Indole Derivatives useful for the treatment of CNS disorders

Details Indole Derivatives useful for the treatment of CNS disorders Indole Derivatives useful for the treatment of CNS disorders

2003-01-17

2004-06-01

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S201000, C546S194000, C546S256000, C546S277400, C544S129000, C544S360000, C514S339000, C514S333000, C514S318000, C514S254080, C514S235200

Reexamination Certificate

active

06743809

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel class of indole derivatives having affinity for the dopamine D
4
receptor. The compounds have antagonistic effect at the dopamine D
4
receptor and are therefore useful in the treatment of certain psychiatric and neurologic disorders, in particular psychoses. Some of the compounds also have affinity for the 5-HT
2A
and/or the 5-HT
2C
receptor and some of the compounds are serotonin reuptake inhibitors.
BACKGROUND OF THE INVENTION
AT 332401 discloses compounds of the general formula
wherein R is hydrogen or alkyl, R
1
and R
2
are hydrogen or alkyl, p is 2 or 3 and X
1
is hydrogen, fluoro, chloro or bromo. The compounds are said to be useful as neuroleptics. The patent does not contain any experimental data.
WO 95/11680 relates to a broad class of compounds having antipsychotic activity. One group of compounds claimed are compounds having the formula
wherein X
1
is O, S, NH or NR
2
, Alk is alkylene, W
1
is CH
2
, O, S or NH, and R is hydrogen, alkyl, alkoxy, hydroxy, carboxyl, halogen, amino, alkylamino, dialkylamino, nitro, alkylthio, trifluoromethoxy, cyano, acylamino, trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, etc. The application does not explain any mechanism of action, but the compounds are said to have a reduced tendency to cause extrapyramidal side effects.
Dopamine D
4
receptors belong to the dopamine D
2
subfamily of receptors which is considered to be responsible for the antipsychotic effect of neuroleptics. The side effects of neuroleptic drugs which primarily exert their effect via antagonism of D
2
receptors are known to be due to D
2
receptor antagonism in the striatal regions of the brain. However, dopamine D
4
receptors are primarily located in areas of the brain other than striatum, suggesting that selective antagonists of the dopamine D
4
receptor will be devoid of extrapyramidal side effects. This is illustrated by the antipsychotic clozapine, which exerts higher affinity for D
4
than D
2
receptors and is lacking extrapyramidal side effects (Van Tol et al.
Nature
1991, 350, 610; Hadley
Medicinal Research Reviews
1996, 16, 507-526, and Sanner
Exp. Opin. Ther. Patents
1998, 8, 383-393).
A number of D
4
ligands, which were postulated to be selective D
4
receptor antagonists (L-745,879 and U-101958), have been shown to possess antipsychotic potential (Mansbach et al.
Psychopharmacology
1998, 135, 194-200). However, recently it has been reported that these compounds are partial D
4
receptor agonists in various in vitro efficacy assays (Gazi et al.
Br. J. Pharmacol
. 1998, 124, 889-896 and Gazi et al.
Br. J. Pharmacol
. 1999, 128, 613-620). Furthermore, it was shown that clozapine, which is an effective antipsychotic, is a silent D
4
antagonist (Gazi et al.
Br. J. Pharmacol
. 1999, 128, 613-620).
Consequently, D
4
ligands which are partial D
4
receptor agonists or antagonists may have beneficial effects against psychoses.
Dopamine D
4
antagonists may also be useful for the treatment of cognitive deficits (Jentsch et al.
Psychopharmacology
1999, 142, 78-84).
Furthermore, evidence for a genetic association between the “primarily inattentive” subtype of attention deficit hyperactivity disorder (ADHD) and a tandem duplication polymorphism in the gene encoding the dopamine D
4
receptor has been published (McCracken et al.
Mol. Psychiatry
2000, 5, 531-536). This clearly indicates a link between the dopamine D
4
receptor and ADHD, and ligands affecting this receptor may be useful for the treatment of this particular disorder.
Various effects are known with respect to compounds which are ligands at the different serotonin receptor subtypes. As regards the 5-HT
2A
