TETRAHYDROINDAZOLE DERIVATIVES AS LIGANDS FOR GABA-A ALPHA 5 RECEPTORS

Abstract: A class of 4-oxo-tetrahydroindazole-3-carboxamides is disclosed. The compounds bind selectively to GABAA alpha -5 receptors, and are useful in therapy where cognition enhancement is required, for example in the treatment of Alzheimer's disease. The compounds are represented by formula (I) wherein R<1> and R<4> are independently chosen from hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C2-6 haloalkenyl and C2-6 haloalkynyl; R<2> is hydrogen or C1-6 alkyl; and Ar is phenyl, a 5-membered heterocyclic group containing 1,2,3 or 4 heteroatoms chosen from N, O and S, no more than one of which is O or S, or a 6-membered heterocyclic group containing one or two nitrogen atoms, each of which groups Ar is unsubstituted or substituted by from one to three groups independently chosen from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynylnoxy, C3-7 cycloalkoxy, C1-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, amino, C1-6 alkylamino, di(C1-6)alkylamino, hydroxy, hydroxy C1-6 alkyl, cyano, nitro, amino C1-6 alkyl, C1-6 alkylaminoC1-6 alkyl, di(C1-6 alkyl)aminoC1-6alkyl or C1-6alkoxycarbonylaminoC1-6alkyl.

Description: TETRAHYDROINDAZOLE DERIVATIVES AS LIGANDS FOR GABA-A ALPHA 5 RECEPTORS The present invention relates to tetrahydroindazole derivatives, pharmaceutical compositions comprising them and to their use in therapy. More particularly, this invention is concerned with substituted derivatives which are ligands for GABAA receptors, in particular for GABAA CC5 receptors and are therefore useful in therapy particularly where cognition enhancement is required. 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) GABAB 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 thirteen (six α subunits, three β subunits, three γ subunits and one δ subunit). It may be that further subunits remain to be discovered; however, none has been reported since 1993. Although knowledge of the diversity of the 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 GABAA receptor expressed by transiently transfecting cDNAs into cells. As indicated above, a δ subunit also exists, but is apparently m ~ r:r ~ιon in the native receptor. Studies of receptor size and visualisation by electron microscopy conclude that, like other members of the ligand-gated ion channel family, the native GABAA receptor exists in pentameric form. The selection of at least one α, one β and one γ subunit from a repertoire of thirteen allows for the possible existence of more than 10,000 pentameric subunit combinations. Moreover, this calculation overlooks the additional permutations that would be possible if the arrangement of subunits around the ion channel had no constraints (i.e. there could be 120 possible variants for a receptor composed of five different subunits). Receptor subtype assemblies which do exist include αlβ2γ2, α2β2/3γ2, α3βγ2/3, cώβγl, α5β3γ2/3, α6βγ2, α6βδ and α4βδ. Subtype assemblies containing an αl subunit are present in most areas of the brain and account for over 40% of GABAA receptors in the rat. Subtype assemblies containing α2 and α3 subunits respectively account for about 25% and 17% of GABAA receptors in the rat. Subtype assemblies containing an α5 subunit are primarily hippocampal and represent about 4% of receptors in the rat. A characteristic property of some GABAA receptors is the presence of a number of modulatory sites, of which the most explored is the benzodiazepine (BZ) binding site through which anxiolytic drugs such as diazepam and temazepam exert their effect. Before the cloning of the GABA A receptor gene family, the benzodiazepine binding site was historically subdivided into two subtypes, 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 β2 and γ2. This is the most abundant GABAA receptor subtype, representing 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 GAB A* receptor repertoire. Pharmacologically this combination appears to be equivalent to the BZ2 subtype as defined previously by radioligand binding, although the BZ2 subtype may also include certain 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. 