GB2345443A

GB2345443A - Use of triazolo-pyridazines for treating premenstrual syndrome

Info

Publication number: GB2345443A
Application number: GB0000113A
Authority: GB
Inventors: Ruth Mckernan; Keith Alan Wafford
Original assignee: Merck Sharp and Dohme Ltd
Current assignee: Organon Pharma UK Ltd
Priority date: 1999-01-08
Filing date: 2000-01-05
Publication date: 2000-07-12
Also published as: GB0000113D0

Abstract

A class of substituted or 7,8-ring fused 1,2,4-triazolo[4,3-b]pyridazine derivatives, possessing an optionally substituted cycloalkyl, phenyl or heteroaryl substituent at the 3-position and a substituted alkoxy moiety at the 6-position, are selective ligands for GABA<SB>A</SB> receptors, in particular having high affinity for the a 2 and/or a 3 and/or a 4 subunit thereof, and are accordingly of benefit in the treatment and/or prevention of premenstrual syndrome. Compounds are of formula Where ```X is H or alkyl ```Y is alkyl, cycloalkyl or cycloalkenyl, aryl (including heteroaryl or dialkylamino or x and y together represent further ring systems ```R<SP>1</SP> is a cyclic group ```and R<SP>2</SP> is an optionally substituted alkyl group.

Description

THE USE OF TRIAZOLO-PYRIDAZINE DERIVATIVES FOR TREATING PREMENSTRUAL SYNDROME 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 [4,3b] pyridazine derivatives which are ligands for GABAA receptors in the treatment and/or prevention of premenstrual syndrome.

Receptors for the major inhibitory neurotransmitter, gammaaminobutyric acid (GABA), are divided into two main classes: (1) GABAA receptors, which are members of the ligand-gated ion channel superfamily; and (2) GABAs receptors, which may be members of the G-protein linked receptor superfamily. Since the first cDNAs encoding individual GABAA receptor subunits were cloned the number of known members of the mammalian family has grown to include at least six a subunits, ss subunits, three y subunits, one 8 subunit, and s subunit and two p subunits.

Although knowledge of the diversity of the GABAA receptor gene family represents a huge step forward in our understanding of this ligandgated ion channel, insight into the extent of subtype diversity is still at an early stage. It has been indicated that an a subunit, a P subunit and a y subunit constitute the minimum requirement for forming a fully functional GABAA receptor expressed by transiently transfecting cDNAs into cells. As indicated above, 6, s and p subunits also exist, but are present only to a minor extent in GABAA receptor populations.

Studies of receptor size and visualisation by microscopy conclude that, like other members of the ligand-gated ion channel family, the native GABAA receptor exists in pentameric form. The selection of at least one a, one P and one y 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, alss2Y2, a2p2/3y2, a3py2/3, a2pyl, a5p3y2/3, a4py2, a6py2, a6p5 and oc4p8. Subtype assemblies containing an al subunit are present in most areas of the brain and are thought to account for over 40% of GABAA receptors in the rat. Subtype assemblies containing a2 and a3 subunits respectively are thought to account for about 25% and 17% of GABAA receptors in the rat. Subtype assemblies containing an a5 subunit are expressed predominantly in the hippocampus and cortex and are thought to represent about 4% of GABAA receptors in the rat. Other subtype assemblies are known to exist in various locations throughout the brain.

A characteristic property of all known GABAA 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 GABAA receptor modulatory sites, and is the site through which anxiolytic drugs such as diazepam and temazepam exert their effect.

Before the cloning of the GABAA 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 GABAA receptor comprising the al subunit in combination with a P subunit and y2. This is the most abundant GABAA receptor subtype, and is believed to represent almost half of all GABAA receptors in the brain.

Two other major populations are the a2py2 and a3ssY213 subtypes.

Together these constitute approximately a further 35% of the total GABAA 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 a5-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 alpy2, a2py2 or a3py2 subunits will possess desirable properties in treating and/or preventing premenstrual syndrome. Compounds which are modulators of the benzodiazepine binding site of the GABAA receptor by acting as BZ agonists are referred to hereinafter as"GABAA receptor agonists". The alselective GABAA 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 GABAA receptors containing the al subunit. Accordingly, it is considered that GABAA receptor agonists which interact more favourably with the a2 and/or a3 subunit than with al will be effective in the treatment of premenstrual syndrome with a reduced propensity to cause sedation.

Premenstrual syndrome (abbreviated to PMS; also known as premenstrual dysphoric disorder or late luteal phase dysphoric disorder) is a condition in which a variety of physical and psychological symptoms occur during the 7 to 14 days before the commencement of a menstrual period. These symptoms, which may be attributable to the hormonal and metabolic fluctuations that occur during the menstrual cycle, include physical changes (such as backache, bloating, breast tenderness and pain, changes in appetite, constipation, dizziness, fainting, headaches, heaviness or pressure in the pelvic area, hot flushes, insomnia, lack of energy, nausea and vomiting, severe fatigue, skin problems including acne and localized scratch dermatitis, tissue swelling or joint pain, and weight gain); mood changes (such as agitation, anger, depression, irritability, mood swings, and nervousness); and mental changes (such as confusion, difficulty in concentrating, emotional upset, and memory loss or forgetfulness).

The manifestations of premenstrual syndrome may be attenuated by careful attention to diet, and possibly also by the administration of dietary supplements containing calcium and magnesium. In particular, vitamin B supplements, especially pyridoxine (vitamin B6), may be beneficial, although the administration of vitamin B6 in excessive doses can give rise to nerve damage. Relief from headaches, pain from uterine cramps, and joint aches may be achieved by the administration of nonsteroidal anti-inflammatory drugs (NSAIDs), although the common NSAIDs are known to be associated with deleterious gastric side-effects.

Irritability, nervousness and stress may be reduced with alprazolam, but drug dependency is a known risk factor associated with treatment by alprazolam. Antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and paroxetine may also be of benefit in treating some of the symptoms of premenstrual syndrome, but their slow onset of action limits their usefulness in this area.

WO 98/04559 describes a class of substituted and 7,8-ring fused 1, 2,4-triazolo [4, 3-b] pyridazine derivatives which are stated to be selective ligands for GABAA receptors beneficial in the treatment and/or prevention of neurological disorders including anxiety and convulsions. There is, however, no disclosure nor any suggestion in WO 98/04559 that the class of compounds described therein might be an effective therapy for premenstrual syndrome.

The present invention provides a new use for a class of triazolopyridazine derivatives which possess desirable binding properties at various GABAA receptor subtypes. The compounds of use in the present invention have good affinity as ligands for the a2 and/or 3"ubunit of the human GABAA receptor. The compounds of use in this invention may interact more favourably with the a2 and/or a3 subunit than with the al subunit. Desirably, the compounds of use in the invention will exhibit functional selectivity in terms of a selective efficacy for the a2 and/or a3 subunit relative to the al subunit.

The compounds of use in the present invention are GABAA receptor subtype ligands having a binding affinity (Ki) for the a2 and/or a3 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 a2 and/or a3 subunit relative to the al subunit. However, the use of compounds which are unselective in terms of their binding affinity for the a2 and/or a3 subunit relative to the al 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 a2 and/or a3 subunit relative to the al subunit.

The present invention provides a method for the treatment and/or prevention of premenstrual syndrome which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof or a prodrug thereof :

wherein Y represents hydrogen or Cl. 6 alkyl ; and Z represents Cl-s alkyl, Cs-7 cycloalkyl, C4-7 cycloalkenyl, aryl, C3. 7 heterocycloalkyl, heteroaryl or di (Cl. 6) alkylamino, any of which groups may be optionally substituted; or Y and Z are taken together with the two intervening carbon atoms to form a ring selected from C5-9 cycloalkenyl, C6-io bicycloalkenyl, tetrahydropyridinyl, pyridinyl and phenyl, any of which rings may be optionally benzo-fused and/or substituted; RI represents C3. 7 cycloalkyl, phenyl, furyl, thienyl or pyridinyl, any of which groups may be optionally substituted; and R2 represents cyano (Cl-6) alkyl, hydroxy (Ci-6) alkyl, C3. 7 cycloalkyl (Cl-6) alkyl, propargyl, C3. 7 heterocycloalkylcarbonyl (Cl-6) alkyl, aryl (Cl-6) alkyl or heteroaryl (Cl-6) alkyl, any of which groups may be optionally substituted.

The present invention also provides the use of a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof or a prodrug thereof, for the manufacture of a medicament for the treatment and/or prevention of premenstrual syndrome.

Where Y and Z are taken together with the two intervening carbon atoms to form a ring, the resulting compounds of formula I above incorporate the relevant cycloalkenyl, bicycloalkenyl, tetrahydropyridinyl, pyridinyl or phenyl ring fused to the central triazolo-pyridazine ring system as depicted in formula I.

Where Y and Z are taken together with the two intervening carbon atoms to form a C5-9 cycloalkenyl ring, this ring may be a cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl or cyclononenyl ring, suitably cyclohexenyl or cycloheptenyl.

Where Y and Z are taken together with the two intervening carbon atoms to form a Ce 10 bicycloalkenyl ring, this ring may be a bicyclo [2.1.1] hex-2-enyl, bicyclo [2.2. l] hept-2-enyl, bicyclo [2.2.2] oct-2-enyl bicyclo [3.2.2] non-6-enyl or bicyclo [3.3.2] dec-9-enyl ring, suitably bicyclo [2.2.1] hept-2-enyl, bicyclo [2.2.2] oct-2-enyl or bicyclo [3.2.2] non-6enyl, and especially bicyclo [2.2.2] oct-2-enyl.

Where Y and Z are taken together with the two intervening carbon atoms to form a ring, this ring may be optionally benzo-fused. By way of illustration, Y and Z taken together with the two intervening carbon atoms may represent a benzo-fused cyclohexenyl ring, whereby the resulting ring is dihydronaphthyl.

The groups Y, Z, Rl and R2 may be unsubstituted, or substituted by one or more, suitably by one or two, substituents. In general, the groups Y, Z, RI and R2 will be unsubstituted or monosubstituted. Examples of optional substituents on the groups Y, Z, RI and R2 include Ci. e alkyi, aryl (Cl. 6) alkyl, pyridyl (C1-6) alkyl, halogen, halo (Cl. 6) alkyl, cyano, cyano (C1- 6) alkyl, hydroxy, hydroxymethyl, C1. 6 alkoxy, C3-7 cycloalkyl (C1-6)alkoxy, C3-7 cycloalkoxy, amino (C1-6) alkyl, di (Ci-6) alkylamino (C1-6) alkyl, di (C1-6) alkylaminocarbonyl (Ci-6) alkyl, N- (Ci. 6) alkylpiperidinyl, pyrrolidinyl (Ci-6) alkyl, piperazinyl (Ci-6) alkyl, morpholinyl (C1-6)alkyl, di (C1-6)alkylmorpholinyl(C1-6)alkyl and imidazolyl (C i-e) alkyi.

As used herein, the expression"Ci.s alkyl"includes methyl and ethyl groups, and straight-chained or branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, tert-butyl and 1,1-dimethylpropyl. Derived expressions such as "C1-6 alkoxy"are to be construed accordingly.

Typical C3-7 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The expression"C3 7 cycloalkyl (Ci-6) alkyl" as used herein includes cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

Typical C4-7 cycloalkenyl groups include cyclobutenyl, cyclopentenyl and cyclohexenyl.

Typical aryl groups include phenyl and naphthyl, preferably phenyl.

The expression"aryl (Cl 6) alkyl''as used herein includes benzyl, phenylethyl, phenylpropyl and naphthylmethyl.

