AZASPIRO DERIVATIVES

Abstract: Compounds of formula (I) where P is a 5- to 7-membered carbocyclic or heterocyclic ring containing one to four heteroatoms selected from oxygen, nitrogen or sulphur, R<4> is O, S, CH2, C=O, NR<5>CO or NR<5>, D is nitrogen or carbon, E is O, CR<18>R<19>, NR<20> with 5HT1B receptor antagonist activity.

Description: AZASPIRO DERIVATIVES The present invention relates to novel piperidine derivatives, processes for their preparation, and pharmaceutical compositions containing them. EPA 0533266/7/8 disclose a series of benzanilide derivatives which are said to possess 5HTID receptor antagonist activity. PCT/EP/95/04889 discloses further 5HTJD receptor antagonists having a spiropiperidine structure. These compounds are said to be of use in the treatment of various CNS disorders. The 5HTjDβ receptor has now been reclassifϊed as the 5HTJB receptor (P.R Hartig et al Trends in Pharmacological Science, 1996, 17, 103 - 105. A structurally distinct class of compounds have now been discovered and have been found to exhibit 5HTIB receptor antagonist activity. In a first aspect, the present invention therefore provides a compound of formula (I) or a salt or N-oxide thereof: (I) in which P is a 5 - to 7-membered carbocyclic or heterocyclic ring containing one to four heteroatoms selected from oxygen, nitrogen or sulphur; R 1 , R 2 and R^ are independently hydrogen, halogen, C^galkyl, C3_<5cycloalkyl, C3_6cycloalkenyl, Ci.βalkoxy, hydroxyCi.galkyl, Cι_6alkylOC gall y 1, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO2R 9 , CONR^R 11 , NR^R 11 where R 9 , R10 and R11 are independently hydrogen or Ci.gal yl, or R 2 and R^ together form a group -(CH 2 ) r R 14 -(CH2) s - where R 14 is O, S, CH 2 or NR 15 where R 1 ^ is hydrogen or Cj^alkyl and r and s are independently 0, 1 or 2; R 4 is O, S, CH2, C=O, NR 5 CO or NR 5 where R 5 is hydrogen or C^alkyl; B is oxygen or sulphur; D is nitrogen, carbon or a CH group; R 6 is hydrogen or C i -6alkyl and R 7 is hydrogen, C i .βalkyl, C i _6alkoxy or halogen or R 6 together with R 7 forms a group -A- where A is (CR 16 R 17 ) t where t is 2, 3 or 4 and R 16 and R 17 are independently hydrogen or Cj.galkyl or A is (CR 16 R 17 ) U -J where u is 0, 1, 2 or 3 and J is oxygen, sulphur, CR 16 =CR 17 , CR 16 =N, =CR 16 O, =CR 16 S or R 8 is hydrogen, Ci.galkyl, Cβ.gcycloalkyl, C2-6aIl enyl or Ci.galkyK^.gcycloalkyl; R and R ^ are independently hydrogen or Ci^alkyl; E is oxygen, CR Rl9 or NR 2 ^ where R* 8 , R* and R 2υ* are independently hydrogen or Ci _6alkyl or E is S(O) v where v is 0, 1 or 2; G is C=O or CR 2 *R 22 where R 2 ^ and R 22 are independently hydrogen or Ci.galkyl; X and Y are independently CR9R10 where R and R ^ are as defined above; and m is 1, 2 or 3. Cj.βalkyl groups, whether alone or as part of another group, may be straight chain or branched. .As used herein the term aryl includes phenyl and naphthyl. Heteroaryl groups include thienyl, furyl, pyridyl, pyrimidyl and pyrazinyl groups. Optional substituents for aryl and heteroaryl groups include those groups listed above for R 1 - R3. Suitably P is a 5- to 7-membered carbocyclic or heterocyclic group containing one to four heteroatoms selected from oxygen, nitrogen or sulphur. Examples of suitable groups inlude cyclohexyl, pyridine, pyrimidine, pyrazine, oxazole or thiazole. Preferably P is pyrimidine. Suitably Rl, R 2 and R^ are independently hydrogen, halogen, Cj.galkyl, C3_6cycloalkyl, C3_6cycloalkenyl, Ci.galkoxy, hydroxyC^alkyl, Ci.gal ylOC^alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO2R^, CONR^RI I NRIORI 1 where