DD155069A5 - METHOD FOR PRODUCING AN INDOLICIN DERIVATIVE - Google Patents

Abstract

The invention relates to a process for the preparation of an indolizine derivative for the treatment of pathological syndromes of the heart, in particular of angina pectoris and cardiac arrhythmias. The aim of the invention is the provision of new indolizine derivatives with a broader spectrum of cardiovascular properties and the like. lower toxicity. According to the invention, indolizine derivatives d. wherein R is a straight or branched chain alkyl radical having 1 to 8 carbon atoms or an optionally substituted phenyl group; X deep 1 hydrogen, chlorine, bromine, iodine, methyl or methoxy; A is a selected group in which X is 2, such as X is deep 1 and X 3 is hydrogen, chlorine, bromine, iodine or methyl; R 1 is methyl, ethyl, n-propyl or n-butyl radical and n = 2 to 6.

Description

Berlin, April 13, 1981 AP C 07 D / 225 817 58 353 12

-A- 22 58 17 Process for the preparation of an indolizine derivative

Field of application of the invention

The invention relates to a process for the preparation of a novel indolizine derivative with valuable pharmacological properties for the treatment of heart diseases, such as angina pectoris and auricular and ventricular cardiac arrhythmias of various origins.

The invention also relates to pharmaceutical and veterinary compositions containing as active ingredient at least one indolizine derivative prepared according to the invention or a pharmaceutically-acceptable acid addition salt thereof in association with a pharmaceutical carrier or additive therefor.

The invention further relates to a process for the preparation of pharmaceutical or veterinary compositions in which at least one indolizine derivative or a pharmaceutically acceptable acid addition salt thereof produced in accordance with the invention is contacted with a pharmaceutical carrier or admixture therefor,

Characteristic of the known technical solutions

Indolizine derivatives are already known which have pharmacological effects, so that they are useful for the treatment of angina pectoris and cardiac arrhythmias.

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In this context, GB-PS 1 518 443 is mentioned, which describes especially 2-ethyl-3-Z4- (3 ~ di-n-butylaminopropyl) oxybenzoyl7 ~ indozilin, as is known under the unprotected hemin butoprozine. In the cited British patent, the compounds cited therein are said to have antiaginous properties, as they produce the following cardiovascular effects;

- Bradycardia

- Reduction of arterial pressure ~ OC anti-adrenergic effect

- / 3-antiadrenergic effect

- Coronary dilator effect

The increase in blood flow to the myocardium caused by these compounds is in reality only slight, since their effect does not last long: it lasts only a few minutes after an intravenous injection.

Furthermore, the compounds described in the above-mentioned British patent have only a weak β-adrenergic antagonistic effect. This effect is only weak at the minimum dose at which the other four cardiovascular effects listed above show a considerable degree.

Aim of the invention

The aim of the invention is to provide novel indole-derivative derivatives which have a broader spectrum of cardiovascular properties and are less toxic.

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It is the subject of the invention

The object of the invention is to substitute dialkylaminoalkyloxybenzoylindolizine derivatives with one or more methyl or methoxy groups or halogen atoms.

According to the invention, indolizine derivatives of the general formula I

-C-A-O- (CH

(D

and the pharmaceutically-acceptable acid addition salts thereof, for example, the oxalate or hydrochloride, wherein

R is a branched or straight-chain alkyl radical having 1 to 8 carbon atoms or a phenyl group which may be unsubstituted or may bear two substituents which may be the same or different and are halogen atoms, for example fluorine, chlorine and bromine, and lower alkyl and alkoxy groups, for example methyl and methoxy, can be selected; X _{1 represents} hydrogen, chlorine, bromine, iodine, methyl or methoxy,

A represents a group selected under

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Cl

and R ₃ =

in which X _{2 is} hydrogen, chlorine, bromine, iodine, methyl or methoxy and X.sup.- is hydrogen, chlorine, bromine, iodine or methyl;

R 1 represents a methyl, ethyl, n-propyl or n-butyl radical, η represents an integer ranging from 2 to 6, inclusive, with the proviso that when X ₂ and Xo are both hydrogen or methyl, X. is something other than hydrogen.

In the formula I set forth above, R preferably represents a branched or straight-chain alkyl radical having 1 to 8 carbon atoms, a phenyl radical, a monofluoro-, monochlor-, monobromo-, monomethyl- or monomethoxyphenyl radical, a difluoro-, dichloro-, dibromophenyl radical or Methylphenylradical which is substituted in the aromatic component by a fluorine, chlorine or bromine atom.

From the novel indolizine derivatives was found to possess useful pharmacological properties which they have acquired considerable value in the treatment of certain pathological syndromes of the heart, especially for the treatment of angina pectoris and - Aurikular- and ventricular cardiac arrhythmias of various origins "

It has surprisingly been found that when Dialkylaminoalkyloxybenzoylindolizinderivate in a corresponding manner with one or more methyl or methoxy groups

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or halogen atoms, for example chlorine, bromine or iodine, compounds which have a much broader spectrum of cardiovascular properties than the derivatives of British Pat. No. 1,518,443 are less toxic.

This would "demonstrate that the indolizine derivatives of the present invention can be considered to be potent coronary dilators because they can increase the bloodstream going to the myocardium to a considerable degree and over a longer period of time than butoprozine.

For this reason, the indolizine derivatives according to the invention are outstandingly suitable for the treatment of pathological syndromes of the heart and

especially angina pectoris and cardiac arrhythmias in a patient in need of such treatment, the method being that the patient is administered an effective dose of at least one indole-zine derivative of formula I or a pharmaceutically-acceptable acid addition salt thereof.

The daily amounts when administered orally will preferably be 100 to 300 mg of active ingredient, and for parenteral administration will preferably be 1 to 3 mg of active ingredient for a 60 kg patient.

The compounds of the formula I can be prepared according to the invention such that in an inert solvent, such as, for example, benzene or toluene, a bromoalkoxybenzoyl-indolizine of the general formula:

-R

-CAO- (CH ₂ ) _n -Br II

wherein X., R, A and η have the same meaning as in formula I, with a secondary amine of the formula:

III

wherein R 1 has the same meaning as in formula I, to form the desired indolizine derivative of formula I, which is reacted with an appropriate organic or inorganic acid if desired, to give a pharmaceutically-acceptable acid addition salt thereof to achieve.

O.-A

Alternatively, the compounds of formula I may be prepared such that, preferably in an aprotic solvent such as acetone, methyl ethyl ketone or toluene, an alkali metal salt, preferably the potassium or sodium salt, of an appropriately substituted indolizine derivative represented by the general formula:

-C-A-OH

wherein R, A and X. are the same meaning as in formula I, with an alkylamino derivative of the general formula:

or an acid addition salt thereof, wherein. Z is a halogen atom, such as chlorine or bromine, or a p-toluenesulfonyloxy group and η and R have the same meaning as in formula I, to give the intended indolizine derivative, optionally with a corresponding organic or inorganic acid for recovery a pharmaceutically-acceptable acid addition salt thereof.

According to a further aspect of the invention, the indolizine derivative of formula I, wherein X, chlorine, bromine or iodine and A represents the group R, or a group Rp, in which X _{2 is} chlorine, bromine, iodine, methyl or methoxy

and Xo for chlorine, bromine _} iodine or methyl _{s are} also prepared so that an indolizine derivative of the general formula:

-O-AO- (OH ₉ J _n -H "VI

wherein R, R ₁ and η have the same meaning as in formula I and A represents the group R ~ or a group Rp, in which Xp is chlorine, bromine, iodine, methyl or methoxy and Xo is chlorine, bromine, iodine or Methyl:

a) is reacted either with E-chlorosuccinimide, the reaction being carried out in a suitable medium such as dichloromethane

Is carried out at temperatures between ⁰ ° C. and room temperature in order to obtain the required compound of the formula I in which X _{1 represents} chlorine in the form of free base,

b) or reacted with bromine or iodine, the reaction being carried out at room temperature in a suitable solvent such as dioxane and in the presence of an alkali metal acetate, for example sodium acetate, to give the required compound of formula I wherein X _{1 is} bromine or iodine represents winning in the form of free base,

the free base thus obtained then being reacted, if desired, with an organic or inorganic acid to obtain a pharmaceutically-acceptable acid addition salt thereof _e

The compounds of formula II can be prepared so that, if possible in an inert medium such as acetone or methyl ethyl ketone, a Alkalime'tallsalz, preferably the potassium or sodium salt of a Verbindung.der above formula IV with a Dibromalkan the general formula:

Br ~ (CH ₂ ) _n -Br 'VII

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wherein η has the same meaning as in formula I, is condensed, so that the required compound of formula II is obtained.

The compounds of formula IV in which A represents the group R _p are either compounds described in co-pending GB Patent Application No. 80 21924, filed July 4, 1980, or in U.S. Patent Nos. 4,165,199; Compounds which can be prepared by methods described in the British patent application cited above.

The other compounds of formula IV, d. h. those in which A represents the group R can be obtained by reacting the corresponding 2-substituted-indolizine with 2,3-dichloro-4-acetyloxy- or 4-tosyloxybenzoyl chloride. This benzoyl chloride derivative itself is prepared by acetylating 1,2-diclhoranisole under the conditions of the Friedel-Crafts reaction, oxidizing the acetyl derivative thus obtained with sodium hypochlorite to give the corresponding benzoic acid derivative, demethylating with hydroiodic acid in acetic acid to give 2 , 3-dichloro-4-hydroxybenzoic acid. This latter compound is then reacted with acetyl chloride or tosyl chloride to form the required 2,3-dichloro-4-acetyloxy or 4-tosyloxybenzoic acid, and the corresponding acyl chloride is then purified by known methods, for example by reaction with thionyl chloride. educated.

