ANTICHOLINERGIC AGENTS

Abstract: Selective muscarinic receptor antagonists of formula (I), wherein R<1> and R<2> are both optionally substituted phenyl, the broken line is an optional bond, X is (a), (b) or CH- when the double bond is absent or is (c) when the double bond is present, X being attached to a carbon atom of A, A is selected from certain piperidine and pyrrolidine groups, n is 1 to 3 and R<3> is optionally substituted phenyl or thienyl, pyridyl or pyrazinyl.

Description: Anticholinercfic Agents 1 This invention relates to certain disubstituted piperidine and pyrrolidine derivatives as selective iπuscarinic receptor antagonists. GB-780,027 discloses, amongst other ccxrpounds, 3-(benzhyd__yloxy)- and 3-(xanthyloxy)-N-a-_a-l_kylpiperidines as oxytocic agents, being devoid of ant_lspasmodic activity at the therapeutic doses employed. No N-phenethyl substituted examples were synthesised or exemplified within the scope. US-2,974,146 provides N-a-_alkyl-3-piperidyl benzhydryl ethers having activity as sedatives and in prolonging the hypnotic effect of bcu±)iturates, with only the corresponding quaternary aiπmαnium salts being stated to possess gastro-intestinal antispasmodic activity. Although N-phenethyl-3-piperidyl benzhydryl ether is listed as "a specific ccnpound provided by the invention", no preparative details or pharmacological data are presented and it is clear that the ccnpound was never actually made. US Patent 4632925 describes N-substituted diphenyl- piperidines which exhibit -tnsul-Ln-lcwering activity. It has now unexpectedly been discovered that the substituted piperidine and pyrrolidine derivatives provided by the present invention are muscarinic receptor antagonists which are selective for smooth muscle muscarinic sites over cardiac muscarinic sites and which do not have any significant antihist-aminic activity. Thus the α-xrpαunds are useful in the treatment of diseases associated with altered mσtility and/or tone of smooth muscle which can, for example, be found in the gut, trachea and bladder. Such diseases include irritable bcwel syndrome, diverticular disease, urinary incontinence, oesphageal achalasia and chronic obstructive airways disease. According to one aspect of the invention, there are provided compounds of the formula (I) : R 1 \ 3 X -A- (Oi^R ΕC (I) and their pharmaceutically acceptable salts, wherein R 1 and R2 are the same or different and each is phenyl which is unsubstituted or -substituted by at least one group selected from C -C al_yl and halo, the broken line represents an optional double bond and X is ^>G0H, ^SiOH- or _^CH- when said double bond is absent or is^rO when said double bond is present, X being attached to a carbon atcm of A, A is or -CH. when said double bond is absent or A is when said double bond is present n is frcm 1 to 3, m is 1 or 2, p is 0 or 1, q is 0 or 1 R 3 is s y R or Het, *• «_ R * «. «* ^ tem H. C.-C. -r-Λ. C.-C. l^ or (αtL) OH wherein r is 0, 1 or 2, or R 4 and R5 together form a -Y-(CI ) -Z- group wherein Y and Z are independently -O- or -CH,- and s is 1, 2 or 3, and Het is thienyl, pyridyl or pyrazinyl, with Het. In the above definitions "thienyl" includes 2- and 3-thienyl and pyridyl includes 2-, 3- and 4- pyridyl. "Halo" means F, Cl, Br or I. Alkyl and alkoxy groups of 3 or more carbon atoms may be straight or branched-chain. Ηιe preferred alkyl and alkoxy groups .are methyl, ethyl, methαxy and ethoxy. 