R9, RIO and R 11 are independently hydrogen or Cj.galkyl or R 2 and R^ together form a group -(CH2) r Rl4 -(CH2) s - where R 14 is O, S, CH2 or NR 15 where R 15 is hydrogen or Ci^al yl and r and s are independently 0, 1 or 2. Preferably R 2 is Cj_6alkyl. Preferably the R 2 group is ortho with respect to the biphenyl linkage. Most preferably R 2 is methyl. Preferably R^ is hydrogen. Suitably D is nitrogen, carbon or a CH group. Preferably D is nitrogen. Suitably R 4 is O, S, CH2, C=O or NR 5 where R 5 is hydrogen or C 1 _6alkyl. Preferably R 4 is oxygen. Suitably R^ is hydrogen or Ci.galkyl and R 7 is hydrogen, Ci^alkyl, Cχ.6alkoxy or halogen or R6 together with R 7 forms a group -A- where A is (CRl6Rl7) t where t is 2, 3 or 4 and R 1 ^ and R 17 are independently hydrogen or C j .galkyl or A is (CR16R17) U _J where u is 0, 1, 2 or 3 and J is oxygen, sulphur, CR 16 =CR 17 , CR 16 =N, =CR 16 O, =CR 16 S or =CR 16 -NR 17 . Preferably R 6 together with R 7 forms a group -A- where A is (CR 16 R 17 ) t where t is 2 or 3 and R 16 and R 17 are both hydrogen. Most preferably R 6 together with R 7 forms a (CH2>2 group. Suitably R 8 is hydrogen, Cj^alkyl, C3_6cycloalkyl, C2-6alkenyl or Cι_6al ylC3_6cycloalkyl. Preferably R 8 is Cι_6alkyl, most preferably R 8 is methyl. Suitably B is oxygen or sulphur, preferably B is oxygen. Suitably R 9 and R 10 are independently hydrogen or Chalky-. Preferably R and R 1 ^ are both hydrogen. Preferably m is 2 forming part of a spiro-piperidine ring, Suitably E is oxygen, CR 18 R 19 or NR 20 where R 18 , R 19 and R 20 are independently hydrogen or or E is S(O) v where v is 0, 1 or 2. Preferably E is oxygen. Suitably G is C=O or CR 21 R 22 where R 21 and R 22 are independently hydrogen or Cι_6alkyl. Preferably G is CH2. Suitably X and Y are independently CR9R10 where R9 and R 1 ^ are as defined above. Preferably X and Y are both CH2. Particularly preferred compounds of the invention include: r-methyl-5-[2 , -methyl-4'-(pyrimidin-2-ylamino)biphenyl-4-carbonyl]-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], l'-Methyl-5-[2'-methyl-4'-(pyrimidin-2-yloxy)biphenyl-4-carbonyl]-2,3,6,7- tetrahydrospiro[furo[2,3-fjindole-3,4'-piperidine], -Methyl-5-[2'-methyl-4'-(pyridin-2-ylamino)biphenyl-4-carbonyI]-2,3,6,7- tetrahydrospiro[furo[2,3-fjindole-3,4'-piperidine], -Methyl-5-[2'-methyl-4'-(pyridazin-3-ylamino)biphenyl-4-carbonyl]-2,3,6,7- tetrahydrospiro[furo[2,3-fJindole-3,4'-piperidine], -MethyI-5-[2'-methyl-4'-(pyridin-4-ylamino)biphenyl-4-carbonyl] -2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], -Methyl-5-[2'-methyl-4'-(pyridine-2-carbonyl)biphenyl-4-carbonyI]-2,3,6,7- tetrahydrospiro-[furo[2,3-f]indole-3,4'-piperidine], 5-[2'-Methyl-4'-(pyrimidin-2-yloxy)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3- fJindole-3,4'-piperidine], or pharmaceutically acceptable salts and N-oxides thereof. Preferred salts of the compounds of formula (I) are pharmaceutically acceptable salts. These include acid addition salts such as hydrochlorides, hydrobromides, phosphates, acetates, fumarates, maleates, tartrates, citrates, oxalates, methanesulphonates and p-toluenesulphonates. Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and the mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the invention. In a further aspect the present invention provides a process for the preparation of a compound of formula (I) which comprises: for compunds of formula (I) where D is nitrogen and B is oxygen, reaction of a compound of formula (II): (II) in which P, R 1 , R 2 , R- and R 4 are groups as defined in formula (I) or protected derivatives thereof and L is a leaving group, with a compound of formula (HI): (in) wherein R^, R 7 , R 8 , R , RIO ^ E, G, X, Y, and m are groups as defined in formula (I) or protected derivatives thereof and optionally thereafter in any order: • removing any protecting groups • converting a compound of formula (I) into another compound of formula (I) • forming a pharmaceutically acceptable salt Suitable activated carboxylic acid derivatives of formula (II) include acyl halides and acid anhydrides. Activated compounds of formula (II) can also be prepared by reaction of the corresponding carboxylic acid with a coupling reagent such as carbonyldiimidazole, dicyclohexylcarbodiimide or diphenylphosphorylazide. Compounds of formulae (II) and (III) are typically reacted together in an inert organic solvent such as DMF, THF or dichloromethane at ambient or elevated temperature in the presence of a base such as an alkali metal hydroxide, triethylamine or pyridine. Alternatively L is an ester forming group such that the resulting esters of formula (II) can be reacted with compounds of formula (in) in the presence of an organo- aluminium reagent such as trimethylaluminium. Such a reaction is typically carried out in the presence of an inert solvent such as toluene. Intermediate compounds of formula (II) and (ITI) can be prepared using standard procedures known in the art. Certain intermediate compounds of formula (II) and (IE) are novel and form a further aspect of the invention. It will be appreciated to those skilled in the art that it may be necessary to protect certain reactive substituents during some of the above procedures. Standard protection and deprotection techniques can be used such as those described in Greene T.W. 'Protective groups in organic synthesis' New York, Wiley (1981). For example, primary amines can be protected as phthalimide, benzyl, benzyloxycarbonyl or trityl derivatives. Carboxylic acid groups can be protected as esters. .Aldehyde or ketone groups can be protected as acetals, ketals, thioacetals or thioketals. Deprotection is achieved using standard conditions. 5HT]B receptor antagonists, and in particular the compounds of the present invention, are useful in the treatment of CNS disorders such as mood disorders, including depression, seasonal affective disorder and dysthymia; anxiety disorders, including generalised anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder; memory disorders, including dementia, amnestic disorders and age-associated memory impairment; and disorders of eating behaviours, including anorexia nervosa and bulimia nervosa. Other CNS disorders include motor disorders such as Parkinson's disease, dementia in Parkinson's disease, neuroleptic- induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders. 5HTJB receptor antagonists, and in particular compounds of the present invention, may also be of use in the treatment of endocrine disorders such as hyperprolactinaemia, in the treatment of vasospasm (particularly in the cerebral vasculature) and hypertension, as well as disorders in the gastrointestinal tract where changes in motility and secretion are involved. They may also be of use in the treatment of sexual dysfunction and hypothermia. Therefore, the present invention provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in therapy. The present invention also provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment of the aforementioned disorders. In another aspect the invention provides the use of a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of the aforementioned disorders. In a further aspect the invention provides a method of treating the aforementioned disorders which comprises administering an effective amount to a patient in need of such treatment of a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof. In particular the invention provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment or prophylaxis of depression. It will be appreciated by those skilled in the art that the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents. The present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred. Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants. For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months. The following Examples illustrate the preparation of compounds of the invention. Description 1 4'-Amino-2'-methyIbiphen γ l-4-carboxylic acid 4-Bromo-3-methylaniline (7.40g, 40 mmol) and 4-carboxybenzeneboronic acid (7.90g, 48 mmol) were stirred in 1,2-dimethyoxyethane (DME) (150 ml). Anhydrous sodium carbonate (19.0g, 179 mmol) was dissolved in water (150 ml) and added to the above. The mixture was then purged with a stream of Ar for 15 min. Tetrakis (triphenylphosphine)palladium (O) (0.25g, 0.2 mmol) was added, and the mixture was stirred at reflux for 20h under Ar. DME was removed by evaporation under reduced pressure, and the clear residue was acidified (5M HCl) to yield a thick grey suspension. The solid was filtered off, washed with water and dried in vacuo at 60°C, to give the title compound (9.60g, quantitative). *H NMR (250 MHz, d 6 DMSO) δ (ppm): 8.02 (d, 2H), 7.47 (d, 2H), 7.30 (d, 1H), 7.20 (m, 2H), 2.24 (s, 3H). Description 2 Methyl 4*-amino-2'-methylbiphenyI-4-carboxylate Thionyl chloride (10 ml) was added dropwise and cautiously to methanol (200 ml) with stirring. 4'-.Amino-2'-methylbiphenyl-4-carboxylic acid (Dl) (8.44g, 37 mmol) was added, and the mixture was then stirred at reflux for 3h. Solvent was then removed in vacuo to yield the title compound (9.16g, 89%) as the hydrochloride salt. l H NMR (HCl salt) (200 MHz, d 6 DMSO/CDCI3) δ (ppm): 10.25 (b), 8.06 (d, 2H), 7.41 (d, 2H), 7.30 (m, 3H), 3.92 (s, 3H), 2.28 (s, 3H). Description 3 Methyl 2'-methyl-4'-(pyrimidin-2-ylamino)biphenyl-4-carboxylate An intimate mixture of methyl 4'-amino-2'-methylbiphenyl-4-carboxylate (D2) (370mg; 1.53 mmol) and 2-bromopyrimidine (244mg; 1.53 mmol) was melted at 140°C, then heated overnight at 100 - 110°C. The cooled reaction mixture was partitioned between K j CO j and ethyl acetate, the organic layer was dried (Na j SO ) and the solvent removed by evaporation under reduced pressure. Chromatography on silica gel, eluting with 60 - 80 petrol ether and diethyl ether, gave the title compound (156mg, 32%) as a white powder. Η NMR (200 MHz, CDC1,) δ (ppm): 8.44 (d, 2H), 8.07 (d, 2H), 7.6 - 7.49 (m, 2H), 7.4 (d, 2H), 7.26 - 7.16 (m, 2H), 6.75 (t, IH), 3.94 (s, 3H), 2.3 (s, 3H) Description 4 4 , -Hydroxy-2'-methylbiphenyl-4-carboxylic acid Using the method outlined in Description 1, 4-bromo-3-methylphenol (12.25g, 0.065 mole) was converted to the title compound as an off-white solid (18.12g, >100%). J H NMR (250 MHz, ≠DMSO) δ (ppm): 7.95 (d, 2H), 7.4 (d, 2H), 7.05 (d, IH), 6.75- 6.65 (m, 2H), 2.18 (s, 3H). (OH and COOH protons not observed) Description 5 Methyl 4'-hydroxy-2'-methyIbiphenyI-4-carboxylate 4'-Hydroxy-2'-methylbiphenyl-4-carboxylic acid (D4, 18.12g; 0.066 mole) was added with stirring, to a solution of concentrated sulfuric acid (7 ml) in methanol (500 ml), and the mixture heated to reflux for 7 h. After cooling to room-temperature, and evaporating under reduced pressure, a pale brown oil remained, which