DD153839A5 - PROCESS FOR PREPARING 4,5 DIALKYL-3-HYDROXY-PYRROL-2-CARBOXYLIC ACID ESTERS - Google Patents

Abstract

The invention relates to substituted piperidine alkyl ethers of 4,5-dialkyl-3-hydroxy-2-pyrrole-2-carboxylic acid esters and their physiologically acceptable acid addition salts, to processes for their preparation and to pharmaceutical compositions containing them which can be used in the treatment of cardiac arrhythmias.

Description

"Piperidine derivatives of 4,5-dialkyl-3-hydroxy-pyrrole-2-carboxylic acid esters and process for their preparation

Field of application of the invention

The invention relates to substituted piperidine alkyl ethers of 4,5-dialkyl-3-hydroxy-2-pyrrole-2-carboxylic acid esters and their physiologically acceptable acid addition salts, to processes for their preparation and to pharmaceutical compositions containing them which can be used in the treatment of cardiac arrhythmias.

10 Characteristic of the known solutions

In DE-OS 26 30 152, for example, derivatives of 1-phenoxy-2-propanol are described with a 4- (2-pyridyl) -piperidin-4-ol radical with antiarrhythmic properties. It is known to the person skilled in the art that the agents used hitherto for combating cardiac arrhythmias are not always satisfactory and these often have too narrow a therapeutic breadth

The aim of the invention object of the invention is the provision that can be used as drugs because of their pharmacological effects of new Verbindun-S ^s "Principle of the invention It has been found that compounds of general formula I

^ I: ^v

R ^ H COOR

ο η n ^: r \ 3 -tu ο η v; j.

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In which R and R are the same or different and are an alkyl radical having 1 to 4 C atoms, an aralkyl radical having 7

1 2

to 9 carbon atoms or R and R together with the two C atoms connecting them form a 6-membered ring with 4 methylene groups and

R is an alkyl radical having 1 to 6 C atoms, R and R are a hydrogen atom or a hydroxyl group and

R is a 6-membered hetaryl or aryl radical, optionally substituted 1 to 2 times by halogen atoms or simply by the trifluoromethyl radical, where m and η are integers from 1 to 5 and the sum of m + η β

4 and when R is a hydrogen atom, additionally m or η can also denote 0, and their physiologically tolerated acid addition salts have valuable pharmacological properties.

1 2 Alkyl and aralkyl radicals for R and R are, for example

Methyl, ethyl, propyl, butyl or benzyl.

1 2 When R and R together with the two C atoms form a ring, it is a 4,5,6,7-tetrahydroindole system.

For example, methyl, ethyl, propyl, i-propyl, butyl, pentyl or hexyl are suitable.

Suitable hetaryl and aryl radicals for R are pyridyl, in particular o-6-pyridyl or phenyl. Examples of radicals which are substituted by halogen atoms, in particular by fluorine, chlorine or bromine atoms, or the CF, radical are, for example, 4-fluoro, 4-chloro, 3-fluoro, 3-chloro or 3-chloro radicals. trifluoromethyl.

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As piperidinoalkyl radicals with which the 3-hydroxy-pyrrole is etherified, there are 3-piperidino-2-hydroxypropoxy radicals, 4-piperidino-butoxy radicals, 2-piperidino-ethoxy radicals or 3-piperidino-propoxy radicals, ie that m and η signify 1 or m 1 and η 2, and, if R represents a hydrogen atom, additionally m 1 and η 0. Particular preference is given to compounds of the formula I in which R is an alkyl radical having 1 to 4 C atoms, in particular methyl, R 1 is methyl, R 1 is methyl or ethyl, R is a hydrogen atom or a hydroxyl group, R is a hydroxyl group and R 6 is pyridyl or a Phenyl ring which is optionally substituted by a fluorine, chlorine or bromine atom, where m and η are 1 or 2 or when R is an Η-atom, additionally m 1 and η are 0, and their physiologically

15. acid addition salts.

Within this group, the compounds in which m is 1 and η is 1 or 2 and when R is an H atom, m 1 and η are 0 are to be emphasized.

Accordingly, compounds of the invention are

of general formula I, for example:

3- [2-Hydroxy-3- (4-phenyl-4-hydroxy-piperidino) -propoxy] - - ^, S-dimethylpyrrole ^ -carboxylic acid ethyl ester

3- [2-hydroxy-3- (4-phenyl- ⁱ J-hydroxy-piperidino) -propoxy] - '-4,5-dimethylpyrrο1-2-carboxylic acids ^ methyl ester 3- [2-hydroxy-3- (4- phenyl- ⁱ l-hydroxy-piperidino) -propoxy] - -4,5 ~ dimethylpyrrole-2-carboxylate 3- [2-hydroxy-3- (4-phenyl-4-hydroxy-piperidino) -propoxy] - ^ -butyl -S-methylpyrrole ^ -carboxylic acid ethyl ester 3- [2-Hydroxy-3- (4-phenyl-4-hydroxy-piperidino) -propoxy] - ^ -ethyl-S-methylpyrrole ^ -carboxylic acid ethyl ester 3- [2-hydroxy-3- (4-phenyl-4-hydroxy-piperidino) -propoxy] - - 4'-ethyl-5-never thypyrrol-2-car bonic acid he read

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3-C 2-Hydroxy-3- (4-phenyl-4-hydroxy-piperidino) -propoxy] -benzyl-S-methylpyrrole-1-carboxylate 3- [2-hydroxy-3- (4- (p-) chlorophenyl) -4-hydroxy-piperidino) -propoxy] -i |, 5-dimethylpyrrole-2-carboxylic acid methyl ester 3 ~ C2-hydroxy-3- (4- (p-chlorophenyl) -4-hydroxy-piperidino) - propoxy ] -4.5 "dimethylpyrrole-2-carboxylic acid ethyl ester 3- [2-hydroxy-3- (4- (p-fluorophenyl) -4-hydroxy-piperidino) -propoxy] -4, S-dimethylpyrrole-1-carboxylic acid methyl ester 3- C2-hydroxy-3- (4- (p-fluorpheny1) -4-hydroxy-piperidino) -

10 -propoxy] - ^ _J 5-dimethylpyΓΓOl-2-caΓsääΓeäthylesteΓ

Methyl 3- [2-hydroxy-3- (4- (m-trifluorophenyl) -4-hydroxy-piperidino) -propoxy] -4,5-dimethylpyrrole-2-carboxylate 3- [2-hydroxy-3- (4- m-trif luorpheny 1) - ⁱ i -hydroxy-piperidino) -propoxy] -4,5-diraethylpyrrole-2-carboxylic acid ethyl ester

β 3 * "C2-Hydroxy-3- (4-phenyl-piperidino) -propoxy] -4,5-dimethylpyrrole-2-carboxylic acid methyl ester 3- [2-hydroxy-3- (4-phenyl-piperidino) -propoxy] - Ethyl 4,5-dimethylpyrrole-2-carboxylate 3- [2-hydroxy-3- (4-phenyl-piperidino) -propoxy] -4-ethyl-

