Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-11-12
2001-01-16
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S340000, C544S236000, C544S239000
Reexamination Certificate
active
06174886
ABSTRACT:
The present invention relates to the use of a class of substituted triazolo-pyridazine derivatives in therapy. More particularly, this invention is concerned with the use of substituted 1,2,4-triazolo[4,3-b]pyridazine derivatives which are ligands for GABA
A
receptors in the treatment and/or prevention of psychotic disorders including schizophrenia.
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 include at least six &agr; subunits, three &bgr; subunits, three &ggr; subunits and one &dgr; subunit.
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 ox 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;2&ggr;2, &agr;2&bgr;&ggr;2 or &agr;3&bgr;&ggr;2 subunits will possess desirable antipsychotic properties. Compounds which are modulators of the benzodiazepine binding site of the GABA
A
receptor by acting as BZ agonists are referred to hereinafter as “GABA
A
receptor agonists”. 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 interact more favourably with the &agr;2 and/or &agr;3 subunit than with &agr;1 will be effective in the treatment of psychotic disorders including schizophrenia with a reduced propensity to cause sedation.
In DE-A-2741763, and in U.S. Pat. Nos. 4,260,755, 4,260,756 and 4,654,343, are described various classes of 1,2,4-triazolo[4,3-b]pyridazine derivatives which are alleged to be useful as anxiolytic agents. The compounds described in DE-A-2741763 and in U.S. Pat. Nos. 4,260,755 and 4,654,343 possess a phenyl substituent at the 6-position of the triazolo-pyridazine ring system. The compounds described in U.S. Pat. No.4,260,756, meanwhile, possess a heteroaryl moiety at the 6- or 8-position. In none of these publications, however, is there any disclosure or suggestion of 1,2,4-triazolo[4,3-b]pyridazine derivatives wherein the substituent at the 6-position is attached through a directly linked oxygen atom. Moreover, these publications nowhere disclose or suggest that the compounds described therein might be an effective therapy for psychotic disorders including schizophrenia.
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 triazolo-phthalazine ring system with any other functionality. Moreover, these publications nowhere disclose or suggest that the compounds described therein might be an effective therapy for psychotic disorders including schizophrenia.
The present invention provides a new use for a class of triazolo-pyridazine derivatives which possess desirable binding properties at various GABA
A
receptor subtypes. The compounds of use in the present invention have good affinity as ligands for the &agr;2 and/or &agr;3 subunit of the human GABA
A
receptor. The compounds of use in this invention may interact more favourably with the &agr;2 and/or &agr;3 subunit than with the &agr;1 subunit. Desirably, the compounds of use in the invention will exhibit functional selectivity in terms of a selective efficacy for the &agr;2 and/or &agr;3 subunit relative to the &agr;1 subunit.
The compounds of use in the present invention are GABA
A
receptor subtype ligands having a binding affinity (K
i
) for the &agr;2 and/or &agr;3 subunit, as measured in the assay described hereinbelow, of 100 nM or less, typically of 50 nM or less, and ideally of 10 nM or less. The compounds of use in this invention may possess at least a 2-fold, suitably at least a 5-fold, and advantageously at least a 10-fold, selective affinity for the &agr;2 and/or &agr;3 subunit relative to the &agr;1 subunit. However, the use of compounds which are unselective in terms of their binding affinity for the &agr;2 and/or &agr;3 subunit relative to the &agr;1 subunit is also encompassed within the scope of the present invention; such compounds will desirably exhibit functional selectivity in terms of a selective efficacy for the &agr;2 and/or &agr;3 subunit relative to the &agr;1 subunit.
In
J. Psychiatr. Res.,
1996, 30, 239-250 are presented the
Castro Pineiro Jose Luis
McKernan Ruth
Whiting Paul John
Lee Shu M.
Merck Sharp & Dohme Ltd.
Owens Howard
Rose David L.
Wilson James O.
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