was partitioned between dichloromethane (300 ml) and Na2CO3 solution (300 ml). The aq. phase was further extracted with dichloromethane, and the combined organic phase was dried (Na2SO4) and evaporated under reduced pressure. The resulting solid was recrystallised from dichloromethane and 60-80 petroleum ether to give the title compound as a white solid (9g, 57%). !H NMR (250 MHz, CDC1 3 ) δ (ppm): 8.07 (d, 2H), 7.36 (d, 2H), 7.1 (d, IH), 6.8-6.7 ( , 2H), 3.95 (s, 3H), 2.22 (s, 3H). (OH proton not observed) Description 6 Methyl 2'-methyl-4'-(pyrimidin-2-yloxy)biphenyl-4-carboxylate A solution of methyl 4'-hydroxy-2'-methylbiphenyl-4-carboxylate (D5, 200 mg; 0.82 mmol), in dimethoxyethane (10 ml), was treated with potassium tert-butoxide (102 mg, 0.91 mmol) at 0°C. After 30 minutes, a solution of 2-chloropyrimidine (95 mg, 0.82 mmol) in dimethoxyethane (5 ml) was added, and the mixture refluxed for 20 h. The cooled mixture was filtered through kieselguhr, washed with dimethoxyethane and evaporated to leave the title compound as a pale yellow oil which crystallised on standing (354 mg, 96%), IH NMR (250 MHz, CDCI3) δ (ppm): 8.6 (d, 2H), 8.1 (d, 2H), 7.41 (d, 2H), 7.31-7.24 (m, IH), 7.18-7.01 (m, 3H), 3.94 (s, 3H), 2.29 (s, 3H). Description 7 2'-Methyl-4 , -(pyridin-2-ylamino)biphenyl-4-carboxylic acid An intimate mixture of 2-chloropyridine (118 mg; 1.03 mmol) and methyl 4'-amino-2'- methylbiphenyl-4-carboxylate (D2, 250 mg; 1.03 mmol) was heated to reflux for 24 h. On cooling, the solid residue was sonicated under dichloromethane and filtered, to leave the title compound as a fine powder (110 mg, 35%). !H NMR (250 MHz, CD3OD) δ (ppm): 8.2-8.02 (m, 3H), 7.95 (d, IH), 7.55-7.25 (m, 6H), 7.08 (t, IH), 2.35 (s, 3H). (NH and COOH protons not observed). Description 8 Methyl 2 , -methyl-4'-(pyridazin-3-ylamino)biphenyl-4-carboxylate The title compound was prepared from 3-chloropyridazine (106 mg; 0.92 mmol) and methyl 4'-amino-2'-methylbiphenyl-4-carboxylate (D2, 223 mg; 0.92 mmol) using a method similar to Description 3, as a brown oil which crystallised to a yellow foam (35 mg, 12%). l H NMR (200 MHz, CDCI3) δ (ppm): 8.7 (d, IH), 8.1 (d, 2H), 7.55-7.16 (m, 8H), 3.95 (s, 3H), 2.3 (s, 3H). Description 9 Methyl 2'-methyl-4'-(pyridin-4-ylamino)biphenyl-4-carboxylate The title compound was prepared from 4-bromopyridine (407 mg; 0.0025 mol) and methyl 4'-amino-2'-methylbiphenyl-4-carboxylate (D2, 619 mg; 0.0025 mol) using a method similar to that of Description 3 to give the title compound as an off-white solid (169 mg, 21%). *H NMR (200 MHz, CDCI3) δ (ppm): 8.31 (d, 2H), 8.1 (d, 2H), 7.4 (d, 2H), 7.27-7.18 (m, IH), 7.1 (s, 2H), 6.88 (d, 2H), 6.28 (s, IH), 3.95 (s, 3H), 2.28 (s, 3H). Description 10 2-(4-Bromo-3-methylbenzoyl)pyridine To a stirred solution of 2-bromopyridine (0.92 ml, 9.69 mmol) in dry ether (20 ml) at -70°C under argon, n-butyllithium (1.6M solution in hexanes, 6.36 ml, 10.17 mmol) was added dropwise. The solution was stirred for 50 mins at -72°C, then a solution of N-methoxy-N- methyl-4-bromo-3-methylbenzamide (Description 17, WO 96/19477) (2.5g, 9.69 mmol) in dry ether (20 ml) was added dropwise to the reaction mixture, keeping the temperature constant at -70°C. Stirring was continued at this temperature for 0.5h and then the reaction mixture was slowly allowed to warm up to room temperature and then heated to reflux for 1 hr. After cooling to room temperature, the reaction solution was concentrated in vacuo, then washed with water, extracted with ethyl acetate and dried (Na2SO4). The filtrate was evaporated and the crude brown solid