Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-18
2004-06-08
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S278000, C544S279000, C544S281000, C544S282000, C514S259410
Reexamination Certificate
active
06747032
ABSTRACT:
SUMMARY OF THE INVENTION
The present invention relates to new pyrimidin-4-one compounds, and to pharmaceutical compositions containing them.
The invention relates also to their use as combined &agr;
2
/5-HT
2c
ligands.
DESCRIPTION OF THE PRIOR ART
1,2,3,3a,4,9b-Hexahydrochromeno[3,4-c]pyrrole compounds have been described in Patent Application EP 691 342 in terms of their serotoninergic antagonist character and in Patent Application EP 887 350 in terms of their D
3
dopaminergic ligand character.
BACKGROUND OF THE INVENTION
The corticolimbic structures play an essential part in the processes controlling the altered functions in psychiatric disorders. In particular, it is now recognised that disturbance of monoaminergic transmission is strongly implicated in the aetiology of those various disorders. For example, in the case of depression, monoaminergic activity is reduced in the frontal cortex, the hippocampus and the nucleus accumbens.
Among the various classes of auto- and hetero-receptors of monoamines implicated in the mechanisms of regulation, &agr;
2
-AR (autoreceptor) and 5-HT
2c
receptors have been found to be of major importance. Those two receptor sub-types act in the same direction by inhibiting dopaminergic and adrenergic transmission. On the one hand, retro-control is exerted by &agr;
2
-AR (autoreceptor) receptors on noradrenergic neurons (J. Pharmacol. Exp. Ther., 1994, 270, 958), and, on the other hand, &agr;
2
-AR receptors and 5-HT
2c
heteroreceptors exert inhibitory control on dopaminergic and noradrenergic transmission (Neuropharmacology, 1997, 36, 609, J. Psychopharmacol. 2000, 14 (2), 114-138).
Compounds binding to one or other of those receptor sub-types have, in the past, demonstrated their potential for the treatment of a number of pathologies.
For example, the beneficial role of &agr;
2
-AR antagonist compounds has been studied in the treatment of cognitive disorders (J. Pharmacol., 1992, 6, 376), Parkinson's disease (CNS Drugs, 1998, 10, 189), schizophrenia (Science 1999, 286, 105-107), depression (J. Psychopharmacol. 1996, 10 Suppl. 3, 35-42), disturbances of libido, and sexual dysfunctions (J. Pharmacol., 1997, 11, 72). Likewise, 5-HT
2c
receptor ligands have demonstrated their usefulness in the treatment of sexual dysfunctions (J. Pharmacol., ibid.) and Parkinson's disease (Drug News Perspect., 1999, 12, 477), as well as anxiety (Br. J. Pharmacol., 1996, 117, 427), depression (Pharmacol. Biochem. Behav. 1988, 29, 819-820), impulsive disorders (Biol. Psych. 1993, 33, 3-14), appetite disorders (British J. Pharmacol. 1998, 123, 1707-1715), sleep disorders (Neuropharmacology 1994, 33 (3/4), 467-471) and schizophrenia (Neurosci. Lett., 1996, 181, 65).
Compounds having a double &agr;
2
-AR and 5-HT
2c
antagonist character may be highly useful to clinicians in obtaining, by administration of a single compound, a reinforced action whilst improving tolerability. A compound of that kind, moreover, has a considerable advantage over the administration of two different compounds.
