Medicaments based on derivatives of 1-(4-quinolyl)-2-(4-piperidyl)-ethanol or 1-(4-quinolyl)-3-(4-piperidyl)-propanol

Antiarhythmic medicaments containing, as active substance, a compound of the formula: ##STR1## in which n is 1 or 2, X and Y are fixed in positions 5, 6, 7 or 8 on the quinoline cycle and each represents a hydrogen atom or an alkoxy group having 1 to 3 carbons, R is a hydrogen atom or an alkyl group having 1 to 4 carbons, cycloalkyl having 3 to 8 carbons, phenyl or phenyl substituted by alkoxy having 1 to 4 carbons, R.sub.1 is a hydrogen atom or an alkyl group having 1 to 4 carbons or a phenylalkyl group of which the alkyl part has 1 to 3 carbons, R.sub.2 is a hydrogen atom, an alkyl group having 1 to 2 carbons or an alkenyl group having 2 to 4 carbons.

The present invention relates to new medicaments, particularly useful as 
antiarhythmics, which contain, as active substance, a compound 
corresponding to the formula: 
##STR2## 
in which n is equal to 1 or 2, X and Y, which are the same or different, 
are fixed in position 5, 6, 7 or 8 on the quinoline cycle and each 
represents a hydrogen atom or an alkoxy group having 1 to 3 carbon atoms, 
R represents a hydrogen atom, a cycloalkyl group having 3 to 8 carbon 
atoms, an alkyl group having 1 to 4 carbon atoms, a phenyl group or a 
phenyl group substituted by an alkoxy group having 1 to 4 carbon atoms, 
R.sub.1 represents a hydrogen atom, an alkyl group having 1 to 4 carbon 
atoms or a phenylalkyl group the alkyl part of which having 1 to 3 carbon 
atoms, R.sub.2 represents a hydrogen atom, an alkyl group having 1 or 2 
carbon atoms or an alkenyl group having 2 to 4 carbon atoms, or a mixture 
of stereoisomeric compounds corresponding to the formula (I), or a salt of 
such a compound or mixture of stereoisomeric compounds with a 
pharmaceutically acceptable acid. 
In formula (I) above, Y is preferably a hydrogen atom, X is preferably a 
hydrogen atom or a methoxy group, R is preferably a hydrogen atom or a 
phenyl or tertiobutyl group, R.sub.1 is preferably a hydrogen atom and 
R.sub.2 is preferably a hydrogen atom or an ethyl or ethenyl group. 
When R.sub.2 represents a hydrogen atom, the molecule of the compounds of 
formula (I) contains an asymmetric carbon atom (carbon atom carrying the 
OH group) and then, for a given significance of X, Y, R, R.sub.1, R.sub.2 
and n, there are a racemic compound and two enantiomers corresponding to 
the plane formula (I). When R.sub.2 does not represent a hydrogen atom, 
the molecule of the compounds of formula (I) contains 3 asymmetric carbon 
atoms and then, for a given significance of X, Y, R, R.sub.1, R.sub.2 and 
n, there are 8 stereoisomers corresponding to the plane formula (I), the 
spatial formulae of which correspond to the combinations 3 to 3 of the 
rectus (R) or sinister (S) configurations of each center of asymmetry. The 
medicaments according to the invention may contain, as active substance, a 
mixture of stereoisomeric compounds corresponding to formula (I) as well 
as a pure isomer corresponding to formula (I). 
Products are known (cf. M. Heidelberger and W. A. Jacobs, J. Am. Chem. Soc. 
44, 1098-1107, (1922); German Pat. No. 330,813) which are probably 
mixtures of isomers and correspond to the formula: 
##STR3## 
in which X' is a hydrogen atom or a methoxy or ethoxy group, R'.sub.1 is a 
hydrogen atom or a methyl or ethyl group and R'.sub.2 is an ethyl or 
ethenyl group, but no pharmacological property or therapeutic application 
has been taught or suggested for these products up to the present. 
According to G. S. Dawes (Brit. J. Pharmacol., 1946, 1, 90-111), the 
compound of the formula: 
##STR4## 
would act on the capacity of the isolated rabbit auricle for responding to 
electrical stimuli caused by an induction coil, but the molar weight (391) 
given by the author for the above compound is inconsistent with the 
formula, so that there is doubt about the true structure of the tested 
compound. 
It has now been found, according to the present invention, that the 
compounds of formula (I) possess remarkable pharmacological properties 
which enable them to be used as an active ingredient of medicaments. 
The racemic, enantiomeric or stereoisomeric compounds of the formula: 
##STR5## 
wherein X, Y, R, R.sub.1 and R.sub.2 have the same significance as in 
formula (I), are new compounds and as such form a part of the invention. 
The racemic, enantiomeric or stereoisomeric compounds of the formula: 
##STR6## 
wherein X, Y, R.sub.1 and R.sub.2 have the same significance as in formula 
(I) and R' represents a cycloalkyl group having 3 to 8 carbon atoms, an 
alkyl group having 1 to 4 carbon atoms, a phenyl group or a phenyl group 
substituted with an alkoxy group having 1 to 4 carbon atoms, are new 
compounds and as such form a part of the invention. 
The racemic or enantiomeric compounds of the formula: 
##STR7## 
wherein X, Y, R and R.sub.1 have the same significance as in formula (I) 
are new compounds and as such form a part of the invention. 
The compounds of formula (I) can be prepared by reduction of the ketones of 
the formula: 
##STR8## 
in which X, Y, R, R.sub.1, R.sub.2 and n have the same significance as in 
formula (I). 