was chromatographed on silica gel eluting with 0- 10% EtOAc/pet. ether to afford the title compound as a white solid. (1.593g, 60%). l NMR (200 MHz, CDCI3) δ (ppm): 8.59-8.44 (m, IH), 7.86 (d, IH), 7.80-7.63 (m, 2H), 7.56 (dd, IH), 7.45 (d, IH), 7.37-7.22 ( , IH), 2.27 (s, 3H). Description 11 2'-Methyl-4'-(pyridine-2-carbonyl)biphenyl-4-carboxylic acid The title compound was afforded as a white solid (415 mg, 90%) from 2-(4-bromo-3- methylbenzoyl)pyridine (D10, 700 mg, 2.536 mmol) following a similar procedure as that in Dl. *H NMR (200 MHz, d 6 DMSO) δ(ppm): 13.06 (br s, IH - low integration), 8.82-8.67 (m, IH), 8.17-7.80 (m, 6H), 7.75-7.62 (m, IH), 7.55 (d, 2H), 7.40 (d, IH), 2.30 (s, 3H), Example 1 l'-Methyl-5-[2 , -methyl-4 , -(pyrimidin-2-ylamino)biphenyl-4-carbonyl]-2 ,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] r-Methyl-2,3,6,7-tetrahydrospiro[furo[2,3-fJindole-3,4'-piperidine] (Description 8, WO 96/19477) (104mg; 0.43 mmol) was stirred under Ar in AR toluene (10 ml) as trimethylaluminium (2M in toluene, 0.23 ml; 0.47 mmol) was added. The clear solution was stirred for 10 minutes, when methyl 2'-methyl-4'-(pyrimidin-2-ylamino)biphenyl-4- carboxylate (D3, 135mg; 0.43 mmol) was added. The mixture was stirred at 80°C for 1.25h, then the solvent removed by evaporation under reduced pressure, and the residue purified by chromatography on silica gel, eluting with methanol and chloroform, to give the title compound (131mg, 58%) as a white powder. Η NMR (250MHz, CDC1 3 ) δ (ppm): 8.44 (d, 2H), 8.13 (br, IH), 7.62 - 7.47 (m, 4H), 7.39 (d, 2H), 7.3 - 7.17 (m, 2H), 6.74 (t, IH), 6.65 (s, IH), 4.45 - 3.97 (m, 4H), 3.05 (t, 2H), 2.95 - 2.75 (m, 2H), 2.3 (s, 6H), 2.17 - 1.5 (m, 6H). Example 2 l , -MethyI-5-[2 , -methyl-4'-(pyrimidin-2-yloxy)biphenyl-4-carbonyl]-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] hydrochloride The title compound was prepared from methyl 2'-methyl-4'-(pyrimidin-2-yloxy)biphenyl-4- carboxylate (D6, 69 mg; 0.215 mmol) and -methyl-2,3,6,7-tetrahydrospiro[furo[2,3- f]indole-3,4'-piperidine] (Description 8, WO 96/19477) (53 mg; 0.215 mmol) following the procedure outlined in Example 1, as a pale lemon white powder (49 mg, 40%). J H NMR (free base) (250 MHz, CDCI3) δ (ppm): 8.51 (d, 2H), 8.13 (br s, IH), 7.6 (d, 2H), 7.4 (d, 2H), 7.3 (d, IH), 7.16-7.02 (m, 3H), 6.66 (s, IH), 4.49-4.3 (m, 2H), 4.25-3.98 (m, 2H), 3.08 (t, 2H), 2.95-2.71 (m, 2H), 2.3 (s, 6H), 2.22-1.48 (m, 6H). Example 3 l'-Methyl-5-[2'-methyl-4 , -(pyridin-2-ylamino)biphenyl-4-carbonyl]-2,3,6,7- tetrahydrospiro[furo[2,3-f]indoIe-3,4'-piperidine] A suspension of 2'-medιyl-4'-(pyridin-2-ylamino)biphenyl-4-carboxylic acid (D7, 97 mg; 0.319 mmol) in dichloromethane (5 ml) was treated with oxalyl chloride (0.042 ml) and 2 drops of dry dimethylformamide. After 25 minutes, the clear solution was evaporated under reduced pressure, and azeotroped once with toluene. The acid chloride thus formed, was dissolved in dichloromethane (5 ml) and treated under argon with l'-methyl-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-pipcridine] (Description 8, WO 96/19477) (78 mg; 0.319 mmol), and triethylamine (0.07 ml). After stiπing for 5 h under argon, the mixture was washed with 10% NaOH, dried (Na2SO4) and evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with methanol and dichloromethane, to afford the title compound as a pale yellow solid. (62 mg, 37%) IH NMR (200 MHz, CDCI3) δ (ppm): 8.21 (d, IH), 8.12 (br s, IH), 7.65-7.46 (m, 3H), 7.36 (d, 2H), 7.3-7.12 (m, 3H), 6.91 (d, IH), 6.75 (dd, IH), 6.62 (d, 2H), 4.39 (s, 2H), 4.2-4.0 (m, 2H), 3.05 (t, 2H), 2.95-2.7 (brs, 2H), 2.3 (s, 6H), 2.15-1.55 (m, 6H). Example 4 l'-Methyl-S-^'-methyl^'^pyridazin-S-ylaminoJbiphenyl^-carbonyl]^^^,?