The compounds of the invention have a novel structure providing them with their double &agr;
2
/5-HT
2c
antagonist character and are therefore useful in the treatment of depression, impulsive behaviour disorders, anxiety, schizophrenia, Parkinson's disease, cognitive disorders, disturbances of libido, sexual dysfunctions, appetite disorders and sleep disorders.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds of formula (I):
wherein:
R
1
, R
2
, R
3
and R
4
, which may be the same or different, each represent a hydrogen atom, a halogen atom or a group selected from linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy, linear or branched (C
1
-C
6
)polyhaloalkyl, hydroxy, cyano, nitro and amino,
or R
1
with R
2
, R
2
with R
3
, or R
3
with R
4
, together with the carbon atoms carrying them, form an optionally substituted benzene ring or an optionally substituted heteroaromatic ring,
X represents an oxygen atom or a methylene group,
A represents a linear or branched (C
1
-C
6
)alkylene chain,
represents an unsaturated nitrogen-containing heterocycle optionally substituted by one or two identical or different substituents selected from halogen atoms and linear or branched (C
1
-C
6
)alkyl, hydroxy, linear or branched (C
1
-C
6
)alkoxy, linear or branched (C
1
-C
6
)polyhaloalkyl, cyano, nitro, amino, optionally substituted phenyl, optionally substituted thienyl, optionally substituted furyl and optionally substituted pyrrolyl groups,
and R
5
represents a linear or branched (C
1
-C
6
)alkyl group,
to their enantiomers and diastereoisomers, and to addition salts thereof with a pharmaceutically acceptable acid or base,
it being understood that:
the term “(C
1
-C
6
)alkyl” denotes a hydrocarbon chain containing from one to six carbon atoms,
the term “(C
1
-C
6
)alkoxy” denotes a (C
1
-C
6
)alkyl-oxy group containing from one to six carbon atoms,
the term “(C
1
-C
6
)alkylene” denotes a bivalent hydrocarbon chain containing from one to six carbon atoms,
the term (C
1
-C
6
)polyhaloalkyl denotes a carbon chain containing from one to six carbon atoms and from 1 to 9 halogen atoms,
the term “heteroaromatic ring” denotes a 5- or 6-membered aromatic ring containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur,
the term “unsaturated nitrogen-containing heterocycle” denotes a 5- to 7-membered unsaturated ring having one, two or three unsaturations and containing one, two or three hetero atoms, one of those hetero atoms being the nitrogen atom and the additional hetero atom(s) optionally present being selected from oxygen, nitrogen and sulphur atoms,
the term “optionally substituted” applied to the expressions “benzene ring”, “heteroaromatic ring”, “phenyl”, “thienyl”, “furyl” or pyrrolyl” indicates that those groups are optionally substituted by one or two identical or different substituents selected from halogen atoms and linear or branched (C
1
-C
6
)alkyl, hydroxy, linear or branched (C
1
-C
6
)alkoxy, linear or branched (C
1
-C
6
)polyhaloalkyl, cyano, nitro and amino groups.
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric 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, oxalic acid etc.
Among the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine etc.
Among the heteroaromatic rings there may be mentioned, without implying any limitation, thiophene, pyridine, furan, pyrrole, imidazole, oxazole, isoxazole, thiazole, isothiazole, pyrmidine.
Preferred unsaturated nitrogen-containing heterocycles are 1,2-dihydropyridine, 2,3-dihydro-1,3-thiazole and 2,3-dihydro-oxazole.
A (3a&agr;,9b&agr;) or (3a&bgr;,9b&bgr;) compound is understood to mean a compound wherein the relevant ring junction is of the cis configuration.
A (3a&agr;,11c&agr;) or (3a&bgr;,11c&bgr;) compound is understood to mean a compound wherein the relevant ring junction is of the cis configuration.
A (3a&agr;,9b&bgr;) or (3a&bgr;,9b&agr;) compound is understood to mean a compound wherein the relevant ring junction is trans.
A (3a&agr;,11c&bgr;) or (3a&bgr;,11c&agr;) compound is understood to mean a compound wherein the relevant ring junction is trans.
In preferred compounds of formula (I), R
1
, R
2
, R
3
and R
4
, which may be the same or different, each represent a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy or hydroxy group.
Preferred compounds of the invention are those wherein R
1
and R
2
, together with the carbon atoms carrying them, form a benzene ring and R
3
and R
4
each represent a hydrogen atom.
X preferably represents an oxygen atom.
The invention advantageously relate
Brocco Mauricette
Dekeyne Anne
Dubuffet Thierry
Lavielle Gilbert
Millan Mark
Berch Mark L.
Habte Kahsay
Les Laboratoires Servier
The Firm of Hueschen and Sage
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