Piperazine derivatives
Compounds of general formula (I) in which R 1 and R 0 have any of the meanings given in the specification have affinity for sigma receptors and are useful in the treatment of disorders of the central nervous system.
1 . A compound of general formula (I)
in which: —
R 0 represents phenyl or 4-fluorophenyl; and
R 1 represents: —
(i) a group of formula
R 2 —(CH 2 ) n CH 2 —
wherein: —
n is 1 or 2; and
R 2 represents a phenyl group that is substituted by one, two, or three substituents selected independently from (1-2C)alkylenedioxy, a halogen atom, a hydroxyl group, a (1-4C) alkyl group, a (3-6C)cycloalkyl group, a halo(1-4C) alkyl group, a (1-4C)alkoxy group and a halo(1-4C)alkoxy group, provided that when R 0 represents phenyl, R 2 is not 3,4,5-trimethoxyphenyl or phenyl substituted by two (1-4C) alkoxy groups;
(ii) a group of formula
R 3 —(CH 2 ) m C(R 4a R 4b )—
wherein: —
m is 1 or 2;
in which: —
R 3 represents a phenyl group that is unsubstituted or substituted by one, two or three substituents selected independently from (1-2C)alkylenedioxy, a halogen atom, a hydroxyl group, a (1-4C) alkyl group, a (3-6C)cycloalkyl group, a halo(1-4C) alkyl group, a (1-4C)alkoxy group and a halo(1-4C)alkoxy group; and one or two of R 4a and R 4b represents a (1-4C) alkyl or a (1-4C)alkoxy(1-4C)alkyl group and any remainder represents a hydrogen atom; or
(iii) 1,2,3,4-tetrahydronaphth-1-yl or 1,2,3,4-tetrahydronaphth-1-yl, each of which may bear a hydroxyl substituent on a non-aromatic carbon atom; or (3-6C) cycloalkyl;
or a pharmaceutically acceptable salt thereof.
2 . A compound of general formula (I)
in which: —
R 0 represents phenyl or 4-fluorophenyl; and,
R 1 represents:
a group of formula
R 2 —(CH 2 ) n CH 2 —
wherein:
n is 1 or 2; and
R 2 represents a phenyl group that is substituted by one fluorine atom or phenyl substituted by one, two, or three substituents selected independently from (1-2C)alkylenedioxy, a hydroxyl group, a (1-4C) alkyl group, a (3-6C)cycloalkyl group, and a halo(1-4C) alkyl group.
3 . A compound of general formula (I)
in which: —
R 0 represents phenyl or 4-fluorophenyl; and
R 1 represents a group of formula
R 3 —(CH 2 ) m C(R 4a R 4b )—
wherein:
m is 1 or 2; and
R 3 represents a phenyl group that is unsubstituted or substituted by one, two, or three substituents selected independently from (1-2C)alkylenedioxy, a halogen atom, a hydroxyl group, a (1-4C) alkyl group, a (3-6C)cycloalkyl group, a halo(1-4C) alkyl group, a (1-4C)alkoxy group, and a halo(1-4C)alkoxy group; and
one or both of R 4a and R 4b represents a (1-4C) alkyl or a (1-4C)alkoxy(1-4C)alkyl group, and any remainder represents a hydrogen atom.
4 . A compound according to claim 2 , in which R 0 represents phenyl.
5 . A compound according to claim 2 , in which R 0 represents 4-fluorophenyl.
6 . A compound according to claim 2 , or claim 4 , or claim 5 , in which n is 1.
7 . A compound according to claim 2 , claim 4 , or claim 5 , in which R 2 represents 3,4-dihydroxyphenyl, 3,4-methylenedioxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-methylphenyl, or 3-trifluoromethylphenyl.
8 . A compound according to claim 2 , in which n is 1, and R 2 represents 3,4-dihydroxyphenyl, 3,4-methylenedioxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-methylphenyl, or 3-trifluoromethylphenyl.
9 . A compound according to claim 3 , in which m is 1.
10 . A compound according to claim 3 , in which m is 2.
11 . A compound according to claim 3 , or claim 9 , or claim 10 , in which R 3 represents a phenyl group.
12 . A compound according to claim 3 , or claim 9 , or claim 10 , in which R 4a represents a methoxymethyl group and R 4b represents a hydrogen atom.
13 . A compound according to claim 3 , or claim 9 , or claim 10 , in which R 3 represents a phenyl group and R 4a represents a methoxymethyl group and R 4b represents a hydrogen atom.
14 . A compound according to claim 2 , which is selected from 1-[2-(2-fluorophenyl)ethyl]-4-(3-phenylpropyl)piperazine and pharmaceutically acceptable salts thereof and 1-[2-(3-methylphenyl)ethyl]-4-(3-phenylpropyl)piperazine and pharmaceutically acceptable salts thereof.
15 . A compound according to claim 2 , which is 1-[2-(2-fluorophenyl)ethyl]-4-(3-phenylpropyl)piperazine, or a pharmaceutically acceptable salt thereof.
16 . A compound as claimed in claim 2 , which is 1-[2-(2-fluorophenyl)ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride.