receptor, which was previously referred to as the 5-HT
2
receptor, the following effects have been reported, e.g.:
Antidepressive effect and improvement of the sleep quality (Meert et al.
Drug. Dev. Res
. 1989, 18, 119), reduction of the negative symptoms of schizophrenia and of extrapyramidal side effects caused by treatment with classical neuroleptics in schizophrenic patients (Gelders
British J. Psychiatry
1989, 155 (suppl. 5), 33). Furthermore, selective 5-HT
2A
antagonists could be effective in the prophylaxis and treatment of migraine (Scrip Report; “Migraine—Current trends in research and treatment”; PJB Publications Ltd.; May 1991) and in the treatment of anxiety (Colpart et al.
Psychopharmacology
1985, 86, 303-305 and Perregaard et al.
Current Opinion in Therapeutic Patents
1993, 1, 101-128).
Some clinical studies implicate the 5-HT
2
receptor subtype in aggressive behaviour. Furthermore, atypical serotonin-dopamine antagonist neuroleptics have 5-HT
2
receptor antagonistic effect in addition to their dopamine blocking properties and have been reported to possess anti-aggressive behaviour (Connor et al.
Exp. Opin. Ther. Patents
1998, 8(4), 350-351).
Recently, evidence has also accumulated which support the rationale for selective 5-HT
2A
antagonists as drugs capable of treating positive symptoms of psychosis (Leysen et al.
Current Pharmaceutical Design
1997, 3, 367-390 and Carlsson
Current Opinion in CPNS Investigational Drugs
2000, 2(1), 22-24).
Compounds which are 5-HT reuptake inhibitors are well-known antidepressant drugs.
5-HT
2C
ligands have been found to augment the effect of 5-HT reuptake inhibitors in microdialysis experiments and animal models, and compounds having 5-HT reuptake inhibiting effect combined with affinity for the 5-HT
2C
receptor may therefore be particularly useful for the treatment of depression and other disorders responsive to serotonin reuptake inhibitors (PCT application No. PCT/DK00/00671).
Accordingly, dopamine D
4
receptor ligands are potential drugs for the treatment of schizophrenia and other psychoses, and compounds with combined effects at the 5-HT transporter may have the further benefit of improved effect on depressive and negative symptoms in schizophrenic patients. Compounds with combined effect at the dopamine D
4
receptor and the 5-HT
2A
receptor may have the benefit of improved effect on positive and negative symptoms of schizophrenia and the benefit of effect on depressive and anxiety symptoms.
In particular, the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia without inducing extrapyramidal side effects.
SUMMARY OF THE INVENTION
The object of the present invention is to provide compounds that are partial agonists or antagonists at the dopamine D
4
receptor and such compounds with combined effects at the dopamine D
4
receptor, the 5-HT
2A
receptor, the 5-HT
2C
and/or the 5-HT transporter.
Accordingly, the present invention relates to novel compounds of the formula I
wherein R
1
is hydrogen or C
1-6
-alkyl, C
2-6
-alkenyl, C
2-6
-alkynyl, C
3-8
-cycloalkyl or C
3-8
-cycloalkyl-C
1-6
-alkyl, all of which may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, hydroxy, thiol, C
1-6
-alkoxy, C
1-6
-alkylthio trifluoromethyl, trifluoromethylsulfonyl and C
1-6
-alkylsulfonyl, or R
1
is aryl, aryl-C
1-6
-alkyl, heteroaryl, heteroaryl-C
1-6
-alkyl where the aryl and heteroaryl groups may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, C
1-6
-alkyl, C
1-6
-alkoxy, C
1-6
-alkylthio, hydroxy, thiol, trifluoromethyl, trifluoromethylsulfonyl and C
1-6
alkylsulfonyl, or R
1
is —NR′R″ wherein R′ and R″ are independently selected from hydrogen and C
1-6
-alkyl, aryl, aryl-C
1-6
-alkyl, heteroaryl and heteroaryl-C
1-6
-alkyl, all of which may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, C
1-6
-alkyl, C
1-6
alkoxy, C
1-6
-alkylthio, hydroxy, thiol, trifluoromethyl, trifluoromethylsulfonyl, and C
1-6
alkylsulfonyl, or R
1
is a saturated or partially saturated 5 to 6 membered ring containing one, two or three hetero atoms selected from O, S and a group N—R
9
wherein R
9
is hy

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