HU185019B - Process for preparing indolizine derivatives - 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

The present invention relates to indolizine derivatives of the formula I and their pharmaceutically acceptable acid addition salts, for example their oxalates or their hydrochlorides.

In the general formula (I)

R is C 1-6 straight or branched chain alkyl, phenyl which is unsubstituted or substituted with one or two substituents and may be the same or different and represents a halogen such as fluorine, chlorine or bromine, or lower alkyl or an alkoxy group such as methyl or methoxy.

X 1 is hydrogen, chlorine, bromine or iodine, or methyl or methoxy,

A is a group of formula (a) or (b) wherein, in formula (a), X ₂ is hydrogen, chlorine, bromine or iodine, or methyl or methoxy, X ₃ is hydrogen, chlorine, bromine or iodine , or methyl,

R 1 is methyl, ethyl, η-propyl or n-butyl, n is 2, 3, 4, 5, or 6, with the proviso that when X ₂ and X ₃ are both hydrogen or methyl, then X! is other than hydrogen.

In the formula (1), R is preferably C 1-6 straight or branched alkyl, phenyl, monochloro, monofluoro, monobromo, monomethyl or monomethoxyphenyl, difluoro, dichloro or dibromo. -phenyl or methylphenyl substituted in the aromatic ring with fluorine, chlorine or bromine.

The compounds of the present invention are useful in the treatment of certain pathological heart syndromes, in particular angina pectoris and cardiac arrhythmias of various origins, auricular and ventricular.

The present invention also relates to compositions for human and veterinary use and to their preparation containing as active ingredient at least one indolizine derivative of the formula (I) or a pharmaceutically acceptable acid addition salt thereof together with pharmaceutically acceptable carriers and excipients.

For pharmaceutical purposes, the compounds of the invention are preferably administered at a daily dose of 100-300 mg orally or at a dose of 1-3 mg parenterally. These doses are for people weighing 60 kilograms.

The compounds of formula (I) according to the invention are prepared by condensing a bromoalkoxy-benzoyl-indolizine of formula (II) in an inert solvent such as benzene or toluene, wherein X, R, A and n are converting the indolizine derivative of formula (I) into a pharmaceutically acceptable acid addition salt thereof, optionally by reaction with an organic or inorganic acid, with a secondary amine of formula (III) wherein R 1 is as defined.

The compounds of formula (I) may also be prepared by reacting an alkali metal salt of an indolizine derivative of formula (IV), preferably a sodium or potassium salt thereof, wherein R, A and Xj are as defined for an alkyl antino derivative of formula (V) or an acid addition salt thereof, wherein Z is a halogen atom such as chlorine or bromine, or p-toluenesulfonyloxy, n and Rj are as defined, preferably in an aprotic solvent such as acetone, methyl ethyl ketone or toluene. and then converting the resulting indolizine derivative of formula (I), if desired, into a pharmaceutically acceptable acid addition salt thereof by reaction with an organic or inorganic acid.

Indolizine derivatives of formula I wherein X ₁ is chloro, bromo or iodo, A is a or b wherein X ₂ is chloro, bromo or iodo, or methyl or methoxy and X ₃ is chlorine, bromine or iodine, or methyl, it may also be prepared by indolizine derivative of formula (VI) wherein R, R 1 and n are as defined and A is (a) or (b) in the latter formulas X ₂ is chlorine, bromine or iodine or methyl or methoxy, X ₃ is chlorine, bromine or iodine or methyl,

i) Reaction with N-chlorosuccinimide in a suitable medium such as dichloroethane at a temperature between 0 ° C and room temperature to give the corresponding compound of formula I wherein Xi is chlorine in free base form, or ii) With chlorine or iodine reaction at room temperature in a suitable solvent such as dioxane in the presence of an alkali phenol acetate such as sodium acetate to give the corresponding compound of formula I wherein X 1 is bromo or iodo as the free base, followed by reaction i) or ii). optionally reacting the resulting free base with an organic or inorganic acid to form a pharmaceutically acceptable acid addition salt thereof.

The compounds of formula (II) may be prepared by reacting an alkali metal salt of a compound of formula (IV), preferably a sodium or potassium salt thereof, wherein X, R and A are as defined, with Br- (CH ₂ ) _n -. condensed with dibromoalkane flr where n is as defined above, preferably in an inert reaction medium such as acetone or methyl ethyl ketone to give compound II.

Compounds of formula IV wherein A is a group are partially described in U.S. Patent No. 80,21924. pending U.S. Patent Application Serial No. 4,672,123, and may in part be prepared by the methods described therein.

Another group of compounds of formula (IV), wherein A is (b), can be prepared by reacting the corresponding 2-substituted indolizine derivative with 2,3-dichloro-4-acetyloxy or 4-tosyloxybenzene. chloride. The benzoyl chloride derivative itself is prepared by acetylating 1,2-dichloroanisole under the conditions of the Eriedel-Crafts reaction and then oxidizing the resulting acetyl derivative with sodium hypochlorite to give the corresponding benzoic acid derivative in acetic acid, e.g. 2,3-dichloro-4-hydroxybenzoic acid is obtained. This product is reacted with acetyl chloride or tosyl chloride to give 9 desired 2,3-dichloro-4 →

Acetyloxy or 4-tosyloxybenzoacetate is obtained which is converted to the corresponding acid chloride by known means, for example thionyl chloride.

Compounds of formula (VI) are a narrower group of compounds of formula (I).

Indolizine derivatives which are curative and useful in the treatment of angina pectoris and cardiac arrhythmia are known.

1.518.443. United Kingdom Patent No. 4,600,125 discloses 2-ethyl-3- [4- (3-di-n-butylaminopropyl) oxybenzoyl] indolizine, which is known under the trade name butoprozine. This compound is said to have anti-angina activity because it has the following cardiovascular effects:

- biadycardia, - reduction of arterial pressure, - α-antiadrenergic effect, - β-antiadrenergic effect, - coronary dilator.

In fact, this compound only slightly increases blood flow to the myocardium, as its effect is not sustained when administered by intravenous injection for only a few minutes.

In addition, the compounds described in the above-mentioned British patent have only a weak O-adrenergic antagonist activity. The effect is minimal at the minimum dose at which the other four cardiovascular effects are significantly manifested. Surprisingly, it has been found that replacing the dialkylaminoalkyloxy-benzoyl-indolizine derivatives with a methyl or methoxy group or a halogen atom such as chlorine, bromine or iodine results in compounds having a much broader spectrum of cardiovascular properties. such as 1.518.443. and the toxicity of our compounds is also lower.

Thus, it has been possible to demonstrate that the compounds of the invention are potent coronary vasodilators because they significantly increase blood flow in the myocardium and have a longer duration of action than butoprozine. In addition, the compounds of the present invention reduce the heart rate and arterial blood pressure of animals.

In addition, the indolizine derivatives have a much more potent O-antiadrenergic effect than the compounds of the above-mentioned British patent. When used in the UK at the minimum dose required to induce bradycardia, to significantly reduce arterial blood pressure, to achieve adequate α-antiadrenergic and coronary vasodilatory activity, the compounds of the present invention exhibit low activity, while the compounds of the present invention are much more potent.

The compounds of the present invention further reduce the oxygen consumption of the myocardium, which is calculated by multiplying the difference in oxygen content of arterial and venous blood with coronary blood flow. The compounds of the present invention significantly reduce the difference in arterial and venous oxygen content, resulting in a decrease in oxygen consumption despite an increase in coronary blood flow,

In addition to bytoprozine, the compounds of the present invention improve oxygen consumption without at the same time reducing myocardial contractility at all.

The new compounds are less toxic than

1518443. United Kingdom Patent Nos. Intravenous and oral acute toxicity tests have shown that the lethal dose for your pet is higher for the new compounds than for the compounds of the British patent.

The new derivatives may be present in the blood in greater amounts than butoprozine. The equivalent oral dose of 1-bromo-2-methyl-3 - [(4-di-n-butylaminopropyl) oxy-3-bromobenzoyl] -indolizine and butoprosine was orally administered to dogs in triplicate. in blood compared to the latter.

Oral administration of the compounds of the invention to dogs for an extended period of time did not result in cardiac injury in the form of ventricular arrhythmia, which is not the case with butoprozine.

Finally, the new compounds reduce myocardial contractility to a lesser extent than butoprosin.

In humans, a significant difference between myocardial oxygen demand and oxygen supply results in angina pectoris seizures. Thus, angina pectoris can be treated either by improving oxygen supply or by reducing oxygen deficiency. Among the drugs commonly used to treat human angina pectoris, dipyridamole has a coronary vasodilator effect and amiodarone reduces myocardial oxygen demand. Comparative studies have shown that the compounds of the present invention are in many respects significantly better than dipyridamole and amiodarone.

Dipyridamole was shown not to reduce myocardial oxygen consumption and amiodarone was not a coronary dilator. The serine compounds of the invention are effective in both respects, because of their metabolic effects, they reduce oxygen consumption in the myocardium and permanently increase coronary blood flow. In addition, they are useful not only for the prevention and treatment of ischemic arrhythmias of the myocardium but also for the prevention and treatment of a variety of auricular and ventricular arrhythmias.

