U.S. patent application number 09/833827 was filed with the patent office on 2002-02-14 for heterocycloalkylbenzocyclobutane and heteroarylbenzocyclobutane compounds.
Invention is credited to Brocco, Mauricette, Dessinges, Aimee, Goument, Bertrand, Lejeune, Francoise, Millan, Mark, Peglion, Jean-Louis.
Application Number | 20020019380 09/833827 |
Document ID | / |
Family ID | 8849212 |
Filed Date | 2002-02-14 |
United States Patent
Application |
20020019380 |
Kind Code |
A1 |
Peglion, Jean-Louis ; et
al. |
February 14, 2002 |
Heterocycloalkylbenzocyclobutane and heteroarylbenzocyclobutane
compounds
Abstract
A compound selected from those of formula (I): 1 wherein:
{overscore (_____)} denotes single bond or double bond, n is
integer from 1 to 6 inclusive, R.sub.1, and R.sub.2 represent a
group selected from hydrogen, linear or branched
(C.sub.1-C.sub.6)-alkyl, aryl, arylalkyl, cycloalkyl,
cycloalkylalkyl, alkenyl, alkynyl, heterocycloalkyl,
heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, X
represents a group selected from --CH.dbd.CH--, oxygen, S(O).sub.m
wherein m is integer from 0 to 2 inclusive, and NR.sub.3 wherein
R.sub.3 represents a group as defined in the description, Y
represents CH or CH.sub.2 depending on whether _____ denotes single
bond or double bond, or may have the additional meaning of oxygen
when X represents oxygen, T represents monocyclic or polycyclic
(C.sub.3-C.sub.10)cycloalkyl optionally containing within the ring
system oxygen, selenium, S(O).sub.p, NR.sub.3, or SiR.sub.4R.sub.5
wherein p, R.sub.3, R.sub.4, and R.sub.5 are as defined in the
description, its isomers and addition salts thereof with a
pharmaceutically-acceptable acid or base, and medicinal products
containing the same are useful in the treatment of CNS
disorders.
Inventors: |
Peglion, Jean-Louis; (Le
Vesinet, FR) ; Dessinges, Aimee; (Rueil Malmaison,
FR) ; Goument, Bertrand; (Viroflay, FR) ;
Millan, Mark; (Le Pecq, FR) ; Lejeune, Francoise;
(Saint Cloud, FR) ; Brocco, Mauricette; (Paris,
FR) |
Correspondence
Address: |
The Firm of Hueschen and Sage
715 The "H" Building
310 East Michigan Avenue
Kalamazoo
MI
49007
US
|
Family ID: |
8849212 |
Appl. No.: |
09/833827 |
Filed: |
April 12, 2001 |
Current U.S.
Class: |
514/183 ;
514/411; 514/443; 514/468; 540/1; 548/427; 549/43; 549/458 |
Current CPC
Class: |
C07D 209/40 20130101;
C07D 333/78 20130101; C07D 209/16 20130101; A61P 43/00 20180101;
C07C 215/42 20130101; C07D 307/93 20130101; A61P 25/20 20180101;
C07D 407/12 20130101; A61P 25/24 20180101; C07D 317/70 20130101;
A61P 3/04 20180101; A61P 25/18 20180101; A61P 25/22 20180101; A61P
25/30 20180101; A61P 25/00 20180101; C07D 319/14 20130101 |
Class at
Publication: |
514/183 ;
514/411; 514/443; 514/468; 540/1; 548/427; 549/43; 549/458 |
International
Class: |
C07D 345/00; C07D
333/50; C07D 37/77; C07D 209/04 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 13, 2000 |
FR |
00.04742 |
Claims
1. A compound selected from those of formula (I): 49wherein:
_____denotes single bond or double bond, n is integer from 1 to 6
inclusive, R.sub.1 and R.sub.2, which may be, identical or
different, each independently of the other, represent a group
selected from hydrogen, linear or branched (C.sub.1-C.sub.6)alkyl,
aryl, aryl-(C.sub.1-C.sub.6)alkyl in which alkyl is linear or
branched, cycloalkyl, cycloalkyl-(C.sub.1-C.sub.6)alkyl in which
alkyl is linear or branched, linear or branched
(C.sub.2-C.sub.6)alkenyl, linear or branched
(C.sub.2-C.sub.6)alkynyl, heterocycloalkyl,
heterocycloalkyl-(C.sub.1-C.sub.6)alkyl in which alkyl is linear or
branched, heteroaryl, and heteroaryl-(C.sub.1-C.sub.6)alkyl in
which alkyl is linear or branched, X represents a group selected
from --CH.dbd.CH--, oxygen, S(O).sub.m wherein m is integer from 0
to 2 inclusive, and NR.sub.3 wherein R.sub.3 represents a group
selected from hydrogen, linear or branched (C.sub.1-C.sub.6)alkyl,
aryl, aryl-(C.sub.1-C.sub.6)-alkyl in which alkyl is linear or
branched, cycloalkyl, cycloalkyl-(C.sub.1-C.sub.6)alkyl in which
alkyl is linear or branched, linear or branched
(C.sub.2-C.sub.6)alkenyl, and linear or branched
(C.sub.2-C.sub.6)alkynyl, Y represents CH or CH.sub.2 depending on
whether _____denotes single bond, or double bond, or may have the
additional meaning of oxygen when X represents oxygen, T represents
monocyclic or polycyclic (C.sub.3-C.sub.12)cycloalkyl, wherein one
of carbon of cycloalkyl may optionally be replaced by a group
selected from oxygen, selenium, S(O).sub.p wherein p is integer
from 0 to 2 inclusive, NR.sub.3 wherein R.sub.3 is as defined
hereinbefore, and SiR.sub.4R.sub.5 wherein R.sub.4 and R.sub.5,
which may be identical or different, represent linear or branched
(C.sub.1-C.sub.6)alkyl, its isomers and addition salts thereof with
a pharmaceutically acceptable acid or base, it being understood
that: "aryl" 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, linear or branched
(C.sub.1-C.sub.6)alkyl, hydroxy, linear or branched
(C.sub.1-C.sub.6)alkoxy, nitro, cyano, linear or branched
trihalo-(C.sub.1-C.sub.6)alkyl, amino, monoalkylamino in which
alkyl has from 1 to 6 carbon atoms and is linear or branched, and
dialkylamino in which each alkyl has from 1 to 6 carbon and is
linear or branched, "heteroaryl" is understood to mean aryl 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 being optionally substituted
by one or more, identical or different, groups selected from
substituents defined above for aryl, "cycloalkyl" is understood to
mean mono- or poly-cyclic system, having from 3 to 12 ring members,
optionally containing one or more unsaturations, which do not
confer aromatic character upon the said ring system,
"heterocycloalkyl" is understood to mean cycloalkyl as defined
hereinbefore, containing within the ring system from one to three,
identical or different, hetero atoms selected from oxygen,
nitrogen, and sulphur.
2. A compound of claim 1, characterised in that n has the value 1,
its isomers and addition salts thereof with a
pharmaceutically-acceptable acid or base.
3. A compound of claim 1, characterised in that R.sub.1, and
R.sub.2, which may be, identical or different, represent hydrogen,
linear or branched (C.sub.1-C.sub.6)alkyl, or
2,3-dihydro-1,4-benzodioxin-2-ylmethy- l, its isomers and addition
salts thereof with a pharmaceutically-acceptab- le acid or
base.
4. A compound of claim 1, characterised in that T represents
saturated monocyclic (C.sub.3-C.sub.8)cycloalkyl, its isomers and
addition salts thereof with a pharmaceutically-acceptable acid or
base.
5. A compound of claim 1, characterised in that T represents
cyclopentyl, or cyclohexyl, its isomers and addition salts thereof
with a pharmaceutically-acceptable acid or base.
6. A compound of claim 1, characterised in that it is a compound of
formula (I/A): 50wherein n, R.sub.1, R.sub.2, and T are as defined
for formula (I), X.sub.10 represents oxygen or sulphur, and
Y.sub.10 represents CH, its isomers and addition salts thereof with
a pharmaceutically-acceptable acid or base.
7. A compound of claim 1, characterised in that it is a compound of
formula (I/B): 51wherein X, Y, n, R.sub.1, R.sub.2, R.sub.3, and T
are as defined for formula (I), its isomers and addition salts
thereof with a pharmaceutically-acceptable acid or base.
8. A compound of claim 7, characterised in that n is 1, and X
represents NR.sub.3 wherein R.sub.3 represents hydrogen or linear
or branched (C.sub.1-C.sub.6)alkyl, its isomers and addition salts
thereof with a pharmaceutically-acceptable acid or base.
9. A compound of claim 1, characterised in that it is a compound of
formula (I/C): 52wherein n, R.sub.1, R.sub.2, X, and T are as
defined for formula (I), and Y.sub.20 represents CH or CH.sub.2,
its isomers and addition salts thereof with a
pharmaceutically-acceptable acid or base.
10. A compound of claim 1, characterised in that it is a compound
of formula (I/D): 53wherein n, R.sub.1, R.sub.2, X, and T are as
defined for formula (I), and Y.sub.20 represents CH or CH.sub.2,
its isomers and addition salts thereof with a
pharmaceutically-acceptable acid or base.
11. A compound of claim 1, characterised in that it is a compound
of formula (I/E): 54wherein n, R.sub.1, R.sub.2, X, and T are as
defined for formula (I), and Y.sub.20 represents CH or CH.sub.2,
its isomers and addition salts thereof with a
pharmaceutically-acceptable acid or base.
12. A compound one of claim 1, characterised in that it is a
compound of formula (I/F): 55wherein n, R.sub.1, R.sub.2, X, and Y
are as defined for formula (I), and Y.sub.20 represents CH or
CH.sub.2, its isomers and addition salts thereof with a
pharmaceutically-acceptable acid or base.
