Indane or dihydroindole derivatives

Details Indane or dihydroindole derivatives Indane or dihydroindole derivatives

1999-08-03

2001-12-18

Bernhardt, Emily (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252010, C514S321000, C514S323000, C544S376000, C544S377000, C546S197000, C546S201000

Reexamination Certificate

active

06331544

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel class of substituted indane or dihydroindole compounds having effects at dopamine D
4
receptors. The compounds are either selective dopamine D
4
ligands or they have combined effects at dopamine D
4
and serotonergic receptors and/or the serotonergic transporter. These compounds are therefore useful in the treatment of certain psychiatric and neurologic disorders, including psychosis, depression and anxiety.
BACKGROUND OF THE INVENTION.
Related compounds are known from WO patents Nos. WO 9421627-A1, WO 9421630-A1, WO 94 21626-A1 describing various series of indolyl- or indazolylmethyl piperidine or piperazine derivatives as selective dopamine D
4
antagonists. No data are given. The compounds are only said to give K
i
values of less than 1.5 &mgr;M in a test for displacement of 3H spiperone from human dopamine D
4
receptor subtypes in clonal cell lines.
EP patent No. 574313 A1 describes compounds with piperidine, tetrahydropyridine, or piperazine rings substituted in position 1 and 4 with various aryl or heteroaryl groups, including certain 1-(indane or indanemethyl)piperidine, tetrahydropyridine, or piperazine derivatives substituted in the 4-position with 1,4-benzodioxane. The compounds are claimed to have effects at dopamine D
2
and D
4
receptors.
Dopamine D
4
receptors belong to the dopamine D
2
receptor family considered to be responsible for antipsychotic effects of neuroleptics. Furthermore, dopamine D
4
receptors are primarily located in areas of the brain other than striatum (Van Tol, et al.
Nature
, 1991, 350, 610), the low level in striatum suggesting lack of extrapyramidal activity. Also, dopamine D
4
receptor levels have been reported to be elevated in schizophrenic patients (Seeman et al.,
Nature
, 1993, 365, 441.) and the antipsychotic clozapine which is lacking extrapyramidal side effects, has a high affinity for dopamine D
4
receptors (Van Tol, et al.
Natuare
, 1991, 350, 610.)
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 e.g. been reported:
Antidepressive effect, improvement of the sleep quality (Meert, T. F.; Janssen, P. A. J. Drug. Dev. Res. 1989, 18, 119.) and the negative symptoms of schizophrenia and reduction of extrapyramidal side-effects caused by treatment with classical neuroleptics in schizophrenic patients (Gelders, Y. G., British J. Psychiatry, 1989, 155 (suppl. 5, 33). Finally, 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).
Clinical studies have shown that 5-HT
1A
partial agonists are useful in the treatment of anxiety disorders such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder (Glitz, D. A., Pohl, R., Drugs 1991, 41, 11). Preclinical studies indicate that also full agonists are useful in the treatment of the above mentioned anxiety related disorders (Schipper, Human Psychopharmacol., 1991, 6, S53).
There is also evidence, both clinical and preclinical, in support of the beneficial effect of 5HT
1A
partial agonists in the treatment of depression, impulse control disorders and alcohol abuse (van Hest, Psychopharmacol., 1992, 107, 474; Schipper et al, Human Psychopharnacol., 1991, 6, S53; Cervo et al, Eur. J. Pharm., 1988, 158, 53; Glitz and Poh, Drugs 1991, 41, 11; Grof et al., Int. Clin. Psychopharmacol. 1993, 8, 167-172; Ansseau et al., Human Psychopharmacol. 1993, 8, 279-283).
5-HT
1A
agonists and partial agonists inhibit isolation-induced aggression in male mice indicating that these compounds are useful in the treatment of aggression (Sanchéz et al., Psychopharmacology, 1993, 110, 53-59).
Furthermore, 5-HT
1A
