PIPERAZINES 4-(.beta.-2-QUINOLYLETHYL) 1-SUBSTITUEES ET ANALOGUES 1,2,3,4-TETRA-HYDRO-QUINOLEINIQUES

1-SUBSTITUTED 4-(.beta.-2-QUINOLYLETHYL)-PIPERAZINES AND 1,2,3,4-TETRAHYDRO QUINOLINE ANALOGUES THEREOF

Abrégé anglais

Abstract of the Disclosure
Pharmacologically active 1-substituted 4-(.beta.-2-quinolylethyl)-
piperazines of the formula:
<IMG>
and their 1,2,3,4-tetrahydroquinoline analogues, wherein R represents a lower
alkyl or an aryl, aralkyl or a phenyl group which is either unsubstituted or
substituted by one or more alkyl, alkoxy, halo or trihaloalkyl groups; and
non toxic acid addition and quaternary ammonium salts thereof. A general
method of preparation of the invention compounds starts from 2-vinylquinoline
with the appropriate 1-substituted piperazine. The positions 1,2,3,4 of the
quinoline ring may then be hydrogenated to give the tetrahydroderivatives.
The products have high hypotensive activity associated with a low degree of
toxicity.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the formula:
<IMG>
(I)
wherein R represents a lower alkyl, an aralkyl group or a phenyl group which
is either unsubstituted or substituted by one or more alkyl, alkoxy, halo or
trihaloalkyl groups, 1,2,3,4-tetrahydroquinolyl analogues thereof and
pharmaceutically acceptable acid addition and quaternary ammonium salts of
all such derivatives, which comprises either:- (a) reacting a piperazine of
the formula:-
<IMG>
(III)
wherein R is as defined above, with 2-vinylquinoline; or (b) carrying out
process step (a) followed by reducing the product so obtained to the corre-
sponding 1,2,3,4-tetrahydroquinoline derivative; or (c) carrying out process
step (a) or process steps (a) and (b) followed by conversion of the base so
obtained to a corresponding pharmaceutically acceptable acid addition or
quaternary ammonium salt.
2. A process according to claim 1 in which step (a) is effected in a
protic solvent.
3. A process according to claim 1 in which step (a) is effected in a
mixture of methanol, ethanol, propanol or butanol and an aliphatic carboxylic
acid.
4. A process according to claim 1 for preparing a compound of the
formula:

<IMG>
(I)
wherein R represents a lower alkyl, an aralkyl group or a phenyl group which
is either unsubstituted or substituted by one or more alkyl, alkoxy, halo or
trihaloalkyl groups, and its 1,2,3,4-tetrahydroquinolyl analogues, which com-
prises reacting equimolecular amounts of 2-vinylquinoline, a lower aliphatic
carboxylic acid and a piperazine substituted at position 1 with a group R of
the above significance.
5. A process according to claim 1 in which step (b) is effected by
means of reaction with an alkali metal in a lower alkanol or hydrogen in the
presence of a catalyst.
6. A compound selected from 1-substituted 4-(.beta.-2-quinolylethyl)-piper-
azines of the formula:
<IMG>
(I)
their analogues hydrogenated in the positions 1, 2, 3, 4 of the quinoline
ring, and pharmaceutically acceptable acid addition and quaternary ammonium
salts thereof, wherein R represents a lower alkyl, an aralkyl group or a
phenyl group which is either unsubstituted or substituted by one or more alkyl,
alkoxy, halo or trihaloalkyl groups whenever prepared by the process of claim
1 or by an obvious chemical equivalent thereof.
7. A process according to claim 1 in which 1-(m-Tolyl)-4-.beta.-2-quinolyl-
ethyl)-piperazine is prepared by reacting 2-vinylquinoline with N-(m-tolyl)-
piperazine.