1 2 R .and R may be unsubstituted phenyl. X is preferably 3 ^C(CH)-. Preferred examples of R are pyridyl, 2,3-dihydro- benzofuraπyl, 3,4-methylenedicκyphenyl, tolyl, methoxyphenyl and hydi-oxymethylphenyl. A particularly preferred ccnpound is 3^(dipheny__hydroxy- methyl)-1-(3,4-_ret_hylenedioxyphenethyl)piperidine. Ihe ccπpounds of the formula (I) contain at least one asyiπmetric centre and will therefore exist as a pair of enantiomers or diastereσπieric pairs of enaπtiomers. Sucii enantiomers or diastereomeric pairs of enaπtiαners may be resolved by physical methods, e.g. by fractional __ecrystallisation, C-__roιιatography or H.P.L.C. of a racemic mixture of the ccnpound f the formula (I) , or of a suitable salt or derivative thereof. Most preferably, the .Individual enanticmers of the ccπpcunds of the formula (I) _tntaining one asymmetric centre are prepared from optically pure intermediates. The pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts such as the hydrochloride, hyd__obromide, sulphate or bisulphate, phosphate or hydrogen j-hosphate, acetate, besylate, citrate, fumarate, gluconate, lactate, maleate, mesylate, succinate and t-artrate salts. For a more comprehensive list of phaπraceutically acceptable salts see, for example, the Journal of RiariTaceutical Sciences, Vol. 66, No. 1, January 1977, pages 1-19. These salts can be prepared conventionally, e.g. by mixing a solution of the free base and the acid in a suitable solvent, e.g. ethanol, and recovering the acid addition salt either as a precipitate, or by evaporation of the solution. The ccπpounds of the formula (I) can be prepared by a number of routes, including the fo- owing:- Rσute A This can be illustrated as follows:- R 1 ^ x -Λ - H + Q(CH ) R 3 ) Com p ound I R 2 (II) (III) 1 2 3 R , R , A, X, n and R are as defined for formula (I) and Q is a leaving group, e.g. Br, Cl, I, C.-C. alkanesulphQηylαxy (e.g. methar_esulphαπyloxy) , benzenesulphoπyloxy, toluenesulphoπyloxy (e.g. p-toluenesulphoπyloxy) or t_rifluoιπ--i-3thanesulphonylθ-^. Preferably, Q is Cl, Br, I or methanesulphαnyloxy. In formula (II) the hydrogen atom shewn is attached to the nitrogen atom of A. The reaction is preferably carried out in the presence of an acid acceptor such as sodium or potassium carbonate, sodium bicarbonate, triet_hylamine or pyridine, and in a suitable organic solvent, e.g. acetonitrile, at up to the reflux terrperature. Reaction teπperatures of 60-120°C are generally desirable and it is most convenient to carry out the reaction under reflux. Iodo is generally the most suitable leaving group but since the .starting materials (III) are generally most conveniently available as chlorides or bromides, the reaction is often most suitably carried out using the ccnpound (III) as a chloride or bromide but in the presence of an iodide such as sodium or potassium iodide. In the preferred technique, the ccπpcunds (II) and (III) , (III) being in bromide or chloride form, are refluxed together in acetonitrile in the presence of sodium carbonate and sodium iodide. The product (I) can be isolated and purified convention-ally. The starting materials of the formula (II) can be obtained by cx-nventional procedures such as those described in the Preparations below. The starting materials of the formula (III) are in general known ccπpcunds which can be prepared by conventional techniques. The preparation of the novel starting materials of the formula (III) used in the Exaπples is described in the following Preparations section. Route B This route is useful for preparing ccπpαunds in which n is 2 3 and R is 2- or 4-pyridyl or pyrazinyl and can be described as follows:- or 1 2 R , R , A and X are as defined for formula (I) . Clearly the vinyl group must be attached to the 2- or 4-position of the pyridine ring. The reaction is typically carried out with heating at up to 160°C, preferably 80° to 140 C, in a suitable organic solvent, e.g. 1-butanol. The use of a basic (preferably a strong base which is soluble in an organic solvent such as N-benzyltrimethyl- a monium hydroxide ["Triton B"- Trade Mark] or acidic (preferably a C -C. alkanoic acid) catalyst is useful. The preferred procedure is to reflux the reactants in an organic solvent in the presence of a basic catalyst such as "Triton B". Route C 1 2 Tins route may be used when R and R are phenyl and X is ^:C(0H)- and may be illustrated as follows: RD-CO-A-fCH^R 3 Compounds (I) Excess PhLi wherein R is a C.