Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-11
2002-12-10
Rao, Deepak R. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252060, C514S258100, C514S266200, C514S314000, C514S417000, C514S421000, C544S235000, C544S239000, C544S298000, C544S315000, C544S316000, C546S113000, C546S152000, C548S400000, C548S152000, C548S465000, C548S484000, C548S490000, C548S492000
Reexamination Certificate
active
06492366
ABSTRACT:
DESCRIPTION OF THE PRIOR ART
Compounds characterised by the combination of an indole ring system and a 2,3-dihydro-1,4-benzodioxin ring system have been described for their serotonin-reuptake inhibiting properties (WO 9717343). Indoles substituted on the aromatic moiety have also been claimed in Patent Application EP 814 084 for their action at the level of the serotonin-reuptake sites. Other compounds having related properties have been claimed in Patent 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).
The compounds of the present invention are characterised by an indole ring system substituted on the benzene moiety by a cyano group and in the 3-position by an N-substituted 3-pyrrolylalkyl group. That novel structure confers upon them 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,
T
1
and T
2
each independently of the other represents a linear or branched (C
1
-C
6
)-alkylene group,
G represents a heterocyclic group of formula (&agr;) or (&bgr;):
wherein:
W
1
to W
5
and X
1
to X
4
are so selected as to form a chemically stable group and are defined as follows:
W
1
, W
2
and W
3
each independently of the others represents a nitrogen atom or a group CR
5
, NR
4
or CO,
W
4
represents a nitrogen atom or a group CR
3
, NR
4
or CO,
W
5
represents a carbon atom or a nitrogen atom,
X
1
represents a bond, a nitrogen atom or a group CR
3
or NR
4
,
X
2
to X
4
each independently of the others represents a group CR
3
, NR
4
, CO, SR
4
or SO
2
or an oxygen, sulphur or nitrogen atom,
R
3
represents a hydrogen or halogen atom or a linear or branched (C
1
-C
6
)alkyl group, hydroxy group, linear or branched (C
1
-C
6
)perhaloalkyl group, nitro group, or amino group (optionally substituted by one or two groups selected from linear or branched (C
1
-C
6
)alkyl and benzyl),
R
4
represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group, optionally substituted aryl group or optionally substituted arylalkyl group,
R
5
represents a group R
3
, or two adjacent groups R
5
form, together with the carbon atoms carrying them, a saturated, partially unsaturated or unsaturated mono- or bi-cyclic group optionally containing from 1 to 5 hetero atoms selected from nitrogen, oxygen and sulphur, the said group being optionally substituted by one or more groups selected from R
3
and oxo,
it being understood that, in formulae (&agr;) and (&bgr;), at least one heteroatom is present, the dotted lines indicate that the groups in question may contain an unsaturated bond or a plurality of conjugated or unconjugated unsaturated bonds and that, if there is no unsaturated bond, the remaining valences are occupied by hydrogen atoms, the groups (&agr;) and (&bgr;) being linked to T
2
by any one of their ring junctions,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned, by way of non-limiting examples, 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 examples, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
An aryl group is understood to mean a phenyl or naphthyl group.
The expression “optionally substituted” applied to aryl or arylalkyl groups means that the groups in question are optionally substituted by one or more groups selected from halogen atoms, linear or branched (C
1
-C
6
)alkyl groups, hydroxy groups, linear or branched (C
1
-C
6
)perhaloalkyl groups, nitro groups, and amino groups (optionally substituted by one or two groups selected from linear or branched (C
1
-C
6
)alkyl and benzyl).
Advantageously, the invention relates to compounds of formula (I) wherein the cyano group is attached in the 5-position of the indole ring system.
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 ring system.
Preferably, in the compounds of formula (I) R
1
and R
2
each represents a hydrogen atom.
Preferred compounds of the invention are those wherein T
1
represents a methylene group.
The preferred aryl group of the invention is the phenyl group. In preferred groups G of the invention, R
3
, R
4
and R
5
are advantageously selected from linear or branched (C
1
-C
6
)alkyl groups, hydrogen atoms and halogen atoms.
Among preferred groups G of the invention there may be mentioned, without implying any limitation, the groups:
2-furyl; 2,4-dioxo-1,4-dihydro-3(2H)-quinazolinyl; 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl; 1-oxo-2(1H)-phthalazinyl; 7-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyridin-6-yl; 6-chloro-2-oxo-2,3-dihydro-1H-indol-5-yl; 2-oxo-2,3-dihydro-1H-indol-5-yl; 2-oxo-1,2,3,4-tetrahydro-6-quinolinyl; 3-benzyl-5-methyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl; 1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl; 1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl; 1,3-dioxo-3,6-dihydropyrrolo[3,4-c]carbazol-2(1H)-yl; 1,3-dioxo-1,3-dihydro-2H-benzo[c]isoindol-2-yl; 3,5-dimethyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl.
An especially advantageous aspect of the invention relates to compounds of formula (I) wherein R
1
and R
2
each represents a hydrogen atom, T
1
represents a methylene group, T
2
represents an alkylene group (for example methylene or ethylene) and G is selected from the groups 2-furyl; 2,4-dioxo-1,4-dihydro-3(2H)-quinazolinyl; 3-oxo-[1,2,4]triazolo-[4,3-a]pyridin-2(3H)-yl; 1-oxo-2(1H)-phthalazinyl; 7-methyl-5-oxo-5H-[1,3]thiazolo-[3,2-a]pyrimidin-6-yl; 6-chloro-2-oxo-2,3-dihydro-1H-indol-5-yl; 2-oxo-2,3-dihydro-1H- indol-5-yl; 2-oxo-1,2,3,4-tetrahydro-6-quinolinyl; 3-benzyl-5-methyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl; 1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl; 1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl; 1,3-dioxo-3,6-dihydropyrrolo[3,4-c]carbazol-2(1H)-yl; 1,3-dioxo-1,3-dihydro-2H-benzo[c]isoindol-2-yl; 3,5-dimethyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl.
Among those compounds preference will be given to those wherein the cyano group is attached in the 5- or 6-position of the indole ring system, more especially those wherein the cyano group is attached in the 5-position.
Among the preferred compounds of the
Cussac Didier
Dekeyne Anne
Lavielle Gilbert
Millan Mark
Muller Olivier
Les Laboratoires Servier
Patel Sudhaker B.
Rao Deepak R.
The Firm of Hueschen and Sage
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