LU82983A1 - NEW INDOLIZINE DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATIONS - Google Patents

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NEW INDOLIZINE DERIVATIVES, THEIR PREPARATION PROCESS AND OPE

9 'THEIR THERAPEUTIC APPLICATIONS

The present invention relates, in general, to heterocyclic derivatives and more particularly to new indoli-zine derivatives as well as to their process of preparation.

The indolizine derivatives of the present invention can be represented by the general formula: I1 10/1

L p-l-C-A-0- (CH) -N 'I

.. 2 n \ 0 XRn and their non-toxic addition salts, for example oxalate or chlorhy-15 drate, in which: R represents linear or branched alkyl radical wine having from 1 to 8 carbon atoms or a group phenyl unsubstituted or substituted "* with one or two substituents, identical or different, selected from halogen atoms, for example fluorine, chlorine and bromine and from lower alkyl or lower alkoxy groups, for example methyl or methoxy, represents hydrogen, chlorine, bromine, iodine, methyl or methoxy, A represents a selected group of: / X2 ci ci r 25 R2 = and R3 = \ jj / h <i.

- 2 - in which represents hydrogen, chlorine, bromine, iodine, methyl or methoxy and X ^ represents hydrogen, chlorine, bromine, iodine or methyl, R ^ represents a methyl, ethyl, n-propyl or n-butyl radical, 5 n represents an integer from 2 to 6 inclusive, provided that when and X ^ each represent hydrogen or * methyl, is other than hydrogen.

X

In formula I above, R preferably represents a linear or branched alkyl radical * having from 1 to 8 carbon atoms, a phenyl, mono-fluoro-, mono-chloro-, mono-bromo- radical, mono-methyl- or mono-methoxy-phenyl, a di-fluoro-, di-chloro-, di-bromo-phenyl radical or a methyl-phenyl radical substituted in the aromatic entity by a fluorine, chlorine or bromine,

The indolizine derivatives of the invention have been found to have remarkable pharmacological properties capable of making them very useful in the treatment of certain pathological syndromes of the heart, in particular in the treatment of angina pectoris and arrhythmias. heart of various origins.

The present invention also relates to pharmaceutical or veterinary compositions containing, as active principle, at least one indolizine derivative of formula I or a non-toxic addition salt of this derivative, in combination with a pharmaceutical vehicle or an appropriate excipient.

Another object of the invention is to provide a process for the preparation of pharmaceutical or veterinary compositions according to which at least one indolizine derivative of formula I or a non-toxic addition salt of this derivative is combined, to a suitable pharmaceutical vehicle or excipient.

Likewise, another subject of the invention relates to a method of treatment of pathological syndromes of the heart, in particular angina pectoris and cardiac arrhythmias in a subject requiring this treatment, method by which the subject is administered reaches an effective dose of at least one indolizine derivative of formula I or a salt J

non-toxic addition of this derivative.

· - 3 - t active according to the invention by the oral route and preferably, from 1 to 3 mg of active ingredient by parenteral route in a human being weighing 60 kgs.

The compounds of formula I can be prepared, according to the invention, by condensing, preferably in an inert medium such as, for example, benzene or toluene, a bromoalkoxy-benzoyl indolizine of formula

general: Y

| 1 * 10 L. N_i-C-A-O- (CH) -Br II 'V / I. 2 n o in which X, E, A and n have the same meaning as in formula I, with a secondary amine of general formula: / R1

3 PM-III

wherein R ^ has the same meaning as in formula I, to form the desired indolizine derivative of formula I which is optionally reacted with an organic or inorganic acid to obtain the corresponding non-toxic addition salt.

The compounds of formula I can also be prepared by condensing, preferably in an aprotic solvent such as acetone, methyl * ethyl ketone or toluene, an alkali metal salt, preferably the potassium or sodium salt, d 'a suitable indolizine derivative represented by the general formula; rA- y / - '1- “® 0 50 in which R, A and have the same meaning as in formula I, with an alkylamino derivative of general formula: /

K / Y

/ 1 lu z- (ch J -rv / // 2 nv C / y ί j ί <- k - or one of its addition salts, in which Z represents a halogen atom such as chlorine or bromine or a p-toluenesulfony-loxy group and n and have the same meaning as in formula I to give the desired indolizine derivative which is optionally reacted with an organic or inorganic acid to obtain the non-addition salt corresponding toxic.

According to another aspect of the invention, the indolizine derivatives of formula I in which X ^ represents chlorine, bromine or iodine and A re-10 has the group R ^ or a group R ^ in which represents chlorine, bromine, iodine, methyl or methoxy and X ^ represents chlorine, bromine, iodine or methyl, can also be prepared by reacting an indolizine derivative of general formula ï / Ri

15 L JI-l-C-A-0- (CH2) n-N ^ VI

V 3 “E1

in which R, R ^ and n have the same meaning as in formula I

and A represents the group R, or a group R_ in which X_ 5 d. to represents chlorine, bromine, iodine, methyl or methoxy and X represents i _ ^ | 20 chlorine, bromine, iodine or methyl: j j a) either with N-chlorosuccinimide, the reaction taking place in an I | suitable medium such as dichloroethane and between 0 ° C and room temperature, to obtain the desired derivative of formula I in the form of free base, in which X ^ represents chlorine, I: 25 b) either with bromine or iodine, the reaction taking place at room temperature in a suitable solvent such as dioxanre and in the presence i of an alkali metal acetate, for example, sodium acetate, to obtain the desired derivative of formula I under free base form, in which represents bromine or iodine, the free base thus obtained being optionally reacted with an organic or inorganic acid, to provide the corresponding non-toxic addition salt.

The compounds of formula II can be obtained by condensing, from pre-ethyl ketone, an alkali metal salt, preferably the potassium or sodium salt, of a compound of formula IV above, with a dibro-moalkane of general formula:

5 Br- (CH) -Br VII

2 n in which n has the same meaning as in formula I to obtain the desired compound of formula II.

The compounds of formula IV in which A represents the group R 1 "are either compounds described in British patent application 10 No. 80 2192 * 1 filed on k July 1980 or compounds which can be prepared according to methods described in the aforementioned British patent application.

The other compounds of formula IV, namely those in which A represents the group R_, can be obtained by reacting the indoli-zine substituted in the appropriate position 2 with 2,3-dichloro-2,3-acetyloxy or tosyloxy-benzoyl chloride. .

This benzoyl chloride derivative is itself prepared by acetylating the 1,2-dichloroanisole according to the reaction conditions of FRIEDEL and CRÂFTS, by oxidizing the acetyl derivative thus obtained with sodium hypochlorite to form the corresponding derivative benzoic acid and demethylating with hydroiodic acid in acetic acid to obtain dichloro-R ^ -hydroxy- ^ benzoic acid. The latter compound is then reacted with acetyl chloride or tosyl chloride to form the desired 2,3-dichloro-acetyloxy-4 or tosyloxy-benzoic acid, the corresponding acyl chloride being by continuation formed according to known methods, for example by reaction with thionyl chloride.

The compounds of formula VI, for their part, are products coming within the scope of formula I above.

50 Indolizine derivatives are already known having pharmacological effects capable of making them useful in the treatment of angina pectoris and cardiac arrhythmias.

To this end, one can cite British Patent No. 1,518. Mv3 which describes / more particularly ethyl-2 [(di-n-butylamino-3 propyl) oxy-4 benzoyl ^ V ^ - 6 - ί * Η

In the British patent in question, we have. attributed antianginal properties to the compounds described there since they are capable of producing the following cardiovascular effects: 5 - bradycardia - decrease in blood pressure - a-antiadrenergic effect „- β-antiadrenergic effect - coronarodilator effect * 10 Increased flow In fact, the cardiac provocation caused by these compounds is only slight, given its temporary action, this increase only takes place for a few minutes after an intravenous injection.

In addition, the compounds described in the above British patent have only a weak β-adrenergic antagonist action. This action is only slight at the dose at which the four other cardiovascular effects mentioned above are manifested significantly.

It has now surprisingly been found that by appropriately substituting dialkylaminoalkyloxy-benzoyl indolizine derivatives by means of one or more methyl or methoxy groups or of halogen atoms, for example chlorine, bromine or iodine, obtains compounds j having a wider spectrum of cardiovascular properties than the derivatives of British Patent No. 1.518.A43 while exhibiting * lower toxicity * 25 Thus, it has been possible to demonstrate that the indolizine derivatives of ·% l The invention can be considered as powerful coronarodilators "since they are able to increase the coronary flow significantly and more prolonged than butoprozine.

It has also been found that compounds of the invention can reduce heart rate and blood pressure in animals.

In addition, the indolizine derivatives of the invention have an effect! β-antiadrenergic more powerful than that of the derivatives of the abovementioned British patent. Indeed, at the minimum dose required to significantly produce bradycardia, a reduction in blood pressure / 35 and α-antiadrenergic and coronarodilator effects, the ß-anti-p 'effect. J * a Iw “.mmkÎ a w I Ί Α /“ λ “Ι / ΐην, η T a rt nr> / 4 An * 3 tfan VkWAtföi · Vvn ·? 4 “n“ T *. AlUb / / "- 7 - in question but much more important in the case of the indolizine derivatives of the invention.

In addition, the compounds of the invention reduce the oxygen consumption of the myocardium calculated by multiplying the difference between the oxygen level of the air and venous blood by the coronary flow. Thus, the compounds of the invention cause a considerable reduction. of the arteriovenous difference which induces a reduction in consumption. oxygen despite the increased coronary flow.

510 In addition, and unlike butoprozine, these beneficial effects on oxygen consumption are obtained, with the compounds, of the invention, without any reduction in the contractility of the myocardium.

It has also been shown that the derivatives of the invention are less toxic than the compounds of British Patent No. 1,518. ^ 43 · Tests of acute toxicity carried out intravenously and orally in animals have shown that the doses The lethal values are higher in the case of the compounds of the invention than in the case of the derivatives of the British patent in question.

In addition, the compounds of the invention make it possible to obtain san-guins levels higher than those obtained with butoprozine.

Thus, it has been shown that the same dose, orally, of bromo-1 methyl-2 [(di-n-butylamino-3 propyl) oxy- * f bromo-3 benzoyl] - 3 indolizine and butoprozine administered in dogs causes the appearance of a blood level * three times higher in the compound of the invention than in butoprozine.