The compounds of the formula II are compounds which fall within the scope of the above formula I.

Compounds of the invention also showed that they lower heart rate and arterial pressure in animals.

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In addition, the indolizine derivatives have a <K- antiperspirant effect, which is much stronger than that of the derivatives of said British patent * At the minimum dose necessary for the production of bradycardia, for the reduction of arterial drought and for o ^ -antiadrenergic and coronary dilatory effects to a certain extent, the / 3 anti-adrenergic effect is actually only slight in the said derivatives of the British patent, whereas it is much stronger in the indolizine derivatives of the invention. In addition, the compounds of the invention reduce the oxygen consumption of the heart muscle, calculated by multiplying the difference between the oxygen in the arterial and venous blood with the coronary blood flow. Therefore, the compounds of the present invention result in a significant reduction in arteriovenous difference, which causes a decrease in oxygen consumption despite an increase in coronary blood flow. In contrast to butoprozin, these beneficial effects on oxygen consumption are achieved with the compounds according to the invention without a decrease in the contractility of the myocardium. "It could also be demonstrated that the derivatives according to the invention are less toxic than the compounds of British Pat 443 are. Intravenous and oral acute animal toxicity tests have shown that the lethal levels in the compounds of the invention are higher than in the derivatives of the subject British patent.

In addition, higher blood levels can be achieved with the compounds according to the invention than with butoprozin.

It has been demonstrated that the same oral dose of 1-bromo-2-methyl-3- / 4- (3-dinitrogen) administered to a dog

-jfl - 2 2 5817

butylaminopropyl) -oxy-3-bromo-benzoyl / -indolizine and from butoprozin induces a blood level which is three times greater than butoprozine in the compound of the present invention. The compounds according to the invention have also shown no cardiac toxicity in the form of ventricular arrhythmia in peroral long-term treatment in dogs, which is not the case with butoprozin.

Finally, the indolizine derivatives according to the invention have a less depressant effect on the contractility of the cardiac muscle than butoprozine. In humans, the occurrence of angina pectoris is the painful consequence of a disturbance between the supply of oxygen to the heart muscle and its oxygen requirement>

A compound can thus be active in the treatment of angina pectoris by either increasing the oxygen supply or lowering the oxygen demand. Among the products commonly used for the treatment of angina in humans are dipyridamole among the coronary dilators and amiodarone among the compounds for lowering the oxygen consumption of the heart muscle,

Comparative experiments, however, have shown that the compounds of the invention are far superior to dipyridamole and amiodarone for several reasons.

In particular, it has been shown that dipyridamole does not reduce the oxygen consumption of the heart muscle and that amiodarone can not be considered a coronary dilator _e

The derivatives according to the invention exert their effect in the form of both factors. Thus, they reduce the oxygen consumption of the heart muscle through their metabolic effects and also increase the coronary blood flow in the long term. In addition, they can not be used to prevent or prevent cardiac arrhythmias induced by cardiac ischemia alone

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It also appears that the halogenation, methoxylation or methylation of the indolizine derivatives of British Pat. No. 1,518,443 leads to compounds possessing a novel spectrum of pharmacological properties, which are also healed, but also auricular and ventricular arrhythmias of various causes are valuable for the treatment of heart disease. For example:

- The sites of the heart muscle, which are inadequately supplied, can be nourished by the coronary dilatory effect, which can lead to the development of an additional collateral circulation. This effect is very valuable for the treatment of anginal disorders and disorders of the rhythm, such as those occurring after myocardial ischemia.

- The anti-adrenergic effect is also useful for the treatment of angina pectoris and cardiac arrhythmia given the important role played by hyperactivity of the sympathetic system in the etiology of these two heart diseases.

Since the physiological amboceptor of the sympathetic system is epinephrine, a compound that inhibits all effects of epinephrine will probably be more effective than a compound that inhibits only a portion of these effects. For this reason, the compounds according to the invention which inhibit both o (~ and β effects of epinephrine offer an advantage over the derivatives of British Pat. No. 1,518,443, which has practically only the oC effects at the minimum dose at which the others pharmacological cardiovascular effects occur.

Of the compounds of the invention which have shown the most prominent antianginal potencies, the following are to be mentioned:

" ίί -. 2 2 5 8 17

1-bromo-2-methyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl / indolizine

2-n-Butyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3-bromobenzoyl / indolizine

2-lthyl-3- / 4- (3-di ~ n-butylaminopropyl) -oxy-3-chlorobenzoyl / indolizine

2-n-Butyl-3- / 4- (3-di-n-butylaminopropyl) oxy-3-ciilobenzoyl / indolizine

2-Isopropyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3 -5-dichloro-benzoyl-indolizine

1-bromo-2-phenyl-3- / 4- (3-di-n-butylaminopropyl) -qxy-3-chloro-benzoyl / indolizine

1-chloro-2-ethyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3-chloro-benzoyl-indolizine

1-chloro-n-butyl ^ -A- (3-di-n-butylaminopropyl) oxybenzoyl / indolizine

1-bromo-2- (4-chloro-phenyl) -3- / 4- (3-di-n-butylaminopropyl) -oxy-3-chloro-benzoyl / indolizine

these compounds being in the form of the free base or a pharmaceutically-acceptable acid addition salt thereof, such as the hydrochloride or hydrogenoxalate,

The results of pharmacological tests j conducted with the aim to determine the cardiovascular properties of erfindungsgemäßen.Verbindungen are then brought _o

I « Antianginal properties

1) influence on the blood stream going to the heart muscle

This test was performed in accordance with the by R. CHARLIER & J. BAUTHIER in Drug Research, "Drug Research", 23 ». Kr. 1.9, 1305 - 1311 (1973).

-η- 225817.

He was done on anae stylized dogs, who received the substance to be examined by intravenous route. The intensity of maximum effect on the cardiac output was given as a percentage of the pre-injection value. The time required for the maximum effect to decrease by 50 % represented the duration of the effect. This time was measured in minutes.

The following results were registered:

R

X ₁ X ₂ X ₃

^R 1

η Dose (mg / kg) Max. He raised Time to 50 % reduction 3 10 60 90 3 10 125 40 , 3 10 100 20 3 10 90 20

Br Br H

Br Br H

Br Br H

Br Br H

Br Br H

Br Br H

H Br H

Br Br H

C ₂ H ₅

JHT

10

10

100

150

20

100

ⁿ - ° 4 ^H 9 3 10 90 25 ⁿ - ^C 4 ^H 9 3 10 77 45

Λ5

-y $ - 225817

H Br H 11-C ₃ H ₇ H Br H 11-C ₄ H ₉ Br Cl H

Cl HH HC ₄ H ₉ H Cl Cl IsO-C ₃ H ₇

H Cl Cl

H Cl Cl IsO-C ₃ H ₇

H Cl. H

H Cl H

H Cl H iso-C ₃ H ₇

11-C ₄ H ₉ 3 2 120 25 HC ₄ H ₉ 3 5 70 60 ⁿ - ^C 4 ^H 9 3 5 133 20 11-C ₄ H ₉ 3 10 60 30 HC ₄ H ₉ 3 10 30 75 HC ₄ H ₉ 3 10 45 15 HC ₄ H 3 10 30 75

nC ₄ H ₉ 3 10 30 45

nC ₃ H ₇ 3 8 45 25 HC ₃ H ₇ 3 5 80 90

Br Cl H

/ T \ HC ₄ H ₉ 3 10

90 90

Br Cl Hn-C 3 10

40 90

Br Cl H

H Cl H

H Cl H

Br Cl H

O " ^Br

HC ₄₁ H ₉

³ 5 -

vci

C ₂ H ₅ HC ₄ H ₉ 3

3 3

HC ₃ H ₇ 3

5 6

50

75 70

63

H Cl H

Br Cl H

Cl Cl H

4Λ-

 br

br

nC ₄ H ₉ 3 10

60

70 90

Cl H C ₂ H ₅ 46 -X- 2 3 19. 58 25 6. 353 8 1981 12 17 15 Cl Cl H C ₂ H ₅ -C ₄ H ₉ 3 1 40 25 Cl Xi-C ₃ H ₇ Third 3 60

Cl H H

vci

21-C ₃ H ₇ 3 5

50 40

Butoprozin Ainiodarone

10 120 4

10 36 7

Ό \

These results clearly show that the compounds of the present invention are four times more potent than butoprocin and amiodarone in their effect on the bloodstream going to the myocardium.