8. A process according to claim 1 in which 1-(o-tolyl)-4-(.beta.-2-quinolyl-
ethyl)-piperazine is prepared by reacting 2-vinylquinoline with N-(o-tolyl)-
piperazine.
9. A process according to claim 1 in which 1-(p-tolyl)-4-.beta.-2-quinolyl-
ethyl)-piperazine is prepared by reacting 2-vinylquinoline with N-(p-tolyl)-
piperazine.
10. A process according to claim 1 in which 1-(p-methoxyphenyl)-4-(.beta.-2-
quinolylethyl)-piperazine is prepared by reacting 2-vinylquinoline with N-(p-
methoxyphenyl)-piperazine.
11. A process according to claim 1 in which 1-(o-methoxyphenyl)-4-.beta.-2-
quinolylethyl)-piperazine is prepared by reacting 2-vinylquinoline with N-(o-
methoxyphenyl)-piperazine.
12. A process according to claim 1 in which 1-phenyl-4-(.beta.-2-quinolyl-
ethyl)piperazine is prepared by reacting N-phenylpiperazine with 2-vinyl-
quinoline.
13. A process according to claim 1 in which 1-(2,5-xylyl)-4-(.beta.-2-quinolyl-
ethyl)-piperazine is prepared by reacting 2-vinylquinoline with N-(2,5-xylyl)-
piperazine.
14. A process according to claim 1 in which 1-(p-chlorophenyl)-4-(.beta.-2-
quinolylethyl)-piperazine is prepared by reacting 2-vinylquinoline with N-(p-
chlorophenyl)-piperazine.
15. A process according to claim 1 in which 1-(methyl)-4-(.beta.-2-quinolyl-
ethyl)-piperazine is prepared by reacting 2-vinylquinoline with N-(methyl)-
piperazine.
16. A process according to claim 1 in which 1-(o-chlorophenyl)-4-(.beta.-2-
quinolylethyl)-piperazine is prepared by reacting 2-vinylquinoline with N-(o-
chlorophenyl)-piperazine.

17. A process according to claim 1 in which 1-(m-chlorophenyl)-4-(.beta.-2-
quinolylethyl)-piperazine is prepared by reacting 2-vinylquinoline with N-(m-
chlorophenyl)-piperazine.
18. A process according to claim 1 in which 1-(m-trifluoromethylphenyl)-
4-(.beta.-2-quinolylethyl)-piperazine is prepared by reacting 2-vinylquinoline
with N-(m-trifluoromethylphenyl)-piperazine.
19. A process according to claim 1 in which 1-(3,4-dichlorophenyl)-4-(.beta.-
2-quinolylethyl)-piperazine is prepared by reacting 2-vinylquinoline with N-
(3,4-dichlorophenyl)-piperazine.
20. A process according to claim 1 in which 1-(2,4-xylyl)-4-(.beta.-2-quinolyl-
ethyl)-piperazine is prepared by reacting 2-vinylquinoline with N-(2,4-xylyl)-
piperazine.
21. A process according to claim 1 in which 1-(3,4-xylyl)-4-(.beta.-2-quinol-
ylethyl)-piperazine is prepared by reacting 2-vinylquinoline with N-(3,4-xylyl)-
piperazine.
22. A process according to claim 1 in which 1-(.beta.-phenethyl)-4-(.beta.-2-
quinolylethyl)-piperazine is prepared by reacting 2-vinylquinoline with N-(.beta.-
phenethyl)-piperazine.
23. A process according to claim 1 in which 1-(o-fluorophenyl)-4-(.beta.-2-
quinolylethyl)-piperazine is prepared by reacting 2-vinylquinoline with N-(o-
fluorophenyl)-piperazine.
24. A process according to claim 1 in which 1-(m-fluorophenyl)-4-(.beta.-2-
quinolylethyl)-piperazine is prepared by reacting 2-vinylquinoline with N-(m-
fluorophenyl)-piperazine.
25. A process according to claim 1 in which 1-(p-fluorophenyl)-4-(.beta.-2-
quinolylethyl)-piperazine is prepared by reacting 2-vinylquinoline with N-(p-
fluorophenyl)-piperazine.
11

26. A process according to claim 1 in which 1-benzyl-4-(.beta.-2-quinolyl-
ethyl)-piperazine is prepared by reacting 2-vinylquinoline with N-benzyl-
piperazine.
27. A process according to claim 1(b) in which 1-phenyl-4-[.beta.-2-(1,2,3,4-
tetrahydroquinolyl)-ethyl]-piperazine and its hydrochloride are prepared by
reducing 1-phenyl-4-(.beta.-2-quinolylethyl)-piperazine and when the corresponding
hydrochloride is required reacting the base so obtained with hydrogen chloride.
28, A process according to claim 1(b) in which 1-(m-tolyl)-4-[.beta.-2-
(1,2,3,4-tetrahydroquinolylethyl)]-piperazine and its hydrochloride are pre-
pared by reducing 1-(m-tolyl)-4-(.beta.-2-quinolylethyl)-piperazine and when the
corresponding hydrochloride is required reacting the base so obtained with
hydrogen chloride.
29. A process according to claim 1(b) in which 1-(o-tolyl)-4-[.beta.-2-
(1,2,3,4-tetrahydroquinolylethyl)]-piperazine and its hydrochloride are pre-
pared by reducing 1-(o-tolyl)-4-(.beta.-2-quinolylethyl)-piperazine and when the
corresponding hydrochloride is required reacting the base so obtained with
hydrogen chloride.
30. A process according to claim 1(b) in which 1-(p-tolyl)-4-[.beta.-2-
(1,2,3,4-tetrahydroquinolylethyl)]-piperazine and its hydrochloride are pre-
pared by reducing 1-(p-tolyl)-4-(.beta.-2-quinolylethyl)-piperazine and when the
corresponding hydrochloride is required reacting the base so obtained with
hydrogen chloride.
31. A process according to claim 1(b) in which 1-(p-methoxyphenyl)-4-
[.beta.-2-(1,2,3,4-tetrahydroquinolylethyl)]-piperazine and its hydrochloride are
prepared by reducing 1-(p-methoxyphenyl)-4-(.beta.-2-quinolylethyl)-piperazine and
when the corresponding hydrochloride is required reacting the base so obtained
with hydrogen chloride.
12