In order to effect this reduction, processes are used known per se, which 
enable a ketone to be converted into an alcohol. An advantageous method, 
applicable in all cases, consists in using as reducing agent a reducing 
metal hydride such as those mentioned in "Complex Hydrides and Related 
Reducing Agents in Organic Synthesis" (Andor Hajos, Elsevier Scientific 
Publishing Company, Amsterdam, Oxford, New York, 1979). Among the most 
common reducing agents may be mentioned the borohydrides of alkali metals 
such as sodium borohydride and potassium borohydride, which are used at 
the ambient temperature in a solvent such as an alcohol (for example 
methanol or ethanol), a water-alcohol mixture or tetrahydrofuran, and 
lithium aluminum hydride, which is used in an inert solvent such as 
diethyl ether, tetrahydrofuran or a hydrocarbon, at a temperature between 
0.degree. C. and the boiling temperature of the solvent. 
When R.sub.2 is a hydrogen atom, reduction of the ketones of formula (II) 
provides the racemic compound. When R.sub.2 is not a hydrogen atom, 
reduction of the ketones of formula (II) provides a mixture of 
diastereoisomeric compounds, which are racemic or optically active 
accordingly as the starting ketone is racemic or optically active. The 
pure diastereoisomers can be isolated from the mixture by conventional 
methods such as chromatography, fractional crystallization, formation of 
salts and regeneration of the base, etc. 
A variant of the above reduction process consists in effecting the 
reduction in the presence of an optically active compound, capable of 
forming a complex with the reducing hydride used, for example an .alpha. 
amino-acid [cf. J. B. Morrison and H. S. Mosher, Asymmetric Organic 
Reactions, Prentice Hall, Englewood Cliffs, N.J. (1972); J. W. Apsimon and 
R. P. Seguin, Tetrahedron, 1979, 35, 2797; J. C. Fiaud, Stereochemistry 
Fundamentals and Methods, Vol. 3, 95, edited by H. B. Kagan, Georg Thieme 
Publishers, Stuttgart, 1977; N. Umino, Chem. Pharm. Bull., 1979, 27, 
1479]. Under these conditions a product of reduction is obtained 
containing in preponderant amount an enantiomer (if R.sub.2 =H) or a 
diastereoisomer (if R.sub.2 .noteq.H), the carbon atom of which carrying 
the OH group having a definite configuration. For example, L-proline 
induces the preponderant formation of an alcohol in which the carbon atom 
carrying the OH group has the sinister (S) configuration and D-proline 
induces the preponderant formation of an alcohol in which the carbon atom 
carrying the OH group has the rectus (R) configuration. This variant is 
advantageous in the case where the starting ketone of formula (II) is 
optically active. A reduction product is then obtained containing 
essentially a definite diastereoisomer, optically active, which is easily 
isolated by the methods indicated above. 
The compounds of formula (I) for which R.sub.1 does not represent a benzyl 
group and R.sub.2 represents an alkyl group having 2 carbon atoms can also 
be prepared by catalytic hydrogenation of the corresponding ketones of 
formula (II) for which R.sub.2 represents an alkenyl group having 2 carbon 
atoms. In this case the reduction of the CO group to CHOH and the 
hydrogenation of the alkenyl group to an alkyl group are effected at the 
same time. The operation is generally effected in the neighborhood of the 
ambient temperature, under a pressure of hydrogen near to the atmospheric 
pressure, the starting ketone (in the form of the free base or one of its 
salts) being in an inert solvent such as an alcohol (for example methanol 
or ethanol), a water-alcohol mixture or an acid (for example acetic acid). 
The catalysts may be palladium, rhodium, ruthenium, platinum and nickel. 
The compounds of formula (I) for which R.sub.1 is a hydrogen atom and 
R.sub.2 is the ethenyl group and for which the carbon atom carrying the 
ethenyl group has a given configuration, rectus (R) or sinister (S), can 
also be prepared by heating, at a temperature greater than 50.degree. C., 
in a protic solvent or a mixture of protic solvents, in the presence of 
formaldehyde, the corresponding compounds of formula (I) for which R.sub.1 
is a hydrogen atom, R.sub.2 is the ethenyl group and the carbon atom 
carrying the ethenyl group has the sinister configuration (S) or rectus 
configuration (R), partially or totally in salt form. 
The compounds of formula (I) for which R.sub.1 is an alkyl or phenylalkyl 
group can also be prepared by the action on the corresponding compounds of 
formula (I) for which R.sub.1 is a hydrogen atom, of an alkylating agent 
such as a halide of formula R".sub.1 Hal, a sulfate of formula 
(R".sub.1).sub.2 SO.sub.4, an arylsulfonate of formula ArSO.sub.3 R".sub.1 
or an alkylsulfonate of the formula R"SO.sub.3 R".sub.1, in which formulae 
R".sub.1 represents an alkyl group having 1 to 4 carbon atoms or a 
phenylalkyl group the alkyl part of which contains 1 to 3 carbon atoms, Ar 
represents an aryl group and R" represents an alkyl group. The reaction 
can be shown graphically as follows in the case where the alkylating agent 
is a halide: 
##STR9## 
The reaction of the alkylating agent with the compounds of formula (I) for 
which R.sub.1 =H is effected according to processes known per se. The 
operation is advantageously effected in the presence of an organic or 
mineral base (for example sodium or potassium carbonate), in an inert 
solvent, for example dimethylformamide. 
An interesting variant for the preparation of the compounds of formula (I) 
for which R.sub.1 =CH.sub.3 consists in acting on the corresponding 
compounds of formula (I) for which R.sub.1 =H with formaldehyde in the 
presence of a reducing agent (Cf. "Complex Hydrides and Related Reducing 
Agents in Organic Synthesis" above cited). As reducing agent is 
advantageously used a borohydride such as sodium or potassium borohydride 
or sodium cyanoborohydride, in an inert solvent, for example an alcohol or 
a mixture of water and alcohol, at a temperature between the ambient 
temperature and the boiling point of the solvent. 
