DERIVATIVES OF 4-[3-(4-QUINOLYL)PROPYL]- PIPERIDINE AND THEIR USE AS MEDICINES

DERIVES DE 4-[3-(4-QUINOLY)PROPYL]-PIPERIDINE, ET LEUR EMPLOI COMME MEDICAMENTS

English Abstract

ABSTRACT OF THE DISCLOSURE
Compounds, which can be used as medicaments,
having the formula:
<IMG>
in which X' is a hydrogen atom or a methoxy group, R' is a
vinyl or ethyl group, the carbon atom carrying the group R'
has the sinister (S) configuration and that carrying the group
3-(4-quinolyl) propyl has the rectus (R) configuration. Prepara-
tion of these compounds. Rapid action in treatment of depres-
sion and of migraines.

Claims

The embodiments of the invention in which an exclu-
sive property or privilege is claimed are defined as follows:
1. Process for preparing compounds having the
formula:
<IMG> (II)
in which X' is a hydrogen atom or a methoxy group, R' is a
vinyl or ethyl group, the carbon atom carrying the group R'
having the sinister (S) configuration and the carbon atom
carrying the 3-(4-quinolyl) propyl group having the rectus (R)
configuration, which comprises:
a) reducing compounds of the formula
<IMG> (III)
in which X' and R' have the same meaning as in formula (II),
the carbon atom carrying the R' group having the sinister (S)
configuration and the carbon atom in the 4 position of the
piperidine ring having the rectus (R) configuration; or
b) when R' is an ethyl group, subjecting a compound
of formula (II) wherein R' is a vinyl group to a catalytic
hydrogenation; or
12

c) when R' is a vinyl group, heating in an acid medium, compounds
of the formula
<IMG>
(IV)
in which X' is the same as defined above, and the carbon atom
carrying the vinyl group and that in position 4 on the piperi-
dine ring having the rectus (R) configuration.
2. Process according to claim l(a), wherein reduc-
tion is carried out by means of hydrazine hydrate in the presence
of alkali metal hydrate and a solvent.
3. Process according to claim 2, wherein the solvent
is an alcohol.
4. Process according to claim l(b), wherein said
catalytic hydrogenation is carried out at ambient temperature,
under a hydrogen pressure equal to the atmospheric pressure, in
an inert solvent.
5. Process according to claim 4, wherein said inert
solvent is an alcohol.
6. Process according to claim 5, wherein said al-
cohol is selected from the group consisting of methanol and
ethanol.
7. Process according to claim 4, wherein said inert
solvent is an acid.
13

8. Process according to claim 7, wherein said acid is
acetic acid.
9. Process according to claim 4, wherein said hydro-
genation is carried out in the presence of a catalyst selected
from the group consisting of palladium, nickel, rhodium,
ruthenium, and platinum.
10. Process according to claim 1, which comprises
converting the compounds of formula (II) into acid addition
salts thereof.
11. Process which comprises reducing 1-(6-methoxy
4-quinolyl)-3[3(S)-vinyl 4(R)-piperidyl]-1- propanone dihydro-
chloride in suspension in diethylene-glycol with potassium
hydroxide and hydrazine hydrate to give 4(R)-[3-(6-methoxy-
4-quinolyl) propyl] 3(S)- vinyl piperidine, and treating the
resulting compound with hydrochloric acid in ether to give the
corresponding hydrochloride.
12. Process which comprises heating 4(R)-[3-(6-
methoxy 4-quinolyl)propyl] 3(R)-vinyl piperidine with sulfuric
acid to give 4(R)-[3-(6-methoxy 4-quinolyl)propyl] 3(S)-vinyl
piperidine, and treating the resulting compound with hydro-
chloric acid to give the corresponding hydrochloride.
13. Process which comprises subjecting 4(r)-[3-(6-
methoxy 4-quinolyl)propyl ] 3(S)-vinyl piperidine monohydro-
chloride in ethanol to catalytic hydrogenation in the presence
of palladium palladized carbon to give 4(R)-[3-(6-methoxy 4-
quinolyl) propyl] 3(S)-ethyl piperidine, and treating the
resulting compound with fumaric acid to give the corresponding
fomarate.
14