-C. alkyl group such as ethyl. In this process a carboxylate of the appropriate piperidine or pyrrolidine derivative is allowed to react with excess pheiryllithium to convert the RD-CO- group to a R C(OH)- grcup. The reaction may be conducted by adding the phenyllithium to the carboxylate in a suitable solvent such as diethyl ether at lew tertperature, allowing the mixture to warm to room temperature, quenciting the ..eiraining phenyllithium with water and extracting the desired ccnpound of formula (I) with a suitable organic solvent. The carboxylate starting ccπpounds may be prepared as described in the Preparations belcw. The selectivity of the ccπpounds as muscarinic receptor antagonists can be measured as follows. Male guinea pigs are sacrificed and the ileum, trachea, bladder and right atrium are removed and suspended in physiological salt solution under a resting tension of 1 g at 32°C aerated with 95% 0 2 and 5% 00-. Contractions of the ileum, bladder and trachea are recorded using an isotonic (ileum) or isometric transducer (bladder and trachea) . The frequency of contraction of the spontaneously beating right atrium is derived frcm iscmetrically recorded contractions. Dose-response curves to either aσetylcholine (ileum) or carbachol (trachea, bladder and right atrium) are determined using a 1-5 minute contact time for each dose of agonist until the maximum response is achieved. The organ bath is drained and refilled with physiological salt solution cαnte-Lning the lcwest dose of the test ccnpound. The test coπpound is allowed to equilibrate with the tissue for 20 minutes and the agonist dose-response curve is repeated until the ιr-_-X___m_tm response is obtained. The organ bc"i is drained and refilled with physiological salt solution coπta-Lning the second concentration of test coπpound and the above procedure is repeated. Typically four concentrations of the test ccnpound are evaluated on each tissue. The concentration of the test coπpcund which causes a doubling of the agonist concentration required to produce the original response is determined ( A^ value - Arunlakshana and Schild (1959), Brit. J. Pharmacol., 14, 48-58). Using the above analytical techniques, tissue selectivity for muscarinic receptor antagonists is determined. Activity against agonist induced bronchoconstriction, gut or bladder contractility in comparison with changes in heart rate is determined in the anaesthetised dog. Oral activity is assessed in the conscious dog dete-_m__ning ccnpcund effects on, for example, heart rate, pupil diameter and gut motility. Ccnpcund affinity for other cholinergic sites is assessed in the mouse on either intravenous or int_-raperitoneal admiini-strat-ion. Thus, the dose to cause a doubling of pupil size is determined as well as the dose to inhibit by 50% the salivation and tremor responses to intravenous oxotremorine. For adrrdnistration to man in the curative or prophylactic treatment of diseases associated with the altered motility and/or tone of smooth muscle, such as irritable bcwel syndrome, diverticular disease, urinary -Incontinence, oesophageal achalasia and chronic obstructive airways disease, oral dosages of the compounds will generally be in the range of from 3.5 to 350 rog daily for any average adult patient (70 kg) . Thus for a typical adult patient, individual tablets or capsules will typically contain from 1 to 250 mg of active ccnpound, in a suitable pharmaceutically acceptable vehicle or carrier for administration singly or in multiple doses, once or several times a day. Dosages for intravenous adπunistration will typically be within the