Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-12
2002-07-16
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S443000, C514S468000, C514S656000, C548S427000, C549S043000, C549S458000, C564S427000
Reexamination Certificate
active
06420413
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new heterocycloalkylbenzocyclobutane and heteroarylbenzocyclobutane compounds, and to pharmaceutical compositions containing them.
The compounds of the present invention act as powerful serotonin and noradrenalin reuptake inhibitors. As such, they are useful as medicaments in the treatment of depression, panic attacks, obsessive-compulsive disorders, phobias, impulsive disorders, drug abuse, anxiety, obesity and bulimia.
Indeed, the compounds of the present invention have shown themselves to be active, on the one hand, in vitro in the characterisation test for the inhibition of serotonin and noradrenalin reuptake and, on the other hand, in vivo. Accordingly, in the microdialysis experiments carried out in rat frontal cortex, the compounds of the invention bring about, in that area, an increase in the release of serotonin, noradrenalin and dopamine. The compounds claimed by the Applicant are therefore entirely suited to use in pathologies which are associated with a defect in the transmission of those two neuromediators. That especially valuable effect of the compounds of the invention is also demonstrated in the marble-burying test in mice.
DETAILED DESCRIPTION OF THE INVENTION
More especially, the present invention relates to compounds of formula (I):
wherein:
denotes a single bond or a double bond,
n is an integer from 1 to 6 inclusive,
R
1
and R
2
, which may be identical or different, each independently of the other represent a group selected from a hydrogen atom, a linear or branched (C
1
-C
6
)alkyl group, an aryl group, an aryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, a cycloalkyl group, a cycloalkyl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, a linear or branched (C
2
-C
6
)alkenyl group, a linear or branched (C
2
-C
6
)alkynyl group, a heterocycloalkyl group, a heterocycloalkyl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, a heteroaryl group, and a heteroaryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched,
X represents a group selected from —CH═CH—, an oxygen atom, a group S(O)
m
wherein m is an integer from 0 to 2 inclusive, and NR
3
wherein R
3
represents a group selected from a hydrogen atom, a linear or branched (C
1
-C
6
)alkyl group, an aryl group, an aryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, a cycloalkyl group, a cycloalkyl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, a linear or branched (C
2
-C
6
)alkenyl group, and a linear or branched (C
2
-C
6
)alkynyl group,
Y represents a CH or CH
2
group depending on whether
denotes a single bond or a double bond, or may have the additional meaning of an oxygen atom when X represents an oxygen atom,
T represents a monocyclic or polycyclic (C
3
-C
12
)cycloalkyl group, wherein one of the carbon atoms of the cycloalkyl may optionally be replaced by a group selected from an oxygen atom, a selenium atom, a group of formula S(O)
p
wherein p is an integer from 0 to 2 inclusive, NR
3
wherein R
3
is as defined hereinbefore, and SiR
4
R
5
wherein R
4
and R
5
, which may be identical or different, represent a linear or branched (C
1
-C
6
)alkyl group,
their isomers and addition salts thereof with a pharmaceutically acceptable acid or base.
“Aryl group” is understood to mean a group selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl and benzocyclobutyl, it being possible for each of those groups to be optionally substituted by one or more identical or different groups selected from halogen atoms, linear or branched (C
1
-C
6
)alkyl groups, hydroxy groups, linear or branched (C
1
-C
6
)alkoxy groups, nitro groups, cyano groups, linear or branched trihalo-(C
1
-C
6
)alkyl groups, amino groups, monoalkylamino groups in which the alkyl moiety has from 1 to 6 carbon atoms and is linear or branched and dialkylamino groups in which each alkyl moiety has from 1 to 6 carbon atoms and is linear or branched.