14. Process which comprises heating 4(R)-[3-(4-
quinolyl) propyl] 3(R)-vinyl piperidine with sulfuric acid to
give 4(R)-[3-(4-quinolyl)propyl] 3(S)-vinyl piperidine.
15. The compounds of the formula:
<IMG> (II)
in which X' is a hydrogen atom or a methoxy group, R' is a
vinyl or ethyl group, the carbon atom carrying the group R'
has the sinister (S) configuration and that carrying the
3-14-quinolyl) propyl group has the rectus (R) configuration,
and their salts of addition with acids, whenever prepared by
the process of claims 1, 2 or 10 or its obvious chemical equi-
valents.
16. The compound 4(R)-[3-(6-methoxy-4-quinolyl)
propyl] 3(S)-sinyl piperidine and the corresponding hydro-
chloride whenever prepared by the process of claim 11 or its
obvious chemical equivalents.
17. The compound 4(R)-[3-(6-methoxy 4-quinolyl)
propyl] 3(S)-vinyl piperidine and the corresponding hydro-
chloride, whenever prepared by the process of claim 12 or
its obvious chemical equivalents.
18. The compound 4(R)-[3-(6-methoxy 4-quinolyl)
propyl] 3(S)-ethyl piperidine and the corresponding fumarate,
whenever prepared by the process of claim 13 or its obvious

chemical equivalents.
19. The compound 4(R)-[3-(4-quinolyl) propyl] 3(S)-
vinyl piperidine, whenever prepared by the process of claim 14
or its obvious chemical equivalents.
16

Description

This inventlon relates to derivatives o-E
(quinolyl-4)-3 propyl-4 piperidine which are useful as medicinal
products. I`he invention also relates to the process of preparing
-these compounds.
In the French patent application No. 76 18555 filed
on June 18, 1976 and published uncler No. 2,354,771, are des-
cribed medicaments containing as the active principle a compound
corresponding to the general formula
CH2- CH2- CH2--CN H ( I)
X ~ R
in which eit.her X and R are hydrogen atoms or R is a vinyl or
ethyl group and X is a hydrogen ato~ or a methoxy group in the
6 position, the carbon atoms of the piperidine ring which bear
the R group and the 3-~4-quinolyl) propyl group both having
the rectus (R) configuration.
The present invention relates to new derivatives
of 4-[3-(4-quinolyl)propyl] - piperidine and their use as medi-
caments.
These new derivatives correspond to the formula:
\0~- CH2- CH2 ~N H ( I I )
in which X' is a hydrogen atom or a methoxy group, R' is a
-1- ~

3~4
vinyl or ethyl group, the carbon atom carrying the group R'
has the sinister configuration (S) and the carbon atom carry-
ing the 3-(4-quinolyl) propyl group, that is the carbon in
position 4 on the piperidine ri.ng, has the rectus configura-
tion (R).
The compounds of formula (II) may be prepared by
reduction particularly by means of hydrazine hydrate in the
presence of an alkali metal hydroxide and a solvent such as an
alcohol, of the compounds of formula:
~ r ;~) ~C ( III)
in which X' and R' have the same meaning as in the formula (II),
the carbon carrying the R' group has the sinister configuration
(S) and the carbon in position 4 on the piperidine ring has the
rectus configuration (R).
The compounds of formula (III) for which R' is a
vinyl group may themselves be prepared by heating in an acid
medium the compounds of formul~:
R~
X ~ ~ ~ N - H (III)bis
in which R' is a vinyl group and the carbon atom carrying the
group R' and that in position 4 on the piperidine ring both

35~
have the rectus configuration (R).
me compounds of formula (II) for which R' is an
ethyl group may also be prepared by catalytic hydrogenation of
the corresponding compounds of formula (II) for which R' is a
vinyl group. This hydrogenation, for example, may be effected
at ambient temperature, under a hydrogen pressure equal to the
atmospheric pressure, in an inert solvent such as an alcohol
(for example methanol or ethanol) or an acid (for example
acetic acid), in the presence of a catalyst such as palladium,
nickel, rhodium, ruthenium or platinum.
Finally the compounds of formula (II) for which R'
is a vinyl gro~lp may also be prepared by heating in acid medium
compounds of the formula:
CH = CH2
S
X ~ 2 H2 ~ N - H (IV)
in which the carbon atom carrying the vinyl group and that in
position 4 on the piperidine ring have the rectus configura-
tion (R).
~ hen the reaction has finished, the reaction mixture
obtained in the above process is treated according to conven-
tional methods, physical (evaporation, solvent extraction, dis-
tillation, crystallisation, chromatography, etc...) or chemical
(formation of the salt and regeneration of the base, etc...) so
as to isolate the products of formula (II) in a pure state,
either as the free base or as a salt thereof with an acid.

