Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-01
2001-11-13
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S323000, C546S197000, C546S201000
Reexamination Certificate
active
06316468
ABSTRACT:
The present invention relates to a class of indole derivatives which act on serotonin receptors (also known as 5-hydroxytryptamine or 5-HT receptors). More particularly, the invention concerns 3-(piperidin-4-yl)-1H-indole derivatives bearing an optionally substituted phenyl moiety at the 2-position of the indole ring system and an alkyl or aryl-alkyl substituent on the nitrogen atom of the piperidine ring. These compounds are selective antagonists of the human 5-HT
2A
receptor and are therefore useful as pharmaceutical agents, especially in the treatment and/or prevention of adverse conditions of the central nervous system, including psychotic disorders such as schizophrenia.
Schizophrenia is a disorder which is conventionally treated with drugs known as neuroleptics. In many cases, the symptoms of schizophrenia can be treated successfully with so-called “classical” neuroleptic agents such as haloperidol. Classical neuroleptics generally are antagonists at dopamine D
2
receptors.
Notwithstanding their beneficial antipsychotic effects, classical neuroleptic agents such as haloperidol are frequently responsible for eliciting acute extrapyramidal symptoms (movement disorders) and neuroendocrine (hormonal) disturbances. These side-effects, which plainly detract from the clinical desirability of classical neuroleptics, are believed to be attributable to D
2
receptor blockade in the striatal region of the brain.
The compound (+)-&agr;-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)-ethyl]-4-piperidinemethanol (also known as MDL-100,907) is described in WO 91/18602. In preclinical studies, MDL-100,907 failed to induce catalepsy and failed to block apomorphine-induced stereotyped behaviour in animal models, strongly suggesting that this compound would be free from any liability to cause extrapyramidal side-effects. MDL-100,907 is currently undergoing clinical trials in schizophrenic patients and has demonstrated efficacy in a multicentre, placebo-controlled study for antipsychotic potential, with no neurological adverse effects. Pharmacologically, MDL-100,907 has been shown to be a potent antagonist of human 5-HT
2A
receptors, whilst being essentially devoid of activity at the human dopamine D
2
receptor. It is accordingly believed that compounds which can interact selectively with the 5-HT
2A
receptor relative to the dopamine D
2
receptor will display the beneficial level of antipsychotic activity associated with 5-HT
2A
receptor antagonism, whilst minimizing or even avoiding the extrapyramidal and other side-effects arising from an interaction with dopamine D
2
receptors.
The compounds of the present invention are potent antagonists of the human 5-HT
2A
receptor, and are accordingly of benefit in the treatment and/or prevention of psychotic disorders such as schizophrenia. The compounds of the invention may display more effective binding to the human 5-HT
2A
receptor than to the human dopamine D
2
receptor, and they can therefore be expected to manifest fewer side-effects than compounds which do not discriminate in their binding affinity as between 5-HT
2A
and D
2
receptors.
By virtue of their potent human 5-HT
2A
receptor antagonist activity, the compounds of the present invention are also effective in the treatment of neurological conditions including depression, anxiety, panic disorder, obsessive-compulsive disorder, pain, sleep disorders such as insomnia, eating disorders such as anorexia nervosa, and dependency or acute toxicity associated with narcotic agents such as LSD or MDMA; and cardiovascular conditions including variant angina, Raynaud's phenomenon, intermittent claudication, coronary and peripheral vasospasms, fibromyalgia, cardiac arrhythmias and thrombotic illness. They may also be generally of benefit in the inhibition of platelet aggregation, as well as in controlling the extrapyramidal symptoms associated with the administration of neuroleptic agents. They may further be effective in the lowering of intraocular pressure and may therefore be beneficial in treating glaucoma (cf. T. Mano et al. and H. Takaneka et al.,
Investigative Ophthalmology and Visual Science
, 1995, vol. 36, pages 719 and 734 respectively).