Thus, according to experimental data, 1.518.443. Halogenation and methoxylation of compounds disclosed in United Kingdom Patent No. 5,600,198 yielded new compounds useful in the treatment of heart failure due to their new pharmacological activity spectrum. so for example:

- inappropriate blood supply to the myocardium can be treated by the coronary dilator, which may lead to the initiation of additive collateral circulation. This effect is suitable for the treatment of anginal pain as well as for the treatment of arrhythmias caused by myocardial ischemia, - the antiadrenergic effect can be applied to the treatment of both angina pectoris and cardiac arrhythmia, given its influence on the sympathetic nervous system hyperactivity mentioned two heart diseases. Because the sympathetic nervous system is mediated by epinephrine, a compound that blocks all of the effects of epinephrine will probably be more effective than one that affects only some of the effects.

For this reason, the compounds of the present invention which have both α- and β-adrenergic effects of epinephrine

185,019 are blocked, more advantageous than 1.518,443. United Kingdom Patent Nos. 5,198,194, which are practically only α-blockers at the minimal dose at which other cardiovascular effects are already present.

Among the compounds of the invention, the most potent anti-angina activity is:

- 1-bromo-2-methyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-bromobenzoyl] indolizine, '

- 2-n-butyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-bromobenzoyl] -indolizine,

- 2-ethyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl] -indolizine,

- 2-isopropyl-3- [4- (3-di-n-butylaminopropyl) oxy] -3,5-dichlorobenzoyl] -indolizine,

- 1-bromo-2-phenyl-3- [4- (3-di-n-butylamino-propyloxy-3-chloro-benzoyl) -indolizine,

- 1-chloro-3-ethyl-3- (4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl) indolizine,

- 1-chloro-2-n-butyl-3- [4- (3-di-n-butylaminopropyl) -20-oxybenzoyl] indolizine,

- 1-Bromo-2- (4-chlorophenyl) -3- [4- (3-di-n-butylamino-propyl) -oxy-3-chlorobenzoyl] -indolizine.

The compounds listed above are also effective in the form of the free base or of a pharmaceutically acceptable acid addition salt, such as the hydrochloride or oxalic acid salt.

The following are the results of pharmacological tests to determine the cardiovascular properties of the compounds of the present invention.

I. Anti-angina properties

1. Effect on myocardial blood supply

The assay was carried out according to the method described by Chariier, R., Bauthier, J., Arzneimittelforschung, 23, No. 19, 1305-1311 (1973).

The assay was performed on anesthetized dogs administered intravenously the test substance. The maximum effect on myocardial blood supply is expressed as a percentage of the corresponding value before injection. The durability of the effect is illustrated by the time required to reduce the maximum effect to 50%, measured in minutes.

The following results were obtained:

Compounds of Formula (I), A is a Powder of Formula (a)

Xj X ₂ X ₃ R Rin Dose Maximum Increase to 50% (mg / kg) required%. time

Br Br H ethyl n-butyl 3 10 60 90 Br Br H methyl n-butyl 3 10 125 40 Br Br H n-butyl n-propyl 3 10 100 20 Br Br H n-propyl n-propyl 3 10 90 20 Br Br H phenyl n-propyl 3 10 100 20 Br Br H m-bromophenyl n-butyl 3 10 150 100 H Br H p-bromophenyl n-butyl 3 10 90 25 Br Br H methyl n-butyl 3 10 77 45 H Br H n-propyl n-butyl 3 2 120 25 H Br H n-butyl n-butyl 3 5 70 60 Br cl H i-propyl n-butyl 3 5 133 20 cl H H n-butyl n-butyl 3 10 60 30 H cl cl i-propyl n-butyl 3 10 30 75 H cl cl p-bromophenyl n-butyl 3 10 45 15 H cl cl i-propyl n-butyl 3 10 30 75 H cl H m-bromophenyl n-butyl 3 10 30 45 H cl H m-bromophenyl n-propyl 3 8 45 25 H cl H i-propyl n-propyl 3 5 80 90 Br cl H phenyl n-butyl 3 10 90 90 Br cl H n-butyl n-propyl 3 10 40 90 Br cl H p-bromophenyl n-propyl 3 10 50 50 H cl H n-butyl n-butyl 3 5 75 30 H cl H ethyl n-butyl 3 6 70 45 Br cl H p-chlorophenyl n-propyl 3 10 63 45 H cl H p-bromophenyl n-butyl 3 10 60 25 Br the H n-propyl n-butyl 3 2.5 50 60 cl cl H m-bromophenyl n-propyl 3 8 70 90 the cl H ethyl n-butyl 3 3.3 60 25 the H H p-chlorophenyl n-propyl 3 5 50 40

Butoprozin 10 120 4

Amiodaron 10 36 7

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The results clearly show that the compounds of the present invention have an improved myocardial blood supply performance over those of butopyrosine and amiodarone known compounds.

2. Antiadrenergic effects

The purpose of the experiment was to determine the effect of some of the compounds of the invention on epinephrine-induced hypertension (anti-effect) and epinephrine-accelerated heart rate (anti-β effect). The experiment was performed on dogs anesthetized with pentobarbital.

Anti-α effect

First, the dose of epinephrine that is reproducible causes a rise in arterial blood pressure of about 100 mmHg (doses of 5 to 10 g / kg) in all dogs.

Thereafter, the determined dose of epinephrine and the test compound were administered intravenously. The percentage reduction in previously measured hypertension of about 100 mmHg as a result of the test compound was measured.

Anti-β effect

The same assay as described above was performed, whereby epinephrine produced a reproducible increase in heart rate, increasing it to about 70 heartbeats / min. The percentage reduction in epinephrine-induced accelerated heart rate by the test compound relative to the previously measured tachycardia (approximately 70 heartbeats) was then determined.

In both cases the results are given as follows:

A + sign indicates a reduction in pressure or heart rate increase of less than 50%.

'5 ++ signal for increase in pressure or heart rate

This means a reduction of 50% or more.

The + *> sign means a complete reduction in the increase in pressure and heart rate.

oo The following results were obtained:

X. x ₂ x ₃ R Rí n Dose (Mg / kg) Anti-a effect Anti-β effect Br Br H ethyl n-butyl 3 10 +++ 444 Br H H ethyl nbutyl 3 6 +++ +4+ Br Br H p-fluorophenyl n-butyl 3 10 +44 ++ Br H Br Br Br H n-propyl phenyl n-propyl 3 n butyl 3 10 10 +44 +44 444 4+ H Br H ethyl n-butyl 3 7.5 +4+ ++ H Br H n-butyl n-butyl 3 5 +4+ + r H Br H n-butyl n-propyl 3 5 444 44 Br Br H methyl n-butyl 3 5 +++ +4 10 4 + 4 444 H Br H n-butyl nbutyl 3 5 444 44 10 444 444 H Br H i-propyl nbutyl 3 6 4 + 4 ++ cl H H n-butyl n butyl 3 10 +++ ++ cl H H n-propyl n-butyl 3 7.5 4 + 4 +44 H cl H n-butyl n butyl 3 10 +++ 44 H cl , H ethyl n-propyl 3 10 44 44 H cl H ethyl n butyl 3 6 44+ ++ H cl cl i-propyl nbutyl 3 10 ++ 44 H cl H m-bromophenyl nbutyl 3 10 4+ +4 H cl H i-propyl n-propyl 3 10 44 44 Br the H phenyl nbutyl 3 10 4+ +4+ Br cl H ethyl n-propyl 3 7.8 44 44 Br cl H p-bromophenyl n-propyl 3 10 44 44 Br cl H n-butyl n-propyl 3 10 +4 4 Br cl H p-chlorophenyl nbutyl 3 10 ++ 44 Br cl H p-bromophenyl n-propyl 3 10 ++ 44 Br cl H ethyl nbutyl 3 10 4 ++ 444 Br the H p-chlorophenyl n-propyl 3 10 +++ 44 H cl H p-bromophenyl nbutyl 3 10 +4 4 Br cl H m-bromophenyl  n-propyl 3 10 +++ 444 Br cl H n-propyl n-butyl 3 10 4 ++ 444 cl cl H m-bromophenyl n-propyl 3 8 +++ 44 cl cl H ethyl n-butyl 3 0.5 4 ++ 4 cl cl H ethyl n-propyl 3 3.3 ♦ + 4 4 + 4 cl H H p-chlorophenyl n-butyl 3 10 444 4+ cl H H p-chlorophenyl n-propyl 3 5 44 4 cl H H phenyl n-butyl 3 5 4 + 4 + + ♦. H Br H i-propyl n-propyl 3 7.5 4 + 4 44 Br methoxy H methyl n-propyl 3 7.5 44 4+ cl cl cl ethyl n-propyl 3 10 +4 44

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ci ci a phenyl n-butyl 3 10 +++ +4 Cl Br H ethyl n-butyl 3 10 4 ++ 4 + 4 Cl Br Br phenyl n-propyl 3 10 4 ♦ Br Ο Cl phenyl n-propyl 3 10 +4 44 Br Cl Cl phenyl n-butyl 3 10 44 +4 Br methyl methyl methyl n-butyl 3 10 444 4+ H Br Br p-bromophenyl n-propyl 3 10 444 +4+ H Br Br phenyl n-butyl 3 10 ++ 4+ methoxy Cl H phenyl n-propyl 3 10 +++ 44+ methoxy methoxy H phenyl n-propyl 3 10 ++ +4 H is methoxy H ethyl n-butyl 3 10 444 4+ Br methoxy H ethyl n-butyl 3 5 ++ 44 Br methoxy H methyl n-butyl 3 7 4+ 44 Br methoxy H methyl n-propyl 3 7.5 ++ 44 butoprozine 5 +4+ 4 amiodarone 10 44 4+

The results show that the compounds of the invention have more valuable properties than those of the prior art.