Likewise, chronic administration of the compounds of the invention by the oral route in dogs has revealed no cardiac toxicity represented by ventricular arrhythmia, which is not the case with butoprozine. Finally, the indolizine derivatives of the invention exert on the con-. myocardial tractility a lighter depressive action than buto-30 prozine.

In men, the angina attack is the painful translation of a deficiency between the supply and the oxygen requirements of the myocardium.

A compound can therefore be active in the treatment of angina pectoris either by increasing the oxygen supply or by reducing the needs in / -

oxygen. rJ

ΏηΝΛ — ι · ΐ T AiH VfvtA Λ ~ Vl * ï âT T am AVI 4- T Ί eop oView * 5 ΠΛΠΤ * TO tuen f ΛΛ1 ΛΛ 4 · / - - 8 - we can cite angina pectoris dipyridamole in the series of coronarodilators and amiodarone in the series of compounds which reduce the oxygen consumption of the myocardium.

However, comparative tests have shown that the compounds of the invention are far superior to dipyridamole and amiodarone in various respects.

; In particular, it has been shown that dipyridamole does not reduce the oxygen consumption of the myocardium and that amiodarone cannot be considered as a coronarodilator.

The derivatives of the present invention exert their effect via these factors: they reduce the oxygen consumption of the myocardium by their metabolic effects and at the same time increase the coronary flow over a prolonged period.

In addition, they are able to prevent or cure not only arrhythmias caused by ischemia of the myocardium but also atrial and ventricular arrhythmias of very diverse origins.

It appears, therefore, that the halogenation, methoxylation or methylation of indolizine derivatives from British Patent No. 1,518.

gives rise to compounds presenting a new spectrum of pharmacological properties valid in the treatment of cardiac deficiencies. For example i - the coronarodilator effect makes it possible to increase the nutritive contributions to the myocardial regions insufficiently irrigated and can allow the development of a supply collateral circulation. This effect is therefore interesting for treating both anginal pain and rhythmic disorders consecutive to myocardial ischemia.

- the antiadrenergic effect is also interesting for treating both angina and cardiac arrhythmia, given the importance of the role of sympathetic hyperactivity in the etiology of! these two heart conditions.

| As the physiological mediator of the sympathetic system is the thorn-

phrine, a compound that inhibits all the effects of epinephrine will probably be more active than a compound that only inhibits part of ^ J

* - 9 - both the a and ß effects of epinephrine have an advantage over the derivatives of British Patent No. 1.5l8 ¥ f3 which practically only inhibit the effects a at the minimum dose at which 5 other pharmacological effects on the cardiovascular system.

Among the compounds of the invention which have shown the best antianginal potential, the following may be mentioned: * 1-Bromo-2-methyl [(di-n-butylaraino-3 propyl) oxy- * f-3-bromo benzoyl] -3 indolizine 10 n-Butyl-2 [(di-n-butylamino-3 propyloxy - ** bromo-3 benzoyl] -3 indolizine Ethyl-2 [(di-n-butylamino-3 propyl) oxy- ^ f chloro-3 benzoyl3 -3 indolizine n-Butyl-2 [(di-n-butylamino-3 propyl) oxy- ^ chloro-3 benzoyl] -3 indolizine Isopropyl-2 [(di-n-butylamino-3 propyl) oxy- ^ dichloro-3 , 5 benzoyl] -3 indolizine 15 Brorao-1 phenyl-2 [(di-n-butylamino-3 propyl) oxy- * f 3-chloro benzoyl] -3 indolizine

Chloro-1 ethyl-2 [(di-n-butylamino-3 propyl) oxy-if chloro-3 benzoyl3-3 indolizine

Chloro-1 n-butyl-2 [(di-n-butylamino-3 propyl) oxy- ^ benzoyl] -3 indolizine 20 Bromo-1 (chloro- ^ phenyl) -2 [(di-n-butylamino-3 propyl) oxy-A · 3-chloro benzoyl] -3 indolizine these compounds being in the form of free base or of non-toxic addition salts, for example hydrochloride or acid oxalate.

The results of pharmacological tests carried out to determine the cardiovascular properties of the compounds of the invention are listed below.

I. Antianginal properties 1) Effect on cardiac output

This test was undertaken according to the technique described by R. CHARLIER and 30 J. BAUTHIER in Arzneimittel-Forschung "Drug Research" 2 ^, n ° 19, 1305-1311 (1973).

It is carried out on anesthetized dogs having received the substance to be studied intravenously. The intensity of the maximum effect on the heart rate is expressed as a percentage of the corresponding value before in- Γ / * - 10 -!

The following results were recorded: X1 Γ # ΐΓΝΥίι ~ Ε [2 / Ki 5 0 i ^ | . 3 i

> ’S

10 Ix,! X.: X; H: R: n! Ttmps! ! ! ! ! ’[Kg)’ mayor ’. ! ; ; ; max. j for • · * ’'* *' 'in%' disbursement1; ; ; ; _; ; ; ; 15! Br Br J H! ! n-C ^! 3 10! 60! 90: Br: Br: H: CH ^: n-C ^: 3: 10 '125! KB

Br! Br! H! n-C.ïï n-C H ’3 | 10] 100 | ‘20 \ • · · · 49 · 3 7 ·:::: î Br: Br: H: n-C H: n-C H: 3: 10: 90: 20:::; ; 3 (.37.....

] Br J Br * H \ - </ J n-C ^: 3: 10 · 100 ♦ 20 ·

···· 5 · Z · * Z

20: î: ï Br::::; : * · Br: Br: H: ^: n-C ^: 3: 10: 150: 100: • * * · 2 dd ···! H; Br; H; -Br J n-C ^ * 3! 10 ï 90 \ 25 \ * ··· · J J J J *: Br: Br: H: CH ^: n-C ^ H ^: 3: 10: 77: k5 ï; h; Br; h; n-c ^; n-o ^; 3; 2; iz>; 25; 25: H: Br: H: n-C ^: n-C ^ H: 3: 3: 70 ï 60: .Br *. Cl | H | iso-C H * n-C, H *; ; : 3 7: k 9 s 3 '5: 133: 20:; this ; h; h; n-c ^; n-c ^; 3; 10; 60; 30-:: H: Cl: Cl: iso-C ^: n-C ^: 3: 10: 30: 75:! H! 01 ci; ^> - Br; n-c ^; 3; 10; k5; 15; • ï ï î; ·· * ·. / 30: H: Cl: Cl: iso-C „H_: n-C, H: 3: 10; V)? i! # · - 11 -; :; ; Br; ; ; ; ; ; ; Η! G1; Η; ; h-c4h9; 3; 10; 30 ; 45; 5: Η; C1; Η:: n-C ^: 3: 8: 45: 25:! Η! C1! Η i iso-c ^; n-c ^; 3; 5; δο; 90; : Br; Cl: Η; ; n-C ^: 3: 10: 90: 90:; Br j Cl; H; n-C ^; n-C ^; 3; 10; 40; 90 [; Br; Cl: H; ^ -Br: n-C ^: 3: 10: 30: 50: 10! H! 01! H! n-C4H9 î! 3! 5 d 75! 50; : H: Cl; H: C ^: η- ^ Η? : 3: 6? 0 ·. 45 i; Br; Cl; H:> C1 3; io; 63; 45 *: H: Cl: H: ^> - Br: n-C ^: 3: 10: 60: 25:; Br; Cl; H; n-c ^; n-c ^ H; 3; 2.5; 50; 60: 15::::: Br! i i! ! . ! : Cl: Cl; H:: η ~ 03Ε7 '3: 8 70! 90 i C1! C1; h; c2H3; n-c ^ H \ J> \ 1; 4o; 15; : Cl: Cl: H: C ^: n-C ^: 3: 3.3 i 60 i 25 ί: 01: ïï! H; * "</ '^> ~ C1 n_c5H7! 3 j 5) 50; 40 1 20 Butoprozine 10 ^

Amiodarone 10 36 7

These results clearly show that the effects on the cardiac output j exerted by the compounds of the invention are more advantageous than those /;, / • of butoprozine and amiodarone. '25 2) Antiadrenergic effects * - 12 -

The purpose of this test is to determine the capacity of the compounds of the invention to reduce the increase in blood pressure induced by epi-nephrine (anti-a effect) and the acceleration of the heart rate in-5 by epinephrine (anti-ß effect) in dogs previously anesthetized with pentobarbital and atropine.

- Anti-a i effect.

; First, for each dog, the dose of epinephrine (between 5 and 10 p, g / kg) is determined, which causes a reproducible increase in blood pressure of about 100 mm.Hg.

The dose of epinephrine thus determined is then administered, followed by an intravenous dose of the test compound. The percentage of reduction in hypertension caused by the compound to be studied is then recorded compared to the hypertension obtained previously (approximately 100 mm.Hg).

15 - Anti-ß effect

During the same test as described above, epinephrine causes a reproducible increase in heart rate of approximately 70 beats / min. The percentage reduction in the acceleration of the heart rate caused by the compound to be studied is then recorded compared to the tachycardia measured previously (approximately 70 beats).

In both cases, the results were expressed as follows; + for a reduction of $ 50 in the increase in pressure or heart rate 25 ++ for a reduction ^. $ 50 in the increase in pressure or - heart rate +++ for a sub-total reduction increase in pressure or heart rate.

The following results were recorded: 30! ! ! ; ; ; Effect Dose; Effect; ; x1; x2; x3; b; ; n; (mg / kg); anti-; anti-; ; l i; ; ; ; α; ß;

Br Br H C_H_ n — Ci H 3 10 +++ +++ / 25 k9 //

Br H H C ^ H- n-Ci E_ 3 6 +++ +++ ’jf - 13 - • · · · m. - - *** · · e Z Γ · ·

Br J Br * H ^ -F · n-C ^; 3: 10: +++: ++: • * · · a _ *** · · * ·! *

; Br. Br. Br. n-C ^. n-C ^: 3; 10. +++. +++ J

• I · «4, -.

