Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-01-14
2002-10-15
Morris, Patricia L. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S234000
Reexamination Certificate
active
06465462
ABSTRACT:
The present invention relates to a class of substituted triazolopyridazine derivatives and to their use in therapy. More particularly, this invention is concerned with substituted 1,2,4-triazolo[4,3-b]pyridazine derivatives which are ligands for GABA
A
&agr;
5
receptors and are therefore useful in the therapy 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 a &bgr; subunit and &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;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 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.
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 has been reported by McNamara and Skelton in Psychobiology, 21:101-108, that the benzodiazepine receptor inverse agonist &bgr;-CCM enhanced spatial learning in the Morris watermaze. However, &bgr;-CCM and other conventional benzodiazepine receptor inverse agonists are proconvulsant which makes it clear that they cannot be used as cognition enhancing agents in humans.
However, we have now discovered that it is possible to obtain medicaments which have cognition enhancing effects, but which do not possess proconvulsant effects previously described with benzodiazepine receptor partial or full inverse agonists.
It has now been discovered that use of an &agr;5 subtype receptor partial or full inverse agonist which is relatively free of activity at &agr;
1
and/or &agr;
2
and/or &agr;
3
subtype receptor binding sites can be used to provide a medicament which is useful for enhancing cognition but which is not proconvulsant. Inverse agonists at &agr;
5
which are not free of activity at &agr;
1
and/or &agr;
2
and/or &agr;
3
but which are selective for &agr;
5
can also be used. Inverse agonists which are both selective for &agr;
5
and are relatively free of activity at &agr;
1
, &agr;
2
and &agr;
3
receptor binding sites are preferred.
EP-A-0085840 and EP-A-0134946 describe related series of 1,2,4-triazolo[3,4-a]phthalazine derivatives which are stated to possess antianxiety activity. However, there is no disclosure nor any suggestion in either of these publications of replacing the benzo moiety of the triazolophthalazine ring system with any other functionality nor is there any suggestion that the compounds have any cognition enhancing properties.
The present invention provides a compound of the formula (I):
X is: NR
2
R
3
; phenyl optionally substituted by one or two groups independently chosen from R
G
, halogen, CN and OR
G
, where R
G
is C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl or CF
3
, or by a methylenedioxy or ethylenedioxy group; or a 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from oxygen, nitrogen and sulphur, at most one of the heteroatoms being oxygen or sulphur, or a 6-membered heteroaromatic ring containing 1, 2, 3, or 4 nitrogen atoms, the ring being optionally fused to a benzene ring and optionally substituted by one or more groups independently chosen from R
7
, OR
7
, OCOR
7
, NR
8
R
9
, NR
8
COR
9
, CN and CF
3
where R
7
is independently as defined for R
G
, R
8
is independently as defined for R
2
and R
9
is independently as defined for R
3
, when the 6-membered heteroaromatic ring is pyridine it is optionally in the form of the N-oxide;
Y is optionally branched C
1-4
alkylidene optionally substituted by an oxo group;
Z is pyrazine, pyrimidine or a 5-membered heteroaromatic ring containing at least one nitrogen or an oxygen and optionally 1, 2 or 3 other heteroatoms independently selected from oxygen, nitrogen and sulphur, at most one of the other heteroatoms being oxygen or sulphur, the ring being optionally substituted by a group R
1
, NR
2
R
3
, NR
2
COR
3
, CN, CF
3
, phenyl, benzyl or pyridyl or a 5-membered heteroaromatic ring containing at least one nitrogen or an oxygen and optionally 1, 2 or 3 other heteroatoms independently selected from oxygen, nitrogen and sulphur, at most one of the other heteroatoms being oxygen or sulphur:
R
1
is C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl or CF
3
;
R
2
and R
3
are each independently hydrogen, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl or CF
3
or R
2
and R
3
, together with the nitrogen atom to which they are attached, form a 4-7 membered ring; and
n is 1 or 2;
or a pharmaceutically acceptable salt thereof or a prodrug thereof.
In one embodiment there is provided a compound of formula I′:
wherein L′, X′, Y′ and Z′ are as defined for L, X, Y and Z, or a pharmaceutically acceptable salt thereof or a prodrug thereof.
As used herein, the expression “C
1-6
alkyl” includes methyl and ethyl groups, and straight-chained, branched or cyclic propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl and cyclohexyl. Derived expressions such as “C
2-6
alkenyl” and “C
2-6
alkynyl” are to be construed in an analogous manner.
Suitable
Carling William Robert
MacLeod Angus Murray
McKernan Ruth
Reeve Austin John
Sternfeld Francine
Lee Shu M.
Merck Sharp & Dohme Ltd.
Morris Patricia L.
Thies J. Eric
Winokur Melvin
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