CS222692B2 - Method of preparation of the new indolizine derivatives - Google Patents

Description

The invention relates to a process for the preparation of heterocyclic compounds. in particular, a process for the preparation of new indolizine derivatives. ^of

The process of the present invention provides indolyzed derivatives of formula (I)

(I) and pharmaceutically acceptable acid addition salts thereof, such as oxalate or hydroccioride, wherein:

R represents a branched or linear alkyl group having 1 to 8 carbon atoms, or a phenyl group, a monofluorophenyl group, a monochlorophenyl group, a monophenylphenyl group, a monoethyylenyl or eonobetononyl group, a dichlorophenyl group, a dibromide group or a fluorine atom on a substrate or bromine, represents a hydrogen atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group or a methyl group,

A represents a group

where

Xg is chloro, bromo, idd, methyl, or oetyl, allo, sloipimine, and

X 3 represents a hydrogen atom, a bromine atom, a chlorine atom, a ship atom or an oetylocyl group,

R is an atylio group, an ethyl group, z-propylcoco or z-botylooco skopizo, n is an integer from 2 to 6, including ptdmOnty, that if Xg and X ^ have a hydrogen atom or a skylp.no, drinking »X means different skopizo than atoa ottek ·

OERIOATES PREPARED BY THE INVENTION OTC OTC, which is useful in the treatment of orbital pathological heart syndromes, in particular in the treatment of angiogenesis of the heart and blood vessels. cardiac arrhythmias of various origins.

By demolition at a weight of about 60 kilograms of weight. The preferred embodiment is an id 100 dr of 300 milligrams of the active ingredient when administered orally and id 1 dl of the 3 milligrams of the active ingredient when used for oral administration.

The compounds of general formula X may be in accordance with the invention and for the preparation of the compounds of the invention in an inert solvent such as, for example, benzene or toluene, brool alkoxybenzylindolizole of general formula II.

(II) wherein X, R, A and n are oyed on general formula I, with the conventional amine of general formula III,

(III) wherein R 1 is characterized by the general formula I, thereby generating the desired isolate of general formula I, which may optionally be reacted with a basic or azoresulfonic acid and a sulfuric acid.

The choroid of general formula II can be prepared by condensation, preferably with an isothermal environment, such as acetone, monoethyl ketone, alkali metal salts, with the advantage of potassium or alumina, the choroid of general formula III

O (III) wherein R, A and X | oojí o general ozcrce I rnoedený oýznaa, with dibrtoalkazeo general ozrce IV

Br- (CHg) _n -Br wherein n is as defined for formula (II).

(IV)

Compounds of formula III wherein A is R8 are either those described in Brissé Patent 2051812 A or compounds that can be prepared according to the methods described in said patent.

Other compounds of formula III, i.e. compounds in which A is a modified R 1 group, can be obtained by reacting the corresponding 2-substituted indolizine with 2,3-dichloro-4-acetyloxy- or 4-tosyloxybenzoyl chloride. This benzoyl chloride derivative can itself be prepared by acetylating 1,2-dichloroanisole under Friedel-Crafts conditions, oxidizing the acetyl derivative so obtained with sodium hypochlorite to form the corresponding benzoic acid derivative and demethylating with hydroiodic acid in acetic acid to give 2.3 Dichloro-4-hydroxybenzoic acid. 2,3-Dichloro-4-hydroxybenzoic acid is then reacted with acetyl chloride or tosyl chloride to form the desired 2,3-dichloro-4-acetyloxy- or 4-tosyloxybenzoic acid and the corresponding acid chloride is subsequently formed in a manner known per se, for example by reaction with thionyl chloride.

Indolizine derivatives are already known in the art and have such a pharmacological effect that they can be used for the treatment of angina and cardiac arrhythmias.

In this connection, United Kingdom Patent No. 1,518,443, which describes in more detail 2-ethyl-3- [4- (3-di-n-butylaminopropyl) oxybenzoyl] indolizine known as butoprozih, may be mentioned. In the UK patent, the compounds described herein are attributed antianginal properties as they produce the following cardiovascular effects:

- bradycardia

- decrease in arterial pressure

- alpha-antiadrenergic effect

- beta-antiadrenergic effect

- corona-dilatation effect.

The increase in myocardial blood flow induced by these compounds is in fact only small, as their effect does not last long. After intravenous injection, the effect is induced for only a few minutes.

In addition, the compounds described in the aforementioned United Kingdom patent show little beta. -adrenergic antagonistic effect. This effect is only negligible at the minimum dose at which the other four cardiovascular effects mentioned above exhibit to a significant extent.

It has now been unexpectedly found that by suitable substitution of one or more methyl or netoxy groups or halogen atoms, such as chlorine, bromine or iodine atoms, for dialkylaminoalkyloxybenzoyl indolizine derivatives, compounds having a much broader spectrum of cardiovascular properties are obtained than the UK patent. 1 516 443, while having lower toxicity.

Thus, it can be shown that the indolizine derivatives prepared by the process of the invention can be considered as effective coronary dllatants since they are capable of significantly increasing the blood flow to the myocardium and retaining this effect for a longer period of time than that of butoprozine.

It has further been found that the compounds prepared by the process of the invention reduce heart rate and arterial pressure in animals.

Moreover, indolizine derivatives exhibit a bata-antiadrenergic effect which is much stronger than that of the derivatives described in the aforementioned United Kingdom patent. At the minimum dose required to induce bradycardia, to reduce arterial pressure, to alpha-antiadrenergic and coronatal effects, the beta-antiadrenergic effect of the derivatives of the United Kingdom patent is very weak, whereas for indolizine derivatives prepared according to the invention this effect is far from stronger.

In addition, the compounds prepared by the method of the invention reduce myocardial oxygen consumption, which is calculated by multiplying the difference between oxygen in arterial and venous blood by coronary blood flow.

Thus, the compounds prepared according to the invention cause a significant reduction in arterio-venous difference, which causes a reduction in oxygen consumption 1 despite the increase in coronary blood flow. This advantageous oxygen consumption effect is additionally obtained with the compounds prepared according to the invention, in contrast to Uutoprozin, without any reduction in myocardial contraction.

Furthermore, it has been found that the derivatives prepared by the process of the invention are less toxic than those disclosed in UK Patent No. 1 §18,443. Acute toxicity tests performed by intravenous and oral administration in animals have shown that lethal doses are administered. prepared by the process according to the invention higher than that of the derivatives of said United Kingdom patent.

In addition, higher blood levels can be achieved with the compounds prepared according to the present invention than with butoprozine. It has been shown that the same oral doses of 1-methyl-2-methyl-3-74- (3-di-n-butylaminopropyl) 10-oxy-3-br (2-urea-1-indole) -indiol and Uutoprline administered to dogs induce blood levels, Similarly, it has been shown that the administration of the compounds of the present invention to dogs does not result in any cardiac toxicities in the treatment of the compounds of the present invention. This phenomenon can be referred to as butymmetric arrhythmia.

The indolizine derivatives prepared by the process of the present invention further exhibit a depressant effect on myocardial contraction than is the case with bismolin.

People suffering from angina pectoris manifest themselves as a painful consequence of the delicacy between supply and oxygen demand in the myocardium.

Thus, the compound may be effective in treating angina peetoris either by increasing oxygen supply or by reducing oxygen demand. Among the substances commonly used for the treatment of angina pectoris in humans, dipyridamole between coronary dilatances and amiodarone may be mentioned among compounds which reduce myocardial oxygen consumption.

However, comparative tests have shown that the compounds to be prepared! of the present invention are in several respects more preferred than dipyridamole and amiodarone. In particular, it has been shown that dipyridamole does not reduce myocardial oxygen consumption and that amiodarone cannot be considered to be coronary.

The derivatives prepared according to the invention are effective in both of these functions. Thus, the compounds - myocardial oxygen consumption through its mmtabolic effects and also increase coronary blood flow with long lasting effect. In addition, these compounds are capable of preventing or treating not only arrhythmias induced by ischemic myocardial disease, but also auricular and virulent arrhythmias of various origins.

Thus, it will be appreciated that by halogenation, mesylation or isolation of indices of the derivatives described in United Kingdom Patent No. 1,518,443, it is obtained. compounds which exhibit a new spectrum of pharmacology desirable in the treatment of cardiac defects.

topexample:

myocardial sites that are under-supplied, can be nourished through coronary-diatomaceous effects (which may cause development) of additional co-circulatory circulation. This effect is valuable - in the treatment of both anginal infections and rhythm irregularities resulting from lschemic myocardial disease.

