mg/kg/day.
It will be appreciated that for therapeutic use the compounds of the invention wil.l normally be administered in the form of a pharmaceutical or veterinaty composition, which may be in a dosage unit form appropriate to the desired mode of administration.
Thus the pharmaceutical or veterinaty composition may be in a dosage unit form suitable for oral administration, for example a coated or uncoated tablet, a hard- or soft-gelatin capsule, a packaged powder, or a discrete amount of a suspension, ~15Z(~

or a syrup. The composition may alternatively take the form of a suppository Eor rectal administration, or of a solution or suspension for parenteral administration.
When in dosage unit form, the composition may contain for example from 15~ to 50~ by weight of the active ingredient per dosage unit for oral administration, from 3% to 15% of the active ingredient per dosage unit for rectal administration and from 3% to 5~ of the active ingredient per dosage unit parenteral administration.
Irrespective of the form which the composition takes, the pharmaceutical or veterinary composition of the invention will normally be prepared by associating at least one of the compounds of formula I or a pharmaceutically acceptable acid addition salt thereof with an appropriate pharmaceutical carrier or excipient therefor, for example one or more of the following substances : milk sugar, starches, talc, magnesium stearate, polyvinylpyrrolidone, alginic acid, colloidal silica, distilled water, benzyl alcohol or flavouring agents.
The following Examples illustrate the invention :

l-Bromo-2-ethyl-3-[4-(3-di-n-propylaminopropyl)-oxy-3-bromo-benzoyl~-indolizine and its acid oxalate.
a) l-bromo-2-ethyl-3-/ 4-(3-bromoeropyl)-oxy-3-bromo-benzoy~_-mdollzlne A mixture of 7.7. g (0.018 mol) of 1-bromo-3-~3-bromo-

4-hydroxy-benzoyl)-indolizine, 5 g (0.036 mol) of anhydrous potassiuM carbonate and 50 ml of methyl ethyl ketone was stirred in a fla9k for 30 minutes. To this reaction medium 14.4 g (0.072 mol) of 1,3-dibromo-propane were then added and the mixture was refluxed for 20 hours. After cooling, the mineral 30 salts were filtered out and wasked with acetone. The solvents were evaporated off together with the 1,3-dibromo-propane in L
excess. In this manner, 13.2 g of a product were obtained which ~152077 were purified by elution chrc~matography on silica using benzene as elution agent. A first fraction of an unknown product was obtained and then a second fraction vf ~ g of the desired product.
In this manner, 1-bromo-2-ethyl-3- L4- (3-bromopropyl)-oxy-3-bn~o-benzoyl7-indolizine was obtained in a yield of 83.6%.
M.P. : 105-106 C.
b) l_Bromo-2-ethyl-3-C4-(3-di-n-~ro~ylamlno~ro~yl)-oxy-3-bromo-benzoylZ-indollzine A mixture of 2.2. g (0.004 mol) of 1-bromo-2-ethyl-3-r4-(3-bromopropyl)-oxy-3-bromo-~enzoyl7-1ndolizlne, 1.2 g (0.012 mol) of N,N-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 off under vacuum. Thus, 2.5 g of a residue were obtained which were purified by elution chromatography on silica using ethyl acetate as eluent. By this method, 2.4 g of 1-bromo-2-ethyl-3-L4-(3-di-n-propylaminopropyl )-oxy-3-bromo-benzoylJ-indolizine in free base form were obtained.
c) 1 Bromo-2-ethyl-3-~4-(3-di-n-propylamino~ropyl)-oxy-3-brom _____________ ____..__ ____.___ __ ______ __ _ ___ _________ benzoyl]- indolizine acid oxalate.
__.__ ____~_______________.________ The base previously obtained was dissolved in 30 ml of ethyl ether and then react~d with 0.55 g of oxalic acid in 7Q ml of ethyl ether to give 2.4 g of the desired salt in crude form. From this quantil:y, 2.0 g of pure 1-bromo-2-ethyl-3-~4-(3-di-n-propylaminopropy])-oxy-3-bromo-benzoyl~- indolizine acid oxalate were obtained by recristallization from 75 ml of isopropanol.
Yield : 75%
M.P. : 139-140C

EX~MPLE 2 l-Bromo-2-methyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-bromo-benzoyl¦-indolizine and salt, thereof.

_ .. _ . . . ..
Into a 1-1 flask, a mixture of 130 ml of water, 180 ml of toluene, 73 g (0.178 mol) of 1-bromo-2-methyl-3-(3-bromo-~ 4-hydroxy-benzoyl)-indolizine, 42.7 g (0.21 mol) of l-di-n butylamino-3-chloro-propane and 34.5 g of potassium carbonate was introduced while stirring. The reaction medium was heated under reflux for 20 hours. ~fter 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, under atmospheric pressure, toluene was distilled off to dryness and the residue so obtained was cooled.
In this manner, crucle l-bromo-2-methyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-bromo-benzoyl]-indolizine was obtained in free base form.
The following salts of this compound were then prepared :

a) hydrochlorlde To the free base previously obtained, a solution of 8 g of hydrochloric acid in 61 ml of ethyl acetate was added.
The precipitate so formed, i.e. 104 g, was suction-filtered, washed with ethyl acetate and recrystallized from 500 rnl of isopropanol. In this manner, 93 g of 1-bromo-2-methyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-bromo-benzoyl~-indolizine hydrochloride were obtained.

~ield : ~4.7% M.P. : 172 C.
b) acid oxalate _____________ To an ethereal solution of the base previously obtained, an equimolecular solution of oxalic acid in ethyl ether was added. The salt so obtained was recrystallized from isopropanol.

l~S;~(~77 In this manner, l-bromo-2-meth~L-3-~4-(3~di-n~
bytylaminopropyl)-oxy-3-bromo-benzoyl]-indolizine acid oxalate was obtained. M P. :89-90 C.

2-Methyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3,5-dibromo-benzoylJ-indo;lizine acid oxa:Late.
Into a 250 ml-flask, a mixture of 4 g (0.01 mol) of 2-methyl-3-(3,5-dibromo-4-hydroxy-benzoyl)-indolizine and 150 ml of acetone was introduced After the indolizine dissolved, there were added 4 g of anhyclrous potassium carbonate and 2.2 g of di-n-butylaminopropyl chloride~
While stirring, the reaction mixture was refluxed for 16 hours. After cooling to room-temperature, the mineral salts were filtered out and washed with acetone on the filter.
The acetone was then distilled off under reduced pressure using a rotatory 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. The reaction medium was allowed to stand and the oxalate which crystalIized was filtered out, washed on the filter with ethyl acetate and dried under vacuum.
In this manner, 6.2 g of 2-methyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3,5-dibromo-benzoyl~-indolizine acid oxalate were obtained.
Yield : 92.7%
M.P. : 96 C.

