1-(4-quinolyl)-2 or 3-(4-piperidyl)-ethanamine and -propanamine derivatives, and their use

The invention provides the compounds of formula ##STR1## in which n equals 1 or 2, PA0 R denotes hydrogen, alkyl of 1 to 4 carbon atoms or phenyl, PA0 R.sub.1 denotes hydrogen, alkyl of 1 to 4 carbon atoms or alkenyl of 2 to 4 carbon atoms, X and Y, which may be identical or different, are each attached to the quinoline ring system in position 5, 6, 7 or 8, and each denote hydrogen or alkoxy of 1 to 3 carbon atoms. These compounds are useful in the treatment of cardiac arrhythmias.

The present invention provides new 1-(4-quinolyl)-2-(4-piperidyl)ethanamine 
and 1-(4-quinolyl)-3-(4-piperidyl)-propanamine derivatives of the formula 
##STR2## 
in which n equals 1 or 2, R denotes hydrogen, alkyl of 1 to 4 carbon atoms 
or phenyl, R.sub.1 denotes hydrogen, alkyl of 1 to 4 carbon atoms or 
alkenyl of 2 to 4 carbon atoms, X and Y, which may be identical or 
different, are each attached to the quinoline ring system in position 5, 
6, 7 or 8, and each denote hydrogen or alkoxy of 1 to 3 carbon atoms, in 
the form of their diastereoisomers, racemates, and enantiomers, and their 
acid salts. These compounds are useful in the treatment or prevention of 
cardiac arrhythmias. 
The preferred compounds are those in which Y is hydrogen, X is hydrogen or 
methoxy, R is hydrogen, tert-butyl group or phenyl, and R.sub.1 is 
hydrogen, ethenyl or ethyl. 
When R.sub.1 is hydrogen, the molecule of the compounds of formula (I) 
contains an asymmetric carbon atom (the carbon atom bearing the amino 
group) and hence, for a given significance of X, Y, R, R.sub.1 and n, 
there are one racemate and two enantiomers. 
When R.sub.1 does not denote a hydrogen atom, the molecule of the compounds 
of formula (I) contains 3 assymmetric carbon atoms and hence, for a given 
significance of X, Y, R, R.sub.1 and n, there are 8 stereoisomers, the 
respective formulae of which correspond to the 3-by-3 combinations of the 
rectus (R) or sinister (S) configurations of each asymmetric centre. 
These various isomers form part of the invention, as do the acid addition 
salts of the compounds of formula (I) with inorganic or organic acids. 
The compounds of formula (I) can be prepared from the ketones of formula 
##STR3## 
in which n, X, Y, R and R.sub.1 are as hereinbefore defined, by processes 
for converting a ketone into a primary amine, such as those, for example, 
described in C. A. BUEHLER and D. E. PEARSON, Survey of Organic Synthesis, 
Wiley Interscience, vol. 1, 1970, p. 423 and 427. 
An advantageous method consists in treating the ketone of formula (II) with 
ammonium formate, e.g. at a temperature from 150.degree. to 200.degree. 
C., and hydrolysing the product, e.g. in an acidic aqueous medium under 
reflux. 
Another method consists in treating the ketone of formula (II) with 
hydroxylamine in a solvent such as ethanol at a temperature from room 
temperature to the boiling point of the solvent, and then reducing the 
oxime obtained, e.g. by a process described in HOUBEN-WEYL, Methoden der 
Organischen Chemie, 11, (1) p. 495 (Georg. Thieme Verlag--Stuttgart, 
1957). 
An especially advantageous method of reducing the oxime consists in using 
zinc powder in aqueous alcoholic ammoniacal medium. 
When R.sub.1 is a hydrogen atom, the ketones of formula (II) lead to 
racemic compounds of formula (I). 
When R.sub.1 is not a hydrogen atom, the ketones of formula (II) leads to a 
mixture of racemic or optically active diastereoisomeric compounds 
depending on whether the starting ketone is racemic or optically active. 