Description

1038389
This invention is concerned with novel pharmacologically active sub-
stances. More particularly, this invention relates to l-substituted 4-(~-2-
quinolylethyl)-piperazines of the formula:
~ CH2 CU2 - N n - R
and their 1,2,3,4-tetrahydroquinoline analogues, wherein R represents a lower
alkyl, aralkyl or a phenyl group which is either unsubstituted or substituted
by one or more alkyl, alkoxy, halo or trihaloalkyl groups.
In the specification and claimsJ the term "lower alkyl" designates
alkyl groups with 1-8 carbon atoms, which may be straight or branched, such as
methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, ter-butyl, amyl, iso-amyl
and so on. The term aralkyl designates groups such as phenethyl or benzyl.
A preferred group of compounds includes those in which R is a phenyl
group, either unsubstituted or substituted with a lower alkyl group. Prefer-
ably, the lower alkyl group is placed at position 3 of the phenyl radical.
The l-substituted 4-~-2-quinolylethyl)-piperazines and their tetra-
hydrogenated analogues as free bases may, if desired, be converted into their
non-toxic pharmaceutically acceptable acid addition and quaternary ammonium
salts. Salts which may thus be formed are the hydrochloride, hydrobromide,
hydroiodide, sulfate, phosphate, acetate, propionate, citrate, tartrate, male-
ate, malate. Among the useful quaternary ammonium salts are those formed by
such alkyl halides as methyl iodide and n-hexyl bromide.
The compounds of this invention have useful biological activities,
and have in particular high hypotensive activity associated with a low degree
of toxicity.
--1--

10383W
The general reaction sequence leading to l-substituted 4-~-2-
quinolylethyl)-piperazines and their 1,2,3,4-tetrahydroquinoline analogues is
shown hereinbelow
~LCH:CH2 I HN N - R
II III
CH CH - N N - R
~n CH2 CH2 - N N - R
The starting compounds are 2-vinylquinoline and a l-substituted
piperazine, which are reacted by methods essentially known in literature. In
practice, the condensation is carried out in a protic solvent like methanol,
ethanol, propanol or butanol by mixing equimolecular amounts of each of the
two reactants and of an aliphatic carboxylic acid, such as acetic acid, and
heating the reaction mixture to reflux for a period of 1-18 hours. The l-sub-
stituted 4-~-2-quinolylethyl)-perazines so obtained are then hydrogenated,
if desired, using hydrogen in the presence of a catalyst, preferably
-2-