2. Anti-adrenergic effects

The purpose of this test was to increase the capacity of the tested compounds to lower epinephrine-elevated blood pressure (anti-^ effect) and epinephrine-accelerated pulse rate (anti-^ effect) in a pre-pentobarbital anesthetized and atropine-treated pulse Dog to determine ₀

- Αη | ί _Ξ ^ effect,

For each dog, the dose of epinephrine was first determined, which produced a reproducible increase in arterial pressure of about 100 mm Hg (between 5 and 10

Subsequently, the epinephrine dose determined on this occasion was administered, followed by intravenous administration of a dose of the compound to be tested. The percent reduction in the elevated blood pressure achieved by the compound tested was registered relative to the previously determined elevated blood pressure (approximately 100 mm Hg)

In the course of the same test described above, the epinephrine gave a reproducible increase in heartbeat of about 70 beats per minute. The percentage decrease in epinephrine-induced heartbeat acceleration to which the tested compound was then registered compared to the previously measured high pulse rate (approximately 70 beats). In both cases the results were given as follows:

- 18 - 2258

+ for a <50 ~% ~ reduction in pressure increase or

Heart rate * ++ for a ^ 50% ~ reduction in pressure increase or heart rate

+++ for a subtotal reduction of the pressure increase or heart rate,

Poling results were registered:

Dose anti-Λ anti- β X ₁ X ₂ X ^ RR ₁ η (mg / kg) effect effect '

Br Br H CH nC H 3 10 Br HHC ₂ H ₅ HC ₄ H ₉ 3 6

Br Br H - / VP nC, H _n 3 10

Br Br Br n CH 11-C ₃ H ₇ 3 10

± 5r x> r 11 U xl ^ n-li.uq j J 0

: ·. I 10

H Br HC ₄ H ₉ HC ₄ H ₉ 3/5

j 10

H Br H ISO-C ₃ H ₇ nC ₄ H ₉ 3 6

Cl H Hn-C-Hq h-C.Hq 3 10

Cl HH nC ₃ H _? HC ₄ H ₉ 3 7.5

H Cl H HC ₇₁ H ₀ nC .H ₀ 3 10

H Cl HC ₂ H ₅ nC ₃ H _? 3 10

H Cl HC ₉ H. nC H _Q 3 '6

H Br H - </ ^N > nC, H _Q 3 10 + -H-

H Br HC ₂ H ₅ HC ₄ H ₉ 3 7.5

H Br H n C ₄ H ₉ HC ₄ H ₉ 3 5

jbsr η η-i / ÜQ η-UoXir ₇ j 0

H Cl Cl

H Cl H

H Cl H

Br Cl H

Br Cl HC ₂ H ₅

br

- 13 -

3 10

3 10

11-C ₃ H ₇ 3 10

3 10

11-C ₃ H ₇ 3 .7.8

Br Cl H - / ^ - Br n -C H 3 10

Br Cl H HC ₄ H ₉ 11-C ₃ H ₇ 3 10

Br Cl HBr Cl HBr Cl HC ₂ H ₅

Br Cl H

H Cl H

Br Cl H

Br Cl H

Cl Cl H

Cl Cl H

₇₁ H ₀ 4 y

· 3 10

-Br 11-C ₃ H ₇ 3 10 Xi-C ₄ H ₉ 3 10

c 1 11-C ₃ H ₇ 3 10

n-C H 4 9 3 10 11-C ₃ H ₇ 3 10 3 10 XI-C ₃ H ₇ 3 8th Xl-C ₄ H ₉ 3 0.5

5ΑΛ7-

Cl Cl H

Cl H H

Cl H H

Cl H H

C ₂ H ₅

- J «- 2 2 5 ^ 8 17 -

HC ₃ H ₇ 3 3 »3 +++ +++

Cl HC ₄ H ₉ 3

H Br H Br OCH ₃ H Cl Cl Cl

Cl Cl Cl

Cl Br H

Cl Br Br Br Cl Cl Br Cl Cl

CH ₃ C ₂ H ₅

HC ₃ H ₇ 3 7.5 +++ ++ Jl-O ₃ H ₇ 3 7.5 ++ ++ n-C 3K 7 3 10 ++ ++ HC ₄ H ₉ 3 10 +++ +++ ⁿ -C ₄ H ₉ 3 10 +++ + nC ₃ H ₇ 3 10 + ++ HC ₃ H ₇ 3 10 , ++ ++ ⁿ - ^c ₄ H ₉ 3 10 ++

Br CH ₃ CH ₃ CH ₃

H Br Br

H Br Br

OCH ₃ Cl H

OCH OCH H

• Br

3 10 +++ ++ 3 10 +++ +++

HC ₄ H ₉ 3

HC ₃ H ₇ 3

10 ++ ++

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H OCH ₃ HC ₂ H ₅ ⁿ - ° 4 ^H 9 ^{3 10}

Br OGH ₃ HG ₃ H ₅ 11-C ₄ H ₉ 3 5

Br OCH ₃ H CH ₃ ⁿ - ° 4 ^H 9 3 7

Br OCH ₃ H CH ₃ 11-G ₃ H ₇ 3 7.5

Butoprozin -5

Amiodarone 10

- 2Ό - ZZ ^ OI /. 2.7.

These results show again that the compounds of the invention are more valuable than those of the prior art.

II. Anti-Arrhythmia Properties

These properties were demonstrated after intragastric administration of the test compound to mice using the LAWSOI assay (J. Pharmac. Exp. Therap. 1968, 160 (1), pp. 22-31).

The arrhythmia was caused by inhaling chloroform to total asphixy and later observing the ventricular rhythm. The dose of the compound that protected 50 % of the animals against ventricular fibrillation, ie ADt-Qj was recorded afterwards. The following results were registeredί

X ₂ X ₃ RR ₁ η AD ₅₀

(Mg / kg)

Br Br H CH ₃ ⁿ ~ ^C 4 ^H 9 3 180

H Br H. nC ₄ H ₉ 11-C ₄ H ₉ 3 170

Butoprozin '· 270

III. Toxicity Acute toxicity

Acute toxicity tests were performed on rats and mice

The following results were registered in comparison with butoprozine.

The compounds according to the invention were used in the form of hydrogenoxalate, with the exception of those marked with (x).

225817

a) 5uEch_intravenöse_Verabreichung_an_Ratten

(Mg / kg)

br br H CH ₃ HC ₄ H ₉ 3 H br H HC ₄ H ₉ HC ₄ H ₉ 3 H Cl H C ₂ H ₅ ⁿ - ^G 4 ^H ₉ 3 H Cl Cl 1 so-C JBL HC ₄ H ₉ 3

(as) Br Cl H

(s) H Cl H HC ₄ H ₉

Cl Cl HC ₂ Ii ₅ Cl II H

Br Cl H

HC ₄ H ₉ HC ₄ H ₉ 70 60

65> 100

> 100

> 50 (LD ₀ > 50 mg / kg)

50 50

> 100 (LD ₀ > 100 mg / kg)

Butoprozin 22

2H

t *

b) By intravenous administration to mice_

LD

50

(Mg / kg)

(5-1) Br Br H butoprozin

CH

50 25

n-C H 3 > 5000 (1D _O) 5000 mg / kg) 1600

c) By intragastric administration an_Mäuse_

(χ) Br Br CH, butoprozine

These results show that the compounds of the invention are much less toxic than butoprozine.

- Heart Tolerance and Toxicity Long Term Test Toxicity

1-Bromo-2-methyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoylZ-indolizine hydrochloride, 2-n-butyl-3 / 4- (3-di-n -butylaminopropyl) oxy-3-bromo-benzoyl / indolizine hydrochloride and 2-n-butyl-3- / 4- (3-di-n-butylaminopropyl) oxy-3-chloro-benzoyl / indolizine hydrochloride resulted in oral administration administered dose of 200 mg / kg / day in dogs neither to ventricular arrhythmia nor to death,

In contrast, butoprozine was found to induce ventricular arrhythmia in dogs at an oral dose of only 50 mg / kg / day in dogs, with the lethal dose of this compound being between 50 and 100 mg / kg / day.

- 22 58 17

It is envisaged that the therapeutic compounds of the present invention should normally be administered in the form of a pharmaceutical or veterinary medicinal composition which may have a unit dosage form appropriate to the intended route of administration,

Thus, the pharmaceutical or veterinary medicinal composition may have a unit dosage form suitable for oral administration, for example a coated or uncoated tablet, a hard or yelloW gelatin capsule. a packaged powder or a certain amount of a suspension or syrup. However, the composition may also be in the form of a suppository for rectal administration or a solution or suspension for parenteral administration,

When the unit dosage form is present, for example, the composition may contain 15 to 50% by weight of active ingredient per unit dose for oral administration, 3 to 15% of active ingredient per unit dose for rectal administration and 3 to 5 % of active ingredient per unit dose for parenteral administration.

Regardless of the external form of the composition, the pharmaceutical or veterinary composition of the invention will normally be prepared so that at least one of the compounds of formula I or a pharmaceutically-acceptable acid addition salt thereof with a suitable pharmaceutical carrier or additive, for example one of the following substances, lactose, starches, talc, magnesium stearate, polyvinylpyrrolidone, alginic acid, colloidal silica, distilled water, benzyl alcohol or flavors.

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Execution ei spi e1

The following examples illustrate the invention:

example 1

1 ~ bromo-2-ethyl- 3-yl ~ ( 3 ~ di -n ° -p- r''pylaminopropyl ) ~ oxy-3 "* bromo- benzoyl-7-indoli- zine and its hydrogenoxalate

A mixture of 7.7 g (0.018 mol) of 1-bromo-3-bis (3-bromo-4-hydroxybenzoyl) -indolizine, 5 g (0.036 mol) of anhydrous potassium carbonate and 50 ml of methyl ethyl ketone was placed in a flask for 30 minutes touched. To this reaction mixture was then added 14 _{t of} 4 g (0.072 mol) of 1,3-dibromopropane, and the mixture was refluxed for 20 hours. After cooling, the mineral salts were filtered off and washed with acetone. The solvents were evaporated along with the excess 1,3-dibromopropane. In this way, 13.2 g of product were recovered which was purified by chromatography on silica using benzene as the eluent. A first fraction of an unknown product was recovered followed by a second fraction of 8 g of the desired product. In this way, 1-bromo-2-ethyl-3-Z4- (3-bromopropyl) -oxybenzoyl-7-indolizine was obtained in a yield of 83% 6%

Melting point: 105 to 106 ^° C.