20 -5-π-ethyl-pyΓΓol-2-caΓsääΓeäthylesteΓ

3-C 2 -hydroxy-3- (4-phenyl-4-hydroxy-piperidino) -propoxy] - ¹ -i5-6,7-tetrahydro-2-indole-carboxylic acid methyl ester 3-C 2-hydroxy-3- ( Ethyl 4-phenyl-4-hydroxy-piperidino) -propoxy] - - - - - - - - - »1-yl-5-yl-2-indole-carboxylate 3- [2-hydroxy-3 - (^ -phenyl- ¹ -hydroxy-piperidino) - propoxy] - "" ^ i5 "6 _i 7-tetrahydro-2-indole-carboxylic acid butyl ester - 3 ~ [2-hydroxy-3- (4- (m-trifluorophenyl) -4-hydroxypiperidino) -propoxy] -4,5 _} 6,7-tetrahydro-2-indole-carboxylic acid ethyl ester 3- [2-hydroxy-3- (4- (p-fluorophenyl) -4-hydroxy-piperidino) - propoxy] -4 ₃ 5 »6,7-tetrahydro 2-indole-carboxylic acid aryl ester 3- [2-Hydroxy-3- (4- (p-chlorophenyl) -4-hydroxy-piperidino) -propoxy] -4,5> 6,7-tetrahydro-2-indole-carboxylic acid ethyl ester 3- [2-phenyl-4-hydroxy-piperidino) -ethoxy] -4,5-dimethylpyrrole-2-carbonsäuremethylester

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^ 3-C 2- (4-phenyl-4-hydroxy-piperidino) ethoxy] -4,5-dimethyl

pyrrol-2-earbonsäureäthylester

3-C2-Hydroxy-3- (4 - ^ - pyridyl-4-hydroxy-piperidino) -propoxy] - - ⁱ l, 5 "dimethylpyrrole-2-carboxylate 3-C3- (4-c-4-hydroxy fpyridyl * piperidino) -propoxy] -4,5-dimethyl

thylpyrrol-2-carboxylic acid ethyl ester

3- [3 ~ (4-pyridyl-1, 4-hydroxy-piperidino) -propoxy] -4,5-dime

thy pyrrole-2-carbonsäuremethylester!

3- [2-Hydroxy-3- (4-o-pyridyl-4-hydroxy-piperidino) -propoxy] -KJ ^ -ethyl-S-methylpyrrole-3-carboxylic acid methyl ester 3- [2-hydroxy-3- (4- o6-pyridyl-4-hydroxy-piperidino) -propoxy] -

-4-ethyl-5-πlethylpyrrol-2-carboxylate

3- [2- (4-phenyl-4-hydroxy-piperidino) -ethoxy] -4,5-dimethylpyrrole-2-carboxylic acid butyl ester 3-C2- (4-phenyl-piperidino) -ethoxy] -4,5-dimethylpyrrole 2

-carbonsäureäthylester

3- [3 ~ (4-Phenyl-4-hydroxy-piperidino) -propoxy] -4,5-dimethyl-

pyrrol-2-carbonsäuremethylester

3- [3 ~ (4-hydroxy-Pheny1-4-piperidino) -propoxy] -4,5-dimethylpyrrole-2-carboxylate

3- [3 ~ (4-Phenyl-4-hydroxy-piperidino) -propoxy] -4,5-dimethyl-

pyrrole-2-carboxylic acid propyl ester

3- [3- (4-phenyl-4-hydroxy-piperidino) -propoxy] -4,5-dimethylpyrrole-2-carboxylic acid butyl ester 3-C4- (4-phenyl-4-hydroxy-piperidino) -butoxy] -4, 5-dimethyl

pyrrol-2-carbonsäuremethylester

3-C 4- (4-phenyl-4-hydroxy-piperidino) -butoxy] -4,5-dimethy1-

pyrrole-2-carboxylic acid ethyl ester

3-C4- (4-phenyl-4-hydroxy-piperidino) -butoxy] -4,5-dimethylpyrrole-2-carboxylate

3-C3- (4-phenylpiperidino) -propoxy] -4 _J 5-dimethylpyrrole-2

-carbonsäureäthylester

3-C4- (4-phenyl-piperidino) butoxy] -4,5-dimethylpyrrole-2-

-carboxylic acid ethyl ester 35

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* 3-C 5- (4-phenyl-4-hydroxy-piperidino) pentoxy] -4,5-dimethyl

pyrrole-2-carboxylic acid ethyl ester

Methyl 3- [5- (4-phenyl-4-hydroxy-piperidino) -pentoxy] -4,5-dimethylpyrrole-2-carboxylate 3- [3- (4-C-pyridyl-4-hydroxy-piperidino) -propoxy ] -4-butyl

• ^ methyl-pyrrole ^ -carbonsäureäthylester

3- [2- (4-phenyl-l ^{i-hydroxy-piperidino)} -ethoxy] -4-butyl-5-

~ Methyl-pyrrol-2-carbonsäuremethylester

Ethyl 3- [2- (4-phenyl-4-hydroxy-piperidino) ethoxy] - ⁱ -butyl-5-K) -methyl-pyrrole-2-carboxylate 3-C 2- (Ί- (p-fluorophenyl) -il-hydroxy-piperidino) -ethoxy] -4,5-

-dimethyl-pyrrol-2-carbonsäuremethylester

Ethyl 3- [2- (4- (p-fluorophenyl) -4-hydroxy-piperidino) ethoxy] -4,5'-dimethyl-pyrrole-2-carboxylate 3-C2- (4- (p-pluorophenyl) -4 hydroxy-piperidino) -ethoxy] -4-

he-butyl-5-never thy! -pyrrol-2-carboxylic acid methyl he reads

3- [2- (4- (p-fluorophenyl) -4-hydroxy-piperidino) -ethoxy] -4-

-butyl-5-Inethyl-pyrrole-2-carboxylic acid ethyl ester

3 "C 2-hydroxy-3- (4- <X / -pyridyl-4-hydroxy-piperidino) -propoxy] -4-butyl-5-ethyl-pyrrole-2-carboxylic acid ethyl ester 3- [2-hydroxy- 3- (4-o6-pyridyl-4-hydroxy-piperidino) -propoxy] -

-4-butyl-5-π ^ ethyl-pyrrol-2-carbonsäuremethylester

3- [2- (4-O-pyridyl-1-4-hydroxy-piperidino) -ethoxy] -4,5-dimethyl-pyrrole-2-carboxylic acid ethyl ester 3- [2- (4-o-i-pyridyl-4- hydroxy-piperidino) -ethoxy] -4 _J 5-dime

thyl-pyrrole-2-carboxylic acid ethyl ester

3- [2- (4-O-Pyridy) 1-4-hydroxy-piperidino) -ethoxy] -4-butyl-5 '

-methyl-pyrrol-2-carbonsäuremethylester

Ethyl 3-C 2- (4-o6-pyridyl-1-4-hydroxy-piperidino) -ethoxy] -4-butoxy 1-5-methyl-pyrrole-2-carboxylate 3- [3- (4-o-pyridyl- 4-hydroxy-piperidino) -propoxy] -4-butyne-1

-5-methyl-pyrrol-2-carbonsäuremethylester

3- [4- (4-o (-pyridyl 1-4-hydroxy-piperidino) -butoxy] -4,5-dime

methyl 2-methyl-3-methylpyrrole-2-carboxylate.