···· f · 5 · Ζ *; H · Br · H · ^: n-C ^ H ^: 3 1 10: +++: ++: • ”· a * ···“ 3 · H! Br! H! C ^ H n-C ^! 3 d 7 * 3 i +++ J ++! : H · Br: H: n-C ^ Hg! n-C ^ H ^: 3: 5: +++: ++: | H | Br! H j n-C ^! nC H, ^: 3: 5: +++: ++:: Br: Br: H: CH ·: 3 * i 3: +++ s ++ s::::: y:: U0: ++ +: +++ '···· · ··· «10! H! Br! H; n-C ^ H ’n-C ^ H j 3 | f 5! +++! ++! :::::; . (10. +++! +++]: H: Br: H; iso-C ^ H ^ 'ï nC ^ H ^: 3: 6: +++: ++: • Cl. H. H. N -CjH ^. Dl-C ^ H ^. 3 10 j +++ j ++]: Cl: H: H: n-C_H_: nC.ïï: 3: 7-5: +++: +++: ::: · 3 /; + 9. -.

15H. Cl. H. n-C ^ H ^. n-C ^ H ^: 3 · 10! +++ ++ [: H: Cl: H ’CH: n-C H: 3: 10: ++: ++: • î s * j j37- · *. .

. H. Cl. H. . 3 6. +++. ++ [: H: Cl: Cl: iso-C H: n-C.H_ · 3: 10: ++:. ++:; :: · 37. + 9 ..

:::: Br · l! ! ! 20! H j Cl I H; ! n-C ^ \ 3 \ 10 j ++ j ++ j -: H: Cl: H: iso-C H: n-C H '· 3' 10 î ++: ++::::: 3 / .37. . . ,: Br: 01: H! ! n-C ^ [3 [10] ++ j +++ * • · · · J * ··· *; Br: Cl: H ï C ^: a-c H î 3 î 7.δ: ++: ++:. Br! Cl j H J ^> - Br | n-C ^ 3! 10! ++ î ++! · · 5 J * ·· “· 25 î Br i Cl: H: n-C ^: n-C ^ H: 3: 10: ++: +! ! Br J Cl J H J \ -Cl î n-CjH ^ j 3 [10 j ++; ++: · * ·· · ·, • * · ·; Br! Cl: H.: ^ -Br: n-C ^: 3: 10: ++; ++ \ ^ * -I ** - • · * ·> 1. "· · ·! ΐ ·! Br: Cl: H: - <ζ \ -Cl * · n-C ^: 3: 10: +++: ++: ···· · · t · · ·: h: 01; h; -AX-bt; π-ο4η9; 3; *>; ++; +; • · * · · · ”···: '::: Br:::::: =. 5: Br: Cl: H: ^: n-C ^ H ^: 3: 10: +++: +++: I. j Br; Cl; H; n-C ^! η ”° ^ Η9: 5: 10: +++ · +++ i:::: Br:: ï:::

| : Cl: Cl: H

: - <S: n-C ^ H ^: 3: 8: +++ ++:; this ; this ; h; c2h5,; n-c, Hg; 3; 0.5; + "·; +; '10: 01! 01: H! C H! n-0 H: 3: 3.3: +++! +++! : 2 7::: s:; this ; h. ; h; - <^ \ - this; n-c ^; 3; 10; ***; ++; ··· · ·····: Cl: H: H: y "'" 01: n-c3H7: 3: 5: ++: +: • · ·: _::::::; ci; h ; h; - <^ X; nc ^; 3; 5; + "; +" ·; * * · · · · S "î H: Br; H î iso — C ^ H ^; n — C ^ H, ^; 3 · 7 »5 ï +++ j ++;, 15; Br; OCH *. H: CH: nC H: 3: 7.5: ++: ++: • ·>: 3: 37 ::: ::: Cl S Cl! Cl! ^ 2 ^ 3 * n-C3H7: 3! 10; ++; ++;; ci; ci j ci; - </; nc ^; 3; 10; +++: ++: ···· "j; ·" 1

: Cl: Br: H: C ^: n-C ^; 3: 10 ί +++ +++ J

i · i S î * ···· · · · · · *; this ; Br; Br; - </ ^; n-c ^; 3; 10: +: +: • · · · * ······ | · · · S> "!; # Î · · * 20: Br: Cl: Cl: - /: nC ^. 3 10 | ++! ++! Î · · · ·“ î · * · · ··· ·; 2 ** ·· 1; Br; 01; 01; - <ζ ^>! Ao ^ 9; 3; 10 j ++ · ++ ·::::: ::::: //. Rr · . A IT. AIT. AIT _ A TT -T - „.. / / - 15 -; H *; Bf *; Br \ - </ ~ ^> - Br i nC ^ | 3! 10 +++ j +++; H: Br: Br:: nC ^: 3 s 10: ++ * · ++:; och3; ci h; - </ ~ "\)> nc ^; 3 d 10 *. +++ \ +++ • '5 ·. OCHy.OŒ ^ s H.:: n-C ^ s 3 * · 10 * ++ * · ++ * ·; h; och3; h; c2h3; n-c ^ * 3! 10 J +++; ++ ‘: Br: 0CH3: H:: n-C ^ i 3 · 5 '· ++: ++:; Br; och3; h; ch3; n-c ^! 3 i 7 ί ++! ++ j: Br: 0CH, ·. H; CH,,: n-C, H_,; 3: 7.5 * · ++ · ++ * 3..3 .3 /. . . . .

* 10 Butoprozine 5 +++ +

Amiodarone 10 ++ ++

These results again show that the compounds of the invention are more advantageous than those of the state of the art.

II. Antiarrhythmic properties These properties have been demonstrated after administration of the compound to be studied intragastrically in mice using the LAWSON test (J. Pharmac. Exp. Therap. 1968, 160 (1) p. 22-31) ·

The arrhythmia was caused by inhalation of chloroform to complete asphyxiation and thereafter observing the ventricular rhythm of the animals.

'-20 The dose of compound protecting $ 50 of the animals against ventricular fibrillation is therefore recorded, namely the AD. The following results were noted: ·· · “* β · · î X-: X: X: R: R.: n: M50:: * -. * · ._: Ί; : (mg / kg): 25; Br; Br | H d CH3 | n-C ^ E | 3 d 180 d: H: Br: H: n-C ^: n-C ^: 3: 170: x

Butoprozine 270 yy III. Toxicity / '/ ΓΠλΜ · Ϊ Λ * î 4 "Λ n" r-m *. Λ ^ / - * 16 - "

Acute toxicity tests have been performed in rats and mice.

The following results were recorded compared to butoprozine.

The compounds of the invention were used in the form of acid oxalate with the exception of those marked (x) which were tested in the form of hydrochloride.

a) Intravenously in rats; y; * 2; s; 8; * i; *; y w>) Er; Br j H j 0Η? j n-0 ^ * 3 * 70 j 10: H: Br: H: n-C ^: a-C ^: 3: 60 ···: u) h: 01; h; o2h5; "^ S,,; 65; : H: Cl: Cl: iso-C ^: a-C ^: 3:> 100: 'jWBr; This; H; -y \; ηΛΗ9 j 3 | > 100 | • · · · · * · “·· * · · · · ·: (x) H: 'Cl: H; n-C, H: n-C.H: 3:> 50::::: 9: 9:: CDLq> 50:::::::: mg / kg): 15! d; d; H; c ^; n-c ^; 3; 50; : Cl: · H: H î nC ^ H: aC ^: 3: 50: • · · t · · · “5 Br S Cl '* H: \ - Cl: nC.H: 3:> 100:: * ·:! : * 9: 1 (DL_> 100:: ’*:::: ° mg / kg) 1::::::::

Butoprozine. B) Intravenously in mice 20; (*) Br; Br; H; CH ^: n-c ^! 3 \ 50d

Butoprozine 25 c) intragastrically in mice; (*) Br; Br; H; CH,; n-C, H: 3; > 5000; : 3::: (¾> 5000; 25:!: I: =! ", E / ks):

Butoprozine 1600 / /

These results show that the compounds of the invention are very raoing y - V - - Cardiac tolerance and general toxicity in chronic toxicity tests

Bromo-1 methyl-2 [(di-n-butylamino-3 propyl) oxy- * l · 5 bromo-3 benzoyl] -3 hydrochloride indolizine and n-butyl-2 [(di-n-butylamino hydrochloride) -3 propyl) 4-oxy-3 chloro benzoyl] -3 indolizine do not cause ventricular arrhythmia or mortality at a dose of 200 mg / kg / day per. oral route in dogs.

On the other hand, it has been found that butoprozine causes venous tricular arrhythmia from 50 mg / kg / day orally in dogs, the “lethal dose of this compound being between 50 and 100 mg / kg /day.

The therapeutic compositions according to the invention can be presented in any form suitable for administration in human or veterinary therapy. As regards the administration unit, this may take the form, for example, of a tablet, a dragee, a capsule, a capsule, a powder, '' a suspension or syrup for oral administration, a suppository for rectal administration or a solution or suspension for parenteral administration.

The administration quantity may include, for example, from 159 "to $ 50 20 by weight of active ingredient, for oral administration, from 3% to $ 15 active ingredient for rectal administration, and from 3 $ to $ 5 of active ingredient for parenteral administration.

Depending on the chosen route of administration, the pharmaceutical or veterinary compositions of the invention will be prepared by combining at least 5 of one of the compounds of formula I or a non-toxic addition salt of this compound with an appropriate excipient, the latter which may consist, for example, of at least one ingredient selected from the following substances: lactose, starches, talc, magnesium stearate, polyvinylpyrroli-done, alginic acid, solloidal silica, distilled water, benzy-lique alcohol or sweetening agents.

The following nonlimiting examples illustrate the invention: EXAMPLE 1

Bromo-1 ethyl-2 [(di-n-propylamino-3 propyl) oxy- * f bromo-5 benzoyll-3 / indolizine and its acid oxalate fj \

_ _ “/ U

35 a} Brnmo-I éthvl — P Γ fbrnrnn- ^ Tvrrmvl} nrv-t ηρη ^ ΛίτΊ nr3n "! Î νλ ne / r! - 18 - f>: * I In a flask, stir a mixture of 7i7 g (0.018 I1 mole) of bromo-1 (bromo-3 hydroxy-Λ benzoyl) -3 indolizine, 5 g (0.036 mole) of anhydrous potassium carbonate and 50 ml of methyl ethyl ketone · To this reaction medium is added then 1 * f, 4 g (0.07.2 mole) of dibromo-5 1> 3 propane and the mixture is heated at reflux for 20 hours, after cooling, the mineral salts are filtered and washed with acetone. The solvents are evaporated with the excess of 1,3-dibromo propane.