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 bind more effectively to the α2 and/or α3 subunit than to 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. A number of dementing illnesses such as Alzheimer's disease are characterised by a progressive deterioration in cognition in the sufferer. It would clearly be desirable to enhance cognition in subjects desirous of such treatment, for example for subjects suffering from a dementing illness. It is believed this can be done utilising compounds which are ligands for the GABAA α5 receptor subtype. The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: (i) wherein: R 1 and R 4 are independently chosen from hydrogen, halogen, Ci-β alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C2-6 haloalkenyl and C2-6 haloalkynyl: R 2 is hydrogen or Ci-β alkyl; and Ar is phenyl, a 5-membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms chosen from N, O and S, no more than one of which is O or S, or a 6-membered heterocyclic group containing one or two nitrogen atoms, each of which groups Ar is unsubstituted or substituted by from one to three groups independently chosen from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, Ci-β alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C3-7 cycloalkoxy, Ci-β haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, amino, C1-6 alkylamino, di(Ci-6)alkylamino, hydroxy, hydroxy Ci-β alkyl, cyano, nitro, amino Ci-β alkyl, Ci-β alkylaminoCi-β alkyl, di(Ci-β alkyDaminoCi-βalkyl or Ci-6alkoxycarbonylaminoCι-6alkyl. R 1 is preferably hydrogen, halogen or Ci-β alkyl and is particularly hydrogen. R 2 is preferably hydrogen or methyl especially hydrogen. R 4 is preferably hydrogen. Ar is preferably phenyl or pyridine. When Ar is pyridine it may be 2-pyridine. Ar is preferably unsubstituted or substituted with one or two groups independently selected from methyl, fluoro, chloro, methoxy, ethoxy, aminomethyl, aminoethyl, hydroxy, methylaminoethyl, dimethylaminoethyl and t-butoxycarbonylaminomethyl, especially from methoxy, fluoro, aminoethyl, methylaminoethyl, dimethylaminoethyl and t-butoxycarbonylaminomethyl . Specific Examples of compounds according to the present invention are: 4-oxo-4,5,6,7-tetrahydro-lH-indazole-3-carboxylic acid phenylamide; 4-oxo-4,5,6,7-tetrahydro-lH-indazole-3-carboxylic acid-2,5- difluorophenylamide; 4-oxo-4,5,6,7-tetrahydro-lH-indazole-3-carboxylic acid pyridin-2- ylamide; 4-oxo-4,5,6,7-tetrahydro-lH-indazole-3-carboxylic acid 4- methoxyphenylamide; and 4-oxo-4,5,6,7-tetrahydro-lH-indazole-3-carboxylic acid 4-(2- aminoethyl)phenylamide; and the pharmaceutically acceptable salts thereof. Further specific examples of compounds according to the present invention are: [N-(4-(2-methylaminoethyl)-phenyl)] -(4-oxo-4,5, 6 ,7-tetrahydro)-lH- indazole-3-carboxamide; [4-[(4-oxo-4,5,6,7-tetrahydro-lH-indazole-3- carbonyl)amino]benzyl]carbamic acid-tert-butyl ester; (N-(4-aminomethyl)phenyl))-4-oxo-4,5,6,7-tetrahydro-lH-indazole-3- carboxamide; and [N-(4-(2-dimethylaminoethyl)phenyl)]-(4-oxo-4,5,6,7-tetrahydro)-lH- indazole-3-carboxamide; and the pharmaceutically acceptable salts thereof. There is also provided a pharmaceutical composition comprising a compound of formula I according to the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Preferably the compositions according to the present invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, by inhalation or insuiiidtion or administration by trans- dermal patches or by buccal cavity absorption wafers. 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 the present invention, or a non-toxic 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. 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, peanut oil or soybean oil, as well as elixirs and similar pharmaceutical vciiicies. 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. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner. Compositions of the present invention may also be presented for administration in the form of trans-dermal patches using conventional technology. The compositions may also be administered via the buccal cavity using, for example, absorption wafers. In disorders associated with GABAA α receptors, 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 present invention also provides a process for the preparation of a pharmaceutical composition which comprises adding a compound of formula (I) or a pharmaceutically acceptable salt thereof to a pharmaceutically acceptable excipient. The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human or animal body, in particular for the treatment or prevention of conditions for which the administration of a cognition enhancing agent is desirable, such as Alzheimer's disease. The compounds of formula (I) are of potential value in the treatment or prevention of a wide variety of clinical conditions which can be alleviated by a ligand selective for GABAA receptors containing