Arylpiperazinyl-cyclohexyl indole derivatives for the...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C514S253040, C514S253060, C514S253090, C514S254090, C544S353000, C544S362000, C544S363000, C544S364000, C544S373000

Reexamination Certificate

active

06313126

ABSTRACT:

FIELD OF INVENTION
This invention relates to compounds useful for the treatment of diseases affected by disorders of the serotonin-affected neurological systems, such as depression and anxiety. More specifically the present invention is directed to arylpiperazinyl cyclohexyl derivatives useful for the treatment of such disorders.
BACKGROUND OF INVENTION
Pharmaceuticals which enhance neurotransmission of serotonin (5-HT) are useful for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of non-selective serotonin-affecting drugs operated through a variety of physiological means which caused them to possess numerous undesired side-effects. The more recently prescribed drugs, the selective serotonin reuptake inhibitors (SSRIs), act predominately by inhibiting 5-HT, which is released at the synapses, from being actively removed from the synaptic cleft via a presynaptic serotonin transport carrier. Since SSRIs require several weeks before they exert their full therapeutic effect, this 5-HT blockade mechanism cannot fully account for their therapeutic activity. It is speculated that this two week induction which occurs before a full antidepressant effect is observed, is due to the involvement of the 5-HTlA autoreceptors which suppress the firing activity of 5-HT neurons, causing a dampening of the therapeutic effect. Studies suggest that after several weeks of SSRI administration, a desensitization of the 5-HT autoreceptors occurs allowing a full antidepressant effect in most patients. (See, e.g., Le Poul et al.,
Arch. Pharmacol
., 352:141 (1995)). Hence, it is believed that overriding this negative feedback by using 5HT1A antagonists would potentially increase and accelerate the clinical antidepressant response. Recent studies by Artigas et al.,
Trends Neurosci
., 19:378-383 (1996), suggest a combination of 5-HT1A activity and inhibition of 5-HT uptake within a single molecular entity can achieve a more robust and fast-acting antidepressant effect.
The present invention relates to a new class of molecules which have the ability to act at the 5-HT1A autoreceptors and concommitantly with the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of depression as well as other serotonin disorders.
U.S. Pat. No. 5,468,767 reports a series of substituted indoles of the following formula for the treatment of disorders associated with dysfunction in serotonergic neurotransmission, including depression
wherein:
R
1
is hydrogen or C
1-4
alkyl and R
2
is C
1-4
alkyl or (CH
2
)pAr.
WO 9415928 discloses a series of piperazine derivatives of the following formula for the treatment of CNS disorders, including depression.
wherein:
R is hydrogen or alkyl;
R
1
and R
2
are each mono- or bicyclic aryl or heteroaryl radicals;
R
3
is hydrogen, alkyl, or a spirocycloalkyl group; and
n is 1 or 2 and m is 1 to 3.
WO 93/10092 discloses a series of cyclohexenes of the following formula for the treatment of dopaminergic disorders.
SUMMARY OF THE INVENTION
The compounds of this invention are arylpiperazinyl-cyclohexyl indole derivatives represented by Formula I:
Wherein:
R
1
, R
2
and R
3
are each, independently, hydrogen, halogen, CF
3
, alkyl, alkoxy, MeSO
2
, or together can form a 5-7 membered carbocyclic or heterocyclic ring;
R
4
is hydrogen, halogen, or alkyl;
R
5
is hydrogen, alkyl, alkylaryl, or aryl;
R
6
is hydrogen, halogen, CF
3
, CN, carbamide, or alkoxy;
X
1
, X
2
and X
3
are each carbon or one of X
1
, X
2
or X
3
may be nitrogen;
Y is carbon or nitrogen; and
Z is carbon or nitrogen; or