The compounds of formula (I) in which R.sub.1 denotes an alkyl group 
containing 2 to 4 carbon atoms can also be prepared by catalytic 
hydrogenation of the corresponding compounds of formula (I) in which 
R.sub.1 denotes an alkenyl group having 2 to 4 carbon atoms. This 
hydrogenation can, for example, be carried out at room temperature under a 
hydrogen pressure equal to atmospheric pressure, in an inert solvent such 
as an alcohol, e.g. methanol or ethanol, in the presence of a catalyst 
such as palladium, nickel, rhodium, ruthenium or platinum. 
The pure diastereoisomers can be isolated from the mixture by conventional 
methods such as chromatography, fractional crystallisation, salt formation 
and regeneration of base. 
The ketones of formula (II) can be prepared by the process described in 
French Pat. No. 2,495,470.

The Examples which follow illustrate the invention. 
EXAMPLE 1 
3-[3(R)-ETHENYL-4(R)-PIPERIDYL]-1-(6-METHOXY-4-QUINOLYL)-1(RS)-PROPANAMINE 
A mixture of quinicine (21 g), hydroxylamine hydrochloride (5.5 g) and 
anhydrous sodium acetate (6.4 g) in ethanol (260 ml) is boiled under 
reflux for 24 hours. The ethanol is evaporated, the residue taken up in 
water, the aqueous solution made alkaline with aqueous ammonia, and the 
insoluble material extracted with ethyl acetate. 
The organic phase is washed with water, dried over anhydrous magnesium 
sulphate and evaporated to dryness under reduced pressure. A product (21 
g) is obtained which is taken up in a mixture of ethanol (125 ml), water 
(125 ml) and concentrated aqueous ammonia (19 ml) to which ammonium 
acetate (5 g) is added. The mixture is stirred at room temperature and 
zinc powder (19 g) added in portions. The mixture is finally refluxed for 
3 hours. 
After cooling, the mixture is filtered through kieselguhr and ethanol 
removed under reduced pressure. The residue is taken up in water, the 
aqueous phase is made alkaline using sodium hydroxide, and the oil which 
separates out is extracted with chloroform. The organic phase is washed 
with water, dried and evaporated to dryness under reduced pressure. A 
product (20 g) is obtained which is chromatographed on silica gel using an 
ethanol/diethylamine (99:1) mixture as eluent. A product (16 g) is 
obtained which is treated with fumaric acid (2.81 g) in ethanol. After 
recrystallisation from the same solvent, 
3-[3R-ethenyl-4(R)-piperidyl]-1-(6-methoxy-4-quinolyl)-1(RS)propanamine 
(5.2 g) is obtained as the sesquifumarate, m.p. 220.degree. C. 
EXAMPLE 2 
1-[2-(1,1-DIMETHYLETHYL)-4-QUINOLYL]-3-(4-PIPERIDYL)-1-PROPANAMINE 
To 1-[2-(1,1-dimethylethyl)-4-quinolyl]-3-(4-piperidyl)-1-propanone (6 g), 
ammonium formate (15 g) is added and the mixture is heated at 160.degree. 
C. for 8 hours. After being cooled, the mixture is taken up in methylene 
chloride and water. The organic phase is washed with water, dried and 
evaporated to dryness under reduced pressure. The residue is taken up in 
6N hydrochloric acid (60 ml) and the mixture is refluxed for 22 hours. 
The mixture is then diluted with water. The solution is made alkaline with 
concentrated caustic soda solution and the insoluble material is extracted 
with methylene chloride. The organic phase is washed with water, dried 
over anhydrous magnesium sulphate and evaporated to dryness under reduced 
pressure. A product (4.1 g) is obtained which is converted into the 
di-hydrochloride in ethanol. After recrystallisation from 95% ethanol, 
1-[2-(1,1-dimethylethyl)-4-quinolyl]-3-(4-piperidyl)-1-propanamine 
dihydrochloride (1.55 g) is obtained, m.p. above 265.degree. C. 