- The anti-adrenergic effect is also valuable for the treatment of both angina and cardiac arrhythmias in view of the important role played by the hyperpective of the sympathetic systems in the ethology of the two heart diseases.

Since the fluorogenic mediator of the synmpathetic system is epinephrine, a compound that suppresses all of the effects of epinephrine is likely to be a compound that suppresses only part of these effects. For this reason, the compounds prepared by the process of the present invention, which inhibit both the alpha and beta effect of epinephrine present, are more potent than the derivatives of the United Kingdom patent δ. No. 1,518,443, which virtually inhibits only alpha effects at minimal doses at which other faimacological cardiovascular effects are studied.

Among the compounds which are prepared by the process of the invention and which exhibit the most pronounced antianginal ability, the following may be named:

- bromo-2-1001x1-3- / 4- (3-di-n-butyaaointn ^г tpnl) -txy-3-BRT □ -bbnnoyt / -indd0lzin, 2-n-butyl-3- / 4- (3ddinn- 2-Ethyl-3 - [- (3-di-n-butyl-mononitrile)] - (3-chloro-benzenesol) -indoline], 2-n-butyl-2-ethyl-3-bromo-benzyl 3 - [- (3-di-n-butylaointin-3-yl) -thoxy-3'-chlorobenzene] -indolizine, 2-isoprotyl] - [4- (3 / di-n-butylamino) -pentyl] -xy-3,5-dichlorobenzene / - / ndotlzine,

-bozo-2-phenoxy-3- / 4- (- di-n-ttytyaoointnrtppl) -txy --- chlorobenzyl-ndrtizine,

-clt / - / ethyl-3 - [- (- di-n-butylao: L-p-opa) -ztplЗ-cCazt ¹ bbnnzptl- / nddtlzine, l-chaor-2 -n-buup 1 --— / 4 - (/ ddinn-lulll · mlintnrtpnl) / txy-bennool / -indotlzine,

-bro [o --- ((1-chloropheninyl) - (- N - (- di-n-bltllaoinopnoonl) -ooyl) ((- chlorobenzyl) ndotlzine);

these compounds are in the form of the free bases or in the form of pharmaceutically acceptable acid addition salts, such as, for example, chloride or acid oxalate.

The results of phalmaktlogic tests which have been carried out to determine the cardiovascular properties of the compounds prepared by the process of the invention are shown (e.

(i) Antianginal properties

- Effect on blood flow to the m-ocard

This test was performed according to the method of R. Chaalier and J. Bau, hiera described in Arzneernittel-Forcchurng Drug Research 2-, No. 19, 1330-1331 (1973).

The test was performed on anesthetically treated dogs who received the test substance intravenously. The intensity of the maximal effect on blood flow to the myocardium was expressed as a percentage of the pre-injection value. The Sas needed to reduce the o-aloal effect by 50% was the duration of action. This time was measured in minutes. Rrly recorded the following results:.

^X 1 x ₂ ^X- R ^R 1 n Dose (mg / kg) Max. increase («) Time to 50% reduction Br Br H ^c -h ₅ nC / H ₉ - 10 60 90 Br Br H CHj nC / H ₉ - 10 125 / 0 Br Br H n ^- C ^H ( ^j n-C? H? - 10 100 ALIGN! 20 May Br Br H n-C? H? n-C? H? - 10 90 20 May

continuation

^X 1 Xž ^X 3 R »1 n Dose (mg / kg) Max. increase (*) Time to 50% reduction Br Br H -Ό Br n-C.sub.1 3 10 100 ALIGN! 20 May Br Br H n-C4H ₉ 3 10 150 100 ALIGN! H Br H \ = / n-C4H ₉ 3 10 90 25 Br Br H CHj n-C4H ₉ 3 10 77 45 H Br H n-C ₇ H ₇ nC ₄ Hg 3 2 120 25 H Br H n-C4Hg nC ₄ H ₉ 3 5 70 60 Br Cl H iso-C-H? n-C1-4 3 5 133 '20' Cl H H nC ₄ H ₉ n-C18 3 10 60 30 H Cl Cl ΙΖΟ-Ο ^ Ηγ nC ₄ H ₉ 3 10 30 75 H CL CL ЧУ ” nC ₄ H ₉ 3 10 45 15 Dec H Cl Cl iso-C? Br 1 n-C4Hg 3 10 30 75 H Cl H Br nC ₄ H ₉ 3 10 30 45 H Cl H n-Cýi? 3 8 45 25 H CL H iso-CH ₇ n-C-ý? 3 5 80 90 Br Cl H O n-C4H9 3 10 ' 90 90 Br Cl H n-C4H ₉ n-C-H? 3 10 40 90 Br CL in H O- n- ^ CgHy 3 10 50 50 H · Cl H n-C4Hg n-C1-4 3 5 75 30 H CL H ^C 2 ^H 5 n ^ Hg 3 6 70 45 Br Cl H n-C-H? 3 10 63 45

Cl

Br n-C ₁₁ H ₁₁ C ₄ H ₉

Br

Cl n C ₄ H ₉

2.5 continued

^X 1 * 3 R R. n Dose (mg / kg) Max. increase (%) Time to 50% reduction Br Cl Cl H чЗ n-C1-4 3 8 70 90 Cl Cl H ^C 2 «5 nC ₄ Hg 3 1 40 15 Dec Cl Cl H c ₂ h ₅ . Π-C 3 3.3 60 25 Cl H H hQhC ' n-C ^H 2 3 5 50 40 butoprozine 10 120 4 amionzron 10 36 7

The results clearly show that the compounds which are prepared according to the invention are far more advantageous in relation to the 'effects' of blood flow to the myocardium than butiprozine or zmodarone.

- Antiadr energetic effect

The purpose of this test was to determine the ability of the test compounds to reduce epinephrine-elevated blood pressure (ant-alpha effect) and epinephrine-accelerated heart rate (m-betz effect) in a dog that had previously been anesthetized with pentobaarital and who had been administered ati-opLn.

Ant-alpha effect

For each dog, a dose of epinephrine was first determined to cause a relapsed arterial pressure increase of about 13 kPa (about 5 to 10 micrograms / kilogram).

The dogs were then dosed with the so-called whore of epinephrine, and then the dose of the test compound was administered in a tracer way. The value of the gift for the reduction in hypertension induced by the compound being tested compared to the previously obtained hyppetension (approximately 13 kPa) was recorded.

Anni-beta effect

During the same test described above, epinephrine produced a reproducible increase. heart rate at approximately 70 beats / min. Then, the revaluation of the decrease in epinephrine-induced heart rate acceleration that was achieved with the test compound compared to the tachycard that was previously (approximately 70 beats) was recorded. In both cases the results were recorded as follows:

+ for less than 50% reduction in pressure or heart rate increase ++ for 5-0% or more reduction in pressure or heart rate increase +++ for almost complete reduction in pressure or heart rate increase.

The following results have been reported:

^χ ι * 2 * 3 R E n Dose (mg / kg) Anti-alpha effect AnH-beta effect Br Br H c ₂ h ₅ n-C4H ₉ 3 10 +++ +++ Br H H ^C 2H ₅ n-C1-4 3 6 +++ +++ Br Br H -O' n-C1-4 3 10 +++ ++ Br Br Br n-CjHy nC ₃ H ₇ 3 10 +++ +++ H Br H n-C4H9 3 10 +++ ++ H Br H c ₂ H ₅ n-C4H9 3 7.5 +++ ++ H Br H nC ₄ H ₉ n-C4H9 3 5 +++ ++ H Br H nC ₄ H ₉ n-C ₇ H ₇ 3 5 +++ ++ Br Br H CHj n-C4H9 3 5 10 +++ +++ ++ +++ H Br H nC ₄ H ₉ n-C4H9 3 5 10 +++ +++ ++ +++ H Br H Izo-C ^ H? n = ^C = ⁹ 3 8 +++ ++ Cl (B) H nC ₄ H ₉ n-C1-4 3 10 +++ ++ Cl H H η-Ο ^ Ηγ n-C4H _$ 3 7.5 +++ +++ H Cl H П-С4Н9 n-C4H ₉ 3 10 +++ ++ H Cl H -2H ₅ n-C ^ ^ 3 10 ++ ++ H Cl H c ₂ h ₅ nC ₄ H9 3 6 +++ ++ H Cl Cl izo-CH? Br AND nC ₄ H ₉ 3 10 ++ ++ H Cl H n-C1-4 3 10 ++ ++ Br Cl H nC ₄ H ₉ 3 10 ++ +++ Br Cl H c ₂ H ₅ η-θΛ 3 7.8 ++ ++ Br Cl. H n-C? H? 3 10 ++ ++ H Cl. H iso-C 3 H? n-C? H? 3 10 ++ ++ Br Cl H nC ₄ H _$ n-CJLj 3 10 ++ + Br Cl H n = C4H9 3 10 ++ ++ Br Cl H n-C ₇ H ₇ 3 10 ++ ++ Br Cl H C2H5 n-C4H9 3 10 +++ +++