II. Anti-arrhythmic properties

The assay was performed by administering the test compounds intragastrically to mice, followed by the Lawson method ¹ (J. Phar20 mac. Exp. Therap., 1968, 160, (1), 22-31).

The arrhythmia was induced by inhaling the animals with chloroform until full asphyxia was reached and subsequently measuring ventricular rit2g must.

Next, AD ₅₀ , the dose of compound that reduces ventricular fibrillation by 50%, was determined. The following results were obtained:

Xj X ₂ X ₃ R

Rin AD50 (mg / kg)

Br Br H methyl

H Br H n-Butyl n-Butyl 3 180 n-Butyl 3 170

III. Toxieitás

Acute toxicity

Acute toxicity studies were performed in rats and 40 mice. The following results were obtained when compared with butoprozine. The compounds of the invention were used in the form of their oxalic acid salts, except for the (-) candidates, which were tested in the form of their hydrochloride.

Br methyl methyl methyl

I methyl methyl ethyl n-butyl 3 n butyl 3 <100 100

Butoprozin 270

(a) Intravenous administration to rats

Xi Xi X3 R Ri n LDj ₀ (mg / kg) Br Br H methyl n-butyl 3 70 H Br H n-butyl n-butyl 3 60 H cl H ethyl n-butyl 3 65 ' H cl cl i-propyl n-butyl 3 > 100 Br -ci- H phenyl n-butyl 3 > 100 H cl II n-butyl n-butyl 3 > 50 (LD _jo> jo mg / kg) cl cl H ethyl n-butyl 3 50 cl H H n-butyl n-butyl 3 50 Br cl H p-chlorophenyl n-butyl 3 > 100

(LD _O > 100 mg / kg)

Butoprozin 22

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b) Intravenous administration to mice

(-) Br Br H H methyl H methyl Br H butoprozine methyl n-butyl n-butyl n-butyl 3 n-propyl 3 n-propyl 3 50> 50 50 25 c) Intimate adhesive application in mice () Br Br H methyl n-butyl 3 > 5000 butoprozine (LD ₀ > 5000 mg / kg) 1600

The results showed that the compounds of the invention were much less toxic than butoprozine.

Cardiac tolerance and general toxicity in long-term toxicity tests

Oral administration to dogs of 200 mg / kg / day in 1-bromo-2-methyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-bromobenzoyl] -indolizine hydrochloride, 2- n-butyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-bromobenzoyl] indolizine hydrochloride or 2-n-butyl-3- [4- (3- di-n-butylaminopropyl) oxy-3-chlorobenzoyl] indolizine hydrochloride showed no vertical arrhythmia and no animal died.

In contrast, oral administration of butoprozine to dogs has already resulted in vertical arrhythmia at 50 mg / kg / day and a lethal dose of 50-100 mg / kg / day.

For therapeutic purposes, the compounds of the invention may generally be administered in the form of pharmaceutical or veterinary compositions, and may be formulated in unit dosage forms according to the desired route of administration.

For example, a formulation for human or veterinary use can be formulated in a unit dosage form for oral administration, for example, as uncoated tablets, hard or soft gelatine capsules, powder formulations, as a suspension or syrup, for rectal administration, as a suppository, .

Unit doses may contain from 15 to 50% by weight of active ingredient per dose for oral administration, from 3 to 15% by weight of active ingredient for rectal administration and from 3 to 5% by weight for parenteral administration.

The composition, regardless of its type, contains at least one active ingredient of the formula I or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable carrier or excipient, such as lactose, starches, talc, magnesium stearate, polyvinylpyrrolidone, silica, distilled water, benzyl alcohol, flavoring agents.

The following examples are intended to illustrate the present invention without limiting it.

Example 1 Preparation of 1-Bromo-2-ethyl-3- [4- (3-di-n-propylaminopropyl) oxy-3-bromobenzoyl] -indolizine and its oxalic acid salt

a) Preparation of 1-Bromo-2-ethyl-3- [4- (3-bromopropyl) oxybenzoyl) indolizine

A mixture of 7.7 g (0.018 mol) of 1-bromo-3- (3-bromo-4-hydroxylbenzoyl) -indolizine, 5 g (0.036 mol) of anhydrous potassium carbonate and 50 ml of methyl ethyl ketone is stirred for 30 minutes. . To the reaction mixture was added 14.4 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, and the solvents and excess 1,3-dibromo-propane were evaporated. 13.2 g of product are obtained,

J ' ³ which is purified by chromatography on silica eluting with benzene. In the first fraction, unidentified product was obtained, in the second fraction, 8 g of the desired product. Yield 83.6%, mp 105-106 ° C.

b) Preparation of 1-Bromo-2-ethyl-3- [4- (3-di-n-propylaminopropyl] oxy-3-bromobenzoyl] indolizine

2.2 g (0.004 mol) of 1-bromo-2-ethyl-3- [4- (3-bromopropyl) oxybenzoyl] -indolizine, 1.2 g (0.012 mol) of di-n-propyl- A mixture of amine and 25 ml of toluene was refluxed for 20 hours. The reaction mixture was cooled, washed with water (2 x 10 ml) and the solvent evaporated under reduced pressure. The resulting residue (2.5 g) was purified by chromatography on silica eluting with ethyl acetate. 2.4 g of the title product are obtained in the form of the free base.

c) Preparation of the oxalic acid salt of 1-Bromo-2-ethyl- [3- (4-di-n-propylaminopropyl) oxy-3-bromobenzoyl] -indolizine cc The base obtained in step b) is dissolved. A solution of 0.55 g of oxalic acid in 70 ml of ethyl ether is added to give 2.4 g of the title salt as a crude product, which is recrystallized from 75 ml of isopropanol to give 2.0 g of the pure title product.

Yield: 75%, m.p. 139-140 ° C.

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Example 2 Preparation of 1-Bromo-2-methyl-3- [4- (3-di-n-butylamino-propyl) -oxy-3-bromo-benzoyl] -indolizine and its salt are added to a one-liter flask with stirring, water, 180 ml of toluene, 73 g (0.178 mol) of 1-bromo-2-methyl-3- (3-bromo-4-hydroxybenzoyl) -indolizine ₎ 42.7 g (0.21 mol) of 1-di- n-butylamino-3-chloropropane and * 34.5 g of potassium carbonate. The reaction mixture was refluxed for 20 hours, cooled to room temperature, the aqueous phase was decanted and the toluene layer was washed with water (3 x 200 mL). The toluene was poured into a flask, evaporated to dryness at atmospheric pressure and the residue cooled.

The title compound is obtained in the form of a crude product, and the salts are prepared from this free base as follows.

(a) Preparation of the hydrochloride salt

To the free base was added a solution of 8 g of hydrochloric acid in 61 ml of ethyl acetate, and the resulting 104 g of precipitate was filtered, filtered off, washed with ethyl acetate and recrystallized from 500 ml of isopropanol to give 93 g of the hydrochloride salt. Yield: 84%. Melting point: 172 C. ^Ű

b) preparation of the oxalic acid salt

To the ethereal solution of the free base was added an equimolar amount of a solution of oxalic acid in ethyl ether. The resulting salt was recrystallized from isopropanol. The oxalic acid salt has a melting point of 89-90 ° C.

Example 3

Preparation of oxalic acid salt of 2-methyl-3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dibromobenzoyl] indolizine

Into a 250 mL flask was placed 4 g (0.01 mol) of 2-methyl-3- (3,5-dibromo-4-hydroxybenzoyl) -indolizine and 150 mL of acetone. After the indolizine has dissolved, 4 g of anhydrous potassium carbonate and 2.2 g of di-n-butylaminopropyl chloride are added. The reaction mixture was stirred and refluxed for 16 hours. then cooled to room temperature, the mineral salt was filtered off and washed on the filter with acetone. The acetone is then evaporated under reduced pressure on a rotary evaporator and the oily residue is dissolved in about 100 ml of ethyl acetate. The solution was filtered and 1.5 g of anhydrous oxalic acid was added to the slice. The mixture was allowed to stand, the crystallized oxalate was filtered off, washed on the filter with ethyl acetate and dried under reduced pressure.

6.2 g (92%) of the title compound are obtained. Melting point: 96 ^d .