_ l-Bromo-2-ethYl-3-~4~3-di-n-Propylaminopropyl)-oxy-3,5-dichlorobenzoyl~-indolizine acid oxalate.
.
Into a 250 ml-flask were introduced 2.8 g (0.005 mol) of 2-ethyl-3-l4-(3-di-n-propylaminopropyl)-oxy-3,5-dichloro-benzoyl]-indolizine acid oxalate and 80 ml of dioxan. The liS2(~77 reaction mixture was stirred and after the indolizine had di.ssolved, 0.8 g of anhydrous sodium acetate was added, dropwise and under vigorous stirring, a solution of 0.8 g of bromine in 20 ml of dioxan. The temperature was mainteined at about 20C during the introduction of the bromine.
After the medium had been stirred for 2 hours at room-temperature, the dioxan was distilled off under vacuum with a rotatory evaporator. The sol:id residue was disso~.ved in water, made alkaline with a sodium hydroxide solution and extracted with chloroform. The chloroformic solution was washed three times with water and the chloroform was distilled off under reduced pressure. The oily residue so obtained was taken up in dry ethyl ether and after f.iltration on a filter the acid oxalate was formed.
In this manner, 1.8 g of 1-bromo-2-ethyl-3-[4-(3-di-n-propylaminopropyl)-oxy-3,5-dichloro-benzoyl~ indolizine acid oxalate was obtained after recristallization from ethyl acetate.
Yield : 55.8%
M.P. : 135C.
Using the appropriate starting-products, the following compounds were prepared by uti.lizing the various processes described in the foregoing Examples.
Compounds M.P._ C
l-Bromo-2-ethyl-3-L4-(3-di-n-butylaminopropyl)-oxy-benzoyl~-indolizine acid oxalate 107-108 (isopropanol) l-Bromo-2-(4-bromo-phenyl)-3- ~-(3-di-n-butylaminopropyl)-oxy-benzoyl]-indolizine92-94 acid oxalate (isopropanol) l-Chloro-2-methy].-3-~4-(3-di-n-butylaminopropyl)-oxy-benzoyl~-indolizine acid oxalate 92-93 (isopropanol) - 2~ _ 11512~77 l-Chlor~-2-ethyl-3-[4-(3-di-n-propylaminopropyL)-oxy-benzoyl~-indolizine acid oxalate 162 (isopropanol) l-Chloro-2-n-propyl-3- L4- (3-di-n-butylaminopropyl)-oxy-benzoyl~-indolizine acid oxalate 111-112 (isopropanol) l-Chloro-2-n-buty-3-~4-(3-di-n-butylaminopropyl)-oxy-benzoyl~-indolizine acid oxalate 106-108 (isopropanol) l-Chloro-2-phenyl-3-C4-(3-di-n-propylaminopropyl)-oxy-benzoyl~-indolizine acid oxalate 161-162 (isopropanol) l-Chloro-2-(4-chloro-phenyl)-:3-L4-(3-di-n-butylaminopropyl)-oxy-benzoyl~-indolizine acid oxalate 158-159 (methanol) l-Chloro-2-phenyl-3-[4-(3-di-n-butylaminopropyl)-oxy-benzoyll-indolizine acid oxalate 160-161 (methanol) l-Chloro-2-n-butyl-3-L4-(6-di-n-butylaminohexyl)-oxy-benzoyl~-indolizine acid oxalate 80-82 (benzene) 20 2-Methyl-3-l4-(3-di-n-butylam.inopropyl)-oxy-3-bromo-benzoyl]-indolizine acid oxalate 141-143 (10/1 ethyl acetate/
isopropanol) 2-Ethyl-3-L4-(3-di-n-propylam:inopropyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 163 (isopropanol) 2-Ethyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 98-99 (isopropanol) 2-n-Propyl-3-r4-(3-di-n-propylaminopropyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 145 (isopropanol) 2-n-Propyl-3-[4-(3-di-n-butylaminopropyl)-oxy 3-bromo-benzoyl~-indolizine acid oxalate 113-115 (isopropanol) ~152,~77 2-Isopropyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate105-107 (benzene) 2-n-Butyl-3-~4-(3-di-n-propylaminoprop~l)-oxy-3-bromo-benzoyl¦-indolizine acid oxalate 136-137 (isopropanol) 2-n-Butyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate86-87 (isopropanol) 2-Phenyl-3-~4-(3-di-n-propylaminopropyl) oxy-3-bromo-benzoyl~-indolizine acid oxalate148-149 (isopropanol) 2-Phenyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate129-130 (isopropanol) 2-(4-Fluoro-phenyl)-3-[4-(3-di-n-butylamino-propyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 110 (isopropanol) 2-(4-Chloro-phenyl)-3-~4-(3-di-n-propylamino-propyl-oxy-3-bromo-benzoylJ-indolizine acid oxalate 163-164 . (methanol) 2-(4-Chloro-phenyl)-3-~4-(3-di-n-butylaminopro-pyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 139-140 (isopro~anol) 2-(3-Bromo-phenyl)-3-[4-(3-di-n-propylaminopro-pyl)-oxy-3-bromo-benzoyl~-ind.olizine acid oxalate 142-143 (isopropanol) 2-(4-Bromo-phenyl)-3-[4-(3-di-n-butylaminopro-pyl)-oxy-3-bromo-benzoylJ-indolizine acid oxalate 147-148.5 (methanol) 2-(4-Methoxy-phenyl)-3-~4-(3-di-n-butylaminopro-pyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 169 (isopropanol) 1~52(~77 2-Isopropyl-3-~4--(5-di-n-butylaminopentyl)-oxy 3-bromo-benzoyl~-indolizine acid oxalate 80-82 (benzene) 2-Isopropyl-3-~4-(3-di-n-propylaminopropyl)-oxy-3 -bromo-benzoyl~-indolizine acid oxalate 179 (isopropanol) 2-Methyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate 141-143 (isopropanol) 2-Ethyl-3-C4-(3-di-n-propylaminopropyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate 161-162 (methanol) 2-Ethyl-3-t4-(3-di-n-butylami:nopropyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate 116-117 . (isopropanol) 2-Isopropyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate 115-117 (isopropanol) 2-Isopropyl-3-L4-(3-di-n-propylaminopropyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate 168-169 (methanol) 2-n-Butyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate 84-85 and (isopropanol) 2-n-Butyl.-3-~4-(3-di-n-propylaminopropyl)-oxy-3-chloro-benzoyl~-indoLizine acid oxalate 130-131 (isopropanol) 2-Phenyl-3-L4-(3-di-n-butylaminopropyl)oxy-3 -chloro-benzoyl]-indolizine acid oxalate 121-122 (isopropanol) 2-Phenyl-3-[4-(3-di-n-propyla:minopropyl)oxy-3-chloro-benzoyl~-indolizine acid oxalate 157-159 (methanol) 2-(4-Methyl-phenyl)-3-L4-(3-di-n-propylaminopro-pyl)-oxy-3-chloro-benzoylJ-indolizine acid oxalate 134-135 (isopropanol) ~lSZ~77 2-(4-Bromo-phenyl)-3-L4-(3-di-n-propylaminopro-pyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate 154-155 (methanol) 2-(4-Bromo-phenyl)-3-C4-(-di-n-butylaminipro-pyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate . 134-135 (isopropanol) 2-(3-Bromo-phenyl)-3-~4-(3-di-n-butylaminopro-pyl)oxy-3-chloro-benzoyl~-indolizine acid 10 oxalate 92-93 (isopropanol) 2-(3-Bromo-phenyl)-3-C4-(3-di-n-propylaminopro-pyl)-oxy-3-chloro-benxoyl~-indolizine acid oxalate 148-150 (isopropanol) 2-(4-Chloro-phenyl)-3-C4-(3-di-n-butylaminopro-pyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate 116-118 (isopropanol) 2-(4-Chloro-phenyl)-3-L4-(3-di-n-propylamino-propyl)oxy-3-chloro-benzoyl~-indolizine acid oxalate 159-160 (methanol) l-Bromo-2-methyl-3 ~4-(3-di-n-butylaminopro-pyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 89-90 (isopropanol) l-Bromo-2-methyl-3-L4-(3-di-n-propylaminopro-pyl~-oxy-3-bromo-benzoyl~-indolizine acid oxalate 164-165 (isopropanol/
methanol) l-Bromo-2-ethyl-3-[4-(2-dimethylaminoethyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 164-165 (dichlorethane) ~s2~7 l-Bromo-2-ethyl-3- L4- ( 3-dimet:hylaminopropyl)-oxy-3-bromo-benzoyl~-indolizi.ne acid oxalate 150-151 (dichlorethane) l-Bromo-2-eth~1-3-~4-(2-diethylaminoethyl)-oxy-3-bromo-benzoyl~-indolizi.ne acid oxalate 16~-169 (dichlorethane) l-Bromo-2-ethy-3-L4-(3-diethylaminopropyl)-oxy-3-bromo-benzoyl¦-indolizine acid oxalate 140-141.5 (isopropanol) l-Bromo-2-ethyl-3-[4-(2-di-n-propylaminoethyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 163-164 (isopropanol) l-Bromo-2-ethyl-3-r4-(3-di-n-propylaminopro-pyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 1.39-140 (isopropanol) l-Bromo-2-ethyl-3 L4-(2-di-n-butylaminoethyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 164-165 (isopropanol) l-Bromo-2-ethy-3-~4-(3-di-n-butylaminopro-pyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 101-101.5 (isopropanol) l-Bromo-2-n-propyl-3-r4-(3-di-n-butylamillopro-pyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 92 (benzene) l-Bromo-2-n-propyl-3-~4-(3-di--n-propylaminopro-pyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 132-136 (isopropanol) l-Bromo-2-n-butyl-3-C4-(3-di-n-propylaminopro-pyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 151-152 (2/1 isopropanol/
methanol) 7~