When R.sub.2 represents the ethenyl group and if the operation is effected 
at a sufficiently high temperature (&gt;50.degree. C.), there is 
simultaneously observed, during the action of the formaldehyde in the 
presence of the reducing agent, the epimerization of the ethenyl group, so 
that in a single reaction there can be prepared, from a single precursor, 
two diastereoisomers differing from one another by the configuration of 
the carbon atom carrying the ethenyl group. The reaction may be shown 
graphically as follows. 
##STR10## 
Each diastereoisomer can be isolated in the pure state from the mixture by 
the methods indicated above. 
The compounds of formula (I) in the free base form may, if desired, be 
converted into salts of addition with a mineral or organic acid by the 
action of such an acid in a suitable solvent. 
Some of the ketones of formula II are known. This is the case in particular 
of quinicine and cinchonicine, which are obtained by rearrangement in acid 
medium of the major alkaloids of the cinchona, that is of quinine or 
quinidine and of cinchonine or cinchonidine (cf. S. W. Pelletier, 
Chemistry of the Alkaloids, p. 313, Reinhold, 1969), and which correspond 
to the formula: 
##STR11## 
in which X" is a hydrogen atom or a methoxy group. 
Generally, the ketones of formula (II) for which R.sub.1 represents a 
hydrogen atom may be prepared by condensation of an ester of 
quinoline-4-carboxylic acid of formula (III) with an ester of 
(4-piperidinyl)-alkylcarboxylic acid of formula (IV), then hydrolysis and 
decarboxylation of the compound of formula (V) thus obtained, according to 
the following reaction scheme: 
##STR12## 
In formulae (III), (IV) and (V) above, X, Y, R, R.sub.2 and n have the same 
significance as in formula (I), R.sub.3 and R.sub.4 represent alkyl groups 
of low molecular weight, for example methyl or ethyl, and B represents a 
group protecting the amine function, stable in anhydrous alkaline medium 
and capable of being eliminated in acid medium, such as those which are 
described by R. A. Boissonnas, Advances in Organic Chemistry 3, p. 159, 
Interscience (1963). The benzoyl group (--B.dbd.--CO--C.sub.6 H.sub.5) or 
the benzyloxycarbonyl group (--B.dbd.--CO--O--CH.sub.2 --C.sub.6 H.sub.5) 
is advantageously used. 
In order to carry out condensation reaction (a) processes known per se are 
made use of (cf. "The Acetoacetic Acid Ester Condensation", C. R. Hauser 
and coll., Organic Reactions, vol. 1, p. 266, Wiley and Sons, 1942). The 
operation is advantageously effected in the presence of a base such as an 
alcoholate (for example potassium tertiobutylate) or a metal hydride (for 
example sodium or potassium hydride), in an inert solvent such as a 
hydrocarbon or another aprotic solvent (for example tetrahydrofuran), at a 
temperature between 0.degree. C. and the boiling temperature of the 
solvent used. 
The hydrolysis reaction (b) is carried out according to processes known per 
se (cf. "Cleavage of .beta. Keto-esters", R. B. Wagner and H. D. Zook, 
Synthetic Organic Chemistry, p. 327, Wiley and Sons, 1953). The most usual 
method consists in heating the product of formula (V) at the boil in an 
aqueous solution of an acid such as hydrochloric or sulfuric acid. 
The ketones of formula (II) for which R.sub.1 does not represent a hydrogen 
atom may be prepared by the action of an alkylating agent on the ketones 
of formula (II) for which R.sub.1 =H. This alkylation is effected under 
the conditions indicated above for the alkylation of the compounds of 
formula (I) for which R.sub.1 =H.

The following examples illustrate the preparation of the compounds of 
formula (I), which are the active substances of the medicaments according 
to the invention. In these examples, the absolute configuration of the 
carbon atom which carries the OH group of the synthesized compounds has 
been determined by the method of J. A. Dale and H. S. Mosher, J. Amer. 
Chem. Soc., 1973, 95, 512. 
EXAMPLE 1 
1-(2-PHENYL-4-QUINOLYL)-2-(4-PIPERIDYL)-ETHANOL (racemic) 
6 g of sodium borohydride were added in 20 minutes, at the ambient 
temperature, to 16 g of 1-(2-phenyl-4-quinolyl)-2-(4-piperidyl)-ethanone 
dihydrochloride in 500 ml of methanol. After reacting for 2 hours at the 
ambient temperature, 350 ml of water were added and the methanol was 
removed by distillation under reduced pressure. The residual aqueous 
suspension was extracted with diethyl oxide, the organic phase was washed 
with water, dried over magnesium sulfate and evaporated under reduced 
pressure. The residue (13 g) was crystallized from petrol ether. 9 g of 
1-(2-phenyl-4-quinolyl)-2-(4-piperidyl)-ethanol (racemic) were thus 
obtained, which melted at 147.degree. C. 
The starting product may be prepared as follows: 
A solution of 21.2 g of methyl(2-phenyl-quinoline)-4-carboxylate in 50 ml 
of dry tetrahydrofuran was rapidly added to a suspension of 27.5 g of 
potassium t-butylate in 215 ml of dry tetrahydrofuran, placed under an 
atmosphere of nitrogen and cooled to 0.degree. C. While maintaining the 
temperature below +10.degree. C., a solution of 22.1 g of 
ethyl(1-benzoyl-4-piperidyl)-acetate in 80 ml of dry tetrahydrofuran was 
introduced slowly over a period of 2 hours. The reaction mixture was then 
stirred for 20 hours at the ambient temperature, and then was brought to 
dryness by evaporation of the solvent. The residue was heated under reflux 
for 18 hours in 650 ml of a 5N aqueous solution of hydrochloric acid. 