range 0.35 to 35 mg per single dose as required. In practice the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with age, weight and response of the particular patient. The above dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are wit_hin the scope of this invention. For human use, the coπpounds of the formula (I) can be admi i-stered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of adπ nistration and standard pharmaceutical practice. For example, they may be admini tered orally in the form of tablets conta-Lning such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions cxmta±n±ng flavouring or colouring agents. They may be injected parenterally, for example, .Intravenously, -Lntxamuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. In a further aspect the invention provides a pharmaceutical ccmposition comprising a coπpound of the formula (I) , or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier. The invention also includes a compound of the formula (I) or a pharmaceutically acceptable salt thereof, for use as a medicament, particularly for use in the treatment of irritable bowel syndrcme. Tϊie invention further includes the use of a compound of the formula (I) , or of a pha__maceutically acceptable salt thereof, for the iranufacture of a medicament for the treatment of diseases associated with the altered motility and/or tone of smooth muscle, such as irritable bcwel syndrome, diverticular disease, urinary __r_continenσe, oesσphageal achalasia and chronic obstructive airways disease. The following Exaπples, in which all teπperatures are in °C, illustrate the invention. Example 1 1-T(2- (2 ,3-D-_hyd-_o-5-ber_zo--uraiTy , l)ethyl]-3-(diphenylhydroxy- methyl)-piperidine A mixture of 3-(dipheny._hyd__oxymet_hyl)piperidine (135 mg, 0.50 mmol) (see J. Org. Chem., 4084, 26, 1961 for preparation), 5-(2-b_-oπκ-et_hyl)-2,3-d-_hydr^^ (115 mg, 0.50 mmol), sodium carbonate (0.50 g) and sodium iodide (50 mg) in acetonitrile (20 ml) was heated under reflux for 16 hours, filtered and evaporated. The residue was partitioned between ethyl acetate and water and the organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was purified by chrαπatography on SiO (6 g) using dic-hloi-omethane plus 0-20% ethyl acetate as eluant. Appropriate fractions were combined and evaporated to give the title compound (110 mg) as a colourless oil which was characterised as a heniihydrate. Analysis %:- Found: C,79.7; H,7.5; N,3.1; C^H^ O^O.SI^ requires: C,79.6; H,7.6; N,3.3. Examples 2-9 The compounds of Table 1 were prepared by the method of Example 1 by reacting the appropriate piperidine derivative with 3 the appropriate alkylating agent Q(CH-) R and were obtained in the form shewn. The starting materials for Exaπples 4 and 5 were each used as their hydrochloride salts. Table 1 Ph \ 3 Ph .(CH-) R Z n Table 1 Example 10 3-(Diphe-τy__hvd-_oχy_ret^^ A mixture of 3-(dipheny-LhydroxymetjTvl)piperidine (267 mg, 1.0 mmol), 2-vinylpyridine (0.32 g, 3.0 mmol) and Triton B (3 drops) in l-butanol (10 ml) was heated under reflux for 18 hours, diluted with water and ethyl acetate and the layers separated. The organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was twice taken up in toluene and evaporated and it was then purified by c_hraιatography on Si0 2 using dichlo-xmethane plus 0-5% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (80 mg) as a pale brown oil which was characterised cx>ntaining 0.25 equivalents of water. Analysis %:- Found: C,79.7 H,7.4; N,7.4; C 25^8 N 2 0,0,25H 2 0 requires: C,79.7; H,7.6; N,7.4. Example 11 1- \2- (2.3-D-Lh\O_ro-5-benzo_ϊuraπyl)ethyl]-4- (2.2-diphenyl-2- hydroxyethyl)piperidine A 1.9 M solution of phenyllithium (1.0 ml, 1.9 mmol) was added dropwise over 10 minutes to a stirred solution of ethyl l-[2-(2,3-d-_hydro-5-benzo-_uranyl)ethyl]piperidine-4-acetate (130 πg, 0.40 mmol) in ether (10 ml) with cooling in an acetone/CO bath. The mixture was stirred at -70°C for 1 hour, allowed to warm to room teπperature and stirred for 16 hours. The mixture was quenched cautiously with water and extracted into ethyl acetate. The ethyl acetate extract was washed with water, dried over magnesium sulphate and evaporated. The residue was purified by eh__omat-og-_aphy on SiO- using dic-hlorcmethane plus 20% ethyl acetate plus 0-5% roethanol as eluant. Appropriate fractions were combined and evaporated to give the title ccnpound (100 mg) as a colourless foam which was characterised as a herrdhydrate. Analysis %:- Found: C,79.7; H,7.7; N,3.5; C^gHg NO . O.δH^O requires: C,79.8; H,7.8; N,3.2. Example 12 4-(2,2-Diτ-henyl-2-hvdroxy)ethyl-1-(3,4-πιethylenedioxyber_zyl)- piperidine The title compound was prepared by the method of Example 11 by -_eacting pheπyllit_hium with ethyl l-(3,4-roet_hylenediσxybenzyl)- piperidine-4-acetate. The title ccnpcund was obtained as a colourless solid, m.p. 142-145°C, which was characterised containing 0.25 equivalents of water. Analysis %:- Found: C,77.2; H,7.1; N,3.2; requires: C,77.2 H,7.0; N,3.3. Example 13 3- (Di -heπyJ-hyrJ-roxymetfayl) -1- (4-ιnet-hoxypherethyl) piperidine The title compound was prepared by the method of Example 11 by reacting pheιτ/llithium with ethyl l-(4-methoxyphenethyl)- piperidine-3-carboxylate. The title compound was obtained as a colourless oil. Analysis %:- Found: C,80.3; H,7.7; N,3.5; C__H_.N0- requires: C,80.8; H,7.8; N,3.5. Example 14 3- (2 , 2-Dipheιτyl-l-et_henyl) -1- (3 , 4-met_hyler-edioxNpher_et-hyl) - piperidine Hydrochloride A solution of 3-(2,2-<iiphe_ l-2-hyd__Oxyet_hyl)-l- (3, 4-methylenedic»-yphenethyl) piperidine hydrate (162mg) (Exaπple 3) in 2M hydrochloric acid (4.5ml) was heated at 100 °C for 30 minutes and evaporated to give the title ccnpound as a colourless foam (165mg, 98%) , which was characterised as a hydrate. Analysis %:- Found: C, 72.4; H, 6.7; N, 3.0; C^H j g O^HCl.I^O requires: C, 72.2; H, 6.9; N, 3.0. Example 15 3-(2.2-Dit-heπylethyl) -1-f 3.4-methylenedioxyr- enethyl) - piperidine A .solution of 3-(2,2-diphenyl-l-ethenyl)-l- (3,4-met-hylenedioxyΛeιιethyl)piperidine hydrcchloride (135mg) (Exaπple 14) in EtOH (20ml) was stirred at 40°C under a hydrogen at_mc-sphere of 45 psi in the presence of 10% palladium on charcoal. The mixture was filtered and the filtrate evaporated. The residue was partitioned between a_ic-__lo__oirethar-e and 2M aqueous sodium hydroxide solution and the organic layer was dried over sodium sulphate and evaporated. The residue was purified by c__u_oπatography on silica using dichloromethane plus 2.5% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound as a colourless oil (60mg, 50%) which was characterised as a hemihydrate. Analysis %:- Found: C, 79.7; H, 7.4; N, 3.2; C 2g H 31 N0 2 .0.5^0 requires: C, 79.6; H, 7.6; N, 3.3. Preparation 1 3-Dir^eπy-_-r3thyler_spiperidine Hydrochloride A mixture of (801 mg, 3.0 mmol) and 2M hydrochloric acid (12 ml) was stirred at 100°C for 2 hours and evaporated. The residue was t_riturated with toluene and recrystallised from methanol to give the title compound (730 mg) as a colourless solid, m.p. 236-237"C. Analysis %:- Found: C,75.3; H,7.1; N,4.6; j ^I gN.HCl requires: C,75.6; H,7.0; N,4.9. Preparation 2 3-Dipher_y-_methylpiperidine Hydrochloride A solution of 3-diphe_^-_met_hylenepiperid_Lne hydrochloride (200 mg, 0.7 mmol) in ethanol (40 ml) was stirred under one atmosphere of hydrogen at 40"C in the presence of 10% palladium on charcoal (20 mg) for 24 hours and filtered. The filtrate was concentrated to give the title ccnpound (200 mg) as a pale brown gum which was characterised by its THNMR .spectrum. ^- MR (d 6 -EMS0) δ =8.7-9.l(lH,broad S), 7.0-7.45(10H,m), 2.4-3.8(4H,m), 1.4-1.8(4H,m) and 