13. A compound of claim 1 which is:
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]benz-
ofuran-5-yl}cyclohexanol,
1-{5-[(dimethylamino)methyl]-5,6-dihydrocyclobut-
a[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-
}cyclohexanol,
1-{5-[(methylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzot-
hien-5-yl}cyclopentanol,
1-{5-[(dimethylamino)methyl]-5,6-dihydrocyclobuta-
[f][1]benzothien-5-yl}cyclopentanol,
(+)-1-{5-[(dimethylamino)methyl]-5,6--
dihydrocyclobuta[f][1]benzothien-5-yl}cyclopentanol,
(-)-1-{5-[(dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzothien-5-y-
l}cyclopentanol,
1-{6-[(dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]be-
nzothien-6-yl}cyclopentanol,
1-{5-[(dimethylamino)methyl]-1-methyl-5,6-dih-
ydro-1H-cyclobuta[f]indol-5-yl}cyclopentanol,
1-{7-[(dimethylamino)methyl]-
-6,7-dihydrocyclobuta[g][1]benzofuran-7-yl}cyclopentanol,
1-{1-[(dimethylamino)methyl]-1,2-dihydrocyclobuta[b]naphthalen-1-yl}cyclo-
pentanol,
1-{7-[(dimethylamino)methyl]-6,7-dihydro-3H-cyclobuta[e]indol-7--
yl}cyclopentanol,
1-{1-[(dimethylamino)methyl]-1,2-dihydrocyclobuta[a]naph-
thalen-1-yl}cyclopentanol. its isomers and addition salts thereof
with a pharmaceutically-acceptable acid or base.
14. A method for treating a living body afflicted with a disease
like depression, panic attacks, obsessive-compulsive disorders,
phobias, impulsive disorders, drug abuse, anxiety, obesity, and
boulimia, comprising the step of administering to the living body
an amount of a compound of claim 1 which is effective for
alleviation of said conditions.
15. A pharmaceutical composition useful in claim 14 comprising as
active principle an effective amount of a compound of claim 1, in
combination with one or more pharmaceutically-acceptable excipients
or vehicles.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to new
heterocycloalkylbenzocyclobuta- ne and heteroarylbenzocyclobutane
compounds, and to pharmaceutical compositions containing them.
[0002] 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.
[0003] 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
[0004] More especially, the present invention relates to compounds
of formula (I): 2
[0005] wherein:
[0006] {overscore (_____)}0 denotes a single bond or a double
bond,
[0007] n is an integer from 1 to 6 inclusive,
[0008] R.sub.1 and R.sub.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.sub.1-C.sub.6)alkyl group,
an aryl group, an aryl-(C.sub.1-C.sub.6)alkyl group in which the
alkyl moiety is linear or branched, a cycloalkyl group, a
cycloalkyl-(C.sub.1-C.sub.6)alkyl group in which the alkyl moiety
is linear or branched, a linear or branched
(C.sub.2-C.sub.6)alkenyl group, a linear or branched
(C.sub.2-C.sub.6)alkynyl group, a heterocycloalkyl group, a
heterocycloalkyl-(C.sub.1-C.sub.6)alkyl group in which the alkyl
moiety is linear or branched, a heteroaryl group, and a
heteroaryl-(C.sub.1-C.su- b.6)alkyl group in which the alkyl moiety
is linear or branched,
[0009] X represents a group selected from --CH.dbd.CH--, an oxygen
atom, a group S(O).sub.m wherein m is an integer from 0 to 2
inclusive, and NR.sub.3 wherein R.sub.3 represents a group selected
from a hydrogen atom, a linear or branched (C.sub.1-C.sub.6)alkyl
group, an aryl group, an aryl-(C.sub.1-C.sub.6)alkyl group in which
the alkyl moiety is linear or branched, a cycloalkyl group, a
cycloalkyl-(C.sub.1-C.sub.6)alkyl group in which the alkyl moiety
is linear or branched, a linear or branched
(C.sub.2-C.sub.6)alkenyl group, and a linear or branched
(C.sub.2-C.sub.6)alkynyl group,
[0010] Y represents a CH or CH.sub.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,
[0011] T represents a monocyclic or polycyclic
(C.sub.3-C.sub.12)cycloalky- l 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).sub.p wherein p is an integer from 0 to 2 inclusive, NR.sub.3
wherein R.sub.3 is as defined hereinbefore, and SiR.sub.4R.sub.5
wherein R.sub.4 and R.sub.5, which may be identical or different,
represent a linear or branched (C.sub.1-C.sub.6)alkyl group,
[0012] their isomers and addition salts thereof with a
pharmaceutically acceptable acid or base.
[0013] "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.sub.1-C.sub.6)alkyl groups, hydroxy groups, linear or branched
(C.sub.1-C.sub.6)alkoxy groups, nitro groups, cyano groups, linear
or branched trihalo-(C.sub.1-C.sub.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.
[0014] "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.
[0015] "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.
[0016] "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.
[0017] Preferred compounds of the invention are the compounds of
formula (I) wherein n has the value 1.
[0018] Preferred R.sub.1 and R.sub.2 substituents according to the
invention are the hydrogen atom, the linear or branched
(C.sub.1-C.sub.6)alkyl group, and the group
2,3-dihydro-1,4-benzodioxin-2- -ylmethyl.
[0019] A preferred substituent T according to the invention is the
saturated monocyclic (C.sub.3-C.sub.8)cycloalkyl group.
[0020] Advantageously, preferred substituents T according to the
invention are the cyclopentyl and cyclohexyl groups.
[0021] According to an advantageous embodiment of the invention,
preferred compounds of the invention are the compounds of formula
(I/A): 3
[0022] wherein n, R.sub.1, R.sub.2 and T are as defined for formula
(I), X.sub.10 represents an oxygen atom or a sulphur atom, and
Y.sub.10 represents a CH group.
[0023] According to another advantageous embodiment of the
invention, preferred compounds of the invention are the compounds
of formula (I/B): 4
[0024] wherein X, Y, n, R.sub.1, R.sub.2, R.sub.3 and T are as
defined for formula (I).
[0025] Advantageously, preferred compounds of the invention are the
compounds of formula (I/B) wherein n is 1, and X represents a group
NR.sub.3 wherein R.sub.3 represents a hydrogen atom or a linear or
branched (C.sub.1-C.sub.6)alkyl group.
[0026] According to a third advantageous embodiment of the
invention, preferred compounds of the invention are the compounds
of formula (I/C): 5
[0027] wherein n, R.sub.1, R.sub.2, X and T are as defined for
formula (I), and Y.sub.20 represents a CH or CH.sub.2 group.
[0028] According to a fourth advantageous embodiment of the
invention, preferred compounds of the invention are the compounds
of formula (I/D): 6
[0029] wherein n, R.sub.1, R.sub.2, X and T are as defined for
formula (I), and Y.sub.20 represents a CH or CH.sub.2 group.
[0030] According to another advantageous embodiment of the
invention, preferred compounds of the invention are the compounds
of formula (I/E): 7
[0031] wherein n, R.sub.1, R.sub.2, X and T are as defined for
formula (I), and Y.sub.20 represents a CH or CH.sub.2 group.
[0032] Lastly, according to a final valuable embodiment of the
invention, preferred compounds of the invention are the compounds
of formula (I/F): 8
[0033] wherein n, R.sub.1, R.sub.2, X and T are as defined for
formula (I), and Y.sub.20 represents a CH or CH.sub.2 group.
[0034] Preferred compounds of the invention are:
[0035]
1-{6-[(dimethylamino)methyl]-1-methyl-2,3,5,6-tetrahydro-1H-cyclobu-
ta[f]indol-6-yl}cyclohexanol,
[0036]
1-{6-[(dimethylamino)methyl]-2,3,5,6-tetrahydro-1H-cyclobuta[f]indo-
l-6-yl}cyclohexanol,
[0037]
1-{5-[(dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzofuran-5-
-yl}cyclohexanol,
[0038]
1-{5-[(dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzothien-5-
-yl}cyclohexanol,
[0039]
1-{6-[(dimethylamino)methyl]-1-methyl-5,6-dihydro-1H-cyclobuta[f]in-
dol-6-yl}cyclohexanol,
[0040]
1-{7-[(dimethylamino)methyl]-2,3,6,7-tetrahydro-1H-cyclobuta[e]indo-
l-7-yl}cyclohexanol,
[0041]
1-{5-[(methylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzothien-5-y-
l}cyclopentanol,
[0042]
1-{5-[(dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzothien-5-
-yl}cyclopentanol,
[0043]
(+)-1-{5-[(dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzothi-
en-5-yl}cyclopentanol,
[0044]
(-)-1-{5-[(dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzothi-
en-5-yl}cyclopentanol,
[0045]
1-{6-[(dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzothien-6-
-yl}cyclopentanol,
[0046]
1-{5-[(dimethylamino)methyl]-1-methyl-5,6-dihydro-1H-cyclobuta[f]in-
dol-5-yl}cyclopentanol,
[0047]
1-{7-[(dimethylamino)methyl]-6,7-dihydrocyclobuta[g][1]benzofuran-7-
-yl}cyclopentanol,
[0048]
1-{1-[(dimethylamino)methyl]-1,2-dihydrocyclobuta[b]naphthalen-1-yl-
}cyclopentanol,
[0049]
1-{7-[(dimethylamino)methyl]-6,7-dihydro-3H-cyclobuta[e]indol-7-yl}-
cyclopentanol,
[0050]
1-{1-[(dimethylamino)methyl]-1,2-dihydrocyclobuta[a]naphthalen-1-yl-
}cyclopentanol.
[0051] The isomers and addition salts with a pharmaceutically
acceptable acid or base of the preferred compounds form an integral
part of the invention.
[0052] Isomers are understood to be the optical isomers, such as
the diastereoisomers and enantiomers.
[0053] Among the pharmaceutically acceptable acids there may be
mentioned by way of non-limiting example hydrochloric acid,
hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid,
trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid,
succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic
acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic
acid, camphoric acid, etc.
[0054] Among the pharmaceutically acceptable bases there may be
mentioned by way of non-limiting example sodium hydroxide,
potassium hydroxide, triethylamine, tert-butylamine, etc.