continuation

^Х 1 * 3 R Br Cl H ^ y _C i Η Cl H O* Br Br Cl H Вт Cl H nC ₃ ^H ₇ Br Cl Cl H -d Cl Cl H c ₂ h ₅ Cl Cl H ^C 2 ^H 5 Cl H H O ^ci Cl H H Cl Cl H H H Br H iso-C ^H H; Br OCH ₃ H сн ₃ Cl Cl Cl ^C 2 ^H ₅ Cl Cl Cl -O Cl Br H ^C 2 ^H 5 Cl Br Br Br Cl Cl Br Cl Cl -Ό Br CH ₃ CH, CH ₃ H Br Br H Br Br OCH ₃ Cl H OCH ₃ OCH ₃ H -Ό

»1 n Dose (mg / kg) Anti-alpha effect Anti-beta effect nC ₃ H _? 3 10 +++ ++ nC ₄ H ₉ 3 10 ++ + n-C1-4 3 10 ♦ ++ +++ BC ₄ h ₉ 3, 10 +++ ♦ ++ nC ₃ H _? 3 8 ♦ + nC ₄ H ₉ 3 0.5 +++ + nC ₃ H ₇ 3 3.3 +++ П-С4Н9 3 10 + ♦ + ++ nC ₃ H ₇ 3 5 ++ ♦ nC ₄ H ₉ 3 5 +++ nC ₃ ^H 7 3 7.5 +++ ++ n-C1-4 3 7.5 ♦♦ ++ η-Ο, Ηγ 3 10 ++ ++ nC ₄ H ₉ 3 10 +++ ++ nC ₄ H ₉ 3 10 +++ +++ n-C1-4 3 10 ♦ + n-C1-4 3 10 ++ ++ nC ₄ H ₉ 3 10 ♦♦ nC ₄ H ₉ 3 10 ♦ ++ ++ ₇ , p 3 10 nC ₄ H ₉ 3 10 ♦ + ++ n-C-iH? 3 10 +++ nc ₃ H _? 3 10 ++ ♦♦

continuation

Y * 2 γ P Bl Dose Aunt-alpha Anni-beta * 1 ъ n (mg / kg) effect effect H ° ™ ³ H. ^C 2 «5 n-C1-4 3 10 +++ ++ Br OCH3 H C2H ₅ ⁿ - ^C 4 ^H 9 3 5 ++ ++ Br OCH ₃ H CH3 nC ₄ H ₉ 3 7 . + ♦ ++ Br OCH ₃ H CH3 n-CjjHy, 3 7.5 ++ ♦ + butoprozine 5 +++  + am ^ de ^ n 10 ++

Again, the results obtained show that the compounds prepared by the process of the present invention are more advantageous than those known in the art.

(ii) Anti-arrhythmic properties

These properties were demoonsored after administration of the test compound to mice by intragastric administration using the Lawson test (J. Pharmac. Exp. Therap. 1963, 160/1 / pp. 22-31 ').

The arrhythmia was induced by the animals inhaling chloroform and even into complete asphyxia, and then a venricular rhythm was observed.

The dose of the compound that protected 50% of the animals from viral fibrillation, i.e., the AD 50, was then recorded. The following results were found:

^X 1 * 2 * ³ R ^R 1 n 50 50 (mg / kg) Br Br H CH3 n ^ H, 3 180 H Br H n- ^ n-C4H ₉ 3 170 butoprozine 270

(iii) Toxicity

- acute toxicity

Acute toxicity tests were performed in rats and mice.

The following results were recorded as compared to the prosin.

The compounds prepared by the process of the present invention were used in the form of acidic oxalate, with the exception of the compound--n, which is labeled with (x), and tested in the form of the hydrochloride.

a) For intravenous administration to rats

^X 1 % * 3 R ^K i n · '50 (mg / kg) (x). Br Br H CH3 n-C ^H, 3 70 H Br H ^α-C4H ₉ 3 60 (X) H CP H ^C 2 ^H 5 α-C4H9 3 65 H Cl CP iso-C CHy α-C ^ 3 > 100 (x) Br CP H n-C4H9 3 > 100 (X) H CP H n / C4H ₉ and · ^ 3 > 50 CL. CL H ^C 2 ^H 5 α-C4H9 3 (M _o > 50 mg / kg) 50 CP H H n-C1-4 n-C ^ c, 3 50 Br CL H α-C4H9 3 > 100 (LD ₀ > 100 mg / kg)

butoprozia 22

b) when administered intravenously in mice

Xi 4 * 3 R ^B 1 n '50' (mg / kg) (x) Br Br H ch ₃ aC ₄ H9 3 50 íipiro ^ ia 25

i) for iniragapttric application in molluscs (x) Br Br CH CH butobutyria aC ₄ H ₉ 3> 5 000 (LD ₀ > 5 000 mg / kg)

600

These results show that the compounds which are prepared according to the process of the invention are much less toxic than butoprozine.

-. Cardiac tension and general toxicity at tettecl long term toxicity

1-Bron-2-methyl-3- / 4- (3-di-n-butylaminopropyl) oxy-3-diabenzoyl-indolium hydrochloride, hydrochloride of 2-methyl-3- / 4- (3-di- The n-tetramyl-3-bromo-3-bromo-p-indole and the 2-α-butyl-3-iodo-d-butyl-3-bromo-3-bromo-3-bromo-3-bromo-3-bromo-3-bromo death at doses of 200 miPigrams / kg / dea when subjected to orafia.

Butoprozine, on the other hand, has been found to induce ventritalarial arrhythmias in dogs from as low as 50 milligrams / kg / day when administered orally, and the lethal dose of this compound is between 50 and 100 milligrams / kg / day.

Compounds prepared by the process of the present invention are prepared. for therapeutic use, they are normally administered in the form of pharmaceutical or veterinary compositions, which may be presented in unit dosage form suitable for the desired mode of administration.

The pharmaceutical or veterinary compositions may thus be in unit dosage form suitable for oral administration, for example in the form of coated or uncoated tablets, in the form of hard or soft gelatin capsules, in the form of packaged powder, fine suspension or syrup. Similarly, the composition may be in the form of suppositories for rectal use, or as a solution or suspension for renal administration.

If. the composition is in the form of a unit dose, for example it may contain from 15% to 50% of active ingredient per unit dose for oral administration, from 3% to 15% of active ingredient per unit dose for rectal administration, and from 38 to 5% of the active ingredient per unit dose for administration.

Regardless of the form you mix. The pharmaceutical or veterinary composition is conveniently prepared by combining at least one compound of formula I or a pharmaceutically acceptable salt thereof with an additional pharmaceutical carrier or excipient, for example, one or more of the following substances: lactose, starches, chalk , magnesium stearate, polyvinylpyrrolidone, alginic acid, colloidal silica, distilled water, benzyl alcohol or aromatic agents.

In order to illustrate the invention, the following examples and formulation compositions are provided.

Example 1

1-Br (1m2-βtt / -3 · '/ 4- (Зdii-n-poo / lithium-propyl) -ox) -3-bromoindolyl-indalzine and its acid oxalate

a) 1-Bromo-2-ethyl / 13- [4- (3-brololyl) -ooylbenzoyl] lintlalitite

A mixture of 7.7 grams (0.018 mol) of 1-bromo-3- (3-bromo-4-hydroxy-benzoyl) -indaline-5 g (0.036 adu) of anhydrous potassium carbonate and - 50 ml of ethyl ether / ketone was stirred in beaker for 30 minutes. 14.4 g was added to this reaction medium. (0.072 moTu) 1.3-100 mmol and the mixture was kept under reflux for 20 hours. After cooling, the mineral salts were washed with acetone. It was evaporated along with excess 1,3-dbboom propane. This afforded 13.2 g of product, which was purified by the elution method using benzene as eluent and the strength as eluent. The first fraction of the unknown product was obtained and then the second fraction of Ьюо ^ о ^! 8 g of the desired product.