- tetrahydrospiro[furo[2,3-f]indoIe-3,4'-piperidine] The title compound was prepared from methyl 2'-methyl-4'-(pyridazin-3-ylamino)biphenyl- 4-carboxylate (D8, 35 mg; 0.109 mmol) and l'-methyl-2,3,6,7-tetrahydrospiro [furo[2,3- f]indole-3,4'-ρiperidine] (Description 8, WO 96/19477) (27 mg; 0.109 mmol) following the procedure outlined in Example 1, as an off-white solid (11 mg, 19%). *H NMR (250 MHz, CDCI3) δ (ppm): 8.7 (d, IH), 8.19 (br s, IH), 7.6 (d, 2H), 7.43-7.12 (m, 8H), 6.69 (s, IH), 4.38 (s, 2H), 4.2-4.0 (m, 2H), 3.14-2.82 (m, 4H), 2.56-1.8 (m, 12H). Example 5 l , -MethyI-5-[2'-methyI-4 , -(pyridin-4-yIamino)biphenyl-4-carbonyI] -2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] The title compound was prepared from methyl 2 , -methyl-4'-(pyridin-4-ylamino)biphenyl-4- carboxylate (D9, 149 mg; 0.468 mmol) and l'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3- fjindole-3,4'-piperidine] (Description 8, WO 96/19477) (114 mg; 0.468 mmol) following the procedure outlined in Example 1, as a white solid (147 mg, 60%). J H NMR (250 MHz, CDCI3/CD3OD) δ (ppm): 8.2 (d, 2H), 8.1 (br s, IH), 7.6 (d, 2H), 7.4 (d, 2H), 7.24 (d, IH), 7.15-7.05 (m, 2H), 6.9 (d, 2H), 6.69 (s, IH), 4.4 (s, 2H), 4.2-4.01 (m, 2H), 3.09 (t, 2H), 2.95-2.8 (m, 2H), 2.3 (s, 6H), 2.18-1.9 (m, 4H), 1.88-1.68 (m, 2H). (NH proton not observed) Example 6 l'-MethyI-5-[2'-methyl-4 , -(pyridine-2-carbonyI)biphenyI-4-carbonyl]-2,3,6,7- tetrahydrospiro-[furo[2,3-f]indole-3,4'-piperidine] The title compound was prepared from 2'-methyl-4'-(pyridine-2-carbonyl)biphenyl-4- carboxylic acid (Dl l, 395 mg, 1.246 mmol) and l'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3- f]indole-3,4'-ρiperidine] (Description 8, WO 96 19477) (304 mg, 1.246 mmol) following a similar procedure to that outlined in Example 3, as a beige solid. The crude product was purified by chromatography on silica gel, eluting with 0-5% methanol/dichloromethane. .After evaporation the title compound was afforded as a dull yellow solid (92 mg, 14%). !H NMR (free base) (250 MHz, CDCI3) δ (ppm): 8.82-8.63 (m, IH), 8.23-8.04 (m, IH), 8.00-7.87 (m, 2H), 7.87-7.75 (m, IH), 7.70-7.13 (m, 7H), 6.67 (s, IH), 4.40 (br s, 2H), 4.25-3.94 (br, 2H), 3.08 (t, 2H), 2.90 (br, 2H), 2.44 (s, 3H), 2.29 (s, 3H), 2.21-1.60 (br m, 6H). Example 7 5-[2'-MethyI-4'-(pyrimidin-2-yloxy)biphenyl-4-carbonyI]-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] hydrochloride r-Methyl-5-[2'-methyl-4'-(pyrimidin-2-yloxy)biphenyl-4-carbonyl]-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E2) (0.354g, 0.66 mmol) was stirred in 1,2-dichloroethane (20 ml) under Ar, and treated with diisopropylethylamine (0.17 ml, 0.98 mmol) and 1-chloroethyl chloroformate (0.18 ml, 1.66 mmol). After stirring for 20 h, the mixture was evaporated to dryness, dissolved in methanol, and heated at reflux for 1 h. After again evaporating to dryness, the material was dissolved in dichloromethane, washed with 10% Na2CO3, dried (Na2SO4) and evaporated. Residual diisopropylethylamine was removed by toluene azeotrope. The crude product was converted to the hydrochloride salt, and recrystallised from ethanol/acetone, giving the title compound as a white powder. *H NMR (250 MHz, d 6 DMSO) δ (ppm): 9.08 (b, IH), 8.69 (d, 2H), 8.60 (m, IH), 8.00 (b s, IH), 7.67 (d, 2H), 7.50 (d, 2H), 7.30 (m, 2H), 7.19 (d, IH), 7.13 (dd, IH), 6.78 (s, IH), 4.53 (s, 2H), 4.08 (t, 2H), 3.35 (m, 2H), 3.04 (t, 2H), 2.97 (m, 2H), 2.29 (s, 3H), 2.1 (m, 2H), 1.83 (m, 2H).