In this way, 1312 g of a product are obtained which is purified by elution chromatography on silica with benzene as eluent. A first fraction of an unknown product is obtained, then a second fraction of 8 g of the desired product.

In this way, 1-bromo-2-ethyl [(3-bromo-propyl) oxy- ^ benzoyll-3 indolizine is obtained with a yield of 83% mp: 105-106 ° C.

B) Bromo-1 ethyl-2 [(di-n-propylamino-3 propyl) oxy- * f bromo-3 benzoyl] - 3 indolizine

In a flask, refluxed for 20 hours is heated a mixture of 2.2 g (0.00 ^ mole) of 1-bromo-2-ethyl [(3-bromo-propyl) oxy- ^ benzoyl] -3 indolizine, 1, 2 g (0.012 mole) of di-n-propylamine and 25 ml of toluene.

After cooling, the reaction medium is washed with 10 ml of water and the solvent is evaporated in vacuo. Thus, 2.5 g of a residue are obtained! which is purified by elution chromatography on silica with ethyl acetate as eluent.

"

By this process, 2½ g of brorao-1 ethyl-2 [(di-n-propylamino-25 3.propyl) oxy ^ bromo-3 benzoyl] -3 indolizine are obtained in the form of the free base, c) Acid oxalate bromo-1 ethyl-2 [(di-n-propylamino-3 propyl) oxy ^ ^ 52221 ^ - 2252 ^ - ^ “3 indolizine

Gn dissolved in OJ ml of ethyl ether the base obtained previously and it is reacted with 0.55 g of oxalic acid in 70 -1 of ethyl ether, which gives 2.5 g of the desired salt under raw form. 2 g of bromo-1 ethyl-2 [[(di-n-propylamino-3, propyl) oxy * 4 bromo-3 benzoyl] -3 indolizine-pure indolizine 3 g are obtained after rf recrystallization in 75 ml of isopropanol. (1 /! / 1 /

Yield i $ 75> Ü? $

M.P .: 139-1 ^ 0oC

- 19 - EXAMPLE 2

Bromo-1 methyl-2 [(di-n-butylarnino-5 propypoxy-lf bromo-3 benzoyl] -3 indolizine and its salts 5 In a 1 1 flask, a mixture of 180 ml of water, 180 ml of toluene, 73 g (0.178 mole) of bromo-1 methyl-2 (bromo-3 hydroxy-Jf benzoyl) -3 indolizine, * f2.7 g (0.21 mole) of di-n-butylamino -1 chloro-3 propane and 3 ^> 3 g of potassium carbonate.

The reaction medium is heated to reflux for 20 hours.

After cooling to room temperature, the aqueous phase is decanted and the toluene layer is washed with three fractions each of 200 ml of water. The toluene solution is transferred to a flask and at atmospheric pressure, the toluene is distilled to dryness and the residue thus obtained is cooled.

In this way, 1-bromo-2-methyl [(di-n-butylamino-3 propyl) oxy- * f-3-bromo-benzoyl] -3 crude indolizine is obtained in base form. free.

The following salts of this compound were then prepared: a) hydrochloride To the base obtained previously, a solution of 8 g of hydrochloric acid in 61 ml of ethyl acetate is added. The precipitate thus formed is drained, viz. 10 g, washed with ethyl acetate and recrystallized from 500 ml of isopropanol.

In this way, 93 g of 1-bromo-2-methyl-methyl [3 (di-n-butylamino-3-propyl) oxy-4-bromo-3 benzoyl] -3 indolizine are obtained.

Yield: 8k, 7% P.F.; 1? 2 ° C.

b) acid oxalate To an ethereal solution of the base <obtained previously, an equimolecular solution of oxalic acid in ethyl ether is added. The salt thus obtained is recrystallized from isopropanol. /

In this way, the acid oxalate of bromo-1 methyl-2 [(di- / y n-butylamino-3 propyl) oxy- * f bromo-3 benzoyl] -3 indolizine is obtained. ! // m.p .: 89-90 ° C Wf

V

i 4 - 20 -

2-Methyl acid oxalate [(di-n-butylamino-3 propyl) -oxy- * t dibromo-3,5 benzoyl] -3 indolizine

A mixture of k g (0.01 mole) 5 of methyl-2 (3,5-dibromo-3-hydroxy- ** benzoyl) -3 indolizine and 150 ml of acetone is introduced into a 250 ml flask. After dissolving the indolizine, ^ g of anhydrous potassium carbonate and 2.2 g of di-n-butylaminopropyl chloride are added.

With stirring, the reaction mixture is brought to reflux for 16 hours. After cooling to room temperature, the 10 mineral salts are filtered and washed, on a filter, with acetone. The acetone is distilled under reduced pressure using a rotary evaporator and the oily residue is dissolved in approximately 100 ml of ethyl acetate. The medium is filtered on filter and added to the filtrate 1.5 g. anhydrous oxalic acid.

The reaction medium is abandoned and the oxalate which has crystallized is filtered. It is washed on the filter with ethyl acetate and dried under vacuum.

In this way, 6.2 g of methyl-2 [(di-n-butylamino-3-propyl) oxy-4-dibromo-3,5-benzoyl] -3 indolizine is obtained.

20 Yield: 92.7 # m.p .: 96 ° C.

FREE .T! b

Indolizine 25, 1-bromo-1 ethyl-2 [(di-n-propylamino-3 propyl) oxy- ^ dichloro-3,5 benzoyl] -3 oxalate indolizine 25, 2.8 g (0.005) are added to a 250 ml flask mole) of oxalate 5 - 2-ethyl acid [(3-di-propylamino-propyl) oxy- * f-3,5-dichloro benzoyl] - 3 indolizine and 80 ml of dioxane. The reaction medium is mixed and after dissolution of the indolizine, 0.8 g of anhydrous sodium acetate is added.

30 Using a separating funnel, a solution of 0.8 g of bromine in 20 ml of dioxanae is added dropwise and with good stirring. The temperature is maintained at around 20 ° C during the introduction of the bromine.

After stirring the medium for 2 hours at room temperature, the dioxane is distilled under vacuum by means of a rotary evaporator. The solid residue is dissolved in water, made basic with a sodium hydroxide solution and extracted with chloroform. The chloroform solution is washed three times with water and the chloroform is distilled under reduced pressure. The oily residue thus obtained is taken up in ethyl ether for 5 sec and, after filtration through a filter, the acid oxalate is formed.

In this way, 1.8 g of bromo-1 ethyl-2/2 acid oxalate are obtained. [(di-n-propylamino-3 propyl) oxy- ^ dichloro-3,5-benzoyl] -3 indolizine after recrystallization from ethyl acetate.

* 10 Yield: $ 3,518

• I

M.p. 135 ° C.

. Starting from the appropriate products, the following compounds were prepared using the various methods described in the preceding Examples.

Compounds P.F. ° C

15 Bromo-1 ethyl-2 [(di-n-butylamino-3-propyl) -oxy-4-benzoyl] -3 indolizine 107-108 (oxalate) oxalate 107-108 (isopropanol)

Bromo-1 (bromo-phenyl) -2 [(di-n-butylamino-propyl) oxy-A · benzoyl] -3 indolizine 20 (isopropanol) acid oxalate

1-chloro-2-methyl-acid oxalate [(di-n-butylamino-3-propyl) oxy- ^ f benzoyl] -3 indolizine 92-93 (isopropanol)

1-chloro-ethyl 2-oxalate [(di-n-propyl-3-amino-propyl) oxy- ^ benzoyl] -3 indolizine 162 (isopropanol)

1-chloro-n-propyl-2 oxalate [(di-n-butylamino-3 propyl) oxy- ^ benzoyl] -3 indolizine 111-112 (isopropanol) 30-chloro-1 n-butyl-2 oxalate [( di-n- butylamino-3 propyl) oxy- ^ t benzoyl] -3 indolizine 106-108 (isopropanol)

1-Chloro-2-phenyl acid oxalate [(di-n-propylamino-3 propyl) 4-oxy benzoyl] -3 indolizine 161-162 35 (isopropanol)

Chloro-1 (chlorophenyl) acid oxalate -2 [(di-n-butylamino-3 propyl) oxy- * t benzoyl] -3 rf inriolï r.ine <in; Q "ica / / 7 j" - 22 -

1-Chloro-2-phenyl acid oxalate [(di-n-butylamino-3 propyl) 4-oxy benzoyl] -3 indolizine 160-161 (methanol) 5 1-Chloro acid n-butyl-2 [(di- n- butylamino-6 hexyljoxy- ^ benzoyl] -3 indolizine 80-82 (benzene)

Methyl-2 [(di-n-butylamino-3 ^ ^ propyl) oxy- * l-bromo-3 benzoyl] -3 indolizine (3/1 ethyl acetate / 10 isopropanol) oxalate

2-ethyl acid oxalate [(di-n-propylamino-3 propyl) 4-oxy-3 bromo-benzoyl] -3 indolizine 163 (isopropanol)

2-Ethyl acid oxalate [(di-n-butylamino-3 propyloxy- ^ f 3-bromo benzoyl] -3 indolizine 98-99 (isopropanol)

N-propyl-2 [(di-n-propylamino-3 propyl) oxy- ^ f bromo-3 benzoyl] -3 indolizine 1¾ (isopropanol) oxalate 20 n-propyl-2 [(di-n- butylamino-3 propyl) oxy- * l · 3-bromo benzoyl] -3 indolizine 113-115 (isopropanol) i

2-isopropyl-acid oxalate [(di-n-butylamino-3 propyDoxy- 3-bromo-benzoyl] -3 indolizine 105-107 25 (benzene) | 2-butyl-acid oxalate [(di-n-propylamino - I 3 propyljoxy- ^ bromo-3 benzoyl] -3 indolizine 136-137 (isopropanol): 2-n-butyl acid oxalate [(di-n-butylamino-3 propyl) 4-oxy-3 bromo benzoyl] - 3 indolizine 86-87 ~ (isopropanol)

Phenyl-2 [(di-n-propylamino-3 propyl) oxy- * f bromo-3 benzoyl'3-3 indolizine oxalate. 148-1 ^ 9 (isopropanol) 35 Phenyl-2-oxalate [(di-n-butylamino-3-propyl) oxy-if bromo-3 benzoyl] -3 indolizine 129-130 (isopropanol)