[0055] The present invention relates also to a process for the
preparation of compounds of formula (I), characterised in that
there is used as starting material:
[0056] a) either a compound of formula (II): 9
[0057] wherein X.sub.a represents a sulphur atom, an oxygen atom,
or an NH group,
[0058] which compound of formula (II) is reacted with a compound of
formula (III):
Z-CH(OA).sub.2 (III)
[0059] wherein A represents a linear or branched
(C.sub.1-C.sub.4)alkyl group and Z represents a formyl group (when
X.sub.a represents an NH group), or a group --CH.sub.2Hal wherein
Hal represents a chlorine, bromine or iodine atom,
[0060] to yield compounds of formula (IV): 10
[0061] wherein X.sub.a and A are as defined hereinbefore,
[0062] which compounds of formula (IV) are subjected:
[0063] either, when X.sub.a has the meaning X.sub.1 representing an
oxygen atom or a sulphur atom, to conditions of cyclisation by the
action of an acid, such as polyphosphoric acid or a Lewis acid, to
yield compounds of formula (V/a): 11
[0064] wherein X.sub.1 represents an oxygen atom or a sulphur
atom,
[0065] which compounds of formula (V/a) are treated:
[0066] either, in the presence of a strong base, with a cyclic
ketone of formula (VI): 12
[0067] wherein T has the same meanings as for formula (I),
[0068] to yield compounds of formula (VII/a), 13
[0069] wherein X.sub.1 and T are as defined hereinbefore,
[0070] which compounds of formula (VII/a) are subjected to the
action of a reducing agent according to conventional conditions of
organic synthesis, to yield compounds of formula (I/a), a
particular case of the compounds of formula (I): 14
[0071] wherein X.sub.1 and T are as defined hereinbefore,
[0072] for which compounds of formula (I/a):
[0073] either the primary amine function is substituted according
to conventional methods of organic synthesis, such as reductive
amination or nucleophilic substitution with a compound of formula
(VIIIa):
R'.sub.1-Z.sub.1 (VIIIa)
[0074] wherein R'.sub.1 has the same meanings as R.sub.1 for
formula (I) with the exception of the meaning of a hydrogen atom,
and Z.sub.1 represents a leaving group customary in organic
chemistry, such as a halogen atom or a mesylate or tosylate
group,
[0075] to yield compounds of formula (I/b.sub.1), a particular case
of the compounds of formula (I): 15
[0076] wherein X.sub.1, T and R'.sub.1, are as defined
hereinbefore,
[0077] or according to an advantageous embodiment of the process,
treatment is carried out with a compound of formula (VIIIb):
R".sub.1--COZ.sub.2 (VIIIb)
[0078] wherein R".sub.1 represents a
heterocycloalkyl-(C.sub.1-C.sub.5)alk- yl group in which the alkyl
moiety is linear or branched, and Z.sub.2 represents a chlorine
atom or an imidazolyl group, to yield compounds of formula
(I/b.sub.2): 16
[0079] wherein X.sub.1, T and R".sub.1 are as defined
hereinbefore,
[0080] which compounds of formula (I/b.sub.2) are reduced with a
reducing agent conventionally used in organic chemistry, to yield
compounds of formula (I/b.sub.3): 17
[0081] wherein X.sub.1, R".sub.1 and T are as defined
hereinbefore,
[0082] the totality of the compounds of formulae (I/b.sub.1) and
(I/b.sub.3) constituting the compounds of formula (I/b),
[0083] which compounds of formula (I/b) are treated according to
the same conditions as those described hereinbefore with a compound
of formula (VIIIc):
R'.sub.2-Z.sub.1 (VIIIc)
[0084] wherein Z.sub.1 is as defined hereinbefore and R'.sub.2 has
the same meanings as R.sub.2 for formula (I) with the exception of
the meaning of a hydrogen atom,
[0085] to yield compounds of formula (I/c), a particular case of
the compounds of formula (I): 18
[0086] wherein X.sub.1, T, R'.sub.1 and R'.sub.2 are as defined
hereinbefore,
[0087] or, in the presence of a strong base, with an amine of
formula (IX): 19
[0088] wherein R.sub.1 and R.sub.2 are as defined for formula (I),
n.sub.1 is an integer from 2 to 6 inclusive, and L represents a
leaving group, such as a halogen atom, or a mesylate, tosylate or
trifluoromethanesulphonate group, to yield compounds of formula
(X): 20
[0089] wherein X.sub.1, n.sub.1, R.sub.1 and R.sub.2 are as defined
hereinbefore,
[0090] which compounds of formula (X) are treated with hydrogen
peroxide in the presence of sodium carbonate, to yield compounds of
formula (XI): 21
[0091] wherein X.sub.1, n.sub.1, R.sub.1 and R.sub.2 are as defined
hereinbefore, which compounds of formula (XI) are reduced by the
action of ammonium formate in the presence of 10% Pd/C, to yield
compounds of formula (XII): 22
[0092] wherein X.sub.1, n.sub.1, R.sub.1 and R.sub.2 are as defined
hereinbefore,
[0093] which compounds of formula (XII) are subjected to the action
of a compound of formula (XIII):
(CH.sub.3).sub.2N--CH(OG).sub.2 (XIII)
[0094] wherein G represents a linear or branched
(C.sub.1-C.sub.6)alkyl group, a benzyl group or a cyclohexyl
group,
[0095] to yield compounds of formula (XIV): 23
[0096] wherein X.sub.1, n.sub.1, R.sub.1 and R.sub.2 are as defined
hereinbefore,
[0097] which compounds of formula (XIV) are treated with a
dimagnesium compound of formula (XV): 24
[0098] wherein Hal represents a halogen atom, and T is as defined
for formula (I),
[0099] to yield compounds of formula (I/d), a particular case of
the compounds of formula (I): 25
[0100] wherein X.sub.1, n.sub.1, R.sub.1, R.sub.2 and T are as
defined hereinbefore,
[0101] the totality of the compounds of formulae (I/a), (I/b),
(I/c) and (I/d), in the particular case when X.sub.1 represents a
sulphur atom, constituting the compounds of formula (I/e): 26
[0102] wherein n, R.sub.1, R.sub.2 and T are as defined for formula
(I),
[0103] which compounds of formula (I/e) are subjected to the action
of an oxidising agent according to conventional conditions of
organic synthesis, to yield compounds of formula (I/f), a
particular case of the compounds of formula (I): 27
[0104] wherein p.sub.1 is an integer selected from 1 and 2, and n,
R.sub.1, R.sub.2 and T are as defined hereinbefore,
[0105] the totality of the compounds of formulae (I/a), (I/b),
(I/c), (I/d) (wherein X.sub.1 represents an oxygen or sulphur atom)
and (I/f) constituting the compounds of formula (I/g): 28
[0106] wherein X.sub.1a represents an oxygen atom or a group of
formula S(O).sub.p wherein p is as defined for formula (I), and n,
R.sub.1, R.sub.2 and T are as defined for formula (I),
[0107] which compounds of formula (I/g) are subjected to the action
of a reducing agent according to conventional conditions of organic
synthesis, to yield compounds of formula (I/h), a particular case
of the compounds of formula (I): 29
[0108] wherein X.sub.1a, n, R.sub.1, R.sub.2 and T are as defined
hereinbefore,
[0109] or, when X.sub.a has the meaning X'.sub.2 representing an NH
group, to the action of a sulphonic acid chloride of formula
(XVI):
E-SO.sub.2Cl (XVI)
[0110] wherein E represents a linear or branched
(C.sub.1-C.sub.4)alkyl group, a phenyl group or a p-toluyl
group,
[0111] to yield compounds of formula (XVII): 30
[0112] wherein X.sub.2 represents a nitrogen atom, and E and A are
as defined hereinbefore,
[0113] which compounds of formula (XVII) are cyclised by the action
of an acid to yield compounds of formula (V/b): 31
[0114] wherein X.sub.2 and E are as defined hereinbefore,
[0115] the cyclic amine of which compounds of formula (V/b) is
deprotected by the action of a basic agent, which are then
subjected to the action of a reducing agent according to
conventional conditions of organic synthesis, to yield compounds of
formula (V/c): 32
[0116] wherein X.sub.2 is as defined hereinbefore,
[0117] which compounds of formula (V/c) are subjected to the action
of a compound of formula (VI) as described hereinbefore to yield
compounds of formula (VII/b): 33
[0118] wherein X.sub.2 is as defined hereinbefore and T is as
defined for formula (I),
[0119] which compounds of formula (VII/b) are:
[0120] either treated according to the same conditions as those
described for the compounds of formula (VII/a), to yield compounds
of formula (I/i), a particular case of the compounds of formula
(I): 34
[0121] wherein X.sub.2 and T are as defined hereinbefore,
[0122] which compounds of formula (I/i) may be treated in
succession with a compound of formula (VIIIa) or (VIIIb), and then
(VIIIc), as defined hereinbefore, to yield compounds of formulae
(I/j) and (I/k), respectively, particular cases of the compounds of
formula (I): 35
[0123] wherein X.sub.2, T, R'.sub.1 and R'.sub.2 are as defined
hereinbefore, and R'.sub.3 has the same meanings and values as
R'.sub.1,
[0124] the totality of the compounds of formulae (I/i), (I/j) and
(I/k) constituting the compounds of formula (I/l): 36
[0125] wherein X.sub.2, R.sub.1, R.sub.2, R.sub.3 and T are as
defined for formula (I),
[0126] which compounds of formula (I/l) are subjected to the action
of an oxidising agent, such as manganese dioxide, to yield
compounds of formula (I/m), a particular case of the compounds of
formula (I): 37
[0127] wherein X.sub.2, R.sub.1, R.sub.2, R.sub.3 and T are as
defined hereinbefore,
[0128] or treated with a compound of formula (XVI) as defined
hereinbefore, to yield compounds of formula (XVIII): 38
[0129] wherein T, X.sub.2 and E are as defined hereinbefore,
[0130] which compounds of formula (XVIII) are reduced according to
conventional conditions of organic synthesis, to yield compounds of
formula (XIX): 39
[0131] wherein T, X.sub.2 and E are as defined hereinbefore,
[0132] the primary amine function of which compounds of formula
(XIX) may be substituted by the action of a compound of formula
(VIII.sub.a) as defined hereinbefore, to yield compounds of formula
(XX): 40
[0133] wherein T, X.sub.2, E and R'.sub.1 have the same meanings as
those described hereinbefore,
[0134] which compounds of formula (XX) may be converted into
tertiary amines by the action of a compound of formula (VIII.sub.b)
as defined hereinbefore, to yield compounds of formula (XXI):
41
[0135] wherein T, X.sub.2, E, R'.sub.1 and R'.sub.2 are as defined
hereinbefore,
[0136] which compounds of formulae (XX) and (XXI) are then
deprotected by treatment with sodium in liquid ammonia, to yield
compounds of formulae (I/n) and (I/o), respectively, particular
cases of the compounds of formula (I): 42
[0137] wherein T, X.sub.2, R'.sub.1 and R'.sub.2 are as defined
hereinbefore,
[0138] b) or a compound of formula (II/1): 43
[0139] wherein Hal represents a halogen atom, and X.sub.b
represents an oxygen atom when Y.sub.b
[0140] represents an oxygen atom and _____ denotes a single
bond,
[0141] or X.sub.b represents a group --CH.dbd.CH-- when Y.sub.b
represents a CH group and _____ denotes a double bond,
[0142] which compounds of formula (II/1) are reacted with
(EtO).sub.2POCH.sub.2CN to yield compounds of formula (II/2):
44
[0143] wherein Hal, X.sub.b and Y.sub.b are as defined
hereinbefore,
[0144] which compounds of formula (II/2) are first subjected to the
action of a reducing agent conventional in organic chemistry and
then reacted with NaNH.sub.2, to yield compounds of formula (II/3):
45
[0145] wherein Xb and Yb are as defined hereinbefore,
[0146] which compounds of formula (II/3) may be treated under the
same conditions as the compounds of formula (V/a),
[0147] either with a compound of formula (VI), then (VIIIa) or
(VIIIb), and then (VIIIc), to yield, in succession, compounds of
formulae (I/3.sub.a), (I/3.sub.b) and (I/3.sub.c): 46
[0148] wherein X.sub.b, Y.sub.b, T, R'.sub.1 and R'.sub.2 are as
defined hereinbefore,
[0149] or with a compound of formula (IX), the resulting product
then being treated in the same manner as the compounds of formulae
(X) and (XI), and then subjected to the successive action of a
compound of formula (XIII) then (XV), as described hereinbefore, to
yield compounds of formula (I/3.sub.d): 47
[0150] wherein X.sub.b, Y.sub.b, n.sub.1, R.sub.1 and R.sub.2 are
as defined hereinbefore,
[0151] which compounds (I/a) to (I/o) and (I/3.sub.a) to
(I/3.sub.d) constitute the totality of the compounds of the
invention, which are purified, if necessary, according to a
conventional purification technique, which may be separated, if
desired, into their different isomers according to a conventional
separation technique, and which are converted, where appropriate,
into their addition salts with a pharmaceutically acceptable acid
or base.