Example 4 Preparation of oxalic acid salt of 1-bromo-2-ethyl-3- [4- (3-di-n-propylaminopropyl) oxy-3,5-dichlorobenzoyl] indolizine

A 250 mL flask was charged with oxalic acid salt of 2-ethyl-3- (4- (3-di-n-propylaminopropyl) oxy-3,5-dichlorobenzoyl) -indolysine (2.8 g, 0.005 mol). The reaction mixture was stirred and after dissolution of the indolizine, 0.8 g of anhydrous sodium acetate was added, and a solution of 0.8 g of bromine in 20 ml of dioxane was added dropwise via dropping funnel under vigorous stirring. Keep at about C.

The mixture was stirred at room temperature for 2 hours, the dioxane was evaporated in a rotary evaporator under reduced pressure, and the solid residue was dissolved in water. The solution was made alkaline with sodium hydroxide solution and extracted with chloroform, the chloroform solution was washed three times with water and the chloroform was evaporated under reduced pressure. The resulting oily residue was taken up in dry ethyl ether and, after filtration, converted to its oxalic acid salt. Recrystallization from ethyl acetate gave 1.8 g of the title compound. Yield: 55.8%. Melting point: 135 ° C.

1-4. In analogy to Examples 1 to 4, the following compounds were prepared:

Example 2Q Compound Melting point (° C) and crystallization solvent

5. 1-Bromo-2-ethyl-3- [4- (3-di-n-butylaminopropyl) -oxybenzoyl] ·

oxalic acid salt of indolizine

6. Oxalic acid salt of 1-bromo-2- (4-bromophenyl) -3- [4- (3-di-n-butylaminopropyl) oxybenzoyl] -indolizine

7. 1-Chloro-2-methyl-3- [4- (3-di-30)

oxalic acid salt of butylaminopropyl) oxybenzoyl] indolizone

8. Oxalic acid salt of 1-chloro-2-ethyl-3- [4- (3-di-n-propylaminopropyl) oxybenzoyl] -indolizine "g 9. l-chloro-2- (n- propyl) -3- [4- (3-di-n-butylaminopropyl) oxybenzoylindolizine oxalic acid salt

10. Oxalic acid salt of 1-chloro-2- (n-butyl) -3- [4- (3-di-n-butylaminopropyl) oxybenzoyl] indolizine

4θ 11. Oxalic acid salt of 1-chloro-2-phenyl-3- [4- (3-di-n-propylaminopropyl) oxybenzoyl] indolizine

12. The oxalic acid salt of 1-chloro-2- (4-chlorophenyl) -3- [4- (3-di-n-butylaminopropyloxybenzoyl) indolizine

107-108 '(isopropanol)

92-94 (isopropanol)

92-93 (isopropanol)

162 (isopropanol)

111-112 (isopropanol)

106-108 (isopropanol)

161-162 (isopropanol)

158-159 (methanol)

13th

14th

15th

16th

17th

oxalic acid salt of -chloro-2-phenyl-3- (4- (3-di-n-butylaminopropyl) oxybenzoyl) 160-161 -inolizine '(methanol)

1-Chloro-2- (n-butyl) -3- [4- (6-di-n-butylamino-hexyl) -oxybenzoyl] -80-82

oxalic acid salt of indolizine (benzene)

Oxalic acid salt of 2-methyl-3- (4- (3-di-n-butylaminopropyl) oxy-3-bromobenzoyl) indolizine

141-143 (10: 1 ethyl acetate / isopropanol)

2-ethyl-3- (4- (3-di-n-propylaminopropyl) oxy-3-bromobenzoyl) - 163

oxalic salt of indolizine (isopropanol)

2-Ethyl-3- [4- (3-di-n-butylamino-propyl) -oxy-3-bromo-benzoyl] - 98-99

oxalic salt of indolizine (isopropanol)

Oxalic acid salt of 2-n-propyl-3- [4- (3-di-n-propylaminopropyl) oxy-3-bromobenzoyl] indolizine 145 (isopropanol)

19. 2-n-Propyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-bromobenzoyl]-113-115

oxalic acid salt of -mdotisin (isopropanol)

20. 2-Isopropyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-bromobenzoyl] 105-107

oxalic acid salt of indolizine (benzene)

21. 2-n-Butyl-3- [4- (3-di-n-propylaminopropyl) oxy-3-bromobenzoyl] - 136-137

oxalic salt of indolizine (isopropanol)

22. 2-n-Butyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-bromobenzoyl] 86-87

oxalic salt of indolizine (isopropanol),

23. 2-Phenyl-3- [4- (3-di-n-propylamino-propyl) -oxy-3-bromobenzoyl] -148-149

oxalic salt of indolizine (isopropanol)

24. 2-Phenyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-bromobenzoyl] 129-130

oxalic salt of indolizine (isopropanol)

25. 2- (4-Fluorophenyl) -3- [4-3-di-n-butylaminopropyl) oxy-3-bromobenzene] - 110

oxalic salt of indolizine (isopropanol)

26. Oxalic acid salt of 2- (4-chlorophenyl) -3- [4- (3-di-n-propylaminopropyl) oxy-3-bromobenzoyl] - 163-164-indolizine (methanol)

27. Oxalic acid salt of 2- (4-chlorophenyl) -3- [4- (3-di-n-butylaminopropyl) oxy-3-bromobenzoyl] -139-140-indolizine (isopropanol)

28. 2- (3-Bromo-phenyl) -3- [4- (3-di-n-propyl-amino-propyl) -oxy--3-bromo-benzoyl] -1 142-143

oxalic salt of indolizine (isopropanol)

29. Oxalic acid salt of 2 - ('4-bromophenyl) -3- [4- (3-di-n-butylamino-propyl) oxy-3-bromobenzoyl] - 147-148,5-indolizine (methanol)

30. 2- (4-Methoxyphenyl) -3- [4- (3-di-n-butylaminopropyl) oxy-3-bromo-169

oxalic salt of benzoyl indoleizine (isopropanol)

31. 2-Isopropyl-3- [4- (5-di-n-butylamino-pentyl) -oxy-3-bromo-80-82

oxalic acid salt of benzoyl indoleizine (benzene)

32. 2-Isopropyl-3- [4- (3-di-n-propylaminopropyl) oxy-3-bromo-179

oxalic acid salt of benzoyl indoleizine (isopropanol) '

33. 2-Methyl-3- [4- (3-di-n-butylamino).

-propyl) oxy-3-chlorobenzoyl] -indo-141-143 lysine oxalic acid salt (isopropanol)

34. Oxalic acid salt of 2-ethyl-3- [4- (3-di-n-propylaminopropyl) oxy-3-chlorobenzoyl] -indo-161-162 lysine (methanol)

35. Oxalic acid salt of 2-ethyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl] -indo-116-117 lysine (isopropanol)

36. Oxalic acid salt of 2-isopropyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl] -115-117-indolizine (isopropanol)

7. Oxalic acid salt of 2-isopropyl-3- (4- (3-di-n-propylaminopropyl) oxy-3-chlorobenzoyl) -168-169-indolizine (methanol)

38. 2-n-Butyl-3- [4- (3-di-n-butylamino-84-85) and

-propyl) oxy-3-chlorobenzoyl] -indo-107-109 lysine oxalic acid salt (isopropanol)

39. Oxalic acid salt of 2-n-butyl-3- [4- (3-di-n-propyl • aminopropyl) oxy-3-chlorobenz-130-131 oil] -indolizine (isopropanol)

40. 2-Phenyl-3- [4- (3-dinbutylaminopropyl) oxy-3-chlorobenzoyl] 121-122

-Indolizine oxalic acid salt (isopropanol)

41. Oxalic acid salt of 2-phenyl-3- [4- (3-di-n-propylaminopropyl) oxy-3-chlorobenzoyl] -indine-157-159 dolizine (methanol)

42. Oxalic acid salt of 2- (4-methylphenyl) -3- [4- (3-di-n-propylaminopropyl) oxy-3-chlorobenzoyl] 134-135-indolizine (isopropanol)

43. 2- (4-Bodo-phenyl) -3- [4- (3-di-n-propylamino-propyl) -oxy-3-chloro-benzoyl] - 154-155-indolizine oxalic acid salt

44. 2- (4-Bromophenyl) -3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl] -134-135-indolizine oxalic acid salt (isopropanol)

45. Oxalic acid salt of 2- (3-bromophenyl) -3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl] -92-93-indolizine (isopropanol)

46. 2- (3-Bromophenyl) -3- [4- (3-di-n-propylaminopropyl) oxy-3-chlorobenzoyl] - 148-150-indolizine oxalic acid salt (isopropanol) '47. Oxalic acid salt of 2- (4-chlorophenyl) -3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl] - 116-118-indolizine (isopropanol)

48. Oxalic acid salt of 2- (4-chlorophenyl) -3- [4- (3-di-n-propylaminopropyl) oxy-3-chlorobenzoyl] -159-160-indolizine (methanol)

49. 1-Bromo-2-methyl-3- [4- (3-di-n-butyl).