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3-C 4- (4-O-Pyridyl-4-hydroxy-piperidino) -butoxy] -4-butyl-5-methyl-pyrrole-carboxylic acid methyl ester 3-C4-O-pyridyl-1-hydroxy-piperidino ) -butoxy] -4,5-dimethylpyrrole-2-carboxylic acid ethyl ester 3- [4- (4-O6-pyridine-4-hydroxy-piperidino) -butoxy] -4-butyl-1-5-methyl-pyrrole 2-Carboxylate ethyl ester 3- [4- (4- (p-fluorophenyl) -4-hydroxy-piperidino) -butoxy] -4,5-dimethyl-pyrrole-2-carboxylic acid methyl ester 3-C4- (4- (p-) Pluorphenyl) -4-hydroxy-piperidino) butoxy] -

10 ^ -butyl-S-methyl-pyrrole ^ -carboxylic acid ethyl ester

Ethyl 3- [4- (p-Pluorophenyl) -4-hydroxy-piperidino) -butoxy] -4,5-dimethyl-pyrrole-2-carboxylate

The compounds according to the invention are prepared by reacting a carboalkoxypyrrole of the formula II

R ¹ 0-CH ₀ -A

20 RJJ COOR ^

1 2 3

in which R, R and R have the meanings given for formula I and A is the radical

25 ^ 0 _χ OH

-CH - CH ₀ -CH-CH ₀ -B or - (CH ₀ ), - B,

where B is a nucleofugic leaving group and 1 is an integer from 1 to 6, means with a piperidine derivative of general formula III

- - OC

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in which R urid R have the meanings given for the formula I, expediently in a solvent and optionally in the presence of an acid-binding agent in a conventional manner and converting the resulting compound optionally in the acid addition salt of a physiologically acceptable acid.

The leaving group B preferably represents a halogen atom, in particular chlorine, bromine or iodine. Further suitable, for example, as nucleofuge leaving groups are aromatic or aliphatic sulfonic acid residues, such as p-toluenesulfonic acid, p-bromobenzenesulfonic acid or methanesulfonic acid.

The reactions are carried out at temperatures of 10 to 12O ⁰ C, ie at room temperatures or at higher temperatures, suitably at temperatures of 50 to 120 ⁰ C. The reactions can be carried out under atmospheric pressure or in a closed vessel under elevated pressure, if appropriate while heating to the specified temperature range.

The starting compounds can be directly, i. be implemented without addition of a diluent or solvent. Conveniently, however, the reactions are in the presence of an inert diluent or solvent, for example a lower alcohol having 1 to 4 carbon atoms, such as methanol, ethanol or propanol, preferably isopropanol or ethanol, a lower saturated dialkyl ether, Dialkylglykolathers or cyclic Ether, such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, an aromatic hydrocarbon, such as benzene or an alkylbenzene, such as toluene or xylene, or a saturated aliphatic hydrocarbon, such as

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ι * ^v hexane, heptane or octane, a lower aliphatic ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, a dialkylforraamide, such as dimethyl or diethylformamide, or of dimethyl sulfoxide or in the presence of water or in mixtures of said solvents performed.

Preferred solvents in the reaction of an epoxide of formula (II), for example, 1- (2-carbomethoxy-4,5-dimethyl-pyrrol-3-oxy) -2,3-epoxypropane; l- (2-carboethoxy-4,5-dimethyl-pyrrol-3-oxy) -2,3-epoxypropane; 1- (2-carbatoethoxy-4,5,6,7-tetrahydro-indole-3-oxy) -2,3-epoxypropane; 1- (2-Carboethoxy-5-methyl-4-n-butyl-pyrrol-3 -oxy) -2,3-epoxypropane with a piperidine derivative of the general formula (III) are lower alcohols, in particular isopropanol, the reaction being preferred at temperatures.

doors from 50 to 120 C and carried out at atmospheric pressure

For nucleophilic substitutions of a radical B in a compound of the formula (II) with a radical - (CHp) -IB, for example of 1- (2-carboethoxy-4,5-dimethyl-pyrrole-3-oxy) -3-chloro -propane; 1- (2-carbomethoxy-4,5-dimethyl-pyrrol-3-oxy) -4-chloro-butane or 1- (2-carboethoxy- "4" 5,6,7-tetrahydro-2-indole-3 -oxy) -3-chloropropane, are as solvents a lower aliphatic ketone, such as acetone, diethyl ketone, methyl isopropyl ketone or methyl isobutyl ketone, a cyclic saturated ether, especially tetrahydrofuran or dioxane, or a dialkylformamide, such as dimethylformamide, and temperatures of 90 to l80 If desired, the reaction is carried out in the presence of a catalytic amount of sodium or potassium iodide.

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** It should be mentioned that the starting compound of the formula II ^Ί optionally also a mixture of the epoxide with a halohydrin into consideration, since in the industrial preparation of the starting compounds of the formula II such mixtures may possibly arise.

In an expedient embodiment for the nucleophilic substitution of the radical B by the piperidine derivative used, the reaction in the presence of a base as

KJ acid-binding agent performed. Preferred bases

are alkali metal hydroxides, carbonates, bicarbonates, alcoholates or a tertiary organic amine such as pyridine or a trialkylamine, such as .Trimethylamin or triethylamine. Come from the alkali compounds

in particular those of sodium or potassium. The base is used in stoichiometric amount or in slight excess. If appropriate, it is expedient for the piperidine derivative (III) used for the reaction to be present in excess at the same time as an acidic

20-binding agent to use.

The complete reaction depends on the reaction temperature and is generally completed within 2 to 15 hours. The reaction product may be recovered in a conventional manner, for example by filtration or by distillation of the diluent or solvent from the reaction mixture. Purification of the compound obtained is carried out in a conventional manner, for example by recrystallization from a solvent

3Q an acid addition compound or by column chromatography.

The starting compounds of formula (II) can be prepared by alkylation of the underlying -pyrrolverbindung of compound 3-hydroxy, for example, ^{von-3-hydroxy-i} J, 5-di-

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'methyl-2-pyrrolcarbonsäureäthylester, 4-butyl-3-hydroxy -5 "inethyl-2-hydroxy ~ 3 pyrrolcarbonsäureäthylester or" ^1} J5 _"6) 7-tetrahydro-2-indolcarbonsäureäthylester with an epihalohydrin, a" i, ^ Dihalo-2-propanol or ο /, ω-dihalopropane. The epihalohydrins used are epichlorohydrin, epibromohydrin and epiiodohydrin, and in particular l, 3-dichloro-2-propanol and 1,3-dibromo-2-propanol and c, W-dihalopropanes are c,?, - dihalo-2-propanols in particular 1,3-chlorobromopropane; 1,3-dichloropropane, 1,3-dibromopropane, 1,2-Chlorbromäthan or 1,4-chlorobromobutane into consideration.

The production of the required hydroxypyrrole-carboxylic acid esters can be taken from Liebigs Annalen der Chemie 1976, pages 384 to 386, or can, for example, methyl 3-hydroxy-4,5-dimethyl-2-pyrrolecarboxylate, analogous to that described in US Pat Liebigs Annalen der Chemie, Vol. 736, pages 1 to 15 (1970).

The alkylation of 2-Carbolkoxy-3 ~ hydroxy-pyrroles for the preparation of the starting compounds of formula (II) are advantageously carried out at temperatures of 50 to 120 ⁰ C and under atmospheric pressure or in a closed vessel under elevated pressure. The reactions are conveniently carried out in an inert diluent or solvent, for example a lower aliphatic ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, a lower alcohol having 1 to 4 carbon atoms, such as methanol, ethanol, propanol or butanol, a lower alkyl acetate, such as Methyl, ethyl or propyl acetate, a dialkylformamide, such as dimethylformamide or diethylformamide, or dimethyl sulfoxide or with excess alkylating agent as a diluent or solvent.

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The bases preferably used are alkali metal carbonates, bicarbonates, hydroxides or alcoholates, in particular of sodium and potassium, basic oxides, such as aluminum oxide or calcium oxide, organic tertiary bases, such as pyridine or lower Trialkylamines, such as trimethyl- or triethylamine, where the bases can be used in a catalytic amount or in a stoichiometric amount or in a slight excess in relation to the alkylating agent used.