(Fluorophenyl) acid oxalate -2 [(dx-n- j butylamino-3 propyl) oxy-4 bromo-3 benzoyl] -3 fj Ί ^ Λ I ri - 23 -

(Chloro - ** phenyl) -2 acid oxalate -2 [(di-n-propylamino-3 propyl) ox $ -k brorao-3 benzoyl] -3 indolizine v 163-16 ^ (methanol) 5 (chloro acid oxalate -4 phenyl) -2 [(di-n-butyl-amino-3 propyl) oxy- * f bromo-3 benzoyl] -3 indolizine 139-1 ^ 0 (isopropanol)

(3-bromo-phenyl) -2 ([(di-n-propyl-3-amino propyl) oxy- ^ v bromo-3 benzoyl] -3 indolizine 1 ^ 2-1 ^ 3, 10. (isopropanol)

(Bromophenyl) acid oxalate -2 [(di-n-butylamino-3 propyl) 4-oxy-3-bromo benzoyl] -3 indolizine 1 ^ 7-148.5 (methanol) 15 Acid oxalate (methoxy- if phenyl) -2 [(di-n-butylamino-3 propylJoxy-A-3-bromo benzoyl] -3 indolizine 169 (isopropanol)

2-isopropyl acid oxalate [(di-n-butylamino-5 pentyl) 4-oxy-3 bromo benzoyl] -3 indolizine 80-82 · (benzene)

2-isopropyl acid oxalate [(di-n-propylamino-3 propyl) oxy-if bromo-3 benzoyl] -3 indolizine 179 (isopropanol) 25 2-methyl acid oxalate [(di-n-butylamino-3 propyl ) oxy- ^ benzoyl] -3 indolizine 1 * H-1 ^ 3 (isopropanol)

2-ethyl acid oxalate [(di-n-propylamino-3 propyl) 4-oxy-3-chloro benzoyl] -3 indolizine 161-162 OJ (methanol)

2-ethyl acid oxalate [(di-n-butylamino-3 propyl) oxy- ^ 3-chloro benzoyl] -3 indolizine 116-117 (isopropanol)

2-isopropyl-acid oxalate [(di-n-butylamino-3-propyl) oxy- 3-chloro-benzoyl] -3 indolizine 115-117 (isopropanol)

Isopropyl-2 acid oxalate [(di-n-propylamino-, j 3 propyl) oxy-if chloro-3 benzoyl] -3 indolizine 168-169 f (methanol) / // 4 - 2k -! N-Butyl-2 acid oxalate [(di-n-butylamino-3 | propyl) oxy- ^ l-3-chloro benzoyl] -3 indolizine 8 * 1-85 '- and 107-109 (Isopropanol) 5 Acid oxalate n-butyl-2 [(di-n-propylamino-3 propyl) oxy- * l-3-chloro benzoyl) -3 indolizine 130-131 (isopropanol)

Phenyl-2 [(di-n-butylamino-3 propyl) oxy - * + chloro-3 benzoyl] -3 indolizine 121-122 (isopropanol) oxalate 2-Phenyl acid [(di-n-propylamino-) '3 propyl) oxy- * l · 3-chloro benzoyl] -3 indolizine 157-159 (methanol)

(Methyl- * f phenyl) -2 oxalate [(di-n- • propylamino-3 propyl) oxy- * f 3-chloro benzoyl] -3 ^ indolizine 13 ^ 135 (isopropanol)

(4-bromo-phenyl) acid oxalate -2 [(di-n-propylamino-3 propyl) oxy- ^ f 3-chloro benzoyl] - 3 indolizine 15 ** - 155 (methanol)

(Bromo- * phenyl) -2 [(di-n-butylamino-3-propyl) oxy-A · 3-chloro benzoyl] -3 acid indolizine 13 ** - 135; (isopropanol) 23 (3-bromo-phenyl) -2-oxalate [[(di-n-butylamino-3 propyl) oxy - * »3-chloro benzoyl] -3! indolizine 92-93 (isopropanol)

(3-bromo-phenyl) -2 ([(di-n-1 propylamino-3 propyl) oxy-4-chloro-3 benzoyl] -3! indolizine 1 * f8-130 (isopropanol)

(Chloro- * phenyl) -2 [(di-n-butylamino-3 propyl) oxy- 3-chloro-benzoyl] -3 i 35 oxalate indolizine 116-118 (isopropanol) /

(4-Chloro-phenyl) acid oxalate -2 [(di-n- / 1 / / i / "ν" ΛΤ \ νΙ βϊΜΊ "Λ_TL r> Yi / \ rvtf1 I" v-ir_LL "Vil nvi / s_TL ^ / // - 25 -

1-bromo-2-methyl acid oxalate [(di-n-butylamino-3 propyljoxy- ^ f 3-bromo benzoyl] - · 3 indolizine 89-90 (isopropanol) 3 1-bromo-2 methyl acid oxalate [(di -n-propyl- amino-3 propyl) oxy- ^ bromo-3 benzoyl] -3 indolizine 16 ^ -165 (isopropanol / methanol)

1-bromo-2-ethyl acid oxalate [(2-dimethylamino-ethyl) oxy- * f 3-bromo benzoyl] -3 indolizine 16 ^ -105 10 (dichloroethane) *

Brora-1 ethyl-2 [(dimethyl-amino-3 propyDoxy-A · 3-bromo-benzoyl] -3 indolizine oxalate # 150-151 (dichlorethane) 15 Bromo-1 ethyl-2 [(diethylamino-) 2 ethyljoxy- ^ brorao-3 benzoyl] -3 indolizine * 168-169 (dichloroethane)

Bromo-1 ethyl-2 [(diethylamino-propyl) oxy- ^ bromo-3 benzoyl] -3 indolizine oxalate 1 * <0-1 * H, 5 20. (isopropanol)

Bromo-1 ethyl-2 £ acid oxalate (di-n-propyl-amino-2 ethyl) oxy-if bromo-3 benzoyl] -3 indolizine 163-164 (isopropanol)

1-bromo-2-ethyl acid oxalate [(di-n-propyl-3-amino-propyl) oxy- ^ f 3-bromo benzoyl] -3 indolizine 139-1 ^ 0 (isopropanol)

1-bromo-2-ethyl acid oxalate [(di-n-butylamino-2 ethyljoxy - ** 3-bromo-benzoyl] -3 indolizine 16 ^ -165 30 (isopropanol)

1-Bromo-2-ethyl acid oxalate [(di-n-butylamino-3 propyl) oxy- ^ f 3-bromo benzoyl] - ^ indolizine 101-101.5 (isopropanol)

1-bromo-n-propyl-2 acid oxalate [(di-n-butyl-3-amino-propyl) oxy-U 3-bromo benzoyl] -3 indolizine 92 (benzene)

Bromo-1 n-propyl-2 acid oxalate [(di-n-propyl- f amino-3 propyl) oxy- ^ f bromo-3 benzoyl] -3 indolizine 132-136 / / I -i cnnrnnannl i / Äf i .

I; I Bromo-1 n-butyl-2 acid oxalate [(di-n-propylamino-3 propyl) oxy-A- 3-bromo-benzoyl] -3 indolizine * 151-152 (2/1 isopropanol / methanol) 5 Acid oxalate of bromo-1 n-butyl-2 [(di-n-butylamino-3 propyl) oxy- ^ bromo-3 benzoyl] -3 indolizine 101-103. (isopropanol)

1-bromo-2-phenyl acid oxalate [(di-n-propyl- ’10 3-amino-propyl) 4-oxy-3-bromo benzoyl] -3 indolizine 169-170 (1/1 methanol / isopropanol)

Bromo-1 phenÿl-2 acid oxalate [(di-n- 'butylamino-3 propyl) oxy- ^ bromo-3 benzoyl] -3 15 indolizine 167-169 (isopropanol)

Bromo-1 (4-methoxyphenyl) -2 [(di-n-butylamino-3-propyl) oxy-1 * bromo-3 "benzoyl] -3 indolizine 178-179 20 (methanol)

Bromo-1 (methyl-Λ phenyl) -2 oxalate -2 [(di-n-butylamino-3 propyl ioxy- ^ f bromo-3 169-170.5 benZoyl] -3 indolizine (1/1 isopropanol / methanol)

Bromo-1 acid oxalate (fluorophenyl) -2. 25 [(di-n-butylamino-3 propyl) oxy-b brorao-3 benzoyl] -3 indolizine 170-171 (methanol)

Bromo-1 acid oxalate (3-bromo-phenyl) -2 • [(di-n-butylamino-3 propyl) oxy- ^ bromo-3 benzoyl] -3 indolizine 172-173 (methanol)

Bromo-1 n-butyl-2 acid oxalate [(di-n-butylamino- ^ butyljoxy- ^ f 3-bromo benzoyl] -3 indolizine 118-120 ^ (isopropanol)

1-chloro-ethyl 2-acid oxalate [(di-n- j butylamino-3 propyl) oxy- ^ 3-chloro benzoyl] -3 \ f. . . /// - 27 -

1-chloro-ethyl 2-acid oxalate [(di-n-propylamino-3 propyl) oxy-1 + 3-chloro benzoyl] -3 indolizine 137-1 ^ 8 (Isopropanol) ^ 1-chloro acid oxalate (bromo-3 phenyl) -2 Ë (di-n-butylamino-3 propyl) oxy- ^ chloro-3 benzoyl] ~ 3 indolizine 171-172. (methanol)

Chloro-1 (3-bromo-phenyl) acid oxalate -2 • ηο [(di-n-propylamino-3 propyl) oxy-k chloro-3 'benZoyl] -3 indolizine 19 ^ -195 (methanol)

1-chloro-ethyl 2-oxalate [(di-n-propylamino-3 propyl) oxy- ^ dichloro-3,5 yj benzoyl] -3 indolizine 1 ^ 1 (ethyl acetate)

1-chloro-ethyl 2-acid oxalate [(di-n-butylamino-3 propyl) oxy- ^ f 3,5-dichloro benzoyl] -3 indolizine 129 (ethyl acetate)