35~
me compounds of formula (II) in the form of the
free base may if desired be converted in-to salts of addition
with a mineral or organic acid by the action of such an acid
in a suitable solvent.
As has been indicated in the French Patent applica-
tion No. 76,18555, the compounds of formula (I) are useful for
the treatment of the pathological states caused by a disturb-
ance in the functioning of the serotoninergical systems and in
particular find applications as psychotropic agents, more es-
pecially as antidepressants. These applications are connected
with the capacity of the compounds of formula (I) for inhibiting
the uptake of the serotonine by the membranes of the cerebral
neurons.
The compounds of formula (I) also possess the proper-
ty of causing the release of the sero-tonine contained either in
the neurones or in the blood platelets.
The compounds of formula (II) have the two properties
mentioned above for the compounds of formula (I). For the com-
pounds of formula (II), the property of causing the release of the
serotonine is considerably more marked than that of inhi~iting
the uptake of this amine. l~is could result therapeutically in
a very rapid action during the treatment of depression (in this
case the product acts on the serotonine of the cerebral neuro-
nes) and during the treatment of migraines (in this case the
product acts on the serotonine of blood platelets).
The following examples illustrate the invention
without it being limited thereto.
_XAMPLE 1 - 4(R)-[3-(6-methoxy-4-quinolyl) propyl] 3(S)-vinyl
piperidine.
0.31 g of potassium hydroxide is added to a suspen-
sion of 1.1 g of 1-(6-méthoxy 4-quinolyl)-3-[3(S)-vinyl 4(R)-

35D,t
piperidyl]-l-propanone dihydrochloride in 3.5 ml of diethylene-
glycol and 0.18 ml of an 85% aqueous solution of hydrazine hy-
drate. The mixture is slowly heated to 150C, then cooled to
100C, and 0.47 g of potassium hydroxyde is introduced. The
reaction mixture is heated to 150C and maintained at this tem-
perature for 5 hours.
After cooling the reaction mixture is treated with
15 ml of water. The oil which separates out is extracted with
ethyl acetate. The organic phase is decanted, washed, dried
over magnesium sulphate and then evaporated. The crude oil ob-
tained is fixed on a column containing 45 g of silica and then
eluted with a mixture containing 90% of chloroform and 10% of
diethylamine.
The purified product thus isolated is dissolved in
acetone and converted into the hydrochloride by addition of a
solution of hydrochloric acid in ether. 0.24 g of 4(R)-[3-(6-
methoxy 4-quinolyl) propyl] 3(S)-vinyl piperidine hydrochloride
is obtained. This product melts at 151C.
The starting ketone was prepared as follows:
20 ml of distilled water were added to 2.1 g of 1-
(6-methoxy 4-quinolyl)-3 [3(R)-vinyl 4(R)-piperidyl]-l-
propanone (quinicine) and the -~H was brought to 3.5 by adding
a lN solution of sulfuric acid. The mixture was introduced in
a 225 ml autoclave made of stainless steel and heated for 48
hours at 140C. The solution was then made alkaline by adding
a 2N solution of sodium hydroxyde and extracted with ether.
The ethereal extract was washed with water, dried over anhydrous
sodium sulfate and evaporated to dryness.
The residue obtained (1.7 g) was dissolved in a small
amount of a 9/1 toluene-diethylamine mixture and fixed on a
column containing 500 g of silica. It was then eluted with a