Preference is given to the 2-carboalkoxy-3-hydroxy-pyrroles with epibromohydrin; l, 3 ~ dibromopropanol-2; 1,3-dibromopropane;

15 1,4-bromochlorobutane or 1,2-Bromchloräthan in one

lower aliphatic ketone, in particular acetone or methyl isobutyl ketone, in the presence of at least one molar equivalent of base, in particular potassium carbonate, based on the alkylating agent, at temperatures of 50 to

20 80 ⁰ C implemented.

It should also be noted that the starting compounds of the formula (II) having an epoxy group or a halohydrin structure can be converted into each other by a simple acid-base reaction. Thus, an l- (2-Carboäthoxy-4,5-dimethyl-pyrrol-3-oxy) -2,3-epoxypropane with the corresponding hydrohalic acid in l- (2-Carboäthoxy- - ¹ l, 5-dimethylpyrrole-3 -oxy) -3-halogen-propanol-2, wherein as diluent or solvent in addition to conventional solvents used preferably an aliphatic or cyclic ether, such as diethyl ether, tetrahydrofuran or dioxane, or a lower alcohol, such as methanol, ethanol or propanol become. On the other hand, the 1- (2-carboethoxy-4,5-dimethyl-pyrrol-3-oxy) -3-halo-2-propanol-2-compounds, especially the 1- (2-

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-Carboäthoxy-4,5-dimethyl-pyrrole-3-oxy) -3-chloro-propanol-2 and the l- ^(2-i Carboäthoxy- 4,5-dimethy pyrrole-3-oxy) - -3 ~ bromo-propanol-2 with a base such as an alkali metal hydroxide, carbonate, bicarbonate, alcoholate or hydride, a tertiary organic amine such as pyridine, piperidine or a tertiary aliphatic amine such as trimethylamine or triethylamine, into l- (2-carboethoxy-4,5-dimethyl-pyrrol-3-oxy) -2,3-epoxypropane.

These reactions can be carried out at room temperatures or accelerated or completed by heat, for example by heating to 60 to 120 ⁰ C, or completed.

The reaction may be carried out under atmospheric pressure or in a closed vessel under elevated pressure, optionally with simultaneous heating. The starting materials for this conversion can be isolated in advance or generated in the reaction mixture and immediately further processed without further isolation and purification.

The compounds of the formula I according to the invention which carry a hydroxy group in the aliphatic side chain have a chiral center and are obtained as racemates prepared by known methods, for example by forming diastereomeric salts with optically active auxiliary acids, such as dibenzoyltartaric acid, camphor-10-sulphonic acid , Ditholuylweinsäure or 3 "* bromine-camphor-8-sulfonic acid are separated into the optically active antipodes

30 can.

The resulting compounds according to the invention are optionally converted by known procedure into the acid addition salt of a physiologically acceptable acid. As usual physiologically acceptable orga-

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Examples of suitable inorganic or inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid and, as organic acids, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid or benzoic acid 224 to 225 »Birkhäuser-Verlag, Basel and Stuttgart, 1966 or the Journal of Pharmaceutical Science, Volume K) 66, pages 1 to 5 (1977).

The compounds of the invention and their physiologically acceptable acid addition salts have valuable pharmacological properties. They have a strong antiarrhythmic activity and are therefore particularly suitable for the pharmacotherapy of cardiac arrhythmias.

To determine the antiarrhythmic activity, the substances rats (strain: Sprague Dawley, weight 200 to 250 g) administered orally 45 minutes before the start of anesthesia.

The animals are anaesthetized with thiobutabarbital sodium (100 mg / kg intraperitoneally, i.p.). The arrhythmogenic substance is Aconitin, which is infused intravenously (i.v.) 60 min after substance administration (dosing rate: 0.005 mg / kg χ min). In non-treated animals (N = 52), electrocardiogram (ECG) arrhythmias occur after 2.74 '+ 0.07 min, and their onset by antiarrhythmics can be dose-dependently delayed.

From the linear relationship between log dose (mg / kg) of the test substance and the relative elongation of the Aconitin-35

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Infusion duration ( %) , the dose is determined, which prolongs the duration of infusion by 50 % (ED 50 %).

To further characterize the substances, the antiarrhythmic effect becomes the decimal geometric dose sequence used in the experiments (Paktor ± -. / Rr)

'10 ·

the maximum tolerated dose. It also determines the dose at which toxic symptoms (changes in baseline ECG, cyanosis, convulsions) occur. As a reference substance is the well-known high-potency antiarrhythmic drug Prajmalium (N-Propylajmalin).

Table 1 shows that the compounds tested are either antiarrhythmic in their rat aconitin arrhythmia or superior to Prajmalium (Examples 2, 11, 13) (Examples 6, 10 and 19). Another advantage is the higher dose compared to Prajmalium in the administration of the highest tolerated dose. Prajmalium prolongs the Aconitininfusionsdauer by a maximum of 174 %. Examples 1, 10, 11 and 19 cause a maximum increase of 324, 347, 308 and 302 t.

The toxic doses of the substances according to the invention are higher, with the exception of the equally toxic example 6. than that of Prajmalium. The increase in tolerability with comparatively corresponding or higher antiarrhythmic activity has in the compounds according to the invention an increase in the therapeutic range - as a quotient of the toxic and the antiarrhythmic effective dose (ED 50 %) - result.

In Prajmalium, toxic symptoms have already occurred when 4.3 times the effective dose is administered. In contrast, the toxic doses in the subject invention are

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punch 5.8 (Example 6) to 1β times (Example 10) greater than the effective.

«A * cn

ul

ro

Table 1

Antiarrhythmic effect and toxicity in the rat. Appl .: per os

Substance example

10 11 13 19 21 Prajmalium

Antiarrhythmic effect on aconitine arrhythmia Effective dose mg / kg Maximum effect ED 50

R.W.

2)

Dose Δ %

4)

R.M.W.

7,80 6,23 3,68 13,5 2,99 5,54

5.93 3.38 9.85 4.99

0.64 46.4 324 0.80 21.5 170 1.36 10 152 0.37 46.4 307 1.67 21.5 347 0.90 21.5 308 0.84 21.5 149 1.48 21.5 302 0.51 46.4 173 1.00 10 174

1.86 0.98 0.87 1.76 1.99 1.77 0.86 1.74 0.99 1.00

Toxicity 6)

dose

100 46.4 21.5

100 46.4 46.4 46.4 46.4

100 21.5

7)

18 7.5 5.8 7.4

16 8.4 7.8

14

10

Dose that increases the duration of aconitine infusion by 50 % RW = Relative Efficacy. Prajmalium = 1,00 Effect of maximum tolerated dose Extension of aconitine infusion time Δ % RMW = Relative maximum effect. Prajmalium = 1.00

Dose, according to whose appl. the first toxic symptoms are observed Toxic dose

Q =

ED 50 %

O O VJl

O co

VO

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Accordingly, the present invention also relates to therapeutic agents or preparations which contain, in addition to customary carriers and diluents, a compound of the formula I or its physiologically tolerated acid addition salt as active ingredient, and to the use of the novel compounds in the pharmacotherapy of cardiac arrhythmias.

The new compounds can be applied in the usual galenic K3 application forms, solid or liquid, such as tablets, capsules, powders, granules, dragees or solutions. These are produced in the usual way. ^N The active ingredients may be with the usual galenic adjuvants such as talc, gum arabic, sucrose, lactose, corn or corn starch, potato flour, magnesium stearate, alginates, gum tragacanth, Carraghenate, polyvinyl alcohol, polyvinylpyrrolidone, aqueous or non-aqueous vehicles, wetting agents, dispersants , Emulsifiers and / or preservatives (see LG Goodman, A. Gilman, The Pharmacological Basis of Therapeutics). The preparations thus obtained normally contain the active substance in an amount of 0.001 and 99% by weight.