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- 225817

b) 1-Bromo-2-ethyl-ethyl-3 "-Z4- (3-di-n-propylaminopropyl) -oxy-3-

A mixture of 2.2 g (0.04 mol) of 1-bromo-2-ethyl-3-Z 4 - (3-bromopropyl) oxy-benzoyl-7-indolizine, 1.2 g (0.012 mol) of di-n Propylamine and 25 ml of toluene was refluxed for 20 hours in a flask. Each time the mixture was cooled, the reaction mixture was washed twice with 10 ml of water and the solvent was evaporated in vacuo. In this way, 2.5 g of residue

l /

obtained by means of elution chromatography on. Silica were purified using ethyl acetate as the eluent. By this method 2.4 g1-bromo-2-ethyl-3- / 4- (3-di-n-propylaminopropyl) oxy-3-bromo-benzoyl / indolizine were obtained in the form of the free base,

c) 1-Bromo-2-ethyl-3- / 4- (3-di-n-propylaminopropyl) -oxy- ^ -bromo-benzo ^ lZ-indolizine hydrochloride

The base obtained above was dissolved in 30 ml of ethyl ether and then reacted with 0.55 g of oxalic acid in. 70 ml of ethyl ether, so that 2.4 g of the intended salt were obtained in crude form. From this amount, 2.0 g of pure 1-bromo-2-ethyl-3- / 4- (3-di-n-propylaminopropyl) -oxy-3-bromo-benzoyl) -indolizine hydrogen oxalate was recovered by recrystallization from 75 ml of isopropanol. Melting point: 139 to 140 ^° C.

Yield: 75 %

Example 2

1-bromo-2-methyl-3- / 4- (3-di-n-butylaminopropyl ) -oxy- β-bromo-benzoyl / -indolizine and salts thereof

Into a 1-1 flask was added a mixture of 180 ml of water, 180 ml of toluene, 73 g (0.178 mol) of 1-bromo-2-methyl-3-i3-bromo-4-hydroxy-benzoyl) -indolizine, 42, 7 g (0.21 mol) of 1-Pi-nbutylamino-0-chloropropane and 34j5 g of potassium carbonate are introduced with stirring. The reaction medium was refluxed for 20 hours. After cooling to room temperature, the aqueous phase was decanted and the toluene layer washed three times with 200 ml each of water. The toluene solution was transferred to a flask, and under atmospheric pressure, the toluene was distilled off to dryness, and the residue thus obtained was cooled.

In this way, crude 1-bromo-2-methyl-3- / 4- (3-di-n-butylaminopropyl) oxy-3-bromo-benzoyl / -indolizine was recovered in the form of the free base.

The following salts of this compound were then prepared:

a) hydrochloride

^ jN η «» «μ w« * -

To the previously obtained free base was added a solution of 8 g of hydrochloric acid in 61 ml of ethyl acetate. The resulting precipitate, i. H. 104 g was vacuum filtered, washed with ethyl acetate and recrystallized from 500 ml of isopropanol. In this way, 93 g of 1-bromo-2-methyl-3- / 4- (3-di-n-butylaminopropyl) oxy-3-bromo-benzoyl / indolizine hydrochloride were recovered

Yield: 84.7 % ₉ Melting point: 172 ⁰ C ₀

b) Hydrogen oxalate ^

To an ethereal solution of the previously recovered base was added an equimolar solution of oxalic acid in ethyl ether. The salt thus obtained was recrystallized from isopropanol. In this way, 1-bromoethyl-3 - / 4- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl / -indolizine hydroxoxalate was recovered,

C.

Melting point: 89 to 90 Example 3

2-Methyl-3- / 4- (3-di-n-butylaminopropyl) oxy-3> 5-dibromo-benzoyl / indolizine hydrogenoxalate

Into a 250 ml flask was added a mixture of 4 g (0.01 mol) of 2-methyl-3- (3> 5-dibromo-4-hydroxybenzoyl) indolizine and 150 ml of acetone. After dissolving

- 22 58 17

so

Indolizine was added to 4 g of anhydrous 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 off and washed on the filter with acetone. The acetone was then distilled off under reduced pressure and with the aid of a rotary evaporator and the oily residue was dissolved in about 100 ml of ethyl acetate. The medium was filtered on a filter _/ and 1.5 g of anhydrous oxalic acid was added to the FiItrat * The reaction medium was left, left ,, and the crystallized oxalate was filtered, washed on the filter with ethyl acetate and dried under vacuum.

In this way, 6.2 g of 2-methyl-3- / 4- (3-di-n-butylaminopropyl) oxy-3> 5-dibromo-benzoyl / indolizine hydrogenoxalate were obtained,

Yield: 92.7%

 Melting point: 96 C »

Example 4

1-bromo-2-ethyl-3- / 4- (3-di-n-propylaminopropyl) -oxy-3, 5 dichlbr-benzoylZ-indolizinhydroftenoxalat

Into a 250 ml flask were added 2.8 g (0.005 mol) of 2-ethyl-3- / 4- (3-di-n-propylaminopropyl) -oxy-3,5-dichloro-benzoyl / indolizine hydrogen oxalate and 80 ml Dioxane filled. The reaction mixture was stirred, and after dissolving indolizine, 0.8 g of anhydrous sodium acetate was added. A solution of 0.8 g of bromine in 20 ml of dioxane was added dropwise and with vigorous stirring through a dropping funnel. The temperature was about 20 ⁰ C during the addition of the bromine held "

2 2 O ö 17

After stirring the medium at room temperature for 2 hours, the dioxane was distilled off under vacuum using a rotary evaporator. The solid residue was dissolved in water, alkalized with sodium hydroxide solution and extracted with chloroform. The chloroform-containing solution was washed with water three times, and the chloroform was distilled off under reduced pressure. The resulting oily residue was taken up in dry ethyl ether, and after filtration on a filter, the hydrogen oxalate was formed.

In this way, 1.8 g of 1-bromo-2-ethyl-3- / 4- (3-di-n-propylaminopropyl) -oxy-3j5-dichloro-benzoyl / indolizine oxalate was recovered after recrystallization from ethyl acetate

Yield: 55 _} 8%

Melting point: 135 ^° C.

Using the appropriate starting materials, the following compounds were recovered using the various processes described in the preceding examples. »

Melting point, compounds , O _n

1-Bromo-2-ethyl-3- / 4- (3-di-n-butylaminopropyl) -oxybenzoyl / indolizinhydrogen oxalate 107-108

(Isopropanol)

1-Bromo-2- (4-bromo-phenyl) -3- / 4- (3-di-n-butylaminopropyl) -oxybenzoyl / -indolizine-92-94 hydrogenoxalate (isopropanol)

1-Chloro-2-methyl-3- / 4- (3-di-n-butylaminopropyl) -oxybenzoyl / indolizine hydrogen oxalate 92-93

(Isopropanol)

Ö I /

1-chloro-2 ~ ethyl-3- / 4- (3-di-n-propylaminopropyl) -oxy-benzoyl / -indolizinhydrogenoxalat

1-chloro-2-n-propyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-benzoyl / -indolizinhydrogenoxalat

1-Chloro-2-n-butyl ~ 3- / 4- (3-di-n-butylaminopropyl) -oxybenzoyl / -indolizine hydrogen oxalate

1-chloro - ^ - phenyl ^ -A- (3-di-n-propylaminopropyl) -oxybenzoyl / -indolizine hydrogenoxalate

1-chloro-2- (4-chloro-phenyl) -3- / 4- (3 ~ di-n-butylaminopropyl) -oxy-benzoyl / -indolizinhydrogenoxalat

1-chloro-2-phenyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-benzoyl / -indolizinhydrogenoxalat

162 (isopropanol)

111-112 (, isopropanol)

106-108 (isopropanol)

161-162 (isopropanol)

158-159 (methanol)

160-161

(Methanol)

1-Chloro-2-n-butyl-3- / 4- (6-di-n-butylaminohexyl) -oxybenzoyl / indolizine oxalate 80-82

(Benzene)

2-Methyl-3- / 4- (3-di-n-butylaminopropyl) oxy-3-bromo-benzoyl / indolizine hydrogen oxalate 141-143

(10/1 ethyl acetate /

isopropanol)

2-ethyl-3- / 4- (3-di-n-propylaminopropyl) oxy-3-bromo-benzoyl / indolizine hydrogenoxalate 163

(Isopropanol)

2-ethyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl / -indolizinhydrogenoxalat

2-n-propyl-3- / 4- (3-di-n-propylaminopropyl) -oxy-3-bromo-benzoyl / -indolizinhydrogenoxalat

2-n-propyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl / -indolizinhydrogenoxalat

98-9? (Isopropanol)

145 (isopropanol)

113-115

2258 17

2-isopropyl-3- / 4 ~ (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl / ~ indolizinhyd.rogenoxalat

2-n-butyl-3- / 4- (3-d i-n-propylaminopropyl) oxy-3-bromo-benzoyl / indolizine hydrogen oxalate