1-[2-(1,1-Dimethylethyl)-4-quinolyl]-3-(4-piperidyl)-1-propanone 
hydrochloride can be prepared as described in French Pat. No. 2,495,470. 
EXAMPLE 3 
1-(2-PHENYL-4-QUINOLYL)-2-(4-PIPERIDYL)ETHANAMINE 
A mixture of 1-(2-phenyl-4-quinolyl)-2-(4-piperidyl)ethanone (11 g) and 
ammonium formate (27.3 g) is heated at 190.degree. C. for 18 hours. After 
being cooled, the reaction medium is taken up in chloroform and water. The 
organic phase is washed with water, dried over magnesium sulphate and 
evaporated to dryness under reduced pressure. The residue is 
chromatographed on silica gel with a chloroform/diethylamine (9:1) mixture 
as eluent. After concentration of the requisite fractions, a product (11.6 
g) is obtained which is taken up in 6N hydrochloric acid (70 ml) and 
boiled for 18 hours. 
After being cooled, the aqueous phase is washed with ethyl ether and made 
alkaline with concentrated ammonia solution. The insoluble material is 
extracted with chloroform. The chloroform solution is washed with water, 
dried over magnesium sulphate and evaporated to dryness under reduced 
pressure. A product (8 g) is obtained which is chromatographed on silica 
gel with a chloroform/methanol/diethylamine (8:1:1) mixture as eluent. On 
concentration of the requisite fractions, a product (4 g) is obtained 
which is treated with ethanolic hydrogen chloride. 
1-(2-Phenyl-4-quinolyl)-2-(4-piperidyl)ethanamine (1.1 g) is thus obtained 
as the dihydrochloride, m.p. 226.degree. C. 
1-(2-Phenyl-4-quinolyl)-2-(4-piperidyl)ethanone can be prepared as 
described in French Pat. No. 2,471,981. 
EXAMPLE 4 
3-[3(R)-ETHYL-4(R)-PIPERIDYL]-1-(6-METHOXY-4 QUINOLYL)-1(RS)-PROPANAMINE 
3-[3(R)-ethenyl-4(R)-piperidyl]-1-(6-methoxy-4 quinolyl)-1(RS)-propanamine 
(1.2 g) dissolved in absolute ethanol (25 ml) is hydrogenated at 
atmospheric pressure and at room temperature in the presence of palladium 
(0.25 g, 10% on carbon). The absorption of hydrogen is complete in 2 
hours. The catalyst is filtered off, the solvent is evaporated under 
reduced pressure, and the residue is recrystallised from isopropanol. 
3-[3(R)-Ethyl-4(R)-piperidyl]-1-(6-methoxy-4 quinolyl)-1(RS)-propanamine 
is thus obtained as the trihydrochloride, m.p. 200.degree. C. 
The proton NMR spectrum of the base is deuterated chloroform has the 
following characteristics: 
CH.sub.3 O--.delta.: 3.9 ppm, H.sub.2 .delta.: 8.7 ppm, H.sub.3 .delta.: 
7.5 ppm, H.sub.5 .delta.: 7.3 ppm, H.sub.8 .delta.: 8.0 ppm. 
##STR4## 
--CH.sub.2 --CH.sub.3 .delta.: 0.8 ppm. 
The antiarrhythmic activity of the compounds of formula (I) has been 
demonstrated by means of the aconitine test. 
The principle of the technique rests on the time taken by aconitine to 
induce ventricular arrhythmias when it is slowly perfused in rats. An 
antiarrhythmic substance delays the appearance of the arrhythmia and this 
delay is proportional to the activity of the substance. 
Groups of 5 male rats are used. Individual anaesthetisation is carried out 
(10% urethane: 1 g/kg/ip) to permit catheterisation of the vein of the 
penis. The electrocardiogram is recorded. At time T=0, the substance being 
studied is injected as an aqueous solution, in the proportion of 2.5 ml of 
solution per kg, in the course of 30 seconds. At time T=60 seconds, i.e. 