10383~
a noble metal catalyst such as platinum,palladium or rhodium with or without
; supports such as charcoal or alumina. The hydrogenation may also be carried
out using alkali metals like lithium, sodium and potassium in lower alkanols
such as methanol, ethanol, propanol or butanol. This latterreaction is best
carried out by adding an excess over the molecular equivalent of the alkali
metal to a solution of the quinoline in the selected alkanol at temperatures
up to the boiling point of the solvent.
The free bases may be converted into the acid addition and quater-
nary ammonium salts by simply contacting equimolecular amounts of the base
and the selected acid through conventional methods.
The compounds of the invention show a marked hypotensive activity as
shown, for instance, by the following pharmacological data, obtained by sub-
jecting to animal tests the compound l-m-tolyl-4-(~-2-quinolylethyl)-piperazine.
The LD50 in mice was 600 mg/Kg intraperitoneally.
In cats anesthesized with 30 mg/Kg of sodium pentobarbitone, the
compound produced dose dependent sustained fall of blood pressure starting
from a dose of 10 ~g/Kg i.v. The hypotension at 10 ~gtKg was 20 mm/Hg for
about an hour and at 100 ~ g/Kg it was 45 mm/Hg for about 1 hour and a half.
At doses of 0.5 mg/Kg and higher the hypotension was more than 90 mm/Hg for
more than 2 hours.
Intraduodenal administration of 1.0 to 2.5 mg/Kg of compound produc-
ed hypotension of 40 to 50 mm/Hg for more than two hours.
Hypotensive response of the animal remained unaltered after pretreat-
ment with anti-histamines and atropine.
In unanesthetised cats a little higher dose of 0.5 to 2.5 mg/Kg i.v.
was required to produce sustained (~ 1.5 hr.) hypotension of 40 to 60 mm/Hg
in decerebrate spontaneously breathing cats. Similar effect was produced in
unanesthetised cats immobilised with d-tubocurarine.
In spontaneously hypertensive rats the compound was effective in
lowering the blood pressure by 50-60 mm/Hg for 3 to 4 hours in a dose range
of 0.5 to 1.0 mg/Kg p.o. The blood pressure was measured by tail plethysmo-
-- 3 --

1038389
graphy. Continuous administration of the compound once a day for 15 days did
not reveal any potentiation or tolerance to the drug effect.
The compound potentiated adrenaline and noradrenaline responses on
blood pressure in cats. Acetylcholine and histamine depressor responses were
not significantly affected.
Effect of the compound in vitro was tested in perfused guinea pig
heart and in vivo it was studied on cat heart utilising Cushney's myocardio-
graph. In low doses (5-10 ~g) it had positive inotropic effect on isolated
perfused heart but higher dosesdepressed it. It, however, potentiated the
adrenaline and noradrenaline responses. The compound stimulated both auricles
and ventricles in the in vivo preparation up to a dose of 0.1 mg/Kg i.v. High-
er doses depressed the heart.
Intravenous administration of the compound up to 0.1 mg/Kg) produc-
ed initial transient respiratory stimulation in cats. Higher doses were follow-
ed by marked hypotension and respiratory depression. Doses above 0.5 mg/Kg i.v.
produced respiratory failure if the hypotension was too severe.
In mice also the compound caused respiratory depression but there
was no mortality up to a dose of 300.0 mg/Kg i.p.
The compound had a depressant effect on the gross behavior of mice.
A dose of 0.5 mg/Kg i.p. antagonized amphetamine induced hyperactivity by 66%
and caused a fall out of 40% in rota rod test in mice. It, however, had no
anti-strychnine effect or anti-metrazol effect up to a dose of 120.0 mg/Kg.
The compound had no significant effect on the isolated guinea pig
ileum up to a concentration of 5 x 10 3 mg/ml. Higher concentration had non-
specific spasmolytic effect.
The anti-arrhytmic action of the compound was studied in isolated
guinea pig auricle on the maximum follow through rate. The compound had no
significant effect up to concentration of 3 x 10 3 mg/ml.
The following are examples of preparation of the invention compounds.

~0383~9
EXAMPLE 1
l-Phenyl-4- ~-2-quinolylethyl)-piperazine
To a mixture of 2-vinylquinoline (0.1 mole, 15g) and glacial acetic
acid (0.1 mole, 6 g) in ethanol (95%, 100 ml) N-phenylpiperazine (0.1 mole)
was added and the solution was refluxed for 15 hours. The solvent was removed
and the remaining oil was heated in vacuo ~1 mm) up to 100C. The oil left in
the flask crystallized out on cooling and was recrystallized from ether-
petroleum ether, m.p. 79C.
EXAMPLES 2 to 20
According to the procedure described in Example 1 the following com-
pounds were prepared:
2) 1-(m-Tolyl)-4- y-2-quinolylethyl)-piperazine by reacting 2-vinylquinoline
with N-(m-tolyl)-piperazine, m.p. 76-7C.
3) 1-to-Tolyl)-4- ~-2-quinolylethyl)-piperazine by reacting vinylquinoline with
N-(o-tolyl)-piperazine, m.p. 61C.
4) 1-(p-Tolyl)-4- ~-2-quinolylethyl)-piperazine by reacting 2-vinylquinoline
with N-(p-tolyl)-piperazine m.p. 88C.
5) 1-(p-Methoxyphenyl)-4-(~-2-quinolylethyl)-piperazine by reacting 2-vinyl-
quinoline with N-(p-methoxyphenyl)-piperazine, m.p. 114C.
6) 1-(o-Methoxyphenyl)-4- ~-2-quinolylethyl)-piperazine by reacting 2-vinyl-
quinoline with N-(o-methoxyphenyl)-piperazine, m.p. 124C.
7) 1-(2,5-Xylyl)-4-(~-2-quinolylethyl)-piperazine by reacting 2-vinylquinoline
with N-(2,5-xylyl)-piperazine m.p. 136C.
8) 1-(p-Chlorophenyl)-4- ~-2-quinolylethyl)-piperazine by reacting 2-vinyl-
quinoline with N-(p-chlorophenyl)-piperazine, m.p. 126C.
9) 1-(Methyl)-4- ~-2-quinolylethyl)-piperazine by reacting 2-vinylquinoline
with N-(methyl)-piperazine, m.p. 126C.
10) 1-(o-Chlorophenyl)-4-(~-2-quinolylethyl)-piperazine by reacting 2-vinyl-
quinoline with N-(o-chlorophenyl)-piperazine m.p. 84C.
11) 1-(m-Chlorophenyl)-4- ~ -2-quinolylethyl)-piperazine by reacting 2-vinyl-
-- 5 --