the α5 subunit. In particular, they are desirably inverse agonists of the α5 subunit. Thus, for example, such a ligand can be used in a variety of disorders of the central nervous system. Such disorders include delirium, dementia and amnestic and other cognitive disorders. Examples of delirium are delirium due to substance intoxication or substance withdrawal, delirium due to multiple etiologies and delirium NOS (not otherwise specified). Examples of dementia are: dementia of the Alzheimer's type with early onset which can be uncomplicated or with delirium, delusions or depressed mood; dementia of the Alzheimer's type, with late onset, which can be uncomplicated or with delirium, delusions or depressed mood; vascular dementia which can be uncomplicated or with delirium, delusions or depressed mood; dementia due to HIV disease; dementia due to head trauma; dementia due to Parkinson's disease; dementia due to Huntington's disease; dementia due to Pick's disease; dementia due to Creutzfeld-Jakob disease; dementia which is substance- induced persisting or due to multiple etiologies; and dementia NOS. Examples of amnestic disorders are amnestic disorder due to a particular medical condition or which is substance-induced persisting or which is amnestic disorder NOS. In particular the compounds of formula (I) may be of use in conditions which require cognition enhancement. Where the compounds of the present invention are selective ligands for GABAA α2 or α3 subtype receptors they may be used 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; and 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. The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a condition requiring the administration of a ligand selective for GABAA receptors containing the α5 subunit, in particular for conditions requiring cognition enhancement such as Alzheimer's disease. There is also disclosed a method of treatment or prevention of a condition associated with GABAA receptors containing the α5 subunit which comprises administering to a subject suffering from or prone to such a condition a therapeutically or prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In particular there is disclosed the treatment and prevention of conditions which require the administration of a cognition enhancing agent, such as Alzheimer's disease. As used herein, the expression "Ci-βalkyl" includes methyl and ethyl groups, and straight-chained and branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl. Derived expressions such as "C2-βalkenyl" and "C2-6alkynyl" are to be construed in an analogous manner. The expression "C3-7cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups. Suitable 5- and 6-membered heteroaromatic rings include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, imidazolyl, tetrazol l, oxadiazolyl and thiadiazolyl groups. These rings also include thiazolyl and triazolyl groups. The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine, especially fluorine, chlorine and bromine. 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 according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to 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, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of 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. Where the compounds of formula (I) have at least one asymmetric centre, they may accordingly exist as enantiomers. Where the compounds of formula (I) possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention. The present invention also provides a process for producing a compound of formula I which comprises reacting a compound of formula II with a compound of formula III: (II) (III) wherein R 1 , R 2 , R 4 and Ar are as defined above. The reaction is generally carried out in a mixture of DMF/DCM and in the presence of a coupling agent such as l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride and dimethylaminopyridine. The reaction is generally carried out for about 36h. If necessary any reactive portions of the moiety Ar are protected with a protecting group such as tert-butyloxycarbonyl. Such protecting groups can be removed after reaction of the compounds of formulae II and III to yield a compound of formula I. The compound of formula II can be made by hydrolyzing a compound of formula IV: (IV) wherein R 1 , R 2 and R 4 are as defined above, with a base such as NaOH generally by heating at reflux for about 3h in a solvent such as EtOH. The compound of formula IV wherein R 2 is other than hydrogen can be made by reaction of a compound