After cooling, the solution obtained was filtered and the filtrate 
extracted twice by 250 ml of diethyl ether each time. The residual aqueous 
solution was concentrated under reduced pressure. The residue obtained was 
extracted by 500 ml of hot methanol and the extraction solution was 
filtered. The filtrate, after evaporation of the methanol, provided 13.8 g 
of 1-(2-phenyl-4-quinolyl)-2-(4-piperidyl)-ethanone dihydrochloride 
melting at 259.degree. C. 
EXAMPLE 2 
1-(4-QUINOLYL)-3-(4-PIPERIDYL)-1-PROPANOL (racemic) 
2 g of sodium borohydride were added in 20 minutes, at the ambient 
temperature, to 13 g of 1-(4-quinolyl)-3-(4-piperidyl)-1-propanone in 200 
ml of methanol. After reacting for 2 hours at the ambient temperature, the 
reaction medium was acidified by addition of an aqueous solution of 
hydrochloric acid, the methanol removed by distillation under reduced 
pressure and the aqueous phase washed with ethyl acetate. The aqueous 
phase was made alkaline by addition of an aqueous solution of sodium 
hydroxide, then extracted with chloroform. The chloroformic phase was 
washed with water, dried over magnesium sulfate and evaporated under 
reduced pressure. 13 g of crude product were thus obtained, which were 
fixed on a column of silica gel. It was then eluted with a mixture of 90 
parts by volume of chloroform and 10 parts by volume of diethylamine. 7 g 
of the desired product were thus isolated in the form of the base, which 
was converted into dihydrochloride by the action of hydrochloric acid in 
ethanol. 3.2 g of 1 -(4-quinolyl)-3-(4-piperidyl)-1-propanol 
dihydrochloride (racemic) which melted at 195.degree. C. were thus 
obtained. 
The starting ketone can be prepared as indicated by P. Rabe, Ber., 55, 532 
(1922). 
EXAMPLE 3 
1-(6-METHOXY-4-QUINOLYL)-3-(4-PIPERIDYL)-1-PROPANOL (racemic) 
The operation was as in Example 2, except that 6.6 g of 
1-(6-methoxy-4-quinolyl)-3-(4-piperidyl)-1-propanone and 1 g of sodium 
borohydride in 100 ml of methanol were used and that the product desired 
in the form of the base was converted into its sesquifumarate. 5 g of 
1-(6-methoxy-4-quinolyl)-3-(4-piperidyl)-1-propanol sesquifumarate 
(racemic) were thus obtained which melted at 154.degree. C. 
The starting ketone was prepared as indicated by M. Kleiman J. Org. Chem., 
1945, 10, 562. 
EXAMPLE 4 
1-(2-PHENYL-4-QUINOLYL)-3-(4-PIPERIDYL)-1-PROPANOL (racemic) 
The operation was as in Example 1, except that 14 g of 
1-(2-phenyl-4-quinolyl)-3-(4-piperidyl)-1-propanone and 2.3 g of sodium 
borohydride in 300 ml of methanol were used. After recrystallization of 
the crude product in isopropanol, 7 g of 
1-(2-phenyl-4-quinolyl)-3-(4-piperidyl)-1-propanol (racemic) were 
obtained, which melted at 162.degree. C. 
The starting ketone can be prepared as indicated in Belgian Pat. No. 
807,491. 
EXAMPLE 5 
Mixture of 3-[3(R)-ETHENYL 
4(R)-PIPERIDYL]-1-(6-METHOXY-4-QUINOLYL)-1-(R)-PROPANOL and 
3-[3(R)-ETHENYL 4(R)-PIPERIDYL]-1-(6-METHOXY-4-QUINOLYL)-1(S)-PROPANOL 
26.6 g of sodium borohydride were added to 194 g of 3-[3(R)-ethenyl 
4(R)-piperidyl]-1-(6-methoxy-4-quinolyl)-1-propanone monohydrochloride and 
32 g of sodium methylate in 2200 ml of methanol. After 2 hours stirring at 
the ambient temperature, the reaction mixture was filtered and the 
methanol evaporated under reduced pressure. The residue was taken up with 
1 liter of methylene chloride and 500 ml of water and extracted, the 
phases were separated and the aqueous phase extracted again with 500 ml of 
methylene chloride. 
The organic phases collected were washed three times with 200 ml of water 
each time, dried over magnesium sulfate and evaporated under reduced 
pressure. The residual oil was dissolved in 500 ml of absolute ethanol and 
the medium brought to pH.perspectiveto.3 by addition of a 10N solution of 
hydrochloric acid in ethanol. The crystals formed were filtered, washed 
and dried. 144 g of a mixture of 3-[3(R)-ethenyl 
4(R)-piperidyl]-1-(6-methoxy-4-quinolyl)-1(R)-propanol and 3-[3(R)-ethenyl 
4(R)-piperidyl]-1-(6-methoxy-4-quinolyl)-1(S)-propanol in the form of 
dihydrochlorides were thus obtained. This mixture melted at 
223.degree.-225.degree. C. Analysis by high pressure liquid chromatography 
of this mixture showed that it consisted in a 50/50 mixture of the two 
diastereoisomers. 
The starting ketone (quinicine hydrochloride) may be prepared as indicated 
by A. Quevauviller et al., Ann. Pharm. Franc. 24, 39 (1966). 
EXAMPLE 6 
3-[3(R)-ETHENYL 4(R)-PIPERIDYL]-1-(6-METHOXY-4-QUINOLYL)-1(S)-PROPANOL 
The product obtained in Example 5 was recrystallized three times from 95% 
ethanol. 18 g of 3[3(R)-ethenyl 
4(R)-piperidyl]-1-(6-methoxy-4-quinolyl)-1(S)-propanol were thus obtained, 
in the form of the dihydrochloride melting at 245.degree.-248.degree. C. 