There was thus obtained 1-bromo-2-ethyl] -3- [4- (boiling piperidin-1-oxybentzil) indalzite in 83.6% yield, m.p. 105-106 ° C.

b) 1-Brol-2-βtt / -3- / 4- (Zddl-n-pgo / methylthioprlp) -oxy-3-bromobenzazole / ltdolizite

A mixture of 2.2 g (0.004 mol) of 1-bromo-2-ethoxy-3- [4- (2-bromoethyl) oxy-biphenyl] -dolizite, 1.2 g (0.012 mol) of di-n-pyrimidine, and Toluene was boiled under reflux for 20 hours.

After cooling, the reaction mixture was washed twice with 10 ml of water and the solvent was evaporated in vacuo. This gave 2.5 g of a residue which was purified by elution chromatography on silica eluting with ethyl acetate as the eluent. In this way, 2.4 g of 1-bromo-2-ethyl-γZ-β4 (α- (η-n-1β / laltithio-opyl-propyl) 10 γ-γZ-bloibentol / itololite) was obtained as the free base.

c) 1-Bromo-2-ethyl-1-3-7 4- (3-di-n-propylamino) oxo-oxo-3-bromobenzoyl / indolizine acid oxalate.

The base obtained above was dissolved in 30 ml of ethyl ether and then treated with 0.55 g of oxalic acid dissolved in 70 ml of ethyl ether. This afforded 2.4 g of the desired salt in the crude recrystallization from 75 ml of isypryloro-yol. 3)

Yield: 75%, mp .: 139-140 ° C.

In the same way, the following compounds were prepared using appropriate starting materials:

Compound

Melting point (° C)

Acid oxalate 1 -brp - e - e.l-3L4´73-di-n-butlla-iioproool / pxybenizyl ^ ndoH zine

Acid oxalate 1-bromo-2'-tertophyl-N- (1'-n-butyl) and [nini^Ooop^Ol / ox^olbezo^Ol^liilⁿd^Oi zi.i^at

Acid šťavnlan ^{chloro-1 - methyl-3 C4} - / 3- ^di -ie- ^b žtylamiioprooo ^l / oxybeniool] indolizine Acid • ^{T 1} Avelana ^-chloo-2-tl e lзЗ- ^[- - ³ - ^di-n-i prolyla- nopropp ^l / oxybbeizyllindoliziiu

Acid Section^Ťavelan¹ -chlorine-^--n-^Oropyl-³- [⁴-7³-^di-n-butylation^andno beizylindinedizine

Acidic Oxalate ¹ -C lpr ^L-2-i-butll --- ^44-3 3 ^{- f} u diie- ^LPL alpha- ^and NP ^{FP pol3} p ^ 3 ^! ^ ^ Eniz] JII ^ ^ C ^ C ^ Oi zine Yssel šťavelai ^{K 1} · 2- -chloo fei ^l l-3- [4- ^{(- di-prolyl-in} lnoproρ ^PL3 oxybennz ^penis í.n ^{d o K} i zin yseZLý ^Juice Avelana ^{1 l} ZP -CH 2- ^{34 y} -CH prfeny ^y3 -3- 73dd ^{44 -} ie- ^{l u} t У ^l of íippropyl oolbenizpl ^3] in ^{K d} Ooi zine Yssel ^ŠL Avelana ^1-chloro-2 -! * Bardsey Island-3-L4- ³ 3-d ^{- in ž} ul ^p l-mino ^p rρ ^p1 . 'Pxybenizp ^y LinidOiziiu

Acidic šlavelan ^1-chloro-2 - (- ^ 1 ^ -3 ^-4 4 - / ^ 01 ^ in ^ t ylmcQn ^ <^ b ^ ^j eo oxybenizplJinádOiziiu

1-Soon-2--1 m, n ^y - ^- -4-3-di-n-pr buyyammi no opyio oxp3 ЗьГрр- benz Ooi it indol ζ (π1 οοο hloride ^K ^ ^š Yssel íavelan 1-bromo-2 ² mt ^nt l-з ^{- 4-3 "<d.} i ^{-b ut-l-acetylamino p} oi oo ^OPL3 ^^ ~ 3-br one indooi zine

Kpse ^y y Mee oxalate ^2-p-2- 4- ^{4 3 3-di-n-butyl-p} iipprp pl ^three Px ^P "3,5-dibpombnnzoyl INDP ^y iziiu Yssel šťavelai ^K ^ V ^ ^^^^ Me --n-hutylam: Lio ^p rρ ^pol3 poy-3- ^b rpm ^m enzyl] ^J ndo ^o zine

Acidic Velan ² S ^ ^l -ethyl-3- ⁴⁴ - ^{3-di-n-oгolP l} of inpprPOУ ^y / oo ^l -3-brombenippOiJuddOizinu ^'Kp Selye'. avelai ^ 2 ^^ ^ 1 ⁴ 4 ^{3 I} N ^F -ddi tιl ^pl -minp ^P ro ^pp l ^y PO E3 ^{3-sel characterized} brommenzpy0linnd0lziiU ^{Kp ST, and} el i ² -i ^{3 e-44} prρpyl- e ³ 3 ^{P diino0P0-yl} and ^p-iipprρ P0L ^3-yl-3-p brombbeiZ lJinidPlziiu

Acidic Velan S ^ ² - ^{p i} to ^p rp yl ^{--- 44} - ^3з -d ^- in- ^'with tlyl шinP ^{FP-yl 3 P} oo e3ebrombeeizyl ^L'] n ^{i i i} d ^{0 l} of Selye also ^{Kp T and} V ^{n i} L ⁱ 2 - ^{b 3} utll- - ^44e3з - i ^{d i} n ^o OOop --iiPpoρ ^{pp pl} l ^{l 3} P0-E3 brpmbeiopyli indzlizinu

107 to 108 (isopropane) 92 to 94 (isopropane) 92 to 93 (isopropane) 162 (isopropane) 111 to 112 (isopropane) 106 to 108 (isopropane) 161 to 162 158-159 (m-eanpl) 16 (0-161 (mmtanpl) 80-82 (bnnoene))

172 (isopropanoP.) To 90. (ethyl acetate) 141-143 (10) 1 ethyl acetate (iodine) 163. (isopropane) 98 to 99 (i ^ s ^^ po ^ op ^^ i ^ O.)

113 to 115 (lzoproolnpl)

105 to 107 (bnnoene)

136-137 (lzooroplnρl)

With 1 English

Melting point (° C)

2-n-Propyl-3- [4/3-di-n-propyananiinopropyl / oxy-3-bromobenzoyl] indolizine acidic salt

2-z-Butyl-3з / 4 - (- design) polybenzoyl 3-oxo-333bromobenzoyl // ndoHoin

2-Phenyl-3 - [? - 33 - (? - p-or (?) 1? - (-) - 1 -) - [beta] -oxo-3-benzo-benzoyl) indole

2-Phenyl-3-44- (3-dn-b-butylpentyl) -oxyl-3-benzylic acid oxalate

2- (4-fluoro) benzoic acid oxazoline 44- (O-dZ-b-butylamin) (oroopP) -oxy-3-benzobenzoyl // bdoУloin

2- (4-Chlorophenyl) -3- [4- (3-methyl-3-chloro-2-propyl) -oxy-3-bromobenzoyl] -benzoyl acid

2- (4-Chlorophenyl) -3- / 4- (3-01-n-butylaminopropoP) -oxy-3-bromobenzoyl / indole oxalate

2- (3-bromo-phenyzP) -3- / 4- (3- (H-z-pyropllmmZzoor10yУ) -1xp-3-bromobenzoyl) indoleoine

Γ- (4-Bomomphenine P) -3- / 4- (3-O-n-eutylaminopolyoyl) acid oxox-3-bromobenzoyl acid

2- (4-mepyyyPfenP) -3- / 4- (33-d-zebutylaminophthalic acid) • oxox-3-benzylbenzoyl // ndoУioin

2-ZzlorlppP-3- / 4- (5-d3zn-butylaminolOpplPP) -oxp-3-bromobenzoyl acid

2-IsopropoPP-3з / 4- (3-d3zn-pyopplamislorlpoP) foroxyz3-bromobenzoyl / indole

2-Methyl-3- (4-33-01zn-butylmino-mono -oyoyl) -oxpз3зchlyrbenzoyУ / in0oOizizu acid

2-Chloro-3 ', 43- (3-dZ-o-oropllemizlprlpoУ) -1xp-3-chlorobenzoyl / indolioic acid hydrochloride

2-пУр1-3-4 - (3-dZ-b-butylar-Znoorlppl) -lxp-3-chlorbtnzoyP / Zz0o0ZoZzu

2-Isooroppl-3- / 4 - (- odzzn-byPplmπlZzooroopl) -oxp163 (isopropanol) 86-87 (Isopropazyl)

148 to 149 (Zzopropanol)

129 to 130 (isopropanyl)

110 (Izo ^ opano!)