ligands have been reported to show antipsychotic effect in animal models (Wadenberg and Ahlenius, J. Neural. Transm., 1991, 83, 43; Ahlenius, Pharmacol. & Toxicol., 1989, 64, 3; Lowe et al., J. Med. Chem., 1991, 34, 1860; New et al., J. Med. Chem., 1989, 32, 1147; and Martin et al., J. Med. Chem., 1989, 32, 1052).
Recent studies also indicate that 5-HT
1A
receptors are important in the serotonergic modulation of haloperidol-induced catalepsy (Hicks, Life Science 1990, 47, 1609, Wadenberg et al. Pharmacol. Biochem. & Behav. 1994, 47, 509-513) suggesting that 5-HT
1A
agonists are useful in the treatment of EPS induced by conventional antipsychotic agents such as haloperidol.
5-HT
1A
agonists have shown neuroprotective properties in rodent models of focal and global cerebral ischaemia and may, therefore, be useful in the treatment of ischaemic disease states (Prehn, Eur. J. Pharm. 1991, 203, 213).
Pharmacological studies have been presented indicating that 5-HT
1A
antagonists are useful in the treatment of senile dementia (Bowen et al, Trends Neur. Sci. 1992, 15, 84).
5-HT reuptake inhibitors are well known antidepressant drugs.
Accordingly, dopamine D
4
receptor ligands are potential drugs for the treatment of psychosis and positive symptoms of schizophrenia and compounds with combined effects at dopamine D
4
and serotonergic receptors may have the further benefit of improved effects on other psychiatric symptoms in schizophrenic patients such as depressive and anxiety symptoms. As 5-HT
1A
and 5-HT
2
A receptor ligand classes of compounds and 5-HT reuptake inhibitors have different activities in different animal models predictive of anxiolytic and antiaggressive effects (Perregaard et al., Recent Developments in Anxiolytics. Current Opinion in Therapeutic Patents 1993, 1, 101-128) and/or in models predictive of effects in other psychic disorders it might also be highly beneficial to have such combined serotonergic effects.
SUMMARY OF THE INVENTION
The object of the invention is to provide compounds with dopamine D
4
activities or with combined effects at dopamine D
4
receptors and serotonergic receptors and/or the serotonergic transporter.
It has now been found that certain substituted indane or dihydroindole compounds have effects at dopamine D
4
receptors. Additionally, many of the compounds interact with central serotonergic receptors, in particular with the 5-HT
1A
and/or the 5-HT
2A
receptors and/or they act as 5-HT reuptake inhibitors.
Accordingly, the present invention relates to novel compounds of the formula I.
wherein A and B are independently O or S;
D is a methylene group optionally substituted with one or two C
1-4
alkyl groups;
Y is a hydrocarbon group completing an indane ring, a group NR
1
completing a dihydroindole ring, or a group N completing a dihydroindole ring attached via the 1 position;
W is a bond, and n+m is 1, 2, 3, 4, 5, or 6;
W is CO, SO, or SO
2
, n is 2, 3, 4, or 5 and m is 0, 1, 2, or 3, provided that n+m is not more than 6; or
W is O, S, n is 2, 3, 4, or 5 and m is 0, 1, 2, or 3, provided that n+m is not more than 6, and
provided that when Y is N completing a dihydroindole ring attached via the 1-position then m is 2, or 3; and when Y is NR
1
completing a dihydroindole ring linked via the 2position then m is 1, 2, or 3;
the dotted line, emanating from X, indicates an optional bond; when it does not indicate a bond X is N, CH or COH; and when it indicates a bond X is C;
R
1
is selected from
hydrogen, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-8
cycloalk(en)yl, C
3-8
cycloalk(en)yl-C
1-6
alk(en/yn)yl, aryl, heteroaryl, aryl- C
1-6
alkyl, heteroaryl-C
1-6
alkyl, acyl, thioacyl, C
1-6
alkylsulfonyl, trifluoromethylsulfonyl, arylsulfonyl or heteroarylsulfonyl, or
R
15
VCO— wherein V is O or S and R
15
is C
1-6
alkyl, C
3-8
cycloalkyl, C
3-8
cycloalkyl-C
1-6
alkyl, aryl or heteroaryl, or
a group R
16
R
17
NCO— or R
16
R
17
NCS— wherein R
16
and R
17
are independently hydrogen, C
1-6
alkyl, C
3-8
cycloalkyl, C
3-8
cycloalkyl-C
1-6
alkyl, aryl or heteroaryl, or R
16
and R
17
together with the N-atom to whi

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