oxy-acid salt of isopropyl) oxy-3-bromobenzoyl-89-90-indolizine (isopropanol)

50. Oxalic acid salt of 1-bromo-2-methyl-3- [4- (3-di-n-propylaminopropyl) oxy-3-ylbenzoyl] - 164-165 -indolizine (isopropanol / methanol) )

51. Oxalic acid salt of 1-bio-2-ethyl-3- [4- (2-dimethylaminoethyl) oxy-3-bromobenzoyl] -164-165-indolizine (dichloroethane)

52. 1-Bromo-2-ethyl-3- [4- (3-dimethylaminopropyl) oxy-3-bromobenzoyl] 150-151

oxalic acid salt of indolizine (dichloroethane)

53. Oxalic acid salt of 1-bromo-2-ethyl-3- [4- (2-diethylaminoethyl) oxy-3-bromobenzoyl] -indo-168-169 (dichloroethane)

54. Oxalic acid salt of 1-bromo-2-ethyl-3- [4- (3-diethylaminopropyl) oxy-3-bromobenzoyl] - 140-141,5-indolizine (isopropanol)

55. 1-Bromo-2-ethyl-3- [4- (2-di-n-propylamino-ethyl) -oxy-3-bromo-benzoyl] - 163-164

oxalic salt of indolizine (isopropanol)

56. 1-Bromo-2-ethyl-3- [4- (3-di-n-propylamino-propyl) -oxy-3-bromo-benzoyl] -139-140

oxalic salt of indolizine (isopropanol)

57. Oxalic acid salt of 1-bromo-2-ethyl-3- [4- (2-di-n-butylaminoethyl) oxy-3-bromobenzoyl] -164-165-indolizine (isopropanol)

58. 1-Bromo-2-ethyl _: 3- [4- (3-di-n-butyl)

oxalic acid salt of isopropyl) oxy-3-bromobenzoyl-101-101,5-indolizine (isopropanol)

59. 1-Bromo-2-n-propyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-bromobenzoyl] - 92

oxalic acid salt of indolizine (benzene)

60. 1-Bromo-2-n-propyl-3- [4- (3-di-n-propylaminopropyl) oxy-3-bromobenzoyl] - 132-136

oxalic salt of indolizine (isopropanol)

61. 1-Bromo-2-n-butyl-3- [4- (3-di-n-151-152 propylaminopropyl) oxy-3-bromo- (2/1 isopropyl-91)

185 019

benzoyl j-indolizine oxalic acid salt (panol / methanol)

-Bromo-2-n-butyl-3- [4- (3-di-n-butylamino-propyl) -oxy-3-bromo-101-103-benzoyl] -indolizine, oxalic acid salt (isopropanol) 1-bromo-2 Oxalic acid salt of phenyl-3- [4- (3-di-n-propylamoylpropyl) oxy-3-bromobenzoyl] -169-170-indolizone (l / l methanol / isopropanol) l-bromo-2 -phenyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-bromobenzoyl] -167-169-indolizine oxalic acid salt (isopropanol) 1-bromo-2- (4- methoxyphenyl) -3- [4- (3-di-nb-utilaminopropyl) oxy-178-179

-3-Bromobenzoyl] -indolizine (methanol) oxalic salt of 1-bromo-2- (4-methylphenyl) -3- [4- 169-170.5

- (3-Di-n-butylaminopropyl) oxy (1/1 isopropyl-3-bromobenzoyl] indolizine panol / methanol) oxalic acid salt 1-bromo-2- (4-fluorophenyl) -3- [4- (3- 170-171)

oxalic acid salt of di-n-butylaminopropyl) oxy-3- (methanol) bromobenzoyl] -indolizine

bromo-2- (3-bromophenyl) -3- [4- (3- 172-173)

oxalic acid salt of di-n-butylaminopropyl) oxy-3-bromobenzoyl] indolizine

oxalic acid salt of -bromo-2-n-b util-3- [4- (4-di-n-butylaminobutyl) oxy-3-bromobenzoyl] -indolizine

oxalic acid salt of -chloro-2-ethyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl] -indolizine

oxalic acid salt of -chloro-2-ethyl-3- [4- (3-di-n-propylaminopropyl) oxy-3-chlorobenzoyl] -indolizine

Oxalic acid salt of -chloro-2- (3-bromophenyl) -3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl] -indolizine 1-chloro-2- Oxalic acid salt of (3-bromophenyl) -3- [4- (3-di-n-propylaminopropyl) oxy-3-chlorobenzoyl] indolizine 1-chloro-2-ethyl-3- [ Oxalic acid salt of 4- (3-di-n-propylaminopropyl) oxy-3,5-dichlorobenzoyl] -indolizine 1-chloro-2-ethyl-3- [4- (3-di-n-butyl) -anino-propyl) -oxy-3,5-dichloro-benzoyl] -indolizine, oxalic salt of 1-chloro-2-phenyl-3-t4- (3-di-n-propyl-aminopropyl) -oxy-3,5 oxalic acid salt of -dichloro-benzoyl-indolizine

oxalic acid salt of -chloro-2-phenyl-3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dichlorobenzoyl] -indolizine

Oxalic acid salt of -bromo-2-methyl-3- [4- (3-di-n-propylaminopropyl) oxy-3-chlorobenzoyl] indolizine

-Bromo-2-methyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl] -indolizine (methanol)

118-120 (isopropanol)

115-117 (isopropanol)

137-138 (isopropanol)

171-172 (methanol)

171-172 (methanol)

141 (ethyl acetate)

129 (ethyl acetate)

156 (isopropanol)

136 (isopropanol / heptane)

110-112 (isopropanol)

108-110 (isopropanol)

80th oxalic acid salt of 1-bromo-2-ethyl-3- [4- (3-di-n- 136.5-138 5 oxalic acid salt of -propylaminopropyl) oxy-3-chlorobenzoyl] -indolizine (Isopropanol) 10 81st - 1-bromo-2-ethyl-3- [4- (3-di-n- oxalic acid salt of butylaminopropyl) oxy-3-chlorobenzoyl] indole 103-105 (Isopropanol) 82nd Oxalic acid salt of 1-bromo-2-n-propyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl] indolizine 95-96 (Isopropanol) 15 83rd Oxalic acid salt of 1-bromo-2-isopropyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl] indolizine 116 (Isopropanol) 20 84th Oxalic acid salt of 1-bromo-2-n-butyl-3- [4- (3-di-n-propylaminopropyl) oxy-3-chlorobenzoyl] indolizine 159-160 (Methanol) 85th Oxalic acid salt of 1-bromo-2-n-butyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzyl] indolizine 101-103 (Isopropanol) 25 86th Oxalic acid salt of 1-bromo-2-phenyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl] indolizine 167.5-169 (Methanol) 30 87 Oxalic acid salt of 1-bromo-2-phenyl-3- [4- (3-di-n-propylaminopropyl) oxy-3-chlorobenzoyl] -indolizine 169-170 (Methanol) 35 88th Oxalic acid salt of 1-bromo-2- (4-chlorophenyl) -3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl] indolizine 160-161 (Isopropanol) 89th Oxalic acid salt of 1-bromo-2- (4-chlorophenyl) -3- [4- (3-di-n-propylaminopropyl) oxy-3-chlorobenzoyl] indolizine 184-185 (Methanol) 90th 1-Bromo-2- (4-bromophenyl) -3- [4 · 176-177 40 - Oxalic acid salt of (3-di-n-propylaminopropyl / β-oxy-3-chlorobenzoyl) -indolizine (Methanol) 45 91st Oxalic acid salt of 1-bromo-2- (4-bromophenyl) -3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl] indolizine 168-169 (Isopropanol) 50 92nd Oxalic acid salt of 1-bromo-2- (3-bromophenyl) -3- [4- (3-di-n-propylaminopropyl) oxy-3-chlorobenzoyl] indolizine 200-201 (Methanol) 93rd Oxalic acid salt of 1-bromo-2- (bromophenyl) -3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl] indolizine 170.5 to 172 (Methanol) 94th 1-Chloro-2-ethyl-3- [4- (3-di-n-butyl) 104 105 55 oxalic acid salt of aminopropyl) oxy-3-bromobenzoyl] -indolizine (Isopropanol) 95th Oxalic acid salt of 1-chloro-2-ethyl-3- [4- (3-di-n-propylaminopropyl) oxy-3,5-dibromobenzoyl] -indolizine 157 (Isopropanol) 96th l-chloro-2-ethyl-3- [4- (3-di-n-butyl 140 60 amino-propyl) oxy-3,5-dipróm- V (Isopropanol)