The preferred formulations consist of a dosage form which is suitable for oral administration. Such administration forms are, for example, tablets, film-coated tablets, dragees, capsules, pills, powders, solutions, suspensions or depot forms. There are also parenteral preparations, such as Inkektionslösungen, into consideration. Further examples of preparations which may be mentioned are suppositories.

4 842 -

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Corresponding tablets may be prepared, for example, by mixing the active ingredient with known excipients, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, calcium carbonate, calcium phosphate or lactose, disintegrants such as corn, starch or alginic acid, binders such as starch or gelatin, lubricants such as Magnesium stearate or talc and / or means for achieving the depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate, are obtained. The tablets can also consist of several layers.

Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. In this case, the dragee wrapper may consist of several layers, using the excipients mentioned above in the tablets

20 can be.

Solutions or suspensions containing the active compounds according to the invention may additionally contain taste-improving agents, such as vanillin or orange extract. They may also contain suspending agents, sodium carboxymethylcellulose, or preservatives, such as p-hydroxybenzoates. Active ingredients containing capsules can be prepared, for example, by mixing the active ingredient with an inert carrier such as lactose or sorbitol and encapsulated in gelatin capsules. Suitable suppositories can be prepared, for example, by mixing with appropriate carriers, such as neutral fats or polyethylene glycol or derivatives thereof.

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The dosage of the compounds according to the invention depends on the age, condition and weight of the patient as well as on the mode of administration. In general, the daily dose of active ingredient is 5 to 100, preferably 10 to 80 mg. 5

The present invention will be explained in more detail by the following embodiments.

Exemplary embodiments KJ I. Preparation of starting compounds

Example I 3-Hydroxy-4,5,6,7-tetrahydro-2-indolecarboxylic acid ethyl ester

To a well-stirred solution of 35 g of sodium in 1.5 liters of ethanol is added dropwise under nitrogen 294 g of 2- (ethoxy- carbonylmethylamino) -l-cyclohexencarbonsäureäthylester in 400 ml of ethanol. After boiling for three hours is added to the cooled solution first 600 ml of water, then 150 ml of concentrated hydrochloric acid. After standing for six hours at -10 ⁰ C 142 g of 3-hydroxy-4,5,6,7-tetrahydro-2-indolcarbonsäureäthylester of mp. 94 to 95 ° C are filtered off with suction. C ₁₁ H ₁₅ NO ₃ (209.2)

 Calc .: 63.2 C 7.2 H 6.7 N

25 Gef .: 63.3 C 7.4 H 6.8 N

Example II 3-Hydroxy-4,5-dimethyl-2-pyrrolecarboxylic acid ethyl ester

According to Example 1, from 35 g of sodium in 1.5 liters of ethanol and 264 g of ethyl 3- (ethoxycarbonylmethylamino) -2-methylcrotonsäure in 400 ml of ethanol 165 g of 3-hydroxy-4,5-dimethyl-2-pyrrolcarbonsäureäthylester of mp 111 to 113 ⁰ C received.

35 · C ₉ H ₁₃ NO ₃ (183.1)

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^r .: 59.0 C 7.1 H 7.7 N vessel: 59.2 C 7.2 H 7.5 N

Example III Methyl 3-hydroxy-4,5-dimethyl-2-pyrrolecarboxylate

According to Example 1, from 5.7 g of sodium in 250 ml of methanol and 40 g of methyl 3- (methoxycarbonylmethylamino) -2-methylcrotonic acid in 90 ml of methanol, 28.1 g of 3 "hydroxy ^, l, 5-dimethyl-2-pyrrolcarbonsäuremethylester obtained from mp. 170 to 172 ° C.

C ₈ H ₁₁ NO ₃ (169, D 6 , 6 H 8th 3 N Calc .: 56.8 C 6 , 6 H 8th , 4 N Gef .: 57.3 C example IV

3- (methoxycarbonylmethylamino) -2-methylcrotonsäuremethylester

To a well-stirred suspension of 50 g Glycinmethylesterhydrochlorid in 20 ml of methanol, 72 g of a 30% sodium methylate solution in methanol are added and after 15 minutes 58 g of 2-Methylacetessigsäureäthylester. Subsequently, it is heated to reflux temperature for 8 hours.

The cooled to room temperature, the reaction mixture is diluted with 400 ml of ether and shaken twice with 300 ml of water. The organic phase is dried over magnesium sulfate, concentrated in vacuo and fractionally distilled crude feed: 47.6 g of 3- (methoxycarbonylamino) -2-methylcrotonsäuremethylester of bp. IO8 to 110 C at

0.2 torr. (201, D 7, 5 H 7 , 0 N C ₉ H ₁₅ NO ₄ 53 ₃ C 7, 5 H 6 , 9 N Ber. : 53 C Gef .: , 7 , 9

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'Example V ^κ l- (2-Carboäthoxy- ⁱ i, 5-dimethyl-pyrrol-3-oxy) -2,3-epoxy propane

100 g of 2-carboethoxy-3-hydroxy-4,5-dimethylpyrrole, 150 g of epibromohydrin and 152 g of dry potassium carbonate are heated in refluxing temperature in 500 ml of acetone for 16 hours. After cooling, the entire reaction mass is poured into 3 liters of ice water, extracted with ether, the collected extracts are washed with 2 N sodium hydroxide solution and water and K) dried over sodium sulfate. The remaining after distilling off ether and excess epibromohydrin Eindampkunqkstand is extracted with heptane. 122 g of 1- (2-carboethoxy-4,5-dimethyl-pyrrol-3-oxy) -2,3-epoxypropyl-

Pan from the Mp. 70 to 71

C ₁₂ H ₁₇ NO ₄ (239, 1) 7 ,1 H 5 , 9 N Calc .: 60.3 C 7 • Ό H 6 , 0 N Found .: 60.1 C example VI

l- (2-Carboäthoxy- ⁱ l, 5,6,7-tetrahydro-indol-3-oxy) -2,3--epoxypropan

According to Example V, from 130 g of 3-hydroxy-4,5,6,7-tetrahydro-2-indolcarbonsäureäthylester, 170 g of epibromohydrin and 172 g of anhydrous potassium carbonate in 500 ml of acetone 165 g l- (2-Carboäthoxy-4,5, 6,7-tetrahydro-indole-3-oxy) -2,3-epoxypropane of mp. 102 to 104 ⁰ C. C ₁₄ H ₁₉ NO ₄ (265.2) Calc .: 63.4 C 7.2 H 5.3 N

30 result: 63.1 C 7.2 H 5.5 N

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Example VII

l- (2-carbomethoxy-4,5-dimethyl-pyrrol-3-oxy) -2,3-epoxypropane

According to Example V, from 17 g of 2-carbomethoxy-3 "-hydro-4,5-dimethylpyrrole, 20 g of epibromohydrin and 28 g of dry potassium carbonate in 100 ml of acetone, 18.5 g of 1- (2-carbomethoxy-4,5- dimethyl-pyrrol-3-oxy) -2,3-epoxypropane of mp. 85 to 87 ° C.