1-chloro-phenyl-2 [(di-n-propylamino-3 propyl) oxy-k dichloro-3,5 benzoyl] -3 indolizine 156 (isopropanol) oxalate 25 1-chloro phenyl-2 ((di -n- butylamino-3 propyl) oxy-Jf 3,5-dichloro benzoyl] -3 indolizine. 136 (isopropanol / heptane)

Bromo-1 methyl-2 acid oxalate [(di-n-propyl-jO 3-amino-propyl) -4-chloro-3 benzoyl] -3 indolizine 110-112 (isopropanol)

Bromo'-1 methyl-2 [(di-n-butylamino-propyl) oxy-4-chloro-3 benzoyl] -3 35 oxalate indolizine 108-110 (isopropanol)

1-Bromo-2-ethyl acid oxalate [(di-n-propyl- ^ ./ / / annnn — rrmnvl \ mnr-4 ehloro— ^ bfiriKovl "! - ^ / i * · # i: j - 28 -

1-bromo-2-ethyl acid oxalate [(di-n-butyl-amino-3 propyljoxy- ^ 3-chloro benzoyl] -3 indolizine 103-105 (isopropanol) 5 1-bromo-n n-propyl-2 oxalate [ (di-n-butylamino-3 propyl) oxy-if chloro-3 benzoyl] -3 „indolizine 95-96 (isopropanol)

Bromo-1 acid isopropyl-2 [(di-n-10 butylamino-3 propyljoxy- ^ chloro-3 benzoyl] -3 'indolizine 116 (isopropanol)

Bromo-1 n-butyl-2 acid oxalate [(di-n-propyl-amino-3 propyDoxy- ^ 3-chloro benzoyl] -3 15 indolizine 159-160 (methanol)

Bromo-1 n-butyl-2 acid oxalate [(di-n-butylamino-3 propyl) oxy-if 3-chloro benzoyl] -3 indolizine 101-103 20 (isopropanol)

1-bromo-2-phenyl acid oxalate [(di-n-butyl4 3-amino propyl) oxy- * f 3-chloro benzoyl] -3 indolizine 167.5-169 (methanol) 25 1-bromo phenyl acid oxalate 2 [(di-n-propyl-3-amino propyl) oxy- ^ 3-chloro benzoyl] -3 indolizine 169-170 (methanol)

Bromo-1 acid oxalate (4-chloro-phenyl) -2 30 [(di-n-butylamino-3 propyl) oxy-if 3-chloro benzoyl] -3 indolizine I6O-161 (isopropanol)

Bromo-l acid oxalate (4-chloro-phenyl) -2 [(di-n-propylamino-3 propyl) oxy-if chloro-3 35 benzoyl] -3 indolizine 18 ^ -185 (methanol) r I Bromo acid oxalate -1 (4-bromo phenyl) -2 ^ d [, / d *

T

- 29 - ·

Bromo-1 acid oxalate (4-bromo phenyl) -2 [(di-n-butylamino-3 propyl) 4-oxy-3-chloro benzoyl] -3 indolizine I68-I69 (isopropanol) 5 Bromo-1 acid oxalate (3-bromo-phenyl) -2 C (di-n-propylamino-3 propyl) 4-oxy-3-chloro benzoyl] -3 indolizine 200-201 (methanol)

Bromo-1 acid oxalate (3-bromo-phenyl) -2 1Ö [(di-n-butylamino-3 propyl) 4-oxy-3-chloro benzoyl] -3 indolizine 170.5-172 (methanol)

Indo-chloro-1 ethyl-2 [(di-n-butylamino-3-propyl) oxy-4-bromo-3 benzoyl] -3 oxalate indolizine 104-105 (isopropanol). 1-chloro-ethyl 2-oxalate [(di-n-propylamino-3 propyl) 4-oxy-3,5-dibromo benzoyl] -3 indolizine 157 20 (isopropanol)

1-chloro-ethyl 2-oxalate [(di-n-butylamino-3 propyl) 4-oxy-3,5-dibromo-benzoyl] -3 indolizine 140 (isopropanol) 25 1-chloro-phenyl-2 acid oxalate [(di -n-propylamino-3 propyl) 4-oxy-3,5-dibromo benzoyl] -3 indolizine 172 (isopropanol)

1-Chloro-2-phenyl acid oxalate [(di-n-30-butylamino-3 propyl) 4-oxy-3,5-dibromo] -3 indolizine 1½ (isopropanol)

2-methyl sesquioxalate [(di-n-propylamino-3 propyl) 4-oxy-3,5-dibromo benzoyl] -3 indolizine 136 35 (ethyl acetate)

2-ethyl acid oxalate [(3-dimethylamino propyl) / 4-oxy-3,5 dibromo benzoyl] -3 indolizine 148 r / (ethyl acetate) / '' / / 1 /

2-Ethyl acid oxalate [(diethylamino-2 1 1!, - JO - ethyl) oxy-h 3,5-dibromo benzoyl] -3 indolizine. . 171 (ethanol)

2-ethyl hydrochloride [(3-diethylamino propyl) 5 oxy-k 3,5-dibromo benzoyl] -3 indolizine - ig-j (50/50 ethyl acetate / acetone)

Ethyl-2 hydrochloride [(di-n-propylamino-3 propyl) oxy- ^ 3,5-dibro-benzoyl] -3 indolizine - | 66. * 10 (ethyl acetate)

2-Ethyl hydrochloride [(di-n-butylamino-3 propyl) oxy- ^ f dibromo-3i5 benzoyl] ~ 3 indolizine. 157 (ethyl acetate) 15 n-propyl-2 hydrochloride [(di-n-propylamino-3 propyl) oxy-Λ 3,5-dibromo benzoyl] -3 indolizine "jlç (ethyl acetate)

N-propyl-2 acid oxalate [(di-n-butylamino-3 propyl) 4-oxy-3,5-dibromo benzoyl] ~ 3 indolizine 107 (ethyl acetate)

2-isopropylacid oxalate [(di-n-propylamino-3'propyl) oxy- 3,5-dibromo-benzoyl] -3 indolizine 126 25 (ethyl acetate / ethanol)

2-isopropyl acid oxalate [(di-n-butylamino-3 propyl) oxy-if dibromo-3,5 benzoyl] -3 indolizine 86 (etiole acetate / ethyl ether) 30 n-butyl-2 acid oxalate [(di-n-propylamino-3 propyl) oxy-l-3,5-dibromo benzoyl] -3 indolizine 1h6 (ethyl acetate)

2-n-butyl acid oxalate [(di-n-butylamino-3 propyl) 3,5-dibromo-benzoyl] -3 indolizine 110 (ethyl acetate) /

Phenyl-2 acid oxalate [(di-n-propylaraino- / j t t - 31 -

Phenyl-2 acid oxalate [(di-n-butylamino-3 propyl) 4-oxy-3,5-dibromo benzoyl] -3 indolizine 86 (ethyl acetate) 5 (4-Fluoro phenyl) acid oxalate -2 [ (di-n-propylamino-3 propyl) oxy- * l-3,5-dibromo benzoyl] -3 indolizine 166 (ethyl acetate / ethanol)

(Fluoro- * phenyl) -2 [(di-n- 5> 10 butylamino-3 propyl) oxy-4 dibromo-3,5 benzoyl] -3 indolizine 152 (isopropanol)

(Chloro- * l · phenyl) -2 [(di-n-propylamino-3 propyl) oxy- ^ dibromo-3,5 benzoyl] -3 indolizine 190 (ethyl acetate) oxalate

(Chlorophenyl) -2 ([di-n-butylamino-propyl) oxy- * f dibromo-3,5 benzoÿl acid oxalate ~ 3 indolizine 88 20 (ethyl acetate)

(3-dichloro-3 * phenyl) sesquioxalate -2 [(di-n-propylamino-3 propyl) oxy- ^ l dibromo-3.5 benzoyl] -3 indolizine 11 ^ (ethyl acetate / isopropanol) 25 Oxalate (3-dichloro-^ phenyl) -2 [(di-n-butylamino-3-propyl) oxy- * l · dibromo-3.5 benzoyl acid] ~ 3 indolizine 95 (ethyl acetate / isopropanol)

(3-bromo-phenyl) -2 [(di-n-propylamino-3 propyl) oxy- * f dibromo-3,5 benzoyl] -3 indolizine 136 (ethanol) oxalate

(3-bromo-phenyl) -2 fumarate acid [(di-n-butylamino-3 propyl) oxy- ^ f 3,5-dibromo benzoyl] -3 indolizine -] pp (ethyl acetate) r

Phenyl deimethyl-if acid oxalate) -2 [(di-n- ^! T - 32 -

(4-methylphenyl) -2 ([(di-n-butylamino-3 propyl) oxy-i + 3,5-dibromo benzoyl] oxalate ~ 3 indolizine 90 (ethyl acetate) 5 (4-methoxy-acid oxalate phenyl) -2 [(di-n-propylamino-3 propyl) 4-oxy-3,5-dibromo benzoyl] -3 indolizine 167 „(acetone)

(4-methoxyphenyl) -2 [(di-n- ’10 'butylamino-propyl) oxy-4 dibromo-3,5 oxalate

benzoyl] -3 pasty indolizine at around 70 ° C

(ethanol / ethyl ether)

2-Methyl acid oxalate [(di-n-propyl-3-amino-propyl) 4-oxy-3,5-dichloro-benzoyl] -3 indolizine 1¾ (ac ethyl acetate / ethanol)

2-methyl acid oxalate [(3-di-n-butylamino-propyl) 4-oxy-3,5-dichloro benzoyl] -3 indolizine 95 20 (ethyl acetate / ethyl ether)

2-Ethyl acid oxalate [(di-n-propyl-araino-3 propyl) 4-oxy dichlor0-3 »5 benzoyl] -3 indolizine 100 (pasty) (ethyl acetate) 25 Ethyl acid oxalate 2 [(di-n-butylamino-3 propyl) 4-oxy-3,5-dichloro benzoyl] -3 indolizine 95 (etiole acetate)

N-propyl-2 acid oxalate [(di-n-propyΙΞΟ amino-3 propyl) 4-oxy-3,5-dichloro benzoyl] -3 indolizine 142 (isopropanol)

N-propyl-2 oxalate [(di-n-butylamino-3 propyl) 4-oxy-3,5-dichloro benzoyl] -3 indolizine 114 35 (isopropanol)

2-isopropyl acid oxalate [(dirn-propylamino- / 3 propyl) 4-oxy-3,5-dichloro benzoyl] -3 indolizine 86 / //> - 33 -

