Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-14
2004-06-01
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C540S597000, C514S217040, C514S316000, C514S318000, C514S319000, C514S324000, C514S337000, C514S357000, C514S339000, C514S323000, C546S187000, C546S191000, C546S193000, C546S201000, C546S202000, C546S196000, C546S208000, C546S273100, C546S274100, C546S269100, C546S281100, C546S329000
Reexamination Certificate
active
06743808
ABSTRACT:
The present invention relates to a novel class of 4-aryl-1-(indanmethyl, dihydrobenzofuranmethyl or dihydrobenzothiophenemethyl)piperidine, -tetrahydropyridine or -piperazine compounds having effects at central serotonergic receptors. These methylamine compounds are therefore useful in the treatment of certain psychic and neurologic disorders.
BACKGROUND OF THE INVENTION
A few aminomethylindan, -dihydrobenzofurane and -dihydrobenzothiophene compounds are known from the prior art.
So, EP patent 0 281 261 discloses 1-aminomethylindan, 3-aminomethylbenzo-furane and 3-aminomthylbenzothiophene derivatives with a hydroxy group or a substituted hydroxy group in the 6-position (indan) or 5-position (benzofurane, benzothiophene). These compounds were found to show central dopamine agonist activity, in particular to show effect at presynaptic dopamine receptors.
In U.S. Pat. No. 4,500,543 certain 1-aminomethylphtalane compounds are said to show adrenergic effects and, accordingly, antihypertensive and heart rate decreasing properties. Said patent generically covers compounds having substituents in the 5-, 6- and/or 7-position.
EP 0325963 A1 discloses among other compounds a class of 1-aminomethyl indan compounds in which the aminomethyl group may constitute a 1-pyrrolylmethyl group which is substituted with thienyl or phenyl. The compounds are claimed to be, &agr;
2
antagonists useful in the treatment of depression, metabolic disorders, glaucoma, migraine and hypertension.
Furthermore, EP 0490772 A1 describes i.a. a class of 4-benzofuranyl- or 4-benzodioxanyl-1-indanylmethyl piperazine compounds being 5-HT
1A
ligands.
EP 0428437 generically covers a very broad class of 1,2-benzoisoxazole compounds including certain 3-[1-[(1-indanyl)methyl]-1,2-benzoisoxazoles. However, only one such compound is exemplified and in that case without giving any data. The compounds are said to show dopamine and serotonin antagonistic activities. U.S. Pat. No. 3,886,168 relates to 1-[(indan-1-yl)methyl]piperidine compounds having antihypertensive activity.
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:
The 5-HT
2A
antagonist ritanserin (Meert, T. F.; Janssen, P. A. J.
Drug. Dev. Res
. 1989, 18, 119.) has been shown to be effective in the treatment of anxiety and depression presumably through improvement of the sleep quality. Furthermore, selective, centrally acting 5-HT
2A
antagonists have been shown to have an effect towards the negative symptoms of schizophrenia and to reduce 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 since it is known that 5-HT is involved in migraine attacks. The links between 5-HT and migraine attacks are several and they suggest a number of mechanisms whereby 5-HT may be involved (Scrip Report; “Migraine—Current trends in research and treatment”; PJB Publications Ltd.; May 1991).
The serotonin 5-HT
2A
antagonist, MDL 100,907 (Sorensen, S. M. et al.,
J. Pharmacol. Exp. Ther
. 1993, 266, 684-691), and certain compounds within series of 1-phenylindoles (WO 93/12790) and 3-phenylindole derivatives (WO 93/14758) have shown anti-psychotic activity in animal models with indication of no liability to cause extrapyramidal side effects (EPS).
Clinical studies of known 5-HT
1A
partial agonists such as e.g. buspirone, 8-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-8-azaspiro[4,5]decane-7,9-dione, gepirone, 4,4-dimethyl-1-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-2,6-piperidinedione, and ipsapirone, 2-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-1,2-benzothiazol-3(2H)-one-1,1-dioxide, 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 5-HT
1A
partial agonists in the treatment of depression, impulse control disorders and alcohol abuse (van Hest,
Psychopharmacol
., 1992, 107, 474; Schipper et al,
Human Psychopharmacol
., 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 (Sanchèz 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 which indicates that 5-HT
1A
antagonists are useful in the treatment of senile dementia (Bowen et al,
Trends Neur. Sci
. 1992, 15, 84).
Both in animal models and in clinical trials it has been shown that 5-HT
1A
agonists exert antihypertensive effects via a central mechanism (Saxena and Villalón,
Trends Pharm. Sci
. 1990, 11, 95; Gillis et al,
J. Pharm. Exp. Ther
. 1989, 248, 851). 5-HT
1A
ligands may, therefore, be beneficial in the treatment of cardiovascular disorders.
5-HT reuptake inhibitors are well known antidepressant drugs.
As 5-HT
1A
and 5-HT
2A
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 treat complex states of anxiety, depression, or other psychic disorders with a drug which have combined serotonergic effects.
SUMMARY OF THE INVENTION
It has now been found that certain novel 4-aryl-1-(indanmethyl, dihydrobenzofuranmethyl or dihydrobenzothiophenemethyl)piperidines, -tetrahydropyridines or -piperazines interact potently with central serotonergic receptors, in particular with the 5-HT
1A
and/or the 5-HT
2A
receptors.
Accordingly, the present invention relates to novel compounds of the formula I.
wherein one of X and Y is CH
2
and the other one is selected from the group consisting of CH
2
, O, and S;
the dotted line, emanating from Z, indicates an optional bond; when it does not indicate a bond Z is N, CH or COH; and when it indicates a bond Z is C;
Ar is phenyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyrimidyl, 1-indolyl, 2-indolyl, 3-indolyl, 1-indol-2-onyl, 3-indol-2-onyl, 2- or 3-benzofuranyl, 2- or 3-benzothiophenyl, 1-naphthyl or 2-naphthyl, eac
Hansen Bitten
Perregaard Jens Kristian
Stenberg John Willie
Darby & Darby
Ford John M.
H. Lundbeck A/S
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