Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-11-06
2002-05-28
Berch, Mark L (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S412000, C548S427000, C548S450000, C548S466000, C548S467000, C548S512000, C548S516000
Reexamination Certificate
active
06395766
ABSTRACT:
This is an application under 35 U.S.C. 371 of PCT/GB99/01799 and claims priority from Great Britain Application No. 9812038.9, filed Jun. 4, 1998.
BACKGROUND
The present invention relates to tetrahydroindolone derivatives, pharmaceutical compositions comprising them and to their use in therapy. More particularly, this invention is concerned with substituted derivatives which are ligands for GABA
A
receptors, in particular for GABA
A
&agr;5 receptors and are therefore useful in therapy particularly where cognition enhancement is required.
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, &agr; &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 apparently uncommon in the native receptor.
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 &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;6and &agr;4&bgr;&dgr;. Subtype assemblies containing an &agr;1 subunit are present in most areas of the brain and account for over 40% of GABA
A
receptors in the rat. Subtype assemblies containing &agr;2 and &agr;3 subunits respectively account for about 25% and 17% of GABA
A
receptors in the rat. Subtype assemblies containing an &agr;5 subunit are primarily hippocampal and represent about 4% of receptors in the rat.
A characteristic property of some GABA
A
receptors is the presence of a number of modulatory sites, of which the most explored is the benzodiazepine (BZ) binding 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 &bgr;2 and &ggr;2. This is the most abundant GABA
A
receptor subtype, representing 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 agoilists 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 al 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.
A number of dementing illnesses such as Alzheimer's disease are characterised by a progressive deterioration in cognition in the sufferer. It would clearly be desirable to enhance cognition in subjects desirous of such treatment, for example for subjects suffering from a dementing illness. It is believed this can be done utilising compounds which are ligands for the GABA
A
&agr;5 receptor subtype.
WO-A-9616954 mentions three thienylcyclohexanone derivatives in substituted by substituted arylaminocarbonyl on the thiophene ring as fungicides.
Van Rhee et al,
J. Med. Chem
., 1996, 39, 398-406 discloses related compounds as adenosine receptor antagonists which differ in having an ester group on the thiophene ring.
SUMMARY OF THE INVENTION
The present invention is directed to compounds according to Formula (I) or a pharmaceutically acceptable salt thereof that are GABA-A Alpha 5 ligands useful for enhancing cognition:
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.
where A is C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-6
cycloalkyl, arylC
1-6
alkyl, or aryl wherein the aryl group is optionally substituted by halogen, C
1-6
alkyl, CF
3
, CN, NO
2
or NH
2
, NR
1
R
10
, S(O)
p
R
1
, heteroarylC
1-6
alkyl or heteroaryl where heteroaryl is a 5- or 6-membered heteroaromatic ring as defined for B below;
B is phenyl or a 5-membered ring having one or two unsaturations containing 1, 2, 3 or 4 heteroatoms chosen from O, N and S provided that not more than one heteroatom is other than N, a 6-membered heteroaromatic ring containing 1, 2, 3 or 4 nitrogen atoms, each of which rings is optionally substituted by one or more substituents independently chosen from: cyano; C
1-6
alkyl; C
1-6
haloalkyl; halogen; S(O)
r
R
4
; COR
5
; and aryl, arylC
1-6
alkyl or a 5-membered ring having one or two unsaturations containing 1, 2, 3 or 4 heteroatoms chosen from O, N and S provided that not more than one heteroatom is other than N wherein the aryl ring or 5-membered ring is optionally substituted by one, two or three substituents independently chosen from halogen, CF
3
, OCH
3
, nitro and cyano; and when a nitrogen ring atom is present it is optionally substituted by oxygen;
R
1
is hydrogen; C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-6
cycloalkyl or C
3-6
cycloalkenyl each of which is optionally substituted by amino, C
1-6
alkylamino, di(C
1-6
alkyl)amino, C
1-6
alkoxy, C
1-6
alkylaminocarbonyl, one, two or three hydroxy groups, one, two or three halogen atoms or a four, five or six-membered saturated heterocyclic ring containing a nitrogen atom and optionally either an oxygen atom or a further nitrogen atom which ring is optionally substituted by C
1-4
alkyl on the further nitrogen atom; aryl, aryl
1-6
alkyl, arylC
2-6
alkenyl or arylC
2-6
alkynyl optionally substituted on the aryl ring by halogen, nitro, cyano, C
1-6
alkylcarbonylamino, hydroxy or C
1-6
alkoxy; or a five-membered aromatic ring containing 1, 2, 3 or 4
Broughton Howard Barff
Bryant Helen Jane
Chambers Mark Stuart
Curtis Neil Roy
Berch Mark L
Habte Al Kahsay
Lee Shu Muk
Merck Sharp & Dohme Limited
Rose David L.
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