C ₁₁ H ₁₅ NO ₁ j (225 C 6 , 7 H 6 2 N Calc .: 58.7 C 6 , 7 H 6 , 5 N Found .: 58.5 example VIII

15 L- (2-Carboethoxy-4-butyl-5-methylpyrrole-3-oxy) -2,3-epoxypropane

According to Example V from 35 g of 2-Carboäthoxy-3-hydroxy-4-butyl-5-niethyl-pyrrole, 32 g of epibromohydrin and hl g of dry potassium carbonate in 100 ml of Ν, Ν-dimethylformamide by heating 8 hours to 50 C 4l g l- (2-Carboäthoxy-

4-butyl-5-methylpyrrole-3-oxy) -2,3-epoxypropane from

Mp. 125-127 ° C.

C ₁₅ H ₂₃ NO ₄ (281.2) 25 calc .: 64.1 C 8.2 H 5.0 N

Found .: 64.4 C 8,1 H 5,3 N

Example IX

1- (2-Carboethoxy-4-benzyl-5-methyl-pyrrol-3-oxy) -2,3'-epoxypropane

According to Example V are from 20 g of 2-Carboäthoxy-3 ~ hydroxy-4-benzyl-5-methyl-pyrrole, 14 g of epibromohydrin and 20 g of dry potassium carbonate in 150 ml of methyl isobutyl ketone 15 g l- (2-Carboäthoxy-4-benzyl 5-Niethyl-pyrrol-3-oxy) -

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- 24 - O.Z. OO5O / O34O89

'"-2,3-epoxypropane obtained as a light yellow, highly viscous oil.

C ₁₈ H ₂₁ NO ₄ (315.2)

Ber .: 68.6 C 6.7 H 4.4 N 5 Found: 68.2 C 6.8 H 4.7 N

Example X 1- (2-carbomethoxy-4,5-dimethyl-pyrrol-3-oxy) -3-chloropropane

12 g of 3-hydroxy-4 _J 5-dimethyl-2-pyrrolecarboxylic acid methyl ester, 13 »8 1,3-bromochloropropane and 13 g of anhydrous potassium carbonate are heated in 50 ml of N, N-dimethylformamide for 18 hours at 50 ⁰ C. After cooling, it is filtered off and the filter residue is washed with acetone. The filtrate is partitioned between water / methylene chloride, the organic phase washed several times with water, dried over sodium sulfate and evaporated in vacuo. The remaining residue is recrystallized from methanol using activated carbon. There remain 9 g l- (2-carbomethoxy-4,5-dimethyl-pyrrol-3 oxy) -3-chloropropane of mp. 117 to 120 ⁰ C.

C ₁₁ H ₁₆ NO. 3 Cl (245 , 5) 6 , 6 H 5 , 7 N 14 , 7 Cl Calc .: 53 8 C 6 , 7 H 5 , 9 N 14 Cl Found .: 53 9 C example XI

- 1- (2-carbomethoxy-4,5-dimethylpyrrol-3-oxy) -2-chloroethane

According to Example X is obtained from 12 g of 3-hydroxy-4,5-dimethyl-3-pyrrole-carboxylic acid methyl ester, l4.2 g of 1,2-bromochloroethane and 13 g of anhydrous potassium carbonate 9> 5 g l- (2-carbomethoxy-4 , 5-dimethylpyrrol-3-oxy) -2-chloroethane of mp. 122 to 123 ° C.

₁₀₁₄₃ (231.5) 35

5ϊ, 8th C - 25 - 6 2 • 2 0th 2 ΟΟ5Ο / Ο34Ο89 51 3 C 61, H 6 1 15: Second Cl Calc .: XII 6.0 H 0 N 15: 3 Cl Found .: N , 6 example

1- (2-carbomethoxy-4,5-dimethyl-pyrrol-3-oxy) -4-chlorobutane

According to Example X is obtained from 12 g of 3-HyCLr-OXy-JJ, 5-dimethyl-2-pyrrole-carboxylic acid methyl ester, 15.5 g of 1,4-bromochlorobutane and 12.3 g of anhydrous potassium carbonate 5.7 g K) l- (2-Carbomethoxy-4,5-dimethyl-pyrrol-3-oxy) -4-chlorobutane, mp. 74 to 76 ⁰ C.

C ₁₂ H ₁₈ NO ₃ C1 (259, 5) 7 , 0 H ul , 4 N 13 , 7 Cl Calc .: 55.5 C 6 ,8th H 5 , 2 N · 13 2 Cl Found .: 55.9 C example XIII

l- (2-carboethoxy-4,5-dimethyl-pyrrol-3-oxy) -4-chlorobutane

According to Example X is obtained from 18.3 g of 3-hydroxy-4,5-dimethyl-2-pyrrolcarbonsäureäthylester, 22.3 g of 1,4-

-Bromochlorobutane and 18 g of anhydrous potassium carbonate

12.5 g of 1- (2-carboethoxy-4,5-dimethyl-pyrrol-3-oxy) -4-

chlorobutane of mp. 58 to 60 C.

C ₁₃ H ₂₀ NO ₃ Cl (273.5) 25 Calcd .: 57.0 C 7.4 H 5.1 N 13.0 Cl

Found: 56.8 C 7.2 H 5.1 N 12.6 Cl

Example XIV

l- (2-carboethoxy-4,5-dimethyl-pyrrol-3-oxy) -3-chloropropane

According to Example X is obtained from 18.3 g of 3-hydroxy-4,5-dimethyl-2-pyrrolcarbonsäureäthylester, 25 g of 1,3-bromochloropropane and 18 g of anhydrous potassium carbonate 11.2 g l- (2-Carboäthoxy-4, 5-dimethylpyrrol-3-oxy) -3-chloropropane from

35 mp. 60 to 63 ⁰ C.

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C ₁₂ H ₁ QNO, , Cl (259, 6) 6 , 9 H 5 , 4 N 13 , 7 Cl Calc .: 55 , 5 C 6 , 7 H 5 ,1 N 13 , 5 Cl Found .: 55 , 2 C example XV

l- (2-carboethoxy-4,5-dimethyl-pyrrol-3-oxy) -2-chloroethane

According to Example X is obtained from 18.3 g of 3 ~ hydroxy-4,5-di-

methyl-2-pyrrolecarboxylic acid ethyl ester, 20.5S 1,2-bromo-K) chloroethane and 18 g of anhydrous potassium carbonate, 10 g of 1- (2-carboethoxy-4,5-dimethyl-pyrrol-3-oxy) -2-chloroethane

from mp 81 to 83 ⁰ C.

C ₁₁ H ₁₆ NO ₃ Cl (245.6)

Ber .: 53.8 C 6.5 H 5.7 N 14.4 Cl 15 Found: 54.2 C 6.5 H 5.9 N 14.7 Cl

Example XVI "

4.0 g of 1- (2-carboethoxy-4,5-dimethyl-pyrrol-3-oxy) -2,3-epoxypropane are dissolved in a mixture of 20 ml of ethanol and 15 ml of about 4 N ethereal hydrochloric acid.

After standing for one day, the volatiles are distilled off and the evaporation residue chromatographed on silica gel with methylene chloride. This gives 2.7 g of pure "1- (2-carboethoxy-4,5-dimethyl-) by NMR spectroscopy.

25 -pyrrol-3-oxy) -3-chloropropanol-2.

^ • H-NMR spectrum (CDCl ₃ , TMS internal):

= 1.4 (broad s, IH); 5.5 (s, OH); 5.7 (g 2H, J = 4.5 Hz);

5.9 (m, 3H); 6.4 (m, 2H); 7.88 (s, 3H); 8.1 (s, 3H); 8.7 (t, 3H, J = 4.5 Hz).