of formula IV where R 2 is hydrogen with a strong base such as Na H followed by alkylation for example with the appropriate alkyl iodide. The compound of formula IV is made by reacting a compound of formula V with a compound of formula VI: (V) (VI) The compound of formula V is made by reacting a compound of formula VII with a compound of formula VIII: (VII) (VIII) wherein R 1 and R 4 are as defined above and the compound of formula VII is generally pre-reacted with trimethylsilyl chloride. wherein R 2 is as defined above, generally in a solvent such as DMF and in the presence of a base such at Et 3 N at about 50°C for about 3 days. Compounds of formulae III, V, VI, VII and VIII are commercially available or can be made from commercially available compounds by methods known in the art. The following Examples illustrate pharmaceutical compositions according to the invention. COMPOSITION EXAMPLE 1A Tablets containing l-25mg of compound Amount mg Active Ingredients(s) 1.0 2.0 25.0 Microcrystalline cellulose 20.0 20.0 20.0 Modified food corn starch 20.0 20.0 20.0 Lactose 58.5 57.5 34.5 Magnesium Stearate 0.5 0.5 0.5 COMPOSITION EXAMPLE IB Tablets containing 26-100mg of compound Amount mg Active Ingredients(s) 26.0 50.0 100.0 Microcrystalline cellulose 80.0 80.0 80.0 Modified food corn starch 80.0 80.0 80.0 Lactose 213.5 189.5 139.5 Magnesium Stearate 0.5 0.5 0.5 The active ingredient(s), cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing l.Omg, 2.0mg, 25.0mg, 26.0mg, 50.0mg and lOOmg of the active compound per tablet. COMPOSITION EXAMPLE 2 Parenteral injection Amount Active Ingredient(s) 1 to lOOmg Citric Acid Monohydrate 0.75mg Sodium Phosphate 4.5mg Sodium Chloride 9mg Water for injection to 10ml The sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in a portion of the water. The active ingredient(s) is (are) dissolved or suspended in the solution and made up to volume. COMPOSITION EXAMPLE 3 Topical formulation Amount Active Ingredient(s) 1-lOg Emulsifying Wax 30g Liquid paraffin 20g White Soft Paraffin to lOOg The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient(s) is (are) is added and stirring continued until dispersed. The mixture is then cooled until solid. The following Examples illustrate the compounds of the present invention. The compounds in accordance with this invention potently inhibit the binding of [ 3 H]-flumazenil to the benzodiazepine binding site of human GABAA receptors containing the α5 subunit stably expressed in Ltk- cells. Reagents • Phosphate buffered saline (PBS). • Assay buffer: 10 mM KH 2 P0 4 , 100 mM 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; 10 nM for α5β3γ2 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; for α5β3γ2: 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 scintillate. 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 compounds of the accompanying Examples were tested in the above assay, and all were found to possess a Ki value for displacement of [ 3 H]Ro 15-1788 from the α5 subunit of the human GABAA receptor of 500 nM or less, preferably of 100 nM or less, and more particularly of 50 nM r less. More preferably the compounds of the present invention are inverse agonists at the GABAA α5 subtype whilst being substantially antagonists at the αi, α2 and α3 subtypes. Details of how the effects at the various subtypes can be measured are given in WO-A-9625948. Further, the present compounds preferably bind preferentially to the GABAA α5 subtype when compared with the αi, α2 and α3 subtypes. The preferential binding is preferably 5-fold, more preferably 10-fold and most preferably 20-fold. 5 EXAMPLE 1 4-Oxo-4,5, 6, 7-tetrahydro-lH-indazole-3-carboxylic acid phenylamide Step 1: 4-Oxo-4.5, 6 N-tetrahydro-lH-indazole-3-carboxyric acid ethyl ester 0 A solution of 2-ethyloxalylcyclohexan-l,3-dione (6g, 28mmol) (Synthesis, 1976, 722) in DMF (30mL) was treated with hydrazine hydrochloride (1.9g, 28mmol) and triethylamine (3.9mL, 28mmol) and heated at 50°C for 3 days. After evaporating to dryness the residue was 5 partitioned between water and DCM and the organic layer separated. The aqueous phase was re-extracted with DCM (x 2) and the combined organic layers dried (MgS0 ) and evaporated. The residue was purified by column chromatography on silica gel, using MeOH:DCM (2:98) as the eluent, to give an orange solid. The solid was trituated with ether to give the title 0 compound (640mg, 11%) as a yellow solid. Η NMR (250MHz, d 6 -DMSO) δ 1.28 (3H, t, J=7.1Hz), 2.00-2.10 (2H, m), 2.41 (2H, t, J=6.8Hz), 2.87 (2H, t, J=6.2Hz), 