2-isopropyl acid oxalate [(di-n-butylamino-3 propyl) 4-oxy-3,5-dichloro benzoyl] -3 indolizine 90 (ethyl acetate) 5 2-phenyl acid oxalate [(di-n -propylamino-3 propyl) oxy- ^ dichloro-3,5-benzoyl] -3. 1½ * indolizine (ethanol)

2-Phenyl acid oxalate [(di-n-butylamino-3 propyl) 4-oxy-3,5-dichloro benzoyl] -3

indolizine pasty at around 90 ° C

(ethyl acetate)

(Bromo-if phenyl) -2 ((di-n-propyl-3-amino propyl) oxy- 3,5-dichloro-3,5-benzoyl] -3 acid oxalate 15 indolizine 17 / f (ethyl acetate)

2-detbromo acid oxalate! Phenyl) -2 [(di-n-butylamino-3 propyl) 2-oxy * 3,5-dichloro-benzoyl] -3 indolizine 133 20 (ethyl acetate)

1-bromo-2-methyl acid oxalate [(di-n-butylamino-3 propyl) oxy- ^ 3,5-dibromo benzoyl] -3 indolizine 1 ^ 1-1 ^ 3 (isopropanol) * 25 Bromo- acid oxalate 1 methyl-2 [(di-n-propylamino-3 propyl) oxy-1 * · 3,5-dibromo benzoyl] -3 indolizine 138-139 (isopropanol)

Bromo-1 ethyl-2 [(di-n-butylamino-3 propyl) oxy-2 * oxy-2 * · 3,5-dibromo benzoyl] -3 indolizine 131-132.5 (isopropanol)

1-bromo-2-phenyl acid oxalate [(di-n-butylamino-3 propyl) oxy-2t 3,5-dibromo benzoyl] -3 indolizine I6O-161 (isopropanol) r

Bromo-1 (methyl- ^ phenyl) -2 [(di-n- f!

Viiifvl aminn-i * nrrtrnr1 /ί'ΐΚγ'ΛτηΛ-.Χ R Vion γτ / · * »ττ · Ί“ 1 ^ ^ * r ^ r Z i * 3 1 λ - -

Bromo-1 (4-bromo-phenyl) -2 ([(di-n-butylamino-3-propyl) oxy-4 dibromo-3,5 benzoyl] -3 indolizine 148-149 (isopropanol) oxalate. bromo-l (3,4-dichloro-phenyl) -2 [(di-n-butylamino-3 propyl) oxy-4 dibromo-3,5 benzoyl] ~ 3 indolizine 196-197 (Îopropopropol)

Bromo-l acid oxalate (3-chloro-methyl 4 * 10 phenyl) -2 [(di-n-butylamino-3 propyl) 4-oxy-3,5-dibromo-benzoyl] -3 indolizine I68-I69 (isopropanol)

1-bromo-2-ethyl acid oxalate [(di-n-butylamino-3 propyl) 4-oxy-3,5-dichloro 15 benzoyl] -3 indolizine 134 (isopropanol)

1-bromo-2-phenyl acid oxalate [(di-n-propylamixio-3 propyl) 4-oxy-3,5-dichloro-benzoyl] -3 indolizine 14-5 20 ^ ethyl acetate)

1-bromo-2-phenyl acid oxalate [(di-n-butylamino-3 propyl) 4-oxy-3,5-dichloro benzoyl] -3 indolizine 106 (^ ethyl acetate) - 25 n-butyl-2 hydrochloride [(di-n-butylamino-3 propyl) 4-oxy-3-bromo-benzoyl] -3 indolizine 113-113.5 (ethyl acetate)

N-propyl-2 hydrochloride [(3-diethylamino propyl) 4-oxy-3,5-dibromo benzoyl] -3 50 indolizine. 154 (80/20 ethyl acetate ^ acetone)

Ethyl-2 hydrochloride [(di-n-butylamino-3 propyl) 4-oxy-3-chloro benzoyl] -3 indolizine 13 ^ -133 (ethyl acetate / isoprapanol)

N-Butyl-2 hydrochloride [(di-n-butylamino-3 propyl) 4-oxy-3-chloro benzoyl] -3 j indolizine 1C & [} ri * ίΊ-Vvo-l o \ /// -35-

1-bromo-phenyl-2 hydrochloride (* (di-n-butylamino-3 propyDoxy- ^ 3-chloro benzoyl] -3 indolizine 156-157 5 Chloro-1 (chloro-phenyl) acid oxalate -2 [(di -n-propylamino-3 propyl) oxy-if benzoyl] -3 indolizine 168-I69 (methanol) *

1-methoxyphenyl-2-acid oxalate [(di-n-. 10-propylamino-3 propyl) oxy- * 1 · benzoyl] -3 indolizine 117 (ethyl acetate)

1-methoxy-phenyl-2-oxalate [(di-n-butylamino-3-propyl) 4-oxy benzoyl] -3 indolizine 80 (ethyl acetate) 15-1-methoxy-2-phenyl acid oxalate [(di-n - propylamino-3 propyl) oxy-lf chloro-3 benzoylG-3 indolizine 172 (ethyl acetate)

1-methoxy-phenyl-2 [(di-n-20-butylamino-3-propyl) oxy-4-chloro-3-benzoyl] -3 indolizine 120 (ethyl acetate)

1-methoxyphenyl-2 [(di-n-propylamino-3-propyl) oxy-4-bromo-3-benzoyl] -3 acid oxalate 25 indolizine 160 (ethyl acetate)

1-methoxy-phenyl-2 [(di-n-. Butylamino-3 propyl) oxy-4 bromo-3 benzoyl] -3 indolizine 78 jq (ethyl acetate)

1-methoxy-2-phenyl acid oxalate [(di-n-propylamino-3 propyl) 4-oxy-3-methoxy benzoyl] -3 indolizine 1 * t8 (ethyl acetate) 35 1-methoxy-phenyl acid oxalate [(di-n- .butylamino-3 propyl) oxy- ^ 3-methoxy benzoyl] -3 / fi indolizine 78 /. . . /; / ^) - 36 -

Methoxy-1 (fluorophenyl) oxalate -2 [(di-n-propylamino-3 propyl) oxy- ^ 3-methoxy benzoyl] -3 indolizine 79 (ethyl acetate) 5 Methyl-2 oxalate [(di-n-butylamino-3 propyl) oxy- * f 3-methoxy benzoyl] -3 indolizine 159 (isopropanol)

Methyl-2 acid oxalate [(di-n-propylamino-3 = propyl) oxy- ^ 3-methoxy benzoyl] -3 indolizine 171 10 (methanol)

D, ethyl-2 [(di-n-butylamino-3-propyl) oxy- ^ t-methoxy-benzoyl] -3 indolizine 88 (ethyl acetate)

2-Ethyl acid oxalate [(di-n-propylamino-3 propyl) oxy- * 1 · 3-methoxy benzoyl] -3 indolizine 121-122 (ethyl acetate)

1-bromo-2-methyl acid oxalate [(di-n-butylamino-3 propyl) oxy- ^ f 3-methoxy benzoyl] -3 indolizine '87-90 20 (benzene) t

1-bromo-2-methyl acid oxalate [(di-n-propylamino-3 propyl) oxy- ^ l · 3-methoxy benzoyl] -3 indolizine 139-1 ^ 1 (isopropanol) 25 1-bromo acid oxalate 2 [(di-n-butyl-3-amino-propyl) oxy- ^ raethoxy-3 benzoyl] -3 • * indolizine 111 (benzene)

Bromo-1 ethyl-2 [(di-n-propylamino-3 propyl) oxy-4-methoxy-3-benzoyl] -3 indolizine oxalate 1 ^ 9 (isopropanol)

Deifluorophenyl) -2 ([(di-n-I butylamino-3 propyl) oxy- ^ 3-methoxy-benzoyl] -3; indolizine 85 35 (ethyl acetate)

Methyl-2 [(di-n-butylamino-1 ^ * 9 J 3 propyl) oxy- ^ methyl-3 benzoyl] -3 indolizine (isopropanol) oxalate! 2-Ethyl acid oxalate [(di-n-butylamino-3 if $ - 37 -

1-methyln-propyl-2-oxalate [(di-n-butylamino-127 3 propyl) οχγ-Λ bromo-3 benzoyl] -3 indolizine - (ethyl acetate)

2-isopropyl acid oxalate [(di-n-butylamino-91 3 propyl) oxy- ^ methyl-3 benzoyl] -3 indolizine (Isopropanol) 5 n-buty acid oxalate 1-2 'f (di-n-butylamino - 89 3 propyl) 4-oxy-3-methyl-benzoyl] -3 indolizine Cisopropanol)

Methyl-1 n-butyl-2 oxalate [(di-n-butylamino-99 3 propyl) oxy- ^ bromo-3 benzoyl] -3 indolizine (ethyl acetate)

1-methyl-2-ethyl acid oxalate [(di-n-butylamino-. 117 10 3 propyl) 4-oxy-3-bromo-benzoyl] -3 indolizine ’(ethyl acetate)

Bromo-1 methyl-2 ([(di-n-butÿlamino-120-122 3 propyl) oxy-4-dimethyl-3,5 benzoyl] -3 indolizine Cisopropanol) oxalate ‘

Iodo-1 ethyl-2 [(di-n-butylamino-113 3 propyl) oxy-4-dimethyl-3,5 benzoyl] -3 indolizine (ethyl acetate) 15 2-ethyl-2 [dichloro-2 , 3 (di-n-propylamino-3 117 propyl) oxy- ^ l · benzoyl] -3 indolizine (heptane)

Ethyl-2 [2,3-dichloro-3 (di-n-butylamino-3 95 propyl) oxy-IV benzoyl] -3 indolizine (heptane)

Phenyl-2 [2,3-dichloro (di-n-propylamino-3 99 20. propyl) oxy- ^ benzoyl] -3 indolizine (heptane)

Phenyl-2 [2,3-dichloro-3 (di-n-butylamino-3 87 propyl) oxy-k benzoyl] -3 indolizine (heptane) (4-fluorophenyl) -2 [2,3-dichloro (di-n- propylamino-3 propyl) oxy-4 benzoyl] -3 119 '25 indolizine (heptane) (fluorophenyl) -2 [dichloro-2,3 (di-n-butylamino-3 propyl) oxy-A- benzoyl] -3 95-96 indolizine (heptane)

1-Bromo-2-ethyl acid oxalate [dichloro-.30 2,3 (di-n-butylamino-3 propyl) oxy- ^ f benzoyl] -3 16A · indolizine Cisopropanol)

1-bromo-2-phenylacid oxalate [dichloro-2,3 (di-n-propylamino-3 propyl) oxy- ^ f benzoyl] -3,171 indolizine Cisopropanol) 35 Chlor-1 phenyl-2 [dxchloro-2,3 (di-n-propylamino-3 propyl) oxybenzoyl) -3 136 / indolizine (heptane) * / l! / / ·! "- 3δ -

2-n-Butyl acid oxalate [(di-n-butylamino-90-92 3 propyl) 4-oxy-3-iodo benzoyl] -3 indolizine (ethyl acetate) i EXAMPLE 5

According to known pharmaceutical techniques, capsules 5 were prepared containing the following ingredients:

Ingredient mg -r ·. · ·.