2-n-Butyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl / -indolizinhydrogenoxalat

2-phenyl-3- / 4- (3-di-n-propylaminopropyl) -oxy-3-bromo-benzoyl / -indolizinhydrogenoxalat

2-phenyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl / -indolizinhydrogenoxalat

2- (4-Pluor-phenyl) -3- / 4- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl / -indolizinhydrogen-

oxalate

2- (4-chloro-phenyl) -3- / 4- (3-di-n-propylaminopropyl) -oxy-3-bromo-benzoyl / -indolizine-hydrogen

oxalate

2- (4-chloro-phenyl) -3- / 4- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl / -indolizinhydrogen-

oxalate

2- (3-Bromo-phenyl) -3- / 4- (3-di-n-propylaminopropyl) -oxy-3-bromo-benzoyl / -indolizinhydrogen-

oxalate

2- (4-Bromo-phenyl) -3- / 4- (3-di-n-butylaminopropyl) -oxy-bromo-benzoyl-Z indolizine hydrogen oxalate

2- (4-Methoxy-phenyl) -3- / 4- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl / -indolizine hydrogenoxalate

2-isopropyl-3- / 4- (5-di-n-butylaminopentyl) oxy-3-bromo-benzoyl / ~ indolizinhydrogenoxalat

105-107 (benzene)

136-137 (isopropanol

86-87

(isopropanol

148-149 (isopropanol

129-130 (isopropanoH

110 (Isopropano)

163-164 (methanol)

139-140 (Isopropano)

142-143 (Isopropano)

147 to 148.5

(Methanol)

169 (isopropanol

80-82 (benzene)

2 2 5 8 1 /

2-Isopropyl-3- / 4- (3-di-n-propylaminopropyl) oxy-3-bromo-benzoyl / indolizine hydrogen oxalate 179

(Isopropanol)

2-methyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3-chloro-benzoyl / -indolizine hydrogen oxalate H1-143

(Isopropanol)

2-ethyl-3- / 4- (3-di-n-propylaminopropyl) -oxy-3-chloro-benzoyl / -indolizine hydrogen oxalate 161-162

(Methanol)

2-ethyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3-chloro-benzoyl / -indolizinhydrogenoxalat

116-117 (isopropanol)

2-isopropyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3-chloro-benzoyl / -indolizinhydrogenoxa-

lat

115-117 (isopropanol)

2-isopropyl-3- / 4- (3-di-n-propylaminopropyl) -oxy-3-chloro-benzoyl / -indolizinhydrogen-168-169

oxalate (methanol)

2-n-Butyl-3- / 4 ~ (3-di-n-butylaminopropyl) -oxy-3-chloro-benzoyl / -indolizinhydrogenoxalat

2-n-butyl-3- / 4- (3-di-n-propylarninopropyl) oxy ^ -chloro-benzoylZ-indolizine-hydrogen

oxalate

2-phenyl-3- / 4- (3-di-n-butylarainopropyl) oxy-3-chloro-benzoyl / -indolizinhydrogenoxalat

2-phenyl-3- / 4- (3-di-n-propylaminopropyl) -oxy ^ -chloro-benzoylZ-indolizinhydrogen-

oxalate

84-85

and 107-109 (isopropanol)

130-131 (isopropanol)

121-122 (isopropanol)

157-159 (methanol)

2- (4-methylphenyl) -3- / 4- (3-di-n-propylaminopropyl) oxy-chloro-benzoylZ-indolizine -hydro-134-135 genoxalate (isopropanol)

υ ι /

2- (4-Bromo-phenyl) -3- / 4- (3-di-n-propylaminopropyl) -oxy-3-chloro-benzoyl-indolizine oxalate.

2- (4-Bromo-phenyl) -3- / 4- (3-di-n-butylaminopropyl) -oxy-3-chloro ~ benzoyl / -indolizinhydrogenoxalat

2- (3-Bromo-phenyl) -3- / 4- (3-di-n-butylaminopropyl) -oxy-3-chloro-benzoyl / -indolizinhydrogen-

oxalate

2- (3-Bromo-phenyl) -3- / 4- (3-di-n-propylaminopropyl) -oxy-3-chloro-benzoyl / -indolizinhydrogen-

oxalate

2- (4-chloro-phenyl) -3- / 4- (3-di-n-butylaminopropyl) -oxy-3-chloro-benzoyl / -indolizinhydrogenoxalat

2- (4-chloro-phenyl) -3- / 4- (3-di-n-propylaminopropyl) -oxy-3-chloro-benzoyl / -indolizinhydrogen-

oxalate

1-bromo-2-methyl-3 ~ / 4- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl / -indolizinhydrogenoxalat

1-bromo-2-methy1-3- / 4- (3-di-n-propylaminopropyl) -oxy-3-bromo-benzoyl / -indolizinhydrogen-

oxalate

i'-bromo-2-ethyl-3- / 4- (2-dimethylaminoethyl) oxy-3-bromo-benzoyl / -indolizinhydrogenoxalat

1-bromo-2-ethyl-3- / 4- (3-dimethylaminopropyl) oxy-3-bromo-ben "zoyl / -indolizinhydrogenoxalat

154-155 (methanol)

134-135 (isopropanol)

92-93 (isopropanol)

148-150 (isopropanol)

116-118 (isopropanol

159-160 (methanol)

89-90 (isopropanol

164-165 (isopropanol methanol)

164-165 (Dichlorätha

150-151 ( T) -i r> h1

£, O ο 7

1-bromo-2-ethyl-3- / 4- (2-diethylaminoethyl) oxy-3-bromo-benzoyl / -indolizinhydrogenoxalat

1-bromo-2-ethyl-3- / 4- (3-diäthylaminopropyl) oxy-3-bromo-benzoyl / ~ indolizinhydrogenoxalat

1-Bromo-ethyl-O-A- (2-di-n-propylaminoethyl) oxy-3-bromo-benzoyl-indolizine oxalate

1-bromo-2-ethyl-3- / 4- (3-di-n-propylaminopropyl) -oxy-3-bromo-benzoyl / -indolizinhydrogenoxalat

1-bromo-2-ethyl-3- / 4- (2-di-n-butylaminoäthyl) oxy-3-bromo-benzoyl / -indolizinhydrogenoxalat

1-Bromo - ^ - ethyl ^ -A- (3-di-n-butylaminopropanol)

pyl) -oxy-3-bromo ~ benzoyl / -indolizinh.ydrogen-

oxalate

-S-A- (3-di-n-butylaminopropar) oxy-3-bromo-benzoyl / indolizine hydrogenoxalate

1-Bromo-2n-propyl-3- / 4- (3-di-n-propylaminopropyl) -oxy-3-bromo-benzoyl / -indolizine-hydrogen

oxalate

1-bromo-2-n-butyl-3- / 4- (3-di-n-propylaminopropyl) -oxy-3-bromo-benzoyl / -indolizinhydrogen

oxalate

1-bromo-2 «n-butyl-3- / 4- (3-di-n-butylaniinopropyl) oxy-3-bromo-benzoyl / -indolizinhydrogen-

oxalate

168-169

(Dichlorätiian /

HO-141.5 (isopropanol)

163-164 (isopropanol)

139-140 (isopropanol)

164-165 (isopropanol)

101 to 101.5

(Isopropanol)

(Benzene)

132-136 (isopropanol)

151-152

(2/1 isopropanol / methanol)

101-103 (isopropanol)

22 5 8

1 -BrQm-2-phenyl-3- / 4- (3-di-n-propylaminopropyl) -oxy-3-bromo-benzoyl / -indolizine-hydrogen

oxalate

169-170

1/1 methanol / isopropanol)

1-bromo-2-phenyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl / -indolizinhydrogenoxalat

1-Bromo-2- (4-methoxy-phenyl) -3- / 4- (3-di-n-butylAlaminopropyl) -oxy-3-bromo-benzoyl-indolizine

hydrogen oxalate

1-Bromo-2- (4-methyl-phenyl) -3- / 4- (3-di-n-butyl-3-aminopropyl) -oxy-3-bromo-benzoyl-indolizine

hydrogen oxalate

1-bromo-2 -. ^(/ 4-fluoro-phenyl) -3- / 4- (3-di-n-buty ^ iaminopropyl) oxy-3-bromo-benzoyl / -indolizinhydrogenoxalat

1-Bromo-2- (3-bromo-phenyl) -3- / 4- (3-di-n-butyl) -aminopropyl) -oxy-3-bromo-benzoyl-indolizine oxalate

1-Bromo-n-butyl-4- (4-di-n-butylaminobutyl) -oxy-3-bromo-benzoyl-indolizine oxalate

^ -A- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl / indolizine hydrogen oxalate

-A- (3-di-n-propylaminopropyl) -oxy-chloro-benzoylZ-indolizine hydrogen oxalate

167-169 (isopropanol)

178-179

(Methanol)

169-170.5 (1/1 isopropanol / methanol)

170-171

(Methanol)

172-173

(Methanol)

118-120 (isopropanol)

115-117 (isopropanol)

137-138 (isopropanol)

Z 2 O B 1 /

1-Chloro-2- (3-bromo-phenyl) -3- / 4- (3-di-n-butylpolyaminopropyl) -oxy-3-chloro-benzoyl-indolizine

hydrogen oxalate

1-chloro-2- (3-bromo-phenyl) -3- / 4- (3-di-n-propylaminopropyl) -oxy-3-chloro-benzoyl / -indolizinhydrogenoxalat