[0152] The compounds of formulae (II), (II/1), (III), (VI),
(VIIIa), (VIIIb), (VIIIc), (IX), (XIII), (XV) and (XVI) are either
known products or are obtained starting from known substances
according to conventional processes of organic chemistry.
[0153] The compounds of the present invention are inhibitors of
serotonin, noradrenalin and dopamine reuptake. They are useful as
medicaments in the treatment of depression, panic attacks,
obsessive-compulsive disorders, phobias, impulsive disorders, drug
abuse, anxiety, obesity and bulimia.
[0154] The present invention relates also to pharmaceutical
compositions comprising as active ingredient at least one compound
of formula (I), an optical isomer, or an addition salt thereof with
a pharmaceutically acceptable acid or base, alone or in combination
with one or more inert, non-toxic pharmaceutically acceptable
excipients or carriers.
[0155] Among the pharmaceutical compositions according to the
invention, there may be mentioned more especially those that are
suitable for oral, parenteral (intravenous, intramuscular or
subcutaneous), per- or trans-cutaneous, nasal, rectal, perlingual,
ocular or respiratory administration, and especially tablets or
drages, sublingual tablets, soft gelatin capsules, hard gelatin
capsules, suppositories, creams, ointments, dermal gels, injectable
or drinkable preparations, aerosols, eye or nose drops, etc.
[0156] The useful dosage varies according to the age and weight of
the patient, the route of administration, the nature and severity
of the disorder, and whether any associated treatments are being
taken and ranges from 0.5 mg to 25 mg in one or more
administrations per day.
[0157] The following Examples illustrate the invention but do not
limit it in any way. The starting materials used are known products
or are prepared according to known procedures. The various
Preparations yield synthesis intermediates for use in the
preparation of the compounds of the invention.
[0158] The structures of the compounds described in the Examples
were determined according to the usual spectrophotometric
techniques (infrared, nuclear magnetic resonance, mass
spectrometry, etc.).
[0159] The melting points were determined using a Kofler hot plate
(K.), or using a hot plate under a microscope (M.K.). When the
compound is present in the form of a salt, the melting point given
corresponds to that of the salt product.
[0160] By way of information, the numbering adopted for the various
tricyclic systems is as follows: 48
PREPARATION 1
6-Cyano-1-methylsulphonyl-5,6-dihydrocyclobuta[f]indole
[0161] Step 1
1-Cyano-5-[(2,2-dimethoxyethyl)amino]benzocyclobutane
[0162] To a suspension of 13.5 g of 1-cyano-5-aminobenzocyclobutane
in 400 ml of 1,2-dichloroethane there are added rapidly, dropwise,
26.5 ml of a 45% solution of 2,2-dimethoxyacetaldehyde in
tert-butyl methyl ether, then 16 ml of acetic acid and finally, in
fractions, 39.7 g of sodium triacetoxyborohydride. After increasing
the temperature to 29.degree. C., the mixture is cooled again to
room temperature, and then stirred for 1 hour 15 minutes and
hydrolysed by pouring into 500 ml of an aqueous saturated sodium
hydrogen carbonate solution. The organic phase is separated off,
washed with water and concentrated under reduced pressure to yield
the desired product in a quantitative yield.
[0163] Step 2
1-Cyano
5-[(N-(2,2-dimethoxyethyl)-N-methylsulphonylamino]benzocyclobutane
[0164] A solution prepared starting from 21.6 g of the product
obtained in the preceding Step 1, 58 ml of pyridine and 225 ml of
dichloromethane is cooled to 0.degree. C. 10.8 ml of mesyl chloride
are added dropwise over the course of 20 minutes and stirring is
carried out for a further 40 minutes at 0.degree. C. and then for
20 hours at room temperature. The reaction mixture is then poured
into 40 ml of an aqueous saturated sodium hydrogen carbonate
solution. After decanting, the aqueous phase is extracted twice
with 150 ml of methylene chloride each time. The combined organic
phases are washed with 1N hydrochloric acid, dried and concentrated
to yield the expected product in a quantitative yield.
[0165] Step 3
6-Cyano-1-methylsulphonyl-5,6-dihydrocyclobuta[f]indole
[0166] A solution of 10.9 ml of titanium chloride in 450 ml of
toluene and a solution of 27.9 g of the product obtained in Step 2
diluted in 450 ml of toluene are poured simultaneously over the
course of 1 hour 15 minutes into 2.1 liters of toluene at reflux.
When the addition is complete, the temperature is left to drop to
40.degree. C., and the mixture is poured into 1.8 liters of an
aqueous saturated sodium hydrogen carbonate solution. After
decanting, the aqueous phase is extracted with toluene, and the
organic phases are combined, washed, dried and concentrated. The
residue is purified by chromatography over silica gel
(dichloromethane/cyclohexane: 75/25) to yield the expected product
and its regioisomer.
[0167] Melting point: 142-144.degree. C. (MK)
PREPARATION 2
6-Cyano-5,6-dihydrocyclobuta[f]indole
[0168] 2.6 g of the product of Preparation 1 are introduced into a
solution of 7.7 g of potassium hydroxide in 190 ml of methanol.
After 12 hours at reflux, the methanol is removed by evaporation
and the residue is taken up in ether. After washing, the organic
phase is dried and concentrated to yield the expected product.
[0169] Melting point: 126-128.degree. C. (MK)
PREPARATION 3
6-Cyano-2,3,5,6-tetrahydrocyclobuta[f]indole
[0170] 3.43 g of the product obtained in Preparation 2 are
dissolved in 55 ml of acetic acid. 3.84 g of sodium
cyanoborohydride are added in portions over the course of 5 minutes
to the reaction mixture which has been cooled to 13.degree. C.
After returning to room temperature, stirring is maintained for 2
hours, and then the reaction mixture is cooled to 0.degree. C. and
brought to pH=11 by the addition of a sodium hydroxide solution (45
g in 250 ml of water). The resulting milky solution is extracted
with ether. The organic phases are washed, dried and concentrated
to yield the expected product in the form of a white solid.
[0171] Melting point: 85-87.degree. C. (MK)
PREPARATION 4
4-Cyano-1-methylsulphonyl-4,5-dihydrocyclobuta[f]indole
[0172] The regioisomer obtained in Step 3 of Preparation 1
corresponds to the expected product.
[0173] Melting point: 118-120.degree. C. (MK)
PREPARATION 5
4-Cyano-4,5-dihydrocyclobuta[f]indole
[0174] The product is obtained according to the process of
Preparation 2, using the product of Preparation 4 as substrate.
[0175] Melting point: 132-134.degree. C. (MK)
PREPARATION 6
4-Cyano-2,3,4,5-tetrahydrocyclobuta[f]indole
[0176] The product is obtained according to the process of
Preparation 3, using the product of Preparation 5 as substrate.
PREPARATION 7
5-Cyano-5,6-dihydrocyclobuta[f]benzothiophene
[0177] Step 1
1-Cyano-4-thiomethylbenzocyclobutane
[0178] Into 3.5 liters of liquid ammonia at reflux containing
catalytic amounts of potassium ferrocyanide and iron trinitrate
monohydrate there are introduced, over the course of 2 hours, 50.8
g of sodium, followed, over the course of 5 minutes, by 153 g of
3-(2-chloro-5-thiomethylphenyl)- propionitrile. The mixture is left
to react for 1 hour at -33.degree. C. and then 118.2 g of solid
ammonium chloride are introduced. After removal of the ammonia by
evaporation, the residue is taken up in ether, the salts are
filtered off and the filtrate is evaporated to dryness, enabling
the expected product to be obtained.
[0179] Step 2
1-Cyano-4-methylsulphinylbenzocyclobutane
[0180] 11 g of the product of the preceding Step 1 are dissolved in
70 ml of dichloromethane. Onto the solution, which has been cooled
to -5.degree. C., there is poured a solution of 15.8 g of
m-chloroperbenzoic acid in 80 ml of dichloromethane. After 10
minutes' stirring, the reaction mixture is poured into 100 ml of
water and 100 ml of 1N sodium hydroxide solution. Decanting is
carried out, and the aqueous phase is extracted again with
dichloromethane. The combined organic phases are washed with sodium
hydrogen sulphate, and then with 1N sodium hydroxide solution, with
sodium hydrogen carbonate and finally with water until neutral. The
organic phase is dried and concentrated to yield the expected
product.
