A SUBSTITUTED TRIAZOLO-PYRIDAZINE DERIVATIVE, PHARMACEUTICAL COMPOSITIONS MADE THEREFROM

Abstract: 7- (1, 1- Dimethylethyl) -6 - (2-ethyl- 2H- 1, 2, 4- triazol- 3-ylmethoxy) -3- (2-fluorophenyl) - 1,2,4-triazolo[4,3-b]pyridazine, and pharmaceutically acceptable salts thereof, are selective ligands for GABAA receptors, in particular having high affinity for the alpha 2 and/or alpha 3 subunit thereof, and are accordingly of benefit in the treatment and/or prevention of disorders of the central nervous system, including anxiety and convulsions.

Description: A SUBSTITUTED TRIAZOLO-PYRIDAZINE DERIVATIVE, PHARMACEUTICAL COMPOSITIONS MADE THEREFROM The present invention relates to a substituted triazolo-pyridazine derivative and to its use in therapy. More particularly, this invention is concerned with a particular substituted l,2,4-triazolo[4,3-6]pyridazine derivative which is a GABAA receptor ligand and is 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) GABAA 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 GABAA receptor sub units were cloned the number of known members of the mammalian family has grown to include at least six α subunits, four β subunits, three γ subunits, one δ subunit, one ε 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 ligand- gated ion channel, insight into the extent of subtype diversity is still at an early stage. It has been indicated that an α subunit, a β subunit and a γ subunit constitute the minimum requirement for forming a fully functional GABA A receptor expressed by transiently transfecting cDNAs into cells. As indicated above, δ, ε and p subunits also exist, but are present only to a minor extent in GABAA 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 GABAA receptor exists in pentameric form. The selection of at least one α, one β and one γ 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, αlβ2γ2, α2β2/3γ2, α3βγ2/3, α2βγl, α5β3γ2/3, α6βγ2, α6βδ and α4βδ. Subtype assemblies containing an αl 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 α2 and α3 subunits respectively are thought to account for about 25% and 17% of GABAA receptors in the rat. Subtype assemblies containing an α5 subunit are expressed predominantly in the hippocampus and cortex and are thought to represent about 4% of GABAA receptors in the rat. 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 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 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 αl subunit in combination with a β subunit and γ2. 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 α2βγ2 and α3βγ2/3 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 α5-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 αlβγ2, α2βγ2 or α3βγ2 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 αl-selective 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 αl subunit. Accordingly, it is considered that GABAA receptor agonists which interact more favourably with the α2 and/or α3 subunit than with αl will be effective in the treatment of anxiety with a reduced propensity to cause sedation. Also, agents which are antagonists or inverse agonists at αl might be employed to reverse sedation or hypnosis caused by αl agonists. The compounds of the present invention, being selective ligands for GABAA 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 GABAA 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 GABAA receptors may also be effective as pre-medication prior to anaesthesia or minor procedures such as endoscopy, including gastric endoscopy. WO 98/04559 describes a class of substituted and 7,8-ring fused l,2,4-triazolo[4,3-6]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. The present invention provides a particular triazolo-pyridazine derivative, and pharmaceutically acceptable salts thereof, which possess desirable binding properties at various receptor subtypes. The compounds in accordance with the present invention have good affinity as ligands for the α2 and/or α3 subunit of the human GABAA receptor. The compounds of this invention interact more favourably with the α2 and/or α3 subunit than with the αl subunit. Indeed, the compounds of the invention exhibit functional selectivity in terms of a selective efficacy for the α2 and/or α3 subunit relative to the αl subunit. The compounds of the present invention are GABAA receptor subtype ligands having a binding affinity (Ki) for the α2 and/or α3 subunit, as measured in the assay described hereinbelow, of less than 1 nM. Furthermore, the compounds in accordance with this invention exhibit functional selectivity in terms of a selective efficacy for the α2 and/or α3 subunit relative to the αl subunit. Moreover, the compounds according to the present invention possess interesting pharmacokinetic properties, notably in terms of improved oral bioavailability. The present invention provides 7-(l,l-dιmethylethyl)-6-(2-ethyl-2H- l,2,4-trιazol-3-ylmethoxy)-3-(2-fluorophenyl)-l,2,4-trιazolo[4,3- 6]pyπdazme of formula I: ω or a pharmaceutically acceptable salt thereof. The compounds in accordance with the present invention are encompassed within the generic scope of WO 98/04559. There is, however, no specific disclosure therein of the compound of formula I as depicted above, or pharmaceutically acceptable salts thereof. For use in medicine, the salts of the compound of formula I above will be pharmaceutically acceptable salts Other salts may, however, be useful in the preparation of the compound of formula I or of its pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compound of formula I include acid addition salts which may, for example, be formed by mixing a solution of the compound of formula I with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphomc acid, fumaπc acid, maleic acid, succmic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Also provided by the