-101

185 019 Oxalic acid salt of benzoyl-indolizine

I-chloro-2-phenyl-3- [4- (3-di-n-propyl 172 117 -aminopropyl) -oxy-3,5-dibromo- (Isopropanol) 5 oxalic acid salt of benzoyl indoleizine Oxalic acid salt of 1-chloro-2-phenyl-3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dibromobenzoyl] -indolizine 2-methyl-3- [4- (3-di-n-propyl 146 (Isopropanol) 136 10 118 aminopropyl> oxy-3,5-dibromo (Ethyl acetate) 119 oxalic acid salt of benzoyl indoleizine 2-ethyl-3- [4- (3-dimethylamino propyl) oxy-3,5-dibromo-benzoilj- oxalic acid salt of indolizine 2- 1- 1- [4- (2-Diethylamino) ethyl) oxy-3,5-dibromo-benzoyl] - 148 (Ethyl acetate) 171 (Ethanol) 15 120 oxalic acid salt of indolizine 2-Ethyl-3- [4- (3-diethylamino- 191 121

propyl) oxy-3,5-dibromobenzoyl] - (50:50 ethylindolizine hydrochloride acetate / acetone)

2-Ethyl-3- [4- (3-di-n-propylaminopropyl) oxy-3,5-dibromobenzoyl] - 166 (Ethyl acetate) 20 122nd indolizine hydrochloride 2-ethyl-3- [4- (3-di-n-butylamino 157 propyl) oxy-3,5-dibromo-benzoilj- (Ethyl acetate) indolizine hydrochloride 123rd 2-n-propyl-3- [4- (3-di-n-propyl 145 25 • aminopropyl) ^ oxy-3,5-dibromo- (Ethyl acetate) benzoyl j-indolizine hydrochloride 2n-pnpil-3- [4- (3-di-n-butylamino 107 124th propyl) oxy-3,5-dibromo-benzoilj- (Ethyl acetate) oxalic acid salt of indolizine 30 2-isopropyl-3-4- (3-di-n-propyl 126 125th amino-propyl) oxy-3,5-dibromo- (Ethyl acetate / oxalic acid salt of benzoyl indolizine ethanol) 2-isopropyl-3- [4- (3-di-n-butyl 86 35 126th amino-propyl) oxy-3,5-dibromo- (Ethyl acetate / oxalic acid salt of benzoyl indoleizine /ether 2-n-butyl-3- [4- (3-di-n-propyl 146 amino-propyl) oxy-3,5-dibromo- (Ethyl acetate) 127th oxalic acid salt of benzoyl indoleizine 2-n-butyl-3- [4- (3-di-n-butyl 110 40 amino-propyl) oxy-3,5-dibromo- (Ethyl acetate) oxalic acid salt of benzoyl j -indolizine 128; 2-phenyl-3- [4- (3-di-n-propyl 142 amino-propyl-3,5-dibromo- (Ethyl acetate / oxalic acid salt of benzoyl indoleizine / EtOH) The f 2-phenyl-3- [4- (3-di-n-butyl 86 45 129th amino-propyl) oxy-3,5-dibromo- (Ethyl acetate) oxalic acid salt of benzoyl indoleizine 2- (4-Fluorocarbonyl) -3- [4- (3-di-n- 166 -propylamino-propyl) oxy-3,5- (Ethyl acetate / 130th dibromo-benzoyl-inHolizin / EtOH) 50 oxalic acid salt w yJ 2- (4-fluorophenyl) -3- [4- (3-di-n- 52 butylamino-propyl) oxy-3,5- (Izonrooanol) 131st -dihromobenzoyl-j-indolizine oxalic acid salt 2- (4-chlorophenyl) -3- [4- (3-di-n- 190 55 propylamino-propyl) oxy-3,5- (Ethyl acetate) 132 -dibromo-benzenesoyl-indolizine oxalic acid salt 2- (4-chlorophenyl> 3- [4- (3-di-n- 88 butylamino-propyl) -oxy-3,5- (Ethyl acetate) 133rd dibromo-benzoyl-indolizine 60

oxalic acid salt

2- (3,4-Dichlorophenyl) -3- [4- (3-di-n-propylaminopropyl) oxy-3,5-dibromobenzoyl] indolizine

Oxalic acid salt of 2- (3,4-dichlorophenyl) -3- [4- (3-di-n-butylaminopropyl) ox1-3,5-dibromobenzoyl] -indolizine

Oxalic acid salt of 2- (3-bromophenyl) -3- [4- (3-di-n-propylaminopropyl) oxy-3,5-dibromobenzoyl] -indolizine

Fumaric acid salt of 2- (3-bromophenyl) -3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dibromobenzoyl] -indolizine

Oxalic acid salt of 2- (4-methylphenyl) -3- [4- (3-di-n-propylaminopropyl) oxy-3,5-dibromobenzoyl] -indolizine

Oxalic acid salt of 2- (4-methylphenyl) -3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dibromobenzoyl] -indolizine

Oxalic acid salt of 2- (4-methoxyphenyl) -3- [4- (3-di-n-propylaminopropyl) oxy-3,5-dibenzobenzoyl] -indolizine

Oxalic acid salt of 2- (4-methoxyphenyl) -3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dibromobenzoyl] -indolizine

Oxalic acid salt of 2-methyl-3- [4- (3-di-n-propylaminopropyl) oxy-3,5-dichlorobenzoyl] -indolizine

Oxalic acid salt of 2-methyl-3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dichlorobenzoyl] -indolizine

Oxalic acid salt of 2-ethyl-3- [4- (3-di-n-propylaminopropyl) oxy-3,5-dichlorobenzoyl] -indolizine

Oxalic acid salt of 2-ethyl-3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dichloro-benzoyl] -indolizine

Oxalic acid salt of 2-n-propyl-3- [4- (3-di-n-propylaminopropyloxy-3,5-dichlorobenzoyl) -indolizine

Oxalic acid salt of 2-n-propyl-3- [4- (3-xi-n-butylaminopropyl] oxy-3,5-dichlorobenzoyl] -indolizine

Oxalic acid salt of 2-isopropyl-3- [4- (3-di-n-propylaminopropyl) oxy-3,5-dichlorobenzoyl] -indolizine

Oxalic acid salt of 2-isopropyl-3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dichlorobenzoyl] -indolizine

2-Phenyl-3- [4- (3-di-n-propylaminopropyl) oxy-3,5-dichloro-114 (ethyl acetate / isopropanol) (ethyl acetate / isopropanol)

136 (ethanol)

122 (ethyl acetate)

126 (ethyl acetate / isopropanol) (ethyl acetate)

167 (acetone) paste-like, about 70 (ethanol / ethyl ether)

145 (ethyl acetate / ethanol) (ethyl acetate / ethyl ether)

100 paste-like (ethyl acetate) (ethyl acetate)

142 (isopropanol)

114 (isopropanol) (ethyl acetate) (ethyl acetate)

146 (ethanol)

-111

oxalic acid salt of benzoyl indoleizine

134. 2-phenyl-3- [4- (3-di-n-butyl-paste),

-aminopropyl) oxy-3,5-di- about 90 chlorobenzoyl] indolizine (ethyl acetate) oxalic acid salt

135. 2- (4-Bromo-phenyl) -3- [4- (3-di-n-174)

-propylaminopropyl) oxy (ethyl acetate)

Oxalic acid salt of -3,5-dichlorobenzoyl] -indolizine

136. 2- (4-Bromophenyl) -3- [4- (3- 133)

-di-n-b util-amino-propyl) - (ethyl acetate)

oxy-3,5-dichlorobenzoyl J-indolizine oxalic acid salt

137. 1-Bromo-2-methyl-3- [4- (3-di-n-141-143)

-butylamino-propyloxy-3,5- (isopropanol)

oxalic acid salt of -dib-benzobenzoyl] -indolizine

138. 1-Bromo-2-n-propyl-3- [4- (3-di-n-138-139)

oxalic acid salt of -propylaminopropyl) oxy-3,5- (isopropanol) dibromobenzoyl] -indolizine

139. 1-Bromo-2-ethyl-3- [4- (3-di-131-132.5)

-b-utilaminopropyl) oxy-3,5 - (isopropanol)

oxalic acid salt of dibromobenzoyl] indolizine

140. Oxalic acid salt of 1-bromo-2-phenyl-3- [4- (3-di-n-butyl-160-161-aminopropyl) oxy-3,5-dibromo-isopropanol-benzoyl] -indolizine .