Rotatory power of the product obtained (measured on a 2% aqueous 
solution): 
EQU .alpha..sub.D.sup.21 .dbd.-122.degree.8 
EXAMPLE 7 
3-[3(R)-ETHENYL 4(R)-PIPERIDYL]-1-(6-METHOXY-4-QUINOLYL)-1(R)-PROPANOL 
The filtrate from the first recrystallization effected in Example 6 was 
evaporated. The residue was recrystallized once in isopropanol, then three 
times in a 1/1 absolute ethanol-isopropanol mixture. 8 g of 
3-[3(R)-ethenyl 4(R)-piperidyl]-1-(6-methoxy-4-quinolyl)-1(R)-propanol 
were thus obtained in the form of the dihydrochloride which melted at 
220.degree.-222.degree. C. The rotatory power of the product obtained 
(measured on a 2% aqueous solution) was: 
EQU .alpha..sub.D.sup.21 .dbd.+197.degree.9 
EXAMPLE 8 
3-[3(R)-ETHYL 4(R)-PIPERIDYL]-1-(6-METHOXY-4-QUINOLYL)-1(S)-PROPANOL and 
3-[3(R)-ETHYL 4(R)-PIPERIDYL]-1-(6-METHOXY-4-QUINOLYL)-1(R)-PROPANOL 
Hydrogenation was effected at the ambient temperature, under a pressure of 
hydrogen equal to the atmospheric pressure and in the presence of 23 g of 
palladium in the form of palladium charcoal with 10% of palladium, on 180 
g of 3-[3(R)-ethenyl 4(R)-piperidyl]-1-(6-methoxy-4-quinolyl)-1-propanone 
monohydrochloride in 2250 ml of absolute ethanol and 250 ml of a 2N 
aqueous solution of hydrochloric acid. When the absorption of hydrogen was 
completed, the reaction mixture was filtered and then evaporated under 
reduced pressure. The residual oil was taken up with 500 ml of hot 
ethanol, and 500 ml of acetone were added in order to start the 
crystallization. The crystalls formed were filtered, washed and dried. 143 
g of a crude product were thus obtained, which was a mixture of equal 
parts of the dihydrochlorides of 3-[3(R)-ethyl 
4(R)-piperidyl]-1-(6-methoxy-4-quinolyl-1(S)-propanol and 3-[3(R)-ethyl 
4(R)-piperidyl]-1-(6-methoxy-4 -quinolyl)-1(R)-propanol. 
The above crude product was recrystallized three times in 95% ethanol and 
the dihydrochloride crystals thus isolated were converted into the 
corresponding base by the action of sodium hydroxide. This base was fixed 
on a column of silica gel and then eluted with a mixture containing 1 part 
by volume of chloroform, 0.1 part by volume of methanol and 0.025 part by 
volume of diethylamine. 11.3 g of product were thus obtained in the form 
of the base, which was converted into the dihydrochloride by the action of 
hydrochloric acid in absolute ethanol. After a recrystallization of this 
dihydrochloride in absolute ethanol, 7 g of 3-[3(R)-ethyl 
4(R)-piperidyl]-1-(6-methoxy-4-quinolyl)-1(S)-propanol dihydrochloride 
were isolated. This product melted at 228.degree.-230.degree. C. and its 
rotatory power, measured on a 2% aqueous solution, was: 
EQU .alpha..sub.D.sup.21 .dbd.-144.degree.2 
The filtrate (about 1300 ml) coming from the first recrystallization of the 
crude product in 95% ethanol was concentrated until its volume was reduced 
by half. The solution obtained was filtered and the filtrate concentrated 
again until its volume was reduced by half. The solution obtained was 
filtered again, and the residual filtrate was evaporated to dryness under 
reduced pressure. 29 g were thus obtained of product in the form of the 
dihydrochloride, which was converted into the corresponding base by the 
action of sodium hydroxide. This base was fixed on a column of silica gel 
and then eluted with a 1/0.1/0.025 chloroform-methanol-diethylamine 
mixture. The product thus isolated in the form of the base was converted 
into the dihydrochloride by the action of HCl in absolute ethanol. The 
dihydrochloride was then recrystallized in n-propanol. 5 g were thus 
obtained of 3-[3(R)-ethyl 
4(R)-piperidyl]-1-(6-methoxy-4-quinolyl)-1(R)-propanol dihydrochloride, 
which melted at 210.degree.-215.degree. C. The rotatory power of this 
product measured on a 2% aqueous solution, was: 
EQU .alpha..sub.D.sup.21 .dbd.+157.degree.4 
EXAMPLE 9 
3-[3(R)-ETHENYL 1-METHYL 
4(R)-PIPERIDYL]-1-(6-METHOXY-4-QUINOLYL)-1(S)-PROPANOL and 3-[3(S)-ETHENYL 
1-METHYL 4(R)-PIPERIDYL]-1-(6-METHOXY-4-QUINOLYL)-1(S)-PROPANOL 
8 g of 3-[3(R)-ethenyl 
4(R)-piperidyl]-1-(6-methoxy-4-quinolyl)-1(S)-propanol (product of Example 
6) were treated for 2 hours, at 70.degree. C., with 24 ml of a 37% aqueous 
solution of formaldehyde and 3.4 g of sodium borohydride in 100 ml of 
methanol. The solvent was evaporated under reduced pressure, the residue 
was taken up with water, the aqueous phase was made alkaline and extracted 
with chloroform. The organic phase was washed with water, dried over 
magnesium sulfate and evaporated under reduced pressure. 
