Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-14
2001-11-06
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S234000
Reexamination Certificate
active
06313125
ABSTRACT:
The present invention relates to a class of substituted triazolo-pyridazine 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
receptors containing the &agr;5 subunit 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 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;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 BZ
1
and BZ
2
, on the basis of radioligand binding studies. The BZ
1
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 which may be employed with less risk of proconvulsant effects previously described with benzodiazepine receptor partial or full inverse agonists.
It has now been discovered that use of an &agr;5 receptor partial or full inverse agonist which is relatively free of activity at &agr;1 and/or &agr;2 and/or &agr;3 receptor binding sites can be used to provide a medicament which is useful for enhancing cognition but in which proconvulsant activity is reduced or eliminated. 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 functionally 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.
European Patent Applications 0085840 and 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 the compounds of the present invention, nor that the compounds disclosed in the Applications have any cognition enhancing properties.
The present invention provides a compound of the formula (I):
wherein:
R
1
is hydrogen, halogen or CN or a group C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl, C
1-4
alkoxy, C
2-4
alkenyloxy or C
2-4
alkynyloxy, each of which groups is unsubstituted or substituted with one or two halogen atoms or with a pyridyl or phenyl ring each of which rings may be unsubstituted or independently substituted by one or two halogen atoms or nitro, cyano, amino, methyl or CF
3
groups;
R
2
is hydrogen, halogen or CN or a group C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl, C
1-4
alkoxy, C
2-4
alkenyloxy or C
2-4
alkynyloxy each of which groups is unsubstituted or substituted with one or two halogen atoms;
L is O, S or NH;
X is 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 or 3 nitrogen atoms, the 5- or 6-membered heteroaromatic ring being optionally fused to a benzene ring and the heteroaromatic ring being optionally substituted by R
x
and/or R
y
and/or R
z
, where R
x
is halogen, R
3
, OR
3
, OCOR
3
, NR
4
R
5
, NR
4
COR
5
, CN or R
9
, R
y
is halogen, R
3
, OR
3
, OCOR
3
, NR
4
R
5
, NR
4
COR
5
or CN and R
z
is R
3
, OR
3
or OCOR
3
, where R
3
is C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-6
cycloalkyl, hydroxyC
1-6
alkyl or CF
3
, R
4
and R
5
are each independently hydrogen, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-6
cycloalkyl or CF
3
or R
4
and R
5
, together with the nitrogen atom to which they are attached, form a 4-7 membered heteroaliphatic ring containing the nitrogen atom as the sole heteroatom, and R
9
is an aromatic ring containing either 6 atoms, 1, 2 or 3 of which are optionally nitrogen, or 5 atoms, 1, 2 or 3 of which are independently chosen from oxygen, nitrogen and sulphur, at most one of the atoms being oxygen or sulphur, and R
9
is optionally substituted by one, two or three substituents independently chosen from halogen atoms and C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl, C
1-4
alkoxy, C
2-4
alkenyloxy and C
2-4
alkynyloxy groups each of which groups is unsubstituted or substituted by one, two or three halogen atoms, and when X is a pyridine derivative, the pyridine derivative is optionally in the form of the N-oxide and providing that when X is a tetrazole derivative it is protected by a C
1-4
alkyl group; or X is phenyl optionally substituted by one, two or three groups independently selected from halogen, cyano, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alky
Carling William Robert
Moore Kevin William
Reeve Austin John
Bernhardt Emily
Lee Shu Muk
Merck Sharp & Dohme Ltd.
Rose David L.
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