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* * !!. Preparation of compounds of the invention

example 1

24 g of 1- (2-carboethoxy-4,5-dimethylpyrrole-3-oxy) -2,3-epoxypropane and 18 g of 4- (2-pyridyl) -piperidin-4-ol are dissolved in 200 ml of ethanol for 4 hours heated to reflux temperature. The remaining after distilling off ethanol residue is dissolved in a little methanol and treated dropwise with ethereal hydrochloric acid. The failed one

K) crystallizate is filtered off with suction, washed with ether and

dried. 29 g of 3- [2-hydroxy-3- (4-C-pyridyl-4-hydroxy-piperidino) -propoxy] -4,5-dimethylpyrrole-2-carboxylic acid ethyl ester dihydrochloride of mp. 227 are obtained up to 229 ° C.

15 C ₂₂ H ₃₃ N ₃ O ₅ Cl ₂ (490.1)

Calc .: ^J 53.8 C 6.7 H 8.6 N 14.5 Cl 53.5 Found .: C 6.7 H 8.5 N 14.3 Cl

Example 2

55 S l- (2-Carboethoxy-4,5-dimethylpyrrole-3-oxy) -2,3-epoxypropane and 41 g of 4-hydroxy-4-phenylpiperidine are heated to reflux temperature in 600 ml of ethanol for 8 hours. The residue remaining after distilling off ethanol is dissolved in a little methanol and

25 added dropwise with ethereal hydrochloric acid. The

Precipitated crystals are filtered off with suction, washed with ether and dried. This gives 8l g of 3- [2-hydroxy-3- - (4-phenyl-4-hydroxy-piperidino) -propoxy] -4,5-dimethylpyrrole-2-carboxylic acid ethyl ester hydrochloride of mp.

30 211 to 212 ⁰ C

C ₂₃ H ₃₃ N ₂ O ₅ Cl (454.0)

Calc .: 6l, 0 C 7.3 H 17.7 0 6.2 N 7.8 Cl

Found: 61.2 C 7.1 H 17.9 O 5.9 N

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"" Example 3 ^x

According to Example 1, from 4.0 g of 1- (2-carboethoxy-4,5,6,7-tetrahydro-indole-3-oxy) -2,3-epoxypropane and 2.8 g of 4-hydroxy-4- phenyl-piperidine in 50 ml of ethanol, 5.7 g of 3- [2-hydroxy-'-3- (4-phenyl-4-hydroxy-piperidino) -propoxy] -4,5,6,7-tetrahydro-2- indole-carboxylic acid ethyl ester hydrochloride of mp. 170 to 173 ° C.

C ₂₅ H ₃₅ N ₂ O ₅ Cl (478.7)

Calc .: 62.7 C 7.4 H 16.7 O 5.8 N K) Found: 62.7 C 7.6 H 17.1 0 5.5 N

Example 4

50 g of 1- (2-carboethoxy-4,5-dimethyl-pyrrol-3-oxy) -3-chloropropane, "35 g of 4-hydroxy-4-phenyl-piperidine and 50 g of sodium carbonate are dissolved in 300 ml of N, N- Dimethylformamide is heated for 20 hours at 100 ^° C. After cooling, it is partitioned between water and methylene chloride and, after evaporation of the organic phase in vacuo, the residue is dissolved in a little methanol and admixed dropwise with ethereal hydrochloric acid, the precipitated crystals are filtered off with suction, washed with ether and . dried to give 56 g of 3 ~ C3 ~ (4-phenyl-4-hydroxy-piperidino) - propoxy] -4,5-dimethyl-pyrrole-2-carbonsäureäthylester- hydrochloride mp I65 to 169 ⁰ C..

25 C ₂₃ H ₃₃ N ₂ O ₄ Cl (437.5)

Ber .: 63.1 C 7.5 H 6.4 N Gef .: 63.2 C 7.7 H 6.7 N

Example 5

In an autoclave, 6.0 g of 1- (2-carboethoxy-4,5-dimethyl-pyrrol-3-oxy) -3-chloropropanol-2 and 3.5 g of 4-hydroxy-4-phenylpiperidine in 150 ml Dioxane heated to 120 ° C for 15 hours. After distilling off the volatiles in vacuo, the high-viscosity crude product is distributed in ether-2N sulfuric acid, the water phase is present.

22 U 842

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* carefully made alkaline with ^ N sodium hydroxide solution and then extracted with ether. After drying the organic phase over magnesium sulfate is freed from the solvent and the remaining residue, as described in Example 2, dissolved in a little methanol and with ethereal hydrochloric acid in 3.2 g of 3- [2-hydroxy-3- (4-phenyl- -4-hydroxy-piperidino) -propoxy] -4,5-dimethyl-pyrrol-2-

-carboxylic acid ethyl ester hydrochloride of mp. 210 to 10

212 ⁰ C transferred.

The compounds shown in Table 2 are prepared according to Example 2 from the corresponding glycidyl ethers and the 4-hydroxy-4-phenyl-piperidines or according to Example 4 from the corresponding 1- (2-carboethoxy-4,5-dimethylpyrrol ^ -3-oxy) Chloroalkanes and the 4-hydroxy-4-phenyl-piperidines.

oil

Table 2

R '

R H

COOR ^J

example

number

10

11

CH-

CIU

CH-

CH-

CH.

CH-

CH.

CH-

CH.

CH-,

CH.

CH-

R-

CH.

CH _x

CH.

C ₂ H ₅

CH-

OH

OH

OH

OH

OH

OH

salt form

HCl

HCl

HCl

C. C

110-1 * 11

220-221

122-123

181-185

227-228

136-137

ο o

for O 00

Ν>

cn

ro ο

cn

cn

example

number

12

16

17

18

19

20

21

CH.

CH-

CH-

CH.

CH.

CH.

CH-

CH.

CH-

CH,

η-C..H,

CH.

CH.

CH.

C ₂ H ₅

CH.

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

IO

-p

salt form

HCl

HCl

HCl

HCl

HCl

uUN

HCl

(COOH).

(COOH).

C. C

211-215

216-218

I96-I98

I96-I98

21 ^ -216

216-217

110-112

121-126

O O

O 00 VO

rs "

tn

ro

example analyzes 67.7 C 7.6 H 7.5 N 67.5 C 7.5 H 7.7 N Surname 6 Ber .: 68.4 C 7.8 H 7.3 N vessel: 68.1 C 7.7 H 7.4 N 63.9 C 7.8 H 6.2 N 7.9 Cl 63.6 C 7.6 II 6.2 N 7.8 Cl 3 ~ [3- (4-phenyl-4-hydroxy-piperidino) -propoxy] -4,5-dimethylpyrrole-2-carboxylic acid methyl ester 7 Calc .: 53.0 C 6 _t 6 II 8.8 N 1 * 1.9 Cl Found: 52.9 C 6 _t 6 H 8.7 N 15.2 Cl 62.5 C 7.4 H 6.6 N 8.4 Cl 62.1 C 7.2 II 6 _Y 6 N 8.3 Cl Methyl 3- [2-hydroxy-3- (4 - "* - pyridyl-4-hydroxy-piperidino) -propoxy] - - ^, S-dimethylpyrrole-1-carboxylate 8th Ber. i Gef .: 69.0 C 8.1 H 7.0 N 68.7 C 7.7 H 7.0 N Methyl 3- [2- (4-phenyl-4-hydroxy-piperidino) ethoxy] -4,5-dimethylpyrrole-2-carboxylate 9 Calc .: Gef. ' 63.2 C 7.6 H 14.7 O 6.4 N 8.1 Cl 62.5 C 7.6 H 14.7 0 '6.4 N 8.3 Cl 3-Γ 4- (4-phenyl-4-hydroxy-piperidino-butoxy] -4,5-dimethylpyrrole-2-carboxylic acid ethyl ester 10 Ber. Gef. Ethyl 3- [2- (4-phenyl-4-hydroxy-piperidino-ethoxy] -4,5-dimethylpyrrole-2-carboxylate 11 Ber. · Gef. Methyl 3- [4- (4-phenyl-4-hydroxy-piperidino-noy-butoxy] -4,5-dimethylpyrrole-2-carboxylate 12 Ber .: Gef .: 3-r2-hydroxy-3- (4-phenyl-piperidino) -propoxy] -4,5-dimethylpyrrole-2-carboxylic acid ethyl ester