l-Bromo-2-n-butyl-3-[4-(3-di-n-butylaminopro-pyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 101-103 . (isopropanol) l-Bromo-2-phenyl-3- [4-(3-di-n-propylaminopro-pyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 169-170 (1/1 metyanol/iso-propanol) l-Bromo-2-phenyl-3-L4-(3-di-n-butylaminopro-pyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 167-169 (isopropanol) l-Bromo-2-(4-methoxy-phenyl)-3-[4-(3-di-n-buty-laminopropyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 17~-179 (methanol) l-Bromo-2-(4-methyl-phenyl)-3-l4-(3-di-n-buty-laminopropyl -oxy-3-bromo-benzoyl~-indolizine acid oxalate 169-170.5 (1/1 isopropanol/
methanol) l-Bromo-2-(4-fluoro-phenyl)-3-l4-(3-di-n-buty-laminopropyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 170-171 (methanol) l-Bromo-2-(3-bromo-phenyl)-3-l4-(3-di-n-buty-laminopropyl)-oxy-3-bromo-berlzoyl~-indolizine acid oxalate . 172-173 (methanol) l-Bromo-2-n-butyl-3-~4-(4-di-n-butylamino-butyl)-oxy-3-bromo-l)cnzoyl~ dolizillc acid oxalate 11~-120 (isopropanol) 30 1-Chloro-2-ethyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate 115-117 (isopropanol) .".,~ - 30 -:115~(~77 l-Chloro-2-ethyl-3- L4- ( 3-di-n-propylamirlopro pyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate 137-133 (isopropanol) 1-Chloro-2-(3-bromo-phenyl)-3- [4- ( 3-di-n-buty-laminopropyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate 171-172 (methanol) l-Chloro-2-(3-bromo-phenyl) 3-~4- (3-di-n-propyl-aminopropyl)-oxy-3-chloro-benzoylJ-indolizine acid oxalate 194-195 (methanol) l-Chloro-2-ethyl-3-L4-(3-di-n-propylaminopro-pyl)-oxy-3,5-dichloro-benzoy~ -indolizine 141 (ethyl acetate ) acid oxalate l-Chloro-2-ethyl-3-[4-(3-di-n-butylaminopro-pyl)-oxy-3,5-dichloro-benzoy~]-indolizine 129 (acid acetate ) acid oxalate l-Chloro-2-phenyl-3-~4-(3-di-n-propylaminopro-pyl)-oxy-3,5-dichloro-benzoyl~-indolizine acid oxalate 156 (isopropanol) l-Chloro-2-phenyl-3- L4- ( 3-di-:n-butylaminopro-pyl)oxy-3,5-dichloro-benzoyl~-indolizine 136 (isopropanol/
acid oxalate heptane) l-Bromo-2-methyl-3-~4-(3-di-n-propylaminopro-pyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate 110-112 (isopropanol) l-Bromo-2-methyl-3-[4-(3-di-n-butylaminopro-pyl)-oxy-3-chloro-benzoylJ-indolizine acid oxalate 103-110 (isopropanol) l-Bromo-2-ethyl-3-C4-(3-di-n-propylaminopro-pyl)-oxy-3-chloro-benzoyl~-indolizine acid l~ SZ~77 oxalate 136.5-138 (isopropanol) l-Bromo-2-ethyl-3-~4-(3-di-n-butylaminopro-pyl)~oxy-3-chloro-benzoyl]-indolizine acid oxalate 103-105 (isopropanol) l-Bromo-2-n-propyl-3-~4-(3-di-n-butylaminopro-pyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate 95-96 (isopropanol) l-Bromo-2-isopropyl-3- ~4-(3-di-n-butylamino-propyl) oxy-3-chloro-benzoyl~-indolizine acid oxalate 116 (isopropanol) l-Bromo-2-n-buty-3- L4- (3-di-n-propylamino-propyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate 159-160 (methanol) l-Bromo-2-n-butyl-3- ~4- (3-di-rl-butylamino-propyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate 101-103 (isopropanol) 20 1-Bromo-2-phenyl-3- ~4-(3-di-n--butylaminopro-pyl)-oxy-3-chloro-benzoyl~-inclolizine acid oxalate 167.5-169 (methanol) l-Bromo-2-phenyl-3- ~4- (3-di-n-propylaminopro-pyl)-oxy-3-chloro-benzoyl]-indolizine acid oxalate 169-170 (methanol) l-Bromo-2-(4-chloro-phenyl)-3-~4-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate 160-161 (isopropanol) l-Bromo-2-(4-chloro-phenyl)-3-[4-(3-di-n-propylaminopropyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate 184-185 (methanol) ~lSZ~77 l-Bromo-2-(4-bromo-phenyl)-3-L4-(3-di-n-propylaminopropyl)-oxy-3-chloro-benzoyll-indolizine acid oxalate 176-177 (methanol) l-Bromo-2-(4-bromo-phenyl)-3- ~4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate 168-169 (isopropanol) l-Bromo-2-(3-bromo-phenyl)-3-L4-(3-di-n-propylaminopropyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate 200-201 (methanol) l-Bromo-2-(3-bromo-phenyl)-3-~4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate 170.5-172 (methanol) l-Chloro-2-ethyl-3-[4-(3-di-npbutylaminopro-pyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 104-105 (isopropanol) l-Chloro-2-ethyl-3- L4-(3-di-n-propylaminopro-pyl)-oxy-3,5-dibromo-benzoyl~-indolizine acid oxalate 157 (isopropanol) l-Chloro-2-ethyl-3-[4-(3-di-n7butylaminopro-pyl)-oxy-3,5-dibromo-benzoy~-indolizine 140 (isopropanol) acid oxalate 1-Chloro-2-phenyl-3-~4-(3-di-n-propylamino-propyl)-oxy-3,5-dibromo-benzoyl~-indo-lizine acid oxalate 172 (isopropanol) l-Chloro-2-phenyl-3-~4-(3-di-n-butylamino-propyl)-oxy-3,5-dibromo-benzoy~ -indolizine acid oxalate 146 (isopropanol) .~ls2a~7 2-Methyl-3-L4-(3-di-n-propylaminopropyl)-oxy-3,5-dibromo-benzoyl~-indolizine sesqui-oxalate 136 (ethyl acetate) 2-Ethyl-3-[4-(3-dimethylaminopropyl)-oxy-.3,5-dibromo-benzoyl~-indolizine acid oxalate 148 (ethyl acétate) 2-Ethyl-3-[4-(2-diethylaminoethyl)-oxy-3,5-dibromo-benzoyl~-indolizine ac:id oxalate 171 (ethanol) 2-Ethyl-3- ~-(3-diethylaminopropyl)-oxy-3,5-dibromo-benzoyl~-indolizine hydrochloride 191 (50/50 ethyl ace-tate/acetone) 2-Ethyl-3- ~4-(3-di-n-propylamlnopropyl)-oxy-3,5-dibromo-benzoyl]-indolizine hydrochloride 166 (ethyl acetate) 2-Ethyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3,5-dibromo-benzoyl~-indolizine hydrochloride 157 (ethyl acetate) 2-n-Propyl-3-~4-(3-di-n-propylaminopropyl)-oxy-3,5-dibromo-benzoyl~-indolizine hydrochloride 145 (ethyl-acetate) 2-n-Propyl-3-L4-t3-di-n-butylaminopropyl)-oxy-3,5-dibromo-benzoyl~_indolizine acid oxalate 107 (ethyl acetate) 2-Isopropyl-3-~4-(3-di-n-propylaminopropyl)-oxy-3,5-dibromo-benzoy~ -indolizine acid oxalate 126 (ethyl acetate/
ethanol) 2-Isopropyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3,5-dibromo-benzoy~ -indolizine acid .