present invention is a method for the treatment and/or prevention of anxiety which comprises administering to a patient in need of such treatment an effective amount of the compound of formula I as depicted above or a pharmaceutically acceptable salt thereof. Further provided by the present invention is a method for the treatment and/or prevention of convulsions (e.g. in a patient suffering from epilepsy or a related disorder) which comprises administering to a patient in need of such treatment an effective amount of the compound of formula I as depicted above or a pharmaceutically acceptable salt thereof. The binding affinity (Ki) of the compounds according to the present invention for the α3 subunit of the human GABAA receptor is conveniently as measured in the assay described hereinbelow. The α3 subunit binding affinity (Ki) of the compounds of the invention is less than 1 nM. The compounds according to the present invention elicit a selective potentiation of the GABA EC20 response in stably transfected recombinant cell lines expressing the α3 subunit of the human GABAA receptor relative to the potentiation of the GABA EC20 response elicited in stably transfected recombinant cell lines expressing the αl subunit of the human GABAA receptor. The potentiation of the GABA EC20 response in stably transfected cell lines expressing the α3 and αl 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 according to the present invention exhibit anxiolytic activity, as demonstrated by a positive response in the elevated plus maze and conditioned suppression of drinking tests (cf. Dawson et al., Psychopharmacology , 1995, 121, 109-117). Moreover, the compounds of the invention are substantially non-sedating, as confirmed by an appropriate result obtained from the response sensitivity (chain-pulling) test (cf. Bayley et al, J. Psychopharmacol, 1996, 10, 206-213). The compounds according to the present invention may also exhibit anticonvulsant activity. This can be demonstrated by the ability to block pentylenetetrazole-mduced seizures in rats and mice, following a protocol analogous to that described by Bπstow et al. in J. Pharmacol. Exp. Ther , 1996, 279, 492-501. Since they elicit behavioural effects, the compounds of the invention plainly are bram-penetrant; in other words, these compounds are capable of crossing the so-called "blood-bram barrier". Advantageously, the compounds of the invention are capable of exerting their beneficial therapeutic action following administration by the oral route The invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier Preferably these compositions are m 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, mtranasal, sub ngual 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 tabletmg ingredients such as corn starch, lactose, sucrose, sorbitol, talc, steaπc 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 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. The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection 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 anxiety, 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 compound of formula I as depicted above may be prepared by a process which comprises reacting a compound of formula III with the compound of formula IV: (HI) αv) wherein L 1 represents a suitable leaving group. The leaving group L 1 is typically a halogen atom, especially chloro. The reaction between compounds III and IV is conveniently effected by stirring the reactants in a suitable solvent, in the presence of a base. Typically, the solvent is N,N-dimethylformamide, and the base is a strong base such a sodium hydride. Preferably, the solvent is dimethyl sulfoxide, and the base is cesium carbonate. More preferably, the solvent is 1- methyl-2-pyrrolidinone, and the base is sodium hydroxide, in which case the reaction is advantageously performed at a temperature in the region of 0°C. The intermediates of formula III above may be prepared by reacting a compound of formula V with a substantially equimolar amount of the hydrazine derivative of formula VI: (V) (VI) wherein L 1 is as defined above, and L 2 represents a suitable leaving group; followed, if necessary, by separation of the resulting mixture of isomers by conventional means. The leaving group L 2 is typically a halogen atom, especially chloro. In the intermediates of formula V, the leaving groups L 1 and L 2 may be the same or different, but are suitably the same, preferably both chloro. The reaction between compounds V and VI is conveniently effected by heating the reactants in the presence of a proton source such as triethylamine hydrochloride, typically at reflux in an inert solvent such as xylene or 1,4-dioxane. Alternatively, the intermediates of formula III above may be prepared by reacting a hydrazine derivative of formula VII with the aldehyde derivative of formula VIII: (VIII) (VII) wherein L 1 is as defined above; followed by cyclization of the intermediate Schiff s base thereby obtained. The reaction between compounds VII and VIII is conveniently effected under acidic conditions, for example in the presence of a mineral acid such as hydrochloric acid. Cyclization of the resulting Schiff s base intermediate may then conveniently be carried out by treatment with iron(III) chloride in a suitable solvent, e.g. an alcoholic solvent such as ethanol, at an elevated temperature, typically at a temperature in the region of 60-70°C. The intermediates of formula VII above may be prepared by reacting the appropriate compound of formula V as defined above with hydrazine hydrate, typically in isobutyl alcohol at an elevated temperature, e.g. a temperature in the region of 90°C, or in 1,4-dioxane at the reflux temperature of the solvent; followed, if necessary, by separation of the resulting mixture of isomers by conventional means. In an alternative