Suitable heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl groups.

Suitable heteroaryl groups include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups.

The expression"heteroaryl (Cl. 6) alkyl" as used herein includes furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl, oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl.

The term"halogen"as used herein includes fluorine, chlorine, bromine and iodine, especially fluorine or chlorine.

For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of use in the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of use in this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound of use in the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, acid, tartaric acid, carbonic acid or phosphoric acid.

Furthermore, where the compounds of use in the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e. g. sodium or potassium salts; alkaline earth metal salts, e. g. calcium or magnesium salts; and salts formed with suitable organic ligands, e. g. quaternary ammonium salts.

The present invention includes within its scope the use of prodrugs of the compounds of formula I above. In general, such prodrugs will be functional derivatives of the compounds of formula I which are readily convertible in vivo into the required compound of formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H.

Bundgaard, Elsevier, 1985.

Where the compounds of use in the invention have at least one asymmetric centre, they may accordingly exist as enantiomers. Where the compounds of use in the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that the use of all such isomers and mixtures thereof in any proportion is encompassed within the scope of the present invention.

Suitably, Y represents hydrogen or methyl, especially hydrogen.

Examples of suitable values for the substituent Z include methyl, ethyl, isopropyl, tert-butyl, 1, 1-dimethylpropyl, methyl-cyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, cyclobutenyl, phenyl, pyrrolidinyl, methyl-pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyridinyl, furyl, thienyl, chloro-thienyl and diethylamino.

In a particular embodiment, the substituent Z represents C3. 7 cycloalkyl, either unsubstituted or substituted by Ci. c alkyi, especially methyl. Favourably, Z represents cyclobutyl.

When Y and Z are taken together with the two intervening carbon atoms to form a ring, representative compounds of use in the invention include those of structure IA to T ; especially IA to IK:

wherein R1 and R2 are as defined above; R3 represents hydrogen, C1-6 alkyl, aryl (Cl. 6) alkyl, halogen, cyano, hydroxy, hydroxymethyl or Cl. 6 alkoxy; and R4 represents hydrogen or Cl. 6 alkyl.

Suitably, R3 represents hydrogen or Cl. 6 alkyl, especially hydrogen or methyl.

Suitably, R4 represents hydrogen or methyl.

Favoured triazolc-pyridazine derivatives of use in the present invention include the compounds represented by formula IE as depicted above.

Examples of typical optional substituents on the group RI include methyl, fluoro and methoxy.

Representative values of Rl include cyclopropyl, phenyl, methylphenyl, fluorophenyl, difluorophenyl, methoxyphenyl, furyl, thienyl, methyl-thienyl and pyridinyl. Particular values include cyclopropyl, phenyl, methylphenyl, fluorophenyl, methoxyphenyl and pyridinyl. More particularly, RI may represent unsubstituted or monosubstituted phenyl. Most particularly, R1 represents phenyl.

Suitable values for the substituent R2 in the compounds of use in the invention include cyanomethyl, hydroxybutyl, cyclohexylmethyl, propargyl, pyrrolidinylcarbonylmethyl, benzyl, pyrazolylmethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, benzimidazolylmethyl, oxadiazolylmethyl, triazolylmethyl, tetrazolylmethyl, pyridinylmethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl, any of which groups may be optionally substituted by one or more substituents.

Examples of suitable optional substituents on the group R2 include Ci. 6 alkyi, aryl (Cl-6) alkyl, pyridyl (Cl. 6) alkyl, halogen, halo (Cl. s) alkyl, cyano, cyano (Cl. 6) alkyl, hydroxymethyl, Cl. 6 alkoxy, Cl. ? cycloalkyl (Ci-6) alkoxy, amino (Cl. 6) alkyl, di (Ci-6) alkylamino (Cl. 6) alkyl, di (Cl-6) alkylaminocarbonyl (Ci-6) alkyl, N- (Ci-6) alkylpiperidinyl, pyrrolidinyl (Ci-6) alkyl, piperazinyl (Ci-6) alkyl, morpholinyl (Cl. 6) alkyl and di (Ci-6) alkylmorpholinyl (Cl. 6) alkyl.

Specific illustrations of particular substituents on the group R2 include methyl, ethyl, n-propyl, benzyl, pyridinylmethyl, chloro, chloromethyl, cyano, cyanomethyl, hydroxymethyl, ethoxy, cyclopropylmethoxy, dimethylaminomethyl, at thyl, dimethylaminoethyl, dimethylaminocarbonylmethyl, N-methylpiperidinyl, pyrrolidinylethyl, piperazinylethyl, morpholinylmethyl and dimethylmorpholinylmethyl.

Representative values of R2 include cyanomethyl, hydroxybutyl, hydroxymethyl-cyclohexylmethyl, propargyl, dimethylaminomethyl propargyl, dimethylmorpholinylmethyl-propargyl, pyrrolidinylcarbonylmethyl, cyanobenzyl, hydroxymethyl-benzyl, pyrazolylmethyl, dimethyl-pyrazolylmethyl, methyl-isoxazolylmethyl, thiazolylmethyl, methyl-thiazolylmethyl, ethyl-thiazolylmethyl, methylthiazolylethyl, imidazolylmethyl, methyl-imidazolylmethyl, ethylimidazolylmethyl, benzyl-imidazolylmethyl, benzimidazolylmethyl, methyl-oxadiazolylmethyl, triazolylmethyl, methyl-triazolylmethyl, propyl-triazolylmethyl, benzyl-triazolylmethyl, pyridinylmethyltriazolylmethyl, cyanomethyl-triazolylmethyl, dimethylaminomethyltriazolylmethyl, aminoethyl-triazolylmethyl, dimethylaminoethyltriazolylmethyl, dimethylaminocarbonylmethyl-triazolylmethyl, Nmethylpiperidinyl-triazolylmethyl, pyrrolidinylethyl-triazolylmethyl, piperazinylethyl-triazolylmethyl, morpholinylethyl-triazolylmethyl, methyl-tetrazolylmethyl, pyridinylmethyl, methyl-pyridinylmethyl, dimethyl-pyridinylmethyl, ethoxy-pyridinylmethyl, cyclopropylmethoxypyridinylmethyl, pyridazinylmethyl, chloro-pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl.

A favoured value of R2 is methyl-triazolylmethyl.

A particular sub-class of compounds of use in the invention is represented by the compounds of formula IIA, and pharmaceutically acceptable salts thereof and prodrugs thereof :

wherein RI is as defined above; n is 1,2,3 or 4, typically 1; and Rl2 represents hydroxy ; or C3. 7 cycloalkyl, C3. 7 heterocycloalkylcarbonyl, aryl or heteroaryl, any of which groups may be optionally substituted.

Examples of optional substituents on the group R12 suitably include Ci-6 alkyi, aryl (Cl-6) alkyl, halogen, cyano, hydroxymethyl, Ci. e alkoxy and C3. 7 cycloalkyl (Cl-6) alkoxy. Typical substituents include methyl, ethyl, benzyl, chloro, cyano, hydroxymethyl, ethoxy and cyclopropylmethoxy.

Particular values of R12 include hydroxy, hydroxymethyl-cyclohexyl, pyrrolidinylcarbonyl, cyanophenyl, hydroxymethyl-phenyl, pyrazolyl, dimethylpyrazolyl, thiazolyl, methylthiazolyl, ethylthiazolyl, imidazolyl, methylimidazolyl, ethylimidazolyl, benzylimidazolyl, methyltriazolyl, pyridinyl, methylpyridinyl, dimethyl-pyridinyl, ethoxypyridinyl, cyclopropylmethoxy-pyridinyl, pyridazinyl, chloropyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl and quinoxalinyl.

Another sub-class of compounds of use in the invention is represented by the compounds of formula IIB, and pharmaceutically acceptable salts thereof and prodrugs thereof :

wherein Y'represents hydrogen or methyl; Zl represents C1. 6 alkyl, C3. 7 cycloalkyl, C4. 7 cycloalkenyl, aryl, Cl. 7 heterocycloalkyl, heteroaryl or di (Ci-6) alkylamino, any of which groups may be optionally substituted; Rl is as defined with reference to formula I above; m is 1 or 2, preferably 1; and R22 represents aryl or heteroaryl, either of which groups may be optionally substituted.

Suitably, Y'represents hydrogen.

Examples of typical substituents on the group Zl include Cl 6 alkyl and halogen, especially methyl or chloro.

Representative values for the group Z1 include methyl, ethyl, isopropyl, tert-butyl, 1,1-dimethylpropyl, methyl-cyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, cyclobutenyl, phenyl, pyrrolidinyl, methyl-pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyridinyl, furyl, thienyl, chloro-thienyl and diethylamino.

A favoured value of Zl is cyclobutyl.

Examples of typical substituents on the group R22 include Ci-6 alkyl, aryl (Cl-6) alkyl, pyridyl (Ci. 6) alkyl, halogen, cyano, cyano (Cl. 6) alkyl, hydroxymethyl, CI-6 alkoxy, Cs-7 cycloalkyl (Ci-6) alkoxy, di (Cl-6) alkylamino (Ci-6) alkyl, amino (Cl-6) alkyl, di (Cl-6) alkylaminocarbonyl (Cl 6) alkyl, N- (Ci-6) alkylpiperidinyl, pyrrolidinyl (Cl-6) alkyl, piperazinyl (Ci-6) alkyl and morpholinyl (Cl-6) alkyl.

Illustrative values of specific substituents on the group R22 include methyl, ethyl, n-propyl, benzyl, pyridinylmethyl, chloro, cyano, cyanomethyl, hydroxymethyl, ethoxy, cyclopropylmethoxy, dimethylaminomethyl, aminoethyl, dimethylaminoethyl, dimethylaminocarbonylmethyl, N-methylpiperidinyl, pyrrolidinylethyl, piperazinylethyl and morpholinylmethyl.

Particular values of R22 include cyanophenyl, hydroxymethylphenyl, pyrazolyl, dimethyl-pyrazolyl, methyl-isoxazolyl, thiazolyl, methylthiazolyl, ethyl-thiazolyl, imidazolyl, methyl-imidazolyl, ethyl-imidazolyl, benzyl-imidazolyl, benzimidazolyl, methyl-oxadiazolyl, triazolyl, methyltriazolyl, propyl-triazolyl, benzyl-triazolyl, pyridinylmethyl-triazolyl, cyanomethyl-triazolyl, dimethylaminomethyl-triazolyl, aminoethyltriazolyl, dimethylaminoethyl-triazolyl, dimethylaminocarbonylmethyltriazolyl, N-methylpiperidinyl-triazolyl, pyrrolidinylethyl-triazolyl, piperazinylethyl-triazolyl, morpholinylethyl-triazolyl, methyl-tetrazolyl, pyridinyl, methyl-pyridinyl, dimethyl-pyridinyl, ethoxy-pyridinyl, cyclopropylmethoxy-pyridinyl, pyridazinyl, chloro-pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl and quinoxalinyl.

A favoured value of R22 is methyl-triazolyl.

A particular subset of the compounds of formula IIB above of use in the present invention is represented by the compounds of formula IIC, and pharmaceutically acceptable salts thereof :

wherein Rl is as defined with reference to formula I above; Q represents the residue of a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring; R5 represents hydrogen or methyl; and R6 represents hydrogen or methyl.

In relation to formula IIC above, Rl suitably represents phenyl.

In a favoured embodiment, Q suitably represents the residue of a cyclobutyl ring.

Suitably, R5 represents hydrogen.

Suitably, R6 represents methyl.