~ 152(~77 oxalate 86 (ethyl acetate/ethyl ether) 2-n-Butyl-3-[4-(3-di-n-propylaminopropyl)-oxy-3,5-dibromo-benzoyl~-indoLizine acid oxalate 146 (ethyl acetate) 2-n-Butyl-3-L4-(3-di-n-butylaminopropyl)-oxy-3,5-dibromo-benzoyl~-indolizine 110 (ethyl acetate) acid oxalate 2-Phenyl-3-~4-(3-di-n-propylaminopropyl)-oxy-3,5-dibromo-benzoyl~-indo:Lizine acid oxalate 142 (ethyl acetate/
ethanol) 2-Phenyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3,5-dibromo-benzoyl~-indol.izine acid oxalate 86 (ethyl acetate) 2-(4-Fluoro-phenyl)-3-[4-(3-di-n-propylamino-propyl)-oxy-3,5-dibromo-benzoyl~-indolizine acid oxalate 166 (ethyl acetate/
ethanol) 2-(4-Fluro-phenyl)-3-~4-(3-di-~-butylami-nopropyl)-oxy-3,5-dibromo-benzoyl]-indoli-zine acid oxalate 152 (isopropanol) 2-(4-Chloro-phenyl)-3-~4-(3-di-n-propyla-minopropyl)-oxy-3,5-dibromo-benzoyl~-indo-lizine acid oxalate 190 (ethyl acetate) 2-(4-Chloro-phenyl)- 3-[4-(3-d:i-n-butylamino-propyl)-oxy-3~5-dibromo-benzoyl~-indolizine acid oxalate 88 (ethyl acetate) 9L~5~(~77 2-(3,4-Dichloro-phenyl)-3-~4-(3-di-n-propyla-minopropyl)-oxy-3,5-dibromo-benzoyl~~indolizine sesquioxalate 114 (ethyl acetate/iso-~ propanol) 2-(3,4-Dichloro-phenyl)-3- [4-(3-di-n-butyl-aminopropyl)-oxy-3,5-dibromo-benzoyl~-indo-lizine acid oxalate 95 (ethyl acetate/iso-propanol) 2-(3-Bromo-phenyl)-3-[4-(3-di-n-propylami-nopropyl)-oxy-3,5-dibromo-benzoyl~-indoli-zine acid oxalate 136 (ethanol) 2-(3-Bromo-phenyl)-3-[4-(3-di--n-butylaminopro-pyl)-oxy-3,5-dibromo-benzoyl~--indolizine acid fumarate 122 (ethyl acetate) 2-(4-Methyl-phenyl)-3- ~4-(3-di-n-propylamino-propyl)-oxy-3,5-dibromo-benzoyl~-indolizine acid oxalate 126 (ethyl acetate/
isopropanol) 2-(4-Methyl-phenyl)-3-[4-(3-di-n-butylamino-propyl)-oxy-3,5-dibromo-benzoyl~-indolizine acid oxalate 90 (ethyl acetate) 2-(4-Methoxy-phenyl)-3-[4-(3-di-n-propylamino-propyl)-oxy-3,5-dibromo-benzoyl~-indolizine acid oxalate 167 (acetone) 2-(4-Methoxy-phenyl)-3-r4-(3-di-n-butylaminopropyl)-oxy-3,5-dibromo-benzoyl~-indolizine acid oxalate pasty at about 70C
(ethanol/ethyl ether) 2-Methyl-3-C4-(3-di-n-propylaminopropyl)-oxy-3,5-dichloro-benzoyl~-indolizine ~L~SZU7t7 acid oxalate 145 tethyl acetate/ethanol) 2-Methyl-3-L4-(3-di-n-butylaminopropyl)-oxy-3,5-dichloro-benzoyl~-indolizine 95 (ethyl acetate/ethyl acid oxalate ether) .2-Ethyl-3- L4-(3-di-n-propylami.nQpropyl,-oxy-3,5-dichloro-benzoyl~-indolizine acid oxalate 100 (pasty)(ethyl acetate) 2-Ethyl-3-~4-(3-di-n-butylaminopropyl)-10 oxy-3,5-dichloro-benzoyl~-indolizine 95 (ethyl acetate) acid oxalate 2-n-Propyl-3-~4-(3-di-n-propylaminopro-pyl)-oxy-3,5-dichloro-benzoyl~-indolizine acid oxalate 142 (isopropanol) 2-n-Propyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3,5-dichloro-benzoyl]-indolizine 114 (isopropanol) acid oxalate 2-Isopropyl-3-~4-(3-di-n-propylaminopropyl)-oxy-3,5-dichloro-benxoyl~-indolizine acid oxalate 36 (ethyl acetate) 2-Isopropyl-3- [4-(3--di-n-butylaminopropyl)-oxy-3,5-dichloro-benzoyl~-indolizine acid oxalate 90 (ethyl acetate) 2-Phenyl-3-~4-(3-di-n-propylaminopropyl)-oxy-3,5-dichloro-benzoy].~-indolizine acid oxalate 146 (ethanol) 2-Phenyl-3-C4-(3-di-n-butylaminopropyl)-oxy-3,5-dichloro-benzoyl~-indolizine acid oxalate (pasty at about 90C
. (ethyl acetate) 2-(4-Bromo-phenyl)-3-[4-(3-di-n-propyl-aminopropyl)-oxy-3 t 5-dichloro-benzoyl]-indolizine acid oxalate 174 (ethyl acetate) 2-(4-Bromo-phenyl)-3- ~4-(3-di-n-butyla-.minopropyl)-oxy-3,5-dichloro-benzoyl~-indolizine acid oxalate . 133 (ethyl acetate) l-Bromo-2-methyl-3- ~4-(3-di-n-butyla-minopropyl)-oxy-3,5-dibromo-benzoyl]-indolizine acid oxalate 141-143 (isopropanol) l-Bromo-2-n-propyl-3-[4-~3-di-n-propyla-minopropyl)-oxy-3,5-dibromo-benzoyl]-indolizine acid oxalate 138-139 (isopropanol) l-Bromo-2-ethyl-3- ~4-(3-di-n-butylamino-propyl)-oxy-3,5-dibromo-benzoyl~-indoli-zine acid oxalate 131-132.5 (isopropanol) l-Bromo-2-phenyl-3- ~4-(3-di-n-butylamino-propyl)-oxy-3,5-dibromo-benzoyl~-indoli-zine acid oxalate 160-161 (isopropanol) l-Bromo-2-(4-methyl-phenyl)-3-~4-(3-di-n-butylaminopropyl)-oxy-3,5-dibromo-benzoyl~-indolizine acid oxalate 105-106 (isopropanol) l-Bromo-2-(4-bromo-phenyl)-3-[4-(3-di-n-butylaminopropyl)-oxy-3,5-dibromo-benzoyl]-indolizine acid oxalate 148-149 (isopropanol) :
l-Bromo-2-(3,4-dichloro-phenyl)-3-[4-(3-di-n-butylaminopropyl)-oxy-3,5-dibromo-ben-zoyl]-indolizine acid oxalate 196-197 (isopropanol) - 3~ -~:152{~7 1-Bromo~2-(3-chloro-4-methyl-phenyl)-3- L4-(3-di-n-butylaminopropyl)-oxy--3,5-dibromo-benzoyl~-indolizine acid oxalate168-169 (isopropanol) l-Bromo-2-ethyl-3- ~4-(3-di-n-butylaminopro-pyl)-oxy-3,5-dichloro-benzoyl~-indolizine acid oxalate 134 (isopropanol l-Bromo-2-phenyl-3-~4-(3-di-n-propylamino-propyl)-oxy-3,5-dichloro-benzoyl~-indolizine 10 acid oxalate 145 (ethyl acetate) l-Bromo-2-phenyl-3-~4-(3-di-n-butylamino-propyl?-oxy-3,5-dichloro-benzoyl~-indolizine acid oxalate 106 (ethyl acetate) 2-n-Butyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-bromo-benzoyl~-indolizine hydrochloride 113-113.5 (ethyl acetate) 2-n-Propyl-3-~4-(3-diethyl-aminopropyl)-oxy-3,5-dibromo-benzoy~ -indolizine hydrochloride 154 (80/20 ethyl ace-tate/acetone) 2-Ethyl-3-t4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl~-indolizine hydrochloride 132-133 (ethyl acetate/
isopropanol) 2-n-Butyl-3-~4-(3-di-n-butyl.aminopropyl)-oxy-3-chloro-benzoy].~-indolizine hydrochloride 104 (ethyl acetate) l-Bromo-2-phenyl-3-[4-(3-di-n butylaminopropyl)-oxy-3-chloro-benzoyl~-indolizine hydrochloride 156-157 l-Chloro--2-(4-chloro-phenyl)-3-~4-(3-di-n-propyl-aminopropyl)-oxy-benzoyl~-indolizine acid oxalate 168-169 (methanol) l-Methoxy-2-phenyl-3- ~4-(3-di-n-propylaminopropyl)-oxy-benzoyl~-indolizine acid oxalate117 (ethyl acetate~