pharmaceutically acceptable salts thereof.
Preferably, the compounds of the present invention are those represented by Formula I, wherein R
1
, R
2
and R
3
are each, independently, hydrogen, halogen, alkyl, alkoxy or together form a 5-7 membered carbocyclic or heterocyclic ring;
R
4
is hydrogen or halogen;
R
5
is hydrogen, alkyl or alkylaryl; and
R
6
is hydrogen, halogen, CN or alkoxy;
X
1
, X
2
, X
3
, Y and Z are each carbon; or
pharmaceutically acceptable salts thereof.
More preferably, the compounds of the present invention are selected from the following:
3-[cis-4-[4-(1H-Indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;
3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;
4-Fluoro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;
4-Fluoro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;
5-Fluoro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;
5-Fluoro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;
6-Fluoro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;
6-Fluoro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;
5-Bromo-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;
5-Bromo-3-[trans-4-[4-(1 H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1 H-indole;
5-Chloro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;
5-Chloro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;
3-{4-[(1,4-cis)-4-(1H-indol-4-yl)-piperazinyl-1-yl]cyclohexyl}-1H-indole-5-carbonitrile;
3-{4-[(1,4-trans)-4-(1H-indol-4-yl)-piperazinyl-1-yl]cyclohexyl}-1H-indole-5-carbonitrile;
5-Methoxy-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;
5-Methoxy-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;
3-[cis-4-[4-(1H-Indol-4-yl)-1-piperazinyl]cyclohexyl]-2-methyl-1H-indole;
3-[trans-4-[4-(1H-Indol-4-yl)-1-piperazinyl]cyclohexyl]-2-methyl-1H-indole;
3-{(1,4-cis)-4-[4-1H-Indole-4-yl)-piperazin-1-yl]-cyclohexyl}-1H-pyrrolo[2,3-b]pyridine;
3-{(1,4-trans)-4-[4-(1H-Indol-4-yl)-piperazin-1-yl]-cyclohexyl}-1H-pyrrolo[2,3-b]pyridine;
6-Fluoro-1-methyl-3-{cis-4-[4-(1-methyl-1H-indol-4-yl)-1-piperazinyl]cyclohexyl}-1H-indole;
3-{(1,4-cis)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]cyclohexyl}-1-methyl-1H-indole-5-carbonitrile;
3-{(1,4-trans)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]cyclohexyl}-1-methyl-1H-5-carbonitrile;
1-Ethyl-3-{(1,4-cis)-4-[4-(1H-indole-4-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile;
3-{(1,4-cis)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]-cyclohexyl}-1-propyl-1H-indole-5-carbonitrile;
3-{(1,4-trans)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]-cyclohexyl;}-1-propyl-1H-indole-5-carbonitrile;
3-{(1,4-cis)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]-cyclohexyl}-1-isopropyl-1H-indole-5-carbonitrile;
3-{(1,4-trans)-4-[4-(1 H-indol-4-yl)-piperazin-1-yl]cyclohexyl}-1-isopropyl-1H-indole-5-carbonitrile;
1-Benzyl-3-{(1,4-cis)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile;
1-Benzyl-3-{(1,4-trans)-4-[4-(1H-indole-4-yl)-piperazin-1-yl]cyclohexyl}-1H-indole-5-carbonitrile;
1-Methyl-3-{(1,4-cis)-4-[4-(1-methyl-1H-indol-4-yl)-piperazine-1-yl]-cyclohexl}-1H-indole-5-carbonitrile;
5-Fluoro-3-{(cis)-4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-cyclohexyl}-1H-indole;
5-Fluoro-3-{(1,4-cis)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-cyclohexyl}-1H-indole;
5-Fluoro-3-{(1,4-trans)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-cyclohexyl}-1H-indole;
5-methoxy-3-{(1,4-cis)-4-[4-(2-methoxy-phenyl)-piperazinyl-1-yl]-cyclohexyl}-1H-indole;
5-Methoxy-3-{(1,4-trans)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-cyclohexyl}-1H-indole;
3-{(1,4-cis)-4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-cyclohexyl}-1H-pyrrolo[2,3-b]piperidine;
5-Fluoro-3-&l

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