Specific compounds of use in the present invention include: 3-phenyl-6- (2-pyridyl)methyloxy-7,8,9,10-tetrahydro- (7, 10-ethano)-1,2,4triazolo [3,4-a] phthalazine; 3,7-diphenyl-6-(2-pyridyl) methyloxy-1,2,4-triazolo [4,3-b] pyridazine; 3-phenyl-6- (2-pyridyl) methyloxy-7,8,9,10-tetrahydro-1,2,4-triazolo [3,4a]phthalazine; 7,8-dimethyl-3-phenyl-6- (2-pyridyl) methyloxy-1,2,4-triazolo [4,3b] pyridazine ; 7-methyl-3-phenyl-6- (2-pyridyl) methyloxy-1, 2,4-triazolo [4,3-b] ; 7-ethyl-3-phenyl-6- (2-pyridyl) methyloxy-1,2,4-triazolo [4,3-b] pyridazine; 7,8-benzo-3-phenyl-6- (2-pyridyl)methyloxy-7,8,9,10-tetrahydro-1,2,4triazolo [3,4-a] phthalazine; 8-methyl-3,7-diphenyl-6-(2-pyridyl) methyloxy-1,2,4-triazolo [4,3b]pyridazine; 3-phenyl-6- (2-pyridyl) methyloxy-7,8,9,10-tetrahydro- (7,10-methano)-1,2,4 triazolo [3,4-a] phthalazine; 3-phenyl-5- (pyridin-2-ylmethoxy)-1, 2,3a, 4,7-pentaazacyclopenta [a] naphthalene ; 3-phenyl-5- (pyridin-2-ylmethoxy)-1, 2,3a, 4,8-pentaazacyclopenta [a]naphthalene; 8-methyl-3-phenyl-6- (2-pyridyl) methyloxy-7, 8,9,10-tetrahydro-1,2,4triazolo [3,4-a] phthalazine; 3-phenyl-6- (2-pyridyl) methyloxy- (7, 8-pentano)-1, 2,4-triazolo [4,3b]pyridazine; 8,8-dimethyl-3-phenyl-6- (2-pyridyl) methyloxy-7,8,9,10-tetrahydro-1', 4triazolo [3,4-a] phthalazine; 3-phenyl-7- (piperidin-1-yl)-6- (pyridin-2-ylmethoxy)-1, 2,4-triazolo [4,3b]pyridazine; 3-phenyl-7- (pyridin-4-yl)-6- (pyridin-2-ylmethoxy)-1, 2,4-triazolo [4,3b] pyridazine ; 3-phenyl-5- (pyridin-2-ylmethoxy)-6, 7,8,9-tetrahydro-1,2,3a, 4,8-pentaazacyclopenta [a] naphthalene; 3-phenyl-5- (pyridin-2-ylmethoxy)-6, 7,8,9-tetrahydro-1,2,3a, 4,7-pentaazacyclopenta [a] naphthalene; 7-methyl-3-phenyl-5- (pyridin-2-ylmethoxy)-6, 7,8,9-tetrahydro-1,2,3a, 4,7pentaazacyclopenta [a] naphthalene; 3-phenyl-6- (pyridin-2-ylmethoxy)-7-(thiophen-2-yl)-1,2,4-triazolo [4,3- b] pyridazine ; 3-phenyl-6- (pyridin-2-ylmethoxy)-7- (thiophen-3-yl)-1, 2,4-triazolo [4,3b]pyridazine; 3-phenyl-6- (2-pyridyl)methyloxy-7,8,9,10-tetrahydro- (7, 10-propano)-1,2,4triazolo [3,4-a] phthalazine; 3- (4-methyl) phenyl-6- (2-pyridyl) methyloxy-7,8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 3- (3-methoxy) phenyl-6- (2-pyridyl) methyloxy-7,8,9,10-tetrahydro- (7,10 ethano)-1, 2,4-triazolo [3,4-a] phthalazine ; 3- (2-fluoro) phenyl-6- (2-pyridyl) methyloxy-7, 8,9,10-tetrahydro- (7, 10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 3- (3-pyridyl)-6- (2-pyridyl) methyloxy-7, 8,9,10-tetrahydro- (7,10-ethano) 1, 2,4-triazolo [3,4-a] phthalazine; 3-cyclopropyl-6- (2-pyridyl) methyloxy-7,8,9,10-tetrahydro- (7,10-ethano) 1, 2,4-triazolo [3,4-a] phthalazine; 6- [ (6-methyl)-2-pyridyl] methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 6- [ (3-methyl)-2-pyridyl] methyloxy-3-phenyl-7, 8,9,10-tetrahydro- (7,10 ethano)-1, 2,'-triazolo [3,4-a] phthalazine; 6- [ (4-methyl)-2-pyridyl] methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 6- [ (5-methyl)-2-pyridyl] methyloxy-3-phenyl-7, 8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 3-phenyl-6- (3-pyridyl) methyloxy-7,8,9,10-tetrahydro- (7,10-ethano)-1,2,4triazolo [3,4-a] phthalazine; 3-phenyl-6- (4-pyridyl) methyloxy-7,8,9,10-tetrahydro- (7,10-ethano)-1,2,4triazolo [3,4-a] phthalazine; 3-phenyl-6- [2- (l-methyl) imidazolyl] methyloxy-7,8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine ; 6- (3-cyanophenyl) methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10-ethano) 1, 2,4-triazolo [3,4-a] phthalazine; 6- [l- (3, 5-dimethyl) pyrazolyl] methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 6- [4- (2-methyl) thiazolyl] methyloxy-3-phenyl-7, 8,9,10-tetrahydro- (7,10ethano)-1,2,4-triazolo [3,4-a] phthalazine ; 3-phenyl-6- (2-quinoxalinyl) methyloxy-7,8,9,10-tetrahydro- (7,10-ethano) 1, 2,4-triazolo [3,4-a] phthalazine; 3-phenyl-6- (3-pyridazinyl) methyloxy-7,8,9,10-tetrahydro- (7,10-ethano) 1, 2,4-triazolo [3,4-a] phthalazine; 6- (l-benzylimidazol-2-yl) methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 3-phenyl-6- (isoquinolin-1-yl)methyloxy-7,8,9,10-tetrahydro- (7,10-ethano) 1, 2,4-triazolo [3,4-a] phthalazine; 6- (l-ethylimidazol-2-yl) methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 3-phenyl-6- (1-pyrazolyl) methyloxy-7,8,9,10-tetrahydro- (7, 10-ethano)-1,2,4triazolo [3,4-a] phthalazine; 3-phenyl-6- (N-pyrrolidinylcarbonyl) methyloxy-7,8,9,10-tetrahydro- (7,10- 1, 2, 4-triazolo [3,4-a] phthalazine; 6- [4- (3-methyl) pyridyl] methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10ethano)-1,2,4-triazolo [3,4-a] phthalazine; 3-phenyl-6- (2-quinolinyl) methyloxy-7,8,9,10-tetrahydro- (7,10-ethano) 1, 2,4-triazolo [3,4-a] phthalazine; 6- (2-imidazolyl)methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10-ethano) 1, 2,4-triazolo [3,4-a] phthalazine; 3-phenyl-6- (2-thiazolyl)methyloxy-7,8,9,10-tetrahydro-(7, 10-ethano)-1,2,4triazolo [3,4-a] phthalazine; 6- [2- (5-methyl) thiazolyl] methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10ethano)-1,2,4-triazolo [3,4-a] phthalazine; 6- [2- (4-methyl) thiazolyl]methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine ; 6- [2- (3, 5-dimethyl) pyridyl] methyloxy-3-phenyl-7, 8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 3-phenyl-6- (2-pyrazinyl) methyloxy-7,8,9,10-tetrahydro- (7, 10-ethano)-1,2,4triazolo [3,4-a] phthalazine ; 6- [2- (4, 6-dimethyl) pyridyl] methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10ethano)-1,2,4-triazolo [3,4-a] phthalazine ; 3-phenyl-6- (4-thiazolyl) methyloxy-7,8,9,10-tetrahydro- (7, 10-ethano)-1,2,4triazolo [3,4-a] phthalazine; 6- [2- (5, 6-dimethyl) pyridyl] methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10 ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 6- (4-methylimidazol-2-yl) methyloxy-3-phenyl-7, 8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 3-phenyl-6- (4-pyrimidinyl) methyloxy-7,8,9,10-tetrahydro- (7,10-ethano) 1, 2,4-triazolo [3,4-a] phthalazine; 6- [4- (2-ethyl) thiazolyl] methyloxy-3-phenyl-7, 8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 6- (6-chloropyridazin-3-yl) methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolor3, 4-a] phthalazine ; 6- (2-imidazolyl) methyloxy-3- (4-methylphenyl)-7, 8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 6- (4-hydroxymethylphenyl) methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 6- (4-hydroxybutyl) oxy-3-phenyl-7,8,9,10-tetrahydro- (7, 10-ethano)-1,2,4triazolo [3,4-a] phthalazine; 6- (4-hydroxymethylcyclohexyl) methyloxy-3-phenyl-7,8,9,10-tetrahydro (7,10-ethano)-1,2,4-triazolo [3,4-a] phthalazine; 6- (3-hydroxymethylphenyl) methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10ethano)-1,2,4-triazolo [3,4-a] phthalazine; 6- (1-methyl-1, 2,4-triazol-3-yl) methyloxy-3-phenyl-7,8,9,10-tetrahydro (7,10-ethano)-1,2,4-triazolo [3,4-a] phthalazine; 6- (2-methyl-1, 2,4-triazol-3-yl) methyloxy-3-phenyl-7,8,9,10-tetrahydro (7,10-ethano)-1,2,4-triazolo [3,4-a] phthalazine; 3-phenyl-6- (3-cyclopropylmethyloxy-2-pyridyl) methyloxy-7,8,9,10tetrahydro- (7, 10-ethano)-1, 2,4-triazolo [3,4-a] phthalazine ; 3-phenyl-6- (3-ethoxy-2-pyridyl) methyloxy-7,8,9,10-tetrahydro- (7,10ethano)-1,2,4-triazolo [3,4-a] phthalazine; 6-(6-methylpyridin-2-yl)methyloxy-3-phenyl-1, 2,4-triazolo [3,4a] phthalazine ; 6- (l-methyl-lH-1, 2,4-triazol-3-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo [4,3b]pyridazine; 6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo [4,3b] pyridazine ; 3,7-diphenyl-6-(2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3b] pyridazine ; 6- (2-methyl-2H-tetrazol-5-ylmethoxy)-3, 7-diphenyl-1, 2,4-triazolo [4, 3-b]pyridazine; 3,7-diphenyl-6- (2-propyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3b] pyridazine ; 3,7-diphenyl-6- (l-propyl-1H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3b] pyridazine ; 6- (l-methyl-lH-imidazol-4-ylmethoxy)-3, 7-diphenyl-1, 2,4-triazolo [4,3b]pyridazine; 6- (3-methyl-3H-imidazol-4-ylmethoxy)-3, 7-diphenyl-1, 2,4-triazolo [4,3b] pyridazine ; 6- (4-methyl-4H-1, 2,4-triazol-3-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo [4,3b] pyridazine ; 6- (5-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo [4,3b]pyridazine; 6- (3-methyl-3H-1, 2,3-triazol-4-ylmethoxy)-3, 7-diphenyl-1,2,4-triazolo [4,3b]pyridazine; 3- (4-methoxyphenyl)-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-7-phenyl- 1, 2,4-triazolo [4,3-b] pyridazine; 6- (3-methylpyridin-2-ylmethoxy)-3-phenyl-7- (piperidin-1-yl)-1, 2,4triazolo [4,3-b] pyridazine; 7- (morpholin-4-yl)-3-phenyl-6-(pyridin-2-ylmethoxy)-1,2,4-triazolo [4,3- b]pyridazine; 3-phenyl-7- (pyridin-3-yl)-6- (pyridin-2-ylmethoxy)-1, 2,4-triazolo [4,3b] pyridazine ; 8-methyl-6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3,7-diphenyl-1,2,4triazolo [4,3-b] pyridazine; 6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-7- (morpholin-4-yl)-3-phenyl 1, 2,4-triazolo [4,3-b] pyridazine; 6-(2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-7- (morpholin-4-yl)-3-phenyl1,2,4-triazolo [4,3-b] pyridazine; 7-cyclohexyl-6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 7-cyclohexyl-6- (l-methyl-lH-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine ; 7-cyclopentyl-6- (2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 8-methyl-6-(1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3,7-diphenyl-1,2,4triazolo [4,3-b] pyridazine; 7-cyclobutyl-6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine ; 7-tert-butyl-6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 7-cyclobutyl-6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 7-ethyl-6-(2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 7-tert-butyl-6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 7-ethyl-6- (1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4, 3-b] pyridazine ; 7-methyl-6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 7- (l-methylcyclobutyl)-6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3phenyl-1, 2,4-triazolo [4,3-b] pyridazine; 7-methyl-6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine ; 7-cyclobutyl-3-phenyl-6-(2H-1, 2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3b] pyridazine; 7-cyclopentyl-6- (pyridin-2-ylmethoxy)-3-(thiophen-2-yl)-1,2,4-triazolo [4,3- b] pyridazine; 7-cyclopentyl-3- (2, 4-difluorophenyl)-6- (1-methyl-1H-1, 2,4-triazol-3ylmethoxy)-1, 2,4-triazolo [4,3-b] pyridazine; 7-cyclopentyl-6-(1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3- (thiophen-2-yl) 1, 2,4-triazolo [4,3-b] pyridazin ; 7-cyclopentyl-6-(2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3- (thiophen-2-yl) 1, 2,4-triazolo [4,3-b] pyridazine; 7-cyclopentyl-6- (2-methyl-2H-1, 2, 4-triazol-3-ylmethoxy)-3-(pyridin-4-yl)- 1,2,4-triazolo [4,3-b] pyridazine; 7-cyclopentyl-3- (2-fluorophenyl)-6- (l-methyl-1H-1, 2,4-triazol-3ylmethoxy)-1, 2,4-triazolo [4,3-b] pyridazine; 7-cyclopentyl-3- (2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3- ylmethoxy)-1, 2,4-triazolo [4,3-b] pyridazine; 7-cyclopentyl-3- (2-fluorophenyl)-6-(pyridin-2-ylmethoxy)-1,2,4-triazolo [4,3- b] pyridazine ; 7-cyclopentyl-3- (2, 4-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3- ylmethoxy)-1,2,4-triazolo [4,3-b] pyridazine ; 7-cyclopentyl-3-phenyl-6- (pyridin-2-ylmethoxy)-1,2,4-triazolo [4,3- b] pyridazine ; 7-cyclopentyl-8-methyl-6-(2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3phenyl-1, 2,4-triazolo [4,3-b] pyridazine; 7-cyclopentyl-3-phenyl-6- (2H-1, 2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3b]pyridazine; 3- (4-methylphenyl)-7-phenyl-6- (pyridin-2-ylmethoxy)-1, 2,4-triazolo [4,3b] pyridazine ; 3- (4-methylphenyl)-6- (3-methylpyridin-2-ylmethoxy)-7-phenyl-1, 2,4triazolo [4,3-b] pyridazine; 6- (1-ethyl-lH-imidazol-2-ylmethoxy)-3- (4-methylphenyl)-7-phenyl-1, 2,4triazolo [4,3-b] pyridazine ; 3-phenyl-6- (pyridin-2-ylmethoxy)-7-(thiomorpholin-4-yl)-1,2,4-triazolo [4,3- b] pyridazine ; 6- [2- (4-methylthiazol-5-yl) ethoxy]-3,7-diphenyl-1,2,4-triazolo [4,3b]pyridazine; ()-7- (2-methylpyrrolidin-1-yl)-3-phenyl-6- (pyridin-2-ylmethoxy)-1, 2,4triazolo [4,3-b] pyridazine; 6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-7- (pyridin-4-yl)-1,2,4triazolo [4,3-b] pyridazine; 7-cyclopentyl-6- (1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 7-isopropyl-6- (l-methyl-lH-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 3-cyclopropyl-6-(1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-7-phenyl-1,2,4triazolo [4,3-b] pyridazine; 3- (2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-7-phenyl- 1, 2,4-triazolo [4, 3-b] pyridazine; 3-(2-fluorophenyl)-6-(1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-7-phenyl 1, 2,4-triazolo [4,3-b] pyridazine; 6- (1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-7-phenyl-3- (thiophen-2-yl) 1, 2,4-triazolo [4,3-b] pyridazine; 6- (1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-7-phenyl-3-(pyridin-3-yl)-1,2,4triazolo [4,3-b] pyridazine ; 6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-7-phenyl-3- (thiophen-2-yl) 1, 2,4-triazolo [4,3-b] pyridazine; 6- (2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-7-phenyl-3- (pyridin-3-yl)-1,2,4triazolo [4,3-b] pyridazine; 3- (furan-3-yl)-6- (1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-7-phenyl-1,2,4triazolo [4,3-b] pyridazine ; 6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-7-phenyl-3- (thiophen-2-yl)1,2,4-triazolo [4,3-b] pyridazine ; 6- (5-methyl-1, 2,4-oxadiazol-3-ylmethoxy)-3, 7-diphenyl-1,2,4-triazolo [4,3b]pyridazine; 7-phenyl-3- (thiophen-2-yl)-6- (2H-1, 2,4-triazol-3-ylmethoxy)-1,2,4triazolo [4,3-b] pyridazine; 3- (furan-2-yl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-7-phenyl-1,2,4- triazolo [4,3-b] pyridazine; 6- (l-methyl-lH-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-7- (thiophen-3-yl)1,2,4-triazolo [4,3-b] pyridazine; 6- (2-methyl-2H 1, 2,4-triazol-3-ylmethoxy)-7- (thiophen-3-yl)-1,2,4triazolo [4,3-b] pyridazine ; 3-phenyl-7- (thiophen-3-yl)-6-(2H-1,2,4-triazol-3-ylmethoxy)-1,2,4- triazolo [4,3-b] pyridazine ; 6- (2-methyl-2H-1, 2, 4-triazol-3-ylmethoxy)-3-phenyl-7- (thiophen-2-yl)- 1, 2,4-triazolo [4,3-b] pyridazine; 6- (l-methyl-lH-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-7- (thiophen-2-yl) 1, 2,4-triazolo [4,3-b] pyridazine ; 7- (furan-2-yl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4- triazolo [4,3-b] pyridazine; 7- (furan-2-yl)-6- (l-methyl-lH-1, 2, 4-triazol-3-ylmethoxy)-3-phenyl-1, 2,4triazolo[4,3-b] pyridazine; 6-(3-methyl-1, 2,4-oxadiazol-5-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo [4,3b] pyridazine ; 3- (4-fluorophenyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-7-phenyl- 1, 2,4-triazolo [4,3-b] pyridazine; 3,7-diphenyl-6- (2H-1,2,3-triazol-4-ylmethoxy)-1,2,4-triazolo[4,3b]pyridazine; 3,7-diphenyl-6-(pyrazin-2-ylmethoxy)-1,2,4-triazolo [4,3-b] pyridazine; 3-(4-methylphenyl)-6-(1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-7-phenyl 1, 2,4-triazolo [4,3-b] pyridazine; 6-(4-methylthiazol-2-ylmethoxy)-3,7-diphenyl-1, 2,4-triazolo [4,3b]pyridazine; 6-(5-methylthiazol-2-ylmethoxy)-3,7-diphenyl-1, 2,4-triazolo [4,3b]pyridazine; 3,7-diphenyl-6- (pyrimidin-4-ylmethoxy)-1,2,4-triazolo [4,3-b] pyridazine; 3,7-diphenyl-6-(pyridazin-3-ylmethoxy)-1,2,4-triazolo [4,3-b] pyridazine; 6-(1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-7-(morpholin-4-yl)-3-(thi ph^ n 2-yl)-1, 2,4-triazolo [4,3-b] pyridazine; 3, 7-diphenyl-6-(thiazol-4-ylmethoxy)-1, 2,4-triazolo [4,3-b] pyridazine; 6-(5-methylisoxazol-3-ylmethoxy)-3,7-diphenyl-1, 2,4-triazolo [4,3b] pyridazine ; 3- (3-fluorophenyl)-6-81-methyl-1H-1,2,4-triazol-3-ylmethoxy)-7- (morpholin- 4-yl)-1, 2,4-triazolo [4,3-b] pyridazine; 3,7-diphenyl-6-(pyrimidin-2-ylmethoxy)-1,2,4-triazolo [4,3-b] pyridazine; 6-(2-methyl-2H-1, 2,3-triazol-4-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo [4,3b]pyridazine; 7- (1-methylcyclobutyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3- phenyl-1,2,4-triazolo [4,3-b] pyridazine; 7-isopropyl-6-(2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine ; 7-tert-butyl-3- (2-fluorophenyl)-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)- 1, 2,4-triazolo [4,3-b] pyridazine; 7-cyclopentyl-3- (4-methoxyphenyl)-6-(2-methyl-2H-1,2,4-triazol-3- ylmethoxy)-1, 2,4-triazolo [4,3-b] pyridazine; 7- (1-methylcyclopentyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3- phenyl-1, 2,4-triazolo [4,3-b] pyridazine; 7- (l-methylcyclopentyl)-6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3phenyl-1, 2,4-triazolo [4,3-b] pyridazine; 7-cyclopentyl-3- (furan-2-yl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)- 1,2,4-triazolo [4,3-b] pyridazine; 7-cyclopentyl-3-(furan-2-yl)-6-(1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)1,2,4-triazolo [4,3-b] pyridazine; 3- (3, 7-diphenyl-1,2,4-triazolo [4,3-b] pyridazin-6-yloxymethyl)-1, 2,4-triazol1-ylacetonitrile; 7-(1-methylcyclopropyl)-6-(2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3phenyl-1, 2,4-triazolo [4,3-b] pyridazine; 7- (1-methylcyclopropyl)-6-(1-methyl-1H-1,2,4-triazol-3 yl ;) oxy)-3- phenyl-1, 2,4-triazolo [4,3-b] pyridazine; 3- (3-fluorophenyl)-6- (1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-7-phenyl1,2,4-triazolo [4,3-b] pyridazine; 7- (1-methylcyclopentyl)-6- (3-methylpyridin-2-ylmethoxy)-3-phenyl-1, 2,4triazolo [4,3-b] pyridazine; 6- (l-methyl-1H-1, 2,3-triazol-4-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo [4,3b] pyridazine ; 3- (5-methylthiophen-2-yl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-7- phenyl-1, 2,4-triazolo [4,3-b] pyridazine; 2- [3- (3, 7-diphenyl-1, 2,4-triazolo [4,3-b] pyridazin-6-yloxymethyl)-1,2,4 triazol-1-yl]-N, N-dimethylacetamide ; 3,7-diphenyl-6- [1-(pyridin-2-ylmethyl)-1H-1, 2,4-triazol-3-ylmethoxy]-1,2,4triazolo [4,3-b] pyridazine; 6-(1-benzyl-lH-1, 2,4-triazol-3-ylmethoxy)-3, 7-diphenyl-1,2,4-triazolo [4,3b] pyridazine ; 2- [5- (3, 7-diphenyl- 1, 2,4-triazolo [4,3-b] pyridazin-6-yloxmethyl)-1, 2,4 triazol-1-yl] acetamide ; N- [2- [3- (3, 7-diphenyl-1, 2,4-triazolo [4,3-b] pyridazin-6-yloxymethyl)-1, 2,4triazol-1-yl] ethyl]-N, N-dimethylamine; 3,7-diphenyl-6-(pyrimidin-5-ylmethoxy)-1,2,4-triazolo [4,3-b] pyridazine; 6- [1-(2-(morpholin-4-yl)-ethyl)-1H-1, 2,4-triazol-3-ylmethoxy]-3,7-diphenyl 1, 2,4-triazolo [4,3-b] pyridazine; 6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-7-(pyrrolidin-1-yl) 1, 2,4-triazolo [4,3-b] pyridazine; 7- (5-chlorothiophen-2-yl)-6- (2-methyl-2H-1, 2, 4-triazol-3-ylmethoxy)-3phenyl-1, 2,4-triazolo [4,3-b] pyridazine; 7- (5-chlorothiophen-2-yl)-6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3phenyl-1, 2,4-triazolo [4,3-b] pyridazine; 6- (lH-benzimidazol-2-ylmethoxy)-3- (2, 4-difluorophenyl)-7- (l methylcyclopentyl)-1, 2,4-triazolo [4,3-b] pyridazine; 3 (2-pyridyl) methyloxy-7,8,9,10-tetrahydro-1,2,4triazolo [3,4-a] phthalazine; 7-cyclobutyl-3-phenyl-6- (prop-2-ynyloxy)-1,2,4-triazolo [4,3-b] pyridazine ; (7-cyclobutyl-3-phenyl-1, 2,4-triazolo [4,3-b] pyridazin-6-yloxy) acetonitrile ; N- [4- (7-cyclobutyl-3-phenyl-1, 2,4-triazolo [4,3-b] pyridazin-6-yloxy) but-2ynyl]-N, N-dimethylamine; 2- [3- (3, 7-diphenyl-1, 2,4-triazolo [4,3-b] pyridazin-6-yloxymethyl)-1, 2,4 triazol-1-yl] ethylamine; 3,7-diphenyl-6- [l- (2- (pyrrolidin-1-yl) ethyl)-1H-1, 2, 4-triazol-3-ylmethoxy]1,2,4-triazolo [4,3-b] pyridazine; 6- [1- (l-methylpiperidin-4-yl)-lH-1, 2,4-triazol-3-ylmethoxy]-3,7-diphenyl 1, 2,4-triazolo [4,3-b] pyridazine; 3,7-diphenyl-6- [1- (2- (piperazin-1-yl) ethyl)-1H-1,2,4-triazol-3-ylmethoxy]1,2,4-triazolo [4,3-b] pyridazine; 7- (l-methylcyclopentyl)-6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3- (2,4difluorophenyl)-1, 2,4-triazolo [4,3-b] pyridazine; 7- (cyclobut-l-enyl)-6- (2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl 1, 2,4-triazolo [4,3-b] pyridazine; 7- (furan-3-yl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4- triazolo [4,3-b] pyridazine; N, N-diethyl-N-[6-(1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazin-7-yl] amine ; 7- (1-methylcyclopentyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3- (2,4- difluorophenyl)-1, 2,4-triazolo [4,3-b] pyridazine; 7- (1, 1-dimethylpropyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3- phenyl-1,2,4-triazolo [4,3-b] pyridazine; 6- (2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3- (4-fluorophenyl)-7- (thiophen3-yl)-1,2,4-triazolo [4,3-b] pyridazine; 6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3- (4-fluorophenyl)-7- (thiophen3-yl)-1,2,4-triazolo [4,3-b] pyridazine; 6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3- (2-fluorophenyl)-7- (thiophen3-yl)-1,2,4-triazolo [4, 3-b] pyridazine ; 3- (2-fluorophenyl)-7- (1-methylcyclobutyl)-6- (2-methyl-2H-1,2,4-triazol-3ylmethoxy)-1,2,4-triazolo [4,3-b] pyridazine; 3- (2-iluorophenyl)-7-(1-methylcyclobutyl)-6-(1-methyl-1H-1,2,4-triazol-3- ylmethoxy)-1, 2,4-triazolo [4,3-b] pyridazine; 6- (l-methyl- 1H-1, 2,4-triazol-3-ylmethoxy)-3- (2-fluorophenyl)-7- (thiophen 3-yl)-1, 2,4-triazolo [4,3-b] pyridazine; 8-methyl-7- (l-methylcyclobutyl)-6- (l-methyl-1H-1, 2,4-triazol-3 ylmethoxy)-3-phenyl-1, 2,4-triazolo [4,3-b] pyridazine; 8-methyl-7- (l-methylcyclobutyl)-6- (2-methyl-2H-1,2,4-triazol-3ylmethoxy)-3-phenyl-1,2,4-triazolo [4,3-b] pyridazine; 6- (1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-7- (pyrrolidin-1-yl)1,2,4-triazolo [4,3-b] pyridazine; 7-cyclobutyl-8-methyl-6-(2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl 1, 2,4-triazolo [4,3-b] pyridazine; 7-cyclobutyl-8-methyl-6-(1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl 1, 2,4-triazolo [4,3-b] pyridazine; 7- (1-methylcyclopentyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3- (2- fluorophenyl)-1, 2,4-triazolo [4,3-b] pyridazine; 7- (l-methylcyclopentyl)-6- (1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3- (2 fluorophenyl)-1, 2,4-triazolo [4,3-b] pyridazine; 7-cyclobutyl-6- [4- (2, 6-dimethylmorpholin-4-yl) but-2-ynyloxy]-3-phenyl- 1,2,4-triazolo [4,3-b] pyridazine; and pharmaceutically acceptable salts thereof and prodrugs thereof.