~,,.
*

~i.5~0~

l-Methoxy-2-phenyl-3-[4-(3-di-n-butylaminopropyl)-oxy-benzoll-indolizine acid oxalate 80 ~ (ethyl acetate) l-Methoxy-2-phenyl-3- l4- ( 3-di-n-propylaminopropyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate 172 (ethyl acetate) l-Methoxy-2-phenyl-3- [4- (3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl~-indolizine acid oxalate 120 . (ethyl acetate) l-Methoxy-2-phenyl-3-[4-(3-di-n-propylaminopropyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 160 (ethyl acetate) l-Methoxy-2-phenyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 78 (ethyl acetate) l-Methoxy-2-phenyl-3- L4- ( 3-di-n-propylaminopropyl)-oxy-3-methoxy-benzoyl~-indolizine acid oxalate 148 (ethyl acetate) l-Methoxy-2-phenyl-3- [4-(3-di-:n-butylaminopropyl)-oxy-3-methoxy-benzoy~ -indolizine acid oxalate 78 (ethyl acetate) l-Methoxy-2-(4-fluoro-phenyl)-:3-l4-(3-di-n-propylaminopropyl)-oxy-3-methoxy-benzoyl~-indolizine acid oxalate 79 (ethyl acetate) 2-Methyl-3-L4-(3-di-n-butylaminopropyl)-oxy-3-methoxy-benzoyl~-indolizine acid oxalate 159 (isopropanol) 2-Methyl-3-L4-(3-di-n-propylami.nopropyl)-oxy-3-methoxy-benzoyl~-indolizine acid oxalate 171 (methanol) 2-Ethyl-3-C4-(3-di-n-butylaminopropyl)-oxy-3-methoxy-benzoyl~-indolizine acid oxalate 88 . (ethyl acetate) 2-Ethyl-3-C4-(3-di-n-propylaminopropyl)-oxy-3-methoxy-benzoyl~-indolizine acid oxalate 121-122 (ethyl acetate) ~15~077 1-Bromo-2-methyl-3-f4-(3-di-n-butylaminopropyl)-oxy-3-methoxy-benzoyl~-indolizine acid oxalate 87-90 (benzene) l-Bromo-2-methyl-3-~4-(3-di-n-propylaminopropyl)-oxy-3-methoxy-benzoyl~ indolizine acid oxalate 139-141 (isopropanol) l-Bromo-2-ethyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-methoxy benzoyl~-indolizine acid oxalate 111 (benzene) l-Bromo-2-ethyl-3-~4-(3-di-n-propylaminopropyl-oxy-3-methoxy-ben`zoyl~--indolizine acid oxalate 149 (isopropanol) 2-(4-Fluoro-phenyl)-3-~4-(3-di-n-butylaminopropyl)-oxy-3-methoxy-benzoyl~-indolizine acid oxalate 85 (ethyl acetate) 2-Methyl-3-~4-(3-di-n-butylaminopropyl)-oxy- 149 (isopropanol) 3-methyl-benzoyl~-indolizine acid oxalate 2-Ethyl-3-~4-(3-di-n-butylami.nopropyl)-oxy- 133 (ethyl acetate) 3-methyl-benzoyl~-indolizine acid oxalate l-Methyl-2-n-propyl-3-~4-(3-d:i-n-butylaminopropyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate127 (ethyl acetate) 2-Isopropyl-3-~4-(3-di-n-buty.laminopropyl)-oxy-3-methyl-benzoyl~-indolizine acid oxalate (isopropanol) 2-n-Butyl-3-~4-(3-di-n-butylaminopropyl)-oxy 89 (isopropanol) 3-methyl-benzoyl~-indolizine acid oxalate l-Methyl-2-n-butyl-3-f4-(3-di-n-butylaminopropyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate(ethyl acetate) l-Methyl-2-ethyl-3-~4-(3-di-n--butylaminopropyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate117 (ethyl acetate) l-Bromo-2-methyl-3-~4-(3-di-n--butylaminopropyl)-oxy-3,5-dimethyl-benzoyl~-indolizine acid oxalate 120-122 (isopropanol) ~.~52077 l-Ido-2-ethyl-3-~4-(3-di-n--butylaminopropyl)-oxy-3,5-dimethyl-benzoyl~-inclolizine acid oxalate 115 (ethyl acetate) 2-Ethyl-3-~,3-dichloro-4-(3-di-n-propylamino-propyl)-oxy-benzoyl~-indolizine 117 (heptane) 2-Ethyl-3-~2,3-dichloro-4-(3-di-n-butylamino-propyl)-oxy-benzoyl~-indolizine 95 (heptane) 2-Phenyl-3-~2,3-dichloro-4-(3-di-n-propylamino-propyl)-oxy-benzoyl~-indolizine 99 (heptane) 2-Phenyl-3-~2,3-dichloro-4-(3-di-n-butylamino-propyl)-oxy-benzoyl~-indolizine 87 (heptane) 2-(4-Fluoro-phenyl)-3-~2,3-dichloro-4-(3-di-n-propylaminopropyl)-oxy-benzoylJ'-indolizine 119 (heptane) 2-(4-Fluoro-phenyl)-3-~2,3-dichloro-4-(3-di-n-butylaminopropyl)-oxy-benzoyl~-indolizine95-96 (heptane) l-Bromo-2-ethyl-3-~2,3-dichloro-4-(3-di-n-butylaminopropyl)-oxy-benzoyl~-indolizine acid oxalate 164 (isopropanol) l-Bromo-2-phenyl-3-~2,3-dichloro-4-(3-di-n-propylaminopropyl)-oxy-benzoyl~-indolizine acid oxalate 171 (isopropanol) l-Chloro-2-phenyl-3- ~ ,3-dichloro-4-(3-di-n-propylaminopropyl)-oxy-benzoyl~'-indolizine 136 (heptane) 2-n-Butyl-3-~4-(3-di-n-butylclminopropyl)-oxy-3-iodo-benzoyl~-indolizine acid oxalate90-92 (ethyl acetate) .. _. . .
In accordance with known pharmaceutical techniques soft-gelatin capsules containing the following ingredients, were prepared:
Inqr_dient mq 2-n-Butyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-bromo/or 3-chloro-benzoyl~-indolizine Hydrochloride 100 Starches 99. 5 10 Colloidal silica 0.5 200.0 BXAMPL:E 6 In accordance with known pharmaceutical techniques, injectable solutions containing the following ingredients, were prepared:
Inqredient mg 2-n-Butyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-bromo/or 3-chloro-benzoyl~-indolizine hydrochloride 150 Polysorbate 80 150 Benzyl alcohol 75 Water to 3 ml EXAMPLE_7 In accordance with known pharmaceutical techniques, suppositories containinq the following ingredients, were prepared:
Inqredient 2-n-Butyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-bromo/or 3-chloro-benzoyl~-indolizine hydrochloride 100 Mixture of mono- and di-glycerides of saturated c (C12 toC18) 1400

Claims

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:

1. A process for preparing indolizine derivatives corresponding to the general formula (I) (I) and pharmaceutically acceptable acid addition salts thereof wherein:
R represents a branched- or straight-chain alkyl radical having from 1 to 8 carbon atoms, or a phenyl group non-substituted or bearing one or two substituents, which may be the same or different selected from halogen atoms and from lower alkyl and alkoxy groups, X1 represents hydrogen, chlorine, bromine, iodine, methyl or methoxy, A represents a group selected from:
R2= and R3= in which X2 represents hydrogen, chlorine, bromine, iodine, methyl or methoxy and X3 represents hydrogen, chlorine, bromine, iodine or methyl, R1 represents a methyl,ethyl , n-propyl or n-butyl radical, n represents an integer in the range of 2 to 6 inclusive with the proviso that when both X2 and X3 represent hydrogen or methyl, X1 is other than hydrogen,characterized in that (A) to obtain an indolizine derivative corresponding to the general formula (I) as defined above and pharmaceutically acceptable acid addition salts thereof, a substituted bromoalkoxy-benzoyl-indolizine of the general formula:

wherein X1, R, A and n have the same meaning as defined above, is condensed, with a secondary amine of the general formula:

in which R1 has the same meaning as defined above, to form the required indolizine derivative which, if desired, is reacted with an appropriate organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt thereof, (B) to obtain an indolizine derivative corresponding to the general formula (I) as defined above and pharmaceutically acceptable acid addition salts thereof, an alkali metal salt of a substituted indolizine derivative represented by the general formula:

in which R, A and X1 have the same meaning as defined above, is condensed with an alkylamino derivative of the general formula:

or an acid addition salt thereof, in which Z
represents a halogen atom or a p-toluenesulphonyl-oxy group and n and R1 have the same meaning as defined above to form the required indolizine derivative which, if desired, is reacted with an appropriate organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt thereof, or (C) to obtain an indolizine derivative correspond-ing to the general formula (I) as defined above and pharmaceutically acceptable acid addition salts thereof, wherein X1 represents chlorine, bromine or iodine, X2 represents chlorine, bromine, iodine, methyl or methoxy and X3 represents chlorine, bromine, iodine or methyl an indolizine derivative of general formula:

in which R, A, n and R1 have the same meaning as given above is reacted:
a) either with N-chlorosuccinimide, between 0°C and room-temperature, to form the required indolizine derivative in which X1 represents chlorine, b) or with bromine or iodine, the reaction taking place at room-temperature in the presence of an alkali metal acetate, to form the required indolizine derivative in which X1 represents bromine or iodine the obtained indolizine derivative being reacted, if desired, with an appropriate organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt thereof.