approach, the intermediates of formula III above may be prepared by reacting the hydrazine derivative of formula VII as defined above with a compound of formula IX: (IX) wherein Q represents a reactive carboxylate moiety; followed by cyclization of the hydrazide derivative of formula X thereby obtained: (X) wherein L 1 is as defined above. Suitable values for the reactive carboxylate moiety Q include esters, for example Cι-4 alkyl esters; acid anhydrides, for example mixed anhydrides with Cι-4 alkanoic acids; acid halides, for example acid chlorides; and acylimidazoles. Suitably, Q represents an acid chloride moiety. The reaction between compounds VII and IX is conveniently effected under basic conditions, e.g. in the presence of triethylamine, suitably in an inert solvent such as diethyl ether, and typically at a temperature in the region of 0°C. Cyclization of the resulting compound of formula X may then conveniently be carried out by treatment with 1,2-dibromo-l, 1,2,2- tetrachloroethane and triphenylphosphine, in the presence of a base such as triethylamine, suitably in an inert solvent such as acetonitrile, and typically at a temperature in the region of 0°C. In a preferred method, the reaction between compounds VII and IX may be effected by mixing the reactants in a solvent such as l-methyl-2- pyrrolidinone at a temperature in the region of 0°C; cyclization of the compound of formula X thereby obtained may then be accomplished in situ by heating the reaction mixture at a temperature in the region of 130°C. The reaction between compound V and hydrazine hydrate or compound VI will, as indicated above, possibly give rise to a mixture of isomeric products depending upon whether the hydrazine nitrogen atom displaces the leaving group L 1 or L 2 . Thus, in addition to the required product of formula III or VII, the alternative isomer will possibly be obtained to some extent. For this reason it might be necessary to separate the resulting mixture of isomers by conventional methods such as chromatography. In another procedure, the compound of formula I as depicted above may be prepared by a process which comprises reacting the compound of formula XI (or its l,2,4-triazolo[4,3-b]pyridazin-6-one tautomer) with a compound of formula XII: (XI) (XII) wherein L 3 represents a suitable leaving group. The leaving group L 3 is suitably a halogen atom, typically chloro or bromo. The reaction between compounds XI and XII is conveniently effected by stirring the reactants in a suitable solvent, typically N,N- dimethylformamide, in the presence of a strong base such as sodium hydride. The intermediate of formula XI above may conveniently be prepared by reacting a compound of formula III as defined above with an alkali metal hydroxide, e.g. sodium hydroxide. The reaction is conveniently effected in an inert solvent such as aqueous 1,4-dioxane, ideally at the reflux temperature of the solvent. In a further procedure, the compound of formula I as depicted above may be prepared by a process which comprises reacting trimethylacetic acid with the compound of formula XIII: (XIII) in the presence of silver nitrate and ammonium persulphate. The reaction is conveniently carried out in a suitable solvent, for example in water or aqueous acetonitrile, optionally under acidic conditions, e.g. using trifluoroacetic acid or sulphuric acid, typically at an elevated temperature. The intermediate of formula XIII corresponds to the compound of formula I as depicted above wherein the tert-hutyl substituent at the 7-position is absent, and the intermediate XIII may therefore be prepared by methods analogous to those described above for preparing the compound of formula I. In a still further procedure, the compound of formula I as depicted above may be prepared by a process which comprises reacting a compound of formula XIV with a compound of formula XV: (XIV) (XV) wherein M represents -B(OH)2 or -Sn(Alk)3 in which Alk represents a Cι.(, alkyl group, typically n-butyl, and L 4 represents a suitable leaving group; in the presence of a transition metal catalyst. The leaving group L 4 is suitably a halogen atom, e.g. bromo. A suitable transition metal catalyst of use in the reaction between compounds XIV and XV comprises dichlorobis(triphenylphosphine)- palladium(II) or tetrakis(triphenylphosphine)palladium(0). The reaction between compounds XIV and XV is conveniently effected in an inert solvent such as N,N-dimethylformamide, typically at an elevated temperature. The intermediates of formula XIV may be prepared by reacting the compound of formula IV as defined above with a compound of formula XVI: (XVI) wherein L 1 and L 4 are as defined above; under conditions analogous to those described above for the reaction between compounds III and IV. The intermediate of formula IV above may be prepared by the procedures described in EP-A-0421210, or by methods analogous thereto. Suitable methods are described in the accompanying Examples. The intermediates of formula V above may be prepared by reacting trimethylacetic acid with a compound of formula XVII: (XVII) wherein L 1 and L 2 are as defined above; in the presence of silver nitrate and ammonium persulphate; under conditions analogous to those described above for the reaction between trimethylacetic acid and compound XIII. Where L 1 and L 2 are both chloro in compound XVII, the reaction is advantageously effected in the presence of trifluoroacetic acid. Where they are not commercially available, the starting materials of formula VI, VIII, IX, XII, XV, XVI and XVII may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art. During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. Four anhydrous polymorphs, two solvates and a dihydrate of 7-(l,l- dimethylethyl)-6-(2-ethyl-2H-l,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)- l,2,4-triazolo[4,3-fe]pyridazine