Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-04-01
2004-08-17
Desai, Rita (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S208000, C546S210000, C546S209000
Reexamination Certificate
active
06777430
ABSTRACT:
The present invention relates to a class of sulphonyl derivatives which act on serotonin receptors (also known as 5-hydroxytryptamine or 5-HT receptors). More particularly, the invention concerns phenylsulphonyl derivatives wherein the sulphonyl moiety is also attached to an N-arylalkyl-substituted azetidine, pyrrolidine or 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 moreover are beneficial 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
Acremonium coenophialum
infected tall fescue (cf. D. C. Dyer,
Life Sciences,
1993, 53, 223-228).
Various classes of compounds containing inter alia a sulphonyl moiety, which are stated to have activity as antipsychotic agents, are described in WO 96/35666, EP-A-0261688, and U.S. Pat. Nos. 4,218,455 and 4,128,552. A further series of compounds, containing inter alia a piperidinyl-sulphonyl-indole moiety, is described in U.S. Pat. No. 5,418,242, and alleged to possess analgesic properties. DE-A-3901735 relates to the use of a class of compounds containing inter alia a sulphonylpyridine moiety in the treatment of depression. None of these publications, however, discloses or suggests the particular class of phenylsulphonyl derivatives provided by the present invention.
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
Z represents hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, —OR
a
, —SR
a
, —SOR
a
, —SO
2
R
a
, —SO
2
NR
a
R
b
, —NR
a
R
b
, —NR
a
COR
b
, —NR
a
CO
2
R
b
, —COR
a
, —CO
2
R
a
or —CONR
a
R
b
; or
Z represents an optionally substituted five-membered heteroaromatic ring selected from furan, thiophene, pyrrole, oxazole, thiazole, isoxazole, isothiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole and tetrazole; or
Z represents an optionally substituted six-membered heteroaromatic ring selected from pyridine, pyrazine, pyrimidine and pyridazine;
R
a
and R
b
independently represent hydrogen or C
1-6
alkyl; or R
a
and R
b
, when linked through a nitrogen atom, together represent the residue of an azetidine, pyrrolidine, piperidine or morpholine ring;
E represents a chemical bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms, optionally incorporating an oxygen atom to form an ether linkage;
M represents the residue of an azetidine, pyrrolidine or piperidine ring;
R
1
represents an optionally substituted aryl(C
2-4
)alkyl group; and
R
2
represents hydrogen or halogen.
Where Z in the compounds of formula I above represents a five-membered heteroaromatic ring, this ring may be optionally substituted by one or, where possible, two substituents. As will be appreciated, where Z represents an oxadiazole, thiadiazole or tetrazole ring, only one substituent will be possible; otherwise, one or two optional substituents may be accommodated around the five-membered heteroaromatic ring Z.
Where Z in the compounds of formula I above represents a six-membered heteroaromatic ring, this ring may be optionally substituted by one or more substituents, typically by one or two substituents.
Examples of suitable substituents on the five-membered or six-membered heteroaromatic ring as specified for Z include halogen, cyano, trifluoromethyl, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylthio, amino, C
1-6
alkylamino and di(C
1-6
)alkylamino, especially methyl.
The aryl(C
2-4
)alkyl group R
1
may be optionally substituted by one or more substituents. Suitably, the aryl(C
2-4
)alkyl group R
1
is unsubstituted, or substituted by one, two or three substituents. More particularly, the aryl(C
2-4
)alkyl group R
1
may be unsubstituted, or substituted by one or two substituents. Any optional substitution on the aryl(C
2-4
)alkyl group R
1
will suitably be on the aryl moiety thereof, although substitution on the alkyl moiety thereof is an alternative possibility.
Representative examples of optional substituents on the group R
1
include halogen, nitro, trifluoromethyl, trifluoromethox
Blurton Peter
Burkamp Frank
Cheng Susan Koon-Fung
Fletcher Stephen Robert
MacLeod Angus Murray
Desai Rita
McGinnis James L.
Merck Sharp & Dohme Ltd.
Winokur Melvin
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