2. Indolizine derivatives corresponding to the general formula:
(I) and pharmaceutically acceptable acid addition salts thereof wherein:
R represents a branched- or straight-chain alkyl radical having from 1 to 8 carbon atoms, or a phenyl group non-substituted or bearing one or two substituents, which may be the same or different selected from halogen atoms and from lower alkyl and alkoxy groups:
X1 represents hydrogen, chlorine, bromine, iodine, methyl or methoxy, A represents a group selected from:

R2= and R3= in which X2 represents hydrogen, chlorine, bromine, iodine, methyl or methoxy and X3 represents hydrogen, chlorine, bromine, iodine or methyl, R1 represents a methyl, ethyl, n-propyl or n-butyl radical, n represents an integer in the range of 2 to 6 inclusive with the proviso that when both X2 and X3 repre-sent hydrogen or methyl, X1 is other than hydrogen, whenever prepared by a process according to Claim 1 or an obvious chemical equivalent thereof.

3. A process for preparing indolizine derivatives corresponding to the general formula (I):

(I) and pharmaceutically acceptable acid addition salts thereof wherein:
R represents a branched- or straight-chain alkyl radical having from 1 to 8 carbon atoms, or a phenyl group non-substituted or bearing one or two substituents, which may be the same or different selected from halogen atoms and from lower alkyl and alkoxy groups, X1 represents hydrogen, chlorine, bromine, iodine, methyl or methoxy, A represents a group selected from:
R2= and R3 = in which X2 represents hydrogen, chlorine, bromine, iodine, methyl or methoxy and X3 represents hydrogen, chlorine, bromine, iodine or methyl, R1 represents a methyl, ethyl, n-propyl or n-butyl radical, n represents an integer in the range of 2 to 6 inclusive with the proviso that when both X2 and X3 represent hydrogen or methyl, X1 is other than hydrogen characterized in that an alkali metal salt of a substituted indolizine deri-vative represented by the general formula (II) (II) in which R, A and X1 have the same meaning as in formula (I), is condensed with an alkylamino derivative of the general formula (III) (III) or an acid addition salt thereof, in which Z represents a halogen atom or a p-toluenesulphonyloxy group and n and R1 have the same meaning as defined above to obtain the required indolizine derivative which, if desired, is reacted with an appropriate organic or inorganic acid to provide a pharma-ceutically acceptable acid addition salt thereof.

4. A process as defined in claim 3 for the pre-paration of indolizine derivatives of general formula (I) and pharmaceutically acceptable acid addition salts thereof wherein R represents a branched- or straight-chain alkyl radical having from 1 to 8 carbon atoms, a phenyl radical, a mono-fluoro-, mono-chloro-, mono-bromo-, mono-methyl-, or mono-methoxy-phenyl radical, a di-fluoro-, di-chloro-, di-bromo-phenyl radical or a methyl-phenyl radical substituted in the aromatic moiety by an atom of fluorine, chlorine or bromine, characterized in that a substituted indolizine derivative of general formula (II) is used wherein R is as defined above.

5. A process according to Claim 3, wherein the condensation between the compounds of the formulae (II) and (III) is effected in an aprotic solvent.

6. A process according to Claim 5, wherein the aprotic solvent is acetone or methyl ethyl ketone.

7. A process according to Claim 3, wherein Z
represents chlorine.

8. A process according to Claim 3, wherein the alkali metal salt of the indolizine derivative of the formula (II) is the potassium or sodium salt.

9. A process according to Claim 3, wherein the indolizine derivative of the formula (I) obtained is reacted with hydrochloric or oxalic acid, to obtain the hydrochloride or oxalic addition salt thereof.

10. Indolizine derivatives corresponding to the general formula (I) (I) and pharmaceutically acceptable acid addition salts thereof wherein:

R represents a branched- or straight-chain alkyl radical having from 1 to 8 carbon atoms, or a phenyl group non-substituted or bearing one or two substituents, which may be the same or different selected from halogen atoms and from lower alkyl and alkoxy groups:
X1 represents hydrogen, chlorine, bromine, iodine, methyl or methoxy, A represents a group selected from:

R2= and R3= in which X2 represents hydrogen, chlorine, bromine, iodine, methyl or methoxy and X3 represents hydrogen, chlorine, bromine, iodine or methyl, R1 represents a methyl, ethyl, n-propyl or n-butyl radical, n represents an integer in the range of 2 to 6 inclusive with the proviso that when both X2 and X3 represent hydrogen or methyl, X1 is other than hydrogen, whenever prepared by a process according to Claim 3 or an obvious chemical equiva-lent thereof.

11. Indolizine derivatives corresponding to the general formula :
and pharmaceutically acceptable acid addition salts thereof wherein:

R represents a branched- or straight-chain alkyl radical having from 1 to 8 carbon atoms, a phenyl radical, a mono-fluoro-, mono-chloro-, mono-bromo-, mono-methyl-or mono-methoxy-phenyl radical, a di-fluoro-, di-chloro-, di-bromo-phenyl radical or a methyl-phenyl radical substi-tuted in the aromatic moiety by an atom of fluorine, chlo-rine or bromine, X1 represents hydrogen, chlorine, bromine, iodine, methyl or methoxy, A represents a group selected from:

R2= and R3= in which X2 represents hydrogen, chlorine, bromine, iodine, methyl or methoxy and X3 represents hydrogen, chlorine, bromine , iodine or methyl, R1 represents a methyl, ethyl, n-propyl or n-butyl radical, n represents an integer in the range of 2 to 6 inclusive, with the proviso that when both X2 and X3 represent hydrogen or methyl, X1 is other than hydrogen, whenever pre-pared by a process according to Claim 4 or an obvious chemical equivalent thereof.

12. Process for preparing indolizine derivatives represented by the general formula (I):
(I) and pharmaceutically acceptable acid addition salts thereof, wherein:
R represents a branched- or straight-chain alkyl radical having from 1 to 8 carbon atoms, or a phenyl group non-substituted or bearing one or two substituents, which may be the same or different selected from halogen atoms and from lower alkyl and alkoxy groups, X1 represents hydrogen, chlorine, bromine, iodine, methyl or methoxy, A represents a group selected from:

and in which X2 represents hydrogen, chlorine, bromine, iodine, methyl or methoxy and X3 represents hydrogen, chlorine, bromine, iodine or methyl, R1 represents a methyl, ethyl, n-propyl or n-butyl radical, n represents an integer in the range of 2 to 6 inclusive with the proviso that when both X2 and X3 represent hydrogen or methyl, X1 is other than hydrogen, characterized in that a substituted bromoalkoxy-benzoyl-indolizine of the general formula (IIa) (IIa) wherein X1, R, A and n have the same meaning as above is condensed with a secondary amine of the general formula (IIIa) (IIIa) in which R1 has the same meaning as above, to form the required indolizine derivative which, if desired is reacted with an appropriate organic or inorganic acid to provide a pharmaceu-tically acceptable acid addition salt thereof.

13. A process according to claim 12 wherein the substituted bromoalkoxy-benzoyl-indolizine of formula (IIa) is obtained by condensing an alkali metal salt of a substi-tuted indolizine represented by the general formula (II):

(II) in which R, A and X1 have the same meaning as above, with a dibromoalkane of the general formula :

Br-(CH2)n-Br (VI) in which n has the same meaning as above.

14. A process as defined in claim 12 for the pre-paration of indolizine derivatives of general formula (I) and pharmaceutically acceptable acid addition salts thereof wherein R represents a branched- or straight-chain alkyl radical having from 1 to 8 carbon atoms, a phenyl radical, a mono-fluoro-, mono-chloro-, mono-bromo-, mono-methyl- or mono-methoxy-phenyl radical, a di-fluoro-, di-chloro-, di-bromo-phenyl radical or a methyl-phenyl radical substituted in the aromatic moiety by an atom of fluorine, chlorine or bromine, characterized in that a substituted bromoalkoxy-benzoyl-indolizine of general formula (IIa) is used wherein R is as defined above.

15. A process according to Claim 12, wherein the condensation between the compounds of the formulae (II) and (III) is effected in an inert solvent.

16. A process according to Claim 15, wherein the inert solvent is benzene or toluene.

17. A process according to Claim 12, wherein the indolizine derivative of formula (I) obtained is reacted with hydrochloric or oxalic acid to obtain the hydrochloride or oxalic addition salt thereof.

18. A process according to Claim 13, wherein the alkali metal salt of the indolizine derivative of the formula (II) is the potassium or sodium salt.

19. A process according to Claim 13, wherein the condensation between the compounds of the formulae (II) and (VI) is effected in an inert medium.