163 to 164 (mmtazole) 139 to 140 Uzopropanyl)

142-143 (Zzopropanyl) 147-143.5 (mmtanol)

169 (Zzopropazyl) 80-82 (ппп24п) 179 (lzo ^ opano!)

141 to 143 (lzypropiazyl)

161 to 162 (mmPwiyl) 116 to 117 (1-pyroazyl)

115 to 117

-3-chlorobezzoyP / Zn0y03oin

2-Isoorlppl-3- / 4 - ((design-pyopplaminooropyr)) oxy-3-chlorobenzoyl acid isolate

2-n-Butyltyl-3- / 4 - (- dl-n-by-yl-methyl-zinc-1-yl) -lxp-84 acid 3-chloro-azyl-acid

2-n-Butyl-3 - [- (3-dZ-o-pyrophenylmethyl) -olyl] -1xp-3-chlorobezzylate

2-Phtpl-3-44- (3-di-z-buPplmmZnУoroopl) -1xp-3-chlorobenzylP / inyllioin acid

2-Phenyl-3 - [- (3-dz-o-oroylmethyl) -zoorooyl) oxo-3-chlorobenzoyl] oxo-oxo acid oxalate

2- (4-Methylphenyl) -3- [4 - (- dl-z-pyopplaminolOryppP) -1xp-3-chlorobezzoyl] -yllzine

KpsePý šlavelan 2- (4-erlmfetnP) -3з / 4-33- (Зl3zz-rУoypPaminopryppP) -. -oxp-3-chPlгbtzzoyP / indylioin

2- (4-ErlmphenzP) -3- / 4 - (- dlznebutpaaminopropoP) -.

з1xp-3-chPorbezz oP / lndy01oin

Kpselý šlavePan 2- (3-eromffnzP) -3- / 4- 3 Зod3zZbbuPpPадlnopropoP) (islorУoanyP)

168 to 169 (mmPazyP) to 85 and 107 to 109 (lzypryoanyP)

130 to 131 (lzyprypabyP)

121 to 122 (Isopropazyl)

157 to 159 (mmetanoP)

134-135 (Izo ^ opany!)

154 to 155 (mmPazyP)

134 to 435 (3-isopropyl) to 92 α-β-3-chPlrbtzzyyP / inyllioin

2- (3-Bromo-benzyl) -3- / 4- (3-di-pyrophenylmorphopropane) -1xp-3-chlorobenzoyl / inddyloin

2- (4-сЬ1ияГппУ1) -3- / 4- (3-Ol-n-buPplaminyproρpl) (3zopryoazol)

148 to 150 (even ravaged!)

116 to 118

-lxp-3зchlorobenzoyl / indolelolo (isooryoazyl)

Compound

2- (4-Chlorophenyl) -3- [4- (3-di-n-propylaminopropyl) oxy-3-chlorobenzoyl] indolizine acid

1-Bromo-2-methyl-3- [4- (3-dibut-3-butylaminopropyl) -3-bis-3-bromobenzoyl] indole] acid oxalate

Acid juice 1-brrø-3-mmtnl-3з / 4- (3з0i-β-propllaisispropyl) -rx1з3зbrrmmbnzoyrlinZorioin

Acid peat 1-erlз-3-en11-3-i / з (- “Zient1llmizolny1) -lX1з3зbrombbnzoyrlimidolloin

Acid peat 1зbroe-3-γnylз3- / 4- (3-dimethylaзinoorooyl) -ox1з з3зbгommenzoyrlinZorloizu

1-Bron-2-enylP-3 - [- (- [alpha] - [11] [11] imino) phenyl] -3-broebenzoyl-zorizine acid

Acid Sulfur 1-bro-2-ynyl-3 - [- (3-0-ethylaminopropylpyrrole)] - ox1333br oy oliznoHo ^ u

1 - ^^^ 32 ^^ 1-3- / 43 (2301-n-proppliminoenyl) -oxi3-bromobenzoyl] oxoic acid

1-broza-2-enyl-3 - [з (3-Zi-Zopropylamizoorrpp1) -oxyl] -3-bromobenzoylrin Zorioin acid

Acidic 1-benzo-2-enylP-3- / 4 - (- α-n-bulminolenyl) acid

KpsePý sivinPin 1зbгom-2-зnlP-3-i4- (3-0i-n-butylaminopropyl) for -rx1-3-errebenzopr1 1ηΖοΠ oinu

1-Bromo-2-zpypyrrole-3з / 4- (3-0i-Zзbu11PamizlpropyP) acid -rx1з3-brremenzoyl / inZori oin

Oxidic acid 1зbгom-3-nz3PO1pl-3- / 4- (3-0i-n-prop1laminopropyl) 3 зrχ1-3зbгombenooprininZorioin

1-bromo-2-zinc-1-bromo-1-bromo-1-bromo-3-oxo-3-benzo-3-oxo-3

Acid Slivnlm 1-Bgom-2-n-butyl-3- / 4 '(3-O-n-bulylazinopugopyP) зOX1з3зbrrmbbnzoyr1inZorl oinu

Pure 1inbrin-2-fnzzPз3 - // - (3-Z3zz-pro1ylmзzzoproo. -Oxy-3-bro1ZenzoyrinZorioin

Sulfuric acid 1-bromo-2-phenyl-3 - [- (3-O-n-ylamino) amino] -pyrrole-3-bromobenzoyl / in-zine

Acidic bivino 1 (/ - mmnooplenine) 33- / 4- (3-β-n-but plasmin-4-propyl) -1X1-3-Ьglmenzenopropylamine

Sulfuric 1-bi-n-m- (4-metnP1βnnZ) pЗз / i4 (3-30-n-butpPzioinopoopyl) -ox1з3зbгlmmbnzoyr1inZori oin

Sulfuric acid 1 - 2 - (2- (4-fluorophenyl)) for (- // - (3-O-n-butylamizo-y-yl) -yl)

1-eroe-2- (3-bromobenzyl) -3- / 4- (3-O-z-eutylaeinoproppl) -oxyl-3-bromobenzoyl-1-zorioin acid

Acidic 1-broll-2-z-butpP-3- / 4 - (/ - di-nizbu11Pimizoret11) acid for з1X1-3-bгoзbbnzoyl1izZorioin

1-Chloro-3-chloro-3- / 4- (3oZ3z- _n- butylsilylpigyl) acidic acid for 3-chlorobenzene / isoZoin

Sulfuric acid 1-chloro-npP-3- / 4- (3o: 3- _n- propylaminrorrppP) for oxy-3-chlorobenzoyl / isoZorPoin *

Acid juice 1-chloro - (3-benzofenzyl) -3-i / z3-z0-z-butylaisisopropyl) · oxi3 3-chlorobenzyl / inZolizizu

Acidic 1-chloro-3- (3-bromophenyl) 33- / 4- (3-O-n-proppolylsulfonyl) iso-3-chlorobenzyl / in-zolizate Lanying temperature (° 0)

159 to 160 (3enazole) to 90 (iooyroyanol)

164-165 (also from oyro panoVe and tanol)

164 to 165 (OichPorntin)

150-151 (dicH-n-amino)

168 to 169 (Oichlorotin) 140 to 141.5 (isryroylnol)

163 to 164 (isopropizole)

139 to 140 (isoyroylzoO)

164 to 165 (isopropinol)

101 to 101.5 (isopropinol) (enzzéz)

132 to 136 (iorproplzole)

151 to 152 (2/1 isl) (en / en)

101 to 103 (isopropizole)

169 to 170 (1/1 een1izr / iso pin)

167 to 169 (isopropinol)

178 to 179 (eenmol)

169 to 170.5 (1/1 meniano)

170 to 171 (menazol)

172 to 173 (ззП1по1)

118 to 120 (isopropizole)

115 to 117 (isopropizole)

137 to 138 (iopropinol) 171 to 172 (min!)