141. 1-Bromo-2- (4-methyl-phenyl) -3- [4- (3-105-106)

- Oxalic acid salt of (3-di-n-butylaminopropyl) oxy (isopropanol) -3,5-dibromobenzoyl] -indolizine

142. 1-Bromo-2- (4-bromophenyl) -3- [4- 148-149;

- (3-Di-n-butylaminopropyl) oxy (isopropanol) -3,5-dibromobenzoyl J -indolizine oxalic acid salt

143. 1-Bromo-2- (3,4-dichlorophenyl) -3- [4- (3- 196-197-di-n-butylaminopropyl) oxy-3,5- (isopropanol) oxalic acid salt of dibromobenzoyl] indolizine

144. 1-Bromo-2- (3-chloro-4-methyl-phenyl) -3-168-169- [4- (3-di-n-butyl-aminopropyl) -oxl- (isopropanol) -3 Oxalic acid salt of 5-dibromobenzoyl J-indolizine

145. 1-Bromo-2-ethyl-3- [4- (3-di-n-butyl-134)

oxalic acid salt of -amino-propyloxy-3,5-dichloro-isopropanol-benzoyl] -indolizine

146. 1-Bromo-2-phenyl-3- [4- (3-di-n-145)

-propylaminopropyl) oxy-3,5- (ethyl acetate)

oxalic acid salt of -dichlorobenzoyl] -indolizine

147. 1-Bromo-2-phenyl-3- [4- (3-di-n-106)

butylaminopropyl) oxy-3,5- (ethyl acetate)

dichloro-benzoyl-indolizine

oxalic acid salt

148. 2-n-Butyl-3- [4- (3-di-n-butyl-113-113.5)

-aminopropyl) oxy-3,5-bromoethyl acetate

benzoyl-indolizine hydrochloride

149. 2-n-Propyl-3- [4- (3-diethylamino-154)

-propyl) oxy-3,5-dibromobenzoyl] - (80:20 ethylindolizine hydrochloride acetate / acetone)

150. 2-Ethyl] -3- [4- (3-di-n-butylamino-132-133)

-propyl) oxy-3-chlorobenzoyl ethyl acetate /

indolizine hydrochloride / Isopropanol) 151, 2-n-butyl-3- [4- (3-di-n-butyl) 104 amino-propyl) -oxy-3-chloro- benzoyl-indolizine hydrochloride (Ethyl acetate) 152. 1-Bromo-2-phenyl-3- [4- (3-di-n- butylaminopropyl) oxy-3-chlorobenzoyl] -indolizine hydrochloride 156-157 153. 1-Chloro-2- (4-chlorophenyl) 3- [4- 168-169 - Oxalic acid salt of (3-di-n-propylaminopropyl) oxybenzoyl] indolizine (Methanol) 154. 1-Methoxy-2-phenyl-3- [4- (3-di-n- 117 oxalic acid salt of -propylaminopropyl) -oxybenzoyl] -indole (Ethyl acetate) 155. 1-Methoxy-2-phenyl-3- [4- (3-di-n- 80 oxalic acid salt of butylaminopropyl) oxybenzoyl] indolizine (Ethyl acetate) 156. 1-Methoxy-2-phenyl-3- [4- (3-di-n- 172 oxalic acid salt of -propylaminopropyl) oxy-3-chlorobenzoyl] -indolizine (Ethyl acetate) 157. 1-Methoxy-2-phenyl-3- [4- (3-di-n- 120 oxalic acid salt of butylaminopropyl) oxy-3-chlorobenzoylindolizine (Ethyl acetate) 158. 1-Methoxy-2-phenyl-3- [4- (3-di-n- 160 oxalic acid salt of -propylaminopropyl) oxy-3-bromobenzoyl] -indolizine (Ethyl acetate) 159. 1-Methoxy-2-phenyl-3- [4- (3-di-n- 78 oxalic acid salt of butylaminopropyl) oxy-3-bromobenzoyl] indolizine (Ethyl acetate) 160. 1-Methoxy-2-phenyl-3- [4- (3-di-n- 148 -propylaminopropyl) oxy-3-methoxybenzoylindolizine oxalic acid salt (Ethyl acetate) 161. 1-Methoxy-2-phenyl-3- [4- (3-di-n- 78 oxalic acid salt of butylaminopropyl) oxy-3-methoxybenzoyl j -indolizine (Ethyl acetate) 162. 1-Methoxy-2- (4-fluorophenyl) -3- [4- 79 - Oxalic acid salt of (3-di-n-propylaminopropyl) oxy-3-methoxybenzoyl] indolizine (Ethyl acetate) 163. 2-Methoxy-3- [4- (3-di-n-butyl) 159 oxalic acid salt of -aminopropyl) -oxy-3-methoxybenzoyl] -indolizine (Isopropanol) 164. 2-Methoxy-3- [4- (3-di-n-propyl) 171 oxalic acid salt of -aminopropyl) -oxy-3-methoxybenzoyl] -indolizine 165 2-Ethyl-3- [4- (3-di-n-butyl) (Methanol) 88 oxalic acid salt of -aminopropyl) -oxy-3-methoxybenzoyl] -indolizine (Ethyl acetate) 166. 2-ethyl-3- [4- (3-di-n-propyl) 121-122 -aminopropyl) oxy-3-methoxybenzoyl] -indolizine oxalic acid salt (Ethyl acetate) 167. 1-Bromo-2-methyl-3- [4- (3-di-n- 87-90 butylamino-propyl) oxy-3- (benzene)

-methoxybenzoyl-indolizine

-121

185.019 oxalic acid salt

168th Oxalic acid salt of 1-bromo-2-methyl-3- [4- (3-di-n-propylamino-propyl) -oxy-3-methoxy-benzoyl] -indolizine 139-141 (Isopropanol) 5 187th 169th 1-Bromo-2-ethyl-3- [4- (3-di-n- 111 188th oxalic acid salt of butylaminopropyl) oxy-3-methoxybenzoyl j -indolizine (benzene) 10 170th l-bromo-2-ethyl-3- [4- (3-di-n- 149 189th -propylaminopropyl) oxy-3-methoxybenzoyl] -indolizine (Isopropanol) oxalic acid salt 190th 171st 2- (4-fluorophenyl) -3- [4- (3-di-n- 85 15 oxalic acid salt of butylaminopropyl) oxy-3-methoxybenzoyl j -indolizine (Ethyl acetate) 191st 172nd 2-methyl-3- [4- (3-di-n-butylamino 149 -propyl) oxy-3-methylbenzoyl] -indolizine oxalic acid salt (Isopropanol) 20 173rd 2-ethyl-3- [4- (3-di-n-butyl-amino 138 192nd -propyl) oxy-3-methylbenzoyl] indolizine oxalic acid salt (Ethyl acetate) 174th l-methyl-2-n-propyl-3- [4- (3-di-n- 127 oxalic acid salt of butylaminopropyl) oxy-3-bromobenzoyl] indolizine (Ethyl acetate) 25 193rd 175th 2-isopropyl-3- [4- (3-di-n-butyl 91 -aminopropyl) oxy-3-methylbenzoyl] -indolizine oxalic acid (Isopropanol) 194th 176th salt 2-n-Butyl-3- [4- (3-di-n-b utilization) , 89 30 oxalic acid salt of amino-propyl) -oxy-3-methyl-benzoyl] -indolizine 1-Methyl-2-n-butyl-3- [4- (3-di-n- (Isopropanol) 195th 177th 99 oxalic acid salt of butylaminopropyl) oxy-3-bromobenzoyl] indolizine (Ethyl acetate) 35 196th 178th l-methyl-2-ethyl-3- [4- (3-di-n-butyl 117 -aminopropyl) oxy-3-bromobenzoyl] -indolizine oxalic acid (Ethyl acetate) 197th salt 179th l-bromo-2-methyl-3- [4- (3-di-n-  120-122 40 oxalic acid salt of butylaminopropyl) oxy-3,5-dimethylbenzoyl-indolizine (Isopropanol) 198th 180th l-iodo-2-ethyl-3- [4- (3-di-n-butyl Π5 oxalic acid salt of aminopropyl) oxy-3,5-dimethylbenzoyl] -indolizine (Ethyl acetate) 45 199th 181st 2-ethyl-3- [2,3-dichloro-4- (3-di-n- 117 propylamino-propyl) -oxy benzoyl-indolizine (heptane) 200th 182nd 2-ethyl-3- [2,3-dichloro-4- (3-di-n- 95 -b-butylamine o-propyl) benzoyl] indolizine (heptane) . 50 Two hundred and first 183rd 2-Phenyl-3- [2,3-dichloro-4- (3-di-n-propylaminopropyl) oxybenzoyl] -indolizine 99 (heptane) 87 202nd 184th 2-Phenyl-3- [2,3-dichloro-4- (3-di-n-butylaminopropyl) oxybenzoyl] -indolizine 55 203rd (heptane) 119 185th 2- (4-Fluorophenyl) -3- [2,3-dichloro-4- (3-di-n-propylaminopropyl) oxybenzoyl] -indolizine (heptane) 95-96 204th 186th 2- (4-fluorophenyl) -3- [2,3-dichloro- 4- (3-di-n-butylamino-propyl) - (heptane) 60

-oxybenzoyl] -indolizine 1-bromo-2-ethyl-3- [2,3-dichloro-4-164

- (3-di-n-butylaminopropyl) - (isopropanol)

-oxybenzoyl] -indolizine oxalic acid oxalic acid,? -bromo-2-phenyl-3- [2,3-dichloro-4- (3-di-n-propylaminopropyl) oxybenzoyl] -indolizine

chloro-2-phenyl-3- [2,3-dichloro-4- (3-di-n-propylamino-propyl) -oxy-benzoyl] -indolizine

Oxalic acid salt of 2-n-butyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-iodobenzoyl] -indolizine

Oxalic acid salt of 2-n-butyl-3- [4- (3-di-n-propylaminopropyl) oxy-3-methylbenzoyl] -indolizine

Oxalic acid salt of 1,2-dimethyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-bromobenzoyl] indolizine

Oxalic acid salt of 2-phenyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-methylbenzoyl] -indolizine

