Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-09-26
2002-09-17
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S597000, C540S604000, C540S606000, C540S611000
Reexamination Certificate
active
06451789
ABSTRACT:
BACKGROUND OF THE INVENTION
Ageing of the population due to increased life expectancy has brought with it a major increase in cognitive disorders associated with normal cerebral ageing and with pathological cerebral ageing occurring in the course of neurodegenerative diseases such as, for example, Alzheimer's disease.
The majority of substances used today in treating cognitive disorders associated with ageing act by facilitating the central cholinergic systems—either directly, as in the case of acetylcholinesterase inhibitors (tacrine, donepezil) and cholinergic agonists (nefiracetam), or indirectly, as in the case of nootropic agents (piracetam, pramiracetam) and cerebral vasodilators (vinpocetine).
Besides their cognitive properties, substances acting directly on the central cholinergic systems often have antalgic properties but also have hypothermic properties, which can be undesirable.
It has been therefore been especially valuable to synthesise new compounds that are capable of opposing the cognitive disorders associated with ageing and/or of improving cognitive processes and that can possess antalgic properties without having hypothermic activity.
DESCRIPTION OF THE PRIOR ART
4-Hydroxy- or 4-oxo-substituted 1-aza-2-alkyl-6-aryl-cycloalkanes and 1-aza-2-alkyl-6-aryl-cycloalkenes have already been described in the literature (J. Org. Chem. 1988, 53, 2426; Liebigs Ann. Chem. 1986, 11, 1823; Synlett 1993, 9, 657; Tet. Lett. 1998, 39(3/4), 217), but no pharmacological activity has been described for those compounds.
DETAILED DESCRIPTION OF THE INVENTION
More specifically, the present invention relates to compounds of formula (I):
wherein:
n represents 0 or 1,
R
1
represents a hydrogen atom or an aryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, a linear or branched (C
1
-C
6
)alkyl group, a linear or branched (C
1
-C
6
)acyl group, a linear or branched (C
1
-C
6
)alkoxycarbonyl group, an aryl-(C
1
-C
6
)-alkoxycarbonyl group in which the alkoxy moiety is linear or branched, or a trifluoro-acetyl group,
R
2
represents a linear or branched (C
1
-C
6
)alkyl group,
X represents an oxygen or chlorine atom or a group OR
3
, SR
4
or NOR
5
,
R
3
represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group, a linear or branched (C
1
-C
6
)acyl group, a linear or branched (C
1
-C
6
)alkoxycarbonyl group or an aryl-(C
1
-C
6
)alkoxycarbonyl group in which the alkoxy moiety is linear or branched,
R
4
represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group or an aryl group,
R
5
represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group optionally substituted by one or more identical or different groups selected from hydroxy, amino (optionally substituted by one or two linear or branched (C
1
-C
6
)alkyl groups) and linear or branched (C
1
-C
6
)alkoxy,
represents a single or double bond, it being understood that the valency of the atoms is respected,
Ar represents an aryl group or a heteroaryl group,
their isomers and addition salts thereof with a pharmaceutically acceptable acid,
with the proviso that the compounds of formula (I) are other than:
6-methyl-2-phenyl-2,3-dihydro-4-pyridinone,
2-methyl-6-phenyl-4-piperidinone,
N-benzyl-2-(R′
2
)-6-phenyl-4-piperidinones wherein R′
2
represents a methyl, ethyl, propyl or isopropyl group,
and 2-(R″
2
)-6-phenyl-4-piperidinols wherein R″
2
represents an isopropyl or butyl group.
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, 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, benzenesulphonic acid, camphoric acid etc.
An aryl group is understood to be phenyl, biphenylyl, naphthyl or tetrahydronaphthyl, each of those groups being optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C
1
-C
6
)alkyl, hydroxy, linear or branched (C
1
-C
6
)alkoxy, trihalomethyl and amino (optionally substituted by one or more linear or branched (C
1
-C
6
)alkyl groups).
A heteroaryl group is understood to be an aromatic, mono- or bi-cyclic, 5- to 12-membered group containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, it being understood that the heteroaryl group may be optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C
1
-C
6
)alkyl, hydroxy, linear or branched (C
1
-C
6
)alkoxy, trihalomethyl and amino (optionally substituted by one or more linear or branched (C
1
-C
6
)alkyl groups). Among the heteroaryl groups there may be mentioned, without implying any limitation, thienyl, pyridyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl groups.
Preferred compounds of formula (I) are those wherein n represents 0.
The group X as defined for formula (I) is preferably an oxygen atom or a group OR
3
wherein R
3
represents a hydrogen atom.
The group R
1
as defined for formula (I) is preferably a hydrogen atom.
The term “aryl” used in respect of the group Ar as defined for formula (I) is preferably an optionally substituted phenyl group.
The term “heteroaryl” used in respect of the group Ar as defined for formula (I) is preferably an optionally substituted thienyl group or an optionally substituted pyridyl group.
The invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that a compound of formula (II):
wherein Ar and n are as defined for formula (I),
is reacted with thionyl chloride to yield the corresponding acid chloride, which is reacted with a compound of formula (III):
wherein R
2
is as defined for formula (I),
in the presence of samarium triiodide,
to yield, after deprotection by an acid HA, the compound of formula (IV):
wherein Ar, n and R
2
are as defined hereinbefore and HA represents a proton donor acid,
which compound of formula (IV) is then reacted in a basic medium to yield the compound of formula (Ia), a particular case of the compounds of formula (I):
wherein Ar, n and R
2
are as defined hereinbefore,
which compound of formula (Ia) is condensed, if desired, with a compound of formula R′
1
—Y, wherein R′
1
, represents an aryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, a linear or branched (C
1
-C
6
)alkyl group, a linear or branched (C
1
-C
6
)acyl group, a linear or branched (C
1
-C
6
)alkoxycarbonyl group, an aryl-(C
1
-C
6
)alkoxycarbonyl group in which the alkoxy moiety is linear or branched, or a trifluoroacetyl group and Y represents a leaving group, to yield the compound of formula (Ib), a particular case of the compounds of formula (I):
wherein Ar, n, R′
1
and R
2
are as defined hereinbefore,
which compound of formula (Ia) or (Ib) is converted, if desired,
either by partial reduction with the aid of an appropriate reducing agent, followed, if desired, by alkylation, acylation or esterification of the hydroxy function to yield the compound of formula (Ic), a particular case of the compounds of formula (I):
wherein Ar, n and R
2
are as defined hereinbefore and R
1
and R
3
are as defined for formula (I),
or by complete reduction with the aid of an appropriate reducing agent to yield the compound of formula (Id), a particular case of the compounds of formula (I):
wherein Ar, n, R
1
and R
2
are as defined hereinbefore,
which compound of formula (Id) is reacted, if desired,
either with a compound of formula R′
3
—Y, wherein R′
3
represents a linear or branched (C
1
-C
6
)alkyl group, a linear or branched (C
1
-C
6
)acyl group, a linear or branched (C
1
-C
6
)alkoxycarbonyl group or an aryl-(C
1
-C
6
)alkoxycarbonyl group in which the alkoxy moiety is linear or branched and Y represents a leaving group, to yield the compound of formula (I
Dallemagne Patrick
Guillon Jean
Lebrun Marie-Cécile
Lestage Pierre
Pfeiffer Bruno
Aulakh Charanjit S.
Les Labortoires Servier
Sage G. Patrick
The Firm of Hueschen and Sage
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