194 to 195 (mnano!)

Compound

Teplrti Uéni (° C)

1/1 (eUplicetate)

129 (etp / icetate)

156 (isopropinzl)

136 (orprrpanzl / heyUin)

110 to 112 (izoyroyinzl) 108 to 110 (izzyrrylnzl)

136.5 to 138 (isotopic)

103 to 105 (isotropic) 95 to 96 (isryroyanz)

116 (iso ^ ropino!)

159 to 160 (methanol) 101 to 103 (ζ ^ γο ^^ Ι)

167.5 to 169 (methane)

169 to 170 (methanzl)

160 to 161 (isopropinzl)

18 to 185 (methanol) 176 to 177 (methanol) 168 to 169 (200) to 201 (methanol)

170.5 to 172 (methanol) 10/105 (isrprrpinol)

157 (isoyroyinol)

1Λ0 (isrpropino!)

172 (isrpropinol)

1/6 (isrprrpinol) .136 (etp / icetate)

1/8 (eUi / icetate)

171 (tUinrl)

1-Chloro-2-ethyl-3- / 4- (3-di-n-propylaminopropyl) oxy-3,5-dichlorobenzoyl / indolizine acid oxalate (3-di-n-Uulylaniloproppl) 2 3-oxy-3,5-dichlorobenzorl / indolizine

Acid oxalate 1 - (1 - 2 - 2 - ₁ - ₁ - ₁ - 3 - ₁ - ₁ - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Onilium-noyro-O, N-oxy-3,5-pyrrolidine / in-olizine

Acid 1-chloro-2-phenyl-23- [4- (3-di-n-uulylalinoyroyyl) oxy-3,5-dichlorobenzorin] in-olefin

1-Bromo-3-zetyl-3- [2- (3-dlpropylpylamino) propyl] -oxp232Cllorbenzzrl / indolizine acid oxalate

Acid oxalic acid 3 - [(3-dimethylamino) -3- (3-dimethylamino) -3-chloro-3-chlorobenzyl] - in-olizine

1-Bromo-2-eeul-3 - [- (Zdd2 --- propylamino-propyl) -acetic acid] for 2-oxo-3-fluorobenzyl / indorlzine

Acidic acid 1-bromo-2-ethylP-3- / 4- (3-ci-2-Uulylaminoproyl) 2-oxo-3-methylpropylzindl / indzrizine

Acid 1-bromo-2-azyrryl-2 H - (32di-n-butylamino-propyl) 2-oxo-3-fluorobenzyl / indole / zinc acid

1-bm-2-Isoric acid 1-33 N - (3-di-n-butylaminoproppl) 2oxy-3-chlorobenzyl / indorizine acid

1-Bromo-2-n-3-yl] -3- [2- (3-d-prroyylaminrproyyl) -azoxy-3-fluorobenzyl] -indorizine acid oxalate

1-Benzoyl-2-n-butyl-3β / 4 - / (32 - / - n-butylamino-propyl) 2-oxy-32-bromobenzyl / indole zinc acid

1-Bromo-2-phenyl-3- / 42 (3-i-n-butylaminopropyl) -oxyoxy-3-chlorobenzyl / indorizine acid

1-Bromo-2-phenyl-3 - [(3-d-propylarainoyl) -poly] 3-oxy-33-chlorobenzoyl] -indoic acid oxalate. i zi nu

1-Brzo-2- (4 H -henyl) -3- [3- (3-d-2-uulylaroinoyrrpyl) 2-oxo-3-carbonylbenzyl] indazole

Acidic štivelin 1-bromo <N-2 (/ -chlorftnrl) 33- / 4- (3-di-n-przpplaminrдодо ¹⁾ -32h -zx ^{p b h} lor enzz ^rp / yn ^d eli zine

Acid SEivtlin 13bromo-2 - (/ - brotfeinl) 33 - [- (3-di-nypyrypyridinopгrpyl) -oxy-3-hrbrbenooyl] indzlizine

Acidic štivelin 12broιn-2 - (/ зbгrmfθlwP) -3- / 4- (n-32di utplaminopгopyl ^b) 3oxp-3-hhlorbenzool / indzoizinu

Acid slivelin 1 зbrrm-2- (32brrmftnnP) -3- / 4- (3зdi-npprppylaminoyгrppl) 2Oxp-32hloroorzorl / indorizine

1-Bromo-2- (3-bromo-phenpP) -3- / 4- (3-di-n-tuulplarine-crypto) 2oxp-32-chlorobenzyl / indprlzine

Acid. 1-hhlzo-2-yl-3- [2- (3-di-n-Uulplaminopropyl) -2-methoxy-33-bromobenzzyl] -indoline tivelin.

1-Hlzg-2-tUp / -3- [3- (3-di-y-r-rolllaminoyropyl) 2-oxo-3,5-diisobenzoyl] inderizine acid

Acidic acid 1-hept-2-yl-3- / 3- (3-di-n-uulylaminoyroyyl) 2

3oxy-3,5-di-bromobenzoyl / indoleizine tartaric 1-chloro-2-phenyl-3- (3-O-dn-p-γgar / laminryroyyl) • η 5 - (1,5-dibromobenzyl) indizine

1-Chloro-2-phenyl-23- [4- (2-di-n-uulylalinoproppl) 20-0,3,5- (bromometenzyl) indio] acid

8e sklivslm 2-me Upl-3 - // - (33-i-pypypyaamines) polyl) 3 rxp33,53-ibrombenzzpl / indrizine

2-tupl-3- / 4 - (- &lt; / RTI &gt; tulyylamino-propyl) 2Oxp 33,5-di-bronbenzoyl-rindine acid Štivelin

2-etp / -3- / 3- (2- (ilaetilaminzetll) oχ: lyзЗ ₎

Compound

2-Ethyl-3- [4- (3-diethylamino-propyl) -oxy-3,5-dibromo-benzoindoline] hydrochloride. -n-poptylaminopropyl) -oxt-

- 3,5-dibromo-benzoicin / zinc

2-Ethyl-3- / 4- (3-ynyl-ethylamino-propyl) -oxt-3,5-dibromo-benzoic acid / innoleizine hydrochloride

2-n-p-o-methyl-3-iodo-3-iodo-2-naphthalenopropilaminopropanilide hydrochloride

Acid Štivelin · 2-n-proppl-3 - [- (3-dinobutylmino-monooropo)] - oxo-3,5-dibromo-benzoic acid

2-Isoorooyl-3 - N - (3-dinoro-amino-amino-topo) -oxy-3,5-dibromo-benzoic acid / indigoin acid oxalate

2-Isooro-ol-3 - N - (3-di-n-butylamino-amino) -oxy-3,5-dibromo-benzoic acid / innoleizine acid oxalate

2-n-butol-3- / 4- (Zodi-n-pooloeaminooropoly) -oxo-3,5-Oi bromobenzozo / indooizine

2-n-Butyl-3- (4-33ddin-bbutilaminopropyl) -oxp-3,5-di-benzoic acid oxalic acid

2-Phenol-1-3- / 4 - (- oinn-poo) -ilaminoproppl) -oxp-3,5-dibromo-benzoic acid

2-Phenyl-3 '- (3-dinobuto-aminooropoly) -oxo-3,5-dibromobbenoo / innoisoizine

2 - (/ - Fluoroenil) - // 4- (dn-o-oolololininopropol) -oxo-3,5-ribrombbenzoate / indigoin

The _y Selye šťivelin 2 - (/ - fluoreen / l) -3 // - (- Odinn-butolaшinooroppl) -oxo-3,5-ribrombbenooO / inndOizinu

2 - (/ - Chlorophenone) -3- / 4- (3-r-n-proo (11-aminopropo)) - oxo · -3,5-ribrommbenoo / innoisoizine

Sickleaf 2 - (/ - chloirfetnt) -3- / 4- (3-di-n-butolaminoproppl) -oxp-3,5-di-benzo-benzo / indole zine

2- (3,4-Dichlorophenyl) -3- [4- (3-di-n-proollamine) opox] -oxp-3,5-ribbromo-benzoine / innoisoine

2 - (3,4-Dicliorphene / i) -3 - / - (- oiinn-betplanino) · po D-oxp-3,5-di-benzobenzoot / indolizine

2- (3-bromophenyl) -3- [4- (3-ri-n-proo / laminooroppt) oxo-3,5-dibromobenzil] / indolizine

