Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-25
2001-05-29
Oswecki, Jane C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S415000, C514S235200, C514S253030, C514S256000, C514S259500, C514S319000, C514S326000, C514S339000, C514S365000, C540S575000, C544S143000, C544S284000, C544S333000, C544S373000, C546S201000, C546S277100, C548S146000, C548S491000
Reexamination Certificate
active
06239129
ABSTRACT:
The present invention relates to new cyano-indole serotonin-reuptake inhibitor compounds, to a process for their preparation and to pharmaceutical compositions containing them.
DESCRIPTION OF THE PRIOR ART
Compounds characterised by the combination of an indole ring and a 2,3-dihydro-1,4-benzodioxine ring have been described for their serotonin-reuptake inhibiting properties (WO 9717343). Indoles substituted on the aromatic ring have also been claimed in Application EP 814 084 for their action at the level of the serotonin-reuptake sites. Other compounds having related properties have been claimed in Application WO 9633710 and have a benzopyran structure.
BACKGROUND OF THE INVENTION
Serotonin-reuptake inhibitors constitute a heterogeneous group of therapeutic agents. They are used in the treatment of pathologies associated with a serotonin deficit at the level of the central neurone synapses. The inhibition of serotonin reuptake by binding to transporters or presynaptic receptors is a means of restoring nerve transmission.
The use of compounds having those inhibitory properties may constitute an alternative to the use of tricyclic antidepressants or of monoamine oxidase inhibitors in the treatment of depression and associated disorders (Annals of Pharmacotherapy, 1994, 28, 1359), panic attacks and obsessive-compulsive disorders (Human Psychopharmacology, 1995, 10, 5199). The efficacy of compounds having such pharmacological properties (Journal of Psychopharmacology, 1994, 8, 238) is reinforced by the fact that they are better tolerated (International Clinical Psychopharmacology, 1995, 9 suppl. 4, 33) and are safer to use (Annals of Pharmacology, reference cited).
SUMMARY OF THE INVENTION
The compounds of the present invention are characterised by an indole ring substituted on the aromatic moiety by a cyano group and on the indole nitrogen by an aminoalkyl chain. That novel structure confers upon them in addition of a great affinity for 5-HT
2c
receptors, a powerful serotonin-reuptake inhibiting character. They will therefore be useful therapeutically in the treatment of depression, panic attacks, obsessive-compulsive disorders, phobias, impulsive disorders associated with drug abuse, bulimia nervosa and anxiety.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds of formula (I):
wherein:
R
1
and R
2
each independently of the other represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group,
A represents a linear or branched (C
1
-C
6
)alkylene group, a linear or branched (C
2
-C
6
)-alkenylene group or a linear or branched (C
2
-C
6
)alkynylene group,
G
1
represents a grouping
wherein R
3
and R
4
each independently of the other represents a hydrogen atom, a linear or branched (C
1
-C
6
)alkyl group, a (C
3
-C
8
)cycloalkyl group, a (C
3
-C8)cycloalkyl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, an optionally substituted aryl group, an optionally substituted aryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, an optionally substituted heteroaryl group, or an optionally substituted heteroaryl-(C
1
-C
6
)-alkyl group in which the alkyl moiety is linear or branched,
or G
1
represents a heterocycloalkyl group, bonded to A by any one of the ring junctions and optionally substituted at any one of the ring positions by a linear or branched (C
1
-C
6
)alkyl group, a (C
3
-C
8
)cycloalkyl group, a (C
3
-C
8
)cycloalkyl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, a nitrile group, a carboxy group, a linear or branched (C
1
-C
6
)alkoxy-carbonyl group, a carbamoyl group (optionally substituted by one or two substituents: linear or branched (C
1
-C
6
)alkyl, (C
3
-C
8
)cycloalkyl, optionally substituted phenyl and/or optionally substituted benzyl), an optionally substituted aryl group, an optionally substituted aryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, an optionally substituted heteroaryl group, or an optionally substituted heteroaryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched,
their enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
“Heterocycloalkyl group” is understood to mean a saturated cyclic group having from 4 to 8 ring members containing 1 or 2 nitrogen and/or oxygen atoms. There may be mentioned more especially the groups piperidine, piperazine, 1,4-diazepan, pyrrolidine and morpholine, etc.
“Aryl” is understood to mean a group selected from phenyl and naphthyl.
“Heteroaryl group” is understood to mean a monocyclic or polycyclic, unsaturated or partially unsaturated, group having from 4 to 22 ring members and containing from 1 to 10 hetero atoms selected from nitrogen, oxygen and sulphur.
The expression “optionally substituted” applied to the terms “phenyl”, “benzyl”, “aryl”, “arylalkyl”, “heteroaryl” and “heteroarylalkyl” means that the groups in question are substituted on their cyclic moiety by one or more halogen atoms and/or linear or branched (C
1
-C
6
)alkyl groups, linear or branched (C
1
-C
6
)alkoxy groups, hydroxy groups, perhalo-(C
1
-C
6
)alkyl groups in which the alkyl moiety is linear or branched, amino groups (optionally substituted by one or two linear or branched (C
1
-C
6
)alkyl groups), and/or nitro groups, it being understood that the heteroaryl and heteroarylalkyl groups can also be substituted by an oxo group.
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, methanesulphonic acid, camphoric acid, etc.
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine., etc.
Advantageously, the invention relates to compounds of formula (I) wherein the cyano group is attached in the 5-position of the indole group.
Another advantageous aspect of the invention relates to compounds of formula (I) wherein the cyano group is attached in the 6-position of the indole group.
In the compounds of formula (I), preferably R
1
and R
2
each represents a hydrogen atom.
The preferred compounds of formula (I) are those wherein A represents a linear or branched (C
1
-C
6
)alkylene group.
In the preferred compounds of formula (I), G
1
represents a grouping
wherein
R
3
and R
4
are preferably selected from a hydrogen atom, a linear or branched (C
1
-C
6
)alkyl group, an aryl group and an aryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched.
In other preferred compounds of the invention, G
1
represents an optionally substituted heterocycloalkyl group.
The preferred heterocycloalkyl groups are the groups piperazine, 1,4-diazepan, pyrrolidine (3-pyrrolidinyl) and piperidine. Those groups are advantageously substituted by a group selected from aryl (for example phenyl) which is optionally substituted, aryl-(C
1
-C
6
)allyl in which the alkyl moiety is linear or branched (for example benzyl, phenethyl or phenylpropyl) which is optionally substituted, and heteroaryl (for example piperazine, pyridine, 2-oxo-2,3-dihydro-1H-indole, 5-oxo-5H-[1,3]thiazolo[3,2-a ] pyrimidine, or 2,4-dioxo-1,4-dihydro-3-(2H)-quinazoline), which is optionally substituted.
An especially advantageous aspect of the invention relates to compounds of formula (I) wherein the cyano group is attached in the 5- or 6-position of the indole group, R
1
and R
2
each represents a hydrogen atom, A represents a linear or branched (C
1
-C
6
)alkylene group, and G
1
represents a grouping
wherein R
3
and R
4
are each independently of the other selected from a hydrogen atom, a linear or branched (C
1
-C
6
)alkyl group, an aryl group and an aryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, or G
1
represents an o
Cimetiere Bernard
Gobert Alain
Lavielle Gilbert
Millan Mark
Muller Olivier
Adir et Compagnie
Oswecki Jane C.
The Firm of Heuschen and Sage
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