Substituted hydrochromenopyrroles

Details Substituted hydrochromenopyrroles Substituted hydrochromenopyrroles

2000-01-10

2002-04-02

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S291000, C514S411000, C546S276700, C548S430000

Reexamination Certificate

active

06365605

ABSTRACT:

The present invention relates to new chromene compounds.
Apart from the fact that the compounds of the present invention are new, they have particularly valuable properties, binding selectively to D
3
receptors compared with D
2
receptors.
BACKGROUND OF THE INVENTION
The discovery of those D
3
dopaminergic receptors (P. Sokoloff et al., Nature, 1990, 347, 147), their strong concentration in the limbic system and their low density in lactotrophic cells and in the nigrostriated system, makes them a choice target for obtaining antipsychotics that do not have effects on the secretion of prolactin and are less liable to cause extrapyramidal-type syndromes. It has, in fact, been established that the dopaminergic pathways extending to the limbic system and the cortex play a decisive role in the control of mood and in the aetiology and treatment of psychiatric Aid disorders such as schizophrenia, depression, anxiety, aggression and other impulsive disorders (M. J. Milian et al., Drug News & Perspectives, 1992, 5, 397-406; A. Y. Deutch et al., Schizophrenia, 1991, 4, 121-156; H. Y. Meltzen et al., Pharmacol. Rev., 1991, 43, 587-604).
DESCRIPTION OF THE PRIOR ART
The compounds of the prior art closest to those forming the subject of this Application were described for their dopaminergic or serotoninergic properties (EP 691342; J. Med. Chem., 1989, 32, 720-7).
The compounds of the present application are characterised by the presence of carboxamide or nitrile-type electron-attracting substituents which, surprisingly, allow enhancement of the D
3
dopaminergic properties in terms of strength and selectivity. The selectivity makes the products of the invention especially valuable for use as medicaments acting on the dopaminergic system that do not have the undesirable effects of D
2
ligands. In the light of results that have appeared in the literature, it is possible for them to be used in the treatment of impulsive disorders (for example those caused by drug abuse, B. Caine, Science, 1993, 260, 1814), aggressiveness (J. W. Tidey, Behavioral Pharm., 1992, 3, 553), Parkinson's disease (J. Carlson, Neur. Transm., 1993, 94, 11), psychoses, memory disorders (P. Sokoloff et al., Nature, 1990, 347, 147), anxiety and depression (P. Willner, Clinical Neuropharm., 1985, 18, suppl. 1, 549-56).
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates more specifically to compounds of formula (I):
wherein:
m is an integer such that 0≦m≦3,
n is an integer such that 0≦n≦3 and 2≦m+n≦3,
p is an integer such that 1≦p≦6,
the junction between the B and C rings is in the trans configuration,
X represents a cyano group or a group —CO—NR
4
R
5
, R
4
and R
5
being selected from hydrogen, linear or branched (C
1
-C
6
)-alkyl, (C
3
-C
7
)-cycloalkyl and optionally substituted aryl,
A represents a &sgr; bond or a group selected from —NR—CO—, —CO—NR—, —NR—SO
2
and —SO
2
—NR wherein R represents a hydrogen atom or a linear or branched (C
1
-C
6
)-alkyl group,
R
1
and R
2
each independently represent a hydrogen atom or a linear or branched (C
1
-C
6
)-alkyl group,
R
3
represents:
a hydrogen atom, or a phenyl, naphthyl or heteroaryl group each of which is optionally substituted by one or more halogen atoms, linear or branched (C
1
-C
6
)-alkyl, linear or branched (C
1
-C
6
)-alkoxy, hydroxy, cyano, amino, nitro, carboxy, linear or branched (C
1
-C
6
)-perhaloalkyl, sulpho, acylamino, linear or branched (C
1
-C
6
)-alkylsulphonyl or linear or branched (C
1
-C
6
)-alkylsulphonylamino groups,
an aryl or heteroaryl group substituted by a group A′-Cy wherein A′ represents a &sgr; bond, a linear or branched (C
1
-C
6
)-alkylene group (in which a carbon atom may optionally be replaced by an oxygen or sulphur atom), a linear or branched (C
1
-C
6