have been synthesised and characterised. All the polymorphs and solvates revert to the most thermodynamically stable form, polymorph A (for formation and characterisation see Example 3), after stirring as a suspension in water. A dihydrate of polymorph A is stable, but only at elevated humidities. The following Examples illustrate the preparation of compounds according to the invention. The compounds in accordance with this invention potently inhibit the binding of [ H]-flumazenil to the benzodiazepine binding site of human GABAA receptors containing the α2 or α3 subunit stably expressed in Ltk ' cells. Reagents • Phosphate buffered saline (PBS). • Assay buffer: 10 mM KH2PO4, 100 M KC1, pH 7.4 at room temperature. • [ 3 H]-Flumazenil (18 nM for αlβ3γ2 cells; 18 nM for α2β3γ2 cells; 10 nM for α3β3γ2 cells) in assay buffer. • Flunitrazepam 100 μM 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 μl of assay buffer. • 50 μl of [ 3 H]-flumazenil (final concentration for αlβ3γ2: 1.8 nM; for α2β3γ2: 1.8 nM; for α3β3γ2: 1.0 nM). • 50 μl 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 μM final concentration. • 100 μl 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 K; can be calculated for each test compound. The compound of the accompanying Examples was tested in the above assay, and was found to possess a Ki value for displacement of [ 3 H]- flumazenil from the α2 and/or α3 subunit of the human GABAA receptor of less than 1 nM. EXAMPLE 1 7-(l.l-Dimethylethyl)-6-(2-ethyl-2H-1.2.4-triazol-3-ylmethoxy)-3-(2- fluorophenyl)-l,2,4-triazolo 4,3-b1pyridazine a) 3,6-Dichloro-4-(l,l-dimethylethyl)pyridazine Concentrated sulphuric acid (53.6 ml, 1.0 mol) was added carefully to a stirred suspension of 3,6-dichloropyridazine (50.0 g, 0.34 mol) in water (1.25 1). This mixture was then heated to 70°C (internal temperature) before the addition of trimethylacetic acid (47.5 ml, 0.41 mol). A solution of silver nitrate (11.4 g, 0.07 mol) in water (20 ml) was then added over approximately one minute. This caused the reaction mixture to become milky in appearance. A solution of ammonium persulphate (230 g, 1.0 mol) in water (0.63 1) was then added over 20-30 minutes. The internal temperature rose to approximately 85°C. During the addition the product formed as a sticky precipitate. Upon complete addition the reaction was stirred for an additional 10 minutes, then allowed to cool to room temperature. The mixture was then poured onto ice and basified with concentrated aqueous ammonia, with the addition of more ice as required to keep the temperature below 10°C. The aqueous was extracted with dichloromethane (3 x 300 ml). The combined extracts were dried (MgS0 4 ), filtered and evaporated to give 55.8 g of crude product as an oil. This was purified by silica gel chromatography using 0-15% ethyl acetate in hexane as eluent to give 37.31 g (53%) of the desired compound. Data for the title compound: Η NMR (360 MHz, d G -DMSO) δ 1.50 (9H, s), 7.48 (1H, s); MS (ES + ) m/e 205 [MH] + , 207 [MH] + . b) 6-Chloro-7-(l.l-dimethylethyl)-3-(2-fluorophenyl)-l,2.4-triazolor4.3- blpyridazine A mixture of 3,6-dichloro-4-(l,l-dimethylethyl)pyridazine (20 g, 0.097 mol), 2-fluorobenzhydrazide (22.6 g, 0.145 mol) and triethylamine hydrochloride (20 g, 0.0145 mol) in dioxan (1.2 1) was stirred and heated at reflux under a stream of nitrogen for 4 days. Upon cooling the volatiles were removed in vacuo and the residue was triturated with dichloromethane (200 ml), filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel eluting with 0%— »25% ethyl acetate/dichloromethane to give the title compound (12.95 g, 44%) as a white solid. Data for the title compound: *H NMR (360 MHz, CDCls) δ 1.57 (9H, s), 7.26-7.35 (2H, m), 7.53-7.60 (1H, m), 7.89-7.93 (1H, m), 8.17 (1H, s); MS (ES + ) m/e 305 [MH] + , 307 [MH] + . c) (2-Ethyl-2H-1.2.4-triazol-3-yl)methanol To a solution of 1,2,4-triazole (10 g, 0.145 mol) in DMF (150 ml) at room temperature was added sodium hydride (6.4 g of a 60% disp. in oil, 0.16 mol) in portions over 15 min. When the addition was complete, the reaction mixture was allowed to cool to room temperature, then cooled in an ice-bath and iodoethane (14 ml, 0.174 mol) added dropwise over 10 min. The reaction mixture was allowed to warm to room temperaure and after stirring for 3 h the solvents were removed under high vacuum to leave a residue which was partitioned between water (300 ml) and ethyl acetate (3 x 300 ml). The combined organic layers were washed with saturated brine and dried (MgS0 4 ), filtered and concentrated under vacuum to leave an oily residue which was purified by distillation (120°C @ -20 mmΗg) to give 1-ethyl- 1,2,4-triazole contaminated with -15% DMF (2.4 g). The crude product (2.4 g, 0.025 mol) was dissolved in dry TΗF (35 ml), cooled to -40°C and /i-butyllithium (16.2 ml of a 1.6 M solution in hexane, 0.026 mol) was added slowly over 20 min keeping the temperature constant. DMF (2.03 ml, 0.026 mol) was then added and after 15 min the reaction mixture was allowed to warm slowly to room temperature over 2 h. To the reaction mixture was added methanol (20 ml) followed by sodium borohydride (1 g, 0.026 mol) and the solution was allowed to stir for 14 h. The solvents were removed under vacuum and the residue was partitioned between brine (50 ml) and dichloromethane (6 x 50 ml). The combined organic layers were dried (MgS0 4 ), filtered and concentrated under vacuum to leave a residue which was purified by silica gel chromatography using 0-5% methanol in dichlorometane as eluent to give the title compound as an off-white solid (0.5 g, 3%). Data for the title compound: Η NMR (250 MHz, CDC1 3 ) δ 1.48 (3H, t, J = 7.3 Hz), 4.25 (2H, q, J = 7.3 Hz), 4.75 (2H, s), 5.14 (1H, br s), 7.78 (1H, s). d) 7-(l.l-Dimethylethyl)-6-(2-ethyl-2H-1.2.4-trιazol-3-ylmethoxy)-3-(2- fluorophenyl)-l,2,4-triazolo 