The residue was subjected to high pressure liquid chromatography (support: 
silica; eluant; mixture of 9 parts by volume of toluene and 1 part by 
volume of diethylamine). The desired products, which were in the form of 
the base in the separated fractions, were converted into hydrochlorides by 
the action of HCl in ethanol. There were thus obtained on the one hand 2.5 
g of 3-[3(R)-ethenyl 
1-methyl-4(R)-piperidyl]1-(6-methoxy-4-quinolyl)-1(S)-propanol in the form 
of the monohydrochloride, which melted at 214.degree. C. and had a 
rotatory power (measured on a 2% aqueous solution) of: 
EQU .alpha..sub.D.sup.23 .dbd.-61.degree.9 
and on the other hand 2.7 g of 3-[3(S)-ethenyl 
1-methyl-4(R)-piperidyl]-1-(6-methoxy-4-quinolyl)-1(S)-propanol in the 
form of the dihydrochloride, which melted at 175.degree. C. and had a 
rotatory power (measured on a 2% aqueous solution) of: 
EQU .alpha..sub.D.sup.22 .dbd.-172.degree.8 
EXAMPLE 10 
3-[3(R)-ETHENYL 1-METHYL 
4(R)-PIPERIDYL]-1-(6-METHOXY-4-QUINOLYL)-1(R)-PROPANOL 
The operation was as in Example 9, starting from 1.15 g of 3-[3(R)-ethenyl 
4(R)-piperidyl]-1-(6-methoxy-4-quinolyl)-1(R)-propanol (product of Example 
7), 3.5 ml of 37% aqueous solution of formaldehyde and 0.5 g of sodium 
borohydride in 15 ml of methanol. After separation by high pressure liquid 
chromatography, 0.6 g were isolated of 3-[3(R)-ethenyl 1-methyl 
4(R)-piperidyl]-1-(6-methoxy-4-quinolyl)-1(R)-propanol in the form of the 
monohydrochloride, which melted at 160.degree.-165.degree. C. and had a 
rotatory power (measured on a 2% aqueous solution) of: 
EQU .alpha..sub.D.sup.23 .dbd.+199.degree.0 
EXAMPLE 11 
Mixture of the two isomers 3-[3(R)-ETHENYL 
4(R)-PIPERIDYL]-1-(6-METHOXY-4-QUINOLYL)-1(R)-PROPANOL and 3-[3(R)-ETHENYL 
4(R)-PIPERIDYL]-1-(6-METHOXY-4-QUINOLYL)-1(S)-PROPANOL 
0.095 g of sodium borohydride and 0.29 g of L-proline in 5 ml of dry 
tetrahydrofuran were stirred for 20 hours at the ambient temperature. Then 
0.9 g of 3-[3(R)-ethenyl 
4(R)-piperidyl]-1-(6-methoxy-4-quinolyl)-1-propanone monohydrochloride was 
added and stirring of the reaction mixture was continued for 4 days. The 
solvent was evaporated under reduced pressure, the residue was taken up 
with water, the aqueous phase was made alkaline and extracted with 
methylene chloride. The organic phase was dried over magnesium sulfate and 
evaporated under reduced pressure. 0.8 g of an oil were obtained which, 
subjected to the action of HCl in ethanol, provided 0.4 g of a mixture of 
the dihydrochlorides of 3-[3(R)-ethenyl 
4(R)-piperidyl]-1-(6-methoxy-4-quinolyl)-1(R)-propanol and 3-[3(R)-ethenyl 
4(R)-piperidyl]-1-(6-methoxy-4-quinolyl)1(S)-propanol. This mixture melted 
at 223.degree.-225.degree. C. and contained 90% of isomer 3R, 4R, 1S and 
10% of isomer 3R, 4R, 1R, as shown by analysis by high pressure liquid 
chromatography of the corresponding mixture of the bases. 
EXAMPLE 12 
1-[2-(1,1-DIMETHYL-ETHYL)-4-QUINOLYL]-3-(4-PIPERIDYL)-1-PROPANOL (racemic) 
The operation was as in Example 5, starting from 14 g of the 
dihydrochloride of 
1-[2-(1,1-dimethyl-ethyl)-4-quinolyl]-3-(4-piperidyl)-1-propanone, 4.15 g 
of sodium methylate and 1.8 g of sodium borohydride in 150 ml of methanol. 
4.1 g were finally obtained of 
1-[2-(1,1-dimethyl-ethyl)-4-quinolyl]-3-(4-piperidyl)-1-propanol 
(racemic), in the form of the dihydrochloride melting at 219.degree. C. 
The starting ketone can be prepared in the following way: 
29.6 g of an 80% suspension of sodium hydride in oil were added to a 
solution of 48 g of ethyl[2-(1,1-dimethyl-ethyl)-quinoline]-4-carboxylate 
in 800 ml of anhydrous tetrahydrofuran, placed in an atmosphere of 
nitrogen. The mixture was brought to the boil and, in 2 hours, there was 
added a solution of 47 g of ethyl 3-(1-benzoyl-4-piperidyl)-propionate in 
100 ml of anhydrous tetrahydrofuran. Boiling was then maintained for 2 
hours. After cooling, 100 ml of ethanol were added, and the mixture was 
evaporated to dryness. The residue was taken up with water and the aqueous 
solution brought to pH 6 by addition of acetic acid. The insoluble 
material was extracted 3 times with 300 ml of ethyl acetate each time, the 
organic phase was washed with water, dried over magnesium sulfate and 
evaporated under reduced pressure. The residue (36 g) was heated under 
reflux for 19 hours in 500 ml of a 5N aqueous solution of hydrochloric 
acid. The aqueous solution was made alkaline by addition of a sodium 
hydroxide lye, the insoluble material was extracted 3 times with 300 ml of 
chloroform each time, the organic phase was washed with water, dried over 
magnesium sulfate and evaporated under reduced pressure. 35 g of crude 
product were thus obtained which, when subjected to the action of 
hydrochloric acid in ethanol, provided 28 g of 
1-[(2-(1,1-dimethyl-ethyl)-4-quinolyl]-3-(4-piperidyl)-1-propanone, in the 
form of the dihydrochloride melting at 200.degree. C. 