Z~35~
9/1 toluene-diethylamine mixture, under a pressure of 4 bars.
0.51 g of the starting product tquinicine) and 1.08 g of 1-(6-
methoxy~-quinolyl)-3-[3~S)-vinyl 4(R)-piperidyl]-l-propanone
were thus isolated. The latter compound was dissolved in
methanol and converted into its hydrochloride by adding a 8N
solution of hydrochloric acid in methanol.
EXAMPLE 2 - ~(R)-[3-(6~methoxy 4-quinolyl)propyl] 3(S)-vinyl
piperidine.
2.1 g of 4(R)-[3-(6-methoxy 4-quinolyl)propyl] 3(R)-
vinyl piperidine were dissolved in 20 ml of distilled water andthe pH was adjusted to 2 by adding a 5N solution of sulfuric
acid. me mixture was introduced into a 225 ml stainless steel
autoclave and heated for 48 hours at 140C. Then the solution
was made alkaline by addin~ a 2N solution of sodium hydroxide
and extracted with ether. The ethereal extract was washed with
water, dried over anhydrous sodium sulfate and evaporated to
dryness. The residue obtained (1.9 g) was dissolved in a little
9/1 toluene-diethylamine mixture and ~ixed on a column contain-
ing 500 g of silica. By eluting with a 9/1 toluene-diethylamine
mixture under a pressure of 4 bars, 0.71 g of the starting
product and 0.68 g of 4 (R)-[3-(6-methoxy 4-quinolyl)propyl]
3(S)-vinyl piperidine were isolated in the form of an oil.
The latter compound was dissolved in methanol and
converted into its hydrochloride by adding a solution of hydro-
chloric acid in methanol.
Characteristics of 4(R)-[3-(6-methoxy 4-quinolyl)
propyl] 3(S)-vinyl piperidine hydrochloride:
melting point 151C
rotary power (measured in water at 25C):

~;~5~
~] = - 31
D
N.M.R. spectrum (solvent: deuterochloroform, reference: tetra-
methylsilane):
The chemical shifts ~ of the hydrogen atoms numbered
10, 11, and 11' in the formula (V) hereinafter are:
lQ = 5-4 ppm
Sll, 11~ 5 Ppm
11 ~ 10
C = C (V)
///~
11' ~ N - H
The preparation of the 4(R)~3-(6-methoxy-4-quinolyl)
propyl] 3(R)-vinyl piperidine used as starting substance is des-
cribed in French application No. 76 185~5.
EXAMPLE 3 - 4(R)-~3-(6-methoxy 4-quinolyl) propyl] 3(S)-ethyl
piperidine.
A well-stirred suspension containing 2 g of 10%
palladium palladized carbon and 6.8 g of 4 (R)-[3-(6-methoxy
4-quinolyl~ propyl~ 3(S)-vinyl piperidine monohydrochloride in
solution in 100 ml of absoluke ethanol was maintained at ambient
temperature under a pressure of hydrogen corresponding to an ex-
cess pressure of 50 mm of water relative to atmospheric pressure,
until the absorption of hydrogen ceased~
The palladized carbon was then separated by filtra-
tion and the alcoholic solution was concentrated. The residue
was then dissolved in 50 ml of water and the solution was
brought to pH 10 by adding a solution of sodium hydroxideO

35~
The oil which salted out was extracted with chloro-
form and the extract was washed with water, then dried over
magnesium sulfate. After evaporation of chloroform, the resi-
dual oil (5.6 g) was converted into fumarate by dissolution in
e-thanol and addition of 2.1 g of fumaric acid.
5.5 g of the acid fumarate of 4(R)-[3-(6-methoxy
4-quinolyl)propyl] 3(S)-ethyl piperidine are obtained. This
compound melts at 180C.
~ nalysis for C20 H28N2~ C4H404
Calculated~ % N = 6.54
Found : % N = 6.47
EXAMPLE 4 - 4(R)-[3-(4-quinolyl)propyl] 3(S) - vinyl piperidine.
~y operating as in example 2, but replacing the 2.1 g
of 4 (R) -C3-(6-methoxy 4-quinolyl) propyl~ 3(R)-vinyl pipe-
ridine with 1.3 g of 4 (R)-[3-(4-quinolyl)propyl] 3(R)-vinyl
piperidine, 0.8 g of 4(R) -[3-(4-quinolyl)propyl] 3(S)-vinyl
piperidine are obtained in the form of an oil.
Characteristics of 4~R)-[3~(4-quinolyl)propyl] 3(S)-
vinyl piperidine:
~.M.R. spectrum:
me chemical shifts ~ of the hydrogen atoms num-
bered 10, 11 and 11' in the formula (~) are:
~10 = 5 4 ppm
~11,11~ = 5-05 ppm
m e preparation of the 4(R)-[3-(4-~uinolyl)propyl]
3(R)_vinyl piperidine used as starting substance is described
in French application No. 76 18S55.
PHARMACOLOGICAL PROPERTIES
_
It is known that the uptake of serotonine by the
blood plates is a good model of the uptake of this amine by
neurons [see ~. TUOMISTO, J. Pharm., Pharmac., ~6, 9~ (1974)].

