Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-01-12
2002-11-12
Rao, Deepak R. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S235200, C514S254090, C514S299000, C514S323000, C514S415000, C540S602000, C544S143000, C544S373000, C546S112000, C546S201000, C548S511000
Reexamination Certificate
active
06479480
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 1H-indole derivatives bearing an optionally substituted phenyl moiety at the 2-position of the indole ring system and a methylene-linked heterocyclic moiety at the 3-position of the indole ring system. 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.
SUMMARY OF THE INVENTION
The present invention is described to compounds according to Formula (I) or a salt thereof which are selective antagonist of the human 5-HT
2A
receptor useful for treatment of adverse conditions of the central nervous system:
DETAILED DESCRIPTION OF THE INVENTION
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 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.,
Investigatiue 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
Acremonium coenophialum
infected tall fescue (cf. D. C. Dyer,
Life Sciences,
1993, 53, 223-228).
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 or C
1-6
alkoxy;
X and Y independently represent hydrogen, halogen, trifluoromethyl, trifluoromethoxy, C
1-6
alkyl, C
1-6
alkoxy or phenyl; and
Q represents a substituted five-, six- or seven-membered monocyclic heteroaliphatic ring containing one nitrogen atom and optionally one other heteroatom selected from oxygen, sulphur and nitrogen; or Q represents a substituted 6- to 11-membered bicyclic heteroaliphatic ring system which contains one nitrogen atom as the sole heteroatom; the moiety Q being linked to the remainder of the molecule via a carbon atom.
When Q represents a monocyclic heteroaliphatic ring, this is suitably a substituted pyrrolidine, piperidine, hexamethyleneimine, morpholine, thiomorpholine or piperazine ring linked through a carbon atom to the remainder of the molecule of formula I as depicted above.
When Q represents a bicyclic heteroaliphatic ring system, this is suitably a substituted 2-azabicyclo[2.2.2]octane or 2-azabicyclo[2.2.1]heptane ring system linked through a carbon atom to the remainder of the molecule of formula I as depicted above.
The moiety Q may typically be substituted by one, two or three substituents, suitably by one or two substituents. Preferably, the moiety Q is substituted, as appropriate, by the substituents R
1
, R
2
and R
3
as defined below.
Typical values for the moiety Q include the structures of formula Qa to Qm:
in which the asterisk denotes the point of attachment to the remainder of the molecule;
Z represents oxygen, sulphur or N—R
1
;
R
1
and R
2
independently represent hydrogen; or C
1-6
alkyl, aryl(C
1-6
)alkyl or C
3-7
heterocycloalkyl(C
1-6
)alkyl, any of which groups may be optionally substituted by one or more substituents; and
R
3
represents hydrogen, halogen, C
1-6
alkyl, hydroxy or C
1-6
alkoxy; provided that at least one of R
1
, R
2
and R
3
is other than hydrogen.
Particular values for the moiety Q include the structures of formula Qa, Qb, Qc, Qd, Qe, Qg, Qk and Qm above.
Where it is other than hydrogen, the group R
2
may be optionally substituted by one or more substituents. Suitably, the group R
2
is unsubstituted, or substituted by one or two substituents. In general, the group R
2
may be unsubstituted or monosubstituted. Examples of optional substituents on the group R
2
include 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
1-6
alkylamino, di(C
1-6
)alkylamino, di(C
1-6
)alkylaminomethyl, C
2-6
alkylcarbonylamino, arylcarbonylamino, C
2-6
alkoxyc
Moyes Christopher Richard
Rowley Michael
Lee Shu M.
Merck Sharp & Dohme Ltd.
Rao Deepak R.
Thies J. Eric
Winokur Melvin
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