[0181] Step 3
1-Cyano-4-mercaptobenzocyclobutane
[0182] 9.76 ml of trifluoroacetic acid dissolved in 20 ml of
dichloromethane are added to a solution of 11 g of the product
obtained in the preceding Step in 100 ml of dichloromethane. The
addition lasts for 45 minutes, during which time the temperature is
maintained at 25.degree. C. The reaction mixture is stirred again
for 1 hour 30 minutes at that temperature, and then evaporated to
dryness. The residue is taken up by stirring for 10 minutes in the
presence of a 50/50 mixture of triethylamine and methanol. After
evaporation, the residue is diluted with dichloromethane, washed
with a saturated ammonium chloride solution and then with water,
dried and concentrated to obtain the expected product in the form
of an oil.
[0183] Step 4
1-Cyano-4-(2,2-diethoxyethylsulphanyl)benzocyclobutane
[0184] 3.65 g of sodium borohydride are added in portions, at
20.degree. C., to a solution of 9.1 g of the product obtained in
the preceding Step 3 in 20 ml of tetrahydrofuran and 140 ml of
ethanol. After 1 hour at 50.degree. C., 2.14 g of solid sodium
borohydride are added again. The reaction mixture is then heated to
80.degree. C. and, at that temperature, 39 ml of bromoacetaldehyde
diethylacetal are poured in over the course of 1 hour. Heating is
maintained for a further 12 hours, and then the cooled reaction
mixture is poured into 1 liter of ice-cold water. The resulting
mixture is extracted with ether and the organic phase is washed
with a 10% sodium hydrogen carbonate solution and then with water.
The ethereal phase is dried and concentrated in vacuo to yield the
expected product in the form of an oil.
[0185] Step 5
5-Cyano-5,6-dihydrocyclobuta[f]benzothiophene
[0186] 10 g of polyphosphoric acid, and 8.5 g of the product
obtained in the preceding Step 4 in 500 ml of chlorobenzene are
heated at 130.degree. C. for 4 hours. After cooling, the
supernatant is drawn off and the residue is rinsed with
dichloromethane. The supernatant and the dichloromethane phase are
combined and neutralised by adding powdered sodium hydrogen
carbonate. After 15 minutes' stirring, filtration is carried out,
followed by evaporation to dryness. The residue is purified by
chromatography over silica gel (cyclohexane/dichloromethane:
50/50), enabling the expected product and a by-product to be
obtained.
[0187] Melting point: 102-103.degree. C. (MK)
PREPARATION 8
6-Cyano-5,6-dihydrocyclobuta[f]benzothiophene
[0188] The product is obtained according to the process of
Preparation 7, Steps 1 to 5, but in Step 1 using
3-(3-bromo-4-thiomethylphenyl)propionit- rile instead of
3-(2-chloro-5-thiomethylphenyl)propionitrile.
PREPARATION 9
5-Cyano-5,6-dihydrocyclobuta[f]benzofuran
[0189] Step 1
1-Cyano-4-(2,2-diethoxyethoxy)benzocyclobutane
[0190] A solution of 16.5 g of 1-cyano-4-hydroxybenzocyclobutane in
205 ml of dimethylformamide is poured into a suspension of 67.8
mmol of sodium hydride in 160 ml of dimethylformamide. The reaction
mixture is stirred for 30 minutes and then a solution of 10.2 ml of
1-bromo-2,2-diethoxyetha- ne in 40 ml is added over the course of
15 minutes and the temperature is then maintained at 60.degree. C.
for 6 hours. The mixture is stirred for a further 12 hours, the
dimethylformamide is removed by evaporation, and the residue is
taken up in water, extracted with dichloromethane, dried and
concentrated in vacuo. The residue is chromatographed over silica
gel (CH.sub.2Cl.sub.2/AcOEt: 95/5), enabling the expected product
to be isolated.
[0191] Step 2
5-Cyano-5,6-dihydrocyclobuta[f]benzofuran
[0192] The product is obtained as in Step 3 of Preparation 1, but
using the product of the preceding Step 1. In the course of
chromatography over silica gel (CH.sub.2Cl.sub.2/cyclohexane:
80/20), the expected product and a by-product are isolated.
PREPARATION 10
6-Cyano-5,6-dihydrocyclobuta[f]benzofuran
[0193] The product is obtained in the same manner as the product of
Preparation 9, but in Step 1 using
1-cyano-5-hydroxybenzocyclobutane and in Step 2 using the mixture
CH.sub.2Cl.sub.2/cyclohexane: 75/25 as eluant for the separation of
the regioisomers. The expected product is isolated in the form of
an oil.
PREPARATION 11
5-Cyano-4,5-dihydrocyclobuta[e]benzothiophene
[0194] The by-product obtained in Step 5 of Preparation 7
corresponds to the expected product.
PREPARATION 12
4-Cyano-4,5-dihydrocyclobuta[e]benzothiophene
[0195] The product is obtained in the course of Step 5 of
Preparation 8.
PREPARATION 13
5-Cyano-4,5-dihydrocyclobuta[e]benzothiophene
[0196] The by-product obtained in Step 2 of Preparation 9
corresponds to the expected product.
PREPARATION 14
4-Cyano-4,5-dihydrocyclobuta[e]benzofuran
[0197] The by-product isolated in the course of the chromatography
of Preparation 10 corresponds to the expected product.
PREPARATION 15
5,6-Dihydrocyclobuta[f][1,3]benzodioxole-5-carbonitrile
[0198] 46 g of 3-(6-bromo-1,3-benzodioxol-5-yl)propanenitrile are
introduced in portions into 1.4 liters of liquid ammonia in which
there is dissolved sodium azide which was prepared previously by
the introduction of 16.7 g of sodium into the liquid ammonia. After
30 minutes' contact, the reaction mixture is treated with 38.7 g of
ammonium chloride, and then the ammonia is distilled off at room
temperature. The residue is taken up in ether and filtered; the
precipitate is washed with ether. The combined ethereal phases are
evaporated and the resulting residue is recrystallised from
isopropyl alcohol, enabling the expected product to be
isolated.
[0199] Melting point: 91.degree. C. (M.K.)
PREPARATION 16
6,7-Dihydrocyclobuta[g][1]benzofuran-7-carbonitrile
[0200] Step 1
1-Cyano-6-(2,2-diethoxyethoxy)benzocyclobutane
[0201] The product is obtained according to the process of Step 1
of Preparation 9 using 1-cyano-6-hydroxybenzocyclobutane as
substrate.
[0202] Step 2
6,7-Dihydrocyclobuta[g][1]benzofuran-7-carbonitrile
[0203] The product is obtained according to the process of Step 3
of Preparation 1 using the product obtained in the preceding Step 1
as substrate.
PREPARATION 17
1,2-Dihydrocyclobuta[b]naphthalene-1-carbonitrile
[0204] The product is obtained according to the process of
Preparation 15 using 3-(3-iodo-2-naphthyl)propionitrile as
substrate.
[0205] Melting point: 98-102.degree. C. (M.K.)
PREPARATION 18
1,2-Dihydrocyclobuta[a]naphthalene-1-carbonitrile
[0206] Step 1
1,1-Diethoxy-1,2-dihydrocyclobuta[a]naphthalene
[0207] 9.4 g of sodium amide are introduced into 350 ml of
tetrahydrofuran. 25.9 g of 1-bromonaphthalene and 28 g of freshly
prepared 1,1-diethoxyethylene are poured in succession into that
mixture. The reaction mixture is refluxed for 16 hours and than
taken up in water and ether. After washing the organic phase to
neutral pH and drying thereof, the expected product is isolated and
chromatographed over silica gel (dichloromethane/cyclohexane:
1/1).
[0208] Step 2
Cyclobuta[a]naphthalen-1(2H)-one
[0209] 10 g of the product obtained in Step 1 are treated at room
temperature with 42 ml of 1N hydrochloric acid dissolved in 170 ml
of tetrahydrofuran. After 1 hour 30 minutes' contact, the solvent
is concentrated and the residue is poured into 170 ml of water. 6.9
g of a solid corresponding to the expected product are then
isolated.
[0210] Melting point: 92-94.degree. C. (M.K)
[0211] Step 3
1,2-Dihydrocyclobuta[a]naphthalen-1-ol
[0212] 1.4 g of sodium borohydride are added to a suspension, at
0-5.degree. C., of 5.2 g of the product obtained in Step 2 in 150
ml of methanol. After 15 minutes at that temperature and then 1
hour at room temperature, the reaction mixture is poured into 300 g
of ice and extracted with dichloromethane. After customary
treatment, 5.2 g of the expected product are isolated.
[0213] Melting point: 96-100.degree. C. (M.K.)
[0214] Step 4
1,2-Dihydrocyclobuta[a]naphthalene-1-carbonitrile
[0215] 5.1 g of the product obtained in Step 3, 14.2 g of
triphenylphosphine, and 12 g of carbon tetrabromide in 150 ml of
ether are refluxed for 2 hours. After cooling, the reaction mixture
is filtered, concentrated, taken up in 50 ml of ether, filtered and
evaporated. The 7.85 g of resulting residue are treated with 10.5 g
of tetrabutylammonium cyanide in 150 ml of tetrahydrofuran. After
64 hours' contact at room temperature, the reaction mixture is
concentrated and taken up in ice and ether. After decanting, an oil
is isolated, which is purified by chromatography over silica gel
(dichloromethane), enabling the expected product to be
isolated.
[0216] Melting point: 78-84.degree. C.
PREPARATION 19
1-(Methylsulphonyl)-5,6-dihydro-1H-cyclobuta[f]indole-5-carbonitrile
[0217] The product is obtained according to the process of
Preparation 1, Steps 1 to 3, using 4-amino-1-cyanobenzocyclobutane
in Step 1.
[0218] Melting point: 164-168.degree. C. (M.K.)
PREPARATION 20
5,6-Dihydro-1H-cyclobuta[f]indole-5-carbonitrile
[0219] The product is obtained according to the process of
Preparation 2 but using the product of Preparation 19 as
substrate.
[0220] Melting point: 109-113.degree. C. (M.K.)
PREPARATION 21
2,3,5,6-Tetrahydro-1H-cyclobuta[f]indole-5-carbonitrile
[0221] The product is obtained according to the process of
Preparation 3 but using the product of Preparation 20 as
substrate.
[0222] Melting point: 100-105.degree. C. (M.K.)