4.26 (2H, q, J=7.1Hz), 13.62 (1H, br s). MS, (CI) + 209 (M+H) + . Found: C, 57.39; H, 5.76; N, 13.37%. C 10 Hi2N 2 θ3 requires: C, 57.69; H, 5.81; N, 13.45%. ,5 Step 2: 4-Oxo-4.5.6.7-tetrahydro-lH-indazole-3-carboxylic acid A solution of the foregoing ethyl ester (450mg, 2.2mmol) in EtOH (3mL) and NaOH (4N, 15mL) was heated at reflux for 3h. The cooled solution 0 was acidified (cone. HCl), and the resultant solid isolated by filtration and washed with water. The solid was dried at 45°C in a vacuum oven to give the title compound (265mg, 67%) as a beige solid. Η NMR (360MHz, d 6 - DMSO) δ 2.08-2.15 (2H, m), 2.60-2.64 (2H, m), 2.84-2.98 (2H, m), 14.03 (IH, br s). MS. (CI) + 181 (M+H) + . Found: C, 52.33; H, 4.24; N, 15.00%. C 8 H 8 N2θ3. 0.2H O requires: C, 52.29; H, 4.61; N, 15.24%. Step 3: 4-Oxo-4,5,6,7-tetrahydro-lH-indazole-3-carboxylic acid phenylamide A suspension of the foregoing carboxylic acid (lOOmg, 0.55mmol) in DMF (2mL) and DCM (5mL) was treated with l-(3-dimethylaminopropyl)-3- ethyl carbodiimide hydrochloride (160mg, 0.83mmol), 4- dimethylaminopyridine (lOlmg, 0.83mmol) and aniline (77mg, 0.83mmol). The resultant solution was stirred for 36h then diluted with DCM (20mL) and washed with water (xl), IN HCl (x2), sat. NaHC0 3 (xl) and water (xl). The organic layer was dried (MgS0 ) and evaporated. The residue was purified by column chromatography on silica gel, eluting with DCM:MeOH (97:3) to give the title compound (90mg, 64%) as a colourless solid, mp 244°C (dec). *H NMR (500MHz, d 6 -DMSO) δ 2.09-2.14 (2H, m), 2.63-2.67 (2H, m), 2.80-2.95 (2H, m), 7.05-7.15 (IH, m) 7.30-7.40 (2H, m), 1.70-1.15 (2H, m) 12.24 (IH, br s), 13.68 and 14.20 (IH, 2 x br s) MS. (CI) + 256 (M+H)+. Found: C, 64.22; H, 5.00; N, 15.97%. C14H13N3O2.O.3H2O requires: C, 64.51; H, 5.26; N, 16. 12%. EXAMPLE 2 4-Oxo-4, 5, 6,7-tetrahydro-lH-indazole-3-carboxyric acid-2,5- difluorophenylamide The title compound was obtained using the procedure described in Example 1, Step 3 using 2,5-difluoroaniline. The amide (15mg, 19%) was isolated as a colourless solid. Η NMR (400 MHz, dβ-DMSO) δ 2.05-2.15 - lo - (2H, m), 2.60-2.68 (2H,m), 2.85-2.98 (2H, br s), 6.92-7.04 (IH, m), 7.30-7.40 (IH, m), 8.20-8.28 (IH, m), 12.43 (IH, br s), 13.83 and 14.35 (IH, 2 x br s). MS, (CI) + 292 (M+H) + . EXAMPLE 3 4-Oxo-4, 5, 6,7-tetrahydro-lH-indazole-3-carboxyric acid pyridin-2-ylamide The title compound was obtained using the procedure described in Example 1, Step 3 using 2-aminopyridine. The amide (33mg, 46%) was isolated as a cream solid, mp 250°C (dec). Η NMR (400MHz, d 6 -DMSO) δ 2.05-2.15 (2H, m), 2.62 (2H, t, J=6.2Hz), 2.85-2.95 (2H, br s). 7.10-7.20 (IH, m), 7.78-7.88 (IH, m), 8.24 (IH, d, J=8.3Hz), 8.35-8.41 (IH, m), 12.55 (IH, s), 13.78 and 14.26 (IH, 2 x br s). Found: C, 60.34; H, 4.34; N, 21.19%. C 13 Hι 2 N4θ2.0.05 CH 2 C1 2 requires: C, 60.17; H, 4.68; N, 21.51%. MS (CI) + 257 (M+H) + . EXAMPLE 4 4-Oxo-4, 5, 6,7-tetrahvdro-lH-indazole-3-carboxyric acid 4- methoxyphenyiamide The title compound was obtained using the procedure described in Example 1, Step 3 using -anisidine. The amide (15mg, 19%) was isolated as a beige solid. Η NMR (400MHz, d 6 -DMSO) δ 2.07-2.13 (2H, m), 2.63 (2H, t, J=6.3Hz), 2.82-2.94 (2H, m), 3.76 (3H, s), 6.95 (2H, d, J=8.9Hz), 7.63 (2H, dd, J=6.8 and 2.1Hz), 12.14 (IH, br s), 13.65 and 14.20 (IH, 2 x br s). MS, (CI) + : 286 (M+H) + . EXAMPLE 5 4-Oxo-4,5,6,7-tetrahydro-lH-indazole-3-carboxylic acid 4-(2- aminoethyDphenylamide Step 1: 2-(4-Aminophenyl)ethyl carbamic acid tert -butyl ester A solution of 2-(4-aminophenyl)ethylamine (lg, 7.3mmol) in DCM (20mL) at room temperature was treated with triethylamine (0.82g, 7.7mmol). After 10 min the solution was cooled to -5°C. Di-tert-butyldicarbonate (1.68g, 7.7mmol) was added portionwise over lOmin and stirred for 30min before warming to room temperature. NaHCOβ (sat. 2mL) was added followed by water (40mL). The organic layer was separated and aqueous re-extracted with DCM (x2). The combined organic layers were dried (K2CO3) and evaporated. The residue was purified by column chromatography on silica gel, eluting with EtOAchexane (1:4) to obtain the title compound (1.4g, 80%) as a yellow solid. Η NMR (360MHz, d 6 - DMSO) δ 1.37 (9H, s), 2.49-2.51 (2H, m), 2.99-3.06 (2H, m), 4.83 (2H, s), 6.49 (2H, d, J=8.3Hz), 6.77-6.80 (IH, m), 6.81 (2H, d, J=8.3Hz) MS (CI) + 237 (M+H) + . Step 2: r2-r4-(4-Oxo-4.5.6.7-tetrahvdro-lH-indazole-3- carbonvDaminolphenvn ethyl carbamic acid fert-butyl ester The title compound was obtained using the procedure described in Example 