Oxalic acid salt of 2-phenyl-3- [4- (3-di-n-propylaminopropyl) oxy-3-methylbenzoyl] -indolizine

oxalic acid salt of methyl 2-phenyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-bromobenzoyl] indolizine

oxalic acid salt of methyl 2-phenyl-3- [4- (3-di-n-propylaminopropyl) oxy-3-bromobenzoyl] -indolizine

oxalic acid salt of methyl 2-phenyl-3- [4- (3-di-n-propylaminopropyl) oxybenzoyl] -indoline

oxalic acid salt of methyl 2-phenyl-3- [4- (3-di-n-butylaminopropyl) oxybenzoyl] -indolizine

Oxalic acid salt of 1-methyl-2-n-butyl-3- [4- (3-di-n-propylaminopropyl) oxy-3-bromobenzoyl] -indolizine

Oxalic acid salt of methyl 2-n-butyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl] -indolizine 1-methyl-2-n-butyl-3 - Oxalic acid salt of [4- (3-di-n-utilaminopropyl) oxybenzoyl] -indolizine

oxalic acid salt of methyl 2-n-butyl-3- [4- (3-di-n-propylaminopropyl) oxybenzoyl] -indolizine

methyl 2-n-butyl-3- [2,3-dichloro-4- (3-di-n-propylaminopropyl) oxybenzoyl] -indolizine 1-methyl-2-n-butyl-3 - [2,3-dichloro-4- (3-di-n-butylamino-propyl) -oxy-benzoyl-indolizine

171 (isopropanol)

136 (heptane)

90-92 (ethyl acetate)

147 (isopropanol)

105 (ethyl acetate)

137 (ethyl acetate)

149 (isopropanol)

143 (ethyl acetate)

160 (ethyl acetate)

130 (ethyl acetate) (ethyl acetate)

143 (acetone) (acetone)

130 (acetone)

133 (acetone)

150 (acetone) (acetone)

-131

185 019

Example 5

Claims (8)

Preparation of oxalic acid salt of 1-chloro-2-ethyl-3- [4- (3-di-n-propylaminopropyl) -5-oxy-3,5-dichlorobenzoyl] -indolizine To a solution of 57.05 g (0.12 mol) of 2-ethyl-3- [4- (3-di-n-plopylaminopropyloxy-3,3-dichlorobenzoyl) -indolizine in 1100 ml of dichloroethane was added in portions. N-Chlorosuccinimide (26.8 µL, 0.2 mol) was added over 2 hours while maintaining the temperature between 0 ° C and 10 ° C. The dichloroethane solution was stirred for one hour and washed with 500 ml of water. The solvent was distilled off under reduced pressure and the oily residue was taken up in dry ethyl ether, an ethereal solution of dry oxalic acid was added to the ethyl ether solution and the resulting salt was recrystallized from ethyl acetate to give 18.3 g of 1-chloro-2-ethyl-3- [ 4- (3-Di-n-propylaminopropyl) oxy-3,5-dichlorobenzoylindolizine is obtained as an oxalic acid salt, m.p. 141 DEG C., 30% yield. Example 6 1-Bromo-2- (4-bromophenyl) -3- [4- (3-di-n-butylaminopropyl) oxybenzoylindolysine Preparation of -oxalic acid salt 2 5 To a solution of 23.5 g (0.05 mol) of 1-bromo-2- (4-bromophenyl) -3- (4-hydroxybenzoyl) -indolizine in 250 ml of formamide is added 7.6 g (0.055 mol) of anhydrous potassium carbonate. After stirring at 70-80 ° C for 1 hour, the mixture was cooled and 18.8 g (0.055 mol) of 1-tosyloxy-3-di-n-butylaminopropane was added. The mixture was stirred at room temperature for 15 hours, then at 70-80 ° C for an additional hour. The resulting base is used to form a salt gc with oxalic acid to give 26.3 g of 1-bromo-2- (4-bromophenyl) -3- [4- (3-di-n-butylaminopropyl) oxybenzoyl] The oxalic acid salt of indolizine is obtained after recrystallization from isopropanol. 92-94 ° C, yield: 72%. Example 7 Injectable solutions of the following composition are prepared 2-n-Butyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-bromo or -3-chlorobenzoyl] -indolizine hydrochloride polysorbate 80 benzyl alcohol water 150 mg 150 mg 75 mg to a volume of 3 ml 5C Example 8 The following suppository compositions are prepared 2-n-Butyl-3- [4- (3-di-n-butylamino-3-bromo or -3-chlorobenzoyl] -indolizine hydrochloride 100 mg The mixture of mono- and diglycerides of saturated fatty acids having 12 to 18 carbon atoms is 1400 mg 1500 mg 60 A process for the preparation of the indolizine derivatives of the formula (I) and their pharmaceutically acceptable acid addition salts, wherein: R is C 1-6 straight or branched chain alkyl, unsubstituted or substituted by one or two identical or different substituents selected from the group consisting of halogen, C 1-4 alkyl and C 1-4 alkoxy, X 1 is hydrogen, chlorine, bromine or iodine or methyl or methoxy, A is a group of formula (a) or (b) wherein, in formula (a), X ₂ is hydrogen, chlorine, bromine or iodine or methyl or methoxy, X ₃ is hydrogen, chlorine, bromine, or iodine brain methyl group, R 1 is methyl, ethyl, n-propyl or n-butyl, n is 2, 3, 4, 5 or 6, with the proviso that when X _a and X ₃ are both hydrogen or methyl, then X ! other than hydrogen, characterized in that a) a bromoalkoxy-benzoyl-indolizine derivative of the Formula II, wherein X 1, R, A and n are as defined herein, in an inert solvent with a secondary amine of Formula III, wherein R, is condensed and converted, if desired, to the acid addition salt of the resulting indolizine derivative of formula (I) by reaction with an inorganic or organic acid in a known manner, or b) an alkali metal salt of an indolizine derivative of the Formula VI wherein R, A and X _t are as defined in the preamble of claim 1; in an aprotic solvent with an alkylamino derivative of formula (V) or an acid addition salt thereof wherein R and n are as defined in claim 1, Z is halogen or p-toluenesulfonyloxy - condensed and optionally reacted with an inorganic or organic acid in a known manner to give a pharmaceutically acceptable salt thereof, or c) an indolizine slag product of the formula VI wherein R, A, n and R _t are as defined in the scope, i) reacting with N-chlorosuccinimide in a suitable medium at a temperature between 0 ° C and room temperature to give the desired indolizine derivative wherein X _t is chlorine, in free base form, or ii) reacting with bromine or iodine in a suitable solvent in the presence of acetate to give the desired indolizine derivative, wherein X 1 is bromo or iodo, in free base form, and converting the resulting free base into a pharmaceutically acceptable acid addition salt thereof, if desired, by reaction with an inorganic or organic acid. A method of carrying out process a) according to claim 1, characterized in that. the solvent used is benzene or toluene. A method of carrying out process b) according to claim 1, characterized in that -141 185,019 solvents used are methyl ethyl ketone, acetone or toluene, the indolizine derivative (IV) is used in the form of its potassium or sodium salt, and the starting compound (V), wherein Z is chlorine or bromine, is used. A process for carrying out variant (i) of process c) according to claim 1, characterized in that the reaction is carried out in dichloroethane. 5. A process according to claim 1, wherein the solvent is dioxane and the alkali metal acetate is sodium acetate. A process for the preparation of any one of the process (a), (b) or (c) according to claim 1 for the preparation of an indolizine derivative of formula (I) wherein R is a straight or branched C 1 -C 6 alkyl, phenyl, monofluoro, monochloro, monobromo-monomethyl or monomethoxyphenyl, difluorodichlorodibromophenyl or toluene substituted in the aromatic ring with a fluorine, chlorine or bromine atom, characterized in that R is a starting material of one of the groups listed II), IV) or VI are used. 7. A process for the preparation of any of the process a), b) or c) according to claim 1, within the scope of the indolizine derivatives of the formula I: 1-bromo-2-phenyl-3- [4- (3-di butylamino-5-propyl) oxy-3-chlorobenzoyl] indolizine and pharmaceutically acceptable salts thereof, characterized in that: a) reacting a compound of formula II wherein R is phenyl, Xi is bromine, A is 3-chloro-1,4-phenylene, and R is n-butyl, or b) reacting a compound of formula (IV) wherein R, Xj and A are substituted with one of the above substituents and a compound of formula (V) wherein Z is as defined in claim 1, or c) reacting a compound of formula V wherein R, A and R are substituted with bromine. A process for the manufacture of a medicament for human or veterinary use for the treatment of cardiac diseases, in particular angina pectoris and cardiac arrhythmia, characterized in that a method according to any one of claims 1-7. The indole derivative of the formula (I) or a pharmaceutically acceptable acid addition salt thereof obtained by the process according to any one of claims 1 to 4. 25 in admixture with conventional carriers and / or excipients and conventionally formulated in a medicament. 1 drawing Published by: National Office of Inventions Responsible publisher: Zoltán Himer o.v. CODE