2- (3-Bromo-phenyl) -3- / 4- (3-r-n-butplaminooropol) fumarate -

oxp-3,5-di-bromobenzonitrile

2- (4-Meeplpheninyl) -3 - [- (3-ri-n-proo / liminopropol) -ox] -3,5-dibromobbenopropanol

2- (4-Methylphenol) -3- [4- (3-di-n-butplamino) ygopolic acid] (oxo-3,5-ribromobenoo) innoisoizine

2- (4-Me toxofeupt) -3- / 4- (3-r-n-propllaminopropol) oxy-3,5-dibromobenzoot / IndoHzine

2 - (/ - meeooχ / ennl) -3 - [- (3-ri-n-poop / laminoproool) -oxO-3,5-dibromobenzenoindoline]

2-Meole-3 - [- (3-d-n-ppoopolaminooropol) -ox] -3,5-dicliorbennool / IndoOizine

2-Methyl-3 - '- [- (3-din-bbulolaminoprop) (1) -ox] -3,5-dicliorbenenzole / IndoOizine

2-Ethyl-3- [4- (Zeddi-n-poo / ilaminopropol) -ox] -3,5-O-cllorobenzonitrile zinc

Melting point (° C)

191

(50/50 et / II acetate / etlnol

166 (ethyl acetate)

157

145 (ethyl acetate)

107 (ethyl acetate) 126 (ethyl acetate / ethanol).

146 (ethyl acetate)

110 (ethyl acetate)

142 (ethyl acetate / ethlnol) (ethyl acetate) 166 (ethyl acetate / etinoo)

152 (iso ^ ropino!)

190 (ethyl acetate)

114 (e so many t / i of opropanno) (ethyl t / i of opinol)

136 (ethinol) 122 (ethyl acetate) 126 (ethyl acetate / isopropanol) (ethyl acetate) 167 (iceton) paitium pH is ⁷⁰ ° C (ethno / ethyltter)

145 (ettlice mt / etinoo) (ettlic e edt / e ^ i-ether)

100 (oasSo ^ d.eý) (ethyl acetate)

Compound

Melting point (° C) 95 (ethyl acetate)

142 (isopropanol)

114 (isopropanol) (ethyl acetate) 90 (ethyl acetate)

146 (ethanol) pale at about 90 ° C (ethyl acetate)

174 (ethyl acetate)

133 (ethyl acetate)

141 to 143 (isopropanol)

138 to 139 (isopropanol)

131 to 132.5 (isopropanol)

160 to 161 (isopropanol)

105 to 106 (isopropanol)

148 to 149 (isopropanol)

196 to 197 (isopropanol)

168 to 169 (isopropanol)

134 (isopropanol)

145 (ethyl acetate)

106 (ethyl acetate) 154 (80/20 ethyl acetate / acetone) 132 to 133 (ethyl acetate / isopropanol)

104 (ethyl acetate) 156-157

2-Ethyl-3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dichlorobenzoyl] indole zinc acid hydrochloride

2-n-Propyl-3- [4- (3-di-n-propylaminopropyl) oxy-3,5-dichlorobenzoyl] indolizine acid hydrochloride

2-n-Propyl-3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dichlorobenzoyl] indoline zinc acid

2-Isopropyl-3- [4- (3-di-n-propylaminopropyl) -oxy-3,5-dlchlorobenzoyl] indolizine acid hydrochloride

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

2-Phenyl-3- [4- (3-di-n-propylaminopropyl) oxy-3,5-dlchlorobenzoyl] indoline zinc acid oxalate

2-Phenyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3,5-dlchlorobenzoyl] indolizine acid hydrochloride

2- (4-Bromo-phenyl) -3- [4- (3-di-n-propylaminopropyl-oxy-3,5-dichlorobenzoyl) -indole zinc acid hydrochloride

2- (4-Bromophenyl) -3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dichlorobenzoyl] indoline zinc acid

1-Bromo-2-methyl-3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dibromobenzoyl] indoline zinc acid

1-Bromo-2-n-propyl-3- [4- (3-di-n-propylaminopropyl) -oxy-3,5-dibromobenzoyl] -indolizine acid hydrochloride

1-Bromo-2-ethyl-3- [4- (3-di-n-butylaminopropyl) oxy-3,5-di bromobenzoyl] indoline zinc acid

1-Bromo-2-phenyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3,5-di-bromobenzoyl] indoline zinc acid

1-Bromo-2- (4-methylphenyl) -3- [4- (3-di-n-butylaminopropyl) -oxy-3,5-dibromobenzoyl] indolizine acid hydrochloride

1-Bromo-2- (4-bromophenyl) -3- [4- (3-di-n-butylaminopropyl) -oxyl-3,5-dibromo-benzyl] -indoline zinc salt

1-Bromo-2- (3,4-dichlorophenyl) -3- [4- (3-dl-n-butylaminopropyl) -oxy-3,5-dibromobenzoyl] indolizine acid oxalate

1-Bromo-2- (3-chloro-4-methylphenyl) -3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dibromobenzoyl] indolizine acid hydrobromide

1-Bromo-2-ethyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3,5-dichlorobenzoyl] indolizine acid hydrochloride

1-Bromo-2-phenyl-3- [4- (3-di-n-propylaminopropyl) oxy-3,5-dichlorobenzoyl] indoline zinc acid

1-Bromo-2-phenyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3,5-dichlorobenzoyl] indolizine acid hydrochloride

2-n-Butyl-3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dibromobenzoyl] indoline zine hydrochloride

2-Ethyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl] indolizine hydrochloride

2-n-Butyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-chlorobenzoyl] indolizine hydrochloride

1-Bromo-2-phenyl-3- [4- (3-dl-n-butylaminopropyl) -oxy-2-chlorobenzoyl] indolizine hydrochloride

1-Chloro-2- (4-chloro-phenyl) -3- [4- (3-di-n-propylaminopropyl) -oxy-benzoyl] -indolizine acid hydrochloride

1-Methoxy-2-phenyl-3- [4- (3-di-n-propylaminopropyl) -oxybenzoyl] indolizine acid hydrochloride

1-Methoxy-2-phenyl-3- [4- (3-di-n-butylaminopropyl) -oxybenzoyl] indolizine acid hydrochloride

1-Methoxy-2-phenyl-3- [4- (3-di-n-propylaminopropyl) oxy-3-chlorobenzoyl] indoline zinc acid

168-169 (methanol) 117 (ethyl acetate) (ethyl acetate)

172 (ethyl acetate)

Compound

1-Methoxy-2-phenyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-chlorobenzoyl] indolizine acid hydrochloride

1-Methoxy-2-phenyl-3- [4- (3-di-n-propylaminopropyl) -oxy-3-bromo-benzyl] -1-indole acid hydrochloride

1-Methoxy-2-phenyl-3- [4- (3-dl-n-butylaminopropyl) -oxy-3-bromobenzoyl] indoline zinc acid oxalate

1-Methoxy-2-phenyl-3- [4- (3-di-n-propylaminopropyl) -oxy-3-methoxybenzoyl] indolizine acid hydrochloride

1-Methoxy-2-phenyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-methoxybenzoyl] indoline zinc acid

1-Methoxy-2- (4-fluorophenyl) -3- [4- (3-di-n-propylaminopropyl) -oxy-3-methoxybenzoyl] indolizine acid hydrochloride

2-Methyl-3- [4- (3-dl-n-butylaminopropyl) -oxy-3-methoxybenzoyl] indole zinc acid hydrochloride

2-Methyl-3- [4- (3-di-n-propylaminopropyl) -oxy-3-methoxybenzoyl] indolizine acid glavelan '

2-Ethyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-methoxybenzoyl] indolizine acid hydrochloride

2-Ethyl-3- [4- (3-di-n-propylaminopropyl) oxy-3-methoxybenzoyl] indoline zinc acid

1-Bromo-2-methyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-methoxybenzoyl] indolizine acid hydrochloride

1-Bromo-2-methyl-3- [4- (3-di-n-propylaminopropyl) -oxy-3-methoxybenzoyl] indoline zinc oxalate

1-Bromo-2-ethyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-methoxybenzoyl] indolizine acid hydrochloride

T-Bromo-2-ethyl-3- [4- (3-di-n-propylaminopropyl) -oxy-3-methoxybenzoyl] indolizine acid hydrochloride

2- (4-Fluorophenyl) -3- [4- (3-di-n-butylaminopropyl) oxy-3-methoxybenzoyl] indoline zinc acid