354L
When it is applied to the investigation of medicaments, a method
which brings into play the blood plates presents a great inte-
rest because it makes it possible to use human cells, which
enables the method to give a good anticipation of the effect of
the products on human beings.
The capacit~ of the products for inhibiting the up-
take of serotonine or for causing its release has been shown on
human blood plates, according to J.L. D~VID et al. "Platelets
Function and thrombosis, a review of methods" p. 335 (Plenum
Press, London, 1972).
a) Inhibition of the uptake of serotonine
The results are expressed by a 50% inhibiting dose
I50, which represents the product dose in micromoles per liter
reducing the uptake of serotonine by 50%.
b) Release of serotonine
The action of the products on the release of sero-
tonine has been tested at two concentrations: 5 x 10 6 mole per
liter and 5 x 10 5 mole per liter.
The results obtained are expressed by a percentage
of increase of the release of serotonine in comparison with the
results obtained with the controls.
The results obtained are compiled in the following
Table. In this table are also given for comparison the results
obtained with two reference products (imipramine, p-chloro
amphetamine).

354
TABLE
_. Inhibi-tion of Percen-tage of increase of th~
the uptake of release of serotonine
serotonine
Product I ( M/l) Concentration Concentration
50 ~ of the product of the product
5 x 10 6 mole 5 x 10 5 mole
~ per liter Per liter
Concentration of 1 ~O 78
example 1
Concentration of
example 3 ~0.1 30 69
4(R~-[3-(6-metho-
xy 4-quinolyl)
propyl] 3(R)-
vinyl piperidine,
epimer of the
compound of
example 1 0.01 7 32
_ _
4(R)-[3-(6-metho-
xy 4-quinolyl)
propyl] 3(R)-
ethyl piperidine,
epimer of the
compound of
example 3 O.Ol _ 67
Imipramine 0.4 3 13
p-chloro
amphetamine 12 6 51
_ .
It can be seen from the Table tha-t the compounds of
examples 1 and 3 are much less ef-fective than their epimers as
inhibitors of uptake of serotonine (the compound of example 1
is one hundred times less effective than its epimer, and the
compound of example 3 is at least ten times less ef-fective than
its epimer).
The compounds of examples 1 and 3 are powerful agents
for the release of serotonine. They are even more effective
than p-chloro amphetamine.
TOXICOLOGICAL PROPERTIES
The acute toxicity of the products has been deter-
--10--

3s4
mined on the male mouse CDl (Charles River) given orally.
The LD50 calculated, after 3 days of observation, bythe cumulative method of ~.J. REED and Coll. (Am.J.Hyg., 1938,
27, 493) is 225 mg/kg for the compound of Example 1 and about
200 mg/kg for the compound of Example 3.
m e compounds according to the invention are atoxic
at 100 mg/kg and then be~ave like substances of relatively
little toxicity to mice.
THERAPEUTIC USE
The compounds of the invention and their pharmaceu-
tically acceptable salts may be used in human therapeutics in
the form of compressed tablets, capsules, gelatine-coated
pills, suppositories, ingestable or injectable solutions, etc
as regulators of the serotonine-dependant vascular tonicity,
especially for the treatment of migraines, and as thymoanaleptic
medicaments with a particularly rapid action (owing to their
action on the release of serotonine).
I~e posology depends on the effects sought and on the
method of administration used. For example, taken orally, it may
be between 15 and 250 mg of active substance per day, with
single doses from 5 to 60 mg.