4,3-b]pyridazine To a solution of (2-ethyl-2H-l,2,4-triazol-3-yl)methanol (0.094 g, 0.74 mmol) and 6-chloro-7-(l,l-dimethylethyl)-3-(2-fluorophenyl)-l,2,4- triazolo[4,3-6]pyridazine (0.15 g, 0.49 mmol) in DMF (10 ml) was added sodium hydride (0.024 g of a 60% dispersion in oil, 1.1 mol eq.) and the reaction mixture was stirred at room temperature for 30 minutes. After this time, the reaction mixture was diluted with water (80 ml) and the solid that precipitated was collected by filtration and washed several times with water in the sinter funnel. The solid was recrystallised from ethyl acetate hexane to give pure title compound (0.085 g, 44%). Data for the title compound: *H NMR (250 MHz, CDCI3) δ 1.40-1.47 (12H, m), 4.14 (2H, t, J = 7.3 Hz), 5.26 (2H, s), 7.26-7.38 (2H, m), 7.53-7.58 (1H, m), 7.86-7.90 (1H, m), 7.93 (1H, s), 7.99 (1H, s); MS (ES + ) m/e 396 [MH] + . Anal. Found C, 61.02; H, 5.45; N, 24.75%. C 2 oH 2 2FN 7 0 requires C, 60.75; H, 5.61; N, 24.79%. EXAMPLE 2 7-(l.l-Dimethylethyl)-6-(2-ethyl-2H-1.2.4-triazol-3-ylmethoxy)-3-(2- fluorophenyl)-l,2.4-triazolo 4,3-blpyridazine: Alternative Synthetic Route a) 3.6-Dichloro- 4- ( 1 , 1 -dimethylethvDp yridazine A mixture of dichloropyridazine (100 g, 0.67 mol), trimethylacetic acid (96 g, 0.94 mol) and water (800 ml) in a 10 1 flask with overhead stirring was warmed to 55°C resulting in a two-phase solution. A solution of AgNθ3 (11.4 g, 0.134 mol) in water (125 ml) was added in one portion resulting in an opaque solution. Trifluoroacetic acid (10.3 ml, 0.134 mol) was added in one portion. Ammonium persulfate (245 g, 1.07 mol) was dissolved in water (500 ml) and added dropwise to the suspension over 45- 60 min resulting in an exotherm (typically temperature increases to between 75-80°C and can be controlled by rate of persulfate addition). The temperature was maintained at 75°C for a further 1 h and then cooled to room temperature. The reaction mixture was extracted with isobutyl alcohol (1 1) and the aqueous layer discarded. The organic layer was washed with water (250 ml) and the aqueous cut discarded. HPLC assay yield is 134 g (97%). The isobutyl alcohol solution was used as is in the next step. b) 6-Chloro-5-(l.l-dimethylethyl)pyridazin-3-ylhydrazine Hydrazine hydrate (95 ml, 1.95 mol) was added to the isobutyl alcohol solution from step a in a 3 1 flask and heated at 90°C for 20 h. The reaction mixture was cooled to room temperature and the lower aqueous layer discarded. The reaction mixture was washed with water (450 ml) and the aqueous cut discarded. The reaction mixture was distilled under reduced pressure until the product started to crystallise and then 1- methyl-2-pyrrolidinone (NMP) (550 ml) was added. Distillation was continued to remove the last of the isobutyl alcohol. The solution was used as is in the next step. c) 6-Chloro-7-(l,l-dimethylethvI)-3-(2-fluorophenyl ) -l,2,4-triazolor4.3- 6]pyridazine 2-Fluorobenzoyl chloride (103 g, 0.65 mol) was added dropwise to the cooled (0°C) NMP solution from step b maintaining the internal temperature <5°C. After the addition the reaction mixture was heated at 130°C for 2 h. The reaction mixture was cooled to room temperature which resulted in the crystallisation of the product. Water (1.3 1) was added dropwise over 30 min. The slurry was cooled to 10°C and the solid isolated by filtration, then dried under reduced pressure to afford product (145 g, 71% yield from 3,6-dichloropyridazine). d) 1-Ethyl- 1,2,4-triazole 1,2,4-Triazole (100.0 g, 1.45 mol) in anhydrous THF (950 ml) was cooled to 0°C and l,8-diazabιcyclo[5.4.0]undec-7-ene (DBU) (220 g, 1.45 mol) was added in one portion. The reaction mixture was stirred for 30 min until complete dissolution was observed. Whilst maintaining the ice/water cooling bath, iodoethane (317 g, 2.03 mol) was added dropwise over a 15 min period resulting in an internal temperature rise to 30°C. The reaction was stirred at room temperature for 16 h, after which the DBU hydroiodide was removed by filtration. The filtrate solution was used as is in the next step. e) (2-Ethyl-2H-l,2,4-triazol-3-yl)methanol The stirred solution from the preceding step was cooled to -75°C internal temperature in a solid Cθ2/acetone slurry bath. Ηexyllithium (458 ml of 33% solution in hexanes) was added dropwise over 25 min keeping the internal temperature below -55°C. The reaction mixture was aged for 30 min (back to -75°C) and then neat DMF (108 ml, 1.39 mol) was added dropwise over 10 min maintaining internal temperature below -60°C. The reaction mixture was aged at -70°C for 90 min before the cooling bath was removed and the reaction mixture allowed to warm to 0°C over 30 min. Industrial methylated spirits (340 ml) was added over 10 min. Sodium borohydride (26.3 g, 0.695 mol) was then added portionwise maintaining internal temperature below 6°C. After the addition the reaction mixture was allowed to warm to room temperature and stirred for 1 h at that temperature. The reaction was quenched by the careful addition of 2M H2SO4 (200 ml) and then stirred at room temperature for 20 h. The reaction mixture was concentrated to 675 ml and sodium sulfate (135 g) was added in one portion. The reaction mixture was warmed to 35°C and stirred for 15 min. The solution was extracted with warm (45°C) isobutyl alcohol (2 x 675 ml). The combined organic fractions were concentrated under reduced pressure 450 ml at which point the product crystallised. Heptane (1.125 1) was added and the slurry concentrated under reduced pressure to remove most of the isobutyl alcohol. Heptane was added to give a final slurry volume of 680 ml. After cooling to 0°C, filtration gave the title compound (137 g, 74% from 1,2,4-triazole). f) 7-(l,l-Dimethylethyl)-6-(2-ethyl-2H-1.2.4-trιazol-3-ylmethoxy)-3-(2- fluorophenvD- 1 , 2, 4-triazoIo [4, 3- b]p yridazine Method A 