20. A process according to Claim 19, wherein the inert medium is acetone or methyl ethyl ketone.

21. Indolizine derivatives having the general formula:

and pharmaceutically acceptable acid addition salts thereof, wherein:
R represents a branched- or straight-chain alkyl radical having from 1 to 8 carbon atoms, or a phenyl group non-substituted or bearing one or two substituents, which may be the same or different selected from halogen atoms and from lower alkyl and alkoxy groups, X1 represents hydrogen, chlorine, bromine, iodine, methyl or methoxy, A represents a group selected from :

and R3=

in which X2 represents hydrogen, chlorine, bromine, iodine, methyl or methoxy and X3 represents hydrogen, chlorine, bromine, iodine or methyl, R1 represents a methyl, ethyl, n-propyl or n-butyl radical, n represents an integer in the range of 2 to 6 inclusive, with the proviso that when both X2 and X3 represent hydrogen or methyl, X1 is other than hydrogen or methyl, whenever obtained by a process according to Claim 12, or an obvious chemical equivalent thereof.

22. Indolizine derivatives having the general formula:

and pharmaceutically acceptable acid addition salts thereof wherein:
R represents a branched- or straight-chain alkyl radical having from 1 to 8 carbon atoms, a phenyl radical, a mono-fluoro-, mono-chloro-, mono-bromo-, mono-methyl-or mono-methoxy-phenyl radical, a di-fluoro, di-chloro-, di-bromo-phenyl radical or a methyl-phenyl radical subs-tituted in the aromatic moiety by an atom of fluorine, chlorine or bromine, X1 represents hydrogen, chlorine, bromine, iodine, methyl or methoxy, A represents a group selected from:
and in which X2 represents hydrogen, chlorine, bromine, iodine, methyl or methoxy and X3 represents hydrogen, chlorine, bromine, iodine or methyl, R1 represents a methyl, ethyl, n-propyl or n-butyl radical, n represents an integer in the range of 2 to 6 inclusive, with the proviso that when both X2 and X3 repre-sent hydrogen or methyl, X1 is other than hydrogen, whenever obtained by a process according to Claim 14, or an obvious chemical equivalent thereof.

23. Process for preparing indolizine derivatives represented by the general formula (I):
(I) and pharmaceutically acceptable acid addition salts thereof, wherein:
R represents a branched- or straight-chain alkyl radical having from 1 to 8 carbon atoms, or a phenyl group non-substituted or bearing one or two substituents, which may be the same or different selected from halogen atoms and from lower alkyl and alkoxy groups, X1 represents chlorine, bromine or iodine, A represents a group selected from:

and in which X2 represents chlorine, bromine, iodine, methyl or methoxy and X3 represents chlorine, bromine, iodine or methyl, R1 represents a methyl, ethyl, n-propyl or n-butyl radical, n represents an integer in the range of 2 to 6 inclusive , characterized in that an indolizine derivative of general formula (IVa):

(IVa) in which R, R1 and n have the same meaning as in formula (I) and A represents the group R3 or a group R2 in which X2 represents chlorine, bromine, iodine, methyl or methoxy and X3 represents chlorine, bromine, iodine or methyl is reacted:
a) either with N-chlorisuccinimide between 0°C and room-temperature , to form the required indolizine derivative of formula (I) in which X1 represents chlorine, b) or with bromine or iodine at room-temperature and in the presence of an alkali metal acetate, to form the required indolizine derivative of formula (I) in which X1 represents bromine or iodine, the obtained indolizine derivative, if desired, being reacted with an appropriate organic or inorganic acid to provide a pharma-ceutically acceptable salt thereof.

24. A process as defined in claim 23 for the prepara-tion of indolizine derivatives of general formula (I) and pharmaceutically acceptable acid addition salts thereof, wherein R represents a branched- or chain-alkyl radical having from 1 to 8 carbon atoms, a phenyl radical, a mono-fluoro-, mono-chloro-, mono-bromo-, mono-methyl- or mono-methoxy-phenyl radical, a di-fluoro, di-chloro-, di-bromo-phenyl radical or a methyl-phenyl radical substituted in the aromatic moiety by an atom of fluorine, chlorine or bromine, characterized in that an indolizine derivative of general formula (IVa) is used wherein R is as defined above.

25. A process according to Claim 23, wherein the reaction between the compound of formula (IVa) and N-chloro-succinimide is effected in an inert solvent.

26. A process according to Claim 25, wherein the inert solvent is dichlorethane.

27. A process according to Claim 23, wherein the reaction between the compound of formula (IVa) and bromine or iodine is effected in an inert solvent.

28. A process according to Claim 27, wherein the inert solvent is dioxan.

29. A process according to claim 23, wherein the alkali metal acetate is sodium acetate.

30. Indolizine derivatives having the general formula:

and pharmaceutically acceptable acid addition salts thereof, wherein:
R represents a branched- or straight-chain alkyl radical having from 1 to 8 carbon atoms, or a phenyl group non-substituted or bearing one or two substituents, which may be the same or different selected from halogen atoms and from lower alkyl and alkoxy group;, X1 represents chlorine, bromine or iodine, A represents a group selected from:

and in which X2 represents chlorine, bromine, iodine, methyl or methoxy and X3 represents chlorine, bromine, iodine or methyl, R1 represents a methyl, ethyl, n-propyl or n-butyl radical, n represents an integer in the range of 2 to 6 inclusive,whenever obtained by a process according to Claim 23, or an obvious chemical equivalent thereof.

31. Indolizine derivatives having the general formula:

and pharmaceutically acceptakle acid addition salts thereof wherein:
R represents a branched- or straight-chain alkyl radical having from 1 to 8 carbon atoms , a phenyl radical, a mono-fluoro-, mono-chloro-, mono-bromo-, mono-methyl- or mono-methoxy-phenyl radical, a di-fluoro-, di-chloro-, di-bromo-phenyl radical or a methyl-phenyl radical substituted in the aromatic moiety by an atom of fluorine, chlorine or bromine, X1 represents chlorine, bromine, iodine, methyl or methoxy, A represents a group selected from:

and in which X2 represents hydrogen, chlorine, bromine, iodine, methyl or methoxy and X3 represents hydrogen, chlorine, bromine, iodine or methyl, R1 represents a methyl, ethyl, n-propyl or n-butyl radical, n represents an integer in the range of 2 to 6 inclusive, whenever obtained by a process according to Claim 24, or an obvious chemical equivalent thereof.

32. A process for preparing 1-bromo-2-methyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-bromo-benzoyl]-indolizine and pharmaceutically acceptable acid addition salts thereof characterized in that an alkali metal salt of 1-bromo 2-methyl-3-(4-hydroxy-3-bromo-benzoyl)-indolizine is condensed with 1-chloro-3-di n-butylamino-propane to obtain 1-bromo-2-methyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-bromo-benzoyl]-indolizine which, if desired, is reacted with an appropriate organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt thereof.

33. A process for preparing 1-bromo-2-methyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-bromo-benzoyl]-indolizine and pharmaceutically acceptable acid addition salts thereof characterized in that 1-bromo-2-methyl-3-[4-(3-bromopropyl) -oxy-3-bromo-benzoyl]-indolizine is condensed with N,N-di-n-butylamine to obtain 1-bromo-2-methyl-3-[4-(3-di-n-butylamino-propyl)-oxy-3-bromo-benzoyl]-indolizine which, if desired, is reacted with an appropriate organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt thereof.

34. 1-bromo-2-methyl-3-[4-(3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl]-indolizine and pharmaceutically accep-table acid addition salts thereof, whenever prepared by a process according to either of claims 32 and 33 or an obvious chemical equivalent thereof.

35. A process for preparing 2-n-butyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-bromo-benzoyl]- indolizine and pharmaceutically acceptable salts thereof characterized in that an alkali metal salt of 2-n-butyl-3-(4-hydroxy-3-bromo-benzoyl)-indolizine is condensed with 1-chloro-3-di-n-butyl-amino-propane to obtain 2-n-butyl-3- [4-(3-di-n-butylamino-propyl)-oxy-3-bromo-benzoyl]-indolizine which, if desired, is reacted with an appropriate organic or inorganic acid to provide a pharmaceutically acceptable salt thereof.

36. A process for preparing 2-n-bu-tyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-bromo-benzoyl]-indolizine and pharmaceutically acceptable acid addition salts -thereof characterized in that 2-n-butyl-3-[4-(3-bromo-propyl)-oxy-3-bromo-benzoyl]-indolizine is condensed with N,N-di-n-butyl-amine to obtain 2-n-butyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-bromo-benzoyl]-indolizine which , if desired, is reacted with an appropriate organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt thereof.

37. 2-n-butyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-bromo-benzoyl]-indolizine and pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process according to either of claims 35 and 36 or an obvious chemical equivalent thereof.

38. A process for preparing 2-ethyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl]-indolizine and pharmaceutically acceptable acid addition salts thereof characterized in that an alkali metal salt of 2-ethyl-3-(4-hydroxy-3-chloro-benzoyl)-indolizine is condensed with 1-chloro-3-di-n-butylamino-propane to obtain 2-ethyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl]-indolizine which, if desired, is reactecl with an appropriate organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt thereof.