30 seconds after completing the injection, aconitine is perfused at the 
rate of 20 .mu.g per minute until supraventricular extrasystoles appear. 
The perfusion time of the aconitine is noted. 
The results are expressed as ED.sub.50, i.e. the dose of the product under 
test in mg/kg which increases by 50% the perfusion time of aconitine 
relative to control animals. 
The results obtained are collated in the Table below: 
______________________________________ 
Product of ED.sub.50 mg/kg i.v. 
______________________________________ 
Example 1 5 
Example 2 1.2 
Example 3 0.38 
QUINDINE 7.5 
______________________________________ 
The compounds of formula (I) thus have exceptional antiarrhythmic 
properties and are more active than quinidine. 
The acute toxicities of the compounds of the invention were determined by 
intravenous administration to male CD.sub.1 mice (Charles RIVER). The 
LD.sub.50 values were calculated after 3 days of observation by the 
cumulative method of J. J. REED and H. MUENCH (Amer. J. Hyg. 1938, 27, 
493). The LD.sub.50 values of the compounds of formula (I) are greater 
than 15 mg/kg i.v. 
The compounds of formula I and their pharmaceutically acceptable acid 
addition salts can be used in human therapy for treating and/or preventing 
disturbances of cardiac rhythm. For this purpose they may be used in the 
form of pharmaceutical compositions comprising, as active ingredient, a 
compound of formula I, or a pharmaceutically acceptable acid addition salt 
thereof. In these compositions, the active ingredient may be in 
association with a compatible pharmaceutically acceptable diluent, 
adjuvant or coating which is usually a solid or semi-solid, a liquid 
containing a sweetener, flavouring, thickener, colorant, stabilizer, 
and/or wetting agent, or a sterile injectable liquid. Such compositions 
may normally contain 1 to 95% by weight of the active ingredient. 
The compositions of the invention may be given by oral (including 
sub-lingual), parenteral, or rectal administration. 
Solid compositions for oral administration may be tablets, pills, powders 
(particularly in gelatin capsules or cachets) or granules. In these 
compositions, the active compound of the invention may be mixed with one 
or more inert diluents such as starch, cellulose, sucrose, lactose or 
silica. These compositions may also contain substances other than 
diluents, for example one or more lubricants such as magnesium stearate or 
talc, a colorant, a coating (coated tablets) or a varnish. 
Liquid compositions for oral administration may be solutions, suspensions, 
emulsions, syrups and pharmaceutically acceptable elixirs containing inert 
diluents such as water, ethanol, glycerol, vegetable oils or paraffin 
oils. These compositions may contain substances other than diluents, for 
example wetting agents, sweeteners, thickeners, flavourings, colorants or 
stabilisers. 
Sterile compositions for parenteral administration are preferably aqueous 
or non-aqueous solutions, suspensions or emulsions. The solvent or vehicle 
may be, for example, water, propylene glycol, polyethylene glycol, a 
vegetable oil, especially olive oil, an injectable organic ester, for 
example ethyl oleate, or other suitable organic solvent. These 
compositions may also contain adjuvants, in particular wetting agents, 
isotonising agents, emulsifiers, dispersants and stabilisers. 
Sterilisation may be carried out in various ways, for example by 
asepticising filtration, by incorporating sterilising agents in the 
composition, by irradiation or by heating. The compositions may also be 
prepared in the form of sterile solid compositions which may be dissolved 
at the time of use in an injectable sterile medium. 
The compositions for rectal administration may be suppositories or rectal 
capsules which, in addition to the active product, contain a semi-solid 
excipient such as cocoa butter, a semi-synthetic glyceride or a 
polyethylene glycol. 
The dosage depends on the effect sought, the condition of the patient, and 
the administration route used. For example, for oral administration to an 
adult of, e.g. 70 kg., it can be between 50 and 800 mg of active 
substance per 24 hours, each unit dose containing from 10 to 100 mg of the 
active ingredient.