Substituted 1H-pyridinyl-2-ones as GABAA-&agr; 2/3 ligands

Details Substituted 1H-pyridinyl-2-ones as GABAA-&agr; 2/3 ligands Substituted 1H-pyridinyl-2-ones as GABAA-&agr; 2/3 ligands

2000-02-11

2001-03-13

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S256000, C514S408000, C544S242000, C546S001000, C546S024000

Reexamination Certificate

active

06200982

ABSTRACT:

This application is a 371 of PCT/aB 98/01593, filed Jun. 1, 1998.
The present invention relates to a class of substituted 1H-pyridinyl-2-one derivatives and to their use in therapy. More particularly, this invention is concerned with substituted 1H-pyridinyl-2-one derivatives which are ligands for GABA
A
receptors and are therefore useful in the therapy of deleterious mental states.
Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two main classes: (1) GABA
A
receptors, which are members of the ligand-gated ion channel superfamily; and (2) GABA
B
receptors, which may be members of the G-protein linked receptor superfamily. Since the first cDNAs encoding individual GABA
A
receptor subunits were cloned the number of known members of the mammalian family has grown to thirteen (six &agr; subunits, three &bgr; subunits, three &ggr; subunits and one &dgr; subunit). It may be that further subunits remain to be discovered; however, none has been reported since 1993.
Although knowledge of the diversity of the GABA
A
receptor gene family represents a huge step forward in our understanding of this ligand-gated ion channel, insight into the extent of subtype diversity is still at an early stage. It has been indicated that an &agr; subunit, a &bgr; subunit and a &ggr; subunit constitute the minimum requirement for forming a fully functional GABA
A
receptor expressed by transiently transfecting cDNAs into cells. As indicated above, a &dgr; subunit also exists, but is present only to a minor extent in GABA
A
receptor populations.
Studies of receptor size and visualisation by electron microscopy conclude that, like other members of the ligand-gated ion channel family, the native GABA
A
receptor exists in pentameric form. The selection of at least one &agr;, one &bgr; and one &ggr; subunit from a repertoire of thirteen allows for the possible existence of more than 10,000 pentameric subunit combinations. Moreover, this calculation overlooks the additional permutations that would be possible if the arrangement of subunits around the ion channel had no constraints (i.e. there could be 120 possible variants for a receptor composed of five different subunits).
Receptor subtype assemblies which do exist include, amongst many others, &agr;1&bgr;2&ggr;2, &agr;2&bgr;2/3&ggr;2, &agr;3&bgr;&ggr;2/3, &agr;2&bgr;&ggr;1, &agr;5&bgr;3&ggr;2/3, &agr;6&bgr;&ggr;2, &agr;6&bgr;&dgr; and &agr;4&bgr;&dgr;. Subtype assemblies containing an &agr;1 subunit are present in most areas of the brain and are thought to account for over 40% of GABA
A
receptors in the rat. Subtype assemblies containing &agr;2 and &agr;3 subunits respectively are thought to account for about 25% and 17% of GABA
A
receptors in the rat. Subtype assemblies containing an &agr;5 subunit are expressed predominantly in the hippocampus and cortex and are thought to represent about 4% of GABA
A
receptors in the rat.
A characteristic property of all known GABA
A
receptors is the presence of a number of modulatory sites, one of which is the benzodiazepine (BZ) binding site. The BZ binding site is the most explored of the GABA
A
receptor modulatory sites, and is the site through which anxiolytic drugs such as diazepam and temazepam exert their effect. Before the cloning of the GABA
A
receptor gene family, the benzodiazepine binding site was historically subdivided into two subtypes, BZ1 and BZ2, on the basis of radioligand binding studies. The BZ1 subtype has been shown to be pharmacologically equivalent to a GABA
A
receptor comprising the &agr;1 subunit in combination with a &bgr; subunit and &ggr;2. This is the most abundant GABA
A
receptor subtype, and is believed to represent almost half of all GABA
A
receptors in the brain.