)-alkenylene group (in which a carbon atom may optionally be replaced by an oxygen or sulphur atom) or a group —NR—CO—, —CO—NR, —NR—SO
2
— or SO
2
—NR (in which R represents a hydrogen atom or a linear or branched (C
1
-C
6
)-alkyl group), and Cy represents an optionally substituted aryl group or an optionally substituted heteroaryl group,
a 2-indolinon-5-yl group,
or an aryloxy or arylthio group (with the proviso that in that case A represents a &sgr; bond),
 provided that:
when n is 0, m is other than 2,
when n is 1, R
1
and R
2
represent a hydrogen atom, A represents a &sgr; bond and p is 1, R
3
is other than phenyl or pyridyl,
when n is 1, R
1
and R
2
represent a hydrogen atom and A represents a &sgr; bond, R
3
is other than a hydrogen atom,
when n is 1, R
1
and R
2
represent a hydrogen atom and A represents an —NH—CO—group, R
3
is other than a hydrogen atom or a phenyl, naphthyl, or heterocyclic group selected from thienyl, furyl, pyrrolyl and pyridyl, each of those groups being optionally substituted by one or more halogen atoms or trihalomethyl, alkoxy or hydroxy groups,
their isomers, enantiomers and diastereoisomers, and also the addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned by way of non-limiting example hydrochloric, hydrobromic, sulphuric, acetic, trifluoroacetic, lactic, malonic, succinic, glutamic, fumaric, maleic, citric, oxalic, methanesulphonic, benzenesulphonic and 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.
An aryl group is to be understood as meaning a phenyl or naphthyl group.
A heteroaryl group is to be understood as meaning a mono- or bi-cyclic aromatic group containing from 5 to 13 chain members and from one to four hetero atoms selected from nitrogen, oxygen and sulphur, for example a furyl, pyridyl or thienyl group.
The expression “optionally substituted” describing aryl and heteroaryl signifies that those groups are optionally substituted by one or more halogen atoms or linear or branched (C
1
-C
6
)-alkyl, hydroxy, linear or branched (C
1
-C
6
)-alkoxy, linear or branched (C
1
-C
6
)-perhaloalkyl, cyano, nitro, sulfo, amino, linear or branched (C
1
-C
6
)-acyl, acylamino, linear or branched (C
1
-C
6
)-alkylsulfonyl or linear or branched (C
1
-C
6
)-alkylsulpholamino groups.
The term “acyl”, alone or in the expression “acylamino”, represents a linear or branched (C
1
-C
6
)-alkylcarbonyl group or a (C
3
-C
8
)-cycloalkylcarbonyl group.
Preferably, the invention relates to compounds of formula (I) wherein m and n are each 1.
Other preferred compounds of the invention are those wherein m is 3 while n is 0.
In compounds of formula (I), X preferably represents a cyano group.
In preferred compounds of the invention, A represents a &sgr; bond or an NR—CO— or NR—SO
2
group, R preferably being a hydrogen atom.
In compounds of formula (I), R
1
and R
2
each more especially represents a hydrogen atom.
Preferred R
3
groups of the invention are optionally substituted phenyl or optionally substituted biphenyl groups.
Another preferred group R
3
is an aryl group (more especially phenyl) substituted by a group A′-Cy wherein A′ preferably represents an NR—CO or NR—SO
2
group (R being more especially a hydrogen atom) and Cy preferably represents an optionally substituted aryl group.
Another preferred R
3
group is the group 2-indolinon-5-yl.
The invention relates more preferably to compounds of formula (I) wherein X represents a cyano group, m and n are each 1, R
1
and R
2
each represent a hydrogen atom, and p is 4 when A represents an NHCO group and R
3
represents an optionally substituted phenyl group or an optionally substituted biphenyl group, or p is 1 or 2 when A represents a &sgr; bond and R
3
represents an optionally substituted phenyl group or an optionally substituted biphenyl group.
The invention extends also to a process for the preparation of compounds of formula (I) which is characterised in that there is used as starting material a compound of formula (II):
wherein X, m and n are as defined for formula (I),
which is tr

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