“Heteroaryl group” is understood to mean an aryl group as defined hereinbefore, containing within the ring system from one to three identical or different hetero atoms selected from oxygen, nitrogen and sulphur, said heteroaryl group being optionally substituted by one or more identical or different groups selected from the substituents defined above for the aryl group. Among the heteroaryl groups there may be mentioned by way of non-limiting example the groups pyridyl, pyrimidinyl, indolyl, benzofuranyl, benzothienyl, quinolyl, isoquinolyl, benzo[1,4]dioxinyl, 2,3-dihydrobenzo[1,4]dioxinyl, etc.
“Cycloalkyl group” is understood to mean a mono- or poly-cyclic system, having from 3 to 12 ring members, optionally containing one or more unsaturations, which do not confer an aromatic character upon the said ring system.
“Heterocycloalkyl group” is understood to mean a cycloalkyl group as defined hereinbefore, containing within the ring system from one to three identical or different hetero atoms selected from oxygen, nitrogen and sulphur.
Preferred compounds of the invention are the compounds of formula (I) wherein n has the value 1.
Preferred R
1
and R
2
substituents according to the invention are the hydrogen atom, the linear or branched (C
1
-C
6
)alkyl group, and the group 2,3-dihydro-1,4-benzodioxin-2-ylmethyl.
A preferred substituent T according to the invention is the saturated monocyclic (C
3
-C
8
)cycloalkyl group.
Advantageously, preferred substituents T according to the invention are the cyclopentyl and cyclohexyl groups.
According to an advantageous embodiment of the invention, preferred compounds of the invention are the compounds of formula (I/A):
wherein n, R
1
, R
2
and T are as defined for formula (I), X
10
represents an oxygen atom or a sulphur atom, and Y
10
represents a CH group.
According to another advantageous embodiment of the invention, preferred compounds of the invention are the compounds of formula (I/B):
wherein X, Y, n, R
1
, R
2
, R
3
and T are as defined for formula (I).
Advantageously, preferred compounds of the invention are the compounds of formula (I/B) wherein n is 1, and X represents a group NR
3
wherein R
3
represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group.
According to a third advantageous embodiment of the invention, preferred compounds of the invention are the compounds of formula (I/C):
wherein n, R
1
, R
2
, X and T are as defined for formula (I), and Y
20
represents a CH or CH
2
group.
According to a fourth advantageous embodiment of the invention, preferred compounds of the invention are the compounds of formula (I/D):
wherein n, R
1
, R
2
, X and T are as defined for formula (I), and Y
20
represents a CH or CH
2
group.
According to another advantageous embodiment of the invention, preferred compounds of the invention are the compounds of formula (I/E):
wherein n, R
1
, R
2
, X and T are as defined for formula (I), and Y
20
represents a CH or CH
2
group.
Lastly, according to a final valuable embodiment of the invention, preferred compounds of the invention are the compounds of formula (I/F):
wherein n, R
1
, R
2
, X and T are as defined for formula (I), and Y
20
represents a CH or CH
2
group.
Preferred compounds of the invention are:
1-{6-[(dimethylamino)methyl]-1-methyl-2,3,5,6-tetrahydro-1H-cyclobuta[f]indol-6-yl}cyclohexanol,
1-{6-[(dimethylamino)methyl]-2,3,5,6-tetrahydro-1H-cyclobuta[f]indol-6-yl}cyclohexanol,
1-{5-[(dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzofuran-5-yl}cyclohexanol,
1-{5-[(dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzothien-5-yl}cyclohexanol,
1-{6-[(dimethylamino)methyl]-1-methyl-5,6-dihydro-1H-cyclobuta[f]indol-6-yl}cyclohexanol,
1-{7-[(dimethylamino)methyl]-2,3,6,7-tetrahydro-1H-cyclobuta[e]indol-7-yl}cyclohex
Brocco Mauricette
Dessinges Aimee
Goument Bertrand
Lejeune Françoise
Millan Mark
Gerstl Robert
Les Laboratories Servier
Sage G. Patrick
The Firm of Hueschen and Sage
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