EXAMPLE 1
1-[6-(Aminomethyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indol-6-yl]cyclohexan-
ol
[0223] Step A
6-(1-Hydroxycyclohexyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-6-carboni-
trile
[0224] 4.1 g of the product obtained in Preparation 3 are dissolved
in 215 ml of tetrahydrofuran. The reaction mixture is cooled to
-80.degree. C. and 19.25 ml of a 2.5M solution of n-butyllithium in
hexane are added. When the addition is complete, stirring is
maintained for 20 minutes and then 6.2 ml of cyclohexanone are
poured in over the course of 3 minutes. After 2 hours' contact at
80.degree. C., the reaction mixture is left to return to room
temperature, and 23 ml of an aqueous saturated ammonium chloride
solution, and then 135 ml of water, are introduced. After
decanting, the organic phase is washed with a saturated sodium
chloride solution, dried and concentrated. The resulting residue is
solidified with isopropyl ether and filtered to obtain the desired
product, and the filtrate is purified by chromatography over silica
gel (CH.sub.2Cl.sub.2/AcOEt: 90/10) to isolate an additional amount
of the expected product.
[0225] Melting point: 168-170.degree. C.
[0226] Step B
1-[6-(Aminomethyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indol-6-yl]cyclohexan-
ol
[0227] 4 g of the product obtained in the preceding Step A are
dissolved in 200 ml of a 3.6N solution of ammoniacal methanol
containing 2 ml of Raney nickel. The reaction mixture is
hydrogenated under a pressure of 30 bars at 60.degree. C. for 24
hours. After filtration and removal of the solvent by evaporation,
the residue is taken up in dichloromethane, washed with water until
neutral, dried and concentrated to isolate the expected product in
the form of an oil.
EXAMPLE 2
1-{6-[(Dimethylamino)methyl]-1-methyl-2,3,5,6-tetrahydro-1H-cyclobuta[f]in-
dol-6-yl}cyclohexanol
[0228] 659 mg of the product of Example 1 are dissolved in 20 ml of
acetonitrile. Into that solution, which has been cooled to
0.degree. C., there are introduced 608 mg of sodium
cyanoborohydride and 1.5 ml of a 37% solution of formaldehyde in
water, whilst maintaining the temperature at 0.degree. C. After 20
hours at room temperature, hydrolysis is carried out with 33 ml of
1N hydrochloric acid and stirring is carried out for 3 hours. The
reaction mixture is washed with 30 ml of ether and then rendered
basic with 20% sodium hydroxide solution. The aqueous phase is
extracted with dichloromethane. After drying and evaporation, the
residue is purified by chromatography over silica gel
(CH.sub.2Cl.sub.2/EtOH: 95/5) to yield the expected product.
[0229] Melting point: 121-124.degree. C. (MK)
EXAMPLE 3
1-{6-[(Dimethylamino)methyl]-2,3,5,6-tetrahydro-1H-cyclobuta[f]indol-6-yl}-
cyclohexanol
[0230] Step A
6-(1-Hydroxycyclohexyl)-1-(methylsulphonyl)-2,3,5,6-tetrahydro-1H-cyclobut-
a[f]indole-6-carbonitrile
[0231] The process is as for Step 2 of Preparation 1 using the
product of Step A of Example 1. The expected product is solidified
from ether in the form of a violet solid.
[0232] Melting point: 174-176.degree. C.
[0233] Step B
1-[6-(Aminomethyl)-1-(methylsulphonyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]i-
ndol-6-yl]cyclohexanol
[0234] The process is as for Step B of Example 1 but using the
product of Step A above. The expected product is obtained in the
form of a yellow meringue.
[0235] Step C
1-[6-[(Dimethylamino)methyl]-1-(methylsulphonyl)-2,3,5,6-tetrahydro-1H-cyc-
lobuta[f]indol-6-yl]cyclohexanol
[0236] The process is as for Example 2 but using the product of
Step B above. The expected product is obtained in the form of a
yellow solid.
[0237] Melting point: 156-158.degree. C. (MK)
[0238] Step D
1-{6-[(Dimethylamino)methyl]-2,3,5,6-tetrahydro-1H-cyclobuta[f]indol-6-yl}-
cyclohexanol
[0239] 40 ml of liquid ammonia are introduced into a three-necked
flask, followed by 380 mg of the product obtained in Step C
dissolved in 10 ml of tetrahydrofuran. The mixture is cooled to
-50.degree. C. and 100 mg of sodium are introduced in several
portions into the reaction mixture. After 15 minutes' contact, 430
mg of powdered ammonium chloride are introduced in fractions. The
reaction mixture is left to return to room temperature. After
removal of all the ammonia by evaporation, the residue is taken up
in water, extracted with ether, dried and concentrated to obtain
the expected product.
[0240] Melting point: 159-161.degree. C. (MK)
EXAMPLE 4
1-[5-(Aminomethyl)-5,6-dihydrocyclobuta[f][1]benzofuran-5-yl]cyclohexanol
[0241] Step A
5-(1-Hydroxycyclohexyl)-5,6-dihydrocyclobuta[f][1]benzofuran-5-carbonitril-
e
[0242] The process is as for Step A of Example 1 but using the
product of Preparation 9 and carrying out the hydrolysis of the
reaction mixture at -75.degree. C. The expected product is isolated
in the form of a solid.
[0243] Melting point: 154-158.degree. C. (MK)
[0244] Step B
1-[5-(Aminomethyl)-5,6-dihydrocyclobuta[f][1]benzofuran-5-yl]cyclohexanol
[0245] A solution of 520 mg of the product obtained in the
preceding Step A in 10 ml of tetrahydrofuran is added dropwise at
0.degree. C., under a stream of nitrogen, to a suspension of 177 mg
of sodium aluminium hydride in 10 ml of ether. The reaction mixture
is stirred for 1 hour at room temperature and then hydrolysed with
0.26 ml of water, 0.79 ml of 20% sodium hydroxide solution and 1.05
ml of water. After 15 minutes' stirring at room temperature,
filtration is carried out, followed by evaporation to dryness. The
expected product is obtained in the form of a sticky meringue.
EXAMPLE 5
1-{5-[(Dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzofuran-5-yl}cyc-
lohexanol
[0246] 400 mg of the product of Example 4 are dissolved in 12 ml of
acetonitrile. After cooling to 0.degree. C., 0.55 ml of a 37%
solution of formaldehyde in water and 185 mg of sodium
cyanoborohydride are added in succession. After 1 hour at 0.degree.
C. and 2 hours at room temperature, 0.55 ml of 37% solution of
formaldehyde in water and 185 mg of sodium cyanoborohydride are
added again and stirring is maintained for a further 12 hours at
20.degree. C. Hydrolysis is carried out at room temperature with
22.3 ml of hydrochloric acid (1N) and the mixture is stirred for 1
hour, rendered basic at 0.degree. C. with 20% sodium hydroxide
solution, extracted with dichloromethane, washed with water, dried
and concentrated. Chromatography over silica gel
(CH.sub.2Cl.sub.2/EtOH: 90/10) enables the expected product to be
isolated in the form of white crystals.
[0247] Melting point: 127-136.degree. C. (M.K)
EXAMPLE 6
1-[5-(Aminomethyl)-5,6-dihydrocyclobuta[f][1]benzothien-5-yl]cyclohexanol
[0248] The process is as for Example 4, Steps A to B, using the
product of Preparation 7 in Step A.
EXAMPLE 7
1-{5-[(Dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzothien-5-yl}cyc-
lohexanol
[0249] The process is as for Example 5 using the product of Example
6 as substrate.
[0250] Melting point: 151-155.degree. C. (MK)
EXAMPLE 8
1-{6-[(Dimethylamino)methyl]-1-methyl-5,6-dihydro-1H-cyclobuta[f]indol-6-y-
l}cyclohexanol
[0251] 0.44 g of the product of Example 1 and 1.23 g of manganese
dioxide are introduced into 15 ml of toluene. The reaction mixture
is stirred for 24 hours at room temperature and then 0.6 g of
manganese dioxide is added again, stirring being maintained for a
further 24 hours. After filtration over Celite and removal of the
solvent by evaporation, the residue is purified by rapid
chromatography over silica gel (CH.sub.2Cl.sub.2/MeOH/N- H.sub.4OH:
98/20/0.2%) to yield the expected product.
[0252] Melting point: 148-150.degree. C. (MK)
EXAMPLE 9
1-{7-[(Dimethylamino)methyl]-2,3,6,7-tetrahydro-1H-cyclobuta[e]indol-7-yl}-
cyclohexanol
[0253] Step A
7-(1-Hydroxycyclohexyl)-2,3,6,7-tetrahydro-1H-cyclobuta[e]indole-7-carboni-
trile
[0254] The product is obtained as for Step A of Example 1 but using
the product of Preparation 6 instead of the product of Preparation
3.
[0255] Step B
1-{7-[(Dimethylamino)methyl]-2,3,6,7-tetrahydro-1H-cyclobuta[e]indol-7-yl}-
cyclohexanol
[0256] The process is as for Example 3, Steps A to D, but using in
Step A of that Example the product of Step A above.
EXAMPLE 10
1-[6-(Aminomethyl)-5,6-dihydrocyclobuta[f][1]benzothien-6-yl]cyclohexanol
[0257] The product is obtained according to the process of Example
4, Steps A to B, using the compound of Preparation 8 as substrate
in Step A.
EXAMPLE 11
1-[6-(Aminomethyl)-5,6-dihydrocyclobuta[f][1]benzofuran-6-yl]cyclohexanol
[0258] The product is obtained according to the process of Example
4, Steps A to B, using the compound of Preparation 10 as substrate
in Step A.
EXAMPLE 12
1-{6-[(Dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzofuran-6-yl}cyc-
lohexanol
[0259] The product is obtained according to the process of Example
5, using the compound of Example 11 as substrate.
EXAMPLE 13
1-[6-(Aminomethyl)-6,7-dihydrocyclobuta[e][1]benzothien-6-yl]cyclohexanol
[0260] The product is obtained according to the process of Example
4, Steps A to B, using the compound of Preparation 11 as substrate
in Step A.
EXAMPLE 14
1-[7-(Aminomethyl)-6,7-dihydrocyclobuta[e][1]benzothien-7-yl]cyclohexanol
[0261] The product is obtained according to the process of Example
4, Steps A to B, using the compound of Preparation 12 as substrate
in Step A.
EXAMPLE 15
1-[6-(Aminomethyl)-6,7-dihydrocyclobuta[e][1]benzofuran-6-yl]cyclohexanol
[0262] The product is obtained according to the process of Example
4, Steps A to B, using the compound of Preparation 13 as substrate
in Step A.