2-Methyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-methylbenzoyl] indolizine acid hydrochloride

2-ethyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-methylbenzoyl] indoline zinc acid

1-Methyl-2-n-propyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-bromobenzoyl] indole zinc acid

2-Isopropyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-methylbenzyl] indoline oleaginic acid šlavelan

2-n-Butyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-methylbenzoyl] indolizine acid hydrochloride

1-Methyl-2-n-butyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3-bromobenzoyl) indolizine acid hydrochloride

1-Methyl-2-ethyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-bromobenzoyl] indoline zinc acid

1-Bromo-2-methyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3,5-dimethylbenzoyl] indolizine acid hydrochloride

1-Iodo-2-ethyl-3- [4- (3-di-n-butylaminopropyl) -oxy-3,5-dimethylbenzoyl] indolizine acid hydrochloride

2-Btyl-3- (2,3-di-chloro-4- (3-di-n-propylaminopropyl) oxybenzyl) indoline

2-Btyl-3- (2,3-dichloro-4- (3-di-n-butylaminopropyl) oxy-benzoyl) indolizine

2-Phenyl-3- (2,3-dichloro-4- (3-di-n-propylaminopropyl) oxybenzoyl / indoline)

2-Phenyl-3- (2,3-dichloro-4- (3-di-n-butylaminopropyl) oxybenzoyl) indolizine

Melting point! ° C)

120 (ethyl acetate) 160 (ethyl acetate) 78 (ethyl acetate)

148 (ethyl acetate) (ethyl acetate) (ethyl acetate)

159 (iopropanol)

171 (methanol) 88 (ethyl acetate)

121 to 122 (ethyl acetate) to 90 (benzene)

139 to 141 (isopropanol)

111 (benzene) 149 (isopropanol) (ethyl acetate) 149 (isopropanol)

133 (ethyl acetate)

127 (ethyl acetate) 91 (isopropanol) (isopropanol) (ethyl acetate)

117 (ethyl acetate) 120 to 122 (isopropanol)

115 (ethyl acetate) 117 (heptane) (heptane) (heptane) (heptane)

S 1 o u e n i n a Melting point (° C) 2- (4-Fluorophenyl) -3- (2,3-dichloro-4- (3-dl-n-propylaminopropyl) oxybenzoyl / indole zinc) 2- (4-Fluorophenyl) -3- (2,3-dichloro-4- (3-di-n-butylaminopropyl) oxybenzoyl) indoline 1-Bromo-2-ethyl-3- (2,3-dichloro-4- (3-di-n-butylaminopropyl) oxybenzoyl) indoline zinc acid Acid Slavelan 1-bromo-2-phenyl-3- (2,3-dichloro-4- (3-di-n-propylaminopropyl) oxybenzoyl) indoline zinc 1-Chloro-2-phenyl-3- / 2,3-dlchloro-4- (3-di-n-propylaminopropyl) - -oxybenzyl / indolizine 2-n-Butyl-3- [4- (3-dl-n-butylaminopropyl) oxy-3-iodobenzoyl] indolizine acid oxalate 119 (heptane) 95 to 96 (heptane) 164 (isopropanol) 171 (isopropanol) 136 (heptane) 90 to 92 (ethyl acetate)

Example 2

Soft gelatin capsules containing the following ingredients were prepared according to conventional pharmaceutical procedures:

Složkamg

2-n-Butyl-3- / 4- (3-dl-n-butylaminopropyl) -oxy-3-bromo or 3-chlorobenzoyl / indolezoline hydrochloride100

Starches99,5 colold silica0,5

200.0

Example 3

Injectable solutions containing the following ingredients have been prepared according to known pharmaceutical procedures:

Složkamg

2-n-Butyl-3- / 4- (3-dl-n-butylaminopropyl) oxy-3-bromo or 3-chlorobenzoyl / indolizine hydrochloride150 polysorbate 80150 benzyl alcohol75 water to 3 ml

Example#

Suppositories containing the following ingredients have been prepared according to known pharmaceutical procedures:

Ingredient mg

2-n-butyl-3- / 4- (3-di-n-butylaminopropyl) oxy-3-bromo or 3-chlorobenzoyl / indolizine hydrochloride 100 mixture of mono *** and saturated acid glycerides <(0 ₂ to (0θ) 1 400

500

Claims (11)

A process for the preparation of novel indolizino derivatives of the general formula I BEFORE THE INVENTION ^{/ R1} CA ^- ° - ^C H ^{₂₎ n N} ^ O ^R 1 and faroaceuticky sooi acceptable addition with acids, wherein R 1 ^X A is a branched or linear alkyl group having 1 to 8 carbon atoms, or a phenyl group, a fluorophenyl group, a monophenyl group, a fluorophenyl group, a fluorophenyl group, a fluorophenyl group, a fluorophenyl group, a fluorophenyl group or a fluorophenyl group; , hydrogen, chloro, bromo, iodo, wherein x ₂ ^X 3 Ri n is substituted is substituted on the aromatic ring by a methyl or MMO group, chlorine, bromine, bromine, chlorine, hydrogen, hydrogen, ethyl, ethyl integers from 2 to 6 including methyl or hydroxy, iodine, iodine or iodine; methyl, n-pmyl or n-butyl that if and Xj is not hydrogen or m is methyl, then X1 | z is a group other than hydrogen, characterized in that the bromoaconybenzoylindolizine of the formula II is condensed X. R C ~ AO (CH ₂₎ n Br O Xp wherein R and AN mm had previously defined in ^intг, noh-solvent with a secondary amine of the formula III H-N (III) wherein R 1 is as defined above, and the product obtained is optionally reacted with a pharmaceutically acceptable inorganic or organic acid. 2. A process according to claim 1 wherein the solvent is benzene or toluene. Third USO ^Zp ^ ^b according to claim ^{1 p} ro ^p s ^p rave 1τbrnm- ^- l- --ot ^{t -} - [4- / 3-di-n-butyl and ^{i j p} noprn yl / ^NXY-3-on broobeenoy yin ⁿ for ^{n lzint,} important ^t Io ^letting REA-1-vat brnno ^- -шotyl "3- [4- / 3-bbOjprnpyl / oxy-3-bnoobtnzoyl indooizin with di-n-buyy amm ^ N-NEM. 4. A process according to claim 1 for the preparation of 2-n-butyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-bromobenzoyl] indolizine, characterized in that 2-n-butyl-3- [ 4- (3-bromopropyl) oxy-3-bromobenzoyl] indolizine with di-n-butylamine. A process according to item 1 for the preparation of 2-ethyl-3- [4- / 3- (31-n-butylaminopropyl) oxy-3-chlorobenzoyl] indolizine, characterized in that 2-ethyl-3- [4- / 3-bromopropyl / oxy-3-chlorobenzoylindolezine with di-n-butylamine. 6. A process according to claim 1 for the preparation of 2-n-butyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl] indolizine, characterized by reacting 2-n-butyl-3- [ 4- (3-bromopropyl) oxy-3-chlorobenzoyl] indolizine with dl-n-butylamine. 7. A process according to claim 1 for the preparation of 2-isopropyl-3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dichlorobenzoyl] indolizine, characterized in that 2-isopropyl-3 is reacted. - [4- (3-bromopropyl) oxy-3,5-dichlorobenzoyl] indolizine with di-n-butylamine. 6. A process according to item 1 for the preparation of 2-phenyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl] indoline, which comprises reacting 2-phenyl-3- [ 4- (3-bromopropyl) oxy-3-chlorobenzoyl] indolizine 8 with di-n-butylamine. 9. A process according to claim 1 for the preparation of 2-ethyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl] indolizine, characterized by reacting 2-ethyl-3- [4- (3-bromopropyl) oxy-3-chlorobenzoyl] indolizine with dl-m-butylamine. 10. A process according to claim 1 for the preparation of 1-chloro-2-n-butyl-3- [4- (3-i-n-butylaminopropyl / oxybenzoyl) indolizine, characterized in that 1-chloro-2 is reacted. n-butyl-3- [4- (3-bromopropyl) oxybenzoyl] indolizine with di-n-butylamine. 11. A process according to claim 1 for the preparation of 1-bromo-2- (4-chlorophenyl) -3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl] indolizine, characterized in that it is reacted 1-Bromo-2- [4-chlorophenyl-3- [4- (2-bromopropyl) oxy-3-chlorobenzoyl] indolizine with di-n-butylamine.