1.0-1.25(2H,m) . Preparation 3 Ethyl 1-(3,4-roethylenedioχybenzyl)piperid__ne-4-acetate A mixture of ethyl piperidine-4-acetate (0.34 g, 2.0 mmol) , 3,4-ιr thyler_edioxvbenzyl chloride (0.34 g, 2.0 mmol), sodium carbonate (1.0 g) and sodium iodide (0.10 g) in acetonitrile (30 ml) was heated under reflux for 16 hours and evaporated. The residue was partitioned between ethyl acetate and water and the organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was purified by ctøcmatography on Si0_ using dic_i θ--t__ret__-ar_e plus 0-20% ethyl acetate as eluant. Appropriate fractions were combined and evaporated to give the title ccnpound (0.52 g) as a colourless oil which was chτ_arac_-t-eri•se~da by • + t.s lH-^NMR s*pectrum , • Η-NMR (CDCL j ) δ = 6.87(1H,S), 6.77(2H,S) , 5.97(2H,s), 4.13(2H,q,J=7Hz), 3.41(2H,s) , 2.94(2H,d,J=8Hz) , 2.23(2H,d,J=6Hz) , 1.6-2.05(5H,m), 1.2-1.45(2H,m) and 1.25(3H,t,J=7Hz) . Preparation 4 Ethyl 1-.2-(2,3-d-_hyd--0-5- 3enzo--uranyl)ethyllpiperidine-4- acetate This compound was prepared as described in Preparation 3 but using 5-(2-brcnoet yl)-2,3-d__hyd__obe-izofuran instead of 3,4- πet-hylenedioxybenzyl chloride. The title ccnpcund was obtained as a colourless oil which was characterised ty its ~ spectrum. " ϊ-N R (CDC1 3 ) δ = 7.08(1H,S), 6.95(lH,d,J=8Hz) , 6.74(2H,d,J=8Hz) , 4.58(2H,t,J=7Hz), 4.16(2H,q,J=7Hz) , 3.21(2H,t,J=7Hz) , 3.03(2H,d,J=8Hz), 2.5-2.8(4H,m) , 2.23(2H,d,J=4Hz) , 2.04(2H,dt,J=8 and 1.5 Hz), 1.6-1.95(2H,m) , 1.3-1.5(2H,m) and 1.25(3H,t,J=7Hz) . Preparation 5 3,4-^fethyle-r.ediαxypheπylacetic acid (18.0 g) was added portionwise over 30 minutes to a stirred, ice-cooled suspension of lit___ium aluntinium hydride (4.0 g) in ether (400 ml) and the mixture was stirred at room temperature for two hours, quenched by the cautious addition of saturated aqueous ammonium chloride solution and filtered. The filtrate was washed with 10% aqueous sodium carbonate solution, dried over magnesium sulphate and• evaporated to give the title σoπpσund as a pale yellow oil (15.01 g, 90%) , which was characterised by its m ~ mR spectrum. • ^ϊ-NMR (CDC1 3 ) δ = 6.69-6.83 (3H,m) ; 5.98(2H,s); 3.82(2H,dt J = 7 and 6Hz) ; 2.81(2H,t,J = 7Hz) and 1.44(lH,t, J = 6Hz, exchangeable with D O) . Preparation 6 3.4-Met-hylenedioχychenethyl bromide A .solution of phosphorus t_ribromide (8.1 g) in carbon tetxachloride (50 ml) was added drcpwise over 30 minutes to a stirred solution of 3,4-ιιet_hylenedioxyphenethyl alcohol (15.0 g) (see Preparation 5) in carbon tetxachloride (200 ml) and the mixture was heated under reflux for 3 hours, washed sequentially with water (twice) , 5M aqueous sodium hydroxide solution and water, dried over magnesium sulphate and evaporated. The residue was purified by C-hromatography on silica (100 g) using carbon tetxachloride as the eluant. Appropriate fractions were combined and evaporated to give the title ccnpound as a pale yellow oil (8.3 g, 40%) , which was characterised by its Tϊ-NMR spectrum. • Sϊ-NMR (CDC1 3 ) δ = 6.80(lH,d,J = 8Hz) , 6.75(lH,s) , 6.71(lH,d,J=8Hz) , 6.00(2H,S) , 3.56(2H,t,J = 7Hz) and 3.13 (2H,t,J = 7HZ) . Preparation 7 5-(2-Hvdroχyethyl)-2,3-d-lhvd_-Ober-Zofuran A .solution of (2,3-d_lhyd__o-5-benzofuranyl)acetic acid (4.9 g - see EP-A-132130) in anhydrous tetxahyd__θ-_uran (50 ml) was added dropwise over 10 minutes to a stirred suspension of lithium alurrdnium hydride (1.57 g) in anhydrous tet___ahydro__uran (50 ml) at 0°C. The mixture was allowed to warm to room teaiperature and stirred for 1 hour. Water (1.5 ml) was cautiously added dropwise followed by 10% aqueous sodium hydroxide solution (1.5 ml) and water (4.5 ml) . The mixture was filtered and the inorganic salts were washed with ethyl acetate. The filtrate and washings were cc ibined and evaporated to give the title compound as an oil, (3.3 g), which