39. A process for preparing 2-ethyl-3-[ 4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl]-indolizine and pharmaceutically acceptable acid addition salts thereof characterized in that 2-ethyl-3-[4-(3-bromopropyl)-oxy-3-chloro-benzoyl]-indolizine is condensed with N,N-di-n-butylamine to obtain 2-ethyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl]-indolizine which, if desired, is reacted with an appropriate organic or inorganic acid to provide a phar-maceutically acceptable acid addition salt thereof.

40. 2-ethyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl]-indolizine and pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process according to either of claims 38 and 39 or an obvious chemical equivalent thereof.

41. A process for preparing2-n-butyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl]-indolizine and phar-maceutically acceptable acid addition salts thereof charac-terized in that an alkali metal salt of 2-n-butyl-3-(4-hydroxy-3-chloro-benzoyl)-inclolizine is condensed with 1-chloro-3-di-n-butylamino-propane to obtain 2-n-butyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl]-indolizine which, if desired, is reacted with an appropriate organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt thereof.

42. A process for preparing 2-n-butyl-3-[4-(3-bromophenyl)-oxy-3-chloro-benzoyl]-indolizine and pharmaceu-tically acceptable acid addition salts thereof characterized in that 2-n-butyl-3-[4-(3-bromopropyl)-oxy-3-chloro-benzoyl-indolizine is condensed with N,N-di-n-butylamine to obtain 2-n-butyl-3- [4-(3-bromophenyl)-oxy-3-chloro-benzoyl]-indo-lizine which, if desired, is reacted with an appropriate organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt thereof.

43. 2-n-butyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl]-indolizine and pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process according to either of claims 41 and 42 or an obvious che-mical equivalent thereof.

44. A process for preparing 2-isopropyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3,5-dichloro-benzoyl]-indolizine and pharmaceutically acceptable acid addition salts thereof characterized in that an alkali metal salt of 2-isopropyl-3-(4-hydroxy-3,5-dichloro-benzoyl)-indolizine is condensed with 1-chloro-3-di-n-butylamino-propane to obtain 2-isopropyl-3-[4-(3-di-n-butyl-aminopropyl)-oxy-3,5-dichloro-benzoyl]-indolizine which, if desired, is reacted with an appropriate organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt thereof.

45. A process for preparing 2-isopropyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3,5-dichloro-benzoyl]-indolizine and pharmaceutically acceptable acid addition salts thereof characterized in that 2-isopropyl-3-[4-(3-bromopropyl)-oxy-3,5-dichloro-benzoyl]-indolizine is condensed with N,N-di-n-butylamine to obtain 2-isopropyl-3-[4,(3-di-n-butylamino-propyl)-oxy-3,5-dichloro-benzoyl]-indolizine which, if desired, is reacted with an appropriate organic or inor-ganic acid to provide a pharmaceutically acceptable acid addition salt thereof.

46. 2-isopropyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3,5-dichloro-benzoyl]-indolizine and pharmaceutically accep-table acid addition salts thereof, whenever prepared by a process according to either of claims 44 and 45 or an obvious chemical equivalent thereof.

47. A process for preparing 1-bromo-2-phenyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl]-indoli-zine and pharmaceutically acceptable acid addition salts thereof characterized in that 1-bromo-2-phenyl-3(4-hydroxy-3-chloro-benzoyl)-indolizine is condensed with 1-chloro-3-di-n-butylaminopropane to obtain 1-bromo-2-phenyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl]-indolizine which, if desired, is reacted with an appropriate organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt thereof.

48. A process for preparing 1-bromo-2-phenyl-3-[ 4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl]-indolizine and pharmaceutically acceptable acid addition salts thereof characterized in that 1-bromo,-2-phenyl-3- [4-(3-bromopropyl)-oxy-3-chloro-benzoyl]-indolizine is condensed with N,N-di-n-butyl-amine to obtain 1-bromo-2-phenyl-3-[ 4-(3-di-n-butylaminopropyl)-oxy- 3-chloro-benzoyl]-indolizine which, if desired, is reacted with an appropriate organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt thereof.

49. 1-bromo-2-phenyl-3- [4-(3-di-n-butylamino-propyl)-oxy-3-chloro-benzoyl]-indolizine and pharmaceuti-cally acceptable acid addition salts thereof, whenever prepared by a process according to either of claims 47 and 48 or an obvious chemical equivalent thereof.

50. A process for preparing 1-chloro-2-ethyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl]-indolizine and pharmaceutically acceptable acid addition salts thereof characterized in that an alkali metal salt of 1-chloro-2-ethyl-3- (4-hydroxy-3-chloro-benzoyl)-indolizine is condensed with 1-chloro-3-di-n-butylamino-propane to obtain 1-chloro-2-ethyl-3-[4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl]-indolizine which, if desired, is reacted with an appropriate organic or inorganic acid to provide a pharmaceutically accep-table acid addition salt thereof.

51. A process for preparing 1-chloro-2-ethyl-3-[ 4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl]-indolizine and pharmaceutically acceptable acid addition salts thereof characterized in that 1-chloro-2-ethyl-3-[ 4-(3-bromopropyl)-oxy-3-chloro-benzoyl]-indolizine is condensed with N,N-di-n-butylamine to obtain 1-chloro-2-ethyl-[ 4-(3-di-n-butylamino-propyl)-oxy-3-chloro-benzoyl]-indolizine which, if desired, is reacted with an appropriate organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt thereof.

52. 1-chloro-2-ethyl-3-[ 4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl]-indolizine and pharmaceutically accep-table acid addition salts thereof, whenever prepared by a process according to either of claims 50 and 51 or an obvious chemical equivalent thereof.

53. A process for preparing 1-chloro-2-n-butyl-3-[ 4-(3-di-n-butylaminopropyl)-oxy-benzoyl]-indolizine and pharmaceutically acceptable acid addition salts thereof characterized in that an alkali metal salt of 1-chloro-2-n-butyl-3-(4-hydroxy-benzoyl)-indolizine is condensed with 1-chloro-3-di-n-butylamino-propane to obtain 1-chloro-2-n-butyl-3- [ 4-(3-di-n-butvlaminopropyl)-oxy-benzoyl]-indolizine which, if desired, is reacted with an appropriate organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt thereof.

54. A process for preparing 1-chloro-2-n-butyl-3-[ 4-(3-di-n-butylaminopropyl)-oxy-benzoyl]-indolizine and pharmaceutically acceptable acid addition salts thereof characterized in that 1-chloro-2-n-butyl-3- [4-(3-bromo-propyl)-oxy-benzoyl]-indolizine is condensed with N,N-di-n-butyl-amine to obtain 1-chloro-2-n-butyl-3-[ 4-(3-di-n-butylamino-propyl)-oxy-benzoyl]-indolizine which, if desired, is reacted with an appropriate organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt thereof.

55. 1-chloro-n-butyl-3- [ 4-(3-di-n-butylamino-propyl)-oxy-benzoyl7-indolizine and pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process according to either of claims 53 and 54 or an obvious che-mical equivalent thereof.

56. A process for preparing l-bromo-2- (4-chloro-phenyl)-3-[ 4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl]-indolizine and pharmaceutically acceptable acid addition salts thereof characterized in that an alkali metal salt of 1-bromo-2-(4-chloro-phenyl)-3-(4-hydroxy-3-chloro-benzoyl)-indolizine is condensed with 1-chloro-3-di-n-butylamino-propane to obtain 1-bromo-2-(4-chlora-phenyl)-3-[ 4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl]-indolizine, which, if desired is reacted with an appropriate organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt thereof.

57. A process for preparing 1-bromo-2-(4-chloro-phenyl)-3-[ 4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl]-indolizine and pharmaceutically acceptable acid addition salts thereof characterized in that 1-bromo-2-(4-chloro-phenyl)-3-[ 4-(3-bromophenyl)-oxy-3-chloro-benzoyl]- indolizine is condensed with N,N-di-n-buty]amine to obtain 1-bromo-2-(4-chloro-phenyl)-3-[ 4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl]-indolizine which, if desired, is reacted with an appropriate organic or inorganic acid to provide a pharma-ceutically acceptable acid acldition salt thereof.

58. 1-bromo-2-(4-chloro-phenyl)-3-[ 4- (3-di-n-butyl-aminopropyl)-oxy-3-chloro-benzoyl]-indolizine and pharma-ceutically acceptable acid addition salts thereof, whenever prepared by a process according to either of claims 56 and 58 or an obvious chemical equivalent thereof.