1, Step 3 using the foregoing amme. The residue was purified by column chromatography on silica gel, eluting with DCM:MeOH (97:3) to give the amide (lOOmg, 45%) and was isolated as a colourless, low-melting solid. H NMR (400MHz, d 6 -DMSO) 1.37 (9H, s), 2.07-2.14 (2H, m), 2.63 (2H, t, J=6.4Hz), 2.69 (2H, t, J=7.1Hz), 2.89 (2H, t, J=6.2Hz), 3.13-3.19 (2H, m), 6.52-6.65 (IH, m), 7.20 (2H, d, J=8.3Hz), 7.63 (2H, d, J=8.4Hz), 12.18 (lH, s), 14.00 (IH, br s). Step 3: 4-Oxo-4,5,6,7-tetrahydro-lH-indazole-3-carboxylic acid 4-(2- aminoethyPphenylamide A suspension of the foregoing carbamate (lOOmg, 0.25mmol) in DCM (5mL) was treated with trifluoroacetic acid (0.5mL) and stirred at room temperature for 5h. The mixture was evaporated and residue partitioned between water and MeOH/DCM (5:95) and neutralised with NaHCOs (sat.). The organic layer was separated and the aqueous phase re- extracted with MeOH/DCM (5:95) (x2). The combined organic layers were dried (K2CO3) and evaporated. The residue was purified using column chromatography on silica gel, eluting MeOH:DCM (10:90) followed by DCM:MeOH:NH 3 (80:20:1). The title compound (35mg, 47%) was isolated as a cream solid, mp 250°C (dec). Η NMR (360MHz, d 6 -DMSO) δ 2.06- 2.14 (2H, m), 2.63 (2H, t, J=6.7Hz), 2.68 (2H, t, J=6.9Hz), 2.84 (2H, t, J=7.6Hz), 2.89 (2H, t, J=6.4Hz), 7.24 (2H, d, J=8.4Hz), 7.67 (2H, d, J=8.5Hz), 12.39 (IH, s). MS, (CI) + 299 (M+H) + . EXAMPLE 6 [N-(4-(2-Methylaminoethyl)-phenyl)l-(4-oxo-4,5,6N-tetrahvdro)-lH- indazole-3-carboxamide Step 1: Methyl- [2-(4-nitropιιenyl)ethyll carbamic acid tβrt-butyl ester The title compound was obtained using the procedure described in Example 5, Step 1 using N-methyl-2-(4-nitrophenyl)ethylamine. The title compound (3g) was isolated as a yellow oil which was used without further purification. Η NMR (400MHz, CDCI3) δ 1.39 (9H, s), 2.83 (3H, s), 2.88-2.96 (2H, m), 3.48 (2H, t, J=6.5Hz), 7.30-7.40 (2H, m), 8.15 (2H, d, J=8.3Hz). A solution of the foregoing nitro derivative (3g), in EtOAc (20mL) and EtOH (20mL) was treated with a slurry of 10% Pd on C (200mg) in water (5mL). The mixture was shaken on parr apparatus at 50 psi H2 for 15 min. after which time no further H2 was consumed. The catalyst was removed by filtration and the solvents evaporated to give title compound (2.2g, 94%) as a pale orange oil. Η NMR (360MHz, CDCI3) δ 1.42 (9H, s), 2.68 (2H, t, J=7.2Hz), 2.80 (3H, s), 3.35 (2H, t, J=6.4Hz), 6.63 (2H, d, J=8.3Hz), 6.92-7.02 (2H, s). Step 3: Methyl-(2-{4-[(4-oxo-4,5,6J-tetrahvdro-lH-indazole-3-carbonyl)- aminolphenyllethyD-carbamic acid isobutyl ester A suspension of 4-oxo-4,5,6,7-tetrahydro-lH-indazole-3-carboxylic acid (200mg, l.lmmol) in isobutyl chloroformate (lOmL) was treated with Et 3 N (0.46mL, 3.3mmol) portionwise at room temperature. After 30 min. further Et 3 N (0.46mL, 3.3mmol) was added and the mixture stirred for 30 min. The mixture was evaporated and residue suspended in 1,2-DCE (15mL). The foregoing amine (0.37g, 1.7mmol) added and the solution was heated at reflux for 6h. The solvent was evaporated, the residue suspended in EtOH (1.5mL) and then treated with 4N NaOH (5mL). The mixture was heated at reflux for lh. Water (50mL) was added to the cooled mixture, the aqueous phase extracted with 10% MeOH/DCM (x3) and the combined organic layers dried (MgS0 4 ) and evaporated. The residue was purified by silica plug chromatography, using MeOH:DCM (6:94) as eluent, to give title compound (250mg, 54%) a cream solid. Η NMR (400MHz, CDCI3) δ 0.94 (6H, d, J=6.4), 1.88-1.98 (2H, m), 2.19-2.27 (2H, m), 2.7 (2H, t, J=6.1Hz), 2.77-2.92 (5H, m), 2.98 (2H, t, J=5.8Hz), 3.40-3.51 (2H, m), 3.85 (2H, d, J=6.44Hz), 7.18-7.26 (2H, m), 7.74 (2H, d, J=7.9Hz), 11.30 (IH, br, s), 12.26 (IH, s). MS, (CI) + 413 (M+H)+. Step 4: [ - ( 4- ( 2-Methylaπιinoethyl) p henyl ) 1 ( 4-oxo-4.5.6.7-tetrahvdro)-lH- indazole-3-carboxamide A solution of the foregoing carbamate (150mg, 0.36mmol) in 45% HBr in acetic acid solution (lOmL) was heated in a sealed tube at 85°C for 6h. After cooling the solution was diluted with water and basified with 4N NaOH. The organic solvent was evaporated and residue extracted with 10% MeOH/DCM (x4). The combined organic layers were washed with water, dried (MgS0 4 ) and concentrated to give a white solid. The solid was triturated with ether and isolated by filtration. Title compound (70mg, 58%) was isolated as a white solid. W NMR (360MHz, d 6 . DMSO) δ 2.05-2.15 (2H, m), 2.32 (3H, s), 2.64 (2H, t, J=5.9Hz), 2.67-2.78 (4H, m), 2.88 (2H, t, J=6.2Hz), 7.24 (2H, d, J=8.4Hz), 7.65 (2H, d, J=8.5Hz), 12.36 (IH, s). MS, (CI) + 313 (M+H) + . EXAMPLE 7 r4-r(4-Oxo-4,5,6,7-tetrahvdro-lH-indazole-3- carbonyDaminolbenzyllcarbamic acid-ferf-butyl ester Step 1: (4-Nitrobenzyl)carbamic acid-tert-butyl ester A solution of 4-nitrobenzylamine hydrochloride (5g, 0.026mol) in DCM (300mL) was treated with Et 3 N (4.0mL, 0.029mol) and stirred at room temperature for 15 min. A solution of di-tert-butyldicarbonate (5.95g, 0.027mol) in DCM (50mL) was then added and the solution stirred for 3h. After this time the mixture was filtered and the filtrate evaporated. The residue was treated with EtOAc, filtered and the filtrate washed with citric acid (10%, lOOmL). The organic layer was separated, dried (MgS0 4 ) and evaporated. The residue was treated with petrokEtOAc (2:1) and the resultant colourless solid (3.44g, 53%) collected by filtration. Step 2: (4-Aminobenzyl)carbarnic acid tert-butyl ester A solution of the foregoing nitro derivative (1.05g, 4.2mmol) in EtOH (lOOmL) was hydrogenated at 25 psi for 20 min. in the presence of 10% Pd on C (200mg). The catalyst was removed by filtration and the solvent evaporated in vacuo. The residue was treated with ether, the mixture filtered and the filtrate evaporated. The residue was chromatographed on silica gel, eluting with petrol:Et2θ (1:1) followed by petrohEtOAc (1:1). The title compound (452mg, 48%) was isolated as a colourless solid. Η NMR (360MHz, CDC1 3 ) δ 1.45 (9H, s), 3.55-3.69 (2H, m), 4.18 (2H, d, J=5.4Hz), 4.7 (2H, br, s), 6.64 (2H, d, J=8.4Hz), 7.07 (2H, d, J=8.2Hz). MS(ES + ) 223 (M+l). Step 3: [4-r(4-Oxo-4.5.6,7-tetrahvdro-lH-indazole-3- carbonyPaminol benzyl! carbamic acid-ferf-butyl ester The title compound was obtained using the procedure described in Example 1, Step 3 using the foregoing amine. The amide (130mg, 40%) was isolated as a cream solid. Η NMR (400MHz, CDCI3) δ 1.46 (9H, s), 2.18-2.27 (2H, m), 2.70 (2H, t, J=5.9Hz), 2.98 (2H, t, J=5.9Hz), 4.30 (2H, d, J=4.8Hz), 4.80-4.88 (IH, m), 7.30 (2H, d, J=8.1Hz), 7.78 (2H, d, J=8.0Hz), 11.25 (IH, br, s), 12.30 (IH, s). MS, (CI) + 385 (M+H) + . EXAMPLE 8 (N-(4-Aminomethyl)phenyl))-4-oxo-4,5,6,7-tetrahydro-lH-indazole-3- carboxamide The title compound was obtained using the procedure described in Example 5, Step 3 using [4-[(4-oxo-4,5,6,7-tetrahydro-lH-indazole-3- carbonyl)amino]benzyl]carbamic acid-te -butyl ester. The residue was triturated with 1:1 DCM/Et2θ to obtain title compound (35mg, 47%) as a white solid. Η NMR (360MHz, d 6 DMSO) δ 2.05-2.13 (2H, m), 2.64 (2H, t, J=6.7Hz), 2.88 (2H, t, J=6.2Hz), 3.73 (2H, s), 7.36 (2H, d, J=8.5Hz), 7.68 (2H, d, J=8.5Hz), 12.39 (IH, s). MS (CI + ) 285 (M+H) + . EXAMPLE 9 [N-(4-(2-Dimethylaminoethyl)phenyl)l-(4-oxo-4,5,6N-tetrahydro)-lH- indazole-3-carboxamide Stepl: 2-(4-Aminophenyl)N,N-dimethylacetamide A suspension of 4-aminophenylacetic acid (5g, 30mmol), l-(3- dimethyaminopropyl)-3 -ethyl carbodiimide hydrochloride (6.9g, 36mmol), and dimethylamine (6.5ml of a 5.6M solution in EtOH 36mmol) in 1,2, DCE was stirred at room temperature for 4h. Silica was added, the suspension evaporated and residue loaded onto silica plug column, eluting with DCM:MeOH/98:2). The title compound (2.6g, 45%) was as an orange solid. Η MNR (400MHz, CDC1 3 ) δ 2.94 (3H, s), δ 2.98 (3H, s), 3.60 (2H, s), 6.64 (2H, d, J=8.3Hz), 7.03 (2H, d, 8.2Hz). MS (CI) + 179 (M+H) + . Step 2: 4-(2-Dimethylaminoethylaniline A solution of the foregoing amide (lOOmg, 0.56mmol) in THF (lOmL) was treated with LiAlH 4 (1.68mL of a 1M solution in THF, 1.68mmol) and the resultant mixture heated at reflux for 16h. Water (0.05mL) was added followed by 4N NaOH (O.OδmL) then water (0.05mL). The suspension was filtered and solvents evaporated. The title compound (80mg) was isolated as a red oil. Η NMR (400MHz, CDC1 3 ) δ 2.31 (6H, s), 2.45-2.49 (2H, m), 2.6δ-2.69 (2H, m), 3.δ4 (2H, s), 6.62 (2H, d, J=8.2Hz), 6.99 (2H, d, J=8.2Hz). MS (CI) + 16δ (M+H) + . Step 3: [N-(4-(2-Dimethylaminoethyl)phenyl)l(4-oxo-4.5,6,7-tetrahydro- lH-indazole-3-carboxamide The title compound was obtained using the procedure described Example 1, Step 3, using the foregoing amine (84mg, O.δlmmol) but heating at reflux for lδh. Silica was added and the mixture was evaporated. The residue was loaded onto silica plug column and title compund eluted with DCM:MeOH:2δ%NH 3 OH (89:10:1) (6mg, 4%) as an orange solid. Η NMR (400MHz, CDCI3) δ 2.19-2.28 (2H, m), 2.32 (6H, s), 2.δ4-2.61 (2H, m), 2.69 (2H, t, J=6.7Hz), 2.77-2.82 (2H, m), 2.98 (2H, t, J=6.1Hz), 7.22 (2H, d, J=8.3Hz), 7.72 (2H, d, J=8.4Hz). MS (CI) + 327 (M+H) + .