was characterised by its m→MR spectrum. • ^→Φ-R (CDC1 3 ) 5 = 7.10 (S,1H), 7.00 (d,lH) , 6.75(m,lH), 4.65-4.55(m,2H), 3.90-3.75(m,2H) , 3.30-3.15(m,2H) , 2.90-2.80(m,2H) and 1.85-1.75(brs,3H) . Preparation 8 5-(2-I-Xomoethyl)-2.3-<_-ihyd_π±>enzθ-ϊuran Phosphorus tr-Lbαmide (0.37 g) was added to a solution of 5-(2^yd__oxyet_hyl)-2,3-d_lhyd__o^ (0.612 g) (Preparation 7) in carbon tetxachloride (3 ml) and the mixture heated under reflux for 3 hours and partitioned between 10% aqueous sodium carbonate solution (20 ml) and dic orcπethane (20 ml) . The layers were separated and the aqueous layer was extracted with dii±ilo-xπethane. The combined dic-hloromethane extracts were dried (MgSO ) and evaporated to give the title ccnpound (0.584 g) as an oil which crystallised en standing, m.p. 60-62 °C, and which was characterised by its speccrum. i NMR (CDCl ) δ = 7.10(S,1H) , 7.00-6.95(d,lH) , 6.80-6.70(d,lH) , 4.65-4.55(t,2H) , 3.60-3.50 (t, 2H) , 3.25-3.15(t,2H) and 3.15-3.10(t,2H) . Preparation 9 Ethyl l-(4-ιi-ethoχyphenet-hyl)piperidine-3--c-arboχylate This ccnpound was prepared as described in P__eparatiαn 3 using ethyl piperid-_ne-3-c._rboxylate and 4-methoxyphenethyl bromide as reagents. The title ccmpound was obtained as a colourless oil. Analysis %:- Found: C,69.2; H,8.3; N,4.8; C 17 -^ 5 N0 3 3_equires: C,70.1; H,8.6; N,4.8. The following compounds may be prepared by methods described in the respective publications given below: 3-(Dipher^__hyd__0-Q et_hyl)piperid__r_e Journal of Organic Chemistry, 4084, 26, (1961) . 3-(2,2-diphe_τyl-2-hydroxy)ethyl British Patent piperidine Specification 765853. Ethyl piperidine-4-acetate Journal of American Chemical Society, 6249, 75, (1953). It will be appreciated from the foregoing that what we will claim may include the following:- (1) The compounds of the fσnraila (I) and pha__maceutically acceptable salts thereof; (2) Processes as described herein for preparing the compounds of the formula (I) and their salts; (3) Irhaj-maceutical σcπpositions ccnprising a compound of the formula (I) or a phaπraσeutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier; (4) Any novel intermediates described herein; (5) A compound of the formula (I) , or a pharmaceutically acceptable salt thereof for use as a medicament. (6) The use of a compound of the formula (I) , or of a pha__maceutically acceptable salt thereof, for the H__-πι__facture of a medicament for the treatment of diseases associated with the altered motility and/or tone of smooth muscle, such as irritable bowel syndrome, diverticular disease, urinary .Incontinence, oesαphageal achalasia and chronic obstructive airways disease.

Claims: Claims 1. A compound of the formula (I) : R X-^-A - (ca,)^ R / R (I) or a pharmaceutically acceptable salt thereof, 1 2 wherein R and R are the same or different and each is phenyl which is unsubstituted or substituted by at least one group selected from C -C alkyl and halo, the broken line represents an optional double bond and X is " ^COH 7 ^ SiOH- or ~~~ CH- when said double bond is absent or is ~~~^C= when said double bond is present, X being attached to a carbon atom of A, A is when said double bond is absent or A is when said double bond is present n is from 1 to 3, is 1 or 2, p is 0 or 1, q is 0 or 1 4 5 R and R are each independently H, C.-C alkyl, C - alkoxy or (CH_) OH wherein r is 0, 1 or 2, or R 4 and R5 together form a -Y-fOL) -Z- group wherein Y and Z are independently -O- or -CH-- and s is 1, 2 or 3, and Het is thienyl, pyridyl or pyrazinyl, with the provisos that when q is 0 or A is then n is 2 or 3, and that when A is 1 2 2. A compound acxx>__ding to claim 1, in which R and R are both unsubstituted phenyl 3. A compound according to claim 1 or 2, in which x is "^C(OH)-. 