17 . A pharmaceutical composition, which comprises a compound of general formula (I)
in which: —
R 0 represents phenyl or 4-fluorophenyl; and,
R 1 represents:
a group of formula
R 2 —(CH 2 ) n CH 2 —
wherein:
n is 1 or 2; and
R 2 represents a phenyl group that is substituted by one fluorine atom or phenyl substituted by one, two, or three substituents selected independently from (1-2C)alkylenedioxy, a hydroxyl group, a (1-4C) alkyl group, a (3-6C)cycloalkyl group, and a halo(1-4C) alkyl group,
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
18 . A pharmaceutical composition, which comprises a compound selected from 1-[2-(2-fluorophenyl)ethyl]-4-(3-phenylpropyl)piperazine, 1-[2-(3-methylphenyl)ethyl]-4-(3-phenylpropyl)piperazine and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable diluent or carrier.
19 . A compound which is 1-(1R)-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-(3-phenylpropyl)piperazine or 1-(1S)-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-(3-phenylpropyl)piperazine, or a pharmaceutically acceptable salt thereof.
20 . A compound which is 1-Cyclopentyl-4-(3-phenylpropyl)piperazine, or 1-(1S,2S)-(2-Hydroxycyclopentyl)-4-(3-phenylpropyl)piperazine, or a pharmaceutically acceptable salt thereof.
21 . A compound according to claim 2 which is
1-(2-Benzo[1,3]dioxol-5-ylethyl)-4-(3-phenylpropyl)piperazine,
1-[2-(2-Fluorophenyl)ethyl]-4-(3-phenylpropyl)piperazine,
1-[2-(3-Fluorophenyl)ethyl]-4-(3-phenylpropyl)piperazine,
1-[2-(4-Fluorophenyl)ethyl]-4-(3-phenylpropyl)piperazine,
1-[2-(3-Methylphenyl)ethyl]-4-(3-phenylpropyl)piperazine,
1-[2-(3-Trifluoromethylphenyl)ethyl]-4-(3-phenylpropyl)piperazine,
1-[2-(3,4-Dihydroxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine,
1-[2-(2-Trifluoromethylphenyl)ethyl]-4-(3-phenylpropyl)piperazine,
1-[2-(4-Trifluoromethylphenyl)ethyl]-4-(3-phenyl propyl)piperazine,
1-[2-(7-Fluorobenzo[1,3]dioxol-5-yl)ethyl)-4-(3-phenylpropyl)piperazine,
or a pharmaceutically acceptable salt thereof.
22 . A compound according to claim 3 which is 1-[(S)-(1-Methoxymethyl-2-phenyl)ethyl]-4-(3-phenylpropyl)piperazine or 1-[(R)-(1-Methoxymethyl-2-phenyl)ethyl]-4-(3-phenylpropyl)piperazine or a pharmaceutically acceptable salt thereof.
23 . The composition according to claim 17 , in which the compound of general formula (I) is
1-(2-Benzo[1,3]dioxol-5-ylethyl)-4-(3-phenylpropyl)piperazine,
1-[2-(2-Fluorophenyl)ethyl]-4-(3-phenylpropyl)piperazine,
1-[2-(3-Fluorophenyl)ethyl]-4-(3-phenylpropyl)piperazine,
1-[2-(4-Fluorophenyl)ethyl]-4-(3-phenylpropyl)piperazine,
1-[2-(3-Methylphenyl)ethyl]-4-(3-phenylpropyl)piperazine,
1-[2-(3-Trifluoromethylphenyl)ethyl]-4-(3-phenylpropyl)piperazine,
1-[2-(3,4-Dihydroxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine,
1-[2-(2-Trifluoromethylphenyl)ethyl]-4-(3-phenylpropyl)piperazine,
1-[2-(4-Trifluoromethylphenyl)ethyl]-4-(3-phenylpropyl)piperazine,
1-[2-(7-Fluorobenzo[1,3]dioxol-5-yl)ethyl)-4-(3-phenylpropyl)piperazine,
or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.
24 . A pharmaceutical composition, which comprises a compound of general formula (I)
in which: —
R 0 represents phenyl or 4-fluorophenyl; and
R 1 represents a group of formula
R 3 —(CH 2 ) m C(R 4a R 4b )—
wherein:
m is 1 or 2; and
R 3 represents a phenyl group that is unsubstituted or substituted by one, two, or three substituents selected independently from (1-2C)alkylenedioxy, a halogen atom, a hydroxyl group, a (1-4C) alkyl group, a (3-6C)cycloalkyl group, a halo(1-4C) alkyl group, a (1-4C)alkoxy group, and a halo(1-4C)alkoxy group; and
one or both of R 4a and R 4b represents a (1-4C) alkyl or a (1-4C)alkoxy(1-4C)alkyl group, and any remainder represents a hydrogen atom,
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
25 . A pharmaceutical composition according to claim 24 , in which the compound of general formula (I) is 1-[(S)-(1-Methoxymethyl-2-phenyl)ethyl]-4-(3-phenylpropyl)piperazine or 1-[(R)-(1-Methoxymethyl-2-phenyl)ethyl]-4-(3-phenylpropyl)piperazine or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.
26 . A pharmaceutical composition which comprises 1-(1R)-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-(3-phenylpropyl)piperazine, or 1-(1S)-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-(3-phenylpropyl)piperazine, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.
27 . A pharmaceutical composition which comprises 1-Cyclopentyl-4-(3-phenylpropyl)piperazine, and 1-(1S,2S)-(2-Hydroxycyclopentyl)-4-(3-phenylpropyl)piperazine, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.