In another aspect, the present invention provides a method for the treatment and/or prevention of premenstrual syndrome, with substantially no sedation, which comprises administering to a patient in need of such treatment an effective amount of a compound which is a modulator of the benzodiazepine binding site of the human GABAA receptor, having a binding affinity (Ki) for the a2 and/or a3 and/or a4 subunit of the human GABAA receptor, mon especially for the a3 subunit, of 10 nM or less, which elicits at least a 30% potentiation of the GABA EC20 response in stably transfected recombinant cell lines expressing the a2 and/or a3 and/or a4 subunit of the human GABAA receptor, more especially the a3 subunit, and which elicits at most a 30% potentiation of the GABA EC20 response in stably transfected cell lines expressing the al subunit of the human GABAA receptor.

This aspect of the present invention also provides the use of a compound which is a modulator of the benzodiazepine binding site of the human GABAA receptor, having a binding affinity (Ki) for the a2 and/or a3 and/or a4 subunit of the human GABAA receptor, more especially for the a3 subunit, of 10 nM or less, which elicits at least a 30% potentiation of the GABA EC2o response in stably transfected recombinant cell lines expressing the a2 and/or a3 and/or a4 subunit of the human GABAA receptor, more especially the a3 subunit, and which elicits at most a 30% potentiation of the GABA EC20 response in stably transfected cell lines expressing the al subunit of the human GABAA receptor, for the manufacture of a medicament for the treatment and/or prevention of premenstrual syndrome with substantially no sedation.

In a preferred feature of this aspect of the present invention, there is provided the use of a compound which is a modulator of the benzodiazepine binding site of the human GABAA receptor, having a binding affinity (Ki) for the a4 subunit of the human GABAA receptor of 10 nM or less, which elicits at least a 30% potentiation of the GABA EC20 response in stably transfected recombinant cell lines expressing the a4 subunit of the human GABAA receptor and which elicits at most a 30% potentiation of the GABA EC2o response in stably transfected cell lines expressing the al subunit of the human GABAA receptor, for the manufacture of a medicament for the treatment and/or prevention of premenstrual syndrome with substantially no sedation.

In a more preferred feature of this aspect of the present invention, there is provided the use of a compound which is a modulator of the benzodiazepine binding site of the human GABAA receptor, which is capable of binding selectively to the a4py2 or a4p8 receptor subtype assembly, for the manufacture of a medicament for the treatment and/or prevention of premenstrual syndrome.

In this aspect of the invention, the binding affinity (Ki) of compounds for the a3 subunit of the human GABAA receptor is conveniently as measured in the assay described hereinbelow. The binding affinity (Ki) of compounds for the al, a2 and a4 subunits of the human GABAA receptor can conveniently be measured by analogous methods. The a2 and/or a3 and/or a4 subunit binding affinity (Ki) of compounds of use in this aspect of the invention is 10 nM or less, preferably 2 nM or less, and more preferably 1 nM or less.

In this aspect of the invention, the potentiation of the GABA EC20 response in stably transfected cell lines expressing the a2, a3, a4 and al subunits of the human GABAA receptor can conveniently be measured by procedures analogous to the protocol described in Wafford et al., Mol.

Pharmacol., 1996, 50,670-678. The procedure will suitably be carried out utilising cultures of stably transfected eukaryotic cells, typically of stably transfected mouse Ltk-fibroblast cells.

The compounds of use in this aspect of the invention will elicit at least a 30%, typically at least a 40%, preferably at least a 50%, and more preferably at least a 60%, potentiation of the GABA EC20 response in stably transfected recombinant cell lines expressing the a2 and/or a3 and/or a4 subunit of the human GABAA receptor, more especially the a3 subunit. Moreover, the compounds of use in this aspect of the invention will elicit at most a 30%, preferably at most a 20%, and more preferably at most a 10%, potentiation of the GABA EC2o response in stably transfected recombinant cell lines expressing the al subunit of the human GABAA receptor.

In order to elicit their behavioural effects, the compounds of use in this aspect of the invention will be brain-penetrant; in other words, these compounds will be capable of crossing the so-called"blood-brain barrier".

Preferably, the compounds of use in this aspect of the invention will be capable of exerting their beneficial therapeutic action following administration by the oral route.

A representative compound of use in this aspect of the invention is 7-cyclobutyl-6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine.

For therapeutic application, pharmaceutical compositions may be provided which comprise one or more compounds of use in this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e. g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e. g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of use in the present invention, or a pharmaceutically acceptable salt thereof.

When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Typical unit dosage forms contain from 1 to 100 mg for example 1,2,5,10,25,50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

Pharmaceutical compositions in liquid form may be adapted for administration orally or by injection and may include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

In the treatment of premenstrual syndrome, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day.

The compounds of formula I of use in the present invention, including the specific compounds disclosed above, may be prepared by the processes described in WO 98/04559.

The compounds of use in this invention potently inhibit the binding of [3H]-flumazenil to the benzodiazepine binding site of human GABAA receptors containing the a2 or a3 subunit stably expressed in Ltk-cells.

Reagents . Phosphate buffered saline (PBS).

* Assay buffer : 10 mM KHzP04, 100 mM KCl, pH 7.4 at room temperature.

* [3H]-Flumazenil (18 nM for alp3y2 cells; 18 nM for a2p3y2 cells; 10 nM for a3p3y2 cells) in assay buffer.

* Flunitrazepam 100 pM in assay buffer.

* Cells resuspended in assay buffer (1 tray to 10 ml).

Harvesting Cells Supernatant is removed from cells. PBS (approximately 20 ml) is added. The cells are scraped and placed in a 50 ml centrifuge tube. The procedure is repeated with a further 10 ml of PBS to ensure that most of the cells are removed. The cells are pelleted by centrifuging for 20 min at 3000 rpm in a benchtop centrifuge, and then frozen if desired. The pellets are resuspended in 10 ml of buffer per tray (25 cm x 25 cm) of cells.