1-chloro-2-ethyl-3- / 4- (3-di-n-propylaminopropyl) oxy-3j S-dichloro-benzoyl Z-indolizine hydrogen oxalate

1-Chloro-2-ethyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3 -5-dichloro-benzoyl-indolizine oxalate

1 -C-chloro-2-phenyl-3- / 4- (3-di-n-propylaminopropyl) oxy-3j S-dichloro-benzoyl Z-indolizine hydrogenoxalate

1-chloro-2-phenyl-3- / 4- (3-di-n-butylaminopropyl) oxy-3> 5-dichloro-benzoyl / indolizine hydrogenoxalate

1-bromo-2-methyl-3- / 4- (3-di-n-propylaminopropyl) -oxy-3-chloro-benzoyl / -indolizinhydrogenoxalat

1-bromo-2-methyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3-chloro-benzoyl / -indolizinhydrogen-

oxalate

1-bromo-2-ethyl-3- / 4- (3-di-n-propylaminopropyl) -oxy-3-chloro-benzoyl / -indolizinhydrogen-

oxalate

171-172 (methanol)

194-195 (methanol)

141 (ethyl acetate)

129

(Ethyl acetate)

156 (isopropanol)

136

(Isopropanol / heptane)

110-112 (isopropanol)

108-110 (isopropanol)

136.5-138 (isopropanol)

33

1-bromo-2-ethyl-3- / 4- (3-di-n-butylaminopropyl) -oxy ~ 3-chloro-benzoyl / -indolizinhydrogen-

oxalate

1 ~ bromo-2-n-propyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3-chloro-benzoyl / -indolizinhydrogen-

oxalate

1-bromo-2-isopropyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3-chloro-benzoyl / -indolizinhydrogen-

oxalate

1-Bromo-2-n-butyl-3- / 4- (3-di-n-propylaminopropyl) oxy-3-cilorobenzoyl / indolizine hydrogenoxalate

1-Bromo-2-n-butyl-3- / 4- (3-di-n-butylaminopropyl) oxy-3-chloro-benzoyl / indolizine oxgen oxalate

1-Bromo - ^ - phenyl - ^ -. A- (3-di-n-butylaminopropyl) oxy-3-chloro-benzoyl / -indolizine hydrogen

oxalate

nyl-O - / ^ - (3-di-n-propylaminopropyl) oxy-chlorobenzoyl Z-indolizine hydrogen oxalate

1-bromo-2- (4-chloro-phenyl) -3- / 4- (3-di-nbutylaminopropyl) oxy-3-benzoyl-ch.lor / -indölizinhydrogenoxalat

1-bromo-2- (4-chloro-phenyl) -3- / 4- (3-di-npropylaminopropyl) oxy-3-chloro-benzoyl / -indolizinhydrogenoxalat

103-105 (isopropanol)

95-96 (isopropanol)

116

(Isopropanol)

159-160 (methanol)

101-103 (isopropanol)

167.5-169 (methanol)

169-170

(Methanol)

160-161 (isopropanol)

184-185 (methanol)

- 2ft -ko

2 2 5 8 17

1-bromo-2- (4-bromo-phenyl) -3- / 4- (3-di-npropylaminopropyl) oxy-3-chloro-benzoyl / -

indolizinhjrdrogenoxalat

1-bromo-2 ~ (4-bromo-phenyl) -3- / 4- (3-di-nbutylaminopropyl) oxy-3-chloro-benzoyl / -

indolizinhydrogenoxalat

1-bromo-2- (3-bromo-phenyl) -3- / 4- (3-di-npropylaminopropyl) oxy-3-chloro-benzoyl / -indolizinhydrogenoxalat

1-bromo-2- (3-bromo-phenyl) -3- / 4- (3-di-nbuts' "laminopropyl) oxy-3-chloro-benzoyl / -

indolizinhydrogenoxalat

O-A- (3-di-n-butylaminopropyl) oxy-3-bromo-benzoyl / indolizine hydrogenoxalate

1-Chloro-2-ethyl-3- / 4- (3-di-n-propylaminopropyl) -oxy-3> S-dibromo-benzoyl Z-indolizine hydrogenoxalate

1-Chloro-2-ethyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3j-5-dibromo-benzoyl / -indolizine hydrogen oxalate

1-chloro -phenyl ^ -A- (3-di-n-propylaminopropyl) -oxy-3j-5-dibromo-benzoyl-indolizine oxalate

1-Chloro-2- ^i- phenyl-3- / 4- (3-di-n-butylamino-propyl) -oxy-3> S-dibromo-benzoylZ-indolizine hydrogenoxalate

176-177

(Methanol)

168-169 (isopropanol)

200-201 (methanol)

170.5 to 172

(Methanol)

104-105 (isopropanol)

157 (isopropanol)

HO

(Isopropanol)

172 (isopropanol)

146

(Isopropanol)

2258 17

2 ~ Methyl 3-Z4- (3-di-n-propylaminopropyl) oxy-3 ', 5-dibromo-benzoylZ indolizine sesquioxalate

2-ethyl-3-Z4 (3-dimethylaminopropyl) oxy-3,5-dibromo-benzoylZ-indolizinhydrogenoxalat

2-ethyl-3-Z4 (2-diäthylarninoäthyl) -oxy-3,5-dibromo-benzoyl / -indolizinhydrogenoxalat

2-ethyl-3- / 4- (3-diethylaminopropyl) -oxy-3> 5-dibromo-benzoylZ-indolizine hydrochloride

2-ethyl-3- / 4- (3-di-n-propylaminopropyl) oxy-3j-S-dibromo-benzoylZ-indolizine hydrochloride

2-lthyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3js-dibromo-benzoylZ-indolizinhydrochlorid

2-n-Propyl-3-Z4- (3-di-n-propylaminopropyl) oxy-3j-5-dibromo-benzoylZ-indolizine hydrochloride

2-n-propyl-3-Z4 (3-di-n-butylaminopropyl) -oxy-3 '5-dibromo-benzoylZ-indolizinhydrogenoxalat

2-isopropyl-3-Z4 (3-di-n-propylaminopropyl) -oxy-3} 5-dibromo-benzoylZ-indolizinhydrogenoxalat

2-Isopropyl-3-Z4- (3-di-n-butylaminopropyl) -oxy-3> 5-dibromo-benzoylZ-indolizine hydrogen oxalate

136

(Ethyl acetate)

148 (ethyl acetate)

171

(Ethanol)

191

(5OZ5O ethyl acetate acetone)

166 (ethyl acetate)

157

(Ethyl acetate)

145

(Ethyl acetate)

107

(Ethyl acetate)

126

(Ethyl acetate / ethanol)

86

(Ethyl acetateZ ethyl ether)

2258 17

2-n-butyl-3 ~ / 4- (3-di-n-propylaminopropyl) -oxy 3j 5-dibroni-benzoyl / indolizine hydrogen oxalate

2-n-butyl-3- / 4- (3-di-n-butylaminopropyl) oxy-3> 5-dibromo-benzoyl / indolizine hydrogen oxalate

2-Phenyl-3- / 4- (3-di-n-propylaminopropyl) -oxy-3S-dibromo-benzoylZ-indolizine hydrogenoxalate

2-phenyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3> -dibromo-benzoylZ-indolizine hydrogen oxalate

2- (4-Pluorophenyl) -3- / 4- (3-di-n-propylaminopropyl) oxy-3j5-dibromobenzoyl / indolizine hydrogen oxalate

2- (4-fluoro-phenyl) -3- / 4- (3-di-n-butylaminopropyl) -oxy-3,5-dibromo-benzoyl / -indolizine hydrogenoxalate , "

2- (4-Chloro-phenyl) -3- / 4- (3-di-n-propylaminopropyl) -oxy-3> 5-dibromo-benzoyl / -indolizine hydrogen oxalate

2- (4-Chloro-phenyl) -3- / 4- (3-di-n-butylaminopropyl) -oxy-3- i S-dibromo-benzoyl-Z indolizine hydrogen oxalate

2- (3,4-dichloro-phenyl) -3- / 4- (3-di-n-propylaminopropyl) -oxy-3> S-dibromo-benzoyl-Z-indolizine-sesquioxalate

146 (ethyl acetate)

110

(Ethyl acetate)

142

(Ethyl acetate / ethanol)

86 (ethyl acetate)

166

(Ethyl acetate / ethanol)

152 (isopropanol)

190 (ethyl acetate)

88 (ethyl acetate)

114 (ethyl acetate /

2- (3,4-dichloro-phenyl) -3- / 4- (3-di-n-butylaminopropyl) -oxy-3,5-dibromo-benzoyl / -indo-1-ethylhydrogen oxalate

2- (3-Bromo-pb.enyl) -3- / 4- (3-d i-n-propylaminopropyl) oxy-3is-dibromo-benzoyl Z-indolizine hydrogenoxalate

2- (3-Bromo-phenyl) -3- / 4- (3-di-n-butylaminopropyl) oxy-3, 5-dibromo-benzoyl-indolizinhydrogen fumarate

2- (4-Methylphenyl) -3- / 4- (3-di-n-propylaminopropyl) oxy-3j S-dibromo-benzoyl Z-indolizine hydrogen oxalate

2- (4-Methylphenyl) -3- / 4- (3-di-n-butylaminopropyl) oxy-3> S-dibromo-benzoylZ-indolizine hydrogen oxalate