Claims: CLAIMS 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: (I) wherein: R 1 and R 4 are independently chosen from hydrogen, halogen, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-β haloalkyl, C2-6 haloalkenyl and C2-6 10 haloalkynyl: R 2 is hydrogen or Ci-β alkyl; and Ar is phenyl, a 5-membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms chosen from N, O and S, no more than one of which is O or S, or a 6-membered heterocyclic group containing one or two nitrogen lδ atoms, each of which groups Ar is unsubstituted or substituted by from one to three groups independently chosen from halogen, Ci-β alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, Ci-β alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C3-7 cycloalkoxy, Ci-β haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, amino, Ci-β alkylamino, di(Ci-6)alkylamino, hydroxy, 20 hydroxy Ci-β alkyl, cyano, nitro, amino Ci-β alkyl, Ci-β alkylaminoCi-β alkyl, di(Cι-β alkyl)aminoCι-6alkyl or Ci-βalkoxy^r^bonylaminoCi-βaikyl. 2. A compound according to claim 1 wherein Ar is unsubstituted or substituted by from one to three groups independently chosen from 2δ halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, Ci-β alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C3-7 cycloalkoxy, Ci-β haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, amino, Ci-β alkylamino, di(Cι-β)alkylamino, hydroxy, hydroxy Ci-β alkyl, cyano, nitro, amino Ci-β alkyl, Ci-β alkylaminoCι-6 alkyl or di(Ci-β alkyPaminoCi-βalkyl. δ 3. A compound according to claim 1 or claim 2 wherein R 1 is hydrogen, halogen or Ci-βalkyl; R 2 is hydrogen or methyl; and R 4 is hydrogen. 10 4. A compound according to claim 1 or claim 3 wherein Ar is phenyl or pyridine and is unsubstituted or substituted with one or two groups independently selected from methyl, fluoro, chloro, methoxy, ethoxy, aminomethyl, aminoethyl, hydroxy, methylaminoethyl, dimethylaminoethyl, and t-butoxycarbonylaminomethyl. lδ δ. A compound according to claim 1 selected from 4-oxo-4,δ,6,7-tetrahydro-lH-indazole-3-carboxylic acid phenylamide; 4-oxo-4, δ, 6, 7-tetrahydro-lH-indazole-3-carboxylic acid-2,δ- difluorophenylamide; 20 4-oxo-4, δ,6,7-tetrahydro-lH-indazole-3-carboxylic acid pyridin-2- ylamide; 4-oxo-4, δ, 6, 7-tetrahydro-lH-indazole-3-carboxylic acid 4- methoxyphenylamide ; 4-oxo-4, δ, 6, 7-tetrahydro-lH-indazole-3-carboxylic acid 4-(2- 2δ aminoethyl)phenylamide; l)-phenyl)]-(4-oxo-4,δ,6,7-tetrahydro)-lH- indazole-3-carboxamide; [4-[(4-oxo-4,δ,6,7-tetrahydro-lH-indazole-3- carbonyl)amino] benzyl] carbamic acid- er -butyl ester; 30 (N-(4-aminomethyl)phenyl))-4-oxo-4,δ,6,7-tetrahydro-lH-indazole-3- carboxamide; and [N-(4-(2-dimethylaminoethyl)phenyl)]-(4-oxo-4,δ,6,7-tetrahydro)-lH- indazole-3-carboxamide; and the pharmaceutically acceptable salts thereof. δ 6. A pharmaceutical composition comprising a compound according to any previous claim or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 7. A process for the preparation of a pharmaceutical composition which 10 comprises adding a compound according to any of claims 1-δ or a pharmaceutically acceptable salt thereof to a pharmaceutically acceptable excipient. 8. A compound according to any of claims 1-δ or a pharmaceutically lδ acceptable salt thereof for use in a method of treating the human or animal body. 9. The compound of claim 8 wherein said method is for treatment or prevention of a clinical condition which can be alleviated by a ligand 20 selective for GABAA receptors containing the αδ subunit. 10. The use of a compound according to any of claims 1-δ or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a condition requiring the 2δ administration of a ligand selective for GABAA receptors containing the αδ subunit. 11. The use according to claim 10 wherein said condition is Alzheimer's disease. 30 12. A method of treatment or prevention of a condition associated with GABAA receptors containing the αδ subunit which comprises administering to a subject suffering from or prone to such a condition a therapeutically or prophylactically effective amount of a compound of δ claim 1 or a pharmaceutically acceptable salt thereof.

Inventors: BRYANT HELEN JANE, CHAMBERS MARK STUART, BRYANT, HELEN, JANE, CHAMBERS, MARK, STUART
Applicants: BRYANT HELEN JANE, CHAMBERS MARK STUART, MERCK SHARP & DOHME, BRYANT, HELEN, JANE, CHAMBERS, MARK, STUART, MERCK SHARP & DOHME LIMITED
Application year: 2000
Main classification: C07D231
IPC codes: A61K31, A61P25, A61P43, C07D231, C07D401