EXAMPLE 16
1-[7-(Aminomethyl)-6,7-dihydrocyclobuta[e][1]benzofuran-7-yl]cyclohexanol
[0263] The product is obtained according to the process of Example
4, Steps A to B, using the compound of Preparation 14 as substrate
in Step A.
EXAMPLE 17
1-{6-[(Dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzothien-6-yl}cyc-
lohexanol
[0264] The product is obtained according to the process of Example
2, using the compound of Example 10 as substrate.
[0265] Melting point: 161-166.degree. C. (M.K.)
EXAMPLE 18
1-{5-[(Dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1,3]benzodioxol-5-yl}-
cyclohexanol
[0266] The product is obtained according to the process of Example
1, Steps A to B, and according to the process of Example 2, using
the product of Preparation 15 as substrate in Step A of Example 1
instead of the product of Preparation 3.
[0267] Melting point: 94-96.degree. C. (M.K.)
EXAMPLE 19
1-{5-[(Dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzofuran-5-yl}cyc-
lopentanol and Its Hydrochloride
[0268] The product is obtained according to the process of Example
4, Steps A to B, and then according to the process of Example 5,
using cyclopentanone as substrate in Step A instead of
cyclohexanone. The free base is converted to its hydrochloride by
the action of ethereal hydrogen chloride.
[0269] Melting point: 258-262.degree. C. (M.K.)
EXAMPLE 20
1-{5-[(Dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1,3]benzodioxol-5-yl}-
cyclopentanol
[0270] The product is obtained according to the process of Example
4, Steps A to B, and then according to the process of Example 5,
using cyclopentanone as substrate in Step A instead of
cyclohexanone and using the product of Preparation 15 instead of
the product of Preparation 9.
[0271] Melting point: 71-74.degree. C. (M.K.)
EXAMPLE 21
1-[5-(Aminomethyl)-5,6-dihydrocyclobuta[f][1]benzothien-5-yl]cyclopentanol
[0272] The product is obtained according to the process of Example
4, Steps A to B, using cyclopentanone as substrate in Step A
instead of cyclohexanone and using the product of Preparation 7
instead of the product of Preparation 9.
[0273] Melting point: 149-153.degree. C. (M.K.)
EXAMPLE 22
1-{5-[(Methylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzothien-5-yl}cyclo-
pentanol
[0274] A solution of 0.29 ml of ethyl chloroformate in 40 ml of
dichloromethane is introduced, at 0.degree. C., to a mixture of 1 g
of the product of Example 21, 1.2 ml of triethylamine and 60 ml of
dichloromethane. After returning to room temperature, the reaction
mixture is washed with 0.1N hydrochloric acid and then with a
saturated sodium hydrogen carbonate solution, dried and then
evaporated. The resulting residue is dissolved in 20 ml of
tetrahydrofuran. The solution is added to a mixture of 1.3 g of
AlLiH.sub.4 in 60 ml of tetrahydrofuran. The reaction mixture is
refluxed for 3 hours and then hydrolysed with 0.65 ml of water,
0.45 ml of 20% sodium hydroxide solution and 2.1 ml of water. After
filtration and concentration, the residue is purified by
chromatography over silica gel (dichloromethane/ethanol/NH.sub.4OH:
95/5/0.5) and recrystallised from isopropyl ether to yield the
expected product.
[0275] Melting point: 166-169.degree. C. (M.K.)
EXAMPLE 23
1-{5-[(Dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzothien-5-yl}cyc-
lopentanol
[0276] The product is obtained according to the process of Example
5, using the product of Example 21 instead of the product of
Example 4.
[0277] Melting point: 93-98.degree. C. (M.K.)
EXAMPLE 24
(+)-1-{5-[(Dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzothien-5-yl-
}cyclopentanol
[0278] The product of Example 23 is injected onto a chiral column
with a mobile phase comprising methanol/diethylamine: 1000/1. The
first product eluted corresponds to the (+) isomer.
[0279] Melting point: 122-126.degree. C. (M.K.)
EXAMPLE 25
(-)-1-{5-[(Dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzothien-5-yl-
}cyclopentanol
[0280] The product of Example 23 is injected onto a chiral column
with a mobile phase comprising methanol/diethylamine: 1000/1. The
second product eluted corresponds to the (-) isomer.
[0281] Melting point: 123-127.degree. C. (M.K.)
EXAMPLE 26
1-[6-(Aminomethyl)-5,6-dihydrocyclobuta[f][1]benzothien-6-yl]cyclopentanol
[0282] The product is obtained according to the process of Example
4, Steps A to B, using cyclopentanone as substrate in Step A
instead of cyclohexanone and using the product of Preparation 8
instead of the product of Preparation 9.
[0283] Melting point: 141-143.degree. C. (M.K.)
EXAMPLE 27
1-{6-[(Methylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzothien-6-yl}cyclo-
pentanol
[0284] The product is obtained according to the process of Example
22, using the product of Example 26 instead of the product of
Example 21.
[0285] Melting point: 117-120.degree. C. (M.K.)
EXAMPLE 28
1-{6-[(Dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzothien-6-yl}cyc-
lopentanol
[0286] The product is obtained according to the process of Example
5, using the product of Example 26 instead of the product of
Example 4.
[0287] Melting point: 94-96.degree. C. (M.K.)
EXAMPLE 29
1-{6-[(Dimethylamino)methyl]-1-methyl-5,6-dihydro-1H-cyclobuta[f]indol-6-y-
l}cyclopentanol
[0288] The product is obtained according to the processes of
Examples 1, 2 and 8 in succession, and using cyclopentanone in Step
A of Example 1 instead of cyclohexanone.
[0289] Melting point: 108-111.degree. C. (M.K.)
EXAMPLE 30
1-{5-[(Dimethylamino)methyl]-1-methyl-5,6-dihydro-1H-cyclobuta[f]indol-5-y-
l}cyclopentanol
[0290] The product is obtained according to the processes of
Examples 1, 2 and 8 in succession, and using cyclopentanone in Step
A of Example 1 instead of cyclohexanone and using the product of
Preparation 21 instead of the product of Preparation 3.
[0291] Melting point: 100-104.degree. C. (M.K.)
EXAMPLE 31
1-{7-[(Dimethylamino)methyl]-6,7-dihydrocyclobuta[g][1]benzofuran-7-yl}cyc-
lopentanol
[0292] The product is obtained according to the process of Example
4, Steps A to B, and then according to the process of Example 5,
using cyclopentanone as substrate in Step A instead of
cyclohexanone and using the product of Preparation 16 instead of
the product of Preparation 9.
[0293] Melting point: 135-137.degree. C. (M.K.)
EXAMPLE 32
1-{6-[(Dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzofuran-6-yl}cyc-
lopentanol and Its hydrochloride
[0294] The product is obtained according to the process of Example
4, Steps A to B, and then according to the process of Example 5,
using cyclopentanone as substrate in Step A instead of
cyclohexanone and using the product of Preparation 10 instead of
the product of Preparation 9. The hydrochloride is prepared by the
action of ethereal hydrogen chloride.
[0295] Melting point (hydrochloride): 225-235.degree. C. (M.K.)
EXAMPLE 33
1-{6-[(Dimethylamino)methyl]-2,3,5,6-tetrahydro-1H-cyclobuta[f]indol-6-yl}-
cyclopentanol
[0296] The product is obtained according to the process of Example
3, Steps A to B, in Step A using the product prepared in Step A of
Example 1 starting from cyclopentanone and not from
cyclohexanone.
[0297] Melting point: 105-108.degree. C. (M.K.)
EXAMPLE 34
1-{6-[(Dimethylamino)methyl]-5,6-dihydro-1H-cyclobuta[f]indol-6-yl}cyclope-
ntanol
[0298] The product is obtained according to the process of Example
8, using the product of Example 33 as substrate.
[0299] Melting point: 180-184.degree. C. (M.K.)
EXAMPLE 35
1-{1-[(Dimethylamino)methyl]-1,2-dihydrocyclobuta[b]naphthalen-1-yl}cyclop-
entanol
[0300] The product is obtained according to the process of Example
4, Steps A to B, and then according to the process of Example 5,
using cyclopentanone as substrate in Step A instead of
cyclohexanone and using the product of Preparation 17 instead of
the product of Preparation 9.
[0301] Melting point: 133-135.degree. C. (M.K.)
EXAMPLE 36
1-{7-[(Dimethylamino)methyl]-6,7-dihydro-3H-cyclobuta[e]indol-7-yl}cyclope-
ntanol
[0302] The product is obtained according to the process of Example
3, Steps A to D, and then Example 8, in Step A of Example 3 using
the product prepared in Step A of Example 1 but on the one hand
using the product of Preparation 9 and on the other hand using
cyclopentanone.
[0303] Melting point: 200-204.degree. C. (M.K.)
EXAMPLE 37
1-{1-[(Dimethylamino)methyl]-1,2-dihydrocyclobuta[a]naphthalen-1-yl}cyclop-
entanol and Its Hydrochloride
[0304] The product is obtained according to the process of Example
4, Steps A to B, and then according to the process of Example 5,
using cyclopentanone as substrate in Step A instead of
cyclohexanone and using the product of Preparation 18 instead of
the product of Preparation 9. The hydrochloride is obtained from
the ethereal hydrogen chloride.
[0305] Melting point (hydrochloride): 258-262.degree. C. (M.K.)
EXAMPLE 38
1-(7-{[((2S)-2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)amino]methyl}-6,7-dihy-
drocyclo-buta[g][1]benzofuran-7-yl)cyclopentanol and Its
Hydrochloride
[0306] Step A
1-[7-(Aminomethyl)-6,7-dihydrocyclobuta[g][1]benzofuran-7-yl]cyclopentanol
[0307] The product is obtained according to the process of Example
4, Steps A to B, using cyclopentanone as substrate in Step A
instead of cyclohexanone and using the product of Preparation 16
instead of the product of Preparation 9.
[0308] Step B
(2R)-N-{[7-(1-Hydroxycyclopentyl)-6,7-dihydrocyclobuta[g][1]benzofuran-7-y-
l]methyl}-2,3-dihydro-1,4-benzodioxine-2-carboxamide
[0309] A solution of 762 mg of
(2R)-2,3-dihydrobenzo[1,4]dioxin-2-ylcarbox- ylic acid chloride is
added, at 0.degree. C., to 900 mg of the compound obtained in Step
A in 30 ml of dichloromethane and 1.2 ml of diisopropylethylamine.