6-Chloro-7-(l,l-dimethylethyl)-3-(2-fluorophenyl)-l,2,4-triazolo[4,3- 6]pyridazine (255 g, 0.819 mol), (2-ethyl-2H-l,2,4-trιazol-3-yl)methanol (125 g, 0.983 mol) and cesium carbonate (640 g, 1.966 mol) were charged to a 10 1 flask equipped with an overhead stirrer. Dimethyl sulfoxide (2.5 1) was added in one portion and the reaction mixture stirred at room temperature for 20 h. The product had crystallised. The reaction mixture was maintained at <25°C whilst water (5 1) was added dropwise over 45 min to the stirred suspension. After cooling to 10°C, the product was isolated by filtration and the cake washed with water (1.75 1). Drying at 50° C in vacuo gave the title compound (317 g, 98%) as a white solid. Method B 6-Chloro-7-(l,l-dimethylethyl)-3-(2-fluorophenyl)-l,2,4-triazolo[4,3- b]pyridazine (10 g, 32.12 mmol) and (2-ethyl-2H-l,2,4-triazol-3- yl)methanol (5.01 g, 38.55 mmol) were charged to a 500 ml flask equipped with an overhead stirrer. NMP (100 ml) was added in one portion and the reaction mixture stirred until complete dissolution was achieved. The reaction mixture was cooled to 0°C and 48% w/w sodium hydroxide solution (4.02 g, 46 mmol) was added in one portion. After stirring for 1 h at 0°C, the product had crystallised. Water (100 ml) was added dropwise over 15 min and the slurry aged for 30 min. The product was isolated by filtration and the cake washed with water (100 ml). Drying at 50°C in vacuo gave the title compound (12.50 g, 98%) as a white solid. EXAMPLE 3 Formation and Characterisation of Polymorphs and Solvates of 7-(l,l- dimethylethyl)-6-(2-ethyl-2H-l,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)- l,2,4-triazolor4,3-έ>lpyridazine 7-(l,l-Dimethylethyl)-6-(2-ethyl-2H-l,2,4-triazol-3-ylmethoxy)-3-(2- fluorophenyl)-l,2,4-triazolo[4,3-6]pyridazine (hereinafter referred to as Compound I) was re crystallised from a selection of organic solvents and the resultant solids were dried in vacuo overnight at 60°C unless otherwise stated. Each batch was then characterised by optical microscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and X-ray powder diffraction (XRPD). Four distinct anhydrous polymorphs, a hydrate and two solvates have been characterised, as summarised in Table 1. Table 1: Polymorphs of Compound I Polymorph A Polymorph A consists of irregular or elongated rectangular birefringent crystals. It shows one major endotherm by DSC at ca. 186°C due to melting. In the case of some of the samples prepared this melt displays several events happening within it, typified by shoulders on the melting endotherm. Polymorph A is anhydrous and displays no losses by TGA. It has a unique XRPD diffractogram, typified by two peaks at 20 « 7.3°. Polymorph B Polymorph B consists of irregular or elongated rectangular birefringent crystals. Polymorph B displays one major endotherm by DSC at ca. 181°C due to melting. It is anhydrous and displa3 s no weight loss by TGA. It has a unique XRPD diffractogram. Polymorph C Polymorph C consists of acicular, birefringent crystals. The DSC thermograms of polymorph C show an endotherm at ca. 170°C, an exotherm at ca. 173°C, a small endotherm at ca. 181°C, and an endotherm due to melting at ca. 186°C. No losses are observed by thermogravimetric analysis. Polymorph D Polymorph D consists of acicular birefringent crystals. The XRPD diffractogram of polymorph D is similar in pattern to that of polymorph C. However, significant differences are observed, notably additional peaks at 20 = 9.861, 15.113, 18.015 and 22.224. The DSC trace of polymorph D displays a very broad exotherm at ca. 108°C, followed by an endotherm and exotherm at 170°C and 173°C, as for polymorph C. The major melting is observed at ca. 181°C, and several events are seen to occur within the melting endotherm, with minor melting at 186°C. No losses are observed by TGA. Methanol Solvate The DSC thermogram of the methanol solvate shows one endotherm at ca. 157°C due to loss of methanol, and one endotherm at 186°C due to melting. A gradual loss is observed by TGA up to ca. 150°C, at which point a step loss is observed, coincident with the endotherm observed by DSC. This step loss is in some instances composed of more than one event, and the amount varies among recrystallised samples and does not appear to correspond to a stoichiometric solvate. However, methanol vapour sorption studies on polymorph A show the presence of a distinct hemisolvate. The XRPD diffractogram of the solvate is unique. Ethanol Solvate The ethanol solvate is typified by its DSC thermogram which shows one endotherm at ca. 111°C due to loss of ethanol, and an endotherm at ca. 186°C due to melting. TGA shows the loss to be variable in different recrystallised samples, between ca. 4 and 6.5%, and does not correspond to a stoichiometric solvate. The XRPD diffractogram is unique. Hydrate of Polymorph A Figure 1 shows the adsorption/desorption isotherm of Compound I polymorph A at 25°C. These moisture vapour sorption studies show formation of a dihydrate above 80% relative humidity (RH) at 25°C. Hysteresis indicative of hydrate formation is seen to occur, with desorption occurring below ca. 60% RH. Figure 2 shows side-by-side XRPD diffractograms of anhydrous Compound I polymorph A and of the dihydrate of polymorph A. The XRPD diffractogram of the dihydrate, obtained on a wetted sample of polymorph A, demonstrates the distinct differences observed between the two forms. The major changes in diffraction can be seen to be loss of the peak at 20 = 11.2°, and the appearance of two major peaks at 2Θ = 11.9° and 12.3°. Conversion of Compound I Polymorphs to Polymorph A On slurrying in water all of the polymorphs and solvates decribed above convert to polymorph A over a period of 1-4 days, indicating that this is the most stable form at room temperature. This conversion is slow due to the low aqueous solubility of Compound