Two other major populations are the &agr;2&bgr;&ggr;2 and &agr;3&bgr;&ggr;2/3 subtypes. Together these constitute approximately a further 35% of the total GABA
A
receptor repertoire. Pharmacologically this combination appears to be equivalent to the BZ2 subtype as defined previously by radioligand binding, although the BZ2 subtype may also include certain &agr;5-containing subtype assemblies. The physiological role of these subtypes has hitherto been unclear because no sufficiently selective agonists or antagonists were known.
It is now believed that agents acting as BZ agonists at &agr;1&bgr;&ggr;2, &agr;2&bgr;&ggr;2 or &agr;3&bgr;&ggr;2 subunits will possess desirable anxiolytic properties. The &agr;1-selective GABA
A
receptor agonists alpidem and zolpidem are clinically prescribed as hypnotic agents, suggesting that at least some of the sedation associated with known anxiolytic drugs which act at the BZ1 binding site is mediated through GABA
A
receptors containing the &agr;1 subunit. Accordingly, it is considered that GABA
A
receptor agonists which bind more effectively to the &agr;2 and/or &agr;3 subunit than to &agr;1 will be effective in the treatment of anxiety with a reduced propensity to cause sedation. Also, agents which are antagonists or inverse agonists at &agr;1 might be employed to reverse sedation or hypnosis caused by &agr;1 agonists.
The compounds of the present invention, being selective ligands for GABA
A
receptors, are therefore of use in the treatment and/or prevention of a variety of disorders of the central nervous system. Such disorders include anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic and acute stress disorder, and generalized or substance-induced anxiety disorder; neuroses; convulsions; migraine; and depressive or bipolar disorders, for example single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorders, and cyclothymic disorder.
The present invention provides a compound which is a derivative of formula I or a salt or prodrug thereof:
wherein:
R is hydrogen, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
1-6
alkoxy, C
2-6
alkenyloxy or C
2-6
alkynyloxy, and when R is not hydrogen, R is optionally independently substituted by one or more halogen atoms or hydroxy, cyano or amino groups;
V is CH or N;
W is O or S;
X is phenyl unsubstituted or substituted with one or more groups independently selected from C
1-6
alkyl, CF
3
, cyano, nitro, halogen, amino, C
1-6
alkoxy, C
1-6
alkylcarbonyloxy or C
1-6
alkylcarbonylamino; a six-membered heteroaromatic group containing one or two nitrogen atoms or a five-membered heteroaromatic group containing one, two, three or four heteroatoms independently selected from N, O and S providing that not more than one heteroatom is selected from O and S, the heteroaromatic group being unsubstituted or substituted with one or more groups independently selected from halogen, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-6
cycloalkyl, C
4-6
cycloalkenyl and CF
3
;
Y is hydrogen, NR
1
R
2
, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, Ar, O(CH
2
)
n
Ar
1
, (CH
2
)
j
Ar
2
, C
k
H
2k-2
Ar
2
, C
k
H
2k-4
Ar
2
or NH(CH
2
)
l
Ar
5
;
R
1
and R
2
are independently selected from hydrogen, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
1-6
hydroxyalkyl and (CH
2
)
m
Ar
3
;
Ar is thienyl, furyl or a six-membered heteroaromatic ring containing one or two nitrogen atoms which is unsubstituted or substituted with one or more groups independently selected from halogen and C
1-6
alkyl groups and which is optionally fused to a benzene ring; or naphthyl or phenyl rings which rings are unsubstituted or substituted with one or more groups independently selected from halogen, cyano, amino, nitro, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, CF
3
, CF
3
O, C
1-6
alkoxy, C
2-6
alkenyloxy, C
2-6
alkynyloxy, C
1-6
alkylthio, C
2-6
alkenylthio, C
2-6
alkynylthio, hydroxy, hydroxyC
1-6
alkyl, NR
3
R
4
, OC(O)NR
3
R
4
, C
1-6
alkoxyphenylC
1-6
alkoxy, cyanoC
1-6
alkyl, cyanoC
2-6
alkenyl, cyanoC
2-6
alkynyl, pyridyl, phenyl, C
1-6
alkoxycarbonyl, C
1-

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