The ethyl[2-(1,1-dimethyl-ethyl)-quinoline]-4-carboxylate may be prepared 
as indicated by J. P. Schaefer et al. (J. Heterocycl. Chemistry, 1970, 
607). 
EXAMPLE 13 
1-[2-(1,1-DIMETHYL-ETHYL)-4-QUINOLYL]-3-[1-(2-PHENYL-ETHYL)-4-PIPERIDYL]-1- 
PROPANOL (racemic) 
The operation was as in Example 5, starting from 10 g of 
1-[2-(1,1-dimethyl-ethyl)-4-quinolyl]-3-[1-(2-phenyl-ethyl)-4-piperidyl]-1 
-propanone dihydrochloride, 2.2 g of sodium methylate and 0.8 g of sodium 
borohydride in 250 ml of methanol. 8.4 g of 
1-[2-(1,1-dimethyl-ethyl)-4-quinolyl]-3-[1-(2-phenyl-ethyl)-4-piperidyl]-1 
-propanol dihydrochloride (racemic), which melted at 190.degree. C. were 
obtained. 
The starting ketone may be prepared in the following way: 
A mixture of 14 g of 
1-[2-(1,1-dimethyl-ethyl)-4-quinolyl]-3-(4-piperidyl)-1-propanone 
dihydrochloride, 9 g of (2-phenyl-ethyl)bromide and 21.3 g of potassium 
carbonate in 140 ml of dimethylformamide was heated for 7 hours at 
70.degree. C. The dimethylformamide was then eliminated by distillation 
under reduced pressure and the residue taken up with 400 ml of water and 
200 ml of toluene. The organic phase was separated, washed with 200 ml of 
water, dried and evaporated under reduced pressure. The crude product thus 
obtained, when subjected to the action of hydrochloric acid in ethanol, 
provided 13.7 g of 
1-[2-(1,1-dimethyl-ethyl)-4-quinolyl]-3-]1-(2-phenyl-ethyl)-4-piperidyl]-1 
-propanone dihydrichloride, which melted at 130.degree. C. 
EXAMPLE 14 
2-[1-METHYL-4-PIPERIDYL)-1-(2-PHENYL-4-QUINOLYL)-ETHANOL (racemic) 
A mixture of 2.55 g of 1-(2-phenyl-4-quinolyl)-2-(4-piperidyl)-ethanol 
(racemic), 1.1 g of methyl iodide and 0.6 g of potassium carbonate in 20 
ml of dimethylformamide was stirred for 2 hours at the ambient 
temperature. 20 ml of water and 30 ml of toluene were then added. The 
organic phase was separated, wahsed with water, dried over magnesium 
sulfate and evaporated under reduced pressure. 1 g of crude product was 
obtained which was fixed on a column of silica gel. The elution was 
effected with a 9/1 chloroform-diethylamine mixture. 0.57 g of 
2-(1-methyl-4-piperidyl)-1-(2-phenyl-4-quinolyl)-ethanol (racemic), which 
melted at 208.degree. C. was thus isolated. 
EXAMPLE 15 
3-[3(S)-ETHYL 4(R)-PIPERIDYL]-1-(6-METHOXY-4-QUINOLYL)-1(S)-PROPANOL 
A mixture of 6 g of 3-[3(R)-ethenyl 
4(R)-piperidyl]-1-(6-methoxy-4-quinolyl)-1(S)-propanol dihydrochloride, 15 
ml of a normal aqueous solution of sodium hydroxide, 1.2 ml of a 0.4% 
aqueous solution of formaldehyde and 60 ml of water was heated at 
120.degree. C. for 24 hours in an autoclave. After cooling, the reaction 
medium was made alkaline by addition of sodium hydroxide lye and extracted 
with methylene chloride. The organic phase was washed with water, dried 
over magnesium sulfate and evaporated under reduced pressure. The oily 
residue obtained was subjected to high pressure liquid chromatography 
(support: silica gel; eluant: 100/7.5/3.75 toluene-methanol-diethylamine 
mixture). The separated fractions containing the desired product were 
evaporated. There was thus recovered 2.6 g of an oil which, by the action 
of HCl in ethanol, was converted into the dihydrochloride. After three 
recrystallizations of this last product in ethanol, 0.7 g of 
3-[3(S)-ethenyl 4(R)-piperidyl]-1-(6-methoxy-4-quinolyl)-1(S)-propanol 
were obtained in the form of the dihydrochloride melting at 204.degree. C. 
EXAMPLE 16 
1-(2-CYCLOHEXYL-4-QUINOLYL)-3-(4-PIPERIDYL)-1-PROPANOL (racemic) 
The operation was as in Example 5, starting from 5.1 g of 
1-(2-cyclohexyl-4-quinolyl)-3-(4-piperidyl)-1-propanone monohydrochloride, 
1.3 ml of a 10N aqueous solution of sodium hydroxide (instead of sodium 
methylate) and 0.53 g of sodium borohydride in 100 ml of ethanol. 1.3 g of 
1-(2-cyclohexyl-4-quinolyl)-3-(4-piperidyl)-1-propanol (racemic) were 
finally obtained in the form of the sulfate melting at 260.degree. C. 
The starting ketone may be prepared as follows: 
350 ml of anhydrous tetrahydrofuran and 27 g of ethyl 
(2-cyclohexyl-quinoline)-4-carboxylate were added to 15 g of an 80% 
suspension of sodium hydride in oil, placed under a nitrogen atmosphere. 