I in relation to the large excess of solid compound slurried. X-Ray Powder Diffraction Data Figure 3 shows side-by-side XRPD diffractograms of anhydrous Compound I polymorphs A, B, C and D, of the methanol and ethanol solvates, and of the dihydrate of polymorph A. Numerical data associated therewith are presented below. Compound I Polymorph A: X-Ray Powder Diffraction Data \ngle d value Intensity sity Angle d value Intensity Intensity 20 A Count 2Θ A Count % 7243 1219523 2214 885 22885 388289 195 78 7559 1168660 613 245 23621 376351 307 123 8601 1027227 50 2 2367 375587 256 102 9694 911647 211 84 23767 374068 253 101 10703 825928 270 108 2412 368684 102 41 11027 801719 213 85 24518 362778 281 112 11239 786640 1464 585 25223 352803 162 65 12943 683420 2501 100 25275 352082 185 74 13441 658218 41 16 25478 349324 808 323 14497 610492 740 296 26088 341292 2178 871 15178 583251 1211 484 26686 333787 86 34 15376 575802 187 75 27093 328857 138 55 1542 574169 144 58 2774 321330 186 74 15854 558536 391 156 28056 317789 87 35 16081 550706 236 94 28607 311788 248 99 16134 548931 250 10 28703 310770 155 62 16419 539437 135 54 29135 306255 131 52 1676 528552 36 14 29267 304911 284 114 17165 516167 304 121 29353 304034 193 77 17199 515149 235 94 29787 299703 71 28 1724 513933 329 132 30357 294205 106 42 17355 510550 281 112 30954 288666 38 15 18556 477774 213 85 31436 284343 52 21 18829 470917 85 34 32618 274309 163 65 1927 460224 372 149 32773 273047 161 65 19499 454892 233 93 33254 269202 64 26 20203 439192 118 47 33897 264245 664 27 20635 430098 238 95 3414 262417 162 65 21584 411385 250 10 36522 245827 53 21 21689 409416 704 282 38532 233459 40 16 21867 406119 1621 648 38859 231564 78 31 2228 398692 154 62 39594 227434 47 19 Compound I Polymorph B: X-Ray Powder Diffraction Data Angle d value Intensity Intensity Angle d value Intensity Intensity 2Θ A Count % 2Θ A Count % 7379 1197023 651 492 20179 439705 119 9 10096 875424 481 364 209 424699 54 41 10821 816974 1323 100 21718 408884 1300 983 12482 708575 61 46 22285 398602 446 337 12739 694328 149 113 2296 387033 87 66 13036 678588 194 147 23304 381394 111 84 13475 656586 123 93 24018 370224 73 55 13828 639890 69 52 24459 363648 75 57 14815 597480 322 243 25081 354765 141 107 15078 587109 307 232 25837 344555 47 36 15584 568147 86 65 26204 339810 193 146 16082 550675 391 296 27078 329031 176 133 16979 521789 147 111 28449 313490 91 69 1702 520548 163 123 28889 308812 51 39 17287 512570 257 194 2984 299177 166 126 17616 503052 72 54 29922 298380 121 91 18125 489033 831 63 30227 295440 58 44 18161 488081 129 97 3194 279975 705 53 18192 487269 143 108 32837 272528 117 88 19022 466174 69 52 33295 268885 40 3 19542 453891 119 9 34407 260440 52 39 1968 450748 705 53 38876 231472 27 2 Compound I Polymorph C: X-Ray Powder Diffraction Data Angle d value Intensity Intensity Angle d value Intensity Intensity 20 A Count % 20 A Count % 7254 1217653 25 06 24647 360908 75 18 8023 1101169 798 193 24961 356448 398 96 9686 912421 4130 100 25341 351181 182 44 10489 842726 64 15 25549 348378 617 149 10813 817559 107 26 25981 342671 832 201 11277 783989 31 08 26794 332466 328 79 12193 725327 48 12 27782 320863 166 4 12961 682506 40 1 27985 318576 158 38 14357 616430 146 35 28257 315573 241 58 14497 610512 213 52 28788 309868 257 62 15225 581495 35 08 29242 305164 322 78 16007 553248 917 222 29301 304560 322 78 16545 535385 681 165 2956 301950 111 27 16951 522646 61 15 30544 292444 158 38 17672 501479 402 97 30942 288768 70 17 18337 483428 536 13 31839 280834 156 38 18578 477228 533 129 32457 275628 157 38 19396 457272 3486 844 32745 273271 369 89 20034 442851 57 14 34246 261626 150 36 20913 424430 193 47 34979 256310 76 18 21189 418959 1917 464 3542 253225 74 18 21523 412543 476 115 35753 250941 92 22 21876 405969 329 8 3671 244615 91 22 22654 392185 151 37 37036 242537 145 35 23207 382968 463 112 37549 239339 137 33 23238 382472 462 112 38915 231247 74 18 24316 365757 87 21 3941 228456 166 4 Compound I Polymorph D: X-Ray Powder Diffraction Data Single d value Intensity Intensity Angle d value Intensity Intensity 20 A Count % 20 A Count % 8024 1100971 501 334 22224 399690 414 276 9664 914458 1501 100 22654 392192 112 75 9861 896259 502 335 2322 382757 322 215 10497 842115 38 25 24052 369702 89 59 108 818489 229 153 24313 365791 295 197 11462 771362 40 27 24948 356619 272 181 12105 730563 216 144 253 351744 120 8 12951 683035 573 382 25543 348455 304 203 13312 664558 107 71 25977 342728 362 241 13817 640392 39 26 26036 341965 416 277 14478 611305 282 188 26789 332518 539 359 14823 597145 76 51 27479 324329 173 115 15113 585746 162 108 27754 321176 198 132 16 553485 396 264 28019 318199 170 113 16533 535742 774 516 28261 315525 314 209 16952 522613 72 48 28478 313170 144 96 17661 501784 509 339 28809 309646 205 137 18015 492003 479 319 29257 305012 176 117 18316 483994 545 363 2983 299276 178 119 1846 480255 512 341 30533 292545 157 105 18543 478110 498 332 30904 289114 96 64 19239 460966 196 131 31818 281015 131 87 1941 456957 775 516 32454 275655 119 79 20005 443493 158 105 32744 273282 182 121 20525 432367 82 55 33654 266094 94 63 20798 426748 386 257 3422 261823 95 63 20.882 425060 416 277 34526 259568 80 53 21188 418982 1344 895 34934 256632 99 66 21509 412810 1313 875 36998 242775 122 81 21853 406378 296 197 37545 239366 97 65 Compound I Methanol Solvate: X-Ray Powder Diffraction Data Angle d value Intensity Intensity Angle d value Intensity Intensity 20 A Count °0 20 A Count % 7357 1200677 9531 904 21153 419677 224 21 7608 1161023 260 25 22081 402236 10545 100 9616 919052 260 25 22588 393327 526 5 9755 905958 433 41 22825 389290 1150 109 10943 807881 1145 109 2314 384065 362 34 11274 784189 406 39 23742 374460 291 28 1236 715546 3517 334 24295 366064 440 42 12942 683511 472 45 24818 358463 3357 318 12981 681447 530 5 25434 349921 933 88 1442 613754 