Claims: CLAIMS: 1. A compound of formula (I) or a salt or N-oxide thereof: (I) in which P is a 5 - to 7-membered carbocyclic or heterocyclic ring containing one to four heteroatoms selected from oxygen, nitrogen or sulphur; R 1 , R 2 and R^ are independently hydrogen, halogen, Ci.galkyl, C3_6cycloalkyl, C3_6cycloalkenyl, Cj.galkoxy, hydroxyCj.galkyl, Cι_6alkylOCι_6alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO2R 9 , CONR^R 1 , NR ORH where R9, RIO and R 1 1 are independently hydrogen or Cj^alkyl, or R 2 and R 3 together form a group -(CH 2 ) r -R 14 -(CH2) S - where R 14 is O, S, CH2 or NR 15 where R 15 is hydrogen or Cj.galkyl and r and s are independently 0, 1 or 2; R 4 is O, S, CH2, C=O, NR 5 CO or NR 5 where R 5 is hydrogen or C^alkyl; B is oxygen or sulphur; D is nitrogen, carbon or a CH group; R is hydrogen or Cj_6alkyl and R 7 is hydrogen, C^galkyl, Ci _6alkoxy or halogen or R > together with R 7 forms a group -A- where A is (CR 6Rl 7 ) t where t is 2, 3 or 4 and R* 0" and RI 7 are independently hydrogen or C j .galkyl or A is (CR16R17) U _J where u is 0, 1, 2 or 3 and J is oxygen, sulphur, CR 16 =CR 17 , CR 16 =N, =CR 16 O, =CR 16 S or =CR 16 -NR 17 ; R 8 is hydrogen, Cj^alkyl, C3_6cycloalkyl, C2- al enyl or Cι_6al k ylC3-6cycloal yl; R and R 10 are independently hydrogen or Cj.galkyl; E is oxygen, CR1 8 R19 or NR 2 0 where R 8 , R i9 and R 20 are independently hydrogen or C\ -6alkyl or E is S(O) v where v is 0, 1 or 2; G is C=O or CR 2 R 22 where R 2 and R 22 are independently hydrogen or Cj^alkyl; X and Y are independently CR R10 where R 9 and Rl° are as defined above; and m is 1, 2 or 3. 2. A compound according to claim 1 in which P is pyrimidine. 3. A compound according to claim 1 or 2 in which R 2 is C^alkyl. 4. A compound according to any one of claims 1 to 3 in which m is 2. 5. A compound according to any one of claims 1 to 4 in which R 8 is C j .galkyl. 6. A compound according to any one of claims 1 to 5 in which E is oxygen. 7 A compound according to claim 1 which is: -methyl-5-[2'-methyl-4'-(pyrimidin-2-ylamino)biphenyl-4-carbonyl]-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], l'-Methyl-5-[2 , -methyl-4'-(pyrimidin-2-yloxy)biphenyl-4-carbonyl]-2,3,6,7- tetrahydrospiro[furo[2,3-fJindole-3,4'-piperidine], -Methyl-5-[2'-methyl-4'-(pyridin-2-ylamino)biphenyl-4-carbonyl]-2,3,6,7- tetrahydrospiro[furo[2,3-fJindole-3,4'-piperidine], -Methyl-5-[2'-methyl-4 , -(pyridazin-3-ylamino)biphenyl-4-carbonyI]-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], r-Methyl-5-[2'-methyl-4'-(pyridin-4-ylamino)biphenyl-4-carbonyI] -2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], r-Methyl-5-[2'-methyl-4'-(pyridine-2-carbonyl)biphenyl-4-carbonyl]-2,3,6,7- tetrahydrospiro-[furo[2,3-f]indole-3,4'-piperidine], 5-[2'-Methyl-4'-(pyrimidin-2-yloxy)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3- f|indole-3,4'-piperidine] , or pharmaceutically acceptable salts or N-oxides thereof. 8. A process for the preparation of a compound of formula (I) which comprises: (ID in which P, R , R 2 , R 3 and R 4 are groups as defined in formula (I) or protected derivatives thereof and L is a leaving group, with a compound of formula (HI): (III) wherein R 6 , R 7 , R 8 , R 9 , R O, E, G, X, Y, and m are groups as defined in formula (I) or protected derivatives thereof and optionally thereafter in any order: • removing any protecting groups • converting a compound of formula (I) into another compound of formula (I) • forming a pharmaceutically acceptable salt. 9. A compound according to any one of claims 1 to 7 for use in therapy. 10. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 7 in association with a pharmaceutically acceptable carrier or excipient.

Inventors: GASTER LARAMIE MARY, WYMAN PAUL ADRIAN, GASTER, LARAMIE, MARY, WYMAN, PAUL, ADRIAN
Applicants: GASTER LARAMIE MARY, SMITHKLINE BEECHAM PLC, WYMAN PAUL ADRIAN, GASTER, LARAMIE, MARY, WYMAN, PAUL, ADRIAN
Application year: 1997
Main classification: C07D491
IPC codes: A61K31, A61P1, A61P5, A61P9, A61P15, A61P25, A61P43, C07D491