3 4. A compound a∞ording to any preceding claim, in which R is pyridyl, 2,3-d__hyd__o-benzofuranyl, tolyl, roethoxyphenyl, hydroxymethylpheπyl or I (j I , CH 2 : 3 5. A ∞mpound ac_σo_-ά_ing to claim 4, in which R is 3,4-_r_atttyler_edioxyphenyl- 6. 3-(Dipheny__hyd__oxymethyl)-3-(3,4-met_hylenedioxyphenethyl) piperidine. 7. A pharmaceutical composition comprising a coπpound as claimed in any one of claims 1 to 6 and a pharmaceutically acceptable diluent or carrier. 8. A coπpound according to any one of claims 1-6, for use in medicine. 9. Use of a coπpound accxDrding to any one of claims 1-6 for making a medicament for use in treating diseases associated with altered motility and/or tone of smooth muscle. 3 3 10. A corrpound of formula EO C-A-(CH ) R wherein A, n and R are as defined in any one of claims 1 to 5 and R is a C -C alkyl group. 11. A method of making a compound of the formula (I) : X — 'A - V ^n 1 / \T (i) or a pharmaceutically acceptable salt thereof, 1 2 wherein R and R are the same or different and each is phenyl which is unsubstituted or substituted by at least one group .selected from C.-C. alkyl and halo, the broken line represents an optional double bond and X is ^OOH7 ; SiOH- or " CH- when said double bond is absent or is __ G= when said double bond is present, X being attached to a carbon atom of A, A is when said double bond is absent or A is when said double bond is present n is from 1 to 3, m is l or 2, p is 0 or l, q is 0 or 1 R 4 and R5 are each independently H, C.-C. alkyl, C -C. alkoxy or (Oi.) OH wherein r is 0, 1 or 2, or R 4 and R5 together form a -Y-(CH_) -Z- group wherein Y and Z are independently -O- or ~CH_- and s is 1, 2 or 3, and Het is thienyl, pyridyl or pyrazinyl, with the provisos that when q is 0 or A is then n is 2 or 3, and that when A is or -CH2-/ N— then R 3 is not Het in which either i) a compound of formula (II) R 1 " ^ ? X - -i: A H ,2 (ID wherein H is attached to the nitrogen atom of A is. caused to 3 react with a compound of formula Q (CH_) R to yield a 1 2 compound of formula (I) wherein R , R , X, A, the broken 3 line, n and R are as defined above and Q is a leaving group, or ii) a compound of formula (U) as defined above is cans d to react with 2- or 4- vinylpyridine or viπ lpyrazine to yield a 3 compound of formula (I) in which n is 2 and R is 2- or 4- pyridyl or pyrazinyl or ... 3 3 in) a compound of formula RCHDCHA-fCH-) R wherein A, n and R are as defined above and R is a C.-C alkyl group is allowed to react with phenyllithium to yield a cxmpcund of formula 1 2 (I) in which R and R are both phenyl and X is ^C(OH)-. 12. A method according to claim 11 alternative i) in which leaving group is Br, Cl, I, C 1 ~C 4 alkanesuløonyloxy, benzenesulphoπyloxy, toluenesulphonyloxy or trifluorσπjethanesulphonylox . 13. A method according to claim 11 alternative i) or claim 12, in which the reaction is carried cut in the presence of an acid acceptor. 14. A method according to claim 11 alternative ii) in which the reaction is carried out in the presence of an acidic or basic catalyst. 15. A method acco__ding to any one of claims 11 to 14, in which R and R are both unsubstituted phenyl. 16. A method according to any one of claims 11 to 15, in which X is ^ C(OH)-. 17. A method acco-_ding to any one of claims 11 to 13 in which R 3 is pyridyl, 2,3-^-_ihyd__obenzo__uraπyl, tolyl, methoxyphenyl, or hyd__oxynet_hylphenyl . 18. A method according to any one of claims 11 to 13, in which R is 3,4-met_hylenediαxypheπyl. 19. A method according to claim 11, in which the compound made is 3- (diphenylLhydi-Oxymettiyl) -3- (3 , 4-methylenedioxyphenyl) piperidine.

Inventors: ALKER DAVID, CROSS PETER EDWARD, ALKER, DAVID, CROSS, PETER, EDWARD
Applicants: PFIZER, PFIZER LTD, PFIZER INC., PFIZER LIMITED
Application year: 1990
Main classification: C07D211
IPC codes: A61K31, A61P25, C07D207, C07D211, C07D401, C07D403, C07D405, C07D409, C07F7