440 42 25967 342863 2020 192 1469 602552 3179 301 26 342428 2000 19 15196 582583 371 35 26761 332860 402 38 15651 565758 767 73 27151 328169 230 22 15913 556476 954 9 28642 311415 273 26 16507 536597 379 36 28951 308162 298 28 16539 535556 426 4 2956 301950 1793 17 16871 525102 1070 101 30365 294130 455 43 17226 514355 237 22 31319 285382 313 3 18.226 486354 372 35 32074 278834 173 16 18613 476331 112 11 32739 273323 134 13 19283 459933 291 28 3377 265210 344 33 19545 453827 195 18 35185 254858 129 12 19961 444452 1703 162 37166 241715 145 14 20675 429264 161 15 37694 238454 218 21 Compound I Ethanol Solvate: X-Ray Powder Diffraction Data Angle d value Intensity Intensity Angle d value Intensity Intensitj 20 A Count % 2Θ A Count % 7357 1200679 943 525 25061 355045 462 257 9541 926191 201 112 25341 351184 1795 100 9809 900980 208 116 25712 346196 290 162 10951 807238 1365 761 26055 341713 463 258 12.031 735019 1500 836 26235 339415 401 224 12499 707637 115 64 26599 334857 178 99 14158 625067 245 137 27054 329329 159 89 14707 601841 236 132 28355 314498 311 173 15719 563302 428 238 28491 313034 190 106 15899 556980 657 366 28667 311154 150 84 16304 543218 869 484 29029 307353 142 79 16895 524359 1076 60 29658 300975 207 115 18227 486334 500 279 29819 299388 604 337 19109 464073 148 82 30421 293596 132 74 1949 455085 1045 582 30609 291837 133 74 20998 422731 211 118 31383 284817 131 73 21177 419195 168 93 32048 279050 154 86 21982 404035 1230 686 32116 278480 146 81 22124 401471 1146 639 3378 265134 233 13 2282 389385 904 504 35079 255608 119 66 23017 386082 475 265 35267 254289 123 69 23321 381127 295 165 36866 243614 89 5 23459 378909 282 157 3784 237564 88 49 23961 371094 701 391 39182 229730 102 57 24159 368094 1504 838 39406 228477 104 58 Compound I Hydrate of Polymorph A: X-Ray Powder Diffraction Data Angle d value Intensity Intensity Angle d value Intensity Intensity 20 A Count 0 0 20 A Count 0 0 7261 1216414 447 100 18657 475222 484 108 91 970988 256 57 18779 472155 357 8 9626 918058 31 69 18859 470171 437 98 10796 818860 283 632 19276 460089 82 183 11858 745707 170 38 19504 454766 46 103 12218 723806 518 116 2022 438821 28 63 12261 721317 794 177 20655 429677 133 297 12302 718922 78 174 2168 409588 163 364 1297 682039 173 387 2186 406263 223 498 14462 611993 132 295 22316 398062 888 198 14518 609637 138 308 22537 394207 254 567 1519 582798 229 512 22579 393478 281 627 15402 574824 114 256 22901 388013 78 174 15866 558141 222 496 23673 375541 84 188 15906 556750 196 439 24507 362946 46 103 1608 550763 102 227 25469 349445 203 454 16127 549137 117 261 26087 341311 128 286 16178 547423 112 251 27754 321175 56 125 16221 546004 78 174 28613 311725 65 145 16357 541482 659 147 29291 304663 57 127 16418 539480 713 159 29935 298248 43 96 17189 515467 146 326 32747 273253 63 141 17345 510866 105 235 34176 262146 32 72 1857 477428 71 159 38848 231630 31 69

Claims: CLAIMS: 1. 7-(l,l-Dimethylethyl)-6-(2-ethyl-2H-l,2,4-triazol-3- ylmethoxy)-3-(2-fluorophenyl)-l,2,4-triazolo[4,3-6]pyridazine. 2. Polymorph A of 7-(l,l-dimethylethyl)-6-(2-ethyl-2H-l,2,4- triazol-3-ylmethoxy)-3-(2-fluorophenyl)-l,2,4-triazolo[4,3-b]pyridazine as characterised herein. 3. A pharmaceutical composition comprising 7-(l,l- dimethylethyl)-6-(2-ethyl-2H-l,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)- l,2,4-triazolo[4,3-6]pyridazine in association with a pharmaceutically acceptable carrier. 4. The use of 7-(l,l-dimethylethyl)-6-(2-ethyl-2H-l,2,4-triazol-3- ylmethoxy)-3-(2-fluorophenyl)-l,2,4-triazolo[4,3-6]pyridazine for the manufacture of a medicament for the treatment and/or prevention of anxiety. 5. A process for the preparation of 7-(l,l-dimethylethyl)-6-(2- ethyl-2H-l,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-l,2,4-triazolo[4,3- 6]pyridazine, which comprises: (A) reacting a compound of formula III with the compound of formula IV: (III) (IV) wherein L 1 represents a suitable leaving group; or (B) reacting the compound of formula XI (or its l,2,4-triazolo[4,3- 6]pyridazin-6-one tautomer) with a compound of formula XII: wherein L 3 represents a suitable leaving group; or (C) reacting trimethylacetic acid with the compound of formula XIII: (XIII) in the presence of silver nitrate and ammonium persulphate; or (D) reacting a compound of formula XIV with a compound of formula XV: (XIV) (XV) wherein M represents -B(OH)2 or -Sn(Alk)3 in which Alk represents a Ci-c alkyl group, and L 4 represents a suitable leaving group; in the presence of a transition metal catalyst. 6. A process as claimed in claim 5 wherein reaction (A) is carried out in l-methyl-2-pyrrolidinone, in the presence of sodium hydroxide, at a temperature in the region of 0°C. 7. A method for the treatment and/or prevention of anxiety which comprises administering to a patient in need of such treatment an effective amount of 7-(l,l-dimethylethyl)-6-(2-ethyl-2H-l,2,4-triazol-3- ylmethoxy)-3-(2-fluorophenyl)-l,2,4-triazolo[4,3-6]pyridazine.

Inventors: CARLING WILLIAM ROBERT, CASTRO PINEIRO JOSE LUIS, COWDEN CAMERON JOHN, DAVIES ANTONY JOHN, MADIN ANDREW, MCCABE JAMES FRANCIS, PEARCE GARETH EDWARD STEPHEN, STREET LESLIE JOSEPH, CARLING, WILLIAM, ROBERT, CASTRO PINEIRO, JOSE, LUIS, COWDEN, CAMERON, JOHN, DAVIES, ANTONY, JOHN, MADIN, ANDREW, MCCABE, JAMES, FRANCIS, PEARCE, GARETH, EDWARD, STEPHEN, STREET, LESLIE, JOSEPH
Applicants: CARLING WILLIAM ROBERT, CASTRO PINEIRO JOSE LUIS, COWDEN CAMERON JOHN, DAVIES ANTONY JOHN, MADIN ANDREW, MCCABE JAMES FRANCIS, MERCK SHARP & DOHME, PEARCE GARETH EDWARD STEPHEN, STREET LESLIE JOSEPH, CARLING, WILLIAM, ROBERT, CASTRO PINEIRO, JOSE, LUIS, COWDEN, CAMERON, JOHN, DAVIES, ANTONY, JOHN, MADIN, ANDREW, MCCABE, JAMES, FRANCIS, MERCK SHARP & DOHME LIMITED, PEARCE, GARETH, EDWARD, STEPHEN, STREET, LESLIE, JOSEPH
Application year: 1999
Main classification: C07D487
IPC codes: A61K31, A61P25, C07D487