1038389
quinoline with N-(m-chlorophenyl)-piperazine, m.p, 97C.
12) 1-(m-Trifluoromethylphenyl)-4-(~-2-quinolylethyl)-piperazine by reacting
2-vinylquinoline with N-(m-trifluoromethylphenyl)-piperazine, m.p. 94C.
13) 1-~3,4-Dichlorophenyl)-4- ~-2-quinolylethyl)-piperazine by reacting 2-
vinylquinoline with N-(3,4-dichlorophenyl)-piperazine, m.p. 88C.
14) 1-t2,4-Xylyl)-4-(~ 2-quinolylethyl)-piperazine by reacting 2-vinylquino-
line with N-(2,4-xylyl)-piperazine, m.p. 126C.
15) 1-(3,4-Xylyl)-4- ~-2-quinolylethyl)-piperazine by reacting 2-vinylquino-
line with N-~3,4-xylyl)-piperazine, m.p. 108C.
16) 1-(~-Phenethyl)-4- ~-2-quinolylethyl)-piperazine by reacting 2-vinylquino-
line with N- y-phenethyl)-piperazine, oil m.p.
17) 1-(o-Fluorophenyl)-4- y-2-quinolylethyl)-piperazine by reacting 2-vinyl-
quinoline with N-(o-fluorophenyl)-piperazine, m.p. 86C.
18) 1-(m-Fluorophenyl)-4- ~-2-quinolylethyl)-piperazine by reacting 2-vinyl-
quinoline with N-(m-fluorophenyl)-piperazine, m.p. 84C.
19) 1-(p-Fluorophenyl)-4-(~-2-quinolylethyl)-piperazine by reacting 2-vinyl-
quinoline with N-(p-fluorophenyl)-piperazine, m.p. 113C.
20) 1-Benzyl-4- ~-2-quinolylethyl)-piperazine by reacting 2-vinylquinoline
with N-benzyl-piperazine, oil.
EXAMPLE 21
l-Phenyl-4- ~-2-(1,2,3,4-tetrahydroquinolyl)-ethyl]-piperazine
l-Phenyl-4- ~-2-quinolylethyl)-piperazine (0.01 mole) as obtained
above was dissolved in dry butanol (100 ml). Sodium ~2 g atom) was added in
small pieces to the solution under occasional stirring. After completion of
the addition the suspension was heated at 120 for 16 hours. The solvent was
removed under vacuum and the residue was taken up in water and extracted with
diethyl ether, the extract dried (Na2S04) and evaporated to get the tetrahydro
compound which was purified by converting into hydrochloride and recrystallized
from absolute EtOH-Et20 mixture, m.p. 198C.

1038389
EXAMPLES 22 to 25
Some of the different tetrahydroquinolyl compounds prepared as in
Example 21 are described below:
22) 1-(m-Tolyl)-4-[~ 2-(1,2,3,4-tetrahydroquinolylethyl)]-piperazine, HCl.
23) 1-(o-Tolyl)-4-[~-2-(1>2,3,4-tetrahydroquinolylethyl)]-piperazine, HCl,
m.p. 165C.
24) 1-(p-Tolyl)-4-[~ 2-(1,2,3,4-tetrahydroquinolylethyl)]-piperazine, HCl,
m.p. 145C.
25) 1-(p-Methoxyphenyl)-4-[~-2-(1,2,3,4-tetrahydroquinolylethyl)]piperazine,
HCl, m.p. 99-101C.