Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-04
2001-11-27
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...
C514S315000, C514S358000, C546S192000, C546S194000, C546S195000, C546S193000
Reexamination Certificate
active
06323220
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new substituted pyridine or piperidine compounds and to their use as facilitators of memory and cognition and as antalgic agents.
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
The literature discloses substituted piperidine compounds which are described as products of synthesis and/or of alkaloids (J. Chem. Soc., Perkin Trans. 1, 1991, (3), pp. 611-616, Heterocycles, 1985, 23 (4), pp. 831-834; Can. J. Chem., 1996, 74 (12), pp. 2444-2453).
Substituted pyridine compounds have also been described with reference to their synthesis (J. Chem. Soc., Dalton Trans., 1998, (6), pp. 917-922) or their interactions in metal complexes (J. Chem. Soc., Chem. Commun., 1987, (19), pp. 1457-1459; J. Am. Chem. Soc., 1985, 107 (4), pp. 917-925).
The compounds of the present invention are new and have properties that, from a pharmacological point of view, are especially valuable.
DETAILED DESCRIPTION OF THE INVENTION
More specifically, the present invention relates to compounds of formula (I):
wherein:
A represents a pyridine, pyridinium or piperidine group,
R
2
represents a hydrogen atom and R
3
represents a hydroxy group, or R
2
and R
3
together form an oxo group,
R
4
represents an unsubstituted or substituted phenyl group, an unsubstituted or substituted naphthyl group or an unsubstituted or substituted heteroaryl group,
R
1
represents a hydrogen atom,
or R
1
and R
4
, together with the two carbon atoms carrying them, form a ring containing 6 carbon atoms,
or R
1
and R
2
form an additional bond and, in that case, R
3
represents a 5- or 6-membered heterocycle that contains a nitrogen atom by which it is bound and that may contain another hetero atom selected from sulphur, oxygen and nitrogen,
R
5
represents:
a 5- or 6-membered heterocycle that contains a nitrogen atom by which it is bonded to the ring A and that may contain another hetero atom selected from sulphur, oxygen and nitrogen,
a group of formula (II)
wherein R′
1
, R′
2
, R′
4
may have the same meanings as R
1
, R
2
, R
3
and R
4
respectively,
or a hydrogen atom and, in that case, R
4
cannot represent an unsubstituted phenyl group, an unsubstituted naphthyl group or an heteroaryl group,
R
6
represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group, the group R
6
being present or absent depending on the nature of the ring A,
heteroaryl being understood to mean any aromatic, mono- or bi-cyclic, 5- to 10-membered group containing from 1 to 3 hetero atoms selected from oxygen, nitrogen and sulphur,
the term “substituted” used in respect of the expressions “phenyl”, “naphthyl” or “heteroaryl” being understood to mean that the groups concerned may be substituted by one or more groups, which may be the same or different, selected from linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy, mercapto, linear or branched (C
1
-C
6
)-alkylthio, amino, linear or branched (C
1
-C
6
)alkylamino, di-(C
1
-C
6
)alkylamino in which each alkyl moiety is linear or branched, linear or branched (C
1
-C
6
)polyhaloalkyl and hydroxy and halogen atoms,
it being understood that:
when R
2
and R
3
together form an oxo group and simultaneously R
5
represents a hydrogen atom and R
6
represents a hydrogen atom or does not exist, then R
4
is other than a phenyl group substituted by one group selected from hydroxy, alkoxy, CF
3
and halogen (except for bromine when A represents a piperidine group), or by several groups selected from hydroxy and alkoxy,
when R
2
represents a hydrogen atom and R
3
represents a hydroxy group and simultaneously R
5
represents a hydrogen atom and R
6
represents a hydrogen atom or does not exist, then R
4
is other than a phenyl group substituted by one group selected from hydroxy, linear or branched (C
1
-C
6
)alkoxy, linear or branched (C
1
-C
6
)alkyl and chlorine, or by several groups selected from hydroxy and alkoxy
the compound of formula (I) may not represent 1-(1,3-benzodioxol-5-yl)-2-(2-pyridinyl)ethanol nor 2-(2-pyridinyl)cyclohexanone,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
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, methane-sulphonic acid, camphoric acid, oxalic acid etc.
Among the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
Preferred compounds of the invention are compounds of formula (I) wherein the group
represents a pyridinyl group, an N-methylpyridinium group, a piperidinyl group or an N-methylpiperidinyl group.
Preferred substituents R
4
are a phenyl group or substituted phenyl group, especially substituted by a halogen atom, preferably a bromine atom.
Advantageously, the invention relates to compounds of formula (I) wherein R
5
represents a hydrogen atom or a group of formula (II).
Preferred groups R
2
and R
3
are those wherein R
2
and R
3
together form an oxo group or R
2
represents a hydrogen atom and R
3
represents a hydroxy group.
Even more advantageously, the invention relates to the compounds of formula (I) which are:
1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanone,
1-(R)-1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanone,
(S)-1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanone,
1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanol,
(S,S)-1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanol,
(R,R)-1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanol,
1-methyl-2-[2-oxo-2-(4-bromophenyl)ethyl]pyridinium iodide.
The enantiomers and diastereoisomers, as well as the addition salts with a pharmaceutically acceptable acid or base, of the preferred compounds of the invention form an integral part of the invention.
The invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that there is used as starting material the compound of formula (III):
wherein X represents a hydrogen or fluorine atom, which is alkylated by means of an agent such as, for example, alkyl para-toluenesulphonate or alkyl trifluoromethanesulphonate to yield the compound of formula (IV):
wherein X is as defined hereinbefore, R′
6
represents a linear or branched (C
1
-C
6
)alkyl group and Y
−
represents a para-toluenesulphonate or trifluoromethanesulphonate group for example,
which is reacted with one or two compounds, which may be the same or different, of formula (V)
wherein R
a
and R
b
, together with the nitrogen atom carrying them, form a 5- or 6-membered heteroc
Caignard Daniel-Henri
Lebrun Marie-Cécile
Lestage Pierre
Meth-Cohn Otto
Renard Pierre
Adir et Compagnie
Rotman Alan L.
Sage G. Patrick
The Firm of Hueschen and Sage
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