2- (4-methoxyphenyl) -3- / 4- (3-di-n-propylaminopropyl) oxy-3j S-dibromo-benzoyl Z indolizine hydrogenboxalate

2- (4-Methoxy-phenyl) -3- / 4- (3-di-n-butylaminopropyl) oxy-3-dibromo-benzoyl-indolizine oxalate

2-Methyl-3- / 4- (3-di-n-propylaminopropyl) oxy-3j S-dichloro-benzoyl Z-indolizine hydrogen oxalate

95

(Ethyl acetate Z isopropanol)

136

(Ethanol)

122

(Ethyl acetate)

126

(Ethyl acetate Z isopropanol)

90 (ethyl acetate)

167 (acetone)

pasty at about

(Ethanol · / ethyl ether)

145

(Ethyl acetate / ethanol)

2-Methyl-3- / 4- (3-di-n-butylaminopropyl) oxy-3,5-dichlorobenzoyl / indolizinhydrogenoxalate

2-ethyl-3 ~ / 4- (3-d i-n-propylaminopropyl) oxy-3 »5-dichloro-benzoyl / -indolizine hydrogen oxalate '-

2-lthyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3,5-dichloro-benzoyl / -indolizinhydrogenoxalat

2-n-propyl-3- / 4- (3-di-n-propylaminopropyl) oxy-3> 5-dichloro-benzoyl / indolizine hydrogen oxalate

2-n-Propropyl-3- / 4- (3-di-n-butylaminopropyl) oxy-3-S-dichloro-benzoylZ-indolizine hydrogenoxalate

2-isopropyl-3- / 4- (3 ~ di-n-propylaminopropyl) -oxy-3,5-dichloro-benzoyl / -indolizin-

hydrogen oxalate

2-isopropyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3, S-dichloro-benzoylZ-indolizinhydrogenoxalat

2-phenyl-3- / 4- (3-di-n-propylarainopropyl) oxy-3,5-dichloro-benzoyl / -indolizinhydrogenoxalat

95

(Ethyl acetate / ethyl ether)

100

(pasty) (ethyl acetate)

95 (ethyl acetate)

142

(Isopropanol)

114

(Isopropanol)

86 (ethyl acetate)

9o

(Ethyl acetate)

146 (ethanol)

Ί ZO ö I /

2-phenyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3,5-dichloro-benzoylZ-indolizinhydrogenoxalat

2- (4-Bromo-phenyl) -3- / 4- (3-di-n-propylaminopropyl) -oxy-3> 5-dichloro-benzoyl-indolizine oxalate

2- (4-Bromo-phenyl) -3- / 4- (3-di-n-butyl-amido-propyl) oxy-3-yl-5-dichloro-benzoyl-indolizine oxalate

1-Bromo-2-methyl-3- / 4- (3-di-n-butylaminopropyl) oxy-3> 5-dibromobenzoyl / indolizine hydrogenoxalate

1-Bromo-2-n-propyl-3- / 4- (3-di-n-propylaminopropyl) oxy-3j-5-dibromobenzoyl / indolizine hydrogenoxalate

1-Bromo-2-ethyl-3- / 4- (3-di-n-butylaminopyryl) -oxy-3> S-dibromo-benzoylZ-indolizine hydrogen oxalate

1-Bromo-2-phenyl-3- / 4- (3-di-n-butylaminopropyl) oxy-3, S-dibromo-benzoyl Z-indolizine hydrogen oxalate

1-bromo-2- (4-methyl-phenyl) -3- / 4- (3-di-nbutylaminopropyl) ~ oxy-3> 5-dibromo-benzoyl / -indolizinhydrogenoxalat

1-bromo-2- (4-bromo-phenyl) -3- / 4- (3-di-nbutylaminopropyl) oxy-3 1 5-dibromo-benzoyl / -indolizinhydrogenoxalat

pasty at about 90 ^° C.

(Ethyl acetate)

174 (ethyl acetate)

133

(Ethyl acetate)

141-143 (isopropanol)

138-139 (isopropanol)

131 to 132.5

(Isopropanol)

I6O-I6I (isopropanol)

105-106 (isopropanol)

148-149 (isopropanol)

1-Bromo-2- (3,4-dichloro-phenyl) -3- / 4- (3-di-n-butylaminopropyl) -oxy-3j-5-dibromo-benzoyl-indolizine oxalate

1-Bromo-2- (3-chloro-4-methylphenyl) -3- / 4- (3-di-n-butylaminopropyl) oxy-3,5-dibromobenzoyl / indolizinhydrogen oxalate

1-Bromo-2-ethyl-3- / 4- (3-di-n-butylaminopropyl) oxy-3j-5-dichloro-benzoyl / indolizine hydrogenoxalate

1-Bromo-phenyl-A- (3-di-n-propylaminopropyl) -oxy-3 -5-dichloro-benzoyl-indolizine oxalate

1-Bromo-2-phenyl-3- / 4- (3-di-n-butylaminopropyl) oxy-3j-5-dichloro-benzoyl / indolizinhydrogen oxalate

2-n-Butyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl / -indolizinhydrochlorid

2-n-Propyl-3- / 4- (3-diethyl-aminopro panyl) oxy-3j S-dibromo-benzoyl Z-indolizine hydrochloride

2-ethyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3-chloro-benzoyl / -indolizinhydrochlorid

2-n-Butyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3-chloro-benzoyl / -indolizinhydrochlorid

1-Bromo-2-phenyl-3- / 4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl / indolizine hydrochloride

196-197 (isopropanol)

168-169 (isopropanol)

134 (isopropanol)

145 (ethyl acetate)

106 (ethyl acetate)

113-113.5 (ethyl acetate)

154

(80/20 ethyl acetate / acetone)

132-133

(Ethyl acetate / isopropanol)

104 (ethyl acetate)

156-157

- 2 2 O ϋ Ι /

1-chloro-2- (4-chloro-phenyl) -3- / 4- (3-di-n-Propyla: ninopropyl) oxy-berizoyl / -indolizinhydrogen-

oxalate '168-169

(Methanol)

1-Methoxy-2-phenyl-3- / 4- (3-di-n-propylaminopropyl) -oxybenzoyl-Z-indolizine hydrogen oxalate 117

(Ethyl acetate)

1-Methoxy-2-phenyl-3- / 4- (3-di-n-butylaminopropyl) -oxybenzoyl / indolizine oxalate 80

(Ethyl acetate)

1-Methoxy-2-phenyl-3/4 - (3-di-n-propylaminopropyl) -oxy-3-chlorobenzoyl / indolizine hydrogen oxalate 172

(Ethyl acetate)

1-Methoxy-2-phenyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3-chloro-benzoyl / -indolizine hydrogenoxalate 120

(Ethyl acetate)

1-Methoxy-2-phenyl-3- / 4- (3-di-n-propylaminopropyl) oxy-3-bromo-benzoyl / indolizine hydrogenoxalate 160

(Ethyl acetate)

1-Methoxy-2-phenyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3-bromo-benzoyl-indole-inoxydoxalate 76

(Ethyl acetate)

1-Methoxy - ^ - phenyl - ^ - A - (3-di-n-propylaminopropyl) oxy-3-methoxy-benzoyl / indolizinhydrogen oxalate 148

(Ethyl acetate)

1-Methoxy-2-phenyl-3- / 4- (3-di-n-butylaminopropyl) oxy-3-methoxybenzoyl / indolizinhydrogen oxalate 78

: '. , · '(Ethyl acetate)

1-methoxy-2- (4-fluoro-phenyl) -3- / 4- (3-dia-npropylaminopropyl) oxy-3-methoxy-benzoyl / -indolizinhydrogenoxalat. ·. 79

(Ethyl acetate)

2-Methyl-3- / 4- (3-di-n-butylaminopropyl) oxy-3-methoxy-benzoyl / indolizine hydrogen oxalate 159

  '' (Isopropanol)

2-Methyl-3- / 4- (3-di-n-propylaminopropyl) oxy-3-methoxybenzoyl / indolizinhydrogen oxalate 171

13, 4th 1981

AP C 07 D / 225 817.