N-Butyl-2 hydrochloride [(di-n-butylamino-, 3 propyl) oxy- ^ bromo / or 3-chloro benzoyl] -3 indolizine 100 10 Starches 99i5

Colloidal silica 0.3 200.0 EXAMPLE 6

According to known pharmaceutical techniques, injectable solutions containing the following ingredients have been prepared:

Ingredient mg

N-butyl-2 hydrochloride [(di-n-butylamino-3 propyl) oxy-4 bromo-3 / or chloro-3 benzoyl] -3 indolizine 150 20 Polysorbate 80 '150

Benzyl alcohol 4 75 'Water up to 3 ml EXAMPLE 7

According to known pharmaceutical techniques, suppositories containing the following ingredients have been prepared:

Ingredient mg

N-Butyl-2 hydrochloride [(di-n-butylamino-3 propyl) oxy-4 bromo-3 / or chloro-3 benzoyl) -3 indolizine 100 30 Mixture of mono- and di-glycerides of saturated acids (C ^ to C ^ g) 1 * K) 0 1500 //

/ L

//

Claims (18)

1. Indolizine derivatives corresponding to the general formula ^ ïl 5 r T / 1 L NUAO-CCH ^ -N ^ ^ 0 and their non-toxic addition salts in which: R represents an alkyl radical, linear or branched, having from 1 10 to 8 carbon atoms or a phenyl group which is unsubstituted or substituted by one or two identical or different substituents selected from halogen atoms and from lower alkyl or lower alkoxy groups, represents hydrogen, chlorine, bromine, iodine, methyl or methoxy, 15. represents a selected group of: X2 Cl Cl * 2> - and s3 - - <^> - X3 in which X2 represents hydrogen, chlorine, bromine, iodine, methyl or * 20 methoxy and X represents hydrogen, chlorine, bromine, iodine or methyl, 5 represents a methyl, ethyl, n-propyl or n-butyl radical, n represents an integer from 2 to 6 inclusive, provided that when X and X each represent hydrogen or methyl, is other than hydrogen. 2. Indolizine derivatives according to Claim 1 in which R represents an alkyl radical, linear or branched, having from 1 to 8 carbon atoms, a phenyl radical, mono-fluoro-, mono-chloro-, mono-bromo -, mono-methyl- or mono-methoxy-phenyl, a di-fluoro-, di-chloro-, di-bromo-phenyl radical or a methyl-phenyl radical substituted> / 30 in the aromatic entity by a fluorine atom , chlorine or bromine “· / / i trtpi * .Kvl β” ΡΓ · ί flfflT ΤΙΛ ·, ^ TiY * / Tmrl ^ Vit * rmiVion7.r \ vl 1 · * ^ / ay. · -Ko - indolizine and their non-toxic addition salts. k. n-Butyl-2 [(di-n-butylamino-3 propyl) 4-oxy-bromo-3 benzoyl] -3 indolizine and their non-toxic addition salts. 5. Ethyl-2 [(di-n-butylamino-3 propyl) oxy- * f 3-chloro benzoyl] -3 indoli-5 zine and their non-toxic addition salts. 6. n-Butyl-2 [(di-n-butylamino-3 propyl) 4-oxy-3-chloro benzoyl] -3 indolizine and their non-toxic addition salts. * 7 · Isopropyl-2 [(di-n-butylamino-3 propyl) 4-oxy-3,5-dichloro benzoyl] r3, indolizine and their non-toxic addition salts. 8. Bromo-1 phenyl-2C (di-n-butylamino-3 propyl) oxy - ** chloro-3 benzoyl] -3 indolizine and their non-toxic addition salts. 9. Chloro-1 ethyl-2 [(di-n-butylamino-3 propyl) oxy- ^ chloro-3 benzoyl] -3 indolizine and their non-toxic addition salts. 10. Chloro-1 n-butyl-2 [(di-n-butylamino-3 propyl) oxy- ^ benzoyl3 ~ 3 indolizine and their non-toxic addition salts. 11. Bromo-1 (chlorophenyl) -2 [(di-n-butylamino-3 propyl) oxy- ^ chloro-3 benzoyl] -3 indolizine and their non-toxic addition salts. 12. Indolizine derivatives according to any one of Claims 1 to 11, characterized in that the non-toxic addition salt is the hydrochloride or the acid oxalate. 13. Process for the preparation of indolizine derivatives according to any one of Claims 1 to 12 as well as their non-toxic addition salts, characterized in that one condenses, in an inert solvent,; a bromoalkoxy-benzoyl-indolizine of general formula: V ^ -0-A "0- (CVn-Br 0 in which X ^, R, A and n have the same meaning as in claim 1, with a secondary amine of general formula: _ / 'ut vt -Zidane which has the same meaning as in Claim 1, to form the desired indolizine derivative which is optionally reacted with an organic or inorganic acid to obtain the salt of Corresponding non-toxic addition 1 ^ Process according to Claim 15 characterized in that the solvent is benzene or toluene 15 * Process for the preparation of indolizine derivatives according to any one of Claims 1 to 12 and their salts non-toxic addition, characterized in that an alkali metal salt of an indolizine derivative of general formula is condensed in an aprotic solvent: ^ _L-a-oh 15. o in which R, A and have the same meaning as in Claim 1, with an alkylamino derivative of formula gener ale: / * 1 Z “(CVn- \ Rn or one of its addition 6els, in which Z represents a halogen atom or a p-toluenesulfonyloxy group and n and R ^ have the same meaning as in Claim 1 to form the desired indolizine derivative 9 as optionally reacted with an organic or inorganic acid to obtain the corresponding non-toxic addition salt. 16. A method according to claim 15 characterized in that: - the solvent is acetone, methyl ethyl ketone or toluene, - the alkali metal salt is the sodium or potassium salt, 50. the atom halogen is chlorine or bromine. ^ 17 · Process for the preparation of indolizine derivatives of general formula AJ /. 1 ”** - 42 -? J1 aAî h W1-l ^ -A-0 - (= H2) n-Nx 5 °, -. E1 * and their non-toxic addition salts, in which: R represents an aliyl radical, linear or branched, having *. · · 1 to 8 atoms of. carbon or a phenyl group unsubstituted or substituted by one or two substituents, which may be identical or different, chosen from halogen atoms and from lower alkyl and lower alkoxy groups, represents chlorine, bromine or iodine, A represents a group selected from: X2 Cl Cl 15 B2 '% - "t dô S} =' in which X ^ represents chlorine, bromine, iodine, methyl or methoxy and X ^ represents chlorine, bromine, iodine or methyl,, R ^ represents a methyl, ethyl, n- radical propyl or n-butyl, f 20 n represents an integer from 2 to 6 inclusive, * characterized in that an indolizine derivative of the general formula is reacted: rrv / 1 Ul-0-AO- (0H2) nN ^ 25 0 ^ in which R, A, n and R ^ have the same meaning as above a) with either N-chlorosuccinimide, the reaction taking place in a suitable medium and between 0 ° C and room temperature, for / / /! obtaining the desired indolizine derivative in which X „represents sj - ^ 3- '* chlorine in the form of free base, b) or either bromine or iodine, the reaction taking place at room temperature in an appropriate solvent and in presence of an alkali metal acetate, to obtain the desired indolizine derivative in which 3 represents bromine or iodine in the form of the free base, the free base thus obtained being optionally reacted with an organic or inorganic acid, to provide the corresponding non-toxic addition salt, - j * 18. Process according to Claim 17, characterized in that: 10. the medium is dichloroethane - the solvent is dioxane - the alkali metal acetate is sodium acetate, 19 · Pharmaceutical or veterinary compositions containing as active ingredient at least one indolizine derivative according to Claim 13 1 or 2 or a non-toxic addition salt of this derivative, in combination with a suitable pharmaceutical vehicle or excipient, 20. Pharmaceutical or veterinary compositions containing as active ingredient at least one indolizine derivative according to any one of Claims 3 to 11 or a non-toxic addition salt of this derivative, in combination with a pharmaceutical vehicle or an appropriate excipient. , 21. Process for the preparation of pharmaceutical or veterinary compositions, characterized in that at least one indolizine derivative "according to any one of Claims 1 to 11 or a non-toxic addition salt" of this derivative is combined, to a pharmaceutical vehicle or a. exci pient appropriate, 22. Method for the treatment of pathological syndromes of the heart and in particular angina pectoris and cardiac arrhythmias in a subject requiring such treatment, characterized in that the affected subject is administered an effective dose of at least an indolizine derivative according to Claim 1 or 2. 2.3 · Method for the treatment of pathological syndromes of the heart and in particular angina pectoris and cardiac arrhythmias in a subject requiring such treatment characterized in that one / j, f jf f / / / 0 * .wl. - kh - administers to the affected subject an effective dose of at least one indolizine derivative according to any one of Claims 3 to 11. 2b. Method according to Claim 22 or 23 characterized in that the 5 effective daily dose is 100 to 300 mg orally or 1 to 3 mS parenterally in a subject weighing 60 kg. Drawings: - planohss "_JdLk ... pscss tooth _JL- pf? Te. I% g ....... p".; - es es g · »4 L et- s s claims _____A ... Descriptive LuxemboLTo.! S DEC. 19B0 Mandates: /// 'cic.rles München * â t 4