Pyridine compounds

Details Pyridine compounds Pyridine compounds

2000-08-18

2002-06-04

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S362000, C546S114000, C546S115000, C514S301000, C514S302000

Reexamination Certificate

active

06399616

ABSTRACT:

FIELD OF THE INVENTION
The compounds of the present invention can be used in the treatment of disorders resulting from problems of which the cause lies in the central serotonergic system and which are known to be mediated in the reuptake of serotonin and/or at the level of 5-HT
1A
receptors, such as anxiety, panic attacks, obsessive-compulsive disorders, impulsive disorders, cognitive disorders, phobias and depression.
Regarding the treatment of depression, selective serotonin reuptake inhibitors (SSRI) currently represent one of the most effective classes of medicaments. Their beneficial therapeutic effects, however, do not become apparent before the end of the second week of treatment at the minimum, and most of the time do not become apparent until during the third or even the fourth week. This major drawback is damaging to the efficacy of that class of products. The latent period can be explained by the desensitisation of the 5-HT
1A
receptors of the cell bodies. Indeed it has been demonstrated (TIPS, 1993, 14, 262) that the efficacy of an SSRI such as fluoxetine may be reduced by the activation of 5-HT
1A
receptors, that activation resulting in a reduction in the discharge frequency of serotonergic neurons.
Consequently, a blockade of 5-HT
1A
receptors could lead to a more effective treatment (by reducing the latent period). Recently, a clinical study carried out with a partial 5-HT
1A
agonist
Clin. Psychopharmacol
., 1995, 15, 217) demonstrated that such a substance may improve the efficacy of a concomitantly administered SSRI and/or may result in a reduction in the time taken for a concomitantly administered SSRI to take effect.
In vitro and in vivo experiments have made it possible to demonstrate that the compounds of the present invention combine a selective inhibitory-type activity in respect of the reuptake of serotonin (SSRI) with a partial agonist or antagonist activity in respect of 5-HT
1A
receptors. Thus, owing to their specific pharmacological activity, in addition to the fact that the compounds of the present invention are new, they may be useful in the treatment of anxiety, depression, panic attacks, obsessive-compulsive disorders, phobias, impulsive disorders and cognitive disorders.
PRIOR ART DESCRIPTION
Compounds of similar structures have already been described in the literature. This applies especially to the Patent Applications FR 2 738 822 and FR 2 738 823, which claim, in particular, compounds having a 4-(1-piperazinyl)thieno[3,2-c]pyridine moiety. Those compounds are useful in the treatment of hypertension, cardiac insufficiency, arthritis and microcirculation disorders. The Patent U.S. Pat. No. 4,677,104 claims compounds having either a 4-(1-piperazinyl)thieno, or furo, or 1H-pyrrolo[3,2-c]pyridine moiety, or a 7-(1-piperazinyl)thieno, or furo, or 1H-pyrrolo[2,3-c]pyridine moiety, those compounds being useful as antipsychotic or anxiolytic agents. Those compounds are substantially distinguished from the compounds described in the present invention by the presence of a very different ring system substituted on the piperazinyl moiety.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates more especially to compounds of formula (I):
wherein:
W represents:
either a naphthyl group 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, cyano, nitro, linear or branched trihalo(C
1
-C
6
)alkyl, methylenedioxy and ethylenedioxy,
or a group of formula Y where:
wherein E, together with the carbon atoms of the phenyl ring to which it is bonded, represents an unsaturated, partially saturated, or aromatic, monocyclic ring having from 5 to 7 ring members and containing at least one hetero atom selected from oxygen, nitrogen and sulphur, it being possible for the said group Y to be bonded to the (CH
2
)
n
group of the compounds of formula (I) either by the phenyl moiety or by the monocyclic ring E, and for each of the said Y groups to be optionally substituted by one or more identical or different groups selected from halogen, hydroxy, cyano, nitro, linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy, linear or branched trihalo(C
1
-C
6
)alkyl, heterocycloalkylalkylene in which the alkylene moiety contains from 1 to 6 carbon atoms and may be linear or branched (and in which the heterocyclic ring is an unsaturated or aromatic monocyclic ring having 5 or 6 ring members and containing from 1 to 4 hetero atoms selected from nitrogen, sulphur and oxygen) and oxo,
provided that in that case the group Y can be substituted only by a single oxo group and that E, together with the carbon atoms of the phenyl ring to which it is bonded, represents then a monocyclic ring having 5 ring members and containing two identical or different hetero atoms selected from oxygen and nitrogen,
n represents an integer from 1 to 6 inclusive,
Z represents a single bond, an oxygen atom, or a nitrogen atom substituted by a group selected from hydrogen, linear or branched (C
1
-C
6
)alkyl (itself optionally substituted by one or more hydroxy groups) and aryl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched,
A represents a CH group or a nitrogen atom,
Q represents a CH group or a nitrogen atom, provided that at least one of the groups A and Q represents a nitrogen atom, and that A represents a nitrogen atom when Z represents a single bond, and
M, together with the carbon atoms of the pyridyl ring to which it is bonded, represents a thieno, furo, pyrrolo or oxopyrrolo group,
to their isomers, and to addition salts thereof with a pharmaceutically acceptable acid or base.
“Aryl” is to be understood as meaning a phenyl, naphthyl, dihydronaphthyl or tetrahydronaphthyl group.
Advantageously, preferred W substituents of the invention are the groups naphthyl, 2,3-dihydro-1,4-benzodioxinyl, chromanyl, 2H-chromenyl, isochromanyl, 2,3-dihydrobenzofuranyl, benzofuranyl, 1,3-dihydro-2H-benzimidazol-2-one, 1,3-benzoxazol-2-one and indolyl.
where W is optionally subdued by a heterocycloalkylalkylene group in which the alkylene moiety is linear or branched and contains from 1 to 6 carbon atoms, the said heterocycloalkylalkylene group is advantageously a heterocycloalkylmethylene group in which heterocycloalkyl is an unsaturated or aromatic monocyclic ring having 5 ring members and containing from 1 to 4 nitrogen atoms. Preferably, the said heterocycloalkylmethylene group is a 1,2,4-triazol-1-ylmethyl, imidazol-1-ylmethyl or 1H-imidazol-5-ylmethyl group.
In an especially advantageous embodiment, the substituents W preferred in accordance with the invention are the groups 1-naphthyl, isochroman-1-yl and 2,3-dihydro-1-benzofuran-5-yl.
In another especially advantageous embodiment, the substituents W preferred in accordance with the invention are the 5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl group, the 5-(imidazol-1-ylmethyl)-1H-indol-3-yl group and the 5-(1H-imidazol-5-ylmethyl)-1H-indol-3-yl group.
In a third especially advantageous embodiment, the substituents W preferred in accordance with the invention are the groups 1,3-benzoxazol-2-on-1-yl and 1,3-dihydro-2H-benzimidazol-2-on-1-yl.
Preferably, Z represents a single bond in the compounds of the invention.
According to a valuable embodiment, preferred compounds of the invention are compounds of formula (I) wherein Z represents a nitrogen atom substituted by a group selected from hydrogen, methyl and hydroxyethylene when A presents a CH group, Q represents a nitrogen atom, n is 1 and W represents a 2-naphthyl group.
According to an advantageous embodiment of the invention, preferred compounds are those wherein n represents 2 or 3.
According to another advantageous embodiment of the invention, preferred compounds are those wherein M, together with the carbon atoms of the pyridyl ring to which it is bonded represents a thieno or furo group.
Preferred compounds of the invention are especially advantageously:
4-{1-[2-(1-naphthyl)ethyl]-4

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