The mixture was brought to the boil, then a solution of 24 g of ethyl 
3-(1-benzoyl-4-piperidyl)-propionate in 100 ml of anhydrous 
tetrahydrofuran and 12 g of potassium ethylate in 45 ml of 
dimethylformamide were added. Boiling was maintained for one hour, then 
the reaction mixture was cooled and 50 ml of ethanol were added. The 
solvents were eliminated by distillation under reduced pressure, water was 
added and the pH of the solution brought to 6 by addition of acetic acid. 
The solution was extracted with ethyl acetate. The organic phase was 
washed with water, dried over anhydrous magnesium sulfate and evaporated 
to dryness under reduction pressure. The residue was taken up with 500 ml 
of a concentrated aqueous solution of hydrochloric acid and the mixture 
heated at the boiling temperature for 23 hours. After cooling, the 
solution was made alkaline by addition of a 10N aqueous solution of sodium 
hydroxide, then the insoluble matter was extracted with methylene 
chloride. The organic phase was washed with water, dried over anhydrous 
magnesium sulfate and evaporated to dryness under reduced pressure. The 
residue was fixed on a column of silica gel, then eluted with a 95/5 
chloroform-diethylamine mixture. 14 g of the desired product were thus 
obtained in the form of the free base, which was then transformed into its 
monohydrochloride by the action of hydrochloric acid in ethanol. After 
recrystallization of said monohydrochloride in ethanol, 6.5 g of 
1-(2-cyclohexyl-4-quinolyl)-3-(4-piperidyl)-1-propanone monohydrochloride, 
which melted at 190.degree.-191.degree. C., were isolated. 
The ethyl (2-cyclohexyl-quinoline)-4-carboxylate may be prepared according 
to the method of J. F. Mead et al., J. Am. Chem. Soc., 1946, 68, 2708. 
Pharmacological properties of the compounds of formula (I): 
The antiarhythmic activity of the compounds of formula (I) has been 
demonstrated by means of two tests: the aconitine test on the rat and the 
chloroform test on the mouse. 
Aconitine test 
The principle of the method rests on the induction time of the ventricular 
arhythmia caused by the aconitine which is slowly fed by perfusion into 
rats. An antiarhythmic substance retards the appearance of the arhythmia 
and the delay is proportional to the activity of the substance. 
Groups of 5 male rats were used. An individual anesthesia was effected (10% 
urethane: 1 g/kg/ip) in order to permit a catheterization of the vein of 
the penis. The electrocardiogram was recorded. At time T=0 the substance 
studied was injected in the form of an aqueous solution, at the rate of 
2.5 ml of solution per kg in 30 seconds. At time T=60 seconds, say 30 
seconds after the end of the injection, the aconitine was perfused at the 
rate of 20 .mu.g per minute up to the appearance of supraventricular extra 
systoles. The time of perfusion of the aconitine was noted. 
The results are expressed by an ED.sub.50, which is the dose of product, in 
mg/kg, increasing by 50% the time of perfusion of the aconitine in 
comparison with the perfusion time of aconitine for the control animals. 
Chloroform test 
The technique of Lawson (J. Pharm. Exp. Therap., 160, 2231, 1968) was used, 
which consists in looking for a possible protection against the 
fibrillations caused by an inhalation of chloroform, which was continued 
up to apnoea. The product to be tested was administered intraperitoneally 
20 minutes before chloroformic intoxication and the possible protection 
against the arhythmia was shown by recording of the electrocardiogram, 
which was effected from the appearance of the apnoea. The activity of the 
products is expressed by an AD.sub.50 (dose of product in mg/kg which 
protects 50% of the animals). 
The results obtained are collected in the following Table, where are also 
given the toxicological data. 
TABLE 
______________________________________ 
Acute toxicity 
Antiarhythmic activity 
to mice Aconitine test 
Chloroform test 
Product of i.v. on the rat on the mouse, 
Example LD.sub.50 mg/kg 
ED.sub.50 mg/kg 
AD.sub.50 mg/kg 
______________________________________ 
4 21 1.22 2.5 
5 21.5 0.44 3 
6 20.3 0.43 3 
7 33 0.45 3 
8 (1(S)-propanol 
17 0.58 2.5 
isomer) 
8 (1(R)-propanol 
29 0.65 2.5 
isomer) 
9 (3(R)-ethenyl 
19 1 5 
isomer) 
9 (3(S)-ethenyl 
33 1.4 &gt;5 
isomer) 
12 26 0.8 -- 
Quinidine sulfate 
60 7.5 18 
(product of 
reference) 
______________________________________ 
It is seen from the above table that the compounds of formula (I) show 
remarkable antiarhythmic properties and are more active than the 
quinidine. 
Toxicological properties of the compounds of formula (I): 
The acute toxicities of the compounds of formula (I) (see results in the 
above Table) have been determined on the male mouse DC.sub.1 (Charles 
River), by the intravenous method. The LD.sub.50 have been calculated, 
after 3 days observation, by the cumulative method of J. J. Reed and H. 
Muench (Amer. J. Hyg., 27, 493, 1938). 
Therapeutic utilization: 
The medicaments according to the invention which contain a compound of 
formula (I) or a mixture of stereoisomeric compounds corresponding to the 
formula (I) or a salt of such a compound or mixture of stereoisomeric 
compounds with a pharmaceutically acceptable acid, associated with a 
pharmaceutically acceptable vehicle, may be used in human therapeutics for 
the treatment and/or the prevention of rhythm disturbances. They may be 
presented in all the forms used in the medicament field, such as 
compressed tablets, capsules, gelatin-coated pills, suppositories, 
ingestable or injectable solutions, etc. 
The dosage or posology depends on the desired effects and the method of 
administration used. For example, taken orally, it can be between 50 and 
800 mg of active substance per 24 hours, with single doses ranging from 10 
to 100 mg of active substance.