Assay Can be carried out in deep 96-well plates or in tubes. Each tube contains: * 300 pl of assay buffer.

* 50 1 of [3EIl-flumazenil (final concentration for al 3y2 : 1.8 nM; for a2p3y2 : 1.8 nM; for a3p3y2 : 1.0 nM).

9 50 Ll of buffer or solvent carrier (e. g. 10% DMSO) if compounds are dissolved in 10% DMSO (total); test compound or flunitrazepam (to determine non-specific binding), 10 ils final concentration.

. 100 pu of cells.

Assays are incubated for 1 hour at 40 C, then filtered using either a Tomtec or Brandel cell harvester onto GF/B filters followed by 3 x 3 ml washes with ice cold assay buffer. Filters are dried and counted by liquid scintillation counting. Expected values for total binding are 3000-4000 dpm for total counts and less than 200 dpm for non-specific binding if using liquid scintillation counting, or 1500-2000 dpm for total counts and less than 200 dpm for non-specific binding if counting with meltilex solid scintillant. Binding parameters are determined by non-linear least squares regression analysis, from which the inhibition constant Ki can be calculated for each test compound.

The specific compounds listed above were tested in the above assay, and all were found to possess a Ki value for displacement of [3H]flumazenil from the a2 and/or a3 subunit of the human GABAA receptor of 100 nM or less.

Claims

CLAIMS:

1. The use, for the manufacture of a medicament for the treatment and/or prevention of premenstrual syndrome, of a compound of formula I, or a pharmaceutically acceptable salt thereof or a prodrug thereof :

wherein Y represents hydrogen or Ci. e alkyi ; and Z representsCl-6alkyl, C3-7cycloalkyl, C4-7cycloalkenyl, aryl, C3-7 heterocycloalkyl, heteroaryl or di (Cl. 6) alkylamino, any of which groups may be optionally substituted; or Y and Z are taken together with the two intervening carbon atoms to form a ring selected from C5 9 cycloalkenyl, C6 lo bicycloalkenyl, tetrahydropyridinyl, pyridinyl and phenyl, any of which rings may be optionally benzo-fused and/or substituted; RI represents C3-7 cycloalkyl, phenyl, furyl, thienyl or pyridinyl, any of which groups may be optionally substituted; and Rrepresentsrr (Ci.6) alkyl, hydroxy (Cl-6) alkyl, ~3-7 cycloalkyl (Cl. 6) alkyl, propargyl, C3. 7 heterocycloalkylcarbonyl (Ci-6) alkyl, aryl (Cl-6) alkyl or heteroaryl (Cl 6) alkyl, any of which groups may be optionally substituted.

2. The use as claimed in claim 1 wherein Y represents hydrogen.

3. The use as claimed in claim 1 or claim 2 wherein Z represents methyl, ethyl, isopropyl, tert-butyl, 1,1-dimethylpropyl, methylcyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, cyclobutenyl, phenyl, pyrrolidinyl, methyl-pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyridinyl, furyl, thienyl, chlorothienyl or diethylamino.

4. The use as claimed in any one of the preceding claims wherein RI represents cyclopropyl, phenyl, methylphenyl, fluorophenyl, difluorophenyl, methoxyphenyl, furyl, thienyl, methyl-thienyl or pyridinyl.

5. The use as claimed in any one of the preceding claims wherein R2 represents cyanomethyl, hydroxybutyl, cyclohexylmethyl, propargyl, pyrrolidinylcarbonylmethyl, benzyl, pyrazolylmethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, benzimidazolylmethyl, oxadiazolylmethyl, triazolylmethyl, tetrazolylmethyl, pyridinylmethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl or quinoxalinylmethyl, any of which groups may be optionally substituted by one or more substituents selected from methyl, ethyl, n-propyl, benzyl, pyridinylmethyl, chloro, chloromethyl, cyano, cyanomethyl, hydroxymethyl, ethoxy, cyclopropylmethoxy, dimethylaminomethyl, aminccthyl, dimethylaminoethyl, dimethylaminocarbonylmethyl, N-methylpiperidinyl, pyrrolidinylethyl, piperazinylethyl, morpholinylmethyl and dimethylmorpholinylmethyl.

6. The use as claimed in claim 1 of a compound represented by formula IIA, and pharmaceutically acceptable salts thereof and prodrugs thereof :

wherein Rl is as defined in claim 1; nis 1, 2,3 or 4; and R12 represents hydroxy; or Cs-7 cycloalkyl, C3 7 heterocycloalkylcarbonyl, aryl or heteroaryl, any of which groups may be optionally substituted.

7. The use as claimed in claim 1 of a compound represented by formula IIB, and pharmaceutically acceptable salts thereof and prodrugs thereof :

wherein Yl represents hydrogen or methyl; Zl represents Cl. 6 alkyl, C3 7 cycloalkyl, C4 7 cycloalkenyl, aryl, C3-7 heterocycloalkyl, heteroaryl or di (Cl 6) alkylamino, any of which groups may be optionally substituted; Rl is as defined in claim 1; m is 1 or 2 ; and R22 represents aryl or heteroaryl, either of which groups may be optionally substituted.

8. The use as claimed in claim 7 of a compound represented by formula IIC, and pharmaceutically acceptable salts thereof :

wherein Rl is as defined in claim 1; Q represents the residue of a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring; Rs represents hydrogen or methyl; and R6 represents hydrogen or methyl.

