Triazolo-pyridazine derivatives as ligands for GABA receptors

Details Triazolo-pyridazine derivatives as ligands for GABA receptors Triazolo-pyridazine derivatives as ligands for GABA receptors

2000-06-28

2003-06-17

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S236000

Reexamination Certificate

active

06579875

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
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 include at least six ax subunits, four &bgr; subunits, three &ggr; subunits, one &dgr; subunit, one &egr; subunit and two &rgr; subunits.
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, &dgr;, &egr; and &rgr; subunits also exist, but are 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 seventeen 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 antagonist 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. 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 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; 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; psychotic disorders including schizophrenia; neurodegeneration arising from cerebral ischemia; attention deficit hyperactivity disorder; and disorders of circadian rhythm, e.g. in subjects suffering from the effects of jet lag or shift work.
Further disorders for which selective ligands for GABA
A
receptors may be of benefit include pain and nociception; emesis, including acute, delayed and anticipatory emesis, in particular emesis induced by chemotherapy or radiation, as well as post-operative nausea and vomiting; eating disorders including anorexia nervosa and bulimia nervosa; premenstrual syndrome; muscle spasm or spasticity, e.g. in paraplegic patients; and hearing loss. Selective ligands for GABA
A
receptors may also be effective as pre-medication prior to anaesthesia or minor procedures such as endoscopy, including gastric endoscopy.
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.
EP-A-0085840 and EP-A-0134946 describe related series of 1,2,4-triazolo[3,4-&agr;]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.
The present invention provides a class of triazolo-pyridazine derivatives which possess desirable binding properties at various GABA
A
receptor subtypes. The com

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