CA1038389A - 1-SUBSTITUTED 4-(.beta.-2-QUINOLYLETHYL)-PIPERAZINES AND 1,2,3,4-TETRAHYDRO QUINOLINE ANALOGUES THEREOF - Google Patents
1-SUBSTITUTED 4-(.beta.-2-QUINOLYLETHYL)-PIPERAZINES AND 1,2,3,4-TETRAHYDRO QUINOLINE ANALOGUES THEREOFInfo
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- CA1038389A CA1038389A CA202,531A CA202531A CA1038389A CA 1038389 A CA1038389 A CA 1038389A CA 202531 A CA202531 A CA 202531A CA 1038389 A CA1038389 A CA 1038389A
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Abstract
Abstract of the Disclosure Pharmacologically active 1-substituted 4-(.beta.-2-quinolylethyl)-piperazines of the formula:
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.
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.
Description
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.
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
~ 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.
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-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 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.
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-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 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-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.
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.
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.
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.
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.
Claims (31)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the formula:
(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:- (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.
(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:- (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:
(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.
(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:
(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.
(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.
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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA202,531A CA1038389A (en) | 1974-06-14 | 1974-06-14 | 1-SUBSTITUTED 4-(.beta.-2-QUINOLYLETHYL)-PIPERAZINES AND 1,2,3,4-TETRAHYDRO QUINOLINE ANALOGUES THEREOF |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA202,531A CA1038389A (en) | 1974-06-14 | 1974-06-14 | 1-SUBSTITUTED 4-(.beta.-2-QUINOLYLETHYL)-PIPERAZINES AND 1,2,3,4-TETRAHYDRO QUINOLINE ANALOGUES THEREOF |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1038389A true CA1038389A (en) | 1978-09-12 |
Family
ID=4100392
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA202,531A Expired CA1038389A (en) | 1974-06-14 | 1974-06-14 | 1-SUBSTITUTED 4-(.beta.-2-QUINOLYLETHYL)-PIPERAZINES AND 1,2,3,4-TETRAHYDRO QUINOLINE ANALOGUES THEREOF |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1038389A (en) |
-
1974
- 1974-06-14 CA CA202,531A patent/CA1038389A/en not_active Expired
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