9. The use as claimed in claim 1 of a compound selected from: 3-phenyl-6- (2-pyridyl) methyloxy-7,8,9,10-tetrahydro- (7, 10-ethano)-1,2,4triazolo [3,4-a] phthalazine; 3,7-diphenyl-6-(2-pyridyl) methyloxy-1,2,4-triazolo [4,3-b] pyridazine; 3-phenyl-6- (2-pyridyl) methyloxy-7,8,9,10-tetrahydro-1,2,4-triazolo [3,4a]phthalazine; 7,8-dimethyl-3-phenyl-6- (2-pyridyl) methyloxy-1, 2,4-triazolo [4,3b]pyridazine; 7-methyl-3-phenyl-6- (2-pyridyl) methyloxy-1, 2,4-triazolo [4,3-b] pyridazine; 7-ethyl-3-phenyl-6- (2-pyridyl) methyloxy-1,2,4-triazolo [4,3-b] pyridazine; 7,8-benzo-3-phenyl-6- (2-pyridyl) methyloxy-7,8,9,10-tetrahydro-1,2,4triazolo [3,4-a] phthalazine; 8-methyl-3,7-diphenyl-6-(2-pyridyl) methyloxy-1,2,4-triazolo [4,3b] pyridazine ; 3-phenyl-6- (2-pyridyl)methyloxy-7,8,9,10-tetrahydro- (7,10-methano)-1,2,4triazolo [3,4-a] phthalazine; 3-phenyl-5- (pyridin-2-ylmethoxy)-1, 2,3a, 4,7-pentaazacyclopenta [a]naphthalene; 3-phenyl-5- (pyridin-2-ylmethoxy)-1, 2,3a, 4,8-pentaazacyclopenta [a] naphthalene ; 8-methyl-3-phenyl-6- (2-pyridyl)methyloxy-7,8,9,10-tetrahydro-1,2,4triazolo [3,4-a] phthalazine; 3-phenyl-6- (2-pyridyl) methyloxy- (7, 8-pentano)-1, 2,4-triazolo [4,3b]pyridazine; 8,8-dimethyl-3-phenyl-6- (2-pyridyl) methyloxy-7,8,9,10-tetrahydro-1,2,4triazolo [3,4-a] phthalazine; 3-phenyl-7- (piperidin-1-yl)-6- (pyridin-2-ylmethoxy)-1, 2,4-triazolo [4,3b] pyridazine ; 3-phenyl-7- (pyridin-4-yl)-6- (pyridin-2-ylmethoxy)-1, 2,4-triazolo [4,3b]pyridazine; 3-phenyl-5- (pyridin-2-ylmethoxy)-6, 7,8,9-tetrahydro-1,2,3a, 4,8-pentaazacyclopenta [a] naphthalene; 3-phenyl-5- (pyridin-2-ylmethoxy)-6, 7,8,9-tetrahydro-1,2,3a, 4,7-pentaazacyclopenta [a] naphthalene; 7-methyl-3-phenyl-5- (pyridin-2-ylmethoxy)-6, 7,8,9-tetrahydro-1,2,3a, 4,7pentaazacyclopenta [a] naphthalene ; 3-phenyl-6- (pyridin-2-ylmethoxy)-7-(thiophen-2-yl)-1,2,4-triazolo [4,3- b]pyridazine; 3-phenyl-6- (pyridin-2-ylmethoxy)-7-(thiophen-3-yl)-1,2,4-triazolo [4,3- b] pyridazine ; 3-phenyl-6- (2-pyridyl) methyloxy-7, 8,9,10-tetrahydro- (7, 10-propano)-1,2,4triazolo [3, 4-a] phthalazine ; 3- (4-methyl) phenyl-6- (2-pyridyl) methyloxy-7,8,9,10-tetrahydro- (7,10ethano)-1,2,4-triazolo [3,4-a] phthalazine; 3- (3-methoxy) phenyl-6- (2-pyridyl) methyloxy-7,8,9,10-tetrahydro- (7,10ethano)-1,2,4-triazolo [3,4-a] phthalazine; 3- (2-ffuoro) phenyl-6- (2-pyridyl) methyloxy-7,8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine ; 3- (3-pyridyl)-6- (2-pyridyl) methyloxy-7,8,9,10-tetrahydro- (7,10-ethano)1,2,4-triazolo [3,4-a] phthalazine; 3-cyclopropyl-6- (2-pyridyl)methyloxy-7,8,9,10-tetrahydro- (7,10-ethano)1,2,4-triazolo [3,4-a] phthalazine; 6- [ (6-methyl)-2-pyridyl]methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10ethano)-1,2,4-triazolo [3,4-a] phthalazine; 6- [ (3-methyl)-2-pyridyl] methyloxy-3-phenyl-7, 8,9,10-tetrahydro- (7,10ethano)-1,2,4-triazolo [3,4-a] phthalazine; 6- [ (4-methyl)-2-pyridyl] methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10 ethano)-1, 2,4-triazolo [3,4-alphthalazine; 6- [ (5-methyl)-2-pyridyl] methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10 ethano)-1, 2, 4-triazolo [3,4-a] phthalazine; 3-phenyl-6- (3-pyridyl) methyloxy-7,8,9,10-tetrahydro- (7,10-ethano)-1,2,4triazolo [3,4-a] phthalazine; 3-phenyl-6- (4-pyridyl)methyloxy-7,8,9,10-tetrahydro- (7, 10-ethano)-1,2,4triazolo [3, 4-a] phthalazine ; 3-phenyl-6- [2- (l-methyl) imidazolyl] methyloxy-7,8,9,10-tetrahydro- (7,10ethano)-1,2,4-triazolo [3,4-a] phthalazine; 6- (3-cyanophenyl) methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10-ethano) 1, 2,4-triazolo [3,4-a] phthalazine; 6- [1- (3, 5-dimethyl) pyrazolyl] methyloxy-3-phenyl-7, 8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 6- [4- (2-methyl) thiazolyl] methyloxy-3-phenyl-7, 8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 3-phenyl-6- (2-quinoxalinyl) methyloxy-7,8,9,10-tetrahydro- (7,10-ethano)1,2,4-triazolo [3,4-a] phthalazine; 3-phenyl-6- (3-pyridazinyl) methyloxy-7,8,9,10-tetrahydro- (7,10-ethano)1,2,4-triazolo [3,4-a] phthalazine; 6- (1-benzylimidazol-2-yl) methyloxy-3-phenyl-7, 8,9,10-tetrahydro- (7,10ethano)-1,2,4-triazolo [3,4-a] phthalazine; 3-phenyl-6- (isoquinolin-1-yl)methyloxy-7,8,9,10-tetrahydro- (7,10-ethano) 1, 2,4-triazolo [3,4-a] phthalazine; 6- (l-ethylimidazol-2-yl) methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 3-phenyl-6- (l-pyrazolyl) methyloxy-7, 8,9,10-tetrahydro- (7,10-ethano)-1,2,4triazolo [3,4-a] phthalazine; 3-phenyl-6- (N-pyrrolidinylcarbonyl) methyloxy-7,8,9,10-tetrahydro- (7,10ethano)-1,2,4-triazolo [3,4-a] phthalazine; 6- [4- (3-methyl) pyridyl] methyloxy-3-phenyl-7, 8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 3-phenyl-6- (2-quinolinyl) methyloxy-7,8,9,10-tetrahydro- (7,10-ethano) 1, 2,4-triazolo [3,4-a] phthalazine; 6- (2-imidazolyl) methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10-ethano) 1, 2,4-triazolo [3,4-a] phthalazine; 3-phenyl-6- (2-thiazolyl) methyloxy-7,8,9,10-tetrahydro- (7, 10-ethano)-1,2,4triazolo [3,4-a] phthalazine; 6- [2- (5-methyl) thiazolyl] methyloxy-3-phenyl-7, 8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 6- [2- (4-methyl) thiazolyl] methyloxy-3-phenyl-7, 8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 6- [2- (3, 5-dimethyl) pyridyl] methyloxy-3-phenyl-7, 8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 3-phenyl-6- (2-pyrazinyl) methyloxy-7,8,9,10-tetrahydro- (7, 10-ethano)-1,2,4triazolo [3,4-a] phthalazine; 6- [2- (4, 6-dimethyl) pyridyl] methyloxy-3-phenyl-7, 8, 9, 10-tetrahydro- (7, 10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 3-phenyl-6- (4-thiazolyl) methyloxy-7,8,9,10-tetrahydro- (7, 10-ethano)-1,2,4triazolo [3,4-a] phthalazine; 6- [2- (5, 6-dimethyl) pyridyl] methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 6- (4-methylimidazol-2-yl) methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 3-phenyl-6- (4-pyrimidinyl) methyloxy-7,8,9,10-tetrahydro- (7,10-ethano) 1, 2,4-triazolo [3,4-a] phthalazine; 6- [4- (2-ethyl) thiazolyl] methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10ethano)-1,2,4-triazolo [3,4-a] phthalazine; 6- (6-chloropyridazin-3-yl) methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10 ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 6- (2-imidazolyl) methyloxy-3- (4-methylphenyl)-7, 8,9,10-tetrahydro- (7,10ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 6- (4-hydroxymethylphenyl) methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10ethano)-1,2,4-triazolo [3,4-a] phthalazine; 6- (4-hydroxybutyl)oxy-3-phenyl-7,8,9,10-tetrahydro- (7, 10-ethano)-1,2,4triazolo [3,4-a] phthalazine; 6- (4-hydroxymethylcyclohexyl) methyloxy-3-phenyl-7,8,9,10-tetrahydro (7,10-ethano)-1,2,4-triazolo [3,4-a] phthalazine; 6- (3-hydroxymethylphenyl) methyloxy-3-phenyl-7,8,9,10-tetrahydro- (7,10 ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 6- (1-methyl-1, 2,4-triazol-3-yl) methyloxy-3-phenyl-7, 8,9,10-tetrahydro (7,10-ethano)-1,2,4-triazolo [3,4-a] phthalazine; 6- (2-methyl-1, 2,4-triazol-3-yl) methyloxy-3-phenyl-7,8,9,10-tetrahydro (7,10-ethano)-1,2,4-triazolo [3,4-a] phthalazine; 3-phenyl-6- (3-cyclopropylmethyloxy-2-pyridyl) methyloxy-7,8,9,10 tetrahydro- (7, 10-ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 3-phenyl-6- (3-ethoxy-2-pyridyl) methyloxy-7,8,9,10-tetrahydro- (7,10 ethano)-1, 2,4-triazolo [3,4-a] phthalazine; 6- (6-methylpyridin-2-yl) methyloxy-3-phenyl-1, 2,4-triazolo [3,4a] phthalazine ; 6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo [4,3b] pyridazine ; 6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo [4,3b]pyridazine; 3,7-diphenyl-6- (2H-1, 2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3b] pyridazine ; 6- (2-methyl-2H-tetrazol-5-ylmethoxy)-3, 7-diphenyl-1, 2,4-triazolo [4,3-b]pyridazine ; 3,7-diphenyl-6- (2-propyl-2H-1,2,4-triazol-3-ylmethoxy)-l, 2,4-triazolo [4,3b]pyridazine; 3,7-diphenyl-6-(1-propyl-1H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3b] pyridazine ; 6- (l-methyl-lH-imidazol-4-ylmethoxy)-3, 7-diphenyl-1, 2,4-triazolo [4,3b] pyridazine ; 6- (3-methyl-3H-imidazol-4-ylmethoxy)-3, 7-diphenyl-1, 2,4-triazolo [4,3b]pyridazine; 6- (4-methyl-4H-1, 2,4-triazol-3-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo [4,3b]pyridazine; 6- (5-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3, 7-diphenyl-1,2,4-triazolo [4,3b] pyridazine ; 6- (3-methyl-3H-1, 2,3-triazol-4-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo [4,3b]pyridazine; 3- (4-methoxyphenyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-7-phenyl- 1,2,4-triazolo [4,3-b] pyridazine; 6-(3-methylpyridin-2-ylmethoxy)-3-phenyl-7-(piperidin-1-yl)-1,2,4triazolo [4,3-b] pyridazine; 7- (morpholin-4-yl)-3-phenyl-6-(pyridin-2-ylmethoxy)-1,2,4-triazolo [4,3- b]pyridazine; 3-phenyl-7- (pyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1,2,4-triazolo [4,3- b]pyridazine; 8-methyl-6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3,7-diphenyl-1,2,4triazolo [4,3-b] pyridazine; 6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-7- (morpholin-4-yl)-3-phenyl 1, 2,4-triazolo [4,3-b] pyridazine; 6-(2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-7- (morpholin-4-yl)-3-phenyl1,2,4-triazolo [4,3-b] pyridazine; 7-cyclohexyl-6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 7-cyclohexyl-6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 7-cyclopentyl-6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 8-methyl-6- (1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3, 7-diphenyl-1,2,4triazolo [4, 3-b] pyridazine; 7-cyclobutyl-6- (1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 7-tert-butyl-6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 7-cyclobutyl-6- (2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 7-ethyl-6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 7-tert-butyl-6-(1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 7-ethyl-6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 7-methyl-6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 7- (l-methylcyclobutyl)-6- (2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3phenyl-1,2,4-triazolo [4,3-b] pyridazine; 7-methyl-6- (1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 7-cyclobutyl-3-phenyl-6- (2H-1, 2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3b]pyridazine; 7-cyclopentyl-6- (pyridin-2-ylmethoxy)-3-(thiophen-2-yl)-1,2,4-triazolo [4,3- b]pyridazine; 7-cyclopentyl-3- (2, 4-difluorophenyl)-6- (l-methyl-1H-1,2,4-triazol-3ylmethoxy)-1,2,4-triazolo [4,3-b] pyridazine; 7-cyclopentyl-6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3- (thiophen-2-yl)1,2,4-triazolo [4,3-b] pyridazine; 7-cyclopentyl-6- (2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3- (thiophen-2-yl) 1, 2,4-triazolo [4,3-b] pyridazine; 7-cyclopentyl-6- (2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3- (pyridin-4-yl) 1, 2,4-triazolo [4,3-b] pyridazine; 7-cyclopentyl-3- (2-fluorophenyl)-6- (l-methyl-1H-1, 2,4-triazol-3ylmethoxy)-1,2,4-triazolo [4,3-b] pyridazine; 7-cyclopentyl-3- (2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3- ylmethoxy)-1, 