58 353

22 58

3 ~ Z / l - (3-di-n'-butylaminopropyl) oxy-3-methoxybenzoyl / ~ inaolizin.hydrogen oxalate

3-Z 1 - (3-di-n-propylaminopropyl) oxy-3-methoxybenzoyl-indolizirhydrogenoxalate

3-Z 1 "" (3-di-n-butyl-amino

1-bromo-2-propyl) -oxy-hydrogenoxalate

(1-Bromo-2-methylsilyl-3 - / 7l - (3-di-n-propylamino-propyl) -oxy-3-methoxy-benzoyl-indolizine hydrogen oxalate

1 ~ bromo ~ 2 ~ ethyl-3 ~ Z4 ~ (3-di-n ~ butylaminopropyl) -oxy ~ 3 ~ ~ benzoyl inethoxy / ~ indolizinhydrogenoxalat

1-bromo-2-ethyl-3 ~ Z ^ ~ (3 "-di-n-propylaminopropyloxy-3 - met.hoxy ~ ~ benzoyl_7 indolizinhydrogenoxalat

2 ~ (4-I'luor-phenyl) -3-Z4 (3 ~ di-n-butylaiid.nopropyl) -ox5 ^r -3-me thoxy-benzoylj-indolizinhydrogenoxalat

2-methyl-3-Z4- (3-di-n-butylaminopropyl) -oxy-3-met.hyl-benzoyl-7-indolizine-hydrogenoxalate

2-Et.-ethyl-3-Z4- (3-di-n-butylaminopropyl) -oxy-3-methylbenzoyl-1-indolizine oxalate

88

(Ethyl acetate)

121-122

(Ethyl acetate)

87-90 (benzene)

139-141 (isopropanol)

111

(Benzene)

149 (isopropanol)

(Ethyl acetate)

149 (isopropanol)

133 (ethyl acetate)

April 13, 1981

AP C 07 D / 225

58 353

2258

1-Metiiyl-2-n-propyl-3- ^ 4- (3-Tu-n-butylaminopropyl) oxy-3 ~ ~ bromo-benzoyl / -indolizinh.ydrogen-

oxalate

2-isopropyl-3-Z4 (3-di-n »butylaminopropyl) -oxy-3 ~ methyl-benzoyl7-indolizinhydrogenoxalat

'-3-Z4 ~ (3-di-n-butylaminopropyl) -oxy-3-methyl-benzoyl7-indolizinhydrogenoxalat

1-Methyl-2-n-butyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-bromo-benzoyl Z-indolizinyl halooxalate

127

(Ethyl acetate)

(Isopropanol)

89 (isopropanol)

99

(Ethyl acetate)

1-methyl-2-ethyl-3 * -Z4- (3- <u ~ n-butylaminopropyl) -oxy-3-bromo-benzoyl7 ~ indolizin.hydrogenoxalat

117

(Ethyl acetate)

1 ~ bromo-2 ~ methyl-3 ~ Z / 5- ~ (3 ~ di-n-butylaminopropyl) ~ oxy ~ 3j5-dimethylbenzoyl / ~ indolizine hydrogen oxalate

1-iodo-2- »ethyl-3 ~ Z4- (3-di-n-butylaminopropyl) -oxy-3 1 5 ~ dimethyl-" bexizoyl7 ~ irdol.icyclohexyl-

oxalate. '·.

120-122

(Isopropanol)

-3- ^ 2,3-dichloro-4- (3-di-n ~ propylaminopropyl) -oxy-benzoylZ indolizine

~ 3r ^ 2,3-dic.hlor-4- (3-di-n-butyl-aminopropyl) oxy-benzoyl-7-indolizine

2-phenyl-3-Z "2,3-dicyclo-4- (3-di-n-propylaminopropyl) -oxybenzoyl-indolizine

115

(Ethyl acetate)

117

(Heptane)

(Heptane)

(Heptane)

13 " Ac 1981

AP C 07 D / 225 817

58 353 12 2258 17

2 ~ phenyl-3 ~ / _2f 3-dichloro-4- (3 ~ di-n-butylaminopropyld-oxybenzoylZ indolizine

2- (4-I'-fluoro-phenyl) -3- / 2,3-dichloro-4- (3-di-propylaminopropyl) -oxybenzoyl-Z-indolizine

2- (4-fluoro-pheJiyl) -3-Z ^ '3-dichloro-4- (3-di-nbutylaminopropyl) ~ benzoyl osy ™ / indolizine

1-bromo ~ 2-äthy1-3- / 2,3-dichloro-4 ~ (3 ~ di-n-butylaminopropyl) oxy-benzoyl7- ~ ± naolizinhydrogenoxalat

87

(Heptane)

119

(Heptane)

95-96 (heptane)

164

(Isopropanol)

1-Bromo-2-Plienyl-3- / 2,3-aichloro-4- (3'-di-n-propylaminopropyl) -oxybenzoyl-7-indo-icizhydrogen oxalate 171

(Isopropanol)

136

(Heptane)

90-92 (ethyl acetate)

-3 - ^ '3 ~ dichloro ~ 4- (3-di-npropylaminopropyl) oxy-benzoylJ-indoIizin

3 - / - (3-di-n-butylaminopropyl) 3-dodecobenzoyl-indolizine oxalate

Example 5:

Soft gelatin capsules containing the following ingredients were prepared using known pharmaceutical techniques:

Ingredient mg

2-n-butyl-3- / 4- (3-di-n-butylaminopropyl) oxy-3-bromo / or 3-chloro-benzoyl / indole

z in-hydrochloric! 100

Strengths 99.5 '

Colloidal silica 0.5

200.0 Example 6

Injectable solutions containing the following ingredients were prepared using known pharmaceutical techniques:

Ingredient 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

V / asser to 3 ml

Example 7 '

Using known pharmaceutical techniques, suppositories containing the following ingredients were prepared:

component

2-n-Butyl-3- / 4- (3-di-n-butylaminopropyl) -oxy-3-bromo / or 3-c-Jalor-benzoyl / -indolizine hydrochloride 100

Mixture of mono- and diglycerides ge1500

saturated acids (C ₁₂ - Cg). 1400

Claims (6)

invention claim 1, Process for the preparation of an indolizine derivative of the general formula ' ⁰ Vn' ¹ ^ wherein R represents a straight or branched chain alkyl radical of 1 to 8 carbon atoms, or a phenyl group which may be unsubstituted or may carry one or two substituents equal to or more? may be different and are selected from halogen atoms and lower alkyl and alkoxy groups, X ". Represents hydrogen, chlorine, bromine, iodine, methyl or methoxy, A one under Cl Cl and represents selected group in which Xp 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, 13 · 4 1981 AP C 07 E / 225 5-if 58 353 12 - 2258 17 η represents an integer ranging from 2 to inclusive, with the proviso that when X ₂ and X _{2 are} both hydrogen or methyl, X 1 is other than hydrogen or a pharmaceutically-acceptable acid addition salt thereof, characterized in that a) a bromoalkoxy-benzene-indolizine of the general formula. , wherein X .., R, A and η have the same meaning as stated above, in an inert solvent with a secondary amine of the general formula ^R 1 R.sup.1 has the abovementioned meaning, is condensed to form the intended indolizine derivative which can be reacted in bulk with a corresponding organic or inorganic acid to obtain a pharmaceutically acceptable acid addition salt thereof; 13. 4- 1981 AP C 07 D / 225 817 58 353 12 Process for the preparation of an indolizine derivative according to item 1, characterized in that R is a branched or straight-chain alkyl radical having 1 to 8 carbon atoms, a phenyl radical, a monofluoro-, monochloro-, monobromo-, monomethyl- or monomethoxyphenyl radical, a difluoro-, Dichloro, di-bromophenyl radical or a methylphenyl radical which is substituted in the aromatic component by a fluorine, chlorine or bromine atom. 13 «4. 1981 AP C 07 D / 225 817 58 58 353 12 - 925817 2 2 5 8 17 b) an alkali metal salt of a Indolizinderivats according to the general formula wherein R, A and X have the abovementioned meaning, in an aprotic solvent with an alkylamino derivative of the general formula ^E 1 or an acid addition salt thereof in which Z is a halogen atom or a p-toluenesulfonyloxy group and η and R- have the abovementioned meaning, is condensed to obtain the intended indolizine derivative which is optionally mixed with a corresponding organic or inorganic acid to form a pharmaceutically an acceptable acid addition salt thereof; c) provided that in the general formula 13. 4 »1981 AP C 07 D / 225 817 58 353 12 C-A-O- (CH) -Ν ι » £ ^Xi \ 0 NO R represents a branched or straight-chain alkyl radical having 1 to 8 carbon atoms or a phenyl group which is unsubstituted or bears one or two substituents which may be identical or different and have been chosen from halogen atoms and lower alkyl and alkoxy groups,
X _{1 is} chlorine, bromine or iodine, A is an under Cl Cl and R- = represents a selected group in which Xp ^is chlorine, bromine, iodine, methyl or methoxy and ^{X.sup.4 represents} chlorine, bromine, iodine or methyl, R.sup.1 represents a methyl, ethyl, n-propyl or n-butyl radical, η represents an integer ranging from 2 to 6 inclusive, an indolizine derivative of the general formula 13. Ao 1981 AP C 07 D / 225 817 5? 58 353 12 - 225817 C-ArO- (CHj -Ν <Γ tr <£. · "Χ wherein R, A, η and R have the same meaning as explained above, is reacted with C-) ENTV / Eder N-chlorosuccinimide, wherein the reaction takes place in a suitable medium, and between 0 ⁰ C and room temperature in order to obtain the required indolizine derivative in which X ₁ is chloro in the form of free base, C ₂ ) or bromine or iodine, the reaction is carried out at room temperature in a suitable solvent and in the presence of an alkali metal acetate to recover the required indolizine derivative in which X _{1 is} bromine or iodine in free base form, the free base thus obtained can then be reacted, if desired, with an organic or inorganic acid to form a pharmaceutically-acceptable acid addition salt thereof. " 3 "process according to item 1a), characterized in that the solvent is benzene or toluene, 4 * method according to item 1b), characterized in that - It is the solvent is acetone, methyl ethyl ketone or toluene - The alkali metal salt is the potassium or sodium salt - The halogen atom is chlorine or bromine. 5 * method according to item 1c), characterized in that - The medium is Dichioräthan - Serves as a solvent dioxane the alkali metal acetate is sodium acetate, A process for the preparation of a pharmaceutical or veterinary medicinal composition, characterized in that at least one indolizine derivative or pharmaceutically-acceptable acid addition salt thereof according to any one of items 1 to 5 is brought together with a pharmaceutical carrier or additive therefor