After 48 hours at room temperature, the reaction mixture is diluted
with water and extracted with dichloromethane. Conventional
treatment of the organic phases enables, after evaporation under
reduced pressure, the expected product to be isolated in the form
of a meringue.
[0310] Step C
1-(7-{[((2S)-2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)amino]methyl}-6,7-dihy-
drocyclobuta[g][1]benzofuran-7-yl)cyclopentanol and Its
Hydrochloride
[0311] 500 mg of lithium aluminium hydride in 20 ml of
tetrahydrofuran are refluxed, and then 1.1 g of the product
obtained in Step B dissolved in 20 ml of tetrahydrofuran are added.
After 3 hours 30 minutes' reflux, the reaction mixture is
hydrolysed by the addition of 0.45 ml of water, 0.31 ml of 20%
sodium hydroxide solution and 1.67 ml of water. After filtration
and evaporation, chromatography over silica gel
(dichloromethane/ethanol: 98/2) enables the expected product to be
isolated, which is converted to its hydrochloride by the action of
ethereal hydrogen chloride.
[0312] Melting point (hydrochloride): 213-235.degree. C.
EXAMPLE 39
1-(5-{[((2R)-2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)amino]methyl}-5,6-dihy-
drocyclobuta[f][1,3]benzodioxol-5-yl)cyclopentanol and Its
Hydrochloride
[0313] The product is obtained according to the process of Example
38, Steps A to C, in Step A using the product of Preparation 15 and
in Step B using (2S)-2,3-dihydrobenzo[1,4]dioxin-2-ylcarboxylic
acid chloride.
[0314] Melting point (hydrochloride): 109-119.degree. C. (M.K.)
EXAMPLE 40
1-(1-{[[2-(5-Fluoro-1H-indol-3-yl)ethyl](methyl)amino]methyl}-1,2-dihydroc-
yclobuta[b]naphthalen-1-yl)cyclopentanol
[0315] Step A
1-{[(Methyl)amino]methyl}-1,2-dihydrocyclobuta[b]naphthalen-1-yl)cyclopent-
anol
[0316] The product is obtained according to the process of Example
22, using
1-[1-(aminomethyl)-1,2-dihydrocyclobuta[b]naphthalen-1-yl]cyclopent-
anol as substrate, which is obtained starting from Preparation
17.
[0317] Step B
2-(5-Fluoro-1H-indol-3-yl)-N-[[1-(1-hydroxycyclopentyl)-1,2-dihydrocyclobu-
ta[b]naphthalen-1-yl]methyl]-N-methylacetamide
[0318] 0.652 g of (5-fluoro-indol-3-yl)acetic acid dissolved in 30
ml of dichloromethane are treated with 0.61 g of
carbonyldiimidazole, at room temperature for 30 minutes. A solution
of 0.95 g of the product obtained in Step A dissolved in 5 ml of
dichloromethane is poured into the solution. When the reaction is
complete, the reaction mixture is taken up in water, decanted,
dried and evaporated to yield the expected product.
[0319] Step C
1-(1-{[[2-(5-Fluoro-1H-indol-3-yl)ethyl](methyl)amino]methyl}-1,2-dihydroc-
yclobuta[b]naphthalen-1-yl)cyclopentanol
[0320] The product is obtained according to the process of Example
39, using the product obtained in the preceding Step B as
substrate.
PHARMACOLOGICAL STUDY OF THE COMPOUNDS OF THE INVENTION
[0321] A. In Vitro Studies
EXAMPLE 41
Determination of the Affinity for Serotonin Reuptake Sites
[0322] The affinity was determined by competition experiments using
[.sup.3H]-paroxetine (NEN, Les Ulis, France). The membranes are
prepared from rat frontal cortex and are incubated in triplicate
for 2 hours at 25.degree. C. with 1.0 nM [.sup.3H]-paroxetine and
cold ligand in a final volume of 0.4 ml. The incubation buffer
contains 50 nM TRIS-HCl (pH 7.4), 120 mM NaCl and 5 mM KCl.
Non-specific binding is determined using 10 .mu.M citalopram. At
the end of the incubation, the incubation medium is filtered and
washed three times with 5 ml of cooled buffer. The radioactivity
retained on the filters is determined by liquid scintillation
counting. The binding isotherms are analysed by non-linear
regression to determine the IC.sub.50 values. Those values are
converted into a dissociation constant (K.sub.i) using the
Cheng-Prusoff equation:
K.sub.1=IC.sub.50/(1+L/K.sub.d)
[0323] wherein L is the concentration of [.sup.3H]-paroxetine and
K.sub.d is the dissociation constant of [.sup.3H]-paroxetine for
the serotonin reuptake site (0.13 nM). The results are expressed in
pK.sub.i (-log K.sub.i).
[0324] The compounds of the present invention demonstrate very good
affinity for serotonin reuptake sites, their pK.sub.i being
.gtoreq.7.
EXAMPLE 42
Determination of the Affinity for Noradrenalin Reuptake Sites
[0325] The affinity was determined by competition experiments using
[.sup.3H]-nisoxetine (Amersham, les Ulis, France). The membranes
are prepared from rat frontal cortex and are incubated in
triplicate for 4 hours at 4.degree. C. with 2 nM
[.sup.3H]-nisoxetine and cold ligand in a final volume of 0.5 ml.
The incubation buffer contains 50 mM TRIS-HCl (pH 7.4), 300 mM NaCl
and 5 mM KCl. Non-specific binding is determined using 10 .mu.M
desipramine. At the end of the incubation, the incubation medium is
filtered and washed three times with 5 ml of cooled filtration
buffer (50 mM TRIS-HCl, pH 7.4, 300 mM NaCl and 5 mM KCl). The
radioactivity retained on the filters is determined by liquid
scintillation counting. The binding isotherms are analysed by
non-linear regression to determine the IC.sub.50 values. Those
values are converted into a dissociation constant (K.sub.i) using
the Cheng-Prusoff equation:
K.sub.1=IC.sub.50/(1+L/K.sub.d)
[0326] wherein L is the concentration of [.sup.3H]-nisoxetine and
K.sub.d is the dissociation constant of [.sup.3H]-nisoxetine for
the noradrenalin reuptake site (1.23 nM). The results are expressed
in pKi (-log Ki).
[0327] The pKi of the compounds of the invention is .gtoreq.6.
[0328] B. In Vivo Studies
EXAMPLE 43
Microdialysis Experiment in the Rat
[0329] Rats are anaesthetised with pentobarbital (60 mg/kg i.p.).
They are placed in a Kopf stereotactic device and the cannula guide
is implanted in the cingulate frontal cortex in accordance with the
coordinates described in the Paxinos and Watson atlas (1982) as
follows: AP=+2.2; L=.+-.0.6; DV=-0.2. The rats are placed in
separate cages and are not used in dialysis until 5 days later. On
the day of the dialysis, the probe is slowly lowered and held in
position. The probe is perfused at a flow rate of 1 .mu.l/mn with a
solution of 147.2 mM NaCl, 4 mM KCl and 2.3 mM CaCl.sub.2 adjusted
to pH 7.3 with a phosphate buffer (0.1 M). Two hours after
implantation, samples are collected every 20 minutes for 4 hours.
Three baseline samples are taken before administration of the
products to be tested. The rats are left in their individual cages
for the whole of the experiment. When the experiment is finished,
the rats are decapitated and the brain is removed and frozen in
isopentane. Sections of a thickness of 100 .mu.m are cut and
stained with cresyl violet, which allows verification of the
location of the probes.
[0330] The simultaneous quantification of dopamine, norepinephrine
and serotonin is carried out as follows: 20 .mu.l dialysis samples
are each diluted with 20 .mu.l of mobile phase (NaH.sub.2PO.sub.4:
75 mM, EDTA: 20 .mu.M, sodium 1-decanesulphonate: 1 mM, methanol:
17.5%, triethylamine: 0.01%, pH: 5.70) and 33 .mu.l samples are
analysed by HPLC using a reverse phase column thermostatically
maintained at 45.degree. C. and quantified by means of a
coulometric detector. The potential of the first electrode of the
detector is set at -90 mV (reduction) and that of the second at
+280 mV (oxidation). The mobile phase is injected at a flow rate of
2 ml/mn using a pump. The sensitivity limits for dopamine,
norepinephrine and serotonin are 0.55 fmol per sample. All the
products of the invention are injected subcutaneously in a volume
of 1.0 ml/kg. The products are dissolved in distilled water to
which a few drops of lactic acid have been added if necessary.
[0331] Results
[0332] By way of example and in order to illustrate the activity of
the products of the invention, the compound of Example 5,
administered subcutaneously at a dose of 10 mg/kg, increases the
level of serotonin by: 250.+-.15%, that of noradrenalin by
500.+-.13% and that of dopamine by 400.+-.50% (maximum % of the
effect compared with the baseline level defined as 0%).
EXAMPLE 44
Marble-Burying Test in Mice
[0333] This test enables evaluation of the capacity of
pharmacological agents to inhibit the spontaneous marble-burying
behaviour of mice, the inhibition being predictive of
antidepressant and/or anti-impulsive action. Male mice of the NMRI
strain (Iffa-Credo, l'Arbresle, France) weighing from 20 to 25 g on
the day of the experiment are placed individually in Macrolon.RTM.
boxes (30.times.18.times.19 cm) containing 5 cm of sawdust and
covered with a perforated plexiglass plate. Twenty-four "tiger's
eye" glass marbles are evenly distributed on the sawdust at the
periphery of the box. At the end of 30 minutes' free exploration,
the animals are removed from the box and the number of buried
marbles is counted.
[0334] Results
[0335] By way of example, the Table shows the effect of a product
of the invention compared with the effect of fluoxetine, a
reference antidepressant.
1 Example Marble-burying in mice, ID.sub.50 Fluoxetine 8.03 5 0.6
ID.sub.50 =inhibitory dose.sub.50 The doses are expressed in mg/kg
s.c.
EXAMPLE 45
Pharmaceutical Composition: Tablets
[0336] Formulation for the preparation of 1000 tablets containing a
dose of 5 mg
[0337] Compound of Example 5
[0338] 5 g
[0339] Hydroxypropylmethylcellulose
[0340] 5 g
[0341] Wheat starch
[0342] 10 g
[0343] Lactose
[0344] 100 g
[0345] Magnesium stearate
[0346] 2 g
* * * * *