P "^ M fO

N>

cn

cn

example analyzes Surname 13 Ber .: 58.7 C 6.9 II 6.0 N 4.0 P 7.3 Cl Found: 58.2 C 6.6 H 5.6 N 3.8 P 7.7 Cl Ethyl 3- [2-hydroxy-3- (4- (p-fluorophenyl) -4- (4-hydroxy-piperidino) -propoxy] -4,5-dimethylpyrrole-2-carboxylate l4 Calc .: 55.3 C 6.1 H 5, ¹ IN 10.9 P 6.8 Cl Found: 55.9 C 6.1 II 5.5 N 11.1 P 7.2 Cl 3- [2-Hydroxy-3- (4- (m-trifluoromethylphenyl) -4-hydroxy-piperidino) - propoxy] -4,5-dimethylpyrrole-2-carboxylic acid ethyl ester 15 Calc .: 57.0 C 6.1 H 5.0 N 10.3 P 6.4 Cl 3- [2-Hydroxy-3- (4- (m-trifluoromethylphenyl) -4-hydroxy-piperidino) - propoxy] -4,5,6,7-tetrahydro-2-indole-carboxylic acid ethyl ester 16 Calcd .: 58.5 C 6.7 H 5.5 N 13.8 Cl Found: 58.1 C 6.5 II 5.2 N 13.8 Cl 3- [2-Hydroxy-3- (4- (p-chlorophenyl) -4-hydroxy-piperidino) -propoxy] - "'', 5,6,7-tetrahydro-2-indole-carboxylic acid ethyl ester 17 Calc .: 58.5 C, 6.3 H, 5.5 N, 6.9 Cl, calc .: 59.0 C, 6.5 H, 5.5 N, 7.0 Cl Methyl 3- [2-hydroxy-3- (4- (p-chlorophenyl) -4-hydroxy-piperidino) -propoxy] -!, S-dimethylpyrrolecarboxylate 18 Ber .: 60.4 C 6.9 II 5.6 N 7.5 Cl Found: 59.9 C 6.8 H 5.5 M 7.5 Cl 3- [2-hydroxy-3- (4- (p-fluorophenyl) - ~ 4-hydroxy-piperidino) -propoxy] - ~ ^ »5,6,7-tetrahydro-2-indole-carboxylic säureüthylester

cn

cn

example analyzes Surname 19 Calc .: 60.0 C 6.9 II 6.5 N 8.2 Cl. Calc .: 6O, 2C 7.1H 6.4.4 8.1 Cl Methyl 3- [2-hydroxy-3- (4-phenyl-4-hydroxy-piperidino) -propoxy] -4,5-dimethylpyrrole-2-carboxylate 20 Calc .: 61.9 C 6.7 H 4.7 N Gef .: 61.5 C 6.5 H 4.7 N Ethyl 3- [2-hydroxy-3- (4-phenyl-4-hydroxy-β-piperidino) propoxy] -4-benzyl-5-ethyl-pyrrole-2-carboxylate 21 Calc .: 6L, 3C, 7.4H, 5.1N, F .: 61.6C, 7.2H, 5.3N. 3- [2-Hydroxy-3- (4-phenyl-4-hydroxy-piperidino) -propoxy] -4-n-butyl-5-methylpyrrole-2-carboxylic acid ethyl ester

O O VJ.

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, Formulation Examples for Use 1. Tablets:

a) An active ingredient of the formula I 5 mg

Lactose 200 mg

Methylcellulose 15 mg

Cornstarch 50 mg

Talc 11 mg

Magnesium stearate 4 mg

b) An active substance of the formula 0 20 mg lactose 178 mg Av-icel 80 mg

Polywax 6000 20 mg

Magnesium stearate 2 mg

c) An active compound of the formula I 50 mg polyvinylpyrrolidone (mean M.W. 25,000) 170 mg

, Polyethylene glycol (avg.G. 4000) 14 mg

Hydroxypropylmethylcellulose 40 mg

Talc '4 mg

Magnesium stearate 2 mg

The active ingredient is mixed with polyvinylpyrrolidone in 10 #iger

moistened aqueous solution, driven through a sieve with the • 1.0 mm mesh size and dried at 50 C. These granules are mixed with polyethylene glycol (mean M.G. 4000), hydroxypropylmethylcellulose, talc and magnesium stearate and pressed into tablets of 280 mg.

35

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2nd example of dragees

An active ingredient of the formula I 60 mg

Lactose 90 mg

Corn starch 60 mg

Polyvinylpyrrolidone. 6 mg

Magnesium stearate 1 mg

The mixture of the active substance with lactose and K) of corn starch is granulated with a 8 jSigen aqueous solution of the polyvinylpyrrolidone through sieve 1,5 mm, dried at 5O ⁰ C. and rubbed through sieve 1.0 mm. The granules thus obtained are mixed with magnesium stearate and pressed into dragee cores. The dragee cores obtained are coated in a conventional manner with a shell consisting essentially of sugar and talc.

3. Capsule formulation

An active ingredient of the formula I 5 mg

Magnesium stearate 2.0 mg

Milk sugar 19.3 mg

25 4. Solution for injection

An active substance of the formula I 10 mg

Sodium chloride 9 mg

distilled water, q.s. to 1.0 ml.

ir

Claims (1)

- 37 - O.Z. 0050/03 ^ 089 invention claim Process for the preparation of compounds of the formula I R ⁶ R ² H ^X COOR ³ in the 1 2 R and R are the same or different and are an alkyl radical having 1 to 4 C atoms, an aralkyl radical having 7 1 2 to 9 carbon atoms or R and R together with the two carbon atoms connecting them form a 6-membered ring with 4 methylene groups and R- an alkyl radical with 1 4 c
to 6 carbon atoms, R and R is a hydrogen atom or a hydroxyl group and R is a 6-membered hetaryl or aryl radical, optionally mono- to disubstituted by halogen atoms or simply substituted by the trifluoromethyl radical, where m and η are integers of 1 ' to mean and does not exceed the sum of m + η 6 and when R is a hydrogen atom, in addition m or η can also be 0, and their physiologically acceptable acid addition salts, characterized in that a carboalkoxypyrrole of the formula II II 35 22A842 - 38 - O.Z. OO5O / O34O89 in the R ¹ , R ² and A have the rest 12 "3 R, R and R ^ are the meaning given for formula I 5 O OH / \ » -CH-CH ₂ , -CH-CH ₂ -B or - (CH ₂ ) -B, where B is a nucleofugic leaving group and 1 is an integer from 1 to 6, means with a piperidine derivative of general formula III , 6 ^Η - \ _ Λ 15 in the B? and R have the meanings given for formula I, expediently in a solvent and optionally in the presence of an acid-binding agent in a conventional manner and converting the resulting compound optionally in the acid addition salt of a physiologically acceptable acid. 25 30 35