2,4-triazolo [4, 3-b] pyridazine ; 7-cyclopentyl-3- (2-fluorophenyl)-6- (pyridin-2-ylmethoxy)-1, 2,4-triazolo [4,3b] pyridazine ; 7-cyclopentyl-3- (2, 4-difluorophenyl)-6- (2-methyl-2H-1, 2,4-triazol-3ylmethoxy)-1, 2,4-triazolo [4,3-b] pyridazine; 7-cyclopentyl-3-phenyl-6- (pyridin-2-ylmethoxy)-1, 2,4-triazolo [4,3b]pyridazine; 7-cyclopentyl-8-methyl-6-(2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3 phenyl-1, 2, 4-triazolo [4,3-b] pyridazine; 7-cyclopentyl-3-phenyl-6-(2H-1, 2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3b]pyridazine; 3- (4-methylphenyl)-7-phenyl-6- (pyridin-2-ylmethoxy)-1, 2,4-triazolo [4,3b]pyridazine; 3-(4-methylphenyl)-6-(3-methylpyridin-2-ylmethoxy)-7-phenyl-1, 2,4triazolo [4,3-b] pyridazine; 6- (l-ethyl-lH-imidazol-2-ylmethoxy)-3- (4-methylphenyl)-7-phenyl-1, 2,4triazolo [4,3-b] pyridazine ; 3-phenyl-6- (pyridin-2-ylmethoxy)-7- (thiomorpholin-4-yl)-1, 2,4-triazolo [4,3b] pyridazine ; 6- [2- (4-methylthiazol-5-yl) ethoxy]-3,7-diphenyl-l, 2,4-triazolo [4,3b]pyridazine; ()-7- (2-methylpyrrolidin-1-yl)-3-phenyl-6- (pyridin-2-ylmethoxy)-1, 2,4triazolo [4,3-b] pyridazine; 6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-7-(pyridin-4-yl)-1,2,4triazolo [4,3-b] pyridazine ; 7-cyclopentyl-6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 7-isopropyl-6-(1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 3-cyclopropyl-6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-7-phenyl-1,2,4triazolo [4,3-b] pyridazine; 3- (2-ffuorophenyl)-6- {2-methyl-2H 1, 2,4-triazol-3-ylmethoxy)-7-phenyl 1, 2,4-triazolo [4,3-b] pyridazine; 3- (2-fluorophenyl)-6- (l-methyl-lH-1, 2,4-triazol-3-ylmethoxy)-7-phenyl 1, 2,4-triazolo [4,3-b] pyridazine; 6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-7-phenyl-3-(thiophen-2-yl)1,2,4-triazolo [4,3-b] pyridazine; 6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-7-phenyl-3- (pyridin-3-yl)-1,2,4triazolo [4,3-b] pyridazine; 6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-7-phenyl-3-(thiophen-2-yl) 1, 2,4-triazolo [4,3-b] pyridazine; 6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-7-phenyl-3-(pyridin-3-yl)-1,2,4triazolo [4,3-b] pyridazine; 3- (furan-3-yl)-6- (1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-7-phenyl-1,2,4triazolo [4,3-b] pyridazine; 6- (1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-7-phenyl-3- (thiophen-2-yl)1,2,4-triazolo [4,3-b] pyridazine; 6- (5-methyl-1, 2,4-oxadiazol-3-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo [4,3b] pyridazine ; 7-phenyl-3- (thiophen-2-yl)-6-(2H-1,2,4-triazol-3-ylmethoxy)-1,2,4- triazolo [4,3-b] pyridazine; 3- (furan-2-yl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-7-phenyl-1,2,4- triazolo [4,3-b] pyridazine; 6-(1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-7- (thiophen-3-yl)1,2,4-triazolo [4,3-b] pyridazine; 6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-7-(thiophen-3-yl)-1,2,4triazolo [4,3-b] pyridazine; 3-phenyl-7- (thiophen-3-yl)-6-(2H-1, 2,4-triazol-3-ylmethoxy)-1,2,4triazolo [4,3-b] pyridazine; 6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-7- (thiophen-2-yl)1,2,4-triazolo [4,3-b] pyridazine; 6-(1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-7- (thiophen-2-yl) 1, 2,4-triazolo [4,3-b] pyridazine; 7- (furan-2-yl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4- triazolo [4,3-b] pyridazine ; 7-(furan-2-yl)-6-(1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine ; 6- (3-methyl-1, 2,4-oxadiazol-5-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo [4,3b]pyridazine; 3- (4-fluorophenyl)-6- (l-methyl-lH-1, 2,4-triazol-3-ylmethoxy)-7-phenyl 1, 2,4-triazolo [4,3-b] pyridazine; 3,7-diphenyl-6-(2H-1,2,3-triazol-4-ylmethoxy)-1,2,4-triazolo [4,3b]pyridazine; 3,7-diphenyl-6-(pyrazin-2-ylmethoxy)-1,2,4-triazolo [4,3-b] pyridazine; 3-(4-methylphenyl)-6-(1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-7-phenyl 1, 2,4-triazolo [4,3-b] pyridazine; 6- (4-methylthiazol-2-ylmethoxy)-3, 7-diphenyl-1, 2,4-triazolo [4,3b]pyridazine; 6- (5-methylthiazol-2-ylmethoxy)-3, 7-diphenyl-1, 2,4-triazolo [4,3b] pyridazine ; 3,7-diphenyl-6-(pyrimidin-4-ylmethoxy)-1,2,4-triazolo [4,3-b] pyridazine; 3,7-diphenyl-6-(pyridazin-3-ylmethoxy)-1,2,4-triazolo [4,3-b] pyridazine; 6-(1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-7- (morpholin-4-yl)-3- (thiophen 2-yl)-1, 2,4-triazolo [4,3-b] pyridazine; 3, 7-diphenyl-6-(thiazol-4-ylmethoxy)-1, 2,4-triazolo [4,3-b] pyridazine; 6- (5-methylisoxazol-3-ylmethoxy)-3, 7-diphenyl-1, 2,4-triazolo [4,3b] pyridazine, 3- (3-flurophenyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-7- (morpholin- 4-yl)-1, 2,4-triazolo [4,3-b] pyridazine; 3,7-diphenyl-6-(pyrimidin-2-ylmethoxy)-1,2,4-triazolo [4,3-b] pyridazine ; 6-(2-methyl-2H-1, 2,3-triazol-4-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo [4,3b]pyridazine; 7- (1-methylcyclobutyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3- phenyl-1, 2,4-triazolo [4,3-b] pyridazine; 7-isopropyl-6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; 7-tert-butyl-3- (2-fluorophenyl)-6- (1-methyl-1H-1, 2,4-triazol-3-ylmethoxy) 1, 2,4-triazolo [4,3-b] pyridazine; 7-cyclopentyl-3- (4-methoxyphenyl)-6- (2-methyl-2H-1, 2,4-triazol-3ylmethoxy)-1, 2,4-triazolo [4,3-b] pyridazine; 7- (1-methylcyclopentyl)-6- (l-methyl-lH-1, 2,4-triazol-3-ylmethoxy)-3phenyl-1, 2,4-triazolo [4,3-b] pyridazine; 7- (1-methylcyclopentyl)-6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3phenyl-1, 2,4-triazolo [4,3-b] pyridazine; 7-cyclopentyl-3- (furan-2-yl)-6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)1,2,4-triazolo [4,3-b] pyridazine; 7-cyclopentyl-3- (furan-2-yl)-6-(1-methyl-1H-1, 2,4-triazol-3-ylmethoxy) 1, 2,4-triazolo [4,3-b] pyridazine; 3- (3, 7-diphenyl-1, 2,4-triazolo [4,3-b] pyridazin-6-yloxymethyl)-1, 2,4-triazol 1-ylacetonitrile ; 7- (1-methylcyclopropyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3- phenyl-1, 2,4-triazolo [4,3-b] pyridazine; 7- (1-methylcyclopropyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3- phenyl-1, 2,4-triazolo [4,3-b] pyridazine; 3- (3-fluorophenyl)-6- (1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-7-phenyl 1, 2,4-triazolo [4,3-b] pyridazine; 7- (1-methylcyclopentyl)-6- (3-methylpyridin-2-ylmethoxy)-3-phenyl-1, 2,4triazolo [4,3-b] pyridazine; 6- (I-methyl-1H-1, 2,3-triazol-4-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo [4,3b] pyridazine ; 3- (5-methylthiophen-2-yl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-7- phenyl-1, 2,4-triazolo [4,3-b] pyridazine; 2- [3- (3, 7-diphenyl-1, 2,4-triazolo [4,3-b] pyridazin-6-yloxymethyl)-1, 2,4 triazol-l-yl]-N, N-dimethylacetamide ; 3,7-diphenyl-6- [l- (pyridin-2-ylmethyl)-1H-1,2,4-triazol-3-ylmethoxy]-1,2,4triazolo [4,3-b] pyridazine; 6- (1-benzyl-1H-1, 2,4-triazol-3-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo [4,3b] pyridazine ; 2-[5-(3,7-diphenyl-1, 2,4-triazolo [4,3-b] pyridazin-6-yloxymethyl)-1, 2,4 triazol-1-yl] acetamide ; N-[2-[3-(3,7-diphenyl-1, 2,4-triazolo [4,3-b] pyridazin-6-yloxymethyl)-1, 2,4 triazol-1-yl] ethyl]-N, N-dimethylamine ; 3,7-diphenyl-6- (pyrimidin-5-ylmethoxy)-1,2,4-triazolo [4,3-b] pyridazine; 6- [1-(2-(morpholin-4-yl)-ethyl)-1H-1, 2,4-triazol-3-ylmethoxy]-3, 7-diphenyl1,2,4-triazolo [4, 3-b] pyridazine ; 6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-7- (pyrrolidin-l-yl) 1, 2,4-triazolo [4,3-b] pyridazine; 7- (5-chlorothiophen-2-yl)-6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3phenyl-1, 2,4-triazolo [4,3-b] pyridazine; 7- (5-chlorothiophen-2-yl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3- phenyl-1,2,4-triazolo [4,3-b] pyridazine; 6- (lH-benzimidazol-2-ylmethoxy)-3- (2, 4-difluorophenyl)-7- (l methylcyclopentyl)-1, 2,4-triazolo [4,3-b] pyridazine; 3- (furan-3-yl)-6- (2-pyridyl) methyloxy-7, 8,9,10-tetrahydro-1,2,4triazolo [3,4-a] phthalazine; 7-cyclobutyl-3-phenyl-6- (prop-2-ynyloxy)-1, 2,4-triazolo [4,3-b] pyridazine; (7-cyclobutyl-3-phenyl-1, 2,4-triazolo [4,3-b] pyridazin-6-yloxy) acetonitrile; N- [4- (7-cyclobutyl-3-phenyl-1, 2,4-triazolo [4,3-b] pyriduLili-6-yloxy) but-2ynyl]-N, N-dimethylamine ; 2- [3-(3,7-diphenyl-1, 2,4-triazolo [4,3-b] pyridazin-6-yloxymethyl)-1, 2,4 triazol-1-yl] ethylamine ; 3,7-diphenyl-6- [1-(2-(pyrrolidin-1-yl) ethyl)-1H-1, 2,4-triazol-3-ylmethoxy]1,2,4-triazolo [4,3-b] pyridazine; 6- [1- (l-methylpiperidin-4-yl)-1H-1, 2, 4-triazol-3-ylmethoxy]-3, 7-diphenyl- 1, 2,4-triazolo [4,3-b] pyridazine; 3,7-diphenyl-6- [1- (2-(piperazin-1-yl) ethyl)-1H-1, 2,4-triazol-3-ylmethoxy] 1, 2,4-triazolo [4,3-b] pyridazine ; 7-(1-methylcyclopentyl)-6-(2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3- (2, 4difluorophenyl)-1, 2,4-triazolo [4,3-b] pyridazine; 7- (cyclobut-1-enyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl- 1,2,4-triazolo [4,3-b] pyridazine; 7- (furan-3-yl)-6- (l-methyl-1H 1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazine; N, N-diethyl-N- [6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4triazolo [4,3-b] pyridazin-7-yl] amine; 7- (l-methylcyclopentyl)-6- (l-methyl-lH-1, 2,4-triazol-3-ylmethoxy)-3- (2,4 difluorophenyl)-1, 2,4-triazolo [4,3-b] pyridazine; 7- (l, 1-dimethylpropyl)-6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3phenyl-1,2,4-triazolo [4,3-b] pyridazine; 6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3- (4-fluorophenyl)-7- (thiophen 3-yl)-1, 2,4-triazolo [4,3-b] pyridazine; 6- (1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3- (4-fluorophenyl)-7- (thiophen 3-yl)-1, 2,4-triazolo [4,3-b] pyridazine; 6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3- (2-fluorophenyl)-7- (thiophen3-yl)-1,2,4-triazolo [4, 3-b] pyridazine ; 3- (2-fluorophenyl)-7- (l-methylcyclobutyl)-6- (2-methyl-2H-1, 2,4-triazol-3ylmethoxy)-1,2,4-triazolo [4,3-b] pyridazine; 3- (2-fluorophenyl)-7-(1-methylcyclobutyl)-6-(1-methyl-1H-1, 2,4-triazol-3ylmethoxy)-1,2,4-triazolo [4,3-bpyridazine; 6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3- (2-fluorophenyl)-7- (thiophen 3-yl)-1, 2,4-triazolo [4,3-b] pyridazine; 8-methyl-7- (l-methylcyclobutyl)-6- (l-methyl-lH-1, 2,4-triazol-3 ylmethoxy)-3-phenyl-1, 2,4-triazolo [4,3-b] pyridazine; 8-methyl-7- (1-methylcyclobutyl)-6- (2-methyl-2H-1, 2,4-triazol-3 ylmethoxy)-3-phenyl-1, 2,4-triazolo [4,3-b] pyridazine; 6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-7- (pyrrolidin-1-yl) 1, 2,4-triazolo [4,3-b] pyridazine; 7-cyclobutyl-8-methyl-6- (2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl1,2,4-triazolo [4,3-b] pyridazine; 7-cyclobutyl-8-methyl-6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl1,2,4-triazolo [4,3-b] pyridazine; 7- (1-methylcyclopentyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3- (2- fluorophenyl)-1, 2,4-triazolo [4,3-b] pyridazine; 7- (l-methylcyclopentyl)-6- (l-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-3- (2 fluorophenyl)-1, 2,4-triazolo [4,3-b] pyridazine; 7-cyclobutyl-6- [4- (2, 6-dimethylmorpholin-4-yl) but-2-ynyloxy]-3-phenyl 1, 2,4-triazolo [4,3-b] pyridazine; and pharmaceutically acceptable salts thereof and prodrugs thereof.