Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-03
2002-11-26
Rao, Deepak R. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S227800, C514S235200, C514S253010, C514S253060, C514S254090, C514S278000, C514S323000, C514S414000, C514S415000, C540S602000, C544S062000, C544S143000, C544S331000, C544S363000, C544S364000, C544S373000, C546S019000, C546S201000, C548S455000, C548S467000, C548S506000
Reexamination Certificate
active
06486153
ABSTRACT:
The present invention relates to the use of a class of indole derivatives which act on serotonin receptors (also known as 5-hydroxytryptamine or 5-HT receptors). More particularly, the invention concerns analogues of tryptamine bearing an optionally substituted phenyl substituent at the 2-position. 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 use in 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 use in 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 use in 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 use in 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 preparation of a series of indole derivatives, including 3-aminoalkyl-2-phenylindoles, for pharmacological study is described in Ames et al.,
J. Chem. Soc.,
1959, 3388-3399. No actual pharmaceutical utility is, however, ascribed to the compounds disclosed therein.
Julia et al. in
Annales de l'Institut Pasteur,
1965, 343-362, describe the preparation of a number of 2-aryltryptamine derivatives, which are stated to have weak antiserotonin (rat uterus) activity.
Agarwal et al. in
Indian Drugs,
1979, 209-212, and in
J. Indian Chem. Soc.,
1980, 57, 742-743, describe the synthesis of inter alia the compound 3- [2-(2-methylpiperidin-1-yl)ethyl]-2-phenyl-1H-indole. However, no pharmacological activity is ascribed in either publication to this specific compound.
In JP-A-55-151505 is described a class of indoles, including 3-aminoalkyl-2-phenylindole derivatives which are optionally substituted on the 2-phenyl moiety and on the benzo moiety of the indole nucleus. These compounds are stated therein to be fungicides.
Hiriyakkanavar & Siddappa in
Indian J. Chem.,
1966, 4, 188-190, describe the synthesis of various 5,7-dimethyl-substituted 2-phenyltryptamine derivatives, which are stated to exhibit antiserotonin activity.
Joshi et al. in
Agric. Biol. Chem.,
1978, 42, 1723-1726, and in
Monatsh. Chem.,
1980:, 111, 1343-1350, describe various fluorinated analogues of 2-phenyltryptamine. Certain of these compounds are stated to act as mild stimulants.
In none of the prior art publications referred to above, in which 2-phenyl analogues of tryptamine are described, is there any disclosure or suggestion that such compounds might be potent and selective antagonists of the human 5-HT
2A
receptor, nor indeed that they might be of particular benefit in the treatment in particular of neurological conditions, including psychotic disorders such as schizophrenia.
FR-A-2102282 and FR-A-2181559 describe separate series of inter alia 2-phenyltryptamine analogues, both of which are stated to possess a variety of actions on the nervous system.
The compounds of use in 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 use in 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 the use of a compound of formula I, or a pharmaceutically acceptable 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, C
1-6
alkyl, C
1-6
alkoxy or phenyl;
R
1
represents hydrogen or C
1-6
alkyl;
R
2
represents hydrogen, methyl, ethyl, 2-methoxyethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl or n-pentyl; and
R
3
represents C
1-6
alkyl, C
2-6
alkenyl, C
3-9
cycloalkyl, aryl, C
3-7
heterocycloalkyl, C
3-7
heterocycloalkyl(C
1-6
)alkyl, heteroaryl or heteroaryl(C
1-6
)alkyl, any of which groups may be optionally substituted by one or more substituents; or
R
2
and R
3
taken together with the intervening nitrogen atom represent a group of formula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l) or (m):
in which the broken line represents an optional chemical bond;
Z represents oxygen, sulphur, N—R
6
or CR
7
R
8
;
R
4
represents hydrogen, C
1-6
alkyl, C
Castro Pineiro Jose Luis
Hutchins Steven Michael
Lewis Stephen John
Rowley Michael
Smith Adrian Leonard
McGinnis James L.
Merck Sharp & Dohme Ltd.
Rao Deepak R.
Winokur Melvin
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