Being 5-HT
2A
receptor antagonists, the compounds of the present invention may also be beneficial in preventing or reducing the toxic symptoms associated with the intake of ergovaline in animals consuming
Acremoniun coenophicalun
infected tall fescue (cf. D. C. Dyer,
Life Sciences
, 1993, 53, 223-228).
In JP-A-3-264581 is described a class of 3-(piperidin-4-yl)-1H-indole analogues bearing inter alia an optionally substituted phenyl group at the 2-position of the indole nucleus and a heterocyclic moiety attached through an alkylene linkage to the nitrogen atom of the piperidine ring. These compounds are stated therein to have a strong serotonin-2 receptor antagonist action and hence to be useful as medicines for the treatment of diseases of the circulatory system, and of psychiatric diseases such as depression or schizophrenia. There is, however, no disclosure nor any suggestion in JP-A-3-264581 of replacing the precisely defined heterocyclyl-alkyl substituent on the piperidine ring with an alkyl or aryl-alkyl moiety.
GB-1465826 describes a variety of indolylpiperidine-butyrophenones bearing inter alia a phenyl group at the 2-position of the indole ring system. These compounds are alleged therein to show activities typical of neuroleptics and therefore to be of potential interest as depressants of the central nervous system, as sedatives and as tranquilizers. However, nowhere in GB-1465826 is there any disclosure or suggestion of replacing the 4-fluorobutyrophenone substituent on the piperidine ring with an alkyl or aryl-alkyl moiety.
The compounds according to the present invention are potent and selective 5-HT
2A
receptor antagonists having a human 5-HT
2A
receptor binding affinity (K
i
) of 100 nM or less, typically of 50 nM or less and preferably of 10 nM or less. The compounds of the invention may possess at least a 10-fold selective affinity, suitably at least a 20-fold selective affinity and preferably at least a 50-fold selective affinity, for the human 5-HT
2A
receptor relative to the human dopamine D
2
receptor.
The present invention provides a compound of formula I, or a salt thereof:
wherein
A and B independently represent hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, C
1-6
alkyl, C
1-6
alkoxy or amino; or
A and B, when attached to adjacent carbon atoms, together represent methylenedioxy;
X and Y independently represent hydrogen, halogen, C
1-6
alkyl, C
1-6
alkoxy or phenyl; and
R
1
represents C
1-6
alkyl or an optionally substituted aryl(C
1-6
)alkyl group.
The present invention also provides a compound of formula I as depicted above, or a salt thereof, wherein A and B independently represent hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, C
1-6
alkyl or C
1-6
alkoxy; and X, Y and R
1
are as defined above.
Where R
1
represents aryl(C
1-6
)alkyl, this group may be optionally substituted by one or more substituents. Suitably, the aryl(C
1-6
)alkyl group R
1
is unsubstituted, or substituted by one, two or three substituents. More particularly, the aryl(C
1-6
)alkyl group R
1
may be unsubstituted, or substituted by one or two substituents. In general, the aryl(C
1-6
)alkyl group R
1
may be unsubstituted or monosubstituted. Any optional substitution on the aryl(C
1-6
)alkyl group R
1
will suitably be on the aryl moiety thereof, although substitution on the alkyl moiety thereof is an alternative possibility. Examples of optional substituents on the group R
1
include halogen, nitro, trifluoromethyl, C
1-6
alkyl, hydroxy, C
1-6
alkoxy, C
1-6
alkylthio or di(C
1-6
)alkylamino.
In an alternative embodiment, the group R
1
may be optionally substituted by one or more substituents selected from halogen, cyano, trifluoromethyl, hydroxy, C
1-6
alkoxy, C
1-6
alkylthio, C
2-6
alkoxycarbonyl, C
2-6
alkylcarbonyl, C
1-6
alkylsulphonyl, arylsulphonyl, amino, C
Maxey Robert James
Rowley Michael
Van Niel Monique Bodil
Covington Raymond
McGinnis James L.
Merck Sharp & Dohme Ltd.
Rose David L.
Rotman Alan L.
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